Synthesis and chemistry of 3,4,7-metheno-3H-cyclopentaApentalenes (bisesquinanes)

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Title:
Synthesis and chemistry of 3,4,7-metheno-3H-cyclopentaApentalenes (bisesquinanes)
Physical Description:
xi, 139 leaves : ill. ; 28 cm.
Language:
English
Creator:
Griggs, Billy Glynn, 1953-
Publication Date:

Subjects

Subjects / Keywords:
Methoxybisesquinene   ( lcsh )
Bisesquinene   ( lcsh )
Polycyclic compounds   ( lcsh )
Chemistry thesis Ph. D
Dissertations, Academic -- Chemistry -- UF
Genre:
bibliography   ( marcgt )
non-fiction   ( marcgt )

Notes

Thesis:
Thesis (Ph. D.)--University of Florida, 1985.
Bibliography:
Bibliography: leaves 135-138.
Statement of Responsibility:
by Billy Glynn Griggs, Jr.
General Note:
Typescript.
General Note:
Vita.

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University of Florida
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All applicable rights reserved by the source institution and holding location.
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Full Text











SYNTHESIS AND CHEMISTRY OF
3,4,7-METIIENO-3H-CYCLOPENTA[A]PENTALENES
(BISESQUINANES)










BY

BILLY GLYNN GRIGGS, JR.


A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN
PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE OF DOCTOR OF PHILOSOPHY


UNIVERSITY OF FLORIDA


1985

























IN MEMORY OF MY GRANDFATHER


who spent 40 years as a high school
teacher of chemistry, math and physics,
and instilled in me a love of science.
















ACKNOWLEDGEMENTS


The author would like to express his gratitude to

Professor M. A. Battiste for his guidance throughout the course of this

work; his willingness to be interrupted to discuss new results or just to

chat was a joy. In his role as academic advisor, Dr. Battiste has helped

the author develop a sense of independence and maturity by knowing when

to offer help and when to leave him time to solve his own problems.

Special thanks are due to all of the author's friends who have

contributed a vital service of babysitting for the past few weeks.

Without their generous support, this manuscript would never have been

completed.

Finally, to the author's typist and helpmate he says your loving

support, understanding of all the late nights in the lab, and eagerness

to help is appreciated beyond description. Your ability to take

everything in stride (almost, anyway) and maintain a semblance of order

in our household has qualified you as a Proverbs 31 woman. "An excellent

wife, who can find? For her worth is far above jewels. The heart of her

husband trusts in her, and he will have no lack of gain."
















TABLE OF CONTENTS


Page

ACKNOWLEDGEMENTS. . . . iii

LIST OF TABLES. . . . .viii

LIST OF FIGURES . . . ix

ABSTRACT. . . . x


CHAPTER ONE

CHAPTER TWO


















CHAPTER THREE


INTRODUCTION . . .

SYNTHESIS OF METHOXYBISESQUINENE . .
Synthetic Strategy . .
Preparation of 7,7-Dimethoxynorbornene (30).
Preparation of 5-Trimethylsilylcyclopenta-
diene (28) . . .
Reaction of 7,7,Dimethoxynorbornene with
Trimethylsilylcyclopentadiene. . .
Structure Determination. . .
Nuclear Magnetic Resonance . .
Mass Spectra . .
Mechanism. . . .
Improved Isolation of 26 from Isomer Mixture

REACTIVITY AND REARRANGEMENTS OF BISESQUINENE. .
Acid Catalyzed Rearrangements in Methoxybises-
quinene. . . .
Addition Reactions of the Double Bond. .
Preparation of Acid Rearrangement Products .
Results of Acid Addition to the Double Bond of
Methoxybisesquinene (26) . .
Conclusions . . .












CHAPTER FOUR























CHAPTER FIVE


STRAIN AND STRUCTURAL EFFECTS IN THE BESESQUINANE
SYSTEM . . .
Strain Energy . .
MM2 Calculations . .
Homoketonization . .
Bisesquinane Structure: Calculated and X-Ray..
Bond Lengths . .
Bond Angles . .
13
C-H Spin-Spin Coupling and Angle Strain.
Interplanar Angles . .
Diels-Alder Reactivity of Bisesquinene:
Adduct Stereochemistry . .
Preparation of Adducts . .
Stereochemistry . .
Suggestions for Future Work . .

EXPERIMENTAL . . .
General . . .
Synthesis . . .
Preparation of 7,7-Dimethoxynorbornene (30).
Preparation of 5-Trimethylsilylcyclopen-
tadiene (28) . .
Reaction of 7,7-Dimethoxynorbornene (30)
with 5-Trimethylsilylcyclopentadiene (28).
Method A: A1C13/CH2C12, -78?C ..
Method B: AlC13/Et20, O?C .
Method C: BF3 Et20/CH2CH2, 25?C .
Method D: BF3 Et20/CH2C12, 5?C.. .
Spectral Data for Isolated Products from
the Reaction of 7,7-Dimethoxy-norbornene
(30) with 5-Trimethylsilylcyclopentadiene
(28) (Hethods A-D).. . ...
7-Norbornylfulvalene (36) .
syn-7-Methoxy-7-(l'-cyclopentadienyl)-
norbornene (37a) and syn-7-methoxy-7-
(1'-cyclopentadienyl)norbornene (37b),
ca. (50:50) . ...
3b-Methoxy-3a,3b,4,6a,7,7a-octahydro-
3,4,7-netheno-3H-cyclopenta?a?pen-
talene (26) . ..


Page









8-Methoxy-3a,3b,4,6a,7,7a-octahydro-
3,4,7-metheno-3H-cyclopenta[a]pen-
talene (38). . ... .. 76
3b-Methoxy-2,3,3a,3b,4,5,6,6a,7,7a-
octahydro-1,4,7-metheno-lH-cyclo-
penta[a]pentalene (39) .... 76
Preparation of 3b-Methoxy-
2,3,3a,3b,4,5,6,6a,7,7a-decahydro-1,4,7-
metheno-1H-cyclopenta[a]pentalene
(39-H2) . . .. 77
Bromination of Methoxybisesquinene (26). 78
Preparation of trans-1,2-dibromo-3b-
methoxy-3a,3b,4,6a,7,7a-decahydro-
3,4,7-metheno-3H-cyclopenta[a]pen-
talene (26-Br2). . 78
Preparation of exo,exo-1,3-dibromo-3b-
methoxy-3a,3b,4,6a,7,7a-decahydro-
2,4,7-metheno-1H-cyclopenta[a]pen-
talene (43). . ... 79
Debromination of 26-Br2 ........ .80
Reaction of 26 with Trimethylsilyl Iodide
(TMS-I). . . ... 80
Preparation of exo-1,2-Epoxy-3b-methoxy-
3a,3b,4,6a,7,7a-decahydro-3,4,7-metheno-
3H-cyclopenta[a]pentalene (67) ..... 81
Preparation of exo-l-Hydroxy-3b-methoxy-
3a,3b,4,6a,7,7a-decahydro-3,4,7-metheno-
3H-cyclopenta[a]pentalene (64-OH). .... .82
Preparation of exo-l-3b-Methoxy-
3a,3b,4,6a,7,7a-decahydro-3,4,7-metheno-3H-
cyclopenta[a]pentalene Acetate (64-OAc). 83
Preparation of 11-Keto-tetracyclo-
[6.2.1.136.07 ]dodec-4-ene (66). .. 84
Preparation of anti-11-Methoxy-tetracyclo-
[6.2.1.136.02'7]dodec-4-ene (72) 85
Preparation of cis,anti-4,5-Epoxy-anti-
tetracyclo[6.2.1.13'6.02'7]dodec-ll-
methyl Ether (73). . 86
Preparation of exo-3b-Methoxy-
3a,3b,4,6a,7,7a-decahydro-2,4,7-metheno-
1H-cyclopenta[a]pentalen-3-ol (65-OH). 87
Preparation of 3b-Methoxy-3a,3b,4,6a,7,7a-
decahydro-3,4,7-metheno-3H-cyclopenta-
[a]pentalene (26-H2) . .. 88


88









Page
Preparation of 3b-Hydroxy-3a,3b,4,6a,7,7a-
decahydro-3,4,7-metheno-3H-cyclopenta-
[a]pentalene (96) . .... 89
Preparation of Tetracyclo[7.2.1.02'6.0712]
dodeca-l-one (98) . .... 90
Reaction of 26 with Trifluoroacetic Acid
(TFA). . . ... 91
Preparation of Diels-Alder Adduct (103a) 92
Treatment of Adduct 103a with TMS-I. ... 93
Preparation of Tetrachloroketone 108 93
Reaction of Tetracyclone (104) with
Methoxybisesquinene (26) to Produce
Diels-Alder Adduct 105a and Diene 106. 95
Spectral data for 105a ... 95
Spectral data for 106. .... 96

APPENDIX 1 Nomenclature and Derivation of Trivial Name
"Bisesquinane" . .. 97

APPENDIX 2 Selected 1H and 1C NMR Spectra. . ... 101

REFERENCES. . . ... .. 135

BIOGRAPHICAL SKETCH .. . .. 139
















LIST OF TABLES


Table Page

2.1 Representative Results of Reaction between Ketal 30
and Silane 28 under Various Conditions ... 12

3.1 Acid Catalyzed Rearrangement of Methoxybisesquinene 26 31

4.1 MM2 Energy Calculation Results (kcal/mole) . 40

4.2 Bond Lengths [R] with Estimated Standard Deviations in
Parentheses for Dibromide 26-Br2 Involving Non-H Atoms 49

4.3 Bond Lengths [A] forDibromide 26-Br2 Involving H Atoms 50

4.4 Bond Angles [O] with Estimated Standard Deviations in
Parentheses for Dibromide 26-Br2 . 53

2
4.5 Bond Angles [] for Dibromide 26-Br2 Involving H Atoms .. 54

5.1 Method D: Fractionation by Flash Chromatography
Correlated with GC Retention Times and Area Percent. 74


viii















LIST OF FIGURES


Figure Page


2.1 GC of reaction mixture showing identification of isomers 13

2.2 Comparison of mass spectral fragmentation patterns for
compounds 36, 37, 26, 38 and 39. . .... 14

4.1 MM2 Calculations of strain energy. . 38

4.2 INEPT 1C NMR spectrum of ketone 98. . ... 46

4.3 MM2 Calculated bond lengths for 4, 80 and 81 ...... 48

4.4 Steroscopic view of the molecular structure of 26-Br2. 47

4.5 MM2 Calculated bond angles for 4, 80 and 81. .. .52

4.6 Perspective drawings of bisesquinane (4) ... 55

4.7 13C-H Coupling constants for methoxybisesquinene (26)
and related bicyclic hydrocarbons. . ... 57

4.8 Crystal structure of 26-Br2 as viewed down the
C(5)-C(12) bond . . 58

4.9 Interplanar Angles . .... .59

4.10 Carbonyl multiplicity. . . ... 65
















Abstract of Dissertation Presented to the Graduate School of
the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy


SYNTHESIS AND CHEMISTRY OF
3,4,7-METHENO-3H-CYCLOPENTA[A]PENTALENES
(BISESQUINANES)

By

Billy Glynn Griggs, Jr.

May 1985

Chairman: Dr. Merle A. Battiste
Major Department: Chemistry



An effective entry into the 3,4,7-metheno-3H-cyclopenta[a]pentalene

(bisesquinane) ring system was achieved via a novel tandem alkylation-

intramolecular [4+2] cycloaddition reaction. The addition of TMS-cyclo-

pentadiene to 5,5-dimethoxynorbornene in the presence of Lewis acid

catalysts produced 3b-methoxy-3a,3b,4,6a,7,7a-octahydro-3,4,7-metheno-3H-

cyclopenta[a]pentalene (methoxybisesquinene) as the major product in

addition to other C13H160 polycyclo-alkene isomers. A mechanism to

account for the isomeric products requires rearrangements via I-bond

bridging to an intermediate allyl silane cation. A simple purification

scheme via a bromination/debromination procedure was developed, thus

affording methoxybisesquinene in high purity in an overall three-step

process.

Addition reactions to methoxybisesquinene were quite facile and

under kinetic conditions gave predominantly exo addition products without









rearrangement. Under equilibrating conditions, Wagner-Meerwein skeletal

rearrangements occurred to produce predominantly 2,4,7-metheno-3H-cyclo-

penta[a]pentalenes (twist-methoxybisesquinenes). In no case was further

rearrangement observed to produce 11-keto-tetracyclo[6.2.1.13'6.02'7 -

dodec-4-ene, the expected frangomeric cleavage product of the interme-

diate twist-methoxybisesquinane cation. In fact, under acidic

conditions, this ketone was found to undergo homoconjugate addition to

produce a twist-bisesquinane diol.

The unusual chemistry of the bisesquinane system can be accounted

for by strain effects. Strain energies were calculated (Ml12) for

bisesquinane and related systems to probe the effect of strain on

structure, bonding and reactivity. The calculated structural parameters

for bisesquinane are compared with those obtained from an x-ray crystal

structure of dibromomethoxybisesquinane. The two central bonds [C(10,11)

and C(5,12)] are substantially longer than normal, implying that these

bonds are stretched as a consequence of strain. As predicted on the

basis of strain relief, homoketonization of bisesquinol produced a single

ketone. The highly compressed bridgehead bond angles of bisesquinane

contribute significantly to the strain energy and result in somewhat

larger JC-H coupling constants than related bicyclo-alkenes. The

structure of bisesquinane is unique compared to norbornane in that the

bridge methylenes are "tied back" by the central C(10)-C(11) bond, which

results in a much more open exo-face. The effects of these structural

perturbations and strain on the stereochemistry of Diels-Alder reactions

with dimethoxytetrachloro-cyclopentadiene and tetracyclone were

investigated.
















CHAPTER ONE

INTRODUCTION



It has long been the goal of the synthetic chemist to construct

complex molecules in as few steps as necessary to perform the task at

hand. Rapid construction of multiple rings is often required in the

elaboration of complex natural and unnatural products. With this in

view, many elegant methodologies have been utilized to construct a wide

variety of polycyclic hydrocarbons.

Multiple sequence Diels-Alder cycloaddition reactions are gaining

prominence as the methods of choice for ring construction steps. One

very useful approach is the intramolecular Diels-Alder reaction, where

after the coupling of diene with a reactive ene (via a single bond

formation), the molecule is then poised to react further via succeeding

Diels-Alder coupling.



+

X Y-31 *'



This methodology also offers the advantages of a convergent synthesis,

whereby portions of the molecule can be formed independently, and finally

brought together at a later stage in the synthetic scheme. Other

examples of multiple sequence Diels-Alder cycloaddition have been called

"Domino",1'2 "Timed",3 "Tandem and "Diene-Transmissive"5 Diels-Alder

reactions.







2

An interesting variation of this theme is the Donino Diels-Alder

reactionI which envokes a cascading sequence of [4+2] cycloadditions.

This may be described generally as an initial intermolecular [4+2] cyclo-

addition, followed by intramolecular [4+2] bonding with the newly formed

olefinic center. This process is illustrated in structures 1-3, and

could be continued if structurally permissible.



X X X




1 2 3


The novel C12116 hydrocarbon skeleton "bisesquinane" (decahydro-

3,4,7-methenocyclopenta[a]pentalene, 4; see Appendix 1 for nomencla-

ture discussion) has been prepared independently by Paquette and Wyvratt1






4


and McNeil et al. utilizing the Domino Diels-Alder process. Their

synthesis formally requires the addition of acetylene to 9,10-dihydroful-

valene (5) producing the intermediate 7-(5'-cyclopentadienyl)norborna-

diene (6), which then undergoes rapid [4+2] cycloaddition to form

bisesquinadiene (7).






