One-pot synthesis of unsymmetrical benzils from aryl methyl ketones and arenes in the presence of selenous acid catalysed by p-toluenesulfonic acid monohydrate

Article abstract of DOI:10.1016/j.tetlet.2012.03.113

A modified one-pot method for the synthesis of unsymmetrical and heteroaryl benzils from substituted acetophenones and unactivated or weakly activated arenes by the use of H₂SeO₃ and p-TsOH·H ₂O as catalysts at 35°C is established. The present method is regioselective and avoids the use of p-TsOH·H₂O in stoichiometric amount in the presence of H₂SeO₃ and afforded unsymmetrical benzils in good yields.

Full text of DOI:10.1016/j.tetlet.2012.03.113

Tetrahedron Letters 53 (2012) 2837–2841
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Tetrahedron Letters
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One-pot synthesis of unsymmetrical benzils from aryl methyl ketones
and arenes in the presence of selenous acid catalysed by p-toluenesulfonic
acid monohydrate
⇑
Icydora Kharkongor, Md. Rumum Rohman, Bekington Myrboh
Department of Chemistry, North-Eastern Hill University, Shillong 793022, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A modified one-pot method for the synthesis of unsymmetrical and heteroaryl benzils from substituted
acetophenones and unactivated or weakly activated arenes by the use of H2SeO3 and p-TsOHꢀH2O as cat-
alysts at 35 °C is established. The present method is regioselective and avoids the use of p-TsOHꢀH2O in
stoichiometric amount in the presence of H2SeO3 and afforded unsymmetrical benzils in good yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 12 December 2011
Revised 27 March 2012
Accepted 28 March 2012
Available online 1 April 2012
Keywords:
Unsymmetrical benzils
Selenous acid
p-TsOHꢀH2O catalyst
The versatility of benzils as organic intermediates is well known
as is evidenced by their practical applications, that is as starting
materials for the synthesis of heterocycles,1 and as photosensitive
agents.2 They also exhibit potential for various biological activities
like inhibition of mammalian carboxylesterases (CE).3 The last two
decades have seen a lot of efforts directed towards the synthesis of
both symmetrical and unsymmetrical benzils.4,5 The preparation of
these 1,2-diketo compounds has been accomplished by several
methods such as oxidation of olefins with selenium dioxide,6,7 or
of H2SeO3, catalysed by p-TsOHꢀH2O. It may be noted that contrary
to the usual pathway where the aryl methyl ketones are oxidized
by SeO2 to glyoxals17,19 and the reported intramolecular condensa-
tion of 2-([1,10-biphenyl]-2-yl)-2-oxoacetaldehyde to give phenan-
threnequinone,20 we wish to report here a modified one-pot
synthesis of unsymmetrical benzils by the oxidative coupling
between aryl/heteroaryl methyl ketones and unactivated arenes
in the presence of H2SeO3 and p-TsOHꢀH2O as catalysts at 35 °C
(Scheme 1).
In the initial reaction, when acetophenone (1a) (1.0 mmol) in
the presence of H2SeO3 (2.00 mmol), and p-TsOHꢀH2O (10 mol %)
in dry benzene (5 mL) was heated at 80 °C for 24 h, the product
(3a) was obtained in 30% yield. However, after optimization, the
same reaction in the presence of 30 mol % of the catalyst proceeded
to afford 3a in 65% within 14 h (Table 1, entry 1). During optimiza-
tion it was observed that the use of 1 and 1.5 equiv of H2SeO3
resulted in the low yields of the product in each case. Evidently
H2SeO3 is required in both the oxidation step where the ketone
potassium permanganate,8,9
a
-hydroxyketones by atmospheric
oxygen,10,11 acetylenes with potassium permanganate,12 methy-
lene ketones by selenium dioxide,13,14 bismuth nitrate–copper(II)
acetate,15 or oxygen in the presence of Fe(III)–EDTA.16 Although,
the reported methods are quite effective, they are often limited
to the synthesis of symmetrical benzils in most of the cases with
the exception of a few where the preparation of unsymmetrical
benzils also requires the use of expensive starting materials.
