Benzotriazole mediated transformations of anilines, phenols, and related compounds

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Title:
Benzotriazole mediated transformations of anilines, phenols, and related compounds
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Lan, Xiangfu, 1965-
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Thesis:
Thesis (Ph. D.)--University of Florida, 1991.
Bibliography:
Includes bibliographical references (leaves 192-214).
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by Xiangfu Lan.
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Typescript.
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Vita.

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BENZOTRIAZOLE MEDIATED TRANSFORMATIONS
OF ANILINES, PHENOLS, AND RELATED COMPOUNDS











BY

XIANGFU LAN


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

UNIVERSITY OF FLORIDA


1991


























To my wife, Huixia, with love












ACKNOWLEDGEMENTS


I am deeply indebted to my advisor, Professor Alan R.

Katritzky, for his invaluable guidance, encouragement, and

trust over the years. It has been a pleasure working with

him.

I would also like to take this opportunity to express

my sincere gratitude to Drs. William M. Jones, Eric J.

Enholm, David E. Richardson, and Bruce R. Stevens for

their helpful suggestions and the time they have spent as

my supervisory committee members.

I would like to thank Drs. Jamshed N. Lam, John V.

Greenhill, Stan Rachwal, Wei-Qiang Fan, and Phil Harris

for their valuable corrections and suggestions during the

preparation of the manuscript of this thesis. Special

thanks are due to Jamshed for all his help during these

years.

Thanks go to my "neighbor" (Dr. Subbu Perumal), the

time we worked together is always memorable, and to "buddy

system" member Wojtek for the evenings we spent in the

lab. To the people in Leigh Hall during these years,

Bogumila, Shibli, Sutha, Yannis, Hassan, Karoly, thanks

for the discussions, companionship, and friendship.

I am indebted to my family for all the love, help,

and encouragement, without which, I would not have had a


iii










chance to get into college, let alone a chance to study in

the United States.

Last but not least, I am deeply grateful to my wife,

Huixia, for standing by me through these years, for

understanding, for criticizing, and above all for

everything she has done for me.














TABLE OF CONTENTS


ACKNOWLEDGEMENTS ................................... iii

ABSTRACTS ........................................... viii

CHAPTERS

I GENERAL INTRODUCTION .............................. 1

1.1 Benzotriazole as a Synthetic Auxiliary ...... 1
1.2 Overview on the Extended Mannich Reactions:
a-Amidoalkylations ............................. 6
1.3 General Outlook ............................. 9

II BENZOTRIAZOLE MEDIATED SYNTHESIS OF METHYLENE-
BISANILINES ....................................... 11

2.1 Introduction ................................ 11
2.1.1 Utilization and Synthesis of Methylene-
bisanilines and an Evaluation
of Previous Methods .................. 11
2.1.2 Aim of the Work ...................... 14
2.2 Results and Discussion ...................... 19
2,.2.1 Preparation of Bis(4-aminoaryl)methanes
(2.9) using N-(Benzotriazol-l-
ylmethyl)arylamines .................. 19
2.2.2 Preparation of 4-(Benzotriazol-l-
ylmethyl)anilines ................... 21
2.2.3 Displacement of Benzotriazole in
4-(Benzotriazol-l-ylmethyl)anilines .. 24
2.3 Conclusions ................................. 30
2.4 Experimental ......................... ....... 30
2.4.1 General Procedure for the Preparation
of Bis(4-aminoaryl)methanes (2.9)
using N-(Benzotriazol-l-ylmethyl)-
arylamines .................... ....... 32
2.4.2 General Procedure for the Preparation
of 4-(Benzotriazol-l-ylmethyl)-
anilines ............................. 36
2.4.3 General Procedure for the Displacement
of Benzotriazole by Anilines ......... 39

III BENZOTRIAZOLE AS A SYNTHETIC AUXILIARY:
ALTERNATIVE SYNTHESIS OF LEUCO DYESTUFFS ......... 45

3.1 Introduction ................................ 45
3.1.1 Leuco Dyes ........................... 45










3.1.2 Overview on the Formation of a-Hetero-
carbanions and Activation of
a-Methylene Groups by a
Heterocyclic Moiety .................. 48
3.1.3 Aim of the Work ..... ................ 52
3.2 Results and Discussion ...................... 53
3.2.1 Lithiation of 4-(Benzotriazol-l-
ylmethyl)-N,N-dialkylanilines ........ 53
3.2.2 Displacement of the Benzotriazolyl
Moiety by Electron-rich Aromatic
Compounds .............................. 58
3.3 Conclusions ................................. 67
3.4 Experimental ................................ 67
3.4.1 General Procedure for the Preparation
of Substituted 4-(Benzotriazol-1-
ylmethyl)anilines ............... ..... 68
3.4.2 General Procedure for the Displace-
ment of the Benzotriazolyl moiety
by Nucleophiles ...................... 75

IV O-(a-BENZOTRIAZOLYLALKYL)PHENOLS: VERSATILE
INTERMEDIATES FOR SYNTHESIS OF
SUBSTITUTED PHENOLS .............................. 87

4.1 Introduction ................................ 87
4.1.1 a-Amidoalkylation of Phenols ......... 87
4.1.2 Importance and Synthesis of Phenols .. 89
4.1.3 Aim of the Work ...................... 91
4.2 Results and Discussion ...................... 92
4.2.1 Reactions of Phenols with 1-Hydroxy-
methylbenzotriazole .................. 92
4.2.2 Reactions of Naphthols with Benzo-
triazole and Other Aldehydes ......... 95
4.2.3 Lithiation of the Phenol
Derivatives 4.11 ..................... 97
4.2.4 Displacement of the Benzotriazole
Group ................................ 100
4.2.5 NMR Spectra of (a-Benzotriazolyl-
alkyl)phenols ........................ 103
4.3 Conclusions ................................. 107
4.4 Experimental ................................ 107
4.4.1 General Procedure for the Alkylation
of Phenols: Preparation of o-(Benzo-
triazol-l-ylmethyl)phenols (4.11) .... 108
4.4.2 General Procedure for the
Condensation of Naphthols, Aldehydes,
and Benzotriazole .................... 112
4.4.3 General Procedure for the Lithiation
of Compound 4.11 ..................... 119
4.4.4 General Procedure for the
Displacement of Benzotriazole ........ 123










V N-[a-(o- AND p-METHOXYARYL)ALKYLIBENZOTRIAZOLES:
PREPARATION AND USE IN SYNTHESIS ................. 129

5.1 Introduction ................................ 129
5.1.1 Importance and Synthesis of
Phenol Ethers ........................ 129
5.1.2 Aim of the Work ...................... 131
5.2 Results and Discussion ..................... 132
5.2.1 Synthesis of (Benzotriazol-l-
ylmethyl)phenyl Methyl Ethers ........ 132
5.2.2 Lithiation of (Benzotriazol-l-
ylmethyl)phenyl Methyl Ethers ........ 136
5.2.3 Displacement of the Benzotriazole
Group ................................. 142
5.3 Conclusions ................................. 149
5.4 Experimental ................................ 149
5.4.1 General Procedure for the Alkylation
of Phenol Ethers ..................... 149
5.4.2 General Procedure for the Conversion
of the Phenol Derivatives 5.11 and
5.19 to the Corresponding Methyl
Ethers 5.12 and 5.7f ................. 153
5.4.3 General Procedure for the Lithiation
of 5.7 and 5.12 ...................... 154
5.4.4 General Procedure for the
Displacement of Benzotriazole by
Grignard Reagents .................... 164
5.4.5 General Procedure for the Displacement
of Benzotriazole by Electron-rich
Aromatic Compounds ................... 167

VI RING FRAGMENTATION OF a-BENZOTRIAZOL-1-YL
CARBANIONS ..... .... ..... ......................... 172

6.1 Introduction ............................... 172
6.1.1 Thermal and Photochemical Stability
of 1-Substituted Benzotriazoles ...... 172
6.1.2 Aim of the Work ...................... 173
6.2 Results and Discussion .................... 175
6.3 Conclusions ................................. 181
6.4 Experimental ................................ 181
6.4.1 General Procedure for the Preparation
of Compounds 6.4, 6.12, 6.16, 6.17,
6.20, and 6.22 ....................... 182
6.4.2 General Procedure for the Preparation
of Compounds 6.21 .................... 187

VII SUMMARY ......................................... 189

BIBLIOGRAPHY ......................................... 192

BIOGRAPHICAL SKETCH .................. ................ 215


vii












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


BENZOTRIAZOLE MEDIATED TRANSFORMATIONS OF ANILINES,
PHENOLS, AND RELATED COMPOUNDS





BY

XIANGFU LAN


May 1991

Chairman: Alan R. Katritzky, FRS
Major Department: Chemistry


The use of benzotriazole as a synthetic auxiliary has

been extended to conjugated systems. A benzotriazol-l-

ylmethyl group was incorporated into anilines, phenols,

and phenol ethers. The parent benzotriazole derivatives

have been elaborated via lithiation. The displacement of

the benzotriazole group in these parent derivatives and in

the lithiated derivatives by various nucleophiles has been

investigated.

N-(Benzotriazol-l-ylmethyl)arylamines were converted

into bis(4-aminoaryl)methanes. Anilines reacted with

1-hydroxymethylbenzotriazole to give 4-(benzotriazol-l-

ylmethyl)anilines and methylenebisanilines. The

benzotriazolyl moiety in 4-(benzotriazol-l-ylmethyl)-


viii










anilines was displaced successfully by anilines,

1,3-dimethoxybenzene, 1,3,5-trimethoxybenzene, pyrroles,

and indoles to give diarylmethanes.

The methylene groups in 4-(benzotriazol-l-

ylmethyl)anilines were deprotonated via lithiation and the

anions were trapped with various electrophiles. The

benzotriazole group in the lithiated derivatives was

displaced by anilines and indole to afford leuco

dyestuffs.

A (a-benzotriazolyl)alkyl group was incorporated into

the phenol systems either by the direct reaction of

phenols with l-hydroxymethylbenzotriazole or by the

condensation of naphthols, aldehydes, and benzotriazole to

give the ortho substituted derivatives. The protection of

the phenolic hydroxyl group with trimethylsilyl chloride

enabled an efficient substitution at the acidic methylene

groups via lithiation in o-(benzotriazol-l-ylmethyl)-

phenols. The displacement of the benzotriazole group in

the parent and in the lithiated derivatives by Grignard

reagents and by hydride ion from lithium aluminum hydride

allowed an efficient synthesis of substituted phenols.

Phenol ethers were similarly benzotriazol-1-yl-

methylated, giving p-(benzotriazol-l-ylmethyl)phenyl

methyl ethers. The methylene groups were easily

substituted with electrophiles via lithiation. The

benzotriazole group was displaced by Grignard reagents and










by nucleophilic aromatic compounds such as anilines and

indole.

The triazole ring of benzotriazole in the

a-benzotriazol-1-yl carbanions underwent smooth opening,

followed by the loss of a molecule of nitrogen, to give an

anion, which was trapped by electrophiles inter- or intra-

molecularly to afford imines or heterocycles.














CHAPTER I
GENERAL INTRODUCTION



1.1 Benzotriazole as a Synthetic Auxiliary


Benzotriazole (1.1) has attracted considerable

attention because of its theoretical interest, and

synthetic values, as well as for its numerous applications

in industry and agriculture. Benzotriazole can be viewed

as the benzo derivative of 1H-1,2,3-triazole in which the

triazole moiety has its two carbon atoms shared with the

benzene ring. One important feature of benzotriazole is

the strong electron-withdrawing nature of the nitrogen-

nitrogen double bond. This feature is reflected in the

high acidity of benzotriazole (pKa 8.35) [88JA4105], which

is comparable to that of uracil (pKa 9.45) [56JA5292] or

phenol (pKa 9.97) [59MI1], rather than to those of similar

heterocyclic systems containing fused five-membered rings

such as pyrrole (pKa 23) [81JOC6321, carbazole (pKa 19.9)

[81JOC632], or benzimidazole (pKa 13.2) [58JCS1974]. This

acidity gives benzotriazole two very important

characteristics. One is that it shows higher reactivity

towards many types of reactions such as nucleophilic

substitution and nucleophilic addition reactions. Another








2

important characteristic is that the benzotriazole anion

has been shown to be a good leaving group.



4 N
N2
67 N1
H
1.1

Figure 1.1 Benzotriazole



Benzotriazole readily adds to aliphatic aldehydes to

give l-(a-hydroxyalkyl)benzotriazoles (1.3a)

[87JCS(P1)791]. Conversion of the hydroxy derivatives to

the corresponding chloro derivatives 1.3b was achieved

with thionyl chloride [52JA3868, 87JCS(Pl)811].

Benzotriazole has also been shown to condense directly

with dialkylamines [46JA2496, 75JCS(Pl)1181] or with

arylamines [52JA3868, 55JA5386, 76IJC(B)718, 80MI1] and

formaldehyde or other aldehydes [87JCS(P1)805,

89JCS(P1)225] to give Mannich-type adducts (1.3c).

Scheme 1.1 illustrates the alternate ways in which

the benzotriazole adducts can ionize. When X is an

electron-donor group, in particular a nitrogen-linked

substituent as 1.3c, ionization occurs to form the

benzotriazole anion. When X is itself a leaving group, for

example, a halogen, then the benzotriazole nitrogen atom








3

can assist the ionization of X as an anion, leaving the

benzotriazole as part of the cationic species. The

chlorine atom in l-chloromethylbenzotriazole (1.3b; R -

H), for example, has been easily displaced by carbon,

nitrogen, oxygen, phosphorus, and sulfur nucleophiles

[87JCS(P1)781]. It has been amply demonstrated that

ionizations of both types occur with many benzotriazole

derivatives.


N N N
jNN
N' N N
H X H X H R

R
1.3a X=OH 1.4
1.2 1.3b X= CI
1.3c X = NR2


Scheme 1.1


The use of benzotriazole as a synthetic auxiliary is

based upon the above rationale that the reactive

benzotriazole can be used as an anchor and as an activator

of neighboring bonds to construct a molecular assembly.

The benzotriazole moiety could then be easily displaced by

cleavage of the C-N bond to afford useful compounds.

In our laboratory, the use of benzotriazole as a

synthetic auxiliary has been explored to a large extent.

It is used for the elaboration of various nitrogen-








4

containing compounds. The Mannich-type condensation of

benzotriazole, an aldehyde, and an NH- compound afforded

adducts of type 1.7. The subsequent displacement of the

benzotriazole moiety in the adduct 1.7 by a nucleophile

has enabled the preparation of amines [87JCS(P1)799,

87JCS(P1)805, 89JCS(P1)225, 89S31], hydrazines

[89JCS(P1)2297], N,N-disubstituted hydroxylamines

[89JCS(P1)225], N-substituted amides [88JCS(P1)2339,

88JOC5854] or thioamides [88JOC5854, 88TL1755], and amino

acid derivatives [89CC337, 89S3231 (Scheme 1.2).


N


H
1.1


+ R'CHO + H-N
R3


N

,N N

1. R2
R1 N R3

1.7


Nu
Nu: 1 .N R2
N-- R1 ^N

'R3
1.8


Scheme 1.2








5

The utility of benzotriazole as a synthetic auxiliary

has been extended to the preparation of oxygen compounds

such as ethers and esters [89J0C6022, 90JCS(Pl)1717], as

well as to the preparation of thiol ethers [91UP1].





RnI Bt R1\ .R4
C C
R2 CXR3 R2 XR3
1.9 1.10
X=O
XR3 = OC(=O)R
X=S

Bt = benzotriazol-1-yl


Scheme 1.3



Another aspect concerning the use of benzotriazole

as a synthetic auxiliary is the elaboration of the

benzotriazole adducts before the displacement is enforced.

Heteroatom facilitated lithiation has become an

increasingly important tool in synthetic chemistry

[69CRV693, 70MI1, 73MI1, 74MI1, 74MI2]. The strong

electron withdrawing ability of the benzotriazole ring

makes the a-groups in certain systems acidic and thus

capable of undergoing deprotonation to generate a

carbanion, which can then be trapped with a variety of

electrophiles. The subsequent removal of the benzotriazole








6

group leads to functionalized molecules. Thus, it was

shown that the benzotriazole adducts of type 1.11 with (a)

X Ph [90MI1], (b) X = SiMe3 [90MI1], (c) X = SPh

[87JCS(P1)781], and (d) X = an N-linked heterocycle

(pyrrole, indole, and carbazole) [89JHC829] undergo smooth

lithiation at the methylene groups to give derivatives of

type 1.12 when trapped with various electrophiles.



n-BuLi
Bt Bt
E further reactions
X E X

1.11 1.12

a X=Ph
b X = SiMe3
c X=SPh
d X= N-Heterocycles

Scheme 1.4



1.2 Overview on the Extended Mannich Reactions:
a-Amidoalkylations


The Mannich reaction has been an important tool for

the synthesis of new compounds and has been well reviewed

in the literature [420R303, 56AG265, 59MI2, 60MI1, 73S703,

90T1791]. In its most general representation, formaldehyde

(rarely other aldehydes) is condensed with a primary or

secondary amine and a compound (substrate) containing an

active hydrogen atom (usually a CH, sometimes an NH)








7

(Scheme 1.5). The significance of the Mannich reaction is

that the Mannich bases are easily obtained and are

sometimes employed as such. On the other hand, the Mannich

bases are also very reactive and are used as synthetic

intermediates to numerous other compounds such as amines,

amino-alcohols, and heterocycles. The most intensively

investigated substrates involve alkyl ketones, phenols,

carboxylic acid derivatives, and NH-heterocyclic

compounds.


