3
-Halo-3-(halomethyl)azetidine-DBU Reactions
J . Org. Chem., Vol. 62, No. 13, 1997 4439
1H NMR (CDCl
) δ 1.19 (t, J ) 7.2 Hz, 3 H), 3.89 (s, 2 H),
reaction mixture then was poured into a mixture of ice (100
g) and 20% aqueous NaHSO (40 mL). The organic layer was
separated, and the aqueous layer was extracted with CH Cl
3
1
3
3
3.99-4.12 (m, 2 H), 4.35 (dd, J ) 10.1, 13.5 Hz, 4 H); C NMR
(CDCl ) δ 14.4 (q), 50.3 (t), 51.0 (s), 61.3 (t), 62.1 (t), 156.0 (s).
2
2
3
(
2 × 40 mL). The combined organic layers were washed
Anal. Calcd for C
32.90; H, 4.55.
7 2
H11BrClNO : C, 32.78; H, 4.32. Found: C,
sequentially with water (30 mL), NaHCO
3
(2 × 30 mL), water
(
(
30 mL), and brine (30 mL). The organic layer was dried
MgSO ) and filtered, and the filtrate was concentrated in
N-(Eth oxycar bon yl)-3-(br om om eth yl)azetidin -3-ol (9a).
A solution of 6 (700 mg, 5.0 mmol) and MCPBA (1.54 g, 9.0
4
vacuo. The residue was purified via column chromatography
on silica gel by eluting with 15% EtOAc-hexane. Pure 8 (250
mmol) in CH
temperature for 2 days. The resulting mixture was cooled to
-40 °C by application of an external dry ice-CH CN cold bath,
and dry HBr (g) was bubbled through the cold reaction mixture
for 10 min. The external cold bath was replaced by an external
ice-water bath, and the reaction mixture was allowed to warm
gradually to 0 °C during 1 h. Dichloromethane (100 mL) was
added to the reaction mixture, and the resulting solution was
2 2
Cl (70 mL) under argon was stirred at ambient
mg, 80%) was thereby obtained as a colorless oil: IR (film)
3
2
7
951 (s), 1712 (s), 773 cm-1 (s); H NMR (CDCl
1
3
) δ 1.22 (t, J )
.2 Hz, 3H), 3.84 (s, 2 H), 4.10 (q, J ) 7.1 Hz, 2 H), 4.32-4.49
1
3
(m, 4 H); C NMR (CDCl
3
) δ 14.6 (q), 39.3 (t), 50.7 (s), 61.5
(
t), 63.2 (t), 156.1 (s); mass spectrum (70 eV) m/ z (relative
intensity) 302 (1.6), 222 (35.4), 220 (36.7), 150 (35.9), 148 (36.9),
1
3
21 (16.1), 119 (17.6), 97 (26.3), 82 (27.5), 69 (100.0), 56 (20.7),
9 (73.0). Anal. Calcd for C NO : C, 27.93; H, 3.68.
washed successively with 10% aqueous NaHCO
and brine (30 mL). The organic layer was dried (MgSO
3
(2 × 20 mL)
7
H
11Br
2
2
4
) and
Found: C, 28.12; H, 3.51.
filtered, and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography on silica gel
by eluting with 40% EtOAc-hexane. Pure 9a (650 mg, 55%)
was thereby obtained as a colorless oil: IR (film) 3385 (br, s),
DBU-P r om oted Deh yd r oh a logen a tion of 8. A mixture
of 8 (200 mg, 0.67 mmol) and DBU (202 mg, 1.33 mmol) was
heated at 90 °C for 30 min. The reaction mixture was allowed
to cool gradually to ambient temperature. Diethyl ether (100
mL) was added, and the resulting mixture was washed
sequentially with water (2 × 30 mL) and brine (20 mL). The
-
1
1
2970 (s), 1700 (vs), 855 cm (s); H NMR (CDCl
3
) δ 1.18 (t, J
) 7.2 Hz, 3 H), 3.62 (s, 2 H), 3.91 (s, 4 H), 4.02-4.15 (m, 3 H);
1
3
C NMR (CDCl ) δ 14.6 (q), 40.2 (t), 60.2 (t), 61.4 (t), 69.3 (s),
3
organic organic layer was dried (MgSO
4
) and filtered, and the
156.8 (s). Anal. Calcd for C
Found: C, 35.53; H, 5.11.
