A novel and unusual method for C-N bond formation in 1-substituted- pyrrolidin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2004.10.162

A novel C-N bond forming reaction is reported, which involves heating 1-substituted-pyrrolidin-2-ones with cyclic amines in the presence of a base. A novel 5-C-N bond forming reaction is reported, which involves heating 1-substituted-pyrrolidin-2-ones with cyclic amines in the presence of a base. This reaction provides a convenient method for the synthesis of 1,5-disubstituted-pyrrolidin-2-ones.

Full text of DOI:10.1016/j.tetlet.2004.10.162

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 153–156
A novel and unusual method for C–N bond formation in
1-substituted-pyrrolidin-2-ones
,
*
Neelima Sinha, Sanjay Jain and Nitya Anand
Division of Medicinal Chemistry, Central Drug Research Institute, Lucknow 226 001, India
Received 17 March 2004; revised 20 October 2004; accepted 28 October 2004
Available online 21 November 2004
Abstract—A novel 5-C–N bond forming reaction is reported, which involves heating 1-substituted-pyrrolidin-2-ones with cyclic
amines in the presence of a base. This reaction provides a convenient method for the synthesis of 1,5-disubstituted-pyrrolidin-2-ones.
ꢀ 2004 Elsevier Ltd. All rights reserved.
N-Methylpyrrolidin-2-one (NMP) is commonly used as
a solvent for difficult reactions on account of its stability
and polarity, especially as it acts as an auxiliary catalyst
and ensures that the reaction proceeds with rapidity and
more smoothly than with other solvents. However, we
have observed that under the conditions described in
this letter NMP itself undergoes an unusual 5-C–N
alkylation, and can also cause formylation of the amines
used. Usually the formation of C–N bonds in 1-substi-
tuted-pyrrolidin-2-ones takes place either by replace-
ment of halides1,2 or through activated forms such as
lactim ethers, lactam acetals,3 etc., but nucleophilic sub-
stitution at the unsubstituted C-5 position of unacti-
vated 1-substituted-pyrrolidin-2-ones has not yet been
reported. We wish to report herein the interesting and
synthetically useful observation that 1-alkyl- or 1-aryl-
alkyl-pyrrolidin-2-ones react with aryl/alkyl-piperazines,
piperidine and morpholine in the presence of sodium or
potassium carbonate at 160ꢁC leading to the formation
of 1-alkyl-5-[(4-alkyl/aryl-piperazin-1-yl)/piperidinyl/mor-
pholinyl]-pyrrolidin-2-ones (3–11a)4 in fair yields along
with small quantities of the corresponding N-formyl
derivatives of the cyclic amines used (3–9b) (Scheme 1,
Table 1). This reaction provides a convenient method
for the preparation of various synthetically and biologi-
cally important 1,5-disubstituted-pyrrolidin-2-ones.
In order to prove the structures of the products 3–11a,
compound 3a was synthesized via an alternative route
by reacting 1-phenylpiperazine 13 with 1-methyl-5-eth-
oxypyrrolidin-2-one 12 at 80ꢁC (Scheme 2).5 The inter-
mediate 12 was, in turn, synthesized via a literature
method.6 Compound 3a was identical in all respects
1
(IR, H NMR, 13C NMR, mass and elemental analy-
sis)7 with that obtained according to Scheme 2. Com-
pounds of type 3 are not well described in the
literature except for 3a in a Patent, which describes the
generality of the reaction of compound 12 with various
K2CO3 or Na2CO3
160 o
O
H
H
N
+ HN
X
+
N
X
O
O
N
R
N
R
C
X
1
2
3—11a
3—9b
R= CH3, C2H5, C6H5CH2
X= NCH3, CH2, O, NAr
Ar= C6H5, 3-ClC6H4, 4-ClC6H4, 4-FC6H4
Scheme 1.
Keywords: 1-Substituted-pyrrolidin-2-ones; 5-C–N bond formation; 1,5-Disubstituted-pyrrolidin-2-ones; Formylation; 1,3-Disubstituted-pyrrolidin-
2-ones.
