BF3·Et2O-catalyzed direct carbon-carbon bond formation of α-EWG ketene-(S,S)-acetals and alcohols and synthesis of unsymmetrical biaryls

Article abstract of DOI:10.1021/jo061775e

A highly efficient BF₃·OEt₂-catalyzed formal dehydration C-C coupling reaction between readily available α-EWG ketene-(S,S)-acetals and various alcohols via direct substitution of the hydroxy group in alcohols has been developed. On the basis of this C-C coupling reaction, a series of alkylated α-EWG ketene-(S,S)-acetals and functionalized 1,4-pentanedienes were prepared in high to excellent yields and the unsymmetrical biaryls were synthesized in good yields from the generated 1,4-pentanedienes and nitroalkanes through a one-pot annulation-aromatization process.

Full text of DOI:10.1021/jo061775e

BF3‚Et2O-Catalyzed Direct Carbon-Carbon Bond Formation of
r-EWG Ketene-(S,S)-Acetals and Alcohols and Synthesis of
Unsymmetrical Biaryls
Qian Zhang,* Shaoguang Sun, Jianglei Hu, Qun Liu,* and Jing Tan
Department of Chemistry, Northeast Normal UniVersity, 5268 Renmin Street,
Changchun 130024, P. R. China
zhangq651@nenu.edu.cn (Q.Z.); liuqun@nenu.edu.cn (Q.L.)
ReceiVed August 29, 2006
A highly efficient BF3‚OEt2-catalyzed formal dehydration C-C coupling reaction between readily available
R-EWG ketene-(S,S)-acetals and various alcohols via direct substitution of the hydroxy group in alcohols
has been developed. On the basis of this C-C coupling reaction, a series of alkylated R-EWG ketene-
(S,S)-acetals and functionalized 1,4-pentanedienes were prepared in high to excellent yields and the
unsymmetrical biaryls were synthesized in good yields from the generated 1,4-pentanedienes and
nitroalkanes through a one-pot annulation-aromatization process.
SCHEME 1
Introduction
The carbon-carbon bond forming reaction is one of the most
fundamental reactions for the construction of the molecular
framework in organic chemistry.1 From the standpoint of atom
efficiency,2 the direct substitution of a hydroxy group in an
alcohol (ROH)3 by a carbon nucleophile (R′H) via a formal
dehydration process is an attractive salt-free method because
there is no requirement for the transformation of nucleophiles
and alcohols to the corresponding reactive organometallic
compounds (R′M) and halides or a related species (RX) (Scheme
1).4a In recent years, increasing attention has been given to the
direct C-C bond forming reactions between ROH and R′H.
Among those reported, the C-C coupling reactions between
allylic or benzylic alcohols and active methylenes,4 indoles,4a,5
SCHEME 2
or alkoxylketones4a have proven successful. In this context,
expanding the scope of the substrates for this type of cross-
coupling reaction to a wide range of carbon nucleophiles and
alcohols is very important.3-5
In our interest in the synthetic applications of the R-EWG
ketene-(S,S)-acetals (1) (Scheme 2, EWG ) electron withdraw-
ing group),6,7 we recently showed that the R-carbon atom of
R-acetyl/cyano ketene-(S,S)-acetals can add to aldehydes or
ketones in the presence of a Lewis acid, affording the corre-
sponding double Baylis-Hillman (BH) adducts.8 Thus, as part
of our continuing research to understand the nucleophilicity of
1, alcohols were chosen as carbon electrophiles (Scheme 2).
(1) (a) March, J. AdVanced Organic Chemistry, 4th ed.; Wiley: New
York, 1992. (b) Scolastico, C., Nocotra, F., Eds. Current Trends in Organic
Synthesis; Plenum: New York, 1999.
(2) (a) Trost, B. M. Science 1991, 254, 1471. (b) Sheldon, R. A. Pure
Appl. Chem. 2000, 72, 1233.
