Synthesis and reaction of 1-azabicyclo[3.1.0]hexane

Article abstract of DOI:10.1248/cpb.57.1142

The effective formation of 1-azabicyclo[3.1.0]hexane (5) by treatment of 2-(bromomethyl)pyrrolidine hydrobromide (4) with n-BuLi was established, with the reaction occurring by a rational reaction pathway via the open chain transition state 8 based on int

Full text of DOI:10.1248/cpb.57.1142

1142
Notes
Chem. Pharm. Bull. 57(10) 1142—1146 (2009)
Vol. 57, No. 10
Synthesis and Reaction of 1-Azabicyclo[3.1.0]hexane
Kazuhiko HAYASHI, ,a Eiko KUJIME,a Hajime KATAYAMA,a Shigeki SANO,b Motoo SHIRO,c and
*
b
Yoshimitsu NAGAO
a College of Pharmacy, Kinjo Gakuin University; 2–1723 Omori, Moriyama-ku, Nagoya 463–8521, Japan: b Graduate
c
School of Pharmaceutical Sciences, The University of Tokushima; Sho-machi, Tokushima 770–8505, Japan: and Rigaku
Corporation; 3–9–12 Matsubara-cho, Akishima, Tokyo 196–8666, Japan.
Received June 5, 2009; accepted July 8, 2009; published online July 10, 2009
The effective formation of 1-azabicyclo[3.1.0]hexane (5) by treatment of 2-(bromomethyl)pyrrolidine hydro-
bromide (4) with n-BuLi was established, with the reaction occurring by a rational reaction pathway via the open
chain transition state 8 based on intermolecular Br···Liꢀ coordination (SN2 process). The reaction of 5 with
electrophiles 13a—n gave the corresponding pyrrolidines 14a—n and piperidine 6, 15a—g, i—n. The selectivity
of the products in this reaction appeared to be controlled by equilibrium.
Key words 1-azabicyclo[3.1.0]hexane; lithium coordination; 3-halopiperidine; X-ray crystallographic analysis; 2-(halomethyl)-
pyrrolidine
We have recently established an efficient method for syn- use of NaOH and KOH (entries 1—3). A lithium cation also
thesis of 1-azabicyclo[1.1.0]butane (ABB) (2) with n-BuLi increased the yield of ABH (5) in the reaction with hydride
from 2,3-dibromopropylamine hydrobromide (1), and devel- reagents (NaH, LiH) and amide reagents (NaNH2, LiNH2,
oped a facile synthetic method for various 3-substituted aze- LDA) as bases (entries 4—7, 9). The employment of n-BuLi
tidine derivatives (3), as represented in Chart 1.1—7) We have gave rise to ABH (5) in quantitative yield and showed the
also reported that a lithium cation of n-BuLi promoted the best result (entry 11). The addition of a crown ether, 12-
cyclization of 1 to ABB (2) bearing a highly strained bicyclic crown-4, trapping a lithium cation into the reaction with
structure.1,4) This effect of a lithium cation prompted us to LiNH2 decreased the yield of ABH (5), and its yield was al-
synthesize other strained bicyclic systems using this method. most the same as that of NaNH2 (entries 6, 8). The similar re-
We focus herein on the synthesis of 1-azabicyclo[3.1.0]- sults were obtained in the reaction with n-BuLi and n-
hexane (ABH) (5), which is known as a strained azabicyclic BuMgCl (entries 10, 12). These results described above indi-
compound,8,9) and describe the results and the mechanistic cate that a lithium cation activated the C–Br bond in 4 by co-
considerations of the cyclization of 2-(bromomethyl)pyrroli- ordination to the Br atom and promoted the cyclization of
dine hydrobromide (4)10,11) with a lithium cation, as well as 4.1,4,13) The reaction pathway was first estimated to involve
the reaction of ABH (5) with some electrophiles.
the five-membered cyclic transition state 7 based on the in-
The cyclization of 4 was attempted in the presence of vari- tramolecular Br···Liꢀ coordination (SNi process), because
ous bases, as shown in Chart 2. Due to the difficulty of direct the intramolecular Br···Liꢀ coordination in 7 seems to be
ABH analysis, the reactions were evaluated instead by HPLC stronger than that in 8, as shown in Chart 3.4) However, it
analysis of 1-benzyl-3-bromopiperidine (6), which was cannot be denied that the cyclization proceeded via the open
formed by the reaction of ABH (5) with benzyl bromide. All chain transition state 8 based on the intermolecular Br···Liꢀ
results are summarized in Table 1.
coordination (SN2 process). Thus, the reaction of two di-
First, the reaction of 4 was examined in aqueous solution astereoisomers of N-benzyl-2-bromo-1,2-diphenylethylamine
(entries 1—3), since ABH (5) was prepared in 25% yield hydrobromide (10, 12) with n-BuLi was examined to clarify
from 2-(chloromethyl)pyrrolidine hydrochloride with aque- the transition state in this cyclization.
ous NaOH by Buyle.12) The cyclization of 4 proceeded dra-
Compounds 10 and 12 were prepared by the ring-opening
matically with the use of LiOH as a base, compared with the
Table 1. Cyclization of 4 with Various Bases
Additive
(mol eq)
Yield (%)a)
Entry
Base
Solvent Temp. Time
of 6
E-Nu: HX (Xꢁhalogen), AcSH, HCO2H, Ac2O, etc.
