Metal triflate-catalyzed cationic benzylation and allylation of 1,3-dicarbonyl compounds

Article abstract of DOI:10.1021/jo0705216

(Chemical Equation Presented) The rare earth metal and hafnium triflate-catalyzed secondary benzylation and allylation of 1,3-diketones, ketoesters, and ketoamides are described. The procedure was carried out under non-anhydrous conditions. Various 1-phenylethyl cations were generated from substituted 1-phenylethanols using 0.5 mol % of the metal triflates in CH ₃NO₂. The cations reacted with 1,3-diketones and ketoesters to give benzylated products in high yields. Following the GC analysis, the reaction conditions were easily optimized by the selection of catalysts based on the Lewis acidity of the triflates and reaction temperature. A tertiary-alkylated diketone and a corresponding ketoester were also benzylated to afford products with a quaternary carbon atom in 57-84% yield. The ketoamide reactions required stronger Lewis acids than those used in the diketone and ketoester reactions. The reactions of benzylic alcohols possessing various substituents on the aromatic ring and dibenzoylmethane (2b) as a diketone were examined in the presence of Hf(OTf)₄. Electron-rich benzylic alcohols reacted with 2b in 86-96% yield, and electron-deficient alcohol gave the desired product in 79-65% yield. Despite possessing a strong electron-withdrawing group, the reaction of 1-(4-nitrophenyl)ethanol gave the corresponding product in 61% yield. It was also possible to use allylic alcohols directly for the allylation of diketone 2b. The catalyst can be recovered by water extraction and reused up to five times.

Full text of DOI:10.1021/jo0705216

Metal Triflate-Catalyzed Cationic Benzylation and Allylation of
1,3-Dicarbonyl Compounds
Masahiro Noji, Yosuke Konno, and Keitaro Ishii*
Meiji Pharmaceutical UniVersity, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
ishiikei@my-pharm.ac.jp
ReceiVed March 14, 2007
The rare earth metal and hafnium triflate-catalyzed secondary benzylation and allylation of 1,3-diketones,
ketoesters, and ketoamides are described. The procedure was carried out under non-anhydrous conditions.
Various 1-phenylethyl cations were generated from substituted 1-phenylethanols using 0.5 mol % of the
metal triflates in CH3NO2. The cations reacted with 1,3-diketones and ketoesters to give benzylated products
in high yields. Following the GC analysis, the reaction conditions were easily optimized by the selection
of catalysts based on the Lewis acidity of the triflates and reaction temperature. A tertiary-alkylated
diketone and a corresponding ketoester were also benzylated to afford products with a quaternary carbon
atom in 57-84% yield. The ketoamide reactions required stronger Lewis acids than those used in the
diketone and ketoester reactions. The reactions of benzylic alcohols possessing various substituents on
the aromatic ring and dibenzoylmethane (2b) as a diketone were examined in the presence of Hf(OTf)4.
Electron-rich benzylic alcohols reacted with 2b in 86-96% yield, and electron-deficient alcohol gave
the desired product in 79-65% yield. Despite possessing a strong electron-withdrawing group, the reaction
of 1-(4-nitrophenyl)ethanol gave the corresponding product in 61% yield. It was also possible to use
allylic alcohols directly for the allylation of diketone 2b. The catalyst can be recovered by water extraction
and reused up to five times.
Introduction
for the alkylation of aromatic compounds, olefins, allylsilanes,
and enol ethers.3 The secondary and tertiary alkylations of 1,3-
dicarbonyl compounds have also been carried out via carboca-
tions4 prepared from alkyl halides,5 alcohols,6 and olefins.7,8
From the atom-economical and synthetic points of view,
alcohols are an attractive source of electrophiles as compared
to alkyl halides because the only byproduct they produce is water
and not HX; moreover, alcohols can be obtained more easily
than the corresponding halides. However, the hydroxyl group
A carbocation is one of the most important intermediates in
carbon-carbon bond formation in organic synthesis. Various
methods for the generation of carbocations have been reported,
including the Brønsted or Lewis acid-catalyzed cleavage of
carbon-heteroatom bonds, protonation or addition to olefins,
and electrochemical oxidation.1,2 These reactions have been used
* To whom correspondence should be addressed. Phone and Fax: + (81)-
42-495-8783.
(1) (a) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. Friedel-Crafts
Alkylations. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 293-339; Sutherland,
J. K. Polyene Cyclizations. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 341-
411. (b) Carbocation Chemistry; Olah, G. A., Prakash, G. K. S., Eds.; John
Wiley & Sons: New Jersey, 2004.
(3) Review: Mayer, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003,
36, 66-77.
(4) Since many secondary and tertiary alkyl halides undergo HX
elimination under the basic conditions, the alkylation using enolate anion
and alkyl halide is limited to primary SN2-active electrophiles. Review:
(a) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 3, pp 55-58. (b) Reetz, M. T. Angew. Chem., Int. Ed. Engl.
1982, 21, 96-108.
(2) Okajima, M.; Soga, K.; Nokami, T.; Suga, S.; Yoshida, J. Org. Lett.
2006, 8, 5005-5007.
10.1021/jo0705216 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/08/2007
J. Org. Chem. 2007, 72, 5161-5167
5161

Noji et al.
SCHEME 1. Catalytic Generation of Benzylic Cation and
is not a good leaving group, and water is released as the reaction
proceeds and rapidly deactivates the Lewis acids. Most of these
methods require both anhydrous reaction conditions and more
than 1 equiv of Lewis acid.9 Therefore, few reports of the Lewis
acid-catalyzed alkylation of 1,3-dicarbonyl compounds using
alcohols are known.10,11
Benzylation of Various Nucleophiles
We have recently developed a highly efficient benzylation
system using benzylic alcohol catalyzed by hafnium triflate and
some rare earth metal triflates in nitromethane under non-
anhydrous conditions.12 Mechanistic investigations revealed that
the benzylation system soon attained equilibrium with alcohol,
symmetrical ether, and water via the benzylic cation. The cation
either reacts with various nucleophiles or decomposes to an
olefin depending on the reactivity of the nucleophile and the
reaction temperature. Our previous research focused on the
reaction with aromatic compounds, olefins, allylsilane, alcohols,
amides, and enol acetates as nucleophiles (Scheme 1).
Silylenol ethers derived from monocarbonyl compounds have
been known to react with benzylic cations to afford secondary-
or tertiary-alkylated ketones.13 Consequently, we are interested
in probing the scope and limitation of the C-C bond formation
of enolized compounds and cationic species. In this paper, we
report the benzylation and allylation of 1,3-dicarbonyl com-
pounds.
