Mechanistic Studies Lead to Dramatically Improved Reaction Conditions for the Cu-Catalyzed Asymmetric Hydroamination of Olefins

Article abstract of DOI:10.1021/jacs.5b10219

Enantioselective copper(I) hydride (CuH)-catalyzed hydroamination has undergone significant development over the past several years. To gain a general understanding of the factors governing these reactions, kinetic and spectroscopic studies were performed on the CuH-catalyzed hydroamination of styrene. Reaction profile analysis, rate order assessment, and Hammett studies indicate that the turnover-limiting step is regeneration of the CuH catalyst by reaction with a silane, with a phosphine-ligated copper(I) benzoate as the catalyst resting state. Spectroscopic, electrospray ionization mass spectrometry, and nonlinear effect studies are consistent with a monomeric active catalyst. With this insight, targeted reagent optimization led to the development of an optimized protocol with an operationally simple setup (ligated copper(II) precatalyst, open to air) and short reaction times (<30 min). This improved protocol is amenable to a diverse range of alkene and alkyne substrate classes.

Full text of DOI:10.1021/jacs.5b10219

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Article
Mechanistic Studies Lead to Dramatically Improved Reaction
Conditions for the Cu-Catalyzed Asymmetric Hydroamination of Olefins
Jeffrey S Bandar, Michael T. Pirnot, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b10219 • Publication Date (Web): 01 Nov 2015
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Mechanistic Studies Lead to Dramatically
Improved Reaction Conditions for the Cu-
Catalyzed Asymmetric Hydroamination of Ole-
fins
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Jeffrey S. Bandar‡, Michael T. Pirnot‡, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
Copper(I) hydride catalysis, hydroamination, mechanistic studies, catalysis
ABSTRACT: Enantioselective copper(I) hydride (CuH)-catalyzed hydroamination has undergone significant development over the past
several years. In order to gain a general understanding of the factors governing these reactions, kinetic and spectroscopic studies were per-
formed on the CuH-catalyzed hydroamination of styrene. Reaction profile analysis, rate order assessment, and Hammett studies indicate that
the turnover-limiting step is regeneration of the CuH catalyst by reaction with a silane, with a phosphine-ligated copper(I) benzoate as the
catalyst resting state. Spectroscopic, electrospray ionization mass spectrometry, and non-linear effect studies are consistent with a monomeric
active catalyst. With this insight, targeted reagent optimization led to the development of an optimized protocol with an operationally simple
setup (ligated copper(II) precatalyst, open to air) and fast reaction times (<30 minutes). This improved protocol is amenable to a diverse
range
of
alkene
and
alkyne
substrate
classes.
Cu(OAc)2 (2 mol%)
NBn2
Me
Introduction
(S)-L (2.2 mol%)
+
Bn2NOBz
Ph
styrene
Ph
Due to their importance and ubiquity, significant efforts have
been made towards the construction of enantioenriched amines.1
Hydroamination, the formal addition of a nitrogen and hydrogen
atom across a carbon−carbon π-bond, represents a particularly
attractive and direct method for appending amino groups onto a
molecule. Although significant progress has been achieved in this
regard using late transition metal catalysis, a number of drawbacks
have limited the utilization of these methodologies.2 In the context
of intermolecular hydroamination, these methods furnish products
with moderate stereoselectivity and rely on the use of activated
alkenes, such as vinyl arenes and acrylate derivatives, while unacti-
vated alkenes typically fail to react. Similarly, lanthanide and early
transition metal catalysts have shown promise as hydroamination
systems although further developments are needed to address the
generally limited substrate scope.3 The development of a general
approach for regio- and enantioselective hydroamination of a broad
range of alkene classes remains an important challenge.4 In 2013,
Miura’s5 and our lab6 disclosed contemporaneous reports describ-
ing a new method of styrene hydroamination that involves a cop-
per(I) hydride (CuH) catalyst and amine electrophiles to generate
α-chiral amines in excellent yields and enantioselectivities. Since
then, CuH-catalyzed hydroamination has been extended to a wide
scope of substrate classes, including vinyl silanes, terminal alkenes,
internal unactivated alkenes, alkynes, and strained cyclic alkenes.7,8
DEMS (2 equiv)
THF, 40 °C, 12 h
3
4
(1.2 equiv)
91% yield, 96% ee
Me
Cu(OAc)2
H
Si OEt
OEt
L*,R3SiH
R3SiOBz
Ph
L*CuH
diethoxymethylsilane
trans-
metalation
1
olefin
insertion
DEMS
R3SiH
catalytic
cycle
O
L*Cu
L*CuOBz (5)
O
PAr2
Ph
Me
PAr2
O
2
O
NBn2
Me
Bn2N–OBz
Ar = 3,5-(t-Bu)2-4-MeOC6H2
L*: (S)-DTBM-SEGPHOS
C-N bond
formation
Ph
3
4
A general catalytic cycle for the hydroamination of styrene is
shown in Scheme 1. Formation of the phosphine-ligated CuH cata-
lyst (L*CuH, 1) occurs from the combination of Cu(OAc)2, a
phosphine ligand, and silane. Olefin insertion into L*CuH 1 pre-
sumably forms copper(I) alkyl species 2. Interception of 2 by
amine electrophile 3 generates chiral amine 4 and phosphine-
ligated copper(I) benzoate (L*CuOBz, 5). Regeneration of L*CuH
1 from L*CuOBz complex 5 closes the catalytic cycle.
