A novel synthesis of 2-alkyl(aryl)pyrrolidines from proline via 2,3-diphenylhexahydropyrrolo[2,1-b]oxazoles

Article abstract of DOI:10.1016/j.mencom.2015.11.014

Diphenyloxapyrrolizidines, products of the reaction between proline and benzaldehyde, are convenient building blocks for synthesizing 2-substituted pyrrolidines. The opening of their oxazolidine ring by treatment with Grignard reagents has been performed

Full text of DOI:10.1016/j.mencom.2015.11.014

Mendeleev
Communications
Mendeleev Commun., 2015, 25, 440–442
A novel synthesis of 2-alkyl(aryl)pyrrolidines from proline
via 2,3-diphenylhexahydropyrrolo[2,1-b]oxazoles
Vladimir S. Moshkin* and Vyacheslav Ya. Sosnovskikh
Department of Chemistry, Institute of Natural Sciences, Ural Federal University, 620000 Ekaterinburg,
Russian Federation. Fax: +7 343 261 5978; e-mail: vladimir.moshkin@urfu.ru, mvslc@mail.ru
DOI: 10.1016/j.mencom.2015.11.014
Diphenyloxapyrrolizidines, products of the reaction between proline and benzaldehyde, are convenient building blocks for synthesizing
2-substituted pyrrolidines. The opening of their oxazolidine ring by treatment with Grignard reagents has been performed and conditions
for subsequent removal of the N-hydroxyethyl moiety have been found. Though the yields are moderate (36–42%), the suggested synthesis
of 2-alkyl(aryl)pyrrolidines is rather simple since it does not require purification of intermediate products and is easy scalable.
a-Substituted pyrrolidine moiety is incorporated in many natural
alkaloids and compounds with high biological activity.1–3 The
principal syntheses of such compounds are documented.1–7
Enantioselective synthesis of 2-substituted pyrrolidines from
(R)-(–)-2-phenylglycinol and 3-acylpropionic acids involving
two subsequent reduction stages was suggested by Burgess and
Meyers.8 The approach implemented by Seidel et al.9 is most
similar to the synthesis of 2-R-pyrrolidines that we suggested.
They carried out a decarboxylative Strecker reaction of proline
with benzaldehyde in the presence of cyanide anion to give
the corresponding a-amino nitrile, which was then used in the
Bruylants reaction with Grignard reagents.9(b) Though the methods
to synthesize the pyrrolidine system are rather abundant, its
simplest a-substituted derivatives are still hardly available and
expensive. This fact gives an impetus to a search for new methods
of their synthesis.
On the other hand, 5-aryloxazolidines, saturated heterocycles
little studied before our publications,10 are readily formed in
reactions of nonstabilized azomethine ylides with carbonyl com-
pounds.11 We turned our attention to a study by Orsini (Scheme 1)
where proline reacted with aromatic aldehydes in DMSO to
afford oxapyrrolizidines I and II with high regio- and stereo-
selectivity.11(c) Hajra et al. elaborated a synthesis of oxapyr-
rolizidines I by treatment of pyrrolidine with aromatic aldehydes
in toluene under microwave irradiation.12 In both cases, non-
stabilized azomethine ylide A is formed, which then undergoes
[3+2]-cycloaddition with a second molecule of the aldehyde.
However, though these compounds are easy to obtain and the
node carbon atom has a semi-aminal nature, the feasibility of
using these compounds as the key building blocks to synthesize
2-alkyl(aryl)pyrrolidines was not examined.
In our studies, we used a readily available adduct I (Ar = Ph)
and repeated Orsini’s reaction with larger amounts of proline
(0.287 mol) and benzaldehyde (0.573 mol). The crude product
(1H NMR) was a mixture of stereoisomeric oxapyrrolizidines 1
(89%), 1' (8%) and traces of the starting benzaldehyde (3%).
Since conversion with respect to benzaldehyde was high (98%)
and the crude product was a thick yellow oil, we used it in the
next stage without purification.
Taking into account the enhanced electrophilicity of the amino
acetal nodal carbon atom in isomers 1 and 1', it could be expected
that their reactions with Grignard reagents would involve oxa-
pyrrolizidine ring opening to yield 1,2-disubstituted pyrrolidines.
In fact, the reaction with ethylmagnesium bromide (2.0 equiv.)
gave a viscous liquid that was a mixture of two isomeric amino
alcohols 2 and 2' (R = Et) with a conversion of 95% (Scheme 2).