*
Corresponding author. Tel.: +91 20 25126689; fax: +91 20 25171329; e-mail addresses: sanjayjain_ran@hotmail.com; sanjayjain@
lupinpharma.com
Present address: New Chemical Entity Research, Lupin Research Park, 46/47A, Village Nande, Taluka Mulshi, Pune 411 042, Maharashtra, India.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.162

154
N. Sinha et al. / Tetrahedron Letters 46 (2005) 153–156
Table 1. Reaction of 1-substituted-pyrrolidin-2-ones with cyclic amines
Cyclic lactam (1)
Amine (2)
5-Substituted product7 (3–11a)
Yield (%)a
38
1-Formyl product13,14 (3–9b)b
Yield (%)a
11
H
O
O
O
N
O
N
N
CH3
N
N
HN
N
N
H
CH3
3a
3b
H
N
Cl
Cl
Cl
O
H
O
N
N
CH3
32
34
41
29
37
34
15
17
14
12
9
N
N
N
N
HN
HN
N
N
CH3
4a
4b
H
O
H
O
O
N
O
N
N
CH3
N
Cl
F
Cl
F
N
CH3
Cl
5a
5b
H
N
O
H
O
N
N
CH3
N
N
N
N
N
HN
HN
HN
HN
N
N
N
CH3
F
6a
6b
H
O
H
O
N
O
O
N
N CH3
7b
CH3
N
CH3
N
CH3
CH3
7a
H
N
O
H
O
N
N
CH3
CH3
8a
8b
H
O
H
O
N
O
O
O
N
11
O
O
N
CH3
O
CH3
9a
9b
H
N
O
H
O
N
N
N
28
23
—
—
10
N
N
N
N
N
HN
HN
HN
HN
N
N
N
N
N
10a
3b
H
N
O
H
O
N
7
N
N
Ph
Ph
11a
3b
O
H
—
—
19
16
N
O
N
CH3
3b
O
H
N
N
CH3
O
3b
a Yields of isolated products are based upon cyclic amines.
b Characterized on the basis of their IR, 1H NMR and MS data.

N. Sinha et al. / Tetrahedron Letters 46 (2005) 153–156
155
80 o
C
H
H
N
+ HN
N
O
OC2H5
O
N
CH3
N
N
CH3
12
13
3a
Scheme 2.
The mechanism of formylation may involve the break-
down of the pyrrolidin-2-one and would be related to
the oxidative potential of the pyrrolidin-2-one to form
succinimide.11 This is also reminiscent of the so-called
tertiary amine effect where a position next to the nitro-
gen in an enamine is activated for substitution.12
H
Br
N
N
Na2CO3, THF
Reflux
+ HN
N
O
N
CH3
O
N
CH3
15
14
13
Scheme 3.
O
OOH
O
N
N
CH3
CH3
amines.8 The present report provides a more direct ap-
proach to 1,5-disubstituted-pyrrolidin-2-ones (3–11a)
(Scheme 1).
16
17
In conclusion, we have demonstrated an unusual, but di-
rect and useful method for the synthesis of 1,5-disubsti-
tuted-pyrrolidin-2-ones from 1-substituted-pyrrolidin-2-
ones and cyclic amines using potassium or sodium carb-
onate under heating. This unusual and facile C–N
bond formation has allowed the synthesis of various
synthetically as well as biologically important 1,5-disub-
stituted-pyrrolidines very conveniently in multigram
quantities. We also describe a convenient method for
the synthesis of 1-substituted-3-amino-pyrrolidin-2-
ones.
To confirm unambiguously the position of C–N bond
formation (C-5 vs C-3), we synthesized 1-methyl-3-(4-
phenylpiperazin-1-yl)-pyrolidin-2-one 159 by reacting
1-phenylpiperazine 13 with 3-bromo-1-methyl-pyrroli-
din-2-one 14, prepared according to a literature meth-
od,10 in the presence of Na2CO3, in THF at reflux
1
(Scheme 3). The H NMR spectrum of compound 3a
was different from that of compound 15 obtained
according to the method shown in Scheme 3. In the
1H NMR of compound 15, the signal for 3-H (d 3.30–
3.50) merged with those of the –NCH2 protons of the
piperazine unlike that of 3a in which the position of
the 5-H signal appeared at d 4.44. Compounds of type
15 are hitherto unknown in the literature.
Acknowledgements
We gratefully acknowledge financial support from the
Council of Scientific and Industrial Research, New Del-
hi, India for this work. We are grateful to Dr. Pravin K.
We examined the generality of the 5-C–N bond forming
reaction and our results are shown in Table 1. 1-Ethyl-
and 1-benzyl-pyrrolidin-2-one also gave the amination
products along with 1-formyl-4-phenylpiperazine. How-
ever, with 1-methylpiperidin-2-one and 1-methylazepan-
2-one, only 1-formyl-4-phenylpiperazine was obtained.
No reaction took place with N,N-diethylpropionamide
and 1-methylpyrrolidin-2-thione. This reaction thus
seems specific for pyrrolidin-2-ones. Pyrrolidin-2-ones
are known to have special reactivity as they undergo
autoxidation and peroxide formation at the C-5
position.11
1
Misra for help with H and 13C NMR experiments and
Drs. Dinesh K. Dikshit, Anil K. Saxena and Sugata
Chatterjee for helpful discussions.
