Copper(I) alkoxide-catalyzed alkynylation of trifluoromethyl ketones

Article abstract of DOI:10.1021/ol071003k

A general method for direct alkynylation of trifluoromethyl ketones was developed by using CuO'Bu-xantphos or phenanthroline complexes as catalysts. The ligands significantly enhanced the catalyst activity. In addition, KOTf, generated in the catalyst pre

Full text of DOI:10.1021/ol071003k

ORGANIC
LETTERS
2007
Vol. 9, No. 16
2997-3000
Copper(I) Alkoxide-Catalyzed
Alkynylation of Trifluoromethyl Ketones
Rie Motoki, Motomu Kanai,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
mshibasa@mol.f.u-tokyo.ac.jp
Received April 30, 2007
ABSTRACT
A general method for direct alkynylation of trifluoromethyl ketones was developed by using CuOtBu
−xantphos or phenanthroline complexes
as catalysts. The ligands significantly enhanced the catalyst activity. In addition, KOTf, generated in the catalyst preparation step, exhibited
some acceleration effects. A preliminary extension to a catalytic enantioselective CF3-substituted tertiary propargyl alcohol synthesis (up to
52% ee) is also described.
The development of new methods for catalytic enantiose-
lective tetrasubstituted carbon-constructing C-C bond-
formation with ketones and ketoimines is highly challenging.1
To overcome the moderate reactivity of these substrates,
organometallic reagents or metal enolates are generally used
as nucleophiles. By contrast, reactions involving in situ
generation of reactive nucleophiles (such as enolates, enam-
ines, or metal alkynides) from stable, purely organic mol-
ecules (such as ketones, aldehydes, or alkynes) via asym-
metric catalyst-mediated deprotonation are more advantageous
in terms of atom economy.2 Although such direct catalytic
asymmetric reactions have been intensively studied by using
aldehydes and aldimines as substrates,3 extension to direct
catalytic asymmetric tetrasubstituted carbon synthesis is still
immature.4,5 In this Letter, we describe a direct catalytic
alkynylation of trifluoromethyl ketones with broad substrate
generality. The methodology can be a platform for a direct
catalytic enantioselective CF3-substituted tertiary propargyl
alcohol synthesis.6-8
(4) HCN is the only nucleophile that can be applied to direct catalytic
enantioselective tetrasubstituted carbon synthesis with unactivated ketones
and ketoimines: (a) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867-
890. (b) Charavot, M.; Byrne, J. J.; Chavant, Y.; Valle´e, Y. Tetrahedron:
Asymmetry 2001, 12, 1147-1150. (c) Kato, N.; Suzuki, M.; Kanai, M.;
Shibasaki, M. Tetrahedron Lett. 2004, 45, 3153. (d) Fuerst, D. E.; Jacobsen,
E. N. J. Am. Chem. Soc. 2005, 127, 8964-8965.
(5) Except for hydrocyanation, R-keto (or imino) carbonyl compounds
(or R-keto phosphonates) are the only substrates used in direct catalytic
asymmetric tetrasubstituted carbon synthesis (nitro-aldol reactions for 5a-
e; direct aldol reactions for 5f-i; alkynylation for 5j): (a) Christensen, C.;
Juhl, K.; Jørgensen, K. A. Chem. Commun. 2001, 2222-2223. (b)
Christensen, C.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem.
2002, 67, 4875-4881. (c) Lu, S.-F.; Du, D.-M.; Zhang, S.-W.; Xu, J.
Tetrahedron: Asymmetry 2004, 15, 3433-3441. (d) Du, D.-M.; Lu, S.-F.;
Fang, T.; Xu, J. J. Org. Chem. 2005, 70, 3712-3715. (e) Li, H.; Wang, B.;
Deng, L. J. Am. Chem. Soc. 2006, 128, 732-733. (f) Zhuang, W.; Saaby,
S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 4476-4478. (g)
Tokuda, O.; Kano, T.; Gao, W.-G.; Ikemoto, T.; Maruoka, K. Org. Lett.
2005, 7, 5103-5105. (h) Tang, Z.; Cun, L.-F.; Cui, X.; Mi, A.-Q.; Jiang,
Y.-Z.; Gong, L.-Z. Org. Lett. 2006, 8, 1263-1266. (i) Samata, S.; Zhao,
C.-G. J. Am. Chem. Soc. 2006, 128, 7442-7443. (j) Jiang, B.; Chen, Z.;
Tang, X. Org. Lett. 2002, 4, 3451-3453.
(1) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388-401. (b) Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5,
873-888.
