NHC Ligands Tailored for Simultaneous Regio- and Enantiocontrol in Nickel-Catalyzed Reductive Couplings

Article abstract of DOI:10.1021/jacs.7b04583

An exceptionally hindered class of enantiopure NHC ligands has been developed. While racemic forms had previously been utilized, a scalable and practical route to the enantiopure form of this ligand class is described utilizing a Buchwald-Hartwig N,N-diarylation in a highly sterically demanding environment. Using this newly accessible ligand class, nickel-catalyzed enantioselective reductive coupling reactions of aldehydes and alkynes have been developed. These studies illustrate that the newly available NHC ligands are well suited for simultaneous control of regio- and enantioselectivity, even in cases with internal alkynes possessing only very subtle steric differences between two aliphatic substituents. The steric demand of the new ligand class enables a complementary regiochemical outcome compared with previously described enantioselective processes. Using this method, a number of allylic alcohol derivatives were efficiently obtained with high regioselectivity (up to >95:5) and high enantioselectivity (up to 94% ee). The reaction conditions can also be extended to the reaction of aldehydes and allenes, providing silyl-protected allylic alcohol derivatives possessing a terminal methylene substituent. Computational studies have explained the origin of the exceptional steric demand of this ligand class, the basis for enantioselectivity, and the cooperative relationship of the aldehyde, alkyne, and ligand in influencing enantioselectivity.

Full text of DOI:10.1021/jacs.7b04583

Subscriber access provided by The University of Liverpool
Article
NHC Ligands Tailored for Simultaneous Regio- and
Enantiocontrol in Nickel-Catalyzed Reductive Couplings
Hengbin Wang, Gang Lu, Grant J. Sormunen, Hasnain A. Malik, Peng Liu, and John Montgomery
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 16 Jun 2017
Downloaded from http://pubs.acs.org on June 16, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 10
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
NHC Ligands Tailored for Simultaneous Regio- and Enantiocontrol
in Nickel-Catalyzed Reductive Couplings
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
Hengbin Wang,1 Gang Lu,2 Grant J. Sormunen,1 Hasnain A. Malik,1† Peng Liu2* and John Montgomꢀ
ery1*
1Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109ꢀ1055, Unitꢀ
ed States
2Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
KEYWORDS regioselective, enantioselective, N-heterocyclic carbene, allylic alcohol, computation
ABSTRACT: An exceptionally hindered class of enantiopure NHC ligands has been developed. While racemic forms had previꢀ
ously been utilized, a scalable and practical route to the enantiopure form of this ligand class is described utilizing a Buchwaldꢀ
Hartwig N,N-diarylation in a highly sterically demanding environment. Using this newly accessible ligand class, nickelꢀcatalyzed
enantioselective reductive coupling reactions of aldehydes and alkynes have been developed. These studies illustrate that the newly
available NHC ligands are well suited for simultaneous control of regioꢀ and enantioselectivity, even in cases with internal alkynes
possessing only very subtle steric differences between two aliphatic substituents. The steric demand of the new ligand class enables
a complementary regiochemical outcome compared with previously described enantioselective processes. Using this method, a
number of allylic alcohol derivatives were efficiently obtained with high regioselectivity (up to >95:5) and high enantioselectivity
(up to 94% ee). The reaction conditions can also be extended to the reaction of aldehydes and allenes, providing silylꢀprotected
allylic alcohol derivatives possessing a terminal methylene substituent. Computational studies have explained the origin of the exꢀ
ceptional steric demand of this ligand class, the basis for enantioselectivity, and the cooperative relationship of the aldehyde, alꢀ
kyne, and ligand in influencing enantioselectivity.
In these cases, access to only one of the two possible regioiꢀ
somers is typically possible, and more commonly, mixtures
Introduction
Tremendous strides have been made in the development of
regioselective and enantioselective CꢀC bondꢀforming proꢀ
cesses. However, the optimization of ligand structures beꢀ
comes complex when high levels of both enantioselectivity
and regioselectivity are desired with a substrate class that does
not possess electronic or steric biases or directing groups that
effectively control regiochemistry. Ligand changes that enable
high degrees of regioselectivity for a challenging substrate
class often compromise the ability to simultaneously tune enꢀ
antioselectivity. Similarly, the most broadly useful classes of
chiral ligands are typically not amenable to modifications that
enable access to elusive regiochemical outcomes.
are obtained. Therefore, the ability to tune regioselectivity
through catalyst control while obtaining high levels of enantiꢀ
oselectivity remains as an unsolved problem in this class of
reactions.
In the reductive coupling of aldehydes and alkynes to preꢀ
pare allylic alcohols, a benchmark challenge in regiocontrol is
presented by internal alkynes that possess two different alkyl
substituents. This class of alkynes leads to the unselective
production of two possible regioisomers in nearly all catalytic
bondꢀforming processes of internal alkynes.5 The previous
advances in enantioselective aldehydeꢀalkyne reductive couꢀ
plings with internal alkynes that lack conjugation or directing
functionality are typically unselective or favor the production
of products 1a and 1b where the least hindered alkyne termiꢀ
nus (alkylS) undergoes addition to the aldehyde (Scheme 1).4hꢀj
However, the products 1c and 1d derived from highly regioseꢀ
lective coupling at the more hindered alkyne terminus (alkylL)
can only be accessed in racemic form using current methods.2aꢀ
Recent advances in regiodivergent processes have focused
on several strategies, including tuning steric interactions beꢀ
tween substrates and ligands, turning on and off directing efꢀ
fects, or changing catalyst class altogether to enable a fundaꢀ
mental change in mechanism.1 Recent studies from our laborꢀ
atory have focused on the ligand steric control strategy by
developing classes of Nꢀheterocyclic carbene (NHC) ligands
that enable regiodivergence (access to either regioisomer from
a common substrate) in catalytic reductive coupling processꢀ
es.1ꢀ3 The high levels of regiodivergence that are now possible
have not yet been paired with an effective strategy for enaꢀ
bling enantioselectivity. Numerous important advances in
enantiocontrol in reductive couplings have been illustrated in
cases where regioselectivity is governed by substrate control.4
c
Building on the insights provided by our previous efforts in
establishing racemic regiodivergent processes,2,6 in this study,
we have now focused on the development of processes that
enable the highly selective production of the more hindered
allylic alcohol regioisomers 1c and 1d, while simultaneously
providing high levels of enantioselectivity.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 10
Scheme 1. Challenge of Simultaneous Regio- and Enantio-
control.
involving N,Nꢀdiarylation of a commercially available enantiꢀ
1
2
3
4
5
6
7
8
opure diamine has not been previously been accomplished due
to the low yields of the twoꢀdirectional BuchwaldꢀHartwig
coupling in an extremely sterically demanding environment.
