Ir(I)-catalyzed intermolecular regio- and enantioselective hydroamination of alkenes with heteroaromatic amines

Article abstract of DOI:10.1021/ol203318z

A cationic Ir(I)-C₃-TUNEPHOS complex catalyzed an intermolecular hydroamination of styrene derivatives with various heteroaromatic amines. The reaction gave Markovnikov products with perfect regioselectivity and good enantioselectivity under solvent-free conditions.

Full text of DOI:10.1021/ol203318z

ORGANIC
LETTERS
2012
Vol. 14, No. 3
780–783
Ir(I)-Catalyzed Intermolecular Regio- and
Enantioselective Hydroamination of
Alkenes with Heteroaromatic Amines
Shiguang Pan,† Kohei Endo,‡ and Takanori Shibata*,†
Department of Chemistry and Biochemistry, School of Advanced Science and
Engineering, Waseda University, Shinjuku, Tokyo, 169-8555, Japan, and
Waseda Institute for Advanced Study, Shinjuku, Tokyo, 169-8050, Japan
tshibata@waseda.jp
Received December 12, 2011
ABSTRACT
A cationic Ir(I)-C3-TUNEPHOS complex catalyzed an intermolecular hydroamination of styrene derivatives with various heteroaromatic amines.
The reaction gave Markovnikov products with perfect regioselectivity and good enantioselectivity under solvent-free conditions.
The hydroamination reaction of alkenes with amines is a
highly atom economical and facile method for the prepa-
ration of substituted amines that are attractive targets
for organic synthesis and the pharmaceutical industry.1 In
extensive studies using various metal catalysts over the last
two decades,2 regioselective intermolecular reactions were
reported, which selectively gave Markovnikov adducts3 or
anti-Markovnikov ones.4 Regarding the intermolecular
enantioselective reaction,5 Togni pioneeringly reported
an Ir-catalyzed reaction of norbornene,6a which was fur-
ther improved by Hartwig.6b The enantioselective hydro-
amination to electron-deficient alkenes was achieved
by chiral Ni and Pd catalysts.7,8 However, there have been
relatively few studies of intermolecular regio- and enantio-
controlled hydroaminations of unactivated alkenes without
† Waseda University.
‡ Waseda Institute for Advanced Study.
€
(1) Reviews: (a) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675. (b)
Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. Adv. Synth. Catal.
2002, 344, 795. (c) Beller, M.; Breindl, C.; Eichberger, M.; Hurtung,
C. G.; Seayad, J.; Thiel, O. R.; Tillack, A.; Trauthwein, H. Synlett 2002,
1579. (d) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int.
Ed. 2004, 43, 3368. (e) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37,
(3) For selected examples: (a) Utsunomiya, M.; Hartwig, J. F. J. Am.
Chem. Soc. 2003, 125, 14286. (b) Li, K.; Horton, P. N.; Hursthouse,
M. B.; Hii, K. K. J. Organomet. Chem. 2003, 665, 250. (c) Kaspar, L. T.;
Fingerhut, B.; Ackermann, L. Angew. Chem., Int. Ed. 2005, 44, 5972.
(d) Qian, H.; Widenhoefer, R. A. Org. Lett. 2005, 7, 2635. (e) Johns,
A. M.; Utsunomiya, M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem.
Soc. 2006, 128, 1828.
€
673. (f) Hartwig, J. F. Nature 2008, 455, 314. (g) Muller, T. E.; Hultzsch,
K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. (h)
Nugent, T., Ed. Chiral Amine Synthesis: Methods, Developments and
Applications; Wiley-VCH: Weinheim, Germany, 2010. (i) Hesp, K. D.;
Stradiotto, M. ChemCatChem 2010, 2, 1192. Review of asymmetric
€
reactions: (j) Roesky, P. W.; Muller, T. E. Angew. Chem., Int. Ed.
(4) For selected examples: (a) Beller, M.; Eichberger, M.; Trauthwein,
H. Angew. Chem., Int. Ed. Engl. 1997, 36, 2225. (b) Utsunomiya, M.;
Kuwano, R.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125,
5608. (c) Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126,
2702. (d) Zhang, X.; Emge, T. J.; Hultzsch, K. C. Angew. Chem., Int. Ed.
2011, 51, 394.
2003, 42, 2708. (k) Hultzsch, K. C. Adv. Synth. Catal. 2005, 347, 367.
(l) Hultzsch, K. C. Org. Biomol. Chem. 2005, 3, 1819.
(2) For selected examples, see: (a) Casalnuovo, A. L.; Calabrese,
J. C.; Milstein, D. J. Am. Chem. Soc. 1988, 110, 6738. (b) Brunet, J.-J.;
Neibecker, D.; Philippot, K. J. Chem. Soc., Chem. Commun. 1992,
1215. (c) Brunet, J.-J.; Commenges, G.; Neibecker, D.; Philippot, K.
J. Organomet. Chem. 1994, 469, 221. (d) Knight, P. D.; Munslow, I.;
O’Shaughnessy, P. N.; Scott, P. Chem. Commun. 2004, 894. (e) Brunet,
J.-J.; Cadena, M.; Chu, N. C.; Diallo, O.; Jacob, K.; Mothes, E.
Organometallics 2004, 23, 1264. (f) Ackermann, L.; Kaspar, L. T.;
Gschrei, C. J. Org. Lett. 2004, 6, 2515. (g) Crimmin, M. R.; Arrowsmith,
M.; Barrett, A. G. M.; Casely, I. J.; Hill, M. S.; Procopiou, P. A. J. Am.
Chem. Soc. 2009, 131, 9670. (h) Mukherjee, A.; Nembenna, S.; Sen,
T. K.; Sarish, S. P.; Ghorai, P. K.; Ott, H.; Stalke, D.; Mandal, S. K.;
Roesky, H. W. Angew. Chem., Int. Ed. 2011, 50, 3968.
(5) Prominent examples of the intramolecular enantioselective reac-
tions: Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673 and ref 4d.
€
(6) (a) Dorta, R.; Egli, P.; Zurcher, F.; Togni, A. J. Am. Chem. Soc.
1997, 119, 10857. (b) Zhou, J.; Hartwig, J. F. J. Am. Chem. Soc. 2008,
130, 12220.
(7) (a) Fadini, L.; Togni, A. Chem. Commun. 2003, 30. (b) Fadini, L.;
Togni, A. Tetrahedron: Asymmetry 2008, 19, 2555.
(8) (a) Li, K.; Hii, K. K. Chem. Commun. 2003, 1132. (b) Gischig, S.;
Togni, A. Eur. J. Inorg. Chem. 2005, 4745.
r
10.1021/ol203318z
Published on Web 01/18/2012
2012 American Chemical Society

