Organic Process Research & Development 2009, 13, 638–640
Practical One-Pot and Large-Scale Synthesis of N-(tert-Butyloxycarbonyl)-3-pyrroline
Tammana Rajesh,† Shaik Abdul Azeez,† Erragunta Naresh,† Gutta Madhusudhan,*,† and Kagga Mukkanti‡
Inogent Laboratories PriVate Limited, (A GVK BIO Company), 28A, IDA, Nacharam, Hyderabad - 500076, India, and
Department of Chemistry, Jawaharlal Nehru Technological UniVersity, Kukatpally, Hyderabad - 500 072, India
Abstract:
liine, retronecine, and heliotridine. One of the pyrroline
derivatives, (3S,4S)-3-methoxy-4-methylamino-pyrroline, is an
important subunit linked at the C-7 position of quinolone
carboxylic acid, a derivative of potent anti-tumor agents such
as I and II and are prepared from 3-pyrroline.16
N-(tert-Butyloxycarbonyl)-3-pyrroline was prepared with high
purity in large scale starting from cis-1,4-dichloro-2-butene via
delepine reaction and subsequent cyclization in the presence of
potassium carbonate followed by N-Boc protection in methanol.
Judicious selection of base and solvent led to the use of a single
solvent, i.e., methanol, for cyclization as well as for N-Boc
protection to render the one-pot process from compound 2 more
practical and greener than the stepwise version.
Recent studies reveal that bovine plasma amine oxidase
(BPAO), working as a mechanism-based inactivator, metabo-
lizes 3-pyrroline.17 3-Pyrroline derivatives are important to a
huge extent in both biologically active molecules as well as
new classes of therapeutics.
Introduction
N-Substituted 3-pyrrolines are an important class of com-
pounds which exhibit biological activity1,2 and serve as useful
synthetic intermediates.3-8 The alkene moiety of 3-pyrroline
serves as an handle for various organic functional group
transformations. N-(tert-Butyloxycarbonyl)-3-pyrroline has been
used to synthesize various ꢀ-aryl-GABA analogues by Heck
arylation with arenediazonium salts,9 and it is also used to
synthesize aryl pyrrolizidines.10
N-(tert-Butyloxycarbonyl)-3-pyrroline is a key starting mate-
rial for the preparation of 3,4-disubstituted pyrrolines,11 pip-
erazines,12 N-substituted pyrroles,13 bicyclic aziridines,14 and
polysubstituted pyrroles.15 3-Pyrroline is an important constitu-
ent of various biologically important molecules such as riddel-
Our need for large quantities of N-(tert-butyloxycarbonyl)-
3-pyrroline led us to develop a scalable synthesis for this
compound. It is possible to purchase this compound (96%) from
Sigma-Aldrich (∼$166/g). 3-Pyrroline is commercially available
as a 3:1 mixture of 3-pyrroline (Figure 1a) and pyrrolidine
(Figure 1b), the mixture being obtained by reduction of pyr-
role with zinc and acetic acid or hydrochloric acid18 (one of
the research publications19 reports about 15% of the content is
pyrrolidine). 3-Pyrroline can be separated from pyrrolidine by
crystallizing its hydrochloride or urethane, but with significant
losses.19,20 Since the difference in boiling points is 1.5 °C only,
separation of 3-pyrroline from pyrrolidine by distillation is
difficult19 and may not be applicable for large-scale laboratory
preparations.
The literature reveals a method for the preparation of
3-pyrroline through 5-endo-trig mode cycloisomerization of
R-amino allenes21 and ring-closing metathesis (RCM) of N-
protected diallyl amines,16,22 but this method may not be
applicable for industrial scale because of its cost and remaining
metallic impurities at ppm levels. Hayes, C. J. et al. used a two-
step alkylation/alkylidene carbene 1,5-CH insertion reaction for
the synthesis of a range of 3-pyrrolines.22c Various other
methods are also described that synthesize 3-pyrroline.23-26
The pyrroline ring system is formed in the reaction of cis-
1,4-dichloro-2-butene with primary amines. Aromatic amines
give higher yields (61-81%)26,27 of N-substituted 3-pyrrolines
than the aliphatic amine (35-60%).27,29 A widely adopted
* Corresponding author. E-mail: madhusudhan.gutta@inogent.com. Fax: +91-
40 2715 1270. Telephone: +91-9849559259.
† Inogent Laboratories Private Limited.
‡ Jawaharlal Nehru Technological University.
(1) Smith, T. A.; Croker, S. J.; Loeffler, R. S. T. Phytochemistry 1986, 2,
683.
(2) Anderson, W. K.; Milowsky, A. S. J. Med. Chem. 1987, 30, 2144.
(3) MacDonald, T. L. J. Org. Chem. 1980, 45, 193.
(4) Brown, H. C.; Vara Prasad, J. V. N.; Gupta, A. K. J. Org. Chem.
1986, 51, 4296.
(5) Palmer, B. D.; Denny, W. A. Synth. Commun. 1987, 17, 601.
(6) Nemia, M. M. B.; Lee, J.; Joulite, M. M. Synth. Commun. 1983, 13,
1117.
(7) Verboom, W.; Van Dijik, B. G.; Reinhoudt, D. N. Tetrahedron Lett.
1983, 24, 3923.
(8) Kawaguchi, M.; Hayashi, O.; Kanamoto, M.; Hamada, M.; Yamamoto,
Y.; Oka, J. Agric. Biol. Chem. 1987, 51, 435.
(9) Garcia, A. L. L.; Carpes, M. J. S.; de Oca, A. C. B. M.; dos Santos,
M. A. G.; Santana, C. C.; Correia, C. R. D. J. Org. Chem. 2005, 70,
1050.
(10) De Oca, A. C. B. M.; Correia, C. R. D. ARKIVOC 2003, 10, 390.
(11) Chapman, T. M.; Courtney, S.; Hay, P.; Davis, B. G. Chem. Eur. J.
2003, 9, 3397.
(12) Kawaguchi, M.; Hayashi, O.; Kanamoto, M.; Hamada, M.; Yamamoto,
Y.; Oda, J. Agric. Biol. Chem. 1987, 51, 435.
(13) Cook, A. G.; Switek, K. A.; Cutler, K. A.; Witt, A. M. Lett. Org.
Chem. 2004, 1, 1.
(14) Akhtar, M. H.; Begleiter, A.; Johnson, D.; Lown, J. W.; McLaughlin,
L.; Sim, S. K. Can. J. Chem. 1975, 53, 2891.
(15) Ko, K. Y.; Lee, K. I.; Kim, J. H.; Jung, M. H.; Kim., W. J. Bull.
Korean Chem. Soc. 1990, 11, 83.
Figure 1. Structures of (a) 3-pyrroline and (b) pyrrolidine.
638
•
Vol. 13, No. 3, 2009 / Organic Process Research & Development
10.1021/op8003037 CCC: $40.75 2009 American Chemical Society
Published on Web 02/12/2009