Palladium-catalyzed intramolecular asymmetric hydroamination, hydroalkoxylation, and hydrocarbonation of alkynes

Article abstract of DOI:10.1021/jo0603835

A conceptually novel approach for asymmetric intramolecular hydroamination, hydroalkoxylation and hydrocarbonation of alkynes using chiral palladium catalysts are described. The reactions of the aminoalkynes 5, alkynols 7, and alkynylmethines 9 in the pre

Full text of DOI:10.1021/jo0603835

Palladium-Catalyzed Intramolecular Asymmetric Hydroamination,
Hydroalkoxylation, and Hydrocarbonation of Alkynes
Nitin T. Patil, Le´opold Mpaka Lutete, Huanyou Wu, Nirmal K. Pahadi,
Ilya D. Gridnev, and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
yoshi@mail.tains.tohoku.ac.jp
ReceiVed February 23, 2006
A conceptually novel approach for asymmetric intramolecular hydroamination, hydroalkoxylation and
hydrocarbonation of alkynes using chiral palladium catalysts are described. The reactions of the
aminoalkynes 5, alkynols 7, and alkynylmethines 9 in the presence of Pd2(dba)3‚CHCl3/PhCOOH/renorphos
4 in benzene (or benzene-hexane) at 100 °C gave the corresponding cyclization products (nitrogen
heterocycles 6, oxygen heterocycles 8, and carbocycles 10) in good yields with good enantioselectivities.
The origins of enantioselectivities in the hydroamination reaction are discussed based on DFT computations.
Introduction
of the most important processes in organic synthesis. The
addition of carbon, amine, and alcohol nucleophiles across an
activated C-C bond is referred as hydrocarbonation,4 hy-
droamination,5 and hydroalkoxylation,6 respectively (Scheme
1, eqs 1-3). In contrast to substitution reactions (eq 4),7 these
processes are very important from the synthetic point of view
because, in principle, the addition reactions can be performed
The metal-catalyzed addition of nucleophiles to activated
C-C bonds such as alkenes,1 allenes,2 and 1,3-dienes3 is one
(1) (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. (d) Molander, G. A.; Pack, S.
K. J. Org. Chem. 2003, 68, 9214-9220. (e) Ryu, J.-S.; Marks, T. J.;
McDonald, F. E. J. Org. Chem. 2004, 69, 1038-1052. (f) Ryu, J.-S.; Li,
G. Y.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 12584-12605. (g) Yao,
X.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 6884-6885.
(2) (a) Yamamoto, Y.; Al-Masum, M.; Asao, N. J. Am. Chem. Soc. 1994,
116, 6019-6020. (b) Yamamoto, Y.; Al-Masum, M.; Fujiwara, N. J. Chem.
Soc., Chem. Commun. 1996, 381-382. (c) Yamamoto, Y.; Al-Masum, M.;
Takeda, A. J. Chem. Soc., Chem. Commun. 1996, 831-832. (d) Yamamoto,
Y.; Al-Masum, M.; Fujiwara, N.; Asao, N. Tetrahedron Lett. 1995, 36,
2811-2814. (e) Yamamoto, Y.; Al-Masum, M. Synlett 1995, 969-970.
(f) Meguro, M.; Kamijo, S.; Yamamoto, Y. Tetrahedron Lett. 1996, 37,
7453-7456. (g) Patil, N. T.; Pahadi, N. K.; Yamamoto, Y. Synthesis, 2004,
2186-2190. (h) Trost, B. M.; Jaekel, C.; Plietker, B. J. Am. Chem. Soc.
2003, 125, 4438-4439. (i) Ackermann, L.; Bergman, R. G.; Loy, R. N. J.
Am. Chem. Soc. 2003, 125, 11956-11963. (j) Ackermann, L.; Bergman,
R. G. Org. Lett. 2002, 4, 1475-1478. (k) Jonasson, C.; Horvath, A.;
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Gerusz, V. J. J. Am. Chem. Soc. 1995, 117, 5156-5157. For a review, see:
(m) Yamamoto, Y.; Radhakrishnan, U. Chem. Soc. ReV. 1999, 28, 199-
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(4) For hydrocarbonation of 1,3-enynes, see: (a) Salter, M. M.; Gevor-
gyan, V.; Saito, S.; Yamamoto, Y. J. Chem. Soc., Chem. Commun. 1996,
17-18. For hydrocarbonation of 3,3-dihexylcyclopropene, see: (b) Naka-
mura, I.; Bajracharya, G. B.; Yamamoto, Y. J. Org. Chem. 2003, 68, 2297-
2299. For hydrocarbonation of methyleneaziridines, see: (c) Oh, B. H.;
Nakamura, I.; Yamamoto, Y. Tetrahedron Lett. 2002, 43, 9625-9628. For
hydrocarbonation of methylenecyclopropanes, see: (d) Tsukada, N.;
Shibuya, A.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 1997, 119,
8123-8124. (e) Tsukada, N.; Shibuya, A.; Nakamura, I.; Kitahara, H.;
Yamamoto, Y. Tetrahedron 1999, 55, 8833-8844. For hydrocarbonation
of terminal alkynes, see: (f) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F.
D. J. Am. Chem. Soc. 2004, 126, 4526-4527.
(5) (a) Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 5421-
5424. (b) Radhakrishnan, U.; Al-Masum, M.; Yamamoto, Y. Tetrahedron
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Lett. 1995, 36, 3857-3860. (d) Armbruster, R. W.; Morgan, M. M.;
Schmidt, J. L.; Lau, C. M.; Riley, R. M.; Zabrowski, D. L.; Dieck, H. A.
