A new and direct synthesis of 2-substituted pyrrolidines

Full text of DOI:10.1021/jo010419n

J . Org. Chem. 2001, 66, 6207-6208
6207
A New a n d Dir ect Syn th esis of
2-Su bstitu ted P yr r olid in es
Miguel Yus,* Tatiana Soler, and Francisco Foubelo*
Departamento de Quı´mica Orga´nica, Facultad de Ciencias,
Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Resu lts a n d Discu ssion
yus@ua.es
Starting chloroimines 1 were easily prepared by reac-
tion of commercially available 3-chloropropylamine hy-
drochloride with the corresponding carbonyl compound
(R1R2CO) and sodium carbonate in water (for R1 * H, R2
) H; compounds 1a -j,l) or methanol (R1,R2 * H; com-
pound 1k ) at room temperature (Table 1).10
The reaction of different N-(3-chloropropyl) imines
1a -l with an excess of lithium powder (1:10 molar ratio)
and a catalytic amount of DTBB (1:0.1 molar ratio; 5%
molar) in THF at -78 °C for 2 h led, after hydrolysis with
water, to the expected pyrrolidines 2a -l (Table 1). In the
case of nornicotine (2l), and due to its high solubility in
water and easy decomposition by column chromatogra-
phy, it was not possible to isolate it in pure form. For
these reasons, we transformed the initially formed nor-
nicotine (2l) into its N-benzoyl derivative (2′l).
From a mechanistic point of view, we think that a
chlorine-lithium exchange takes place (without changing
the imine functionality) giving an intermediate of type
IV, in which an intramolecular addition occurs via a
endo-trig process, generating the corresponding cycliza-
tion to yield the expected N-lithium pyrrolidines. Final
lithium-hydrogen exchange affords pyrrolidines 2.
In summary, the methodology reported here represents
a new route to prepare 2-substituted pyrrolidines, includ-
ing nornicotine, starting from very simple materials, such
as carbonyl compounds (mainly aromatic aldehydes) and
3-chloropropylamine, this being a new disconnection to
generate this type of biologically interesting units (Scheme
1). In the case of imines derived from aliphatic ketones
and aldehydes, this methodology gives significantly lower
yields.
Received April 23, 2001
In tr od u ction
Pyrrolidines are important structural units because
they take part in many natural occurring alkaloids, such
as hygrine, nicotine, tropine, or cocaine, which show
strong biological activity.1,2 Other compounds having this
moiety belong to the amino acids kingdom, such as
proline or kainic acid. In addition, prolinol derivatives,
such as the couple (S)/(R)-1-amino-2-(methoxymethyl)-
pyrrolidines (SAMP/RAMP) have found important ap-
plications as chiral auxiliaries, mainly in stereoselective
deprotonation of hydrazones.3
Methodologies to construct the pyrrolidine ring include
inter- or intramolecular reactions.4-6 To the first group
belong (a) radical, electrophilic, or metal-mediated me-
tathesis of diallylamines; (b) 1,3-dipolar cycloaddition
starting from aziridines; (c) samarium diiodide-promoted
cyclization of bis(â-ketoalkyl)amine derivatives; and (e)
aminomercuration of 1,5-hexadiene.7 Among procedures
involving intramolecular reactions, the most useful meth-
ods start from bishomoallylamines (I), or 4-chloroalkyl-
amines (II) by radical (or electrophilic) cyclization, or an
SN reaction, respectively.5 In this paper we propose a new
approach to synthesize the pyrrolidine ring starting from
chloroimines III (easily available from the corresponding
carbonyl compounds and 3-chloropropylamine) and per-
forming a chlorine-lithium exchange using a 4,4-di-tert-
butylbiphenyl (DTBB) catalyzed lithiation,8 so the cor-
responding functionalized intermediate9 of type IV can
undergo intramolecular addition to the imine group
giving the expected cyclization reaction.
Exp er im en ta l Section
(1) See, for instance: Dewick, P. M. Medicinal Natural Products;
J . Wiley & Sons: Chichester, 1997; chapter 6.
