CHAPTER - I

REVIEW OF AZEPINB CHEMISTRY

GENERAL REMARKS

Nuclear magnetic resonance spectra were recorded

on a Varian T-60 Spectrometer in CDGlg or CCl^ or CFgCOGH

solutions using TMS as an internal standard. The chemical

shifts (6 ) values are reported in ppm.

Infrared spectra were recorded on a Perkin-Elmer

Infracord 137 spectrophotometer in nujol mull. The IR

values are recorded in cm’"'1',

fill mass spectra were recorded on CEC-21-110B

mass spectrometer at 70 eV. The samples were introduced

through direct inlet probe and were volatalised at minimum

source temperature. The source temperature was between

150°-200°C for most of the samples.

Spectral charts, wherever necessary, have been

reduced to standard size and attached at the end of the

discussion. The actual values are given in the discussion.

Temperatures are in °G. Melting points are

uncorrected.

The figures underlined are structure numbers

and the figures in superscript are literature references.

1
REVIEW OF AZEPINE CHEMISTRY

Interest in seven-membered heterocyclic rings with

three double brnds has increased in the last few years.

Nitrogen heterocycles with their generally easier syntheses

and greater stability are more widely investigated than

heterocycles containing oxygen or sulphur. The earlier

emphasis on compounds which were saturated or relied for

their unsaturation on annelated benzene rings, has now

shifted towards unsaturated monocyclic compounds. Compounds

in which the ring is saturated or partially saturated have

properties which are predictable from our knowledge of

similar aliphatic compounds.

Current interest in these ring systems arises from

a variety of reasons. The parent ring systems and their

substituted derivatives have provided a means of checking

theoretical predictions concerning *aromaticity 1, stability,

physical properties and reactivity. AP ?t from this there

is also interest in the synthesis of these novel heterocyclic

systems as an end in itself. As the range of these hetero­

cyclic compounds increased, so did the scope for studies

specific to cyclic systems including reactions to increase

or decrease ring size, ring-bridging reactions and ring-chain

or transannular tautomerism. The application of orbital

symmetry concepts in this field has led to added interest both

2
3

in synthesis by cycloaddition, and in the study of photo­

lysis and thermolysis of heterocyclic compounds. New

stereochemical problems relating to conformation, ring

inversion and functional group interaction are also to be

found in this area.

There is also a strong commercial interest in

seven-membered heterocyclic compounds as is evident from

the extensive patent literature on these compounds. One

of the most important monomers, caprolactam, and the widely

prescribed drug chlorodiazepoxide and diazepam contain a

seven-membered nitrogen system. A large number of medium

sized heterocycles have been synthesized for evaluation as

polymer intermediates, dyestuffs, pharmaceuticals and

agricultural chemicals.

With such wide area to be covered certain topics

have been omitted or have received only cursory treatment

in the present review. The aim of this review is to

summarize the large volume of work on the chemistry of

seven-membered nitrogen heterocyclics. Although more recent

work has been emphasised some pertinent literature on

earlier work has also been included in this review. More

stress is given on the synthetic methods leading to various

azepine ring systems, and the properties of such ring

systems.
The present review deals only with azepines since

benzazepines, diazepines and benzdiazepines have been

extensively discussed in a volume in the "Advances in

Heterocyclic Compounds"^ series. Finally, a reference is

made to the chemotherapeutic properties of azepines and

diazepines.

Four tautomeric forms, designated as IB-, 2H-,

3H- and 4H- azepine, are possible for az^cycloheptatriene.

None of the parent heterocycles have yet been isolated,

although 3H-azepine has been characterized by GLC and mass

2
spectrum as a product from the pyrolysis of the carbinol .

N-lH-A-zepines without a substituent on the nitrogen

atom are rare since they readily tautomerize to the 3H-

isomer, in whose preparation they are often considered to

be formed as transient intermediates. This rearrangement

is particularly apparent with 2 -amino and 2 -alkoxy

derivatives since stabilization of the 3H-'zepine is

rendered possible by amidine and imidate type of mesomeric

inter-conversion. The stability of lH-azepine is enhanced

by electron-withdrawing substituents, especially at the

3
1-position. Many such derivatives have been prepared ,

Of the remaining isomers the order of stability is

3H > 4H > 2H4 *^. Relatively few 4H- and 3H-azepines

lacking a 2 -substituent have been synthesized; even

more rare are 2H-azepines, although their benzo derivatives
4
have recently been reported .

1H-A.ZEPINBS

lH-Azepine (I; R=H), a thermally unstable compound,

spectroscopically resembling pyrrole, has been obtained in

solution after alkaline hydrolysis of N-carbethoxyl

azepine (I; R = CC^Et). This N-lH-tautomer is probably the

least stable form in direct contrast to pyrrole of which

it is the vinylogue. N-IH-Azepine rapidly rearranges to

3H — azepine .

However, electronegative substituents, especially

at position 1 and 3, stabilise the azepine ring and several

such derivatives have been reported.

[A] Synthesis of Azepines

(1) Through Nitrene Insertion

The most frequently used synthetic method for

azepine is the insertion of a stabilised singlet nitrene in

a benzenoid hydrocarbon. Insertion into the benzene ring

7
by a concerted cycloaddition mechanism gives a 1 -azanor-

caradiene(II), which being unstable changes to azepine.

Besides, thermolysis and photolysis of azides,

deoxygenation of nitrosobenzene with triethyl phosphite in

8 9
the presence of trifluoroethanol ’ and the base catalyzed
°<-elimination of ethyl N-P nitrosobenzenesulphonyloxy
7 10
carbamate ’ also provide the reactive nitrene for

insertion.

Interaction of various nitrenes (generated by

azide decomposition) with aromatic systems leading to

azepines are described below:-

(i) Carbonyl azepines : The first lH-azepine

was prepared by ring expansion of the azanorcaradiene formed

by attack of a thermally"^, photochemically^"1^ or base

catalytically derived singlet ethoxycarbonylnitrene

#* 16
(N CO Et) on benzene. 1-Carbethoxy-lH-azepine(1) was

characterized by reduction (Pd/Hg) to the known N-carbethoxy-

perhydroazepine. It has been shown that it is the singlet

17
nitrene that adds to the benzene double bond . With more

reactive aromatic residues e.g., anthracene, phenanthrene,

and pyrenes or with mesitylene, azepines are not obtained;

instead the N-arylurethanes are formed. The latter are

formed either from the benzaziridene via a dipolar

intermediate or directly through a (f complex, perhaps

18 19
involving some triplet nitrene . Photis has prepared

different alkyl substituted carbonylazepines by decomposing

ethyl azidoformate in toluene, ethyl benzene, n-propyl-

benzene, cumene, p-xylene, etc.