Organometallics 1986, 5, 234-237. (e) Nakamura, I.; Itagaki, H.; Yama-
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M. F.; Rutjes, F. P. J. T.; Hiemstra, H.; Schoemaker, H. E. Tetrahedron
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125, 15878-15892. (b) Hong, S.; Marks, T. J. J. Am. Chem. Soc. 2002,
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10.1021/jo0603835 CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/29/2006
4270
J. Org. Chem. 2006, 71, 4270-4279

Palladium-Catalyzed Reactions of Alkynes
SCHEME 1. Cyclization via Addition of Pronucleophiles to Activated C-C Bonds
with 100% atom efficiency,8 without any waste formation.
Although tremendous amounts of the related work have been
carried out in the field of hydrocarbonation and hydroamination
reactions, very few reports are known for hydroalkoxylation
reactions partly due to the diminished nucleophilicity and the
weaker Lewis base character of oxygen nucleophiles compared
to those of amines. Although some progress has been made in
this area, reports on asymmetric versions of these processes are
scarce.9 Therefore, the development of enantioselective methods
for the formation of C-C and C-X bonds by these processes
is highly desired.
Recently, we reported a new approach for the addition of
carbon10 nucleophiles to alkynes in the presence of a Pd(0)/
carboxylic acid11 combined catalyst.12 Later we extended our
work to the addition of nitrogen13 and oxygen14 nucleophiles
to alkynes (eq 5). Since the product is obtained via formal
reactions. Particularly interesting is the intramolecular asym-
metric version of these reactions, which would lead to the
synthesis of a variety of chiral building blocks (eq 5).
After a detailed literature survey we found that the only
successful examples toward this goal involved the hydroami-
nation/cyclization of aminoalkenes and aminodienes using
lanthanide complexes to form chiral piperidines.15 Although
good enantioselectivities (ee up to 89%) were achieved, the
susceptibility of these complexes to moisture and oxygen
constituted a serious drawback. The intermolecular enantiose-
lective hydroamination of olefins catalyzed by late transition
metals has also been reported.16 However, to the best of our
knowledge, there have been no reports on intramolecular
asymmetric hydroalkoxylation17 and hydrocarbonation. We
realized that the scope and synthetic utility of our newly
discovered process (eq 5) would be enhanced dramatically if a
chiral ligand which allows the reaction to be carried out in an
enantioselective manner could be found. Since then we initiated
our search for a proper chiral ligands. Finally, we found that a
chiral palladium catalyst, derived from Pd2(dba)3‚CHCl3 and
(R,R)-renorphos, is highly effective for catalyzing asymmetric
intramolecular hydroamination.18
In this paper we report that (i) the intramolecular catalytic
asymmetric hydroamination, hydroalkoxylation, and hydrocar-
substitution at the propargylic position with X- and subsequent
addition of H-H to alkyne, no waste elements are produced.
Moreover, the presence of a base, which is required in the case
of Tsuji-Trost allylation (eq 4), was not needed in these
(13) (a) Kadota, I.; Shibuya, A.; Lutete, M. L.; Yamamoto, Y. J. Org.
Chem. 1999, 64, 4570-4571. (b) Lutete, M. L.; Kadota, I.; Shibuya, A.;
Yamamoto, Y. Heterocycles 2002, 58, 347-357. (c) Bajracharya, G. B.;
Huo, Z.; Yamamoto, Y. J. Org. Chem. 2005, 70, 4883-4886. (d) Patil, N.
T.; Huo, Z.; Bajracharya, G. B.; Yamamoto, Y. J. Org. Chem., in press. (e)
Ref 10d.
(14) (a) Kadota, I.; Lutete, M. L.; Shibuya, A.; Yamamoto, Y. Tetra-
hedron Lett. 2001, 42, 6207-6210. (b) Patil, N. T.; Pahadi, N. K.;
Yamamoto, Y. Can. J. Chem. 2005, 83, 569-573. For the related reference,
see: (c) Patil, N. T.; Khan, N. F.; Yamamoto, Y. Tetrahedron Lett., 2004,
45, 8497-8499. (d) Zhang, W.; Haight, A. R.; Hsu, M. C. Tetrahedron
Lett. 2002, 43, 6575-6578.
(6) (a) Coulson, D. R. J. Org. Chem. 1973, 38, 1483-1490. (b) Camacho,
D. H.; Nakamura, I.; Saito, S.; Yamamoto, Y. Angew. Chem., Int. Ed. 1999,
38, 3365-3367. (c) Camacho, D. H.; Nakamura, I.; Saito, S.; Yamamoto,
Y. J. Org. Chem. 2001, 66, 270-275 and references therein. (d) Utsunomiya,
M.; Kawatsura, M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2003, 42, 5865-
5868 and references therein.
(7) (a) Trost, B. M J. Org. Chem. 2004, 69, 5813-5837. (b) Trost, B.
M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395-422. (c) Tsuji, J.
Transition Metal Reagents and Catalysts; Wiley: New York, 2000; Chapter
4.
(8) (a) Trost, B. M. Science 1991, 254, 1471-1477. (b) Trost, B. M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281. (c) Sheldon, R. A. Pure
Appl. Chem. 2000, 72, 1233-1246.
(9) Intramolecular asymmetric hydroalkoxylation and hydrocarbonation
are not known in the literature. For asymmetric intramolecular hydroami-
nation, see refs 15 and 16.
(10) For the references on the addition of carbon nucleophiles to alkynes,
see: (a) Kadota, I.; Shibuya, A.; Gyoung, Y. S.; Yamamoto, Y. J. Am.
Chem. Soc. 1998, 120, 10262-10263. (b) Patil, N. T.; Kadota, I.; Shibuya,
A.; Gyoung, Y. S.; Yamamoto, Y. AdV. Synth. Catal. 2004, 346, 800-
804. (c) Patil, N. T.; Yamamoto, Y. J. Org. Chem. 2004, 69, 6478-6481.
