A convenient synthesis of N-acylpyrroles from primary aromatic amides

Article abstract of DOI:10.1055/s-2003-41020

Synthesis of N-acylpyrroles in 45-85% isolated yield from primary aromatic amides and excess 2,5-dimethoxytetrahydrofuran in presence of one equivalent of thionyl chloride is reported. This method has several advantages including short reaction times, mild reaction conditions, and easy workup. The technique works particularly well for deactivated aromatic amides.

Full text of DOI:10.1055/s-2003-41020

SHORT PAPER
1959
A Convenient Synthesis of N-Acylpyrroles from Primary Aromatic Amides
A
Convenient
Syn
n
thesis of
N
-A
i
cylpyr
l
rolesfrom Pr
R
A
.
mides Ekkati, Dallas K. Bates*
Department of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, MI 49931, USA
Fax +1(906)4872061; E-mail: dbates@mtu.edu
Received 20 May 2003
with amides, this method requires longer reaction times
Abstract: Synthesis of N-acylpyrroles in 45–85% isolated yield
from primary aromatic amides and excess 2,5-dimethoxytetrahy-
drofuran in presence of one equivalent of thionyl chloride is report-
ed. This method has several advantages including short reaction
than with amines because the amide nitrogen is not partic-
ularly nucleophilic and this method is not applicable to
compounds that are acid or heat sensitive. Recently, it was
times, mild reaction conditions, and easy workup. The technique reported11 that the reaction of amides with 2,5-dimethox-
works particularly well for deactivated aromatic amides.
ytetrahydrofuran in the presence of P2O5 gives good
yields of N-acylpyrroles. However, P2O5 is very hygro-
scopic and reaction conditions must avoid moisture. Ni-
triles are by-products in this process and in some cases are
the sole products, as with acetamide. Based on our expe-
rience, if this reaction is not conducted under rigorously
dry conditions, yields of the nitrile side product will in-
crease.
Key words: N-acylpyrroles, primary amides, condensation, 2,5-
dimethoxytertahydrofuran
N-Acylpyrroles are useful compounds; they have been
used as acylating agents, they can be regarded as activated
carboxylic acid equivalents1 and many are biologically
active.2 Delocalization of the nitrogen lone pair into the
pyrrole ring of pyrrole amides alters amide reactivity sig-
nificantly. The reduced electron density on the N-acylpyr-
role carbonyl favors nucleophilic attack and the derived
tetrahedral intermediate in many cases readily ejects pyr-
role. Thus, conversion to the corresponding N-acylpyrrole
permits facile transformation of primary amides into es-
ters, secondary amides and tertiary amides as well as re-
duction to aldehydes and alcohols.1c N-Acylpyrroles are
also useful in other synthetic methodologies. Reaction be-
tween lithium ester enolates and N-acylpyrroles produces
isolable carbinols, which upon heating or treatment with
basic reagents afford b-ketoesters in good yields.1a Enol-
silanes derived from N-acylpyrroles exhibit high levels of
diastereoselection in concert with good enantioselection
in Lewis acid catalyzed Mukaiyama–Michael reaction
with acryloyl oxazolidinones.3 Our interest in N-acylpyr-
roles derives from their use as precursors for SES reac-
tions.4
2,5-Dichloro-2,5-dimethoxybutane has also been used to
prepare N-acylpyrroles.1c For reactive amides formation
of N-acylindoles4b and N-acylcarbazoles12 can occur and
the procedure does not work well for deactivated aromatic
amides. For example, 2-methylthionicotinamide is recov-
ered unchanged under this protocol.13 Additionally, 2,5-
dichloro-2,5-dimethoxybutane14 has a short shelf life and
is not commercially available.
In an attempt to overcome problems with existing meth-
ods, we sought to improve the reaction of 2,5-dimethox-
ytetrahydrofuran with amides by attempting to prepare in
situ an activated 1,4-butanedial equivalent. To this end,
we have found that addition of one equivalent of thionyl
chloride to a mixture of the amide in 2,5-dimethoxytet-
rahydrofuran (as both solvent and reactant) rapidly pro-
duces N-acylpyrroles. We have not studied the
mechanism of the conversion, but the reaction gives poor
yields if substantially less than one equivalent of SOCl2 is
added. Addition of a second equivalent of SOCl2 im-
proves neither rate nor yield. Finally, substituting P2O5 for
SOCl2 produces the product in poor yield accompanied by
black polymeric material.
