AlCl3-mediated direct carbon-carbon bond-forming reaction of α-hydroxyketene-S,S-acetals with arenes and synthesis of 3,4-disubstituted dihydrocoumarin derivatives

Article abstract of DOI:10.1021/jo702414y

A simple and efficient AlCl3-mediated C-C coupling reaction between readily available α-hydroxyketene-S,S-acetals and various arenes via direct substitution of the hydroxy group in alcohols has been developed. On the basis of this C-C coupling reaction, a series of bio- and pharmacologically important 3,4-disubstituted dihydrocoumarins, difficult to obtain by other methods, were prepared in high yields by a sequential Friedel-Crafts alkylation and intramolecular annulation reaction of α-hydroxyketene acyclic-S,S-acetals with phenols under mild conditions.

Full text of DOI:10.1021/jo702414y

AlCl3-Mediated Direct Carbon-Carbon Bond-Forming Reaction of
r-Hydroxyketene-S,S-acetals with Arenes and Synthesis of
3,4-Disubstituted Dihydrocoumarin Derivatives
Cheng-Ri Piao, Yu-Long Zhao,* Xiao-Dan Han, and Qun Liu*
Department of Chemistry, Northeast Normal UniVersity, Changchun, 130024, People’s Republic of China
zhaoyl351@nenu.edu.cn
ReceiVed NoVember 8, 2007
A simple and efficient AlCl3-mediated C-C coupling reaction between readily available R-hydroxyketene-
S,S-acetals and various arenes via direct substitution of the hydroxy group in alcohols has been developed.
On the basis of this C-C coupling reaction, a series of bio- and pharmacologically important
3,4-disubstituted dihydrocoumarins, difficult to obtain by other methods, were prepared in high yields
by a sequential Friedel-Crafts alkylation and intramolecular annulation reaction of R-hydroxyketene
acyclic-S,S-acetals with phenols under mild conditions.
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 Therefore, continuous efforts have been devoted to the
direct C-C bond-forming reactions between ROH and R′H in
recent years. Among those reported, the C-C coupling reactions
between allylic or benzylic alcohols and active methylenes4 or
arenes5 have proven successful. In this context, the selection of
a suitable alcohol component for the carbon-carbon bond-
forming reaction is of great significance in achieving the
synthetic applications.3-5
As a special type of allylic alcohol, the R-hydroxyketene-
S,S-acetals have been applied in the synthesis of substituted
pyridines,6 R,â-unsaturated dithioesters,7 and conjugated polyene
esters.8 During the course of our studies on the chemistry of
functionalized ketene dithioacetals,9-12,13a the R-hydroxyketene-
S,S-acetal intermediates were involved in the Morita-Baylis-
Hillman (MBH) type reactions with R-EWG ketene-S,S-acetals
(EWG ) electron withdrawing group) as the activated alkenes.10
Meanwhile, it was found that the resulting R-hydroxyketene-
(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. (c) Li, C.-J. Chem. ReV. 2005, 105,
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10.1021/jo702414y CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/22/2008
2264
J. Org. Chem. 2008, 73, 2264-2269

Synthesis of Disubstituted Dihydrocoumarin DeriVatiVes
TABLE 1. Synthesis of r-Hydroxyketene-S,S-acetals 2a
S,S-acetals can further react with R-EWG ketene-S,S-acetals and
nitriles to give the corresponding double MBH adducts10a,b and
aza-MBH adducts, respectively.10c Recently, the carbon-carbon
bond-forming reaction of R-hydroxyketene-S,S-acetals with
active methylene compounds was also performed successively
in the presence of boron trifluoride etherate.11 These studies
and our continued interest in the development of synthetic
applications of R-hydroxyketene-S,S-acetals12 prompted us to
explore the feasibility of the C-C coupling reactions between
R-hydroxyketene-S,S-acetals and arenes.5 In this paper we
describe the results of the C-C coupling reactions between
R-hydroxyketene-S,S-acetals with various arenes and their
applications in the synthesis of 3,4-disubstituted dihydrocou-
marins and highly functionalized chromenes.
