Facile and highly chemoselective synthesis of benzil derivatives via oxidation of stilbenes in an I2-H2O system

Article abstract of DOI:10.1039/c3ra41489b

A facile and highly chemoselective protocol for the synthesis of benzil derivatives has been developed by oxidation of stilbenes in an I ₂-H₂O system under air. Notably, the method was applicable to 26 examples and provided up to 98% yield, avoiding the use of acid, metal catalysts and so on.

Full text of DOI:10.1039/c3ra41489b

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Facile and highly chemoselective synthesis of benzil
derivatives via oxidation of stilbenes in an I2–H2O
system3
Cite this: RSC Advances, 2013, 3, 9666
Received 27th March 2013,
Accepted 29th April 2013
Xianghua Zeng,ab Chengxia Miao,a Shoufeng Wang,a Chungu Xiaa and Wei Sun*a
DOI: 10.1039/c3ra41489b
www.rsc.org/advances
A facile and highly chemoselective protocol for the synthesis of
benzil derivatives has been developed by oxidation of stilbenes in
an I2–H2O system under air. Notably, the method was applicable
to 26 examples and provided up to 98% yield, avoiding the use of
acid, metal catalysts and so on.
chemoselective, metal-free and cleaner method toward the
oxidation of stilbenes to benzil derivatives is highly desirable.
The two key principles of Green Chemistry are the elimination
of solvents in chemical processes or the replacement of hazardous
solvents with environmentally friendly ones, and the replacement
of metals with organic catalysts.12 As we all know, water is the
most economical and eco-friendly media in the world,13 and the
wide use of benzils in many fields has stimulated much interest in
the development of new methods for their synthesis in water. On
the other hand, molecular iodine has been found to be an efficient
oxidizing reagent for both the oxidation of alkenes to diols and
alcohols to aldehydes or ketones in water.14–16 In our continuing
effort towards the transformation of alkenes,17 we herein wished
to develop a facile and highly chemoselective system including I2–
H2O to oxidize stilbenes to benzils without the addition of any acid
or metal under air.
Firstly, trans-stilbene (1a) was chosen as the model substrate to
test the protocol and screen the reaction conditions by employing
the iodine–water system under air. To our delight, only 2a as the
oxidation product was formed in 4% yield, and no other by-
product was detected in the presence of 0.1 equiv. iodine at 105 uC
using water as the solvent (Table 1, entry 1). However, still only 5%
of 2a was obtained when the temperature was elevated to 130 uC
(entry 2). Interestingly, 2a was obtained in 41% yield by increasing
the amount of iodine to one equivalent with respect to the
substrate (entry 3). Encouraged by this result, we next focused our
attention on the investigation of the influences of temperature and
the loading of iodine on the reaction. It was found that just two
equivalents of iodine are sufficient to give a yield of 96% of the
benzyl product 2a at 140 uC for 20 h under air (entry 5). The yield
decreased to 85% when the oil bath temperature was lowered to
130 uC (entry 4). Besides, we also attempted to use catalytic
amounts of I2 in the presence of 2.0 equiv. H2O2 or 1 atm of
oxygen to achieve the synthesis of the benzils. Unfortunately, only
trace amounts or 5% of 2a were obtained (entries 6 and 7).
