A new entry into cis-3-amino-2-methylpyrrolidines via ring expansion of 2-(2-hydroxyethyl)-3-methylaziridines

Article abstract of DOI:10.1039/b816617j

3-Amino-2-methylpyrrolidines were prepared via a novel protocol, involving the reductive ring closure and O-deprotection of γ-acetoxy-α- chloroketimines towards 2-(2-hydroxyethyl)-3-methylaziridines, followed by ring expansion of the latter into 3-bromopy

Full text of DOI:10.1039/b816617j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A new entry into cis-3-amino-2-methylpyrrolidines via ring expansion
of 2-(2-hydroxyethyl)-3-methylaziridines†
Matthias D’hooghe, Wim Aelterman and Norbert De Kimpe*
Received 22nd September 2008, Accepted 10th October 2008
First published as an Advance Article on the web 6th November 2008
DOI: 10.1039/b816617j
3-Amino-2-methylpyrrolidines were prepared via a novel protocol, involving the reductive ring closure
and O-deprotection of g-acetoxy-a-chloroketimines towards 2-(2-hydroxyethyl)-3-methylaziridines,
followed by ring expansion of the latter into 3-bromopyrrolidines via intermediate bicyclic aziridinium
salts and consecutive nucleophilic displacement of the bromo atom by azide towards
3-azidopyrrolidines. A final reduction of the azide moiety furnished 3-amino-2-methylpyrrolidines in
high yields. Thus, a new formal synthesis of the antipsychotic emonapride was developed through
preparation and further aroylation of cis-3-amino-1-benzyl-2-methylpyrrolidine.
Introduction
3-Aminopyrrolidines have received considerable interest from a
medicinal point of view due to their broad applicability. For
example, 7-(3-aminopyrrolidin-1-yl)-substituted naphthyridones
and quinolones (such as clinafloxacine and tosufloxacine) have
been described as broad-spectrum antibacterial agents,1 and
different types of 3-aminopyrrolidines have been reported in the
framework of anti-cancer research.2 Furthermore, the antipsy-
chotic emonapride 1, a benzamide derived from the 3-amino-
2-methylpyrrolidine scaffold, is of significant pharmacological
interest.3 Consequently, a variety of 3-amino-2-methylpyrrolidine
Results and discussion
derived benzamides has been prepared and evaluated in terms of
potential bioactivity.4 Despite the pharmaceutical importance of
the 3-amino-2-methylpyrrolidine motif, few general and conve-
nient approaches towards this class of compounds are known.
3-Amino-1-benzyl-2-methylpyrrolidine has been prepared from
the corresponding pyrrolidin-3-one via imination with hydroxyl-
amine and subsequent reduction,3 and different chiral 3-amino-
1-(2-hydroxy-1-phenylethyl)-2-methylpyrrolidines have been syn-
thesized via asymmetric conjugate additions to chiral bicyclic
lactams followed by reductive cleavage.5 The first asymmetric
synthesis of (2R,3R)-3-amino-1-benzyl-2-methylpyrrolidine via a
diastereoselective reductive alkylation has been reported starting
from (S)-malic acid in 11 steps6 and, more recently, a one-pot
synthesis of 2-substituted 3-nitropyrrolidines has been published
based on a multicomponent domino reaction between imines and
3-nitro-1-(methanesulfonyloxy)propane.7
As a model substrate for ring expansions of aziridines into pyrro-
lidines, the synthesis of 2-(2-hydroxyethyl)-2,3-dimethylaziridine 4
was envisaged. Thus, regiospecific alkylation of a-chloroketimine
28 was performed by treatment of the corresponding 3-chloro-
1-azaallyl anion, obtained via a-deprotonation by means of
1.2 equivalents of lithium diisopropylamide (LDA) in ice-
cooled THF for one hour, with 1.05 equivalents of 1-bromo-2-
[(trimethylsilyl)oxy]ethane in THF, affording the functionalized
ketimine 3 in 70% yield (Scheme 1). Further reaction of the
latter imine 3 with 2 molar equivalents of sodium borohydride
in methanol under reflux furnished the corresponding 2-(2-
hydroxyethyl)aziridine 4 as a 1/1 mixture of cis- and trans-
isomers through hydride addition across the imino bond and
subsequent cyclization upon expulsion of chloride (Scheme 1).
During the reductive cyclization, hydride-induced deprotection
of the silyl ether occurred, resulting in a free hydroxyl terminus.
Attempted purification of aziridine 4 by distillation led only
to a moderate yield of 44% and a purity of 85%. Treatment
of distilled 2-(2-hydroxyethyl)aziridine 4 with 1.2 equivalents of
triphenylphosphine and 1.2 equivalents of N-bromosuccinimide
(NBS) in THF at room temperature for 20 hours furnished
3-bromopyrrolidine 6 as a mixture of cis- and trans-isomers,
which could be separated and isolated by means of column
chromatography on silica gel, albeit in low yield due to the
small scale experiment. The formation of pyrrolidine 6 can be
rationalized considering the initial replacement of the hydroxyl
group by a bromo atom, followed by intramolecular nucleophilic
substitution by nitrogen upon expulsion of bromide. The thus
In the present paper, a short and straightforward synthetic
approach towards cis-3-amino-2-methylpyrrolidines via ring ex-
pansion of 2-(2-hydroxyethyl)-3-methylaziridines is disclosed.
Moreover, the high yielding preparation of cis-3-amino-1-benzyl-
2-methylpyrrolidine implies a new formal synthesis of the antipsy-
chotic emonapride 1.
