Enantioselective diynylation of cyclic N-acyl ketimines: Access to chiral trifluoromethylated tertiary carbinamines

Article abstract of DOI:10.1002/adsc.201100926

A novel enantioselective diynylation of cyclic N-acyl trifluoromethylketimines with chloramphenicol-amine derivatives as chiral additives has been successfully developed. A series of diynylated tertiary trifluoromethylcarbinamines were obtained in high yields with good to excellent enantioselectivities (with up to 99% ee). Copyright

Full text of DOI:10.1002/adsc.201100926

COMMUNICATIONS
DOI: 10.1002/adsc.201100926
Enantioselective Diynylation of Cyclic N-Acyl Ketimines: Access
to Chiral Trifluoromethylated Tertiary Carbinamines
Fa-Guang Zhang,a Hai Ma,a Jing Nie,a Yan Zheng,a Qingzhi Gao,a
and Jun-An Maa,b,*
a
Department of Chemsitry, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Tianjin University,
Tianjin 300072, Peopleꢀs Republic of China
Fax : (+86)-22-2740-3475; e-mail: majun_an68@tju.edu.cn
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic of China
b
Received: November 29, 2011; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201100926.
Abstract: A novel enantioselective diynylation of
cyclic N-acyl trifluoromethylketimines with chlor-
amphenicol-amine derivatives as chiral additives
has been successfully developed. A series of diyny-
lated tertiary trifluoromethylcarbinamines were ob-
tained in high yields with good to excellent enantio-
selectivities (with up to 99% ee).
able methodologies for the preparation of diyne car-
binamines remains scarce. They are mainly based on
the oxidative coupling transformations involving ter-
minal propargylic amines and propargylic alcohols.[9]
Thus, the development of a direct asymmetric diyny-
lation reaction of imines is highly desirable. Inspired
by the recent pioneering work of Carreira,[10a]
Trost,[10b] and Mikami[10c] on the metal-triggered asym-
metric addition of diynes to aldehydes and ketones,
we decided to develop a direct enantioselective addi-
tion of terminal 1,3-diynes to imines. Herein we
report the results of our preliminary investigations on
asymmetric diynylation of cyclic N-acyl trifluorome-
thylketimines, wherein chiral tertiary carbinamines
Keywords: addition reaction; asymmetric synthesis;
chiral additives; enantioselectivity; ketimines
Chiral propargylic amines are important building were obtained with up to 99% ee. Owing to the
blocks for the preparation of polyfunctional amino unique properties of trifluoromethylated compounds,
derivatives, pharmaceuticals, and biologically active the asymmetric construction of chiral CF3-containing
compounds. Many synthetic methodologies have been molecules under mild conditions has become a highly
developed to access these useful intermediates.[1] desirable methodology in organic and medicinal
Among them, the metal-triggered direct asymmetric chemistry.[11] This diynylation reaction provides a prac-
alkynylation of imines and analogues represents the tical and operationally simple method for the installa-
most convergent and efficient approach to the synthe- tion of a trifluoromethyl group and a butadiyne
sis of optically active propargylic amines. Over the moiety within a chiral molecule (Scheme 1).
past decade, a great effort has been devoted to the
In an initial investigation, the use of chiral Cu(I)-
development of highly selective metal-promoted sys- Pybox,[3a] Cu(I)-Quinap,[3c] and Cu(I)-Pinap[3e] com-
tems for these enantioselective alkynylation reac-
tions.[2–7] Despite significant progress in this area,
most studies are focused on the preparation of enan-
tioenriched secondary carbinamines, and methods for
the asymmetric synthesis of chiral tertiary carbina-
mines are very limited.[2,4a,e] Moreover, to date, there
has been no attention paid to exploring terminal 1,3-
diyne compounds as nucleophilic species in the enan-
tioselective addition reaction of imines.
Diyne carbinamines, an important subset of propar-
gylic amines, are useful building blocks for the synthe-
sis of agrochemicals and compounds with potential
biological activity.[8] However, the number of avail- Scheme 1. Addition of diynes to cyclic N-acyl ketimines
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

Fa-Guang Zhang et al.
COMMUNICATIONS
Table 1. Screening of chiral additives and reaction conditions for the diynylation of ketimines.
Entry
Additive (equiv.)
