Alkylaluminum derivatives as oxophiles in organic synthesis


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Alkylaluminum derivatives as oxophiles in organic synthesis structure and reactivity studies
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vi, 91 leaves : ill. ; 29 cm.
Campbell, Curtis R., 1963-
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Thesis (Ph. D.)--University of Florida, 1991.
Includes bibliographical references (leaves 88-90).
Statement of Responsibility:
by Curtis R. Campbell.
General Note:
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University of Florida
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Full Text







To my parents, with thanks
for their never ending
support and encouragement


The author would like to express his appreciation

to Professor Merle Battiste for the guidance provided

in this work, the late night philosophical

discussions, and the occasional "attitude adjustment."

My gratitude is also expressed to the other faculty

members that made life a little more interesting and

lively during my stay at UF. Special thanks go to

Professor Jim Deyrup who taught me many things in and

out of the classroom. A debt of gratitude is owed to

Dr. Radi Awartani for those "special lab skills" that

he has passed on to me. My appreciation is also

extended to Dr. Dave Powell and his staff for their

assistance and special handling of those "dissertation

making, gotta have 'em yesterday mass spectra".

"Merle's Perles," both past and present, deserve a

unique thanks for the unique outings and lab

conversations embarked upon. Finally, greatest thanks

and best wishes go to Kristen for just being there and

putting up with me.




* camT x m












SUMMARY. .. ..

General Experimental ..
Apparatus and Technique. .
Reagents and Solvents. .











* 91

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



Curtis R. Campbell

December 1991

Chairman: Merle A. Battiste
Major Department: Chemistry

A new synthetic approach for the more volatile

alpha-vinyl oxiranes required for subsequent studies

with organoaluminum reagents has been developed. This

the Horner-Wittig reaction of diphenylphosphinoyl-

methyl lithium with a,p-unsaturated ketones, e.g.

2-cyclohexen-l-one, is the key step in the sequence

producing stable crystalline intermediates, in

contrast to previous schemes in which volatile liquids

are realized at each stage. These solid intermediates

can then be stereoselectively epoxidized with MCPBA to

give a penultimate crystalline precursor to the

desired vinyl oxirane. Treatment of this 2,3-oxido

Horner-Wittig intermediate under basic conditions

results in the loss of the diphenylphosphinoyl group

as the water soluble phosphinous acid, thus

simplifying final workup and isolation of the volatile

vinyl oxiranes. The synthetic sequence as presented

proceeds with good to excellent yields.

The reaction of diethyl-carbo-tert-butoxymethyl-

alane (Rathke alane, RkeAl) with vinyl oxiranes has

been studied in order to determine the necessary

stoichiometry for optimum yields of the product

hydroxy ester. Several NMR studies were carried out

in an attempt to elucidate the structure of the RkeAl

in tetrahydrofuran (THF) solution. A mechanism for

the reaction of RkeAl with vinyl oxiranes is proposed

based on the reactivity and structural investigations.

Reactions of the RkeAl with aldehydes and ketones were

also demonstrated to proceed with good yields.

Structural variations of the ester moiety of the alane

were investigated in order to expand the reagent's

applicability to organic synthesis. Preliminary

studies on chiral induction via the RkeAl type

reaction are described.

Formation of alkenes through the thermal reaction

of trimethylaluminum with ketones, an overlooked

reaction, has been demonstrated. The possible

synthetic utility of this reaction may be seen in the

formation of 2-methylcamphene in one step from camphor

in high yield. Reaction conditions are described for

alkene isolation for several ketones. A mechanism for

the formation of these alkenes is offered.



The field of organometallic chemistry has

undergone a tremendous surge in popularity in research

over the last quarter century. One of the main goals

of this research has been the development and

application of organometals as synthetic reagents for

selective organic transformations. In particular,

investigations into the application and scope of

organoaluminum compounds has garnered significant

interest due to their application in natural product

synthesis and their somewhat unique properties.1 As

early as 1955 aluminum alkyl species were noted to

exhibit unusual behavior.2 Aluminum alkyls, R3A1,

react with carbonyl compounds in an analogous fashion

to that of Grignard reagents; however, only a single

aluminum-carbon bond reacts in an additive fashion,

leaving the remaining two alkyl substituents

deactivated. This deactivation is associated with

bond formation in the product between aluminum and the

oxygen atom of the former carbonyl group, but the

precise reasons for the greatly reduced reactivity of

the remaining aluminum bound alkyls is still open to


In general, organometallic compounds may act as

either a Lewis acid or as a nucleophile in their

reactions with carbonyl compounds and oxiranes. From

an antithetic standpoint oxiranes are seen to have

greater synthetic potential than carbonyl compounds

owing to their greater flexibility as starting

materials for advanced syntheses since two

carboncenters are available for substitution, rather

than one. In addition two different pathways are

available for the reaction of saturated oxiranes with

organometals: 1) direct addition resulting in two

possible isomeric alcohols; 2) rearrangement to either

the aldehyde or ketone and subsequent addition to the

resulting carbonyl group. The pathway taken can be

dependent on the metal atom involved and the

structural (steric) environment of the oxirane sites.

For example, nucleophilic ring opening at the least

hindered site of an epoxide is generally the main

reaction seen with alkyl cuprates,3 whereas

trialkylaluminums yield predominantly the addition

product resulting from ring opening and addition to

the more substituted site.4 Also seen in some of

these reactions are products resulting from

rearrangement and subsequent addition. Reactions

involving trialkylaluminum reagents appear to be

sensitive to the choice of reaction solvent and

conditions as demonstrated by the reaction of styrene

oxide with trimethylaluminum as shown in Figure 1-1.5

O (CH)3A1
350C Ph Y

S(C2H5)20 CH3


0 (CH3)3Al H
6 14 Ph


Figure 1-1

An additional illustration of the condition dependent

reactions of trimethylaluminum is presented later in

this work (Chapter IV).

A common nucleophilic addition to epoxides is

through the malonic ester synthesis. The resulting

product, a hydroxy ester, can be further manipulated

enroute to a desired target molecule. A major problem

associated with this approach is the rather harsh

conditions necessary for the reaction to proceed, e.g.

refluxing, alkaline ethanol solution. In order to

alleviate this situation, a concentrated research

effort has been dedicated to the exploitation of metal

mediated enolate/anion transfer reagents. Work

throughout the field has been focused in the two main

areas of reactivity and selectivity. Prostaglandin

synthesis is itself a very active area of chemical

research. It follows that a breakthrough in metal

mediated anion addition could likely evolve from this

field. Fried demonstrated a useful synthetic approach

0 + Et2AlC=CR --
(2 2- OH

1 R -C6H13; -CHC5H 3
H 30-80 %

Figure 1-2

shown in Figure 1-2 involving the opening of cyclic

oxiranes with various alanes while working in the area

of prostaglandin synthesis.6 These reagents were

prepared in toluene by addition of diethylchloroalane

(Et2AlCl) to various lithium acetylides to give the

alkynylaluminums 2. Yields of these reactions ranged

from 30-80% of the anticipated trans-cycloalkanols.6

Somewhat later (1976) Danishefsky demonstrated

the first examples of the reaction of an aluminum

ester enolate with oxiranes.7 This acetate equivalent

was prepared in an analogous way to that of Fried's

alkynylalmuinums. Lithio tert-butylacetate, prepared

I 8 % CO2But
1 + Li-O-C=CH2,
v "OH

4 + Et2A1C1 Et2Al[CH2CO2But]


68 %
1 + 6 R 5
6 hr

Figure 1-3

as described by Rathke,8 on treatment with Et2AlCl

afforded the diethylcarbo-tert-butoxymethyl alane

(Rathke alane or RkeAl) reagent as a toluene solution.

The resulting aluminum enolate gave a 34% yield of the

trans-hydroxy ester 5 when reacted with

epoxycyclohexane (Figure 1-3); however, when

epoxycyclohexane was reacted with the Rathke lithium

salt in the absence of the Et2AlCl, a yield of only 8%

of 4 is realized. Through manipulation of the

reaction temperature and time the yield of the

aluminum enolate reaction was ultimately increased to

68%.7 However, after a failed attempt at using this

methodology on an oxirane in a steroidal ring system,

Danishefsky discontinued investigations in this area.

This research group became involved in the area

of organoaluminum chemistry in 1982 when Dr. Melean

Visnick utilized the Rathke alane in the synthesis of

()-anastrephin.9 Visnick realized only one regio-

and stereoisomer of 8 in a 24 % yield from the

reaction of the Rathke alane with the vinyl epoxide

shown in Figure 1-4. This reaction was carried out in

toluene as were all previous examples involving the

acetate equivalent. Visnick increased the yield of

the reaction to 87 % by a solvent change to

tetrahydrofuran (THF) after conducting a solvent study

to investigate the reactivity of the reagent.9


S,, CO2Bu
0 + RkeAl OH

CH3 6 'CH
7 8

8 1 ()-anastrephin

Figure 1-4

A previous investigation into the reactivity of

an alkynylalane with 3,4-epoxycyclopentene showed that

the solvent exerted a marked effect on the resulting

product distribution (Figure 1-5).10 A non-polar

S.. OH ..C CR
PhCH + + C C_
10 11 12 CECR
+ 2

9 0
R --Bu PhCH3

13 14
Figure 1-5

reaction medium (toluene) resulted in rearrangement of

the epoxide to the enone 13 followed by the addition

of the alkyne to give alcohol 14. Changing the

solvent to a 1:1 mixture of toluene and THF eliminated

products resulting from the rearrangement pathway.

The conclusion arrived at is based on the oxophilicity

of the aluminum atom. A polar solvent such as THF

would satisfy the aluminum atom's oxophilicity and

result in better solvation of the reagent as well as

promote dissociation of the aluminum dimer (Figure

1-6). The lack of such a polar nucleophilic medium

(R3Al), 2 2 R3A1 THF
15 16

Figure 1-6

requires the reagent to become associated as dimers

and larger aggregates thus reducing its nucleophilic

character while not seriously affecting its catalytic

activity for epoxide rearrangement. This is

consistent with previous reports and applications of

organoaluminums in hydrocarbon solvents such as

toluene. While Visnick's solvent study on the Rathke

alane echoed these results, regardless of the reaction

solvent, nucleophilic attack occurred exclusively at

the allylic position with no evidence of any products

resulting from rearrangement of the oxirane9.

Prompted by the favorable results obtained by

Visnick, further studies were deemed necessary to

investigate the scope of the Rathke alane in the ring

opening reactions of a,p-unsaturated epoxides. Dr.

Mapi Cuevas carried out a study designed to probe the

scope, regiospecificity, and synthetic application of

the Rathke alane.11

Cuevas' results on the applicability of the

Rathke alane to cyclic and acyclic a,p-unsaturated

oxiranes are summarized in Table 1-1 and 1-2,

respectively.w As seen in Table 1-1 the 5- and

Table 1-1 Reactions of Vinyl Oxiranes with RkeAl

Oxirane Product Yield

& 0 % CO2But 61

19 20 OH

"0 CO2But 50

9 21 OH


CO But 94
0 2
22 23 OH

S0 CO2But
0 80

24 25

a c"CO2But
26 27

CO But
0 10
28 29

6-membered cyclic vinyl oxiranes generally give good

yields in their reactions with the Rathke alane while

the 7-membered ring 28 gave an unexpectedly low yield.

This can be explained by the locked planar geometry of

Table 1-2 RkeAl Reactions on Acyclic Vinyl Oxiranes






Ph ^-"



^^ sCO2But


Pho oooCO2But

the olefin and oxirane in the smaller sized rings.

The medium sized 7-membered ring 28 is inherently more

conformationally flexible allowing the olefin and

oxirane to exist in a non-planar relationship which

reduces the stabilizing effect of the vinyl group

adjacent to oxirane. This argument is further

demonstrated by the poor yields and lack of

regiospecificity realized with acyclic vinyl epoxides

as documented in Table 1-2.

A number of experiments were carried out by

Cuevas, in conjunction with this worker and others,

that were aimed at determining the nature of the RkeAl


Yield %




reagent. The question of the location of the metal,

whether bonded to oxygen or carbon, was investigated

along with the mechanism of reaction. Results of

these inquiries are detailed herein and by Cuevas.11

In addition to the above studies, Cuevas further

demonstrated the application of organoaluminum species

to advanced synthetic techniques. Two formal

syntheses of interesting molecules were demonstrated,

that of cis-jasmone, 17, and an advanced

intermediate, 18, (Figure 1-7) that has been

cis-Jasmone, 17


11-Deoxy-prostaglandin PG series

Figure 1-7

elaborated by Corey to prostaglandins ll-deoxy-PGE2

and 11-deoxy-PGF2.11, 12


As demonstrated above by Visnick and Cuevas the

a,p-unsaturated epoxide is a very powerful starting

material for the construction of a variety of natural

products. The current preparation of these building

blocks involves the alkaline epoxidation of cyclic

a,p-unsaturated ketones followed by a Wittig

olefination.13 The preparation suffers from problems

associated with the isolation of the final volatile

product from the Wittig olefination reaction mixture

in the final step of the sequence. Therefore, a more

efficient synthesis was desired for preparation of

this series of oxiranes. The first section of this

dissertation will deal with the development of a new

synthetic sequence for vinyl oxiranes and discuss its

advantages over the previous preparations.

