Synthetic and Computational Studies on the Rhodium-Catalyzed Hydroamination of Aminoalkenes

Article abstract of DOI:10.1021/acscatal.6b01320

The influence of ligand structure on rhodium-catalyzed hydroamination has been evaluated for a series of phosphinoarene ligands. These catalysts have been evaluated in a set of catalytic intramolecular Markovnikov hydroamination reactions. The mechanism o

Full text of DOI:10.1021/acscatal.6b01320

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Article
Synthetic and Computational Studies on the
Rhodium-Catalyzed Hydroamination of Aminoalkenes
Alexandra E Strom, David Balcells, and John F. Hartwig
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01320 • Publication Date (Web): 13 Jul 2016
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Synthetic and Computational Studies on the Rhodium-Cata-
lyzed Hydroamination of Aminoalkenes.
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Alexandra E. Strom†, David Balcells**, and John F. Hartwig†*
**Center for Theoretical and Computational Chemistry (CTCC), Dept. of Chemistry, University of Oslo, Oslo, 0315 Nor-
way.
†Department of Chemistry, University of California, Berkeley, California 94720, United States.
Supporting Information Placeholder
ABSTRACT: The influence of ligand structure on rhodium-catalyzed hydroamination has been evaluated for a series of phos-
phinoarene ligands. These catalysts have been evaluated in a set of catalytic intramolecular Markovnikov hydroamination reactions.
The mechanism of hydroamination catalyzed by the rhodium(I) complexes in this study was examined computationally, and the
turnover-limiting step was elucidated. These computational studies were extended to a series of theoretical hydroamination catalysts
to compare electronic effects of the ancillary ligand substituents. The relative energies of intermediates and transition states were
compared to intermediates in the reaction catalyzed by the unsubstituted catalyst. The experimental difference in the reactivity of
electron-rich and electron-poor catalysts was compared to the computational results, and it was found that the activity for the electron-
poor catalysts predicted from the reaction barriers was overestimated. Thus, the analysis of the catalysts in this study was expanded
to include the binding preference of each ligand, compared to that of the unsubstituted ligand. This information accounts for the
disparity between observed reactivity and the calculated overall reaction barrier for electron-poor ligands. The ligand-binding pref-
erences for new ligand structures were calculated, and ligands that were predicted to bind strongly to rhodium improved reactivity in
the experimental catalytic reactions.
KEYWORDS: hydroamination, rhodium, mechanism, computation, theory, phosphine ligands.
by the metal center to form a bond between the metal and an X-
type nitrogen ligand.
INTRODUCTION
Hydroamination is defined as the addition of an N-H bond
Early reports of hydroamination of alkenes were limited to
across an alkene or alkyne. Catalysts are required for this trans-
reactions with high temperature and pressures, harsh reaction
formation because the transition state for a concerted, uncata-
conditions, and limited substrates, such as ethylene and sty-
lyzed [2s+2p] reaction is thermally disallowed by the Wood-
rene.2,3 Other alkenes that are activated for hydroamination in-
ward-Hoffman rules1 and the stepwise reaction requires the in-
clude those possessing substituents that enable a stepwise path-
teraction of two electron-rich components.2-4 Although the first
way. Examples of such alkenes include Michael acceptors, al-
hydroamination reactions were reported as early as the 1950s,2,3
kenes bearing directing groups,12-14 and alkenes that react to
development of improved catalysts for the hydroamination of
form allyl or benzyl complexes, such as dienes,15-17 allenes, and
unactivated alkenes has been slow. Catalysts based on lantha-
vinylarenes.18-26 Likewise, strained bicyclic alkenes27,28 undergo
nides and early transition metals have been developed for hy-
migratory insertion steps faster than unstrained alkenes and
form alkyl intermediates that do not undergo β-hydrogen elim-
droamination, but catalysts based on late transition metals offer
many advantages, such as improved functional group tolerance
ination to form oxidized products. Intermolecular hydroamina-
and greater stability toward air and water. Despite more than 40
tion of unactivated alkenes with unactivated amines has been
years of research in the field of late-transition metal catalyzed
limited to lanthanide-catalyzed examples that require long reac-
hydroamination, there are few additions of the N-H bonds of
tion times and elevated temperatures.29-31
amines across alkenes that are suitable for practical applica-
Although rhodium catalysts were among the first systems re-
tions.4,5,6
ported for alkene hydroamination,5 improved rhodium catalysts
Because both reactants in hydroamination reactions are elec-
were not identified until much later. In 2003, our group reported
tron-rich, either the amine or alkene can be rendered more reac-
the intermolecular, anti-Markovnikov addition of amines to vi-
tive for the addition process by modification with electron-with-
nylarenes,25 and the origin of selectivity in this system has been
drawing groups. Reagents containing activated N-H bonds in-
studied computationally.32 Hull recently showed this combina-
clude amides and sulfonamides7, ureas8,9, carbamates10, and in-
tion of cationic rhodium precursor and DPEPhos to catalyze the
dole-type heterocycles.11 The N-H bonds in these nucleophiles
reaction of amines with N-allyl imines with Markovnikov se-
are more acidic than those of unactivated alkylamines and ar-
lectivity,12 and homoallyl amines with anti-Markovnikov selec-
ylamines, and the proposed mechanisms for hydroamination
tivity.13 Rhodium catalysts for intermolecular hydroamination
with these nucleophiles often involve cleavage of the N-H bond
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of dienes also have been reported.15 The intramolecular addi-
amines; even primary aminoalkenes lacking geminal disubsti-
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tions of unactivated amines to unactivated alkenes are also lim-
ited. Prior to the work by our research group (vide infra), the
addition of unactivated alkylamines to unactivated alkenes were
limited to those catalyzed by lanthanide and electrophilic group
IV metal systems.
tution underwent cyclization in the presence of this catalyst un-
der mild conditions.36 Although the mechanism of hydroamina-
tion with this catalyst was studied extensively, efforts to modify
the catalyst to expand the scope did not lead to intermolecular
reactions, and studies on catalysts bearing phosphorus ligands
derived from chiral diamines reacted with modest enantioselec-
tivities.
In 2008 and 2010 our group reported rhodium catalysts for
intramolecular cyclization reactions of primary and secondary
aminoalkenes to form 5- or 6-membered rings. Aminoalkenes
containing one or more substituents on the tether between the
amine and the alkene reacted faster and at lower temperatures
than aminoalkenes lacking substituents on the tether (a mani-
festation of the Thorpe-Ingold effect).33 In 2008, the authors’
laboratory reported a catalyst for the hydroamination of primary
and secondary aminoalkenes generated from a cationic rho-
dium(I) precursor and biaryl phosphine ligand.34 An enantiose-
lective version of this process was then reported by Shen and
Buchwald with a catalyst containing chiral binaphthyl mono-
phosphine ligands.35 The scope of these methods catalyzed by
rhodium complexes ligated by phosphines containing biaryl and
binaphthyl scaffolds, are limited to secondary aminoalkenes
and to primary aminoalkenes possessing geminal substitution.
The enantioselective reactions reported by Shen and Buchwald
require N-benzyl substitution for aminoalkenes that lack gemi-
nal substituents and these catalysts react with only moderate en-
antioselectivity.
The structure of the active catalyst in the system developed
by Liu and Hartwig and the mechanism by which it reacts have
been reported.37 The active catalyst was found to be the com-
plex in Figure 1 containing a biarylphosphine in which one
arene ring and the phosphorus atom are bound to rhodium in an
η6,κ1 binding mode. The experimental data from this study are
consistent with the catalytic cycle shown in Figure 1. In this
pathway, the amine reversibly bonds to the coordinated alkene,
and intramolecular, rate-limiting protonolysis of the rhodium
alkyl intermediate subsequently occurs. Importantly, the active
catalyst has only one available coordination site; the absence of
a second site was proposed to suppress undesired side reactions,
such as β-hydrogen elimination. The structure of the resting
state for the hydroamination reactions of secondary aminoal-
kenes was determined by 1D and 2D NMR spectroscopy and
X-ray crystallographic analysis to be a complex bound to the
alkene unit of the aminoalkene and with one arene of the biaryl
phosphine ligand bound in an η6 fashion. The structure of the
resting state for hydroamination reactions of primary aminoal-
kenes was determined by the same methods to be the four-co-
ordinate, η2,κ1 complex in Figure 1 in which the alkene and
amine of the aminoalkene are both bound to rhodium. Primary
aminoalkenes lacking geminal substituents do not undergo hy-
droamination reactions in the presence of this catalyst.
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We sought to evaluate the effect of the steric and electronic
properties of the ancillary ligand on the overall rate, the relative
rates of individual steps of the catalytic cycle, and the reactivity
of primary aminoalkenes and unbiased substrates. Our approach
included both experimental and computational studies. We
studied a series of ligands with modified arene and phosphine
substituents and modified tethers between the arene and phos-
phine. These studies showed that changes to the tether led to
greater increases in reactivity than did changes to the arene or
phosphine substituents. To help reveal how subtle changes in
the structure of the catalyst resulted in vastly different reactiv-
ity, we studied the system computationally. Through computa-
tional analysis we gained insight into (1) the mechanism of the
turnover-limiting protonolysis step, (2) the origin of the effect
of structural changes on the reactivity of different substrates,
and (3) the influence of relative binding affinity of altered lig-
ands on reactivity. With this information, we developed a com-
putational model to evaluate new ligands for rhodium–cata-
lyzed hydroamination of aminoalkenes. In addition, these com-
putational studies suggest that differences in stabilities of the
most stable form of the catalyst give rise to the common
Thorpe-Ingold effect on cyclization of aminoalkenes in these
reactions and explain the different reactivity of primary and sec-
ondary aminoalkenes. Upon establishing steric and electronic
requirements for catalyst activity in the computational study,
we prepared catalysts for the hydroamination reactions of ami-
noalkenes that react to form product in higher yield than reac-
tions catalyzed by the previously reported rhodium catalyst li-
gated by a biarylphosphine in an η6, κ1-fashion.33,36
Figure 1. Mechanism of hydroamination with (L1a)Rh+ as cata-
lyst.
