Copper(I{cyrillic, ukrainian}) hexafluorophosphate: a dual functional catalyst for three-component reactions of methyl phenyldiazoacetate with alcohols and aldehydes or α-ketoesters

Article abstract of DOI:10.1016/j.tetlet.2008.09.090

Oxonium ylides in situ generated from methyl phenyldiazoacetate and alcohols in the presence of CuPF₆(CH₃CN)₄ underwent an aldol-type reaction with aldehydes or α-ketoesters in a convergent, three-component fashion to give α-alkoxyl-β-hydroxyl acid derivatives in good yields.

Full text of DOI:10.1016/j.tetlet.2008.09.090

Tetrahedron Letters 49 (2008) 6862–6865
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Copper(I) hexafluorophosphate: a dual functional catalyst for
three-component reactions of methyl phenyldiazoacetate with
alcohols and aldehydes or a-ketoesters
Yongli Yue a,b,c, Xin Guo a, Zhiyong Chen b,c, Liping Yang a, Wenhao Hu a,
*
a Department of Chemistry, East China Normal University, Shanghai 200062, China
b Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
c Graduate School of Chinese Academy of Sciences, Beijing, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 June 2008
Revised 7 September 2008
Accepted 16 September 2008
Available online 19 September 2008
Oxonium ylides in situ generated from methyl phenyldiazoacetate and alcohols in the presence of
CuPF6(CH3CN)4 underwent an aldol-type reaction with aldehydes or
three-component fashion to give -alkoxyl-b-hydroxyl acid derivatives in good yields.
Ó 2008 Elsevier Ltd. All rights reserved.
a-ketoesters in a convergent,
a
The chemistry of onium ylides is an area of continuing interest.
Carbonyl,1 phosphorus,2 sulfur,3 ammonium,4 and oxonium5 ylides
have been widely utilized in organic synthesis. In the study of oxo-
nium ylides derived from metal carbenoids, the [2,3]-sigmatropic6
and [1,2]-stevens7 rearrangements have been shown to be power-
ful strategies for synthesis of hetero-atom-containing compounds.
We have discovered a new chemistry of oxonium ylides that alco-
holic oxonium ylides generated in situ from a diazocompound and
an alcohol catalyzed by Rh2(OAc)4 can be trapped by aldehydes and
imines through an aldol-type nucleophilic addition.8 A proposed
reaction pathway is shown in Scheme 1. Due to competiting
intramolecular 1,2-H shift reaction of the ylide intermediates Ia/
Ib, the dirhodium-catalyzed reaction was limited to electron-defi-
cient aromatic aldehydes in the absence of other additives.9
Copper is a versatile, abundant, and cheap catalyst in organic
synthesis.1b Cu complexes show many differences in cyclopropana-
tion, aziridination, O–H insertion, N–H insertion, etc. versus rho-
dium-catalyzed diazo decomposition reactions.10 In the alcoholic
oxonium ylide trapping process, a copper catalyst may play a dual
role. On the one hand, it serves as a catalyst for the diazo decom-
position to generate the alcoholic oxonium ylide in situ. On the
other hand, it may function as a Lewis acid to activate trapping re-
agents such as aldehydes to be more reactive electrophiles. We
envision that, by employing an appropriate copper catalyst, the
current reaction scope could be greatly extended. In this Letter,
we report that CuPF6(CH3CN)4 is an excellent catalyst for the
three-component aldol-type reaction. With the use of the copper
catalyst, the reaction is not only good for various aldehydes, but
it also extends the available electrophilic substrates to include
Ar
HC COOMe
1,2-H shift
OR
5
1,2-H shift
-Rh2Ln
Ar
COOMe
a-ketoesters to give good yields of a-alkoxyl-b-hydroxyl acid
N2
Ar
derivatives bearing two vicinal tetrasubstituted carbon centers.
Such compounds are highly important intermediates in the
synthesis of a variety of medicinal agents and natural products.11
To validate our hypothesis regarding the potential of copper
catalysts in the three-component reactions of methyl aryl diazoac-
etates, alcohols, and aldehydes, a number of Cu complexes were
screened in the reaction. While Cu(OTf)2, CuOTf, Cu(acac)2, and
Cu(pfacac)2 gave only the O-H insertion product with benzalde-
Ar
+
1
Rh2Ln
LnRh
C
O
COOMe
C
O
COOMe
+
R1CHO
3
Rh2Ln
ROH
2
H
R
H
R
Ia
Ib
3
3
nucleophilic addition
-Rh2Ln
nucleophilic addition
Ar
RO
MeOOC
OH
H
R1
Ar
RO
MeOOC
H
OH
R1
+
12
hyde (3a), we were glad to find that the use of CuPF6(CH3CN)4
erythro-4
threo-4
gave a 74% yield of the desired three-component reaction product
4a. In contrast, the use of the Rh2(OAc)4 catalyst gave only a 6%
yield of the desired product (Table 1, entry 1). A series of aldehydes
have been investigated using CuPF6(CH3CN)4 (Table 1).13 Both
aromatic and aliphatic aldehydes9 gave the desired products with
reasonable yields (Table 1, entries 10 and 11). To the best of our
Scheme 1. A proposed reaction pathway for trapping alcoholic oxonium ylides
with aldehydes.
* Corresponding author. Tel.: +86 13 6363 07166; fax: +86 21 6223 3176.
E-mail address: whu@chem.ecnu.edu.cn (W. Hu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.090

