Synthesis of alkylpyrroles by use of a vinamidinium salt

Article abstract of DOI:10.1016/j.tetlet.2010.06.009

The synthesis of alkyl-substituted 2-pyrrolecarboxylate esters has been accomplished by the condensation reaction of a symmetrical vinamidinium salt and glycine ester derivatives.

Full text of DOI:10.1016/j.tetlet.2010.06.009

Tetrahedron Letters 51 (2010) 4150–4152
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Tetrahedron Letters
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Synthesis of alkylpyrroles by use of a vinamidinium salt
Mathew T. Wright a, David G. Carroll a, Timothy M. Smith b, Stanton Q. Smith a,
*
a Department of Chemistry, Virginia Military Institute, Lexington, VA 24450, USA
b Department of Chemistry, University of Richmond, Richmond, VA 23173, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of alkyl-substituted 2-pyrrolecarboxylate esters has been accomplished by the condensa-
tion reaction of a symmetrical vinamidinium salt and glycine ester derivatives.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 3 November 2008
Revised 31 May 2010
Accepted 2 June 2010
Available online 8 June 2010
Keywords:
2-Pyrrolecarboxylate esters
Pyrroles
Vinamidinium salts
1. Introduction
form of an ester, but the carbonyl group could also belong to an
amide. The substituents on pyrrole in the Barton–Zard reaction at
Symmetrical vinamidinium salts undergo condensation reac-
tions, similar to malonaldehyde derivatives, with bifunctional
nucleophiles to form heterocycles. These organic salts have been
used to prepare many different monocyclic heterocycles including
isoxazoles,1 pyrazoles,1 pyrimidines,1 and pyrroles.2 Most of these
studies have used an aryl vinamidinium salt to synthesize an aryl-
appended heterocycle. Aryl vinamidinium salts are easily prepared
under Vilsmeier–Haack conditions from the corresponding aryl
acetic acid.1,2 Using alkyl acetic acids to synthesize alkyl vinamid-
inium salts does not work effectively. Davies has reported that al-
kyl vinamidinium salts could be prepared from alkyl acetic acids in
low yield.3 Other methods to prepare alkyl vinamidinium salts
usually involve multiple steps and start with material other than
carboxylic acids.4–6 Because of the more involved procedures to
make alkyl vinamidinium salts these compounds are not typically
used in synthetic studies.
the 3- and 4-position are typically alkyl or aryl groups, but it is pos-
sible for the 3-position to be unsubstituted.
Alkyl pyrroles have some important uses in organic chemistry.
Some examples of their utility include, but are not limited to the
following: used as building blocks preparing the pharmaceutically
important pyrrolo[1,2-a]quinoxalines9 structural core; compound
3f has been used to prepare intermediates for compounds tested
to treat multiple sclerosis;10 compound 3b has been used to pre-
pare pyrazolylpyrrole ERK inhibitors.11 Pyrroles 3a and 3b have
been used to prepare ring-annulated pyrroles.12 Pyrrole 3e is an
ant trail pheromone of Atta Texana and was first reported by Tuml-
inson in 1971.13,14 Most of these simple alkyl pyrroles were syn-
thesized starting with the pyrrole ring already present. Because
of the limited use of alkyl vinamidinium salts and the fact that al-
kyl pyrroles can be important synthetic building blocks a new syn-
thesis of alkyl pyrroles was explored by using alkyl vinamidinium
salts. This route is expected to complement the existing procedures
by Walizei and Barton.
Two examples that use a condensation reaction to produce alkyl
pyrroles have been reported by Walizei7 and Barton.8 In the report
by Walizei7 2-carboxy-4-alkyl-substituted pyrroles have been pre-
pared in average yield by the condensation of 3-alkoxyacroleins
with glycine derivatives; sacrosine derivatives will produce an N-
methylpyrrole. In the report by Barton8 the procedure involves
2. Results and discussion
The vinamidinium salts used in these experiments were pre-
pared by the 1996 procedure according to Arnold.15 Ethyl vinyl
ether was subjected to Vilsmeier–Haack conditions to prepare
the unsubstituted vinamidinium salt (1, R = H). In a similar fashion
the use of ethyl propenyl ether prepared the 2-methylvinamidini-
um salt (1, R = CH3) and the use of 1-butenyl ethyl ether produced
the 2-ethylvinamidinium salt (1, R = CH2CH3). All of these symmet-
rical vinamidinium salts were isolated as the perchlorate in good
the condensation of an
a-isocyanoester and a nitroolefin. By the
nature of the traditional Barton–Zard procedure, the product will
be an N–H pyrrole. The Barton–Zard method gives pyrroles that
are 2,3,4-trisubstituted with a carbonyl at the 2-position in the
* Corresponding author. Tel.: +1 540 464 7426; fax: +1 540 464 7261.
E-mail address: smithsq@vmi.edu (S.Q. Smith).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.009

