Palladium-Catalyzed Intramolecular Asymmetric Hydroamination of Alkynes

Article abstract of DOI:10.1021/ja039774g

The Pd-catalyzed reaction of internal alkynes with tethered amino groups in the presence of PhCO₂H and RENORPHOS as chiral phosphine ligand is reported. Various five- and six-membered nitrogen-containing heterocycles were obtained in good to hi

Full text of DOI:10.1021/ja039774g

Published on Web 01/21/2004
Palladium-Catalyzed Intramolecular Asymmetric Hydroamination of Alkynes
Le´opold M. Lutete, Isao Kadota, and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
Received November 24, 2003; E-mail: yoshi@yamamoto1.chem.tohoku.ac.jp
Nitrogen-containing heterocycles are the main components of
many biologically important compounds. Their synthesis via the
intramolecular hydroamination of C-C multiple bonds, an atom
economical process,1 is a subject of great interest in synthetic
organic chemistry. The metal-catalyzed intramolecular hydroami-
nation/cyclization of aminoalkenes,2 aminoallenes,3 aminodienes,4
and aminoalkynes5 has been abundantly documented. However,
little progress has been made in the exploration of the enantiose-
lective version of this process. To our knowledge, the only
successful examples toward this goal involve the hydroamination/
cyclization of aminoalkenes and aminodienes using lanthanide
complexes.4,6 Although good enantioselectivities (ee up to 69%)
were achieved, the susceptibility of these complexes to moisture
and oxygen constitute a serious drawback. Recently, the intermo-
lecular enantioselective hydroamination of olefins catalyzed by late
transition metals has been an area of intense investigation.6a,7 As
part of an ongoing program directed to the development of new
methodologies for the transition metal-catalyzed addition of pro-
nucleophiles to C-C multiple bonds in our laboratory,8 we pre-
viously reported an efficient hydroamination of alkynes using
catalytic amounts of Pd(PPh3)4.5d It was anticipated that the intra-
molecular reaction in the presence of a chiral palladium complex
would lead to the synthesis of optically active cyclic amines. We
now wish to report the first example of palladium-catalyzed
intramolecular asymmetric hydroamination of alkynes. In this
process, five- and six-membered nitrogen heterocycles are synthe-
sized in high yields with high levels of enantioselectivity (eq 1).9
results are summarized in Table 1. The reaction of 1b having a
Nf protecting group proceeded in the presence of 5 mol % of
Pd2(dba)3‚CHCl3 and 25 mol % of (R,R)-RENORPHOS (conditions
A) to afford the vinylpyrrolidine 2b in 68% yield and 83% ee (entry
2). It was interesting to note that by increasing the amounts of
palladium precursor and ligand to 20 and 100 mol %, respectively
(conditions B), better chemical and optical yields were obtained.
Comparison of compounds 1c and 1d having methoxy and
trifluoromethyl groups, respectively (entries 3 and 4, conditions
A), shows that an electron-rich alkyne favors the reaction rate as
the corresponding cyclized products 2c and 2d were obtained in
90% and 52% yield, respectively.10 The enantiomeric excess,
however, followed the opposite pattern. Perhaps the intermediate
involved during the cyclization phase needs to adjust itself to the
chiral environnement faster than the C-N bond formation step.11
The reaction of 1e having a pentyl-substituted alkyne under
conditions B required a longer reaction time (5 days), and 2e was
obtained in 82% yield as a 1:1 mixture of cis and trans isomers
(entry 5). However, at this stage, attempts to determine the
enantiomeric excess all failed.12 Compound 1f with a one carbon-
longer tether cyclized to give the vinylpiperidine 2f in good yield
and ee (entry 6, conditions A) or high yield and ee (entry 6,
conditions B), indicating that five- and six-membered heterocycles
can be synthesized with similar efficiency.13 The reaction of 1g
having a benzene ring linker on the tether gave the tetrahydroiso-
quinoline 2g in good yield and ee (entry 7, conditions A) or high
yield and ee (entry 7, conditions B). The absolute configuration of
2a (82% ee) was determined by transformation to the known
compound 3 (eq 2). The literature14 attributes the R configuration
to (+)-2-phenethylpyrrolidine, although no value of ee is stated.
