Perchloric acid catalyzed homogeneous and heterogeneous addition of β-dicarbonyl compounds to alcohols and alkenes and investigation of the mechanism

Article abstract of DOI:10.1021/jo100517k

(Figure presented) The direct addition of various β-dicarbonyl compounds to a series of secondary alcohols and alkenes has been achieved using 1 mol % perchloric acid (HClO₄) as the catalyst. The HClO ₄-catalyzed reactions could be conveniently conducted in commercial solvent and gave moderate to excellent yields. Moreover, the silica gel-supported HClO₄ could also catalyze the heterogeneous addition for a series of substrates with similar or even higher yields in comparison with the homogeneous ones. The supported catalyst could be readily recovered and reused for four runs. Furthermore, the mechanism of the HClO₄- catalyzed addition of the β-diketone to alcohol was investigated, and an S_N1 mechanism was proved unambiguously for the first time through a series of experiments. The discrimination of catalytic abilities among different Bronsted acids was also rationalized by DFT calculations.

Full text of DOI:10.1021/jo100517k

pubs.acs.org/joc
Perchloric Acid Catalyzed Homogeneous and Heterogeneous Addition of
β-Dicarbonyl Compounds to Alcohols and Alkenes and Investigation
of the Mechanism
Pei Nian Liu,*,†,‡ Li Dang,§ Qing Wei Wang,† Shu Lei Zhao,† Fei Xia,† Yu Jie Ren,*,†
Xue Qing Gong,† and Jun Qin Chen†
†Key Lab for Advanced Materials and Institute of Fine Chemicals, School of Chemistry and Molecular
Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237,
P. R. China, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000,
‡
P. R. China, and §Department of Chemistry, Hong Kong University of Science & Technology,
Clear Water Bay, Kowloon, Hong Kong, P. R. China
liupn@ecust.edu.cn
Received March 31, 2010
The direct addition of various β-dicarbonyl compounds to a series of secondary alcohols and alkenes
has been achieved using 1 mol % perchloric acid (HClO4) as the catalyst. The HClO4-catalyzed
reactions could be conveniently conducted in commercial solvent and gave moderate to excellent
yields. Moreover, the silica gel-supported HClO4 could also catalyze the heterogeneous addition for a
series of substrates with similar or even higher yields in comparison with the homogeneous ones. The
supported catalyst could be readily recovered and reused for four runs. Furthermore, the mechanism
of the HClO4-catalyzed addition of the β-diketone to alcohol was investigated, and an SN1
mechanism was proved unambiguously for the first time through a series of experiments. The
discrimination of catalytic abilities among different Brønsted acids was also rationalized by DFT
calculations.
Introduction
limited due to the low reactivity of alcohols toward the
nucleophiles.3 Recently, some Lewis acidic metal catalysts such
as InCl3,4 InBr3,5 FeCl3,6 Bi(OTf)3,7 and Ln(OTf)3 (Ln = La,
Yb, Sc, Hf)8 have been described as effective catalysts for the
addition of β-dicarbonyl compounds to allylic and benzylic
alcohols. Besides, Brønsted acids, such as H-montmorillonite,9
The construction of C-C bonds is always one of the
central themes in organic synthesis.1 Because of the call of
“green chemistry”,2 the direct reaction of alcohols (ROH)
and active methylenes (R0-CH2-R00) has attracted much
attention in recent years because only H2O is generated as
the side product and the preparation of the active interme-
diates, such as organometallic compounds and halides or a
related species, is not required. Although the advantages of
enhancing atom efficiency and avoiding waste are realized,
the successful examples of such “green” transformation are
ꢀ
(3) Guillena, G.; Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2007, 46,
2358.
(4) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int. Ed. 2006, 45,
793.
(5) Vicennati, P.; Cozzi, P. G. Eur. J. Org. Chem. 2007, 2248.
(6) (a) Kischel, J.; Mertins, K.; Michalik, D.; Zapf, A.; Beller, M. Adv.
Synth. Catal. 2007, 349, 865. (b) Yuan, Y.; Shi, Z.; Feng, X.; Liu, X. Appl.
Organomet. Chem. 2007, 21, 958. (c) Jana, U.; Biswas, S.; Maiti, S. Tetra-
hedron Lett. 2007, 48, 4065.
(7) Rueping, M.; Nachtsheim, B. J.; Kuenkel, A. Org. Lett. 2007, 9, 825.
(8) (a) Noji, M.; Konno, Y.; Ishii, K. J. Org. Chem. 2007, 72, 5161. (b)
Huang, W.; Wang, J.; Shen, Q.; Zhou, X. Tetrahedron Lett. 2007, 48, 3969.
(9) (a) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. Angew. Chem., Int. Ed. 2006, 45, 2605. (b) Motokura, K.;
Nakagiri, N.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Org. Chem. 2007,
72, 6006.
(1) (a) March, J. Advanced Organic Chemistry, 4th ed.; Wiley: New York,
1992. (b) Current Trends in Organic Synthesis; Scolastico, C., Nicotra, F., Eds.;
Plenum: New York, 1999.
(2) (a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice;
Oxford University, Press: New York, 1988. (b) Matlack, A. S. Introduction to
Green Chemistry; Marcel Dekker Inc.: New York, 2001. (c) Lancester, M. Green
Chemistry: An Introductory Text; Royal Society of Chemistry: Cambridge,
2002. (d) Clark, J. H.; Macquarrie, D. Handbook of Green Chemistry &
Technology; Blackwell Publishers: Oxford, 2002.
DOI: 10.1021/jo100517k
r
Published on Web 06/25/2010
J. Org. Chem. 2010, 75, 5017–5030 5017
2010 American Chemical Society

Liu et al.
JOCArticle
“dodecylbenzenesulfonic acid,10 p-toluenesulfonic acid,11,12
triflic acid,12” and 12-phosphotungstic acid,13 have been found
to be the effective catalysts for the addition of β-diketones to
secondary alcohols in recent years.
TABLE 1. Reactions of 1a and 2a Using Brønsted Acids As Catalysts
under Various Conditionsa
Although remarkable progress has been made in the Lewis
acid or Brønsted acid catalyzed addition of β-dicarbonyl
compounds to alcohols, few investigations of the reaction
mechanism have been conducted and no single process has
been established. Recently, we have successfully applied a
perchloric ruthenium complex to the addition of β-diketones
to secondary alcohols and alkenes.14 Further mechanistic
investigation of this Lewis acid catalyzed addition has
revealed that the ruthenium complex reacts first with the
β-diketone to form a stable β-diketone chelate ruthenium
complex and concomitantly yields an equivalent of perchlo-
ric acid, which proved to be the true catalyst for the addition
reaction. From this preliminary study, we became interested
in the addition of β-dicarbonyl compounds to alcohols and
alkenes catalyzed directly by HClO4 and the reaction mec-
hanism of the Brønsted acid catalyzed addition. Herein, we
report our results of the efficient homogeneous and hetero-
geneous addition of β-dicarbonyl compounds to alcohols
and alkenes catalyzed by perchloric acid (HClO4) and the
silica gel supported perchloric acid (HClO4-SiO2), as well as
the investigation of the reaction mechanism through experi-
mental and theoretical studies.
entry
acid
HCl
HBF4
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
temp (°C)
yield (%)b
1
2
3
4
5
6
7
8
70
70
70
70
70
70
70
70
70
70
70
70
60
80
70
70
70
70
0
0
0
0
0
HNO3
CF3CO2H
CH3CO2H
H2SO4
TfOH
9
74
83
73
70
0
76
57
68
63
88
74d
80e
HClO4
HClO4
HClO4
HClO4
HClO4
HClO4
HClO4
HClO4
HClO4
HClO4
HClO4
9
DCE
CHCl3
10
11
12
13
14
15c
16
17
18
1,4-dioxane
solvent-free
solvent-free
solvent-free
toluene
toluene
toluene
toluene
aReaction conditions: acid (0.01 mmol), 1a (1.5 mmol), 2a (1.0 mmol),
17 h, 2.0 mL of solvent was added where noted. bBased on 2a except for
entry 16 where 1.0 mmol of 1a and 2.0 mmol of 2a were used. c0.004 mmol
of HClO4 was used. dThe reaction time was 6 h. eThe reaction time was 12h.