H
H









In practice, a reactive dienophile, acetylene dicarboxylate (9),

was employed (Scheme 1.1) to produce a mixture of dicarboxylate cycload-

ducts 10 and 11. The isomeric mixture can be rationalized by the

approach of the dienophile (9) along coordinates a and b, respectively,

followed by the intramolecular [4+2] closure. Reduction, hydrolysis, and

oxidative decarboxylation of the minor isomer (11) afforded bisesquina-

diene (7) in an overall yield of 7.3%.






HE E


-- a









7 1
E
E -COOMe CrSO 4H20












Scheme 1.1


The research group of Paquette has recently completed the synthesis

of dodecahedrane (14), which had its genesis in the Domino Diels-Alder

reaction. This process allowed the multiple fusion of cyclopentane

rings conveniently and in good yield to produce the pentacyclic diester

10 which served as the "cornerstone" precursor of the elusive dodecahe-

drane (14).









E E

4'- hi- __ 023


E

10 13 1



A key step in the synthesis involves cleavage of the central C-C bond,8

which was facilitated by the high degree of ring strain in 10.

In view of the synthetic and theoretical interest of dodecahedrane

and its C12 precursors, our group began exploration of alternate avenues

to polyfused cyclopentanoid systems. Synthesis of bisesquinadiene (7) was

achieved by a novel approach we have termed a "tandem alkylation-[4+2]

cycloaddition." Essentially, this strategy requires the coupling of a

norbornadienyl cation (15) with a cyclopentadienyl anion (8) followed by

rapid intramolecular [4+2] cycloaddition of the intermediate 7-(5'-cyclo-

pentadienyl)norbornadiene (6).







i3I





For synthetic manipulation, this is most easily accomplished by the

in situ formation of these reactive species from 7-norbornadienyl

chloride (16) and thallium cyclopentadiene (TlCp, 17) refluxed in dry

diglyme. Thus, as outlined in Scheme 1.2, bisesquinadiene (7) was pre-

pared in 8-12% yield by a convenient one-pot reaction from commercially

available starting materials.


terials.









Ci




16


T1




17


6 7


Rearrangement


20


21


22


Scheme 1.2


One of the major problems in this scheme is the formation of unde-

sired side products. The 7-norbornadienyl cation-cyclopentadienyl anion

pair (18) can collapse at either C(7) or C(2) of the cation skeleton to pro-

duce 6 and the tricyclic hydrocarbon 19. After a series of sigmatropic

rearrangements, 19 produces a mixture of dihydro-as-indacenes (20-22).

Therefore, to improve on this methodology, one would need to increase

the charge density/localization at the 7-position of the norbornadienyl

cation (23) in order to prevent attack at C(2).


-4-Ah


4-.r
/I


+r


24 25









This may be accomplished by the introduction of an electron-donating

moiety at C-7 to localize the charge (e.g., 24 => 25). The methoxy group

has been shown to stabilize the incipient carbocation to such an extent

that participation by the double bond is relatively ineffective.10

With these considerations in mind, our goal was to try to improve

this methodology to increase the yield of the reaction and to introduce

additional functionality. The target compound selected for study was

2a-methoxyoctahydro-3,4,7-methenocyclopenta[a]pentalene (26), or more

simply, methoxybisesquinene (26). Its synthesis and reaction by-products

will be discussed in Chapter Two.


01Me





26



Methoxybisesquinene (26) offers many possibilities for mechanistic

study concerning the effect of ring strain and possible anchimeric assis-

tance for thermal or acid catalyzed rearrangement. Also of interest is

the unusual reactivity of the double bond in addition reactions, and

these points will be addressed in Chapter Three.

The unusual chemistry of the bisesquinane system can be accounted

for in part due to its high ring strain. .olecular mechanics calcula-

tions, an x-ray crystal structure, and a novel homoketonization experi-

ment help to define the effects of this ring strain. In addition, the

facile participation of 26 as a dienophile in [4+2] cycloaddition

reactions and the questions of stereochemistry of the adducts will be

discussed in Chapter Four.















CHAPTER TWO

SYNTHESIS OF METHOXYBISESQUINENE



Synthetic Strategy


Utilizing a retrosynthetic analysis for methoxybisesquinene (26),

the application of an intramolecular Diels-Alder process preceded by the

requisite alkylation is readily apparent.


SiMe3




28


8.


Me OMe





30


Preparation of 7,7-Dimethoxynorbornene (30)


The synthetic equivalency of 7,7-dimethoxynorbornene (30) to oxonium

ion 29 is based upon the results of acidic hydrolysis of ketals in which

an oxo-carbonium ion is an assumed intermediate.13 Treatment of ketal 30









with a Lewis acid should provide the stabilized oxonium ion (29).


0Me
MeO OMe

Lewis
Acid
30 29


The ketal (30) is readily available from hexachlorocyclopentadiene (31)

via the three step reaction sequence illustrated in Scheme 2.1, as previ-
ously described.1415
ously described.


MeO OMe

NaO
EtOH


:VCI CH3COH
I-
CI KOH

014

31


Scheme 2.1



Preparation of 5-Trimethylsilylcyclopentadiene (28)


The synthetic equivalence of 5-trimethylsilylcyclopentadiene (28)

for the cyclopentadienyl anion (8) is perhaps less evident. There is by

now ample precedent for the reaction of allyl silanes with appropriate

electrophiles6-18 in the presence of Lewis acids.



NOu R3S .... -- Nu-SiR.+ E









This reactivity has recently been extended to include additions to

ketals.19



OR OR
RO SMe3 RO

RO Z Lewis Acid RO




At the initiation of our studies, however, there was relatively little

information on this aspect of our synthesis. Even to date there have

been no reported analogous studies of the electrophilic alkylation of

28 with ketals.

Treatment of a tetrahydrofuran (THF) solution of cyclopentadiene

with sodium metal, or preferably sodium hydride, provides the rose-

colored sodium cyclopentadienyl anion (8), which then reacts with

trimethylsilylchloride (TMS-C1) to generate silane 28.20



1 NaH f ,+TMS-C1 T5-
SNorQ T -SiMe,3
Na -10 THF

8 28



A complicating property of 28 is its facile rearrangement to isomers

34 and 35, presumably via 1,5-hydrogen shifts, but if the reaction

SiMe3



3 2
Si'ie
28 33 35


is kept cold (<200 C), essentially most of the material isolated is









isomer 28.21,22 Ashe21 has reported an equilibrium ratio of 90:7:3 for

isomers 28, 34 and 35, respectively, in C 6D which provides baseline

resolution of the 1H NMR signals of the SiMe3 groups. In CDC13,

isomers 34 and 35 have identical SiMe3 chemical shifts, but isomer 28 is

resolved and is present to the extent of 87%.23 It may be noted that

this tendency of the trimethylsilyl group to favor substitution on the

5-position is remarkable compared to alkyl groups which seek out only the

1- and 2-positions.24 It has been reported that fractional crystalliza-

tion by a successive partial freeze-thaw-filter technique affords pure 28

(mp -190C).21 This method was found to be too tedious in our hands for

synthetic scale; therefore, the isomer mixture (28, 34 and 35) was used

directly with no apparent ill effects.



Reaction of 7,7-Dimethoxynorbornene
with Trimethylsilylcyclopentadiene


After translation, a relatively simple one-pot synthesis of

methoxybisesquinene (26) now appears



MeO OMe + TMS OMe OMe

LEWIS
ACID

30 N9 ?s -i-



Scheme 2.2


The problem becomes to find the proper reaction conditions to favor the

coupling. This primarily depends upon the choice of Lewis acid, solvent,

and temperature.








The reaction was run under a variety of conditions utilizing various

Lewis acids and solvents (see Table 2.1). Surprisingly, upon capillary

GC-MS analysis, we observed not only 26 in the reaction mixture but at

least three other (C13H160) isomers (see Figures 2.1 and 2.2). The yield

and ratio of these various isomers were very dependent upon the reaction

conditions, particularly the nature of the Lewis acid and solvent.

Scheme 2.3 summarizes these results and shows the major isomers obtained

(26 or 39). In addition, most reaction methods were accompanied by the

formation of a yellow polymeric material, which was insoluble in pentane,

and contained a relatively large amount of trimethylsilyl residues.

Separation of the crude reaction mixture by flash chromatography on

silica gel afforded a mixture of four C13 H60 isomers (ca. 8-57% yield).

It was extremely difficult to resolve this isomer mixture, but by careful

flash chromatography followed by preparative TLC or GC, the major isomer

(26 or 39) could be obtained relatively pure (>95%).






+MeM
TMS MeO. Me o
/ BF3Eto/CHCC1 RT


28 30 Ac1 3/H 2,c2 -78

39

Scheme 2.3



Structure Determination


Nuclear Magnetic Resonance


Fulvalene 36 was isolated as a minor product in the best yield

(2.5%) from Method A. The symmetrical nature of fulvalene 36 was readily



















a) 0 6o

HC) X
>- -i--


ON


cc N
C C-



0O 00


Nn
cli
I


o

C)
N








N

0







S0






a













E
1-1














COE
0)

M-4n
S0

0 E
L*
t- i


f-

0
o
Lt)




N


0






0
CN




cQ


03

E-
coo

N.E

N.




r,)
ri
--s
CO 0


0 E

CN
00O


0)
1-4

I c



10-



I -


0)

-I

I c
-41




o
I -CO
0
r.


o
cO








C)
N
-i











a0










E
-4
0
i-4









0E




c 0
1-1





-4
00 0

E






Sin







*


o
0
0










CM









1-4
C)






c0
e-D 0









00 )
0-' E




E 0




*E
02
e-s





*-- ti


C N
0)
>
- N





*o



cu
*I <-

00




CM 00 0

(l
SE o
C CO

4




c


EE
CO
0 -ri


co 0


eLn
0) Ll


,--
0)
e-4
00 0

cc
02
UriN





















I,* 3
v. M


A'

, +I







TMS


r.
r')
-t
*' 1 I


I`)
I+ '
l-' r"


Me 0 j

(IQ


28 36 37





Figure 2.1. GC of reacti
isomers.


O.. oe
26 37 38 39


on mixture (Method D) showing identification of







14


Base Peak = 128.0 Base Peak Abundance = 1664


5.. I L .10
-I-0-1- -----I---- 1 -,-
59 100


36


150 2
150 200 250


1284.


Base P.ak = 128. 0 ase Peak abundance = 473




37





50 100 150 200 250
=asePeak __881_ Base Peak Abundance = 3464





26




50 100 150 2 0 250
--------------- ---------------------
BEase P_ k = 138. 1 Base Peak Abundance = 1122





38




---T-t----------1---^- --^- -- --------_-,-*- -^----^-^-^---
50 100 150 200 250

Base Peak = 188.1 -Base Peak Abundance = 1399










10 150
5i0 k)O 150 -*C' 2 1i


MeO










108 4-


OMe






,4173(108)
MeO F65




S123.-
-160


Figure 2.2. Comparison of mass spectral fragmentation patterns for
compounds 36, 37, 26, 38, 39.






15

13
apparent by inspection of its 1C NMR spectrum. At a short pulse delay,

the two quaternary vinyl carbon signals were missing, and only 5 signals

were observed: three vinyl carbons (=CH), one methyne (CH), and one

methylene (CH2). When the pulse delay was increased to allow for the

longer relaxation times (T1) of the quaternary carbons, 2 new peaks

appeared in the vinyl region. The 1H NMR spectrum for 36 was also

characteristically symmetrical with a complex vinyl multiple (6 6.4, 6H)

bridgehead multiple (6 3.5, 2H), and endo/exo ethylene multiplets

(6 2-1.2, 2H, 2H).

Isomer 37 equilibrated to form a ca. 50:50 mixture of 37a and 37b

as evidenced by doubling of peaks in the 13C NMR spectrum, with four CH2

peaks, two CH peaks, two -OMe peaks, one small quaternary -C-OMe peak,

and nine vinyl peaks. In the IH NMR spectrum, the vinyl region contained

a multiple for the cyclopentadienyl residues (ca. 6 6.2, 6H) and a close

triplet (6 6.0, 4H) which is characteristic of symmetrical 7-substituted

norbornenes. Farther upfield appeared two -OMe signals superimposed on

two sets of bridgehead and cyclopentadienyl methylene multiplets (ca.

6 3, 12H), followed by two well-separated multiplets for the endo and exo

ethylene hydrogens (6 1.6, 4H and 6 0.9, 4H, respectively).

From mechanistic considerations, we could predict at least four

other C13H160 isomers. To distinguish among these possibilities, we made

use of existing molecular symmetry and in some cases created symmetry for

spectral simplification. Scheme 2.4 outlines the symmetry results after

reduction of the double bond in compounds 26, 38, 39 and 40 with the

bracket numbers indicating the total number of carbon signals expected in
13C NMR.









OMe OMe


8 26 O H2 e -
Pd/C 2








13

3 Pd/C13



1d/C 9
40 40-H
OMe OMe

Scheme 2.4


The 26 was confirmed by its expected simple eight-
13 1
line C NMR spectrum (due to its symmetry), with one quaternary (-C-),

one vinyl (=CH), four methyne (-CH), one methylene ('CH2), and one -OMe

signals. The 'H NMR spectrum of 26 was also characteristic, with a

virtual triplet (J=1.9 Hz) for the two vinyl protons. At high field, a

pentet (J=2.95 Hz) was observed for H(3a) which arises from vicinal

coupling to bridgehead hydrogens H(3)-H(7a) and long-range "W" coupling

to endo hydrogens H(7) and H(8).

The 13C NMR spectrum for isomer 39 was much more complex, with

13 resonances. The question of structure assignment between isomer 39

and 38 was resolved by taking advantage of the resulting symmetry of 38

after catalytic reduction of the double bond. Upon removal of the vinyl

carbons in 39, there still remained 13 resonances with two new CH2 carbon

signals. Analysis of the selective decoupled high field 300 MHz 1H NMR


er 39

and 38 was resolved by taking advantage of the resulting symmetry of 38

after catalytic reduction of the double bond. Upon removal of the vinyl

carbons in 39, there still remained 13 resonances with two new CH2 carbon

signals. Analysis of the selective decoupled high field 300 MHz 1H NMR









spectrum was consistent with the structural assignment for 39 (see

Appendix 2).

The mixture of isomers 26 + 38 could not be resolved easily, but on

chromatography with AgNO3 impregnated silica gel, it was possible to
13
achieve a 40:60 enhancement (26:38, respectively). A 1C NMR spectrum

for this mixture revealed 21 resonances, 8 of which were identified as

belonging to 26, with 13 signals remaining. At this point, the identity

of 38 was still in question. Due to its asymmetry, isomer 40 was also

consistent with this spectrum. To distinguish between these two possibil-
13
ities, the mixture of 26 + 38 was catalytically reduced. The 1C NMR

spectrum of the resulting mixture exhibited only 16 signals, 8 of which

were again assignable to 26-H2. Therefore, the structure of 33 was

confirmed by its unusual symmetry after reduction.

The remaining postulated isomer 40 was not observed and from

mechanistic considerations is the least likely to be formed. A peak of

similar retention time as the other isomers was observed only in very low

amounts in the GC (<0.6%) and could not be isolated.



Mass Spectra


Examination of the 70 eV GC-MS obtained of the mixture of isomers is

particularly interesting (Figure 2.2). There is a striking similarity of

the spectrum for 37 compared with 36. Apparently, isomer 37 fragments

initially (M+ MeOH = 156) and enters the fulvalene 36 (M+ 156)

manifold. Both compounds exhibit a large 128 peak corresponding to loss

of ethylene to produce a stable fulvalene ion. For the remaining C13H160

isomers (26, 38 and 39), the parent ion (m/z 188) is observed as the base

peak in all cases. A very characteristic fragment ion (m/z 123) arises











due to a retro-Diels-Alder process (loss of C5H5) and corresponds to the

intermediate oxonium ion produced in the reaction mechanism for 26 and 39

(see Scheme 2.5).