In 2010, our group reported a rhodium(I) catalyst containing
a derivative of Xantphos bearing diethylamino groups at phos-
phorus. This catalyst was more reactive for additions of primary
RESULTS AND DISCUSSION
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bearing diethylamino and ethyl groups at phosphorus were in-
REACTIVITY OF CATALYSTS BOUND BY A
SERIES OF MODULAR PHOSPHINO ARENE
LIGANDS
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active (L1b-c). This result, combined with the results of prior
studies on binaphthyl-based ligands, in which ligands contain-
ing phenyl and tert-butyl substituents on phosphorus generated
catalysts that were less active than those from ligands contain-
ing cyclohexyl groups on phosphorus,35 indicates that modifi-
cation of the cyclohexyl group leads to less active catalysts. The
activities of the catalysts generated from ligands possessing
more than one electron-donating group on the coordinated aryl
ring were similar to that of the benchmark catalyst formed from
L1a (e.g., L2a-b and L3) for cyclization of the more reactive
secondary aminoalkene substrate 2s, but were lower for cycliza-
tion of primary aminoalkene 1s and mono-substituted second-
ary aminoalkene 3s. The results from this set of ligands show
that the catalyst is sensitive to the steric and electronic parame-
ters of the components of the catalyst that are bound directly to
the metal. Further variations of the ligand focused on the re-
maining component of the ligand, the tether between the bound
arene, and the phosphino group (Scheme 2).
To examine the influence of each component of the ligand on
catalyst activity, a series of systematically varied ligands that
would be bound to the metal through a phosphino group and a
pendant arene were synthesized. The structures of the ligands
are shown in Scheme 1. Ligands containing 1, 2, and 3 ether or
amine substituents on the arene, as well as ligands containing
ethyl or amino groups were varied while maintaining the bi-
phenyl structure. Ligands L2a-b and L3, possessed different
substituents on the arene but contained the same dicyclohex-
ylphosphine group; ligands L1b-c possessed different substitu-
ents at phosphorus, but contained the same dimethylamino
group on the aryl ring distal from phosphorus. The catalysts for
the hydroamination of a set of aminoalkenes were generated by
combining these ligands with [Rh(COD)2]BF4 (Scheme 1).
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Scheme 1. Evaluation of ligands with varied substituents on
phosphorus and on the tethered arene for hydroamination
of primary and secondary aminoalkenes.a
Scheme 2. Evaluation of modified ancillary ligands with dif-
ferent scaffolds for hydroamination of primary and second-
ary aminoalkenes.a
a
Conditions: 0.040 mmol substrate, 5 mol% [Rh(COD)2]BF4,
10 mol% ligand, 0.1 mL 1,4-dioxane, 70 °C. Yields were deter-
mined by GC analysis, and measured at 2 h and 18 h. Yields shown
are at 18 h.
The two catalysts formed from L1a or L2c and the cationic
rhodium precursor were used as benchmarks. Ligand L1a had
previously been shown to form an active catalyst, and thus was
chosen as one benchmark to compare with catalysts bearing the
new ligands. Ligand L2c was chosen as a second benchmark to
compare with catalysts bearing ligands that lack electron-donat-
ing groups on the bound arene. By comparing the activity of
catalysts containing these ligands to those containing L2c, the
influence of the structure of the tether and the dimethylamino
group can be assessed separately. The influences of the tether,
the arene, and the substituents on the phosphorus atom were ex-
amined by comparison of the reactivity of the catalyst formed
from each ligand.
a
Conditions: 0.040 mmol substrate, 5 mol% [Rh(COD)2]BF4,
10 mol% ligand, 0.1 mL 1,4-dioxane, 70 °C, 2-18 h. Yields were
determined by GC analysis, and conversion was measured at 2 h
and 18 h. Yields shown are at 18 h.
The previously reported structure of the rhodium-ethylene
The yields of reactions catalyzed by complexes of the various
ligands are shown in Scheme 1. Catalysts containing ligands
complex in which L1a is bound in an η6, κ1 fashion served as a
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guideline for designing new ligands (Scheme 2). We hypothe- bond lengths of a two-carbon alkyl tether would be longer than
sized that the arene may slip from η6 to η2 to relieve strain in-
duced by binding to the metal, because this slipped complex
was isolated from the reaction of the primary aminoalkene 1s,
characterized by X-ray crystallography, and determined to be
the resting state of the reaction of this aminoalkene by NMR
spectroscopy (Figure 1). We proposed thatthe η6 arene-binding
mode would be favored for complexes containing a longer
tether between the phosphorus and the pendant arene. The C-C
those of the phenylene linker in the parent ligand. Thus, L5 was
synthesized as an analog of L2c containing an alkyl tether. An
analog containing a vinyl linker (L4) also was synthesized be-
cause the steric properties of this ligand would be similar to
those of L5 and the electronic properties and bond lengths
would be similar to those of L2c. Both L4 and L5, in combina-
tion with a cationic rhodium precursor,
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Figure 2. ORTEP representation of rhodium(ethylene) complexes ligated by L4, L5, and L2c. The complex formed from L6 yielded poor
quality crystals, but a structural assignment was made that matches the structure of the other complexes in this series.
catalyzed the cyclization of 2s to form 2p in low yield. The
catalyst containing the more rigid KitPhos ligand L6 was no
more active for hydroamination of 2s than was that containing
L2c.
d, containing indole linkers formed less reactive hydroamina-
tion catalysts, the yield from the reaction catalyzed by rhodium
and L8 containing a cyclopropyl tether was only slightly lower
than that of the benchmark reaction catalyzed by rhodium and
phenylene-linked L2c. The activities of catalysts generated
from commercially available ligands L9a and L9b containing
alkene linkers both were higher than that of the catalyst gener-
ated from ligand L2c, and the activity of the catalyst generated
from ligand L9b was higher for all substrates than that for the
catalyst generated from ligand L1a, despite the absence of an
electron-donating substituent on the η6 arene (Scheme 2). This
result indicates that the structure of the backbone in L9b
(Scheme 2) is more favorable than that of the starting biaryl
backbone in L1a and L2c. However, the catalyst bound by the
ligand containing an alkene tether lacking substituents (L4) was
found to be much less active. Ligand L9a was synthesized to
evaluate the effect of the methyl substituent in L9b on catalyst
activity. The catalyst containing ligand L9a was much less re-
active than that containing ligand L9b, indicating that substitu-
tion at the ipso carbon to phosphorus leads to a more active cat-
alyst.
To determine if these ligands bind to the metal to form com-
plexes that are similar to the active catalyst in Figure 1, the rho-
dium-ethylene complexes ligated by the various phosphines
were synthesized and characterized by X-ray diffraction. Single
crystals suitable for X-ray diffraction were obtained for eth-
ylene adducts of cationic rhodium bound to the ligands linked
by alkyl, vinyl, and phenylene units (Figure 2). Polycyclic lig-
and L6 formed a rhodium complex that is similar to the rhodium
complexes formed by the other ligands, but the quality of the
data was only suitable for the structural assignment. All of these
ligands formed rhodium complexes having similar structural
parameters, despite the marked difference in reactivity of the
corresponding catalysts. Namely, Rh-P bond lengths, C-C bond
lengths in ethylene, and the angles between the tether carbon,
ipso carbon, and distal carbon of the bound arene varied less
than 0.1 Å or 1˚. Therefore, we conclude that changes in reac-
tivity are not controlled by the most stable structures of the of
the alkene complexes.
COMPUTATIONAL STUDY OF RHODIUM-
CATALYZED HYDROAMINATION
In these preliminary studies with a range of ligands, the sub-
stituents at phosphorus and the identity of the tether had the
largest effects on the yields of desired product in the catalytic
reaction. Further studies focused on ligands with cyclohexyl
groups on phosphorus, and structural variation focused on eval-
uating a wider range of tethers. Although ligands, such as L7a-
To help elucidate how subtle structural changes in the ancil-
lary ligand of the rhodium catalyst affect the reactivity of the
catalyst toward hydroamination, we studied the effect of the
structure on the individual steps of the catalytic cycle by DFT
calculations with the M06 functional (see Computational De-
tails). With these DFT calculations, we hoped to accomplish
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three goals. First, we sought to determine the mechanism of the experimental data on the hydroamination of secondary amino-
turnover-limiting protonolysis step38 and to use this information
to design ligands that would reduce the barrier to this step. Sec-
ond, we sought to elucidate the origin of the higher reactivity of
substrates bearing geminal disubstitution that biases the sub-
strate toward cyclization. This reactivity could not be explained
by the traditional kinetic origin of the Thorpe-Ingold effect be-
cause the cyclization step is fast and reversible (Scheme 1).
Third, we hoped to determine the effects of steric and electronic
perturbation of the ancillary ligand by varying the components
of the structure and computing the effect of these changes on
individual steps of the catalytic cycle. Although the previous
alkenes catalyzed by rhodium and L1a was collected with the
N-benzyl substrate in Figure 1, the simplified secondary amino-
alkene A was used for the initial computations of potential
mechanistic pathways for the reaction catalyzed by the rhodium
complex of L1a (Figure 3).
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We compared the energies of different resting states in which
the aminoalkene was bound to the metal through the amine
(complex 2) or alkene (complex 3) and the ancillary phos-
phinoarene ligand was bound in an η6,κ1 fashion. We compared
the energies of these η6,κ1 complexes to the energy of complex
1, containing the amino
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Figure 3. Calculated mechanism of hydroamination of secondary aminoalkenes catalyzed by (L1a)rhodium(I). Energies listed are ΔG values
with solvent correction in kcal/mol. Protons are omitted from calculated transition state structures, except when participating in bond-forming
or bond-cleaving events.
alkene bound in a bidentate fashion and the ancillary ligand
bound in an η2,κ1 fashion. The energy of the alkene complex
was found to be lower than the energy of the amine complex,
but the difference in energy was small (0.7 kcal/mol). By exper-
iment, the alkene complex was observed as the resting state for
reactions of sterically hindered secondary aminoalkenes (Figure
1). The computation indicated that nucleophilic attack of the
amine on the bound alkene is uphill with a low barrier to rever-
sion to the alkene complex. Calculation of an alternative initial
step, oxidative addition of the amine N-H bond, indicated that
the thermodynamics for this step are prohibitively unfavorable
(~45 kcal/mol uphill to form a rhodium(III) intermediate).
