20. S. Tanaka, M. Tajima, M. Tsukada, and M. Tabata, J. Nat. Prod., 49, No.

3, 466-469
(1986).
21. Y. Tanaka and T. Odani, Yakugaku Zasshi, 92, No. 5, 525-530 (1972).
22. Fan Hunsya Chu Yunchua, Yaosyuz Syuebao, 23, No. 9, 716-720 (1988).
23. T . J . Zaughlin and T. M. Ferre11, Biotechnology, ~, 1035-1037 (1987).

SYNTHETIC METHODS AND DRUG MANUFACTURE TECHNOLOGY

THE NENITZESCU REACTION (REVIEW)

V. G. Granik, V. M. Lyubchanskaya, UDC 547.728+547.752.2'567:541.124

and T. I. Mukhanova

Literature data of the last 20 years on the synthesis of 5- and 6-hydroxyindoles and
5-hydroxybenzofurans using the Nenitzescu reaction are correlated in the review. The effect
of the structure of the quinone and of the enamine and the character of the solvent used on
the course of the processes occurring are considered. New data on the mechanism of the
Nenitzescu reaction are analyzed. The synthesis of 5-hydroxyindole and 5-hydroxybenzofuran
derivatives by the condensation of quinones with various enamines (the Nenitzescu reaction)
is the most expedient approach to compounds of this type.* The significant synthetic possi-
bilities of this reaction are demonstrated currently by the large number of examples with a
wide variation in the structure of the initial quinone and enamine. Among the indole and
benzofuran derivatives synthesized by the Nenitzescu reaction there is a large group of com-
pounds possessing high biological activity [i-ii], which is one of the reasons investi-
gations in this area have continued to develop vigorously.
Many data on the Nenitzescu reaction were correlated in the review by G. R. Allen [12]
in 1973. Analysis of these data showed that at that time many theoretical problems con-
nected with the reaction mechanism were unresolved. Many investigations devoted to studying
the mechanism of this complex and ambiguous reaction have appeared in the literature during
the last twenty years~ Although many problems are far from being solved there are numerous
new data worthy of consideration and generalization. This also applies to the synthetic
aspects of the Nenitzescu reaction. The broadening of the range of quinones and enamines
used and the modification of the reaction conditions, mainly using new reaction solvents,
have enabled the synthesis of compounds previously poorly available to be effected, and new
ways of using this extremely fruitful synthetic method to be put into practice.
The aim of the present review is to correlate the literature data of the past 20 years
on the Nenitzescu reaction, to clarify the main trends of this reaction in the synthesis of
various types of indole and benzofuran systems, and to analyze critically the results of in-
vestigations devoted to the different aspects of this complex and unusual reaction.
The review is arranged traditionally and consists of three sections. The effects of
quinone and enamine structure on the course of the reaction are considered in the first and
second sections and theoretical problems connected with this reaction are considered in the
third. It is fully understood that so strict a demarcation of the investigations analyzed
is impossible and inexpedient since many studies are discussed in several sections of the
review.

*The synthesis of 5-hydroxyindoles by the reaction of quinones with enamines is usually

called the Nenitzescu reaction. However, since the formation of the corresponding benzo-
furan derivatives is essentially comparable and occasionally the predominating process (see
below), a wider definition of the Nenitzescu reaction is taken in the present review, viz.
the condensation of quinones and enamines leading to indole and benzofuran derivatives.

Center for Drug Chemistry, All-Union Scientific-Research Institute for Pharmaceutical

Chemistry, Moscow. Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 27, No. 6, pp.
37-55, June, 1993. Original article submitted September 29, 1992.

0091-150X/93/2706-0413512.50 9 1993 Plenum Publishing Corporation 413

 I. Effect of Quinone Structure
The structure of the initial quinone has a significant and in some cases a decisive ef-
fect on the rate and even the course of the Nenitzescu reaction. An extremely interesting
comparison of using benzo- and naphthoquinones in this reaction has been carried out [13-17].
It was established that the reaction of the naphthoquinone (I) with the N-substituted ena-
mine (II) proceeds best in acetic acid with the formation of the benzoindole (III). How-
ever, nitromethane is the optimum solvent for the analogous indolization of benzoquinone
(IV) [13] (Scheme i).

Scheme i

+ ~ - c-c~
o cf%c~(o ~e)~ ~ ~tkC~'(oMe)~

It was shown in the same study that (I) reacts with the cyclic enamine (V) with the for l
mation of the tetracycle (VI), while quinone (IV) under the same conditions forms a hydro-
quinone adduct which is converted into the stable quinone adduct (VII). On heating in ace-
tic acid the latter is transformed into the 4,5-dihydroxyindole (VIII), i.e., the cycliza-
tion occurs in a different way (a similar type of reaction is discussed in detail below).
It was established in this study that the acetoxy group is, as a rule, found at position 5
(Scheme 2).

Scheme 2
/ COOMe HO. ~. ~COOMe

0[•0 0
2"
+ I

I"
---- Y" i'r--rr"

Ig
~

I~=H or Aei l~tHorAe

It is interesting to note that the use of the naphthoquinone (I) in the Nenitzescu re-
action made possible a new approach to the synthesis of 4-hydroxyindeno[l,2-b]pyrrole (IX)
derivatives, among which are substances possessing antiviral and antitubercular activity
[15] (Scheme 3).

Scheme 3

I~COOEt
+

o o
COOE% COOH IIOC COOE~

ItJ

cooll _OOOE~ o

A series of complex conversions with the formation of various derivatives of benzoin-

dole and naphthofuran was observed during investigations of the reaction of the 2-acyloxy-
naphthoquinone (X) with N-substituted 5-aminocrotonate esters (XI) [16]. It was shown that
the reaction route depended significantly on the temperature and on the solvent used. Deriv-

414
atives of benzoindole (XII) and naphthofurans (XIII) and (XIV) were isolated on conducting
the condensation in acetic acid at 20~ for 24 h (Scheme 4).

Scheme 4
o
o o~ II
I-I~-C--CIEI
5~ t. II II _j._
+ =

Z O E~l-i,x~, FhcHz,Ar ~9- E .,Rr

R=Me, E~ (Yield 14-3~%)
0
o~ II ~ ?,
+
- | 0 "Me
OAe

The quinone (XV) is formed together with compounds (XII)-(XIV) when carrying out this
reaction by h e a t i n g in a c e t i c a c i d , b u t on h e a t i n g in b e n z e n e t h e 5 - h y d r o x y i n d o l e (XVI) i s
o b t a i n e d i n low y i e l d (Scheme 5 ) .