S -H20
R-H + CH20 + H-N -- R N


1.13 1.14 1.15 1.16


Scheme 1.5



Important extensions of the Mannich reaction where

amides, imides, ureas, thioureas, etc. replace the amine

component, known as a-amidoalkylations, are also well

documented in the literature [63MI1, 64AG909, 650R52,

70S49, 73S243, 84S85]. Acetanilide, phenols, and phenol

ethers as well as other substrates have been employed as

the active CH- compounds in these Mannich condensations

with aldehydes and amides or imides under various

conditions. For acetanilide and phenol ethers, the amido-

alkylation occurs at the para-position or at both the








8

ortho- and the para-positions depending the reaction

conditions and the reagents used [66JOC133, 69CC376]. For

phenols, the ortho-substituted derivatives are obtained

unless both ortho positions are occupied, in which case

the Mannich reaction occurs at the para-position

[57RTC249].

The a-amidoalkylation reaction is invariably acid-

catalyzed. The first step consists of the addition of the

NH group to the carbonyl carbon of formaldehyde (or rarely

another aldehyde) giving rise to an a-alkylol compound

1.19. This derivative is converted (via acid catalysis)

into a carbonium/imonium ion (1.20 -- 1.21) which then

reacts with the substrate to yield the condensation

product 1.23.


H + HNx X= RC=O,RC=S
/ + Y Y=X,H
Z Z = H (rarely otherwise)





H HA H H
NX AH
HO -- + N N A










1.23


Scheme 1.6








9

Compounds 1.19 can be isolated prior to use. These

and other analogous reagents include N-hydroxyalkylamides

[69JOC14], N-alkoxyalkylamides [66JOC133], N-haloalkyl-

amides [63JOC2925], and N,N'-(arylmethylene)bisamides

[57RTC249]. In most of these cases, the carbonyl compound

has been formaldehyde.


1.3 General Outlook



The aim of the overall project is briefly mentioned

in this section. The specific details are discussed more

throughly in the respective chapters.

Work in our laboratory concerning the use of

benzotriazole as a synthetic auxiliary has succeeded in

the elaboration of many types of nitrogen containing

compounds as well as oxygen and sulfur containing

compounds. In all these cases, the benzotriazole ring and

a heteroatom bearing an electron pair are connected to the

same carbon. The lone electron pair assists in the

displacement of the benzotriazole anion; a subsequent

attack by a nucleophile affords the products. Until now,

systems in which the benzotriazole ring and a heteroatom

are connected through a conjugated system have remained

virtually unexplored.

The objective of the present project is to

investigate the use of benzotriazole as a synthetic

auxiliary in a conjugated system. A benzene ring is








10

suitable for such a conjugated system. Amino, hydroxy, or

alkoxy groups should activate the benzene ring for the

construction of the benzotriazole adducts and assist in

the subsequent displacement of the benzotriazole group by

nucleophiles.















CHAPTER II
BENZOTRIAZOLE MEDIATED SYNTHESIS OF
METHYLENEBISANILINES



2.1 Introduction


2.1.1 Utilization and Synthesis of Methylenebisanilines
and an Evaluation of Previous Methods


4,4'-Methylenebisanilines (2.2) represent a class of

well known compounds. A large number of papers and patents

exist which deal with the preparation and wide application

of such compounds in polymers.

4,4'-Methylenebisaniline (2.2; R1-R6 H) is used as

a curing agent for epoxy resins and urethane elastomers

[75JAP7439671, 88JAP6345242], as an intermediate in the

preparation of polyurethanes [74JAP7428022, 87MI1], in the

synthesis of polyamides [67FRP1474509, 88MI1], and also in

the preparation of azo dyes [75MI1, 75USP3890257, 87MI2].

The dialkylaniline analogues (2.2; R1,R2,R3,R4 H) have

found applications in the production of dyes

[79GEP2739953, 87ZOR1516] and recording materials

[75GEP2446892, 84JAP59208546, 87MI3], as antioxidants for

lubricating oils [77GEP2538445, 84JAP59230094], as curing

agents for epoxy resins [66NEP6608593, 73JAP7344382,








12

85GEP3327712], and as electrically insulating composite

materials [75BRP1396371, 85GEP3327711].

The symmetrical analogues of type 2.2 have been

synthesized by several methods. The major methods include

the reaction of an arylamine (or N,N-dialkylaniline) with

formaldehyde in the presence of concentrated hydrochloric

acid (Route A) [14CB1161, 34JA1944, 35JA887, 54JOC1862,

55JCS83, 67JOC3101, 87JCR(S)194, 87MI4]; the reaction of

an N,O-aminal 2.1 with an arylamine hydrochloride under

acidic conditions (Route B) [88JCS(P1)1631]; the use of

mercury reagents 2.3 (Route C) [79CC339, 80JCS(Pl)1420];

and the use of 4-hydroxymethyl-N,N-dialkylaniline (2.4)

(Route D) [55MI1, 55MI2, 55MI3] (Scheme 2.1). Other

methods include the reduction of appropriate

4,4'-diaminobenzophenones [50JA3586, 54MI1, 81JOC2579] or

the corresponding thiones [74JOM359, 75JOC2694, 83JOC250,

85JA6121] and the alkylation of bisanilines [80MI2].

The syntheses and applications of unsymmetrical

analogues are less common. There are only a few

preparative methods for the unsymmetrical methylene-

bisanilines. Compounds 2.3 [79CC339] and 4-hydroxymethyl-

N,N-dialkylanilines (2.4) [55MI1, 55MI2, 55MI3] react with

a variety of arylamines to afford the unsymmetrical

methylenebisanilines. Other methods involve an arylamine

exchange [1894CB1804, 1900CB2586] or an alkylation of

4,4'-methylenebisaniline [82MI1].












ArNHCH20R' + ArNH2 HCI


ArNR2 + CH20


Route A


Route B


R5 R6

R'R2N N CH2 ^NR3R4


NR1R2





HgCI


ArNR3R4
CH2N2
Route C


2.3


ArNR HgC
ArNR1R2 + HgCI2


ArNR3R4
Route D


NR1R2





CH2OH


Scheme 2.1




Most of the methods described above have some

setbacks such as low yields, tedious work-up and

purifications, or other synthetic limitations. The

reaction between arylamines and formaldehyde (Route A) and








14

the reaction of N,O-aminals [88JCS(Pl)1631] (Route B) give

only symmetrical analogues. The reduction reactions are

limited by availability of the starting materials. On the

other hand, the alkylation of 4,4'-methylenebisaniline

often leads to a mixture which is difficult to separate

and purify. The use of compound 2.3 affords good yields in

some cases [79CC339], yet the specific reaction conditions

prevent this method from wide-range application.

4-Hydroxymethyl-N,N-dialkylanilines (2.4) seem to be

good reagents. However, they are extremely sensitive to

traces of acids, especially at higher temperatures where

they can decompose to the N,N-dialkylanilines and

formaldehyde. Moreover, they are oxidized rather readily

on exposure to air. Thus, they are not easy to handle and

often give mixtures and very low yields of the desired

products in the preparation of methylenebisanilines

[34JCS730].


2.1.2 Aim of the Work


Although the Mannich reaction has been an important

tool in synthetic organic chemistry for many years, its

application is subject to several limitations [420R303,

60MI1, 73S703, 90T1791]. One such limitation is that the

products initially formed in the condensation of

formaldehyde with ammonia, or with a primary amine,

undergo further transformations with participation of the








15

remaining N-H bonds leading to mixtures [57MI1, 60MI1,

65MI1]. To overcome these difficulties, several papers

have recently reported efficient synthetic equivalents for

methyleneimines (2.5). Thus it has been demonstrated that

derivatives 2.6 with Y = alkoxyl (2.6a) [83CC1109], Y -

SAr (2.6b) [71JHC597, 8051025, 81JCS(P1)1569, 84CC427], Y

- CN (2.6c) [84TL1635, 85CC951, 85JA1698, 86TL1147], and Y

- SiHR2 (2.6d) [73TL2475, 84CC794, 84CC883, 84CC1055] can

all eliminate the Y group to afford, in situ, reactive

methyleneimines such as 2.5 or their protonated forms 2.7.


R- N = CH2


RNHCH2-Y


2.6a
2.6b
2.6c
2.6d


-NHCH
R-- NH CH2


Y=OR
= SAr
=CN
= SiHR2


ArNHCH2NHAr' kH2N


2.8


Figure 2.1 Synthetic Equivalents for Methyleneimines


Barluenga and co-workers have achieved monoalkylation

of primary aromatic amines [83CC1109] and have synthesized








16

symmetrical and unsymmetrical bis(arylamino)methanes (2.8)

[88CB18131 using the masked form 2.6a of a reactive

methyleneimine. They have also reported a high yielding

synthesis of N-(2-alkynyl)arylamines in a one-pot reaction

of N-(methoxymethyl)arylamines with 1-alkynyllithium

[89S33].

A comparison of the properties of benzotriazole with

those of an alkoxyl group reveals similar roles played in

certain types of reactions by these groups. The use of

benzotriazole as a synthetic auxiliary has successfully

achieved the alkylation of aromatic amines [87JCS(P1)799,

87JCS(P1)805, 90CJC446, 90CJC456], synthesis of aliphatic

amines [89JCS(P1)225, 89S66, 90CB1443], the alkylation of

hydroxyamines, hydrazines and amides [88JCS(P1)2339,

88JOC5854, 88TL1755, 89JCS(Pl)225, 89JCS(Pl)2297], and

synthesis of tertiary propargylamines by reaction of

N-(benzotriazol-l-yl)alkylamines with 1-alkynyllithium

[89S31].

In a recent report [88JCS(P1)1631], the aminals 2.1

were easily converted into bis(4-aminoaryl)methanes (2.9)

upon treatment with arylamine hydrochlorides (Scheme 2.1;

Route B). This promoted us to investigate the use of

benzotriazole for such a purpose.

Thus, one of the objectives of the present work is to

investigate the use of benzotriazole as an alkoxyl

equivalent, and consequently its use for the conversion of








17

N-(benzotriazol-l-ylmethyl)anilines (2.10) to bis(4-amino-

aryl)methanes (2.9) (Scheme 2.2).



NHCH2Bt NHg-HCI / R

Sj j H+ R ---N CH2
R R R


2.10 2.11 2.9


Scheme 2.2


Previous studies on the use of benzotriazole as a

synthetic auxiliary have been for derivatives of type 2.12

in which the benzotriazole group and the heteroatoms are

connected to the same carbon. In these derivatives, the

lone electron pair from the heteroatom is believed to

assist the displacement of the benzotriazole group to give

stabilized cations 2.13. The systems in which the

benzotriazole group and the heteroatom are connected

through a conjugated system of type 2.14 have remained

virtually unexplored.


R
R-CH-X R-CH=X
I Bt X
Bt

2.12a X=NR2 2.13 2.14
2.12b X=OR
2.12c X=SR


Figure 2.2 Benzotriazole Derivatives








18

Therefore, another aim of this work is to investigate

the use of benzotriazole as a synthetic auxiliary in a

conjugated system. In particular, anilines were chosen as

the substrates in which the phenyl ring was the conjugated

backbone and the amino group was the assisting group. An

amino or a dialkylamino group should activate the benzene

ring in the electrophilic substitution reactions. The

direct alkylation of anilines by a benzotriazol-1-ylmethyl

group would be possible. The lone electron pair from the

amino nitrogen would then assist the leaving of the

benzotriazole group. A subsequent attack by an aniline

would lead to a variety of 4,4'-methylenebisanilines

(Scheme 2.3).


+ +
NR2 NR2 NR2
BtCH20H
(2.16)


CH2Bt CH2
2.15 2.17
2.18


I/ NR'R2


CH2



R2N NR'R2
2.19


Scheme 2.3








19

2.2 Results and Discussion


2.2.1 Preparation of Bis(4-aminoaryl)methanes (2.9) using
N-(Benzotriazol-l-ylmethyl)arylamines

Bis(4-aminoaryl)methanes (2.9) were obtained from
reaction of N-(benzotriazol-l-ylmethyl)arylamines (2.10)
and two equivalents of arylamine hydrochlorides (2.11) in
a 50% aqueous methanol solution (Scheme 2.4). The adducts
2.10 were readily prepared by stirring a mixture of the
arylamine, formaldehyde and benzotriazole in methanol at
room temperature [87JCS(Pl)799]. The arylamine hydro-
chlorides 2.11 were obtained by mixing the corresponding
arylamines with concentrated hydrochloric acid.

R

~-v
l/aNH2

2.20

BtH/HCHO conc. HCI


R R ( 1 \H
R


\ -NHCH2Bt + 2 --NH2HCI -- N CH2
6 5
2.10 2.11 2.9


2.9, 2.10-2.11, 2.20 a b c d e
R H 2-CI 3-CI 2-Me 3-Me


Scheme 2.4








20

However, in two cases, 4-(benzotriazol-l-ylmethyl)-2-

chloroaniline (2.22b) and 4-(benzotriazol-l-ylmethyl)-3-

chloroaniline (2.22c) were obtained as by-products in

yields of 26% and 7%, respectively. Heating N-(benzo-

triazol-1-ylmethyl)aniline (2.10a) alone in 50% aqueous

methanol in the presence of one equivalent of concentrated

hydrochloric acid, followed by basic hydrolysis, afforded

4-(benzotriazol-l-ylmethyl)aniline (2.22a) in a yield of

59%. Compounds 2.22 could be intermediates in the

preparation of bis(4-aminoaryl)methanes (2.9) and may be

formed from the reactive cation 2.21. Supporting evidence

for this was the formation of compound 2.9a from the

reaction of 2.22a with 2.11a. Other mechanisms are also

possible such that proposed by Wagner [54JOC1862] for the

acid-induced reactions of formaldehyde and amines.




NH2
NHCH2 Bt NH

6H+ 6 2
R + H2C= Bt R 3
R R ---" 5 4 3

CH2Bt

2.10 2.21 2.22


2.10, 2.22 a b c

R H 2-CI 3-CI


Scheme 2.5










Table 2.1


21

Preparation of Bis(4-aminoaryl)methanes (2.9)


Product Yielda (%) M.p. (C) Lit. m.p. (*C)


2.9a 58 90-92 91.5-92 [35JA8871

2.9b 44 107-109 110 [14CB1161]

2.9c 32 99-101 100-103 [55JCS83]

2.9d 50 155-157 149-155 [35JA887]

2.9e 50 117-119 119-120 [34JA1944]



a Isolated yields.



2.2.2 Preparation of 4-(Benzotriazol-l-ylmethyl)anilines

N,N-Dimethylaniline and 1-hydroxymethylbenzotriazole

(2.16) when heated under reflux in acetic acid for 5 min

(following the conditions reported for the tritylation of

aniline hydrochloride with triphenylmethanol [630SC47])

afforded a mixture of 4-(benzotriazol-l-ylmethyl)-

N,N-dimethylaniline (2.17a) and 4,4'-methylenebis-

(N,N-dimethylaniline) (2.23a) (Scheme 2.6). Evidently,

2.17a undergoes displacement of the benzotriazole group by

a second molecule of N,N-dimethylaniline under the acidic

conditions. The lone electron pair of the amino nitrogen

atom in 2.17 assists in the displacement of benzotriazole

to form the reactive intermediate 2.18 (Scheme 2.3), which








22

then reacts with N,N-dialkylaniline to give the bis-
product. When two equivalents of N,N-dialkylaniline were
reacted with 2.16, only the bis-product 2.23 was isolated.


0.5 eq. 2.16


NR2




2.15


1.0 eq. 2.16


(R2N -2 CH2


2.23


NR2




CH2Bt
2.17


+ 2.23


2.15, 2.17, 2.23 a b
R Me Et



Scheme 2.6




If the electrons on the nitrogen are less available,
the benzotriazole adducts can be isolated in higher

yields. Thus, aniline hydrochloride was heated under

reflux in acetic acid with 2.16 to give only the alkylated

product 2.22a (Scheme 2.7). Obviously the coordination of










the electron pair on the nitrogen to the proton in

compound 2.24 prevents the displacement of the

benzotriazole group. When N,N-dimethylaniline was treated

with one equivalent of concentrated hydrochloric acid,

then refluxed with one equivalent of 2.16 in 1-propanol,

the yield of 2.17a was increased dramatically, although a

small percent of bis-product 2.23a was still formed.




NH2-HCI NH2
NH2HCI
Base
+ BtCH20H -

CH2Bt CH2Bt

2.11a 2.16 2.24 2.22a




Scheme 2.7



The mixtures of the benzotriazole adducts 2.17 and

the bis-products 2.23 were easily separated due to their

different solubilities in hot hexane; the bis-products

2.23 dissolved, but the benzotriazole adducts 2.17 were

insoluble and could easily be isolated by filtration.

