Chemoselective Cross-Coupling of gem-Borazirconocene Alkanes with Aryl Halides

Article abstract of DOI:10.1021/jacs.0c03821

The direct and chemoselective conversion of the carbon-metal bond of gem-dimetallic reagents enables rapid and sequential formation of multiple carbon-carbon and carbon-heteroatom bonds, thus representing a powerful method for efficiently increasing structural complexity. Herein, we report a visible-light-induced, nickel-catalyzed, chemoselective cross-coupling reaction between gem-borazirconocene alkanes and diverse aryl halides, affording a wide range of alkyl Bpin derivatives in high yields with excellent regioselectivity. This practical method features attractively simple reaction conditions and a broad substrate scope. Additionally, we systematically investigated a Bpin-directed chain walking process underlying the regioselectivity of alkylzirconocenes, thus uncovering the mechanism of the remote functionalization of internal olefins achieved with our method. Finally, DFT calculations indicate that the high regioselectivity of this reaction originates from the directing effect of the Bpin group.

Full text of DOI:10.1021/jacs.0c03821

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Article
Chemoselective Cross-coupling of gem-
Borazirconocene Alkanes with Aryl Halides
Chao Yang, Yadong Gao, Songlin Bai, Chao Jiang, and Xiangbing Qi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03821 • Publication Date (Web): 04 Jun 2020
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Journal of the American Chemical Society
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Chemoselective Cross-coupling of gem-Borazirconocene Alkanes
with Aryl Halides
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Chao Yang,†‡ Yadong Gao,†‡ Songlin Bai,‡ Chao Jiang,* † and Xiangbing Qi* ‡, §,¶
†School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China.
‡National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
§Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 100084, China.
¶Lead Contact
ABSTRACT: The direct and chemoselective conversion of the carbon-metal bond of gem-dimetallic reagents enables rapid and
sequential formation of multiple carbon-carbon and carbon-heteroatom bonds, thus representing a powerful method for efficiently
increasing structural complexity. Herein, we report a visible-light-induced, nickel-catalyzed, chemoselective cross-coupling reaction
between gem-borazirconocene alkanes and diverse aryl halides, affording a wide range of alkyl Bpin derivatives in high yields with
excellent regioselectivity. This practical method features attractively simple reaction conditions and a broad substrate scope.
Additionally, we systematically investigated a Bpin-directed chain walking process underlying the regioselectivity of
alkylzirconocenes, thus uncovering the mechanism of the remote functionalization of internal olefins achieved with our method.
Finally, DFT calculations indicate that the high regioselectivity of this reaction originates from the directing effect of the Bpin group.

INTRODUCTION
transmetalation.6 Furthermore, the considerable steric
hindrance caused by the zirconium complex decreases the
nucleophilicity of the alkyl group with coupling partners.
(Figure 1B).3j
The selective cross-coupling of bimetallic nucleophiles is
attracting increasing attention because it facilitates diverse
transformations to rapidly elaborate structural complexity.1
Among reported bimetallic reagents,1b,
gem-
1g,
2
A)
Previous strategy for the direct functionalization of gem-borazirconocene alkanes
Br
Bpin
borazirconocene alkanes are recognized as particularly valuable
synthons that possess great synthetic potential (Figure 1A).3
This stable reagent is easily generated from hydrozirconation of
R
O
R
D
R1
a) D2O
d) R1COCl
NBS
O
O
various
alkenyl
boronic
esters
with
Bpin
Bpin
Br
Bpin
Cu
b) NBS
CuCN 2LiCl
R
R
R
bis(cyclopentadienyl)zirconium chloride hydride (Schwartz
reagent) in high yield and with excellent functional group
tolerance. The difference in the polarity of the carbon-
zirconium bond vs the carbon-boron bond allows for the
sequential functionalization of gem-borazirconocene alkanes
via a variety of reactions such as cross-coupling, nucleophilic
substitution, or nucleophilic addition. Organozirconium
compounds are much more reactive than organoboranes, which