Gen er a l Meth od s. All reactions were carried out under an
atmosphere of nitrogen in oven-dried glassware. All reagents
were commercially available and were used as received. THF
was distilled from sodium benzophenone ketyl. IR spectra were
measured (neat) with a Nicolet Impact 400 D-FT Spectrometer.
NMR spectra were recorded with a Bruker AC-300 using CDCl3
as the solvent. LRMS and HRMS were measured with Shimadzu
GC/HS QP-5000 and Finingan MAT95 S spectrometers, respec-
tively. The purity of volatile products and the chromatographic
analyses (GLC) were determined with a Hewlett-Packard HP-
5890 instrument equipped with a flame ionization detector and
a 12 m capillary column (0.2 mm diameter, 0.33 µm film
(2) For biosynthesis studies, see: (a) Terssell, K. B. G. Natural
Product Chemistry, 2nd ed.; Apotekarsocieteten: Stokholm, 1977;
chapter 8. (b) Misra, N.; Luthra, R.; Singh, K. L.; Kumar, S. In
Comprehensive Natural Products Chemistry; Barton, D.; Nakanishi,
K.; Meth-Cohn, O.; Kelly, I. W., Eds.; Elsevier: Amsterdam, 1999; vol
4, chapter 4.03.
(3) Enders, D. In Asymmetric Synthesis; Morrison, J . D.; Ed.;
Academic Press: Orlando, 1984; vol 3, chapter 4, pp 275-339.
(4) For general information, see: Mitchinson, A.; Nadin, A. J . Chem.
Soc., Perkin Trans. 1 2000, 2862-2892 (Contemporary review) and
former reviews on “Saturated nitrogen heterocycles” cited therein.
(5) For a review, see: Pichon, M.; Figade`re, B. Tetrahedron: Asym-
metry 1996, 7, 927-964.
thickness), using nitrogen (2 mL/min) as carrier gas, Tinjector
)
(6) Pyrrolidine is prepared industrially following two procedures:
(a) Hydrogenation of pyrrole using a Rh-Al catalyst, and (b) reaction
of 1,4-butanediol with ammonia at 350 °C in the presence of aluminum
oxide. See, for instance Acheson, R. M. An Introduction to the Chemistry
of Heterocyclic Compounds; J ohn Wiley & Sons: New York, 1976;
chapter III.
(7) (a) Go´mez-Aranda, V.; Barluenga, J .; Yus, M. An. Quim. 1972,
68, 221-222. (b) Barluenga, J .; Na´jera, C.; Yus, M. J . Heterocycl. Chem.
1981, 18, 1297-1299.
(8) Reviews: (a) Yus, M. Chem. Soc. Rev. 1996, 155-161. (b) Ramo´n,
D. J .; Yus, M. Eur. J . Org. Chem. 2000, 225-237 (Microreview).
275 °C, Tdetector ) 300 °C, Tcolumn ) 80 °C (3 min), and 80-270
°C (15 °C/min), P ) 40 kPa; tr values are given in min under
these conditions.
(9) Reviews: (a) Na´jera, C.; Yus, M. Trends Org. Chem. 1991, 1,
155-181. (b) Na´jera, C.; Yus, M. Recent Res. Dev. Org. Chem. 1997, 1,
67-96. (c) Yus, M.; Foubelo, F. Rev. Heteroatom. Chem. 1997, 17, 73-
107.
(10) Grigg, R.; Nimal Gunaratne, H. Q.; Kemp, J . J . Chem. Soc.,
Perkin Trans. 1 1984, 41-46.
10.1021/jo010419n CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/08/2001

6208 J . Org. Chem., Vol. 66, No. 18, 2001
Notes
Ta ble 1.
Yields are included in Table 1. Spectroscopic and analytical data
are included as Supporting Information.