Scheme 5
o o
o Ii II

xz xzT, ~=Fhc~z

In the opinion of the authors of [16] the reaction of the components (X) and (XI) oc-
curs according to the following pathways (Scheme 6).
Scheme 6

l I , Oxidation

OeON Ooo~
a

a) Cyclization with acyl migration.

b) A t t a c k by c a r b o n C(2) a t t h e e n a m i n e ~ - p o s i t i o n .
c) O x i d a t i o n and c y c ! i z a t i o n by t h e u s u a l scheme a c c o m p a n i e d by a c y l m i g r a t i o n with
the formation of a 5-acyloxy derivative.
I t m u s t be n o t e d t h a t t h e t r a n s f o r m a t i o n of the 4-acyloxy group into a 5-acyloxy group
o c c u r s b o t h i n t r a - and i n t e r m o l e c u l a r l y . T h i s was e s t a b l i s h e d by c a r r y i n g o u t r e a c t i o n o f
the 4-acetyloxycarbinolamine (A) i n p r o p i o n i c a c i d . A c c o r d i n g t o PMR s p e c t r o s c o p y t h e r e a c -
t i o n p r o d u c t c o n t a i n s up t o 30-50% p r o p i o n y l o x y d e r i v a t i v e ( a l s o d e t e c t e d by mass s p e c t r o m e -
t r y and TLC) t o g e t h e r w i t h t h e 5 - a c e t o x y d e r i v a t i v e . Two r o u t e s w e r e p r o p o s e d f o r t h e m i -
g r a t i o n o f t h e a c y l g r o u p , one o f w h i c h i s t h r o u g h t h e i n t e r m e d i a t e (B) (Scheme 7),

415
 Scheme 7
-oO
On

and the other involves solvent participation (Scheme 8).

Scheme 8

In a continuation of this investigation the quinone (X) was reacted with the tertiary
enamine (XVII) which cannot form an indole derivative [17]. In this case compound (XVIII)
was successfully isolated, together with compounds (XIII) and (XIV), and was formed by mi-
gration of the acetyl group to the ~-methyl group of the enamine (Scheme 9).

Scheme 9
,COOF~ O
z + cH~ c~c%cooH ~ + ~ +
z~176 (ao~) (zoo) c~zcocn~
0
. z ~ Fl, 5 ok)

The f o r m a t i o n of (XVIII) may be r e p r e s e n t e d in the following way (Scheme 1 0 ) .

Scheme 10

~ ~ ~ Oxidation
X +~l~r ~ _ T ~--
OH
o ooo~ ~ ~ ~

- n -Q~l

Transfer of the acetyl fragment is linked with the enamine-enamine tautomerism (equili-
brium A), a phenomenon well studied for a series of enamines of various structure [18].
Several studies [19-23] have been devoted to the behavior of 2-acetylbenzoquinone (XIX) deriv-
atives in the Nenitzescu reaction.. Apparently the introduction of an unsymmetrical quinone
derivative into reaction with enamines dictates the need for a careful study of the struc-
ture of the compounds obtained. The product of reacting the quinone (XIX) with the enamine
(XVII) was assigned the structure of a 5-hydroxy-6-acetyl derivative of benzofuran (XX) [19].
However, it was subsequently established [20] that this reaction proceeds differently with
the formation of the 4-acetyl derivative (XXI). Essentially in this study [20] the authors
succeeded in isolating the intermediate (XXIa) in which the H-3 and the piperidine residue
are located trans to one another and the piperidine is readily eliminated at 20~ in DMSO
(Scheme ii).

416
 Scheme ii
O

Some investigations have been devoted to the addition of enamines to quinone by a type
of Nenitzescu reaction with subsequent study of the acidic rearrangement of the resulting
2,3-dihydrobenzofuran derivatives. The reaction of the quinone derivatives (XIX) with $-
mono- and $,~-disubstituted enamines was studied [21, 22]. The general scheme of the pro-
cesses investigated may be summarized in the following manner (Scheme 12).

Scheme 12
O
~zMe ~CCMe H /Me
o

OJ]MeMe
HO~Me COM~s
H O ~ M e

I u i~--Y I U ~iik--/

COM~
S H
- OOM~ -
HO..~_.__~/~fe H 0 ~ M e

qj(d~o"M~ ~ U~ ~
I -OH I Oil
R

OH O
1
OH 0 1
Pl H OH
~. OH j
22~

HO 0 O OH

I~M e
z~

It is extremely interesting that when a $-monosubstituted enamine is used the reaction

is accompanied by oxidation of the dihydroxyphenyl fragment, but when a ~,~-disubstituted
enamine is used this oxidation does not take place. This is probably linked with the pres-
ence of an electron-acceptor in compound (XXII) and an electron-donating group in the inter-
mediate (XXIII).
The isomeric dihydrofurans (XXIV) and (XXV) were isolated when studying the reaction of
acylquinones with the morpholine enamines (XXVI) [23] (Scheme 13).
Scheme 13
!
a OOCIIz~

0 xxw
Cis adducts

417
 Scheme 13 (continued)
7
ooc~zm

Trans adducts

IEJ 0 0t:I 0 OH
C O C H z 1~7

t=t

As already mentioned above, only in the event of a trans disposition of the amino frag-
ment in position 2 and the proton in position 3 is elimination leading to the formation of
benzofuran derivatives possible. Other processes are characteristic of cis adducts which
are linked with rearrangements by the action of an acid catalyst.
Analogs of quinone, such as the arenesulfonamido derivatives (XXVII), also take part in
the Nenitzescu reaction. Dibenzofurans are formed in good yield on reacting the derivatives
(XXVII) with tertiary enamines [24] (Scheme 14).

Scheme 14
H

~xviF

Analogs of t11~ s o - c a l l e d hydroquinone adducts (70(VlII) were i s o l a t e d on c a r r y i n g out the

r e a c t i o n of (XXVII) w i t h secondary enaminocarbonyl compounds. On h e a t i n g i n e t h y l e n e g l y c o l
or aqueous a c e t i c a c i d these were c o n v e r t e d i n t o the 5-aminobenzofuran d e r i v a t i v e s (XXIX)
and by s u l f u r i c a c i d i n t o the enaminolactones (XXX) [25] (Scheme 15).
Scheme 15
,~ . 80zAr
OOZ m~z~r I
/ GOZ I-IN GOZ

It 2oG / ~ . 7 ~ d q - O - M = . ~ . ~

It must be noted that a similar lactonization was also observed recently for the series
of normal hydroquinone adducts obtained by reacting 2-chloro-5-methylquinone and derivatives
of ~-aminocrotonic acid ester [26]. Derivatives of 5-aminoindole are obtained in moderate
yield on reacting compounds of type (XXVII) with N-arylaminocrotonic acid esters [27]. Ref-
erence may also be made to an extremely interesting study [28] based on the use of 2,6-di-
chloro derivatives of benzoquinonimines (XXXI). Derivatives of 6-hydroxyindole are obtained
on reaction with enamines. In the opinion of the authors there are two possible routes for
forming these products (Scheme 16).

