Synthesis of chiral tertiary trifluoromethyl alcohols by asymmetric nitroaldol reaction with a Cu(ii)-bisoxazolidine catalyst

Article abstract of DOI:10.1039/c0cc02378g

A highly enantioselective and diastereoselective copper(ii)-bisoxazolidine catalyzed nitroaldol reaction with aliphatic and aromatic trifluoromethyl ketones is described.

Full text of DOI:10.1039/c0cc02378g

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Synthesis of chiral tertiary trifluoromethyl alcohols by asymmetric
nitroaldol reaction with a Cu(II)-bisoxazolidine catalystw
Hanhui Xu and Christian Wolf*
Received 5th July 2010, Accepted 23rd August 2010
DOI: 10.1039/c0cc02378g
A highly enantioselective and diastereoselective copper(II)-
bisoxazolidine catalyzed nitroaldol reaction with aliphatic and
aromatic trifluoromethyl ketones is described.
During recent years, the nitroaldol reaction has found wide-
Fig. 1 Structure of bisoxazolidine (+)-1.
spread attention and many asymmetric methods using
aldehydes as substrates in the presence of excess of nitromethane
or its homologues have been developed.1 This reaction
provides synthetically useful b-hydroxy nitroalkanes that
can be readily transformed to b-amino alcohols, aziridines,
a-hydroxy carboxylic acids and other complex target compounds.2
Asymmetric Henry reaction protocols typically involve a
chiral catalyst derived from Co(II),3 Mg(II),4 Zn(II),5 Cr(III),6
Cu(I),7 Cu(II)8 or rare earth metals.9 The activation of the
prenucleophilic nitroalkane is often accomplished with excess
of dimethyl zinc for deprotonation or through formation of
silyl nitronates,10 and superior results are generally obtained
with aromatic aldehydes compared to aliphatic substrates.11 In
contrast to the wealth of asymmetric nitroaldol reactions with
aldehydes, relatively few examples with ketones are known.
In several cases, keto esters have been transformed to chiral
b-nitro a-hydroxy esters which are important precursors for
functionalized b-lactams and other useful building blocks.12
Despite the well known importance of chiral trifluoromethyl-
derived tertiary alcohols, which are vital structural motifs in
anticonvulsants, anesthetics, Merck’s anti-HIV agent efavirenz
and other pharmaceuticals,13 few enantioselective nucleophilic
additions to trifluoromethyl ketones have been reported.14
Examples of nitroaldol reactions with trifluoromethyl ketones
are scarce and only one method based on Lewis acid catalysis
producing tert-2-nitro 1-trifluoromethyl alcohols in 50–93%
yield and 67–96% ee has been published to date.15 This
protocol requires 25 mol% of both a La(Binolam)3 complex
and proton sponge at À40 1C and the reaction is generally
completed after 4 days. Alternatively, a cupreine-derived
catalyst has been used to generate a limited number of 1-tri-
fluoromethyl alkohols in high yields and ee within 48 hours.16
To the best of our knowledge, substrates carrying ester,
alkoxy, thioalkoxy or other functional groups that often
diminish yields and asymmetric induction as well as nitro-
methane homologues, which would give rise to two chiral
centers, have not been introduced to the asymmetric nitroaldol
reaction with trifluoromethyl ketones to date. As a result, the
formation of chiral alcohols bearing a trifluoromethyl group
still relies predominantly on the cinchona alkaloid catalyzed
addition of (trifluoromethyl)trimethylsilane, CF3TMS, to aryl
ketones followed by TBAF promoted cleavage of the inter-
mediate silyl ethers.17 Alternatively, tertiary trifluoromethyl
alcohols have been prepared via Sharpless dihydroxylation,18
as well as Friedel–Crafts,19 ene20 and aldol reactions.21
A few years ago, we introduced bisoxazolidine 1 to asymmetric
catalysis and showed several applications of this new class of
chiral ligands (Fig. 1).22 We realized that 1 effectively catalyzes the
enantioselective alkynylation of aromatic and aliphatic aldehydes,
producing propargylic alcohols in high yield and ee.23 This ligand
was also successfully applied in the alkylation of aldehydes with
Me2Zn and Et2Zn.24 More recently, we employed bisoxazolidine
(+)-1 in the asymmetric nitroaldol reaction utilizing either several
equivalents of dimethylzinc in apolar solvents or catalytic
amounts of copper(I) acetate in ethanol.25 In both cases, excellent
yields and ee’s were obtained with a wide range of substrates, and
with opposite sense of asymmetric induction.
