A cycloalkane-based thermomorphic system for organocatalytic cyclopropanation using ammonium ylides

Article abstract of DOI:10.1246/cl.2011.1077

Highly polar ammonium ylide intermediates derived from α-halocarbonyl compounds were successfully trapped by cycloalkane phase-tagged activated alkenes via a cycloalkane-based thermomorphic (CBT) process, which allows for facile product isolation using a

Full text of DOI:10.1246/cl.2011.1077

doi:10.1246/cl.2011.1077
Published on the web September 17, 2011
1077
A Cycloalkane-based Thermomorphic System
for Organocatalytic Cyclopropanation Using Ammonium Ylides
Shokaku Kim, Naoki Ikuhisa, and Kazuhiro Chiba*
Laboratory of Bio-organic Chemistry, Tokyo University of Agriculture and Technology,
3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509
(Received June 17, 2011; CL-110507; E-mail: chiba@cc.tuat.ac.jp)
Highly polar ammonium ylide intermediates derived from
¡-halocarbonyl compounds were successfully trapped by cyclo-
alkane phase-tagged activated alkenes via a cycloalkane-based
thermomorphic (CBT) process, which allows for facile product
isolation using a single liquid-liquid extraction step to effectively
generate cyclopropane libraries in the cyclohexane phase.
Solution-phase combinatorial chemistry has emerged as a
useful alternative to solid-phase combinatorial chemistry in the
advancement of drug discovery.1,2 Currently, our laboratories are
developing a CBT system that promotes reactions in monophasic
solution, then allows product isolation upon cooling and phase
separation (Figure 1). The CBT system can allow not only for
selective separation of cycloalkane phase (CP)-tagged products
from a reaction mixture, but also enables the practice of a wide
range of existing reactions with higher reactivity than in solid
phase, even in combination with CP-tagged substances and
insoluble species: substrates, reagents catalysis.3,4 Furthermore,
the highly selective formation of separable CP-tagged products
confers a significant advantage in monitoring reaction progress and
identification of the products. In particular, the remarkable phase-
miscibility of cycloalkanes in polar solvents enables efficient
interactions between the highly polar intermediates and the CP-
tagged substrate. Despite such attractive features, however, this
methodology has been limited to peptide synthesis and palladium-
catalyzed reactions.
Figure 1. Schematic view of a CBT system.
O
X
i
R3N
O
CP
ii
NR3X
ammonium ylide precursor
O
CBT system
CP
R'
in cycloalkane phase
O
Recently, organocatalytic reactions have gained much atten-
tion due to: i) the absence of toxic transition metals, ii) readily
available starting materials, and iii) ease of handling.5 In
particular, ammonium ylide species have been successfully
applied in various synthetic methodologies in the construction
of unique building blocks.6,7 To apply a CBT system toward
organocatalytic cyclopropanation, a suitable CP-tag must be
introduced onto one of the two starting substrates to assemble
product libraries in the cycloalkane phase (Figure 2). In fact,
inadequate construction of the CBT media and CP tags can
often preclude the generation and stabilization of the highly
polar ylide species, thus impeding subsequent intermolecular
carbon-carbon bond-forming reactions. As a consequence, this
challenge provided the impetus for us to develop a CBT method
that would efficiently generate and stabilize such unstable am-
monium ylides. In this paper, we report the application of a
CBT system to organocatalytic cyclopropanation via ammonium
ylides, with modifications of a CP tag, to generate cyclopropane
libraries in a cycloalkane phase. Accordingly, the development
of this CBT system provides a significant opportunity to extend
the applicability to a wider variety of organocatalytic reaction
processes.
=Cycloalkane phase tag
CP
Figure 2. Two possible routes for a CBT synthesis of a CP-tagged
product in cycloalkane phase. i) Modification of the CP-tag onto an
¡-halocarbonyl compound. ii) Modification of the CP-tag onto an ¡,¢-
unsaturated carbonyl compound.
Br
CP
CP
DABCO
O
O
Br
N
O
O
N
1
O
ammonium ylide precursor
OC18H37
O
no
cycloadduct
C18H37
C18H37
Scheme 1.
O
Cs2CO3
CP
O
nucleophilic tertiary amine), and t-butyl acrylate. After stirring
