Reductive acylation of 2- and 3-nitropyrroles-efficient syntheses of pyrrolylamides and pyrrolylimides

Article abstract of DOI:10.1016/j.tetlet.2007.10.113

An efficient one-pot synthesis of pyrrolylamides and pyrrolylimides is described under mild reaction conditions by the catalytic hydrogenation of 2- and 3-nitropyrroles.

Full text of DOI:10.1016/j.tetlet.2007.10.113

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 9155–9158
Reductive acylation of 2- and 3-nitropyrroles—efficient
syntheses of pyrrolylamides and pyrrolylimides
Liangfeng Fu and Gordon W. Gribble*
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
Received 17 September 2007; revised 20 October 2007; accepted 22 October 2007
Available online 25 October 2007
Abstract—An efficient one-pot synthesis of pyrrolylamides and pyrrolylimides is described under mild reaction conditions by the
catalytic hydrogenation of 2- and 3-nitropyrroles.
Ó 2007 Elsevier Ltd. All rights reserved.
Pyrrolylamides and pyrrolylimides are potentially useful
intermediates for the construction of pyrrole-based
heterocycles and medicinal compounds.1,2 For example,
pyrrolylimide 6c was employed in the first synthesis of
the naturally occurring bipyrrole Q1,1c and the well-
known distamycin antitumor agents are pyrrolylamides
(e.g., netropsin).
We now report that 2- and 3-nitropyrroles are smoothly
reduced and N-acylated under atmospheric catalytic
hydrogenation conditions in the presence of carboxylic
acid anhydrides to afford the expected pyrrolylamides
(Scheme 1 and Tables 1 and 2). A previously reported
reductive acylation of nitropyrrole 1a was carried out
under high pressure in THF.1a Four readily prepared
nitropyrroles (1-methyl-3-nitropyrrole (1a), 3-nitro-1-
(phenylsulfonyl)pyrrole (1b), 1-methyl-2-nitropyrrole
(1c), and 2-nitro-1-(phenylsulfonyl)pyrrole (1d))6 were
subjected to catalytic reductive acylation.
Cl
Cl
Cl
Cl
Cl
Q1
N
N
Me
NH
Cl
Cl
H
N
NO2
H2N
N
H
NO2
H
N
O
N
H
N
NO2
NO2
N
N
N
N
NH2
O
Me
N
SO2Ph
SO2Ph
Me
Me
O
NH
Me
1a
netropsin
1b
1c
1d
As an extension of our recent catalytic reductive acyl-
ation of 2- and 3-nitroindoles,3 we now describe a new
route to pyrrolylamides and pyrrolylimides via the Pd/
C catalyzed reductive acylation of 2- and 3-nitropyr-
roles. Catalytic hydrogenation has long been utilized
as a convenient and efficient nitro group to primary
amine reduction method.4 However, in the present case
the relative instability of 2- and 3-aminopyrroles nor-
mally precludes their isolation and handling.5
Thus, 1-methyl-3-nitropyrrole (1a) is hydrogenated
using 10% palladium on carbon in the presence of acetic
anhydride in MeOH at 70 °C at atmospheric pressure to
H2, 10% Pd/C
H
NO2
N
Ac2O
N
N
O
MeOH, 60-70 ºC
55-99%
PG
PG
2a-d
1a-d
*
Corresponding author. Tel.: +1 603 646 3118; fax: +1 603 646
3946; e-mail: ggribble@dartmouth.edu
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.113

9156
L. Fu, G. W. Gribble / Tetrahedron Letters 48 (2007) 9155–9158
Table 1. Catalytic reductive acylation of nitropyrroles with H2, Pd/C,
and acetic anhydride in methanol at 70 °Ca
R
H2, 10% Pd/C
(RCO)2O
NO2
HN
Yieldb (%)
O
Nitropyrrole
PG
Product
N
N
1a
1b
1c
Me
SO2Ph
Me
2a
2b
2c
91
99
MeOH, 60-70 ºC
75-92%
PG
PG
Decomposition
during workup
55
1a-b
3a-b, 4a-b, 5a-b
1d
SO2Ph
2d
Scheme 2.
a Temperature of the oil bath.
b Yield after column chromatography.