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent
University, Coupure Links 653, B-9000, Ghent, Belgium
† Electronic supplementary information (ESI) available: Additional exper-
imental data. See DOI: 10.1039/b816617j
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Scheme 1
formed bicyclic aziridinium salt 5 is prone to ring opening
by bromide towards pyrrolidine 6 (Scheme 1). Alternatively,
the reaction could proceed via an oxyphosphorane intermediate
instead of via the bromide, leading to the same bicyclic inter-
mediate 5. The ring expansion of 2-(2-hydroxyethyl)aziridines
into pyrrolidines via intermediate 1-azoniabicyclo[2.1.0]pentanes
comprises an unexplored field of research, as only one litera-
ture example is known to date.9 Previously, the alcoholysis of
different a-chloro-g-[(trimethylsily)oxy]ketimines such as 3 has
been described, affording a stereospecific entry into cis-2-alkoxy-
3-aminooxolanes,10 which underlines the synthetic versatility of
this class of imines.
Despite the synthetic relevance of the transformations depicted
in Scheme 1, the low yield and purity in which aziridine 4 was
isolated called for a different approach. As the hydride-induced
in situ formation of a free hydroxyl group might be responsible
for side reactions in the synthesis of 2-(2-hydroxyethyl)aziridine 4,
a different type of O-protecting group was required which is less
reactive towards sodium borohydride. Thus, g-acetoxyketimines
8a–c were prepared via imination of 5-acetoxy-3-chloropentan-
2-one 711 utilizing 4 equivalents of a primary amine in diethyl
ether in the presence of 0.6 equivalents of titanium(IV) chloride
at room temperature (Scheme 2). Subsequent reduction of the
imino moiety and ring closure by means of 1.5 equivalents of
sodium borohydride in methanol at room temperature furnished
2-(2-acetoxyethyl)aziridines 9a–c as mixtures of cis- and trans-
isomers (1/1–1/3) in excellent yields (Scheme 2). The O-protecting
group in the latter aziridines 9 was easily removed upon reaction
with a methanolic solution of 1.5 equivalents of potassium
carbonate at room temperature for 24 hours, yielding 2-(2-
hydroxyethyl)aziridines 10a–c in high yields and purity (Scheme 2).
Scheme 2
The ratio of cis/trans-isomers for aziridines 9 and 10 could be
assigned by comparison of 13C NMR values for both isomers with
literature data of analogous 2,3-dimethylaziridines.12
In the next step, 2-(2-hydroxyethyl)-3-methylaziridines 10 were
converted into 3-bromo-2-methylpyrrolidines 11a–c via interme-
diate bicyclic aziridinium salts 12 by the action of 1.2 equivalents
of triphenylphosphine and 1.2 equivalents of NBS in THF at room
temperature (Scheme 3). Although cis- and trans-pyrrolidines
11 could be separated by means of column chromatography,
a convenient alternative for this laborious method comprised
heating of the mixtures of cis/trans-11 in DMSO at 70–80 ◦C
for 5–20 hours, followed by aqueous workup and extraction with
diethyl ether. In this way, only trans-pyrrolidines trans-11 were
obtained in high yields (49–52% after purification by column
chromatography).
Scheme 3
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At first instance, an equilibrium shift from the bridged bi-
cyclic ammonium ions 12–formed by heating of the mixture of
cis/trans-11 in DMSO–to the corresponding carbenium ions by
spontaneous ring opening, followed by neutralization of the latter
carbenium ions by bromide was assumed to be responsible for
the preferential formation of the more stable trans-pyrrolidines
trans-11. However, this assumption could not be supported by
experimental observations, as no isomerisation of cis-11 into
trans-11 occurred by simply heating pure cis-pyrrolidines cis-11
under the same conditions (DMSO, 70 ◦C, 20 h). At present,
no conclusive explanation can be provided for the experimental
observation that only trans-pyrrolidines trans-11 were obtained
upon heating of the mixtures of cis/trans-11 in DMSO at 70–
80 ◦C for 5–20 hours, followed by aqueous workup and extraction
with diethyl ether. The fact that heating of cis/trans-pyrrolidines
cis/trans-11 was performed on the crude reaction mixture, inwhich
presumably some bromine or another weak Lewis acid activator
was present, might be of importance in that respect.
extent, the N-substituent in the substrate (isopropyl vs. tert-
butyl and benzyl). In the literature, nucleophilic substitutions
of 3-halo- or 3-(sulfonyloxy)pyrrolidines usually proceed via a
direct SN2 process, although also double substitution reactions via
intermediate bicyclic aziridinium salts are known.14 The preference
for one of these routes has been described to be dependant on
different factors such as the solvent,15 the type of nucleophile16
and the relative stereochemistry of the substrate.17
The final goal of this work comprised the synthesis of bio-
logically relevant 3-amino-2-methylpyrrolidines 16, which were
obtained by azide reduction upon treatment of pyrrolidines 14
with 1.5 equivalents of tin(II) chloride in methanol at room
temperature (for R = iPr and tBu) or with 2 equivalents of lithium
aluminium hydride in THF under reflux (for R = Bn) (Scheme 4).
The relative stereochemistry of pyrrolidines 11, 13, 14 and 16 could
be assigned based on NOE effects between the 2-methyl group and
the hydrogen atoms at the 2- and the 3-position (for example, a
NOE of 1.8% and 2.5% was observed between 2-H and 3-H for cis-
1-isopropylpyrrolidines 13 and 14a, respectively). Besides substitu-
tion reactions, dehydrobromination of 3-bromopyrrolidine trans-
11a was evaluated using 1.5 equivalents of potassium tert-butoxide
in THF under reflux, affording 2-methyl-3-pyrroline 17 in 58%
yield (Scheme 4).
The stereochemical assignment of cis-/trans-pyrrolidines 11a–c,
14a and 16a was further supported by careful analysis of spectro-
scopical data. In the literature, 2,3-disubstituted pyrrolidines are
characterized by a so called “g-gauche effect” in 13C NMR for
the carbon atom present at the 2-position. This effect results in
a significant difference in chemical shift D(dtrans - dcis) of 3–5 ppm
between cis and trans isomers.18 Also for pyrrolidines 11a–b, 14a
and 16a, a D(dtrans - dcis) ranging from 2.2 to 3.8 was observed,
which confirmed the postulated stereochemical assignment.