Y. Yue et al. / Tetrahedron Letters 49 (2008) 6862–6865
6863
Table 1
CuPF6(CH3CN)4-catalyzed three-component reactions of methyl phenyldiazoacetate (1) with benzyl alcohol (2a) and aldehydes (3)a
O
COOMe
Ph
BnO
MeOOC
OH
H
R1
CuPF6(CH3CN)4
CH2Cl2
Ph
R1CHO
+
+
+
Ph
BnOH
C
H
OBn
OMe
N2
1
2a
3a-i
4a-i
5
Entry
R1
Yield of 4b (%)
4:5c
Isomer ratio of 4 threo:erythroc
e
1d
2g
3
4
5
6
7
8
9
Ph(3a)
Ph(3a)
Ph(3a)
p-NO2Ph(3b)
o-NO2Ph(3c)
6(4a)
—
10:90
0:100
79:21
89:11
92:8
93:7
92:8
83:17
56:44
53:47
41:59
—
—
f
f
74(4a)
83(4b)
78(4c)
85(4d)
75(4e)
62(4f)
50(4g)
48(4h)
38(4i)
81:19
74:26
69:31
27:73
83:17
83:17
72:28
83:17
81:19
2,4-NO2Ph(3d)
p-CF3Ph(3e)
p-CN Ph(3f)
p-MeOPh(3g)
Et(3h)
10
11
nPr(3i)
a
All the reactions were carried out in refluxing CH2Cl2 for 2 h with 1:2:3 = 1.0:1.2:1.2 (mmol) by using 10 mol % CuPF6(CH3CN)4.
Isolated yields after column chromatography purification.
Determined by 1H NMR of the unpurified reaction mixtures.
Using 1 mol % Rh2(OAc)4 in stead of CuPF6(CH3CN)4.
Not determined.
b
c
d
e
f
Not detected.
g
The reaction was carried out with 10 mol % CuOTf catalyst.
knowledge, this is the first such demonstration for aliphatic
aldehydes.
With the CuPF6(CH3CN)4 catalyst, the substrates were extended
-ketoesters. While Rh2(OAc)4 gave no desired three-compo-
nent reaction product with methyl phenyl -ketoester 6a (Table
2, entry 1), copper(I) hexafluorophosphate generated the antici-
pated -hydroxyl-b-alkoxyl acid derivatives bearing two tetrasub-
stituted carbon centers in 68% yield (Table 2, entry 2). The results
for methyl phenyldiazoacetate with a number of alcohols and
ketoesters are summarized in Table 2 (entries 3–14). The resulting
-hydroxyl-b-alkoxyl ester derivatives are not readily synthesized
ysis to be threo. Extending the method with the CuPF6(CH3CN)4
catalyst to other electrophiles, such as ketones and ,b-unsatu-
rated ketones, did give the desired products but with much lower
a
to
a
yield (<30%).
a
The proposed reaction mechanism for the Cu-catalyzed three-
component reaction is shown in Scheme 2.1b,10d,12 CuPF6(CH3CN)4
not only catalyzes diazo decomposition in the presence of an alco-
hol to form an alcoholic oxonium ylide but also serves as a Lewis
acid to activate the aldehydes or a-ketoesters.
In conclusion, we have found that CuPF6(CH3CN)4 is an effective
catalyst in the three-component reaction of methyl phenyldiazo-
a
a
-
a
using traditional methods. The structure and relative configuration
acetate with alcohols and aldehydes or
(CH3CN)4 plays a dual role in the reaction, the scope of which
a-ketoesters. CuPF6-
of isomer 7a was confirmed by single-crystal X-ray14 (Fig. 1) anal-
Table 2
CuPF6(CH3CN)4-catalyzed three-component reactions of methyl phenyldiazoacetate (1) with alcohols (2) and
a
-ketoesters (6)a
O
COOMe
O
Ph
R2O
MeOOC
OH
COOMe
R3
OR2
CuPF6(CH3CN)4
CH2Cl2
Ph
Ph
C
H
OMe
+
2
+
+
R3
R OH
OMe
N2
1
O
7a-l
5
2a-d
6a-j
Entry
R2
R3
Yield of 7b (%)
7:5c
threo-7:erythro-7c
e
1d
2
3
4
5
6
7
8
9
10
11
12
13
14
Bn(2a)
Bn(2a)
Me(2b)
Et(2c)
Ph(6a)
Ph(6a)
Ph(6a)
Ph(6a)
Ph(6a)
p-ClPh(6b)
m-ClPh(6c)
o-ClPh(6d)
p-BrPh(6e)
p-FPh(6f)
p-NO2Ph(6g)
p-MeOPh(6h)
(E)-styryl(6i)
Me(6j)
—
0:100
85:15
84:16
88:12
0:100
94:6
90:10
48:52
93:7
90:10
95:5
72:28
95:5
—
68(7a)
69(7b)
72(7c)
—
75(7d)
72(7e)
40(7f)
75(7g)
71(7h)
76(7i)
65(7j)
60(7k)
80(7l)
41:59
50:50
43:57
—
50:50
41:59
41:59
49:51
49:51
47:53
50:50
48:52
22:78
iPr(2d)
Bn(2a)
Bn(2a)
Bn(2a)
Bn(2a)
Bn(2a)
Bn(2a)
Bn(2a)
Bn(2a)
Bn(2a)
92:8
a
All the reactions were carried out in refluxing CH2Cl2 for 2h with 1:2:6 = 1.0:1.2:1.2 (mmol) by using 10 mol % CuPF6(CH3CN)4.
Isolated yields after chromatography purification.
b
c
Determined by 1H NMR of the unpurified reaction mixtures.
Using 1 mol % Rh2(OAc)4 in stead of CuPF6(CH3CN)4.
d
e
Not detected.