1H — 2 H — 3H ~ 4 H -
AZFPINES

N
R
I

SCHEME 1

H
ha
N COpEt n - c o 2e i
* or A

- :N -C 02R

X H

(4 ) c o 2 c 2h 5

SCHEME 2

n 3c n A
DIMERS
4 5 - 6 0 °C

CN

h 3o

NHCN

(6 ) (7) ( 8)
Since singlet nitrenes appear to be involved in

such cycloadditions, a concerted process (i.e. 2 ) is

expected to operate in preference to a stepwise mechanism

involving a transition state species such as (3). Small

substituent effect should be noted, since the former profile

exhibits little, if any, charge separation. Baldwin and

Smith have measured the relative rates of reaction of

20
carbethoxylnitrene with various benzene derivatives .

Although this reaction has served well for the synthesis

of unsubstituted lH-azepines, the overall process suffers

from serious drawbacks with substituted aromatics. When

the reaction is extended to substituted aromatics such as

toluene, bromobenzene and anisole, however, there results

a mixture of isomeric lH-azepines which, in general, defy

pi ^on
preparative scale VPC separation

(11) Cyanoazepines : Cyanonitrene reacts readily

with aromatic substrates*^. Thus, at 45-60°, solutions of

cyanogen azide in aromatic hydrocarbons smoothly evolve

nitrogen to produce N-cyanoazepines (5). These products,

though isolable upon careful workup at or below ambient

temperature, readily dimerize on mild heating and isomerize

to aryIcyanamines (6 ) in the presence of trace of acids.

Acid hydrolysis of the arylcyanamines leads first to

arylureas (7) and eventually to the corresponding anilines (8).

The intermediacy of NCN in the formation of
26
azepine was demonstrated through reaction of

appropriately labeled N^CN with p-xylene. Pertinent

information with regard to the multiplicity of azepine

forming NCN was obtained from competitive experiments

between cyclohexane and benzene, toluene and trifluoro-

26
methylbenzene. As can be readily seen from the results

of these competitive runs, the C-H bonds of cyclohexane are

apparently less reactive towards NCN than the double bond

of either of the three aromatic substrates examined.

26
Marsh and Simmons have claimed 74# yield of

hexafluoro-N-cyanoazepine (12) by the reaction of

hexafluorobenzene with cyanoazide.

(iii) Sulphonyl azepines : Even though

formation of aryl sulphonamido derivatives by the thermal

of
interaction/aromatic substrates with sulphonylazides has
27 17
been reported by several authors » there was no report

of azepine formation by intermolecular nitrene insertion

28
until Abramovitch et al carried out thermal decomposition

of methanesulphonylazide in benzene and reported the

formation of N-methanesulphonyl-lH-azepine. The latter

was characterized as an adduct with tetracyanoethylene.

29
Earlier they had shown that unlike the reaction of

carbethoxynitrene with benzene which gives N-carbethoxy-

azepine, no N-methylsulphonylazepine (16) could be detected

in
SCHEME 3

+ +
\ /
CN
(9) (10) ( 11)

n 3c n

4 5 °C

SCHEME 4
H
RSCpN, —— ► rso 2 n N S 0 ?R p Nn s o 2 r
2
H
(13) (14)
4

TCNE NHS02R
NSO?R

(17) (15)

SCHEME 5

A
‘ S 0 2N3

a . X=0 b. X = C 0 (18a) (18b)

SCHEME 6
R< R
N S02 -HQ>-CH 3 r^ k ^ N S 0?-{g>-CH 3 I r-v
N HS 02 ~ C H ■
► CT
R2 R.

(19) (20)
Where a R 1= R 2 = C 0 2 CH^
j f ___^ ~ S 02-h@)- CH,
b . R1= C 0 2C H 3 , R2 = H

(21 )
in the thermolysis of MeSOgN^ in benzene or substituted

benzene at 120°. This was shown to be due to the fact

that (16) was the product of kinetic control of the

rearrangement of (14), whereas (13) was the product of

thermodynamic control. At 120°, the equilibrium

14 ^=±13 ^ 16 lies almost exclusively on the side of

(14), but the activation energy for (13)— >(16) is lower

30
than for (13)--- >(14). Earlier Abramovitch et al had

reported the intramolecular cyclization of ortho­

substituted arylsulphonyInitrenes during the thermal

decomposition of sulphonylazides leading to oxathiazepine

derivatives (18a) (Scheme V). A recent report by the same

31
authors has revealed the formation of thiazepine deri­

vative (18b). Abramovitch et al have also described the

scope and limitations of these intramolecular cyclization

reactions.

During the study on the mechanism of inter-

32
action of azido dyes with polyester fibre, Tilak et al

have noticed the formation of N-sulphonylazepine derivative

(2 1 ) along with the expected sulphanilamido derivative (20 )

during thermolysis of p-toluenesulphonyl azide (PTSA) in

presence of dimethyl terephthalate (DMT) (Scheme VI).

The formation of azepine derivative was also

observed during thermal decomposition of FTSA in methyl

32
benzoate . A more complex sulphonylazide such as
12

4 -(2 f-hydroxy-5 1-methyl)-phenylazobenzenesulphonylazide (22)

also yielded an azepine derivative (23) on thermal interaction
33
with DMT - Formation of 2,5-diaarbmethoxy lp-acetamido-

sulphonyl-lH-azepine 5 2 ,5-dicarbmethoxy-lp-methanesulphonyl-

1H-azepine \ 2,5-dic arbmethoxy-lp-benzenesulphony1-lH-azepine

and 2,5-dicarbmethoxy-lp-aminobenzenesulphonyl-lH-azepine has

34
also been reported by Tilak et al’

However, the method of synthesizing lH-azepine by

nitrene insertion appears to be limited to the preparation of

lH-azepine bearing electron-withdrawing substituents on

nitrogen that stabilize the ring, presumably by decreasing the

electron density of the azepine ring system. Another dis­

advantage is that in the majority of cases insertion of nitrene

in mono-substituted benzenes is non-regiospecific and mixtures

i 19 a
of difficulty separable isomeric azepines are formed

However., some measure of regiospecificity is observed if

nq V\
bulky groups, e.g. ter-butyl are present .

(2) Valence Bond Isomerization Approach

With a view to bypassing the early difficulties in

obtaining lH-azepines with specifically positioned ring

substituents or with functional groups other than carbalkoxy

and cyano on nitrogen via nitrene chemistry, a mew synthetic

approach based on reacting 1 ,4 -dihydrobenzene with iodine

isocyanate has been developed ’ ” . Mono-addition of iodine

isocyanate to a 1,4-dihydrobenzene (available by Birch

Reduction) followed by methanol addition and base catalyzed

cyclization of the resulting iodocarbamate (25), yields the

fused aziridine (26). Low temperature bromine addition and

then dehydrohalogenation produces the azancFcardiene (27)

which undergoes spontaneous valeice-bond isomerization to

lH-azepine (28).