Solvent
Temperature [oC]
Time [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
I (1)
II (1)
III (1)
IV (1)
V
VI (1)
VII (1)
VIII (1)
VII (1)
VII (1)
VII (1)
VII (1)
VII (0.2)
VII (0.2)
VII (0.2)
VII (0.1)
VII (0.2)
VII (0.2)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
DCE
Et2O
THF
toluene
toluene
toluene
toluene
toluene
toluene
25
25
25
25
25
25
25
25
25
25
25
25
25
0
À10
À10
À20
À10
12
12
12
12
12
12
12
12
12
12
12
12
12
48
48
48
96
48
99
95
99
97
99
97
99
97
75
89
99
12
97
97
97
90
81
98
46
50
77
55
90
71
91
60
80
82
78
70
91
92
94
90
88
94
9
10
11
12
13
14
15
16
17
18[c]
[a]
Isolated yield.
[b]
[c]
Enantiomeric excess was determined by chiral HPLC analysis.
The recovered diyne 2a was used.
plexes in the addition of phenylbuta-1,3-diyne 2a to tries 4–8, additives IV–VIII), we were pleased to find
cyclic N-acyl trifluoromethylketimine 1a failed to that the chiral additive VII affords the desired diyny-
afford the desired adduct, probably due to the attenu- lation product 3a in 99% yield with the best enantio-
ated nucleophilicity of hypercojugative 1,3-diynes selecitivity (91% ee). A comparison of the results ob-
compared to more reactive alkynes. Subsequently, we tained in different solvents showed that this enantio-
found that the addition of the in situ-generated di- selective diynylation is highly sensitive to the solvent
ACHTUNGTRENNUNGynylzinc species to ketimine 1a proceeds well to pro- used (entries 9–12). Chloroalkanes and ethers gener-
duce the diynylation product 3a. A series of chiral ad- ally gave lower ee values, and toluene was found to
ditives was then screened and the results are listed in be the best solvent for this addition reaction. Decreas-
Table 1. The use of chloramphenicol-amine derivative ing the amount of chiral additive to 0.2 equivalents
I quantitatively provided the adduct 3a, but with only caused only a slight decrease in the yield (entry 13).
46% ee (Table 1, entry 1). tert-Butyldimethylsilyl-sub- Further optimization of the enantioselectivity of the
stituted additive II gave similar results (entry 2). The process could be achieved with additive VII by lower-
enantioselectivity was increased to 77% when using ing the reaction temperature (entries 14–17). Thus,
triphenylmethyl-substituted compound III as an addi- the addition of diyne 2a to cyclic N-acyl trifluorome-
tive. After a systematic study of various substituents thylketimine 1a could be efficiently performed in tol-
in the amino moiety of chloramphenicol-amine (en- uene at À108C, delivering the adduct 3a in 97% yield
2
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Enantioselective Diynylation of Cyclic N-Acyl Ketimines
Table 2. The scope of the addition of diynes to cyclic N-acyl ketimines.
Entry
Product 3 (R; R’)
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
6-Cl; C6H5
6-F; C6H5
5-F, 6-Cl; C6H5
6-MeO; C6H5
6-Cl; 4-MeC6H4
6-F, 4-MeC6H4
6-Cl: 4-MeOC6H4
6-F: 4-MeOC6H4
5-F, 6-Cl; 4-MeOC6H4
6-Cl; 2-MeOC6H4
6-F; 2-MeOC6H4
5-F, 6-Cl; 2-MeOC6H4
5,6-F2; 2-MeOC6H4
6-Cl; 3-MeOC6H4
6-F; 3-MeOC6H4
6-Cl; 4-FC6H4
97 (91)
92 (82)
94 (70)
95 (88)
97 (75)
86 (70)
97 (90)
97 (88)
98 (80)
97 (90)
97 (91)
97 (82)
90 (77)
97 (79)
97 (80)
98 (80)
98 (93)
97 (72)
97 (80)
93 (72)
96 (82)
97 (88)
97 (90)
97 (85)
97 (90)
93 (77)
93 (79)
(50)
94 (99)
91 (99)
77 (97)
80 (93)
76 (90)
80 (97)
93 (99)
92 (97)
83 (99)
90 (94)
94 (99)
86 (99)
85 (95)
80 (96)
80 (94)
83 (99)
96 (97)
75 (99)
79 (96)
78 (98)
84 (98)
91 (99)
94 (99)
85 (92)
92 (95)
84 (97)
85 (99)
(97)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26[c]
27[c]
28[c]
29
30
6-F; 4-FC6H4
6-Cl; 4-ClC6H4
6-F; 4-ClC6H4
6-Cl; 4-BrC6H4
6-F; 4-BrC6H4
3s
3t
3u
3v
3w
3x
3y
3z
3a’
3b’
3c’
3d’
6-Cl; 2-ClC6H4
6-F; 2-ClC6H4
6-Cl; 1-cyclohexenyl
6-F; 1-cyclohexenyl
6-Cl; cyclopropyl
6-F; cyclopropyl
5,6-F2; cyclopropyl
6-Cl; n-butyl
95
97
76
70
6-F; n-butyl
[a]
Yield of isolated product.