The above-described methodology for the preparation of cis-
3-amino-1-benzyl-2-methylpyrrolidine cis-16c allows the formal
synthesis of the antipsychotic ( )-emonapride 1 in high overall
yield, as the coupling of pyrrolidine cis-16c with 5-chloro-2-
methoxy-4-(methylamino)benzoic acid in the presence of ethyl
chloroformiate and triethylamine has been described in the
literature to afford emonapride 1 (Scheme 5).3 In the light of the
pharmaceutical importance of emonapride 1 and its derivatives,
the present methodology offers a useful and efficient alternative
3-Bromopyrrolidines 11 constitute suitable substrates for fur-
ther functionalization upon nucleophilic substitution of the halo
atom. Treatment of trans-11a with 2 equivalents of potassium
cyanide in DMSO for 24 hours at 90 ◦C afforded the corresponding
cis-3-cyanopyrrolidine cis-13 via a clean SN2 protocol (Scheme 4).
Recently, a variety of 2-substituted pyrrolidine-3-carbonitriles
has been prepared as potential therapeutics for the treatment
of glaucoma.13 When azide was used instead of cyanide, 3-
azidopyrrolidines 14a–c were formed utilizing 3–5 equivalents of
◦
sodium azide in DMSO at 80–90 C for 8–18 hours (Scheme 4).
Remarkably, 3-azido-1-isopropylpyrrolidine 14a was obtained as
a mixture of cis/trans-isomers (cis/trans 3/2), whereas 3-azido-
substituted 1-tert-butyl- and 1-benzylpyrrolidines 14b and 14c
were formed predominantly as cis-isomers (cis/trans > 20/1).
The formation of trans-3-azidopyrrolidines 14 can be explained
considering the formation of an intermediate bicyclic aziridinium
salt 15, followed by ring opening by azide at the more hindered
position. In this case, double Walden inversion – i.e. two times
SN2 reaction – results in retention of configuration, affording
trans-pyrrolidines as the substitution products. Obviously, the
competition between direct SN2 substitution and formation of a
constrained bicyclic intermediate in these reactions is dependant
on the type of nucleophile (cyanide vs. azide) and, to a lesser
Scheme 4
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agent and evaporation of the solvent afforded the crude aziridine
4, which was purified by distillation (Bp. 50–54 ◦C/0.3 mmHg).
1H NMR (270 MHz, CDCl3): d 1.05 (3H, d, J = 6.6 Hz); 1.09
and 1.10 (6H, 2 ¥ d, J = 6.3 Hz); 1.00-1.24 (11H, m); 1.25 and
1.26 (6H, 2 ¥ s); 1.61 (4H, ~t, J = 6.3 Hz); 2.19 (2H, ~septet, J =
6.3 Hz); 3.56–3.92 (4H, m). 13C NMR (68 MHz, CDCl3): d 14.9,
17.2, 20.6, 23.1, 23.2, 23.3, 23.4, 35.9, 36.5, 41.8, 43.2, 43.5, 44.4,
52.8, 52.9, 60.77, 60.81. IR (NaCl): nOH = 3570–3050 cm-1. MS
(70 eV): m/z (%): 157 (M+, 1); 142 (5); 128 (3); 126 (6); 124 (5);
114 (16); 112 (13); 98 (10); 96 (4); 94 (5); 86 (32); 84 (29); 82 (8);
70 (79); 67 (6); 58 (10); 55 (12); 53 (6).
Scheme 5
for the limited number of known synthetic methodologies towards
this class of compounds.
Synthesis of 3-bromo-1-isopropyl-2,3-dimethylpyrrolidine 6
In conclusion, a novel and efficient approach towards biolog-
ically relevant 3-amino-2-methylpyrrolidines has been developed
starting from g-acetoxy-a-chloroketimines. This methodology in-
volves the reductive ring closure and O-deprotection of g-acetoxy-
a-chloroketimines towards 2-(2-hydroxyethyl)-3-methylaziridines,
followed by ring expansion of the latter into 3-bromopyrrolidines
via intermediate bicyclic aziridinium salts and consecutive nucle-
ophilic displacement of the bromo atom by azide. A final reduction
of the azide moiety afforded the title compounds in good yields.
Furthermore, the straightforward preparation of cis-3-amino-1-
benzyl-2-methylpyrrolidine implies a new formal synthesis of the
antipsychotic emonapride.
To a solution of aziridine 4 (5 mmol) in THF (30 mL) was added N-
bromosuccinimide (6 mmol) and triphenylphosphine (6 mmol) at
room temperature, after which the mixture was stirred for 20 hours
at room temperature. Afterwards, the reaction mixture was poured
into water (30 mL) and extracted with Et2O (3 ¥ 25 mL). Drying
(MgSO4), removal of the drying agent and evaporation of the
solvent afforded a residue, to which Et2O (25 mL) was added.
After a second filtration, Et2O (25 mL) was added and the
suspension was stored at -20 ◦C for 15 hours. A final filtration
and evaporation of the solvent afforded the crude pyrrolidine
cis/trans-6, which was purified by column chromatography on
silica gel (hexane/EtOAc/MeOH 90/7/3) in order to separate
both isomers.