Furthermore, the reactions were performed using different
oxidants, such as NaIO4, Br2 and NaClO, where no reaction
occurred under the same conditions based on GC-MS analysis
(entries 8–10). Additionally, 2a was obtained in 20% yield using
Benzil derivatives are important building blocks of many
biologically active compounds or chemical intermediates.1
A
typical method for the preparation of benzil derivatives is the
oxidation of substituted alkynes. Various catalytic systems have
been built in previous years, mainly containing transition metals,
such as Cu,2 Pd,3 Au/Ag,4 Ru5 and Mn6 in combination with
oxidants. However, alkenes are cheaper and more easily available
than alkynes. Alternatively, the oxidation of stilbenes provides a
simple and efficient route to benzil derivatives in both academia
and industry. Initially, stoichiometric amounts of oxidizing
reagents such as KMnO4 and SeO2 with some acids were usually
used and easily led to the cleavage of the C–C bond.7 As early as
1991, Filimonov et al. reported using dimethyl sulfoxide–hydro-
bromic acid or dimethyl sulfoxide–iodine as novel systems for the
oxidation of alkynes and alkenes to benzils.8 Recently, several Ru-
catalyzed systems successfully mediated the functionalization of
alkenes to a-diketones using TBHP or NaIO4 as the oxidant.9
Besides, Bielawski reported the oxidation of cis-stilbene to benzil
using graphene oxide as the catalyst with an isolated yield of
49%,10 and Yoshida et al. used an integrated electrochemical–
chemical method to oxidize alkenes in dimethyl sulfoxide with
moderate yields.11 Despite the fact that great progress has been
made in the field of alkene oxidation, these processes generally
suffer from poor chemoselectivity, the use of expensive or toxic
metals, or the use of toxic solvents. Therefore, developing a highly
aState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, China.
E-mail: wsun@licp.cas.cn
bGraduate School of the Chinese Academy of Sciences, Beijing, 100039, China
Electronic supplementary information (ESI) available: Experimental procedures,
3
supporting table, scheme and figures, characterization data, and copies of the 1H
NMR and 13C NMR spectra for the products. See DOI: 10.1039/c3ra41489b
9666 | RSC Adv., 2013, 3, 9666–9669
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Table 1 Optimization of the reaction conditions for the oxidation of 1,2-
diphenylethene to benzila
Table 2 Oxidation of stilbenes in an I2–H2O systema
Entry
Substrate
Product
Yield (%)b
Entry
Additive (equiv.)
T/uCb
Yield (%)c
1
2
3
4
5
6
7
8
1a, R1 = H, R2 = H
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
96
94
97
1b, R1 = p-Me, R2 = H
1c, R1 = m-Me, R2 = H
1d, R1 = o-Me, R2 = H
1e, R1 = p-O-Me, R2 = H
1f, R1 = p-Cl, R2 = H
1g, R1 = m-Cl, R2 = H
1h, R1 = o-Cl, R2 = H
1i, R1 = p-Br, R2 = H
1j, R1 = m-Br, R2 = H
1k, R1 = o-Br, R2 = H
1l, R1 = 2,4-Cl, R2 = H
1m, R1 = 2,6-Cl, R2 = H
1n, R1 = 1-Nap, R2 = H
1o, R1 = p-F, R2 = H
1
2
3
4
5
6
7
8
I2 (0.1)
I2 (0.1)
I2 (1.0)
I2 (2.0)
105
130
130
130
140
140
140
140
140
140
140
140
140
140
140
4
5
41
85
97
56c
98
I2 (2.0)
96
96
91
89
92
I2 (0.1)–H2O2 (5.0)
I2 (0.1)–O2 (1 atm)
NaIO4 (2.0)
Br2 (2.0)
NaClO (2.0)
HI (2.0)–H2O2 (2.0)
I2 (2.0)
I2 (3.0)
I2 (0.1)
I2 (2.0)
trace
5
9
NRd
NRd
NRd
20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
9
88
10e
11f
12g
13g
14h
15i
78 (90)d
51 (78)d
90
79
93
trace
81
98
91
96
96
1p, R1 = p-CF3, R2 = H
1q, R1 = p-Cl, R2 = p-Me
1r, R1 = p-Cl, R2 = m-Me
1s, R1 = p-Cl, R2 = o-Me
1t, R1 = p-Cl, R2 = p-F
1u, R1 = p-Cl, R2 = p-Br
1v, R1 = p-Cl, R2 = m-Cl
1w, R1 = p-Cl, R2 = o-CF3
a
Reaction conditions: 1a (0.2 mmol), additive and H2O (1.0 mL)
2s
2t
2u
2v
2w
95
were stirred in a sealed tube at the given temperature for 20 h under
aerobic conditions. Oil bath temperature. Isolated yield. NR =
93
b
c
d
49 (78)d
97
e
f
no reaction. NaClO (aq., 9%). HI (aq., 48%), H2O2 (aq., 50%).
g
h
The reactions were carried out in an argon atmosphere. The
45 (81)d
i
reactions were carried out in an oxygen atmosphere (25 atm). The
reaction was carried out with 1a (10.0 mmol), I2 (21.0 mmol) and
H2O/MeCN (10 mL/0.5 mL) for 20 h.
