One-pot, three-component, highly diastereoselective metal-free synthesis of 2,3,4,5-tetrasubstituted pyrrolidines

Article abstract of DOI:10.1055/s-2008-1078566

An extremely efficient, highly diastereoselective, metal-free synthesis of 2,3,4,5-tetrasubstituted pyrrolidines is described. The three-component reaction between aldehydes, aminomalonates, and nitroalkenes proceeds with high diastereoselectivities and h

Full text of DOI:10.1055/s-2008-1078566

1840
LETTER
One-Pot, Three-Component, Highly Diastereoselective Metal-Free Synthesis
of 2,3,4,5-Tetrasubstituted Pyrrolidines
S
ynthesis of 2,3
u
,4,5-Tetrasu
i
s
d Pyrrolidines Crovetto,a Ramon Rios*a,b,1
a
Departamento de Química Física, Universidad de Granada, 18071 Granada, Spain
Departament de Química Orgànica, Facultat de Química, Universitat de Barcelona, C. Martí i Franquès 1-11, 08028 Barcelona, Spain
Fax +34(93)3397878; E-mail: rios.ramon@icrea.cat
b
Received 7 April 2008
into peptides.5 In addition to pharmaceuticals, the pyrroli-
dine moiety has also seen widespread use as a chiral aux-
iliary and catalyst for asymmetric synthesis.6
Abstract: An extremely efficient, highly diastereoselective, metal-
free synthesis of 2,3,4,5-tetrasubstituted pyrrolidines is described.
The three-component reaction between aldehydes, aminoma-
lonates, and nitroalkenes proceeds with high diastereoselectivities
and high yields.
1,3-Dipolar cycloadditions are one of the simplest ap-
proaches for the construction of five-membered heterocy-
clic rings. The straightforward generation of 1,3-dipoles
coupled with the often observed highly regio- and stereo-
selective nature of their cycloaddition reactions have led
to a number of syntheses which utilize such reactions as
the key step.7
Key words: metal-free, cycloaddition, three component, pyrro-
lidines, stereoselectivity
Multicomponent metal-free reactions are a very rapidly
growing field of research. The operational and economic
advantages associated with this methodology, together
with the fact that metal-free reactions are environmentally
friendly, robust, and very often the starting materials are
commercially available, have led many research groups to
engage in the development of new asymmetric or racemic
multicomponent metal-free reactions.2
In organocatalysis, 1,3-dipolar reactions have been used
extensively. In 2001, MacMillan8 and co-workers devel-
oped a 1,3-dipolar cycloaddition between a,b-unsaturated
aldehydes and N-hydroxylamines, catalyzed by imidoox-
azolidine catalyst, obtaining the corresponding heterocy-
cles with excellent enantioselectivities and diastereo-
selectivities. Following this concept, Cordova and co-
workers developed a three-component version of this re-
action using prolinol derivatives as catalyst.
In 2007, the research groups of Vicario9 and Cordova10 in-
dependently developed a very elegant approximation to
the synthesis of pyrrolidines. They reacted preformed
imines derived from 2-aminomalonates with a,b-unsatur-
ated aldehydes, using diphenylprolinol derivatives as cat-
Pyrrolidine derivatives are an important class of organic
compounds due to their frequent occurrence in nature and
their use as intermediates in the synthesis of natural prod-
ucts and pharmaceuticals.3 Several polysubstituted pyr-
rolidines have shown very potent activities as enzyme
inhibitors or as antagonists of receptors.4 Proline deriva-
tives are also used to induce conformational constraints
CO2Et
H2N
CO2Et
CO2Et
2a
N
CO2Et
+
O
Ar
H
Ar
H
3
O
H
+
N
–
Ar
Ar
R
OEt
H
O2N
Ar
CO2Et
–
H
CO2Et
CO2Et
NO2
N
NO2
H
EtO2C
R
N
H
1
O
R
EtO
4
Scheme 1 Reaction proposal
SYNLETT 2008, No. 12, pp 1840–1844
x
x
.x
x
.2
0
0
8
Advanced online publication: 02.07.2008