In the final third stage of the synthesis of 2-ethylpyrrolidine
3a, we had to remove the hydroxy(diphenyl)ethyl substituent
from the nitrogen atom. The best result was achieved on driving
the vicinal C–C cleavage with lead tetraacetate (1.35 equiv.) in
†
General procedure. Proline (33.0 g, 0.287 mol), benzaldehyde (58.5 ml,
60.8 g, 0.573 mol) and DMSO (330 ml) were placed in a round-bottom
one-necked 1 dm3 flask equipped with a reflux condenser. The mixture
was heated with magnetic stirring in a glycerol bath at 90–97°C for
1 h. The resulting solution was cooled, diluted with water (500 ml) and
extracted with Et2O (3×130 ml). The extract was dried with Na2SO4.
The solvent was removed in vacuo. The resulting mixture of isomeric
oxapyrrolizidines 1 and 1' (75 g) obtained as a light-yellow thick oil
was dissolved in 220 ml of dry PhMe to make dosing more convenient.
It was used in the next stage without any purification.
Part of the previously prepared solution of oxapyrrolizidines 1 and 1'
(50 mmol) in toluene was placed in a 250 ml round-bottom flask equipped
with a dropping funnel, reflux condenser and magnetic stirrer. The mixture
was cooled with an ice salt bath. A solution of pre-prepared RMgBr
(100 mmol, 2 equiv.) from equal molar amounts of an appropriate RBr
and magnesium turnings in dry Et2O (for bromoalkanes) or dry THF (for
bromoarenes) was slowly added to the solution. The ice bath was removed
and the mixture was refluxed for 15 min, then cooled with ice once more.
Excess saturated NH4Cl solution was added from the dropping funnel.
The organic layer was separated and the aqueous layer was extracted with
a small amount of PhMe. The extracts were dried with Na2SO4, then the
solvents were removed in vacuo to give a mixture of isomeric amino
alcohols 2 and 2' as a thick light-yellow oil.
CO2H
H
N
H
N
H
ArCHO
ArCHO
H
O
KOAc
H
N
N
– AcOH
N
– CO2
O
Ar
Ar
A
Ar
ArCHO
H
H
O
O
+
N
N
Ar
II (traces)
Ar
Ar
Ar
I
Scheme 1
© 2015 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2015, 25, 440–442
alcohol cleavage,13 we also used acid dehydration followed by
H
H
hydrolysis, oxidative cleavage with potassium dichromate with
subsequent heating in sulfuric acid, and treatment with cerium
ammonium nitrate in a water–acetonitrile mixture. Neither of
these methods provided usable results (see Table S1, Online
Supplementary Materials).
O
O
2 PhCHO
N
N
+
CO2H
DMSO,
– CO2
Ph
Ph
N
H
Ph
Ph
1' (8%)
1 (89%)
Similarly, 2-propylpyrrolidine 3b was obtained in 40% yield.
Interestingly, 2-alkylpyrrolidines 3a,b give low-boiling (up to
115°C) mixtures with water. We failed to isolate them in pure
form, neither by prolonged drying of an ethereal extract of
the crude product with KOH/NaOH, nor by replacement of the
solvent by hexane. Eventually we had to introduce a stage of
picrate preparation. Furthermore, pyrrolidines 3a,b give hygro-
scopic hydrooxalates, which can be dried only by prolonged
heating at 60–110°C in a rotary evaporator.
2-Pentylpyrrolidine 3c that has a higher boiling point was
fractionated in vacuo of a water-jet pump and was isolated in
42% yield. Using a similar approach, we obtained 2-phenyl- and
2-(p-tolyl)pyrrolidines 3d and 3e in 37 and 36% yields, respec-
tively (purification was carried out by distillation under reduced
pressure).‡ Note that all the yields indicated were calculated with
respect to the starting proline. Since the described method does
not require purification of intermediate products, it is rather
simple to perform and can easily be scaled for even larger loads.
In conclusion, we proposed a new three-stage protocol for
the preparation of 2-substituted pyrrolidines from proline, benz-
aldehyde and Grignard reagents. It formally looks like replace-
ment of the carboxy group in proline by a hydrocarbon residue
and makes available a series of simplest 2-alkyl- and 2-arylpyr-
rolidines that can be of interest for synthesizing more complex
molecules with potential biological activity.
R
R
RMgBr
Pb(OAc)4
– AcOH
N
N
+
OH
Ph
OH
Ph
Ph
Ph
2
2'
OAc
Pb
OAc
R
N
R
N
OAc
– Pb(OAc)2
– PhCHO
O
Ph
Ph
OAc
Ph
– PhCHO
– AcOH
H2O
a R = Et, 39%
b R = Pr, 40%
c R = n-C5H11, 42%
d R = Ph, 37%
R
N
H
e R = 4-MeC6H4, 36%
3a–e
Scheme 2
toluene on cooling. Using this method, 2-ethylpyrrolidine 3a
was obtained in 39% yield after fractional distillation.† A likely
mechanism of the redox process is shown in Scheme 2. In
fact, it is a modification of the known Criegee cleavage of
1,2-diols, where the nitrogen atom acts as an electron donor
in the initial process stage. Of the reported methods for amino
This work was supported by the Russian Science Foundation
(grant no. 14-13-00388).
