Bromination of tert-butyl esters of 7α-chloro and 7-alkylidenedeacetoxycephalosporanic acid sulfones

Article abstract of DOI:10.1007/s10593-005-0199-z

The action of N-bromosuccinimide on tert-butyl esters of 7α-chloro- and 7-alkylidenedeacetoxycephalosporanic acid sulfones upon irradiation with visible light leads to the formation of a mixture of the product of allylic bromination of the 3-methyl group,

Full text of DOI:10.1007/s10593-005-0199-z

Chemistry of Heterocyclic Compounds, Vol. 41, No. 5, 2005
BROMINATION OF tert-BUTYL ESTERS
OF 7α-CHLORO AND 7-ALKYLIDENEDEACETOXY-
CEPHALOSPORANIC ACID SULFONES
M. Vorona, G. Veinberg, I. Turovskis, and E. Lukevics
The
action
of
N-bromosuccinimide
on
tert-butyl
esters
of
7α-chloro-
and
7-alkylidenedeacetoxycephalosporanic acid sulfones upon irradiation with visible light leads to the
formation of a mixture of the product of allylic bromination of the 3-methyl group, namely,
3-bromomethyldeacetoxycephalosporanate, and the product of replacement of a proton at C(2) in the
latter, namely, 2-bromo-3-bromomethyldeacetoxycephalosporanate. Small amounts of E-isomers were
also obtained in the case of the Z-isomer of the 7-(4-nitrobenzylidene) derivative. In the case of the
7α-chloro derivative only substitution of one or two protons at C(2) occurs during bromination without
irradiation, the same as the isomerization of the double bond in the cepheme system.
Keywords: N-bromosuccinimide, tert-butyl esters of substituted deacetoxycephalosporanic acid
sulfones, allylic bromination.
The allylic bromination of deacetoxycephalosporin is an efficient method for the structural modification
of its 3-methyl group in the synthesis of antibiotic analogs with improved antibacterial properties and obtaining
precursors of compounds with antibacterial and anticancer activity released by enzymatic hydrolysis of the β-
lactam ring [1-3]. Recent research has concerned the inhibitory properties of some cephalosporin sulfone esters
synthesized by analogous modification of the methyl group relative to serine proteases [4-6].
The allylic bromination of the tert-butyl ester of 7α-chlorodeacetoxycephalosporanic acid sulfone (1) by
N-bromosuccinimide (NBS) was carried out in CCl4 at reflux in the presence of azodiisobutyronitrile (AIBN)
over 5 h [4].
In the present work, the reaction of 1 with NBS was carried out using external irradiation of the flask
containing the reagent mixture in benzene at reflux using a 250-500-W incandescent lamp or by irradiation of a
solution of the reagents in methylene chloride at room temperature using an immersed 12-W halogen lamp.
In both cases, thin-layer chromatographic analysis of the reaction solution showed the starting ester 1,
which disappeared in 20-20 min, as well as the desired product 2 and an unstable, less polar product, which
disappeared after adding triphenylphosphine. The previously described formation of the trimethylsilyl ester of
the sulfoxide of 3-methyl-7α-phenylacetamidocephalosporanic acid and its 2-bromo-3-bromomethyl derivative
by allylic bromination and the debromination of the latter derivative at C(2) [7] suggest that the unstable product
is the 2-bromo-3-bromomethylcephalosporanate ester 3 (see Scheme 1).
_______
* Dedicated to Academician N. K. Kochetkov on the occasion of this ninetieth birthday.
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia; e-mail: vorona@osi.lv. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 767-774, May, 2005. Original article submitted
February 15, 2003, submitted after revision March 10, 2004.
662
0009-3122/05/4105-0662©2005 Springer Science+Business Media, Inc.