6864
Y. Yue et al. / Tetrahedron Letters 49 (2008) 6862–6865
References and notes
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West, F. G.; Naidu, B. N.; Tester, R. W. J. Org. Chem. 1994, 59, 6892; (c)
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P.; Vanecko, J. A.; West, F. G. Tetrahedron 2002, 58, 2027; (e) Marmsater, F. P.;
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Huang, H. X.; Guo, X.; Hu, W. H. Angew. Chem., Int. Ed. 2007, 46, 1337; (c) Hu, W.
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Figure 1. X-ray structure of threo-7a.
was extended to aliphatic aldehydes and a-ketoesters. We expect
that employing appropriate chiral ligands would allow asymmetric
catalysis in the current three-component reaction, and are
currently pursuing such research in our laboratory.
Acknowledgements
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Frankfurt, 1980; (b) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem.
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MacMillan, D. W. C. J. Am. Chem. Soc. 1998, 119, 7893; (e) Grover, P. T.; Bhongle,
N. N.; Wald, S. A.; Senanayake, C. H. J. Org. Chem. 2000, 65, 6283.
This work was supported by National Science Foundation of
China (Grant Nos. 20772033 and 20502025) and Shanghai Pujiang
Program.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.09.090.
R5=H, COOMe
CuLn=CuPF6(CH3CN)4
Ph
COOMe
CuLn
R4COR5
CuLn
O
6
O
5
Bn
N2
R4
R5
proton
transfer
Ph
COOMe
1
CuLn
nucleophilic addition
Ph
CuLn
MeOOC
CuLn
O
R5
Ph
BnOH 2
MeOOC
R4
MeOOC
Bn
H
O
MeOOC
Ph
Bn
O
Bn
H
O
-CuLn
Ph
LnCu
H
"delayed proton transfer"
Ic
Ib
R5
OH
R4
threo-7
OH
R5
Ph
BnO
MeOOC
Ph
BnO
MeOOC
+
R4
erythro-7
Scheme 2. Proposed reaction mechanism for CuPF6(CH3CN)4 catalyzed three-component reactions of methyl phenyldiazoacetate with benzyl alcohol and aldehydes or
-ketoesters.
a