(3) For reviews, see: (a) Muzart, J. Tetrahedron 2005, 61, 4179. (b)
Tamaru, Y. Eur. J. Org. Chem. 2005, 2647.
(4) (a) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int. Ed. 2006,
45, 793. (b) Ozawa, F.; Okamoto, H.; Kawagishi, S.; Yamamoto, S.;
Minami, T.; Yoshifuji, M. J. Am. Chem. Soc. 2002, 124, 10968. (c) Bisaro,
F.; Prestat, G.; Vitale, M.; Poli, G. Synlett 2002, 1823. (d) Motokura, K.;
Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Angew. Chem.,
Int. Ed. 2006, 45, 2605. (e) Kinoshita, H.; Shinokubo, H.; Oshima, K. Org.
Lett. 2004, 6, 4085. (f) Manabe, K.; Kobayashi, S. Org. Lett. 2003, 5, 3241.
(5) (a) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem.
Soc. 2005, 127, 4592. (b) Trost, B. M.; Quancard, J. J. Am. Chem. Soc.
2006, 128, 6314.
(6) For reviews, see: (a) Kolb, M. Synthesis 1990, 171. (b) Dieter, R.
K. Tetrahedron 1986, 42, 3029. (c) Junjappa, H.; Ila, H.; Asokan, C. V.
Tetrahedron 1990, 46, 5423.
10.1021/jo061775e CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/02/2006
J. Org. Chem. 2007, 72, 139-143
139

Zhang et al.
TABLE 1. Acid-Catalyzed C-C Coupling Reactions of 1a with
1, entries 5 and 6). Other Lewis acids, such as AlCl3 and FeCl3,
appeared to be effective, although a prolonged reaction time
was required to achieve a comparable level of product formation
(Table 1, entries 8 and 9). All the reactions between 1a and
benzhydryl alcohol (2a) afforded 3aa in the tested solvents
(tetrahydrofuran, dichloromethane, and acetonitrile; Table 1,
entries 10 and 11), and acetonitrile was shown to be the best
solvent in the case of reaction time and yield. Therefore, the
best results were obtained using an equal amount of BF3‚OEt2
as the catalyst in acetonitrile (Table 1, entry 3). It should be
noted that an equal amount of the general protic acid H2SO4 is
as efficient as BF3‚OEt2 for the reaction between 1a and
benzhydryl alcohol (2a) to provide 95% yield of 3aa within 15
min (Table 1, entry 10). However, the yield of 3aa was reduced
to 84% (Table 1, entry 11) employing a catalytic amount of
H2SO4 (0.1 equiv). Furthermore, when a relatively less reactive
alcohol, for example, 1-(4-methoxyphenyl)ethanol (2b), was
used to react with 1a, only a 64% yield of 3ab (Table 2, entry
1) was obtained with concentrated H2SO4 as a catalyst.
Comparatively, catalyzed by BF3‚OEt2, the reaction between
2b and 1a provided an 88% yield of 3ab (Table 2, entry 1).
To examine the scope of the C-C coupling reaction, different
types of alcohols (2) were selected to react with 1-(1,3-dithiolan-
2-ylidene)propan-2-one (1a) under the optimized conditions
(Table 1, entry 3). Remarkably, as for the reaction of phenyle-
thanol (2b) with 1a (Table 2, entry 1), the reactions between
the selected phenylethanol (2c) or phenylmethanols (2e-2g)
(with electron donating groups on the benzene ring) and 1a
afforded the desired alkylated R-acetyl ketene-(S,S)-acetals (3ac)
and (3ae-3ag) in high to excellent yields (Table 2, entries 2,
4-6). Phenylethanol (2d) with an electron withdrawing chloro
group on the benzene ring gave 3ad in 65% isolated yield under
the reflux temperature of acetonitrile for 3 days (Table 2, entry
3). When (E)-1,3-diphenylprop-2-en-1-ol (2h) was taken as the
alcohol component, 3ah was also obtained in 95% yield (Table
2, entry 7). In addition, the selected allylic alcohols, for instance,
cinnamyl alcohol (2i) and 2-methyl-3-(p-tolyl)prop-2-en-1-ol
(2j), gave the desired product 3ai and 3aj in excellent yields
with high regioselectivity (Table 2, entries 8 and 9). However,
under the above identical conditions, some less reactive simple
aliphatic alcohols, such as ethanol (2k) and tert-butyl alcohol
(2l), did not react with 1a and the substrate 1a was recovered
after 10 h (Table 2, entries 10 and 11).