The original strategy to this ligand class from Sigman, involvꢀ
ing a pinacol coupling of Nꢀaryl imines followed by separation
of racꢀ and meso isomers of the resulting diamine,9a has been
employed to prepare racemic ligand 4a. This ligand provided
unique regiochemical outcomes in several different contexts in
our own laboratory,2 and these promising outcomes motivated
us to better explore the synthesis and utility of the enantiopure
ligand class.
9
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
Ligand Synthesis and Optimization
Initial studies in aldehydeꢀalkyne reductive couplings were
conducted with ligand 4a (Scheme 2) obtained in enantiopure
form by preparative chiral SFC chromatography.10 Given the
promise of preliminary results in asymmetric couplings, the
more straightforward route involving palladiumꢀcatalyzed CꢀN
couplings was then explored. Considering the low cost of 1ꢀ
bromoꢀ2,4,6ꢀtriisopropylbenzene, we opted to explore this
substrate in the synthesis of ligand 4b (Scheme 2). Under a
variety of standard conditions for BuchwaldꢀHartwig aminaꢀ
tion, low yields of product 5b were obtained. For example,
employing BINAP as ligand at 115 °C in neat bromoarene,
only 17% of the desired diarylated product 5b was obtained,
with monoarylated product 6b being the major product obꢀ
tained in 47% yield (Table 1, entry 1). Similarly, a number of
NHC ligands (IMes, SIMes, SIPr, and IPr*OMe) in combinaꢀ
tion with Pd(dba)2 failed to produce significant yields of the
desired diarylated product 5 (see supporting information).11
The unsaturated bulky ligand IPr, however, provided some
level of improvement and was thus selected for further optimiꢀ
zation (Table 1).
Results and Discussion
Design of a Ligand Class to Exert Regio- and Enantio-
control
The most robust classes of NHC ligands in exerting steric
control in catalytic processes are those that possess branched
2,6ꢀdisubstitution within an N,Nꢀdiaryl imidazolium frameꢀ
work. For example, the IPr and IPr*OMe classes of ligands 2a
and 2b have been widely exploited in a vast array of catalytic
processes that are governed by ligand steric control.1ꢀ2 Toꢀ
wards the goal of achieving enantioselectivity, multiple types
of chiral NHC ligands exist for catalytic asymmetric processꢀ
es.4,7 While many of these possess chirality within the Nꢀ
substituent, these ligand classes designed for enantioselectivity
typically lack a steric environment that is well positioned for
regiocontrol. Installation of backbone chirality within the imꢀ
idazolidine core enables a variety of Nꢀaryl substituents to be
utilized in ligand framework 3,7,8 but none of the previously
utilized chiral ligands of this class possess secondary branchꢀ
ing of both substituents at the ortho positions. The ligand class
4 that possesses Cꢀ2 backbone chirality and N-aryl substituents
that possess a bulky 2,6ꢀdisubstitution pattern seems an obviꢀ
ous choice, but this ligand type has only been exploited in
racemic form in catalytic processes.
Using IPr as ligand in toluene at 115 °C afforded the deꢀ
sired bisꢀarylation product 5b in 17% NMR yield together
with 12% NMR yield of the monoarylated product 6b (Table
1, entry 2). Other structurally related NHC ligands (IPrCl and
IPrMe) were then evaluated (Table 1, entries 3ꢀ4). Promising
results were obtained with the IPrMe ligand,12 with which the
reaction afforded product 5b in 73% NMR yield with no obꢀ
servation of the monoꢀarylated product. It was then found that
increased amounts of the NHC ligands improved yields furꢀ
ther. As illustrated (Table 1, entries 4ꢀ6), when a 1:1 ratio of
IPrMe•HCl to Pd(dba)2 was used, the NMR yield of 5b deꢀ
creased to 12%, and the major product of the reactions is the
monoarylated compound 6b. On the contrary, when the ratio
of IPrMe/Pd was increased to 3:1, the NMR yield of 5b rose to
93% after stirring the reaction at 115 °C for 60 hours (Table 1,
entry 6). Reducing the reaction time to 20 hours decreased the
NMR yield of 5b to 77% (Table 1, entry 7). While dioxane as
solvent lowered the chemical yield (Table 1, entry 8), further
Scheme 2. NHC templates for steric control and asymmet-
ric catalysis.
study showed that more polar solvent
α,α,αꢀtrifluorotoluene
was the optimal solvent for the reaction. With this solvent, the
NMR yield of the reaction rose to 94% (Table 1, entry 9). Altꢀ
hough all previous studies used a large excess of the aryl broꢀ
mide reactant (9 equiv), the same level of the reaction yield
was observed when the amount of the bromide was reduced to
3 equiv (Table 1, entry 10). A lower yield of product 5b (77%)
was obtained after decreasing the reaction temperature to 90
°C (Table 1, entry 11). Therefore, the optimized conditions
from entry 10 were selected for the preparation of a range of
new ligand motifs.
Chiral ligands of the type 4 have rarely been obtained in
enantiopure form, and never by a route that avoids multistep
synthesis including a resolution.9 The obvious synthetic route
ACS Paragon Plus Environment

Page 3 of 10
Journal of the American Chemical Society
Table 1. Optimization of the N,N-diarylation reaction. Table 2. Application of the diarylation reaction conditions
1
in the synthesis of chiral bulky NHC ligands
2
3
4
5
6
7
8
9
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
entry
ligand (mol %)a
solvent
time 5b yield 6b yield
(h)
20
60
60
60
60
60
20
20
20
20
20
(%)b
17
17
16
73
12
93
77
49
94
93
77
(%)b
47
12
39
ꢀꢀc
1
BINAP (24)
neat
2
IPr•HCl (20)
PhMe
3
IPrCl•HCl (20)
IPrMe•HCl (20)
IPrMe•HCl (10)
IPrMe•HCl (30)
IPrMe•HCl (30)
IPrMe•HCl (30)
IPrMe•HCl (30)
IPrMe•HCl (30)
IPrMe•HCl (30)
PhMe
4
PhMe
5
PhMe
56
ꢀꢀc
ꢀꢀc
ꢀꢀc
ꢀꢀc
ꢀꢀc
ꢀꢀc
6
PhMe
7
PhMe
8
dioxane
C6H5CF3
C6H5CF3
C6H5CF3
9
10d
11d,e
aLigand scaffolds are shown in Scheme 2. IPr = ligand 2a, R1 = iꢀ
Pr, R2, R3 = H; IPrCl = ligand 2a, R1 = iꢀPr, R2 = Cl, R3 = H; IPrMe
= ligand 2a, R1 = iꢀPr, R2 = Me, R3 = H. NMR yields with diꢀ
b
bromomethane as the internal standard. cNot observed. d3 equiv of
bromide was used. eReaction was conducted at 90 °C.
