A short synthesis of polysubstituted pyrrolidines via α-(Alkylidene- amino)nitriles

Article abstract of DOI:10.1055/s-2004-817774

α-(Alkylideneamino)nitriles can be deprotonated under mild conditions. Their conjugated anions react with enones in a 1,4-addition to yield δ-keto-α-(alkylideneamino)nitriles which in turn can be reduced to form pyrrolidines in a one-pot reaction sequence

Full text of DOI:10.1055/s-2004-817774

LETTER
787
A Short Synthesis of Polysubstituted Pyrrolidines via a-(Alkylidene-
amino)nitriles
A
Short Synthesis
i
of Poly
n
substituted
P
o
yrrolidines via
a-(
M
lkylideneamino)nitril
ees yer, Till Opatz*
Insitut für Organische Chemie, Johannes Gutenberg-Universität Mainz, 55099 Mainz, Germany
Fax +49(6131)3924786; E-mail: opatz@uni-mainz.de
Received 9 December 2003
of the desired a-alkyl substituted pyrrolidines due to the
relatively high basicity of deprotonated a-aminonitriles.
Deprotonation of the enone dominates over 1,4-addition
in this case. This problem can be circumvented by using
a-(alkylideneamino)nitriles which can be obtained by re-
action of Strecker products with aldehydes (see Table 1)
or by a-alkylation of a-(alkylideneamino) acetonitriles.9,10
Abstract: a-(Alkylideneamino)nitriles can be deprotonated under
mild conditions. Their conjugated anions react with enones in a 1,4-
addition to yield d-keto-a-(alkylideneamino)nitriles which in turn
can be reduced to form pyrrolidines in a one-pot reaction sequence.
Key words: pyrrolidines, Michael additions, reductions, imines,
combinatorial chemistry
a-(Alkylideneamino)nitriles are more acidic than a-ami-
nonitriles by several orders of magnitude since they yield
stabilized 2-azaallyl anions with an extended p-system
upon deprotonation. For the N-benzylidene compounds,
the amidine base DBU (THFpKa = 16.6)11 is sufficient to
effect their addition to Michael acceptors in THF at ambi-
ent temperature. Tsuge and coworkers investigated the ad-
dition of a-(alkylideneamino)nitriles to various a,b-
unsaturated carbonyl compounds in detail. They found
that the choice of the base is crucial for the course of the
reaction: Metal free bases like DBU lead to 1,4-addition
whereas the use of metal bases such as lithium diisopro-
pylamide results in the formation of N-metalated azome-
thine ylides which undergo rapid cycloaddition to the
electron deficient double bond of the acceptor molecule to
yield products 5 (Scheme 2).9 Although this reaction is
commonly described as a concerted 1,3-dipolar cycload-
dition, a stepwise mechanism has also been discussed.5c,12
Substituted pyrrolidines display a variety of biological ac-
tivities by interacting with G-protein coupled receptors,1
ion channels,2 transporter proteins3 or enzymes4 and con-
stitute a pharmacologically interesting class of com-
pounds. Although a plethora of syntheses of the
pyrrolidine framework have been developed,5 only a lim-
ited number of them allow the functionalization of all po-
sitions and do not leave certain functionalities such as
activating groups for 1,3-dipolar cycloadditions in the
products.6 Herein, we report on a novel short synthesis of
polysubstituted pyrrolidines from readily available start-
ing materials (Scheme 1).
R3
R4
R2
R5
N
R1
The d-keto-a-(alkylideneamino)nitriles 4 resulting from a
vinylogous addition can be cyclized to products of type 5
that still contain an acceptor moiety which may be diffi-
cult to remove.9a To obtain pyrrolidines devoid of such
undesired functionalities, compounds 4 can be isolated
and subjected to a cascade of three reduction reactions
with NaBH3CN, which presumably begins with the reduc-
tion of the imine, followed by reductive ring closure to a
proline nitrile and subsequent reduction of the iminium
R4
R4
R3
R5
R3
R5
O
+
NC
R2
NC
R2
or
N
NH
N
R2
R1
R1
R1
Table 1 Preparation of a-(Alkylideneamino)nitriles
Scheme 1 Retrosynthetic analysis of the pyrrolidine ring
R2
CN
R1 CHO
+
A representation of such a double donor synthon is an a-
aminonitrile, which can be deprotonated at the a-position.