time
(min) product
yieldb
(%)
entry substrate
R, R
R1
R2
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
(CH2)2
(CH2)2
Et
Me
Et
H
H
CN
CO2Me
30
30
30
20
30
30
60
2a
2b
2c
2d
2e
2f
90
91
94
90
95
90
95
Me CO2Me
H
H
Me CN
Me CONHPh
CO2Et
CN
Et
Et
1g
2g
Results and Discussion
a The reactions were carried out in ethanol (8.0 mL) with 1 (1.0 mmol)
and NaBH4 (1.2 mmol) at room temperature. b Isolated yields.
Synthesis of R-Hydroxyketene-S,S-acetals 2. Initially, a
variety of R-hydroxyketene-S,S-acetals 2a-g were prepared in
excellent yields (90-95%) by the reduction reaction of the cor-
responding R-oxoketene-S,S-acetals 1a-g13 with sodium boro-
hydride (NaBH4) in ethanol at room temperature11 (Table, 1).
Carbon-Carbon Bond-Forming Reactions of R-Hydroxy-
ketene Cyclic-S,S-acetals 2a and 2b with Arenes 3. With the
readily available R-hydroxyketene-S,S-acetals 2 in hand, we next
turned to the study of the C-C coupling reaction of 2 with
various arenes. A model reaction between 2a with toluene 3a
Table 2. Acid-Catalyzed C-C Coupling Reaction of 2a with Toluene
3a under Various Reaction Conditions
ratio
(3a/2a)
time
(h)
yielda
(%)
entry
catalyst (equiv)
solvent
CH2Cl2
CH2Cl2
CH2Cl2
(4) (a) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int. Ed. 2006,
45, 793-796. (b) Ozawa, F.; Okamoto, H.; Kawagishi, S.; Yamamoto, S.;
Minami, T.; Yoshifuji, M. J. Am. Chem. Soc. 2002, 124, 10968-10969.
(c) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda,
K. Angew. Chem., Int. Ed. 2006, 45, 2605-2609. (d) Sanz, R.; Miguel, D.;
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2027-2030. (e) Noji, M.; Konno, Y.; Ishii, K. J. Org. Chem. 2007, 72,
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3244. (h) Bisaro, F.; Prestat, G.; Vitale, M.; Poli, G. Synlett 2002, 1823-
1826.
1
2
3
4
5
6
7
8
9
AlCl3 (1.0)
AlCl3 (1.0)
AlCl3 (1.0)
AlCl3 (0.5)
AlCl3 (1.0)
AlCl3 (1.0)
AlCl3 (1.0)
BF3OEt2 (1.0)
FeCl3 (1.0)
H2SO4 (1.0)
1:1
4:1
5:1
4:1
4:1
4:1
4:1
4:1
4:1
4:1
5
5
5
12
5
12
12
5
35
75
74
25
73
CH2Cl2
CH2ClCH2Cl
C2H5OH
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
62
50
5
12
10
(5) (a) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem.
Soc. 2005, 127, 4592-4593. (b) Trost, B. M.; Quancard, J. J. Am. Chem.
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Chem. 2003, 68, 9340-9347. (f) Sanz, R.; Mart´ınez, A.; Miguel, D.;
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S.; Liu, Q. J. Org. Chem. 2006, 71, 1094-1098. (d) Dong, D.; Bi, X.; Liu,
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6274.
a Isolated yields.