The structures of the benzotriazole adducts 2.17 and

2.22 were confirmed by their spectral and analytical

properties. The 13C NMR spectra showed the characteristic








24

patterns for 1-substituted benzotriazole derivatives. The

quaternary carbons, C-3a and C-7a, of the benzotriazole

moiety appeared between 143.1-146.3 ppm and between 132.4-

132.8 ppm, respectively. The regio chemistry of these

adducts was determined from the number of resonances in

the 13C NMR spectra. The most indicative methylene groups,

attached to an electron-withdrawing benzotriazole group,

appear in the 13C NMR spectra between 48.0-52.1 ppm and in

the 1H spectra as a singlet at 5.66-5.85 ppm (Table 2.2).


Table 2.2


NMR Chemical Shifts (6) for the Characteristic
Benzotriazole Carbons C-3a and C-7a, and
Methylene Groups in Products 2.17 and 2.22


Prod. 6C(C-3a) 6C(C-7a) SC(CH2) 6H(CH2)


2.17a 146.2 132.5 52.0 5.70

2.17b 146.2 132.6 52.1 5.70

2.22a 145.4 132.4 51.1 5.76

2.22b 143.1 132.5 51.4 5.66

2.22c 146.3 132.8 48.0 5.85


2.2.3 Displacement of Benzotriazole in 4-(Benzotriazol-l-
ylmethyl)anilines


The benzotriazole group in 4-(benzotriazol-l-

ylmethyl)anilines (2.17) or (2.22) was easily displaced by








25

different types of anilines, as expected, to afford a

series of 4,4'-methylenebisanilines. This type of

displacement was assisted by the electron pair from the

amino nitrogen.

Two types of reaction conditions have been utilized.

One was to reflux a mixture of the benzotriazole adduct

and the aniline in acetic acid. On work up, the solution

was neutralized and then basified, thus removing the

benzotriazole by-product as its anion and making isolation

of the product easier. Under alternative reaction

conditions, a mixture of the benzotriazole adduct and an

aniline was heated with concentrated hydrochloric acid in

50% aqueous methanol, followed by neutralization. Thus,

4-(benzotriazol-l-ylmethyl)aniline (2.22a) was heated with

arylamines to give symmetrical and unsymmetrical

bis(4-aminoaryl)methanes 2.9 and 2.25, respectively. With

N-substituted anilines, the mixed bis-anilines of type

2.26 were formed (Scheme 2.8).

4-(Benzotriazol-l-ylmethyl)-N,N-dialkylanilines

(2.17) reacted with N,N-dialkylanilines to give very high

yields of the symmetrical 4,4'-methylenebis(N,N-

dialkylanilines) (2.23) if the same N,N-dialkylaniline was

used. When a different N,N-dialkylaniline was used, the

unsymmetrical 4,4'-methylenebis(N,N,N',N'-tetraalkyl-

anilines) (2.19) were obtained in excellent yields. Such

unsymmetrical analogues have previously not been reported.








26

Thus this method provides a novel synthetic route to the

unsymmetrical analogues of type 2.19 (Scheme 2.9).

Compound 2.17a also reacted with aniline hydrochloride to

give compound 2.26a in 70% yield.


-N- NH2 HCI
\--j


NH2




CH2Bt

2.22a


H2N- /CH2
-2


2.9a


R

SNH2 HCI


H2N


2.25a R =2-Me
2.25b R = 2-CI


NR1R2



H2N


2.26a R1= R =Me
2.26b R1 = H, R2 = Me


Scheme 2.8


CH2



NR'R2














NR2


NR2




CH2Bt

2.17a R=Me
2.17b R= Et


SR2N CH2
-2


2.23a
2.23b


1R-NRR2


- NH2 HCI


R =Me
R = Et


CH2



R2N NR1R2

2.19

2.19 R R1 R2
a Me Me Et
b Et(Me) Me(Et) Me(Et)
c Et Me Et


CH2



NH2


2.26a


Scheme 2.9











Table 2.3 Displacement of Benzotriazole


Prod. Sub- Methoda React. Yieldb M.p.
state time (h) (%) (OC)


2.9a

2.19a

2.19b

2.19b

2.19c

2.23a

2.23a

2.23b

2.23b

2.25a

2.25b

2.26a

2.26a

2.26b


2.22a

2.17a

2.17a

2.17b

2.17b

2.17a

2.15a

2.17b

2.15b

2.22a

2.22a

2.22a

2.17a

2.22a


72

1

1.5

1

2.5

3

3

3

3

72

72

72

72

72


80

96

99

100

96

97

85

90

95

78

72

83

70

66


90-92

oil

oil

oil

oil

89-90c


127-129e

80-82

88-90f


a Method A: The reactants were
methanol solution.
Method B: The reactants were
Method C: N,N-Dialkylaniline
were heated in acetic acid.
b Isolated yields.
c Lit. [87JCR(S)194] m.p. 88-89
d Lit. (54MI1] m.p. 42-44 C.
e Lit. [80JCS(P1)1420] m.p. 127
f Lit. [55MI1] m.p. 89-90 C.
9 Lit. [80JCS(P1)1420] reported


heated in 50% aqueous

heated in acetic acid.
and l-hydroxymethylbenzene


CC.

C.

it as an oil.








29

The structures of these 4,4'-methylenebisanilines

were confirmed by their spectral data and elemental

analysis. Known compounds have been compared to those

reported in the literature. All methylenebisanilines

display the characteristic methylene singlets between 6

3.67-3.94 in the 1H NMR spectra and the corresponding

signals between 6 34.8-40.2 in the 13C spectra. The

upfield shift of both protons and carbons, compared to

those of the benzotriazole adducts 2.17 and 2.22,

indicated that the methylene group was connected to two

phenyl rings (Table 2.4).



Table 2.4 1H and 13C NMR Chemical Shifts (6) for
Characteristic Methylene Groups in
4,4'-Methylenebisanilines


Prod. SH(CH2) 6C(CH2) Prod. 6H(CH2) 6C(CH2)



2.9a 3.74 40.0 2.19c 3.77 39.8

2.9b 3.68 39.5 2.23a 3.78 39.8

2.9c 3.94 34.8 2.23b 3.75 39.7

2.9d 3.72 40.2 2.25a 3.67 39.3

2.9e 3.68 34.9 2.25b 3.79 39.7

2.19a 3.79 39.8 2.26a 3.78 40.0

2.19b 3.78 39.8 2.26b 3.75 40.0












2.3 Conclusions



Bis(4-aminoaryl)methanes are prepared by the reaction

of N-(benzotriazol-l-ylmethyl)arylamines with arylamine

hydrochlorides in moderate to good yields. Methylene-

bis(N,N-dialkylaniline)s are prepared by the reactions of

1-hydroxymethylbenzotriazole with N,N-dialkylanilines

under acidic conditions. The intermediates 4-(benzo-

triazol-l-ylmethyl)anilines and their N,N-dialkyl analogs

can be isolated and then used in reactions with different

types of anilines allowing for the efficient preparation

of both symmetrical and unsymmetrical methylenebis-

anilines.



2.4 Experimental



Melting points were determined on a Kofler hot-stage

microscope and are uncorrected. 1H NMR spectra were

obtained on a Varian VXR 300 (300 MHz) spectrometer with

tetramethylsilane as an internal standard. 13C NMR spectra

were obtained on a Varian VXR 300 (75 MHz) spectrometer,

referring to the central signal of CDC13 (77.0 ppm) or

DMSO-d6 (39.5 ppm), respectively. CDC13 was used as the

solvent for both 1H and 13C NMR spectra except where

stated otherwise. Elemental analyses were performed using










a Carlo Erba 1106 elemental analyzer at the University of

Florida, Department of Chemistry under the supervision of

Dr. D.H. Powell.

Column chromatography was carried out on Alumina

Basic (Brockman Activity I, 80-200 mesh, Fischer).

l-Hydroxymethylbenzotriazole (2.16) was prepared

according to the modified literature procedure, m.p. 149-

151 OC (lit. [52JA3868] m.p. 148-151 OC). The arylamine

hydrochlorides 2.11 were prepared by mixing the

corresponding arylamines and concentrated hydrochloric

acid. N-(Benzotriazol-l-ylmethyl)arylamines (2.10) were

prepared by the method of Katritzky et al. [87JCS(P1)799].

N-(Benzotriazol-l-ylmethyl)aniline (2.10a). M.p. 138-

139 OC (lit. [90CJC446] m.p. 138-139 OC).

2-Chloro-N-(benzotriazole-1-ylmethyl)aniline (2.10b).

Obtained as plates (recrystallized from methanol), m.p.

134-136 C. 1H NMR 6 6.31 (d, J 6.6 Hz, 2 H), 6.70 (t, J

- 7.0 Hz, 1 H), 7.18 (t, J = 8.0 Hz, 1 H), 7.26-7.63 (m, 5

H), 8.1-8.3 (m, 2 H); 13C NMR 6 56.6, 111.3, 112.2, 118.3,

118.6, 119.1, 124.0, 127.2, 127.8, 129.3, 132.2, 141.6,

145.5.

Anal. Calcd for C13H11NCN4: C, 60.35; H, 4.29; N,

21.66. Found: c, 60.75; H, 4.28; N, 21.97.

3-Chloro-N-(benzotriazol-l-ylmethyl)aniline (2.10c).

M.p. 174-176 C (lit. [90CJC446] m.p. 176 OC).








32

2-Methyl-N-(benzotriazol-l-ylmethyl)aniline (2.10d).

m.p. 146-147.5 OC (lit. [90CJC446] m.p. 146 C).

3-Methyl-N-(benzotriazol-l-ylmethyl)aniline (2.10e).

Obtained as needles (recrystallized from ethanol), m.p.

156-157 C. 1H NMR 6 2.15 (s, 3 H), 6.15 (d, J 7.5 Hz, 2

H), 6.43 (d, J = 7.5 Hz, 1 H), 6.70 (t, J 7.0 Hz, 2 H),

6.90 (t, J 7.0 Hz, 1 H), 7.25-7.55 (m, 3 H), 8.0-8.1 (m,

2 H); 13C NMR 6 21.2, 57.0, 109.9, 111.2, 113.6, 118.7,

119.0, 123.9, 127.0, 128.9, 132.2, 138.1, 145.5, 145.7.

Anal. Calcd for C14H14N4: C, 70.57; H, 5.92; N,

23.51. Found: C, 70.49; H, 5.89; N, 23.65.


2.4.1 General Procedure for the Preparation of Bis(4-
aminoaryl)methanes (2.9) using N-(Benzotriazol-1-
ylmethyl)arylamines


To a stirred solution of N-(benzotriazol-l-

ylmethyl)arylamine (2.10) (20 mmol) in methanol (30 ml)

was added a solution of the corresponding arylamine

hydrochloride (2.11) (40 mmol) dissolved in water (30 ml).

The resulting mixture was heated under reflux for 3 h,

hydrolyzed with aqueous potassium hydroxide (1 M; 50 ml)

and extracted with diethyl ether (3 x 100 ml). The organic

layer was dried (MgSO4), the solvent evaporated and the

excess arylamine distilled off under reduced pressure, the

residue purified as described for each individual

compound. Yields and melting points of 2.9a-e are given in

Table 2.1.








33

Bis(4-aminophenyl)methane (2.9a). Obtained as needles

(recrystallized from hexane/EtOAc). 1H NMR 6 3.50 (broad,

4 H, -NH2), 3.74 (s, 2 H, -CH2-), 6.56 (d, J = 8.0 Hz, 4

H), 6.92 (d, J 8.0 Hz, 4 H); 13C NMR 6 40.0 (-CH2-),

115.1, 129.5, 131.8, 144.2.


Reaction of 2.10b with 2-chloroaniline hydrochloride

(2.11b). The crude product was chromatographed from

hexane/EtOAc, 2:1, v/v, to give bis(4-amino-3-

chlorophenyl)methane (2.9b) (44%) as needles and

4-(benzotriazol-1-ylmethyl)-2-chloroaniline (2.22b) (26%)

as microcrystals.


Bis(4-amino-3-chlorophenyl)methane (2.9b). 1H NMR 6

3.68 (s, 2 H, -CH2-), 3.91 (broad, 4 H, -NH2), 6.63-6.66

(m, 2 H), 6.81-6.84 (m, 2 H), 7.01-7.02 (m, 2 H); 13C NMR

6 39.5 (-CH2-), 115.9, 119.2, 128.0, 129.4, 132.1, 141.0.


4-(Benzotriazol-l-ylmethyl)-2-chloroaniline (2.22b).

M.p. 106-1090C. 1H NMR 6 4.15 (broad, 2 H, -NH2), 5.66 (s,

2 H, -CH2-), 6.66 (d, J = 8 Hz, 1 H), 6.96-6.97 (m, 1 H),

7.21-7.39 (m, 4 H), 8.01-8.05 (m, 1 H); 13C NMR 6 51.4 (-

CH2-), 109.7, 115.8, 119.1, 119.9, 123.8, 124.9, 127.2,

127.3, 128.8, 132.5, 143.1, 146.2.

Anal. Calcd for C13H11C1N4: C, 60.35; H, 4.29; N,

21.66. Found: C, 60.65; H, 4.30; N, 21.41.








34

Reaction of 2.10c with 3-chloroaniline hydrochloride

(2.11c). The crude product was chromatographed from

hexane/EtOAc, 2:1, v/v, to give bis(4-amino-2-

chlorophenyl)methane (2.9c) (32%) as microcrystals and

4-(benzotriazol-l-ylmethyl)-3-chloroaniline (2.22c) (7%)

as needles.



Bis(4-amino-2-chlorophenyl)methane (2.9c). 1H NMR 6

3.62 (broad, 4 H, -NH2), 3.94 (s, 2 H, -CH2-), 6.44-6.48

(m, 2 H), 6.70 (d, J = 2.0 Hz, 2 H), 6.78 (d, J = 8.0 Hz,

2 H); 13C NMR 6 34.8 (-CH2-), 113.7, 115.6, 127.3, 131.1,

134.5, 145.7.


4-(Benzotriazol-l-yl)-3-chloroaniline (2.22c). M.p.

136-1380C. 1H NMR 6 3.82 (broad, 2 H, -NH2), 5.85 (s, 2 H,

-CH2-), 6.46 (dd, J = 8.0, 2.0 Hz, 1 H), 6.71 (d, J 2.0

Hz, 1 H), 6.93 (d, J = 8.0 Hz, 1 H), 7.26-7.46 (m, 3 H),

8.02-8.07 (m, 1 H); 13C NMR 6 49.0 (-CH2-), 109.9, 113.9,

115.3, 119.9, 121.5, 123.8, 127.3, 130.9, 133.9, 146.2,

147.8.

Anal. Calcd. for C13H11C1N4: C, 60.35; H, 4.29; N,

21.66; Found: C, 60.04; H, 4.29; N, 21.56.


Bis(4-amino-3-methylphenyl)methane (2.9d). Obtained

as plates (recrystallized from hexane/EtOAc). 1H NMR 6

2.10 (s, 6H, -CH3), 3.46 (broad, 4 H, -NH2), 3.68 (s, 2 H,








35

-CH2-), 6.56 (d, J = 8.0 Hz, 2 H), 6.82-6.85 (m, 4H); 13C

NMR 6 17.3 (-CH3), 40.2 (-CH2-), 115.0, 122.4, 127.1,

130.8, 132.1, 142.4.


Bis(4-amino-2-methylphenyl)methane (2.9e). Obtained

as microcrystals (column chromatography from hexane/EtOAc,

2:1, v/v). 1H NMR 6 2.15 (s, 6H, -CH3), 3.49 (broad, 4 H,

-NH2), 3.68 (s, 2 H, -CH2-), 6.41-6.43 (m, 2 H), 6.51 (d,

J 2.0 Hz, 2 H), 6.66 (d, J 8.0 Hz, 2 H); 13C NMR 8

19.5 (-CH3), 34.9 (-CH2-), 112.6, 117.0, 129.0, 129.8,

137.3, 144.3.


Procedure for the Rearrangement of N-(Benzotriazol-l-

ylmethyl)aniline (2.10a). To a stirred solution of

N-(benzotriazol-l-ylmethyl)aniline (2.10a) (1.12 g, 5

mmol) in methanol (30 ml) under reflux was added dilute

hydrochloric acid (3%; 30 ml). The resulting mixture was

heated under reflux for 4 h and then hydrolyzed with

aqueous potassium hydroxide (1 M; 50 ml). The product was

extracted with diethyl ether (3 x 60 ml) and the organic

extracts dried (MgSO4). Evaporation of the solvent

followed by recrystallization from toluene gave

4-(benzotriazol-l-ylmethyl)aniline (2.22a) (0.52 g, 59%)

as needles, m.p. 144-146 C. 1H NMR (DMSO-d6) 8 5.20

(broad, 2 H, -NH2), 5.75 (s, 2 H, -CH2-), 6.50 (d, J 8.0

Hz, 2 H), 7.10 (d, J = 8.0 Hz, 2 H), 7.37 (t, J 7.0 Hz,








36

1 H), 7.50 (t, J 8.0 Hz, 1 H), 7.80 (d, J = 8.0, 1 H),

8.04 (d, J 8.0 Hz, 1 H); 13C NMR (DMSO-d6) 6 51.2 (-CH2-

), 110.9, 113.8, 119.1, 122.3, 123.8, 127.1, 129.1, 132.4,

145.4, 148.7.