Recently, a short synthesis of pyrrolidines based upon this
strategy has been reported.8 However, the use of a,b-un-
saturated carbonyl compounds containing acidic protons
such as methyl vinyl ketone did not result in the formation
R1
N
CN
R2
NH2
1
2
3
R1
R2
Yield (%)
3,4-(MeO)2Ph
2-Naph
Ha
56
75
66
Ha
SYNLETT 2004, No. 5, pp 0787–0790
0
2.
0
4.
2
0
0
4
3,4-(MeO)2Ph
PhCH2
Advanced online publication: 10.02.2004
DOI: 10.1055/s-2004-817774; Art ID: G35003ST
© Georg Thieme Verlag Stuttgart · New York
a Aminoacetonitrile sulfate was used.

788
N. Meyer, T. Opatz
LETTER
R2
MeO
MeO
CHO
R1
N
CN
3
DBU
R2
LiNR2
MeO2C
NH3 Cl
NEt3, MgSO4,
CH2Cl2, r.t.
R2
MeO
MeO
R1
N
CN
R1
N
CN
81%
N
CO2Me
Li
azomethine ylide
2-azaallyl anion
9
R4
R4
R3
O
1)
R3
O
O
R5
R5
DBU, THF, r.t.
O
2) NaBH3CN, AcOH,
EtOH, r.t.
R5
R4
R1
R3
R2
R4
R2 CN
O
R1
N
N
CN
R3
R5
MeO2C
N
Li
4
5
OMe
50%
cis/trans = 3:1
Scheme 2 1,4-Addition versus 1,3-dipolar cycloaddition
10
OMe
ion formed by expulsion of the cyano substituent
(Scheme 3).
Scheme 4 Synthesis of a substituted proline ester
Alternatively, intermediates 4 can be reduced directly
without isolation by addition of NaBH3CN, acetic acid
and ethanol. After alkaline workup, pyrrolidines 8 were
isolated from the reaction mixture by extractive or chro-
matographic methods in moderate to good yield
(Table 2).13–15 The relative configurations of the products
were determined by NOE experiments.15
of polysubstituted pyrrolidines from simple precursors in
a one-pot reaction. In contrast to the corresponding con-
version of a-aminonitriles, the reaction can also be per-
formed with enones bearing acidic protons.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
and the Emil und Paul Müller-Gedächtnisstiftung. We thank Aven-
tis Pharma Deutschland GmbH for a donation of laboratory equip-
ment.
In a similar reaction sequence, imines of a-amino acid es-
ters can be converted to substituted proline esters
(Scheme 4).16,17
Since enantioselective a-alkylations of glycine ester imi-
nes have been reported,18 a catalytic asymmetric variant of
this reaction can be envisaged.
References
(1) (a) Fisher, L. E.; Rosenkranz, R. P.; Clark, R. D.;
Muchowski, J. M.; McClelland, D. L.; Michel, A.; Caroon,
J. M.; Galezzi, E.; Eglen, R.; Whiting, R. L. Bioorg. Med.
Chem. Lett. 1995, 5, 2371. (b) Sonesson, C.; Wikström, H.;
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In summary, the use of a-(alkylideneamino)nitriles as
double donor synthons allows the combinatorial assembly
R4
R4
R2 CN
R2 CN
NaBH3CN
O
O
R1
N
R1
N
H
R3
R5
R3
R5
4
6
NaBH3CN
R4
R3
R4
R3
NaBH3CN
R2
R2
R5
R5
N
N
NC
(2) (a) Elliott, R. L.; Ryther, K. B.; Anderson, D. J.; Piattoni-
Kaplan, M.; Kuntzweiler, T. A.; Donnelly-Roberts, D.;
Arneric, S. P.; Holladay, M. W. Bioorg. Med. Chem. Lett.
1997, 7, 2703. (b) Kim, K. H.; Lin, N.-H.; Anderson, D. J.
