Ni-Catalyzed Enantioselective Conjunctive Coupling with C(sp3) Electrophiles: A Radical-Ionic Mechanistic Dichotomy

Article abstract of DOI:10.1021/jacs.7b10519

The catalytic enantioselective conjunctive coupling of C(sp³) electrophiles can be accomplished with Ni catalysis. The enantioselectivity of the reaction is dependent on reaction mechanism with many substrates able to engage in an asymmetric process with Pybox-Ni complexes, whereas other substrates provide racemic product mixtures. The link between substrate structure and selectivity is addressed.

Full text of DOI:10.1021/jacs.7b10519

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Communication
Ni-Catalyzed Enantioselective Conjunctive Coupling with
C(sp3) Electrophiles: A Radical-Ionic Mechanistic Dichotomy
Gabriel J. Lovinger, and James P. Morken
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b10519 • Publication Date (Web): 08 Nov 2017
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Ni-Catalyzed Enantioselective Conjunctive Coupling with C(sp3)
Electrophiles: A Radical-Ionic Mechanistic Dichotomy
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Gabriel J. Lovinger and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
Supporting Information Placeholder
,
elaborated by Studer5 and Aggarwal6 7 – is intimately linked
ABSTRACT: The catalytic enantioselective conjunctive
coupling of C(sp3) electrophiles can be accomplished with
to substrate structure and therefore controllable by judicious
substrate selection.
Ni catalysis. The enantioselectivity of the reaction is de-
pendent on reaction mechanism with many substrates able to
engage in an asymmetric process with Pybox-Ni complexes,
whereas other substrates provide racemic product mixtures.
The link between substrate structure and selectivity is ad-
dressed.
While most research in the field of catalytic cross-cou-
pling8 has focused on the construction of C(sp2)–C(sp2)
bonds, recent advances have expanded the scope of cross-
coupling methods to include C(sp2)–C(sp3) and C(sp3)–
C(sp3) couplings.9 The latter class of C–C bonds are often
difficult to forge by cross-coupling due to mechanistic con-
siderations involving challenging oxidative addition, slow
transmetallation, and facile b-hydride elimination. In this
light, use of alkyl halide electrophiles in conjunctive cross-
coupling might appear to be fraught with complication.
However, it was considered that the use of Ni complexes10
might ameliorate challenges associated with b-hydrogen
elimination from Ni(alkyl) catalytic intermediates. Moreo-
ver, barriers to cross-coupling that arise from transmetalla-
tion of alkyl-M reagents11 to catalytic centers might be
avoided in conjunctive coupling since the transmetallation
step is replaced with a metal-induced metallate rearrange-
ment. We therefore began our investigations by subjecting
boron “ate” complex 1, generated from PhBpin and vinyl-
lithium, to 3-phenyl-iodopropane (2) and either Ni(acac)2
alone, or in combination with diamine L112, the optimal lig-
and for Ni-catalyzed conjunctive coupling of aryl electro-
philes.3d As depicted in Table 1, neither reaction furnished
detectable quantities of conjunctive coupling product (4). A
survey of other ligands indicated that bis(oxazoline), phos-
phine-oxazoline, and pyridyl-oxazoline are ineffective lig-
and scaffolds; however, tri-coordinate Pybox ligands fur-
nished conjunctive coupling products with good levels of
asymmetric induction. Modification of the ligand and nickel
source revealed L7 and [(methallyl)NiCl]2 as a particularly
competent combination, delivering 70% yield of conjunctive
coupling product 4 in 96% ee (entry 10). In contrast to the
enantioselective reaction with substrate 2, when a-bromo-
methyl acetate 3 was employed, the reaction furnished race-
mic product (entries 11 and 12). Unlike reaction of unacti-
vated substrate 2, reaction of compound 3 is efficient in the
absence of ligand and, with addition of NaI, can furnish the
racemic product 5 in outstanding yield.