allows for the chemoselective conversion of organozirconium
reagents to afford versatile organic boron intermediates.3j
Despite the multiple advantages offered by these reagents, they
have received substantially less attention for cross-couplings
compared with alternative nucleophilic substitutions like
halogenation,3a-d deuteration,3e amination,3j, 3k as well as Michael
addition,3f or nucleophilic addition to acyl chlorides (Figure
1A).3g Indeed, the efficient utilization of organozirconium
reagents for cross-coupling reaction would be of great value to
rapidly increase structural complexity.4 While cross-coupling
reaction of primary alkylzirconocene reagents has been
reported recently by our group,5 to date, no general cross-
coupling reaction has been developed for secondary
alkylzirconocene including gem-borazirconocene alkanes,3h
likely owing to the lack of available π-systems to stabilize the
binding capability of zirconium to achieve suitable
ZrCp2Cl
e)
R
Br
(SN2)
Bpin
f)
Bpin
c) MSH reagent
Bpin
R
R
NH2
B)
Challenges of the chemoselective cross-coupling of the gem-borazirconocene alkanes
Lack of -systems to stabilize the binding capability of zirconium
Bpin
Steric hindrance around the zirconium atom decreases its nucleophilicity
Chemoselective transmetalation
R
ZrCp2Cl
C)
This work: Chemoselective cross-coupling of gem-borazirconocene alkanes
pinB
Cp2ZrHCl
Chain walking selectivity
B-direction
pinB
Steric release
ZrCp2Cl
2-m
pinB
ZrCp2Cl
m
Steric
release
B-direction m = 1 or 2
Bpin
hv
Bpin
R
R
ZrCp2Cl
+
Ar-X
Ni
Ar
gem-Borazirconocene alkanes
X= I, Br
35-88%
63 examples,
regioisomeric ratio>
yield
40:1
First secondary alkylzirconocenes in cross-coupling
Bpin directed chain walking & cross-coupling strategy Chemoselective cross-coupling
Mild conditions & broad substrate scope High regioselectivity
Ni-catalyzed light-induced cross-coupling
Figure 1. A) Previous strategy for the direct functionalization of
gem-borazirconocene alkanes. B) Challenges with chemoselective
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Page 2 of 9
cross-coupling
of
gem-borazirconocene
alkanes.
C)
Our initial efforts focused on examining ethyl gem-
borazirconocene with iodobenzene under blue light excitation.
After an extensive survey of catalysts, additives, solvents, and
light sources (for detailed optimization studies, see Table S1-
S7.), the desired cross-coupling product of aryl ethylboronate
was achieved in 86% yield using a nickel precatalyst containing
a 4,4'-tert-butyl-2,2'-bipyridine ligand in THF, with the aid of
irradiation from blue-light-emitting bulbs at room temperature.
Various control experiments including light–dark intervals
revealed that the nickel catalyst and continuous irradiation with
visible light are both essential for the reaction (Table 1, entries
2, 3, 8, 9, and the supplemental information, Figure S1). The
reaction yield was increased upon addition of TBAB and by
simply increasing the power of the light source from 15 W to 36
W (Table 1, entries 5 vs 7, entries 1 vs 5). We determined that
the highly efficient nickel precatalyst could be reduced as low as
1 mol% (Table 1, entries 1 vs 4). Finally, we found that
bromobenzene possesses comparable reactivity to iodobenzene
under the optimized reaction conditions (Table 1, entry 10).
1
2
3
4
5
6
7
8
Chemoselective cross-coupling of gem-borazirconocene alkanes.
The development of remote functionalization methods is
receiving growing interest, probably because such methods
allow for the activation of challenging C−H and C−C bonds
distant from the initiation position via a fascinating “chain
walking” process.7 However, the manipulation of remote
functional groups at different carbon centers represents a major
challenge in synthetic chemistry.8 Hydrozirconation of internal
alkenes produces primary alkylzirconocene complexes wherein
facile Zr–H eliminations and reinsertions enable the Cp2ZrCl
moiety to “chain walking” to the least sterically hindered
terminal position of the alkyl chain.6 To the best of our
knowledge, there is no general method to selectively direct this
chain walking process to afford stable secondary
alkylzirconocenes with predictable regioselectivity.
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The present study describes, for the first time, a Bpin group
directed “chain walking” process for alkylzirconocenes,
selectively generating diverse gem-borazirconocene alkanes.
