Phosphine-Catalyzed Asymmetric Umpolung Addition of Trifluoromethyl Ketimines to Morita–Baylis–Hillman Carbonates

Article abstract of DOI:10.1002/anie.201607918

A novel phosphine-catalyzed, highly enantioselective umpolung addition of trifluoromethyl ketimines to Morita–Baylis–Hillman carbonates was developed and it provides facile access to optically active trifluoromethyl amines with a chiral tertiary stereocenter under mild reaction conditions. The salient features of this reaction include general substrate scope, mild reaction conditions, good yields, high enantioselectivity, ease of scale-up to gram scale, and further transformations of the products.

Full text of DOI:10.1002/anie.201607918

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201607918
German Edition: DOI: 10.1002/ange.201607918
Organocatalysis
Phosphine-Catalyzed Asymmetric Umpolung Addition of
Trifluoromethyl Ketimines to Morita–Baylis–Hillman Carbonates
Peng Chen, Zhenting Yue, Junyou Zhang, Xi Lv, Lei Wang, and Junliang Zhang*
Abstract: A novel phosphine-catalyzed, highly enantioselec-
tive umpolung addition of trifluoromethyl ketimines to
Morita–Baylis–Hillman carbonates was developed and it
provides facile access to optically active trifluoromethyl
amines with a chiral tertiary stereocenter under mild reaction
conditions. The salient features of this reaction include general
substrate scope, mild reaction conditions, good yields, high
enantioselectivity, ease of scale-up to gram scale, and further
transformations of the products.
T
he presence of fluorine in organic molecules of pharma-
ceutical and agrochemical importance has had a beneficial yet
unique impact on the bioactivities of the molecules, and led to
a rapidly increasing demand for developing novel method-
ology to efficiently synthesize organofluorine compounds.[1]
Among fluorinated compounds, chiral trifluoromethyl amines
were widely found as the key structural subunits in many
biologically interesting compounds, and were recognized to
improve lipophilicity and metabolic stability over that of the
corresponding methyl amines (Figure 1).[2]
Figure 1. Biologically active natural products containing pyrrolidine
and azepine skeletons. Fmoc=9-fluorenylmethyloxycarbonyl.
In light of their importance, various powerful strategies
for the synthesis of chiral trifluoromethyl amines have been
developed in the past years. The strategy which takes
advantage of the inherent electrophilicity of prochiral tri-
fluoromethyl imines and their reaction with various nucleo-
philes has received much attention and several elegant
reactions have been reported (Scheme 1a, left-hand side).[3]
For example, the groups of Hoveyda,[3b] Ye,[3c] and Huang,[3d]
disclosed highly enantioselective nucleophilic additions to
trifluoromethyl ketimines catalyzed by chiral metal or organic
catalysts. Although these methods are effective, they are often
hampered by the multistep preparation of the reactants as
well as the narrow range of products, that is, only aromatic
trifluoromethyl amines could be obtained. Consequently, the
development of novel and general method for enantioen-
riched trifluoromethyl amines bearing a chiral tertiary
stereocenter is still highly desirable.
In contrast, umpolung of trifluoromethyl imines, that is,
inverting the polarization of imines as a nucleophile, may
provide alternative access to structures and addition patterns
Scheme 1. Asymmetric synthesis trifluoromethylamine bearing a tertiary
stereocenter through an umpolung strategy. Boc=tert-butoxycarbonyl,
PG=protecting group.
[*] P. Chen, Z. Yue, J. Zhang, X. Lv, L. Wang, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and Chemical Pro-
cesses, School of Chemistry and Molecular Engineering
East China Normal University
Shanghai, 200062 (P.R. China)
E-mail: jlzhang@chem.ecnu.edu.cn
Homepage: http://faculty.ecnu.edu.cn/s/1811/main.jspy
which are not (or hardly) accessible by previous methods
(Scheme 1a, right-hand side).[4,5] However, this strategy poses
considerable challenges because of the unavoidable reversal
of the inherent electrophilicity of imines. Only one example of
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201607918.