7 12 3
H O BrN: C, 35.31; H, 5.08.
filtrate was concentrated in vacuo. The residue was purified
via column chromatography on silica gel by eluting with 20%
N-(Eth oxycar bon yl)-3-(ch lor om eth yl)azetidin -3-ol (12).
Meth od A. A solution of 6 (600 mg, 4.26 mmol) and MCPBA
Et O-pentane. Pure 4a (110 mg, 75%) was thereby obtained
2
1 13
as a viscous, colorless oil. The IR, H NMR, and C NMR
spectra of the material thereby obtained are identical in all
respects with that of 4a which had been prepared previously
(1.30 g, 6.24 mmol) in CH
at ambient temperature for 2 days. The resulting mixture was
cooled to -40 °C via application of an external dry ice-CH
2 2
Cl (70 mL) under argon was stirred
3
-
via Wittig reaction of 5 with Ph
3
PdCHBr (vide supra).
CN cold bath, and dry HCl(g) was bubbled through the cold
reaction mixture for 10-15 min. The external cold bath was
replaced by an external ice-water bath, and the reaction
mixture was allowed to warm gradually to 0 °C during 1 h.
Dichloromethane (100 mL) was added to the reaction mixture,
and the resulting solution was washed successively with 10%
Rea ction of N-(Eth oxyca r bon yl)-3-m eth ylen ea zetid in e
w ith N-Br om osu ccin im id e in Aqu eou s DMSO. A solution
of 6 (700 mg, 5.0 mmol) in DMSO (60 mL) under argon was
cooled to 0 °C via application of an external ice-water bath.
To this cooled solution under argon were added sequentially
with stirring water (180 mg, 10 mmol) and N-bromosuccin-
imide (NBS, 1.78 g, 10 mmol). After the addition of reagents
had been completed, the external cold bath was removed, and
the reaction mixture was allowed to warm gradually to
ambient temperature during 2 h and then stirred at that
temperature for an additional 1 h. A solution of EtOAc (100
aqueous NaHCO
layer was dried (MgSO
3
(2 × 20 mL) and brine (30 mL). The organic
4
) and filtered, and the filtrate was
concentrated in vacuo. The residue was purified by column
chromatography on silica gel by eluting with 40% EtOAc-
hexane. Pure 12 (467 mg, 57%) was thereby obtained as a
colorless oil: IR (film) 3387 (br, s), 2975 (s), 1700 (vs), 1445
-
1
1
mL) in Et
the resulting mixture was washed sequentially with water (30
mL) and brine (30 mL). The organic layer was dried (MgSO
2
O (150 mL) was added to the reaction mixture, and
(s), 775 cm (m); H NMR (CDCl
3.69 (s, 2 H), 3.83-4.12 (m, 6 H), 4.48 (br s, 1 H); C NMR
(CDCl ) δ 14.4 (q), 50.0 (t), 59.7 (t), 61.4 (t), 69.6 (s), 156.9 (s).
3
) δ 1.18 (t, J ) 7.2 Hz, 3 H),
13
4
)
3
and filtered, and the filtrate was concentrated in vacuo. The
residue was purified via column chromatography on silica gel
by eluting with 40% EtOAc-hexane. An inseparable mixture
of 9a and 9b (900 mg, 76%, ratio 9a :9b ) 50:50, as determined
Anal. Calcd for C
43.18; H, 6.22.
