The application of vinamidinium salts to the synthesis of 1,2,4-trisubstituted pyrroles

Article abstract of DOI:10.1016/j.tetlet.2013.05.080

The synthesis of 1-methyl-2-cyano-4-arylsubstituted pyrroles by the condensation of symmetrical vinamidinium salts with methyl aminoacetonitrile has been accomplished for the first time. Simple experimental conditions were used to prepare seven different

Full text of DOI:10.1016/j.tetlet.2013.05.080

Tetrahedron Letters 54 (2013) 3965–3966
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Tetrahedron Letters
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The application of vinamidinium salts to the synthesis
of 1,2,4-trisubstituted pyrroles
⇑
Stanton Q. Smith , Sean T. Dudek, Shu-Hui He, Jarod A. Girod, Shane R. Nunes
Department of Chemistry, Virginia Military Institute, Lexington, VA 24450, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 March 2013
Revised 7 May 2013
Accepted 17 May 2013
Available online 23 May 2013
The synthesis of 1-methyl-2-cyano-4-arylsubstituted pyrroles by the condensation of symmetrical vina-
midinium salts with methyl aminoacetonitrile has been accomplished for the first time. Simple experi-
mental conditions were used to prepare seven different pyrroles, six of which are not reported in the
literature.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Vinamidinium salt
Cyano
Pyrrole
Methyl aminoacetonitrile
Introduction
tion, and condensation reactions to form the ring with the cyano
group in place. Several routes exist for direct cyanation of the
Vinamidinium salts are examples of push–pull alkenes with en-
hanced stability and will undergo condensation reactions with
bifunctional nucleophiles to form heterocycles.1 2-Aryl vinamidini-
um salts are prepared under Vilsmeier–Haack conditions from the
corresponding aryl acetic acid.1,2 While it would seem more effi-
cient to isolate these salts as the chloride this is usually not done.
While stable the chloride salt is quite hygroscopic and therefore
not very appealing. The vinamidinium salts are generally isolated
as the perchlorate or the hexafluorophosphate as these salts are
stable and not nearly as hygroscopic as the chloride.3 The ease of
preparation and stability of vinamidinium salts make them a suit-
able precursor for the synthesis of heterocycles such as isoxazoles,1
pyrazoles,1 pyrimidines,1 and pyrroles.2
pyrrole ring which include a
modified Vilsmeier reaction,12
reaction with 1-cyanobenzotrizole,13 and a hypervalent iodine
mediated reaction with TMSCN.14 Condensation reactions to form
2-cyanopyrroles include condensation of isocyanoacetonitrile with
a
-acetoxynitro compounds15,16 and condensation of 3-alkoxyac-
roleins with aminoacetonitrile.10 The route by Adamczyk15,16
prepared 2-cyano-3,4-substituted pyrroles in good yield where
the substituents at the 3 and 4 positions are primarily alkyl groups
with one example of an aromatic group. The route reported by
Walizei and Breitmaier10 prepared 2-cyano-4-substituted pyrroles
in low to moderate yield where the substituents at the 4-position
are exclusively alkyl groups.
The work reported here expands upon the previous strategies
and allows synthesis of a 2-cyanopyrrole with an aromatic group
at the 4-position. Due to the symmetrical nature of the 2-arylvina-
midinium salts used in this study only the 4-arylpyrroles can be
formed.2 The 3-aryl or 5-arylpyrroles would arise from an unsym-
metrical vinamidinium salt undergoing a condensation reaction
with N-methylaminoacetonitrile. Also due to the nature of this
reaction only the 2-cyanopyrroles can be synthesized; other regio-
chemical outcomes for placement of the cyano-group are not pos-
sible. These reactions proceed in good yield under relatively mild
conditions.
Pyrroles are important heterocycles and have attracted much
interest due to their diverse and widespread nature.4 In addition
to the classic Paal-Knorr5 and Hantzsch6 synthesis of pyrroles some
recent synthetic strategies include iron (III) mediated Paal-Knorr7
reaction, phosphine-mediated reaction between an acid chloride
and
a a-isocy-
,b-unsaturated imines,8 nitroolefins reacting with
anoesters,9 and condensation of 3-alkoxyacroleins with glycine
derivatives.10
Of specific interest in this Letter is the synthesis of 2-cyanopyr-
roles, which are important intermediates for the synthesis of por-
phyrins.11 The three main strategies for incorporating a cyano
group on the ring are direct cyanation, functional group manipula-
Results and discussion
The vinamidinium salts (1a–g) used in this study were prepared
by the standard Vilsmeier–Haack reaction of the appropriate aryl
⇑
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 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.080

