The enantioselective organocatalytic 1,4-addition of electron-rich benzenes to α,β-unsaturated aldehydes

Article abstract of DOI:10.1021/ja025981p

The first enantioselective organocatalytic alkylation of electron-rich benzene rings with α,β-unsaturated aldehydes has been accomplished. The use of iminium catalysis has provided a new strategy for the enantioselective construction of benzylic stereogenicity, an important chiral synthon for natural product and medicinal agent synthesis. The (2S,5S)-5-benzyl-2-tert-butylimidazolidinone amine catalyst has been found to mediate the conjugate addition of a wide variety of substituted and unsubstituted anilines to unsaturated aldehydes. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 10 mol % were generally employed in this study, successful alkylations conducted with catalyst loadings as low as 1 mol % are described. Copyright

Full text of DOI:10.1021/ja025981p

Published on Web 06/12/2002
The Enantioselective Organocatalytic 1,4-Addition of Electron-Rich Benzenes
to r,â-Unsaturated Aldehydes
Nick A. Paras and David W. C. MacMillan*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received February 20, 2002
Table 1. Organocatalyzed Alkylation of Anilines 1a, 1b, and 1c
with Representative R,â-Unsaturated Aldehydes
One of the most important chiral synthons throughout the realm
of organic architecture is represented by the benzylic carbon stereo-
center. Found in over 5000 natural product isolates,1 this stereochemi-
cal motif has also gained a “privileged” status in medicinal chemis-
try due to its recurring presence among therapeutic agents (e.g., Zoloft,2
Paxil,3 Detrol4). While catalytic access to enantioenriched benzylic
architecture has been accomplished with hydrogenation5 or metal-
lobenzene addition technologies,6 a complimentary approach might
involve the enantioselective alkylation of benzene rings with elec-
tron deficient olefins.7 In this context, we have recently reported
that the LUMO-lowering activation of R,â-unsaturated aldehydes
via the reversible formation of iminium ions is a valuable platform
for the development of enantioselective cycloadditions8 and het-
eroaromatic substitutions.9 In this communication, we further ad-
vance this iminium activation strategy to achieve the first enantio-
selective organocatalytic alkylation of aniline rings (eq 1). Impor-
tantly, this strategically new approach to asymmetric conjugate
addition allows the construction of complex benzylic carbon stereo-
genicity with simple R,â-unsaturated aldehydes and aryl substrates.
a Ratios determined by chiral HPLC analysis of corresponding alcohol
after NaBH4 reduction. b Using 20 mol % catalyst. c 1.0 M in CHCl3.
d Absolute configuration assigned by chemical correlation.
â-aromatic substituents on the olefin can be employed to construct
bis-benzylic stereogenicity, a structural motif commonly found
among drug candidates2,4 that is not readily accessible via asym-
metric hydrogenation10 (entries 7-10, 80-85% yield, 84-92% ee).
Significant structural variation in the aniline component can also
be realized (Table 2). The reaction appears quite general with
respect to the nature of the nitrogen substituents (entries 1-8, NMe2,
NBn2, 1-pyrrolidino, indoline, 93-99% ee). Initial studies have
revealed that the pyrrolidino-benzene and indoline rings are
significantly more reactive than the N,N-dimethyl or N,N-dibenzyl
anilines (cf. entries 2, 3, 5, and 8, krel pyrrolidino:indoline:NMe2:
NBn2 ) 48:48:4:1). As revealed in Table 2, a variety of alkyl and
heteroatom substituents can be incorporated on the aniline ring at
both the ortho and meta positions without loss in reaction efficiency
or enantiocontrol (entries 6-13, R1 or R2 ) Ph, Me, OMe, SMe,
84-99% ee). Moreover, the aryl framework can be successfully
extended to naphthalene-derived systems (entry 9, 93% ee). We
have also utilized relatively electron deficient anilines in the context
of a 3-chloro-substituted ring (entry 14, 73% yield, 93% ee). Such
halogenated benzene adducts should prove to be valuable synthons
for use in conjunction with organometallic technologies (e.g., Stille11
Our enantioselective organocatalytic benzene alkylation was first
evaluated with anilines 1a-c, imidazolidinone catalyst 2, and a
series of R,â-unsaturated aldehydes (Table 1). Initial investigations
revealed that the (2S,5S)-5-benzyl-2-tert-butyl-imidazolidinone cata-