(2) Trost, B. M. Science 1991, 254, 1471-1477.
(3) Catalytic asymmetric hydrocyanation, Michael reaction, nitro-aldol
reaction, nitro-Mannich reaction, direct aldol reaction, direct Mannich
reaction, and alkynylation are in this categorey. For a general review of
asymmetric catalysis, see: ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, Germany,
1999.
10.1021/ol071003k CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/13/2007

Recently, there has been increasing attention and demand
for CF3-containing chiral drugs. Substitution of a methyl
group by a trifluoromethyl group generally influences the
biologic activity by changing the molecule’s solubility,
lipophilicity, and electronic properties. An especially inter-
esting example is Merck’s anti-HIV drug Efavirenz (1) and
its related compound 2, which contain a trifluoromethyl
group at the tetrasubstituted chiral center at a propargyl
position (Figure 1).9 Inspired by the structure of Efavirenz,
Brønsted basic characteristic of copper(I) alkoxide.11 Previ-
ously, we developed a catalytic enantioselective direct
nitrile-aldol reaction of aldehydes using a copper alkoxide-
chiral phosphine complex catalyst.12 This reaction proceeded
through nucleophile generation in situ via selective depro-
tonation from nitriles (pKa ≈ 31 in DMSO) by copper
alkoxide, even in the presence of aliphatic aldehydes
containing more acidic R-protons (pKa ≈ 23). The selective
deprotonation was attributed to the selective coordination of
soft nitriles to the soft metal,13 copper. On the basis of those
previous studies, we expected that “soft” alkynes (pKa ≈
29) would be selectively activated (deprotonated) by copper
alkoxide catalyst in the presence of trifluoromethyl ketones
(pKa ≈ 15). Indeed, copper alkynide formation by mixing
terminal alkynes and copper salts is well-established in
coupling reactions, such as the Castro-Stephens reaction,14
Glaser coupling,15 and Sonogashira coupling.16 The copper
alkynides generated under catalytic in metal conditions,
however, have not been utilized in alkynylation of carbonyl
groups.17,18
Figure 1. Examples of biologically significant molecules contain-
ing CF3-substituted tetrasubstituted carbons.
The reaction between trifluoroacetophenone (3a) and
phenylacetylene (4a; 2 equiv) was first studied with use of
CuOtBu (10 mol %; prepared in situ from CuOTf‚1/2benzene
and KOtBu12b) as a catalyst. Only a trace amount of product
(5aa) was formed in the absence of any ligands (yield )
2%, THF, 60 °C, 22 h). Because the ligands can enhance
the nucleophilicity of copper alkynides, we next examined
the effects of phosphine ligands.19 Xantphos was determined
to be the optimum ligand; product 5aa was obtained in a
quantitative yield in the presence of the CuOtBu-xantphos
complex (Table 1, entry 1). The reaction has a wide substrate
scope with regard to the trifluoromethyl ketones and alkynes
(Table 1). Therefore, chemoselective deprotonation from
alkynes by the soft metal (copper) alkoxide catalyst and the
subsequent addition of the in situ generated copper alkynides
to trifluoromethyl ketones were realized. It is noteworthy
we began a project toward developing a direct catalytic
enantioselective alkynylation of trifluoromethyl ketones.
Although there have been several excellent catalytic enan-
tioselective alkynylations of aldehydes and aldimines re-
ported after the pioneering work of Carreira,10 none of the
methods have been applied to trifluoromethyl ketones.
To establish the basic conditions of catalytic alkynylation
of trifluoromethyl ketones, we focused on the unique
(6) For catalytic enantioselective synthesis of CF3-substituted tertiary
alcohols or amines, see: (a) Wang, X.-J.; Zhao, Y.; Liu, J.-T. Org. Lett.
2007, 9, 1343-1345. (b) Lauzon, C.; Charette, A. B. Org. Lett. 2006, 8,
2743-2745. (c) Martina, S. L. X.; Jagat, R. B. C.; de Vries, J. G.; Feringa,
B.; Minnaard, A. J. Chem. Commun. 2006, 4093-4095. (d) Motoki, R.;
Tomita, D.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2006, 47, 8083-
8086.
(7) Highly electrophilic trifluoropyruvates have been used as substrates
for catalytic enantioselective Friedel-Crafts reaction (7a), ene reaction (7b),
and direct aldol reaction (7c). For examples, see: (a) Bandini, M.; Melloni,
A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550-556. (b)
Mikami, K.; Kakuno, H.; Aikawa, K. Angew. Chem., Int. Ed. 2005, 44,
7257-7260. (c) Gathergood, N.; Juhl, K.; Poulsen, T. B.; Thordrup, K.;
Jørgensen, K. A. Org. Biomol. Chem. 2004, 2, 1077-1085.
