Intermolecular, Markovnikov Hydroamination of Vinylarenes with Alkylamines

Article abstract of DOI:10.1021/ja0375535

A transition metal-catalyzed intermolecular hydroamination of vinylarenes with alkylamines is reported. The combination of Pd(O₂CCF₃)₄, DPPF, and TfOH was the most effective catalyst of those tested. Control experiments without palladium, acid, or ligand all occurred in low yield. The reaction of various vinylarenes with cyclic and acyclic alkylamines in the presence of 5 mol % of this catalyst formed the corresponding arylethylamine products in moderate to high yields. For example, reactions of morpholine, 4-phenylpiperazine, 4-Boc-piperazine, isoindoline, and tetrahydroisoquinoline with styrene all occurred in 58?75% yield. Acyclic amines such as N-benzylmethylamine and n-hexylmethylamine reacted with 2-vinylnaphthalene in 63% and 53% yields, respectively. Mechanistic investigations showed that the reaction occurred through an η³-arylethyl palladium complex. The reactions of this complex with alkylamines generated product in combination with regenerating free vinylarene, Pd(0), and ammonium salt. Thus, one hurdle to developing hydroamination of vinylarenes with palladium complexes is the faster elimination of free vinylarene from the η³-arylethyl complex than addition to form the C?N bond. The feasibility of conducting enantioselective hydroaminations with alkylamines was also examined. The product from addition of N-benzylmethylamine to 2-vinylnaphthalene was generated in 63% ee and 36% yield in the presence of Pd(OCOCF₃)₂, a ferrotane ligand, and TfOH cocatalyst. Copyright