Chiral alkylboronate esters are important building blocks
in contemporary organic chemistry and have been adopted
for both academic and industrial asymmetric synthesis.1
New methods for constructing these motifs from untapped
classes of starting materials can therefore have a significant
impact in a number of venues.2 In this connection, we have
been developing transition-metal catalyzed conjunctive
cross-coupling reactions as a means to produce alkyl-
boronate esters from vinylboron "ate" complexes and or-
,
ganic electrophiles.3 4 Preliminary studies have indicated
that conjunctive coupling can be conducted catalytically and
enantioselectively with either Ni3d or Pd3a-c complexes and,
mechanistically, appears to proceed by way of a metal-in-
duced metallate rearrangement. While these processes op-
erate efficiently and enantioselectively with C(sp2) electro-
philes, an important additional dimension in conjunctive
coupling would arise by the introduction of reactions that
employ C(sp3) electrophiles. In this report, we describe the
utility of chiral Ni complexes in efficient catalytic conjunc-
tive coupling reactions with alkyl electrophiles and describe
how the reaction path – proceeding either through an enan-
tioselective metal-induced metallate rearrangement, or
through a non-selective radical-polar cross over manifold as
Scheme 1. Ni-Catalyzed Conjunctive Coupling of C(sp3)
Electrophiles.
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above-described mechanistic proposals, substrates that
Table 1. Ni-Catalyzed Conjunctive Cross-Coupling with
C(sp3) Electrophiles
1
2
3
4
5
6
7
8
would furnish an electrophilic radical would be more prone
to react with the electron-rich vinyl boron "ate" complex15
and undergo the radical chain process described by the Stu-
der-Aggarwal cycle. Substrates leading to non-stabilized
radicals could favor the metallate shift pathway since A
would be expected to rapidly recombine with the initially-
formed radical, or these substrates might operate the Fu-type
cycle since single-electron transfer from B to an alkyl halide
might be impeded by the redox potential of the nonactivated
electrophile.
Li
5% Ni, 6% ligand
B(pin)
B(pin)
Ph B(pin) 2 or 3 (1.2 equiv)
OMe
or
Ph
Ph
Ph
THF, 60 °C, 15 h
O
1
4
5
entry E-X
ligand
none
L1
Ni salt
% yielda
<10%
<10%
<10%
<10
<5%
17
er
1
2
2
2
2
2
2
2
2
2
2
3
3
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
nd
nd
9
2
10
11
12
13
14
15
16
17
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60
3
L2
nd
Scheme 2. Prospective Mechanisms for Ni-catalyzed
Conjunctive Coupling of C(sp3) Electrophiles.
4
L3
nd
5
6b
7b
L4
nd
BL2
C(sp3)
L5
89:11
99:1
98:2
98:2
98:2
50:50
nd
RM
M
L6
36
RM BL2
BL2
C(sp3)
8b,c
9b,c
10b,c
11b,c
12d
L6
49
-MX
LnNi
C(sp3)
X
RM
E
L6
[(methallyl)NiCl]2
[(methallyl)NiCl]2
Ni(acac)2
51
LnNi(n)
Fu-type
cycle
X
C(sp3)
L7
70
A
M
L7
34
RM BL2
M
C(sp3)
BL2 C(sp3)
metallate
shift
cycle
RM BL2
Ni(acac)2
92
3
X
Ni(n+1)Ln C(sp )
+
NiLn
RM
(a) Determined by NMR versus an internal standard. (b) Deter-
mined by chiral SFC analysis. (c) Catalyst solution pre-complexed
for 1.5 h. (d) Reaction conducted at 22 °C without ligand and with
one equivalent NaI added.
