A new 'one-pot' synthesis of 2-substituted 3-nitro pyrrolidines through a multicomponent domino reaction

Article abstract of DOI:10.1016/j.tetlet.2003.12.071

An efficient 'one-pot' synthesis of the title compounds based on a multicomponent domino reaction between imines and 3-nitro-1-propanol methanesulfonate has been developed.

Full text of DOI:10.1016/j.tetlet.2003.12.071

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1373–1375
A new Ôone-potÕ synthesis of 2-substituted 3-nitropyrrolidines
through a multicomponent domino reaction
Nikla Baricordi,a Simonetta Benetti,a,* Gisella Biondini,a Carmela De Risib
and Gian P. Pollinib
aDipartimento di Chimica, Universitꢀa di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy
bDipartimento di Scienze Farmaceutiche, Universitꢀa di Ferrara, Via Fossato di Mortara 19, 44100 Ferrara, Italy
Received 5 November 2003; revised 24November 2003; accepted 11 December 2003
Abstract—An efficient Ôone-potÕ synthesis of the title compounds based on a multicomponent domino reaction between imines and
3-nitro-1-propanol methanesulfonate has been developed.
Ó 2003 Elsevier Ltd. All rights reserved.
Pyrrolidines are ubiquitous structural units in many
naturally occurring alkaloids with biological activity,
such as hygrine, nicotine, tropine or cocaine, and in drug
and drug candidates displaying a wide variety of activ-
ities.1 Other compounds having this moiety include
amino acids such as proline or kainic acid. Furthermore,
these heterocyclic rings are of interest in synthetic
organic chemistry as chiral auxiliaries2 as well as for
their unique ability to induce well-defined molecular
architecture in peptidomimetic compounds.3 As a result,
much effort has been expended on the development of
stereocontrolled syntheses of substituted pyrrolidines.4;5
in preliminary form the results of our recent efforts de-
voted to the synthesis of functionalized pyrrolidines.
The new methodology allowed us to prepare 2-substi-
tuted 3-nitro-pyrrolidines 5a–k (Scheme 1) through a
one-pot process, which can be defined both as an aza-
Henry6 and a nitro-Mannich reaction7 between imines
3a–k and 3-nitro-1-propanol methanesulfonate 4. This
hitherto unknown compound8 was efficiently prepared
by esterification with triethylamine/methanesulfonyl
chloride of the readily available 3-nitro-1-propanol, in
turn conveniently prepared by sodium borohydride
reduction of the corresponding aldehyde.9
Recently multicomponent reactions have attracted a
great deal of interest due to the possibility of generating
molecular diversity in a minimum number of steps. As a
part of our continuous interest directed towards the
development of new methodologies for the synthesis of
five- and six-membered nitrogen heterocycles, we report
We anticipated that this bifunctional reagent could take
part in a domino sequence initiated by addition to the
carbon–nitrogen double bond of an imine derivative by
virtue of the well-known properties of the nitro group
followed by subsequent intramolecular substitution of
O2N
OMs
O2N
R
4
MgSO4
R-CH=N-R1
R-CHO
+
R1NH2
N
R1
DABCO (cat)
or basic Al2O3
1
2
3a-k
5a-k
Scheme 1.
Keywords: Multicomponent domino reactions; Aza-Henry reactions; Nitro-Mannich reactions; Pyrrolidines.
* Corresponding author. Tel.: +39-532291174; fax: +39-532240709; e-mail: bns@ifeuniv.unife.it
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.071

1374
N. Baricordi et al. / Tetrahedron Letters 45 (2004) 1373–1375
Table 1
Entry
Aldehydes R
Amines R1
Aldimines
Pyrrolidinesa (% yield)
General procedure
1
2
CH3
C2H5
C3H7
Bn
Bn
3a
3b
3c
3d
3e
3f
5a (63)
5b (65)
5c (65)
5d (90)
5e (89)
5f (70)
5g (55)
5h (67)
5i (70)
(69)b;e
A
A
A
A
A
A
B
B
B
B
3
Bn
Bn
4
n-C6H13
n-C9H19
C6H5
5
Bn
Bn
6
7
3-Pyridyl
3-Pyridyl
C6H5
Bn
C6H5
3g
3h
3i
8
9
10
C6H5
C6H5CH(CH3)
n-C7H15
3j5j
5k (52)c;e
A
B
O
O
11
Bn
3k
(67)d;e
a Isolated yields after flash chromatography.
b 9:1 mixture of diastereomers.
c 3:1 mixture of diastereomers.
d 4:1 mixture of diastereomers.
e Dr values were measured by HPLC.
the mesyl moiety by nucleophilic attack of the b-nitro-
amine generated during the first addition.
satisfactory diastereoisomeric excess. Our results are
summarized in Table 1.
