Conjugate addition of nitroalkanes to N-substituted maleimides. Synthesis of 3-alkylsuccinimides and pyrrolidines

Article abstract of DOI:10.1016/S0040-4020(03)00508-8

3-Alkylidenesuccinimides obtained by conjugate addition of nitroalkanes to N-substituted maleimides can be reduced to the corresponding 3-alkyl derivatives by catalytic hydrogenation. 3-Alkylsuccinimides can be further reduced using BH₃·Me

Full text of DOI:10.1016/S0040-4020(03)00508-8

Tetrahedron 59 (2003) 3603–3608
Conjugate addition of nitroalkanes to N-substituted maleimides.
Synthesis of 3-alkylsuccinimides and pyrrolidines
*
Roberto Ballini, Giovanna Bosica, Gianluca Cioci, Dennis Fiorini and Marino Petrini
*
`
Dipartimento di Scienze Chimiche, Universita di Camerino, via S. Agostino 1, I-62032 Camerino, Italy
Received 8 January 2003; revised 3 March 2003; accepted 27 March 2003
Abstract—3-Alkylidenesuccinimides obtained by conjugate addition of nitroalkanes to N-substituted maleimides can be reduced to the
corresponding 3-alkyl derivatives by catalytic hydrogenation. 3-Alkylsuccinimides can be further reduced using BH3·Me2S complex to
afford 3-alkylpyrrolidines in good yield. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
maleimides 1.6 Better results in terms of regioselectivity
can be obtained adding carbon centered radicals7 or
exploiting ‘ene’ reactions to compounds 1.8 In this context,
among various sources of stabilized carbanions, nitro-
alkanes occupy a prominent position since it is known that
their reaction with a,b-unsaturated derivatives affords only
1,4-adducts.9 Furthermore, the relatively high acidity of the
hydrogens in adjacent position to the nitro group (CH3NO2:
pKa¼10) makes the generation of the corresponding
nitronate anion fully compatible with a large array of
other functionalities such as hydroxy and carbonyl groups.
Substituted pyrrolidines are frequently included in many
substances endowed of biological and industrial interest.1 A
large body of synthetic approaches leading to these five-
membered heterocycles involves a ring closure process that
can be carried out both intra- and intermolecularly.2 An
alternative procedure concerns functionalization of com-
mercially available pyrrolidines and similar derivatives.3
Partial reduction of N-acylpyrrolidin-2-ones and function-
alized succinimides usually provides a rapid entry to
2-hydroxy or 2-alkoxypyrrolidines that can be used as
precursors of N-acyliminium ions. These reactive inter-
mediates can be suitably employed for the synthesis of
2-substituted pyrrolidines.4 Reaction of enolates obtained
from pyrrolidin-2-ones with various electrophilic reagents
represents a viable route to 3-alkylpyrrolidines.5 A comple-
mentary strategy involves conjugate addition to N-sub-
stituted maleimides 1 followed by a reduction of the
obtained succinimides 2 to give the pyrrolidine ring system
3 (Scheme 1). Common organometallic reagents give
exclusively (alkynyllithium) or consistent amounts
(Grignard reagents) of 1,2-addition products with
2. Results and discussion
Several years ago, we observed that nitroalkanes 4 react
with N-substituted maleimides 1 in the presence of DBU to
afford the corresponding adducts 5 that suffer elimination of
nitrous acid by the excess of the base employed giving the
unsaturated derivative 6 in good yield (Scheme 2).10
Scheme 1.
Keywords: addition reactions; imides; nitro compounds; pyrrolidines;
reduction.
*
Corresponding authors. Tel.: þ39-737402270/402253; fax: þ39-
737402297; e-mail: roberto.ballini@unicam.it,
marino.petrini@unicam.it.
Scheme 2.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00508-8

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R. Ballini et al. / Tetrahedron 59 (2003) 3603–3608
Scheme 5.
Scheme 3.
in THF at reflux affords pyrrolidine 8d and 3-pentyl-N-
ethylpyrrole 9 in a 2:1 ratio (Scheme 5).
This reactivity is peculiar to enone systems and has been
recently used for the synthesis of pyrroles,11 furans,12
cyclopentenones,13 as well as 3-alkylidene pyrrolidines.14
A similar behavior has been previously reported by
Abramovitch and C0hapman in the reaction of N-methyl-
anilinomethylene-N -phenylsuccinimide with the same
reducing agent.18 Formation of pyrrole 9 may be ascribed
to the basicity of LiAlH4 that favors an elimination leading
to a thermodynamically stable aromatic ring. Lowering the
temperature to 08C did not suppress the formation of pyrrole
9 and therefore, we decided to exploit a complementary
approach for the reduction of substrates 7. Borane is able to
reduce substituted succinimides to the corresponding
pyrrolidines.17 It is commercially available as a complex
with various Lewis bases, or can be generated in situ from
NaBH4/I2 couple. For our purposes, we have observed that
BH3·Me2S complex in THF is the reagent of choice to carry
out efficient reduction of succinimides 7 to 3-alkypyrroli-
dines 8 (Scheme 6, Table 2).
