A new facile approach to N-alkylpyrroles from direct redox reaction of 4-hydroxy-l-proline with aldehydes

Article abstract of DOI:10.1007/s11426-011-4445-1

An unprecedented acetic acid-catalyzed efficient access to N-alkylpyrroles from reaction of 4-hydroxy-l-proline with a variety of aldehydes has been achieved in good to excellent yields under mild reaction conditions.

Full text of DOI:10.1007/s11426-011-4445-1

SCIENCE CHINA
Chemistry
January 2012 Vol.55 No.1: 43–49
doi: 10.1007/s11426-011-4445-1
• ARTICLES •
· SPECIAL TOPIC · The Frontiers of Chemical Biology and Synthesis
A new facile approach to N-alkylpyrroles from direct redox
reaction of 4-hydroxy-L-proline with aldehydes
ZOU ZhiQin1, DENG ZeJun1, YU XinHong1*, ZHANG ManMan1, ZHAO SiHan2,
LUO Ting1, YIN Xin1, XU Hui1 & WANG Wei1,2*
1School of Pharmacy, Easy China University of Science & Technology, Shanghai 200237, China
2Department of Chemistry & Chemical Biology, University of New Mexico, MSC03 2060, NM 87131, USA
Received September 17, 2011; accepted October 22, 2011; published online November 14, 2011
An unprecedented acetic acid-catalyzed efficient access to N-alkylpyrroles from reaction of 4-hydroxy-L-proline with a variety
of aldehydes has been achieved in good to excellent yields under mild reaction conditions.
aromatization, decarboxylation, enamines, iminium, redox isomerization
product formation [6, 7].
1 Introduction
Redox isomerization accompanied by selective C–H bond
functionalization using the inherent reducing power of hy-
drogen without any other oxidant and reducing agents in a
single step is a potentially valuable, yet fully realized tool in
organic synthesis [1–3]. Recently, increasing attention has
been directed toward the development of metal-free redox
amination reactions as results of significant improvement of
atom- and step-economy and synthetic efficiency, whereas
the avoidance of the use of toxic reagents and the reduction
of waste and hazardous by-products [3].
Pyrroles are versatile synthetic building blocks and very
important molecular architectures featured in a large array
of natural products and therapeutic agents [4]. Accordingly,
the development of new practical synthetic methodologies for
pyrroles has been a mainstay in organic synthesis [5]. Herein
we report a new, alternative approach to N-alkylpyrroles from
readily available 4-hydroxy-L-proline (3) and aldehydes,
which are generally prepared from reductive amination or
N-alkylation processes. Notably an interesting redox imin-
ium-enamine transformation is a possible pathway for the
2 Results and discussion
During our investigation of a three-component Knoevenagel-
SNAr cascade reaction [8], surprisingly an unexpected
N-(4-chlorobenzyl)pyrrole (1a) was isolated (29%) in addi-
tion to the Knoevenagel condensation product 6 (47%)
while Knoevenagel-nucleophilic aromatic substitution
product 7 was not observed among the reaction of trans-4-
hydroxy-L-proline (3), para-chlorobenzaldehyde (4a) and
ethyl cyanoacetiate (Scheme 1). Obviously, the product 1a
was produced from reaction of para-chlorobenzaldehyde
(4a) with trans-4-hydroxy-L-proline (3).
The unexpected product 1a prompted us to investigate
the interesting process. Survey of literature revealed that
Cook and coworkers reported a thermodynamic controlled
condensation of 3-pyrroline with cyclohexanone at 140 °C
in xylenes to produce N-cyclohexylpyrrole in 47% yield
while other ketones provided even poorer yields [9]. Tunge
and coworkers improved this reaction under milder condi-
tions at 110 °C in toluene with benzoic acid as catalyst and
N2 as inert atmosphere in excellent yields [3b].
*Corresponding authors (email: xhyu@ecust.edu.cn; wwang@unm.edu)
In the initial attempt, under the same reaction conditions
© Science China Press and Springer-Verlag Berlin Heidelberg 2011
chem.scichina.com www.springerlink.com

44
Zou ZQ, et al. Sci China Chem January (2012) Vol.55 No.1
soluble trans-4-hydroxy-L-proline reacted with 4-chloro-
benzaldehyde (4a) gradually to minimize the formation of
byproducts [10]. Indeed, the yield was improved dramati-
cally from 18% up to 51% with fewer by-products observed
(entry 2).
Encouraged by the outcome, we then further optimized
the reaction conditions. Since the amination reaction was
facilitated by acids, a variety of acids with 10 mol% loading
were screened accordingly. As shown, indeed an acid was
beneficial to the reaction (entries 3–9). The acid promoters
significantly shortened the reaction times from 10 h to 10
min while achieving better yields. Among the acids probed,
acetic acid was of choice (entry 5). In this case, a highest
yield (90%) was achieved. The examination of catalyst
loadings revealed that the use of 10 mol% acetic acid was
optimal (entries 5, 10 and 11). Finally, survey of solvent
effects on the reaction led to the selection of DMF (entries 5
and 12–14), although a similar result was obtained with
DMSO, much longer reaction time was required.