The reaction of ester 1 with NBS in benzene at room temperature without irradiation or catalyst is
complete after 2 h. The replacement of benzene by dichloromethane reduces the reaction rate. The reaction is
complete in only a few minutes when lutidine is added. The reaction yields products of the bromination of the
cephalosporin system at C(2) 4-6, which are converted to starting compound 1 upon the addition of PPh3. The
separation of the reaction mixture by column chromatography using 1:2 ethyl acetate–hexane as the eluent gave
two fractions. The less polar fraction with Rf 0.71 contained a 3:7 mixture of esters 4 and 5 as indicated by
1H NMR spectroscopy and HPLC, while the more polar fraction with Rf 0.66 was a 4:6 mixture of esters 5 and 6.
HPLC analysis indicated that use of Br2 instead of NBS leads to the formation of a 3:7 mixture of 4 and 5, which
could not be resolved.
1H NMR spectral analysis of the fractions with Rf 0.71 and 0.66 showed that products 4-6 differ only in
the substitution of the protons at C(2) and position of the double bond in the cepheme system. Comparison of the
signals of the methine protons with the literature values for analogous signals of structurally similar
cephalosporin analogs and the ratio of the integral intensities and percentage composition of the products in each
fraction permitted identification of isomeric monobromides 4 and 6 and dibromide 5.
Allylic bromination of the Z-isomers of alkylidenecephalosporanate sulfones 7a and 7b gave the desired
Z-isomers of 3-bromomethylcephalosporanates 8a and 8b as well as the Z-isomers of dibromides 9a and 9b,
which are readily converted to Z-monobromides 8a and 8b upon treatment with triphenylphosphine (Scheme 2).
Dibromides Z-9a and Z-9b, in contrast to their 7α-chloro analogs 3, proved stable, which permitted their
isolation and characterization.
In the case of Z-7b with a 7-Z-4-nitrobenzylidene side chain, we isolated the Z-isomers of monobromide
8b and dibromide 9b as well as small amounts of E-isomers of 8b and 9b, which is in accord with the ability of
the starting ester Z-7b to convert to a 43:57 mixture of the Z- and E-isomers upon brief irradiation with a
halogen lamp.
The reaction of ester Z-7a with NBS without irradiation proceeded through an ionic mechanism to give
2-bromocephalosporanate Z-10, which converts to starting ester Z-7a upon debromination using
triphenylphosphine.
Scheme 1
PPh3, H2O
–Ph3P=O, HBr
Cl
SO2
SO2
SO2
Cl
O
Cl
Br
NBS, hν
+
N
PhH / CH2Cl2
N
N
Me
O
CH2Br
CH2Br
O
COOBu-t
COOBu-t
COOBu-t
2
3
1
SO2
SO2
SO2
Cl
Cl
Cl
Br
Br
Br
NBS
+
+
PhH
PPh3, H2O
Br
N
N
O
N
Me
Me
Me
O
O
–Ph3P=O, HBr
H
COOBu-t
COOBu-t
COOBu-t
6
5
4
Br2
+
4
5
PhH
663

Scheme 2
PPh3, H2O
–Ph3P=O, HBr
R
O
R
R
O
SO2
SO2
SO2
Br
H
H
H
NBS, hν
+
PhH/CH2Cl2
N
N
N
Me
CH2Br
CH2Br
O
COOBu-
t
COOBu-
COOBu-
t
t
Z-8a
Z-9a
Z-7a
R
SO2
NBS
Br
H
N
Me
O
COOBu-
t
Z-10
PPh3, H2O
–Ph3P=O, HBr
R
R
O
R
SO2
SO2
SO2
Br
H
H
H
+
NBS, hν
+
PhH/CH2Cl2
N
N
N
Me
CH2Br
O
CH2Br
O
COOBu-
COOBu-
t
t
COOBu-
t
Z-8b
Z-9b
Z-7b
H
O
H
SO2
SO2
Br
R
R
+
+
N
N
CH2Br
CH2Br
O
COOBu-
t
COOBu-
t
E-9b
E-8b
a R = COOBu-t, b R = 4-O2NC6H4
EXPERIMENTAL
1
The H NMR spectra were taken on a Bruker WH-90/DS spectrometer for CDCl3 solutions at 90 MHz
using TMS as the internal standard. The elemental analysis was carried out on a Carlo Erba 1108 analyzer. The
reaction course was monitored by thin-layer chromatography on Merck Keiselgel plates with UV detection. The
HPLC data were obtained on a Dupont Model 8800 chromatograph equipped with a UV detector (λ = 254 nm)
and 4.6×250-mm column packed with Ultrasphere Si using 1:3 ethyl acetate–hexane as the eluent. The flow rate
was 0.8 1.5 ml/min. Preparative column chromatography was carried out on Merck Kieselgel silica gel (0.063-
0.230 mm). Acros and Aldrich reagents were used. The bromination was carried out in absolute benzene
subjected to prior treatment with concentrated sulfuric acid or methylene chloride.
664

