Copper(ii)-catalyzed highly diastereoselective three-component reactions of aryl diazoacetates with alcohols and chalcones: An easy access to furan derivatives

Article abstract of DOI:10.1039/b924845e

Copper(ii) complexes are efficient catalysts in three-component reactions of aryl diazoacetates with alcohols and chalcones to give γ-hydroxyketone derivatives in high yield with excellent diastereoselectivity. The resulting coupling adducts can be easily

Full text of DOI:10.1039/b924845e

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Copper(II)-catalyzed highly diastereoselective three-component reactions
of aryl diazoacetates with alcohols and chalcones: an easy access
to furan derivativesw
Yingguang Zhu, Changwei Zhai, Liping Yang and Wenhao Hu*
Received (in College Park, MD, USA) 25th November 2009, Accepted 8th February 2010
First published as an Advance Article on the web 4th March 2010
DOI: 10.1039/b924845e
Table 1 Catalyst screening and optimization of reaction conditionsa
Copper(II) complexes are efficient catalysts in three-component
reactions of aryl diazoacetates with alcohols and chalcones to
give c-hydroxyketone derivatives in high yield with excellent
diastereoselectivity. The resulting coupling adducts can be easily
converted into furan-containing oligoaryls, tetrahydrofuran and
Drc
2,3-dihydrofuran derivatives.
Entry Catalyst
Solvent
T/1C Yieldb (%) (syn : anti)
1d
2e
3
4
5
Rh2(OAc)4
Rh2(OAc)4
Cu(CH3CN)4PF6 CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
rt
rt
rt
rt
rt
rt
19
37
71
69
84
39
80
78
72
88
69
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
94 : 6
Development of highly efficient synthetic strategies for rapid
construction of complex molecular architectures is of growing
interest and remains a great challenge in modern synthetic
organic chemistry.1 Compared to traditional chemical
reactions, multi-component reactions2 (MCRs) make it possible
to accomplish these goals due to their high synthetic efficiency,
atom economy, flexibility and simplicity.
CuOTf
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
ClCH2CH2Cl rt
CH2Cl2
CH2Cl2
Cu(OTf)2
Cu(acac)2
CuSO4
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
6
7f
8
9
10
11
92 : 8
495 : 5
495 : 5
Ylide chemistry is an area of continuing interest.3 We have
discovered a novel oxonium ylide chemistry that alcoholic
oxonium ylides generated in situ from diazo compounds and
alcohols in the presence of Rh2(OAc)4 can be trapped by
aldehydes and imines.4 Most recently, the efficient trapping
process was extended to a,b-unsaturated 2-acyl imidazoles by
40
0
a
Unless otherwise noted, the reaction was carried out on 0.2 mmol
scale, and to a mixture of 2a (0.24 mmol), 3a (0.2 mmol) , catalyst and
solvent (2 mL) was slowly added 1a (0.24 mmol) in the corresponding
b
solvent (1 mL) over 3 h via a syringe pump. Isolated yield.
d
c
Determined by 1H NMR of the crude reaction mixture. 2 mol%
applying
a
co-catalysis strategy.5 However, expensive
e
f
of catalyst loading. 10 mol% of Zn(OTf)2 was added. 20 mol% of
catalyst loading.
Rh2(OAc)4 catalyst has to be employed in most cases in the
reactions.6 Copper catalysts are highly attractive for chemical
synthesis from environmental and economic points of view,7
and copper complexes have shown different properties in
transition-metal catalyzed diazo decomposition reactions
including cyclopropanation,8a–d aziridination,8e,f O–H
insertion,8g,h N–H insertion.8i,j Herein, we report that copper
complexes are superior catalysts than Rh2(OAc)4 in the stereo-
selective three-component reactions of aryl diazoacetates,
alcohols and chalcones. Thus, g-hydroxyketone derivatives
can be efficiently constructed. Notably, the three-component
reaction can be scaled up to multigram scale by using CuSO4
as the catalyst.