Anal. Calcd for C13H12N4: C, 69.62; H, 5.39; N,

24.98; Found: C, 69.68; H, 5.50; N, 24.91.


2.4.2 General Procedure for the Preparation of
4-(Benzotriazol-1-ylmethyl)anilines


Method (A). A mixture of N,N-dialkylaniline or

aniline hydrochloride (0.0385 mol) and 1-hydroxymethyl-

benzotriazole (5.74 g, 0.0385 mol) in acetic acid (25 ml)

was heated under reflux for 5 min and then poured into

ice-water (200 ml). The resulting solution was rendered

basic with aqueous sodium hydroxide (50%; 10 ml),

extracted with diethyl ether (3 x 100 ml) and the ethereal

solution dried (MgSO4). Evaporation of the solvent

afforded products which were purified as described for

each individual compound.

Method (B). A mixture of N,N-dimethylaniline (6.06 g,

0.05 mol) and concentrated hydrochloric acid (4.3 ml, 0.05

mol) was heated under reflux for 1 h. A solution of

1-hydroxymethylbenzotriazole (7.46 g, 0.05 mol) in

propanol (25 ml) was then added, the mixture heated under

reflux for 7.5 h and then stirred at room temperature

overnight. The solvent was evaporated to give a sticky








37

oil, to which was added a sodium hydroxide solution (15%;

30 ml) and a small amount of diethyl ether. The white

precipitate obtained was collected and washed with a small

amount of diethyl ether to give pure 2.17a (5.75 g, 46%).

The residue was extracted with diethyl ether (3 x 50 ml)

and dried (MgS04). Evaporation of the solvent gave

4,4'-methylenebis(N,N-dimethylaniline) (2.23a) (1.90 g,

30%).



4-(Benzotriazol-l-ylmethyl)aniline (2.22a). The

precipitate obtained after rendering the solution basic

(by method (A)) was collected and recrystallized from

toluene to give 2.22a in 60% yield. It is identical in all

aspects with the sample prepared earlier.


Reaction of N,N-dimethylaniline with 1-hydroxymethyl-

benzotriazole. The crude product from the reaction by

method (A) was boiled with hexane. The insoluble solid was

filtered and recrystallized from methanol to give

4-(benzotriazol-l-ylmethyl)-N,N-dimethylaniline (2.17a)

(19%) as needles. Evaporation of hexane followed by

recrystallization from petroleum ether gave

4,4'-methylenebis(N,N-dimethylaniline) (2.23a) (80%) as

plates. A reaction by method (B) gave 46% of 2.17a along

with 30% of 2.23a.








38

4-(Benzotriazol-l-ylmethyl)-N,N-dimethylaniline

(2.17a). M.p. 167-168.5 C. 1H NMR 6 2.92 (s, 6 H, N-CH3),

5.74 (s, 2 H, -CH2-), 6.62 (d, J = 8.8 Hz, 2 H), 7.16-7.35

(m, 5 H), 8.00 (d, J 8.0 Hz, 1 H); 13C NMR 6 40.2 (N-

CH3), 52.0 (-CH2-), 110.0, 112.7, 119.7, 121.8, 123.6,

126.9, 128.8, 132.5,'146.2, 150.3.

Anal. Calcd for C15H16N4: C, 71.40; H, 6.39; N,

22.20. Found: C, 71.34; H, 6.44; N, 22.18.


4,4'-Methylenebis(N,N-dimethylaniline) (2.23a). 1H

NMR 6 2.90 (s, 12 H, N-CH3), 3.80 (s, 2 H, -CH2-), 6.68

(d, J = 8.0 Hz, 4 H), 7.05 (d, J = 8.0 Hz, 4 H); 13C NMR 6

39.8 (-CH2-), 40.8 (N-CH3), 112.9, 129.3, 130.2, 146.9.


Reaction of N,N-diethylaniline with 1-hydroxymethyl-

benzotriazole. The precipitate after rendering the

reaction solution basic (by method (A)) was collected and

recrystallized from hexane/benzene to give

4-(benzotriazol-1-ylmethyl)-N,N-diethylaniline (2.17b)

(14%) as prisms. The solution was extracted with diethyl

ether (3 x 100 ml) and the ethereal solution dried

(MgSO4). Evaporation of the solvent gave an oil, which
upon stay for several days crystallized to give

4,4'-methylenebis(N,N-diethylaniline) (2.23b) (52%) as

plates.








39
4-(Benzotriazol-1-ylmethyl)-N,N-diethylaniline

(2.17b). M.p. 104-106 OC. 1H NMR 6 1.11 (t, J = 7.0 Hz, 6

H, NCH2-CH3), 3.28 (q, J = 7.0 Hz, 4 H, N-CH2CH3), 5.70

(s, 2 H, -CH2-), 6.60 (d, J 8.8 Hz, 2 H), 7.16 (d, J =

8.8 Hz, 2 H), 7.29-7.40 (m, 3 H), 8.02 (d, J = 8.0 Hz, 1

H); 13C NMR 6 12.4 (NCH2-CH3), 44.2 (N-CH2CH3), 52.2 (-

CH2-), 110.1, 111.5, 119.7, 120.6, 123.7, 127.0, 129.1,

132.6, 146.1, 147.7.

Anal. Calcd for C17H20N4: C, 72.83; H, 7.19; N,

19.98. Found: C, 72.84; H, 7.24; N, 20.19.



4,4'-Methylenebis(N,N-diethylaniline) (2.23b). 1H NMR

6 1.10 (t, J 7.0 Hz, 12 H, NCH2-CH3), 3.27 (q, J 7.0

Hz, 8 H, N-CH2CH3), 3.76 (s, 2 H, -CH2-), 6.60 (d, J = 8.7

Hz, 4 H), 7.00(d, J = 8.7 Hz, 4 H); 13C 6 12.5 (NCH2-CH3),

39.7 (-CH2-), 44.3 (N-CH2CH3), 112.1, 129.1, 129.5, 146.0.


2.4.3 General Procedure for the Displacement of
Benzotriazole by Anilines


Method (A). To a stirred solution of 4-(benzotriazol-

l-ylmethyl)-N,N-dialkylanilines (2.17) (or with alkyl = H;

2.22) (5 mmol) in methanol (30 ml) under reflux was added

a mixture of the appropriate aniline (10 mmol) and dilute

hydrochloric acid (10%; 30 ml). The resulting mixture was

then heated under reflux for 3 days, hydrolyzed with

aqueous potassium hydroxide (1 M; 50 ml) and extracted








40

with diethyl ether (3 x 100 ml). The organic layer was

dried (MgSO4) and the solvent evaporated, the residue

purified as described for each individual compound.

Method (B). A mixture of N,N-dialkylaniline (0.01

mol) and 4-(benzotriazol-l-ylmethyl)-N,N-dialkylaniline

(2.17) (0.01 mol) in acetic acid (25 ml) was heated under

reflux for the appropriate time (see Table 2.3), then

poured into ice-water (50 ml). The resulting solution was

rendered basic with aqueous sodium hydroxide (50%; 40 ml),

extracted with diethyl ether (3 x 60 ml) and the ethereal

solution dried (MgS04). The solvent was evaporated to give

the essentially pure product.

Method (C). A mixture of N,N-dialkylaniline (0.081

mol) and l-hydroxymethylbenzotriazole (5.74 g, 0.0385 mol)

in acetic acid (25 ml) was heated under reflux for 3 h and

then poured into ice-water (60 ml). The resulting solution

was rendered basic with aqueous sodium hydroxide (50%; 40

ml), extracted with diethyl ether (3 x 60 ml) and the

ethereal solution dried (MgSO4). The solvent was

evaporated to give the essentially pure product.

Physical data of the products, yields, and methods of

the preparation are given in Table 2.3.


Bis(4-aminophenyl)methane (2.9a). Obtained by method

(A) from 2.22a and aniline hydrochloride (column

chromatography from hexane/EtOAc, 2:1, v/v). It is

identical in all aspects with the sample prepared earlier.








41

4,4'-Methylenebis(N,N,N'-trimethyl-N'-ethylaniline)

(2.19a). Obtained by method (B) from N-methyl-N-

ethylaniline and 2.17a as an oil. 1H NMR 6 1.06 (t, J -

7.0 Hz, 3 H, NCH2-CH3), 2.82 (s, 3 H, CH3CH2N-CH3), 2.85

(s, 6 H, N(CH3)2), 3.31 (q, J = 7.0 Hz, 2 H, N-CH2CH3),

3.78 (s, 2 H, -CH2-), 6.63-6.69 (m, 4 H), 7.02-7.07 (m, 4

H); 13C NMR 6 11.1 (NCH2-CH3), 37.5 (CH3-NCH2CH3), 39.8 (-

CH2-), 40.8 (N(CH3)2), 46.9 (N-CH2CH3), 112.6, 112.9,

129.3, 129.4, 129.6, 130.3, 147.3, 148.9.

Anal. Calcd for C18H24N2: C, 80.55; H, 9.01. Found:

C, 80.53; H, 9.04.


4,4'-Methylenebis(N,N-dimethyl-N',N'-diethylaniline)

(2.19b). Obtained by method (B) from 2.17a and

N,N-diethylaniline, or from 2.17b and N,N-dimethylaniline,

as an oil. 1H NMR 6 1.10 (t, J = 7.0 Hz, 6 H, NCH2CH3),

2.85 (s, 6 H, N-CH3), 3.26 (q, J = 7.0 Hz, 4 H, N-CH2CH3),

3.78 (s, 2 H, -CH2-), 6.63-6.69 (m, 4 H), 7.02-7.07 (m, 4

H); 13C NMR 6 12.5 (N-CH2CH3), 39.8 (-CH2-), 40.8 (N-CH3),

44.3 (N-CH2CH3), 112.1, 112.9, 128.9, 129.3, 129.4, 130.3,

146.0, 149.0.

Anal. Calcd for C19H26N2: C, 80.80; H, 9.28. Found:

C, 80.58; H, 9.26.


4,4'-Methylenebis(N,N,N'-triethyl-N'-methylaniline)

(2.19c). Obtained by method (B) from N-methyl-N-








42

ethylaniline and 2.17b as an oil. 1H NMR 8 1.05-1.13 (m, 9

H, N(CH2CH3)2 + CH3NCH3-CH3), 2.83 (s, 3 H, CH3-NCH2CH3),

3.27-3.31 (m, 6 H, CH3NCH2CH3 + N(CH2CH3)2), 3.78 (s, 2 H,

-CH2-), 6.59-6.65 (m, 4 H), 7.00-7.03 (m, 4 H); 13C NMR 6

11.1 (CH3NCH2-CH3), 12.5 (N(CH2CH3)2), 37.5 (-CH2-), 39.8

(CH3-NCH2CH3), 44.4 (CH3N-CH2CH3), 47.0 (N(CH2CH3)2),

112.2, 112.3, 112.7, 129.1, 129.4, 129.8, 146.0, 147.4.

Anal. Calcd for C20H28N2: C, 81.03; H, 9.52. Found:

C, 81.07; H, 9.52.


4,4'-Methylenebis(N,N-dimethylaniline) (2.23a).

Obtained by method (B) from N,N-dimethylaniline and 2.17a,

or by method (C) from N,N-dimethylaniline and 2.16. It is

identical in all aspects with the sample prepared earlier.


4,4'-Methylenebis(N,N-diethylaniline) (2.23b).

Obtained by method (B) from N,N-diethylaniline and 2.17b,

or by method (C) from N,N-diethylaniline and 2.16. It is

identical in all aspects with the sample prepared earlier.


4-(4-Aminobenzyl)-2-methylaniline (2.25a). Obtained

by method (A) from 2-methylaniline hydrochloride and 2.22a

as plates (column chromatography from hexane/EtOAc, 1:1,

v/v). 1H NMR 6 2.08 (s, 3 H, -CH3), 3.67 (s, 2 H, -CH2-),

3.86 (broad, 4 H, -NH2), 6.5-6.6 (m, 3 H), 6.7-6.8 (m, 4

H); 13C NMR 6 16.5 (-CH3), 39.3 (-CH2-), 113.9, 114.0,

121.0, 126.0, 128.4, 129.7, 130.3, 130.4, 142.1, 144.1.








43

4-(4-Aminobenzyl)-2-chloroaniline (2.25b). Obtained

by method (A) from 2-chloroaniline hydrochloride and 2.22a

as microcrystals (column chromatography from hexane/EtOAc,

2:1, v/v). 1H NMR 6 3.50 (broad, 2 H, -NH2), 3.70 (s, 2 H,

-CH2-), 3.90 (broad, 2 H, -NH2), 6.5-6.6 (m, 3 H), 6.83

(dd, J 8.0, 2.0 Hz, 1 H), 6.90-6.93 (m, 2 H), 7.02 (d, J

= 2.0 Hz, 1 H); 13C NMR 6 39.7 (-CH2-), 115.2, 115.8,

119.1, 127.9, 129.3, 129.5, 131.0, 132.8, 140.7, 144.4.

Anal. Calcd for C13H13C1N2: C, 67.10; H, 5.63; N,

12.04. Found: C, 67.17; H, 5.66; N, 12.03.



4-(4-Aminobenzyl)-N,N-dimethylaniline (2.26a).

Obtained by method (A) from aniline hydrochloride and

2.17a (column chromatography from hexane/EtOAc, 1:1, v/v),

or by method (A) from 2.22a and N,N-dimethylaniline

(recrystallized from hexane) as microcrystals. 1H NMR 6

2.88 (s, 6 H, N-CH3), 3.50 (broad, 2 H, -NH2), 3.77 (s, 2

H, -CH2-), 6.57 (d, J 8.0 Hz, 2 H), 6.66 (d, J 8.0 Hz,

2 H), 6.94(d, J 8.0 Hz, 2 H), 7.02 (d, J = 8.0 Hz, 2 H);

13C NMR 6 40.0 (-CH2-), 40.8 (N-CH3), 112.9, 115.2, 129.3,

129.5, 130.0, 132.0, 144.2, 149.0.



4-(4-Aminobenzyl)-N-methylaniline (2.26b). Obtained

by method (A) from 2.22a and N-methylaniline as

microcrystals (column chromatography from hexane/EtOAc,

1:2, v/v). 1H NMR 6 2.74 (s, 3 H, N-CH3), 3.45 (broad, 3








44

H, -NH2 + CH3-NH), 3.75 (s, 2 H, -CH2-), 6.4-6.6 (m, 4 H),

6.9-7.0 (m, 4 H); 13C NMR 6 30.8 (N-CH3), 40.0 (-CH2-),

112.4, 115.1, 129.37, 129.43, 130.5, 132.0, 144.1, 147.4.

Anal. Calcd for C14H16N2: C, 79.21; H, 7.60; N,

13.20. Found: C, 78.83; H, 7.61; N, 13.15.















CHAPTER III
BENZOTRIAZOLE AS A SYNTHETIC AUXILIARY:
ALTERNATIVE SYNTHESIS OF LEUCO DYESTUFFS



3.1 Introduction


3.1.1 Leuco Dyes


A "leuco dye" is generally defined as a compound

which yields a dye on oxidation. Di- and tri-arylmethanes

containing electron-donating substituents such as amino

groups and the hydroxy group (as well as its conjugate

base) in the ortho or para positions are leuco dyes.

Hydride abstraction by oxidizing agents gives colored

cations. Some of the common dyes of this type are

Michler's hydrol (3.1), Crystal Violet (3.2) and Malachite

Green (3.3). Lead dioxide has been the traditional

oxidizing agent. However, the search for lead-free

processes has given rise to the use of other oxidizing

agents such as chloranil, or air in the presence of

catalytic amounts of cobalt or iron chelates. The general

method of synthesis of these leuco bases involves the

treatment of a one carbon electrophilic reagent

(formaldehyde, chloroform, etc) with arene nucleophiles

(usually substituted by electron donors such as NR2, NHR,

NH2, OH) via an SE2 mechanism [87MI5]. Scheme 3.1








46

illustrates in general the typical methods for the
preparation of this type of leuco base by demonstrating
three different pathways for the synthesis of Crystal
Violet [87MI5].