Scheme 1. Proposed catalytic cycle for CuH-catalyzed hy-
droamination of styrene.
Given that this CuH-catalyzed hydroamination strategy has
undergone rapid development in terms of substrate scope, we felt a
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general understanding and improvement of these processes would
ymethylsilane (DEMS) and an apparent fractional-order11 was
1
2
3
4
5
6
7
8
be welcomed. In particular, identification of the turnover-limiting
step and resting state of the copper catalyst might provide a founda-
tion for the development of a more efficient and practical protocol.
Herein we report detailed kinetic and spectroscopic studies of the
CuH-catalyzed hydroamination of styrene. These studies have
provided evidence that the phosphine-ligated CuOBz complex 5 is
the resting state of the catalyst and the turnover-limiting step en-
tails regeneration of the CuH catalyst via its reaction with a silane
reagent. Through this mechanistic insight, rational optimization of
several parameters has led to fast reaction times (<30 minutes) and
operational simplicity (simple copper(II) precatalyst and open to
air) for an array of olefin and alkyne substrates. Similarly, a separate
modified protocol is amenable to the use of low loadings of the
chiral ligand (0.1 to 0.2 mol%). This is important as it is the most
expensive component of this catalyst system.
observed while simultaneously changing the concentration of
Cu(OAc)2 and DTBM-SEGPHOS.
Scheme 3. Model system used for initial-rate kinetics deter-
mined by GC analysis and the observed rate orders. L =
DTBM-SEGPHOS.
component rate order
Cu(OAc)2 (2 mol%)
styrene
Bn2NOBz
DEMS
zero
zero
first
NBn2
Me
(S)-L (2.2 mol%)
9
+
Bn2NOBz
Ph
Ph
10
11
12
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DEMS (2 equiv)
THF, 40 °C
Cu(OAc)2 + L fractional
3 (1.2 equiv)
4
Hammett studies were conducted to determine the impact
that electronic variation of the styrene and the amine electrophile
components had on the rate of hydroamination.12 In the first
Hammett study, a series of para-substituted styrenes reacted with
amine electrophile 3 at similar rates (Scheme 4a), implying that the
olefin is most likely not involved in the turnover-limiting step of
this process. A second Hammett study showed that electronic vari-
ation of the amine electrophile had a significant impact on the rate
of styrene hydroamination (Scheme 4b). A linear correlation was
observed with σpara Hammett constants (ρ = –0.71, R2 = 0.97) indi-
cating more electron rich amine-O-benzoates led to increased reac-
tion rates.13
Mechanistic Studies of the CuH-Catalyzed Hydroamination of
Styrene
The hydroamination of styrenes was chosen as the model sys-
tem for our detailed kinetic studies. To begin, the reaction profile
for the hydroamination of 4-fluorostyrene was studied. In our ini-
tial report we detailed a reaction time of 36 hours to give the de-
sired product in 86% yield and 97% ee. Using in situ 19F-NMR
spectroscopy, the reaction, under the previously reported condi-
tions, was found to be complete in approximately nine hours.
Moreover, the process appeared to be overall zero-order in sub-
strate (Scheme 2).9 Same-excess experiments10 were also conduct-
ed and displayed a similar reaction profile, indicating that catalyst
deactivation and product inhibition were not significant in this
system (see Supporting Information for details).
Scheme 4. a) Hammett study with para-substituted styrenes.
b) Hammett study with para-substituted amine-O-benzoates.a
a)
NBn2
Me
Cu(OAc)2 (2 mol%)
(S)-L (2.2 mol%)
+
Bn2NOBz
DEMS (2 equiv)
THF, 40 °C, 2 h
X
3 (1.2 equiv)
X
Scheme 2. Reaction progress monitored by in situ 19F-NMR.a
Cu(OAc)2 (2 mol%)
NBn2
Me
(S)-L (2.2 mol%)
+
Bn2NOBz
DEMS (2 equiv)
THF, 40 °C
F
3 (1.2 equiv)
F
H
F
OMe
CF3
σpara
time, h
a
L = DTBM-SEGPHOS; 1 equiv of 1-fluoronapthalene added as in-
ternal standard.
