Allylic amines via iridium-catalyzed C-C bond forming hydrogenation: Imine vinylation in the absence of stoichiometric byproducts or metallic reagents

Article abstract of DOI:10.1021/ja073018j

Exposure of aromatic, heteroaromatic, and aliphatic N-arylsulfonyl aldimines 1a-12a in toluene solution at 60 °C to 2-butyne and hydrogen at ambient pressure in the presence of a cationic iridium(I) catalyst modified by BIPHEP enables formation of reducti

Full text of DOI:10.1021/ja073018j

Published on Web 06/16/2007
Allylic Amines via Iridium-Catalyzed C-C Bond Forming Hydrogenation:
Imine Vinylation in the Absence of Stoichiometric Byproducts or Metallic
Reagents
Andriy Barchuk, Ming-Yu Ngai, and Michael J. Krische*
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin, Austin, Texas 78712
Received April 30, 2007; E-mail: mkrische@mail.utexas.edu
Elemental hydrogen is the cleanest, most cost-effective reductant
available. Accordingly, reductions mediated by hydrogen, termed
“hydrogenations”, are practiced industrially on vast scale.1,2 Con-
ventional hydrogenation involves delivery of hydrogen to a single
functional group. The addition of hydrogen across multiple
functional groups accompanied by C-C bond formation is observed
in hydroformylation, the largest volume application of homogeneous
metal catalysis,3 and the parent Fischer-Tropsch reaction, a process
enabling production of petroleum from hydrogen and carbon
monoxide.4 These prototypical hydrogen-mediated C-C bond
formations require carbon monoxide as a coupling partner. Given
the impact of these processes, systematic efforts toward hydrogen-
mediated C-C bond formations beyond carbon monoxide coupling
are warranted.5,6
Table 1. Iridium Catalyzed Hydrogenative Coupling of 2-Butyne to
Aromatic and Aliphatic N-Arylsulfonyl Aldiminesa
We have developed a novel class of hydrogenations wherein two
or more unsaturated molecules combine to furnish a single, more
complex molecule upon exposure to gaseous hydrogen in the
presence of a metal catalyst.5,6 Such “C-C bond forming hydro-
genations” enable direct coupling of diverse π-unsaturated com-
pounds to conventional electrophiles, such as carbonyl compounds
and imines, providing an alternative to stoichiometrically preformed
organometallic reagents in certain CdX (X ) O, NR) addition
processes. In the specific case of imine addition, the asymmetric
coupling of 1,3-enynes and 1,3-diynes to ethyl (N-sulfinyl)-
iminoacetates7a and the enantioselective coupling of acetylene to
N-arylsulfonyl aldimines7b were devised. These transformations,
which employ rhodium-based catalysts, furnish dienyl allylic
amines. Attempted imine vinylation under the conditions of rhodium
catalysis using 1,2-dialkyl-substituted alkynes led to conventional
alkyne hydrogenation.
Recently, under the conditions of iridium-catalyzed hydrogena-
tion,8 we found that simple 1,2-dialkyl-substituted alkynes undergo
reductive coupling to R-ketoesters to furnish â,γ-unsaturated
R-hydroxy esters.7c,9 Here, we report that iridium-catalyzed hydro-
genation of simple nonconjugated alkynes in the presence of
N-arylsulfonyl aldimines provides the corresponding trisubstituted
allylic amines with complete levels of E:Z selectivity (g95:5).
Remarkably, the unsaturated products are not subject to over-
reduction under the conditions of hydrogen-mediated coupling.
Further, nonsymmetric alkynes are found to couple with excellent
levels of regiocontrol. This protocol enables direct imine vinylation
in the absence of preformed organometallic reagents and represents
the first iridium-catalyzed alkyne-imine reductive coupling.10-16
Initial studies involved hydrogenation of 2-butyne in the presence
of furfural-derived aldimines employing [Ir(cod)2]BARF and BI-
PHEP as catalyst precursors. The selection of the N-substituent
proved critical. For example, attempted hydrogenative coupling of
2-butyne to the “PMP”-protected imine derived from p-anisidine
and furfural under conditions cited in Table 1 provides the product
of conventional imine reduction in 65% isolated yield. In contrast,
the corresponding p-toluenesulfonyl imine 7a smoothly couples to
a Cited yields are of isolated material (Ps ) benzenesulfonyl, Ts )
p-toluenesulfonyl). 2-Butyne is delivered as a vapor via cannula transfer
with the assistance of a hydrogen balloon to a 60 °C toluene solution of
imine. See Supporting Information for detailed experimental procedures.
