A facile non-oxidative method for synthesizing 1,3-disubstituted pyrroles from pyrrolidine and aldehydes

Article abstract of DOI:10.1016/j.tetlet.2007.10.108

Reactions of pyrrolidine with 2 equiv of aldehydes without any catalyst in a pressurized vessel at 140-200 °C yielded 1,3-disubstituted pyrroles. α-Branched aldehydes gave fairly good yields of the corresponding products by this method, which provides a f

Full text of DOI:10.1016/j.tetlet.2007.10.108

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 9159–9162
A facile non-oxidative method for synthesizing 1,3-disubstituted
pyrroles from pyrrolidine and aldehydes
Mitsunori Oda,a,* Yosuke Fukuchi,a Satoshi Ito,a Nguyen Chung Thanhb
and Shigeyasu Kurodab
aDepartment of Chemistry, Faculty of Science, Shinshu University, Asahi 3-1-1, Matsumoto, Nagano 390-8621, Japan
bDepartment of Applied Chemistry, Graduate School of Science and Engineering, University of Toyama,
Gofuku 3190-8555, Toyama 930-8555, Japan
Received 10 September 2007; revised 16 October 2007; accepted 22 October 2007
Available online 25 October 2007
Abstract—Reactions of pyrrolidine with 2 equiv of aldehydes without any catalyst in a pressurized vessel at 140–200 °C yielded 1,3-
disubstituted pyrroles. a-Branched aldehydes gave fairly good yields of the corresponding products by this method, which provides a
facile non-oxidative procedure for synthesizing 1,3-dialkylpyrroles from inexpensive pyrrolidine and aldehydes.
Ó 2007 Elsevier Ltd. All rights reserved.
Various substituted pyrroles can be synthesized from
pyrrole or simply substituted pyrroles by derivatization
according to its inherent reactivity,1,2 for example, N-
substitutions under basic conditions, normal electro-
philic substitutions with suitable electrophiles at the
a-carbon atom, and triisopropylsilyl (TIPS)-directed
electrophilic substitutions at the b-carbon atom.3 Other-
wise, organic chemists must assemble a four-carbon unit
in a heterocyclic skeleton to obtain the desired pyrrole
molecules,4 as observed in Paar–Knorr and Knorr syn-
theses.5 Although pyrrole derivatives have been widely
used as pharmaceuticals and functional materials, prep-
arations of pyrroles from primary starting materials
such as commercially available inexpensive pyrrolidine
(1) and easily accessible 1-pyrroline (2) are quite lim-
ited.6 The difficulty can be ascribed mainly to the inabi-
lity of 1 to be oxidized and easy dimerization of 2.7
Herein we present a facile non-oxidative method of
synthesizing 1,3-disubstituted pyrroles from 1 and
various aldehydes Chart 1.
On heating a mixture of 1 and an excess of cyclohexane-
carbaldehyde (3) in toluene using a Dean–Stark appara-
tus,8 under typical conditions of enamine synthesis,
1,3-bis(cyclohexylmethyl)pyrrole (4) was obtained in
17% yield, accompanied with enamine 5 (Scheme 1).
The yield of 4 was improved up to 32% when a mixture
of 3 and 5 was refluxed in toluene for 19 h and the addi-
tion of a catalytic amount of a Brønsted acid, such as
p-toluenesulfonic acid, pyridinium p-toluenesulfonate
and sulfuric acid, was ineffective under the conditions.
Our attention was then directed toward pressurized
reaction conditions because the reaction is basically
to assemble three components, two aldehydes and
one pyrrolidine. Under pressurized conditions, various
N
H
N
R
N
CHO
Δ
1
2
1
N
– H2O
Chart 1.
R
3
4
5
Keywords: Pyrrole; Pyrrolidine; Aldehyde; Enamine; Hydride shift.
(R = cyclohexyl)
*
Corresponding author. Tel./fax.: + 81 263 37 3343; e-mail: mituoda@
shinshu-u.ac.jp
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.108

9160
M. Oda et al. / Tetrahedron Letters 48 (2007) 9159–9162
aldehydes were transformed into the corresponding 1,3-
disubstituted pyrroles.9 Results are shown in Table 1.
