Nucleophilic Opening of the Aziridine Ring in 1-Alkyl-1-azoniatricyclo[2.2. 1.02,6]heptanes

Article abstract of DOI:10.1023/A:1025554100991

Opening of the aziridine ring in 3-bromo-1-alkyl-1-azoniatricyclo[2.2.1. 0^2,6]heptane bromides by the action of various nucleophiles leads to formation of the corresponding 6-substituted 2-alkyl-2-azabicyclo-[2.2.1] heptanes.

Full text of DOI:10.1023/A:1025554100991

Russian Journal of Organic Chemistry, Vol. 39, No. 3, 2003, pp. 415 421. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 3, 2003,
pp. 443 448.
Original Russian Text Copyright
2003 by Bulanov, Sosonyuk, Zyk, Zefirov.
Dedicated to Full Member of the Russian Academy of Sciences
I.P. Beletskaya on Her Jubilee
Nucleophilic Opening of the Aziridine Ring
in 1-Alkyl-1-azoniatricyclo[2.2.1.02,6]heptanes
M. N. Bulanov, S. E. Sosonyuk, N. V. Zyk, and N. S. Zefirov
Faculty of Chemistry, Moscow State University, Vorob’evy gory, Moscow, 119992 Russia
e-mail: ses@org.chem.msu.su
Received July 10, 2002
Abstract Opening of the aziridine ring in 3-bromo-1-alkyl-1-azoniatricyclo[2.2.1.02,6]heptane bromides by
the action of various nucleophiles leads to formation of the corresponding 6-substituted 2-alkyl-2-azabicyclo-
[2.2.1]heptanes.
Compounds of the azabicyclo[2.2.1]heptane series
exhibit biological activity [1, 2]. For example, the
azabicyclic fragment is present in a number of natural
moleculs, such as alkaloids anatoxin and epibatidine
and drug cocaine. It should also be noted that 2-aza-
bicyclo[2.2.1]heptane is a heterocyclic analog of
norbornane which is a classical subject of studies in
the field of physical organic chemistry. We previously
described properties of polyhalogenides derived from
2-alkyl-2-azabicyclo[2.2.1]hept-5-enes [3]. We found
that the aziridine ring in these salts is readily opened
by the action of various nucleophiles, affording the
corresponding substituted 2-azabicyclo[2.2.1]heptanes.
In the present work we performed the above trans-
formations with a wide series of nucleophiles, thus
advancing a new approach to functionalization of
2-alkyl-2-azabicyclo[2.2.1]hept-5-enes. The bromina-
tion of some 2-alkyl-2-azabicyclo[2.2.1]hept-2-enes
Ia Ic was reported in [3] (Scheme 1).
Scheme 1.
The resulting tribromides IIa IIc reacted with
an equimolar amount of initial azabicycloheptene
Scheme 3.
R = Me (a), Et (b), PhCH2 (c).
Scheme 2.
Nu = MeO (a c), EtO (d), AcO (e, f), SCH (g i),
PhCH2S (j), N3 (k, l), CH(COMe)2 (m); R = Me (a, d, e,
g, j, k, m), Et (b, f, h, l), PhCH2 (c, i).
Alk = Me, Et; R = Me (d), Et (e), PhCH2 (f).
1070-4280/03/3903-0415$25.00 2003 MAIK Nauka/Interperiodica

416
BULANOV et al.
Table 1. Reaction of compounds IId IIf with various
nucleophiles
bromides gives various substituted 2-alkyl-2-azabi-
cyclo[2.2.1]heptanes. The reaction involves formation
of a new C O, C S, C N, or C C bond.
Product (yield, %)
Nucleophile
Scheme 4.
R = Me
R = Et
R = PhCH2
MeONa
IIIa (30)
IVa (57)
IIId (34)
IIIe (54)
IVe (63)
IVg (49)
IVj (55)
IVk (52)
IVm (71)
IIIb (54)
IIIc (61)
EtONa
AcONa
IVf (82)
IVh (34)
IVl (52)
KSCN
PhCH2SNa
NaN3
IVi (96)
NaCH(COMe)2
Ia Ic in various solvents to give unstable mono-
bromides IId IIf (Scheme 2). The present com-
munication reports on the reactions of compounds
IId IIf (which were obtained by one-pot procedure)
with various nucleophiles. We have found that nucleo-
phile attacks the aziridinium ring at the C6 atom.