2-butyne under these conditions to deliver allylic amine 7b in 82%
isolated yield. A range of aromatic, heteroaromatic, and aliphatic
N-arylsulfonyl imines 1a-12a couple under these conditions,
enabling access to trisubstituted allylic amines 1b-12b, which
appear as single geometrical isomers (Table 1). As previously
observed,7c carboxylic acid cocatalysts enhance rate and conversion,
presumably by circumventing highly energetic four-centered transi-
tion structures for σ-bond metathesis, as required for direct
hydrogenolysis of azametallacyclic intermediates I, with six-
centered transition structures for hydrogenolysis of iridium car-
boxylates II derived upon protonolytic cleavage of the nitrogen-
iridium bond (Scheme 1).17
To probe regioselectivity, nonsymmetric alkynes 4-methyl-2-
pentyne and 2-hexyne were used as nucleophilic partners in
hydrogenative couplings to imines 6a, 12a, and 13a under standard
conditions cited in Table 1. Using 4-methyl-2-pentyne, the isopro-
pyl-substituted allylic amines 13b, 14b, and 15b are formed as
single regioisomers. Hydrogenative couplings employing 2-hexyne
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J. AM. CHEM. SOC. 2007, 129, 8432-8433
10.1021/ja073018j CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Reductive Coupling under an Atmosphere of
Deuterium
GM069445) for partial support of this research. Umicore is
acknowledged for the donation of [Ir(cod)2]BARF.
Supporting Information Available: Experimental procedures and
spectral data (1H NMR, 13C NMR, IR, HRMS) for all new compounds,
2
including H NMR spectra of deuterio-2b. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) For use of catalytic hydrogenation in the large-scale production of
pharmaceutical agents, see: (a) Farina, V.; Reeves, J. T.; Senanayake, C.
H.; Song, J. J. Chem. ReV. 2006, 106, 2734. (b) Ja¨kel, C.; Paciello, R.
Chem. ReV. 2006, 106, 2734. (c) Asymmetric Catalysis on Industrial Scale;
Blaser, H. U., Schmidt, E., Eds.; Wiley-VCH: Weinheim, Germany, 2004.
(d) Heterogeneous Catalysis and Fine Chemicals IV; Blaser, H. U., Baiker,
A., Prins, R., Eds.; Elsevier: Amsterdam, 1997.
Table 2. Regioselective Hydrogenative Coupling of Nonsymmetric
Alkynes to Imines 6a, 12a, and 13aa
(2) It is estimated that asymmetric hydrogenation accounts for over half the
chiral compounds made by man not produced via physical or enzymatic
resolution: (a) Thommen, M. Spec. Chem. Mag. 2005, 25, 26. (b) Thayer,
A. M. C&E News 2005, 83 (36), 40. (c) Jakel, C.; Paciello, R. Chem.
ReV. 2006, 106, 2912.
(3) (a) Fischer, F.; Tropsch, H. Brennstoff Chem. 1923, 4, 276. (b) Fischer,
F.; Tropsch, H. Chem. Ber. 1923, 56B, 2428. (c) Jacoby, M. C&E News
2006, 84 (23), 57.
(4) (a) Roelen, O. German Patent DE 849,548, 1938. (b) Frohning, C. D.;
Kohlpaintner, C. W. In Applied Homogeneous Catalysis with Organo-
metallic Compounds; Cornils, B., Herrmann, W. A., Eds.; VCH: Wein-
heim, Germany, 1996; Vol. 1, p 29. (c) van Leeuwen, P. W. N. M.
Homogeneous Catalysis, Understanding the Art; Kluwer: Dordrecht, The
Netherlands, 2004.
(5) For a recent review of hydrogen-mediated C-C coupling, see: Ngai, M.
a Standard conditions described in Table 1. Couplings to form 16b, 17b,
and 18b were conducted at 80 °C. Cited yields are of isolated material.
Y.; Krische, M. J. J. Org. Chem. 2007, 72, 1063.
(6) Prior to our work, two isolated reports of hydrogen-mediated C-C bond
formation beyond carbon monoxide coupling were reported: (a) Molander,
G. A.; Hoberg, J. O J. Am. Chem. Soc. 1992, 114, 3123. (b) Kokubo, K.;
Miura, M.; Nomura, M. Organometallics 1995, 14, 4521.
(7) (a) Kong, J. R.; Cho, C. W.; Krische, M. J. J. Am. Chem. Soc. 2005, 127,
11269. (b) Skucas, E.; Kong, J.-R.; Krische, M. J. J. Am. Chem. Soc.
2007, 129, 7242. (c) Ngai, M. Y.; Barchuk, A.; Krische, M. J. J. Am.
Chem. Soc. 2007, 129, 280.
(8) For reviews of iridium-catalyzed hydrogenation, see: (a) Pfaltz, A.;
Blankenstein, J.; Hilgraf, R.; Ho¨rmann, E.; McIntynre, S.; Menges, F.;
Scho¨nleber, M.; Smidt, S. P.; Wustenberg, B.; Zimmerman, N. AdV. Synth.
Catal. 2003, 345, 33. (b) Cui, X.; Burgess, K. Chem. ReV. 2005, 105,
3272. (c) Kaellstroem, K.; Munslow, I.; Andresson, P. G. Chem.sEur. J.
