Trans-4-Hydroxy-l-proline: A novel starting material for N-alkylpyrroles synthesis

Article abstract of DOI:10.1016/j.tetlet.2011.04.045

The reaction of aldehydes with trans-4-hydroxy-l-proline was studied for the first time, resulting in the formation of N-alkylpyrroles in good to excellent yields, via decarboxylation followed by redox isomerization under neutral conditions. The neutral c

Full text of DOI:10.1016/j.tetlet.2011.04.045

Tetrahedron Letters 52 (2011) 3237–3239
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
trans-4-Hydroxy-L-proline: a novel starting material for N-alkylpyrroles
synthesis
⇑
A. Vijay Kumar, K. Rama Rao
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 January 2011
Revised 7 April 2011
Accepted 12 April 2011
Available online 18 April 2011
The reaction of aldehydes with trans-4-hydroxy-L-proline was studied for the first time, resulting in the
formation of N-alkylpyrroles in good to excellent yields, via decarboxylation followed by redox isomer-
ization under neutral conditions. The neutral conditions allow access to efficient synthesis of N-alkyl pyr-
roles with high functional group tolerance.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aldehydes
Azomethine ylide
N-alkyl pyrroles
Redox isomerization
trans-4-Hydroxy-L-proline
N-alkyl pyrroles are an important class of organic compounds in
medicinal chemistry and material science. They are precursors for
the synthesis of poly N-alkyl pyrroles which have wide ranging
applications in electronics and sensors due to their tunable opto-
electronic properties.1 Several N-alkyl pyrrole derivatives have also
shown interesting medicinal properties such as HMG-COA reduc-
tase inhibition and others.2 But traditional methods of synthesis
of N-alkyl pyrroles involve harsh basic/acidic conditions viz reflux
of amines and 2,5-dimethoxytetrahydrofuran in the presence of
Table 1
Optimization conditions for N-alkylpyrrole synthesis with 4-nitrobenzaldehydea
HO
O
OH
N
H
NO2
(1a)
Solvent
(2)
N
OHC
O2N
Additive
(3a)
Yieldb (%)
glacial acetic acid,3a,b direct heating of pyrrole with benzyl/alkyl
Entry
T (°C)
3d
halides in ionic liquids in the presence of KOH,3c K2CO3
.
How-
1
2
3
4
5
6
7
8
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
1,4-Dioxane
THF
CH3CN
Toluene
NMP
rt
80
None
None
0
ever, the recent synthesis of N-alkylpyrroles involves 3-pyrroline4
via decarboxylative azomethine ylide generation by reaction of
3-pyrroline with aldehydes. To the best of our knowledge the reac-
12
18
25
11
23
31
16
28
86
55
36
16
33
<5
57
—
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
Cs2CO3
Pd(OAc)2
Cu(OAc)2
FeCI3
LiHMDS
PhCOOH
None
None
None
None
None
None
None
None
None
None
None
tion of aldehydes with trans-4-hydroxy-L-proline for the
generation of N-alkylpyrroles is not investigated. Thus, herein,
we present the study of azomethine ylide generation by the reac-
9
tion of aldehydes and trans-4-hydroxy-L-proline via decarboxyl-
10
11
12
13
14
15
16
17
18
19
ation followed by redox isomerization reaction for the
a
formation of N-alkyl pyrroles under neutral conditions. Initially
the reaction of 4-nitrobenzaldehyde (1a, Table 1) with trans-4-hy-
droxy-L-proline (2, Table 1) was tested in DMSO for the formation
of N-alkylpyrrole (3a, Table 1), which gave 28% yield of the product
with a reaction time of 1 h for the complete consumption of alde-
hyde at 110 °C.5 Various conditions with catalysts have failed to
H2O
MeOH
EtOH
7
10
a
General conditions: aldehyde (1) (1 mmol), trans-4-hydroxy-
L
-proline (2)
⇑
(1.5 mmol), solvent (2 mL). For entries 10–19 the aldehyde (1 mmol) taken in 5 mL
DMSO was slowly added using syringe pump at a rate of 1 mL/h.
Corresponding author. Tel.: +91 40 27193164; fax: +91 40 27160512.
E-mail addresses: drkrrao@yahoo.com, kakulapatirama@gmail.com (K. Rama
b
Isolated yield.
Rao).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.045