Promising more insight into the still young field

of organoaluminum chemistry, additional studies were

undertaken to probe the scope of the reaction of vinyl

oxiranes with Rathke alane and other organoaluminum

reagents with the view to provide insight into the

mechanism of such reactions. In addition to the work

on unsaturated epoxides, the application of the Rathke

alane and structural variations of it will be

demonstrated on several aldehydes and ketones. As

mentioned previously, a study of the reaction of

trimethyl aluminum with various ketones at elevated

temperatures was undertaken as a natural outgrowth of


the above investigations. This brief study will look

at the reaction and its condition dependent products

in an attempt to demonstrate the utility of the

reaction beyond current applications.



As a result of an evolving study of the scope and

mechanism of the highly selective ring opening

reactions of vinyl oxiranes with organoaluminium

reagents, 9 11, 14 a need arose in our laboratories

for the development of a convenient and efficient

synthesis of the more volatile members of this series

of epoxides including the cyclic exomethylene

derivative 24. The standard route to the methylene

0 0

-OH Wittig

H_ _I 0 I >

39 40 24

Figure 2-1

oxirane involves alkaline epoxidation of the

respective 2-cycloalken-l-one followed by Wittig

olefination as shown if Figure 2-1.13 While the

yields associated with the epoxidation step are in the

80-90% range, the isolated yields from the olefination

step were lower and often unacceptable (25-70%). The

major isolation problems stem from the surprising

volatility and partial miscibility with water of

oxirane 24.

In an attempt to alleviate the isolation problems

encountered in the current method we chose to explore

an alternative pathway illustrated in Figure 2-2.

0 0
P(Ph)2 P(Ph)2
39 -b r % -
39 41 ,0 1 24

41 42

Figure 2-2

This route was suggested by the earlier investigations

of Warren and coworkers on the utility of the

diphenylphosphinoylethyl group in a two-step

olefination procedure.15 The initially attractive

feature of this alternative scheme was the expectation

of stable crystalline solids for intermediates 41 and

42. Subsequently, the methylene oxirane 24 could be

generated on demand from the stockpiled epoxide 42

using potassium hydride (KH) under non-aqueous

conditions and workup. Ultimately, isolation would

depend on the individual properties of the product

epoxides: i) distillation directly from the reaction

solvent or ii) utilization of the oxirane as a

solution of the reaction solvent. Although modest in

scope as a pilot approach, we were also aware of the

potential synthetic bonuses of such a scheme. For

example, the hydroxyl directed syn-epoxidation of the

allylic alcohol 41 would, in a more substituted

system, lead to an alternative diastereoselectivity

not available through current means. Additionally,

our method potentially offers a convenient three step

protocol for the synthesis of chiral vinyl epoxides

via enantioselective epoxidation of the

diphenylphosphinoylmethylallylic alcohol (e.g. 41).

The first reaction attempted was the that of

0 HO o"
00 CPh
+ Li+ -CH2P(O)Ph2

43 44 45

Figure 2-3

lithiomethyldiphenylphosphine oxide with cyclohexanone

which resulted in the formation of a white crystalline

compound that was identified as l-(diphenyl-

phosphinoyl)methylcyclohexanol 45 from its IH NMR

spectrum (Figure 2-3).16 Encouraged by this result,

the synthesis of the vinyl oxiranes was undertaken.

Treatment of 2-cyclohexen-l-one with the lithium salt

generated from methyldiphenylphosphine oxide and

n-butyl lithium in THF at 00 C resulted in exclusive

1,2-addition to afford the crystalline alcohol 41 in

greater than 95% yield. Ohler and Zbiral have

reported the synthesis of 41 under different

conditions in somewhat lower yields. 7 Epoxidation of

allylic alcohol 2 with m-chloroperbenzoic acid (MCPBA)

in methylene chloride gave excellent yields (>90%) of

a crude oily epoxide mixture from which a single,

crystalline epoxide was isolated as the predominant

product on chromatography or trituration of the oil

with pentane (94.8% yield). We tentatively assigned

the cis-structure to this product on mechanistic

grounds,18 literature precedent,19 and the results of

a Nuclear Overhauser Effect (NOE) difference

experiment. A 14 % enhancement of the C-2 methine

proton signal of 42 was noted upon irradiation of the

methylene protons adjacent to the phosphinoyl group.

By contrast the C-2 vinyl proton for the unsaturated

alcohol 41 showed a lesser enhancement of 10 %. The

minor product, presumably the trans-isomer of 42, was

not obtained in sufficient quantities for


To verify the role of the hydroxyl group in

MCPBA epoxidation of 41, we next examined the

epoxidation of the methyl ether 46 prepared by

O-methylation of 41 with potssium hydride (KH) and

excess methyl iodide (Mel) as shown in Figure 2-4.

Treatment of 46 with MCPBA yielded an intractible

0 0
HO 11 CHO 3011
PPh, PPh,
i P^1. KH

2. Mel

41 46

Figure 2-4

mixture of products which resisted crystallization or

attempted purification. Proton and 13C-NMR

examination of the oil afforded evidence for two

epoxides in ca. 1:1 ratio. This result is consistent

with at least a significant fraction of hydroxyl

directed cis-epoxidation for alcohol 41.

The epoxide 42 demonstrated an unexpected and

surprisingly facile ring opening of the oxirane by

traces of water on attempted recrystallization from an

ethyl acetate-hexane (75:25) mixture to form a single

crystalline compound. NMR and mass spectral

examination confirmed the

1-(diphenylphosphinoyl)methyl-1,2,3-cyclohexane triol

structure 47 for the homogeneous white solid deposited

during the recrystallization attempt (Figure 2-5). Of

the four possible diastereomeric structural candidates




Figure 2-5

for 47 (Figure 2-6), two, the cis, cis (48) and trans,

trans (51) hydroxyl configurations of C-2 and C-3, can

be eliminated on the basis of the proton coupling data

2 HO

48 49

Figure 2-6

for the less shielded C-3 methine hydrogen (ddd, J =

11.50, 8.78, 4.5 Hz) which revealed two diaxial

couplings. Assuming the bulky (Ph)2P(O)CH2- group is

locked into the equatorial position, it is then clear

the C-3 hydroxyl must also be in the equatorial

position. Likewise, the C-2 hydroxyl must be

equatorial in order for its methine proton (d, J =

8.77 Hz) to experience the observed diaxial coupling,

thus ruling out structure 50. To confirm the

assignment of structure 49 the triol was converted to

its acetonide 52 (Figure 2-7) which, on NMR

H 0
CH30 OCH, 3I
49 HOTs O PPh2
49 +
reflux H

Figure 2-7

examination, revealed the identical downfield eight

line multiple (ddd, J = 11.64, 9.06, 4.0 Hz).

Final confirmation of the structures of 41 and 42

came in the form of single-crystal X-ray

examination.20 The crystal structure obtained for 42

afforded final proof of the cis relationship that

exists between the hydroxyl group and the oxirane

oxygen as supported by the above data and discussions.

Both compounds 41 and 42 exist in the half chair

conformation as expected; however, the bulky

diphenylphosphinoylmethyl group occupies the

pseudo-axial position. Molecular models of 41 suggest

that in order to accommodate hydrogen bonding the bulky

diphenylphosphinoyl group assumes the pseudoaxial

position to relieve severe steric crowding with the


cyclohexene ring protons. Additionally, both alcohols

41 and 42 contain an intramolecular hydrogen bond

between the hydroxyl and phosphine oxide groups, in

contrast to published structures of similar

compounds.21 Curiously, crystals of both 41 and 42

occupy unit cells of the same dimension.

Elimination of the diphenylphosphinoyl group from

42 was initially achieved by treatment of the

epoxyalcohol with KH or sodium hydride (NaH) in

N,N-dimethylformamide (DMF) at 60-650 C according to

literature precedent.15b The desired methylene

epoxide was obtained as a solution (50:50) in DMF;

however, attempts to separate the volatile oxirane

from DMF by vacuum distillation were unsuccessful.

Due to the nature of the subsequent reactions to be

carried out on the epoxides, DMF contamination was not

acceptable. Therefore, a change of reaction solvent

to THF was deemed advisable as subsequent

organoaluminum reactions are normally carried out in

THF. Treatment of 42 in THF under the above

conditions afforded the epoxide as a solution

containing ~25% THF as determined by 'H-NMR


The synthesis of the methyl substituted oxirane

56 was accomplished in a similar fashion to 24 except

for a slight modification in the first step (Figure

2-8). Addition of the diphenylphosphinoyl group to

3-methylcyclohex-2-enone required lowering of the

oo II
44 P(Ph)2


53 54

HO 11
54 ---
CH2C1 2


55 -----


Figure 2-8

reaction temperature to -300 C in order to avoid

severe side reactions that were encountered at a

reaction temperature of 00 C. Operation at the lower

temperature resulted in the isolation of a single

crystalline solid, 54, in 97 % yield. Epoxidation

with MCPBA was carried out in the same manner as that

of 41 to form a single epoxide, 55, in good yields

(>85 %). In an analogous fashion to 42, epoxide 55

readily opened to give the crystalline triol 57


depicted in Figure 2-9. Single-crystal X-ray analysis

showed this compound to exist in the chair


Silica Gel



Figure 2-9

conformation with the bulky diphenyphosphinoylmethyl

group in the equatorial position and hydrogen bonded

intramolecularly to the C-1 tertiary hydroxyl group.

Additionally, intermolecular hydrogen bonding

involving all three hydroxyl groups exists in a

network throughout the crystal lattice. The X-ray

structure also demonstrates the 1,2-cis-3-trans

relationship between the hydroxyl groups and the

methyl group occupying an axial position. Finally,

the methylene oxirane 56 was generated under the same

conditions as 24, but due to its lower volatility it

was isolated (65 % yield) as a pure compound by vacuum

distillation through a Vigreaux column.

Further attempts were made to demonstrate the

usefulness of intermediates such as 41 to different

epoxidation techniques and possibly isolate the

trans-isomer of 42. The first reagent studied was

magnesium monoperoxyphthalate (MMPP, Figure 2-10).


0 Mg 6 H



Figure 2-10

This reagent is marketed as a replacement for the

commercial grade of MCPBA (80-85 %) that is no longer

available due to hazards associated with its

preparation. MCPBA is now available in only a 50-55 %

grade from the chemical supply houses. MMPP is sold

as its hydrated salt containing 80 % of the active

oxidant. Successful oxidations of several different

substrates and systems have been accomplished with

MMPP and it was shown to be a suitable replacement for

MCPBA.22 Oxidations carried out with MMPP are

normally run in halogenated or alcoholic solvents

under phase transfer catalysis (PTC) conditions.

Reactions with MMPP were run on the methyl ether 46

and 2-cyclohexenol. The reaction of 46 was carried

out in two-phase methylene chloride/water solution


under (PTC) conditions with tert-butylammonium bromide

at 00 C. Monitoring of the reaction by thin layer

chromatography (TLC) revealed no product formation

after 20 hr of stirring so the reaction was warmed

slowly to reflux. A product more polar than the

starting material was detected in a small amount by

TLC. Preparatory TLC was used in an attepmt to

isolate this new compound; however,liberation of the

compound from the silica media was not possible,

indicating an extremely polar species or one that is

difficultly soluble such as the triol 49. If any of

the epoxide did form it would follow that it further

reacted to open the oxirane to the diol.

The reaction of MMPP with cyclohex-2-enol was

carried out at room temperature in iso-propanol under

PTC conditions. Previous reports have demonstrated

the epoxidation of cyclohexene under similar

conditions in 85 % yield after 7hr (Figure 2-11).22

O 58, IPrOH/H O2

R.T., 7 hr, 85 %

59 1

Figure 2-11

This precedent would predict that the reaction of MMPP

with 2-cyclohexenol would afford the epoxy alcohol in

good yield. After stirring for 17 hr at room


temperature resulted in no reaction, the solution was

warmed to reflux for an additional 2 hr with no effect

on the progress of the reaction (Figure 2-12).

Further literature search revealed no previous

examples, successful or otherwise, demonstrating the

58, IPrOH/H 0
Et4NBr, R.T.

Figure 2-12

utility of MMPP on allylic alcohols. One well known

technique for the epoxidation of allylic alcohols is

the Sharpless reaction.

The metal-catalyzed epoxidation by

tert-butylhydroperoxide was first reported as a useful

synthetic tool for the epoxidation of olefinic

alcohols in 1973.19 Since this time much work has

been dedicated to expanding the scope and

enantioselectivity of the now so-called "Sharpless

epoxidation." Success of this epoxidation reaction

would then open up the possibility of achieving the

stereoselective oxidation of chiral olefins through

the use of tartrate esters in the reaction medium.23

Figure 2-13 illustrates one example noted in the

original communication of the procedure by Sharpless

which was the oxidation of 2-cyclohexenol by

tert-butylhydroperoxide in refluxing benzene in the

presence of a vanadium catalyst (vanadyl acetyl

acetonate, VO(acac)2) which resulted in very good

yields and excellent isomeric purity (98 % syn

addition). Unfortunately, our product epoxide 42

60 0 + ..0
reflux 98 : 2
61 62

Figure 2-13

would not survive under such harsh conditions due to

its facile ring opening to the triol 49. A later

review by Sharpless and Verhoeven on these oxidation

reactions noted that the heating of reactions

catalyzed by vanadium was unnecessary and, in fact,

"proceed readily at, or below, room temperature."24

Encouraged by this, a room temperature solution of 41

in methylene chloride was subjected to a toluene

solution of tert-butylhydroperoxide in the presence of

VO(acac)2 catalyst. The reaction was checked by TLC

after 5 hr to show product formation along with

unreacted starting material. No notable change after

an additional 15 hr of stirring prompted the addition

of a second equivalent of the oxidizing agent.