Cleavage of the C6 N bond results in formation of
exo-6-substituted 2-alkyl-syn-7-bromo-2-azabicyclo-
[2.2.1]heptanes IIIa IIIm (Scheme 3).
Z = MeO (a, n), AcO (e, o).
EXPERIMENTAL
The H and 13C NMR spectra (400 and 100 MHz,
1
respectively) were recorded on a Varian VXR-400
spectrometer at 28 C using TMS as internal reference.
The proton signals were assigned on the basis of
1H {1H} double-resonance experiments and published
data [5]. In some cases, APT pulse sequence (which
allows edition of spectra) was applied to assign 13C
The following compounds were used as nucleo-
philes: sodium methoxide, sodium ethoxide, and
sodium acetate (C O bond formation); potassium
thiocyanate and sodium phenylmethanethiolate (C S
bond formation); sodium azide (C N bond forma-
tion); and sodium acetylacetonate (C C bond forma-
tion). The syn,exo-orientation of substituents in the
products was assigned on the basis of our previous
data for compound IIIa [3]. Irradiation at a frequency
corresponding to resonance of the 7-H proton revealed
W-coupling with 6-H and endo-5-H (J = 1.3 Hz).
1
signals. The H NMR spectral parameters of com-
pounds III and IV are given in Table 2, and Table 3
contains the yields, melting points, IR spectra, and
analytical data of hydrochlorides IV.
Sodium phenylmethanethiolate. Metallic sodium,
0.69 g (30 mmol), was cut into small pieces and was
added to a solution of 3.72 g (30 mmol) of phenyl-
methanethiolate in 50 ml of dry diethyl ether. The
mixture was stirred until the metal dissolved com-
pletely, and the product was filtered off. Yield 4.2 g
(96%), mp 180 182 C.
Sodium acetylacetonate. Metallic sodium, 1.38 g
(60 mmol), was dissolved in 50 ml of ethanol, and
6.00 g (60 mmol) of acetylacetone was added drop-
wise with stirring. The mixture was cooled, and the
precipitate was filtered off. Yield 6.30 g (86%),
mp 234 236 C (217 219 C [6]).
Tributylstannane was prepared by the procedure
reported in [7]. The other reagents used were com-
mercial products.
1
Taking into account that the H NMR spectra of the
other compounds contain analogous set of signals
(except to those corresponding to the substituents),
they were assigned the same structure as IIIa.
Compounds IIIa IIIm were converted (without
isolation from the reaction mixture) into hydro-
chlorides IVa IVm. In some cases, the corresponding
free bases (compounds IIIa IIIe) were isolated. The
yields of the products are given in Table 1.
Using compounds IIIa and IIIe as examples, we
have shown that the bromine atom in position 7 of
the azanorbornane skeleton can be reduced with tri-
butylstannane (Scheme 4; cf. [4]).
syn-7-Bromo-exo-6-methoxy-2-methyl-2-azabi-
cyclo[2.2.1]heptane (IIIa). A solution of 1.75 g
(16 mmol) of compound Ia in 15 ml of methanol
was added under stirring and cooling with ice to
Thus nucleophilic opening of the aziridine ring in
1-alkyl-3-bromo-1-azoniatricyclo[2.2.1.02,6]heptane
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 3 2003

NUCLEOPHILIC OPENING OF THE AZIRIDINE RING
417
Table 2. 1H NMR spectra (chemical shifts , ppm, and coupling constants J, Hz) of compounds III IIIe, IIIn, IIIo,
and IV IVma
Comp.
no.