1
2
3
4
5
6
7
8
9
NaOH
KOH
LiOH·H2O
NaH
LiH
NaNH2
LiNH2
None
None
None
None
None
None
None
H2O
H2O
H2O
THF
THF
THF
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
18 h
18 h
18 h
18 h
18 h
18 h
18 h
18 h
18 h
1 h
4
N.D.b)
68
31
64
33
90
27
90
Chart 1
LiNH2 12-Crown-4 (2.1) THF
LDA
None
None
None
THF
THF ꢂ78 °C
THF ꢂ78 °C
10 n-BuMgCl
11
12
69
Quant.
64
n-BuLi
1 h
1 h
n-BuLi 12-Crown-4 (2.1) THF ꢂ78 °C
Chart 2
a) Determined by HPLC analysis. b) Not detected.
© 2009 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: hayashi@kinjo-u.ac.jp

October 2009
1143
Chart 5
Chart 3
Chart 6
Table 2. Reaction of ABH (5) with 13a—n
Yield (%)a) of
14a—n
Yield (%)a) of
6, 15a—g, i—n
Entry
R
X
1
2
3
4
Cl
Cl
Cl
Cl
14a
14b
14c
14d
60
73
72
76
15a
15b
15c
15d
26
24
19
24
Chart 4
5
Cl
14e
35
72
15e
18
6
7
Cl
Cl
14f
15f
23
7
14g
N.D.b)
N.D.b)
72
15g
8
9
Br
Br
Br
14h
14i
14j
6
Quant.
18
15i
15j
10
N.D.b)
74
11
12
13
14
Br
Br
Br
Br
14k
14l
N.D.b)
N.D.b)
N.D.b)
N.D.b)
15k
15l
72
81
69
9
14m
14n
15m
15n
Fig. 1. Computer-Generated Drawing Derived from the X-Ray Coordi-
nates of Compound 12
a) Isolated yields. b) Not detected.
reaction of the corresponding aziridines 914,15) and 1114,15)
with HBr (Chart 4). The structures of 10 and 12 were con-
1
firmed by H- and 13C-NMR analyses and X-ray crystallo-
graphic analysis of 12 (Fig. 1). The reactions of 10 and 12
with n-BuLi at ꢂ78 °C for 1 h afforded the aziridines 9 and
11 having an inverted configuration at the 2-position carbon,
Chart 7
respectively, as shown in Chart 4. These results suggest that chlorides 13a—f gave the corresponding pyrrolidines 14a—f
the cyclization proceeded in the SN2 process by a back-side as the major product (entries 1—6). The piperidines 6,
approach of the nitrogen anion. We therefore altered the SNi 15g, j—n were formed as the major product in the reaction
process proposed previously to an SN2 process.
with alkyl halides 13g—n, except for 15i (entries 7—14).
Subsequently, the reaction of 4 with n-BuLi was per- The selectivity of products in the reaction of ABH (5) with
formed at ꢂ78 °C for 1 h (entry 11, Table 1), and ABH (5) electrophiles was rationalized by equilibrium, as Harding and
was isolated in 69% yield by distillation, as shown in Chart Burks have proposed24) and as shown in Chart 7. Although
5. The resulting ABH (5) was allowed to react with acyl the kinetic products of the ring opening of ABH (5) may be
chlorides 13a—f and alkyl halides 13g—n (Chart 6), as the the pyrrolidines 14a—n, equilibrium leads to the thermody-
reaction with electrophiles has rarely been reported.17—23) All namically favored piperidines 6, 15a—g, i—n. The genera-
results are summarized in Table 2. The reaction with acyl tion of piperidines 6, 15g, j—n as major products in the reac-

1144
Vol. 57, No. 10
bromic acid (48%, 1.18 ml) at 0 °C. After being stirred for 1.5 h at room
temperature, Et2O was added to the reaction mixture and the precipitate was
filtered off. The filtrate was washed with Et2O to give 10 (519 mg, 66%) as
a white solid, mp 169 °C. [a]D25 ꢀ72.3° (cꢁ1.045, MeOH), 1H-NMR
(400 MHz, CD3OD) d: 4.08 (1H, d, Jꢁ13.4 Hz), 4.15 (1H, d, Jꢁ13.4 Hz),
4.83 (1H, d, Jꢁ6.6 Hz), 5.78 (1H, d, Jꢁ6.6 Hz), 7.2—7.3 (2H, m), 7.3—7.4
(7H, m), 7.4—7.5 (5H, m), 7.52 (1H, tt, Jꢁ1.5, 7.3 Hz). 13C-NMR
(100 MHz, CD3OD) d: 51.8, 54.3, 67.0, 130.2, 130.29, 130.30, 130.5, 130.9,
131.0, 131.2, 131.67, 131.69, 131.72, 132.6, 137.7. IR (KBr) cmꢂ1: 2960,
1541, 1506, 1456, 1394. FAB-MS m/z: 368.0825 [Mꢀ1]ꢀ (Calcd for
C21H21NBr: 368.0837). Anal. Calcd for C21H21NBr2: C, 56.40; H, 4.73; N,
3.13. Found: C, 56.71; H, 4.77; N, 3.15.
a) Determined by 1H-NMR analysis.
