Efficient solvent-free knoevenagel condensation between -diketone and aldehyde catalyzed by silica sulfuric acid

Article abstract of DOI:10.1080/00397910903576594

Silica sulfuric acid has been utilized as an efficient heterogeneous recyclable catalyst for Knoevenagel condensation between poorly reactive β-diketones and aldehydes under solvent-free conditions. This protocol also works well with more reactive β-ketoesters. The condensation is efficient, clean, and mild. The scope and generality of the Knoevenagel condensation were investigated. The procedure led only to the Knoevenagel product, and no side product derived from a subsequent Michael βaddition of -diketone to alkene was detected at rt. Increasing temperature led to a subsequent Michael addition, and it was applied to the efficient synthesis of 9-aryl-1,8-dioxo- octahydroxanthene derivatives.

Full text of DOI:10.1080/00397910903576594

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Efficient Solvent-Free Knoevenagel
Condensation Between β-Diketone and
Aldehyde Catalyzed by Silica Sulfuric
Acid
Fuyi Zhang a , Yu-Xin Wang a , Feng-Ling Yang a , Hong-Yu Zhang a &
Yu-Fen Zhao a
a Chemistry Department, Key Laboratory of Chemical Biology and
Organic Chemistry of Henan Province, New Drug Research and
Development Center, Zhengzhou University, Zhengzhou, China
Version of record first published: 13 Jan 2011.
To cite this article: Fuyi Zhang , Yu-Xin Wang , Feng-Ling Yang , Hong-Yu Zhang & Yu-Fen Zhao (2011):
Efficient Solvent-Free Knoevenagel Condensation Between β-Diketone and Aldehyde Catalyzed by
Silica Sulfuric Acid, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:3, 347-356
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Synthetic Communications1, 41: 347–356, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903576594
EFFICIENT SOLVENT-FREE KNOEVENAGEL
CONDENSATION BETWEEN b-DIKETONE AND
ALDEHYDE CATALYZED BY SILICA SULFURIC ACID
Fuyi Zhang, Yu-Xin Wang, Feng-Ling Yang,
Hong-Yu Zhang, and Yu-Fen Zhao
Chemistry Department, Key Laboratory of Chemical Biology and Organic
Chemistry of Henan Province, New Drug Research and Development Center,
Zhengzhou University, Zhengzhou, China
Silica sulfuric acid has been utilized as an efficient heterogeneous recyclable catalyst for
Knoevenagel condensation between poorly reactive b-diketones and aldehydes under
solvent-free conditions. This protocol also works well with more reactive b-ketoesters.
The condensation is efficient, clean, and mild. The scope and generality of the Knoevenagel
condensation were investigated. The procedure led only to the Knoevenagel product, and no
side product derived from a subsequent Michael addition of b-diketone to alkene was
detected at rt. Increasing temperature led to a subsequent Michael addition, and it was
applied to the efficient synthesis of 9-aryl-1,8-dioxo-octahydroxanthene derivatives.
Keywords: 9-Aryl-1,8-dioxo-octahydroxanthene derivatives; Knoevenagel condensation; silica sulfuric
acid
INTRODUCTION
Knoevenagel condensation between an aldehyde and a methylene active
=
compound is an important C C bond-formation reaction and has been largely
employed to synthesize Knoevenagel products, such as coumarin derivatives, cos-
metics, perfumes, and pharmaceuticals.[1] In general, the condensations have been
performed in the presence of a base.[2] Lewis acids such as TiCl4,[3] ZnCl2,[4]
CeCl3 ꢀ 7H2O,[5] NbCl5,[6] Mg(ClO4)2,[7] and SmI3[8] known to promote Knoevenagel
condensations are employed as alternative catalysts. Various protocols performed in
ionic liquids[9] or by microwave irradiation and fluorous biphasic system[10] have also
been reported. To accomplish cleaner syntheses, different heterogeneous catalysts
such as sepiolites,[11] zeolite,[12] faujasite,[13] layered silicate PLS-1,[14] clays,[15]
layered double hydroxides (LDHs),[16] hydrotalcites,[17] and MgO=ZrO2
have
[18]
been employed to do Knoevenagel condensations. Most of these are solid base
catalysts. Solid-supported acid as an alternative catalyst also has many advantages
Received March 29, 2009.
Address correspondence to Fuyi Zhang, Chemistry Department, Key Laboratory of Chemical
Biology and Organic Chemistry of Henan Province, New Drug Research and Development Center,
Zhengzhou University, Zhengzhou, China. E-mail: zhangfy@zzu.edu.cn
347

348
F. ZHANG ET AL.
Scheme 1. Preparation of silica sulfuric acid by the reaction of silica gel with chlorosulfuric acid in CH2Cl2
at rt.
such as air and moisture tolerance, low toxicity, recovery and reuse, and low price.
Because a reagent is dispersed on the surface of the support, the effective surface area
of the reagent can be increased and the activity and selectivity of a reagent can be
improved. The reaction is performed better than with the individual reagents.[19]
However, very few examples of Knoevenagel condensation catalyzed by solid-
supported acid have been reported.[20]
Silica sulfuric acid (SSA), a good solid acid introduced by M. A. Zolfigol in
2001,[21a] is easily and cleanly prepared by the reaction of silica gel with neat chlor-
osulfonic acid at rt. This method of preparation was slightly modified by performing
the reaction in CH2Cl2 by Z. Li as shown in Scheme 1.[21b] SSA can make reaction
processes convenient, more economical, and environmentally benign.[22] In recent
years, SSA has been explored as a powerful catalyst for organic conversions under
mild conditions.[21,23] Herein, we report an efficient solvent-free Knoevenagel
condensation between b-diketone and aldehyde catalyzed by SSA.