Experimental section
Synthesis of N-[2-chloro-1-methyl-2-(2-trimethylsilyloxyethyl)pro-
pylidene] isopropylamine 3
cis-3-Bromo-1-isopropyl-2,3-dimethylpyrrolidine cis-6
1
Rf 0.11 (hexane/EtOAc/MeOH 90/7/3). H NMR (270 MHz,
To an ice-cooled solution of diisopropylamine (12 mmol) in dry
THF (10 mL) under nitrogen atmosphere was added n-BuLi
(12 mmol, 2.5 M in hexane) via a syringe. After 10 minutes,
a solution of a-chloroketimine 28 (10 mmol) in THF (5 mL)
was added via a syringe, after which the resulting solution was
stirred for 1 hour at 0 ◦C. Subsequently, a solution of 1-bromo-2-
[(trimethylsilyl)oxy]ethane (10.5 mmol) in THF (5 mL) was added
via a syringe at 0 ◦C, and the resulting solution was stirred for
15 hours at room temperature. Afterwards, the reaction mixture
was poured into an aqueous solution of NaOH (15 mL, 0.5 M)
and extracted with Et2O (3 ¥ 15 mL). Drying (K2CO3), removal
of the drying agent and evaporation of the solvent afforded◦the
crude imine 3, which was purified by distillation (Bp. 60–62 C/
0.05 mmHg).
CDCl3): d 0.91 and 1.15 (6H, 2 ¥ d, J = 6.6 Hz); 1.14 (3H,
d, J = 5.9 Hz); 1.79 (3H, s); 1.97 (1H, d ¥ d ¥ d, J = 14.1, 9.9,
7.7 Hz); 2.27 (1H, q, J = 5.9 Hz); 2.46 (1H, d ¥ d ¥ d, J = 14.1,
7.9, 3.6 Hz); 2.68 (1H, t ¥ d, J = 9.9, 3.6 Hz); 3.01-3.12 (1H,
m); 3.09 (1H, septet, J = 6.6 Hz). 13C NMR (68 MHz, CDCl3):
d 13.3, 16.8, 22.1, 30.0, 42.3, 43.1, 47.4, 65.8, 75.5. IR (NaCl):
nmax = 2958, 1448, 1375, 1358, 1100 cm-1. MS (70 eV): m/z (%):
219/21 (M+, 11); 204/6 (49); 140 (50); 137 (11); 125 (21); 124
(61); 122 (12); 110 (18); 98 (91); 96 (21); 94 (31); 84 (22); 83 (28);
82 (25); 81 (19); 69 (17); 56 (100); 53 (19); 49 (11). Anal. Calcd
for C9H18BrN: C 49.10, H 8.24, N 6.36. Found: C 49.73, H 8.56,
N 6.52.
1H NMR (270 MHz, CDCl3): d 0.10 (9H, s); 1.10 (6H, d, J =
6 Hz); 1.70 (3H, s); 1.99 (3H, s); 2.0-2.4 (2H, m); 3.6-3.8 (1H,
m); 3.76 (2H, t, J = 7 Hz). 13C NMR (68 MHz, CDCl3): d -0.5,
trans-3-Bromo-1-isopropyl-2,3-dimethylpyrrolidine trans-6
1
Rf 0.29 (hexane/EtOAc/MeOH 90/7/3). H NMR (270 MHz,
12.9, 23.2, 28.4, 44.5, 50.7, 59.3, 74.9, 164.5. IR (NaCl): nC
=
=
CDCl3): d 1.00 and 1.11 (6H, 2 ¥ d, J = 6.6 Hz); 1.02 (3H, d, J =
6.6 Hz); 1.77 (3H, s); 2.04 (1H, d ¥ d ¥ d, J = 13.6, 9.0, 7.6 Hz);
2.27 (1H, d ¥ d¥d, J = 13.6, 7.1, 2.6 Hz); 2.82-3.00 (2H, m); 3.00
(1H, septet, J = 6.6 Hz); 3.36 (1H, q, J = 6.6 Hz). 13C NMR
(68 MHz, CDCl3): d 16.9, 22.3, 17.9, 28.5, 42.2, 45.6, 50.4, 68.0,
72.2. IR (NaCl): nmax = 2960, 1500, 1378, 1210, 1170, 1074 cm-1.
MS (70 eV): m/z (%): 219/21 (M+, 16); 204/6 (77); 140 (58); 137
(16); 125 (45); 124 (87); 122 (14); 110 (33); 98 (99); 96 (22); 94
(36); 83 (30); 82 (35); 81 (20); 70 (16); 56 (100). Anal. Calcd for
C9H18BrN: C 49.10, H 8.24, N 6.36. Found: C 49.39, H 8.38,
N 6.27.
N
1651 cm-1. MS (70 eV): m/z (%): no M+; 248/50 (7); 228 (5); 147/9
(92); 132 (17); 112 (23); 96 (20); 84 (100); 73 (21).
Synthesis of 2-(2-hydroxyethyl)-1-isopropyl-2,3-dimethylaziridine 4
To an ice-cooled solution of imine 3 (5 mmol) in methanol (10 mL)
was added NaBH4 (10 mmol) in small portions, and the resulting
mixture was heated under reflux for 2 hours. Afterwards, the
reaction mixture was poured into water (15 mL) and extracted
with CH2Cl2 (3 ¥ 15 mL). Drying (MgSO4), removal of the drying
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Synthesis of N-(4-acetoxy-2-chloro-1-methylbutylidene)amines 8
(64); 69 (8); 68 (12); 67 (6); 58 (5); 57 (6); 56 (23); 55 (25); 54 (13);
42 (100). Anal. Calcd for C10H19NO2: C 64.83, H 10.34, N 7.56.
Found: C 64.59, H 10.10, N 7.54.
General procedure: To a solution of 5-acetoxy-3-chloropentan-
2-one 711 (10 mmol) in dry Et2O (25 mL) was added amine
(40 mmol), followed by the gentle addition of a solution of TiCl4
(6 mmol) in pentane (10 mL) at 0 ◦C, after which the resulting
mixture was stirred for 2 hours at room temperature. Afterwards,
the reaction mixture was poured into an aqueous solution of
NaOH (15 mL, 0.5 M) and extracted with Et2O (3 ¥ 25 mL).