Using the optimized conditions, the synthesis of a range of
bulky NHC salts was carried out (Table 2). The reaction of
1,2ꢀdiphenylethaneꢀ1,2ꢀdiamine
with
1ꢀbromoꢀ2,4,6ꢀ
triisopropylbenzene was conducted on a 10 mmol scale, which
furnished product 5b in 78% isolated yield. Employing previꢀ
ously reported conditions, the subsequent cyclization reaction
of 5b produced its corresponding NHC salt 4b in 79% yield
(Table 2, entry 1). The initially explored NHC salt 4a, previꢀ
ously utilized in exploratory studies as material obtained by
chiral chromatography, was also successfully synthesized unꢀ
der these conditions (Table 2, entry 2). Incorporating 1ꢀ
naphthyl and 9ꢀanthracenyl at the paraꢀposition of the broꢀ
moarenes decreases the yields for the diarylation reaction, and
diamine 5c and 5d were obtained in 39% and 36% yield reꢀ
spectively. No monoarylated product was observed in either
case. Compared to the synthesis of ligands 4a and 4b, NHC
salts 4c and 4d were obtained in lower yields (Table 2, entries
3ꢀ4). The decrease in preparative efficiency may result from
the extended conjugation of the Nꢀaryl moiety in compounds
5c and 5d, which decreased the nucleophilicity of the nitrogen
towards the cyclization reaction. Increasing the electron densiꢀ
ty on the bromide reactant by introducing a paraꢀmethoxy
group resulted in no formation of arylated products (Table 2,
entry 5). We were also unable to apply these reaction condiꢀ
tions to the reaction of 1ꢀbromoꢀ2,4,6ꢀtri(tertꢀbutyl)benzene,
suggesting that 2,6ꢀdiisopropyl substitution marks the limit of
steric hindrance tolerated by this procedure. (Table 2, entry 6).
a10 mmol scale.
Regio- and Enantioselective Reductive Couplings
With the new classes of chiral ligands in hand, the asymꢀ
metric reductive coupling of aldehydes and alkynes was exꢀ
plored (Table 3). As highlighted above, the control of regioꢀ
chemistry in additions of internal alkynes that bear aliphatic
substituents of similar size are exceptionally challenging in
virtually all classes of catalytic reactions. For this reason, our
initial explorations focused on alkyne 7, which possesses cyꢀ
clohexyl and ethyl groups that must be differentiated during
the coupling process. With this substrate, the catalyst must be
able to distinguish a secondary from a tertiary propargylic
substitution pattern in order to exert regiocontrol in the forꢀ
mation of product 8. While processes involving the influence
of directing functionality are typically employed to obtain
highly regioselective outcomes with this substitution patꢀ
tern,2e,13 nonꢀdirected processes involving internal alkynes of
this type are exceedingly rare.
In initial explorations of regioꢀ and enantioselective couꢀ
plings with Et3SiH as the reducing reagent and tetrahydrofuran
as the solvent, the nickel(0) catalyst of ligand 4b produced the
desired regioisomer with high regioselectivity and excellent
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 10
enantioselectivity (82% ee) but in low yield (Table 3, entry 1). role of silane structure and temperature was explored, but these
1
2
3
4
5
6
7
8
It was then found that toluene was a superior solvent for this
reaction, which improved the reaction yield to 62% and enanꢀ
tioselectivity to 92% ee (Table 3, entry 2). Further optimizaꢀ
tion showed that tꢀBuMe2SiH was the best reducing agent for
the reaction. With this silane, high reaction yield (80% yield)
was obtained and the high enantioselectivity (92% ee) was
maintained (Table 3, entry 3). The reaction mediated with
bulky (iꢀPr)3SiH afforded only trace amounts of the reductive
coupling product (Table 3, entry 4). This is likely due to inefꢀ
ficiencies of the bulky silane to participate in an effective σ–
bond metathesis with the metallacycle intermediate.1a,14 In
addition to 4b, other ligands 4a, 4c, and 4d were also tested,
and slightly decreased enantioselectivity was observed for all
cases (Table 3, entries 5ꢀ7). Next, the possibility of decreasing
the catalyst loading was examined. Although the level of enanꢀ
tioselectivity was maintained by reducing the active catalyst
loading to 5 mol %, the reaction yield decreased to 47% (Taꢀ
ble 3, entry 8). A slight decrease in the enantioselectivity was
observed after reducing the catalyst loading to 2 mol % (Table
3, entry 9). Therefore, the optimal conditions for the reductive
coupling reaction (Table 3, entry 3) involves the use of 10 mol
% active catalyst loading (10 mol % Ni(COD)2 and 11 mol %
ligand 4b), toluene as the reaction solvent and tꢀBuMe2SiH as
the reducing reagent, with no slow addition of the substrates
being required.15 The absolute configuration of the product 8
was determined by Mosher ester analysis16 of the correspondꢀ
ing alcohol generated by TBAF deprotection, and an assignꢀ
ment as the Sꢀconfiguration was made (see supporting inforꢀ
mation).
changes failed to improve the reaction enantioselectivity (Taꢀ
ble 4, entries 3ꢀ6). Comparing the data in Tables 3 and 4, this
outcome clearly demonstrates that the small substituent of the
alkyne strongly influences enantioselectivity. The origin of
this effect is discussed in a computational analysis below.
Table 4. Couplings involving methyl-substituted alkynes
9
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
entry RL
R3
temp rr
yield
(%)
ee
(%)
(°C)
1
2
3
4
5
6
Cy
tꢀBuMe2
tꢀBuMe2
(iꢀPr)3
rt
>95:5
79
83
74
78
74
70
28
36
11
38
33
32
nꢀPr
nꢀPr
nꢀPr
nꢀPr
nꢀPr
rt
>95:5
>95:5
>95:5
>95:5
>95:5
rt
tꢀBuMe2
tꢀBuMe2
tꢀBuMe2
50
ꢀ20
ꢀ78
With the understanding that substituents larger than methyl
are essential as the small, distal substituent, the scope of enanꢀ
tioselective and regioselective couplings was explored with a
range of aldehydeꢀalkyne combinations (Table 5). To first
focus on enantioselectivity, the reactions of symmetrical alꢀ
kynes were examined to probe the influence of the length of
the alkyl chain on the enantioselectivity. Compared to the reꢀ
action of 7, the removal of the propargylic branched substituꢀ
ent of the alkyne produced the silyl protected allylic alcohols
in high yield with slightly decreased enantioselectivity (comꢀ
pounds 9aꢀ9c). Compared to the results of the reaction with
unbranched alkynes, improved enantioselectivity was obꢀ
served for the reaction of the alkyne having homopropargylic
branched substituent (compound 9d). Good regioselectivity
(88:12) was also obtained. Alkynes with phenyl, silyloxy, and
phthalimido groups were tolerated under the reaction condiꢀ
tions. Compounds 9eꢀ9g were all obtained with high enantiꢀ
oselectivity, and the enantioselectivity of the minor regioisoꢀ
mers was also determined, which is the same level as that of
the major regioisomers. The absolute configurations of the
silylꢀprotected allylic alcohols were assumed to be the same as
compound 8 by analogy.
