InBr3 catalyzed three-component reactions of an aryldiazoacetate, an alcohol, and a carbonyl compound

Article abstract of DOI:10.1016/j.tetlet.2011.11.005

InBr₃ promoted three-component reactions of an aryldiazoacetate, an alcohol, and an electron deficient carbonyl compound gave α,β-dihydroxyl acid derivatives in good yield with high diastereoselectivity. The reaction is proposed through a protic oxonium ylide trapping process. The reaction mechanism for the formation of the protic oxonium ylide via Lewis acid InBr₃ catalyzed diazo decomposition is suggested through a vinyl cationic intermediate.

Full text of DOI:10.1016/j.tetlet.2011.11.005

Tetrahedron Letters 53 (2012) 182–185
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
InBr3 catalyzed three-component reactions of an aryldiazoacetate,
an alcohol, and a carbonyl compound
⇑
Jingjing Ji, Xia Zhang, Liqing Jiang, Wenhao Hu
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai 200062, China
Department of Chemistry, East China Normal University, Shanghai 200062, China
a r t i c l e i n f o
a b s t r a c t
Article history:
InBr3 promoted three-component reactions of an aryldiazoacetate, an alcohol, and an electron deficient
Received 28 August 2011
Revised 24 October 2011
Accepted 3 November 2011
Available online 9 November 2011
carbonyl compound gave
a,b-dihydroxyl acid derivatives in good yield with high diastereoselectivity.
The reaction is proposed through a protic oxonium ylide trapping process. The reaction mechanism for
the formation of the protic oxonium ylide via Lewis acid InBr3 catalyzed diazo decomposition is sug-
gested through a vinyl cationic intermediate.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Lewis acid
Indium tribromide
Diazo decomposition
Oxonium ylide
Three-component reaction
Transition-metal catalyzed diazo decomposition through
a
curred in the presence of InBr3 to afford three-component
dihydroxyl acid derivatives efficiently.
a,b-
carbenoid intermediate plays an important role in organic synthe-
sis.1 Rhodium and copper complexes are the most widely used
transition-metal catalysts for the diazo decomposition.2 In addi-
tion, some other transition metals such as Pd,3a Ni,3b Ru,3c Co,3d
and Fe3e,f have been reported to catalyze diazo decomposition
reactions. In contrast, less attention has been paid to use Lewis
acids to successfully catalyze diazo decomposition.4 This is par-
tially because Lewis acids are commonly considered to be compat-
ible to diazo compounds, and they are mostly employed as
catalysts to activate other electrophilic substrates in the reaction
that involves diazo compounds. Nevertheless, some Lewis acids
with stronger Lewis acidity have been reported to catalyze diazo
decomposition via reaction pathways other than metal carbe-
noid.4a,b For example, Padwa et al. reported Lewis acids (such as
We have recently shown that InBr3 served as an effective additive
helping to control the diastereoselectivity in Rh2(OAc)4 catalyzed
three-component reactions of an aryldiazoacetate, an alcohol, and
a b,c-unsaturated a
-keto ester.6 Since InBr3 was reported to be an
effective catalyst for the diazo decomposition,4d we wondered if
InBr3 alone can promote the three-component reaction. We first
examined InBr3 catalyzed O–H insertion of a diazo compound and
an alcohol, because this reaction can provide useful information
regarding protic oxonium ylide formation. It was found that when
an electron donating aryldiazo acetate, such as methyl para-
methoxyphenyl diazoacetate (1a), was used as a substrate, InBr3 cat-
alyzed reaction with BnOH gave the corresponding O–H insertion
product 9a in a 60% yield. No reaction occurred when an electron
BF3ÁEt2O) catalyzed decomposition of
a-hydroxyl diazoacetate, in
which, the reaction was proposed through a vinyl cationic interme-
diate (Scheme 1).4a We have reported novel transition-metal cata-
lyzed three-component reactions of a diazo compound, an alcohol,
and an electrophile to give polyfunctional molecules in an efficient
fashion.5 A protic oxonium ylide, that is in situ generated from a
metal carbenoid and an alcohol, was proposed as an intermediate
in the reaction. We report here the first example of employing Le-
wis acid InBr3 to successfully catalyze such a three-component
reaction. Thus, diazo decomposition reactions of an aryldiazoace-
tate, an alcohol with an electron deficient carbonyl compound oc-
N2
BF3
HO
BF3 N2
HO
R1
N2
BF3.Et2O
HO
R1
CO2Et
CO2Et
CO2Et
R1
R2
R2
R2
-BF3OH
CO2Et
- N2
N2
R1
CO2Et
R2
additional
transformation
R1
R2
vinyl cation
Scheme 1. Lewis acid catalyzed diazo decomposition proposed by Padwa.4a
⇑
Corresponding author. Tel.: +86 13636307166; fax: +86 21 6223 3176.
E-mail address: whu@chem.ecnu.edu.cn (W. Hu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.005