Drying (K2CO3), removal of the drying agent and evaporation
of the solvent afforded the crude imine 8, which was purified by
distillation. For the synthesis of N-benzylimine 8c, a mixture of
1 equiv of benzylamine and 3 equiv of Et3N was used instead of
4 equiv of benzylamine.
Synthesis of 2-(2-hydroxyethyl)-3-methylaziridines 10
General procedure: To a solution of aziridine 9 (10 mmol) in dry
methanol (20 mL) was added K2CO3 (15 mmol), and the resulting
mixture was stirred at room temperature for 24 hours. Afterwards,
the reaction mixture was poured into water (25 mL) and extracted
with CH2Cl2 (3 ¥ 15 mL). Drying (MgSO4), removal of the drying
agent and evaporation of the solvent afforded the crude aziridine
10, which was purified by distillation.
2-(2-Hydroxyethyl)-1-isopropyl-3-methylaziridine 10a
N-(4-Acetoxy-2-chloro-1-methylbutylidene)isopropylamine 8a
◦
1
Bp. 85–92 C/8 mmHg. H NMR (270 MHz, CDCl3): d 1.11,
1.13, 1.15, 1.16 and 1.28 (2 ¥ 9H, 5 ¥ d, J = 6.2 Hz); 1.39-2.25 (2 ¥
5H, m); 3.57-3.92 (2 ¥ 2H, m). 13C NMR (68 MHz, CDCl3): dcis-10a
13.6, 21.8, 21.9, 29.9, 37.6, 40.8, 61.1, 61.3. dtrans-10a 10.8, 22.7, 23.0,
32.8, 36.2, 42.6, 50.9, 60.3. IR (NaCl): nOH = 3540–3020 cm-1. MS
(70 eV): m/zcis-10a (%): 143 (M+, 4); 128 (17); 112 (57); 100 (27);
98 (11); 84 (11); 70 (100); 57 (17); 56 (82); 55 (14). m/ztrans-10a (%):
143 (M+, 8); 128 (19); 112 (55); 100 (28); 99 (11); 98 (13); 84 (25);
70 (100); 56 (84). Anal. Calcd for C8H17NO: C 67.09, H 11.96, N
9.78. Found: C 67.27, H 12.19, N 7.66.
◦
1
Bp. 53–56 C/0.03 mmHg. H NMR (270 MHz, CDCl3): d 1.10
and 1.13 (6H, 2 ¥ d, J = 6.3 Hz); 1.94 (3H, s); 2.05-2.35 (2H, m);
3.69 (1H, septet, J = 6.3 Hz); 4.15–4.30 (2H, m); 4.49 (1H, d ¥ d,
J = 8.9, 6.0 Hz). 13C NMR (68 MHz, CDCl3): d 12.9, 20.9, 23.0,
34.1, 50.8, 61.2, 64.0, 163.2, 170.9. IR (NaCl): nC = 1740 cm-1,
=
O
nC N = 1658 cm-1. MS (70 eV): m/z (%): 218/220 (M+, 0.4); 184/6
=
(3); 144/6 (5); 134/6 (3); 133/5 (21); 120 (3); 119 (2); 118 (5); 112
(2); 108 (2); 104 (2); 98 (7); 85 (4); 84 (37); 82 (4); 80 (2); 76 (4);
70 (2); 68 (2); 67 (3); 61 (3); 60 (2); 55 (5); 54 (3); 53 (2); 49 (2); 42
(100).
Synthesis of 3-bromo-2-methylpyrrolidines 11
Synthesis of 2-(2-acetoxyethyl)-3-methylaziridines 9
General procedure: To a solution of aziridine 10 (5 mmol) in
THF (30 mL) was added N-bromosuccinimide (6 mmol) and
triphenylphosphine (6 mmol) at room temperature, after which
the mixture was stirred for 6–21 hours at room temperature.
Afterwards, the reaction mixture was poured into water (30 mL)
and extracted with Et2O (3 ¥ 25 mL). Drying (MgSO4), removal of
the drying agent and evaporation of the solvent afforded a residue,
to which Et2O (25 mL) was added. After a second filtration◦, Et2O
(25 mL) was added and the suspension was stored at -20 C for
15 hours. A final filtration and evaporation of the solvent afforded
the crude pyrrolidine cis/trans-11, which was purified by column
chromatography on silica gel in order to separate both isomers.
General procedure: To an ice-cooled solution of imine 8 (5 mmol)
in methanol (10 mL) was added NaBH4 (7.5 mmol) in small
portions, and the resulting mixture was stirred at room temper-
ature for 4 hours. Afterwards, the reaction mixture was poured
into water (15 mL) and extracted with CH2Cl2 (3 ¥ 15 mL).
Drying (MgSO4), removal of the drying agent and evaporation
of the solvent afforded aziridine 9. The isomers cis/trans-9a and
cis/trans-9b were separated by preparative gas chromatography.
cis-2-(2-Acetoxyethyl)-1-isopropyl-3-methylaziridine cis-9a
1H NMR (270 MHz, CDCl3): d 1.09 and 1.11 (6H, 2 ¥ d, J =
6.3 Hz); 1.15 (3H, d, J = 5.6 Hz); 1.36-1.58 (3H, m); 1.60-1.88
(2H, m); 2.07 (3H, s); 4.20 (2H, t, J = 6.5 Hz). 13C NMR (68 MHz,
CDCl3): d 13.7, 21.0, 21.9, 27.5, 37.8, 40.1, 61.1, 63.2, 171.1. IR
(NaCl): nC = 1738 cm-1. MS (70 eV): m/z (%): 185 (M+, 4); 170
Remark. As an alternative for the separation of cis/trans-
pyrrolidines 11 by column chromatography, the following proce-
dure can be applied. Heating of the crude mixture of cis/trans-11
in DMSO at 70–80 ◦C for 5–20 hours, followed by aqueous workup
and extraction with diethyl ether afforded only trans-pyrrolidines
trans-11, which were purified by column chromatography on silica
gel to furnish pure trans-11 in 49–52% yield.
