Direct catalytic asymmetric alkynylation of ketoimines

Article abstract of DOI:10.1021/ol3035609

An efficient protocol for direct catalytic alkynylation of ketoimines is described. The simultaneous activation of a soft Lewis basic terminal alkyne and a ketoimine bearing a thiophosphinoyl group by soft Lewis acid Cu(I) is crucial for high conversion. The reaction can be rendered asymmetric with a chiral bisphosphine ligand (S,S)-Ph-BPE.

Full text of DOI:10.1021/ol3035609

ORGANIC
LETTERS
2013
Vol. 15, No. 3
698–701
Direct Catalytic Asymmetric Alkynylation
of Ketoimines
Liang Yin,† Yasunari Otsuka,† Hisashi Takada,† Shinsuke Mouri,† Ryo Yazaki,†
Naoya Kumagai,*,† and Masakatsu Shibasaki*,†,‡
Institute of Microbial Chemistry (BIKAKEN), Tokyo 3-14-23 Kamiosaki,
Shinagawa-ku, Tokyo 141-0021, Japan, and JST, ACT-C, 3-14-23 Kamiosaki,
Shinagawa-ku, Tokyo 141-0021, Japan
nkumagai@bikaken.or.jp; mshibasa@bikaken.or.jp
Received January 3, 2013
ABSTRACT
An efficient protocol for direct catalytic alkynylation of ketoimines is described. The simultaneous activation of a soft Lewis basic terminal alkyne
and a ketoimine bearing a thiophosphinoyl group by soft Lewis acid Cu(I) is crucial for high conversion. The reaction can be rendered asymmetric
with a chiral bisphosphine ligand (S,S)-Ph-BPE.
Construction of a tetrasubstituted stereogenic center is
still a subject of intensive research in organic chemistry.1
Approaches that incorporate the atom-economical proton-
transfer reaction are highly desirable.2 A generally adopted
method to access R-tetrasubstituted amines 1 is a catalytic
asymmetric CÀN bond-forming reaction (Scheme 1a).3 The
alternative way to access 1 is by a catalytic asymmetric
addition of carbon nucleophiles to ketoimines 2.4 The latter
would be more favorable because the stereogenic center
is produced with concomitant formation of carbon frame-
works (Scheme 1b). However, the scope of a catalytic asym-
metric addition of carbon pronucleophiles to ketoimines 2
that proceeds with perfect atom economy is severely limited,
presumably because of a highly congested transition state.
Enantioselective additions under proton-transfer conditions
have been sporadically reported using HCN,5 allylic cya-
nides,6 and nitromethane.7,8 Herein we report the first
example of a direct catalytic asymmetric addition of terminal
alkynes to ketoimines under proton-transfer conditions.9
The simultaneous activation of pronucleophiles and electro-
philes, terminal alkynes and ketoimines, is key to achieving
this unprecedented reaction.
The direct catalytic addition of terminal alkynes to
ketoimines is in its infancy and has suffered from low yield
(4) General catalytic asymmetric addition to ketoimines using orga-
nometallic nucleophiles: (a) Chavarot, M.; Byrne, J. J.; Chavant, P. Y.;
ꢀ
Vallee, Y. Tetrahedron: Asymmetry 2001, 12, 1147. (b) Masumoto, S.;
Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2003, 125, 5634. (c) Saaby, S.; Nakama, K.; Lie, M. A.; Hazell, R. G.;
Jørgensen, K. A. Chem.;Eur. J. 2003, 9, 6145. (d) Berger, R.; Duff, K.;
Leighton, J. L. J. Am. Chem. Soc. 2004, 126, 5686. (e) Huang, X.; Huang,
J.; Wen, Y.; Feng, X. Adv. Synth. Catal. 2006, 348, 2579. (f) Lauzon, C.;
Charette, A. B. Org. Lett. 2006, 8, 2743. (g) Wada, R.; Shibuguchi, T.;
Makino, S.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2006, 128, 7687. (h) Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2007, 129, 500. (i) Wang, J.; Hu, X.; Jiang, J.; Gou, S.; Huang, X.;
Liu, X.; Feng, X. Angew. Chem., Int. Ed. 2007, 46, 8468. (j) Fu, P.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 5530.