1-H,
br.s
3-H
4-H
5-H
6-H
7-H
Other protons
IIIa
IIIb
IIIc
IIId
3.15
2.48 m (3H)
2.03 d.q
(1H, exo-5-H,
2J = 13.0,
Jexo-5, 4 = 3.7,
Jexo-5, 6 = 3.7,
Jexo-5, exo-3 = 3.7),
1.88 d.d.d
3.62 d.d.d (1H, 4.06 t (1H,
3.31 s (3H, MeO),
J6, endo-5 = 7.5, J7, endo-5 = 1.3, 2.40 s (3H, MeN)
J6, exo-5 = 3.7, J7, 6 = 1.3)
J6, 7 = 1.3)
(1H, endo-5-H,
2J = 13.0,
Jendo-5, 6 = 7.5,
Jendo-5, 7 = 1.3)
3.29 2.56 d.d.d
2.48 m
2.05 d.d.t
3.62 d.d.d (1H, 4.03 t (1H,
J6, endo-5 = 7.5, J7, endo-5 = 1.3, 2.50 d.q and
J6, exo-5 = 3.8, J7, 6 = 1.3)
3.32 s (3H, MeO),
(1H, exo-3-H, (1H)
(1H, exo-5-H,
2J = 9.0,
2J = 13.0,
2.63 d.q [1H each,
Jexo-3, 4 = 3.8,
Jexo-5, 4
=
3.8, J6, 7 = 1.3)
2J = 11.9,
Jexo-3, exo-5
=
Jexo-5, 6 = 3.8,
Jexo-5, exo-3 = 2.7),
1.90 d.d.d
J(CH2, Me) = 7.2],
1.03 t [3H,
MeCH2N,
2.7), 2.41 d
(1H, endo-
3-H, J = 9.0)
2
(1H, endo-5-H,
J(Me, CH2) = 7.2]
2J = 13.0,
Jendo-5, 6 = 7.5,
Jendo-5, 7 = 1.3)
3.27 2.56 d.d.d
(1H, exo-3-H, J4, exo-3
2J = 9.1,
3.7,
Jexo-3, 4 = 3.7, J4, exo-5
2.50 t (1H, 2.06 d.d.t
3.71 d.d.d (1H, 4.09 t (1H,
J6, endo-5 = 7.6, J7, endo-5 = 1.4, 3.75 d and 3.68 d
J6, exo-5 = 3.7, J7, 6 = 1.4)
3.26 s (3H, MeO),
=
(1H, exo-5-H,
2J = 13.0,
(1H each, CH2N,
=
Jexo-5, 4
Jexo-5, 6
Jexo-5, exo-3 = 2.8),
1.93 d.d.d
=
=
3.7, J6, 7 = 1.4)
3.7,
2J = 13.4),
Jexo-3, exo-5
2.8),
=
3.7)
7.19 7.33 m
(5H, Harom)
2.43 d (1H,
endo-3-H,
2J = 9.1)
(1H, endo-5-H,
2J = 13.0,
Jendo-5, 6 = 7.6,
Jendo-5, 7 = 1.4)
3.13
2.47 m (3H)
2.03 d.q
3.71 d.d.d (1H, 4.05 m (1H)
J6, endo-5 = 7.6,
J6, exo-5 = 3.8,
3.47 d.q and
(1H, exo-5-H,
3.49 d.q [1H each,
2J = 13.0,
CH2O, J = 12.9,
2
Jexo-5, 4 = 3.8,
Jexo-5, 6 = 3.8,
Jexo-5, exo-3 = 3.8),
1.87 d.d.d
J6, 7 = 1.3)
J(CH2, Me) = 7.0],
1.18 t
[3H, MeCH2O,
J(Me, CH2) = 7.0],
2.39 s (3H, MeN)
(1H, endo-5-H,
2J = 13.0,
Jendo-5, 6 = 7.6,
Jendo-5, 7 = 1.0)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 3 2003

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BULANOV et al.
Table 2. (Contd.)
Comp.
no.