DOI: 10.1055/s-2008-1078566; Art ID: D09208ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2,3,4,5-Tetrasubstituted Pyrrolidines
1841
Table 1 Catalyst and Solvent Screeninga
Ph
O2N
Ph
CHO
CO2Et
CO2Et
catalyst (20 mol%)
solvent, r.t.
CO2Et
CO2Et
NO2
+
+
H2N
Ph
N
H
1a
2a
3a
4a
CF3
S
S
Et3N
H2N
NH2
Ph
N
N
CF3
H
H
5
6
7
Entry
Catalyst
Solvent12
CHCl3
CHCl3
CHCl3
CHCl3
MeOH
toluene
DMSO
Time (h)
14
Yield (%)b
drc
1
2
3
4
5
6
7
–
5
6
7
–
–
–
99
80
15
30
0
>25:1
1.2:1
1.1:1
1:1
14
14
14
14
–
14
70
>25:1
14
trace
n.d.
a Experimental conditions: A mixture of 2a (0.375 mmol) and benzaldehyde 3a (0.375 mmol) in 0.5 mL of solvent was stirred at r.t. for 30 min.
Then, nitrostyrene 1a (0.25 mmol) and catalyst (20 mol%) were added.
b Isolated yield of pure compound 4a.
c Determined by NMR analyses.
alyst. In both cases, the results were excellent, affording ethyl 2-aminomalonate (2a) and nitrostyrene 1a to afford
the pyrrolidine derivatives in almost enantiopure form.
the corresponding pyrrolidine 4d in 95% yield and >25:1
diastereoselectivity.13
With these ideas in mind, we envisioned an easy entry to
pyrrolidines by reaction of imines derived from 2-ami- The relative configurations of the pyrrolidines 4 were es-
nomalonates and different nitroalkenes (Scheme 1).
tablished by nuclear Overhauser effect (NOE) experi-
ments. This configuration could be explained by an exo
approach in the 1,3-dipolar cycloaddition (Scheme 2).
Several reactions are known between iminoesters and ni-
troalkenes,11 but these reactions are commonly catalyzed
by metal salts or require high temperatures. To our knowl- The next step was the evaluation of different nitroalkenes.
edge, this is the first example of metal-free 1,3-dipolar cy- To our delight, the reaction worked well with any kind of
cloadditions between iminomalonates and nitroalkenes.
nitroalkene, however, the reaction with aliphatic nitroal-
kenes rendered pyrrolidines with lower yields (Table 3).
For example, the three-component reaction of 3a, ami-
nomalonate 2a, and nitrostyrene 1b afforded pyrrolidine
derivative 4f in 97% yield and in diastereopure form.
In an initial catalyst screening, we found that the reaction
between 2-nitrostyrene 1a, aminomalonate 2a and benzal-
dehyde (3a) works best without any additive at room tem-
perature, affording the corresponding pyrrolidine
derivative in almost quantitative yield and excellent dia- In summary, we have reported a highly diastereoselective
stereoselectivity. The addition of different additives such synthesis of polysubstituted pyrrolidines, which are
as triethylamine or thiourea gave disordered reactions formed in high yields and diastereopure form. Moreover,
with low diastereoselectivities.
the metal-free tandem reaction represents a versatile
asymmetric entry to different proline derivatives. Mecha-
nistic studies, synthetic applications, and the development
of a chiral version are ongoing in our laboratory.
For instance, the additive-free reaction of 1a, 2a, and 3a
in CHCl3 afforded the desired pyrrolidine 4a in 99% yield
in diastereopure form. Hence, we decided to investigate
the scope of the metal-free reaction using the former reac-
tion conditions and different aldehydes and nitrostyrenes.
OEt
R
O
O2N
Ar
CO2Et
H
The reactions between nitrostyrene, 2-aminomalonate,
and different benzaldehydes were highly chemoselective
and furnished the corresponding pyrrolidine derivatives in
high yields and in high diastereoselectivities (Table 2).
For example, 4-bromo-benzaldehyde (3d) reacts with di-
R
CO2Et
CO2Et
–
N
H
N
H
Ar
NO2
4
Scheme 2 The exo approximation in cycloaddition
Synlett 2008, No. 12, 1840–1844 © Thieme Stuttgart · New York

