Direct synthesis of highly substituted 2-cyclohexenones and sterically hindered benzophenones based on a [5C + 1C] annulation

Article abstract of DOI:10.1021/jo9013386

(Chemical Equation Presented) The regiospecific [5C+1C] annulation of readily available R-alkenoyl ketene (S,S)-acetals 1 with aryl methyl ketones 2, the less active methylene compounds, has been developed. Upon treatment of 1 with 2 in the presence of t-

Full text of DOI:10.1021/jo9013386

pubs.acs.org/joc
Direct Synthesis of Highly Substituted 2-Cyclohexenones and Sterically
Hindered Benzophenones Based on a [5C þ 1C] Annulation
Zhenqian Fu,† Mang Wang,*,†,‡ Ying Dong,† Jun Liu,† and Qun Liu*,†
†Department of Chemistry, Northeast Normal University, Changchun 130024, China, and ‡State Key
Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, China
wangm452@nenu.edu.cn
Received June 23, 2009
The regiospecific [5C þ 1C] annulation of readily available R-alkenoyl ketene (S,S)-acetals 1 with aryl
methyl ketones 2, the less active methylene compounds, has been developed. Upon treatment of 1
with 2 in the presence of t-BuOK in DMF at room temperature, highly substituted 2-cyclohexenones
3 were synthesized in high to excellent diastereoselectivities with high yields. On the basis of this
strategy, sterically hindered benzophenones 4 were conveniently prepared via the iodonation-
aromatization of 2-cyclohexenones 3 with I2 in MeONa/MeOH basic medium. Furthermore,
benzophenones 4 were also obtained directly from 1 and 2 following a sequential [5 þ 1] annula-
tion-iodonation-aromatization procedure in a one-pot operation.
Introduction
our studies,2-4 we found that R-alkenoyl ketene (S,S)-acetals
1 (Scheme 1), the cross-conjugated dienones with gem-di-
alkylthio substituents on the terminal carbon of a CdC
double bond, showed promising structural features as novel
synthetic intermediates because of their (i) five-carbon 1,5-
bielectrophilic nature, (ii) dense substitution patterns, and
(iii) flexible alkylthio functionality able to play multiple
roles.3,4 Thus, on the basis of the regiospecific [5C þ 1C]
annulation reactions (a sequence of inter- and intramolecu-
lar Michael additions) of R-alkenoyl ketene (S,S)-acetals and
their equivalents with nitroalkanes,5 substituted phenols
Over the past decades, the utility of R-functionalized
ketene (S,S)-acetals as versatile intermediates in organic
synthesis has been well-recognized.1 During the course of
(1) For reviews on R-oxo ketene (S,S)-acetals, see: (a) Dieter, R. K.
Tetrahedron 1986, 42, 3029. (b) Junjappa, H.; Ila, H.; Asokan, C. V.
Tetrahedron 1990, 46, 5423. (c) Elgemeie, G. H.; Sayed, S. H. Synthesis
2001, 1747.
(2) Selected examples for C-C bond-forming reactions at the R-position
of functionalized ketene (S,S)-acetals: (a) Yuan, H.-J.; Wang, M.; Liu, Y.-J.;
Liu, Q. Adv. Synth. Catal. 2009, 351, 112. (b) Ma, Y.; Wang, M.; Li, D.;
Bekturhun, B.; Liu, J.; Liu, Q. J. Org. Chem. 2009, 74, 3116. (c) Fu, Z.; Wang,
M.; Ma, Y.; Liu, Q.; Liu, J. J. Org. Chem. 2008, 73, 7625.
(3) Selected examples of intramolecular anti-Michael addition: (a) Bi, X.;
Zhang, J.; Liu, Q.; Tan, J.; Li, B. Adv. Synth. Catal. 2007, 349, 2301. Domino
reaction: (b) Liang, F.; Zhang, J.; Tan, J.; Liu, Q. Adv. Synth. Catal. 2006,
348, 1986. [5C þ 1N] annulations: (c) Dong, D.; Bi, X.; Liu, Q.; Cong, F.
Chem. Commun. 2005, 3580. (d) Hu, J.; Zhang, Q.; Yuan, H.; Liu, Q. J. Org.
