Nickel-Catalyzed Enantioconvergent Borylation of Racemic Secondary Benzylic Electrophiles

Article abstract of DOI:10.1002/anie.201806015

Nickel-catalyzed cross-coupling has emerged as the most versatile approach to date for achieving enantioconvergent carbon–carbon bond formation using racemic alkyl halides as electrophiles. In contrast, there have not yet been reports of the application of chiral nickel catalysts to the corresponding reactions with heteroatom nucleophiles to produce carbon–heteroatom bonds with good enantioselectivity. Herein, we establish that a chiral nickel/pybox catalyst can borylate racemic secondary benzylic chlorides to provide enantioenriched benzylic boronic esters, a highly useful family of compounds in organic synthesis. The method displays good functional group compatibility (e.g., being unimpeded by the presence of an indole, a ketone, a tertiary amine, or an unactivated alkyl bromide), and both of the catalyst components (NiCl₂?glyme and the pybox ligand) are commercially available.

Full text of DOI:10.1002/anie.201806015

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Accepted Article
Title: Nickel-Catalyzed Enantioconvergent Borylation of Racemic
Secondary Benzylic Electrophiles
Authors: Gregory C Fu, Zhaobin Wang, Shoshana Bachman, and
Alexander Dudnik
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806015
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10.1002/anie.201806015
Angewandte Chemie International Edition
COMMUNICATION
Nickel-Catalyzed Enantioconvergent Borylation of Racemic
Secondary Benzylic Electrophiles**
Zhaobin Wang, Shoshana Bachman, Alexander S. Dudnik, and Gregory C. Fu*
Abstract: Nickel-catalyzed cross-coupling has emerged as the most
versatile approach to date for achieving enantioconvergent carbon–
carbon bond formation using racemic alkyl halides as electrophiles.
In contrast, there have not yet been reports of the application of
chiral nickel catalysts to corresponding reactions with heteroatom
nucleophiles to produce carbon–heteroatom bonds with good
enantioselectivity. Herein, we establish that a chiral nickel/pybox
catalyst can borylate racemic secondary benzylic chlorides to
provide enantioenriched benzylic boronic esters, a highly useful
family of compounds in organic synthesis. The method displays
good functional group compatibility (e.g., unimpeded by the
presence of an indole, a ketone, a tertiary amine, or an unactivated
alkyl bromide), and both of the catalyst components (NiCl2•glyme
and a pybox ligand) are commercially available.
Nickel-catalyzed enantioconvergent cross-couplings:
a) Previous work: Limited to C–C bond formation
X
R2
R2
M
R1
racemic
*
R1
R
R
enantioenriched
b) This study: C–B bond formation
Bpin
X
B2pin2
R1
Ar
R1
enantioenriched
Ar
*
racemic
Figure 1. Nickel-catalyzed enantioconvergent cross-couplings of alkyl
electrophiles.
Enantioenriched benzylic boronic esters are an important family
of target compounds in organic synthesis.[1,2,3,4] From a practical
perspective, boronic esters are attractive compared with
organometallic reagents such as Grignard reagents and
trialkylboranes due to their comparatively high air- and moisture-
stability.[5] Furthermore, the ability to transform the C–B bond of
boronic esters, with stereochemical fidelity, into bonds such as
C–C, C–N, C–O, and C–halogen render them highly versatile
intermediates in organic chemistry.[6] Due to these appealing
features, an array of methods have been developed for the
synthesis of enantioenriched benzylic boronic esters,[1] including
catalytic asymmetric processes such as the hydroboration of
alkenes[2] and the hydrogenation of alkenylboronic esters.[3,4]
We and others have recently described a variety of nickel-
catalyzed enantioconvergent cross-couplings of nucleophiles
with racemic alkyl electrophiles; to date, progress in this area
has been limited to the use of carbon-based nucleophiles to
form C–C bonds (Figure 1a).[7] Clearly, expanding the scope to
include C–heteroatom bond construction would substantially
enhance the usefulness of this strategy in synthesis. Aware of
the importance of enantioenriched organoboron compounds, we
chose to explore the possibility that a boron reagent might serve
as the first effective heteroatom-based nucleophile in nickel-
catalyzed enantioconvergent cross-couplings.[8,9,10,11] Herein, we
establish the viability of this approach (Figure 1b), specifically,
we report a nickel/pybox-catalyzed borylation that provides
enantioenriched boronic esters in good enantiomeric excess
from an array of racemic secondary benzylic chlorides [Eq. (1)].
10% NiCl2•glyme
Bpin
R
Cl
12% L1
(1)
B2pin2
Ar
R
Ar
1.4 equiv KOt-Bu
1.5 equiv PhCH2CH2OH
DME/CPME, r.t.
