Efficient Baylis-Hillman reactions of cyclic enones in methanol as catalyzed by methoxide anion

Article abstract of DOI:10.1021/jo0491760

The Baylis-Hillman reactions of cyclic enones with a variety of aldehydes were investigated. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was found to be a viable catalyst in promoting the reactions of sterically retarded substrates in methanol. The reactions showed clear solvent dependence and only occurred in hydroxylic solvents, especially in methanol. Further consideration on the steric character of DBU and its high basicity jointly with other experimental observations suggests that the methoxide anion should be the "true" Baylis-Hillman catalyst. This has been confirmed by the effectiveness of similar reactions directly employing methoxide as the catalyst. The reaction pathways of this type of catalysis are proposed to depend on the choice of substrates. Supporting experimental observations were demonstrated and discussed in relation to mechanistic considerations. This study also reveals that both DBU and sodium methoxide can be successfully applied as effective catalysts in methanol to promote the Baylis-Hillman reactions for a range of cyclic enones including cyclopent-2-enones, cyclohex-2-enones, γ-pyrone, and 1-benzopyran-4(4H)- ones.

Full text of DOI:10.1021/jo0491760

Efficient Baylis-Hillman Reactions of Cyclic Enones in Methanol
As Catalyzed by Methoxide Anion
Sanzhong Luo,† Xueling Mi,‡ Hui Xu,† Peng George Wang,§ and Jin-Pei Cheng*,†,‡
Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100080, China, Department of Chemistry, State Key Laboratory of Elemento-organic Chemistry,
Nankai University, Tianjin, 300071, China, and The State Key Laboratory of Microbial Technology,
School of Life Science, Shandong University, Jinan, Shandong 250100, China
jpcheng@nankai.edu.cn
Received May 15, 2004
The Baylis-Hillman reactions of cyclic enones with a variety of aldehydes were investigated. 1,8-
Diazabicyclo[5.4.0]undec-7-ene (DBU) was found to be a viable catalyst in promoting the reactions
of sterically retarded substrates in methanol. The reactions showed clear solvent dependence and
only occurred in hydroxylic solvents, especially in methanol. Further consideration on the steric
character of DBU and its high basicity jointly with other experimental observations suggests that
the methoxide anion should be the “true” Baylis-Hillman catalyst. This has been confirmed by
the effectiveness of similar reactions directly employing methoxide as the catalyst. The reaction
pathways of this type of catalysis are proposed to depend on the choice of substrates. Supporting
experimental observations were demonstrated and discussed in relation to mechanistic consider-
ations. This study also reveals that both DBU and sodium methoxide can be successfully applied
as effective catalysts in methanol to promote the Baylis-Hillman reactions for a range of cyclic
enones including cyclopent-2-enones, cyclohex-2-enones, γ-pyrone, and 1-benzopyran-4(4H)-ones.
Introduction
Bu4NX, amine, or alcohol in the Baylis-Hillman reaction
of methyl vinyl ketone.5 In these cases, Lewis acids were
considered to facilitate reactions by activating the sub-
strates. More recently, the proazaphosphatrane sulfide/
TiCl4 combination was shown to be an excellent catalyst
for a range of Baylis-Hillman substrates including
enones, acrylonitrile, and acrylates.6
Previously, we found that imidazole and its derivatives
could effectively catalyze Baylis-Hillman reactions of
enones in aqueous media.7 Remarkable rate enhance-
ment was observed simply on conducting the reactions
in weakly basic NaHCO3 solution.8 However, in our
Baylis-Hillman reaction (or Morita-Baylis-Hillman
reaction), a versatile carbon-carbon bond-forming reac-
tion, has attracted tremendous research activities in the
past decade. Considerable progress has been achieved in
enlarging the substrate scope, developing effective cata-
lysts, and establishing methodologies for asymmetric
catalysis.1,2 This type of reaction is generally initiated
by a Michael addition of a nucleophile, i.e., the Baylis-
Hillman catalyst. Among the traditional nucleophilic
catalysts, tertiary amines and phosphines were the ones
most frequently explored.1c Chalcogenide/TiCl4 was also
found to be an effective Baylis-Hillman catalyst in some
cases.3 Recently, the in situ generated halide ion was
demonstrated to behave like a nucleophile when TiCl4
or Et2AlI alone was employed as a catalyst in certain
Baylis-Hillman reactions.4 A similar mechanism was
also proposed when TiX4 was used in combination with
(3) (a) Kataoka, T.; Iwama, T.; Tsujiyama, S. J. Chem. Soc., Chem.
Commun. 1998, 197-198. (b) Kataoka, T.; Iwama, T.; Tsujiyama, S.;
Iwamura, T.; Watanabe, S. Tetrahedron 1998, 54, 11813-11824. (c)
Kataoka, T.; Kinoshita, H.; Kinoshita, S.; Iwamura, T.; Watanabe, S.
Angew. Chem., Int. Ed. 2000, 39, 2358-2360. (d) Kinoshita, S.;
Kinoshita, H.; Iwamura, T.; Watanabe, S.; Kataoka, T. Chem. Eur. J.
2003, 9, 1496-1502. (e) Kinoshita, H.; Osamura, T.; Kinoshita, S.;
Iwamura, T.; Watanabe, S. I.; Kataoka, T.; Tanabe, G.; Muraoka, O.
J. Org. Chem. 2003, 68, 7532.
(4) (a) Li, G.; Wei, H.-X.; Gao, J.; Caputo, T. D.Tetrahedron Lett.
2000, 41, 1. (b) Pei, W.; Wei, H.-X.; Li, G. Chem. Commun,. 2002, 2412.
(c) Pei, W.; Wei, H.-X.; Li, G. Chem. Commun. 2002, 1856.
(5) (a) Han, Z.; Uehira, S.; Shinokubo, H.; Oshima, K. J. Org. Chem.
2001, 66, 7854. (b) Shi, M.; Feng, Y. J. Org. Chem. 2001, 66, 406. (c)
Shi, M.; Jiang, J.; Feng, Y. Org. Lett. 2000, 2, 2397. (d) Shi, M.; Jiang,
J. K.; Cui, S. C. Tetrahedron 2001, 57, 7343. (e) Shi, M.; Jiang, J. K.;
Cui, S. C.; Feng, Y. S. J. Chem. Soc., Perkin Trans. 1 2001, 390.
(6) You, J. S.; Xu, J. H.; Verkada, J. G. Angew. Chem., Int. Ed. 2003,
42, 5054.
† Chinese Academy of Sciences.
‡ Nankai University.
§ Shandong University.
(1) (a) Ciganek, E. Org. React. 1997, 51, 201. (b) Langer, P. Angew.
Chem., Int. Ed. 2000, 39, 3049. (c) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. Rev. 2003, 103, 811.
(2) For examples of asymmetric catalysis, see: (a) Mocquet, C. M.;
Warriner, S. L. Synlett 2004, 356. (b) McDougal, N. T.; Schaus, S. E.
J. Am. Chem. Soc. 2004, 125, 12094. (c) Kawahara, S.; Nakano, A.;
Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2003, 5, 3013. (d)
Shi, M.; Chen, L. H. Chem. Commun. 2003, 1310. (e) Yang, K. S.; Lee,
W. D.; Pan, J. F.; Chen, K. M. J. Org. Chem. 2003, 68, 915. (f) Shi, M.;
Xu, Y. M. Angew. Chem., Int. Ed. 2002, 41, 4507. (g) Imbriglio, J. E.;
Vasbinder, M. M.; Miller, S. J. Org. Lett. 2003, 5, 3741. (h) Iwabuchi,
Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc.
1999, 121, 10219.
(7) (a) Luo, S. Z.; Zhang, B.; He, J.; Janczuk, A.; Wang, P. G.; Cheng,
J.-P. Tetrahedron Lett. 2002, 43, 7369. (b) Catri, R.; El Gaied, M. M.
Tetraheron Lett. 2002, 43, 7835.
(8) (a) Luo, S. Z.; Wang, P. G.; Cheng, J.-P. J. Org. Chem. 2004, 69,
555. (b) Luo, S. Z.; Mi, X. L.; Wang, P. G.; Cheng, J.-P. Tetrahedron
Lett. 2004, 45, 5171.
10.1021/jo0491760 CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/04/2004
J. Org. Chem. 2004, 69, 8413-8422
8413

Luo et al.