References and notes
1. Lowry, T. H.; Richardson, K. S. Mechanism and Theory in
Organic Chemistry, 3rd ed.; Harper Collins, 1987;
Chapter 4.
2. Mitsunobu, O. In Comprehensive Organic Synthesis;
Pergamon: Oxford, 1991; Vol. 6, p 65.
The above experiments confirm that nucleophilic substi-
tution takes place at C-5 position of 1-substituted-pyrr-
olidin-2-ones and not at C-3 position. No mechanistic
study was carried out to investigate the pathway of
nucleophilic displacement at the unactivated C-5 centre,
however, this must involve the generation of the immo-
nium species 17, which would readily undergo nucleo-
philic addition with cyclic amines. The immonium
species could be formed through the known propensity
of 1-methylpyrrolidin-2-one to undergo hydroperoxida-
tion11 at C-5 to form 16, which could lose hydroper-
oxide under thermal conditions, or through
intermolecular hydride transfer at high temperature.
3. Anand, N.; Singh, J. Tetrahedron 1988, 44, 5975–5999.
4. Typical procedure: Initially, the reaction was carried out by
taking 1-substituted-pyrrolidin-2-ones as solvent (in
excess) but later on we used 1.2molar equivalents. We
observed that the yields were very similar using either
method. Both procedures are described below.
Method A: A mixture of 1-phenylpiperazine (13, 1.0g,
6.17mmol), oven-dried Na2CO3 (0.327g, 3.09mmol) in 1-
methylpyrrolidin-2-one (5mL, 52.17mmol) was heated at
160ꢁC with stirring for 24h. 1-Methylpyrrolidin-2-one was
evaporated at reduced pressure; the residue was suspended
in water (30mL) and extracted with diethyl ether
(3 · 30mL). The combined organic layers were washed
with water (3 · 30mL), dried over anhydrous Na2SO4 and

156
N. Sinha et al. / Tetrahedron Letters 46 (2005) 153–156
filtered. The filtrate was concentrated under reduced
21.30%. Found: C, 61.19; H, 10.04; N, 21.59%. Compound
8a: thick oil. 1H NMR (400MHz, CDCl3): d 1.30–1.60 (m,
6H), 1.70–2.05 (m, 2H), 2.20–2.50 (m, 6H), 2.78 (s, 3H),
4.25 (dd, J = 6.0Hz, J = 3.0Hz, 1H). MS: m/z 182 (M+).
Anal. Calcd for C10H18N2O: C, 65.90; H, 9.95; N, 15.37%.
Found: C, 66.17; H, 10.27; N, 15.52%. Compound 9a: thick
oil. 1H NMR (400MHz, CDCl3): d 1.30–1.50 (m, 2H),
1.70–2.05 (m, 2H), 2.50–2.70 (m, 6H), 2.78 (s, 3H), 3.10–
3.30 (m, 2H), 4.25 (dd, J = 6.0Hz, J = 3.0Hz, 1H). MS: m/z
184 (M+). Anal. Calcd for C9H16N2O2: C, 58.67; H, 8.75;
N, 15.21%. Found: C, 58.44; H, 8.93; N, 15.33%.
Compound 10a: thick oil. IR (neat) cmÀ1: 3010, 2960,
1660, 1600, 1470, 1200, 1000, 730. 1H NMR (400MHz,
CDCl3): d 1.13 (t, J = 6.0Hz, 3H), 1.93–2.09 (m, 4H), 2.31–
2.45 (m, 4H), 2.58–2.70 (m, 4H), 3.43 (q, J = 6.0Hz, 2H),
4.55 (dd, J = 6.0Hz, J = 3.0Hz, 1H), 5.89–6.95 (m, 3H),
7.22–7.31 (m, 2H). MS: m/z 273 (M+). Anal. Calcd for
C16H23N3O: C, 70.29; H, 8.48; N, 15.37%. Found: C, 70.02;
H, 8.53; N, 15.59%. Compound 11a: thick oil. IR (neat)
cmÀ1: 3000, 2960, 1660, 1590, 1480, 1430, 1200, 990, 720.
1H NMR (400MHz, CDCl3): d 1.89–2.11 (m, 4H), 2.66–
2.70 (m, 4H), 2.95–3.03 (m, 4H), 4.31 (d, J = 6.0Hz, 1H),
4.62–4.70 (m, 2H), 6.77–6.82 (m, 3H), 7.22–7.50 (m, 7H).