Inspired by our own recent findings5, we speculated that the -
radical stabilizing effect of boron is likely to favor homolytic
cleavage of the C–Zr bond, thus the gem-borazirconocene
alkanes may serve as especially attractive secondary sp3-
hybridized alkylzirconocenes that undergo C-Zr activation in
the presence of boron to enable chemoselective cross-coupling
reactions (Figure 1C). Herein, we report a visible-light-induced
nickel-catalyzed chemoselective cross-coupling reaction of gem-
borazirconocene alkanes with aryl halides, affording a wide
range of alkylborane derivatives. Such derivatives are well-
established high-value building blocks, which can be employed
for lithiation-borylation,9 Zweifel olefinations,10 Suzuki cross-
couplings,1h, 1j, 1l, 11 as well as the recently reported alkylborane
cross-coupling reaction from the Fu group that enables rapid
and efficient formation of sp3 C-C bonds under mild conditions
while offering both high regioselectivity and excellent substrate
scope.12
Table 2. The scope of gem-borazirconocene alkanes componenta
tBu
tBu
Bpin
Bpin
R1
Ni(dtbbpy)Br2 (1 mol%)
+
R1
Ar-I
N
N
THF (0.15 M), Ar, rt, 24 h
36 W blue LED bulbs
Ni
Ar
ZrCp2Cl
Single regioisomer
Br Br
Ni(dtbbpy)Br2
Substrate
Product No.
2a
Product
Yield (%)
Entry
Bpin
71
(72)b
pinB
3
1
Ar1
5
Bpin
Bpin
pinB
Cl
Cl
75
2b
2
Ar1
Ar1
4
74
(61)b
tBu
tBu
pinB
2c
2d
3
4
Bpin
TMS
pinB
TMS
TIPS
83
81
68
Ar1
Bpin
Bpin
TIPS
pinB
Ar1
Ar1
2e
5
6
2f
OPh
pinB
pinB
pinB
OPh
3
Bpin
Bpin
OTBDPS
Ar1
Ar2
OTBDPS 74
Ts
Table 1. Variation of reaction parameters
2g
7
8
3
Ts
Bpin
N
N
2h
3
66
I
Bpin
Ni(dtbbpy)Br2 (1 mol%)
Bpin
Bpin
+
ZrCp2Cl
2.0 equiv.
Ar1
Ar2
OMe
THF (0.15 M), Ar, rt, 24 h
36 W blue LED bulbs
pinB
pinB
pinB
OMe
63
2i
2j
9
1.0 equiv.
Yield (%)a
Ph
Ph
Entry
Change from standard conditions
10
75
73
3
1
2
none
96 (86)
0
Bpin
Bpin
Ph
2k
2l
11
12
Ph
w/o Ni(dtbbpy)Br2
Ar2
Ar1
Cl
Cl
3
w/o light
0
68
(65)b
4
Ni(dtbbpy)Br2 (2 mol%)
91
pinB
OMe
15 W blue Light strip, instead of LED bulbs
15 W blue Light strip, instead of LED bulbs, + Bu4N+OTs- (1 equiv.)
15 W blue Light strip, instead of LED bulbs, + TBAB (1 equiv.)
NiCl2, instead of Ni(dtbbpy)Br2
Ni(COD)2, instead of Ni(dtbbpy)Br2
PhBr, instead of PhI
5
84
Bpin
OMe
2m
2n
13
14
81
68
6
82
Ar2
Ar1
pinB
7
94
Bdan
8
trace
trace
92
danB
3
5
9
BNeol
75
85
2o
2p
15
16
10
Ar1
Ar1
NeolB
3
5
Bpin
Bpin
aAll optimization reactions were carried out at a 0.1 mmol scale.
1
Bpin
Ph
The yields determined by H NMR of crude samples using 1,3,5-
Bpin
Bpin
2q
2r
17
18
53
86
0c
Ar1
Ar1
Ar1
trimethoxybenzene as an internal standard, in parenthesis is the
isolated product yield (0.30 mmol scale). TBAB:
Tetrabutylammonium bromide.
pinB
Bpin
3
pinB
2s
19

RESULTS AND DISCUSSION
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aUnless otherwise noted, yields of isolated products given at a 0.3
Regarding the scope of heteroaromatic halides, thiophene
(3u), non-protected indole (3v), furan (3w), pyrimidine (3x),
and pyrazole (3y), were all well tolerated, affording the
corresponding products in moderate yields. Finally, aryl iodide
derivatives from natural products, including xylofuranose (3ab),
cholesterol (3ac), and aminopenicillanic acid (3ad), were
compatible with the optimized cross-coupling conditions,
showcasing the utility of this new process for the late-stage
modification of complex natural products. Additional cross-
coupling reactions of different electrophilic partners have been
conducted to extend the scope of this method (discussed in
detail in supplemental information, Table S8). Substrates,
including primary alkyl and alkenyl halides were feasible cross-
coupling partners although the yield of products were moderate
(35-68%).14
1
2
3
4
5
6
7
8
mmol scale; all reactions were performed with Ni(dtbbpy)Br2 (1
mol%), gem-borazirconocene alkanes (0.6 mmol), aryl iodides (0.3
mmol), and THF (2 mL), at 25-30 °C with two 36 W blue LED
bulbs for 24 hours. See the supplemental information for detailed
reaction conditions, Ar1
AcNH(C6H4). The gem-borazirconocene alkanes were generated
in situ from alkynes, HBpin, and the Cp2ZrHCl reagents. c85% of
starting material S3o was recovered.