Results and Discussion
HClO4-Catalyzed Reactions. In the screening of effective
catalysts and reaction conditions, we chose acetylacetone
(1a) and 1-phenylethanol (2a) as the substrates for model
reaction. It can be seen from Table 1 that some usual
Brønsted acids such as HCl, HBF4, HNO3, CF3CO2H, and
CH3CO2H were all ineffective for the reaction of 1a and 2a,
except that H2SO4 gave 9% yield after 17 h (Table 1, entries
1-6). TfOH and HClO4 proved to be effective catalysts for
the addition of 1a to 2a to generate 3a, and HClO4 gave the
higher yield (Table 1, entries 7 and 8). In this HClO4-
catalyzed addition, only 1 mol % catalyst loading was
needed compared with 5 mol % TfOH in the early report.12
The reactions of 1a and 2a catalyzed by HClO4 could be
conveniently conducted in air in the absence of solvent or in
commercial grade solvents such as toluene, 1,2-dichlor-
oethane (DCE) or CHCl3; the reaction in toluene gave the
best result (Table 1, entries 8-12). When the temperature
was increased or decreased, the yields were affected nega-
tively after the same reaction time (Table 1, entries 13 and
14). Moreover, this reaction also proceeded smoothly when
only 0.4 mol % HClO4 was used (Table 1, entry15). Inter-
estingly, the best result (88% yield) was obtained when 2
equiv of 2a relative to 1a were used, although better reaction
results are observed when excess molar of 1a are used in most
related reports8-12 (Table 1, entry 16). If the reaction time
was shortened, the reactions gave worse yields (Table 1,
entries 17 and 18).
Subsequently, the addition of β-diketones to various
alcohols was examined in commercial grade toluene at
70 °C, using 1 mol % HClO4 as the catalyst (Table 2). The
reactions of β-diketones 1a-c with benzylic alcohols 2a-e
were all highly effective, giving products in excellent yields
(Table 2, entries 1-5, 10, 12-14). Note that when 1-(4-
nitrophenyl)ethanol with a strong electron-withdrawing
group on the aromatic ring was used to react with 1a and
1c, no addition product (with 1a) or only trace product (with
1c) was observed. Acetylacetone 1a also reacted with 1-(2-
naphthyl)ethanol 2f smoothly to give 3f in moderate (65%)
yield, and this yield could not be enhanced even when the
reaction time was prolonged (Table 2, entry 6). The reactions
of β-diketones and diphenylmethanol 2g also afforded the
products in excellent to good yields (Table 2, entries 7 and
15). In the allylation of 1a with allylic alcohol 2h, product 3h
was obtained with 75% yield after 70 h, although only 59%
yield was observed after 17 h (Table 2, entry 8). Moreover,
the allylations of 1a and 1c with allylic alcohol 2i proceeded
smoothly, although the yields of the products 3i and 3p were
a little lower than those using benzylic alcohols (Table 2,
entries 9 and 16). Note that the identity of 3p has been
confirmed from X-ray crystallography analysis (Supporting
Information).15 The reaction of 1c and exo-norborneol 2j
produced 3q in 98% yield but needed a prolonged reaction
time due to the rigid structure of 2j (Table 2, entry 17). When
the sterically hindered cyclic diketone 1d was used in the
reaction with 2g, product 3r with a quaternary carbon atom
(10) Shirakawa, S.; Kobayashi, S. Org. Lett. 2007, 9, 311.
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(11) (a) Sanz, R.; Martınez, A.; Miguel, D.; Alvarez-Gutierrez, J. M.;
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Rodrıguez, F. Adv. Synth. Catal. 2006, 348, 1841. (b) Sanz, R.; Miguel, D.;
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Martınez, A.; Alvarez-Gutierrez, J. M.; Rodrıguez, F. Org. Lett. 2007, 9, 727.
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(12) Sanz, R.; Miguel, D.; Martınez, A.; Alvarez-Gutierrez, J. M.;
Rodrıguez, F. Org. Lett. 2007, 9, 2027.
(13) Wang, G.-W.; Shen, Y. -B.; Wu, X.-L. Eur. J. Org. Chem. 2008, 29,
4999.
(14) Liu, P. N.; Zhou, Z. Y.; Lau, C. P. Chem.;Eur. J. 2007, 13, 8610.
(15) See Supporting Information.
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a
TABLE 2. Reactions of Various β-Dicarbonyl Compounds and Alcohols Catalyzed by HClO4
J. Org. Chem. Vol. 75, No. 15, 2010 5019

Liu et al.
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TABLE 2. Continued
aReaction conditions: HClO4 (0.01 mmol), β-dicarbonyl compound (1.0 mmol), alcohol (2.0 mmol), toluene (2 mL), 70 °C, 17 h unless noted. bBased
on β-dicarbonyl compounds used. c2 mL of DCE was used as the solvent. dThe reaction time was 70 h. eThe diastereomer ratio was determined by 1H
NMR. f0.03 mmol of HClO4 was used. g20 mmol of alcohol and 10 mmol of β-diketone were used
5020 J. Org. Chem. Vol. 75, No. 15, 2010

Liu et al.
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a
TABLE 3. Addition of Various β-Diketones to Alkenes Catalyzed by HClO4
aReaction conditions: HClO4 (0.01 mmol), β-diketone (1.0 mmol), alkene (2.0 mmol), toluene (2 mL), 70 °C, 20 h, unless noted. bBased on β-diketone
used. cThe reaction was performed at 80 °C. dThe diastereomer ratio was determined by 1H NMR. eThe reaction was performed in 2 mL of CH3NO2 with
5 mol % HClO4.
at C2 of the five-membered ring was obtained in 96% yield,
using 3 mol % HClO4 as the catalyst (Table 2, entry18). In an
expansion of the substrates, β-keto esters 1e and 1f were used
in reaction with diphenylmethanol 2g, and products 3s and 3t
were obtained successfully in high yields (Table 2, entries 19
and 20). However, the HClO4-catalyzed addition of β-diester
to secondary alcohols was not successful under the present
reaction conditions, nor was the addition of β-diketones to
primary alcohols. By increasing the reaction scale to 10
mmol of 1c and 20 mmol of 2a, 2.92 g (89% yield) of product
was isolated, thereby demonstrating the applicability of this
HClO4-catalyzed reaction in organic compound preparation
(Table 2, entry 21).
The addition of β-dicarbonyl compounds to olefins, which
yields alkylated dicarbonyls, is considered to be a highly atom-
economical process.16 Several cases of palladium-catalyzed
intramolecular17 and intermolecular addition18 of β-dicarbo-
nyl compounds to olefins have been described. Li and co-
workers have employedsilver triflate orcombinations ofsilver
and gold salts as catalysts for the addition of β-dicarbonyl
compounds to styrenes, dienes, trienes, and cyclic enol
ethers.19 Recently, H-montmorillonite,9 Bi(OTf)3,20 FeCl3,21
Cu(OTf )2,22 and phosphotungstic acid23 were also reported
to be effective to catalyze the addition of β-diketones to
(18) (a) Leitner, A.; Larsen, J.; Steffens, C.; Hartwig, J. F. J. Org. Chem.
2004, 69, 7552. (b) Wang, X.; Widenhoefer, R. A. Chem. Commun. 2004, 660.
(19) (a) Yao, X.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 6884. (b) Nguyen,
R.-V.; Yao, X.-Q.; Bohle, D. S.; Li, C.-J. Org. Lett. 2005, 7, 673. (c) Yao, X.;
Li, C.-J. J. Org. Chem. 2005, 70, 5752.
(20) Rueping, M.; Nachtsheim, B.; J. Kuenkel, A. Synlett 2007, 9, 1391.
(21) Duan, Z.; Xuan, X.; Wu, Y. Tetrahedron Lett. 2007, 48, 5157.
(22) Li, Y.; Yu, Z.; Wu, S. J. Org. Chem. 2008, 73, 5647.
(23) Wang, G.-W.; Shen, Y.-B.; Wu, X.-L.; Wang, L. Tetrahedron Lett.
2008, 49, 5090.
(16) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259. (c) Trost, B. M. Acc. Chem. Res. 2002, 35,
695.
(17) (a) Pei, T.; Widenhoefer, R. A. J. Am. Chem. Soc. 2001, 123, 11290.
(b) Pei, T.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125, 648.
(c) Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125, 2056. (d) Han,
X.; Wang, X.; Pei, T.; Widenhoefer, R. A. Chem.;Eur. J. 2004, 10, 6333.
J. Org. Chem. Vol. 75, No. 15, 2010 5021

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alkenes. At this stage, we were curious to see whether HClO4
was alsoactiveincatalyticaddition of acetylacetone to styrene
(4a) and yielded the same product 3a.