The isomeric 2-, 3-, and 4-methyl-l-carbmethoxy-lH-

azepines were likewise obtained in good yield by an identical

sequence of reactions commencing with the appropriate 1,4-

dihydrobenzene derivative.

Additional studies have shown that the dehydro­

halogenation of l,2-aziridino-4,5-dibromocyclohexanes

provided a simple scheme for synthesizing many lH-azepines.

4,5-Disubstituted lH-azepines are available by

rearrangement of the thermally labile 3-azaquadricyclanes

(29) (Scheme VII, path b). That the lH-azepines are

substituted at nitrogen by electron-withdrawing' groups

appears to be essential in promoting formation of the

precursory (4 + 2) pyrrole-acetylene-dicarboxylate adducts.

h 3c
$
c o 2c h 3
/ - ( 2 - h y d r o x y - 5 - me thy ! \ h)-,
-)\V riV <

L't'

n ==n ~ \ 0 )

2 ,5 ~ d ic a rb m e th o x y -1 -p (2 '-h y d ro x y -
^ ' - m e t h y l p h e n y l a z o ) benze nes ulp ho nyl- 1 H - a z e p i n e

SCHEME 7

(a)
NCCLR
\/^N h CO;R (i)

(25) (26'
R
N-

(bi (iii)

(28) (29)

( i) Powdered NaOMe , THF , (ii) B r ? , CH Ci at-70°C.

(iii) hi) , P = p - tosyI , COMe , CO ^Me , CONH, or p - N 0 - . C 6H4 , E = COgMe

SCHEME 8
N- ■R
CO? CH ?

N- R + C
III
C
I
C 0 2 CH3

R = - COCH3

= - S 0 2C6H4- C H 3 ( p
(3) Thermal rearrangement of azaquadricyclones

Synthesis of lH-azepine has also been accomplished

by Diels-Alder addition of dimethyl acetylenedicarboxylate

to pyrrole derivative substituted with a powerful electron-

withdrawing |pouj> on nitrogen, followed by irradiation >

of the (4+2) J~r adduct. Such excitation induces almost

quantitative conversion of (31) to the thermally labile

3-azaquadricyclane (32). Thermal rearrangement of (32) at

approximately 20-40° leads to 4,5-disubstituted a z e p i n e s ^ * ^ .

Particularly relevant is the fact that the photocyclization

of (31) to (32) is not reversed thermally, presumably

because the process is disallowed4®.

(4) Ring-expansion of substituted

1 ,4-dihydropyridine

When the substituted 4-chloromethyl-l,4-dihydro-l-

methylpyridine (34) is treated with potassium-t-butoxide in

1 ,2 -dimethoxyethane, ring expansion occurs and two isomeric

41 42
products are formed ’ . DihydroazGipines with methylene

substituents are formed as intermediates, but they isomerize

43
to IH-azepines in the presence of acids (Scheme 9) .

(5) Miscellaneous synthesis

Sundberg et al has reported the synthesis of

44
1-phenyl-lH-azepine . Deoxygenation of nitrosobenzene by

triethylphosphite in benzene-trifluoroethanol as solvent

SCHEME 9

(34)

K01 - Bu c h 3o c h 2c h 2 o c h 3
H

CH3 0 2C- co2c h 3

h3c - - n ^ c h 3
ch3
( 35) ia)

(38)

SCHEME 10

. N - 0 —P - ( O E t ) :

c f 3 c h 2oh

( 39)

N ~ S 02 - @ > - 8 r

a . R =H
b R = S 0 2 C6 H4 Br (p)
R
c . R = C 0 2 C H3
(41)
(40)

N— R

(42) (43)
gives, 3,0,(3,trifluoro-p-phenetidine (21$), N-ethyl-

|3,|3,(3-trifluoro-p-phenetidine as an orange solid, m.p.

49-49.5° (34$). The latter compound is identified as

1-phenyl-lH-azepine (39) (Scheme 10). The azepine forma­

tion presumably proceeds via a nitrenoid mechanism.

[B] Structure features and spectral

characteristics of IH-azepines

(a) X-ray studies

The lH-azepine molecules (40a) is isoelectronic

45
with the cycloheptatrienide anion , and if planar, may in

actuality be antiaromatic . Interestingly molecular quantum

mechanical calculations for such a model predict marked

polyenic character and strong localization of the j y -electrons

on nitrogen and the double bonds of the seven-membered ring

47
with little, if any, tendency for delocalization

48
Azepines (41a) exist in 'boat' conformation . The

double bonds are localized at Cg-C^, C4" C5 an& Cg-C?, in

contrast to the situation observed in tropolone (in both

anionic and cationic forms)4^ ’0®, and in 2 -chlorotropone^,

although bond alteration has been recognized in cupric

52
tropolone . The two atoms comprising each double bond and

their immediate neighbours are coplanar (max. deviation

0.01 A) deviates by 0.22° from the plane defined by

Cg, Cy and Sg. This is a relatively small deviation for

3
the Sp hybridization, and together with the valence angles
p
around N^, implies substantial Sp character for the nitrogen

atom. The dimension of the benzenesulphonyl group attached

to nitrogen are similar to those reported in sulfaguanidine

5*p
monohydrate .
I

The present study reveals that (40b) and presumably

all closely related lH-azepine, exhibit little propensity to

exist in the azancfcaradiene tautomeric forms (42) or as

azahomoaromatic entities of type (43), but are true polyenes.

It follows that lH-azepines are non-planar in the crystalline

state and very likely, when in solution.

(b) Ultraviolet spectra

3 *^0
The UV spectra of lH-azepines have been reported ’ .

The UV spectra of lH-azepine derivatives generally consist of

three major bands comprising a low intensity maximum of

variables position in the 285-330 m^. region, a medium intensity

band (frequently seen only as a shoulder) at 240-247 mu, and

strong end absorption. The location of the first band is

notably dependent upon ring substitution, particularly at

the 2- and 7-positions, and is probably associated with

interaction of the nitrogen electron pair and the carbocyclic

f\ system. The greater the steric hindrance about the

nitrogen atom, the more the particular lH-azepine derivative

is constrained in the boat comformation. When this long

wavelength reaches a maximum at 320-330 m|U, the absorption

extends to about 430 m|i accounting for the yellow to orange

colour of such azepines. In contrast, no tailing into the

visible region is seen when this band is blue-shifted to

below 300 m(j. and such azepines, e.g. l-carbmethoxy-2,7-

dimethyl-lH-azepine, are colourless. It may be concluded

therefore, that the electronic transition energy of this

azepine chromophore is quite sensitive to distortions in

molecular geometry.