Because the optical rotation of 3 was [R]22D -8.7 (c 0.75, CHCl3),
it was confirmed that the absolute configuration of 2a is S.
Using 1a as a model substrate, initial studies aimed at developing
reaction conditions revealed that benzene as solvent and tris-
(dibenzylideneacetone)dipalladium [Pd2(dba)3‚CHCl3] as the pal-
ladium precursor were the suitable starting point for the optimization
of the chiral induction. At this early stage, a trial using the
monodentate phosphine ligand (S)-neomenthyl-diphenylphosphine
proved unsuccessful for the enantioselectivity. A variety of bidentate
phosphine ligands were then examined; among MOP, BPPFOAc,
DIOP, BINAP, BPPM, PYRPHOS, CHIRAPHOS, NORPHOS, and
RENORPHOS tested, RENORPHOS gave the best combination
of yield and enantioselectivity. The protecting groups, such as
benzyl, acetyl, Boc, and tosyl, on the amino moiety gave unsatisfac-
tory results. The trifluoromethanesulfonyl (Tf) group gave a better
result, but nonafluorobutanesulfonyl (Nf) gave the best result under
the Pd/L ratio of 1/2.5 (see Supporting Information). The scope of
the reaction was evaluated using two sets of conditions, and the
A plausible mechanism is shown in Scheme 1, although it is
highly speculative. Hydropalladation of 1a with the hydridopalla-
dium species generated from Pd0 and benzoic acid would produce
the vinylpalladium intermediate 4, which would undergo â-elimina-
tion to give allene 5 coordinated with the hydridopalladium. Subse-
quent hydropalladation of 5 would furnish the π-allylpalladium
species 6. Nucleophilic attack of the amine on the π-allyl moiety
would give the product 2a along with the hydridopalladium catalyst.
To obtain insight into the mechanism of the present chiral
induction, aminodiene 7 and aminoallene 8 were prepared, and their
reactivity was examined. When 7 was submitted to conditions A,
the cyclized product 2b was obtained in only 15% yield and 24%
ee (eq 3). Under the same conditions, 8 gave exclusively trans-(9)
in 85% yield after 12 h (eq 4).15 In this case, however, no
asymmetric induction was observed at all. It is generally thought
9
1622
J. AM. CHEM. SOC. 2004, 126, 1622-1623
10.1021/ja039774g CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Probable Transition State Models
Table 1. Catalytic Intramolecular Asymmetric Hydroamination of
Alkynes
chain attached to the π-allyl to move freely. In B, a phenyl ring
emanating from the phosphorus atom at the backside of the catalyst
restricts the movement of the tether. Accordingly, the reaction
proceeds through a transition state model A to give (S)-2a
predominantly.
In conclusion, we have developed the first palladium-catalyzed
intramolecular asymmetric hydroamination of alkynes. Various
optically active nitrogen heterocycles were prepared by using readily
available aminoalkynes. Application to the synthesis of natural
products is underway in our laboratory and will be reported in due
course.
Supporting Information Available: Spectroscopic and analytical
data of new compounds and information on procedures (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675-703.
(2) (a) Kim, Y. K.; Livinghouse, T.; Bercaw, J. E. Tetrahedron Lett. 2001,
42, 2933-2935. (b) Tian, S.; Arredondo, V. M.; Stern, C. L.; Marks, T.
J. Organometallics 1999, 18, 2568-2570. (c) Molander, G. A.; Dowdy,
E. D. J. Org. Chem. 1998, 63, 8983-8988.
a Conditions A: 5 mol % of Pd2(dba)3‚CHCl3, 10 mol % of PhCO2H,
and 25 mol % of (R,R)-RENORPHOS in benzene at 100 °C for 72 h.
Conditions B: 20 mol % of Pd2(dba)3‚CHCl3, 40 mol % of PhCO2H, and
100 mol % of (R,R)-RENORPHOS in benzene/hexane (2:1) at 80 °C for
72 h. b Isolated yield. c The ee was determined by chiral HPLC. d 30 mol
% of ligand was used. e The ee was not determined.
(3) (a) Arredondo, V. M.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc.
1998, 120, 4871-4872. (b) Meguro, M.; Yamamoto, Y. Tetrahedron Lett.