(5) Cationic alkylation with RX. Alkylation of Co(acac)3 derivatives:
(a) Marquet, J.; Moreno-Man˜as, M. Synthesis 1979, 348-350. (b) Cervello´,
J.; Marquet, J.; Moreno-Man˜as, M. J. Chem. Soc., Chem. Commun. 1987,
644-645. (c) Marquet, J.; Moreno-Man˜as, M.; Pacheco, P.; Vallribera, A.
Tetrahedron Lett. 1988, 29, 1465-1468. (d) Moreno-Man˜as, M.; Gonza´lez,
A.; Jaime, C.; Lloris, M. E.; Marquet, J.; Mart´ınez, A.; Siani, A. C.;
Vallribera, A. Tetrahedron 1991, 47, 6511-6520. (e) Moreno-Man˜as, M.;
Marquet, J.; Vallribera, A. Tetrahedron 1996, 52, 3377-3401. Silver-
mediated reaction: (f) Kraus, G. A.; Hon, Y.-S. J. Org. Chem. 1985, 50,
4605-4608. Zinc Lewis acid-mediated reaction: (g) Koschinsky, R.; Ko¨hli,
T.-P.; Mayer, H. Tetrahedron Lett. 1988, 29, 5641-5644. Aluminum and
boron Lewis acid-mediated reaction: (h) von Boldt, P.; Militzer, H.;
Thielecke, W.; Schulz. L. Liebigs Ann. Chem. 1968, 718, 101-114.
(6) Cationic alkylation with ROH. BF3-mediated reaction: (a) Adams,
J. T.; Abramovitch, B.; Hauser, C. R. J. Am. Chem. Soc. 1943, 65, 522-
554. (b) Crimmins, T. F.; Hauser, C. R. J. Org. Chem. 1967, 32, 2615-
2616. (c) Bisaro, F.; Prestat, G.; Vitale, M.; Poli, G. Synlett 2002, 1823-
1826. Formic acid-mediated reaction: (d) Gullickson, G. C.; Lewis, D. E.
Aust. J. Chem. 2003, 56, 385-388. Sulfuric acid-mediated reaction: (e)
Jiao, W.; Lash, T. D. J. Org. Chem. 2003, 68, 3896-3901.
Results and Discussion
The generation of cations may be influenced by the electronic
and steric factors of benzylic alcohols, and the nucleophilic
reaction may depend on the keto/enol ratio and the steric factor
of the 1,3-dicarbonyl compounds. In addition, 1,3-dicarbonyl
compounds act as bidentate ligands to decrease the Lewis acidity
of the catalysts. Therefore, the best reaction conditions should
be adjusted to the combination of benzylic alcohols and 1,3-
dicarbonyl compounds (eq 1).
(7) Cationic alkylation with olefin. SnCl4-catalyzed reaction: (a) Reetz,
M. T.; Chatziiosifidis, I.; Schwellnus, K. Angew. Chem., Int. Ed. Engl. 1981,
20, 687-689. Ga(OTf)3-catalyzed reaction: (b) Nguyen, R.-V.; Li, C.-J.
J. Am. Chem. Soc. 2005, 127, 17184-17185.
(8) Transition-metal-catalyzed secondary alkylation of active methylene
compounds. Au-catalyzed reaction with olefin: (a) Yao, X.; Li. C.-J. J.
Am. Chem. Soc. 2004, 126, 6884-6885. (b) Yao, X.; Li. C.-J. J. Org. Chem.
2005, 70, 5752-5755. Pd-catalyzed reaction with olefin: (c) Pei, T.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2001, 123, 11290-11291. (d) Pei,
T.; Widenhoefer, R. A. Chem. Commun. 2002, 650-651. (e) Pei, T.; Wang,
X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125, 648-649. (f) Qian,
H. J. Am. Chem. Soc. 2003, 125, 2056-2057. (g) Wang, X.; Pei, T.; Han,
X.; Widenhoefer, R. A. Org. Lett. 2003, 5, 2699-2701. (h) Wang, X.;
Widenhoefer, R. A. Chem. Commun. 2004, 660-661. (i) Leitner, A.; Larsen,
J.; Steffens, C.; Hartwig, J. F. J. Org. Chem. 2004, 69, 7552-7557.
Lanthanide- and Pd-catalyzed reaction with olefin: (j) Yang, D.; Li, J.-H.;
Gao, Q.; Yan, Y.-L. Org. Lett. 2003, 5, 2869-2871. (k) Yip, K.-T.; Li,
J.-H.; Lee, O.-Y.; Yang, D. Org. Lett. 2005, 7, 5717-5719. Mn- and Co-
catalyzed reaction with olefin: (l) Hirase, K.; Iwahama, T.; Sakaguchi, S.;
Ishii, Y. J. Org. Chem. 2002, 67, 970-973.
(9) The benzylic alcohol bearing a strong electron-donating group reacts
without any catalyst in aquous solutions: Takahashi, H.; Kashiwa, N.;
Kobayashi, H.; Hashimoto, Y.; Nagasawa, K. Tetrahedron Lett. 2002, 43,
5751-5753.
(10) InCl3-catalyzed reaction: (a) Yasuda, M.; Somyo, T.; Baba, A.
Angew. Chem., Int. Ed. 2006, 45, 793-796. Brønsted acid-mediated
reaction: (b) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani,
K.; Kaneda, K. Angew. Chem., Int. Ed. 2006, 45, 2605-2609. Ruthenium-
catalyzed reaction via an allenylidene intermeditate: (c) Nishibayashi, Y.;
Wakiji, I.; Ishii, Y.; Uemura, S.; Hidai, M. J. Am. Chem. Soc. 2001, 123,
3393-3394. (d) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Hidai, M.;
Uemura, S. J. Org. Chem. 2004, 69, 3408-3412.
Fortunately, rare earth metal triflates have similar chemical
properties but different Lewis acidities.14 We have been using
four metal triflatessthe rare earth metals La, Yb, Sc, and Hf
(13) Secondary and tertiary alkylation of carbonyl compounds using
silylenol ethers have been extensively investigated. (a) Chan, T. H.; Paterson,
I.; Pinsonnault, J. Tetrahedron Lett. 1977, 18, 4183-4186. (b) Paterson, I.
Tetrahedron Lett. 1979, 20, 1519-1520. (c) Reetz, M. T.; Maier, W. F.