We explored both the stepwise and concerted pathways for
the turnover-limiting proton transfer from the nitrogen atom to
the rhodium-bound carbon atom. Prior experimental studies by
our group showed that proton transfer from nitrogen to the
metal-carbon bond of the intermediate formed by nucleophilic
attack on the bound olefin was turnover limiting. Subsequent
kinetic studies by Stradiotto and Tobisch on the mechanism of
hydroamination catalyzed by (cod)IrCl (cod = cycloocta-1,5-
diene) were consistent with rate-limiting proton transfer; further
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studies on this system by DFT suggested that the proton transfer dium(I)-alkyl intermediates were found upon relaxing 1TS to-
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3
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occurs by formation of a hydrido iridium(III) alkyl intermedi-
ate, which undergoes reductive elimination to form the C-H
bond in the product.37 The rhodium and iridium systems are
similar because the mechanism involves nucleophilic attack and
protonolysis of the metal-carbon bond. However, the difference
in basicity of the metal center in the two systems and the num-
ber of available coordination sites could lead to different path-
ways for proton transfer by the two aminoalkyl intermediates.
ward products (4a) and 2TS toward reactants (4b). These min-
ima are separated by a low-barrier rotation around the Rh-C
bond.39 We were unable to find a transition state for a concerted
intramolecular protonolysis of the rhodium-carbon bond.
A mechanism for the catalytic cycle that is consistent with
these computational results and previous experimental evi-
dence, thus, comprises 1) initial, reversible nucleophilic attack
of the amine on the bound alkene to form a rhodium(I) alkyl
intermediate, which can rotate to facilitate proton transfer to the
metal center; 2) proton transfer from the nitrogen atom to the
metal center to form an alkylrhodium(III) hydride complex that
undergoes C-H bond-forming reductive elimination to form the
tertiary amine product; 3) displacement of the product from the
metal by an aminoalkene reactant to complete the catalytic cy-
cle.
The barrier to proton transfer from the nitrogen atom to the
neutral rhodium(I) center in 4b to form a rhodium (III) hydride
intermediate 5, followed by reductive elimination, was com-
puted to be 12.5 kcal/mol, with an overall barrier of 20.9
kcal/mol (Figure 3). The calculated kinetic isotope effect (KIE)
of 4.2 for this proton transfer to the metal was consistent with
the primary KIE of 2.6 measured experimentally.37 Two rho-
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Figure 4. Relative energies of key intermediates and transition states for different substrates. Energies listed are ΔG values with solvent
correction in kcal/mol.
For all of the substrates A-D the structure computed to be
EFFECTS
OF
THE
AMINOALKENE
most stable is the one containing an η2 arene and the amino al-
kene bound through both the alkene and the amino groups. Ac-
cording to these computations, the difference in energy between
the η2 arene complex 1 and the alkene complex 3 is larger for
primary aminoalkenes and for substrates lacking geminal disub-
stitution than it is for secondary aminoalkenes and geminally
disubstituted primary aminoalkenes. Although the computed
energy of the η2 arene complex was lower than that of the η6
arene complex with the aminoalkene bound solely through the
alkene (complex 3), the resting state of the catalyst was ob-
served by experiment to be the η6 arene complex 3 for reactions
of secondary aminoalkenes and the η2 arene complex 1 for re-
actions of primary aminoalkenes (vide supra, Figure 1). The dif-
ference between the most stable species determined by compu-
SUBSTITUTENTS AT NITROGEN ON THE
ENERGETICS OF THE CATALYTIC CYCLE
From this mechanistic study, we identified nine stationary
points; three saddle points (transition states) with a single im-
aginary frequency and six minima (intermediates) with only
real frequencies. To compare the energies of these stationary
points for the reactions of different aminoalkenes, the corre-
sponding nine stationary points generated from reactants B-D
in Figure 4 were optimized. These substrates vary in the pres-
ence or absence of geminal disubstitution and include primary
and secondary amino groups. We also examined the energetics
of the intermolecular reactions of ethylene and 2-methyl-1-pro-
pene with dimethylamine.40
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tation and the experimentally observed resting states is pro-
1
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posed to result from kinetic barriers that prohibit formation of
the η2 arene complex 1 from the η6 arene complexes containing
a bound olefin or amine (2 or 3). However, we were unable to
quantify this barrier because we were unable to find a transition
state for the reorganization required to interconvert these struc-
tures.
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The computed difference in energy between the highest-en-
ergy transition state and the experimental resting states explains
the relative reactivity of the different alkenes (Figure 5) and of-
fers a strategy for the development of more active catalysts.
Comparing the experimental relative rates of a set of aminoal-
kenes containing different substituents with the computed acti-
vation energies for complexes that lie on and off the catalytic
cycle provides the true overall reaction barrier (Figure 5). For
example, the computed barrier for reaction of the unsubstituted
aminoalkene D is 20.6 kcal/mol starting from the alkene com-
plex, but this substrate forms a lower energy, off-cycle complex
by chelating the metal center. The barrier for reaction from this
more stable complex is 15.2 kcal/mol higher than that from the
alkene complex. These data suggest that the barriers to cycliza-
tion of primary aminoalkenes could be as much as 15 kcal/mol
lower if the resting state of the catalyst during reactions of these
substrates were the higher-energy η6 arene complexes 2 and 3
that lie on the catalytic cycle, instead of the η2 arene complex 1
that lies off the catalytic cycle.
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EFFECTS OF THE AMINOALKENE BACKBONE
COMPOSITION
REACTIONS
ON
HYDROAMINATION
The kinetic data show that the nucleophilic attack forming the
C-N bond is fast and reversible. Thus, we sought to determine
if the origin of the effect of the two geminal substituents in the
tether linking the alkene and the amine on the rate is different
from that in uncatalyzed or base-catalyzed cyclizations. For the
rhodium-catalyzed process described here, the effect of the
geminal substituents could result from destabilization of the off-
cycle resting state of the catalyst or it could result from an effect
on the events occurring within the catalytic cycle (Figure 4).
Figure 5. Relative stability of bidentate η2 complex 1 and olefin-
bound η6 complex 3.
The barrier to nucleophilic attack during reaction of the un-
substituted primary aminoalkene D is 0.9 kcal/mol lower than
the barrier to nucleophilic attack during reaction of the substi-
tuted primary aminoalkene C. However, the off-cycle η2-arene
complex 1 containing the chelating aminoalkene is 5.8 kcal/mol
more stable when generated from D than when generated from
C. This greater stability of the off-cycle complex 1 generated
from the unsubstituted primary aminoalkene D causes the over-
all calculated barrier for the reaction of D to be 35.8 kcal/mol.
This high barrier is consistent with the lack of reactivity of un-
substituted primary aminoalkenes, such as D in hydroamination
reactions catalyzed by the combination of L1a and rhodium.
To test our hypothesis about the origin of the decreased reac-
tivity of primary aminoalkenes, a competition reaction between
primary and secondary aminoalkenes 1s and 2s was performed
(Figure 6). The resting states of the catalyst during reaction of
these substrates are different from each other (vide supra). The
alkene-bound (on-cycle) complex 3 of the primary aminoalkene
containing methyl backbone substituents is 9.4 kcal/mol higher
in energy than the (off-cycle) complex 1, which is the experi-
mentally observed resting state. However, the experimentally
observed resting state during reaction of the secondary amino-
alkene in Figure 6 is the alkene complex 3. The two alkene com-
plexes formed from the two aminoalkenes can be assumed to
have the same relative energies because the distal amines should
not affect the strength of the bond between the alkene and the
metal. Therefore, the lower-energy resting state 1 is presumed
to be the predominant species in the competition reaction.
We propose that the greater stability of complex 1 containing
the unsubstituted aminoalkene than of complex 1 containing the
gem-disubstituted aminoalkene is due to steric crowding be-
tween the ancillary ligand and substrate. This effect is con-
sistent with the experimental and computational data on the
mechanism of hydroamination. Because the nucleophilic attack
is fast and reversible, the substituent effect arises from the ther-
modynamics for the reversible binding of the aminoalkene
within the coordination sphere of the metal, rather than an effect
on the barrier to cyclization.
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only 5% of the secondary aminoalkene had reacted. The high
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yields of both products in separate reactions after 48 h show that
the catalyst does not decompose in the presence of the primary
amine. Instead, these results are consistent with stronger bind-
ing of the primary aminoalkene than of the secondary aminoal-
kene to the rhodium and either a larger difference in binding
energies than barriers for reaction of the two amines or, less
likely, slower displacement of the primary aminoalkene by the
secondary aminoalkene than reaction of the bound primary ami-
noalkene. We favor the former explanation because the version
of complex 3 containing the secondary aminoalkene was shown
in a previous study to react with primary aminoalkene to form
exclusively the primary aminoalkene complex 1.37
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BARRIERS TO HYDROAMINATION CATALYZED
BY COMPLEXES OF DIFFERENT LIGANDS
The effect of the ligand on the barriers to reaction of second-
ary aminoalkene A was computed by DFT. Electronic effects
were evaluated by varying substituents on the bound arene and
the aryl linker of the ancillary ligand for each of the same 9 sta-
tionary points as studied for substrates A-D. The results of these
computations are summarized in Figure 7. For more electron-
rich ligands, the olefin complex 3 is lower in energy than the
amine-bound complex 2, but for more electron poor ligands, the
amine-bound complex 2 is lower in energy than the olefin com-
plex 3. Thus, the transition-state energies reported in Figure 7
for proton transfer and reductive elimination are given relative
to both the alkene complex 3 and the amine complex 2. The
barriers for reaction of the more electron-rich catalysts were
generally lower than those for reaction of the more electron-
poor catalysts, but competing ground- and transition-state ef-
fects attenuate the electronic influence.