Mechanism


The reaction mechanism apparently involves intermediate carbocation

species which can rearrange via various pathways leading to isomers 26,

37-40 as illustrated in Scheme 2.5. Presumably, when the Lewis acid

complexes with ketal 30, it promotes the loss of a methoxide moiety to

generate oxonium ion 29. The silyl alkylating agent (28) may then


-Si-



S2Acid
30 29


-SiMe


37a 3-)


-c'ba
MeO Me0o


cie






O1e OMe


Scheme 2.5











approach ion 29 from either face (a: syn to the double bond or b: anti to

the double bond). Approach from the "wrong side" (b) produces isomer 37

after loss of the silyl group and rearrangement. Approach over the

double bond (a) should be favored sterically to generate intermediate

ion 41, which can suffer either of two fates described by Path I or

Path II. Path I depicts direct loss of the silyl group followed by rapid

[4+2] closure to form 26. Alternatively, Path II depicts double bond

bridging of the intermediate cation 41 to form 42, which could undergo

Wagner-Meerwien rearrangement. Loss of the silyl group then promotes

closure by any of the four modes indicated to produce 26 and 39-40.

In the presence of BF3*Et20, 26 is formed preferentially, while

A1C13 favors production of 39. These results may be rationalized by

considering that BF3 Et20 favors early loss of the silyl group (by F

displacement), with subsequent Diels-Alder cyclization producing 26 as

the major isomer via Path I. On the other hand, AlC13 is less nucleo-

philic (toward silyl group displacement) and could favor a longer-lived

carbocation species, which subsequently undergoes further rearrangement

via Path II to produce predominantly isomer 39.



Improved Isolation of 26 from Isomer Mixture


An improved method of purification of 26 was devised which employed

a bromination/debromination procedure. A mixture of the isomers was

treated with Br2/CH2C12 to brominate the double bond. This gave rise to

a mixture of dibromides which were easily separated by flash chromatog-

raphy on silica gel. The two major isomers isolated are depicted in

Scheme 2.6 (see Chapter 3 for further discussion of bromination). The

trans-dibromide (26-Br2) was crystalline and facilitated easy clean-up to









a high purity (>99% by GC). The debromination was attempted by treatment

under standard conditions of Zn/EtOH + acetic acid25 or Zn-Cu couple26

with heating. This gave little success with a large amount of rearranged

dibromide (43) being formed (apparently due to thermal rearrangement).

However, it was noted that utilizing these same conditions, with the reac-

tion flask immersed in a sonicating cleaning bath, led to a quantitative

debromination in <5 min! It was then determined that bromination of a

clean sample (>97%) of 26 at -60 to -500 C led to pure 26-Br, without
-- 2
rearrangement.

This procedure now allows the rapid preparation of 26 in high yield

and purity as illustrated in the overall Scheme 2.6.







21











0













r4







1.











10 C).
CQC


















1c |
col











CQ
ca















CHAPTER THREE

REACTIVITY AND REARRANGEMENTS OF BISESQUINENE



Previous work in our group has investigated the solvolytic behavior

of bisesquinane brosylates to delineate the factors affecting rearrange-
27
ments of these systems.27 Apparently, there exists a delicate balance

between thermodynamic and bond alignment factors which affect the outcome

of rearrangements in these and other related systems. In the twist-

brendyl system (44), rearrangement into two manifolds is possible due to

direct participation by either of two adjacent C-C bonds.28



3 +



44 45 45



Products derived from 45 predominate by 2.2:1 over those from 46, presum-

ably due to more favorable C(1)-C(6) bond alignment, even though 46 leads

to a more thermodynamically stable skeleton.

Interconversion of the Wagner-Meerwein related pair, 47 and 48, is
27
believed to involve the Y-bridged cation 50. Acetolysis of brosylate

49 produces predominantly acetate 48-OAc with a small amount of acetate

47-OAc, possibly due to leakage from ion 51 to 50.

Acid catalyzed equilibration of acetates 47-OAc and 48-OAc produces the

product ratio 99.5% 48-OAc to 0.5% 47-OAc. This corresponds to a free

energy difference of 3.7 kcal mole-I. Thus, the conclusion was made that









34 36 3- X



47 1 J449


*---



50 51




thermodynamic considerations favor the participation of bond C(3a)-C(3b)

in 48 despite the ideal C(2)-C(8) bond alignment.27 These findings are

contrary to the results of the twistbrendyl system28 and underscore the

fact that both factors (bond alignment and thermodynamic product stabil-

ity) must be carefully considered for prediction of Wagner-Meerwein

rearrangements.



Acid Catalyzed Rearrangements in Methoxybisesquinene


Previous results by Grob and co-workers have demonstrated the facile

cleavage on solvolysis of 6-exo-substituted-2-exo-norbornyl toluene-

sulfonates (52) by a concerted fragmentation involving rupture of the

C(1), C(6) bond in cases where the substituent is an n-electron donor,

such as CH3S, CH30, HO, or (CH3)2N.29,30





OTs -


J2 53 54








,,31
These accelerated cleavages have been called "frangomeric effects" and

operate in the 6-norbornyl case to produce exclusively the intermediate

salts 53 which are immediately hydrolyzed to (3-cyclopentenyl)acetalde-

hyde (54). Another example of this type of cleavage was reported by
32
Gassman and Macmillan for the ketal 55 which, on solvolysis followed by

reduction with lithium aluminum hydride (LAH), produced (3-cyclohexyl)-

methanol (57) in 57% yield.



0 0 0..+,0 CHOH

S1) HOAc
2) LAH
TS
55 56 57

Previous work on dimethyl ketal 58 showed no similar fragmentation but

instead produced the 2-exo-methoxy-7-norbornone (61) via neighboring

group participation of the syn-methoxy moiety.33

+le Me\ 0
MeO OMe MeO




Ts
58 59 50 51

This difference of reactivity can be explained as a result of "tying

back" the syn-oxygen in ketal 55 to inhibit its participation and

thereby afford the anti-oxygen the opportunity to participate in the

frangomeric cleavage.

In view of the frangomeric effect, the results for the unsubstituted

bisesquinane (47) solvolysis and acid catalyzed rearrangements prompted

us to consider the effect of a methoxy substituent on carbon-3b (e.g.,

methoxybisesquinene, 26). Under acidic conditions (see Scheme 3.1), it


s (see Scheme 3.1), it








3a 3b OMe OMe OMe

H 1 7 .. .__.-. + /Me

26 62 b 63a 0
t i b -
Me OMe
XAf 63b


64-X 65-X 66


Scheme 3.1


was anticipated that the methoxy moiety should facilitate the leakage of

ion 62 to ion 63a and thence to the localized cation 63b. The presence

of ion 63b would be manifested by the formation of ketone 66. Solvent

capture by either ion 62 or ion 63a could produce products 64-X and 65-X.

Product 64-X could also arise from direct addition to the double bond in

26 before rearrangement to ion 62.



Addition Reactions of the Double Bond


A series of electrophilic addition reactions to the double bond of

bisesquinene (26) were studied to gain insight into its unusual reactiv-

ity and tendency toward rearrangement.

One of the first indications of this unusual reactivity was the

observation that the neat methoxybisesquinene (26) on standing several

months in the refrigerator partially decomposed to produce a polymeric

material and the exo-epoxide (67). This epoxidation is presumably due

to facile air oxidation of the alkene.













MCPBA

26 67



That this material was the exo-epoxide was demonstrated by the authentic

synthesis of 67 by treatment of 26 with 3-chloroperoxybenzoic acid

(MCPBA), which produced the single exo-isomer 67 (87% yield). The 1H ::iF

spectrum contained a very characteristic singlet (6 3.24, 271) for the

endo hydrogens adjacent to the epoxide confirming its expected exo stereo-

chemistry.

Bromination of the double bond in methoxybisesquinene (26) at room

temperature produced a mixture of isoners 26-Br2 and 43 (82% and 18%,

respectively).

OMe OMe OMe
k Br2 BrB


26 Br 26-Br 43
2--


OMe OMe

BrBrr +


3r- 68a 68b

The rearrangement to dibromide 43 probably proceeds via bromonium ion 68a

and a subsequent Wagner-Meerwein shift to 68b. When the alkene 26 is bro-

minated at -78 to -600C, only the crystalline trans-dibromide 26-Br2 is

produced with no evidence for the rearrangement product 43. The structure

of 26-Br2 was confirmed by x-ray crystallography and is discussed in Chap-

ter Four. Tne H I-R spectrum for 26-Br2 was distinctly different from
2








that of the rearranged dibromide 43, with elements of its pseudo-symmetry

apparent. The signal for H(3a) was still quite clearly a pentet

(J=2.7 Hz) in 26-Br2 while in 43 it was observed as a broad multiple.

The most characteristic signals came from the protons alpha to Br at

6 4.53 (dd, J=2.7, 5.2 Hz) and 6 4.19 (d, 2.7 Hz), corresponding to the

exo and endo hydrogens, respectively, in 26-Br2. The corresponding

protons in 43 appeared at 6 4.85 (broad t, J=1.2 Hz) and 6 4.08

(t, J=1.46 Hz).

That the double bond of methoxybisesquinene (26) is particularly

susceptible to acid was first realized during the attempted de-methyla-

tion with trimethylsilyl iodide (TMS-I). This reaction is thought to

proceed by complexation of the ether oxygen with the silyl moiety fol-

lowed by SN2 displacement of the methyl group by iodide.34



R-O-Me + TMS-I --- R-0-Me I -- R-0-THS R-OH
I +
TMS Mel


Subsequent hydrolysis of the silyl ether produces the desired alcohol.

However, treatment of alkene 26 with TMS-I did not produce the expected

alcohol. Instead, a complex mixture resulted which, upon GC-MS analysis,

indicated that addition of HI to the double bond had occurred. The major

product was isolated by prep GC and tentatively identified as exo-iodide

64-I based on 1H NMR and MS fragmentation patterns.


OMe OMe

STNIS-I S I
TM17 S 1 I
S(HI)

26









The formation of HI could result from adventitious water present in the

reaction or upon quenching of excess TMS-I on work-up. Removal of the

double bond by reduction followed by treatment with TMS-I led to clean

production of the saturated alcohol (see Chapter Four), thus demonstrat-

ing the sensitivity of the alkene to acid addition.



Preparation of Acid Rearrangement Products


To study the acid catalyzed rearrangements of 26, we needed

authentic samples of the possible alcohols, acetates and ketone. The

epoxide 67 was opened smoothly with diisobutylaluminum hydride (DIBAL-H)

to produce a clean sample of exo-alcohol 64-OH (78.5% yield). The HM NIR

spectrum of exo-alcohol 64-OH exhibited a quite characteristic pattern of

doublet of doublets (6 3.94, J=2.4, 7.1 Hz) for the endo-hydrogen alpha

to the hydroxyl moiety. The carbon spectrum contained only 12 visible

peaks, but one was slightly more intense, suggesting overlap. The I'EPT

pulse sequence confirmed the presence of 3 methylene peaks, two of which

were almost superimposed, indicating the molecule's more symmetrical

appearance at sites removed from the added functionality.

OMe OMe

0 DIBAL-lH HO



67 6g-OH



It was anticipated that the rearranged alcohol 65-0!! could be

obtained by the reaction sequence as outlined in Scheme 3.2. This

approach depends upon a previously described rearrangement of epoxide 69









to alcohol 70, apparently via carbene insertion into the bridge C-H

bond 35,36
bond.



tLNEt2 H
Et2O

69 70



Treatment of alcohol 71 with sodium hydride and methyl iodide cleanly

produced the methyl ether 72 (98% yield). Epoxidation was smoothly

accomplished with 3-chloroperoxybenzoic acid (MCPBA) to yield epoxide 73

(95% yield). Attempted rearrangement of epoxide 73 with lithium diethyl-

amide in refluxing diethyl ether (Et20) gave only starting material on

work-up. However, refluxing in THF with lithium diethylamide produced

the desired alcohol 65-OH (53% yield). A point of confusion arose

initially in that both epoxide 73 and alcohol 65-0H had identical

retention times on the GC capillary column being utilized; however, the

transformation of 73 to 65-OH was readily distinguished spectroscopically

due to its loss of symmetry. The IH "P: spectrum for 55-0 contained a

diagnostic doublet 6 4.3 (J=2.4 Hz) for the hydrogen alpha to the -OH,

which is quite characteristic for this twisted ring system. The 13C NMR

spectrum clearly indicated rearrangement of the symmetrical epoxide 62

(8 signals) to the unsymmetrical alcohol 55-OH (12 signals, one peak

overlapped).

Ketone 66 was also obtained as previously described from alcohol 71

by treatment with pyridinium dichromate37 (Scheme 3.2).









SNOH MCPBA
HOeMO
71 72 73 LiNE,/THF
0
HO
Cr3' Pyr


66 65-0H


Scheme 3.2

Alcohols 64-OH and 65-OH were cleanly converted to their correspond-
ing acetates by treatment with acetic anhydride in the presence of a
catalytic amount of dimethylaminopyridine (DMAP).38 The IH and 13C NMR
spectra were not significantly changed except for the observation of the
acetate residue.

OMte OMe OHe
7LHO ( AC 2 rArO e
HO + D;L7tLci cL0Ji + ^

64-OHi 65-0H -OAc 65-OAc



Results of Acid Addition to the
Double Bond of Methoxybisesquinene (26)

With the probable products of acid addition to methoxybisesquinene
in hand, it was now a simple matter to identify the rearrangement prod-
ucts. The results of the treatment of methoxybisesquinene (26) with
various acids are summarized in Table 3.1. In no case was the formation
of ketone 66 observed.









Table 3.1. Acid Catalyzed Rearrangement of Methoxybisesquinene (26)




APMe RAcO Rc
---- Po. RO


64-X 65-X


Conditions




TFA/CDCl3
RT, 12 h





HOAc/TsoH
600C
30 days


Product Ratioa


H2SO4/H20/THF

38% :21%:41%b
(1 : 1 : 2) vol
RT, 6 h



H2S04/H20/THF

60% :20%:20%
RT, 4 h


40% H 2SO/H20

a) 600C, 2 h
b) 600C, 12 h


a Determined by capillary GC; no other significant products were
detected
b wt/wt%


0
II
wt/wt%





0
II
CH C-
3


II
CH C-
3









Trifluoroacetic acid (TFA) adds rapidly at room temperature to

methoxybisesquinene (26) in CDC13 solution, producing a 90:10 ratio of

64-TFA and 65-TFA, respectively. The 64-TFA isomer was isolated and

fully characterized. Its 1H and 13C NMR spectra were quite similar to

64-0Ac. The mixture of TFA-isomers was treated with DIBAL-H and con-

verted cleanly to a mixture of alcohols 64-OH and 65-OH, for confirmation

of their structures by GC retention times.

Treatment of methoxybisesquinene (26) with glacial acetic acid and

catalytic tosylic acid, although much more sluggish, gave similar

results. The mixture was maintained at 600C for 30 days and resulted in

the partial equilibration of acetates 64-OAc and 65-0Ac (60:40, respec-

tively), with ca. 18% unreacted methoxybisesquinene (26) remaining. To

assess the equilibration, acetate 64-0Ac was heated in glacial acetic

acid, 1% acetic anhydride, and catalytic tosylic acid at 750C. After

1 week, GC analysis indicated a relative ratio of 45:55, 64-0Ac to

65-0Ac, respectively. Allowing the equilibration to continue for an

additional week produced a relative ratio of 16:84. The equilibration is

clearly quite slow under these conditions. Noteworthy is the fact that

no additional products appeared.

OMe OMe

~T HOAc Al
AcO


64-OAc 65-OAc


The results of sulfuric acid catalysis indicate a significant

increase in the rearrangement of 64-OH to 65-OH with increasing acid

strength and temperature. Tetrahydrofuran (THF) was used as a cosolvent

to maintain solubility; however, analysis was complicated by the










formation of THF decomposition products. This problem was circumvented

by use of H2SO4/H20 solutions without THF, and although this resulted in

a heterogeneous mixture, clean conversion of methoxybisesqinene 26 to

alcohols 64-OH and 65-OH was observed.

