1114
S. Kotha et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1113–1115
At this juncture, the change of glycine equivalent from
Schiff-base to ethyl isocyanoacetate was considered.
When the dibromide 4 was treated with ethyl iso-
cyanoacetate under PTC conditions,7a the alkylated
product 11 (mp 190–192 ꢀC) was isolated in 3.5% yield
(Scheme 3). Compound 11 was characterized on the
1
basis of H NMR and mass spectral data. 13C NMR
Scheme 1. (i) CNCH2CO2Et, NaH, DMSO, ether, rt;(ii) H +, ether or
H
spectral data shows the mixture of two isomers in 5:6
ratio, which were separated after hydrolysis. It is known
in the literature that the bromide 4 can form radical
intermediates under thermal or photochemical reaction
conditions to give disproportion/polymerization reac-
tion,7b and the low coupling yield of the product can be
explained due to this possible unwanted side reaction.
To test this idea, alkylation reaction was carried out in
absence of ethyl isocyanoacetate under PTC conditions
and the poor recovery (28%) of the starting bromide 4
was observed. To improve the yield of 11, alkylation
reaction was attempted under different reaction condi-
tions. For example, alkylation of ethyl isocyanoacetate
with bromide 4 under NaH/DMSO conditions gave the
low yield of the product 11 when compared to PTC
conditions. It is known that the phosphazene bases
improve the yields of the coupling product when sensi-
tive substrates are involved where the unwanted side
reactions are minimized.8 In this regard, 2-tert-butyli-
mino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-dia-
zaphosphorine (BEMP) has been used as a base in
acetonitrile at 0 ꢀC and the coupling product 11 was
isolated in 14% yield (4-fold increased as compared to
PTC conditions) as an isomeric mixture. Hydrolysis of
the isonitrile derivative 11 in presence of HCl/diethyl
ether gave the trans form of N-formyl derivative 12 (mp
210 ꢀC decomp.) in 48% isolated yield, whose structure
has been determined by X-ray crystallography studies
and another isomer 13 (mp 220ꢀC decomp.) in 40%
isolated yield. 13C NMR spectral data of trans isomer 12
(d 14.2, 34.7, 40.0, 62.0, 66.7, 128.5, 129.3, 133.2, 138.9,
160.7, 171.8) supported the formation of 12. The struc-
ture of trans isomer 12 was further supported by FAB
mass spectral data (675 M+1) and single crystal X-ray
studies.9 The 11-line 13C NMR spectral data of 13 (d
14.2, 34.0, 39.8, 62.0, 68.0, 128.4, 128.9, 133.0, 138.6,
161.5, 172.3) and FAB mass spectral data (675 M+1)
+, EtOH, Ac2O;(iii) Grubbs’ catalyst.
mass (m/z=345) spectral data supported its formula-
tion. The isonitrile derivative 6 was hydrolyzed with
HCl/ether to give N-formyl derivative 7a. The dis-
appearance of peak at 2137 cmÀ1 and appearance of
peak at 1667 cmÀ1 in the IR spectrum indicate the pre-
sence of N–CHO group;in 1H NMR (300 MHz) spec-
trum signal at d 8.18 due to aldehyde proton supports
the formation of N-formyl derivative 7a. When the
RCM reaction3b was carried out with the compound 7a
in presence of Grubbs’ catalyst [bis(tricyclohexyl-phos-
phine)benzylidine ruthenium(IV) dichloride] in either
degased refluxing benzene or in dichloromethane under
argon atmosphere, the required cyclophane derivative 8
was not formed and the unreacted starting material was
recovered. Alternatively, N-acetyl derivative 7b was also
prepared and found to be inert to RCM reaction under
similar reaction conditions.
Then, the alternate strategy (path b), involving alkyla-
tion of N-(diphenylmethylene)glycine ethyl ester (Schiff-
base) with dibromide 4 was attempted. The required
dibromide 4 was prepared by bromomethylation of 1,2-
diphenylethane according to the known procedure.4a
Alkylation of Schiff-base4b with 4 in presence of KOH/
TBAB (tetra-n-butylammonium bromide) in acetonitrile
at 0 ꢀC followed by hydrolysis and protection with ace-
tic anhydride gave N-acetyl derivatives 9 (8%) and 10
(7%) (Scheme 2). Compounds 9 and 10 were isolated by
silica gel column chromatography5 and were character-
ized by 1H NMR and mass spectral data. 12-Line
13C NMR spectral data (d 14.2, 23.2, 37.5, 37.6, 53.2,
61.5, 128.6, 129.3, 133.5, 140.5, 169.6, 171.7) also sup-
ported the presence of C2 symmetry in the molecule 10.
Since the phase transfer catalysis (PTC) conditions did
not deliver the coupling product related to 3, alkylation
in presence of micelle, cetyltrimethyl-ammonium bro-
mide (CTAB) was attempted where the favorable
entropy conditions may aid the formation of the
required cyclophane derivative.6 Surprisingly, under
these conditions, reaction of 4 with Schiff-base followed
by hydrolysis and acetylation gave 9 (6%) and 10
(13%).5
Scheme 3. (i) CNCH2CO2CH2CH3, K2CO3, CH3CN, ꢀ or BEMP
CH3CN, 0 ꢀC;(ii) H +, ether, 0 ꢀC –rt.
Scheme 2. (i) Schiff-base;(ii) KOH, TBAB or Micelle (CTAB),
CH3CN;(iii) H +, ether, rt;(iv) Ac 2O, DMAP, CH2Cl2, rt.