Rhodium-catalyzed anti-Markovnikov hydroamination of vinylarenes

Article abstract of DOI:10.1021/ja0293608

The transition metal-catalyzed anti-Markovnikov hydroamination of unactivated vinylarenes with a rhodium complex of DPEphos is reported. The reaction of electron-neutral or electron-rich vinylarenes with a variety of secondary amines in the presence of catalyst forms the products from anti-Markovnikov hydroamination in high yields. Reactions of morpholine, N-phenylpiperazine, N-Boc-piperazine, piperidine, 2,5-dimethylmorpholine, and perhydroisoquinoline reacted with styrene to form the amine product in 51-71% yield. Reactions of a variety of vinylarenes with morpholine generated amine as the major product. Reactions of morpholine with electron-poor vinylarenes gave lower amine:enamine ratios than reactions of electron-rich vinylarenes at the same concentration of vinylarene, but conditions were developed with lower concentrations of electron-poor vinylarene to maintain formation of the amine as the major product. Reactions of dimethylamine with vinylarenes were fast and formed amine as the major product. Mechanistic studies on the hydroamination process showed that the amine:enamine ratio was lower for reactions conducted with higher concentrations of vinylarene and that one vinylarene influences the selectivity for reaction of another. A mechanism proceeding through a metallacyclic intermediate that opens in the presence of a second vinylarene accounts for these and other mechanistic observations. Copyright