To determine the stability of ketone 66 under these conditions, the

ketone was treated with acid as above (40% H2SO4/H20, 600C) for 2.5 hr.

Upon GC analysis, there was no trace of ketone 56, but a new peak was

observed at longer retention tiee (which had not been observed in any of

the previous acid rearrangements of methoxybisesquinene). The 1H NMR

spectrum of the crude reaction mixture exhibited somewhat broadened peaks

suggesting a mixture of polymeric material. After prep TLC, a relatively

pure material was obtained, and its 1H NMR spectrum was remarkably simi-

lar to that of 65-OH, exhibiting a characteristic doublet (6 4.4 ppm,

J=2 Hz)and a parent ion of 192 m/z in the GC-MS. This material is tenta-

tively identified as the diol 74 and could originate as shown:

0 OH
+20






66 74


Confirmation of this structure was attempted by treatment of 65-OH

with TMS-I in C6D6 to effect de-methylation and hopefully produce diol

74. As the reaction was monitored in the IH NMR, broadening of the

proton alpha to the -OH occurred, and a new methoxy signal began to

appear soon after the addition of TES-I. At longer times, both methoxy

peaks diminished as a peak for methyl iodide developed. After standing

overnight, the signals for -OMe virtually disappeared. Following work-up,

gas chromatographic analysis confirmed the absence of starting material


ial








(65-OH) and showed two new major peaks at 5.23 min (25.8%) and 7.88 min

(68.2%) and two minor components at 7.63 min (2.82%) and 8.05 min (3.25%).

The peak at 5.23 min corresponded to the retention time for ketone 66,

but the later peaks were at longer times than diol 74 (6.68 min). The 1H

NMR spectrum showed a broadened doublet (6 4.8, J=2 Hz) which was quite

similar to the rearranged ring system but no evidence of a vinyl peak at

6 6.0 for ketone 66. Analysis of the mixture by GC-MS confirmed the

presence of ketone 66 (M 174, 19%); however, the later peaks were

extremely broad due to decomposition on the column and, except for m/z

175 (10%), showed only mass fragments corresponding to ketone 66.

Analysis of the mixture by direct vaporization on the solids probe

allowed detection of a small molecular ion at m/z 302 (0.33%), a now

substantially larger peak at m/z 175 (100%, M+-I), and peaks for HI+

(128, 55%) and I+ (127, 33%), which indicate the formula C12H150I.

Therefore, the major component is tentatively identified as iodo-alcohol

78 which may be formed as shown in Scheme 3.3.

The NMR results may be explained by formation of an initial silane

complex (75) followed by rearrangement to ion 76 or 63a. Collapse of the

ion pair (76 or 63a) would produce 64-I and 65-I, which would account for

the broadened alpha proton and shifted -OMe signals. A second equivalent

of TMS-I then complexes with the -OMe and after work-up produces iodo-

* alcohols 77 and 78. Since there was no observation of the ketone 66

vinyl during the reaction, we suggest the capillary GC results (peak at

5.23 min) are due to thermal rearrangement in the injector of 78 with

loss of HI. This is consistent with the GC-MS observations which

utilized a packed glass column (more reactive surface for decomposition

compared to fused silica).
















l/ I


TMS-I
*<--------


75


65-OH


I_
-- -
.4---


64-I

1) TMS-I
2) Work-up


OH




77


OMe



65-I

1) TMS-I
2) Work-up


OH




78


Scheme 3.3


4-
I-"
'..


Me I
+ /
0


63b






+


------e
r------









Conclusions


Apparently the addition of the methoxy moiety to the C(3b) position

of bisesquinene has little effect as far as the predicted frangomeric

cleavage of bond C(3b)-C(3a) to produce ketone 66. These results imply

that ion 63a does not contribute significantly to the rearrangement of

the bisesquinane skeleton since leakage to 63b and thence to ketone would

be expected. A better representation of ion 63a may be the degenerate

rapidly equilibrating ions Q9a and 79b).

OMe Me

/T"--/+/---



79a 79b



It is difficult to rationalize why we did not observe any ketone 66 or

subsequent ketone-derived products, since the energy of bond C(3b)-C(3a)

cleavage should be regained by formation of the carbonyl. In addition,

strain energy calculations39 for the related hydrocarbon ring systems

show that the skeleton of 66 is ca. 4 kcal/mole more stable than that of

65. However, additional strain is contributed by the double bond and

carbonyl and may significantly raise the strain energy of 66 to a level

comparable or even higher than that of 65--0. As a consequence, there

would be little driving force for frangomeric cleavage to occur. Some

support for this argument is the rearrangement of ketone 66 under acid

conditions to the 65-X framework.















CHAPTER FOUR

STRAIN AND STRUCTURAL EFFECTS
IN THE BISESQUINANE SYSTEM



Relief of skeletal strain is frequently cited as a contributing
40
factor in rearrangements of polycyclic skeletons to more stable ones.4

When predicting and interpreting these skeletal rearrangements, it has

been helpful to use computer calculations of strain energies to compare
41 42
molecular stabilities of possible products.442 In this fashion, the

chemist can gain insight into the complexities of a reaction, and more

accurately determine the probable fate of a rearrangement which could

follow more than one course. A study of the structure and inherent ring

strain in the parent bisesquinane (4) and its effects on reactivity and

rearrangements is presented here. The goal of this study is to discrimi-

nate between various C-C bonds in order to partition the overall ring

strain and assign the "most strained" portions of the molecule.



Strain Energy


MM2 Calculations


Molecular mechanics calculations of strain energy utilizing
43
Allinger's MM2 program43 were carried out on the parent bisesquinane

(4) and compared with various derivations obtained by 1-bond cleavages

(see Figure 4.1). The molecular mechanics method calculates a geometry

for the molecule which minimizes its total energy. The amount of strain












4.









to.0
o0 0
c0 n




C5-


oo ao
m 4

rB.

-4-


4o
4n CM

14 -1 71 ^ s




I-N < q


C5
W %
Pr


am
4 .0
C.M 0

0












r..0
3


m .0




O
4 .













00
MO C
*-* *-


C
4.0
-4


cu

.-4







uJ o
co-i




C,.c] ,


00
C









present is reflected by the extent to which the molecule's structural

parameters (bond angles and lengths) deviate from their ideal values in

order to reduce the molecule's total energy. As can be seen from

Table 4.1, the total steric energy (E) results from the summation of

several contributing energies: bond compression (or stretching), bond

bending (angle distortion), stretch-bend, van der Waals (non-bonded inter-

actions between atoms or groups), and torsional (function of dihedral

angle). Inspection of these energy factors for compounds 4, 80-82 is

instructive in determining the major sources of high steric energy. In

all cases, the torsional interactions contribute greatly to the observed

steric energy. These bridged polycyclic systems, by their nature, force

sterically demanding eclipsing interactions which give rise to the ob-

served large torsional energies (20-26 kcal/mole). Another major contri-

bution to steric energy comes from the bending, which decreases substanti-

ally (32-6 kcal/mole), as angle strain is relieved. Most of the other

energy factors are relatively insignificant, except for the van der Waals

1,4 interactions (4-9 kcal/mole). Interestingly, in the bisesquinane

skeleton (4), these interactions are the lowest of the four compounds

compared.

The bond enthalpy (BE) and strainless bond enthalpy (SBE) can be

calculated from standard values for the total number and types of bonds

in the molecule. The partition function contribution (PFC) is the sum of

population (POP), torsional (TOR), and translation/rotation (T/R) contri-

butions and is constant for all four structures due to their rigidity.

Utilizing these values and the steric energy (E), the heat of formation

(HFO) may be obtained from the following equation:


HFO = E + BE + PFC








Table 4.1. 1M2 Energy Calculation Results (kcal/mole)








4 80 81 82

Compression 1.5970 2.144 1.409 0.970
Bending 32.332 22.211 15.598 6.074
Stretch-Bend -1.375 -0.899 -0.546 -0.187

van der Waals 1,4 4.345 7.481 8.917 6.479
Other -2.043 0.597 -2.298 -2.356
Torsional 24.238 19.677 20.972 26.289
Total Steric Energy (E) 59.093 52.211 44.051 37.269



Bond Enthalpy (BE) -50.72 -57.28 -57.28 -57.28
Strainless Bond Enthalpy (SBE) -42.70 -49.29 -49.29 -49.29



Population (POP) 0.00 0.00 0.00 0.00
Torsional (TOR) 0.00 0.00 0.00 0.00
Translation/Rotation (T/R) 2.40 2.40 2.40 2.40
Partition Function 2.40 2.40 2.40 2.40
Contribution (PFC)



Heat of Formation 10.77 -3.67 -10.83 -17.61
(HFO) = E + BE + PFC

Strainless Heat of Formation -40.30 -46.89 -46.89 -46.89
(HFS) = SBE + T/R

Inherent Strain 51.07 43.22 36.06 29.28
(SI) = E + (BE-SBE)

Strain Energy 51.07 43.22 36.06 29.28
(S) = POP + TOR + SI






41

The strainless heat of formation (HFS) results from the translation/rota-

tion addition to the strainless bond enthalpy (SBE):


HFS = SBE + T/R


The inherent strain (SI) is calculated by adding the steric energy (E)

to the difference between the bond enthalpy (BE) and strainless bond

enthalpy (SBE):


SI = E + (BE SBE)


Finally, the strain energy (S) is obtained by correcting the inherent

strain (SI) for any torsional (TOR) and population (POP) contributions:


S = SI + TOR + POP


These results predict the greatest relief of strain (ca. 22 kcal/mole)

when cleaving the central bond c which correlates well with previous
8
experimental observations. Thus, in the case where this bond is substi-

tuted with diester groups (10), facile cleavage occurs to produce the

tetraquinacene 13.


Homoketonization


The calculated strain energies of 80 and 81 reveal a 7 kcal/.ole

preference for breaking bond b over bond a in bisesquinane (4). To









devise an experimental test for the relative bond strengths of a and b in

the bisesquinane system (i.e., which is more highly strained?), we consid-
44
ered a homoketonization type rearrangement. Generally, this can be

considered as the reverse homo-enolization process depicted below for

camphenilone (83).45



Homo-enolization

Homoketonization
0 0

83 84


44
There are numerous examples of base-induced homoketonization, from

which some general factors relating to control of the regiochemistry of

the cleavage can be obtained. Relief of strain, product stability, and

the stability of the incipient carbanion are the major considerations for

determining regiochemistry. For example, preferential cleavage of bond a

in 85 results from the delocalization of the incipient carbanion (86) and

produces aldehyde 88 exclusively.46




0 0 0-- 0
"86 H 88 H
ro
b-5 00-
85


87



Relief of strain and product stability dictate bond cleavage in 89 which

leads to the formation of noradamantone (90).47






43





0-

89 90

The bisnoradamantyl alcohol (91) homoketonizes in t-BuOK/t-BuOD (700C) to

yield exclusively 92, resulting from cleavage of bond a with retention

of configuration.48

OH H
+OK/-HOD
70

91 92

In the case of the hydroxybisesquinane skeleton (93), these concepts

were utilized to probe the relative bond strain of a and b as illustrated

in Scheme 4.1. If homoketonization occurs, a choice of which bond(s) to

break must be made. Cleavage of bond a would lead to "homo-enolate" 94

while cleavage of bond b would produce "homo-enolate" 95. Inspection of

molecular models indicates that in 94, the carbanion is rigidly held in

close proximity to the newly formed carbonyl (unlike the intermediate




oi 0
rb
9 91 \





S0

Scheme 4.1









carbanion in the transformation of 91 to 92). Hence, we might expect

rapid equilibration to reform bond a. However, this is not the case in

the formation of 95 since, due to the greater flexibility of the newly

opened cyclohexyl ring, the carbanion is removed from the vicinity of the

carbonyl. Thus after equilibration, we would expect to produce the more

thermodynamically stable ketone via "homo-enolate" 95.

Armed with these predictions, we attempted to confirm them experimen-

tally (Scheme 4.2). In this regard, methoxybisesquinene (26) was con-

verted by reduction to methoxybisesquinane (26-H2). This was cleanly

de-methylated to the crystalline bisesquinol (96) by treatment with

trimethylsilyliodide (TMS-I). The bisesquinol (96) was subjected to

homoketonization conditions similar to those utilized for 91 (t-butoxide/

t-butanol, 900C, 20.75 h), and GC analysis indicated only starting

material present. Under more vigorous conditions (2000C, 22 h) GC analy-

sis indicated a mixture of starting material (20%) and a single major new

component (72%). The mixture was fractionated by prep TLC to afford a

ketone, as evidenced by IR (1740 cm- ). The 1C NMR spectrum showed the

presence of 12 peaks, thereby excluding ketone 97 (by symmetry only

7 peaks are expected). The INEPT 13C NMR spectrum (Figure 4.2) clearly

shows the presence of 5 methylene peaks and 6 methine peaks, consistent

with the structure of ketone 98.

In summary, we have shown that exclusive cleavage of bond b occurs

to produce the more stable ketone 98 in preference to ketone 97.






45










Homoketonlzation



OMe



226

| H2 Pd/C
OMe


26-H

TMS-I
a OH




S/+OH8 20C






98


Scheme 4.2


97























O

















CD


.1i









Bisesquinane Structure: Calculated and X-Ray


Bond Lengths


From the MM2 calculations, we can obtain structural information

regarding bond lengths and bond angles. One might suspect that a more

strained bond, as a consequence, would be longer than normal. Close

inspection of the calculated bond lengths of bisesquinane (4)

(Figure 4.3) reveals that bonds a and c are the longest bonds. That

this is indeed significant becomes more obvious when comparison is made

with compounds 80 and 81. There is a clear trend indicating that as the

strain is relieved in the molecule, the bond lengths tend toward the

normal C-C bond distance of 1.54 X.

To substantiate the theoretical prediction of longer bond lengths

for bonds a and c, an x-ray crystal structure was obtained for the

dibromomethoxybisesquinane derivative (26-Br2). An ORTEP drawing of

the crystal structure for 26-Br2 is presented in Figure 4.4 and a summary

of the bond lengths in Tables 4.2 and 4.3.


Figure 4.4. Stereoscopic view of the molecular structure of 26-Br2
2




























































Figure 4.3.








Figure 4.3.


MM2 calculated bond lengths.








Table 4.2.


Br(1)-C(2)

C(2)-C(1)

C(1)-C(12)

C(1)-C(11)

C(9)-C(12)

C(9)-C(8)

C(9)-C(10)

C(2)-C(3)

C(5)-C(12)

0(1)-C(10)


Bond Lengths [A] with Estimated Standard Deviations in
Parentheses for Dibromide 26-Br2 Involving Non-H Atoms


1.968(8)

1.500(11)

1.530(12)

1.556(10)

1.539(12)

1.523(13)

1.516(11)

1.515(12)

1.612(11)

1.423(9)


Br(2)-C(3)

C(3)-C(4)

C(4)-C(5)

C(4)-C(11)

C(6)-C(5)

C(6)-C(7)

C(6)-C(10)

C(7)-C(8)

C(10)-C(11)

0(1)-C(13)


1.987(8)

1.490(12)

1.549(11)

1.561(11)

1.515(12)

1.523(13)

1.553(11)

1.538(13)

1.588(11)

1.398(10)








Table 4.3. Bond Lengths [A] for Dibromide 26-Br2 Involving H Atoms
2inHAtm


H(2)-C(2)

H(1)-C(1)

H(12)-C(12)

H(9)-C(9)

H(81)-C(8)

H(82)-C(8)

H(11)-C(11)

H(M2)-C(13)


1.16

0.98

1.04

1.11

1.00

1.15

1.00

0.74


H(3)-C(3)

H(4)-C(4)

H(5)-C(5)

H(6)-C(6)

H(71)-C(7)

H(72)-C(7)

H(M1)-C(13)

H(M3)-C(13)


1.06

0.94

1.14

1.16

1.01

1.01

0.95

0.95









The bond lengths are grouped according to similar bond types for facility

of comparison. It is immediately obvious that the conclusions based upon

MM2 calculated bond lengths are reflected in the long bond lengths of

a [C(10)-C(11) = 1.488 A] and c [C(5)-C(12) = 1.612 A] in the crystal

structure of 26-Br It appears that the tendency of the bisesquinane

skeleton is to relieve large strain contributions by stretching these two

bonds.