Preparation of N-acylpyrroles traditionally has involved
pyrrole acylation by reaction of an alkali salt of pyrrole
with an equivalent amount of acyl halide.5 Due to the typ-
ical harshly basic reaction conditions this procedure is un-
suitable for the preparation of substituted pyrroles
containing base labile protecting groups or p-deficient ar-
omatics containing ring functionality sensitive to nucleo-
philic displacement.6,7
Reaction times are short (10 min to 2 h) and workup is
simple since 2,5-dimethoxytetrahydrofuran is both vola-
tile (bp 143–146 °C) and water soluble. The results ob-
tained for a variety of primary aromatic amides are shown
in Table 1. The only byproduct sometimes observed is the
corresponding indole derivative; the amount depends both
on reaction time and amide reactivity.15 For very reactive
amides (acetamide), the indole is the sole product even af-
ter short reaction times.
An alternative route involves formation of the pyrrole ring
from a primary amide. Gross8 and Menger and Donohue9
applied the general Clauson-Kaas10 method for converting
primary amines into pyrroles (2,5-dialkoxytetrahydrofu-
ran in refluxing acetic acid) to primary amides. However
All chemicals were obtained from commercial suppliers and used
without further purification. Thin layer chromatography was per-
formed on E. Merck silica gel 60 F254 plates (0.25 mm). Compounds
were visualized with UV light. Column chromatography was per-
Synthesis 2003, No. 13, Print: 18 09 2003. Web: 19 08 2003.
Art Id.1437-210X,E;2003,0,13,1959,1961,ftx,en;M02303SS.pdf.
DOI: 10.1055/s-2003-41020
© Georg Thieme Verlag Stuttgart · New York

1960
A. R. Ekkati, D. K. Bates
SHORT PAPER
Table 1 Summary of N-Acylpyrroles Prepared
O
Product
Yield of N- Time (min)/ Temp Mp (°C)
IR (C=O, cm–1)
Partial 1H NMR (d)f
(pyrrole proton
absorptions)
Acylpyrrole (°C)a
(%)
Ar
NH2
Ar =
1
2
Ph
78
75
68
85
75
70
66
60
80
45
10/r.t. to 80
oil9
1694 (neat)
7.27, 6.33
7.27, 6.31
7.46, 6.35
6.86, 6.28
7.12, 6.26
7.20, 6.37
7.22, 6.39
7.22, 6.36
7.19, 6.36
7.12, 6.32
4-OMePh
10/r.t. to 80
10/r.t. to 80
10/r.t. to 80
10/r.t. to 80
120/50–60
120/50–60
120/50–60
120/50–60
60/80–90
oil5a
1693 (neat)
3
Cinnamyl
108–110 (108)16
oilb
1688 (CHCl3)
1704 (neat)
4
2-Cl-4-OMePh
2-MeS-4-OMePh
4-NO2Ph
5
oilc
1694 (neat)
6
131–133 (127–128)9
oil5e
1703 (CHCl3)
1698 (neat)
7
3-NO2Ph
8
4-CF3Ph
92.5–93.5d
84–86 (87)5e
80–82 (78–79)13
1701 (CHCl3)
1698 (CHCl3)e
1698 (CHCl3)
9
4-CNPh
10
2-Methylthiopyridinyl
a For activated compounds 1–5 the reaction mixture was heated from r.t. to 80 °C over 10 min, then immediately cooled.
b Anal. Calcd for C12H10ClNO2: C, 61.16; H, 4.28; N, 5.94. Found: C, 60.81; H, 4.26; N, 6.12.
c Anal. Calcd for C13H13NO2S: C, 63.13; H, 5.30; N, 5.66. Found: C, 62.92; H, 5.36; N, 5.81.
d Anal. Calcd for C12H8F3NO: C, 60.26; H, 3.37; N, 5.86. Found: C, 60.26; H, 3.36; N, 5.8.
e IR (CΩN) = 2234 cm–1.
f Multiplicity = both pyrrole signals appear as an apparent triplet with apparent J = ca. 2.3 Hz.
formed using silica gel (0.060–0.200 nm, pore diameter ca. 6 nm).
Table 2 13C NMR and EIMS Data Summary for N-Acylpyrroles
Melting points are uncorrected. 1H and 13C NMR spectra were ac-
quired at 400 MHz and 100 MHz, respectively, in CDCl3 solution
unless otherwise specified. 2-Chloro-4-methoxybenzamide17 and 2-
methylthionicotinamide13 were prepared according to literature pro-
cedures.
Nr 13C NMR (d)
EIMS [m/z (%)]
1
2
3
4
5
6
7
8
167.6, 133.2, 132.2, 129.4, 128.4,
121.3, 113.1
171 (27), 105 (100)
Synthesis of N-Acylpyrroles; General Procedure
167.1, 162.9, 131.9, 125.2, 121.3,
113.7, 112.7, 55.4
201 (19), 135 (100)
197 (31), 131 (100)
235 (100), 169 (100)
247 (9), 181 (100)
216 (36), 150 (100)
216 (32), 150 (100)
To the amide (1 g) in 2,5-dimethoxytetrahydrofuran (20 mL) was
added drop-wise thionyl chloride (1 equiv). The mixture was heated
(see Table 1), during which time the mixture turned brown or black,
then cooled to 40 °C by immersion of the reaction flask into an ice
water bath. In cases where the starting material was not completely
soluble, dissolution occurred after SOCl2 addition or upon heating.