Angew. Chem., Int. Ed. Engl. 1978, 17, 48-49. (d) Reetz, M. T.; Schwellnus,
K. Tetrahedron Lett. 1978, 19, 1455-1458. (e) Reetz, M. T.; Hu¨ttenhain,
S.; Waltz, P.; Lo¨we, U. Tetrahedron Lett. 1979, 20, 4971-4974. (f) Reetz,
M. T.; Sauerwald, M.; Waltz, P. Tetrahedron Lett. 1981, 22, 1101-1104.
(g) Reetz, M. T.; Maier, W. F.; Chatziiosifidis, I.; Giannis, A.; Heimbach,
H.; Lo¨we, U. Chem. Ber. 1980, 113, 3741-3757. (h) Reetz, M. T.;
Hu¨ttenhain, S.; Hu¨bner, F. Synth. Commun. 1981, 13, 217-222. (i) Reetz,
M. T. Angew. Chem., Int. Ed. Engl. 1982, 21, 96-108. (j) Reetz, M. T.;
Schwellnus, K.; Hu¨bner, F.; Massa, W.; Schmidt, E. Chem. Ber. 1983, 116,
3708-3724. (k) Reetz, M. T.; Waltz, P.; Schwellnus, K.; Hu¨bner, F.;
Hu¨ttenhain, S. H.; Heimbach, H.; Schwellnus, K. Chem. Ber. 1984, 117,
322-335. (l) Reetz, M. T.; Sauerwald, M. J. Organomet. Chem. 1990, 382,
121-128.
(11) Very recently, Bi(OTf)3-catalyzed benzylation and allylation of 2,4-
pentanediones was reported. (a) Rueping, M.; Nachtsheim, B. J.; Kuenkel,
A. Org. Lett. 2007, 9, 825-828. (b) Rueping, M.; Nachtsheim, B. J.;
Ieawsuwan, W. AdV. Synth. Catal. 2006, 348, 1033-1037.
(12) Noji, M.; Ohno, T.; Fuji, K.; Futaba, N.; Tajima, H.; Ishii, K. J.
Org. Chem. 2003, 68, 9340-9347.
(14) (a) Kagan, H. B.; Namy, J. L. Tetrahedron 1986, 42, 6573-6614.
(b) Molander, G. A. Chem. ReV. 1992, 92, 29-68. (c) Kobayashi, S. Synlett
1994, 689-701. (d) Inanaga, J.; Sugimoto, Y.; Hanamoto, T. New J. Chem.
1995, 19, 707-712. (e) Kobayashi, S. Eur J. Org. Chem. 1999, 15-27. (f)
Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. ReV. 2002,
102, 2227-2302.
5162 J. Org. Chem., Vol. 72, No. 14, 2007

Benzylation and Allylation of 1,3-Dicarbonyl Compounds
TABLE 1. Reaction of Various 1,3-Diketones 2a-d
temp
(°C)
time
(h)
yieldb
(%)
FIGURE 1. Yields of secondary-benzylated acetylacetone 3a for La,
Yb, Sc, and Hf triflate-catalyzed reactions at 20, 50, and 80 °C in
nitromethane (A) and 1,2-dichloroethane (B).
entry
1
2
cat.a
3
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
2a
2b
2c
2d
2a
2b
2c
2d
Yb
Hf
Yb
La
Sc
Hf
Hf
La
50
20
50
50
70
60
70
90
24
7
13
11
21
5
3a
3b
3c
3d
3e
3f
97
89
75
54
83
94
31
56
triflatesswhose Lewis acidities increase in the following
order: La(OTf)3 < Yb(OTf)3 < Sc(OTf)3 < Hf(OTf)4.15 To
find the best conditions quantitatively, reactions with different
catalysts and temperatures were carried out using GC analysis.
Optimization of Reaction Conditions. For optimizing the
reaction conditions, the general procedure was as follows: A
nitromethane solution of benzylic alcohol (1 equiv), diketone
(1 equiv), and an internal standard (ca. 0.2 equiv of nitro-
cyclohexane or nitrohexane) was partitioned into 12 reaction
vessels containing La, Yb, Sc, and Hf triflates. The mixtures
were stirred at 20, 50, and 80 °C either until the complete
consumption of the alcohol and symmetrical ethers16 or up to
24 h. Then, the reaction mixtures were analyzed by GC.
Figure 1 shows the yield of 3a obtained from the reaction of
1-(4-methoxyphenyl)ethanol (1a) and acetylacetone (2a) in
nitromethane (A) and 1,2-dichloroethane (B).17
At 20 °C, a considerable amount of 1a, 2a, and symmetrical
ether 1218 remained in the La(OTf)3- and Yb(OTf)3-catalyzed
reaction mixtures using nitromethane and 1,2-dichloroethane.
In both solvents, the best results were obtained with Yb(OTf)3-
catalyzed reactions conducted at 50 °C (98%).19 The decrease
in the yields at 80 °C were due to the formation of olefins,
4-vinylanisole, and 1,3-bis(4-methoxyphenyl)-1-butene as byprod-
ucts. The structure and formation mechanism of the butene from
1-(4-methoxyphenyl)ethyl cations were previously reported.20
The best reaction temperatures were higher than those for ether
formation and lower than those for olefin formation. The
bisbenzylation and O-benzylation21 of 2a were not observed in
all cases. Nitromethane has compatibility over a wide range of
catalysts and temperature conditions.
24
13
3g
3h
a La: La(OTf)3, Yb: Yb(OTf)3, Sc: Sc(OTf)3, Hf: Hf(OTf)4. b Isolated
yield.
in nitromethane. The reaction conditions were optimized
using GC analysis by the same procedure as that shown in
Figure 1. The data in Table 1 were obtained from isolation
reactions carried out under optimized conditions. The reactions
of electron-rich benzylic alcohol 1a and unsubstituted benzylic
alcohol 1b with acetylacetone (2a) and dibenzoylmethane (2b)
gave the corresponding secondary-benzylated products 3a, 3b,
3e, and 3f in good yields (entries 1, 2, 5, and 6, respectively).
The yields in entries 3 and 7 using cyclic diketone 2c were
lower than those using linear diketones 2a and 2b. The reason
for the moderate yields of 3c and 3g might be the low solubility
of 2c in nitromethane. Methyl-substituted diketone 2d also
reacted to afford quaternary carbon products 3d and 3h in
moderate yields (entries 4 and 8). The reuse of the catalyst was
examined under the condition of entry 1. Ytterbium triflate was
extracted directly from the reaction mixture of nitromethane
solution by water. The water extract was concentrated, and the
residue was dried under vacuum at 200 °C for 3 min to give a
colorless crystalline Yb(OTf)3 catalyst. The catalyst was used
without further purification. The procedure was repeated five
times, and the yields of each run were 99% (24 h), 98% (24 h),
97% (24 h), 97% (48 h), and 96% (48 h).