Y. Yue et al. / Tetrahedron Letters 49 (2008) 6862–6865
6865
P.; Hu, W. H. J. Org. Chem. 2000, 65, 8839; (g) Doyle, M. P.; Hu, W. H.; Chapman,
B.; Marnett, A. B. J. Am. Chem. Soc. 2000, 122, 5718.
14. CCDC 686084, Crystal data for threo-7a: C25H24O6, Mw = 420.44, monoclinic,
space group P2(1)/c, a = 13.0138(3) Å, b = 8.7546(2) Å, c = 18.6199(3) Å, b =
13. General procedure: To
a
CH2Cl2 solution of CuPF6(CH3CN)4 (0.10 mmol),
100.958(1), V = 2082.70(8) Å3, Z = 4, catcd = 1.341 Mg/m3, F(000) = 888,
q
aldehydes (1.2 mmol), and alcohols (1.2 mmol) was added methyl
phenyldiazoacetate (1.0 mmol) in CH2Cl2 via a syringe pump over 1 h under
refluxing. After completing the addition, the reaction mixture was cooled to
room temperature. Solvent was removed, and CuPF6 was removed from the
residue by flash column chromatography on silica gel by using EtOAc as an
eluent. A portion of the resulting crude product was subjected to 1H NMR
analysis for the determination of product ratio and diastereoselectivities. The
crude product was further purified by column chromatography on silica gel
using EtOAc–light petroleum as eluents to give desired products.
k = 0.71073 Å, T = 153(2) K,
were collected on Siemens P-4X four-circle diffractometer. Intensity
measurements were performed on
l(Mo-Ka
) = 0.096 mmÀ1. Data for the structure
a
a
crystal (dimensions 0.54 Â
0.50 Â 0.38 mm). In the range 6.28 < 2h < 54.96, of the 4766 measured
reflections, 4336 were independent (Rint = 0.014). The structures were solved
by direct methods (SHELXS-97) and refined by full-matrix least-squares on F2.
The final refinements converged at R1 = 0.0352 for I > 2r(I) and wR2 = 0.0983
for all data. The final difference Fourier synthesis gave a min/max residual
electron density of À0.225/+0.358 e ÅÀ3
.