Iridium-catalyzed anti-diastereo- and enantioselective carbonyl (α-trifluoromethyl)allylation from the alcohol or aldehyde oxidation level

Article abstract of DOI:10.1002/anie.201008296

A flourish of fluorine: Exposure of α-trifluoromethyl allyl benzoate to alcohols in the presence of an ortho-cyclometalated iridium catalyst results in the generation of aldehyde-allyliridium intermediates to form enantiomerically enriched products of anti-(α-trifluoromethyl)allylation. An identical set of products is obtained from aldehydes under related transfer hydrogenation conditions employing isopropyl alcohol as terminal reductant. Copyright

Full text of DOI:10.1002/anie.201008296

DOI: 10.1002/anie.201008296
Enantioselective Allylation
Iridium-Catalyzed anti-Diastereo- and Enantioselective Carbonyl
(a-Trifluoromethyl)allylation from the Alcohol or Aldehyde Oxidation
Level**
Xin Gao, Yong Jian Zhang, and Michael J. Krische*
It is estimated that 20% of approved pharmaceutical agents
and 30–40% of commercially available agrochemicals contain
one or more fluorine atoms.[1a,b] Additionally, in 2006, 80% of
the small-molecule drugs entering the market were estimated
to contain one or more chiral centers.[1c,2] These facts under-
score the importance of developing enantioselective methods
for the preparation of organofluorine compounds.[3,4] Toward
this end, highly enantioselective nucleophilic trifluoromethy-
lations of aldehydes and ketones have been developed.[3a,e,4]
Nucleophilic (a-trifluoromethyl)allylation might also serve to
establish absolute stereochemistry at CF3-bearing carbon
centers.[5] Yet, despite persistent efforts aimed at the develop-
ment of asymmetric carbonyl allylation protocols,[6] enantio-
selective carbonyl (a-trifluoromethyl)allylation remains an
in related (a-trimethylsilyl)allylations,[8k] the presence of
water (200 mol%) improved conversion and suppressed
byproduct formation, including formation of transesterifica-
tion products. The stoichiometry of base (Na2CO3 or K3PO4)
and water are adjusted such that the benzoic acid generated
over the course of the reaction is neutralized, yet transesteri-
fication is suppressed. At this point, an assay of chiral ligands
was undertaken and it was found that the iridium complex
modified by (R)-Cl,MeO-BIPHEP, designated “(R)-I”, pro-
vides the highest levels of enantiomeric enrichment. Thus,
upon exposure of primary alcohols 1a–1i to a-trifluoromethyl
allyl benzoate (200 mol%) in the presence of (R)-I, Na2CO3
(100 mol%), and water (200 mol%) in THF (0.2m) at 708C,
the desired products of (a-trifluoromethyl)allylation 3a–3i
were generated in moderate to good yields with high levels
anti-diastereo- and enantioselectivity (Table 1). Notably, in
the presence of isopropyl alcohol, but under otherwise
unmet challenge.[5,6] Here, under the conditions of C C bond
À
forming transfer hydrogenation,[7] we report the first exam-
ples of enantioselective carbonyl (a-trifluoromethyl)allyla-
tion: a process in which carbonyl addition occurs with equal
facility from the alcohol or aldehyde oxidation level.
Our approach takes advantage of carbonyl allylation
protocols recently developed in our laboratory, wherein
primary alcohol dehydrogenation triggers reductive genera-
tion of allyliridium nucleophiles, enabling carbonyl allylation
from the alcohol oxidation level.[7,8] In initial experiments,
carbonyl (a-trifluoromethyl)allylation was attempted using
the ortho-cyclometalated catalyst generated in situ from
[{Ir(cod)Cl}2] (cod = cyclooctadienyl), various 4-substituted
3-nitrobenzoic acids, BIPHEP (2,2’-bis(diphenylphosphino)-
biphenyl), and a-trifluoromethyl allyl benzoate in THF (1m).
Table 1: anti-Diastereo- and enantioselective carbonyl (a-trifluoromethy-
l)allylation from the alcohol oxidation level.[a]
=
1a, R=6-Br-2-Pyr
1d, R=(CH2)2Ph
1g, R=CH2OBn
1b, R=2-Furyl
1c, R=CH CHPh
1e, R=(CH2)7Me
1h, R=(CH2)2OBn
1 f, R=c-C6H11
1i, R=(CH2)2NHBoc
À
However, C C coupling products were not observed in
reactions involving in situ catalyst generation. Rather,
products of transesterification, the benzoates derived from
alcohols 1, were obtained. Eventually, it was found that
transesterification is suppressed for reactions employing the
isolated p-allyl iridium C,O-benzoate modified by BIPHEP
and 4-cyano-3-nitrobenzoic acid in THF (0.2m). As observed
60% yield, ꢀ20:1 d.r. 70% yield, ꢀ20:1 d.r. 60% yield, ꢀ20:1 d.r.
95% ee, 3a[b]
94% ee, 3b 87% ee, 3c
61% yield, ꢀ20:1 d.r. 64% yield, ꢀ10:1 d.r. 77% yield, ꢀ20:1 d.r.
94% ee, 3d
92% ee, 3e
91% ee, 3 f[b]
[*] X. Gao, Dr. Y. J. Zhang, Prof. M. J. Krische
University of Texas at Austin
Department of Chemistry and Biochemistry
1 University Station–A5300, Austin, TX 78712-1167 (USA)
Fax: (+1)512-471-8696
57% yield, ꢀ20:1 d.r. 63% yield, 10:1 d.r.
99% ee, 3g 94% ee, 3h
73% yield, ꢀ20:1 d.r.
96% ee, 3i[b]
E-mail: mkrische@mail.utexas.edu
[**] Acknowledgements is made to the Robert A. Welch Foundation (F-
0038) and the NIH-NIGMS (RO1-GM069445). Y.J.Z. acknowledges
partial financial support from Shanghai Jiao Tong University.
[a] Yields are of isolated material. Diastereoselectivity was determined by
1H NMR analysis of crude reaction mixtures. Enantiomeric excess was
determined by chiral stationary phase HPLC analysis. See Supporting
Information for further details. [b] K3PO4 (100 mol%), H2O (500 mol%),
THF (1.0m).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201008296.
Angew. Chem. Int. Ed. 2011, 50, 4173 –4175
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4173