Benzhydryl Alcohol (2a)a
entry
acid (equiv)
solvent
time (min)
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
BF3‚OEt2 (2.5)
BF3‚OEt2 (1.0)
BF3‚OEt2 (1.0)
BF3‚OEt2 (0.5)
BF3‚OEt2 (0.5)
BF3‚OEt2 (0.1)
no acid
AlCl3 (1.0)
FeCl3 (1.0)
H2SO4 (1.0)
H2SO4 (0.1)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
THF
5
5
12
99
76c
99
60d
96
95
0e
94
95
95
84
87
40g
12
120
720
120
120
120
15
300f
40
120
BF3‚OEt2 (1.0)
BF3‚OEt2 (1.0)
a All reactions were carried out in a solvent (5 mL) with 1a (1.0 mmol)
and 2a (1.0 mmol) at room temperature. b Isolated yield. c 22% of 1a was
recovered. d 40% of 1a was recovered. e 1a and 2a were recovered. f The
yield could not be further increased with longer reaction time. g 55% of 1a
was recovered.
Although the substitution reaction of ketene-(S,S)-acetals with
allylic ethers as carbon electrophiles by the promotion of trityl
chloride-tin(II) chloride or a trimethylsilyl chloride-tin(II)
chloride catalyst system had been reported,9 the C-C coupling
reaction between ketene-(S,S)-acetals and alcohols had not been
investigated. In the present work, the preliminary results of BF3‚
OEt2-catalyzed direct C-C bond formation reactions between
R-EWG ketene-(S,S)-acetals (1) and various alcohols, including
benzhydryl alcohol, phenylmethanols, phenylethanols, and al-
lylic alcohols, and BH adducts10 together with their synthetic
applications are described.
Results and Discussion
The reaction was first carried out by introducing BF3‚OEt2
to a mixture of 1-(1,3-dithiolan-2-ylidene)propan-2-one (1a) and
benzhydryl alcohol (2a) (1:1 ratio) in acetonitrile. A quantitative
yield of a direct substitution product, 3-(1,3-dithiolan-2-ylidene)-
4,4-diphenylbutan-2-one (3aa), was obtained in no more than
12 min at room temperature (Table 1, entries 1 and 3). When
a catalytic amount of BF3‚OEt2 was used, excellent yields of
3aa could also be obtained by increasing the reaction time (Table
All the results described above indicate that R-acetyl ketene-
(S,S)-acetal (1a) could be used as an efficient carbon nucleophile
for the BF3‚OEt2-catalyzed direct dehydrative alkylation of
benzhydryl, benzylic, and allylic alcohols. Therefore, the scope
of the C-C coupling reaction toward a variety of R-EWG
ketene-(S,S)-acetals was then examined. Accordingly, various
R-EWG ketene-(S,S)-acetals (1)7,8 were prepared to react with
benzhydryl alcohol (2a) under conditions identical to those
above. Fortunately, regardless of the different types of electron
withdrawing groups in the R-position of R-EWG ketene-(S,S)-
acetals (1), all of the ketene cyclic-(S,S)-acetals (1b-1g) were
successfully reacted with 2a to give the corresponding alkylated
(7) Selected examples: (a) Kang, J.; Liang, F.; Sun, S.; Liu, Q.; Bi, X.
