Synthesis of 1-azabicyclic systems by double cyclization

Article abstract of DOI:10.1002/jhet.5570400126

5-Cyano-1-azabicyclo[3.3.0]octane (1) was prepared in one step from 1,7-dichloro-4-heptanone (4) under mild conditions. The application of this method for the preparation of 5-cyano-4,6-dimethyl-1-azabicyclo [3.3.0] octane (11) gave two diastereomers in equilibrium. The NMR measurements of 11 and its reduced compound 15 showed that the major isomer is the cis-exo form, and the minor isomer is the trans form. Molecular orbital calculations indicated that the cis-exo form is more stable than the trans form, in agreement with the experimental results. Furthermore, 6-cyano-1-azabicyclo[4.3.0]nonane (17) and 1-azabicyclo[4.4.0]decane (19), both including a six-membered ring, were prepared from appropriate haloketones by using this double cyclization method.

Full text of DOI:10.1002/jhet.5570400126

Jan-Feb 2003
Synthesis of 1-Azabicyclic Systems by Double Cyclization
Mitsuru Oka [a]*, Kunihisa Baba [a], Kensuke Nakamura [b] , Lulu Dong [c],
177
†
Hitoshi Hamajima [a], Ryoichi Unno [a] and Yukiharu Matsumoto [a]
[a] Central Research Laboratory, Sanwa Kagaku Kenkyusho, Co., Ltd.,
363 Shiosaki, Hokusei-cho, Inabe-gun, Mie 511-0406, Japan
[b] Institute of Medicinal Molecular Design, 5-24-5 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
[c] Chemistry Department of Harbin Medical University, Harbin, Heilongjiang 150086, China
Received September 13, 2002
5-Cyano-1-azabicyclo[3.3.0]octane (1) was prepared in one step from 1,7-dichloro-4-heptanone (4) under
mild conditions. The application of this method for the preparation of 5-cyano-4,6-dimethyl-1-azabicy-
clo[3.3.0]octane (11) gave two diastereomers in equilibrium. The NMR measurements of 11 and its reduced
compound 15 showed that the major isomer is the cis-exo form, and the minor isomer is the trans form.
Molecular orbital calculations indicated that the cis-exo form is more stable than the trans form, in agree-
ment with the experimental results. Furthermore, 6-cyano-1-azabicyclo[4.3.0]nonane (17) and 1-azabicy-
clo[4.4.0]decane (19), both including a six-membered ring, were prepared from appropriate haloketones by
using this double cyclization method.
J. Heterocyclic Chem., 40, 177 (2003).
Scheme 1
Introduction.
1-Aazabicyclo[3.3.0]octane is a useful amine moiety for
producing biologically active substances, for example,
antiarrhythmic agents, cerebral function activators, and
muscarinic M receptor agonists (Figure 1) [1]. 5-Cyano-
1
1-azabicyclo[3.3.0]octane (1) is a useful intermediate for
introducing a 1-azabicyclo[3.3.0]octane ring through a
conversion of a cyano group to various functional groups
[2]. However, the known preparation methods for 1 require
many steps, as well as the handling of an unstable interme-
diate [3,4]. In this paper, we describe a novel preparation
method for 1 that avoids these disadvantages [5]. We dis-
cuss the stereochemistry involved in the formation of this
ring with methyl groups. We also describe the formation of
1-azabicyclic compounds containing a six-membered ring.
which is an intermediate of the Strecker reaction [6] of 1,7-
dichloro-4-heptanone (4) [7] via imine 3. Alternatively,
double cyclization of 3 can lead to 1-azoniabicyclo-
[3.3.0]oct-1(5)-ene chloride (5); the known perchlorate 6
[3a] can be transformed to 1 via addition of cyanide ion.
When we first stirred 4 in MeOH with acetone cyano-
hydrine (8) and ammonia, we obtained a mixture of 1 and
2-(3-chloropropyl)tetrahydrofuran-2-carbonitrile (7) (Table
1, entry 1). Compound 7 was formed by transcyanation of
4 prior to imine formation, and subsequent cyclization.