The cooled reaction mixture was poured into H2O (200 mL), shaken
thoroughly and allowed to settle. For solids, vacuum filtration was
used to collect the product. Liquid products pool at the bottom of the
flask. A majority of the aqueous layer (ca. 100 mL) was decanted
away from the pooled liquid and discarded. Another portion of H2O
(100 mL) was added, gently swirled, and the aqueous layer decant-
ed away from the pooled liquid product and discarded. After repeat-
ing this process again, CH2Cl2 was added to the pooled liquid and
the mixture gently shaken. The organic layer was collected, washed
with H2O (2 × 100 mL), and dried (Na2SO4). The solvent was evap-
orated to give the crude acylpyrrole which was purified by silica gel
column chromatography (eluant: CH2Cl2) to afford pure products in
the yields listed in Table 1. Additional spectral data for 1–10 are
provided in Table 2.
162.9, 147.5, 134.2, 130.9, 129.0,
128.4, 119.2, 115.7, 113.3
165.1, 161.8, 133.0, 130.5, 125.6,
120.4, 115.5, 113.5, 112.6, 55.6
166.3, 161.7, 141.3, 130.9, 124.9,
120.7, 113.0, 112.9, 109.2, 55.3, 16.2
165.6, 149.8, 138.8, 130.3, 123.7,
121.0, 114.2
165.2, 148.0, 134.9, 134.8, 129.9,
126.7, 124.3, 121.0, 114.2
166.4, 136.6, 133.9 (q, JC-F = 33.7 Hz), 239 (28), 173 (100)
129.7, 125.6 (q, JC-F = 4.6 Hz), 123.5
(q, JC-F = 272.6 Hz), 121.1, 113.8
9
165.8, 137.1, 132.3, 129.8, 120.9,
117.6, 115.8, 114.0
196 (33), 130 (100)
218 (26), 152 (100)
4-Methoxy-2-(methylthio)benzamide
To an ice-cold, stirred solution of 4-methoxy-2-(methylth-
io)benzonitrile18 (1.38 g, 7.7 mmol) in DMSO (17 mL), 30% H2O2
(6.9 mL) and anhyd K2CO3 (0.27 g) were added. The mixture was
allowed to warm to r.t. After 1 h, H2O (75 mL) was added, the prod-
uct isolated by filtration and dried to yield 1.1 g of the solid product.
10 165.3, 158.8, 151.1, 135.8, 127.8,
120.5, 118.1, 113.9, 13.4
Synthesis 2003, No. 13, 1959–1961 © Thieme Stuttgart · New York

SHORT PAPER
A Convenient Synthesis of N-Acylpyrroles from Primary Aromatic Amides
1961
Yield 74%; mp 180–182 °C.
IR (Nujol): 3363 (NH), 3189 (NH), 1622 (CO) cm–1.
1H NMR: d = 7.68 (d, 1 H, J = 8.5 Hz), 6.82 (d, 1 H, J = 2.4 Hz),
6.69 (dd, 1 H, J = 2.4, 8.9 Hz), 3.83 (s, 3 H), 2.45 (s, 3 H).
13C NMR: d = 169.2, 161.7, 139.9, 131.3, 125.5, 113.6, 109.8, 55.4,
16.9.
(5) (a) D’Silva, C.; Iqbal, R. Synthesis 1996, 457. (b) Beach, L.
J.; Batchelor, R. J.; Einstein, F. W. B.; Bennet, A. J. Can. J.
Chem. 1998, 76, 1410. (c) Lee, C. K.; Jun, J. H.; Yu, J. S. J.
Heterocycl. Chem. 2000, 37, 15. (d) Itahara, T.; Kawasaki,
K.; Ouseto, F. Bull. Chem. Soc. Jpn. 1984, 57, 3488.
(e) Cipiciani, A.; Linda, P.; Savelli, G. J. Heterocycl. Chem.
1979, 16, 673.
(6) For example, reaction of either 4-chloro-8-methoxy-3-
quinoline carboxylic acid chloride or the corresponding 4-
methylthio derivative with pyrrole under standard phase
transfer conditions (powdered KOH/CH2Cl2/tetrabutyl-
ammonium hydrogen sulfate) or via prior reaction with NaH
in DMF–THF solution provided <10% of the desired N-
acylated pyrrole product: (a) Xiang, H. MSc Thesis;
Michigan Technological University: Houghton, 1998. (b)
See: Illi, V. O. Tetrahedron Lett. 1979, 2431.