Among the solvents used in the reaction of isobutyralde-
hyde (entries 2–8), toluene gave slightly better yields
than the other solvents used. Without any solvent, the
product was obtained in moderate yield (entry 1). Vari-
ous benzaldehydes (entries 14–16) gave moderate yields
of dibenzylpyrroles, whereas furan- and thiophenecar-
baldehydes provided only low yields of the correspond-
ing products (entries 17 and 18). The yields of 1,
3-dioctyl- and 1,3-dihexylpyrroles from octanal and
haxanal were low (entries 19 and 20). The reaction pro-
cedure is very simple. A solution of aldehyde and pyrrol-
idine in a solvent or without a solvent was charged in an
autoclave and heated at 140–200 °C for an appropriate
reaction time. The inner pressure was in the range of
0.5–2.0 MPa depending on the aldehyde and solvent
used. After being cooled to room temperature, the
reaction mixture was filtrated to remove the solids
formed and the solvent and water formed were removed
with an evaporator. The residue was distilled or chro-
matographed to give the product.
Table 1. Results of the reactions of pyrrolidine with various aldehydes
under pressure
R
Δ
The proposed reaction mechanism is illustrated in
Scheme 2. The mechanism involves enamine 910 as a
key intermediate, which can be formed via a hydride
shift from 6 to 8 in either intramolecular or intermole-
cular fashion and subsequent deprotonation. Enamine
9 captures another aldehyde to introduce a substituent
at the three position of the pyrroline, followed by proton
shift leading to 4. Enamine 7 can be formed when at
least one hydrogen exists at the a position of the alde-
hyde. However, enamines 7 derived from a-branched
aldehydes have two alkyl substituents at the reacting
olefinic carbon site and should show reduced reactivity
toward aldehyde due to a steric hindrance.11 In fact,
reactions with a-branched aldehydes provided better
yields of products than others, while those with n-alka-
nals gave low yields of products (entries 17 and 18).
Gaining an aromatic ring in final products may be a
driving force for this one-pot multi-stepped and multi-
component reaction. The resemblance to a hydride shift
and the reaction of the similar enamine intermediate
with the aldehyde was proposed in the formation of
2
R CHO
N
H
N
1
4
R
Entry Aldehyde
Reaction conditions
Yielda (%)
8
CHO
1
No solvent, 180 °C, 24 h
2
3
4
5
6
7
8
EtOHb, 180 °C, 24 h
Hexaneb, 180 °C, 20 h
Dioxaneb, 160 °C, 60 h
Tolueneb, 200 °C, 12 h
Tolueneb, 180 °C, 20 h
Tolueneb, 160 °C, 60 h
Tolueneb, 140 °C, 72 h
51
58
61
66
79
76
71
CHO
9
10
Tolueneb, 200 °C, 12 h
Tolueneb, 180 °C, 20 h
62c
74c
CHO
11
12
13
14
15
Tolueneb, 200 °C, 12 h
Tolueneb, 180 °C, 21 h
Tolueneb, 180 °C, 20 h
Tolueneb, 200 °C, 20 h
Tolueneb, 200 °C, 24 h
65
76
79c
47
60
CHO
Enamine,
when an α-
hydrogen
exists
N
R CHO
CHO
N
H
–OH
R
Ph
1
6
7
CHO
Hydride
shift
HO
R
CHO
Cl
N
N
N
R CHO
–H2O
–OH
R
16
Tolueneb, 200 °C, 24 h
53
R
R
CHO
10
9
8
17
18
Tolueneb, 200 °C, 24 h
Tolueneb, 180 °C, 20 h
11
5
CHO
S
R
R
Proton
shift
CHO
O
N
N
– H2O
19
20
n-C5H11CHO
n-C7H15CHO
Tolueneb, 180 °C, 20 h
Tolueneb, 180 °C, 20 h
15
13
–OH
R
R
11
4
a Isolated yield after distillation.
b For 50 mmol of pyrrolidine, 100 ml of solvent was used.
c A mixture of the diastereomers was obtained.
Scheme 2. A possible reaction mechanism for the synthesis of 4 from
1.