RESULTS AND DISCUSSION
The condensation of aldehydes with methylene active compounds such as
malononitrile, cyanoacetates, malonates, and b-ketoesters have been extensively
explored and largely used to prepare Knoevenagel products. Very few examples
about b-diketones were reported, mainly because b-diketones easily form stable cyc-
lic enols and thus have fewer activities.[20,24] The solvent-free reaction of benzal-
dehyde 1a and acetoacetone 2a (Table 1) was first investigated in the presence of
various amounts of SSA at different temperatures. The best conditions for obtaining
the desired ab-unsaturated diketone 3aa required the use of 10 mol% SSA with stir-
ring for 10 h at rt. Increase of the temperature or the amount of catalyst (>10 mol%)
led to the side product, which was formed by the subsequent Michael addition of
acetoacetone 2a to 3aa. Addition of a solvent slows the reaction, which was the same
as that of the Mg(ClO4)2=MgSO4-promoted Knoevenagel condensation.[7]
The best reaction conditions were applied to the other substrates. The results
are also shown in Table 1. The aromatic aldehydes 1b–1f having electron-
withdrawing groups showed more reactivity toward acetoacetone 2a (entries 2–6)
than benzaldehyde 1a, and the Knoevenagel products 3ba,[7,25] 3ca,[7,26] 3da,[7]
3ea,[7,8] and 3fa[8] were obtained in good to excellent yields. The presence of the
electron-releasing group MeO on aromatic aldehyde 1g retarded the reaction
(entry 7).[12b] The ab-unsaturated aldehydes did not give satisfactory condensation
with b-diketones. For example, cinnamaldehyde 1h was employed to react with acet-
oacetone 2a at rt for 32 h, but only 25% yield of desired product 3ha was obtained
and the other unidentified side products were complicated (entry 8). Aliphatic alde-
hydes reacted smoothly with b-diketones (entries 9 and 10). The condensation of
butyraldehyde and hexanal with acetoacetone 2a produced only a,b-unsaturated

SSA-CATALYZED KNOEVENAGEL CONDENSATION
349
Table 1. Solvent-free Knoevenagel condensation between aldehydes 1 and b-diketones 2 catalyzed by
SSA at rt
Yielda,b (%)
(Z:E ratio)
Entry
1
R1
b-Diketone
Time (h)
10
Product[lit]
C6H5
66
3aa[7,8,10b]
2
3
4-NO2C6H4
2-NO2C6H4
4-CNC6H4
4-ClC6H4
2a
2a
2a
2a
2a
2a
2a
2a
2a
8
8
85
83
80
72
70
61
25
81
68
3ba[7,25]
3ca[7,26]
3da[7]
4
7
5
9
3ea[7,8]
3fa[8]
6
4-BrC6H4
4-MeOC6H4
=
trans-PhCH CH
9
7
12
32
8
3ga[12b]
3ha[7,8]
3ia[7,27]
3ja[7,28]
8
9
10
n-C3H7
n-C6H13
8
11
C6H5
12
60
3ab[30]
12
13
4-NO2C6H4
4-CNC6H4
2b
2b
10
12
67
73
3bb[7]
3db[7]
14
4-NO2C6H4
12
72 (5:1)
3bc[7]
15
C6H5
8
87 (2:1)
3ad[8,31]
16
17
18
4-NO2C6H4
2-furyl
4-MeOC6H4
2d
2d
2d
6
7
88 (1.5:1)
85 (1:0)
70 (2.5:1)
3bd[31]
3jd[9a,31]
3gd[31]
12
aIsolated yield.
bThe ratio found from 1H NMR.
diketone 3ia[7,27] and 3ja[7,28] respectively in good yields, and no isomerization to b,c-
unsaturated ones was detected,[29] although there are two a-protons in the aldehydes.
We extended the procedure to the more bulkier b-diketones. The desired pro-
ducts were also obtained in good yields (entries 11–14). 3,5-Heptanedione 2b exhib-
ited a similar reactivity toward aldehydes, compared to the less bulky acetoacetone
2a. The corresponding Knoevenagel products 3ab,[30] 3bb,[7] 3db,[7] and 3bc[7] were
obtained in around 70% yields. Encouraged by this result, we extended the conden-
sation reaction to asymmetric and bulkier 5-methylhexane-2,4-dione 2c (entry 14).
The corresponding desired product 3bc was generated as a mixture of Z- and
E-isomers in 72% with the Z-isomer as a major product. This protocol was then
extended to the reaction of aromatic aldehydes with ethyl 3-oxobutanoate 2d, the gen-
erally used reaction in the Knoevenagel condensation (entries 15–18). The substituted

350
F. ZHANG ET AL.
Table 2. Solvent-free synthesis of 9-aryl-1,8-dioxo-octahydroxanthene derivatives 5 in the presence of
10 mol% SSA
Entry
R
Temperature (ꢁC)
Time (h)
Yield (%)a
Product[lit]
1
2
3
4
5
6
H
2-Br
80
60
1.5
1
82
87
90
85
76
73
5a[20,32]
5l[32]
5m[20b,32]
5n[20,32]
5o[20a,32]
5p[20a,32]
2-Cl
3-Cl
60
60
1
1.5
2
4-Me
4-MeO
100
100
2.5
aIsolated yield.
alkenes 3ad,[8,31] 3bd,[31] 3jd,[31] and 3gd[31] were obtained in good or excellent yields, also
with Z-isomers as major products.