A
B
Studer-Aggarwal
cycle
C(sp3)
X
Ni(n+2)Ln
set
Ph
Ph
X
C(sp3)
M
I
Ph
RM BL2
D
O
O
O
BL2
RM BL2
N
MeHN
NHMe
L1
2
C(sp3)
C(sp3)
Ph2P
N
N
N
RM
Me Me
L3
L4
+
MX
O
tBu
R
R
(racemic)
C
O
O
O
N
L5: R = i-Pr
L6: R = Ph
L7: R = m-xylyl
Br
OMe
N
N
3
N
L2
Ph
Ph
Ph
To disentangle the operative pathways for these conjunc-
tive coupling reactions, a series of mechanistic experiments
were undertaken. First, we examined reactions of a-bromo
ester 3 in the presence of TEMPO. As depicted in equation
1 (Scheme 3), addition of one equivalent of the radical scav-
enger is sufficient to inhibit formation of 5, thereby suggest-
ing that radicals are indeed involved in the reaction of this
substrate. Consistent with the non-stereospecific nature of
the radical-polar crossover mechanism, conjunctive cou-
pling between 3 and isotopically labeled "ate" complex 6
furnished the reaction product as a mixture of diastereomers
(eq. 2). Of note, radical intermediates still appear to inter-
vene in the enantioselective reactions of non-activated
haloalkanes as indicated by the ring-opening and ring-clos-
ing reactions in equations 3 and 4 (Scheme 3)16 as well as the
observation that TEMPO inhibits reaction of 1-iodobutane
(eq. 5). However, the "Fu-type" cycle is ruled out as a mech-
anistic possibility by the observation that the enantioselec-
tive conjunctive coupling of iodobutane is a stereospecific
process (eq. 6).
The marked difference in reaction selectivity when using
substrate 2 versus 3 suggested that the operative mechanisms
for these reactions are likely different. In light of recent
studies by Studer5 and Aggarwal6 on radical-polar crossover
reactions between organic halides and vinyl boron “ate”
complexes, it was suspected that radical processes might in-
tervene in the Ni-catalyzed conjunctive coupling reactions
of particular substrates and alter their course. Three mecha-
nistic scenarios were considered as plausible reaction path-
ways (Scheme 2), with all involving initial halogen atom ab-
straction13 to convert the C(sp3) halide to a carbon-centered
radical and nickel complex A. In one direction, following
the precedent of Studer and Aggarwal, reaction of the carbon
radical with the olefinic "ate" complex might deliver a-boryl
radical B, which undergoes single-electron-transfer with the
organohalide substrate thereby regenerating the carbon rad-
ical and delivering transient carbocation C; cation C would
be expected to undergo metallate shift and necessarily de-
liver racemic reaction product. Formation of enantiomeri-
cally-enriched reaction product could occur by one of two
routes: first, recombination of the initially-generated carbon
radical with Ni complex A might deliver complex D – a
compound that could engage in selective metal-induced
metallate shift similar to previously described Pd and Ni
complexes. Alternatively, aligned with recent observations
by Fu14 on cross-coupling of a-haloboronic esters, a-boryl
radical B might reengage Ni complex A to furnish E; subse-
quent intramolecular transmetallation and reductive elimina-
tion would furnish nonracemic product. Following the
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adjacent to the halide follow the metallate-shift based path-
Scheme 3. Mechanistic Experiments on Ni-catalyzed
Conjunctive Coupling of C(sp3) Electrophiles.
1
2
way and provide access to products with oxidized hydrocar-
bon functional groups (18).
2.5% [(methallyl)NiCl]2
6% (S,S)-PhPybox
NaI (1.0 eq.)
3
Li
Table 2. Impact of Substrate Functionality on Ni-Cata-
lyzed Conjunctive Coupling with C(sp3) Electrophiles.a
O
B(pin)
4
Ph B(pin)
Br
+
(1)
OMe
5
6
7
8
OMe
Ph
THF, 60 °C
15 h
TEMPO (1.0 equiv)
O
(1.2 eq.)
5, <5%
Ni catalyst
ligand
Li
O
O
B(pin)
RE
N
Ph B(pin)
+
RE
X
5% Ni(acac)2
6% (S,S)-PhPybox
NaI (1.0 eq.)
N
N
RM
B(pin)
D
Li
THF, 60 °C
15 h
9
(1.2 equiv)
O
Ar
Ar
OMe
L7: Ar = m-xylyl
Ph B(pin)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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36
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57
58
59
60
Ph
Br
+
(2)
(3)
OMe
THF, 60 °C
18 h
O
B(pin)
(pin)B
(pin)B
Ph
Et
B(pin)
Ph
5-d1, 94%
1:1 dr, 50:50 er
(1.2 eq.)