When we replaced 8 by the more stable 2-amino-2-methyl-
propanenitrile (9) [8] as a cyanide source, we obtained 1 in
83% yield without the formation of 7 (Table 1, entry 2).
The reaction of 10 [9] with 9 and ammonia in a sealed
tube at 50° gave 11 as a mixture of two diasteroisomers in
Figure 1. Biologically active substances with 1-azabicylco[3.3.0]octane.
Results and Discussion.
1
40% yield. The H NMR spectrum analysis indicated that
The retrosynthesis of 1 is shown in Scheme 1.
Compound 1 might be synthesized by double cyclization of
2-amino-5-chloro-2-(3-chloropropyl)pentanenitrile (2),
the major (cis) isomer had only one signal peak for the
methyl hydrogens at δ 1.25 ppm, and the minor (trans) iso-
mer had two signal peaks for the methyl hydrogens at δ

178
M. Oka, K. Baba, K. Nakamura, L. Dong, H. Hamajima, R. Unno and Y. Matsumoto
Vol. 40
Table 1
Double Cyclization of 4 to 1
entry
cyanide source
(CH ) C(OH)CN (8) (10 eq.)
conditions
products (%)
cis-exo-11: -498.512278 (0.0)
trans-11: -498.509445 (1.8)
1
2
20°, 24 hours
20°, 24 hours
1 (60), 7 (8.2)
1 (83)
3 2
(CH ) C(NH )CN (9) (3 eq.)
3 2
2
Figure 2. Optimized structures and energies (Hartree) of cis-exo-11 and
trans-11 at the MP2/6-31G* level. Numbers in parentheses are relative
-1
energies in kcal mol .
1.14 ppm and δ 1.23 ppm. The observed cis/trans ratio was
79:21 (Scheme 2). Furthermore, the fact that the methine
protons at the 4- and 6-positions of 11 were replaced with
deuterium at room temperature in deuterated methanol
indicated that cis-11 and trans-11 are in a thermodynamic
equilibrium via 12, 13, and 14 (Scheme 2). The ab initio
MO calculations at MP2/6-31G* showed that cis-exo-11 is
Scheme 3
-1
1.8 kcal mol more stable than trans-11, a finding in
accord with the experimental results (Figure 2).
Meanwhile, cis-endo-11 could not be formed because of
the instability caused by the steric repulsion between the
methyl groups; the relative energy difference between cis-
exo-11 and the hypothetical cis-endo-11 was calculated as
-1
6.7 kcal mol .
Scheme 2
Reagents and Conditions: (a) LiAlH , Et O, reflux, 3 hours (78%);
4 2
(b) CbzCl, NaOH, dioxane/H O, room temperature, overnight; (c) chroma-
2
tography on Al O ; (d) H , 5% Pd/C, EtOH, room temperature, overnight
2
3
2
(cis-exo-15, 49%; trans-15, 8.9%); (+) NOE correlations observed from
NOESY spectra.
showed two signal peaks (δ 0.97 ppm and δ 1.04 ppm) for
the methyl hydrogens, and the methylene protons of the
CH -NH group are in this case nonequivalent. These
2
2
results indicate that the major isomer is in the symmetric
cis form, while the minor isomer is in the trans form.
Furthermore, a NOE correlation from the NOESY spec-
trum of the cis isomer was observed between the signals at
δ 2.52 ppm, corresponding to the CH -NH methylene
2
2
group, and at δ 1.03 ppm, corresponding to the methyl
groups; this result indicated the cis-exo configuration. In
the trans isomer, a NOE correlation was observed between
the signals (δ 2.50 ppm and δ 2.56 ppm) corresponding to
the CH -NH methylene group and the signal at δ 0.97
Reagents and Conditions: (a) NH (excess), 9 (3 eq.), MeOH in sealed
tube, 50°, overnight (40%).