SCHEME 1
SCHEME 2
TABLE 1. Tertiary Amine Catalyzed Reactions of
4,4-Dimethylcyclopent-2-enone (1) with
p-Chlorobenzaldehydea
DBU shortened the reaction time to 6 h, but the product
yield remained the same (Table 1, entry 8). The use of
hydroxylic solvents was shown to be critical for DBU-
promoted reactions. In CH3CN and DMF, even with 50
mol % hydroxylic solvent added, no reactions were
observed (Table 1, entries 10-13). Methanol was shown
to be a superior medium to ethanol (Table 1, entries 8
and 9).
entry
catalyst (mol %)
solvent time (h) yieldb (%)
1
2
DABCO (50)
DMAP (50)
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
DMF
12
12
20
20
20
12
8
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
99
3
3-quinuclidinone (50)
3-quinuclidinol (50)
quinuclidine (50)
Et3N (50)
4
It is known that DBU is a hindered and non-nucleo-
philic base with relatively strong basicity.9 Recently,
Aggarwal reported that DBU could act as a powerful
Baylis-Hillman catalyst for a range of substrates includ-
ing cyclohex-2-enone.10 The reaction of cyclohex-2-enone
with benzaldehyde afforded the Baylis-Hillman product
in 60% yield in 1 h. However, in our trials under
conditions similar to those in Aggarwal’s work, the
reaction of 4,4-dimethylcyclic enones with benzaldehyde
was very sluggish, and only trace product was detected
after 24 h with most of the starting materials decomposed
(Scheme 2). The low reactivity of 4,4-dimethylcyclic
enones may be ascribed to the steric effect of the two
methyl groups at C4 position. This result, together with
the inert character of DBU as a nucleophile in aprotic
solvents as observed in this work (Table 1), indicates that
DBU should be sensitive to steric effect. However, the
steric issue cannot explain the fact that DBU was
actually observed to be a highly effective catalyst in
methanol (see Table 1). On the basis of the above
observations, it can be envisioned that DBU is most likely
not a direct Baylis-Hillman catalyst in methanol. Con-
sidering DBU’s strong basicity, the methoxide anion, as
in situ generated by DBU, should be the acting catalyst
that directly initiated the reaction. This is also consistent
with the present observations that the less basic tertiary
amines (e.g., DABCO, DMAP, etc.) showed very low
catalytic activity in Baylis-Hillman reactions (Table 1,
entries 1-6).
5
6
7
DBU (30)
8
DBU (50)
6
99
9
DBU (50)
24
16
16
24
24
83
10
11
12
13
DBU (50)
N.R.
N.R.
N.R.
N.R.
DBU (50)
MeCN
DBU (50) + MeOH (50) MeCN
DBU (50) + phenol (50) MeCN
a Reactions were carried out on 0.5 mmol scale in 1 mL of
solvent, molar ratio of aldehyde/enone ) 1: 1.2. b Isolated yield
based on aldehyde. N.R. ) no reaction.
recent investigation of the similar reactions using hin-
dered enones such as 4,4-dimethylcyclopentenone and
4,4-dimethylcyclohexenone, the reactions were observed
to be substantially slower due probably to steric effects
but were able to afford the desired Baylis-Hillman
products in moderate yields (Scheme 1). Later, we found
that DBU could accelerate the reaction very efficiently
in methanol. This finding may be quite surprising
especially when the steric character of DBU is considered.
Consequently, we expanded the DBU-promoted reaction
to a broader scope and found that it should be the
methoxide anion rather than DBU that played the real
role as an effective catalyst. Now we wish to report the
details of this study.
Results and Discussion
To seek further evidence for the proposed methoxide
anion catalysis, sodium methoxide was tested in the
model reaction of 4,4-dimethylcyclopentenone and 4-chlo-
robenzaldehyde in methanol. To our delight, the reaction
was found to proceed very smoothly and afforded the
desired product with 98% yield after 3 h (Table 2, entry
1). Compared with DBU-promoted reaction, this reaction
is slightly faster with 98% yield of the desired product.
Other alkoxides as well as sodium 1,2,4-triazolium were
also examined, but inferior results or decomposition were
observed in these cases (Table 2, entries 3-6).
The Catalysts. As mentioned, the imidazole-catalyzed
Baylis-Hillman reactions of 4,4-dimethyl-substituted
cyclic enones were substantially slower than those of the
corresponding unhindered cyclic enones due to steric
retardation. To improve the reaction, we examined a
variety of tertiary amine catalysts taking the reaction of
4,4-dimethylcyclopent-2-enone with p-chlorobenzalde-
hyde as a model. The results are summarized in Table
1.
As shown in Table 1, among the amines examined, only
DBU can effectively promote the reaction. In the presence
of DBU (30 mol %), the reaction proceeded smoothly to
give the desired Baylis-Hillman product in quantitative
yield in 8 h (Table 1, entry 7). Increasing the loading of
(9) (a) Oediger, H.; Mo¨ller, F.; Eiter, K. Synthesis 1972, 591. (b)
Ghosh, N. Synlett 2004, 574.
(10) Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311.
8414 J. Org. Chem., Vol. 69, No. 24, 2004

Efficient Baylis-Hillman Reactions of Cyclic Enones in Methanol
TABLE 2. Alkoxide-Catalyzed Reactions of
4,4-Dimethylcyclopent-2-enone with
p-Chlorobenzaldehydea
TABLE 3. Sodium Methoxide Catalyzed Reactions of
4,4-Dimethylcyclopent-2-enone with Aldehydesa
entry
R
product
time (h)
yieldb (%)
1
2
3
4
5
6
Ph
2b
2c
2d
2e
2f
4
3
91
90
92
77
33
56
2-ClPh
4-NO2Ph
4-MePh
4-MeOPh
i-Bu
1
12
24
11
2g
a Reactions were carried out on 0.5 mmol scale in 1 mL of
solvent, molar ratio of aldehyde/enone ) 1:1.2 b Isolated yield
based on aldehyde.
with enone 1 satisfactorily, providing the desired adducts
in 33% yield after 24 h (Table 3, entry 5). Aliphatic
aldehydes such as isovaleraldehyde worked well too,
albeit with moderate yield (Table 3, entry 6). In all the
cases tested, the Baylis-Hillman adducts were predomi-
nant with little or no aldol-type product detected.
a Reactions were carried out on 0.5 mmol scale in 1 mL of
solvent, molar ratio of aldehyde/enone ) 1: 1.2. b Isolated yield
based on aldehyde. c Uncharacterized byproducts observed. d In
2 mL of methanol.
Reactions with 4,4-dimethylcyclohexenone (3) were
also examined using sodium methoxide (100 mol %) as
the catalyst. Unlike 4,4-dimethylcyclopent-2-enone (1),
the reactions of enone 3 afforded the domino-Baylis-
Hillman and aldol condensation product 5 besides the
expected Baylis-Hillman adducts 4 (Scheme 4, Table 4).
This difference in product formation between 1 and 3 may
be rationalized by considering the steric hindrance of the
R′ position. In cyclopent-2-enone 1, the 5 (R′) position is
steric hindered by the two neighboring methyl groups;
thus, the R′-aldolization is forbidden. In cyclohex-2-enone
3, the 6 (R′)-position is less hindered, and so a significant
amount of subsequent Baylis-Hillman-aldol condensa-
tion product was obtained.12 As shown in Table 4, the
reactions were applied well for aromatic aldehydes. The
use of K2CO3 or sodium methoxide gave similar results.
In the cases of aliphatic aldehydes, self-condensation of
aldehyde occurred due to the relatively low reactivity of
4,4-dimethylcyclohex-2-enone 3, which led to poor results.
Next, the reaction was extended to a new class of cyclic
enones, 1-benzopyran-4(4H)-ones and γ-pyrone. Since the
R′-positions of these substrates are masked, the aldol
pathway can thus be avoided and the reactions occurred
very cleanly in methanol to give the desired Baylis-
Hillman adducts under the catalysis of sodium methoxide
(Scheme 5, Table 5). Most recently, Basavaiah reported
that methanolic trimethylamine (100 mol %) could medi-
ate the Baylis-Hillman reaction of 1-benzopyran-4(4H)-
ones.13 However, the reaction was applicable only to
active aromatic aldehydes such as nitrobenzaldehydes
and pyridinecarboxaldehydes and required very long
reaction time which generally ranged from 2 to 5 days.
In comparison with Basavaiah’s results, the methoxide
anion catalyzed Baylis-Hillman reaction of 1-benzopy-
ran-4(4H)-ones produced higher yields of the desired
adducts but in much shorter reaction time (see Table 5,
entries 8 and 10). The reactions also worked well with
less reactive aromatic aldehydes and aliphatic aldehydes,
affording the desired Baylis-Hillman adducts in moder-
ate to high yields (Table 5, entries 11, 16-18). Mean-
SCHEME 3
Solvent effect was obvious in the methoxide-catalyzed
reactions. In the presence of 50 mol % of sodium meth-
oxide, the reaction in nonhydroxylic solvent MeCN gave
only 37% yield along with some uncharacterized byprod-
ucts over 7 h (Table 2, entry 2). It is noteworthy that the
inorganic base K2CO3 can also effectively catalyze the
reaction (Table 2, entry 7). In the presence of K2CO3 (100
mol %), the reaction gave 88% yield over 3 h in methanol.