NMe2


+
Me2N NMe2


C
1


3.1b


Michler's hydrol


Me2N


NMe2


Crystal Violet


Malachite Green


Figure 3.1 Triarylmethane Dyes


Me2N


a


3.1a


Me2N












Route I


CI
O=C
Cl
I + HAr


Route II


H2C=O

S+ HAr


H2C
OH


Ar
0=c0
O=Cl
CI


I +HAr


O-=C
Ar


Michler's ketone



I +H


+ HAr

Ar
H21C
Ar
Leuco base of
Michler's hydrol


[o] /

+,Ar
HC
Ar
Michler's hydrol 3.1
+ HAr

HCAr3
Leuco base of
Crystal Violet

[o]


+,Ar
HO-C


+ HAr


CAr3


Route III


ArCHO


+ HAr

Ar
HO-HC


+ H+


HO-CAr3


Crystal Violet 3.2


H-Ar = H NMeg

[o] = oxidation


Carbinol base


ArCHO = OHC NMe2


Scheme 3.1










A large number of vinylogous di- and tri-arylmethane

dyes including a few heteroaromatic analogs have been

described in the literature [52MI1, 76JOC870, 81MI1].

Among the hetarylmethane derivatives, Naef [81MI1] has

synthesized trihetaryl dyes in yields of 20-85% by

treatment of unsymmetrical dihetaryl ketones with

1,2-dimethylindole in the presence of phosphorus

oxychloride. However, the cationic dyes were directly

formed without isolation of the leuco bases. Other hetaryl

dyes that have been prepared are diindolylpyridylmethanes

[76JOC870] which afford colored compounds upon proton

abstraction and hence cannot be considered as leuco dyes.



3.1.2 Overview on the Formation of x-Heterocarbanions and
Activation of a-Methylene Groups by a Heterocyclic
Moiety


Metalation reactions have long been known and have

been reviewed by Gilman and Morton [540R2581 and more

recently by Gschwend and Rodriguez [790R1]. The term

"metalation" in general and "lithiation" in particular,

represents proton abstraction by a metal or lithium.

Research efforts in this area have been dedicated to the

search for new functional groups that promote lithiation,

elaboration of novel heterocyclic and olefinic substrates

as metalable species, recognition of new types of

lithiating agents, and to the investigation of the

mechanism of metalation.








49

Many lithiating reagents have been developed over the

years and can be divided into two types. The first type,

lithium alkyls and lithium aryls, are oligomers of varying

complexity in solution [53JA3278, 62JOC1667, 64JA2076,

65MI2, 70JA4664, 73JOM1, 74JOM327, 76JOC3653]. The

electron-deficient lithium can coordinate with the solvent

to form aggregates. Kinetically, these reagents become

more basic as the aggregate size diminishes. The second

type includes butyllithium/amine complexes and lithium

dialkylamides. It has been found [59CB192, 60AG91] that

lithium dialkylamides are generally more effective

metalating agents than the thermodynamically more basic

lithium alkyls and lithium aryls. This is explained by the

increased kinetic basicity due to the availability of a

free electron pair permitting the formation of a four-

membered transition state (Scheme 3.2).




X
H X
Li-Li + H-N



Scheme 3.2




Lithiation on a carbon adjacent to a heteroatom has

become an increasingly important tool in synthetic








50

chemistry [69CRV693, 70MI1, 73MI1, 74MI1, 74MI2]. The

presence of a heteroatom has both stabilization and

destabilization effects on an a-carbanion. Formation of

the negative charge is disfavored in cases where the

adjacent heteroatom carries an electron pair (nitrogen or

oxygen). Such atoms destabilize the carbanionic center. On

the other hand, the inductive and resonance effects

greatly increase the acidity of the adjacent carbon-

hydrogen bond, thus making alpha lithiations facile

[66JA943, 72ACR102, 75JA2209, 76JA5435, 76JA7498,

77JA5633, 78JA1604].

Much work has been done concerning activation of the

methylene protons alpha to a nitrogen incorporated in a

five-membered heterocyclic ring such as an N-alkylpyrazole

[83T2023, 83T4133]. Metalation of N-alkyl heterocycles

usually results in the replacement of a ring proton,

although in some cases mixtures are obtained [53JA375,

71CJC2139, 72JOC215, 73CB2815, 76JOC163, 83T2023,

87JCS(P1)775]. Therefore in order to provide better

regioselectivity at the a-C, other carbanion stabilizing

substituents must be introduced. An aryl substituent has

been used successfully to facilitate lithiation in

N-benzylpyrazole (3.4) [83T2023], in N-benzyl-3,4,5-

triphenyl-1,3-dihydroimidazol-2-one (3.5) [82JCR(S)26], in

N-benzylimidazole (3.6) [74JOC1374, 84JCS(P1)481], and in

N-arylmethylimidazoles [85S302]. Other activating groups

include a second nitrogen-linked heterocyclic ring as seen








51

in methylenebispyrazoles (3.7) [83T4133], and in

p-(bisbenzotriazol-l-ylmethyl)toluene (3.8)

[87JCS(Pl)819]; sulfur moieties such as phenylthio in

l-(phenylthiomethyl)benzimidazole (3.9) [87JCS(P1)775], in

9-(phenylthiomethyl)carbazole (3.10) (85JOC1351], and in

l-(phenylthiomethyl)benzotriazole (3.11) [87JCS(P1)781].


,Ph
N


Ph- .


0N

ph--

3.6


N

N
N

3.7


C7N

PhS >

3.9


Bt
Bt

3.8


PhS "

3.10


PhS


3.11


Bt = benzotriazol-1-yl


Figure 3.2 Activation and Lithiation of c-Heterocyclic Compounds










3.1.3 Aim of the work

In Chapter II, we have shown that aniline and

N,N-dialkylanilines are readily alkylated by 1-hydroxy-

methylbenzotriazole to give 4-(benzotriazol-l-ylmethyl)-

anilines (3.12). Subsequent displacements of the

benzotriazole group by arylamines or N,N-dialkylanilines

give either symmetrical or unsymmetrical 4,4'-methylene-

bis(N,N,N',N'-tetraalkylanilines) (3.13).


R5 R6

R2N CH2Bt R1R2N CH2 NR3R4

3.12a R=H
3.12b R=Me 3.13
3.12c R=Et

Figure 3.3 4-(Benzotriazol-1-ylmethyl)anilines and
4,4'-Methylenebisanilines



Compounds of type 3.13 have found numerous

applications in industry. They are used as curing agents

for epoxy resins and urethane elastomers, as intermediates

in the preparation of polyurethanes, in the synthesis of

polyamides and in the production of dyes and recording

materials (For references, see section 2.1.1 in Chapter

II). Modification of the molecule, such as by inter-

changing an aryl ring with a heterocyclic ring, or by

introducing a functional group onto the methylene carbon,








53

should diversify the properties of these materials and

perhaps widen their synthetic applications.

N-Benzylbenzotriazole has been shown to undergo

lithiation at the benzylic carbon atom (90MI1]. Although

N,N-dimethylaniline and 4,4'-methylenebis(N,N-dimethyl-

aniline) both undergo ortho- metalation (due to chelation

effects) [66JOC2047, 79JOC237], it was anticipated that

the electron withdrawing nature of the benzotriazolyl

moiety could direct the lithiation towards the benzylic

position in derivatives of type 3.12. The benzotriazole

group could then be displaced by nucleophiles.

The objective of the project was to investigate the

displacement of benzotriazole by potential nucleophiles,

other than anilines, thus preparing methylene derivatives

with two different aromatic substituents. On the other

hand, introduction of functional groups into the

benzotriazole derivatives via lithiation with subsequent

displacement of the benzotriazole group would afford

methine derivatives with three different substituents.


3.2 Results and Discussion



3.2.1 Lithiation of 4-(Benzotriazol-l-ylmethyl)-N,N-
dialkylanilines


4-(Benzotriazol-l-ylmethyl)-N,N-dimethylaniline

(3.12b) underwent lithiation smoothly with n-butyllithium








54

in tetrahydrofuran at -78 OC to form a deep blue colored

solution. When the anion was quenched with deuterium

oxide, the 1H NMR spectrum of the isolated compound

displayed the methylene proton, with a chemical shift

similar to that of the starting material 3.12b, but with

its integration corresponding to one proton. This

indicated that the lithiation occurred exclusively at the

relatively acidic benzylic methylene carbon. The chelation

effect of the dimethylamino group [66JOC2047, 79JOC237]

diminished due to the large acidity difference between the

benzene ring proton and the methylene proton alpha to the

strongly electron-withdrawing benzotriazolyl group.

The corresponding anion 3.14 also decolorized

immediately on addition of one equivalent of an

electrophile indicating high reactivity of the anion.

Reaction of the anion 3.14 with electrophiles such as

methyl iodide, benzyl bromide, aldehydes and ketones

afforded the desired products 3.16 in high yields (Scheme

3.3, Table 3.1). With aldehydes, generally two diastereo-

meric isomers were obtained. In particular, when

p-tolualdehyde was used, the diastereomers, obtained in a

ratio of 2.5:1, were isolated by repeated

recrystallization of the crude product from methanol,

followed by column chromatography. With pyridine-4-

carboxaldehyde, the two isomers, obtained in equal

amounts, were similarly isolated. With esters as








55

electrophiles, the yields were low, possibly due to

further attacks of the lithio salt 3.14 on the products

yielding enolate anions. The reaction mixtures in these

cases turned dark upon warming to room temperature. Work-

up at -78 OC did not alter the outcome. With ethyl

isonicotinate, a complex mixture was obtained which was

not characterized. Treatment of the anion 3.14 with iodine

gave 1,2-bis(4-N,N-dimethylaminophenyl)-1,2-bis(benzo-

triazol-1-yl)ethane (3.15). Reactions of the lithio

derivative of 4-(benzotriazol-l-ylmethyl)-N,N-diethyl-

aniline 3.12c with methyl iodide and cyclohexanone

afforded the corresponding products 3.16i-j indicating

again that lithiation occurred completely at the

relatively acidic benzylic methylene carbon.



NMe2 NMe2



NR2 NR2 For R =Me
NRt NRBt

n- BuLi Bt 3.15


NR2
Bt Bt Li NR2

3.12 3.14


Bt E

3.16


Scheme 3.3






























0 0
- 4 r-4 r-4 r '- -4 r- I








O O













u U
r- r-









mm -









,. I I .0
o o U o U n
00


\o4
* a
MM


%O%
'.4,4
S Sr
mm


r- oC e'
, -4 I O-
I I I I

om H0 o
oI -I ,-


to o
U U

101O











-~ I I
a




00 0
0 1m m
11 uu




in U U- *-



I 1>1 >1
13 04o< o


fn fn c


4J 0 0
a o


m 0 *c II 0
w U 0C C 0
O 0 U O i u .4 --4 in
c M LI m a a m
i a a M U Nr M -M C H M
csO MU U U N- W U -I m
4 M 4 1 1 U > > u
a u14 &04 4 C4 4 a C4 4 U





( S ( < N U N S N S S S (N N

M MM M M M MM


(N

u -
U,


*re
M-


0
U)





0

-4 0



S1-W
0







0 0- 0




0 0






0- 0-Ic 01

M 1-1 E-4 M
I ,, Uo't








57

The structures of the products 3.15 and 3.16 were

confirmed by their NMR spectra and elemental analyses. The

methine carbons were observed at 58.7-70.4 ppm (the

corresponding carbon for 3.16a was observed as a triplet

centered at 51.8 ppm). The methine protons usually

resonated between 5.50-5.98 ppm except for compounds 3.16g

and 3.15. The carbonyl group shifted the methine proton in

3.16g downfield to 7.78 ppm. The corresponding methine

proton in 3.15 was observed as a singlet at 7.67 ppm as

evidenced by 2-D NMR spectra (COSY and HETCOR).


Table 3.2


1H and 13C NMR
Methine Groups


Chemical Shifts (6) for the
in 3.15 and 3.16


Compoud Substituent SH(R3CH) &C(R3CH)


3.15a 7.67 63.3
3.16a D 5.70 51.8
3.16b Me 5.98 58.7
3.16c PhCH2 5.90 64.9
3.16d p-CH3C6H4CH(OH) 5.72 70.0
3.16d p-CH3C6H4CH(OH) 5.65 68.8
3.16e Ph2C(OH) 5.83 68.2
3.16f (CH2)5C(OH) 5.50 70.4
3.16g p-CH3C6H4C(=O) 7.78 68.3
3.16h Pyridine-4-CH(OH) 5.61 69.8
3.16h Pyridine-4-CH(OH) 5.63 68.3
3.16i Me 5.96 58.7
3.16j (CH2)5C(OH) 5.50 70.4

a For structure of compound 3.15, see Scheme 3.3.








58

3.2.2 Displacement of the Benzotriazolyl Moiety by
Electron-rich Aromatic Compounds


The benzotriazolyl moiety in compounds 3.12a-c has

been displaced efficiently by a series of aromatic

systems, including 1,3-dimethoxybenzene, 1,3,5-trimethoxy-

benzene, indoles, pyrroles, and 2-naphthol under reaction

conditions similar to those for the synthesis of

bisanilines (see section 2.4.3 in Chapter II). Thus,

heating a mixture of 3.12 and the appropriate aromatic

compound, in a 50% aqueous methanolic solution in the

presence of concentrated hydrochloric acid, gave the

desired products 3.17-3.21 in good to excellent yields

(See Scheme 3.4 and Table 3.3). Except for 3.19 and 3.20b,

all these compounds are novel. Thus this method provides

an effective synthesis of compounds containing two

aromatic rings connected via a methylene bridge.

The 4-(N,N-dimethylanilino) analogs, 3.19 and 3.20b,

have been frequently reported in the literature. The

2-naphthol derivative 3.19 can be directly prepared by the

reaction of 2-naphthol, paraformaldehyde and N,N-dimethyl-

aniline in the presence of piperidine [45USP2375168]. With

aqueous formaldehyde and acetic acid in the presence of a

catalytic amounts of N-methylaniline, 3.19 was obtained in

90% yield (Scheme 3.5). The indole derivative 3.20b has

been prepared by initial treatment of the salt 3.24 with

phenylhydrazine to afford 3.25, which by treatment with












OMe




X
MeO -0 -a NR2



3.17 X=H
3.18 X= OMe

3.17, 3.18 R1
a H (
b Me
c Et


HO


Me2N CH2




3.19


1
NR2


3.20
a H-
b M
c E
d H
e M
f E


S(c)
20

R1 R2

S H
e H
.t H
e Me (e)
e Me
t Me


NMe2





CH2CH(COPh)2


1
NR2





CH2Bt

3.12


(d)


3.21


3.21 R1 R2
a H H
b Me H
c Et H
d Me Me


NMe2





CH2CH2COR


3.22 3.23a R=Ph
3.23b R=Me

(a) 1,3-Di- or 1,3,5-Trimethoxybenzene. (b) 2-Naphthol. (c) Indole or N-Methylindole.
(d) Pyrrole or N-Methylpyrrole. (e) (PhCO)2CH2, ZnBr2 (anhydrous). (f) (RCO)2CH2,
MeOH/H20/HCI.


Scheme 3.4


R2 3.










Table 3.3 Reaction of 4-(Benzotriazol-l-ylmethyl)anilines
with Nucleophiles.



Entry Reaction Yielda M.p. Purification
time (h) (%) (OC) solvent

3.17a 3 db 53 oil 1:2c
3.17b 3 d 50 oil 2:1c
3.17c 4 d 68 oil pet. etherc
3.18a 57 80 123-124 1:1c
3.18b 27 73 89-90 8:1c
3.18c 3 d 72 96-97 hexaned
3.19 7 d 64 141-143e aq. ethanold
3.20a 2 d 92 130-132 -f
3.20b 7 96 143-1459 -f
3.20c 3 d 95 134-136 -f
3.20d 3 d 85 75-76 2:1c
3.20e 20 98 oil -f
3.20f 44 82 oil 18:1c
3.21a 55 29 oil 2:lc
3.21b 21 52 oil 2:1c
3.21c 5 d 41 72-74 40:1c
3.21d 24 45 130-132 40:1c
3.22 27 25 131-133h 15:1i
3.23a 6 d 48 oilJ 40:lc
3.23b 6 d 36 44-46k 12:1c


a Isolated
b d days


yields.


c Column chromatography on alumina basic. The ratio
indicates petroleum ether (38-56 OC) to EtOAc, v/v.
Further purification for the analytically pure sample is
described for the particular compound in the
Experimental section.
d Recrystallization solvent.
e Lit. [34JCS1136] m.p. 143 *C.
f After cooling the reaction mixture, the precipitate was
collected as the essentially pure product.
g Lit. [67JOC3101] m.p. 141-144 OC.
h Lit. [34JCS1136] m.p. 132-133 OC.
1 Column chromatography on silica gel, the ratio indicates
petroleum ether (38-56 OC) to EtOAc, v/v.
J Lit. [56JA4950] m.p. 51 C.
k Lit. [63JMC153] m.p. 47-48 C.








61

N,N-dimethylaniline afforded 3.20b in 96% yield
[56CB1195]. These literature yields are comparable with
those obtained by our method, and some of the other

methylene compounds discussed in this Chapter could
probably also be made by the literature methods. However,
those methods are strictly restricted to compounds with
-CH2- linkages and no previous examples are known for a
-CHX- linkage. Thus, the preparation of such -CHX-
derivatives by our method, as will be described later,

makes it uniquely valuable.


