Nickel-Catalyzed Umpolung Arylation of Ambiphilic α-Bromoalkyl Boronic Esters

Article abstract of DOI:10.1002/anie.201712428

A nickel-catalyzed reductive arylation of ambiphilic α-bromoalkyl boronic esters with aryl halides is described. This platform provides an unrecognized opportunity to promote the catalytic umpolung reactivity of ambiphilic reagents with aryl halides, thus unlocking a new cross-coupling strategy that complements existing methods for the preparation of densely functionalized alkyl-substituted organometallic reagents from simple and readily accessible precursors.

Full text of DOI:10.1002/anie.201712428

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Accepted Article
Title: Ni-catalyzed Umpolung Arylation of Ambiphilic a-Bromo Boronic
Esters
Authors: Ruben Martin and Shang-Zheng Sun
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712428
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10.1002/anie.201712428
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COMMUNICATION
a
Ni-catalyzed Umpolung Arylation of Ambiphilic -Bromo Boronic
Esters
Shang-Zheng Sun and Ruben Martin*
Abstract: A Ni-catalyzed reductive arylation of ambiphilic a-bromo
boronic esters with aryl halides is described. This platform provides
an unrecognized opportunity to promote catalytic umpolung reactivity
of ambiphilic reagents with aryl halides, thus unlocking a new cross-
coupling strategy that complements existing technologies for the
preparation of densely functionalized alkyl organometallic reagents
from simple and accessible precursors.
transient radical intermediates II that might be stabilized by the
adjacent a-boron atom,[10],[11] setting the basis for
a
recombination with III prior to C–C reductive elimination (RE),
and a final single-electron transfer (SET). We anticipated that
such umpolung route would result in a pathway that might be
complementary to existing protocols for the preparation of alkyl
boronic esters,[12],[13] including the use of I with well-defined alkyl
organozinc reagents via nucleophilic/electrophilic regimes
(Scheme 2, path a).[14] Herein, we describe the successful
realization of this goal. This protocol is characterized by its mild
conditions and excellent chemoselectivity profile while obviating
the need for carbogenic nucleophilic organometallic species
without compromising its application profile.
The dual role of ambiphilic reagents as nucleophiles and
electrophiles has attracted considerable attention, holding
promise to provide new knowledge in synthetic design (Scheme
1).[1] Despite the synthetic potential of ambiphilic a-halogenated
organometallics (I),[2],[3] their use remains confined to their innate
reactivity profile; while nucleophiles react at the electrophilic C–
X site (Scheme 2, path a), functionalization at the nucleophilic
C–M terminus occurs with electrophilic species (Scheme 2, path
b). These observations contribute to the perception that I cannot
be used in cross-electrophile coupling reactions,[4] one of the
most rapidly growing disciplines of catalysis research with
improved practicality and versatility when compared to
conventional nucleophilic/electrophilic regimes. Such a void
terrain, however, might provide an unrecognized opportunity to
alter the innate reactivity of ambiphilic reagents I in the presence
of easy-to-handle electrophiles via catalytic reversal of polarity.[5]
If successful, such a platform might offer a counterintuitive new
approach for preparing densely functionalized organometallic
reagents,[6] key carbon synthons of paramount synthetic
importance for building up molecular complexity.
innate reactivity ambiphilic reagents (δ+/δ- regimes)
I as
electrophile
I as
nucleophile
δ–
δ+
X
X
path a
path b
[M]
I
C–X cleavage
C–[M] cleavage
[M]
(δ+/δ-) coupling
ambiphilic
reagent
(δ+/δ-) coupling
this work: catalytic umpolung of ambiphilic reagents (δ+/δ+ regimes)
δ+
X
δ+ Br
δ–
BPin
umpolung (δ+/δ+)
δ–
Ni
BPin
this work
ambiphilic reagent
RE
&
SET
SET
X
L
L
Ni
X
· H
BPin
L
Ni
III
H
BPin
II
recombination
boron-stabilized
radical
IV
electrophile
dual reactivity
nucleophile
δ–
X
δ+
δ–
[M]
δ+
[M]
X
Scheme 2. Catalytic Umpolung Reactivity with Ambiphilic Reagents.