Chart 8
Cyclization of (ꢀ)-(1R,2S)-N-Benzyl-2-bromo-1,2-diphenylethylamine
Hydrobromide (10) To a suspension of 10 (50 mg, 0.112 mmol) in THF
(0.5 ml) was added n-BuLi (1.58 mol/l, 0.142 ml, 0.224 mmol) at ꢂ78 °C
under N2 atmosphere. After being stirred for 1 h at ꢂ78 °C, the reaction
mixture was quenched with a phosphate buffer solution (pH 6.0, 0.05 mol/l,
10 ml) and then extracted with AcOEt. The AcOEt extract was washed with
brine, dried over MgSO4, and evaporated in vacuo. The residue was purified
by PTLC (eluent n-hexane–AcOEt, 9/1) to give 9 (24 mg, 74%) as a white
solid. The cis azetidine 11 was not detected by TLC. [a]D25 ꢀ92.0°
(cꢁ0.935, CHCl3), 1H-NMR (400 MHz, CDCl3) d: 3.20 (1H, br s), 3.34
(1H, d, Jꢁ14.2 Hz), 3.42 (1H, br s), 3.66 (1H, d, Jꢁ14.2 Hz), 7.1—7.5 (15H,
m) [lit.,15) 1H-NMR (CDCl3) d: 3.32 (2H, br s), 3.38 (1H, d, Jꢁ14 Hz), 3.66
(1H, d, Jꢁ14 Hz), 7.1—7.5 (15H, m)]. IR (KBr) cmꢂ1: 3020, 1651, 1522,
1421, 1215. EI-MS m/z: 285.1512 [Mꢀ] (Calcd for C21H19N: 285.1517).
Preparation of (ꢁ)-(1R,2R)-N-Benzyl-2-bromo-1,2-diphenylethyl-
amine Hydrobromide (12) To a solution of 11 (414 mg, 1.45 mmol) in
tion with alkyl halides 13g—n was explained to be due to
rapid equilibrium by the stronger nucleophilicity of the N
atoms in 14g, h, j—n, which were formed first, rather than by
that of the N atoms in 14a—f. The above hypothesis was
supported by the fact that the pyrrolidine 14i dissolved in
tetrahydrofuran (THF) was completely converted to the
piperidine 15i under reflux for 16 h, though the piperidine
15i was not transformed to 14i under the same conditions, as
shown in Chart 8.
In conclusion, we have established an efficient method for
synthesizing 1-azabicyclo[3.1.0]hexane (5) by the cyclization
of 2-(bromomethyl)pyrrolidine hydrobromide (4) with n- MeCN (4 ml) was added hydrobromic acid (48%, 0.65 ml) at ꢂ35 °C. After
being stirred for 30 h at ꢂ35 °C, Et2O was added to the reaction mixture and
the precipitate was filtered off. The filtrate was recrystallized from
BuLi, and propose a rational SN2 process for this reaction in-
volving the open chain transition state 8 based on the inter-
MeOH–Et2O to give 12 (519 mg, 66%) as colorless prisms, mp 142—
molecular Br···Liꢀ coordination. In addition, the reactions
143 °C. 1H-NMR (400 MHz, CD3OD) d: 4.15 (1H, d, Jꢁ13.7 Hz), 4.20 (1H,
of ABH (5) with acyl chlorides 13a—f and alkyl halides
13g—n were demonstrated to give the pyrrolidines 14a—n
and the piperidines 6, 15a—g, i—n. The selectivity of the
products in this reaction appears to have been controlled by
equilibrium.
d, Jꢁ13.7 Hz), 5.05 (1H, d, Jꢁ11.0 Hz), 5.73 (1H, d, Jꢁ11.0 Hz), 7.1—7.2
(3H, m), 7.2—7.3 (4H, m), 7.3—7.4 (5H, m), 7.4—7.5 (3H, m). 13C-NMR
(100 MHz, CD3OD) d: 51.4, 54.4, 68.9, 129.6, 130.1, 130.5, 130.6, 130.9,
131.2, 131.4, 131.7, 132.1, 132.7, 138.9. IR (KBr) cmꢂ1: 2931, 1541, 1506,
1456, 1404, 1267. FAB-MS m/z: 368.0847 [Mꢀ1]ꢀ (Calcd for C21H21NBr:
368.0837). Anal. Calcd for C21H21NBr2: C, 56.40; H, 4.73; N, 3.13. Found:
C, 56.26; H, 4.79; N, 3.04.
Experimental
X-Ray Crystallographic Analysis of (ꢁ)-(1R,2R)-N-Benzyl-2-bromo-
1,2-diphenylethylamine Hydrobromide (12) The crystalline compound
All melting points were determined on a Yanaco micro melting point ap-
paratus and are uncorrected. IR spectra were obtained on a JASCO FT/IR- 12 was recrystallized from CHCl3 in order to subject to the X-ray crystallo-
420 or JASCO FT/IR-4100 IR Fourier transform spectrometer. 1H-NMR graphic analysis. The measurement was made on a Rigaku RAXIS-RAPID
spectra were recorded on a JEOL JNM-ECA500 (500 MHz) or JEOL JNM-
AL400 (400 MHz) spectrometer. 13C-NMR spectra were recorded on a tion. The data were processed using the PROCESS-AUTO program package.
JEOL JNM-ECA500 (125 MHz) or JEOL JNM-AL400 (100 MHz) spec-
The linear absorption coefficient, m, for MoKa radiation is 1.0 cmꢂ1. A
Imaging Plate diffractometer with graphite monochromated MoKa radia-
trometer with complete proton decoupling. Chemical shifts are given in d symmetry-related absorption correction using the program ABSCOR was
values (ppm) using tetramethylsilane (TMS) as an internal standard. Elec- applied.25) The data were corrected for Lorentz and polarization effects. The
tron spray ionization (ESI)-MS were recorded on a Waters LCT Premier structure was solved by directed methods and expanded using Fourier tech-
spectrometer. Fast atom bombardment mass spectra (FAB-MS) and electron niques.26,27) The non-hydrogen atoms were refined anisotropically. Hydrogen
ionization mass spectra (EI-MS) were recorded on a JEOL JMS SX-102A atoms were included but not refined. Natural atom scattering factors were
spectrometer. Elementary combustion analyses were performed on a Yanaco taken from Cromer and Waber.28) The values for the mass attenuation coeffi-
CHN CORDER MT-5. All reactions were monitored by TLC employing cients are those of Creagh and Hubbel.29) All calculations were performed
0.25 mm silica gel plates (Merck 5715; 60 F254). Preparative TLC (PTLC) using the teXsan crystallographic software package.30)
was performed on 0.5 mm silica gel plates (Merck 5744; 60 F254). Column
chromatography was carried out on silica gel [Kanto Chemical 60N; 63— less prism crystal, triclinic, space group P-1(#2), aꢁ9.995(1) Å, bꢁ
210 mm]. All reagents were used as purchased.