M. Oda et al. / Tetrahedron Letters 48 (2007) 9159–9162
9161
References and notes
1. Patterson, J. M. Synthesis 1976, 281–304.
2. Anderson, H. J.; Loader, C. E. Synthesis 1985, 353–364.
3. Bray, B. L.; Mathies, P. M.; Naef, R.; Solas, D. R.;
Tidwell, T. T.; Artis, D. R.; Muchowski, J. M. J. Org.
Chem. 1990, 55, 6317–6328.
Ph
Ph
Ph
Ph
CH–NLiPh
C=NPh
N
Li
N
12
13
2
4. (a) Sundberg, R. J. In Comprehensive Heterocyclic Chem-
istry; Katritzky, A. R., Rees, C. W., Scriven, E. F. V.,
Eds.; Pergamon: Oxford, 1996; Vol. 2, pp 119–206; (b)
Balme, G. Angew. Chem., Int. Ed 2004, 43, 6238–6241.
PhLiN
Ph
Ph
13
Ph
Ph
CH–NHPh
´
5. Kurti, L.; Czako, B. In Strategic Applications of Named
¨
N
Li
N
Reactions in Organic Synthesis; Elsevier Academic Press:
Amsterdam, 2005; pp 244–245.
6. (a) Baxter, G.; Melville, J. C.; Robins, D. J. Synlett 1991,
359–360; (b) Struve, C.; Christophersen, C. Heterocycles
15
14
PhNHLi
2003, 60, 1907–1914; (c) Hugel, H. M.; Nurlawis, F.
¨
Heterocycles 2003, 60, 2349–2354.
Ph
7. For oxidation of pyrrolidines and pyrrolines to pyrroles,
see the following references: (a) Fuhlhage, D. W.;
VanderWerf, C. A. J. Am. Chem. Soc. 1958, 80, 6249–
6254; (b) Shim, Y. K.; Toun, J. I.; Chun, J. S.; Park, T. H.;
Kim, M. H.; Kim, W. J. Synthesis 1990, 753–754; (c)
Declerck, V.; Allouchi, H.; Martinez, J.; Lamaty, F. J.
Org. Chem. 2007, 72, 1518–1521.
Ph
Ph
Ph
Proton
shift
N
N
H
16
17
8. Kane, V. V.; Jones, M., Jr. Org. Syn. 1990, Coll. Vol. 7,
473–476.
Scheme 3. The proposed reaction mechanism for the Wittig’s reaction.
9. All new compounds were characterized by spectroscopic
and/or combustion analyses. Their selected data are as
3,5-dibenzylpyridine from piperidine and benzalde-
hyde,12 although the yield of pyridine was found to be
less than 50%. In addition, Cook et al. proposed the
formal 1,3-hydride shift in a conversion process between
3-pyrroline and ketones to N-substituted pyrroles.13 In
the literature, we found only one similar reaction that
yields 3-substituted pyrroles from 1 with imines under
basic conditions;14 Wittig et al. reported that lithium
pyrrolidine amide (12) reacted with benzophenone imine
(13) to give 3-(diphenylmethyl)pyrrole (17) in 35% yield.
The proposed reaction mechanism requires the oxida-
tion of the amide by the imine 13 to produce 1-pyrroline
(2), which is deprotonated and then reacts with another
13 to give 17 via 15 and 16 (Scheme 3). Our method is
clearly superior to Wittig’s method due to the facility
of our procedure and the substrates used, and, of course,
the yields provided.