418
 Scheme 16

Ar~ ~1 + 7 E,

XXXI

Ol NSOzAI" COOEr

The a u t h o r s c o n s i d e r e d r o u t e B t o be l e s s p r o b a b l e . L a t e r , when d i s c u s s i n g s e v e r a l i n -
vestigations d e v o t e d t o t h e s y n t h e s i s o f 6 - h y d r o x y i n d o l e s , i t w i l l be shown t h a t t h i s h y -
p o t h e s i s i s p r o b a b l y c o r r e c t and t h a t r o u t e A p r e d o m i n a t e s . The i n t r o d u c t i o n o f s u b s t i t u -
ents into the 2,6-positions o f q u i n o n e (XXVII) changed t h e c o u r s e o f t h e i n d o l i z a t i o n p r o -
cess. 6 - H y d r o x y i n d o l e s w e r e o b t a i n e d in p l a c e o f 5 - h y d r o x y d e r i v a t i v e s [28]. Such a d e -
p e n d e n c e o f t h e c o u r s e o f t h e N e n i t z e s c u r e a c t i o n on t h e q u i n o n e s t r u c t u r e has been ob-
served in other investigations. On r e a c t i n g 2 , 6 - d i b r o m o b e n z o q u i n o n e (XXXII) w i t h N - s u b s t i -
tuted ~-aminocrotonic acid esters only the first stage of the process, a Michael-type addi-
tion, occurs [29]. S t a b l e h y d r o q u i n o n e a d d u c t s (XXXIII) a r e f o r m e d which do n o t c y c l i z e
i n t o d e r i v a t i v e s o f i n d o l e o r b e n z o f u r a n (Scheme 17).
Scheme 17
I3r
O. B).r C OOI9. go [ . ~OE~

R=R'=Me: R=H, R'=PhCH2; R=H, R~=Ar

The anomalously high stability of the adducts (XXXIII) is explained by the authors by
the steric hindrance of the two large substituents (Br, COOEt) which prevent the hydroquin-
one ring from conjugating with the enamine fragment. In its turn this hinders benzofuran
cyclization due to the removal of the phenolic hydroxyl away from the s-position of the en-
amine and prevents oxidation to the corresponding quinone by inhibiting the electron-donat-
ing effect of the enamine grouping. The latter undoubtedly leads to inhibition of the in-
dolization process (see discussion of the reaction mechanism below). A real effect of re-
placing the hydrogen atoms in positions 2 and 6 of the benzoquinone by bromine was also ob-
served when investigating the reaction of the quinone (XXXII) with various S-substituted
enamines [30]. These special features are discussed in detail in later sections of the re-
view. Finally, an investigation [31] of the reaction of enamines with 2,3-dichlorobenzo-
quinone may be mentioned. Derivatives of 6,7-dichloro-5-hydroxyindole and benzofuran were
synthesized and the difficulty of the benzofuran cyclization of the adducts (XXXIIIa) was
demonstrated. This is also probably due to steric reasons (the presence of a chlorine atom
together with the phenolic group participating in cyclization) which however are not so sig-
nificant as in the case considered above when two bulky groupings are overlapping (Scheme
18).
Scheme 18

KO•cooEt
C1
C1
- A e OII~ boili~ ~
]iO

CI
COOEr

If the quinone contains a strong electron-donating group, addition of the enamine oc-
curs exclusively at the position para to this group [32] (Scheme 19).

419
 Scheme 19
+ .[]...C00Et H0 C00E,
0

M~ xxxlV iff~ c--._l

The regioselectivity of the process is changed fundamentally on using the corresponding

quinone monoketals. The reaction in this case proceeds by a completely different route in-
volving addition of the enamine (XXXIV) at the B-position to the activated double bonds of
the quinone [32]. The presence of an electron-accepting nitro group in the quinone does not
affect the course of the heterocyclization process (in difference to the use of nitroen-
amines, see below) [33] (Scheme 20).
Scheme 20
O

0 1)2)Nali,PizTHF
O M__~",...
900D,~/~.~
~0Me -{- xxx;v ~---
~r~- o~T-o!~e ~ I ~", 1
Y

o
0 hi ~

In concluding this section we note the reaction of o-benzoquinone with enamines [34].
The first step of this process is a Michael addition but the subsequent reaction occurs in
a different way than in the Nenitzescu synthesis of indoles since the quinone carbonyl does
not participate (Scheme 21).
Scheme 21

~hmv
F~00C

-----. H0H
.~OHM~'e ~ --Fh ~ ~~oom~]----t
C00Ez 5,8%

II. Effect of Enamine Structure

The structure of the enamines used in the Nenitzescu reaction has been varied to a pos-
sibly greater extent than the structure of the initial quinone.
One of the principal problems of the Nenitzescu reaction is the possibility (in many
cases) of two alternative processes occurring as a result of which derivatives of indole
and benzofuran are formed [12]. One further course of the reaction, to form 6-hydroxyin-
doles (in place of the 5-hydroxy derivatives usually isolated), is extremely important.
Examination of the latter problem shows that important roles are played both by the struc-
ture of the enamine used and by the reaction conditions. The problem of forming 6-hydroxy-
indoles when carrying out the Nenitzescu reaction in acetic acid [12, 36, 37] has been in-
vestigated [35]. The quinone was added slowly to an excess of enamine in acetic acid. The
enamines used were amino-, N-methylamino-, and N-benzylaminocrotonic acid esters (XI, R z =
H, Me, PhCH2). Distinct variations in the yield of the 5-hydroxybenzofuran (XXXV), 5-hy-
droxyindole (XXXVI), and the benzodifuran (XXXVII) were observed depending on enamine struc-
ture. However isolation of 6-hydroxyindole derivatives was unsuccessful in every case*
(Scheme 22).

*Considering the relatively low yields of the compounds isolated and the fact that the au-
thors did not use any analytical methods to study the reaction mixture (which is often ex-
tremely complex due to resinification during the Nenitzescu reaction) the conclusions drawn
must be regarded with caution.