Reduction of the alkylidene moiety in compounds 6 allows
the synthesis of 3-alkylsuccinimides 7. These compounds
are precursors of a wide range of functionalized open chain
derivatives that can be obtained by nucleophilic ring
opening reactions (Scheme 3).15 Reduction of unsaturated
succinimides 6 can be readily accomplished by catalytic
hydrogenation in the presence of 10% Pd/C in very high
yields (Table 1). Rather surprisingly, compound 6g has been
revealed practically inert towards these reductive con-
ditions. Therefore, the double bond in compound 6g has
been reduced using the NaBH4/NiCl2 couple in 80% yield
(Scheme 4).16
A large number of reducing agents are available in literature
to carry out the conversion of cyclic imides into saturated
nitrogen heterocycles.17 LiAlH4 is one of the most
operationally simple reagents for this purpose. However, a
preliminary test using succinimide 7d revealed that LiAlH4
It is worth noting that the amount of pyrrole formed using
borane reagents with compounds 7 is negligible even at
reflux conditions. However, owing to the formation of an
acid–base complex between boron and pyrrolidine nitro-
gen, strong hydrolytic conditions must be applied to the
reaction mixture after reduction.
Table 1. Synthesis of 3-alkylsuccinimides 7
Entry
Alkenylimide 6
R
Alkylimide 7, yield (%)a
R1
R2
a
b
c
d
e
f
g
h
i
CH3
CH3CH2
H
H
H
H
H
H
H
H
CH3
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
Ph
95
98
96
99
97
96
80b
98
99
95
94
98
99
CH3CH2CH2
CH3(CH2)2CH2
CH3(CH2)3CH2
(CH3)2CH
Ph
HO(CH2)4CH2
CH3
–(CH2)5–
CH3
Scheme 6.
Table 2. Synthesis of 3-alkylpyrrolidines 8
j
k
l
Entry
Alkylimide 7
Alkylpyrrolidine 8
Yield (%)a
H
H
CH3
CH3CH2CH2
CH3
Ph
Ph
1
2
3
4
5
6
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
63
67
72
78
83
76
81
73
70
80
85
79
77
m
a
Yields of pure, isolated products.
Reduction has been carried out using NaBH4/NiCl2.
b
7
8
9
10
11
12
13
7 g
7 h
7i
7j
7k
7l
8 g
8 h
8i
8j
8k
8l
7m
8m
a
Scheme 4.
Yields of pure, isolated products.

R. Ballini et al. / Tetrahedron 59 (2003) 3603–3608
3605
3. Conclusions
C10H17NO2 (183.25) C, 65.54; H, 9.35; N, 7.64. Found C,
65.51; H, 9.38; N, 7.62.
Reaction of nitroalkanes to N-substituted maleimides
affords 3-alkylidenesuccinimides 6 by a tandem conjugate
addition–elimination process. Compounds 6 can be par-
tially reduced to 3-alkyl derivatives 7 by catalytic
hydrogenation. Further reduction of succinimides 7 with
BH3·Me2S complex gives 3-alkylpyrrolidines 8 in good
yield. This overall procedure provides a rapid entry to an
important class of synthetic intermediates.
4.2.4. 1-Ethyl-3-pentylpyrrolidin-2,5-dione, 7d. Yield
99%; oil; IR (cm21, neat) 1774, 1701, 1443, 1376; 1H
NMR d (ppm) 0.81 (t, 3H, J¼7.3 Hz), 1.08 (t, 3H,
J¼7.3 Hz), 1.18–1.48 (m, 7H), 1.76–1.90 (m, 1H), 2.22–
2.36 (m, 1H), 2.64–2.80 (m, 2H), 3.46 (q, 2H, J¼7.3 Hz).
Anal. calcd for C11H19NO2 (197.87) C, 66.97; H, 9.71; N,
7.10. Found C, 66.93; H, 9.73; N, 7.12.
4.2.5. 1-Ethyl-3-hexylpyrrolidin-2,5-dione, 7e. Yield
97%; oil; IR (cm21, neat) 1774, 1700, 1443, 1376; 1H
NMR d (ppm) 0.85 (t, 3H, J¼7.0 Hz), 1.12 (t, 3H,
J¼7.3 Hz), 1.20–1.36 (m, 7H), 1.38–1.54 (m, 2H), 1.80–
1.93 (m, 1H), 2.26–2.40 (m, 1H), 2.68–2.83 (m, 2H), 3.51
(q, 2H, J¼7.3 Hz). Anal. calcd for C12H21NO2 (211.30) C,
68.21; H, 10.02; N, 6.63. Found C, 68.25; H, 10.04; N, 6.60.
