Direct access to: N -unprotected tetrasubstituted propargylamines via direct catalytic alkynylation of N -unprotected trifluoromethyl ketimines

Article abstract of DOI:10.1039/c7cc02194a

Direct catalytic alkynylation of N-unprotected trifluoromethyl ketimines is reported for the first time. A combination of catalytic amounts of diethylzinc and carboxylic acids promoted the reactions under proton-transfer conditions, allowing an unprecedented direct access to N-unprotected α-tetrasubstituted primary amines without additional deprotection steps.

Full text of DOI:10.1039/c7cc02194a

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Direct access to N-unprotected tetrasubstituted
propargylamines via direct catalytic alkynylation
of N-unprotected trifluoromethyl ketimines†
Cite this:DOI: 10.1039/c7cc02194a
Received 23rd March 2017,
Accepted 20th April 2017
Kazuhiro Morisaki, Hiroyuki Morimoto * and Takashi Ohshima
*
DOI: 10.1039/c7cc02194a
rsc.li/chemcomm
Direct catalytic alkynylation of N-unprotected trifluoromethyl
ketimines is reported for the first time. A combination of catalytic
amounts of diethylzinc and carboxylic acids promoted the reac-
tions under proton-transfer conditions, allowing an unprecedented
direct access to N-unprotected a-tetrasubstituted primary amines
without additional deprotection steps.
Propargylamines are useful, valuable building blocks and
important structural motifs in organic chemistry for synthesiz-
ing functionalized molecules, such as natural products and
pharmaceuticals.1 Metal-assisted alkynylation of N-protected
imines is one of the most straightforward and concise methods
to obtain propargylamines,2 and various methodologies using
stoichiometric amounts of metal reagents, such as dialkylzinc
and alkyllithium, are reported (Scheme 1, path a). Catalytic
generation of nucleophilic metal acetylide species directly from
terminal alkynes in situ and subsequent C–C bond formation is,
however, more desirable in terms of atom economy (path b).3
Direct catalytic alkynylation of imines is well explored for
N-protected aldimines and ketimines.2 Although these alkynyla-
Scheme 1 Catalytic alkynylation of ketimines to produce N-unprotected
propargylamines.
tion reactions are effective for synthesizing N-protected propargyl- however, alkynylation of N-unprotected ketimines is unprece-
amines, their products require additional deprotection steps to dented, and their use in C–C bond formation under proton-
obtain N-unprotected propargylamines. These deprotection steps transfer conditions has been limited to the addition of HCN,10
potentially limit the synthetic utility of propargylamines, because Mannich-type reactions of acetone,11 annulation via directed C–H
some functional groups may not be compatible under the depro- bond functionalization,8i and Friedel–Crafts-type addition of
tection conditions.4
electron-rich heteroarenes.12,13 In addition, potential challenges
A promising strategy to circumvent these problems is the for the use of N-unprotected imines listed in Scheme 1 hamper
use of N-unprotected imines, which could directly provide the development of such reactions. Herein we report the direct
the desired N-unprotected amine products without additional catalytic alkynylation of N-unprotected trifluoromethyl ketimines,
protection/deprotection steps (path c).5 N-Unprotected ketimines allowing for a direct access to a-tetrasubstituted primary propar-
and their salts are valuable substrates, especially for the direct gylamines bearing a trifluoromethyl moiety in high yields under
synthesis of unprotected amines.6–9 To the best of our knowledge, proton-transfer conditions. The unique chemoselectivity of the
catalytic system was demonstrated in a direct alkynylation of
Graduate School of Pharmaceutical Sciences, Kyushu University,
N-unprotected ketimines in the presence of N-protected ketimines
and aldimines.
Maidashi 3-1-1 Higashi-ku, Fukuoka, 812-8582, Japan.
E-mail: ohshima@phar.kyushu-u.ac.jp, hmorimot@phar.kyushu-u.ac.jp
Our investigation began with N-unprotected trifluoromethyl
† Electronic supplementary information (ESI) available: Experimental procedures
ketimines 1 because of the importance of the a-trifluoromethyl
and characterization data of synthesized compounds. See DOI: 10.1039/
c7cc02194a
amine moiety in pharmaceuticals.14 Notably, the reported
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Table 1 Substrate scope
Scheme 2 Optimized reaction conditions.