Org. Lett. 2006, 8, 2547. (b) Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao, L.;
Li, B. J. Am. Chem. Soc. 2005, 127, 4578. (c) Dong, D.; Ouyang, Y.; Yu,
H.; Liu, Q.; Liu, J.; Wang, M.; Zhu, J. J. Org. Chem 2005, 70, 4535. (d)
Zhao, Y.; Liu, Q.; Zhang, J.; Liu, Z. J. Org. Chem. 2005, 70, 6913. (e)
Dong, D.; Bi, X.; Liu, Q.; Cong, F. Chem. Comm. 2005, 3580. (f) Zhao,
L.; Liang, F.; Bi, X.; Sun, S.; Liu, Q. J. Org. Chem. 2006, 71, 1094.
(8) (a) Yin, Y.; Wang, M.; Liu, Q.; Hu, J.; Sun, S.; Kang, J. Tetrahedron
Lett. 2005, 46, 4399. (b) Pan, W.; Dong, D.; Sun, S.; Liu, Q. Synlett 2006,
1090. (c) Zhang, Q.; Liu, Y.; Wang, M.; Liu, Q.; Hu, J.; Yin, Y. Synthesis
2006, 3009. Similar reactions of trimethylsilylketene bis(ethylthio)acetal
with aldehydes or amines were reported by Toru Minami and co-workers;
see: (d) Okauchi, T.; Tanaka, T.; Minami, T. J. Org. Chem. 2001, 66, 3924.
(e) Yahiro, S.; Shibata, K.; Saito, T.; Okauchi, T.; Minami, T. J. Org. Chem.
2003, 68, 4947.
(10) The Baylis-Hillman (BH) adduct is a kind of important allylic
alcohol containing at least three functional groups, i.e., hydroxy, alkene,
and electron withdrawing groups obtained from Baylis-Hillman reaction
(the C-C coupling reaction of an activated alkene and a carbon nucleophile).
For reviews, see: (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem.
ReV. 2003, 103, 811. (b) Drewes, S. E.; Ross, G. H. P. Tetrahedron 1988,
44, 4653. (c) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron, 1996,
52, 8001. (d) Kataoka, T.; Kinoshita, H. Eur. J. Org. Chem, 2005, 45.
(9) Mukaiyama, T.; Sugumi, H.; Uchiro, H.; Kobayashi, S. Chem. Lett.
1988, 8, 1291.
140 J. Org. Chem., Vol. 72, No. 1, 2007

Acetals, Alcohols, and Biaryls Syntheses
TABLE 2. BF3‚OEt2-Catalyzed C-C Coupling Reactions of 1a with Alcohols (2)a
alcohol
time
(h)
product
yieldb
(%)
entry
2
R1
4-MeOC6H4
R2
3
1
2
3
4
5
6
7
8
9
2b
2c
2d
2e
2f
2g
2h
2i
Me
Me
Me
H
H
H
3.0 /2.0c
3.5
72
3.0
5.0
4.0
1.0
10.0
7.0
10.0
10.0
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
88/64c
83
Ph
4-ClC6H4
3,4-CH2O2C6H3
4-MeOC6H4
4-Me2NC6H4
Ph
PhCHdCH
4-MeC6H4CHdC(CH3)
Me
65d
91
86
90
PhCHdCH
95
H
H
H
88d
90
2j
2k
2l
3aj
3ak
3al
10
11
0e
t-BuOH
0e
a The reactions were carried out in acetonitrile (5 mL) with 1a (1.0 mmol), 2 (1.0 mmol), and BF3‚OEt2 (1.0 mmol) at room temperature unless otherwise
stated. b Isolated yield. c With concentrated H2SO4 (1.0 mmol) as catalyst. d Under the reflux temperature. e The starting materials were recovered even with
alcohol itself as the solvent.
