Enantioselective Synthesis of Functionalized Arenes by Nickel-Catalyzed Site-Selective Hydroarylation of 1,3-Dienes with Aryl Boronates

Article abstract of DOI:10.1002/anie.202004982

A catalytic method for the site-selective and enantioselective synthesis of functionalized arenes by the intermolecular hydroarylation of terminal and internal 1,3-dienes with aryl pinacolato boronates is reported. The reactions are promoted by 5.0 mol %

Full text of DOI:10.1002/anie.202004982

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Enantioselective Synthesis of Functionalized Arenes by Nickel-
Catalyzed Siteselective Hydroarylation of 1,3-Dienes with Aryl
Boronates
Authors: Justin S. Marcum, Tiffany R. Taylor, and Simon John Meek
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202004982
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10.1002/anie.202004982
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Synthesis of Functionalized Arenes by Nickel-
Catalyzed Siteselective Hydroarylation of 1,3-Dienes with Aryl-
Boronates
Justin S. Marcum, Tiffany R. Taylor, and Simon J. Meek*[a]
Abstract: A catalytic method for the site- and enantioselective
synthesis of functionalized arenes by the intermolecular
hydroarylation of terminal and internal 1,3-dienes with aryl pinacolato
boronates is disclosed. Reactions are promoted by 5.0 mol % of a
readily available monodentate phosphoramidite-Ni complex in
ethanol, affording a variety of enantioenriched products in up to 96%
yield and 99:1 er. Mechanistic studies indicate Ni-allyl formation is
irreversible and related to the nature of the arylboronate.
development and application of chiral N,N and P,N bidentate
ligands. Included in
A. Our Previous Work: Enantioselective (CDC)-Rh-catalyzed Hydroarylation (2017)
R3
2.5 mol % [Rh(C2H4)2Cl]2
R2
PhN NPh
G
6.0 mol %
BF4
NR1
G
N
N
+
NR1
• up to 98:2 er
• With nucleophilic
N-heteroarenes
R2
R3
Ar2P
PAr2
10 mol % NaBArF
4
B. Nickel-Catalyzed Enantioselective Hydroarylation of 1,3-Dienes: Mei and Zhou (2019)
R2
Catalytic carbon-carbon bond forming methods that efficiently
convert unsaturated hydrocarbons into chiral organic molecules
in a site- and enantioselective manner has long been recognized
as important processes in organic synthesis.[1] Thus, catalytic
hydroarylation of olefins, transformations that formally add
C(sp2)–H across C–C p-bonds, has attracted considerable
interest as an attractive, atom economical approach for the
generation of functionalized arenes.[2] Consequently, several
catalytic enantioselective protocols (intra- and intermolecular)
have been developed in response.[3–4] In contrast, corresponding
methods for the enantioselective hydroarylation of 1,3-dienes are
scarce.[5, 6] The reasons for this is related to several challenges
associated with identifying catalysts that are able to control
multiple aspects of selectivity to synthetically useful levels (>95:5
er, dr, and rr). Nonetheless, transformations involving 1,3-dienes
are particularly noteworthy as they deliver products that contain a
pendant alkene for further chemical elaboration. [7, 8, 9] And yet,
there are only a few catalytic methods for the hydroarylation of
1,3-dienes in high enantiomeric purity. In spite of these
challenges, a few catalytic enantioselective examples are known.
5.0 mol %
Chiral (L)-Ni catalyst
R2
Ar B(OH)2
Ar
+
R1
Alcohol
R1
• (L)-Ni: (BOX)-Ni; Alcohol: MeOH (Single example; symmetric diene; 77:23 er)
• (L)-Ni: (spiro-AP)-Ni; Alcohol: nPrOH (4 dienes; 88.5:11.5–92:8 er)
C. This Work:
R2
G
H
chiral
Ni complex
R2
Ar
Ar
G
B(pin)
alcohol
PR3
Ni0
n Proposed
catalytic cycle:
EtOH
R’
R
R
A
Optimal catalyst?
Efficiency?
Scope?
PR3
Ni
PR3
Ni
R
R
H
G
OEt
Yield? Er?
rr? E:Z?