Initial attempts to carry out the reaction simply by
mixing equimolar amounts of the three components,
namely aldehyde, amine and 3-nitro-1-propanol me-
thanesulfonate in dichloromethane at room temperature
produced very low yields of the expected product (5–
15%). However, we were able to optimize the reaction
conditions by separately forming the aldimine compo-
nent (prepared by treating equimoleculars amounts of
aldehyde and amine in the presence of anhydrous
magnesium sulfate) followed by reaction with 1 equiv of
3-nitro-1-propanol methanesulfonate in the presence of
a catalytic amount of DABCO or basic aluminium
oxide.10
These preliminary results demonstrate that the meth-
odology reported here represents a new short and effi-
cient route to the preparation of 2,3-disubstituted
pyrrolidines starting from very simple materials, such as
aldehydes and 3-nitro-1-propanol methanesulfonate.
This strategy is widely applicable to the synthesis of
both simple and complex structures enabling the prep-
aration of additional compounds owing to the versatility
of the nitro group.12 As an example, the pyrrolidine 5g
could be easily converted to a nicotine precursor13 by
tributyltin hydride-promoted radical substitution of the
nitro group by hydrogen.
In this way, the expected pyrrolidines 5a–k were formed
in satisfactory yields (52–90%) in most cases as a single
diastereomer, namely that possessing the trans-stereo-
chemistry between the nitro group at position 3 and the
substituent at position 2, the cis-isomer being in some
cases present in trace amounts.11 The structures of
compounds 5a–k could be unambiguously assigned by
1H NMR analysis on the basis of the low value of the
coupling constant between H-2 and H-3 (J ¼ 0–2.5 Hz),
which is consistent with a ꢀ90° dihedral angle.
In conclusion, we have identified suitable conditions
employing an experimentally simple pathway for the
synthesis of 2-substituted 3-nitro-pyrrolidines, which are
useful building blocks in organic synthesis. We are now
actively studying a new catalytic version of this strategy
inspired by the recent attention dedicated to the asym-
metric version14 of the nitro-Mannich reaction as a tool
for the synthesis of 1,2-diamines.
Acknowledgements
Moreover, we have also tried to induce asymmetry in
our protocol using chiral amine or aldehyde compo-
nents. To this end, we investigated the reaction of the
imine component 3j derived from (S)-())-phenylethyl-
amine and 1-heptanal with 3-nitro-1-propanol me-
thanesulfonate, which afforded the expected pyrrolidine
5j with good asymmetric induction (de 80% by HPLC).
We wish to thank the Ministry of University (MIUR)
for financial support (PRIN 2002).
References and notes
Analogously, the reaction of the aldimine 3k derived
from D-glyceraldehyde-isopropylidene acetal and benz-
1. OÕHagan, D. Nat. Prod. Rev. 2000, 17, 435–446, and
previous annual reports in this series.
ylamine with 3-nitro-1-propanol methanesulfonate pro-
duced the expected pyrrolidines 5k in good yield and
2. Wang, Q.; Sasaki, N. A.; Riche, C.; Potier, P. J. Org.
Chem. 1999, 64, 8602–8607, and references cited therein.

N. Baricordi et al. / Tetrahedron Letters 45 (2004) 1373–1375
1375
3. Millet, R.; Domarkas, J.; Rombaux, P.; Rigo, B.; Houssin,
R.; Henichart, J.-P. Tetrahedron Lett. 2002, 34, 5087–
5088.
ꢀ
4. Pichon, M.; Figadere, B. Tetrahedron: Asymmetry 1996, 7,
927–964.
5. Hartley, R. C.; Caldwell, S. T. J. Chem. Soc., Perkin
Trans. 1 2000, 477–501.
