Ruthenium-Catalyzed Anti-Markovnikov Hydroamination of Vinylarenes

Article abstract of DOI:10.1021/ja031542u

A ruthenium-catalyzed intermolecular, anti-Markovnikov hydroamination of vinylarenes with secondary aliphatic and benzylic amines is reported. The combination of Ru(cod)(2-methylallyl)₂, 1,5-bis(diphenylphosphino)pentane, and triflic acid was the most effective catalyst of those tested. Control reactions conducted without ligand or acid did not form the amine. The reaction of morpholine, piperidine, 4-phenylpiperazine, 4-BOC-piperazine, 4-piperidone ethylene ketal, and tetrahydroisoquinoline with styrene in the presence of 5 mol % of this catalyst formed the corresponding β-phenethylamine products in 64?96% yield, with 99% regioselectivity, and without enamine side products. Acyclic amines such as n-hexylmethylamine and N-benzylmethylamine reacted with styrene in 63 and 50% yields, respectively. Alkyl-, methoxy-, and trifluoromethyl-substituted styrenes reacted with morpholine in the presence of this catalyst or a related one containing 1,1′-bis(diisopropylphosphino)ferrocene as ligand to give the products in 51?91%. Further, the hydroamination of α-methyl styrene was observed for the first time with a homogeneous transition metal catalyst. Preliminary mechanistic studies showed that the reaction occurred by direct, irreversible, anti-Markovnikov hydroamination and that the mechanism of the ruthenium-catalyzed hydroamination is likely to be distinct from that of the recently reported rhodium-catalyzed reaction. Copyright