4. Experimental
4.1. General
1H NMR were recorded at 300 MHz on a Varian VXR300 in
CDCl3 as solvent. 13C NMR were recorded at 75 MHz in
CDCl3 as solvent. Microanalyses were performed with a
CHNS-O analyzer Model EA 1108 from Fisons Instru-
ments. IR spectra were recorded with a Perkin–Elmer
Paragon 500 FT-IR. GLC analyses were performed on a
Hewlett–Packard 5890 equipped with a capillary column of
fused silica (0.32 mm£25 m), stationary phase SE54. Mass
spectra were performed on a Hewlett–Packard GC/MS
5970 by means of the EI technique (70 eV). THF was dried
by refluxing it over sodium wire then distilled. All
chemicals used are available commercially. 3-Alkylidene-
succinimides 6 were prepared using a previously reported
method.10
4.2.6. 1-Ethyl-3-(2-methylpropyl)pyrrolidin-2,5-dione,
7f. Yield 96%; oil; IR (cm21, neat) 1774, 1701, 1443,
1376; 1H NMR d (ppm) 0.93 (d, 3H, J¼6.2 Hz), 0.97 (d, 3H,
J¼6.2 Hz) 1.17 (t, 3H, J¼7.3 Hz), 1.25–1.42 (m, 1H),
1.65–1.90 (m, 2H), 2.25–2.44 (m, 1H), 2.73–2.92 (m, 2H),
3.55 (q, 2H, J¼7.3 Hz). Anal. calcd for C10H17NO2
(183.25) C, 65.54; H, 9.35; N, 7.64. Found C, 65.58; H,
9.36; N, 7.63.
4.2.7. 1-Ethyl-3-(5-hydroxyhexyl)pyrroldin-2,5-dione,
7h. Yield 98%; oil; IR (cm21, neat) 1774, 1701, 1443,
1376; 1H NMR d (ppm) 1.12 (t, 3H, J¼6.2 Hz), 1.28–1.41
(m, 5H), 1.42–1.58 (m, 4H), 1.80–1.94 (m, 1H), 2.25–2.39
(m, 2H), 2.68–2.84 (m, 2H), 3.51 (q, 2H, J¼7.3 Hz), 3.61 (t,
2H, J¼6.6 Hz). Anal. calcd for C12H21NO3 (287.30) C,
63.41; H, 9.31; N, 6.16. Found C, 63.38; H, 9.34; N, 6.13.
4.2. General procedure for the preparation of 3-alkyl-
succinimides 7
3-Alkenylsuccinimide 6 (10 mmol) was dissolved in EtOAc
(100 mL) and 10% Pd/C (0.2 g) was added. The suspension
was hydrogenated at 2 atm at room temperature for 5 h and
then filtered on a celite pad. The clear solution was
evaporated at reduced pressure and the resulting alkyl-
succinimides showed a purity .98% by glc analysis.
4.2.8. 1-Ethyl-3-(1-methylethyl)pyrrolidin-2,5-dione,
7i.10b Yield 99%; oil; IR (cm21, neat) 1774, 1701, 1443,
1376; 1H NMR d (ppm) 1.01 (d, 3H, J¼6.6 Hz), 1.09 (d, 3H,
J¼6.9 Hz), 1.12 (t, 3H, J¼7.3 Hz), 2.36–2.54 (m, 1H),
2.58–2.71 (m, 1H), 2.81–2.88 (m, 1H), 2.95–3.04 (m, 1H),
3.55 (q, 2H, J¼7.3 Hz). Anal. calcd for C9H15NO2 (169.22)
C, 63.88; H, 8.93; N, 8.28. Found C, 63.93; H, 8.95; N, 8.25.
4.2.1. 1,3-Diethylpyrrolidin-2,5-dione, 7a. Yield 95%; oil;
IR (cm21, neat) 1774, 1701, 1443, 1376; 1H NMR d (ppm)
1.08 (t, 3H, J¼7.3 Hz), 1.16 (t, 3H, J¼7.3 Hz), 1.60–1.85
(m, 1H), 1.95–2.15 (m, 1H), 2.50–2.70 (m, 1H), 2.89–3.11
(m, 2H), 3.55 (q, 2H, J¼7.3 Hz). Anal. calcd for C8H13NO2
(155.19) C, 61.91; H, 8.44; N, 9.03. Found C, 61.97; H,
8.48; N, 8.98.