Having established the optimal reaction conditions, we
then determined the scope of the reaction. As summarized
in Table 2, the powerful process serves as a general ap-
proach to N-alkylpyrroles with a wide range of structurally
diverse aldehydes. Remarkably, all reactions were accom-
plished within 40 min in good to high yields (71%–98%).
Furthermore, the reactions seem to inert to both electronic
and steric effects. Regardless of the aromatic systems bear-
ing electron-donating (entries 4, 6–10), -neutral (entry 2)
and -withdrawing (entries 1,3 and 5, 11–15) substituents, in
all cases the processes proceeded with high efficiency.
Moreover, the steric effects are limited too (entries 11 and
15). Heterocyclics (entries 16–18) and ,-unsaturated al-
dehyde (entry 19) could also efficiently participate in the
reactions. Furthermore, less reactive aliphatic aldehyde (en-
try 20 and 21) as well as activated ketones (entry 22 and 23)
allowed the process to occur smoothly. But, less reactive
ketones (entry 24 and 25) reacted with trans-4-hydroxy-L-
proline in low conversation rate.
Scheme 1 Reaction of 4-chlorobenzaldehyde with ethyl cyanoacetiate
and trans-4-hydroxy-L-proline.
as the above mentioned 3-component process, a mixture of
trans-4-hydroxy-L-proline (3) and 4-chlorobenzaldehyde
(4a) without ethyl cyanoacetiate in DMF was refluxed (Ta-
ble 1, entry 1). As expected, the desired product 1a was
obtained but in 18% yield when the process was conducted
under atmosphere or by N2 protection. The low reaction
yield might attribute to the poor solubility of highly polar
and zwitterionic trans-4-hydroxy-L-proline (3) in DMF
while long reaction time and high reaction temperature gen-
erated more side reactions. We surmised that slow addition
of a DMF solution of 4-chlorobenzaldehyde (4a) into a
trans-4-hydroxy-L-proline suspended DMF reaction at re-
flux could improve reaction efficiency because the partially
Table 1 Exploration of reaction of trans-4-hydroxy-L-proline (3a) with
4-chlorobenzaldehyde (4a) a)
A possible mechanism for the formation of N-alkylpy-
rroles 1 from 4-hydroxyproline (3) and aldehydes (or ke-
tones) (4) in DMF catalyzed by acetic acid is proposed
(Scheme 2) [7]. In the presence of acetic acid, an iminium
ion I is formed. Upon heating, decarboxylation process oc-
curs to give rise a new iminium ion II. Reversible imini-
um-enamine transformation leads an enamine III, which
undergoes a favorable aromatization process by dehydration
to afford final products 1.
Entry
1b)
2
Cat.
Solvent
DMF
Time
10 h
Yield (%)c)
no catalyst
no catalyst
PhCO2H
18
51
67
71
90
76
76
84
79
79
86
90
21
28
DMF
10 h
3
DMF
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 h
4
PhCH2CO2H
CH3CO2H
CF3CO2H
p-TsOH
DMF
5
DMF
6
DMF
7
DMF
8
conc. H2SO4
conc. HCl
CH3CO2Hd)
CH3CO2He)
CH3CO2H
CH3CO2H
CH3CO2H
DMF
9
DMF
10
11
12
13
14
DMF
DMF
3 Conclusions
DMSO
toulene
xylenes
24 h
In summary, we have developed a new alternative method
for the rapid preparation of N-alkylpyrroles from 4-
hydroxy-L-proline and aldehydes in DMF catalyzed by acetic
acid in good to excellent yields within 40 min. Notably, a
20 h
a) Unless specified, a solution of 4a in DMF was added dropwise over
30 min into 3 in DMF refluxing mixture; b) 3 and 4a in one-pot; c) isolated
yields; d) 5 mol% used; e) 20 mol% used.

Zou ZQ, et al. Sci China Chem January (2012) Vol.55 No.1
45
Table 2 Reaction scope a)
Entry
1
Substrate (4)
Product (1)
Yield (%)b)
90
Entry
14
Substrate (4)
Product (1)
Yield (%)b)
96
2
3
4
84
87
92
15
16
17
91
91
93
5
94
18
71
6
7
8
95
95
96
19
20
21
74
71
81
9
98
22
82c)
10
11
88
77
23
24
25
86
68d)
88e)
12
13
99
91
a) Unless specified, see experimental section for detail; b) isolated yields; c) 4-hydroxy-L-proline methyl ester reacted with isatin in 65% yield; d)cata-
lyzed by 1 equiv concentrated sulfuric acid, reflux in DMF for 48 h with 22% conversation rate and 68% yield; e) catalyzed by 1 equiv concentrated sulfuric
acid, MW (800 w, 120 °C) in DMF for 1.5 h with 31% conversation rate and 88% yield.

46
Zou ZQ, et al. Sci China Chem January (2012) Vol.55 No.1
mixture over 30 min. After 10 min, the solvent was evapo-
rated under reduced pressure and the residue was purified
by silica gel column.