1-H,
br.s
3-H
4-H
5-H
6-H
7-H
Other protons
IIIe
3.23 2.66 d.t (1H, 2.51 t (1H, 2.14 d.d.t
4.85 d.d (1H, 4.10 br.s (1H) 2.03 s (3H,
exo-3-H,
J4, exo-3
3.2,
=
(1H, exo-5-H,
J6, endo-5 = 7.9,
J6, exo-5 = 3.8)
MeCO),
2.42 s (3H, MeN)
2J =9.0,
2J = 13.3,
Jexo-3, 4 = 3.2, J4, exo-5
=
Jexo-5, 6 = 3.8,
Jexo-5, 4 = 3.2,
Jexo-5, exo-3 = 3.2),
2.04 d.d
Jexo-3, exo-5
=
3.2)
3.2),
2.40 d (1H,
endo-3-H,
(1H, endo-5-H,
2J = 9.0)
2J = 13.3,
Jendo-5, 6 = 7.9)
IIIn
3.06 2.40 d.t (1H, 2.34 t (1H, 1.34 m (1H,
3.52 d.d.d (1H, 1.43 d.d
3.27 s (3H, MeO),
exo-3-H,
J4, exo-3
2.9,
=
exo-5-H,
J6, endo-5 = 6.9, (1H, syn-7-H, 2.36 s (3H, MeN)
2J = 8.9,
2J = 13.0),
J6, exo-5 = 2.3, 2J = 10.1,
Jexo-3, 4 = 2.9, J4, exo-5
=
1.65 d.d.d
J6, anti-7 = 1.3) Jsyn-7, endo-3 =
Jexo-3, exo-5
2.9),
=
2.9)
(1H, endo-5-H,
1.0), 1.49 d.d.d
(1H, anti-7-H,
2J = 10.1,
2J = 13.0,
2.32 d.d (1H,
endo-3-H,
Jendo-5, 6 = 6.9,
Jendo-5, anti-7 = 2.4)
Janti-7, endo-5
=
2J = 8.9,
2.4,
Jendo-3, syn-7
=
Janti-7, 6 = 1.3)
1.0)
IIIo
3.10 2.62 d.t (1H, 2.37 m
1.45 d.d.d.d
4.88 d.d.d (1H, 1.47 d.d
1.99 s (3H,
exo-3-H,
(1H)
(1H, exo-5-H,
J6, endo-5 = 7.3, (1H, syn-7-H, MeCO),
2J = 8.9,
Jexo-3, 4 = 3.0,
2J = 3.5,
J6, exo-5 = 2.5, 2J = 10.1,
J6, anti-7 = 1.3) Jsyn-7, endo-3
1.1),
2.39 s (3H, MeN)
Jexo-5, 4 = 4.5,
Jexo-5, exo-3 = 3.0,
Jexo-5, 6 = 2.5),
1.83 d.d.d
=
Jexo-3, exo-5
3.0),
=
1.58 d.d.d
2.20 d.d (1H,
endo-3-H,
(1H, anti-7-H,
(1H, endo-5-H,
2J = 10.1,
2J = 8.9,
2J = 13.5,
Janti-7, endo-5 =
Jendo-3, syn-7
1.1)
=
Jendo-5, 6 = 7.3,
Jendo-5, anti-7 = 2.5)
2.5,
Janti-7, 6 = 1.3)
IVf
4.10 3.74 m (1H, 2.82 m
2.51 d.q
5.17 d.d (1H, 4.78 br.s (1H) 2.10 s (3H,
exo-3-H),
(1H)
(1H, exo-5-H,
J6, endo-5 = 7.5,
J6, exo-5 = 3.7)
MeCO), 3.18 m
2.99 d (1H,
endo-3-H,
2J = 10.6)
2J = 13.7,
and 3.31 m (1H
each, CH2N),
1.54 t [3H,
MeCH2N,
J(Me, CH2) = 7.3],
5.76 br.s (1H, NH)
Jexo-5, 6 = 3.7,
Jexo-5, 4 = 3.7,
Jexo-5, exo-3 = 3.7),
2.32 d.d
(1H, endo-5-H,
2J = 13.7,
Jendo-5, 6 = 7.5)
IVg
4.27 3.41 d (1H, 2.99 m
2.50 d.d.t
4.41 d.d (1H, Overlapped by 2.93 s (3H, MeN)
J6, endo-5 = 8.3, the H2O signal
J6, exo-5 = 4.5)
exo-3-H,
(1H)
(1H, exo-5-H,
2J = 11.7),
3.24 d (1H,
endo-3-H,
2J = 14.0,
Jexo-5, 6 = 4.5,
Jexo-5, 4 = 3.8,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 3 2003

NUCLEOPHILIC OPENING OF THE AZIRIDINE RING
419
Table 2. (Contd.)
Comp.
no.
