Organocatalytic asymmetric direct alkylation of α-diazoester via C-H bond cleavage

Article abstract of DOI:10.1021/ja051922a

A new variant of phosphoric acid-catalyzed C-C bond forming reaction, direct alkylation of α-diazoester, via C-H bond cleavage is presented. The resulting products, β-amino-α-diazoesters, are highly functionalized and useful synthetic precursors for vario

Full text of DOI:10.1021/ja051922a

Published on Web 06/09/2005
Organocatalytic Asymmetric Direct Alkylation of r-Diazoester via C-H Bond
Cleavage
Daisuke Uraguchi,† Keiichi Sorimachi, and Masahiro Terada*
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
Received March 25, 2005; E-mail: mterada@mail.tains.tohoku.ac.jp
The catalytic asymmetric sp2 C-H bond addition reaction to
carbonyl, imine, and R,â-unsaturated carbonyl compounds, such
as Friedel-Crafts (F-C) alkylations, is a powerful yet challenging
organic transformation.1 It has attracted much attention from
industry as well as the academic community due to its atom
efficiency.2 Recently, highly enantioselective 1,2- and 1,4-F-C
alkylations were achieved using metal-based Lewis acid3 and small
organomolecule4,5 catalysts. Mechanistically, these F-C alkylations
are regarded to proceed via an addition-elimination pathway
(Scheme 1a). For instance, an electron-rich aromatic or hetero-
aromatic compound attacks an activated sp2 carbon, and subsequent
deprotonation provides an F-C alkylation product exclusively.
(1a) with an acyl imine (2, R′, Ar ) Ph) was attempted at room
temperature in chloroform-d1 under the influence of 2 mol % of
achiral phosphoric acid (4, eq 1). As desired, clean conversion of
the starting imine (2, R′, Ar ) Ph) to the direct alkylation product
(3a, R′, Ar ) Ph) was observed within 1 h, and the product was
isolated in 70% yield. Although it is difficult to clarify the action
of the phosphoryl oxygen work in the deprotonation stage, this result
indicates that a phosphoric acid catalyst such as 4 can efficiently
promote direct alkylation of R-diazoesters via C-H bond cleav-
age.12 Herein, we describe development of the asymmetric form
by means of a binaphthol monophosphoric acid catalyst.13
Scheme 1. Mechanism for Friedel-Crafts Alkylations and
Reaction Modes of Diazoacetate with Imine
Catalyst (R)-514 provided the best enantioselectivity of the
reactions attempted, and its selectivity was dramatically influenced
by tuning of the ester moiety of 1. For example, the 79% ee obtained
for the ethyl ester was ameliorated to 84% ee when using isopropyl
ester in toluene at room temperature and was further improved to
90% ee using commercially available tert-butyl diazoacetate (1b)
as a substrate. Interestingly, the electronic character of the acyl
protective group of the imine nitrogen also strongly affected
selectivity as well as reactivity (Table 1). Introduction of ortho- or
meta-substituents to the acyl aromatic moiety indicated a small
effect on the selectivity (entries 1-6). However, para-substituents
strongly impacted on the reaction selectivity as well as frequency
and introduction of electron-donating substituents provided better
results (entries 7-9). The highest selectivity was displayed by para-
dimethylaminobenzoyl aldimine (2, R′ ) p-Me2N-C6H4, Ar ) Ph)
although with a slight reduction in reaction frequency (entry 10).
Fortunately, a prolonged reaction time improved the yield (entry
11).
In conjunction with our recent efforts to develop chiral Brønsted
acids for catalyzed asymmetric carbon-carbon bond forming
reactions,6-9 we recently demonstrated a highly enantioselective
1,2-aza-F-C reaction of a furan derivative to N-protected aldimines
catalyzed by chiral phosphoric acid.9 In consideration of the catalytic
cycle of this reaction, the phosphate anion receives a proton in the
elimination stage, and it is even possible that the phosphoryl oxygen
functions as an intracomplex basic site. Diazoacetate, which has
an electronically unique sp2 carbon, is a rather interesting motif
from this viewpoint because of the similarity of the addition
