Conversion of aryl methyl ketimines to 2,5-diarylpyrroles using TiCl4/Et3N

Full text of DOI:10.1021/jo982342h

4204
J . Org. Chem. 1999, 64, 4204-4205
Ta ble 1. th e Rea ction of Ketim in es w ith TiCl4/Et3N
Con ver sion of Ar yl Meth yl Ketim in es to
2,5-Dia r ylp yr r oles Usin g TiCl4/Et3N
Mariappan Periasamy,* Gadthula Srinivas, and
Pandi Bharathi
School of Chemistry, University of Hyderabad,
Central University P.O., Hyderabad 500 046, India
Received November 30, 1998
The 2,5-diarylpyrroles are generally synthesized by
following the classical Paal-Knorr synthesis involving
the reaction of 1,4-diketone with amines.1 Some of the
shortcomings in this reaction were overcome by a later
method reported by McEwen.2 Other methods available
for pyrrole synthesis are Hantzsch synthesis using chlo-
roacetone and 3-amino ethyl crotonate,3 1,3-dipolar cy-
cloaddition reactions involving azalactones, oxazolones,
and alkynes followed by carbon dioxide elimination,4 1,3-
dipolar cycloaddition reaction of nitrile ylides with elec-
tron deficient alkynes and alkenes,5 and TiCl3/C8K-
induced cyclization of amido-enones to substituted
pyrroles.6 However, all these methods of synthesis of
pyrroles involve multistep synthetic operations. Herein,
we wish to report a one-pot synthesis of 2,5-diarylpyrroles
from the ketimines using the TiCl4/Et3N reagent combi-
nation (eq 1).
In connection with efforts toward the synthesis of the
C2-chiral 2,5-diarylpyrrolidine system, we were looking
for a simple convenient method of preparation of the
corresponding 1,4-diketones. Preliminary studies re-
vealed that the reaction of aryl methyl ketones with
TiCl4/Et3N results in the corresponding 1,4-diketone in
∼20% yield in addition to the undesired aldol condensa-
tion product.7 It was thought that the corresponding
imines would not lead to such aldol-type reactions. Hence,
we have examined the reaction using the imines. Sur-
prisingly, the corresponding 2,5-diarylpyrroles were formed
directly with these substrates (eq 1). The transformation
was found to be general for several ketimines, and the
results are summarized in Table 1.
Whereas ketimines derived from acetophenone and the
N-alkylamines (N-benzyl, N-ethyl, N-octyl, and N-butyl)
gave lower yields of pyrrole (8%, 15%, 10% and 12%,
respectively), the anils of cyclohexanone and cyclopen-
tanone gave several unidentified products and the reac-
tions were not clean. The anils derived from propiophe-
none, isobutyrophenone, and camphor remained unreacted
under these conditions. In the case of the anil of p-
methoxyacetophenone, one more equivalent of titanium
tetrachloride was necessary to obtain optimum yield
(75%, Table 1, entry 5) of the corresponding pyrrole. The
reaction goes well at 0-25 °C. Also, change in the order
of addition of the reagents did not have any effect on the
course of the reaction.
Since the TiCl4 is known to mediate the formation of
imines from ketones in the presence of excess primary
amine, we have decided to examine the pyrrole synthesis
by preparing the anil of acetophenone in situ, followed
by reaction with additional amounts of TiCl4/Et3N.
Surprisingly, the reaction did not proceed beyond the
ketimine stage in this case. Only the ketimines were
isolated in very good yields. We find that this method of
preparation of imines is operationally simple compared
to the hitherto reported methods of synthesis of imines.8,9
Also, this method is advantageous since the reaction is
(1) Broadbent, H. S.; Burnharm, W. S.; Olsen, R. K.; Sheely, R. M.
J . Heterocycl. Chem. 1968, 5, 757.
(2) Cooney, J . V.; McEwen, W. E. J . Org. Chem. 1981, 46, 2570.
(3) Hantzsch, A. Chem. Ber. 1890, 23, 1474.
(4) (a) Bayer, H. O.; Gotthardt, H.; Huisgen, R. Chem. Ber. 1970,
103, 2356. (b) Huisgen, R.; Gotthardt, H.; Bayer, H. O.; Schaefter, F.
C. Chem. Ber. 1970, 103, 2611.
(5) Berree, F.; Marchand, E.; Morel, G. Tetrahedron Lett. 1992, 33,
6155.