Bond Angles


Marked distortion of bridgehead angles from tetrahedral has been
49
cited as a major source of skeletal strain.9 Calculation by M12 of bond

angles in 4, 80 and 81 (Figure 4.5) reveals cases of substantial compres-

sion and accounts for a large portion of the strain energy of these mole-

cules. Comparison of bond angles in norbornane49'50 with those calcu-

lated for bisesquinane (4) is very informative. As expected, the

central bridge angle C(1)-I(11)-C(4) at 93.00 is approximately equal to

the norbornane bridge angle of 93.10. Somewhat surprising is the angle

C(5)-C(4)-C(11) which is compressed even more to 91.40! This compares

with the similar norbornane angle at 1010. Careful examination of the

model of bisesquinane reveals that this unusual bond angle is a conse-

quence of the molecular framework. Viewed from a different perspective

(Figure 4.6), this "bridgehead" carbon (in the sense of norbornane)

becomes a "bridge" carbon; consequently, the 91.40 bond angle appears to

be somewhat more normal.






































































Figure 4.5.


305: q














102.-
41 80



325.9












2 calculated bond anglesand values




32(see text).

Mi2 calculated bond anglesand Z values
(see text).








Table 4.4. Bond Angles [o] with Estimated Standard Deviations in Paren-
theses for Dibromide 26-Br
-- 2


Br(1)-C(2)-C(3)

Br(1)-C(2)-C(1)

C(1)-C(2)-C(3)

C(2)-C(1)-C(11)

C(2)-C(1)-C(12)

C(11)-C(1)-C(12)

C(1)-C(12)-C(9)

C(1)-C(12)-C(5)

C(5)-C(12)-C(9)

C(12)-C(9)-C(8)

C(12)-C(9)-C(10)

C(10)-C(9)-C(8)

C(9)-C(8)-C(7)

C(1)-C(11)-C(10)

C(11)-C(10)-C(9)

C(1)-C(11)-C(4)

C(9)-C(10)-0(1)

C(11)-C(10)-O(1)


110.6(6)

113.7(6)

104.2(7)

104.7(6)

115.8(7)

93.8(6)

98.7(6)

102.4(6)

101.4(6)

114.6(7)

93.2(6)

105.9(7)

103.8(7)

103.0(6)

104.9(6)

92.6(6)

113.1(6)


Br(2)-C(3)-C(2)

Br(2)-C(3)-C(4)

C(4)-C(3)-C(2)

C(3)-C(4)-C(11)

C(3)-C(4)-C(5)

C(11)-C(4)-C(5)

C(4)-C(5)-C(6)

C(4)-C(5)-C(12)

C(12)-C(5)-C(6)

C(5)-C(6)-C(7)

C(5)-C(6)-C(10)

C(10)-C(6)-C(7)

C(6)-C(7)-C(8)

C(4)-C(11)-C(10)

C(11)-C(10)-C(6)

C(9)-C(10)-C(6)

C(6)-C(10)-0(1)


117.2(6) C(10)-0(1)-C(13)


110.3(6)

112.2(6)

104.1(7)

107.5(6)

112.0(7)

93.2(6)

99.7(6)

101.6(6)

103.1(6)

113.7(7)

92.4(6)

105.9(7)

103.6(7)

103.1(6)

104.9(6)

94.8(6)

119.0(6)

113.8(6)








Table 4.5. Bond Angles [0] for Dibromide 26-Br Involving H Atoms


H(2)-C(2)-Br(1)

H(2)-C(2)-C(3)

H(2)-C(2)-C(1)

H(1)-C(1)-C(2)

H(1)-C(1)-C(11)

H(1)-C(1)-C(12)

H(12)-C(12)-C(1)

H(12)-C(12)-C(5)

H(12)-C(12)-C(9)

H(9)-C(9)-C(12)

H(9)-C(9)-C(10)

H(9)-C(9)-C(8)

H(81)-C(8)-C(9)

H(81)-C(8)-C(7)

H(81)-C(8)-H(82)

H(82)-C(8)-C(9)

H(82)-C(8)-C(7)
H(11)-C(11)-C(1)

H(11)-C(11)-C(10)

H(M1)-C(13)-0(1)
H(M3)-C(13)-0(1)

H(M1)-C(13)-H(M3)


H(3)-C(3)-Br(2)
H(3)-C(3)-C(2)

H(3)-C(3)-C(4)

H(4)-C(4)-C(3)

H(4)-C(4)-C(11)

H(4)-C(4)-C(5)

H(5)-C(5)-C(4)

H(5)-C(5)-C(12)

H(5)-C(5)-C(6)

H(6)-C(6)-C(5)

H(6)-C(6)-C(10)

H(6)-C(6)-C(7)

H(71)-C(7)-C(6)

H(71)-C(7)-C(8)

H(71)-C(7)-H(72)

H(72)-C(7)-C(6)
H(72)-C(7)-C(8)

H(11)-C(11)-C(4)


H(M2)-C(13)-0(1)
H(M1)-C(13)-H(M2)
H(M2)-C(13)-C(M3)









3









Figure 4.6. Perspective drawings of bisesquinane (4).


One method of gauging bridgehead angle distortion is to compare the

sum of the three internal skeletal angles around the central bridgehead

carbon (Z value, Figure 4.5). The value for norbornane is 311 which,

when compared to the normal tetrahedral arrangement (Z = 328.50 from

109.5 x 3) indicates significant angle distortion. Inspection of

Figure 4.5 reveals a trend in the Z values for compounds 4, 80 and 81.

Apparently in bisesquinane (4), C(11) and C(5) possess significantly

more angle strain than C(4). Cleavage of bond a or b (80 or 81) results

in a substantial increase of the Z value for C(5), thus indicating a

decrease in angle distortion (i.e., the values become much more tetrahe-

dral-like as bonding restrictions are relieved).


13
3C-H Spin-Spin Coupling and Angle Strain


It is well known that the 13C nuclear spin-spin coupling constant

appears to be a linear function of the amount of s-character in the

carbon-hydrogen orbital.51 A linear relationship has been demonstrated

between the JC-H nuclear spin-spin coupling constant and C-C-C bond
52
angles in simple cyclic hydrocarbons.52 This correlation has been

attributed to a change in hybridization to increase the s-character in

external bonds as internal bond angles are decreased. It has been

suggested that the decreased internal skeletal bond angles of norbornyl









derivatives require an increase in the p-character of the bridgehead car-
49
bon bonds. As a result, there is an increase in the s-character of the

bridgehead C-H bonds. Although estimates of % s-character53 have been

made using the simple relationship % s = JC-H/500, quantitative extrapola-

tion of % s-character in strained systems directly from JC-H is not now
-4
considered justified.' However, one can still make qualitative com-

parisons of angle strain by inspection of JC-H coupling constants.

Figure 4.7 summarizes the coupling constants for methoxybisesquinene (26)

along with values for other related bicyclic systems. Based on our previ-

ous analysis of angle distortion in bisesquinane (E values), we predicted

enhanced s-character (and consequently larger coupling contents) for

C(11) and C(5); however, there is no apparent correlation. Noteworthy is

the unusually high value coupling constant for the central carbon C(5)

(J=150.8 Hz) when compared to C(1) (J=144.6 Hz). The effect of decreas-

ing skeletal bond angles can be seen clearly by comparing bicyclo[2.2.2]-

octene (J=134 Hz) with norbornene (J=145 Hz). Considering norbornane,

norbornene and norbornadiene, there is an obvious trend of increasing

JC-H in the bridgehead carbons as the ring strain is increased (ca. 3 Hz/

double bond). The bridgehead [C(4) and C(6)] coupling constants for

methoxybisesquinene correlate reasonably well to what one might predict

based on a simple "fusion" of norbornadiene and norbornane.



Interplanar Angles


An unusual consequence of the molecular framework in bisesquinane

(4) is the "tying back" of the two bridging methylenes by bond a. This

structural effect may be seen clearly in the crystal structure of 26-Br2

as viewed down the C(5)-C(12) bond (Figure 4.8).
















OMe
141.1


166.4


136 134


166.5


131-134


131-135


131.0


13C-H Coupling constants.55,56


Figure 4.7.

























IaBll


Figure 4.8. Crystal structure of 26-Br2 as viewed down the C(5)-C(12) bond.
-- 2

Interplanar angles were calculated by a least-squares type analysis for

26-Br2 from x-ray crystal data, bisesquinane (4) and exo-exo-sesquinor-

bornane (80) from MM2 structures, and norbornane (Figure 4.9). The

results show a substantial opening of the exo face of bisesquinane

(136.70), compared to norbornane (123.50). Interestingly, the exo face

of sesquinorbornane (80) is compressed (117.40) due to van der Waals

repulsions between the internal bridge hydrogens.



Diels-Alder Reactivity of Bisesquinene:
Adduct Stereochemistry


It is well established that norbornene is a reasonably reactive

dienophile in Diels-Alder reactions with activated dienes and generally

gives exo adducts.57 Because of its structural similarity with norbor-

nene, we have investigated the reactivity of methoxybisesquinene (26) as

a novel dienophile. It was anticipated that the greater accessibility of

the exo face of methoxybisesquinene may affect the stereochemistry of the

resulting adducts.


















































0

C0
e-4


C.4

I -
p





PO








The determination of Diels-Alder adduct stereochemistry has been the

subject of many investigations utilizing various chemical and physical

methods including Cope rearrangements,58 intramolecular cyclization,59

1H NMR proton-proton coupling,60 solvent induced shift method,61 phenyl

multiplicity method,62 and x-ray crystallography.3 All of these methods

suffer from limitations which have hampered research in this area.

A fairly recent addition to the list of physical methods utilizes
13
coupled 1C NMR to probe adduct stereochemistry. It has been shown that
3
JC-H coupling is dependent upon the torsion angle 0 between the coupling
64
nuclei in a Karplus-type relationship.64 The method is particularly

useful for bridged carbonyl adducts of tetraphenylcyclopentadiene (tetra-

cyclone) and has been called the carbonyll multiplicity technique."65

The adduct 99 derived from tetracyclone and diethyl fumarate exhibits a

doublet (J = 7.1 Hz) for the carbonyl resonance in the coupled 13C NMR.

The splitting results from long-range coupling only between the carbonyl

and the endo proton (H-2, 0 = 160-1700) since the exo proton (11-3) is

improperly aligned (( = 900). Consequently, it is now a simple to distin-

guish between exo and endo adducts by examination of the long-range car-

bonyl coupling patterns (eg., 100 = triplet, 101 = singlet).


100 101








Preparation of Adducts


Diels-Alder adducts of methoxybisesquinene (26) were prepared from

the dienes tetraclorodimethoxycyclopentadiene (102) and tetracyclone

(104). A benzene solution of methoxybisesquinene (26) and tetrachloro-

dimethoxycyclopentadiene (102) was heated at 800C for 10-12 hr to cleanly

produce the single crystalline adduct 103 (69% yield).



e MeO OMe C OMe MeO Me Me
CIS 1 C1 I

E Me1 or
Me 1 Cl Cl

26 102 103a 103b
(endo, exo) (exo, exo)
Tetracyclone (tetracyclone, 104) is a much less reactive diene than

ketal 102 and requires more vigorous conditions for reaction with 26.

Tetracyclone has a characteristic deep purple color which disappears upon

cycloaddition and thus provides a convenient indicator of the reaction

progress. Gentle heating to melt a 1:1 mixture of methoxybisesquinene

(26) and tetracyclone (104) produces the crystalline adduct 105 and a

substantial amount of the decarbonylated diene 106 (25% and 68% yield,

respectively). The mixture was cleanly separated by prep TLC (benzene)

to remove the unreacted purple tetracyclone (104) and the decarbonylated

diene (106) which showed a characteristic blue fluorescence under UV

light. Adduct 103 melted with decomposition (mp 2150 dec) to liberate CO

and also turned pink indicating some retro-cycloaddition back to tetracy-

clone. This behavior is quite normal for tetracyclone adducts which have

been shown to readily decarbonylate.62






62




Me






S(exo, exo) 0


26 104 O
S OMeb




105b
(endo,exo)
Stereochemistry


The exo stereochemistry (with respect to the bisesquinane ring

system) of the adduct 103 was confirmed in the 1H NMR spectrum by the

lack of vicinal coupling between the endo hydrogens H-1,2 (6 2.64, s) and

bridgehead hydrogens H-3,7a (6 2.32, d, J=2.7 Hz; coupled to H-3a). The

relative stereochemistry of the dimethoxy bridge is not readily discern-

ible. However, by steric arguments we would predict the stereochemistry

as shown for adduct 103a (endo, exo) rather than adduct 103b (exo, exo)

due to the incursion of extensive van der Waals repulsions between the

methoxy and bridge hydrogens in the transition state for formation of

103b. To rigorously prove the stereochemistry of 103 required the trans-

formation of the ketal to a carbonyl moiety. It has been reported that

trimethylsilyliodide (TMS-I) is effective in the hydrolysis of ketals to

produce ketones.66 Treatment of adduct 103 with TMS-I resulted in selec-

tive demethylation, producing alcohol 107 with the ketal moiety remaining

intact, presumably due to steric hindrance by the flanking chlorine atoms






63

as well as inductive retardation of initial oxygen coordination to sili-
1 13
con prior to the first demethylation step. The H and 1C NMR spectra

of 107 were not significantly changed from that of 103a except for the

absence of the methoxy signal.


C1




Cl OMe MeO C1 107


MeO
l H2S4 Cl OMe
MeO
103a Cl 1


108
When adduct 103 was subjected to cold H2S04 (conc), clean conversion to

the ketone 108 resulted.67 The fully coupled 3C NMR spectrum of ketone

108 shows no long-range coupling of the carbonyl (6 186.87), thereby

confirming its assigned stereochemistry and that of adduct 103a as endo,

exo.

The stereochemistry of adduct 105 was similarly established to be

the exo adduct of methoxybisesquinene due to the lack of vicinal 1H

coupling (6 2.97, H-1,2, s). Previously, the tetracyclone adduct of

norbornene had been assigned the endo, exo (ll0a) configuration based

principally on the phenyl multiplicity patterns.62





0 0 0

S04 OR

109 104 11Oa 110b







64

By analogy, we fully expected the methoxybisesquinene-tetracyclone adduct

to be endo, exo (105b) as well. That this was not the case was clearly

demonstrated by the 13C NMR carbonyl multiplicity (6 202.7, J=7.0 Hz, t)

which dictates the exo, exo stereochemistry for adduct 105a. Somewhat

puzzled by this discrepancy, we prepared62 the norbornene-tetracyclone

adduct (110) for direct comparison with 105a (see Figure 4.10). The
13
coupled 1C NMR spectrum of 110 exhibited a triplet for the carbonyl

(6 202.1, J=6.9 Hz), thereby necessitating the reversal of the stereo-

chemical assignment for the norbornene adduct to 110b (exo, exo).

These results may be explained by considering the facile cyclorever-

sion which often occurs in some Diels-Alder adducts and has been shown to

equilibrate the kinetically formed endo adducts to the more stable exo

adducts (e.g., maleic anhydride endo adducts equilibrate to exo on heat-

ing). Additionally, it has been noted that decarbonylation occurs more

readily for endo tetracyclone adducts, presumably due to relief of strain

and favored stereo electronic alignment.68 Since the reaction conditions

promoted extensive decarbonylation, it is conceivable that our results

reflect only the thermodynamic product being isolated. Preliminary

results for the adduction of tetracyclone to norbornadiene at room temper-

ature indicate that the endo, endo isomer is formed exclusively. If a

chloroform solution of this adduct is warmed, rapid cycloreversion occurs

as evidenced by the purple color. Thus, we must conclude that a delicate

balance exists for the preference of stereochemistry in tetracyclone

adducts, the nature of which is still little understood.






















LINE HEIGHT FREO(HZ) PPN
1 139.51 15313.49 202.813
2 310.68 15296.43 212.711
3 153.57 15289.39 212.618




J=7.0 Hz


2 I I I r
20-l.0 203.5 203.0
20qi.0 203.5 203.0


LINEl HEIGHT FItE111 ) IPP
S 139. 1S3257.19 212.191
2 303.18 15251.25 292.99
3 164.73 15243.37 212.198



J=6.9 Hz


I I


202.5 202.0 201.5 PPM


S10b


203.5 203.0


202.5 202.0 201.5 201.0 PPM


Figure 4.10. Carbonyl multiplicity patterns.


105a









Suggestions for Future Work

An interesting synthetic application for these bridged ketone

adducts of methoxybisesquinene was suggested by inspection of the mass

spectral fragmentations of adducts 108 and 105a. After loss of CO, the

tetrachloroketone 108 fragments quite readily into tetrachlorobenzene and

a triquinocene derivative (111) (C11H140, m/z 162, 49% rel intensity).

The tetracyclone adduct 105a behaves similarly with initial loss of CO

(m/z 544, 100% rel intensity) followed by loss of C12H140 to produce

C30H22 (m/z 382, 25% rel intensity) which corresponds to tetraphenylben-

zene. Thus, as outlined in Scheme 4.3, a thermal cycloreversion process

should extrude the tetrasubstituted benzene derivative 112 with concom-

itant formation of the novel bridgehead substituted tetraquinacene 111.



R R OfMe





R WMe
R
i
^R*T R=CI or 0










112 111

Scheme 4.3















CHAPTER FIVE

EXPERIMENTAL



General


Melting points were recorded using a Thomas-Hoover capillary melting

point apparatus and are uncorrected. Analyses were performed by Atlantic

Microlab, Inc., of Atlanta, Georgia.

Proton NMR spectra were run on either a Varian EM-360, a JEOL FX-

100, or a Nicolet 300 spectrometer. Chemical shifts were recorded

relative to tetramethylsilane (TMS) at 6 0.00. After the chemical shift,

values are given in parentheses for the multiplicity of the peaks, the

apparent splitting (J) where applicable, and the relative integration.

The symbols used for multiplicities are: s = singlet, d = doublet, t =

triplet, q = quartet, pent = pentet, and mult = multiple.

Carbon NMR spectra were recorded on a JEOL FX-100 instrument with

chemical shifts relative to the deuterochloroform reasonance at 6 77.00.

After the chemical shift, values are given in parentheses for the multi-

plicity of the peaks as determined by off-resonance or INEPT decoupling.6

The symbols used are: s = -C-, quaternary; d = -CH, methine; t = ,CH2,

methylene; and q = -CH3, methyl.

Infrared spectra were recorded on a Perkin-Elmer 283B spectrophotom-

eter. The KBr pellets were made of the solids, and the liquids were run

neat between NaC1 windows.

Mass spectra were obtained either on an Associated Electronics

Industries (AEI) model MS-30 mass spectrometer at 70 eV equipped with a

67








68

Nova Systems 4 computer or on a Nicolet Fourier Transform mass spectrom-

eter model FT/ms 1000.

Analytical gas chromatography was performed with a Hewlett-Packard

5880A equipped with a flame ionization detector and a cross-linked

dimethylsilicone capillary column (fused silica, 12.5 m x 0.2 mm ID).

The standard temperature program conditions were 800C (1 min), then

200C/min to a maximum temperature of 2500C (15 min). All retention times

are reported under these conditions, unless otherwise specified.

Preparative GC was performed with a Varian Associates model A-90-P

utilizing a thermal conductivity detector, and a 10% SE-30 on Chromosorb

W (6 ft x 1/4 in).
70
Flash chromatography was performed as described by Still70 utilizing

MCB 230-400 mesh silica gel. All solvents were distilled prior to use or

were HPLC grade.

Analytical and preparative thin layer chromatography (TLC or prep

TLC were performed on glass-backed E. Merk TLC plates (silica gel

60 F-254), which were cut to the desired size with a diamond scribe glass

cutter. The spots were visualized either by UV fluorescence quenching or

adsorption of 12. A useful technique for prep TLC staining was to place

a thin strip of filter paper (soaked in an I2/pentane solution) on the

edge of the developed TLC plate. This was covered with a glass plate.

Adsorption of the iodine by the sample on the TLC plate allowed the

selective staining of only a small portion, thereby visualizing the

sample streaks.







69

Synthesis


Preparation of 7,7-Dimethoxynorbornene (30)


The reaction sequences were carried out as previously described to

afford 30.14 Specific details of a sample procedure are given below.

An aliquot of 5,5-dimethoxytetrachlorocyclopentadiene (32, 200 g)

was placed in a Pyrex gas scrubber tube which contained a frit in the

bottom and was fitted with a condenser. The ketal 32 was heated in an

oil bath (160-1700C) while bubbling a gentle stream of ethylene gas

through solution. After ca. 48 h, IH NMR analysis of an aliquot indi-

cated loss of the -OMe peak for 32 (6 3.30) and two new -OMe peaks for 33

(6 3.50, 3.55). The crude material was purified by bulb distillation

(kugelrohr apparatus available from Aldrich; 95-1000C at 0.2 mm Hg) to

afford 32 as a colorless oil which crystallized at room temperature.

The chlorinated ketal 32 was dechlorinated by the improved method of

Lap and Paddon-Rowl5 using sodium/EtOH as follows. A sample of tetra-

chloroketal 32 (5.37 g, 0.021 moles) was placed in a flask equipped with

a mechanical stirrer, N2 inlet, and a condenser. Absolute EtOH (100 mL)

was added followed by the addition of small pieces of clean sodium (ca.

15 g) until no more would dissolve in the refluxing solution (small beads

of liquid Na formed on the surface). The reaction was then cautiously

quenched by the addition of MeOH to consume unreacted Na, and the mixture

was poured over crushed ice. The aqueous mixture was extracted with Et20

(3x100 mL). The combined ether extracts were washed with brine until the

washings were clear, dried (MgSO4), and solvent removed in vacuo to

afford the dechlorinated ketal 30 as a yellow oil (2.15 g, 67% yield, 90%

pure by GC). The ketal was subsequently purified by fractional









distillation with a 6 in vigereaux column and reflux head (7-10 mm Hg,

bp 48-54oC, 97% pure by GC).

The 1H NNR spectrum (CDC13, 60 MHz) contained the following

resonances: 6 6.05(t, J=2.0 Hz, 2H), 3.20(s,3H), 3.15(s,3H), 2.76(m,2H),

2.18-1.68(m,2H), 1.06-0.78(m,2H).
13
The proton decoupled 1C NMR spectrum (CDC13 contained the following

6 resonances: 6 132.51(d), 117.94(s), 50.97(q), 48.44(q), 43.37(d),

22.22(t).

The mass spectrum (70 eV) had m/z (% rel intensity): 154(M+,20),

139(15), 123(35), 107(22), 95(15), 91(18), 79(100), 77(22), 59(34),

55(16), 45(22).



Preparation of 5-Trimethylsilylcyclopentadiene (28)


Trimethylsilylcyclopentadiene (28) was prepared as previously
20
described20 but with the substitution of NaH for Na sand. Freshly

distilled cyclopentadiene (33 g, 0.5 mole) was added dropwise via cannula

to a flask containing NaH (12 g, 0.5 mole) and dry THI (250 mL) which was

fitted with a reflux condenser, magnetic stir bar, and argon inlet. With

each addition, smooth evolution of H2 occurred. When all of the NaH was

consumed, the rose-colored THF solution of sodium cyclopentadienide was

cooled (-100C to 0C). To the stirred solution, TMS-C1 (54 g, 0.5 mole,

ca. 63 mL) was added dropwise over a 1 hr period. The ice bath was

removed and the reaction stirred for an additional 3 hr. The reaction

was quenched by the addition of H20 (5 mL) (note: a better procedure

would be to use MeOH instead), and the contents of the flask decanted to

leave behind a brown sludge (soluble in H20) The excess THF was removed

in vacuo (no heat), washed with H20, and finally extracted into Et20.
2'2









The Et20 extracts were dried (Na2SO4) and solvent removed in vacuo.

Capillary GC (500C to 2000C at 10C/min) indicated two major components:

silane 28 (2.59 min, 47.6%) and an unknown high boiling material

(6.50 min, 33.5%, possibly trimethylsilanol). Pure silane 28 was

obtained by fractional distillation (11 mm Hg, bp 290C, 97% pure by GC).



Reaction of 7,7-Dimethoxynorbornene (30) with 5-Trimethylsilylcyclopenta-
diene (28)


Method A: AlC13/CH2C12, -780C.

To a 50 mL flask fitted with an addition funnel, magnetic stir bar,
0
and N2 inlet, were added dry CH2C12 (10 mL, 3 A molecular sieves) and

AlC13 (520 mg, 3.9 mmole). The mixture was cooled to -780C (dry ice/ace-

tone), and a mixture of 7,7-dimethoxynorbornene (30, 500 mg, 3.25 mmole)

and TMS-cyclopentadiene (28, 448 mg, 3.25 mmole) was dissoved in 10 mL

dry CH2C12. This was added dropwise to the stirred suspension of A1C13.

The reaction was quenched after 1.25 hr by the addition of saturated

NH4C1 (20 mL). After allowing the mixture to warm to room temperature,

the organic phase was washed with saturated NH4C1 (2x20 mL), saturated

NaC1 (2x20 mL), deionized H20 (2x20 mL), and dried over MgSO4. The

solvent was removed in vacuo leaving a yellow-brown oily residue which

was fractionated on a 2 mm silica gel TLC plate (5% Et20/hexane).

Isolated from the plate as colorless oils were alkenes 39 (106 mg, 17%,

Rf 0.45) and 36 (15 mg, 2.5%, Rf 0.71). All spectral data videe infra)

were consistent with their proposed structures.

Method B: AlC13/Et20, 00C.

Typically to a flame dried 100 mL flask fitted with a septum, mag-

netic stir bar, and N2 inlet, AlC13 (1.0 g, 7.5 mmole) was added. After

flushing with N2 anhydrous Et20 (40 mL) was added via syringe, and the








72

mixture was stirred at 00C for 10 min (until AlC13 dissolved). To the

stirred solution of AiC13, 7,7-dimethoxynorbornene (30, 1.0 mL,

6.6 mmole) was added dropwise via syringe and allowed to stir for an addi-

tional 5 min. Next TMS-cyclopentadiene (28, 1.1 mL, 0.89 g, 6.5 mmole)

was added dropwise via syringe. The solution turned light brown after

the addition of the silane. After 3-4 hr, the solution turned very dark

(almost black), and the reaction was quenched by the addition of

saturated NH4C1 (40 mL). The organic phase was separated, washed again

with saturated NH4C1 (2x40 mL), and subsequently dried over MgSO The

solvent was removed in vacuo and a brown oil recovered (1.3 g). After

flash chromatography on silica gel (3% Et20O/pentane) and further

purification on 1 mm prep TLC, relatively pure 26 was obtained (15-20%

yield).

Method C: BF3.Et20/CH2CH2, 250C.

To a solution of TMS-cyclopentadiene (2 mL), 1.62 g, 11.7 mmole) in

CH2C12 (25 mL, dried over 3 A sieves), freshly distilled BF3Et20O (1 mL,

7.9 mmole) was added. There was an immediate yellow color upon mixing.

To this mixture, 7,7-dimethoxynorbornene (1 mL, 1.02 g, 6.6 mmole) was

added dropwise. The reaction was quenched after 1.75 hr by the addition

of 25 mL saturated NaHCO3(aq). After separating the phases, the organic

layer was washed twice with brine and dried over MgSO 4. The methylene

chloride was removed in vacuo leaving a yellow oily residue. Capillary

GC-MS analysis of the crude oil indicated at least three C13H 160 isomers

with approximately 45% of the mixture to be 26, with 5% as 39, and 8%

to be 38. Fractionation of the crude reaction oil by flash

chromatography on silica gel (5% Et20O/pentane) afforded a mixture of

C13H160 isomers in 29% yield.









Method D: BF3.Et20/CH2C12, 5C.

To a 100 mL 3-neck flask fitted with a magnetic stir bar, thermom-

eter, dropping funnel, N2 inlet, and septum was added a solution of

TMS-cyclopentadiene (28, 8.97 g, 65.0 mmole) in CH2C12 (25 mL, dried

over 3 A molecular sieves). After cooling the solution to 50C (ice/water

bath), BF3 Et20 (4 mL, 32.0 mmole) was added via syringe. To the stirred

mixture a solution of ketal 30 (5.0 g, 32.0 mmole, in 25 mL CH2C12 was

added dropwise over a 20 min period, while maintaining the temperature

95C. After a total reaction time of 1.5 hr at s50C, the reaction was

quenched by the careful addition of saturated NaHCO3 (20 mL). The

organic phase was separated and then washed with NaHCO3 (2x20 mL), satu-

rated NaC1 (2x20 mL), and dried over MgSO4. After solvent removal in

vacuo, a yellow oil was recovered (7.9 g) which was immediately fraction-

ated by flash chromatography to afford a mixture of isomers 26, 39 and 38

in 55.8% yield (see Table 5.1 for a summary of results). In other experi-

ments employing Method D, the oily residue was left to stand for a short

period (overnight, 5-100C). The addition of pentane to the oily residue

(6.91 g) produced a precipitate, which was filtered to afford a pale

yellow solid (1.66 g). This precipitate was seemingly polymeric in

nature, as evidenced by a broadened 1H NMR spectrum, and contained a

large percentage of trimethylsilyl moieties.



Spectral Data for Isolated Products from the Reaction of 7,7-Dimethoxy-
norbornene (30) with 5-Trimethylsilylcyclopentadiene (28) (Methods A-D)

7-Norbornylfulvalene (36)

The 1H NMR spectrum (CDC13, 60 MHz) contained the following

resonances: 6 6.35(m,6H), 3.5(m,2H), 1.9-1(m,4H).




































c0
5:
-)







0



4
o w
o










ca 0


c c -
=a
5-












M0 5









0 0


0




0 ()
C =
u"m ^
z"a ^


-4







a,
.0

*H




0


- 4


R- B-1 bll
-4 0\


C N 0 0
cr
*H





E 6KS
0 CO







E e

68.0











00












COLO
.H
col co *
C 1 0 0
*H















NN
c7
*i-
















EN













aua
*H &

0O en0
* *i






*i-i
E B
CO 01
CN <0 I
0 COO
N C


b'

In







c-4
* I

CM









r-- 0
i-4


N 0\

in CN
-4 l0


-0-

0
cn


u c
S 0* *
-.-

N -
I N .H cZ -:.- -
v v v v
0 *H '
co E ) U co
cc >1 C u
S-H ca co 1-i in
S0 4-1 l) co
.* 4 *
N N '- '- N oN


o n
OD
3 .0 I
I CN -r
u


U U U "0 -"
O N cn -T
-4 1- I- -


c
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E



NC

-Li
o

0
c





o

0
-4






0

C
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CO ) 0) c
r = to 4-1
0 C (U


ca 0 0


cP -a u -a


-N N
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C0 LA
i-4
MM






N
i-4

0









I 'I c *
r- r'-~ r-~
~Ob\O



090\
O LO 01








The proton decoupled 13C NMR spectrum (CDC13) contained the

following 7 resonances: 6 168.33(s), 135.44(d), 130.70(d), 125.15(s),

121.39(d), 43.42(d), 23.93(t).