Figure 6. Competition of primary and secondary aminoalkenes. At
12 hours the primary amine has reacted before the secondary
amine. At 48 hours both substrates have reached full conversion.
The computed barriers for cyclization of secondary aminoal-
kene 2s starting from the alkene complex is 21.4 kcal/mol, and
the barrier for cyclization of the primary aminoalkene is a sim-
ilar 23.6 kcal/mol (normalized to 0.0 kcal/mol for both amino-
alkene complexes with methyl substituents on the back-
bone).Figure 6 shows the results from the reactions of each sub-
strate alone catalyzed by the rhodium(I) precursor and L1a and
the reaction of both substrates together. The conversion of the
secondary aminoalkene alone is higher than that of the primary
aminoalkene after 2 h in side-by-side reactions. However, in the
reaction of the two amines together, all of the primary aminoal-
kene had converted to the cyclized product after 12 h, whereas
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Figure 7. Overall computed barriers for hydroamination of A catalyzed by complexes with electronically-varied ancillary ligands, starting
from amine-bound (2) and olefin-bound (3) complexes. Each bar represents the energy difference between the transition-state for proton
transfer or reductive elimination and either the alkene-bound or amine-bound intermediate. The highest bar for each ligand represents the
predicted highest barrier to hydroamination.
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Figure 8. Overall computed barriers for hydroamination of A catalyzed by complexes with ancillary ligands with varied tether structures,
starting from amine-bound (2) and olefin-bound (3) complexes. Each bar represents the energy difference between the transition-state for
proton transfer or reductive elimination and either the alkene-bound or amine-bound intermediate. The highest bar for each ligand represents
the predicted highest barrier to hydroamination.
In addition to the electronic properties of the ancillary ligand,
the structure of the unit connecting the bound arene and phos-
phino group was varied. These data are summarized in Figure
8. The ligands that generate the most reactive catalysts experi-
mentally do not lead to the lowest computed overall barriers for
cyclization of A by the phosphine-ligated Rh(I) complexes. For
example, the catalyst generated from ligand L2c is predicted to
be less reactive than the catalyst generated from ligand L9a, and
the catalyst generated from ligand L9b is predicted to be less
reactive than the catalyst generated from ligand L2c (Figure 8).
Thus, we hypothesized that competitive binding of the substrate
and the ligand to rhodium could lead to different concentrations
of the active catalyst and, therefore, different activities than are
predicted by computations that include only the phosphine-li-
gated species.
electron-poor ligands may not form active catalysts for hy-
droamination even though the computed barriers to the reaction
of aminoalkenes from these bound complexes are similar to the
barriers to hydroamination from complexes ligated by electron-
rich ligands because the more electron-poor ligands binds more
weakly.
The relative binding affinities of the ligands correlates more
strongly with the activity of the corresponding catalysts than
does the computed reaction barriers from the phosphine-ligated
species. For example, catalysts generated from ligands with par-
ticularly large binding affinities (L1a and L9b) are more reac-
tive than those generated from ligands with particularly small
binding affinities (L5 and L9a, vide supra). This correlation
suggests that identification of ligands with high binding en-
thalpies could lead to the discovery of improved catalysts for
hydroamination.
COMPUTED RELATIVE BINDING ENERGIES OF
THE ANCILLARY LIGANDS
The relative free energies for binding of the phosphine lig-
ands to rhodium were determined by computing the energetics
of the isodesmic reaction in Figure 9. The relative free energies
and enthalpies were calculated, and it was found that the ligands
containing more electron-donating substituents bind much more
strongly to the rhodium center than those containing more elec-
tron-poor substituents. Substituents on the arene (Y, Figure 9)
affected the binding energy more strongly than did substituents
on the phosphine (X, Figure 9). Based on the data in Figure 9,
the substituent effects on the binding enthalpies are approxi-
mately additive. These data show that there is a ~12 kcal/mol
difference in the relative binding energies of ligands with dif-
ferent electronic properties. These calculations indicate that
Figure 9. Isodesmic equation comparing relative binding energies
of different ligands. ΔH and ΔG in kcal/mol.
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The relative binding affinity of the ligand containing the Derivatives of ligand L13a containing electron-donating and
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8
tether with longer bonds, L5, was compared computationally to
a ligand containing even longer C-Si bonds, L5-Si. Ligand L5-
Si is predicted to bind even more weakly than the electron poor
ligand in Figure 9 bearing two trifluoromethyl substituents. The
catalyst generated from rigid ligand L13a, however, is com-
puted to have a large binding energy and a low overall reaction
barrier (Figure 8 and 10). On the basis of this prediction, a series
of dihydronaphthyl-based ligands were synthesized, and cata-
lysts generated from them were tested for hydroamination.
electron-withdrawing groups on the bound arene were synthe-
sized to evaluate the computational prediction that ligands con-
taining pendant electron-poor arenes would form less active cat-
alysts. The complex of L13a and of the electron-rich ligand
L13b were more active catalysts for cyclization of 3s than those
of the electron-poor ligand L13c. Most generally, the results in
Scheme 3 show that the complexes with the lowest predicted
activation barriers for hydroamination are not necessarily the
most active catalysts, and that incorporating the ligand binding
energies into the design of new catalysts is advantageous. Cal-
culation of the relative ligand binding energy is a simple ap-
proximation of the efficacy of these catalysts for hydroamina-
tion, without the need for calculation of multiple resting states,
intermediates, and transition states.
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SYNTHETIC
STUDIES
BASED
ON
COMPUTATIONAL MODELS
Ligands containing varied structures based on those of L9b
and L13a (Scheme 3) were synthesized. Ligands L9a and L9c-
d, which are variants of ligand L9b containing a series of sub-
stituents in place of the methyl group in L9b, generated com-
plexes that catalyzed the reactions of aminoalkene 3s with sim-
ilar or lower reactivity than the catalyst formed from L9b
(Scheme 3). Based on the previous experimental results
(Scheme 1) and the analysis of the binding energies of the lig-
ands, electron-rich variants of L9b should form more active cat-
alysts for the hydroaminations than electron-neutral ligands.
However, the reactivity of the catalyst generated from the elec-
tron rich ligand L9e was similar to that of ligand L9b. Ligand
L9e is more sterically congested at the proposed η6, κ1 binding
pocket, and for this ligand to bind to the metal the two aryl
groups must be configured with the coordinating aryl group per-
pendicular to the plane of the vinyl tether. Thus, to favor the
desired conformation, we synthesized variants of ligand L13a
that have a more defined conformation of the backbone. The
reaction of 3s catalyzed by the complex generated from L13a
formed the product in quantitative yield. The related ligand L12
is less rigid, and the catalyst formed from this ligand formed the
product from cyclization of 2s in lower yield than did the cata-
lysts formed from the more rigid ligand L13a. The reactivity of
the catalyst formed from aromatic naphthyl-bridged ligand L11
was similar to that of the catalyst formed from ligand L13a.
REACTIONS OF PRIMARY AND SECONDARY
AMINOALKENES WITH A RHODIUM ETHYLENE
PRECATALYST
During our evaluation of ligand L9e (Scheme 4), we found
that the yields at 18 h of reactions catalyzed by the rhodium
COD precursor and L9e were comparable to those of reactions
with the benchmark catalyst formed from rhodium COD and
L1a, but the yield at 2 h was variable (5-15%) and lower for the
reaction of 1s (Scheme 4, entry 9). We hypothesized that the
formation of the active catalyst from the rhodium COD precur-
sor and L9e might be slow and that a rhodium species that is
smaller or more labile than [Rh(COD)2]BF4 could form the ac-
tive catalyst more rapidly under the catalytic conditions. There-
fore, a solution of the cationic ethylene complex ([Rh(eth-
ylene)2(1,4-dioxane)2]BF4) was prepared and added to the re-
action mixture as a solution in 1,4-dioxane (see Supplementary
Information). As shown in Scheme 4, the yield at 2 h was higher
for the reaction catalyzed by the rhodium ethylene complex and
L9e or L9b (entries 1-4) than that for the reaction catalyzed by
the rhodium COD complex with these ligands. Reactions of pri-
mary aminoalkene 1s were also run with the ethylene complex
precursor to test if the faster rates with this precursor were ob-
served for reactions of primary aminoalkenes. Entry 10 shows
that the yield of the reaction initiated with this precursor was
higher after 2 h than that of the reactions with the rhodium-COD
precursor, indicating that the active catalysts formed faster from
the ethylene complex than from the COD complex and that the
rate of formation of the active catalyst influenced the apparent
catalyst activity.
However, in contrast to the yields of reactions of secondary
aminoalkenes, the yields for reactions of primary aminoalkenes
were lower in general when initiated with the ethylene complex
than when initiated with the COD complex. This result might
be due to catalyst stabilization by COD in reactions of primary
aminoalkenes. Thus, the hindered and electron-rich ligand L9e
forms an active catalyst more rapidly with a rhodium(ethylene)
precursor, but reactions of primary aminoalkenes occur in lower
yield when initiated with this catalyst precursor due to catalyst
deactivation.
Figure 10. Influence of ligand scaffold structure on ligand
binding
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Scheme 3. Evaluation of rigid ligands in catalytic hydroam-
CONCLUSIONS
ination reactions.a
1
We report a systematic study of cationic rhodium hydroami-
nation catalysts, with modified substituents at phosphorus, sub-
stituents on the arene, and structure linking the phosphino group
to the arene. Initial findings indicated that the backbone of the
ancillary ligand could be modified to improve catalyst activity,
and this change in reactivity was evaluated computationally.
Our computational study suggests that the mechanism of the
turnover-limiting protonolysis is a stepwise proton transfer to
rhodium, followed by reductive elimination.