In light of the efficacy of our bisoxazolidine ligand in
enantioselective additions of several nucleophiles to aldehydes,
we decided to explore the feasibility of asymmetric catalysis
with trifluoromethyl ketones. To our surprise, the combina-
tion of 1 and CuOAc, which gave excellent results in the
nitroaldol reaction with aldehydes, furnished racemic product
mixtures when trifluoromethyl ketones were used. After initial
screening of reaction conditions, we found that 10 mol% of a
complex formed from (+)-1 and Cu(OTf)2 catalyzes the
reaction between 1,1,1-trifluoroacetophenone and nitromethane
with promising asymmetric induction at room temperature.
Using THF as solvent and 20 mol% of triethylamine, we
obtained (S)-1,1,1-trifluoro-3-nitro-2-phenyl-propan-2-ol, 2,
in 96% yield and 50% ee (Scheme 1).
We then screened various parameters including metal salts
and solvents and carefully optimized catalyst loading, effects
of amine additives, and temperature. We were pleased to find
Department of Chemistry, Georgetown University, Washington,
DC 20057, USA. E-mail: cw27@georgetown.edu;
Fax: +1 202 687 6209; Tel: +1 202 687 3468
w Electronic supplementary information (ESI) available: Synthetic
procedures, NMR spectra, HPLC chromatograms. CCDC 783420.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c0cc02378g
Scheme 1 Asymmetric nitroaldol reaction between 1,1,1-trifluoro-
acetophenone and nitromethane in the presence of 10 mol% of 1 and
Cu(OTf)2 at room temperature.
c
8026 Chem. Commun., 2010, 46, 8026–8028
This journal is The Royal Society of Chemistry 2010

View Article Online
Table 1 Effect of amine additives on the asymmetric nitroaldol
reaction with 1,1,1-trifluoroacetophenone
Table 2 Scope of the asymmetric nitroaldol reaction
Time/ Yield ee
(%)b (%)c
ha
Entry
1
Amine additive
Yield (%)a
91
ee (%)
20
Entry Substrate
1
Product
24
92
91
86 (S)
84 (S)
2
85
69
2
24
3
4
5
6
92
93
90
86
40
29
56
60
3
4
5
6
7
8
9
24
24
24
24
24
24
24
89
93
91
95
86
90
94
80 (S)
83 (S)
84 (S)
86 (S)
76 (S)
84 (S)
84 (S)
7
91
58
8
90
89
92
96
77
74
72
70
9
10
11
12
92
86
13
14
93
82
94
59
21
70
15
10
11
24
91
80 (S)
a
Isolated yields.
48
36
92
87
75 (S)
88 (S)
that reduction of the reaction temperature to À10 1C gave 2 in
96% yield and 70% ee within 24 hours. Further analysis
revealed a pronounced effect of the amine additive on the
asymmetric induction (Table 1). Replacement of the catalytic
amounts of triethylamine with other secondary or tertiary
amines had minor effects on yields. However, alcohol 2
was obtained in poor ee upon introduction of pyrrolidine,
piperidine and TMEDA (entries 1, 4 and 14). The highest
asymmetric induction was observed when 20 mol% of tributyl-
amine were used (entry 12). In this case, 2 was isolated in 92%
yield and 86% ee.
