Regiospecific C-acylation of pyrroles and indoles using N-acylbenzotriazoles

Article abstract of DOI:10.1021/jo034187z

Reactions of pyrrole (2) or 1-methylpyrrole (4) with readily available N-acylbenzotriazoles 1a - g (RCOBt, where R = 4-tolyl, 4-nitrophenyl, 4-diethylaminophenyl, 2-furyl, 2-pyridyl, 2-indolyl, or 2-pyrrolyl) in the presence of TiCl₄ produced 2

Full text of DOI:10.1021/jo034187z

The most common methods for the preparation of
3-acylindoles include Friedel-Crafts10a,b or Vilsmeier-
Haack11a,b acylations; use of nitrilium,6,12a,b dialkoxy
carbenium,13 or N-(R-haloacyl)- pyridinium14 salts; and
the acylation of indole magnesium15a,b or zinc16a,b re-
agents.
However, there are limitations associated with the
literature methods: selective direct Friedel-Crafts acy-
lations of electron-rich heterocycles can require the
presence of an electron-withdrawing substituent, diacy-
lation may occur, or mixtures of isomers may be
obtained.11a,17-19 Some heterocycles are sensitive to acids
such as HCl. Vilsmeier-Haack acylations are mostly
limited to formamide and alkylcarboxamides.11b
N-Acylbenzotriazoles have been previously reported by
us as mild neutral N-acylating agents for the preparation
of primary, secondary, and tertiary amides20a and specif-
ically for formylation20b and trifluoroacylation.20c We
have also used N-acylbenzotriazoles for the O-acylation
of aldehydes20d and for regioselective C-acylation of
ketone enolates into â-diketones.20e We now apply N-
acylbenzotriazoles for mild regioselective and regiospe-
cific C-acylations of pyrroles and indoles, including
preparations of several acyl-pyrroles and -indoles not
easily available by known methods.
Regiosp ecific C-Acyla tion of P yr r oles a n d
In d oles Usin g N-Acylben zotr ia zoles
Alan R. Katritzky,* Kazuyuki Suzuki,
Sandeep K. Singh, and Hai-Ying He§
Center for Heterocyclic Compounds, Department of
Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received February 11, 2003
Abstr a ct: Reactions of pyrrole (2) or 1-methylpyrrole (4)
with readily available N-acylbenzotriazoles 1a -g (RCOBt,
where R ) 4-tolyl, 4-nitrophenyl, 4-diethylaminophenyl,
2-furyl, 2-pyridyl, 2-indolyl, or 2-pyrrolyl) in the presence
of TiCl4 produced 2-acylpyrroles 3a -g and 5a -g in good to
excellent yields. 1-Triisopropylsilylpyrrole (6) under the
same conditions gave the respective 3-acylpyrroles 7a -g.
Similarly, indole (9) and 1-methylindole (11) gave the
corresponding 3-acylated derivatives 10a -g and 12a -g.
These results demonstrate that N-acylbenzotriazoles
such as 1c,f,g are mild, regioselective, and regiospecific
C-acylating agents of particular utility when the correspond-
ing acid chlorides are not readily available.
P r ep a r a tion of N-Acylben zotr ia zoles. The present
work concentrated on (i) previously less studied arylcar-
bonyl or heterocyclocarbonyl examples as compared to
the more common alkylcarbonyl derivatives and (ii) cases
where the corresponding acyl chlorides are unstable or
inconvenient to prepare, for example, 4-diethylaminoben-
The synthesis and reactions of acylpyrroles and acylin-
doles have received continued attention. Acylpyrroles are
intermediates in the multistep synthesis of chemothera-
peutic agents, occur in nature, and possess medicinal
value.1,2 Acylindoles are precursors to a variety of biologi-
cally important alkaloids.3
General methods for the introduction of an acyl sub-
stituent at C-2 of pyrroles include reactions with acid
chlorides, Vilsmeier-Haack reagents,4a,b seleno-esters,5a
thiol-esters5b nitrilium salts,6a,b and the use of R-(di-
methylamino)-R-pyrrolylacetonitrile7 or pyrrylmagne-
sium halide8 precursors. Similar synthesis of 3-acylpyr-
roles requires the presence of sterically or electronically
effective directing substituents on the nitrogen atom.9
(9) (a) Simchen, G.; Majchrzak, M. W. Tetrahedron Lett. 1985, 26,
5035. (b) Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell, T.
T.; Artis, D. R.; Muchowski, J . M. J . Org. Chem. 1990, 55, 6317. (c)
Anderson, H. J .; Loader, C. E.; Xu, R. X.; Le, N.; Gogan, N. J .;
McDonald, R.; Edwards, L. G. Can. J . Chem. 1985, 63, 896.