Continued stirring for a further 48 hr resulted in the

consumption of all starting olefin and a reduction in

the Rf value of the product. Workup was carried out

as described in the original literature and the

I I 49

Figure 2-14

product was isolated as a yellow-tinted solid that

precipitated upon washing with water. Spectral

investigation by 1H NMR showed this compound to be the

ring opened epoxide 49 (Figure 2-14). Apparently, 42

is extremely sensitive to any sort of acid present in

the reaction solution or in the reaction workup. The

success found in the MCPBA oxidation must be

contingent on the buffering effect of the sodium

bicarbonate present in the reaction mixture.

A further example of the possible synthetic uses

of compounds similar to 41 and 54 is demonstrated by

their ability to undergo both 0- and C-alkylation.

The O-alkylation was demonstrated in the formation of

the methyl ether 46 shown above in Figure 2-4. The

ability to be alkylated on the carbon alpha to the

phosphinoyl group was noted in an attempted


preparation of 46. Upon generation of the anion of 41

with BuLi at 00 C a deep red solution resulted when a

slight excess of base was added. Quenching of this

reaction mixture with excess Mel resulted in the

isolation of a mixture of the 0- and C-alkylated

products and recovered starting material. Subsequent

generation of the dianion with BuLi and quenching with

Mel afforded two diastereomers (3:1 ratio) of the

C-alkylation product in good yield (86 %) with no

O-alkylation product observed (Figure 2-15). The

SLi Me 0
0 0 HO

2 eq BuLi Ph Mel PPh


Figure 2-15

resultant C-alkylation product can be subjected to

conditions necessary for elimination of the

phosphorous group to yield the ethylidene sidechain.

The yield and ratio of these E- and Z-alkenes could be

of synthetic interest.

Warren has demonstrated the use of lithioethyl-

diphenylphosphine oxide on benzaldehyde in the

selective synthesis of Z-1-phenylpropene following the

,Ph-P Me
0 EtP(0)Ph2 Ph NaH

65 H 67

Figure 2-16

elimination of the diphenylphosphinoyl group as shown

in Figure 2-16.15b The initial addition to the

aldehyde results in the formation of the erythro

isomer (1RS, 2SR) as the major product, 78 %, which

upon elimination of the diphenylphosphinoyl group

affords the Z-alkene in 75 % yield. The E-alkene is

accessible via oxidation of the isomeric alcohols to

the ketone, followed by the sodium borohydride (NaBH4)

reduction to primarily the threo isomer (89 % of the

mixture), which gives the E-alkene upon elimination.

An investigation was undertaken to obtain the threo

isomer in a more direct route, thereby providing a

complimentary method to Warren's Z-alkene synthesis.

Benzaldehyde was subjected to lithiomethyl-

diphenyphosphine oxide in THF at -78 C and allowed to

warm to room temperature to yield the anticipated

addition product (Figure 2-17).25 Treatment of the

substituted ethanol with 2.0 eq of BuLi resulted in

HO 0Ph Me
65 MeP(O)Ph2 \ H 1. BuLi Ph I M
65 PPh, No- Ph
THF Ph 2. Mel ,,
68 H
Figure 2-17

the formation of the dianion which was quenched by the

addition of excess Mel. Spectral examination of the

crude reaction mixture revealed two diastereomers

present in a ratio of approximately 5:1. Separation

of these isomers by flash column chromatography

resulted in the isolation of the major component as a

pure compound that 1H NMR confirmed to be the threo

isomer as assigned by Warren.15b The minor component

was not obtained in sufficient quantities from the

chromatography for accurate characterization; however,

the peaks present in the 1H NMR of the mixture

belonging to the minor isomer are in good agreement

with those published for the erythro isomer.15b The

method described herein allows isolation of the

intermediate alcohol responsible for the complimentary

alkene to that of the Warren method. This success has

spawned continued work in the area of alkylphosphinoyl

addition to carbonyl compounds and subsequent


alkylation alpha to the phosphine oxide and its

application to natural product synthesis.26



The earliest examples of aluminum mediated anions

in oxirane ring opening reactions employed for the

synthesis of prostaglandins reported the use of the

alane species in an 8.5 molar excess.6 Danishefsky's

report of the initial success of the Rathke alane

noted a 2.5 molar excess ot the organometal.7

Likewise, Visnick found the optimal stoichiometry to

be a 2.3 molar excess of the Rathke alane in reactions

with vinyl oxiranes.9 The work described by Cuevas

with the Rathke alane on cyclic and acyclic

a,p-unsaturated epoxides was accomplished with a

working stoichiometry of a 2.5-3.0 molar alanyl

excess.11 With the general acceptance of a necessity

of 2.0 equivalents of the organoaluminum species a

simple mechanism of coordination to the oxirane by one

equivalent and subsequent delivery of the anion by a

second equivalent may be proposed as shown in Figure


O [CH COR] AlEt, H2R


Figure 3-1

In the case of the vinyl oxiranes this could

explain the regiospecificity demonstrated in attack at

the allylic site due to stabilization of the charge

build up upon weakening of the carbon-oxygen bond. A

mechanism of this sort would allow for the reaction to

proceed with a single equivalent of the enolate and a

catalytic excess of the Lewis acid (Et2AlCl). A

series of experiments were undertaken to test this

assumption and determine the necessary stoichiometry

of the reaction. The three key reactions investigated

subjected 3-methylene-l,2-oxidocyclohexane, 24, to

varying amounts of the Rathke alane; the results of

these reactions are collected in Table 3-1. The

standard reaction was carried out with 3.0 equivalents

of the Rathke alane 6 to determine the yield under

established conditions. Thereafter the remaining

reactions utilized 1.5 equivalents of the alane 6. A

final attempt to establish a cooperative competition

Table 3-1 Stoichiometric Studies on RkeAl

24 + 4 + RkeAl THF 2

6 OH

Rxn 6 (eq) 4 (eq) Yield (%)

1 3.0 0 75

2 1.5 0 48

3 1.5 1.5 3.4

reaction between the Rathke alane (., 1.5 eq) and the

Rathke lithium enolate (4, 1.5 eq) was examined to

determine if the reaction is indeed catalyzed by the

aluminum species. The results of these experiments

(Table 3-1) clearly support the need for more than a

single equivalent of the aluminum species in order for

the reaction to proceed with good yields and dismiss

the assertion that the aluminum is only acting in a

catalytic fashion. In view of the observed

requirement for at least two equivalents of the alane

species one might envisage a dimeric species as the

reactive intermediate.

In fact Fried6a has proposed a mechanism

involving an alane dimer derived 6-membered ring

transition state in the reaction of alkynylalanes with

epoxides to form the trans substituted alcohols as

shown in Figure 3-2. It would follow that the Rathke


+ Me2A1C-CR' -
0' 0HO C CR'


-. I-C
Al-:- ^CR'


Figure 3-2

alane could react in an analogous fashion with the

vinyl oxiranes through a hemi ring-opened 8-membered

dimer as shown in Figure 3-3. The suggested mechanism

for addition as depicted in Figure 3-4 begins with the

coordination of the oxirane oxygen to the aluminum and

subsequent rupture of the dimer 74. Displacement of

the THF ligand by the oxiranyl oxygen results in

formation of a reactive complex in which oxiranyl

coordination to the metal weakens the allylic

( Al--Et

I 0 0 t
Et OBu

Figure 3-3

carbon-oxygen bond thereby increasing the positive

character of the allylic carbon. This electron

deficient carbon is then attacked by the reverse end

of the opened dimer 74 which then delivers the enolate

moiety. One may view this mechanism in colloquial

terms as the "ice-tong" mechanism. In view of the

postulation of a dimeric structure for the RkeAl, an

investigation into its structure in solution was

deemed necessary.

A sample of the Rathke alane was prepared in the

usual manner as described in the experimental section.

Neat dimethylaluminum chloride rather than the hexane

solution of the Et2AlCl was used in an attempt to aide

in the simplification and interpretation of the NMR

spectra. The reagent solution was warmed to 00 C and

the solvents removed in vacuo to give the aluminum

-, \/ 3

0 \



oO 0

S0 /


salt which was then dissolved in THF-d8 and cooled to

-780 C. The resulting spectra, recorded at various

temperatures, were sufficiently complex to indicate

the presence of more than one species or perhaps

unsymetrical dimers or oligomers.27 The absence of

signals in the vinylic region of the 1H NMR would

suggest the lack of a true enolate structure similar

to that reported by Rathke for the lithium salt of

tert-butyl acetate.8 Spectral evidence obtained on

the lithium salt in benzene-d6 included two doublets

at 3.14 and 3.44 ppm and the absence of a signal in

the IR spectrum between 1650 and 2000 cm-1

corresponding to a carbonyl stretch. Figure 3-5

illustrates the enolate structure of A supportive of

this evidence.

0- Li+

Ce2 OBu


Figure 3-5

Researchers in the area of aluminum enolates have

depicted many different structures for these species

without citing experimental data or literature

precedent. Japanese workers have used aluminum

enolates in aldol condensation reactions where they

depict an O-metallated species with no substantiating

evidence.28 Mole and coworkers have reported the

S0 Bu AlMe
Me3Al B OA1Me2 Bu Me

H Me H OA1Me2
75 76 77

Figure 3-6

isolation and characterization of the Z- (76) and

E-enolates (77) shown in Figure 3-6 from the reaction

of trimethylaluminum on mesityl oxide.29 Further

investigations revealed that the Z-enolate 76 existed

in the dimeric form and the E-enolate 77 was made up

of dimers and trimers. The lack of a monomeric

species in this study encouraged us with respect to

our proposal of the dimeric nature of the Rathke

alane; however, the exact structure of the dimer was

still in question.

A report on the X-ray diffraction study of the

Reformatsky reagent generated from tert-butyl

bromoacetate was published in 1983. The structure

arrived at by the workers was that of a dimeric

species with each metal atom in the environment of two

oxygens, a bromine, and a carbon atom (Figure 3-7).30


Br- Zn

Zn- Br

t /THF


Figure 3-7

All of the bonds in the non-planar species are of

typical single bond lengths. With this information on

hand we have greater confidence in the suggestion of

the dimeric species 74 for the Rathke alane and the

associated reaction mechanism shown in Figures 3-3 and

3-4, respectively.

Side products observed in these aluminum enolate

reactions include the self-condensation products of

the ester enolate and chlorohydrin and glycol

formation. In carrying out reactions with the Rathke

alane it is imperative that all reagents are dried

prior to use; otherwise, any water present in the

system will quench the enolate and subject the

starting material to the unreacted Et2AlCl resulting

in the formation of the ring opened products as shown

in Figure 3-8. Intentional treatment of the vinyl



24 79 80


Et2AlCl 1 : 2.1

HCl/ice 1.6 : 1

Figure 3-8

oxirane with the chloroalane resulted in formation of

79 and 80 in a ratio of 2.1:1 in favor of the glycol.

Subjecting the starting oxirane to the standard workup

conditions (10% HC1 and ice) afforded the same two

compounds to a lesser extent in a ratio of 1.6:1 in

favor of the 1,2-halohydrin. The presence of glycol

80 could lead one to suggest it originates from

unreacted starting oxirane; though this can not be

ruled out, one must also consider the possibility of

it being generated upon hydrolysis of the chlorohydrin


The reactions of the Rathke alane with carbonyl

compounds follow a different course. Rathke's lithium

salt will react with aldehydes and ketones to give the

hydroxy esters.8 In our hands 1.2 equivalents of the

lithium salt resulted in only 38.5% conversion of

0 HO t
0 \ CO2Bu

0 + RkeLi ----

43 81

43 + RkeAl -- 81

Figure 3-9

cyclohexanone to 81 after 20 min at -600 C whereas 1.2

equivalents of the Rathke alane afforded 76.7% of the

adduct after 30 min under the same conditions (Figure

3-9). In this instance the aluminum may be acting as

a catalyst and activating the carbonyl group for

addition through a 4 membered transition state, Figure


Several para-substituted benzaldehydes were

subjected to 1.2 equivalents of the Rathke alane in

the presence of 0.4 equivalent excess Et2AlCl in THF

at -600 C (Figure 3-11). The various substituents

were chosen to determine if the rate of the addition

reaction was dependent on any electronic factors in

the molecule. All of the aldehydes studied resulted

in similar yields of 60-70% with the reaction being

essentially complete in under 10 min.


