Application of Trimethylgermanyl-Substituted Bisphosphine Ligands with Enhanced Dispersion Interactions to Copper-Catalyzed Hydroboration of Disubstituted Alkenes

Article abstract of DOI:10.1021/jacs.0c08746

We report the incorporation of large substituents based on heavy main-group elements that are atypical in ligand architectures to enhance dispersion interactions and, thereby, enhance enantioselectivity. Specifically, we prepared the chiral biaryl bisphosphine ligand (TMG-SYNPHOS) containing 3,5-bis(trimethylgermanyl)phenyl groups on phosphorus and applied this ligand to the challenging problem of enantioselective hydrofunctionalization reactions of 1,1-disubtituted alkenes. Indeed, TMG-SYNPHOS forms a copper complex that catalyzes hydroboration of 1,1-disubtituted alkenes with high levels of enantioselectivity, even when the two substituents are both primary alkyl groups. In addition, copper catalysts bearing ligands possessing germanyl groups were much more active for hydroboration than one derived from DTBM-SEGPHOS, a ligand containing 3,5-di-tert-butyl groups and widely used for copper-catalyzed hydrofunctionalization. This observation led to the identification of DTMGM-SEGPHOS, a bisphosphine ligand bearing 3,5-bis(trimethylgermanyl)-4-methoxyphenyl groups as the substituents on the phosphorus, as a new ligand that forms a highly active catalyst for hydroboration of unactivated 1,2-disubstituted alkenes, a class of substrates that has not readily undergone copper-catalyzed hydroboration previously. Computational studies revealed that the enantioselectivity and catalytic efficiency of the germanyl-substituted ligands is higher than that of the silyl and tert-butyl-substituted analogues because of attractive dispersion interactions between the bulky trimethylgermanyl groups on the ancillary ligand and the alkene substrate and that Pauli repulsive interactions tended to decrease enantioselectivity.

Full text of DOI:10.1021/jacs.0c08746

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Article
Application of Trimethylgermanyl-Substituted Bisphosphine
Ligands with Enhanced Dispersion Interactions to Copper-
Catalyzed Hydrobo-ration of Disubstituted Alkenes
Yumeng Xi, Bo Su, Xiaotian Qi, Shayun Pedram, Peng Liu, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c08746 • Publication Date (Web): 22 Sep 2020
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Application of Trimethylgermanyl-Substituted Bisphosphine Ligands
with Enhanced Dispersion Interactions to Copper-Catalyzed Hydrobo-
ration of Disubstituted Alkenes
Yumeng Xi,a,b,†,‡ Bo Su,a,†,# Xiaotian Qi,c Shayun Pedram,a Peng Liu,*,c and John F. Hartwig*,a,b
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aDepartment of Chemistry, University of California, Berkeley, CA 94720, United States
bDivision of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, United States
cDepartment of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
‡Present Address: Materials Research Laboratory, University of California, Santa Barbara, CA 93106, United States
#Present Address: College of Pharmacy, Nankai University, Tianjin, 300071, China
†These authors contribute equally to this work
ABSTRACT: We report the incorporation of large substituents based on heavy main group elements that are atypical in ligand
architectures to enhance dispersion interactions and, thereby, enhance enantioselectivity. Specifically, we prepared the chiral biaryl
bisphosphine ligand (TMG-SYNPHOS) containing 3,5-bis(trimethylgermanyl)phenyl groups on phosphorus and applied this ligand
to the challenging problem of enantioselective hydrofunctionalization reactions of 1,1-disubtituted alkenes. Indeed, TMG-SYNPHOS
forms a copper complex that catalyzes hydroboration of 1,1-disubtituted alkenes with high levels of enantioselectivity, even when
the two substituents are both primary alkyl groups. In addition, copper catalysts bearing ligands possessing germanyl groups were
much more active for hydroboration than one derived from DTBM-SEGPHOS, a ligand containing 2,5-di-tert-butyl groups and
widely used for copper-catalyzed hydrofunctionalization. This observation led to the identification of DTMGM-SEGPHOS, a
bisphosphine ligand bearing 3,5-bis(trimethylgermanyl)-4-methoxyphenyl groups as the substituents on the phosphorus, as a new
ligand that forms a highly active catalyst for hydroboration of unactivated 1,2-disubstituted alkenes, a class of substrates that has not
readily undergone copper-catalyzed hydroboration previously. Computational studies revealed that the enantioselectivity and cata-
lytic efficiency of the germanyl-substituted ligands is higher than that of the silyl and tert-butyl substituted analogs because of attrac-
tive dispersion interactions between the bulky trimethylgermanyl groups on the ancillary ligand and the alkene substrate and that
Pauli repulsive interactions tended to decrease enantioselectivity.
are often invoked to rationalize selectivity, we conjectured that
1. INTRODUCTION
C-H–H-C dispersion interactions involving phosphine ligands
could be modulated to increase the enantioselectivity of certain
reactions that have occurred with moderate stereoselectivity
previously. More specificially, we wondered whether changing
the elements within substituents (e.g. tert-butyl groups) to heav-
ier main-group elements could be a modular approach to en-
hance the attractive dispersion interactions by tuning the dis-
tance of the C-H–H-C pairs, thereby leading to improved enan-
tioselectivities.
The enantioselectivity of reactions of prochiral substrates cata-
lyzed by transition-metal complexes typically requires the
metal-ligand system to distinguish between two substituents on
the substrate. This distinction is most commonly thought to re-
sult from coordination of a functional group on one substituent
to the metal, or by greater steric repulsion between one of the
substituents and the ligands, often depicted in “quadrant dia-
grams.”1 Thus, the differentiation between two substituents that
are similar in steric properties and lack a functional group, such
as two primary alkyl groups, can be particularly challenging to
achieve.