H
H
E
B
PR3
Ni
PR3
Ni
R
H
(RO)2B–OEt
OEt
OEt
H
H
C
G–B(OR)2
diene
D
We have previously reported catalytic site- and
enantioselective reactions between N-heteroarenes to terminal
and internal 1,3-dienes promoted by (CDC)-Rh-complex that
proceeds via an electrophilic Rh(III)-p-allyl (Scheme 1A).[10,11]
Although the method is efficient, site- and enantioselective, the
scope of the reaction centers on nucleophilic arenes, since C–C
bond formation occurs by outer sphere nucleophile addition. In
2019, Zhou reported a strategy for the catalytic hydroarylation of
alkenyl arenes that involves reaction between an olefin, aryl
boronic acid, and an alcohol in the presence of a (phosphine)-
nickel complex.[6f] Subsequently, Mei[12] and Zhou[13]
independently disclosed enantioselective versions through
Scheme 1. Catalytic Enantioselective Hydroarylations of 1,3-Dienes.
both of these studies 1,3-dienes provide low levels of
enantioselectivity (Scheme 1B).
In the case of the (bis-
oxazoline)-Ni catalyst system, a single example of a symmetric
1,3-diene is described in 77:23 er.[12] In the closely related report
by Zhou, several examples of 1,3-dienes promoted by a spiro-
N,P-Ni complex are reported, with products formed in 88.5:11.5–
92:8 er.[13] In the case of the nickel-catalyzed processes,
substrate scope is very limited, with methods relying on relatively
unfunctionalized
or
symmetric
1,3-dienes,
and
enantioselectivities lower than synthetically desirable (>95:5 er).
Our previous (CDC)-Rh method requires nucleophilic N-
heteroarenes and, due to the electrophilic nature of the cationic
Rh(I)/(III) intermediates and catalytic acid, is less tolerant of Lewis
basic functionality.[10]
[a]
J. S. Marcum, T. R. Taylor, Prof. S. J. Meek
Department of Chemistry
The University of North Carolina at Chapel Hill
Chapel Hill, NC 27599 (USA)
With these limitations in mind, we hypothesized that
development of an efficient and enantioselective Ni-catalyzed
hydroarylation would be complementary, more functional group
tolerant (vs Rh), and enable access to a broader array of chiral
arenes. The ability to employ readily accessible aryl boronic
esters, as well as control the site of C–C bond formation by inner
E-mail: sjmeek@unc.edu
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.202004982
Angewandte Chemie International Edition
COMMUNICATION
sphere reductive elimination, would be advantageous. In light of
these goals, we set out to pursue the development of a general
nickel catalyst system for the enantioselective hydroarylation of
1,3-dienes. We reasoned that identification of new ligand
scaffolds that promote hydroarylation with high levels of site- and
enantioselectivity was a crucial objective.
phosphoramidite ligands L5–L6, led to increased reactivity and
selectivity with partially hydrogenated L6 (vs binaphthyl L5)
furnishing 3a in 83:17 rr and 68:32 er (entry 6). Further ligand
modification, for example incorporation of 3,3’-aryl units onto the
diol backbone (e.g., L7–8), resulted in marked improvement in rr
(>95:5) likely due to increased sterics, however, enantioselectivity
remained unchanged (entries 7–8). In an effort to improve the
facial selectivity of 1 binding to the nickel catalyst, sterically
hindered L9 bearing 3,3’-mesityl groups was examined. The
effect of increasing sterics is significant; reaction of 5.0 mol %
Ni(cod)2 with 10.0 mol % L9 affords 3a in 43% conversion, 92:8
rr, and 95:5 er (entry 9). The use of ethanol as alcohol led to slight
increase in selectivity to 97:3 er (entry 10), while EtOH in
combination with [Ni(C3H5)Br]2 and KOtBu yielded optimal
conditions (entry 11).[15]
The proposed mechanism for the Ni-catalyzed olefin
hydroarylation reaction is outlined in Scheme 1C.[6f] The
transformation proceeds via the intermediacy of a Ni(II)–H (C)
generated by O–H oxidative addition by Ni(0) (B®C) (or ligand-
to-ligand proton transfer).[14] Subsequent, Ni(II)-alkyl formation (D)
followed by transmetalation (E) and reductive elimination affords
product and regenerates the Ni(0) catalyst A.