R R2






.- [Al(Et)2CH2COBut]




Figure 3-10

Explorations into variations of the enolate 6 to

expand its utility for the synthetic chemist was the

next logical step in these studies. The first change

was from an acetate to a propionate equivalent in the

form of the tert-butylpropionate. The aluminum

propionate enolate (MeRkeAl, 95) was prepared in the

same fashion as the Rathke alane and used in the same

stoichiometric proportions. The reaction of the

MeRkeAl 95 with 3-methylene-l,2-oxidocyclohexane

resulted in the expected addition products (Figure

+ RkeAl

X H; 85
CH3; 87
OCH3; 89
Cl; 91
NO2; 93

X- H; 86
CH3; 88
OCH3; 90
Cl; 92
NO ; 94

Figure 3-11

3-12). The goal of obtaining a diastereoselective

addition was not realized as a 68% yield of 96 was

obtained in a 1.2:1 ratio of isomers.


-600 C
24 + Et2A[CH3C3CH-CO2Bu ]

Figure 3-12

An interesting and quite possibly more

synthetically useful adaptation of the enolate may be

found in the variation of the alcohol portion of the

alanyl ester. Thus acetylation of a chiral alcohol or

one having sufficient bulk to induce severe steric

bias could result in the formation and isolation of

predominantly one stereoisomer (diastereomer or

enantiomer) from the Rathke type reactions. The bulky

Et3 N
97 99

Figure 3-13

adamantyl group in 1-Adamantyl acetate, prepared from

1-adamantanol and acetic anhydride as shown in Figure

3-13,was examined as a steric biasing agent to help

induce stereoselectivity during acetate delivery. A

second consideration was the identification of the

products by GC/MS through a parent mass peak that is

not present in the tert-butyl ester due to facile loss

of the tert-buty group as isobutylene or as C4H90.

The aluminum enolate (AdmAl, 100) was generated

analogously to RkeAl and its reactions were run under

the standard Rathke alane conditions with various

functionalities (Table 3-2). The yield of the p- and

T-hydroxy esters were good to modest with the

exception of styrene oxide (36). Unfortunately, upon

analysis of the reaction mixture by GC/MS, no parent

mass peak was realized due to the facile loss of the

adamantyl cation; therefore, without further


Table 3-2 Reactions of Adamantyl Acetate Alane with Carbonyl
Compounds and Oxiranes

X + AdmAl







Intractable Solid

purification the esters were hydrolyzed to their

respective carboxylic acids for characterization.

The reaction of the AdmAl with styrene oxide

failed to give any addition products even after

extended reaction times and warming to room

temperature. Reaction mixture analysis by capillary

GC revealed peaks attributable to the styrene oxide,

1-adamantyl acetate, and 1-adamantanol. The presence

of the adamantanol indicates that some form of

reaction has taken place in order to liberate it from

the ester. Continued monitoring of the reaction via

GC showed a steady decline in the styrene oxide signal

and growth of the alcohol signal; however, no response

was detected for any sort of addition product leading

us to believe that the aluminum species facilitated

polymerization of the epoxide to a nonvolatile

species. This was surprising owing to the fact that

styrene oxide reacts with the Rathke alane in a 64 %

yield to form the two isomeric addition products in a

4:1 ratio favoring attack at the benzylic site.1



The reactions involving alkylaluminum compounds

with carbonyl compounds are well documented,31, 32

and some of these reactions and their anomalies were

described in Chapter I. In particular, Mole has

demonstrated the ability of trimethylaluminum (Me3Al)

Me3A1 Me Me

2 eq ^'
R R' R R'
104 105
Figure 4-1

to act as an exhaustive methylating agent in the

presence of tertiary or benzylic alcohols and an

assortment of ketones (Figure 4-1).33, 34 Prior to

this, no method existed for the direct exhaustive

methylation of carbonyl compounds. Yields of the

gem-dimethylation product in the work reported by Mole

range from 30% to complete conversion. The reactions

were carried out with a 2-3 mole excess of Me3Al in a

sealed reaction vessel under various solvent,

temperature and reaction time conditions. A

three-step pathway for this reaction has been proposed

by Mole as shown in Figure 4-2. A persistent side



Me OAlMe

R R'



107 105

Me2 AlMe2


Figure 4-2

reaction noted in many of the examples investigated by

Mole is alkene formation which is believed to result

from elimination after initial methyl addition.34 The

contribution of alkene formation to the product

distribution ranges from a trace amount to as much as

50%, the major component. Herein we report conditions

that allow the isolation of alkenes as the

predominant, if not sole, reaction product.

Entry into this area of research was gained

through an attempted methylation of (+)-d-camphor,

109, as illustrated in Figure 4-3, to obtain the

tertiary alcohol 110 for use as a chiral auxilliary in

+ RM o-
0 Me
109 R Me 110
M metal

Figure 4-3

the Rathke alane investigations. Initial attempts at

preparation of the desired alcohol through the

traditional means of a Grignard (MeMgBr) reaction or

addition of methyl lithium gave less than satisfactory

yields of ~50% conversion to 110. Starting ketone was

always recovered despite the use of a large excess of

the organometallic reagent. Treatment of camphor with

excess trimethylaluminum in refluxing hexane resulted

in a ~60% conversion to the carbinol 110 after 40

hours. Still, considerable camphor was recovered from

this reaction. Alternatively, a somewhat greater

yield of -70% was realized upon subjecting the camphor

to excess Me3Al in refluxing toluene for 5.5 hr. The

most profitable conditions discovered depend on

pretreatment of an ethereal solution of ketone 109

with Me3Al (2.0 eq, 1 hr) followed by MeMgBr (5.0 eq,

3.5 days) which resulted in an ~80% transformation to

110. The question remained as to whether the two

organometals react to form an alanate (R4A1-) as the

active methylating agent or if the Me3A1 acts in the

capacity of a Lewis acid and activates the carbonyl

toward nucleophilic addition. A subsequent search of

the literature uncovered similar results using LiAlMe4

in an ether solution as reported by Ashby's group in

1974.35 Our attempts to carry out the LiAlMe4

reaction in toluene resulted in no reaction even after

prolonged heating, further demonstrating the effect of

solvation on organoaluminum reagents. When the

reaction of Me3Al in toluene shown in Figure 4-4 was

109 + Me3Al PhCH

Figure 4-4

allowed to continue for 24 hr a hydrocarbon product,

2-methylcamphene, 111, was isolated in 81% yield.

Noteworthy is the fact that the solvent had largely

evaporated and the pot temperature had increased

overnight. This result prompted the investigations

into the possible synthetic utility of this

transformation as discussed herein.

A summary of the reactions carried out in this

study can be found in Table 4-1. The reactions are

TABLE 4-1 Reaction of Trimethylaluminumon Various Ketones


Products in Decreasing Concentration




Ph Ph(H)
123 H(Ph)
123 H(Ph)

Ph 2 Ph



Ph ~Ph


Ph Ph




run with 4.0 equivalents of Me3Al in m-xylene at

150-2100 C for up to 30 hours in a simple reflux

apparatus. At the end of the reaction time most of the

solvent had evaporated to leave a brown oil that was

washed with 10% hydrochloric acid (HC1) and extracted

with diethyl ether (Et20). The various products

realized include tertiary alcohols, alkenes, and

gem-dimethylated hydrocarbons. In accordance with the

results obtained, the ketones studied follow the same

general reaction pathway: methyl addition to form the

tertiary alcohol followed by elimination to form the

alkene productss. Exhaustive methylation products

similar to those reported by Mole are also seen in

some instances at higher reaction temperatures.

The most interesting and by far the most

synthetically useful example demonstrated to date is

the reaction of Me3A1 and (+)-d-camphor as shown in

Figure 4-4 to yield 2-methylcamphene. A small amount

of the tertiary alcohol 110 is seen if the reaction is

stopped prior to completion or not heated strongly

enough. No other products are seen by capillary GC in

the reaction mixture in concentrations greater then

one percent. Product determination was accomplished

by 1H and 13C NMR and GC/MS. The one step isolation

of 2-methycamphene is interesting because of the

different alcohols that can subsequently be achieved,

by various forms of hydroxylation reactions, and their

potential use in natural product synthesis.

The other ketones presented in this study form

the expected alkenes as the major product with the

only exception being a-tetralone. Table 4-1 shows the

reactions and products obtained under the conditions

found for optimum alkene formation. The reactions

reported in the table were run under two different

sets of conditions: 1) ~1500 C for 30 hr and/or 2)

~2000 C for 15 hr. As demonstrated in the camphor

case, it appears that the reaction temperature is the

major factor in determining the product distribution

of the reactions. For example, the reaction of

2-indanone produced the methyl addition product

exclusively at the lower temperature while at the

elevated temperature only the one alkene product was


The reaction of 1-indanone demonstrates the

ability of the resultant alkenes to rearrange under

the reaction conditions. This result is consistent

with the extreme reaction conditions present, high

temperature coupled with a strong Lewis acid. The

presence of the isomeric alkenes was confirmed by 1H

NMR and GC/MS. The diagnostic information, in this

case, was gleaned from the vinylic region of the 1H

NMR which clearly depicts resonances for the two

isomeric alkenes.

A further example of this temperature effect may

give an insight to the route of the gem-dimethylation

reaction of fluorenone reported by Mole. In our hands

fluorenone gave as the major product

9-methylenefluorene at the milder conditions. Also

seen in the reaction mixture were the alcohol and

dimethylation products, 41% and 12% respectively. It

is believed that a longer reaction time would have

resulted in more alkene by elimination of the alcohol.

At the same time more of the dimethylation product

could have resulted, this could possibly be alleviated

by a decrease in the reaction temperature. However,

at the elevated temperature 9,9-dimethylfluorene is

the dominant product with only trace amounts of the

alkene and unreacted starting material present, thus

demonstrating the inability of the alcohol to survive

under the reaction conditions.

This result prompts us to suggest that the

dimethylation product seen in other studies results

from the alkene as shown in Figure 4-5. In the cases

where there are a-protons on either R or R',

rearrangement of the alkene can occur, as seen in the

reaction of deoxybenzoin. Both the cis- and

trans-stilbene type structures and the

l-methylene-1,2-diphenylethane structure are seen in

the product mixture. Interestingly, the dimethylation

product was noted in both reactions but to a lesser

extent, with respect to total alkene, in the higher

temperature reaction. This would lead one to consider

that the intermediate responsible for dimethylation

must form prior to rearrangement of the alkene species

-- --





107 No

Me OA1Me2

R R'

Me Me
CH, Al AlHe

R R'

+ 108


112 -

105 + possible rearrangement

Figure 4-5

in order to form the gem-dimethylation product.

Support for this assertion comes out of the Allen

group. 36 They demonstrated the decrease in reactivity


Figure 4-6

of alkenes toward alkylation as its substitution

increases as shown in Figure 4-6.36

In stark contrast to the above results is the

case of a-tetralone. At either set of conditions the

major product isolated was that of the dimethylation

reaction. Some alkene (23.6%) and 1-methylnapthalene

(16.9%) were noted at the lower temperature; only

trace amounts of these compounds were observed in the

reaction mixture when subjected to the higher

temperature conditions. It is believed that the

isolation of the alkene in greater amounts is possible

by variation of the reaction time and, most

importantly, reaction temperature.



A new synthetic route to vinyl oxiranes that is

superior in some aspects to previous methods has been

demonstrated in the second chapter of this work. This

route utilizes the diphenylphosphinoyl group as an

anchor to give stable crystalline intermediates rather

than the volatile liquids encountered in other

schemes. The structure of 42 was assigned the cis

configuration through mechanistic, chemical and

spectral considerations, and ultimately through single

crystal X-ray analysis. Yields of the vinyl oxiranes

24 and 56 obtained by this sequence range from 55-65%.

Although these non-optimized yields are somewhat lower

than anticipated, it is believed that the advantages

associated with this modified Horner-Wittig approach

merit consideration for the generation of the more

volatile vinyl oxiranes. Additionally, this work has

spurred continued studies devoted to the extension of

the use of the diphenylphosphinoyl group as a

synthetically useful tool for the synthetic organic


The work contained in the third chapter of this

dissertation, in conjunction with that of Cuevas, has

presented the use of aluminum enolate methodology in

organic synthesis. The scope and reactivity of these

reagents has been investigated yielding favorable

results and suggest continued investigation and

exploitation of this methodology. Though the exact

structure of Rathke alane has not yet been proven and,

therefore, the details of the mechanism of reaction

with vinyl oxiranes remain unclear, ample evidence

exists to support the suggested "ice-tong" pathway for

ring-opening. Continued studies in this area should

include investigations incorporating chiral induction

agents on the aluminum atom as well as continued

efforts with the enolate.

The fourth section of this dissertation

demonstrates a use of the Me3Al species as an

additionelimination reagent under thermal conditions.

The key reaction demonstrated is the formation of

2-methylcamphene from camphor in a single, high-

yielding step. This previously overlooked application

demonstrates the need for continued expansion of the

research into this field. Studies of more complex

alkylaluminum reagents on structurally useful

skeletons, e.g. camphor, may yield incredibly powerful

synthetic tools.



General Experimental

Melting points were taken on a Thomas-Hoover

capillary melting point apparatus. Elemental

analyses were performed by the University of Florida

Spectroscopic Services. Proton and carbon NMR spectra

were recorded on either of two instruments, a Varian

VXR XL-300 or a General Electric QE-300, unless noted

otherwise. Proton chemical shifts were recorded

relative to the residual solvent peak (chloroform @

7.26 ppm, unless otherwise noted). Carbon chemical

shifts are reported relative to the deuteriochloroform

resonance at 77.00 ppm. Coupling constants are

reported in Hertz (Hz). Infra-red spectra were run on

a Perkin-Elmer Model 1600 FT-IR spectrophotometer.