I
[M] = Li, Mg, Zn, B
X = I, Br, Cl
ambiphilic reagent
Our study began by evaluating the reductive arylation of
easily-accessible 1a with 2a (Scheme 3). After careful
optimization of all reaction parameters,[15] a cocktail consisting of
Ni(COD)2 (5 mol%) and 4,4'-dimethoxy-2,2'-bipyridine (L3, 5
mol%) in THF/DMPU at 30 ºC with Zn as reducing agent
afforded 3a in 80% isolated yield. As shown in entries 2 and 3,
the use of nickel(II) precatalysts resulted in a significant lower
yield.[16] Likewise, the use of structurally-related 1,10-
phenanthroline (L5) or 2,2’-bipyridines other than L3 resulted in
markedly lower yields of 3a (entries 4-7). A significant erosion in
yield was observed in THF or DMPU, tacitly indicating that the
combination of THF/DMPU was critical for obtaining good yields
of 3a (entries 8-9). Notably, modest results were observed with
Mn or even TDAE as reducing agent (entries 10-11). The latter
finding is particularly noteworthy,[17] leaving a reasonable doubt
that an in situ generated organozinc species comes into play.[18]
As anticipated, rigorous control experiments revealed that all of
the reaction parameters were critical for the catalytic umpolung
arylation to occur (entry 12).[15],[19]
Scheme 1. Ambiphilic Reagents
As part of our interest in Ni-catalyzed reductive coupling
reactions,[7] we questioned whether a generic umpolung strategy
could be designed for the direct arylation of readily-accessible a-
bromo alkylboronic esters with aryl halides (Scheme 2,
bottom).[8],[9] Our design principle is based on the intermediacy of
[a]
S.-Z. Sun, Prof. R. Martin
Institute of Chemical Research of Catalonia (ICIQ)
The Barcelona Institute of Science and Technology
Av. Països Catalans 16, 43007 Tarragona (Spain)
E-mail: rmartinromo@iciq.es
Prof. R. Martin
Catalan Institution for Research and Advanced Studies (ICREA)
Passeig Lluïs Companys, 23, 08010 Barcelona Spain
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201712428
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COMMUNICATION
Ni(COD)2 (5 mol%)
Br
CO2Me
2a
Het
R
Br
L3 (5 mol %)
R
Het
2a-2w
X
+
CO2Me
Zn (2 equiv)
THF/DMPU, 30 ºC
Ni(COD)2 (5 mol%)
BPin
BPin
3a-3w; 4-11
L3 (5 mol %)
1a-1i
n-C6H13
Br
n-C6H13
Zn (2.0 equiv)
THF/DMPU, 30 ºC
3a (R = CO2Me), 80%[a]
3b (R = F), 67%[b]
scope of aryl halides
R
BPin
BPin
1a
3a
NHCOMe
3c (R = Cl), 69%,[b] 75%[b],[c]
3d (R = CF3), 73%[a]
Entry Deviation from standard conditions 3a (%)[a]
R
R
84 (80)[b], 54[c]
n-C6H13
1
None
n-C6H13
3e (R = CN), 81%[a]
3f (R = OMe), 54%[b]
3g (R = Ph), 76%[b]
2
3
0
Using NiBr2 (5 mol%)
Using Ni(acac)2 (5 mol%)
L1 instead of L3
N
N
BPin
BPin
3
3h, 60%[a]
R=H (L1) R=OMe (L3)
R=Me (L2) R=tBu (L4)
O
4
58
80
73
59
20
28[d]
54
51
0
R
BPin
n-C6H13
O
5
L2 instead of L3
n-C6H13
6
L4 instead of L3
n-C6H13
BPin
7
L5 instead of L3
BPin
3j, 65%[a]
N
N
BPin
8
3k (R = COPh), 74%[a],[d]
3l (R = CO2Me), 63%[a]
THF as the solvent
DMPU as the solvent
Mn instead of Zn
L5
3i, 50%[a],[d]
R2
9
Me2N
Me2N
NMe2
NMe2
3m (R1 = COMe; R2 =H), 60%[a]
3n (R1 = OH; R2 =H), 53%[b],[d]
3o (R1 = R2 = Me), 67%[b]
10
11
12
O
TDAE instead of Zn
No NiBr2·diglyme, no L5 or no Zn
n-C6H13
n-C6H13
O
R1
TDAE
3p, 58%[b],[d]
BPin
BPin
R1
CO2Me
S
Scheme 3. Optimization of the reaction conditions. 1a (0.20 mmol), 2a (0.22
mmol), Ni(COD)2 (5 mol%), L3 (5 mol%), Zn (0.40 mmol), THF/DMPU (20:1,
0.20 M) at 30 ºC. [a] Yields determined by NMR spectroscopy using CH2Br2 as
internal standard. [b] Isolated yields. [c] Ni(COD)2 (1 mol%), 12 h. [d] Ni(COD)2
