One-pot synthesis of polyfunctionalized 4H-chromenes and dihydrocoumarins based on copper(II) bromide-catalyzed C-C coupling of benzylic alcohols with ketene dithioacetals

Article abstract of DOI:10.1002/adsc.201000062

The synthesis of polyfunctionalized 4Hchromenes 3 and dihydrocoumarins 4 has been developed from the same substrates. Catalyzed by copper(II) bromide (0.3 equiv.), the reactions of the easily available ketene dithioacetals 1 with 2-(hydroxymethyl)phenols 2 lead to 4/7-chromenes 3 in high to excellent yields in dichloromethane solvent, whereas, 3,4-trans-disubstituted dihydrocoumarins 4 are obtained in high yields with high diastereoselectivities by prolonging the reaction time or changing the solvent from dichloromethane to acetonitrile.

Full text of DOI:10.1002/adsc.201000062

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DOI: 10.1002/adsc.201000062
One-Pot Synthesis of Polyfunctionalized 4H-Chromenes and
Dihydrocoumarins Based on Copper(II) Bromide-Catalyzed
À
C C Coupling of Benzylic Alcohols with Ketene Dithioacetals
Deqiang Liang,a Mang Wang,a,b,* Bahargul Bekturhun,a Binbin Xiong,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 or liuqun@nenu.edu.cn
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, Peopleꢀs Republic of China
b
Received: January 25, 2010; Revised: May 21, 2010; Published online: June 30, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000062.
Abstract: The synthesis of polyfunctionalized 4H-
chromenes 3 and dihydrocoumarins 4 has been de-
veloped from the same substrates. Catalyzed by
copper(II) bromide (0.3 equiv.), the reactions of the
easily available ketene dithioacetals 1 with 2-(hy-
droxymethyl)phenols 2 lead to 4H-chromenes 3 in
high to excellent yields in dichloromethane solvent,
whereas, 3,4-trans-disubstituted dihydrocoumarins 4
are obtained in high yields with high diastereoselec-
tivities by prolonging the reaction time or changing
the solvent from dichloromethane to acetonitrile.
lyzed reactions, such as cycloaddition of propargylic
alcohols with phenol derivatives[6a] and ring-closing
metathesis (RCM) reaction of o-allylaryl vinyl
ethers,[6b] or CuI-catalyzed intramolecular coupling of
aryl bromides with 1,3-dicarbonyls via a six-mem-
bered ring closure.[6c] Very recently, Fan and Wang re-
ported a FeCl3-catalyzed tandem benzylation–cycliza-
tion of 2-(hydroxymethyl)phenols with excess b-keto
esters or b-diketones (2.0 equiv.) in the presence of a
dehydrating agent, which provides a facile route to
functionalized 4H-chromenes with readily available
substrates.[6d]
À
À
Keywords: C C coupling; chromenes; copper; cy-
In recent years, transition metal catalyzed C C cou-
A
pling reactions have been increasingly employed.[7] In
this context, copper catalysts have received much at-
tention due to their low cost, easily handling, and
good functional tolerance.[8] In our research on the
chemistry of functionalized ketene dithioacetals,[9,10] it
Benzopyrans with various levels of saturation and oxi- was found that CuBr2 was a very efficient catalyst for
À
dation are frequently found in natural products and the C C bond-forming reaction of ketene dithioace-
biologically active compounds.[1] In benzopyran deriv- tals with aldehydes/simple ketones[10a] and quin-
ones.[10b] Our continuing interest in the C C coupling
À
atives, 4H-chromenes (also known as 4H-1-benzopyr-
ans) exhibit interesting biological activities[2] and syn- reactions of functionalized ketene dithioacetals and
thetic applications.[3] Thus, the development of effi- their applications in organic synthesis[9d,e,10] led us to
cient synthetic methods for 4H-chromenes is an im- examine the use of benzylic alcohols as carbon elec-
portant task for organic and medicinal chemists.[4–6] In trophiles since this procedure would be an attractive
this field, base-catalyzed tandem reactions of salicylic salt-free and atom-economic process with water being
aldehydes or salicylic imines with a,b-unsaturated the only by-product.[6d,11] In this communication, we
compounds,[4a–d] including the reaction of 2-(E)-(2-ni- wish to report a new strategy for the one-pot con-
trovinyl)phenol with alkynals catalyzed by a chiral or- struction of polyfunctionalized 4H-chromenes 3 based
ganocatalyst,[4e] are efficient route toward 4H-chro- on a novel tandem benzylation–cyclization of func-
mene scaffold. In addition, the condensations of sali- tionalized ketene dithioacetals 1 with 2-(hydroxyme-
cylaldehydes with malononitrile/cyanoacetic esters thyl)phenols 2 catalyzed by CuBr2. In addition, the
have also been developed for the construction of 2- direct diastereoselective synthesis of 3,4-disubstituted
amino-4H-chromenes.[5] Recent studies have focused dihydrocoumarins 4[12,13] via this catalytic procedure is
on metal-catalyzed approaches, for example, Ru-cata- also emphasized.
