SCHEME 1
pyridines.5 We have discovered that this undesirable
isomerization is not seen by the use of potassium tri-
methylsilanolate as base, such as shown in two steps of
the synthesis in Scheme 1. This basic reagent is soluble
in organic solvents, which obviates the need for use of
aqueous or mixed aqueous/organic conditions.
h resulted in a clean conversion of the Z to E isomer. A
similar isomerization has been reported in the literature
under this condition.9 Figure 1 documents the progress
of isomerization in an NMR tube.
The important aspects of this synthetic route to ni-
torcefin are the entire avoidance of the well-precedented
and undesirable ∆3 f ∆2 isomerization of the dihydrothi-
azine ring and the facility of the complete conversion of
the Z to E isomer. We hasten to add that chromato-
graphic separation of the ∆3 and ∆2 isomers is difficult
and often the need for oxidation/reduction at the cephem
sulfur is mandated. However, the synthetic route pre-
sented in Scheme 1 bypasses these steps in simplifying
the procedures considerably. The three-pot synthesis of
nitrocefin was accomplished in 44% overall yield.
As shown in Scheme 1, the 7-amino group of cepha-
losporin 7 was acylated with 2-thienylacetyl chloride in
the presence of stoichiometric potassium trimethylsil-
anolate to give compound 8. The chloro moiety of 8 was
converted to iodo by the Finkelstein reaction, which was
allowed to undergo reaction with triphenylphosphine in
situ to result in 9. The Wittig reaction of compound 9
with 2,4-dinitrobenzaldehyde was also carried out in the
presence of potassium trimethylsilanolate (KOSiMe3), a
reaction that proceeded in 70% yield (from compound 8)
to afford a 7:1 mixture of Z:E isomers (10). Potassium
trimethylsilanolate has been used previously for mild
hydrolyses of carboxylic esters6 or nitrile derivatives.7
There is no report of the use of this reagent for Wittig
reaction in the literature that we are aware of. This
reagent is useful as a good base for the Wittig reaction
in anhydrous conditions. The yield was as good as typical
Wittig reactions with cephalosporin derivatives (aqueous
NaOH or NaHCO3 in methylene chloride).3,4,8-10 Depro-
tection of the p-methoxybenzyl group of compound 10 was
achieved by treatment with trifluoroacetic acid at ice-
water temperature for 15 min, resulting in nitrocefin as
a mixture of Z and E isomers (the ratio became 6:5). The
Z to E isomerization for some cephalosporin derivatives
has been reported in the literature during the acid-
promoted deprotection of 4-carboxylates with TFA8 or
with Lewis acid (TiCl4, SnCl4, etc)4,11 A more prolonged
treatment with TFA resulted in an increased ratio of E/Z
but was accompanied by the decomposition of the desired
product. However, we found that storage of the mixture
of the isomers of 4 in 10% DMSO in chloroform over 24
Experimental Section
p-Methoxybenzyl (6R,7R)-3-Chloromethyl-7â-(2-thien-
ylacetamido)-3-cephem-4-carboxylate (8). Potassium trim-
ethylsilanolate (2.85 g, 20.0 mmol, 90% purity) in CH3CN (30
mL) and 2-thienylacetyl chloride (1.30 mL, 10.0 mmol) were
added simultaneously to a suspension of compound 7 (4.00 g,
10.0 mmol) in CH2Cl2 (50 mL) over 1 h in an ice-water bath.
The resulting suspension was stirred at room temperature for
1 h, and the solvent was then evaporated under reduced
pressure. The residue was taken up with CH2Cl2 and water, and
the layers were separated. The organic layer was washed with
water and brine, dried over MgSO4, filtered, and evaporated.
The resulting solid material was recrystallized from ethyl acetate
and hexane to afford the desired product (3.80 g, 78%): 1H NMR
(500 MHz, CDCl3) δ 3.41, 3.60 (2d, 2H, J ) 18.2 Hz, H2), 3.79
(s, 3H, OCH3), 3.83 (s, 2H, thiophene-CH2), 4.39, 4.52 (2d, 2H,
J ) 11.9 Hz, CH2Cl), 4.92 (d, 1H, J ) 5.1 Hz, H6), 5.19 (s, 2H,
CH2Ar), 5.81 (dd, 1H, J ) 5.1 Hz, J ) 9.1 Hz, H7), 6.65 (d, 1H,
J ) 9.1 Hz, NH), 6.88 (d, 2H, J ) 8.6 Hz, ArH), 6.95 (m, 1H,
thiophene-H), 6.98 (dd, 1H, J ) 3.5 Hz, J ) 5.1 Hz, thiophene-
H), 7.24 (dd, 1H, J ) 1.5 Hz, J ) 5.1 Hz, thiophene-H), 7.32 (d,
2H, J ) 8.6 Hz, ArH); 13C NMR (125 MHz, CDCl3) δ 27.3 (C2),
37.2 (thiophene-CH2), 43.4 (CH2Cl), 55.4 (OCH3), 57.8 (C6), 59.3
(C7), 68.4 (CH2Ar), 114.1, 125.6, 126.1, 126.5, 126.7, 127.6, 127.9,
130.9, 134.9, 160.1, 161.2, 164.8, 170.4; MS (ESI) m/z 515.07
[M + Na]+.
p-Methoxybenzyl (6R,7R)-3-(2,4-Dinitrostyryl)-7â-(2-thien-
ylacetamido)-3-cephem-4-carboxylate (10). A mixture of
compound 8 (1.00 g, 2.0 mmol), sodium iodide (1.52 g, 10.1
mmol), and triphenylphosphine (0.96 g, 3.7 mmol) in methylethyl
ketone (15 mL) was stirred overnight in the dark at room
temperature. The resulting suspension was filtered through a
small layer of silica gel and washed with CH2Cl2 and acetone.
The combined filtrate was evaporated under reduced pressure
and was taken up into CH2Cl2 (20 mL). Potassium trimethyl-
silanolate (0.27 g, 1.9 mmol, 90% purity) in CH3CN (5 mL) was
added to the above solution at -10 °C in the dark. After 1 h,
2,4-dinitrobenzaldehyde (0.39 g, 2.0 mmol) in CH2Cl2 (10 mL)
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368 J. Org. Chem., Vol. 70, No. 1, 2005