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the asymmetric umpolung addition of trifluoromethyl keti-
mines to electrophiles has been documented so far.[6] Very
recently, Deng and co-workers successfully applied this
umpolung strategy to the synthesis of optically active
trifluoromethyl amines, with a chiral tertiary stereocenter,
from readily available trifluoromethyl ketimines (1) and enals
by the employing a chiral phase-transfer catalyst (PTC;
Scheme 1b). Inspired by Dengꢀs work and our continual
interest in asymmetric phosphine catalysis,[7,8] we envisaged
that the Morita–Baylis–Hillman (MBH) carbonates 2,
another very readily available and widely used compounds
in organocatalytic reactions,[9] would generate the chiral
quaternary phosphonium salts 3 in the presence of chiral
phosphine catalyst (Scheme 1c). Subsequent SN2’ reaction
with the in situ generated 2-azaallyl anions 4 would deliver
the corresponding enantioenriched trifloromethyl amines 5
with a chiral tertiary stereocenter. Herein, we report a novel
phosphine-catalyzed and highly enantioselective umpolung
addition of trifluoromethyl ketimines to MBH carbonates
under mild reaction conditions, and it provides facile access to
optically active trifluoromethyl amines with a chiral tertiary
stereocenter. Moreover, synthetically valuable a-methylene
g-lactams could be achieved through further transformations
of the products by the use of a simple protocol.
Figure 2. The screened chiral phosphine catalysts.
catalysts were examined at room temperature. Our recently
developed chiral phosphine catalysts Xiao-Phos (S,RS)-X1
and (S,RS)-X10 (Figure 2), as well as Wei-Phos (S,RS)-W1
gave the adduct 5aa in moderate enantioselectivities (Table 1,
entries 1–3). The substituent effect at the ortho-position of the
phenyl ring, such as in (S,RS)-P1–P8, was then investigated.
(S,RS)-P5, with the rigid 9-anthracenyl substituent gives better
results (entry 8). To further enhance the capability of hydro-
gen-bonding or proton donation, two new catalysts, (S)-P9
with 3,5-bistrifluoromethylphenyl thiourea and (S)-P10 with
3,5-bistrifluoromethyl benzoyl, were prepared from P5 in two
steps (entries 12 and 13). To our delight, 78% yield and 81%
ee could be obtained for the product when using (S)-P10 as
the catalyst. Further studies showed that the ee values and
yields could be further improved with increasing the size of
the ester group of the MBH carbonate from methyl to ethyl,
isopropyl, and tert-butyl (entries 14–17), and the adduct 5ae
was obtained in 85% yield with 98% ee from 2e. The
evaluation of the solvents showed that toluene was the best
reaction medium in terms of reactivity and enantioselectivity
(entries 17–19). And an 82% yield with 99% ee could be
furnished when running the reaction of 1a with 2e at À108C
instead of room temperature. Remarkably, the catalyst
loading could be further reduced to 2.5 mol%, thus delivering
52% yield and 94% ee.
With the optimized reaction conditions in hand, the scope
with respect to the aryl trifluoromethyl ketimines 1 was
investigated by reaction with 2e (Scheme 2). To our delight,
the aryl trifluoromethyl ketimines bearing diverse functional
groups, such as the halogens (F, Cl, Br), an electron-with-
drawing group (CF3), and electron-donating groups (tBu, Me,
OMe) at the para-position of the phenyl ring generally react
well, thus delivering the corresponding products 5de–he in
good yields with 93–99% ee values under the optimal reaction
conditions. Further substrate scope investigation demon-
strated that the meta-substituent of the aryl trifluoromethyl
ketimines is also compatible and delivers the desired products
5ie–je in good yields and high enantioselectivities. High
ee values and good yields could be also obtained when phenyl
was replaced by other aryl groups such as naphthyl (5ke) and
thienyl (5le). For example, the thienyl-derived 1l delivered
the corresponding amine 5le in 70% yield with 96% ee.