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Computational analysis of the energetics of the reaction with
different substrates and catalysts containing a series of ancillary
ligands showed that changes in catalyst structure did not have a
large effect on the overall reaction barriers starting from the
phosphine-ligated complexes. Instead, these calculations
showed that the relative binding energies of the ligand to rho-
dium correlate with catalyst activity. These calculations showed
that rigid, electron-rich ligands bind favorably to rhodium.
These binding energies were combined with calculations of the
overall reaction barriers to predict catalyst structures that would
result in improved activity. Following the development of a
computational model to evaluate new ligand structures based on
ligand binding affinity, we applied the model to the develop-
ment of improved modular catalyst structures for hydroamina-
tion. Additionally, our computations suggest that the experi-
mentally observed faster cyclization of gem-disubstituted ami-
noalkenes resulted from destabilization of an off-cycle com-
plex, rather than an enhancement of the rate of nucleophilic at-
tack. Although reactions of primary aminoalkenes are slower
than reactions of secondary aminoalkenes, the primary amino-
alkenes react faster than the secondary aminoalkenes when the
two substrates are present in the same vessel. A catalyst precur-
sor with ligands more labile than COD was found to form the
active catalyst with hindered ancillary ligands rapidly and reli-
ably, but yields were found to be higher for reactions of primary
aminoalkenes when the rhodium COD precursor was used, pre-
sumably due to inhibition of catalyst decomposition pathways
by the presence of COD.
a Conditions: 0.040 mmol substrate, 5 mol% Rh(COD)2BF4, 10
mol% ligand, 0.1 mL 1,4-dioxane, 70 °C. Yields were determined
by GC analysis, and measured at 2 h and 18 h. Yields shown are
those measured after 18 h.
Scheme 4. Evaluation of rhodium precatalyst in hydroami-
nation reactions of primary and secondary aminoalkenes. a
EXPERIMENTAL SECTION
Unless noted otherwise, all manipulations were performed using
standard Schlenk techniques or in a nitrogen-filled glovebox. Glass-
ware was dried at 130 °C overnight before use. Pentane, Et2O, THF,
benzene, and toluene were collected from a solvent purification system
containing a 0.33 m column of activated alumina under nitrogen. All
other solvents and reagents were purchased from commercial suppliers,
stored in the glove box, and used as received. The authors thank John-
son Matthey for a gift of [Rh(COD)2]BF4. Substrates 1s, 2s, and 3s
were synthesized through literature procedures. 36 Ligands L1a, L2a-c,
L3, L7a, L7c-d, L8, and L9b were purchased from Aldrich or Strem.
Computational Details. Calculations were conducted by density
functional theory (DFT) with the M0641,42 set of functionals using the
Gaussian09 program at the CTCC (Center for Theoretical and Compu-
tational Chemistry) at the University of Oslo, Norway, and at the
MCGF (Molecular Graphics and Computation Facility) at the Univer-
sity of California, Berkeley, with assistance from Dr. Kathleen Durkin
at UC Berkeley. Two basis sets, BS-1 and BS-2, were used. With BS-
1, (M06) all elements were described with the full-electron double-ζ 6-
31G** basis set, except the heaviest elements (Rh and P), which were
described with the small-core LANL2DZ(d,f) ECP-adapted basis set.
Geometries were fully optimized with BS-1 without any geometry or
symmetry constraint. BS-1 was also used in the analytic calculation of
frequencies, which identified each stationary point as either a minimum
(reactants, intermediates and products) or saddle point (transition
a Conditions: 0.040 mmol substrate, 5 mol% rhodium, 10 mol%
ligand, 0.1 mL 1,4-dioxane, 70 °C, 2-18 h. Yields were determined
by GC analysis, and conversion was measured after 2 h and 18 h.
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state). The identity of the transition states was further confirmed by in-
7.7 Hz, 1H), 3.80 (s, 3H), 3.21 (t, J = 8.2 Hz, 2H), 3.05 – 2.78 (m,
trinsic reaction coordinate (IRC) calculations. The frequency calcula-
tions were also used to estimate the thermochemistry corrections as the
difference between the Gibbs (G) and potential (E) energies, G - E.
With BS-2, all elements were described with a triple-ζ basis set includ-
ing the LANL2TZ(d,f) for Rh and P and 6-311++G** for all other ele-
ments. BS-2 (SMD-M06) was used to compute the energy in solution
(Esol) of all stationary points by modeling solvent effects at the
DFT/M06/SMD level. The energy profiles were constructed by using
the Gibbs energy in solution (Gsol), which was calculated by adding the
thermochemistry corrections (G - E) to the energy in solution (Esol).
Representative procedure for catalytic reactions with
[Rh(COD)2]BF4. In a N2-filled glovebox, a 1 dram vial was charged
with a stir bar and the substrate (0.040 mmol). A solution of
[Rh(COD)2]BF4 (0.70 mg, 0.0020 mmol) in 40 μL 1,4-dioxane was
added, and a solution of ligand L1a (1.6 mg, 0.0040 mmol) in 40 μL
1,4-dioxane was added. The vial was sealed with a Teflon-lined cap
and removed from the glovebox. The reaction was heated to 70 °C in
an aluminum heating block, and aliquots at 2 h and 18 h were analyzed
by GC.
2H). 19F NMR (376 MHz, CDCl3) δ -74.3 (s).
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1-(2-methoxyphenyl)-2-dicyclohexylphosphino-3,4-dihy-
dronaphthalene (L13b). In a N2-filled glovebox, a 1-dram vial was
charged with a stir bar, the enol triflate (256 mg, 0.667 mmol),
Pd(OAc)2 (16.3 mg, 10 mol%), DPPB (1,4-bis(diphenylphosphino)bu-
tane, 28.4 mg, 10 mol%), DIPEA (N,N-diisopropylethylamine, 174 μL,
1.00 mmol), and toluene (5 mL). Dicyclohexylphosphine (202 μL, 1.00
mmol) was added, and the vial was sealed with a Teflon-lined cap. The
reaction was removed from the glovebox and heated to 120 °C in an
aluminum heating block. The reaction was monitored by 31P NMR
spectroscopy and was allowed to cool to 25 °C when dicyclohex-
ylphosphine was consumed. The reaction was diluted with toluene in
the glovebox, filtered through silica, and concentrated in vacuo. The
crude reaction mixture was purified by column chromatography in the
glovebox, eluting with toluene to yield 214 mg of white solid (74%
yield).
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1H NMR (400 MHz, C6D6) δ 7.31 – 7.23 (m, 3H), 7.11 (m, 2H),
7.04 (m, 2H), 6.70 (d, J = 8.1 Hz, 1H), 3.35 (s, 3H), 2.92 – 2.73 (m,
2H), 2.49 (m, 2H), 1.95 – 1.69 (m, 12H), 1.41 – 1.16 (m, 10H).13C{1H}
NMR (126 MHz, CDCl3) δ 157.1, 146.2 (d, J = 4.1 Hz), 136.4, 135.3,
132.3, 132.2, 129.8, 128.5, 127.09, 126.99, 126.3, 126.0, 119.9, 110.1,
55.0, 34.3 (d, J = 14.5 Hz), 33.8 (d, J = 2.8 Hz), 33.7 (d, J = 4.7 Hz),
31.4 (d, J = 19.0 Hz), 30.6 (d, J = 5.8 Hz), 30.5 (d, J = 4.8 Hz), 28.7,
27.6 (d, J = 6.7 Hz), 27.5 (d, J = 9.1 Hz), 27.4, 27.3, 26.6 (d, J = 9.7
Hz), 26.3, 26.0.31P{1H} NMR (202 MHz, CDCl3) δ -3.47. HRMS–ESI
(m/z) [M+H]+ calcd for C29H38OP, 433.2660; found 433.2646.
1-(2-trifluoromethylphenyl)-2-dicyclohexylphosphino-3,4-dihy-
dronaphthalene (L13c). The title compound was prepared from 2-bro-
Representative procedure for catalytic reactions with [Rh(eth-
ylene)2(1,4-dioxane)2]BF4
1. A stock solution of the [Rh(ethylene)2(1,4-dioxane)2]BF4 was
prepared according to literature procedure.
In a N2-filled glovebox in the dark, a 1 dram vial was charged with
a stir bar, [rhodium(ethylene)2Cl]2, AgBF4, and 1 mL methylene chlo-
ride, and the vial was capped. The solution was stirred in the dark at
room temperature in the glovebox for 1 h. The solution was filtered
through celite, and the filtrate was concentrated under high vacuum.
The resulting orange solid was dissolved in 1,4-dioxane (1 mL).
2. A 1 dram vial was charged with a stir bar and the ligand L1a as a
solution in 40 μL 1,4 dioxane (0.0040 mmol). The solution of Rh(eth-
ylene)2(1,4-dioxane)2]BF4 was added (40 μL, 0.0020 mmol), and the
substrate (0.040 mmol) was added to the mixture of rhodium and lig-
and. The vial was sealed with a Teflon-lined cap and removed from the
glovebox. The reaction was heated to 70 °C in an aluminum heating
block, and aliquots at 2 h and 18 h were analyzed by GC.
Representative procedure for synthesis of dihydronaphthyl-
based ligands. 1-(2-methoxyphenyl)-2-tetralone. In a N2-filled glove-
box, a 1 dram vial was charged with a stir bar, NaOtBu (264 mg, 2.75
mmol), (dtbpf)PdCl2 (dtbpf = 1,1’-bis(di-tert-butylphosphino)ferro-
cene) (32.9 mg, 2 mol%), 2-methoxychlorobenzene (317 μL, 2.50
mmol), and β-tetralone (330 μL, 2.50 mmol), l). 1,4-dioxane (2.0 mL)
was added, and the vial was sealed with a Teflon-lined cap, shaken to
dissolve the solid reagents, removed from the glovebox, and heated to
80 °C in an aluminum heating block. Reaction progress was monitored
by GC analysis, and the reaction was allowed to cool to 25 °C when the
aryl chloride was consumed (after 24 h). The reaction was diluted with
hexane and filtered through silica, washing with 1:1 hexane: EtOAc.