6
D
N(Ph)Bn
OtBu
Ph
Me Ph
O
O
12c
10
71%, 94:6 er
11b
35%, 83:17 er
13
86%, 50:50 er
(88%)
Li
2.5% [(methallyl)NiCl]2
6% (S,S)-PhPybox
83%, 51:49 er
1.6:1 dr
(84%)
B(pin)
Ph B(pin)
I
(1.2 eq.)
+
Ph
THF, 60 °C
15 h
B(pin)
(pin)B
B(pin)
Me
B(pin)
Ph
7
OMe
C4F9
40%, 94:6 er
OtBu
OtBu
Ph
Ph
Ph
2.5% [(methallyl)NiCl]2
6% (S,S)-PhPybox
NaI (1.0 eq.)
O
O
Me
16d
27%, 50:50 er
1.4:1 dr
O
Li
5
14b
56%, 50:50 er
(55%)
15d
Br
B(pin)
Ph B(pin)
92%, 50:50 er
(91%)
84%, 50:50 er
(83%)
+
(4)
(5)
Ph
THF, 60 °C
15 h
8
(pin)B
Ph
B(pin)
(pin)B
Ph
Me
(1.2 eq.)
40%, 98:2 er
Ph
Ph
O
Ph
2.5% [(methallyl)NiCl]2
6% (S,S)-PhPybox
NaI (1.0 eq.)
O
O
O
19c
Li
17c
53%, 50:50 er
18
35%, 96:4 er
B(pin)
9, <5%
B(pin)
72%, 51:49 er
1.6:1 dr
(71%)
Ph B(pin)
+
n-Bu-I
Ph
Me
THF, 60 °C
15 h
TEMPO (1.0 equiv)
(1.2 eq.)
(pin)B
(pin)B
OMe
Ph
O
O
N
Me
20
73%, 50:50 er
(70%)
21
5% Ni(acac)2
6% (S,S)-PhPybox
NaI (1.0 eq.)
Li
88%, 50:50 er
(90%)
Ph B(pin)
+
(6)
n-Bu-I
Ph
Me
(a) Unless otherwise noted, the "ate" complexes were prepared
by addition of the alkenyllithium to RB(pin). Data for compounds
10, 11 and 12 from reactions that employed 5% [(methallyl)NiCl]2
and 6% (R,R)-L7, others are for 5% Ni(acac)2 and 6% (R,R)-L7.
Yields in parentheses are for reactions that are ligand-free and em-
ploy 3% Ni(acac)2 at 22 °C. All yields represent isolated product
obtained after chromatographic purification. Products 10 and 11
are derived from the alkyliodide, whereas the others employed the
organobromide and one equivalent of NaI. (b) Product isolated as
the derived alcohol after peroxide oxidation. (c) The reactions were
also conducted by addition of PhLi to vinylB(pin) and gave similar
results. (d) Data is for reaction conducted by addition of PhLi to
vinylB(pin).
THF, 60 °C
18 h
(1.2 eq.)
D
9-d1, 56%
>11:1 dr, >99:1 er
D
6
With an appreciation of operative mechanisms that can in-
tervene in conjunctive coupling reactions with Ni-catalysts,
we set out to probe classes of C(sp3) electrophiles that might
avoid the radical-polar crossover path and instead engage in
enantioselective conjunctive coupling by the metallate shift-
based pathway (Table 2). Using enantioselectivity in con-
junctive coupling as a guide to reaction mechanism, it can
be concluded that whereas primary and secondary alkyl hal-
ides can engage in conjunctive coupling by the metallate
shift pathway (products 10, 11), the presence of a single
electron-withdrawing conjugating group is sufficient to ren-
der the reaction non-selective. Thus, alkyl halides bearing
an adjacent ketone (17, 19), ester (5, 13, 15-16, 20), or amide
(12) result in high yielding but non-enantioselective con-
junctive coupling, presumably because the intermediate car-
bon radical is electrophilic enough to engage in rapid reac-
tion with the nucleophilic alkene of the boron "ate" complex.
Similar to the observations of Studer5 and Aggarwal6, fluor-
inated alkyl halides (14) also appear to react by the radical-
polar crossover path and provide racemic reaction product.
