Metal-free denitrative arylation of β-nitrostyrenes using benzoyl peroxide: An easy access to: Trans -stilbenes

Article abstract of DOI:10.1039/c7nj02997g

A simple, novel and stereoselective synthesis of trans-stilbenes has been described using denitrative arylation of β-nitrostyrenes in the presence of benzoyl peroxide under metal-free conditions. The reaction is assumed to involve homolytic cleavage of benzoyl peroxide followed by decarboxylation to generate a phenyl radical, which brings about ipso-substitution of the nitro group of nitrostyrenes to afford trans-stilbenes.

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Metalꢀfree denitrative arylation of βꢀnitrostyrenes using benzoyl peroxide: an easy
access to transꢀstilbenes†
Arvind Kumar Yadav and Krishna Nand Singh*
Department of Chemistry (Centre of Advanced Study), Institute of Science, Banaras Hindu University, Varanasi-221005, India.
E-mail: knsinghbhu@yahoo.co.in; knsingh@bhu.ac.in; Fax: +91-542-236812; Tel:+91-9415992580
5
1
13
†
1
Electronic supplementary information (ESI) available: Experimental details and copies of H & C spectra for the products, See DIO:
0.1039/c0xx00000x
A simple, novel and stereoselective synthesis of transꢀstilbenes has 50 reaction mixture is also cumbersome, and requires longer reaction
1
0
been described using denitrative arylation of βꢀnitrostyrenes in the
presence of benzoyl peroxide under metalꢀfree conditions. The
reaction is assumed to involve homolytic clevage of the benzoyl
peroxide followed by decarboxylation to generate phenyl radical,
which brings about ipsoꢀsubstitution of the nitro group of
time. Therefore, a facile and efficient alternative to synthesize
transꢀstilbenes is exigent and useful.
Inspired by the recent work on βꢀnitrostyrenes under transition
9
metal catalysis by Yuan and Yadav groups, it was envisioned
55
that the phenyl radical generated from tertꢀbutylperoxybenzoate
(
TBPB) or benzoyl peroxide (BPO) could be judiciously used for
1
5
nitrostyrenes to afford the transꢀstilbenes.
its coupling with β-nitrostyrenes. This is worthwhile to mention
that benzoyl peroxide has been recently utilized as phenyl radical
Introduction
10
source, but the use of benzoyl peroxide as a phenyl radical
1
1
Stilbenes have broad applications in the synthesis of small to 60 source under metalꢀfree conditions is rather limited. Further,
medium ring cyclic compounds, enantiomerically pure 1,2ꢀ
diphenylethanes, 1,2ꢀdiamines, 1,2ꢀdiols and phenanthrene
there is no report on the free radical reactions of β-nitrostyrene
without the use of a catalyst. In view of the above and as a part of
1
12
2
2
3
3
4
4
0
5
0
5
0
5
alkaloids. They are also used as optical brighteners and
our ongoing research programme in organic synthesis, we
1
therapeutic agents for liver disorders. Because of their
describe herein a novel, metalꢀfree and stereoselective synthesis
importance in the synthesis of such valuable molecules, a variety 65 of transꢀstilbenes adoping denitrative arylation of βꢀnitrostyrenes
2
of preparative methods for stilbenes have been developed.
Among them, Heck reaction is one of the most frequently used
methods for the synthesis of arylꢀsubstituted olefins (Scheme 1,
Approach A). However, metal (Pd/Ni/Co/Cu/Fe) and ligand
based methods in general have some limitations, such as high
cost, generation of toxic waste, protection from air and moisture,
using benzoyl peroxides (Scheme 1, This work).
2,3
and substrate limitations (not applicable to halogen substituent).
Some other useful alternative methodologies to prepare stilbenes
include condensation of aldehyde tosylhydrazones with stabilized
1
d
4
carbanions,
Wittig type reaction, reductive coupling of
5
carbonyl compounds, and selfꢀcoupling of αꢀlithiated benzylic
6
sulfones.