alkynylation of trifluoromethyl ketimines has been limited to
N-protected trifluoromethyl ketimines with the use of stoichio-
metric amounts of metal reagents.15 In the initial study, Cu(I)16
and Rh(III)17 catalysts, known to be effective for direct catalytic
alkynylation of N-protected ketimines, were examined; how-
ever, they did not promote the reaction with N-unprotected
trifluoromethyl ketimine 1a.18 We next examined the use of
catalytic amounts of (dialkyl)zinc in combination with the appro-
priate proton source because the use of (dialkyl)zinc is known to
be effective for the alkynylation of N-protected trifluoromethyl
ketimines,15d although a stoichiometric amount of (dialkyl)zinc is
used under the reaction conditions. We were delighted to find
that the combination of catalytic amounts of Et2Zn and AcOH in a
1 : 1 ratio gave the desired product 3a in 60% yield, confirming the
utility of N-unprotected trifluoromethyl ketimine 1a under
proton-transfer conditions. Further screening of carboxylic acids
and solvents18 revealed that 4-nitrobenzoic acid in chlorobenzene
gave the best reactivity, allowing for reduction of the catalyst
loading to 5 mol% and amount of alkyne 2a to 1.5 equivalent
(Scheme 2).
With the optimized conditions in hand, we next investigated
the substrate scope (Table 1). A gram-scale reaction and further
reduction of catalyst loading to 2.5 mol% was successfully
performed. Various aryl- and alkyl-substituted alkynes were
applicable to the reaction. Unprotected aniline, acid-labile
acetal, and N-Boc indole were compatible under the reaction
conditions, highlighting the broad functional group tolerance
of the catalytic system. Trimethylsilylacetylene, an acetylene equi-
a
b
5.0 mmol of 1a was used in chlorobenzene (2.0 M). 2.5 mol% of Et2Zn
c
and 4-nitrobenzoic acid was used. 3.0 equiv. of alkynes 2 were used.
valent, also gave the product 3o. In addition, base-sensitive species under our catalytic conditions (reaction (b), top). It is
heteroatom-attached aliphatic alkynes were successfully trans- noteworthy that alkynylation of aldimine 6 proceeded pre-
formed into the products 3p–r. We then screened N-unprotected dominantly in the presence of a Cu(I) catalyst20 to give 7a, which is
trifluoromethyl ketimines. N-Unprotected trifluoromethyl ketimines complementary to our reaction conditions (reaction (b), bottom).
1 were readily synthesized in one step from the corresponding The unique chemoselectivity of our catalytic system allowed for a
trifluoromethyl ketones and imino(triphenyl)phosphorane.10,18 reaction between 1a and alkyne 2s with N-PMP-protected aldimine
Various aryl-substituted N-unprotected trifluoromethyl ketimines moiety, and the desired product 3z was obtained in 72% yield
were applicable for the reaction to afford the products 3s–w. It is (reaction (c)).
notable that even enolizable aliphatic trifluoromethyl ketimines
afforded the products 3x and 3y in high yields.
To demonstrate the utility of N-unprotected propargyla-
mines, we performed a transformation of the product 3a
Consistent with our recent interest in catalyst control of (Scheme 4). Partial and full reductions of the alkynyl moiety
chemoselectivity,19 we performed competitive experiments of 3a were realized under the appropriate hydrogenation con-
between N-unprotected trifluoromethyl ketimine 1a and ditions to give products 8 and 9, respectively. The unprotected
N-( p-methoxyphenyl) (PMP) imines, one of the most frequently primary amino group of 3a was directly used for coupling
used N-protected imines for alkynylation reactions (Scheme 3). reactions with quinolinoyl chloride and isocyanate to give 10
A competitive reaction between 1a and N-PMP-protected and 11, both of which are alkynylated analogs of biologically
trifluoromethyl ketimine 4 revealed that 1a was more reactive active compounds.21
than 4 under our reaction conditions (reaction (a)). Similar
Although the exact reaction mechanism is yet to be clarified, we
chemoselectivity was observed even in the case of more reactive obtained preliminary experimental results that support the presence
N-PMP-protected aldimine 6, and 3a was obtained as a major of (alkynyl)(carboxylato)zinc(II) as the active species (Scheme 5).
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Scheme 5 Preliminary mechanistic studies.
(amido)(carboxylato)zinc(II) species.18 After generation of the
(amido)zinc(II) species, the desired product would be released
through the mechanism where terminal alkynes function as the
proton source.26
In summary, we developed a direct catalytic alkynylation of
N-unprotected trifluoromethyl ketimines that directly afforded
N-unprotected a-tetrasubstituted propargylamines bearing an
a-trifluoromethyl group without the need for additional depro-
tection steps. The combination of catalytic amounts of diethyl-
zinc and carboxylic acids was essential for such transformations.