4.2.9. 3-Cyclohexyl-1-ethylpyrrolidin-2,5-dione, 7j. Yield
95%; oil; IR (cm21, neat) 1774, 1701, 1443, 1376; 1H NMR
d (ppm) 1.00–1.50 (m, 6H), 1.15 (t, 3H, J¼7.3 Hz), 1.60–
1.85 (m, 4H), 1.85–2.05 (m, 1H), 2.40–2.80 (m, 3H), 3.55
(q, 2H, J¼7.3 Hz). Anal. calcd for C12H19NO2 (209.28) C,
68.87; H, 9.15; N, 6.69. Found C, 68.83; H, 9.18; N, 6.71.
4.2.2. 1-Ethyl-3-propylpyrrolidin-2,5-dione, 7b. Yield
98%; oil; IR (cm21, neat) 1774, 1701, 1443, 1376; 1H
NMR d (ppm) 0.96 (t, 3H, J¼7.3 Hz), 1.16 (t, 3H,
J¼7.3 Hz), 1.30–1.60 (m, 3H), 1.80–1.98 (m, 1H), 2.26–
2.46 (m, 1H), 2.71–2.90 (m, 2H), 3.55 (q, 2H, J¼7.3 Hz).
Anal. calcd for C9H15NO2 (169.22) C, 63.88; H, 8.93; N,
8.28. Found C, 63.82; H, 8.96; N, 8.24.
4.2.10. 3-Ethyl-1-phenylpyrrolidin-2,5-dione, 7k. Yield
95%; oil; IR (cm21, neat) 1774, 1701, 1443, 1376; 1H NMR
d (ppm) 1.08 (t, 3H, J¼7.3 Hz), 1.60–1.85 (m, 1H), 1.95–
2.15 (m, 1H), 2.50–2.70 (m, 1H), 2.89–3.11 (m, 2H), 7.24–
7.60 (m, 5H). Anal. calcd for C12H13NO2 (203.24) C, 70.92;
H, 6.45; N, 6.89. Found C, 70.88; H, 6.47; N, 6.91.
4.2.3. 3-Butyl-1-ethylpyrrolidin-2,5-dione, 7c. Yield 96%;
1
4.2.11. 3-Butyl-1-phenylpyrrolidin-2,5-dione, 7l. Yield
98%; oil; IR (cm21, neat) 1774, 1701, 1443, 1376; 1H NMR
d (ppm) 0.97 (t, 3H, J¼7.0 Hz), 1.34–1.48 (m, 4H), 1.56–
1.80 (m, 1H), 1.94–2.12 (m, 1H), 2.50–2.70 (m, 1H), 2.90–
3.12 (m, 2H), 7.28–7.55 (m, 5H). Anal. calcd for
oil; IR (cm21, neat) 1774, 1701, 1443, 1376; H NMR d
(ppm) 0.92 (t, 3H, J¼7.0 Hz), 1.15 (t, 3H, J¼7.3 Hz), 1.30–
1.60 (m, 4H), 1.80–2.00 (m, 2H), 2.25–2.47 (m, 1H), 2.69–
2.90 (m, 2H), 3.55 (q, 2H, J¼7.3 Hz). Anal. calcd for

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R. Ballini et al. / Tetrahedron 59 (2003) 3603–3608
C14H17NO2 (231.29) C, 72.70; H, 7.41; N, 6.06. Found C,
72.75; H, 7.40; N, 6.09.
2.58 (m, 4H), 2.65–2.92 (m, 2H). 13C NMR d (ppm) 12.2,
13.8, 20.7, 33.5, 34.5, 43.1, 48.2, 52.9, 62.9. MS m/z (%):
141 (Mþ, 15), 140 (18), 126 (100), 71 (25), 55 (16), 42 (16),
29 (5). Anal. calcd for C9H19N (141.25) C, 76.53; H, 13.56;
N, 9.92. Found C, 76.48; H, 13.53; N, 9.95.
4.2.12. 3-(1-Methylethyl)-1-phenylpyrrolidin-2,5-dione,
7m. Yield 99%; oil; IR (cm21, neat) 1774, 1701, 1443,
1376; 1H NMR d (ppm) 1.01 (d, 3H, J¼6.6 Hz), 1.09 (d, 3H,
J¼6.9 Hz), 2.36–2.54 (m, 1H), 2.58–2.71 (m, 1H), 2.81–
2.88 (m, 1H), 2.95–3.04 (m, 1H), 7.25–7.55 (m, 5H). Anal.
calcd for C13H15NO2 (217.26) C, 71.87; H, 6.96; N, 6.45.
Found C, 71.91; H, 6.99; N, 6.43.