β-Nitrostyrenes constitute an important class of synthetic
intermediate and are easily prepared by the Henry reaction. They
have been successfully used for CꢀC/CꢀS bond formation by
denitrative additionꢀelimination reaction to prepare a variety of
7
biologically and pharmaceutically important compounds. The
process involves the crossꢀcoupling of nitroalkenes, where NO2
eventually acts as a leaving group. Further exploration on the
application of this stable and easily available intermediate is
highly demanding and interesting in organic synthesis.
Recently, König and Wang groups have developed new
methodologies for the synthesis of stilbenes from β-nitrostyrene
8
using visible light photoredox catalysts (Scheme 1, Approach B).
Despite their intrinsic advantages, yet, photoredox catalysts are
often expensive, potentially toxic and undergo decomposition on
long irradiation. The recovery of the photocatalyst from the
70
Scheme 1 Synthesis of transꢀstilbenes.
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DOI: 10.1039/C7NJ02997G
Results and discussion
nitrostyrenes with benzoyl peroxide to afford a variety of trans-
stilbenes 2aꢀ2o. The outcome is given in Table 2. The reaction
works well in almost all the cases of β-nitrostyrenes containing
substituent like Me, MeO, Cl, Br, F and NO2 at different
In order to optimize the reaction conditions, a detailed study
employing βꢀnitrostyrene (1a) as model reactant was undertaken
5
by varying different parameters and the findings are given in 45 positions; and also with a heteroaromatic ring. However,
Table 1. The reaction was initially carried out using equimolar
aromatic substrates bearing electronꢀdonating substituent afford
somewhat higher yield of the products in comparison to those
bearing electronꢀwithdrawing group (cf. Table 2; 2bꢀ2n). This is
perhaps due to the formation of the benzylic intermediate during
quantities (1.0 mmol) of 1a and tertꢀbutylperoxybenzoate (TBPB)
°
in CH CN (3 mL) at 110 C for 4 h in a sealed tube, which did not
3
give the desired product (Table 1, entry 1). Then was added a
10
catalytic amount (10 mol%) of Cu(OAc)2 to the same blend, 50 the course of reaction, which is destablised by an electronꢀ
which gave rise to the transꢀstilbene (2a) in 38% yield (Table 1,
entry 2).
withdrawing substituent. In order to establish the scope and utility
of the chemistry, diversely substituted BPOs containing pꢀMe, mꢀ
Me, pꢀMeO and pꢀCl were also prepared from the corresponding
carboxylic acids, and then allowed to undergo reaction with βꢀ
nitrostyrenes having substituent like pꢀMe, pꢀMeO and oꢀF under
the established conditions, which successfully led to the
a
Table 1 Optimization of reaction conditions
.
55
formation of the transꢀstilbenes 2pꢀ2t (cf. Table 2).
a,b
15
Table 2 Substrate scope.
Entry Catalyst
mol%)
Ph Source
(mmol)
Solvent Temp.
Time Yield
b
(
(h)
(%)
traces
38
1
2
3
4
5
6
7
8
9
1
1
1
ꢀ
TBPB (1)
CH
CH
CH
CH
CH
3
3
3
3
3
CN 110
CN 110
CN 110
CN 110
CN 110
4
Cu(OAc)
Cu(OTf)
CuCl (10)
Ni(OAc) (10)
2
(10) TBPB (1)
4
4
4
4
4
4
4
2
2
2
2
2
2
(10)
TBPB (1)
TBPB (1)
TBPB (1)
32
2
27
2
35
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
(10) TBPB (1)
(10) TBPB (1)
(10) TBPB (1)
(10) BPO (1)
BPO (1)
DCE
DMF
110
110
30
37
DMSO 110
34
CH
3
3
3
CN 110
CN 110
CN 110
90
0
1
2
3
ꢀ
CH
88
ꢀ
ꢀ
ꢀ
BPO (0.5) CH
87
BPO (0.5) CH
BPO (0.5) CH
3
CN 100
87
1
a
3
CN 90
70
Reaction conditions: 1 (1.0 mmol), Catalyst (10 mol%), Phenyl source
°
b
(1ꢀ0.5 mmol), Solvent (3 mL), 100ꢀ110 C, 2ꢀ4 h, in sealed tube. Isolated
product yield.