= = 4-
4-HOCH2(C6H4), Ar2
b
With the optimal reaction conditions in hand, we next turned
our attention to investigate the synthetic utility of this visible-
light-induced nickel-catalyzed reaction. First, the substrate
scope of gem-borazirconocene alkanes was examined, which
were prepared in situ from hydrozirconation of corresponding
alkenyl boronic esters. As illustrated in Table 2, a series of
simple (2a, 2j, 2n, 2o) and substituted borazirconocene alkanes
containing chloro (2b), silane (2d, 2e), ether (2f, 2g, 2i), or
sulfonamide groups (2h), were viable coupling partners in our
cross-coupling method. Substrates generated from
hydrozirconation of electron-rich and electron-deficient aryl
alkenyl boronic esters (2k-2m), as well as more sterically
hindered alkenyl boronic esters (2c-2e) were also amenable to
the cross-coupling reaction. The gem-borazirconocene alkanes
generated simply in situ from alkynes, HBpin, and Cp2ZrHCl
reagents (2a, 2c, 2l) were also found to be productive coupling
partners. (See the supplemental information for detailed
reaction conditions). Notably, the alkenylboronate systems,
such as entries 16-18, exhibit 1,2-boron migration during
hydrozirconation until the stable gem-borazirconocene alkanes
are generated, which also possess moderate to high reactivity in
our cross-coupling reaction (2p-2r, 53-86 yield).13 However,
when the Bpin group is located further away from the terminal
position (more than 2 carbons), neither boron migration nor
cross-coupling product was observed. This indicated that long
chain boron migration is likely more difficult than boron-
directed zirconocene migration (entry 19, 2s, 0% yield).
9
10
11
12
13
14
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16
17
18
19
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Table 3. The scope of aryl halide coupling partnersa
Bpin
Cp2ZrHCl,
THF
Bpin
Bpin
Bpin
Bpin
X
Bpin
Ni(dtbbpy)Br2 (1 mol%)
R
+
+
+
R
R
THF (0.15 M), Ar, rt, 24 h
36 W blue LED bulbs
ZrCp2Cl
major
ClCp2Zr
X = I or Br
minor
major
minor
> 40:1
regioisomers
Bpin
Bpin
Bpin
X
X
X
3a,
3b,
3c,
,
3d,
3e,
3f,
X = NHAc, 71%
86%
X = Cl 81%
X = F, 75%
X = OMe, 83%
X = Me, 75%
3g,
X = CO2Me, 73%
Bpin
Bpin
Bpin
OMe Bpin
MeO2
C
OMe
CH2OH
3h,
3i,
3j,
3k,
66%
80%
79%
86%
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
MeO2
C
OMe
b
TsO
AcO
HOH2C
3l,
3n,
3o,
82%
83%
Bpin
82%
3m,
3q,
74%
Bpin
pinB
HO
F3C
c
3r,
3s,
77%
Bpin
64%
Bpin
75%
Bpin
3p,
78%
Bpin
d
To further assess the scope of this selective coupling reaction,
a series of aryl iodides and bromides were investigated for this
reaction. As shown in Table 3, this method displayed excellent
functional group tolerance for the aryl iodides bearing chloro
(3b), fluoro (3c), methoxy (3d, 3i, 3j, 3m), methyl (3e), and
trifluoromethyl (3q) groups, as well as more reactive functional
groups such as amides (3f), esters (3g, 3h, 3m, 3r, 3ab -3ad),
primary alcohols (3k, 3o), phenols (3p), anilines (3z), and
nitriles (3aa). Additionally, we observed that aryl tosylates and
aryl boronic esters were also well tolerated under the mild
conditions (3l, 3n), illustrating a facile access to these
compounds for further chemical modification. Notably, the
electronic properties and substitution pattern had a negligible
effect on the yield, and the corresponding cross-coupling
products were all obtained in good to excellent yields with high
S
O
N
H
Ph
b
3u,
3v,
55%
Bpin
57%
Bpin
3t,
3w,
55%
88%, (73%)
Bpin
Bpin
N
N
N
NC
H2
N
MeO
N
b
b
3y,
3z,
61%
62%
3x
3aa,
68%
, 56%
Bpin
Bpin
Bpin
O
O
O
OH
O
H
O
H
O
HN
Boc
N
O
O
O
O
H
S
H
H
3ab,
3ac,
3ad, 72%
82%
75%
aUnless otherwise noted, yields of isolated products given at a 0.3
mmol scale; all reactions were performed with Ni(dtbbpy)Br2 (1
mol%), ethyl gem-borazirconocene (0.6 mmol), aryl iodides (0.3
mmol), and THF (2 mL), at 25-30 °C with two 36 W blue LED
bulbs for 24 hours. The regioisomeric ratio (branch/linear) in
parentheses was determined by 1H NMR of crude samples. See the
supplemental information for detailed reaction conditions.