Electron impact/low resolution mass spectra were

obtained on a Finnigan MAT 4500 mass spectrometer at

70 eV. A Finnigan MAT 95 spectrometer was used for

high resolution electron impact and chemical

ionization exact mass determination.

Apparatus and Technique

All glassware used for air-sensitive reactions

was flame dried under vacuum and filled with an inert

atmosphere of either argon or nitrogen by successive

purging and charging using a dual manifold vacuum

line. Standard syringe technique was used for the

introduction of liquid reagents and solutions to the

reaction vessels. Purified samples were obtained by

distillation, recrystallization, or flash column


Reagents and Solvents

The strength of the alkyl lithium reagents used

was determined by titration with 2,5-dimethoxybenzyl-

alcohol.38 Tetrahydrofuran (THF), hexane, toluene,

and diethyl ether, when used as reaction solvents,

were distilled from sodium-benzophenone.3

Diisopropyl amine and methylene chloride were

distilled from calcium hydride.

1-(Diphenvlphosphinoyl)methylcyclohexanol (45).

Cyclohexanone (1.17 g, 12.0 mmol) was added to a

stirred solution of the lithium salt 44 (1.2 eq, 14.4

mmol) in THF (3o mL) at -780 C. The reaction was

stirred at dry ice temperatures for 15 min before

being allowed to warm slowly to room temperature where

a solid began to precipitate. THe solid was filtered,

dissolved in methylene chloride (CH2C12), dried over

magnesium sulfate (MgSO4), and solvents removed to

yield a white powder 45 (3.32 g, 10.6 mmol) with a

m.p. = 163-166 C. 1H NMR 8 7.75 (m, 4HAr), 7.48 (m,

6HAr), 4.82 (br s, 1Hon), 2.56 (d, J = 9.9 Hz, 2Hcp),

1.67 (m, 4Hring), 1.29 (m, 6Hring). 13C NMR 8 133.6

(d, J = 98.1, Cipo), 131.8 (d, J = 2.8, CAr), 130.4

(d, J = 9.6, CAr), 128.7 (d, J = 11.8, CAr), 72.2 (d,

J = 6.0, COH), 40.7 (d, J = 3.8, Cp6), 39.7 (d, J =

8.3, Ca-oH), 25.4 (Cring), 22.0 (Cring). High

Resolution Mass Spectrum (HR/MS) for C19H2302P -

314.1430found, 314.1436caic; Fragmentation (70 eV):

315 (M + 1 [self C.I.], 26.1), 314 (M+, 35.2), 296

(44.9), 271 (82.3), 258 (35.3), 215 (Ph2P(O)CH2+,

base), 201 (Ph2P(O)+, 79.5), 91 (24.5), 77 (41.5).

Anal. Calcd: C, 72.60; H, 7.32. Found: C, 72.15; H,


1-(Diphenvlphosphinovl)methvlcvclohex-2-en-l-ol (41).

Methyldiphenylphosphine oxide (26.9 g; 0.124 mol)

was dissolved in dry THF (100 mL) and cooled to 00 C

under an Ar blanket. n-Butyl lithium (BuLi, 2.5 M,

49.6 mL; 0.124 mol) was added dropwise via syringe to

yield a bright yellow-orange solution which was

stirred an additional 15 min. Dropwise addition of

the 2-cyclohexen-l-one (12.6 g; 0.131 mol) produced a

blood-red solution, which after stirring a further 15

min, was quenched by addition of water (50 mL). The

reaction solution was extracted with methylene

chloride (CH2C12, 3 x 100 mL), the organic layers

combined, washed with brine and dried over magnesium

sulfate (MgS04). Removal of the solvent left a white

powder (35.98 g, 93 %), m.p.(acetone) 152-154o C.12
H NMR 8 7.80 ( m, 4 HAr), 7.50 (m, 6 HAr), 5.72 (d, J

= 10.2 Hz, 1 HVynyl), 5.64 (dt, Jd = 10.2, Jt = 3.5, 1

Hvinyl), 5.10 (br s, 1 HOH), 2.84 (dd, J = 15.2, 10.6,

1 Hcp), 2.65 (dd, (J = 15.2, 8.6, 1 Hcp), 2.10 1.40

(m, 6 Hring). 13C NMR 8 134.1 (d, J = 95.4 Hz,

Cipso), 133.9 (d, J = 95.2, Cipo), 132.6 (d, J = 9.7,

Cvinyl), 131.8 (d, J = 2.7, CAr), 130.5 (d, J = 9.5,

CAr), 130.4(d, J = 9.6, CAr), 129.0 (S, Cvinyl), 128.8

(d, J = 11.9, CAr), 128.7 (d, J = 11.9, CAr), 70.2 (d,

J = 5.3, COH), 40.4 (d, J = 69.0, Cp), 37.6 (d, J =

7.0, CaoH), 24.7 (s, Ca-vinyl), 19.0 (s, Cring). High

Resolution Mass Spectrum (HR/MS) for C19H2102P -

312.1272found, 312.1279caic; Fragmentation (70 eV):

313 (M + 1 [self C.I.], 42.2 %), 295 (base), 284

(27.7), 215 (Ph2P(O)CH3+, 85.5), 202 (Ph2P(O)H+,

33.0), 91 (25.8), 77 (30.8). IR(cm-1): 3500-3100

broad, 3063, 2980, 1438 (P-C), 1182, 1167. Anal.

Calcd: C, 73.08; H, 6.73. Found: C, 72.93; H, 6.76.


To a solution of 41 (4.00 g, 12.8 mmol) in

methylene chloride (CH2C12, 40 mL) at 0 C was added,

with stirring, a solution of m-chloroperbenzoic acid

(MCPBA, 65 %, 5.34 g, 30.9 mmol) in CH2C12 (25 mL) at

approximately 1 drop per second. This solution was

stirred for 24 hr at which time thin layer

chromatography (TLC) indicated no starting material

remained. The reaction was quenched with 0.32 M

aqueous sodium thiosulfate (NaS203, 40 mL).The organic

layer was then washed with 1.0 M NaOH followed by

brine solution, dried (MgSO4), and concentrated in

vacuo to yield a yellow-tinted oil. This oil was

triturated with pentane to afford 42 (3.98 g, 12.1

mmol, 94.8 %) as a white solid: m.p. 120-124 oC ; 1H

NMR 8 7.80 (m, 4 HAr), 7.50 (m, 6 HAr), 4.39 (br s, 1

HOH), 3.25 (d, J = 3.5 Hz, 1 Hepox), 3.17 (dt, Jd =

3.6, Jt = 1.2, 1 Hepox), 2.75 (16 line m, 2 Hep),

1.96-1.11 (4 m, 6 Hring). 13C NMR 6 133.9 d, J = 99.7

Hz, Cipso), 133.6 (d J = 99.7, Cipo), 131.9 (3 lines,

CAr), 130.5 (3 lines, CAr), 128.7 (4 lines, CAr), 70.9

(d, J = 4.6, COH), 58.3 (d, J = 9.6, Cepox), 54.8 (s,

Cepox), 38.0 (d, J = 70.5, Cp), 34.4 (d, J = 5.8,

CaOH), 22.6 (s, Caepox), 16.6 (S, Cring). HR/MS for

C19H2103P 328.1229found, 328.1219cale; Fragmentation

(70 eV): 329 (M + 1 [self C.I.], 26.3 %), 328 (M+,

8.7), 311 (12.8), 258 (24.1), 215 (Ph2P(O)CH3+, 51.1),

202 (Ph2P(O)H+,base), 91 (12.9), 77(33.5). IR (cm-1):

3600-3100 broad, 2987, 1437, 1166, 1119.

Preparation and attempted epoxidation of 1-(diphenyl-
phosphinovl)methvl-l-methoxycvclohex-2-ene (46).

Hydroxyalkene 41 (0.80 g, 2.6 mmol) was dissolved

in 5 mL of dry THF and the solution cooled to 00 C.

While stirring, potassium hydride (0.11 g, 2.8 mmol)

was added in one portion and the resulting yellow

solution was stirred for an additional 15 min.

Addition of excess methyl iodide (Mel, 1.1g, 7.8 mmol)

resulted in immediate disappearance of the yellow

color. After further stirring (15 min) brine was

added and the aqueous solution extracted with

methylene chloride (3 x 10 mL). The organic layers

were combined, dried (MgSO4), and concentrated in

vacuo to yield a thick, yellow oil. 1H NMR of the

crude oil showed complete conversion to the methyl

ether, 46; 1H NMR 6 7.75 (m, 4HAr), 7.45 (m, 6HAr),

5.83 (dt,Jd = 10.4 Hz, Jt = 3.9, Hvinyl), 5.68 (d, J =

10.4, Hvinyl), 2.99 (s, 3HoMe), 2.70 (d, J = 2.1,

Hcp), 2.66 (d, J = 1.6, Hcp), 2.05-1.55 (m, 6Hring);

13C NMR 8 135.1 (d, J = 99.7 Hz, Cipso), 134.7 (d, J =

99.6, Cipo), 131.7 (Cvinyl), 131.6 (d, J = 2.9,

Cvinyl), 131.0 (d, J = 2.7, CAr), 130.7 (d, J = 9.2,

CAr), 130.6 (d, J = 9.2, CAr), 128.5 (d, J = 12.0,

CAr), 128.1 (d, J = 11.6, CAr), 128.0 (d, J = 11.7,

CAr), 74.5 (d, J = 4.2, COH), 49.9 (CoMe), 40.3 (d, J

= 69.9, Cp), 33.0 (d, J = 5.0, Co-coH), 24.7

(Ca-vinyl), 19.3 (Cring).
Without further characterization the crude methyl

ether, 46, from above was treated with 1.5 equivalents

of MCPBA (55 %) in CH2C12 at 00 C with slow warming to

room temperature. Workup as in the epoxidation of 41

yielded a crude yellow oil on solvent removal which on

1H NMR examination (CDC13) revealed a rather congested

epoxide region (8 3.15-3.30) suggesting a mixture of

cis and trans isomers of the epoxide. The methoxy

peak lies in the middle of this epoxide region,

further complicating the interpretation. A 1:1

solvent mixture of benzene-ds and CDC13 did little to

resolve the region. The 13C NMR is very complex with

peaks from the alkene 46 and what looks like two

isomers of the epoxide.

hexane (49).

Attempts to recrystallize (3:1 EtOAc: hexane) the

epoxide, 42, with heating (550 C) resulted in the

formation of a difficultly soluble white powder, m.p.

183.5-187.50 C, and recovery of epoxide 42 as a yellow

oil. Attempts to recrystallize the white solid were

unsuccessful. 6: 1H NMR 8 7.85 (m, 2 HAr), 7.70 (m,

2 HAr), 7.50 (m, 6 HAr), 4.94 (baseline roll, 1 HOH),

3.76 (br s, 1 HOH), 3.65 (ddd, J = 11.5, 8.8, and 4.5

Hz, 1 Hc3-OH), 3.29 (d, J = 8.8, 1 Hc2-OH), 2.78

(overlapping dd, J = 15.3, 14.2, 1 HCp), 2.59 (dd, J =

15.4, 8.1, 1 Hcp), 2.02-1.21 (m, 6 Hring). 13C NMR 8

Ipso carbons not seen, 132.1 (d, J = 3.7 Hz, CAr),

130.9 (d, J = 9.6, CAr), 130.3 (d, J = 9.2, CAr),

128.8 (d, J = 12.0, CAr), 79.7 ( d, J = 5.3, C2-0H),

75.3 (d, J = 4.8, CI-on), 71.2 (s, C3-on), 40.0 (d, J

= 68.9, Cp), 38.5 (d, J = 8.3, Cai-oH), 31.3 (s,

Ca3-OH), 18.9 (s, Cring). HR/MS for C19H2304P -

346.1330found, 346.1370cale; Fragmentation (70 eV):

347 (M + 1, [self C.I.], 49.8 %), 328 (M 17, 9.6),

311 (7.6), 258 (21.2), 215 (Ph2P(O)CH3+, 23.7), 202

(Ph2P(O)H+,base), 77 (19.3). IR(cm-1): 3401, 3248,

2931, 1437, 1173, 1114, 1079, 979. Anal. Calcd: C,

65.89; H, 6.65. Found: C, 65.53; H, 6.65.