Me
5.0 mol % Ni(cod)2
10.0 mol % Ligand
B(pin)
Ph
Ph
H
+
2.5 mol% [Ni(C3H5)Br]2
3a
Solvent, 60 °C, 4 h
10 mol% L9
10 mol% KOtBu
B(pin)
+
2
1
Ph
Ar
Ph
Ph
+
(2.0 equiv)
(1.0 equiv)
3a’
Ph
Ar
EtOH, 60 °C
4 h
% Yield[a] rr (3a:3a’)[a] E/Z[a]
er[b]
1
2a–m
(2 equiv)
Entry Ligand
Solvent
3a–m
(1 equiv)
1[c]
2[c]
42
72
<2
<2
60
71
90
73
43
95
90
75:25
90:10
–
>95:5
>95:5
–
55:45
51:49
–
MeOH/THF (1:1)
MeOH/THF (1:1)
MeOH
L1
L2
L3
L4
L5
L6
L7
L8
Me
Me
3
Ph
Ph
4
–
–
–
MeOH
5
67:33
83:17
88:12
>95:5
92:8
92:8
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
95:5
52:48
68:32
55:45
69:31
95:5
97:3
97:3
MeOH
R
6
MeOH
3a: R = H; 82% yield, >95:5 rr, 95:5 E/Z, 97:3 er
3b: R = Me; 74% yield, >95:5 rr, 95:5 E/Z, 96:4 er
3c: R = OMe; 86% yield, 93:7 rr, 94:6 E/Z, 97:3 er
3d: R = CF3; 81% yield, 94:6 rr, 94:6 E/Z, 95:5 er[a]
3e: R = Cl; 80% yield, 94:6 rr, 93:7 E/Z, 95:5 er
3f: R = NHAc; 69% yield, >95:5 rr, 95:15 E/Z, 96:4 er
3g
7
MeOH
96% yield, 92:8 rr
>95:5 E/Z, 97:3 er
8
MeOH
9
MeOH
L9
L9
L9
10
11[d]
EtOH
EtOH
Me
Me
Me
O
Ph
Ph
BF4
BF4
Ph
Me
CO2Me
Cl
NPh
PhN
Ph
Ph
Ph
O
O
PPh2
PPh2
PPh2
PPh2
N
N
N
N
Ph
Me
O
3i
3j
3h
Ph2P
L1
L2
L3
L4
61% yield, 94:6 rr
94:6 E/Z, 97.5:2.5 er
75% yield, 95:5 rr
95:5 E/Z, 97.5:2.5 er
94% yield, 94:6 rr
>95:5 E/Z, 97:3 er
Me
R
Me
Me
L6: (R = H)
L7: (R = C6H5)
O
O
O
O
P
NMe2
O
O
P
NMe2
Ph
Ph
Ph
L8: (R = 3,5-Me-C6H3)
L9: (R = 2,4,6-Me-C6H2)
N
L5
N
Me
R
O
3m
3k
3l
Table 1. Optimization of Nickel-Catalyzed Hydroarylation of 1,3-Dienes.
Reactions performed under an N2 atmosphere on a 0.1 mmol scale with 1.0
equiv of 1 and 2.0 equiv 2. [a] Yields, regioselectivity, and E/Z ratios determined
by analysis of the crude reaction mixture using hexamethyldisiloxane as an
internal standard. [b] Enantiomeric ratios were obtained by chiral SFC or HPLC
analysis; see Supporting Information for details. [c] 10 mol % KOtBu used. [d]
Reaction with 2.5 mol % [Ni(C3H5)Br]2 and 10 mol % KOtBu.
89% yield, >95:5 rr
>95:5 E/Z, 96:4 er
71% yield, 94:6 rr
94:6 E/Z, 96.5:3.5
64% yield, 91:9 rr
94:6 E/Z, 97.5:2.5
Scheme 2.
Aryl-Boronate Scope. Reactions performed under an N2
atmosphere on 0.1 mmol scale with 1.0 equiv of 1 and 2.0 equiv Ar–B(pin).
Yields, rr, er, and E/Z ratio of the purified products are indicated beneath each
entry and are the averages of two runs; see supporting information for crude
ratios. [a] i-PrOH used as solvent.