As described previously, the solvent-free Knoevenagel condensation between
aldehyde and b-diketone catalyzed by 10 mol% SSA at rt. gave a,b-unsaturated dike-
tone. Increasing the temperature led to subsequent Michael addition of b-diketone
to newly formed ab-unsaturated diketone. Based on this experience, we extended
this procedure to the Knoevenagel condensation between aromatic aldehydes and
dimedone 4 (Table 2) and found an alternative method for the synthesis of
9-aryl-1,8-dioxo-octahydroxanthene derivatives 5. These compounds were pre-
viously synthesized.[20,32] We investigated SSA-catalyzed reaction of aromatic alde-
hydes with dimedone 4 under solvent-free conditions. The reaction proceeded
smoothly at 60–100 ꢁC to give the corresponding products 5, which were obviously
formed by the Knoevenagel condensation, followed by Michael addition and cyclo-
dehydration in one pot.[20a] The reaction of benzaldehyde 1a with dimedone 4 was
performed at 80 ꢁC to generate 9-phenyl-1,8-dioxo-octahydroxanthene 5a in 82%,
and no other intermediate was isolated (Table 2, entry 1). The presence of an
electron-withdrawing group on the aromatic aldehyde, such as Br and Cl, increases
the reactivity and the desired products 5l–n were obtained in excellent yields at 60 ꢁC
(entries 2–4). The aldehyde with strong electron-withdrawing groups, such as NO2
and CN, has a high melting point and cannot perform a solvent-free reaction with
dimedone 4. The presence of an electron-releasing group on the aromatic aldehyde
such as CH3 and MeO decreases the reactivity, and the reaction worked at a slower
rate to give less yield of 5o and 5p compared with the aldehyde having an
electron-withdrawing group (entries 5 and 6).
CONCLUSION
In conclusion, we have used an inexpensive, easily prepared heterogenous
catalyst (SSA) to carry out a Knoevenagel condensation between various aldehydes

SSA-CATALYZED KNOEVENAGEL CONDENSATION
351
and poorly active diketones to produce trisubstituted functionalized alkenes under
solvent-free conditions. The procedure led only to the Knoevenagel product, and
no side product derived from a subsequent Michael addition of b-diketone to alkene
was detected at rt. Increasing the temperature led to a subsequent Michael addition.
The aliphatic aldehyde gave the only product, and no isomerization of a newly
formed double bond was detected. SSA-promoted condensation was applied to
the solvent-free synthesis of 9-aryl-1,8-dioxo-octahydroxanthene derivatives in one
pot. The reaction of aromatic aldehydes with dimedone at 60–100 ꢁC gave good to
excellent yields of the desired products. The aromatic aldehyde having an electron-
withdrawing group works better than that with an electron-releasing group.
EXPERIMENTAL
SSA was prepared according to the reported modified protocol.[21b] All of the
products are known compounds and were characterized by comparision of their
spectroscopic data with those reported in the literature. NMR spectra were recorded
on a Bruker DXP-400 spectrometer in pure deuterated solvents. Chemical shifts (d)
are reported in parts per million (ppm), and coupling constants (J) are given in hertz
(Hz). The multiplicities of the signals are abbreviated by s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), and br (broad). Electrospray ionization
(ESI)–high resolution (HR) mass spectra were determined on a Waters Micromass
Q-Tof Micro instrument. Thin-layer chromatography (TLC) was performed on
precoated plates of silica gel 60 F254
.
General Procedure for the Synthesis of a,b-Unsaturated Diketones
and a,b-Unsaturated Ketoesters
A mixture of aldehyde 1 (1 mmol) and b-diketone or ethyl 3-oxobutanoate 2
(1 mmol) was stirred at rt. If the aldehyde was solid, the stirring continued until
the solution became clear. SSA (10 mol%) was added. The mixture was stirred at
rt and monitored by TLC. After completion, the reaction mixture was filtered,
washed with CH2Cl2, and evaporated. The crude product 3 was purified by flash
chromatography on silica gel, eluting with an appropriate mixture of petroleum
ether=EtOAc. The products were characterized, and the spectroscopic data were
identical with the reported ones.
Selected Spectroscopic Data
3-Benzylidene-pentane-2,4-dione (Table 1, Entry 1). Mp 184–187 ꢁC (lit.
185–188 ꢁC);[10b] 1H NMR (400 MHz, CDCl3): 7.47 (s, 1H, CH), 7.39 (s, 5H, Ph),
13
2.42 (s, 3H, CH3), 2.30 (s, 3H, CH3); C NMR (100 MHz, CDCl3): 205.3 (C O),
=
=
196.2 (C O), 142.6 (C), 139.7 (CH), 132.8 (CH), 130.7 (CH), 129.5 (C), 128.9
(CH), 31.5 (CH3), 26.6 (CH3). HRMS (ESI) (m=z): 211.0735 ([M þ Na]þ).