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Table 1. Optimization of reaction conditions.[a],[14]
sults are in accordance with the result of our previous
work[10a,b] and give further support for the activation
of ketene dithioacetals by CuBr2 for more efficiency
of the reaction.
With these optimized conditions (Table 1, entry 4),
the scope of this CuBr2-catalyzed tandem reaction
was explored using various ketene dithioacetals 1 and
2-(hydroxymethyl)phenols 2 (Table 2). Clearly, a-cya-
noketene dithioacetal 1a could react with various 2-
aryl-substituted 2-(hydroxymethyl)phenols 2 bearing
either electron-withdrawing or electron-donating sub-
stituents on the phenyl ring to give the desired 4H-
chromenes 3a–e in excellent yields (entries 1–5). In
the case of the reaction 1a and 2f with an aliphatic R1
substituent, an unstable mixture was obtained
(entry 6). When a-acetyl/a-alkoxycarbonyl ketene di-
thioacetals 1b/1c were used as the nucleophiles, all
the reactions proceeded smoothly to give 4H-chro-
menes 3f–n in good to high yields (60–88%) with rel-
atively short reaction time (entries 7–15). In the case
of the reaction of 1b and 2f with an aliphatic R1
group (entry 11), 4H-chromene 3j could be obtained
as a stable product in 70% yield under identical con-
ditions.
Entry 1a:2a Cat. [equiv.]
Solvent Yield of 3a [%][b]
1
2
3
4
5
6
1:1.1 CuBr2 [0.1]
1:1.5 CuBr2 [0.1]
1:1.5 CuBr2 [0.2]
1:1.5 CuBr2 [0.3]
1:1.6 CuBr2 [0.3]
1:1.5 CuBr2 [0.3]
1:1.5 CuBr2 [0.3]
1:1.5 CuBr2 [0.3]
1:1.5 CuCl2 [0.3]
CH2Cl2 25
CH2Cl2 49
CH2Cl2 72
CH2Cl2 87
CH2Cl2 87
MeCN 81
7
THF
32
8[c]
9
DMF
nr[d]
CH2Cl2 nr[d]
10
11
12
13
14
1:1.5 CuACHTUNGTRENNUNG
(OAc)2 [0.3] CH2Cl2 nr[d]
1:1.5 CuBr [0.3]
1:1.5 CuI [0.3]
1:1.5 TiCl4 [0.3]
1:1.5 FeCl3 [0.3]
CH2Cl2 nr[d]
CH2Cl2 nr[d]
CH2Cl2 27
CH2Cl2 64
[a]
Reaction conditions: 1a (1.0 mmol), solvent (5.0 mL),
reflux, 18 h.
Isolated yields.
808C, 24 h.
