Tandem and chemoselective synthesis of benzil derivatives from styrene and arene diazonium salts

Article abstract of DOI:10.1016/j.tetlet.2017.03.076

A facile and practically applied protocol for synthesis of benzil derivatives using styrene and arene diazonium salts is reported. Pd(OAc)₂/SeO₂ catalytic system was found to be efficient for chemoselective synthesis of benzil. Selenium dioxide works well as an oxidant under milder reaction conditions. Moderate to very good yields of the desired products were obtained.

Full text of DOI:10.1016/j.tetlet.2017.03.076

Accepted Manuscript
Tandem and chemoselective synthesis of benzil derivatives from styrene and
arene diazonium salts
Vilas G. Jadhav, Sachin A. Sarode, Jayashree M. Nagarkar
PII:
S0040-4039(17)30397-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.076
TETL 48777
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
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22 March 2017
25 March 2017
Please cite this article as: Jadhav, V.G., Sarode, S.A., Nagarkar, J.M., Tandem and chemoselective synthesis of
benzil derivatives from styrene and arene diazonium salts, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.03.076
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Tandem and chemoselective synthesis of
benzil derivatives from styrene and arene
diazonium salts.
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Vilas G. Jadhava , Sachin A. Sarodea and Jayashree M. Nagarkara∗