N-(4-chlorobenzyl)-1H-pyrrole (1a): 0.86 g, colorless oil,
yield: 92%; 1H NMR (400 MHz, CDCl3) : 7.16 (2H, d, J =
8.56 Hz), 6.94 (2H, d, J = 8.61 Hz), 6.76 (2H, t, J = 1.96
Hz), 6.26 (2H, t, J = 1.98 Hz), 5.07 (2H, s), 3.86 (3H, s);
13C NMR (101 MHz, CDCl3) : 159.22, 130.23, 128.54,
121.00, 114.16, 108.46, 55.34, 52.87; Calcd. HRMS for
C12H14NO (M+H), 188.1075; Found, 188.1072.
Scheme 2 Proposed mechanism for the formation of N-alkylpyrroles 1
from 4-hydroxyproline 3 and aldehydes 4.
N-Benzyl-1H-pyrrole (1b): 0.66 g, colorless oil, yield:
84%; H NMR (400 MHz, CDCl3) : 7.45 (3H, m), 7.26
1
(2H, d, J = 7.08 Hz), 6.84 (2H, t, J = 1.99 Hz), 6.36 (2H, t,
J = 2.01 Hz), 5.18 (2H, s); 13C NMR (101 MHz, CDCl3) :
138.37, 128.86, 127.77, 127.14, 121.30, 108.68, 53.43;
Calcd. HRMS for C11H12N (M+H), 158.0970; Found,
158.0970.
wide range of aldehydes are able to participate in the pro-
cess. Operational simplicity and high reaction efficiency
render the method attractive in the synthesis of broadly in-
teresting N-alkylpyrroles.
4 Experimental
N-(4-Fluorobenzyl)-1H-pyrrole (1c): 0.76 g, colorless oil,
yield: 87%; H NMR (400 MHz, CDCl3) 7.16 (2H, dd, J =
1
4.1 General experimental section
8.32, 5.57 Hz), 7.07 (2H, t, J = 8.63Hz), 6.75 (2H, d, J =
1.87 Hz, CH2NCH), 6.28 (2H, m, NCHCH), 5.10 (2H, s,
CH2); 13C NMR (101 MHz, CDCl3) : 162.33, 134.01,
128.77, 121.07, 115.65, 108.76, 52.65; Calcd. HRMS for
C11H11FN (M+H), 176.0876; Found, 176.0874.
All chemical reagents were commercially available and
were used without prior purification. N,N-Dimethylfor-
mamide (DMF) was dried by anhydrous magnesium sulfate
and toluene and xylenes were dried by sodium metal. Ana-
lytical thin-layer chromatography (TLC) was performed on
glass-backed silica gel plates containing ultraviolet-active
phosphor and the compounds were visualized either by UV
illumination (254 nm), or by means of lime or ink powder.
Preparative separations were performed by one of the fol-
lowing methods: (1) the solvent was removed through vac-
uum distillation and the crude products were purified by
column chromatography on silica gel (100–200 mesh) or (2)
poured the reaction mixtures into plenty of water then ex-
tracted by dichloromethane three times. After dried with an-
hydrous magnesium, removed solvent by vacuum distillation,
the crude products were purified by column chromatography
on silica gel (100–200 mesh) as same. Melting points were
N-(4-Methoxybenzyl)-1H-pyrrole (1d): 0.86 g, colorless oil,
yield: 90%; 1H NMR (400 MHz, CDCl3) : 7.35 (2H, d, J =
8.38 Hz), 7.10 (2H, d, J = 8.36 Hz), 6.74 (2 H, t), 6.28 (2H, t),
5.09 (2 H, s); 13C NMR (101 MHz, CDCl3) : 136.79, 133.53,
128.93, 128.37, 121.14, 108.87, 52.67; Calcd. HRMS for
C11H11ClN (M+H), 192.0580; Found, 192.0578.
N-(4-Bromobenzyl)-1H-pyrrole (1e): 1.11 g, colorless oil,
yield: 94%; 1H NMR (400 MHz, CDCl3) : 7.51 (2H, d, J =
8.35 Hz), 7.04 (2H, d, J = 8.28 Hz), 6.74 (2 H, s), 6.28 (2H,
s), 5.07 (2H, s); 13C NMR (101 MHz, CDCl3) : 137.33,
131.90, 128.71, 121.62, 121.16, 108.90, 52.73; Calcd.
HRMS for C11H11BrN (M+H), 236.0075; Found, 236.0076.
1
recorded on a WRS-1B apparatus and were uncorrected. H
and 13C Nuclear Magnetic Resonance (NMR) spectra were
measured on a Bruker Avance 400 MHz and 101 MHz spec-
trometers, respectively, using tetramethylsilane (TMS) as the
internal standard and CDCl3 as the solvent.
N-(4-Hydroxybenzyl)-1H-pyrrole (1f): 0.82 g, white
crystal, yield: 95%; mp: 74.5–74.8 °C; 1H NMR (400 MHz,
CDCl3) : 7.09 (2H, d, J = 8.41 Hz), 6.79 (4H, d, J = 8.89
Hz), 6.32 (2H, m), 5.64 (1H, s), 5.04 (2H, s); 13C NMR (101
MHz, CDCl3) : 155.01, 130.37, 128.91, 121.25, 115.64,
108.46, 52.90; Calcd. HRMS for C11H12NO (M+H),
174.0919; Found, 174.0914.
