Regioselectivity in electrophilic substitution of 5-aminoindoles and 5-aminoindolines: Synthesis of pyrrolo[3,2-e]indoles and isomeric pyrrolo[2,3-f]indoles

Article abstract of DOI:10.1016/S0040-4039(00)93421-X

An FMO Theory prediction that 5-aminoindoles, 5, should react with electrophiles preferentially at C₄ rather than at C₆ whereas N₁-acyl-5-aminoindolones, 6, should react preferentially at C₆ rather than C₄ is borne out experimentally by the synthesis of a pyrrolo[3,2-e]indole from 5 and pyrrolo[2,3-f]indoles from 6.

Full text of DOI:10.1016/S0040-4039(00)93421-X

Tetrahedron Letters, Vol.32, No.38, pp 5035-5038, 1991
Printed in Great Britain
0040-4039/91 $3.00 + .00
Pergamon Press pie
REGIOSELECTIVITY IN ELECTROPHILIC SUBSTITUTION OF 5-AMINOINDOLES
AND 5-AMINOINDOLINES: SYNTHESIS OF PYRROLO[3,2-e]INDOLES AND
ISOMERIC PYRROLO[2,3-f]INDOLES t
Ganesh K.B. Prasad, Andrew Burchat, Gamini Weeratunga, Ian Watts, and Gary I. Dmitrienko*
Guelph-Waterloo Centre for Graduate Work in Chemistry, Waterloo Campus, Department of Chemistry,
University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
Abstract: An FMO Theory prediction that 5-aminoindoles, 5, should react with electrophiles preferentially at
C4 rather than at C6 whereas Nl-acyl-5-aminoindolines, 6, should react preferentially at C6 rather than C4 is
borne out experimentally by the synthesis of a pyrrolo[3,2-e]indole from 5 and pyrrolo[2,3-f]indoles from 6.
Recent interest in derivatives of pyrrolo[3,2-e]indole, 1, has been stimulated by the presence of this ring
system in a dihydro form in the naturally occurring potent antitumour agent CC-1065.1.2 The isomeric pyrrolo-
[2,3-f]indole system, 2, has been of interest as a precursor to conducting polymers produced by elec-
tropolymerization of 2.3 In this laboratory an interest has developed in studying the possibility of employing
Figure 1
R'
FI"
!
R--
N
R"
R'
-
N
R'
i
R
R
2
1
pyrrolo[2,3-f]indoles in the construction of bridged analogs 3 of polyaniline 4 4j in order to explore the
influence of such bridging on the electrical conductivity properties of this class of polymers. As indicated in
Figure 2
H
I
N
H
I
N
H
I,,
H
I
+
N
H
4
Scheme 1, one potential approach to the construction of derivatives of I or 2 could involve electrophilic substi-
tution of a 5-aminoindole 5 which might occur via path a or path b. On the other hand, 5-aminoindoline 6
might lead to dihydro analogs 7 or 8 which might be converted to 1 or 2 by appropriate dehydrogenation
processes.
Reported herein, in preliminary form, are the results of theoretical and experimental studies which
define the regioselectivity of processes designed to produce 1 or 2 through variations of the general pathways
shown in Scheme 1.
+ Dedicated to the memory of David A. Holden
5035