3238
A. Vijay Kumar, K. Rama Rao / Tetrahedron Letters 52 (2011) 3237–3239
Table 2
N-alkylpyrrole synthesis from various aldehydesa
HO
O
OH
N
H
R
CHO
N
R
DMSO, 110 °C
(2)
(1)
Entry
1
R-CHO (1)
Product (2)
t (h)
Yieldb (%)
86
CHO
N
2a
5
O2N
O2N
2b
2
3
5
5
93
75
CHO
CHO
N
N
2c
Ph
Cl
Ph
CHO
Cl
N
4
5
5
5
88
74
2d
OHC
N
2e
F
F
2f
6
7
5
5
61
77
N
CHO
CHO
N
2g
Br
Br
OHC
O
O
N
8
5
97
2h
CHO
N
9
5
5
83
85
O
O
2i
CHO
N
10
S
S
S
2j
S
S
CHO
11
5
63
N
S
2k
O
O
12
13
5
5
87
89
CHO
2l
N
CHO
N
N
N
O
2m
CHO
14
5
81
52
N
N
2n
N
15c
10
N
2o
a
General conditions: trans-4-hydroxy-
1 mL/h
L-proline (1.5 mmol), solvent (2 mL), aldehyde (1) (1 mmol) taken in 5 mL DMSO was slowly added using syringe pump at a rate of
b
Isolated yield.
Racemic mixture.
c