2006, 12, 3194.
furnish adducts 16b, 17b, and 18b in 10:1 regiochemical ratios for
each case. Interestingly, coupling proximal to the more highly
substituted alkyne terminus is observed, and regioselectivity was
found to improve with increasing reaction temperature. Regioiso-
meric ratios (rr) were determined by 1H NMR analysis of the crude
reaction product (Table 2). For certain examples cited in Tables 1
and 2, unreacted starting material and competitive imine reduction
are observed. Aryl-substituted alkynes, such as 1-phenylpropyne,
do not couple efficiently under standard conditions due to competi-
tive imine reduction. Deprotection of the sulfonamide moiety occurs
readily under standard conditions, as demonstrated by the conver-
sion of 9b to the corresponding Cbz-protected allylic amine 9c
(eq 1).
(9) π-Backbonding in the metal-alkyne complex, as described by the Dewar-
Chatt-Duncanson model, may facilitate alkyne-CdX (X ) O, NR)
oxidative coupling by conferring nucleophilic character to the bound
alkyne. Due to relativistic effects, iridium is a stronger π-donor than
rhodium: (Ph3P)2M(Cl)(CO), M ) Ir, νco ) 1965 cm-1; M ) Rh, νco
)
1980 cm-1 (Vaska, L.; Peone, J. Chem. Commun. 1971, 419). This may
account for the ability of iridium-based catalysts to activate nonconjugated
alkynes, which embody higher lying LUMOs.
(10) Ni-catalyzed alkyne, imine, triethylborane three-component coupling has
been reported, wherein vinylation is accompanied by ethyl transfer: Patel,
S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2004, 42, 1364.
(11) For preparation of allylic alcohols via direct Ni-catalyzed alkyne-aldehyde
reductive coupling, see: (a) Oblinger, E.; Montgomery, J. J. Am. Chem.
Soc. 1997, 119, 9065. (b) Huang, W.-S.; Chan, J.; Jamison, T. F. Org.
Lett. 2000, 2, 4221. (c) Mahandru, G. M.; Liu, G.; Montgomery, J. J.
Am. Chem. Soc. 2004, 126, 3698.
(12) The catalyzed addition of vinylzirconocenes to imines has been de-
scribed: (a) Kakuuchi, A.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett.
2003, 44, 923. (b) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am.
Chem. Soc. 2003, 125, 761.
(13) For reviews encompassing catalytic enantioselective aldehyde vinylations
employing vinylzirconocenes, see: (a) Wipf, P.; Kendall, C. Chem.s
Eur. J. 2002, 8, 1778. (b) Wipf, P.; Nunes, R. L. Tetrahedron 2004, 60,
1269. (c) For a seminal contribution in corresponding ketone vinylations,
see: Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 6538.
(14) For reviews encompassing the synthesis of allylic amines, see: (a) Cheik,
R. B.; Chaabouni, R.; Laurent, A.; Mison, P.; Nafti, A. Synthesis 1983,
685. (b) Laurent, A.; Mison, P.; Nafti, A.; Cheik, R. B.; Chaabouni, R. J.
Chem. Res. (S) 1984, 354. (c) Johannsen, M.; Jorgensen, K. A. Chem.
ReV. 1998, 98, 1689. (d) Overman, L. E.; Carpenter, N. E. Org. React.
2005, 66, 1.
(15) For reviews encompassing the preparation of optically enriched allylic
amines via enantioselective iridium-catalyzed allylic alkylation, see: (a)
Miyabe, H.; Takemoto, Y. Synlett 2005, 1641. (b) Takeuchi, R.; Kezuka,
S. Synthesis 2006, 3349. (c) For a seminal contribution, see: Hartwig, J.
F.; Ohmura, T. J. Am. Chem. Soc. 2002, 124, 15164.
To corroborate the proposed catalytic mechanism, the reductive
coupling of 2-butyne to imine 2a was conducted under an
atmosphere of deuterium. As revealed by 2H NMR analysis,
deuterio-2b incorporates deuterium at the vinylic position (83%
2H). Small quantities of deuterium also are incorporated at the allylic
methyl groups (5% 2H). The equal distribution of deuterium at the
allylic methyl groups suggests H-D exchange at the propargylic
positions of 2-butyne in advance of C-C coupling. As previously
observed in iridium-catalyzed couplings of 2-butyne to R-ketoesters,7c
excess Brønsted acid cocatalyst does not influence the extent of
deuterium incorporation (Scheme 1).
In summary, allylic amines are formed upon hydrogenation of
1,2-dialkyl-substituted alkynes in the presence of N-arylsulfonyl
aldimines. Our collective studies reveal that organometallics arising
transiently under hydrogenation conditions may be coupled to
conventional electrophiles, thus circumventing use of preformed
organometallic reagents as nonstabilized carbanion equivalents in
certain carbonyl and imine addition processes.
(16) For recent reviews encompassing catalytic enantioselective addition of
nonstabilized carbanions to imines, see: (a) Vilaivan, T.; Bhanthumnavin,
W.; Sritana-Anant, Y. Curr. Org. Chem. 2005, 9, 1315. (b) Friestad, G.
K.; Mathies, A. K. Tetrahedron 2007, 63, 2541.
(17) Musashi, Y.; Sakaki, S. J. Am. Chem. Soc. 2002, 124, 7588.
Acknowledgment. We thank Johnson & Johnson, Merck, the
Robert A. Welch Foundation, and the NIH-NIGMS (RO1-
JA073018J
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