Heavy main-group elements have large covalent radii, thereby
forming longer covalent bonds than their light congeners. Due
to this feature, new reactivity of complexes containing these
heavy elements has been explored extensively,19 but their use as
simple substituents to modulate the reactivity or selectivity of a
catalyst has been limited. We envisioned that the attractive dis-
persion between the substrate and substituents containing such
elements, such as trimethylsilyl and trimethylgermanyl groups,
would be larger than those between the substrate and hydro-
carbyl substituents, such as tert-butyl groups, because the main-
group substituents are larger in volume. This change could ulti-
mately lead to a catalyst that is highly active and enantioselec-
tive for reactions of 1,1-disubstituted alkenes, such as hydrobo-
ration.
Some of the most effective phosphine ligands for enantioselec-
tive chemistry contain bulky tertiary alkyl groups in the 3,5-po-
sitions of phosphine-bound aryl groups.2-3 However, selectivi-
ties with such ligands for many reactions are low, even after
varying other reaction parameters. Recent reports4-5 from one of
our groups provided evidence that attractive dispersion interac-
tions,6-7 rather than repulsive steric interactions, between bulky
alkyl substituents on a ligand and the substrate can increase re-
action rates.8-15 However, ligands that can increase enantiose-
lectivity by enhanced attractive C-H–H-C dispersion intereac-
tions are lacking.16 Although attractive C-H–p interactions17-18
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DTBM-SEGPHOS, and combining the 3,5-trimethylgermanyl
1
2
3
4
5
6
7
8
groups with the 4-methoxy donor in the form of DTMGM-
SEGPHOS created a catalyst for the hydroboration of unacti-
vated internal alkenes that reacts in much higher yields than ca-
talysts formed from DTBM-SEGPHOS. Computational studies
strongly suggest that the higher enantioselectivity and catalytic
efficiency of the germanyl-substituted ligands than of the silyl
and tert-butyl substituted analogs result from attractive disper-
sion interactions, not repulsive steric interactions, between the
bulky trimethylgermanyl groups on the ancillary ligand and the
alkene .
Scheme 1. Development of trimethylgermanyl-substituted
ligands for copper-catalyzed hydroboration of 1,1-disubsti-
tuted alkenes
A Challenge in asymmetric catalysis - differentiation of alkyl groups
(re face)
H
[M]
RS
RL
[M]
RS
RS
stereocenter set
[M]
by
[M]-H
RL
RL
alkene insertion
(si face)
H
RL, RS: alkyl groups
9
B Asymmetric synthesis of boronates with β-stereocenters by ligand development
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RS
RS
X
2. RESULTS AND DISCUSSION
HBpin
[Cu]-H
Bpin
P
P
X
X
P
P
Ar
Ar
Cu
H
RL
RL
2.1 Design of new bisphosphine ligands for asymmetric hy-
droboration of 1,1-disubstituted alkenes. To develop a metal-
ligand system that catalyzes the hydroboration of 1,1-disubsti-
tuted alkenes bearing two primary alkyl groups with high levels
of enantioselectivity, we sought to modify the aryl substituents
on the phosphorus of DTBM-SEGPHOS. For many reactions
catalyzed by complexes with axially chiral biaryl bisphos-
phines, larger substituents on the P-aryl groups lead to higher
enantioselectivity. Previous studies on copper-catalyzed enan-
tioselective hydroboration have shown that the large substitu-
ents on the phosphorus-bound aryl rings increase enantioselec-
tivity31 and a rhodium complex containing the trimethylsilyl-
substituted ligand (S)-TMS-SEGPHOS catalyzed enantiose-
letive silylations of C-H bonds with higher selectivities than
that with related ligands containing tert-butyl groups.32-33 We
postulated that trimethylgermanyl group, which has a larger
volume than trimethylsilyl and tert-butyl groups because car-
bon-germanium bonds are longer than carbon-carbon and car-
bon-silicon bonds, would lead to a system that could catalyze
the hydroboration of 1,1-disubstituted alkenes with high enan-
tioselectivity.
RL
RS
X
attractive dispersive interaction?
C Structures of the new ligands reported in this study
Me3Ge
OMe
GeMe3
Me3Ge
O
O
GeMe3
2
2
O
O
P
P
O
O
P
P
(R)-TMG-SYNPHOS
(L13)
rac-DTMGM-SEGPHOS
(L15)
GeMe3
GeMe3
O
O
2
2
Me3Ge
OMe
Me3Ge
The utility of 3,5-disubstituted biaryl bisphosphines for enanti-
oselective hydroboration and the the unsolved problem of con-
ducting enantioselective reactions of 1,1-disubstituted alkenes
that must differentiate between two alkyl substituents (Scheme
1A, 1B) led us to assess this approach for developing ligands
for the asymmetric hydroborations of 1,1-disubtituted alkenes.
Such reactions are particularly valuable because they form en-
antioenriched products that can readily undergo reactions to af-
ford a series of functionalized molecules with b-sterogenic cen-
ters.
To test this hypothesis, we conducted density functional theory
(DFT) calculations on the transition states of hydrocupration of
2-methyl-1-pentene (1) with copper hydride complexes ligated
by a series of SEGPHOS-derived ligands containing different
3- and 5-substituents on the P-aryl groups (Scheme 2). The ole-
fin insertion was shown to be the enantioselectivity-determin-
ing step of the hydroboration in our previous report.31 The dif-
ference in computed activation free energies (ΔΔG‡) between
transition states leading to the major and minor enantiomeric
products increased as the size of the substituents at the 3- and
5-positions increased from tert-butyl to trimethylsilyl and tri-
methylgermanyl. In addition, the computed barrier of hydrocu-
pration (ΔG‡) decreases when a bulkier substituent was placed
on the ligand. This suggests that the greater enantioselectivity
of the reaction with the (S)-TMG-SEGPHOS ligand is a result
of stabilizing the transition state leading to the major enantio-
mer (TS-3A), rather than destabilizing the disfavored transition
state (TS-3B) by steric effects (see later for detailed computa-
tional analysis of the origin of the ligand effects).
