Synthesis of 2H-pyrroles by treatment of pyrrolidines with DDQ

Article abstract of DOI:10.1016/S0040-4039(03)00740-8

A mild and efficient synthesis of 2,2-dialkyl-3,5-diaryl-2H-pyrroles is described. Treatment of 2,2-dialkyl-3,5-diarylpyrrolidines with DDQ in dioxane for 12-24 h at rt afforded the corresponding 2H-pyrroles in 55-81% overall yields.

Full text of DOI:10.1016/S0040-4039(03)00740-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3701–3703
Synthesis of 2H-pyrroles by treatment of pyrrolidines with DDQ
Srinivasa R. Cheruku, Maniyan P. Padmanilayam and Jonathan L. Vennerstrom*
College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, USA
Received 14 January 2003; revised 5 March 2003; accepted 6 March 2003
Abstract—A mild and efficient synthesis of 2,2-dialkyl-3,5-diaryl-2H-pyrroles is described. Treatment of 2,2-dialkyl-3,5-
diarylpyrrolidines with DDQ in dioxane for 12–24 h at rt afforded the corresponding 2H-pyrroles in 55–81% overall yields.
© 2003 Elsevier Science Ltd. All rights reserved.
In our ongoing search for novel classes of biologically
active heterocycles, we became interested in the explo-
ration of the 2H-pyrrole framework. There are five
general routes for synthesis of 2H-pyrroles: (i) elec-
trophilic addition to C-2 monosubstituted 1H-pyrroles
and subsequent isomerization;1 (ii) 1,3-dipolar cycload-
dition of azomethine ylides to alkynes followed by
dehydrogenation;2a–e (iii) cyclocondensation of amines
or azaallyl anions with ketones;3a–c (iv) reaction of
vinylic derivatives with nitrenes generated in situ by
thermolysis of 3-vinylazirines;4a–e and (v) reductive
cyclization of g-nitroketones to 2H-pyrroles via 1-
pyrroline oxides or 1-pyrrolines.4c,5a–d
with Zn/HCOOH–EtOH invariably produced a mixture
of pyrroline N-oxides 4 and pyrrolines 5.4c,5a–d More
conveniently, however, we cleanly obtained the corre-
sponding pyrrolidines 6 by treatment of g-nitroketones
3 with nickel catalyst (Raney® 2800 nickel) in ethanol
at room temperature under a hydrogen atmosphere
(Scheme 2).8 Treatment of these pyrrolidine intermedi-
ates 6a–h with DDQ (2.2 equiv.) in dioxane at room
temperature afforded the desired 2H-pyrroles 7a–h in
55–81% yields, and the reaction appeared to be quite
general (Scheme 2, Table 1). Initial trials using dry
benzene as solvent were unsatisfactory. At least 2 equiv.
of DDQ were required to drive the reaction to comple-
tion. One critical advantage of this method is that no
isomeric 1H-pyrroles were formed.
For our 2H-pyrrole synthesis, we selected the reductive
cyclization route as a general synthetic strategy5c in
view of the structural diversity of the many chalcones 1
that can be easily obtained from the many commer-
cially available and relatively inexpensive starting mate-
rial acetophenones and benzaldehydes.6 Conjugate
addition of secondary nitroalkanes 2 to the chalcone
DDQ is very commonly used for aromatization of
carbocyclic and fused heterocyclics, but in only one
case9 was this reagent applied to the conversion of
pyrrolines to 2H-pyrroles. Other reagents such as the
closely related chloranil3b,9 and MnO2
tend to form
9,10
intermediates
1
was carried out using tetra-
methylguanidine (TMG) in dry CH3CN (Scheme 1).7
isomeric mixtures of 1H- and 2H-pyrroles due to sig-
Reductive cyclization of the resulting g-nitroketones 3
matropic rearrangements at the elevated reaction tem-
Scheme 1.
Keywords: DDQ; reductive cyclization; g-nitroketones; pyrrolines; pyrroldines; 2H-pyrroles.
* Corresponding author. Tel.: 402-559-5362; fax: 402-559-9543; e-mail: jvenners@unmc.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00740-8