Full text of DOI:10.1021/ja0293608

Published on Web 04/18/2003
Rhodium-Catalyzed Anti-Markovnikov Hydroamination of Vinylarenes
Masaru Utsunomiya, Ryoichi Kuwano, Motoi Kawatsura, and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520-8107
Received November 15, 2002; E-mail: john.hartwig@yale.edu
Table 1. Ligand Effects on the Reaction of Styrene with
Morpholine in the Presence of Catalysts Containing DPEphos and
Related Ligandsa
The transition metal-catalyzed anti-Markovnikov hydroamination
of olefins was named1 as one of 10 challenges for homogeneous
catalysis because terminal amines are common commodity chemi-
cals2 and subunits of pharmaceuticals.3 Nearly 10 years later, the
reaction remains unknown, except for additions of amines to
Michael acceptors such as acrylates and acrylonitriles.4 Lanthanide
complexes catalyze the intramolecular hydroamination of terminal
alkenes.5-7 Early metals catalyze additions to allenes,8 and pal-
ladium complexes catalyze additions to vinylarenes,9 but all these
reactions give Markovnikov regioselectivity.10-15 Anti-Markovni-
kov, rhodium-catalyzed oxidative aminations of olefins to form
enamines have been reported recently by Beller,16 but vinylpyri-
dine17 is the only olefin that gives amine as the major product. We
report the transition metal-catalyzed anti-Markovnikov hydroami-
nation of unactivated vinylarenes. The reaction occurs regio-
specifically between a variety of vinylarenes and secondary amines
in the presence of a rhodium complex of DPEphos.
During studies on the palladium-catalyzed Markovnikov addition
of amines to vinylarenes,9 we found that rhodium complexes of
DPEphos generated high amine:enamine ratios and the same anti-
Markovnikov regiochemistry as the oxidative aminations. Table 1
summarizes the selectivity of catalysts containing ligands related
to DPEphos for the reaction of morpholine with styrene. Only
DPEphos showed high conversion with amine as the major product.
Even closely related analogues such as Xantphos and DBFphos
generated little or no hydroamination product.
entry
ligand
amine yieldb (%)
enamine yieldb (%)
1
2
3
4
5
6
7
8
DPEphos (eq 1)
PPh3
62
17
0
0
1
trace
3
0
20
78
1
0
1
9
40
0
DPPEc
DPPBd
DPPPente
Xantphos (1)
DBFphos (2)
BIPHEphos (3)
a Reaction were run for 48 h at 70 °C. Morpholine:styrene:[Rh(cod)2]BF4:
ligand ) 1:4:0.05:0.05 (0.2 mmol of morpholine, PPh3 ) 0.1) in 0.2 mL
of toluene. b GC yield. c 1,2-Bis(diphenylphosphino)ethane. d 1,4-Bis(di-
phenylphosphino)butane. e 1,5-Bis(diphenylphosphino)pentane.
Table 2. Anti-Markovnikov Hydroamination of Vinylarenes with
Secondary Aminesa
c
entry
amine
vinylarene
time (h)
yieldb (%)
amine/enamine
1
2
3
1a
1a
1a
1a
1a
1a
1b
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
2a
2d
2a
2a
2a
2c
2b
2d
2g
48
48
48
48
72
72
72
48
72
72
72
48
72
72
48
71
72
71
70
48
41
57
66
58
53
51k
62l
50d
74
79d
75:25
79:21
85:15
78:22
60:40
57:43
63:37
77:23
86:14
96:4
76:24
72:28
54:46
82:19
90:10
4
5e
6e,f
7g
8
9g
10
11g,h
12
13i
14i,j
15i
After optimization of the reaction conditions, the addition of
morpholine to styrene occurred at 70 °C in toluene solution in the
presence of 5 mol % [Rh(COD)(DPEphos)]BF4 to produce the anti-
Markovnikov hydroamination product in 71% yield (eq 1). The
enamine from oxidative amination was formed as a minor product
along with equimolar amounts of ethylarene. The reaction rate was
faster with higher concentrations of styrene, but the selectivity for
hydroamination vs oxidative amination product was lower (vide
infra). Thus, we adopted for further studies reaction conditions for
each substrate that provided an appropriate balance of rate and
selectivity.
As summarized in Table 2, reactions of electron-poor and
electron-rich vinylarenes with various cyclic secondary amines and
the acyclic dimethylamine formed â-phenethylamines in the pres-
ence of 5 mol % [Rh(COD)(DPEphos)]BF4. Isolated yields were
above 70% for reactions of morpholine with these vinylarenes
(entries 1-4), and the amine:enamine ratio was between 3:1 and
5.6:1. Reactions of piperidine and N-phenylpiperazine also gave
mainly the products from hydroamination (entries 7-9), while
reactions of N-Boc piperazine gave exclusively the amine product.
1g
1g
1g
a Amine:vinylarene:Rh catalyst ) 1:4:0.05 (1 mmol of amine) in 1 mL of
toluene. b Isolated yield by silica gel column chromatography. c Selectivity
was calculated from the GC area. d GC yield. e 10 mol % Rh catalyst was
used. f 2.0 equiv of vinylarene was used. g 75 °C. h 0.5 mL of toluene was
used. i Dimethylamine 2.0 M in THF solution (0.5 mL) and 0.5 mL toluene
was used. j No toluene was added. k Diastereomer ratio of starting amine
was 74:26, ratio of products was 82:18. The ratio was determined by GC
area. l Diastereomer ratio of starting amine was 7:93, ratio of products was
17:83. The ratio was determined by GC area.
Reactions of substituted cyclic amines, such as 2,5-dimethylmor-
pholine and perhydroisoquinoline with vinylarenes occurred in
9
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J. AM. CHEM. SOC. 2003, 125, 5608-5609
10.1021/ja0293608 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
Scheme 3
Scheme 2
rationalizes the effect of the second styrene. A metallacyclic
â-amino, R-arylalkyl complex could form by either attack on
coordinated olefin or insertion into a species formed by N-H
activation. This metallacycle would favor formation of amine
because the â-hydrogen would be inaccessible to the metal, but
the alkyl and hydride could be mutually cis. Coordination of a
second vinylarene21 could then open the metallacycle to allow
â-hydrogen elimination, or insertion of the vinylarene could
generate a dialkyl complex that must undergo â-hydrogen elimina-
tion. Coordination of the electron-poor vinylarene is likely to be
favored.21 Reaction solutions containing electron-poor vinylarene
would, therefore, create more enamine from â-hydrogen elimination
than those with only electron-rich vinylarene. We cannot explain
at this time the low selectivity from reactions of pyrrolidine, but
further investigation of the reaction mechanism, studies toward
synthesis of aminoalkyl intermediates, and an understanding of the
role of DPEphos on selectivity are in progress.
a Ratios were determined from GC peak areas and are uncorrected.
moderate yields, but with high selectivity for amine over enamine
(entries 11 and 12). Dimethylamine was the most reactive acyclic
amine. Reactions of this substrate gave high yields of hydroami-
nation products with electron-rich or -neutral styrenes and, in
contrast to previous results with other catalysts, gave good yields
of amine from reaction with 2-vinylpyridine.17 Primary aliphatic
and aromatic amines did not react, and pyrrolidine gave poor
selectivity for the amine product.
Electron-rich and electron-poor vinylarenes both gave amine as
the dominant product under the appropriate reaction conditions.
Reactions of electron-rich vinylarenes generally gave higher
selectivities than the reactions of electron-poor vinylarenes under
the same conditions. However, reactions at lower concentrations
of vinylarene gave higher selectivities. Therefore, reactions of
electron-poor vinylarenes, which were more reactive, were con-
ducted at lower concentrations of olefin and gave acceptable
selectivities for formation of amine versus enamine (entries 5 and
6).
Acknowledgment. We thank the NIH (GM-55382) for support.
M.U. was supported by Mitsubishi Chemical Corporation.
Supporting Information Available: Procedures for synthetic and
µ studies and characterization of reaction products (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
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Although further mechanistic studies are needed to define clearly
the catalytic pathway, Scheme 3 provides one mechanism that
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