lyst 2 (10 mol %, CH2Cl2) promotes the addition of N,N-dimethyl-
3-anisidine (1a) and N-phenyl pyrrolidine (1b) to crotonaldehyde
with high levels of enantioselectivity (entries 1 and 2, 70-86%
yield, 87-89% ee). As revealed in Table 1, variation in the steric
contribution of the olefin substituent (X ) Me, Et, CH2OBz, entries
1-5) is possible without substantial loss in yield or enantiocontrol
(68-89% yield, 87-92% ee). There appears to be broad scope in
the electronic nature of the R,â-unsaturated aldehyde component.
For example, the reaction can accommodate enals that do not readily
participate in iminium formation (entry 6, X ) CO2Me, 90% yield,
92% ee), as well as aldehydes that provide stable iminium
intermediates (entry 7, X ) Ph, 82% yield, 84% ee). A variety of
* Corresponding author. E-mail: dmacmill@caltech.edu.
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J. AM. CHEM. SOC. 2002, 124, 7894-7895
10.1021/ja025981p CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Organocatalyzed Alkylation of Methyl 4-Oxobutenoate
with Representative Anilines
organocatalytic alkylations, it is important to note that (i) the sense
of asymmetric induction observed in all cases was readily anticipa-
ted by the previously described model9b and (ii) all of the alkylations
described herein were performed under an aerobic atmosphere, using
wet solvents and an inexpensive bench stable catalyst.
Last, we have recently developed a new sequence for the direct
deamination of N,N-dialkyl aniline rings. As revealed in eq 2,
treatment of aniline 4 with methyl iodide followed by exposure of
the resulting quaternary amine to reductive conditions provides the
parent aromatic system 5 in excellent yield. Importantly, this
operationally simple protocol effectively enables dialkylanilines to
be employed as benzene surrogates in this new organocatalytic
alkylation strategy.
In summary, we have further established iminium catalysis as a
valuable strategy for asymmetric synthesis in the context of
enantioselective benzene alkylations. Further studies to determine
the utility of amine catalyst 2 are underway.
a Ratios determined by chiral HPLC analysis of corresponding alcohol
after NaBH4 reduction. b Absolute configuration assigned by chemical
correlation. c Using catalyst 2 (20 mol % amine, 15 mol % HCl).
Acknowledgment. Financial support was provided by Astra-
Zeneca, GlaxoSmithKline, Johnson and Johnson, Materia, Merck
Research Laboratories, Research Corporation (Cottrell Scholarship)
and Roche Biosciences. We also thank Great Lakes for their
generous donation of amino acids.
Table 3. Effect of Catalyst Loading on Organocatalyzed
Alkylations
Supporting Information Available: Experimental procedures,
structural proofs, and spectral data for all new compounds (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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a NR2 ) 1-pyrrolidino. b Ratios determined by chiral HPLC.
and Suzuki couplings12-13). As expected, subambient temperatures
(-10 to -20 °C) provide optimal levels of asymmetric induction
(91-98% ee); however, alkylations conducted at room temperature
provide operationally convenient reaction times without significant
loss in enantioselectivity (e.g., entries 1 and 2, -10 °C, 96% ee,
48 h; 20 °C, 94% ee, 5 h). It should be noted that only products
arising from regioselective alkylation of the aniline para position
were observed throughout this study.
The effect of catalyst loading on reaction efficiency has been
evaluated (Table 3). While 10 mol % of imidazolidinone 2 was
routinely employed in this investigation, it appears that catalyst
loadings as low as 1 mol % provide useful levels of enantioselec-
tivity (10 mol % 2, 95% ee; 1 mol % 2, 88% ee). Preliminary kinetic
studies have revealed that the observed change in reaction rate as
a function of catalyst loading is consistent with second-order kinetics
in the amine‚HCl component. To demonstrate preparative utility,
the addition of N-phenyl pyrrolidine to methyl 4-oxobutenoate was
performed on a 50 mmol scale with 2 mol % of catalyst 2 (240
mg) to afford 12.2 g (97% yield) of the aniline adduct (R)-3 in
92% ee (87% yield, 96% ee after recrystallization).
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With regard to the synthetic and operational advantages of these
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