Chem. 2008, 73, 2442. [5C þ 1S] and [5C þ 1Se] annulations: (e) Bi, X.;
Dong, D.; Li, Y.; Liu, Q. J. Org. Chem. 2005, 70, 10886. (f) Li, D.; Xu, X.;
Liu, Q.; Dong, S. Synthesis 2008, 1895.
(4) Selected examples for [5C þ 1C] annulations: (a) Bi, X.; Dong, D.;
Liu, Q.; Pan, W.; Zhao, L.; Li, B. J. Am. Chem. Soc. 2005, 127, 4578. (b)
Zhang, L.; Liang, F.; Cheng, X.; Liu, Q. J. Org. Chem. 2009, 74, 899. (c)
Zhang, Q.; Sun, S.; Hu, J.; Liu, Q.; Tan, J. J. Org. Chem. 2007, 72, 139.
(5) For a review of applications of nitroalkanes in the synthesis of benzene
derivatives, see: Ballini, R.; Palmieri, A.; Barboni, L. Chem. Commun. 2008,
2975.
DOI: 10.1021/jo9013386
r
Published on Web 07/27/2009
J. Org. Chem. 2009, 74, 6105–6110 6105
2009 American Chemical Society

Fu et al.
JOCArticle
SCHEME 1. [5C þ 1C] Annulation Strategies Based on R-Alke-
SCHEME 2. Preparation of R-Alkenoyl Ketene (S,S)-Acetals 1
noyl Ketene (S,S)-Acetals 1
TABLE 1. Optimization of the Reaction Conditionsa
(Scheme 1, Path A),4a p-terphenyls,4b and biaryls4b were
constructed in a single step. Very recently, we also described
the synthesis of pyrrolizidine derivatives through the [5C þ
1C] annulation of R-alkenoyl ketene (S,S)-acetals with ethyl
isocyanoacetate (Scheme 1, Path B).6 As part of a continu-
ing study of the [5 þ 1] annulation strategy with the aim to
exploit suitable carbon nucleophiles,4-6 the reactions of
easily available R-alkenoyl ketene (S,S)-acetals 1 with aryl
methyl ketones 2,7 the less active methylene compounds, as
one-carbon component were examined. As a result, highly
substituted 2-cyclohexenones 3 were synthesized via the
[5C þ 1C] annulation reactions of 1 with 2 (Scheme 1, Path
C). To our knowledge, this represents the first example of the
use of a methyl ketone as one-carbon nucleophile in the
sequential inter- and intramolecular Michael additions4,6-9
and provides a facile and direct method for the synthesis of
sterically hindered benzophenones 4. In this paper, we are
pleased to report these experimental results.
entry
base (equiv)
solvent
time (h)
yield (%)b
1
2
3
4
5
6
7
8
9
t-BuOK (1.0)
t-BuOK (2.0)
t-BuOK (3.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
NaOH (2.0)
NaH (2.0)
DMF
DMF
DMF
THF
MeCN
t-BuOH
DMF
DMF
DMF
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
10
44c
90
87
86
85
67
49
82
nrd
DBU (2.0)
aReaction conditions: 1a (1.0 mmol), 2a (1.1 mmol), solvent (10 mL),
rt. bIsolated yield. c43% of 1a was recovered. dNo reaction.
reaction of the corresponding R-acetyl ketene (S,S)-acetals
with various aldehydes, including aromatic and aliphatic
aldehydes, under basic conditions (Scheme 2).2b,3,4a,6
Synthesis of 2-Cyclohexenones 3 Based on [5 þ 1] Annula-
tions of R-Alkenoyl Ketene (S,S)-Acetals 1 with Methyl
Ketones 2. 2-Cyclohexenones are useful building blocks in
organic synthesis,10 and the procedures for their synthesis
from simple acyclic precursors in a single operation have
attracted increasing attention in recent years.11-14 In this
Results and Discussion
Preparation of r-Alkenoyl Ketene (S,S)-Acetals 1. Accord-
ing to the procedures described in our previous reports, the
selected substrates, R-alkenoyl ketene (S,S)-acetals 1a-j,
were prepared in high to excellent yields by the condensation
(6) Tan, J.; Xu, X.; Zhang, L.; Li, Y.; Liu, Q. Angew. Chem., Int. Ed. 2009,
48, 2868.