We initiated our studies by investigating the reaction of
phenylbuta-1,3-diene (1) with phenyl-B(pin) (2) in the presence of
5.0 mol % Ni(cod)2 and MeOH at 60 °C (Table 1). Drawing from
our previous work on diene hydrofunctionalization with
carbodicarbene ligands,[7,8] we began by screening bidentate
CDC–phosphine L1, which resulted in conversion to 3a but with
low site- and enantioselectivity (entry 1). An improvement in
conversion and site-selectivity (90:10 rr) for 3a was observed by
switching to chiral NHC L2, but enantioselectivity remained
absent (51:49 er) (entry 2). Reactions performed with bis-
phosphine ligands, are particularly noteworthy, as a <2%
conversion is detected, an observation also noted by Zhou
(entries 3–4).[6f] In contrast, switching to monodentate
Next, we set out to explore the scope of the transformation,
beginning with the arylboronate fragment (Scheme 2). Under
optimized conditions a variety of aryl pinacolato borons reacted
efficiently, and with high site- (>91:9 rr) and enantioselectively
(>95:5 er), including those with an electron-donating (3b-c, 3f, 3h,
3k–l), electron-withdrawing (3d–e, 3i–j), or a naphthyl moiety
(3g). In all cases examined, substitution is well tolerated with no
loss in catalytic activity or site- and enantioselectivity. Moreover,
products are generated as the E alkene isomer in >93:7 E/Z
selectivity. Other noteworthy features of the method include, the
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10.1002/anie.202004982
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COMMUNICATION
tolerance of aryl boronates containing an aryl chloride, as well as
a heteroarene moiety; for example, the selective formation of m-
chloro 3j in 97.5:2.5 er and 5-substituted indole 3m in 96:4 er, are
illustrative. Lastly, the stereochemical assignment of the products
as (R) was determined though correlation of 3a to known
compound.[16]
groups at various positions furnish allyl-substituted arenes in up
>95:5 rr and 99:1 er. Particularly noteworthy, is the observation
that 1,3-dienes can be used as impure E/Z mixture of isomers,
without
detriment to reaction
efficiency, site- and
enantioselectivity. Such an attribute is highly advantageous from
a practicality standpoint as methods for the synthesis of
stereodefined E- or Z-dienes are not always highly selective.
Heteroarene substituted dienes also undergo efficient and
enantioselective hydroarylation, including those containing a
furan (5i), thiophene (5j), thiazole (5k), and carbazole (5l) moiety.
As illustrated by 5n, products derived from alkyl dienes can be
prepared in good yield but with significantly reduced selectivity.
Cyclohexenyl 5m, formed in 75% yield, >95:5 rr, and 97.5:2.5 er,
illustrates reactions with alkenyl boronates proceed with high er
and rr. Lastly, application of the Ni-catalyzed protocol to the
enantioselective derivatization of bioactive molecules is
highlighted by the formation of fenofibrate-derived 5o, in 90:10 rr
and 97:3 er.
Me
2.5 mol% [Ni(C3H5)Br]2
Me
H
G
10 mol% L9
O
Ar2–B(pin)
Me
G
+
10 mol% KOtBu
Me
Ar1
NMe2
O
P
Ar1
Ar2
4
EtOH, 60 °C
4 h
Me
(E/Z mixture)
(1 equiv)
2
L9
5a–o, 6a–f
Me
(2 equiv)
A. Terminal 1,3-Dienes
Me
Me
Ph
Me
Ph
R1
F
Ph
R
F
R2
5f
74% yield, 93:7 rr
95:5 E/Z, 95.5:4.5 er
5a: R1 = R2 = 3,5-Me: 79% yield
>95:5 rr, 89:11 E/Z, 98:2 er
5d: R1 = 4-CO2Me: 64% yield
94:6 rr, >95:5, E/Z, 94.5:5.5 er
5e: R1 = 4-Cl: 80% yield
5b: R1= H, R2 = 3-OMe: 80% yield
91:9 rr, 92:8 E/Z, 96:4 er
94:6 rr, >95:5, E/Z, 95.5:4.5 er
5c: R1= H, R2 = 3-CF3: 79% yield
Reactions of internal 1,4-disubstituted dienes are synthetically
desirable, however, the presence of an additional substituent
renders site-selectivity more difficult due to the closer steric parity
of the 1- and 4-positions that the Ni catalyst needs to differentiate.
