Catalytic enantioselective petasis-type reaction of quinolines catalyzed by a newly designed thiourea catalyst

Article abstract of DOI:10.1021/ja071470x

A newly designed thiourea catalyst provides sufficient activation of organoboronic acids to facilitate the enantioselective Petasis transformation of quinolines even at low temperatures. A high degree of stereocontrol was achieved in the reaction of vario

Full text of DOI:10.1021/ja071470x

Published on Web 05/08/2007
Catalytic Enantioselective Petasis-Type Reaction of Quinolines Catalyzed by
a Newly Designed Thiourea Catalyst
Yousuke Yamaoka, Hideto Miyabe, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received March 2, 2007; E-mail: takemoto@pharm.kyoto-u.ac.jp
Nucleophilic addition to quinolines has been developed as a key
step in the synthesis of tetrahydroquinolines, which are important
synthetic intermediates and structural units of alkaloids and
biologically active compounds.1 However, less is known about
asymmetric addition to quinolines because the resonance stability
of heteroaromatic compounds might impede enantioselective trans-
formation. The first enantioselective reaction of quinolines with
TMSCN was achieved by Shibasaki’s group, who relied on an
unique Lewis acid-Lewis base catalyst.2 Alexakis also investigated
the addition of organolithium reagents to quinolines as well as
isoquinolines.3 As a related example, an organocatalyst has recently
been reported to promote the enantioselective addition of silyl
ketene acetal to isoquinoline by Jacobsen’s group.4 Despite such
significant advances,2-4 a high degree of stereocontrol has not been
achieved and still remains a major challenge.
Figure 1. Concept of a newly designed thiourea catalyst.
Scheme 1
As a modern variation of the Mannich reaction using organobo-
ronic acids, the Petasis reaction has recently been of great impor-
tance in synthetic chemistry.5,6 However, the full potential of this
reaction remains unrealized. Although studies on asymmetric induc-
tion have achieved some remarkable success by using chiral
R-hydroxy aldehydes, amines, or boronates (eq 1), there have been
no reports on catalytic asymmetric processes.7 In this paper, we
describe the first catalytic enantioselective variant of the Petasis
transformation of quinolines. In our concept, the thiourea moiety
could activate N-acylated quinolinium salts as a Brønsted acid
(Figure 1).8
Table 1. Reaction of 2a with 4A in the Presence of Catalysts
1a-ia
entry
catalyst
ROCOCl
additive
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
1a
1b
1b
1b
1c
1h
1i
PhOCOCl
PhOCOCl
EtOCOCl
BnOCOCl
PhOCOCl
PhOCOCl
PhOCOCl
PhOCOCl
PhOCOCl
none
none
none
none
none
none
none
H2Ob
34
70
33
44
47
60
70
27
65
-9
90
42
67
27
68
50
93
94
1b
1b
b
H2O and NaHCO3
Recently, our laboratory introduced thiourea 1a as a bifunctional
organocatalyst, which accelerates the aza-Henry reaction and the
Michael reaction of nitroolefins or R,â-unsaturated imides (Scheme
1).9,10 However, the scope of suitable nucleophiles for catalyst 1a
was mainly limited to 1,3-dicarbonyl compounds. In the Petasis
reaction, the formation of reactive “ate” complex A is assumed to
play an important role in the reactivity and diastereoselectivity,
although the intermediates are not well defined (eq 1).5-7 On the
basis of this mechanism, we have newly designed several catalysts
1b-i that have a chelating functionality, which could activate the
boronic acids and direct the stereochemical outcome, as shown for
B in Figure 1.11 We first reported the results of an experiment to
probe the utility of new functionalized catalyst 1b in the transfor-
mation of quinoline 2a with vinylboronic acid 4A into 1,2-adduct
5a. All reactions were run in CH2Cl2 at -65 °C for 24 h.12
Representative results are shown in Table 1. As an activating
reagent, the addition of phenyl chloroformate (2 equiv) promoted
the reaction at -65 °C (entries 1 and 2), while practically no
reaction occurred in the absence of activating reagent, even after
a Reaction was carried out with catalysts 1a-i (10 mol %) in CH2Cl2 at
-65 °C. b NaHCO3 (2 equiv) and H2O (56 equiv, CH2Cl2/H2O ) 10:1).
the reaction mixture was stirred at room temperature for 24 h. As
expected, the use of new thiourea 1b with a 1,2-amino alcohol
functionality (10 mol %) increased the chemical efficiency to give
the 1,2-adduct 5a in 70% yield with 90% ee without formation of
a 1,4-adduct (entry 2), while the reaction with the original catalyst
1a gave the nearly racemic product adduct 5a in 34% yield (entry
1). The activating reagent affected the enantioselectivity. Among
several reagents tested,13 phenyl chloroformate gave the best results
(entries 2-4). Yoon and co-workers recently reported that dihyd-
roquinoline 3 coupled with electron-sufficient boronic acids.14
Although the dihydroquinoline 3 showed excellent reactivity toward
4A, stereocontrol was not achieved and the racemic product 5b
was obtained in 68% yield. Several catalysts 1c-h were also tested
to determine the role of the amino alcohol moiety (entries 5-7).
When the reaction was performed in the presence of catalyst 1c
9
6686