=
O
(5); 142 (14); 126 (24); 125 (6); 112 (45); 110 (16); 100 (9); 85 (7); 84
(16); 83 (13); 82 (100); 72 (5); 71 (5); 70 (64); 69 (8); 68 (12); 67 (6);
58 (5); 57 (6); 56 (23); 55 (25); 54 (13); 42 (100). Anal. Calcd for
C10H19NO2: C 64.83, H 10.34, N 7.56. Found: C 64.62, H 10.07,
N 7.44.
cis-3-Bromo-1-isopropyl-2-methylpyrrolidine cis-11a
1
Rf 0.15 (hexane/EtOAc/MeOH 90/8/2). H NMR (270 MHz,
trans-2-(2-Acetoxyethyl)-1-isopropyl-3-methylaziridine trans-9a
CDCl3): d 0.95 and 1.12 (6H, 2 ¥ d, J = 6.4 Hz); 1.14 (3H, d, J =
6.3 Hz); 2.15-2.47 (2H, m); 2.65 (1H, d ¥ t, J = 8.9, 6.5 Hz); 2.84–
3.05 (3H, m); 4.40 (1H, d ¥ t, J = 6.6, 5.3 Hz). 13C NMR (68 MHz,
CDCl3): d 15.6, 16.7, 21.9, 34.5, 44.6, 48.5, 55.5, 58.2. IR (NaCl):
nmax = 2960, 1450, 1380, 1188 cm-1. MS (70 eV): m/z (%): 205/7
(M+, 24); 190/2 (100); 148/50 (11); 126 (43); 111 (26); 110 (26); 96
(20); 85 (13); 84 (77); 83 (15); 82 (22); 81 (10); 80 (16); 69 (38); 68
(22); 67 (29); 57 (34); 56 (69); 55 (28); 54 (12); 53 (11). Anal. Calcd
1H NMR (270 MHz, CDCl3): d 1.10 (6H, d, J = 6.1 Hz); 1.28 (3H,
d, J = 5.9 Hz); 1.10-1.25 (1H, m); 1.45-1.92 (3H, m); 2.06 (3H, s);
2.21 (1H, septet, J = 6.1 Hz); 4.18 (2H, d ¥ d, J = 7.4, 5.8 Hz). 13
C
NMR (68 MHz, CDCl3): d 11.1, 21.0, 22.9, 23.0, 32.5, 38.2, 41.5,
50.8, 63.0, 171.1. IR (NaCl): nC = 1739 cm-1. MS (70 eV): m/z
=
O
(%): 185 (M+, 4); 170 (5); 142 (14); 126 (24); 125 (6); 112 (45); 110
(16); 100 (9); 85 (7); 84 (16); 83 (13); 82 (100); 72 (5); 71 (5); 70
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for C8H16BrN: C 46.62, H 7.82, N 6.80. Found: C 46.49, H 7.73,
N 6.85.
(14); 70 (100); 68 (14); 68 (14); 56 (86); 55 (17). Anal. Calcd for
C8H16N4: C 57.11, H 9.59, N 33.30. Found: C 57.37, H 9.95, N
33.54.
trans-3-Bromo-1-isopropyl-2-methylpyrrolidine trans-11a
trans-3-Azido-1-isopropyl-2-methylpyrrolidine trans-14a
1
Rf 0.11 (hexane/EtOAc/MeOH 90/8/2). H NMR (270 MHz,
1
Rf 0.20 (hexane/EtOAc/MeOH 76/19/5). H NMR (270 MHz,
CDCl3): d 0.97 and 1.12 (6H, 2 ¥ d, J = 6.6 Hz); 1.14 (3H, d, J =
CDCl3): d 0.96, 1.11 and 1.13 (9H, 3 ¥ d, J = 6.3 Hz); 1.68-1.81
and 2.08-2.21 (2H, m); 2.61-2.73 and 2.82-3.05 (4H, m); 3.51 (1H,
t ¥ d, J = 8.1, 4.0 Hz). 13C NMR (68 MHz, CDCl3): d 15.8, 18.3,
21.9, 28.7, 45.0, 48.8, 61.0, 67.3. IR (NaCl): nN3 = 2085 cm-1. MS
(70 eV): m/z (%): 168 (M+, 7); 153 (7); 125 (11); 113 (15); 98 (9);
85 (16); 84 (25); 83 (12); 70 (100); 68 (11); 56 (69); 55 (13). Anal.
Calcd for C8H16N4: C 57.11, H 9.59, N 33.30. Found: C 57.43, H
9.82, N 33.46.
6.3 Hz); 1.98-2.11 and 2.32-2.50 (2H, 2 ¥ m); 2.74–3.10 (3H, m);
3.02 (1H, septet, J = 6.6 Hz); 3.89 (1H, d ¥ t, J = 7.6, 5.0 Hz). 13
C
NMR (68 MHz, CDCl3): d 15.5, 18.9, 21.9, 33.8, 45.2, 49.3, 54.5,
65.1. IR (NaCl): nmax = 2960, 1455, 1381, 1363, 1208, 1171 cm-1.
MS (70 eV): m/z (%): 205/7 (M+, 20); 190/2 (100); 148/50 (15);
126 (20); 111 (33); 110 (25); 96 (21); 84 (45); 83 (11); 82 (16); 80
(12); 69 (37); 68 (22); 67 (21); 57 (23); 56 (52); 55 (23); 54 (10).
Anal. Calcd for C8H16BrN: C 46.62, H 7.82, N 6.80. Found: C
46.81, H 8.06, N 6.93.