Reaction of Ketoesters. Next, we optimized the reactions
of ketoesters 4a-c using GC analyses for all the entries in
Table 2. Secondary-benzylated ketoesters 5a and 5b were
obtained in high yields by using a Yb(OTf)3 catalyst (entries 1
and 2). In spite of the lower enol ratios,22 the reactivities of
ketoesters 4a and 4b toward 1a were similar to that of the
corresponding diketones 2a and 2b. The cyclic ketoester 4c also
reacted to give quaternary carbon products 5c and 5f in moderate
yields (entries 3 and 6). The yields of 5d and 5e were lower
than those of 5a and 5b (entries 4 and 5). In general, the reaction
of 1b required a stronger catalyst and higher temperature than
the reaction of electron-rich 1a. The diastereomeric ratios of
the products in Table 2 were less than 1.1/1.
Reaction of Various 1,3-Diketones. Next, we examined the
reaction of alcohols (1a,b) with various 1,3-diketones (2a-d)
(15) (a) Waller, F. J.; Barrett, A. G. M.; Braddock, D. C.; McKinnell,
R. M.; Ramprasad, D. J. Chem. Soc., Perkin Trans. 1 1999, 967-871. (b)
Tsuruta, H.; Yamaguchi, K.; Imamoto, T. Chem. Commun. 1999, 1703-
1704.
(16) Mixture of DL and meso-bis-1-(4-methoxyphenyl)ethyl ethers. The
typical structures are shown in Scheme 1.
(17) Octadecane was used as an internal standard for the reactions in
1,2-dichloroethane.
(18) See eq 2.
(19) The GC yield was calculated based on the calibration line prepared
from pure 3a and nitrocyclohexane. The isolated yield of the reaction
conditions was 97%.
(20) The structure is 4-MeO-Ph-CHdCH-CH(4-MeO-Ph)-CH3. Rao, V.
J.; Prevost, N.; Ramamurthy, V.; Kojima, M.; Johnston, L. J. Chem.
Commun. 1997, 2209-2210.
(21) (a) Arumugam, S.; McLeod, D.; Verkade, J. G. J. Org. Chem. 1998,
63, 3677-3679. (b) Shono, T.; Kashimura, S.; Sawamura, M.; Soejima, T.
J. Org. Chem. 1988, 53, 907-910.
(22) Enol ratios of the 1,3-dicarbonyl compounds were measured by 1H
NMR in CD3NO2 at 23-25 °C. 1,3-Diketones: 2a, 55%; 2b, 95%; 2c,
6%; 2d, 34%. 1,3-Ketoesters: 4a, 4%; 4b, 13%; 4c, 72%. 1,3-Keto-
amides: 6a, 11%; 6b, 5%; 6b (70 w/w% in H2O), 4%. Dimethyl
malonate: 0%. Detailed conditions are given in the Supporting Information.
J. Org. Chem, Vol. 72, No. 14, 2007 5163

Noji et al.
TABLE 2. Reaction of Various 1,3-Ketoesters 4a-c
TABLE 4. Reaction of Various Benzylic Alcohols
temp
(°C)
time
(h)
yieldb
(%)
entry
R1
R2
Me
3
1
2
3
4-MeO
2,6-di-Me
4-Me
20
60
40
45
60
60
90
100
20
20
3b
3i
3j
3k
3f
3l
3m
3n
3o
3p
3q
7
13
12
13
5
89
86
93
96
93
79
65
61
99
89
44
Me
Me
Me
Me
Me
Me
Me
4
5
6
2-Me
temp
(°C)
time
(h)
yieldb
(%)
H
4-Cl
entry
1
4
cat.a
5
6
7
4-CO2Me
4-NO2
1-ferrocenylethanol
4-MeO
H
19
24
0.5
7
1
2
3
4
5
6
1a
1a
1a
1b
1b
1b
4a
4b
4c
4a
4b
4c
Yb
Yb
Hf
Sc
Sc
Hf
50
60
20
80
85
60
24
24
24
12
8
5a
5b
5c
5d
5e
5f
98
96
84
77
70
57
8a
9
10
11
H
H
100
4
a 2.5 mol % of Hf(OTf)4was used. b Isolated yield.
21
a La: La(OTf)3, Yb: Yb(OTf)3, Sc: Sc(OTf)3, Hf: Hf(OTf)4. b Isolated
yield.
Hf(OTf)4 in nitromethane. Each reaction temperature in Table
4 was obtained from preliminary GC analyses before the
isolation of the products.
TABLE 3. Reaction of 1,3-Ketoamides 6a,b
Sterically hindered 1-(2,6-dimethylphenyl)- and 1-(2-methyl-
phenyl)ethanol also gave products 3i and 3k, respectively, in
high yields (entries 2 and 4, respectively). A relatively low
reaction temperature was suitable for the reaction of benzyl
alcohols possessing electron-donating alkyl and alkoxy groups
because olefinic byproducts were formed at higher temperatures
(entries 1-4). Although the reactions of electron-deficient
4-chloro-, 4-methoxycarbonyl-, and 4-nitrophenethylalcohols
required a higher temperature, the corresponding desired ben-
zylated products were obtained in 79-61% yield (entries 6-8).
On the other hand, ferrocenylethanol, which is the most electron-
rich alcohol in Table 4, reacted smoothly at 20 °C to give
product 3o in 99% yield (entry 9). For the primary benzylation,
the electron-donating methoxy group was necessary to increase
the yield of the desired product (entry 10). In entry 11, the
Hf(OTf)4-catalyzed reaction at 100 °C, benzylalcohol, and
dibenzyl ether25 were completely consumed even though the
yield was moderate, and a considerable amount of a viscous
residue was obtained. It appears that the primary unstable
carbocation reacted unselectively to afford polymeric byprod-
ucts. The role of the hyperconjugation26 of the methyl group is
more significant than that of the electronic character of the
aromatic ring.
temp
(°C)
time
(h)
yielda
(%)
entry
1
6
7
1
1a
1a
1b
1b
6a
6b
6a
6b
60
60
100
100
12
12
24
24
7a
7b
7c
7d
98
2
80 (76)b
35
3c
4c
11 (6)b
a Isolated yield. b Values in parenthesis are the yields obtained using a
commercially available 70% water solution of 6b. c 5 mol % of Hf(OTf)4
was used.
