A novel strategy for the synthesis of 3-(N-heteryl)pyrrole derivatives

Article abstract of DOI:10.1021/ol3016594

A flexible approach to unknown 1-(1H-pyrrol-3-yl)pyridinium salts with selective control of the substitution patterns, by the reaction of pyridinium ylides with 2H-azirines, is disclosed. 3-(Pyridinium-1-yl)pyrrolides, a new type of stable ylide, were prepared from these salts in high yields by treatment with base. Atmospheric-pressure hydrogenation of the ylides with Adams' catalyst lead to 1-(pyrrol-3-yl)piperidines in good yields.

Full text of DOI:10.1021/ol3016594

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Novel Strategy for the Synthesis of
3-(N-Heteryl)pyrrole Derivatives
Alexander F. Khlebnikov,*,† Maria V. Golovkina,† Mikhail S. Novikov,† and
Dmitry S. Yufit‡
Department of Chemistry, Saint Petersburg State University, Universitetskii pr. 26,
198504 St. Petersburg, Russia, and Department of Chemistry, University of Durham,
Durham, South Road, DH1 3LE, U.K.
alexander.khlebnikov@pobox.spbu.ru
Received June 16, 2012
ABSTRACT
A flexible approach to unknown 1-(1H-pyrrol-3-yl)pyridinium salts with selective control of the substitution patterns, by the reaction of pyridinium
ylides with 2H-azirines, is disclosed. 3-(Pyridinium-1-yl)pyrrolides, a new type of stable ylide, were prepared from these salts in high yields by
treatment with base. Atmospheric-pressure hydrogenation of the ylides with Adams’ catalyst lead to 1-(pyrrol-3-yl)piperidines in good yields.
Pyrrole is one of the most important simple heterocycles,
whose structural unit is present in a large number of
natural compounds, medical and material molecules.1 By
limiting ourselves to a short introduction it is impossible to
reflect adequately the variety of chemistry and the value of
pyrrole derivatives, so we will mention only recently
published works in which the bioactivity of compounds
containing 3-(pyridine-1-yl)pyrrole fragments were inves-
tigated, since compounds of this type are a subject of our
research. The mentioned structural units are present in
compounds which are antibacterial agents targeting DNA
gyrase,2 inhibitors of human DPP-4 for the treatment of
type 2 diabetes,3 NMDA receptor antagonists,4 selective
NK1 antagonists,5 and potent antagonists of VLA-4.6
Although excellent preparative methods for the synthesis
of substituted pyrroles have been developed,1 it is still a
great challenge to synthesize functionalized pyrroles from
readily available and easily varied starting materials using
a simple procedure. One such approach to the synthesis of
pyrrole derivativesisbased on the reactionsofnucleophiles
with 2H-azirines. The first example of reactions of 3-phe-
nyl-2H-azirine with enolates leading to pyrrole derivatives
was published by Sato.7 2H-Pyrroles were prepared in
good yields from 2H-azirines and enolates from activated
† Saint Petersburg State University.
‡ University of Durham.
(1) (a) Young, I. S.; Thornton, P. D.; Thompson, A. Nat. Prod. Rep.
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2010, 27, 1801. (b) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem.
Soc. Rev. 2010, 39, 4402. (c) Thirumalairajan, S.; Pearce, B. M.;
Thompson, A. Chem. Commun. 2010, 46, 1797. (d) Fan, H.; Peng., J.;
Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008, 108, 264. (e) Loudet, A.;
Burgess, K. Chem. Rev. 2007, 107, 4891. (f) Wood, T. E.; Thompson, A.
Chem. Rev. 2007, 107, 1831.
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F.; Bettini, E. Bioorg. Med. Chem. Lett. 2011, 21, 2059.
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C.; Stengone, C.; Tsui, H.-C.; Xiao, D.; Shih, N.-Y.; Duffy, R. A.;
Lachowicz, J. E.; Varty, G. B.; Nomeir, A. A. Bioorg. Med. Chem. Lett.
2008, 18, 4168.
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B.; Green, M. D.; Gardner, M. F.; James, J. P.; Chen, W.; Alves, K.; Si,
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A. E. Bioorg. Med. Chem. Lett. 2011, 21, 7416.