20
25
30
35
40
Thereafter, some other catalysts such as Cu(OTf) , CuCl and
Ni(OAc)2 were used under identical conditions to test their
efficacy (entries 3 to 5), but none of them could match the
2
2
productivity of Cu(OAc) . Then was tested the effect of some
2
other solvents like DCE, DMF and DMSO, yet no improvement
in the product yield was observed (entries 6ꢀ8). Then, we resorted
to the use of benzoyl peroxide (BPO) as phenyl radical source, as
BPO is readily available, inexpensive, and easy to handle. To our
utmost delight, when the reaction was carried out using BPO in
the presence of Cu(OAc) , a dramatic increase in the product
2
yield and a considerable reduction in the reaction time (2h) was
observed (entry 9). Encouraged by this result, the reaction was
afterwards conducted with BPO in the absence of Cu(OAc)2,
which delightedly led to almost identical product yield (entry 10).
In order to avoid the use of metal salt, entry 10 was opted as the
best fit. The molar ratio of reactants and the effect of temperature
were also optimized, which came out to be 0.5 mmol of BPO at
°
1
00 C (entries 11ꢀ13).
a
60
Reaction conditions: 1 (1.0 mmol), benzoyl peroxide/substituted benzoyl
Under the established set of reaction conditions (entry 12), the
generality and scope of the present protocol was examined in
detail by using crossꢀcoupling reaction of diversely substituted β-
°
b
3
peroxide (0.5 mmol), CH CN (3 mL), 100 C, 2ꢀ4 h, in a sealed tube.
Isolated product yield (For general procedure and characterization of the
product, see: ESI†).
2
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Green Chem., 2013, 15, 1030; (g) Z. Wang, Q. Ding, X. He
and J. Wu, Org. Biomol. Chem., 2009, 7, 863.
J. Xiao, J. Yang, T. Chen, L.ꢀB. Han, Chem. Commun., 2016,
To demonstrate the workability of the reaction, a gram scale
reaction using 1a (0.74 g) and BPO (0.60 g) was carried out,
which afforded the product 2a in 82% yield (0.73 g) without
compromising the reaction conditions.
To look into the mechanistic insights of the reaction, a typical
reaction of 1a with BPO was carried out in the presence of
3
.
5
2, 2157.
4. (a) P. F. Hurdlick, D. Peterson, J. Am. Chem. Soc., 1975, 97,
464; (b) M. Julia, Pure Appl. Chem., 1985, 57, 763.
J. E. McMurry, M. P. Fleming, J. Am. Chem. Soc., 1974, 96,
708.
L. Engman, J. Org. Chem., 1984, 49, 3559.
55
5
1
5
6
.
.
2
,2,6,6ꢀtetramethylpiperidineꢀ1ꢀoxyl (TEMPO, 2 equiv.), which
4
completely suppressed the formation of 2a, thereby revealing the
involvement of a radical pathway. Based on this observation,
60
7. (a) Y.ꢀJ. Jang, M.ꢀC. Yan, Y.ꢀ F. Lin and C.ꢀF. Yao, J. Org.
Chem., 2004, 69, 3961; (b) Y.ꢀJ. Jang, Y.ꢀK. Shih, J.ꢀY. Liu,
Y. Kuo and C.ꢀF. Yao, Chem. Eur. J., 2003, 9, 2123; (c) J.ꢀT.
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Chu and J.ꢀT. Liu, J. Org. Chem., 1998, 63, 719.
8
,9,11
1
0
isolation of products and literature precedents,
a plausible
mechanism is outlined in Scheme 2. Benzoyl peroxide on
thermolysis undergoes successive cleavage of OꢀO bond and
decarboxylation to afford the phenyl radical, which subsequently
reacts with βꢀnitrostyrene to form the benzylic radical species A,
followed by denitration giving rise to the product 2.
6
7
5
0
8
.
For recent work to access stilbenes form nitrostyrenes, see: (a)
P. Schroll, D. P. Hari and B. K nig, ChemistryOpen, 2012, 1,
30; (b) N. Zhang, Z.ꢀJ. Quan, Z. Zhang, Y.ꢀX. Da and X.ꢀC.
Wang, Chem. Commun., 2016, 52, 14234.