Synthesis of 3-amino-2-methylpyrrolidines 16a,b
Synthesis of cis-3-cyano-1-isopropyl-2-methylpyrrolidine cis-13
General procedure: To a solution of pyrrolidine 14 (1 mmol) in
dry methanol (3 mL) under nitrogen atmosphere was added SnCl2
(1.5 mmol), and the resulting mixture was stirred for 10–22 hours
at room temperature. Afterwards, the reaction mixture was poured
into an aqueous solution of NaOH (30 mL, 0.5 M) and extracted
with CH2Cl2 (3 ¥ 20 mL). Drying (MgSO4), removal of the drying
agent and evaporation of the solvent afforded the crude pyrrolidine
16, which was purified by column chromatography on silica gel.
To a solution of pyrrolidine trans-11a (2 mmol) in DMSO (10 mL)
was added KCN (4 mmol), and the resulting mixture was heated
at 90 ◦C for 24 hours. Afterwards, the reaction mixture was
poured into water (15 mL) and extracted with Et2O (3 ¥ 10 mL).
The combined organic extracts were then washed with brine
(2 ¥ 20 mL). Drying (MgSO4), removal of the drying agent
and evaporation of the solvent afforded 3-cyanopyrrolidine cis-
13, which was purified by column chromatography on silica gel
(hexane/EtOAc/MeOH 76/19/5).
cis-3-Amino-1-isopropyl-2-methylpyrrolidine cis-16a
Rf 0.20 (hexane/EtOAc/MeOH 76/19/5). 1H NMR (270 MHz,
CDCl3): d 0.93 and 1.13 (6H, 2 ¥ d, J = 6.6 Hz); 1.20 (3H, d, J =
5.9 Hz); 1.97 and 2.18 (2H, 2 ¥ d, J = 12.9 Hz); 2.53 (1H, d ¥
d¥d, J = 9.6, 7.9, 6.5 Hz); 2.60-2.72 and 2.85-3.01 (2H, m); 2.81-
2.95 (1H, m); 3.07 (1H, septet, J = 6.6 Hz). 13C NMR (68 MHz,
CDCl3): d 13.8, 22.1, 18.1, 26.9, 35.0, 44.3, 47.4, 59.7, 121.9. IR
(NaCl): nCN = 2213 cm-1. MS (70 eV): m/z (%): 152 (M+, 13); 137
(100); 109 (6); 95 (23); 84 (7); 71 (5); 70 (8); 68 (10); 57 (15); 56
(18). Anal. Calcd for C9H16N2: C 71.01, H 10.59, N 18.40. Found:
C 71.16, H 10.70, N 18.32.
1
Rf 0.11 (CH2Cl2/MeOH/NH4OH(25%) 43.7/10.9/1). H NMR
(270 MHz, CDCl3): d 0.98 and 1.15 (6H, 2 ¥ d, J = 6.6 Hz); 1.04
(3H, d, J = 6.3 Hz); 1.44-1.55 and 1.96-2.15 (2H, 2 ¥ m); 2.56
(1H, ~q, J = 8.6 Hz); 2.79 (1H, pent, J = 6.3 Hz); 2.92 (1H, t ¥
d, J = 8.6, 4.0 Hz); 2.99 (1H, septet, J = 6.6 Hz); 3.30 (1H, q, J =
6.3 Hz). 13C NMR (68 MHz, CDCl3): d 12.6, 15.4, 21.6, 32.5, 44.4,
48.8, 54.3, 58.7. IR (NaCl): nNH2 = 3560–3000 cm-1. MS (70 eV):
m/z (%): 142 (M+, 26); 127 (31); 99 (38); 86 (25); 85 (25); 84 (50);
82 (23); 80 (24); 72 (26); 71 (32); 70 (26); 57 (88); 56 (100). Anal.
Calcd for C8H18N2: C 67.55, H 12.75, N 19.69. Found: C 67.72, H
12.91, N 19.51.
Synthesis of 3-azido-2-methylpyrrolidines 14
trans-3-Amino-1-isopropyl-2-methylpyrrolidine trans-16a
General procedure: To a solution of pyrrolidine trans-11 (6 mmol)
in DMSO (30 mL) was added NaN3 (18-30 mmol), and the result-
ing mixture was heated at 80–90 ◦C for 8–18 hours. Afterwards, the
reaction mixture was poured into water (45 mL) and extracted with
Et2O (3 ¥ 30 mL). The combined organic extracts were then washed
with brine (2 ¥ 50 mL). Drying (MgSO4), removal of the drying
agent and evaporation of the solvent afforded 3-azidopyrrolidine
14, which was purified by column chromatography on silica gel.
1
Rf 0.14 (CH2Cl2/MeOH/NH4OH(25%) 43.7/10.9/1). H NMR
(270 MHz, CDCl3): d 0.96 and 1.14 (6H, 2 ¥ d, J = 6.5 Hz); 1.11
(3H, d, J = 6.2 Hz); 1.33-1.46 (1H, m); 1.45-1.90 (2H, m); 2.15
(1H, d ¥ q, J = 12.7, 7.9 Hz); 2.34 (1H, pent, J = 6.0 Hz); 2.70
(1H, d ¥ t, J = 8.9, 8.2 Hz); 2.88 (1H, t ¥ d, J = 8.9, 4.0 Hz); 2.90–
3.02 (1H, m); 3.03 (1H, septet, J = 6.5 Hz). 13C NMR (68 MHz,
CDCl3): d 14.7, 17.1, 21.8, 32.5, 44.0, 48.4, 58.4, 64.5. IR (NaCl):
nNH2 = 3590–3000 cm-1. MS (70 eV): m/z (%): 142 (M+, 40); 127
(47); 99 (54); 86 (39); 85 (42); 84 (64); 80 (36); 72 (41); 71 (46); 70
(41); 58 (40); 57 (97); 56 (100). Anal. Calcd for C8H18N2: C 67.55,
H 12.75, N 19.69. Found: C 67.80, H 12.97, N 19.81.
cis-3-Azido-1-isopropyl-2-methylpyrrolidine cis-14a
1
Rf 0.18 (hexane/EtOAc/MeOH 76/19/5). H NMR (270 MHz,
CDCl3): d 0.90 and 1.12 (6H, 2 ¥ d, J = 6.6 Hz); 1.09 (3H, d, J =
6.3 Hz); 1.89 and 2.10 (2H, d ¥ d¥d ¥ d, J = 13.4, 9.0, 7.3, 4.5 Hz);
2.55 (1H, t ¥ d, J = 9.0, 7.3 Hz); 2.81-2.98 (2H, m); 3.00 (1H,
septet, J = 6.6 Hz); 3.78 (1H, d ¥ t, J = 7.3, 4.5 Hz). 13C NMR
(68 MHz, CDCl3): d 13.5, 14.2, 22.0, 28.7, 43.6, 47.5, 58.4, 64.3.