(d) Patil, N. T.; Wu, H.; Kadota, I.; Yamamoto, Y. J. Org. Chem. 2004,
69, 8745-8750.
(11) Enhancement of reaction rate by the use of the Pd(0)/carboxylic
acid combined catalytic system is also observed by others. See: (a) Trost,
B. M.; Rise, F. J. Am. Chem. Soc. 1987, 109, 3161-3163. (b) Trost, B.
M.; Jakel, C.; Plietker, B. J. Am. Chem. Soc. 2003, 125, 4438-4439. For
a review, see: (c) Trost, B. M. Chem. Eur. J. 1998, 4, 2405-2412.
(12) This process is similar to the hydroacylation process for the allylation
of acetic acid with alkynes which gives allylic acetates. See: Trost, B. M.;
Brieden, W.; Baringhaus, K. H. Angew. Chem., Int. Ed. Engl. 1992, 31,
1335-1336.
(15) (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. (c) Roesky, P. W.; Muller, T. E. Angew. Chem.,
Int. Ed. 2003, 42, 2708-2710. (d) Oshaughnessy, P. N.; Knight, P. D.;
Morton, C.; Gillespie, K. M.; Scott, P. Chem. Commun. 2003, 1770-1771.
(e) Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. Chem. Eur. J. 2003, 9,
4796-4810. (f) Douglass, M. R.; Ogasawara, M.; Hong, S.; Metz, M. V.;
Marks, T. J. Organometallics 2002, 21, 283-292. (g) Giardello, M. A.;
Conticello, V. P.; Brard, L.; Gagne, M. R.; Marks, T. J. J. Am. Chem. Soc.
1994, 116, 10241-10254. (h) Gagne, M. R.; Brard, L.; Conticello, V. P.;
Giardello, M. A.; Stern, C. L.; Marks, T. J. Organometallics 1992, 11,
2003-2005. Recently, Kim and Livinghouse reported enantioselective
intramolecular hydroamination of alkene with ee’s ranging from 69% to
89%. See: (i) Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 1737-1739.
(16) (a) Fadini, L.; Togni, A. Chem. Commun. 2003, 30-31. (b) Lober,
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.; Sturmer, 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. (f) Ref 15c.
(17) Uozumi, Y.; Kyota, H.; Kato, K.; Ogasawara, M.; Hayashi, T. J.
Org. Chem. 1999, 64, 1620-1625.
(18) For a preliminary communication, see: Lutete, M. L.; Kadota, I.;
Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 1622-1623.
J. Org. Chem, Vol. 71, No. 11, 2006 4271

Patil et al.
TABLE 1. Selected Ligand Screeninga
SCHEME 2. Structure of Some Ligands
entry
ligand
yieldb
ee
1
2
3
4
5
Trost ligand (1)
51
92
5
54
65
12
25
98
81
82c
(R,R)-chiraphos (2)
(R,R)-norphos (3)
(R,R)-renorphos (4)
(R,R)-renorphos (4)
a The reactions of alkyne 5a (0.125 mmol) in the presence of
Pd2dba3‚CHCl3 (5 mol %), ligands (25 mol %), and benzoic acid (10 mol
%) were carried out at 100 °C in benzene for 72 h. b Isolated yields. c An
amount of 30 mol % of (R,R)-renorphos was used.
bonation of alkynes using chiral palladium catalyst [prepared
in situ by mixing Pd2(dba)3‚CHCl3 and (R,R)-renorphos]19 give
the corresponding heterocycles and carbocycles in good yields
and with good enantioselectivities and (ii) DFT computational
studies help to clarify the origin of the enantioselectivities of
the present catalytic asymmetric cyclization.
ligand the product 6a was obtained in 92% yield with 25% ee
(entry 2). Although the ee was not satisfactory, this result led
us to examine diphosphine ligands because the bite angle of
ligands often changes the nature of palladium catalysts and
dramatically increases the reactivity. The use of (R,R)-norphos
3 gave 6a with 98% ee; however, the yield was only 5% (entry
3). Encouraged by this result we next tried (R,R)-renorphos 4,
and to our pleasure 6a was obtained in 65% yield with 82% ee.
We next examined the effect of various protecting groups;
instead of -Tf, (65%, 82% ee), benzyl (95%, 8% ee), acetyl
(0%), Boc (0%), and tosyl (25%, 47% ee) were used, but
unsatisfactory results were obtained. We were pleased to find
that nonafluorobutanesulfonyl (-Nf) as an amine protecting
group gave the best result. The reactions were examined under
two conditions that differ about the relative stoichiometries of
Pd2(dba)3‚CHCl3, PhCOOH, and the ligand 4: condition A, 5
mol % of Pd2(dba)3‚CHCl3, 10 mol % of PhCOOH, and 25
mol % of (R,R)-renorphos 4 in benzene at 100 °C for 72 h;
condition B, 20 mol % of Pd2(dba)3‚CHCl3, 40 mol % of
PhCOOH, and 100 mol % of (R,R)-renorphos 4 in benzene/
hexane (2:1) at 80 °C for 72 h. Various nitrogen heterocycles
6b-g were synthesized from aminoalkynes 5b-g under those
conditions, and the results are summarized in Table 2.