(c) NMR spectra

In azepines substituted only on nitrogen, it is

to be expected that the differing electron density at the

three types of ring carbon atoms will profoundly affect the

ring proton chemical shifts. Schmidt's molecular orbital

calculation have indicated that the 3 -carbon bears the

highest charge density, on this basis the |3-protons are

expected to be more shielded than the remaining vinyl

protons. The protons °< to the nitrogen atom are located

in the centre of multiplet, the overall pattern is seen to

be a doublet which is skewed in the direction of the

|3-proton absorption. The slight broadening observed is

most likely caused by long range coupling effects with the

T-protons which appear at lowest field.

Symmetrical dialkyl substitution of the ring

results in simplification of the nmr spectrum. Replacement

of hydrogen by methyl groups at the 3 and 4 positions

causes the most dramatic spectral alteration, the °<- and

20

T-proton pairs appearing as singlet absorptions. The greater

line broadening apparent in the singlet due to the °<-proton

is congnient with aH y l i c coupling to the methyl groups not

available to the T-position because of the fixed nature of

the f f -bonds.

In the 2,7-dimethyl isomer, the p-protons appear

as a broadening multiplet. The situation is much the same

as the annelated azepine. Perhaps the most remarkable

feature of these spectra is the marked down field shift of

(3-protons.

Especially noteworthy is the fact that all of the

nmr spectra of these IH-azepines proved to be invariant over

a substantial temperature range (-90 to 130°). This lack of

change with temperature points to the absence of valence

tautomerism of the lH-azepine-benzanimine type.

(d) Mass spectra

Mass spectral data for lH-azepines have been

36
tabulated . The overwhelming favoured electron impact

fragmentation of the ring unsubstituted lH-azepines occurs

between the ring nitrogen atom and the 1 -substituent,

giving the corresponding azatropylium cation (45) [base

peak, (m/e 92)]. Although the azepinium molecular ion (44)

is always seen, its intensity is variable within the series,

presumably because it tends to convert to cation (48) in

SCHEME 11

-e -R
i+
V\ •• II ».♦//
-N- N* ■N*
R (44) (45)
c
,H
- HCN
♦
VJ -N
\_/

(M/e 65)
(48) ( 46)
- H C = CH
HC s CH
+
-HCN

N‘
(M /e 39)
(47)

(50)

SCHEME 12

N — C 0 2Me
^ v ^ N H C 02CH 3

CH,
c o 2c h 3
(52) (53)
(51)

6
H^C CH.
200'

10 min
I
co2c h 3

(54)

W II
h 3c
‘ N' A
CH,
c o 2c h 3

(57)
certain derivatives. The second most pronounced feature of

the spectra is due mainly to loss of the element of HCN from

(48). The fragment thus formed, is presumably the cyclo-

pentadienyl cation. It decomposes further by the loss of

acetylene to yield the cyclopropenium cation. Alternate

bond reorganisation in (48) can lead to (46) from which the

elements of acetylene can be expelled producing (47).

However, this mode of cleavage does not seem to be important.

In fact, the mass spectral fragmentation of lH-azepines

parallels the behaviour of anilines under such conditions;

the latter compounds fragment by way of the intermediate

54
azepinium ions

[C] Reactions of IH-azepine derivatives

(1) Dimerization - Dimerization of lH-azepines

is well studied phenomenon involving a temperature depen-

3 55-62
dent cycloaddition process ’ . The two series of dimers

formed on heating lH-azepines appear to have symmetrical (49)

and unsymmetrical structures (50). The latter is the

product of a thermally allowed (6+4 ) Jf -cycloaddition, and

it is formed when lower temperatures are employed.

Dimerization is subject to steric restraint and is

inhibited by 2-, 4- and 7-substituents. In such cases

thermolysis of the lH-azepine brings about aromatization

56
to the corresponding substituted N-arylurethanes
23

(2) AROMATIZATION AND PHOTO-RING CONTRACTION (SCHEME 12)

Heating of the 2-methyl derivative (51) at 130° for

periods upto 2 hours leads to no reaction. At 200° (51) shows

no tendency to dimerize; instead, (51) is converted quantita-

56
tively to the aromatic urethan (53) . In a similar fashion,

the 4,5-dimethyl derivative (54) is transformed at this

temperature range to (56). The reaction path involved in

the conversion of such azepines to their aromatic isomers

very probably proceeds through aziridinobenzene valence

tautomers (52) and (55). Homolytic rupture of the more

highly substituted c-N bond with synchronous hydrogen atom

transfer permits ultimate benzenoid stabilization.

In case of 1-carbmethoxy-2,7-dimethy1-lH-azepine

(57), the corresponding valence tautomer (58) cannot undergo

hydrogen atom migration. Although in a formal sense this

molecule (57) contains the three conjugated double bonds

and is entirely azepine-like in its spectral characteristics,

it shows no tendency to dimerize and is not converted to a

benzenoid isomer at elevated temperatures. Remarkably,

azepine (54) withstands prolohged heating (24 hours) at 200°

without noticeable dire effect. The marked difference in

reactivity between (57), on the one hand, and (51) and (54),

on the other, is very likely due to the absence of a proton

in (58) which can migrate. Perhaps most striking is the

fact that thermally induced suprafacial sigmatropic shifts of

63
order [1,5] " (e.g. 58 - 59), such as those observed in
s* a C.C.
tropylidine skeletal rearrangements do not occur in

these heterocyclic examples under the stated conditions.