1.4 equiv
racemic
O
O
N
N
N
L1
(R,S)
Upon exploring a range of conditions, we determined that the
enantioconvergent borylation of the racemic secondary benzylic
chloride by B2pin2 that is illustrated in Table 1 can be achieved in
87% yield and 85% ee in the presence of a chiral nickel/pybox
catalyst (entry 1); NiCl2•glyme, the pybox ligand L1, and B2pin2
are all commercially available.
Essentially no C–B bond
formation is detected if NiCl2•glyme is omitted (entry 2), whereas
a small amount is observed if pybox ligand L1 or the primary
alcohol is absent (entries 3 and 4).[12] The use of pybox ligands
L2 and L3, rather than L1, leads to excellent yield but low
enantioselectivity (entries 5 and 6), whereas bis(oxazoline)
ligand L4 provides poor yield and ee (entry 7). Lowering the
temperature does not result in an enhancement in
enantioselectivity (entry 8), and the use of a single solvent leads
to a loss in yield with no change in ee (entries 9 and 10).
Decreasing the catalyst loading (10%→5%) or the amount of
nucleophile (1.4 equiv→1.1 equiv) has only a minor impact on
the course of the reaction (entries 11 and 12).
The
[*]
Z. Wang, S. Bachman, A. S. Dudnik, Prof. G. C. Fu
Division of Chemistry and Chemical Engineering
California Institute of Technology
Pasadena, CA, 91125 (USA)
E-mail: gcfu@caltech.edu
Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences, grant R01–
GM062871). We thank Dr. Scott C. Virgil, Dr. David G.
VanderVelde, Dr. Xin Mu, and Dr. Yufan Liang for assistance and
helpful discussions.
enantioconvergent borylation is not highly water- or air-sensitive:
even if it is conducted in the presence of a full equivalent of
water or in a capped vial under air, a substantial amount of
product is formed, in fairly good ee (entries 13 and 14).
[**]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201806015
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Enantioconvergent borylation of a racemic benzylic chloride: effect of
reaction parameters.[a]
Table 2. Enantioconvergent borylations of racemic benzylic chlorides: scope.[a]
10% NiCl2•glyme
Bpin
Et
Cl
12% L1
B2pin2
10% NiCl2•glyme
Ph
Et
Ph
1.4 equiv KOt-Bu
1.5 equiv PhCH2CH2OH
DME/CPME, r.t.
Bpin
R
Cl
12% L1
racemic
1.4 equiv
B2pin2
Ar
R
Ar
1.4 equiv KOt-Bu
1.5 equiv PhCH2CH2OH
DME/CPME, r.t.
"standard conditions”
racemic
1.4 equiv
ee (%)[c]
yield (%)[b]
entry
variation from the "standard conditions”
Ar
R
entry
yield (%)[b]
ee (%)
1
2
none
85
–
87
<2
16
24
95
98
17
52
80
61
78
79
no NiCl2•glyme
1
2
3
Et
Ph
Ph
Ph
81
64
80
86
82
88
3
no L1
–
Me
n-Bu
4
no PhCH2CH2OH
L2, instead of L1
L3, instead of L1
L4, instead of L1
0 °C, instead of r.t.
DME only
73
<2
–40
–6
84
84
84
80
84
5
Me
Me
6
4
Ph
82
88
CH2
7
5
6
Ph
Ph
Ph
Ph
Ph
Cy
Bn
61
79
66
74
82
64
77
69
88
85
90
78
83
80
83
86
82
82
80
86
81
83
8
9
7
(CH2)5–OBn
10
11
12
CPME only
8
(CH2)5–OBz
5% NiCl2•glyme, 6% L1
1.1 equiv B2pin2, 1.1 equiv KOt-Bu,
1.2 equiv PhCH2CH2OH
1.0 equiv H2O
9
(CH2)5–Cl
10
11
12
13
14
15
p-tolyl
Et
Et
Et
Et
Et
Et
m-tolyl
13
14
79
80
58
47
m-anisyl
o-tolyl
under air in a closed vial
[a] All data are the average of two experiments. [b] The yield was determined
through GC analysis with n-dodecane as an internal standard. [c] A negative
value for ee signifies that the major product is the R enantiomer.
o-fluorophenyl
1-naphthyl
Me Me
O
O
O
O
O
O
O
N
16
17
Et
86
81
51
81
N
Ph
Ph
N
N
N
N
N
N
i-Pr
i-Pr MeOCH2
L3
CH2OMe
Ph
L4
Ph
L2
Cl
Next, we explored the scope of this new method for the
catalytic asymmetric synthesis of enantioenriched benzylic
boronic esters (Table 2). We have determined that the alkyl
group (R) of the electrophile can vary in steric demand from Me
to Cy (entries 1–5), although the presence of a bulky cyclohexyl
substituent leads to somewhat lower yield and ee (entry 5).