Initial rate experiments were next performed with styrene and
amine electrophile 3 to gather more detailed information about the
catalytic cycle of this hydroamination process (Scheme 3). Cor-
roborating our full kinetic analysis, initial-rate kinetics demonstrat-
ed that the reaction was zero-order in styrene and amine electro-
phile 3 across a range of concentrations for each component. In
addition, a clear first-order dependence was observed for diethox-
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peaks that are attributed to a monomeric DTBM-SEGPHOS-
b)
Cu(OAc)2 (2 mol%)
O
NBn2
(S)-L (2.2 mol%)
1
2
bound copper(I) species and the unbound DTBM-SEGPHOS
ligand (see Supporting Information for details). A CuH cluster or
copper aggregate could readily decompose on ionization and can-
not be ruled out with these experiments. Nonlinear effect studies
on the enantiomeric composition of the chiral ligand and amine
product indicated a linear relationship (see Scheme 5). These re-
sults are consistent with an active catalyst being of a monomeric
nature, however we cannot exclude the possibility that higher order
species are involved. 22,23,24
+
Ph
O
NBn2
Ph
Me
DEMS (2 equiv)
THF, 40 °C, 2 h
(1.2 equiv)
4
3
4
5
6
7
8
9
X
y = -0.71x - 0.016
R2 = 0.97
OMe
NEt2
H
10
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Scheme 5. Nonlinear effect study on the enantiomeric compo-
sition of DTBM-SEGPHOS and amine product 4.
F
CF3
Cu(OAc)2 (2 mol%)
NBn2
Me
% ee (4)
(S)-L (2.2 mol%, ee)
σpara
+
Ph
Bn2NOBz
Ph
DEMS (2 equiv)
THF, 40 °C, 12 h
3 (1.2 equiv)
a
Each data point is the average of three experiments with standard
deviations included as error bars; L=DTBM-SEGPHOS.
The observations described above suggested that regeneration
of the CuH catalyst 1 from the presumed ligated CuOBz complex 5
and silane is the turnover-limiting step of the CuH-catalyzed hy-
droamination process (Scheme 1).14 This interpretation is support-
ed by (a) the zero-order dependence on styrene and amine electro-
phile; (b) the first-order dependence on the silane, DEMS; and (c)
the linear free energy relationship between the Hammett electronic
parameter of the amine electrophile benzoate and the initial rate.
The enhanced initial rates observed with more electron-rich ben-
zoates is consistent with a faster transmetalation of phosphine li-
gated CuOBz complex 5 with silane. Interestingly, independent
initial-rate measurements collected with diphenylsilane and deutero-
diphenylsilane (Ph2SiD2) of the model reaction did not show a meas-
urable kinetic isotope effect (KIE) (kH/kD= 1.06 ± 0.10). 15
y = 0.95x - 0.53
R2 = 0.99
ee, DTBM-SEGPHOS
We next sought to identify the enantioselectivity-determining
step (EDS) of the styrene hydroamination reaction. To this end,
we searched for linear free energy relationships (LFERs) between
substrate Hammett electronic parameters and the observed enanti-
oselectivities for a variety of para-substituted styrenes.25,26 A linear
relationship was observed with para-substituted styrenes as enanti-
oselectivity decreased with the introduction of electron-
withdrawing substituents (ρ = −0.50, R2 = 0.98, Scheme 6): 98% ee
The fractional order dependence observed while manipulating
[Cu(OAc)2] and [DTBM-SEGPHOS] inspired a closer examina-
tion of the active catalytic species. A series of studies were em-
ployed to investigate the possible nature of the copper catalyst in
the CuH-catalyzed hydroamination of styrene. Historically, CuH
complexes with sterically unencumbered ligands have been isolated
as higher-order species and aggregates.16-19 Our initial 31P-NMR
studies on the CuH catalyst solution (Cu(OAc)2, (S)-DTBM-
SEGPHOS, and DEMS in THF)20 did not allow identification of a
distinct CuH species. However, the major new species observed in
the spectrum does have a similar 31P-NMR shift and peak shape
attributed to phosphine-ligated CuH clusters reported in the litera-
ture.21 When this CuH solution was subjected to the model hy-
droamination reaction 31P-NMR showed that a new species at-
tributed to LCuOBz (5) accounts for the majority of the ligated
species observed. The assignment of LCuOBz 5 is supported by its
independent preparation. These observations are consistent with
intermediate 5 acting as the catalyst resting state prior to the turno-
ver-limiting step of the hydroamination reaction. Surprisingly, ap-
proximately 50% of the DTBM-SEGPHOS ligand remains un-
bound throughout the course of the reaction. Additional details
and a discussion of these experiments are provided in the Support-
ing Information. Efforts toward isolation and characterization of
discrete copper(I) intermediates is ongoing.