MS: m/z 335 (M+). Anal. Calcd for C21H25N3O: C, 75.19;
H, 7.51; N, 12.53%. Found: C, 75.44; H, 7.42; N, 12.87%.
8. Fabre, J. L.; Farge, D.; James, C.; Lave, D. Eur. Pat.
Appl. EP 110795, 1984; Chem. Abstr. 1984, 101, 110726.
9. Experimental procedure (Scheme 3): A mixture of com-
pounds 14 (0.730g, 4mmol), 13 (0.66g, 4mmol) and oven-
dried Na2CO3 (0.212g, 2mmol) in tetrahydrofuran
(25mL) was heated at reflux with stirring for 3h. The
solvent was removed under reduced pressure and water
(25mL) was added to the residue. The reaction mixture
was extracted with diethyl ether (2 · 20mL), dried over
anhydrous Na2SO4 and filtered. The filtrate was concen-
trated under reduced pressure to give a crude product,
which was purified by column chromatography over silica
gel (230–400mesh) using chloroform–methanol (99:1) as
eluent to afford 0.32g (31%) of 15 as a dense oil. IR (neat)
pressure to give the crude product, which was purified
by column chromatography over silica gel (230–400mesh)
using 1% methanol–chloroform as eluent to afford 0.61g
(38%) of 3a and 3b (0.13g, 11%).
Method B: A mixture of compound 13 (1.0g, 6.17mmol),
oven-dried Na2CO3 (0.327g, 3.09mmol) in 1-methylpyrro-
lidin-2-one (0.71mL, 7.40mmol, 1.2equiv) was heated at
160ꢁC with stirring for 24h. Water (30mL) was added and
the reaction mixture extracted with diethyl ether
(3 · 30mL). The combined organic layers were washed
with water (3 · 30mL), dried over anhydrous Na2SO4 and
filtered. The filtrate was concentrated under reduced
pressure to give the crude product. Purification by flash
column chromatography (230–400mesh silica gel, 1%
methanol–chloroform) provided 0.59g (37%) of 3a and
3b (0.12g, 11%).
The other compounds given in Table 1 were synthesized
by the same procedures described above.
5. Experimental procedure (Scheme 2): A mixture of com-
pounds 12 (0.715g, 5mmol) and 13 (0.810g, 5mmol) was
heated at 80ꢁC with stirring for 3h. Water (25mL) was
added and the reaction mixture extracted with diethyl
ether (2 · 25mL). The combined organic layers were
washed with water (1 · 20mL), dried over anhydrous
Na2SO4 and filtered. The filtrate was concentrated under
reduced pressure to yield the crude product. Purification
by column chromatography over silica gel (230–400mesh)
using chloroform–methanol (99:1) as eluent yielded 0.66g
(51%) of compound 3a as a white solid.
6. Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am.
Chem. Soc. 1989, 111, 2588–2595.
7. All new compounds reported here were fully characterized
on the basis of complementary spectroscopic (IR, 1H
NMR, 13C NMR and MS) and analytical data. Analytical
data for the compounds 3–11a.
Compound 3a: mp 94–95ꢁC (lit.8 mp 96–97ꢁC). IR (KBr)
1
cmÀ1: 2960, 2820, 1670, 1600, 1240, 1140, 750. H NMR
(400MHz, CDCl3):
d 1.92–2.14 (m, 2H), 2.38 (t,
1
J = 6.0Hz, 2H), 2.55–2.78 (m, 4H), 2.89 (s, 3H), 3.10–
3.30 (m, 4H), 4.44 (dd, J = 6.0Hz, J = 3.0Hz, 1H), 6.84–
7.35 (m, 5H). 13C NMR (100.6MHz, CDCl3): d 17.65,
29.82, 48.23, 49.38, 27.79, 79.83, 117.45, 128.92, 124.79,
149.85, 174.53. MS: m/z 259 (M+). Anal. Calcd for
C15H21N3O: C, 69.47; H, 8.16; N, 16.20%. Found: C,
69.23; H, 8.23; N, 15.97%. Compound 4a: mp 98–100ꢁC.