(k) Du, Y.; Xu, L.-W.; Shimizu, Y.; Oisaki, K.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2008, 130, 16146. (l) Wieland, L. C.; Vieira, E. M.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 570.
(m) Shintani, R.; Takeda, M.; Tsuji, T.; Hayashi, T. J. Am. Chem. Soc.
2010, 132, 13168. (n) Shintani, R.; Takeda, M.; Soh, Y.-T.; Ito, T.;
Hayashi, T. Org. Lett. 2011, 13, 2977. (o) Huang, G.; Yang, J.; Zhang, X.
Chem. Commun. 2011, 47, 5587. (p) Nishimura, T.; Noishiki, A.; Tsui,
G. C.; Hayashi, T. J. Am. Chem. Soc. 2012, 134, 5056. (q) Nishimura, T.;
Noishiki, A.; Tsui, G. C.; Hayashi, T. J. Am. Chem. Soc. 2012, 134, 5056.
† Institute of Microbial Chemistry (BIKAKEN).
‡ JST.
(1) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
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r
10.1021/ol3035609
Published on Web 01/18/2013
2013 American Chemical Society

Scheme 1. Enantioselective Access to R-Tetrasubstituted
Amines 1 via (a) CÀN Bond Formation and (b) CÀC Bond
Formation
Scheme 2. Direct Alkynylation of Ketoimine Based on Simul-
taneous Activation of Terminal Alkyne and Ketoimine
and low catalytic efficiency, even in the racemic manifesta-
tion. Due to steric constraints and electronic factors, the
susceptibility of ketoimines toward nucleophilic attack is
significantly lower compared with the corresponding
aldimines.10 Ketoimines derived from cyclic ketones
exhibit generally higher electrophilicity, and the direct cata-
lytic addition to them has been partly addressed by the use
of Ir/Mg,11 Cu(I),12 and Au catalysis.13 Quite recently,
Larsen et al. disclosed a high-yielding protocol for the
direct addition of a terminal alkyne to in situ generated
ketoimines derived from acyclic ketones using Cu/Ti bi-
metallic catalysis.14,15 Despite the successful broadening of
substrategenerality, therequirementsforhigh temperature
and a substoichiometric amount of Ti(OEt)4 (50 mol %)
may be the subject of further improvement.14
We hypothesized that simultaneous activation of term-
inal alkynes and ketoimines compensates for the intrinsic
low reactivity of this specific reaction, allowing for the
efficient production of the desired propargyl amines bear-
ing a tetrasubstituted carbon (Scheme 2). Catalytic gen-
eration of the active nucleophile, Cu-alkynylide, can be
achieved by using a soft Lewis acid/hard Brønsted base
cooperative catalytic system.16,17 To render the simulta-
neous activation in close proximity, soft Lewis basic
functionality was installed on the ketoimine. The thiopho-
sphinoyl group18 emerged as a suitable soft Lewis basic
functionality, and the direct addition ofphenylacetylene 3a
to ketoimine 2a proceeded smoothly at 50 °C with 5 mol %
of the soft Lewis acid/hard Brønsted base cooperative
catalyst comprising [Cu(CH3CN)4]PF6, Xantphos, and Li-
(OC6H4-p-OMe) (Scheme 2a).16b,19 The analogous phosphi-
noyl-type ketoimine20 substrate 5 lacking soft Lewis basic
functionality failed to afford the corresponding alkynylation
product, indicating that the activation of ketoimine 2a
through the interaction between sulfur and copper is crucial
to promote the reaction (Scheme 2b). The catalytic system
was simplified to mesitylcopper/Xantphos.21 Cu-phenylace-
tylide 7 was formed with the liberation of mesitylene in the
(5) (a) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867. (b)
ꢀ
Chavarot, M.; Byrne, J. J.; Chavant, P. Y.; Vallee, Y. Tetrahedron:
Asymmetry 2001, 12, 1147. (c) Vachal, P.; Jacobsen, E. N. J. Am. Chem.
