Sulfuric acid catalyzed addition of β-dicarbonyl compounds to alcohols under conventional heating and microwave-assisted conditions

Article abstract of DOI:10.1016/j.tetlet.2012.03.104

The highly efficient direct addition of β-dicarbonyl compounds to secondary alcohols has been achieved using one of the cheapest acids, H ₂SO₄, as the catalyst. For a series of β-dicarbonyl compounds and various secondary alcohols, t

Full text of DOI:10.1016/j.tetlet.2012.03.104

Tetrahedron Letters 53 (2012) 2828–2832
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sulfuric acid catalyzed addition of b-dicarbonyl compounds to alcohols
under conventional heating and microwave-assisted conditions
⇑
Fei Xia, Zheng Le Zhao, Pei Nian Liu
Shanghai Key Laboratory of Functional Materials Chemistry and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237,
PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The highly efficient direct addition of b-dicarbonyl compounds to secondary alcohols has been achieved
using one of the cheapest acids, H2SO4, as the catalyst. For a series of b-dicarbonyl compounds and var-
ious secondary alcohols, the addition reactions all complete in 5 min with high yields both under the con-
ventional heating condition and under the microwave heating condition. The comparison of the results
obtained from the microwave heating condition with those obtained from the conventional heating con-
dition shows that no obvious specific or nonthermal microwave effects exist in the microwave-assisted
addition reactions.
Received 15 February 2012
Revised 16 March 2012
Accepted 27 March 2012
Available online 30 March 2012
Keywords:
Addition
Sulfuric acid
Ó 2012 Elsevier Ltd. All rights reserved.
Catalysis
Microwave-assisted synthesis
Dicarbonyl compounds
The carbon–carbon bond formation is the most fundamental
strategy for the construction of molecular framework and thus
undisputedly is one of the central themes in modern organic
chemistry.1 In recent years, the direct addition of b-dicarbonyl
compounds to alcohols affording the alkylated b-dicarbonyl com-
pounds has attracted much interest due to the green features. In
comparison with the traditional synthetic procedures, the prepara-
tion of halides or related species is unnecessary and the usage of
stoichiometric bases can be avoided, and only H2O is generated
as a side product.2 Since the pioneering work of Baba and co-work-
ers etc. in 2006 using InCl3 as the effective catalyst,3 various Lewis
acidic metal catalysts, such as InBr3,4 FeCl3,5 Bi(OTf)3,6 and Ln(OTf)3
(Ln = La, Yb, Sc, Hf)7 etc. have been discovered to be effective in cat-
alyzing the direct addition of b-dicarbonyl compounds to allylic
and benzylic alcohols. Recently, we reported a perchloric ruthe-
nium complex as the effective catalyst for the addition of b-dike-
tones to secondary alcohols,8 but further detailed mechanistic
investigations illustrate that an equivalent of perchloric acid gen-
erated from the fast and irreversible reaction of the ruthenium
complex and b-diketone is the true catalyst for the addition. Our
results alert that the investigators have to be prudent to elucidate
that the true catalytic species in a metal catalyzed catalytic reac-
tion is the metal complex or the proton produced by the reaction
of the metal with the substrate.
acid,12 H-montmorillonite,13 and triflic acid14 have also been re-
ported to be effective in catalyzing the addition of b-diketones to
benzylic alcohols. Very recently, we demonstrated that perchloric
acid can be used as the effective catalyst for the addition, and
proved that the mechanism of the Brønsted acid catalyzing addi-
tion is an SN1 mechanism.15 As a further extension, we successfully
prepared the silica gel supported TfOH and applied it as an efficient
and recoverable heterogeneous catalyst for the addition.16
Whereas prominent progress has been made in the direct addition
of b-dicarbonyl compounds to secondary alcohols, exceedingly
long reaction time (several hours to dozens of hours) is needed
in all the catalytic reactions under the conventional heating condi-
tions and the enhancement of the reactivity of the catalytic reac-
tions is still challenging. Herein, we report the highly efficient
addition of b-dicarbonyl compounds to secondary alcohols using
sulfuric acid (H2SO4) as the catalyst, which can be completed in
5 min.
In the former studies, H2SO4 has been reported ineffective in
catalyzing the addition of acetylacetone to 2-phenylethanol with
toluene as the solvent.15 But in the reaction of 1,3-diphenylpro-
pane-1,3-dione (1a) and 1-phenylethanol (2a), we surprisingly
found H2SO4 was a highly effective catalyst in 1,2-dichloroethane
(DCE) and the reaction completed in 5 min under reflux with 67%
yield (Table 1, entry 1). Encouraged by this exciting result, we
screened various solvents for the reactions of 1a and 2a in the pres-
ence of 5 mol % H2SO4 and found that the reactions in THF, dioxane,
EtOAc, heptane, CH2Cl2, CHCl3, and toluene afforded no or trace
amount of the product (Table 1, entries 2–8). But when CH3NO2
was used as the solvent, the reaction of 1a and 2a catalyzed by
Molecular iodine9 and various Brønsted acids, such as dodecyl-
benzenesulfonic acid,10 p-toluenesulfonic acid,11 phosphotungstic
⇑
Corresponding author. Tel.: +86 21 64250552; fax: +86 21 64252758.
E-mail address: liupn@ecust.edu.cn (P.N. Liu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.104