Table 3. Optimization of the reductive coupling reaction
with bulky NHC ligands
entry
ligand solvent R3
rra
yieldb eec (%)
(%)
1
4b
4b
4b
4b
4a
4c
4d
4b
4b
THF
Et3
>95:5
>95:5
>95:5
ꢀ
28
62
80
<5
65
53
85
47
46
82
92
92
ꢀ
2
PhMe
PhMe
PhMe
PhMe
Et3
3
tꢀBuMe2
(iꢀPr)3
4
5
tꢀBuMe2
tꢀBuMe2
tꢀBuMe2
tꢀBuMe2
tꢀBuMe2
>95:5
>95:5
>95:5
>95:5
>95:5
86
81
84
91
87
The scope for the aldehyde was found to be quite broad
(Table 6). Both electronꢀrich and electronꢀpoor aldehydes
were tolerated under the reaction conditions, and compounds
10aꢀ10c, possessing paraꢀmethoxy, fluoro, and methyl ester
substituents were all formed with >90% ee. For the synthesis
of compounds 10a and 10c, 20 mol % catalyst loading was
required to ensure full conversion. In addition to benzaldehyde
derivatives, naphthalenyl and heteroaryl aldehydes were also
tolerated, and compounds 10d, 10e, 10f and 10g were obtained
with 90%, 84%, 89% and 90% ee respectively. The reactivity
of aliphatic aldehydes was also evaluated. To facilitate the
analysis of enantioselectivity, the alkyne having a phenethyl
6
PhMe
PhMe
PhMe
PhMe
b
7
8d
9e
aRatio of regioisomer. Isolated yield. Determined by Supercritiꢀ
c
cal Fluid Chromatography (SFC) analysis of the correspond alcoꢀ
d
hols generated by nꢀBu4NF deprotection. 5 mol % catalyst loadꢀ
ing; 72 hours. e2 mol % catalyst loading; 72 hours.
Compared to the excellent enantioselectivity obtained with
the alkyne having an ethyl group as the small substituent, the
reaction of propꢀ1ꢀynꢀ1ꢀylcyclohexane provided the TBS proꢀ
tected allylic alcohol in 79% yield with >95:5 regioselectivity
but only 28% ee (Table 4, entry 1). Similar results were obꢀ
tained from the reaction of 2ꢀhexyne (Table 4, entry 2). The
substituent was employed. Both linear and
αꢀbranched aldeꢀ
hydes, such as octanal and cyclohexyl carboxaldehyde, reacted
with the alkyne under the standard conditions to furnish prodꢀ
ucts 10h and 10i with moderate regioselectivity and good enꢀ
ACS Paragon Plus Environment

Page 5 of 10
Journal of the American Chemical Society
antioselectivity. The decrease of the regioselectivity of 10i As expected, based on the above observations that groups
1
2
3
4
5
6
7
8
compared to 10h illustrates that increasing steric interactions
between the aldehyde substituent and the large group on the
alkyne compromises the normal regiochemistry preference for
the more hindered regioisomer.
larger than methyl are required as the small alkyne substituent
for high enantioselectivity, the reaction of a terminal alkyne
afforded the terminal methylene product 11a with low enantiꢀ
oselectivity (Scheme 3). Compared to reactions of internal
alkynes, the slow addition of the solution of the reactants benꢀ
zaldehyde, cyclohexylacetylene and tertꢀbutyldimethylsilane
in toluene is necessary for the reaction of terminal alkynes to
achieve good yield with minimal alkyne trimerization. As seen
in the reactions of compound 7 and of propꢀ1ꢀynꢀ1ꢀ
ylcyclohexane, (iꢀPr)3SiH was ineffective in producing the
branched terminal alkyne, affording a very low yield of the
product 11b.
Table 5. Exploration of alkyne scopea
9
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
As an alternative, the terminal methylene product can be
synthesized by the reaction of aldehydes with allenes (Scheme
3). The nickelꢀcatalyzed reductive coupling reaction of aldeꢀ
hydes and allenes were previously developed by Jamison.17
While excellent chirality transfer utilizing enantiopure allenes
was exploited in that study, highly enantioselective variants
using achiral allenes have not been developed. Employing the
reaction conditions developed above for the reaction of aldeꢀ
hydes and alkynes, the reaction of benzaldehyde and cycloꢀ
hexylallene using tꢀBuMe2SiH as reductant provided the prodꢀ
uct 12a in promising yield (73%) and enantioselectivity (79%
ee). The absolute stereochemistry was determined to be of the
Sꢀconfiguration through Mosher ester analysis of the correꢀ
sponding alcohol generated by TBAF deprotection of 12a. In
this instance, the use of the bulkier silane iꢀPr3SiH afforded
considerably improved results, with product 12b being obꢀ
tained with high enantioselectivity (94% ee), albeit with lower
regioselectivity (79:21).
aEnantioselectivity was determined by SFC analysis of the correꢀ
sponding alcohols generated by nꢀBu4NF deprotection.
Table 6. Exploration of aldehyde scopea
Scheme 3. Comparison of terminal alkynes and allenes
Computational Evaluation
A number of key mechanistic questions emerge from the
above experimental data. First, ligands 4a and 4b demonstratꢀ
ed unique regiochemical control in the enantioselective couꢀ
plings examined in this study as well as in the racemic reacꢀ
tions in previous studies.2a While the steric bulk of the 2,6ꢀ
disubstitution pattern of the ligand Nꢀaryl group is well docuꢀ
mented as a key factor in ligand sterics of the widely used IPr
and SIPr ligands,18 the identical 2,6ꢀdiisopropylphenyl substitꢀ
uent of ligands 4a and 4b exerts a regiochemical influence
consistent with a much greater degree of steric demand. To
reveal the effects of backbone substitution on the steric propꢀ
erties of the NHC ligands, we calculated the percent buried
volumes (%Vbur, Table 7) of a series of ligands using structures
b
aEnantioselectivity was determined by SFC analysis. 20 mol %
Ni(COD)2 and 4b were used.