420
 Scheme 22
0 O00F~ H O ~ T E ~

I:1=I%Me, P h c I ~ whenI~=Me, y i e l d &-%

~18=n R=l~nC~ z,I,~-
k IR=Ii.
Me 0 CO0~

- o ~ ~~~~m'~'o'" +
for ~ 1~=ll,yieldl#% #.r*v,l ke
1~=IVfe , Z3 % -
H=PhclIz,Z5% 4% ~'~

It was shown in another investigation [38] that 6-hydroxyindoles (XXXVIII) are formed
from (XI, R = o- and p-CIC~H~) on conducting the reaction in the absence of an excess of
enamine (the enamine is added slowly to the quinone) in cooled acetic acid. 5-Hydroxyin-
doles are obtained from N-alkylenamines and the same order of addition. When using acetone
as solvent (in place of acetic acid) only 5-hydroxyindole derivatives are formed (Scheme
23).
Scheme 23

T ~OH ~ acetone ;F~

X%;fVl x x x v/"

Similar results, i.e., a change in the course of the process on changing from N-alky-
lenamines (5-hydroxyindoles are obtained) to N-arylenamines (6-hydroxyindoles are isolated),
were observed in another investigation [39]. Reaction was carried out in a mixture of ace-
tic acid and dichloroethane at 0~
The synthesis of 2-alkoxy- and of 2-methylthio-5-hydroxyindoles was effected using $-
amino-B-ethoxyacrylic acid ester [40] and $-amino-~-methylthioacrylonitrile [41], which had
not previously been used for this purpose. In the first case ethyl alcohol was used as sol-
vent and in the second acetic acid (Scheme 24).
Scheme 24
Z 2
o ~ HO H

! I
I~ =At(for XI~ = ~%2vfe)
I~2=COOgt, CN-

Since the amide- and lactamacetals (XXXIX) exist in solution in equilibrium with the
corresponding a-alkoxyenamines (XL) [42-44] it is possible to react the latter with the
quinone (IV) with the formation of the condensed benzofurans (XLI) [45, 46] (Scheme 25).

Scheme 25

~N" ~OZ~
Me Me

In the case examined above the polymethylene chain is added to the B-position of the
enamine (XL). Although in many studies devoted to the Nenitzescu reaction there is an elec-
tron-accepting group in the B-position of the enamine, data are presented in several inves-
tigations on the use of ~-alkyl- or $,B-dialkylenamines. On reacting substituted quinones
with the morpholine enamine of benzyl methyl ketone the stepwise course of the synthesis of
the benzofuran derivative (XLII) was followed [47] (Scheme 26).

421
 Scheme 26
IR /_~N_ f h HO R HH
0~0 ~ 0 Me Benzene~
zooc -
~~IN/=~.O
v 0 ~HIPh
H
Alcohol § li3l~O~~ R=Cbli4h[Oz_
p
~o" "catzvh
ZL~

This conversion was effected for a whole series of examples. It is extremely signifi f
cant that the reaction occurs in all cases exclusively at the methyl group (the correspond-
ing tautomeric form of the initial enamine probably participates in the cyclization) and the
authors failed to detect even traces of the other isomer with a substituent at position 3
of the benzofuran ring. S,S-Dialkylenamines also take part in the Nenitzescu reaction. 2-
Substituted amino-3,3-dialkyl-5-hydroxy-2,3-dihydrobenzofurans are then obtained [48].
Several studies are devoted to the use of various enamino ketones in the Nenitzescu reac-
tion. The bis-benzofuryl ketones (XLIII) were synthesized when using 2-R-5-methoxy-3-~-
dimethylacryloyl-benzofurans as the enamine [49] (Scheme 27).

Scheme 27
o
MeO~_~CO ~,fMeZ 1~"7M ~ O ~ O H
- o "-
ZL~
The enamine components S-methylaminovinyl methyl ketone (XLIV) and S-methylamino- ~-
methylvinyl ethyl ketone (XLV) have been studied in order to clarify the influence of the
steric effects of the substituent in the B-position of the enamine on the course of the
Nenitzescu reaction [50]. In the first case, when steric hindrance is absent, the reaction
proceeds by the usual course and 3-acetyl-5-hydroxybenzofuran is isolated in 30% yield. In
the second case the steric factor is so significant in the authors' opinion that the process
occurs in a different way with the formation of the benzodioxepine derivative (XLVI). It
was suggested that the initial attack in this case is the addition of quinone to the oxygen
atom of the enamino ketone (attack at the carbonyl of enaminoketones is a very characteris-
tic property of the latter and data on the ortho addition of electrophilic reagents are well
documented in this series of compounds [51, 52]) (Scheme 28).
Scheme 28

o
+ ~-c-c-~
0 0 0
XZI:r | Et

I o ''l'mli'x~ _ ~' o. ~

i za~" Oxidationi E,
NO GOGII5 9 O

Et

One further investigation of the action of steric factors on the course of the Nenitze-
scu reaction is devoted to the study of the reaction of 2-chloro-5-methylbenzoquinone
(XLVII) with derivatives of B-aminocrotonic acid ester (XIa-d) having differently sized
substituents on the nitrogen atom [53] (Scheme 29). (See Scheme 29 on following page.)
It was established in this work that the indolization rate depended appreciably on the
size of the N-substituent. The application of iH NMR spectroscopy to the analysis of the
reaction mixture when comparing the reaction of the quinone (XLVII) with the enamines (XIb)
and (XId) showed that for (XIb) the ratio of hydroquinone adduct (HQA):quinone adduct (QA):

422
 Scheme 29
C1 C1
AeOH, S 0 - $ 5 ~ ~- I
HN--O--Me
Me 2Za-d Me I~
Xs r 1~= I-I(a), Me (b), FhoHz(c ), E%[d) HPA

C]
0 ~ ~ 0 0 _ M e C~176 =o
QA .
.Y/"~P" a-d

2-chloro-5-methylhydroquinone (HQ):indole (XLVIIIb) was 1.5:2:3:4.5 after 2 h heating and

the main product was the indole (XLVIIIb) with a little initial quinone and HQ. On increas-
ing the size of the N-substituent the indolization process was retarded and the reaction re-
quired 14 days in place of 72 h.
Cyclic enaminoketones of various types must be mentioned among the nontraditional en-
amines used in the Nenitzescu reaction. Various 2-aminomethylene derivatives of cyclopen-
tanone, cyclohexanone, and cycloheptanone were reacted with quinones [54-57] with the aim
of obtaining condensed 5-hydroxyindoles (XLIX). The synthesis of a large group of analogs
of the drug pyrazidol was effected in this way [58] (Scheme 30).
Scheme 30
h~D

The reaction of 2-arylaminomethylenecyclohexanones (L) with 2,3- and 2,6-dichloroquin-

ones occurs in a significantly more complex manner. Features linked with the quinone struc-
ture (see section I) are here added to those arising from the cyclic structure of the enamine.
In difference to the investigations considered above the quinones used here [59] contain two
electron-accepting substituents, i.e., the quinones have an enhanced oxidative ability. As
a result the course of the reaction linked with the preparation of an analog of (XLIX) (n =
2) is not effected fully. In the first step oxidation of the enaminoketones (L) by the di-
ha!oquinone to the dienaminoketones (LI) occurs and these then undergo a Nenitzescu reac-
tion as vinylogs of enamines~ The reaction scheme consists of the formation of a hydro-
genated intermediate (LII), which was isolated, characterized, and subsequently converted
into the dibenzofuran (LIII) [59] (Scheme 31).
Scheme 31

s
L

I Oxidation

is
---~ ' ~ 0 Oxidation= ~ ~

ff

Oxidati2~~r
~ o H
L~
423
 Enaminoketones of another type (LIV) also add to quinone with the formation of stable
hydroquinone adducts (LV) which may be oxidized to the corresponding quinone adducts (LVI).
The latter may be converted either into cyclic quinones of the indole series (LVII) or into
condensed benzazepines (LVIII) depending on the conditions [60].
It is interesting that when there is a substituent with a free ~-CH 2 group on the en-
amine nitrogen the reaction proceeds differently and derivatives of oxazepine (LIX) are
formed [61] (Scheme 32).