11.019(1) Å, cꢁ14.201(1) Å, aꢁ100.379(7)°, bꢁ93.704(7)°, gꢁ111.722(6)°;
General Procedure for HPLC Analysis (Table 1) The reaction were Vꢁ1414.4(3) Å3; Zꢁ4, Dcalcdꢁ1.611 g/cm3, Rꢁ0.079, Rwꢁ0.171; GOFꢁ
Crystallographic Data for 12: C21H21NBr2·2CHCl3, MWꢁ685.97, color-
performed by using a suspension of 4 (122.5 mg, 0.50 mmol) and each bases
(1.05 mmol) in THF (1.5 ml) under the conditions shown in Table 1. After
1.060.
Cyclization of (ꢁ)-(1R,2R)-N-Benzyl-2-bromo-1,2-diphenylethyl-
the reaction was completed, the reaction mixture was quenched with a phos- amine Hydrobromide (12) To a suspension of 12 (50 mg, 0.112 mmol) in
phate buffer solution (pH 7.0, 1/15 mol/l, 3 ml), extracted with CH2Cl2, and THF (0.5 ml) was added n-BuLi (1.58 mol/l, 0.142 ml, 0.224 mmol) at
then dried over MgSO4. To the resulting CH2Cl2 solution was added benzyl ꢂ78 °C under N2 atmosphere. After being stirred for 1 h at ꢂ78 °C, the reac-
bromide (65 ml, 0.55 mmol) at 0 °C, and the mixture was stirred at room
tion mixture was quenched with a phosphate buffer solution (pH 6.0,
temperature for 16 h to afford a crude reaction solution, which was analyzed 0.05 mol/l, 10 ml) and then extracted with AcOEt. The AcOEt extract was
by HPLC under the following conditions. Mobile phase: phosphate buffer washed with brine, dried over MgSO4, and evaporated in vacuo. The residue
solution (pH 7.0, 1/15 mol/l)/MeCNꢁ5/5, UV: 230 nm, flow rate: 1.0 was purified by PTLC (eluent n-hexane–AcOEt, 9/1) to give 11 (10 mg,
1
ml/min, column: TOSOH TSK-GEL 80Ts (4.6 mmfꢃ15 cm). 1-Benzyl-3- 33%) as a white solid. The trans azetidine 9 was not detected by TLC. H-
bromopiperidine (6) (retention timeꢁ22 min) was used as the standard sam- NMR (400 MHz, CDCl3) d: 3.06 (2H, s), 3.89 (2H, s), 7.0—7.3 (11H, m),
ple.
7.32 (2H, t, Jꢁ7.6 Hz), 7.43 (2H, d, Jꢁ7.6 Hz) [lit.,16) 1H-NMR (CDCl3) d:
Preparation of (ꢀ)-(1R,2S)-N-Benzyl-2-bromo-1,2-diphenylethyl- 3.08 (2H, s), 3.90 (2H, s), 7.05—7.55 (15H, m)]. IR (KBr) cmꢂ1: 3020,
amine Hydrobromide (10) To
solution of 914,15) ([a]D25 ꢀ95.3° 1558, 1522, 1419, 1215, 928. EI-MS m/z: 285.1512 [Mꢀ] (Calcd for
(cꢁ1.175, CHCl3), 503 mg, 1.75 mmol) in MeCN (5 ml) was added hydro- C21H19N: 285.1517).
a

October 2009
1145
1
Isolation of ABH (5)12,20,21) To a suspension of 4 (25.0 g, 0.102 mol) in
THF (300 ml) was added n-BuLi (2.64 mol/l, 81.2 ml, 0.214 mol) at ꢂ78 °C
under N2 atmosphere. After being stirred for 1 h at ꢂ78 °C, the reaction
mixture was quenched with 1 N HCl (100 ml) and washed with Et2O. The re-
3-Chloro-1-(4-chlorobenzoyl)piperidine (15d) Colorless oil. H-NMR
(500 MHz, CDCl3) d: 1.39—2.38 (4H, m), 3.12—4.50 (5H, m), 7.34—7.45
(4H, m). 13C-NMR (125 MHz, CDCl3) d: 22.0/24.3, 33.9, 42.4, 47.6/49.3,
54.4/55.5, 128.6, 128.8, 134.0, 135.8, 169.9. IR (neat) cmꢂ1: 2950, 2861,
sultant HCl solution was made alkaline with 50% KOH, and extracted with 1637, 1430, 1273, 1092, 840, 754. ESI-MS m/z: 258.0451 [MꢀꢀH] (Calcd
Et2O. The Et2O layer was dried over MgSO4, and distilled at atmospheric for C12H14Cl2NO: 258.0452).