OH


^OH PhNHMe (cat.) / \
+ HCHO + PhNMe2 H- -
AcOH, 0C

3.19 NMe2





\ p^ NMe3 -(a NNH2 (b) or
NH2
N MeS04- N Ph : N
H H H NMe2
3.24 3.25 3.20b

(a) PhNHNH2, NaOH, H20
(b) i) PhNMe2, EtOH/THF (1:1); ii) 5 N HCI; iii) 2 N NaOH


Scheme 3.5








62

Regiospecificity in the displacement reactions is

controlled both by the electron densities at different

positions and by steric hindrance. Electrophilic substitu-

tion at the C-3(0) position is characteristic of the

indole ring [79MI1, 85JOC5451]. Consequently, reaction of

3.12 with indoles gave derivatives 3.20. Pyrrole reacts

with electrophiles exclusively at the a-positions

[81TL4901, 84MI1, 85S353, 88H1855]. In our case, both the

2- and the 5-positions of pyrrole reacted to afford the

products 3.21. 1,3-Dimethoxybenzene reacts at the

4-position since the 2-position is more sterically

hindered. For 1,3,5-trimethoxybenzene, there is only one

kind of reactive site. 2-Naphthol has its highest electron

density at the 1-position, thus the 1-substituted product

3.19 was obtained.

The reaction of 3.12b with other nucleophiles was

also tested and it was shown to be reactive towards

1,3-dicarbonyl compounds. The product obtained was

dependent on the conditions employed. Thus, heating a

mixture of 3.12b with the appropriate 1,3-dicarbonyl

compound in 50% aqueous methanol containing concentrated

hydrochloric acid under reflux for several days, afforded

compounds of type 3.23, where one of the carbonyl groups

had been displaced. The properties of the compounds thus

obtained have been compared with those reported in the

literature and their structures were further confirmed by








63

their NMR spectra. When the reaction was carried out in an

aprotic solvent such as toluene using a Lewis acid

catalyst (zinc bromide), the product 3.22 was obtained in

25% yield by direct displacement of the benzotriazole.

The displacement of benzotriazole from the lithiated

derivatives 3.16 was also effected by various nucleo-

philes. Reaction of 3.16a with N,N-diethylaniline afforded

the desired product 3.26. The displacement of the benzo-

triazolyl moiety was also accomplished by indole, as

evidenced by the production of compounds 3.27a-f in

moderate to high yields (Scheme 3.6 and Table 3.4).





NMe2 Me
E = Me
PhNEt2

Me2N NEt2

Bt E
B 3.26
indole
3.16
3.27 E

E a Me
b PhCH2
c p CH3C6H4CH(OH)
Me2N N d (CH2)5C(OH)
H e Py-4-CH(OH)

3.27 f Ph2C(OH)


Scheme 3.6








64

In the instances where the electrophile contained a

phenyl ring, low yields were obtained. With the

benzophenone derivative (3.16e), the formation of 3.27f in

26% yield was accompanied by the formation of other

compounds of which three were isolated and characterized.

These arose from (i) the migration of the phenyl group to

give the ketone 3.28, (ii) the direct displacement of the

benzotriazolyl by methoxy group (from methanol) giving

3.29, and (iii) the dehydration of 3.27f to produce 3.30

(Scheme 3.7). This strengthens our belief that in such

reactions, the initial ionization generated the

benzotriazolyl anion and the relatively stable benzylic

cation which was then trapped by the various nucleophiles.


NMe2 NMe2 NMe2
H -=\ indole t
MeOH/H20
S HcI + o
HOHO +
Ph Bt Ph Ph
Ph N
h PHPh
Ph H
3.16e 3.27f 3.28


NMe2
NMe2



HO OMe Ph
Ph Ph "
Ph H
3.29 3.30


Scheme 3.7











Table 3.4 Reactions of Substituted Products 3.16
with N,N-Dialkylaniline and Indole



Substrate Compound Reaction Yielda M.p.

time (h) (%) (C)


3.16b 3.26 4b 67 oil
3.16b 3.27a 18 91c 152-154
3.16c 3.27b 40 82c 119-121
3.16d 3.27c 72 38d 170-172
3.16f 3.27d 18 86c 162-164
3.16h 3.27e 20 70c 183-185
3.16e 3.27f 18 26e 211-213
3.16e 3.28 18 5e 127-129
3.16e 3.29 18 9e 184-186
3.16e 3.30 18 10e 209-211



a Isolated yields.
b HOAc was used as the solvent.
c After cooling the reaction mixture, the precipitate
was collected as the essentially pure product.
d Chromatography on silica gel from petroleum ether (38-
56 oC)/EtOAc, 2:1, v/v.
e Chromatography on silica gel from petroleum ether (38-
56 oC)/EtOAc, 12:1, v/v, followed by recrystallization
from hexane/EtOAc.


The structures of the derivatives 3.17-3.21, 3.26-

3.27 were confirmed by their spectral data and elemental

analyses. The methylene protons appeared in the region of

3.73-4.33 ppm (and between 3.96-5.43 ppm for the methine

protons). The corresponding methylene carbon resonated in








66

the region of 27.0-34.1 ppm (35.8-51.3 ppm for the methine

carbon). The upfield shift of the methylene and the

methine signals, compared to those of the corresponding

benzotriazolyl adducts, indicated the loss of the

electron-withdrawing benzotriazolyl moiety.


Table 3.5


1H and 13C NMR Chemical Shifts (6) for the
Methylene or Methine Groups in 3.17-3.21, 3.26-
3.27


Comp. SH(CH2) 8C(CH2) Comp. 6H(CH2) SC(CH2)
or (CH) or (CH)


3.17a

3.17b

3.17c

3.18a

3.18b

3.18c

3.19

3.20a

3.20b

3.20c

3.20d

3.20e

3.20f


3.77

3.80

3.78

3.81

3.83

3.81

4.33

3.99

4.01

3.98

3.95

3.97

3.97


34.1

34.0

33.9

27.2

27.0

27.0

29.7

30.7

30.5

30.3

30.5

30.3

30.3


3.21a

3.21b

3.21c

3.21d





3.26

3.27a

3.27b

3.27c

3.27d

3.27e

3.27f


3.73

3.73

3.77

3.80





3.96

4.28

4.39

4.49

4.21

4.47

5.43


33.1

32.9

33.0

32.3





42.7

35.8

43.7

50.7

51.3

50.5

50.6








67

3.3 Conclusions



4-(Benzotriazol-l-ylmethyl)-N,N-dialkylanilines

undergo smooth lithiation at the methylene carbon and give

derivatives upon treatment of the anion with a variety of

electrophiles. Displacement of the benzotriazolyl moiety

in compounds 3.12 and their substituted products 3.16 lead

to a series of novel unsymmetrical methanes containing two

or three fragments. These compounds, containing an aniline

fragment, if oxidized, could find potential applications

as dyestuffs due to the extended conjugation.


3.4 Experimental



The apparatus and general procedures applied in this

Chapter are identical to those described in Chapter II

with the following additions.

Tetrahydrofuran (THF) was distilled from

sodium/benzophenone immediately prior to use. Electro-

philes were purified by standard methods before use.

Lithiation reactions were performed in oven-dried

glassware under a nitrogen atmosphere. Column chromato-

graphy was carried out using alumina basic (Brockman

Activity I, 80-200 mesh) or MBS silica gel (230-400 mesh)

as indicated. Exact mass measurements were performed on a

KRATOS/AE1-MS 30 mass spectrometer.








68

Compounds 3.12a-c were prepared according to the

procedure described in Chapter II.



3.4.1 General Procedure for the Preparation of
Substituted 4-(Benzotriazol-1-ylmethyl)anilines


To a solution of the substrate (2.5 mmol) in THF (80

ml) at -78 OC was added dropwise n-BuLi (2.5 M in hexane;

1.0 ml, 2.5 mmol). The mixture was stirred at -78 OC for 2

h and then a solution of the appropriate electrophile (2.5

mmol) in THF (5 ml) was added slowly. The mixture was kept

at -78 OC for a few hours and allowed to warm to room

temperature overnight. Water (30 ml) was added to quench

the reaction, and the solution was extracted with diethyl

ether (3 x 50 ml). The combined ether extracts were washed

with water (50 ml) and dried over MgSO4. The solvent was

removed and the residue purified as described for each

individual compound.

This general procedure applies to the preparation of

3.16a-j. Physical data of the products, substrates and

electrophiles used, and yields are given in Table 3.1.


1,2-Bis(4-N,N-dimethylaminophenyl)-1,2-bis(benzo-

triazol-l-yl)ethane (3.15). To a solution of 4-(benzo-

triazol-l-ylmethyl)-N,N-dimethylaniline (1.26 g, 5 mmol)

in THF (160 ml) at -78 OC was added n-BuLi (2.5 M in

hexane; 2.0 ml, 5 mmol) via a syringe under nitrogen. The








69

mixture was stirred at -78 OC for 1 h and then a solution

of iodine (1.4 g, 5.5 mmol) in THF (10 ml) was added. The

whole was stirred at -78 OC for 2 h and water (30 ml) was

added at -78 OC. The resultant mixture was allowed to warm

to room temperature overnight and extracted with methylene

chloride (3 x 80 ml). The organic layer was washed with

saturated sodium thiosulfate solution (150 ml) and dried

(MgS04). The solvent was evaporated and the black residue

chromatographed on alumina basic from petroleum ether (38-

56 OC)/EtOAc, 6:1, v/v, to give 3.15 (0.38 g, 30%) as

microcrystals. 1H NMR 6 2.77 (s, 12 H), 6.56 (d, J 8.8

Hz, 4 H), 7.28 (t, J = 8.0 Hz, 2 H), 7.53 (t, J = 8.0 Hz,

2 H), 7.67 (s, 2 H), 7.72 (d, J 8.8 Hz, 4 H), 7.80 (d, J

- 8.0 Hz, 2 H), 8.34 (d, J 8.0 Hz, 2 H); 13C NMR 6 39.7,

63.3, 111.1, 111.7, 118.7, 123.2, 124.0, 127.1, 129.3,

132.5, 144.5, 149.9.

Anal. Calcd for C30H30N8: C, 71.69; H, 6.02; N,

22.29. Found: C, 71.50; H, 6.02; N, 22.54.


(Benzotriazol-1-yl)-(4-N,N-dimethylaminophenyl)-

deuteriomethane (3.16a). Obtained as needles

(recrystallized from methanol). 1H NMR 6 2.89 (s, 6 H),

5.70 (s, 1 H), 6.62-6.65(m, 2 H), 7.18-7.37 (m, 5 H),

8.00-8.03 (m, 1 H); 13C NMR 6 40.3, 51.8 (t, J = 21 Hz),

110.0, 112.3, 119.8, 121.8, 123.6, 127.0, 128.8, 132.6,

146.3, 150.4. MS (HR) for C15H15DN4 Calcd: 253.1437.

Found: 253.1423.








70

4-[l-(Benzotriazol-l-yl)ethyl]-N,N-dimethylaniline

(3.16b). Obtained as prisms (recrystallized from

methanol). 1H NMR 6 2.10 (d, J = 7 Hz, 3 H), 2.89 (s, 6

H), 5.98 (q, J = 7 Hz, 1 H), 6.63 (d, J 8.8 Hz, 2 H),

7.17 (d, J = 8.8 Hz, 2 H), 7.24-7.30 (m, 3 H), 8.00-8.04

(m, 1 H); 13C NMR 6 20.9, 40.3, 58.7, 110.4, 112.2, 119.7,

123.5, 126.6, 127.20, 127.24, 132.2, 146.3, 150.1.

Anal. Calcd for C16H18N4: C, 72.15; H, 6.81; N,

21.04. Found: C, 72.32; H, 6.92; N, 21.28.


4-[(l-Benzotriazol-l-yl)-(l-benzyl)]methyl-N,N-

dimethylaniline (3.16c). Obtained as plates

(recrystallized from methanol/EtOAc). 1H NMR 6 2.88 (s, 6

H), 3.70 (dd, J = 6.6, 14.0, Hz, 1 H), 4.07 (dd, J 8.8,

14.0 Hz, 1 H), 5.90 (dd, J = 6.6, 8.8 Hz, 1 H)), 6.61 (d,

J = 8.8 Hz, 2 H), 7.03-7.30 (m, 10 H), 7.95-7.99 (m, 1 H);
13C NMR 6 40.3, 41.2, 64.9, 109.8, 112.2, 119.7, 123.5,

126.1, 126.5, 126.8, 127.8, 128.3, 129.0, 132.7, 137.5,

146.0, 150.2.

Anal. Calcd for C22H22N4: C, 77.16; H, 6.48; N,

16.36. Found: C, 77.15; H, 6.52; N, 16.64.


1-(4-Tolyl)-2-(benzotriazol-l-yl)-2-(4-dimethylamino-

phenyl)ethanol (3.16d). Recrystallization of the crude

product from methanol gave the pure isomer I (50%) as

needles. The residue after evaporation of the solvent was








71

chromatographed on alumina basic from petroleum ether (38-

56 oC)/EtOAc, 4:1, v/v, to give the pure isomer II (17%)

as microcrystals and a mixture of both isomers (12%). The

total yield was 79%.


Isomer I. 1H NMR S 2.26 (s, 3 H), 2.80 (s, 6 H), 4.12

(d, J = 4.0 Hz, 1 H), 5.72 (d, J 8.8 Hz, 1 H), 5.89 (dd,

J = 4.0, 8.8 Hz, 1 H), 6.44 (d, J 8.8 Hz, 2 H), 6.94 (d,

J 8.8 Hz, 2 H), 7.01 (d, J 8.0 Hz, 2 H), 7.12 (d, J -

8.0 Hz, 2 H), 7.21-7.35 (m, 3 H), 7.96 (d, J 8.0, 1 H);
13C NMR 6 21.1, 40.1, 70.0, 76.0, 110.2, 111.9, 119.5,

123.3, 123.9, 126.9, 127.2, 128.4, 128.8, 133.5, 136.7,

137.3, 145.6, 150.0.

Anal. Calcd for C23H24N40: C, 74.17; H, 6.49; N,

15.04. Found: C, 73.86; H, 6.57; N, 15.12.


Isomer II. 1H NMR 6 2.22 (s, 3 H), 2.88 (s, 6 H),

3.60 (s, br, 1 H), 5.65 (d, J 6.0 Hz, 1 H), 5.93 (d, J -

6.0 Hz, 1 H), 6.57-6.60 (m, 2 H), 6.96-6.98 (m, 2 H),

7.12-7.26 (m, 7 H), 7.92-7.96 (m, 1 H); 13C NMR 6 21.0,

40.2, 68.8, 75.0, 109.7, 111.9, 119.6, 122.0, 123.8,

126.5, 127.1, 128.7, 129.4, 132.9, 136.8, 137.4, 145.2,

150.4.

Anal. Calcd for C23H24N40: C, 74.17; H, 6.49; N,

15.04. Found: C, 74.06; H, 6.69; N, 14.80.








72

2-(Benzotriazol-l-yl)-2-(4-dimethylaminophenyl)-l,l-

diphenylethanol (3.16e). Obtained as plates (recrystal-

lized from methanol). 1H NMR 6 1.65 (s, 1 H), 2.81 (s, 6

H), 5.83 (s, 1 H), 6.39-6.41 (m, 2 H), 6.55 (s, 1 H),

6.84-6.87 (m, 2 H), 7.00-7.55 (m, 12 H), 7.96 (d, J 8.0

Hz, 1 H); 13C NMR 6 40.2, 68.2, 81.4, 109.5, 111.3, 120.0,

122.1, 124.2, 125.5, 126.5, 126.8, 126.9, 127.7, 127.8,

128.2, 129.7, 133.2, 143.3, 144.8, 145.7, 149.9.

Anal. Calcd for C28H26N40: C, 77.39; H, 6.03; N,

12.89. Found: C, 77.01; H, 6.06; N, 12.97.


1-[(Benzotriazol-1-yl)(4-dimethylaminophenyl)]methyl

cyclohexan-l-ol (3.16f). Obtained as needles (recrystal-

lized from methanol). 1H NMR 6 1.20-1.66 (m, 10 H), 2.88

(s, 6 H), 4.01 (s, 1 H), 5.50 (s, 1 H), 6.62 (d, J 8.8

Hz, 2 H), 7.26-7.53 (m, 5 H), 8.03 (d, J = 8.0 Hz, 1 H);
13C NMR 6 21.5, 21.8, 25.5, 35.0, 36.1, 40.2, 70.4, 74.3,

109.8, 111.8, 119.8, 122.8, 124.1, 127.5, 129.8, 133.8,

144.9, 150.3.

Anal. Calcd for C21H26N40: C, 71.97; H, 7.48; N,

15.99. Found: C, 71.89; H, 7.51; N, 16.37.


2-(Benzotriazol-1-yl)-2-(4-dimethylaminophenyl)-4'-

methylacetophenone (3.169). Obtained as plates (triturated

with diethyl ether). 1H NMR 6 2.32 (s, 3 H), 2.87 (s, 6

H), 6.61 (d, J = 8.8 Hz, 2 H), 7.17-7.30 (m, 7 H), 7.78








73

(s, 1 H), 7.91-8.00 (m, 3 H); 13C NMR 8 21.5, 39.8, 68.3,

111.8, 112.1, 119.1, 119.5, 123.4, 127.0, 129.0, 129.4,

130.2, 131.9, 133.3, 144.8, 146.4, 150.5, 192.7.

