Reformatsky reaction of methyl 1-bromocyclobutane- and 1- bromocycloheptanecarboxylates with Schiff bases

Article abstract of DOI:10.1134/S1070428007110085

Reformatsky reagents derived from methyl 1-bromocyclobutane- and 1-bromocycloheptanecarboxylates reacted with Schiff bases to give 2,3-diaryl-2-azaspiro[3.3]heptane-1-ones and 2,3-diaryl-2-azaspiro-[3.6]decan-1- ones, respectively.

Full text of DOI:10.1134/S1070428007110085

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 11, pp. 1632–1634. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © V.V. Shchepin, V.S. Melekhin, N.F. Kirillov, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 11,
pp. 1637–1639.
Reformatsky Reaction of Methyl 1-Bromocyclobutane-
and 1-Bromocycloheptanecarboxylates with Schiff Bases
V. V. Shchepin†, V. S. Melekhin, and N. F. Kirillov
Perm State University, ul. Bukireva 15, Perm, 614990 Russia
Received September 10, 2006
Abstract—Reformatsky reagents derived from methyl 1-bromocyclobutane- and 1-bromocycloheptanecarbox-
ylates reacted with Schiff bases to give 2,3-diaryl-2-azaspiro[3.3]heptane-1-ones and 2,3-diaryl-2-azaspiro-
[3.6]decan-1-ones, respectively.
DOI: 10.1134/S1070428007110085
Compounds possessing a β-lactam fragment were
shown to exhibit versatile biological activity [1]. We
previously reported on reactions of methyl 1-bromo-
cyclopentane- and 1-bromocyclohexanecarboxylates
with zinc and Schiff bases, which led to the formation
of spiro-β-lactams having tetra- and pentamethylene
substituents [2]. The goal of the present work was to
synthesize analogous spiro-β-lactams with tri- and
hexamethylene fragments.
1-[(4-bromophenyl)(phenylamino)methyl]cyclobutane-
carboxylate (Va) as a result of hydrolysis of inter-
mediate product IIIa.
Likewise, reactions of Schiff bases IIa–IId with
organozinc derivative VI prepared from methyl
1-bromocycloheptanecarboxylate gave the correspond-
ing spiro-fused β-lactams, 2,3-diaryl-2-azaspiro[3.6]-
decan-1-ones VIIIa–VIIId through intermediates
VIIa–VIId (Scheme 2) Schiff base IIe failed to react
with compound VI and was recovered from the reac-
tion mixture.
Reformatsky reagent I prepared from methyl
1-bromocyclobutanecarboxylate added at the C=N
bond of Schiff bases IIa–IIe in toluene–ethyl acetate–
HMPA (10:5:1, by volume) to give intermediates
IIIa–IIIe which underwent spontaneous cyclization to
2,3-diaryl-2-azaspiro[3.3]heptan-1-ones IVa–IVe
(Scheme 1). In the reaction of organozinc compound
I with Schiff base IIa we also isolated methyl
The structure of compounds IVa–IVe, Va, and
VIIIa–VIIId was proved by the data of elemental
1
analysis and H NMR and IR spectroscopy. Com-
pounds IVa–IVe and VIIIa–VIIId characteristically
showed in the IR spectra an absorption band in the
region 1725–1745 cm–1 due to stretching vibrations of
Scheme 1.
Ar
Ar'
Ar
Br
ZnBr
N
Zn
ArCH=NAr' (IIa–IIe)
ZnBr
Ar'
N
–MeOZnBr
COOMe
COOMe
COOMe
O
I
IIIa–IIIe
IVa–IVe
Ar
NHAr'
H+/H2O
IIIa
–Zn(OH)Br
COOMe
Va
Ar = 4-BrC6H4, Ar′ = Ph (a), 4-BrC6H4 (b), 4-MeOC6H4 (c); Ar = 4-ClC6H4, Ar′ = 4-MeOC6H4 (d);
Ar = 4-MeOC6H4, Ar′ = 4-MeOC6H4 (e).
†
Deceased.
1632