(7) For selective reports on the Michael reactions of R-oxo ketene (S,S)-
acetals with acetophenones, see: (a) Potts, K. T.; Cipullo, M. J.; Ralli, P.;
Theodoridis, G. J. Am. Chem. Soc. 1981, 103, 3584. (b) Potts, K. T.; Cipullo,
M. J.; Ralli, P.; Theodoridis, G. J. Am. Chem. Soc. 1981, 103, 3585. (c)
Tinggaard, M.; Hansen, P.; Mogensen, P. K.; Simonsen, O.; Becher, J. J.
Heterocycl. Chem. 1989, 26, 439. (d) Kumar, S.; Ila, H.; Junjappa, H.
Tetrahedron 2007, 63, 10067.
(8) For reports on inter- and intramolecular Michael addition of an 1,5-
electrophilic double Michael acceptor and certain nucleophilic addend, see:
(a) Bergmann, E. D.; Ginsburg, D.; Pappo, R. Org. React. 1959, 10, 179. (b)
(10) For selected recent reports of the synthetic applications of substi-
tuted 2-cyclohexenones, see: (a) Herzon, S. B.; Myers, A. G. J. Am. Chem.
Soc. 2005, 127, 5342. (b) Yang, J.; Dewal, M. B.; Shimizu, L. S. J. Am. Chem.
Soc. 2006, 128, 8122. (c) Paczkowski, R.; Maichle-Mo1ssmer, C.; Maier,
M. E. Org. Lett. 2006, 8, 151. (d) Linghu, X.; Kennedy-Smith, J. J.; Toste, F.
D. Angew. Chem., Int. Ed. 2007, 46, 7671.
(11) For recent examples of the synthesis of substituted 2-cyclohexenones
from acyclic precursors, see: (a) Pei, T.; Wang, X.; Widenhoefer, R. A. J. Am.
Chem. Soc. 2003, 125, 648. (b) Lee, S. I.; Park, J. H.; Chung, Y. K.; Lee, S. J.
Am. Chem. Soc. 2004, 126, 2714. (c) Seiser, T.; Cramer, N. Angew. Chem., Int.
Ed. 2008, 47, 9294. (d) Zhang, C.; Cui, D.; Yao, L.; Wang, B.; Hu, Y.;
Hayashi, T. J. Org. Chem. 2008, 73, 7811. (e) Sudo, Y.; Shirasaki, D.;
Harada, S.; Nishida, A. J. Am. Chem. Soc. 2008, 130, 12588. (f) Murakami,
M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc. 2005, 127, 6932.
(12) (a) Magomedov, N. A.; Ruggiero, P. L.; Tang, Y. J. Am. Chem. Soc.
2004, 126, 1624. (b) Lu, Z.; Chai, G.; Ma, S. Angew. Chem., Int. Ed. 2008, 47,
6045. (c) Carlone, A.; Marigo, M.; North, C.; Landa, A.; Jorgensen, K. A.
Chem. Commun. 2006, 4928.
ꢀ
Britten-Kelly, M.; Willis, B. J. Synthesis 1980, 27. (c) Gomez-Bengoa, E.;
Cuerva, J. M.; Mateo, C.; Echavarren, A. M. J. Am. Chem. Soc. 1996, 118,
8553. (d) Rule, N. G.; Detty, M. R.; Kaeding, J. E.; Sinicropi, J. A. J. Org.
Chem. 1995, 60, 1665. (e) Chande, M. S.; Khanwelkar, R. R. Tetrahedron
Lett. 2005, 46, 7787. (f) Rosiak, A.; Frey, W.; Christoffers, J. Eur. J. Org.
Chem. 2006, 4044. (g) Krishna, P. R.; Sreeshailam, A. Tetrahedron Lett.
2007, 48, 6924. (h) Rosiak, A.; Hoenke, C.; Christoffers, J. Eur. J. Org. Chem.
2007, 4376.
(9) For reports on intermolecular double Michael additions of methyl
ketones to electron-deficient alkenes, see: (a) Basu, B.; Das, P.; Hossain, I.
Synlett 2004, 2224. (b) DeGraffenreid, M. R.; Bennett, S.; Caille, S.; Turiso,
F. G.-L.; Hungate, R. W.; Julian, L. D.; Kaizeman, J. A.; McMinn, D. L.;
Rew, Y.; Sun, D.; Yan, X.; Powers, J. P. J. Org. Chem. 2007, 72, 7455. (c)
Ishikawa, T.; Kudo, K.; Kuroyabu, K.; Uchida, S.; Kudoh, T.; Saito, S. J.