(3) Andrews, K. M.; Beebe, D. A.; Benbow, J. W.; Boyer, D. A.; Doran,
S. D.; Hui., Y.; Liu, S.; McPherson, R. K.; Neagu, C.; Parker, J. C.;
Piotrowski, D. W.; Schneider, S. R.; Treadway, J. L.; Vanvolkenberg,
M. A.; Zembrowski, W. J. Bioorg. Med. Chem. Lett. 2011, 21, 1810.
(7) Sato, S.; Kato, H.; Ohta, M. Bull. Chem. Soc. Jpn. 1967, 2936.
r
10.1021/ol3016594
XXXX American Chemical Society

carbonylcompounds.8 Itwasshownthatenolescanalsobe
used as nucleophiles in such reactions.9 Enamines, another
synthetic equivalent of enolate anions, react with substituted
2H-azirines to give a mixture of 2,3- and 3,4-dihydropyr-
roles which on acid treatment yields 1H-pyrrole-2-car-
boxylic acid derivatives.10 Alkyl 2H-azirine-2-carboxylates
react with acetylacetone or Cu(acac)2 to give the corre-
sponding 1H-pyrroles.11 Tri- or tetra-substituted pyrroles
were synthesized by reaction of 1,3-dicarbonyl com-
pounds with 2H-azirine, which is itself generated in situ
by thermolysis of vinyl azides.11b,12 A selective synthesis
of substituted pyrrole-2-phosphane oxides and -phospho-
nates from 2H-azirines and enolates from acetyl acetates
and malonates was recently developed.13 The reported
reaction between stabilized phosphorus ylides and highly
electrophilic dimethyl 2H-azirine-2,3-dicarboxylate afforded
the corresponding pyrroles in low yield.10a Reactions of
azirines with nitrogen ylides are, to the best of our knowledge,
unknown to date.
Based on our research interest concerning the synthesis
of nitrogenated heterocycles via nitrogen ylide reactions14
and thechemistryofazirines14b,d,e,i,15 wecouldenvisionthe
possibility of assembling a new heterocyclic system 1, by
1,3-dipolar cycloaddition of pyridinium ylide 2a to the
CdN bond of 2H-azirine 3a. But by serendipity we found
thatylide 2a, generated from salt4a, reacted withazirine 3a
as a nucleophile, disclosing a methodology for the synth-
esis of unknown 1-(1H-pyrrol-3-yl)pyridinium salts 5
(Scheme 1).
Scheme 1
pycolinium 4d, and isoquinolinium analogs 4e with
3-mono- and 2,3-disubstituted azirines 3aꢀf (Table 1).
The reaction of salts 4 with azirines 3 in CH2Cl2 with
Et3N at rt gives after ∼1 day the corresponding salts 5 in
good yields. In boiling methylene chloride the reaction is
completed about 10 times faster, but this variant of the
procedure is less appropriate for thermally unstable azir-
ines 3c,e,f.
To study the scope of this approach we performed the
reaction of salts 4aꢀc containing both electron-donating
and -withdrawing substituents on the benzoyl group,
(8) (a) Laurent, A.; Mison, P.; Nafti, A.; Pellissiere, N. Tetrahedron
1979, 35, 2285. (b) Padwa, A.; Kulkarni, Y. Tetrahedron Lett. 1979, 107.
(c) Laurent, A.; Mison, P.; Nafti, A.; Pellissiere, N. Tetrahedron Lett.
1982, 655.
(9) (a) Narasimhan, N. S.; Heimgartner, H.; Hansen, H.-J.; Schmid,
H. Helv. Chim. Acta 1973, 56, 1351. (b) Dos Santos Filho, P. F.;
Schuchardt, U. Angew. Chem., Int. Ed. 1977, 647.
(10) (a) L’abbe, G.; Van Stappen, P.; Dekerk, J.-P. J. Chem. Soc.,
Chem. Commun. 1982, 784. (b) Law, K. W.; Lai, T.-F.; Sammes, M. P.;
Katritzky, A. R.; Mak, T. C. W. J. Chem. Soc., Perkin Trans. 1 1984, 111.
(11) (a) Alves, M. J.; Gilchrist, T. L.; Sousa, J. H. J. Chem. Soc.,
Perkin Trans. 1 1999, 1305. (b) Chiba, S.; Wang, Y.-F.; Lapointe, G.;
Narasaka, K. Org. Lett. 2008, 10, 313. (c) Qi, X.-X.; Jiang, Y.-J.; Park,
C.-M. Chem. Commun. 2011, 47, 7848.
(12) Ng, E. P. J.; Wang, Y.-F.; Hui, B. W.-Q.; Lapointe, G.; Chiba, S.
Tetrahedron 2011, 67, 7728.
(13) Palacios, F.; Ochoa de Retana, A. M.; Velez del Burgo, A.