5036
Scheme 1
W
R
N
R"
~t-
R, ._p. b..~ 4~..
R"
R"
R
~
.
1
5
2
7
8
e
Semi-empirical molecular orbital calculations employing the AM1 method 6.7 reveal that the HOMO
coefficient at C4 of 5-aminoindoles (0.409 for 5-aminoindole; 0.417 for 5-amino-2,3-dimethylindole) is sub-
stantiaUy larger than that at C6 (0.166 for 5-aminoindole; 0.115 for 5-amino-2,3-dimethylindole). Based on
these coefficients, FMO arguments 8-1o would predict preferential electrophilic attack at C4. In practice,
reaction of 5-amino-2,3-dimethylindole, 11, with 3-bromo-2-butanone under Bischler conditions 11.12 gave a
product (40% yield) with spectroscopic features compatible a priori with the pyrro!o[3,2-e]indole structure 12
or the isomeric pyrrolo [2,3-f]indole structure 13 (Scheme 2). The same product was obtained by reaction of
Scheme 2
Me
H
"%
,
~/S"
Me/
H
9
Ft~
~
~
-N - Me
H
13
12
1 ~ _ _ ~
NO2
~
I0
15
3-bromo-2-butanone with p-phenylenediamine (35% yield). That this product was 12 and not 13 was demon-
strated by reaction with one equivalent of o-nitrophenylsulfenyl chloride, 14, 13 which led to desymmetrization
of the system and removal of the chemical shift equivalence of the aromatic hydrogens. The magnitude of the
coupling constant (6Hz) of the aromatic AB quartet in the sulfenylated product clearly established the ortho
relationship of the aromatic hydrogens thus ruling out structure 16 and indicating that the Bischler cyclization
proceeded predominantly in the direction predicted by FMO analysis.
In contrast, AM1 computations on Nl-formyl-5-aminoindoline reveal that the HOMO coefficient at C6
(0.261) exceeds that at C4 (0.194) leading to the FMO prediction that electrophilic attack should occur prefer-
entially at C6. This prediction has now been borne out experimentally in that Bischler indolization of Nracetyl-
5-aminoindoline, 19, yields the dihydropyrrolo[2,3-f]indole 21 in which the para relationship of the aromatic
hydrogens is readily established by the magnitude of the coupling constant 04.8 < 1 Hz) between the aromatic-

5037
hydrogens. N-Acetylation of 21 followed by dehydrogenation with DDQ yielded the pyrrolo[2,3-f]-indole 25.
An analogous sequence of reactions employing N-acetyl-5-arnino-2,3-dimethylindoline, 20, (cis/trans mixture)
as starting material has furnished the pyrrolo[2,3-f]indole 26.
Scheme 3
ar
~Me
=Me
R2
N - RI 1) Ae20 / p-TSA H2N~..
~=
~
~
O
~
~T'~ ' ~ R ~
~
R~
H
I
Me
~c
Ac
17 Rl=Rz=H
18 RI=R2=Me
19 Rt=Rz=H
20 RI=R2=Me
21 RlfR2=H
84%
22 RI=R2=Me 90%
O£t
1) BrCH=CH(OEt)2/
/
[
J Ac20 / p.TSA
~1
~
.
~2) (NCaF:C,COO3)/zEOtOI HTEA/ Hexane
c F , c o
E
~
I
"
,o~
"
,",
CF3CO ~'N
N
R
AC
AC
Me
Ac
28 86%
27 48%
23 RI=Rz=H
24 RI=Rz=M¢
IDDQ / C6H6
Reflux
| DDQ / C~H6
~ Reflux
CFaCO~
H%N
ACXN
Me
R2
AC
H
Ac
29 76%
30 91%
25 R:=R2=H 60%
26 Rx=R2=Me 50%
In addition, it has been possible to generate the known unsubstituted pyrrolo[3,2-e]indole 30 3c from 19
employing the indolization strategy developed by Norlander and coworkers.~4 Reaction of 19 with bromo-
acetaldehyde diethylacetal followed by trifluoroacetylation gave 27 which cyclized smoothly in the presence of
trifluoroacetic acid and trifluoroacetic anhydride to yield the dihydropyrrolo[3,2-e]indole 28. DDQ dehydro-
genation followed by alkaline hydrolysis, yielded 30.
Thus, pyrrolo[3,2-e]indoles 1 are accessible in moderate yield from 5-aminoindole and the isomeric[2,3-
f]-indoles 2 are accessible from 5-aminoindolines via electrophilic cyclizations which occur in accord with
predictions of FMO analysis.
Vilsmeier formylation of 30 yields the dialdehyde 32 which is a potential precursor to bridged polyani-
lines of the type 3 described above. Preliminary experiments indicate that 32 undergoes sulfuric acid catalyzed
~chem¢ 4
OHO
H
H
2) H30*
~
~
N/
H
H
H
31 ~35% H.',S04, 100%
30
1
33
35% H2SO4, 1500c
y
H
H
32
34