Results and Discussion
Asymmetric Hydroamination of Alkynes. The Trost ligand
17 (Scheme 2) emerges as the ligand of choice for the highly
enantioselective allylic alkylation of various nucleophiles with
allylic substrates through intermediacy of the π-allyl-Pd
complex A (eq 6, path a). Pioneering work from the same group
Asymmetric Hydroalkoxylation of Alkynes. Next, we
envisioned that, in the presence of the chiral palladium catalyst,
oxygen nucleophiles (alkynols) must undergo catalytic asym-
metric intramolecular hydroalkoxylation in a similar manner,
allowing the synthesis of optically active cyclic ethers21 which
are known to be structural elements of many naturally occurring
compounds. Thus, the alkynol 7a was treated with the palladium
catalyst under condition A, which gave the corresponding cyclic
ether 8a in 20% yield with 79% ee. Although the ee was not
bad, the yield was very low. After detailed investigation on
various chiral ligands, we found that renorphos 4 gave the best
result again, and the combination of Pd2(dba)3‚CHCl3 (10 mol
%), PhCOOH (20 mol %), and (R,R)-renorphos 4 (60 mol %)
(condition C) gave better results than conditions A and B. As
shown in Table 3, the optimized conditions were applied to a
also revealed the asymmetric allylation of carbon nucleophiles
with allenes,2h wherein allenes form the chiral π-allyl-Pd
complex A (eq 6, path b). As we proposed the intermediacy of
allenes in our reaction, we envisioned that, in the presence of
the ligand 1, chiral π-allyl-Pd complex B would be generated
and the enantiopure products would be obtained after subsequent
reaction with the tethered nucleophiles (eq 7). Accordingly, the
aminoalkyne 5a was treated with Pd2(dba)3‚CHCl3 (5 mol %),
1 (25 mol %), and benzoic acid (10 mol %) in benzene at 100
°C for 72 h. Disappointingly, the reaction was very sluggish,
and the product 6a was isolated in 51% yield with 12% ee (Table
1, entry 1). Although we investigated various palladium sources
in the presence of 1 and changed stoichiometries of the
palladium sources and the ligand, the enantioselectivity could
not be improved. Then we screened a variety of chiral
nonracemic phosphine ligands (monophosphines, bisphosphines,
and mixed P, N ligands) using the aminoalkyne 5a as a model
substrate.20 The results of selected ligand screening are sum-
marized in Table 1. When we employed (R,R)-chiraphos 2 as a
(21) There are innumerable reports on the synthesis and importance of
optically active cyclic ethers. For instance, see: (a) Pohlhaus, P. D.; Johnson,
J. S. J. Org. Chem. 2005, 70, 1057-1059. (b) Ghosh, A. K.; Xu, C.-X.;
Kulkarni, S. S.; Wink, D. Org. Lett. 2005, 7, 7-10. (c) Boto, A.; Hernandez,
D.; Hernandez, R.; Suarez, E. J. Org. Chem. 2003, 68, 5310-5319. (d)
Tanaka, K.; Pescitelli, G.; Bari, L. D.; Xiao, T. L.; Nakanishi, K.; Armstrong,
D. W.; Berova, N. Org. Biomol. Chem. 2004, 2, 48-58. (e) Ghorai, S.;
Mukhopadhyay, R.; Kundu, A. P.; Bhattacharjya, A. Tetrahedron 2005,
61, 2999-3012.
(19) The formation of the chiral rhodium complex Rh(I)-renorphos is
known; see ref 32. However the formation of the Pd-renorphos complex
has not been known in the literature.
(20) See the Supporting Information for details.
4272 J. Org. Chem., Vol. 71, No. 11, 2006

Palladium-Catalyzed Reactions of Alkynes
TABLE 2. Catalytic Intramolecular Asymmetric Hydroamination
of Alkynes
TABLE 3. Catalytic Intramolecular Asymmetric
Hydroalkoxylation of Alkynesa
a Condition A: 5 mol % of Pd2(dba)3‚CHCl3, 10 mol % of PhCOOH,
and 25 mol % of (R,R)-renorphos 4 in benzene at 100 °C for 72 h. Condition
B: 20 mol % of Pd2(dba)3‚CHCl3, 40 mol % of PhCOOH, and 100 mol %
of (R,R)-renorphos 4 in benzene/hexane (2:1) at 80 °C for 72 h. b Isolated
yield. c The ee was determined by chiral HPLC. d The ee was not
determined.
wide range of substrates. Hydroalkoxylation of 7a under the
best conditions that we found gave the desired product 8a in
52% yield with 80% ee (entry 1). The alkynol 7b having the
-OMe group at the para position gave 8b in 48% yield;
however, the enantioselectivity was low (entry 2). The alkynol
7c having the -CF3 group at the para position gave 8c in 60%
yield with 82% ee. Six-membered cyclic ethers 8d and 8e were
obtained, in good yields and with good enantioselectivities, from
the corresponding alkynols 7d and 7e (entries 4 and 5). The
hydroalkoxylation reaction of the substrates wherein alkynes
were tethered with alcohols through the aromatic ring was found
to be a good substrate for this reaction. Thus, when 7f was
employed as a substrate, the reaction proceeded smoothly to
produce 8f in 92% yield with 88% ee (entry 6). The alkynol 7g
produced the isochromane 8g in a high enantioselectivity (86%
ee) with 57% yield (entry 7). Introduction of the -CF3 group
at the para position of the aryl group substituted at the terminus
of the alkyne resulted in slight decrease of yield, but the
enantioselectivity remained unaffected (entry 8). As shown in
entry 9, substrate 7i gave the corresponding heterocycle 8i in a
lower yield and with lower enantioselectivity. It becomes clear
that this hydroalkoxylation reaction is very sensitive to the
electronic effect of substituents at the aromatic ring attached at
the terminus of the alkynes. Electron-donating substituents
attached at the para position of the aromatic group gave lower
yields and ee’s.
a Condition C: 10 mol % of Pd2(dba)3‚CHCl3, 20 mol % of PhCOOH,
and 60 mol % of (R,R)-renorphos in benzene (0.5 M) at 100 °C for 72 h.
b Isolated yield. c The ee was determined by chiral HPLC.
softer nucleophiles in comparison with amines and alcohols.