Nonetheless, treatment of a variety of E/Z mixtures of internal
dienes with 5.0 mol % (L9)-Ni and an aryl-B(pin) in EtOH at 60 °C
delivers functionalized aryl products efficiently and selectively
(Scheme 3B). For example, products containing an alkyl (6a–b),
allylic NBoc carbamate (6c), ester (6d), ketone (6e), and silylether
(6f) moiety are tolerated. In general, high levels of
enantioselectivity are maintained, however, 6d and 6e are
generated in diminished 80:20 rr, possibly resulting from the
carbonyl interacting with the catalyst. Of note, the method is
compatible with enolizable ketones and esters.
91:9 rr, >95:5 E/Z, 96:4 er
Me
Me
Ph
Me
Ph
Me
O
O
O
Ph
Ar
S
NC
5i
5j
5h
5g
78% yield, 95:5 rr
86:14 E/Z, 96:4 er
93% yield, 95:5 rr
94:6 E/Z., 97:3 er
72% yield, 91:9 rr
94:6 E/Z, 95:5 er
Ar = 4-OMeC6H4, 70% yield
>95:5 rr, >95:5 E/Z, 94.5:5.5 er
Me
Ph
Me
Ph
Me
Me
S
Et
N
Me
N
Me
5m
5k
5l
75% yield, >95:5 rr
91:9 E/Z, 97.5:2.5 er
80% yield, 92:8 rr
93:7 E/Z, 91.5:8.5 er
78% yield, 93:7 rr
>95:5 E/Z, 97.5:2.5 er
O
Me
S
Me Me
i-PrO
O
O
Me
5o[a]
5n
During the course of our study a number of mechanistic
questions were raised. (1) Does the nickel catalyst isomerize the
mixture of E/Z dienes prior to hydroarylation? (2) If the reaction is
run in deuterated alcohol which positions, if any, of the product
have deuterium incorporated? (3) Does the structure of the boron
reagent play a role in reaction selectivity? To answer these
questions, first we compared reactions conducted with
isomerically enriched E and Z diene 7 (Scheme 4A). Under
standard conditions 5e is formed in identical 95.5:4.5 er but
reaction with E-7 furnishes the product in slightly diminished 92:8
rr vs 94:6 rr from Z enriched 7. In both cases the same major
enantiomer (R) of product is formed. These results indicates
(fenofibrate derived)
72% yield, 90:10 rr, 93:7 E/Z, 97:3 er
73% yield, 90:10 E/Z
67:33 rr, 78:22 er
B. Internal 1,3-Dienes
Cl
S
Ph
nPr
Ph
NHBoc
Me
Me
MeO
Ph
6a
6b
6c
54% yield, 93:7 rr
91:9 E/Z, 94:6 er
53% yield, 90:10 rr
91:9 E/Z, 95:5 er
63% yield, 92:8 rr
93:7 E/Z, 92:8 er
OMe
O
O
O
Me
Ph
OMe
OTBDPS
Ph
4
4
either the diene is isomerized prior to reaction, or
stereoconvergent process where the Z-diene initially reacts to
afford (S)–Z–Ni-p-allyl with the opposite sense of
a
O
Cl
6d
6e
6f
83% yield, 80:20 rr
83:17 E/Z, 98:2 er
63% yield, 80:20 rr
92:8 E/Z, 95:5 er
61% yield, >95:5 rr
86:14 E/Z, 90.5:9.5 er
a
enantioselectivity. Fast isomerization of (S)–Z–Ni-p-allyl via p–s–
p to the (R)–E–Ni-p-allyl, then affords (R)–E–stereoisomer as the
major product (Scheme 4B). To determine if the latter scenario is
taking place we analyzed product 5i formed in 90:10 E:Z, and
determined the enantioselectivity of Z-5i as 98:2 er (Scheme 4B).