1842
L. Crovetto, R. Rios
LETTER
Table 2 Reactions with Different Aldehydesa
Ph
O2N
R
CO2Et
CO2Et
O
CO2Et
CO2Et
NO2
+
H2N
+
Ph
CHCl3, r.t., 14 h
R
H
N
H
4
1a
2a
3
Entry
R
Product
Yield (%)b
99
drc
Ph
O2N
CO2Et
CO2Et
1
Ph
>25:1
N
Ph
H
4a
Ph
O2N
CO2Et
CO2Et
2
3
4
5
94
93
95
96
>25:1
>25:1
>25:1
>25:1
N
H
O2N
O2N
4b
Ph
O2N
CO2Et
CO2Et
N
H
4c
Ph
O2N
CO2Et
CO2Et
N
H
Br
Br
4d
Ph
O2N
CO2Et
CO2Et
N
H
NC
NC
4e
a Experimental conditions: A mixture of 2a (0.375 mmol) and aldehyde 3a–e (0.375 mmol) in 0.5 mL of solvent was stirred at r.t. for 30 min.
Then, nitrostyrene 1a (0.25 mmol) was added.
b Isolated yield of pure compound 4.
c Determined by NMR analyses.
(3) Pandey, G.; Banerjee, B.; Gadre, S. R. Chem. Rev. 2006,
Acknowledgment
106, 4484.
We gratefully acknowledge Dr Jan Vesèly and Dr Omer Reis for
helpful discussions.
(4) (a) Hanessian, S.; Baykadarian, M.; Luo, X. J. Am. Chem.
Soc. 2002, 124, 4716. (b) DeGoey, D. A.; Chen, H.-J.; Flosi,
W. J.; Grampovnik, D. J.; Yeung, C. M.; Klein, L. L.;
Kempf, D. J. J. Org. Chem. 2002, 67, 5445. (c)Zaccardi, J.;
Alluri, M.; Ashcroft, J.; Bernan, V.; Korshalla, J. D.;
References and Notes
Morton, G. O.; Siegel, M.; Tsao, R.; Williams, D. R.;
Maeiese, W.; Ellestad, G. A. J. Org. Chem. 1994, 59, 4045.
(d) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102,
1669. (e) Hanessian, S. ChemMedChem 2006, 1, 1300.
(f) da Silva, K. P.; Godoi, M. N.; Correia, C. R. D. Org. Lett.
2007, 9, 2815. (g) Morita, Y.; Tokuyama, H.; Fukuyama, T.
Org. Lett. 2005, 7, 4337.
(1) ICREA Researcher at University of Barcelona.
(2) (a) For an excellent review of enamine catalysis, see:
Erkkila, A.; Majander, I.; Pihko, P. Chem. Rev. 2007, 107,
5416. (b) For an excellent review of asymmetric synthesis
enabled by metal-free catalysis, see: Lelais, G.; MacMillan,
D. W. C. Aldrichimica Acta 2006, 3, 79. (c) For an
excellent review of Michael additions, see: Tsogoeva, S. B.
Eur. J. Org. Chem. 2007, 1701.
Synlett 2008, No. 12, 1840–1844 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,3,4,5-Tetrasubstituted Pyrrolidines
1843
Table 3 Reactions with Different Nitro Olefinsa
R
O2N
Ph
CO2Et
CO2Et
O
CO2Et
CO2Et
NO2
+
+
H2N
R
CHCl3, r.t., 14 h
N
Ph
H
H
1
2a
3a
4
Entry
R
Product
Yield (%)b
drc
Br
1
97
>25:1
O2N
CO2Et
CO2Et
Br
N
H
Ph
4f
NO2
2
96
>25:1
O2N
Ph
CO2Et
CO2Et
O2N
N
H
4g
Cl
Cl
3
4
5
95
94
76
>25:1
>25:1
>25:1
O2N
CO2Et
CO2Et
N
H
Ph
4h
Br
Br
O2N
CO2Et
CO2Et
N
H
Ph
4i
O2N
CO2Et
CO2Et
N
H
Ph
4j
a Experimental conditions: A mixture of 2a (0.375 mmol) and aldehyde 3a (0.375 mmol) in 0.5 mL of solvent was stirred at r.t. for 30 min.
Then, nitrostyrene 1 (0.25 mmol) was added.
b Isolated yield of pure compound 4.
c Determined by NMR analyses.
(5) (a) Najera, C.; Sansano, J. M. Angew. Chem. Int. Ed. 2005,
44, 6272. (b) Hucinec, S.; Savic, V. Tetrahedron:
Asymmetry 2005, 16, 2047.
(6) (a) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2001, 40,
3726. (b) Duthaler, R. O. Angew. Chem. Int. Ed. 2003, 42,
975. (c) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed.
2004, 43, 5138. (d) Enders, D.; Grondal, C.; Huttl, M. R. M.
Angew. Chem. Int. Ed. 2007, 46, 1570.
(7) (a) Garner, P.; Ho, W. B.; Shin, C. J. Am. Chem. Soc. 1993,
115, 10742. (b) Coldham, I.; Crapnell, K. M.; Fernandez,
J.-C.; Moseley, J. D.; Rabot, R. J. Org. Chem. 2002, 67,
6181. (c) Pandey, G.; Banerjee, P.; Kumar, R.; Puranik, V.
G. Org. Lett. 2005, 7, 3713. (d) Hong, S. W.; Yang, J. H.;
Weinreb, S. M. J. Org. Chem. 2006, 71, 2078.
(8) (a) Jem, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 9874. (b) Rios, R.; Ibrahem, I.;
Synlett 2008, No. 12, 1840–1844 © Thieme Stuttgart · New York