TABLE 4. Reactions of 1a and 2a Using HClO4-SiO2 as Catalysts
under Various Conditionsa
With 1 mol % HClO4 as catalyst, various diketones 1a-c
reacted with styrenes 4a-d and 2-norbornene 4e in toluene at
70 °C to yield the corresponding addition products in
moderate yields (Table 3). Compared with the corresponding
addition of β-diketones to alcohols, the yields were generally
lower and probably result from side reaction forming dimer
or oligomers.
entry
HClO4-SiO2
solvent
1a:2a
run
yield (%)b
HClO4-SiO2 Catalyzed Reactions. On the demanding of
“green chemistry”, catalyst immobilization has attracted lots
of attention in the past decades, because heterogeneous cata-
lysis provides for easy separation of the products from the
catalysts without tedious experimental workup. Moreover, it
enables the efficient recovery of the catalysts and allows for the
potential adaptation of the immobilized catalysts in contin-
uous flow-type processes.24 In recent years, a series of reactions
were studied using silica gel supported perchloric acid
(HClO4-SiO2) as the catalyst.25
To expand the versatility of HClO4-catalyzed addition of
β-diketones to alcohols, we tried the heterogeneous addition
of β-diketones to alcohols and styrene in the presence of
HClO4-SiO2 (containing 1 mol % HClO4). We were grati-
fied to find that the addition proceeds smoothly and displays
even better reaction result than the homogeneous reaction
with the acid. As shown in Table 4, immobilized catalysts A,
B, and C, prepared respectively by simple absorption of
HClO4 onto 100-200 mesh, 200-300 mesh, or H-type silica
gel, demonstrated similar reactivity for the reaction of 1a and
2a in toluene, and catalyst B gave the best yield (94%;
Table 4, entries 1-3). Further optimization of the reaction
conditions showed that the solvent-free reaction afforded
even better result (96% yield) than the reaction in toluene
(Table 4, entries 2 and 4). Recycling of the supported catalyst
B was readily achieved by simple filtration and it could be
used for four runs (Table 4, entries 4-7). However, if the
ratio of 1a to 2a is changed from 1:2 to 2:1, both the product
yield and recyclability of the catalyst diminished (Table 4,
entries 8-11). This heterogeneous reaction is a rather nice case
of green chemistry with the advantages of recyclable catalyst,
solvent-free conditions, and only water as the byproduct.
Following the successes recorded above, we applied
HClO4-SiO2 B to the heterogeneous addition of a range of
1
2
3
4
5
6
7
8
A
B
C
B
B
B
B
B
B
B
B
toluene
toluene
toluene
neat
neat
neat
neat
neat
neat
neat
1:2
1:2
1:2
1:2
1:2
1:2
1:2
2:1
2:1
2:1
2:1
1
1
1
1
2
3
4
1
2
3
4
93
94
92
96
92
79
70
92
91
73
0
9
10
11
neat
aReaction conditions: HClO4-SiO2 (containing 0.01 mmol HClO4),
1a (1.0 mmol), 2a (2.0 mmol) as 1a:2a = 1:2 or 1a (2.0 mmol), 2a (1.0
mmol) as 1a:2a = 2:1, 70 °C, 17 h, 2.0 mL of solvent were added if noted.
bIsolated yields based on 1a as 1a:2a = 1:2 or based on 2a as 1a:2a = 2:1.
β-dicarbonyl compounds to various alcohols and styrene
under solvent-free conditions at 70 °C; the results are listed in
Table 5. In the benzylation of β-diketones 1a-c with benzylic
alcohols 2a-d, the reactions generating 3a and 3c provided
better product yields while the other reactions listed led to
similar or slightly worse yields compared with those from the
homogeneous reactions (Table 5, entries 1-4, 7, 9, and 10).
When the solid substrates were used, in some cases a small
amount of solvent was needed to dissolve the reagents
(Table 5, entries 5, 6, 8, 11, 12, and 14). The reaction of 1a
with 1-(2-naphthyl)ethanol 2f gave much higher yield (93%)
than the homogeneous reaction (65%) with 3 mol % catalyst
loading (Table 5, entry 5). The addition of 1a-c to diphe-
nylmethanol 2g also generated the products in excellent
yields (Table 5, entries 6, 8, and 11). The sterically hindered
cyclic diketone 1d afforded the product 3r in moderate yield
with 2g and 3 mol % HClO4-SiO2 B (Table 5, entry 12).
When the substrates expanded to include β-keto esters 1e and
1f, the reactions also gave the products 3s and 3t smoothly
in 85% and 98% yields, respectively (Table 5, entries 13
and 14). Moreover, the HClO4-SiO2 catalyzed addition of
diketone 1a to styrene 4a gave 63% isolated yield (Table 5,
entry 15).
Mechanism. The mechanism of addition of β-diketones to
alcohols and alkenes catalyzed by Brønsted acids is generally
thought to involve the formation of a carbocation inter-
mediate and subsequent SN1 attack on the β-dicarbonyl
compound to yield the addition product.2,12-14 However,
no detailed experimental investigation on the mechanism of
Brønsted acid catalyzed reaction has been reported in recent
times. As the first stage of our mechanistic study, we
performed the reaction of diketone 1c and chiral alcohol
(S)-2a (99% ee) in the presence of 1 mol % HClO4 in toluene
at 70 °C. After 17 h, the product 3l, which could be analyzed
by HPLC on chiral OJ-H column, was obtained as a race-
mate (Scheme 1). Such racemization has been regarded as the
main proof for the SN1 mechanism proposal in the early
reports.2,7,14
(24) (a) Melero, J. A.; Iglesias, J.; Morales, G. Green Chem. 2009, 11,
1285. (b) Gu, Y.; Li, G. Adv. Synth. Catal. 2009, 351, 817. (c) Song, C. E.; Lee,
S. Chem. Rev. 2002, 102, 3495. (d) Fan, Q.-H.; Li, Y.-M.; Chan, A. S. C.
Chem. Rev. 2002, 102, 3385. (e) Vos, D. E. D.; Dams, M.; Sels, B. F; Jacobs,
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Y. J.; Chen, J. Q. Green. Chem. 2010, 12, 1049.
(25) Some selected reports of organic reactions using HClO4-SiO2 as the
catalyst: (a) Shaterian, H. R.; Yarahmadi, H.; Ghashang, M. Tetrahedron
2008, 64, 1263. (b) Chakraborti, A. K.; Gulhane, R. Chem. Commun. 2003,
1896. (c) Kumar, R.; Kumar, D.; Chakraborti, A. K. Synthesis 2007, 299.
(d) Shaterian, H.; Shahrekipoor, R.; Ghashang, F. M. J. Mol. Catal. A: Chem.
2007, 272, 142. (e) Das, B.; Laxminarayana, K.; Ravikanth, B. J. Mol. Catal.
A: Chem. 2007, 271, 131. (f) Kantevari, S.; Bantu, R.; Nagarapu, L. J. Mol.
Catal. A: Chem. 2007, 269, 53. (g) Bigdeli, M. A.; Heravi, M. M.; Mahdavinia,
G. H. J. Mol. Catal. A: Chem. 2007, 275, 25. (h) Das, B.; Damodar, K.;
Chowdhury, N.; Kumar, R. A. J. Mol. Catal. A: Chem. 2007, 274, 148. (i)
Kamble, V. T.; Jamode, V. S.; Joshi, N. S.; Biradara, A. V.; Deshmukh, R. Y.
Tetrahedron Lett. 2006, 47, 5573. ( j) Das, B.; Venkateswarlu, K.; Majhi, A.;
Reddy, M. R.; Reddy, K. N.; Rao, Y. K.; Ravikumar, K.; Sridhar, B. J. Mol.
Catal. A: Chem. 2006, 246, 276. (k) Das, B.; Venkateswarlu, K.; Suneel, K.;
Majhi, A. Tetrahedron Lett. 2007, 48, 5371. (l) Khatik, G. L.; Sharma, G.;
Kumar, R.; Chakraborti, A. K. Tetrahedron 2007, 63, 1200.
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TABLE 5. Reactions of Various Alcohols and β-Dicarbonyl Compounds Catalyzed by HClO4-SiO2 Ba
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TABLE 5. Continued
aReaction conditions: HClO4-SiO2 B (20 mg, containing 0.01 mmol HClO4), β-diketone (1.0 mmol), alcohol (2.0 mmol), solvent-free, 70 °C, 17 h unless
noted. bBased on β-diketone used. cToluene (2 mL) was used as the solvent. dHClO4-SiO2 B (60 mg, containing 0.03 mmol HClO4) was used. eDCE (2 mL)
was used as the solvent. fThe reaction time was 70 h. gThe diastereomer ratio was determined by 1H NMR. hThe reaction was performed at 80 °C.
We suspected that the racemization of chiral alcohol likely
occurred before the reaction of the alcohol with the
β-diketone. To gain experimental evidence for the racemiza-
tion of chiral alcohol, the same reaction of (S)-2a (99% ee)
and 1c with 1 mol % HClO4 catalyst was carried out in
toluene at 70 °C. HPLC analysis of the reaction mixture
showed that the ee value of (S)-2a had decreased to 65% ee
after 10 min, at which point only trace of 3l could be detected.