[b]
[c]
[d]
Interestingly, when a-benzoyl ketene dithioacetal
1d (1.0 mmol) was employed to react with 4-chloro-2-
(hydroxyACTHNUTRGNEUG(N phenyl)methyl)phenol 2a (1.5 mmol) under
nr: no reaction.
the catalysis of CuBr2 (0.3 equiv.) in dichloromethane
(5.0 mL), dihydrocoumarin 4a was always obtained
along with the formation of the desired product 3-
Initially, the model reaction of 3,3-bis(methylthio)- benzoyl-4H-chromene 3o even at room temperature
acrylonitrile 1a with 4-chloro-2-[hydroxy- in shorter reaction time (Scheme 1, A). Further in-
ACHTUNGTRENNUNG(phenyl)methyl]phenol 2a was examined and the re- creasing the reaction time to 5.0 h could afford 4a in
ACHTUNGTRENNUNG
sults are presented in Table 1. On treatment of 1a 76% yield (Scheme 1, B). In fact, this experimental
(1.0 mmol) with 2a (1.1 mmol) in dichloromethane result highlights the possibility of a direct synthesis of
(5.0 mL) catalyzed by CuBr2 (0.1 equiv.) at reflux 3,4-disubstituted dihydrocoumarins 4 from the same
temperature for 18 h, 6-chloro-2-(methylthio)-4- substrates [i.e., ketene dithioacetals 1 and 2-(hydroxy-
phenyl-4H-chromene-3-carbonitrile 3a was obtained methyl)phenols 2]. Indeed, under identical conditions
in 25% yield (entry 1). Then, the optimization of the as above, the reactions of a-benzoyl ketene dithioace-
reaction conditions with respect to the molar ratio of tal 1d with 2-(hydroxymethyl)phenols 2b–2d gave the
1a to 2a, the amount of catalyst, and the reaction sol- corresponding dihydrocoumarins 4b–4d in high yields
vent was investigated. It was found that the reaction at room temperature in 0.5–2.0 h (Scheme 2, A). Simi-
À
performed in dichloromethane at reflux with 1:1.5 larly, the corresponding C C coupling-cyclization–hy-
molar ratio of 1a to 2a under the catalysis of drolysis products 4e’ (an enol form of dihydrocoumar-
0.3 equiv. of CuBr2 led to higher yield of 3a (87%, in 4e) and 4f could also be obtained in 68% and 84%
entry 4). Under otherwise the same conditions, the re- yields, respectively, by increasing the reaction time of
action carried out in acetonitrile gave 3a in 81% yield a-acetyl ketene dithioacetal 1b with 2a and a-alkoxy-
(entry 6). By comparison, THF (entry 7) and DMF carbonyl ketene dithioacetal 1c with 2a to 18 h at
(entry 8) were not suitable solvents. Next, a series of reflux temperature (Scheme 2, B). However, under
simple copper salts, including CuCl2, CuACHTNUTRGNE(NUG OAc)2, the same conditions, no desired dihydrocoumarin de-
CuBr, and CuI was evaluated in the model reaction rivative 4g was detected from the reaction of a-cyano
of 1a with 2a in CH2Cl2. However, no reaction was ketene dithioacetal 1a with 2a even with a prolonged
detected after reacting for 18 h as depicted in Table 1, reaction time (24 h).
entries 9–12. When other metal salts, such as TiCl4
As described above, we have provided an efficient
and FeCl3, were chosen as catalyst for this process, a route to polyfunctionalized 4H-chromenes 3 with var-
lower yield of 3a was obtained under otherwise iden- iable functionality suitable for further elaboration.