Although hydroboration of 1,1-aryl,alkyl-disubstituted alkenes
has occurred with high levels of enantiocontrol (>95:5 er),20-22
the hydroboration of 1,1-alkyl,alkyl-disubstituted alkenes in
which the alkyl groups are similar in size has generally occurred
with low enantioselectivity.20-23 For example, Yun and co-work-
ers reported a copper system that catalyzed the hydroboration
of 1,1-disubstituted alkenes that contain one primary alkyl
group and one secondary alkyl group with high enantioselectiv-
ity,24 but the same reaction of 1,1-disubstituted alkenes that con-
tain two different primary alkyl groups occurred with only mod-
est enantioselectivity (below 85:15 er). In fact, examples of any
type of hydrofunctionalization of 1,1-disubstituted alkenes that
bear two different primary alkyl groups with high enantioselec-
tivity25 are rare.26-30
Herein, we report two new bisphosphine ligands (R)-TMG-
SYNPHOS (L13) and DTMGM-SEGPHOS (L15) that are ba-
sed on the principle of enhancing attractive interactions
(Scheme 1C). They bear trimethylgermanyl groups at the 3- and
5-positions of the phenyl groups on the phosphorus of the ligand,
and they generate more active and selective copper catalysts for
hydroboration, including enantioselective hydroboration of 1,1-
disubstituted alkenes that bear two different primary alkyl
groups over the most selective current catalysts, which are de-
rived from DTBM-SEGPHOS. These trimethylgermanyl-sub-
stituted catalysts are more active than those formed from
Scheme 2. DFT calculations of reactivity and enantioselec-
tivity of olefin hydrocupuration with copper hydride com-
plexes ligated by SEGPHOS-derived ligands. All energies
are in kcal/mol.
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Table 1. Evaluation of ligands for enantioselective hydrob-
*
*
P
P
oration of 1,1-disubstituted alkene 3aa
Me
P
P
H
H
Cu
*
Cu
P
P
+
+
Cu
H
Me
Me
nPr
Me
TS-1B - TS-3B
5 mol % CuMes
10 mol % KOtBu
6 mol % ligand
nPr
1
TS-1A - TS-3A
Me
Me
HBpin
Bpin
Bn
Bn
Me3Ge
cyclohexane, rt, 24 h
tBu
TMS
4a
3a
O
GeMe3
O
O
tBu
TMS
2
2
2
selected ligand structures
R2
O
O
P
P
O
O
O
O
R1
tBu
OMe
OMe
tBu
R2
R1
P
P
P
P
8
9
O
R2
R2
GeMe3
O
tBu
TMS
2
2
O
O
2
2
2
2
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MeO
MeO
P
P
O
O
P
P
MeO
MeO
P
P
Me3Ge
tBu
TMS
(S)-TMG-SEGPHOS (L3)
(S)-DTB-SEGPHOS (L1)
(S)-TMS-SEGPHOS (L2)
R2
tBu
R2
ΔG‡ (TS-1A) = 18.0
ΔG‡ (TS-1B) = 18.5
ΔG‡ (TS-2A) = 16.7
ΔG‡ (TS-2B) = 18.0
ΔG‡ (TS-3A) = 15.0
ΔG‡ (TS-3B) = 17.9
O
2
2
2
OMe
R2
R1
tBu
OMe
R2
R1
ΔΔG‡ = 0.5
ΔΔG‡ = 1.3
ΔΔG‡ = 2.9
(R)-L5: R1=OMe, R2=tBu
(R)-L6: R1=H, R2=tBu
(R)-L7: R1=H, R2=Me
(R)-L8: R1=H, R2=TMS
(R)-L11: R1=OMe, R2=tBu
(R)-L12: R1=H, R2=TMS
(R)-L13: R1=H, R2=GeMe3
(R)-L9
Synthesis of (R)-TMG-SYNPHOS and (R)-TMS-
SYNPHOS. The trend of enantioselectivity predicted by DFT
calculations prompted us to devise a synthetic route to prepare
ligands that contain 3,5-trimethylgermanyl groups. We chose to
prepare SYNPHOS derivatives first, instead of SEGPHOS de-
rivatives, because it is convenient to access enantioenriched
SYNPHOS ligands by laboratory resolution. Ligands that con-
tain 3,5-trimethylstannyl groups would have the potential to
create catalysts that are more active and enantioselective than
ligands that contain 3,5-trimethylgermanyl groups. However,
the high toxicity of organostannane compounds and potential
modification of the ligand by reactions at the C-Sn bonds led us
to pursue the synthesis of germanyl-substituted ligands instead
of stannyl-substituted ligands.
yieldb
er
entry
ligand
T
rt
(%)
1
(S)-DTBM-SEGPHOS (L4)
93 17:83
81 80:20
95 18:82
2
(R)-DTBM-MeOBIPHEP (L5) rt
3
(S)-DTB-MeOBIPHEP (L6)
(R)-DM-MeOBIPHEP (L7)
(R)-TMS-MeOBIPHEP (L8)
(R)-DTBM-garphos (L9)
rt
rt
rt
rt
rt
rt
rt
4
<5
-
5
83 86:14
81 78:22
91 79:21
93 85:15
87 88:12
6
7
(R)-DTBM-BINAP (L10)
(R)-DTBM-SYNPHOS (L11)
(R)-TMS-SYNPHOS (L12)
(R)-TMS-SYNPHOS (L12)
(R)-TMG-SYNPHOS (L13)
(S)-DTBM-SEGPHOS (L4)
8
9
Scheme 3. Synthesis of (R)-TMG-SYNPHOS (L13) and (R)-
TMS-SYNPHOS (L12)
10c
11c
12c
-15 °C 48 92:8
-15 °C 93 94:6
-15 °C <5
-
O
O
O
ArMgBr
THF, rt
HSiCl3, Bu3N
aReaction conditions: 3a (0.25 mmol, 2.5 equiv), HBpin (0.10
mmol, 1 equiv), CuMes (5 mol %), KOtBu (10 mol %) and ligand
(6 mol %) in cyclohexane (0.15 mL), rt, 24 h; bDetermined by GC
against dodecane as an internal standard; 3a (0.2 mmol), HBpin
(0.24 mmol, 1.2 equiv), CuMes (5 mol %), KOtBu (10 mol %) and
O
O
POAr2
POAr2
O
O
PAr2
PAr2
O
O
POCl2
POCl2
p-xylene
120 ºC
O
O
c
O
2
(R)-L13 oxide (61%)
(R)-L12 oxide (66%)
(R)-L13 (83%)
(R)-L12 (81%)
ligand (5 mol %) in decalin (0.14 mL), 72 h.
