Decarboxylative formation of N-alkyl pyrroles from 4-hydroxyproline

Article abstract of DOI:10.1039/c1cc11560j

N-Alkyl pyrroles are obtained in a single step from 4-hydroxyproline and aldehydes in just 15 min under microwave irradiation.

Full text of DOI:10.1039/c1cc11560j

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Decarboxylative formation of N-alkyl pyrroles from 4-hydroxyprolinew
Indubhusan Deb, Daniel J. Coiro and Daniel Seidel*
Received 17th March 2011, Accepted 18th April 2011
DOI: 10.1039/c1cc11560j
N-Alkyl pyrroles are obtained in a single step from 4-hydroxy-
of N-cyclohexylpyrrole from cyclohexanone and 1 under
thermal, additive-free conditions.8
proline and aldehydes in just 15 min under microwave irradiation.
As part of a program aimed at developing new strategies
for the rapid synthesis of various heterocycles,9 we recently
established that azomethine ylides are likely intermediates in
Tunge’s reaction.9i Specifically, we found that a reaction of 1
and an aldehyde with a pendant dipolarophile provided a
single diastereomer of an apparent intramolecular [3 + 2]
cycloaddition product. In the course of this study, we developed
a method that furnishes N-alkyl indoles from indoline and
aldehydes (eqn (2)). Again, azomethine ylides are thought to
be intermediates in this process. Sun, Pan and coworkers
independently reported the synthesis of N-alkyl indoles from
indoline and aldehydes under reflux conditions.10
Pyrroles are ubiquitous as components of natural products1
and medicinal drugs.2 Due to their favorable electronic
properties, pyrroles are also prime candidates for applications
in materials research.3 Although numerous methods for the
synthesis of pyrroles exist,4–6 there is still major interest in new
methods that rapidly produce pyrroles in a single step starting
from cheap and readily available materials. Here we report
an approach that reliably furnishes N-alkyl pyrroles 2 from
trans-4-hydroxyproline (3) and aldehydes.
In considering potential new applications for azomethine
ylide intermediates,11,12 it occurred to us that trans-4-hydroxy-
proline (3) might be used as a replacement for 3-pyrroline (1) in
the formation of N-alkyl pyrroles 2 (eqn (3)). This would result
in a more economically viable approach, as 3-pyrroline (1) is
relatively expensive.13 Also, in contrast to trans-4-hydroxy-
proline (3) which is a stable, crystalline solid, 3-pyrroline (1) is
prone to air oxidation, resulting in the formation of unsubstituted
pyrrole. Previous reports have described the use of 3 in the
formation of N-alkyl pyrroles, however, these studies have
focused on the use of highly activated a-carbonyl ketones.14,15
The proposed mechanism for N-alkyl pyrrole formation
from trans-4-hydroxyproline (3) is outlined in Fig. 1. Decarboxy-
lative condensation16 of 3 and an aldehyde or ketone gives
rise to the azomethine ylide 4. Subsequent protonation
of 4 results in the formation of iminium ion 5 which then
undergoes proton loss to give enamine 6. Acid catalyzed
dehydration of enamine 6 results in the formation of pyrrole 2.
ð1Þ
ð2Þ
ð3Þ
Tunge and coworkers recently reported an interesting and
efficient redox-neutral approach to the synthesis of N-alkyl
pyrroles 2 (eqn (1)).7 Starting from 3-pyrroline (1) and
aldehydes or ketones, a variety of different N-alkyl pyrroles
2 can be obtained in generally excellent yields. This reaction is
conducted under reflux in toluene and provides optimal results
in the presence of catalytic amounts of benzoic acid.
Previously, Cook and coworkers have reported the formation
Department of Chemistry and Chemical Biology, Rutgers, The State
University of New Jersey, 610 Taylor Road, Piscataway, New Jersey
08854, USA. E-mail: seidel@rutchem.rutgers.edu
w Electronic supplementary information (ESI) available: Experimental
details and characterization data for all new compounds. See DOI:
10.1039/c1cc11560j
Fig. 1 Proposed mechanism for the formation of pyrroles from
4-hydroxyproline and aldehydes or ketones.
c
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Chem. Commun., 2011, 47, 6473–6475 6473