tical reaction conditions (entries 13 and 14). These re- For example, the in situ hydrolysis of 4H-chromenes 3
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One-Pot Synthesis of Polyfunctionalized 4H-Chromenes and Dihydrocoumarins
Table 2. Synthesis of 4H-chromenes 3 from reactions of 1 with 2 in dichloromethane.[a]
Entry
1
EWG
2
R1
R2
Time
3
Yield of 3 [%][b]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1c
CN
CN
CN
CN
CN
CN
MeCO
MeCO
MeCO
MeCO
MeCO
CO2Et
CO2Et
CO2Et
CO2Et
2a
2b
2c
2d
2e
2f
2a
2b
2c
2d
2f
2a
2c
2d
2e
Ph
Ph
Ph
4-MeC6H4
4-ClC6H4
Me
Ph
Ph
Ph
4-MeC6H4
Me
Ph
Ph
4-Cl
H
4-OMe
4-Cl
4-Cl
H
4-Cl
H
4-OMe
4-Cl
H
18 h
18 h
18 h
18 h
18 h
24 h
4.0 h
4.0 h
10 min
4.0 h
2.0 h
10 min
5.0 min
10 min
10 min
3a
3b
3c
3d
3e
87
98
85
98
97
–
85
84
72
88
70
86
61
60
76
[c]
–
3f
3g
3h
3i
3j
3k
3l
9
10
11
12
13
14
15
4-Cl
4-OMe
4-Cl
4-Cl
4-MeC6H4
4-ClC6H4
3m
3n
[a]
Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), CuBr2 (0.3 mmol), CH2Cl2 (5.0 mL), reflux.
Isolated yields.
Unstable mixture.
[b]
[c]
Scheme 1. CuBr2-catalyzed reactions of 1d and 2a in dichloromethane.
Scheme 2. Synthesis of dihydrocoumarins 4 from reactions of 1 with 2 in dichloromethane.
Adv. Synth. Catal. 2010, 352, 1593 – 1599
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Table 3. Synthesis of dihydrocoumarins 4 from reactions of 1 with 2 in acetonitrile.[a]
Entry
1
EWG
2
R1
R2
Time
4
Yield of 4 [%][b]
1[c]
2
1b
1c
1d
1c
1c
1c
1c
MeCO
CO2Et
PhCO
CO2Et
CO2Et
CO2Et
CO2Et
2a
2a
2a
2b
2c
2d
2e
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
4-ClC6H4
4-Cl
4-Cl
4-Cl
H
4-OMe
4-Cl
4-Cl
1.0 h
4e’
4f
4a
4h
4i
4j
4k
67
98
81
72
91
74
70
45 min
30 min
2.0 h
5.0 min
10 min
10 min
3[d]
4
5
6
7
[a]
Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), CuBr2 (0.3 mmol), MeCN (5.0 mL), reflux.
Isolated yields.
Only in this case was the dihydrocoumarin product obtained as its enol form.
The reaction was performed at room temperature.
[b]
[c]
[d]
should be a useful transformation to achieve 3,4-dis- mechanism is proposed as shown in Scheme 3. The
À
ubstituted dihydrocoumarins 4 starting from the same C C bond-forming reaction between CuBr2-activated
starting materials (Scheme 1). Thus, the direct synthe- ketene dithioacetals 1 and CuBr2-activated 2-(hy-
sis of 3,4-disubstituted dihydrocoumarins 4 via the
ACHTUNGTRENdNGNU roxymethyl)phenols 2 first gives intermediate I with
À
tandem C C coupling reaction-intramolecular cycliza- elimination of CuBr(OH). Then, deprotonation of I
tion-hydrolysis by the reaction of 1 with 2 was further affords intermediate II[16] followed by an intramolecu-
investigated. As shown in Table 3, entry 1, interesting- lar SNV reaction[9c,d,10a,b] to furnish 4H-chromenes 3.
ly, when the CuBr2-catalyzed reaction of a-acetyl The hydrolysis of 4H-chromenes 3 is found to be sub-
ketene dithioacetal 1b with 4-chloro-2-[hydroxy- strate-dependent and reaction condition-dependent
ACHTUNGTRENNUNG(phenyl)methyl]phenol 2a was conducted in acetoni- and leads to enol products 4’ which can be trans-
trile at reflux temperature only for 1.0 h, 4e’ was formed into dihydrocoumarins 4 with the 3,4-anti-con-
formed as a single product in 67% yield. Under iden- figuration as thermodynamically stable products.
tical conditions, the corresponding dihydrocoumarins Clearly as described in Scheme 3, the catalyst CuBr2
4 were obtained in good to excellent yields in short can be recycled by a neutralization reaction of
reaction time from the reactions of the selected 1 and CuBr(OH) and HBr generated from the reaction.