(10) (a) Ketcha, D. M.; Gribble, G. W. J . Org. Chem. 1985, 50, 5451.
(b) Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.; Yoshino,
H. Org. Lett. 2000, 2, 1485.
(11) (a) Sundberg, R. J . In The Chemistry of Indoles; Academic
Press: New York, 1970. (b) Remers, W. A.; Brown, R. K. In The
Chemistry of Heterocyclic Compounds; Houlihan, W. J ., Ed.; J ohn
Wiley: New York, 1972; Vol. 25, p 116.
(12) (a) Allen, M. S.; Hamaker, L. K.; La Loggia, A. J .; Cook, J . M.
Synth. Commun. 1992, 22, 2077. (b) Powers, J . C. J . Org. Chem. 1965,
30, 2534.
(13) Pindur, U.; Flo, C.; Akgun, E.; Tunali, M. Liebigs Ann. Chem.
1986, 1621.
(14) Bergman, J .; Backvall, J .-E.; Lindstrom, J .-O. Tetrahedron
1973, 29, 971.
(15) (a) Heacock, R. A.; Kasparek, S. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Boulton, A. J ., Eds.; Academic Press: New
York, 1969; p 43. (b) Bergman, J .; Venemalm, L. Tetrahedron Lett.
1987, 28, 3741.
§ New address: ImClone Systems Incorporated, 180 Varick St., New
York, NY 10014
(1) Gribble, G. W. In Comprehensive Heterocyclic Chemistry; Katritz-
ky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: New
York, 1996; Vol. 2, p 207.
(2) Massa, S.; Di Santo, R.; Artico, M. J . Heterocycl. Chem. 1990,
27, 1131.
(3) Gribble, G. W. In Rodd’s Chemistry of Carbon Compounds, 2nd
ed.; Sainsbury, M., Ed.; Elsevier: Amsterdam, 1997; p 69.
(4) (a) J ones, R. A.; Bean, G. P. In The Chemistry of Pyrroles;
Academic Press: New York, 1977; p 151. (b) Candy, C. F.; J ones, R.
A.; Wright, P. H. J . Chem. Soc. C 1970, 2563. (c) White, J .; McGillivray,
G. J . Org. Chem. 1977, 42, 4248.
(16) (a) Yang, C.; Patel, H. H.; Ku, Y.-Y.; Shah, R.; Sawick, D. Synth.
Commun. 1997, 27, 2125. (b) Bergman, J .; Venemalm, L. Tetrahedron
1990, 46, 6061.
(5) (a) Kozikowski, A. P.; Ames, A. J . Am. Chem. Soc. 1980, 102,
860. (b) Nicolaou, K. C.; Claremon, D. A.; Papahatjis, D. P. Tetrahedron
Lett. 1981, 22, 4647.
(6) (a) Eyley, S. C.; Giles, R. G.; Heaney, H. Tetrahedron Lett. 1985,
26, 4649. (b) Black, D. St. C. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
New York, 1996; Vol. 2, p 44.
(17) Belanger, P. Tetrahedron Lett. 1979, 2505.
(18) Harsanyi, M. C.; Norris, R. K. J . Org. Chem. 1987, 52, 2209.
(19) Carson, J . R.; Davis, N. M. J . Org. Chem. 1981, 46, 839.
(20) (a) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J . Org. Chem. 2000,
65, 8210. (b) Katritzky, A. R.; Chang, H.-X.; Yang, B. Synthesis 1995,
503. (c) Katritzky, A. R.; Yang, B.; Semenzin, D. J . Org. Chem. 1997,
62, 726. (d) Katritzky, A. R.; Pastor, A.; Voronkov, M. V. J . Heterocycl.
Chem. 1999, 36, 777. (e) Katritzky, A. R.; Pastor, A. J . Org. Chem.
2000, 65, 3679.
(7) Bray, B. L.; Muchowski, J . M. J . Org. Chem. 1988, 53, 6115.
(8) Patterson, J . M. Synthesis 1976, 281.