3
Compound 11 was reduced to generate 15 using LiAlH
2
2
4
ppm, corresponding to the exo-methyl group.
without changing the ratio of the diastereoisomers. The
mixture of diastereoisomers was converted to benzyl car-
bamates, separated by chromatography on alumina, and
hydrogenated with 5% Pd-C to give each isomer of 15
(Scheme 3). The H NMR spectrum showed that the major
isomer had one signal peak (δ 1.03 ppm) for the methyl
The reaction of 16 [10] at 20° for 24 hours with ammo-
nia and 9 gave 6-cyano-1-azabicyclo[4.3.0]nonane (17)
[11] in 57% yield (Scheme 4); the reaction of 18 [10] gave
6-cyano-1-azabicyclo[4.4.0]decane (19) [11] in 21% yield.
In conclusion, we have developed a novel method for
preparing 1 by double cyclization of 4. The application of this
method to the preparation of 11 gave two diastereoisomers
1
hydrogens, and the protons of the CH -NH methylene
2
2
group are magnetically equivalent. The minor isomer

Jan-Feb 2003
Synthesis of 1-Azabicyclic Systems by Double Cyclization
179
Scheme 4
residue was dissolved in 1 N aqueous solution, and extracted with
CH Cl . The organic layers were combined, dried over Na SO ,
2
2
2
4
concentrated, and purified by chromatography on silica (n-
1
hexane/EtOAc) to give 7 (39 mg, 8.2%) as a colorless oil, H
NMR (CDCl ): δ 1.86-2.46 (m, 8H, H3, H4, H2’, H1’), 3.58-3.65
3
13
(m, 2H, H3’), 4.01 (t, J = 6.8 Hz, 2H, H5); C NMR (CDCl ): δ
3
24.78 and 27.88 (C4, C2’), 35.88 and 37.52 (C3, C1’), 44.22
(C3’), 68.83 (C5), 78.92 (C2), 120.46 (CN); IR (neat): 2963,
Reagents and Conditions: (a) NH (excess), 9 (3 eq.), MeOH, room
temperature, 24 hours (17, 57%; 19, 21%).
-1
3
2882 (C-H), 2232 (CN) cm ; HRMS (EI): calcd for C H ClNO
8
12
+ 35
(M , Cl) 173.0607, found 173.0596.
5-Cyano-4,6-dimethyl-1-azabicyclo[3.3.0]octane (11).
To a solution of 10 (1.0 g, 4.7 mmol) and 9 (1.2 g, 14 mmol) in
reflecting possible configurations of the methyl groups.
The observed ratio of the isomers as determined by NMR
measurements is consistent with the relative energies esti-
mated by ab initio MO calculations. Furthermore, this reac-
tion was applied to prepare six-five and six-six fused-ring
systems in the case of compounds 17 and 19. The conver-
sion of the nitrile group to various functional groups allows
the transformation of bicyclic amine moieties into various
biologically active substances. The introduction of a
cyanomethyl group [12], an ethoxycarbonylmethyl group
[12], and a nitromethyl group [1b] to this ring has been
reported by modifications of the presented method. Further
applications of this method are expected.