Soc. 2002, 124, 10012. (d) Rueping, M.; Sugiono, E.; Moreth, S. A. Adv.
Synth. Catal. 2007, 349, 759.
(6) Yazaki, R.; Nitabaru, T.; Kumagai, N.; Shibasaki, M. J. Am.
Chem. Soc. 2008, 130, 14477.
(16) For recent reviews on cooperative catalysis, see: Lewis acid/
Brønsted base: (a) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102,
2187. (b) Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2011, 50,
4760. Lewis acid/Lewis base: (c) Kanai, M.; Kato, N.; Ichikawa, E.;
Shibasaki, M. Synlett 2005, 1491. (d) Paull, D. H.; Abraham, C. J.;
Scerba, M. T.; Alden-Danforth, E.; Lectka, T. Acc. Chem. Res. 2008, 41,
655. Lewis acid/Brønsted acid and Lewis acid/Lewis acid: (e) Yamamoto,
H.; Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924. (f) Yamamoto, H.;
Futatsugi, K. In Acid Catalysis in Modern Organic Synthesis; Yamamoto, H.,
Ishihara, K., Eds.; Wiley-VCH: Weinheim, 2008.
(7) Tan, C.; Liu, X.; Wang, L.; Wang, J.; Feng, X. Org. Lett. 2008, 10,
5305.
(8) For examples using highly active R-alkoxycarbonylketoimines as
an electrophile, see: (a) Zhuang, W.; Saaby, S.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2004, 43, 4476. (b) Sukach, V. A.; Golovach, N. M.;
Pirozhenko, V. V.; Rusanov, E. B.; Vovk, M. V. Tetrahedron: Asym-
metry 2008, 19, 761.
(17) Yazaki, R.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2010,
132, 10275.
(9) Direct catalytic asymmetric alkynylation of C,N-cyclic azo-
methine imines to construct a tetrasubstituted stereogenic center:
Hashimoto, T.; Omote, M.; Maruoka, K. Angew. Chem., Int. Ed. 2011,
50, 8952.
(18) Synthesis of N-(thiophosphinoyl)imines: (a) Xu, X.; Wang, C.;
Zhou, Z.; Zeng, Z.; Ma, X.; Zhao, G.; Tang, C. Heteroat. Chem. 2008,
19, 238. Application of N-thiophosphinoylimines as an electrophile:
(b) Ma, X.; Wang, C.; Xu, X.; Zhao, G.; Zhou, Z.; Tang, C. Lett. Org.
Chem. 2007, 4, 51. (c) Ma, X.; Xu, X.; Wang, C.; Zhao, G.; Zhou, Z.;
Tang, C. J. Organomet. Chem. 2007, 692, 3685. (d) Xu, X.; Wang, C.;
Zhou, Z.; Tang, X.; He, Z.; Tang, C. Eur. J. Org. Chem. 2007, 4487.
(e) Lu, A.; Xu, X.; Gao, P.; Zhou, Z.; Song, H.; Tang, C. Tetrahedron:
Asymmetry 2008, 19, 1886. (f) Zhang, B.; He, Z.; Xu, S.; Wu, G.; He, Z.
Tetrahedron 2008, 64, 9471. (g) Hu, K.; Wang, C.; Ma, X.; Wang, Y.;
Zhou, Z.; Tang, C. Tetrahedron: Asymmetry 2009, 20, 2178.
(19) A review on a soft Lewis acid/hard Brønsted base cooperative
catalyst comprising cationic Cu(I) and Li aryloxide for asymmetric
proton-transfer catalysis: Kumagai, N.; Shibasaki, M. Isr. J. Chem.
2012, 52, 604.