Accordingly, we tried several nonracemic chiral ligands that
were tested for the hydroamination reaction. However, all of
them gave unsatisfactory results except (R,R)-renorphos 4. Thus,
the catalytic system, Pd-renorphos, was extended to the
asymmetric hydrocarbonation of alkynes tethered with active
methines. Similar to the hydroamination, two conditions were
examined; conditions A and B. Condition C gave results more
or less similar to those using condition A. The results are
summarized in Table 4. Under condition A, the substrate 9a
underwent cyclization to give the carbocycle 10a in 70% yield
with 65% ee. However, when 9a was treated under condition
B, a dramatic increment in yield and enantioselectivity was
observed giving 10a in 80% yield with 90% ee (entry 1). The
substrates 9b, 9c, and 9d bearing -OMe, -CF3, and -CH3 at
the para position of the aromatic ring at the terminus of the
alkyne gave the corresponding chiral carbocycles 10b, 10c, and
10d, respectively, in good to high yields with good to high
enantioselectivities (entries 2-4). Interestingly, the cyclization
of 9e smoothly proceeded to give the product 10e in a high
yield; however, determination of the ee proved difficult (entry
Asymmetric Hydrocarbonation of Alkynes. We envisioned
that, in the case of hydrocarbonation, the mode of reaction might
be different from that of the hydroamination and hydroalkoxy-
lation since carbon analogues are generally regarded as much
J. Org. Chem, Vol. 71, No. 11, 2006 4273

Patil et al.
SCHEME 3. Plausible Mechanism for the Intramolecular
TABLE 4. Catalytic Intramolecular Asymmetric
Hydrocarbonation of Alkynes
Cyclizations
out that those reactions were not applicable to the cyclization
forming larger ring sizes.24 It is also notable that only renorphos
is applicable to the catalytic asymmetric hydroamination,
hydroalkoxylation, and hydrocarbonation, and the other well-
known ligands are not useful.
Determination of Absolute Configurations. The absolute
configuration of hydroamination product 6a (82% ee) was
determined by transforming it to the known compound 11 (eq
8). The literature25 attributes the R-configuration to (+)-2-
a Condition A: 5 mol % of Pd2(dba)3‚CHCl3, 10 mol % of PhCO2H, 25
mol % of (R,R)-renorphos 4 in benzene, 100 °C, 72 h. Condition B: 20
mol % of Pd2(dba)3‚CHCl3, 40 mol % of PhCO2H, 100 mol % of (R,R)-
renorphos 4 in benzene, 100 °C, 72 h. b Isolated yield. c The ee was
determined by chiral HPLC. d (S,S)-renorphos was used. e Determination
of ee proved difficult.
phenethylpyrrolidine, although no value of ee is stated. Because
the optical rotation of 11 was [R]22 ) -8.7 (c 0.75, CHCl3),
D
it was confirmed that the absolute configuration of 6a is S. In
a similar way, the absolute configuration of the hydroalkoxy-
lation product 8a (80% ee) was determined by transforming it
to the known compound 12 (eq 9). It is known in the literature
5).22 Thus, the mode of the intramolecular cyclization strongly
depends on the ring size of the products. This result is in contrast
to the hydroamination and hydroalkoxylation results wherein
the reactions of the corresponding aminoalkynes and alkynols
did not give the desired products; the starting materials were
recovered.23 As stated in the entries 6-8, this method is also
suitable for synthesizing six-membered carbocycles in good
yields and with good enantioselectivities. It should be noted
that the hydroamination, hydroalkoxylation, and hydrocarbon-
ation reactions described herein are applicable to the cyclization
forming five- and six-membered rings; however, it has turned
that (+)-2-phenethyltetrahydrofuran [R]23 ) +4.2 (c 1.06,
D
CHCl3) has S-configuration.26 Since the optical rotation of 12
was [R]25 ) +2.8 (c 1.0, CHCl3), it was unequivocally
D
confirmed that the absolute configuration of 8a is S. However,
in the case of asymmetric hydrocarbonation, it proved difficult
to assign the absolute configuration of the products.
Computational Studies. In our previous communication we
proposed the catalytic cycle of hydroamination (Scheme 3).18
(24) We also tried the reaction of alkynes, bearing various electron-
withdrawing groups (SO2Ph and COOEt, instead of CN) at the end of the
tethered carbon chain; however, the desired products were not obtained at
all; instead, the corresponding dienes were obtained. For the formation of
1,3-dienes from π-allyl-Pd species, see: (a) Takacs, J. M.; Lawson, E.
C.; Clement, F. J. Am. Chem. Soc. 1997, 117, 55956-5957. (b) Trost, B.
M.; Schmidt, T. J. Am. Chem. Soc. 1988, 110, 2301-2303.
(22) Efforts to determine the ee of 10e were undertaken using GC with
different chiral columns. However, no satisfactory separation of enantiomers
could be obtained.
(23) We tested the reactivity of the following substrates. Unlike the
hydrocarbonation, these substrates proved inert under conditions A and
B.
(25) Armstrong, D. W.; Li, W.; Stacup, A. M.; Secor, H. V.; Izac, R.
R.; Seeman, J. I. Anal. Chim. Acta 1990, 234, 365-380.
(26) Aquino, M.; Cardani, S.; Fronza, G.; Fuganti, C.; Fernandez, R. P.;
Tagliani, A. Tetrahedron 1991, 47, 7887-7896.
4274 J. Org. Chem., Vol. 71, No. 11, 2006

Palladium-Catalyzed Reactions of Alkynes
FIGURE 1. Origin of enantioselectivity in Pd-catalyzed intramolecular hydroamination. Parts A and B represent 4 as a C2-symmetric ligand;
equatorial phenyls of the diphosphine constitute hindered quadrants shown with filled blue squares; axial phenyls provide relatively smaller hindrance,
and the corresponding quadrants are marked with hollow squares. Parts C and D represent the arrangement of the aminoalkyl chain in the precursors
of S- (C) and R- (D) enantiomers in which the Pd complex is not shown for clarity, and the quadrants are marked in the same fashion as above.