bBromoarene was used. c4 equiv. alkylzirconocene was used. dyields
of isolated products given at a 3.6 mmol scale (1.008 g).
1
regioselectivity (branch:linear >40:1, for detailed H NMR of
the crude samples, see supplemental information, Spectral
data.). Compared with aryl iodides, aryl bromides were also
feasible cross-coupling partners (3m, 3w, 3x, 3aa). Furthermore,
the potential application of this cross-coupling method in
modern synthesis was demonstrated by carrying out at a gram
scale process without compromising much efficiency (3t, 73%
yield).
Under thermodynamic control, the general terminal or
internal alkenes would all generate terminal linear
alkylzirconocenes from hydrozirconation and subsequent rapid
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Journal of the American Chemical Society
“chain walking” in the latter case that occurs to relieve the steric
Page 4 of 9
Further exploration showed that, in a more regio-biased case,
when the double bond is much far away (such as more than five
carbons) from the Bpin group and closer to the unsubstituted
terminal carbon (less than two carbons), gem-borazirconocene
alkane is still the main product (4a, branch:linear = 2:1),
although the terminal linear alkylzirconocenes can also be
generated as minor products. Interestingly, allylic and
homoallylic boronates exclusively generate the linear
alkylzirconocenes and afford the corresponding products (4f-
4h), findings in accordance with previous studies.13
hindrance.6 However, in the presence of terminal Bpin, we
wondered whether this Bpin could be harnessed as a directing
group to reverse the chain walking selectivity. To pursue this
and gain insights about the regioselectivity of this type of chain
walking and cross-coupling protocol, we designed a series of
terminal Bpin substituted internal alkenes with different chain
lengths and geometric isomers of the double bonds (Table 4).
To our delight, when the double bonds are located in a
reasonable range (half way or closer) to the Bpin group, the
Bpin group directs the hydrozirconation and the “chain
walking” process, generating the branched gem-
borazirconocene alkanes exclusively, which further cross
couples with aryl iodides to afford the benzylic secondary Bpin
products in high regioselectivity (4b-4e, >40:1).
1
2
3
4
5
6
7
8
9
G Kcal/mol
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
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Cp
Cp
Cl
H
Cp
Cl
Zr
Cl
Zr
Cp
Cl
H
Cp
Cp
Cl
H
Cl
Zr
H
Zr
H
Zr
Cp
Cp
BPin
H
Zr
Cp
Cp
Cp
BPin
Cp
BPin
BPin
BPin
BPin
TS6
TS1
TS2
TS3
TS4
TS5
25.4
TS2
22.8
TS4
20.8
TS1
19.5
TS5
19.2
TS3
Table 4. The scope of chain walking strategya
16.2
TS6
backward
forward
Bpin
[Zr]
[Zr]
R1
FG
Bpin
n
ClCp2Zr
Bpin
m
Steric release
B-direction
ZrCp2Cl
3.2
2.6
Zr-3
Ar-I [Ni]
Bpin
Ar-I [Ni]
0.9
Zr-2
0.0
-0.4
-2.6
Ar
Bpin
m
Zr-4
(S4g)
-5.8
R1
Bpin
(S4e)
(1-ene)
Bpin
Ar
Bpin
+
+
P1
P2
+
Zr-1
Zr-0
(
)
Cp2ZrHCl
Zr-0
)
Cp2
ZrH
Cl
(
Zr-0
(
)
Cp2ZrHCl
P1
P2
Entry
Substrate
Product
Ratio (P1:P2) Yield (%)
Cp
Cp
Cp Zr
Cp
Cp Zr
Cp
Cp Zr
Cl
Cl
pinB
pinB
Cl
Cl
BPin
Bpin
Cp Zr
1
4
75b
2:1
4a
4b
4c
Ar1
Ar1
Bpin
Ar1
Ar1
7
Bpin
Bpin
BPin
6
7
Zr-1
Bpin
Zr-4
Zr-3
Zr-2
74
2
>40:1
2
Bpin
3
8
Figure 2. The DFT calculation result of the hydrozirconation
process of 1-pinacolboron-2-butene (S4e). More details of the
calculations are described in the supplementary information.