was first examined to optimize the reaction conditions (Table
2). It was found that, with AlCl3 (1.0 equiv) as a promoter, the
C-C coupling reaction of 2a (1.0 equiv) with toluene 3a (1.0
equiv) can easily proceed to give a mixture of the 4-/2-alkylated
products 4a1 and 4′a1 (the isomer (4-/2-position ratio of 85/
15) in 35% yield in CH2Cl2 at room temperature for 5 h (Table
2, entry 1). It was pleasing to see that the mixture 4a1 and 4′a1
could be obtained in 75% yield by raising the ratio of 3a/2a to
4:1 (Table 2, entry 2). However, the yield of the isomers 4a1
and 4′a1 could not be increased by further raising the ratio of
3a/2a (Table 2, entry 3) and a catalytic amount of AlCl3 (0.5
equiv) led to lower yields (Table 2, entry 4). Among the solvents
tested, dichloromethane seemed to be the best choice although
comparable results were obtained with 1,2-dichloroethane as
the solvent (Table 2, entry 5). No desired product was observed
(monitored by TLC) when the reaction was carried out in ethanol
or acetonitrile (Table 2, entries 6 and 7). Meanwhile, it was
found that other promoters tested, such as FeCl3, BF3‚OEt2,
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72, 4401-4405.
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Catal. 2006, 348, 206-210. (b) Anabha, E. R.; Asokan, C. V. Synthesis
2006, 151-155.
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J. Org. Chem, Vol. 73, No. 6, 2008 2265

Piao et al.
TABLE 3. AlCl3-Catalyzed C-C Coupling Reaction of r-Hydroxyketene Cyclic Dithioacetals 2 with Arenes 3a
a Reaction conditions: 2 (1.0 equiv), 3 (4.0 equiv), AlCl3 (1.0 equiv) in CH2Cl2 (5.0 mL) at room temperature. b Isolated yields. c 2.0 equiv of 3 was used.
1
d The isomer (4-/2-position) ratio was determined by the H NMR spectra of the mixture 4 and 4′.
and H2SO4, appeared to be effective but with relatively lower
yields (Table 2, entries 8 and 9) or ineffective (Table 2, entry
10).
essentially the identical conditions as above, when R-hydroxy-
ketene acyclic-S,S-acetals 2c (R2 ) CO2Me) and 2d (R2 )
CO2Et) were treated with â-naphthol and 4-methylphenol,
respectively, the desired products, 3,4-disubstituted dihydro-
coumarins 5c1, 5c2, and 5d1 were afforded in high yields (Table
4, entries 1-3). It should be noted that coumarin derivatives
are found in a variety of biologically important natural pro-
ducts and widely used as intermediates in organic synthesis.14
Classical routes to coumarins include Pechmann,15a,b Perkin,15c
Knoevenagel,15d Reformatsky,15e and Wittig15f reactions and
their variants.16 In recent years versatile coumarin syntheses
could be achieved through transition-metal-catalyzed reactions.17
However, most of these approaches are focused on monosub-
stituted coumarins. Though the preparation of 3,4-disubstituted
coumarins may be accomplished in different ways,18 only limited
synthesis of 3,4-disubstituted dihydrocoumarins was reported.19
Undoubtedly, the above one-pot annulation reaction provides a
As is widely known, functionalized arenes are important
building blocks and lead structures in medicinal and agricultural
chemistry. Obviously, the above results provide an efficient route
to functionalized arenes with the nature of further elaboration
of the ketene-S,S-acetal and related functionality. Therefore, the
scope of the C-C coupling reaction was extended to some other
substrates 2a or 2b and various arenes 3 under optimal
conditions (Table 2, entry 2) and the results are described in
Table 3. As expected, a variety of electron-rich arenes, such as
toluene, ethylbenzene, p-xylene, anisole, and phenol, could
efficiently react with 2a to give the corresponding mixture of
the 4-/2-alkylated products 4 and 4′ in good to high yields (Table
3, entries 1-5). In the case of the reaction of 2a with
4-methylphenol, the 2-alkylated product 4′a6 was obtained in
90% yield (Table 3, entry 6). More importantly, even nonac-
tivated arene, benzene, could also afford the alkylated product
4a7 in 50% yield (Table 3, entry 7). In addition, the desired
4-/2-alkylated products 4b1 and 4′b1 were also produced in high
yield (85%) by reacting 2b with anisole under the identical
conditions as above (Table 3, entry 8).