IR (NaCl): nN3 = 2100 cm-1. MS (70 eV): m/z (%): 168 (M+, 14);
153 (13); 125 (12); 113 (15); 98 (8); 85 (18); 84 (28); 83 (21); 82
Synthesis of cis-3-amino-1-benzyl-2-methylpyrrolidine cis-16c
To an ice-cooled solution of pyrrolidine 14c (4 mmol) in dry
THF (10 mL) was added LiAlH4 (8 mmol) in small portions,
and the resulting suspension was heated under reflux for 1 hour.
Afterwards, water (3 mL) was added at 0 ◦C in order to neutralize
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the excess of LiAlH4. The mixture was stirred for 10 minutes, after
which the grey suspension was filtered over K2CO3 and celite.
The filter cake was then washed thoroughly with dry ether (3 ¥
20 mL). Removal of the solvent in vacuo afforded pyrrolidine cis-
16c (purity > 97% based on GC).
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Maeno, K. Hidaka, K. Nakato, S. Sakamoto and S.-i. Tsukamoto,
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1H NMR (270 MHz, CDCl3): d 1.12 (3H, d, J = 6.4 Hz); 1.35-
1.51 and 1.96-2.19 (5H, 2 ¥ m); 2.34 (1H, quint, J = 6.4 Hz); 2.89
(1H, t ¥ d, J = 8.7, 2.3 Hz); 3.14 (1H, d, J = 13.1 Hz); 3.21-3.29
(1H, m); 3.97 (1H, d, J = 13.1 Hz); 7.19-7.38 (5H, m). 13C NMR
(68 MHz, CDCl3): d 13.6, 33.0, 51.8, 54.6, 57.9, 63.0, 126.8, 128.1,
128.8, 139.5. IR (NaCl): nNH2 = 3380–3200 cm-1. MS (70 eV): m/z
(%): 190 (M+, 1); 173 (12); 147 (19); 91 (30); 65 (6); 56 (100). Anal.
Calcd for C12H18N2: C 75.74, H 9.53, N 14.72. Found: C 75.96, H
9.70, N 14.87.
5 C. J. Andres, P. H. Lee, T. H. Nguyen and A. I. Meyers, J. Org. Chem.,
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7 N. Baricordi, S. Benetti, G. Biondini, C. De Risi and G. P. Pollini,
Tetrahedron Lett., 2004, 45, 1373.
8 (a) N. De Kimpe, R. Verhe´, L. De Buyck, L. Moens and N. Schamp,
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Chem. Int. Ed., 1985, 24, 88.
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2006, 8, 1105.
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Chem., 1997, 62, 5138.
11 E. R. Buchman, J. Am. Chem. Soc., 1936, 58, 1803.
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15 P. Di Cesare, D. Bouzard, M. Essiz, J. P. Jacquet, B. Ledoussal, J. R.
Kiechel, P. Remuzon, R. E. Kessler, J. Fung-Tomc and J. Desiderio,
J. Med. Chem., 1992, 35, 4205.
Synthesis of 1-isopropyl-2-methyl-3-pyrroline 17
To a solution of pyrrolidine 11a (2.5 mmol) in THF (5 mL) was
added KOtBu (3.75 mmol), and the resulting mixture was heated
under reflux for 1 hour. Afterwards, the reaction mixture was
poured into water (10 mL) and extracted with Et2O (3 ¥ 10 mL).
Drying (MgSO4), removal of the drying agent and evaporation of
the solvent afforded pyrroline 17 (purity > 95% based on GC).
1H NMR (270 MHz, CDCl3): d 1.03 and 1.12 (6H, 2 ¥ d, J =
6.4 Hz); 1.15 (3H, d, J = 6.3 Hz); 2.92 (1H, septet, J = 6.4 Hz);
3.46 and 3.67 (2H, 2 ¥ d, J = 13.9 Hz); 3.68-3.83 (1H, m); 5.62 and
5.71 (2H, 2 ¥ d, J = 6.1 Hz). 13C NMR (68 MHz, CDCl3): d 18.9,
22.0, 21.5, 50.9, 55.8, 62.0, 125.9, 133.4. IR (NaCl): nmax = 2960,
1382, 1365, 1180 cm-1. MS (70 eV): m/z (%): 125 (M+, 19); 110
(67); 82 (19); 80 (7); 68 (100); 55 (21). Anal. Calcd for C8H15N: C
76.74, H 12.07, N 11.19. Found: C 76.97, H 12.26, N 11.04.
Acknowledgements
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(b) K. Hashimoto and H. Shirahama, Tetrahedron Lett., 1991, 32, 2625;
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Gmeiner, F. Orecher, C. Thomas and K. Weber, Tetrahedron Lett.,
1995, 36, 381.
The authors are indebted to the “Fund for Scientific Research –
Flanders (Belgium)” (FWO–Vlaanderen) and to Ghent University
(GOA) for financial support.
17 C. Gallina, C. Marta, C. Colombo and A. Romeo, Tetrahedron, 1971,
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References
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The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 135–141 | 141
©