Efficient condensation between glyoxal hydrates and sulfonium salts leading to highly functionalized 1,4-diketones

Article abstract of DOI:10.1055/s-2008-1078267

α-Alkylthio-substituted α,β-unsaturated 1,4-dicarbonyl compounds with three different functionalities are easily available through condensation of sulfonium salts and various aromatic or aliphatic glyoxal hydrates catalyzed by Na₂SeO₃ or a combination of selenium dioxide and Na₂CO₃. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078267

LETTER
2317
Efficient Condensation between Glyoxal Hydrates and Sulfonium Salts
Leading to Highly Functionalized 1,4-Diketones
S
ynthesis of Funct
i
ionalize
y
d 1,4-Diketo
u
nes n Shao, Chunbao Li*
Department of Chemistry, College of Science, Tianjin University, Tianjin, 300072, P. R. of China
Fax +86(22)27403475; E-mail: lichunbao@tju.edu.cn
Received 4 May 2008
er or lower amount of SeO2 gave lower chemical yields
(entry 10, 11, Table 1). In contrast, without SeO2 the reac-
tion was far from complete (<1% yield) even after 72
hours in the presence of 10 mol% Na2CO3 (entry 8,
Table 1). A decrease in the amount of base (Na2CO3, 5
mol%) reduced the efficiency of the reaction (entry 12,
Table 1). When phenyl glyoxal hydrate (1a) was replaced
by phenyl glyoxal, the reaction was completed within two
hours, with a decreased yield (entry 13, Table 1). When
water (1.0 equiv) was added, fair yield was obtained with
a prolonged reaction time (entries 14, Table 1). This sug-
gests that small amount of water is needed in the conden-
Abstract: a-Alkylthio-substituted a,b-unsaturated 1,4-dicarbonyl
compounds with three different functionalities are easily available
through condensation of sulfonium salts and various aromatic or al-
iphatic glyoxal hydrates catalyzed by Na2SeO3 or a combination of
selenium dioxide and Na2CO3.
Key words: alkenes, catalysis, condensation, sulfur, selenium
a-Alkylthio-substituted a,b-unsaturated 1,4-dicarbonyl
compounds are useful building blocks in the field of
chemical synthesis.1 Attractively, this trifunctional-sub-
stituted alkenes allow access to a range of potential build-
ing blocks through further selective transformations.2 For
example, such compounds have been used to synthesize
substituted furans1a,c and 1,4-dicarbonyl compounds.1b
Two other procedures are known to prepare this type of
compounds. One method based on the oxidation of ace-
tophenones using DMSO, CuO, and I2 can only lead to
symmetric diaryl 1,4-diketones.3 The other method is
photoaddition of 1,2-diketones and phenylglyoxal to al-
kylthioacetylenes, which are difficult to prepare.1c Herein,
we report a new and efficient reaction to synthesize a-
alkylthio-substituted a,b-unsaturated 1,4-dicarbonyl
compounds from sulfonium salts and various glyoxal hy-
drates catalyzed by SeO2 and Na2CO3. It is noteworthy
that Na2SeO3 or a combination of SeO2 and Na2CO3 serve
as a condensation catalyst for the first time.
Table 1 Optimization Studies for the Reaction of Phenyl Glyoxal
Hydrate (1a) with Dimethyl Phenacyl Sulfonium Bromide (2a) Cata-
9
lyzed by Bases and SeO2
O
O
S
O
Br–
OH
OH
S+
Ph
+
Ph
Ph
Ph
O
1a
2a
3a
Entry
Base
(mol%)
SeO2
(mol%) (h)
Time
Yield
(%)a
Z/Ea
1
2
Na2CO3 (10)
Cs2CO3 (10)
K2CO3 (10)
NaOH (20)
5
5
7
6
77
64
71
79
71
74
71
0
2.3:1
1.5:1
2.0:1
1.6:1
1.5:1
2.0:1
2.6:1
3
5
7
Several bases (10 mol%) were tested in the reaction of
phenyl glyoxal hydrate (1a) with dimethyl phenacyl sul-
fonium bromide (2a) in the presence of selenium dioxide
(5 mol%) in dry acetonitrile at room temperature. Strong
inorganic bases such as Na2CO3, K2CO3, Cs2CO3, and
NaOH are more reactive than weak bases such as NaOAc,
NaHCO3 (entries 1–6, Table 1). Using Na2SeO3 alone can
also catalyze the condensation reaction to produce 3a in
71% yield (entry 7, Table 1). Considering the milder con-
ditions of Na2CO3 and SeO2, we chose them as catalysts
for the condensation, although NaOH and SeO2 gave sim-
ilar yield (entry 4, Table 1).