under reflux conditions for 24 h, the CBT solution was allowed to
cool to room temperature to afford a distinct cyclohexane phase
under biphasic conditions. Under these reaction conditions,
however, the expected cycloadduct was not obtained; the failure
can attributed to the hydrophobic modification of an inappropriate
As shown in Scheme 1, the organocatalytic cyclopropanation
via a CBT process was initially investigated using hydrophobic
¡-bromo ester 1, DABCO (1,4-diazobicyclo[2.2.2]octane, as a
Chem. Lett. 2011, 40, 1077-1078
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1078
Table 1. A CBT system for organocatalytic cyclopropanations using
¡-chlorocarbonyl compouds 3d-3f
CP
O
DABCO
Cs2CO3
2
O
R1
O
CP
DABCO
R1
R1
Cs2CO3
cHex
MeCN
CP
R1
2
O
Cl
O
O
Br
cHex
EtCN
O
4
O
O
4a; 96%, 4b; 91%
4c; 93%, 4d; 99%
3a; R1=OMe, 3b; R1=Ot-Bu
Entry
1
Substrate
O
Producta,b
3c; R1=Ph, 3d; R1=4-bromophenyl
Cl
CP
CP
O
O
O
Scheme 2.
3e
NEt2
3f
O
O
O
O
4e (91%)
NEt2
4f (98%)
substrate site that cannot generate the ylide moiety, and to the
amphipathic properties of the hydrophobic ammonium ylide that
form undesirable aggregation structures interfering with CBT
cyclopropanation.
Cl
Cl
2
3
O
O
Subsequently, as shown in Scheme 2, a CP tag was introduced
onto activated olefins to carry out the cyclopropanation reaction of
2 with methyl bromoacetate (3a) in a similar manner.8 In this case,
the expected cycloaddition reaction proceeded efficiently to afford
cyclopropane 4a (96% yield), which was almost exclusively
distributed in the cyclohexane phase. As a note, the syn product
was not detected (1H NMR and HPLC analysis). The results
demonstrate that the CBT system enables effective interactions
between polar and apolar substrates in a monophasic solution,
followed by product isolation upon cooling and phase separation.
Additionally, for such organocatalytic CBT reactions, hydrophobic
modifications of activated olefins, rather than those of ylide
precursors, was found to be more effective. Subsequently, as
shown in Scheme 2, organocatalytic cyclopropanation reactions
of t-butyl bromoacetate (3b), 2-bromoacetophenone (3c), and 2,4¤-
dibromoacetophenone were shown to successfully afford the CP-
tagged cyclopropanes in high yields.
These results prompted us to apply the CBT technique in the
reactions of several commercially available ¡-chlorocarbonyl
compounds. Using allyl chloroacetate (3e), however, the reaction
proceeded with merely 17% conversion, which is attributable
to the lower reactivity and nucleophilicity of the ammonium
ylide intermediates generated by ¡-chlorocarbonyl moieties to
¡,¢-unsaturated carbonyl compounds, and to the use of a cHex/
MeCN mixture, which cannot completely form a monophasic
solution.
In order to increase the interactions between ¡-chlorocarbon-
yls and the CP-tagged substrate, a more appropriate CBT solution
system was required. Accordingly, CBT cyclopropanation was
studied using a combination of cHex and EtCN, which forms
a complete monophase, resulting in an increased yield of the
targeted products to 91%. Using the optimized procedures,
treatment of 2-chloro-N,N-diethylacetamide (3f) and 2-chloro-N-
methoxy-N-methylacetamide (3g) furnished the cycloadduct prod-
ucts in high yields (Table 1). In these cases, the alternative method
for the CBT process involved addition of n-hexane (and/or
MeCN) to form a biphasic mixture at room temperature allowing
separation of the upper phase without cooling.
N
CP
OMe
3g
O
N
OMe
O
4g (93%)
O
O
aSyn stereoisomer was not observed by 1H NMR experiments.
bIsolated yied.
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology.
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efficient in forming the monophasic solution during organocata-
lytic cyclopropanation reactions. In contrast, complete reactions
were not observed in conventional biphasic solutions, even under
a partially miscible CBT system such as a cHex/MeCN mixture
(Figure 2). Obviously, the effective mutual miscibility of the
cosolvents plays a significant role in the reactions between the
hydrophobic phase-tagged substrate and the highly polar quater-
nary ammonium salt.
6
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Chem. Lett. 2011, 40, 1077-1078
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/