To assess whether the relative configuration of the allylic
stereocenter in E-5i and Z-5i is formed with opposite sense of
enantioinduction, the inseparable mixture was reduced with Pd/C
in MeOH. Unfortunately, reduction of the alkene resulted in partial
reduction of the furan; as such, for analysis purposes, the
Scheme 3. Scope of Reaction with 1,3-Dienes. Reactions performed under an
N2 atmosphere on a 0.1 mmol scale with 1.0 eq of 4 and 2.0 eq 2. Yields,
regioselectivity, and E/Z ratio of the purified products are indicated beneath
each entry; see supporting information for crude ratios. The isolated yields, rr,
er, and E/Z ratio are the average of two runs. [a] With 1.5 equivalents of Ph-
B(pin)
Reactions were also extended to variations of the 1,3-diene
component (Scheme 3). Substituted aryl 1,3-dienes bearing
electron-donating (5a, h, m) and electron-withdrawing (5b–g)
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10.1002/anie.202004982
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COMMUNICATION
A. Effect of 1,3-Diene E/Z Isomer Ratio on Selectivity: Stereoconvergent
substrate was fully reduced to 8. Hydrogenation of the furan
afforded 8 in 50:50 dr, with both diastereomers formed in 85:15
er. The theoretical calculated selectivity for opposite enantiomers
is 84:16 er, confirming that Z-dienes react with the opposite facial
selectivity but Ni-p-allyl isomerizes faster than transmetalation
and C–C bond formation. Further evidence for an irreversible Ni-
p-allyl formation followed by rapid isomerization was garnered by
analyzing reactions run with CD3OD (Scheme 4C). Treatment of
E-1 with either 2c or 9 with 5.0 mol % (L9)-Ni in CD3OD affords
3c and 10 with high deuterium incorporation at the expected
homoallylic and allylic positions: >95%-D incorporation into the
methyl group of the 1,2-arylation product and 64–75% deuterium
incorporation into the methylene group of the 1,4-arylation
product. In addition, analysis of unreacted E-1 showed <2%
deuterium indicating lack of scrambling prior to transmetalation.
Lastly the effect of the boron reagent on site-selectivity was
investigated (Scheme 4D). Catalytic enantioselective reaction of
E-7 in the presence of either 2, 9, or 11 revealed an significant
variance in site-selectivity. With all three Ph–B(OR)2 reagents, 5e
is formed in high yield and 95.5:4.5 er, however, the site-
selectivity of the reactions with phenyl boronic acid and neopentyl
glycol ester 9, are significantly worse compared to pinacol ester
11. It should be emphasized, that the difference in site-selectivity
arises from hydrogen incorporation at either carbon-4 (5e and 12)
or carbon-1 (13 and 14), which occurs in the Ni-p-allyl formation
step of the mechanism. The trend follows the size of the B(OR)2
group, and an argument could be made for transmetalation being
controlled by sterics; however, this explanation does not agree
with the data in 6B. If transmetalation determines site-selectivity
then deuterium incorporation would be expected at the styrenyl
position in 3c as hydrogen incorporation at C1 reverses to C4.
Furthermore, the Ni-p-allyl leading to the formation of 13 is
sterically less hindered compared to the Ni-p-allyl that afforded
5e, and would favour transmetalation. Nevertheless, these results
indicate that the identity of the boronate plays an important role in
determining site-selectivity. A possible rationale is that site-
selective protonation occurs at the sterically least hindered
position of a (L)-Ni-diene complex (e.g., I vs II) by EtOH activated
by Ph–B(pin), either at the diene or at nickel followed by rapid
hydride migratory insertion (Scheme 4D).[17]
Standard
Conditions
• (E)-diene
Cl
78% yield
92:8 rr, >95:5 E/Z
95.5:4.5 er
Me
Ph
Ph–B(pin)
E-7 (>20:1 E/Z)
(1 equiv)
Cl
Standard
80% yield
94:6 rr, >95:5 E/Z
95.5:4.5 er
5e
Conditions