It is known that K2CO3 is partially soluble in methanol
in the form of potassium methoxide, which acts as the
“real” catalyst to promote the reaction.11 Thus, the use
of K2CO3 may provide a convenient alternative to meth-
oxide anion in synthetic applications.
Substrate Scopes. The catalytic conditions employed
for investigating the scope and limitation of this version
of reactions were usually 50 mol % of sodium methoxide
or 50 mol % of DBU; in some cases, K2CO3 (100 mol %)
was used for convenience.
Initially, the reactions of 4,4-dimethylcyclopent-2-
enone with various aldehydes were investigated (Scheme
3, Table 3). Aromatic aldehydes bearing either an electron-
withdrawing group or an electron-donating group all
worked well under the current conditions. In the presence
of sodium methoxide (50 mol %), the reactions proceeded
very smoothly to afford the corresponding adducts with
moderate to high isolated yields. Notably, the highly
electron-rich p-methoxybenzaldehyde could also couple
(12) For steric effects in directing Baylis-Hillman reaction and Aldol
reaction, see: Basavaiah, D.; Sreenivasulu, B.; Rao, A. J. J. Org. Chem.
2003, 68, 5983.
(13) For a recent example, see: Basavaiah, D.; Rao, A. J. Tetrahe-
dron Lett. 2003, 44, 4365.
(11) KHCO3 deposited upon the formation of KOMe was shown to
be inert for catalysis. For solubility of K2CO3 in methanol, see:
Platonov, A. Y.; Evdokimov, A. N.; Kurzin, A. V.; Maiyorova, H. D. J.
Chem. Eng. Data 2002, 47, 1175.
J. Org. Chem, Vol. 69, No. 24, 2004 8415

Luo et al.
SCHEME 4
TABLE 4. Sodium Methoxide Catalyzed Reactions of
4,4-Dimethylcyclohex-2-enone with Aldehydesa
SCHEME 6
yieldb (%)
entry
X
time (h)
4
5
1
2
3
4
5
6
4-Cl
H
3-NO2
2-Cl
3-Br
3-Me
20
24
6
20
15
36
4a
4b
4c
4d
4e
4f
37
26
35
17
36
20
5a
5b
5c
5d
5e
5f
55
45
51
41
38
16
a Reactions were carried out on 0.5 mmol scale in 1 mL of
methanol, molar ratio of aldehyde/enone ) 1:2.0; when K2CO3 was
tried, the reaction was conducted in 2 mL of methanol. b Isolated
yield based on aldehyde.
readily to provide the corresponding adducts in high
yields (Table 6, entries 1-4).
SCHEME 5
Using sodium methoxide or potassium carbonate as
catalyst, the reactions of common cyclic enones such as
cyclopent-2-enone (13) and cyclohex-2-enone (15) were
also investigated. As shown in Table 7, the reactions
afforded reasonable yields of the desired Baylis-Hillman
adducts within 1 h and demonstrated good applicability
for a wide range of aldehydes. It should be pointed out
that the Baylis-Hillman products were the dominant
products although the reactions were generally not highly
clean under the basic conditions. Decomposition was
observed when extending the reaction time. In these
cases, some non-Baylis-Hillman pathway may exist in
the presence of methoxide anion (see discussion below).
Nevertheless, the current reactions provide fast and
convenient alternatives for the synthesis of densely
functionalized cyclic allylic alcohols.
Previously, Ciganek reported that sodium methoxide
in THF could mediate the coupling of methyl acrylate
with aromatic aldehydes.15 The reactions produced R-meth-
oxymethylcinnamic acids (after hydrolysis) with moder-
ate yields via Baylis-Hillman-type reactions (Scheme 6).
In our studies, Baylis-Hillman substrates such as acry-
lates and acrylonitrile were also attempted. However, the
examined reactions did not give any Baylis-Hillman
products in methanol in the presence of sodium meth-
oxide (50 mol %) (Scheme 6). This is consistent with
Aggarwal’s observation that sodium methoxide itself
could not catalyze the Baylis-Hillman reaction of methyl
acrylate in methanol.16 All together, it seems likely that
the R,â-unsaturated ketone structure may be essential
for the success of methoxide anion catalysis in methanol.
Mechanism Consideration. Among various nucleo-
philes exploited for Baylis-Hillman catalysis in the
literature, oxy nucleophiles have rarely been attempted
as catalysts.15 Shi and co-workers previously reported
that combination of titanium tetrachloride and oxy
while, both of the chromone derivatives (8 and 10) were
proved to be effective Michael acceptors under the
present conditions. It is noted that even 5 mol % of
sodium methoxide was able to facilitate efficient coupling
of 1-benzopyran-4(4H)-one with nitrobenzaldehydes (Table
5, entries 8-10).
The Baylis-Hillman reaction of γ-pyrone proceeded
smoothly giving moderate to good product yields in the
presence of sodium methoxide (Table 5, entries 2, 4-7).
Although there are two identical R-positions in γ-pyrone,
only the mono-Baylis-Hillman adducts were obtained in
the cases examined. Generally, 50 mol % of sodium
methoxide were required to obtain good yields. In the
presence of 10 mol % of sodium methoxide, the reaction
between γ-pyrone and p-nitrobenzaldehyde afforded the
Baylis-Hillman adduct in 40% yield after 2 h. The yield
can be improved to 62% by loading 50 mol % of sodium
methoxide (Table 5, entries 1 and 2). There was no
further improvement on yield by loading more sodium
methoxide or extending the reaction time.
As shown in Table 5, DBU also served as an efficient
Baylis-Hillman catalyst for 1-benzopyran-4(4H)-ones
and γ-pyrone (entries 3 and 12) in methanol. Comparable
or even better results were obtained when DBU was used
in place of sodium methoxide.
Isatin was reported as being able to serve as an
electrophile in Baylis-Hillman reactions.13,14 Accordingly,
isatin was employed to couple with the chromone deriva-
tives γ-pyrone 6 and cyclopentenone 1. In the presence
of 50 mol % of sodium methoxide, the reactions occurred
(15) Ciganek, E. J. Org. Chem. 1995, 60, 4635.
(16) Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem. 2003,
68, 692.
(14) Garden, S. J.; Skakle, J. M. S. Tetrahedron Lett. 2002, 43,
1969-1972.
8416 J. Org. Chem., Vol. 69, No. 24, 2004

Efficient Baylis-Hillman Reactions of Cyclic Enones in Methanol
TABLE 5. Sodium Methoxide Catalyzed Reactions of 1-Benzopyran-4(4H)-ones and γ-Pyrone with Aldehydesa
a Reactions were carried out on 0.5 mmol scale in 1 mL of solvent, molar ratio of aldehyde/enone ) 1.0:1.0. b Isolated yield of pure
product. c Data in parentheses refer to literature results.
SCHEME 7
compounds promoted the Baylis-Hillman reactions of
methyl vinyl ketones.5d However, the oxy compound was
not the real catalyst, and the reaction was most likely
initialized by chloride ion from the neutral oxy-Ti com-
plex. Most recently, the reaction of 2-hydroxybenzalde-
hyde and cyclohex-2-enone, a typical Baylis-Hillman
coupling, was suggested to occur through a domino oxa-
Micheal addition/aldol condensation pathway in the
presence of DABCO under aqueous conditions.17 The in
situ generated phenoxide anion acted as the nucleophile
to facilitate the coupling of aldehyde and enone in an
intramolecular manner (Scheme 7).
In the present study, sodium methoxide may act either
product. As shown in Scheme 8 (taking the reaction of
2-cyclohexenone as an example), methoxide as a base
may absorb a γ-proton to form the corresponding dieno-
late anion II, which is thermodynamically more stable
than its cross-conjugated isomer I as generated by
as a nucleophile or a base when interacting with enone.
Accordingly, there may be two alternative pathways
accounting for the formation of the Baylis-Hillman
(17) Bra¨se, S.; Lesh, B. Angew. Chem., Int. Ed. 2004, 43, 115.
J. Org. Chem, Vol. 69, No. 24, 2004 8417

Luo et al.
TABLE 6. Sodium Methoxide (50 mol %) Catalyzed
Reactions of Isatina
TABLE 7. Sodium Methoxide Catalyzed Reactions of
Cyclopent-2-enone and Cyclohex-2-enone with
Aldehydesa
a Reactions were carried out on 0.5 mmol scale in 1 mL of
solvent, molar ratio of isatin/enone ) 1:1.2. b Isolated yield of pure
product after chromatography or recrystallization.
abstraction of an R′-proton.18 The subsequent R-aldol
reactions lead preferentially to Baylis-Hillman product
under the experimental conditions (Scheme 8). When
methoxide anion acts as a nucleophile, a slightly different
mechanism should apply. In this connection, the Baylis-
Hillman product should be obtained by following an oxa-
Michael addition/aldol reaction pathway (B), reminiscent
of the typical Baylis-Hillman process. However, the dual
character of methoxide anion as a base and a nucleophile
makes two reaction pathways less discernible.