ACS Paragon Plus Environment

Journal of the American Chemical Society
optimized with density functional theory (DFT).19 Percent
Page 6 of 10
the orthoꢀisopropyl group on the NHC ligand and the phenyl
1
2
3
4
5
6
7
8
buried volume describes the percentage of space occupied by
the NHC ligand within the first coordination sphere that is 3.5
Å from the metal center.20 Both 4a and 4b have greater %Vbur
than SIPr and IPr, indicating an increased steric demand of the
C2 symmetric ligands. Since the backbone phenyl substituents
of 4a and 4b are outside of the first coordination sphere, they
indirectly influence the steric properties of these NHC ligands
by controlling the conformation of the Nꢀaryl groups and placꢀ
ing the orthoꢀisopropyl groups closer to the metal center. This
illustrates that the modification of backbone substitution and
stereochemistry as an effective approach to increasing the
steric demand of NHC ligands, in addition to the more comꢀ
monly employed alteration of the size of the Nꢀaryl group.18b
group on the benzaldehyde. This tilted Nꢀaryl conformation is
induced by the phenyl substituent on the NHC backbone as
well as the distal ethyl group on the alkyne. In the favored
transition state TS1, the Nꢀaryl group is almost perfectly horiꢀ
zontal. Thus, the steric clashes between the NHC ligand and
the aldehyde are diminished.22 The cooperative effects of the
NHC backbone and the distal alkyne substituent on enantioseꢀ
lectivity are confirmed by examining the TS structures with a
terminal alkyne, cyclohexylacetylene, and the same NHC ligꢀ
and 4b (Figure 1b). With the distal ethyl group replaced with a
hydrogen, the Nꢀaryl group is not tilted in either transition
state. Thus, the level of chiral induction is diminished.
9
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
(a)
Table 7. Percent buried volumes (%Vbur) of NHC ligands.
L
Ni cat.
ligand 4b
O
+ R3SiH
Et
Ni
R2
OSiR3
Cy
R2
+
Et
Cy
O
Ph
H
Cy
enantioselective
oxidative
cyclization
Ph
Et
R1
iꢀPr
iꢀPr
iꢀPr
7
N
N
N
N
Ph
major enantiomeric product
R1
iꢀPr
iꢀPr
IPr
iꢀPr
R3
R3
4b, R1 = iꢀPr, R2 = Ph, R3 = iꢀPr
4a, R1 = iꢀPr, R2 = Ph, R3 = H
H
H
H
H
Ph
Ph
chiral center
on the ligand
Ph
Ph
SIPr, R1 = iꢀPr, R2 = H, R3 = H
3a, R1 = H, R2 = Ph, R3 = H
NN
Ni
NN
Ni
i
i
i
Pr
Pr
Pr
i
Pr
Et
Cy
O
Et
Cy
O
new chiral
center
ligand
%Vbur
Ph
Ph
TS1 (favored)
TS2 (disfavored)
ꢀꢀG‡ = 2.6 kcal/mol
4b
4a
37.5
37.5
36.1
31.6
31.6
ꢀꢀG‡ = 0.0 kcal/mol
(b)
O
L
SIPr
3a
Ni cat.
ligand 4b
+ R3SiH
H
Ni
OSiR3
Cy
+
H
O
Ph
H
Cy
oxidative
cyclization
Ph
H
Ph
Cy
IPr
low enantioselectivity
Furthermore, the above experimental study demonstrates
that the small alkyne substituents, which are positioned as the
distal substituent with respect to the bondꢀforming process in
aldehydeꢀalkyne couplings, play a significant role in determinꢀ
ing the reaction enantioselectivity. This feature is illustrated
by the simple change of an ethyl to a methyl substituent (comꢀ
pare Tables 3 and 4), which results in enantioselectivities
dropping from 92% to 28% ee under otherwise identical conꢀ
ditions in couplings of benzaldehyde with cyclohexyl acetyꢀ
lene derivatives. Coupling with cyclohexylacetylene further
reduced the enantioselectivity to 13% ee (Scheme 3). We perꢀ
formed DFT calculations of the oxidative cyclization transiꢀ
tion states to investigate the origin of enantioselectivity and
the effects of the alkyne substituents.21 We first investigated
the reaction of alkyne 7 and benzaldehyde using ligand 4b
(Figure 1a). The transition state that eventually leads to the
(S)ꢀproduct (TS1) is 2.6 kcal/mol more stable than the transiꢀ
tion state that gives the (R)ꢀproduct (TS2), in agreement with
the high level of enantioselectivity for the (S)ꢀproduct in exꢀ
periment. Considering the chiral center on the NHC backbone
is more than 6 Å away from the prochiral aldehyde, the level
of enantiocontrol is remarkable. This remote chiral induction
operates through the conformational change of the Nꢀ2,4,6ꢀ
triisopropylphenyl groups on the C2 symmetric ligand. In the
disfavored transition state TS2, the highlighted Nꢀ2,4,6ꢀ
triisopropylphenyl group is significantly tilted towards the
benzaldehyde and causes unfavorable steric clashes between
H
H
H
H
Ph
Ph
Ph
Ph
NN
Ni
NN
Ni
i
i
i
i
Pr
Pr
Pr
Pr
H
H
O
O
Ph
Cy
Cy
Ph
TS3
TS4
ꢀꢀG‡ = 0.0 kcal/mol
ꢀꢀG‡ = −0.2 kcal/mol
Figure 1. Remote chiral induction by the C2 symmetric ligand
4b in the oxidative cyclization transition states. Energies are
computed at the M06/SDD–6ꢀ311+G(d,p)/SMD (toluene) level of
theory with geometries optimized at the B3LYP/LANL2DZ–6ꢀ
31G(d) level. The 4ꢀiꢀPr group of ligand 4b is omitted for clarity
in the Chemdraw structures.
To obtain a better understanding of the steric environment
of the C2ꢀsymmetric ligand, we created the 2D steric contour
plot of ligand 4b in the oxidative cyclization transition states
TS1 and TS2 (Figure 2). Following previously reported proꢀ
cedure,23ꢀ24 the ligand steric contour was derived from the van
der Waals surface of the NHC ligand and colorꢀcoded based
on the distance from the substrate – red and yellow indicate
regions on the ligand surface that are closer to the halfꢀspace
containing the substrate, while blue and green indicate regions
that are more distant from the substrate. In TS1, the alkyne
and the nickel catalyst attack the (Si)ꢀface of the benzaldeꢀ
ACS Paragon Plus Environment

Page 7 of 10
Journal of the American Chemical Society
hyde, placing the phenyl group in the less sterically encumꢀ reactions of aldehydes and alkynes. This study has identified
1
2
3
4
5
6
7
8
bered quadrant (II) and the hydrogen in the occupied quadrant
(III). In contrast, in the disfavored (Re)ꢀface attack (TS2), the
phenyl group is positioned in the occupied quadrant (III),
leading to much more significant steric repulsions with the
NHC ligand. The ligand contour plots highlight the conformaꢀ
tional change of the Nꢀ2,4,6ꢀtriisopropylphenyl groups inꢀ
duced by the backbone phenyl substituents that are positioned
in quadrants I and III. The distal ethyl substituent on the alꢀ
kyne is positioned in quadrant IV and accentuates the rotation
of the Nꢀtriisopropylphenyl group towards the substrate in the
occupied quadrant III. As a result, quadrant III becomes highꢀ
ly encumbered, leading to the unfavorable steric repulsion
with benzaldehyde in TS2. In accordance with the analysis in
Figure 1, these results again indicate that the enantioselectivity
is influenced by the cooperative effects of the chiral NHC
backbone and the distal alkyne substituent.