The reaction of 1-carbalkoxy-IH-azepines with acid

also leads rapidly to N-phenylurethane which presumably

result from protonation on oxygen, valence bond isomeri-

zation and irreversible rupture of aziridinium ring 1 1

In addition to the ring transformation of IH-

azepines to substituted benzene under thermal, acidic and

acylating conditions azepines undergo photo-ring

contraction to bicyclic valence tautomers of the type shown

in Scheme 13. These transformations which parallel those

undergone by cycloheptatrienes, are often thermally

reversible and occur by an orbital symmetry-controlled

disrotatory electrocyclic process. The methyl substituted

azepines, e.g. (60, H = Me) gives a mixture of isomers

(61 and 62, R = Me) corresponding to the two allowed

electrocyclic reactions (Scheme 13, paths a and b

69
respectively)

Ring contractions of yet a different kind are

observed with lH-N-methylazepines of type (63), which on

heating yields 6-substituted fulvenes$ e.g. (64), as

70
illustrated in Scheme 14
25

SCHEME 13

hi)
\ R or \
N‘ R' N
I
CO? Me C02Me

(61) (62)

SCHEME 14

N - C ^ / = \ ... I'm

i'* *
Me' N.^ ^Me Me Me
f~
Me Me

( 63 )
CN
NC\

Me

H3C — N = C CN

‘ CH:
(64)

SCHEME 15

CO ^C H a

( 65)
ChUO X CH j

h 3c

(6 6 )
(3) ADDITIONAL REARRANGEMENTS

When dimethyl-1,2,7-trimethyl-lH-azepine-3, 6-

dicarboxylate (65) is heated under reflux in benzene, it

undergoes almost quantitative rearrangement to the

41 42
6 -aminofulvene (66 ) ’ (Scheme 15). The same thermal

reorganisation also occurs when (65) is passed through a

tube containing fine sand at 130°. A possible mechanism

for this complex rearrangement is shown in Scheme 15.

(4) CYCLOADDITION REACTIONS

[4+2] Cycloaddition of IH-azepines with some

common dienophiles (e.g. azodicarboxylate or maleic

71
anhydride) have been unsuccessful . However, cyclo­

addition with tetra cyanoethylene (TONE) takes place

readily in benzene solution at room temperature to give

adduct of type (67)19a,7S. With the 3-methyl derivative

1 2
mixture of isomeric adducts (67, R = H, R =Me; R = Me

R g = H) corresponding to 2,5- and4,7-addition to the

72
azepine ring is obtained f N-^thoxycarbonylazepine

(I, R = COgEt) also reacts with 4-phenyl-l,2,4-triazoline

3,5-dione, 1,4-phthalizenedione and N-phenylmaleimide,

in a (2-*4) 7J~ cycloaddition across positions 2 and 5 (not

73-75
2 and 7 as originally proposed)

TONE has been used to trap transient azepines as

adducts (68 ), the structure of which have been determined

27

76 77
by X-ray analysis ’ . Diethyl transazodicarboxylate and

nitrosobenzene both add across positions 2 and 7 [e.g. as

in adduct (69)]. As concerted (2+6) JT cycloadditions are

thermally forbidden, a two-step route to these adducts is

proposed7 4 ’7 8 .

Azepines I (R = COgEt; SOgMe) also behaves as

dienophiles in reaction with substituted cyclopentadienes

or 1 ,3-diphenylisobenzofuran to give adducts across

positions 4 and 5, e.g. (70) (R = COgEt, SOgMe;. They

also act as both diene and dienophile with 2,5-dimethyl-

79
3,4-diphenylcyclopentadiene . 1,3-Dipolar addition of

diazomethane to 4,5-dicarbornethoxy-lH-azepine (R = Tosyl,

Ac$ gives adduct (71) and (72), respectively. The isolation

of (70) provides the only evidence for the existence of

80
azanorcaradiene tautomers (Scheme 15).

Polar stepwise cycloaddition at the 2,7-positions

81
have been realized with azadicarboxylates and nitrosobenzene

and using phenylcyclone, a novel non-concerted (6+2) Jf

op
cycloaddition at the azepine 2,3-double bond is claimed .

Curiously all attempts to coax lH-azepines into functioning

as 6 J T -system towards other dienes (6+4 cycloaddition)

have failed8*^.
C02 Me (69)
(68 )
(67)

Ac ( 72)
(70)

SCHEME 16

Me

(74)
(I)

[H ]
ij Hydrogen sulphide

(75)
(la ) C0N = CONH.

SCHEME 17

N - C 0 2Me
E E
R

(78)
(76)
Me Ph
l\i — C02Me

(79) (81)
(5) REDUCTION

Catalytic reduction of lH-azepines usually give

perhydroazepine (azepane) derivatives, but in methanol,

azepine loses the nitrogen atom and give dimethyl 2,3-

dimethylterephthalate. Reduction of I (R = COgEt) with

lithium tetrahydroaluminate at low temperatures gives

(73) (R = CHgOH) but in refluxing ether (74) (I, R = Me)

84
is obtained . Reduction of I (R = CONg) with hydrogen
OC
sulphide yields (75) (I, R = CONHg) .

(6 ) OXIDATION

Information on the oxidation of azepines is

scarce. However, recent results of Sundberg and co-

85
workers suggest that 3-alkyl-2-dialkylamino-lH-azepines

undergo aerial oxidation to lH-azepin-2-ones(2-azatropones)

whereas in certain cases oxidation in thepresence of cupric

ion yields to isomeric 4H-azepin-4-ones (4-azatropones)*

Ring contraction products e.g. 3-alky1-2-alkylamino

pyridine are also produced.

(7) ADDITION AND SUBSTITUTION

Iodine azide reacts with I (R = COgEt) to give

87
dihydro-2,3- and 4,5-bisazides . The iron tricarbonyl

adduct of I (R = COgEt) is acylated and formylated at

position 3, and the 3-acetyl complex is decarboxylated on

alkaline hydrolysis, allowing N-methylation by methyl

88
iodide and sodium hydride
(8 ) VALENCE ISOMERISM

A feature of lH-azepine chemistry that intrigued

early research workers was the possibility ofazepine-

89
azanorcaradiene isomerism (7€**77), such as exists in
o
the benzene oxide-oxepine system . Paquette and his
3 36
coworkers ’ have demonstrated that bridging the 2 ,7 -

positions by a trimethylene chain forces the lH-azepine

into adopting the iminobenzene or azanorcaradiene

structure (77). The methylene chain length is critical

and the tetramethylene derivative exists solely as the

bridged azepine (78). Early variable temperature (-90 to

+ 130°C) "4^ r
studies on other IH-azepines, however,
q
failed to detect any bicyclic isomers1". Later studies by

Prinzbach and his coworkers^® were more successful and

provide evidence for the existence of an azepine-

azanorcaradiene equilibrium in system of type (76; R^ =

2
H, R = p-tosyl or Ac, E = COgMe). The iminobenzene form

(77) has been trapped as a bis 1,3-dipolar adduct with

diazomethane, and the spectrum (CDClo solution) of

i i •m • r • o
the N-(p-tosyl)derivative shows temperature dependence

between -68 to + 40°G. Subsequently the diphehyl derivative

(76; R^ = Ph, R 2 = p-tosyl, E = COgMe) was shown to be

97:3:azepine (76) : benzeneimine (77) mixture at room

86
temperature , and it was concluded that the bicyclic isomer

is stabilized by electron-withdrawing group. The equilibrium

31

position of this type of valence isomeric system, together

with the effect of electron-withdrawing substituents on the

stability of lH-azepines and their dimerization, have been

92
considered theoretically using extended Huckels calculations

(9) TRANSITION METAL COMPLEXES OF 1H-AZEPINES

Brief treatment of N-carbmethoxyazepine with iron

enneacar^jbonyl in warm hexane produced the air-stable,

highly crystalline iron tricarbonyl complex (82a)(yield 69 %).