On heating a solution of (S)-2a (99% ee) in toluene to 70 °C
in the presence of 1 mol % HClO4, (S)-2a became achiral
(<5% ee) in 30 min. This demonstrates that (S)-2a racemizes
before its reaction with 1c, and one can not judge the process
to be SN1 or SN2 just on the observation of racemic 3l at the
completion of the reaction.
The observed racemization of chiral alcohol in the HClO4-
catalyzed reaction argues that SN2 mechanisms cannot be
dismissed. In the early studies, the change of the cationic SN1
mechanism to a concerted SN2 mechanism has been reported
for 1-phenylethyl substrates as the carbocation becomes
less stable.26 Recently, a concerted, eight-membered-ring
SCHEME 1. Reaction of (S )-2a and Diketone 1c with 1 mol %
HClO4 as the Catalyst
transition structure was proposed for the addition of
alcohol/amine to the alkene with TfOH as a catalyst.27
Moreover, Brønsted acid oriented reactions, especially chiral
Brønsted acid catalyzed asymmetric reactions, have at-
tracted great attention in recent years.28 In these transforma-
tions, a hydrogen bond is formed between the donor site of
the acid catalyst and the acceptor site of the electrophile, and
it is critical in achieving high reaction selectivity.29 We were
curious to see whether HClO4 could also donate the proton
to OH of the alcohol to form a hydrogen bond, which might
assist an SN2 reaction with the β-diketone. So, we carried out
the DFT calculations on the HClO4-catalyzed reaction of 1a
with 2a through an SN2 mechanism and found that the
energy profiles seemed reasonable because the barrier of
the SN2 process was only 26.5 kcal/mol (the relative free
(26) (a) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1982, 104, 4689.
(b) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1982, 104, 4691.
(c) Richard, J. P.; Rothenberg, M. E.; Jencks, W. P. J. Am. Chem. Soc.
1984, 106, 1361. (d) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106,
1373. (e) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106, 1383.
(f ) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106, 1396.
(g) Ta-Shama, R.; Jencks, W. P. J. Am. Chem. Soc. 1986, 108, 8040.
(27) Li, X.; Ye, S.; He, C.; Yu, Z.-X. Eur. J. Org. Chem. 2008, 4296.
(28) (a) Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) Terada, M. Chem.
Commun. 2008, 4097. (c) Doyle, A. D.; Jacobsen, E. N. Chem. Rev. 2007, 107,
5713. (d) Xu, S.; Wang, Z.; Zhang, X.; Ding, K. Angew. Chem., Int. Ed. 2008,
47, 2840. (e) Akiyama, T.; Itoh, J.; Yokota, D.; Fuchibe, K. Angew. Chem.,
Int. Ed. 2004, 43, 1566. (f ) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004,
126, 5356.
(29) (a) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc. 2009,
131, 3430. (b) Lu, M.; Zhu, D.; Lu, Y.; Zeng, X.; Tan, B.; Xu, Z.; Zhong, G. J.
Am. Chem. Soc. 2009, 131, 4562. (c) Vachal, P.; Jacobsen, E. N. J. Am. Chem.
Soc. 2002, 124, 10012. (d) Zhang, X.; Du, H.; Wang, Z.; Wu, Y.-D.; Ding, K.
J. Org. Chem. 2006, 71, 2862. (e) Gridnev, I. D.; Kouchi, M.; Sorimachi, K.;
Terada, M. Tetrahedron Lett. 2007, 48, 497. (f ) Yamanaka, M.; Itoh, J.;
ꢀ
Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 129, 6756. (g) Simon, L.;
Goodman, J. M. J. Am. Chem. Soc. 2008, 130, 8741. (h) Anderson, C. D.;
Dudding, T.; Gordillo, R.; Houk, K. N. Org. Lett. 2008, 10, 2749.
5024 J. Org. Chem. Vol. 75, No. 15, 2010

Liu et al.
JOCArticle
FIGURE 2. Conversion of 1a into 3a (based on 5) versus time plots
of HClO4-catalyzed reaction of 1a and 5 with 2:1 and 8:1 ratios.
FIGURE 1. Conversion of 1a into 3a (based on 2a) versus time plots
of HClO4-catalyzed reaction of 1a and 2a with 1:1 and 4:1 ratios.
Subsequently, two parallel HClO4-catalyzed reactions of
1a with meso- and (()-ether 5 (1a:5 = 2:1 and 8:1) were
carried out under identical reaction conditions, except the
4-fold change in ratio of 1a to 5. The conversion of 1a into 3a
at different reaction times was measured, and the results
showed that the concentration of 1a had no obvious effect on
the reaction rate (Figure 2). This result also proves that the
reaction of 1a and 5 is by an SN1 mechanism involving
carbocation intermediate 6 because the rate of addition is
in direct proportion to the concentration of 1a in an SN2
mechanism but independent of it in an SN1 mechanism.
Moreover, we analyzed product 3l from 1c and (S)-2a (99% ee)
at 10 min, when (S)-2a still possessed 65% ee; <2% ee was
observed for 3l (Scheme 2). This result is also consistent with the
SN1 mechanism for the HClO4-catalyzed reaction of 1c and
(S)-2a, because the reaction of 1c with chiral (S)-2a (>65% ee)
should give 3l in >65% ee at 10 min in an SN2 mechanism but
with 0% ee in an SN1 mechanism.
On the basis of the observations, we are prompted to
propose the SN1 mechanism of Scheme 3 (using acetylace-
tone 1a and 1-phenylethanol 2a as examples) for the addition
of β-diketones to the secondary alcohols. The perchloric acid
protonates the alcohol and carbocation intermediate 6
would rapidly be generated by loss of water. Intermediate 6
would then attack an alcohol molecule to give the symmetric
meso- and (()-ether 5 or undergo electrophilic attack at the
R-carbon of the β-diketone to give the addition product, with
regeneration of a proton. Note that the β-diketone might be
preferentially in an enol tautomeric form in the nonpolar
solvent (toluene) at higher temperature (70 °C).31 Through
the series of experiments described above, we have proved
that the various reactions involve in the conversion, includ-
ing 2a and 1a to 3a, 2a and 2a to 5, 5 and 1a to 3a, all proceed
via SN1 mechanisms. Although the mechanism discovered
here is similar to those formerly proposed,2,13,14 it is the first
energy, ΔG) and further lowered in calculations that in-
cluded the solvation effect of toluene.15
The rate of addition is in direct proportion to the concen-
tration of 1a in an SN2 mechanism and independent of it in an
SN1 mechanism. To further clarify the mechanism of the
HClO4-catalyzed addition of β-diketone to the alcohol, we
carried out two parallel HClO4-catalyzed reactions of 1a and
2a under identical reaction conditions, with one containing 1
equiv of 1a and the other containing 4 equiv of 1a. The
conversions at different times were measured, and the results
showed that the reactions proceeded with the same reaction
rates (Figure 1). This observation demonstrates that the
concentration of 1a does not affect the reaction rate and
that the reaction proceeds by an SN1 mechanism.
It is known that acids can act as promoters for conversion
of alcohols to symmetrical ethers.12,14,30 In the reaction of 1a
and 2a with 1 mol % HClO4 as the catalyst, we noticed that
the symmetric ether meso- and (()-Ph(CH3)CH-O-CH-
(CH3)Ph (5) was generated rapidly and consumed later with
the formation of the addition product 3a. For example, in the
reaction of 1a (1 mmol) and 2a (1 mmol), 1H NMR analysis
at different reaction times showed 2a:5:3a ratios of 0.83:6.7:1
(0.5 h), 0.12:1.31:1 (1 h), 0.02:0.17:1 (1.5 h), and 0:0:1 (2 h).
Subsequent etherification of (S)-2a with 1 mol % HClO4 as
catalyst in toluene at 70 °C was complete in 40 min, and 1H
NMR analysis of the reaction mixture at 10 min showed the
ratio of (R,S)-5 to (S,S)-5 to be 1:1, while 2a still possessed
75% ee. This result is unambiguous in demanding that
carbocation 6 is formed in the etherification reaction of
(S)-1-phenylethanol through an SN1 process (Scheme 3).
Nucleophilic attack of chiral (S)-2a on another (S)-2a should
generate (R,S)-5 as the main product in the SN2 reaction,
whereas attack of chiral (S)-2a (>75% ee) to both faces of
cation 6 would afford the equal amount of (R,S)-5 and (S,S)-5
in an SN1 process.
(31) (a) Schlund, S.; Janke, E. M. B.; Weisz, K.; Engels, B. J. Comput.
Chem. 2010, 31, 665. (b) Drexler, E. J.; Field, K. W. J. Chem. Educ. 1976, 53,
392. (c) Chan, S. I.; Lin, L.; Clutter, D.; Dea, P. Proc. Natl. Acad. Sci. U.S.A.