4
4
6
5
NaOAc (10)
NaHCO3 (20)
Na2SeO3 (10)
Na2CO3 (10)
Na2CO3 (10)
Na2CO3 (10)
Na2CO3 (10)
Na2CO3 (5)
Na2CO3 (10)
Na2CO3 (10)
5
24
45
4
6b
7
5
0
8
0
72
4
9b
10
11
12
13b,c
14b,d
4
81
58
35
73
51
53
1.3:1
2.7:1
2.3:1
1.5:1
1.3:1
1.9:1
1
12
24
24
20
5
Next, the effect of the molar ratio of SeO2 to Na2CO3 on
the yield was investigated and is presented in Figure 1.
The highest yield was achieved for 4 mol% of SeO2 and
10 mol% of Na2CO3 (entry 9, Table 1). The use of a high-
4
2.5
30
5
a Yields and isomer ratios determined by HPLC.
SYNLETT 2008, No. 15, pp 2317–2320
Advanced online publication: 21.08.2008
DOI: 10.1055/s-2008-1078267; Art ID: W07308ST
© Georg Thieme Verlag Stuttgart · New York
1
5
.0
9
.2
0
0
8
b Isolated yields, and isomer ratios determined from isolated products.
c Using phenyl glyoxal instead of phenyl glyoxal hydrate (1a).
d Water (1 equiv) was added.

2318
Q. Shao, C. Li
LETTER
with the sulfonium salts to give the corresponding prod-
ucts in good yields. However, the aliphatic glyoxal hy-
drate (1e) was less reactive than the aromatic ones and
longer reaction time was needed (entry 11, Table 2), prob-
ably due to the electron-donating nature of the alkyl group
attached to the carbonyl group of the glyoxal. Double
bond and ester groups are tolerated under these conditions
(entries 3, 7, 8, 12, Table 2).
Counterions of the sulfoniums were found to have a pro-
found effect on the yields and the configurations of the
products as shown in Table 3. Sulfonium salt 2h (X = Cl)
condensed with 1a gave 3a in only 34% yield with the
worst Z/E selectivity (entry 1, Table 3). For 2i (X = I), the
yield of 3a was slightly lower (66%) than for 2a (X = Br)
and it had better Z/E selectivity (entry 3, Table 3). When
dipropyl phenacyl sulfonium bromide (2j) was treated
with 1a, (Z,E)-1,4-diphenyl-2-propylsulfanyl-but-2-ene-
1,4-dione (3m) was obtained in 81% yield (entry 4,
Table 3). For methyl propyl phenacyl sulfonium bromide
(2k), a mixture of 3a and 3m was obtained in 68% yield
(3m/3a ca. 3:1, entry 5, Table 3).
Figure 1 Yields of the reactions between 1a and 2a in the presence
of SeO2 (0–50 mol%) and Na2CO3 (10 mol%) in MeCN for 12 h
sation to generate hydroxide from Na2SeO3, and
beneficial to the catalytic reaction.