L13: Ar = 3,5-Me3Ge-C6H3
L12: Ar = 3,5-TMS-C6H3
Effects of the ligands on enantioselectivity. Initial studies to
evaluate the effect of a series of axially chiral biaryl bisphos-
phines on the enantioselectivity of the copper-catalyzed hy-
droboration are shown in Table 1. These reactions were con-
ducted with 2-methyl-1-phenylpropene (3a), which contains a
benzyl and a methyl group on the olefin. Yun reported that the
enantiomeric ratio of the reaction of 3a under conditions they
developed with (S)-DTBM-SEGPHOS as ligand was only
82:18.24 This prior result implies that the catalyst formed from
(S)-DTBM-SEGPHOS inadequately differentiates a benzyl
from a methyl group to achieve high enantioselectivity. We re-
peated this reaction with the conditions of 5 mol % mesity-
lcopper, 10 mol % potassium tert-butoxide, and 5.5 mol % (S)-
DTBM-SEGPHOS and obtained the hydroboration product
with 83:17 er (entry 1).37
As depicted in Scheme 3, (R)-TMG-SYNPHOS was prepared
in just two steps starting from known intermediates.34-35 The
Grignard reaction between (R)-(2,2',3,3'-tetrahydro-[5,5'-
bibenzo[b][1,4]dioxine]-6,6'-diyl)bisphosphonic dichloride (2),
which was synthesized in three steps,34 and the corresponding
aryl magnesium bromide, which was generated from 3,5-bis(tri-
methylgermanyl)phenyl bromide36 afforded (R)-TMG-
SYNPHOS oxide in 61% yield. (R)-TMS-SYNPHOS oxide
was prepared in 66% yield by an analogous route. Reduction of
the phosphine oxide in the presence of trichlorosilane and tribu-
tylamine afforded the corresponding phosphines in 81-83%
yield. The overall yields from the two-step syntheses were close
to 50%. Based on this procedure, a total of one gram of each
ligand was prepared.
The effect of the ligand backbone on enantioselectivity is shown
by entries 1, 2, and 6-8. These reactions were conducted with
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10 mol % CuMes
10 mol % KOtBu
5 mol % (R)-TMG-SYNPHOS
several classes of ligands containing the same 3,5-di-tert-butyl-
R'
R'
1
2
3
4
5
6
7
8
4-methoxyphenyl (DTBM) groups. The ligand (L11) that con-
tains a 2,2',3,3'-tetrahydro-[5,5'-bibenzo[b][1,4]dioxine back-
bone (SYNPHOS) led to the highest enantioselectivity among
a SEGPHOS ligand, a BIPHEP ligand, a SYNPHOS ligand, a
garphos ligand, and a BINAP ligand.
Bpin
+
H-Bpin
R
R
decalin, -15 °C
3
4
OMe
Bpin
Me
Me
Bpin
Bpin
Bn
Bn
Bn
Having found that the backbone of SYNPHOS ligands leads to
the highest enantioselectivity, we examined reactions catalyzed
by copper complexes of (R)-TMS-SYNPHOS (L12) in more
detail. The enantioselectivity of the reaction conducted at room
temperature with (R)-TMS-SYNPHOS (88:12 er, entry 9) was
higher than that with (R)-DTBM-SYNPHOS (85:15 er). Reduc-
ing the reaction temperature from room temperature to -15 °C
increased the enantioselectivity of the reaction with (R)-TMS-
SYNPHOS further to 92:8 er (entry 10). The reaction conducted
with (R)-TMG-SYNPHOS (L13) that contains 3,5-bis(trime-
thylgermanyl)phenyl groups proceeded with a higher enantiose-
lectivity than that conducted with TMS-SYNPHOS and was a
high 94:6 er at -15 °C (entry 11). This new ligand, (R)-TMG-
SYNPHOS, formed a catalyst that was particularly active for
the reactions of 1,1-disubstituted alkenes, in addition to one that
reacts with high enantioselectivity. For comparison, the catalyst
formed from (S)-DTBM-SEGPHOS was inactive for hydrobo-
ration of alkene 3a at -15 °C (entry 12) whereas the catalyst
formed from (R)-TMG-SYNPHOS gave the hydroboration
product in high yield, as well as high er, at this temperature. A
few factors were essential to achieve the high enantioselectiv-
ity. First, the catalyst formed from (R)-TMG-SYNPHOS that
contains large 3,5-bis(trimethylgermanyl)phenyl substituents
most effectively differentiates the two prochiral faces of 3a
among the complexes formed from all the ligands examined.
Second, the large 3,5-bis(trimethylgermanyl)phenyl sub stitu-
ents on the ligand caused the catalyst to be highly active, and
this activity allowed the reaction to be conducted at low tem-
peratures.
4a
4b
4c
80% yield, 94:6 er
58% yield, 95:5 er
50% yield, 92:8 er
OTBS
OMOM
F
9
Bpin
Bn
Bpin
Bn
Bpin
Bn
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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34
35
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37
38
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45
46
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60
4d
4e
4f
78% yield, 87:13 er
71% yield, 93:7 er
72% yield, 97:3 er
CF3
O
MeO
N
N
Me
Me
Me
Bpin
F3C
Bpin
N
Bpin
4g
4h
4i
66% yield, 92:8 er
81% yield, 91:9 er
93% yield, 93:7 er
Me
Me
Me
Bpin
S
Me
Bpin
N
Bpin
4j
4k
4l
85% yield, 90:10 er
87% yield, 86:14 er
81% yield, 88:12 er
Me Me
Me
Me
Bpin
Me
Bpin
Ph
TrO
Bpin
4mb,c
70% yield, 86:14 er
4ob
90% yield, 91:9 er
4n
83% yield, 86:14 er
Me
Ph
N
Bpin
Me
4p
52% yield, 90:10 er
Scope of the asymmetric hydroboration of 1,1-disubstituted
alkenes. Having established conditions for the asymmetric hy-
droboration, we examined the scope of the asymmetric hydrob-
oration of 1,1-disubstituted alkenes that contain two different
primary alkyl groups (Table 2). First, the reactions proceeded
with consistently high enantioselectivity with 1,1-alkenes that
contain a benzyl group and a primary alkyl group, such as a
methyl group (3a), an ethyl group (3b), a methoxymethyl group
(3c), a 2-methoxyethoxymethyl group (3d), a silyloxymethyl
group (3e), and a fluoromethyl group (3f). Enantioselectivity
equal to or higher than 95:5 er was obtained for the reactions of
3b and 3f. Second, the reactions of 1,1-alkenes that contain a
methyl group and an aryl- or heteroarylmethyl group proceeded
with high enantioselectivity when the aryl group was either
electron-rich or electron-poor or was a heteroaryl ring, such as
pyrimidine (3i), indole (3j), or benzothiophene (3k). The reac-
tions of alkenes containing 6,5-fused electron-rich heterocycles
were less enantioselective than those containing electron-poor
heterocycles.