10.1021/jo034187z CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/07/2003
5720
J . Org. Chem. 2003, 68, 5720-5723

TABLE 1. 2-Acyla tion of P yr r ole (2) a n d 1-Meth ylp yr r ole (4) Usin g N-Acylben zotr ia zoles 1a -g
previous work
entry
reactants
R
product (yield %)
reagent
yielda
%
ref
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2 + 1a
2 + 1b
2 + 1c
2 + 1d
2 + 1e
2 + 1f
2 + 1g
4 + 1a
4 + 1b
4 + 1c
4 + 1d
4 + 1e
4 + 1f
4 + 1g
4-CH3C6H4
4-NO2C6H4
4-Et2NC6H4
2-furyl
2-pyridyl
2-indolyl
2-pyrrolyl
4-CH3C6H4
4-NO2C6H4
4-Et2NC6H4
2-furyl
3a (87)
3b (60)
3c (21)
3d (91)
3e (47)
3f (39)
3g (47)
5a (90)
5b (74)
5c (51)
5d (94)
5e (54)
5f (51)
5g (75)
4-CH3C6H4COAb/POCl3
4-CH3C6H4COAb/POCl3
86
91
4c
4c
thiolester/Grignard methodc
2-pyridylCOCl/AlCl3
90
62
5b
24
2,2′-dipyrrylthioketone/KOH/H2O2
4-CH3C6H4COAd/POCl3
4-NO2C6H4COCle
76
65
73
25
26
27
acylation of furanf
2-pyridylCOCl‚HCl/3 N NaOH
76
34
28
29
2-pyridyl
2-indolyl
2-pyrrolyl
a
b
Isolated yield. A ) morpholide (freshly prepared from acid chloride and an equimolar mixture of morpholine and triethylamine), 20
h, 25 °C. c 2-Furoyl-S-2-pyridyl, MeMgCl. A ) morpholide, 45 h, 25 °C. e Refluxing in toluene for 18 h. f N-Methyl-2-pyrrolylCOOH,
(CF3CO)2O, phosphonic resin.
d
TABLE 2. 3-Acyla tion of TIP S-P yr r ole (6) Usin g
zoyl, indolyl-3-carboxyl, or pyrrolyl-2-carboxyl deriva-
N-Acylben zotr ia zoles 1a -g
tives. The starting N-acylbenzotriazoles 1a -g with aryl
or heterocyclic groups (R ) 4-tolyl, 4-nitrophenyl, 4-di-
ethylaminophenyl, 2-furyl, 2-pyridyl, 2-indolyl, or 2-pyr-
rolyl) were prepared from the corresponding carboxylic
acids by treatment with 1-(methylsulfonyl)benzotriazole
following the previously reported one-step general
procedure.20e
entry
reactants
R
product (yield %)a
P r ep a r a tion of 2-Acylp yr r oles. Regioselectivity in
the acylation of pyrroles is a function of the Lewis acid,21
reaction solvent,22 and the acylating agent.4a Accordingly,
we studied the effect of these parameters to optimize the
reaction conditions. Our initial results in the acylation
of pyrrole using 1H-1,2,3-benzotriazolyl(4-methylphenyl)-
methanone (1a ) in the presence of ZnBr2 as the Lewis
acid in dichloroethane gave low regioselectivity: a 3:1
ratio of 2- and 3-isomers (4-methylphenyl)(1H-pyrrol-2-
yl)methanone and (4-methylphenyl)(1H-pyrrol-3-yl)meth-
anone, respectively, was detected in the reaction mixture
after 3 h (1H NMR analysis of an aliquot). This ratio
changed to 5:1 on continuing the reaction for 12 h, and
2- and 3-isomers were obtained in a combined yield of
75%. No diacylation products were formed under these
reaction conditions. Formation of mixtures of 2- and
3-isomers in the acylation of pyrroles and the intercon-
version of the isomers has been observed previously.19
The use of TiCl4 as the Lewis acid proved to be benefi-
cial: the acylation of pyrrole using 1H-1,2,3-benzotri-
azolyl(4-methylphenyl)methanone (1a) in dichloromethane
produced regiospecifically the 2-isomer, (4-methylphenyl)-
(1H-pyrrol-2-yl)methanone (3a ), in 87% yield in a short
reaction time of 2 h. No formation of the 3-isomer was
detected in the crude reaction mixture by 1H NMR. Thus,
1
2
3
4
5
6
7
6 + 1a
6 + 1b
6 + 1c
6 + 1d
6 + 1e
6 + 1f
6 + 1g
4-CH3C6H4
4-NO2C6H4
4-Et2NC6H4
2-furyl
2-pyridyl
2-indolyl
7a (92)
7b (72)
7c (90)
7d (89)
7e (54)
7fb
2-pyrrolyl
7g (78)
a
b
Isolated yield. Could not be isolated in a pure form.
a set of appropriate reaction conditions was developed
for the regiospecific 2-acylation of pyrroles using N-
acylbenzotriazoles.