1
4.3.3. 3-Butyl-1-ethylpyrrolidine, 8c. Yield 72%; oil; H
NMR d (ppm) 0.90 (t, 3H, J¼6.6 Hz), 1.11 (t, 3H,
J¼7.3 Hz), 1.20–1.43 (m, 6H), 1.90–2.20 (m, 3H), 2.26–
2.56 (m, 4H), 2.64–2.90 (m, 2H). 13C NMR d (ppm) 12.2,
14.0, 22.5, 29.6, 30.1, 33.3, 43.1, 47.9, 52.8, 62.6. MS m/z
(%): 155 (Mþ, 14), 154 (15), 140 (100), 126 (8), 98 (8), 82
(15), 71 (24), 55 (18), 42 (21), 29 (11). Anal. calcd for
C10H21N (155.28) C, 77.35; H, 13.63; N, 9.03. Found C,
77.40; H, 13.59; N, 9.00.
4.2.13. 1-Ethyl-3-phenylmethylpyrrolidin-2,5-dione, 7g.
Alkenylimide 6g (2 mmol) was added to a solution of
NiCl2·6H2O (3.32 g) in MeOH–THF (3:1, 65 mL). The
mixture was cooled at 08C by ice bath and then NaBH4
(40 mmol, 1.52 g) was added portionwise over 30 min. The
black slurry was stirred at room temperature for 4 h and then
filtered over a short pad of Florisilw. The Florisilw pad was
washed with CH2Cl2 (3£10 mL) and then the collected
solutions were evaporated at reduced pressure. The crude
alkylimide 7g was purified by column chromatography (8:2
hexanes–ethyl acetate) giving 0.35 g (80%) of pure product
as an oil. IR (cm21, neat) 1774, 1701, 1443, 1376; 1H NMR
d (ppm) 1.12 (t, 3H, J¼7.3 Hz), 2.37–2.51 (m, 1H), 2.62–
2.72 (m, 1H), 2.84–2.98 (m, 1H), 3.06–3.28 (m, 2H), 3.57
(q, 2H, J¼7.3 Hz), 7.15–7.40 (m, 5H). Anal. calcd for
C13H15NO2 (217.26) C, 71.87; H, 6.96; N, 6.45. Found C,
71.90; H, 6.99; N, 6.47.
4.3.4. 1-Ethyl-3-pentylpyrrolidine, 8d. Yield 78%; oil; 1H
NMR d (ppm) 0.90 (t, 3H, J¼6.2 Hz), 1.11 (t, 3H,
J¼7.3 Hz), 1.20–1.46 (m, 9H), 1.70–2.24 (m, 2H), 2.28–
2.58 (m, 4H), 2.65–2.79 (m, 1H), 2.80–2.91 (m, 1H). 13C
NMR d (ppm) 12.2, 14.1, 22.7, 28.5, 29.4, 31.0, 33.2, 41.7,
47.9, 52.3, 62.5. MS m/z (%): 169 (Mþ, 14), 168 (15), 154
(100), 140 (12), 98 (6), 82 (13), 71 (20), 58 (14), 42 (14), 29
(8). Anal. calcd for C11H23N (169.31) C, 78.03; H, 13.69; N,
8.27. Found C, 77.99; H, 13.72; N, 8.24.
4.3.5. 1-Ethyl-3-hexylpyrrolidine, 8e. Yield 83%; 1H
NMR d (ppm) 0.90 (t, 3H, J¼6.2 Hz), 1.11 (t, 3H,
J¼7.3 Hz), 1.22–1.45 (m, 11H), 1.80–2.20 (m, 2H),
2.28–2.56 (m, 4H), 2.64–2.89 (m, 2H). 13C NMR d
(ppm) 12.2, 14.1, 22.7, 26.9, 29.1, 30.3, 31.9, 32.9, 43.1,
47.9, 52.3, 62.3. MS m/z (%): 183 (Mþ, 13), 184 (14), 168
(100), 154 (9), 126 (4), 98 (6), 82 (10), 71 (17), 58 (14), 29
(5). Anal. calcd for C12H25N (183.33) C, 78.62; H, 13.74; N,
7.64. Found C, 78.57; H, 13.71; N, 7.66.
4.3. General procedure for the preparation of 3-
alkylpyrrolidines 8
Succinimide 7 (5 mmol) was dissolved in dry THF (70 mL),
and the solution was cooled at 08C by ice bath. BH3·Me2S
(25 mmol, 2.5 mL, 10 M in THF) was then added dropwise
over 30 min and after removal of the cooling bath the
mixture was refluxed for 3 h. The reaction mixture was then
cooled at room temperature and the excess of BH3 was
eliminated by dropwise addition of MeOH (10 mL). After
removal of the solvent at reduced pressure the residue was
dissolved in MeOH (25 mL) and then 37% HCl (5 mL) was
added. The mixture was refluxed for 3 h and the solvent was
then evaporated at reduced pressure. The crude pyrrolidine
hydrochloride was dissolved in 4N NaOH (15 mL) and the
resulting solution was saturated with NaCl. The solution
was extracted with CH2Cl2 (3£20 mL) and dried over
Na2SO4. After evaporation of the solvent at reduced
pressure the crude pyrrolidine was purified by column
chromatography (8:4:1:0.1 hexane–ethyl acetate–ethanol–
38% NH4OH).