Bpin
Bpin
Bpin
Bpin
Ar1
Ar1
Ar1
Ar2
Bpin
Bpin
Bpin
Bpin
72
72
3
4
5
>40:1
Ar1
Ar1
Ar1
Ar2
pinB
3
8
2
7
3
2s (4d)
2r (4e)
only P1
pinB
pinB
4
To gain insights into the relative propensity of Bpin directed
effect of chain walking versus other potential directing group
such as heteroatom, we designed several substrates containing
different type of functional groups, which might affect the chain
walking direction (entries 9-13). Substrates containing phenyl,
ether, silane groups would not affect the migration selectivity of
the Zr moiety and the corresponding cross-coupling products
can be afforded in moderate to high yield (4i-4k, 54-81%).
However, when thioether or thiophene groups were installed at
the other terminal position, the Bpin directed chain walking
process was almost completely inhibited (entries 12-13). The
D2O-quenching reaction showed the major products were the
isomeric mixtures of the reduced substrates. And only trace
amount of D-incorporation at the α-carbon of Bpin or
thiophene group were observed, which indicated the chain
walking selectivity in these substrates is not optimal due to the
interruption by the thioether or thiophene groups.
72
>40:1
2
pinB
pinB
only P2
only P2
only P2
75c
4f
6
7
Bpin
Bpin
74c
72c
Bpin
4g
Ar2
Ar2
Ar2
Ar2
Bpin
pinB
Bpin
pinB
4h
4i
8
9
3
4
3
4
Ph
Bpin
Bpin
54d
78e
Ar1
Ar1
Bpin
only P1
only P1
Ph
Ar1
Ar1
Ph
OPh
OPh
TMS
4j
10
11
Bpin
5
OPh
5
pinB
pinB
TMS
Bpin
Bpin
81e
4k
only P1
Ar1
Ar1
Bpin
Bpin
Ar1
Ar1
TMS
SMe
5
5
5
SMe
SMe
0e,f
12
13
4l
--
--
5
Bpin
S
pinB
Ar1
0e,f
S
4m
5
Ar1
Bpin
S
5
To illustrate the chemical selectivity of the chain walking
process, we carried out a DFT calculation of zirconocene
“walking” forward (towards Bpin group) or backward on 1-
pinacolboron-2-butene substrate (S4e). Analysis of the
transition state of hydrozirconation revealed two clear types of
TSs: endo-type and exo-type. For an endo-type TS, an alkylene
inserts the Zr-H bond inside the H-Zr-Cl angle in 138 degrees
(TS1-TS6); and for an exo-type TS, an alkylene inserts the Zr-H
bond inside the H-Zr-Cl angle in 73 degrees (TS7-TS12). The
DFT analysis indicated that the endo-type is more favorable
than exo-type, and the Gibbs free energies are about 10
Kcal/mol lower for endo-type (discussed in detail in
supplemental information, Table S10). The calculation results
of endo-types are shown in Figure 2: terminal alkylzirconocene
aUnless otherwise noted, yields of isolated products given at a 0.3
mmol scale; the temperature of hydrozirconation is 50 0C. all
reactions were performed with Ni(dtbbpy)Br2 (1 mol%), gem-
borazirconocene alkanes (0.6 mmol), aryl iodides (0.3 mmol), and
THF (2 mL), at 25-30 °C with two 36 W blue LED bulbs for 24
hours, the regioisomeric ratio (branch/linear) in parentheses was
1
determined by H NMR of crude samples. See the supplemental
information for detailed reaction conditions. Ar1
= 4-
HOCH2(C6H4), Ar2
=
4-AcNH(C6H4). b4 equiv. gem-
borazirconocene alkanes was used. c1 equiv. of Bu4N+OTs- was
e
added. d35% of starting material S3o was recovered. yields of
f
isolated products given at a 0.2 mmol scale. More than 90% of
starting material S3o was recovered.