Anal. Calcd for C23H22N40: C, 74.57; H, 5.99; N,

15.12. Found: C, 74.60; H, 6.17; N, 15.14.



2-(Benzotriazol-l-yl)-2-(4-dimethylaminophenyl)-1-

(pyrid-4-yl)ethanol (3.16h). Recrystallization of the

crude product from methanol gave the pure isomer I (18%)

as microcrystals. The residue after evaporation of the

solvent was recrystallized again from methanol to give the

pure isomer II (10%) as plates. The residue consisted of a

mixture of both isomers (37%). The total yield was 65%.


Isomer I. 1H NMR 6 2.00 (s, br, 1 H), 2.87 (s, 6 H),

5.61 (d, J 8.0 Hz, 1 H), 5.93 (d, J = 8.8 Hz, 1 H), 6.48

(d, J 8.0 Hz, 2 H), 6.90 (d, J 8.0 Hz, 2 H), 7.11 (d,

J = 5.0 Hz, 2 H), 7.3-7.4 (m, 3 H), 8.00 (d, J = 8.0 Hz, 1

H), 8.41 (d, J = 5.0 Hz, 2 H); 13C NMR 6 40.1, 69.8, 75.2,

110.1, 112.0, 119.8, 122.1, 122.2, 124.3, 127.6, 128.4,

133.4, 145.7, 148.8, 149.4, 150.4.

Anal. Calcd for C21H21N50: C, 70.18; H, 5.89; N,

19.48. Found: C, 69.94; H, 5.94; N, 19.54.



Isomer II. 1H NMR 6 2.88 (s, 6 H), 4.90 (s, br, 1 H),

5.63 (d, J = 6.0 Hz, 1 H), 5.98 (d, J = 6.0 Hz, 1 H), 6.55








74

(d, J = 8.8 Hz, 2 H), 7.1-7.3 (m, 7 H), 7.96 (d, J = 7.0

Hz, 1 H), 8.30 (d, J = 3.0 Hz, 2 H); 13C NMR 6 40.1, 68.3,

73.8, 109.7, 110.8, 119.7, 121.1, 121.7, 124.1, 127.4,

129.4, 132.9, 145.3, 149.2, 149.4, 150.5.

Anal. Calcd for C21H21N50: C, 70.18; H, 5.89; N,

19.48. Found: C, 70.30; H, 5.91; N, 19.72.


4-(l-Benzotriazol-l-yl)ethyl-N,N-diethylaniline

(3.16i). Obtained as plates (column chromatography on

silica gel from petroleum ether (38-56 oC)/EtOAc, 9:1,

v/v). 1H NMR 6 1.10 (t, J = 7.0 Hz, 6 H), 2.10 (d, J 7.0

Hz, 3 H), 3.28 (q, J = 7.0 Hz, 4 H), 5.96 (q, J = 7.0 Hz,

1 H), 6.57 (d, J 8.8 Hz, 2 H), 7.15 (d, J 8.8 Hz, 2

H), 7.23-7.30 (m, 3 H), 8.00 (d, J = 8.0 Hz, 1 H); 13C NMR

6 12.4, 20.9, 44.1, 58.7, 110.5, 111.5, 119.6, 123.4,

126.1, 126.5, 127.5, 132.2, 146.3, 147.5.

Anal. Calcd for C18H22N4: C, 73.44; H, 7.53; N,

19.03. Found: C, 73.16; H, 7.67; N, 19.08.


1-[(Benzotriazol-1-yl)(4-N,N-diethylaminophenyl)]-

methyl cyclohexan-1-ol (3.16j). Obtained as microcrystals

(recrystallized from methanol). 1H NMR 6 1.08 (t, J 7.0

Hz, 6 H), 1.2-1.8 (m, 10 H), 3.26 (q, J = 7.0 Hz, 4 H),

4.02 (s, 1 H), 5.50 (s, 1 H), 6.55 (d, J 8.0 Hz, 2 H),

7.3-7.6 (m, 5 H), 8.03 (d, J = 8.0 Hz, 1 H); 13C NMR 6

12.4, 21.5, 21.7, 25.5, 34.9, 36.0, 44.0, 70.4, 74.3,








75

109.8, 110.8, 119.7, 121.4, 124.0, 127.3, 130.0, 133.7,

144.8, 147.5.

Anal. Calcd for C23H30N40: C, 72.98; H, 7.99; N,

14.80. Found: C, 72.71; H, 8.14; N, 14.96.



3.4.2 General Procedure for the Displacement of the
Benzotriazolyl Moiety by Nucleophiles


To a stirred solution of the substrate (5 mmol) in

MeOH (30 ml) under reflux was added a solution of the

appropriate nucleophile (5 mmol) and dilute hydrochloric

acid (3%; 30 ml). The resulting mixture was heated under

reflux for the appropriate time followed by addition of an

aqueous KOH solution (1 M; 50 ml) and subsequently cooled.

The products were isolated by filtration for 3.20a-c,

3.20e, 3.27a-b, and 3.27d-e. For other products, the

reaction mixture was extracted with diethyl ether (3 x 40

ml) and dried (MgSO4). The solvent was evaporated and the

residue was purified.

This general procedure applies to the displacement

products except 3.22. Physical data of all the products,

yields, reaction time, and methods of purification are

given in Tables 3.3 and 3.4. Further purification for the

analytically pure sample is described for the particular

compound.



2-(4-Aminophenylmethyl)-1,5-dimethoxybenzene (3.17a).

Obtained as an oil. 1H NMR 6 3.42 (s, br, 2 H), 3.73 (s,








76

br, 6 H), 3.77 (s, 2 H), 6.3-6.4 (m, 2 H), 6.5-6.6 (m, 2

H), 6.90-6.97 (m, 3 H); 13C NMR 6 34.1, 55.12, 55.15,

98.3, 103.7, 115.0, 122.7, 129.5, 130.2, 131.1, 144.1,

158.0, 159.0.

Anal. Calcd for C15H17NO2: C, 74.05; H, 7.04. Found:

C, 74.33; H, 7.09.


2-(4-N,N-Dimethylaminophenylmethyl)-1,5-dimethoxy-

benzene (3.17b). Obtained as an oil. 1H NMR 6 2.87 (s, 6

H), 3.74 (s, 3 H), 3.76 (s, 3 H), 3.80 (s, 2 H), 6.3-6.7

(m, 4 H), 6.92 (d, J 8.0 Hz, 1 H), 7.0-7.1 (m, 2 H); 13C

NMR 6 34.0, 40.8, 55.2, 55.3, 98.4, 103.8, 112.9, 122.9,

129.4, 129.5, 130.2, 148.9, 158.1, 159.1.

Anal. Calcd for C17H21NO2: C, 75.25; H, 7.80. Found:

C, 75.42; H, 7.82.



2-(4-N,N-Diethylaminophenylmethyl)-1,5-dimethoxy-

benzene (3.17c). Obtained as an oil. 1H NMR 6 1.09 (t, J -

7.0 Hz, 6 H), 3.25 (q, J 7.0 Hz, 4 H), 3.70 (s, 3 H),

3.73(s, 3 H), 3.78 (s, 2 H), 6.35 (dd, J = 8.0, 2.0 Hz, 1

H), 6.41 (d, J 2.0 Hz, 1 H), 6.58 (d, J = 8.8 Hz, 2 H),

6.93 (d, J 8.0 Hz, 1 H), 7.02 (d, J = 8.8 Hz, 2 H); 13C

NMR 6 12.5, 33.9, 44.3, 55.06, 55.11, 98.3, 103.7, 112.0,

123.0, 128.1, 129.5, 130.2, 145.9, 158.0, 159.0.

Anal. Calcd for C19H25NO2: C, 76.22; H, 8.42. Found:

C, 76.00; H, 8.45.








77

2-(4-Aminophenylmethyl)-1,3,5-trimethoxybenzene

(3.18a). Obtained as needles. 1H NMR 6 3.75 (s, 6 H), 3.77

(s, 3 H), 3.81 (s, 2 H), 6.12 (s, 2 H), 6.51-6.54 (m, 2

H), 7.01 (d, J = 8.5 Hz, 2 H); 13C NMR 6 27.2, 55.2, 55.6,

90.5, 110.8, 115.0, 129.1, 132.3, 143.7, 158.7, 159.3.

Anal. Calcd for C16H19N03: C, 70.31; H, 7.01; N,

5.12. Found: C, 70.55; H, 7.11; N, 5.01.


2-(4-N,N-Dimethylaminophenylmethyl)-1,3,5-trimethoxy-

benzene (3.18b). Obtained as plates. 1H NMR 8 2.81 (s, 6

H), 3.73 (s, 9 H), 3.83 (s, 2 H), 6.10 (s, 2 H), 6.60 (d,

J = 8.6 Hz, 2 H), 7.10 (d, J = 8.0 Hz, 2 H); 13C NMR 8

27.0, 40.8, 55.0, 55.4, 90.4, 110.8, 112.8, 128.8, 130.5,

148.6, 158.6, 159.3.

Anal. Calcd for C18H23N03: C, 71.73; H, 7.69; N,

4.65. Found: C, 71.45; H, 7.75; N, 4.63.


2-(4-N,N-Diethylaminophenylmethyl)-1,3,5-trimethoxy-

benzene (3.18c). Obtained as needles. 1H NMR 6 1.09 (t, J

- 7.0 Hz, 6 H), 3.26 (q, J 7.0 Hz, 4 H), 3.77 (s, 6 H),

3.78 (s, 3 H), 3.81 (s, 2 H), 6.13 (s, 2 H), 6.56 (d, J =

8.8 Hz, 2 H), 7.08 (d, J 8.8 Hz, 2 H); 13C NMR 8 12.6,

27.0, 44.4, 55.3, 55.6, 90.6, 111.2, 112.1, 129.1, 129.3,

145.7, 158.7, 159.3.

Anal. Calcd for C20H27NO3: C, 72.92; H, 8.26; N,

4.25. Found: C, 72.82; H, 8.37; N, 4.19.








78

1-(4-N,N-Dimethylaminophenylmethyl)-2-naphthol

(3.19). Obtained as plates. 1H NMR 6 2.84 (s, 6 H), 4.33

(s, 2 H), 5.40 (s, br, 1 H), 6.62-6.65 (m, 2 H), 7.06 (dd,

J = 8.7, 3.0 Hz, 3 H), 7.29 (dt, J = 8.0, 1.0 Hz, 1 H),

7.42 (dt, J = 8.0, 1.0 Hz, 1 H), 7.64 (d, J = 8.8 Hz, 1

H), 7.76 (d, J 8.0 Hz, 1 H), 7.94 (d, J 8.5 Hz, 1 H);

13C NMR 6 29.7, 40.9, 113.3, 118.0, 118.7, 123.0, 123.3,

126.5, 127.7, 128.2, 128.4, 128.8, 129.4, 133.6, 149.3,

151.4.


3-(4-Aminophenylmethyl)indole (3.20a). Obtained as

microcrystals (recrystallized from aqueous methanol). 1H

NMR 8 3.51 (s, br, 2 H), 3.99 (s, 2 H), 6.57-6.61 (m, 2

H), 6.81-6.82 (m, 1 H), 7.0-7.3 (m, 5 H), 7.50 (d, J 8.0

Hz, 1 H), 7.87 (s, br, 1 H); 13C NMR 6 30.7, 111.0, 115.2,

116.4, 119.2, 119.3, 121.8, 122.2, 127.4, 129.4, 131.3,

136.4, 144.2.

Anal. Calcd for C15H14N2: C, 81.05; H, 6.35; N,

12.60. Found: C, 80.91; H, 6.39; N, 12.44.


3-(4-N,N-Dimethylaminophenylmethyl)indole (3.20b).

Obtained as needles (recrystallized from hexane). 1H NMR 8

2.89 (s, 6 H), 4.01 (s, 2 H), 6.68 (d, J = 8.0 Hz, 2 H),

6.82 (s, 1 H), 7.06 (t, J = 7.7 Hz, 2 H), 7.14-7.30 (m, 3

H), 7.53 (d, J = 8.0 Hz, 1 H), 7.85 (s, br, 1 H); 13C NMR

6 30.5, 40.9, 110.9, 113.0, 116.6, 119.1, 119.2, 121.8,

122.1, 127.5, 129.2, 129.4, 136.4, 149.0.








79

3-(4-N,N-Diethylaminophenylmethyl)indole (3.20c).

Obtained as plates (recrystallized from aqueous methanol).

1H NMR 6 1.10 (t, J = 7.0 Hz, 6 H), 3.27 (q, J = 7.0 Hz, 4

H), 3.98 (s, 2 H), 6.60 (d, J = 8.5 Hz, 2 H), 6.75 (d, J -

1.2 Hz, 1 H), 7.0-7.2 (m, 5 H), 7.54 (d, J = 8.0 Hz, 1 H),

7.69 (s, br, 1 H); 13C NMR 6 12.5, 30.3, 44.4, 111.0,

112.2, 116.5, 119.0, 119.1, 121.7, 122.2, 127.5, 128.2,

129.4, 136.3, 146.1.

Anal. Calcd for C19H22N2: C, 81.97; H, 7.97; N,

10.06. Found: C, 81.77; H, 8.05; N, 10.09.


3-(4-Aminophenylmethyl)-N-methylindole (3.20d).

Obtained as plates. 1H NMR 6 3.40 (s, br, 2 H), 3.57 (s, 3

H), 3.95 (s, 2 H), 6.51 (dt, J = 8.0, 2.0 Hz, 2 H), 6.64

(s, 1 H), 7.00-7.06 (m, 3 H), 7.13-7.23 (m, 2 H), 7.49

(dt, J 8.0, 1.0 Hz, 1 H); 13C NMR 6 30.5, 32.3, 108.9,

114.9, 115.0, 118.5, 119.1, 121.3, 126.8, 127.7, 129.3,

131.2, 137.0, 144.2.

Anal. Calcd for C16H16N2: C, 81.32; H, 6.82; N,

11.85. Found: C, 81.66; H, 6.95; N, 11.87.


3-(4-N,N-Dimethylaminophenylmethyl)-N-methylindole

(3.20e). Obtained as an oil. 1H NMR 6 2.81 (s, 6 H), 3.52

(s, 3 H), 3.95 (s, 2 H), 6.60-6.66 (m, 3 H), 7.0-7.2 (m, 5

H), 7.51 (dt, J 8.0, 1.0 Hz, 1 H); 13C NMR 6 30.3, 32.3,

40.7, 108.9, 112.8, 115.0, 118.5, 119.1, 121.3, 126.8,








80

127.8, 129.1, 129.4, 137.0, 148.9.

Anal. Calcd for C18H20N2: C, 81.78; H, 7.63; N,

10.60. Found: C, 82.01; H, 7.92; N, 10.63.


3-(4-N,N-Diethylaminophenylmethyl)-N-methylindole

(3.20f). Obtained as an oil. 1H NMR 6 1.09 (t, J 7.0 Hz,

6 H), 3.25 (q, J = 7.0 Hz, 4 H), 3.57 (s, 3 H), 3.97 (s, 2

H), 6.59 (dt, J = 8.7, 2.0 Hz, 2 H), 6.85 (s, 1 H), 7.01-

7.23 (m, 5 H), 7.54 (dt, J 8.0, 1.0 Hz, 1 H); 13C NMR 6

12.5, 30.3, 32.3, 44.3, 108.9, 112.1, 115.2, 118.5, 119.2,

121.3, 126.8, 127.9, 128.2, 129.3, 137.0, 146.0.

Anal. Calcd for C20H24N2: C, 82.15; H, 8.27; N, 9.58.

Found: C, 82.03; H, 8.39; N, 9.47.


2,5-Bis(4-aminophenylmethyl)pyrrole (3.21a). Obtained

as an oil. 1H NMR 6 3.46 (s, br, 4 H), 3.73 (s, 4 H), 5.78

(d, J = 2.6 Hz, 2 H), 6.53-6.56 (m, 4 H), 6.90-6.94 (m, 4

H), 7.58 (s, br, 1 H); 13C NMR 6 33.1, 105.9, 115.2,

129.3, 129.6, 130.6, 144.5. MS (HR) for C18H19N3 Calcd:

277.1579. Found: 277.1576.


2,5-Bis(4-N,N-dimethylaminophenylmethyl)pyrrole

(3.21b). Obtained as an oil. 1H NMR 6 2.85 (s, 12 H), 3.73

(s, 4 H), 5.78 (d, J 2.6 Hz, 2 H), 6.62-6.65 (m, 4 H),

7.00-7.03 (m, 4 H), 7.45 (s, br, 1 H); 13C NMR 6 32.9,

40.7, 105.8, 112.8, 127.7, 129.1, 130.6, 149.1.








81

Anal. Calcd for C22H27N3: C, 79.24; H, 8.16. Found:

C, 79.06; H, 8.11.


