Iridium-catalyzed intermolecular hydroamination of unactivated aliphatic alkenes with amides and sulfonamides

Article abstract of DOI:10.1021/ja3052848

The intermolecular addition of N-H bonds to unactivated alkenes remains a challenging, but desirable, strategy for the synthesis of N-alkylamines. We report the intermolecular amination of unactivated α-olefins and bicycloalkenes with arylamides and sulfonamides to generate synthetically useful protected amine products in high yield. Mechanistic studies on this rare catalytic reaction revealed a resting state that is the product of N-H bond oxidative addition and coordination of the amide. Rapid, reversible dissociation of the amide precedes reaction with the alkene, but an intramolecular, kinetically significant rearrangement of the species occurs before this reaction with alkene.

Full text of DOI:10.1021/ja3052848

Communication
pubs.acs.org/JACS
Iridium-Catalyzed Intermolecular Hydroamination of Unactivated
Aliphatic Alkenes with Amides and Sulfonamides
Christo S. Sevov,‡,§ Jianrong (Steve) Zhou,§ and John F. Hartwig*,‡,§
‡Division of Chemical Sciences, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California,
Berkeley, California 94720, United States
§Department of Chemistry, University of Illinois, 600 South Matthews Avenue, Urbana, Illinois 61801, United States
S
* Supporting Information
Recent work in our laboratory has demonstrated the high
ABSTRACT: The intermolecular addition of N−H bonds
to unactivated alkenes remains a challenging, but desirable,
strategy for the synthesis of N-alkylamines. We report the
intermolecular amination of unactivated α-olefins and
bicycloalkenes with arylamides and sulfonamides to
generate synthetically useful protected amine products in
high yield. Mechanistic studies on this rare catalytic
reaction revealed a resting state that is the product of N−
H bond oxidative addition and coordination of the amide.
Rapid, reversible dissociation of the amide precedes
reaction with the alkene, but an intramolecular, kinetically
significant rearrangement of the species occurs before this
reaction with alkene.
activity and selectivity of bisphosphine-ligated iridium com-
plexes for the intermolecular hydroamination of bicycloalkenes
with arylamines.3a On the basis of this observation, we sought
to develop the catalytic addition of N−H bonds to unactivated
alkenes with more versatile nitrogen donors, such as amides
and sulfonamides, than had been added to unstrained alkenes
previously.2b,c,e
The combination of [Ir(coe)2Cl]2 and a series of bis-
phosphine ligands was tested as catalyst for the addition of 4-
tert-butylbenzamide to 1-octene. The results are summarized in
Table 1. Ir complexes of aryl bisphosphines containing ethyl,
propyl, and ferrocenyl backbones did not form active catalysts
for the desired transformation (see SI for full ligand set). A
small amount of product was observed for reactions catalyzed
by complexes of methylene-bridged bisphosphines (entry 1),
mine functionality is ubiquitous in biologically active and
Aindustrially useful molecules. Many strategies to form C−
N bonds provide access to this functional group in fine
chemical building blocks, pharmaceuticals, agrochemicals,
solvents, and surfactants. Classical methodologies for C−N
bond formation involve reductive aminations of carbonyl
compounds or substitution reactions of prefunctionalized
aliphatic starting materials. An alternative, more synthetically
efficient route to construct C−N bonds is the addition of an
N−H bond across an unsaturated C−C bond, a transformation
formally known as hydroamination. A majority of metal-
catalyzed hydroaminations are intramolecular cyclizations of
aminoalkenes to form amine heterocycles. Few complexes
catalyze intermolecular hydroamination of alkenes.1
Table 1. Reaction Development for Ir-Catalyzed
Intermolecular Addition of 4-tert-Butylbenzamide to 1-
a
Octene
equivs of temp % yield of ratio
b
entry
ligand
1-octene (°C)
7 + 7a
7:7a
c
1
2
dcpm
5
5
120
120
120
120
120
120
120
120
100
140
8
2
12:1
4.1:1
1.8:1
2.0:0
1.9:1
1.9:1
3.3:1
1.3:1
1.8:1
1.4:1
(R)-DM-BINAP
3
(R)-DM-MeOBIPHEP
5
12
18
28
44
13
74
47
96
With few exceptions,2 intermolecular hydroaminations are
limited to reactions of activated alkenes, such as bicycloal-
kenes,3 1,3-dienes,4 allenes,5 and vinylarenes,2b,6 or the
unsubstituted ethylene.7 Examples of intermolecular additions
of N−H bonds across unactivated alkenes are rare, and
additions of amides and sulfonamides to higher α-olefins are
particularly unusual.8 Here, we report a well-defined transition-
metal complex that catalyzes the intermolecular hydroamina-
tion of unactivated alkenes with amides and sulfonamides to
form N-alkylamides and sulfonamides. The same system
catalyzes additions of amides to norbornene (nbe) and
norbornadiene (nbd) that are highly enantioselective. Mecha-
nistic studies on these additions to unstrained and strained
alkenes reveal the resting state of the catalyst and the turnover-
limiting steps of the hydroamination processes.