On the basis of the short reaction time observed for
the common enones 13 and 15, it is very likely that a
base initialized γ-dienolate anion intermediate (pathway
A) is probably invoked in their reaction coordinates, of
which the sequence of R-aldol reaction and isomerization
provides the Baylis-Hillman adducts. This was further
supported by the reaction of 3-methyl-2-cyclohexenone
17. In the presence of potassium carbonate in methanol,
the reaction of 17 with p-nitrobenzaldehyde afforded the
γ-aldol condensation product 18 as the major product. A
similar result was also observed in the reaction with
p-chlorobenzaldehyde, which afforded the γ-aldol adduct
19 as the dominant product (Scheme 9). Thus, it is
obvious that the reactions proceeded through γ-dienolate
anion III to furnish the γ-aldol products. In these cases,
where the R-position is less accessible than the γ-position,
the reaction gives the γ-aldol product (18 or 19) as the
a Reactions were carried out on a 0.5 mmol scale in 1 mL of
solvent, molar ratio of aldehyde/cyclopent-2-enone ) 1.0:1.5;
aldehyde/cyclohex-2-enone ) 1.0:2.0. b Isolated yield of pure prod-
uct. c Decomposition occurred upon extending the reaction time.
dominant product. Presently, the oxa-Micheal addition/
aldol pathway (B) cannot be ruled out for the reactions
of 13 and 15.
On the other hand, for enones 1, 3, 6, 8, and 10, it is
believed that the reactions should follow an oxa-Michael
addition/aldol reaction pathway B, as their γ-positions
are either masked (1 and 3) or heterosubstituted (6, 8,
and 10). In these cases, the aldol reaction of methoxylated
enolate with aldehydes and the subsequent elimination
of methoxyl group afford the desired Baylis-Hillman
adducts.19 Methoxylated aldol products may also be
produced in this process and were indeed obtained from
the reaction of methyl vinyl ketone (MVK). The reaction
of MVK with p-nitrobenzaldehyde was observed to give
methoxylated aldol product 21 as a major product and
(19) Previously, it was reported that the sequential Michael addition
of methoxide ion and elimination of the methoxy group with a base
could be employed as an efficient method for protecting methylene
lactone in the total synthesis of deoxocrispolide. Paquette, L. A.;
Sturino, C. F.; Wang, X.; Prodger, J. C.; Koh, D. J. Am. Chem. Soc.
1996, 118, 5620.
(18) (a) Lee, R. A.; McAndrews, C.; Patel, K. M.; Reusch, W.
Tetrahedron Lett. 1973, 14, 965. (b) Lee, R. A.; Reusch, W. Tetrahedron
Lett. 1973, 14, 969.
8418 J. Org. Chem., Vol. 69, No. 24, 2004

Efficient Baylis-Hillman Reactions of Cyclic Enones in Methanol
SCHEME 8
SCHEME 9
SCHEME 10
the Baylis-Hillman product 20 as a minor.20 The meth-
oxylated R′-aldol product 22 was also obtained as an
additional minor product (Scheme 10). The use of DBU
in this case gave similar product distribution, albeit with
lower yield of 22. These results further support the
assumption that the Baylis-Hillman reactions of enones
1, 3, 6, 8, and 10 proceed via an oxa-Micheal addition/
aldol pathway (B).
In conclusion, we have shown, for the first time, that
methoxide anion can effectively catalyze the Baylis-
Hillman-type reaction of enones. For common enones
such as cyclopent-2-enone and cyclohex-2-enone, the
reactions occurred most likely through a γ-dienolate
anion intermediate generated from deprotonation by the
methoxide base, whereas for enones without γ-protons
such as 1, 3, 6, 8, and 10 the reaction followed an oxa-
Micheal addition/aldol pathway (B) with the methoxide
anion as the nucleophile. DBU was shown to be effective
in promoting this series of reactions in methanol, and
the in situ generated methoxide anion accounted for its
catalytic activity. Generally, the reactions are quite fast
and afford the desired Baylis-Hillman products with
moderate to good yields; thus, it provides a convenient
and efficient approach for the synthesis of allylic alcohols
under mild conditions.
Experimental Section
General Procedure. To a stirred mixture of sodium
methoxide and aldehyde (0.5 mmol) in 2 mL of methanol was
added the respective R,â-unsaturated ketones (0.6 mmol). The
resulted mixture was stirred at room temperature. Upon
completion or after the time indicated in the tables, the
reaction was quenched with 1 N HCl and concentrated under
reduced pressure. The residue was extracted with ethyl
acetate. The combined organic layer was dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography on
(20) Compound 20 and its methoxylated isomers 21 were isolated
as inseparable mixtures and appeared as one point on TLC. However,
their respective NMR signals were obviously discernible (see the
Supporting Information), and the ratio was therefore estimated by the
corresponding integration.
J. Org. Chem, Vol. 69, No. 24, 2004 8419

Luo et al.
silca gel to afford the desired product. For the reactions in
Tables 5 (entries 1-3, 8-10, and 13-15) and 6, the reaction
mixture was filtered after the indicated time and the filtered
solid was recrystallized from methanol-acetonitrile to afford
the pure product. The filtrate was worked up as mentioned
above to give another portion of pure product.
2-(Hydroxyphenylmethyl)-4,4-dimethylcyclohex-2-en-
one (4b). Known compound.22 Colorless syrup. IR (KBr, cm-1):
3435, 1669. 1H NMR (CDCl3, 300 MHz): δ 1.16 (3H, s), 1.18
(3H, s), 1.86 (2H, t, J ) 6.6 Hz), 2.48 (2H, t, J ) 6.6 Hz), 3.23
(1H, br s), 5.48 (1H, s), 6.49 (1H, s), 7.27-7.35 (5H, m). 13C
NMR (CDCl3, 75 MHz): δ 28.0, 28.2, 33.3, 35.3, 36.0, 73.1,
126.7, 127.8, 128.7, 138.0, 142.2, 156.5, 200.5. HRMS for
C15H18O2: calcd 230.1307, found 230.1301.
2-[(4-Chlorophenyl)hydroxymethyl]-4,4-dimethylcy-
clopent-2-enone (2a). Known compound.21 Pale yellow solid.
1
Mp: 49-50 °C. IR (KBr, cm-1): 3426, 1697. H NMR (CDCl3,
2-[Hydroxy(3-nitrophenyl)methyl]]-4,4-dimethylcyclo-
hex-2-enone (4c). Pale yellow syrup. IR (KBr, cm-1): 3435,
300 MHz): δ 1.20 (3H, s), 1.22 (3H, s), 2.34 (2H, s), 3.55 (1H,
s), 5.50 (1H, s), 7.02 (1H, s), 7.29-7.36 (4H, m). 13C NMR
(CDCl3, 75 MHz): δ 27.9, 39.2, 50.9, 68.8, 127.8, 128.6, 133.5,
139.8, 144.2, 168.2, 209.1. Anal. Calcd: C, 67.07; H, 6.03.
Found: C, 67.01; H, 6.02.
1
2959, 1667, 1530, 1350. H NMR (CDCl3, 300 MHz): δ 1.16
(3H, s), 1.18 (3H, s), 1.84 (2H, t, J ) 6.9 Hz), 2.45 (2H, t, J )
6.9 Hz), 3.30 (1H, br s), 5.49 (1H, s), 6.56 (1H, s), 7.48 (1H, t,
J ) 7.8 Hz), 7.68 (1H, d, J ) 7.8 Hz), 8.08 (1H, d, J ) 7.8 Hz),
8.18 (1H, s). 13C NMR (CDCl3, 75 MHz): δ 27.6, 27.8, 33.1,
34.9, 35.6, 72.0, 121.3, 122.4, 129.3, 132.5, 136.9, 144.5, 148.3,
157.0, 200.0. HRMS for C15H18O4 N (M + 1): calcd 276.1230,
found 276.1227.
2-(Hydroxyphenylmethyl)-4,4-dimethylcyclopent-2-
1
enone (2b). Colorless syrup. IR (KBr, cm-1): 3430, 1699. H
NMR (CDCl3, 300 MHz): δ 1.17 (3H, s), 1.19 (3H, s), 2.31 (2H,
s), 3.28 (1H, br s), 5.49 (1H, s), 7.01 (1H, s), 7.28-7.35 (5H,
m). 13C NMR (CDCl3, 75 MHz): δ 27.9, 28.0, 39.2, 50.9, 69.5,
126.5, 127.8, 128.5, 141.3, 144.5, 168.2, 209.3. HRMS for
C14H17O2 (M + 1): calcd 217.1223, found 217.1222.