O
O
H2, 10% Pd/C
Anhydride
provide the desired pyrrole acetoamide 2a in 91% yield
(Scheme 1 and Table 1).7 Likewise, nitropyrroles 1b
and 1d are converted to 2b and 2d under the same reac-
tion conditions in 99% and 55% yields, respectively.8
The attempted reductive acylation of nitropyrrole 1c
led to decomposition and product 2c was not isolated.
NO2
N
N
OR
O
N
N
AcOH, 125 ºC
54-77%
O
N
PG
PG
PG
1a-c
6a-c
7a-b
Scheme 3.
Moreover, the reductive acylation using other carb-
oxylic acid anhydrides and Boc anhydride is successful.
As shown in Table 2 and Scheme 2, benzoic acid
anhydride gives pyrrole benzamides 3a and 3b in 79%
and 80% yields, respectively.8 Hexanoic anhydride
affords the expected pyrrole hexamides 4a and 4b in
88% and 92% yields, respectively.8 The t-butoxy-
carbonyl-protected amides 5a and 5b are obtained in
yields of 79% and 75%, respectively.8
and 1c were hydrogenated in the presence of succinic
anhydride in acetic acid at 125 °C to give the desired
pyrrolylimides 6a, 6b, and 6c in 77%, 72%, and 54%
yields, respectively.8 In addition, phthalic anhydride
furnishes pyrrolylimides 7a and 7b in 75% and 69%
yields, respectively.8
In summary, we have described an efficient synthesis of
pyrrolylamides and pyrrolylimides via the reductive
acylation of 2- and 3-nitropyrroles in the presence of
carboxylic acid anhydrides. In general, 3-nitropyrroles
afford higher yields of reductive acylation products than
do 2-nitropyrroles. Noteworthy is the synthesis of t-
butoxylcarbonyl-protected pyrrolylamides 5a and 5b,
which could serve as precursors for in situ generation
of 2- and 3-aminopyrroles for use in synthesis.
The same reaction conditions were extended to the
preparation of pyrrolylimides. Unfortunately, when
1-methyl-3-nitropyrrole (1a) was hydrogenated in the
presence of succinic anhydride, none of the expected
succinimide was obtained and 1a was recovered. In con-
trast, when acetic acid rather than methanol was used as
the solvent, the desired pyrrolylimides were obtained
(Scheme 3 and Table 3). Thus, nitropyrroles 1a, 1b,
Table 2. Catalytic reductive acylation of 3-nitropyrroles with H2, Pd/C and different anhydrides in methanol at 70 °Ca
Entry
Nitropyrrole
PG
Anhydride
R
Product
Yieldb (%)
1
2
3
4
5
6
1a
1b
1a
1b
1a
1b
Me
SO2Ph
Me
SO2Ph
Me
SO2Ph
(PhCO)2O
(PhCO)2O
(C5H11CO)2O
(C5H11CO)2O
(Boc)2O
Ph
Ph
3a
3b
4a
4b
5a
5b
79
80
88
92
79
75
(CH2)4CH3
(CH2)4CH3
Boc
(Boc)2O
Boc
a Temperature of the oil bath.
b Yield after column chromatography.
Table 3. Reductive acylation of nitropyrroles with H2, Pd/C, and cyclic anhydrides in acetic acid at 125 °Ca
Entry
Nitropyrrole
PG
Anhydride
Product
Yieldb (%)
1
2
3
4
5
1a
1b
1c
1a
1b
Me
SO2Ph
Me
Me
SO2Ph
Succinic anhydride
Succinic anhydride
Succinic anhydride
Phthalic anhydride
Phthalic anhydride
6a
6b
6c
7a
7b
77
72
54
75
69
a Temperature of the oil bath.
b Yield after column chromatography.

L. Fu, G. W. Gribble / Tetrahedron Letters 48 (2007) 9155–9158
9157
Calcd for C12H12N2O3S: C, 54.53; H, 4.58; N, 10.60; S,
12.13. Found: C, 54.27; H, 4.58; N, 10.48; S, 12.28.
Compound 3a: white solid; mp 169–170.5 °C; 1H NMR
(CDCl3): d 7.84–7.86 (m, 2H), 7.81 (br s, 1H), 7.45–7.53 (m,
3H), 7.32 (t, 1H,), 6.49 (t, 1H,), 6.05 (dd, 1H, J), 3.65 (s,
3H); 13C NMR (CDCl3): d 164.6, 135.1, 131.6, 128.9, 127.1,
122.8, 120.0, 113.5, 100.7, 36.8; Anal. Calcd for
C12H12N2O: C, 71.98; H, 6.04; N, 13.99. Found: C, 71.92;
H, 6.06; N, 14.02.