d
4
(S)-DM-SEGPHOS
5
5
(R)-DTBM-MeOBIPHEP
5
e
6
(S)-DTBM-SEGPHOS
5
7
(S)-DTBM-SEGPHOS
(S)-DTBM-SEGPHOS
(S)-DTBM-SEGPHOS
(S)-DTBM-SEGPHOS
1
8
20
20
20
9
10
a
Reactions were performed neat in 1-octene with 0.1 mmol of 4-tert-
b
butylbenzamide. Yields and conversions were determined by GC
c
analysis with dodecane as an internal standard. dcpm = bis-
d
(dicyclohexylphosphino)methane. DM = 3,5-dimethylphenyl.
e
DTBM = 3,5-di-tert-butyl-4-methoxyphenyl.
Received: June 6, 2012
Published: July 10, 2012
© 2012 American Chemical Society
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suggesting that a small bite angle in the ligand was important
for generating an active catalyst.
were slightly lower than those of less hindered alkenes, but still
substantial. Finally, additions of sulfonamides occurred without
alkene isomerization to form the Markovnikov product in high
yield.
The scope of this methodology also encompasses the
addition of N−H bonds of amides and sulfonamides to
bicycloalkenes. As shown in Table 3, products of the reactions
A similar effect of the ligand bite angle on the yield of the
catalytic reaction was observed for reactions catalyzed by Ir
complexes of bisphosphine ligands containing biaryl backbones,
and a survey of commercially available bisphosphines
containing biaryl backbones led to a system that formed N-
alkylamide and enamine products in high combined yield.
Studies of ligands with varied dihedral angles of the ligand
backbone showed that the yields were higher for reactions
conducted with ligands having smaller dihedral angles (entries
2−4). An increase in the steric bulk from the parent Segphos
ligand to the DTBM-Segphos (DTBM = 3,5-di-tert-butyl-4-
methoxy) derivative led to an increase in yield of addition
products. Furthermore, the lipophilicity of the tert-butyl groups
imparted greater solubility of the catalyst in the alkene. An
excess of the α-olefin was required to effect the transformation
in high yield. Low conversion to the alkylamide and alkyl
enamide products was observed with 1 equiv of 1-octene to the
amide catalyzed by the Ir catalyst ligated by DTBM-Segphos.
Ultimately, reaction of the benzamide with 20 equiv of the
alkene formed the hydroamination product in 56% yield and
the corresponding enamide in 40% yield. The alkene is the
terminal reductant for the enamide side product; the
corresponding alkane was also formed in 40% yield.
Table 3. Ir-Catalyzed Enantioselective Intermolecular
Addition of Amides and Sulfonamides to Bicycloalkenes
a
a
Reactions were performed with 0.3 mmol of amide or sulfonamide
and 4.0 equiv of nbe or 1.2 equiv of nbd. Reported yields are isolated
yields. ee was determined by chiral HPLC analysis.
To generate a single amination product, the enamide was
reduced to the alkylamide by subjecting the crude reaction
mixture to 1 atm of H2 or an excess of isopropanol after the
amination process. Thus, a one-pot reaction workup with
isopropanol formed the saturated product exclusively and in
high yield. The alkylamide products were formed with low 10−
19% ee, but these measurable values do rule out hydro-
amination of the alkene by a proton-catalyzed process alone.8
Moreover, the enamide product was found to be stable to the
catalytic conditions, indicating that the stereogenic center of the
N-alkylamide is set by the C−N bond-forming step rather than
asymmetric hydrogenation of an enamide intermediate.