(6) Furstner, A.; Weintritt, H.; Hupperts, A. J . Org. Chem. 1995,
60, 6637.
(7) Periasamy, M. Unpublished results.
10.1021/jo982342h CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/12/1999

Notes
J . Org. Chem., Vol. 64, No. 11, 1999 4205
was distilled over CaH2. All imines were prepared by the method
developed in this laboratory.11 Chromatographic purification was
conducted by column chromatography using 100-200 mesh silica
gel obtained from Acme Synthetic Chemicals, India. All reactions
Sch em e 1
and manipulations were carried out under
a dry nitrogen
atmosphere. All yields reported are isolated yields of materials,
adjusted homogeneous by TLC analysis.
Rep r esen ta tive P r oced u r e. Dichloromethane (25 mL),
Et3N (15 mmol), and ketimine (10 mmol) were taken under an
N2 atmosphere. TiCl4 (10 mmol) in CH2Cl2 (10 mL) was added
dropwise under N2 at 0 °C for 15 min. The reaction mixture was
stirred for 0.5 h at 0 °C and stirred further for 7-8 h at 25 °C.
It was quenched with a saturated K2CO3 solution (30 mL), and
the reaction mixture was filtered through a Buchner funnel. The
organic layer was separated, and the aqueous layer was ex-
tracted with CH2Cl2 (2 × 25 mL). The combined organic extract
was washed with a brine solution (10 mL) and dried over
anhydrous MgSO4. The solvent was removed, and the residue
was chromatographed on a silica gel column. Hexane eluted the
corresponding pyrrole.
1a . 1,2,5-Tr ip h en ylp yr r ole: mp 233-234 °C (lit.2 mp 234-
236 °C); 13C NMR 138.0, 135.0, 133.29, 128.93-126.20, 109.93;
1H NMR 7.05-7.35 (15H, m), 6.5 (2H, s).
2a . 1-Meth yl-2,5-d ip h en ylp yr r ole: mp 197-199 °C (lit.12
mp 200-202 °C); 13C NMR 136.92, 133.67, 128.78, 128.42,
126.81, 108.75, 34.21; 1H NMR 7.3-7.6 (10H, m), 6.4 (2H, s),
3.65 (3H, s). Anal. Calcd for C17H15N: C, 87.52; H, 6.48; N, 6.00.
Found: C, 87.86; H, 6.84; N, 6.17. Mass: M+ (m/e) 233.
3a . 1-P h en yl-2,5-bis(p-tolyl)p yr r ole: mp 208-210 °C; 13C
NMR 139.24, 135.79, 130.52, 129.0, 128.62, 127.10, 109.50,
21.06; 1H NMR 6.85-7.3 (13H, m), 6.4 (2H, s), 2.3 (6H, s). Anal.
Calcd for C24H21N: C, 89.13; H, 6.54; N, 4.33. Found: C, 89.32;
H, 6.58; N. 4.35. Mass: M+ (m/e) 323.
carried out under mild conditions, at 0-25 °C in CH2-
Cl2. This modified procedure was adopted for the prepa-
ration of the ketimines used.
The interesting feature of the transformation reported
here is that there is no need to prepare a 1,4-diketone
intermediate. Recently, Matsumara et al.10 reported that
methyl phenylacetate undergoes oxidative coupling with
TiCl4/Et3N to give the corresponding 2,3-diphenylsucci-
nate ester. Presumably, the aryl methyl ketimines also
undergo a similar oxidative coupling on reaction with
TiCl4/Et3N followed by cyclization to give the correspond-
ing pyrroles. Accordingly, the transformation can be
visualized by a tentative mechanism outlined in Scheme
1.
4a . 1-P h en yl-2,5-bis(p-ch lor op h en yl)p yr r ole: mp 264-265
°C; 13C NMR 134.97, 132.35, 131.58, 129.79-128.33, 127.69,
110.28; 1H NMR 6.9-7.4 (13H, m). 6.45 (2H, s). Anal. Calcd for
C
22H15NCl2: C, 72.54; H, 4.15; N, 3.85. Found: C, 72.80; H, 4.20;
N, 3.90. Mass: M+ (m/e) 364.
