Synthesis of 2-azabicyclo[2.1.0]pentanes by the intramolecular nucleophilic substitution of cyclopropylmagnesium carbenoids with magnesium anilide

Article abstract of DOI:10.1016/j.tet.2017.03.045

A variety of 2-azabicyclo[2.1.0]pentanes were synthesized by the intramolecular nucleophilic substitution of cyclopropylmagnesium carbenoids with magnesium anilide. The 1-chlorocyclopropyl p-tolyl sulfoxides possessing an N-aryl-substituted aminomethyl group were prepared from dichloromethyl p-tolyl sulfoxide, α,β-unsaturated carboxylic acid esters, and anilines in four steps. The deprotonation of the amine with t-BuMgCl followed by sulfoxide/magnesium exchange of the sulfoxides with i-PrMgCl led to the generation of the cyclopropylmagnesium carbenoids possessing a magnesium anilide moiety. Subsequent intramolecular nucleophilic substitution of the cyclopropylmagnesium carbenoids occurred in a 4-exo-tet manner to give the 2-azabicyclo[2.1.0]pentanes. The optically active 2-azabicyclo[2.1.0]pentane was synthesized using a p-tolylsulfinyl group as a chiral auxiliary.

Full text of DOI:10.1016/j.tet.2017.03.045

Tetrahedron xxx (2017) 1e6
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Synthesis of 2-azabicyclo[2.1.0]pentanes by the intramolecular
nucleophilic substitution of cyclopropylmagnesium carbenoids with
magnesium anilide
Tsutomu Kimura*, Toshiki Nishimura, Natsumi Wada, Tsuyoshi Satoh
Graduate School of Chemical Sciences and Technology, Tokyo University of Science, Ichigayafunagawaramachi 12, Shinjuku-ku, Tokyo, 162-0826, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of 2-azabicyclo[2.1.0]pentanes were synthesized by the intramolecular nucleophilic substitu-
tion of cyclopropylmagnesium carbenoids with magnesium anilide. The 1-chlorocyclopropyl p-tolyl
sulfoxides possessing an N-aryl-substituted aminomethyl group were prepared from dichloromethyl p-
Received 4 February 2017
Received in revised form
13 March 2017
Accepted 15 March 2017
Available online xxx
tolyl sulfoxide, a,b-unsaturated carboxylic acid esters, and anilines in four steps. The deprotonation of the
amine with t-BuMgCl followed by sulfoxide/magnesium exchange of the sulfoxides with i-PrMgCl led to
the generation of the cyclopropylmagnesium carbenoids possessing a magnesium anilide moiety. Sub-
sequent intramolecular nucleophilic substitution of the cyclopropylmagnesium carbenoids occurred in a
4-exo-tet manner to give the 2-azabicyclo[2.1.0]pentanes. The optically active 2-azabicyclo[2.1.0]pentane
was synthesized using a p-tolylsulfinyl group as a chiral auxiliary.
Keywords:
Cyclopropylmagnesium carbenoid
Intramolecular nucleophilic substitution
4-exo-tet cyclization
© 2017 Elsevier Ltd. All rights reserved.
2-Azabicyclo[2.1.0]pentane
Asymmetric synthesis
1. Introduction
naphtholates, and lithium anilides to give multi-substituted cy-
clopropanes and cyclobutanes.5,6 If cyclopropylmagnesium carbe-
2-Azabicyclo[2.1.0]pentanes are a class of highly strained bicy-
clic compounds in which cyclopropane and azetizine are fused
across a CeC bond. The 2-azabicyclo[2.1.0]pentane skeleton is
found in SF-1836 and attracts attention as a conformationally
restricted pyrrolidine analog in the field of drug development.1,2 2-
Azabicyclo[2.1.0]pentanes are also used as synthetic intermediates
in the total synthesis of natural products.3 Despite their potential
utility, the chemistry of 2-azabicyclo[2.1.0]pentanes is scarce
mainly due to the lack of efficient synthetic method of 2-azabicyclo
[2.1.0]pentanes. One of the most straightforward synthetic
methods of 2-azabicyclo[2.1.0]pentanes is the nucleophilic substi-
tution of halocyclopropanes with intramolecular nitrogen nucleo-
philes in a 4-exo-tet manner. However, in general, the nucleophilic
substitution at the carbon atom of small rings does not proceed
efficiently because of the inaccessibility of nucleophiles to the CeX
antibonding orbital and a disadvantageous highly strained transi-
tion state structure.4 Nevertheless, cyclopropyl- and cyclo-
noids possessing a nitrogen nucleophile can be generated,
intramolecular nucleophilic substitution is expected to occur to
give 2-azabicyclo[2.1.0]pentanes. Herein, we report the synthesis of
2-azabicyclo[2.1.0]pentanes by the 4-exo-tet cyclization of cyclo-
propylmagnesium carbenoids possessing a magnesium anilide
moiety.
2. Results and discussion
2.1. Preparation of cyclization precursors
As cyclization precursors, we designed the 1-chlorocyclopropyl
p-tolyl sulfoxides 1 possessing N-aryl-substituted aminomethyl
groups (Scheme 1). Deprotonation and sulfoxide/magnesium ex-
change of the sulfoxides 1 are expected to generate bifunctional
species in which an electrophilic cyclopropylmagnesium carbenoid
moiety and a nucleophilic magnesium amide moiety coexist in each
molecule. A variety of N-aryl-substituted 2-(aminomethyl)-1-
butylmagnesium carbenoids react with nucleophiles such as (a-
sulfonylalkyl)lithiums, Grignard reagents, lithium phenolates and
chlorocyclopropyl p-tolyl sulfoxides
dichloromethyl p-tolyl sulfoxide, -unsaturated carboxylic acid
esters, and anilines in four steps.7 Annulation of
-unsaturated
carboxylic acid esters with dichloromethyl p-tolyl sulfoxide in the
1 were prepared from
a,b
a,b
* Corresponding author.