Full text of DOI:10.1021/ja0375535

Published on Web 11/01/2003
Intermolecular, Markovnikov Hydroamination of Vinylarenes with Alkylamines
Masaru Utsunomiya and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520-8107
Received July 25, 2003; E-mail: John.Hartwig@yale.edu
Catalysts for the hydroamination of olefins have been actively
pursued because this process could create an efficient synthesis of
amines with regio- and enantiocontrol.1 However, few intermo-
lecular additions of amines to olefins have been reported.3 Only
one high-yield Markovnikov addition of an alkylamine to an alkene
or vinylarene catalyzed by a d- or f-block metal is known,11 and
Table 1. Effects of Catalyst, Acid, and Solvent on the Hydro-
amination of Styrene with Morpholine at 120 °Ca
,2
yieldb
entry
catalyst
solvent
-11
1
2
3
4
5
6
7
8
9
5% Pd(O2CF3)2/10% DPPF/20% TfOH
5% Pd(O2CF3)2/10% DPPF/20% TfOH
5% Pd(O2CF3)2/5% DPPF/20% TfOH
5% Pd(DPPF)(OTf)2
5% Pd(DPPF)(OTf)2/5% DPPF/10% TfOH
5% Pd(PPh3)4/20% TfOH
20% TfOH
5% Pd(O2CF3)2/20% TfOH
5% Pd(O2CF3)2/10% DPPF
dioxane
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
dioxane
79
25
2
1
74
6
1
1
2
this reaction was conducted with 20 mol % of a lanthanide catalyst
and a 70:1 ratio of olefin to amine.
Late transition-metal catalysts are likely to be more convenient
to handle and tolerant of functional groups than lanthanide or early
metal catalysts. However, late metal-catalyzed pathways for hy-
droaminations with alkylamines initiated by activation of amine or
activation of olefin have been challenging to develop. Activation
of alkylamines by oxidative addition remains unknown, and
although addition of amines to coordinated olefins is common, the
aminoalkyl group resulting from this addition is difficult to cleave
from the metal under catalytic conditions. Acid could cleave this
group in a catalytic cycle,12 but the high basicity of alkylamine
reagents level the strength of strong acids.
1
1
0
1
5% Pd(O2CF3)2/10% DPPF/20% TFA
19
72
67
c
5% Pd(O2CF3)2/10% DPPF/20% NFA
5% Pd(O CF ) /10% DPPF/20% NFAc
12
2
3 2
a
Reaction conditions: 0.4 mmol morpholine, 0.8 mmol styrene, 0.2 mL
dioxane, 24 h. b GC yields, in percent. c NFA ) nonafluorobutane sulfonic
acid.
Results from reactions with different catalyst compositions are
summarized in Table 1. Reactions of vinylarenes with aliphatic
amines conducted with a 1:1 ratio of metal to bisphosphine and
We recently showed that palladium-catalyzed additions of aryl-
3
amines to vinylarenes occurred by addition of the amine to an η -
reactions catalyzed by isolated (DPPF)Pd(OTf)
yield (entries 3 and 4). However, reactions catalyzed by 5% (DPPF)-
Pd(OTf) with 5% added DPPF and TfOH cocatalyst (entry 5)
occurred in good yield. Reactions catalyzed by Pd(PPh and TfOH
2
occurred in low
phenethylpalladium intermediate instead of N-H activation or
attack of amine on a coordinated olefin.13 We now report the first
transition metal-catalyzed olefin hydroamination with alkylamines
to form products with Markovnikov regiochemistry (eq 1). Mecha-
nistic studies show that the palladium catalysts confront a new
hurdle in this process: reaction of the more basic alkylamine with
2
3 4
)
as cocatalyst were slow (entry 6), despite the high activity of this
8
catalyst for addition of aromatic amines to vinylarenes.
Palladium, ligand, and acid cocatalysts were each required to
form substantial amounts of product. As shown in Table 1, entries
3
the η -phenethylpalladium intermediate leads to an elimination of
olefin that is competitive with the addition of amine to form the
hydroamination product.
7-9, reactions lacking one or more of these components occurred
in low yield. Reaction with trifluoroacetic acid instead of TfOH as
cocatalyst (entry 10) also occurred in low yield.
Reaction of morpholine with styrene in the presence of catalyst
and the longer chain fluoroalkylsulfonic acid, nonafluorobutane-
sulfonic acid (NFA), consisted of a single phase in toluene and
occurred in good yield (Table 1, entry 11). However, the longer
chain sulfonic acid did not improve reaction yields in dioxane (entry
12), and reaction of other amines with styrene in the presence of
NFA in toluene solvent occurred in lower yields than they did with
TfOH in dioxane.
The scope of the reaction of alkylamines with vinylarenes is
summarized in Table 2. The reaction of morpholine with electron-
rich or electron-poor vinylarenes occurred in moderate to good
yields (Table 2, entries 1-6). Reactions of 2-vinylnaphthalene
occurred fastest and in the highest yields, as was observed for
reactions of aromatic amines.
Modestly basic cyclic aliphatic or benzylic amines such as
N-phenylpiperazine, N-Boc piperazine, isoindoline, and 1,2,3,4-
tetrahydroisoquinoline also reacted with styrene in good yields
(Table 2, entries 7-10). The more basic14 piperidine reacted with
lower conversions and formed the products from addition to
2-vinylnaphthalene (entry 11) and styrene in lower 52% and 20%
yields. Pyrrolidine also reacted with styrene in low yields.
The previously reported, palladium-catalyzed additions of aro-
matic amines to vinylarenes occurred in toluene solvent with
catalysts bearing either mono- or bidentate ligands. In contrast,
8
the addition of aliphatic amines to vinylarenes required an alterna-
tive reaction medium, higher temperatures, and a change in catalyst
composition. After testing a variety of reaction conditions, the
addition of morpholine to styrene was found to occur in 79% yield
at 120 °C in dioxane solvent with a catalyst generated from 2 equiv
of the bidentate ligand DPPF (DPPF ) 1,1′-bis(diphenylphosphino)-
ferrocene) and palladium trifluoroacetate (Table 1, entry 1).
The reactions of morpholine with styrene in toluene at 120 °C
separated into two phases and occurred in only 25% yield (Table
1, entry 2). These two phases consisted of vinylarene in toluene
and, presumably, the ammonium salt from amine and acid.
Reactions in ether solvents consisted of a single phase, and the
reaction of morpholine with styrene in dioxane occurred faster than
it occurred in toluene and in high yield.
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10.1021/ja0375535 CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
3
Table 2. Pd-Catalyzed Hydroamination of Alkylamines with
Vinylarenes
vinylarene would regenerate the η -arylethyl intermediate. Because
the formation of this intermediate from alkylammonium salts is
thermodynamically less favorable than that from arylammonium
3
salts, the concentration of the η -arylethyl intermediate should be
lower and the concentration of Pd(0) species higher in reactions of
alkylamines. Indeed, the major palladium phosphine complex in
solution during the catalysis with alkylamines is (DPPF) Pd(0).
2
To test for the potential to develop an enantioselective hydroami-
nation16 of alkylamines, several nonracemic chiral ligands were
examined. Reaction of N-methylbenzylamine with 2-vinylnaphtha-
17
2 3 2
lene catalyzed by Pd(O CCF ) and (R,R)-Et-FerroTANE occurred
in 36% yield and 63% ee (eq 3) Though modest in yield and
selectivity, these data demonstrate the feasibility of enantioselective
additions of alkylamines.
a
Amine/vinylarene/Pd(TFA)2/DPPF/TfOH ) 1:2:0.05:0.10:0.20 (1 mmol
b
c
d
e
of amine) in 0.50 mL of dioxane. Isolated yield. 48 h. 100 °C. 4.0
mmol of vinylarene was used. 0.20 mL of dioxane. 110 °C. 80 °C.
0% of dibenzylmethylamine was obtained as side product. 18 h.
f
g
h
i
j
1
Thus, the scope of the palladium-catalyzed hydroamination of
vinylarenes has been significantly expanded, and mechanistic data
show a challenge confronted when conducting palladium-cata-
lyzed reactions of vinylarenes with aliphatic amines. Further inves-
tigations to increase catalyst activity, reaction scope, and selectivities
are in progress.
Acyclic aliphatic and benzylic amines also underwent hydroami-
nation with vinylarenes. N-Benzylmethylamine added to 2-vinylnaph-
thalene in 63% yield (Table 2, entry 12) and to 4-methyl styrene
in 43% yield (entry 13). The purely aliphatic acyclic n-hexyl meth-
ylamine added to 2-vinyl naphthalene in moderate yield (entry 14).
The known exchange of alkyl groups between amines15 competed
Acknowledgment. We thank the NIH (GM-55382) for support,
Merck Research Laboratories for unrestricted support, and Johnson-
Matthey for palladium. M.U. thanks Mitsubishi Chemical Corpora-
tion for support.
with hydroamination. For example, dibenzylmethylamine was
formed from reaction of N-methylbenzylamine with 4-methylsty-
rene. The formation of this exchange product decreased the yield
of product formed by hydroamination.
Supporting Information Available: Procedures for synthetic and
mechanistic studies and characterization of reaction products (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
To understand the differences in reactions of alkyl and aryl-
amines, we evaluated if the C-N bond in the alkylamine products
3
was formed by addition of alkylamine to an η -phenethylpalladium
complex as it was during palladium-catalyzed additions of aryl-
amines to vinylarenes.13 Thus, DPPF-ligated η -4-methylphenyl-
ethylpalladium complex 1 in eq 2 was allowed to react with 2 equiv
of morpholine in the presence of added DPPF to trap a Pd(0)
3
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