pressure to give 5 (5.87 g, 69%) as a colorless oil, bp 110—112 °C. 1H-NMR
2-Chloromethyl-1-(4-nitrobenzoyl)pyrrolidine (14e) Pale yellow
(500 MHz, CDCl3) d: 1.16 (1H, d, Jꢁ3.4 Hz), 1.36—1.50 (1H, m), 1.52 prisms (THF–n-hexane). mp 79.5—80.5 °C. 1H-NMR (500 MHz, CDCl3) d:
(1H, d, Jꢁ5.2 Hz), 1.60 (1H, dt, Jꢁ13.4, 7.6 Hz), 1.80—1.92 (1H, m), 2.05 1.73—1.89 (1H, m), 1.96—2.29 (3H, m), 3.32—3.60 (2H, m), 3.79 (1H, dd,
(1H, dd, Jꢁ13.2, 8.6 Hz), 2.33 (1H, ddd, Jꢁ8.6, 5.2, 3.4 Hz), 2.86 (1H, dt,
Jꢁ11.2, 2.0 Hz), 4.16 (1H, dd, Jꢁ11.2, 5.4 Hz), 4.49—4.63 (1H, m), 7.71
Jꢁ11.6, 7.6 Hz), 2.95 (1H, dd, Jꢁ11.6, 8.6 Hz). 13C-NMR (125 MHz,
(2H, d, Jꢁ8.6 Hz), 8.28 (2H, d, Jꢁ8.6 Hz). 13C-NMR (125 MHz, CDCl3) d:
CDCl3) d: 19.3, 25.7, 26.4, 39.3, 52.4. IR (neat) cmꢂ1: 2940, 2793, 1457, 25.1, 28.1, 45.6, 51.1, 57.8, 123.7, 128.4, 142.7, 148.7, 167.9. IR (KBr)
1339, 1096. ESI-MS m/z: 106.0641 [MꢀꢀNa] (Calcd for C5H9NNa:
cmꢂ1: 2991, 2883, 1625, 1599, 1520, 1421, 1349, 851, 721. ESI-MS m/z:
291.0504 [MꢀꢀNa] (Calcd for C12H13ClN2O3Na: 291.0512). Anal. Calcd
106.0633).
General Procedure for the Reaction of ABH (5) with Electrophiles for C12H13ClN2O3: C, 53.64; H, 4.88; N, 10.43. Found. C, 53.51; H, 4.87; N,
13a—f (Table 2, Entry 1) To a solution of ABH (5) (42 mg, 0.50 mmol)
in THF (5 ml) was added benzoyl chloride (13a) (59 ml, 0.50 mmol) at 0 °C
under N2 atmosphere. After being stirred for 16 h at room temperature, the
10.35.
3-Chloro-1-(4-nitrobenzoyl)piperidine (15e) Colorless oil. 1H-NMR
(500 MHz, CDCl3) d: 1.46—1.75 (1H, m), 1.84—2.32 (3H, m), 3.17—3.77
reaction mixture was evaporated in vacuo. The residue was purified by col- (3H, m), 3.94—4.34 (2H, m), 7.55—7.66 (2H, m), 8.29 (2H, d, Jꢁ8.6 Hz).
umn chromatography on silica gel (eluent n-hexane–AcOEt, 4/1) to give 14a
(67 mg, 60%) as a colorless oil and 15a (30 mg, 26%) as a colorless oil.
13C-NMR (125 MHz, CDCl3) d: 21.4/23.9, 33.4/34.1, 42.4/47.5, 49.2/54.1,
54.4/55.6, 123.9, 127.9/128.3, 141.8, 148.4, 168.4/168.8. IR (neat) cmꢂ1
:
1-Benzoyl-2-chloromethylpyrrolidine (14a) Colorless oil. 1H-NMR 2951, 2862, 1637, 1521, 1439, 1349, 1274, 861, 725. ESI-MS m/z: 291.0532
(500 MHz, CDCl3) d: 1.56—2.26 (4H, m), 3.36—3.61 (2H, m), 3.82 (1H, [MꢀꢀNa] (Calcd for C12H13ClN2NaO3: 291.0512).
dd, Jꢁ10.7, 2.0 Hz), 4.08 (1H, dd, Jꢁ10.7, 5.8 Hz), 4.43—4.61 (1H, m),
2-Chloromethyl-1-(2-naphthoyl)pyrrolidine (14f) Colorless oil. 1H-
7.33—7.59 (5H, m). 13C-NMR (125 MHz, CDCl3) d: 25.1, 28.2, 45.9, 51.3, NMR (500 MHz, CDCl3) d: 1.69—1.85 (1H, m), 1.91—2.29 (3H, m),
57.6, 127.4, 128.3, 130.2, 136.8, 170.2. IR (neat) cmꢂ1: 2974, 2876, 1629, 3.44—3.72 (2H, m), 3.86 (1H, d, Jꢁ10.3 Hz), 4.13 (1H, dd, Jꢁ10.3,
1447, 1410, 1212, 719, 700, 656. ESI-MS m/z: 246.0665 [MꢀꢀNa] (Calcd 6.0 Hz), 4.54—4.67 (1H, m), 7.48—7.67 (3H, m), 7.82—7.94 (3H, m), 8.03
for C12H14ClNNaO: 246.0662).
(1H, s). 13C-NMR (125 MHz, CDCl3) d: 25.1, 28.2, 45.9, 51.3, 57.7, 124.4,
126.6, 127.2, 127.3, 127.7, 128.1, 128.5, 132.5, 133.9, 134.0, 170.2. IR
1-Benzoyl-3-chloropiperidine (15a)31) Colorless oil. 1H-NMR (500
MHz, CDCl3) d: 1.32—2.42 (4H, m), 3.08—4.62 (5H, m), 7.41 (5H, s). 13C- (neat) cmꢂ1: 2973, 2876, 1623, 1472, 1411, 1349, 1197, 826, 777, 760. ESI-
NMR (125 MHz, CDCl3) d: 22.6/24.6, 34.3, 42.2, 47.6/49.3, 54.5/55.4, MS m/z: 296.0825 [MꢀꢀNa] (Calcd for C16H16ClNNaO: 296.0818).