In order to expand the scope of the catalytic reaction, the
condensation between substituted sulfonium salts (2a–g,
Table 2) and substituted glyoxals (1a–f, Table 2) were
also examined using the optimized conditions. As shown
in Table 2, a variety of aromatic and heteroaromatic sub-
stituted carbonyl sulfonium salts reacted readily with 1a
in dry acetonitrile catalyzed by SeO2 and Na2CO3 to af-
ford the corresponding compound 3 in good to high yields
(entries 1–5, Table 2). Aliphatic substituted sulfonium
salts did not react with 1a to give the desired products (en-
try 6, Table 2), which is probably due to the slightly weak-
er acidity of the aliphatic substituted sulfonium salts. Both
aromatic and aliphatic glyoxal hydrates readily reacted
With cyclosulfonium salts, a similar pattern of condensa-
tion and dealkylation was followed. Dealkylation resulted
in the fission of the rings, leading to the more functional-
ized a-alkylthio-substituted a,b-unsaturated 1,4-dicarbo-
nyl compounds. Sulfonium salt 2l (X = Cl) gave 3n in
73% yield, (entry 6, Table 3). In the case of 2n (X = I), 3p
was formed in only 6% yield (entry 9, Table 3), probably
due to the ring closure of product 3p to form the polar vi-
9
Table 2 Scope of the Reaction of the Glyoxal Hydrate (1) with the Sulfonium Salt 2 Catalyzed by SeO2 and Na2CO3
O
SeO2 (4 mol%)
Na2CO3 (10 mol%)
O
S
O
Br–
OH
OH
R2
R1
S+
R1
+
R2
MeCN, r.t.
O
2
3
1
Entry
1
R1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1
R2
Ph
2
Time (h)
3
Yield (%)a Z/Eb
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
4.5
2.5
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
81
79
79
77
72
0
1.3:1
1.8:1
1.6:1
1.0:1
1.8:1
2
4-FC6H4
4-AcOC6H4
3
4
2-MeO-C6H4
2-furyl
t-Bu
15
4
5
6
40
2
7
Styryl
Ph
2g
2a
2b
2a
2a
2a
66
72
85
58
80
34
3.3:1
1.4:1
1.9:1
1.6:1
2.8:1
1.5:1
8
4-AcOC6H4
4-FC6H4
2-furyl
t-Bu
10
3
9
4-FC6H4
Ph
10
11
12
9
3j
3k
3l
Ph
30
2
Styryl
Ph
a Isolated yields.
b Isomeric ratios determined from isolated products.
Synlett 2008, No. 15, 2317–2320 © Thieme Stuttgart · New York

LETTER
Synthesis of Functionalized 1,4-Diketones
2319
9
Table 3 Reactions of Phenyl Glyoxal Hydrate (1a) with (Cyclo)sulfonium salts 2 Catalyzed by SeO2 and Na2CO3
R2
SeO2 (4 mol%)
Na2CO3 (10 mol%)
R1
S+
O
O
S
X–
R1
1a
Ph
+
Ph
Ph
MeCN, r.t.
3
2
O
Entry
1
X
R1
2
Time (h)
R2
3
Yield (%)a Z/Eb
Cl
Br
I
Me
2h
2a
2i
11
4
Me
3a
3a
3a
3m
34
81
66
81
68
73
50
43
6
1.8:1
2.3:1
3.2:1
1.7:1
1.5:1
1.0:1
2.2:1
2.0:1
4.6:1
1.4:1
1.9:1
2
Me
Me
3
Me
1.1
7
Me
4
Br
Br
Cl
Br
Br
I
Pr
2j
Pr
5c
6
Pr (Me)
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)5
(CH2)6
2k
2l
6
Pr (Me)
(CH2)4Cl
(CH2)4Br
(CH2)4Br
(CH2)4I
(CH2)5Br
(CH2)6Br
–
c
17
12
30
2
3n
3o
3o
3p
3q
3r
7
2m
2m
2n
2o
2p
8d
9
10
11
Br
Br
13
20
50
56
a Isolated yields.
b Isomeric ratios determined from isolated products.
c For methyl propyl phenacyl sulfonium bromide (2k), a mixture of 3a and 3m was obtained.
d Catalyzed by Na2SeO3 (10 mol%) alone.
nyl sulfonium salt during purification. When sulfoniums nyl centres of a,b-diketones6 and aromatic aldehydes7 to
2m, 2o, and 2p (X = Br) were, respectively, condensed form corresponding epoxides.