(10) Recent reviews on alkynylation of aldimines: (a) Blay, G.;
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Monleon, A.; Pedro, J. R. Curr. Org. Chem. 2009, 13, 1498. (b) Yoo,
W. J.; Zhao, L.; Li, C.-J. Aldrichimica Acta 2011, 44, 43.
(11) Fischer, C.; Carreira, E. M. Synthesis 2004, 1497.
(12) (a) Pereshivko, O. P.; Peshkov, V. A.; Van der Eycken, E. V. Org.
Lett. 2010, 12, 2638. (b) Pierce, C. J.; Larsen, C. H. Green Chem. 2012,
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(14) Pierce, C. J.; Nguyen, M.; Larsen, C. H. Angew. Chem., Int. Ed.
Early view. doi: 10.1002/anie.201206674.
(15) A partly successful example of direct catalytic alkynylation to
(20) For a review on the utility of N-(diphenylphosphinoyl)imines,
see: Weinreb, S. M.; Orr, R. K. Synthesis 2005, 1205.
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ketoimines derived from acyclic ketones: Aliaga, M. J.; Ramon, D. J.;
Yus, M. Org. Biomol. Chem. 2010, 8, 43.
(21) A recent review on mesitylcopper: Stollenz, M.; Meyer, F.
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Org. Lett., Vol. 15, No. 3, 2013
699

Table 2. Direct Catalytic Asymmetric Alkynylation of
Ketoiminesa
Scheme 3. Direct Alkynylation of Ketoimine Based on the
Simultaneous Activation of Terminal Alkyne and Ketoimine
Table 1. Direct Catalytic Alkynylation of Ketoiminesa
a 2, 0.1 mmol; 3, 0.2 mmol. “P” stands for diphenylthiophosphinoyl
group. b Reaction time was 72 h. c Reaction temperature was 50 °C.
d 5 equiv of alkyne were used. e O-THP protected propargyl alcohol was
used. Acidic treatment (10 mol % of NH2SO3H, THF/H2O = 1/1, at rt,
1 h) afforded 4y. THP = tetrahydro-2H-pyran-2-yl.
initial cycle, and the reaction intermediate Cu-amido complex
8 functioned as a soft Lewis acid/hard Brønsted base co-
operative catalyst to drive the following catalytic cycle
(Scheme 3).22
These reaction conditions showed broad substrate gen-
erality (Table 1). High conversion was observed with a
5 mol % catalyst loading irrespective of the electronic nature
of the aromatic group or steric factors of the alkyl group
adjacent to the ketoimine carbon (entries 1À5). The reaction
could be run with as little as a 1 mol % catalyst loading at a
marginally higher temperature with a longer reaction time
(entry 3). Substituted phenylacetylenes served as suitable
substrates in this direct alkynylation, affording the corre-
sponding propargylamine in high yield (entries 6À11). No
detrimental effect was observed in the reaction employ-
ing terminal alkynes bearing soft Lewis basic thienyl or
pyridyl functionality (entries 12, 13). Terminal alkynes
bearing branched or linear alkyl substituents could be used
(22) Recent examples of asymmetric proton-transfer catalysis utiliz-
ing a mesitylcopper/chiral phosphine precatalyst: (a) Yazaki, R.;
Kumagai, N.; Shibasaki, M. Chem.;Asian J. 2011, 6, 1778. (b) Kawato,
Y.; Iwata, M.; Yazaki, R.; Kumagai, N.; Shibasaki, M. Tetrahedron
2011, 67, 6539. (c) Ogawa, T.; Mouri, S.; Yazaki, R.; Kumagai, N.;
Shibasaki, M. Org. Lett. 2012, 14, 110. (d) Ogawa, T.; Kumagai, N.;
Shibasaki, M. Angew. Chem., Int. Ed. 2012, 51, 8551.
a 2, 0.1 mmol; 3, 0.2 mmol. “P” stands for diphenylthiophosphinoyl
group. b Reaction was run at 60 °C for 48 h. c 5 equiv (0.5 mmol) of
alkyne were used. d Reaction was run at 70 °C for 48 h. 1.0 g of ketoimine
was used. e Reaction was run with dried MS4A (50 mg) in toluene/
THF = 1/1 for 48 h.