HI–H2O2 (2.0 equiv. each) instead of (2.0 equiv.) iodine (entry 11).
To check the scalability of the present method, even a gram-scale
reaction proceeded well, giving the desired benzil in 81% yield
under the optimized conditions (entry 15).
24
25
26
1x, R1 = H, R2 = p-Me
1y, R1 = H, R2 = p-Cl
1z, R1 = H, R2 = p-F
2b
2f
2o
95
96
96
a
Unless otherwise noted, all reactions were conducted with 1 (0.2
mmol), I2 (0.4 mmol), MeCN (25 mL) and H2O (1.0 mL) at 140 uC (oil
Afterwards, a broad range of substituted stilbenes was
examined in order to assess the applicability and scope of the
system, and the results are summarized in Table 2. Fortunately, it
was found that the electronic properties, the steric hindrance of
the substituents on the benzene rings and use of the cis- or trans-
isomer have no significant influence on the reactivity. Obviously,
almost all substituted trans-stilbenes were converted to their
corresponding benzil derivatives in high yields (88–98%, 2a–d, 2f–
k, 2n–t, 2v, Table 2). However, the methoxy-substituted substrate
(1e) gave only 56% yield due to its decomposition under the
reaction conditions (entry 5). Besides, a series of trans-stilbenes
such as 2l–m, 2t and 3w could be obtained in high yields after
prolonging the reaction time (entries 12, 13, 21 and 23). On the
other hand, the cis-stilbenes could be smoothly transformed into
the desired benzil products in excellent yields under the optimal
reaction conditions (95–96%, entries 24–26).
b
bath temperature) for 20 h under air in a sealed tube. Isolated
c
yield. The substrate decomposes under the reaction conditions.
d
The reaction time was 36 h.
good yields in the I –H O system (92–95%, Table S1, ESI , entries
6–7).
3
2
2
Meanwhile, several control experiments were performed in an
attempt to investigate the reaction mechanism. Initially, 1,2-
diiodo-1,2-diphenylethane was thought to be the intermediate
resulting from the addition of iodine to 1,2-diphenylethene in the
I2–H2O system. Accordingly, a series of methods were used for the
synthesis of 1,2-diiodo-1,2-diphenylethane. However, this was not
successful, possibly due to its instability. As mentioned before,
Filimonov et al. reported that 1,2-dibromo-1,2-diphenylethane or
1,2-diphenylethane-1,2-diol can be oxidized to benzil in a DMSO–
HBr system at 100–120 uC.8a Hence, we carried out the oxidation of
1,2-dibromo-1,2-diphenylethane or 1,2-diphenylethane-1,2-diol
instead of 1,2-diiodo-1,2-diphenylethane in the I2–H2O system.
Interestingly, the reactions proceeded well, and high yields were
Internal alkenes substituted with aliphatic groups or hetero-
aromatic rings did not convert well under these reaction
conditions (Table S1, ESI , entries 1–4). Furthermore, alkenes
3
which were tri-substituted at the CLC bond were found to be inert
(Table S1, ESI , entry 5). Gratifyingly, alkynes performed well with
3
obtained (Scheme 1, I and II-2). In addition, Fig. S5, ESI indicates
3
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Scheme 2 The proposed mechanism for the oxidation of stilbenes in an I2–H2O
system under aerobic conditions.
products, based on the GC-MS spectra (Scheme 1, IV, Scheme S1,
ESI and Fig. S1 and S2 in ESI ). Besides, whether ketones
3
3
exchanged their oxygen atom with water under optimized reaction
conditions was also tested by 18O isotopic labelling experiments
(Scheme S2, ESI and Fig. S3 and S4 in ESI ).
3
3
Conclusion
Scheme 1 Study of the reaction mechanism.