127.0, 128.5, 129.8, 135.6, 170.9. IR (neat) cmꢂ1: 2949, 2860, 1635, 1428,
3-Chloro-1-(2-naphthoyl)piperidine (15f) Colorless plates (THF–n-
1273, 702. ESI-MS m/z: 246.0664 [MꢀꢀNa] (Calcd for C12H14ClNNaO: hexane). mp 115.2—116.0 °C. 1H-NMR (500 MHz, CDCl3) d: 1.40—2.36
246.0662).
(4H, m), 3.04—4.66 (5H, m), 7.46—7.58 (3H, m), 7.81—7.95 (4H, m). 13C-
2-Chloromethyl-1-(4-methylbenzoyl)pyrrolidine (14b)32) Colorless NMR (125 MHz, CDCl3) d: 22.8/24.6, 34.4, 42.4, 47.7/49.4, 54.7/55.6,
1
plates (THF–n-hexane). mp 85.0—87.0 °C. H-NMR (500 MHz, CDCl3) d: 124.3, 126.7, 126.9, 127.1, 127.8, 128.4, 128.4, 132.7, 132.9, 133.7, 170.9.
1.64—1.82 (1H, m), 1.88—2.02 (1H, m), 2.02—2.23 (2H, m), 3.38 (3H, s), IR (KBr) cmꢂ1: 2955, 2923, 2857, 1627, 1478, 1444, 1268, 1065, 867, 834,
3.43—3.62 (2H, m), 3.82 (1H, d, Jꢁ10.6 Hz), 4.05 (1H, dd, Jꢁ10.6, 808, 757. ESI-MS m/z: 296.0830 [MꢀꢀNa] (Calcd for C16H16ClNNaO:
5.8 Hz), 4.46—4.60 (1H, m), 7.20 (2H, d, Jꢁ7.7 Hz), 7.44 (2H, d, 296.0818). Anal. Calcd for C16H16ClNO: C, 70.20; H, 5.89; N, 5.12. Found.
Jꢁ7.7 Hz). 13C-NMR (125 MHz, CDCl3) d: 21.4, 25.2, 28.2, 46.0, 51.3, C, 70.04; H, 5.84; N, 5.14.
57.5, 127.5, 128.9, 133.9, 140.4, 170.3. IR (KBr) cmꢂ1: 2980, 2953, 2885,
1-Benzyl-3-chloropiperidine (15g) Colorless oil. 1H-NMR (500 MHz,
1624, 1416, 843, 758. ESI-MS m/z: 238.0997 [MꢀꢀH] (Calcd for CDCl3) d: 1.49—1.67 (2H, m), 1.73—1.82 (1H, m), 2.01—2.26 (3H, m),
C13H17ClNO: 238.0999). Anal. Calcd for C13H16ClNO: C, 65.68; H, 6.78; N, 2.65—2.75 (1H, m), 2.99—3.09 (1H, m), 3.54 (2H, s), 3.93—4.04 (1H, m),
5.89. Found. C, 65.56; H, 6.72; N, 5.94.
7.22—7.35 (5H, m). 13C-NMR (125 MHz, CDCl3) d: 24.8, 34.9, 52.8,
3-Chloro-1-(4-methylbenzoyl)piperidine (15b) Colorless oil. 1H-NMR 56.1, 61.3, 62.7, 127.1, 128.3, 129.0, 137.9. IR (neat) cmꢂ1: 2945, 2800,
(500 MHz, CDCl3) d: 1.35—2.33 (4H, m), 2.38 (3H, s), 3.03—4.70 (5H, 1454, 1154, 757, 739, 698. ESI-MS m/z: 210.1032 [MꢀꢀH] (Calcd for
m), 7.21 (2H, d, Jꢁ8.0 Hz), 7.31 (2H, d, Jꢁ8.0 Hz). 13C-NMR (125 MHz,
CDCl3) d: 21.4, 22.7/24.6, 34.4, 42.3, 47.6/49.5, 54.7/55.3, 127.1, 129.1,
132.7, 140.0, 171.1. IR (neat) cmꢂ1: 2949, 2861, 1634, 1427, 1273, 830,
752. ESI-MS m/z: 238.1006 [MꢀꢀH] (Calcd for C13H16ClNO: 238.0999).
2-Chloromethyl-1-(4-methoxybenzoyl)pyrrolidine (14c) Colorless
C12H17ClN: 210.1050).
1-Benzyl-3-bromopiperidine (6) Colorless oil. 1H-NMR (500 MHz,
CDCl3) d: 1.53—1.84 (3H, m), 2.04—2.43 (3H, m), 2.66—2.82 (1H, m),
3.00—3.17 (1H, m), 3.53 (2H, d, Jꢁ2.3 Hz), 4.06—4.19 (1H, m), 7.22—
7.38 (5H, m). 13C-NMR (125 MHz, CDCl3) d: 25.9, 35.7, 48.4, 52.8, 61.8,
needles (THF–n-hexane). mp 84.0—85.0 °C. 1H-NMR (500 MHz, CDCl3) 62.6, 127.1, 128.3, 129.0, 137.9. IR (neat) cmꢂ1: 2943, 2798, 1455, 1149,
d: 1.53—1.88 (1H, m), 1.89—2.29 (3H, m), 3.44—4.15 (4H, m), 3.84 (3H, 739, 712, 698. ESI-MS m/z: 254.0547 [MꢀꢀH] (Calcd for C12H17BrN:
s), 4.44—4.66 (1H, m), 6.88—6.94 (2H, m), 7.45—7.64 (2H, m). 13C-NMR 254.0544). Anal. Calcd for C12H16BrN: C, 56.71; H, 6.35; N, 5.51. Found. C,
(125 MHz, CDCl3) d: 25.3, 28.3, 46.0, 51.5, 55.4, 57.6, 113.5, 128.9, 129.5,
56.57; H, 6.31; N, 5.43.