Reaction of Ketoamides. Ketoamides were more Lewis basic
nucleophiles than diketones and ketoesters because of the
electron donation by the amide nitrogen to the carbonyl group.
Therefore, a stronger Lewis acid catalyst, Hf(OTf)4, was
necessary for the reaction. The reactions (Table 3) using
electron-rich 1a proceeded well and afford the corresponding
products in yields ranging from excellent (entry 1) to good (entry
2) even with the use of a commercially available 70% water
solution of 6b. In our previous report,12 we showed that the
addition of water prolonged the reaction time due to the Lewis
basic nature of water. However, in this case, the electron
densities of the benzylic alcohols were more critical than the
effect of water, and the reaction of 1b was very slow; moreover,
even after 24 h, a considerable amount of alcohol and ketoamide
remained unchanged.
Although we attempted the reaction of dimethyl malonate
with 1a, only a trace amount (0.5%) of the benzylated product
was obtained.23 The enol ratio of the malonate ester was not
sufficient for benzylation to occur because the ester group
decreases the enol ratio of 1,3-dicarbonyl compounds.24
Reaction of Various Benzylic Alcohols. The reactions of
various primary and secondary benzylic alcohols were inves-
tigated with dibenzoylmethane (2b) as a nucleophile using
A tertiary benzylated product was difficult to obtain in this
system. Although we attempted the reactions of several tertiary
alcohols (e.g., 2-phenyl-2-propanol, 1-phenylcyclohexanol, and
1-methyl-1,2,3,4-tetrahydronaphthol) with dibenzoylmethane
(23) The reaction of 1a with dimethyl malonate was carried out with
0.5 mol % of Yb(OTf)3 at 100 °C for 19 h to give the benzylated product
in 0.5% yield.
(24) Reported enol ratio of diketone, ketoester, and diester in pure liquid
form; acetylacetone (81%, rt), ethyl acetoacetate (8%, 33 °C), diethyl
malonate (7.7 × 10-3%, rt). (a) Gero, A. J. Org. Chem. 1954, 19, 1960-
1970. (b) Burdett. J. L.; Rogers, M. T. J. Am. Chem. Soc. 1964, 86, 2105-
2109.
(25) The structure was PhCH2-O-CH2Ph, which is an intermediate of
the reaction. See Scheme 1.
(26) (a) Carbocation Chemistry; Olah, G. A., Prakash, G. K. S., Eds.;
John Wiley & Sons: New Jersey, 2004, p 29. (b) Krygowski, T. M.; Ste¸pien´,
B. T. Chem. ReV. 2005, 105, 3482-3512. (c) Vrcˇek, V.; Kronja, O.; Siehl,
H.-U. J. Chem. Soc., Perkin Trans. 2 1999, 1317-1321.
5164 J. Org. Chem., Vol. 72, No. 14, 2007

Benzylation and Allylation of 1,3-Dicarbonyl Compounds
SCHEME 2. Reaction of Optically Active Alcohols
SCHEME 3. Reaction of Allylic Alcohols
a Isolated yield.
retention of configuration.30 In our system, the reaction of (S)-
ferrocenyl ethanol (97% ee) and 2b gave (-)-3o in 95% ee.
Reaction of Allylic Alcohols. Next, we examined the
allylation of 1,3-dicarbonyl compounds (Scheme 3). The ally-
lations are usually carried out by using allyl ester or allyl halide
derivatives with the metal enolate of 1,3-dicarbonyl compounds
using palladium catalysts in an inert atmosphere.31 In our system,
allylic alcohols can be directly used as allylic cation precursors
without any inert atmosphere.
Cinnamyl alcohol (8) and 2-cyclohexenol (10) were examined
for this system using preliminary GC analyses. A cinnamyl
product 9 was obtained in moderate yield with several unidenti-
fied products. The reactivity of 10 was similar to that of
1-phenylethanol (1b), and 11 was obtained in good yield. In
both cases, symmetrical ethers were observed by GC-MS at a
reaction temperature of 40 °C.
Use of Symmetrical Ether as Cation Precursor. Sym-
metrical ethers were frequently observed at the initial stage of
the reactions. We tried to use one of the ethers as a source of
benzylic cations. The symmetrical ether 12 was synthesized from
4-methoxyphenethylalcohol (1a) using a La(OTf)3 catalyst in
CH3NO2 at 20 °C as a meso and DL mixture (89%, 27% de).32
Under the best benzylation condition in Figure 1A, the reaction
of half-equivalent ether 12 with 1 equiv of 2a gave 3a in 87%
yield (eq 2). The yield was lower than that in entry 1 of Table
(2b) at 20-100 °C using La, Yb, Sc, and Hf catalysts, no desired
products were obtained without the olefinic byproduct formation.
In contrast, the less sterically hindered diketone, 1-phenyl-1,3-
butanedione, reacted with 2-phenyl-2-propanol at 20 °C when
Hf(OTf)4 was used to afford a tertiary benzylated product in
9% yield.27
Reaction of Optically Active Alcohols. We have proposed
a mechanism involving discrete cationic intermediates for the
direct substitution of benzylic hydroxy groups. The cationic
mechanism is certainly suitable for the reaction of phenylethyl
alcohols bearing electron-donating substituents. However, a
change in the reaction mechanism has been reported28 for the
reaction of 1-phenylethyl substrates from the cationic SN1 to
the concerted SN2 as the carbocation becomes less stable.
Therefore, electron-deficient 1-(4-nitrophenyl)ethanol might
proceed under a concerted SN2 mechanism. The reactions of
optically active alcohols were examined for the possibility of
concerted substitution with an inversion of the configuration.
Optically active alcohols were prepared by the oxazaborolidine-
catalyzed asymmetric borane reduction29 of corresponding
ketones. The reactions were carried out under the same reaction
condition shown in Table 4, and the enantiomeric excesses of
the products were examined by HPLC (Scheme 2).
In both the electron-rich and electron-deficient cases, the
chemical yields of 3b and 3n were almost the same as those of
the reactions in Table 4. No enantiomeric excess was observed
for 3n. Unfortunately, these results cannot exclude the concerted
SN2 mechanism for 1-(4-nitrophenyl)ethyl alcohol because the
repeated SN2 reaction of the hydroxy group by water before
the SN2 reaction of 2b would give racemic 3n. Kinetic
measurements of the reaction are necessary for further inves-
tigation. The ferrocenylethyl cation is known to react with the
1. Because 12 was less Lewis basic than benzylic alcohol 1a,
the best condition for 1a was slightly stronger than that for 12.