1970, 65, 316.
(30) Diaz, D. D.; Martın, V. S. Tetrahedron Lett. 2000, 41, 9993.
J. Org. Chem. Vol. 75, No. 15, 2010 5025

Liu et al.
JOCArticle
SCHEME 2. Reaction of (S)-2a and Diketone 1c with 1 mol % HClO4 as Catalyst
SCHEME 3. Proposed Mechanism of the HClO4-Catalyzed
Addition of β-Diketones to Alcohols
yields of the product 3a after 2 h in the two reactions were
42% and 43%, respectively, demonstrating that the concen-
tration of 1a has no effect on the reaction rate and that the
addition of 1a to 4a also proceeds through a carbocation
intermediate. So, a mechanism very similar to the addition of
β-diketones to alcohols is proposed as operative for the HClO4-
catalyzed addition of β-diketones to styrenes (Scheme 5, using
1a and 4a as examples). Again, the crucial species is the
carbocation intermediate 6; it attacks the β-diketone (or in
enol form) to yield the addition product or reacts with styrene
to yield dimer and higher oligomers as byproduct,32 which
might result in the observed relatively low yield for the reac-
tions of β-diketones with styrene.
Conclusion
In summary, very cheap HClO4 (1 mol %) has been used
for the first time as an effective catalyst for the direct addition
of various β-dicarbonyl compounds to a series of sluggish
alcohols or alkenes. The metal-free reactions gave out mode-
rate to excellent yields with water as the only byproduct.
Moreover, silica-gel-supported HClO4 has also been success-
fully applied to give a solvent-free catalytic addition as an
environmentally benign protocol. The supported catalyst
could be readily recovered and reused for 4 runs. For a series
of substrates, the heterogeneous catalytic reactions provided
similar or better results in comparison with the homoge-
neous ones. Furthermore, the mechanism of the HClO4-
catalyzed addition of the β-diketone to alcohol was investi-
gated in detail, and an SN1 mechanism was unambiguously
established for the first time. The catalytic abilities of diffe-
rent Brønsted acids was investigated through DFT calcula-
tions and HClO4 was found to be the stronger promoter for
the generation of the carbocation intermediate than TfOH
and H2SO4.
unambiguous proof of an SN1 mechanism for the addition of
β-diketones to alcohols by experiments that include kinetic
studies and racemization experiments. Note that in this
HClO4-catalyzed addition, the substitution of carbocations
into the toluene ring have not been observed in the substrate
scope we investigated. Moreover, with the mechanism estab-
lished as SN1, the reaction of allylic alcohols 2h and 2i must
proceed via the delocalized allylic cation and the products
were formed with the probability to capture at both C1
and C3.
To understand the discrimination of the catalytic abilities
among various Brønsted acids, we carried out DFT calcula-
tions on the effect of different acids in carbocation forma-
tion. As shown in Scheme 4, the relative free energy
(ΔGtoluene) at 25 °C for the formation of carbocation 6 with
HClO4 in toluene is 32.7 kcal/mol (eq 1),15 and correspond-
ing ΔGtoluene with TfOH and H2SO4 in toluene are 33.0 and
40.2 kcal/mol (eqs 2 and 3), respectively. The calculations
suggest that HClO4 and TfOH are more powerful in facili-
tating generation of carbocation 6 in comparison with
H2SO4. The calculations are also consistent with the experi-
ment in that HClO4 and TfOH are effective catalysts and
H2SO4 exhibits only a very low reactivity in the addition of
β-diketone to the alcohol (Table 1, entries 6-8). At the same
time, compared with TfOH, a slightly smaller energy diffe-
rence between reactants and carbocation intermediate for
HClO4 is consistent with the higher yield obtained with it as
the catalyst (Table 1, entries 7 and 8). Our calculated free
energies in gas phase at 70 °C are smaller than those at room
temperature (see Table 3 in Supporting Information). This
result is consistent with the experimental fact that the reac-
tions carried out at higher temperature proceed more
smoothly than those at room temperature.
Experimental Section
General. 1-(4-Methylphenyl)ethanol 2c, 1-(4-chlorophenyl)-
ethanol 2d, 1-(4-fluororophenyl) ethanol 2e, and 1,3-diphenyl-
2-propenol 2h were prepared by reduction of the corresponding
ketone precursors with NaBH4 in methanol. Chemical shifts
(δ, ppm) in the 1H spectra were recorded using TMS as internal
standard. Chemical shifts in 13C{1H} NMR spectra were intern-
ally referenced to CHCl3 (δ = 77.0 ppm). The silica gel was dried
at 110 °C for 2 h before loading with HClO4.
Typical Procedure A for the Reaction of β-Dicarbonyl Com-
pound with Alcohol (or Styrene) Catalyzed by HClO4. β-Dicar-
bonyl compound (1.0 mmol) and alcohol (or styrene, 2.0 mmol)
were combined in 2 mL of toluene, and HClO4 (1 μL, 60%,
(32) (a) Noji, M.; Ohno, T.; Fuji, K.; Futaba, N.; Tajima, H.; Ishii, K.
J. Org. Chem. 2003, 68, 9340. (b) Alesso, E.; Torviso, R.; Erlich, M.;
To investigate whether a carbocation intermediate is also
generated in the HClO4-catalyzed addition of β-diketones to
styrenes,27 we performed two parallel reactions of 1a and 4a
in 1:1 and 4:1 ratios, with 1 mol % HClO4 as the catalyst. The
~
Finkielsztein, L.; Lantano, B.; Moltrasio, G.; Aguirre, J.; Vazquez, P.;
Pizzio, L.; Caceres, C.; Blanco, M.; Thomas, H. Synth. Commun. 2002,
ꢀ
ꢀ
3803. (c) Xu, T.; Haw, J. F. J. Am. Chem. Soc. 1994, 116, 10188. (d) Mayo,
F. R. J. Am. Chem. Soc. 1968, 90, 1289.
5026 J. Org. Chem. Vol. 75, No. 15, 2010

Liu et al.
JOCArticle
SCHEME 4. Computed Relative Free Energies (kcal/mol) for the Formation of Carbocation 6 from 1a with HClO4, TfOH, or H2SO4
as the Catalysts in Toluene (see Table 3 in Supporting Information)
SCHEME 5. Proposed Mechanism of the HClO4-Catalyzed Addition of β-Diketone to Styrene
0.01 mmol) was added. The mixture was stirred at 70 °C and
monitored by TLC or H NMR. When maximum conversion
was reached, the solvent was removed under reduced pressure,
and the residue was flash column chromatographed over silica
gel to give the product.
Preparation of Silica Gel Supported Perchloric Acid (HClO4-
SiO2). 25c. To a suspension of silica gel (10.00 g) in Et2O (35 mL)
was added 70% aqueous solution of HClO4 (0.75 g, 5.0 mmol),
and the mixture was stirred magnetically for 30 min at room
temperature. The Et2O was removed under reduced pressure,
and the residue was dried at 110 °C for 2 h to afford HClO4-
SiO2 (0.5 mmol g-1) as a white powder.
Typical Procedure B for the Reaction of β-Dicarbonyl Com-
pound with Alcohol (Or Styrene) Catalyzed by HClO4-SiO2 and
the Recycling Reactions. A mixture of the β-dicarbonyl com-
pound (1.0 mmol), alcohol (or alkene, 2.0 mmol), and HClO4-
SiO2 (20 mg, containing 0.01 mmol HClO4) was combined and
stirred vigorously at 70 °C (2 mL of toluene or DCE was added
to dissolve the solid substrates as noted in entries 5, 6, 8, 11, 12,
and 14 in Table 5). The reaction was monitored by TLC. After
the completion of the reaction, CH2Cl2 (1 mL) was added, and
the mixture was stirred for 1 min. Then the reactor was
centrifuged (2000 rpm) for 1-2 min, and the solution was
removed by syringe. The catalyst was then washed with CH2Cl2
(1 mL) twice, and the solution was removed; a new reaction
could be conducted by adding the new batch of β-dicarbonyl
compound (1.0 mmol) and alcohol (or alkene, 2.0 mmol) to the
recovered catalyst. The solution containing the product was
passed through a silica gel flash column to afford the product.