1
5
ö
1
9. For recent work on nitrostyrenes involving transition metal
catalyst, see: (a) S.ꢀR. Guo and Y.ꢀQ. Yuan, Synlett, 2015, 26,
1
961; (b) T. Keshari, R. Kapoorr and L.D. S. Yadav, Eur. J.
Org. Chem., 2016, 2695.
1
0. For recent work emploing benzoyl peroxide as phenyl radical
source, see: (a) W. Y. Yu, W. N. Sit, Z. Zhou and A. S. C.
Chan Org. Lett., 2009, 11, 3174; (b) D. Li, N. Xu, Y. Zhang
and L. Wang, Chem. Commun. 2014, 50, 14862; (c) M. Sun,
Z. Wang, J. Wang, P. Guo, X. Chen and Y.ꢀM. Li, Org.
Biomol. Chem., 2016, 14, 10585; (d) Y. Deng, X.ꢀQ. Zhang,
H. Jiang, G. Miao, X. Tang and W. Zeng, Org. Biomol. Chem.,
7
8
8
9
9
5
0
5
0
5
Scheme 2 Plausible reaction mechanism
.
2
2
014, 12, 5866; (e) K. R. Babu, N. Zhu and H. Bao, Org. Lett.,
017, 19, 46.
2
2
3
3
0
5
0
5
Conclusions
1
1. For recent work emploing benzoyl peroxide as phenyl radical
source under metalꢀfree condition, see: (a) C. Pan, H. Zhang,
J. Han, Y. Cheng and C. Zhu, Chem. Commun., 2015, 51,
In conclusion, a convenient, metalꢀfree and efficient method
for the synthesis of transꢀstilbenes has been developed by the
cross coupling of easily accessible βꢀnitrostyrenes and benzoyl
peroxide. The protocol describes the firstꢀtime free radical
reaction of βꢀnitrostyrenes without using a catalyst.
3
2
786; (b) C. Pan, Y. Fu, Q. Ni and J.ꢀT. Yu, J. Org, Chem.,
017, 82, 5005; (c) J.ꢀJ. Cao, T.ꢀH. Zhu, S.ꢀY. Wang, Z.ꢀY.
Gu, X. Wang and S.–J. Ji, Org. Biomol. Chem., 2017, 15,
6467.
12. (a) P. Kumar, T. Guntreddi, R. Singh and K. N. Singh, Org.
Chem. Front. 2017, 4, 147; (b) R. Vanjari, T. Guntreddi and
K. N. Singh, Chem. Asian J., 2016, 11, 696; (c) R. Singh, B.
K. Allam, N. Singh, K. Kumari, S. K. Singh and K. N. Singh,
Org. Lett., 2015, 17, 2656; (d) T. Guntreddi, R. Vanjari and K.
N. Singh, Org. Lett., 2014, 16, 3624; (e) T. Guntreddi, R.
Vanjari and K. N. Singh, Org. Lett., 2015, 17, 976; (f) R.
Vanjari, T. Guntreddi and K. N. Singh, Org. Lett., 2013, 15,
Acknowledgment
We are thankful to SERB, New Delhi for the National Post
Doctorate Fellowship (File No. PDF/2016ꢀ003325) to Dr. A. K.
Yadav, and for the finantial support (File No.
EMR/2016/000750).
4
908; (g) R. Singh, D. S. Raghuvanshi and K. N. Singh, Org.
Notes and references
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D. S. Yadav, Chem. Commun., 2013, 49, 2154; (i) A. K.
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1
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Table of Contents Entry:
Metalꢀfree denitrative arylation of βꢀnitrostyrenes using benzoyl peroxide: an
easy access to transꢀstilbenes
Arvind Kumar Yadav and Krishna Nand Singh*
A novel, efficient and stereoselective synthesis of transꢀstilbenes has been achieved from βꢀnitrostyrenes
and benzoyl peroxide without using any catalyst.
Catalyst
O
R'
R'
NO
+ 1/2 R'
2
O
O
R
R
o
CH CN, 100 C, 2-4 h
O
3
20 examples
up to 94% yield
R = H, p-Me, o/p-OMe, o/m/p-Cl, o/m-Br, o/p-F, o/m/p-NO
R' = H, p/m-Me, p-OMe, p-Cl
2