1-H,
br.s
3-H
4-H
5-H
6-H
7-H
Other protons
IVg
IVh
2J = 11.7)
Jexo-5, exo-3 = 3.8),
2.40 d.d
(1H, endo-5-H,
2J = 14.0,
Jendo-5, 6 = 8.3)
4.28 3.24 m (2H) 2.91 m
(1H)
2.43 br.d
4.36 m (1H)
4.50 br.s (1H) 3.12 d.q and
(1H, exo-5-H,
2J = 14.1),
2.32 d.d
3.27 d.q [1H each,
CH2N, 2J = 12.8,
J(CH2, Me) = 7.3],
1.17 t
[3H, MeCH2N,
J(Me, CH2) = 7.3]
(1H, endo-5-H,
2J = 14.1,
Jendo-5, 6 = 8.3)
IVi
IVj
4.39 3.09 m (2H) 2.90 m
(1H)
2.38 m
(1H, exo-5-H),
2.23 br.d
5.05 m (1H)
5.35 br.s (1H) 4.35 d and 4.56 d
(1H each, CH2N,
2J = 12.8),
(1H, endo-5-H,
7.28 7.93 m
(5H, Harom),
8.54 br.s (1H, NH)
2J = 13.0)
3.85 3.60 m (1H, 2.91 m
2.36 m
(1H, exo-5-H),
2.24 d.d
4.04 d.d.d (1H, 4.20 m (1H)
J6, endo-5 = 9.1,
J6, exo-5 = 6.5,
3.84 d and 3.91 d
(1H each, PhCH2S,
2J = 13.3),
2.64 s (3H, MeN),
4.65 br.s (1H, NH),
7.22 7.58 m
exo-3-H),
(1H)
2.83 br.d (1H,
endo-3-H,
(1H, endo-5-H,
J6, 7 = 1.3)
2J = 9.5)
2J = 13.5,
Jendo-5, 6 = 9.1)
(5H, Harom
)
IVk
4.09 3.41 d
2.92 m
2.20 m (2H)
4.20 m (1H)
4.56 br.s (1H) 2.90 s (3H, MeN)
(1H, exo-3-H, (1H)
2J = 9.2),
3.19 d (1H,
endo-3-H,
2J = 9.2)
IVl
4.20 3.35 m (2H) 2.96 m
(1H)
2.26 m (2H)
2.00 m (2H)
4.28 m (1H)
2.70 m (1H)
4.51 br.s (1H) 3.22 m and 3.35 m
(1H each, CH2N),
1.27 t
[3H, MeCH2N,
J(Me, CH2) = 7.1]
IVm
3.61 3.74 m (1H, 2.73 m
4.73 br.s (1H) 4.61 d
[1H, CH (CO)2,
exo-3-H),
(1H)
3.13 m (1H,
endo-3-H)
J
= 11.6],
, 6
2.31 s and 2.33 s
(3H each, MeCO),
2.91 s (3H, MeN)
a
1
The H NMR spectra of compounds IIIa IIIe, IIIn, IIIo, IVf, IVj, and IVm were recorded in chloroform-d, of IVg, IVh, IVk,
and IVl, in D2O, and of IVi, in DMSO-d6.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 3 2003

420
BULANOV et al.
Table 3. Yields, melting points, elemental analyses, and IR spectra of substituted 2-azabicyclo[2.2.1]heptane hydro-
chlorides IVa IVo
1
Found, %
H
Calculated, %
IR spectrum,a , cm
Comp. Yield,
mp,
C
Formula
no.
%
C
N
C
H
N
C O
NH+
IVa
IVb
IVc
IVd
IVe
IVf
IVg
IVh
IVi
IVj
IVk
IVl
IVm
IVn
IVo
57
227b 37.38 5.96
198b 39.67 6.23
200b 50.76 5.68
174b 39.64 6.32
5.30 C8H14NOBr HCl
5.06 C9H16NOBr HCl
4.04 C14H18NOBr HCl
5.27 C9H16NOBr HCl
4.76 C9H14NO2Br HCl
4.38 C10H16NO2Br HCl 40.20 6.03
9.62 C8H11N2SBr HCl
9.01 C9H13N2SBr HCl
37.45 5.89
39.93 6.28
50.55 5.76
39.95 6.33
37.99 5.31
5.46
5.18
4.21
5.18
4.92
4.69
63
82
49
34
86
55
52
52
71
228c
37.69 5.27
1755
1755
2435
2450
2490
2490
2480
134b 40.33 6.09
222c
170c
157c
171c
216c
200c
178c
33.86 4.17
35.98 4.19
47.14 4.64
48.25 5.57
31.45 4.66 20.69 C7H11N4Br HCl
34.23 5.12 19.48 C8H13N4Br HCl
33.88 4.27
36.32 4.74
9.88 2140 (SCN)
9.41 2170 (SCN)
7.79 2120 (SCN)
7.63 C14H15N2SBr HCl 46.75 4.48
3.82 C14H18NSBr HCl 48.22 5.49
d
4.02
31.42 4.52 20.94
34.12 5.01 19.90
4.31
68.05 10.71
63.88 8.93
2130 (N3)e
2125 (N3)e
1710
43.85 5.59
3.93 C12H18NO2Br HCl 44.40 5.90
9.69 C8H15NO HCl
7.98 C9H15NO2 HCl
2530
178b 66.51 10.12
195b 62.78 8.07
9.92
8.28
1755
2440
a
b
c
In mineral oil.