161.2, 169.9. IR (KBr) cmꢂ1: 2977, 2950, 2883, 2840, 1625, 1424, 1406,
2-Bromomethyl-1-cyanomethylpyrrolidine (14i) Colorless oil. 1H-
1253, 1184, 1027, 852, 769. ESI-MS m/z: 276.0767 [MꢀꢀNa] (Calcd for NMR (500 MHz, CDCl3) d: 1.74—1.92 (3H, m), 2.07 (1H, dq, Jꢁ12.0,
C13H16ClNNaO2: 276.0767).
8.0 Hz), 2.74 (1H, q, Jꢁ8.6 Hz), 2.98—3.14 (2H, m), 3.30 (1H, dd, Jꢁ10.3,
6.3 Hz), 3.39 (1H, dd, Jꢁ10.3, 4.6 Hz), 3.70 (1H, d, Jꢁ17.6 Hz), 3.81 (1H,
3-Chloro-1-(4-methoxybenzoyl)piperidine (15c) Colorless oil. 1H-
NMR (500 MHz, CDCl3) d: 1.42—2.34 (4H, m), 3.12—4.56 (5H, m), 3.81 d, Jꢁ17.6 Hz). 13C-NMR (125 MHz, CDCl3) d: 22.9, 30.3, 35.5, 41.1, 54.0,
(3H, s), 6.89 (2H, d, Jꢁ8.9 Hz), 7.38 (2H, d, Jꢁ8.9 Hz). 13C-NMR
(125 MHz, CDCl3) d: 23.4, 34.4, 42.9, 47.8/50.2, 55.2, 55.4, 113.8, 127.7, MS m/z: 203.0182 [MꢀꢀH] (Calcd for C7H12BrN2: 203.0184).
129.1, 160.8, 170.9. IR (neat) cmꢂ1: 2950, 2859, 1631, 1608, 1426, 1251,
3-Bromo-1-cyanomethylpiperidine (15i) Colorless plates (Et2O–n-
1174, 1027, 841, 763. ESI-MS m/z: 254.0973 [MꢀꢀH] (Calcd for hexane). mp 57.5—58.5 °C. 1H-NMR (500 MHz, CDCl3) d: 1.58—1.98
C13H17ClNO2: 254.0948). (3H, m), 2.08—2.24 (1H, m), 2.40—2.56 (1H, m), 2.60—2.76 (2H, m),
61.8, 115.3. IR (neat) cmꢂ1: 2962, 2817, 1420, 1217, 1122, 860, 634. ESI-
1-(4-Chlorobenzoyl)-2-chloromethylpyrrolidine (14d) Colorless 2.96—3.10 (1H, m), 3.55 (2H, d, Jꢁ1.7 Hz), 4.08—4.22 (1H, m). 13C-NMR
prisms (THF–n-hexane). mp 87.5—88.5 °C. 1H-NMR (500 MHz, CDCl3) d: (125 MHz, CDCl3) d: 24.6, 34.0, 46.0, 46.6, 51.6, 60.1, 114.3. IR (KBr)
1.69—1.85 (1H, m), 1.92—2.27 (3H, m), 3.41—3.61 (2H, m), 3.79 (1H, d, cmꢂ1: 2947, 2800, 1465, 1420, 1158, 878, 721, 635. ESI-MS m/z: 203.0172
Jꢁ10.7 Hz), 4.09 (1H, dd, Jꢁ10.7, 5.6 Hz), 4.48—4.60 (1H, m), 7.39 (2H, [MꢀꢀH] (Calcd for C7H12BrN2: 203.0184). Anal. Calcd for C7H11BrN2: C,
d, Jꢁ8.3 Hz), 7.50 (2H, d, Jꢁ8.3 Hz). 13C-NMR (125 MHz, CDCl3) d: 25.2, 41.40; H, 5.46; N, 13.79. Found. C, 41.44; H, 5.25; N, 13.61.
28.1, 45.8, 51.3, 57.6, 128.6, 128.9, 135.1, 136.3, 169.1. IR (KBr) cmꢂ1
:
3-Bromo-1-ethoxycarbonylmethylpiperidine (15j) Colorless oil. 1H-
2952, 2886, 1626, 1417, 1091, 848, 753, 714. ESI-MS m/z: 258.0454 NMR (500 MHz, CDCl3) d: 1.28 (3H, t, Jꢁ6.9 Hz), 1.60—1.85 (3H, m),
[MꢀꢀH] (Calcd for C12H14Cl2NO: 258.0452). Anal. Calcd for 2.18—2.41 (2H, m), 2.54—2.64 (1H, m), 2.79—2.88 (1H, m), 3.17—3.24
C12H13Cl2NO: C, 55.83; H, 5.08; N, 5.43. Found. C, 55.82; H, 5.04; N, 5.35.