4.2 Experimental procedures and characterization of
products
To a 25 mL three-necked round bottomed flask was added
trans-4-hydroxy-L-proline (3, 0.983 g, 7.5 mmol), 10 mol%
of acetic acid (0.03 mL, 0.5 mmol) and DMF (10 mL), then
heated to reflux. The aldehyde (4, 5.0 mmol) was dissolved
in DMF (5 mL) and added dropwise into the above reaction
N-(3,4-Dimethoxybenzyl)-1H-pyrrole (1g): 1.00 g, white
solid, yield: 95%; mp: 40.1–40.2 °C; H NMR (400 MHz,
CDCl3) : 6.86 (1H, d, J = 8.15 Hz), 6.73 (4H, t, J = 11.28
Hz), 6.24 (2H, s), 5.04 (2 H, s), 3.90 (3H, s), 3.87 (3H, s);
1

Zou ZQ, et al. Sci China Chem January (2012) Vol.55 No.1
47
13C NMR (101 MHz, CDCl3) : 149.26, 148.63, 130.65,
121.03, 119.61, 111.26, 110.47, 108.48, 55.97, 55.87, 53.13;
Calcd. HRMS for C13H16NO2 (M+H), 218.1181; Found,
218.1181.
7.92 Hz), 7.36 (1H, d, J = 7.65 Hz), 6.70 (2H, d, J = 1.83
Hz), 6.22 (2H, t, J = 1.81 Hz), 5.16 (2H, s); 13C NMR (101
MHz, CDCl3) : 148.55, 140.59, 132.87, 129.87, 122.74,
121.78, 121.16, 109.42, 52.48; Calcd. HRMS for
C11H11N2O2 (M+H), 203.0821; Found, 203.0818.
N-(3,4,5-Trimethoxybenzyl)-1H-pyrrole (1h): 1.18 g, white
1
solid, yield: 96%; mp: 54.8–54.9 °C; H NMR (400 MHz,
N-(4-Cyanobenzyl)-1H-pyrrole (1n): 0.87 g, white solid,
yield: 96%; mp: 48.3–48.4 °C; 1H NMR (400 MHz, CDCl3)
: 7.58 (2H, d, J = 8.26 Hz), 7.13 (2H, d, J = 8.24 Hz), 6.67
(2H, t, J = 1.98 Hz), 6.22 (2H, t, J = 2.01 Hz), 5.12 (2H, s);
13C NMR (101 MHz, CDCl3) : 143.85, 132.59, 127.32,
121.28, 118.64, 109.30, 52.78; Calcd. HRMS for C12H11N2
(M+H), 183.0922; Found, 183.0922.
CDCl3) : 6.74 (2H, t, J = 1.97 Hz), 6.38 (2H, s), 6.24 (2H,
t, J = 2.01 Hz), 5.03 (2H, s), 3.87 (3H, s), 3.83 (6 H, s); 13C
NMR (101 MHz, CDCl3) : 153.52, 137.41, 133.94, 121.19,
108.61, 104.08, 60.85, 56.08, 53.47; Calcd. HRMS for
C14H18NO3 (M+H), 248.1287; Found, 248.1286.
N-(3-Methoxy-4-hydroxybenzyl)-1H-pyrrole (1i): 0.90 g,
1
white solid, yield: 97%; mp: 54.7–55.1 °C; H NMR (400
N-(2-Cyanobenzyl)-1H-pyrrole (1o): 0.83 g, yellow oil,
yield: 91%; 1H NMR (400 MHz, CDCl3) : 7.63 (1H, d, J =
7.60 Hz), 7.49 (1H, t, J = 7.67, 7.67 Hz), 7.35 (1H, t, J =
7.60 Hz), 6.96 (1H, d, J = 7.84 Hz), 6.71 (2H, m), 6.20 (2H,
m), 5.24 (2H, s); 13C NMR (101 MHz, CDCl3) : 142.04,
133.50, 132.88, 128.28, 127.98, 121.35, 117.22, 110.90,
109.31, 51.30; Calcd. HRMS for C12H11N2 (M+H),
183.0922; Found, 183.0920.
MHz, CDCl3) : 6.95 (1H, d, J = 8.06 Hz), 6.77 (3H, m),
6.70 (1H, s), 6.27 (2H, t, J = 1.95 Hz), 5.75 (1H, s), 5.05
(2H, s), 3.88 (3H, s); 13C NMR (101 MHz, CDCl3) :
146.86, 145.28, 130.02, 121.05, 120.46, 114.52, 109.93,
108.48, 55.95, 53.26; Calcd. HRMS for C12H14NO2 (M+H),
204.1025; Found, 204.1022.