M. T. Wright et al. / Tetrahedron Letters 51 (2010) 4150–4152
4151
.HCl
ClO4
R
R
O
TEA
H
O
Me2N
NMe2
N
+
R'
OR"
N
CH3CN, Δ
OR"
1
2
R'
R = H, CH3, CH2CH3
R' = H, CH3
3a-l
R" = CH3, CH2CH3
Compound
R
R’
R”
% crude yield % purity*
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
H
H
H
H
H
H
CH3
CH3
H
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
CH3
CH2CH3
CH3
CH3
86
68
83
67
60
75
85
93
69
66
92
98
49
81
77
82
>95
>95
80.6
>95
93
>95
>95
88.0
>95
91
CH3
CH3
CH3
CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
C6H5
H
CH3
CH3
H
H
CH3
CH3
H
>95
>95
C6H5
CH3
* as indicated by GC/MS
Scheme 1. Synthesis of alkyl pyrroles.
yield and good purity and were used without further purification
for the synthesis of pyrroles.
3. Conclusion
In a typical procedure16 the vinamidinium salt was allowed to
react with 2 equiv of the glycine ester hydrochloride derivative
(2) with 2 equiv of triethylamine while refluxing in acetonitrile
overnight (Scheme 1). After extractive workup the pyrroles were
isolated in reasonable yield; the table of results is also shown in
Scheme 1. Pyrroles 3a,12 3b,12 3c,17 3d,18 3e,7 3f,10 3g,19 3h,7 3i,7
and 3l7 are all known compounds and the synthesized pyrroles
were in good agreement with the reported literature spectroscopic
data. Pyrroles 3j20 and 3k21 are new compounds and were charac-
terized by NMR, GC/MS, HRMS, and FTIR. The regiochemistry of the
pyrrole ring was confirmed by the C-3 and C-5 proton NMR signals
d = 6.70 and 6.51 (J = 2.0 Hz), respectively, for compound 3k. Simi-
lar resonances (within 0.1 ppm) were also observed for the C-3 and
C-5 hydrogens of pyrroles such as 3e, 3h, 3i, and 3l.7
Generally the crude yields were quite good and the reaction
products looked relatively clean by TLC. The type of vinamidinium
salt (1, R = H, CH3, or CH2CH3) did not substantially affect the yield;
nor did the fact that some of the glycine derivatives were methyl or
ethyl esters (where R00 = CH3 or CH2CH3). A slight trend might be
present when sarcosine (2, R0 = CH3) derivatives were used. The
yields were generally higher and the pyrroles more pure by GC/
MS when a sarcosine derivative was used, but it is not completely
conclusive with our data. By comparison to the Walizei7 method
using 3-alkoxyacroleins for the synthesis of compounds 3e, 3h,
3i, and 3l the yields by our procedure were approximately twice
as high in some cases.
In summary, a dozen different alkyl pyrroles, including two new
compounds, has been efficiently synthesized by a new route
involving the condensation of a symmetrical vinamidinium salt
and a glycine ester under simple experimental conditions.
Acknowledgments
We would like to thank the VMI Chemistry Department, VMI
Grants-in-Aid of Research and the VMI Jackson-Hope Faculty
Development Program for financial support of this work.
References and notes
1. Lloyd, D.; McNabb, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 459–468.
2. Gupton, J. T.; Krolikowski, D. A.; Yu, R. H.; Riesinger, S. W.; Sikorski, J. A. J. Org.
Chem. 1990, 55, 4735–4740.
3. Davies, I. M.; Marcoux, J.-F.; Wu, J.; Palucki, M.; Corley, E. G.; Robbins, M. A.;
Tsou, N.; Ball, R. G.; Dormer, P.; Larson, R. D.; Reider, P. J. J. Org. Chem. 2000, 65,
4571–4574.
4. Arnold, Z.; Šorm, F. Collect. Czech. Chem. Commun. 1958, 23, 452–461.
5. Arnold, Z.; Holy´, A. Collect. Czech. Chem. Commun. 1963, 28, 2040–2046.
ˇ
6. Kucera, J.; Arnold, Z. Collect. Czech. Chem. Commun. 1967, 32, 3792–3793.
7. Walizei, G. H.; Breitmaier, E. Synthesis 1989, 337–340.
8. Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron 1990, 46, 7587–7598.
9. Yuan, Q.; Ma, D. J. Org. Chem. 2008, 73, 5159–5162.
10. Bouéret, L.; Fensholdt, J.; Liang, X.; Havez, S.; Nielson, S. F.; Hansen, J. R.; Bolvig,
S.; Andersson, C. J. Med. Chem. 2005, 48, 5412–5414.
11. Aronov, A. M.; Baker, C.; Bemis, G. W.; Cao, J.; Chen, G.; Ford, P. J.; Germann, U.
A.; Green, J.; Hale, M. R.; Jacobs, M.; Janetka, J. W.; Maltais, F.; Martinez-Botella,
G.; Namchuk, M. N.; Straub, J.; Tang, Q.; Xie, X. J. Med. Chem. 2007, 50, 1280–
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12. Blaszykowski, C.; Aktoudianakis, E.; Alberico, D.; Bressey, C.; Hulcoop, D. G.;
Jafarpour, F.; Joushaghani, A.; Laleu, B.; Lautens, M. J. Org. Chem. 2008, 73,
1888–1897.
To determine the influence of the substituent of the vinamidini-
um salt similar experiments were conducted with the 2-phenylvi-
namidinium salt (1, R = C6H5). The phenyl vinamidinium salt was
allowed to react under the same conditions with the appropriate
glycine derivatives to prepare pyrroles 3m and 3n. The yields
and % purity were consistent with the results for the 4-alkyl pyr-
roles, therefore showing that the substituent on the vinamidinium
salt was not a major factor in these experiments.
13. Tumlinson, J. H.; Silverstein, R. M.; Moser, J. C.; Brownlee, R. G.; Ruth, J. M.
Nature 1971, 234, 348–349.
14. Tumlinson, J. H.; Moser, J. C.; Silverstein, R. M.; Brownlee, R. G.; Ruth, J. M. J.
Insect Physiol. 1972, 18, 809–814.
ˇ
15. Arnold, Z.; Dvorák, D.; Havránek, M. Collect. Czech. Chem. Commun. 1996, 61,
1637–1641.