12
13
14
24
24
24
81
89
90
80 (S)
91 (S)
82 (S)
15
We then employed a wide range of trifluoromethyl ketones in
the optimized Henry reaction to evaluate the substrate scope
(Table 2). Eleven aromatic substrates were tested and the
corresponding tertiary trifluoromethyl alcohols were isolated
in up to 95% yield and 86% ee. Both electron-rich and electron-
poor benzaldehyde derivatives gave excellent results, and
methoxy, methylthio, ester and nitrile groups are well tolerated
in this reaction (entries 7–9 and 11). Similarly, aliphatic
substrates including ethyl 6,6,6-trifluoro-5-oxohexanoate,
which was converted to alcohol 16 in 90% yield and 82% ee,
can be used (entries 12–15).26
a
All reactions were performed on a 1 mmol scale using 10 mol% of
(+)-1, 10 mol% of Cu(OTf)2, 20 mol% n-Bu3N and 10 equiv. of
b
c
nitromethane in 0.35 mL of THF. Isolated yields. The ee’s were
determined by chiral HPLC on Chiralcel OD and Chiralcel OJ. The
absolute configuration was determined by comparison of the elution
order as described in ref. 15a or by analogy.
A major challenge in asymmetric nitroaldol additions is to
maintain stereocontrol when higher homologues of nitro-
methane are used. The introduction of nitroalkanes other than
nitromethane is important because it provides instant access to
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 8026–8028 8027

View Article Online
J. Am. Chem. Soc., 2003, 125, 12692; (c) S. Selvakumar,
D. Sivasankaran and V. K. Singh, Org. Biomol. Chem., 2009, 7,
3156; (d) M. Zielinska-Blajet and J. Skarzewski, Tetrahedron:
Asymmetry, 2009, 20, 1992.
9 (a) J. Sasai, T. Suzuki, S. Arai, T. Arai and M. Shibasaki, J. Am.
Chem. Soc., 1992, 114, 4418; (b) H. Sasai, N. Zuzuki, K. Itoh,
T. Tanaka, K. Date, K. Okamura and M. Shibasaki, J. Am. Chem.
Soc., 1993, 115, 10372; (c) Y. Sohtome, Y. Kato, S. Handa,
N. Aoyama, K. Nagawa, S. Matsunaga and M. Shibasaki, Org.
Lett., 2008, 10, 2231; (d) T. Nitabaru, N. Kumagai and
M. Shibasaki, Tetrahedron Lett., 2008, 49, 272.
10 (a) K. V. Risgaard, K. A. Gothelf and K. A. Jorgensen, Org.
Biomol. Chem., 2003, 1, 153; (b) T. Ooi, K. Doda and K. Maruoka,
J. Am. Chem. Soc., 2003, 125, 2054.
11 (a) C. Palomo, M. Oiarbide and A. Mielgo, Angew. Chem., Int.
Ed., 2004, 43, 5442; (b) M. Colak and N. Demirel, Tetrahedron:
Asymmetry, 2008, 19, 635; (c) T. Arai, N. Yokoyama and
A. Yanagisawa, Chem.–Eur. J., 2008, 14, 2052.
Scheme 2 Nitroaldol reaction with nitroethane and X-ray structure
of 17.
multifunctional building blocks carrying two chiral centers. Since
this had not been accomplished with trifluoromethyl ketones, we
decided to apply our protocol to the reaction between 1,1,1-
trifluoroacetophenone and nitroethane (Scheme 2). We found
that this reaction occurs with excellent diastereoselectivity and
without compromising the yields and ee’s obtained with nitro-
methane. The tertiary alcohol 17 was produced in 94% yield,
91% ee and 89% de. Similarly, 18–20 were produced with high
yields and stereoselectivities. Careful evaporation of a scalemic
mixture of 17 in diethyl ether gave a single crystal and X-ray
analysis confirmed the relative configuration (see ESIw).
In summary, we have demonstrated that bisoxazolidine 1 is
an effective catalyst in the Cu(II)-catalyzed asymmetric nitroaldol
reaction of trifluoromethyl ketones. A wide range of tertiary
trifluoromethyl alcohols derived from aliphatic and aromatic
substrates were obtained in high yield and enantiomeric excess.