The scope of the Ir-catalyzed addition of amides to
unactivated α-olefins by this procedure is summarized in
Table 2. Following a one-pot reductive workup, high yields
were obtained from reactions of the arylamides possessing
electron-donating and electron-withdrawing aryl substituents.
Products of more hindered alkenes were formed in yields that
of norbornadiene and norbornene with arylamides and
tosylamide were formed in high yield and ee. These types of
amides added to nbd in slightly lower yields than to nbe, but
with ee’s that were similar to those for the reactions with nbe.
The catalytic process proceeds with excellent diastereoselectiv-
ity to form the monoalkylated exo product. Hydrolysis of the
amide led to the 2-norbornylamine building block with no
erosion of the ee. Much effort has been spent to form
norbornylamine by a catalytic process in enantioenriched
form,10 and this hydroamination provides the most direct route.
The absolute stereochemistry of the amide was determined by
optical rotation of the 2-aminonorbornane to be 2R. These
results constitute the first intermolecular asymmetric hydro-
amination of an alkene with amides and sulfonamides in high
yield and ee.
This catalytic process proved amenable to mechanistic
studies. The combination of [Ir(coe)2Cl]2, 4-CF3-benzamide,
and DTBM-Segphos formed a clear solution (from the initial
orange solution) within 15 min at room temperature (Figure
1a). A similar color change was observed at the start of the
catalytic reaction. This finding suggested that the catalyst
resting state did not contain an alkene.
Table 2. Ir-Catalyzed Intermolecular Addition of Amides
a
and Sulfonamides to Unactivated α-Olefins
The structure of the complex formed from the amide, ligand,
and Ir was determined by X-ray diffraction (Figure 1b) and
solution NMR spectroscopy. This complex results from
oxidative addition of the N−H bond of the amide and
coordination of a second amide to Ir through an unusual M−N
dative bond. The assignment of the amide and amidate ligands
of 1 was based on the difference between the two Ir−N bond
lengths (2.076 Å for the amidate and 2.117 Å for the amide)
and the Ir−N−C−O dihedral angle. The group assigned as a
bound amide has a larger Ir−N−C−O dihedral angle (22°)
than that of the nearly planar amidate (5°) because of the
absence of a free lone pair to interact with the carbonyl group.
The 31P and 19F NMR resonances of 1 matched the respective
resonances of the complex that was formed in the catalytic
a
Reactions were performed neat in 20 equiv of alkene with 0.3 mmol
of amide or sulfonamide. Reported yields are isolated yields following a
reductive workup with isopropanol. ee was determined by chiral
b
c
d
HPLC analysis prior to reductive workup. 12% ee. 13% ee. 19% ee.
e
12% ee.
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order at high concentrations of the alkene. No intermediate
that might contain the alkene was observed during these
reactions. At high [nbe] (0.5 M), under which conditions the
reaction is zero-order in alkene, the reaction is inverse first-
order in amide. These data indicate that the amide amidate
complex 1 undergoes reversible dissociation of the amide,
followed by an intramolecular rearrangement before reacting
with the alkene.
To gain information on the dynamics of complex 1, we
conducted variable-temperature (VT) NMR spectroscopy on a
p-fluorobenzamide analogue of 1 (1-p-F). Spectra with added
amide were most informative. The 19F NMR spectrum of the
combination of 1-p-F and 1 equiv of added amide contained
three distinct 19F NMR resonances for the amide and amidate
ligands and for the free amide. Exchange between the free
amide (signal a) and the datively bound amide (signal b) was
observed between room temperature and 60 °C; the resonance
for amidate ligand c remained unchanged (Figure 3) in this
Figure 1. (a) Synthesis and (b) X-ray structure of 1. (c)
Stoichiometric reaction of 1 with nbe. (d) Structure and quadrant
diagram of the coordination sites of 1. Ar = 3,5-di-tert-butyl-4-
methoxyphenyl; Ar′ = 4-trifluoromethylphenyl.
Scheme 1. Dynamic Ligand Exchange Processes for 1-p-F
reaction at room temperature and 50 °C. Thus, 1 is the resting
state of the catalyst in these additions of amides to alkenes.