an electron-deficient group, which gave chiral branched
amines by Markovnikov selectivity. Chiral Pd catalysts
realized the regio- and enantioselectivity in the reaction
of styrene derivatives.9 Recently chiral gold and lantha-
nide catalysts made it an open possibility to use aliphatic
alkenes.10,11
was not observed under ligand-free conditions (entry 1).
When BINAP was used as a chiral ligand, the desired
product 3aa was obtained with moderate ee (entry 2),
and an S isomer was a major enantiomer.14 The yield
was low, but the Markovnikov adduct was exclusively
formed, and the anti-Markovnikov linear amine 4aa could
not be detected. Among the BINAP derivatives, tolBINAP
realized good yields, but the ee was moderate (entry 3).
We here disclose a regio- and enantioselective hydro-
amination of unactivated alkenes with heteroaromatic
Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Examples of Iridium-Catalyzed Intermolecular En-
antioselective Hydroamination of Alkenes
time
(h)
yield
(%)b
entry
X
chiral ligand
none
ee (%)
1c
2
BF4
18
6
ND
35
70
<5
29
9
À
BF4
(S)-BINAP
56
47
33
59
73
72
74
71
74
68
78
70
69
72
3
BF4
(S)-tolBINAP
6
4
BF4
(S)-Cy-BINAP
6
5
BF4
(S)-H8ÀBINAP
6
6
BF4
(S)-SYNPHOS
6
7
BF4
(S)-SEGPHOS
6
<5
19
15
52
83
27
85
82
90
8
BF4
(S)-C3-TUNEPHOS
(S)-C3-TUNEPHOS
(S)-C3-TUNEPHOS
(S)-C3-TUNEPHOS
(S)-C3-TUNEPHOS
(S)-C3-TUNEPHOS
(S)-C3-TUNEPHOS
(S)-C3-TUNEPHOS
6
amines using a chiral cationic Ir catalyst. Perfect
Markovnikov selectivity was achieved by various nitrogen-
containing heteroaromatic amines (Scheme 1). In previous
reactions,6 an intermolecular reaction of norbornene
derivatives with anilines proceeded using chiral neutral
Ir catalysts.
9
OTf
6
10
11
12e
13f
14f,g
15f,h
BARFd
BARFd
BARFd
BARFd
BARFd
BARFd
6
18
18
12
24
72
We have focused on the development of cationic iridium-
catalyzed reactions initiated by CÀH bond activation12
and recently developed an enantioselective sp3 CÀH bond
activation of 2-(alkylamino)pyridine with alkenes.13 Based
onthe reportedprotocol, we studieda cationic Ir-catalyzed
NÀH bond activation using pyridyl as a directing group.
The reaction of 2-aminopyridine (1a) with excess amounts
of styrene (2a) (8 equiv) was investigated in the presence of
cationic Ir catalysts using chlorobenzene as a solvent
(Table 1). But the formation of a hydroaminated product
a Conditions: 2-aminopyridine (1a) (0.1mmol),styrene(2a) (0.8 mmol),
PhCl (0.2 mL), unless otherwise noted. b Isolated yield. c The reaction
was examined at 135 °C. d Tetrakis(3,5-bis(trifluoromethyl)phenyl)-
borate. e The reaction was examined at 90 °C. f The reaction was
examined without solvent. g The catalyst loading was 5 mol %. h The
catalyst loading was 2 mol %.
SYNPHOS and SEGPHOS achieved good enantio-
selectivity, but the yields were poor (entries 6 and 7). When
C3-TUNEPHOS was utilized, 3aa was obtained with
the highest ee in promising yield (entry 8). As a result of
counteranion screening, we were pleased to find that
BARF dramatically improved the yield without loss of
ee, but the substrate 1a was not completely consumed
(entry 10).15 The prolonged reaction time enabled a fur-
ther increase of yield along with a slight decrease of ee
(entry 11).16 At a lower temperature of 90 °C, the reaction
sluggishly proceeded and the yield was low, but the ee was
sigificantly improved (entry 12). The present reaction
(9) (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122,
€
9546. (b) Lober, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc.
2001, 123, 4366. (c) Li., K.; Phua, P. H.; Hii, K. K. Tetrahedron 2005,
61, 6237. (d) Hu, A.; Ogasawara, M.; Sakamoto, T.; Okada, A.;
Nakajima, K.; Takahashi, T.; Lin, W. Adv. Synth. Catal. 2006, 348,
2051.
(10) Reznichenko, A. L.; Nguyen, H. N.; Hultzsch, K. C. Angew.
Chem., Int. Ed. 2010, 49, 8984.
(11) Zhang, Z.; Lee, S. D.; Widenhoefer, R. A. J. Am. Chem. Soc.
2009, 131, 5372.
(12) (a) Tsuchikama, K.; Kasagawa, M.; Hashimoto, Y.; Endo,
K.; Shibata, T. J. Organomet. Chem. 2008, 693, 3939. (b) Tsuchikama,
K.; Hashimoto, Y.; Endo, K.; Shibata, T. Adv. Synth. Catal. 2009,
351, 2850. (c) Tsuchikama, K.; Kasagawa, M.; Endo, K.; Shibata, T.
Org. Lett. 2009, 11, 1821. (d) Tsuchikama, K.; Kasagawa, M.; Endo,
K.; Shibata, T. Synlett 2010, 97. (e) Shibata, T.; Hashimoto, Y.;
Otsuka, M.; Tsuchikama, K.; Endo, K. Synlett 2011, 2075. (f) Shibata, T.;
Hirashima, H.; Kasagawa, M.; Tsuchikama, K.; Endo, K. Synlett 2011,
2171.
(14) Shen, Q.; Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130,
6586.
(15) When [Rh(cod)2]BARF was used in place of [Ir(cod)2]BARF, no
hydroaminated adduct was detected.
(16) In the presence of three equivalent amounts of styrene, the ee was
slightly improved, but the yield was low (35%, 73% ee).
(13) Pan, S.; Endo, K.; Shibata, T. Org. Lett. 2011, 13, 4692.
Org. Lett., Vol. 14, No. 3, 2012
781