F. Xia et al. / Tetrahedron Letters 53 (2012) 2828–2832
2829
Table 1
under MW condition with 5 mol % H2SO4 as the catalyst, and 95%
yield was obtained (Table 1, entry 15). During the reaction course,
the reaction mixture was kept under 101 °C (refluxing) in the open
vessel, which assured that the reaction under MW condition pos-
sessed the same reaction temperature to the conventional heating
condition. For the addition of b-dicarbonyl compounds to alcohols,
no obvious specific or non-thermo effects can be derived from the
result of microwave-assisted reaction in comparison with that un-
der the conventional heating condition (Table 1, entries 15 and 9).
Subsequently, the addition of various b-dicarbonyl compounds
to a series of alcohols was examined in CH3NO2, using 5 mol %
H2SO4 as the catalyst. As indicated in Table 2, the reactions were
all carried out under 101 °C both under the conventional heating22
and MW conditions,23 and all the reactions completed in 5 min.
When b-diketone 1a reacted with the benzylic alcohol 2b and 2c
bearing a fluoride or a chloride group, excellent 97% and 95% yields
were obtained, illustrating that the electron-withdrawing substitu-
tion on the aromatic ring has no obvious effect on the reactivity
under current reaction conditions (Table 2, entries 2 and 3). By
contrast, the reaction of 1a with 4-methoxy-1-phenylethanol bear-
ing an electron-donating methoxyl group afforded very low yield
both under conventional heating and MW conditions, mainly due
to the decomposition of the methoxy substituted phenylethanol
under strong acidity. As 1-(2-naphthyl)ethanol 2d and benzhydrol
2e were applied as the substrates in the reactions with 1a, the
products 3d and 3e were generated smoothly in good to excellent
yields both under conventional heating and MW conditions (Table
2, entries 4 and 5). For the reaction of 1a with the propargylic alco-
hol 2f, good yields were observed both under the conventional
heating and MW conditions (Table 2, entry 6).
Reactions of 1a and 2a using H2SO4 as the catalyst under various conditionsa
O
O
OH
Ph
Ph
O
O
5 mol% H2SO4
+
Ph
Ph
1a
2a
3a
Entry
Solvent
Temp. (°C)
1a:2a
Yieldb (%)
1
2
3
4
5
6
7
8
DCE
THF
Reflux
Reflux
101
Reflux
Reflux
Reflux
Reflux
101
101
85
70
101
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
2:1
1:1
1:2
3:1
67
0
0
Dioxane
EtOAc
Heptane
CH2Cl2
CHCl3
Toluene
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
2
11
21
24
28
98
76
44
81
74
61
95
9
10
11c
12
13
14d
15e
101
101
101 (MW)
a
Reaction conditions: H2SO4 (0.05 mmol), 2a (1.0 mmol), solvent (2 mL), 5 min,
unless noted.
b
Isolated yields based on 2a.
Reaction time: 20 min.
Compound 1a (1.0 mmol) was used and the isolated yield was based on 1a.
The conventional heating condition was changed to MW condition.
c
d
e
When the b-diketone benzoylacetone 1b was employed in the
reactions with secondary alcohols 2a, 2b, 2d, and 2e, high yields
(83–97%) of the corresponding products were obtained both under
conventional heating and MW conditions, and no obvious differ-
ence was observed between the two reaction conditions for all
substrates (Table 2, entries 7–10). Furthermore, when the diketone
1a with two phenyl substitutes was changed to acetylacetone 1c,
the nucleophilicity of the enol form of the diketone decreases be-
cause the methyl group is less electron rich compared with phenyl
group in the diketones. But the reaction of 1c with 2d and 2e also
afforded 3k and 3l in excellent yields both under the conventional
heating and MW conditions (Table 2, entries 11 and 12). When the
allylic alcohol 2g was used to react with 1c, the reaction proceeded
smoothly and similar results were observed both under the con-