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M. T. Wright et al. / Tetrahedron Letters 51 (2010) 4150–4152
16. General experimental procedure: All reagents and solvents were obtained from
Aldrich, ACROS, or Fluka and used without further purification. To a flame dried
one-necked round-bottomed flask equipped with magnetic stirring, reflux
condenser, and nitrogen atmosphere (or drying tube) was added the
vinamidinium salt (1.0 mmol) and glycine ester hydrochloride (2.0 mmol).
17. Nakamura, I.; Siriwardana, A. I.; Saito, S.; Yamamoto, Y. J. Org. Chem. 2002, 67,
3445–3449.
18. Yang, Z.; Zhang, Z.; Meanwell, N. A.; Kadow, J. F.; Wang, T. Org. Lett. 2002, 4,
1103–1105.
19. Barker, P. L.; Bahia, C. Tetrahedron 1990, 46, 2691–2694.
20. Ethyl 4-ethyl-1H-pyrrole-2-carboxylate (3j): mp = 115 °C; 1H NMR (CDCl3) d 8.86
(br s, 1H), 6.71 (m, 1H), 6.67 (m, 1H), 4.43 (q, 2H, J = 7.2 Hz), 4.23 (q, 2H,
J = 7.6 Hz), 1.28 (t, 3H, J = 7.2 Hz), 1.12 (t, 3H, J = 7.6 Hz); 13C NMR (CDCl3) d
161.46, 128.54, 122.75, 120.19, 114.62, 60.42, 20.09, 15.43, 14.71; FTIR (neat)
3321, 1701 cmꢀ1; LREIMS 167 (56), 152 (61), 122 (32), 106 (100), 94 (20), 78
(10); HRMS calcd for C9H13NO2 M+1 168.1019, obsd 168.1039.
21. Methyl 4-ethyl-1-methyl-1H-pyrrole-2-carboxylate (3k): bp = 101–102 °C
Anhydrous acetonitrile (5 mL) was added via
a syringe. Triethylamine
(2.0 mmol) was added via a microliter syringe. The mixture was allowed to
reflux overnight (15–18 h) under a nitrogen atmosphere (or drying tube). The
flask was cooled to room temperature and the solvent was removed by rotary
evaporation. The residue was partitioned between methylene chloride and
water. The aqueous layer was extracted with fresh methylene chloride, and the
combined organic layers were then dried over sodium sulfate. The drying agent
was filtered and the solvents were removed in vacuo to give the crude material.
The crude material was run through a short pad of silica gel with methylene
chloride and the organic solvent was removed in vacuo. At this point the crude
yield and percent purity were obtained. Analytical samples were obtained by
either column chromatography with hexanes and ethyl acetate or low pressure
distillation.
(1 mmHg); 1H NMR (CDCl3)
d 6.70 (d, 1H, J = 2.0 Hz), 6.51 (d, 1H,
J = 2.0 Hz), 3.79 (s, 3H), 3.71 (s, 3H), 2.36 (q, 2H, J = 7.6 Hz), 1.09 (t, 3H,
J = 7.6 Hz); 13C NMR (CDCl3) d 160.72, 126.22, 124.59, 120.66, 115.73, 49.87,
35.50, 18.63, 14.21; FTIR (neat) 1708 cmꢀ1; LREIMS 167 (32), 152 (100), 136
(11), 108 (10), 93 (6), 65 (4); HRMS calcd for C9H13NO2 M+1 168.1019, obsd
168.0924.