This procedure has several merits including simplicity of
operation, relatively short reaction times and wide functional
group tolerance. In particular, the excellent stereocontrol
observed for the unprecedented reaction with nitroethane
extends the scope of this reaction. The use of bisoxazolidines
in other asymmetric reactions is currently investigated in our
laboratory.
12 (a) C. Christensen, K. Juhl and K. A. Jørgensen, Chem. Commun.,
2001, 2222; (b) D.-M. Du, S.-F. Lu, T. Fang and J. Xu, J. Org.
Chem., 2005, 70, 3712; (c) H. Li, B. Wang and L. Deng, J. Am.
Chem. Soc., 2006, 128, 732; (d) S. U. Pandya, R. S. Dickins and
D. Parker, Org. Biomol. Chem., 2007, 5, 3842; (e) B. Qin, X. Xiao,
X. Liu, J. Huang, Y. Wen and X. Feng, J. Org. Chem., 2007, 72,
9323; (f) G. Blay, V. Hernandez-Olmos and J. R. Pedro, Org.
Biomol. Chem., 2008, 6, 468; (g) K. Takada, N. Takemura, K. Cho,
Y. Sohtome and K. Nagasawa, Tetrahedron Lett., 2008, 49, 1623;
(h) A. Bulut, A. Aslant and O. Dogan, J. Org. Chem., 2008, 73,
7373.
13 (a) J. W. Corbett, S. S. Ko, J. D. Rodgers, L. A. Gearhart,
N. A. Magnus, L. T. Bacheler, S. Diamond, S. Jeffrey,
R. M. Klabe, B. C. Cordova, S. Garber, K. Logue, G. L. Trainor,
P. S. Anderson and S. K. Erickson-Vittanen, J. Med. Chem., 2000,
43, 2019; (b) I. Choudhury-Mukherjee, H. A. Schenck, S. Cechova,
T. N. Pajewski, J. Kapur, J. Ellena, D. S. Cafiso and M. L. Brown,
J. Med. Chem., 2003, 46, 2494; (c) H. A. Schenck, P. W. Lenkowski,
I. Choudhury-Mukherjee, S.-H. Ko, J. P. Stables, M. K. Patel and
M. L. Brown, Bioorg. Med. Chem., 2004, 12, 979; (d) Y. Xue,
E. Chao, W. J. Zuercher, T. M. Willson, J. L. Collins and
M. R. Redinbo, Bioorg. Med. Chem., 2007, 15, 2156.
14 (a) S. L. X. Martina, R. B. C. Jagt, J. G. de Vries, B. L. Feringa
and A. J. Minnaard, Chem. Commun., 2006, 4093; (b) R. Motoki,
D. Tomita, M. Kanai and M. Shibasaki, Tetrahedron Lett., 2006,
47, 8083; (c) R. Motoki, M. Kanai and M. Shibasaki, Org. Lett.,
2007, 9, 2997; K. Yearick and C. Wolf, Org. Lett., 2008, 10, 3915.
15 (a) F. Tur and J. M. Saa, Org. Lett., 2007, 9, 5079; (b) J. M. Saa,
F. Tur and J. Gonzalez, Chirality, 2009, 21, 836. In addition, a single
case of a nitroaldol reaction with a-trifluoromethyl pyruvate has
been reported to proceed with 36% yield and 13% ee: see ref. 12b.
16 M. Bandini, R. Sinisi and A. Umani-Ronchi, Chem. Commun.,
2008, 4360.
17 (a) K. Iseki, T. Nagai and Y. Kobayashi, Tetrahedron Lett., 1994, 35,
3137; (b) K. Mikami, Y. Itoh and M. Yamanaka, Chem. Rev., 2004,
104, 1; (c) J.-A. Ma and D. Cahard, Chem. Rev., 2004, 104, 6119.