700
Org. Lett., Vol. 15, No. 3, 2013

direct catalytic asymmetric alkynylation of acyclic ketoi-
mines derived from simple ketones, displaying the utility of
a simultaneous activation strategy in asymmetric proton-
transfer catalysis.24
Scheme 4. Transformation of the Alkynylation Product
Subjection of 4v to K2CO3/18-crown-6 in refluxing
toluene led to the loss of the acetone unit to afford terminal
alkyne 9 in 86% yield (Scheme 4).25 Diimide reduction of 9
afforded the corresponding saturated product, and subse-
quent treatment with Raney-Ni under a hydrogen atmo-
sphere cleaved the NÀP bond to give free amine 10.18b The
reduction of 4a with LiAlH4 converted the alkyne part to
an E-configured double bond in quantative yield. Raney-
Ni reduction in acetonitrile at 50 °C followed by acidic
treatment produced allylic amine 11 in 80% yield.26
In conclusion, an efficient protocol for the direct cata-
lytic alkynylation of ketoimines was disclosed. The simulta-
neous activation of both pronucleophiles and electrophiles,
terminal alkynes and ketoimines, is key to achieving high
conversion. Despite the moderate enantioselectivity, the
present catalysis was implemented to render the reaction
asymmetric. Improvements in the enantioselectivity and
application of the protocol to the enantioselective synthesis
of biologically active compounds are currently underway.
(entries 14À22). In particular, the successful adaptation of
alkynes bearing a free hydroxyl group highlighted the utility
of this alkynylation protocol (entries 20À22). The reaction
using 2-methylbut-3-yn-2-ol is worth noting because it is an
acetylene equivalent, and basic treatment of the product
generated a synthetically versatile terminal alkyne (entries
21, 22, vide infra). The reaction could scaled to proceed
using 1 g of ketoimine. A ketoimine derived from aliphatic
ketone was sufficiently stable under the reaction conditions,
and the corresponding alkynylation products 4w and 4x
were produced (entries 23, 24).
The disclosed efficient protocol for direct alkynylation
of ketoimines was rendered asymmetric with the use of (S,S)-
Ph-BPE as a chiral bisphosphine ligand (Table 2). With a
range of substrates studied in a racemic system, direct
catalytic asymmetric alkynylation proceeded with 10 mol %
of a mesitylcopper/(S,S)-Ph-BPE precatalyst, affording the
propargylamines 4 with 50À80% ee.
Acknowledgment. This work was financially supported
byJSPSKAKENHI (Grant Nos. 20229001and 23590038)
and JST, ACT-C. L.Y. thanks JSPS for a postdoctoral
fellowship.
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.
A screening of chiral ligands showed (S,S)-Ph-BPE to
outperform the other chiralphosphine ligands.23 Although
there is still room for improvement in enantioselectivity, to
the best of our knowledge, this is the first example of a
(26) Any attempts at removing the thiophosphinoyl group from the
alkynylation product such as 9 under acidic conditions resulted in the
formation of 1,3-enyne compounds via β-elimination. Extensive inves-
tigation to overcome the problem mentioned above is currently
underway.
(23) See Supporting Information.
(24) A catalytic asymmetric alkynylation of highly electrophilic
ketoimines derived from R-ketoeters was reported in BOSS XIII;
Ohshima, T.; Morisaki, K.; Nomaguchi, J.; Morimoto, H.; Kawabata,
T.; Takeuchi, Y.; Mashima, K. Book of abstract, BOSS XIII, P089.
ꢀ
(25) Boyall, D.; Lopez, F.; Sasaki, H.; Frantz, D.; Carreira, E. M.
The authors declare no competing financial interest.
Org. Lett. 2000, 2, 4233.
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