N-(3-Hydroxy-4-methoxybenzyl)-1H-pyrrole (1j): 0.89 g,
1
white solid, yield: 88%; mp: 70.5–70.9 °C; H NMR (400
N-(Pyridinyl-2-methyl)-1H-pyrrole (1p): 0.72 g, colorless
oil, yield: 91%; 1H NMR (400 MHz, CDCl3) : 8.59 (1H, d,
J = 4.57 Hz), 7.63 (1H, dd, J = 10.93, 4.44 Hz), 7.20 (1H,
m), 6.82 (1H, d, J = 7.87 Hz), 6.77 (2H, s), 6.26 (2H, s),
5.23 (2H, s); 13C NMR (101 MHz, CDCl3) : 158.40,
149.26, 137.18, 122.45, 121.40, 120.82, 108.99, 55.17;
Calcd. HRMS for C10H11N2 (M+H), 159.0922; Found,
159.0920.
MHz, CDCl3) : 6.86 (1H, d, J = 8.23 Hz), 6.84 (1H, d, J =
1.88 Hz), 6.76 (2H, t, J = 1.95 Hz), 6.71 (1H, dd, J = 8.19,
1.81 Hz), 6.27 (2H, t, J = 2.00 Hz), 5.78 (1H, s), 5.02 (3H,
s), 3.92 (3H, s); 13C NMR (101 MHz, CDCl3) : 146.21,
145.88, 131.49, 121.06, 118.92, 113.76, 110.84, 108.46,
56.08, 53.00; Calcd. HRMS for C12H14NO2 (M+H),
204.1025; Found, 204.1023.
N-(Thienyl-2-methyl)-1H-pyrrole (1q): 0.76 g, white solid,
yield: 93%; mp: 39.1–39.8 °C; 1H NMR (400 MHz, CDCl3)
: 7.31 (1H, d, J = 4.86 Hz), 7.03 (2H, dd, J = 7.98, 2.90
Hz), 6.81 (2H, s), 6.27 (2H, s), 5.28 (2H, s); 13C NMR (101
MHz, CDCl3) : 140.69, 126.98, 126.05, 125.63, 120.75,
108.78, 48.09; Calcd. HRMS for C9H10NS (M+H),
164.0534; Found, 164.0533.
N-(2-Fluorobenzyl)-1H-pyrrole (1k): 0.67 g, colorless oil,
yield: 76%; H NMR (400 MHz, CDCl3) : 7.31 (1H, m),
1
7.13 (2H, m), 7.01 (1H, t, J = 7.33 Hz), 6.78 (2 H, s), 6.26
(2H, s), 5.18 (2H, s); 13C NMR (101 MHz, CDCl3) :
160.24 (1C, d, J = 246.72 Hz), 129.54 (1C, d, J = 8.05 Hz),
129.23 (1C, d, J = 3.79 Hz), 125.49 (1C, d, J = 14.72 Hz),
124.50 (1C, d, J = 3.61 Hz), 121.18 (2C, s), 115.40 (1 C, d,
J = 21.22 Hz), 108.71 (2 C, s), 46.99 (1C, d, J = 4.59 Hz);
Calcd. HRMS for C11H11FN (M+H), 176.0876; Found,
176.0868.
N-(Furan-2-ylmethyl)-1H-pyrrole (1r): 0.76 g, colorless
oil, yield: 71%; 1H NMR (400 MHz, CDCl3) : 7.50 (1H, s),
6.86 (2H, s), 6.47 (1H, s), 6.38 (1H, d, J = 2.46 Hz), 6.34
(2H, s), 5.13 (2H, s); 13C NMR (101 MHz, CDCl3) :
151.00, 142.82, 120.85, 110.57, 108.72, 108.27, 46.15;
Calcd. HRMS for C9H10NO (M+H), 148.0762; Found,
148.0766.
N-(4-Nitrobenzyl)-1H-pyrrole (1l): 1.0 g, yellowish solid,
1
yield: 99%; mp: 59.9–60 °C; H NMR (400 MHz, CDCl3)
: 8.17 (2H, d, J = 8.67 Hz), 7.20 (2H, d, J = 8.57 Hz), 6.70
(2H, t, J = 1.97, 1.97 Hz), 6.25 (2H, t, J = 1.99, 1.99 Hz),
5.19 (2H, s); 13C NMR (101 MHz, CDCl3) : 147.46,
145.76, 127.38, 124.02, 121.26, 109.41, 52.56; Calcd.
HRMS for C11H11N2O2 (M+H), 203.0821; Found, 203.0820.
N-Cinnamyl-1H-pyrrole (1s): 0.68 g, yellow liquid, yield:
1
74%; H NMR (400 MHz, CDCl3) : 7.27 (5H, m), 6.68 (2
H, s), 6.44 (1H, d, J = 15.83 Hz), 6.28 (1H, td, J = 15.77,
6.10 Hz), 6.18 (2H, s), 4.58 (2H, d, J = 6.00 Hz); 13C NMR
(101 MHz, CDCl3) : 136.34, 132.60, 128.67, 127.96,
126.58, 125.57, 120.70, 108.49, 51.62; Calcd. HRMS for
N-(3-Nitrobenzyl)-1H-pyrrole (1m): 0.92 g, yellow solid,
yield: 91%; mp: 40.8–41 °C; H NMR (400 MHz, CDCl3)
: 8.10 (1H, d, J = 8.06 Hz), 7.95 (1H, s), 7.47 (1H, t, J =
1

48
Zou ZQ, et al. Sci China Chem January (2012) Vol.55 No.1
1
For recent review of redox isomerization, see: (a) Burns NZ, Baran
C13H14N (M+H), 184.1126; Found, 184.1127.