3-Butylidenepentane-2,4-dione (Table 1, Entry 9). Oil (lit. liquid);[27]
1H NMR (400 MHz, CDCl3): 6.62 (t, J ¼ 7.7 Hz, 1H, CH), 2.24 (s, 3H, CH3), 2.27
(s, 3H, CH3), 2.12–2.19 (m, 2H, CH2), 1.41–1.52 (m, 2H, CH2), 0.91 (t, J ¼ 7.5 Hz,

352
F. ZHANG ET AL.
13
=
=
3H, CH3); C NMR (100 MHz, CDCl3): 203.6 (C O), 197.2 (C O), 146.7 (C),
145.1 (CH), 31.7 (CH3), 31.3 (CH2), 26.0 (CH3), 21.7 (CH2), 13.8 (CH3). HRMS
(ESI) (m=z): 177.0891 ([M þ Na]þ).
4-Benzylidene-heptane-3,5-dione (Table 1, Entry 11). Oil (lit. clear
oil);[30b] 1H NMR (400 MHz, CDCl3): 7.54 (s, 1H, CH), 7.23–7.40 (m, 5H, Ph),
2.8 (q, J ¼ 7.2 Hz, 2H, CH2), 2.48 (q, J ¼ 7.2 Hz, 2H, CH2), 1.14 (t, J ¼ 7.2 Hz, 3H,
13
=
CH3), 1.05 (t, J ¼ 7.2 Hz, 3H, CH3); C NMR (100 MHz, CDCl3): 208.7 (C O),
=
199.1 (C O), 142.5 (C), 138.7 (CH), 133.6 (CH), 130.5 (CH), 129.6 (C), 129.0
(CH), 37.2 (CH2), 31.7 (CH2), 7.8 (CH3), 7.3 (CH3). HRMS (ESI) (m=z): 239.1048
([M þ Na]þ).
(Z)-Ethyl 2-benzylidene-3-oxobutanoate (Table 1, Entry 15). Mp
79–81 ꢁC (lit. 78–80 ꢁC);[31c] 1H NMR (400 MHz, CDCl3): 7.58 (s, 1H, CH),
7.41–7.49 (m, 5H, Ph), 4.36 (q, J ¼ 7.0 Hz, 2H, CH2), 2.45 (s, 3H, CH3), 1.30 (t,
13
=
J ¼ 7.0 Hz, 3H, CH3); C NMR (100 MHz, CDCl3): 194.7 (C O), 167.9 (COO),
141.3 (CH), 134.7 (C), 133.0 (C), 130.8 (CH), 129.6 (CH), 128.9 (CH), 61.6 (CH2),
26.4 (CH3), 13.7 (CH3). HRMS (ESI) (m=z): 241.0841 ([M þ Na]þ).
(E)-Ethyl 2-benzylidene-3-oxobutanoate (Table 1, Entry 15). Mp
43–44 ꢁC (lit. 44–45 ꢁC);[10b] 1H NMR (400 MHz, CDCl3): 7.68 (s, 1H, CH),
7.36–7.39 (m, 5H, Ph), 4.28 (q, J ¼ 7.0 Hz, 2H, CH2), 2.35 (s, 3H, CH3), 1.33 (t,
13
=
J ¼ 7.0 Hz, 3H, CH3); C NMR (100 MHz, CDCl3): 203.4 (C O), 164.2 (COO),
140.5 (CH), 133.8 (C), 132.9 (C), 130.4 (CH), 129.4 (CH), 128.7 (CH), 61.4 (CH2),
31.2 (CH3), 14.1 (CH3). HRMS (ESI) (m=z): 241.0841 ([M þ Na]þ).
(Z)-Ethyl 2-(4-nitrobenzylidene)-3-oxobutanoate (Table 1, Entry 16).
Mp 159–161 ꢁC (lit. 160–161 ꢁC);[31b] 1H NMR (400 MHz, CDCl3): 8.25 (d,
J ¼ 8.8 Hz, 2H, ArH), 7.60 (s, 1H, CH), 7.61 (d, J ¼ 8.8 Hz, 2H, ArH), 4.33 (q,
J ¼ 7.2 Hz, 2H, CH2), 2.46 (s, 3H, CH3), 1.27 (t, J ¼ 7.2 Hz, 3H, CH3); 13C NMR
=
(100 MHz, CDCl3): 193.8 (C O), 166.7 (COO), 148.5 (C), 139.5 (C), 138.0 (CH),
137.3 (C), 129.8 (CH), 123.9 (CH), 62.3 (CH2), 26.7 (CH3), 13.7 (CH3). HRMS
(ESI) (m=z): 302.0425 ([M þ K]þ).
(E)-Ethyl 2-(4-nitrobenzylidene)-3-oxobutanoate (Table 1, Entry 16).
1
Mp 60–62 ꢁC; H NMR (400 MHz, CDCl3): 8.21 (d, J ¼ 8.8 Hz, 2H, ArH), 7.67 (s,
1H, CH), 7.55 (d, J ¼ 8.8 Hz, 2H, ArH), 4.32 (q, J ¼ 6.8 Hz, 2H, CH2), 2.35 (s,
3H, CH3), 1.36 (t, J ¼ 6.8 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3): 202.3
=
(C O), 163.5 (COO), 148.0 (C), 139.2 (C), 137.7 (CH), 137.5 (C), 130.0 (CH),
124.0 (CH), 62.1 (CH2), 31.2 (CH3), 14.1 (CH3). HRMS (ESI) (m=z): 302.0425
([M þ K]þ), 286.0691 ([M þ Na]þ).
(Z)-Ethyl 2-((furan-2-yl)methylene)-3-oxobutanoate (Table 1, Entry 17).