Based on our earlier work17 and the ongoing study on the
synthetic application of SeO2 for C–C bond formation,18 we have
further established a modified method for the synthesis of benzils
by using selenous acid (H2SeO3) and catalytic amount of p-toluene-
sulfonic acid monohydrate (p-TsOHꢀH2O), in contrast to the previ-
ous method where equivalent amount of p-TsOHꢀH2O is required.
The present methodology thus describes the oxidative coupling
involving the use of substituted acetophenones and unactivated
or weakly activated arenes as the starting materials in the presence
H2SeO3
O
O
p-TsOH.H2O (30 mol%)
Ar'
H Ar'
Het/Ar
Het/Ar
CH3CN, 35 °C
O
1
2
3
Ar = aryl, Het = heteroaryl; Ar' = benzene, toluene, xylene,
anisole, naphthalene, anthracene
⇑
Corresponding author. Tel.: +91 364 272 2612; fax: +91 364 255 0076.
E-mail address: bmyrboh@nehu.ac.in (B. Myrboh).
Scheme 1. Synthesis of unsymmetrical benzils.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.113

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I. Kharkongor et al. / Tetrahedron Letters 53 (2012) 2837–2841
Table 1
One-pot synthesis of unsymmetrical benzils (3) via Scheme 1
Entry
Substrate 1 (Ar/Het)
Substrate 2 (Ar0)
Time (h)
14
Productb,c
3
Yielda (%)
O
1
C6H5 (1a)
C6H5 (2a)
65
O
(3a)c
O
2
3
4-BrC6H4 (1b)
2a
14
14
63
60
O
Br
(3b)c
O
1b
CH3C6H4 (2b)
O
(3c)c
Br
O
O2N
4
3-NO2C6H4 (1c)
1,2-(CH3)2C6H3 (2c)
14
65
O
(3d)c
O
5
6
7
4-NO2C6H4 (1d)
3-NHCOCH3C6H4 (1e)
1d
2b
14
14
12
68
70
70
O
O2N
(3e)c
O
O
H
N
CH3OC6H4 (2d)
1-Naphthyl (2e)
O
O
(3f)c
O
O
O2N
(3g)c
O
8
9
2,4-(CH3)2C6H3 (1f)
3-CH3OC6H4 (1g)
2-OHC6H4 (1h)
1e
2e
2e
2e
2e
12
12
12
12
62
65
69
75
O
(3h)c
O
H3CO
OH
O
(3i)c
O
10
11
O
(3j)c
O
H
N
O
O
(3k)c

I. Kharkongor et al. / Tetrahedron Letters 53 (2012) 2837–2841
2839
Table 1 (continued)
Entry
Substrate 1 (Ar/Het)
2-Furanyl (1i)
Substrate 2 (Ar0)
Time (h)
12
Productb,c
3
Yielda (%)
O
12
13
14
2e
57
61
65
O
O
(3l)c
O
5-Methyl-2-furanyl (1j)
2-Thiophenyl (1k)
2e
2e
12
12
O
O
S
(3m)
O
O
c
(3n)
Cl
O
15
16
17
2-ClC6H4 (1l)
9-Anthracenyl (2f)
13
13
13
63
64
56
O
(3o)c
O
1c
2f
2f
O2N
O
(3p)c
O
2,4,6-(CH3)3C6H2 (1m)
O
(3q)c
O
18
19
4-OHC6H4 (1n)
2f
2f
13
13
54
56
O
(3r)c
HO
O
1j
O
O
(3s)
O
20
21
1k
2f
13
12
58
70
S
O
(3t)c
O
2-Naphthyl (1o)
2e
O
(3u)c
a
Isolated yields.
b
Products were fully characterized by recording their 1H, 13C NMR, IR spectral and elemental analyses and comparing with the authentic samples.
Literature Ref. 17.
c

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I. Kharkongor et al. / Tetrahedron Letters 53 (2012) 2837–2841
It is important to highlight that the use of H2SeO3 and catalytic
R'
O
O
H
amounts of p-TsOHꢀH2O offered a cleaner reaction with perceptible
increase in the yield of the products especially in the case of 3l, 3n
and 3t where, the isolated yields range between 57%, 65% and 58%,
respectively, which is a significant improvement from the earlier
procedure (Table 1, entries 12, 14 and 20).17 The present method
also allows for the regioselective formation of the products 3c–f
and also afforded the unsymmetrical benzils substituted at C1
and C9 for the reaction of 2e–f as shown in Table 1.