Similar reaction of the N-carbophenoxy and N-methanesulphonyl

analogs gave rise to (82b) and (82c), respectively. Fischer

93
and Ruhle have found that irradiation of N-carbethoxyazepine

and iron pentacarbonyl in tetrahydrofuran solution gave the

desired Fe(CO)g complex* Paquette et al’" h^ve applied their

procedure to the synthesis of (82a), (82d) and (82c), and

concluded that the iron enneacarbonyl method is simpler and

leads to cleaner products. Both procedures failed in

attempts to prepare iron tricarbonyl derivatives of

alkylsubstituted azepines. PMR spectra of the various

iron tricarbonyl complexes are dramatically temperature

dependent. This characteristic was also recognized, by

Gunther and Wenzl94.

Thus, the lH-azepine iron tricarbonyl represent new

examples in the rapidly expanding number of fluxional

7T-bonded organometallic molecules.

SCHEME 18
32
a . R = C 0 2 CH3
/=^\/Fe(C0)3 b . R = C 0 2CgH5
c • R = S 0 2 CH3
0
V ( 82 ) d . R = COOC (CH3)3
R
e . R = C 0 2 CH2 C6H5

(OCL Fe
Fe (COL Fe(CO), Fe(CO),

V * I J y j
I !
R R .cV.
V W r R0 ^ 0
(83a) (83b) ( 84 a) ( 84 b)

SCHEME 19
H u
h-j)
\\ n THF
•N^
I
C 0 2 C?Hc
(85)
H,C

h-D
\\ h CH3 0H
+
■N CH3
co2c h 3 (87) c o 2c h 3

CH;
h-D
c h 3o h
-f
•N^ H,C
I
c o 2c h 3 c o 2c h 3
(89)

ch3

hO
+
CH30H
o
co2c h 3
(90) C 0 2CH 3

CO? Et CO?Et
I I
hi

(92)
(10) PH0TORiT.ARRANGEMENT OF 1H-AZEPINES

Irradiation of 2% tetrahydrofuran solution of

N-ethoxycarbonylazepine under nitrogen for 2-3 days with

a 450-W mercury arc lamp led to the total disappearance of

the azepine and the concominant formation of a singlet

95
photo product identified as (85) . The isomeric nature of

(85) was deduced from its spectral characteristics and its

facile thermal reversal to azepine at about 100°C. Clearly,

therefore, the photochemical behaviour of lH-azep'ines

parallels the general photoisomerization pathway of

96
cycloheptatrienes and cycloheptadienes

Irradiation of methanolic solution of 2-, and 3-

and 4-methy1-N-carbmethoxyazepines with a Hanovia 450-W

mercury arc lamp under nitrogen through Pyrex yields in

each instance a two component mixture containing both

97 _
possible bicyclic valence tautomer . Photolysis of

1-ethoxycarbanyl-lH-azepine at 325-385 nm gives

quantitatively the valence isoiaer, 2,-ethoxycarbonyl-2 -

98
azabicyclo-[3,2,0]-hepta-3,6-diene (92)
34

2H-AZEPINES

Fully unsaturated 2H-azepines have not yet been

obtained, but a few 2H-azepine-2-ones (2-azatropones), e.g.

(93), are known. Photolysis of ortho-substituted phenyl

azides in presence of oxygen, and o-alkylation of 2,5-

dihydro-lH-azepine-2,5-diones with trialkyloxonium

99
tetrafluoroborate are the synthetic routes employed

2-Azatropones show no evidence of 6 7'P-delocalisa-

tion. Catalytic reduction of compound (93) (R = Me), m.p.

52°, gave the perhydroderivative, but (91) (R = Et) m.p.

71-72°, yielded the dihydrodiones ( 9 4 ) ^ ^ ’^°^.

A remarkable simple one-step synthesis of arylated

1,3-dihydro-2H-azepines (99) from spiroquinol ethers (95-97)

is shown in scheme20. The spiro compounds, in turn, are

easily obtained in high yield by oxidative coupling of 2,4-

102
disubstituted phenols .

Thermolysis of N ,0-bis(trimethysilyl) -N-phenyl-

hydroxylamine in a 125-fold molar excess of diethylamine

solvent affords Me^SiOSiMeg and a 95$ yield of well

characterized 2-diethyl-amino-2H-azepine product without

103
de I- ctable amount of aniline
SCHEME 2 0

OR Me

./
HN
V

( 98)

^N^-nrr'

(100 )

cH c
( 101)

Q -
OMe

(104) (105)

SCHEME 21

W
R
. +
iy R‘

rk (106)
R R1 R R'
Phh / " V

R‘
Ph
hrVn
R 2-^'Ni^'R
H

(107) ( 10 8 )
3H-AZEPINES

Many members of the 3H-azepine series are known,

of which "dibenzamil" (100, R = ^ R 1 = Ph) was the first

i 04
monocyclic unsaturated azepine to be described .

3H-azepine is probably the most stable tautomeric

form as 4H-azepines are converted to their 3H-tautomer

on heating, alone or with b a s e s ^ 5 ’^0^.

[A] SYNTHESIS OF 3H-AZEPINES

(1) A frequently used route to 3H-azepines is

the generation of arylnitrenes in the presence of primary

1 07 108
aromatic or secondary aliphatic amines. Pyrolysis *
109
or photolysis of arylazides and deoxygenation of nitro-

iuenzenes with triethylphosphite^^ or nitrosobenzenes

are source of aryl nitrenes. In the photolysis of ortho­

substituted phenylazides ring expansion takes place on

the substituted side and 1H-azepines (101) are shown to be

the products formed. They revert to 3H-azepine (100) if

oxygen is absent, but in the presence of oxygen, oxygen and

cupric ions, respectively 2- and 4-azepinones are obtained.

The photolysis of oxaziridine (102)' in diethylamine

similarly yields (100) (RjR1 = Et)112. In the absence

of amines, the use of phosphorous reagents may lead to

the isolation of phosphorous substituted 3H-azepines,

113
e.g. (103)
37

Azepines are also postulated as intermediates in

the gas phase pyrolysis of phenylazides which leads to

114
cyanocyclopentadiene and pyridines

The photolysis of 2-azidoacetophenone in methanol

gives 2-methoxy-3H-azepines (104 and 105; R = Me) ; but

anthranil [3-phenylbenzo(c)isoxazole] gives only (104)

"11^
(R = Ph) under these conditions .