1844
L. Crovetto, R. Rios
LETTER
in CHCl3 (0.5 mL) at r.t., diethyl 2-aminomalonate (2a,
0.375 mmol, 1.5 equiv) was added. The reaction was stirred
at r.t. for 30 min and then nitroalkene 1 was added. The
reaction was then stirred at r.t. overnight. Next the crude was
purified by silica gel column chromatography to afford the
pyrrolidine derivative 4.
Vesely, J.; Zhao, G.-L.; Cordova, A. Tetrahedron Lett. 2007,
48, 5701.
(9) Vicario, J. L.; Reboredo, S.; Badía, D.; Carrillo, L. Angew.
Chem. Int. Ed. 2007, 46, 5168.
(10) (a) Ibrahem, I.; Rios, R.; Vesely, J.; Cordova, A.
Tetrahedron Lett. 2007, 48, 6252. (b) Rios, R.; Ibrahem, I.;
Vesely, J.; Sundén, H.; Cordova, A. Tetrahedron Lett. 2007,
48, 8695.
(11) Viranyi, A.; Marth, G.; Dancso, A.; Blasko, G.; Toke, L.;
Nyerges, M. Tetrahedron 2006, 62, 8720; and references
cited therein.
(12) Chloroform was bought from Aldrich and was used as
received.
Compound 4d: colorless oil. 1H NMR (400 MHz, CDCl3):
d = 7.48–7.44 (m, 2 H), 7.33–7.28 (m, 7 H), 5.58 (dd,
J = 6.8, 8.0 Hz, 1 H), 5.46 (d, J = 8.4 Hz, 1 H), 5.12 (d,
J = 7.2 Hz, 1 H), 4.42–4.21 (m, 2 H), 3.91 (q, J = 7.6 Hz, 1
H), 3.46 (q, J = 7.6 Hz, 1 H), 1.29 (t, J = 7.6 Hz, 3 H), 0.78
(t, J = 7.6 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 171.1,
168.4, 135.7, 134.9, 132.4, 131.6, 130.9, 128.9, 128.7,
128.6, 128.3, 122.9, 93.5, 75.9, 63.8, 62.2, 62.0, 51.9, 14.0,
13.3.
(13) Typical Experimental Procedure for the Three-
Component Synthesis of Pyrrolidine Derivatives
To a stirred solution of aldehyde 3 (0.375 mmol, 1.5 equiv)
Synlett 2008, No. 12, 1840–1844 © Thieme Stuttgart · New York

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