Org. Chem. 2008, 73, 7498.
(13) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 10204.
(14) (a) Hayashi, Y.; Toyoshima, M.; Gotoh, H.; Ishikawa, H. Org. Lett.
2009, 11, 45. (b) Inokuchi, T.; Okano, M.; Miyamoto, T.; Madon, H. B.;
Takagi, M. Synlett 2000, 1549.
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TABLE 2. Synthesis of Highly Substituted 2-Cyclohexenones 3a
entry
1
R1
R2
2
Ar
time (h)
3
yield of 3 (%)b
de of 3 (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14d
1a
1b
1c
1d
1e
1f
1g
1h
1i
1a
1a
1a
1a
1j
H
H
H
H
H
H
H
H
PhCO
H
H
H
H
Ph
4-ClC6H4
4-MeC6H4
3,4-CH2O2C6H3
4-MeOC6H4
2-furyl
2-thienyl
Cy
Ph
Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
20
1.0
1.0
1.0
1.0
1.0
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
90
90
88
87
89
85
87
84
76
89
88
84
89
91
>98
>98
>98
>98
>98
84
82
>98
>98
>98
>98
81
4-ClC6H4
4-MeC6H4
2-MeCONHC6H4
2-furyl
Ph
Ph
Ph
Ph
>98
>98
H
Ph
aReaction conditions: 1 (1.0 mmol), 2 (1.1 mmol), t-BuOK (2.0 mmoL), DMF (10 mL), rt. bIsolated yield. cDiastereomeric excesses determined by 1H
NMR. dThe substrate with SMe.
SCHEME 3. Possible Mechanism for the [5 þ 1] Annulations of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in DMF (Table 1,
1 with 2
entry 9). By comparison, t-BuOK/DMF was a more
efficient basic media and was selected for the following
investigations.
Encouraged by the above results, the scope and limita-
tions of the reactions between R-alkenoyl ketene (S,S)-
acetals 1 and acetophenones 2 were investigated, and the
results are described in Table 2. It is evident that 1 bearing
either an aromatic substituent (electro-neutral, electron-
rich, or electron-deficient, Table 2, entries 1-7) or an
aliphatic substituent (Table 2, entry 8) at the β-position of
the R-alkenoyl moiety of 1 can efficiently react with acet-
ophenone 2a to give the desired 2-cyclohexenones 3a-h in
high yields with high stereoselectivities in short reaction
time. In the case of 1i (having an R-PhCO group) as
substrate, the reaction afforded cyclohexenone 3i in 76%
yield with longer reaction time (Table 2, entry 9). The
tolerance of methyl ketones 2 was then examined. It
was proved that all the selected aryl methyl ketones 2b-e
were efficient nucleophiles and led to the desired 2-cyclo-
hexenones 3j-m in 84-89% yields, respectively (Table 2,
entries 10-13). In addition, 1j (with SMe group) also
allowed the formation of 3n in 91% isolated yield
(Table 2, entry 14).
As we know, [5 þ 1] annulation reaction of an 1,5-
electrophilic double Michael acceptor and certain nucleo-
philic addend via a sequential inter- and intramolecular
Michael addition provides a useful method for the construc-
tion of six-membered ring compounds.8 In this context, as
one-carbon components, activated methylene compounds,
such as ethyl 2-cyanoacetate, 2-tosylacetonitrile, β-ketoe-
sters, dialkyl malonate, Meldrum’s acid, or nitroalkanes, are
well used for efficiency of the annulation. While Basu et al.
reported in 2004 the first example of the intermolecular
double Michael additions of aryl methyl ketones, the less
active methylene compounds, to electron-deficient alkenes
mediated by KF-alumina,9a the study on efficient forma-
tion of the [5 þ 1] cycloadducts by the inter- and intramole-
cular Michael addition of methyl ketones as one-carbon
context, cycloaddition reactions, including [3 þ 2 þ 1],11b
[3 þ 3],12c,14a and [4 þ 2],14b provide direct routes toward
2-cyclohexenones. In the present study, the [5 þ 1] cyclo-
addition of (E)-1,1-bis(ethylthio)-5-phenylpenta-1,4-dien-
3-one 1a with acetophenone 2a was initially selected as a
model reaction for the preparation of 2-cyclohexenones.