(10 mol%). DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
n-C6H13
n-C6H13
n-C6H13
R2
BPin
3u, 63%[a],[d]
BPin
BPin
3t, 77%[a]
3q (R1 = CH2CN; R2 = CF3), 54%[a]
3r (R1 = OMe; R2 = Cl), 71%[b]
3s (R1 = CN; R2 = Me), 82%[a]
BPin
n-C6H13
Me
Me
Me
Me
H
Me
N
Me
H
As shown in Scheme 4, a host of electron-rich and electron-
poor aryl halides reacted with good to excellent yields with the
Ni/L3 couple, independent of whether they were sterically biased
or not.[19] Heteroaryl halides could also be employed as
substrates, albeit giving slightly lower yields (3u, 3v). Particularly
noteworthy is the chemoselectivity profile of this method, as
esters (3a, 3j, 3l, 3t, 3w), nitriles (3e, 3q, 3s), alkenes (3j, 3w)
amides (3h), free hydroxyl groups (3n), ketones (3k, 3m) and
acetals (3p) were all well-accommodated, thus constituting a
useful supplement to existing catalytic methods for preparing
alkyl organometallic reagents.[6] Equally interesting was the
ability to tolerate aryl boron reagents (3i) and a diverse set of
aryl halides (3b, 3c, 3r), leaving ample room for subsequent
manipulation. Notably, this reaction could be executed on a
gram scale, affording 3c in 75% yield. Encouraged by these
initial findings, we turned our attention to exploring the
substitution pattern on the a-bromo alkylboronic ester backbone.
n-C6H13
H
H
3w, 63%[a],[e]
3v, 55%[a],[d]
BPin
O
O
scope of α-bromo alkylboronic esters (Ar = p-CO2MeC6H4)
CN
Ar
H
H
Ar
Ar
Ar
O
Ph
BPin
4, 74%[d]
BPin
6, 59%[d]
BPin
5, 60%[d]
Me
BPin
7, 63%[d]
Cl
Me
Ar
Ar
Ar
Ar
Me
H
BPin
11, 55%[d]
BPin
9, 64%[d]
BPin
10, 58%[d]
BPin
8, 61%[d]
Scheme 4. Generality of the nickel-catalyzed cross-electrophile coupling of
ambiphilic a-bromo boronic esters: As scheme 3 (entry 1); yields of isolated
product, average of at least two independent runs. [a] X = Br. [b] X = I. [c] 4
mmol 1a were utilized. [d] Ni(COD)2 (10 mol%), 12 h. [e] dr = 1:1.
As shown,
a variety of differently-substituted side-chains,
including those containing ethers (6), nitriles (7), alkyl halides (8)
or alkenes (9), could be well-tolerated. Likewise, the reaction
could be applied for unsubstituted side-chains (4) or for b-
substituted branched products (10, 11). Unfortunately, however,
a-bromo alkylated boronic esters bearing a quaternary carbon
could not participate in the targeted arylation event. with
substantial amounts of the starting material being recovered
unaltered. Taken together, these results serve as a testament to
the prospective impact of our method, representing an
alternative catalytic platform for preparing functionalized alkyl
organometallic reagents.[6],[12-14]
The utility of this method is further illustrated in Scheme 5. As
expected, 3c could participate in conventional oxidations with
NaBO3 (17)[20] or carbon homologations for incorporating alkene
functions at the C–B terminus with Grignard reagents (12)[21] or
bromoethylene (13).[22] The introduction of (hetero)aryl or
carbonyl motifs was within reach by treatment with organolithium
reagents (14, 16)[23] or Suzuki-Miyaura protocols (15).[24] If
boron-stabilized radical intermediates II intervene (Scheme 2),
we anticipated that enantioconvergent reductive arylations could
be developed when using racemic precursors and appropriate
chiral ligands.[25] As shown in Scheme 5 (bottom), 18 could be
preliminary obtained with modest enantioselectivities under a
Ni/L6 regime. However, it is worth noting that the current
