Copper(II)-catalyzed C-C bond-forming reactions of α-electron- withdrawing group-substituted ketene S,S-acetals with carbonyl compounds and a facile synthesis of coumarins

Article abstract of DOI:10.1002/adsc.200800584

A new catalytic C-C bond-forming reaction has been developed. Catalyzed by cheap and commercially available copper(II) bromide (CuBr₂; 10 mol%), the reactions of α-electron-withdrawing group (EWG)-substituted ketene S,S-acetals with aldehydes or ketones in acetonitrile at room temperature gave a variety of densely functionalized coupling products in excellent yields (80-98%). Based on this catalytic process, coumarin derivatives were efficiently synthesized when salicylaldehydes were selected as the carbonyl components.

Full text of DOI:10.1002/adsc.200800584

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DOI: 10.1002/adsc.200800584
À
Copper(II)-Catalyzed C C Bond-Forming Reactions of
a-Electron-Withdrawing Group-Substituted Ketene S,S-Acetals
with Carbonyl Compounds and a Facile Synthesis of Coumarins
Hong-Juan Yuan,a Mang Wang,a,* Ying-Jie Liu,a and Qun Liua,*
a
Department of Chemistry, Northeast Normal University, Changchun, 130024, Peopleꢀs Republic of China
Fax : (+86)-431-8509-9759; e-mail: wangm452@nenu.edu.cn
Received: September 21, 2008; Published online: December 19, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800584.
À
Abstract: A new catalytic C C bond-forming reac-
tion has been developed. Catalyzed by cheap and
commercially available copper(II) bromide (CuBr2;
10 mol%), the reactions of a-electron-withdrawing
group (EWG)-substituted ketene S,S-acetals with
aldehydes or ketones in acetonitrile at room tem-
perature gave a variety of densely functionalized
coupling products in excellent yields (80–98%).
Based on this catalytic process, coumarin deriva-
tives were efficiently synthesized when salicylalde-
hydes were selected as the carbonyl components.
of making the above reactions more efficient for fur-
ther applications, we are interested in the catalytic
version of these processes. Transition metal catalysts
[10]
À
are widely used in the C C coupling reactions.
Among them, copper catalysts have received much at-
tention due to their low cost, easily handling, and
good functional tolerance.[11] Herein, we report a cop-
À
per(II) salt-catalyzed C C bond forming reaction be-
tween nucleophilic a-EWG-substituted ketene S,S-
acetals 1 and electrophilic aldehydes/ketones 2, which
leads to the formation of 2:1 adducts 3 or coumarin
derivatives 4 in high to excellent yields under very
mild conditions.
À
Keywords: carbonyl compounds; C C bond forma-
tion; copper catalysis; coumarins; a-electron-with-
drawing group (EWG)-substituted ketene S,S-ace-
tals
Initially, a series of simple copper salts, including
CuBr2, CuCl2, CuACTHNUGRTNE(NUG OAc)2 and CuBr were evaluated in
the model reaction of a-cyanoketene cyclic S,S-acetal
1a with 4-chlorobenzaldehyde 2a as depicted in
Table 1. After extensive experiments, the best results
were obtained with CuBr2 as the catalyst. Under the
optimized conditions, i.e., the mixture of 1a
Functionalized ketene S,S-acetals are versatile inter- (1.0 mmol), 2a (0.5 mmol), and CuBr2 (0.05 mmol) re-
mediates in organic synthesis.[1–4] With the recent ad- acted at room temperature in acetonitrile (4.0 mL)
vances in the wide applications of these intermediates for 12 h, the 2:1 adduct 3aa[7d] was obtained in excel-
for the construction of a diverse array of polysubsti- lent yield (Table 1, entry 2).
tuted carbo- and heterocyclic compounds,[1–6] some ef-
Under the conditions described in Table 1, entry 2,
forts have focused on the design and synthesis of new the scope of the reaction was studied and some repre-
ketene S,S-acetal-based synthons via a-functionaliza- sentative results are listed in Table 2. It was found
tion of a-EWG-substituted ketene S,S-acetals that a wide range of electrophiles, including benzalde-
(EWG=electron-withdrawing group).[7–9] In this con- hyde (entry 2), aromatic aldehydes having both elec-
À
text, the C C bond forming reactions at the nucleo- tron-withdrawing (entries 1 and 3) and electron-do-
philic a-carbon atom of these b,b-dialkylthio-activat- nating (entry 4) substituents, heteroaromatic alde-
ed alkenes have been found to be reliable and incor- hydes (entry 5), a,b-unsaturated aldehydes (entry 6),
porate a wide variety of carbon electrophiles.[7,8] Our aliphatic aldehydes (entry 7), and ketones (entries 8
previous research revealed that the reactions of Lewis and 9), reacted smoothly with 1a to give the corre-
acid-activated aldehydes,[7a–d,g] simple ketones,[7d] or sponding 2:1 adducts 3aa–3ai in excellent yields. The
enones[7e] with a-EWG-substituted ketene S,S-acetals tolerance of substrates 1 was then investigated by
were accessible in the presence of over stoichiometric varying the EWG and SR groups. It is clear from
amounts of TiCl4. Taking consideration of the impor- Table 2 that the reactions of 1b–1d with 2a could give
À
tance of the C C bond construction and with the aim the desired products 3ba–3da in 82–94% yields, re-
112
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Copper(II)-Catalyzed C C Bond-Forming Reactions
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Table 1. Optimization of the reaction conditions.[a]
the acyclic alkylthio functionality of 1. Upon treat-
ment with 4-chlorobenzaldehyde 2a, the acyclic ana-
logues 1f and 1g afforded the corresponding 3fa and
3ga in 95% and 94% yields, respectively, under CuBr2
catalysis (entries 14 and 15).