Fortunately, as shown in Table 1, entry 1, 4-benzoyl-
3-(ethylthio)-5-phenylcyclohex-2-enone 3a could be ob-
tained in 44% yield upon treatment of 1a (1.0 mmol) with
2a (1.1 mmol) in DMF (10 mL) in the presence of t-BuOK
(1.0 equiv) under ambient conditions for 2.0 h. It was found
that the yield of 3a was significantly improved to 90% when
2.0 equiv of t-BuOK was used (Table 1, entry 2).15 The
reaction media and the base were then examined. Clearly,
all of the reactions could proceed to afford 3a in the
tested basic systems, such as t-BuOK/THF, t-BuOK/
MeCN, t-BuOK/t-BuOH, NaOH/DMF, and NaH/DMF,
except that no reaction was detected in the presence of
(15) For experimental details, see Supporting Information.
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TABLE 3. Synthesis of Benzophenones 4 from Cyclohexenones 3a
thus allow for the efficient and divergent synthesis of sub-
stituted 2-cyclohexenones in a regiospecific manner under
mild reaction conditions.16 Notably, the reaction proceeded
1
with high to excellent diastereoselectivity based on the H
NMR spectral analysis of cyclohexenones 3 (de, 81-98%,
Table 2). All products 3 were well-characterized by their
spectra and analytical data, and the configuration of products
3 wasfurther confirmedascis-isomersbythe X-raydiffraction
studies of 3i.17
Proposed Mechanism for the [5 þ 1] Annulation of 1 with 2.
On the basis of all of the obtained results along with our
previous work,3c-f,4,6 a plausible mechanism for the annula-
tion of 1 with 2 is presented in Scheme 3. The reaction begins
with the Michael addition of the enol anion of aryl methyl
ketone 2, formed in the presence of t-BuOK, to the
R-alkenoyl moiety of 1 leading to intermediate I.4a Then
the intramolecular Michael addition of the enol anion II to
the dithiolacetal moiety in the manner with R2 away from the
SR group to avoid the steric hindrance and subsequent
elimination of a thiol leads to the formation of cyclohex-
enones 3 with cis configuration.
Synthesis of Benzophenones 4. Polysubstituted benzophe-
nones are encountered in numerous natural products as well
as in organic materials.18 Therefore, the facile synthesis of
sterically hindered benzophenones is highly desired. In the
present work, the convenient preparation of 3,5-disubstituted
4-aroyl 2-cyclohexenones 3 may serve as an easy pathway to
sterically hindered benzophenones. With the aim to explore
the synthetic potential of 3 to benzophenone frameworks, the
selected cyclohexenones 3 were thus treated with iodine/
sodium methoxide in methanol following the procedures
described by Hegde et al.19 Table 3 summarizes the transfor-
mation of 2-cyclohexenones 3 into benzophenones 4. As
shown in Table 3, all substrates 3 were suitable precursors
for this tandem double iodination-dehydroiodination-iso-
merization process15 and led to benzophenones 4a-j in high
yields. Interestingly, benzophenone 4i with three ortho-sub-
stituents was also constructed in 86% yield (Table 3, entry 9).
Furthermore, a one-pot procedure for the direct synthesis
of benzophenones 4 starting from 1 and 2 was developed as
well. For example, the selected benzophenones 4a-d and 4j
could be obtained in 76-82% isolated yields, respectively, by
treatment of an acetonitrile solution of the corresponding 1
(16) As a comparison, divinyl ketone 10a without dithioacetal function-
ality was prepared toward the [5 þ 1] annulation conditions (Table 1, entry
2). It was found that the reaction usually resulted in an unidentified complex
mixture. One of the isomers of 30a was obtained only in 8.0% isolated yield by
careful flash silica gel chromatography and further recrystallization from a
mixture of petroleum ether and ethyl ether (3/1, v/v).