[b]
[c]
The ee value was determined by chiral HPLC analysis, and values in parentheses are for recrystallized products.
The reaction was run at 08C.
with 94% ee. Although excess diyne is required for 98% yields with 75–96% ee (entries 1–23). Alicyclic
high reactivity and enantioselectivity, the unreacted diynes also gave the diynylation adducts 3x–b’ in ex-
diyne could be recovered and reused without any loss cellent yields with high enantioselectivities (en-
of reactivity and enantioselectivity (entry 18).
tries 24–28). Linear alkyl-substituted 1,3-diynes are
With the optimized reaction conditions in hand, the also viable substrates, affording the desired products
scope of the diynylation of cyclic N-acyl trifluorome- in excellent yields, albeit with somewhat reduced
thylketimines was explored by varying the terminal enantioselectivity relative to the alicyclic partners (en-
1,3-diynes. The results are summarized in Table 2. tries 29 and 30). All such products were isolated uni-
Various aromatic diynes were studied by using formly in the form of white solid powders. Notewor-
(1R,2R)-VII as the additive. Electron-neutral, elec- thily, in most cases an improvement of the enantio-
tron-withdrawing, and electron-donating groups as purity of the adducts could be achieved by simple re-
well as substrates substituted at different positions on crystallizaiton (entries 1–28). Although crystals suita-
the aromatic rings were good partners for the reac- ble for X-ray diffraction analysis were not obtained
tion. The desired products 3a–w were obtained in 86– for these diynylation adducts, further transformation
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

Fa-Guang Zhang et al.
COMMUNICATIONS
Scheme 2. Further transformation of product 3u to 4 (top) and X-ray structure of 4 (bottom) for determination of the abso-
lute configuration (Flack parameter 0.0009).
of the adduct 3u furnished the crystalline derivative 4 products 5 in 65–75% yields without any erosion of
whose absolute stereochemistry was determined from the enantiopurity (Scheme 4). Direct reduction of the
single-crystal X-ray structural analysis (Scheme 2).[12] adducts 5a and ent-5a in the presence of LiAlH4 gave
Thus, we established that the absolute configuration (E)-eneynes 6a and ent-6a in high yields with excel-
of our diynylation products is R.
lent enantiomeric purity.[2b] It is likely that the com-
Studies on the scope of the reaction demonstrate pounds prepared here will provide novel therapeutic
the flexibility of the zinc-mediated asymmetric diyny- agents and useful biological tools.
lation process to efficiently generate a range of new
In conclusion, we have successfully developed
enantioenriched tertiary carbinamines. From both a new and highly efficient procedure for the enantio-
fundamental and practical standpoints, it is very im- selective addition of various terminal 1,3-diynes to
portant to provide methods to access both enantio- cyclic N-acyl trifluoromethylketimines. A range of
mers. Hence, we prepared and characterized the addi- new trifluoromethylated tertiary carbinamines can be
tive ent-VII, which is derived from commercially accessed in good to high yields (up to 98%) and enan-
available (1S,2S)-chloramphenicol-amine. This novel tioselectivities (up to 96% ee) from inexpensive and
chiral additive allowed us to prepare the opposite easily available chiral additives, and under mild condi-
enantiomers (ent-3z, ent-3a’, and ent-3b’) with excel- tions. Furthermore, higher enantiopurity of the ad-
lent enantiopurity (Scheme 3). In addition, by remov- ducts could be achieved by simple recrystallizaiton.
al of the p-methoxybenzyl (PMB) group in the ad- These advantages make this procedure more suitable
ducts, and further reduction, the deprotected adducts for practical use. In future studies we plan to investi-
can be readily transformed into functionalized amine gate the biological activity of this intriguing class of
derivatives. For example, treatment of the adducts trifluoromethylated tertiary carbinamines, and to
(3z, 3a’, ent-3z, and ent-3a’) with a solution of ceric expand the application of this diynylation addition to
ammonium nitrate (CAN) delivered the deprotected other substrates.