In conclusion, an acid- and metal-free system including molecular
iodine and water was developed toward the oxidation of stilbenes
to benzil derivatives in air. This novel system exhibited high
that two equivalents of iodine are necessary for a complete
transformation under air. Furthermore, the oxidation of 1,2-
diphenylethene also worked well with 2.0 equiv. of NIS instead of 2
equiv. of I2 (Scheme 1, III). Accordingly, we propose that the
formation of an iodonium ion may be the first and also the rate-
determining step of the reaction (Table 1, entry 5 vs. Scheme 1, II-
1).16 Besides, just 79% of 2a was afforded from 1a when the
reactions were performed under degassed and strictly oxygen-free
conditions (Table 1, entry 12). The result indicates that molecular
oxygen participates in the reaction. However, the reaction did not
proceed well using a catalytic amount of I2 and large amounts of
O2 (Table 1, entry 14). Based on the above results, molecular
iodine is most likely to be the true oxidant. Some of the molecular
iodine may be generated through the oxidation of HI by oxygen,
and this oxidation would occur when the concentration of HI is
relatively high, which is further indicated by a 93% benzil yield
when employing 3 equiv. of I2 under oxygen-free conditions
(Table 1, entry 13). Scheme 2 shows a simplified proposed
sequence of events beginning with the generation of an iodonium
ion A. The second step of the reaction is the attack of water at the
equivalent carbon of the iodonium ion A, resulting in the ring-
opened product B. Tentatively, benzil derivatives could be directly
derived from the oxidation of B with iodine in water under air; on
the other hand, the subsequent replacement reaction could be
easily achieved by the attack of water to provide the corresponding
diol C according to the previous report.18 Then, the desired
product could also be generated from C by reaction with I2–H2O–
O2 (Scheme 2). Isotopic labelling experiments further revealed that
water also participates in the transformation of stilbenes to
benzils. When the oxidation reaction was performed in the
presence of 97% H218O, 18O labelled benzils were the main
chemoselectivity and
a broad substrate scope, and benzil
derivatives could be provided in up to 98% yield. Besides, a
reaction mechanism involving an iodonium ion as the inter-
mediate was proposed. Isotopic labelling experiments provided
evidence that the oxygen atom of the benzils could derive from
water, and a control experiment indicated that oxygen from the air
participated in the reaction process. The further application of this
methodology to other reactions is now in progress in our
laboratory.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21133011 and 21103207).
Notes and references
1 For selected examples, see: (a) K. Murata, K. Okano, M. Miyagi,
H. Iwane, R. Noyori and T. Ikariya, Org. Lett., 1999, 1, 1119; (b)
D. H. Slee, S. J. Romano, J. Yu, T. N. Nguyen, J. K. John, N.
K. Raheja, F. U. Axe, T. K. Jones and W. C. Ripka, J. Med. Chem.,
2001, 44, 2094; (c) V. Nair, A. N. Pillai, R. S. Menon and
E. Suresh, Org. Lett., 2005, 7, 1189; (d) V. Nair, A. T. Biju, K.
G. Abhilash, R. S. Menon and E. Suresh, Org. Lett., 2005, 7,
2121; (e) M. K. Skjel, A. Y. Houghton, A. E. Kirby, D. J. Harrison,
R. McDonald and L. Rosenberg, Org. Lett., 2010, 12, 4376; (f)
X. Feng, Y. Nie, J. Yang and H. Du, Org. Lett., 2010, 12, 376.
2 C. Zhang and N. Jiao, J. Am. Chem. Soc., 2010, 132, 28.
3 (a) S. Chen, Z. Liu, E. Shi, L. Chen, W. Wei, H. Li, Y. Cheng and
X. Wan, Org. Lett., 2009, 11, 1841; (b) S. Mori, M. Takubo,
9668 | RSC Adv., 2013, 3, 9666–9669
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T. Yanase, T. Maegawa, Y. Monguchi and H. Sajikia, Adv. Synth.
Catal., 2010, 352, 1630.
4 C.-F. Xu, M. Xu, Y.-X. Jia and C.-Y. Li, Org. Lett., 2011, 13, 1556.
5 W. Ren, J. Liu, L. Chen and X. Wan, Adv. Synth. Catal., 2010,
352, 1424.