aReaction conditions: 3 (0.2 mmol), HBpin (0.24 mmol, 1.2 equiv),
CuMes (10 mol %), KOtBu (10 mol %) and L13 (5 mol %) in de-
calin, 72 h, -15 °C; yields refer to those of the isolated prod-
ucts;breactions conducted at -5 °C;c3 equivalent of alkene instead
of 1 equiv used.
Reactions of alkenes containing a methyl group and a primary
alkyl group that is not benzyl also were investigated. In general,
the enantioselectivities of these reactions were lower (<90:10
er) than those of the reactions of alkenes 3a, 3g, and 3h just
discussed that contain arylmethyl groups, but the enantioselec-
tivities were still substantial. Alkenes containing an sp3-hybrid-
ized carbon containing a substituent at the position b to the al-
kene (3m) were less reactive towards the hydroboration than
those lacking a group at this position (3l) or those containing an
sp2-hybridized carbon b to the alkene (3a). This lower reactivity
is likely due to weaker binding of an alkene that contains sub-
stituents at this position. Thus, the reaction was conducted at -5
°C instead of -15 °C to obtain the corresponding product in a
reasonable yield. Finally, the reaction of alkenes containing a
trityl ether moiety (3o) and a tertiary amine moiety (3p) pro-
ceeded with good enantioselectivity.
Table 2. Scope of enantioselective hydroboration of 1,1-di-
substituted alkenes
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A) Distortion-interaction analysis
Although the majority of the hydroborations proceeded in good
to high yields, the reactions of a few alkenes (3b, 3c, 3p) oc-
1
2
3
4
5
curred in lower yields at 72 h due to slower reaction rates than
those with the majority of the reactions. The absence of side
products in these cases implies that the yields would likely be
higher at higher loadings of catlayst.
2.2 Computational analysis of the origin of the high enanti-
oselectivity with TMG-substituted bisphosphine ligands.
The ascending trend of the calculated DDG‡ values in hydrocu-
pration with DTB-, TMS-, and TMG-SEGPHOS ligands
(Scheme 2) is consistent with the experimentally observed en-
antioselectivity shown in Table 1, in which the highest enanti-
oselectivity was obtained with TMG-SYNPHOS as the ligand.
To reveal the origin of the improved enantioselectivity with lig-
ands containing trimethylgermanyl groups, we conducted cal-
culations by energy decomposition analysis (EDA) to analyze
the different types of ligand-substrate interactions in the transi-
tion states for hydrocupration.
6
7
8
9
10
11
12
13
14
15
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45
46
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48
49
50
51
52
53
54
55
56
57
58
59
60
B) Energy-decomposition analysis of ΔEint-space
Following the approach used in our previous computational
studies,4-5, 15, 38 we dissected the computed activation energies
(DE‡) into three terms:
DE‡ = DEdist + DEint-bond + DEint-space
(1)
DEdist is the total energy required to distort the LCuH fragment
and the alkene fragment from the ground state into their transi-
tion state geometries. DEint-space is the through-space interaction
energy calculated from a supramolecular complex of the
bisphosphine ligand and the alkene at the transition state geom-
etry in the absence of the CuH moiety. DEint-bond is the through-
bond interaction energy between the CuH moiety and the alkene.
This procedure allows the through-space interaction energy
(DEint-space) between the ligand and the substrate to be dissected
further using the second-generatioin ALMO-EDA39-41 method
implemented in Q-Chem 5.2:42
Figure 1. Distortion-interaction analysis and energy decomposi-
tion analysis (EDA) to reveal factors that determine the enantiose-
lectivity of olefin hydrocupration. All energies are in kcal/mol.
The EDA calculations (Figure 1B) indicated that the differences
between the through-space interaction energies are mainly af-
fected by the attractive London dispersion (DDEdisp) and Pauli
repulsion terms (DDEPauli). The influences of electrostatics
(DDEelstat) and orbital interactions (DDEorb) on the enantioselec-
tivity are small.
DEint-space = DEPauli + DEelstat + DEorb + DEdisp (2)
In this equation, DEPauli, DEelstat, DEorb and DEdisp are the energies
of Pauli repulsions, electrostatic interactions, orbital interac-
tions (i.e. polarization and charge transfer), and London disper-
sion interactions, respectively.
The values for the individual energy terms were computed for
all of the six hydrocupration transition states (TS-1A–TS-3A
and TS-1B–TS-3B, Scheme 2) and are provided in Table S1.
To identify factors that control the enantioselectivity, we ana-
lyzed the difference in each energy term (DDE) between pairs
of transition states leading to the major (TS-A) and minor en-
antiomeric products (TS-B) (Figure 1).
The EDA analysis showed that dispersion is the major interac-
tion that causes the overall DDE‡ values to be positive, resulting
in a higher enantioselectivity from reactions with the TMG-
containing ligands than with the DTB-containing ligands. Spe-
cifically, the germanyl-groups, which are larger in volume than
tert-butyl groups, in TMG-SEGPHOS lead to DDEdisp values
(7.3 kcal/mol) that are more than twice the DDEdisp value (2.7
kcal/mol) corresponding to the transition state with the DTB-
SEGPHOS ligand.