The mixture of amino alcohols 2 and 2' (50 mmol) was dissolved in
60 ml of PhMe in a round-bottom one-necked 250 ml flask, cooled in an
ice-salt bath, and Pb(OAc)4 (29.9 g, 67.5 mmol, 1.35 equiv.) was added
in portions with stirring. The mixture was allowed to warm to room tem-
perature and stirred for 1 h. Concentrated HCl (29 ml) and water (100 ml)
were added, and the mixture was boiled for 15 min. After cooling to room
temperature, the aqueous and toluene layers were decanted from the
remaining PbCl2 + resin. The remaining product was extracted with an
additional amount of water (30 ml) from the residue in the flask; the
extraction was carried out with heating and stirring followed by cooling.
All the liquid phases were combined, toluene was separated, and the
aqueous layer was extracted with diethyl ether (2×25 ml). A large excess
of NaOH (60 g, 1.5 mol) was added to the solution. Pyrrolidine 3 that
separated was extracted with diethyl ether (2×25 ml). The extract was
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2015.11.014.
References
1
(a)A. O. Plunkett, Nat. Prod. Rep., 1994, 11, 581; (b) G. Pandey, P. Banerjee
and S. R. Gadre, Chem. Rev., 2006, 106, 4484; (c) A. Mitchinson and
A. Nadin, J. Chem. Soc., Perkin Trans. 1, 2000, 2862.
2 Tobacco Alkaloids and Related Compounds, ed. U. S. von Euler, Pergamon,
New York, 1965.
3 N. E. Shevchenko, K. Vlasov, V. G. Nenajdenko and G.-V. Röschenthaler,
Tetrahedron, 2011, 67, 69.
4 L. C. Craig, H. Bulbrook and R. M. Hixon, J. Am. Chem. Soc., 1931, 53,
1831.
5 J. H. Burckhalter and J. H. Short, J. Org. Chem., 1958, 23, 1281.
6 K. L. Sorgi, C. A. Maryanoff, D. F. McComsey and B. E. Maryanoff,
Org. Synth., 1998, 75, 215.
7 (a) C. J. Dunsmore, R. Carr, T. Fleming and N. J. Turner, J. Am. Chem.
Soc., 2006, 128, 2224; (b) J. I. Seeman, Synthesis, 1977, 498; (c) D. H. Hua,
S. W. Miao, S. N. Bharathi, T. Katsuhira and A. A. Bravo, J. Org. Chem.,
1990, 55, 3682; (d) C. A. Willoughby and S. L. Buchwald, J. Org.
Chem., 1993, 58, 7627.
8 L. E. Burgess and A. I. Meyers, J. Org. Chem., 1992, 57, 1656.
9 (a) C. Zhang and D. Seidel, J. Am. Chem. Soc., 2010, 132, 1798;
(b) D. Das, M. T. Richers, L. Ma and D. Seidel, Org. Lett., 2011, 13,
6584; (c) L. Ma, W. Chen and D. Seidel, J. Am. Chem. Soc., 2012, 134,
15305; (d) D. Das, A. X. Sun and D. Seidel, Angew. Chem. Int. Ed.,
2013, 52, 3765; (e) W. Chen, R. G. Wilde and D. Seidel, Org. Lett.,
2014, 16, 730; (f) D. Seidel, Acc. Chem. Res., 2015, 48, 317.
10 (a) V. S. Moshkin and V. Y. Sosnovskikh, Tetrahedron Lett., 2013, 54,
2455; (b) V. S. Moshkin and V.Y. Sosnovskikh, Tetrahedron Lett., 2013,
54, 2699; (c) V. S. Moshkin and V. Y. Sosnovskikh, Tetrahedron Lett.,
2014, 55, 6121; (d) V. Y. Sosnovskikh, M. Y. Kornev and V. S. Moshkin,
Tetrahedron Lett., 2014, 55, 212; (e) V. Y. Sosnovskikh, M. Y. Kornev,
V. S. Moshkin and E. M. Buev, Tetrahedron, 2014, 70, 9253.
dried and fractionally distilled.