In this catalytic system, alkynylation of N-unprotected ketimines
proceeded selectively over the reaction with N-PMP-protected
imines, which is complementary in the chemoselectivity of
commonly used Cu(I) catalysis. Furthermore, the a-tertiary primary
propargylamine product can be directly used for derivatization,
including the synthesis of alkynylated analogs of biologically active
molecules. Application of this methodology to other N-unprotected
imines, further elucidation of the reaction mechanism, and
development of the enantioselective version are ongoing in our
laboratory.
Scheme 3 Chemoselective alkynylation of N-unprotected trifluoro-
methyl ketimines over N-protected ketimines and aldimines.
Scheme 4 Transformation of the product.
This work was supported by Grant-in-Aid for Scientific
Research (C) (JSPS KAKENHI Grant Number JP15K07860 for
H. M.) and Grant-in-Aid for Scientific Research on Innovative
Areas (JSPS KAKENHI Grant Number JP15H05846 in Middle
Molecular Strategy for T. O.) from JSPS, Platform for Drug
Discovery, Informatics, and Structural Life Science from AMED,
Uehara Memorial Foundation and Takeda Science Foundation.
K. M. thanks JSPS for Research Fellowships for Young Scientists.
First, control experiments using different ratios of Et2Zn and
AcOH revealed that the use of Et2Zn and AcOH in a 1 : 1 ratio
gave the desired product 3a in 60% yield, whereas Et2Zn in the
absence of AcOH and Et2Zn and AcOH in a 1 : 2 ratio gave 3a in
low yields (eqn (1)).22 These results and information from the
literature that (alkynyl)zinc(II) and (carboxylato)zinc(II) species
readily forms from diethylzinc23 suggest (alkynyl)(carboxylato)-
zinc(II) as the most likely species to be involved during the
reactions.24 Second, the use of chiral acid 12 as a co-catalyst of
Et2Zn revealed that both 3a and 3k were obtained in an enantio-
selective fashion, suggesting the presence of (alkynyl)zinc(II)
species associated with the chiral counter anion as the active
species (eqn (2)).25 From these experimental results, we propose
that (alkynyl)(carboxylato)zinc(II) species I would form under
the catalytic conditions (eqn (3)) and promote the addition
reactions to N-unprotected trifluoromethyl ketimines to give
Notes and references
1 For examples, see: (a) M. A. Huffman, N. Yasuda, A. E. DeCamp and
E. J. J. Grabowski, J. Org. Chem., 1995, 60, 1590; (b) G. S. Kauffman,
G. D. Harris, R. L. Dorow, B. R. P. Stone, R. L. Parsons, Jr., J. A. Pesti,
N. A. Magnus, J. M. Fortunak, P. N. Confalone and W. A. Nugent,
Org. Lett., 2000, 2, 3119; (c) B. Jiang and M. Xu, Angew. Chem., Int. Ed.,
2004, 43, 2543; (d) B. M. Trost, C. K. Chung and A. B. Pinkerton,
Angew. Chem., Int. Ed., 2004, 43, 4327; (e) J. J. Fleming and J. Du Bois,
J. Am. Chem. Soc., 2006, 128, 3926.
2 For recent reviews, see: (a) V. A. Peshkov, O. P. Pereshivko and
E. V. Van der Eycken, Chem. Soc. Rev., 2012, 41, 3790; (b) N. Uhlig,
This journal is ©The Royal Society of Chemistry 2017
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View Article Online
Communication
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W.-J. Yoo, L. Zhao and C.-J. Li, in Modern Alkyne Chemistry: Catalytic
and Atom-Economic Transformations, ed. B. M. Trost and C.-J. Li,
Wiley-VCH, Weinheim, Germany, 2014, ch. 8, pp. 239–268;
(c) T. Ohshima, H. Morimoto and K. Morisaki, in Reference Module
in Chemistry, Molecular Sciences and Chemical Engineering, Elsevier,
G. C. Nandi and M. S. Singh, Tetrahedron Lett., 2010, 51, 5555.
For direct catalytic alkynylation of trifluoromethyl ketones, see:
(c) R. Motoki, M. Kanai and M. Shibasaki, Org. Lett., 2007, 9, 2997;
(d) J.-I. Ito, S. Ubukata, S. Muraoka and H. Nishiyama, Chem. – Eur. J.,
2016, 22, 16801.
2015 (an update of Comprehensive Chirality, 2012, vol. 4, pp. 355–377). 14 For reviews, see: (a) J. Nie, H.-C. Guo, D. Cahard and J.-A. Ma, Chem.
´
´
˜
3 B. M. Trost, Science, 1991, 254, 1471.
4 P. G. M. Wuts, Greene’s Protective Groups in Organic Synthesis, John
Wiley & Sons, Hoboken, 5th edn, 2014.