4
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Enantioselective Diynylation of Cyclic N-Acyl Ketimines
Scheme 3. ent-VII-mediated addition of cyclopropyl-substituted diyne to ketimines.
Scheme 4. Deprotection of the adducts 3 and further reduction to give the products 5 and 6.
tion by flash chromatography on silica gel (petroleum ether/
Experimental Section
ethyl acetate=10:1) afforded the white solid powder 3 (un-
reacted equivalents of 2 could be recovered and reused). A
simple recrystallization of this product from CH2Cl2/hexane
gave the crystals with poor enantiopurity (ee <20%), and
the mother liquid was concentrated under reduced pressure
to afford the desired product with high enantioselectivity
(90–99% ee).
General Procedure
A solution of Me2Zn in toluene (1.2M, 0.35 mL, 0.4 mmol)
was added dropwise to the 1,3-diyne[10b] 2 (0.4 mmol) at
room temperature under argon. The reaction mixture was
stirred for 1 h, after which chloramphenicol-base derivative
ligand VII (11.8 mg, 0.02 mmol) was added as a solid in one
portion. After stirring for about 15–30 min, a solution of
cyclic N-acylketimine 1 (0.1 mmol) in toluene (0.5 mL) was
added by syringe, and the reaction mixture was stirred at
under À108C until the reaction was complete (detected by
TLC). The reaction mixture was quenched with 1M aqueous
HCl (5 mL), extracted with EtOAc (10 mL ꢂ 3), dried over
MgSO4, and concentrated under reduced pressure. Purifica-
Acknowledgements
We gratefully appreciate financil support from the National
Natural Science Foundation of China (NSFC) (No. 20972110
and 21002068).
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

Fa-Guang Zhang et al.
COMMUNICATIONS
References
[8] For reviews, see: a) Modern Acetylene Chemistry, (Eds.:
P. J. Stang, F. Diederich), VCH, Weinheim, Germany,
1995; b) R. E. Minto, B. J. Blacklock, Prog. Lipid Res.
2008, 47, 233. For selected examples, see: <c) J. Kato,
K. Nakamura, Chem. Express. 1989, 4, 443; d) M.
Alami, F. Ferri, Tetrahedron Lett. 1996, 37, 2763;
e) E. M. Shepard, J. Smith, B. O. Elmore, J. A. Kuchar,
L. M. Sayre, D. M. Dooley, Eur. J. Biochem. 2002, 269,
3645; f) H. Kosuge, S. Okada, H. Oikawa, H. Naka-
nishi, Mol Cryst Liq Cryst A 2002, 377, 13; g) H.-B.
Jeon, L. M. Sayre, Biochem. Biophys. Res. Commun.
2003, 304, 788; h) L. M. Sayre, Amine compounds for
amine oxidase inhibitors, and therapeutic use, Patent
WO 2007005737, 2007; i) H. Moser, Q. Lu, P. A. Patten,
D. Wang, R. Kasar, S. Kaldor, B. D. Patterson, Prepara-
tion of antibacterial agents, Patent WO 2008154642,
2008; j) T. Odani, S. Okada, C. Kabuto, T. Kimura, S.
Shimada, H. Matsuda, H. Oikawa, A. Matsumoto, H.
Nakanishi, Cryst. Growth Des. 2009, 9, 3481.
[9] Fior a review, see: a) P. Siemsen, R. C. Livingston, F.
Diederich, Angew. Chem. 2000, 112, 2740; Angew.
Chem. Int. Ed. 2000, 39, 2632. For selected examples,
see: b) J. Kato, K. Nakamura, Amino-containing diace-
tylene derivatives, Japanese Patent JP 62267248, 1987;
c) O. J. Dautel, M. Robitzer, J.-P. Lere-Porte, F. Serein-
Spirau, J. J. E. Moreau, J. Am. Chem. Soc. 2006, 128,
16213; d) B. I. Shir, S. Sasmal, T. Mejuch, M. K. Sinha,
M. Kapon, E. Keinan, J. Org. Chem. 2008, 73, 8772;
e) E. Ko, J. Liu, L. M. Perez, G. Lu, A. Schaefer, K.
Burgess, J. Am. Chem. Soc. 2011, 133, 462.
[10] a) S. Reber, T. F. Knçpfel, E. M. Carreira, Tetrahedron
2003, 59, 6813; b) B. M. Trost, V. S. Chan, D. Yamamo-
to, J. Am. Chem. Soc. 2010, 132, 5186; c) K. Aikawa, Y.