(1H, m), 3.26 (2H, d, Jꢁ2.3 Hz), 4.12—4.23 (1H, m), 4.18 (2H, q,

1146
Vol. 57, No. 10
Jꢁ6.9 Hz). 13C-NMR (125 MHz, CDCl3) d: 14.3, 25.7, 35.1, 47.5, 52.3,
58.9, 60.6, 61.3, 170.2. IR (neat) cmꢂ1: 2944, 2817, 1739, 1449, 1166, 1101,
714, 559. ESI-MS m/z: 250.0442 [MꢀꢀH] (Calcd for C9H17BrNO2:
250.0443).
5) Hayashi K., Kujime E., Katayama H., Sano S., Nagao Y.,
Heterocycles, 78, 1777—1786 (2009).
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metry, 17, 2028—2033 (2006).
3-Bromo-1-phenacylpiperidine (15k) Pale yellow oil. 1H-NMR (500
MHz, CDCl3) d: 1.60—1.94 (3H, m), 2.20—2.42 (2H, m), 2.52—2.66 (1H,
m), 2.82—2.96 (1H, m), 3.18—3.34 (1H, m), 3.85 (2H, s), 4.14—4.27 (1H,
m), 7.46 (2H, t, Jꢁ7.8 Hz), 7.58 (1H, t, Jꢁ7.8 Hz), 7.99 (2H, d, Jꢁ7.8 Hz).
13C-NMR (125 MHz, CDCl3) d: 25.7, 35.2, 47.4, 52.9, 61.9, 63.9, 128.2,
128.6, 133.3, 135.8, 196.4. IR (neat) cmꢂ1: 2944, 2796, 1697, 1448, 1218,
754, 714, 689. ESI-MS m/z: 282.0492 [MꢀꢀH] (Calcd for C13H17BrNO:
282.0494).
3-Bromo-1-(2-propenyl)piperidine (15l) Colorless oil. 1H-NMR (500
MHz, CDCl3) d: 1.56—1.86 (3H, m), 2.00—2.40 (3H, m), 2.68—2.83 (1H,
m), 3.02 (2H, d, Jꢁ6.6 Hz), 3.04—3.18 (1H, m), 4.06—4.18 (1H, m),
5.11—5.24 (2H, m), 5.84 (1H, ddt, Jꢁ17.2, 10.3, 6.6 Hz). 13C-NMR
(125 MHz, CDCl3) d: 25.8, 35.6, 48.1, 52.9, 61.4, 61.7, 118.2, 134.7. IR
(neat) cmꢂ1: 2944, 2789, 1644, 1150, 995, 922, 715, 638. ESI-MS m/z:
204.0372 [MꢀꢀH] (Calcd for C8H15BrN: 204.0388).
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352—353 (1973).
3-Bromo-1-(2-propynyl)piperidine (15m) Colorless oil. 1H-NMR
(500 MHz, CDCl3) d: 1.54—1.90 (3H, m), 2.14—2.42 (3H, m), 2.51—2.64
(1H, m), 2.69—2.80 (1H, m), 3.08—3.18 (1H, m), 3.35 (2H, t, Jꢁ2.2 Hz),
4.09—4.22 (1H, m). 13C-NMR (125 MHz, CDCl3) d: 25.4, 34.9, 46.8, 47.8,
51.5, 60.5, 73.5, 78.2. IR (neat) cmꢂ1: 3294, 2944, 2804, 1467, 1438, 1152,
1089, 717, 638. ESI-MS m/z: 202.0224 [MꢀꢀH] (Calcd for C8H13BrN:
202.0231).
3-Bromo-1-(3-butenyl)piperidine (15n) Colorless oil. 1H-NMR (500
MHz, CDCl3) d: 1.57—1.84 (3H, m), 2.04—2.54 (7H, m), 2.69—2.91 (1H,
m), 3.05—3.26 (1H, m), 4.07—4.22 (1H, m), 5.01 (1H, dd, Jꢁ1.1, 10.3 Hz),
5.06 (1H, dd, Jꢁ1.1, 17.2 Hz), 5.79 (1H, ddt, Jꢁ17.2, 10.3, 6.6 Hz). 13C-
NMR (125 MHz, CDCl3) d: 25.8, 29.7, 31.2, 35.7, 52.8, 57.6, 61.8, 115.9,
136.2. IR (neat) cmꢂ1: 2925, 2853, 1457, 1153, 912, 712. ESI-MS m/z:
218.0546 [MꢀꢀH] (Calcd for C9H17BrN: 218.0544).
Equilibrium of 14i and 15i (Chart 8) To a solution of 14i (14i/15iꢁ
90/10, 20 mg, 0.10 mmol) in THF (1 ml) was refluxed for 16 h under Ar
atmosphere. The mixture was concentrated in vacuo to give 15i (14i/15iꢁ
2/98, 20 mg, quantitative yield) as a colorless oil. Then, a solution of 15i
(14i/15iꢁ0/100, 27 mg, 0.13 mmol) in THF (1 ml) was treated in the same
manner, and 15i (14i/15iꢁ0/100, 27 mg, quantitative recovery) was recov-
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J. Appl. Cryst., 32, 115—119 (1999).
1
ered as a colorless solid. The resultant oil and solid were analyzed by H-
27) DIRDIF94: Beurskens P. T., Admiraal G., Beurkens G., Bosman W. P.,
de Gelder R., Israel R., Smits J. M. M., “The DIRDIF94 Program Sys-
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NMR (500 MHz, CDCl3).
Acknowledgement This work was supported by a Grant-in-Aid for Sci-
entific Research (C) (20550102) from the Japan Society for the Promotion
of Science.
References and Notes
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