Communications
Table 2: anti-Diastereo- and enantioselective carbonyl (a-trifluorometh-
yl)allylation from the aldehyde oxidation level.[a]
equivalent conditions, an identical set of adducts 3a–3i are
generated from aldehydes 2a–2i with similar levels of relative
and absolute stereocontrol (Table 2). Superstoichiometric
loadings of a-trifluoromethyl allyl benzoate (200 mol%) are
required to offset competing protonolysis of the transient
allyliridium intermediate.
Exposure of optically enriched alcohol 1j to standard
conditions for anti-diastereo- and enantioselective (a-trifluor-
omethyl)allylation employing (R)-I as the precatalyst produ-
ces compound 3j as a single stereoisomer, as determined by
1H and 19F NMR analysis. Similarly, using (S)-I as the
precatalyst, alcohol 1j is converted into the isomeric adduct
iso-3j as a single stereoisomer, as determined by 1H and
19F NMR analysis. Using the catalyst modified by the achiral
ligand, BIPHEP, compounds 3j and iso-3j are produced in a
1:1.5 ratio, respectively. These data establish high levels of
catalyst-directed stereoselectivity.[9] Exposure of compound
3i to ozone followed by NaBH4-mediated decomposition of
the ozonide produces 1,3-diol 4i in 94% yield of isolated
product. The primary alcohol of diol 4i was converted into the
primary p-toluenesulfonate 5i in 99% yield of isolated
product. Conversion of p-toluenesulfonate 5i into piperidine
6 was accomplished in analogy to an established procedure.[10]
Alternatively, elimination of p-toluenesulfonate 5i followed
by hydrogenation of the resulting terminal olefin provides the
syn-1,1,1-trifluoroisopropyl secondary alcohol 7 as a single
=
2a, R=6-Br-2-Pyr
2d, R=(CH2)2Ph
2g, R=CH2OBn
2b, R=2-Furyl
2e, R=(CH2)7Me
2h, R=(CH2)2OBn
2c, R=CH CHPh
2 f, R=c-C6H11
2i, R=(CH2)2NHBoc
72% yield, ꢀ20:1 d.r. 69% yield, ꢀ20:1 d.r. 67% yield, ꢀ20:1 d.r.
95% ee, 3a[b]
95% ee, 3b
89% ee, 3c
65% yield, ꢀ20:1 d.r. 69% yield, 10:1 d.r.
94% ee, 3d 92% ee, 3e
81% yield, ꢀ20:1 d.r.
93% ee, 3 f[b]
55% yield, ꢀ20:1 d.r. 67% yield, 10:1 d.r.
99% ee, 3g 93% ee, 3h
70% yield, ꢀ20:1 d.r.
97% ee, 3i[b]
[a] As described for Table 1.
1
diastereomer, as determined by H and 19F NMR
analysis (Scheme 1).[11]
In summary, we report the first protocol for
anti-diastereo- and enantioselective carbonyl (a-
trifluoromethyl)allylation. Notably, asymmetric
carbonyl addition is possible from the alcohol
oxidation level, bypassing discrete alcohol oxida-
tion and the use of stoichiometric organometallic
reagents. Future studies will focus on the develop-
À
ment of related C C couplings of amines.
Received: December 31, 2010
Revised: February 28, 2011
Published online: April 6, 2011
Keywords: allylation · enantioselectivity ·
.
iridium complexes · transfer hydrogenation ·
trifluoromethyl
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