The filtrate was concentrated in vacuo and used without further purifi-
cation. 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.28 (m, 1H), 7.26 (d, J
= 8.3 Hz, 1H), 7.22 – 7.06 (m, 3H), 7.04 – 6.96 (m, 1H), 6.91 (d, J =
8.2 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 4.80 (s, 1H), 3.66 (s, 3H), 3.29 –
3.11 (m, 2H), 2.89 – 2.65 (m, 2H).
1
mobenzotrifluoride by the representative procedure above. H NMR
(600 MHz, CDCl3) δ 7.70 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 7.0 Hz, 2H),
7.50 – 7.44 (m, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.18 (d, J = 7.2 Hz, 1H),
7.13 (t, J = 7.0 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.40 (d, J = 7.5 Hz,
1H), 3.00 – 2.80 (m, 2H), 2.63 (dd, J = 9.9, 5.5 Hz, 1H), 2.56 – 2.38
(m, 1H), 1.95 – 1.56 (m, 12H), 1.33 – 1.01 (m, 10H). 13C{1H} NMR
(151 MHz, CDCl3) δ 148.0, 147.8, 138.9, 136.41, 136.35, 136.1, 136.0,
135.8, 133.74, 133.72, 133.0, 132.2, 131.6, 131.3, 130.9, 130.64,
130.61, 129.2, 129.1, 129.0, 128.7, 128.0, 127.54, 127.45, 127.3, 127.2,
126.91, 126.88, 126.73, 126.69, 126.66, 126.63, 126.5, 126.2, 126.1,
125.2, 123.2, 35.4, 35.3, 34.2, 34.1, 31.5, 31.4, 31.11, 31.09, 31.04,
31.02, 30.9, 30.38, 30.33, 30.31, 28.4, 27.8, 27.71, 27.66, 27.54, 27.48,
27.41, 27.3, 27.2, 26.4, 26.42, 26.35, 26.27, 23.35 (complexity due to
C-P and C-F splitting). 31P{1H} NMR (243 MHz, CDCl3) δ -5.5.
HRMS–ESI (m/z) [M+H]+ calcd for C29H35F3P, 471.2429; found
471.2414.
1-phenyl-2-dicyclohexylphosphinocyclohex-1-ene (L12).
The title compound was prepared from 2-phenylcyclohexanone by
the representative procedure above. 1H NMR (500 MHz, CDCl3) δ 7.35
– 7.26 (m, 2H), 7.26 – 7.19 (m, 1H), 7.06 (d, J = 7.1 Hz, 2H), 2.42 –
2.31 (m, 2H), 2.24 (m, 2H), 1.85 – 1.58 (m, 16H), 1.33 – 1.03 (m,
10H). 13C{1H} NMR (126 MHz, CDCl3) δ 152.6 (d, J = 30.8 Hz), 145.6
(d, J = 11.3 Hz), 130.0 (d, J = 17.5 Hz), 128.9 (d, J = 2.8 Hz), 127.6,
126.1, 35.0 (d, J = 6.8 Hz), 34.0 (d, J = 13.5 Hz), 31.4 (d, J = 18.8 Hz),
30.5 (d, J = 9.8 Hz), 27.6 (d, J = 7.8 Hz), 27.3 (d, J = 11.7 Hz), 26.7 (d,
J = 4.6 Hz), 23.4 (d, J = 21.8 Hz). 31P{1H} NMR (202 MHz, CDCl3) δ
-7.8. HRMS–ESI (m/z) [M+H]+ calcd for C24H36P, 355.2555; found
355.2543.
1-(2-methoxyphenyl)-3,4-dihydronaphthalen-2-yl
trifluoro-
methanesulfonate. To a solution of KHMDS (293 mg, 1.47 mmol) in
THF at -78 °C was added a solution of 1-(2-methoxyphenyl)-2-tetra-
lone (237 mg, 1.34 mmol) in 10 mL of THF in two portions. The reac-
tion was stirred at 30 min at -78 °C, allowed to warm to 25 °C, and
stirred for 1 h at 25 °C. The reaction was cooled to -78 °C and PhN(Tf)2
(525 mg, 1.47 mmol) was added in one portion. The reaction was al-
lowed to warm to 25 °C and stirred overnight. The reaction mixture
was concentrated, and the PhNHTf byproduct was recrystallized from
cold pentane to yield a more concentrated solution of the desired prod-
uct. The resulting solution was concentrated and purified by silica gel
chromatography, eluting with 99:1 hexanes: EtOAc, to yield 256 mg of
white solid (50% yield). Note: isolated yield reflects pure product ob-
tained from one column, higher yields could be obtained by additional
purification of the remaining solid. 1H NMR (400 MHz, CDCl3) δ 7.51
– 7.43 (m, 1H), 7.30 – 7.19 (m, 3H), 7.18 – 7.00 (m, 3H), 6.81 (d, J =
2-Phenethyl(dicyclohexyl)phosphine, fluoroboric acid salt (L5).
To a solution of dicyclohexylphosphine in THF at -78 °C was added
n-BuLi (2.6 M solution in hexane) dropwise over 5 min. The mixture
was stirred at -78 °C for 1 h, and 2-phenethylbromide was added drop-
wise over 10 min. The reaction was allowed to warm to room temper-
ature, and after stirring at room temperature for 30 min, the reaction
was cooled to 0 °C and excess HBF4(aq) was added. The reaction mix-
ture was transferred to a round-bottomed flask and concentrated in
vacuo. The crude solid was washed with pentane and purified by re-
crystallization from a mixture of pentane and ether to yield 200 mg of
1
white solid (70% yield). H NMR (400 MHz, CD2Cl2) δ 7.46 – 7.03
(m, 5H), 2.90 – 2.57 (m, 1H), 1.96 – 1.62 (m, 12H), 1.55 (s, 2H), 1.25
(d, J = 6.4 Hz, 10H). 13C{1H} NMR (151 MHz, CD2Cl2) δ 145.70 (d,
J = . 8 Hz), 130.11, 129.92, 127.54, 36.72 (d, J = 22.4 Hz), 35.33 (d, J
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= 13.4 Hz), 32.31 (d, J = 14.7 Hz), 31.54, 30.99 (d, J = 8.8 Hz), 29.28
stirred for 30 min. Dicyclohexylchlorophosphine (0.852 mL, 3.86
mmol) was added in one portion and the reaction was stirred for an
additional 30 min at -78 °C. The reaction was allowed to warm to room
temperature and the solvent was evaporated under high vacuum. The
crude mixture was transferred into the glovebox and was filtered
through 0.5 mL silica, washing with toluene, and concentrated under
(d, J = 12.3 Hz), 29.21 (d, J = 7.9 Hz), 25.66 (d, J = 18.3 Hz),
1.44. 31P{1H} NMR (162 MHz, CD2Cl2) δ -2.04. HRMS–ESI (m/z)
[M+H]+ calcd for C20H32P, 303.2242; found 303.2233.
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(Z)-phenyl(dicyclohexylphosphino)ethene (L4).
To a solution of 2-dicyclohexylphosphino-1-phenylethyne (1.00
mmol, 298 mg) at -78 °C was added dropwise a solution of diisobutyl-
aluminum hydride (1.50 mmol, 0.750 mL, 2.0 M in ether). The reaction
was allowed to warm to room temperature and was stirred for 2 h at
room temperature. The reaction was cooled to 0 °C, and excess satu-
rated, degassed, NH4Cl(aq) was added. The organic phase was trans-
ferred via cannula to a flask containing dry MgSO4, under nitrogen. To
the remaining aqueous liquid was added 10 mL dry, degassed, ether,
and the organic phase was transferred into the receiving flask via can-
nula. The organic phase was concentrated to approx. 2 mL in vacuo,
and the flask was moved into the glovebox. The organic phase was con-
centrated in vacuo and the crude solid was purified by recrystallization
from cold pentane to yield 276 mg of white solid in 92% yield. 1H NMR
(400 MHz, C6D6) δ 8.05 (d, J = 7.5 Hz, 1H), 7.27 (t, J = 5.7 Hz, 2H),
7.11 (t, J = 7.4 Hz, 1H), 6.10 (dd, J = 13.0, 5.9 Hz, 1H), 2.04 – 1.57 (m,
12H), 1.57 – 1.12 (m, 11H). 13C{1H} NMR (101 MHz, C6D6) δ 145.3
(d, J = 16.3 Hz), 138.1, 130.2 (d, J = 10.9 Hz), 129.8, 129.5, 128.3,
35.0 (d, J = 11.6 Hz), 30.4 (d, J = 15.9 Hz), 28.8 (d, J = 8.0 Hz), 27.3
(d, J = 3.9 Hz), 27.2, 26.6. 31P{1H} NMR (162 MHz, CDCl3) δ -6.35.
HRMS–ESI (m/z) [M+H]+ calcd for C20H30P, 301.2085; found
301.2074.
2-diethylphosphino-2’-(N,N-dimethylamino)biphenyl (L1c).