E-mail address: kimtwo@rs.tus.ac.jp (T. Kimura).
http://dx.doi.org/10.1016/j.tet.2017.03.045
0040-4020/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kimura T, et al., Synthesis of 2-azabicyclo[2.1.0]pentanes by the intramolecular nucleophilic substitution of
cyclopropylmagnesium carbenoids with magnesium anilide, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.045

2
T. Kimura et al. / Tetrahedron xxx (2017) 1e6
carbenoids will abstract the proton of the secondary amine to give
the undesirable chlorocyclopropanes (Scheme 2, Eq. 2). We chose t-
BuMgCl, which was unreactive towards the p-tolylsulfinyl group, as
a base. A solution of t-BuMgCl in THF was added to a solution of the
sulfoxide 1a in THF at ꢀ78 ꢁC, and then, a solution of i-PrMgCl in
THF was added to the resulting solution. The reaction mixture was
warmed to ꢀ20 ꢁC and quenched with aqueous NH4Cl. As a result,
the desired 2-azabicyclo[2.1.0]pentane 2a was obtained in 71%
yield.
The scope of the cyclization was explored with a variety of
sulfoxides 1beh (Table 1). When sulfoxides 1b, 1c, and 1e pos-
sessing one or two methoxy groups at the o- or m-positions were
subjected to the reaction with t-BuMgCl and i-PrMgCl, the corre-
sponding 2-azabicyclo[2.1.0]pentanes 2b, 2c, and 2e were formed
in 59e78% yields, whereas 2-azabicyclo[2.1.0]pentane 2d possess-
ing a N-(4-methoxyphenyl) group could not be isolated because of
its instability (entries 1e4). The reaction of sulfoxide 1f possessing
an electron-withdrawing trifluoromethyl group at the m-position
also gave the bicyclic product 2f in 58% yield (entry 5). The cycli-
zation of the cyclopropylmagnesium carbenoid generated from
sulfoxide 1g possessing a 2-phenylethyl group on the cyclopropane
ring occurred to give 2-azabicyclo[2.1.0]pentane 2g in 74% yield
(entry 6). The crude 4,5-dimethyl-2-azabicyclo[2.1.0]pentane 2h
was obtained in 60% yield after short silica gel column purification
(entry 7). Further purification of the crude product by column
chromatography on silica gel resulted in the decomposition of 2h.
In all cases, small amounts of the chlorocyclopropanes, which
originated from the protonation of the cyclopropylmagnesium
carbenoids, were formed as by-products. The 2-azabicyclo[2.1.0]
pentanes 2, except the N-(4-methoxyphenyl)- and 4,5-dimethyl-
substituted derivatives 2d and 2h, were sufficiently stable and were
purified by column chromatography on silica gel. For instance, neat
2-azabicyclo[2.1.0]pentane 2c could be stored at ꢀ15 ꢁC for several
months. When a solution of 2-azabicyclo[2.1.0]pentane 2c in CHCl3
was left at room temperature for two weeks, a slight amount of
decomposition occurred. Approximately half of 2-azabicyclo[2.1.0]
pentane 2c decomposed under reflux in toluene for one week.
To gain insight into the reaction mechanism, the reaction of
sulfoxide 1c with t-BuMgCl and i-PrMgCl was quenched with
CH3OD (Scheme 3). As a result, 2-azabicyclo[2.1.0]pentane 2c0
possessing a deuterium atom was formed with a high deuterium
content. This result indicates the intermediacy of the organo-
magnesium chloride 3c. In addition, the reaction of sulfoxide 1c
with t-BuMgCl did not afford 1-(p-tolylsulfinyl)-2-azabicyclo[2.1.0]
pentane. Therefore, we speculate that the nucleophilic substitution
Scheme 1. Synthesis of cyclization precursors 1.
presence of NaHMDS gave 1-chlorocyclopropyl p-tolyl sulfoxides
possessing an ethoxycarbonyl group. Reduction of the ethox-
ycarbonyl group and iodination of the resulting hydroxy group
afforded 1-chloro-2-(iodomethyl)cyclopropyl p-tolyl sulfoxides.8
The reaction of the alkyl iodides with the anilines in the presence
of K2CO3 gave the cyclization precursors 1 in 40e98% yields.
2.2. Cyclization reaction
With the key precursors 1 in hand, the synthesis of 2-azabicyclo
[2.1.0]pentanes was examined (Scheme 2, Eq. 1). Deprotonation of
the secondary amine should be carried out in advance of the sulf-
oxide/magnesium exchange reaction to generate the bifunctional
species. Otherwise, the generated cyclopropylmagnesium
Table 1
Synthesis of 2-azabicyclo[2.1.0]pentanes 2.
Entry
1
R
R0
Ar
2
Yield of 2 (%)
1
2
3
4
5
6
7
1b
1c
1d
1e
1f
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
PhCH2CH2
Me
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3,5-(MeO)2C6H3
3-CF3C6H4
2b
2c
2d
2e
2f
59
76
0
78
58
74
60
1g
1h
3-MeOC6H4
3-MeOC6H4
2g
2h
Scheme 2. Synthesis of 2-azabicyclo[2.1.0]pentane 2a.
Please cite this article in press as: Kimura T, et al., Synthesis of 2-azabicyclo[2.1.0]pentanes by the intramolecular nucleophilic substitution of
cyclopropylmagnesium carbenoids with magnesium anilide, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.045

T. Kimura et al. / Tetrahedron xxx (2017) 1e6
3
with t-BuMgCl followed by i-PrMgCl gave (1R,4R)-2-azabicyclo
[2.1.0]pentane (1R,4R)-2c with 99% ee.
3. Conclusion
In summary, we developed an efficient method for the synthesis
of 2-azabicyclo[2.1.0]pentanes. The high reactivity of the cyclo-
propylmagnesium carbenoids enabled the formation of a CeN bond
between the carbon atom of the cyclopropane ring and the nitrogen
atom by intramolecular nucleophilic substitution. The asymmetric
synthesis of azabicyclo[2.1.0]pentane was successfully attained
utilizing the S-chiral p-tolylsulfinyl group as a chiral auxiliary.