6. Westerman, B. Angew. Chem., Int. Ed. 2003, 42, 151–153.
7. Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K.
J. Org. Chem. 1998, 63, 9932–9934.
J ¼ 6.6 Hz), 1.20–1.88 (10H, m), 2.40–2.70 (2H, m), 2.52
(1H, ddd, J ¼ 10.2, 6.4, 6.6 Hz), 2.98 (1H, dt, J ¼ 8.0,
2.4Hz), 3.05 (1H, ddd, J ¼ 10.2, 7.8, 3.8 Hz), 3.38 (1H, d,
J ¼ 13.0 Hz), 4.00 (1H, d, J ¼ 13.0 Hz), 4.73 (1H, ddd,
J ¼ 8.2, 4.6, 2.4 Hz), 7.20–7.40 (5H, m); 13C NMR
(75 MHz, CDCl3) d: 14.3, 22.4, 25.1, 29.6, 30.2, 32.0,
32.8, 52.5, 58.3, 69.9, 90.0, 127.4, 128.6, 128.9, 138.3. 5e:
1
oil; IR (film): 1540 cmÀ1; H NMR (300 MHz, CDCl3) d:
0.89 (3H, t, J ¼ 6.4Hz), 1.19–1.82 (16H, m), 2.05–2.40
(2H, m), 2.50–2.31 (1H, m), 2.94(1H, dt, J ¼ 8.8, 2.2 Hz),
2.95–3.10 (1H, m), 3.35 (1H, d, J ¼ 14Hz), 4.00 (1H, d,
J ¼ 14.0 Hz), 4.73 (1H, ddd, J ¼ 7.4, 4.2, 2.2 Hz), 7.20–7.40
(5H, m); 13C NMR (75 MHz, CDCl3) d: 14.2, 22.6, 25.0,
29.4, 30.0, 30.1, 30.2, 30.3, 31.8, 32.6, 52.4, 58.2, 69.7, 89.5,
127.2, 128.4, 128.8, 138.8. 5f: mp 45.5 °C; IR (nujol):
1540 cmÀ1; 1H NMR (300 MHz, CDCl3) d: 2.39–2.45 (2H,
m), 2.60–2.75 (1H, m), 3.15–3.20 (1H, m), 3.21 (1H, d,
J ¼ 12.8 Hz), 3.85 (1H, d, J ¼ 12.8 Hz), 3.95 (1H, d,
J ¼ 2.5 Hz), 4.82 (1H, ddd, J ¼ 9.5, 6, 2.5 Hz), 7.21–7.55
(10H, m); 13C NMR (75 MHz, CDCl3) d: 29.6, 51.6, 57.3,
74.1, 92.3, 127.3, 127.7, 128.4, 128.7, 129.0, 129.1, 138.3,
8. Preparation of 3-nitro-1-propanol methanesulfonate 4: To
a cooled (0 °C) solution of 3-nitro-1-propanol9 (2 g,
1.9 mmol) in dichloromethane (4mL), methanesulfonyl
chloride (2.18 g, 1.9 mmol) and triethylamine (1.92 g,
1.9 mmol) were added. After stirring at 0 °C for 15 min
the reaction mixture was washed with brine, dried (anhy-
drous Na2SO4) and the solvent evaporated under reduced
pressure. The crude oil was dissolved in dichloromethane
and rapidly passed through a short column of Florisilâ
(Fluka, 60–100 mesh).
IR (film): 1540, 1360, 1340, 1160 cmÀ1
;
1H NMR
1
(300 MHz, CDCl3) d: 2.21 (quintet, 2H, J ¼ 7 Hz, CH2),
3.05 (s, 3H, CH3OSO3), 4.18 (t, 2H, J ¼ 7 Hz, CH2OMs),
4.56 (t, 2H, J ¼ 7 Hz, CH2NO2); 13C NMR (75 MHz,
CDCl3) d: 26.8, 37.4, 65.6, 71.2.