MeOH (1 mL), NH (1.8 g, 0.11 mol) was introduced at -50°. The
3
mixture was stirred in a sealed tube at 50-60° overnight. After
cooling, the resulting mixture was poured into Et O, and a
2
precipitate was filtered off. The filtrate was concentrated, and
purified by chromatography on alumina (n-hexane/EtOAc 50:1)
to give 11 (0.31 g, 40%, the ratio of the isomers was 79:21) as a
1
colorless oil, H NMR (CDCl ): major isomer δ 1.25 (d, J = 6.4
3
Hz, 6H, CH x2), 1.84-2.13 (m, 6H, H3, H4, H6, H7), 2.47-2.56
3
and 3.21-3.28 (m, 4H, H2, H8); minor isomer δ 1.14 (d, J = 7.3
Hz, 3H, CH ), 1.23 (d, J = 5.9 Hz, 3H, CH ), 1.46-1.60 and 1.88-
3
3
2.10 (m, 5H, H3, H7, one proton of H4 and H6), 2.41-2.69 (m,
3H, one proton of H4 and H6, two protons of H2 and H8), 3.04-
13
3.15 (m, 2H, two protons of H2 and H8); C NMR (CDCl ):
3
major isomer δ 15.89 (CH ), 36.53 (C3, C7), 43.50 (C4, C6),
3
54.53 (C2, C8), 77.79 (C5), 119.93 (CN); minor isomer δ 13.89,
EXPERIMENTAL
15.75, 32.36, 35.22, 37.62, 43.06, 53.83, 55.33, 74.23, 122.53; IR
-1
(neat): 2964, 2926 (C-H), 2219 (CN) cm ; HRMS (EI): calcd for
Infrared (IR) spectra were obtained on a JASCO FT/IR-8000
or a PERKIN ELMER FTIR 1600, and NMR spectra were
obtained using a JEOL JNM-GSX270 spectrometer (270 MHz
+
C H N (M ) 164.1313, found 164.1289.
10 16
2
5-Aminomethyl-4,6-dimethyl-1-azabicyclo[3.3.0]octane (15).
A solution of 11 (0.38 g, 2.3 mmol) in ether (3 mL) was added
1
13
for H and 68 MHz for C) or a JEOL JNM-ECP400 (400 MHz
1
13
for H and 100 MHz for C) using tetramethylsilane (TMS) as
an internal standard. The mass spectra were obtained on a JEOL
JMS-DX 300 spectrometer.
dropwise to a suspension of LiAlH (0.26 g, 6.8 mmol) in ether
4
(7 mL) under reflux. The mixture was refluxed for 3 hours,
quenched with water (0.26 mL), 15% NaOH (0.26 mL) and water
(0.79 mL). The white precipitate was filtered off, and the filtrate
was concentrated to give a mixture of two diastereoisomers of 15
(0.30 g, the ratio of the isomers was 77:23) as a colorless oil. To a
solution of 15 (0.30 g, 1.8 mmol) in dioxane (0.5 mL) and 5 N
NaOH (0.54 mL, 2.7 mmol), CbzCl (0.40 g, 2.3 mmol) was
added at 4°. The solution was stirred overnight at room tempera-
ture, and extracted with EtOAc. The organic layer was dried over
Na SO and concentrated. The resulting mixture was separated
into a major isomer (0.28 g) and a minor isomer (0.053 g) by
chromatography on alumina (n-hexane/EtOAc). Each solution of
the isomers in EtOH was stirred under H with 5% Pd-C (20
wt%) overnight at room temperature, and filtered. The filtrates
were concentrated to give cis-exo-15 (0.15 g, 49%) and trans-15
(0.027 g, 8.9%) as colorless oils, respectively. cis-exo-15: H
NMR (CDCl ): δ 1.03 (d, J = 7.0 Hz, 6H, CH x2), 1.73-2.03 (m,
6H, H3, H4, H6, H7), 2.52 (s, 2H, CH NH ), 2.49-2.55 and 3.14-
Computational Methods.
All of the ab initio MO calculations were carried out using the
Gaussian98 software package [13]. Geometries were fully opti-
mized at the MP2/6-31G* level.
5-Cyano-1-azabicyclo[3.3.0]octane (1).