To a solution of 2-bromo-2’-(N,N-dimethylamino)biphenyl (250
mg, 0.905 mmol) at -78 °C was added n-BuLi (1.6 M solution in hex-
ane, 0.566 mL, 0.905 mmol) dropwise over 10 minutes, and the reac-
tion was stirred for 30 min. Diethylchlorophosphine (110 μL, 0.905
mmol) was added in one portion and the reaction was stirred for an
additional 30 min at -78 °C. The reaction was allowed to warm to room
temperature and the solvent was evaporated under high vacuum. The
crude mixture was transferred into the glovebox and was filtered
through 0.5 mL silica. The silica was rinsed with toluene, and the mix-
ture was concentrated under high vacuum. The filtered solid was dis-
solved in pentane and filtered again through 0.5 mL of silica to yield
168 mg of the title compound as a white solid after concentration in
vacuo (63%). 1H NMR (300 MHz, CDCl3) δ 7.64 – 7.50 (m, 1H), 7.44
– 7.26 (m, 4H), 7.14 – 6.89 (m, 3H), 2.46 (s, 3H), 1.66 (q, J = 7.7 Hz,
1H), 1.47 (q, J = 7.4 Hz, 1H), 1.01 (dt, J = 15.5, 7.7 Hz, 2H), 0.75 (dt,
J = 14.9, 7.6 Hz, 1H).13C{1H} NMR (126 MHz, CDCl3) δ 151.6, 148.6
(d, J = 30.5 Hz), 137.8 (d, J = 16.0 Hz), 135.5 (d, J = 5.2 Hz), 131.9,
130.4 (d, J = 3.5 Hz), 123.0 (d, J = 5.8 Hz), 128.7, 128.3, 126.8, 121.1,
117.4, 43.2, 22.3 (d, J = 12.3 Hz), 21.0 (d, J = 12.2 Hz), 10.4 (d, J =
17.1 Hz), 10.0 (d, J = 13.9 Hz).31P{1H} NMR (CDCl3) δ -27.6 ppm.
HRMS–ESI (m/z) [M+H]+ calcd for C18H25NP, 286.1725; found
286.1714.
2-bis(N,N-diethylamino)phosphino-2’-(N,N-dimethylamino)bi-
phenyl (L1b). To a solution of 2-bromo-2’-(N,N-dimethylamino)bi-
phenyl (250 mg, 0.905 mmol) at -78 °C was added n-BuLi (1.6 M so-
lution in hexane, 0.566 mL, 0.905 mmol) dropwise over 10 minutes,
and the reaction was stirred for 30 min. bis-(N,N-Diethylamino)chlo-
rophosphine (191 μL, 0.905 mmol) was added in one portion and the
reaction was stirred for an additional 30 min at -78 °C. The reaction
was allowed to warm to room temperature and the solvent was evapo-
rated under high vacuum. The crude solid was transferred to the glove-
box and recrystallized from pentane at -35 °C to yield 212 mg of white
waxy solid (63% yield). 1H NMR (600 MHz, CDCl3) δ 7.81 – 7.65 (m,
1H), 7.40 – 7.17 (m, 4H), 7.03 – 6.78 (m, 3H), 3.01 – 2.78 (m, 4H),
2.76 – 2.58 (m, 4H), 2.50 (s, 6H), 1.15 – 0.94 (m, 6H), 0.89 – 0.62 (m,
6H). 13C{1H} NMR (151 MHz, CDCl3) δ 151.0 (d, J = 3.2 Hz), 145.1,
141.2, 134.8, 131.8, 131.0, 130.5, 127.7, 125.9, 120.2, 117.5, 43.4 (d,
J = 19.4 Hz), 43.0, 41.9 (d, J = 18.2 Hz), 14.5, 14.2. 31P{1H} NMR (243
MHz, CDCl3) δ 95.4. HRMS–ESI (m/z) [M+H]+ calcd for C22H34N3P,
371.2490; found 371.2414.
1
high vacuum to yield 1.08 g of off-white solid (75% yield). H NMR
(600 MHz, CDCl3) δ 7.34 (d, J = 6.6 Hz, 3H), 7.29 (m, 5H), 7.22 (d, J
= 6.9 Hz, 2H), 6.51 (d, J = 5.7 Hz, 1H), 1.89 – 1.55 (m, 12H), 1.21 (dd,
J = 27.1, 11.8 Hz, 10H). 13C{1H} NMR (126 MHz, CDCl3) δ 141.1 (d,
J = 6.3 Hz), 130.5 (d, J = 3.0 Hz), 131.6, 128.2, 127.9, 127.7, 127.6,
127.5, 127.3, 100.0, 34.5 (d, J = 10.5 Hz), 30.3 (d, J = 15.9 Hz), 29.0
(d, J = 7.1 Hz), 27.4 (d, J = 5.5 Hz). 31P{1H} NMR (243 MHz, CDCl3)
δ -18.7. HRMS–ESI (m/z) [M+H]+ calcd for C26H34P 377.2398; found
377.2386.
Representative procedure for synthesis of vinyl-bridged ligands.
1,1-diphenylbut-1-ene To a solution of methyl butyrate (1.70 mL, 15.0
mmol) in THF (60 mL) at 0 °C was added PhMgBr (1.0 M in THF).
The reaction was allowed to warm to room temperature and stirred
overnight. The reaction was cooled to 0 °C and quenched with sat
NH4Cl(aq). The mixture was transferred into a separatory funnel and
was diluted with EtOAc. The organic phase was separated and the
aqueous phase was extracted 3 times with EtOAc (10 mL). The com-
bined organic phases were dried (MgSO4) and concentrated in vacuo.
The crude mixture was added to a solution of pyridium p-toluenesul-
fonate monohydrate that had been dried at reflux with a Dean-Stark
apparatus and cooled to room temperature. The reaction was heated to
reflux with a Dean Stark apparatus and refluxed overnight. The reaction
was cooled to 25 °C and concentrated in vacuo. The crude mixture was
diluted with hexanes, filtered through silica, concentrated in vacuo, and
used without purification in the next reaction.
1,1-diphenyl-2-bromobut-1-ene. To a solution of 1,1-diphenylbut-1-
ene (2.81 g, 13.5 mmol) in 1,2-DCE (10 mL) at 0 °C a solution of bro-
mine (695 μL, 13.5 mmol) in 1,2-DCE (5 mL) was added dropwise.
The reaction was stirred at 0 °C for 30 min and pyridine (4.35 mL, 54.0
mmol) was added dropwise. The reaction was heated to reflux and
stirred overnight. The reaction was cooled to 0 °C and quenched with
sat Na2S2O4(aq). The mixture was transferred to a separatory funnel,
the organic layer was separated and the aqueous layer was extracted
with CH2Cl2 (2x20 mL). The organic layer was concentrated and the
crude solid was recrystallized from hot MeOH. 1,1-diphenyl-2-dicy-
clohexylphosphinobut-1-ene (L9d). To a solution of 1,1-diphenyl-2-
bromobut-1-ene (718 mg, 2.50 mmol) in THF (10 mL) at -78 °C was
added n-BuLi (1.6 M solution in hexane) dropwise over 10 minutes,
and the reaction was stirred for 2 h. Dicyclohexylchlorophosphine (552
μL, 2.50 mmol) was added in one portion and the reaction was stirred
for an additional 30 min at -78 °C. The reaction was allowed to warm
to room temperature and the solvent was evaporated under high vac-
uum. The crude mixture was transferred into the glovebox and was fil-
tered through 0.5 mL silica, washing with pentane, and concentrated
under high vacuum to yield 819 mg of white solid (81% yield). 1H
NMR (500 MHz, CDCl3) δ 7.37 – 7.02 (m, 10H), 2.50 – 2.32 (m, 2H),
1.96 – 1.60 (m, 12H), 1.42 – 1.08 (m, 10H), 0.83 (m, 3H). 13C{1H}
NMR (126 MHz, CDCl3) δ 144.5 (d, J = 12.2 Hz), 138.6 (d, J = 23.5
Hz), 129.8 (2C), 129.8 (2C), 128.3 (2C), 127.6, 126.4 (d, J = 10.6 Hz),
34.8 (d, J = 15.1 Hz), 31.3 (d, J = 18.1 Hz), 31.1 (d, J = 11.2 Hz), 27.4
(d, J = 8.6 Hz), 27.3 (d, J = 11.7 Hz), 14.5. 31P{1H} NMR (202 MHz,
CDCl3) δ 1.5. HRMS–ESI (m/z) [M+H]+ calcd for C28H34P, 405.2711;
found 405.2696.
1,1-diphenyl-2-dicyclohexylphosphino-3-methylprop-1-ene
(L9c). The title compound was prepared from methyl isobutyrate by
the representative procedure above. 1H NMR (600 MHz, CDCl3) δ 7.29
– 7.22 (m, 4H), 7.22 – 7.15 (m, 4H), 7.13 (d, J = 7.4 Hz, 2H), 2.84 –
2.70 (m, 1H), 2.06 – 1.96 (m, 2H), 1.85 – 1.76 (m, 2H), 1.72 – 1.62 (m,
6H), 1.52 – 1.41 (m, 2H), 1.31 – 1.10 (m, 10H), 1.03 (d, J = 6.9 Hz,
6H). 13C{1H} NMR (126 MHz, CDCl3) δ 145.1 (d, J = 3.6 Hz), 144.5
(d, J = 6.9 Hz), 141.7, 141.5, 128.3, 128.1, 128.0, 127.7, 126.4, 126.3,
35.4 (d, J = 14.1 Hz), 33.3 (d, J = 16.9 Hz), 32.4 (d, J = 20.0 Hz), 31.7
(d, J = 11.2 Hz), 27.4 (d, J = 8.7 Hz), 27.3 (d, J = 12.6 Hz), 26.5, 23.3
(d, J = 7.6 Hz). 31P{1H} NMR (243 MHz, CDCl3) δ -2.6. HRMS–ESI
(m/z) [M+H]+ calcd for C29H40P, 419.2868; found 419.2853.
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1,1-diphenyl-2-dicyclohexylphosphinoethene (L9a).
To a solution of 1,1-diphenyl-2-bromoethene (1.00 g, 3.86 mmol) in
THF (10 mL) at -78 °C was added n-BuLi (1.6 M solution in hexane,
2.41 mL, 3.86 mmol) dropwise over 10 minutes, and the reaction was
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1,1-(2-methoxyphenyl)-2-dicyclohexylphosphinoprop-1-ene
(L9e).