Parts E and F represent optimized structures (B3LYP/SDD) of the corresponding π-allyl complexes: carbons are sea-green, hydrogens are gray, P
is orange, Pd is marine blue, N is blue, S is yellow, O is red, and F is green. Hindrance between the aminoalkyl chain and the central C-H group
of the π-allyl moiety is shown with red brackets.
Hydropalladation of the alkynes 5, 7, and 9 with the hydri-
dopalladium species 22 generated from Pd(0) and benzoic acid
produces the vinylpalladium species 19, which, via â-elimina-
tion, gives substituted phenyl allene 20.27 Subsequent hydro-
palladation of the allene 20 with 22 gives the π-allyl-Pd species
21. Intramolecular nucleophilic attack of the tethered nucleo-
philes to the π-allyl carbon gives the products 6, 8, and 10 along
with the hydridopalladium species 22.
computations28 of the selected intermediates of the proposed
catalytic cycle. First, we have considered the possibility of
stereoselection on the last cyclization step, suggesting that under
the reaction conditions different diastereomeric π-allyl-Pd
species might interconvert reversibly, and the stereoselectivity
appears as a result of selective cyclization of one diastereomer.
Regarding 4 as a ligand creating a C2-symmetric environment
(28) The theoretical data on the Pd-catalyzed enantioselective reactions
is rather limited, see: (a) Tang, D.; Luo, X.; Shen, W.; Li, M. J. Mol.
Struct.: THEOCHEM 2005, 716, 79-87. Before the recent DFT study of
asymmetric allylic alkylation only the mechanism of the epimerization of
π-allyl-Pd intermediates was studied, see: (b) Sakaki, S.; Nishikawa, M.;
Ohyoshi, A.; J. Am. Chem. Soc. 1980, 102, 4062-4069. (c) Braunstein, P.;
Naud, F. Organometallics 2001, 20, 2966-2981. (d) Solin, N.; Szabo, K.
J. Organometallics 2001, 20, 5464-5471.
To get insight into the possible origins of enantioselectivity
in the Pd-catalyzed cyclizations, we have carried out DFT
(27) Palladium-catalyzed isomerization of alkynes to allenes, see: (a)
Sheng, H.; Lin, S.; Huang, Y. Tetrahedron Lett. 1986, 27, 4893-4894. (b)
Lu, X.; Ji, J.; Ma, D.; Shen, W. J. Org. Chem. 1991, 56, 5774-5778. (c)
See refs 24a and 24b.
J. Org. Chem, Vol. 71, No. 11, 2006 4275

Patil et al.
TABLE 5. Relative Energies (B3LYP/SDD) and Selected Interatomic Distances for the π-Allyl Intermediates in the Catalytic Cycles of
Intramolecular Hydroamination, Hydroalkoxylation, and Hydrocarbonation
around the metal complex (Figure 1, parts A and B) one can
build two isomers of the syn,syn-π-allyl-Pd complexes 21
(Figure 1, parts C and D) with Pd bound to either face of the
π-allyl moiety. The most characteristic structural feature of the
optimized geometries of the π-allyl intermediates (Figure 1, parts
E and F) is that the definite conformation of the amino-
alkyl chain is invariably acquired in the optimization pro-
cess demonstrating the existence of a specific attraction between
the nitrogen atom and the Pd-π-allyl moiety. Furthermore, in
both optimized π-allyl complexes the folded aminoalkyl
chain resides in the less-hindered quadrant made by the axial
phenyl of the chiral ligand (Figure 1, parts C and D). Attempts
to locate the structures with the folded chain in a hindered
quadrant invariably led to the conformational reorganization
during the optimization resulting in essentially the same
structures with the folded aminoalkyl chain in the less-hindered
quadrant.
carbon at 3.44 Å. On the other hand, in the precursor of the
R-product (Figure 1D) the hindrance provided by the central
proton of the π-allyl moiety does not allow the C-N distance
to be made shorter than 4.30 Å. Since it is evident that the same
stereoregulating factors must be operative during the formation
of the cyclization transition state, we concluded that the
predominant formation of the S-product might be thus suf-
ficiently accounted. Similar results have been obtained for the
corresponding π-allyl intermediates of the hydroalkoxylation
and hydrocarbonation catalytic cycles: the stereodetermining
features for all π-allyl intermediates are listed in Table 5. From
examination of Table 5 one can see that the general trend is
uniformly reproduced for the π-allyl intermediates from different
reactions: the folding of the functionalized alkyl chain is
observed; it takes place in the less-hindered quadrant, and as a
result, the formation of the R-product must overcome the
inevitable steric hindrance of the C-H part of the π-allyl
moiety.
The relative energies of the diastereomers are very close (see
Table 5); therefore, the stereoselection cannot take place on the
stage of formation of these complexes. However, in the
cyclization step the nitrogen atom must approach the carbon
atom of the π-allyl moiety. And the structures of the π-allyl
complexes suggest that this approach can be stereoselective,
because to accommodate the aminoalkylchain in the less-
hindered quadrant, the π-allyl moiety must take a certain
orientation. As a result, in the precursor of the S-product (Figure
1C) the aminoalkyl chain does not meet any hindrance, and the
nitrogen atom spontaneously approaches the bond-forming
If the stereoregulating step is the final cyclization, then how
the π-allyl intermediates are generated must not be important.