7 12 3
H O ClN: C, 43.42; H, 6.25. Found: C,
Meth od B. A solution of 6 (550 mg, 3.9 mmol) and MCPBA
(1.20 g, 5.7 mmol) in CH Cl (70 mL) under argon was stirred
2
2
1
by careful integration of the H NMR spectrum of the product
at ambient temperature for 2 days. Dichloromethane (100 mL)
was added to the reaction mixture, and the resulting solution
mixture) was thereby obtained as a colorless oil: IR (neat) 3390
-
1
1
(
br, s), 2966 (s), 1700 (vs), 904 (m), 769 cm (m); H NMR
was washed successively with 10% aqueous NaHCO
mL), water (20 mL), and brine (30 mL). The organic layer
was dried (MgSO ) and filtered, and the filtrate was concen-
3
(2 × 20
(
3
CDCl
3
) δ 1.14-1.26 (m, 6 H), 3.62 (s, 2 H), 3.83 (s, 2 H), 3.88-
.93 (m, 5 H), 3.98-4.12 (m, 4 H), 4.21-4.42 (m, 5 H); 13C NMR
4
(CDCl
3
) δ 14.4 (q), 14.5 (q), 39.9 (t), 54.0 (s), 60.2 (2 C, t), 61.4
trated in vacuo to a total volume of 40 mL. The concentrated
solution was cooled to 0 °C by application of an external ice-
(
2 C, t), 61.5 (2 C, t), 67.9 (t), 69.3 (s), 156.6 (s), 156.9 (s). Anal.
12BrNO : C, 35.31; H, 5.08. Found: C, 35.12;
Calcd for C
7
H
3
water bath. To this cooled solution was added dropwise with
8
H, 5.27. This mixture of 9a and 9b was used as obtained in
the next synthetic step without further purification or char-
acterization (vide infra).
N-(E t h oxyca r b on yl)-3-b r om o-3-(ch lor om et h yl)a zet i-
d in e (10). To a 1:1 mixture of 9a and 9b (900 mg, 3.8 mmol)
in DMF (20 mL) under argon was added pyridine (0.4 mL, 5
stirring a solution of freshly prepared Ph
mmol) in CH Cl
3
PCl
2
(1.3 g, 4.0
2
2
(30 mL). The external ice-water bath was
removed, and the reaction mixture was allowed to warm
gradually to ambient temperature during 2 h. The reaction
mixture then was concentrated in vacuo, and the residue was
purified by column chromatography on silica gel by eluting
with 40% EtOAc-hexane. Pure 12 (330 mg, 44%) was thereby
mmol). To the resulting solution under argon was added with
8
1
13
stirring a solution of freshly prepared Ph
3
PCl
2
(1.33 g, 4.0
obtained as a colorless oil. The IR, H NMR, and C NMR
spectra of the material thereby obtained were essentially
identical to the corresponding spectra obtained for authentic
12 that had been prepared previously via method A, above.
DBU-P r om oted Deh yd r oh a logen a tion of 10. A mixture
of 10 (100 mg, 0.39 mmol) and DBU (120 mg, 0.78 mmol) was
heated at 90 °C for 30 min. The reaction mixture was allowed
to cool gradually to ambient temperature. Diethyl ether (100
mL) was added, and the resulting mixture was washed
sequentially with water (2 × 30 mL) and brine (20 mL). The
mmol) in DMF (10 mL), and the resulting mixture was stirred
at 60 °C for 2 h. The reaction mixture was allowed to cool to
ambient temperature, and Et O (100 mL) was added. The
2
resulting ethereal solution was washed sequentially with
water (30 mL) and brine (2 × 30 mL). The organic layer was
4
dried (MgSO ) and filtered, and the filtrate was concentrated
in vacuo. The residue was purified via column chromatogra-
phy on silica gel by eluting with 20% EtOAc-hexane. Pure
1
0 (390 mg, 80%) was thereby obtained as a colorless oil: IR
-
1
(neat) 2988 (vs), 1715 (vs), 1445 (vs), 781 (vs), 714 cm (s);
4
organic organic layer was dried (MgSO ) and filtered, and the