Finally, it is noteworthy that this reaction is amenable to gram
scale without obvious loss of the efficiency and enantioselec-
tivity, even with a lower catalyst loading. 5ae could be
With this hypothesis in mind, we chose the phenyl
trifluoromethyl ketamine 1a with the MBH carbonate 2a as
model substrates (Table 1). Awide variety of chiral phosphine
Table 1: Reaction optimization.[a]
Entry
2, R=
Cat.
Solvent
Yield [%][b] (ee [%])[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21[d]
22[e]
22[f]
2a, Me
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b, Et
2c, Bn
2d, iPr
2e, tBu
2e
(S,RS)-X1
(S,RS)-X10
(S,RS)-W1
(S,RS)-P1
(S,RS)-P2
(S,RS)-P3
(S,RS)-P4
(S,RS)-P5
(S,RS)-P6
(S,RS)-P7
(S,RS)-P8
(S)-P9
(S)-P10
(S)-P10
(S)-P10
(S)-P10
(S)-P10
(S)-P10
(S)-P10
(S)-P10
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
THF
5aa, 61 (62)
5aa, 67 (63)
5aa, 64 (42)
5aa, 67 (60)
5aa, 62 (57)
5aa, 65 (62)
5aa, 68 (58)
5aa, 72 (75)
5aa, 67 (55)
5aa, 66 (66)
5aa, 71 (60)
5aa, 70 (42)
5aa, 78 (81)
5ab, 74 (92)
5ac, 77 (80)
5ad, 75 (96)
5ae, 85 (98)
5ae, 78 (95)
5ae, 84 (95)
5ae, 79 (94)
5ae, 82 (99)
5ae, 73 (97)
5ae, 52 (94)
2e
2e
2e
2e
DCM
Et2O
PhMe
PhMe
PhMe
(S)-P10
(S)-P10
(S)-P10
2e
[a] Unless otherwise specified, 1a (0.2 mmol), 2 (0.3 mmol), catalyst
(0.02 mmol), solvent (2 mL), RT. [b] Yield of isolated product. [c] Deter-
mined by HPLC analysis using a chiral stationary phase. [d] 08C.
[e] 5.0 mol% catalyst, 24 h. [f] 2.5 mol% catalyst, 48 h.
2
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Scheme 3. Asymmetric umpolung reaction of alkyl trifluoromethyl
imines with MBH carbonate. [a] The gram-scale experiment was
carried out with 5 mmol of 1m and 6 mmol of 2e and (S)-P10
(5 mol%).
Scheme 2. Asymmetric umpolung reaction of aryl trifluoromethyl
imines with MBH carbonates. [a] The gram-scale experiment was
carried out with 5 mmol of 3a and 6 mmol of 2e and (S)-P10
(5 mol%) at RT.
obtained in 78% yield with 97% ee for a 5 mmol scale
reaction with the use of 5 mol% (S)-P10.
Encouraged by the above results, we extended the scope
of aryl trifluoromethyl ketimines to alkyl trifluoromethyl
ketimines (Scheme 3). To our delight, a broad range of either
linear or a,b-branched alkyl trifluoromethyl ketimines
worked well with 2e to furnish the desired products 5me–te
in 81–90% yields with 90–99% ee values. It is noteworthy that
even the pretty challenging substrate, the methyl trifluoro-
methyl ketimine 1m, with two similarly bulky groups,
delivered the desired adduct 5me in 90% yield with 98%
ee, and again this reaction was amenable to gram scale, with
a lower catalyst loading (5 mol%), without loss of the
efficiency and enantioselectivity. Moreover, the trifluoro-
methyl ketimines 1u, 1v, and 1w with diverse functional
groups gave the desired products 5ue–we in good yields and
excellent ee values.[10] When the substituted MBH adducts 2 f
and 2g were used, the direct substitution without polarity
inversion (umpolung) of the imine[3n] instead of the umpolung
addition was observed, thus delivering moderate yields of 5mf
and 5mg, having two contiguous stereocenters, in moderate to
good stereoselectivities.