catalytic enantioconvergent cross-electrophile portfolio remain
predominantly confined to the use of benzyl electrophiles.[26],[27]
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10.1002/anie.201712428
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COMMUNICATION
homologation of alkyl boronic esters
substrate, resulting in a 1:2 mixture of direct arylation product 20
to ring-closed 5-exo-trig cyclization 21 (Scheme 6, bottom).[30]
Taken together, these results can be tentatively be ascribed to a
mechanism consisting of an oxidative addition of 2 to Ni(0)/L3
followed by recombination with II. Reductive elimination from IV
delivers the product and Ni(I)/L3 that triggers a SET to 1a,
leading to Ni(II)/L3 that ultimately recovers the propagating
Ni(0)/L3 with Zn.[31],[32]
PhI
Pd2dba3 (4 mol%)
PPh3 (16 mol%)
Ar
MgBr
Ar
R
then
R
Ag2O, THF
I2, MeOH
12, 63%
15, 59%
Ar
Br
, LDA
OEt
, tBuLi
Ar
Ar
Me
R
BPin
then
then
R
R
3c
Ar = p-ClC6H4
R = n-C6H13
I2, MeOH
then aq. NH4Cl
I2, MeOH
O
Br
In summary, we have designed a Ni-catalyzed protocol that
unlocks an opportunity to promote a reversal of polarity in
ambiphilic a-bromo boronic esters within the cross-electrophile
coupling arena. The mild conditions, excellent chemoselectivity
profile and ready availability of its easy-to-handle precursors
constitute a straightforward alternative to existing technologies
en route to densely functionalized alkyl organometallics. Further
investigations into related processes, and the identification of the
mechanistic intricacies, are currently ongoing in our laboratories.
13, 64%
16, 75%
Ar
Ar
Li
O
then
O
NaBO3
R
R
OH
THF/H2O
NBS
14, 51%
17, 84%
preliminary enantioconvergent coupling reaction
1a
racemic
+
Ni(COD)2 (5 mol%)
Ar
O
L6 (5 mol%)
OH
18
n-C6H13
N
Zn (2.0 equiv)
THF/DMPU, -20 ºC
then, NaBO3, THF-H2O
tBu
N
H
2a
L6
Ar = p-CO2MeC6H4
Acknowledgements
38% yield
27% ee
We thank ICIQ, MINECO (CTQ2015-65496-R & Severo Ochoa
Accreditation SEV-2013-0319) and the Cellex Foundation for
support. We also thank E. Escudero/E. Martin for X-ray
crystallographic data. S. –Z. Sun thanks MINECO and Severo
Ochoa for a FPI fellowship.
Scheme 5. Synthetic Application Profile.
reactivity of the oxidative addition species Ni-1
1a
Zn (x equiv)
Br
L3 Ni
3d
THF/DMPU
30 ºC, 9h
Keywords: cross-coupling • nickel • umpolung • C–C formation
34% (x = 0)
61% (x = 2)
CF3
Ni-1
Ni-1
[1]
For selected examples on the importance of ambiphilic reagents: (a) Z.
He, A. Zajdlik, A. K. Yudin, Acc. Chem. Res. 2014, 47, 1029; (b) A. S.
Dudnik, N. Chernyak, C. Huang, V. Gevorgyan, Angew. Chem. Int. Ed.
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P. Gillis, M. D. Burke, J. Am. Chem. Soc. 2007, 129, 6716.
Ni-1 (10 mol%)
Zn (2.0 equiv)
n-C6H13
Br
BPin
+
3d
75% yield
2d
THF/DMPU
30 ºC, 9h
1a
radical-trap experiments
[2]
[3]
(a) C. Cárdenas, N. Rabi, P. W. Ayers, C. Morell, P. Jaramillo, P.
Fuentealba, J. Phys. Chem. A, 2009, 113, 8660; (b) Metal-Catalyzed
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Wiley-VCH: Weinheim, Germany, 2004; (c) G. Köbrich, Angew. Chem.
Int. Ed. 1972, 11, 473; Angew. Chem. 1972, 84, 557.
Ar
as Scheme 3 (entry 1)
then
Br
Ar
OH
+
+
2d
NaBO3, THF-H2O
Ar = p-CF3C6H4
19
20
21
BPin
OH
45% yield
20:21 = 1:2
Selected references: (a) E. La Cascia, A. B. Cuenca, E. Fernandez,
Chem. Eur. J. 2016, 22, 18737; (b) L. –P. B. Neaulieu, J. F. Schneider,
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4546; (g) D. S. Matteson, R. Ray, J. Am. Chem. Soc. 1980, 102, 7590,
and citations therein.