side product was observed (Table 1, entry 1). To enhance the
product yield, Lewis acids such as Zn(OTf)2, which was
demonstrated as an effective co-catalyst,5 were employed to
activate the enone substrate. The product yield was increased
slightly to 37% (entry 2). To our delight, the yield was
sharply increased to 71% when CuPF6(CH3CN)4 was used
as a catalyst (entry 3). Encouraged by the result, a number
of copper complexes including Cu(II) were screened
(Table 1, entries 3–7). Among the copper catalysts tested,
Cu(OTf)2 was the best giving the highest yield of 84%
with 495 : 5 diastereoselectivity, favoring the syn diastereomer
(Table 1, entry 5). Other solvents such as CHCl3 and
ClCH2CH2Cl were used, and slightly lower product yields
and decreased diastereoselectivity were observed in comparison
with CH2Cl2 (Table 1, entries 8 and 9 vs. entry 5). The effect of
reaction temperature on the yield was also investigated. The
highest yield of 88% was obtained when the reaction was
carried out at 40 1C without compromising of the diastereo-
selectivity (495 : 5) (Table 1, entry 10).
In continuation of our research interest by using an enone to
trap an alcoholic oxonium ylide,5 we first examined the
reaction of methyl phenyl diazoacetate (1a), benzyl alcohol
(2a) and chalcone (3a) in the presence of Rh2(OAc)4. The
desired Michael addition trapping product was obtained in a
very low yield (19%). Significant amount of O–H insertion
East China Normal University, 3663 Zhongshan Bei Road,
Shanghai 200062, China. E-mail: whu@chem.ecnu.edu.cn
w Electronic supplementary information (ESI) available: Experimental
section, crystallography and NMR spectra. CCDC 756639, 756904
and 756905. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b924845e
With the optimized reaction conditions in hand, we then
proceeded to investigate the reaction scope. As shown
in Table 2, the present three-component reaction was well
tolerated to electronic properties of the substrates. Good to
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Table 2 Michael addition three-component reaction of aryl diazo-
acetates with alcohols and enonesa
Scheme 1 Scale-up of the Michael-type three-component reaction.
Entry 1
2
R2, Ar2 (3)
Product Yieldb (%) Drc (syn : anti)
1
2
3
4
5
6
7
8
1a 2a Ph, Ph (3a)
4a
4b
4c
4d
4e
4f
88
85
83
86
89
82
93
92
86
81
63
94
86
88
81
78
92
83
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
90 : 10
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
495 : 5
1a 2a p-ClPh, Ph (3b)
1a 2a o-ClPh, Ph (3c)
1a 2a p-BrPh, Ph (3d)
1a 2a o-BrPh, Ph (3e)
1a 2a m-BrPh, Ph (3f)
1a 2a p-MeOPh, Ph (3g) 4g
1a 2a Ph, p-ClPh (3h) 4h
1a 2a Ph, p-MeOPh (3i) 4i
1a 2a 2-Thienyl, Ph (3j) 4j
1c 2a Me, p-MeOPh (3k) 4k
1a 2b Ph, Ph (3a)
1a 2c Ph, Ph (3a)
1a 2d Ph, Ph (3a)
1a 2e Ph, Ph (3a)
1a 2f Ph, Ph (3a)
1b 2a Ph, Ph (3a)
1c 2a Ph, Ph (3a)
Scheme 2 Synthetic application of the Michael adduct.
9
10
11
12
13
14
15
16
17
18
was demonstrated in a facile access to the furan-containing
oligoaryls (Scheme 2). For example, deprotection of syn-4l
with cerium(IV) ammonium nitrate (CAN) in wet CH3CN gave
g-hydroxyketone syn-5 in 93% yield. Oxidation of syn-5 with
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) followed by
treatment with a catalytic amount of pyridinium p-toluene-
sulfonate (PPTS) afforded 2,3,5-triphenylfuran (7) in 94%
overall yield.z This should represent a novel and convenient
approach to furan-containing oligoaryls. In direct treatment
of syn-5 with PPTS (20 mol%), polysubstituted 2,3-dihydro-
furan cis-8 was obtained in 91% yield.11 Alternatively, syn-5
can be converted into polysubstituted tetrahydrofuran cis-9 as a
single diastereomer under reducing conditions by using Et3SiH/
BF3ꢁEt2O.12 The relative stereochemistry of cis-9 was confirmed
by single-crystal X-ray structure analysisz to show the all
cis-relationship of the three phenyl substituents (see ESIw).
Polysubstituted furan,13 tetrahydrofuran14 and dihydrofuran15
moieties are frequently found in numerous biologically active
natural products and pharmaceutical agents.
4l
4m
4n
4o
4p
4q
4r
a
Unless otherwise noted, the reaction was carried out with
(0.36 mmol), 2 (0.36 mmol) and 3 (0.3 mmol) in the presence of
1
b
Cu(OTf)2 (10 mol%) in CH2Cl2 at 40 1C for 3 h. Isolated yield.