Hioki, K. Mikami, Org. Lett. 2010, 12, 5716. Recently,
three groups reported their investigations on catalytic
enantioselective diynylation of aldehydes and ketones,
see: d) M. Turlington, Y. Du, S. G. Ostrum, V. Santosh,
K. Wren, T. Lin, M. Sabat, L. Pu, J. Am. Chem. Soc.
2011, 133, 11780; e) E. R. Graham, R. R. Tykwinski, J.
Org. Chem. 2011, 76, 6574; f) T.-L. Liu, H. Ma, F.-G.
Zhang, Y. Zheng, J. Nie, J.-A. Ma, Chem. Commun.
2011, 47, 12873.
[11] For selected reviews, see: a) Enantiocontrolled Synthe-
sis of Fluoroorganic Compunds: Stereochemical Chal-
lenges and Biomedicinal Targets, (Ed.: V. A. Solosho-
nok), Wiley, New York, 1999; b) Asymmetric Fluoroor-
ganic Chemistry, (Ed.: Ramachandran, P. V.), American
Chemical Society, Washington, DC, 2000; c) K.
Mikami, Y. Itoh, M. Yamanaka, Chem. Rev. 2004, 104,
1; d) Y.-F. Gong, K. Kato, Curr. Org. Chem. 2004, 8,
1659; e) J.-P. Bꢄguꢄ, D. Bonnet-Delpon, B. Crousse, J.
Legros, Chem. Soc. Rev. 2005, 34, 562; f) T. Billard,
B. R. Langlois, Eur. J. Org. Chem. 2007, 891; g) J.-A.
Ma, D. Cahard, Chem. Rev. 2008, 108, PR1; h) K. L.
Kirk, Org. Process Res. Dev. 2008, 12, 305; i) N. Shiba-
ta, S. Mizuta, H. Kawai, Tetrahedron: Asymmetry 2008,
19, 2633; j) Y. Zheng, J.-A. Ma, Adv. Synth. Catal.
2010, 352, 2745; k) J. Nie, H.-C. Guo, D. Cahard, J.-A.
Ma, Chem. Rev. 2011, 111, 455. For selected recent ex-
amples, see: l) G.-W. Zhang, L. Wang, J. Nie, J.-A. Ma,
Adv. Synth. Catal. 2008, 350, 1457; m) D. A. Nagib,
M. E. Scott, D. W. C. MacMillan, J. Am. Chem. Soc.
[1] For recent reviews, see: a) P. G. Cozzi, R. Hilgraf, N.
Zimmermann, Eur. J. Org. Chem. 2004, 4095; b) L.
Zani, C. Bolm, Chem. Commun. 2006, 4263; c) B. M.
Trost, A. H. Weiss, Adv. Synth. Catal. 2009, 351, 963;
d) D. Tejedor, S. Lꢃpez-Tosco, F. Cruz-Acosta, G.
Mꢄndez-Abt, F. Garcꢅa-Tellado, Angew. Chem. 2009,
121, 2124; Angew. Chem. Int. Ed. 2009, 48, 2090; e) P.
de Armas, D. Tejedor, F. Garcꢅa-Tellado, Angew. Chem.
2010, 122, 1029; Angew. Chem. Int. Ed. 2010, 49, 1013.
[2] Li-mediated enantioselective alkynylation of imines,
see: a) G. S. Kauffman, G. D. Harris, R. L. Dorow,
B. R. P. Stone, J. R. L. Parsons, J. A. Pesti, N. A.
Magnus, J. M. Fortunak, P. N. Confalone, W. A. Nugent,
Org. Lett. 2000, 2, 3119; b) 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, S. K.
Erickson-Viitanen, J. Med. Chem. 2000, 43, 2019.
[3] For selected examples on Cu-catalyzed asymmetric syn-
thesis of chiral secondary propargylic amines, see: a) C.
Wei, C.-J. Li, J. Am. Chem. Soc. 2002, 124, 5638; b) C.
Koradin, K. Polborn, P. Knochel, Angew. Chem. 2002,
114, 2651; Angew. Chem. Int. Ed. 2002, 41, 2535; c) N.
Gommermann, C. Koradin, K. Polborn, P. Knochel,
Angew. Chem. 2003, 115, 5941; Angew. Chem. Int. Ed.
2003, 42, 5763; d) C. Wei, J. T. Mague, C.-J. Li, Proc.