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species are the most stable, and the branch gem-
Inspired by the DFT calculation result mentioned above, we
then investigate the possibility of reversing the chain walking
selectivity of terminal-Zr motifs (Table 4, entries 1, 6, 8). As
illustrated in Table 6, when the temperature of
hydrozirconation of S4a and S4g-h were increased from 50 oC to
110 oC, which should be sufficient for the terminal-Zr motifs to
cross the energy barrier (>27 kcal/mol), the terminal-Zr motifs
could be gradually converted into the corresponding gem-
borazirconocene via the Bpin directed chain walking process
and further cross couples with aryl iodides to afford the benzylic
secondary Bpin products in high regioselectivity (entries 1 vs 2,
entries 3 vs 4, entries 5 vs 6). More interestingly, with these data
in hand, we are able to design substrates (as entries 3-6) to
synthesize a variety of broad branch (>110 oC) or linear (room
1
2
3
4
5
6
7
8
borazirconocene alkane Zr-1 is more stable than the linear
alkylzirconocene Zr-4 (ΔG (Zr-1, Zr-4) = -3.2 kcal/mol).
Considering that the walking processes of the non-terminal
species are reversible at room temperature (ΔGTS<23kcal/mol)
(Table 4, entries 1-5), we speculate that the zirconocene should
move from the middle position to Bpin side under
thermodynamic control due to the stability of branch gem-
borazirconocene alkane Zr-1. Kinetically, for the non-terminal
species, the barrier of Zr walking forward is 22.8 kcal/mol,
which is 2.6 kcal/mol lower than the barrier of walking
backward. Using the Boltzmann distribution, we can calculate
the ratio of Zr-4 to Zr-1 as 1.2%, which is close to the
experimental ratio (<1:40). However, once the zirconocene has
already isomerized to the terminal (Table 4, entries 6-8, S4f-S4h,
and the more region-biased substrate, entry 1, S4a), the barrier
to walk back to another side would be significantly high
(>27kcal/mol) due to the stability of terminal-
alkylzirconocene species. This calculation data was also
confirmed by the experimental data of the chemoselectivity of
substrate 4g.
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
o
temperature to 50 C) alkylborane derivatives selectively. To
the best of our knowledge, this is the first study demonstrating
the conversion of primary zirconium alkane to secondary
zirconium alkane with high regioselectivity via Bpin directed
chain walking process.
Table 6. The study of chain walking selectivitya
Alkyl
Bpin
n
[Zr]
[Zr]
B-direction
X oC/ Y hours
Steric release
X oC/ Y hours
Bpin
R1
Bpin
R1
Ar-I
[Ni]
G >27 kcal/mol
Ar-I
Ar
Bpin
ClCp2Zr
Bpin
m
Ar
110 o
C
m
ClCp2Zr
Substrate
4
[Ni]
P2
P1
X oC/ Y hours
Entry
Product
P1
Bpin
P2
Ratio (P1:P2) Yield (%)
pinB
1
75b
2:1
50/36
4a
6a
Ar1
7
Bpin
Bpin
Ar1
6
pinB
Bpin
2
110/24
42c
only P1
Ar1
7
4
Ar1
6
Bpin
Bpin
50/1
3
4
74d
78
Bpin
pinB
pinB
4g
only P2
only P1
Ar2
Ar1
Ar2
Ar1
110/24
Bpin
2r (6b)
Figure 3. The localized molecular orbitals (LMO) of the Zr-1(gray:
Carbon, white: Hydrogen, red: Oxygen, green: Chlorine, cyan:
Zirconium, pink: Boron). (a) The bonding orbital of C-B bond. (b)
The bonding orbital of C-Zr bond. LMOs were generated by
Multiwfn 3.6 program15 and drawn by VMD program16.
Bpin
72d
35c
Bpin
Bpin
Ar2
3
only P2
only P1
5
6
pinB
pinB
50/1
4h
6c
Ar2
Ar2
Bpin3
Ar2
3
110/24
3
aUnless otherwise noted, yields of isolated products given at a 0.3
mmol scale; all reactions were performed with Ni(dtbbpy)Br2 (1
mol%), gem-borazirconocene alkanes (0.6 mmol), aryl iodides (0.3
mmol), and THF (2 mL), at 25-30 °C with two 36 W blue LED
bulbs for 24 hours, the regioisomeric ratio (branch/linear) in
parentheses was determined by 1H NMR of crude samples. See the
supplemental information for detailed reaction conditions. Ar1 = 4-
Table 5. Mayer Bond Orders of C-Zr bond and C-B bond. Generate
by Multiwfn 3.6 program.
Mayer Bond Orders17
C-Zr
0.88
0.97
C-B
1.14
1.05
Zr-1
Zr-4
HOCH2(C6H4), Ar2
borazirconocene alkanes was used. More than 40% of starting
material S3o was recovered. d1 equiv. of Bu4N+OTs- was added.