Scheme 3. Deuteration of organomagnesium intermediate 3c.
of the cyclopropylmagnesium carbenoids with intramolecular
magnesium anilide occurs to give the organomagnesium interme-
diate 3c.
To compare the reactivity of the cyclopropylmagnesium carbe-
noids towards nucleophiles with that of chlorocyclopropanes, the
chlorocyclopropane 4c was subjected to the reaction conditions
similar to those of the cyclization of the cyclopropylmagnesium
carbenoids (Scheme 4). The cyclization did not proceed at all, and
chlorocyclopropane 4c was recovered quantitatively. This result
suggests that the reactivity of the cyclopropylmagnesium carbe-
noids is higher than that of chlorocyclopropanes. In our DFT study,
we found that 1-chlorocyclopropylmagnesium chloride has a long
CeCl bond and expanded bond angles around the carbenoid carbon
atom compared with those of chlorocyclopropane.6h,9 These
structural features seem to mitigate a disadvantage associated with
nucleophilic substitution at the carbon atom of small rings to a
certain extent.
4. Experimental section
4.1. General methods
All reactions involving air- or water-sensitive compounds were
conducted under an argon atmosphere. Argon gas was dried by
passage through P2O5. Anhydrous THF was purchased from Kanto
Chemical and was used as supplied. The 1-chloro-2-(iodomethyl)
cyclopropyl p-tolyl sulfoxides and (R)-dichloromethyl p-tolyl sulf-
oxide were prepared according to the procedure described in the
literature.7,10a Silica gel (60 N, Kanto Chemical) containing 0.5%
fluorescence reagent 254 and a quartz column were used for col-
umn chromatography, and the products that absorbed UV light
were detected by UV irradiation.
The melting points were measured using a Yanaco MP-S3
apparatus and are uncorrected. IR spectra were recorded on a
PerkineElmer Frontier FT IR in ATR mode. NMR spectra were
measured in a CDCl3 solution with JEOL JNM-LA 300 and JEOL JNM-
LA 500 spectrometers. Mass spectra (MS) were obtained at 70 eV by
direct injection with a HITACHI M-80B mass spectrometer. Fast
atom bombardment (FAB) mass spectra were obtained with a
mixture of m-nitrobenzyl alcohol and glycerol as the matrix. Optical
rotations were measured on a JASCO DIP-1000 Polarimeter. Enan-
tiomeric excess was determined using HPLC analysis (JASCO Gul-
2.3. Asymmetric synthesis
Previously, we developed an efficient method for the optical
resolution of dichloromethyl p-tolyl sulfoxide using (e)-menthone
as a resolving agent.10 We performed the asymmetric synthesis of
2-azabicyclo[2.1.0]pentane (1R,4R)-2c using (R)-dichloromethyl p-
tolyl sulfoxide as the starting material (Scheme 5). The cyclization
precursor (1R,2S,RS)-1c was prepared according to the synthetic
method described above. The reaction of sulfoxide (1R,2S,RS)-1c
liver) with a Chiralcel AD or OD column (
f
0.46 cm ꢂ 25 cm).
4.2. Typical procedure for the synthesis of sulfoxides 1
Aniline (4.85 g, 5.21 mmol) was added to a mixture of 1-
{[(1R*,2R*)-1-chloro-2-(iodomethyl)-2-methylcyclopropyl]sul-
finyl}-4-methylbenzene (1.28 g, 3.46 mmol) and K2CO3 (1.45 g,
10.5 mmol) in DMSO (7.0 mL) at room temperature, and the
mixture was stirred at that temperature for 12 h. Toluene (15 mL)
and water (15 mL) were added to the mixture, and the aqueous
layer was extracted with toluene (2 ꢂ 5 mL). The combined organic
layer was dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by column chroma-
tography on silica gel (hexane/EtOAc, 5:1) to give 1a [813 mg,
2.77 mmol, 70%, Rf ¼ 0.29 (hexane/EtOAc, 2:1)].
Scheme 4. Attempt at cyclization of chlorocyclopropane 4c.
4.2.1. N-{[(1R*,2S*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)
cycropropyl]methyl}aniline (1a)
Colorless crystals (hexane/EtOAc); mp 139.1e140.5 ꢁC; IR (ATR)
3350, 3033, 2924, 1600, 1531, 1498, 1261, 1223, 1089, 1059, 1047,
801, 746, 691 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
1.30 (d, J ¼ 7.1 Hz,
1H), 1.49 (s, 3H), 2.08 (d, J ¼ 7.1 Hz, 1H), 2.43 (s, 3H), 3.51 (d,
J ¼ 12.8 Hz, 1H), 3.64 (d, J ¼ 12.8 Hz, 1H), 3.78 (br s, 1H), 6.63e6.67
(m, 2H), 6.76 (tt, J ¼ 1.1, 7.4 Hz, 1H), 7.19e7.24 (m, 2H), 7.33 (d,
J ¼ 8.1 Hz, 2H), 7.62 (d, J ¼ 8.1 Hz, 2H); 13C NMR (126 MHz, CDCl3)
d
20.7 (CH3), 21.5 (CH3), 25.2 (CH2), 32.5 (C), 48.2 (CH2), 66.7 (C),
113.1 (CH), 118.1 (CH), 126.1 (CH), 129.4 (CH), 129.6 (CH), 138.8 (C),
Scheme 5. Asymmetric synthesis of 2-azabicyclo[2.1.0]pentane (1R,4R)-2c.
142.5 (C), 147.7 (C); MS (FABþ) m/z (%) 334 ([MþH]þ, 100), 192 (21),
Please cite this article in press as: Kimura T, et al., Synthesis of 2-azabicyclo[2.1.0]pentanes by the intramolecular nucleophilic substitution of
cyclopropylmagnesium carbenoids with magnesium anilide, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.045

4
T. Kimura et al. / Tetrahedron xxx (2017) 1e6
133 (39), 93 (27); HRMS (FABþ) calcd for C18H21ClNOS: 334.1032,
found: 334.1031.