To a solution of NH (27 g, 1.6 mol) in MeOH (150 g), 4 (30 g,
3
0.16 mol) and 9 (41 g, 0.49 mol) were added at 5°. The mixture
was stirred at 20° for 24 hours, and concentrated. The residue
was dissolved in 5 N NaOH aqueous solution, and extracted with
CH Cl . The organic layer was dried over Na SO , concentrated,
2
4
2
2
2
2
4
and distilled to give 1 (18 g, 81%) as a colorless oil, bp 91-94°
1
(4.4 mmHg) [Lit. [3a] 93-94° (5 mmHg)]; H NMR (CDCl ): δ
3
1
1.76-2.10 (m, 6H, H3, H7, two protons of H4 and H6), 2.27-2.38
(m, 2H, two protons of H4 and H6), 2.53-2.63 and 3.07-3.25 (m,
3
3
13
4H, H2, H8); C NMR (CDCl ): δ 26.40 (C3, C7), 38.45 (C4,
2
2
3
13
3.18 (m, 4H, H2, H8); C NMR (CDCl ): δ 14.40 (CH ), 37.51
C6), 55.33 (C2, C8), 67.09 (C5), 124.56 (CN); IR (neat): 2969,
3
3
-1
(C3, C7), 43.63 (CH NH ), 45.13 (C4, C6), 55.27 (C2, C8),
75.14 (C5); IR (neat): 3329 (N-H), 2953, 2876 (C-H) cm ;
2870 (C-H), 2232 (CN) cm ; HRMS (EI): calcd for C H N
2
2
8
12
2
-1
+
(M ) 136.1000, found 136.0982.
+
HRMS (EI): calcd for C H N (M-CH NH ) 138.1283, found
9
16
2
2
2-(3-Chloropropyl)tetrahydrofuran-2-carbonitrile (7).
1
138.1278. trans-15: H NMR (CDCl ): δ 0.97 (d, J = 7.0 Hz, 3H,
3
To a solution of NH (0.60 g, 35 mmol) in MeOH (5 mL), 4
exo-CH ), 1.04 (d, J = 7.0 Hz, 3H, endo-CH ), 1.46-1.96 (m, 4H,
3
3
3
(0.50 g, 2.7 mmol) and 8 (2.3 g, 27 mmol) were added at 5°. The
mixture was stirred at 20° for 24 hours, and concentrated. The
H3, H7), 1.80-1.96 (m, 1H, endo-CH), 2.14-2.24 (m, 1H, exo-
CH), 2.50 and 2.56 (d, J = 12.5 Hz, 2H, CH NH ), 2.37-2.43,
2
2

180
M. Oka, K. Baba, K. Nakamura, L. Dong, H. Hamajima, R. Unno and Y. Matsumoto
Vol. 40
13
Japan.
2.56-2.60, 2.75-2.82 and 3.11-3.15 (m, 4H, H2, H8); C NMR
[1a] S. Miyano, K. Sumoto, F. Satoh, K. Shima, M.
Hayashimatsu, M. Morita, K. Aisaka and T. Noguchi, J. Med. Chem.,
28, 714 (1985); [b] M. Oka, Y. Matsumoto, K. Hirooka and T.
Suzuki, Chem. Pharm. Bull., 48, 1121 (2000); [c] T. Suzuki, M. Oka,
K. Maeda, K. Furusawa, H. Uesaka and T. Kataoka, Chem. Pharm.
Bull., 47, 28 (1999).
[2] S. Miyano, O. Yamashita, K. Sumoto, K. Shima, M.
Hayashimatsu and F. Satoh, J. Heterocyclic Chem., 24, 47 (1987).
[3a] S. Miyano, T. Somehara, M. Nakao and K. Sumoto,
Synthesis, 701 (1978); [b] S. Miyano, S. Fujii, O. Yamashita, N.
Toraishi and K. Sumoto, J. Heterocyclic Chem., 19, 1465 (1982).
[4] Y. Arata, K. Tanaka, S. Yoshifuji and S. Kanatomo, Chem.
Pharm. Bull., 27, 981 (1979).
(CDCl ): δ 13.68 (s, 3H, exo-CH ), 14.05 (s, 3H, endo-CH ),
3
3
3
32.04 and 34.19 (C3, C7), 37.39 and 37.82 (C4, C6), 44.75
(CH NH ), 54.63 and 55.34 (C2, C8), 74.55 (C5); IR (neat):
2
2
-1
3364 (N-H), 2957, 2875 (C-H) cm ; HRMS (EI): calcd for
+
C H N (M-CH NH ) 138.1283, found 138.1294.
9
16
2
2
6-Cyano-1-azabicyclo[4.3.0]nonane (17).