The above optimized reaction conditions were used for
the synthesis of a variety of 2-acylpyrroles. Reactions of
unsubstituted pyrrole (2) with N-acylbenzotriazoles 1b-g
gave 2-acylpyrroles 3b-g in 21-91% yields. Similar
results were obtained when N-methylpyrrole (4) was
acylated under these reaction conditions: the corre-
sponding 2-acylated N-methylpyrroles 5a -g were pro-
duced in 51-94% yields. Again, no formation of the
3-isomer was detected in the crude reaction mixtures.
Structures 3a -g and 5a -g are supported by their 1H
and 13C NMR spectra and microanalysis or HRMS data.
These results illustrate the general applicability of this
method for the preparation of 2-acylpyrroles under mild
conditions (25 °C) and short reaction times (2 h). In
comparison, literature procedures for the known com-
pounds usually involve at least one of the following: (i)
(21) Kakushima, M.; Hamel, P.; Frenette, R.; Rokach, J . J . Org.
Chem. 1983, 48, 3214.
(22) Ottoni, O.; Neder, A. de V. F.; Dias, A. K. B.; Cruz, R. P. A.;
Aquino, L. B. Org. Lett. 2001, 3, 1005.
J . Org. Chem, Vol. 68, No. 14, 2003 5721

TABLE 3. 3-Acyla tion of In d ole (9) a n d 1-Meth ylin d ole (11) Usin g N-Acylben zotr ia zoles 1a -g
previous work
entry
reactants
R
product (yield %)a
reagent
yielda
%
ref
1
2
3
4
5
6
7
8
9
10
11
12
13
14
9 + 1a
4-CH3C6H4
4-NO2C6H4
4-Et2NC6H4
2-furyl
2-pyridyl
2-indolyl
2-pyrrolyl
4-CH3C6H4
4-NO2C6H4
4-Et2NC6H4
2-furyl
10a (92)
10b (66)
10c (66)
10d (64)
10e (73)
10f (86)
10g (15)
12a (92)
12b (74)
12c (79)
12d (90)
12e (70)
12f (27)
12g (48)
EtMgI/4-CH3C6H4COCl
4-NO2C6H4COCl/AlCl3
65
34
30
31
9 + 1b
9 + 1c
9 + 1d
9 + 1e
9 + 1f
2-furylCOCl/Et2AlCl
indirect methodb
indirect methodc
91
48
10b
32
33
9 + 1g
11 + 1a
11 + 1b
11 + 1c
11 + 1d
11 + 1e
11 + 1f
11 + 1g
4-CH3C6H4COCl/AlCl3
40
34
2-pyridyl
2-indolyl
2-pyrrolyl
a
b
Isolated yield. DDQ oxidation of 3-(2-pyridylmethyl)-indole. c From bis(N-phenylsulfonylindol-2-yl) derivative.
requirement of the preparation of morpholides prior to
acylation, (ii) low regioselectivity, or (iii) requirement of
long reaction times (25-45 h) (Table 1).4c,26
1a -g in the presence of TiCl4 produced exclusively the
corresponding 3-acylated N-triisopropylsilylpyrroles 7a-g
in 54-92% yields, except 7f, which could not be isolated
in a pure form. 3-Acylated N-triisopropylsilylpyrroles
7a -e and 7g are all novel compounds and have been fully
characterized by 1H and 13C NMR spectroscopy and
elemental analysis or high-resolution mass spectrometry
(Table 2). Fluoride ion-induced desilylation9b of 3-acylated
N-triisopropylsilylpyrrole 7a occurred readily at room
temperature to give (4-methylphenyl)(1H-pyrrol-3-yl)-
methanone (8a ) in 98% yield.
P r ep a r a tion of 3-Acylp yr r oles. Regioselective syn-
thesis of 3-acyl-1H-pyrroles have until recently been
time-consuming and problematic, requiring indirect meth-
ods.23 The most effective device has been the use of a
bulky group on the nitrogen atom: tert-butyldimethylsilyl
(TBDMS)9a and especially triisopropylsilyl (TIPS)9b groups
allow easy 3-acylation of pyrroles as sterically effective,
stable, and easily cleavable N-substituents. Accordingly,
following Tidwell and Muchowski, we have utilized the
N-triisopropylsilyl substituent for the preparation of
3-acylpyrroles using N-acylbenzotriazoles as the acylat-
ing agents. Thus, TIPS-pyrrole (6) was prepared from the
sodium salt of pyrrole and triisopropylsilyl chloride in
90% yield.9b Reaction of 6 with N-acylbenzotriazoles
P r ep a r a tion of 3-Acylin d oles. The method devel-
oped above for the 2-acylation of pyrroles and N-meth-
ylpyrroles was applied to the acylation of unsubstituted
indole (9). 3-Acylindoles 10a -g were obtained exclusively
and in good yields in reactions of indole (9) with N-
acylbenzotriazoles 1a -g in the presence of TiCl4. Simi-
larly, reactions of N-methylindole (11) gave the corre-
sponding acylated N-methylindoles 12a -g in 27-92%
yields (Table 3). Novel 3-acylated indoles were character-
ized by their 1H and 13C NMR spectra and elemental
analysis. The previously observed complications in the
acylation of unsubstituted indole such as simultaneous
formation of 1-acylated and/or 1,3-diacylated products
were absent.11a,b Our method also removes the possibility
of decomposition or self-polymerization of indole com-
monly observed due to the release of HCl when acyl
chlorides are employed.22
(23) Anderson, H. J .; Loader, C. E. Synthesis 1985, 353.