Oil (lit. yellowish liquid);[9a] 1H NMR (400 MHz, CDCl3): 7.55 (d, J ¼ 1.8 Hz, 1H),
7.31 (s, 1H), 6.80 (d, J ¼ 3.6 Hz, 1H), 6.50 (dd, J1 ¼ 3.6 Hz, J2 ¼ 1.8 Hz, 1H), 4.41
(q, J ¼ 6.8 Hz, 2H), 2.35 (s, 3H), 1.37 (t, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): 193.8 (C), 167.3 (C), 148.7 (C), 146.4 (CH), 129.7 (C), 126.4 (CH), 118.8
(CH), 112.8 (CH), 61.7 (CH2), 26.4 (CH3), 14.1 (CH3). HRMS (ESI) (m=z):
231.0630 ([M þ Na]þ), 247.0361 ([M þ K]þ).

SSA-CATALYZED KNOEVENAGEL CONDENSATION
353
(Z)-Ethyl 2-(4-methoxybenzylidene)-3-oxobutanoate (Table 1, Entry 18).
Mp 91–92 ꢁC (lit. 90–92 ꢁC);[31a] 1H NMR (400 MHz, CDCl3): 7.51 (s, 1H), 7.43 (d,
J ¼ 8.7 Hz, 2H), 6.90 (d, J ¼ 8.7 Hz, 2H), 4.37 (q, J ¼ 7.4 Hz, 2H), 3.86 (s, 3H), 2.41
(s, 3H), 1.33 (t, J ¼ 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): 194.6 (C), 168.4 (C),
161.6 (C), 141.1 (CH), 132.3 (C), 131.6 (CH), 125.1 (C), 114.3 (CH), 61.4 (CH2), 55.2
(CH3), 26.5 (CH3), 14.1 (CH3). HRMS (ESI) (m=z): 271.0941 ([M þ Na]þ).
(E)-Ethyl 2-(4-methoxybenzylidene)-3-oxobutanoate (Table 1, Entry 18).
1
Mp 65–68 ꢁC; H NMR (400 MHz, CDCl3): 7.60 (s, 1H), 7.35 (d, J ¼ 8.8 Hz, 2H),
6.87 (d, J ¼ 8.8 Hz, 2H), 4.28 (q, J ¼ 7.2 Hz, 2H), 3.84 (s, 3H), 2.39 (s, 3H), 1.34 (t,
J ¼ 7.2 Hz, 3H); NMR (100 MHz, CDCl3): 204.1 (C), 164.6 (C), 161.5 (C), 140.2
(CH), 131.8 (CH), 131.5 (C), 125.4 (C), 114.2 (CH), 61.2 (CH2), 55.3 (CH3), 31.2
(CH3), 14.1 (CH3). HRMS (ESI) (m=z): 271.0941 ([M þ Na]þ), 287.0681 ([M þ K]þ).
General Procedure for the Synthesis of 9-Aryl-1,8-dioxo-
octahydroxanthene Derivatives
A mixture of aldehyde 1 (1 mmol) and dimedone 4 (2 mmol) was heated to
60–100 ꢁC, to which SSA (10 mol%) was added. The reaction was monitored by
TLC. After completion, the mixture was cooled to rt and diluted with EtOAc.
The catalyst was filtered off, washed with EtOAc, and evaporated. The residue
was crystallized from ethanol to give pure 9-aryl-1,8-dioxooctahydroxanthene 5 as
a crystal.
Selected Data
3,3,6,6-Tetramethyl-9-phenyl-1,8-dioxo-octahydroxanthene (Table 2,
Entry 1). Mp 203–205 ꢁC (lit. 204–206 ꢁC);[20b] 1H NMR (400 MHz, DMSO-d6):
7.20 (m, 5H, Ph), 4.67 (s, 1H, H-9), 2.46 (s, 4H, 2 ꢂ CH2, H-2, H-7), 2.21 (dd,
J1 ¼ 1.8 Hz, J2 ¼ 2.4 Hz, 4H, 2 ꢂ CH2, H-4, H-5), 1.13 (s, 6H, 2 ꢂ CH3), 0.97 (s,
6H, 2 ꢂ CH3). HRMS (ESI) (m=z): 373.1773 ([M þ Na]þ).
3,3,6,6-Tetramethyl-9-(2-bromophenyl)-1,8-dioxo-octahydroxanthene
(Table 2, Entry 2). Mp 227–229 ꢁC (lit. 226–229 ꢁC);[32a] 1H NMR (400 MHz,
DMSO-d6): 7.22–7.31 (m, 4H, ArH), 4.62 (s, 1H, H-9), 2.48 (s, 4H, 2 ꢂ CH2, H-2,
H-7), 2.31 (dd, 4H, J1 ¼ 1.8 Hz, J2 ¼ 3.2 Hz, 2 ꢂ CH2, H-4, H-5), 1.03 (s, 6H,
2 ꢂ CH3), 1.01 (s, 6H, 2 ꢂ CH3). HRMS (ESI) (m=z): 451.0880 ([M þ Na]þ),
429.1061 ([M þ 1]þ).