Acknowledgments
This work was supported by the Donors of the Petro-
leum Research Fund (PRF), administrated by the Amer-
ican Chemical Society, and by Wyeth.
References and notes
Compound 3b: white solid; mp 170.5–172 °C; 1H NMR
(CDCl3): d 7.90–7.92 (m, 2H), 7.85 (t, 1H), 7.80–7.82 (m,
3H), 7.45–7.60 (m, 6H), 7.14 (dd, 1H), 6.32 (dd, 1H); 13C
NMR (CDCl3): d 165.0, 138.9, 134.2, 134.1, 132.2, 129.7,
129.1, 127.2, 127.1, 127.0, 120.0, 110.3, 107.7; Anal. Calcd
for C17H14N2O3S: C, 62.56; H, 4.32; N, 8.58; S, 9.83.
Found: C, 62.40; H, 4.28; N, 8.56; S, 9.90.
1. Pyrrole-based heterocycles: (a) Grehn, L. Chem. Scripta
1980, 16, 77–84; (b) Grehn, L. Chem. Scripta 1980, 16, 85–
96; (c) Wu, J.; Vetter, W.; Gribble, G. W.; Schneekloth, J.
S., Jr.; Blank, D. H.; Gorls, H. Angew. Chem., Int. Ed. 2002,
41, 1740–1743.
2. Pyrrole-based drugs: (a) Baraldi, P. G.; Preti, D.; Frutta-
rolo, F.; Tabrizi, M. A.; Romagnoli, R. Bioorg. Med.
Chem. 2007, 15, 17–35; (b) Baraldi, P. G.; Zaid, A. N.;
Preti, D.; Fruttarolo, F.; Tabrizi, M. A.; Iaconinoto, A.;
Pavani, M. G.; Carrion, M. D.; Cara, C. L.; Romagnoli, R.
Arkivoc 2006, 7, 20–34; (c) Broggini, M.; Marchini, S.;
Fontana, E.; Moneta, D.; Fowst, C.; Geroni, C. Anti-cancer
Drugs 2004, 15, 1–6; (d) Baraldi, P. G.; Nuˆnez, M. D. C.;
Espinosa, A.; Romagnoli, R. Curr. Top. Med. Chem. 2004,
4, 231–239; (e) Neamati, N.; Mazumder, A.; Sunder, S.;
Owen, J. M.; Tandon, M.; Lown, J. W.; Pommier, Y. Mol.
Pharmacol. 1998, 54, 280–290.
3. (a) Roy, S.; Gribble, G. W. Heterocycles 2006, 70, 51–56;
(b) Roy, S.; Roy, S.; Gribble, G. W. Tetrahedron Lett.,
submitted for publication.
4. (a) Smith, H. A.; Bedoit, W. C., Jr. Catalysis 1955, 3, 149–
170; (b) Downing, R. S.; Kunkeler, P. J.; van Bekkum, H.
Catal. Today 1997, 37, 121; (c) Figueras, F.; Coq, B. J. Mol.
Catal. A: Chem. 2001, 173, 223–230.
1
Compound 4a: yellow solid (solid upon staying); H NMR
(CDCl3): d 7.27 (br s, 1H), 7.15 (t, 1H), 6.42 (t, 1H), 5.92
(dd, 1H), 3.60 (s, 3H), 2.29 (t, 2H, J = 7.6 Hz), 1.70 (m,
2H), 1.33 (m, 4H), 0.90 (t, 3H, J = 7.0 Hz); 13C NMR
(CDCl3): d 170.4, 122.8, 119.7, 113.2, 100.5, 37.2, 36.7, 31.7,
25.8, 22.7, 14.2; MS (EI): m/z (%) = 194 ([M+]), 156, 138,
123, 112, 96 (100), 81, 68, 57; HRMS (EI): m/z calcd for
C11H18ON2: 194.1419. Found: 194.1420.