and 95% ee was observed for 4-methylstyrene (σp = −0.14) and 4-
(trifluoromethyl)styrene (σp = 0.53), respectively.13,27 In contrast, a
linear free energy relationship was not observed between the elec-
tronic nature of the amine electrophile (varying the para-
substituent of the benzoate of the amine O-benzoate) and the en-
antioselectivity of the product (see Supporting Information for
details). Additionally, the identity of the silane did not appear to
affect the enantioselectivity of the process. Taken together, these
results indicate that hydrocupration is most likely the enantio-
determining step.
Scheme 6. Hammett plot for the enantiomeric ratio of hy-
droamination products using para-substituted styrenesa
Electrospray ionization mass spectrometric (ESI-MS) analysis
of aliquots taken from the purported CuH mixture gave major
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NBn2
Cu(OAc)2 (2 mol%)
nificantly diminishing the enantioselectivity of the reaction since
(S)-L (2.2 mol%)
1
the rate- and enantio-determining steps are presumed to be sepa-
rate processes. The independent and rational optimization of these
components is described below.32
Me
+
Bn2NOBz
2
3
DEMS (2 equiv)
THF, 40 °C, 20 h
X
3 (1.2 equiv)
X
4
5
6
7
8
9
Table 1 shows the observed initial rates of hydroamination us-
ing a variety of readily available silanes. Most notably, by using
dimethoxymethylsilane (DMMS), a three-fold initial-rate en-
hancement was observed relative to DEMS (entries 1 and 2). Em-
ploying other siloxanes, such as 1,1,2,2-tetramethyldisiloxane and
PMHS, resulted in lower reaction rates (entries 3 and 4). The use
of diphenylsilane provided product, whereas trialkylsilanes, such as
triethylsilane, were ineffective hydride sources (entries 5 and 6).
Due to safety concerns, trialkoxysilanes were not investigated.33 In
terms of performance and practicality, DMMS was chosen as the
optimal silane among those that we examined.34
Me
H
F
CF3
y = -0.50x + 1.89
R2 = 0.98
10
11
12
13
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56
57
58
59
60
σpara
a er = enantiomeric ratio; L = DTBM-SEGPHOS.
Table 1. Effect of silane on initial-rate measurementsa
We expected hydrocupration to be irreversible since it appears
to be the enantio-determining step and occurs before the rate-
determining step.28 To provide further support that hydrocupration
is enantiodetermining, styrene-α, β, β-d3 (6) was subjected to the
standard hydroamination conditions using DEMS as the hydride
source. If hydrocupration is reversible due to β-hydride elimination
of copper(I) alkyl 7, then isotopic isomers 8 and 9 should be ob-
served throughout the reaction due to potential β-deuteride elimi-
Cu(OAc)2 (2 mol%)
NBn2
(S)-L (2.2 mol%)
+
Bn2NOBz
Ph
silane (2 equiv)
Ph
Me
3 (1.2 equiv)
4
THF, 40 °C
rel rate
entry
silane
rate (M/min)
1
2
3
4
5
6
HSiMe(OEt)2
HSiMe(OMe)2
(HMe2Si)2O
PMHS
5.6(3) x 10-4
1.8(1) x 10-3
3.1(4) x 10-4
1.9(1) x 10-4
1.3(4) x 10-3
nr†
1
3.1
0.6
0.3
2.3
-
nation.29 The reaction was monitored by H-NMR spectroscopy
1
and no signals attributable to olefinic protons were observed
throughout the course of the reaction, indicating that β-deuteride
elimination did not occur. Further, we would expect to see some
proportion of 10 containing only two deuteria. In fact a single iso-
topic product 10 was isolated from the crude reaction mixture
(Scheme 7). Taken together, these results strongly support the
notion that hydrocupration is irreversible.30 In addition, these re-
sults are consistent with previous reports that β-hydride elimina-
tion most likely does not occur during the CuH-catalyzed hydrosi-
lylation of ketones.11,31
Ph2SiH2
Et3SiH
† no reaction; a L = DTBM-SEGPHOS.