3-(1-Phenylethyl)pentane-2,4-dione (3a)12. The compound was
prepared from 1a (0.100 g, 1.0 mmol) and 2a (0.244 g,
2.0 mmol). Following typical procedure A, 0.180 g (88% yield)
of product was obtained after column chromatography (eluent =
petroleum ether/acetone, 20:1 v/v); following typical procedure B,
0.196 g (96% yield) of product was obtained after column
chromatography. Mp: 42-44 °C (lit. 43-45 °C);12 1H NMR
(400 MHz, CDCl3) δ 1.21 (d, J = 6.8 Hz, 3H), 1.83 (s, 3H), 2.27
(s, 3H), 3.57-3.62 (m, 1H), 4.04 (d, J = 11.2 Hz, 1H), 7.18-7.22
(m, 3H), 7.27-7.31 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 20.7,
29.6, 29.7, 40.3, 76.5, 126.8, 127.1, 128.7, 142.9, 203.2, 203.3; MS
(ESI) m/z (%) 227.03 (M þ Naþ, 100), 205.02.
1
3-[1-(4-Methoxyphenyl)ethyl]pentane-2,4-dione (3b)8a. The com-
pound was prepared from 1a (0.100 g, 1.0 mmol) and 2b (0.304 g,
2.0 mmol). Following typical procedure A, 0.194 g (83% yield)
of product after column chromatography (eluent = petroleum
ether/acetone, 20:1 v/v); following typical procedure B, 0.192 g
(82% yield) of product was obtained after column chromatog-
raphy. Mp: 54-55 °C (lit. 52-53 °C);8a 1H NMR (400 MHz,
CDCl3) δ 1.18 (d, J = 6.8 Hz, 3H), 1.84 (s, 3H), 2.26 (s, 3H),
3.51-3.59 (m, 1H), 3.77 (s, 3H), 3.99 (d, J = 11.2 Hz, 1H), 6.83
(d, J = 6.8 Hz, 2H), 7.10 (d, J = 6.8 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 20.8, 29.5, 29.7, 39.5, 55.0, 114.0, 128.1, 134.8,
158.2, 203.3, 203.4; MS (ESI) m/z (%) 257.11 (M þ Naþ, 100),
135.02.
3-[1-(4-Tolylethyl)]pentane-2,4-dione (3c)14. The compound
was prepared from 1a (0.100 g, 1.0 mmol) and 2c (0.272 g, 2.0
mmol). Following typical procedure A, 0.176 g (81% yield) of
product after column chromatography (eluent = petroleum
ether/acetone, 20:1 v/v); following typical procedure B, 0.201 g
(92% yield) of product was obtained after column chromato-
graphy. Mp: 55-56 °C; 1H NMR (400 MHz, CDCl3) δ 1.19 (d,
J = 6.8 Hz, 3H), 1.84 (s, 3H), 2.26 (s, 3H), 3.00 (s, 3H),
J. Org. Chem. Vol. 75, No. 15, 2010 5027

Liu et al.
JOCArticle
3.53-3.58 (m, 1H), 4.02 (d, J = 11.2 Hz, 1H), 7.06-7.11 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 20.8, 29.6, 39.9, 76.6, 127.0,
129.3, 136.3, 139.8, 203.4; MS (ESI) m/z (%) 241.07 (M þ Naþ,
100).
1.98-2.00 (m, 2H), 2.18 (s, 3H), 2.20 (s, 3H), 3.00-3.04 (m,
1H), 3.61(d, J = 10.6 Hz, 1H), 5.38 (t, J1 =10.2 Hz, J2 = 2.4 Hz,
1H), 5.75-5.80 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 20.4,
24.7, 26.4, 29.4, 29.9, 35.4, 74.5, 126.9, 129.7, 203.5, 203.7; MS
(ESI) m/z (%) 203.02 (M þ Naþ, 100).
3-[1-(4-Chlorophenyl)ethyl]pentane-2,4-dione (3d)12. The com-
pound was prepared from 1a (0.100 g, 1.0 mmol) and 2d (0.312 g,
2.0 mmol). Following typical procedure A, 0.167 g (70% yield) of
product after column chromatography (eluent = petroleum ether/
acetone, 20:1 v/v); following typical procedure B, 0.136 g (57%
yield) of product was obtained after column chromatography.
Mp: 77-79 °C (lit. 77-79 °C);12 1H NMR (400 MHz, CDCl3) δ
1.19 (d, J = 7.2 Hz, 3H), 1.87 (s, 3H), 2.26 (s, 3H), 3.55-3.63 (m,
1H), 3.98 (d, J = 11.6 Hz, 1H), 7.14 (dd, J1 = 6.4 Hz, J2 = 2.0 Hz,
2H), 7.26 (d, J = 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
20.5, 29.5, 29.6, 39.5, 76.3, 128.5, 128.7, 132.4, 141.5, 202.7, 202.8;
MS (ESI) m/z (%) 261.05 (M þ Naþ, 100).
2-(1-Phenylethyl)-1-phenylbutane-1,3-dione (3j)14. The com-
pound was prepared from 1b (0.162 g, 1.0 mmol) and 2a (0.244 g,
2.0 mmol) following typical procedure A, 0.260 g (98% yield) of
product after column chromatography (eluent = petroleum
ether/acetone, 20:1 v/v); following typical procedure B, 0.258 g
(97% yield) of product was obtained after column chromato-
1
graphy. Diastereomer with lower polarity: Mp: 83-85 °C; H
NMR (400 MHz, CDCl3) δ 1.22 (d, J = 6.9 Hz, 3H), 1.91 (s,
3H), 3.85-3.91 (m, 1H), 4.92 (d, J = 10.9 Hz, 1H), 7.20-7.22
(m, 1H), 7.28-7.32 (m, 4H), 7.47-7.52 (m, 2H), 7.60-7.61 (m,
1H), 8.08-8.10 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 21.5,
27.9, 40.9, 70.8, 126.9, 127.4, 128.8, 133.8, 137.2, 143.2, 195.1,
203.1; MS (ESI) m/z (%) 289.20 (M þ Naþ, 100), 163.10.
Diastereomer with higher polarity: Mp: 84-86 °C; 1H NMR
(400 MHz, CDCl3) δ 1.31(d, J = 7.0 Hz, 3H), 2.24 (s, 3H),
3.82-3.87 (m, 1H), 4.82 (d, J = 11.0 Hz, 1H), 7.06-7.08 (m,
1H), 7.14-7.20 (m, 4H), 7.33-7.37 (m, 2H), 7.47-7.49 (m, 1H)
7.77-7.80 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 20.2, 27.5,
40.3, 71.5, 126.6, 127.3, 128.4, 128.6, 133.4, 137.0, 143.4, 195.2,
203.7; MS (ESI) m/z (%) 289.11 (M þ Naþ, 100), 163.15.
2-Diphenylmethyl-1-phenylbutane-1,3-dione (3k)33. The com-
pound was prepared from 1b (0.162 g, 1.0 mmol) and 2g (0.368 g,
2.0 mmol). Following typical procedure A, 0.315 g (96% yield)
of product after column chromatography (eluent = petroleum
ether/acetone, 20:1 v/v); following typical procedure B (2 mL
of toluene was added), 0.324 g (99% yield) of product was
obtained after column chromatography. Mp: 150-152 °C (lit.
149.8-150.7 °C);33 1H NMR (400 MHz, CDCl3) δ 2.04 (s, 3H),
5.10 (d, J = 12.0 Hz, 1H), 5.61 (d, J = 12.0 Hz, 1H), 7.02-7.11
(m, 3H), 7.13-7.18 (m, 3H), 7.28-7.37 (m, 6H), 7.44-7.56 (m,
1H), 7.93-7.95 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 27.7,
51.4, 68.8, 126.6, 127.1, 127.6, 128.1, 128.6, 128.7, 128.9, 133.6,
136.9, 141.2, 141.6, 194.2, 202.9; MS (MALDI) m/z (%) 351.13
(M þ Naþ, 100).
3-[1-(4-Fluorophenyl)ethyl]pentane-2,4-dione (3e)14. The com-
pound was prepared from 1a (0.100 g, 1.0 mmol) and 2e (0.280 g,
2.0 mmol). Following typical procedure A, 0.231 g (96% yield)
of product after column chromatography (eluent = petroleum
1
ether/acetone, 20:1 v/v). Mp: 57-58 °C; H NMR (400 MHz,
CDCl3) δ 1.20 (d, J = 6.9 Hz, 3H), 1.86 (s, 3H), 2.26 (s, 3H),
3.58-3.63 (m, 1H), 4.01 (d, J = 11.3 Hz, 1H), 6.96-7.00 (m,
2H), 7.15-7.19 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 20.7,
29.5, 29.7, 39.5, 76.6, 115.4, 115.6, 128.6, 128.7, 138.7, 160.3,
162.7, 202.9, 203.1; MS (ESI) m/z (%) 245.10.
3-[1-(2-Naphthalenyl)ethyl]pentane-2,4-dione (3f)14. The com-
pound was prepared from 1a (0.100 g, 1.0 mmol) and 2f (0.344 g,
2.0 mmol). Following typical procedure A, 0.165 g (65% yield)
of product after column chromatography (eluent = petroleum
ether/acetone, 20:1 v/v); following typical procedure B (2 mL of
toluene was added and 3 mol % catalyst was used), 0.236 g (93%
yield) of product was obtained after column chromatography.