(7) For other problems see: D’Silva, C.; Walker, D. A. J. Org.
Chem. 1998, 63, 6715.
MS (EI): m/z (%) = 197 (M+, 53), 182 (100), 180 (69), 135 (67), 63
(90).
Anal. Calcd for C9H11NO2S: C, 54.80; H, 5.62; N, 7.10. Found: C,
54.81; H, 5.79; N, 7.12.
Acknowledgment
The authors thank the NSF for an equipment grant (CHE-9512445).
A. R. E. thanks Michigan Technological University for financial
support. The assistance of J. L. Lutz (NMR) and S. Crist (computer
system administration) is gratefully acknowledged.
(8) Gross, H. Chem. Ber. 1962, 95, 2270.
(9) Menger, F. M.; Donohue, J. A. J. Am. Chem. Soc. 1973, 95,
432.
(10) (a) Clauson-Kass, N.; Tyle, Z. Acta Chem. Scand. 1952, 6,
667. (b) Elming, N.; Clauson-Kass, N. Acta Chem. Scand.
1952, 6, 867.
(11) Fang, Y.; Leysen, D.; Ottenheijm, H. C. J. Synth. Commun.
1995, 25, 1857.
References
(1) (a) Brandange, S.; Rodriguez, B. Acta Chem. Scand., Ser. B
1987, 41, 740. (b) Brandange, S.; Holmgren, E.;
Leijonmarck, H.; Rodriguez, B. Acta Chem. Scand. 1995,
49, 922. (c) Lee, S. D.; Brook, M. A.; Chan, T. H.
Tetrahedron Lett. 1983, 24, 1569.
(12) Chung, B. Y.; Bae, D. J.; Jin, J.; Lee, S. D. J. Korean Chem.
Soc. 1992, 36, 603.
(2) (a) Blackaby, W. P.; Castro, J. L.; Lewis, R. T.; Russell, M.
G.; Street, L. J. PCT Int. Appl., WO9948892, 1999; Chem.
Abstr. 1999, 131, 257559. (b) Havez, S. E. PCT Int. Appl.
WO0283622, 2002; Chem. Abstr. 2003, 137, 325234.
(c) Trew, S. J.; Wrigley, S. K.; Pairet, L.; Sohal, J.; Shanu-
Wilson, P.; Hayes, M. A.; Martin, S. M.; Manoher, R. N.;
Chicarelli-Robinson, M. I.; Kau, D. A.; Byrne, C. V.;
Wellington, E. M. H.; Moloney, J. M.; Howard, J.; Hupe, D.;
Olson, E. R. J. Antibiot. 2000, 53, 1. (d) Ueda, A.;
Miyazawa, Y.; Sato, D.; Koguchi, M.; Matsumoto, I.;
Kawana, T. PCT Int. Appl. WO9636613, 1996; Chem.
Abstr. 1997, 126, 74874.
(3) (a) Evans, D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M.
C. J. Am. Chem. Soc. 2001, 123, 4480. (b) Evans, D. A.;
Willis, M. C.; Johnston, J. N. Org. Lett. 1999, 1, 865.
(c) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595.
(4) (a) Tafel, K. A.; Bates, D. K. J. Org. Chem. 1992, 57, 3676.
(b) Bates, D. K.; Xia, M. J. Org. Chem. 1998, 63, 9190.
(13) Tafel, K. A. Dissertation; Michigan Technological
University: Houghton, 1992.
(14) (a) Chan, T. H.; Lee, S. D. J. Org. Chem. 1983, 48, 3059.
(b) Chan, T. H.; Lee, S. D. Tetrahedron Lett. 1983, 24, 1225.
(15) For example, benzamide in this reaction mixture (50–60 °C)
formed N-benzoylindole and N-benzoylpyrrole after 5 h in
75% and 17% yield (GC), respectively.
(16) Gupta, S.; Jha, A.; Prasad, A. K.; Rajwanshi, V. K.; Jain, S.
C.; Olsen, C. E.; Wengel, J.; Parmar, V. S. Indian J. Chem.,
Sect. B. 1999, 38, 823.
(17) (a) Imamoto, T.; Tsuno, Y.; Yukawa, Y. Bull. Chem. Soc.
Jpn. 1971, 44, 1644. (b) Katritzky, A. R.; Pilarski, B.;
Urogdi, L. Synthesis 1989, 949.
(18) Kagano, H.; Goda, H.; Yoshida, K.; Yamamoto, M.; Sakaue,
S. Can. Pat. Appl. CA2151074, 1996; Chem. Abstr. 1996,
124, 317152.
Synthesis 2003, No. 13, 1959–1961 © Thieme Stuttgart · New York