18 Y. L. Bennani, K. P. M. Vanhessche and B. Sharpless, Tetra-
hedron: Asymmetry, 1994, 5, 1473.
Funding from the National Science Foundation
(CHE-0848301) is gratefully acknowledged.
Notes and references
1 For reviews on the asymmetric Henry reaction, see: (a) J. Boruwa,
N. Gogoi, P. P. Saikia and N. C. Barua, Tetrahedron: Asymmetry,
2006, 17, 3315; (b) C. Palomo, M. Oiarbide and A. Laso, Eur. J.
Org. Chem., 2007, 2561.
2 (a) B. M. Trost, V. S. C. Yeh, H. Ito and N. Bremeyer, Org.
Lett., 2002, 4, 2621; (b) M. Bandini, F. Piccinelli, S. Tommasi,
A. Umani-Ronchi and C. Ventrici, Chem. Commun., 2007, 616.
3 Y. Kogami, T. Nakajima, T. Ikeno and T. Yamada, Synthesis,
2004, 1947.
19 (a) W. Zhuang, N. Gathergood, R. G. Hazell and K. A. Jørgensen,
J. Org. Chem., 2001, 66, 1009; (b) M. P. A. Lyle, N. D. Draper and
P. D. Wilson, Org. Lett., 2005, 7, 901; (c) B. Torok, M. Abid,
G. London, J. Esquibel, M. Torok, S. C. Mhadgut, P. Yan and
G. K. S. Prakash, Angew. Chem., Int. Ed., 2005, 44, 3086.
20 K. Mikami, H. Kakuno and K. Aikawa, Angew. Chem., Int. Ed.,
2005, 44, 7257.
4 B. M. Choudary, K. V. S. Ranganath, U. Pal, M. L. Kantam and
B. Sreedhar, J. Am. Chem. Soc., 2005, 127, 13167.
5 (a) B. M. Trost and V. S. C. Yeh, Angew. Chem., Int. Ed., 2002, 41,
861; (b) C. Palomo, M. Oiarbide and A. Laso, Angew. Chem., Int. Ed.,
2005, 44, 3881; (c) H. Y. Kim and K. Oh, Org. Lett., 2009, 11, 5682.
6 R. Kowalczyk, P. Kwiatkowski, J. Skarzewski and J. Jurczak,
J. Org. Chem., 2009, 74, 753.
21 (a) N. Gathergood, K. Juhl, T. B. Poulsen, K. Thordrup and
K. A. Jørgensen, Org. Biomol. Chem., 2004, 2, 1077;
(b) X.-J. Wang, Y. Zhao and J.-T. Liu, Org. Lett., 2007, 9, 1343.
22 This ligand is commercially available at Strem (catalogue no.
07-0488), US 20070265255A1 patent pending.
7 (a) Y. Xiong, F. Wang, X. Huang, Y. Wen and X. Feng, Chem.–Eur. J.,
2007, 13, 829; (b) T. Arai, R. Takashita, Y. Endo, M. Watanabe and
A. Yanagisawa, J. Org. Chem., 2008, 73, 4903.
8 Selected examples: (a) C. Christensen, K. Juhl, R. G. Hazell and
K. A. Jørgensen, J. Org. Chem., 2002, 67, 4875; (b) D. A. Evans,
D. Seidel, M. Rueping, H. W. Lam, J. T. Shaw and C. W. Downey,
23 C. Wolf and S. Liu, J. Am. Chem. Soc., 2006, 128, 10996.
24 S. Liu and C. Wolf, Org. Lett., 2007, 9, 2965.
25 (a) S. Liu and C. Wolf, Org. Lett., 2008, 10, 1831; (b) K. Yearick
Spangler and C. Wolf, Org. Lett., 2009, 11, 4724.
26 Low yields and ee’s were obtained with ortho-substituted trifluoro-
methyl ketones.
c
8028 Chem. Commun., 2010, 46, 8026–8028
This journal is The Royal Society of Chemistry 2010