Compared with the results mentioned above and
our previous reports,[7] a different reaction process of
À
this new catalytic C C bond-forming reaction is pre-
Entry Cat. [equiv.][b]
Solvent Time [h] Yield [%][c]
dictable. Although the mechanism is not yet clear at
this stage, the reaction of 1e with allyl iodide
(10 equiv.) in the presence of 10 mol% of CuBr2
1
2
3
4
5
6
7
8
CuBr2 (1.0)
CuBr2 (0.1)
CuBr2 (0.05)
CuCl2 (1.0)
CuCl2 (0.1)
CH3CN 8.0
CH3CN 12
CH3CN 48
CH3CN 23
CH3CN 48
98
98
42
90
45
À
(Scheme 1) to deliver the C C coupling product 2-
(1,3-dithian-2-ylidene)pent-4-enenitrile 3’ (70% isolat-
ed yield) might indicate that CuBr2 plays a duplicate
role and results in the activation not only of the car-
bonyl electrophiles,[7] but also of the b,b-dialkylthio-
activated alkenes 1.[12,13]
Attracted by the advantages, such as cheap catalyst,
broad scope of carbonyl compounds and a-EWG-sub-
stituted ketene S,S-acetals, high product yields, and
[d]
Cu
N
–
–
[d]
CuBr (1.0)
CuBr2 (0.1)
CH3CN 72
CH2Cl2 14
95
[a]
Reaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), sol-
vent (4.0 mL), room temperature.
Equivalents based on 2a.
Isolated yield.
No reaction.
[b]
[c]
[d]
spectively (entries 10–12). In particular, the reaction
of 1d with 2a was much faster and was complete
within 3.0 h (entry 12). Similarly, when cyclic sub-
strate 1e was subjected to identical reaction condi-
tions, 3ea was obtained in 95% yield in a short time
(entry 13). In addition, this reaction can also tolerate
Scheme 1. Coupling of 1e with allyl iodide catalyzed by
CuBr2.
À
Table 2. CuBr2-catalyzed C C bond forming reactions of a-EWG-substituted ketene S,S-acetals 1 with aldehydes/ketones
2.[a]
Entry
1
EWG
R or R,R
2
R1
R2
3
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
1g
CN
CN
CN
CN
CN
CN
CN
CN
U
2a
2b
2c
2d
2e
2f
2g
2h
2i
2a
2a
2a
2a
2a
2a
4-ClC6H4
C6H5
4-NO2C6H4
4-MeOC6H4
2-furyl
E-C6H5CH=CH
Me
Me
H
H
H
H
H
H
H
Me
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3ba
3ca
3da
3ea
3fa
3ga
12
12
18
15
9.0
14
24
35
18
22
24
3.0
3.0
19
16
98
93
96
97
88
90
86
85
85
82
80
94
95
95
94
9
CN
ACHTUGNTERN(NUNG CH2)5
10
11
12
13
14
15
MeCO
PhCO
CO2Et
CN
CN
CN
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
H
H
H
H
H
H
[a]
Reaction conditions: 1 (1.0 mmol), 2 (0.5 mmol), CuBr2 (0.05 mmol), CH3CN (4.0 mL), room temperature.
Isolated yield.
[b]
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Hong-Juan Yuan et al.