(17) Crystal data for 3i: C28H24O3S, M = 440.53, monoclinic, P21/n, a =
3
˚
˚
13.159(2), b = 14.135(2), c = 13.883(3) A, V = 2306.3(7) A , R = 90.00, β =
116.723(3), γ = 90.00, Z = 4, T = 293(2) K, F000 = 928, R1 = 0.0618, wR2 =
0.1112.
aReaction conditions: 3 (1.0 mmol), I2 (2.0 mmol), MeONa/MeOH
(10 mL, M = 0.6 mol/L), -78 °C to rt. bIsolated yield.
(18) For recent examples on the synthesis of benzophenones, see: (a)
Srivastava, A. K.; Panda, G. Chem.;Eur. J. 2008, 14, 4675. (b) Terzidis, M.
A.; Tsoleridis, C. A.; Stephanidou-Stephanatou, J.; Terzis, A.; Raptopoulou,
C. P.; Psycharis, V. Tetrahedron 2008, 64, 11611. (c) Chuzel, O.; Roesch, A.;
Genet, J.-P.; Darses, S. J. Org. Chem. 2008, 73, 7800 and references therein. .
(19) Hegde, S. G.; Kassim, A. M.; Ingrum, A. I. Tetrahedron Lett. 1995,
36, 8395.
nucleophile with a double Michael acceptor is rare. Obvi-
ously, the above [5 þ 1] annulations of R-alkenoyl ketene
(S,S)-acetals 1 and acetophenones 2 proceeded smoothly
with a broad range of substituents for both components and
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Fu et al.
JOCArticle
SCHEME 4. One-Pot Synthesis of Benzophenones 4 Starting
from 1 and 2
SCH2CH3), 3.83 (s, 3H, OCH3), 6.28 (s, 1H, COCHdC), 6.69 (d,
J = 15.5 Hz, 1H, COCHdCH), 6.89 (d, J = 9.0 Hz, 2H, 2 ꢀ
ArH), 7.51 (d, J = 9.0 Hz, 2H, 2 ꢀ ArH), 7.57 (d, J = 15.5 Hz,
1H, COCHdCH); 13C NMR (CDCl3, 125 MHz) δ = 184.0,
162.4, 160.9, 140.8, 129.5 (2C), 127.8, 125.1, 114.4 (2C), 114.1,
55.2, 28.1, 25.6, 13.7, 12.4; IR (KBr) ν = 3060, 2967, 2923, 1643,
1584,1478, 1253, 1124, 831; ES-MS calcd m/z 308.1, found 309.0
[(M þ 1)]þ. Anal. Calcd for C16H20O2S2: C, 62.30; H, 6.54.
Found: C, 62.35; H, 6.52.
Typical Procedure for Preparation of 2-Cyclohexanones 3 (3a
as an Example). To a well-stirred solution of acetophenone 2a
(0.13 mL, 1.1 mmol) in DMF (10 mL) was added t-BuOK (224
mg, 2.0 mmol) at room temperature. After the reaction mixture
was stirred for 10 min, (E)-1,1-bis(ethylthio)-5-phenylpenta-1,4-
dien-3-one 1a (278 mg, 1.0 mmol) was added and stirred for an
additional 1.0 h at room temperature. After completion of the
reaction as indicated by TLC (diethyl ether/petrolum ether, 1/1),
the reaction mixture was quenched by saturated aqueous NaCl
(100 mL), neutralized with dilute hydrochloric acid, and ex-
tracted with CH2Cl2 (3 ꢀ 30 mL). The combined organic phase
was washed with water, dried over anhydrous MgSO4, filtered,
and evaporated in vacuo. The crude product was purified by
flash silica gel chromatography (petroleum ether/ethyl ether =
3/1, v/v) to give 3a as a white solid (90% yield).
and 2 with t-BuOK at room temperature for 1.0 h at first and
then with iodine and MeONa/MeOH for an additional 10 h
(Scheme 4).15 Some notable features of benzophenones 4
obtained above include the following: (i) the multiple sub-
stituents and functional groups incorporated on the benzo-
phenone framework (hydroxy, iodo, ethylthio, aryl, alkyl,
etc.) provide the structural diversity and potential for further
modification;20 (ii) the sterically congested structure (at least
di-ortho-substituted) is required in the majority of biologi-
cally active benzophenones.18c
Conclusion
In summary, an efficient and regiospecific [5C þ 1C]
annulation reaction of R-alkenoyl ketene (S,S)-acetals with
aryl methyl ketones, the less active methylene compounds,
was disclosed, and thus highly substituted 2-cyclohexanones
were synthesized in high yields with high stereoselectivities.