TABLE 3. BF3‚OEt2-Catalyzed C-C Coupling Reactions of r-EWG Ketene-(S,S)-Acetals (1) with Benzhydryl Alcohol (2a)a
R-EWG ketene-(S,S)-acetal
EWG
time
(h)
product
yieldb
(%)
entry
1
R
3
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
CH3CO
H2NCO
CN
-CH2CH2CH2-
-CH2CH2-
-CH2CH2-
-CH2CH2-
-CH2CH2-
-CH2CH2-
Me
1.5
5.0
0.2
0.5
1.0
0.7
2.0
4.0
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
87
90
99
99
98
99
88
89
4-Me-C6H4CHdCHCO
4-Cl-C6H4CHdCHCO
PhCHdCHCO
CN
CN
Et
a The reactions were carried out in acetonitrile (5 mL) with 1 (1.0 mmol), 2a (1.0 mmol), and BF3‚OEt2 (1.0 mmol) at room temperature. b Isolated yield.
ketene cyclic-(S,S)-acetals (3ba-3ga) in excellent yields (Table
3, entries 1-6). However, for R-EWG ketene acyclic-(S,S)-
acetals, only 3,3-bis(methylthio)acrylonitrile (1h) and 3,3-bis-
(ethylthio)acrylonitrile (1i) could efficiently undergo this reac-
tion to afford 3ha and 3ia (Table 3, entries 7 and 8), which are
consistent with our previous findings that R-acetyl ketene
acyclic-(S,S)-acetals are inert toward aldehydes8a and R-cy-
anoketene-(S,S)-acetals are more reactive than R-acetyl ketene-
(S,S)-acetals toward carbonyl electrophiles.8c
SCHEME 3. Proposed Mechanism of the C-C Coupling of
1 and 2
On the basis of all of the above results, together with the
related work in the literature,4c,11 a possible mechanism for this
C-C coupling reaction is proposed in Scheme 3. The hydroxyl
group in an alcohol (2) is activated by BF3‚OEt2 to generate a
carbocation, which is then trapped by an R-EWG ketene-(S,S)-
acetal (1) to give the more stable carbocation intermediate A
stabilized by the adjacent two alkylthio groups. Finally, the
release of a BF3 from A provides the desired alkylated R-EWG
ketene-(S,S)-acetal (3).
Due to the high reactivity of 3,3-bis(ethylthio)acrylonitrile
(1i) (Table 3, entry 8), as mentioned above, we turned our
(11) De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46, 8345.
J. Org. Chem, Vol. 72, No. 1, 2007 141

Zhang et al.
TABLE 4. Preparation of 1,4-Pentanedienes (5) and Their Annulation-Aromatization Reactions with Nitroalkanes (6)
BH adduct
nitroalkane
entry
4
Ar
5/time (h)/yielda (%)
6
R3
Me
Et
COOEt
Me
7/time (h)/yielda (%)
1
2
3
4
5
4a
4a
4a
4b
4c
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3,4-O2CH2C6H3
4-EtOC6H4
5a/2.0/85
5a/2.0/85
5a/2.0/85
5b/2.0/84
5c/3.0/78
6a
6b
6c
6a
6a
7aa/1.0/60
7ab/1.0/45
7ac/2.0/48
7ba/1.0/64
7ca/1.0/52
Me
a Isolated yield.
SCHEME 4. Possible Mechanism for the Formation of
Unsymmetric Biaryls
attention to the reactions of 1i with BH adducts with the aim to
construct the C-C bonds and develop their synthetic potential.