(2) A series of 3H-azepines of type (108) is obtained

by reacting 2 -phenylaziridines with tetrasubstituted cyclo-

pentadienones. Tricyclic cycloaddition products (106),

1X7 118
and 2H-azepines (107) are postulated as intermediates ’

in this reaction.

(3) Arylnitrenes and subsequently 3H-azepines have

119
been generated by decomposition of oxaziranes and

synthesized also in almost quantitative yield by thermolysis

(1 1 0 °) of N , 0-bis(trimethylsilyl)phenylhydroxylamine
120
[Fh(OSiMeg)NSiMeg] in the presence of dialkylamines

(4) Although there seems to be no tendency for

dihydroazepines to exist in enol form, 2-oxo-2, 3-dihydro-

lH-azepines and their thioanalogues may be 0- and S-

alkylated with trialkyloxonium tetrafluoroborates giving

121
the 3H-azepines (111)

The thermal ring expansion of 1,2-dihydro-

pyridine (110) yields dimethyl 2,7-dimethyl-3H-azepine-

122
4, 6-dicarboxylate (111) . Dimethyl-2,7-dimethyl-3H-

azepine-3,6-dicarboxylate and the diethyl ester are

*1
obtained by heating the corresponding 4H-azepines

(5) Reaction of the dihydroazepinones with

triethyloxonium fluoroborate proceeds readily to afford

1 9 *P 1 9 4
2-ethoxy-3H-azepines (e.g. 113) in excellent yield

The dihydroazepinones can also be converted to their thio

analogues (114) with phosphorous pent a,sulphide in pyridine?

the resulting thioamides are likewise capable of smooth

.12*3 194
conversion to 3H-azepine derivative (115) ’.

(6 ) Vogel and coworkers have reported a novel

five-step synthesis of the parent 1,3-dihydro-3H-azepine-

2 - one (116)125’126 (Scheme 23).

(117)
(7) Irradiation of anthr aiiils/in methanol solution
127
through pyrex optics leads to 2-methoxy-3H-azepines (120)

(Scheme 24). A reasonable mechanism for such photo­

rearrangement involves initial N-O-bond cleavage to give

an arylnitrene. This is followed by ring closure to a

stabilized azirine which undergo addition of methanol and

ring expansion to the azepine.

C02Me
H 2
M6 O C ,C02 Me

o
■H
XR Me^
1 ■Me
MeOgC^/^K/H

Me - ^ N ^ M e
1 X H
'CH2 0 Tosyl
(109) (110) ( 111 )

SCHEME 22
H,C ch3
ch3 (C?H5) OBF 4 ) = \ /CH3
H 'H
^ [j o H3C
1 X
oc 2h 5

(112) (113)
ch3
0
(C2 H5) obf4

it? "'
H.C ^ n ^ s c 2h 5
(115)

(1) N 2 CHCOpCoHc. SCHEME 23

( 2) N q OH

hi
CH3OH

0
II
hi
CH 3 0 H r V n C H 3

OCH,
(119) ( 120 )

H HP 126 4 /
114 6 .
/ = \ / ^ C 0 2Me
49-3

116 4
NH
137 I N*ys-
*CH0r 3
H 145-7
51-74
( 121)
(122) (123)
40

[B] PHYSICAL AND SPECTROSCOPIC PROPERTIES

"Hl . _ _ data on 3H-azepines are available109’128“132 #

n • in* r •
In the parent compound (121), the position of the ring

methylene group wasobvious from the chemical shift of its

two protons C L 7.2). The only alternative structure which

would fit other spectral data was the 7H-isomer (122) but in

this case the methylene protons, adjacent to an amide

nitrogen atom, would absorb at much lower field.

13 (
C N,n.r. chemical shifts ( ,c, CCl^ solution) for

2-methoxy-3-methoxycarbonyl-3H-azepine are appended to

formula (123).

Historically, ^H was vital for determining

n .m # r•
113
the structure of 3H-azepines and has since proved

invaluable in the conformational analysis of 3-substituted

3H-azepines 3 ’ 134 and in determining ring inversion activation

. 16
energies

[C] REACTIONS

(1) Oxidation and Reduction

The early general chemistry of 2-amino-3H-azepine

has been well documented ’ . 2-Dimethylamino-3H-azepine

is reduced in the presence of 5% Pd/C to a mixture of 4,5-

dihydro (70$) and 4,5,6,7-tetrahydro-3H-azepine (30$)138.

Reduction of 3H-azepin-2-ones with a platinum catalyst

yield caprolactams whereas reduction with lithium aluminium

Ih • C1
41

hydride 1 ,3,5,7-tetramethyl-3H-azepin-2-one gives the

unstable dieneamine 1,3,5,7-tetramethyl-l,2-dihydro-3H-azepine,

in 91.8$ yield1".

(2) Reaction with electrophilic reagents

Amino-3H-azepines possess an amidine unit and as such

they are readily soluble in dilute acids, from which solution

they are precipitated on basification. Acylating agents

bring about ring contraction of 2-substituted-3H— azepines

to N-acyl-substituted anilines1363’ 3 . A typicgi highly

substituted 3H-azepine, on treatment with benzoyl chloride

in the presence of 1,4-diazabicyclo[2,2,2]octane (Dubco),

yields the 1 -benzoyl derivatives .

Other general reactions of 2-substituted-3H-azepines

and 3H-azepine-2-ones are summarized in Scheme 25.

The reaction of 2-amino-3H-azepines with acid

chlorides and anhydrides leads to ring contraction and

formation of o-acylaminoaniline derivatives140’141’109.

When the 3H-azepine ester (124) is heated with warm

conc. sulphuric acid or with hot methanolic sodium methoxide,

142
rearrangement to pyridine derivative (125) occurs . The

formation of this pyridylacetic ester from the 3H-azepine

can be formulated as resulting from attack of acidic

reagents on the valence tautomer (126) as depicted.