Formation of acetonide 52.

p-Toluenesulfonic acid monohydrate (5 mg) and

2,2-dimethoxypropane (3.0 g, 29 mmol) were refluxed

in 5 mL benzene for 10 min and allowed to cool under

an Ar blanket. Triol 49 (0.45 g, 1.3 mmol), dissolved

in 10 mL of benzene and 2.5 mL of methylene chloride,

was added and the reaction mixture was refluxed with

stirring for 2 hr. TLC examination indicated a single

component with a different Rf than that of the

starting material. Solvent removal afforded a white

powder (0.46 g, 1.2 mmol, 91.6 %), m.p.(acetone)

164-1680 C. 8: 1H NMR 8 7.80 (m, 4 HAr), 7.50 (m, 6

HAr), 4.74 (br s, 1 HoH), 3.93 (ddd, J = 11.6, 9.1,

and 4.0 Hz, 1 Hc3-oH), 3.08 (d, J = 9.0, Hc2-oH), 2.52

(dd, J = 15.2, 12.0, 1 Hcp), 2.52 (dd, J = 15.2, 8.2,

1 Hcp), 2.07 (br d, 1 Hring), 1.93 (br d, 1 Hring),

1.73-1.04 (m, including two methyl singlets at 1.45

and 1.25, 10 H). 13C NMR (Ipso carbons not seen) 8

131.8 (d, J = 2.8 Hz, CAr), 131.7 (d, J = 2.2, CAr),

130.5 (d, J = 9.1, CAr), 130.3 (d, J = 9.8, CAr),

128.7 (d, J = 11.5, CAr), 128.5 (d, J = 12.0, CAr),

108.7 (s, Cacetal), 85.6 (d, J = 9.9, Co), 73.7 (d, J

= 2.0, Co), 73.1 (d, J = 6.3, Co), 37.8 (d, J = 65.6,

Cp), 37.3 (s, Ca-acetal), 28.8 (s, Ca-OH), 27.0 (s,

CH3), 26.7 (s, CH3), 19.8 (s, Cring). HR/MS
(chemical ionization) for C22H2804P 387.1739found,

387.1725caic; Fragmentation (70 eV): 387 (M + 1, self

C.I.), 347 (M CH3C(O)CH2, 4.21 %), 328 (5.1), 310

(14.5), 258 (16.8), 215 (Ph2P(O)CH3*, 33.1), 202

(Ph2P(O)H+, base), 155 (13.8), 125 (12.3),

77 (14.4). IR (cm-1): 3330 (broad), 3074, 2932,

1712, 1590, 1439, 1175, 1112, 1081.

3-methylene-1.2-oxidocyclohexane (24).

Epoxide 42 (3.0 g, 9.2 mmol) was dissolved in 5

mL dry THF and warmed to 600 C with stirring. Sodium

hydride (0.26 g, 11 mmol), previously washed with

pentane, was suspended in 2 mL of dry THF and the

hydride slurry added slowly to the warm epoxide

solution causing a color change from yellow to brown

and evolution of hydrogen. Upon completion of hydride

addition (20 min) the solution was allowed to stir for

an additional 0.5 hr during which time a suspended

solid formed. The solution was allowed to cool to

room temperature and an equal volume of water was

added to dissolve the solid. The resulting single

phase solution was extracted with ether (3 x 5 mL)

and the combined ether extracts were washed with 1 M

NaOH and brine solutions. Drying (MgS04) and solvent

removal in vacuo yielded a yellow tinted oil, 1.03 g

(25% THF by 1H NMR) 77 %. 1H NMR 8 5.23 (dd, J = 1.4,

1.7 Hz, 1 Hvinyl), 5.11 (dd, J = 1.4, 1.5, 1 Hvinyl),

3.42 (d, J = 3.9, 1 Hepox), 3.38 (7 line m, 1 Hepox),

2.27 (m, 1 Hring), 2.03 (m, 2 Hring), 1.83 (m, 1

Hring), 1.59 (m, 1 Hring), 1.40 (m, 1 Hring). 13C NMR

6 142.6 (Cvinyi), 116.1 (Cvinyl), 55.1 (Cepox), 54.2

(Cepox), 28.6 (Cring), 24.0 (Cring), 19.7 (Cring).

LR/MS fragmentation (70 eV) 110 (M+, 28.2 %), 95

(40.4), 81 (57.8), 67 (46.5), 53 (43.3), 41 (79.1), 39


2-en-l-ol (54).

To a cooled solution (00 C) of diphenylmethyl-

phosphine oxide (13.9 g, 64.4 mmol) in THF (50 mL)

under argon was added a hexane solution of BuLi (2.5

M, 25.8 mL, 64.5 mmol). The resulting golden yellow

solution was stirred for an additional 20 min and then

cooled to -25 C, whereupon

3-methylcyclohex-2-en-l-one (7.09 g, 64.4 mmol) was

added dropwise to give a red-orange solution. Stirring

was continued at -250 C for 20 min before the solution

was allowed to warm slowly to room temperature. After

a total of 6 hr stirring at room temperature the

reaction flask was opened to the atmosphere and

stirring continued until color abatement.

Concentration of the reaction mixture in vacuo

followed by addition of water resulted in the

precipitation of a white solid (20.2 g, 97.1 %) which

was recrystallized from acetone to yield 17.9 g (54.9

mmol) of 54: 126-1290 C; 1H NMR 8 7.69 (m, 4 HAr),

7.41 (m, 6 HAr), 5.30 (s, 1 HOH), 4.92 (S, 1 Hvinyl),

2.63 (dd, J = 15.0, 8.4 Hz, 1 Hep), 2.50 (dd, J =

15.0, 10.6, 1 HCP), 1.72 (m, 4 Hring), 1.43 (m, methyl

singlet at 1.42, 5 H ,2 Hring and CH3). 13C NMR 8

136.7 (S, Cvinyl), 133.9 (d, J = 99.6 Hz, Cipo),

133.6 (d, J = 98.1, Cipso), 131.5 (d, J = 3.0, CAr),

131.4 (d, J = 3.1, CAr), 130.3 (d, J = 8.2, CAr),

130.1 (d, J = 9.3, CAr), 128.5 (d, J = 11.9, CAr),

128.4 (d, J = 11.8, CAr), 127.5 (d, J = 9.8, Cvinyl),

70.5 (d, J = 5.0, COH), 40.6 (d, J = 69.0, Cp), 36.9

(d, J = 6.7, Ca-oH), 29.4 (s, Ca-vinyi), 23.1 (s,

CH3), 19.1 (s, Cring). HR/MS for C20H2302P -

326.1422found, 326.1436caic; Fragmentation (70 eV):

327 (M + 1, self C.I., 5.7 %), 309 (M OH, base), 215

(Ph2P(O)CH3*, 80.5), 202 (Ph2P(O)H*, 33.1), 91 (28.5),

77 (34.6). IR (cm-1): 3419 (broad), 3058, 2938,

1438, 1160. Anal. Calcd: C, 73.61; H, 7.06. Found:

C, 73.54; H, 7.10.

cvclohexan-1-ol (55).

The phosphinoylmethylcyclohexenol 54 (15.9 g,

48.7 mmol) was dissolved in 100 mL of methylene

chloride and the solution cooled to 00 C. MCPBA (60

%, 19.6 g, 68.2 mmol), suspended in methylene chloride

(100 mL ) was added in portions over a 1 hr period

such that any heat generated by the addition was

allowed to dissipate before further addition was

carried out. The reaction was stirred (42 Hr) until

TLC showed complete consumption of the starting

material. Quenching was accomplished by the addition

of Na2S203 at room temperature with stirring (15 min).

Usual workup afforded a sticky white solid which on

trituration with pentane gave 14.5 g (42.4 mmol, 87 %)

of a white solid, m.p. 115-1200 C: 'H NMR & 7.82 (m,

6 HAr), 7.48 (m, 4 HAr), 4.16 (br s, 1 HOH), 2.99 (s,

1 Hepox), 2.64 (16 line m, 2 Hcp), 2.25-1.30 (m, 6

Hring), 1.05 (s, 3 Hmethyl). 13C NMR 8 134.2 (d, J =

111 Hz, Cip,,,), 134.1 (d, J = 114, Cip.o), 131.9 (3

lines CAr), 130.5 (3 lines, CAr), 128.6 (3 lines,

CAr), 70.8 (d, J = 3.0, Con), 65.2 (d, J = 9.1,

Cepox), 61.1 (s, Cepox), 38.9 (d, J = 70, Cp), 34.7

(d, J = 5.3, Ca-oH), 28.2 (s, Ca-epox), 23.8 (s,

Cmethyl), 16.9 (s, Cring). HR/MS for C2oH2303P -
342.1392found; 342.1385caic; Fragmentation (70 eV) 342

(M+, 5.1 %), 328 (1.7), 323 (16.5), 258 (20.1), 215

(Ph2P(O)CH3+, base), 202 (Ph2P(O)H+, 61.0), 91 (8.1).

IR (cm-1): 3363 (broad), 2938, 1437, 1157, 1119.

3-methylcyclohexane (57).

Upon chromatography of the above oxirane 55, a

late eluting compound was realized in the form of

large colorless crystals, m.p. (EtOAc) 166-1680 C. 1H

NMR 6 7.82 (m, 2 HAr), 7.69 (m, 2 HAr), 7.48 (m, 6

HAr), 4.46 (d, J = 5.7 Hz, 1 H), 4.13 (s, 1 H), 3.52

(d, J = 5.8, 1 H), 2.95 (dd, J = 15.3, 13.1, 2 H, HCP

and HOH), 2.62 (dd, J = 15.4, 8.5, 1 Hcp), 1.90-1.26

(m, 6 Hring), 1.24 (S, 3 Hmethyl). 13C NMR 8 133.7

(d, J = 100.9 Hz, Cip,o), 132.7 (d, J = 99, Cipso),

131.9 (d, J = 3.3, CAr), 131.8 (d, J = 3.1, CAr),

130.7 (d, J = 9.6, CAr), 130.3 (d, J = 9.6, CAr),

128.7 (d, J = 12.6, CAr), 80.0 (d, J = 6.1, Cc2-OH),

75.2 (d, J = 5.3, CC1-OH), 73.4 (s, CC3-oH), 39.5 (d,

J = 69.1, Cp), 37.6 (d, J = 6.9, Ca-ci-oH), 36.8 )s,

Ca-c3-oH), 23.5 (S, Cmethyl), 18.7 (S, Cring). HR/MS

(chemical ionization) mass for C20H2504P -

361.1571found, 361.1569cale; Fragmentation ( 70 eV):

361 (M + 1, 99.7 %), 342 (M H20, 22.0), 324 (14.9),

271 (15.7), 258 (14.6), 243 (11.4), 215 (Ph2P(O)CH3+,

56.7), 202 (Ph2P(O)H+, base). IR (cm-1): 3460

(broad), 3342 (broad), 2943, 1431, 1167, 1120. Anal.

Calcd: C, 66.66; H, 6.94. Found: C, 66.63; H, 7.10.

1-Methyl-3-methvlene-1.2-oxidocyclohexane (56).

To a solution of potassium hydride (1.54 g, 38.5

mmol) in 20 mL of dry THF warmed to 60 0 C was added

a CH2C12 (100 mL) solution of epoxide 55 (12.0 g, 35.1

mmol) via cannula transfer. An immediate color change

of the solution from colorless to a brown accompanied

this addition. Continued addition was carried out in

such a way as to minimize foaming due to gas

evolution. After addition of 3b was completed the

solution was stirred for an additional 2.5 Hr and then

cooled to room temperature. Cooling led to the

precipitation of a white solid. The reaction was

quenched by the addition of aqueous K2C03 (1.1 eq) and

the aqueous mixture extracted with ether. The

combined organic layers were washed with brine and

dried (MgSO4). Analysis of the etheral solution by

GC/MS showed the presence of the desired methylene

oxirane 56 as the predominant component other than

THF. Distillation (b.p. 30-320 C at 3 mmHg) provided

2.82 g of lb (65 % yield): IH NMR 8 5.16 (br d, J =

1.4 Hz, Hyinyl), 5.05 (dd, J = 3.2, 1.6, Hyinyl), 3.21

(s, Hepox), 2.23 (m, 1 Hring), 1.94 (m, 2 Hring), 1.53

(m, 3 Hring), 1.33 (s, 3 Hmethyl)- 13C NMR 8 142.9

(Cvinyi), 115.9 (Cvinyl), 62.2 (Cepox), 59.5 (Cepox),
29.4 (Cring), 28.3 (Cring), 23.3 (Cmethyl), 19.9

(Cring). LR/MS Fragmentation (70 eV) 124 (M+, 9.6),
109 (M CH3, 21.1), 95 (16.8), 81 (50.4), 55 (30.9),

43 (base).

Preparation of the C-methylation product 64.

One equivalent of BuLi (2.4 M, 0.5 mL; 1.2 mmol)

was added to 41 (0.39 g; 1.2 mmol) dissolved in dry

THF at 00 C to yield a bright yellow solution. One

additional drop of the BuLi beyond 1 eq turned the

solution orange in color which darkened with continued

addition up to 2 eq. This solution of the dianion was

stirred for 15min and then quenched with Mel (1.2 g, 7

eq) to give a colorless solution. A white, waxy,

solid was isolated (0.35 g, 86 % yield). The crude 1H

NMR of the solid showed it to be the C-methylation

product 64.

Preparation of tert-butylpropioate.

Propionyl chloride (74.6 g, 0.806 mol) was slowly

added to a stirred ethereal solution of tert-butanol

(65.2 g, 0.881 mol) and N,N-dimethylaniline (110 g,

0.909 mol) to yield a pale blue solution that darkened

over time to a dark blue. The reaction was quenched

after 30 hr by careful addition of water (30 mL) then

the mixture was extracted with ether (2 X 15 mL). The

organic layers were combined and washed successively

with 10% HC1 (6 X 5 mL), saturated NaHC03 (3 x 5 mL),

and brine (2 X 10 mL) and dried over MgSO4.