4.3.6. 1-Ethyl-3-(2-methylpropyl)pyrrolidine, 8f. Yield
76%; oil; 1H NMR d (ppm) 0.88 (d, 3H, J¼6.6 Hz), 0.89 (d,
3H, J¼6.6 Hz), 1.11 (t, 3H, J¼7.3 Hz), 1.65–1.80 (m, 4H),
1.85–1.95 (m, 2H), 2.25–2.54 (m, 4H), 2.68–2.79 (m, 2H).
13C NMR d (ppm) 12.2, 22.3, 22.5, 27.9, 33.7, 40.3, 41.2,
47.9, 52.7, 63.0. MS m/z (%): 155 (Mþ, 20), 154 (17), 140
(100), 112 (5), 96 (7), 71 (22), 58 (25), 42 (14), 29 (5). Anal.
calcd for C10H21N (155.28) C, 77.35; H, 13.63; N, 9.03.
Found C, 77.31; H, 13.60; N, 9.05.
4.3.7. 1-Ethyl-3-phenylmethylpyrrolidine, 8g. Yield 81%;
oil; 1H NMR d (ppm) 1.07 (t, 3H, J¼7.3 Hz), 1.42–1.54 (m,
1H), 1.88–2.01 (m, 1H), 2.15–2.30 (m, 1H), 2.37–2.54
(m, 4H), 2.59–2.73 (m, 4H), 7.12–7.28 (m, 5H). 13C
NMR d (ppm) 14.1, 30.7, 39.0, 41.8, 50.6, 53.9, 60.0, 126.0,
128.4, 128.9, 141.2. MS m/z (%): 189 (Mþ, 33), 188
(28), 174 (100), 131 (24), 111 (14), 97 (47), 91 (42), 82 (25),
71 (20), 65 (16), 42 (19). Anal. calcd for C13H19N (189.30)
C, 82.48; H, 10.12; N, 7.40. Found C, 82.43; H, 10.15; N,
7.38.
4.3.1. 1,3-Diethylpyrrolidine, 8a. Yield 63%; oil; 1H NMR
d (ppm) 1.00 (t, 3H, J¼7.3 Hz), 1.11 (t, 3H, J¼7.3 Hz),
1.20–1.30 (m, 2H), 1.62–1.90 (m, 3H), 2.29–2.57 (m, 4H),
2.64–2.91 (m, 2H). 13C NMR d (ppm) 11.5, 12.2, 25.5,
32.1, 44.8, 47.7, 52.5, 61.5. MS m/z (%): 127 (Mþ, 22), 126
(23), 112 (100), 82 (8), 71 (19), 55 (10), 42 (18), 29 (4).
Anal. calcd for C8H17N (127.23) C, 75.52; H, 13.47; N,
11.01. Found C, 75.47; H, 13.50; N, 11.04.
4.3.8. 1-Ethyl-3-(5-hydroxyhexyl)pyrrolidine, 8h. Yield
1
73%; H NMR d (ppm) 1.06 (t, 3H, J¼7.3 Hz), 1.20–1.40
(m, 10H), 1.46–1.57 (m, 2H), 1.62–1.53 (m, 1H), 1.79–
2.14 (m, 2H), 2.20 (bs, 1H), 2.27–2.50 (m, 2H), 2.61–2.71
(m, 1H), 2.76–2.83 (m, 1H), 3.58 (t, 2H, J¼6.7 Hz). 13C
NMR d (ppm) 13.5, 25.5, 28.1, 29.2, 30.5, 32.5, 35.3, 37.1,
4.3.2. 1-Ethyl-3-propylpyrrolidine, 8b. Yield 67%; oil; 1H
NMR d (ppm) 0.90 (t, 3H, J¼7.0 Hz), 1.11 (t, 3H,
J¼7.3 Hz), 1.24–1.46 (m, 4H), 1.64–2.00 (m, 3H), 2.30–

R. Ballini et al. / Tetrahedron 59 (2003) 3603–3608
3607
50.2, 53.4, 60.0, 62.5. MS m/z (%): 199 (Mþ, 9), 198 (15),
184 (100), 140 (12), 100 (39), 71 (34), 58 (31), 43 (37), 44
(37), 32 (44). Anal. calcd for C12H25NO (199.33) C, 72.31;
H, 12.64; N, 7.03. Found C, 72.29; H, 12.61; N, 7.00.
References
1. Review (a) Mitchinson, A.; Nadin, A. J. Chem. Soc. Perkin
`
Trans. 1 2000, 2862–2892. (b) Pinchon, M.; Figadere, B.
Tetrahedron: Asymmetry 1996, 7, 927–964.