=
4-AcNH(C6H4). b4 equiv. gem-
c
After localized the molecular orbital of Zr-1, as shown in
Figure 3, the C-Zr bonding orbital delocalized to boron’s p
orbital. This σ-p hyperconjugation between C-Zr bond to
boron’s unoccupied p orbital enhances the C-B bond strength.
Further evidence comes from the Mayer bond order, which
indicates the electron pairs that are shared between two atoms.
Table 5 shows that the Mayer bond order of C-Zr in Zr-1(gem-
borazirconocene alkane) is decreased comparing with the Zr-4’s
(terminal alkylzirconocene), while it’s increased in C-B bond.
This complementary variation also indicates the σ-p
hyperconjugation. This unique effect in Zr-1 might raise the
activity of C-Zr bond and stabilized the gem-borazirconocene
alkane species.
Scheme 1. Synthetic application and preliminary result of
enantioselective reaction.
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Journal of the American Chemical Society
Page 6 of 9
A) Synthetic application
*Xiangbing Qi - National Institute of Biological Sciences, 7 Science
I
1
2
3
4
Park Road, Zhongguancun Life Science Park, Beijing 102206,
China. Tsinghua Institute of Multidisciplinary Biomedical
Research, Tsinghua University, Beijing 100084, China. Email:
qixiangbing@nibs.ac.cn.
Ni(dtbbpy)Br2 (1 mol%)
THF (0.15 M), Ar, rt, 24 h
36 W blue LED bulbs
S
OH
NaBO3, THF/H2
BrMg
O
n-BuLi, NBS
Bpin
S
THF
7a,
85% yield
7e,
83% yield
3t
, 73% yield
5
6
7
8
n-BuLi, pOMe-PhCHO,
I
I2, MeOH
DMP,
Notes
Pd2(dba)3
PPh3
O
OMe
Ag2
O
The authors declare no competing financial interests.
OMe
7b,
82% yield
THF
OMe
7d,
55% yield
ACKNOWLEDGMENT
7c,
53% yield
9
B) Preliminary result of enantioselective reaction
Bpin
This work was supported by Chinese Ministry of Science and
Technology 973 grant (2014CB849603), the National Natural
Science Foundation of China (NSFC) (Grant No. 21772092) and
the Priority Academic Program Development of Jiangsu Higher
Education Institutions – China (PAPD). We thank Dr. Jianwei Bian
for crucial comments and suggestions. The computational
resources utilized in this research were provided by the Shanghai
Supercomputer Center.
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
Bpin
Ni(glyme)Br2 (5 mol%)
I
+
ZrCp2Cl
2 equiv.
O
O
1 equiv.
-3t
(S)
N
N
Cy
Cy
71% yield, 56% ee
(7 mol%)
THF, Ar, rt, 36 W blue LED bulbs
The utility of our method is also summarized in Scheme 1. As
illustrated, the Bpin group can act as a starting point, affording
a series of different derivatizations of 3t in moderate to high
yield (7a-7e, 53%-85% yield), including the oxidation,
lithiation-borylation, Zweifel olefinations, and Suzuki cross-
couplings. Since enantiomerically enriched organoboron
compounds are important and versatile intermediates in
chemical synthesis18 due to the wide applicability of the C-B
bond and their stereospecific transformation, the development
of enantioselective version of our method is of great
significance. From our preliminary results, (S)-3t could be
obtained with moderate enantioselectivity (56% ee) and yield
(71%) using a chiral (R, R)-Cy-Biox ligand, which showed great
potential to develop the enantioselective cross-coupling
reaction between gem-borazirconocene alkanes and a variety of
aryl halides.
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
CONCLUSION
In conclusion, we have disclosed a visible-light-induced
nickel-catalyzed chemoselective cross-coupling reaction
between the gem-borazirconocene alkanes and aryl halides,
affording a range of secondary alkyl boronic esters in high
regioselectivtity. Furthermore, by selectively harnessing the
directing effect of the Bpin group, we have demonstrated that
internal alkenes bearing a terminal Bpin can be converted into
the desired coupled products with high regioselectivtity.
Further ongoing work is focusing on the flow chemistry setting
of hydrozirconation, chain walking and sequential cross-
coupling of resulting gem-borazirconocene alkanes and
R1R2B(pin). The catalytic asymmetric version is also under
investigation.
ASSOCIATED CONTENT
Supporting Information.
Supporting information includes synthetic procedures, spectral
data, compound characterization, and cartesian coordinates of
computational structures. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
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