1
Tetrahedron Letters
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Tandem and chemoselective synthesis of benzil derivatives from styrene and
arene diazonium salts.
Vilas G. Jadhava, Sachin A. Sarodea and Jayashree M. Nagarkara∗
a Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai – 400019, India. Fax: +91 22 33611020; Tel.: +91 22-33611111/2222;
E-mail: jm.nagarkar@ictmumbai.edu.in
ARTICLE INFO
ABSTRACT
Article history:
Received
A facile and practically applied protocol for synthesis of benzil derivatives using styrene and
arene diazonium salts is reported. Pd(OAc)2/SeO2 catalytic system was found to be efficient for
chemoselective synthesis of benzil. Selenium dioxide works well as an oxidant under milder
reaction conditions. Moderate to very good yields of the desired products were obtained.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Benzil
Styrene
Tandem synthesis
Selenium dioxide
Arene diazonium salts
oxide was used for the preparation of benzil from cis stilbene
with moderate yield24,25. Sun et al. reported an efficient I2-H2O
Benzil, an aromatic 1,2 diketone is an important intermediate in
chemical industry having wider applications in pharmaceuticals1–
3. Various biologically active heterocyclic compounds, such
as triazine4, quinoxaline5 and imidazole3 can be synthesized from
1,2 diketones. Recently benzil derivatives have been found to
show antitumor activity6. They are also reported as
photosensitive agents and photoinitiators7.
catalytic system for the synthesis of benzil derivatives 10
.
O
O
HO
Benzils can be prepared from oxidation of benzyl phenyl
ketone8,9. Arene alkene10,11 and arene alkyne12,13 (Scheme 1)
which can be easily obtained from Heck and Sonogashira
reactions are also employed to obtain benzils. Oxidation of
olefins for the formation of fine chemicals using transition metal
catalysts in combination with peroxides, peracids, and other
oxidizing reagents has been widely employed14–17. An alkene can
be oxidized to aldehyde and epoxides. Therefore, selective
oxidation of alkene towards the desired product is the promising
challenge18,19. Hurran et al. synthesized benzil from benzyl
phenyl ketone using SeO220. Riley et al. first reported stilbene to
benzil oxidation using selenium dioxide as an oxidant at higher
temperatures in the range of 190 to 235°C 21,22. Selenium dioxide
is known to be active at higher temperatures.
O
Oxidation
Oxidation
O
Pd(OAc)2, SeO2
DMSO, 130 oC, 36h
N2BF4
Coupling and Oxidation
+
Present work
Scheme 1. Different route towards synthesis of benzil.
Recently, dimethyl sulfoxide-iodine as a novel system for the
oxidation of alkynes and alkenes to benzils have been reported.
All above reported methods require starting material stilbene. It
is synthesized by reacting styrene with arene halide in presence
of palladium catalyst which is a very well known Heck-Mizoroki
reaction. Arene diazonium salts were used instead of arene
halide with styrene as a coupling partner in the Heck-
23
However, the reaction was carried out at high temperature
Wan et al. reported Ru catalyzed oxidation of stilbene in presence
.
of TBAI/TBHP oxidants giving benzil derivatives 11. Graphene
———
∗ Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
Tetrahedron
Matsuda(HM) reaction26–28. The rate of reaction is very high
Even though we increased the reaction time up to 72 hours,
only 28% of the desired product was obtained (Table 1 entry 5).
Then we applied different oxidants such as KIO4, I2, and K2S2O8.
benzoyl peroxide and SeO2. KIO4 furnished 10% of diketone
whereas molecular iodine produced only trace amount of
diketone giving 4-Methyl stilbene, and methyl idobenzene as
byproducts at 120°C (Table 1 entry 6, 7). K2S2O8 was unable to
give benzil where as benzoyl peroxide offered 20% yield (Table
1 entry 8, 9). When the reaction was carried out with SeO2 for
24 hours at 120°C, we got 76 % yield of the desired product
chemoselectively. (Table 1 entry 11) With these interesting
results, various parameters such as catalyst loading, temperature
and reaction time have been optimized. We studied the reaction
for Pd(OAc)2 loading from 0.1 mol % to 1 mol %. It was found
that 0.5 mol% of catalyst yielded 76% of the benzil derivative
(Table 2 entry 4). Morever, no significant increase in the yield of
desired product above 0.5 mol% of Pd(OAc)2 was observed.
Hence 0.5 mol% was the optimum amount of catalyst required
for the reaction.
even at room temperature. Keeping all these merits in mind, we
planned the direct synthesis of benzil from styrene and arene
diazonium salts.
Arene diazonium salts are found to be alternative reagent for
arene halide29. They have attracted much attention in the area of
organic synthesis due to their higher reactivity30,31. Diazonium
salts can be easily prepared from inexpensive anilines and are
stable for long periods. In continuation with our work with arene
diazonium salts for C-C32,33 and C-N34 coupling reactions here in
we report one pot synthesis of benzil derivatives using arene
diazonium salts and styrene in presence of catalytic amount of
Pd(OAc)2 and SeO2. Therefore, to develop collective
methodology which will reduce one step of the formation and
separation process for stilbene and also achieve chemoselective
oxidation of stilbene would be highly desirable.
Results and discussion.
Initially the reactions of styrene (1mmol) with p-
toluenediazonium salt (1.2 mmol) in DMSO solvent with various
catalytic systems and oxidants were carried out and the results
are presented in Table 1. The reaction of styrene and p-
toluenediazonium salt with Pd(OAc)2(0.5 mol%) and TBHP (2
eq.) furnished only trace amount of diketone along with aldehyde
and phenol as side products (Table 1 entry 1). The reaction did
not proceed without catalyst (Table 1 entry 2). The reaction was
carried out in presence of copper bromide as a co-catalyst with
atmospheric molecular oxygen at 120°C. 15% of the desired
product was obtained along with bromo benzene in presence of
When the reaction was carried out only in the presence of SeO2
no desired product was obtained (Table 2 entry 7). 1 mmol of
SeO2 was found to be the optimum concentration to bring out the
oxidation of stilbene to benzil (Table 2 entry 4). The reaction of
1 mmol styrene with p-toluene diazonium salt was treated as the
model reaction for the optimization of parameters such as time,
temperature and solvent. The reaction was carried out in different
solvents and DMSO was found to be the most suitable solvent
(Table 2 entry 8-14). Increasing temperature from 120-130°C we
are able to get 80 % yield of the desired product. When we
increased the time from 24-36 h, we obtained 92% yield of p-
methyl 1,2 diketone chemoselectively (Table 2 entry 12). Hence
DMSO as solvent, 130°C temperature and 36 h were the
optimum reaction parameters for the synthesis of benzils.
35
copper bromide as per Sandmayer reaction (Table 1 entry 3).
where as copper acetate gave 19 % of the desired product (Table
1 entry 3 and 4).
Table 1. Optimization of the reaction parameters.a
Table 2. Effect of catalyst and oxidant loading.a
Entry Pd(OAc)2 SeO2
Solvent
Time Temperature Yieldb
(%)
(Mol %)
0.1
0.2
0.5
0.5
1
(mmol)
1
0.5
0.5
0.5
1
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
24
24
24
24
24
24
24
24
120
120
120
120
120
120
120
120
120
130
130
42
2
48
3
58
4
76
Entry Catalyst
Oxidant
Temperature Time Yieldb
5
1
80
(°C)
(h)
(%)
6
1.5
-
1
80
7
1
N.R
42
1
2
3
4
5
6
7
8
9
Pd(OAc)2
TBHP
TBHP
O2
100
100
120
120
120
120
120
120
120
12
12
24
24
72
24
24
12
24
Trace
-
8
0.5
0.5
0.5
0.5
1
-
10
11
12
1
Dioxane 24
Trace
80
Pd(OAc)2/CuBr2
15
1
DMSO
24
Pd(OAc)2/Cu(OAc)2 O2
Pd(OAc)2/Cu(OAc)2 O2
Pd(OAc)2 Cu(OAc)2 KIO4
Pd(OAc)2 Cu(OAc)2 I2
Pd(OAc)2 Cu(OAc)2 K2S2O8
Pd(OAc)2 Cu(OAc)2 Benzoyl
peroxide
19
1
DMSO
36
92
28
aReaction conditions : styrene (1 mmol), diazonium salt(1.2 mmol),
DMSO(2mL), bisolated yield
10
Trace
-
With the optimized conditions in hand, the scope of this
reaction was assessed with a representative selection of styrene
and arene diazonium salts. As shown in Table 3, a variety of
functional groups, including Cl, Br, methyl, nitro were well
tolerated under the optimized reaction conditions. Electron
donating substituent present at the para position of the arene
diazonium salt gave higher yield (Table 3 entry 2 and 3).
Whereas when NO2 group present at meta position, yield of the
desired product decreased dramatically (Table 3 entry 6).
20
10
11
Pd(OAc)2/Cu(OAc)2 SeO2
120
120
24
24
74
76
Pd(OAc)2
SeO2
aReaction conditions : styrene (1 mmol), diazonium salt(1.2 mmol),
DMSO(2mL),Catalyst (0.5:0.5 mol%), Oxidants(2 eq), O2(1atm), bisolated
yield