2-(2-Chlorophenylhydroxymethyl)-4,4-dimethylcyclo-
hex-2-enone (4d). Colorless syrup. IR (KBr, cm-1): 3434,
1670. 1H NMR (CDCl3, 300 MHz): δ 1.13 (3H, s), 1.15 (3H, s),
1.88 (2H, d, J ) 6.9 Hz), 2.53-2.58 (2H, m), 3.04 (1H, br s),
5.89 (1H, s), 6.22 (1H, s), 7.25-7.38 (3H, m), 7.64 (1H, d, J )
7.8 Hz). 13C NMR (CDCl3, 75 MHz): δ 27.2, 27.6, 32.8, 34.7,
35.5, 69.0, 125.8, 128.0, 128.5, 129.2, 132.2, 135.7, 138.3, 156.7,
200.5. HRMS for C15H18O2 Cl (M + 1): calcd 265.0990, found
265.0989.
2-(3-Bromophenylhydroxymethyl)-4,4-dimethylcyclo-
hex-2-enone (4e). Pale yellow syrup. IR (KBr, cm-1): 3432,
1666. 1H NMR (CDCl3, 300 MHz): δ 1.18 (3H, s), 1.19 (3H, s),
1.86 (2H, t, J ) 6.9 Hz), 2.48 (2H, t, J ) 6.9 Hz), 3.20 (1H, br
s), 5.42 (1H, s), 6.50 (1H, s), 7.20-7.27 (2H, m), 7.40 (1H, d,
J ) 7.5 Hz), 7.51 (1H, s). 13C NMR (CDCl3, 75 MHz): δ 27.6,
27.8, 32.9, 34.8, 35.6, 72.2, 122.5, 124.9, 129.3, 129.8, 130.5,
137.1, 144.3, 156.5, 200.0. HRMS for C15H18O2Br (M + 1):
calcd 311.0464, found 311.0463.
2-(Hydroxy-m-tolylmethyl)-4,4-dimethylcyclohex-2-en-
one (4f). Yellow syrup. IR (KBr, cm-1): 3436, 1670. 1H NMR
(CDCl3, 300 MHz): δ 1.18 (3H, s), 1.19 (3H, s), 1.88 (2H, t,
J ) 6.9 Hz), 2.38 (3H, s), 2.50 (2H, t, J ) 6.9 Hz), 2.95 (1H, br
s), 5.47 (1H, s), 6.52 (1H, s), 7.09-7.14 (2H, m), 7.20-7.27 (2H,
m). 13C NMR (CDCl3, 75 MHz): δ 21.4, 27.6, 27.8, 32.9, 34.9,
35.6, 72.6, 123.3, 127.0, 128.1, 137.6, 137.9, 141.7, 156.0, 200.1.
HRMS for C16H20O2 (M): calcd 244.1463, found 244.1458.
6-(4-Chlorobenzylidene)-2-[(4-chlorophenyl)hydroxy-
methyl]-4,4-dimethylcyclohex-2-enone (5a). Colorless syrup.
IR (KBr, cm-1): 3443, 1661, 1603, 1489. 1H NMR (CDCl3, 300
MHz): δ 1.11 (3H, s), 1.13 (3H, s), 2.77 (2H, s), 3.63 (1H, br
s), 5.55 (1H, s), 6.65 (1H, s), 7.28-7.38 (8H, m), 7.60 (1H, s).
13C NMR (CDCl3, 75 MHz): δ 28.7, 28.8, 34.0, 40.7, 72.4, 127.7,
127.9, 128.7, 128.8, 130.9, 133.3, 133.9, 134.5, 136.1, 138.5,
140.5, 155.6, 188.6. HRMS for C22H21Cl2O2 (M + 1) calcd
387.0913, found 387.0915.
2-[(2-Chlorophenyl)hydroxymethyl]-4,4-dimethylcy-
clopent-2-enone (2c). Colorless syrup. IR (KBr, cm-1): 3396,
1705. 1H NMR (CDCl3, 300 MHz): δ 1.18 (3H, s), 1.22 (3H, s),
2.38 (2H, s), 3.73 (1H, br s), 5.90 (1H, s), 6.87 (1H, s), 7.27-
7.38 (3H, m), 7.63-7.65 (1H, m). 13C NMR (CDCl3, 75 MHz):
δ 27.6, 27.9, 39.1, 50.7, 66.0, 127.0, 127.8, 129.3, 132.0, 138.5,
142.3, 169.0, 209.5. HRMS for C14H16O2 Cl (M + 1): calcd
251.0833, found 251.0836.
2-[Hydroxy(4-nitrophenyl)methyl]-4,4-dimethylcyclo-
pent-2-enone (2d). Pale yellow solid. Mp: 88-90 °C. IR (KBr,
1
cm-1): 3436, 1689. H NMR (CDCl3, 300 MHz): δ 1.18 (3H,
s), 1.19 (3H, s), 2.32 (2H, s), 3.50 (1H, br s), 5.60 (1H, s), 7.03
(1H, s), 7.54 (2H, d, J ) 8.7 Hz), 8.17 (2H, d, J ) 8.7 Hz). 13
C
NMR (CDCl3, 75 MHz): δ 27.7, 39.3, 50.7, 68.5, 123.6, 127.0,
143.4, 147.3, 148.4, 168.6, 208.8. HRMS for C14H15NO4: calcd
261.1001, found 261.1005.
2-(Hydroxy-p-tolylmethyl)-4,4-dimethylcyclopent-2-
enone (2e). Pale yellow syrup. IR (KBr, cm-1): 3430, 1700.
1H NMR (CDCl3, 300 MHz): δ 1.20 (3H, s), 1.22 (3H, s), 2.33
(2H, s), 2.36 (3H, s), 3.36 (1H, br s), 5.48 (1H, s), 7.05 (1H, s),
7.17 (2H, d, J ) 7.8 Hz), 7.27 (2H, d, J ) 7.8 Hz). 13C NMR
(CDCl3, 75 MHz): δ 21.1, 27.9, 39.0, 50.9, 69.4, 126.4, 129.1,
137.4, 138.3, 144.6, 167.9, 209.1. HRMS for C15H19O2 (M + 1):
calcd 231.1379, found 231.1383.
2-[Hydroxy(4-methoxyphenylmethyl)-4,4-dimethylcy-
clopent-2-enone (2f). Yellow syrup. IR (KBr, cm-1): 3444,
1704. 1H NMR (CDCl3, 300 MHz): δ 1.22 (3H, s), 1.24 (3H, s),
2.36 (2H, s), 3.50 (1H, br s), 3.84 (3H, s), 5.49 (1H, s), 6.91
(2H, d, J ) 8.4 Hz), 7.04 (1H, s), 7.31 (2H, d, J ) 8.4 Hz). 13
C
NMR (CDCl3, 75 MHz): δ 28.0, 39.0, 50.9, 55.2, 69.3, 113.8,
127.7, 133.3, 144.6, 159.2, 167.8, 209.1. HRMS for C15H19O3
(M + 1): calcd 247.1329, found 247.1329.
6-Benzylidene-2-(hydroxyphenylmethyl)-4,4-dimethyl-
2-(1-Hydroxy-3-methylbutyl)-4,4-dimethylcyclopent-2-
enone (2g). Pale yellow syrup. IR (KBr, cm-1): 3436, 1698.
1H NMR (CDCl3, 300 MHz): δ 0.93-0.95 (6H, m), 1.22 (6H,
s), 1.43-1.48 (1H, m), 1.58-1.61 (1H, m), 1.75-1.81 (1H, m),
2.31 (2H, s), 2.51 (1H, br s), 4.46 (1H, dd, J ) 4.5, 9.3 Hz),
7.16 (1H, s). 13C NMR (CDCl3, 75 MHz): δ 21.7, 23.3, 24.3,
27.9, 28.0, 38.9, 44.6, 50.8, 65.5, 144.8, 166.6, 209.7. HRMS
for C12H21O2 (M + 1): calcd 197.1536, found 197.1535.
cyclohex-2-enone (5b). Yellow syrup. IR (KBr, cm-1): 3442,
1
1659, 1601. H NMR (CDCl3, 300 MHz): δ 1.11 (3H, s), 1.14
(3H, s), 2.50 (1H, br s), 2.82 (2H, s), 5.59 (1H, s), 6.63 (1H, s),
7.28-7.42 (10H, m), 7.68 (1H, s). 13C NMR (CDCl3, 75 MHz):
δ 29.1, 29.2, 34.3, 40.7, 73.6, 126.8, 127.6, 127.9, 128.5, 128.8,
130.0, 133.9, 136.0, 137.6, 139.0, 142.3, 155.8, 189.4. HRMS
for C22H23O2 (M + 1): calcd 319.1692, found 319.1688.