J ¼ 12.8 Hz, 1H), 3.77 (s, 6H), 3.83 (br s, 1H), 5.83 (d, J ¼ 2.2 Hz, 2H),
5.92 (t, J ¼ 2.2 Hz,1H), 7.33 (d, J ¼ 8.1 Hz, 2H), 7.61 (d, J ¼ 8.1 Hz, 2H);
13C NMR (76 MHz, CDCl3)
d 20.9, 21.6, 25.1, 32.4, 48.1, 55.2, 66.7,
4.2.2. N-{[(1R*,2S*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)
cycropropyl]methyl}-2-methoxyaniline (1b)
90.3, 91.9, 126.1, 129.6, 138.8, 142.6, 149.6, 161.8; MS (FABþ) m/z (%)
394 ([MþH]þ, 100), 193 (48), 166 (28), 137 (28), 93 (35); HRMS
(FABþ) calcd for C20H25ClNO3S: 394.1244, found: 394.1238.
Yield 98% (14 h); brown crystals (hexane/EtOAc); mp
101.8e103.1 ꢁC; IR (ATR) 3393, 3013, 2990, 2962, 2939, 2835, 1600,
1509, 1455, 1250, 1212, 1126, 1084, 1060, 1044, 1019, 810, 748 cmꢀ1
;
4.2.7. N-{[(1R*,2S*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)
cycropropyl]methyl}-3-(trifluoromethyl)aniline (1f)
1H NMR (500 MHz, CDCl3)
d
1.35 (d, J ¼ 7.1 Hz, 1H), 1.50 (s, 3H), 2.10
(d, J ¼ 7.1 Hz, 1H), 2.43 (s, 3H), 3.51 (d, J ¼ 12.6 Hz, 1H), 3.62 (d,
J ¼ 12.6 Hz, 1H), 3.88 (s, 3H), 4.36 (br s, 1H), 6.64 (dd, J ¼ 1.4, 8.0 Hz,
1H), 6.72 (dt, J ¼ 1.4, 8.0 Hz, 1H), 6.81 (dd, J ¼ 1.4, 8.0 Hz, 1H), 6.89
(dt, J ¼ 1.4, 8.0 Hz, 1H), 7.31 (d, J ¼ 8.1 Hz, 2H), 7.64 (d, J ¼ 8.1 Hz,
Yield 44% (86 h); yellow crystals (hexane/EtOAc); mp
81.4e82.8 ꢁC; IR (ATR) 3351, 3313, 3063, 2937, 2923, 2889, 2846,
1616,1597,1539,1498, 1476,1347,1316,1304,1164,1122, 1090, 1062,
1039, 808, 784, 701 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 1.24 (d,
2H); 13C NMR (126 MHz, CDCl3)
d
20.3 (CH3), 21.6 (CH3), 26.0 (C),
J ¼ 7.2 Hz, 1H), 1.51 (s, 3H), 2.07 (d, J ¼ 7.2 Hz, 1H), 2.44 (s, 3H), 3.54
(dd, J ¼ 6.3, 12.9 Hz,1H), 3.65e3.70 (dd, J ¼ 5.1, 12.9 Hz,1H), 4.04 (br
t, 1H), 6.80 (d, J ¼ 7.9 Hz, 1H), 6.84 (s, 1H), 6.98 (d, J ¼ 7.9 Hz, 1H),
7.29 (t, J ¼ 7.9 Hz,1H), 7.33 (d, J ¼ 8.1 Hz, 2H), 7.61 (d, J ¼ 8.1 Hz, 2H);
32.6 (C), 48.3 (CH2), 55.4 (CH3), 67.2 (C), 109.6 (CH), 110.2 (CH), 117.3
(CH), 121.3 (CH), 126.0 (CH), 129.6 (CH), 137.5 (C), 138.7 (C), 142.2
(C), 146.8 (C); MS (FABþ) m/z (%) 364 (Mþ, 100), 163 (45), 136 (28),
93 (30); HRMS (FABþ) calcd for C19H23ClNO2S: 364.1138, found:
364.1136.
13C NMR (101 MHz, CDCl3)
d 21.2, 21.6, 23.9, 32.2, 47.5, 65.9, 109.4
3
3
1
(q, JC-F ¼ 3.9 Hz), 114.3 (q, JC-F ¼ 3.9 Hz), 115.8, 124.3 (q, JC-
2
¼ 272.3 Hz), 126.2, 129.7, 129.8, 131.7 (q, JC-F ¼ 31.8 Hz), 138.9,
F
4.2.3. N-{[(1R*,2S*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)
cycropropyl]methyl}-3-methoxyaniline (1c)
142.8, 148.0; MS (FABþ) m/z (%) 402 ([MþH]þ, 100), 262 (21), 201
(45), 185 (33), 154 (27), 93 (47); HRMS (FABþ) calcd for
Yield 76% (12 h); brown crystals (hexane/EtOAc); mp
C19H20ClF3NOS: 402.0906, found: 402.0903.