As noted earlier, the electronic nature of the amine electro-
phile dramatically affected the initial rate of the hydroamination
reaction, which is believed to influence the regeneration of the
CuH catalyst from copper(I) benzoate intermediate 5 (Scheme
4b). For example, use of amine electrophile 11, bearing a 4-
diethylaminobenzoate group, led to a three-fold rate enhancement
compared to amine 3 with an unsubstituted benzoate group
(Scheme 8). This rate enhancement could be increased further by
using 2,4,6-trimethoxybenzoate (12), acetate (13) or pivalate (14)
bearing amine electrophiles (initial-rates 2.5−2.8 x 10-3 M/min).
We selected the pivalate-appended oxidant (14) as the optimal
amine electrophile due to its accessibility and long-term stability.35
An amine electrophile featuring a carbonate (15), which could
potentially decarboxylate to access a copper alkoxide intermediate,
was found to provide a comparable rate of reaction to amine elec-
trophile 3.
Scheme 7. Hydroamination of styrene-α, β, β-d3 (6) under
standard reaction conditions.a
Cu(OAc)2 (2 mol%)
D
(S)-L (2.2 mol%)
Bn2N
Ph
D
D
+
Bn2NOBz
Ph
CHD2
DEMS (2 equiv)
THF, 40 °C, 20 h
6
3
10
D
(1.2 equiv)
95% yield
via:
not
observed:
Me
D
D
LCu
Ph
H
H
Si OEt
OEt
H
D
Ph
Ph
D
D
D
D
H
7
8
9
DEMS
Reaction monitored by 1H-NMR spectroscopy. L = DTBM-
SEGPHOS.
a
Scheme 8. Effect of amine electrophile on initial-rate kinetics.
L = DTBM-SEGPHOS.
Rational Optimization of Hydroamination Reagents
With a good understanding of the factors controlling the rate
and selectivity of this CuH-catalyzed hydroamination process, we
next turned our attention to improving the overall efficiency of the
reaction. We focused our efforts on the identity of the silane and
amine electrophile components since these appear to be directly
involved in the rate-determining step. Importantly, we expected to
be able to increase the overall rate of hydroamination without sig-
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Cu(OAc)2 (2 mol%)
O
droamination reaction was carried out in and required up to 30
NBn2
Me
(S)-L (2.2 mol%)
1
2
3
4
5
6
7
8
minutes for activation due to the slow complexation of Cu(OAc)2
with DTBM-SEGPHOS ligand and subsequent reaction with
DEMS. We have found that this two-pot procedure is unnecessary
and instead are able to perform a simple one-pot operation in
which the silane is added once all the other reagents are in solution.
Traditionally, reactions that proceed through copper(I) alkyl in-
termediates are performed under an inert atmosphere due to their
incompatibility with oxygen and moisture.38 We wished to remove
this constraint for as many hydroamination reactions as possible,
and the reaction setups described below are carried out fully open-
to-air unless otherwise noted.39
+
R
O
NBn2
Ph
Ph
DEMS (2 equiv)
THF, 40 °C
4
(1.2 equiv)
O
O
OMe O
O
NBn2
O
NBn2
O
NBn2
Et2N
MeO
OMe
12
2.5(1) x 10-3 M/min
4.5
3
11
5.6(7) x 10-4 M/min
1
1.6(2) x 10-3 M/min
2.9
rel rate:
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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53
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55
56
57
58
59
60
O
O
O
Me
O
NBn2
tBu
O
NBn2
EtO
O
NBn2
After optimizing temperature and concentration parameters,
we found that the CuH-catalyzed hydroamination of styrene could
be completed in 10 minutes at 60 °C while open to the atmosphere,
delivering the chiral amine product 4 in 90% isolated yield and 95%
ee (entry 1, Table 2). It is worth noting that this reaction is com-
plete in a third of the time previously required to prepare the active
CuH solution and only a fraction of the 36 hour total reaction time
originally reported.6
13
14
15
2.8(2) x 10-3 M/min
2.5(2) x 10-3 M/min
7.2(2) x 10-4 M/min
5.0
4.5
1.3
rel rate:
Lipshutz has reported that secondary ligands, such as PPh3,
can be employed in CuH catalysis to lower catalyst loadings and
improve overall reactivity for certain systems.36 Addition of 2.2
mol% PPh3 to our model system did indeed result in a slight rate
enhancement (1.2-fold increase), but higher loadings of PPh3 did
not result in any further increase in reaction rate. Testing the addi-
tion of other achiral phosphine additives led only to slightly in-
creased reaction rates and variable levels of enantioselectivity (see
Supporting Information for details).