ventional heating and MW conditions (Table 2, entry 13). At last,
with the hope to expand the substrate scope, b-keto esters 1d
and 1e with relatively low reactivities were applied as the nucleo-
philes to react with benzhydrol 2e, and the products 3n and 3o
were obtained successfully in 95% and 93% yields under the con-
ventional heating and MW conditions, respectively (Table 2, en-
tries 14 and 15). It is noteworthy that the addition of 1a to the
secondary alkyl alcohols such as 2-octanol did not proceed both
under the conventional heating and MW conditions, due to the
instability of the alkyl cation intermediate.
In summary, we have demonstrated that H2SO4, one of the
cheapest Brønsted acids, is a highly efficient catalyst for the direct
addition of b-dicarbonyl compounds to secondary alcohols both
under conventional heating condition and under MW condition.
For various b-dicarbonyl compounds and a series of secondary
alcohols, the addition reactions afford high yields in most cases
only after 5 min. To date, H2SO4 is the most effective catalyst for
the addition of b-dicarbonyl compounds to alcohols and possesses
the potential for the application in industry. Moreover, the reac-
tions under conventional heating condition or under MW condition
afford similar results and no obvious specific or nonthermal micro-
wave effects have been observed in the addition reactions.
5 mol % H2SO4 gave out exceptionally high yield of 98% after 5 min
under 101 °C (Table 1, entry 9). In former reports of the addition of
b-dicarbonyl compounds to alcohols using Brønsted acids as the
catalysts, CH3NO2 was also proved to be the best solvent,14,16 prob-
ably due to the strong polarity stabilizing the cation intermediates.
If the reaction temperature was decreased to 85 °C or 70 °C, the
yields concomitantly reduced to 76% or 44% (Table 1, entries 10
and 11). Moreover, if the ratio of 1a to 2a was changed from 3:1
to 2:1, 1:1, or 1:2, the reaction yields were affected negatively
(Table 1, entries 12–14), which was mainly caused by the etherifi-
cation of the alcohol as a side reaction.
Since the first example in 1986,17 microwave irradiation (MW)
has matured into a highly useful technique in organic synthesis to
promote numerous organic reactions.18 Compared with the con-
ventional thermal heating method, controlled microwave heating
approach often elicits a dramatic increase of the reaction rate
and yields. However, the exact reasons for the enhancement of
the reaction rate and yields are still ambiguous and ongoing debate
remains in the scientific community until now. In particular, some
reports declared that non-thermal microwave effects exist and
attributed the remarkable increase of the reaction rate and yields
to the selective interactions of the electromagnetic field with spe-
cific substrate molecules, reagents, or catalysts.19 On the other
hand, recent investigations using accurate on-line reaction temper-
ature measurements demonstrate that the specific microwave ef-
fects on the standard synthetic organic reactions in solvents
probably do not exist, and the observed enhancements are the re-
sult of purely thermal effects induced by the rapid heating and
high bulk reaction temperatures through microwave heating.20
The ongoing argument about the intrinsic reason (thermal or
non-thermo effect) promoting the reaction rate and yields in
MW-assisted reactions triggered our interest to compare the reac-
tion results under conventional heating condition with those under
MW condition for the addition of b-dicarbonyl compounds to alco-
hols.21 Then, the reactions of 1a and 2a in CH3NO2 were carried out