ꢀ
J. Org. Chem. 2011, 76, 9472.
(14) For recent publications, see: (a) Khlebnikov, A. F.; Novikov,
M. S.; Petrovskii, P. P.; Magull, J.; Ringe, A. Org. Lett. 2009, 11, 979. (b)
Khlebnikov, V. A.; Novikov, M. S.; Khlebnikov, A. F.; Rostovskii,
N. V. Tetrahedron Lett. 2009, 50, 6509. (c) Khlebnikov, A. F.; Novikov,
M. S.; Petrovskii, P. P.; Konev, A. S.; Yufit, D. S.; Selivanov, S. I.;
Frauendorf, H. J. Org. Chem. 2010, 75, 5211. (d) Khlebnikov, A. F.;
Novikov, M. S. Russ. J. Gen. Chem. 2010, 80, 1652. (e) Khlebnikov,
A. F.; Novikov, M. S.; Petrovskii, P. P.; Stoeckli-Evans, H. J. Org.
Chem. 2011, 76, 5384. (f) Konev, A. S.; Khlebnikov, A. F.; Frauendorf,
H. J. Org. Chem. 2011, 76, 6218. (g) Kobylianskii, I. J.; Novikov, M. S.;
Khlebnikov, A. F. J. Fluorine Chem. 2011, 132, 175. (h) Khlebnikov,
A. F.; Novikov, M. S.; Golovkina, M. V.; Petrovskii, P. P.; Konev, A. S.;
Yufit, D. S.; Stoeckli-Evans, H. Org. Biomol. Chem. 2011, 9, 3886. (i)
Khlebnikov, A. F.; Novikov, M. S. Chem. Heterocycl. Compd. 2012, 48,
Figure 1. Molecular structure of compounds 5e,h.
The reaction conditions and yields of tri- and tetrasub-
stituted pyrrole derivatives are presented in Table 1. The
structures of compounds 5 were verified by 1H, 13C NMR,
IR spectroscopy, HRMS, and elemental analysis. Struc-
tures of compounds 5e,f,h were confirmed by X-ray ana-
lysis (Figure 1 and Supporting Information). Salts 5 are
stable bright yellow crystalline compounds with high
melting points. These hygroscopic substances are soluble
in water and methanol and insoluble in diethyl ether,
methylene chloride, and hexane.
ꢀ
179. (j) Kadina, A. P.; Khlebnikov, A. F.; Novikov, M. S.; Perez, P. J.;
Yufit, D. S. Org. Biomol. Chem. 2012, 10, 5582.
(15) Khlebnikov, A. F.; Novikov, M. S.; Pakalnis, V. V.; Yufit, D. S.
J. Org. Chem. 2011, 76, 9344.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Synthesis of 3-(1H-Pyrrol-3-yl)pyridinium Salts 5
entry
R1
R2
R3
R4
R5
R6
salt 4
azirine 3
procedure,a t (h)
yield of 5 (%)
1
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
H
a
a
a
b
c
a
b
c
a
a
a
a
d
d
d
e
f
A(24)/B(2)
A(24)/B(2)
A(24)
B(2)
a (76/72)
b (74/71)
c (70)
d (80)
e (85)
f (79)
2
H
4-BrC6H4
H
3
H
4-MeOC6H4
H
4
MeO
NO2
H
Ph
H
5
Ph
H
B(2.5)
B(3)
6
Ph
H
d
e
a
b
c
7
H
(CHdCH)2
Ph
H
A(24)
B(3)
g (60)
h (79)
i (85)
8
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Me
9
MeO
NO2
MeO
MeO
Ph
B(2)
10
11
12
Ph
B(3)
j (71)
Ph
b
b
A(24)
A(24)
k (87)
l (69)
CO2Me
4-ClC6H4
a A: stirring at rt. B: reflux in CH2Cl2.
The probable mechanism for the formation of 1-(1H-
pyrrol-3-yl)pyridinium salts 5 by the reaction of azirines 3
with ylides 2 is shown in Scheme 2.
for the formation of salts 5, the reaction could proceed in an
autocatalytic mode using only catalytic amounts of Et3N. A
special experiment showed, however, that under these con-
ditions the reaction proceeds very slowly.
Scheme 2
Scheme 3
The structures of compounds 11 were verified by stan-
dard spectroscopic methods. There is a long-wave absorp-
tion band in the UV spectra of ylides 11 (λ 485ꢀ500 nm,
ε = 300ꢀ500), which is responsible for the color of these
compounds (from brick-red to dark-violet). It is easy to
change the counterion in salts 5 via ylide 11. For example,
consecutivereactionsofsalt5dwithKOH and thenwithan
excess of hydrochloric acid leads to the chloride 14 in
quantitative yield (Scheme 4).
On contact with air the ylides11react, incrystalline form
or dissolved in methanol, with carbonic acid in the air to
give the corresponding hydrocarbonates (Scheme 4). The
structure of the hydrocarbonate 15, prepared by keeping
the ylide 11b in air, was established by X-ray analysis (see
Supporting Information).