85.6e86.8 ꢁC; IR (ATR) 3349, 2993, 2931, 2834, 1611, 1595, 1513,
1495, 1454, 1207, 1161, 1084, 1039, 809, 751 cmꢀ1
;
1H NMR
4.2.8. N-{[(1R*,2S*)-2-Chloro-1-phenethyl-2-(p-tolylsulfinyl)
cycropropyl]methyl}-3-methoxyaniline (1g)
Yield 40% (14 h); colorless crystal (hexane/EtOAc); mp
72.4e73.5 ꢁC; IR (ATR) 3347, 3026, 3001, 2956, 2932, 2862, 2835,
1612, 1597, 1495, 1453, 1208, 1162, 1087, 1042, 752, 730, 699,
(500 MHz, CDCl3)
d
1.29 (d, J ¼ 7.2 Hz, 1H), 1.48 (s, 3H), 2.07 (d,
J ¼ 7.2 Hz, 1H), 2.44 (s, 3H), 3.49 (d, J ¼ 12.9 Hz, 1H), 3.62 (d,
J ¼ 12.9 Hz, 1H), 3.79 (s, 3H), 3.81 (br s, 1H), , 6.21 (t, J ¼ 2.3 Hz, 1H),
6.27 (ddd, J ¼ 0.7, 2.3, 8.1 Hz, 1H), 6.32 (ddd, J ¼ 0.7, 2.3, 8.1 Hz, 1H),
7.11 (t, J ¼ 8.1 Hz, 1H), 7.33 (d, J ¼ 8.1 Hz, 2H), 7.62 (d, J ¼ 8.1 Hz, 2H);
688 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
1.35 (d, J ¼ 7.0 Hz, 1H), 1.90
13C NMR (126 MHz, CDCl3)
d
20.7 (CH3), 21.6 (CH3), 25.2 (CH2), 32.4
(ddd, J ¼ 5.0, 11.2, 14.5 Hz, 1H), 2.06 (d, J ¼ 7.0 Hz, 1H), 2.22 (ddd,
J ¼ 6.2, 11.0, 14.5 Hz, 1H), 2.44 (s, 3H), 2.59e2.70 (m, 2H), 3.64 (br s,
2H), 3.77 (s, 1H), 3.80 (s, 3H), 6.22 (t, J ¼ 2.1 Hz, 1H), 6.28 (dd, J ¼ 2.1,
8.1 Hz, 1H), 6.35 (dd, J ¼ 2.1, 8.1 Hz, 1H), 7.11 (d, J ¼ 7.3 Hz, 2H),
7.12e7.18 (m, 2H), 7.24 (t, J ¼ 7.3 Hz, 2H), 7.35 (d, J ¼ 8.2 Hz, 2H), 7.62
(C), 48.2 (CH2), 55.1 (CH3), 66.7 (C), 99.1 (CH), 103.1 (CH), 106.1 (CH),
126.1 (CH), 129.6 (CH), 130.2 (CH), 138.7 (C), 142.5 (C), 149.1 (C),
160.9 (C); MS (FABþ) m/z (%) 364 ([MþH]þ, 100), 163 (38), 136 (33),
93 (39); HRMS (FABþ) calcd for C19H23ClNO2S: 364.1138, found:
364.1139.
(d, J ¼ 8.2 Hz, 2H); 13C NMR (126 MHz, CDCl3)
d 21.6 (CH3), 25.5
(CH2), 32.4 (CH2), 35.4 (CH2), 35.8 (C), 45.3 (CH2), 55.2 (CH3), 67.5
(C), 99.3 (CH), 103.2 (CH), 106.2 (CH), 125.9 (CH), 126.2 (CH), 128.3
(CH), 128.5 (CH), 129.7 (CH), 130.3 (CH), 138.5 (C), 141.0 (C), 142.7
(C), 149.0 (C), 161.0 (C); MS (FABþ) m/z (%) 454 ([MþH]þ, 100), 312
(25), 162 (33), 136 (35), 91 (22); HRMS (FABþ) calcd for
4.2.4. N-{[(1R,2S,RS)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)
cycropropyl]methyl}-3-methoxyaniline [(1R,2S,RS)-1c]
24
[a
]
þ76.5 (c 0.10, EtOH); HPLC, DAICEL CHIRALCEL AD (
f
D
0.46 cm
ꢂ
25 cm), i-PrOH/hexane/EtOH
¼
1:9:0.1, flow
rate ¼ 0.5 mL/min, detection at 220 nm, retention time ¼ 49.1 min
C26H29ClNO2S: 454.1608, found: 454.1609.
(minor), 51.6 min (major), 99%ee.
4.2.9. N-([(1R*,2S*,3S*)-2-chloro-1,3-dimethyl-2-(p-tolylsulfinyl)
cyclopropyl]methyl)-3-methoxyaniline (1h)
4.2.5. N-{[(1R*,2S*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)
cycropropyl]methyl}-4-methoxyaniline (1d)
Yield 95% (48 h); brown crystals (hexane/EtOAc); mp
94.0e94.9 ꢁC; IR (ATR) 3326, 3057, 3030, 2996, 2949, 2815, 1621,
1524, 1506, 1451, 1441, 1254, 1230, 1211, 1080, 1051, 1037, 816,
Yield 67% (73 h); colorless crystals (hexane/EtOAc); mp
117.2e118.0 ꢁC; IR (ATR) 3353, 2931, 1596, 1538, 1491, 1463, 1311,
1211, 1157, 1086, 1053, 809, 764 cmꢀ1 1H NMR (500 MHz, CDCl3)
;
d
1.15 (d, J ¼ 6.4 Hz, 3H), 1.27 (s, 3H), 2.13 (q, J ¼ 6.4 Hz, 1H), 2.43 (s,
784 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
1.30 (d, J ¼ 7.1 Hz, 1H), 1.48
3H), 3.46 (d, J ¼ 13.0 Hz, 1H), 3.61 (d, J ¼ 13.0 Hz, 1H), 3.81 (s, 3H),
3.85 (br s, 1H), 6.20 (t, J ¼ 2.2 Hz, 1H), 6.26 (dd, J ¼ 2.2, 8.0 Hz, 1H),
6.31 (dd, J ¼ 2.2, 8.0 Hz, 1H),7.11 (t, J ¼ 8.0 Hz, 1H), 7.31 (d, J ¼ 8.1 Hz,
(s, 3H), 2.07 (d, J ¼ 7.1 Hz, 1H), 2.43 (s, 3H), 3.46 (d, J ¼ 12.6 Hz, 1H),
3.51 (br s, 1H), 3.57 (d, J ¼ 12.6 Hz, 1H), 3.76 (s, 3H), 6.63 (d,
J ¼ 9.0 Hz, 2H), 6.81 (d, J ¼ 9.0 Hz, 2H), 7.32 (d, J ¼ 8.1 Hz, 2H), 7.63
2H), 7.60 (d, J ¼ 8.1 Hz, 2H); 13C NMR (126 MHz, CDCl3)
d 8.9, 15.1,
(d, J ¼ 8.1 Hz, 2H); 13C NMR (126 MHz, CDCl3)
d
20.6, 21.5, 25.4, 32.5,
21.6, 24.7, 33.9, 49.5, 55.1, 70.7, 99.1, 103.0, 106.1, 126.1, 129.6, 130.1,
139.0,142.4,149.2, 160.9; MS (FABþ) m/z (%) 378 ([MþH]þ,100), 238
(38), 163 (42), 93 (27); HRMS (FABþ) calcd for C20H25ClNO2S:
378.1295, found: 378.1294.
