S. M. Bhosale et al. / Tetrahedron Letters 55 (2014) 155–162
157
OH
OH
Ph
O
O
Ph
CHO
a
CHO
CHO
CHO
X
c
b
N
H
3
N
N
N
H
Br
OMe
Br
Ph
Ph
7
6
8
c
OMe
OMe
OMe
OMe
CHO
CHO
OH
OH
N
N
N
N
OMe
, 40%
OMe
, 27%
Br
Br
Ph
Ph
Ph
Ph
9
12
11
10, 11%
, 20%
Scheme 3. Reagents and conditions: (a) NBS, DMF, rt, 1 h, 95%; (b) NaH, DMF, Benzyl bromide, 0 °C–rt, (c) NaOMe in MeOH, CuI, DMF, 10 h, 120 °C.
Ph
Ph
H
Ph
H
H
O
O
O
O
O
O
N
N
N
C
Ph
CH3ONa
Ph
B
A
Ph
Ph
H
H3C
N
H
O
O
H3CO
N
O
ONa
D
Ph
Ph
E
Scheme 4. Possible mechanism for nucleophilic substitution.
source. This has an analogy with the Meerwein–Ponndorf–Verley
reduction where aluminum isopropoxide is used as the hydride
source. The possible mechanism for reduction of aldehyde is given
in Scheme 5.
DCM, furnished compound 13 as a major product where deformy-
lation and dibromination occurred. The possible mechanism for the
formation of product 13 is shown in Scheme 6. The observed
deformylation can be attributed to the methoxy group at ortho to
aldehyde.
Use of sodium methoxide for reduction is not known in the lit-
erature and this was generalized by carrying out the same reaction
using other aromatic aldehydes (Table 4). Benzaldehyde in contrast
to the earlier observation, gave the reduced product 12g in 70%
yield. Interestingly, the use of p-nitrobenzaldehyde (Entry 5) fur-
nished a mixture of 4,40-bis(hydroxymethyl)azoxybenzene 12h
and 4,40-bis(hydroxymethyl)azobenzene 12i in the ratio 4:1 as re-
vealed from 1H NMR instead of the expected p-nitrobenzyl alcohol.
The formation of products 12h and 12i indicated that sodium
methoxide reduced the nitro group to azoxy and azo group along
with reduction of aldehyde. This was a new observation. As azoxy
compounds have applications in various fields,16 this observation
was generalized using various aromatic nitro compounds to fur-
nish corresponding azoxyarenes in good yields (entries 6–9). In
addition to azo and azoxyarenes, amino compound was also ob-
tained in small amount in one case (entry 7). There is a report
available in the literature17 indicating the reduction of nitro to
azoxy, azo, and amino group in various proportions using other
reducing agents. Thus, all these results established the use of sim-
ple and inexpensive reagent sodium methoxide for the reduction of
aldehyde to alcohol as well as nitro to azoxy compounds.
Finally, synthesis of the target molecule calothrixin B was
achieved from alcohol 12 (Scheme 7). Alcohol 12 was directly trea-
ted with o-iodoaniline in the presence of catalytic amount of pTSA
under reflux condition in THF for 15 min to furnish product 14 in
83% yield. Further, N-acylation with acetyl chloride and triethyl
amine in DCM gave compound 15. Treatment of compound 15 with
Pd(OAc)2 furnished cyclized product 16 in 90% yield. Surprisingly,
⁄CH2 in the expected structure 16 was not observed in 1H and
13C NMR spectra. Subsequently, single crystal analysis8 supported
structure 16 and identified the presence of ⁄CH2 group. To investi-
⁄
gate the anomalous behavior of the CH2 group in NMR, tempera-
ture dependant NMR study was carried out.
Thus, 400 MHz 1H NMR spectrum of compound 16 was re-
corded in DMSO-d6 and CDCl3. In both these solvents some of the
signals obtained in the 1H NMR spectrum were found to be broad.
The broadness was more for the benzylic protons at C14 and the
⁄CH2 protons at C6 could not even be detected clearly. The 13C spec-
trum was also relatively broad. Broadness of the proton and 13C
NMR spectra seems to suggest the presence of slow motion at
the NMR time scale. The presence of motional effects can very well
be established by variable temperature NMR studies. On heating
the sample in DMSO d6 narrowing of most of the signals of 1H spec-
trum and also emergence of a broad signal at ꢀ5.0d corresponding
to two protons were observed. Nevertheless, the 13C NMR spec-
Coming back toward the synthetic target compound 1, it was
decided to carry out bromination of compound 11 at ortho to alde-
hyde group followed by Ullmann coupling reaction with o-iodoan-
iline. Unexpectedly, treatment of compound 11 with bromine in