(30) (a) Turbitt, T. D.; Watts, W. E. J. Chem. Soc., Chem. Commun.
1973, 182-183. (b) Ratajczak, A.; Misterkiewicz, B. J. Organomet. Chem.
1975, 91, 73-79. (c) Patin, H.; Mignani, G.; Mahe, C. J. Organomet. Chem.
1980, 193, 93-103. (d) Woltersdorf, M.; Kranich, R.; Schmalz, H.-G.
Tetrahedron 1997, 53, 7219-7230.
(31) (a) Trost, B. M. Acc. Chem. Res. 1980, 13, 385-393. (b) Trost, B.
M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4730-4743. (c) Tsuji,
J.; Minami, I. Acc. Chem. Res. 1987, 20, 140-145.
(32) Other examples of cationic etherification of benzylic alcohols: (a)
Kim, S.; Chung, K. N.; Yang, S. J. Org. Chem. 1987, 52, 3917-3919. (b)
Zhu, Z.; Espenson, J. H. J. Org. Chem. 1996, 61, 324-328. (c) Bouquillon,
S.; He´nin, F.; Muzart, J. Organometallics 2000, 19, 1434-1437. (d)
Kawada, A.; Yasuda, K.; Abe, H.; Harayama, T. Chem. Pharm. Bull. 2002,
50, 380-383. (e) Manabe, K.; Ilimura, S.; Sun, X.-M.; Kobayashi, S. J.
Am. Chem. Soc. 2002, 124, 11971-11978. (f) Miller, K. J.; Abu-Omar, M.
M. Eur. J. Org. Chem. 2003, 1294-1299. (g) Kim, S. L.; Shin, C.; Pae, A.
N.; Koh, Y. H.; Chang, M. H.; Chung, B. Y. Synthesis 2004, 1581-1584.
(h) Firouzabadi, H.; Iranpoor, N.; Jafari, A. A. J. Mol. Catal. A 2005, 227,
97-100. (i) Shibata, T.; Fujiwara, R.; Ueno, Y. Synlett 2005, 152-154. (j)
Handlon, A. L.; Guo, Y. Synlett 2005, 111-114.
(27) The reaction with 2-phenyl-2-propanol with 2 equiv of 2-methylfuran
(Friedel-Crafts alkylation) using 0.5 mol % of Yb(OTf)3 in nitromethane
at 60 °C for 2 h gave 2-methyl-5-(1-methyl-1-phenyl)ethylfuran in 99%
yield.
(28) (a) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1982, 104, 4689-
4691. (b) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1982, 104, 4691-
4692. (c) Richard, J. P.; Rothenberg, M. E.; Jencks, W. P. J. Am. Chem.
Soc. 1984, 106, 1361-1372. (d) Richard, J. P.; Jencks, W. P. J. Am. Chem.
Soc. 1984, 106, 1373-1383. (e) Richard, J. P.; Jencks, W. P. J. Am. Chem.
Soc. 1984, 106, 1383-1396. (f) Richard, J. P.; Jencks, W. P. J. Am. Chem.
Soc. 1984, 106, 1396-1401. (g) Ta-Shama, R.; Jencks, W. P. J. Am. Chem.
Soc. 1986, 108, 8040-8050.
(29) (a) Xu, J.; Wei, T.; Zhang, Q. J. Org. Chem. 2004, 69, 6860-
6866. (b) Wright, J.; Frambes, L.; Reeves, P. J. Organomet. Chem. 1994,
476, 215-217.
J. Org. Chem, Vol. 72, No. 14, 2007 5165

Noji et al.
(Yb), 78% (Sc), and 71% (Hf) at 50 °C; 91% (La), 15% (Yb), 1%
(Sc), and 0% (Hf) at 80 °C.
Conclusion
We have developed a convenient secondary benzylation
system for 1,3-dicarbonyl compounds. During the optimization
process, the formation of symmetrical ether was observed at
lower temperatures. The cation generation and nucleophilic
attack of the alcohols proceeded faster than the reaction of the
dicarbonyl compounds. In most cases, the reaction conditions
of various combinations of benzylic alcohols and nucleophiles
were easily optimized by the two-dimensional catalyst temper-
ature screenings by GC analysis.
Diketones (2a,b,d), ketoesters (4a-c), and ketoamides (6a,b)
exhibit similar reactivities toward the benzylic cation, but the
ketoamides required a stronger Lewis acid because of their
higher Lewis basicities. The benzylation of dimethyl malonate
was unsuccessful under these conditions probably due to the
low enol ratio. Methyl acetoacetate (4a) has a 4% enol ratio,
and it reacted with 1a to give 5a in 97% yield. An enol ratio of
more than 4% may be sufficient for the benzylation. The effect
of the hyperconjugation of the alkyl group that stabilized the
cation was more important than the electronic character of the
aromatic ring, and the yields of the primary benzylation were
lower than that of the secondary one. Although the generation
of tertiary cations from tertiary benzylic alcohols proceeded
readily at a lower temperature when weaker catalysts were used,
the tertiary benzylation of 2b did not proceed and the cation
rapidly decomposed to form the corresponding olefins. Allylic
alcohols (8, 10) also reacted with 2b without using any inert
atmosphere; this reaction would be a convenient alternative for
the Pd-catalyzed allylic substitution.
Typical Procedure for Isolating Benzylated Product.
Table 1, Entry 1. 3-[1-(4-Methoxyphenyl)ethyl]pentane-2,4-
dione (3a). To a mixture of Yb(OTf)3 (9.68 mg, 15.6 µmol) and
2a (323.86 mg, 3.235 mmol) in CH3NO2 (3.12 mL) was added 1a
(487.53 mg, 3.203 mmol) at room temperature. The resulting
mixture was stirred at 50 °C for 24 h under a rubber balloon stopper.