1
Compound 4b: Brown oil; H NMR (CDCl3): d 7.89 (br s,
1H), 7.81–7.82 (m, 2H), 7.66 (dd, 1H), 7.42–7.56 (m, 3H),
7.03 (dd, 1H), 6.18 (dd, 1H), 2.26 (t, 2H, J = 7.6 Hz), 1.59–
1.65 (m, 2H), 1.22–1.28 (m, 4H), 0.84 (t, 3H, J = 6.8 Hz);
13C NMR (CDCl3): d 171.3, 138.8, 134.1, 129.6, 127.3,
127.1, 119.8, 109.8, 107.8, 36.9, 31.6, 25.5, 22.6, 14.1; MS
(EI): m/z (%) = 320 ([M+]), 277, 264, 238, 222 (100), 179,
157, 141, 126, 99, 81; HRMS (EI): m/z calcd for
C16H20N2O3S: 320.1195. Found: 320.1190.
Compound 5a: white solid; mp 88–89 °C; 1H NMR
(CDCl3): d 6.84 (m, 1H), 6.41 (t, 1H), 6.27 (br s, 1H),
5.88 (m, 1H), 3.59 (s, 3H), 1.50 (s, 9H); 13C NMR (CDCl3):
d 153.6, 123.0, 120.0, 111.8, 100.7, 79.9, 36.7, 28.7; MS (EI):
m/z (%) = 196 ([M+]), 153, 140 (100), 123, 96, 81, 68, 57;
HRMS (EI): m/z calcd for C10H16O2N2: 196.1212. Found:
196.1213.
5. (a) De Rosa, M.; Stepani, N.; Cole, T.; Fried, J.; Huang-
Pang, L.; Peacock, L.; Pro, M. Tetrahedron Lett. 2005, 46,
5715–5717; (b) De Rosa, M.; Sellitto, L.; Issac, R. P.;
Ralph, J.; Timken, M. D. J. Chem. Res. (S) 1999, 262–
263.
6. Fu, L.; Gribble, G. W. Synthesis, submitted for publication.
7. Representative procedure (2a): To a solution of 1-methyl-3-
nitropyrrole (1a) (32 mg, 0.25 mmol) and acetic anhydride
(77 mg, 0.75 mmol) in anhydrous methanol (3 mL) was
added 10% palladium on carbon (10 mg). The atmosphere
of the flask was replaced by hydrogen gas and the reaction
was cooled to À78 °C. After three vacuum/hydrogen cycles
to remove air from the reaction flask, the reaction mixture
was heated to 60 °C under atmospheric pressure for 2.5 h,
having the hydrogen atmosphere maintained by a balloon.
The catalyst was removed by filtration through Celite. The
filtrate was evaporated and the crude product was purified
by column chromatography (Hex/EtOAc = 2:1) to give the
desired product (2a) (32 mg, 91%) as a yellow solid: mp
121–122 °C (lit.1a mp 120.5–121 °C); 1H NMR (acetone-d6):
d 9.01 (br s, 1H), 7.10 (t, 1H), 6.47 (t, 1H), 5.93 (dd, 1H),
3.61 (s, 3H), 2.02 (s, 3H); 13C NMR (acetone-d6): d 166.1,
124.2, 119.3, 112.1, 100.0, 35.6, 22.6.
Compound 5b: white solid; mp 172–173 °C; 1H NMR
(CDCl3): d 7.86 (m, 2H), 7.58 (m, 1H), 7.48 (m, 2H), 7.35
(br s, 1H), 7.05 (t, 1H), 6.34 (m, 1H), 6.14 (m, 1H), 1.48 (s,
9H); 13C NMR (CDCl3): d 152.7, 139.1, 134.0, 129.5, 128.1,
127.8, 127.1, 120.1, 107.9, 80.8, 28.5; MS (EI): m/z
(%) = 322 ([M+]), 266 (100), 248, 222, 191, 158, 141, 125,
108, 77; HRMS (EI): m/z calcd for C15H18O4N2S: 322.0987.
Found: 322.0988.