Functional groups such as an ether, an ester, and an
unactivated primary alkyl chloride are compatible with the
borylation conditions (entries 7–9). With regard to the aryl
substituent, it may be substituted in the para, meta, or ortho
position (entries 10–14), and it can be a 1-naphthyl group (entry
15); however, if it is a 6-dibenzofuryl substituent, the reaction
proceeds in good yield but moderate ee (entry 16). The method
can be applied not only to an acyclic, but also to a cyclic,
benzylic chloride (entry 17). On a gram-scale (1.42 g of product),
the borylation illustrated in entry 3 proceeds in 85% yield and
88% ee.
[a] All data are the average of two experiments. [b] Yield of purified
product.
By conducting an enantioconvergent borylation in the
presence of a variety of additives, we have further examined the
functional-group tolerance of the method (Figure 2). We have
determined that an aryl chloride, aryl tosylate, epoxide,
unactivated secondary alkyl bromide, tertiary amide, ketone,
tertiary amine, benzofuran, and indole have little or no impact on
C–B bond formation, and the additive can be recovered virtually
quantitatively at the end of the reaction (>90%). On the other
hand, the presence of a thioether, aldehyde, or nitroalkane
impedes the borylation.
Figure 2. Enantioconvergent borylation of a racemic benzylic chloride:
functional-group compatibility. Each additive was examined individually.
As mentioned at the outset, enantioenriched benzylic boronic
esters are versatile intermediates in organic synthesis that can
be converted with high stereochemical fidelity into other useful
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10.1002/anie.201806015
Angewandte Chemie International Edition
COMMUNICATION
families of compounds; several representative examples are
provided in Figure 3. Thus, the illustrated boronic ester can be
aminated, hydroxymethylated, and arylated (a variety of
bioactive compounds include tertiary stereocenters that bear two
different aryl substituents[13]) without erosion in enantiomeric
excess.[6]
Keywords: asymmetric catalysis • boron • cross-coupling •
nickel
[1] For an overview with leading references, see: B. S. L. Collins, C. M.
Wilson, E. L. Myers, V. K. Aggarwal, Angew. Chem. Int. Ed. 2017, 56,
11700–11733.
[2] a) T. Hayashi, Y. Matsumoto, Y. Ito, J. Am. Chem. Soc. 1989, 111, 3426–
3428.
b) J. M. Brown, B. N. Nguyen, Science of Synthesis,
Stereoselective Synthesis 2011, 1, 295–324.
[3] M. Ueda, A. Saitoh, N. Miyaura, J. Organomet. Chem. 2002, 642, 145–
147.
[4] For representative recent reports of methods for the synthesis of generic
(i.e., no extraneous directing/functional group) enantioenriched benzylic
boronic esters, see: a) G. J. Lovinger, J. P. Morken, J. Am. Chem. Soc.
2017, 139, 17293–17296. b) J. Guo, B. Cheng, X. Shen, Z. Lu, J. Am.
Chem. Soc. 2017, 139, 15316–15319. c) C. Sun, B. Potter, J. P.
Morken, J. Am. Chem. Soc. 2014, 136, 6534–6537.
[5] Boronic Acids: Preparation and Applications in Organic Synthesis,
Medicine and Materials, D. G. Hall, Ed., Wiley–VCH, Weinheim, 2011.
[6] For representative examples and leading references, see: a) D. Leonori,
V. K. Aggarwal, Angew. Chem. Int. Ed. 2015, 54, 1082–1096. b) S. N.
Mlynarski, A. S. Karns, J. P. Morken, J. Am. Chem. Soc. 2012, 134,
16449–16451. c) A. Chen, L. Ren, C. M. Crudden, J. Org. Chem. 1999,
64, 9704–9710. d) J. Llaveria, D. Leonori, V. K. Aggarwal, J. Am. Chem.
Soc. 2015, 137, 10958–10961. e) A. Bonet, M. Odachowski, D. Leonori,
S. Essafi, V. K. Aggarwal, Nat. Chem. 2014, 6, 584–589. f) R. Larouche-
Gauthier, T. G. Elford, V. K. Aggarwal, J. Am. Chem. Soc. 2011, 133,
16794–16797.
Figure 3. Representative transformations of an enantioenriched benzylic
boronic ester.