At this point in our study, all of the hydroamination reactions
described have involved unsubstituted styrenes, a relatively unhin-
dered and reactive class of alkene. We wanted to see whether this
optimized protocol would be amenable to other classes of alkenes
and alkynes. Table 2 highlights the broad scope of this hydroamina-
tion protocol. Trans-β-substituted styrenes, vinylsilanes, alkynes,
and terminal alkenes all underwent hydroamination in high yield in
short reaction times (entries 2, 4, 6 and 7, 88%−91% yield,
98%−99% ee, 15−20 minutes). These results suggest that regenera-
tion of the CuH catalyst is likely rate limiting for the hydroamina-
tion of these substrate classes. Cis-β-substituted styrenes and 1,1-
disubstituted terminal alkenes proved to be less reactive. However,
by performing the hydroamination of these substrates under an
inert atmosphere, we were able to significantly decrease the previ-
ously reported reaction times of 36 hours to under four hours (en-
tries 3 and 5).6,7a
By employing the optimized reagents, O-pivaloyl-N,N-
dibenzylhydroxylamine (14), DMMS, and PPh3 additive, the hy-
droamination of styrene was complete in one hour at 40 °C with a
high yield and enantioselectivity (eq 1, 99% yield, 96% ee). For
comparison, our previous report detailed reaction times at 36 hours
at this temperature, while we found (see above) that the reaction
actually required nine hours to proceed to completion. The greatly
reduced reaction time suggests that the increased reaction rates
observed while optimizing these reagents independently are indeed
additive. Final optimization of the hydroamination protocol is de-
scribed in the following section.
Cu(OAc)2 (2 mol%)
Table 2. Hydroamination of various substrates under opti-
mized protocol.a
(S)-L (2.2 mol%)
PPh3 (2.2 mol%)
NBn2
1 h
+
(1)
Bn2NOPiv
99% yield
Me
96% ee
Ph
Ph
DMMS (2 equiv)
THF, 40 °C
14
(1.2 equiv)
4
Optimized Protocol for a Range of Substrate Classes
At the outset of this study, our ultimate goal was to improve
the efficiency and practicality of our previously reported asymmet-
ric hydroamination methodologies. We specifically sought to de-
crease the relatively long reported reaction times (24−36 hours),
enable lower catalyst loadings, and make reaction setup more ro-
bust and user-friendly.
To these ends, we first prepared a precomplexed copper cata-
lyst mixture that contained Cu(OAc)2, (S)-DTBM-SEGPHOS,
and PPh3 (1:1.1:1.1 ratio) that was used throughout this section
(see Supporting Information for details of the preparation of this
precatalyst).37 This air-stable free-flowing powder rapidly dissolves
in a variety of organic solvents and enables quick reaction setup. In
our previous reports, the preparation of the active CuH catalyst was
performed in a separate reaction flask than the one that the hy-
5
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Page 6 of 9
eration of the CuH catalyst 1 from the phosphine-bound CuOR
18.
Conditions:
1
2
Bn2NOPiv (1.2 equiv), CuCatMix (2 mol%), DMMS (2 equiv), THF, 60 °C, air
Entry
Substrate
Product
Scheme 9. Modified catalytic cycle for the CuH-catalyzed hy-
droamination of styrene.
3
4
5
6
7
8
9
NBn2
10 m
91% yield
95% ee
1
Ph
Ph
Me
16
purported
L*
NBn2
20 m
89% yield
98% ee
CuxHyL*z
Cu(OAc)2
Me
2
CuH cluster
R3SiH
Ph
Ph
Ph
Et
NBn2
2 h
83% yield
96% ee
R3SiOR
Ph
3b
4
L*CuH
Ph
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Et
1
rate-limiting
R3SiH
enantio-determining
irreversible
20 m
91% yield
NBn2
NBn2
Ph
Ph
catalytic
cycle
Me
3 h
95% yield
95% ee
L*Cu
L*CuOR(18)
resting state
5b
PhMe2Si
PhMe2Si
Ph
Me
2
of the catalyst
NBn2
SiMe3
15 m
88% yield
99% ee
6
Ph
SiMe3
3
Ph
3
NBn2
Me
Bn2N–OR
4
Bn2N
Ph
17
Ph
15 m
91% yieldc
7
Ph
Ph
Ph
Rate enhancement is observed with judicious choice of silane,
amine electrophile, and secondary phosphine ligand additive. We
have developed an efficient and optimized protocol for the hy-
droamination of a variety of olefins and alkynes that is insensitive to
air and uses a simple copper precatalyst that incorporates DTBM-
SEGPHOS, PPh3, and Cu(OAc)2. Further mechanistic work, in
particular stoichiometric studies and computational investigations
for the mechanism of the C–N bond formation step in this process,
is in progress.40 Lastly, new avenues for asymmetric olefin function-
alization through CuH catalysis are also under development.
a
CuCatMix = Cu(OAc)2, (S)-DTBM-SEGPHOS, PPh3 (1:1.1:1.1
ratio, precomplexed). reaction performed under argon atmosphere.
b
c
1H NMR yield.