The reaction between 1i and the BH adduct 4a10 was investi-
gated as a typical example. Under the above optimized condi-
tions (Table 1, entry 3), the reaction of 4a with 1i gave the
C-C coupling product, 2-(bisethyl(ethylthio)methylene)-4-(4-
methoxybenzylidene)pentanedinitrile (5a), in 85% isolated yield
with high regioselectivity on the basis of the 1H NMR spectrum
(Table 4, entry 1). Similar reactions of 1i with the BH adducts
4b and 4c led to the corresponding 1,4-pentanedienes (5b and
5c) (Table 4, entries 4 and 5) in 84% and 78% isolated yields,
respectively. Very recently, although Darses and co-workers
reported that, in the presence of a rhodium catalyst, BH adducts
can react directly with potassium trifluoro(organo)borates12a or
arylboronic acids12b to afford trisubstituted alkenes, most of the
transformations of BH adducts required the activation of their
hydroxy groups in the form of acetates or carbonates.13 So far,
to the best of our knowledge, the C-C coupling reactions
between the BH adducts 4 and 1i present the first direct
substitution reaction between an active alkene (as the carbon
nucleophile) and a BH adduct, although Friedel-Crafts reactions
of a BH adduct with an aromatic hydrocabon have been
described.14 It should also be noted that the 1,4-diene framework
constitutes an important structural unit in many molecules of
biological and synthetic importance.15 Obviously, the direct
C-C coupling reaction provides a facile route to the substituted
1,4-pentanedienes (5). More importantly, on the basis of our
previous work for the synthesis of highly functionalized phenols
via the [5C+1C] annulation strategy (the generated 1,4-dienes
(5) possess the promising structural features as five-carbon 1,5-
bielectrophilic species),7b the application of 1,4-dienes (5) to
construct aromatic compounds was next examined by exploring
the annulation reactions of 5 with nitroalkanes. In the presence
of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), the one-pot an-
nulation-aromatization reaction between 5a and nitroethane
(6a) did occur to afford the unsymmetrical biaryls (7aa) (Table
4, entry 1) in 60% isolated yield in DMF at 100 °C within 1 h.
Accordingly, the unsymmetrical biaryls (7ab-7ca) (Table 4,
entries 2-5) were obtained in good yields by reacting
(5a-5c) with nitroalkanes (6a-6c). Because biphenyl deriva-
tives are generally prepared via metal-catalyzed cross-coupling
reactions,16 the above annulation reaction describes a very simple
alternative route to the unsymmetrical biaryls starting directly
from BH adducts.17
On the basis of our previous work7b and the above experi-
mental results, a possible mechanism for the annulation-
aromatization is proposed in Scheme 4. In the annulation step,
intermediate C could be formed via a sequence involving the
intermolecular Michael, intramolecular Michael-SNV from
reactions of 1,4-pentanedienes (5) and nitroalkanes (6). The
following aromatization step for unsymmetrical biaryls (7)
involved the elimination of a nitrous acid molecule from
intermediate C and, finally, the elimination of the second
ethanethiol molecule in the presence of DBU. Interestingly, in
the annulation-aromatization process, the third unsaturated
degree of aromatization is attained through the elimination of
the second alkylthio group. Unlike our previous report of the
(15) (a) Durand, S.; Parrain, J.-L.; Santelli, M. J. Chem. Soc., Perkin
Trans. 1 2000, 253. (b) Andrey, O.; Glanzmann, C.; Landais, Y.; Parra-
Rapado, L. Tetrahedron 1997, 53, 2835. (c) Nicolaou, K. C.; Ramphal, J.
Y.; Petasis, N. A.; Serhan, C. N. Angew. Chem., Int. Ed. Engl. 1991, 30,
1100. (d) Basavaiah, D.; Sharada, D. S.; Kumaragurubaran, N.; Reddy, R.
M. J. Org. Chem. 2002, 67, 7135. (e) Tsukada, N.; Sato, T.; Inoue, Y.
Chem. Commun. 2001, 237.
(16) Anastasia, L.; Negishi, E. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed. Wiley: New York, 2002,
311.
(17) Although the construction of polysubstituted benzenes from BH
adducts via a [4+2] annulation strategy had been developed, however, the
activation process of the hydroxy group in BH adducts were required and
four-step reactions were needed; see: Lee, M. J.; Lee, K. Y.; Gowrisankar,
S.; Kim, J. N. Tetrahedron Lett. 2006, 47, 1355.
(12) (a) Navarre, L.; Darses, S.; Genet, J. P. AdV. Synth. Catal. 2006,
348, 317. (b) Navarre, L.; Darses, S.; Genet, J. P. Chem. Comm. 2004,
1108.
(13) (a) Saxena, R.; Patra, A.; Batra, S. Synlett 2003, 1439. (b) Kim, J.