Full text of DOI:10.1021/ja031542u

Published on Web 02/13/2004
Ruthenium-Catalyzed Anti-Markovnikov Hydroamination of Vinylarenes
Masaru Utsunomiya and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520-8107
Received December 5, 2003; E-mail: john.hartwig@yale.edu
Many ruthenium complexes catalyze additions of hydrogen1,2 and
silanes3,4 to olefins. Ruthenium complexes also catalyze additions
Table 1. Effects of Catalyst Components on the Hydroamination
of Styrene and Morpholine in Dioxane at 100 °Ca
of amines5 and water6 to terminal alkynes. However, no complexes
of this metal have been shown to catalyze additions of amines to
olefins,7,8 despite increasing focus on the development of catalysts
for the hydroamination of olefins.9-11
entry
Ru (%)
ligand
acid
yields: 1b (%)
2b (%)
Much effort has been spent seeking late-metal catalysts for anti-
Markovnikov hydroamination because they are easily accessible,
simple to handle, and could tolerate an array of functional groups.12
Yet, such catalysts for selective anti-Markovnikov hydroamination
are lacking. Palladium complexes catalyze the Markovnikov
addition of amines13,14 to vinylarenes. Iridium complexes catalyze
only the addition of aniline to norbornene.15,16 We recently reported
a rhodium complex that catalyzes the anti-Markovnikov addition
of secondary amines to vinyl arenes,17 but oxidative aminations to
form enamines18 competed with hydroamination.
We disclose here selected ruthenium complexes that catalyze
with exquisite chemo- and regioselectivity the anti-Markovnikov
hydroamination of vinylarenes. Reactions of cyclic or acyclic,
functionalized or unfunctionalized secondary amines with vinyl-
arenes form terminal amines. In addition to demonstrating high
selectivity for formation of terminal amines, these results demon-
strate the tolerance of these late-metal catalysts toward Lewis basic
and acid-labile functionality.
1
2
5
5
5
5
2
5
5
5
5
5
5
7% DPPPent
-
7% DPPPent
7% DPPPent
3% DPPPent
14% PPh3
14% PEtPh2
7% DPPBc
7% DPPHexd
7% DPPFe
7% DPEphosf
10% TfOH
10% TfOH
-
96
0
<1
<1
0
3
0
4
10% TFA
5% TfOH
10% TfOH
10% TfOH
10% TfOH
10% TfOH
10% TfOH
10% TfOH
8
0
5
90
36
61
54
33
55
19
<1
6
9
7
3
8
12
2
9
10
11
44
2
a Reaction conditions: morpholine 0.4 mmol, styrene 0.8 mmol, dioxane
0.2 mL, 100 °C, 24 h. b GC yields. c 1,4-Bis(diphenylphosphino)butane.
d 1,6-Bis(diphenylphosphino)hexane. e 1,1′-Bis(diphenylphosphino)fer-
rocene. f Bis(2-diphenylphosphinophenyl)ether.
dimethyl-1,3-butadiene)(acac)2 generated the product in lower yield,
even under more forcing conditions.
The effects of ligand structure are revealed by entries 6-11.
Monodentate ligands, such as PPh3 and PEtPh2, generated product
in moderate yields (entries 6-7). The lower reactivity of catalysts
generated from PEtPh2 suggests that DPPPent acts as a chelating
ligand. Reactions with catalysts generated from related biphos-
phines, such as DPPB and DPPHex, formed the hydroamination
product in lower yield (entries 8-9). Reactions with catalysts gen-
erated from common biphosphines, such as BINAP, DPEphos (entry
11), and Xantphos, as well as triphos,19 gave the product in lower
yields. All reactions formed only hydroamination products and
polyvinylarenes. Reaction with the catalyst generated from DPPF
gave full conversion to a mixture of Markovnikov and anti-
Markovnikov products, but in a high combined yield (entry 10).
The scope of the reactions catalyzed by Ru(cod)(2-methylallyl)2,
DPPPent, and TfOH cocatalyst is summarized in Table 2. Reactions
of vinylarenes with a series of cyclic and acyclic secondary amines
formed â-phenethylamines with >99% regioselectivity. In most
cases, the reaction yields were limited by conversion, not formation
of side products. Polymerization of styrene competed with hy-
droamination, but no enamine from oxidative amination was formed.
Various cyclic amines reacted with styrene in good to excellent
yields (entries 1-5). High yields for reaction of 4-piperidone
ethylene ketal and Boc-piperazine underscore that the strength of
the triflic acid is leveled by the presence of the alkylamine and
that late-metal catalysts tolerate Lewis basic carbonyl groups and
acid-labile functionality. In contrast to hydroamination or oxidative
amination with rhodium catalysts, benzylic amines such as 1,2,3,4-
tetrahydroisoquinoline reacted in good yield (entry 6) but with only
65% conversion.
To uncover ruthenium catalysts for hydroamination, combinations
of common ruthenium complexes and phosphine ligands were tested
as catalyst for the addition of morpholine to styrene in the presence
and absence of acid cocatalyst. Selected results are provided in
Table 1. The reaction of styrene with morpholine occurred in the
presence of Ru(cod)(2-methylallyl)2 and a variety of phosphine
ligands. The ratio of Markovnikov to anti-Markovnikov addition
products depended on the ligand. Most striking, reactions of
morpholine with 2 equiv of styrene in the presence of 5 mol %
[Ru(cod)(2-methylallyl)2], 7 mol % 1,5-bis-diphenylphosphinopen-
tane (DPPPent), and 10 mol % TfOH (Table 1, entry 1) occurred
in 96% yield with >99% selectivity for the terminal amine. The
reaction with 1 equiv of styrene occurred with the same regio-
selectivity in 77% yield.
As shown in entries 2 and 3 of Table 1, reactions conducted
without ligand or TfOH did not occur, and reactions with trifluo-
roacetic acid as cocatalyst occurred in lower yield (entry 4). The
reaction conducted with 2% Ru(cod)(2-methylallyl)2, 3% DPPPent,
and 5% TfOH (entry 5) gave the product in slightly lower yield
than that with 5% ruthenium. Use of [Ru(cod)(2-methylallyl)2] as
catalyst precursor was crucial to obtain the product in high yield.
Catalysts generated from [Ru(p-cymene)Cl]2 and [Ru(cod)Cl]x gave
only trace amounts of product, and that generated from Ru(2,3-
The acyclic, secondary aliphatic, and benzylic amines n-hexyl
methylamine (entry 7) and N-benzyl methylamine (entry 8) added
across styrene. In contrast to the palladium-catalyzed Markovnikov
9
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J. AM. CHEM. SOC. 2004, 126, 2702-2703
10.1021/ja031542u CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ruthenium-Catalyzed Hydroamination of Vinylarenes
morpholino group. With 10% catalyst and conversion of the styrene
and piperidine to 94% of the hydroamination product, half the added
enamine remained, and no enamine from piperidine accumulated
(eq 4).
with Alkylaminesa
The precise mechanism of the ruthenium-catalyzed hydroami-
nation has not yet been revealed, but it is likely to be distinct from
that of the rhodium-catalyzed process. The rhodium catalysts for
hydroamination and oxidative amination induced isomerization of
N-deuteriomorpholine to form 2-deuteriomorpholine.21,22 This
exchange did not occur in the presence of the ruthenium catalysts.
Studies to increase catalyst activity by determining the detailed
mechanism of this reaction are in progress.
a Amine/vinylarene/Ru/DPPPent/TfOH ) 1:2:0.05:0.07:0.10 (1 mmol of
amine) in 0.50 mL of dioxane. b Isolated yield. c 4 mmol of vinylarene was
used. d 80 °C. e 48 h. f 0.25 mL of dioxane. g 110 °C. h DiPPF was used as
ligand. i 1.5 mmol of vinylarene was used. j 72 h.
hydroamination,14 the exchange of benzyl groups between amines20
was not observed. Thus, the lower yields of product from addition
of these less reactive amines reflects 67 and 53% conversions. More
hindered acyclic, aliphatic amines, such as dibutylamine, generated
only trace product at 100 °C.
Acknowledgment. We thank the NIH-NIGMS (GM55382) for
support. M.U. thanks Mitsubishi Chemical Corporation for support.
Supporting Information Available: Experimental procedures for
catalytic reactions (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
The hydroamination of vinylarenes with morpholine in the
presence of Ru(cod)(2-methylallyl)2 and DPPPent encompassed
electron-poor to electron-neutral styrenes (entries 9-11). Further,
the first transition metal-catalyzed hydroamination of R-methyl
styrene was observed (entry 14). Conversions of R-methyl styrene
were modest, but a single-addition product was observed.
The combination of Ru(cod)(2-methylallyl)2 and di-isopropyl-
phosphinoferrocene (DiPPF) was more active for hydroaminations
of vinylarenes containing electron-withdrawing groups. For ex-
ample, the reactions of vinylarenes containing 3- and 4-CF3 groups
in the presence of 5% Ru(cod)(2-methylallyl)2 and 7% DiPPF gave
the addition products in good to moderate yields (entries 12-13),
while the same reactions in the presence of the catalyst with
DPPPent occurred in less than 20% yield.
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