Scheme 32

l~ A

,"F" o
~ 0

a~Hhr g "x~
o ~ f.l~"
n ~ ~ o

o ].-! o
o- Ho

1 ~ ~ 0

A whole group of investigations has been devoted to studying the reaction of quinone
(IV) with $-nitroenamines. Reaction of (IV) with derivatives of s-amino- or ~-S-methyl-$ -
nitroethylene (LX) leads to a mixture of 5-hydroxybenzofurans (LXI) and 5-hydroxyindoles
(LXII)* [62] (Scheme 33).
Scheme 33

0 Jr H y N O z~I-Io~__~2r z
~ 0 I~tN-~ "~X - 0 -X
ZZ L,Kr L~F
X=NItNy, ~
or XI~=CIIzOHZjq~I

When studying the reaction of benzoquinone derivatives with l-dimethylamino-2-nitro-

ethylene (LXIIa) and l-nitro-2-dimethylamino-l-propene (LXIIb) it was established [63, 64]
that the complete absence of water, achieved by adding Ac20 to the AcOH in which the reac-
tion is carried out, was necessary for the efficient conduct of the reaction with (LXIIb).
In the case of (LXIIa) the presence of I-3% water in the reaction mixture has no effect on

*The authors of [62] assigned the structure of 5-hydroxyindoles to the compounds obtained
without considering the possibility of forming 6-hydroxyindoles in addition.

424
the course of the reaction. On the other hand, the reaction of quinones with (LXIIb) occurs
without the use of catalysts but (LXIIa) requires the use of an acid catalyst (toluene-p-
sulfonic acid was added) (Scheme 34).
Scheme 34

f~Fa, tR~H, Me

Interpretation of these data is based on the fact that enamines having a methyl group
in the e-position are characterized by a high basicity linked with the large contribution of
C-profionation and a correspondingly high tendency to hydrolyze [65, 66]. Hence the need to
dehydrate the medium in the case of the enamine (LXIIb) and also the need to increase the
acidity of the medium for a more efficient C-protonation of enamine (LXIIa).
The reaction of quinone with the secondary nitroenamines (LXllla-d) depends on the
character of the substituent on the nitrogen atom of the enamine [67]. When using (LXIIia)
(R = H) only the benzofuran (LXIV) is isolated in 57% yield. From (LXIIIb) (R = Me) an in-
dole derivative was isolated in 7% yield in addition to the benzofuran (LXIV) (67% yield)
and it was clearly shown that the 6-hydroxyindole derivative (LXV) was obtained.* The ratio
of 6-hydroxyindole to benzofuran increased on changing to N-benzyl- and even more so to N-
arylnitroenamines. According to the data of IH NMR spectroscopy when using (LXIIIb) and
(LXIIId) (R = p-MeOC6H 4) the ratio of 6-hydroxyindole to benzofuran in the reaction mixture
was 0.07:1 and 0.32:0.68 respectively (Scheme 35).

Scheme 35

0 HO ~ ~f "Me
R
K~ a-d f.~7
~zY17"a-d
~=H(a) , M e ( b ) , rhC!~l?(c/, p-~-::(~61-I4 (d)
Investigation of the reaction of benzoquinone with cyclic secondary nitroenamines [68]
in acetic acid showed that the size of the enamine ring was one of the factors determining
the course of the reaction. Use of the five-membered enamine (LXVIa) does not give an in-
dole derivative (Scheme 36).

Scheme 36
NO~

HO NO z

fZ~ra Ae
NO Z

In the case of the six-membered derivative (LXVIb) the process occurs mainly by the
same route but leads to the dihydroxyindole derivative (LXVII) (Scheme 37). (See Scheme 37
on following page.)
However, derivatives of indole predominate among the compounds isolated from the reac-
tion of benzoquinone (IV) with the seven-membered enamine (LXVIc) (Scheme 38). (See Scheme
38 on following page.)
Many data on the effect of enamine structure on the result of the reaction with quin-
ones were obtained in the study already cited above [30]. In this investigation (the sol-

*This was demonstrated by IH NMR spectroscopy using the nuclear Overhauser effect arising
from the steric proximity of the N-methyl group and the proton at position 7 of the indole.

425
 Scheme 37

217" +
..r --"
i,r z
<i--i
~ b-"(cHz)4,r~.~
+

Lz~r OAe

+ ~c~ + u~ ~z
z.z1~

Scheme 38

c~z)z m_ .L OAe
~oz A~O ~
OH
~NOz

"'-,.-, ~ (cm)o v

~-oz
~ ~z ~o. ~ So~ ~o~..___...~
+ + ~ .... +

vent was acetic acid in all cases) it was shown that the reaction of quinones with N-
alkyl- and N-aryl-8-cyanoenamines occur in different ways. A 5-hydroxyindole is formed
in the first case and a 6-hydroxy derivative in the second. On the other hand only 6-hy-
droxyindole derivatives* (in addition to 5-hydroxybenzofuran derivatives) were isolated
from p-nitroenamines (Scheme 39).
Scheme 39
O ON F~9 C~

At"

HO ~ ~ "Me
/

In concluding this section of the review we note an interesting investigation in

which a 6-aminouracil derivative is used as the enamine in the Nenitzescu reaction. The
authors successfully isolated the heterocyclic analog of a hydroquinone adduct (LXVIII),
the product of bis-addition of the heterocyclic enamine to the quinone (LXIX), and also the
desired pyrimidoindole derivative (LXVIIIa) [69] (Scheme 40). (See Scheme on following page.)
It must be noted that the indole cyclization occurs significantly better in nitrometh-
ane than in acetic acid. In nitromethane the yields of (LXVIIIa), (LXVIII), and (LXIX) were
41%, traces, and 17%, respectively, and in acetic acid 8, 25, and 15%.
*The proposed interpretation of the data obtained regarding nitroenamines is considered be-
low in the section where the mechanism of the Nenitzescu reaction is discussed.