On the basis of this synthetic strategy, a facile route to
sterically hindered benzophenones was developed via the
iodonation-aromatization of 2-cyclohexenones obtained
above with I2 in MeONa/MeOH basic medium. Further-
more, the direct preparation of benzophenones from
R-alkenoyl ketene (S,S)-acetals and aryl methyl ketones
following a sequential [5 þ 1] annulation-iodonation-
aromatization procedure in a one-pot operation was
achieved as well. The synthetic strategy is associated with
readily available starting materials, mild conditions, high
yields, and wide range of synthetic potential of the products.
Further investigations are in progress.
4-Benzoyl-3-(ethylthio)-5-phenylcyclohex-2-enone (3a): Mp
1
94-96 °C; H NMR (CDCl3, 500 MHz) δ = 1.30 (t, J = 7.5
Hz, 3H, SCH2CH3), 2.56 (dd, J = 4.5, 16.5 Hz, 1H, COCHHCH),
2.83-2.88 (m, 2H, SCH2CH3), 3.46 (dd, J = 14.5, 16.5 Hz, 1H,
COCHHCH), 3.82-3.86 (m, 1H, COCH2CH), 4.69 (d, J = 5.0
Hz, 1H, COCHC), 6.13 (s, 1H, COCHdC), 7.03-7.06 (m, 1H,
ArH), 7.09-7.12 (m, 4H, 4 ꢀ ArH), 7.20-7.23 (m, 2H, 2 ꢀ ArH),
7.37-7.40 (m, 1H, ArH), 7.48-7.50 (m, 2H, 2 ꢀ ArH); 13C NMR
(CDCl3, 125 MHz) δ = 197.1, 195.7, 161.0, 138.9, 137.4, 133.0,
128.6 (2C), 128.3 (2C), 128.2 (2C), 127.5 (3C), 121.3, 52.4, 44.2,
37.4, 25.7, 12.6; IR (KBr) ν = 3049, 2967, 2923, 1647, 1578,
1248, 1213, 992, 760, 678; ES-MS calcd m/z 336.1, found 337.1
[(M þ 1)]þ. Anal. Calcd for C21H20O2S: C, 74.97; H, 5.99. Found:
C, 74.99; H, 5.95.
General Procedure for Preparation of Benzophenones 4 (4a as
an Example). To a well-sirred solution of cyclohexenone 3a (336
mg, 1.0 mmol) in MeONa/MeOH (10 mL, M = 0.6 mol/L) was
added iodine (508 mg, 2.0 mol) in small portions at -78 °C. The
reaction was allowed to run at -78 °C for 3.0 h and then at room
temperature overnight. The reaction mixture was quenched by
dilute HCl to pH 7 and was extracted with CH2Cl2 (3 ꢀ 15 mL).
The combined organic phase was washed with saturated aqu-
eous Na2S2O3 (2 ꢀ 15 mL) and water (1 ꢀ 20 mL), dried over
anhydrous MgSO4, filtered, and evaporated in vacuo. The crude
product was purified by flash silica gel chromatography
(petroleum ether/ethyl ether = 3/1, v/v) to give 4a as a colorless
oil (419 mg, 91% yield).
(3-(Ethylthio)-5-hydroxy-4-iodobiphenyl-2-yl)(phenyl)metha-
none (4a): 1H NMR (CDCl3, 500 MHz) δ = 1.12 (t, J = 7.5 Hz,
3H, SCH2CH3), 2.70-2.72 (m, 1H, SCHHCH3), 2.84-2.87 (m,
1H, SCHHCH3), 5.86 (s, 1H, OH), 7.05 (s, 1H, ArH), 7.17-7.22
(m, 5H, 5 ꢀ ArH), 7.30 (t, J = 7.5 Hz, 2H, 2 ꢀ ArH), 7.43 (t, J =
7.5 Hz, 1H, ArH), 7.60 (d, J = 7.5 Hz, 2H, 2 ꢀ ArH); 13C NMR
(CDCl3, 125 MHz) δ = 195.6, 156.1, 142.3, 138.3, 138.1, 137.7,
136.8, 133.0, 129.4 (2C), 128.9 (2C), 128.3 (2C), 128.1 (2C), 127.7,
116.6, 102.2, 32.3, 13.9; IR (KBr) ν = 3246, 3057, 2924, 2854, 1649,
1565, 1381, 1233, 1073, 957, 698; ES-MS calcd m/z 460.0, found
461.0 [(M þ 1)]þ. Anal. Calcd for C21H17IO2S: C, 54.79; H, 3.72.