• (Z)-diene
Cl
Ph–B(pin)
Z-7 (4:1 Z/E)
(1 equiv)
B. Effect of E/Z 1,3-Diene on Enantioselectivity:
Me
Me
Ph
• Lower 85:15 er of
indicates Z-5i is formed
with the opposite sense
8
H
Pd/C, H2 (1 atm)
O
O
Ph
MeOH, 22 °C, 18 h
of enantioinduction vs
-5i, via reaction of the
opposite C=C π face of
the diene
E
5i
8
>95:5 rr, 90:10 E/Z
96:4 er (E): 98:2 er (Z)
95% yield, 50:50 dr
85:15 er, 85:15 er
(calc. 84.5:15.5 er)
l
(L9)-Ni-allyl Stereochemical Pathway:
(L)Ni OEt
Ar–B(pin)
Ar
cat. (L)-Ni
(EtOH
G
G
Me
G
Me
Me
(R)-E-Ni
(formed in high er)
E-diene
(R)-E
product
fast
G
Ar
G (L)Ni OEt
Ar–B(pin)
G
cat. (L)-Ni
(EtOH
Me
(S)-Z
product
(S)-Z-Ni
(formed in high er)
Z-diene
C. Reaction with CD3OD:
75% D: B(pin)
96% D: B(pin)
95% D: B(neo)
• Unreacted
Diene:
64% D: B(neo)
D
E-1
(1 equiv)
+
CH2D
5.0 mol % Ni(cod)2
10 mol% L9
Ar
Ph
Ph
+
Ph
Ar
1
D3COD, 60 °C
30 min
<2% D
3c
<2% D
4-OMeC6H4–B(OR)2
10
2c: B(pin)
9: B(neo)
(2 equiv)
B(pin): 35% yield (91:9 rr), >95:5 E/Z
B(neo): 89% yield (82:18 rr), >95:5 E/Z
H
D. Effect of Boronate Ester on Site-Selectivity:
4
Ph
1
2.5 mol% [Ni(allyl)Br]2
H
4
Ar
Ph
Ar
1
10 mol% L9
10 mol% KOtBu
H
(RO)2B Ph
Ar
5e
12
+
H
1
4
Ar
1
EtOH, 60 °C, 4 h
Ph
Ar = 4-ClC6H4
Ar
Ph
14
4
E-7
(1 equiv)
2, 9, 11
(2 equiv)
13
n
Proposed Rationale:
• Ph–B(OR)2: (rr = 5e:12:13:14)
78% yield
B(OH)2
Ar
b
a
R3P
a = diene
protonation
b = via Ni–H
60:0:22:18 rr
95.5:5.5 er
B(pin)
Ph
Ni
O
H
11
Et
R
l Increasing size
of B(OR)2
→ increase in
site-selectivity
I
90% yield
61:0:24:15 rr
95.5:5.5 er
O
B
vs
Ph
Ph
O
(R3P)Ni
R
R3P
Ni
Ar
In summary, we show that enantioselective Ni-catalyzed
hydroarylations of 1,3-dienes provides efficient access to
functionalized arenes. The protocol is tolerant of aryl halides,
heterocycles, and Lewis basic functionality. In addition, the above
findings indicate reactions proceed via an E/Z stereoconvergent
enantioselective process that is influenced by the identity of the
9
(pin)B
O
H
O
III
H
80% yield
93:4:1:2 rr
95.5:5.5 er
Et
R
B
II
O
• Reaction at 1-position disfavored by sterics
2
Scheme 4. Mechanistic insight into the enantioselective 1,3-diene
hydroarylation. [a] 24 h reaction; see supporting information for more details.
aryl boronate.
Further studies of enantioselective
hydrofunctionalization reactions are ongoing.
Keywords: Hydroarylation • Hydrofunctionalization • Nickel •
Enantioselective • Catalysis
Acknowledgements
[1]
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Financial support was provided by the National Science
Foundation (CHE-1665125). Mass spectrometry facilities in the
Department of Chemistry at University of North Carolina are
supported by the National Science Foundation (CHE1726291).
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10.1002/anie.202004982
Angewandte Chemie International Edition
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Justin S. Marcum, Tiffany Taylor, and
Simon J. Meek*
Page No. – Page No.
((Insert TOC
Layout 2:
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Author(s), Corresponding Author(s)*
Me
Ar2–B(pin)
+
2.5 mol% [Ni(C3H5)Br]2
10 mol% Ligand
Me
Ar2
O
Me
Page No. – Page No.
10 mol% KOtBu
Me
O
NMe2
G
G
P
Ar1
Ar1
EtOH, 60 °C
4 h
Me
Enantioselective
Functionalized Arenes by Nickel-
Catalyzed Siteselective
Synthesis
of
H
used as
E/Z mixture
Me
Hydroarylation of 1,3-Dienes with
Aryl-Boronates
A catalytic method for the site- and enantioselective synthesis of functionalized
arenes by the intermolecular hydroarylation of 1,3-dienes with aryl pinacolato
boronates is disclosed. Reactions are promoted by 5.0 mol % of a readily available
phosphoramidite-Ni complex in ethanol, affording a variety of enantioenriched
products in up to >95:5 rr and 99:1 er. Mechanistic studies indicate Ni-allyl formation
is irreversible and related to the nature of the arylboronate.
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