N.; Kim, J. M.; Lee, K. Y. Synlett 2003, 821. (c) Lee, M. J.; Park, D. Y.;
Lee, K. Y.; Kim, J. N. Tetrahedron Lett. 2006, 47, 1833. (d) Kabalka, G.
W.; Venkataiah, B.; Dong, G. Org. Lett. 2003, 5, 3803. (e) Kabalka, G.
W.; Dong, G.; Venkataiah, B.; Chen, C. J. Org. Chem. 2005, 70, 9207.
(14) Basavaiah, D.; Krishnamacharyulu, M.; Suguna Hyma, R.; Pandi-
araju, S. Tetrahedron Lett. 1997, 38, 2141.
142 J. Org. Chem., Vol. 72, No. 1, 2007

Acetals, Alcohols, and Biaryls Syntheses
found 327.1 [(M + 1)]+; IR (KBr) 3055, 1629, 1462, 1242, 705
cm-1. Anal. Calcd for C19H18OS2: C, 69.90; H, 5.56. Found: C,
69.81; H, 5.61.
[5C+1C] annulation,7b,18 in which one alkylthio group would
remain in the target aromatic compounds, this one-pot annula-
tion-aromatization sequence involved the novel elimination of
the two alkylthio groups connected to one terminal alkene
carbon atom in 1,4-pentanedienes (5). The synthetic applications
of 1,4-pentanedienes (5) for the construction of various het-
eroaromatic compounds19 are in progress.
General Procedure for the Preparation of 5 (with 5a as an
Example). To a well-stirred solution of 3,3-bis(ethylthio)acryloni-
trile (1i) (865 mg, 5.0 mmol) and the Baylis-Hillman adduct 4a
(945 mg, 5.0 mmol) in 10 mL of acetonitrile was added BF3‚OEt2
(0.63 mL, 5.0 mmol) dropwise. The reaction system was stirred
for 2.0 h and monitored by TLC, and the above mixture was
quenched by the addition of a saturated aqueous NaHCO3 solution.
The mixture was then extracted with dichloromethane (20 mL ×
3) and dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure, and the residue was purified by shot flash
silica gel column chromatography to give compound 5a (1460 mg,
85%) as a colorless crystal (eluent: diethyl ether/petroleum ether
Conclusion
In summary, a new acid-catalyzed direct C-C coupling
reaction via the substitution of the hydroxyl group in various
alcohols by readily available R-EWG ketene-(S,S)-acetals (1)
was developed, in which the reaction between the R-cyanoketene
acyclic-(S,S)-acetal (1i) and the BH adduct 4 realized the first
direct substitution reaction between an active alkene (as the
carbon nucleophile) and a BH adduct. Some advantages, such
as being a salt-free and energy-saving process, requiring very
mild reaction conditions, affording high yields, and the broad
range of alcohols able to be employed, made this direct C-C
coupling method attractive. On the basis of this reaction, a series
of alkylated R-EWG ketene-(S,S)-acetals, functionalized 1,4-
pentanedienes, and unsymmetrical biaryls were efficiently
prepared. Further applications are currently under way in our
laboratory.
1
) 1/6): mp 66-68 °C; H NMR (500 MHz, CDCl3) δ 1.30 (t, J
) 7.5 Hz, 3H), 1.36 (t, J ) 7.5 Hz, 3H), 2.95-3.01 (m, 4H), 3.65
(s, 2H), 3.85 (s, 3H), 6.93 (d, J ) 8.5 Hz, 2H), 6.98 (s, 1H), 7.74
(d, J ) 8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 15.1, 15.5,
29.6, 30.0, 39.4, 55.7, 102.8, 113.7, 114.5, 117.8, 118.7, 126.1,
131.1, 145.8, 157.1, 161.6; IR (KBr) 2920, 2206, 1605, 1511, 1261
cm-1; MS calcd m/z 344.1, found 345.1 [(M + 1)]+. Anal. Calcd
for C18H20N2OS2: C, 62.76; H, 5.85; N, 8.13. Found: C, 62.81;
H, 5.97; N, 8.22.