Gen er a l P r oced u r e for th e P r ep a r a tion of Su bstitu ted
P yr r olid in es 2. To a blue suspension of lithium powder (75 mg,
10 mmol) and a catalytic amount of DTBB (30 mg, 0.10 mmol;
5% molar) in THF (5 mL) was added the corresponding imine 1
(1 mmol) at -78 °C, and the resulting mixture was stirred for 2
h at the same temperature. Then, it was hydrolyzed with water
(20 mL) allowing the temperature to rise to 20 °C, and the
resulting solution was purified by successively acid-base extrac-
tion with 2 M hydrochloric acid (3 × 15 mL) and 4 M sodium
hydroxide (3 × 20 mL). The final solution was extracted with
ethyl acetate (3 × 20 mL) and the organic layer dried over
Na2SO4 and evaporated (15 Torr) to give pure title compounds
2 (g95% for GLC and/or 300 MHz 1H NMR). In the case of
nornicotine (2l), after acidic extraction, the aqueous layer was
basified with 4 M sodium hydroxide, and benzoyl chloride (0.35
mL, 3.0 mmol) was added dropwise at 0 °C to the resulting
mixture. After 4 h stirring allowing the temperature to rise to
20 °C, the resulting solution was extracted with dichloromethane
(3 × 20 mL) and evaporated (15 Torr) to give a residue, which
was purified by column chromatography (silica gel, hexane/ethyl
acetate/dichloromethane) to yield the expected compound 2′l.
Yields corresponding to compounds 2 are included in Table 1.
Spectroscopic and analytical data are included as Supporting
Information.
step 1 (%)
step 2 (%)
a : R1 ) Ph, R2 ) H
84
88
84
50
70
55
75
70
48
8911
90
87
>9912
>99
b: R1 ) 2-MeC6H4, R2 ) H
c: R1)2,5-Me2C6H3, R2 ) H
d : R1 ) 2,4,6-Me3C6H2, R2 ) H
e: R1 ) 4-MeOC6H4, R2 ) H
f: R1 ) 3,4-(MeO)2C6H3, R2 ) H
g: R1 ) 3,5-(MeO)2C6H3, R2 ) H
h : R1 ) 3,4-(CH2O2)C6H3, R2 ) H
i: R1 ) 4-Me2NC6H4, R2 ) H
j: R1 ) Cy, R2 ) H
98
67
>9913
92
84
90
>9914
50
41
k : R1 ) Ph, R2 ) Me
l: R1 ) 3-pyridyl, R2 ) H
40 (as N-benzoyl
derivative, 2′l)15
Ack n ow led gm en t. Financial support by the DGES
of the Spanish Ministerio de Educacio´n y Cultura (MEC,
no. PB97-0133) is gratefully acknowledged.
Sch em e 1
Su p p or tin g In for m a tion Ava ila ble: Spectral data of
compounds 1 and 2 as well as copies of 1H and 13C NMR
spectra for new compounds 1 and 2. This material is available
free of charge via the Internet at http://pubs.acs.org.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ch lor oim in es
1. A mixture of 3-chloropropylamine hydrochloride (0.29 g, 2.2
mmol), the corresponding aldehyde 1 (R2 ) H; 2.0 mmol), and
sodium carbonate (0.32 g, 2.0 mmol) in water (10 mL) was stirred
at room-temperature overnight. Then, the resulting solution was
extracted with ethyl acetate (3 × 20 mL), and the organic layer
was dried over Na2SO4) and evaporated (15 Torr) to give an
J O010419N
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50, 1083-1092.
1
essentially pure (>90% from GC and/or 300 MHz H NMR) oily
residue containing the title compounds 1, which were used for
the next reaction without further purification. In the case of the
acetophenone derivative 1k , the reaction was performed in
methanol (1 mL) under the same reaction conditions as above.
(14) Mutel, V.; Vieira, E.; Wichmann, J . WO 2000058285; Chem.
Abstr. 2000, 133, 266722.
(15) Seeman, J . I.; Secor, H. V.; Armstrong, D. W.; Timmons, K. E.;
Ward, T. J . Anal. Chem. 1988, 60, 2120-2127.