follows. Compound
4 (R = 2-propyl): colorless oil,
bp = 65–68 °C/0.1 mmHg. 1H NMR (CDCl3) d = 0.87
(d, J = 6.8 Hz, 6H), 0.89 (d, J = 6.8 Hz, 6H), 1.74 (nonet,
J = 6.8 Hz, 1H), 1.98 (nonet, J = 6.8 Hz, 1H), 2.30 (d,
J = 6.8 Hz, 2H), 3.57 (d, J = 6.8 Hz, 2H), 5.92 (dd,
J = 2.4, 1.7 Hz, 1H), 6.36 (dd, J = 2.1, 1.7 Hz, 1H), 6.50
(dd, J = 2.4, 2.1 Hz, 1H) ppm; 13C NMR (CDCl3)
d = 20.0, 22.5, 29.9, 30.6, 36.6, 57.3, 108.3, 119.1, 120.4,
122.8 ppm; IR (liq. film) mmax = 2954 s, 2925 m, 2904 m,
2869 m, 2844 w, 2358 w, 2343 w, 1498 m, 1467 m, 1386 w,
1365 w, 1354 w, 1324 w, 1278 w, 1162 m, 1066 w, 767 m,
750 w, 705 w, 684 w, 667 w, 649 w cmÀ1; MS (70 eV) m/z
(rel int) 179 (M+, 23), 137 (12), 136 (100), 80 (26); UV
(methanol) kmax = 222sh (loge = 3.74) nm; HRMS found:
179.1660. Calcd for C12H21N: M, 179.1674. Compound 4
(R = 2-butyl, a mixture of diastereomers): 1H NMR
(CDCl3) d = 0.83 (d, J = 6.6 Hz, 3H), 0.86 (d,
J = 6.6 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H), 0.90 (t,
J = 7.4 Hz, 3H), 1.05–1.17 (m, 2H), 1.31–1.43 (m, 2H),
1.50–1.54 (m, 1H), 1.73–1.79 (m, 1H), 2.23 (dd, J = 14.1,
7.7 Hz, 1H), 2.43 (dd, J = 14.1, 5.9 Hz, 1H), 3.54 (dd,
J = 13.7, 7.6 Hz, 1H), 3.70 (dd, J = 13.7, 6.7 Hz, 1H), 5.92
(dd, J = 2.4, 1.7 Hz, 1H), 6.36 (dd, J = 2.1, 1.7 Hz, 1H),
6.50 (dd, J = 2.4, 2.1 Hz, 1H) ppm. Compound 4 (R =
3-pentyl): 1H NMR (CDCl3) d = 0.87 (t, J = 7.6 Hz, 12H)
1.22–1.37 (m, 8H), 1.37 (septet, J = 6.4 Hz, 1H), 1.61
(septet, J = 6.4 Hz, 1H), 2.37 (d, J = 6.4 Hz, 2H), 3.68 (d,
J = 6.4 Hz, 2H), 5.92 (dd, J = 2.4, 1.7 Hz, 1H), 6.36 (dd,
J = 2.1, 1.7 Hz, 1H), 6.50 (dd, J = 2.4, 2.1 Hz, 1H) ppm;
13C NMR (CDCl3) d = 10.6, 11.0, 23.3, 25.1, 30.4, 42.2,
42.7, 52.7, 108.3, 119.2, 120.4, 122.4 ppm. Compound 4
(R = cyclohexyl): 1H NMR(CDCl3) d = 0.85–0.94 (m,
4H) 1.08–1.26 (m, 6H), 1.39 (ttt, J = 11.2, 6.8, 3.4 Hz,
1H), 1.58–1.75 (m, 11H), 2.30 (d, J = 6.8 Hz, 2H), 3.59 (d,
J = 7.1 Hz, 2H), 5.91 (dd, J = 2.4, 1.7 Hz, 1H), 6.34 (dd,
J = 2.1, 1.7 Hz, 1H), 6.49 (dd, J = 2.4, 2.1 Hz, 1H) ppm;
13C NMR (CDCl3) d = 25.7, 26.3, 26.4, 26.7, 30.8, 33.3,
35.2, 39.5, 39.8, 56.1, 108.2, 119.1, 120.4, 122.3 ppm.
Compound 4 (R = 1-phenethyl, a mixture of diastereo-
mers): 1H NMR (CDCl3) d = 1.17 (d, J = 7.2 Hz, 3H),
In summary, we have found a facile non-oxidative
method for synthesizing 1,3-disubstituted pyrroles from
pyrrolidine and aldehyde. a-Branched aldehydes and
benzaldehyde provided moderate to good yields of the
products, although heterocyclic carbaldehydes and alde-
hydes with primary a carbon atom gave low yields of the
products. The use of pyrrolidine is one of the advantages
of this new method and the facility of the method
increases the availability of these pyrroles as starting
materials for functionalized materials. Mechanistic
study and the applications of this method for synthesiz-
ing biologically active and functionalized pyrroles are
now in progress.