The distortion-interaction analysis (Figure 1A) suggests that the
impacts of through-bond interaction (DDEint-bond) on the enanti-
oselectivity are negligible and the through-space interactions
(DDEint-space) are the dominant factors that affect the enantiose-
lectivity. In particular, the through-space interactions between
the TMS- and TMG-SEGPHOS ligand and the alkene in TS2A
and TS3A are significantly more favorable than those in TS2B
and TS3B (DDEint-space = 4.7, 4.5 kcal/mol, respectively), while
the through-space ligand-substrate interactions of transition
state TS1A are comparable to those of transition state TS1B
(DDEint-space = 1.5 kcal/mol).
In contrast, the DDEPauli terms are negative, indicating that tran-
sition states leading to the major enantiomer of the product
(TS1A–TS3A) have greater steric repulsions between the lig-
and and the substrate than those leading to the minor enantiomer
(TS1B–TS3B). This influence of the steric effect contrasts the
typical presumption that the sterically encumbered ligands im-
prove the enantioselectivity of transition metal-catalyzed asym-
metric reactions due to increased steric interactions between the
ligand and the substrate. Instead, here, the dominant factor con-
trolling the enantioselectivity is the London dispersion interac-
tions between the ligand and the alkene substrate (DDEdisp). The
attractive dispersion forces in TS1A–TS3A completely com-
pensate the disfavored steric repulsions and cause the overall
5
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through-space ligand-substrate interactions to be more favora-
Page 6 of 11
1
ble and the energy of the transition state to be lower for TS1A–
2
TS3A than for TS1B–TS3B.
3
4
5
6
7
8
9
To obtain further insights into this unusual dispersion-con-
trolled enantioselectivity, we plotted the quadrant diagrams of
the transition states for hydrocupration (Figure 2). Conforma-
tional analysis of the alkene in the transition states for hydrocu-
pration revealed that the n-propyl substituent on the alkene
adopts two different conformations in transition states leading
to the different enantiomers. Because the 1,1-disubstituted al-
kene favors the eclipsed conformation to minimize allylic-1,2-
interactions,43-44 the n-Pr group can be oriented toward or away
from the LCuH catalyst. In the most stable conformers of the
transition states leading to the major enantiomer (TS-1A and
TS-3A), the n-Pr group points towards the LCuH catalyst. Be-
cause the n-Pr group in these transition states is in a less occu-
pied quadrant, this conformation allows the alkyl chain to be
closer to the ligand and, thus, to have stronger dispersion inter-
actions. On the other hand, the n-Pr group in the disfavored tran-
sition states (TS-1B and TS-3B) is in the more occupied quad-
rant and adopts a different conformation in which it points away
from the ligand. Although this conformation leads to a slight
decrease in ligand-substrate Pauli repulsions, the dispersion in-
teractions are significantly decreased due to the conformational
change in TS-1B and TS-3B. Thus, the transition states leading
to the major enantiomer (TS-1A and TS-3A) are more stable
than those leading to the minor enantiomer (TS-1B and TS-3B)
because the conformation of the substrate in TS-1A and TS-3A
allows more favorable dispersion interactions with the bisphos-
phine ligand than it does in TS-1B and TS-3B.
10
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14
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54
55
56
57
58
59
60
This dispersion effect is sensitive to the size of the 3,5-substit-
uents on the P-aryl groups of the ligand. The dispersion inter-
action between the substrate and TMG-SEGPHOS in TS-3A
(∆Edisp = −26.9 kcal/mol) is 2.7 kcal/mol stronger than that with
the DTB-SEGPHOS ligand in TS-1A (∆Edisp = −24.2 kcal/mol).
The computed pairwise dispersion interaction energies between
each of the t-Bu/TMG substituents and the alkene substrate re-
vealed stabilizing interactions with multiple TMG substituents
in TS-3A that are all slightly stronger than the corresponding
dispersion interactions with t-Bu groups in TS-1A. In contrast,
in the transition states leading to the minor enantiomer, TS-3B
with the TMG-SEGPHOS ligand has a smaller dispersion en-
ergy than TS-1B with DTB-SEGPHOS (∆Edisp = −19.6 and
−21.5 kcal/mol respectively). This is in part due to the confor-
mation of the alkene, which points the n-Pr group away from
the ligand. In addition, the bulky TMG substituents decrease the
conformational flexibility of the P-aryl groups and lead to a
longer CH–π distance between the n-Pr and P-aryl group (3.43
Å) in TS-3B than that in TS-1B (2.71 Å).
Figure 2. Optimized structures of alkene hydrocupration transition
states. The pairwise dispersion interactions between alkene and the
highlighted t-Bu or TMG substituents of ligands in TS-1A and TS-
3A are shown in kcal/mol. The CH–π distances in TS-1B and TS-
3B are given in orange.
Overall, the EDA calculations show that ligand-substrate dis-
persion interactions constitute the dominant factor that controls
the enantioselectivity. Bulkier substituents at the 3,5-positions
of the P-aryl groups of the ligand enhance the ligand-substrate
dispersion interaction (DEdisp) in the favored transition state
(e.g. TS-3A) and weaken the dispersion in the disfavored tran-
sition state (e.g. TS-3B). In addition, the computational results
corroborate our experimental finding that ligands containing
larger 3,5-substituents led to a higher catalytic activity than
those containing smaller substituents. The EDA calculations in-
dicate that the reactivity enhancement is also due to the greater
stabilizing dispersion interactions in the transition states ligated
with TMG-SEGPHOS (see Supporting Information for more
detailed discussions on factors controlling reactivity). These
analyses highlight the importance of understanding non-cova-
lent ligand-substrate interactions to enhance reactivity and se-
lectivity of transition metal-catalyzed reactions and show how
the use of main group elements in the design of ligands can en-
hance these intereactions.