Bioorg. Med. Chem. 1996, 4, 2211. (c) Guzikowski, A. P.;
Tamiz, A. P.; Acosta-Burruel, M.; Hong-Bae, S.; Cai, S. X.;
R1
R1
8
7
Scheme 3 Presumed course of the cascade reduction of compounds
2
Synlett 2004, No. 5, 787–790 © Thieme Stuttgart · New York

LETTER
A Short Synthesis of Polysubstituted Pyrrolidines via a-(Alkylideneamino)nitriles
789
Table 2 Preparation of Substituted Pyrrolidines (One-pot Procedure)
a-(Alkylideneamino)nitrile
Electrophile
Major product
dra
Combined yield
(%)
OMe
NC
N
O
N
OMe
OMe
–
64
46
58
51
3a
3b
OMe
8a
8b
8c
NC
NC
NC
N
N
N
O
N
–
–
–
OMe
OMe
N
O
OMe
OMe
3a
3b
O
N
8d
OMe
O
N
N
OMe
OMe
OMe
1.4:1
77
CN
3c
8e
OMe
NC
N
OMe
O
3a
trans-compound
not detected
50
N
MeO
MeO
8f
OMe
N
all-cis/
OMe
2,3-trans-3,5-cis/
2,3-cis-3,5-trans/
2,3-trans-3,5-trans
O
CN
36
N
3c
MeO
MeO
14:20:1:5
8g
a Determined by 1H NMR or analytical HPLC of the crude product
Synlett 2004, No. 5, 787–790 © Thieme Stuttgart · New York

790
N. Meyer, T. Opatz
LETTER
Hawkinson, J. E.; Keana, J. F. W.; Kesten, S. R.; Shipp, C.
T.; Tran, M.; Whittemore, E. R.; Woodward, R. M.; Wright,
J. L.; Zhou, Z.-L. J. Med. Chem. 2000, 43, 984.
mmol, 1.1 equiv) in THF (2 mL) under argon at r.t. After
addition of a solution of methyl vinyl ketone (1.59 mmol, 1.1
equiv) in THF (3 mL), the mixture was stirred for 90 min.
The reaction was stopped by addition of a mixture of EtOH
(87 mmol, 60 equiv) and HOAc (11.6 mmol, 8 equiv). After
NaBH3CN (5.8 mmol, 4 equiv) was added, the mixture was
stirred at r.t. overnight. The reaction mixture was washed
twice with 1 N NaOH and the combined aqueous phases
were reextracted with EtOAc. The combined organic layers
were extracted three times with 1 N HCl and the combined
aqueous phases were made alkaline by addition of NaOH.
Extraction with CH2Cl2, drying over Na2SO4 and evapora-
tion of the solvent in vacuo gave a crude product, which was
further purified by column chromatography, preparative
TLC or HPLC if necessary. Note: Compounds 8f and 8g
were too lipophilic for an efficient extraction with 1 N HCl.
They were directly purified by chromatographic methods.
(14) Under identical conditions, compounds 3a and 3b could not
be reacted cleanly with a,b-unsaturated aldehydes.
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P. T.; Gynther, J. Bioorg. Med. Chem. 2002, 10, 2199.
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P. L.; Rose, D.; Leesnitzer, M. A.; Brawley, E. S.;
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Bateman-Fite, R.; Noel, L. S.; Sekut, L.; Stimpson, S. A. J.
Med. Chem. 1995, 38, 1505.
(5) For reviews, see: (a) Pichon, M.; Figadère, B. Tetrahedron:
Asymmetry 1996, 7, 927. (b) 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley: New York, 1984.
(c) Pearson, W. H.; Stoy, P. Synlett 2003, 903. (d) For
recent examples, see: Tietze, L. F.; Evers, H.; Töpken, E.
Helv. Chim. Acta 2002, 85, 4200. (e) Casas, J.; Grigg, R.;
Nájera, C.; Sansano, J. M. Eur. J. Org. Chem. 2001, 1971.
(f) Davis, A. S.; Gates, N. J.; Lindsay, K. B.; Tang, M.; Pyne,
S. G. Synlett 2004, 49. (g) Mota, A. J.; Chiaroni, A.;
Langlois, N. Eur. J. Org. Chem. 2003, 4187.