2830
F. Xia et al. / Tetrahedron Letters 53 (2012) 2828–2832
Table 2
Addition reactions of b-dicarbonyl compounds to alcohols catalyzed by H2SO4 under conventional heating and MW conditions
Entry
b-Dicarbonyl compound
Alcohol
Product
Yielda (%)
Yieldb (%)
O
O
O
O
O
O
OH
O
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
1a
1a
1a
1
98
95
2a
3a
O
OH
Ph
Ph
2
3
93
90
97
95
F
2b
F
3b
O
OH
O
Ph
Ph
Cl
2c
Cl
3c
O
O
O
OH
O
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1a
1a
4
5
97
82
92
83
2d
3d
O
O
O
OH
O
Ph
Ph
2e
3e
O
OH
O
O
Ph
Ph
Ph
1a
6
86
85
2f
3f
O
O
O
OH
O
O
Ph
Ph
Ph
1b
1b
7
8
88
92
83
91
2a
3g
O
OH
O
O
Ph
F
2b
F
3h
O
O
O
O
OH
O
O
Ph
Ph
Ph
1b
1b
9
97
90
92
86
2d
3i
OH
O
O
Ph
10
2e
3j

F. Xia et al. / Tetrahedron Letters 53 (2012) 2828–2832
2831
Table 2 (continued)
Entry
b-Dicarbonyl compound
Alcohol
Product
Yielda (%)
Yieldb (%)
O
O
OH
O
O
O
11
98
92
80
94
1c
1c
2d
OH
3k
O
O
O
12
13
14
91
87
2e
3l
O
O
O
O
OH
O
O
O
1c
2g
3m
OH
O
OEt
OEt
1d
95
93
90
87
2e
3n
O
O
O
OH
O
Ph
OEt
Ph
OEt
15
1e
2e
3o
a
Reaction conditions: H2SO4 (0.05 mmol), alcohol (1.0 mmol), b-dicarbonyl compound (3.0 mmol), CH3NO2 (2 mL), 101 °C, 5 min, isolated yield based on alcohol.
Reaction conditions: H2SO4 (0.05 mmol), alcohol (1.0 mmol), b-dicarbonyl compound (3.0 mmol), CH3NO2 (2 mL), 101 °C, MW for 5 min, isolated yield based on alcohol.
b
9. Rao, W.; Tay, A. H. L.; Goh, P. J.; Choy, J. M. L.; Ke, J. K.; Chan, P. W. H.
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This work was supported financially by the National Natural
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and 21190033), the Innovation Program of Shanghai Municipal
Education Commission (Project No. 12ZZ050) and the Fundamental
Research Funds for the Central Universities.
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Supplementary data
Supplementary data (list of compounds along with their yield,
analytical data, and copies of 1H NMR and 13C NMR spectra are
included) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2012.03.104.
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stirred under 101 oC in oil bath for 5 min. Then Na2CO3 (10 mg) was added to
the reaction mixture to quench the reaction and the solvent was removed
under reduced pressure, and the residue was flash column chromatographed
over silica gel to afford the product.
23. Typical procedure
B for the microwave-assisted addition of b-dicarbonyl
compounds to alcohols catalyzed by H2SO4: b-Dicarbonyl compound
(3.0 mmol) and alcohol (1.0 mmol) were combined in 2 mL of nitromethane,
and H2SO4 (2.7 lL, 0.05 mmol) was added, and the resulting mixture was
21. Babu, S. A.; Yasuda, M.; Tsukahara, Y.; Yamauchi, T.; Wada, Y.; Baba, A.
Synthesis 2008, 1717–1724.
22. Typical procedure A for the reaction of b-dicarbonyl compound with alcohol
catalyzed by H2SO4 under conventional heating condition: b-Dicarbonyl
compound (3.0 mmol) and alcohol (1.0 mmol) were combined in 2 mL of
stirred under 101 oC with the microwave irradiation (650 W, 70%) for 5 min.
Then Na2CO3 (10 mg) was added to the reaction mixture to quench the
reaction and the solvent of the reaction mixture was removed under reduced
pressure and the residue was passed through the flash column
chromatography on silica gel to afford the product.