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Table 1 Optimization of reaction parametersa
Entry Additive/equiv.
Solvent/M
Temperature/1C Yield (%)
1
2
3
4
5
6
7
8
—
PhMe (0.5) 250
PhMe (0.5) 250
PhMe (0.5) 240
PhMe (0.5) 240
PhMe (0.5) 240
PhMe (0.5) 240
50
50
56
Trace
56
73
68
66
33
68
53
64
61
66
56
70
63
68
70
45
68
61
AcOH (0.2)
TFA (0.2)
p-TSA (0.2)
Pivalic acid
PhCO2H (0.2)
m-Cl–PhCO2H (0.2) PhMe (0.5) 240
p-MeO–PhCO2H
Et3N (0.2)
PhCO2H (0.2)
PhCO2H (0.2)
PhCO2H (0.2)
PhCO2H (0.2)
PhCO2H (0.2)
PhCO2H (0.2)
PhCO2H (0.2)
PhCO2H (0.1)
PhCO2H (0.5)
PhCO2H (1.0)
PhMe (0.5) 240
PhMe (0.5) 240
Xylenes (0.5) 240
9
10
11
12
13
14
15
16
17
18
19
DMF (0.5)
240
n-BuOH (0.5) 240
C2H4Cl2 (0.5) 200
PhMe (0.25) 240
PhMe (0.75) 240
PhMe (1.0) 240
PhMe (0.5) 240
PhMe (0.5) 240
PhMe (0.5) 240
PhMe (0.5) 240
PhMe (0.5) 240
PhMe (0.5) 240
20b PhCO2H (0.2)
21c PhCO2H (0.2)
22d PhCO2H (0.2)
a
Reactions were performed on a 1 mmol scale in the presence of a
silicon carbide heating element. b 1.0 equiv. of 4-hydroxyproline. c 1.5 equiv.
of 4-hydroxyproline. d 2 equiv. of 4-hydroxyproline.
Chart 1 Scope of the reaction. Reactions were performed on a 1
mmol scale in the presence of a silicon carbide heating element. The
a
reaction was performed at 150 1C. bThree equiv. of 3 was used.
cObtained as a 10 : 1 mixture of stereoisomers.
To test the viability of this proposed reaction, trans-4-hydro-
xyproline (3) and p-chlorobenzaldehyde were allowed to react
under a variety of different conditions. Thermal conditions were
initially evaluated but quickly abandoned in favor of reactions
performed under microwave irradiation, as the latter led to
vastly accelerated reaction rates. The results obtained under
microwave conditions are summarized in Table 1. Whereas the
additive-free process gave rise to the formation of pyrrole 2a in
50% yield, the use of different acid additives led to an increase
in yield. Among the acids tested, benzoic acid emerged as the
most effective catalyst. A catalyst loading of 20 mol% was
found to be optimal and toluene proved to be the best solvent at
a 0.5 M substrate concentration. The highest yield of 2a (73%)
was obtained with 1.2 equivalents of trans-4-hydroxyproline (3)
(Table 1, entry 6). The use of otherwise identical, but thermal
conditions (reflux in toluene) required a reaction time of
24 hours and provided 2a in 64% yield.
to be an issue in the decarboxylative formation of azomethine
ylides, and enolizable aldehydes readily engaged in N-alkylpyrrole
formation upon reacting with 3, we rationalized that indoline-2-
carboxylic acid (7) should enable the formation of N-alkylindoles
derived from enolizable aldehydes.17 Indeed, as shown in eqn (6),
using the previously optimized conditions for the formation of
N-alkylpyrroles, indoline-2-carboxylic acid (7) engaged in
reactions with two representative enolizable aldehydes to furnish
the corresponding N-alkylindoles 8a and 8b in reasonable
yields.
ð6Þ
With the optimized reaction conditions in hand, a series of
different aldehydes was evaluated (Chart 1). Electron rich and
electron poor aromatic aldehydes with different substitution
patterns provided products in generally moderate to good yields.
Heteroaromatic aldehydes were also viable substrates. Enolizable
aliphatic aldehydes also engaged in reactions with 3 to give N-alkyl
pyrroles. Although ketones appeared to be generally less reactive
under these conditions, products 2s and 2t could be obtained in
moderate yields when three equivalents of 3 were used.
In summary, we have introduced a method for the rapid
synthesis of N-alkylpyrroles from trans-4-hydroxyproline (3)
and aldehydes. This method complements approaches that
form N-alkylpyrroles from amines and 2,5-dimethoxytetra-
hydrofuran18 and is thus particularly useful in cases where the
carbonyl starting materials are more readily available than
the corresponding amines. The simplicity of this method and
the short reaction times compensate for the moderate yields
that are obtained in some cases.
In our previous synthesis of N-alkylindoles from indoline and
aldehydes (eqn (2)), enolizable aldehydes failed to yield indoles,
presumably due to the facile formation of enamines, preventing
access to azomethine ylides. Since enamine formation is not likely
We thank the National Science Foundation for partial
support of this research (Grant CHE-0911192). D.J.C.
c
6474 Chem. Commun., 2011, 47, 6473–6475
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acknowledges support from the Aresty Research Center for
Undergraduates. D.S. is a fellow of the A.P. Sloan Foundation
and the recipient of an Amgen Young Investigator Award.
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13 Aldrich prices based on largest package size available: 3-pyrroline
(65% technical grade) $ 24.50 gꢀ1 (based on 25 g); 3-pyrroline
(97%) $ 143 gꢀ1 (based on 1 g); trans-4-hydroxy-L-proline (499%)
$ 1.85 gꢀ1 (based on 100 g).
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conditions: H. Mao, S. C. Wang, P. Yu, H. Q. Lv, R. S. Xu and
Y. J. Pan, J. Org. Chem., 2011, 76, 1167–1169.
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6473–6475 6475