PS, Hoffmann RW. Redox economy in organic synthesis. Angew
Chem Int Ed, 2009, 48(16): 2854–2867; (b) Mahrwald R. The aldol-
Tishchenko reaction: A tool in stereoselective synthesis. Curr Org
Chem, 2003, 7(17): 1713–1723
For recent examples of redox isomerization, see: (a) Richter JM,
Ishihara Y, Masuda T, Whitefield BW, Llamas T, Pohjakallio A.
Baran PS. Enantiospecific total synthesis of the hapalindoles, fisch-
erindoles, and welwitindolinones via a redox economic approach. J
Am Chem Soc, 2008, 130(52): 17938–17954; (b) McQuaid KM, Long
JZ, Sames D. C–H bond functionalization via hydride transfer: Syn-
thesis of dihydrobenzopyrans from ortho-vinylaryl akyl ethers. Org
Lett, 2009, 11(14): 2972–2975
N-n-Butyl-1H-pyrrole (1t): 0.44 g, colorless liquid, yield:
71%; 1H NMR (400 MHz, CDCl3) : 6.78 (2H, dd, J = 1.98,
1.91 Hz), 6.28 (2H, dd, J = 1.91, 1.86 Hz), 4.00 (2H, t, J =
7.15 Hz), 1.89 (2H, dt, J = 14.82, 7.34 Hz), 1.45 (2H, dt, J =
14.72, 7.39 Hz), 1.08 (3H, t, J = 7.39 Hz); 13C NMR (101
MHz, CDCl3) ppm 120.54, 107.89, 49.41, 33.76 20.05,
13.76; Calcd. HRMS for C8H14N (M+H), 124.1126; Found,
124.1125.
2
3
For recent examples of redox amination, see: (a) Zhang C, De CK,
Mal R, Seidel D. α-Amination of nitrogen heterocycles: Ring fused
aminals. J Am Chem Soc, 2008, 130(2): 416–417; (b) Pahadi NK, Paley
M, Jana R, Waetzig SR, Tunge JA. Formation of N-alkylpyrroles via
intermolecular redox amination. J Am Chem Soc, 2009, 131(46):
16626–16627; (c) Murarka S, Zhang C, Konieczynska MD, Seidel D.
Lewis acid catalyzed formation of tetrahydroquinolines via an intra-
molecular redox process. Org Lett, 2009, 11(1): 129–132; (d) Zhang
C, Murarka S, Seidel D. Facile formation of cyclic aminals through a
Brønsted acid promoted redox process. J Org Chem, 2009, 74(1):
419–422; (e) Murarka S, Deb I, Zhang C, Seidel D. Catalytic enanti-
oselective intramolecular redox reactions: Ring-fused tetrahydroquino-
lines. J Am Chem Soc, 2009, 131(37): 13226–13227; (f) Zhang C,
Seidel D. Nontraditional reactions of azomethine ylides: Decarboxy-
lative three-component couplings of -amino acids. J Am Chem Soc,
2010, 132(6): 1798–1799; (g) Deb I, Seidel D. Retro-Claisen condensa-
tion vs. pyrrole formation in reactions of amines and 1,3-diketones.
Tetrahedron Lett, 2010, 51: 2945–2497; (h) Mao H, Xu R, Wan J, Jiang
Z, Sun C, Pan Y. Tunable hydride transfer in the redox amination of
indoline with aldehyde: An attractive intramolecular hydrogen-bond
effect. Chem Eur J, 2010, 16(45): 13352–13355; (i) Mao H, Wang S,
Yu P, Lv H, Xu R, Pan Y. Brønsted acid-catalyzed decarboxylative
redox amination: formation of N-alkylindoles from azomethine ylides
by isomerization. J Org Chem, 2011, 76(4): 1167–1169; (j) Deb I, Das
D, Seidel D. Redox isomerization via azomethine ylide intermediates:
N-alkyl indoles from indolines. Org Lett, 2011, 13(4): 812–815
N-i-Butyl-1H-pyrrole (1u): 0.50 g, colorless liquid, yield:
1
81%; H NMR (400 MHz, CDCl3) : 6.69 (2H, t, J = 1.84
Hz), 6.20 (2H, t, J = 1.91 Hz), 3.72 (2H, d, J = 7.23 Hz),
2.08 (1H, m), 0.96 (6H, d, J = 6.69 Hz); 13C NMR (101
MHz, CDCl3) : 120.99, 107.69, 57.48, 30.67, 20.11.