J. Ji et al. / Tetrahedron Letters 53 (2012) 182–185
183
withdrawing aryldiazoacetate was used in the O–H insertion
reaction. A possible reaction pathway for the O–H insertion was sug-
gested through a metal associate protic oxonium ylide intermediate
as shown inScheme 2: co-ordination of p-methoxyphenyl diazoace-
tate with InBr3 gives the intermediate I. Loss of N2 may occur to form
a vinyl cationic intermediate II.4a Reaction of the electrophilic inter-
mediate II with BnOH may result in the metal associate protic oxo-
nium ylide intermediate III, which undergoes a proton transfer to
give the O–H insertion product 9a. An electron-donating substitu-
tion on the phenyl ring of the diazo compound should help to stabi-
lize the vinyl cationic intermediate IIa. Based on the assumption of
the oxonium ylide formation, we envisioned that the protic oxonium
intermediate III could be trapped by an electrophile, such as a car-
bonyl compound to give IV, which leads to the corresponding
three-component product via a ‘delayed proton transfer’ process
(Scheme 2).
Initially, p-NO2 benzaldehyde (3a) was selected to verify our
hypothesis. para-Methoxyphenyl diazoacetate 1a was added to a
mixture of benzyl alcohol 2a and 3a in the presence of InBr3. Grat-
ifyingly, the reaction gave excellent yield (95%) and high diastere-
oselectivity (96:4) favoring erythro isomer (Table 1, entry 2). In
contrast, the same reaction catalyzed by Rh2(OAc)4 alone gave
the same product in low dr (62:38) (Table 1, entry 1). Inspired by
such a promising result, the reaction was extended to additional
substrates and representative results are summarized in Table 1.
Similarly high dr (95:5) was obtained when using phenyl diazoace-
tate (1b) and p-methylphenyl diazoacetate (1c) as substrates,
whereas product yields are little lower (entries 3 and 4). The
N2
N2
O
N2
InBr3
O
O
O
O
O
Br3In
OMe
Br3In
OMe
OMe
- N2
1a
І
O
O
MeO
MeO
proton
transfer
H
OBn
BnOH
OBn
O
Br3In
O
O
O
Br3In
Br3In
O
O
O
O
9a
Ⅱa
Ⅱb
Ⅲ
O
R3 R4
MeO
"delayed
proton
H
OBn
PMP
MeOOC
BnO
R3
OH
R4
transfer"
R3
MeO
- InBr3
R4
O
O
Three-component product
Br3In
IV
Scheme 2. Proposed diazo decomposition pathways catalyzed by InBr3.
Table 1
Three-component reactions of an aryldiazoacetate, an alcohol and an electron-deficient aldehydea
Ar1
N2
1
Ar3
H
OH
Ar1
OH
H
InBr3
DCM
Ar2H2CO
Ar2H2CO
+
Ar2
OH
CHO
Ar3
Ar1
CO2Me
+
+
Ar3
MeO2C
MeO2C
2
3
erythro-6
threo-6
Entry
Ar1
Ar2
Ar3
6
InBr3
Dr(erythro:threo)e
d
Yield %
1b,c
2
3
4
5
6
7
8
p-OMe Ph
POMePh
Ph
p-CH3Ph
p-OMePh
p-OMePh
p-OMePh
p-OMePh
Ph
Ph
Ph
Ph
Ph
Ph
p-NO2 Ph
p-NO2Ph
p-NO2Ph
p-NO2Ph
o-NO2Ph
p-CF3Ph
p-NO2Ph
p-NO2Ph
6a
6a
6b
6c
6d
6e
6f
87
95
52
62
73
50
75
69
62:38
96:4
95:5
95:5
90:10
96:4
96:4
95:5
p-ClPh
p-CH3Ph
6g
a
b
c
All reactions were carried out in CH2Cl2 at 40 °C for 4 h with 1:2:3 = 1.5:1.5:1.0 (mmol) by using 20 mol % InBr3.
Reaction was carried out in CH2Cl2 at 40 °C for 1 h with 1:2:3 = 1.0:1.1:1.1 (mmol) by using 1 mol % Rh2(OAc)4.
Isolated yield of both isomers after column chromatography purification.
d
e
Isolated yield of erythro-isomer after column chromatography purification.
Determined by 1H NMR of unpurified reaction mixtures.