Rev., 2011, 111, 455; (b) J. Wang, M. Sanchez-Rosello, J. L. Acena,
C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok and
H. Liu, Chem. Rev., 2014, 114, 2432; (c) Y. Zhou, J. Wang, Z. Gu,
˜
5 R. W. Hoffmann, Synthesis, 2006, 3531.
S. Wang, W. Zhu, J. L. Acena, V. A. Soloshonok, K. Izawa and H. Liu,
6 For selected examples of C–N bond formation, see: (a) J. P. Wolfe,
Chem. Rev., 2016, 116, 422.
J. Åhman, J. P. Sadighi, R. A. Singer and S. L. Buchwald, Tetrahedron 15 For selected examples of alkynylation of N-protected trifluoromethyl
Lett., 1997, 38, 6367; (b) G. Mann, J. F. Hartwig, M. S. Driver and
ketimines, see: (a) B. Jiang and Y.-G. Si, Angew. Chem., Int. Ed., 2004,
43, 216; (b) H. Xiao, Y. Huang and F.-L. Qing, Tetrahedron: Asym-
metry, 2010, 21, 2949; (c) F.-G. Zhang, H. Ma, J. Nie, Y. Zheng, Q. Gao
and J.-A. Ma, Adv. Synth. Catal., 2012, 354, 1422; (d) G. Huang, Z. Yin
and X. Zhang, Chem. – Eur. J., 2013, 19, 11992.
´
C. Fernandez-Rivas, J. Am. Chem. Soc., 1998, 120, 827; (c) R. S. Manan,
P. Kilaru and P. Zhao, J. Am. Chem. Soc., 2015, 137, 6136.
7 For selected examples of the reduction and hydrogenation of CQN
bonds, see: (a) F. Gosselin, P. D. O’Shea, S. Roy, R. A. Reamer, C.-Y.
Chen and R. P. Volante, Org. Lett., 2005, 7, 355; (b) G. Hou, 16 (a) L. Yin, Y. Otsuka, H. Takada, S. Mouri, R. Yazaki, N. Kumagai
F. Gosselin, W. Li, J. C. McWilliams, Y. Sun, M. Weisel, P. D.
O’Shea, C.-Y. Chen, I. W. Davies and X. Zhang, J. Am. Chem. Soc.,
2009, 131, 9882; (c) T. B. Nguyen, H. Bousserouel, Q. Wang and
and M. Shibasaki, Org. Lett., 2013, 15, 698; (b) H. Takada, N. Kumagai
and M. Shibasaki, Org. Lett., 2015, 17, 4762. See also: (c) T. Hashimoto,
M. Omote and K. Maruoka, Angew. Chem., Int. Ed., 2011, 50, 8952.
´
F. Gueritte, Org. Lett., 2010, 12, 4705; (d) Q. Zhao, J. Wen, R. Tan, 17 (a) K. Morisaki, M. Sawa, J.-y. Nomaguchi, H. Morimoto, Y. Takeuchi,
K. Huang, P. Metola, R. Wang, E. V. Anslyn and X. Zhang, Angew.
Chem., Int. Ed., 2014, 53, 8467; (e) K. Mori, N. Umehara and
T. Akiyama, Adv. Synth. Catal., 2015, 357, 901.
K. Mashima and T. Ohshima, Chem. – Eur. J., 2013, 19, 8417;
(b) K. Morisaki, M. Sawa, R. Yonesaki, H. Morimoto, K. Mashima
and T. Ohshima, J. Am. Chem. Soc., 2016, 138, 6194.
8 For a review, see: (a) Z. Chen, B. Wang, J. Zhang, W. Yu, Z. Liu and 18 See ESI† for details.
Y. Zhang, Org. Chem. Front., 2015, 2, 1107. For examples in C–H 19 For reviews on chemoselectivity, see: (a) N. A. Afagh and A. K. Yudin,
functionalizations, see: (b) K. Ueura, T. Satoh and M. Miura, Org.
Lett., 2005, 7, 2229; (c) T. Fukutani, N. Umeda, K. Hirano, T. Satoh
and M. Miura, Chem. Commun., 2009, 5141; (d) Z.-M. Sun, S.-P. Chen
and P. Zhao, Chem. – Eur. J., 2010, 16, 2619; (e) Y. Kuninobu,
P. Yu and K. Takai, Org. Lett., 2010, 12, 4274; ( f ) D. N. Tran and
N. Cramer, Angew. Chem., Int. Ed., 2010, 49, 8181; (g) D. N. Tran and
Angew. Chem., Int. Ed., 2010, 49, 262; (b) J. Mahatthananchai, A. M.