5038
condensation polymerization by analogy with the known conversion of 3-formylindole 30 into urorosein 31 15
to yield a purple polymeric material with physical properties similar to those of polyanilines. The physical and
electrical properties of this material will be described in detail elsewhere.
Acknowledgements:
The authors would like to acknowledge the assistance of L.A. Burke in identifying bridged polyanilines
as worthy targets for synthetic investigation and of H. Nandin de Carvalho and P. Dibble in preparing samples
of authentic pyrrolo[2,3-f]indole. The contribution of the late Professor David Holden to this research project
through numerous valuable discussions is gratefully acknowledged. Financial support for this study has been
provided by the Natural Sciences and Engineering Research Council of Canada in the form of a Strategic
Operating Grant.
References and Notes:
1.
2.
For a review of synthetic approaches toward CC-1065 see: Rawal, J.H.; Jones, R.J.; Cava, M.P. Hetero-
cycles (1987), 25,701.
For more recent developments regarding CC-1065 see: Boger, D.L.; Coleman, R.S.; Invergo, B.J.;
Sakya, S.M.; Ishizoki, T.; Munk, S.A.; Zarrinmoyeh, H.; Kites, P.A.; Thompson, S.C. J ,~m. Chem.
Soc. (1990), 112. 4623.
3.
4.
(a) Zotti, G.; Shiavon, G. Makromol. Chem. (1989), 190, 405. (b) Shravon, G.; Zotti, G. Svnth. Met.
(1989), 28, C199. (c) Berlin, A.; Bradamante, R.; Ferraccioli, R.; Pagani, G.A.; Sannicol6, F-. J. Chem.
Sot.. Chem. Commun. (1987), 1176.
The current literature concerning polyanilines is very extensive. There are more than 800 chemical
abstract listings for the period 1987-1991. For a good introduction to polyanilines which offers useful
insight into molecular structure see: Wudl, F.; Angus, R.O.; Lu, F.L.; Allemand, P.M.; Vachon, D.J.;
Nowak, M.; Liu, Z.X.; Huger, A.J. J, Am, Chum, Soc. (1987), 109, 3677 and references cited therein.
For a recent review of heterocyclic ladder polymers see: Yu, L.; Chen, M. and Dalton, L.R. Chem.
5.
6.
Mater. (1990), 2, 649.
All molecular orbital calculations were performed with full geometry optimization employing the AM1
program 7 as contained in the AMPAC program package (QCPE program #506) provided with the
molecular modelling system SYBYL 5.3 (TRIPOS Associates).
7.
8.
Dewar, M.J.S.; Zoebisch, E.G.; Healy, E.F.; Stewart, J.P.J. Am. Chem. Soc. (1985), 107, 3902.
Fleming, I. "Frontier Orbitals and Organic Chemical Reactions", Wiley, New York (1976).
Fukui, K. "Theory of Orientation and Stereoselection" Springer-Verlag, N.Y. (1975).
(a) For a discussion of FMO analysis of electrophilic aromatic substitution in general see: Reference 8,
pp 47-66; (b) For a recent review of quantitative and theoretical analysis of electrophilic substitution of
heterocyclic compounds see: Katritsky, R.A.; Taylor, R. "Electrophilic Substitution of Heterocycles:
Quantitative Aspects; Advances in Heterocyclic Chemistry" 47, (1990), Academic Press, Inc., New
9.
10.
York.
I 1.
In a typical experiment the aniline (I1, 19 or 20) and 3-bromo-2-butanone (0.5 equivalents) were dis-
solved in n-butanol (14 mL/mmol of aniline) containing acetic acid (58 ~L/mmol of aniline) and the
solution was heated at reflux in a nitrogen atmosphere for 24 hr. Aqueous workup involving extraction
with evaporation of the solvent in vacuo and purification of crude residue by column chromatography
on silica gel gave the final product.
12.
13.
For a review of the Bischler reaction see: Sundberg, R.J. "The Chemistry of Indoles", Academic Press,
New York (1970), pp 164-171.
For a discussion of C-3 sufenylation of 2,3-dialkylindoles with 14 see: Dmitrienko, G.I.; Friesen, R.W.;
Carson, L.; Vice, S.F. Tetrahedron Lett. (1982), 23, 821.
Norlander, J.E.; Catalane, D.B.; Kotian, K.D.; Stevens, R.M.; Haky, J.E.J. Qrg. Chem. (1981), 46, 778.
Fearon, W.R.; Boggust, W.A. Biochem. J. (1950), 46, 62.
14.
15.
(Received in USA 14 June 1991)