intermediates A and B. Although diazoacetate is commonly used
in aziridine formation reactions (aza-Darzens reaction) under
Lewis10 and Brønsted11 acidic conditions (Scheme 1b), a possible
intracomplex deprotonation from intermediate C by phosphoryl
oxygen may allow direct alkylation of diazoacetate via C-H bond
cleavage, giving an R-diazo-â-amino acid ester through an “F-C-
type” pathway (Scheme 1c). Thus, treatment of ethyl diazoacetate
Experiments that probe the scope of this transformation are
summarized in Table 2. Para-substituted aromatics showed generally
excellent enantioselectivity irrespective of its electronic character
(entries 1-4). Ortho- and meta-substitution as well as a fused ring
system was also tolerated (entries 5-8).
Next, we attempted to derive the common synthetic intermedi-
ates, â-amino acid derivatives, from 3b. Hydrogenation of the diazo
† Present address: Sagami Chemical Research Center, Ayase 252-1193, Japan.
9
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J. AM. CHEM. SOC. 2005, 127, 9360-9361
10.1021/ja051922a CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Electronic Effect of Acyl Protective Group on the Imine
Nitrogen (Eq 1, Ar ) Ph, 1b, and (R)-5 Were Used)a
syntheses of â-amino acid derivatives with high optical purity by
means of functionalization of diazo moiety clearly highlight the
diverse synthetic potential of this direct asymmetric transformation.
In conclusion, a new variant of phosphoric acid-catalyzed C-C
bond forming reaction, direct alkylation of R-diazoester, via C-H
bond cleavage was presented. The resulting products, â-amino-R-
diazoesters, are highly functionalized and useful synthetic precursors
for various types of â-amino acids. Further synthetically useful
direct transformations promoted by chiral phosphoric acid catalysts
are underway.
entry
R
′
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Ph
59
80
84
77
76
82
68
72
73
57
81
90
90
90
92
91
90
86
91
93
96
97
o-Br-C6H4-
o-Me-C6H4-
o-MeO-C6H4-
m-MeO-C6H4-
1-naphthyl-
p-Br-C6H4-
p-Me-C6H4-
p-MeO-C6H4-
p-Me2N-C6H4-
p-Me2N-C6H4-
9
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, and The Sumitomo
Foundation.
10
11d
a Unless otherwise noted, all reactions were carried out with 0.1 mmol
of 1 in 1 mL of toluene at room temperature for 5 h. b Isolated yield.
c Enantiomeric excess was determined by HPLC analysis. See Supporting
Information for details. d The reaction was carried out for 24 h.
Supporting Information Available: Representative experimental
procedures and spectroscopic data for 2-7. This material is available
free of charge via the Internet at http://pubs.acs.org.
Table 2. Organocatalyzed Direct Alkylation of tert-Butyl
Diazoacetate (1b) with Representative Aldimine Derivatives (2)
(Eq 1, R′ ) p-Me2N-C6H4, 1b, and (R)-5 Were Used)a
References
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a All reactions were carried out with 0.1 mmol of 1 in 1 mL of toluene
at room temperature for 24 h. b Isolated yield. c Enantiomeric excess was
determined by HPLC analysis. See Supporting Information for details. d 3
mol % of (R)-5 was used.
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Scheme 2. Synthetic Utility of â-Amino-R-Diazoestersa
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a Conditions: (i) PtO2, H2, EtOAc/AcOH, room temperature (rt), 79%.
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conditions.
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been reported. See: Zhao, Y.; Ma, Z.; Zhang, X.; Zou, Y.; Jin, X.; Wang,
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moiety of 3b (R′ ) p-Me2N-C6H4, Ar ) Ph, 97% ee) with Adams’
catalyst under a hydrogen atmosphere and successive deprotection
provided â-amino acid tert-butylester (6) without any loss of
enantiomeric excess. R-Oxo-functionality was efficiently introduced
by oxone, and subsequent diastereoselective reduction enabled us
to synthesize anti-â-amino-R-hydroxy acid tert-butylester (7) from
3b (R′, Ar ) Ph, recrystallized, >99% ee).15 These short step
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