Scheme 6. Preliminary Mechanistic Experiments
Next, we decided to gather indirect evidence about the
mechanism by studying the reactivity of the oxidative addition
species (Scheme 6). Although we were unable to identify the
oxidative addition of 1a to Ni/L3, exposure of 2d to Ni(COD)2
and L3 cleanly delivered Ni-1 as a crystalline solid, the structure
of which was characterized by X-ray crystallography.[15],[28] Ni-1
was shown to be catalytically competent, as 3d was obtained in
75% yield. More importantly, Ni-1 was found to react in a
stoichiometric fashion with 1a regardless of whether Zn was
present or not. The non-negligible yield of 3d in the absence of
Zn is particularly noteworthy, suggesting an initiation consisting
of SET from Ni-1 to 1a, leading to a boron-stabilized radical
intermediate II (Scheme 2, bottom).[29] The intermediacy of II
was further corroborated in radical-trap experiments with 19 as
[4]
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This article is protected by copyright. All rights reserved.

10.1002/anie.201712428
Angewandte Chemie International Edition
COMMUNICATION
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to that shown for Zn (-0.76V vs SCE). For selected recent Ni-catalyzed
cross-electrophile couplings conducted with TDAE in lieu of Mn or Zn,
see: (a) L. L. Anka-Lufford, K. M. M. Huihui, N. J. Gower, L. K. G.
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in 1a-I, but rather recovered 1a unaltered. These results argue against
the intervention of organozinc derivatives as reaction intermediates.
[19] The mass balance of the reactions accounts for unreacted starting
material and homocoupling of aryl halide.
[8]
[9]
Preparation of a-bromo alkylborons: D. S. Matteson, R. Soundararajan,
O. C. Ho, W. Gatzweiler, Organometallics 1996, 15, 152.
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II; A. Katritzky, R. J. K. Taylor, Eds.; Elsevier: Oxford, 2004.
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K. Scott, V. K. Aggarwal, Angew. Chem., Int. Ed., 2011, 50, 3760;
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Carboni, R. Nziengui, J. Am. Chem. Soc. 2000, 122, 5455; (b) B.
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Chem., 2014, 6, 584; b) See ref. 21.
[11] Such stabilization is probably due to the effective delocalization of the
radical through the vacant p orbital of the neighboring boron atom,
suggesting substantial stabilization by C–B p-bonding.
[24] D. Imao, B. W. Glasspole, V. S. Laberge, C. M. Crudden, J. Am. Chem.
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[12] (a) Boronic acids: preparation and applications in organic synthesis and
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Crudden, D. Edwards, Eur. J. Org. Chem. 2003, 4695. (c) N. Miyaura in
Catalytic Heterofunctionalization (Eds.: A. Togni, H. Grüzmacher),
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Vogels, Curr. Org. Chem. 2005, 9, 687.
[25] For excellent reviews on enantiodivergent cross-coupling reactions: (a)
A. H. Cherney, N. T. Kadunce, S. E. Reisman, Chem. Rev. 2015, 115,
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[26] For a selection of enantioconvergent cross-electrophile reactions of
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[28] CCDC 1588879 (Ni-1) contain the supplementary crystallographic data
for this paper and can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac/uk/data_request/cif
[29
For mechanistic intricacies of cross-electrophile couplings via SET: (a)
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[30] A linear relationship of 20:21 was observed at different Ni/L3 ratios,
suggesting that radical-escape rebound-type mechanism might
a
[15] For details, see Supporting Information
intervene in this reaction. See ref. 15.
[16] The addition of COD to entries 2-3 did not lead to improved yields. For
the use of COD as non-innocent ligand, see: (a) A. J. Nett, W. Zhao, P.
M. Zimmerman, J. Montgomery, J. Am. Chem. Soc. 2015, 137, 7636;
(b) J. Cornella, E. Gómez-Bengoa, R. Martin, J. Am. Chem. Soc. 2013,
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[31] For a similar mechanistic scenario, see refs. 17b and 29.
[32] For a mechanistic hypothesis, see ref. 15.
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10.1002/anie.201712428
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Ni-catalyzed umpolung arylation of
ambiphilic a-bromo boronic esters
A nickel-catalyzed reductive arylation of ambiphilic a-bromo boronic esters with aryl
halides has been developed. This mild and exceedingly tolerant methodology
unlocks an opportunity to promote a catalytic cross-electrophile coupling of
ambiphilic reagents with aryl halides via formal reversal of polarity, representing a
straightforward alternative for preparing densely functionalized organometallics.
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