proceeded without any solvent in high yield with perfect
regioselectivity and good enantioselectivity (entry 13). A
long reaction time was required but a low catalyst loading
of2 mol % was achieved (entry 15). Weusedthe conditions
employed in entry 13 for further investigation.
yields with good enantiomeric excesses (entries 1 and 2).
Inthe reactionof styrene derivatives 2dÀf withanelectron-
withdrawing group, in contrast to electron-donating groups,
the enantioselectivity was slightly decreased (entries 3À5).
The steric effect played an important role in this reaction,
and ortho-bromo-substituted styrene gave the product 3ah
in low yield with moderate enantiomeric excess (entry 7).
Aliphatic alkenes, 1-nonene (2i) and 3,3-dimethylbut-
1-ene (2j), could be also used as a coupling partner, and
Markovnikov adducts 3ai and 3aj were exclusively ob-
tained, although the ee was low (entries 8,9). It is note-
worthy that, in all the entries, including bulky alkenes
such as 2j, perfect regioselectivity was achieved, and the
branched amines were the only products.
Subsequently, the scope of heteroaromatic amines was
examined for the present transformation using styrene (2a)
asa standard alkene (Table 2). 2-Aminopyrimidine (1b) led
to the corresponding product 3ba with good yield, albeit
with low enantiomeric excess (entry 1). 2-Aminopyrazine
(1c) remained unconsumed, and amine 3ca was obtained in
moderate yield and enantiomeric excess (entry 2). Methyl-
substituted 2-aminopyridines 1d and 1e reacted with
styrene to giveproducts in highyield, butwithlow enantio-
selectivity (entries 3 and 4). The coordination of the nitro-
gen of the pyridine ring to Ir would be crucial for the con-
trol of regioselectivity, and anti-Markovnikov adduct 4ea
was ascertained as a minor product in the reaction of 1e
(entry 4). 1-Aminoisoquinoline (1f) was a favorable sub-
strate, and the highest ee was achieved along with perfect
regioselectivity (entry 5).
Table 3. Reaction of Various Alkenes with 2-Aminopyridinea
Table 2. Reaction of Heteroaromatic Amines with Styrenea
a Conditions: 2-aminopyridine (1a) (0.1 mmol), alkene 2 (0.8 mmol),
unless otherwise noted. b Isolated yield. c 3,3-Dimethylbut-1-ene
(1.6 mmol) was subjected in PhCl (0.2 mL) at 135 °C for 24 h.
Norbornene derivatives were good substrates, giving bi-
cyclic amines 3ak and 3al in high yield (Scheme 2). In par-
ticular, the enantioselectivity exceeded 90% in the reaction
of norbornene.
a Conditions: heteroaromatic amine 1 (0.1 mmol), styrene (2a)
(0.8 mmol), unless otherwise noted. b Isolated yield. c PhCl (0.2 mL)
was used as a solvent. d The ratio was determined by 1H NMR.
For a preliminary mechanistic study, the reaction of
aniline with styrene was examined under the same reaction
conditions. But only a trace amount of the hydroaminated
product was detected. A tentative mechanism for Ir-
catalyzed hydroamination of alkenes with heteroaromatic
We next investigated the scope of alkenes in the reaction
of 2-aminopyridine (1a) as a standard amine (Table 3).
4-Methoxy- and 4-methyl-substituted styrenes 2b and 2c
led to the corresponding products 3ab and 3ac in high
782
Org. Lett., Vol. 14, No. 3, 2012