3,3,6,6-Tetramethyl-9-(2-chlorophenyl)-1,8-dioxo-octahydroxanthene
(Table 2, Entry 3). Mp 225–226 ꢁC (lit. 225–227 ꢁC);[20b] 1H NMR (400 MHz,
DMSO-d6): 7.25–7.36 (m, 4H, ArH), 4.65 (s, 1H, H-9), 2.50 (s, 4H, 2 ꢂ CH2, H-2,
H-7), 2.07 (dd, J1 ¼ 1.8 Hz, J2 ¼ 3.2 Hz, 4H, 2 ꢂ CH2, H-4, H-5), 1.11 (s, 6H,
2 ꢂ CH3), 0.98 (s, 6H, 2 ꢂ CH3). HRMS (ESI) (m=z): 407.1383 ([M þ Na]þ).
3,3,6,6-Tetramethyl-9-(3-chlorophenyl)-1,8-dioxo-octahydroxanthene
(Table 2, Entry 4). Mp 183–185 ꢁC (lit. 182–184 ꢁC);[20b] 1H NMR (400 MHz,
DMSO-d6): 7.10–7.24 (m, 4H, ArH), 4.73 (s, 1H, H-9), 2.48 (s, 4H, 2 ꢂ CH2, H-2,
H-7), 2.31 (dd, 4H, J1 ¼ 1.8 Hz, J2 ¼ 3.8 Hz, 2 ꢂ CH2, H-4, H-5), 1.13 (s, 6H,

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F. ZHANG ET AL.
2 ꢂ CH3), 1.01 (s, 6H, 2 ꢂ CH3). HRMS (ESI) (m=z): 407.1380 ([M þ Na]þ),
423.1121 ([M þ K]þ).
3,3,6,6-Tetramethyl-9-(4-methylphenyl)-1,8-dioxo-octahydroxanthene
(Table 2, Entry 5). Mp 216–217 ꢁC (lit. 217–218 ꢁC);[20b] 1H NMR (400 MHz,
CDCl3): 7.12 (d, J ¼ 8.7 Hz, 2H, ArH), 6.68 (d, J ¼ 8.7 Hz, 2H, ArH), 4.61 (s, 1H,
CH, H-9), 2.45 (s, 3H, ArCH3), 2.43 (s, 4H, 2 ꢂ CH2, 2 ꢂ CH2, H-2, H-7), 2.17
(dd, J1 ¼ 1.6 Hz, J2 ¼ 2.4 Hz, 4H, 2 ꢂ CH2, H-4, H-5), 1.12 (s, 6H, 2 ꢂ CH3), 1.02
(s, 6H, 2 ꢂ CH3). HRMS (ESI) (m=z): 387.1931 ([M þ Na]þ).
3,3,6,6-Tetramethyl-9-(4-methoxyphenyl)-1,8-dioxo-octahydroxanthene
(Table 2, Entry 6). Mp 242–243 ꢁC (lit. 240–242 ꢁC);[20b] 1H NMR (400 MHz,
DMSO-d6): 6.66–7.27 (m, 4H, ArH), 4.71 (s, 1H, H-9), 3.74 (s, 3H, CH3O), 2.47
(s, 4H, 2 ꢂ CH2, H-2, H-7), 2.21 (dd, J1 ¼ 1.8 Hz, J2 ¼ 2.2 Hz, 6H, 2 ꢂ CH2, H-4,
H-5), 1.10 (s, 6H, 2 ꢂ CH3), 1.02 (s, 6H, 2 ꢂ CH3). HRMS (ESI) (m=z): 403.1885
([M þ Na]þ), 365.2110 ([M þ H]þ).
ACKNOWLEDGMENTS
The authors thank NNSF of China (No. 20972142), the State Key Laboratory
of Bio-organic and Natural Products Chemistry, The Chinese Academy of Sciences
(No. 08417), the Natural Science Project of Henan Province (2009A150030,
082300420110), and the Innovation Fund of Zhengzhou University (2008CXSY147)
for financial support.
REFERENCES
1. Tietze, L. F.; Beifuss, U. In Comprehensive Organic Synthesis; Pergamon: Oxford, 1991;
vol. 2, pp. 341–394.
2. (a) Choudary, B. M.; Lakshmi Kantam, M.; Kavita, B.; Venkat Reddy, C.; Figueras, F.
Catalytic CꢃC bond formation promoted by MgꢃAlꢃOꢃt-Bu hydrotalcite. Tetrahedron
2000, 56, 9357–9364; (b) Sugino, T.; Tanaka, K. Solvent-free coumarin synthesis. Chem.
Lett. 2001, 110–111.
3. Lehnert, W. Knoevenagel kondensationen mit TiCl4=base-IV: Umsetzungen von aldehy-
den und ketonen mit phosphonoessigester und methylendiphosphonsa¨ureestern. Tetra-
hedron 1974, 30, 301–305.
4. Shanthan Rao, P.; Venkataratnam, R. V. Zinc chloride as a new catalyst for Knoevenagel
condensation. Tetrahedron Lett. 1991, 32, 5821–5822.
5. Bartoli, G.; Beleggia, R.; Giuli, S.; Giuliani, A.; Marcantoni, E.; Massaccesi, M.; Paletti,
M. The CeCl3 ꢀ 7H2O–NaI system as promoter in the synthesis of functionalized trisubsti-
tuted alkenes via Knoevenagel condensation. Tetrahedron Lett. 2006, 47, 6501–6504.
6. Leelavathi, P.; Ramesh Kumar, S. Niobium(V) chloride–catalyzed Knoevenagel conden-
sation: An efficient protocol for the preparation of electrophilic alkenes. J. Mol. Catal. A:
Chem. 2005, 240, 99–102.