184
J. Ji et al. / Tetrahedron Letters 53 (2012) 182–185
reaction proceeded well with electron deficient aromatic alde-
hydes due to enhanced electrophilicity of the aldehydes that en-
able them to efficiently trap the protic oxonium intermediate
(entries 2–8). When using electron rich para-methoxyl benzalde-
hyde as a substrate, corresponding trapping product was obtained
in only a 22% yield with 50:50 dr.
using the InBr3 catalyst (Table 3, entries 2–5). The InBr3 catalyzed
three-component reactions with isatins gave good yield with mod-
erate to high dr favoring threo isomer.
Several control experiments were carried out to exclude the pos-
sibility that the three-component products 6 or 7 were formed from
the O–H insertion product 9a via a stepwise reaction pathway. The
reaction of 9a with 3a or 4a did not provide any three-component
product 6a or 7a in the presence of InBr3. Treatment of diazo com-
pound 1a and aldehyde 3a in the presence of InBr3 afforded only
dimerization product of the diazo compound (Scheme 3). The con-
trol experiments indicate that the three-component reaction only
occurs when the all three substrates are concurrent, and are in
agreement with the proposed reaction pathway shown in Scheme 2.
In conclusion, we first report InBr3 catalyzed three-component
reactions of aryldiazoacetates, alcohols and carbonyl compounds
The InBr3 catalyzed three-component reaction was further ex-
tended to other electron deficient carbonyl compounds. The reac-
tion proceeded smoothly with aryl keto esters and isatins, and
the results are summarized in Tables 2 and 3, respectively. In the
case of using aryl keto esters, InBr3 gave higher dr than copper cat-
alyst. While CuPF6(CH3CN)4 gave the product in very low dr
(51:49) (Table 2, entry 1), dr of greater than 80:20 was observed
when using InBr3 as the catalyst (Tale 2, entries 2–6). The more
electron rich diazo compounds gave both higher yield and dr
Table 2, entries 2–4). Significant effect of the substitution of benzyl
alcohol on the reaction outcome was observed in this case, as elec-
tron rich p-methylbenzyl alcohol gave both decreased yield and dr
(Table 2, entry 6 versus entries 2 and 5). Istains were identified as
good substrates as well. While Rh2(OAc)4 gave the reaction with
good yield and excellent dr (99:1) favoring erythro isomer (Table
3, entry 1), the diastereoselectivity was switched to threo when
to afford
a,b-dihydroxyl acid derivatives in an efficient and cost
effective way. InBr3 acts as a Lewis acid to decompose a diazo com-
pound in generating a protic oxonium ylide intermediate, which is
trapped by an electron deficient carbonyl compound in a highly
diastereoselective manner. The reactions still have some limita-
tions in substrate scope. Further work will emphasize on expand-
ing the substrate scope and managing enantioselective control.
Table 2
Three-component reactions of an aryldiazoacetate, an alcohol, and a ketoestera
Ar1
Ar1
O
4
N2
1
OH
CO2Me
Ph
erythro-7
Ph
CO2Me
InBr3
DCM
Ar2H2CO
Ar2H2CO
Ar2
OH
O
Ar1
CO2Me
+
+
+
Ph
OH
MeO2C
threo-7
MeO2C
O
2
Entry
Ar1
Ar2
7
InBr3
Yield %d
Dr(threo: erythro)e
1b,c
2
3
4
5
Ph
Ph
Ph
Ph
Ph
p-ClPh
p-CH3Ph
7c
7a
7b
7c
7d
7e
68
62
55
26
63
34
41:59
95:5
90:10
86:14
92:8
p-OMePh
p-CH3Ph
Ph
p-OMePh
p-OMePh
6
80:20
a
b
c
All reactions were carried out in CH2Cl2 at 25 °C for 4 h with 1:2:4 = 1.2:1.2:1.0 (mmol) by using 20 mol % InBr3.
Reactions were carried out in CH2Cl2 at 40 °C for 2 h with 1:2:3 = 1.0:1.2:1.2 (mmol) by using 10 mol % CuPF6(CH3CN)4.
Isolated yield of both isomers after column chromatography purification.
d
e
Isolated yields of threo-isomer after column chromatography purification.
Determined by 1H NMR of unpurified reaction mixtures.
Table 3
Three-component reactions of an aryldiazoacetate, an alcohol, and an isatina
BnO
HO
PMP
HO
PMP
CO2Me
OBn
CO2Me
O
InBr3
DCM
N2
1
+ BnOH +
O
+
R1
O
O
R1
R1
PMP
CO2Me
N
N
N
2
5
threo-8
erythro-8
Entry
R1
8
InBr3
Yield %c
Dr(threo:erythro)d
1b
2
3
4
5
H
H
4-Cl
5-Cl
6-Cl
8a
8a
8b
8c
8d
80
90
84
56
67
1:99
90:10
68:32
62:38
69:31
a
b
c
All reactions were carried out in CH2Cl2 at 40 °C for 4 h with 1:2:5 = 2.0:2.0:1.0 (mmol) by using 40 mol % InBr3.
Reaction was carried out in CH2Cl2 at 40 °C for 1 h with 1:2:3 = 1.2:1.5:1.0 (mmol) by using 1 mol % Rh2(OAc)4.
Isolated yields of threo and erythro-isomers after column chromatography purification.
Determined by 1H NMR of unpurified reaction mixtures.
d