It is well-known that the Pd-catalyzed hydroamination of dienes
and allenes takes place through the formation of π-allyl
intermediates.3,2m We thought therefore that the intramolecular
hydroamination of dienes and allenes yielding the same π-allyl
intermediates might be also enantioselective. Accordingly, the
aminodiene 23 and aminoallene 24 were prepared and tried in
the reaction. When 23 was submitted to condition A, the
4276 J. Org. Chem., Vol. 71, No. 11, 2006

Palladium-Catalyzed Reactions of Alkynes
cyclized product 6b was obtained in only 15% yield and
with24% ee (eq 10). Under the same conditions, 24 gave 25 in
formed after addition of the hydride to the acetylene complex,
thus provoking the formation of the chiral allene complex in a
fixed coordination state. The latter must rearrange into the
π-allyl complex without dissociation of allene, since free allene
as a substrate fail to provide stereoselective reaction. At present
we are unable to provide a detailed analysis of the stereodis-
criminating formation of the coordinated chiral allene. However,
we believe that the participation of the aminoalkyl chain in the
stereoselective process of the reactions described here is well
established in the present study. This fact gives stimulating ideas
for the further development of the enantioselective catalytic
transformations.
Conclusions
85% yield after 12 h (eq 11);29 however, no asymmetric
induction was observed at all. Moreover, the same result has
been obtained when only one enantiomer of 24 has been used
in the reaction (both enantiomers were tried).30 These results
suggest that the chiral discrimination does not take place at the
stage of π-allyl-Pd complex 21.
Since the use of a chiral allene does not result in the formation
of the chiral product, we concluded that in the course of the
enantioselective reaction the formation of the allene intermediate
20 is not only stereoselective but proceeds without dissociation
of the substrate that might keep a definite coordination mode
throughout the whole transformation. We argued that the
attractive interaction between the aminoalkyl chain and the metal
atom found in the π-allyl intermediates might serve as a
stereodiscriminating factor even in the case of nonchiral
intermediates.
To check this idea, we looked more closely at the initial
acetylene association step. The rodlike symmetry of the triple
bond does not imply the possibility of a prochiral coordination.
However, if the aminoalkyl chain is folded in a way similar to
that in the optimized geometries of the π-allyl complexes (Figure
1), then the substrate becomes prochiral, and the stereodiscrimi-
nation on the alkyne association step becomes theoretically
possible (Figure 2). We have looked for the conformational
minima of the alkyne complexes with alternatively coordinated
substrates (Figure 2, parts E and F). If we suggest that the initial
coordination of alkyne determines the stereochemistry of the
product, then the complex preceding the S-product (Figure 2E)
is 1.7 kcal/mol more stable than the complex ultimately yielding
the R-product (Figure 2F). Moreover, and more important for
the reactivity is the almost ideal coplanar orientation of the
Pd-H and CtC bonds acquired in the coordinated substrate
of the complex ultimately yielding the S-product (the deviation
from the parallel orientation is less than 9°, Figure 2C). In the
case of alternative coordination of acetylene the unfavorable
interaction between the folded aminoalkyl chain and the
hindered quadrant of the chiral Pd complex forces the triple
bond to rotate far away from the coplanar orientation with the
Pd-H bond (the deviation from the parallel orientation is over
50°, Figure 2D). In the same fashion, the additional interaction
between the aminoalkyl chain and palladium may favor a certain
conformation of the nonchiral vinylpalladium intermediate 19
In conclusion, we developed a catalytic enantioselective
intramolecular asymmetric hydroamination, hydroalkoxylation,
and hydrocarbonation of alkynes using the chiral palladium
catalyst derived from Pd2(dba)3‚CHCl3 and (R,R)-renorphos.
Various optically active heterocycles and carbocycles could be
prepared using simple and readily available starting materials.
To our knowledge, it represents the first example of transition
metal catalyzed asymmetric intramolecular addition of oxygen
and carbon nucleophiles to an activated C-C bond. The reaction
has some limitations, for example, high catalyst loading, high
temperature, and longer reaction time. The chemical and optical
yields are also not excellent in some cases. Nevertheless, the
reaction presented herein is promising because these studies
disclose a versatile mechanistic platform for the development
of novel carbon-carbon and carbon-heteroatom bond-forming
processes through the intermediacy of the chiral π-allyl-Pd
complex.
The computational studies suggest that the important stereo-
regulating factor in the intramolecular hydroamination31 is being
created by the particular conformational folding of the ami-
noalkyl chain directed by the attractive interaction between the
positively charged π-allyl moiety and the nucleophilic amino
group. Once this folding is established, the substrate becomes
prochiral, and the enantioselection is regulated via normal
stereochemical preferences of the C2-symmetric diphosphine
complexes. These findings can be useful for understanding the
important difference between intra- and intermolecular enanti-
oselective hydroaminations, clarifying the reasons for the latter
being more difficult.
Experimental Section
1. General Procedures for Asymmetric Intramolecular Hy-
droamination, Hydroalkoxylation, and Hydrocarbonation Reac-
tions. 1.1. Condition A. To Pd2(dba)3‚CHCl3 (5 mol %), PhCOOH
(10 mol %), and (R,R)-renorphos32 (25 mol %) was added a
substrate (0.125 mmol) in 1.5 mL of benzene under Ar atmosphere
in a screw-capped vial. After heating at 100 °C for 72 h, the reaction
mixture was filtered through a short silica gel column using diethyl
ether as an eluent. After evaporation of the solvent, the residue
was purified by silica gel column chromatography to afford the
corresponding cyclization product.
(29) The -Ts protecting group was used because the determination of
the ee of the product from the corresponding Nf-protected compound proved
difficult.
(30) The method for the preparation of racemic 24 is known, see ref 2k.
The chiral allene 24 was prepared from (S)-(-)-1-octyn-3-ol following the
same procedure {[R]25D ) -60 (c 1.0, CHCl3), 94% ee}. For the preparation
of chiral allene from chiral propynyl methanesufonates, see: Elsevier, C.
J.; Vermeer, P. J. Org. Chem. 1989, 54, 3726-3730.