with 1a, the corresponding products were obtained in fair
yields (entries 7, 8, 10, 11, Table 3). These types of com-
An early report also demonstrated that, following its inde-
pendent generation, betaine I decomposes to give only
pounds are more functionalized than those accessible
benzaldehyde and the stabilized ylide (R1 = PhCO), the
from current procedures,1c,3 and are potentially useful for
epoxide is not formed (Scheme 2).8 Thus, while it is clear
building multifunctionalized medium-sized thioether
that the betaine formed upon reaction of aldehydes with
rings via an intramolecular reaction.
nonstabilized sulfur ylides undergoes elimination of sul-
fide faster than it reverts to ylide and aldehyde, it is diffi-
O–
–
cult for the betaine from a stable ylide to undergo
elimination of sulfide. In fact, without SeO2, neither ep-
oxide nor expected olefin was formed in our experiments
(entry 8, Table 1).
R2CHO
O
+
S
base
+
S
R1
R1
R1
R2
R2
R1
baseH+
S+
Scheme 1 General mechanism for the sulfur ylide epoxidation reac-
tion via a betaine intermediate
Based on these facts, a plausible reaction mechanism is
proposed in Scheme 3. The sulfonium salt 2 is deprotonat-
ed by the hydroxide or the basic salt (Na2SeO3) to gener-
ate the sulfur ylide 4, which then attack the phenyl glyoxal
(1) to give the anti- or syn-betaine intermediates 5a or 5b.
Since these betaine intermediates cannot eliminate sulfide
immediately, 5a and 5b could then react with selenium di-
oxide to give the intermediates 6a and 6b, respectively,
which release hydrogenselenite ion via a six-membered
cyclic transition state to give 7a and 7b followed by the
products (Z/E)-3. The released hydrogenselenite ion can
then regenerate the hydroxide ion and selenium dioxide.
O
O–
O
O
O
S+
+ PhCHO
Ph
Ph
Ph
Ph
Ph
–
S+
I
Scheme 2 Decomposition of betaine I from stable ylide8
It is known that sulfonium ylides react with aldehydes to
give epoxides via betaine intermediates4 (Scheme 1). It
has also been reported that the formation of betaines from
stabilized ylides is reversible.5 In addition, stabilized sul-
fur ylides, such as dimethylsulfonium phenacylide
(R1 = PhCO) react only with the very electrophilic carbo-
In conclusion, we have developed a simple and efficient
procedure to produce a-alkylthio-substituted a,b-unsatur-
ated 1,4-dicarbonyl compounds in good to high yields
from glyoxal hydrates and sulfonium salts catalyzed by a
Synlett 2008, No. 15, 2317–2320 © Thieme Stuttgart · New York

2320
Q. Shao, C. Li
LETTER
O
O
O
O
+
S
O
O
X–
Se
O–
S+
O O
O
R1
R2
O
R2
R1
R1
R2
H
R2
R2
R1
H
2
S+
6a
S+
(Z)-3
S
O–
O
X–
7a
O
anti-betaine 5a
S
O
R2
O
OH–
SeO2
4
Se
R1
–O
OH
H
O
+
S
O
O
1
O
+
O
O
S
R1
S
X–
Se
O–
R2
O
R2
+
R1
H
R1
S
R1
R2
7b
(E)-3
O
O–
O
O
R2
O
syn-betaine 5b
6b
Scheme 3 Plausible mechanism of Na2SeO3 (SeO2 and Na2CO3)-catalyzed condensation of sulfonium salt and glyoxal hydrate
(5) (a) Aggarwal, V. K.; Hynd, G.; Picoul, W.; Vasse, J.-L.
J. Am. Chem. Soc. 2002, 124, 9964. (b) Johnson, C. R.;
Schroeck, C. W.; Shanklin, J. R. J. Am. Chem. Soc. 1973, 95,
7424.
(6) (a) Payne, G. B. J. Org. Chem. 1968, 33, 3517. (b) Trost,
B. M.; Arndt, H. C. J. Org. Chem. 1973, 38, 3140.
(7) (a) Johnson, A. W.; Amel, R. T. J. Org. Chem. 1969, 34,
1240. (b) Ratts, K. W.; Yao, A. N. J. Org. Chem. 1966, 31,
1689.
combination of SeO2 and Na2CO3 or mineral salt
Na2SeO3. The reaction conditions are milder than the pro-
cedures reported before. Additionally, to our knowledge,
this is the first use of selenium dioxide or sodium selenite
as a condensation catalyst.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(8) Gosselck, J.; Schmidt, G.; Béress, L.; Schenk, H.