Further, we tried to generate a new type of pyridinium
ylide, 3-(pyridinium-1-yl)pyrrolides 11, by treating salts 5
with a base (Table 2). It was found that NaOH, KOH, and
K2CO3 convert the salts 5 to ylides 11 practically quantita-
tively. The use of pyridine or Et3N does not lead to the
desirable result, due to the relatively high basicity of
pyridinium-pyrrolides 11. In particular, this follows from
free energy parameters for isodesmic reactions (Scheme 3),
obtained by DFT B3LYP/6-31G(d) calculations.16 The
high basicity of ylides 11 means that if they were intermediate
(16) The details of calculations will be published elsewhere.
Org. Lett., Vol. XX, No. XX, XXXX
C

11b is reduced with Adams’ catalyst in methanol (entry 4).
These conditions were used for the hydrogenation of ylides
11a,d,f giving piperidines 19a,c,d in good yields.
Table 2. Synthesis of 3-(Pyridinium-1-yl)pyrrolides 11
Table 3. Hydrogenation of 3-(Pyridinium-1-yl)pyrrolides 11
entry
R1
R5
R6
5
yield of 11 (%)
1
4
5
2
3
8
9
H
Ph
Ph
Ph
H
a
d
e
b
c
h
i
a (98)
b (95)
c (91)
d (91)
e (92)
f (93)
g (96)
MeO
NO2
H
H
H
4-BrC6H4
4-MeOC6H4
Ph
H
H
H
H
Ph
Ph
MeO
Ph
time
(h)
yield of
entry
substrate
catalysta
solvent
19 (%)
1
20 þ 21
20 þ 21
11b
PtO2
EtOH
EtOH
EtOH
MeOH
MeOH
MeOH
EtOH
MeOH
EtOH
MeOH
MeOH
MeOH
MeOH
MeOH
11
10
6
b (66)
b (46)
b (51)
b (87)
b (39)
b (33)
b (37)
b (59)
b (49)
b (63)
0
2
10%Pt/C
PtO2
Scheme 4
3
4
11b
PtO2
0.5
1.5
1.5
5
5
11b
PtO2 (5%)
PtO2 (3%)
10%Pt/C
10%Pt/C
5%Pt/C
5%Pt/C
10%Pd/C
PtO2
6
11b
7
11b
8
11b
0.5
2
9
11b
10
11
12
13
14
11b
0.5
22
0.5
0.5
0.5
Because compounds with the fragment of 3-(piperidin-
1-yl)pyrrole demonstrate a varied bioactivity2ꢀ6 the reduc-
tion of salts 5 and ylides 11 were investigated. The reduc-
tion of salt 5d or ylide 11d by complex metal hydrides led to
the mixtures of di- and tetrahydropyridine derivatives
(Scheme 5) which were impossible to separate because of
the very close Rf parameters and the instabilty under
chromatography on SiO2 or Al2O3.
11b
11a
a (84)
c (75)
d (89)
11d
PtO2
11f
PtO2
a Entries 1ꢀ4, 7ꢀ14: 10% w/w of catalyst.
In summary, a novel effective approach to the synthesis
of unknown 1-(1H-pyrrol-3-yl)pyridinium salts by the reac-
tion of pyridinium ylides with 2H-azirines was disclosed.
1-(1H-Pyrrol-3-yl)pyridinium salts can be easily tranformed
into 3-(pyridinium-1-yl)pyrrolides, a new type of stable ylide.
Catalytic atmospheric-pressure hydrogenation of 3-(pyridi-
nium-1-yl)pyrrolides with Adams’ catalyst lead to 1-(pyrrol-
3-yl)piperidines in good yields. Further applications of the
suggested methodology are currently under investigation.
Scheme 5
Acknowledgment. We gratefully acknowledge the fi-
nancial support of the Russian Foundation for Basic
Research (Grant No. 11-03-00186), the Federal Grant-
in-Aid Program “Human Capital for Science and Educa-
tion in Innovative Russia” (Governmental Contract No.
16.740.11.0442), and Saint Petersburg State University
(Grant No. 12.38.78.2012).
Supporting Information Available. Experimental pro-
cedures, spectroscopic data for all new compounds, CIF
files for 5e,f,h and 15. This material is available free of
charge via the Internet at http://pubs.acs.org.
Catalytic hydrogenation at atmospheric pressure of 3-
(pyridinium-1-yl)pyrrolides 11 or of the mixtures of dihy-
dropyridines 16,17 lead to the corresponding 1-(pyrrol-3-yl)-
piperidines 19 (Table 3). The best results (highest yield and
the shortest reaction time) were obtained when the ylide
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX