Catalytic enantioselective addition of diethylzinc to trifluoromethyl ketones

Article abstract of DOI:10.1021/ol8015012

(Figure Presented) A procedure for nucleophilic addition of diethylzinc to trifluoramethyl ketones was developed. The TMEDA-catalyzed method converts aromatic substrates to the corresponding 2-aryl-1,1,1-trifluorobutan-2-ols in up to 99% yield, and it is also applicable to less reactive aliphatic ketones if stoichiometric ligand amounts are employed. The first asymmetric variant producing tertiary alcohols with up to 61% ee when TBOX is used as catalyst is described.

Full text of DOI:10.1021/ol8015012

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3915-3918
Catalytic Enantioselective Addition of
Diethylzinc to Trifluoromethyl Ketones
Kimberly Yearick and Christian Wolf*
Department of Chemistry, Georgetown UniVersity, Washington, D.C. 20057
cw27@georgetown.edu
Received July 2, 2008
ABSTRACT
A procedure for nucleophilic addition of diethylzinc to trifluoromethyl ketones was developed. The TMEDA-catalyzed method converts aromatic
substrates to the corresponding 2-aryl-1,1,1-trifluorobutan-2-ols in up to 99% yield, and it is also applicable to less reactive aliphatic ketones
if stoichiometric ligand amounts are employed. The first asymmetric variant producing tertiary alcohols with up to 61% ee when TBOX is used
as catalyst is described.
Numerous examples of asymmetric additions of diethylzinc
to aldehydes, ketones, and imine analogues have been
reported to date, but to the best of our knowledge, this
otherwise extensively studied reaction has not been success-
fully applied to trifluoromethyl ketones.1 Despite the sig-
nificance of trifluoromethyl-substituted tertiary alcohols,
which exhibit an important subunit in several pharmaceuticals
including anticonvulsants, anesthetics, and Merck’s anti-HIV
agent efavirenz,2 enantioselective carbon-carbon bond for-
mation with trifluoromethyl ketones and organometallic
reagents has been barely developed and is restricted to
nucleophiles devoid of a ꢀ-hydrogen.3 As a result, the
synthesis of chiral trifluoromethyl-derived tertiary alcohols
mostly relies on the asymmetric cinchona alkaloid-catalyzed
addition of (trifluoromethyl)trimethylsilane, CF3TMS, to aryl
ketones followed by TBAF-promoted cleavage of the
intermediate silyl ethers (Scheme 1).4 Noteworthy, catalytic
(1) Selected examples of asymmetric 1,2-additions of diethylzinc to
aldehydes: (a) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem.
Soc. 1986, 108, 6071–6072. (b) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa,
K. J. Am. Chem. Soc. 1987, 109, 7111–7115. (c) Kitamura, M.; Okada, S.;
Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028–4036. (d) Schmidt,
B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1991, 30, 1321–1323. (e)
Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am. Chem. Soc. 1998, 120,
9800–9809. (f) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757–824. (g) Wolf,
C.; Francis, C. J.; Hawes, P. A.; Shah, M. Tetrahedron: Asymmetry 2002,
13, 1733–1741. (h) Wolf, C.; Hawes, P. A. J. Org. Chem. 2002, 67, 2727–
2729. (i) Kozlowski, M. C.; Dixon, S. L.; Panda, M.; Lauri, G. J. Am. Chem.
Soc. 2003, 125, 6614–6615. (j) Liu, S.; Wolf, C. Org. Lett. 2007, 9, 2965–
2968. Selected examples of asymmetric 1,2-additions of diethylzinc to
ketones: (k) DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2002, 4, 3781–
3784. (l) Garcia, C.; Larochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc.
2002, 124, 10970–10971. (m) DiMauro, E. F.; Kozlowski, M. C. J. Am.
Chem. Soc. 2002, 124, 12668–12669. (n) Ramon, D.; Yus, M. Angew.
Chem., Int. Ed. 2004, 43, 284–287. (o) Jeon, S.-J.; Li, H.; Walsh, P. J.
J. Am. Chem. Soc. 2005, 127, 16416–16425. (p) Hui, A.; Zhang, J.; Fan,
J.; Wang, Z. Tetrahedron: Asymmetry 2006, 17, 2101–2107. (q) Forrat,
V. J.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry 2006, 17, 2054–
2058. (r) Forrat, V. J.; Prieto, O.; Ramon, D. J.; Yus, M. Chem.-Eur. J.
2006, 12, 4431–4445. Recent reviews on nucleophilic additions to imines,
see: (s) Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873–888.
(t) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541–2569. (u)
Ferraris, D. Tetrahedron 2007, 63, 9581–9597.
(2) (a) Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Gearhart, L. A.; Magnus,
N. A.; Bacheler, L. T.; Diamond, S.; Jeffrey, S.; Klabe, R. M.; Cordova,
B. C.; Garber, S.; Logue, K.; Trainor, G. L.; Anderson, P. S.; Erickson-
Vittanen, S. K. J. Med. Chem. 2000, 43, 2019–2030. (b) Choudhury-
Mukherjee, I.; Schenck, H. A.; Cechova, S.; Pajewski, T. N.; Kapur, J.;
Ellena, J.; Cafiso, D. S.; Brown, M. L. J. Med. Chem. 2003, 46, 2494–
2501. (c) Schenck, H. A.; Lenkowski, P. W.; Choudhury-Mukherjee, I.;
Ko, S.-H.; Stables, J. P.; Patel, M. K.; Brown, M. L. Bioorg. Med. Chem.
2004, 12, 979–993. (d) Xue, Y.; Chao, E.; Zuercher, W. J.; Willson, T. M.;
Collins, J. L.; Redinbo, M. R. Bioorg. Med. Chem. 2007, 15, 2156–2166.
(3) (a) Martina, S. L. X.; Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.;
Minnaard, A. J. Chem. Commun. 2006, 4093–4095. (b) Motoki, R.; Tomita,
D.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2006, 47, 8083–8086. (c)
Motoki, R.; Kanai, M.; Shibasaki, M. Org. Lett. 2007, 9, 2997–3000. For
a catalytic enantioselective nitroaldol reaction of trifluoromethyl ketones,
see: (d) Tur, F.; Saa, J. M. Org. Lett. 2007, 9, 5079–5082.
10.1021/ol8015012 CCC: $40.75
Published on Web 08/08/2008
2008 American Chemical Society

Scheme 1
.
Asymmetric Addition of CF3TMS to Aromatic
Table 2. TMEDA-Catalyzed Addition of Et2Zn to
2,2,2-Trifluoroacetophenone, 6a
Ketones and Alternative Approach to Trifluoromethyl-Derived
Tertiary Alcohols Using Trifluoromethyl Ketones and
Diethylzinc
enantioselective synthesis of tertiary trifluoromethyl alcohols
has also been accomplished via Sharpless dihydroxylation,5
Friedel-Crafts acylation,6 ene reaction,7 and aldol reaction.8
Table 1. Screening of the Ligand-Catalyzed Nucleophilic
Addition of Et2Zn to 2,2,2-Trifluoroacetophenone, 6
a All reactions were performed on a 0.24 mmol scale using 5 mol % of
TMEDA and 1.2 equiv of Et2Zn in toluene at 10 °C unless otherwise noted.
b 5 °C. c -10 °C, 10 mol % of TMEDA. d -10 °C. e 5 °C, 10 mol % of
TMEDA. f 1 equiv of TMEDA and 2.4 equiv of Et2Zn.
amine, 2, N,N,N’,N’-tetramethyl ethylenediamine, 3, 1,2-
dimethoxyethane, 4, and morpholine, 5, in toluene at -10
°C indicated that this can be achieved with 3 equiv of Et2Zn
although the alkylation of 2,2,2-trifluoroacetophenone, 6,
appeared to be relatively slow and was accompanied by
substantial reduction unless TMEDA was used (Table 1).
In particular, ligands 1 and 4 did not favor the alkylation,
and more than 20% of 2,2,2-trifluoro-1-phenylethanol, 7, was
formed within 4 h (entries 2 and 5). Employing ligands 2
and 5 in the reaction showed little improvement. The desired
1,1,1-trifluoro-2-phenylbutan-2-ol, 8, was produced in low
yields, and the reduction was still significantly faster (entries
3 and 6). By contrast, the reaction outcome changed
dramatically in the presence of 10 mol % of TMEDA: 8
The lack of a method that allows direct alkylation of
trifluoromethyl ketones with organometallic reagents origi-
nates from the unique reactivity of these substrates. Unlike
the well-established nucleophilic additions of organozinc
reagents to aldehydes or other carbonyl functionalities,
trifluoromethyl ketones have been known to undergo pre-
dominant reduction upon addition of diethylzinc.9
We anticipated that activation of diethylzinc by bidentate
ligands 1-5 might favor carbon-carbon bond formation over
ꢀ-hydride elimination and subsequent reduction, thus provid-
ing a new entry toward the synthesis of trifluoromethyl-
derived tertiary alcohols. Initial screening of catalytic
amounts of ethylenediamine, 1, N,N’-dimethyl ethylenedi-
3916
Org. Lett., Vol. 10, No. 17, 2008

Table 4. TBOX-Catalyzed Addition of Et2Zn to
2,2,2-Trifluoroacetophenone, 6a
Figure 1. Structures of chiral ligands screened.
Table 3. Chiral Ligand Screening Resultsa
yield (%)
entry
ligand
time (h)
6
7
8
% ee
1
2
3
4
5
6
7
8
9b
4
10
4
1
10
23
1
2
12
0
10
1
2
10
76
0
0
0
0
0
21
63
0
21
13
60
80
94
97
80
0
99
98
88
99
99
0
13
97
3
1
0
14
5
6
10
11
12b
13
14
15
16
17
18
19c
20
21d
22c
23
24e
0.5
0.5
4
0
5
n/a
37
8
1
7
0.5
0.1
0.2
0.5
0.5
0.5
5
0.6
0.4
0.5
3
a All reactions were performed on a 0.24 mmol scale in toluene/hexanes
(1/3 v/v) using 10 mol % of TBOX and 1.2 equiv of Et2Zn at -35 °C
unless otherwise noted. b -78 °C. c 50 mol % of TBOX, 25 °C.
9
10
11
12
13
14
15
16
0
0
78
24
3
76
86
40
n/a
n.d.
0
n/a
n/a
n/a
(Table 2). Under these conditions, trifluoroacetophenone gives
1,1,1-trifluoro-2-phenylbutan-2-ol in 93% yield within 1 h (entry
1, Table 2). We found that this reaction furnishes a wide range
of tertiary alcohols in 81-99% yield, and ester, nitrile, nitro,
halo, and other aryl substituents are tolerated (entries 2-11).
Aliphatic substrates proved to be significantly less reactive and
required the use of stoichiometric amounts of TMEDA.
Nevertheless, 2-cyclohexyl-1,1,1-trifluorobutan-2-ol and 2-(cy-
clohexylmethyl)-1,1,1-trifluorobutan-2-ol were obtained in
82-84% yield (entries 12 and 13).
a All reactions were performed on a 0.24 mmol scale using 10 mol %
of the ligand and 1.2 equiv of Et2Zn at 5 °C in hexanes/toluene (1/1 v/v)
unless otherwise noted. b Hexanes. c Hexanes/THF (1/1). d -35 °C. e 25
°C, 1 equiv of Ti(Oi-Pr)4.
was obtained in 61% yield, while only 3% of the reduction
product 7 was isolated and 36% of the starting material was
recovered (entry 4, Table 1).
Further optimization of the catalyst loading, reaction tem-
perature, and amount of diethylzinc revealed that aromatic
trifluoromethyl ketones undergo fast ethylation in the presence
of 5-10 mol % of TMEDA and 1.2 equiv of Et2Zn at 10 °C
With a racemic method in hand, we decided to explore
an asymmetric variant. On the basis of the success with
TMEDA, chiral diamines and bisoxazolines as well as other
ligands that have proved to be very useful in asymmetric
Org. Lett., Vol. 10, No. 17, 2008
3917