49.5, 55.8, 66.9, 114.6, 115.0, 126.1, 129.6, 138.8, 141.8, 142.4, 152.6;
MS (FABþ) m/z (%) 364 ([MþH]þ, 100), 222 (50), 163 (42), 136 (35);
HRMS (FABþ) calcd for C19H23ClNO2S: 364.1138, found: 364.1138.
4.2.6. N-{[(1R*,2S*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)
cycropropyl]methyl}-3,5-dimethoxyaniline (1e)
4.3. Typical procedure for the synthesis of 2-azabicyclo[2.1.0]
pentanes 2
Yield 64% (14 h); brown crystals (hexane/EtOAc); mp
83.5e84.2 ꢁC; IR (ATR) 3345, 3328, 3000, 2962, 2935, 2844, 2815,
A 1.0 mol/L solution of t-BuMgCl in THF (0.38 mL, 0.38 mmol)
was added to a solution of 1a (107 mg, 0.320 mmol) in THF
(21.0 mL) at ꢀ78 ꢁC, and the mixture was stirred at that tempera-
ture for 10 min. A 2.0 mol/L solution of i-PrMgCl in THF (0.48 mL,
1596, 1471, 1458, 1200, 1175, 1149, 1062, 1038, 815, 747 cmꢀ1 1H
;
NMR (500 MHz, CDCl3)
d
1.28 (d, J ¼ 7.2 Hz, 1H), 1.48 (s, 3H), 2.06 (d,
J ¼ 7.2 Hz, 1H), 2.44 (s, 3H), 3.48 (d, J ¼ 12.8 Hz, 1H), 3.61 (d,
Please cite this article in press as: Kimura T, et al., Synthesis of 2-azabicyclo[2.1.0]pentanes by the intramolecular nucleophilic substitution of
cyclopropylmagnesium carbenoids with magnesium anilide, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.045

T. Kimura et al. / Tetrahedron xxx (2017) 1e6
5
0.96 mmol) was added to the mixture at ꢀ78 ꢁC, and the mixture
was allowed to warm to ꢀ20 ꢁC over a period of 1.5 h. The reaction
was quenched with saturated aqueous NH4Cl (3 mL). CHCl3 (15 mL)
and water (10 mL) were added to the mixture, and the aqueous
layer was extracted with CHCl3 (2 ꢂ 10 mL). The combined organic
layer was dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by column chroma-
tography on silica gel (hexane/AcOEt, 200:1) to give 2a [36.0 mg,
0.226 mmol, 71%, Rf ¼ 0.62 (hexane/AcOEt, 2:1)].
detection at 254 nm, retention time ¼ 13.4 min (major), 14.6 min
(minor), 99%ee.
4.3.6. (1R*,4R*)-2-(3,5-dimethoxyphenyl)-4-methyl-2-azabicyclo
[2.1.0]pentane (2e)
Yellow oil; IR (ATR) 2941, 2863, 1586, 1459, 1264, 1201, 1178,
1147, 1058, 814 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
0.54 (dd, J ¼ 3.5,
5.3 Hz, 1H), 0.88 (d, J ¼ 5.3 Hz, 1H), 1.41 (s, 3H), 3.23 (dd, J ¼ 2.2,
7.5 Hz, 1H), 3.49 (dd, J ¼ 2.2, 3.5 Hz, 1H), 3.75 (s, 6H), 3.94 (d,
J ¼ 7.5 Hz, 1H), 5.75 (d, J ¼ 2.2 Hz, 2H), 5.91 (t, J ¼ 2.2 Hz, 1H); 13C
4.3.1. (1R*,4R*)-2-phenyl-4-methyl-2-azabicyclo[2.1.0]pentane
(2a)
NMR (126 MHz, CDCl3)
d
15.6, 16.4, 20.7 (1JCH ¼ 160 Hz), 44.6
(1JCH ¼ 195 Hz), 55.2, 60.9, 90.5, 92.7, 153.3, 161.4; MS (EI) m/z (%)
219 (Mþ, 85), 204 (100), 164 (48), 137 (59), 122 (38); HRMS (EI)
calcd for C13H17NO2: 219.1259, found: 219.1263.
Yellow oil; IR (ATR) 3055, 3034, 2943, 2924, 2863, 1598, 1495,
1321, 752, 693 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
0.54 (dd, J ¼ 3.5,
5.3 Hz, 1H), 0.86 (d, J ¼ 5.3 Hz, 1H), 1.42 (s, 3H), 3.25 (dd, J ¼ 2.3,
7.6 Hz, 1H), 3.54 (dd, J ¼ 2.3, 3.5 Hz, 1H), 3.99 (d, J ¼ 7.6 Hz, 1H), 6.59
(dd, J ¼ 1.1, 8.5 Hz, 2H), 6.74 (tt, J ¼ 1.1, 7.3 Hz, 1H), 7.19 (dd, J ¼ 7.3,
4.3.7. (1R*,4R*)-2-[3-(trifluoromethyl)phenyl]-4-methyl-2-
azabicyclo[2.1.0]pentane (2f)
8.5 Hz, 2H); 13C NMR (126 MHz, CDCl3)
d
15.9, 16.5, 20.5, 44.7, 61.0,
Yellow oil; IR (ATR) 2929, 2868, 1609, 1492, 1455, 1345, 1313,
114.0, 118.1, 128.7, 151.2; MS (EI) m/z (%) 159 (Mþ, 51), 158 (51), 144
(100), 104 (95), 77 (89); HRMS (EI) calcd for C11H13N: 159.1048,
found: 159.1047.