The initial conversion of the aryl methyl ketone 1 to glyoxals
(4)17,19 by H2SeO3 and the acid catalysed formation of the O–Se
bond through carbonyl oxygen of the aldehydic group in the pres-
ence of p-TsOHꢀH2O generate a strong electrophilic centre at the
aldehydic carbon of 5 (path a). The attack of the electron rich arenes
2 to the electrophilic centre presumably resulted in the formation
of the selenium intermediate (6). Finally, oxidative decomposition
of the selenium intermediate (Scheme 2) led to the formation of
unsymmetrical benzils (3). Alternatively, the glyoxal (4) may un-
dergo acid (H+) catalysed Friedel Craft reaction with arenes to give
the intermediate 6 as shown in Scheme 2 (path b).
In summary, we have developed a modified one-pot method for
the preparation of unsymmetrical and heteroaryl 1,2-diketones
from substituted acetophenones and unactivated or weakly acti-
vated arenes by the use of H2SeO3 catalysed by p-TsOHꢀH2O. The
present oxidative coupling process avoids the use of p-TsOHꢀH2O
in stoichiometric amount in the presence of H2SeO3 and in many
instances gave better yields of the products. The method is general,
regioselective and provides an important alternative for the syn-
thesis of unsymmetrical benzils.
R'
HO
O
OH
O
2
R
R
Se
H
OH
OH
7
8
Path-b
H
H
R'
O
O
Se
O
H
O
R'
O
HO
OH
2
R
R
R
OH
H
O
Path-a
OH
Se
4
OH
OH
5
6
Se
OH
OH
H2SeO3,
p-TsOH.H2O
H
1
3
Scheme 2. Plausible mechanism.
is oxidized to the glyoxal and the subsequent arylation step. It was
also observed that the use of anhydrous p-TsOH resulted in low
yields of the product besides the increase in reaction time. This
observation indicates that the presence of water may be necessary
to promote the reaction.
Similarly the substrate 1b furnished the product 3b in 63% with
H2SeO3 (2 equiv), and p-TsOHꢀH2O (30 mol %) at 80 °C (Table 1, en-
try 2).
In another trial the reaction of 1b with toluene (2b) afforded the
product 3c in 60% within 14 h at 35 °C without the need to raise
the temperature. The methodology was then extended to the reac-
tion of 1c and 1d with the weakly activated arenes 2b and 2c and
in both cases the substituted acetophenones reacted cleanly with
the arenes 2b and 2c at 35 °C to give the desired benzils (3c–d)
in good yields (Table 1, entries 4 and 5). Notably substituted ace-
tophenones bearing N-acetyl groups such as 1e also undergo the
same coupling reaction with stoichiometric amount of anisole
(2d) in acetonitrile at 35 °C (Table 1, entry 6).
Encouraged by these results the broad scope and limitation of
the methodology were studied by the reaction of various substi-
tuted acetophenones with polynuclear hydrocarbons such as naph-
thalene (2e) and anthracene (2f). Irrespective of the presence of
electron withdrawing or donating groups such as chloro, nitro,
methyl, methoxy and hydroxy on the ortho, meta or para-positions,
the aryl methyl ketones 1c–h and 1l–n reacted smoothly with stoi-
chiometric amount of polynuclear hydrocarbons 2e–f in the pres-
ence of H2SeO3 (2 equiv) and p-TsOHꢀH2O (30 mol %) in
acetonitrile at 35 °C (Table 1, entries 7–10 and 15–18) in consis-
tently good yields. Furthermore, the substituted acetophenone 1e
also reacted smoothly with 2e under the experimental condition
Acknowledgments
I.K. thanks the University Grants Commission (UGC) for Rajiv
Gandhi National Fellowship (RGNF) and Sophisticated Analytical
Instrument Facility (SAIF), North-Eastern Hill University for NMR
and mass spectral analysis and acknowledges the UGC for financial
assistance vide Project F. No. 40-83/2011(SR).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
03.113.