2 (Table 3, entries 2–7). Clearly, the hydrolysis of 3 to
In conclusion, we have developed a convenient syn-
4 is remarkably accelerated by using acetonitrile as thesis of polyfunctionalized 4H-chromenes 3 and di-
solvent (Scheme 1A versus Table 3, entry 3).[15] In ad- hydrocoumarins 4 from the easily available ketene di-
dition, the reaction proceeded in a highly diastereose- thioacetals 1 and 2-(hydroxymethyl)phenols 2. The
lective manner and led to the thermodynamically con- protocol is controlled through the choice of solvents
trolled products, 3,4-trans-disubstituted dihydrocou- or the reaction time and features mild reaction condi-
marins 4. In all cases tested above (Scheme 1, 2 and tions, high yields and multifunctionality of products.
Table 3), no 3,4-cis-disubstituted dihydrocoumarins 4 As the applications of the protocol, our further efforts
1
were detected in the H NMR spectra of the crude will focus on the synthesis of chromene-containing
products.
Although the mechanism for the catalytic activation
natural products.
of CuBr2 on a-EWG ketene dithioacetals 1 is not
clear at this stage, previous works provide obvious
proof of this catalysis.[10a,b] Based on the experimental
fact that CuBr2 is a more effective catalyst than
CuCl2, TiCl4, FeCl3 in this coupling reaction (Table 1,
entry 4 versus entries 9–14), we suggest that CuBr2
plays a co-catalytic role which is not only for the acti-
vation of ketene dithioacetals but also for the activa-
Experimental Section
General Procedure for the Synthesis of 4H-
Chromenes 3 from Reactions of 1 with 2 in
Dichloromethane (3a as example)
To a solution of 3,3-bis(methylthio)acrylonitrile 1a (145 mg,
tion of 2-(hydroxymethyl)phenols. Thus, a reaction 1.0 mmol) and 4-chloro-2-(hydroxyACTHNUTRGENUGN(phenyl)methyl) phenol
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One-Pot Synthesis of Polyfunctionalized 4H-Chromenes and Dihydrocoumarins
Scheme 3. Proposed mechanism for the CuBr2-catalyzed reaction of 1 and 2.
2a (352 mg, 1.5 mmol) in CH2Cl2 (5.0 mL) was added CuBr2
(67 mg, 0.3 mmol) at room temperature. The resulting mix-
ture was refluxed under stirring for 18 h, then cooled to
room temperature and quenched with water (50 mL). The
resulting mixture was extracted with CH2Cl2 (3ꢂ20 mL).
The combined organic extracts were washed with saturated
aqueous NaCl (3ꢂ20 mL), dried over MgSO4, filtered, and
concentrated under vacuum. Purification was carried out by
flash silica gel chromatography using petroleum ether/dieth-
yl ether (16/1, v/v) as eluent to give 6-chloro-2-(methylthio)-
4-phenyl-4H-chromene-3-carbonitrile 3a as a white solid;
yield: 273 mg (87%); mp 136–1378C. 1H NMR (500 MHz,
CDCl3): d=2.55 (s, 3H), 4.71 (s, 1H), 6.95 (d, J=2.5 Hz,
1H), 7.03 (d, J=8.5 Hz, 1H), 7.16–7.21 (m, 3H), 7.29 (d, J=
7.0 Hz, 1H), 7.35 (t, J=7.5 Hz, 2H); 13C NMR (125 MHz,
CDCl3): d=160.2, 147.9, 142.2, 130.6, 129.2, 129.1 (2C),
128.7, 127.9 (3C), 123.5, 117.8, 116.9, 88.9, 43.0, 13.6; IR
(KBr): n=3023, 2929, 2194, 1560, 1477, 1225 cmÀ1; MS
(ESI): m/z=314.0 [(M+1)]+; anal. calcd. for C17H12ClNOS:
C 65.07, H 3.85, N 4.46; found: C 65.22, H 3.96, N 4.49.