2.3 Development of hydroboration of unactivated 1,2-disub-
stituted alkenes. Having observed a significant increase in the
activity and selectivity of the copper catalyst for the hydrobora-
tion of 1,1-disubstituted alkenes, we tested whether ligands that
contain trimethylgermanyl groups would also enhance the rate
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of the hydroboration of alkenes that have generally undergone The synthetic route to DTMSM-SEGPHOS and DTMGM-
1
2
3
4
5
6
7
8
SEGPHOS is depicted in Scheme 4. Analogous to the synthesis
shown in Scheme 3, these two ligands were assembled by the
reaction between the bisphosphonic dichloride (11) and the Gri-
gnard reagent derived from the corresponding aryl bromide.
However, the corresponding aryl bromides for the 3,5-substi-
tuted 4-methoxyaryl ligands could not be synthesized by se-
quential lithium-halogen exchange reactions of 2,4,6-tribro-
moanisole, which was used for the synthesis of 3,5-bis(trime-
thylgermanyl)phenyl bromide and 3,5-bis(trimethylsilyl)phe-
nyl bromide,35 because the exchange reaction on the tribro-
moanisole was not sufficiently selective for the positions ortho
to the methoxy group.
metal-catalyzed hydroboration with low rates.
Many catalysts promote the hydroboration of nonconjugated in-
ternal alkenes, but catalysts that directly add B-H bonds across
such alkene double bonds without chain-walking isomeriza-
tion45-53 are rare.54-55 The rarity of such catalysts is due to faster
b-hydrogen elimination from the secondary alkylmetal species
formed by insertion of the internal alkene than from the corre-
sponding primary alkylmetal species.56
Previously, we showed that the reactions of internal alkenes
bearing electron-withdrawing groups b to the alkene moiety oc-
curred in high yield and without the formation of side products
resulting from chain-walking processes. However, the reactions
of unactivated 1,2-disubstituted alkenes required a large excess
of alkenes and proceeded in lower yields than did reactions of
nonconjugated 1,2-disubstituted alkenes that are electronically
activated.55 Our previous mechanistic study showed that the re-
actions of 1,2-disubstituted alkenes is inverse-order in [HBpin]
and positive-order in [alkene] and that the olefin insertion is the
rate-limiting step.31 Thus, if a ligand that increases the rate of
alkene insertion could be identified, then the reaction of unacti-
vated 1,2-disubstituted alkenes might proceed in high yields
and the need for excess of such alkenes could be eliminated.
9
10
11
12
13
14
15
16
17
18
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22
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Instead, 3,5-bis(trimethylsilyl)-4-methoxyphenyl bromide (5)
was prepared by a sequence consisting of C-H borylation and
bromination, which was developed by our group.57 Starting
with 2,6-bis(trimethylsilyl)anisole (6), the iridium-catalyzed C-
H borylation occurred with complete para-selectivity to afford
2,6-bis(trimethylsilyl)-4-(pinacolato)boryl anisole (7), which
was used as a crude material in the subsequent copper-mediated
bromination to afford the aryl bromide in 40% overall yield.
However, when we used the same procedure for the synthesis
of 3,5-bis(trimethylgermanyl)-4-methoxyphenyl bromide, we
observed the formation of degermanylation products that were
inseparable from the desired bromination product. Therefore,
we prepared 3,5-bis(trimethylgermanyl)-4-methoxyphenyl
chloride (9) from 2,6-dibromo-4-chlorophenol (8). Methylation
of 8 proceeded in quantitative yield to afford 2,6-dibromo-4-
chloroanisole (9). The carbon-bromine bonds in 9 were con-
verted to C-GeMe3 bonds by a sequence of lithium-halogen ex-
change reactions and germanylation, while the carbon-chlorine
bond remained intact. Overall, chloride 10 was obtained in 90%
yield over two steps from 2,6-dibromo-4-chlorophenol (8).
Scheme 4. Synthesis of DTMSM-SEGPHOS (L14) and
DTMGM-SEGPHOS (L15)
OMe
OMe
[Ir(COD)OMe]
2 TMS
dtbpy, B2pin2
OMe
TMS
TMS
TMS
CuBr2
TMS
TMS
MeOH/H2O
80 ºC
THF, 80 ºC
Bpin
6 (not isolated)
Br
7 (40% yield
over two steps)
5
With bromide 7 and chloride 10 prepared in multigram scale,
DTMSM-SEGPHOS and DTMGM-SEGPHOS were synthe-
sized in two steps in 35-42% yield, respectively. The racemic
forms of these ligands were used to evaluate the effect of sub-
stituents on reaction rate and conversion. We did not attempt to
resolve the enantiomers of these ligands to access the enanti-
oenriched samples.
OH
OMe
OMe
1. nBuLi, -78 ºC;
Me3GeCl, rt
Br
Br
Br
Br
Me3Ge
GeMe3
NaH, MeI
0 ºC to rt
99%
2. nBuLi, -78 ºC;
Me3GeCl, rt
Cl
8
Cl
9
Cl
10 (90%)
O
O
O
Effects of the ligands on catalyst activity. To determine the
effect of the TMS and TMG substituents on the reactivity of the
copper catalyst for hydroboration of internal alkenes, we con-
ducted the hydroboration reactions of trans-4-octene with the
catalysts formed from the ligand used in previous studies,55
DTBM-SEGPHOS (L4), and the two ligands introduced in this
work, DTMSM-SEGPHOS (L14), and DTMGM-SEGPHOS
(L15). These data are summarized in Table 3. The reactions
were conducted with Cu(tBuCN)2OTf, a copper salt reported by
our group,58 as the copper source. The catalyst formed from
Cu(tBuCN)2OTf was more active than that formed from CuCl,
which was used previously.55, 59 This change allowed the reac-
tion to be evaluated with only 1.2 equivalents of alkene, instead
of the 3 equivalents of alkene used in earlier studies.