Mp: 86-88 °C (lit. 86-88 °C);14 1H NMR (400 MHz, CDCl3) δ
1.27 (d, J = 6.7 Hz, 3H), 1.81 (s, 3H), 2.28 (s, 3H), 3.74-3.79 (m,
1H), 4.17 (d, J = 11.3 Hz, 1H), 7.31-7.34 (m, 1H), 7.41-7.43
(m, 2H), 7.62 (s, 1H), 7.76-7.78 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 20.7, 29.6, 40.3, 76.3, 125.2, 125.6, 125.8, 126.1, 127.5,
127.6, 128.5, 132.3, 133.3, 140.4, 203.2; MS (ESI) m/z (%) 277.09
(M þ Naþ, 100), 155.01.
1,3-Diphenyl-2-(1-phenylethyl)propane-1,3-dione (3l)14. The com-
pound was prepared from 1c (0.224 g, 1.0 mmol) and 2a (0.244 g,
2.0 mmol). Following typical procedure A, 0.312 g (95% yield)
of product after column chromatography (eluent = petroleum
ether/acetone, 20:1 v/v); following typical procedure B, 0.312 g
(95% yield) of product was obtained after column chromato-
graphy. Mp: 129-131 °C (lit. 129-131 °C);14 1H NMR (400
MHz, CDCl3) δ 1.34 (d, J = 6.8 Hz, 3H), 4.06-4.10 (m, 1H),
5.60 (d, J = 10.0 Hz, 1H), 7.08-7.10 (m, 1H), 7.16-7.19 (m,
2H), 7.25-7.30 (m, 4H), 7.40-7.43 (m, 3H), 7.44-7.56 (m, 1H),
7.73-7.75 (m, 2H), 8.03-8.05 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 20.1, 41.1, 64.6, 126.5, 127.6, 128.3, 128.4, 128.7,
128.8, 133.0, 133.5, 136.8, 137.1, 143.7, 194.5, 194.9; MS (ESI)
m/z (%) 351.16 (M þ Naþ, 100), 329.46. HPLC analysis:
Chiralcel OJ-H column, 2-propanol/hexane = 5:95 (1.0 mL/
min), t1 = 24.8 min, t2 = 33.0 min.
3-(Diphenylmethyl)pentane-2,4-dione (3g)6b. The compound was
prepared from 1a (0.100 g, 1.0 mmol) and 2g (0.368 g, 2 mmol).
Following typical procedure A (2 mL of DCE was used instead of
toluene), 0.260 g (98% yield) of product after column chromato-
graphy (eluent = petroleum ether/acetone, 20:1 v/v); following
typical procedure B (2 mL of DCE was added), 0.253 g (95% yield)
of product was obtained after column chromatography. Mp:
117-118 °C (lit. 115-117 °C);6b 1H NMR (400 MHz, CDCl3) δ
2.00 (s, 6H), 4.75 (d, J = 12.0 Hz, 1H), 4.82 (d, J = 12.0 Hz, 1H),
7.16-7.19 (m, 2H), 7.26-7.27 (m, 8H); 13C NMR (100 MHz,
CDCl3) δ 29.5, 51.0, 74.2, 126.8, 127.6, 128.7, 141.1, 202.7; MS
(ESI) m/z (%) 289.12 (M þ Naþ, 100).
3-(1,3-Diphenyl-2-propenyl)pentane-2,4-dione (3h)14. The com-
pound was prepared from 1a (0.100 g, 1.0 mmol) and 2h (0.420 g,
2.0 mmol). Following typical procedure A, 0.172 g (75% yield) of
product after column chromatography (eluent = petroleum ether/
acetone, 20:1 v/v). Mp: 85-87 °C (lit. 85-87 °C);14 1H NMR
(400 MHz, CDCl3) δ 1.85 (s, 3H), 2.17 (s, 3H), 4.27 (d, J = 2.4 Hz,
2H), 6.09-6.15 (m, 1H), 6.35 (d, J = 15.6 Hz, 1H), 7.12-7.26 (m,
10H); 13C NMR (100 MHz, CDCl3) δ 29.7, 30.0, 49.1, 74.5, 126.3,
127.2, 127.7, 127.9, 128.5, 128.9, 129.2, 131.6, 136.5, 140.0, 202.7,
202.8; MS (ESI) m/z (%) 315.14 (M þ Naþ, 84), 193.11 (100).
3-(2-Cyclohexen-1-yl)pentane-2,4-dione (3i)14. The compound
was prepared from 1a (0.100 g, 1 mmol) and 2i (0.196 g, 2.0 mmol).
Following typical procedure A, 0.131 g (73% yield) of product
after column chromatography (eluent = petroleum ether/acetone,
20:1 v/v). Mp: 94-96 °C; 1H NMR (400 MHz, CDCl3) δ
1.19-1.22 (m, 1H), 1.57-1.59 (m, 1H), 1.68-1.74 (m, 2H),
2-(1-(4-Chlorophenyl)ethyl)-1,3-diphenylpropane-1,3-dione (3m)14.
The compound was prepared from 1c (0.224 g, 1.0 mmol) and 2d
(0.312 g, 2.0 mmol). Following typical procedure A, 0.355 g (98%
yield) of product after column chromatography (eluent = petro-
leum ether/acetone, 20:1 v/v); following typical procedure B, 0.319 g
(88% yield) of product was obtained after column chromato-
graphy. Mp: 107-109 °C (lit.107-109 °C);14 1H NMR (400 MHz,
CDCl3) δ 1.31 (d, J = 7.2 Hz, 3H), 4.02-4.10 (m, 1H), 5.53 (d,
J = 10.0 Hz, 1H), 7.13-7.21 (m, 4H), 7.29-7.33 (m, 2H),
7.42-7.48 (m, 3H), 7.55-7.59 (m, 1H), 7.73-7.76 (m, 2H),
8.02-8.05 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 20.1, 40.5,
(33) Li, Z. P.; Cao, L.; Li, C. J. Angew. Chem., Int. Ed. 2007, 46, 6505.
5028 J. Org. Chem. Vol. 75, No. 15, 2010

Liu et al.
JOCArticle
64.4, 128.3, 128.4, 128.6, 128.8, 129.0, 132.1, 133.1, 133.6, 136.6,
136.9, 142.3, 194.3, 194.6; MS (ESI) m/z (%) 385.11 (M þ Naþ,
79%), 225.10 (100%).
Ethyl-2-diphenylmethyl-3-oxobutanoate (3s).34. The compound
was prepared from 1e (0.130 g, 1.0 mmol) and 2g (0.368 g, 2.0
mmol). Following typical procedure A, 0.243 g (82% yield) of
product after column chromatography (eluent = petroleum ether/
acetone, 20:1 v/v); following typical procedure B (3 mol % catalyst
was used), 0.252 g (85% yield) of product was obtained after
1,3-Diphenyl-2-[1-(4-fluorophenyl)ethyl]propane-1,3-dione (3n)14.
The compound was prepared from 1c (0.224 g, 1.0 mmol) and 2e
(0.280 g, 2.0 mmol). Following typical procedure A, 0.298 g (86%
yield) of product after column chromatography (eluent = petro-
leum ether/acetone, 20:1 v/v). Mp: 110-112 °C (lit. 110-112 °C);14
1H NMR (400 MHz, CDCl3) δ1.34 (d, J = 7.0 Hz, 3H), 4.06-4.14
(m, 1H), 5.66 (d, J = 10.0 Hz, 1H), 6.81-6.86 (m, 2H), 7.23-7.28
(m, 4H), 7.39-7.43 (m, 3H), 7.51-7.53 (m, 1H), 7.77 (d, 2H), 8.06
(d, 2H); 13C NMR (100 MHz, CDCl3) δ 20.2, 40.4, 64.4, 114.8,
115.1, 128.3, 128.4, 128.6, 128.7, 129.1, 129.2, 133.1, 133.5, 136.6,
136.9, 139.3, 160.0, 162.5, 194.4, 194.6; MS (ESI) m/z (%) 369.13
[M þ Na]þ.
column chromatography. Mp: 88-90 °C (lit. 89-91 °C);34 1
H
NMR (400 MHz, CDCl3) δ 0.99 (t, J = 7.2 Hz, 3H), 2.09 (s, 3H),
3.97 (q, J1 = 14.0 Hz, J2 = 7.2 Hz, 2H), 4.53 (d, J = 12.4 Hz, 1H),
4.76 (d, J = 12.4 Hz, 1H), 7.14-7.15 (m, 2H), 7.16-7.30 (m, 8H);
13C NMR (100 MHz, CDCl3) δ 13.7, 30.0, 50.8, 61.4, 65.1, 126.8,
126.9, 127.7, 127.8, 128.6, 128.8, 141.2, 141.5, 167.6, 201.7; MS
(MALDI,) m/z (%) 319.07 (M þ Naþ, 100).