Natl. Acad. Sci. USA 2004, 101, 5749; e) T. F. Knçpfel,
P. Aschwanden, T. Ichikawa, T. Watanabe, E. M. Car-
reira, Angew. Chem. 2004, 116, 6097; Angew. Chem.
Int. Ed. 2004, 43, 5971; f) M. Benaglia, D. Negri, G.
Dell’Anna, Tetrahedron Lett. 2004, 45, 8705; g) F. Co-
lombo, M. Benaglia, S. Orlandi, F. Usuelli, G. Celenta-
no, J. Org. Chem. 2006, 71, 2064; h) Z. Shao, J. Wang,
K. Ding, A. S. C. Chan, Adv. Synth. Catal. 2007, 349,
2375; i) Z. Sun, S. Yu, Z. Ding, D. Ma, J. Am. Chem.
Soc. 2007, 129, 9300; j) M. Irmaka, M. M. K. Boysena,
Adv. Synth. Catal. 2008, 350, 403.
[4] For selected examples on Zn-triggered enantioselective
alkynylation of imines, see: a) B. Jiang, Y.-G. Si,
Angew. Chem. 2004, 116, 218; Angew. Chem. Int. Ed.
2004, 43, 216; b) W. Wei, M. Kobayashi, Y. Ukaji, K.
Inomata, Chem. Lett. 2006, 35, 176; c) L. Zani, T. Eich-
horn, C. Bolm, Chem. Eur. J. 2007, 13, 2587; d) G. Blay,
L. Cardona, E. Climent, J. R. Pedro, Angew. Chem.
2008, 120, 5675; Angew. Chem. Int. Ed. 2008, 47, 5593;
e) G. Huang, J. Yang, X. Zhang, Chem. Commun. 2011,
47, 5587.
[5] For one example on Zr-catalyzed asymmetric alkynyla-
tion of imines, see: J. F. Traverse, A. H. Hoveyda, M. L.
Snapper, Org. Lett. 2003, 5, 3273.
[6] For two examples on B-mediated enantioselective alky-
nylation of imines, see: a) T. R. Wu, J. M. Chong, Org.
Lett. 2006, 8, 15; b) A. Z. Gonzalez, E. Canales, J. A.
Soderquist, Org. Lett. 2006, 8, 3331.
[7] For two examples on combined enantioselective
Brønsted acid and metal catalyzed alkynykation of
imines; a) M. Rueping, A. P. Antonchick, C. Brink-
mann, Angew. Chem. 2007, 119, 7027; Angew. Chem.
Int. Ed. 2007, 46, 6903; b) Y. Lu, T. C. Johnstone, B. A.
Arndtsen, J. Am. Chem. Soc. 2009, 131, 11284.
6
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Enantioselective Diynylation of Cyclic N-Acyl Ketimines
2009, 131, 10875; n) H. Kawai, A. Kusuda, S. Naka-
mura, M. Shiro, N. Shibata, Angew. Chem. 2009, 121,
6442; Angew. Chem. Int. Ed. 2009, 48, 6324; o) J. Nie,
G.-W. Zhang, L. Wang, A. Fu, Y. Zheng, J.-A. Ma,
Chem. Commun. 2009, 2356; p) H. Kawai, K. Tachi, E.
Tokunaga, M. Shiro, N. Shibata, Org. Lett. 2010, 12,
5104; q) T. Wang, G.-W. Zhang, Y. Teng, J. Nie, Y.
Zheng, J.-A. Ma, Adv. Synth. Catal. 2010, 352, 2773;
r) G.-W. Zhang, W. Meng, H. Ma, J. Nie, W.-Q. Zhang,
J.-A. Ma, Angew. Chem. 2011, 123, 3600; Angew.
Chem. Int. Ed. 2011, 50, 3538; s) A. E. Allen, D. W. C.
MacMillan, J. Am. Chem. Soc. 2010, 132, 4986; t) H.
Kawai, T. Kitayama, E. Tokunaga, N. Shibata, Eur. J.
Org. Chem. 2011, 30, 5959.
[12] CCDC 830330 contains the supplementary crystallo-
graphic data for the compound 4. These data can be
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
8 Enantioselective Diynylation of Cyclic N-Acyl Ketimines:
Access to Chiral Trifluoromethylated Tertiary Carbinamines
Adv. Synth. Catal. 2012, 354, 1 – 8
Fa-Guang Zhang, Hai Ma, Jing Nie, Yan Zheng,
Qingzhi Gao, Jun-An Ma*
8
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!