References and notes
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4. For the synthesis of symmetrical benzils, see: (a) Schraufstatter, E. Chem. Ber.
1948, 239; (b) VanAllan, J. A. J. Org. Chem. 1958, 23, 1682; (c) Mohr, B.;
Enkelmann, V.; Wegner, G. J. Org. Chem. 1994, 59, 638; (d) Nudelman, N.;
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Chung, S. K. Bull. Korean Chem. Soc. 2003, 24, 231; (f) Yasuike, S.; Kishi, Y.;
Kawara, S.-i.; Kurita, J. Chem. Pharm. Bull. 2005, 53, 427.
5. For the synthesis of unsymmetrical benzils, see: (a) Suginome, H. J. Org. Chem.
1958, 23, 1046; (b) Yusubov, M. S.; Zholobova, G. A.; Vasilevsky, S. F.;
Tretyakov, E. V.; Knight, D. W. Tetrahedron 2002, 58, 1610; (c) Katritzky, A. R.;
Zhang, D.; Kirichenko, K. J. Org. Chem. 2005, 70, 3274.
21
to give benzil 3k in 75% yield in 12 h.
The present method was further extended to the reaction of
heteroaryl or fused aromatic methyl ketones with 2e and 2f. The
same reaction trend was observed for the oxidative coupling of
1-(2-furanyl)ethanone (1i), 5-methyl-(2-furanyl)ethanone (1j),
1-(2-thiophenyl)ethanone (1k) and 1-(2-naphthyl)ethanone (1o)
with 2e and 2f to give the corresponding 1,2-diketone in 56–70%
yields (Table 1, entries 12–14 and 19–21)21. Notably, the reaction
goes to completion in each case as the starting ketone is com-
pletely consumed. Besides the isolated product, no other products
could be isolated except for several minor impurities which were
not further identified. However, the nitrogen containing aromatic
methyl ketones, for example, pyran and pyrrole, and the haloge-
nated arenes do not give the desired results. All the unsymmetrical
benzils synthesized were fully characterized by 1H, 13C NMR, IR
spectral and elemental analyses and by comparison with authentic
samples.17,22
6. Fitzi, K. Ger. Patent 2,221,546, 1972; U.S. Patent 3,929,807, 1975; Chem. Abstr.
1973, 78, 58428.
7. Buehler, C. A.; Harris, J. O.; Arendale, W. F. J. Am. Chem. Soc. 1950, 72, 4953.
8. Kozlov, N. S.; Shmanal, G. S. Chem. Heterocycl. Compd. (Engl. Transl.) 1974, 974.

I. Kharkongor et al. / Tetrahedron Letters 53 (2012) 2837–2841
2841
9. Barta, T. E.; Stealey, M. A.; Collins, P. W.; Weier, R. M. Bioorg. Med. Chem. Lett.
1998, 8, 3443.
10. Cremlyn, R. J.; Lynch, J. M.; Swinbourne, F. J. Phosphorus Sulfur 1991, 57, 173.
11. (a) Fischer, E. Justus Liebigs Ann. Chem. 1882, 211, 214; (b) Buehler, C. A.; Harris,
J. O. J. Am. Chem. Soc. 1950, 72, 5015; (c) Katritzky, A. R.; Lang, H.; Wang, Z.;
Zhang, Z.; Song, H. J. Org. Chem. 1995, 60, 7619.
washed with saturated aqueous sodium bicarbonate solution followed by
water (10 mL) and brine (10 mL). The organic layer was separated, dried over
anhydrous sodium sulphate (Na2SO4) and concentrated under reduced
pressure. The crude mass was purified by column chromatography on silica
gel (100–200 mesh) using ethyl acetate and hexane as eluent to give the
benzyls in pure form.
12. Walsh, C. J.; Mandal, B. K. J. Org. Chem. 1999, 64, 6105.
In case of arene 2a (5 mL) the reaction was carried out at 80 °C and for the
13. Chang, L. L.; Sidler, K. L.; Cascieri, M. A.; de Laszlo, S.; Koch, G.; Li, B.; MacCoss,
M.; Mantlo, N.; O’Keefe, S.; Pang, M.; Rolando, A.; Hagmann, W. K. Bioorg. Med.