REFORMATSKY REACTION OF METHYL 1-BROMOCYCLOBUTANE-...
1633
Scheme 2.
Ar
Ar'
Br
ZnBr
N
Zn
ArCH=NAr' (IIa–IId)
ZnBr
COOMe
COOMe
COOMe
VI
VIIa–VIId
Ar
Ar'
N
–MeOZnBr
O
VIIIa–VIIId
Ar = 4-BrC6H4, Ar′ = Ph (a), 4-BrC6H4 (b), 4-MeOC6H4 (c); Ar = 4-ClC6H4, Ar′ = 4-MeOC6H4 (d).
the lactam carbonyl group, while the spectrum of Va
7.00 d, 7.02 d, 7.24 d, and 7.42 d (2H each, 4-BrC6H4,
J = 8.3 Hz). Found, %: C 51.23; H 3.71; Br 38.08;
N 3.22. C18H15Br2NO. Calculated, %: C 51.34; H 3.59;
Br 37.95; N 3.33.
contained an ester carbonyl band at 1715 cm–1. The
1
CHAr signal appeared in the H NMR spectra at
δ 4.52–4.72 ppm.
3-(4-Bromophenyl)-2-(4-methoxyphenyl)-2-aza-
spiro[3.3]heptan-1-one (IVc). Yield 1.19 g (32%),
mp 125–126°C. IR spectrum: ν 1740 cm–1 (C=O).
1H NMR spectrum, δ, ppm: 1.40–2.70 m (6H, CH2),
3.68 s (3H, MeO), 4.68 s (1H, CHN), 6.68 d and
7.04 d (2H each, 4-MeOC6H4, J = 8.7 Hz), 7.10 d and
7.41 d (2H each, 4-BrC6H4, J = 8.3 Hz). Found, %:
C 61.23; H 4.75; Br 21.67; N 3.83. C19H18BrNO2. Cal-
culated, %: C 61.30; H 4.87; Br 21.46; N 3.76.
EXPERIMENTAL
The IR spectra were obtained on a Specord 75IR
spectrophotometer from samples dispersed in mineral
oil. The 1H NMR spectra were recorded from solutions
in CDCl3 on a Tesla BS-576A instrument (100 MHz);
the chemical shifts were measured relative to hexa-
methyldisiloxane as internal reference.
2,3-Diaryl-2-azaspiro[3.3]heptan-1-ones IVa–IVe
(general procedure). A mixture of 2 g of activated zinc
powder, 15 mmol of methyl 1-bromocyclobutane-
carboxylate, 10 mmol of Schiff base IIa–IIe, 10 ml of
anhydrous toluene, 5 ml of anhydrous ethyl acetate,
and 1 ml of HMPA was heated for 2 h under stirring.
The mixture was cooled, treated with 5% acetic acid,
and extracted with ethyl acetate. The extracts were
dried over anhydrous sodium sulfate, the solvent was
distilled off, and the residue was recrystallized from
methanol–ethyl acetate (10:1).
3-(4-Chlorophenyl)-2-(4-methoxyphenyl)-2-aza-
spiro[3.3]heptan-1-one (IVd). Yield 1.48 g (45%),
mp 113–114°C. IR spectrum: ν 1745 cm–1 (C=O).
1H NMR spectrum, δ, ppm: 1.41–2.71 m (6H, CH2),
3.68 s (3H, MeO), 4.70 s (1H, CHN), 6.68 d and
7.04 d (2H each, 4-MeOC6H4, J = 8.5 Hz), 7.13 d and
7.27 d (2H each, 4-ClC6H4, J = 8.3 Hz). Found, %:
C 69.82; H 5.55; Cl 11.01; N 4.38. C19H18ClNO2. Cal-
culated, %: C 69.62; H 5.53; Cl 10.82; N 4.27.
2,3-Bis(4-methoxyphenyl)-2-azaspiro[3.3]hep-
tan-1-one (IVe). Yield 1.10 g (34%), mp 153–154°C.
3-(4-Bromophenyl)-2-phenyl-2-azaspiro[3.3]hep-
1
IR spectrum: ν 1730 cm–1 (C=O). H NMR spectrum,
tan-1-one (IVa). Yield 0.89 g (26%), mp 134–135°C.
1
IR spectrum: ν 1735 cm–1 (C=O). H NMR spectrum,
δ, ppm: 1.45–2.63 m (6H, CH2); 3.67 s (3H, MeO);
3.74 s (3H, MeO); 4.67 s (1H, CHN); 6.66 d, 6.79 d,
7.04 d, and 7.13 d (2H each, 4-MeOC6H4, J = 8.3 Hz).
Found, %: C 74.43; H 6.71; N 4.22. C20H21NO3. Cal-
culated, %: C 74.28; H 6.55; N 4.33.
δ, ppm: 1.40–2.70 m (6H, CH2), 4.72 s (1H, CHN),
7.02 d and 7.42 d (2H each, 4-BrC6H4, J = 8.3 Hz),
7.12 s (5H, Ph). Found, %: C 63.29; H 4.78; Br 23.58;
N 4.22. C18H16BrNO. Calculated, %: C 63.17; H 4.71;
Br 23.35; N 4.09.
Methyl 1-[(4-bromophenyl)(phenylamino)meth-
yl]cyclobutanecarboxylate (Va) was isolated in the
reaction of organozinc compound I with Schiff base
IIa. Yield 0.86 g (23%), mp 152–153°C. IR spectrum:
ν 1715 cm–1 (C=O). 1H NMR spectrum, δ, ppm: 1.02–
2,3-Bis(4-bromophenyl)-2-azaspiro[3.3]heptan-
1-one (IVb). Yield 1.73 g (41%), mp 140–141°C. IR
1
spectrum: ν 1740 cm–1 (C=O). H NMR spectrum, δ,
ppm: 1.40–2.70 m (6H, CH2); 4.69 s (1H, CHN);
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 11 2007