Ester 1 was prepared according to Alpegiani et al. [4].
Z-Isomers of tert-Butyl Ester of 7-Alkylidenecephalosporanic Acid Sulfones (Z-7a and Z-7b) were
prepared according to our previous procedure [10]. An alkylidenetriphenylphosphorane was added to a solution
of 5 mmoles tert-butyl ester of 7-oxodeacetoxycephalosporanic acid (11) [9] in 20 ml dichloromethane and the
mixture was stirred at room temperature for 40 min. The solvent was then evaporated at reduced pressure and the
residue was purified on a chromatographic column using 1:1 ethyl acetate–hexane as the eluent. The resultant
mixture of isomeric tert-butyl esters of 7-alkylidenedeacetoxycephalosporanates was oxidized with
3-chloroperbenzoic acid (12 mmol) in dichloromethane (20 ml) over 2 h at room temperature. The reaction
mixture was washed with 5% aqueous sodium carbonate and, then, water. The organic phase was dried over
anhydrous Na2SO4. The solvent was evaporated off at reduced pressure. Column chromatography using 1:1 ethyl
acetate–hexane as the eluent gave ester Z-7.
Z-Isomer of tert-Butyl Ester of 7-(tert-Butoxycarbonylmethylene)diacetoxycephalosporanic Acid
Sulfone (Z-7a) was obtained from tert-butoxycarbonylmethylenetriphenylphosphorane in 28% yield (relative to
1
starting ester 11), Rf 0.43 (1:1 ethyl acetate–hexane); mp 65-67°C (ethyl acetate). H NMR spectrum, δ, ppm,
(J, Hz): 1.53 (18H, s, 2C4H9); 2.15 (3H, s, CH3); 3.64 (2H, AB system, J = 18.0, SCH2); 5.51 (1H, br. s, 6-H);
6.51 (1H, d, J = 1.0, –CH=). Found, %: C 54.42; H 6.49; N 3.63. C18H25NO7S. Calculated, %: C 54.12; H 6.31;
N 3.51.
Z-Isomer of tert-Butyl Ester of 7-(4-Nitrobenzylidene)deacetoxycephalosporanic Acid Sulfone
(Z-7b) was obtained from (4-nitrobenzylidene)triphenylphosphorane in 21% yield (relative to ester 11), Rf 0.34
1
(1:1 ethyl acetate–hexane); mp 115-116°C (ethyl acetate). Content of ester Z-7b 97% (HPLC data). H NMR
spectrum, δ, ppm, (J, Hz): 1.55 (9H, s, C4H9); 2.08 (3H, s, CH3); 3.71, 4.06 (2H, AB system, J = 18.0, SCH2);
5.57 (1H, br. s, 6-H); 7.42 (1H, br. s, –CH=); 7.93 and 8.28 (2H, d, J = 8.0, C6H4).
Allylic Bromination of tert-Butyl Esters of 7α-Chloro- (1) and Z-7-Alkylidene-
deacetoxycephalosporanic Acid Sulfones (7a, 7b) (General Procedure). A. A mixture of ester 1, Z-7a or Z-7b
(1.0 mmol), and NBS (1.1 mmol) in benzene (50 ml) heated at reflux was irradiated with a 100-W incandescent
lamp for 30 min until completion of the reaction as indicated by thin-layer chromatography. The solvent was
then evaporated. Product 2 was isolated from the residue by column chromatography with 1:2 ethyl acetate–
hexane as the eluent (in the case of starting ester 1). Products Z-8a and Z-9a were obtained from starting ester Z-
7a. Products Z-8b, Z-9b, E-8b, and E-9b were obtained from starting ester Z-7b [7].
B. A mixture of ester 1 (1 mmol) and NBS (1.1 mmol) in absolute methylene chloride (50 ml) was
irradiated with a 12-W halogen lamp immersed directly in the solvent at room temperature until completion of
the reaction as indicated by thin-layer chromatography (~30 min). The reaction mixture was then worked up and
the products were isolated as in procedure A.
tert-Butyl Ester of 3-Bromomethyl-7α-chlorodeacetoxycephalosporanic Acid Sulfone (2) was
obtained in 40% yield according to procedure A and 53% yield according to procedure B; mp 139-141°C (ethyl
acetate). 1H NMR spectrum, δ, ppm, (J, Hz): 1.58 (9H, s, C4H9); 3.82 and 4.22 (2H, AB system, J = 18.0, SCH2);
4.17 and 4.51 (2H, AB system, J = 10.0, CH2Br); 4.82 (1H, br. s, H-6); 5.24 (1H, br. s, H-7). Found, %: C 35.57;
H 3.75; N 3.29. C12H15BrClNO5S. Calculated, %: C 35.97; H 3.77; N 3.50.
tert-Butyl Ester of Z-3-Bromomethyl-7-(tert-butoxycarbonylmethylene)deacetoxycephalosporanic
Acid Sulfone (Z-8a) was obtained in 67% yield according to procedure A and 71% yield according to procedure
1
B, Rf 0.37 (1:3 ethyl acetate–hexane); mp 146-147°C (ethyl acetate). H NMR spectrum, δ, ppm, (J, Hz): 1.55
(18H, s, 2C4H9); 3.77 and 4.20 (2H, AB system, J = 18.0, SCH2); 4.24, 4.58 (2H, AB system, J = 10.0, CH2Br);
5.69 (1H, d, J = 1.0, H-6); 6.57 (1H, d, J = 1.0, –CH=). Found, %: C 45.29; H 5.11; N 3.05. C18H24BrNO7S.
Calculated, %: C 45.20; H 5.06; N 2.93.
tert-Butyl Ester of Z-3-Bromomethyl-7-(4-nitrobenzylidene)deacetoxycephalosporanic Acid
Sulfone (Z-8b) was obtained from ester Z-7b in 43% yield according to procedure A and 56% yield according to
1
procedure B, Rf 0.17 (1:2 ethyl acetate–hexane); mp 139-141°C. H NMR spectrum, δ, ppm, (J, Hz): 1.57
665