As a final demonstration of the improvements made by the
new hydroamination protocol, Table 3 shows that high yields were
obtained when using just 0.1-0.2 mol% (S)-DTBM-SEGPHOS
ligand in the hydroamination of styrene and 4-phenyl-1-butene.
Reactions that employ low ligand loadings are more air-sensitive
and require setup in an inert atmosphere glove box with longer
reaction times (24 hours).
ASSOCIATED CONTENT
Supporting Information
Table 3. Hydroamination of styrene and 4-phenyl-1-butene
using low loadings of (S)-DTBM-SEGPHOS.
Experimental procedures and characterization data for all compounds.
The Supporting Information is available free of charge on the ACS
Publications website.
Conditions:
Bn2NOPiv (1.2 equiv), Cu(OAc)2 (2 mol%), PPh3 (2 mol%),
DMMS (2 equiv), THF, 60 °C, N2, 24 h
Entry (S)-DTBM-SEGPHOS
Substrate
Product
AUTHOR INFORMATION
NBn2
88% yield
92% ee
1
2
0.1 mol%
0.2 mol%
Corresponding Author
Ph
Ph
Me
sbuchwal@mit.edu
85% yield
NBn2
Ph
Ph
Author Contributions
‡These authors contributed equally to this work.
Conclusion
Notes
The authors declare no competing financial interests.
A modified and more detailed mechanistic picture is present-
ed in Scheme 9. Spectroscopic studies suggest a phosphine-ligated
CuH cluster 16 is formed when Cu(OAc)2 is treated with silane
and DTBM-SEGPHOS (L), although our current view is that the
active catalyst is of a monomeric nature. Linear free energy rela-
tionship studies indicate that hydrocupration to form aliphatic
copper(I) species 2 is the enantio-determining step in this catalytic
cycle, and deuterium-labeling studies show that this step is likely
irreversible. Interception of this species with amine electrophile 17
produces chiral amine 4 and phosphine-ligated copper(I) carbox-
ylate 18, which is the resting state of the catalyst, as shown through
ACKNOWLEDGMENT
Research reported in this publication was supported by the National
Institutes of Health (GM58160, GM112197 for J. S. B., GM113311 for
M. T. P.). The content is solely the responsibility of the authors and
does not necessarily represent the official views of the National Insti-
tutes of Health. We thank Dr. Yi-Ming Wang for his advice in the prep-
aration of this manuscript. We also thank Dr. Jeff Simpson and Dr. Eric
Standley for their help with NMR and ESI-MS studies, respectively.
31
REFERENCES
ESI-MS and P-NMR studies. The turnover-limiting step is regen-
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Journal of the American Chemical Society
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(a) Lawrence, S. A. Amines; Cambridge University Press:
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17
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40
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42
43
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(5) Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem. Int.
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(6) Zhu, S.; Niljianskul, N.; Buchwald, S. L. J. Am. Chem. Soc.
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Miura, M. J. Am. Chem. Soc. 2013, 135, 4934. (b) Sakae, R.;
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(9) Similar reaction profiles have been observed in other CuH-
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Lalic, G. J. Am. Chem. Soc. 2015, 137, 1424. (b) Van Hov-
eln, R.; Hudson, B. M.; Wedler, H. B.; Bates, D. M.; Le
Gros, G.; Tantillo D. J.; Schomaker, J. M. J. Am. Chem. Soc.
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(10) For perspectives on reaction progress kinetic analysis
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2005, 44, 4302. (b) Blackmond, D. G. J. Am. Chem. Soc.
2015, 137, 10852.
(11) Other CuH-catalyzed processes have observed fractional
order dependencies on the catalyst, see: Issenhuth, J.-T.;
Notter, F.-P.; Dagorne, S.; Dedieu, A.; Bellemin-Laponnaz,
S. Eur. J. Inorg. Chem. 2010, 529.
(22) We cannot discount that the active catalyst could be an ag-
gregate that forms from a single enantiomer of the ligand.
We thank a reviewer for the suggestion of this possibility.
(23) Linearity has been observed for several other CuH-catalyzed
processes: (a) Appella, D. H.; Moritani, Y.; Shintani, R.; Fer-
reira, E. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
9473. (b) Lipshutz, B. H.; Noson, K.; Chrisman, W.; Lower,
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cluster could break apart to form a monomeric species that
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Am. Chem. Soc. 1989, 111, 8818. (b) Chen, J.-X.; Daeuble, J.