3-(1H-Pyrrol-1-yl)indolin-2-one (1v): 0.813 g, yellow solid,
yield: 82%; 1H NMR (400 MHz, CDCl3) : 9.39 (1H, bs,
NH ), 7.28 (1H, t, J = 7.65 Hz), 7.23 (1H, d, J = 7.21 Hz),
7.05 (1H, t, J = 7.49 Hz), 6.89 (1H, d, J = 7.76 Hz), 6.70
(2H, bs), 6.24 (2H, bs), 5.49 (1H, bs); 13C NMR (101 MHz,
CDCl3) : 175.79, 141.50, 130.23, 125.45, 125.22, 123.30,
120.41, 111.01, 109.56, 61.11.
Ethyl 1-(pyridinyl-2-phenyl)propionate (1w): 1.04 g,
1
yellowish oil, yield: 86%; H NMR (400 MHz, CDCl3) :
7.31–7.28 (3H, m), 7.12–7.10 (2H, dd, J = 9.14, 7.29 Hz),
6.81 (2H, t, J = 2.12 Hz), 6.25 (2H, t, J = 17.49, 2.02 Hz),
4.82 (1H, dd, J = 8.58, 6.82 Hz), 4.21 (2H, m), 3.48 (1H, dd,
J = 13.77, 6.77 Hz), 3.33 (1H, dd, J = 13.76, 8.63 Hz), 1.26
(3H, t, J = 7.14 Hz).
4
Pyrroles in natural products and medicinal agents, see: (a) Liu K, Lu H,
Hou L, Qi Z, Teixeira C, Barbault F, Fan B-T, Liu S, Jiang S，Xie L.
Design, synthesis, and biological evaluation of N-carboxyphenylpyrrole
derivatives as potent HIV fusion inhibitors targeting gp41. J Med
Chem, 2008, 51(24): 7843–7854; (b) Teixeira C, Barbault F,
Rebehmed J, Liu K, Xie L, Lu H, Jiang S, Fan B-T, Maurel F. Molecu-
lar modeling studies of N-substituted pyrrole derivatives––Potential
HIV-1 gp41 inhibitors. Bioorg Med Chem, 2008, 16(6): 3039–3048;
(c) Fabio B, Renzo R. Synthesis and biological activity of pyrrole,
pyrroline and pyrrolidine derivatives with two aryl groups on adja-
cent positions. Tetrahedron, 2006, 62(31): 7213–7256
For synthetic methodologies for pyrroles, see: (a) Azizian J, Karimi
AR, Kazemizadeh Z, Mohammadi AA, Mohammadizadeh MR. A
novel one-pot synthesis of some new interesting pyrrole derivatives. J
Org Chem, 2005, 70(4): 1471–1473; (b) Radha RV, Srinivas N, Kul-
karni SJ, Raghavan KV. Amino cyclization of terminal (,)-diols
over modified ZSM-5 catalysts. J Mol Catal A: Chem, 2002, 187(2):
237–246; (c) Kamiguch S, Nakamura A, Suzuki A, Kodomari M,
Nomura M, Iwasawa Y, Chihara T. Catalytic dehydrogenation of al-
iphatic amines to nitriles, imines, or vinylamines and dealkylation of
tertiary aliphatic amines over halide cluster catalysts of group 5 and 6
transition metals. J Catal, 2005, 230(1): 204–213; (d) Srivastava P,
Srivastava R. Catalytic investigations of calix[4]arene scaffold based
phase transfer catalyst. Tetrahedron Lett, 2007, 48(26): 4489–493; (e)
Fegley MF, Bortnick NM, Mckeever CH. J Am Chem Soc, 1957,
79(15): 4144; (f) Chan TH, Lee SD. 1,4-Dichloro-1,4-dimethoxybutane
as a mild reagent for the conversion of primary amines to pyrroles.
Synthesis of a pyrrole compound from tobacco. J Org Chem, 1983,
48(18): 3059–3061; (g) D’Silva C, Walker DA. Acid-base catalysis
N-[(1-Phenyl)-2-phenylethyl]-1H-pyrrole (1x): 0.185 g
1
yellowish oil, yield: 68%; H NMR (400 MHz, CDCl3) :
7.20 (8 H, m ), 6.97 (2H, d, J = 5.93 Hz), 6.70 (2H, bs), 6.12
(2H, bs), 5.24 (1H, m), 3.52 (1H, dd, J = 13.70, 8.68 Hz),
3.39 (1H, dd, J = 13.71, 6.49 Hz); 13C NMR (101 MHz,
CDCl3) : 141.55, 137.95, 129.02, 128.65, 128.44, 127.75,
126.68, 119.78, 108.18, 64.96, 42.22.
5
N-(1-Phenyl)ethyl-1H-pyrrole (1y): 0.103 g colorless
liquid, yield: 72%; 1H NMR (400 MHz, CDCl3) : 7.24 (3H,
dt, J = 24.63, 7.08 Hz), 7.06 (2H, d, J = 7.27 Hz), 6.72 (2H,
bs), 6.17 (2H, bs), 5.23 (1H, dd, J = 7.01, 7.00 Hz), 1.79
(3H, d, J = 7.08 Hz, CH3); 13C NMR (101 MHz, CDCl3) :
143.70, 128.74, 127.54, 125.97, 119.61, 108.18, 58.21,
22.23.