(8) Catalytic asymmetric trifluoromethylation (8a) and dihydroxylation
(8b) are alternative methods. For reviews, see: (a) Billard, T.; Langlois, B.
R. Eur. J. Org. Chem. 2007, 891-897. (b) Herrmann, W. A.; Eder, S. J.;
Scherer, W. Angew. Chem., Int. Ed. 1992, 31, 1345-1347.
(11) Tsuda, T.; Hashimoto, T.; Saegusa, T. J. Am. Chem. Soc. 1972, 94,
658-659.
(12) (a) Suto, Y.; Kumagai, N.; Matsunaga, S.; Shibasaki, M. Org. Lett.
2003, 5, 3147-3150. (b) Suto, Y.; Tsuji, R.; Kanai, M.; Shibasaki, M. Org.
Lett. 2005, 7, 3757-3760.
(13) For similar approaches, see: (a) Kumagai, N.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 13632-13633. (b) Kumagai,
N.; Matsunaga, S.; Shibasaki, M. Tetrahedron 2007, doi: 10.1016/
j.tet.2007.04.051. (c) Fan, L.; Ozerov, O. V. Chem. Commun. 2005, 4450-
4451.
(14) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 3313-3315.
(9) 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.
(15) Glaser, C. Ber. 1869, 2, 422-424.
(16) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron, Lett. 1975,
16, 4467-4470.
(17) Addition reactions of copper alkynides to acid chlorides have been
reported: (a) Normant, J. F.; Bourgain, M. Tetrahedron Lett. 1970, 2659-
2662. (b) Lewis, M. D.; Duffy, J. P.; Heck, J. V.; Menes, R. Tetrahedron
Lett. 1988, 29, 2279-2282. In very rare cases, alkynyl cuprates react with
reactive ketones, including a trifluoromethyl alkynyl ketone. (c) Linderman,
R. J.; Lonikar, M. S. J. Org. Chem. 1988, 53, 6013. (d) Palmisano, G.;
Pellegata, R. J. Chem. Soc., Chem. Commun. 1975, 892-893. These
reactions utilized a stoichiometric amount of copper species.
(18) Catalytic enantioselective conjugate alkynylation of in situ prepared
copper alkynides has been reported: (a) Kno¨pfel, T. F.; Carreira, E. M. J.
Am. Chem. Soc. 2003, 125, 6054-6055. (b) Kno¨pfel, T. F.; Zarotti, P.;
Ichikawa, T.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 9682-9683.
(c) Fujimori, S.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 4964-
4967. For examples of catalytic enantioselective addition of copper alkynides
to imines, see refs 10h and 10j.
(10) Selected examples of catalytic enantioselective alkynylation of
aldehydes: (a) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001,
123, 9687-9688. (b) Fa¨ssler, C. S.; Tomooka, C. S.; Frantz, D. E.; Carreira,
E. M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5843-5845. (c) Takita, R.;
Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127,
13760-13761. (d) Yamashita, M.; Yamada, K.-i.; Tomioka, K. AdV. Synth.
Catal. 2005, 347, 1649-1652. (e) Emmerson, D. P. G.; Hems, W. P.; Davis,
B. G. Org. Lett. 2006, 8, 207-210. Selected examples of catalytic
asymmetric alkynylation of simple ketones with a stoichiometric amount
of zinc alkynides: (f) Cozzi, P. G. Angew. Chem., Int. Ed. 2003, 42, 2895-
2898. (g) Lu, G.; Li, X.; Jia, X.; Chan, W. L.; Chan, A. S. C. Angew. Chem.,
Int. Ed. 2003, 42, 5057-5058. Selected examples of catalytic enantiose-
lective alkynylation of imines: (h) Wei, C.; Li, C. J. J. Am. Chem. Soc.
2002, 124, 5638-5639. (i) Gommermann, N.; Koradin, C.; Polborn, K.;
Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763-5766. (j) Bisai, A.;
Singh, V. K. Org. Lett. 2006, 8, 2405-2408.
(19) See the Supporting Information for details. KOtBu itself (in the
absence of Cu salt) did not promote the reaction at all.