(31) For selected examples on the computational studies, see: (a) Motta,
A.; Lanza, G.; Fragala, I. L.; Marks, T. J. Organometallics 2004, 23, 4097-
4104. (b) Tobisch, S. J. Am. Chem. Soc. 2005, 127, 11979-11988. (c)
Tobisch, S. Chem. Eur. J. 2005, 11, 6372-6385. (d) Straub, B. F.; Bergman,
R. G. Angew. Chem., Int. Ed. 2001, 40, 4632-4635.
(32) Kyba, E. P.; Davis, R. E.; Juri, P. N.; Shirley, K. R. Inorg. Chem.
1981, 20, 3616-3623.
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Patil et al.
FIGURE 2. Possibility of enantioselection on the acetylene association step. Parts A and B represent 4 as a C2-symmetric ligand; equatorial
phenyls of the diphosphine constitute hindered quadrants shown with filled blue squares; axial phenyls provide relatively smaller hindrance, and the
corresponding quadrants are marked with hollow squares. Part C and D demonstrate that if the aminoalkyl substituent acquires a definite conformation,
the molecule becomes prochiral; the Pd complex is not shown for clarity, and the quadrants are marked in the same fashion as above. Parts E and
F represent optimized structures (B3LYP/SDD) of the corresponding acetylenic complexes: carbons are sea-green, hydrogens are gray, P is orange,
Pd is marine blue, N is blue, S is yellow, O is red, and F is green.
1.2. Condition B. To Pd2(dba)3‚CHCl3 (20 mol %), PhCOOH
(40 mol %), and (R,R)-renorphos (100 mol %) was added a substrate
(0.125 mmol) in 1.5 mL of benzene/hexane (2:1) under Ar
atmosphere in a screw-capped vial. After heating at 80 °C for 72
h, the reaction mixture was filtered through a short silica gel column
using diethyl ether as an eluent. After evaporation of the solvent,
the residue was purified by silica gel column chromatography to
afford the corresponding cyclization product.
1.3. Condition C. To Pd2(dba)3‚CHCl3 (10 mol %), PhCOOH
(20 mol %), and (R,R)-renorphos (60 mol %) was added a substrate
(0.125 mmol) in benzene (0.5 M) under Ar atmosphere in a screw-
capped vial. After heating at 100 °C for 72 h, the reaction mixture
was filtered through a short silica gel column using diethyl ether
as an eluent. After evaporation of the solvent, the residue was
purified by silica gel column chromatography to afford the
corresponding cyclization product.
2. Computational Details. Geometries of all stationary points
were optimized using analytical energy gradients of self-consistent-
field33 and density functional theory (DFT).34 The latter utilized
Becke’s three-parameter exchange-correlation functional35 including
the nonlocal gradient corrections described by Lee-Yang-Parr
(LYP),36 as implemented in the Gaussian 03 program package.37
All geometry optimizations were performed using the SDD basis
(33) Pulay, P. In Modern Theoretical Chemistry; Schaefer, H. F., Ed.;
Plenum: New York, 1977; Vol. 4, p 153.
(34) (a) Parr, R. G.; Yang, W. Density Functional Theory of Atoms and
Molecules; Oxford University Press: New York, 1989. (b) Cheeseman, J.
R.; Frisch, M. J.; Devlin, F. J.; Stephens, P. J. Chem. Phys. Lett. 1996, 52,
211.
(35) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(36) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785. (b)
Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157,
200.
4278 J. Org. Chem., Vol. 71, No. 11, 2006

Palladium-Catalyzed Reactions of Alkynes
set.38 This approach is widely used for the recent computational
studies of transition metal complexes and was shown to yield results
conforming with experimental data in the works of our group39
and those of others.40
fellowship. The computational results in this research were
obtained using supercomputing resources at Information Synergy
Center, Tohoku University.
Supporting Information Available: Experimental details
for the preparation of starting materials, characterization data, H
NMR spectra of newly synthesized compounds, Cartesian coordi-
nates of the optimized structures, complete ref 37. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. N.T.P. thanks the Japan Society for the
Promotion of Science (JSPS) for a postdoctoral research
1
(37) Frisch, M. J.; et al. Gaussian 03, revision B.05; Gaussian, Inc.:
Pittsburgh PA, 2003.
(38) (a) Dunning, T. H., Jr.; Hay, P. J. In Modern Theoretical Chemistry;
Schaefer, H. F., III, Ed.; Plenum: New York, 1976; Vol. 3, p 1. (b)
Leininger, T.; Nicklass, A.; Stoll, H.; Dolg, M.; Schwerdtfeger, P. J. Chem.
Phys. 1996, 105, 1052.
JO0603835
(39) (a) Nakamura, I.; Bajracharya, G. B.; Wu, H.; Oishi, K.; Mizushima,
Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 15423. (b)
Nakamura, I.; Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem.
Soc. 2005, 127, 9844. (c) Nishikata, T.; Yamamoto, Y.; Gridnev, I. D.;
Miyaura, N. Organometallics 2005, 25, 5025. (d) Gridnev, I. D.; del Rosario,
M. K. C.; Zhanpeisov, N. U. J. Phys. Chem. B 2005, 109, 12498.
(40) (a) Bittner, M.; Koppel, H. J. Phys. Chem. A 2004, 108, 11116. (b)
McKee, M. L.; Swart, M. Inorg. Chem. 2005, 44, 6975. (c) Kondo, T.;
Tsunawaki, F.; Ura, Y.; Sadaoka, K.; Iwasa, T.; Wada, K.; Mitsudo, T.
Organometallics 2005, 24, 905. (d) Nowroozi-Isfahani, T.; Musaev, D. G.;
McDonald, F. E.; Morokuma, K. Organometallics 2005, 24, 2921.
J. Org. Chem, Vol. 71, No. 11, 2006 4279