Determined by H NMR of the crude reaction mixture.
c
1
excellent yields (81–94%) were obtained with substrates bearing
either electron-withdrawing or donating groups on the aryl
rings of chalcones (Table 2, entries 2–9), benzyl alcohols
(entries 12–15) and aryl diazoacetates (entries 17 and 18).
Good yield and excellent stereoselectivity were also observed
in the reaction with a chalcone bearing heteroaromatic
substituent (entry 10). The use of the enone substrate 3k
bearing an alkyl substituent on the CQC bond also gave the
desired product, but with slightly lower yield (63%) and
decreased diastereoselectivity (90 : 10) (Table 2, entry 11).
Other alcohols such as isopropyl alcohol (2f) was also a
suitable substrate to give the corresponding product 4p in
78% yield (Table 2, entry 16).
In summary, we have developed a novel three-component
reaction of an aryl diazoacetate, an alcohol and chalcone.
Copper complexes were found to be effective and efficient
catalysts in the reaction. The Michael-type reaction performed
well over a broad range of substrates to give the desired
products in high yields (up to 94%) with excellent diastereo-
selectivity (495 : 5). The present synthetic approach can also
be scaled up to a multigram scale and the product can be
readily converted into furan-containing oligoaryls, polysubstituted
tetrahydrofuran and 2,3-dihydrofuran derivatives.
The relative stereochemistry of the product was established
by single-crystal X-ray analysis of syn-4r (see ESIz).
The present three-component reaction can be scaled up to a
multigram scale as exemplified in Scheme 1. In this case, we
used the cheapest copper salt, CuSO4, as a catalyst. Thus, the
three-component reaction of chalcone 3a (10 g, 1 equiv.) with
methyl phenyl diazoacetate 1a (1.2 equiv.) and p-methoxybenzyl
alcohol 2b (1.2 equiv.) afforded the product syn-4l in 81%
yield with excellent diastereoselectivity (syn : anti 4 95 : 5).
Furan-containing oligoaryls have been reported to exhibit
promising characteristics as hole transporting materials for
organic light-emitting diodes (OLEDs),9 and many efforts
have been made for the efficient preparation of oligoaryl
compounds.9a,e,10 The synthetic utility of the current method
We are grateful for financial support from the National
Science Foundation of China (Grant No. 20932003, 20872036)
and for sponsorship from Shanghai Science and Technology
and Commission of Shanghai Municipality (Nos.
09JC1404901, 07dz22005).
Notes and references
z Crystal data for syn-4r: C31H27BrO4, M = 543.44, monoclinic, space
group P21/c, 0.48 ꢂ 0.26 ꢂ 0.22 mm, a = 11.0837(4), b = 12.5162(4),
c = 19.9846(7) A, b = 105.7030(10), V = 2668.91(16) A3, Z = 4,
ꢀc
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Dc = 1.352 Mg mꢃ3, T = 296(2) K, 30 268 reflections collected, 4691
unique (Rint = 0.0283). Final R indices R1 = 0.0471 with I 4 2s(I),
wR2 = 0.1251 for all data.
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Crystal data for 7: C22H16O, M = 296.35, orthorhombic, space
group Pbca, 0.52 ꢂ 0.48 ꢂ 0.36 mm, a = 7.7124(4), b = 19.8082(9),
c = 20.3303(10) A, V = 3105.8(3) A3, Z = 8, Dc = 1.268 Mg mꢃ3
,
T = 173(2) K, 32737 reflections collected, 2731 unique (Rint = 0.0247).
Final R indices R1 = 0.0501 with I 4 2s(I), wR2 = 0.1334 for all data.
Crystal data for cis-9: C24H22O3, M = 358.42, orthorhombic, space
group P212121, 0.52 ꢂ 0.44 ꢂ 0.32 mm, a = 8.6978(3), b = 9.0256(3),
c = 23.8222(9) A, V = 1870.11(11) A3, Z = 4, Dc = 1.273 Mg mꢃ3
,
T = 173(2) K, 21736 reflections collected, 1903 unique (Rint = 0.0862).
Final R indices R1 = 0.0293 with I 4 2s(I), wR2 = 0.0742 for all data.
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ꢀc
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Chem. Commun., 2010, 46, 2865–2867 | 2867