2-[Hydroxy(3-nitrophenyl)methyl]-4,4-dimethyl-6-(3-
2-(4-Chlorophenylhydroxymethyl)-4,4-dimethylcyclo-
hex-2-enone (4a). Colorless syrup. IR (KBr, cm-1): 34440,
1668. NMR (CDCl3, 300 MHz): δ 1.12 (3H, s), 1.14 (3H, s),
1.82 (2H, t, J ) 6.9 Hz), 2.41 (2H, d, J ) 6.9 Hz), 3.50 (1H, br
s), 5.41 (1H, s), 6.42 (1H, s), 7.23-7.29 (4H, m). 13C NMR
(CDCl3, 75 MHz): δ 27.6, 27.8, 33.0, 34.9, 35.6, 72.0, 127.7,
128.5, 137.4, 140.4, 156.3, 200.1. HRMS for C15H17ClO2: calcd
264.0917, found 264.0916.
nitrobenzylidene)cyclohex-2-enone (5c). Yellow syrup. IR
1
(KBr, cm-1): 3442, 1662, 1612, 1528, 1350. H NMR (CDCl3,
300 MHz): δ 1.16 (3H, s), 1.18 (3H, s), 2.82 (2H, s), 3.00 (1H,
br s), 5.68 (1H, s), 6.83 (1H, s), 7.52-7.66 (4H, m), 7.74-7.80
(1H, m), 8.14-8.22 (3H, m), 8.29 (1H, s). 13C NMR (CDCl3, 75
MHz): δ 28.7, 28.8, 34.3, 40.2, 72.1, 121.4, 122.6, 123.3, 124.0,
129.4, 129.7, 132.6, 134.6, 135.4, 135.7, 137.0, 137.9, 144.3,
(21) Leonard, W. R.; Livinghouse, T. J. Org. Chem. 1984, 50, 730.
8420 J. Org. Chem., Vol. 69, No. 24, 2004
(22) Pei, W.; Wei, H.-X.; Li, G.Chem. Commun. 2002, 2412.

Efficient Baylis-Hillman Reactions of Cyclic Enones in Methanol
148.3, 148.4, 156.6, 187.9. HRMS for C22H21O6 N2 (M + 1):
calcd 409.1394, found 409.1397.
Hz), 7.45 (1H, t, J ) 7.5 Hz), 7.63 (1H, d, J ) 8.4 Hz), 7.70
(2H, d, J ) 8.7 Hz), 7.78 (1H, J ) 7.5, 8.4 Hz), 7.98 (1H, d,
J ) 7.5 Hz), 8.14 (2H, d, J ) 8.7 Hz), 8.44 (1H, s). 13C NMR
(DMSO, 75 MHz): δ 67.0, 118.7, 123.5, 125.2, 125.8, 126.6,
128.1, 134.3, 134.6, 146.8, 151.5, 154.8, 156.1, 175.4. Anal.
Calcd: C, 64.65; H, 3.73; N, 4.71. Found: C, 64.68; H, 3.75;
N, 4.62.
3-[Hydroxy(3-nitrophenyl)methyl]-4H-chromen-4-
one (9b). White solid. Mp: 134-136 °C. IR (KBr, cm-1): 3379,
1627. 1H NMR (DMSO, 300 MHz): δ 5.83 (1H, s), 6.20 (1H, d,
J ) 4.2 Hz), 7.39 (1H, t, J ) 7.5 Hz), 7.49-7.59 (2H, m), 7.69-
7.74 (1H, m), 7.82 (1H, d, J ) 7.5 Hz), 7.91-7.94 (1H, m),
8.00-8.03 (1H, m), 8.22 (1H, m), 8.40 (1H, m). 13C NMR
(DMSO, 75 MHz): δ 67.1, 118.9, 121.7, 122.6, 123.7, 125.4,
126.0, 126.8, 130.0, 133.9, 134.8, 146.4, 148.0, 154.9, 156.3,
175.7. Anal. Calcd: C, 64.65; H, 3.73; N, 4.71. Found: C, 64.77;
H, 3.73; N, 4.68.
3-[Hydroxy(2-nitrophenyl)methyl]-4H-chromen-4-
one (9c). Known compound.13,23 Pale yellow solid. Mp 148-
149 °C (lit.13 mp 150-152 °C). IR (KBr, cm-1): 3381, 1638. 1H
NMR (DMSO, 300 MHz): δ 6.30 (1H, d, J ) 4.8 Hz), 6.38 (1H,
d, J ) 4.2 Hz), 7.45-7.54 (2H, m), 7.64-7.73 (3H, m), 7.78-
7.83 (1H, m), 7.88-7.92 (1H, m), 7.98-8.01 (1H, m), 8.26 (1H,
s). 13C NMR (DMSO, 75 MHz): δ 62.8, 118.9, 124.4, 125.4,
126.0, 126.6, 129.0, 129.7, 133.4, 134.8, 137.3, 148.9, 154.6,
156.3, 175.7. Anal. Calcd: C, 64.65; H, 3.73; N, 4.71. Found:
C, 64.59; H, 3.72; N, 4.66.
6-(2-Chlorobenzylidene)-2-[(2-chlorophenyl)hydroxy-
methyl]-4,4-dimethylcyclohex-2-enone (5d). Colorless syrup.
IR (KBr, cm-1): 3434, 1663, 1619. 1H NMR (CDCl3, 300
MHz): δ 1.10 (6H, s), 2.67 (2H, s), 3.10 (1H, br s), 5.99 (1H,
s), 6.39 (1H, s), 7.21-7.48 (7H, m), 7.68 (1H, m), 7.77 (1H, s).
13C NMR (CDCl3, 75 MHz): δ 28.3, 28.4, 34.1, 40.4, 69.5, 126.4,
127.0, 128.3, 128.7, 129.4, 129.6, 129.7, 130.1, 132.5, 134.3,
134.4, 134.7, 135.1, 135.8, 138.5, 156.6, 189.0. HRMS for
C22H21O2 Cl2 (M + 1): calcd 387.0913, found 387.0908.
6-(3-Bromobenzylidene)-2-[(3-bromophenyl)hydroxy-
methyl]-4,4-dimethylcyclohex-2-enone (5e). Yellow syrup.
IR (KBr, cm-1): 3439, 1660, 1591. 1H NMR (CDCl3, 300
MHz): δ 1.13 (3H, s), 1.15 (3H, s), 2.79 (1H, s), 5.55 (1H, s),
6.68 (1H, s), 7.21-7.34 (5H, m), 7.42-7.48 (3H, m), 7.57-7.59
(1H, m). 13C NMR (CDCl3, 75 MHz): δ 28.6, 28.8, 34.1, 40.2,
72.5, 122.6, 122.7, 125.0, 128.1, 129.5, 129.9, 130.0, 130.6,
131.5, 132.2, 134.6, 135.6, 137.6, 138.2, 144.3, 156.0, 188.4.
HRMS for C22H21O2Br2 (M + 1): calcd 474.9903, found
474.9908.
2-(Hydroxy-m-tolylmethyl)-4,4-dimethyl-6-(3-methyl-
benzylidene)cyclohex-2-enone (5f). Yellow syrup. IR (KBr,
1
cm-1): 3443, 1661, 1604. H NMR (CDCl3, 300 MHz): δ 1.14
(3H, s), 1.15 (3H, s), 2.38 (3H, s), 2.43 (3H, s), 2.83 (2H, s),
2.57 (1H, s), 6.65 (1H, s), 7.10-7.18 (4H, m), 7.23-7.30 (4H,
m), 7.67 (1H, s). 13C NMR (CDCl3, 75 MHz): δ 21.3, 21.4, 28.6,
28.7, 33.8, 40.2, 73.1, 123.4, 126.5, 127.1, 128.1, 129.2, 130.3,
133.2, 135.5, 137.3, 137.9, 138.0, 138.5, 141.7, 155.2, 188.9.
HRMS for C24H27O2 (M + 1): calcd 347.2005, found 347.2007.
3-[Hydroxy(4-nitrophenyl)methyl]-4H-pyran-4-one (7a).
Pale yellow solid. Mp: 163-164 °C. IR (KBr, cm-1): 3403, 1649.
1H NMR (CDCl3, 300 MHz): δ 3.50 (1H, br, s), 5.86 (1H, s),
6.32 (1H, d, J ) 5.7 Hz), 7.67 (2H, d, J ) 8.7 Hz), 7.86 (1H, d,
J ) 5.7 Hz), 7.97 (1H, s), 8.18 (2H, d, J ) 8.7 Hz). 13C NMR
(DMSO, 75 MHz): δ 66.5, 116.6, 123.4 (×2), 127.8 (×2), 131.9,
146.7, 151.0, 154.2, 156.9, 175.9. Anal. Calcd: C, 58.30; H, 3.67;
N, 5.67. Found: C, 58.34; H, 3.66; N, 5.62.
3-(1-Hydroxy-3-methylbutyl)-4H-chromen-4-one (9d).