A. Vijay Kumar, K. Rama Rao / Tetrahedron Letters 52 (2011) 3237–3239
3239
HO
We have succeeded in isolating 1-(biphenyl-4-ylmethyl)-1H-
pyrrole (4d) in an overall yield of 57% for this one-pot transforma-
tion. We also propose a possible mechanistic pathway through
which N-alkylpyrroles can be formed based on azomethine ylide
chemistry of proline and aldehydes.6 At first, the aldehyde and
O
N
N
CHO
N
H
OH
PhB(OH)2 (1.5 equiv)
(4b)
DMSO,
110 °C
Pd(PPh3)4 (15 mol%)
K3PO4 (2 equiv)
trans-4-hydroxy-L-proline imine adduct formation takes place fol-
(4d)
(4c)
(4a)
Br
Br
Ph
57 % overall yield
lowed by the generation of oxazolidine-5-one. This oxazolidine-
5-one undergoes decarboxylation to form an azomethine ylide,
which upon further elimination of water and redox isomerization
forms the final product N-alkylpyrrole (Scheme 2).
In conclusion we have studied for the first time the reaction of
aldehydes with inexpensive and readily available trans-4-hydroxy-
Scheme 1. One-pot synthesis of 1-(biphenyl-4-ylmethyl)-1H-pyrrole from
4-bromobenzaldehyde.
L
-proline, by decarboxylation followed by redox isomerization
HO
HO
reaction to form N-alkylpyrroles in the absence of any catalyst un-
der neutral conditions, thus making this process operationally sim-
ple and elegant.7,8
HO
O
O
N
H
- H
CHO
OH
N
N
O
OH
O
N
R
Acknowledgment
-CO2
R
R
A.V.K. is thankful to UGC, New Delhi for the research fellowship.
HO
1,3-hydride
shift
Supplementary data
- H2O
N
H
N
N
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.045.
R
R
R
R
azomethine-ylide
References and notes
Scheme 2. Possible mechanistic pathway for the N-alkylpyrroles formation.
1. (a) Ajayaghosh, A.; Chenthamarakshan, C. R.; Das, S.; George, M. V. Chem. Mater.
1997, 9, 644; (b) Schalkhammer, T.; Mann-Buxbaum, E.; Pittner, F.; Urban, G.
Sens. Actuators, B 1991, 4, 273; (c) Diaz, A. F.; Castillo, J.; Kanazawa, K. K.; Logan,
J. A.; Salmon, M.; Fajardo, O. J. Electroanal. Chem. Interfacial Electrochem. 1982,
133, 233.
give good conversions and the yields were improved only when the
aldehyde was added very slowly using a syringe pump at 1 mL/h
(entries 10–19, Table 1). The optimization studies for the best sol-
vent was carried out by varying different solvents like 1,4-dioxane,
THF, DMF, toluene, CH3CN, NMP, ethanol, methanol, and DMSO.
Among these, only DMSO was found to be the best for attaining
optimum yields of N-alkylpyrrole (86%, entry 10, Table 1). After
optimizing the reaction conditions, we tested various aldehydes
with different functional groups.
Aldehydes like anthracene, naphthalene, and biphenyl gave
good conversions (2b, 2c, 2d, Table 2). The halogen substituted
benzaldehydes gave fair yields of pyrroles, whereas the presence
of substituent at the ortho-position resulted in lower yields. Sub-
stituents with phenoxy and allyloxy groups were easily converted
and the aldehyde with phenoxy substituent at meta-position gave
the highest yield (2h, Table 2). Hetero arylaldehydes like thio-
phenes, benzofuran, and pyridines were also easily converted to
their respective N-alkylpyrrole derivatives (Table 2). The aliphatic
derivative citronellal took 10 h to achieve a moderate yield of
52% (2o, Table 2), whereas the reaction with ketones was not suc-
cessful under all the optimized conditions. Further we have also
tried one-pot transformation in which N-alkylpyrrole synthesis
and Suzuki–Miyaura cross-coupling reaction were carried out.
At first 4-bromobenzaldehyde (4a) was subjected to react with
2. U.S. Patent US2005154042 (A1).
3. (a) D’Silva, C.; Walker, D. A. J. Org. Chem. 1998, 63, 6715; (b) Lee, C. K.; Jun, J. H.;
Yu, J. S. J. Heterocycl. Chem. 2000, 37, 15; (c) Lea, Z.-G.; Chen, Z.-C.; Hu, Y.; Zheng,
Q.-G. Synthesis 2004, 12, 1951; (d) Jorapur, Y. R.; Jeong, J. M.; Chi, D. Y.
Tetrahedron Lett. 2006, 47, 2435.
4. Pahadi, N. K.; Paley, M.; Jana, R.; Waetzig, S. R.; Tunge, J. A. J. Am. Chem. Soc. 2009,
131, 16626.
5. Unidentified products were formed.
6. (a) Orsini, F.; Pelizzoni, F.; Forte, M.; Destro, R.; Gariboldi, P. Tetrahedron 1988,
44, 519; (b) Zhang, C.; Siedel, D. J. Am. Chem. Soc. 2010, 132, 1798.
7. Typical general procedure for N-alkylpyrrole synthesis: To a 25 mL double necked
round bottom flask, with one neck sealed by a rubber septum and the other one
fitted with a reflux condenser was added trans-4-hydroxy-L-proline (196.5 mg,
1.5 equiv) in DMSO (0.5 mL) under nitrogen atmosphere .The mixture was
heated in an oil bath at 110 °C. To this, aldehyde (1 mmol) taken in 5 mL of
DMSO was slowly added using a syringe pump at a rate of 1 mL/h. The progress
of the reaction was monitored by TLC and then allowed to cool to room
temperature. Water 5 mL was added and the product was extracted with ethyl
acetate (3 Â 5 mL). The organic phase was separated and dried over anhydrous
Na2SO4. The combined organic phases were concentrated under reduced
pressure and column chromatographed on silica gel (60–120 mesh size) using
hexanes/ethyl acetate as eluent to obtain the analytically pure product, which
was characterized by 1H, 13C NMR and elemental analysis.
8. Data for the representative examples of synthesized compounds: 1-(4-nitrobenzyl)-
1H-pyrrole6a (2a, Table 2): 86%, reddish orange oil, 1H NMR (300 MHz; CDCl3;
TMS) 5.18 (s, 2H,CH2), 6.18 (t, 2H, J = 2.2, CH), 6.63 (t, 2H, J = 2.2, CH), 7.15 (d, 2H,
J = 8.7, Ph), 8.16 (d, 2H, J = 8.7, Ph). 13C NMR (75 MHz; CDCl3; TMS) 52.42,
109.27, 121.14, 123.47, 127.25, 145.66, 147.32.
1-(anthracen-9-ylmethyl)-1H-pyrrole (2b, Table 2): 93%,yellow solid, mp 152–
155 °C, 1H NMR (300 MHz; CDCl3; TMS) 5.99 (m, 4H, CH2, CH), 6.56 (t, 2H, J = 2.0,
CH), 7.42–7.52 (m, 4H, Ph), 7.98 (m, 2H, Ph), 8.22 (m, 2H, Ph), 8.47 (s, 1H, Ph). 13
C
trans-4-hydroxy-L-proline (4b) and later, the formed 4-bromo
substituted pyrrole (4c) was reacted in situ with phenylboronic
acid in the presence of palladium catalyst (Scheme 1).
NMR (75 MHz; CDCl3; TMS) 45.09, 108.07, 120.44, 123.47, 125.03, 126.43,
126.81, 128.70, 129.17, 130.91, 131.38. Anal. calcd for: (C19H15N) C, 88.7, H, 5.9,
N, 5.4 found C, 88.5, H, 5.6, N, 5.2.