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S. R. Cheruku et al. / Tetrahedron Letters 44 (2003) 3701–3703
Scheme 2.
Table 1. Synthesis of 2H-pyrroles (7a–h) from pyrrolidines (6a–h)
Pyrrolidine
R1
R2
R3
R4
2H-Pyrrole
Yield (%)
Mp (°C)a
6a
6b
6c
6d
6e
6f
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-CH3-C6H4
4-Pyridyl
C6H5
C6H5
4-CH3-C6H4
CH3
CH3
7a
7b
7c
7d
7e
7f
81
72
67
71
69
74
55
78
58–60 (59–61)4b
97–99
-(CH2)4-
-(CH2)5-
CH3
109–111 (112–114)4b
85–87 (275)12
111–113 (115)5c
89–91 (93–94)13
82–84 (270)12
91–93 (285)12
CH3
CH3
CH3
CH3
CH3
C6H5
CH3
CH3
CH3
CH3
4-Pyridyl
4-CH3-C6H4
4-CH3-C6H4
6g
6h
7g
7h
a Literature values in parentheses for known 2H-pyrroles or the corresponding hydrochloride salts.
peratures. Interestingly, few reports11a–e describe dehy-
drogenation of pyrrolidines to pyrrolines or 1H-
pyrroles; to our knowledge the direct conversion of
pyrrolidines to 2H-pyrroles has yet to be documented.
2. (a) Belloir, P. F.; Laurent, A.; Mison, P.; Lesniak, S.;
Bartnik, R. Synthesis 1986, 8, 683–686; (b) Lui, K. H.;
Sammes, M. P. J. Chem. Soc., Perkin Trans. 1 1990,
457–468; (c) Texier, F.; Mazari, M.; Yebdri, O.; Tonnard,
F.; Carrie, R. Tetrahedron 1990, 46, 3515–3526; (d)
Berree, F.; Marchand, E.; Morel, G. Tetrahedron Lett.
1992, 33, 6155–6158; (e) Bohm, T.; Weber, A.; Sauer, J.
Tetrahedron 1999, 55, 9535–9558.
3. (a) Fuks, R.; Viehe, H. G. Tetrahedron 1969, 25, 5721–
5732; (b) Koch, J.; Robert, J. F.; Panouse, J. J. C.R.
Acad. Sci. Paris 1978, 286, 95–98; (c) Konakahara, T.;
Watanabe, A.; Maehara, K.; Nagata, M.; Hojahmat, M.
Heterocycles 1993, 35, 1171–1184.
4. (a) Gilgen, P.; Heimgartner, H.; Schmidt, H. Heterocycles
1977, 6, 143–212; (b) Laurent, A.; Mison, P.; Nafti, A.;
Pellissier, N. Tetrahedron Lett. 1978, 1, 4511–4514; (c)
Aeppli, L.; Bernauer, K.; Schneider, F.; Strub, K.; Ober-
hansli, W. E.; Pfoertner, K. H. Helv. Chim. Acta 1980,
63, 630–644; (d) Pfoertner, K. H.; Zell, R. Helv. Chim.
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1896.
Typical procedure: To a stirred solution of pyrrolidine
6a (5.0 mmol) in dioxane (20 ml) at room temperature
was added DDQ (11.0 mmol). The reaction mixture
immediately turned deep green, and it was allowed to
stir until the starting material was consumed (16 h in
this case). The solvent was removed in vacuo, and dry
benzene (15 ml) was added to the resulting residue and
the insoluble hydroquinone was filtered. It was rinsed
with benzene (2×10 ml) and the combined filtrates were
concentrated under reduced pressure to give a dark
brown oil. Crystallization of this crude material from
benzene:hexanes (2:1) afforded 2H-pyrrole 7a as a col-
orless solid.
In conclusion, a mild and direct method was developed
for the conversion of pyrrolidines to 2H-pyrroles, thus
expanding the utility of the reductive cyclization route.
5. (a) Bapat, J. B.; Black, D. St. C. Aust. J. Chem. 1968, 21,
2483–2495; (b) Bapat, J. B.; Black, D. St. C.; Newland,
G. Aust. J. Chem. 1974, 27, 1591–1595; (c) Pfoertner, K.
H.; Foricher, J. Helv. Chim. Acta 1980, 63, 658–663; (d)
Turner, M. J.; Luckenbach, L. A.; Turner, E. L. Synth.
Commun. 1986, 16, 1377–1385.
Acknowledgements
This work was supported in part by UNDP/World
Bank/WHO Special Programme for Research and
Training in Tropical Diseases (TDR ID No. 980211).
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1955, 20, 1785–1792.
7. Ono, N.; Kamimura, A.; Miyake, H.; Hamamoto, I.;
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