The mass spectrum (70 eV) had m/z (% rel intensity): 156(M ,49),

141(22), 128(100), 115(23), 102(11), 91(7), 78(12), 77(11).

syn-7-Methoxy-7-(1'-cyclopentadienyl)norbornene (37a) and syn-7-methoxy-
7-(1'-cyclopentadienyl)norbornene (37b), ca. (50:50)

The H NMR spectrum (CDC13, 60 MHz) contained the following

resonances: 6 6.42(mult,6H),6.09(t, J=1.7 Hz, 4H), 3.06(m,2H),

2.97(m,2H), 2.95(s,3H), 2.90(s,3H).

The proton decoupled 1C NMR spectrum (CDC13) contained the

following 19 resonances: 6 145.43(s), 144.11(s), 135.39(d), 133.24(d),

132.71(d), 132.51(d), 132.02(d), 131.20(d), 130.56(d), 129.59(d),

96.01(s), 52.83(q), 52.63(q), 46.88(d), 46.44(d), 41.33(d), 39.72(d),

22.90(t), 22.80(t).

The mass spectrum (70 eV) had m/z (% rel intensity): 188(M ,59),

187(18), 173(20), 160(19), 159(36), 158(11), 157(36), 156(49), 155(44),

154(7), 153(11), 147(35), 145(25), 143(10), 142(18), 141(42), 134(14),

130(17), 129(55), 128(72), 127(19), 123(15), 115(55), 93(50), 91(88),

65(100).

Accurate mass of C13H160:

Calcd 188.1201 amu
Found 188.1192 amu

3b-Methoxy-3a,3b,4,6a,7,7a-octahydro-3,4,7-metheno-3H-cyclopenta[a]pen-
talene (26)

The 1H NMR spectrum (CDC13, 60 MHz) contained the following

resonances: 6 5.8(t, J=1.9 Hz, 2H), 3.3(s,3H), 2.9(m,2H), 2.64(pent,

J=2.95 Hz, 1H), 2.5(m,2H), 1.7(br s,4H), 1.47(d, J=2.74 Hz, 2H).









76
The proton decoupled 13C NR spectrum (CDC13) contained the

following 8 resonances: 6 130.36(d), 94.39(s), 62.96(d), 56.43(d),

55.94(d), 54.29(q), 43.96(d), 23.49(t).

The mass spectrum (70 eV) had m/z (% rel intensity): 188(M ,100),

173(10), 160(28), 145(21), 123(91), 108(61), 91(60), 77(30), 65(44).

Accurate mass of C13H160:
13 16
Calcd 188.1201 amu
Found 188.12680.0009 amu

8-Methoxy-3a,3b,4,6a,7,7a-octahydro-3,4,7-metheno-3H-cyclopenta[a pen-
talene (38) (mixture with 26)

The IH NMR spectrum (CDC13, 100 MHz) contained the following

resonances: 6 5.96(d,d,d; J=6.0, 2.9, 0.86 Hz, 1H), 5.79(mult,2H),

5.76(d,d; J=2.9, 0.85; 1H), 3.27(s,3H), 3.23(s,3H), 2.87(mult,2H),

2.70(mult,2H), 2.65(mult,1H), 2.48(m,2H), 2.0-1.2(mult).

The proton decoupled 13C NMR spectrum (CDC13) contained the follow-

ing 13 resonances (after subtraction of peaks for 26): 6 137.04(d),

129.64(d), 93.57(s), 52.97(q), 50.90(d), 494.22(d), 47.81(d), 45.66(d),

42.30(d), 39.47(d), 39.08(d), 26.02(t), 24.51(t).

The mass spectrum (70 eV) had m/z (% rel intensity): 189(14), 188(M+

100), 173(14), 160(42), 159(22), 145(41), 129(24), 128(28), 123(68), 122(19),

121(27), 117(21), 115(29), 109(20), 108(45), 95(42), 93(23), 91(69), 79(29),

78(18), 77(33), 67(17), 65(43), 51(20), 45(30), 41(26), 39(41).

Accurate mass of C13H160:

Calcd 188.1201 amu
Found 188.12330.002 amu

3b-Methoxy-2,3,3a,3b,4,5,6,6a,7,7a-octahydro-1,4,7-metheno-iH-cyclo-
penta[a]pentalene (39)

The 1H NMR spectrum (CDC13, 60 MHz) contained the following

resonances: 6 6.3(d,d;J=2.6, 5.6 Hz; 1H), 5.6(d,d; J=2.2, 5.6 Hz, 1H),

3.3(s,3H), 2.9(mult,2H), 2.5-1.0(mult,511).








77
The proton decoupled 13C NMR spectrum (CDC13) contained the

following 13 resonances: 6 137.04(d), 129.64(d), 93.57(s), 52.97(q),

50.90(d), 49.22(d), 47.81(d), 45.66(d), 42.30(d), 39.47(d), 39.08(d),

26.02(t), 24.51(t).

The mass spectrum (70 eV) had m/z (% rel intensity): 188(M+,100),

173(13.6), 160(41.8), 145(40.9), 123(67.7), 109(19.7), 108(44.8),

95(42.4), 91(69.1), 77(32.6), 65(43.0).

Accurate mass of C13H160:

Calcd 188.1201 amu
Found 188.12330.002 amu



Preparation of 3b-Methoxy-2,3,3a,3b,4,5,6,6a,7,7a-decahydro-1,4,7-
metheno-1H-cyclopenta[a]pentalene (39-H2)


To a standard hydrogenation apparatus was added 25 mL ethyl acetate

and 5 mg 10% Pd-C. The suspension was allowed to equilibrate with stir-

ring under 1 atm of H2, and a solution of alkene 39 (61 mg, 0.32 mmole,

in 10 mL ethyl acetate) was added. The reaction was allowed to stir for

4 hr during which time 5.8 mL of H2 was consumed. The reaction mixture

was filtered through celite, the solvent removed in vacuo, and a color-
1 13
less oil recovered (57 mg, 94% yield). The H and 1C NMR indicated

complete reduction of the double bond.

The 1H NMR spectrum (CDC13, 60 MHz) contained the following

resonances: 6 3.2(s,3H,-OMe), 2.9-0.5(br m,15H).
13
The proton decoupled 13C NMR spectrum (CDC13) contained the

following 13 resonances: 6 95.08(s), 51.90(q), 46.05(d), 44.79(d),

42.97(d), 42.25(d), 42.15(d), 41.67(d), 40.50(d), 28.36(t), 27.78(t),

27.34(t), 23.10(t).










78

Bromination of Methoxybisesquinene (26)

Preparation of trans-1,2-dibromo-3b-methoxy-3a,3b,4,6a,7,7a-decahydro-
3,4,7-metheno-3H-cyclopenta[a]pentalene (26-Br2)

To a flame dried flask, fitted with a rubber septum, N2 inlet, and a

magnetic stir bar, was added a solution of the crude C13H 160 isomer

mixture (405.6 mg, 2.15 mmole) in 10 mL methylene chloride and cooled to

-780C. A 10% (v/v) Br2/CH2C12 solution was added dropwise via syringe,

while stirring, until a faint orange color persisted. The flask was

removed from the cold bath and allowed to warm to room temperature while

stirring. The solvent was removed in vacuo, and a reddish oil was recov-

ered (850 mg). Gas chromatographic analysis indicated two major compo-

nents with retention times of 8.65 min (75.3%), 9.58 min (9.6%), which

were the trans-dibromide 26-Br2 and rearranged dibromide 43, respec-
---2
tively. Flash chromatography on silica gel (5% Et20O/pentane) afforded

the pure trans-dibromide 26-Br2 as a white solid (433 mg, 57% yield,
--2
mp 98-1000C) which gave the following spectral data.

The 1H NMR spectrum (CDC13, 100 MHz) contained the following

resonances: 6 4.53(d,d; J=2.7, J=5.2 Hz, 1H), 4.19(d, J=2.7 Hz, 1H),

3.30(s,3H), 2.85(pent, J=2.7 Hz, 1H), 2.60(mult,2H), 2.20(mult,2H),

2.05(mult,1H), 1.65(mult,4H).
13
The proton decoupled C NMR spectrum (CDC13) contained the

following 13 resonances: 6 96.98, 59.94, 58.33, 58.04, 56.33, 54.78,

53.61, 52.58, 48.69, 44.20, 40.84, 23.10, 22.80

The Mass spectrum (70 eV) had m/z: 348(M ,0.3), 270(14), 269(98),

268(15), 267(100), 237(12), 189(19), 188(58), 187(61), 173(13), 160(15),

159(22), 157(35), 156(34), 155(78), 145(23), 129(36), 128(29), 123(55),








121(28), 115(36), 109(33), 108(39), 97(28), 95(25), 93(24), 91(76),

82(49), 80(52), 79(45), 77(38), 71(58), 65(41), 57(35), 55(36), 41(34).

Accurate mass of: C13H16079Br2 C13H160 Br81Br

Calcd 345.9568 amu 347.9547 amu
Found 345.95600.0053 amu 347.95490.0077 amu

Anal. Calcd. for C13H16Br20:

%C %H

Calcd 44.86 4.63
Found 44.94 4.68

Preparation of exo,exo-1,3-dibromo-3b-methoxy-3a,3b,4,6a,7,7a-
decahydro-2,4,7-metheno-1H-cyclopentafa]pentalene (43)

Bromination of the C13H160 isomer mixture (54.1 mg) at room

temperature produced a mixture of dibromides (82:18, 26-Br2 and 43,

respectively) which were separated by flash chromatography to afford the

rearranged dibromide 43 as a colorless oil (33 mg, 33% yield) and 26-Br2

(45 mg, 45% yield). Spectral data for the rearranged dibromide 43 is as

follows.

The IH NMR spectrum (CDC13, 100 MHz) contained the following

resonances: 6 4.85(t, J=1.2 Hz, 1H), 4.08(t, J=1.46 Hz, 1H), 3.32(s,3H),

2.85(mult,2H), 2.70(mult,1H), 2.20(d, J=4.5 Hz, 1H), 2.10(d, J=3.0 Hz,

1H), 1.9-0.9(mult,6H).

The proton decoupled 13C NMR spectrum (CDC13) contained the

following 12 resonances: 6 98.44(s), 54.43(d), 53.46(q), 51.32(d),

50.97(d), 48.25(d), 45.81(2 peaks?, d), 43.47(d), 42.50(d), 41.52(d),

24.12(t), 22.95(t).

The infrared spectrum (film) contained the following absorption

bands: 2950, 1465, 1300, 1250, 1110, 1025, 1005, 906, 835.

The mass spectrum (70 eV) had m/z (% rel intensity): 348(M ,0.59),

270(14), 269(97), 268(15), 267(100), 189(9), 188(21), 187(36), 159(13),











156(30), 155(63), 145(11), 129(27), 128(22), 123(55), 121(14), 117(13),

115(28), 109(17), 108(18), 93(15), 91(85), 79(44), 78(22), 77(41),

71(74), 66(11), 65(53), 51(26), 45(46), 41(36), 39(60).
79 81
Accurate mass of C 13H 0 Br Br:

Calcd 347.9548 amu
Found 347.96420.0134 amu



Debromination of 26-Br2


The dibromide 26-Br2 (843 mg, 2.42 mmole) was added to a 50 mL

flask and was dissolved with gentle heating in absolute ethanol (30 mL).

To this solution Zn dust (0.5 g, 7.65 mmole) was added followed by

5 drops of glacial acetic acid. The flask was stoppered and immersed in

a warm (50C) sonicator cleaning bath (Bransonic 220) for 7 min. A GC

aliquot indicated complete loss of 26-Br2. The Zn powder was removed by

filtration through celite, and the solvent was removed in vacuo. The

oily residue was dissolved in pentane, washed with saturated NaHCO3, and

filtered again to remove a white precipitate (ZnCO3?). The pentane was

removed in vacuo to produce pure 26 (>99% by GC) in quantitative yield.



Reaction of 26 with Trimethylsilyl Iodide (TMS-I)


An oven-dried NMR tube was fitted with a septum and flushed with

argon. A solution of 26 (+ isomers) (17 mg, 0.09 mmole) in CDC13

(0.5 mL, dried over 3 X molecular sieves) was added. To this solution

trimethylsilyl iodide (25 yL, 0.18 mmole) was added via syringe. The

sample was incubated 24 hr at 400C in a thermostated oil bath, and the

reaction was monitored by IH NMR. After the incubation period, the most

noticeable change in the IH NMR was the appearance of a new -OMe peak at










3.3 ppm. The reaction was quenched by the addition of 2 drops of

methanol saturated with NaHC03. The solvent was removed in vacuo, and

the residue was taken up in ether. The ether phase was washed with 5%

NaHSO3 (3x5 mL), saturated NaC1 (3x5 mL), and dried over MgSO4. The

solution was filtered, the solvent removed in vacuo, and redissolved in

CDC13. Analysis by GC-MS [3% SP2100, 5 ft x 1/4 in, 1000C (2 min) to

300C at 7C/min] indicated a mixture of at least 6 components.

Following are the values for the retention times, % relative peak height,

apparent M and suggested structures: 11.23 min, 6%, M 188, (26);

11.68 min, 24%, M+ 188, (39); 12.97 min, 12%, M'+ 174 (hydroxybises-

quinene?); 15.4 min, 6%, M+ 220, unknown?; 19.18 min, 100%, M+ (not

visible), 316-127 = 189 (100%) (26-I); 14.8 min, 8%, M+ 332,

C13H160(188) + 1(127) + OH(17) = C13H1702I(332).

The major component (26-I) of this mixture was collected by

preparative GC and its structure determined by 1H NMR and MS.

The 1H NMR spectrum (CDC13, 100 MHz) contained the following

resonances: 6 4.7(mult,lH), 6.9 (s,3H), 2.5-1.0(mult).

The mass spectrum (70 eV) had m/z (% rel intensity): (M+ not

visible), 190(12), 189(M -I,100), 188(11), 157(16), 142(21), 129(16),

128(16), 127(18), 123(30), 117(15), 115(15), 109(60), 108(25), 105(12),

91(49), 80(23), 79(64), 78(18), 77(33), 71(17), 67(20), 66(22), 65(26),

53(13), 51(16), 45(19), 41(31), 39(44), 32(14).


Preparation of exo-1,2-Epoxy-3b-methoxy-3a,3b,4,6a,7,7a-decahydro-3,4,7-
metheno-3H-cyclopenta[a]pentalene (67)

Typically, a CH2C12 solution (10 mL) containing alkene 26 (193 mg,

1.06 mmole) was cooled to 00C and treated with Na2CO3 (400 mg, 4 mmole),

purified mCPBA (276 mg, 1.6 mmole) and stirred for 2 hr. After addition








82

of 50 mL pentane, the mixture was washed with 10% NaHSO3 (4x50 mL), 10%

NaHCO3 (4x50 mL), saturated NaC1 (2x50 mL), and dried over Na2SO4.

Removal of the solvent in vacuo afforded a pale yellow oil (187.6 mg, 87%

yield, 94% pure by GC). The material was further purified by flash

chromatography on silica gel (10% Et20/pentane).

The IH NMR spectrum (CDC13, 100 MHz) contained the following

resonances: 6 3.29(s,3H), 3.24(s,2H), 2.68(d, J=3.2 Hz, 2H),

2.25(mult,2H), 2.04(pent, J=3.1 Hz, 1H), 1.65(mult,6H).
13
The proton decoupled 1C NMR spectrum (CDC13) contained the

following 8 resonances: 6 94.74(s), 54.48(q), 53.17(d), 51.66(d),

50.29(d), 42.89(d), 39.08(d), 23.24(t).

