Bronsted acid-catalyzed insertion of aryldiazoacetates to sp 2 carbon-CHO bond: Facile construction of chiral all-carbon quaternary center

Article abstract of DOI:10.1021/ja710532j

Aryldiazoacetates could be formally inserted into the carbon-carbon bond of the Bronsted acid-activated aromatic and α,β-unsaturated aldehydes. Use of phenylmenthyl esters allowed the asymmetric induction at the inserted all-carbon quaternary carbon cente

Full text of DOI:10.1021/ja710532j

Published on Web 02/02/2008
Brønsted Acid-Catalyzed Insertion of Aryldiazoacetates to sp2 Carbon-CHO
Bond: Facile Construction of Chiral All-Carbon Quaternary Center
Takuya Hashimoto, Yuki Naganawa, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received November 22, 2007; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Scheme 1. Evaluation of Acid Catalysts
C-C bond insertion reaction has attracted much attention in the
synthetic community as an ideal means of realizing truly efficient
organic transformations. In addition to the direct activation of a
C-C bond by the aid of transition metal catalysts,1 the formal C-C
bond insertion reaction, in which the skeletal rearrangement of the
initially generated unstable intermediate is involved, seems to be a
highly attractive method for the expeditious synthesis of complex
molecules.2
During the course of our study on the use of diazoacetates in
Table 1. Stereoselective Insertion of Phenyldiazoacetate to
acid catalysis,3 we became aware of the reaction of ethyl diazoac-
etate and aldehydes providing R-formyl ester, reported by Hossain
and Kanemasa independently.4 Namely, under the influence of a
proper acid catalyst, ethyl diazoacetate reacts with the acid activated
arylaldehyde to generate diazonium intermediate A, which then
rearranges by the migration of aryl group to give the one-carbon
homologated aldehyde (path a). The whole process can be
considered as a formal insertion of methylenecarboxylate to the
sp2 C-CHO bond. Since the migration of hydride to the diazonium
carbon is also a feasible process providing â-keto ester (path b),
careful examination of the reaction conditions are required for the
selective generation of the C-C bond insertion product.5
p-Tolualdehyde Using Chiral Auxiliarya
entry
R
solvent
yield (%)b
dec
1
CH2Cl2
88
47
2
toluene
61
22
3
4
5
(-)-menthyl
CH2Cl2
toluene
CH2Cl2
toluene
toluene
42
11
74
55
74
22
20
32
>95
>95
(-)-phenyl- menthyl
6
7d
a Reactions were performed with p-tolualdehyde (0.24 mmol) and
phenyldiazoacetate (0.20 mmol) in the presence of 20 mol % TfOH.
b Isolated yield. c Determined by the 1H NMR of the crude reaction mixture.
d Performed with 5 equiv of aldehyde (1.0 mmol).
Stimulated by this research and our recent finding regarding the
use of R-aryldiazoacetates in acid catalysis,3c we assumed that
addition of R-aryldiazoacetates to aldehydes would lead to the
formation of R,R-disubstituted-R-formyl esters by the judicious
choice of acid catalysts.6 As chiral auxiliary can be introduced at
the ester moiety of diazo compounds, asymmetric induction at the
all-carbon quaternary center might be also anticipated.7,8
To prove this concept, some acid catalysts were initially screened
in the reaction of benzaldehyde and tert-butyl phenyldiazoacetate
(Scheme 1). The reaction catalyzed by BF3‚Et2O provided the
expected tert-butyl R,R-diphenyl-R-formyl ester 1 in moderate yield
concomitant with some amounts of undesired R-phenyl-â-keto ester
2. Use of aluminum Lewis acid led to the increased ratio of â-keto
ester. The reaction catalyzed by TiCl4 was sluggish at -78 °C. To
our delight, TfOH was found to be a suitable catalyst, providing
the aldehyde 1 in good yield accompanied by only a small amount
of â-keto ester 2.
able (-)-trans-2-phenyl-1-cyclohexanol, (-)-menthol, and (-)-
phenylmenthol were selected as key chiral components,9,10 and
TfOH-catalyzed reaction of the corresponding phenyldiazoacetate
and 4-tolualdehyde was surveyed. Consequently, the superiority of
phenylmenthyl ester became obvious by performing the reaction
in toluene, providing the essentially single diastereomer of R-phen-
yl-R-(4-tolyl)-R-formyl ester in 55% yield (entry 6). An additional
investigation revealed the use of 5 equiv of the aldehyde optimal
(entry 7). In all of the experiments above, the amount of â-keto
ester was suppressed to less than 10% yield.
With this optimized condition in hand, the scope of this C-C
bond insertion was investigated as shown in Table 2. Use of 3- or
2-tolualdehyde could lead to the inserted product in moderate yields
with exclusive diastereoselectivities, regardless of the severe steric
hindrance around the quaternary center generated in the case of
2-tolualdehyde. The reaction could also be applied to the aldehydes
bearing electron-donating or withdrawing group (entries 3 and 4).
Further investigation on the use of R,â-unsaturated aldehydes
bearing two â-substituents unraveled the feasibility of such a
transformation, providing R-alkenyl-R-aryl-R-formyl esters in fairly
good yields and diastereomeric excesses (entries 5-7). Subse-
quently, the scope of aryldiazoacetates was examined. Irrespective
Encouraged by this successful implementation of the formal C-C
bond inserton of phenyldiazoacetate to the aldehyde, our focus then
moved to the asymmetric induction at the newly formed all-carbon
quaternary center by the introduction of a chiral auxiliary on the
ester moiety of phenyldiazoacetate (Table 1). Commercially avail-
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10.1021/ja710532j CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Stereoselective Insertion of (-)-Phenylmenthyl
Aryldiazoacetates to Aldehydesa
Figure 2. Possible explanation of the observed stereochemistry.
aldehyde by the inversion of the configuration at the diazonium
carbon followed by denitrogenation.
entry
R1
Ar
yieldb (%)
dec (%)
1
3-tolyl
2-tolyl
4-MeOC6H4
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
67
65
42
62f
89
>95
>95
89
>95
87
In summary, we have realized the triflic acid-catalyzed formal
C-C bond insertion of aryldiazoacetates to aldehydes as a means
of constructing an all-carbon quaternary center. Introduction of the
phenylmenthyl moiety as chiral auxiliary allowed the facile access
to a variety of optically active R,R-disubstituted-R-formyl esters.
2
3d
4
5e
6e
7e
Ph
Ph
85
89
94
94
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.
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
8d
9
10
11
4-MeOC6H4
Ph
4-ClC6H4
Ph
4-tolyl
56
85
>95
>95
>95
3-MeOC6H4
3-MeOC6H4
4-ClC6H4
72f
53f
73f
References
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mmol). b Isolated yield. c Determined by 1H NMR of the crude reaction
mixture. d Performed at -40 °C. e Performed with 1.2 equiv of aldehyde.
f Yield determined after the reduction of the aldehyde.
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Figure 1. Ortep representation of (-)-phenylmenthyl R-phenyl-R-(2-tolyl)-
R-formyl ester with elipsoids shown at 50% probability level. Hydrogen
atoms are omitted for clarity.
of the substituent and substitution pattern, the desired product could
be obtained in moderate yields with high stereoinduction. The major
limitation we found during this study was the inapplicability of
o-substituted aryldiazoacetate.
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(Table 2, entry 2) as shown in Figure 1.
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of aryldiazoacetate to aldehyde. Effective shielding of one diaste-
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