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Table 1 Optimization of sugars for Suzuki coupling-nitro reduction
greener and economical chemical protocols, we have recently
reported D-glucosamine as an efficient alternative to phos-
phines in Pd-catalyzed Heck coupling of aryl and heteroaryl
halides under microwave conditions.27 In continuation of these
ongoing efforts, we explored the possibility of designing a one-
pot cross coupling-reduction sequence using simple sugars.
Multistep one-pot processes, so-called tandem processes, have
the potential to impact the manufacturing of ne chemicals and
pharmaceutical intermediates.28 Compared with stepwise
synthesis, the combination of multiple catalytic reactions into
one synthetic operation reduces the number of purication
steps, provides better substrate scope, and enhances reactivity
and selectivity by allowing equilibrium reactions to proceed to
nearly full conversion, thus contributing to an improved
process economy as well as to more sustainable synthetic
routes. Herein, we demonstrate D-mannose for the rst time as
an efficient ligand for Pd catalyzed cross-coupling, as well as
hydrogen source for nitro reduction. Both the properties have
been utilized in developing an efficient one-pot tandem
protocol for aminobiphenyl and aminostilbene synthesis start-
ing from halonitroarenes.
and Heck coupling-nitro reductiona
2. Results and discussion
a
Reaction conditions: for Suzuki, 1a (1.0 equiv., 0.1 mmol), 2a
We began our investigation by heating 3-nitrobromobenzene
(1a, 1.0 equiv.) with phenyl boronic acid (2a, 1.0 equiv.) in DMF/
H2O (3 : 1) using K2CO3 (3.0 equiv.), glucose (3.0 equiv.) and
Pd(OAc)2 (5 mol%) as catalyst at 130 ꢀC. Aer 14 hours of
reaction, the desired product biaryl amine (3a) was isolated in
65% yield. Pleased with the one-pot cross-coupling and nitro
reduction, we explored if the same reaction could be carried out
under microwave conditions with an intention of reducing the
reaction time, side reactions and increasing the product yield.
We were quite delighted to nd that changing from conven-
tional to MW heating drastically reduced the reaction time to
1 hour, and 3a was isolated in 67% yield. The results indicated
that as anticipated, the reaction followed a tandem cross-
coupling nitro-reduction sequence mediated by Pd–glucose
system. Further, we found that lowering the Pd loading to
3 mol% did not affect the product yield. However, decreasing it
further to 2 mol% and 1 mol% led to substantial reduction in
the yield of reduced product 3a. Therefore, it was decided to
carry out further optimization studies with 3 mol% Pd(OAc)2. To
establish the role of sugars in promoting the reaction, a variety
of sugars such as galactose, glucosamine, arabinose, ribose,
fructose, sucrose, mannose and 1,2-protected glucose (L1–9)
were examined. The results as shown in Table 1 indicated
D-mannose to be the most potent of all the sugars in effecting
the cross-coupling cum reduction. No prior report on use of
D-mannose as a ligand and reducing agent exists in literature.
With the non-reducing sugar sucrose (L7), the reduced product
3a was not obtained at all and the reaction stopped aer cross-
coupling to yield 3-nitrobiphenyl (7b) in 90% yield. Optimiza-
tion of reaction with respect to solvent, temperature, and base
was carried out; and the results are summarized in Table 2. A
series of organic solvents such as DMF, CH3CN and DCE
(Table 2; entry 1–3) were screened. It was found that reaction
(1.0 equiv., 0.1 mmol); for Heck, 4a (1.0 equiv., 0.08 mmol), 5a
(1.0 equiv., 0.08 mmol), sugar (3.0 equiv., 0.3 mmol), Pd(OAc)2
(0.03 equiv., 3 mol%), K2CO3 (3.0 equiv., 0.3 mmol), DMF/H2O (3 : 1),
b
c
60 min (MW), 130 ꢀC, power 20 watts. HPLC yield of 3a. HPLC
d
e
yield of 6a. Suzuki coupling with 2.0 equiv. of mannose. Suzuki
coupling with 1.0 equiv. of mannose.
did not take place in CH3CN and DCE while 20% product was
formed in DMF. In water alone as solvent, 3a was obtained in
30%. The stalling of reaction in organic medium suggested the
necessity of water as a co-solvent to solubilize sugar required for
the reaction. Based on this observation, mixtures of organic
solvent and water in the ratio 3 : 1 were examined. Amongst
DMSO/H2O, CH3CN/H2O, dioxane/H2O and DMF/H2O combi-
nations (Table 2; entry 5–8), highest yield of 3a (88%) was
obtained in DMF/H2O. Changing the ratio of DMF/H2O to 1 : 1,
2 : 1 and 4 : 1 resulted in reduced product yield 50–71% (Table
2, entry 9). Further, variation of temperature in the range 80–
140 ꢀC revealed that the optimum temperature for the reaction
was 130 ꢀC. Raising the temperature to 140 ꢀC or lowering to 100
ꢀC reduced the yield of 3a (Table 2; entry 10–13). Furthermore,
effect of base on the reaction was investigated. Different bases
such as KOH, Et3N, Cs2CO3 and K2CO3 were tested (Table 2;
entry 8, 14–16), and highest yield was obtained with K2CO3.
Lowering the equivalents of K2CO3 resulted in reduced yield of
the product while increasing it to 4 equivalents did not bring
about much change (Table 2; entry 17).
The same protocol was extended to investigate the feasibility
of a one-pot Heck coupling-nitro reduction. The reaction of
3-iodonitrobenzene (4a, 1.0 equiv.) with styrene (5a, 1.0 equiv.)
in presence of Pd(OAc)2 (3 mol%), mannose (3 equiv.) and
K2CO3 (3.0 equiv.) in DMF/H2O (3 : 1) for 60 minutes yielded
31312 | RSC Adv., 2015, 5, 31311–31317
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