(9H, s, C4H9); 3.86, 4.31 (2H, AB system, J = 18.0, SCH2); 4.20, 4.57 (2H, AB system, J = 10.0, CH2Br); 5.66
(1H, br. s, H-6); 7.49 (1H, br. s, –CH=); 7.84, 8.29 (2H, d, and 2H, d, J = 9.0, C6H4). Found, %: C 45.94; H 4.15;
N 5.49. C19H19BrN2O7S. Calculated, %: C 45.70; H 3.84; N 5.61.
tert-Butyl Ester of
E-3-Bromomethyl-7-(4-nitrobenzylidene)deacetoxycephalosporanic Acid
Sulfone (E-8b) was obtained in 6% yield according to procedure A, Rf 0.17 (1:2 ethyl acetate–hexane);
1
mp 105-107°C (ethyl acetate). H NMR spectrum, δ, ppm, (J, Hz): 1.64 (9H, s, C4H9); 3.82, 4.28 (2H, AB
system, J = 17.0, SCH2); 4.20, 4.57 (2H, AB system, J = 10.0, CH2Br); 5.31 (1H, br. s, H-6); 7.00 (1H, br. s,
–CH=); 8.13, 8.33 (2H, d, and 2H, d, J = 10.0, C6H4). Found, %: C 45.98; H 4.10; N 5.33. C19H19BrN2O7S.
Calculated, %: C 45.70; H 3.84; N 5.61.
tert-Butyl
Ester
of
Z-2-Bromo-3-bromomethyl-7-tert-butoxycarbonylmethylenedeacetoxy-
cephalosporanic Acid Sulfone (Z-9a) was obtained in 6% yield according to procedure A, Rf 0.17 (1:3 ethyl
acetate–hexane); mp 124-126°C (ethyl acetate). 1H NMR spectrum, δ, ppm, (J, Hz): 1.55 (18H, s, 2C4H9); 4.11,
4.57 (2H, AB system, J = 10.0, CH2Br); 4.95 (1H, s, 2-H); 6.22 (1H, d, J = 1.0, H-6); 6.64 (1H, d, J = 1.0,
–CH=). Found, %: C 39.12; H 4.30; N 2.61%. C18H23Br2NO7S. Calculated, %: C 38.80; H 4.16; N 2.51.
tert-Butyl Ester of Z-2-Bromo-3-bromomethyl-7-(4-nitrobenzylidene)deacetoxycephalosporanic
Acid Sulfone (Z-9b) was obtained in 1.5% yield according to procedure A, Rf 0.54 (1:2 ethyl acetate–hexane);
1
mp 82-85°C (ethyl acetate). The content of ester Z-9b was >93% (HPLC data). H NMR spectrum, δ, ppm,
(J, Hz): 1.62 (9H, s, C4H9); 4.15, 4.58 (2H, AB system, J = 10.0, CH2Br); 5.62 (1H, s, 2-H); 6.26 (1H, d, J = 1.0,
6-H); 7.58 (1H, br. s, –CH=); 7.86, 8.33 (2H, d, and 2H, d, J = 9.0, C6H4).
tert-Butyl Ester of E-2-Bromo-3-bromomethyl-7-(4-nitrobenzylidene)deacetoxycephalosporanic
Acid Sulfone (E-9b) was obtained in 1% yield according to procedure A as an amorphous substance, Rf 0.46
1
(1:2 ethyl acetate–hexane). The content of ester E-9b was >94% (HPLC data). H NMR spectrum, δ, ppm,