vacuum. Purification was carried out by flash silica gel chro-
matography using petroleum ether/diethyl ether (20/1, v/v)
as eluent to give ethyl 6-chloro-2-oxo-4-phenylchroman-3-
carboxylate 4f as a white solid; yield: 324 mg (98%). mp
124–1268C. 1H NMR (500 MHz, CDCl3): d=1.08 (t, J=
7.0 Hz, 3H), 3.96 (d, J=8.5 Hz, 1H), 4.11 (q, J=7.0 Hz,
2H), 4.69 (d, J=8.5 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 7.10
(d, J=9.0 Hz, 1H), 7.16 (d, J=7.0 Hz, 2H), 7.28 (dd, J=2.0,
8.5 Hz, 1H), 7.32–7.38 (m, 3H); 13C NMR (125 MHz,
CDCl3): d=166.3, 163.5, 149.5, 137.3, 130.2, 129.3 (2C),
129.2, 128.5, 128.3, 127.8 (2 C), 125.8, 118.3, 62.2, 53.5, 44.2,
13.8; IR (KBr): n=3064, 2978, 2936, 1772, 1730, 1477,
1145 cmÀ1; MS (ESI): m/z=331.1 [(M+1)]+; anal. calcd. for
C18H15ClO4: C 65.36, H 4.57; found: C 65.19, H 4.50.
Acknowledgements
Financial support of this research by NNSFC-20972029/
20872015, NENU-STC08007/07007, the State Key Laboratory
of Fine Chemicals (KF0807) and the analysis and testing
foundation of Northeast Normal University (2008) is greatly
acknowledged.
General Procedure for the Synthesis of Dihydro-
coumarins 4 from Reactions of 1 with 2 in
Acetonitrile (4f as example)
To
a
solution of ethyl 3,3-bis(methylthio)acrylate 1c
(phenyl)methyl)
(192 mg, 1.0 mmol) and 4-chloro-2-(hydroxyACHTUNGTRENNUNG
phenol 2a (352 mg, 1.5 mmol) in CH3CN (5.0 mL) was References
added CuBr2 (67 mg, 0.3 mmol) at room temperature. The
resulting mixture was refluxed under stirring for 45 min.
After the completion of the reaction as indicated by TLC,
the reaction mixture was quenched with water (50 mL) and
extracted with CH2Cl2 (3ꢂ20 mL). The combined organic
extracts were washed with saturated aqueous NaCl (3ꢂ
20 mL), dried over MgSO4, filtered, and concentrated under
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[14] In all cases except entries 8–12, the coupling product
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[15] In order to get more proof for the accelerated hydroly-
sis of 3 to 4 in MeCN, we also carried out the reaction
of 1c and 2a in MeCN at lower temperature (408C) for
a shorter reaction time (10 min); 4H-chromene 3k was
isolated only in 45% yield with the formation of the
corresponding hydrolysis product 4f in 27% yield. By
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1593 – 1599

One-Pot Synthesis of Polyfunctionalized 4H-Chromenes and Dihydrocoumarins
comparison, 3k was found to be obtained in 86% yield
when the reaction was performed in CH2Cl2 for 10 min
at reflux (Table 2, entry 12).
[16] Intermediate IIa could be isolated from the CuBr2-cat-
alyzed reaction mixture of 1a and 2a in CH2Cl2. Its
spectroscopic data are included in the Supporting Infor-
mation..
Adv. Synth. Catal. 2010, 352, 1593 – 1599
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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