ligands that are able to distinguish electronically and sterically
similar alkyne substituents in a highly regioselective manner
while also inducing high levels of enantioselectivity in the
process. Computational studies have elucidated the origin of
the substantial steric influence exerted by the ligand class exꢀ
plored. Additionally, the origin of enantioselectivity is exꢀ
plained, including the significant role that alkyne sterics play
in influencing the ligandꢀaldehyde interactions. Future work
will focus on employing these ligands in other organic transꢀ
formations and developing other NHC ligands designed to
simultaneously control enantioselectivity and regioselectivity.
9
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
ASSOCIATED CONTENT
Supporting Information
Experimental details, copies of spectra, computational details and
Cartesian coordinates of optimized geometries This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
* jmontg@umich.edu; pengliu@pitt.edu
Present addresses
† Department of Global Discovery Chemistry, Novartis Institutes
for BioMedical Research, Inc., Cambridge, Massachusetts 02139.
ACKNOWLEDGMENT
We are grateful to the National Institutes of Health
(R35GM118133; JM) and the National Science Foundation
(CHEꢀ1654122; PL) for support of this work. We greatly appreciꢀ
ate assistance from Christina Kraml from Lotus Separations, LLC
for the preparative separation of the enantiomers of chiral ligand
4a for preliminary study. DFT calculations were performed at the
Center for Research Computing at the University of Pittsburgh
and the Extreme Science and Engineering Discovery Environment
(XSEDE) supported by the NSF.
REFERENCES
(1) For reviews of regiodivergent reactions: (a) Jackson, E. P.; Maꢀ
lik, H. A.; Sormunen, G. J.; Baxter, R. D.; Liu, P.; Wang, H.; Shareef,
A.ꢀR.; Montgomery, J. Acc. Chem. Res. 2015, 48, 1736. (b) Mahatꢀ
thananchai, J.; Dumas, A. M.; Bode, J. W. Angew. Chem., Int. Ed.
2012, 51, 10954ꢀ10990. (c) Montgomery, J. Organonickel Chemistry.
In Organometallics in Synthesis; Lipshutz, B. H., Ed.; John Wiley &
Sons, Inc.: Hoboken, 2013; pp 319−428.
(2) For regiodivergent nickelꢀcatalyzed reductive couplings: (a)
Malik, H. A.; Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc.
2010, 132, 6304ꢀ6305. (b) Jackson, E. P.; Montgomery, J. J. Am.
Chem. Soc. 2015, 137, 958ꢀ963. (c) Wang, H.; Negretti, S.; Knauff,
A. R.; Montgomery, J. Org. Lett. 2015, 17, 1493ꢀ1496. (d) Shareef,
A.ꢀR.; Sherman, D. H.; Montgomery, J. Chem. Sci. 2012, 3, 892ꢀ895.
(e) Miller, K. M.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 15342ꢀ
15343. (f) Moragas, T.; Cornella, J.; Martin, R. J. Am. Chem. Soc.
2014, 136, 17702ꢀ17705.
Figure 2. van der Waals surface and steric contour plot of
ligand 4b in the oxidative cyclization transition states TS1 and
TS2. The geometries of the benzaldehyde and the alkyne are overꢀ
laid onto the contour plots. Red and yellow in the contour plots
indicate regions that are occupied by the NHC ligand. The 4ꢀiꢀPr
group of ligand 4b is omitted for clarity.
(3) For other examples of regiodivergent reactions: (a) Kennemur,
J. L.; Kortman, G. D.; Hull, K. L. J. Am. Chem. Soc. 2016, 138,
11914ꢀ11919. (b) Ding, D.; Mou, T.; Feng, M.; Jiang, X. J. Am.
Chem. Soc. 2016, 138, 5218ꢀ5221 (c) Xu, B.; Tambar, U. K. J. Am.
Chem. Soc. 2016, 138, 12073ꢀ12076. (e) Du, X.; Zhang, Y.; Peng, D.;
Huang, Z. Angew. Chem., Int. Ed. 2016, 55, 6671. (f) Sakae, R.; Hiraꢀ
no, K.; Miura, M. J. Am. Chem. Soc. 2015, 137, 6460ꢀ6463. (g) Doꢀ
nets, P. A.; Cramer, N. Angew. Chem., Int. Ed. 2015, 54, 633ꢀ637. (h)
Conclusions
In conclusion, an effective synthesis of a novel class of enꢀ
antiopure NHC ligands with exceptional steric demand has
been developed. The catalytic reactivity of these ligands was
evaluated in the Niꢀcatalyzed asymmetric reductive coupling
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 10
Cahard, E.; Male, H. P. J.; Tissot, M.; Gaunt, M. J. J. Am. Chem. Soc.
K.; Cordes, D. B.; Slawin, A. M. Z.; Nolan, S. P. Organometallics
2015, 137, 7986ꢀ7989. (i) Tani, Y.; Fujihara, T.; Terao, J.; Tsuji, Y. J.
Am. Chem. Soc. 2014, 136, 17706ꢀ17709. (j) Shiroodi, R. K.; Koleda,
O.; Gevorgyan, V. J. Am. Chem. Soc. 2014, 136, 13146ꢀ13149. (k)
Köpfer, A.; Sam, B.; Breit, B.; Krische, M. J. Chem. Sci. 2013, 4,
1876ꢀ1880. (l) Zhao, Y.; Weix, D. J. J. Am. Chem. Soc. 2013, 136,
48ꢀ51. (m) Yang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135,
10642ꢀ10645. (n) Worthy, A. D.; Sun, X.; Tan, K. L. J. Am. Chem.
Soc. 2012, 134, 7321ꢀ7324. (o) Bausch, C. C.; Patman, R. L.; Breit,
B.; Krische, M. J. Angew. Chem., Int. Ed. 2011, 50, 5687ꢀ5690. (p)
Miller, Z. D.; Dorel, R.; Montgomery, J. Angew. Chem., Int. Ed.