We gratefully acknowledge financial support from the National Natural
Science Foundation of China (20972051), the Science and Technology
Commission of Shanghai Municipality (08430703900 & 08431901800),
the 111 Project (B07023), and East China University of Science & Tech-
nology.

Zou ZQ, et al. Sci China Chem January (2012) Vol.55 No.1
49
in the synthesis of arylmethylene and alkylmethine pyrroles. J Org
Chem, 1998, 63(19): 6715–6718; (h) Polshettiwar V, Baruwati B,
Varma RS. Palladium-catalyzed cross-couplings of 1,3-butadien-2-yl
species with organoindiums generated from allenylmethyl bromide and
indium. Chem Commun, 2009, (14): 1837; (i) Azizi N, Khajeh-Amiri A,
Ghafuri H, Bolourtchian M, Saidi MR. Iron-catalyzed inexpensive and
practical synthesis of N-substituted pyrroles in water. Synlett, 2009,
(14): 2245–2248; (j) Polshettiwar V, Varma RS. Nano-organocatalyst:
magnetically retrievable ferrite-anchored glutathione for micro-
wave-assisted Paal-Knorr reaction, aza-Michael addition, and pyra-
zole synthesis. Tetrahedron, 2010, 66(5): 1091–1097; (k) Jafarpour F,
Soraya R, Hazrati H. Triethanolamine-mediated palladium-catalyzed
regioselective C-2 direct arylation of free NH-pyrroles. J Org Chem,
2010, 75(9): 3109–3112
Previous reports about the use of 4-hydroxy-L-proline and highly ac-
tivated -carbonyl ketones or aromatic halides in the formation of
N-alkylpyrroles, see: (a) Reddy VP, Kumar AV, Rao KR. New strategy
for the synthesis of N-aryl pyrroles: Cu-catalyzed C–N cross-coupling
reaction of trans-4-hydroxy-L-proline with aryl halides Tetrahedron
Lett, 2011, 52(7): 777–780; (b) Meshram HM, Prasad BRV, Kumar
DA. A green approach for efficient synthesis of N-substituted pyr-
roles in ionic liquid under microwave irradiation. Tetrahedron Lett,
2010, 51(27): 3477–3480; (c) Karimi AR, Behzadi F, Amini MM.
Highly efficient synthesis of 3-pyrrolyl-indolinones and pyrrol-
yl-indeno[1,2-b]quinoxalines catalyzed by heteropolyacids. Tetrahe-
dron Lett, 2008, 49(37): 5393–5396; (d) Sridhar R, Srinivas B, Ku-
mar VP, Reddy VP, Kumar AV, Rao KR. Adv Synth Catal, 2008, 350:
1489; (e) Kumar MA, Krishna AB, Babu BH, Reddy CB, Reddy CS.
Phosphomolybdic acid/SiO2 as heterogeneous solid acid catalyst for
the rapid synthesis of N-substituted pyrroles. Synth Commun, 2008,
38(20): 3456–3464; (f) Yadav JS, Reddy BVS, Jain R, Reddy CS.
Dy(OTf)3 as a versatile catalyst for the synthesis of 3-pyrrolyl-indo-
linones and pyrrolyl-indeno[1,2-b]quinoxalines. Tetrahedron Lett,
2007, 48(18): 3295–33298 and ref. 5(a)
During the preparation of this manuscript, Seidel and Rao respec-
tively reported similar protocols: (a) Deb I, Coiro DJ, Seidel D. De-
carboxylation formation of N-alkyl pyrroles from 4-hydroxyproline.
Chem Commun, 2011, 47(22): 6473–6475; (b) Kumar AV, Rao KR.
trans-4-Hydroxy-L-proline: A novel starting material for N-alkyl-
pyrroles synthesis. Tetrahedron Lett, 2011, 52(25): 3237–3239
(a) Xu H, Yu XH, Sun L, Liu J, Fan W, Shen YJ ,Wang W. Micro-
wave-assisted three component Knoevenagel-nucleophilic aromatic
substitution reactions. Tetrahedron Lett, 2008, 49(32): 4687–4689; (b)
Wang J, Zhang M, Zhang S-L, Xu Z, Li H, Yu X-H, Wang W. Chiral
pyrrolidine sulfonamide catalyzed enantioselective Michael addition
of cyclic ketones to maleimides. Synlett, 2011, (4): 473–476; (c) Zu
LS, Xie HX, Li H, Wang J, Yu XH, Wang W. Chiral amine catalyzed
enantioselective cascade aza-ene-type cyclization reactions. Chem
Eur J, 2008, 14(21): 6333–6335
7
8
6
9
Cook AG, Switek KA, Cutler KA, Witt AM. Synthesis and isomeri-
zation of 3-pyrroline enamines. Lett Org Chem, 2004, 1(1): 1–5
10 Cinzia B, Maurizio B, Laura R Franco C. Organocatalytic synthesis
of dipyrromethanes by the addition of N-methylpyrrole to aldehydes.
Tetrahedron, 2006, 62(52): 12375–12379