After the reaction mixture was filtered through a short silica gel
pad with ethyl acetate, the filtrate was concentrated under reduced
pressure and the residue was purified by column chromatography
(silica gel, hexane/ethyl acetate ) 20/1 to 4/1) to afford 3a
(728.62 mg, 97%) as a colorless prism: mp 52-53 °C; TLC Rf )
1
0.40 (hexane/ethyl acetate ) 3/1); H NMR (300 MHz, CDCl3) δ
7.11 (2H, d, J ) 8.8 Hz), 6.83 (2H, d, J ) 8.8 Hz), 3.98 (1H, d,
J ) 11.4 Hz), 3.78 (3H, s), 3.55 (1H, dq, J ) 11.4, 6.8 Hz), 2.26
(3H, s), 1.84 (3H, s), 1.19 (3H, d, J ) 6.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 203.0, 202.9, 158.0, 134.7, 127.9, 113.8, 76.6,
55.0, 39.6, 29.7, 29.6, 20.9; IR (KBr) 1723 (s), 1518 (s), 1365 (s),
1294 (m), 1251 (s), 1183 (s), 1147 (m), 1036 (m), 818 (m) cm-1
;
EI-MS (70 eV) m/z (relative intensity) 234 (M+, 10), 191 (90),
173 (15), 135 (100), 43 (18); HRMS-EI (m/z) M+ calcd for
C14H18O3, 234.1256; found, 234.1259. Anal. Calcd for C14H18O3:
C, 71.77; H, 7.74. Found: C, 71.80; H, 7.87. GC analysis: 10.15
min (150 °C, 2 min, 10 °C/min, 260 °C, 17 min).
2-[1-(4-Nitrophenyl)ethyl]-1,3-diphenylpropane-1,3-dione (3n).
Pale yellow prism: mp 100-103 °C; TLC Rf ) 0.44 (hexane/ethyl
acetate ) 7/3); 1H NMR (300 MHz, CDCl3) δ 8.08-8.04 (4H, m),
7.77-7.74 (2H, m), 7.63-7.26 (8H, m), 5.61 (1H, d, J )
10.2 Hz), 4.20 (1H, dq, J ) 10.2, 6.9 Hz), 1.36 (3H, d, J ) 6.9
Hz); 13C NMR (100 MHz, CDCl3) δ 193.9, 193.6, 151.5, 146.7,
136.6, 136.2, 133.7, 133.4, 128.9, 128.7, 128.6, 128.5, 128.3, 123.5,
64.5, 41.0, 20.3; IR (KBr) 1694 (s), 1599 (m), 1518 (s), 1448 (m),
1346 (s), 1270 (m), 1224 (m), 1201 (m), 978 (m), 859 (m), 712
(m), 688 (m) cm-1; EI-MS (70 eV) m/z (relative intensity) 373
(M+, 0.2), 269 (10), 268 (58), 252 (14), 251 (39), 105 (100), 77
(53); HRMS-EI (m/z) M+ calcd for C23H19NO4, 373.1314; found,
373.1312. Anal. Calcd for C23H19NO4: C, 73.98; H, 5.13; N, 3.75.
Found: C, 74.22; H, 5.40; N, 3.51. GC analysis: 25.86 min
(150 °C, 2 min, 10 °C/min, 300 °C, 17 min).
Experimental Section
Typical Procedure for Optimizing Reaction Conditions. A
nitromethane solution (20 mL) of 1-(4-methoxyphenyl)ethanol (1a)
(3.04 g, 20.0 mmol, 1 mol/L), acetylacetone (2a) (2.00 g,
20.0 mmol, 1 mol/L), and nitrocyclohexane (995 mg, 7.71 mmol,
as an internal standard, 0.3-0.4 mol/L) was prepared. (Warning:
Nitromethane is hazardous because of the possibility of an
explosion.) The solution was mixed with catalysts in 20 mL test
tubes equipped with glass stoppers. At 20 °C: 2.97 mg of La(OTf)3
and 1.01 mL of the solution; 4.50 mg of Yb(OTf)3 and 1.45 mL of
the solution; 2.70 mg of Sc(OTf)3 and 1.10 mL of the solution;
4.60 mg of Hf(OTf)4 and 1.19 mL of the solution. At 50 °C: 2.31
mg of La(OTf)3 and 0.79 mL of the solution; 5.20 mg of Yb(OTf)3
and 1. 68 mL of the solution; 2.25 mg of Sc(OTf)3 and 0.91 mL of
the solution; 4.72 mg of Hf(OTf)4 and 1.22 mL of the solution. At
80 °C: 3.14 mg of La(OTf)3 and 1.07 mL of the solution; 4.46 mg
of Yb(OTf)3 and 1.44 mL of the solution; 2.70 mg of Sc(OTf)3
and 1.10 mL of the solution; 3.89 mg of Hf(OTf)4 and 1.00 mL of
the solution. The mixtures in the test tubes were stirred at the
corresponding temperatures. The reactions were followed by TLC.
After the complete consumption of 1a and the symmetrical ethers
(meso- and DL-1-(4-methoxyphenyl)ethyl ethers), 65 µL of the
reaction mixtures was taken and filtered through a short silica gel
pad with 2 mL of ethyl acetate to remove insoluble materials. The
filtrates were analyzed by GC and GC-MS. The programmed GC
analysis temperature condition was 150 °C for 2 min, 10 °C/min,
260 °C for 17 min. The yields were determined using the calibration
line prepared from nitrocyclohexane and 3a using GC. For preparing
the calibration line, three standard samples containing nitrocyclo-
hexane (50, 50, 50 mg) and pure 3a (50, 100, 150 mg) were
analyzed by GC and [GC area (3a)]/[GC area (nitrocyclohexane)]
was then plotted against [mol (3a)]/[mol (nitrocyclohexane)] to
obtain the slope.33 The yields of the reaction were as follows: 8%
(La), 51% (Yb), 83% (Sc), and 85% (Hf) at 20 °C; 90% (La), 98%
Methyl 2-acetyl-3-(4-methoxyphenyl)butyrate (5a, diastereo-
mixture). Colorless oil: TLC Rf ) 0.43 (hexane/ethyl acetate )
1
7/3); H NMR (300 MHz, CDCl3) δ 7.15-7.08 (2H, m), 7.15-
7.11 (2H, m), 6.84-6.80 (2H, m), 6.84-6.80 (2H, m), 3.78 (3H,
s), 3.77 (3H, s), 3.75 (3H, s), 3.45 (3H, s), 3.78-3.68 (1H, m),
3.78-3.68 (1H, m), 3.55-3.43 (1H, m), 3.55-3.43 (1H, m), 2.28
(3H, s), 1.91 (3H, s), 1.27 (3H, d, J ) 6.9 Hz), 1.22 (3H, d, J )
6.9 Hz); 13C NMR (100 MHz, CDCl3) δ 202.14, 202.06, 168.8,
168.4, 158.2, 158.1, 135.1, 134.7, 128.2, 128.1, 114.0, 113.7, 67.7,
67.1, 55.23, 55.23, 52.5, 52.2, 39.5, 39.1, 30.1, 30.0, 20.9, 20.3;
IR (neat) 2950 (m), 1740 (s), 1710 (s), 1610 (m), 1510 (s), 1460
(m), 1440(m), 1360 (m), 1260 (s), 1190 (s), 1040 (m), 840 (m)
cm-1; EI-MS (70 eV) m/z (relative intensity) 250 (M+, 12), 232
(19), 175 (17), 161 (8), 135 (100); HRMS-EI (m/z) M+ calcd for
C14H18O4, 250.1205; found, 250.1208. Anal. Calcd for C14H18O4:
C, 67.18; H, 7.25. Found: C, 67.43; H, 7.42. GC analysis: 10.62
min, 10.95 min (major) (150 °C, 2 min, 10 °C/min, 260 °C,
17 min).