139.2. 5g: oil; IR (film): 1540 cmÀ1; H NMR (300 MHz,
CDCl3) d: 2.35–2.55 (2H, m), 2.60–2.70 (1H, m), 3.20–3.41
(1H, m), 3.45 (1H, d, J ¼ 12.8 Hz), 3.78 (1H, d,
J ¼ 12.8 Hz), 4.00 (1H, d, J ¼ 6.0 Hz), 4.68–4.78 (1H, m),
7.19–7.35 (5H, m), 7.43 (1H, dd, J ¼ 7.8, 5.2 Hz), 7.90 (1H,
dt, J ¼ 7.8, 1.8 Hz), 8.70 (1H, dd, J ¼ 5.2, 1.8 Hz), 8.80
(1H, s); 13C NMR (75 MHz, CDCl3) d: 29.7, 31.7, 37.3,
71.3, 91.7, 124.3, 127.3, 128.4, 128.6, 135.7, 136.3, 137.5,
149.2, 149.7. 5h: mp 119 °C (1:1 ether/petroleum ether); IR
€
€
9. (a) Ohrlein, R.; Schwab, W.; Ehrler, R.; Jager, V. Synthesis
€
1986, 535–538; (b) Griesser, H.; Ohrlein, R.; Schwab, W.;
€
Ehrler, R.; Jager, V. Org. Synth. 1999, 77, 236.
10. General procedure A: A mixture of aldehyde (0.1 mmol),
amine (0.1 mmol) and anhydrous MgSO4 (1.5 g) in CH2Cl2
(4mL) was stirred at room temperature for 12 h. The solid
was removed by filtration and the solvent was reduced to
half of its original volume in vacuo. Nitro derivative 4
(0.1 mmol) and a catalytic amount of DABCO were added
and the reaction mixture was stirred overnight. After
removal of the solvent under reduced pressure the residual
oil was purified by flash chromatography (ethyl acetate/
cyclohexane).
1
(nujol): 1540 cmÀ1; H NMR (300 MHz, CDCl3) d: 2.41–
2.59 (1H, m), 2.79–2.91 (1H, m), 3.65–3.81 (1H, m), 3.85–
3.98 (1H, m), 4.90 (1H, d, J ¼ 6.0 Hz), 5.40 (1H, s), 6.50
(2H, d, J ¼ 7.8 Hz), 6.76 (1H, t, J ¼ 7.8 Hz), 7.16 (2H, d,
J ¼ 7 Hz), 7.24(1H, m), 7.64(1H, m), 8.60 (1H, m), 8.75
(1H, s); 13C NMR (75 MHz, CDCl3) d: 22.9, 46.9, 69.7,
85.7, 113.2, 119.3, 127.7, 128.9, 136.9, 138.1, 144.7, 149.8,
156.8. 5i: mp 92.5 °C (1:1 ether/petroleum ether); IR
1
General procedure B: The nitro derivative 4 (1 mmol) and
basic aluminium oxide (1 g) were added to a solution of
the imine (1 mmol) in CH2Cl2 (4mL). The reaction
mixture was left at room temperature overnight, then
diluted with ethyl acetate, filtered and the solvent removed
under reduced pressure. The residual oil was purified by
flash chromatography (ethyl acetate/cyclohexane).
(nujol): 1540 cmÀ1; H NMR (300 MHz, CDCl3) d: 2.35–
2.59 (1H, m), 2.72 (1H, ddd, J ¼ 1.6, 4.0, 14.4 Hz), 3.65–
3.85 (1H, m), 3.87 (1H, dt, J ¼ 13.0, 1.4Hz), 4.91 (1H, d,
J ¼ 6.0 Hz), 5.20 (1H, s), 6.50 (2H, d, J ¼ 7.6 Hz), 6.73
(1H, t, J ¼ 7.6 Hz), 7.18 (2H, d, J ¼ 7.6 Hz), 7.22–7.55 (5H,
25
m). 5j: major diastereomer: oil, ½aꢁ )1.81° (c 0.83,
D
CHCl3); IR (film): 1540 cmÀ1
;
1H NMR (300 MHz,
11. Selected data for compounds 5a–k. 5a: oil; IR (film):
1540 cmÀ1 1H NMR (300 MHz, CDCl3) d: 1.39 (3H, d,
;
CDCl3) d: 0.85 (3H, t, J ¼ 6.6 Hz), 1.38 (3H, d, J ¼ 6.2 Hz),
1.20–1.88 (10H, m), 2.05–2.22 (2H, m), 2.35–2.42 (1H, m),
2.80–2.98 (2H, m), 3.30–3.40 (1H, m), 3.80 (1H, q,
J ¼ 6.2 Hz), 4.65 (1H, ddd, J ¼ 7.4, 4.2, 2.0 Hz), 7.20–
7.40 (5H, m); 13C NMR (75 MHz, CDCl3) d: 14.0, 17.9,
J ¼ 6.2 Hz), 2.19–2.32 (1H, m), 2.35–2.42 (1H, m), 2.45–
2.60 (m, 1H), 2.93–3.20 (m, 2H), 3.25 (1H, d, J ¼ 13.0 Hz),
4.10 (1H, d, J ¼ 13.0 Hz), 4.61 (1H, ddd, J ¼ 9.5, 6.0,
2.5 Hz), 7.20–7.40 (5H, m); 13C NMR (75 MHz, CDCl3) d:
17.9, 28.5, 52.1, 57.3, 65.3, 91.2, 127.2, 128.7, 128.8, 138.3.