Scheme 4. Further transformations of the products 5ae and 5me.
Reaction conditions: a) 1m HCl, THF, RT; b) 1. CF3CO2H, 2. EDC,
DCM, RT. DCM=dichloromethane, EDC=1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide hydrochloride.
trifluoromethyl amines 6ae (92%) and 6me (90%), respec-
tively, without loss of the chiral information. Further trans-
formations of 5ae and 5me were realized by treatment with
CF3CO2H and then EDC, thus providing the synthetically
valuable a-methylene g-lactams 7ae and 7me, respectively, in
good yields with the excellent ee values. They could serve as
valuable synthetic building blocks, and are often found in
many anticancer drugs because of its cytotoxic properties.[11]
The structures and absolute configurations of 7ae and 7me
were established by X-ray crystallographic analysis and other
products were assigned by analogy.[12]
It appears that the enantioselectivity is primarily influ-
enced by the MBH carbonate moiety, and might provide
a certain rationale for the stereochemical outcome. A
plausible chirality induction model is proposed in Scheme 5,
where the hydrogen bonding between the amide NH with the
imine might play a crucial role in chirality induction. Indeed,
the N-methylated chiral phosphine catalyst (S)-P11[13] deliv-
To illustrate the synthetic utility of the present trans-
formation, two representative transformations of the prod-
ucts were performed as shown in Scheme 4. Upon subjection
of 5ae and 5me to 1m HCl at room temperature, the imine
moiety readily underwent hydrolysis to give the desired chiral
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2007, 50, 319; c) G. L. Grunewald, T. M. Caldwell, Q. Li, K. R.
Criscione, J. Med. Chem. 1999, 42, 3315; d) G. L. Grunewald, J.
Lu, K. R. Criscione, C. O. Okoro, Bioorg. Med. Chem. Lett. 2005,
15, 5319; e) P. D. OꢀShea, C.-Y. Chen, D. Gauvreau, F. Gosselin,
G. Hughes, C. Nadeau, R. P. Volante, J. Org. Chem. 2009, 74,
1605; f) A. Dal Pozzo, M. Ni, L. Muzi, R. D. de Castiglione, R.
Mondelli, S. Mazzini, S. Penco, C. Pisano, M. Castorina, G.
Giannini, J. Med. Chem. 2006, 49, 1808.
[3] For a review of catalytic asymmetric synthesis of trifluoromethyl
amines, see: a) J. Nie, H.-C. Guo, D. Cahard, J.-A. Ma, Chem.
Rev. 2011, 111, 455; for leading examples of catalytic asymmetric
synthesis of trifluoromethylated amines, see: b) P. Fu, M. L.
Snapper, A. H. Hoveyda, J. Am. Chem. Soc. 2008, 130, 5530;
c) L.-H. Sun, Z.-Q. Liang, W.-Q. Jia, S. Ye, Angew. Chem. Int.
Ed. 2013, 52, 5803; Angew. Chem. 2013, 125, 5915; d) L.-M.
Wang, J.-A Chen, Y. Huang, Angew. Chem. Int. Ed. 2015, 54,
15414; Angew. Chem. 2015, 127, 15634; e) Y.-L. Liu, T.-D. Shi, F.
Zhou, X.-L. Zhao, X. Wang, J. Zhou, Org. Lett. 2011, 13, 3826;
f) G. Huang, J. Yang, X. Zhang, Chem. Commun. 2011, 47, 5587;
g) C. Lauzon, A. B. Charette, Org. Lett. 2006, 8, 2743; h) D.
Enders, K. Gottfried, G. Raabe, Adv. Synth. Catal. 2010, 352,
3147; i) N. Hara, R. Tamura, Y. Funahashi, S. Nakamura, Org.
Lett. 2011, 13, 1662; j) R. Husmann, E. Sugiono, S. Mersmann, G.
Raabe, M. Rueping, C. Bolm, Org. Lett. 2011, 13, 1044; k) S.