2015, 54, 9088ꢀ9091. (q) Miller, Z. D.; Li, W.; Belderrain, T. R.;
Montgomery, J. J. Am. Chem. Soc. 2013, 135, 15282ꢀ15285.
(4) For nickelꢀcatalyzed asymmetric reactions involving alkynes:
(a) Kumar, R.; Tokura, H.; Nishimura, A.; Mori, T.; Hoshimoto, Y.;
Ohashi, M.; Ogoshi, S. Org. Lett. 2015, 17, 6018ꢀ6021. (b) Fu, W.;
Nie, M.; Wang, A.; Cao, Z.; Tang, W. Angew. Chem., Int. Ed. 2015,
54, 2520ꢀ2524. (c) Nie, M.; Fu, W.; Cao, Z.; Tang, W. Org. Chem.
Front. 2015, 2, 1322ꢀ1325. (d) Check, C. T.; Jang, K. P.; Schwamb,
C. B.; Wong, A. S.; Wang, M. H.; Scheidt, K. A. Angew. Chem., Int.
Ed. 2015, 54, 4264ꢀ4268. (e) Ahlin, J. S. E.; Donets, P. A.; Cramer,
N. Angew. Chem., Int. Ed. 2014, 53, 13229ꢀ13233. (f) Zhou, C.ꢀY.;
Zhu, S.ꢀF.; Wang, L.ꢀX.; Zhou, Q.ꢀL. J. Am. Chem. Soc. 2010, 132,
10955ꢀ10957. (g) Yang, Y.; Zhu, S.ꢀF.; Zhou, C.ꢀY.; Zhou, Q.ꢀL. J.
Am. Chem. Soc. 2008, 130, 14052ꢀ14053. (h) Chaulagain, M. R.;
Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2007, 129, 9568ꢀ
9569. (i) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2004, 43,
3941ꢀ3944. (j) Miller, K. M.; Huang, W.ꢀS.; Jamison, T. F. J. Am.
Chem. Soc. 2003, 125, 3442ꢀ3443.
2013, 32, 330ꢀ339.
1
2
3
4
5
6
7
8
(12) For the synthesis and application of IPrMe in transition metal
catalysis: (a) Gaillard, S.; Bantreil, X.; Slawin, A. M. Z.; Nolan, S. P.
Dalton Trans. 2009, 6967ꢀ6971. (b) Harkal, S.; Jackstell, R.; Nierlich,
F.; Ortmann, D.; Beller, M. Org. Lett. 2005, 7, 541ꢀ544.
(13) (a) Reichard, H. A.; McLaughlin, M.; Chen, M. Z.; Micalizio,
G. C. Eur. J. Org. Chem. 2010, 2010, 391ꢀ409. (b) Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307ꢀ1370.
(14) For mechanistic studies on the nickelꢀcatalyzed redcutive
coupling reactions: (a) Baxter, R. D.; Montgomery, J. J. Am. Chem.
Soc. 2011, 133, 5728ꢀ5731. (b) Liu, P.; McCarren, P.; Cheong, P. H.ꢀ
Y.; Jamison, T. F.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 2050ꢀ
2057. (c) Ogoshi, S.; Arai, T.; Ohashi, M.; Kurosawa, H., Chem.
Commun. 2008, 1347ꢀ1349. (d) Hoshimoto, Y.; Ohashi, M.; Ogoshi,
S., Acc. Chem. Res. 2015, 48, 1746ꢀ1755. (e) Liu, T.; Bi, S.,
Organometallics 2016, 35, 1114ꢀ1124. (f) Rodrigo, S. K.; Guan, H. J.
Org. Chem. 2017, 82, 5230ꢀ5235.
(15) In comparison to the optimum results with ligand 4b (Table 3,
entry 3), a previously reported ligand variation possessing a 2,4ꢀ
dicyclohexylꢀ6ꢀmethyl substituent (reference 4h) was less effective.
Using this previously reported ligand, couplings of benzaldehyde with
alkyne 7 proceeded in reduced chemical yield (52%), modestly
reduced regioselectivity (92:8), and substantially lower ee (62%).
Alternatively, reactions with ligands with orthoꢀmonosubstituted Nꢀ
aryl substituents (type 3, Scheme 1) proceeded in low yield favoring
the opposite regioisomer from that described in Table 3. For a
computational study describing the origin of regioselectivity reversal
in the absence of ortho substituents on the Nꢀaryl group, see reference
6.
(16) (a) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nat. Protocols 2007,
2, 2451ꢀ2458. (b) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973,
95, 512ꢀ519.
(17) (a) Ng, S.ꢀS.; Jamison, T. F. Tetrahedron 2006, 62, 11350ꢀ
11359. (b) Ng, S.ꢀS.; Jamison, T. F. J. Am. Chem. Soc. 2005, 127,
7320ꢀ7321.
(18) (a) Ragone, F.; Poater, A. Cavallo, L. J. Am. Chem. Soc.,
2010, 132, 4249–4258. (b) Nelson, D. J.; Collado, A.; Manzini, S.;
Meiries, S.; Slawin, A. M. Z.; Cordes, D. B.; Nolan, S. P.,
Organometallics 2014, 33, 2048ꢀ2058.
9
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
(5) For a rare exception, see: Wipf, P.; Janjic, J; Stephenson, C. R.
J. Org. Biomol. Chem. 2004, 2, 443ꢀ445.
(6) Liu, P.; Montgomery, J.; Houk, K. N. J. Am. Chem. Soc. 2011,
133, 6956ꢀ6959.
(7) For examples of chiral NHC ligands: (a) Ahlin, J. S. E.;
Cramer, N. Org. Lett. 2016, 18, 3242ꢀ3245. (b) Ho, C.ꢀY.; Chan, C.ꢀ
W.; He, L. Angew. Chem., Int. Ed. 2015, 54, 4512ꢀ4516. (c) Jang, H.;
Jung, B.; Hoveyda, A. H. Org. Lett. 2014, 16, 4658ꢀ4661. (d) Grassi,
D.; Dolka, C.; Jackowski, O.; Alexakis, A. Chem. Eur. J. 2013, 19,
1466ꢀ1675. (e) Jung, B.; Hoveyda, A. H. J. Am. Chem. Soc. 2012,
134, 1490ꢀ1493. (f) Liu, L.; Ishida, N.; Ashida, S.; Murakami, M.
Org. Lett. 2011, 13, 1666ꢀ1669. (g) Luan, X.; Mariz, R.; Robert, C.;
Gatti, M.; Blumentritt, S.; Linden, A.; Dorta, R. Org. Lett. 2008, 10,
5569ꢀ5572. (h) Brown, M. K.; May, T. L.; Baxter, C. A.; Hoveyda, A.