Acknowledgments
We thank Kazuhiro Kitahara, Takayuki Kotani, and
Kunihiro Ito and Ms Ran Ito at Shinshu University
for their preliminary technical assistance.

9162
M. Oda et al. / Tetrahedron Letters 48 (2007) 9159–9162
1.21 (d, J = 6.8 Hz, 3H), 2.58 (m, 1H), 2.74 (m, 1H), 2.86
120.2, 120.7, 140.9, 142.6, 150.7, 155.8 ppm. Compound 4
(R = 1-pentyl): H NMR (CDCl3) d = 0.86–0.90 (m, 6H),
1
(m, 1H), 3.04 (m, 1H), 3.78 (dd, J = 13.6, 7.8 Hz, 1H),
3.91 (dd, J = 13.6, 6.8 Hz, 1H), 5.82 (m, 1H), 6.16 (m,
1H), 6.36 (dd, J = 2.4, 2.2 Hz, 1H), 7.08–7.30 (m, 10H)
ppm. Compound 4 (R = phenyl): 1H NMR (CDCl3)
d = 3.81 (s, 2H), 4.94 (s, 2H), 6.00 (dd, J = 2.4, 1.7 Hz,
1H), 6.41(dd, J = 2.1, 1.7 Hz, 1H), 6.58 (dd, J = 2.4,
2.1 Hz, 1H), 7.07–7.34 (m, 10H) ppm; 13C NMR (CDCl3)
d = 33.5, 53.2, 109.0, 119.3, 121.2, 123.5, 125.6, 126.9,
127.5, 128.2, 128.6, 128.6, 138.2, 142.3 ppm. Compound 4
(R = p-chlorophenyl): 1H NMR (CDCl3) d = 3.76 (s, 2H),
4.93 (s, 2H), 5,98 (dd, J = 2.4, 1.7 Hz, 1H), 6.38 (dd,
J = 2.1, 1.7, 1H), 6.57 (dd, J = 2.4, 2.1 Hz, 1H), 7.01 (dm,
J = 8.3 Hz, 2H), 7.15 (dm, J = 8.3 Hz, 2H), 7.22 (dm,
J = 8.3 Hz, 2H), 7.27 (dm, J = 8.3 Hz, 2H) ppm; 13C
NMR (CDCl3) d = 32.8, 52.6, 109.2, 119.1, 121.3, 123.4,
128.3, 128.3, 128.8, 129.9, 131.3, 133.4, 136.7, 140.7 ppm.
Compound 4 (R = o-tolyl): 1H NMR (CDCl3) d = 2.24 (s,
3H), 2.29 (s, 3H), 3.79 (s, 2H), 4.96 (s, 2H), 5.97 (dd,
J = 2.4, 1.7 Hz, 1H), 6.30–6.32 (m, 1H), 6.53 (dd, J = 2.4,
2.1 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 7.09–7.19 (m, 7H)
ppm; 13C NMR (CDCl3) d = 18.9, 19.4, 31.2, 51.3, 108.9,
119.4, 121.1, 122.6, 125.8, 125.9, 126.3, 127.7, 127.7, 129.2,
1.28–1.30 (m, 12H), 1.51–1.59 (m, 2H), 1.68–1.76 (m, 2H),
2.44 (t, J = 7.8 Hz, 2H), 3.77 (t, J = 7.4 Hz, 2H), 5.95 (dd,
J = 2.4, 1.7 Hz, 1H), 6.40 (dd, J = 2.1, 1.7 Hz, 1H), 6.52
(dd, J = 2.4, 2.1 Hz, 1H) ppm; 13C NMR (CDCl3)
d = 14.0, 14.1, 22.5, 22.7, 26.5, 27.1, 29.2, 31.3, 31.4,
31.5, 31.8, 49.5, 107.7, 117.7, 120.0, 124.4 ppm. Com-
pound 4 (R = 1-heptyl): 1H NMR (CDCl3) d = 0.87 (t,
J = 6.8 Hz, 6H), 1.25–1.28 (m, 22H), 1.73 (m, 2H), 2.43 (t,
J = 7.8 Hz, 2H), 3.78 (t, J = 7.2 Hz, 2H), 5.96 (dd,
J = 2.4, 1.7 Hz, 1H), 6.41 (dd, J = 2.1, 1.7 Hz, 1H), 6.54
(dd, J = 2.4, 2.1 Hz, 1H) ppm; 13C NMR (CDCl3)
d = 14.1, 14.1, 22.6, 22.7, 26.8, 27.1, 29.2, 29.2, 29.3,
29.5, 29.6, 31.3, 31.6, 31.8, 31.9, 49.5, 107.7, 117.7, 120.1,
124.5 ppm.