1998, 39, 5421-5424.
(4) (a) Hong, S.; Kawaoka, A. M.; Marks, T. J. J. Am. Chem. Soc. 2003,
125, 15878-15892. (b) Hong, S.; Marks, T. J. J. Am. Chem. Soc. 2002,
124, 7886-7887.
Scheme 1. Plausible Mechanism
(5) (a) Ackermann, L.; Bergman, R. G.; Loy, R. N. J. Am. Chem. Soc. 2003,
125, 11956-11963. (b) Bytschkov, I.; Doye, S. Tetrahedron Lett. 2002,
43, 3715-3718. (c) Mu¨ller, T. E.; Grosche, M.; Herdtweck, E.; Pleier,
A.-K.; Walter, E.; Yan, Y.-K. Organometallics 2000, 19, 170-183. (d)
Kadota, I.; Shibuya, A.; Lutete, L. M.; Yamamoto, Y. J. Org. Chem. 1999,
64, 4570-4571. (e) Fairfax, D.; Stein, M.; Livinghouse, T.; Jensen, M.
Organometallics 1997, 16, 1523-1525. (f) Li, Y.; Marks, T. J. J. Am.
Chem. Soc. 1996, 118, 9295-9306.
(6) (a) Roesky, P. W.; Mu¨ller, T. E. Angew. Chem., Int. Ed. 2003, 42, 2708-
2710. (b) O’Shaughnessy, P. N.; Knight, P. D.; Morton, C.; Gillespie, K.
M.; Scott, P. Chem. Commun. 2003, 1770-1771. (c) Gribkov, D. V.;
Hultzsch, K. C.; Hampel, F. Chem.-Eur. J. 2003, 9, 4796-4810. (d)
Douglass, M. R.; Ogasawara, M.; Hong, S.; Metz, M. V.; Marks, T. J.
Organometallics 2002, 21, 283-292. (e) Giardello, M. A.; Conticello,
V. P.; Brard L.; Gagne´, M. R.; Marks, T. J. J. Am. Chem. Soc. 1994, 116,
10241-10254. (f) Gagne´, M. R.; Brard, L.; Conticello, V. P.; Giardello,
M. A.; Stern, C. L.; Marks, T. J. Organometallics 1992, 11, 2003-2005.
(7) (a) Fadini, L.; Togni, A. Chem. Commun. 2003, 30-31. (b) Lo¨ber, O.;
Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366-4367.
(c) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546-
9547. (d) Vasen, D.; Salzer, A.; Gerhards, F.; Gais, H.-J.; Stu¨rmer, R.;
Bieler, N. H.; Togni, A. Organometallics 2000, 19, 539-546. (e) Dorta,
R.; Egli, P.; Togni, A. J. Am. Chem. Soc. 1997, 119, 10857-10858.
(8) Yamamoto, Y.; Radhakrishnan, U. Chem. Soc. ReV. 1999, 28, 199-207.
(9) The reaction shown in eq 1 is a formal 1,3-addition of N-H to a triple
bond involving the shift of one proton similar to known allylic amination
reactions.
Scheme 2
(10) The starting material 1d was recovered in ca. 40% yield.
(11) Trost, B. M.; Vranken, V. L. D. Chem. ReV. 1996, 96, 395-422.
(12) Efforts to determine the ee of 2e were undertaken using GC with different
chiral columns. However, no satisfactory separation of enantiomers could
be obtained.
(13) The synthesis of seven-membered rings was not achieved under these
conditions.
(14) Armstrong, D. W.; Li, W.; Stacup, A. M.; Secor, H. V.; Izac, R. R.;
Seeman, J. I. Anal. Chim. Acta 1990, 234, 365-380.
(15) 8 was used because the determination of the ee of the product from the
corresponding Nf-protected compound proved difficult.
that the palladium-catalyzed hydroamination of dienes7b and
allenes3b takes place through the formation of π-allyl intermediates.
The precise reason for the different observations in Scheme 2 and
in the above alkyne case is not clear at present.
Probable transition state models are shown in Scheme 3. In A,
the space at the lower front side of the catalyst allows the alkyl
JA039774G
9
J. AM. CHEM. SOC. VOL. 126, NO. 6, 2004 1623