From CHCl3 Et2O.
From 95% ethanol.
d
13C NMR spectrum (CDCl3), C, ppm: 139.1, 129.6, 129.0, 127.4 (Carom); 72.6 (C7), 58.3 (PhCH2S), 45.2 (C6), 43.0 (MeN), 42.8
(C1), 42.7 (C3), 40.3 (C4), 34.9 (C5).
In ethanol.
e
a suspension of 6.85 g (16 mmol) of tribromide IIa in
15 ml of methanol, and the mixture was stirred until
it became colorless. A solution of sodium methoxide
prepared by dissolution of 0.75 g (32 mmol) of
metallic sodium in 20 ml of methanol was added
dropwise on cooling with ice. The resulting solution
was heated for 30 min under reflux, the solvent was
removed under reduced pressure, the residue was
extracted with ether, the extract was filtered and
evaporated, and the residue was distilled under
reduced pressure. Yield 2.10 g (30%), bp 135 C
(35 mm), n1D6 1.5181. 13C NMR spectrum (CDCl3),
(5 mmol) of tribromide IIc, 0.87 g (5 mmol) of amine
Ic, and 0.23 g (10 mmol) of sodium. Yield 1.80 g
(61%), bp 215 C (1 mm), mp 62 64 C.
syn-7-Bromo-exo-6-ethoxy-2-methyl-2-azabi-
cyclo[2.2.1]heptane (IIId) was obtained from 2.15 g
(5 mmol) of tribromide IIa, 0.55 g (5 mmol) of amine
Ia, and 0.23 g (10 mmol) of sodium, using ethanol
as solvent. Yield 0.80 g (34%), bp 73 C (1 mm),
n1D6 1.5141. 13C NMR spectrum, (CDCl3), , ppm:
81.2 (C7), 67.1 (CH2O), 64.3 (C5), 57.8 (C3), 48.6
(C6), 43.6 (C1), 42.5 (MeN), 35.9 (C4), 15.4
(MeCH2O).
C, ppm: 81.3 (C7), 66.8 (MeO), 57.4 (C5), 56.9 (C3),
48.0 (C6), 43.4 (C1), 42.1 (MeN), 35.5 (C4).
exo-6-Acetoxy-syn-7-bromo-2-methyl-2-azabi-
cyclo[2.2.1]heptane (IIIe). A solution of 1.09 g
(10 mmol) of amine Ia in 10 ml of acetonitrile was
added dropwise with stirring and cooling with ice to
a solution of 4.29 g (10 mmol) of tribromide IIa in
20 ml of acetonitrile. The mixture was stirred until it
became colorless, 1.64 g (20 mmol) of anhydrous
sodium acetate was added, and the mixture was heated
for 2 h under reflux with stirring. The precipitate
was filtered off, and the filtrate was evaporated under
reduced pressure. The residue was extracted with
Compounds IIIb IIId were synthesized following
a similar procedure.
syn-7-Bromo-2-ethyl-exo-6-methoxy-2-azabi-
cyclo[2.2.1]heptane (IIIb) was obtained from 2.22 g
(5 mmol) of tribromide IIb, 0.62 g (5 mmol) of amine
Ib, and 0.23 g (10 mmol) of sodium. Yield 1.27 g
(54%), bp 57 C (1 mm), n1D9 1.5084.
2-Benzyl-syn-7-bromo-exo-6-methoxy-2-azabi-
cyclo[2.2.1]heptane (IIIc) was obtained from 2.47 g
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NUCLEOPHILIC OPENING OF THE AZIRIDINE RING
421
ether, and the extract was filtered and evaporated.
obtained from 2.15 g (5 mmol) of tribromide IIa,
0.55 g (5 mmol) of amine Ia, and 1.46 g (10 mmol)
of sodium phenylmethanethiolate.
exo-6-Azido-syn-7-bromo-2-methyl-2-azabicyclo-
[2.2.1]heptane hydrochloride (IVk) was obtained
from 2.15 g (5 mmol) of tribromide IIa, 0.55 g
(5 mmol) of amine Ia, and 0.65 g (10 mmol) of
sodium azide.