Corresponding Author
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* jhartwig@berkeley.edu
The title compound was prepared from methyl propionate by the rep-
resentative procedure above. 1H NMR (600 MHz, CDCl3) δ 7.25 – 7.01
(m, 4H), 6.95 – 6.78 (m, 3H), 6.77 (d, J = 7.7 Hz, 1H), 3.80 (br s, 6H),
1.91 – 1.56 (m, 15H), 1.31 – 1.11 (m, 10H). 13C{1H} NMR (126 MHz,
CDCl3) δ 156.24 – 154.68 (m), 146.9 (d, J = 32.3 Hz), 134.84 – 133.85
(m), 133.65 – 132.94 (m), 133.23 – 132.17 (m), 131.82 – 130.84 (m),
129.7, 127.8, 127.7, 120.4, 119.5, 111.59 – 110.33 (m), 110.33 –
109.49 (m), 36.10 – 34.64 (m), 55.4, 54.9, 34.2 (dd, J = 15.9, 5.0 Hz),
32.08 – 31.17 (m), 31.24 – 30.58 (m), 30.66 – 29.99 (m), 28.33 – 27.58
(m), 27.70 – 27.22 (m), 26.8, 17.0 (d, J = 1.9 Hz). 31P{1H} NMR (243
MHz, CDCl3) δ -5.1. HRMS–ESI (m/z) [M+H]+ calcd for C29H40O2P,
451.2766; found 451.2760.
1-methyl-2-phenyl-3-dicyclohexylphosphinoindole (L7b).
1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 7.8 Hz, 1H), 7.54 – 7.46
(m, 3H), 7.40 (dd, J = 16.4, 7.3 Hz, 3H), 7.31 (d, J = 7.6 Hz, 1H), 7.22
(t, J = 7.2 Hz, 1H), 3.57 (s, 3H), 2.32 (s, 2H), 1.82 (dd, J = 47.3, 11.3
Hz, 5H), 1.63 (d, J = 6.4 Hz, 5H), 1.43 – 0.95 (m, 15H). 13C{1H} NMR
(126 MHz, CDCl3) δ 138.1, 132.7 (d, J = 3.1 Hz), 131.5, 131.5, 130.7,
128.4, 127.9, 121.9, 121.6, 119.8, 109.7, 104.1 (d, J = 13.1 Hz), 34.2
(d, J = 8.1 Hz), 32.0 (d, J = 20.3 Hz), 31.2, 30.5 (d, J = 8.1 Hz), 27.3
(d, J = 7.8 Hz), 27.2, 26.5. 31P{1H} NMR (202 MHz, CDCl3) δ -17.6.
HRMS–ESI (m/z) [M+H]+ calcd for C27H35NP, 404.2507; found
404.2493.
ACKNOWLEDGMENT
This work was supported by the NIH (GM-55382), the Research
Council of Norway (RCN) through CoE Grant No. 179568/V30
(CTCC) and through NOTUR Grant No. NN4654K for HPC re-
sources. Computational support at UC Berkeley is supported by the
NSF (CHE-0840505). AES thanks the Peder Sather Center for Ad-
vanced Study for support of this collaboration. DB thanks the EU
REA for a Marie Curie Fellowship (Grant CompuWOC/618303).
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1-phenyl-2-dicyclohexylphosphinonaphthalene (L11).
To a solution of 1-phenyl-2-iodonaphthalene (419 mg, 1.27 mmol)
in THF (10 mL) at -78 °C was added n-BuLi (1.6 M solution in hexane,
0.794 mL, 1.27 mmol) dropwise over 10 minutes, and the reaction was
stirred for 30 min. Dicyclohexylchlorophosphine (0.280 mL, 1.27
mmol) was added in one portion and the reaction was stirred for an
additional 30 min at -78 °C. The reaction was allowed to warm to room
temperature and the solvent was evaporated under high vacuum. The
crude mixture was transferred into the glovebox and was filtered
through 0.5 mL alumina, washing with CH2Cl2, and concentrated un-
der high vacuum to yield 437 mg of off-white solid (86% yield).
HRMS–ESI (m/z) [M+H]+ calcd for C28H34P, 401.2398; found
401.2384.
12. Ickes, A. R.; Ensign, S. C.; Gupta, A. K.; Hull, K. L. J. Am.
Chem. Soc. 2014, 136, 11256–11259.
13. Ensign, S. C.; Vanable, E. P.; Kortman, G. D.; Weir, L. J.; Hull,
K. L. J. Am. Chem. Soc. 2015, 137, 13748–13751.
14. Gurak, J. A.; Yang, K. S.; Liu, K, Engle, K. M. J. Am. Chem.
Soc. [Just Accepted]. DOI: 1 0.1021/jacs.6b02718. Published online:
Apr. 19, 2016.
15. Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. F. J. Am.
Chem. Soc. 2002, 124, 3669–3679.
16. Löber, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001,
123, 4366–4367.
17. Goldfogel, M. J.; Roberts, C. C.; Meek, S. J. J. Am. Chem. Soc.
2014, 136, 6227–6230.
18. Johns, A. M.; Utsunomiya, M.; Incarvito, C. D.; Hartwig, J. F. J.
Am. Chem. Soc. 2006, 128, 1828–1839.
19. Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
1166–1167.
20. Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125,
14286–14287.
21. Musacchio, A. J.; Nguyen, L. Q.; Beard, G. H.; Knowles, R. R.
J. Am. Chem. Soc. 2014, 136, 12217–12220.
22. Johns, A. M.; Sakai, N.; Ridder, A.; Hartwig, J. F. J. Am. Chem.
Soc. 2006, 128, 9306–9307.
23. Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122,
9546–9547.
24. Takaya, J.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 5756–
5757.
25. Utsunomiya, M.; Kuwano, R.; Kawatsura, M.; Hartwig, J. F. J.
Am. Chem. Soc. 2003, 125, 5608–5609.
26. Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126,
2702–2703.
27. McBee, J. L.; Bell, A. T.; Tilley, T. D. J. Am. Chem. Soc. 2008,
130, 16562–16571.
28. Zhou, J. S.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 12220–
12221.
29. Reznichenko, A. L.; Nguyen, H. N.; Hultzsch, K. C. Angew.
Chem. Int. Ed. 2010, 49, 8984–8987.
1-phenyl-2-dicyclohexylphosphino-3,4-dihydronaphthalene
(L13a).
To a solution of 1-phenyl-2-iodo-3,4-dhydronaphthalene (200 mg,
0.602 mmol) in THF (10 mL) at -78 °C was added n-BuLi (1.6 M so-
lution in hexane, 0.376 mL, 0.602 mmol) dropwise over 10 minutes,
and the reaction was stirred for 30 min. Dicyclohexylchlorophosphine
(0.133 mL, 0.602 mmol) was added in one portion and the reaction was
stirred for an additional 30 min at -78 °C. The reaction was allowed to
warm to room temperature and the solvent was evaporated under high
vacuum. The crude mixture was transferred into the glovebox and was
filtered through 0.5 mL alumina, washing with CH2Cl2, and concen-
trated under high vacuum to yield 204 mg of off-white solid (84%
yield). 1H NMR (300 MHz, CDCl3) δ 7.48 – 7.27 (m, 4H), 7.21 – 6.94
(m, 4H), 6.60 (d, J = 7.8 Hz, 1H), 2.92 – 2.80 (m, 2H), 2.59 – 2.47 (m,
2H), 1.68 (m, 12H), 1.32 – 1.07 (m, 10H).13C{1H} NMR (126 MHz,
CDCl3) δ 136.6 (d, J = 34.4 Hz), 130.9 (d, J = 1.9 Hz), 131.6, 128.8,
128.2, 127.8, 127.3, 127.0, 126.9, 126.7, 126.3, 125.5, 34.2 (d, J = 13.9
Hz), 31.1 (d, J = 19.2 Hz), 30.6 (d, J = 9.3 Hz), 28.7, 27.5 (d, J = 7.6
Hz), 27.3 (d, J = 12.3 Hz), 26.5, 26.0 (d, J = 5.5 Hz). 31P{1H} NMR
(CDCl3) δ -5.6 ppm. HRMS–ESI (m/z) [M+H]+ calcd for C28H36P,
403.2555; found 403.2541.
ASSOCIATED CONTENT
Supporting Information
Summary of computed energies and list of Cartesian coordinates
for all optimized structures, NMR spectra of new compounds, X-
ray crystallographic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
30. Yin, P.; Loh, T.-P. Org. Lett. 2009, 11, 3791–3793.
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31. Reznichenko, A. L.; Hultzsch, K. C. Organometallics 2013, 32,
1394–1408.
32. Couce-Rios, A.; Lledós, A.; Ujaque, G. Chem. Eur. J..
doi:10.1002/chem.201504645.
33. Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans.
1915, 107, 1080.
34. Liu, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 1570–1571.
35. Shen, X.; Buchwald, S. L. Angew. Chem. Int. Ed. 2009, 49, 564–
567.
36. Julian, L. D.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 13813–
13822.
37. Liu, Z.; Yamamichi, H.; Madrahimov, S. T.; Hartwig, J. F. J.
Am. Chem. Soc. 2011, 133, 2772–2782.
38. Hesp, K. D.; Tobisch, S.; Stradiotto, M. J. Am. Chem. Soc. 2010,
132, 413–426.
40. Reaction barriers and relative energies of intermediates are
shown in the Computational Details section of the Supporting Infor-
mation. Although the barriers to these reactions are low, these energies
do not take into account the bimolecular nature of intermolecular reac-
tions
41. For examples of comparison of M06 to other hybrid functionals,
see Zhao, Y.; Truhlar, D. G. Acc. Chem. Res., 2008, 41, 157–167.
42. For examples of DFT(M06) used in calculations of hydroami-
nation reactions, see Ciancaleoni, G.; Rampino, S.; Zuccaccia, D.; Tar-
antelli, F.; Belanzoni, P.; Belpassi, L. J. Chem. Theory Comput., 2014,
10, 1021–1034; Couce-Rios, A.; Kovács, G.; Ujaque, G.; Lledós, A.
ACS Catal., 2015, 5, 815–829; Wang, Z. J.; Benitez, D.; Tkatchouk,
E.; Goddard, W. A.; Toste, F. D. J. Am. Chem. Soc., 2010, 132, 13064–
13071.
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39. Fixing the dihedral at incremental steps and optimizing each in-
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barrier to rotation of 3-4 kcal/mol; this rotation is, therefore, presumed
to be facile under the reaction conditions
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