General Procedure for the Preparation of 7 (with 7aa as an
Example). To a well-stirred solution of 5a (172 mg, 0.5 mmol)
and nitroethane (6a) (150 mg, 2.0 mmol) in 2 mL of N,N-
dimethylformamide (DMF) was added 1,8-diazabicyclo(5.4.0)-
undec-7-ene (DBU) (0.30 mL, 2.0 mmol) dropwise. The reaction
mixture was stirred for 1.0 h at 100 °C and monitored by TLC.
The above mixture was poured into ice-water and quenched with
hydrogen chloride to a pH value of 7-8. The mixture was then
extracted with dichloromethane (10 mL × 3) and dried over
anhydrous Na2SO4. The solvent was removed under reduced
pressure, and the residue was purified by flash silica gel column
chromatography to give the product 7aa (75 mg, 60%) as a yellow
solid (eluent: diethyl ether/petroleum ether ) 1/25): mp 114-
116 °C; 1H NMR (500 MHz, CDCl3) δ 2.26 (s, 3H), 3.88 (s, 3H),
7.04 (d, J ) 8.0 Hz, 2H), 7.21 (d, J ) 8.0 Hz, 2H), 7.75 (s, 1H),
7.86 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 20.9, 55.6, 112.2,
114.6, 115.2, 116.9, 117.2, 128.1, 130.2, 133.9, 137.3, 140.1, 149.8,
160.5; IR (KBr) 2975, 2802, 2234, 1610, 1458, 1248 cm-1; MS
calcd m/z 248.1, found 249.1 [(M + 1)]+. Anal. Calcd for
C16H12N2O: C, 77.40; H, 4.87; N, 11.28. Found C, 77.29; H, 4.98;
N, 11.45.
Experimental Section
General Procedure for the Preparation of 3 (with 3aa as an
Example). To a stirred solution of 1-(1,3-dithiolan-2-ylidene)-
propan-2-one (1a) (160 mg, 1.0 mmol) and benzhydryl alcohol (2a)
(182 mg, 1.0 mmol) in CH3CN (5 mL) in a round-bottom flask
was added BF3‚OEt2 (0.12 mL, 1.0 mmol) at room temperature.
The reaction system was stirred for 12 min (monitored by TLC)
before cold saturated NaHCO3 solution (10 mL) was added. A white
solid was precipitated, filtrated off, and dried in vacuum to obtained
1
compound 3aa (323 mg, 99%): mp 147-149 °C; H NMR (500
MHz, CDCl3) δ 1.87 (s, 3H), 3.25-3.32 (m, 4H), 5.86 (s, 1H),
7.20 (d, J ) 7.5 Hz, 4H), 7.27 (t, J ) 6.5 Hz, 2H), 7.33 (t, J ) 7.0
Hz, 4H); 13C NMR (125 MHz, CDCl3) δ 29.2, 36.3, 38.6, 54.4,
126.7, 127.2, 128.4, 129.2, 140.9, 164.3, 195.7; MS calcd m/z 326.1,
(18) The proposed mechanism in our previous report of annulation (also
see ref 7b):
Acknowledgment. Financial supports of this research by the
Key Grant Project of Chinese Ministry of Education (10412)
and Science Foundation for Young Teachers of Northeast
Normal University (20060301) are greatly acknowledged.
Supporting Information Available: Experimental details and
1
full characterization data, copies of H and 13C NMR spectra for
(19) The synthesis of cyclic molecules using BH adducts, including
quinolines, quinolines N-oxides, naphthalenes, indolizines, benzenes, py-
ridines, and 2,4-diaminopyrimidines, etc; see: (a) Kim, J. N.; Lee, K. Y.
Curr. Org. Chem. 2002, 6, 627. (b) Lee, M. J.; Lee, K. Y.; Park, D. Y.;
Kim, J. N. Tetrahedron 2006, 62, 3128.
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO061775E
J. Org. Chem, Vol. 72, No. 1, 2007 143