4.3.9. 1-Ethyl-3-(1-methylethyl)pyrrolidine, 8i. Yield
1
2. For some recent examples see: (a) Verma, S. K.; Atanes, M. N.;
Busto, J. H.; Thai, D. L.; Rapoport, H. J. Org. Chem. 2002, 67,
1314–1318. (b) Schlummer, B.; Hartwig, J. F. Org. Lett. 2002,
4, 1471–1474. (c) Palacios, F.; Alonso, C.; Amezua, P.;
Rubiales, G. J. Org. Chem. 2002, 67, 1941–1946. (d) Smith,
S. C.; Bentley, P. D. Tetrahedron Lett. 2002, 43, 899–902.
70%; oil; H NMR d (ppm) 1.00 (d, 6H, J¼6.2 Hz), 1.11
(t, 3H, J¼7.3 Hz), 1.50–1.75 (m, 2H), 1.87–2.06 (m, 1H),
2.08–2.23 (m, 1H), 2.30–2.58 (m, 4H), 2.65–2.92 (m, 2H).
13C NMR d (ppm) 12.2, 18.6, 20.6, 26.8, 31.1, 32.1, 48.0,
53.3, 59.8. MS m/z (%): 141 (Mþ, 20), 140 (20), 126 (100),
83 (12), 71 (18), 55 (11), 42 (11), 29 (4). Anal. calcd for
C9H19N (141.25) C, 76.53; H, 13.56; N, 9.92. Found C,
76.59; H, 13.59; N, 9.89.
¨
(e) Karlsson, S.; Hogberg, H.-E. Tetrahedron: Asymmetry
2001, 712, 1977–1982.
3. (a) Krow, G. R.; Yuan, J.; Lin, G.; Sonnet, P. E. Org. Lett.
2002, 4, 1259–1262. (b) Greenwood, E. S.; Parsons, P. J.
Synlett 2002, 167–169. (c) Li, Z.; Feiten, H.-J-; Chang, D.;
Duetz, W. A.; van Beilen, J. B.; Witholt, B. J. Org. Chem.
2001, 66, 8424–8430.
4.3.10. 3-Cyclohexyl-1-ethylpyrrolidine, 8j. Yield 85%;
oil; 1H NMR d (ppm) 1.07 (t, 3H, J¼7.3 Hz), 1.55–1.95 (m,
14H), 1.99–2.10 (m, 1H), 2.20–2.52 (m, 3H), 2.70–2.86
(m, 2H). 13C NMR d (ppm) 13.6, 26.2, 28.6, 30.0, 31.7,
32.0, 44.9, 50.5, 53.6, 58.4, 61.8. MS m/z (%): 181 (Mþ, 17),
180 (16), 166 (100), 98 (5), 81 (13), 71 (20), 58 (17), 41
(10). Anal. calcd for C12H23N (181.32) C, 79.49; H, 12.79;
N, 7.72. Found C, 79.45; H, 12.82; N, 7.75.
4. Reviews: (a) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron
2000, 56, 3817–3856. (b) De Koning, H.; Speckamp, W. N.
Stereoselective Synthesis (Houben-Weyl); Helmchen, G.,
Hoffman, R. W., Mulzer, J., Schaumann, E., Eds.; Georg
Thieme: Stuttgart, 1995; Vol. E21, pp 1953–2009.
5. (a) Enders, D.; Teschner, P.; Raabe, G.; Runsink, J. Eur.
J. Org. Chem. 2001, 4463–4477. (b) Zhang, X.; Jang, W.;
Schmitt, A. C. Tetrahedron Lett. 2001, 42, 4943–4945.
(c) Hitchcock, P. B.; Starkmann, B. A.; Young, D. W.
Tetrahedron Lett. 2001, 42, 2381–2384. (d) Cossy, J.;
Tresnard, L.; Belotti, D.; Gomez Pardo, D. Tetrahedron Lett.
2001, 42, 251–254.
4.3.11. 3-Ethyl-1-phenylpyrrolidine, 8k. Yield 85%; oil;
1H NMR d (ppm) 0.98 (t, 3H, J¼7.5 Hz), 1.42–1.70 (m,
3H), 2.09–2.28 (m, 2H), 2.86–2.92 (m, 1H), 3.22–3.47 (m,
3H), 6.50–6.68 (m, 3H), 7.18–7.27 (m, 2H). 13C NMR d
(ppm) 12.8, 26.8, 31.4, 40.6, 47.5, 53.3, 111.4, 115.27,
129.12, 148.0. MS m/z (%): 175 (Mþ, 68), 174 (68), 144 (9),
119 (33), 104 (30), 91 (100), 77 (44), 51 (13), 41 (9). Anal.
calcd for C12H17N (175.27) C, 82.23; H, 9.78; N, 7.99.
Found C, 82.18; H, 9.82; N, 8.03.