SHCHEPIN et al.
1634
2.68 m (6H, CH2); 3.58 s (1H, OMe); 4.52 s (1H,
CHN); 4.70 br.s (1H, NH); 6.39 d, 6.51 t, and 6.99 t
(5H, Ph, J = 8 Hz); 7.07 d and 7.31 d (2H each,
4-BrC6H4, J = 8.3 Hz). Found, %: C 60.80; H 5.48;
Br 21.47; N 3.52. C19H20BrNO2. Calculated, %:
C 60.97; H 5.39; Br 21.35; N 3.74.
3-(4-Bromophenyl)-2-(4-methoxyphenyl)-2-aza-
spiro[3.6]decan-1-one (VIIIc). Yield 2.32 g (56%),
mp 105–106°C. IR spectrum: ν 1735 cm–1 (C=O).
1H NMR spectrum, δ, ppm: 1.03–2.37 m (12H, CH2),
3.68 s (3H, MeO), 4.67 s (1H, CHN), 6.69 d and
7.00 d (2H each, 4-MeOC6H4, J = 8.8 Hz), 7.10 d and
7.38 d (2H each, 4-BrC6H4, J = 8.3 Hz). Found, %:
C 63.52; H 5.75; Br 19.50; N 3.53. C22H24BrNO2. Cal-
culated, %: C 63.77; H 5.84; Br 19.28; N 3.38.
2,3-Diaryl-2-azaspiro[3.6]decan-1-ones VIIIa–
VIIId were synthesized as described above for com-
pounds IVa–IVe from methyl 1-bromocycloheptane-
carboxylate.
3-(4-Chlorophenyl)-2-(4-methoxyphenyl)-2-aza-
spiro[3.6]decan-1-one (VIIId). Yield 1.89 g (51%),
mp 114–115°C. IR spectrum: ν 1725 cm–1 (C=O).
1H NMR spectrum, δ, ppm: 1.03–2.30 m (12H, CH2);
3.69 s (3H, MeO); 4.69 s (1H, CHN); 6.69 d (J =
8.7 Hz) and 6.92–7.32 m (8H, 4-MeOC6H4, 4-ClC6H4).
Found, %: C 71.42; H 6.72; Cl 9.50; N 3.97.
C22H24ClNO2. Calculated, %: C 71.44; H 6.54;
Cl 9.58; N 3.79.
3-(4-Bromophenyl)-2-phenyl-2-azaspiro[3.6]-
decan-1-one (VIIIa). Yield 1.27 g (33%), mp 137–
1
138°C. IR spectrum: ν 1740 cm–1 (C=O). H NMR
spectrum, δ, ppm: 0.94–2.35 m (12H, CH2), 4.70 s
(1H, CHN), 7.02 d and 7.39 d (2H each, 4-BrC6H4, J =
8.3 Hz), 7.17 s (5H, Ph). Found, %: C 65.82; H 5.71;
Br 20.98; N 3.32. C21H22BrNO. Calculated, %: C 65.63;
H 5.77; Br 20.79; N 3.64.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
nos. 04-03-96036, 04-03-97505).
2,3-Bis(4-bromophenyl)-2-azaspiro[3.6]decan-1-
one (VIIIb). Yield 1.49 g (32%), mp 110–111°C. IR
1
spectrum: ν 1740 cm–1 (C=O). H NMR spectrum, δ,
ppm: 1.03–2.37 m (12H, CH2); 4.67 s (1H, CHN);
6.99 d, 7.03 d, 7.26 d, and 7.45 d (2H each, 4-BrC6H4,
J = 8.3 Hz). Found, %: C 54.28; H 4.74; Br 34.27;
N 3.20. C21H21Br2NO. Calculated, %: C 54.45; H 4.57;
Br 34.50; N 3.02.
REFERENCES
1. Romanova, N.N., Khim.-Farm. Zh., 1990, vol. 24, p. 19.
2. Kirillov, N.F. and Shchepin, V.V., Russ. J. Gen. Chem.,
2005, vol. 75, p. 590.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 11 2007