7. Bartoli, G.; Bosco, M.; Carlone, A.; Dalpozzo, R.; Galzerano, P.; Melchiorre, P.; Sambri,
L. Magnesium perchlorate as efficient Lewis acid for the Knoevenagel condensation
between b-diketones and aldehydes. Tetrahedron Lett. 2008, 49, 2555–2557.
8. Bao, W.; Zhang, Y.; Wang, J. Aldol condensation of b-diketones and b-ketoesters with
aldehydes catalyzed by samarium(III) iodide. Synth. Commun. 1996, 26, 3025–3028.

SSA-CATALYZED KNOEVENAGEL CONDENSATION
355
9. (a) Ranu, B. C.; Jana, R. Ionic liquid as catalyst and reaction medium—A simple,
efficient, and green procedure for Knoevenagel condensation of aliphatic and aromatic
carbonyl compounds using a task-specific basic ionic liquid. Eur. J. Org. Chem. 2006,
16, 3767–3770; (b) Hangarge, R. V.; Jarikote, D. V.; Shingare, M. S. Knoevenagel con-
densation reactions in an ionic liquid. Green Chem. 2002, 4, 266–268; (c) Harjani, J.
R.; Nara, S. J.; Salunkhe, M. M. Lewis acidic ionic liquids for the synthesis of elec-
trophilic alkenes via the Knoevenagel condensation. Tetrahedron Lett. 2002, 43,
1127–1130.
10. (a) Yadav, J. S.; Subba Reddy, B. V.; Basak, A. K.; Visali, B.; Narsaiah, A. V.; Nagaiah,
K. Phosphane-catalyzed Knoevenagel condensation: A facile synthesis of a-cyanoacry-
lates and a-cyanoacrylonitriles. Eur. J. Org. Chem. 2004, 3, 546–551; (b) Yi, W.-B.;
Cai, C. Perfluoroalkylated pyridine-catalyzed Knoevenagel condensation: An important
complement of fluorous catalysis without fluorous solvent. Catal. Commun. 2008, 9,
1291–1296.
´
11. Corma, A.; Martın-Aranda, R. M. Alkaline-substituted sepiolites as a new type of strong
base catalyst. J. Catal. 1991, 130, 130–137.
12. Wang, Q. L.; Ma, Y. D.; Zuo, B. J. Knoevenagel condensation catalyzed by USY zeolite.
Synth. Commun. 1997, 27, 4107–4110.
13. Lai, S. M.; Martin-Arand, R.; Yeung, K. L. Knoevenagel condensation reaction in a
membrane microreactor. Chem. Commun. 2003, 218–219.
14. Komura, K.; Kawamura, T.; Sugi, Y. Layered silicate PLS-1: A new solid base catalyst for
C–C bond-forming reactions. Catal. Commun. 2007, 8, 644–648.
15. (a) Rao, Y. V. S.; Choudary, B. M. Knoevenagel condensation catalysed by new
montmorillonitesilylpropylethylenediamine. Synth. Commun. 1991, 21, 1163–1166.
16. Lakshmi Kantam, M.; Ravindra, A.; Venkat Reddy, C.; Sreedhar, B.; Choudary, B. M.
Layered double hydroxides-supported diisopropylamide: Synthesis, characterization,
and application in organic reactions. Adv. Synth. Catal. 2006, 348, 569–578.
17. Kantam, M. L.; Choudary, B. M.; Reddy, V. K.; Rao, K.; Figueras, F. Aldol and Kno-
evenagel condensations catalysed by modified Mg–Al hydrotalcite: A solid base as catalyst
useful in synthetic organic chemistry. Chem. Commun. 1998, 1033–1034.
18. Gawande, M. B.; Jayaram, R. V. A novel catalyst for the Knoevenagel condensation of
aldehydes with malononitrile and ethyl cyanoacetate under solvent-free conditions. Catal.
Commun. 2006, 7, 931–935.
19. Corma, A.; Garcia, H. Silica-bound homogenous catalysts as recoverable and reusable
catalysts in organic synthesis. Adv. Synth. Catal. 2006, 348, 1391–1412.
20. (a) Kantevari, S.; Bantu, R.; Nagarapu, L. HClO4–SiO2 and PPA–SiO2 catalyzed efficient
one-pot Knoevenagel condensation. J. Mol. Catal. A: Chem. 2007, 269, 53–57; (b)
Karade, H. N.; Sathe, M.; Kaushik, M. P. An efficient synthesis of 1,8-dioxo-octahydro-
xanthenes using tetrabutylammonium hydrogen sulfate. Arkivoc 2007, 13, 252–258.
21. (a) Zolfigol, M. A. Silica sulfuric acid=NaNO2 as a novel heterogeneous system for
production of thionitrites and disulfides under mild conditions. Tetrahedron 2001, 57,
9509–9511; (b) Li, Z.; Ding, R.; Lu, Z.; Xiao, S.; Ma, X. J. Mol. Catal. A: Chem. 2006,
250, 100–103.
22. For a review, see Salehi, P.; Zolfigol, M. A.; Shirini, F.; Baghbanzadeh, M. Silica sulfuric
acid and silica chloride as efficient reagents for organic reactions. Curr. Org. Chem. 2006,
10, 2171–2189.