426
 Scheme 40

O O

+ +

g~a O

OH- nzg g o 0

III. Mechanism of the Nenitzescu Reaction

The main stages of the conversion of quinones and enamines into derivatives of 5-hy-
droxyindole and 5-hydroxy-benzofuran have been studied fairly thoroughly. Many intermedi-
ates formed during the Nenitzescu reaction have been isolated and their properties examined.
The overall pathway which occurs in these investigations [12, 51, 53, 70] is shown below
(Scheme 41).
Scheme 41

O ~ X o ~ jH
§ - -

i~ IR + I

Hydroquinone adduct (HQA) Quinone adduct (QA)

O X
--In-- ~ Reduction y

Carbinolamine
In one of the studies devoted to the stepwise synthesis of 5-hydroxyindoles [70] it
was shown that the HQA may be cyclized to the indole in acetic acid only in the presence of
quinone, which definitely indicates the requirement for an oxidative step in the course of
indolization. The acidic medium, in the authors' opinion, is necessary to induce cis-
trans isomerism at the stage of converting the QA to the carbinolamine. In our view such
isomerism may also occur in the absence of acidic reagents in view of the tendency of en-
amines towards some restriction of the rotation about the carbon-carbon double bond which
has been studied in detail for several examples [71, 72]. It was also established in [70]
that if a quinone is absent from the reaction mixture (in CH3COOH) then the HQA is converted
into the corresponding benzofuran. In the investigation cited above [53] it was established
by NMR spectroscopy that on mixing equimolar amounts of hydroquinone adduct with the corre-
sponding quinone in deuteroacetic acid for 6 h the formation was observed of derivatives of
5-hydroxyindole, hydroquinone, quinone, and quinone adduct in the ratio 1:2:3:3, and after
24 h a mixture of indole and quinone in a i:i ratio was found. In a completely analogous
manner, mixing the quinone adduct with hydroquinone for 24 h gave the same mixture in the
same ratio (Scheme 42). (see Scheme on following page)
It is well known, and has been discussed above in this review, that derivatives of 4,5-
dihydroxyindole are formed in the Nenitzescu reaction in addition to 5-hydroxyindole deriv-
atives.
A significant step forward in understanding the indolization process in general and the
formation of dihydroxyindoles in particular was the isolation and study of the properties of

427
 Scheme 42

HQA + QA + OH'-'--""
/3 H
z z
O. ~HQ ~K~ ~ i~ O~o

N ~ N ~ IR IN

the intermediate carbinolamines (LXX). It was established [73, 74] that on reacting the
carbinolamine (LXX) with amines and anions of activated methylene compounds [71] the nu-
cleophile attacks the a-methylene group (Scheme 43).

Scheme 43

O. ~ .COOE~ HO COOE~ HQ COOEr

2.,E~
XH = piperidine, morpholine, 2-aminopyridine, cyanoacetic ester (in the presence of i-
Pr2NEt), and dimedone (in the presence of MeONa).
4-Substituted indoles are formed when the reaction occurs under the action of acidic
reagents [73]. However acid chlorides react differently, initially acylating the hydroxyl
on the quaternary carbon atom with subsequent addition of halogen anion at position 6 of
the molecule. On carrying out the same reaction with acetyl chloride in pyridine the lat-
ter acts as a competing nucleophile [73] attacking position 4 (Scheme 44).

Scheme 44
x

ioxan X=CI, OH, OAe

I ~coc~ o~1~__jco~ 2o~000m

ipyridine ~ i X-
' noc(J L ~e x ~e ~'~

Mo Me.

Extremely important information contained in the above studies concerns the ability of
carbinolamines to add such groups as acetoxy at position 4 with the formation of 4,5-dihy-
droxyindole derivatives. However, as already mentioned above, migration of the acyl group
to position 5 occurs in these cases (see also [16, 17]) as was observed in the reaction of
carbinolamines with carboxylic acids [75, 76] (Scheme 45).

Scheme 45

OAe Ol~
~o~__~coo~ AeO~cooEt

T h i s was p r o v e d s t r i c t l y u s i n g t h e f o l l o w i n g c h a i n of c o n v e r s i o n s [77] (Scheme 46),

(see Scheme 46 on following page)

428
 Scheme 46

++,,rot .RH2 OId:

?,.A.,..5<
'< < k - s
c.~o i
+ .... '
..coc+:t
- +
k __coo +

IHtph Clltl~ /HZPh

Participation of the intermediate carbinolamine in the Nenitzescu reaction may come

about in two ways. First, when hydroquinone or the hydroquinone adduct are present in the
mixture the carbinolamine is reduced to a 5-hydroxyindole derivative [76], and secondly,
the formation of 5-acetoxy-4-hydroxy derivatives is observed [75-77]. It must be noted that
an important role in the preparation of aromatic indole derivatives is played by the medium
and there is an indication [78] that it is not possible to reduce carbinolamines in an apro-
tic nonpolar medium. In the same study [78] the author successfully isolated several new
products together with the usual compounds from the Nenitzescu reaction (Scheme 47).

Scheme 47

0 IR~ OH NI- Me
% > < o .~/ I L NttH
-
zr H

Me ~ Me_ COOEr

+ -t- +
E~ OOC Me - N _~ '
I
R M-e
It was established that the carbinolamine (LXX) is capable of adding enamines at the
4-position of the indole ring as well with the formation of the 4-indolylenamines (LXXI)
which however are incapable of further cyclizalion to the corresponding pyrroloindoles
(Scheme 48).
Scheme 48

Me ~ COOPA

Me
z~Zr

Enamines may also add to the quinone adduct [79]. This process is the final step in
the synthesis of pyrrolo[2,3-f]indoles (Scheme 49). (see Scheme on following page)
When summarizing the data presented above it may be noted that the first step of the
Nenitzescu reaction, the formation of a hydroquinone adduct, guarantees the further possi-
bility of 5-hydroxyindole synthesis only under conditions of a subsequent oxidation stage.
The conversion of the HQA into benzofuran derivatives is observed in the absence of an oxi-
dizing agent or under conditions when oxidation is impossible for some other reason.
An unusual conversion accompanied by acyl migration of a different type from that dis-
cussed above has been investigated [80]. It was shown that ~-alkylenaminoketones react at

429
 Scheme 4g

o A

H~ L
~'

14e

~~176 ~-~6 ~, ~ I
Me J

low temperature with quinone at the B-position with subsequent acyl migration and further
addition of quinone (Scheme 50).

Scheme 50

0 _

COll

One more process, which frequently accompanies the synthesis of 5-hydroxyindoles, viz.
the formation of the 6-hydroxy isomers, is probably also unconnected with the oxidation-re-
duction stages. Several investigations have been devoted to consideration of this route for
the Nenitzescu reaction. It is still unclear at present which of the stages, either the ad-
dition of the NH of the enamine to the 2-position of the quinone or attack by the enamine S-
carbon atom at position 1 of the quinone occurs first (Scheme 51).