Scheme 2. Enantioselective Reaction of Norbornene
Derivatives
Scheme 3. Tentative Mechanism for Regioselective
Intermolecular Hydroamination
amines was shown in Scheme 3. Pyridine-directed NÀH
bond activation of 2-aminopyridine is an initial step to
afford intermediate A.17 An alkene inserts into the IrÀN
bond to give the more favored intermediate C, which is
derived into Markovnikov hydroaminated products 3.
In summary, we described a protocol for the chiral
cationic Ir(I)-catalyzed intermolecular regio- and enantio-
selective hydroamination of styrene derivatives with het-
eroaromatic amines, which afforded various chiral
branched amines exclusively. Further studies on substrate
scope and the precise mechanism are in progress in our
laboratory.
Acknowledgment. This research was supported by
Grant-in-Aid for Scientific Research on Innovative Areas,
“Molecular Activation Directed toward Straightforward
Synthesis,” MEXT, Japan, and Global COE program
“Practical Chemical Wisdom,” Waseda University, Japan.
Supporting Information Available. The experimental
procedure and physical property of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) By the stoichiometric reaction of 2-aminopyridine (1a) with the
chiral Ir catalyst in an NMR tube, a small peak for MÀH (À12.5 ppm)
1
was observed in the H NMR, but the intermediate could not be fully
characterized yet.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
783