3
Table 3. Substrate scope of the reactiona
.
Entry Styrene
Arenediazonium salt
Diketone
Yieldb(%)
90
1
2
3
92
95
4
5
88
85
6
56
7
8
72
88

4
9
Tetrahedron
94
90
43
10
11
O
12
13
75
O
OMe
96c
N2BF4
14
15
16
77
92
62
Cl
aReaction conditions : styrene (1 mmol), arenediazonium salt (1.2 mmol), Pd(OAc)2(0.5 mol%), SeO2(1mmol) DMSO (2mL), time 36h, bisolated yield, c24h.
gave very good yield (Table 3 entries 8- 10 and 12) and 3-
methoxy styrene afforded moderate yield of the desired product
Then we studied stericaly hindered arene diazonium salts,
(Table 3 entry 11). The methoxy group is ortho para directing
and obtained good yield of the desired product. This indicates
that substituent at ortho positions are well tolerated (Table 3
Entry 12). The reaction was found to be chemo selective in
presence of Cl and Br substituted arene diazonium salts and no
other coupling reaction with Cl or Br was observed under
optimized reaction conditions. It also afforded very good yield of
the respective diketones (Table 3 entry 4,5,7,8 ). Then we studied
the reaction with substituted styrene derivatives. 4-methyl styrene
and vinyl group is present at meta position which may be the
reason of less yield of the desired product. We have also studied
the reaction with 4-methoxy styrene and 4-bromo styrene. It was
found that the reaction with 4-methoxy styrene was completed in
lesser time as compared to other styrene derivatives affording
96% yield of the desired product in 24 hours (Table 3 entry
13).We also carried out the reaction of p-Br styrene with 2-
chloro arene diazonium salt and p-toluene diazonium salt and

5
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b hydride
elemination
H
Ar
Ar'
Pd(OAc)2
N2
Ar
AcO
H
Ar'
BF
Ar-N2BF4
[ArPd(OAc)2]
1
4
Pd
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Ar
[HPd(OAc)2]
OAc
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[HPd(OAc)2]
2
SeO2
OAc
Pd
H
H
O
Se
Ar
Ar
Ar
H
Ar
AcHO
AcO Pd
Ar'
O
AcO
H
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O
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Pd
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O
O
H
O
β
Ar'
hydride
elimination
O
O
Ar'
Ar'
AcOH
H
Pd
H
π
AcO
complex
4
p complex
6
H2Pd(OAc) + AcOH +SeO2
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β hydride
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Pd(OAc)2/SeO2. Easily available arene diazonium salts and
styrenes were used as starting materials which make this protocol
cost effective. This novel system exhibited high chemoselectivity
and a broad substrate scope with moderate to very good yield of
benzil derivatives. We believe that the excellent functional group
tolerance and practical convenience of this protocol would prove
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Acknowledgments
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Author VGJ is thankful to University Grant Commission New
Delhi for providing fellowships. Author is also thankful to LOBA
chemie for providing chemicals.
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References and notes
1. Lindsley, C. W.; Zhao, Z.; Leister, W. H.; Robinson, R. G.;
Barnett, S. F.; Defeo-Jones, D.; Jones, R. E.; Hartman, G. D.;
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Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
2. Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori, R.;

6
Tetrahedron
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Highlights of the work
ꢀ Tandem synthesis of the benzil derivatives.
ꢀ Arene diazonium salts as cheaper arylating
agent.
ꢀ Chemo selective reaction.