Yield 2.70 g (54%), bp 110 C (1 mm), n2D4 1.5083.
Hydrochloride IVe was obtained by adding a satu-
rated solution of hydrogen chloride in ether to the
ether extract of IIIe (see above). The precipitate was
filtered off. Hydrochlorides IVa IVd, IVn, and
IVo were obtained in a similar way from solutions of
IIIa IIId, IIIn, and IIIo in ether.
exo-6-Methoxy-2-methyl-2-azabicyclo[2.2.1]-
heptane (IIIn). A solution of 1.30 g (5.9 mmol) of
compound IIIa in 20 ml of benzene was heated to
the boiling point, and a solution of 1.89 g (6.5 mmol)
of tributylstannane and 0.10 g (0.6 mmol) of azobis-
(isobutyronitrile) in 10 ml of benzene was added
dropwise with stirring. The mixture was heated for 2 h
under reflux and evaporated under reduced pressure.
The residue was purified by distillation. Yield 0.68 g
(82%), bp 160 C, n2D0 1.4682. 13C NMR spectrum
(CDCl3), C, ppm: 81.3 (C6), 64.8 (MeO), 60.5 (C3),
56.4 (C1), 42.5 (C4), 37.6 (C7), 36.9 (MeN), 31.5 (C5).
exo-6-Acetoxy-2-methyl-2-azabicyclo[2.2.1]-
heptane (IIIo) was synthesized as described above for
amine IIIn from 2.70 g (10.9 mmol) of compound
IIIe, 3.48 g (12.0 mmol) of Bu3SnH, and 0.18 g
(1.1 mmol) of azobis(isobutyronitrile). Yield 1.41 g
(77%), bp 100 C (15 mm), n2D1 1.4688.
exo-6-Azido-syn-7-bromo-2-ethyl-2-azabicyclo-
[2.2.1]heptane hydrochloride (IVl) was obtained
from 0.89 g (2 mmol) of tribromide IIb, 0.25 g
(2 mmol) of amine Ib, and 0.26 g (4 mmol) of
sodium azide.
syn-7-Bromo-exo-6-(diacetylmethyl)-2-methyl-2-
azabicyclo[2.2.1]heptane hydrochloride (IVm) was
obtained from 2.15 g (5 mmol) of tribromide IIa,
0.55 g (5 mmol) of amine Ia, and 1.22 g (10 mmol)
of sodium acetylacetonate.
This study was financially supported by the Rus-
sian Foundation for Basic Research (project no. 99-
03-33093).
REFERENCES
1. Spande, T.F., Garraffo, H.M., Edwards, M.W.,
Yeh, H.J.C., Pannell, L., and Daly, J.W., J. Am.
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[2.2.1]heptane hydrochloride (IVf) was synthesized
without isolation of amine IIIf, from 0.44 g (1 mmol)
of tribromide IIb, 0.12 g (1 mmol) of amine Ib, and
0.16 g (2 mmol) of sodium acetate. A saturated solu-
tion of HCl added to the ether extract obtained as
described above for compound IIIe.
Hydrochlorides IVg IVm were synthesized in
a similar way. Their yields, melting points, elemental
analyses, and IR spectral data are given in Table 3.
syn-7-Bromo-2-methyl-exo-6-thiocyanato-2-aza-
bicyclo[2.2.1]heptane hydrochloride (IVg) was ob-
tained from 0.43 g (1 mmol) of tribromide IIa, 0.11 g
(1 mmol) of amine Ia, and 0.19 g (2 mmol) of potas-
sium thiocyanate.
syn-7-Bromo-2-ethyl-exo-6-thiocyanato-2-azabi-
cyclo[2.2.1]heptane hydrochloride (IVh) was ob-
tained from 0.44 g (1 mmol) of tribromide IIb, 0.12 g
(1 mmol) of amine Ib, and 0.19 g (2 mmol) of potas-
sium thiocyanate.
2-Benzyl-syn-7-bromo-exo-6-thiocyanato-2-aza-
bicyclo[2.2.1]heptane hydrochloride (IVi) was ob-
tained from 0.50 g (1 mmol) of tribromide IIc, 0.19 g
(1 mmol) of amine Ic, and 0.19 g (2 mmol) of potas-
sium thiocyanate.
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exo-6-Benzylthio-syn-7-bromo-2-methyl-2-aza-
bicyclo[2.2.1]heptane hydrochloride (IVj) was
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