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mild reaction conditions, of the above catalytic C C along with the recovery of 1g (in 30% yield) by react-
bond-forming reactions, efforts were then focused on ing 1g with 2j for 24 h under identical conditions, but
developing a facile synthesis of coumarin derivatives. mediated with overstoichiometric amounts of TiCl4
Thus, salicylaldehydes 2j–2l were selected as the elec- (1.2 equiv.).
trophiles to react with acyclic ketene S,S-acetals 1g–1j
Coumarins are important heterocycles widely pres-
catalyzed by CuBr2. As expected, all the reactions ent in natural products exhibiting a broad range of
proceeded smoothly to afford coumarins 4 in good to biological and therapeutic activities.[14] A number of
high yields in a single operation (Table 3). As a com- classical approaches for accessing coumarins are avail-
parison, 4gj was obtained only in 35% isolated yield able and novel synthetic routes are attracting much
attention in organic chemistry.[15] Recently, Pd-cata-
lyzed coumarin syntheses presented a new promising
strategy.[16] In 2006, Rao and Sivakumar reported a
route to the synthesis of 3-aroylcoumarins by the con-
densation of a-aroylketene S,S-acetals and salicylalde-
Table 3. Synthesis of coumarins via the reaction of 1 and 2
catalyzed by CuBr2.[a]
hydes in the presence of catalytic amount of piperi-
dine at reflux temperature.[8a] It is noteworthy that
our method for the synthesis of coumarins represents
a general route using a wide range of a-EWG-substi-
tuted ketene S,S-acetals, including a-aroyl, acetyl,
Entry 1 EWG
2
R’
Time [h] 4
Yield [%][b]
4gj 82
cyano, ethoxycarbonyl groups and the reactions can
be carried out under very mild conditions (Table 3).
Thus, this new protocol allows the more effective syn-
thesis of a combinatorial library of coumarins. The
proposed mechanism is described in Scheme 2. The
reaction begins with the addition of 1 to 2 catalyzed
by CuBr2 to give intermediate A along with the loss
of a molecule of HBr. Then, an intramolecular conju-
gate displacement leads to the formation of inter-
mediate B and Cu(OH)Br. Finally, coumarin 4 is
formed by hydrolysis of B. In the course of this reac-
tion, catalyst CuBr2 can be recycled by the reaction of
Cu(OH)Br with HBr. Clearly, this novel procedure
for the synthesis of coumarin derivatives has the ad-
vantages of mild reaction conditions and a broad
scope of substrates.[8a,15,16]
1
1g CN
2j
H
H
H
H
3.0
6.0
4.0
2.0
2
3
4
1h MeCO 2j
1i PhCO 2j
1j CO2Et 2j
4hj 50
4ij 84
4jj 86
4gk 70
4hk 86
4ik 82
4jk 74
4gl 79
4hl 77
4il 76
4jl 90
5
1g CN
2k 5-MeO 3.5
6
7
8
1h MeCO 2k 5-MeO 3.0
1i PhCO 2k 5-MeO 4.0
1j CO2Et 2k 5-MeO 2.0
9
1g CN
2l 5-Cl
5.0
5.0
3.0
1.0
10
11
12
1h MeCO 2l 5-Cl
1i PhCO 2l 5-Cl
1j CO2Et 2l 5-Cl
[a]
Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), CuBr2
(0.1 mmol), CH3CN (4.0 mL), room temperature.
Isolated yield.
[b]
Scheme 2. Proposed mechanism for the synthesis of coumarins from 1 and salicylylaldehydes 2j–2l catalyzed by CuBr2.
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Copper(II)-Catalyzed C C Bond-Forming Reactions
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Portella, Tetrahedron 2005, 61, 4395–4402, and referen-
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In summary, we have developed a new Cu(II)-cata-
lyzed C C bond forming reaction. A wide range of
À
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were obtained in excellent yields by reacting the read-
ily available a-EWG-substituted ketene S,S-acetals
with a variety of aldehydes and ketones under very
mild reaction conditions. Based on this catalytic pro-
cess, coumarin derivatives were synthesized in high
yields. The efficiency and convenience of the coumar-
in syntheses along with a broad range of EWG groups
at the 3-position make this synthetic strategy very at-
tractive for practical applications. Further studies on
the reaction mechanism and synthetic potential of this
catalytic reaction are in progress.
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Experimental Section
À
General Procedure for the CuBr2-Catalyzed C C
Bond-Forming Reactions of 1 with 2 (taking the
Reaction of 1a and 2a as an Example)
To a solution of 2-(1,3-dithiolan-2-ylidene)acetonitrile 1a
(143 mg, 1.0 mmol) and 4-chlorobenzaldehyde 2a (70 mg,
0.5 mmol) in dry acetonitrile (4.0 mL) was added CuBr2
(11.2 mg, 0.05 mmol). The reaction mixture was stirred for
12 h at room temperature and monitored by TLC. After
completion, the reaction mixture was poured into ice-water
(20 mL). The precipitate was collected by filtration, washed
with water (3ꢂ20 mL), and dried under vacuum to afford
the product 3aa as a white solid; yield: 199 mg (98%).
[8] a) H. S. P. Rao, S. Sivakumar, J. Org. Chem. 2006, 71,
8715–8723; b) E. R. Anabha, C. V. A. Asokan, Synthe-
sis 2006, 151–155.
Acknowledgements
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Financial support of this research by the National Natural
Science Foundation of China (20672019 and 20872015), the
Ministry of Education of China (108044), and the Training
Fund of NENUꢀs Scientific Innovation Fund are greatly ac-
knowledged.
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