Ethyl-2-benzhydryl-3-oxo-3-phenylpropanoate (3t)33. The com-
pound was prepared from 1f (0.192 g, 1.0 mmol) and 2g (0.368 g,
2.0 mmol). Following typical procedure A, 0.354 g (99% yield) of
product after column chromatography (eluent = petroleum ether/
acetone, 20:1 v/v); following typical procedure B (2 mL of toluene
was added and 3 mol % catalyst was used), 0.351 g (98% yield) of
product was obtained after column chromatography. Mp:
138-140 °C (lit. 141.9-143.1 °C);33 1H NMR (400 MHz, CDCl3)
δ 0.93 (t, J = 7.2 Hz, 3H), 3.87-3.96 (m, 2H), 5.07(d, J = 11.6 Hz,
1H), 5.41(d, J = 11.6 Hz, 1H), 7.03-7.06 (m, 1H), 7.07-7.45 (m,
7H), 7.53-7.57 (m, 5H), 8.00-8.02 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 13.6, 50.8, 59.4, 61.6, 126.5, 126.8, 127.7, 128.5, 128.6,
128.7, 133.6, 136.6, 141.7, 167.7, 192.8; MS (MALDI) m/z (%)
381.17 (M þ Naþ, 100).
1,3-Diphenyl-2-(diphenylmethyl)propane-1,3-dione (3o)33. The
compound was prepared from 1c (0.224 g, 1.0 mmol) and 2g
(0.368 g, 2 mmol). Following typical procedure A, 0.300 g (77%
yield) of product after column chromatography (eluent =
petroleum ether/acetone, 20:1 v/v); following typical procedure
B (2 mL of toluene was added), 0.386 g (99% yield) of product
was obtained after column chromatography. Mp: 232-234 °C
(lit. 228.6-230.2 °C);33 1H NMR (400 MHz, CDCl3) δ 5.25 (d,
J = 11.6 Hz, 1H), 6.27 (d, J = 11.6 Hz, 1H), 6.96-7.00 (m, 2H),
7.05-7.16 (m, 4H), 7.24-7.26 (m, 4H), 7.30-7.34 (m, 4H),
7.44-7.46 (m, 2H), 7.82-7.84 (m, 4H); 13C NMR (100 MHz,
CDCl3)
δ 52.4, 62.4, 126.6, 128.3, 128.4, 128.5, 128.6,
133.2, 137.0, 141.7, 194.0; MS (ESI) m/z (%) 413.16 (M þ
Computational Details. Molecular geometries of the model
complexes were optimized without constraints via DFT calcula-
tions using the Becke3LYP (B3LYP)35 functional. Frequency
calculations at the same level of theory have also been performed
to identify all stationary points as minima (zero imaginary
frequencies) to provide free energies at 298.15 K that include
entropic contributions by taking into account the vibrational,
rotational, and translational motions of the species under con-
sideration. The effective core potentials (ECPs) of Hay and
Wadt with double-ζ valence basis sets (LanL2DZ)36 were used
to describe Cl and S. Polarization functions were also added for
Naþ, 100).
1,3-Diphenyl-2-(2-cyclohexen-1-yl)propane-1,3-dione (3p)14. The
compound was prepared from 1c (0.224 g, 1.0 mmol) and 2i
(0.196 g, 2.0 mmol). Following typical procedure A, 0.207 g
(68% yield) of product after column chromatography (eluent =
petroleum ether/acetone, 20:1 v/v). Mp: 96-98 °C (lit. 96-98 °C);14
1H NMR (400 MHz, CDCl3) δ 1.37-1.41 (m, 1H), 1.57-1.59 (m,
1H), 1.70-1.79 (m, 2H), 1.98-2.00 (m, 2H), 3.48-3.50 (m, 1H),
5.32 (d, J = 10.0 Hz, 1H), 5.52 (dd, J1 = 10.2 Hz, J2 = 2.1 Hz, 1H),
5.70-5.73 (m, 1H), 7.39-7.50 (m, 4H), 7.52-7.54 (m, 2H),
7.98-8.01 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 21.0, 25.0,
27.3, 37.1, 62.2, 128.4, 128.6, 128.7, 129.2, 133.3, 133.4, 136.9, 137.1,
194.7, 195.1; MS (ESI) m/z (%) 327.14 (M þ Naþ, 100), 225.10.
1,3-Diphenylpropane-2-(bicyclo[2.2.1]heptan-2-yl)-1,3-dione (3q)22.
The compound was prepared from 1c (0.224 g, 1.0 mmol) and 2j
(0.224 g, 2.0 mmol). Following typical procedure A (2 mL of DCE
was used instead of toluene), 0.312 g (98% yield) of product after
column chromatography (eluent = petroleum ether/acetone, 20:1
v/v). Mp: 119-121 °C; 1H NMR (400 MHz, CDCl3) δ 1.18-1.19
(m, 1H), 1.21-1.22 (m, 2H), 1.27-1.34 (m, 1H), 1.43-1.50 (m,
3H), 1.60-1.64 (m, 1H), 1.94 (s, 1H), 2.24 (s, 1H), 2.69-2.75 (m,
1H), 5.01 (d, J = 11.2 Hz, 1H), 7.37-7.39 (m, 2H), 7.40-7.44 (m,
3H), 7.58-7.59 (m, 1H), 7.92-7.95 (m, 2H), 8.03-8.05 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 28.3, 29.9, 35.8, 36.5, 37.1, 39.4,
43.5, 63.9, 128.5, 128.7, 133.1, 133.3, 136.9, 137.0, 195.0, 195.7; MS
(ESI) m/z (%) 341.16 (M þ Naþ, 32%), 319.18 (MþHþ, 37%),
225.10 (100%).
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Gaussian 03, Revision E.01; Gaussian, Inc.: Wallingford, CT, 2004.
2-Acetyl-2-benzhydrylcyclopentanone (3r). The compound was
prepared from 1d (0.126 g, 1.0 mmol) and 2g (0.368 g, 2.0 mmol).
Following typical procedure A (3 mol % catalyst was used), 0.280 g
(96% yield) of product after column chromatography (eluent =
petroleum ether/acetone, 20:1 v/v); following typical procedure B
(2 mL of toluene was added and 3 mol % catalyst was used), 0.178 g
(61% yield) of product was obtained after column chromatogra-
phy. Mp: 156-158 °C; 1H NMR (400 MHz, CDCl3) δ 1.31-1.40
(m, 1H), 1.63-1.76 (m, 2H), 2.05-2.22 (m, 5H), 3.12-3.17 (m,
1H), 5.34 (s, 1H), 7.00-7.02 (m, 2H), 7.16-7.30 (m, 8H); 13C
NMR (100 MHz, CDCl3) δ 19.6, 25.9, 27.4, 38.9, 55.1, 74.3, 126.9,
128.3, 128.8, 128.9, 129.8, 140.4, 202.6, 215.2; HRMS (þESI) calcd
for C20H20O2þ: 292.1458, found 292.1460 [M]þ.
J. Org. Chem. Vol. 75, No. 15, 2010 5029

Liu et al.
JOCArticle
Cl (ζd = 0.640) and S (ζd = 0.503).37 The 6-311G(d,p) Pople
basis set was used for water molecule and the O atom of acid that
were connected to the water molecule.38 The 6-31G basis set was
used for all the other atoms.39 The solvent effect was examined by
performing single-point self-consistent reaction field (SCRF)
calculations based on the polarizable continuum model
(PCM)40 for the gas-phase optimized species. Toluene was used
as the solvent, corresponding to the experimental conditions, and
the atomic radii used for the PCM calculations were specified
using the BONDI keyword. All of the DFT calculations were
performed with the Gaussian 03 package.41
in the Hong Kong University of Science & Technology for
the generous helps and discussions. We greatly appreciate
one of the reviewers for her/his thorough revisions for this
paper. This work was supported financially by NSFC
(Project No. 20902020), the Shanghai Pujiang Talent Pro-
gram (Project No. 09PJ1403500) and the Fundamental
Research Funds for the Central Universities.
Supporting Information Available: The crystal data of 3p,
1H spectra of all products 3a-t and 13C NMR spectra of new
compound 3r, and the computation details can be found in the
Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank Prof. Chak-Po Lau in the
Hong Kong Polytechnic University and Prof. Zhenyang Lin
5030 J. Org. Chem. Vol. 75, No. 15, 2010