10. Molander, G. A.; Hasegawa, H. Heterocycles 2004, 64,
467–474.
11. (a) Birkofer, L.; Kim, S. M.; Engels, H. D. Chem. Ber.
1962, 95, 1495–1504; (b) Alt, G. H. In Enamines:
Synthesis, Structure, and Reactions; Cook, A. G., Ed.;
Marcel Dekker: New York, 1969, Chapter 4; pp 115–168;
(c) Hayashi, Y.; Sumiya, T.; Takahashi, H.; Gotoh, T.;
Urashima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45,
958–961; (d) Brogan, A. P.; Dickerson, T. J.; Janda, K. D.
Angew. Chem., Int. Ed. 2006, 45, 8100–8102; (e) Hayashi,
Y. Angew. Chem., Int. Ed. 2006, 45, 8103–8104.
12. (a) Poirier, R. H.; Morin, R. D.; McKim, S. M.; Bearse, A.
E. J. Org. Chem. 1961, 26, 4275–4278; (b) Burrows, E. P.;
Hutton, R. F.; Burrows, W. D. J. Org. Chem. 1962, 27,
316–317; (c) Burrows, W. D.; Burrows, E. P. J. Org.
Chem. 1963, 28, 1180–1182; (d) Blokhin, A. V.;
Tyurekhodzhaeva, M. A.; Bazhenov, D. V.; Bobrovskii,
S. I.; Bundel, Y. G. Chem. Heterocycl. Compd. 1990, 26,
1022–1225.
130.0, 130.2, 135.7, 136.2 ppm. Compound
4 (R =
2-thienyl): 1H NMR (CDCl3) d = 3.99 (s, 2H), 5.12 (s,
2H), 6.06 (dd,J = 2.4, 1.7 Hz, 1H), 6.55 (dd, J = 2.1, 1.7
1H), 6.63 (dd, J = 2.4, 2.1 Hz, 1H), 6.80–6.81 (m, 1H),
6.88–6.94 (m, 3H), 7.08–7.10 (m, 1H), 7.20–7.22 (m, 1H)
ppm. 13C NMR (CDCl3) d = 27.7, 48.0, 109.1, 118.8,
120.8, 123.1, 123.2, 124.2, 125.5, 125.9, 126.6, 126.9, 140.6,
1
145.8 ppm. Compound 4 (R = furyl): H NMR (CDCl3)
d = 3.80 (s, 2H), 4.94 (s, 2H), 5.99 (dd, J = 3.2, 0.6 Hz,
1H), 6.05 (dd, J = 2.4, 1.7 Hz, 1H), 6.23 (dd, J = 3.2,
0.6 Hz, 1H), 6.27 (dd, J = 3.2, 1.6 Hz, 1H), 6.31 (dd,
J = 3.2, 1.6 Hz, 1H), 6.54 (dd, J = 2.1, 1.7 Hz, 1H), 6.61
(dd, J = 2.4, 2.1 Hz, 1H), 7.30 (dd, J = 1.8, 0.6 Hz, 1H),
7.36 (dd, J = 1.8, 0.6 Hz, 1H) ppm; 13C NMR (CDCl3)
d = 26.1, 46.0, 105.1, 108.1, 109.0, 110.1, 110.4, 118.8,
13. Cook, A. G.; Switek, K. A.; Cutler, K. A.; Witt, A. M.
Lett. Org. Chem. 2004, 1, 1–5.
14. Wittig, G.; Hesse, A. Liebigs Ann. 1971, 746, 174–184.