Zhang, L.-J. Li, Y.-B. Hu, Y.-A. Li, Y. Yang, Z.-G. Zha, Z. Wang,
Org. Lett. 2015, 17, 5036; l) B. Jiang, Y.-G. Shi, Angew. Chem. Int.
Ed. 2004, 43, 216; Angew. Chem. 2004, 116, 218; m) a racemic
[3+2] cycloaddition of MBH adduct with trifluoromethyl imine:
L.-J. Yang, H. Cai, J. Nie, J.-A. Ma, Eur. J. Org. Chem. 2013,
4434; n) an interesting direct reaction of MBH with 2,2,2-
trifluoroethylamine derived imines without polarity inversion
(umpolung) of the imine: X. Li, J. Su, Z. Liu, Y. Zhu, Z. Dong, S.
Qiu, J. Wang, L. Lin, Z. Shen, W. Yan, K. Wang, R. Wang, Org.
Lett. 2016, 18, 956.
Scheme 5. The NH-effect study and the chirality induction model.
ered 5ae in only 33% yield with 51% ee after 24 hours, thus
indicating that the hydrogen-bonding interaction might
indeed contribute significantly to the catalytic activity and
enantioselectivity control.
In summary, we have developed a new method for
asymmetric synthesis of enantioenriched trifluoromethyl
amines with a chiral tertiary stereocenter by a highly effective
and enantioselective phosphine-catalyzed umpolung addition
of trifluoromethyl imines to MBH carbonates under mild
reaction conditions. The salient features for this transforma-
tion include general substrate scope, mild reaction conditions,
good yields, high enantioselectivity, ease of scale-up to gram
scale, and easy conversion into valuable chiral g-trifluoro-
methyl amines, a-methylene esters, and a-methylene
g-lactams. Further studies, including the application of this
new type of chiral phosphine to other related reactions, and
the metal-catalyzed asymmetric umpolung coupling reaction
of trifluoromethyl ketimines are underway, and will be
reported in due course.
[4] For reviews of umpolung reactions, see: a) D. Seebach, Angew.
Chem. Int. Ed. Engl. 1979, 18, 239; Angew. Chem. 1979, 91, 259;
b) A. B. Smith, C. M. Adams, Acc. Chem. Res. 2004, 37, 365;
c) H. U. Vora, T. Rovis, Aldrichimica Acta 2011, 44, 3.
[5] For examples of catalytic umpolung of imines, see: a) X. Xiao, Y.
Xie, C. Su, M. Liu, Y. Shi, J. Am. Chem. Soc. 2011, 133, 12914;
b) M. Liu, J. Li, X. Xiao, Y. Xie, Y. Shi, Chem. Commun. 2013,
49, 1404; c) Y. Wu, L. Deng, J. Am. Chem. Soc. 2012, 134, 14334;
d) Y. Zhu, S. Buchwald, J. Am. Chem. Soc. 2014, 136, 4500; e) M.
Matsumoto, M. Harada, Y. Yamashita, S. Kobayashi, Chem.
Commun. 2014, 50, 13041.
[6] Y. Wu, L. Hu, Z. Li, L. Deng, Nature 2015, 523, 445.
[7] a) X. Su, W. Zhou, Y. Li, J. Zhang, Angew. Chem. Int. Ed. 2015,
54, 6874; Angew. Chem. 2015, 127, 6978; b) W. Zhou, X. Su, M.
Tao, C. Zhu, Q. Zhao, J. Zhang, Angew. Chem. Int. Ed. 2015, 54,
14853; Angew. Chem. 2015, 127, 15066; c) Y. Li, X. Su, W. Zhou,
W. Li, J. Zhang, Chem. Eur. J. 2015, 21, 4224; d) W. Zhou, P.
Chen, M. Tao, X. Su, Q. Zhao, J. Zhang, Chem. Commun. 2016,
52, 7612.
Acknowledgments
We are grateful to the 973 Programs (2015CB856600), the
National Natural Science Foundation of China (21372084,
21425205), and Changjiang Scholars and Innovative Research
Team in University (PCSIRT) for financial support.