(J, Hz): 1.62 (9H, s, C4H9); 4.13, 4.53 (2H, AB system, J = 11.0, CH2Br); 5.57 (1H, s, 2-H); 5.93 (1H, d, J = 0.5,
6-H); 7.07 (1H, d, J = 0.5, –CH=); 8.13, 8.31 (2H, d, J = 10.0 and 2H, d, J = 10.0, C6H4).
Ionic Bromination of Esters 1 and Z-7a. A mixture of ester 1 (100 mg, 0.30 mmol) and NBS (66 mg,
0.37 mmol) in absolute benzene (10 ml) was stirred in the dark at room temperature for 2 h. The solvent was
evaporated. The residue was subjected to column chromatography using 1:3 ethyl acetate–hexane as the eluent to
give 23 mg of a 3:7 mixture of 4 and 5 (as indicated by HPLC), Rf 0.71 (1:3 ethyl acetate–hexane) and 25 mg of
a 4:6 mixture of 4 and 6, Rf 0.66 (1:3 ethyl acetate–hexane). The total yield of these products in the mixtures was
>97% (HPLC data).
When Br2 (0.30 mmol) was used instead of NBS, a 3:7 mixture of 4 and 5 was obtained, Rf 0.71 (1:3
ethyl acetate–hexane).
tert-Butyl Ester of 2-Bromo-7α-chlorodeacetoxycephalosporanic Acid Sulfone (4). 1H NMR
spectrum, δ, ppm, (J, Hz): 1.55 (9H, s, C4H9); 2.28 (3H, s, CH3); 4.95 (1H, s, 2-H); 5.37 (1H, d, J = 0.5, 7-H).
1
tert-Butyl Ester of 2,2-Dibromo-7α-chlorodeacetoxycephalosporanic Acid Sulfone (5). H NMR
spectrum, δ, ppm, (J, Hz): 1.51 (9H, s, C4H9); 2.13 (3H, s, CH3); 4.82 (1H, d, J = 0.5, 6-H); 5.49 (1H, d, J = 0.5,
7-H).
tert-Butyl Ester of 2-Bromo-7α-chloro-3-methylceph-2-eme-4-carboxylic Acid Sulfone (6). 1H NMR
spectrum, δ, ppm, (J, Hz): 1.55 (9H, s, C4H9); 2.08 (3H, s, CH3); 4.66 (1H, d, J = 0.5, 6-H); 5.42 (1H, d, J = 0.5,
7-H); 6.28 (1H, s, 4-H).
tert-Butyl Ester of Z-2-Bromo-7α-tert-butoxycarbonylmethylenedeacetoxycephalosporanic Acid
Sulfone (10) was obtained under the bromination conditions described above from ester Z-7a (25 mg, 0.1 mmol)
and NBS (18.4 mg, 0.1 mmol) in absolute benzene (3 ml) over 30 min. The reaction yielded 10 mg of an oily
1
substance containing >97% ester 10 (HPLC data). Yield 20%, Rf 0.60 (1:1 ethyl acetate–hexane). H NMR
spectrum, δ, ppm: 1.55 (18H, s, 2C4H9); 2.17 (3H, s, CH3); 5.00 (1H, s, 2-H); 6.20 (1H, br. s, 6-H); 6.62 (1H,
br. s, –CH=). Found, %: C 45.42; H 5.21; N 3.11. C18H24BrNO7S. Calculated, %: C 45.20; H 5.06; N 2.93.
666

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