2-[1-(4-Methoxyphenyl)ethyl]-N,N-dimethyl-3-oxobutyr-
amide (7a, diastereomixture). Colorless oil: TLC Rf ) 0.48
(hexane/ethyl acetate ) 1/4); 1H NMR (300 MHz, CDCl3) δ 7.17-
7.12 (2H, m), 7.17-7.12 (2H, m), 6.84-6.79 (2H, m), 6.84-6.79
(2H, m), 3.93 (1H, d, J ) 10.8 Hz), 3.79 (1H, d, J ) 10.5 Hz),
3.78 (3H, s), 3.77 (3H, s), 3.74-3.60 (1H, m), 3.74-3.60 (1H,
m), 3.13 (3H, s), 3.02 (3H, s), 2.78 (3H, s), 2.72 (3H, s), 2.28 (3H,
s), 1.97 (3H, s), 1.23 (3H, d, J ) 6.9 Hz), 1.20 (3H, d, J )
6.6 Hz); 13C NMR (100 MHz, CDCl3) δ 204.8, 204.4, 167.4, 167.4,
(33) In several cases, the slopes were deduced from the isolated yields.
5166 J. Org. Chem., Vol. 72, No. 14, 2007

Benzylation and Allylation of 1,3-Dicarbonyl Compounds
158.1, 158.0, 135.5, 135.1, 128.3, 128.1, 114.0, 113.6, 66.4, 65.6,
55.6, 55.2, 40.0, 39.4, 37.8, 37.5, 36.3, 35.9, 27.2, 27.0, 22.1,
19.7; IR (neat) 2950 (m), 1715 (m), 1650 (s), 1520 (m), 1475 (m),
1410 (m), 1370 (m), 1260 (s), 1195 (m), 1155 (m), 1130 (m), 1050
(m), 845 (m) cm-1; EI-MS (70 eV) m/z (relative intensity) 263
(M+, 11), 220 (100), 175 (22), 135 (32), 72 (17); HRMS-EI (m/z)
M+ calcd for C15H21NO3, 263.1521; found, 263.1525. Anal. Calcd
for C15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C, 68.39; H,
8.21; N, 5.04. GC analysis: 12.72 min, 13.29 min (major)
(150 °C, 2 min, 10 °C/min, 300 °C, 13 min).
Reuse of the Catalyst. In a 20 mL test tube, 1a (488.15 mg,
3.208 mmol) was added to a mixture of Yb(OTf)3 (9.77 mg,
15.75 µmol) and 2a (316.85 mg, 3.165 mmol) in CH3NO2
(3.150 mL) at room temperature. The resulting mixture was stirred
at 50 °C for 24 h under a rubber balloon stopper. After cooled to
room temperature, the Yb(OTf)3 catalyst was extracted with six
3 mL portions of water (upper phase) from the reaction mixture of
CH3NO2 solution (lower phase). The trace amount of contaminated
CH3NO2 in the water phase was extracted with ethyl acetate and
combined with the CH3NO2 layer. The organic layer was concen-
trated under reduced pressure, and the resulting oil was purified
by bulb to bulb distillation (185 °C/0.26 Torr) to afford 3a
(730.8 mg, 99%) as a colorless oil. The oil crystallized on standing
at room temperature. The water extract was concentrated under
reduced pressure and dried under vacuum (1 Torr) at room
temperature for 10 min and then at 200 °C for 3 min with a heating
gun to give a white crystalline Yb(OTf)3 catalyst. The catalyst was
used for the next run. For the second run, 2a (329.5 mg,
3.291 mmol), CH3NO2 (3.150 mL), and 1a (487.7 mg, 3.205 mmol)
were stirred at 50 °C for 24 h. After bulb to bulb distillation,
736.8 mg of 3a (99%) was obtained. For the third run, 2a
(328.5 mg, 3.281 mmol), CH3NO2 (3.150 mL), and 1a (481.2 mg,
3.162 mmol) were stirred at 50 °C for 24 h. After bulb to bulb
distillation, 716.5 mg of 3a (97%) was obtained. For the fourth
run, 2a (329.4 mg, 3.290 mmol), CH3NO2 (3.150 mL), and 1a
(492.1 mg, 3.233 mmol) were stirred at 50 °C for 48 h. After bulb
to bulb distillation, 733.0 mg of 3a (97%) was obtained. For the
fifth run, 2a (327.8 mg, 3.274 mmol), CH3NO2 (3.150 mL), and
1a (479.7 mg, 3.152 mmol) were stirred at 50 °C for 48 h. After
bulb to bulb distillation, 708.5 mg of 3a (96%) was obtained.
Measurement of Enol Ratio in CD3NO2 by NMR. The NMR
spectra of dicarbonyl compounds were measured in CD3NO2 at 23-
25 °C (0.11-0.18 mol/L, except 2b and 2c because of their low
solubilities).
Acknowledgment. This work was supported, in part, by the
Ministry of Education, Culture, Sports, Science and Technology,
a Grant-in-Aid for Young Scientists (B) (No. 18790016), and a
President’s Special Research Grant from Meiji Pharmaceutical
University.
Supporting Information Available: Tables and graphs of the
GC analysis for optimizing the reaction conditions (3a-n, 3p-q,
5a-f, 7a-d, 9, and 11), procedure of the isolation reaction (3a-
q, 5a-f, 7a-d, 9, 11, and 12), reuse of the catalyst, characterization
of all new compounds, 1H and 13C spectra of the products, and the
table of enol ratios for dicarbonyl compounds (2a-d, 4a-c, and
6a,b). This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0705216
J. Org. Chem, Vol. 72, No. 14, 2007 5167