23. (a) Zarei, A.; Hajipour, A. R.; Khazdooz, L.; Mirjalili, B. F.; Najafi, C. A. Rapid and
efficient diazotization and diazo coupling reactions on silica sulfuric acid under
solvent-free conditions. Dyes Pigments 2009, 81, 240–244; (b) Hajipour, A. R.; Zarei,
A.; Khazdooz, L.; Ruoho, A. E. Silica sulfuric acid=NaNO3 as a new reagent for the
deprotection of S,S-acetals under mild conditions. Synthesis 2006, 9, 1480–1484;

356
F. ZHANG ET AL.
(c) Hajipour, A. R.; Zarei, A.; Khazdooz, L.; Pourmousavi, S. A.; Zahmatkesh, S.;
Ruoho, A. E. Efficient deprotection of tetrahydropyranyl ethers by silica sulfuric acid.
Ind. J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2006, 45B(1), 305–308; (d) Hajipour,
A. R.; Zarei, A.; Khazdooz, L.; Mirjalili, B. B. F.; Sheikhan, N.; Zahmatkesh, S.; Ruoho,
A. E. Silica sulfuric acid as an efficient heterogeneous catalyst for the synthesis of 1,1-dia-
cetates under solvent-free conditions. Synthesis 2005, 20, 3644–3648; (e) Hajipour, A. R.;
Zarei, A.; Khazdooz, L.; Mirjalili, B. B. F.; Sheikhan, N.; Zahmatkesh, S.; Ruoho, A. E.
Silica sulfuric acid as an efficient heterogeneous catalyst for the synthesis of 1,1-diacetates
under solvent-free conditions. Synthesis 2005, 20, 3644–3648; (f) Hajipour, A. R.; Zarei,
A.; Khazdooz, L.; Pourmousavi, S. A.; Ruoho, A. E. Silica sulfuric acid=NaNO2 as a
new reagent for deprotection of S,S-acetals under solvent-free conditions. Bull. Korean
Chem. Soc. 2005, 26, 808–810; (g) Hajipour, A. R.; Mirjalili, B. B. F.; Zarei, A.;
Khazdooz, L.; Ruoho, A. E. A novel method for sulfonation of aromatic rings with silica
sulfuric acid. Tetrahedron Lett. 2004, 45, 6607–6609; (h) Gawande, M. B.; Polshettiwar,
V.; Varmab, R. S.; Jayarama, R. V. An efficient and chemoselective Cbz-protection of
amines using silica–sulfuric acid at room temperature. Tetrahedron Lett. 2007, 48,
8170–8173.
24. Su, C.; Chen, Z.-C.; Zheng, Q.-G. Organic reactions in ionic liquids: Knoevenagel conden-
sation catalyzed by ethylenediammonium diacetate. Synthesis 2003, 555–559.
25. Mao, H.; Wan, J.; Pan, Y. Facile and diastereoselective synthesis of b-acetamido ketones
and keto esters via direct Mannich-type reaction. Tetrahedron 2009, 65, 1026–1032.
26. Memarian, H. R.; Abdoli-Senejani, M.; Doepp, D. Z. Naturforsch. B 2006, 61, 50–56.
27. Verhe, R.; De Kimpe, N.; Courtheyn, D.; De Buyck, L.; Schamp, N. Acid-catalyzed ring
closure reactions of electrophilic alkenes. Tetrahedron 1982, 38, 3649–3660.
28. Hiramatsu, H.; Harada, K.; Kojima, Y.; Fujiwara, K. The Knoevenagel reaction of alde-
hydes with active methylene compounds having keto-enol tautomerism. Nippon Kagaku
Kaishi 1989, 4, 714–721.
29. Wilson, B. D. The condensation products of aldehydes and aldol-sensitive b-dicarbonyl
compounds. J. Org. Chem. 1963, 28, 314–320.
30. (a) Antonioletti, R.; Bovicelli, P.; Malanacona, S. A new route to 2-alkenyl-1,3-dicarbonyl
compounds, intermediates in the synthesis of dihydrofurans. Tetrahedron 2002, 58, 589–
596; (b) Bernasconi, C. F.; Stronach, M. W. Kinetics of amine addition to benzylidene-1,3-
indandione and other vinylic b-diketones: Effect of cyclic structure and steric strain on
intrinsic rate constants. J. Am. Chem. Soc. 1991, 113, 2222–2227.
31. (a) Barluenga, J.; Riesgo, L.; Vicente, R.; Lopez, L. A.; Toms, M. Rearrangement of pro-
pargylic esters: Metal-based stereospecific synthesis of (E)- and (Z)-Knoevenagel deriva-
tives. J. Am. Chem. Soc. 2007, 129, 7772–7773; (b) Stanchev, S.; Momekov, G.; Jensen,
F.; Manolov, I. Synthesis, computational study and cytotoxic activity of new 4-hydroxy-
coumarin derivatives. Eur. J. Med. Chem. 2008, 43 (4), 694–706; (c) Muthusubramanian,
L.; Mitra, R. B. Convenient synthesis of 1-acetyl-2,2-dimethyl-3-arylcyclopropanes. Org.
Prep. Proc. Int. 2008, 40 (3), 311–315.
32. (a) Zhang, Z.-H.; Liu, Y.-H. Antimony trichloride=SiO2–promoted synthesis of
9-aryl-3,4,5,6,7,9-hexahydroxanthene-1,8-diones. Catal. Commun. 2008, 9, 1715–1719;
(b) Jin, T. S.; Zang, J. S.; Xiao, J. C.; Wang, A. Q.; Li, T. S. Clean synthesis of
1,8-dioxo-octahydroxanthene derivatives catalyzed by p-dodecylbenezenesulfonic acid in
aqueous media. Synlett 2004, 866–870.