6 S. Trosien and S. R. Waldvogel, Org. Lett., 2012, 14, 2976.
7 (a) M. S. Yusubov, V. D. Filimonov and V. D. Ogorodnikov, Bull.
Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.), 1991, 10, 766; (b)
G. L. Southard, B. R. Zaborowsky and J. M. Pettee, J. Am. Chem.
Soc., 1971, 93, 3303.
8 M. S. Yusybov and V. D. Filimonov, Synthesis, 1991, 131.
9 (a) F. A. Khan, B. Prabhudas, J. Dash and N. Sahu, J. Am. Chem.
Soc., 2000, 122, 9558; (b) S. Chen, Z. Liu, F. Shi, L. Chen,
W. Wei, H. Li, Y. Cheng and X. Wan, Org. Lett., 2011, 13, 2274;
(c) X. Liu and W. Chen, Organometallics, 2012, 31, 6614.
10 D. R. Dreyer, H.-P. Jia and C. W. Bielawski, Angew. Chem., Int.
Ed., 2010, 49, 6813.
M. Fitzpatrick, T. R. Farren and P. T. Anastas, Science, 2002,
297, 807; (f) C.-J. Li, Chem. Rev., 2005, 105, 3095; (g) D.
G. Blackmond, A. Armstrong, V. Coombe and A. Wells, Angew.
Chem., Int. Ed., 2007, 46, 3798; (h) S. Minakata and M. Komatsu,
Chem. Rev., 2008, 108, 825; (i) C. I. Herrerias, X. Yao, Z. Li and
C.-J. Li, Chem. Rev., 2007, 107, 2546; (j) R. A. Sheldon, Green
Chem., 2005, 7, 267; (k) A. Chanda and V. V. Fokin, Chem. Rev.,
2009, 109, 725; (l) R. N. Butler and A. G. Coyne, Chem. Rev.,
2010, 110, 6302.
14 L. Cao, J. Ding, M. Gao, Z. Wang, J. Li and A. Wu, Org. Lett.,
2009, 11, 3810.
15 P. Gogoi and D. Konwar, Org. Biomol. Chem., 2005, 3, 3473.
16 R. B. Woodward and F. V. Brutche, J. Am. Chem. Soc., 1958, 80,
209.
17 (a) M. Wu, B. Wang, S.-F. Wang, C.-G. Xia and W. Sun, Org.
Lett., 2009, 11, 3622; (b) M. Wu, C.-X. Miao, S.-F. Wang, X.-
X. Hu, C.-G. Xia, F. E. Ku¨hn and W. Sun, Adv. Synth. Catal.,
2011, 353, 3014; (c) B. Wang, C.-X. Miao, S.-F. Wang, C.-G. Xia
and W. Sun, Chem.–Eur. J., 2012, 18, 6750; (d) B. Wang, S.-
F. Wang, C.-G. Xia and W. Sun, Chem.–Eur. J., 2012, 18, 7332; (e)
X. H. Zeng, C. X. Miao, S. F. Wang, C. G. Xia and W. Sun, Chem.
Commun., 2013, 49, 2418.
11 Y. Ashikari, T. Nokami and J. Yoshida, J. Am. Chem. Soc., 2011,
133, 11840.
12 (a) P. T. Anastas and J. C. Warner, Green Chemistry: Theory and
´
Practice, Oxford University Press, Oxford, 1998; (b) I. T. Horvath,
Green Chem., 2008, 10, 1024.
13 (a) U. M. Lindstrcm, Chem. Rev., 2002, 102, 2751; (b)
S. Kobayahi and K. Manabe, Acc. Chem. Res., 2002, 35, 209;
(c) N. Akiya and P. E. Savage, Chem. Rev., 2002, 102, 2725; (d) J.
M. DeSimone, Science, 2002, 297, 799; (e) M. Poliakoff, J.
18 (a) S. von Angerer, E. von Angerer, R. Ambros and W. Wiegrebe,
Arch. Pharm., 1992, 325, 425; (b) I. A. R. Derrick, M. Iqbal,
R. Livingstone and B. J. McGreevy, J. Chem. Res., 1999, 9, 2308.
This journal is ß The Royal Society of Chemistry 2013
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