2,5-Bis(4-N,N-diethylaminophenylmethyl)pyrrole

(3.21c). Obtained as plates. 1H NMR 6 1.13 (t, J 7.0 Hz,

12 H), 3.26 (q, J = 7.0 Hz, 8 H), 3.77 (s, 4 H), 5.81 (d,

J 2.6 Hz, 2 H), 6.59-6.62 (m, 4 H), 7.00-7.03 (m, 4 H),

7.48 (s, br, 1 H); 13C NMR 6 12.5, 33.0, 44.4, 105.8,

112.1, 126.5, 129.4, 130.8, 146.3.

Anal. Calcd for C26H35N3: C, 80.16; H, 9.06; N,

10.79. Found: C, 79.79; H, 9.21; N, 10.55.


2,5-Bis(4-N,N-dimethylaminophenylmethyl)-N-methyl-

pyrrole (3.21d). Obtained as plates. 1H NMR 6 2.88 (s, 12

H), 3.19 (s, 3 H), 3.80 (s, 4 H), 5.78 (s, 2 H), 6.47 (d,

J 8.8 Hz, 4 H), 7.01 (d, J = 8.8 Hz, 4 H); 13C NMR 6

30.4, 32.3, 40.8, 105.9, 112.8, 127.5, 129.0, 131.8,

149.1.

Anal. Calcd for C23H29N3: C, 79.50; H, 8.41; N,

12.09. Found: C, 79.51; H, 8.61; N, 12.14.



l,l-Dibenzoyl-2-(4-N,N-dimethylaminophenyl)ethane

(3.22). A mixture of 4-(benzotriazol-l-ylmethyl)-N,N-

dimethylaniline (3.12b) (0.63 g, 2.5 mmol), dibenzoyl-

methane (0.56 g, 2.5 mmol) and anhydrous zinc bromide

(0.84 g, 3.75 mmol) in dry toluene was heated under reflux








82

for 27 h, then cooled, poured into aqueous NaOH solution

(10%; 30 ml), extracted with ether (3 x 30 ml) and dried

over MgSO4. The solvent was evaporated, the residue

chromatographed (see Table 3.3) then recrystallized from

ethanol to give 3.22 (0.22 g, 25%) as needles. 1H NMR 6

2.84 (s, 6 H), 3.37 (d, J = 6.6 Hz, 2 H), 5.51 (t, J 6.6

Hz, 1 H), 6.60 (d, J = 8.8 Hz, 2 H), 7.11 (d, J 8.8 Hz,

2 H), 7.3-7.5 (m, 6 H), 7.89-7.91 (m, 4 H); 13C NMR 6

34.2, 40.6, 59.4, 112.8, 126.8, 128.5, 128.7, 129.5,

133.3, 136.0, 149.3, 195.5.


3-(4-N,N-Dimethylaminophenyl)propiophenone (3.23a).

Obtained as an oil. 1H NMR 6 2.86 (s, 6 H), 2.95 (t, J -

8.0 Hz, 2 H), 3.21 (t, J 8.0 Hz, 2 H), 6.67 (d, J 8.8

Hz, 2 H), 7.11 (d, J 8.8 Hz, 2 H), 7.35-7.50 (m, 3 H),

7.91-7.94 (m, 2 H); 13C NMR 6 29.1, 40.6, 40.7, 112.9,

127.9, 128.4, 128.8, 129.1, 132.7, 136.8, 149.0, 199.4.


4-(4-N,N-Dimethylaminophenyl)-2-butanone (3.23b).

Obtained as plates (triturated with hexane). 1H NMR 6 2.12

(s, 3 H), 2.65-2.82 (m, 4 H), 2.90 (s, 6 H), 6.68 (d, J -

8.7 Hz, 2 H), 7.05 (d, J 8.7 Hz, 2 H); 13C NMR 6 28.8,

30.0, 40.8, 45.6, 112.9, 128.8, 128.9, 149.1, 208.5.


l-(4-N,N-Dimethylaminophenyl)-l-(4-N,N-diethylamino-

phenyl)ethane (3.26). Obtained as an oil. 1H NMR 6 1.12








83

(t, J 7.0 Hz, 6 H), 1.55 (d, J 7.0 Hz, 3 H), 2.88 (s,

6 H), 3.29 (q, J = 7.0 Hz, 4 H), 3.96 (q, J = 7.0 Hz, 1

H), 6.60 (d, J = 8.8 Hz, 2 H), 6.67 (d, J = 8.8 Hz, 2 H),

7.05 (d, J = 8.8 Hz, 2 H), 7.10 (d, J 8.8 Hz, 2 H); 13C

NMR 6 12.6, 22.3, 40.9, 42.7, 44.3, 111.9, 112.8, 128.1,

128.2, 134.1, 135.7, 146.0, 148.9.

Anal. Calcd for C20H28N2: C, 81.03; H, 9.52. Found:

C, 81.44; H, 9.74.


3-[1-(4-N,N-Dimethylaminophenyl)ethyl]indole (3.27a).

Obtained as microcrystals. 1H NMR 6 1.65 (d, J = 7.0 Hz, 3

H), 2.87 (s, 6 H), 4.28 (q, J = 7.0 Hz, 1 H), 6.67 (d, J -

8.5 Hz, 2 H), 6.89-7.41 (m, 7 H), 7.82 (s, br, 1 H); 13C

NMR 6 22.5, 35.8, 40.8, 110.9, 112.9, 119.0, 119.8, 120.9,

121.7, 122.1, 126.9, 128.0, 135.1, 136.6, 148.9.

Anal. Calcd for C18H20N2: C, 81.78; H, 7.63; N,

10.60. Found: C, 81.54; H, 7.66; N, 10.75.


4-[Benzyl(indol-3-yl)methyl]-N,N-dimethylaniline

(3.27b). Obtained as microcrystals. 1H NMR 8 2.82 (s, 6

H), 3.24 (dd, J = 8.4, 13.6 Hz, 1 H), 3.46 (dd, J 13.6,

6.8 Hz, 1 H), 4.39 (dd, J = 8.4, 6.8 Hz, 1 H), 6.59 (d, J

8.5 Hz, 2 H), 6.86-7.43 (m, 12 H), 7.71 (s, br, 1 H);
13C NMR 6 40.7, 42.6, 43.7, 110.9, 112.7, 119.0, 119.6,

120.2, 121.4, 121.7, 125.6, 126.9, 127.9, 128.6, 129.0,

132.7, 136.4, 141.0, 148.9.








84

Anal. Calcd for C24H24N2: C, 84.67; H, 7.11; N, 8.23.

Found: C, 84.65; H, 7.17; N, 8.00.


1-(4-Tolyl)-2-(4-N,N-dimethylaminophenyl)-2-(indol-3-

yl)ethanol (3.27c). Obtained as microcrystals. 1H NMR 6

2.26 (s, 3 H), 2.45 (s, br, 1 H), 2.81 (s, 6 H), 4.49 (d,

J 8.0 Hz, 1 H), 5.25 (d, J = 8.0 Hz, 1 H), 6.52 (d, J -

8.8 Hz, 2 H), 6.9-7.3 (m, 10 H), 7.47 (d, J 8.0 Hz, 1

H), 8.10 (s, br, 1 H); 13C NMR 6 21.1, 40.6, 50.7, 77.5,

111.0, 112.5, 115.8, 119.3, 119.5, 122.0, 122.4, 126.7,

127.6, 128.5, 129.2, 130.0, 136.3, 136.5, 139.7, 149.0.

Anal. Calcd for C25H26N20: C, 81.05; H, 7.07; N,

7.56. Found: C, 80.81; H, 7.13; N, 7.43.


1-[(4-N,N-Dimethylaminophenyl)(indol-3-yl)methyl]

cyclohexan-1-ol (3.27d). Obtained as microcrystals. 1H NMR

8 1.20-1.72 (m, 10 H), 2.86 (s, 6 H), 4.21 (s, 1 H), 6.65

(d, J 8.5 Hz, 2 H), 7.03-7.43 (m, 7 H), 7.62 (d, J 8.0

Hz, 1 H), 8.09 (s, br, 1 H); 13C NMR 6 22.3, 25.8, 36.7,

37.0, 40.7, 51.3, 73.9, 110.8, 112.5, 116.5, 118.9, 119.1,

121.6, 122.4, 128.4, 129.9, 130.1, 135.4, 149.1.

Anal. Calcd for C23H28N20: C, 79.27; H, 8.10; N,

8.04. Found: C, 79.27; H, 8.07; N, 8.39.


1-(Pyrid-4-yl)-2-(4-N,N-dimethylaminophenyl)-2-

(indol-3-yl)ethanol (3.27e). Obtained as microcrystals. 1H








85

NMR 6 2.72 (s, br, 1 H), 2.86 (s, 6 H), 4.47 (d, J 7.0

Hz, 1 H), 5.28 (d, J = 7.0 Hz, 1 H), 6.56 (d, J 8.8 Hz,

2 H), 7.01-7.33 (m, 10 H), 7.43 (d, J = 7.6 Hz, 1 H), 8.28

(s, br, 1 H), 8.40 (d, J = 6.0 Hz, 2 H); 13C NMR 6 40.6,

50.5, 76.5, 111.1, 112.6, 114.7, 119.3, 119.7, 121.7,

122.5, 127.4, 128.6, 129.2, 136.3, 149.2, 149.4, 151.7.

Anal. Calcd for C23H23N30: C, 77.28; H, 6.49; N,

11.76. Found: C, 77.04; H, 6.64; N, 11.63.



2-(4-N,N-Dimethylaminophenyl)-2-(indol-3-yl)-1,1-

diphenylethanol (3.27f). Obtained as plates. 1H NMR 6 2.74

(s, 6 H), 3.03 (s, 1 H), 5.43 (s, 1 H), 6.38 (d, J 8.6

Hz, 2 H), 6.77-7.32 (m, 16 H), 7.49 (d, J 7.4 Hz, 1 H),

7.73 (s, br, 1 H); 13C NMR 6 40.4, 50.6, 81.0, 110.7,

112.1, 115.3, 118.9, 119.0, 121.4, 125.0, 125.7, 125.9,

126.0, 126.3, 127.3, 127.6, 127.7, 130.6, 135.4, 146.5,

147.6, 149.0.

Anal. Calcd for C30H28N20: C, 83.30; H, 6.52; N,

6.48. Found: C, 83.04; H, 6.62; N, 6.29.



2-Phenyl-2-(4-N,N-dimethylaminophenyl)acetophenone

(3.28). Obtained as plates. 1H NMR 8 2.90 (s, 6 H), 5.93

(s, 1 H), 6.68 (d, J = 8.8 Hz, 2 H), 7.1-7.5 (m, 10 H),

8.00-8.02 (m, 2 H); 13C NMR 6 40.5, 58.6, 112.8, 126.5,

126.8, 128.48, 128.5, 128.9, 129.1, 129.8, 132.7, 137.1,

140.0, 149.6, 198.7.








86

Anal. Calcd for C22H21NO: C, 83.78; H, 6.71; N, 4.44.

Found: C, 83.41; H, 6.86; N, 4.35.


2-(4-N,N-Dimethylaminophenyl)-2-methoxy-1,1-

diphenylethanol (3.29). Obtained as plates. 1H NMR 6 2.86

(s, 6 H), 3.16 (s, 1 H), 3.26 (s, 3 H), 4.95 (s, 1 H),

6.50 (d, J 8.0 Hz, 2 H), 6.86 (d, J 8.0 Hz, 2 H), 7.0-

7.4 (m, 8 H), 7.5-7.6 (m, 2 H); 13C NMR 6 40.4, 56.5,

80.7, 86.5, 111.4, 123.6, 126.3, 126.4, 126.7, 127.1,

127.4, 127.8, 129.7, 144.1, 146.2, 149.9.

Anal. Calcd for C23H25N02: C, 79.51; H, 7.25; N,

4.03. Found: C, 79.11; H, 7.36; N, 3.92.


l,l-Diphenyl-2-(indol-3-yl)-2-(4-N,N-dimethylamino-

phenyl)ethylene (3.30). Obtained as microcrystals. 1H NMR

8 2.81 (s, 6 H), 6.4-7.3 (m, 17 H), 7.6-7.8 (m, 2 H), 8.0

(s, br, 1 H); 13C NMR 6 40.3, 110.7, 111.5, 119.2, 119.6,

121.0, 121.4, 125.5, 126.6, 127.4, 127.5, 127.6, 128.0,

130.8, 131.1, 131.6, 132.0, 134.0, 135.7, 137.6, 144.7,

145.8, 148.8.

Anal. Calcd for C30H26N2: C, 86.92; H, 6.32; N, 6.76.

Found: C, 86.52; H, 6.32; N, 6.57.















CHAPTER IV
o-(a-BENZOTRIAZOLYLALKYL)PHENOLS:
VERSATILE INTERMEDIATES FOR SYNTHESIS OF
SUBSTITUTED PHENOLS



4.1 Introduction


4.1.1 a-Amidoalkylation of Phenols


Classical Mannich reactions condense active CH-

compounds, including phenols, with formaldehyde and an

amine [420R303, 73S703, 90T1791]. Important extensions of

Mannich reactions in which amides, imides, ureas,

thioureas, etc. replace the amine component are well

documented in the literature [63MI1, 650R52, 70S49,

76AG909, 73S243, 84S85]. Phenols have been employed as

active CH- compounds in such Mannich condensations with

aldehydes and amides or imides under various conditions.

The ortho-substituted derivative is obtained unless both

ortho positions are occupied, in which case the Mannich

reaction occurs at the para-position [57RTC249]. Zaugg

[63JOC2925] attributed the high ortho- to para- preference

to the assistance of the phenolic hydroxyl group. The

first step is the addition of the NH group to the carbonyl

carbon of formaldehyde (or rarely other aldehydes) giving

rise to an a-alkylol compound 4.1 (Scheme 4.1). Compound









88

4.1 is converted (generally via acid catalysis) into a

carbonium/imonium ion (4.2 4- 4.3) which then reacts with

the phenol to yield the condensation product 4.5. A quasi

six-membered chelate ring 4.4 preceding the carbon carbon

bond formation is believed to be responsible for the

preferred ortho- substitution of phenols [61JOC4078,

64TL1353].


-X
HNI~


X = Alkyl, aryl, RC(=O), RC(=S)
Y = X,H
Z = H (rarely otherwise)


H

HO N
Z Y


4.1


OH


R


HA
H
- NX

Z Y

4.2


H +,X
N% A-
Z Y

4.3


OH H X

R N
_j Rie"


Scheme 4.1


H
O +
Z








89

Compounds 4.1 can be isolated prior to use. An

example is the Tseherniac-Einhorn reaction [69JOC14],

where N-hydroxymethylphthalimide is the electrophilic

reagent in the aromatic substitution process. Other

analogous reagents that have been isolated prior to use

are N-alkoxyalkylamides [66JOC133], N-haloalkylamides

[63JOC2925], and N,N'-(arylmethylene)bisamides [57RTC249].

In most of these cases the carbonyl compound has been

formaldehyde.



4.1.2 Importance and Synthesis of Phenols



Phenols represent a class of compounds which has

found numerous applications in the transformation of

organic compounds and in industry. Many natural products,

such as lignans and neolignans, as well as alkaloids which

possess phenolic fragments, have been synthesized by

phenolic oxidation or by anodic oxidation of phenols as

the key step. These biosynthetic methods have been subject

to several reviews [72S657, 82CSR75, 85MI1, 88MI2]. On the

other hand, the Mannich bases derived from phenols are

versatile synthons which are widely employed in diverse

types of organic transformations [73S703]. Also, quinone

methides from phenol derivatives play an important role in

biosynthesis and in the biological activity of many

quinonoid antitumor compounds. They are very reactive and

unstable and have proven very valuable as intermediates








90

especially for the construction of condensed benzopyran

rings [74MI3, 80JOC3726].

Phenols have also long been used in the fragrance and

flavor industries, and this is well documented in the

literature [68MI1, 68MI2, 71MI1, 80MI3]. Reactions between

phenols and formaldehyde under strictly controlled

conditions give phenolic alcohols of low molecular weight

which serve as starting materials for the synthesis of

phenolic aldehydes. These phenolic aldehydes such as

vanillin (4-hydroxy-3-methoxybenzaldehyde) are the

intermediates from which a large number of important

fragrance and flavor substances are derived.

The usual methods for the preparation of alkyl

phenols are based upon the reactions of alcohols, alkyl

halides, and alkenes with phenols in the presence of acid

catalysts [490R58, 63MI2]. Generally, o-mono or o,p-di

substituted phenols are obtained; if the p- position is

blocked, substitution occurs at the o- position. In

particular, under Friedel-Crafts conditions, the reactions

of phenols with alkyl halides usually afforded p-isomers

[30JA4484, 31JA2379, 32JA1506]. The preparation of

substituted phenols was also achieved by Claisen

rearrangement of phenol ethers [440R1] and by reduction of

Mannich bases from phenols [420R303, 88SC1207]. A recent

report appeared in which phenol was acylated with acyl

chloride under Friedel-Crafts conditions to give ketones,