Distillation through a Vigreaux column afforded the

tert-butyl propionate as a colorless liquid, b. p.

117-1200 C (lit. 119-1210 C40), 69.0 g, 65.7%. 1H NMR

8 2.23 (q, 2H), 1.44 (s, 9H), 1.08 (t, 3H). 13C NMR 6

173.7 (Cester), 79.7 (COR), 28.6 (Ca-c-o), 27.9

(Cmethyl), 9.00 (Cp-c-o).

Preparation of 1-adamantylacetate (99).

To 20 mL anhydrous triethylamine was added

1-adamantanol (10 g, 65.7 mmol), N,N-dimethyl-

aminopyridine (DMAP, 20 mg), and acetic anhydride

(14.8 g, 144.6 mmol) and the resulting mixture was

heated with stirring to 90-950 C under an argon

atmosphere for 30 hr. The reaction solution was

concentrated on the rotary evaporator to give a yellow

oil. The oil was taken up in ether and washed with 1

N sodium hydroxide (NaOH) and brine and dried over

MgS04. Concentration under vacuum gave a clear oil

that crystallized upon sitting to give colorless

needles (12.33 g, 96% yield, m.p. 31.5-32.00 C, lit.

32.5-33.50 C).41 1H NMR (ppm): 2.07, broad,

irregular d, 6 H; 1.89, s, 3 H; 1.64, s, 3 H; 1.56,

broad, irregular d, 6 H. 13C NMR (ppm): 170.3,

80.2, 41.3, 36.2, 30.8, 22.7 Mass Spectrum: 194

(M+, 2.25%), 134 (base), 95 (36.0), 92 (73.5), 79

(23.42), 43 (41.5).

General procedure for the reaction of aluminum
enolates on electrophiles.

The aluminum enolate reactions were carried out

with a 2.0 molar excess of the organoaluminum species

(3.0 eq alane to 1.0 eq of the electrophile) except

where noted. Diisopropyl amine at 00 C was dissolved

in hexane and BuLi added to it dropwise to generate

the lithium diisopropyl amide which was then stirred

for 30 min. The dropwise addition of the ester

(tert-butyl acetate, tert-butyl propionate, or

1-adamantyl acetate) was carried out at -780 C and the

resulting enolate was stirred for 30 min before

warming to 0C and opening to vacuum to remove the

reaction solvents. The lithium salt obtained was

pumped on for 30-60 min before being dissolved in THF

and cooled to dry ice/acetone temperature. The

dialkylchloroalane was added dropwise keeping the

temperature below -600 C after which the electrophile

epoxidee, ketone, or aldehyde) was immediately added,

dropwise. The reaction was generally allowed to stir

for one hour before being quenched via cannula

transfer into a rapidly stirring solution of 10% HC1

and ice. The reaction mixture was extracted with

diethyl ether, washed with water and brine, dried with

MgSO4 and solvents removed in vacuo to yield the


Reaction of RkeAl 6 with 3-methvlene-1.2-oxidocvclo-
hexane 24.

The oxirane 24 (0.179 g, 1.63 mmol) was reacted

under three stoichiometric ratios with the Rathke

metals; the results of these studies are collected in

Table 3-1. The yield of the hydroxy ester 25 was

determined by capillary GC analysis against an

internal standard (tridecane). 1H NMR 8 4.82 (s,

1Hvinyl), 4.68 (s, iHvinyl), 3.27 (br s, 1HoH), 2.55

(m, 1Ha-oH), 2.41 (m, 2Ha-c-o), 2.18 (dt, J = 17.1,

7.6, lHallylic), 1.94 (m, 2Hring), 1.70 (m, 2Hring),

1.39 (m, 2Hring), 1.35 (s, 9Ht-Bu). 13C NMR 8 172.9

(Cester), 148.3 (Cvinyl), 108.3 (Cvinyl), 80.5 (CoR),

74.3 (COH), 48.0 (Callyiic), 35.9 (Cring), 34.8

(Cring), 34.1 (Cring), 28.0 (Ct-Bu), 24.4 (Ca-c-o).
Ring opening to form chlorohydrin 79 and glycol
80 from oxirane 24.

The ring opened products (79, 80) were formed

from 24 in two different ways: 1) reaction of 24

(0.10 g, 0.93 mmol) with Et2AlCl (0.54 mL, 0.93

mmol)in THF at -650 C for 25 min followed by an

aqueous workup and 2) a THF solution of 24 (0.12 g,

1.1 mmol) was subjected to standard dilute acid workup

conditions (5 mL 10% HC1, ~50 g ice). Both reactions

were extracted with ether (3 X 25 mL), washed with

brine (1 X 10 mL), and dried over MgSO4. The products

were separated by gradient elution flash column

chromatography (hexane to EtOAc). The chloroalane

reaction favored formation of the later eluting glycol

80 (1:2.1) while the workup conditions produced more

of the chlorohydrin 79 (1.6:1). 79: 1H NMR 8 5.24

(s, 1Hvinyl), 5.00 (S, 1Hvinyl), 4.27 (d, J = 8.6 Hz,

lHallylic), 3.62 (m, 1Ha-oH), 2.2.48 (m, 2Hring), 2.18

(m, 1Hring), 2.04 (m, IHring), 1.76 (m, 1Hring), 1.53

(m, 1Hring). 13C NMR 8 143.9 (Cvinyl), 112.2

(Cvinyl), 75.0 (COH), 68.7 (Cci), 33.4 (Cring), 31.4

(Cring), 23.3 (Cring). 80: 5.02 (br s, IHyinyl),

4.86 (br s, 1Hyinyl), 3.88 (d, J = 8.3, 1HC2-0H), 3.36

(m, 1Hcl-oH), 2.78 (br s, 1HoH), 2.59 (br s, 1HoH),

2.37 (m, 1Hring), 2.03 (m, 2Hring), 1.76 (m, 2Hring),

1.49 (m, 1Hring), 1.32 (m, 2Hring). 13C NMR 8 148.6

(Cvinyl), 107.2 (Cvinyl), 78.8 (Con), 77.1 (COH), 34.6

(Cring), 33.4 (Cring), 25.2 (Cring).
Formation of hydroxyester 81 from cyclohexanone (43).

The hydroxyester 81 was formed from cyclohexanone

in two ways: 1) by action of 1.0 eq Rathke's salt 4

to give 38.5% conversion (GC) and 2) reaction with 1.0

eq of RkeAl 6 to give 76.7% conversion (GC). The

procedure followed was as outlined in the general

procedure above. 81: H NMR 6 3.63 (s, 1HOH), 2.38

(s, 2Ha-c-o), 1.66 (m, 4Hring), 1.47 (s, 9Hmethyl),

1.44 (m, 2Hring), 1.29 (m, 4Hring). 13C NMR 6 172.0

(Cester), 81.4 (COR), 70.0 (COH), 46.3 (Ca-c-o), 37.5

(Cring), 28.2 (Cmethyl), 25.7 (Crins), 22.1 (Cring).

Reaction of RkeAl 6 with benzaldehyde (85).

Benzaldehyde (1.76 g, 16.6 mmol) was added to a

-650 C solution of the Rathke alane (20.0 mmol) and

excess Et2AlCl (6.6 mmol). No change was noted on the

reaction mixture composition after 15 min reaction

time; the reaction was worked up as described in the

general RkeAl procedure above to yield, after

Kugelrohr distillation (2.40 g, 10.8 mmol), 86: 1H

NMR 8 7.38 (m, 5HAr), 5.17 (br s, 2Ha-Ar & OH), 2.62

(br d, 2Ha-c-o), 1.43 (s, 9Ht-Bu).

Reaction of RkeAl 6 with anisaldehyde (89).

Anisaldehyde (2.27 g, 16.6 mmol) was added to a

-650 C solution of the Rathke alane (20.0 mmol) and

excess Et2AlCl (6.6 mmol). No change was noted on the

reaction mixture composition after 15 min reaction

time; the reaction was worked up as described in the

general RkeAl procedure above to yield 90 after column

chromatography (4% EtOAc in CH2C12): 1H NMR 6 7.27

(d, J = 13.3 Hz, 2HAr), 6.84 (d, J = 13.3, 2HAr), 5.00

(m, lHa-Ar), 3.61 (br s, 1HoH), 2.62 (irr t, 2Ha-c-o),

1.43 (s, 9Ht-Bu).

Reaction of MeRkeAl 91 with 3-methvlene-1.2-oxido-
cyclohexane (24).

This reaction resulted in the formation of two

isomers in a 1.2:1 ratio (0.30 g, 68%); the spectral

data is listed with what is believed to be isomeric

signals in brackets. 1H NMR 8 4.92 [4.79] (s,

1Hvinyl), 4.84 [4.71] (s, 1Hvinyl), 3.83 (dq, lHa-oH),

3.71 13.60] (t, 1Hallylic), 2.66 (m, lHa-c.o),

1.80-1.40 (m, 6Hring), 1.36 (s, 9Ht-Bu), 1.11 [0.94]

(d, J = 8.24 Hz, 3HMethyl). 13C NMR 6 175.2 [173.8]

(Cester), 146.5 [145.2] (Cvinyl), 113.6 [111.8]

(Cvinyl), 80.4 [79.8] (COR), 69.6 [69.0] (Ca-oH), 54.5
(53.4] (Callylic), 40.6 [40.0] (Cring), 32.5 [31.1]

(Cring), 28.7 [28.2] (Cring), 28.0 (Ct-Bu), 22.5

[21.9] (Ca-c-o), 16.0 [14.1] (CMethyl).

Reaction of AdmAl 100 with cyclohexanone (43).

The general aluminum enolate reaction procedure

was followed with 100 (5.45 mmol) on cyclohexanone

(0.104 g, 1.02 mmol). Following workup, the crude

reaction product mixture was dissolved in methanol (15

mL) and aqueous NaOH (5 mL, 6 M) and warmed to a

gentle reflux for 3.5 hr. Upon cooling the reaction

mixture pH was lowered to ~10 by addition of 10% HC1

and extracted with ether (2 X 15 mL) to remove the

1-adamantanol. Continued acidification followed by

ether extraction (2 X 15 mL), drying (MgS04), and

solvent removal in vacuo to give a yellow oil 101

(0.12 g, 0.41 mmol, 40%). 1H NMR 8 6.34 (baseline

roll), 2.53 (s, 2Ha-c-o), 1.68 (m, 4Hring), 1.49 (m,

4Hring), 1.31 (m, 2Hring). 13C NMR 8 176.8 (Cc.o),

70.6 (COH), 45.0 (Ca-c.o), 37.2 (Cring), 25.4 (Cring),

21.9 (Cring).

Reaction of AdmAl 100 with benzaldehyde (85).

The general aluminum enolate reaction procedure

was followed with 100 (3.06 mmol) on benzaldehyde

(0.115 g, 1.00 mmol). Following workup, the crude

reaction product mixture was dissolved in methanol (15

mL) and aqueous NaOH (5 mL, 6 M) and warmed to a

gentle reflux for 3.5 hr. Upon cooling the reaction

mixture pH was lowered to ~10 by addition of 10% HC1

and extracted with ether (2 X 15 mL) to remove the

1-adamantanol. Continued acidification followed by

ether extraction (2 X 15 mL), drying (MgSO4), and

solvent removal in vacuo to give a yellow oil 102

(0.11 g, 0.37 mmol, 37%). 1H NMR 8 7.27 (m, 5HAr),

6.30 (baseline roll), 5.06 (dd, J = 9.3, 4.1 Hz,

iHbenzyl), 2.68 (m, 2Ha-c.o). 13C NMR 6 176.7 (Cc-o),

142.1 (CAr), 128.6 (CAr), 128.0 (CAr), 125.7 (CAr),

70.3 (COH), 43.1 (Ca-c-o).

Reaction of AdmAl 100 with 1-methyl-3-methylene-1.2-
oxidocyclohexane (56).

The general aluminum enolate reaction procedure

was followed with 100 (5.45 mmol) on the vinyl oxirane

56 (0.23 g, 1.8 mmol). Following workup, the crude

reaction product mixture was dissolved in methanol (15

mL) and aqueous NaOH (5 mL, 6 M) and warmed to a

gentle reflux for 3.5 hr. Upon cooling the reaction

mixture pH was lowered to ~10 by addition of 10% HC1

and extracted with ether (2 X 15 mL) to remove the

1-adamantanol. Continued acidification followed by

ether extraction (2 X 15 mL), drying (MgSO4), and

solvent removal in vacuo to give an off-white solid

(m.p. 125-127.50 C, 0.10 g, 0.54 mmol, 30%). 1H NMR 8

5.0 (baseline roll), 4.86 (s, 1Hvinyl), 4.69 (s,

1Hvinyl), 2.78 (dd, J = 14, 4 HZ, 1Ha-c.o), 2.49 (dd,

J = 14, 9, 1Ha-c-o), 2.20 (m, 4Hring), 1.72 (dt, J =

10, 2, 1Hailyllc), 1.62 (m, 2H), 1.10 (s, 2Hrins).

13C NMR 8 178.0 (Cco0), 147.7 (Cvinyl), 109.4

(Cvinyl), 73.7(CoH), 51.1 (Callylic), 40.2 (Ca-c-o),

36.0 (Cring), 34.2 (Cring), 32.3 (Cring), 30.7


General procedure for the reaction of trimethyl-
aluminum with ketones.