Dumas and J. W. Bode, Angew. Chem., Int. Ed., 2012, 51, 10954. For
our recent contributions regarding catalyst-controlled chemo-
selectivity, see: (c) S. Uesugi, Z. Li, R. Yazaki and T. Ohshima, Angew.
Chem., Int. Ed., 2014, 53, 1611; (d) K. Tokumasu, R. Yazaki and
T. Ohshima, J. Am. Chem. Soc., 2016, 138, 2664.
N. Cramer, Angew. Chem., Int. Ed., 2011, 50, 11098; (h) J. Zhang, 20 C. Wei and C.-J. Li, J. Am. Chem. Soc., 2002, 124, 5638.
A. Ugrinov and P. Zhao, Angew. Chem., Int. Ed., 2013, 52, 6681; 21 (a) G. A. M. Giardina, L. F. Raveglia, M. Grugni, H. M. Sarau, C. Farina,
(i) D. N. Tran and N. Cramer, Angew. Chem., Int. Ed., 2013, 52, 10630.
9 For selected examples of nucleophilic addition to N-unprotected
imines using pre-activated nucleophiles, see: (a) M. Sugiura,
K. Hirano and S. Kobayashi, J. Am. Chem. Soc., 2004, 126, 7182;
(b) S. Kobayashi, K. Hirano and M. Sugiura, Chem. Commun., 2005,
A. D. Medhurst, D. Graziani, D. B. Schmidt, R. Rigolio, M. Luttmann,
S. Cavagnera, J. J. Foley, V. Vecchietti and D. W. P. Hay, J. Med. Chem.,
1999, 42, 1053; (b) K. Biswas, J. J. Chen, J. R. Falsey, V. K. Gore, Q. Liu,
V. V. Ma, S. J. Mercede, R. M. Rzasa, C. M. Tegley and J. Zhu, WO Pat.,
2009137404 A1, 2009.
104; (c) B. Dhudshia, J. Tiburcio and A. N. Thadani, Chem. Commun., 22 10 mol% of Zn(OAc)2 also gave the product 3a in low yield,
2005, 5551; (d) F. Palacios, A. M. O. de Retana, S. Pascual, G. F. de
suggesting that such bis(carboxylato)zinc(II) species are not likely
to be the catalytically active species under the reaction conditions.
´
Troconiz and J. M. Ezpeleta, Eur. J. Org. Chem., 2010, 6618;
´
(e) F. Palacios, A. M. O. de Retana, S. Pascual and G. F. de Troconiz, 23 (a) K. Okura, H. Kawashima, F. Tamakuni, N. Nishida and E. Shirakawa,
´
Tetrahedron, 2011, 67, 1575.
Chem. Commun., 2016, 52, 14019; (b) J. Lewinski, W. Bury, M. Dutkiewicz,
10 M. Koos and H. S. Mosher, Tetrahedron, 1993, 49, 1541.
11 (a) V. A. Sukach, N. M. Golovach, V. V. Pirozhenko, E. B. Rusanov
M. Maurin, I. Justyniak and J. Lipkowski, Angew. Chem., Int. Ed., 2008,
47, 573.
and M. V. Vovk, Tetrahedron: Asymmetry, 2008, 19, 761; (b) N. Hara, 24 For protic additives in related alkynylation reactions, see: L. Tan,
R. Tamura, Y. Funahashi and S. Nakamura, Org. Lett., 2011, 13, 1662;
(c) Y. V. Rassukana, I. P. Yelenich, Y. G. Vlasenko and P. P. Onys’ko,
Tetrahedron: Asymmetry, 2014, 25, 1234.
C.-Y. Chen, R. D. Tillyer, E. J. J. Grabowski and P. J. Reider, Angew.
Chem., Int. Ed., 1999, 38, 711.
25 For
a review on chiral counter anion-directed catalysis, see:
12 (a) Y. V. Rassukana, Synthesis, 2011, 3426; (b) Y. V. Rassukana, I. P.
M. Mahlau and B. List, Angew. Chem., Int. Ed., 2013, 52, 518.
Yelenich, A. D. Synytsya and P. P. Onys’ko, Tetrahedron, 2014, 26 For the related mechanism in which terminal alkynes act as proton
70, 2928.
source to release products, see ref. 16 and 17. See also: G. J. Griffiths
and A. Warm, Org. Process Res. Dev., 2016, 20, 803 and references
therein.
13 For exceptional examples of A3-coupling using ammonia, see:
(a) P. Casara and C. Danzin, EP Pat., 0351475 A1, 1990; (b) S. Samai,
Chem. Commun.
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