ArMgX
O
O
O
O
O
HSiCl3, Bu3N
POAr2
POAr2
PAr2
POCl2
POCl2
PAr2
O
p-xylene
120 ºC
THF, rt
(±)
O
O
O
L14 (42% over two steps)
L15 (35% over two steps)
11
L14 oxide
L15 oxide
L14: Ar = 3,5-TMS-4-OMe-C6H2
L15: Ar = 3,5-TMG-4-OMe-C6H2
Synthesis of DTMSM-SEGPHOS and DTMGM-
SEGPHOS. To test the effect of silyl and germanyl substituents
on the rate of reactions of 1,2-disubstituted alkenes, we pre-
pared two new ligands, DTMSM-SEGPHOS (L14) and
DTMGM-SEGPHOS (L15), which contain 3,5-bis(trimethylsi-
lyl)-4-methoxyphenyl groups and 3,5-bis(trimethylgermanyl)-
4-methoxyphenyl groups, respectively. Previously in this paper
we showed that the catalysts formed from ligands that contain
trimethylgermanyl groups at the 3- and 5-positions of the phe-
nyl group on the phosphorus are more active for copper-cata-
lyzed hydroboration than those formed from ligands that have
trimethylsilyl or tert-butyl groups at the 3- and 5-positions.
Table 3. Evaluation of ligands for hydroboration of unacti-
vated internal alkene 12a
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5 mol % Cu(tBuCN)2OTf
10 mol % KOtBu
ASSOCIATED CONTENT
Supporting Information
Me
1
2
6 mol % ligand
Me
Me
HBpin
+
Me
Bpin
13
cyclohexane, rt, 24 h
12 (1.2 equiv)
The Supporting Information is available free of charge on the ACS
Publications website.
3
4
5
6
7
8
9
Me3Ge
OMe
tBu
OMe
TMS
OMe
TMS
O
GeMe3
Experimental procedures, characterization data, Cartesian coordi-
nates for all computed structures (PDF)
O
O
tBu
tBu
2
2
2
2
O
O
P
P
O
O
O
O
P
P
P
P
AUTHOR INFORMATION
Corresponding Author
GeMe3
O
TMS
OMe
O
O
2
2
Me3Ge
OMe
tBu
OMe
TMS
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
*jhartwig@berkeley.edu
*pengliu@pitt.edu
rac-DTMGM-SEGPHOS
(S)-DTBM-SEGPHOS
(L4)
rac-DTMSM-SEGPHOS
(L15)
(L14)
26% yield (1 h)
88% yield (12 h)
88% yield (24 h)
13% yield (1 h)
32% yield (12 h)
33% yield (24 h)
22% yield (1 h)
80% yield (12 h)
80% yield (24 h)
ACKNOWLEDGMENT
This work was supported by the Director, Office of Science, of the
U.S. Department of Energy under contract No. DE-AC02-
05CH11231. P.L. and X.Q. thank the University of Pittsburgh and
the NIH (R35GM128779) for financial support of the computa-
tional work. DFT calculations were conducted in the Molecular
Graphics and Computation Facility at UC Berkeley (NSF CHE-
0840505) and the Center for Research Computing at the University
of Pittsburgh, and the Extreme Science and Engineering Discovery
Environment (XSEDE), and the TACC Frontera Supercomputer.
We thank Takasago for gifts of (S)-DTBM-SEGPHOS. Y.X.
thanks Bristol-Myers Squibb for a graduate fellowship.
aReaction conditions: 12 (0.24 mmol, 1.2 equiv), HBpin (0.2 mmol,
1 equiv), Cu(tBuCN)2OTf (5 mol %), KOtBu (10 mol %), and lig-
and (6 mol %) in cyclohexane, rt, 24 h.
We found that reactions conducted with catalysts derived
from DTMSM-SEGPHOS, and DTMGM-SEGPHOS reacted
faster and in higher yield (>80% yield) than did that with
DTBM-SEGPHOS (33% yield). The reactions with the catalyst
containing DTBM-SEGPHOS as ligand stopped after 12 hours,
presumably due to catalyst decomposition. These results sug-
gest that the catalysts ligated by DTMSM-SEGPHOS, and
DTMGM-SEGPHOS are more reactive towards insertion of un-
activated internal alkenes than that ligated by DTBM-
SEGPHOS.
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3. CONCLUSION
In conclusion, we have developed two new ligands that contain
trimethylgermanyl groups at the 3- and 5-positions of the phos-
phine-bound aryl ring and applied these ligands to the copper-
catalyzed hydroboration of alkenes. The enantioselectivity of
the reactions of 1,1-disubstituted alkenes that contain two pri-
mary alkyl groups catalyzed by the copper complex derived
from (R)-TMG-SYNPHOS is significantly higher than that of
these reactions with prior catalysts. This higher enantioselecti-
vity results from improved differentiation of the two primary
alkyl groups on the alkene by the catalyst ligated by bisphos-
phines that contain bulky groups at the 3- and 5-positions of the
phenyl ring at phosphorus. The modification of existing ligands
containing these bulky germanium-containing groups also sub-
stantially enhances the activity of the copper catalyst toward
hydroboration. The catalyst ligated by DTMGM-SEGPHOS is
particularly active toward the hydroboration of unactivated in-
ternal alkenes. The high activity of the catalyst allowed the reac-
tion to be conducted with 1.2 equivalents of alkene, which is
sufficiently lower than the 3 equivalents required by previous
methods. DFT calculations revealed that the improved enantio-
selectivity of the reaction and higher catalytic activity of the co-
pper catalysts derived from these trimethylgermanyl-containing
ligands resulted from attractive dispersion interactions between
the bulky germanium-containing groups and the substrate. We
anticipate that the unique properties and the facile synthesis of
these two ligands containing trimethylgermanyl groups would
lead to applications in other transition-metal-catalyzed reac-
tions.
Chemoselectivity
in
Reactions
with
Pd[P(iPr)(tBu2)]2.
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Insert Table of Contents artwork here
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5
P
[Cu] H (re face)
P
RS
RS
RS
L*Cu-H
HBpin
Bpin
RL
RL
RL
(si face)
high enantioselectivity
RL, RS: primary alkyl groups
6
7
8
X
2
9
tBu TMS GeMe3
X
X
P
P
P
P
Cu
H
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RL
RS
increased volume
increased dispersion
increased enantioselectivity
X
2
attractive dispersive interaction
(revealed by DFT calculation)
new bisphosphine ligand
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