H. Angew. Chem., Int. Ed. 2007, 46, 1097ꢀ1100. (i) Funk, T. W.;
Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 1840ꢀ1846.
(j) Clavier, H.; Coutable, L.; Toupet, L.; Guillemin, J.ꢀC.; Mauduit,
M. J. Organomet. Chem. 2005, 690, 5237ꢀ5254.
(19) The %Vbur of ligands 4a, 4b, 3a, IPr and SIPr were calculated
using
the
webꢀbased
SambVca
2.0
program
Ref
(https://www.molnac.unisa.it/OMtools/sambvca2.0/index.html
(24a), based on the geometries of (NHC)Ir(CO)2Cl, which were
optimized using the BP86 functional and a mixed basis set of SDD for
Ir and 6ꢀ31G(d) for other atoms. The default parameters in SambVca
2.0 were used as suggested by Cavallo: sphere radius: 3.5 Å, distance
from the center of the sphere: 2.1 Å, mesh spacing: 0.1 Å, H atoms
omitted, atom radii: Bondi radii scaled by 1.17.
(20) (a) Poater, A.; Cosenza, B.; Correa, A.; Giudice, S.; Ragone,
F.; Scarano, V.; Cavallo, L. Eur. J. Inorg. Chem. 2009, 2009, 1759ꢀ
1766. (b) Clavier, H.; Nolan, S. P. Chem. Commun. 2010, 46, 841ꢀ
861.
(21) Previous mechanistic studies indicated the oxidative cyclizaꢀ
tion of the alkyne and the aldehyde is the rateꢀdetermining step in
reactions with sterically less hindered silanes, while this step may be
reversible in reactions with more sterically demanding silanes (see
Ref. 2b; for a detailed computational study on the steric effects of
silane on the rateꢀdetermining step, see Ref. 14e). The identical ee
obtained with two different silanes in Table 3, entries 2 and 3 is conꢀ
sistent with the oxidative cyclization being enantioselectivityꢀ
determining. However, the decrease of ee with TIPSH in Table 4
(entries 2 versus 3) suggests that metallacycle formation becomes
reversible and is no longer enantioselectivityꢀdetermining under these
conditions. In the DFT calculations, we considered the enantioselecꢀ
tivity in the oxidative cyclization step, which is expected to determine
the ee in reactions with sterically less hindered silanes.
(8) Anderson, D. R.; O'Leary, D. J.; Grubbs, R. H. Chem. Eur. J.
2008, 14, 7536ꢀ7544.
(9) (a) Mercer, G. J.; Sturdy, M.; Jensen, D. R.; Sigman, M. S. Tet-
rahedron 2005, 61, 6418ꢀ6424. (b) Zinner, S. C.; Herrmann, W. A.;
Kühn, F. E. Tetrahedron Asymm. 2008, 19, 1532ꢀ1535. (c) Liu, L.;
Ishida, N.; Ashida, S.; Murakami, M. Org. Lett. 2011, 13, 1666ꢀ1669.
(10) Lotus Separations, LLC. conducted preparative separation of
the enantiomers of chiral ligand 4a for preliminary study.
(11) For reviews on Nꢀarylation reactions: (a) RuizꢀCastillo, P.;
Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137,
3085ꢀ3092. (b) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27ꢀ
50. (c) Klinkenberg, J. L.; Hartwig, J. F. Angew. Chem., Int. Ed. 2011,
50, 86ꢀ95. (d) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed.
2008, 47, 6338ꢀ6361. (e) Hartwig, J. F. Acc. Chem. Res. 2008, 41,
1534ꢀ1544. (f) Hartwig, J. F. Nature 2008, 455, 314. (g) Valente, C.;
Pompeo, M.; Sayah, M.; Organ, M. G. Org. Process Res. Dev. 2014,
18, 180ꢀ190. (h) Valente, C.; Çalimsiz, S.; Hoi, K. H.; Mallik, D.;
Sayah, M.; Organ, M. G. Angew. Chem., Int. Ed. 2012, 51, 3314ꢀ
3332. (i) Fortman, G. C.; Nolan, S. P. Chem. Soc. Rev. 2011, 40,
5151ꢀ5169. (j) Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008, 41,
1440ꢀ1449. For Nꢀarylation reactions using IPr*OMe ligand: (k)
Martin, A. R.; Nelson, D. J.; Meiries, S.; Slawin, A. M. Z.; Nolan, S.
P. Eur. J. Org. Chem. 2014, 2014, 3127ꢀ3131. (l) Meiries, S.; Speck,
(22) It should be noted that the steric interactions between the terꢀ
minal Et group and the NHC ligand are comparable in TS1 and TS2.
In both transition states, one of the Nꢀ2,4,6ꢀtriisopropylphenyl groups
is tilted to avoid the steric repulsion with the terminal Et group. In
ACS Paragon Plus Environment

Page 9 of 10
Journal of the American Chemical Society
TS2, the tilted Nꢀaryl group (highlighted and pointing outꢀofꢀtheꢀ
(24) (a) Falivene, L.; Credendino, R.; Poater, A.; Petta, A.; Serra,
L.; Oliva, R.; Scarano, V.; Cavallo, L. Organometallics 2016, 35,
2286ꢀ2293. (b) Wang, T.; Yu, Z.; Hoon, D. L.; Huang, K.ꢀW.; Lan,
Y.; Lu, Y. Chem. Sci. 2015, 6, 4912ꢀ4922.
paper in Figure 1a) is on the same side with the phenyl group on the
aldehyde. In TS1, the tilted Nꢀaryl group (not highlighted and pointꢀ
ing into the paper in Figure 1a) is on the opposite side, and thus does
not cause steric repulsions with the aldehyde.
1
2
3
4
5
6
(23) (a) Lu, G.; Fang, C.; Xu, T.; Dong, G.; Liu, P. J. Am. Chem.
Soc. 2015, 137, 8274ꢀ8283. (b) Huang, G.; Liu, P. ACS Catal. 2016,
6, 809ꢀ820.
7
8
9
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
ACS Paragon Plus Environment

Journal of the American Chemical Society
SYNOPSIS TOC (Word Style “SN_Synopsis_TOC”).
Page 10 of 10
1
2
3
Ph
iꢀPr
Ph
iꢀPr
N
N
4
iꢀPr iꢀPr
5
6
7
8
H
efficient synthesis
no resolution required
H
Ph
Ph
NN
Ni
+ R23SiH
OSiR2
iPr
iPr
alkylS
3
alkylS
O
+
R1
alkylS
R1
alkylL
H
alkylL
O
9
alkylL
R1
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
enantioselective oxidative cyclization
ACS Paragon Plus Environment