¨
6. Chihab-Eddine, A.; Daıch, A.; Jilale, A.; Decroix, B.
Tetrahedron Lett. 2001, 42, 573–576.
7. (a) Curran, D. P.; Geib, S.; De Mello, N. Tetrahedron 1999,
55, 5681–5704. (b) Mikami, T.; Harada, M.; Narasaka, K.
Chem. Lett. 1999, 425–426. (c) Gutemberger, G.; Steckhan,
E.; Blechert, S. Angew. Chem. Int. Ed. 1998, 37, 660–662.
(d) Meggers, E.; Steckhan, E.; Blechert, S. Angew. Chem. Int.
Ed. 1995, 34, 2137–2139.
4.3.12. 3-Butyl-1-phenylpyrrolidine, 8l.19 Yield 79%; oil;
1H NMR d (ppm) 0.92 (t, 3H, J¼6.2 Hz), 1.25–1.58 (m,
4H), 1.62–1.97 (m, 3H), 2.12–2.40 (m, 2H), 2.90–3.06
(m, 1H), 3.33–3.60 (m, 3H), 6.50–6.68 (m, 3H), 7.18–7.27
(m, 2H). 13C NMR d (ppm) 14.0, 22.5, 29.9, 30.4, 34.6,
44.3, 47.5, 54.3, 111.5, 115.4, 129.1, 148.0. MS m/z (%):
203 (Mþ, 88), 202 (72), 144 (16), 119 (38), 106 (57), 91
(100), 77 (42), 55 (12), 41 (12), 29 (10). Anal. calcd for
C14H21N (203.32) C, 82.70; H, 10.41; N, 6.89. Found C,
82.65; H, 10.38; N, 6.86.
8. Cunningham, I. D.; Brownhill, A.; Hamerton, I.; Howlin, B.
Tetrahedron 1997, 53, 13473–13494.
9. (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-
VCH: New York, 2001. (b) Perlmutter, P. Conjugate
Addition Reactions in Organic Synthesis; Pergamon: Oxford,
1992.
10. (a) Ballini, R.; Bosica, G. Tetrahedron 1995, 51, 4213–4222.
(b) Ballini, R.; Bosica, G. Liebigs Ann. 1996, 2087–2089.
11. Ballini, R.; Barboni, L.; Bosica, G.; Petrini, M. Synlett 2000,
391–393.
4.3.13. 3-(1-Methylethyl)-1-phenylpyrrolidine, 8m. Yield
77%; waxy solid; 1H NMR d (ppm) 1.00 (d, 6H, J¼6.2 Hz),
1.50–1.75 (m, 2H), 1.87–2.06 (m, 1H), 2.08–2.23 (m, 1H),
2.90–3.00 (m, 1H), 3.22–3.50 (m, 3H), 6.50–6.68 (m, 3H),
7.18–7.27 (m, 2H). 13C NMR d (ppm) 21.4, 21.8, 30.5,
32.7, 46.7, 48.1, 52.5, 112.5, 115.4, 129.3, 148.1. MS m/z
(%): 189 (Mþ, 67), 188 (56), 146 (12), 119 (36), 104 (31),
91 (100), 77 (46), 51 (11), 41 (16). Anal. calcd for C13H19N
(189.30) C, 82.48; H, 10.12; N, 7.40. Found C, 82.51; H,
10.08; N, 7.38.
12. Ballini, R.; Bosica, G.; Fiorini, D.; Giarlo, G. Synthesis 2001,
2003–2006.
13. Ballini, R.; Bosica, G.; Fiorini, D.; Gil, M. V.; Petrini, M. Org.
Lett. 2001, 3, 1265–1267.
`
14. Ballini, R.; Bosica Mase, A.; Petrini, M. Eur. J. Org. Chem.
2000, 2927–2931.
15. Katritzky, A. R.; Yao, J.; Qi, M.; Chou, Y.; Sikora, D. J.;
Davis, S. Hetrocycles 1998, 48, 2677–2691.
16. (a) Ballini, R.; Bosica, G. Synlett 1996, 1115–1116. For a
review on this reducing couple see: (b) Ganem, B.; Osby, J. O.
Chem. Rev. 1986, 86, 763–780.
Acknowledgements
Financial support from University of Camerino and
17. (a) Tsuzuki, Y.; Chiba, K.; Hino, K. Tetrahedron: Asymmetry
2001, 12, 1793–1799. (b) Zhang, H. K.; Chen, Q. F.; Huang,
P. Q. Synth. Commun. 2000, 30, 2431–2444. (c) Rao, V. D.;
Perisamy, M. Synthesis 2000, 703–706. (d) Kuwano, R.;
`
`
MIUR (National Project ‘Sintesi e Reattivita–attivita di
Sistemi Insaturi Funzionalizzati’) is gratefully
acknowledged.

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