The mass spectrum (70 eV) had m/z (% rel intensity): 204(M+,69),

189(12), 188(14), 176(17), 175(61), 173(24), 161(23), 148(34), 147(36),

129(33), 128(38), 124(91), 123(68), 121(39), 117(37), 115(34), 109(63),

108(38), 98(48), 97(90), 96(39), 91(100), 81(61), 79(66), 77(55),67(45),

65(43), 55(42), 45(50), 41(52).

Accurate mass of C13H1602:

Calcd 204.1150 amu
Found 204.11480.0028 amu



Preparation of exo-l-Hydroxy-3b-methoxy-3a,3b,4,6a,7,7a-decahydro-3,4,7-
metheno-3H-cyclopenta[a]pentalene (64-OH)


In a typical reaction, epoxide 67 (157.3 mg, 0.771 mmole) was added

in a pentane solution (15 mL) to a flame dried flask fitted with a septum

and a magnetic stir bar. The flask was flushed with argon, cooled to

00C, and DIBAL-H (1.6 mL, 1.5 mmole, 1 M in hexane) was added via

syringe. After stirring for 1 hr at 00C, the reaction was quenched by

addition of 15 mL MeOH. The gelatinous aluminum salts were removed by










filtration through celite and washed with hot MeOH (3x10 mL). The com-

bined methanol washings were removed in vacuo and the residue was redis-

solved in 10% Et20/pentane. Initial clean-up was accomplished by flash

chromatography on a short silica gel column (1 in) eluted with 400 mL 10%

Et20/pentane, 100 mL 10% MeOH/pentane, and 100 mL 20% MeOH/pentane, with

the product eluting in the final fraction. Removal of the solvent in

vacuo produced a colorless oil (124.7 mg, 78.5% yield, 96% pure by GC).

Further purification was achieved by flash chromatography on silica gel,

eluted with 50% EtOAc/pentane.

The IH NMR spectrum (CDC13, 100 MHz) contained the following reso-

nances: 6 3.94(dd,J=2.4 Hz, 7.1 Hz), 3.35(s,3H), 2.58(pent, J=2.9 Hz,

1H), 2.34(mult,2H), 2.22(s,2H), 2.1-1.3(mult).

The proton decoupled 13C NMR spectrum (CDC13) contained the

following 12 resonances: 6 96.84(s), 71.40(d), 59.41(d), 54.53(q),

53.22(d,2 peaks?), 50.19(d) 46.64(d), 43.81(d), 41.33(d), 37.67(t),

23.24(t), 22.85(t).

The mass spectrum (70 eV) had m/z (% rel intensity): 206(M ,17),

188(3.4), 163(15), 162(100), 147(18), 134(10), 131(39), 130(24), 123(24),

121(18), 109(26), 97(20), 96(34), 91(35), 79(19), 67(17), 65(14), 49(20),

41(25).

Accurate mass of C13H1802

Calcd 206.1307 amu
Found 206.12930.0026 amu



Preparation of exo-l-3b-Methoxy-3a,3b,4,6a,7,7a-decahydro-3,4,7-metheno-
3H-cyclopenta[a]pentalene Acetate (64-OAc)


In a typical experiment, Et3N (49 pL, 2 equiv) and Ac20 (18.4 WL,

1.1 equiv) were added to 64-OH (36.4 mg, 0.177 mmole) dissolved in








CH2C12 (2 mL). The reaction was stirred for 10 min at room temperature,

and an aliquot analyzed on the GC indicated no reaction. Addition of

DMAP (1.08 mg, 0.05 equiv) and stirring for 3 hr afforded nearly complete

conversion of the alcohol to the acetate, as indicated by GC. After

solvent removal in vacuo, the residue was dissolved in 5 mL Et20 and

washed with 5% v/v HC1 (3x5 mL), saturated NaCI (3x5 mL) and dried over

MgSO4. Removal of the solvent in vacuo afforded a colorless oil (34.9 mg,

80% yield, 92.8% pure by GC). Further purification was effected by prep

TLC (10% Et2O/pentane) to finally recover 64-OAc (30.5 mg, 70% yield,

97% pure by GC).

The 1H N1LR spectrum (CDC13, 100 MHz) contained the following

resonances: 6 4.80(dd, J=2.6 Hz, J=7.3 Hz, 1H), 3.35(s,3H), 2.55(pent,

J=2.8 Hz, 1H), 2.42(mult,2H), 2.23(mult,2H), 2.01(s,3H),

1.8-1.4(mult,7H).

The proton decoupled 13C NMR spectrum (CDC13) contained the

following 14 resonances: 6 170.58(s), 96.64(s), 74.56(d), 55.95(d),

54.53(q), 53.27(d), 50.00(d), 47.37(d), 43.81(d), 41.28(d), 34.84(t),

23.15(t), 22.76(t), 21.30(q).

The mass spectrum (70 eV) had m/z (% rel intensity): 248(M+,11.9),

189(31.6), 188(67.0), 162(62.4), 123(36.4), 109(56.1), 108(30.0),

91(41.2), 84(38.9), 79(29.4), 51(28.4), 49(66.1), 43(100), 41(33.0).

Accurate mass of C15H2003

Calcd 248.1412 amu
Found 248.14120.0028 amu



Preparation of 11-Keto-tetracyclo[6.2.1.1' 6.0 '7]dodec-4-ene (66)


To a flame dried flask alcohol 71 (127.5 mg, 0.72 mmole) and

Cr03 2pyr (0.94 g, 3.6 mmole) were added and fitted with a magnetic stir








85

bar and a septum. The flask was flushed with argon and dry pyridine

(5 mL) was added via syringe. After stirring for 1.5 hr, an aliquot on

GC indicated complete reaction. The pyridine solution was poured into

50 mL H20 and extracted with pentane (3x20 mL). The combined pentane

extracts were washed with 10% HC1 (3x25 mL), saturated NaHCO3 (25 mL),

H20 (25 mL), and dried over MgSO4. Removal of the solvent in vacuo

afforded a white solid (120 mg, 95.7% yield, 95% pure by GC). Recrystal-

lization from pentane gave a white solid (mp 53-570C, 99% pure by GC).

The IH NMR spectrum (CDC13, 100 MHz) contained the following

resonances: 6 5.98(t, J=1.7 Hz, 2H), 2.9(mult,2H), 2.2(mult,2H),

1.8-0.6(mult,8H).

The proton decoupled 13C NMR spectrum (CDC13) contained the

following 7 resonances: 6 216.06(s), 136.61(d), 49.15(t), 48.88(d),

45.12(d), 42.13(d), 22.53(t).



Preparation of anti-ll-Methoxy-tetracyclo[6.2.1.13 '.0 ]dodec-4-ene (72)


To a flame dried flask transferred to a dry box, alcohol 71 (200 mg,

1.14 mmole) and dry NaH (55 mg, 2.3 mmole) were added. The flask was

fitted with a magnetic stir bar and a septum and cooled to -780C in a dry

ice bath. Dry THF (20 mL) was slowly added via syringe to the cold flask

was allowed to stir 1-2 min after which the flask was allowed to warm to

room temperature. Freshly distilled Mel (143 yL, 2.3 mmole) was then

added via syringe, and the mixture was stirred overnight. The contents

of the flask were poured onto ice/H20 and extracted with ether. After

drying over Na2SO4, the solvent was removed in vacuo to yield a colorless

oil (212.4 mg, 98% yield).







86

The 1H NMR spectrum (CDC13, 100 MHz) contained the following reso-

nances: 6 6.04(t, J=1.8 Hz, 2H), 4.3(s,1H), 3.08(s,3H), 2.8(mult,2H),

2.02(mult,4H), 1.74(mult,2H), 1.4-0.9(mult,4H).

The proton decoupled 13C NMR spectrum (CDC13) contained the follow-

ing 8 resonances: 6 137.34(d), 85.14(d), 56.29(q), 52.97(t), 48.29(d),

46.49(d), 39.62(d), 29.19(t).



Preparation of cis,anti-4,5-Epoxy-anti-tetracyclo[6.2.1.1 .0 ]dodec-
11-methyl Ether (73)


A solution of alkene 72 (212.4 mg, 1.12 mmole) in 15 mL CH2Cl2 was

cooled to 00C. After addition of Na2CO3 (466 mg, 4.4 mmole) and mCPBA

(290 mg, 1.68 mmole, purified by washing with phosphate buffer), the reac-

tion was stirred at 00C for 1 hr, whereupon GC analysis indicated com-

plete loss of starting material. The reaction mixture was worked up by

the addition of pentane (50 mL) to the solution. The organic phase was

washed with 10% NaHSO3 (4x50 mL), 10% NaHCO3 (4x50 mL), saturated NaCI

(2x50 mL), and dried over Na2SO4. Removal of the solvent in vacuo

afforded a colorless oil (218 mg, 94.8% yield). Gas chromatograph anal-

ysis indicated 93% purity with all impurity peaks <1%. Previous attempts

at purification on silica gel resulted in decomposition, so the product

was used in subsequent steps without further purification.

The IH NMR spectrum (CDC13, 100 MHz) contained the following reso-

nances: 6 4.2(s,lH), 3.22(s,3H), 3.18(s,2H), 2.56(s,2H), 2.21(mult,2H),

1.82(mult,4H), 1.5-0.5(mult,4H).
13
The proton decoupled 1C NMR spectrum (CDC13) contained the

following 8 resonances: 6 85.72(s), 56.38(q), 51.51(d), 48.00(d),

41.08(d), 38.25(d), 28.12(t), 27.63(t).










The mass spectrum (70 eV) had m/z (% rel intensity): 206(M ,4.8),

149(86.5), 123(20.6), 117(39.2), 109(41.4), 93(48.8), 92(43.3),

91(81.7), 82(43.7), 81(63.0), 79(67.0), 77(40.8), 71(100.0), 67(51.9),

66(44.2), 45(73.2), 41(99.3), 39(59.3).

Accurate mass of C13H1802:

Calcd 206.1307 amu
Found 206.12990.0024 amu



Preparation of exo-3b-Methoxy-3a,3b,4,6a,7,7a-decahydro-2,4,7-metheno-1H-
cyclopenta[a]pentalen-3-ol (65-OH)


To a flame dried flask, fitted with a stir bar, septum and purged

with N2, dry THF (15 mL) and freshly distilled Et2iH (250 pL, 2.4 mrole)

were added. The solution was cooled to 00C, and n-butyl lithium

(1.5 mL, 1.7 mmole, 1.1 M in hexane) was added and stirred for 10 min.

A solution of epoxide 73 (105 mg, 0.52 mmole) in THF (5 mL) was added

via syringe, the solution was refluxed overnight, and then stirred at

room temperature for 7 days. The brown solution was diluted with 20 mL

H20, then extracted with Et20 (2x20 mL). The combined Et20 extracts
were washed with saturated NaC1 (2x20 mL), dried over Na2SO4, and the

solvent removed in vacuo. After flash chromatography on silica gel (2%

MeOH/CH2Cl2 then 4% MeOH/CH2C12), a yellowish oil was recovered (57 mg,

53% yield).

The 1H NMR spectrum (CDC13, 60 MHz) contained the following

resonances: 6 4.3(d, J=2.4 Hz, 1H), 3.3(s,3H), 2.6-0.9(mult,13H).

The proton decoupled 13C NMR spectrum (CDC13) contained the

following 12 resonances: 6 95.62(s), 73.25(d), 53.92(q), 48.73(d),

44.84(d, 2 peaks?), 44.54(d), 43.18(d), 41.28(d), 40.30(d), 31.38(t),

25.24(t), 22.41(t).










The mass spectrum (70 eV) had m/z (% rel intensity): 206(M ,3),

150(11), 149(100), 125(22), 124(4), 123(1), 117(14), 109(5), 97(4),

91(12), 79(6), 67(5), 66(2), 65(3), 55(3), 53(4), 45(4), 41(8), 39(5).

Accurate mass of C13H1802:

Calcd 206.1307 amu
Found 206.13060.0014 amu



Preparation of 3b-Methoxy-3a,3b,4,6a,7,7a-decahydro-3,4,7-metheno-3H-
cyclopenta[a]pentalene (26-H2)


A standard atmospheric hydrogenation apparatus was charged with 20 mL

EtOAc and 50 mg 10% Pd-C. After the stirred suspension was allowed to

equilibrate under 1 atm H2, a solution of 26 (500 yL, 543 mg, 2.87 mmole

in 10 mL EtOAc) was added. After stirring for 40 min approximately 60 mL

of H2 was consumed. The reaction mixture was filtered through celite, and

the solvent was removed in vacuo to give a colorless oil in quantitative

yield (91% pure by GC). The reduced material was used without further

purification for the next step (reaction with TMS-iodide).

The 1H NMR spectrum (CDC13, 60 MHz) contained the following

resonances: 6 3.4(s,3H); 2.26-2.15(mult,5H); 1.56-1.50(mult,lH).

The proton decoupled 13C NMR spectrum (CDC13) contained the

following 8 resonances: 6 96.93, 54.29, 53.17, 51.36, 48.88, 45.18,

25.05, 23.10.

The mass spectrum (70 eV) had m/z (% rel intensity): 191(M+,46.0),

189(88.8), 188(12.9), 162(45.8), 129(43.1), 123(69.2), 109(100),

96(63.3), 95(53.5), 91(97.4), 81(40.5), 80(39.2), 79(85.8), 77(57.8),

67(75.2), 65(41.0), 55(45.0), 41(78.8), 39(64.1).

Accurate mass of C13H180:

Calcd 190.1358 amu
Found 190.13480.0019 amu







89

Preparation of 3b-Hydroxy-3a,3b,4,6a,7,7a-decahydro-3,4,7-metheno-3H-
cyclopenta[a]pentalene (96)


In a typical reaction, to a flame dried NMR tube fitted with a

septum, 26-H2 (50 1L, 0.26 mmole), TMS-I (50 uL, 0.35 mmole), and C6 D

(0.5 mL) were added via microliter syringe. After mixing, the solution

was allowed to stand at room temperature overnight, whereupon NMR analy-

sis indicated the reaction was complete (loss of -OMe signal). The

reaction was quenched by pouring into 10 mL saturated NaHCO3 and the tube

rinsed with 10 mL Et20. The Et20 layer was washed with saturated NaHCO3

(2x10 mL), 5% NaHSO3 (10 mL, to remove red color of 12), saturated NaC1

(10 mL), dried over MgSO4, and the solvent removed in vacuo. A white

solid was recovered (46 mg, 99.5% crude yield, mp 100-1050C). After

recrystallization three times in pentane, pure alcohol 96 was recovered

(mp 122.5-1230C,19 mg, 41% yield).

The IH NMR spectrum (CDC13, 100 MHz) contained the following

resonances: 6 2.35(mult,2H), 2.16(pent, J=2.9 Hz, 1H), 2.00(t, J=2.0 Hz,

2H), 1.85(s,-OH), 1.68(mult,2H), 1.61(d, J=2.68 Hz, 2H), 1.5(mult,6H).

The proton decoupled 13C NMR spectrum (CDCI3) contained the

following 7 resonances: 6 91.55(s), 56.68(d), 54.22(d), 51.29(d),

46.05(d), 25.14(d), 23.15(d).

The infrared spectrum (KBr pellet) contained the following absorp-
-1
tion bands: 3280 (OH), 2950, 2860, 1295 (C-0) cm-1

The mass spectrum (70 eV) had m/z (% rel intensity): 176(M ,47.5),

159(1.6), 148(28.4), 133(21.0), 109(29.5), 96(100), 95(77.5), 91(28.9),

81(37.3), 79(32.1), 78(10.1), 77(20), 67(38.2), 55(19.0), 41(22.9).

Accurate mass of C12H160:
12 16
Calcd 176.1201 amu
Found 176.11950.0013 amu