‡
2-Pentylpyrrolidine 3c. Yield 42%, colourless liquid, bp 70–75°C/10 Torr
(lit.,14 bp 153°C/760 Torr). 1H NMR (500 MHz, CDCl3) d: 0.89 (t, 3H,
Me, J 6.9 Hz), 1.22 (ddt, 1H, J 12.2, 9.3 and 8.0 Hz), 1.26–1.50 (m, 8H),
1.65–1.79 (m, 2H), 1.82–1.91 (m, 2H), 2.81 (ddd, 1H, CHHN, J 10.5,
8.0 and 7.1 Hz), 2.92 (quintet, 1H, CHN, J 6.9 Hz), 3.01 (ddd, 1H,
CHHN, J 10.5, 7.6 and 5.3 Hz).
2-Phenylpyrrolidine 3d. Yield 37%, colourless liquid, bp 102–106°C/
10 Torr (lit.,15 bp 104–108°C/10 Torr), picrate mp 147–150°C (lit.,5
bp 148–149°C). 1H NMR (400 MHz, CDCl3) d: 1.61–1.73 (m, 1H),
1.79–1.98 (m, 2H), 2.13–2.23 (m, 1H), 2.25 (s, 1H, NH), 3.01 (ddd, 1H,
CHHN, J 10.1, 8.2 and 6.8 Hz), 3.20 (ddd, 1H, CHHN, J 10.1, 7.7 and
5.3 Hz), 4.11 (t, 1H, CHN, J 7.7 Hz), 7.22 (tt, 1H, Ph, J 7.1 and 1.6 Hz),
7.28–7.38 (m, 4H, Ph).
2-(p-Tolyl)pyrrolidine 3e.Yield 36%, colourless liquid, bp 120–123°C/
1
10 Torr (lit.,16 bp 128–130°C/9 Torr). H NMR (500 MHz, CDCl3) d:
1.60–1.67 (m, 1H), 1.78–1.95 (m, 2H), 1.99 (s, 1H, NH), 2.11–2.19 (m,
1H), 2.32 (s, 3H, Me), 2.98 (ddd, 1H, CHHN, J 10.1, 8.3 and 6.9 Hz),
3.19 (ddd, 1H, CHHN, J 10.1, 7.8 and 5.2 Hz), 4.06 (t, 1H, CHN, J 7.7 Hz),
7.12 (d, 2H, Ar, J 8.0 Hz), 7.24 (d, 2H, Ar, J 8.0 Hz).
– 441 –

Mendeleev Commun., 2015, 25, 440–442
11 (a) G. P. Rizzi, J. Org. Chem., 1970, 35, 2069; (b) A. Padwa and W. Dent,
2007, 63, 625; (f) H. Poerwono, K. Higashiyama, T. Yamauchi, H. Kubo,
. Ohmiya and H. Takahashi, Tetrahedron, 1998, 54, 13955; (g)T. Kobayashi,
F. Hasegawa, Y. Hirose, K. Tanaka, H. Mori and S. Katsumura, J. Org.
Chem., 2012, 77, 1812; (h) H. Takahashi, B. C. Hsieh and K. Higashiyama,
Chem. Pharm. Bull., 1990, 38, 2429.
J. Org. Chem., 1987, 52, 235; (c) F. Orsini, F. Pelizzoni, M. Forte, R. Destro
and P. Gariboldi, Tetrahedron, 1988, 44, 519; (d) M. Nyerges, I. Fejes,
A. Virányi, P. W. Groundwater and L. Töke, Synthesis, 2001, 1479;
(e) J. H. Ryan, N. Spiccia, L. S.-M. Wong and A. B. Holmes, Aust. J.
Chem., 2007, 60, 898.
S
14 J. M. Patterson, J. Brasch and P. Drenchko, J. Org. Chem., 1962, 27,
1652.
12 M. Rahman, A. K. Bagdi, S. Mishra and A. Hajra, Chem. Commun.,
2014, 50, 2951.
15 M. Malmberg and K. Nyberg, Acta Chem. Scand., Ser. B, 1981, 35, 411.
16 D. F. Starr, H. Bulbrook and R. M. Hixon, J. Am. Chem. Soc., 1932, 54,
3971.
13 (a) L. Guerrier, J. Royer, D. S. Grierson and H.-P. Husson, J. Am. Chem.
Soc., 1983, 105, 7754; (b) A. Cisneros, S. Fernández and J. E. Hernández,
Synth. Commun., 1982, 12, 833; (c) Y. Génisson, M. Mehmandoust,
C. Marazano and B. C. Das, Heterocycles, 1994, 39, 811; (d) C. Agami,
F. Couty and G. Evano, Tetrahedron Lett., 1999, 40, 3709; (e) H. Fujioka,
H. Hirose, Y. Ohba, K. Murai, K. Nakahara and Y. Kita, Tetrahedron,
Received: 15th May 2015; Com. 15/4625
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