It is worth noting that with activated substrates, the reaction
could be conducted equally well with or without the Pybox
ligand (Table 2), was generally more effective with
Ni(acac)2 as the Ni source, and remained racemic even with
very different migrating groups (20, 21). Lastly, whereas
substrates with conjugating heteroatoms do not engage in
asymmetric couplings, those bearing s-bonded heteroatoms
The scope of the asymmetric conjunctive coupling reac-
tion employing unactivated primary and secondary organo-
halides was further examined as depicted in Table 3. In ad-
dition to 3-phenyliodopropane, iodoethane (product 10) and
iodobutane (9) also engage in the reaction suggesting that
there is no chelating effect from a tethered functionality that
assists in the stereocontrol of this process. β-Branched elec-
trophiles (23, 28, 29) and cyclic secondary electrophiles (24,
25, 39) were also successfully engaged in the reaction
though iodocyclohexane (11, Table 2) gave low yield of the
conjunctive coupling product. Electron rich (35, 37-39),
electron poor (33, 34), sterically encumbered (32), and het-
erocyclic (37-39) migrating groups can also be successfully
employed in the reaction. Lastly, it is worth noting that the
reaction appears to be compatible with labile functional
groups such as methyl esters (27) and nitriles (33), free car-
bamate NH groups (26), and TBS-protected alcohols (28,
29). Also of note, it is possible to selectively transform
C(sp3) iodides in the presence of C(sp2) bromides (31, 36).
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Lastly, for electrophiles with labile b-substituents (30), elim-
Table 3. Ni-Catalyzed Enantioselective Conjunctive Coup-
ling with C(sp3) Electrophiles.a
1
2
3
4
ination is not observed. Current challenges to this catalytic
cross-coupling include methyl-, t-butyl-, and benzyl-based
electrophiles as well as alkyl migrating groups (inset, Table
3).
5
6
7
8
In conclusion, we have developed a highly enantioselec-
tive nickel-catalyzed conjunctive cross-coupling that can en-
gage primary and secondary C(sp3) electrophiles and can tol-
erate a range of functional groups in the production of chiral
alkylboronate ester products. Mechanistic experiments have
elucidated the origin of the divergent reactivity between ac-
tivated and unactivated electrophilic substrates and we an-
ticipate that this knowledge will be useful in the design of
new processes.
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■ ASSOCIATED CONTENT
Supporting Information. Procedures, characterization
and spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
■ AUTHOR INFORMATION
Corresponding Author
*morken@bc.edu
ORCID
James P. Morken 0000-0002-9123-9791
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGEMENTS
This work was supported by the NIH (GM-118641).
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lated product obtained after chromatographic purification. (b)
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PhLi to vinylB(pin) and provide products in 67, 65, 57, 47 and 44%
yield, respectively. (c) Product isolated as the derived alcohol after
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Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299.
(11) Overview: Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev.
2011, 111, 1417.
(12) For selected enantioselective Ni-catalyzed cross-coupling with
Ni/diamine catalysts, see: (a) Schmidt, J.; Choi, J.; Liu, A. T.; Slusar-
czyk, M.; Fu, G. C. Science, 2016, 354, 1265. (b) Wilsily, A.; Tramu-
tola, F.; Owston, N. A.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 5794.
(c) Lu, Z.; Wilsily, A.; Fu, G. C. J. Am. Chem. Soc. 2011, 133, 8154.
(d) Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 9602.
(13) For lead references, see: (a) Fu, G. C. ACS Cent. Sci. 2017, 3,
692. (b) Jahn, U. Top. Curr. Chem. 2012, 320, 323.
(14) Schmidt, J.; Choi, J.; Liu, A. T.; Slusarczyk, M.; Fu, G. C. Sci-
ence, 2016, 354, 1265.
(15) For polar effects in radical addition reactions, see: Giese, B.
Angew. Chem. Int. Ed. Engl. 1983, 22, 753.
(16) For a review of cyclopropylcarbinyl radical chemistry, see:
Nonhebel, D. C. Chem. Soc. Rev. 1993, 347.
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