1
Yellow syrup. IR (KBr, cm-1): 3439, 1640. H NMR (CDCl3,
300 MHz): δ 0.96-0.99 (6H, m), 1.58-1.62 (1H, m), 1.76-
1.87 (1H, m), 3.50 (1H, br s), 4.73-4.77 (1H, m), 7.40-7.46
(2H, m), 7.64 (1H, t, J ) 4.2 Hz), 7.89 (1H, s), 8.21 (1H, d,
J ) 8.1 Hz). 13C NMR (CDCl3, 75 MHz): δ 21.8, 23.3, 24.7,
45.1, 67.3, 118.1, 123.9, 125.2, 125.6, 126.3, 133.8, 152.3, 156.3,
178.2. HRMS for C14H16O3: calcd 232.1099, found 232.1100.
3-[Hydroxy-(4-nitrophenyl)methyl]-6-methyl-4H-chro-
men-4-one (11a). White solid. Mp: 198-199 °C. IR (KBr,
1
cm-1): 3387, 1630. H NMR (DMSO, 300 MHz): δ 2.40 (3H,
s), 5.90 (1H, s), 6.26 (1H, d, J ) 4.2 Hz), 7.54-7.64 (2H, m),
7.72 (2H, d, J ) 8.7 Hz), 7.79 (1H, s), 8.17 (2H, d, J ) 8.7 Hz),
8.42 (1H, s). 13C NMR (DMSO, 75 MHz): δ 20.9, 67.1, 118.7,
123.5, 123.7, 124.6, 126.7, 128.3, 135.6, 135.9, 147.0, 151.8,
154.6, 154.8, 175.5. Anal. Calcd: C, 65.59; H, 4.21; N, 4.50.
Found: C, 65.55; H, 4.23; N, 4.40.
3-[(4-Chlorophenyl)hydroxymethyl]-4H-pyran-4-one
(7b). Pale yellow syrup. IR (KBr, cm-1): 3351, 1655. 1H NMR
(CDCl3, 300 MHz): δ 4.30 (1H, br s), 5.74 (1H, s), 6.35 (1H, d,
J ) 5.7 Hz), 7.30-7.37 (4H, m), 7.50 (1H, s), 7.74 (1H, d, J )
5.7 Hz). 13C NMR (CDCl3, 75 MHz): δ 69.3, 117.2, 127.9, 128.6,
131.6, 133.7, 138.6, 153.2, 155.6, 178.5. HRMS for C12H9ClO3:
calcd 236.0240, found 236.0248.
3-(Hydroxyphenylmethyl)-4H-pyran-4-one (7c). Pale
yellow syrup. IR (KBr, cm-1): 3384, 1652. 1H NMR (CDCl3,
300 MHz): δ 4.53 (1H, br s), 5.79 (1H, s), 6.35 (1H, d, J ) 5.7
Hz), 7.32-7.44 (5H, m), 7.48 (1H, s), 7.72 (1H, d, J ) 5.7 Hz).
13C NMR (CDCl3, 75 MHz): δ 69.9, 117.2, 126.6, 128.0, 128.5,
132.0, 140.0, 153.4, 155.5, 178.7. HRMS for C12H10O3: calcd
202.0630, found, 202.0623.
3-(Hydroxy-p-tolylmethyl)-4H-pyran-4-one (7d). Yellow
syrup. IR (KBr, cm-1): 3408, 1650. 1H NMR (CDCl3, 300
MHz): δ 2.34 (3H, s), 4.30 (1H, br s), 5.76 (1H, s), 6.36 (1H, d,
J ) 5.7 Hz), 7.17 (2H, d, J ) 7.8 Hz), 7.30 (2H, J ) 7.8 Hz),
7.48 (1H, s), 7.73 (1H, d, J ) 5.7 Hz). 13C NMR (CDCl3, 75
MHz): δ 21.1, 69.8, 117.2, 126.6, 129.3, 132.1, 137.0, 137.8,
153.5, 155.6, 178.8. HRMS for C13H12O3: calcd 216.0786, found
216.0785.
3-[Hydroxy-(3-nitrophenyl)methyl]-6-methyl-4H-chro-
men-4-one (11b). White solid. Mp: 153-154 °C. IR (KBr,
1
cm-1): 3377, 1627. H NMR (DMSO, 300 MHz): δ 2.38 (3H,
s), 5.91 (1H, s), 6.26 (1H, d, J ) 4.5 Hz), 7.52-7.62 (3H, m),
7.78 (1H, s), 7.88 (1H, d, J ) 7.5 Hz), 8.08 (1H, d, J ) 7.5 Hz),
8.29 (1H, s), 8.44 (1H, s). 13C NMR (DMSO, 75 MHz): δ 20.9,
67.1, 118.7, 121.6, 122.5, 123.4, 124.6, 126.7, 130.0, 133.8,
135.5, 135.8, 146.5, 148.0, 154.6, 154.7, 175.6. Anal. Calcd: C,
65.59; H, 4.21; N, 4.50. Found: C, 65.25; H, 4.15; N, 4.46.
3-[Hydroxy(2-nitrophenyl)methyl]-6-methyl-4H-chro-
men-4-one (11c). Pale yellow solid. Mp: 183-184 °C. IR (KBr,
1
cm-1): 3332, 1638. H NMR (DMSO, 300 MHz): δ 2.36 (3H,
s), 6.25 (1H, d, J ) 4.2 Hz), 6.35 (1H, s), 7.45-7.52 (2H, m),
7.56-7.69 (3H, m), 7.74 (1H, s), 7.86 (1H, d, J ) 8.1 Hz), 8.19
(1H, s). 13C NMR (DMSO, 75 MHz): δ 19.4, 61.3, 117.2, 121.8,
122.9, 123.2, 125.0, 127.5, 128.2, 131.9, 134.1, 134.3, 136.0,
147.4, 152.9, 153.1, 174.1. Anal. Calcd: C, 65.59; H, 4.21; N,
4.50. Found: C, 65.52; H, 4.19; N, 4.46.
3-(1-Hydroxy-3-methylbutyl)-4H-pyran-4-one (7e). Yel-
1
low syrup. IR (KBr, cm-1): 3411, 1652. H NMR (CDCl3, 300
3-[Hydroxy(4-chlorophenyl)methyl]-6-methyl-4H-chro-
MHz): δ 0.94-0.97 (6H, m), 1.49-1.55 (1H, m), 1.69-1.85 (2H,
m), 3.50 (1H, br s), 4.58-4.63 (1H, m), 6.35 (1H, d, J ) 5.7
Hz), 7.74 (1H, d, J ) 5.7 Hz), 7.76 (1H, s). 13C NMR (CDCl3,
75 MHz): δ 21.6, 23.1, 24.4, 44.4, 66.8, 117.2, 131.7, 151.8,
155.2, 178.7. HRMS for C10H14O3: calcd 182.0943, found
182.0939.
men-4-one (11d). White solid. Mp: 122-123 °C. IR (KBr,
1
cm-1): 3423, 1629. H NMR (CDCl3, 300 MHz): δ 2.46 (3H,
s), 4.15 (1H, br s), 5.87 (1H, s), 7.34-7.52 (6H, m), 7.63 (1H,
s), 7.99 (1H, s). 13C NMR (CDCl3, 75 MHz): δ 20.8, 69.9, 117.8,
123.4, 124.8, 125.7, 127.9, 128.6, 133.6, 135.3, 135.4, 139.2,
153.2, 154.6, 178.2. Anal. Calcd: C, 67.89; H, 4.36. Found: C,
67.55; H, 4.40.
3-[Hydroxy(4-nitrophenyl)methyl]-4H-chromen-4-
one (9a). Known compound.13,23 Pale yellow solid. Mp: 186-
187 °C (lit.13 mp 186-187 °C). IR (KBr, cm-1): 3390, 1627. 1H
NMR (DMSO, 300 MHz): δ 5.88 (1H, s), 6.26 (1H, d, J ) 4.2
(23) Fritz, E.; Holger, H. Chem. Ber. 1967, 100, 2554.
J. Org. Chem, Vol. 69, No. 24, 2004 8421

Luo et al.
3-(Hydroxyphenylmethyl)-6-methyl-4H-chromen-4-
one (11e). Pale yellow syrup. IR (KBr, cm-1): 3424, 1642. 1H
NMR (CDCl3, 300 MHz): δ 2.45 (3H, s), 3.10 (1H, br s), 5.92
(1H, s), 7.30-7.40 (4H, m), 7.47-7.49 (3H, m), 7.59 (1H, s),
7.99 (1H, s). 13C NMR (CDCl3, 75 MHz): δ 19.5, 69.0, 116.5,
122.0, 123.5, 124.7, 125.1, 126.5, 127.1, 133.6, 133.9, 139.2,
152.0, 153.2, 176.9. HRMS for C17H14O3: calcd 266.0943, found
266.0937.