Tetrahedron Lett. 1968, 9, 331.
(9) Typical Procedure for Preparing Compound 3
A mixture of 1a (152 mg, 1.0 mmol), 2a (261 mg, 1.0
mmol), SeO2 (4.4 mg, 0.04 mmol), and Na2CO3 (10.6 mg,
0.1 mmol) in MeCN (10 mL) was stirred for 4.5 h at r.t. After
complete consumption of starting material (TLC), MeCN
was removed in vacuum to give yellow syrup. The residue
was extracted with CH2Cl2 (2 × 30 mL). The combined
organic layers were washed with brine (10 mL) and dried
over anhyd Na2SO4. The extracts were then concentrated
under reduced pressure, and the residue was purified by
column chromatography (eluent: PE–EtOAc) on SiO2 to
give an 81% yield of 3a [(Z)-3a, 129 mg; (E)-3a, 100 mg].
Compound (Z)-3a: 1H NMR (400 MHz, CDCl3): d = 8.08 (d,
J = 8.5 Hz, 2 H), 7.95 (d, J = 8.5 Hz, 2 H), 7.69–7.44 (m, 6
H), 7.10 (s, 1 H), 2.17 (s, 3 H). 13C NMR (100 MHz, CDCl3):
d = 191.9, 188.2, 160.6, 137.8, 134.9, 134.8, 132.7, 130.0,
129.1, 128.6, 128.1, 116.0, 15.4. IR (KBr): n = 2926, 1670,
1635, 1596, 1537, 1246, 1023, 699 cm–1.
Acknowledgment
We thank NSFC (20572078) and TMSTC (05YFGPGX07500) for
financial support.
References and Notes
(1) (a) Chen, A.; Yin, G.; Gao, M.; Wang, Z.; Wu, A. Chin. J.
Org. Chem. 2007, 27, 220; suppl.. (b) Jiao, Y.; Da, S.; Xie,
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Nakagawa, M. Tetrahedron Lett. 1979, 20, 2809.
(b) Dieter, R. K.; Silks, L. A. III. J. Org. Chem. 1986, 51,
4687. (c) Kang, W.; Sekiya, T.; Toru, T.; Ueno, Y. J. Chem.
Soc., Perkin Trans. 1 1990, 441.
Compound (E)-3a: 1H NMR (400 MHz, CDCl3): d = 8.00 (d,
J = 8.0 Hz, 2 H), 7.89 (d, J = 8.0 Hz, 2 H), 7.57–7.43 (m, 6
H), 7.04 (s, 1 H), 2.45 (s, 3 H). 13C NMR (100 MHz, CDCl3):
d = 193.7, 185.1, 160.8, 137.2, 134.9, 133.6, 133.0, 128.8,
128.7, 128.6, 128.4, 115.8, 14.9. IR (KBr): n = 3413, 1674,
1637, 1540, 1220, 781, 703, 632 cm–1. Spectral data were in
agreement with those previously reported.3
(3) (a) Yin, G.; Zhou, B.; Meng, X.; Wu, A.; Pan, Y. Org. Lett.
2006, 8, 2245. (b) Furukawa, N.; Akasaka, T.; Aida, T.;
Oae, S. J. Chem. Soc., Perkin Trans. 1 1977, 7, 372.
(4) (a) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37,
611. (b) Li, A.; Dai, L.; Aggarwal, V. K. Chem. Rev. 1997,
97, 2341. (c) Edwards, D. R.; Du, J.; Crudden, C. M. Org.
Lett. 2007, 9, 2397. (d) Aggarwal, V. K.; Harvey, J. N.;
Richardson, J. J. Am. Chem. Soc. 2002, 124, 5747.
Synlett 2008, No. 15, 2317–2320 © Thieme Stuttgart · New York

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