1H NMR (400MHz, CDCl3): d 1.93–2.10 (m, 2H), 2.39 (t,
J = 6.0Hz, 2H), 2.62 (t, J = 6.0Hz, 4H), 2.89 (s, 3H), 3.10–
3.32 (m, 4H), 4.44 (dd, J = 6.0Hz, J = 3.0Hz, 1H), 6.70–
6.90 (m, 4H). MS: m/z 293 (M+), 295 (M+2). Anal. Calcd
for C15H20ClN3O: C, 61.32; H, 6.86; N, 14.30%. Found:
C, 61.08; H, 6.54; N, 13.92%. Compound 5a: mp 149–
150ꢁC. 1H NMR (400MHz, CDCl3): d 1.90–2.10 (m, 2H),
2.40 (t, J = 6.0Hz, 2H), 2.62 (t, J = 6.0Hz, 4H), 2.88 (s,
3H), 3.10–3.28 (m, 4H), 4.42 (dd, J = 6.0Hz, J = 3.0Hz,
1H), 6.82 (d, J = 9.0Hz, 2H), 7.20 (d, J = 9.0Hz, 2H). MS:
m/z 293 (M+), 295 (M+2). Anal. Calcd for C15H20ClN3O:
C, 61.32; H, 6.86; N, 14.30%. Found: C, 61.53; H, 6.47; N,
13.93%. Compound 6a: mp 161–162ꢁC. 1H NMR
cmÀ1: 3025, 2940, 1670, 1440, 1220. H NMR (400MHz,
CDCl3): d 2.05–2.20 (m, 2H), 2.65–2.80 (m, 2H), 2.85 (s,
3H), 2.90–3.05 (m, 2H), 3.10–3.40 (m, 6H), 3.55 (t,
J = 6.0Hz, 1H), 6.80–7.00 (m, 3H), 7.20–7.40 (m, 2H).
13C NMR (100.6MHz, CDCl3): d 19.70, 29.36, 45.96,
48.69, 64.05, 115.58, 119.06, 128.56, 150.90, 171.96. MS:
m/z 259 (M+). Anal. Calcd for C15H21N3O: C, 69.47; H,
8.16; N, 16.20%. Found: C, 69.31; H, 8.57; N, 16.32%.
10. Ikuta, H.; Shirota, H.; Kobayashi, S.; Yamagishi, Y.;
Yamada, K.; Yamatsu, I.; Katayama, K. J. Med. Chem.
1987, 30, 1995–1998.
11. Technical Leaflet on N-Methylpyrrolidone. Badische
Anilin- & Soda-Fabrik (BASF) AG, Germany, Revised
edition, 1967, p 6.
12. Jiang, S.; Janosuek, Z.; Viehe, H. G. Tetrahedron Lett.
1994, 35, 1185–1188.
13. (a) GolÕdberg, Yu. Sh.; Shimanskaya, M. V. Zh. Org.
Khim. 1982, 18, 2036–2042, Chem. Abstr. 1983, 98 89318;
(b) Archer, S.; Rosi, D. Fr. Pat. Appl. FR 1482920, 1967;
Chem. Abstr. 1968, 69, 36175; (c) Fujii, K.; Watanabe, H.
Japan 8878, 1956; Chem. Abstr. 1958, 52, 11971c.
14. All the 1-formyl products reported here, were fully
(400MHz, CDCl3):
d 1.95–2.12 (m, 2H), 2.38 (t,
J = 6.0Hz, 2H), 2.65 (t, J = 6.0Hz, 4H), 2.90 (s, 3H),
3.11–3.30 (m, 4H), 4.44 (dd, J = 6.0Hz, J = 3.0Hz, 1H),
6.80–7.25 (m, 4H). MS: m/z 277 (M+). Anal. Calcd for
C15H20FN3O: C, 64.96; H, 7.27; N, 15.15%. Found: C,
65.31; H, 7.59; N, 15.50%. Compound 7a: thick oil. 1H
NMR (400MHz, CDCl3): d 1.80–2.10 (m, 2H), 2.28 (s,
3H), 2.35 (t, J = 6.0Hz, 2H), 2.41–2.60 (m, 8H), 2.85 (s,
3H), 4.35 (dd, J = 6.0Hz, J = 3.0Hz, 1H). MS: m/z 197
(M+). Anal. Calcd for C10H19N3O: C, 60.88; H, 9.71; N,
1
characterized on the basis of their IR, H NMR and MS
data and were consistent with reported data. Analytical
data for the compound 3b: mp 80–81ꢁC (lit.13c mp
83.5ꢁC). IR (KBr) cmÀ1: 3500, 2820, 1670, 1600, 1400,
1
1230, 1000, 910, 750, 670. H NMR (400MHz, CDCl3): d
3.12 (t, J = 6.0Hz, 2H), 3.20 (t, J = 6.0Hz, 2H), 3.54 (t,
J = 6.0Hz, 2H), 3.74 (t, J = 6.0Hz, 2H), 6.84–7.40 (m,
5H), 8.12 (s, 1H). MS: m/z 190 (M+).