The ketone (1.38 mmol) is dissolved in 2 mL of

dry m-xylene in round bottom flask. A blanket of Ar

is maintained throughout the duration of the reaction.

The Me3Al hexane solution (5.60 mmol, 4.0 eq) is

added using standard syringe technique at room

temperature. After the evolution of heat and gas is

complete the reaction flask is heated in a sand bath

to the desired reaction temperature for the

appropriate length of time. Upon completion the

reaction is allowed to cool and an additional 3 mL of

xylene is added. The reactions are quenched by

pouring over a solution of 10 % HC1 and ice. Ether

extraction, drying with MgS04, and removal of solvent

under reduced pressure complete the work-up. An

etheral solution is made up for GC and CG/MS analysis.

Product identification was made through comparison of

the EI/MS to published spectral data.42 It is

necessary to note that the reported yields are

uncorrected GC percentages unless otherwise noted..

Trimethylaluminum reaction with camphor (109).

The sole product realized was 2-methylcamphene:

Mass Spectrum: 150 (M+, 13.3 %), 135 (M CH3, 28.3),

121 (15.0), 107 (82.9), 93 (59.4), 79 (87.8), 41

(base). 1H NMR 8 4.62-4.54 (d of m, 1 H) 13C NMR 8

158.9 (Calkene), 100.5 (Calkene), 44.3 (Cmethyl), 36.5

(Cmethylene), 34.7 (Cmethylene), 29.2 (Cmethine), 27.5

(Cquat), 22.2 (Cquat), 19.1 (Cmethyl), 18.4 (Cmethyl),

12.0 (Cmethyl)-

Trimethylaluminum reaction with 2-indanone (113).

At a reaction temperature of 1500 C for 24 Hr the

only product isolated was the 30 alcohol resulting

from methyl addition to the carbonyl. Mass Spectrum:

148 (M+, 15.6 %), 105 (M COCH3, 54.4), 91 (C7H7*,

8.2), 43 (base). Under the harsher conditions of a

reaction temperature of 2000 C for 15 Hr the sole

product isolated was the alkene 114. Mass Spectrum:

130 (M+, base), 115 (M CH3, 78.6%), 64 (34.8), 51


Trimethylaluminum reaction with 1-indanone (115).

The reaction was run at 1500 C for 34 Hr and gave

a product mixture 4:1 of the two possible alkenes.

Mass Spectrum: (Major, 116) 130 (M+, base), 115 (M -

CH3, 77.9 %), 63 (15.0), 51 (17.9); (Minor, 117) 130

(M*, base), 115 (M CH3, 53.5%), 64 (11.8), 51

(17.1). 1H NMR 8 (peaks attributed to major isomer

116 are underlined): 7.45-7.10 (Aromatic), 6.27 (br

s), 5.53 (t), 5.10 (t), 3.37 (t), 2.93-2.66 (m), 2.24


Trimethylaluminum reaction with Fluorenone (118).

The alkene 119 is the major product seen at the

lower temperature (46 % with 41 % ROH and 12 %

dimethylation) while the dimethylation product 121 is

dominant at the elevated temperature (trace amounts of

the alkene noted). Mass Spectrum: 119 178 (M+,

base), 152 (M C2H2. 13.5 %), 89 (27.0), 76 (37.6);

120 196 (M+, 23.8), 181 (M CH3, base), 152 (35.6),

91 (22.9), 76 (54.1); 121 194 (M+, 35.0), 179 (M -

CH3, base), 152 (9.6), 89 (38.6), 76 (21.3).

Trimethylaluminum reaction with Deoxybenzoin (122).

Lower temperature reaction conditions gave a

mixture of three alkenes, 74.7 % (1:3.4:3.3;

cis-123:124:trans-123), and the dimethylation product

(25.3 %). The higher temperature conditions afforded

the same products but in different ratios and

concentrations: alkenes, 89.5 % (1:0.56:0.37);

dimethylation, 10.5 %. Compound 124 was tentatively

assigned the structure shown based on its

fragmentation as no published data was forthcoming.

Mass Spectrum: cis-123 194 (M+, 76.1 %), 179 (M -

CH3, base), 115 (41.7), 89 (22.9), 77 (24.1), 51

(27.3); trans-123 194 (M+, 46.2 %), 179 (M CH3,

33.5), 116 (51.7), 103 (M CH2Ph, base), 91 (27.3),

77 (50.3); (124) 194 (M+, 80.0 %), 179 (M CH3,

base), 115 (42.9), 89 (26.5), 77 (20.0), 51 (22.1);

125 210 (M+, 0.06 %), 152 (0.81), 119 (M CH2Ph,

base), 103 (3.55), 91 (58.7), 41 (23.9).

Trimethylaluminum reaction with a-Tetralone (126).

The dimethylation product was the major product

seen at either set of conditions; 59.5 % with 23.6 %

alkene and 16.9 % 1-methylnapthalene at the lower


temperature and only trace alkene and methylnapthalene

at the elevated temperatures. Mass Spectrum: 127 160

(M+, 16.5 %), 145 (M CH3, base), 117 (18.8), 91

(15.3); 128 144 (M+, 49.3 %), 129 (M CH3, base), 115

(14.4), 43 (32.9); 129 142 (M+, base), 115 (29.5 %),

71 (14.6), 43 (17.8).


1. G. Zweifel and J. A. Miller, "Synthesis Using
Alkyne-Derived Alkenyl- and Alkynylaluminum
Compounds," Organic Synthesis, 32, John Wiley and
Sons, New York, Chapter 2, 1984.

2. K. Ziegler, Expereintia Suppl. II, 278 (1955).

3. C. R. Johnson, R. W. Herr, and D. M. Wieland, J.
Org. Chem., 38, 4263 (1973).

4. W. Kuran, S. Pasykiewicz, and J. Serzyks, J.
Organometal. Chem., 73, 187 (1984).

5. J. L. Namy, E. Henry-Basch, and P. Freon, Bull.
Soc. Chim., ., 2249 1970).

6. a) J. Fried, J. C. Sih, C. H. Lin, and P.
Dalven, J. Am. Chem. Soc., 94, 4343 (1972). b)
J. Fried and J. C. Sih, Tet. Lett., 1379 (1973).

7. S. Danishefsky and R. K. Singh, J. Org. Chem.,
41, 1669 (1976).

8. M. W. Rathkeand D. F. Sullivan, J. Am. Chem.
Soc., 95, 3050 (1972).

9. M. Visnick, Ph. D. dissertation, University of
Florida, 1982.

10. G. A. Crosby and R. A. Stephenson, J. C. S. Chem.
Comm., 287 (1975).

11. M. Cuevas, Ph. D. dissertation, University of
Florida, 1988.

12. E. J. Corey, Tet. Lett, 4753 (1971).

13. J. P. Marino and H. Abe, Synthesis, 872 (1980).

14. M. Visnick, L. Strekowski, and M. A. Battiste,
Synthesis, 284 (1983).

15. a) A. D. Buss and S. Warren, J. C. S. Chem.
Comm., 100 (1981). b) A. D. Buss, W. B. Cruse,
O. Kennard, and S. Warren, J. C. S. Perkin Trans.
1, 243 (1984).

16. A. H. Davidson and S. Warren, J. C. S. Perkin
1, 639 (1976).

17. E. Ohler and E. Zbiral, Synthesis, 357 (1991).

18. H. B. Henbest and R. A. L. Wilson, J. Chem. Soc.,
1958 (1957).

19. K. B. Sharpless and R. C. Michaelson, J. Am.
Chem. Soc., 95,6136 (1973).

20. a) X-ray crystal determinations were carried out
by Peter J. Steel at the Chemistry Department,
University of Canterbury, Christchurch, New
Zealand. b) P. J. Steel, M. A. Battiste, and C.
R. Campbell, Acta Crvstalloqr. Part C, submitted
for publication.

21. V. V. Tkachev, N. A. Bondarenko, E. I. Matrosov,
E. N. Cvetkov, L. O. Atovmjan, and M. I.
Kabachnik, Izv. Akad. Nauk SSSR, Ser. Khim., 209

22. P. Brougham, M. S. Cooper, D. A. Cummerson, H.
Heaney, and N. Thompson, Synthesis, 1015 (1987).

23. a) B. E. Rossiter, T. Katsuki, and K. B.
Sharpless, J. Am. Chem. Soc., 103, 464 (1981).
b) T. Katsuki, and K. B. Sharpless, J. Am. Chem.
Soc., 102, 5974 (1980).

24. K. B. Sharpless and T. R. Verhoeven, Aldrichimica
Acta, 12, 63 (1979).

25. R. D. Hoffman and M. A. Battiste, unpublished

26. J. R. Caesar and M. A. Battiste, ongoing

27. Spectroscopic studies carried out by J. Rocca,
M. Cuevas, and C. R. Campbell.

28. a) K. Oshima, N. Tsuboniwa, S. Matsubara, Y.
Morizawa, and H. Nozaki, Bull. Chem. Soc. Jpn.,
57, 3242 (1984). b) K. Oshima, N.Tsuboniwa, S.
Matsubara, Y. Morizawa, and H. Nozaki, Tet.
Lett., 2569 (1984).

29. A. Jeffrey, A. Meisters, and T. Mole, J.
Oraanometal. Chem., 74, 365 (1974).

30. J. Dekker, J. Boersma, G. J. M. Van der Kerk, J.
C. S. Chem. Comm., 553 (1983).

31. T. Mole and E. A. Jeffery, Oraanoaluminum
Compounds, Chapter 12, Elsevier, Amsterdam,

32. G. Bruno, The Use of Aluminum Alkyls in Organic
Synthesis, Ethyl Corp., Baton Rouge, LA, 1970,
and supplements.

33. a) A. Meisters and T. Mole, J. C. S. Chem.
Comm., 595 (1972). b) D. W. Harney, A. Meisters,
and T. Mole, Aust. J. Chem., 27, 1639 (1974).

34. A. Meisters and T. Mole, Aust. J. Chem., 27,
1655 (1974).

35. E. C. Ashby, L. Chao, anf J. T. Laemmle, J. Org.
Chem., 19, 3258 (1974).

36. P. E. M. Allen, J. N. Hay, G. R. Jones, and J. C.
Robb, J. C. S. Fardav Trans, 67, 1718 (1971).

37. W. C. Still, J. Orc. Chem., 43, 2923 (1978).

38. R. M. Coates, J. Am. Chem. Soc., 97, 1619 (1975).

39. H. C. Brown, Organic Synthesis via Boranes, John
Wiley and Sons, New York, 1975.

40. R. H. Schlessinger, J. Am. Chem. Soc., 101, 1548

41. B. R. Ree and J. C. Martin, J. Am. Chem. Soc.,
92, 1660 (1970).


Curtis R. Campbell was born on October 30, 1963,

in Beaver, Pennsylvania. He recieved a B.S. in

chemistry from the Pennsylvania State University in

May of 1986. The freshman and sophomore years of his

undergraduate studies were spent at the Beaver Campus

of Penn State where he worked part time in a quality

control lab. That work experience convinced him to

further his education beyond the B.S. due to the

limitations to advancement and lack of responsibility.

The summers after his junior and senior years were

spent working for the Mobay Corporation in Pittsburgh

where he got his first taste of the industrial world.

The lure of warmer climes brought him to the

University of Florida where he quickly picked up the

sport of cave diving in the many springs of the area.

He completed 99 penetrations without incident before

he was awarded a fellowship from the Division of

Sponsored Research that focused his energies on his

research. Over the years his area of interest has

swung toward environmental organic chemistry and the

fate of pollutants in the environment which has lead

to a position with Environmental Science and

Engineering in Gainesville starting in January 1992.

I certify that I have read this study and that in
my opinion it conforms to acceptable standards of
scholarly presentation and is fully adequate, in scope
and quality, as a dissertation for the degree of
Doctor of Philosophy.

Merle A. Battiste, Chairman
Professor of Chemistry

I certify that I have read this study and that in
my opinion it conforms to acceptable standards of
scholarly presentation and is fully adequate, in scope
and quality, as a dissertation for the degree of
Doctor of Philosophy.

William M. Jones
Professor of Chemi try

I certify that I have read this study and that in
my opinion it conforms to acceptable standards of
scholarly presentation and is fully adequate, in scope
and quality, as a dissertation for the degree of
Doctor of Philosophy.

Kenneth B. Wagener
Associate Professor of

I certify that I have read this study and that in
my opinion it conforms to acceptable standards of
scholarly presentation and is fully adequate, in scope
and quality, as a dissertation for the degree of
Doctor of Philosophy.

,4a'mes M. Boncella
SAssistant Professor of

I certify that I have read this study and that in
my opinion it conforms to acceptable standards of
scholarly presentation and is fully adequate, in scope
and quality, as a dissertation for the degree of
Doctor of Philosophy.

Chases L. Beatty
Professor of Materials
Science and Engineering

This dissertation was submitted to the Graduate
Faculty of the Department of Chemistry in the College
of Liberal Arts and Sciences and to the Graduate
School and was accepted as partial fulfillment of the
requirements for the degree of Doctor of Philosophy.

December 1991

Dean, Graduate School

126 II02 5U I I