1282, 1160, 1115, 1065, 785, 696 cmꢀ1 1H NMR (500 MHz, CDCl3)
;
d
0.60 (dd, J ¼ 2.6, 5.4 Hz, 1H), 0.84 (d, J ¼ 5.4 Hz, 1H), 1.44 (s, 3H),
3.27 (dd, J ¼ 2.6, 7.5 Hz, 1H), 3.56 (t, J ¼ 2.6 Hz, 1H), 4.01 (d,
J ¼ 7.5 Hz,1H), 6.71 (d, J ¼ 7.9 Hz,1H), 6.77 (s,1H), 6.97 (d, J ¼ 7.9 Hz,
4.3.2. (1R*,4R*)-2-(2-methoxyphenyl)-4-methyl-2-azabicyclo[2.1.0]
pentane (2b)
1H), 7.26 (t, J ¼ 7.9 Hz, 1H); 13C NMR (126 MHz, CDCl3)
d 16.1, 16.3,
20.7, 44.7, 61.1, 110.2 (q, 3JC-F ¼ 3.9 Hz), 114.5 (q, 3JC-F ¼ 3.9 Hz), 116.9
4
1
2
Yellow oil; IR (ATR) 3057, 2943, 2869, 2833, 1594, 1498, 1454,
(q, JC-F ¼ 1.4 Hz), 124.4 (q, JC-F ¼ 272.4 Hz), 129.1, 131.1 (q, JC-
1305, 1228, 1131, 1027, 736 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
0.57
¼ 31.7 Hz), 151.5; MS (EI) m/z (%) 227 (Mþ, 35), 226 (40), 212 (100),
F
(dd, J ¼ 3.5, 5.4 Hz, 1H), 0.91 (d, J ¼ 5.4 Hz, 1H), 1.42 (s, 3H), 3.21
(dd, J ¼ 2.2, 8.4 Hz, 1H), 3.48 (dd, J ¼ 2.2, 3.5 Hz, 1H), 3.78 (s, 3H),
4.03 (d, J ¼ 8.4 Hz, 1H), 6.75e6.88 (m, 4H); 13C NMR (126 MHz,
172 (80), 145 (90); HRMS (EI) calcd for C12H12F3N: 227.9022, found:
227.0919.
CDCl3)
d
16.5, 17.4, 20.2, 43.8, 55.3, 62.0, 111.0, 115.6, 120.0, 120.7,
4.3.8. (1R*,4R*)-2-(3-methoxyphenyl)-4-phenethyl-2-azabicyclo
[2.1.0]pentane (2g)
140.0, 150.2; MS (EI) m/z (%) 189 (Mþ, 78), 174 (100), 134 (100), 92
(22), 77 (42); HRMS (EI) calcd for C12H15NO: 189.1154, found:
189.1151.
Yellow oil; IR (ATR) 3026, 3001, 2925, 2858, 1597, 1579, 1491,
1454, 1337, 1285, 1250, 1205, 1162, 1108, 1041, 837, 751, 689 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
0.57 (dd, J ¼ 3.5, 5.5 Hz, 1H), 0.86 (d,
4.3.3. (1R*,4R*)-2-(3-methoxyphenyl)-4-methyl-2-azabicyclo[2.1.0]
pentane (2c)
Yellow oil; IR (ATR) 2942, 2924, 2863, 1611, 1596, 1587, 1579,
1491, 1455, 1336, 1318, 1286, 1256, 1205, 1175, 1162, 1107, 1045, 757,
J ¼ 5.5 Hz, 1H), 1.86 (ddd, J ¼ 6.2, 8.7, 14.7 Hz, 1H), 2.14e2.21 (ddd,
J ¼ 7.2, 8.6, 14.7 Hz, 1H), 2.67e2.74 (m, 2H), 3.10 (dd, J ¼ 2.2, 7.6 Hz,
1H), 3.52 (dd, J ¼ 2.2, 3.5 Hz,1H), 3.76 (s, 3H), 3.91 (d, J ¼ 7.6 Hz,1H),
6.10 (t, J ¼ 2.2 Hz, 1H), 6.17 (dd, J ¼ 2.2, 8.1 Hz, 1H), 6.31 (dd, J ¼ 2.2,
8.1 Hz,1H), 7.08 (t, J ¼ 8.1 Hz, 1H), 7.17e7.29 (m, 5H); 13C NMR
688 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
0.53 (dd, J ¼ 3.0, 5.4 Hz, 1H),
0.87 (d, J ¼ 5.4 Hz, 1H), 1.42 (s, 3H), 3.24 (dd, J ¼ 3.0, 7.5 Hz,1H), 3.51
(t, J ¼ 3.0 Hz, 1H), 3.77 (s, 3H), 3.96 (d, J ¼ 7.5 Hz, 1H), 6.13 (d,
J ¼ 2.2 Hz, 1H), 6.20 (dd, J ¼ 2.2, 8.1 Hz, 1H), 6.31 (dd, J ¼ 2.2, 8.1 Hz,
(126 MHz, CDCl3) d 19.5 (CH2), 20.1 (C), 32.5 (CH2), 33.9 (CH2), 44.0
(CH), 55.1 (CH3), 59.7 (CH2), 100.1 (CH), 103.4 (CH), 106.9 (CH), 126.0
(CH), 128.39 (CH), 128.42 (CH), 129.5 (CH), 141.7 (C), 152.6 (C), 160.4
(C); MS (EI) m/z (%) 279 (Mþ, 10), 188 (100); HRMS (EI) calcd for
1H), 7.09 (t, J ¼ 8.1 Hz, 1H); 13C NMR (126 MHz, CDCl3)
d 15.7 (C),
16.4 (CH3), 20.5 (CH2), 44.6 (CH), 55.1 (CH3), 60.9 (CH2), 100.1 (CH),
103.3 (CH), 106.9 (CH), 129.5 (CH), 152.7 (C), 160.4 (C); MS (EI) m/z
(%) 189 (Mþ, 76), 174 (100), 134 (85), 107 (55), 77 (27); HRMS (EI)
calcd for C12H15NO: 189.1154, found: 189.1156.
C19H21NO: 279.1623, found: 279.1621.