J. Ji et al. / Tetrahedron Letters 53 (2012) 182–185
185
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.11.005.
OBn
O
CHO
InBr3, 40oC
InBr3, 25oC
O
O
+
+
N.R.
N.R.
O
O2N
MeO
MeO
3a
O
References and notes
9a
OBn
1. (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds; John Wiley and Sons: New York, 1998; (b)
Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577; (c) Zhang, Y.; Wang, J. Chem.
Commun. 2009, 5350; (d) Lian, Y.; Miller, L. C.; Born, S.; Sarpong, R.; Davies, H. M.
L. J. Am. Chem. Soc. 2010, 132, 12422; (e) Schwartz, B. D.; Denton, J. R.; Lian, Y.;
Davies, H. M. L.; Williams, C. M. J. Am. Chem. Soc. 2009, 131, 8329.
2. (a) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704; (b)
Davies, H. M. L.; Morton, D. Chem. Soc. Rev. 2011, 40, 1857; (c) Liu, B.; Zhu, S.-F.;
Zhang, W.; Chen, C.; Zhou, Q.-L. J. Am. Chem. Soc. 2007, 129, 5834; (d) Lee, E. C.;
Fu, G. C. J. Am. Chem. Soc. 2007, 129, 12066; (e) Flynn, C. J.; Elcoate, C. J.;
Lawrence, S. E.; Maguire, A. R. J. Am. Chem. Soc. 2010, 132, 1184.
O
O
O
9a
4a
OMe
O
O
N2
CHO
O
InBr3
+
O
O2N
MeO
O
3a
1a
MeO
3. (a) Peng, C.; Wang, Y.; Wang, J. J. Am. Chem. Soc. 2008, 130, 1566; (b) Ni, Y.;
Montgomery, J. J. Am. Chem. Soc. 2006, 128, 2609; (c) Che, C.-M.; Huang, J.-S.; Lee,
F.-W.; Li, Y.; Lai, T.-S.; Kwong, H.-L.; Teng, P.-F.; Lee, W.-S.; Lo, W.-C.; Peng, S.-M.;
Zhou, Z.-Y. J. Am. Chem. Soc. 2001, 123, 4119; (d) Zhu, S.; Perman, J. A.; Zhang, X.
P. Angew. Chem., Int. Ed. 2008, 47, 8460; (e) Wang, S. R.; Zhu, C.-Y.; Sun, X.-L.;
Tang, Y. J. Am. Chem. Soc. 2009, 131, 4192; (f) Zhu, S.-F.; Cai, Y.; Mao, H.-X.; Xie, J.-
H.; Zhou, Q.-L. Nat. Chem. 2010, 2, 546.
Scheme 3. Control reactions.
Acknowledgments
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5821.
We wish to thank the National Science Foundation of China
(20932003, 21002033) and the MOST of China (2011CB808600)
for financial support and Shanghai (09JC1404901, 10XD1401700)
for sponsorship.
Supplementary data
Supplementary data (complete experimental details and spec-
troscopic characterization of all new compounds) associated with