Scheme 51

I j A

On reacting benzoquinone with N-arylenamino esters in propionic acid at low temperature

a mixture is obtained of the corresponding 6-hydroxyindoles (10-30% yield), 4-hydroxy-5-pro-
pionyloxyindoles (20-35%), and 6-arylamino-5-hydroxybenzofurans (LXXII) (10-15%) [81]. The
formation of the latter was treated by the authors in the following way (Scheme 52). (See
Scheme 52 on following page.)
Proceeding from this scheme the authors considered it logical to propose that a similar
addition of enamine to the quinone (involving NH) is possible in the first stage of the re-
action and that route A is more probable. However it was concluded subsequently in detailed
investigations that the conclusion indicated was not true [82]. The authors of this study
proposed that if a system is generated in which the NH group is secured at a distance from
the quinone fragment and at the same time is included in an enamine system, cyclizations are
possible with the formation of bicyclic structures, including indoles (Scheme 53). (See
Scheme on following page.)

430
 Scheme 52

HvCOO~ HO.~_ ~ C O O E ~
~
-- \TC-i ---

I ~
COOE~

Me V f[--I

COOE~ O(X]~

HO-.f-2.~__~COOE~
+ m m ~ ~

f~

Scheme 53

o O~

However in all the cases considered in this investigation [82] only those processes
linked with attack by the enamine g-position at the s-position of the quinone were observed.
For example (Scheme 54):

Scheme 54
O O

191 O
Yield ~ 70 %
O

It follows from these model reactions that although addition of the enamine NH to the
quinone is possible [68, 81] the low nucleophilicity of this group makes such a closure of
the five-membered ring, and correspondingly the formation of 6-hydroxyindoles by route A,
less probable.
An even more persuasive argument in favor of route B (see Scheme 51) is the synthesis
of the N-quinonylenaminoketone (LXXIII) and the unsuccessful attempt to convert it into a
6-hydroxyindole derivative [83] (Scheme 55). (see Scheme on following page)
The authors were unsuccessful in achieving a 6-hydroxyindole cyclization under any of
the conditions usually used for indole synthesis. This points in favor of the fact that
compound (LXXIII) and analogous quinonylenamines are not intermediates in the preparation of
6-hydroxyindoles by the Nenitzescu reaction.
Before summarizing the results of the investigations on all the heterocyclizations ob-
served in the reaction of enamines with quinones we will consider one more most important
factor frequently determining the predominant route of the Nenitzescu reaction, viz. the ef-

431
 Scheme 55

OCHT.Ph ,OCI-[9_I~ O OH .0

Ph
O O O

O I~ H
LI2~
fect of the solvent. It has been established [37] t h a t t h e r e a c t i o n o f ( X I ) (R = Ar) and
( I V ) i n a c e t o n e l e a d s o n l y t o a 5 - h y d r o x y t i n d o l e w h i l e 6 - h y d r o x y i n d o l e s a r e f o r m e d when u s -
i n g a c e t i c a c i d * (Scheme 5 6 ) .

Scheme 56

0 OO0~ ItO COOEr.

HO Me ~ O HN !d~ Me
A~ flz I
Ar Ar

xz (l~=Ar)
A more striking picture is observed when studying the reaction of (IV) with G-amino-
crotonic acid ester (LXXIV) [84]. In chloroform a mixture is formed of the hydroquinone
and quinone adducts, in acetic acid a 5-hydroxyindole derivative, and in butanol a mixture
of the indolylenamine (LXXV) and the diazaheptalenedione (LXXVI). The mechanism proposed
for forming the latter involving a nitrene intermediate is shown in [84] (Scheme 57).

Scheme 57

~igtt ph ~r~tz

EtOOC v
3.-. 'J
COOEr
4

Buo~l .NH~
_., coo~ v ~ooo~e h
OH

coo~
v -~-"I:'h 0
A study on the use of nitromethane as solvent for the Nenitzescu reaction is extremely
interesting [85]. It may be concluded overall from this investigation that the use of this
solvent generates a whole series of preparative facilities for indole synthesis. Although
there is no clear interpretation of the data obtained in the study it is evident that the
use of this solvent opens new possibilities for obtaining indoles by the Nenitzescu reaction.
A detailed investigation [86] of the reaction of enaminoketones with quinone in various
media showed that in some cases the solvent has a decisive effect on the course of the reac-
tion. The main investigative method in this work was PMR spectroscopy. The reaction mix-
tures resulting after interacting the components were investigated. The ratio of 5-hydroxy-

*It should be noted that the low yields of the indoles obtained obviously reduce the relia-
bility of the conclusions.

432
indole to benzofuran was studied by PMR spectroscopy in various solvents (CH~COOH, dichloro-
ethane, ethanol, acetone, nitromethane).* The most important conclusion arising from this
work was that in acetic acid benzofuran synthesis is effected practically completely, but in
dichloromethane, and especially in nitromethane, 5-hydroxyindole derivatives are formed pref-
erentially. To explain the data obtained it is relevant to present and discuss the overall
scheme of the processes occurring in this reaction (Scheme 58).

Scheme 58

2V I ~ 1=1
I

R OH j+H+ H O ~ CO1~I

~ v [ e ' H O ~ I~l-~ ~ _H+~ ~"~,"'~ipq_/,~tv[ e

I
f~b !~
1=1 1N
f 2Tw]"a ~
' It'
~v~

f
II I

Y~

The intermediate hydroquinone adduct is protonated at the oxygen atom in acetic acid
which is very characteristic of enaminoketones [51]. The O-protonated form (LXXVIIa) is in
equilibrium with the C-protonated which is significantly more prone to react with nucleo-
philic reagents [87]. It is probable that just the immonium cation (LXXVIIb) is subject to
benzofuran cyclization although it is impossible to exclude the cation (LXXVIa) from con-
tributing to this process. The protonation also therefore determines the acceleration of
benzofuran cyclization. On the other hand oxidation of the hydroquinone adduct is effected
in the nonprotonated form, i.e., indolization is retarded in acetic acid.t
The situation is changed in dichloroethane. The sole (and just as weak) protonating
agent in this case is the hydroquinone adduct itself. Consequently, the rate of benzofuran
formation is reduced while transfer of an electron from this adduct to the quinone (IV) is
accelerated (compared with the reaction in CH3COOH). However dichloroethane also is not
the optimum solvent for indole synthesis. In reality, oxidation of the hydroquinone adduct
to the auinone adduct proceeds through the formation of the corresponding cation radical,
the efficient stabilization of which by solvation accelerates the oxidation process.
The oxidizing agent, the quinone (IV), is converted to an anion radical, the
protonation of which (on minimizing the protonation of the hydroquinone adduct)
must also accelerate the oxidation. All these conditions are fulfilled when using
nitromethane, which is a weak (acid (pK a 10.6) capable of solvating cations due to
the presence of the nitro group [89, 90]. Consequently, inhibition of benzofuran cycliza-
tion in nitromethane (due to too much weak acid) and acceleration of the oxidation~eduction
processes must lead to preferential synthesis of the indole, as is observed in practice [86].