5b: oil; IR (film): 1540 cmÀ1; 1H NMR (300 MHz, CDCl3)
d: 0.99 (3H, t, J ¼ 7.0 Hz), 2.60 (2H, quintet, J ¼ 7.0 Hz),
2.38 (4H, m), 2.99 (1H, dt, J ¼ 7.0, 2.5 Hz), 3.37 (1H, d,
J ¼ 13.0 Hz), 4.00 (1H, d, J ¼ 13.0 Hz), 4.73 (1H, ddd,
J ¼ 7.6, 5.0, 2.5 Hz), 7.20–7.40 (5H, m); 13C NMR
(75 MHz, CDCl3) d: 11.3, 14.0, 21.3, 29.3, 51.5, 57.1,
88.1, 127.2, 128.3, 128.6, 138.8. 5c: oil; IR (film):
22.5, 25.4, 26.9, 28.4, 31.7, 32.8, 47.9, 59.9, 67.1, 89.7,
127.2, 127.6, 128.3, 137.9. 5k: major diastereomer: oil, ½aꢁ
25
D
)4.29° (c 0.21, CHCl3); IR (film): 1540 cmÀ1
;
1H NMR
(300 MHz, CDCl3) d: 1.32 (3H, s), 1.41 (3H, s), 2.15–2.40
(2H, m), 2.70–2.85 (1H, m), 2.97–3.17 (1H, m), 3.40–3.49
(1H, m), 3.73 (1H, d, J ¼ 13.0 Hz), 3.75–3.82 (1H, m),
3.97–4.05 (3H, m), 4.97 (1H, ddd, J ¼ 7.4, 2.4, 1.2 Hz),
7.20–7.40 (5H, m); 13C NMR (75 MHz, CDCl3) d: 25.0,
26.5, 30.9, 52.8, 60.0, 66.7, 70.5, 75.1, 87.4, 109.6, 127.5,
128.5, 128.8, 138.6.
1540 cmÀ1 1H NMR (300 MHz, CDCl3) d: 0.90 (3H, t,
;
J ¼ 6.4Hz), 1.25–1.80 (4H, m), 2.10–2.23 (1H, m), 2.25–
2.36 (1H, m), 2.45–2.61 (1H, m), 2.90–2.98 (1H, m), 3.01–
3.08 (1H, m), 3.37 (1H, d, J ¼ 13.0 Hz), 4.00 (1H, d,
J ¼ 13.0 Hz), 4.75 (1H, m), 7.20–7.40 (5H, m); 13C NMR
(75 MHz, CDCl3) d: 14.2, 18.3, 30.0, 34.8, 52.2, 58.0, 69.5,
89.8, 127.1, 128.3, 128.6, 138.8. 5d: oil; IR (film):
12. Adams, J. P. J. Chem. Soc., Perkin Trans. 1 2002, 2586–
2597.
13. Baxendale, I. R.; Brusotti, G.; Matsuoka, M.; Ley, S. V. J.
Chem. Soc., Perkin Trans. 1 2002, 143–154.
14. Tsuritani, N.; Yamada, K.; Yoshikawa, N.; Shibasaki,
M. Chem. Lett. 2002, 276–277, and references cited
therein.
1540 cmÀ1 1H NMR (300 MHz, CDCl3) d: 0.89 (3H, t,
;