additions of diethylzinc to carbonyl electrophiles were
screened (Figure 1).
In conclusion, we have developed the first general
procedure for ligand-catalyzed nucleophilic addition of
diethylzinc to trifluoromethyl ketones. A range of 2-aryl-
1,1,1-trifluorobutan-2-ols have been prepared in up to 99%
yield using 10 mol % of TMEDA to favor alkylation over
ꢀ-hydride elimination. The reaction of aliphatic substrates
proved more difficult and was found to require stoichiometric
ligand amounts. These findings provide a new route for
asymmetric synthesis of trifluoromethyl-derived tertiary
alcohols which are important components in many pharma-
ceuticals. Accordingly, we have introduced the first asym-
metric variant of this reaction. Screening of 16 chiral ligands
revealed that excellent yields and ee’s up to 61% can be
obtained with TBOX as catalyst.
Diamines 9-12 and bisoxazolines 15-18 and 21 proved
to effectively catalyze the formation of tertiary alcohol 8
which was obtained in 80-99% yield within 4 h albeit in
low ee’s (entries 1-4, 7-10, and 13, Table 3). The
competing reduction of 6 to 7 was favored in the presence
of prolinol 13, bisoxazolines 19, 20, 22, and 23, and
disulfonamide 24, which was used in conjunction with
titanium tetraisopropoxide (entries 5, 11, 12, and 14-16).
The most promising results were observed with 14. Literally
quantitative amounts of 8 exhibiting 37% ee were produced
when 10 mol % of this bisoxazoline was employed in an
apolar solvent system at 5 °C (entry 6).
Variation of reaction parameters showed that the best
results are obtained when the asymmetric nucleophilic
addition of diethylzinc to aryl trifluoromethyl ketones is
conducted in the presence of 10 mol % of ligand 14 in
hexanes/toluene (3/1 v/v) at -35 °C (Table 4). Although
superior results can be achieved in some cases when pure
hexanes are used, we decided to continue with a binary
solvent mixture consisting of 25% toluene in hexanes to
maintain a homogeneous solution throughout the reaction.
Under these conditions, the reaction is generally completed
in less than 3 h and the corresponding 2-aryl-1,1,1-trifluo-
robutan-2-ols are obtained in 77-99% yield. A further
decrease in the reaction temperature slightly increased ee’s,
but yields were usually lower (entry 1, Table 4). We found
that the enantioselectivity of this reaction varies considerably.
2,2,2-Trifluoroacetophenone and its methoxy, methylthio,
methyl, and tert-butyl analogues gave tertiary alcohols in
51-60% ee (entries 1, 4, 5, 6, and 9), but significantly lower
ee’s were obtained when aryl halides, nitriles, esters, and
nitro groups were present (entries 2, 3, 7, 8, 10, and 11). In
analogy to the cinchona alkaloid-catalyzed C-C bond
formation using CF3TMS and aliphatic ketones, unsatisfac-
tory yields and ee’s were produced with aliphatic substrates
(entries 12 and 13).
Supporting Information Available: Synthetic procedures
and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL8015012
(4) (a) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron Lett. 1994, 35,
3137–3138. (b) Caron, S.; Do, N. M.; Larivee, A. Synthesis 2003, 1693–
1698. (c) Mikami, K.; Itoh, Y.; Yamanaka, M. Chem. ReV. 2004, 104, 1–
16. (d) Ma, J.-A.; Cahard, D. Chem. ReV. 2004, 104, 6119–6146. (e) Billard,
T.; Langlois, B. R. Eur. J. Org. Chem. 2007, 891–897. (f) Ma, J.-A.; Cahard,
D. J. Fluorine Chem. 2007, 128, 975–996.
(5) Bennani, Y. L.; Vanhessche, K. P. M.; Sharpless, B. Tetrahedron:
Asymmetry 1994, 5, 1473–1476.
(6) (a) Zhuang, W.; Gathergood, N.; Hazell, R. G.; Jørgensen, K. A. J.
Org. Chem. 2001, 66, 1009–1013. (b) Lyle, M. P. A.; Draper, N. D.; Wilson,
P. D. Org. Lett. 2005, 7, 901–904. (c) Torok, B.; Abid, M.; London, G.;
Esquibel, J.; Torok, M.; Mhadgut, S. C.; Yan, P.; Prakash, G. K. S. Angew.
Chem., Int. Ed. 2005, 44, 3086–3089.
(7) (a) Aikawa, K.; Kainuma, S.; Hatano, M.; Mikami, K. Tetrahedron
Lett. 2004, 45, 183–185. (b) Mikami, K.; Aikawa, K.; Kainuma, S.;
Kawakami, Y.; Saito, T.; Sayo, N.; Kumobayashi, H. Tetrahedron:
Asymmetry 2004, 15, 3885–3889. (c) Mikami, K.; Kakuno, H.; Aikawa, K.
Angew. Chem., Int. Ed. 2005, 44, 7257–7260.
(8) (a) Gathergood, N.; Juhl, K.; Poulsen, T. B.; Thordrup, K.; Jørgensen,
K. A. Org. Biomol. Chem. 2004, 2, 1077–1085. (b) Wang, X.-J.; Zhao, Y.;
Liu, J.-T. Org. Lett. 2007, 9, 1343–1345.
(9) An asymmetric addition of organozinc reagents to trifluoromethyl
ketimines has been described: Lauzon, C.; Charette, A. B. Org. Lett. 2006,
8, 2743–2745.
3918
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