J. AM. CHEM. SOC. 2007, 129, 6686-6687
10.1021/ja071470x CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
provides a powerful method for the enantio- and regioselective
synthesis of the 1,2-adduct.
In conclusion, an organocatalyst provides sufficient activation
of organoboronic acids to facilitate stereocontrol in the Petasis
transformation of quinolines as a result of the catalytic generation
of a chiral complex as well as the dual activation of an electrophile
and nucleophile.
Acknowledgment. This work was supported in part by a Grant-
in-Aid for Scientific Research (B) (Y.T.) and Scientific Research
on Priority Areas: Advanced Molecular Transformations of Carbon
Resources (Y.T. and H.M.) from the Ministry of Education, Culture,
Sports, Science and Technology of Japan, 21st Century COE Pro-
gram “Knowledge Information Infrastructure for Genome Science”.
Table 2. Reaction of 2a-f with 4A-F in the Presence of Catalyst
1ba
entry
substrate
boronic acid
T (°
C)
product (yield)
ee (%)
1
2
2b
2c
2d
2e
2f
2a
2a
2a
2a
2a
4A
4A
4A
4A
4A
4B
4C
4D
4E
4F
-65
-78
-65
-65
-65
-78
-78
-78
-65
-40
6bA (75%)
6cA (70%)
6dA (63%)
6eA (78%)
6fA (61%)
6aB (70%)
6aC (59%)
6aD (60%)
6aE (60%)
6aF (28%)
95
96
94
95
96
97
82
89
91
95
Supporting Information Available: Experimental procedures and
characterization data of all obtained compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
3
4
5
6
References
7
8
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9
10
a Reaction was carried out with 1b (10 mol %) in CH2Cl2 by using
PhOCOCl (2 equiv), NaHCO3 (2 equiv), and H2O (56 equiv) for 24 h.
with a 1,3-amino alcohol functionality, only moderate selectivity
was achieved (entry 5). The use of catalysts 1d-g led to lower
ee.15 A 1,2-amino alcohol functionality on the catalyst was necessary
for valuable stereocontrol, as shown in the reaction with catalyst
1h as well as 1b (entry 6). The effect of a thiourea moiety in
catalysts was confirmed by using the simple 1,2-amino alcohol
catalyst 1i (entry 7). As expected, catalyst 1i also showed excellent
catalytic activity in this process, although the enantioselectivity was
decreased. These observations indicate that a 1,2-amino alcohol
functionality on catalysts activates boronic acid and the thiourea
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bond in N-phenoxycarbonyl quinolinium salt.2a To improve the
enantioselectivity of 5a, various reaction conditions were exam-
ined.16 The addition of H2O as a proton source increased the
enantioselectivity with a decrease in the yield (entry 8), and the
combination of H2O and NaHCO3 improved the chemical yield
(entry 9). A remarkable effect of H2O and NaHCO3 is assumed to
be the in situ regeneration of catalyst 1b promoted by a proton
source and removal of the resulting boronic acid by base.17An
outstanding level of enantioselectivity was also achieved in the
reaction of other quinolines 2b-f (Table 2, entries 1-5). The
reaction of quinoline 2c proceeded smoothly despite the presence
of a methyl group at the 3-position (entry 2). Under analogous
conditions, various boronic compounds 4B-E gave good results
(entries 6-9). As a general trend, electron-rich boronic acids are
more reactive in the Petasis reaction.5-7 Indeed, the reaction with
4B-D, which have an electron-donating substituent, took place even
at -78 °C. Although the formation of 6aF, which has an electron-
withdrawing substituent, was remarkably diminished, a high degree
of stereocontrol was achieved (entry 10).18
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(11) Urea catalyst with a sulfinamide moiety was recently reported to promote
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(12) The solvent influenced the reactivity and enantioselectivity. A protic
solvent such as EtOH increased the addition rate, although no enantiose-
lectivity was observed. Good stereocontrol was achieved with the use of
aprotic and nonpolar solvents such as CH2Cl2 and toluene.
(13) The addition of AcCl, BzCl, Tf2O, Ac2O, or Boc2O instead of chloro-
formate led to lower ee.
(14) Chang, Y. M.; Lee, S. H.; Nam, M. H.; Cho, M. Y.; Park, Y. S.; Yoon,
C. M. Tetrahedron Lett. 2005, 46, 3053.
(15) The results of reactions using catalysts 1d-g are given in the Supporting
Information.
(16) For example, the addition of Et3N or Na2CO3 as a base gave product 5a
in 32 or 91% ee, respectively. The addition of EtOH or CF3CH2OH as a
proton source was less effective and led to a lower ee.
(17) A similar trend was observed in the reaction of another quinoline 2b.
Thus, the use of H2O and NaHCO3 was found to be optimal for not only
enantioselectivity but also chemical efficiency.
The absolute configuration was determined by converting the
adduct 6aC into (+)-galipinine 7 (eq 2).1 The reaction of quinolines
is frequently plagued by the generation of regioisomeric 1,2- and
1,4-adducts;3 thus, it is also specifically noteworthy that this reaction
(18) The reaction with arylboronic acids bearing phenyl and p-methoxyphenyl
groups gave no desired products owing to their low reactivities.
JA071470X
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