3-(1-Hydroxy-3-methylbutyl)-6-methyl-4H-chromen-4-
one (11f). Pale yellow solid. Mp: 67-69 °C. IR (KBr, cm-1):
3352, 1634. 1H NMR (CDCl3, 300 MHz): δ 0.97-1.00 (6H, m),
1.58-1.65 (1H, m), 1.78-1.88 (2H, m), 2.46 (3H, s), 3.00 (1H,
br s), 4.70-4.75 (1H, m), 7.34-7.51 (2H, AB peaks), 7.88 (1H,
s), 7.99 (1H, s). 13C NMR (CDCl3, 75 MHz): δ 20.8, 21.7, 23.1,
24.6, 44.9, 67.3, 117.7, 123.5, 124.7, 125.8, 135.0, 151.9, 154.4,
178.2. Anal. Calcd: C, 73.15; H, 7.37. Found: C, 73.28; H, 7.33.
3-(4,4-Dimethyl-1-oxocyclopent-2-en-2-yl)-3-hydroxy-
indolin-2-one (12a). Orange powder. IR (KBr, cm-1): 3427,
3300, 1729, 1688. 1H NMR (CDCl3, 300 MHz): δ 1.22 (6H, s),
2.36 (2H, s), 6.90 (1H, d, J ) 7.5 Hz), 7.05-7.08 (1H, m), 7.27-
7.31 (3H, m), 8.18 (1H, br s). 13C NMR (CDCl3, 75 MHz): δ
27.8, 27.9, 39.3, 50.9, 75.0, 110.5, 123.3, 124.9, 129.4, 130.3,
140.6, 140.8, 140.9, 169.2, 207.8. HRMS for C15H15N Na O3
(M + Na): calcd 280.0950, found 280.0951.
2.49-2.53 (2H, m), 2.63-2.67 (2H, m), 6.17 (1H, s), 7.04 (2H,
s), 7.63-7.67 (2H, m), 8.23-8.27 (2H, m). 13C NMR (CDCl3,
75 MHz): d 22.2, 24.9, 37.7, 124.2, 127.7, 130.0, 132.4, 133.6,
142.2, 147.6, 155.8, 200.2. HRMS for C14H14NO3 (M + 1): calcd
244.0968, found 244.0967.
3-[2-(4-Chlorophenyl)-2-hydroxyethyl]cyclohex-2-en-
1
one (19). Pale yellow syrup. IR (KBr, cm-1): 3407, 1655. H
NMR (CDCl3, 300 MHz): δ 1.87-1.93 (2H, m), 2.21-2.29 (4H,
m), 2.44-2.61 (3H, m), 4.83 (1H, m), 5.86 (1H, s), 7.20-
7.27(4H, m). 13C NMR (CDCl3, 75 MHz): d 22.6, 30.2, 37.2,
47.6, 71.8, 127.1, 128.0, 128.8, 133.7, 142.1, 162.4, 199.9.
HRMS for C14H15ClNaO2 (M + Na): calcd 273.0653, found
273.0658.
4-Hydroxy-3-methoxymethyl-4-(4-nitrophenyl)butan-
2-one (21). Pale yellow syrup, inseparable anti and syn
diastereoisomer mixture. IR (KBr, cm-1): 3431, 1710, 1521,
1
1348. H NMR (CDCl3, 300 MHz): δ 2.16 (1.14H, minor, syn
isomer, -CH3), 2.21 (1.86H, major, anti isomer, -CH3), 3.05-
3.09 (1H, m), 3.26 (1.86H, major, anti isomer, -OCH3), 3.31
(1.14H, minor, syn isomer, -OCH3), 3.34-3.39 (1H, m), 3.49-
3.54 (1H, m), 3.63-3.66 (1H, m), 5.14 (0.62H, anti isomer,
-CHOH, d, J ) 7.2 Hz), 5.26 (0.38H, syn isomer, -CHOH, d,
J ) 5.1 Hz). 13C NMR (CDCl3, 75 MHz): anti isomer, δ 31.4,
59.1, 59.2, 70.9, 71.9, 123.7, 127.2, 147.5, 149.3, 210.9; syn
isomer, δ 31.1, 58.4, 59.2, 70.3, 72.5, 123.6, 126.9, 147.3, 149.1,
209.5. HRMS for C12H15O5NNa (M + Na): calcd 276.0842,
found 276.0843.
3-Hydroxy-3-(4-oxo-4H-pyran-3-yl)indolin-2-one (12b).
Yellow solid. IR (KBr, cm-1): 3412, 3201, 1725, 1641. 1H NMR
(DMSO, 300 MHz): δ 6.19 (1H, d, J ) 6.0 Hz), 6.50 (1H, br s),
6.79-6.87 (2H, m), 6.98-7.01 (1H, m), 7.15-7.21 (1H, m), 8.18
(1H, d, J ) 6.0 Hz), 8.43 (1H, s), 10.36 (1H, s). 13C NMR
(DMSO, 75 MHz): δ 73.1, 109.4, 116.0, 121.2, 123.4, 129.2,
129.9, 130.8, 143.4, 154.5, 156.6, 175.1, 176.4. HRMS for
C13H10NO4 (M + 1): calcd 244.0604, found 244.0604.
1-Hydroxy-5-methoxy-1-(4-nitrophenyl)pentan-3-one
(22). Known compound.25Yellow syrup. IR (KBr, cm-1): 3433,
1710, 1520, 1348. 1H NMR (CDCl3, 300 MHz): δ 1.60 (1H, br
s), 2.70 (2H, t, J ) 6.0 Hz), 2.86 (2H, d, J ) 6.0 Hz), 3.33 (3H,
s), 3.66 (2H, t, J ) 6.0 Hz), 5.28 (1H, t, J ) 6.0 Hz), 7.53 (2H,
d, J ) 8.7 Hz), 8.20 (2H, d, J ) 8.7 Hz). 13C NMR (CDCl3, 75
MHz): δ 43.4, 51.6, 58.9, 67.4, 68.9, 123.9, 126.4, 147.3, 150.0,
209.3. HRMS for C12H16O5N (M + 1): calcd 254.1023, found
254.1025; for C12H15O5NNa (M + Na): calcd 276.0842, found
276.0842.
3-Hydroxy-3-(4-oxo-4H-chromen-3-yl)-1indolin-2-one
(12c). Brown solid. IR (KBr, cm-1): 3437, 3243, 1705, 1645.
1H NMR (DMSO, 300 MHz): δ 6.70 (1H, br s), 6.82-6.87 (2H,
m), 7.05 (1H, d, J ) 7.5 Hz), 7.21 (1H, t, J ) 7.5 Hz), 7.47
(1H, t, J ) 7.5 Hz), 7.70-7.73 (1H, m), 7.80-7.89 (2H, m),
8.63 (1H, s), 10.5 (1H, s). 13C NMR (DMSO, 75 MHz): δ 70.9,
107.0, 116.0, 118.8, 120.4, 121.1, 122.1, 122.3, 123.1, 126.8,
128.8, 131.9, 140.9, 152.4, 153.4, 171.9, 174.3. HRMS for
C17H11NNaO4 (M + Na): calcd 316.0580, found 316.0579.
3-Hydroxy-3-(6-methyl-4-oxo-4H-chromen-3-yl)indolin-
2-one (12d). Known compound.13 Yellow solid. IR (KBr, cm-1):
3381, 3264, 1702, 1637. 1H NMR (DMSO, 300 MHz): δ 2.37
(3H, s), 6.68 (1H, s), 6.85 (2H, t, J ) 7.2 and 7.5 Hz), 7.04 (1H,
d, J ) 7.2 Hz), 7.21 (1H, t, J ) 7.5 Hz), 7.62-7.65 (3H, m),
8.59 (1H, s), 10.45 (1H, s). 13C NMR (DMSO, 75 MHz): δ 19.6,
72.4, 108.6, 117.3, 120.3, 121.7, 122.6, 123.0, 123.4, 128.3,
130.4, 134.2, 134.5, 142.5, 153.2, 153.8, 173.5, 175.9. HRMS
for C18H13NNaO4 (M + Na): calcd 330.0737, found 330.0732.
(Z)-3-[2-(4-Nitrophenyl)vinyl]cyclohex-2-enone (18).
Known compound.24 Brown syrup. IR (KBr, cm-1): 1657, 1594,
1513, 1341. 1H NMR (CDCl3, 300 MHz): δ 2.10-2.19 (2H, m),
Acknowledgment. We thank the National Science
Foundation (NSFC) and the Ministry of Science and
Technology (MoST) of China for financial support.
Supporting Information Available: NMR spectra for all
the new compounds and spectra data for the known compounds
14a-i, 16a-f, and 20. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0491760
(24) Yasumitsu, T.; Tomohisa, M.; Yasuyuki, K. J. Chem. Soc.,
Chem. Commun. 1974, 531.
(25) Maggiotti, V.; Wong, J.-B.; Razet, R.; Cowley, A. R.; Gouverneur,
V. Tetrahedron: Asymmetry 2002, 13, 1789.
8422 J. Org. Chem., Vol. 69, No. 24, 2004