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ric Synthesis II: More Methods and Applications; Christ-
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(26) For selected examples examining the LFER of electronic ef-
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Ishida, T.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 948.
For selected studies on the LFER of electronic effects of
substrate structure in enantioselective reactions: (c) Jensen,
(12) Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96.
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K. H.; Sigman, M. S. J. Org. Chem. 2010, 75, 7194. (d) Jen-
(33) Our lab has previously reported on the dangers of working
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7
8
sen, K. H.; Webb, J. D.; Sigman, M. S. J. Am. Chem. Soc.
2010, 132, 17471. (e) Denmark, S. E.; Bui, T. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5439. (f) Ahkani, R. K.; Moore,
M. I.; Pribyl, J. G.; Wiskur, S. L. J. Org. Chem. 2014, 79,
2384.
with trialkoxysilanes: (a) Berk, S. C.; Buchwald, S. L. J. Org.
Chem. 1992, 57, 3751. (b) Berk, S. C.; Buchwald, S. L. J.
Org. Chem. 1993, 58, 3221.
(34) A recent report noted that the activation barrier for CuH re-
generation in the hydrosilylation of ketones correlated with
the hydride character of the silane employed, which fol-
lowed a trend similar to what we found with testing various
silanes in the CuH-catalyzed hydroamination of styrene,
see: Vergote, T.; Nahra, F.; Merschaert, A.; Riant, O.;
Peeters, D.; Leyssens, T. Organometallics 2014, 33, 1953.
(35) O-acetyl-N,N-dibenzylhydroxylamine (13) undergoes slow
hydrolysis while stored at cryogenic temperatures.
(27) The para-OMe product was not included in the Hammett
plot for the minor enantiomer could not be accurately inte-
grated on the HPLC due to the broadness of the peak.
(28) A report has also indicated that the CuH-catalyzed hydrosi-
lylation of ketones has an enantioselectivity-determining
step that is distinct from the rate-determining step, see ref
11.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
34
35
36
37
38
39
40
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42
43
44
45
46
47
48
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53
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(36) (a) ref 23b. (b) ref 7a. (c) Ascic, E.; Buchwald, S. L. J. Am.
Chem. Soc. 2015, 137, 4666.
(37) For a related precomplex, see: Cirriez, V.; Rasson, C.; Her-
mant, T.; Petrignet, J.; A Álvarez, J. D.; Robeyns, K.; Riant,
O. Angew. Chem. Int. Ed. 2013, 52, 1785.
(29) For studies on the β-hydride elimination of phosphine-
ligated alkylcopper species, see: (a) Whitesides, G. M.;
Stedronsky, E. R.; Casey, C. P.; San Filippo Jr., J. J. Am.
Chem. Soc. 1970, 92, 1426. (b) Miyashita, A.; Yamamoto,
T.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1977, 50, 1109. For a
discussion of KIE studies in relation to β-hydride elimina-
tion, see ref 15.
(30) Previous observations are also consistent with irreversible
hydrocupration. Products derived from chain walking have
not been observed in CuH-catalyzed hydroamination pro-
cesses studied in our lab. In addition, isotope-labeling stud-
ies performed with vinyl silanes and deutero-diphenylsilane
(D2SiPh2) in a previous report indicated that hydrocupra-
tion is not reversible. See ref 7c for the isotope-labeling stud-
ies.
(38) Miyashita, A.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1977, 50,
1102.
(39) Copper-catalyzed hydrosilylation of ketones are known in
many cases to be insensitive toward oxygen. For selected
disclosures, see: (a) Sirol, S.; Courmarcel, J.; Mostefai, N.;
Riant, O. Org. Lett. 2001, 3, 4111. (b) Mostefaï, N.; Sirol, S.;
Riant, O. Synthesis, 2007, 1265. (c) Wu, J.; Ji, J.-X., Chan, A.
S. C. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 3570.
(40) Multiple mechanistic pathways are possible for C-N bond
formation. For a mechanistic study on a related Cu-
catalyzed amination process, see: Campbell, M. J.; Johnson,
J. S. Org. Lett. 2007, 9, 1521.
(31) For a related experiment, see: Noh, D.; Yoon, K.; Won, J.;
Lee, J. Y.; Yun. J. Chem. Asian J. 2011, 6, 1967.
(32) Since full reaction kinetic analysis revealed that the rate did
not change over the course of the reaction in the model sys-
tem, we assumed that initial rates would be a good approxi-
mation of the general trend observed when optimizing other
parameters in the reaction.
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■ fast reaction times
■ open to air
Bn2N–OPiv
+
NBn2
Me
CuCatMix
open to air
10 minutes
Ph
■ Cu(II) precatalyst
■ broad alkene scope
Ph
91% yield
95% ee
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