Carbon-Carbon Bond-Forming Reactions of R-Hydroxy-
ketene Acyclic-S,S-acetals 2c-g with Phenols and Applica-
tions in the Synthesis of 3,4-Disubstituted Dihydrocoumarins
5 and 7 and Functionalized Chromenes 6. On the basis of
the above results and especially the highly regioselective reaction
of 2a with 4-methylphenol (Table 3, entry 6), together with the
consideration of the structural feature of alkylthio as a good
leaving group in nucleophilic vinyl substitution reactions,9a-d
we reasoned that the hydroxyl group of an alkylated phenol
from an R-hydroxyketene acyclic-S,S-acetal and a suitable
phenol may lead to a coumarin derivative via an alkylation and
intramolecular addition-elimination sequence. Indeed, under
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2266 J. Org. Chem., Vol. 73, No. 6, 2008

Synthesis of Disubstituted Dihydrocoumarin DeriVatiVes
TABLE 4. Synthesis of 3,4-Disubstituted Dihydrocoumarins 5 and Chromenes 6a
a The reactions were carried out in CH2Cl2 (5.0 mL) with 2 (1.0 mmol), 3 (2.0 mmol), and AlCl3 (1.0 mmol) at room temperature. b Isolated yields.
SCHEME 2. Preparation of Alkylated Products 4g and 3,4-Disubstituted Dihydrocoumarins 7g
facile and efficient access to 3,4-disubstituted dihydrocoumarins
from readily available starting materials under mild conditions.
In further experiments, we found that the substituents R2 of
R-hydroxyketene acyclic-S,S-acetals 2 had a significant influence
on the above one-pot annulation reaction. As a result, when
the reactions of 2e (R2 ) CN) with 4-methylphenol, 4-chlo-
rophenol, and â-naphthol were carried out under essentially
identical conditions as above, the corresponding functionalized
chromenes 6e1, 6e2 and 6e3 were produced in high yields (Table
4, entries 4-6), respectively, which are important organic
molecules present in numerous natural products along with wide
bio- and pharmacological activities.20 Similarly, the chromene
6f1 was also successfully prepared in 70% yield by the one-
pot annulation reaction of 2f with â-naphthol (Table 4, entry
7).21 However, in the case of the reactions of 2g (R2
)
CONHPh) with â-naphthol and 6-Br-â-naphthol, the annulation
reaction could not occur and only the corresponding alkylated
products 4g1 and 4g2 were afforded in 95% and 94% yields,
respectively (Scheme 2). Interestingly, when the alkylated
products 4g1 and 4g2 were treated with excessive amounts of
HCl (10.0 equiv) in CH3OH at room temperature for 5 h, a
novel intramolecular annulation reaction proceeded smoothly
to give the corresponding 3,4-disubstituted dihydrocoumarins
7g1 and 7g2 in 85% and 84% yields, respectively (Scheme 2).
Indeed, selective synthesis has been a challenge in organic
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(21) In the further experiments, the transformation feasibility of chromenes
6 to dihydrocoumarins 5 was also examined. We found that, when the
chromene 6e3 was treated with Brønsted acid HCl (1.0-5.0 equiv) or Lewis
acid AlCl3 (1.0-5.0 equiv) either at room temperature or under reflux
conditions in the different solvents, such as CH3OH, CH3OH/H2O (v/v,
10:1), CH3CN, CH3CN/H2O (v/v, 10:1), DMF, and DMF/H2O (v/v, 10:1),
no desired product was produced and 6e3 was recovered in nearly
quantitative yield.
J. Org. Chem, Vol. 73, No. 6, 2008 2267

Piao et al.
SCHEME 3. Proposed Mechanisms for the Formation of 4-7
synthesis, especially controlled highly selective synthesis derived
from similar starting materials.22 Therefore, the above divergent
method for the synthesis of 3,4-disubstituted dihydrocoumarins
5 and 7 and highly functionalized chromenes 6 from R-hydroxy-
ketene acyclic-S,S-acetals 2c-g is important for academic
research and potential applications.