Found: C, 54.71; H, 3.66.
Experimental Section
Representative Procedure for the Preparation of r-Alkenoyl
Ketene (S,S)-Acetals 1 (1e as an Example)2b,3,4a,6. To a solution
of 4,4-bis(ethylthio)but-3-en-2-one (1.9 g, 10 mmol) and
4-methoxybenzaldehyde (1.33 mL, 11 mmol) in EtOH (10 mL)
was added NaOH (200 mg, 5.0 mmol) in one portion at room
temperature. The reaction mixture was stirred overnight. After
the starting material was consumed as indicated by TLC,
the resulting mixture was quenched by ice-water (20 mL)
under stirring and neutralized with dilute hydrochloric acid.
The precipitate was collected by filtration, washed with water
(100 mL), and dried under vacuum to afford the product 1e (2.68
g, 87%) as a yellow solid.
(E)-1,1-Bis(ethylthio)-5-(4-methoxyphenyl)penta-1,4-dien-3-
one (1e): Mp 86-88 °C; 1H NMR (CDCl3, 500 MHz) δ = 1.36 (t,
J = 7.5 Hz, 3H, SCH2CH3), 1.41 (t, J = 7.5 Hz, 3H, SCH2CH3),
3.01 (q, J = 7.5 Hz, 2H, SCH2CH3), 3.06 (q, J = 7.5 Hz, 2H,
(20) For recent examples of the synthetic applications of o-iodophenol
derivatives, see: (a) Kadnikov, D. V.; Larock, R. C. Org. Lett. 2000, 2, 3643.
(b) Miao, H.; Yang, Z. Org. Lett. 2000, 2, 1765. (c) Bates, C. G.; Saejueng, P.;
Murphy, J. M.; Venkataraman, D. Org. Lett. 2002, 4, 4727. (d) Kadnikov, D.
V.; Larock, R. C. J. Org. Chem. 2003, 68, 9423. (e) Liu, Z.; Larock, R. C. Org.
Lett. 2004, 6, 3739. (f) Bi, H.; Liu, X.; Gou, F.; Guo, L.; Duan, X.; Shu, X.;
Liang, Y. Angew. Chem., Int. Ed. 2007, 46, 7068.
Typical Procedure for One-Pot Synthesis of Benzophenones 4
(4a as an Example). To a well-stirred solution of acetophenone
2a (0.13 mL, 1.1 mmol) and t-BuOK (224 mg, 2.0 mmol) in
MeCN (10 mL) was added (E)-1,1-bis(ethylthio)-5-phenylpen-
ta-1,4-dien-3-one 1a (278 mg, 1.0 mmol) at room temperature.
J. Org. Chem. Vol. 74, No. 16, 2009 6109

Fu et al.
JOCArticle
The reaction was allowed to run at room temperature for 1.0 h.
Then, MeONa/MeOH (10 mL, M = 0.6 mol/L) and iodine (2.0
mmol) were added. After reacting for an additional 10 h, the
resulting mixture was quenched by dilute HCl to pH 7 and was
extracted with CH2Cl2 (3 ꢀ 15 mL). The combined organic
extracts were washed with saturated aqueous Na2S2O3 (2 ꢀ 15
mL) and water (1 ꢀ 20 mL), dried over anhydrous MgSO4,
filtered, and evaporated in vacuo. The crude product was
purified by flash silica gel chromatography (petroleum ether/
ethyl ether = 3/1, v/v) to give 4a as a colorless oil (81% yield).
Acknowledgment. Financial support of this research
by NNSFC-20872015, NENU-STC08007/07007, and the
State Key Laboratory of fine chemicals is greatly appre-
ciated.
Supporting Information Available: Experimental details,
spectral and analytical data for compounds 1, 3, and 4, copies of
1H NMR and 13C NMR spectra of all new compounds (PDF),
and crystallographic data for 3i (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
6110 J. Org. Chem. Vol. 74, No. 16, 2009