Chem. Lett. 2001, 11, 2553.
arene 2b–d (5 mL) at 35 °C without any solvent.
22. Spectroscopic data for compounds: 1-(5-methylfuran-2-yl)-2-(naphthalen-1-
yl)ethane-1,2-dione (3m): Yellow solid; mp 85–87 °C; 1H NMR (400 MHz,
CDCl3) d 9.04 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 7.2 Hz, 1H),
7.86 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.45 (t,
J = 7.6 Hz, 1H), 7.25 (d, J = 3.2 Hz, 1H), 6.20 (d, J = 3.2 Hz, 1H), 2.40 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3) d 194.5, 180.5, 161.2, 149.1, 135.7, 134.6, 134.0,
131.1, 129.2, 128.8, 127.0, 125.8, 124.5, 124.4, 110.1, 14.3 ppm; IR (KBr film)
3162, 3139, 3058, 3045, 2923, 2819, 1645, 1506, 1367, 1201, 1035 cmꢂ1; MS
14. Buehler, C. A.; Addleburg, J. W.; Glenn, D. M. J. Org. Chem. 1955, 20, 1350.
15. Tymonko, S. A.; Nattier, B. A.; Mohan, R. S. Tetrahedron Lett. 1999, 40, 7657.
16. Rao, T. V.; Dongre, R. S.; Jain, S. L.; Sain, B. Synth. Commun. 2002, 32, 2637.
17. Rohman, M. R.; Kharkongor, I.; Rajbangshi, M.; Mecadon, H.; Laloo, B. M.; Sahu,
P. R.; Kharbangar, I.; Myrboh, B. Eur. J. Org. Chem. 2012, 2012, 320.
18. Laloo, B. M.; Mecadon, H.; Rohman, M. R.; Kharbangar, I.; Kharkongor, I.;
Rajbangshi, M.; Nongkhlaw, R.; Myrboh, B. J. Org. Chem. 2012, 77, 707.
19. (a) Riley; Morley; Friend J. Chem. Soc. 1932, 1881; (b) Riley; Gray In Organic
Synthesis; John Wiley and Sons: New York, 1935; Vol. XV,
(ES+) Calcd for
17H12O3: C, 77.26; H, 4.58. Found: C, 77.38; H, 4.50.
C
16H12O3 264.1. Found m/z 287 [M+Na]+. Anal. Calcd for
C
1-(Anthracen-9-yl)-2-(5-methylfuran-2-yl)ethane-1,2-dione (3s): Yellow solid;
mp 127–129 °C; 1H NMR (400 MHz, CDCl3) d 8.54 (s, 1H), 7.99–7.97 (m, 2H),
7.87–7.84 (m, 2H), 7.65 (d, J = 3.2 Hz, 1H), 7.43–7.41 (m, 4H), 6.28 (d,
J = 3.2 Hz, 1H), 2.42 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) d 197.9, 176.8,
161.8, 148.1, 131.2, 130.9, 130.6, 129.7, 129.0, 127.6, 126.9, 125.6, 124.5,
110.5, 14.4 ppm; IR (KBr film) 3091, 3052, 3045, 2992, 2859, 1652, 1506,
1446, 1373, 1168, 1035 cmꢂ1; MS (ES+) Calcd for C21H14O3 314.1. Found m/z
337 [M+Na]+. Anal. Calcd for C21H14O3: C, 80.24; H, 4.49. Found: C, 80.36; H,
4.41.
20. Fuson, R. C.; Talbott, R. L. J. Org. Chem. 1961, 26, 2674.
21. General experimental procedure: To a pre-stirred (stirred at 23 °C for 15 min)
mixture of substituted acetophenones (1.0 mmol), arenes (1.0 mmol) and
selenous acid (2 mmol) in acetonitrile (5 mL) was added p-toluene sulfonic
acid monohydrate (p-TsOHꢀH2O) (30 mol %) at 23 °C. The reaction mixture was
allowed to stir at 35 °C for 12–14 h. On completion, the reaction mixture was
diluted with ethyl acetate and filtered through a Celite bed. The Celite bed was
washed thoroughly with ethyl acetate (3 ꢁ 5 mL). The combined filtrate was