Conclusion
In summary, we have developed a new and efficient AlCl3-
mediated direct C-C coupling reaction of R-hydroxyketene-
S,S-acetals 2 and various arenes 3 under mild conditions. The
simplicity of manipulation, salt-free and energy-saving process,
good to high yields, readily available or cheap starting materials,
and wide arene components make this direct C-C coupling
method most attractive for academic research and potential
applications. On the basis of this reaction, a series of bio- and
pharmacologically important compounds, such as 3,4-disubsti-
tuted dihydrocoumarins 5 and 7 and highly functionalized
chromenes 6, were efficiently prepared in high yields by the
annulation reaction of R-hydroxyketene acyclic-S,S-acetals 2c-g
with phenols. Further studies on the extension of the scope of
this C-C bond-forming reaction, as well as synthetic applica-
tions, are currently under way in our laboratory.
Possible Reaction Mechanism. On the basis of the above
experimental results together with the related reports,4,5,10,11 the
possible mechanisms for the formation of 4-7 are proposed
and depicted in Scheme 3. Initially, the hydroxyl group in
alcohol 2 is activated by AlCl3 to form carbocation intermediate
A, which is then trapped by arene 3 to give the corresponding
alkylated products 4 and 4′ (Scheme 3). To intermediate B,
generated by the Friedel-Crafts alkylation reaction of R-hy-
droxyketene acyclic-S,S-acetals 2c-g with phenols, the further
orientation of reaction may be directed by the electronic effects
of substituents R2 of R-hydroxyketene acyclic-S,S-acetals 2.
When the R2 substituent is a stronger electron-withdrawing
group (R2 ) CN, CO2Et or CO2Me), the hydroxyl group of
intermediate B would attack the carbon atom bonded to the
alkylthio group and then undergo an intramolecular addition-
elimination reaction to furnish chromenes 6 (R2 ) CN) or
intermediate C (R2 ) CO2Et or CO2Me), which is followed
by further hydrolysis to give the corresponding dihydrocou-
marins 5 (Scheme 3). When the R2 substituent is a relatively
weak electron-withdrawing group (R2 ) CONHPh) as in the
case of B (4g1 or 4g2), the hydroxyl group of B is likely to
attack the carbonyl carbon in the presence of Brønsted acid
HCl to produce the dihydrocoumarins 7g1 and 7g2 (Scheme
3). In comparison, for the 2-alkylated products 4′a5 and
4′a6 with a more rigid 1,2-dithiolane unit (Table 3, entries
5 and 6), the attack of the hydroxyl group at the carbon atom
bonded to the alkylthio group would have difficulty in pro-
ceeding and any further cyclization reaction also would not
occur.
Experimental Section
General Procedure for Preparation of 4, 5, and 6 (4′a3 for
example). To a stirred solution of R-hydroxyketene-S,S-acetal 2a
(1.0 mmol, 173 mg) and p-xylene (4.0 mmol, 0.49 mL) in CH2Cl2
(5 mL) was added AlCl3 (1.0 mmol, 132 mg) in one portion. Then
the reaction mixture was stirred for 2 h at room temperature. After
2a was consumed (monitored by TLC), the reaction mixture was
poured into water (20 mL), followed by acidification with HCl
solution to adjust the pH value of the solution to 3, and extracted
with CH2Cl2 (2 × 10 mL). The combined organic extracts were
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure to yield the corresponding crude product, which
was purified by silica gel chromatography (diethyl ether/hexane )
1/20, v/v) to give 188 mg (72%) of 4′a3 as a white solid. Mp 116-
118 °C; 1H NMR (CDCl3, 500 MHz) δ 2.28 (s, 3H), 2.31 (s, 3H),
3.54-3.55 (m, 4H), 3.57 (s, 2H), 6.98 (d, J ) 8.0 Hz, 1H), 7.0 (s,
1H), 7.05 (d, J ) 7.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ
19.1, 21.0, 37.8, 38.3, 39.4, 95.6, 118.8, 127.9, 129.7, 130.2, 133.2,
134.6, 135.6, 160.8; IR (KBr, cm-1) 2921, 2193, 1546, 816; MS
(ESI) m/z 262 [(M + 1)]+. Anal. Calcd (found) for C14H15NS2: C,
64.33 (64.45); H, 5.78 (5.73); N, 5.36 (5.26).