To determine if the observed complex is competent to be an
intermediate in the catalytic reaction, a stoichiometric amount
of 1 was subjected to a 10-fold excess of nbe (Figure 1c). After
1 h at 90 °Ca time that is much shorter and a temperature
that is lower than those of the catalytic processcomplete
consumption of the complex was observed. N-Norbornylamide
16 was formed in 94% yield, based on consumption of both
amides in the complex. The ee of 16 was similar to those of the
catalytic processes. Therefore, complex 1 is kinetically
competent to be an intermediate in the catalytic cycle.
Kinetic measurements of the catalytic reaction as a function
of the concentration of substrates were performed. The
reactions were conducted with 2 mol % of isolated 1 at 100
°C, and initial rates (to 15% conversion) were measured by GC
(see the Supporting Information). An inverse first-order
dependence of the rate on the concentration of amide was
observed. This order implies that the amide ligand dissociates
reversibly prior to the turnover-limiting step (TLS). This
system is, therefore, an unusual example of a catalytic process
that is inverse-order in a reactant.11 A first-order dependence of
the rate on the concentration of 1-octene was observed,
indicating that olefin coordination occurs before the TLS.
In contrast, the rate of the reaction was independent of the
concentration of nbe under the standard catalytic conditions. A
plot of the initial rate vs the concentration of nbe shows that
the value of the rate saturates at high [nbe] (Figure 2). The
reaction is first-order in nbe at low concentrations and zero-
Figure 3. VT 19F NMR spectroscopy of complex 1-p-F (resonances b
and c) with 1 equiv of 4-F-benzamide (resonance a) in toluene.
regime. The lack of exchange of the amide and amidate
indicates that the five-coordinate intermediate 2-p-F formed by
amide dissociation is stereochemically rigid on the NMR time
scale below 60 °C. Above 60 °C, the resonance for the amidate
ligand (signal c) broadened, and VT NMR EXSY experiments
confirmed that exchange occurred between the amide and
amidate ligands as illustrated in Scheme 1 (see SI for further
discussion). The reversible dissociation of the amide is
consistent with the inverse first-order dependence of the rate
on the amide. Line-shape analysis on resonance a showed that
the activation parameters for ligand dissociation from 2-p-F are
ΔH⧧ = 20.7 kcal/mol and ΔS⧧ = 12.4 eu. This positive entropy
is consistent with a dissociative process.
Consideration of the steric effects of the DTBM-Segphos
ligand on the sites of amide and amidate ligands helps
rationalize the preference for ligation of the amidate to one of
the two diastereotopic coordination sites. The bulky aryl groups
on the phosphorus atom in the chiral, C2-symmetric ligand that
is cis to the dative amide ligand (P2) both project toward the
coordination site. This steric demand of one phosphino group
contrasts the antipodal orientation of the aryl groups on the
other phosphorus atom, which is located cis to the covalent
amidate ligand (P1). One aryl substituent of this group projects
Figure 2. Plot of initial rate vs [nbe] for the addition of 4-
trifluoromethylbenzamide to nbe catalyzed by 1. Data for reactions
with varied [trifluoromethylbenzamide] are included in the SI.
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toward the coordination site of the amidate ligand, whereas the
other aryl group occupies space away from the amide and
amidate ligands. The C1-symmetric quadrant diagram for 1
(Figure 1d) deviates from the classical C2-symmetric quadrant
diagram for BINAP-ligated complexes.12 This difference in
ligand coordination can be attributed to the different steric
properties of the axial ligands (H vs Cl).
AUTHOR INFORMATION
Corresponding Author
jhartwig@berkeley.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Director, Office of Science, of
the U.S. Department of Energy under Contract No. DE-AC02-
05CH11231. We thank Johnson-Matthey for a gift of IrCl3, and
Takasago for a gift of (S)-DTBM-Segphos. C.S.S. thanks the
NSF and the Springborn family for graduate research
fellowships.
Scheme 2. Proposed Catalytic Cycle for the Ir-Catalyzed N−
H Bond Addition of Arylamides to α-Olefins
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization of all new
compounds, including NMR spectroscopy data, conditions for
chiral HPLC separations, optical rotations, kinetic studies,
optimization data, and CIF data. This material is available free
of charge via the Internet at http://pubs.acs.org.
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