2998
Org. Lett., Vol. 9, No. 16, 2007

Table 1. Alkynylation of Trifluoromethyl Ketones with
CuOtBu-Xantphos Catalyst
Table 2. Optimization of Alkynylation of Trifluoromethyl
Ketone with Cu(II)-Diamine Precatalyst
entry
liganda
catalyst
yieldb (%)
1
2
3
4
5
6
7
8
9
none
Cu(OTf)2-2KOtBu
Cu(OTf)2-2KOtBu
Cu(OTf)2-2KOtBu
Cu(OTf)2-2KOtBu
CuOTf‚1/2benzene-KOtBu
Cu(OTf)2-KOtBu
Cu(OMe)2
Cu(OMe)2-2KOTf
Cu(OTf)2-2LiOtBu
Cu(OTf)2-2NaOtBu
Cu(OTf)2-2CsOtBu
12
61
94c
6
94
78
54
73
13
66
40
6
7
8
7
7
7
7
7
7
7
entry
ketone (R1)
alkyne (R2)
yield (%)a
1
2
3
4
5
3a (Ph)
3a (Ph)
3a (Ph)
3b (Ph(CH2)2)
3b (Ph(CH2)2)
4a (Ph)
>99
>99
71b
>99
76
4b (Ph(CH2)2)
4c (Et3Si)
4a (Ph)
4b (Ph(CH2)2)
10
11
a NMR yield with (CHCl2)2 as an internal standard. b Isolated yield. 40%
of 5ac (free OH) and 31% of O-triethylsilylated product were obtained.
a 6: 2,2′-bipyridyl. 7: 1,10-phenanthroline. 8: 2,2′:6′2′′-terpyridine.
b NMR yield with (CHCl2)2 as an internal standard. c Isolated yield.
that in entry 3 the alkyne deprotonation was a more favorable
pathway than the transmetalation pathway.6d To our knowl-
edge, this is the first example of a catalytic alkynylation of
trifluoromethyl ketones.
Before extending these conditions to a catalytic enanti-
oselective variant, we next investigated the use of amine
ligands. Structural modification of amine ligands is generally
much easier than that of phosphine ligands. This fact will
be important when ligand structure tuning is necessary for
the enantioselective reaction. In addition, we used air-stable
Cu(OTf)2 as a source of Cu(I)OtBu to avoid having to use a
glove box manipulation. Cu(II) should be reduced to Cu(I)
by terminal alkynes during the reaction.20
in moderate yield when copper alkoxide catalyst was
prepared from Cu(OTf)2 and alkaline metal tert-butoxides
other than KOtBu (entries 9-11).
We then examined the substrate generality of the Cu-
diamine catalysis under the optimized conditions (Table 3).
Table 3. Alkynylation of Trifluoromethyl Ketones with a
Cu-Diamine Catalyst
Three findings are noteworthy in the Cu(II)-diamine
precatalyst system (Table 2): (1) There was again significant
ligand acceleration in this system (entries 1-4). In the
absence of any ligands, product 5ca was produced in only
12% yield (entry 1). By contrast, yield was improved up to
94% in the presence of bipyridine-type ligands, especially
phenanthroline (7: entry 3). Use of trivalent terpyridine (8),
however, markedly decreased the yield (entry 4). Cu(I)
alkoxide is likely the actual catalyst because a comparable
yield was obtained with Cu(I)OtBu (entry 5). (2) A catalyst
prepared from Cu(OTf)2 and KOtBu in a 1:2 ratio produced
higher activity than that prepared from a 1:1 combination
of Cu(OTf)2 and KOtBu (entry 3 vs 6). (3) The presence of
KOTf (generated as a side product in the copper alkoxide
generation step) improved product yield (entries 7-11).21
By using commercially available Cu(OMe)2 in the presence
of phenanthroline produced 5ca in only 54% (entry 7), the
yield was improved to 73% when 20 mol % of KOTf was
added (entry 8). In addition, the product was obtained only
entry
ketone (R1)
3a (Ph)
3c (p-Me-C6H4)
alkyne (R2)
time (h) yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4a (Ph)
4a (Ph)
14
28
45
27
17
20
22
17
26
16
12
14
24
20
20
95
94
75
91
72
70
81
79
96
87
73
80
80b,c
95
86d
3d (p-MeO-C6H4) 4a (Ph)
3e (p-Cl-C6H4)
3f (p-Br-C6H4)
3i (o-Me-C6H4)
3j (m-Me-C6H4)
4a (Ph)
4a (Ph)
4a (Ph)
4a (Ph)
3g (3-thiophene) 4a (Ph)
3b (Ph(CH2)2)
3h (CH3(CH2)9)
3k (c-Hex)
3a (Ph)
3a (Ph)
4a (Ph)
4a (Ph)
4a (Ph)
4b (Ph(CH2)2)
4c (Et3Si)
4b (Ph(CH2)2)
4c (Et3Si)
3b (Ph(CH2)2)
3b (Ph(CH2)2)
a Isolated yield. b O-Triethylsilylated product was obtained. c NMR yield
with (CHCl2)2 as an internal standard. d Combined yield of 5bc (75%) and
the corresponding O-triethylsilylated product (11%).