(22) (a) Cuny, G.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2004,
126, 14475-14484. (b) Panne, P.; Fox, J. M. J. Am. Chem. Soc. 2007,
129, 22-23. (c) Barluenga, J.; Alonso, J.; Fan˜ana´s, F. J. J. Am. Chem. Soc.
2003, 125, 2610-2616. (d) Doyle, M. P.; Yan, M.; Hu, W.; Gronenberg,
L. S. J. Am. Chem. Soc. 2003, 125, 4692-4693.
General Procedure for Preparation of 7g (7g1 for example).
To a stirred solution of 4g1 (1.0 mmol, 437 mg) in CH3OH (8
2268 J. Org. Chem., Vol. 73, No. 6, 2008

Synthesis of Disubstituted Dihydrocoumarin DeriVatiVes
mL) was added HCl (10.0 mmol) in one portion. Then the reaction
mixture was stirred for 5 h at room temperature. After 4g1 was
consumed (monitored by TLC), the reaction mixture was poured
into water (25 mL), followed by basification with saturated aqueous
NaHCO3 solution to adjust the pH value of the solution to 7, and
extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts
were dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure to yield the corresponding crude product, which
was purified by silica gel chromatography (diethyl ether/hexane )
1/15, v/v) to give 292 mg (85%) of 7g1 as a white solid. Mp 47-
152.2, 161.5; IR (KBr, cm-1) 2965, 1734, 1513, 1450, 1260, 1217,
813, 747; MS (ESI) m/z 345 [(M + 1)]+. Anal. Calcd (found) for
C19H20O2S2: C, 66.24 (66.43); H, 5.85 (5.80).
Acknowledgment. Financial support from the National
Natural Sciences Foundation of China (20602006), Training
Fund of NENU’S Scientific Innovation Project (NENU-
STC07017), Science Foundation for Yong Teachers of Northeast
Normal University (20070301), and Analysis and Testing
Foundation of Northeast Normal University is greatly acknowl-
edged.
1
49 °C; H NMR (CDCl3, 500 MHz) δ 1.23 (t, J ) 8.0 Hz, 3H),
1.30 (t, J ) 7.5 Hz, 3H), 1.40 (d, J ) 7.0 Hz, 3H), 2.84 (dd, J )
7.5, 13.0 Hz, 1H), 2.97 (q, J ) 7.5 Hz, 2H), 3.03 (dd, J ) 7.5,
13.0 Hz, 1H), 5.38 (q, J ) 7.0 Hz, 1H), 7.25 (d, J ) 9.0 Hz, 1H),
7.46 (t, J ) 8.5 Hz, 1H), 7.60 (t, J ) 7.5 Hz, 1H), 7.74 (d, J ) 9.0
Hz, 1H), 7.85 (d, J ) 8.0 Hz, 1H), 8.03 (d, J ) 8.0 Hz, 1H); 13C
NMR (CDCl3, 125 MHz) δ 14.5, 15.5, 21.1, 29.9, 30.2, 34.9, 117.4,
121.2, 122.5, 125.1, 127.4, 128.9, 129.1, 129.6, 130.2, 131.2, 147.6,
Supporting Information Available: Experimental procedures,
NMR spectra, and characterization data for new compounds 2 and
4-7. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO702414Y
J. Org. Chem, Vol. 73, No. 6, 2008 2269