5a . 1-(p-Meth oxyp h en yl)-2,5-d ip h en ylp yr r ole: mp 229-
230 °C (lit.2 mp 227-229 °C); 13C NMR 158.52, 135.97, 133.39,
131.96, 129.84-126.13, 113.95, 109.66, 55.35; 1H NMR 6.8-7.2
(14H, m), 6.5 (2H, s), 3.8 (3H, s); (imine 10 mmol, TiCl4 20 mmol,
and Et3N 30 mmol were used).
Coordination of TiCl4 to the imine nitrogen would make
the methyl proton acidic enough to be pulled by Et3N.
The resulting complex could produce a radical on decom-
position that can undergo coupling to give the diimine
(A) followed by aromatization leading to pyrrole (Scheme
1). Alternatively, the intermediate can dimerize to give
two TiCl3 and the diketimine. We have observed that
neither TiCl4 nor Et3N alone effects this transformation.
In conclusion, the simple, convenient method described
here for the conversion of ketimines to the corresponding
pyrroles using TiCl4/Et3N should be attractive for syn-
thetic applications as the transformation requires ambi-
ent conditions.
6a . 1-(p-Ch lor op h en yl)-2,5-d ip h en ylp yr r ole: mp 227-228
°C (lit.2 mp 226-227 °C); 13C NMR 137.58, 135.83, 133.0, 130.0-
1
126.48, 110.28; H NMR 7.3-6.9 (14H, m), 6.45 (2H, s).
7a . 1-P h en yl-2,5-bis(2-n a p h th yl)p yr r ole: mp 222-224 °C;
13C NMR 139.5, 136.03, 133.2, 131.9, 130.7, 129.88-125.66,
123.9, 110.67; 1H NMR 7.8-7.1 (19H, m), 6.65 (2H, s). Anal.
Calcd for C30H21N: C, 91.11; H, 5.35; N, 3.54. Found: C, 91.12;
H, 5.36; N, 3.58. Mass: M+ (m/e) 395.
Ack n ow led gm en t. We are grateful to the UGC and
DST (New Delhi) for financial support. We are also
thankful to the UGC for support under Special As-
sistance Programme.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra for
compounds 1-7. This material is available free of charge via
the Internet at http://pubs.acs.org.
Exp er im en ta l Section :
Gen er a l. 1H NMR (200 MHz) and 13C NMR (50 MHz) spectra
were recorded in CDCl3 unless otherwise stated, and TMS was
used as reference (δ ) 0 ppm). The chemical shifts are reported
in ppm on the δ scale relative to CDCl3 (77.0 ppm). Melting
points are uncorrected. Dichloromethane was distilled over
calcium hydride and dried over molecular sieves. Triethylamine
J O982342H
(11) P r ep a r a tion of Ar yl Meth yl Ketim in es. Dichloromethane
(25 mL), Et3N (20 mmol), ketone (10 mmol), and amine (12 mmol) were
taken under an N2 atmosphere. TiCl4 (5 mmol) in CH2Cl2 (10 mL) was
added dropwise under N2 at 0 °C for 15 min. The reaction mixture
was stirred for 0.5 h at 0 °C and stirred further for 7-8 h at 25 °C. It
was quenched with a saturated K2CO3 solution (30 mL), and the
reaction mixture was filtered through a Buchner funnel. The organic
layer was separated from the filtrate, and the remaining aqueous layer
was extracted with CH2Cl2 (2 × 25 mL). The combined organic layer
was washed with a brine solution (10 mL) and dried over anhydrous
Na2CO3. The solvent was removed, and the ketimine was recrystallized
from ethanol. The yields of the ketimines: 1. 91%, 3. 93%, 4. 89%, 5.
90%, 6. 92%, 7. 88%.
(8) (a) Weingarten, H.; Chupp, J . P.; White, W. A. J . Org. Chem.
1967, 32, 3246. (b) Moretti, I.; Torre, G. Synthesis 1970, 141. (c) Corey,
E. J .; Gross, A. W. J . Org. Chem. 1985, 50, 5391.
(9) (a) Varma, R. S.; Dahiya, R.; Kumar, S. Tetrahedron Lett. 1997,
38, 2039. (b) Selva, M.; Tundo, P.; Marques, C. A. Synth. Commun.
1995, 25, 369. (c) Taguchi, K.; Westheimer, F. H. J . Org. Chem 1971,
36, 1570. (d) Texier-Boullet, F. Synthesis 1984, 679.
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(12) Zakrzewski, J . J . Organomet. Chem. 1987, 333, 71.