(20) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int.
Ed. 2000, 39, 2632-2657.
(21) The actual catalyst might be a bimetallic complex (or higher
aggregates) of Cu and K. For an example of a Cu-K bimetallic complex,
see: (a) Ahlrichs, R.; Anson, C. E.; Fenske, D.; Hampe, O.; Rothenberger,
A.; Sierka, M. Angew. Chem., Int. Ed. 2003, 42, 4036-4029. (b) Heller,
M.; Sheldrick, W. S. Z. Anorg. Allg. Chem. 2004, 630, 1191-1195.
High reactivity was consistently observed when aromatic
(entries 1-7), heteroaromatic (entry 8), and enolizable
aliphatic trifluoromethyl ketones (entries 9-11) were used
Org. Lett., Vol. 9, No. 16, 2007
2999

as electrophiles. In addition, various alkynes, including
phenylacetylene (4a), alkylacetylene (4b), and synthetically
useful silylacetylene (4c), were applicable.
mol %) in the presence of 9, product 5aa was produced with
comparable enantioselectivity (43% ee23 vs 42% ee in
Scheme 1) and reactivity as when using CuOTf-KOtBu-9
as a catalyst. On the basis of this result, we propose the
catalytic cycle as shown in Scheme 2. Selective activation
The described reactions could, in principle, be extended
to a catalytic enantioselective reaction. Screening several
available ligands indicated that DTBM-SEGPHOS (9) and
pybox 10 are promising chiral ligands (Scheme 1). Thus,
Scheme 2. Proposed Catalytic Cycle
Scheme 1. Preliminary Extension to Catalytic Enantioselective
Alkynylation of Trifluoromethyl Ketones
of alkynes by the soft metal (Cu)-soft alkyne π orbital
interactions and the enhanced nucleophilicity of the resulting
copper alkynide by the ligands are key to the success of this
catalytic cycle.
In summary, we achieved the first general catalytic
alkynylation of trifluoromethyl ketones using a copper
alkoxide-diphosphine or diamine complex. This process is
an atom-economic C-C bond-formation, which proceeds
through proton transfer from teminal alkynes to the product
tertiary alcohol. The methodology can be a platform for
catalytic enantioselective synthesis of CF3-substituted tertiary
propargyl alcohols, which are important chiral building
blocks for pharmaceuticals. Further studies focusing on
improving the enantioselectivity are ongoing.
with Cu-9 as a catalyst (10 mol %), product 5aa was
obtained in greater than 99% yield with 42% ee. On the other
hand, the Cu-10 complex afforded 5aa in 43% yield with
49% ee (10 mol % of catalyst), and 66% yield with 52% ee
(20 mol % of catalyst).22 Although enantioselectivity is
moderate at this stage, this catalytic enantioselective direct
alkynylation of trifluoromethyl ketones is a new entry for
the construction of enantiomerically enriched tertiary CF3-
substituted propargyl alcohols.
Acknowledgment. Financial support was provided by a
Grant-in-Aid for Specially Promoted Research of MEXT.
R.M. thanks JSPS for the research fellowships. We thank
Mr. H. Morimoto for the calculation of pKa value of
trifluoromethyl ketones.
Although the detailed reaction mechanism (especially, the
origin of the beneficial effect of KOTf) remains unclear, the
reaction likely proceeds via copper alkynides, which are
generated in situ through chemoselective deprotonation of
alkynes by copper alkoxide. This hypothesis is partially
supported by the following result. When commercially
available copper phenylacetylide was used as a catalyst (10
Supporting Information Available: Experimental pro-
cedures and characterization of the products. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
OL071003K
(22) Cu(I)OTf was used as the copper source in the catalytic enantiose-
lective reactions. When Cu(II)(OTf)2-2KOtBu was used as a precatalyst
in combination with pybox 10, the results were variable in each run.
(23) 5 mol % of KOTf was added to the reaction mixture. In the absence
of KOTf, copper phenylacetylide-9 catalyst produced 5aa with 38% ee.
Therefore, the addition of KOTf slightly improved the enantioselectivity.
3000
Org. Lett., Vol. 9, No. 16, 2007