3966
S. Q. Smith et al. / Tetrahedron Letters 54 (2013) 3965–3966
R
R
.HCl
H
N
ClO4
triethylamine
N
+
CN
(H3C)2N
N
N(CH3)2
CH3CN, reflux
CH3
2
1a-g
3a-g
R
%CrudeYield
%Purity by GC/MS
81
59
85
70
93
88
67
91
94
88
72
68
77
90
H, 3a
Br, 3b
Cl, 3c
OCH3, 3d
CH3, 3e
NO2, 3f
C6H5, 3g
Scheme 1. Preparation of 2-cyanopyrroles.
acetic acid.1 Walizei and Breitmaier10 report higher yields with N-
methylaminoacetonitrile than with aminoacetonitrile so it was
decided to keep the scope of this study limited to the synthesis
of N-methylpyrroles with N-methylaminoacetonitrile. In a typical
procedure17 to prepare the 2-cyanopyrrole the vinamidinium salt
was allowed to react with 1 equiv of N-methylaminoacetonitrile
hydrochloride (2) in refluxing acetonitrile in the presence of
2.1 equiv of triethylamine 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, 3b, 3c, 3e, 3f,
and 3g, are all new compounds and were characterized by NMR,
GC/MS, HRMS, and FTIR. Pyrrole 3d is a known compound and is
reported in the patent literature.18 This pyrrole was also character-
ized by NMR, GC/MS, HRMS, and FTIR. The type of vinamidinium
salt (1) did not substantially affect the yield. Analytical samples
of the pyrroles could be obtained by column chromatography.
The geometry of the pyrrole ring was established by the C-3 and
C-5 proton NMR signal (CDCl3) d = 6.97 and 7.01 (J = 2.0 Hz),
respectively, for compound 3a. Similar resonances were also ob-
served for the C-3 and C-5 hydrogens of the other pyrroles. The
chemical shift was dependent on the choice of NMR solvent with
acetone causing a downfield shift of approximately 0.2–0.5 ppm.
The experimental HRMS data of 3a–g matched the calculated data.
References and notes
1. Lloyd, D.; McNabb, H. Angew. Chem., Int. Ed. Engl. 1976, 88, 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. W.; Marcoux, J.; Corley, E. G.; Journet, M.; Cai, D.; Palucki, M.; Wu, J.;
Larsen, R. D.; Rossen, K.; Pye, P. J.; DiMichele, L.; Dormer, P.; Reider, P. J. J. Org.
Chem. 2000, 65, 8415–8420.
4. Jones, R. A.; Bean, G. P. In The Chemistry of Pyrroles; Academic Press: London,
New York, San Francisco, 1977; 34, pp. 51–103.
5. Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474–1483.
6. Paal, C. Chem. Ber. 1885, 18, 367–370.
7. Azizi, H.; Khajeh-Amiri, A.; Ghafuri, H.; Bolourtchian, M.; Saidi, M. R. Synlett
2009, 2245–2248.
8. Lu, Y.; Arndtsen, B. A. Org. Lett. 2009, 11, 1369–1372.
9. Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron 1990, 46,
7587–7598.
10. Walizei, G. H.; Breitmaier, E. Synthesis 1989, 337–340.
11. The Porphyrins; Dolphin, D., Ed.; Acad. Press: New York, 1978; Vol. I–VIII,. pp
1978–1979.
12. Barnett, G. H.; Anderson, H. J.; Loader, C. E. Can. J. Chem. 1980, 58,
409–411.
13. Katritzky, A. R.; Akue-Gedu, R.; Vakulenko, V. ARKIVOC 2007, 5–12.
14. Dohi, T.; Morimoto, K.; Kiyono, Y.; Tohma, H.; Kita, Y. Org. Lett. 2005, 7, 537–
540.
15. Adamczyk, M.; Reddy, R. E. Tetrahedron 1996, 52, 14689–14700.
16. Adamczyk, M.; Reddy, R. E. Tetrahedron Lett. 1995, 36, 7983–7986.
17. Representative procedure for pyrrole synthesis
A dry one neck 50 mL round bottomed flask equipped with magnetic stirring,
reflux condenser, and nitrogen atmosphere (or drying tube) was charged with
the 2-phenyl-vinamidinium salt (1.00 g, 3.30 mmol), methylaminoacetonitrile
hydrochloride (0.355 g, 3.33 mmol) and triethylamine (0.97 mL, 6.95 mmol).
Anhydrous acetonitrile (10 mL) was added and the mixture was allowed to stir
at reflux overnight. The flask was cooled to room temperature and the volatiles
were removed in vacuo. The remaining solid was partitioned between water
and ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and
concentrated in vacuo to give 0.487 g (81%) of a solid.
Conclusion
In summary, it has been demonstrated that vinamidinium salts
can be effectively used for the regioselective preparation of 4-aryl-
2-cyano-N-methylpyrroles using simple experimental conditions
in a minimum number of steps from commercially available start-
ing materials.
2-Cyano-1-methyl-4-phenylpyrrole [3a]
Mp = 128–131 °C; 1H NMR (CDCl3)
d 7.38 (d, 2H, J = 7.2 Hz), 7.29 (t, 2H,
J = 7.6 Hz), 7.17 (t, 2H, J = 6.6 Hz), 7.01 (d, 1H, J = 2.0 Hz), 6.97 (d, 1H, J = 2.0 Hz),
3.75 (s, 3H); 13C NMR (CDCl3) d 132.47, 127.86, 125.66, 124.82, 124.24, 123.10,
116.02, 112.57, 104.35, 34.56; LREIMS 182 (100), 181 (19), 188 (48), 154 (6),
140 (28), 114 (9), 77 (3); IR (solid) 2217 cmÀ1; HRMS m/z calcd for C12H10N2,
182.0844; found 182.0843.
Acknowledgments
18. Wennerstaal, M.; Loefstedt, J.; Wu, X.; Krueger, L.; Hagberg, L. WO Patent
2,011,042,477, 2011.
We would like to thank the VMI Chemistry Department and
VMI Grants-in-Aid of Research for financial support of this work.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.05.
080.