*6-Hydroxyindoles and 4,5-dihydroxyindole derivatives were not confirmed in these reactions.

tWe have already indicated that cis-trans isomerism scarcely exerts a significant effect on
the indolization process. This follows particularly clearly from the spectroscopic study of
nitroenaminoquinones which showed that even under mild conditions restricted rotation rela-
tive to the enamine C=C bond was observed [88].

433
 In any attempt to describe fairly completely the processes occurring in the reaction of
quinones with enamines it is necessary to consider the preparation of 5-hydroxyindoles, 4,5-
dihydroxyindole derivatives, 5-hydroxybenzofuran derivatives, and 6-hydroxyindoles. In this
review such a discussion, accompanied by an interpretation of the experimental data avail-
able, has been carried out for the example of the reaction of quinones with nitroenamines
and related compounds [30, 67, 68]. The reaction of 2-amino-l-nitropropene derivatives
(LXIII) with quinone was investigated in [67]. As already mentioned an increase in the vol-
ume of the substituent leads to a reduction in the quantity of benzofuran formed (note that
the same picture is observed on increasing the volume of the substituent at positions 1 and
3 of the enaminoketone [86]). This phenomenon is explained successfully following consider-
ation of the structure of the primary product of benzofuran cyclization. A feature of the
structure of these intermediates is the presence of two sp3-hybridized atoms in the five-
membered ring. This is disadvantageous energetically [91] due to the screening of the
groupings in positions 2 and 3 of the dihydrofuran ring. If it is accepted that the cycliz-
ation stage limits the rate of forming benzofurans then it is understandable that the in-
crease in these nonbonding interactions on increasing the size of substituents must lead to
a slowing down of the cyclization (Scheme 59).

Scheme 59
O IR H

The synthesis of 5- and 6-hydroxyindoles is not linked with the formation of sp3-hy -
bridized atoms in neighboring positions of the five-membered ring and does not depend so
significantly on the volume of the substituents in the enamines. A second problem of the
use of nitroenamines is the formation of 6- and not 5-hydroxyindoles. This observation is
probably explained mainly by the sudden deceleration of the oxidation stage linked with the
presence of the electron-accepting nitro group in the hydroquinone adduct. Hence a reduc-
tion in the rate of 5-hydroxyindole cyclization is observed and the process shifts to the
direction of obtaining 6-hydroxyindoles, a process unconnected with the oxidation-reduction
stages. It was already noted above that the reaction of quinone with enamines depends ex-
tremely markedly on the ring size of these initial compounds [68]. Although this problem,
which is outside the scope of this review, is not resolved in detail we note particularly
that derivatives of 4,5-dihydroxyindole were isolated in this work, viz. 4-acetoxy-5-hy-
droxy-3-nitro-l,2-pentamethyleneindole and 5-acetoxy-4-hydroxy-3-nitro-l,2-pentamethylene-
indole. In this case migration of the acetyl group to position 5, although occurring, is
not as rapid as described for the 3-ethoxycarbonyl derivatives (see above). Finally, a
significant proportion of the problems mentioned above on the mechanism of the Nenitzescu
reaction are considered in [30], in which the reaction of 2,6-dibromoquinone with ~-cyano-,
~-acetyl-, and ~-nitroenamines was investigated.
investigated.
When summarizing the results obtained in this work it is possible to state the follow-
ing.
i. The course of the reaction changes on changing from N-methyl- to N-aryl-~-cyano-
enamines. 5-Hydroxyindoles are formed predominantly in the first case and 6-hydroxyin-
doles i n t h e second. Similar results have already been observed in other investigations
[38, 81].
2. As the electron-accepting strength of the ~-substituent in the initial enamine is
increased the tendency to form 6-hydroxyindoles increases. This process becomes predomi-
nant for ~-nitroenamines (as on reaction with the unsubstituted quinone).
3. During the reaction of ( X ~ I ) with cyano-, acetyl-, and nitroenamines an unexpected
dehalogenation occurs with the formation of 5-bromo-6-hydroxyindole derivatives, one more
process in the Nenitzescu reaction.
Replacement of an N-alkyl substituent by N-aryl reduces the electron density at the 6-
carbon atom and leads to a reduction in the rate of addition of enamine to quinone. Prob-
ably the less electron-deficient position 2 is more sensitive to such a reduction in nucleo-
philicity than the carbon of the quinone carbonyl group. Consequently, the first type of ad-

434
dition is responsible for the formation of 5-hydroxyindoles and the second for 6-hydroxyin-
doles. The course of the process is shifted in the direction of the latter. It seems
probable that the oxidation of the intermediate hydroquinone adduct plays an important role
in this case. The presence of an N-aryl group (in place of N-alkyl) reduces to a large ex-
tent the electron-donating effect of the enamine fragment, it reduces the rate of oxidation,
and consequently the rate of forming 5-hydroxyindoles. As already mentioned above an in-
crease in the electron-accepting strength of a substituent increases the stability of the
hydroquinone adducts towards oxidation. This also leads to a shift of the process in the
direction of forming 6- (and not 5-) hydroxyindoles. Extremely important data were obtained
on dehalogenation during the reaction of dibromoquinone (XXXI) with enamines. A possible
explanation is given in the following scheme (Scheme 60).

Scheme 60

+ i~ ~ o ~ i _ R, ~
i ~- - 6 - ~ -

Br HI t~ H N-I "
0 / r O- x ~ s
r~ O H ~ - ~ gz-addition w- ~ ~
B
1:1

I 1
I~'- 0 ~ 3"1- ~

When summarizing all the data presented in this part of the review it is possible to
cite a general scheme for the main processes occurring during the Nenitzescu reaction lead-
ing to the main types of compounds considered above (Scheme 61).
Scheme 61

oi, ol 1
R iH ~ l-H(3
[ ']~ < 5_hydrOxybenzofurans

I I 5-hydroxyindo
Ies [

"-.,. =o... ',

6-hydroxyindoles 5-bromo-6-hydroxyindoles A o . O ~

I
4-hydroxy-5-acy I_oxyindoles

435
 In conclusion it must be noted that it is necessary to carry out further, more pene-
trating investigations in order finally to clarify the numerous and ambiguous processes oc-
curring during this complex multistage reaction. It is without doubt however that investi-
gations on the Nenitzescu reaction are important and fruitful both from theoretical and syn-
thetic aspects, opening significant possibilities for the synthesis of new heterocyclic com-
pounds, including some of interest in the search for different effective drugs.

LITERATURE CITED
i. M. D. Mashkovskii, Drugs [in Russian], Vol. i, Moscow (1984), pp. 447, 452.
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