(6) See for example: (a) Pearson, W. H.; Szura, D. P.; Postich,
M. J. J. Am. Chem. Soc. 1992, 114, 1329. (b) Zimmer, R.;
Hoffmann, M.; Reissig, H.-U. Chem. Ber. 1992, 125, 2243.
(c) Pulz, R.; Al-Harrasi, A.; Reissig, H.-U. Org. Lett. 2002,
4, 2353. (d) Vanucci, C.; Brusson, X.; Verdel, V.; Zana, F.;
Dhimane, H.; Lhommet, G. Tetrahedron Lett. 1995, 36,
2971. (e) Lorthiois, E.; Marek, I.; Normant, J. F.
(15) Spectroscopic Data of Compound cis-8e: 1H NMR (400
MHz, CDCl3): d = 7.28–7.21 (m, 2 H, Ph), 7.19–7.10 (m, 3
H, Ph), 6.92 (d, 1 H, J2¢,6¢ = 1.8 Hz, H-2¢), 6.90 (dd, 1 H,
J5¢,6¢ = 8.1 Hz, J2¢,6¢ = 1.8 Hz, H-6¢), 6.83 (d, 1 H, J5¢,6¢ = 8.1
Hz, H-5¢), 3.90, 3.88 (2 s, 6 H, OCH3), 3.81 [d, 1 H, J = 14.1
Hz, CH2C6H3 (OMe)2], 3.75 [d, 1 H, J = 14.1 Hz, CH2C6H3
(OMe)2], 2.93–2.81 (m, 2 H, CH2Ph, H-2), 2.74–2.60 (m, 1
H, H-5), 2.38 (dd, 1 H, Jgem = 12.4 Hz, Jvic = 9.2 Hz, CH2Ph),
1.81–1.70 (m, 1 H, H-4a), 1.67–1.44 (m, 2 H, H-3a, H-3b),
1.42–1.30 (m, 1 H, H-4b), 1.07 (d, 3 H, J = 6.0 Hz, CH3).
Irradiation (transient NOE) at d = 2.68 ppm (H-5) enhances
the signals at d = 6.90 ppm (H-6¢, 0.8%), 6.83 ppm (H-5¢,
0.2%), 3.81 ppm [CH2C6H3 (OMe)2, 1.1%], 3.75 ppm
[CH2C6H3 (OMe)2, 1.0%], 2.83 ppm (H-2, 0.6%), 1.72 ppm
(H-4a, 2.2%), 1.55 ppm (H-3, 0.8%), 1.35 ppm (H-4b,
0.6%), 1.07 ppm (CH3, 1.1%). 13C NMR (100.6 MHz,
CDCl3): d = 148.60, 147.87 (C-3¢, C-4¢), 140.30 (C-1 Ph),
137.28 (C-1¢), 129.18, 128.08, 125.77 (Ph), 121.14 (C-6¢),
112.56 (C-2¢), 110.65 (C-5¢), 66.11 (C-2), 60.09 (C-5), 56.28
[CH2C6H3 (OMe)2], 55.85 (OCH3), 42.46 (CH2Ph), 31.55
(C-4), 28.80 (C-3), 20.80 (CH3).
Tetrahedron Lett. 1997, 38, 89. (f) Broka, C. A.; Shen, T. J.
Am. Chem. Soc. 1989, 111, 2981. (g) Coldham, I. J. Chem.
Soc., Perkin Trans. 1 1993, 1275.
(7) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239;
Angew. Chem. 1979, 91, 259.
(8) Meyer, N.; Opatz, T. Synlett 2003, 1427.
(9) (a) Tsuge, O.; Ueno, K.; Kanemasa, S.; Yorozu, K. Bull.
Chem. Soc. Jpn. 1987, 60, 3347. (b) Tsuge, O.; Kanemasa,
S.; Yorozu, K.; Ueno, K. Bull. Chem. Soc. Jpn. 1987, 60,
3359. (c) Tsuge, O.; Ueno, K.; Kanemasa, S.; Yorozu, K.
Bull. Chem. Soc. Jpn. 1986, 59, 1809. (d) See also: Roux-
Schmitt, M. C.; Croisat, D.; Seyden-Penne, J.; Wartski, L.;
Cossentini, M. Pol. J. Chem. 1996, 70, 325. (e) Opio, J. O.;
Labidalle, S.; Galons, H.; Miocque, M. Synth. Commun.