Keywords: asymmetric catalysis · enantioselectivity · fluorine ·
organocatalysis · umpolung
[8] For reviews of asymmetric phosphine catalysis, see: a) X. Lu, C.
Zhang, Z. Xu, Acc. Chem. Res. 2001, 34, 535; b) J. L. Methot,
W. R. Roush, Adv. Synth. Catal. 2004, 346, 1035; c) L.-W. Ye, J.
Zhou, Y. Tang, Chem. Soc. Rev. 2008, 37, 1140; d) B. J. Cowen,
S. J. Miller, Chem. Soc. Rev. 2009, 38, 3102; e) A. Marinetti, A.
Voituriez, Synlett 2010, 174; f) W. Li, J. Zhang, Chem. Soc. Rev.
2016, 45, 1657; for selected examples of asymmetric phosphine
catalysis, see: g) J. Sun, G. C. Fu, J. Am. Chem. Soc. 2010, 132,
4568; h) Y. Fujiwara, G. C. Fu, J. Am. Chem. Soc. 2011, 133,
12293; i) S. Y. Lee, Y. Fujiwara, A. Nishiguchi, M. Kalek, G. C.
Fu, J. Am. Chem. Soc. 2015, 137, 4587; j) S. Kramer, G. C. Fu, J.
Am. Chem. Soc. 2015, 137, 3803; k) T. Wang, Z. Yu, D. Hoon, C.
Phee, Y. Lan, Y.-X. Lu, J. Am. Chem. Soc. 2016, 138, 265.
[1] H. Hiyama, Organofluoroine Compounds: Chemistry and Ap-
plications, Springer, Berlin, 2000; For selected reviews, see: a) J.-
A. Ma, D. Cahard, Chem. Rev. 2004, 104, 6119; b) M. Shimizu, T.
Hiyama, Angew. Chem. Int. Ed. 2005, 44, 214; Angew. Chem.
2005, 117, 218; c) K. Mꢁller, C. Faeh, F. Diederich, Science 2007,
317, 1881; d) L. E. Zimmer, C. Sparr, R. Gilmour, Angew. Chem.
Int. Ed. 2011, 50, 11860; Angew. Chem. 2011, 123, 12062.
[2] For selected examples, see: a) J. Lim, B. Taoka, R. D. Otte, K.
Spencer, C. J. Dinsmore, M. D. Altman, G. Chan, C. Rosenstein,
S. Sharma, H.-P. Su, A. A. Szewczak, L. Xu, H. Yin, J. Zugay-
Murphy, C. G. Marshall, J. R. Young, J. Med. Chem. 2011, 54,
7334; b) N. Zhang, S. Ayral-Kaloustian, T. Nguyen, J. Afragola,
R. Hernandez, J. Lucas, J. Gibbons, C. Beyer, J. Med. Chem.
4
www.angewandte.org
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Angewandte
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Chemie
[9] For reviews on the MBH reactions, see: a) D. Basavaiah, B. S.
[11] For a review on the importance of a-methylene g-lactams, see:
Reddy, S. S. Badsara, Chem. Rev. 2010, 110, 5447; b) P. Langer,
Angew. Chem. Int. Ed. 2000, 39, 3049; Angew. Chem. 2000, 112,
3177; c) Y. Wei, M. Shi, Chem. Rev. 2013, 113, 6659; d) Y. Wei,
M. Shi, Chem. Asian J. 2014, 9, 2720; e) S. Wang, X.-Y. Han, F.-R.
Zhong, Y.-Q. Wang, Y.-X. Lu, Synlett 2011, 2766; f) D. Basa-
vaiah, A. J. Rao, T. Satyanarayana, Chem. Rev. 2003, 103, 811;
g) D. Basavaiah, K. V. Rao, R. J. Reddy, Chem. Soc. Rev. 2007,
36, 1581; h) Y.-L. Shi, M. Shi, Eur. J. Org. Chem. 2007, 2905; i) G.