4.3.9. (1R*,4R*,5S*)-2-(3-methoxyphenyl)-4,5-dimethyl-2-
azabicyclo[2.1.0]pentane (2h)
Yellow oil; 1H NMR (400 MHz, CDCl3)
d
0.94 (d, J ¼ 6.4 Hz, 3H),
4.3.4. (1R*,4R*)-2-(3-methoxyphenyl)-4-methyl-2-aza[1-2H]
bicyclo[2.1.0]pentane (2c0)
1.11 (q, J ¼ 6.4 Hz, 1H), 1.35 (s, 3H), 3.11 (d, J ¼ 2.0 Hz, 1H), 3.24 (dd,
J ¼ 2.0, 7.5 Hz, 1H), 3.77 (s, 3H), 3.97 (d, J ¼ 7.5 Hz, 1H), 6.13 (t,
J ¼ 2.2 Hz, 1H), 6.18 (dd, J ¼ 2.2, 8.0 Hz, 1H), 6.31 (dd, J ¼ 2.2, 8.0 Hz,
1H), 7.09 (t, J ¼ 8.0 Hz, 1H).
Yield 76%; 97% deuterium content; yellow oil; IR (ATR) 2924,
2863,1597, 1491, 1455,1333,1286,1242, 1208, 1177,1165, 1141, 1040,
837, 757, 688 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
0.53 (d, J ¼ 5.4 Hz,
1H), 0.86 (d, J ¼ 5.4 Hz, 1H), 1.41 (s, 3H), 3.23 (d, J ¼ 7.5 Hz, 1H), 3.77
(s, 3H), 3.96 (d, J ¼ 7.5 Hz, 1H), 6.13 (t, J ¼ 2.2 Hz, 1H), 6.19 (dd,
4.3.10. N-{[(1R*,2S*)2-Chloro-1-methylcyclopropyl]methyl}-3-
methoxyaniline (4c)
J ¼ 2.2, 8.0 Hz, 1H), 6.31 (dd, J ¼ 2.2, 8.0 Hz,1H), 7.08 (t, J ¼ 8.0 Hz,
Yellow oil. IR (ATR) 3410, 2932, 2835, 1614, 1588, 1510, 1496,
1H); 13C NMR (126 MHz, CDCl3)
d
15.6, 16.4, 20.4, 44.3 (t, JC-
1461, 1207, 1160, 1037, 825, 755, 686 cmꢀ1 1H NMR (500 MHz,
;
1
¼ 29.4 Hz), 55.1, 61.0, 100.1, 103.4, 106.9, 129.5, 152.7, 160.4; MS
CDCl3)
d
0.66 (dd, J ¼ 4.1, 6.3 Hz, 1H), 1.06 (dd, J ¼ 6.3, 7.6 Hz, 1H),
D
(EI) m/z (%) 190 (Mþ, 78), 175 (100), 135 (74), 107 (52), 92 (18);
1.34 (s, 3H), 2.98 (d, J ¼ 12.6 Hz, 1H), 3.05 (dd, J ¼ 4.1, 7.6 Hz, 1H),
3.06 (d, J ¼ 12.6 Hz, 1H), 3.68 (br s, 1H), , 3.77 (s, 3H), 6.13 (t,
J ¼ 2.1 Hz, 1H), 6.20 (dd, J ¼ 2.1, 8.1 Hz, 1H), 6.28 (dd, J ¼ 2.1, 8.1 Hz,
HRMS (EI) calcd for C12H14DNO: 190.1216, found: 190.1218.
4.3.5. (1R,4R)-2-(3-methoxyphenyl)-4-methyl-2-azabicyclo[2.1.0]
1H), 7.07 (t, J ¼ 8.1 Hz, 1H); 13C NMR (126 MHz, CDCl3)
d 17.3, 20.5,
pentane ((1R,4R)-2c)
22.2, 38.1, 51.4, 55.1, 98.7, 102.8, 105.8, 130.0, 149.7, 160.9; MS (EI) m/
z (%) 225 (Mþ, 78), 190 (36), 162 (22), 148 (12), 136 (100); HRMS (EI)
calcd for C12H16ClNO: 225.0920, found: 225.0922.
25
[
a]
e260 (c 0.10, EtOH); HPLC, DAICEL CHIRALCEL OD (f
D
0.46 cm ꢂ 25 cm), i-PrOH/hexane ¼ 1:9, flow rate ¼ 0.5 mL/min,
Please cite this article in press as: Kimura T, et al., Synthesis of 2-azabicyclo[2.1.0]pentanes by the intramolecular nucleophilic substitution of
cyclopropylmagnesium carbenoids with magnesium anilide, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.045

6
T. Kimura et al. / Tetrahedron xxx (2017) 1e6
(b) Satoh T, Miura M, Sakai K, Yokoyama Y. Tetrahedron. 2006;62:4253;
Acknowledgements
(c) Yajima M, Nonaka R, Yamashita H, Satoh T. Tetrahedron Lett. 2009;50:4754;
(d) Yamada Y, Mizuno M, Nagamoto S, Satoh T. Tetrahedron. 2009;65:10025;
(e) Satoh T, Kasuya T, Ishigaki M, et al. Synthesis. 2011:397;
(f) Satoh T, Kashiwamura G, Nagamoto S, Sasaki Y, Sugiyama S. Tetrahedron Lett.
2011;52:4468;
This work was supported by the JSPS KAKENHI Grant Number
25810030, which is gratefully acknowledged.
(g) Satoh T, Kimura T, Sasaki Y, Nagamoto S. Synthesis. 2012;44:2091;
(h) Kimura T, Inumaru M, Migimatsu T, Ishigaki M, Satoh T. Tetrahedron.
2013;69:3961.
7. (a) Miyagawa T, Tatenuma T, Tadokoro M, Satoh T. Tetrahedron. 2008;64:5279;
(b) Satoh T, Tsuru T, Ikeda S, Miyagawa T, Momochi H, Kimura T. Tetrahedron.
2012;68:1071;
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Please cite this article in press as: Kimura T, et al., Synthesis of 2-azabicyclo[2.1.0]pentanes by the intramolecular nucleophilic substitution of
cyclopropylmagnesium carbenoids with magnesium anilide, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.045