(24) Rao, K. V.; Reddy, G. C. J . Agric. Food Chem. 1990, 38, 1260.
(25) Shi, D.-F.; Wheelhouse, R. T.; Sun, D.; Hurley, L. H. J . Med.
Chem. 2001, 44, 4509.
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Chem. 1982, 19, 1493.
(27) Carmosin, R. J .; Carson, J . R.; Pitis, P. U.S. Pat. 5418236, 1995;
Chem. Abstr. 1995, 123, 286086.
(28) Fayed, S.; Delmas, M.; Gaset, A. Synth. Commun. 1982, 12,
1121.
(29) Carson, J . R.; Pitis, P. M. PCT Int. Appl. 0202521, 2002; Chem.
Abstr. 2002, 136, 102279.
(30) N. V. Koninklijke Pharmaceutische Fabrieken voorheen Bro-
cades-Stheeman & Pharmacia Belg. Pat. 637352, 1964; Chem. Abstr.
1965, 62, 10415b.
(31) Sawada, K.; Okada, S.; Kuroda, A.; Watanabe, S.; Sawada, Y.;
Tanaka, H. Chem. Pharm. Bull. 2001, 49, 799.
(32) Oikawa, Y.; Yonemitsu, O. J . Org. Chem. 1977, 42, 1213.
(33) Mahboobi, S.; Kuhr, S.; Pongratz, H.; Popp, A.; Hufsky, H.;
Bohmer, F.; Teller, S.; Uecker, A.; Beckers, T. U.S. Pat. 6407102, 2002;
Chem. Abstr. 2002, 131, 336939.
(34) Wang, S.-F.; Chuang, C.-P. Heterocycles 1997, 45, 347.
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W.-Q. Tetrahedron 1992, 48, 7817.
In summary, we have introduced a convenient and
general method for direct access to isomerically pure
2-acylpyrroles, 3-acylpyrroles, or 3-acylindoles under mild
reaction conditions using readily available N-acylbenzo-
triazoles. Use of N-acylbenzotriazoles 1c,f,g illustrates
the preparation of acyl derivatives not easily available
by other methods.
(36) Nicolaou, I.; Demopoulos, V. J . J . Heterocycl. Chem. 1998, 35,
1345.
5722 J . Org. Chem., Vol. 68, No. 14, 2003

residue was subjected to column chromatography on silica gel
using hexanes/ethyl acetate (2:1) as the eluent to give the
C-acylated pyrroles 3a -g, 5a -g, and 7a -g or indoles 10a -g
and 12a -g in pure form.
Exp er im en ta l Section
Melting points are uncorrected. H NMR (300 MHz) and 13C
NMR (75 MHz) spectra were recorded in CDCl3 (with TMS for
1H and chloroform-d for 13C as the internal references) unless
specified otherwise.
1
Su p p or tin g In for m a tion Ava ila ble: Characterization
data and general procedure for the preparation of N-acylben-
zotriazoles 1a -g, characterization data for compounds 3a -g,
5a -g, 7a -g, 8a , 10a -g, and 12a -g, and 1H and 13C NMR
spectra of compound 3f. This material is available free of
charge via the Internet at http://pubs.acs.org.
Gen er a l P r oced u r e for C-Acyla tion of P yr r oles (2, 4, 6)
or In d oles (9, 11) Usin g N-Acylben zotr ia zoles 1a -g. To a
mixture of pyrrole (2, 4, 6) or indole (9, 11) (2.5 mmol) and
N-acylbenzotriazole (2.0 mmol) in CH2Cl2 (15 mL) was added
TiCl4 (1.0 M in CH2Cl2, 4 mL, 4 mmol), and the mixture was
stirred for a specified time and temperature (see Tables 1-3
for details). The reaction was quenched by adding MeOH (2 mL).
The solvents were evaporated under reduced pressure, and the
J O034187Z
J . Org. Chem, Vol. 68, No. 14, 2003 5723