Ma, J. Jiang, M. Shi, Y. Wei, Chem. Commun. 2009, 5496; j) V.
Declerck, J. Martinez, F. Lamaty, Chem. Rev. 2009, 109, 1; k) T.-
Y. Liu, M. Xie, Y.-C. Chen, Chem. Soc. Rev. 2012, 41, 4101; for
selected examples of MBH carbonates, see: l) F. Zhong, X. Han,
Y. Wang, Y. Lu, Angew. Chem. Int. Ed. 2011, 50, 7837; Angew.
Chem. 2011, 123, 7983; m) F. Zhong, J. Luo, G. Chen, X. Dou, Y.
Lu, J. Am. Chem. Soc. 2012, 134, 10222; n) L. Zhang, H. Liu, G.
Qiao, Z. Hou, Y. Liu, Y. Xiao, H. Guo, J. Am. Chem. Soc. 2015,
137, 4316; o) J. Peng, G. Ran, W. Du, Y.-C. Chen, Org. Lett. 2015,
17, 4490; p) Y. Jiang, Y. Shi, M. Shi, J. Am. Chem. Soc. 2008, 130,
7202; q) C.-W. Cho, M. J. Krische, Angew. Chem. Int. Ed. 2004,
43, 6689; Angew. Chem. 2004, 116, 6857; r) Q. Wang, S. Zhu, L.
Ye, C. Zhou, X. Sun, Y. Tang, Q. Zhou, Adv. Synth. Catal. 2010,
352, 1914; s) B. Tan, N. R. Candeias, C. F. Barbas III, J. Am.
Chem. Soc. 2011, 133, 4672.
a) A. Janecka, A. Wyrebska, K. Gach, J. Fichna, T. Janecki, Drug
Discovery Today 2012, 17, 561; for selected examples on the
importance of a-methylene g-lactams, see: b) X. Companyꢂ, P.-
Y. Geant, A. Mazzanti, A. Moyano, R. Rios, Tetrahedron 2014,
70, 75; c) F. Pan, J. Chen, Z. Zhuang, Y. Fang, S. Zhang, W. Liao,
Org. Biomol. Chem. 2012, 10, 2214; d) X. Companyꢂ, A.
Mazzanti, A. Moyano, A. Janecka, R. Rios, Chem. Commun.
2013, 49, 1184; e) T. Janecki, E. Blaszczyk, K. Studzian, A.
Janecka, U. Krajewska, M. Rꢂzalski, J. Med. Chem. 2005, 48,
3516; f) Y. Zhu, X. Li, Q. Chen, J. Su, F. Jia, S. Qiu, M. Ma, Q.
Sun, W. Yan, K. Wang, R. Wang, Org. Lett. 2015, 17, 3826; g) J.
Xu, J. Chen, Q. Yang, L. Ding, X. Liu, D. Xu, B. Zhao, Adv.
Synth. Catal. 2014, 356, 3219.
[12] CCDC 1474183 (7ae) and 1474183 (7me) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre.
[13] a) Y. Xia, Y. Liang, Y. Chen, M. Wang, L. Jiao, F. Huang, S. Liu,
Y. Li, Z. Yu, J. Am. Chem. Soc. 2007, 129, 3470; b) G. Huang, T.
Lankau, C. Yu, J. Org. Chem. 2014, 79, 1700.
[10] Unfortunately, we made much effort but failed to make the
corresponding imine derived from propargylic trifluoromethyl
ketones.
Received: August 14, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Organocatalysis
P. Chen, Z. Yue, J. Zhang, X. Lv, L. Wang,
J. Zhang*
&&&& — &&&&
Phosphine-Catalyzed Asymmetric
Umpolung Addition of Trifluoromethyl
Ketimines to Morita–Baylis–Hillman
Carbonates
Flip flop: The title reaction provides facile
access to optically active trifluoromethyl
amines with a tertiary stereocenter under
mild reaction conditions. The salient
features of this reaction include a general
substrate scope, good yields, and high
enantioselectivities. Boc=tert-butoxycar-
bonyl.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!