We have determined that, with a given enantiomer of
catalyst, nickel-catalyzed borylation proceeds with essentially
identical yield and enantioselectivity, regardless of the original
configuration of the electrophile, establishing that the
stereochemistry of the borylation is fully controlled by the chiral
catalyst [Eq. (2) and (3)]. Furthermore, at partial conversion, the
ee of the electrophile is unchanged, indicating that the chiral
catalyst reacts with the two enantiomers of the electrophile at
essentially identical rates, that the electrophile does not undergo
racemization under the reaction conditions, and that C–Cl
cleavage by the catalyst is irreversible.[14]
[7] For reviews, see: a) G. C. Fu, ACS Cent. Sci. 2017, 3, 692–700. b) T.
Iwasaki, N. Kambe, Top. Curr. Chem. 2017, 374, 1–36.
[8] To the best of our knowledge, the only transition-metal-catalyzed
enantioconvergent borylation of an alkyl electrophile that has been
reported to date is
a copper-catalyzed coupling of cyclic allylic
ethers/carbonates: H. Ito, S. Kunii, M. Sawamura, Nat. Chem. 2010, 2,
972–976.
[9] For stereospecific nickel-catalyzed borylations of enantioenriched
electrophiles, see: C. H. Basch, K. M. Cobb, M. P. Watson, Org. Lett.
2016, 18, 136–139.
[10] For early examples of metal-catalyzed, non-enantioselective borylations
of primary benzylic halides, see: A. Giroux, Tetrahedron Lett. 2003, 44,
233–235.
[11] For
a review of metal-catalyzed borylations of aryl and alkenyl
electrophiles, see: T. Ishiyama, N. Miyaura, Boronic Acids; D. G. Hall,
Ed.; Wiley–VCH, Weinheim, 2011, pp 135–169.
[12] We have established that, in the presence of the diboron reagent (11
NMR: δ 30 vs. BF3•Et2O), KOt-Bu, and PhCH2CH2OH, a boron-ate
complex is formed
11B NMR: δ 3), which likely serves as the
B
(
nucleophile in the transmetalation step of the catalytic cycle,
generating a nickel–boryl intermediate.
[13] For example: ZoloftTM (H. R. Khouzam, R. Ernes, T. Gill, R. Roy, Compr.
Ther. 2003, 29, 47–53) and DetrolTM (D. S. Elterman, B. Chughtai, S. A.
Kaplan, J. Barkin, Expert Opin. Pharmacother. 2013, 14, 1987–1991).
[14] a) For an example of (modest) kinetic resolution in a nickel-catalyzed
enantioconvergent cross-coupling of a racemic alkyl electrophile, see:
P. M. Lundin, G. C. Fu, J. Am. Chem. Soc. 2010, 132, 11027–11029. b)
For an example of stereoisomerization of an alkyl electrophile in a
nickel-catalyzed stereoconvergent cross-coupling, see: X. Mu, Y.
Shibata, Y. Makida, G. C. Fu, Angew. Chem. Int. Ed. 2017, 56, 5821–
5824.
In summary, we have enlarged the scope of nickel-
catalyzed
stereoconvergent
cross-couplings
of
alkyl
electrophiles to include C–heteroatom bond construction for the
first time, specifically, transforming racemic benzylic chlorides
into enantioenriched benzylic boronic esters, a useful family of
compounds in organic synthesis. The method displays good
functional-group compatibility, and both of the catalyst
components (NiCl2•glyme and pybox ligand L1) are
commercially available. Investigations of other C–heteroatom
bond-forming processes, including enantioconvergent reactions,
as well as mechanistic studies, are underway.
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10.1002/anie.201806015
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COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Text for Table of Contents
Zhaobin Wang, Shoshana Bachman,
Alexander S. Dudnik, and Gregory C.
Fu*
Page No. – Page No.
Nickel-Catalyzed Enantioconvergent
Borylation of Racemic Secondary
Benzylic Electrophiles
((Insert TOC Graphic here))
Layout 2:
COMMUNICATION
10% NiCl2•glyme
Zhaobin Wang, Shoshana Bachman,
Alexander S. Dudnik, and Gregory C.
Fu*
Bpin
R
Cl
12% chiral pybox ligand
B2pin2
Ar
R
Ar
1.4 equiv KOt-Bu
1.5 equiv PhCH2CH2OH
DME/CPME, r.t.
Page No. – Page No.
1.4 equiv
racemic
Nickel-Catalyzed Enantioconvergent
Borylation of Racemic Secondary
Benzylic Electrophiles
Nickel-catalyzed stereoconvergent cross-couplings of racemic alkyl electrophiles have been expanded
to include C–heteroatom bond construction for the first time, specifically, a chiral nickel/pybox catalyst
has been shown to borylate benzylic chlorides to produce enantioenriched benzylic boronic esters, a
useful family of compounds in organic synthesis.
This article is protected by copyright. All rights reserved.