By using a similar procedure as that described for 1, 17 was
prepared from 16 (0.50 g, 1.7 mmol) and isolated after chro-
matography on alumina (n-hexane/EtOAc) as a colorless oil
1
(0.15 g, 57%), H NMR (CDCl ): δ 1.38-1.90 and 2.34-2.53 (m,
3
10H, H3, H4, H5, H7, H8), 2.08-2.27 and 2.92-3.01 (m, 4H, H2,
13
H9); C NMR (CDCl ): δ 19.28 (C8), 21.55 (C4), 24.51 (C3),
3
[5] Preliminary report: M. Oka, Y. Matsumoto and R. Unno,
Heterocycles, 45, 1447 (1997).
[6] N. Zelinsky and G. Stadnikoff, Chem. Ber., 39, 1722 (1906).
[7] H. Hart and O. E. Curtis, Jr., J. Am. Chem. Soc., 78, 112
(1956).
34.07 and 36.78 (C5 and C7), 48.01 and 51.11 (C2 and C9),
-1
63.86 (C6), 118.71 (CN); IR (neat): 2938 (C-H), 2214 (CN) cm ;
+
HRMS (EI): calcd for C
150.1148.
H
N
(M ) 150.1157, found
10 16
2
[8] R. A. Jacobson, J. Am. Chem. Soc., 68, 2628 (1946).
[9] G. Böhrer and R. Knorr, Tetrahedron Lett., 25, 3675
(1984).
[10a] R. E. Ireland and D. Häbich, Chem. Ber., 114, 1418
(1981); [b] H. Stetter and H. Rauhut, Chem. Ber., 91, 2543 (1958).
[11] N. J. Leonard and A. S. Hay, J. Am. Chem. Soc., 78, 1984
(1956).
6-Cyano-1-azabicyclo[4.4.0]decane (19).
By using the same procedure as described for 17, 19 (34 mg,
21%) was prepared from 18 (300 mg, 1.0 mmol) as a colorless
1
oil, H NMR (CDCl ): δ 1.48-1.87 (m, 12H, H3, H4, H5, H7, H8,
3
13
H9), 2.33-2.40 and 2.65-2.69 (m, 4H, H2, H10); C NMR
(CDCl ): δ 21.42 (C4, C8), 25.01 (C3, C9), 36.89 (C5, C7),
3
[12] M. Oka, K. Baba, T. Suzuki and Y. Matsumoto,
Heterocycles, 45, 2317 (1997).
52.43 (C2, C10), 64.34 (C6), 118.04 (CN); IR (neat): 2939 (C-H),
-1
+
2215 (CN) cm ; HRMS (EI): calcd for C
H N (M )
10 16 2
[13] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, V. G. Zakrzewski, J. A. Montgomery,
R. E. Stratmann, Jr., J. C. Burant, S, Dapprich, J. M. Millam, A. D.
Daniels, K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi, V. Barone,
M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C. Adamo, S.
Clifford, J. Ochterski, G. A. Petersson, P. Y. Ayala, Q. Cui, K.
Morokuma, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B.
Foresman, J. Cioslowski, J. V. Ortiz, B. B. Stefanov, G. Liu, A.
Liashenko, P. Piskorz, I. Komaromi, R. Gomperts, R. L. Martin, D. J.
Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, C.
Gonzalez, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M.
W. Wong, J. L. Andres, C. Gonzalez, M. Head-Gordon, E. S.
Replogle and J. A. Pople, Gaussian 98, Revision A.9; Gaussian, Inc.,
Pittsburgh, PA, 1998.
164.1313, found 164.1312.
Acknowledgment.
The authors thank Professor Masayuki Shibuya (Tokushima
University) for his helpful suggestions.
REFERENCES AND NOTES
*
Author for correspondence. E-mail: m_oka@mb6.skk-
Present address: Graduate School of Information Science,
net.com
†
Nara Institute of Science and Technology, Ikoma-shi, Nara 630-0101,