42
SCHEME 25

(2 ) Rc
(4)
H
(3) 'N
H 0

(5)

(6)
Q «
?A o
Me
(1) RNH , , boil , (2) hot H ; (3) E t 3 0 BF4 ; (4) P4 S 1C, C , H , N ,
e
(5) Me 3 , No ; ( 6) M e l , t h e n OH

SCHEME 26
COCl N(C2HJ.
Pyr i di ne
NO;
( ^ T NHC0
NO;

CHjOC-- fyj

A c l,0 H-

H/\=
>
w
•NHCOCH^
NHCf-H« .N
CfiH
6n5

NHCgH5

NHCOCH,

H
0
CH302C . ^ . C CH.
H 2CO.
C02CH,
CH3 CH30 2C C — OCH3
» °
h3c ^ n ^ Ch ? H,C H
ch3

(125) (126)

(128)
43

(3) Photo ring contractions

Ring-contractions of 3H-azepines can give rise to

either a cyclobutene (127) or an azetine (128). Odum and

143
Schmall found exclusive cyclobutene (127) formation for

3H-azepines. They argued that the alternative pathway to

the bicyclic azetine (128) would involve loss of amidine

or imidate resonance in the product. Similar results have

132
been observed with 1-alkyl-3H-azepin— 2-ones

A bicyclic azetine has been isolated from the

photosensetized (PhgCO or PhCOMe) ring-con traction of the

otherwise photo-stable 4,5-dihydro-2-ethoxy-4,4,6-trimethyl-

1 44
3H-azepine .

2-Alkoxy-3-acylpyridines have been obtained in poor

145
yield from the photolysis of 3-acyl-2-alkoxy-3H-azepines

4H-AZEPINES

4H-/}zepines are more rare than the 1H- and 3H-isomers

and only a few synthetic approaches have been developed.

Highly substituted 4H-azepines may be obtained by base-

catalyzed ring expansion of 4 - (chlorometnyl)-l,4-dihydro-

g
pyridines . However, the reaction is temperature and solvent

sensitive as illustrated in Scheme 27a. Azepines (129 - 131)

146
have been isolated and characterized, but as later studies

on cyano derivatives (Scheme 27b) show, the reaction is even

more complex than was first thought. The azabicyclo[4,1,0]

SCHEME 2 7 44

IN SCHEME 2 7 a ; R 1= R 2= H , E = C 0 2 Me

IN SCHEME 2 7 b v R 1= Me , R2 = Ph , E = C N

(5)

"O f"
Me^N^Me

(131)

(133) (134)
(1) N a O M e , MeOH , Cold ; (2) Warm EtOH ; (3) N a O M e , Et- 0 ;

(4) N a O M e , hot EtOH ; (5) H®, (6) C5H5 N ; ( 7 ) Bu OK at 0°C

SCHEME 2 8
Ph
N

Nc^N +
Ph
E

eS k E

(135)

SCHEME 29

CO?R
CO^C^H r.

C2H5Q2CN / - k K co2C2H5 N°OC2H5 C2H.°2CY = N V m

\\ CH,
c2h5oh N
H3C h ,c ^ n^ Ch ,
I
(137) h 3c CHC02R
(136) NH3 , H2 0

(138)
45

hept-4-ene(132) has been isolated, whereas methyleno-4H-

azepine (133) has been detected only by „ . All

n.m.r.
attempts to isolate (133) were failed and only rearrange­

ment product (134) is isolated.

(4+2) Cycloaddition of cyclopropenes to 1,2,4-

triazines provides alternative access to 4H-azepines

(135) (Scheme 28)147»148.

^N _ data on 4H-azepines'I'?8,^47,'1"4^ are

n.m.r.
available. The 4H-azepine-azanorcaradiene valence
150
isomerism has also come under close scrutiny , the

conclusion being that the 4H-azepine is energetically more

favourable than its bicyclic isomer.

The dihydropyridines are formed when the 4H-

ici ncq
azepine esters are treated with halogen acids or bromine

When 4H-azepine (136) is treated with sodium ethoxide in hot

ethanol, the corresponding 3H-azepine ester (137) is obtained.

The pyrrole derivative (138) has been found as the

product of rearrangement of the 4H-azepines (136) in the

U *
presence of ammonium hydroxide 151,152
’

HOMO AZEPINES

The 2,3- and 4,5-cyclopropeno-lH-azepines (140)

(R = Et) and (142) (R = Et) are obtained by the thermolysis

of azidoformates or dimethyl azodicarboxylate in the presence

of cycloheptatriene, unstable aziridine (139) and (141) are

46

1 K.A 1 tzc
probable intermediates'^ in the reaction. No valence

isomerism is observed in (140) and (142), nor does either show

cycloaddition. Irradiation leaves (142) unaffected but (140)

156 157
undergoes ring contraction * .

AZEPINES AND DIAZEPINES OF MEDICINAL VALUE

Important factor in the growth of interest in seven-

membered heterocyclic rings has been the discovery of

physiologically active compounds, characterized by greater

potency and/or significantly lower addiction or narcotic

effects compared with the drugs they replaced. "Librium"

(chlorodiazepinoxide, methaminodiazepinoxide introduced

1961) is now the most widely prescribed of all drugs for

the treatment of mental disorder.

Like Librium, Valium (Diazepam) and Impramine

hydrochloride (Tofranil) are clinically useful psycho

sedatives, but Ethoheptazine is an analgesic, showing the

unusual property that both enantiomers are equally active.

Azepetine (Illidar) shows useful peripheral vasodilating

effect. The antibiotic, Anthramycin, is also a derivative

of 1,4-benzo-diazepine.

Tranqualising activity in the 1,4-benzodiazepine

derivatives seems to be associated with electron-withdrawing

substituents in the annealated benzene ring (e.g. Cl, NOg

especially at position 7 ) a methyl group at N(l) (although

47

SCHEME 3 0

A
N — C0?R
\
H
c o 2r c o2r
(139)
(140)

N
I co2r
C02 R

(141) (142)

Me
0

(CH2 ) 3

NMe 2 , H C l
Librium Val ium

I mp r a mi n e hydrochloride

OH
, - C 0 2 Et

E t h o h e p t a r ine
CH2 • CH = C H 2
Anthramycin
Azapetine
a des-methyl metabolite of Valium has been suggested as

the active agent), and an ortho-halogen substituent on the

5-phenyl group. Partial reduction of the heterocyclic

ring does not affect activity completely, but replacement

of the nitrogen at position 4 by carbon inactivates these

compounds. Two or three carbon side-chains terminating

in a dialkyl amino group or a saturated nitrogen hetero­

cycle are also a common feature of biologically active

compounds in this series.

More recently, many other medium ring heterocyclic

compounds incorporating these features have been

synthesized and evaluated as pharmaceuticals with some

success.
49

REFERENCES

1. Advances in Heterocyclic Compounds, ed. A. Katritzky,

and A. J. Boulton, Academic Fress, Vol. 17, 1974,
p. 2 and 45.

2. G. Schaden, Chem. Ber. 1973, 106. 2084 and references

cited therein.

3. L. A. Paquette in "Non-Benzenoid Aromatics", ed. J.P.

Snyder, Academic Fress, New York, 1969, Vol.l, p.287.

4. D. J. Anderson and A.Hassner, J. Org. Chem., 1974,

3£, 3070.

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