1991, 21, 1743.
(10) General Procedure for the Preparation of a-
(Alkylideneamino)nitriles 3a–c: To a solution of the
aminonitrile (10 mmol) in dry CH2Cl2 (20 mL) were added
MgSO4 (1.1 equiv) and the aldehyde (1.1 equiv). The
suspension was stirred overnight. The MgSO4 was filtered
off and the organic phase was partitioned between a sat.
NaHCO3 solution and CH2Cl2. The organic layer was dried
over Na2SO4 and the solvent was evaporated in vacuo.
Recrystallization yielded the pure imines. In the case of
products 3a and 3b, aminoacetonitrile sulfate was used and
1 equiv of Et3N was added to the reaction mixture.
(11) Rodima, T.; Kaljurand, I.; Pihl, A.; Mäemets, V.; Leito, I.;
Koppel, I. A. J. Org. Chem. 2002, 67, 1873.
Spectroscopic Data of Compound trans-8e: 1H NMR (400
MHz, CDCl3): d = 7.26–7.20 (m, 2 H, Ph), 7.18–7.12 (m, 1
H, Ph), 7.05 (d, 2 H, J = 7 Hz, H-2, H-6 Ph), 6.98 (br s, 1 H,
H-2¢), 6.92 (dd, 1 H, J5¢,6¢ = 8.1 Hz, J2¢,6¢= 1.3 Hz, H-6¢), 6.83
(d, 1 H, J5¢,6¢ = 8.1 Hz, H-5¢), 3.92 [d, 1 H, J = 13.6 Hz, CH2-
C6H3 (OMe)2], 3.90, 3.89 (2 s, 6 H, OCH3), 3.62 [d, 1 H,
J = 13.6 Hz, CH2C6H3(OMe)2], 3.17–3.05 (m, 2 H, H-2, H-
5), 2.96 (dd, 1 H, Jgem = 12.9 Hz, Jvic = 3.5 Hz, CH2Ph), 2.36
(dd, 1 H, Jgem = 12.9 Hz, J = 10.0 Hz, CH2Ph), 2.05–1.92 (m,
1 H, H-4a), 1.83–1.70 (m, 1 H, H-3a), 1.56–1.46 (m, 1 H, H-
3b), 1.44–1.33 (m, 1 H, H-4b), 0.99 (d, 3 H, J = 6.2 Hz,
CH3). 13C NMR (100 MHz, CDCl3): d = 148.87, 147.69
(C-3¢, C-4¢); 140.49 (C-1 Benzyl), 136.52 (C-1¢), 129.26,
128.12, 125.67 (Benzyl); 120.35 (C-6¢); 111.72 (C-2¢);
110.71 (C-5¢); 61.91 (C-2); 55.89 (OCH3); 55.40 (C-5);
51.71 [CH2C6H3(OMe)2]; 37.63 (CH2Ph); 30.77 (C-4);
27.55 (C-3); 16.76 (CH3).
(16) (a) van der Werf, A.; Kellogg, R. M. Tetrahedron Lett. 1991,
32, 3727. (b) Kanemasa, K.; Uchida, O.; Wada, E. J. Org.
Chem. 1990, 55, 4411. (c) Alvarez-Ibarra, C.; Csákÿ, A. G.;
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(17) Scott, W. L.; Alsina, J.; O’Donnell, M. J. J. Comb. Chem.
2003, 5, 684.
(12) (a) Tatsukawa, A.; Kawatake, K.; Kanemasa, S.; Rudziski, J.
M. J. Chem. Soc., Perkin Trans. 2 1994, 2525.
(b) Domingo, L. R. J. Org. Chem. 1999, 64, 3922.
(13) General Procedure for the Preparation of Pyrrolidines
8a–g: To a solution of the a-(alkylideneamino)nitrile (1.45
mmol) in THF (5 mL) was added a solution of DBU (1.59
(18) (a) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem.
Soc. 1989, 111, 2353. (b) For a review, see: O’Donnell, M.
J. Aldrichimica Acta 2001, 34, 3.
Synlett 2004, No. 5, 787–790 © Thieme Stuttgart · New York