Compound 6a: white solid; mp 99.5–101 °C; 1H NMR
(acetone-d6): d 7.11 (m, 1H), 6.61 (m, 1H), 6.48 (m, 1H),
3.68 (s, 3H), 2.77 (s, 4H); 13C NMR (acetone-d6): d 176.0,
119.9, 117.9, 115.6, 103.3, 35.8, 28.1; Anal. Calcd for
C9H10N2O2: C, 60.66; H, 5.66; N, 15.72. Found: C, 60.62;
H, 5.66; N, 15.71.
Compound 6b: white solid; mp 161–162 °C; 1H NMR
(acetone-d6): d 8.02 (m, 2H), 7.77–7.80 (m, 2H), 7.67 (m,
2H), 7.34 (dd, 1H), 6.99 (dd), 2.82 (s, 4H); 13C NMR
(acetone-d6): d 175.8, 138.9, 134.8, 130.1, 127.2, 123.1,
119.6, 112.8, 109.0, 28.2; Anal. Calcd for C14H12N2O4S: C,
55.26; H, 3.97; N, 9.16; S, 10.59. Found: C, 55.00; H, 4.16;
N, 9.16; S, 10.59.
8. Compound 2b: White solid; mp 169–170.5 °C; 1H NMR
(acetone-d6): d 9.27 (br s, 1H), 7.94–7.97 (m, 2H), 7.71–7.74
(m, 1H), 7.69 (t, 1H), 7.62–7.66 (m, 2H), 7.18 (dd, 1H), 6.27
(dd, 1H), 2.01 (s, 3H); 13C NMR (acetone-d6): d 167.8,
139.8, 134.9, 130.4, 129.1, 127.6, 120.5, 109.6, 108.5, 23.1;
Anal. Calcd for C12H12N2O3S: C, 54.53; H, 4.58; N, 10.60;
S, 12.13. Found: C, 54.36; H, 4.49; N, 10.49; S, 12.05.
Compound 2d: white solid; mp 128–129 °C; 1H NMR
(CDCl3): d 8.57 (br s, 1H), 7.74–7.76 (m, 2H), 7.62 (m,
2H), 7.52 (m, 2H), 6.90 (dd, 1H), 6.55 (t, 1H), 6.24 (t, 1H),
2.18 (s, 3H); 13C NMR (CDCl3): d 166.8, 138.5, 134.6,
130.0, 128.6, 126.8, 116.7, 113.1, 104.0, 24.3; Anal.
Compound 6c: white solid; mp 166–167 °C (lit.9 mp 163–
1
164 °C); H NMR (acetone-d6): d 6.72 (dd, 1H), 6.05 (dd,
1H), 5.93 (dd, 1H), 3.41 (s, 3H), 2.89 (s, 4H); 13C NMR
(acetone-d6): d 176.8, 121.5, 120.6, 106.7, 106.4, 32.4,
28.5.
Compound 7a: yellow solid; mp 172.5–174 °C; 1H NMR
(CDCl3): d 7.73–7.91 (m, 4H), 7.07 (t, 1H), 6.63 (t, 1H),
6.53 (dd, 1H), 3.71 (s, 3H); 13C NMR (CDCl3): d 167.5,

9158
L. Fu, G. W. Gribble / Tetrahedron Letters 48 (2007) 9155–9158
134.3, 132.3, 123.6, 121.0, 116.4, 116.3, 104.5, 37.0; Anal.
NMR (CDCl3): d 166.5, 138.9, 134.7, 134.4, 131.9, 130.0,
127.3, 123.9, 122.1, 120.0, 112.9, 108.9; Anal. Calcd for
C18H12N2O4S: C, 61.35; H, 3.43; N, 7.95; S, 9.10. Found:
C, 61.56; H, 3.44; N, 8.03; S, 9.10.
Calcd for C13H10N2O2: C, 69.02; H, 4.46; N, 12.38. Found:
C, 68.80; H, 4.40; N, 12.33.
Compound 7b: yellowish solid; mp 166–168 °C; 1H NMR
(CDCl3): d 7.89–7.94 (m, 4H), 7.85 (dd, 1H), 7.75–7.85 (m,
2H), 7.52–7.64 (m, 3H), 7.22 (dd, 1H), 7.03 (dd, 1H); 13C
9. De Rosa, M.; Nieto, G. C.; Gago, F. F. J. Org. Chem. 1989,
54, 5347–5350.