Nickel-Catalyzed Enantioselective Conjunctive Cross-Coupling of 9-BBN Borates

Article abstract of DOI:10.1002/anie.201706719

Catalytic enantioselective conjunctive cross-coupling between 9-BBN borate complexes and aryl electrophiles can be accomplished with Ni salts in the presence of a chiral diamine ligand. The reactions furnish chiral 9-BBN derivatives in an enantioselective fashion and these are converted to chiral alcohols and amines, or engaged in other stereospecific C?C bond forming reactions.

Full text of DOI:10.1002/anie.201706719

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Accepted Article
Title: Ni-Catalyzed Enantioselective Conjunctive Cross-Coupling of 9-
BBN Borates
Authors: James Patrick Morken, Matteo Chierchia, and Chunyin Law
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10.1002/anie.201706719
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COMMUNICATION
Ni-Catalyzed Enantioselective Conjunctive Cross-Coupling of 9-
BBN Borates
Matteo Chierchia, Chunyin Law, and James P. Morken*[a]
Abstract: Catalytic enantioselective conjunctive cross-coupling be-
tween 9-BBN borate complexes and aryl electrophiles can be
accomplished with Ni salts in the presence of a chiral diamine ligand.
The reactions furnish chiral 9-BBN derivatives in an enantioselective
fashion and these are converted to chiral alcohols and amines, or
engaged in other stereospecific C-C bond forming reactions.
pinacol boronic esters, organolithium or Grignard reagents, and
, ]
organic electrophiles to furnish chiral organoboron products.[6 7
Preliminary mechanistic studies suggest that this process occurs
by π-activation of a reacting alkenyl boron "ate" complex by a
Pd(II) intermediate (see box, Scheme 1), followed by 1,2-
]
metalate shift.[8 This elementary step results in simultaneous
addition of the migrating group and the Pd complex to opposite
faces of the reacting alkene and is followed by reductive
elimination. In an effort to expand the scope of the reaction
towards 9-BBN derivatives, we studied the reaction of borate
complexes formed by hydroboration of 1-octene, followed by
addition of vinyllithium (Table 1). When this complex was
treated with the Pd/Mandyphos complex that is effective for
pinacolato boronate substrates (entry 1), the reaction proceeded
efficiently; however, the coupling product 1 was racemic. After a
survey of other chiral ligands provided only modest improvement
in selectivity we considered the efficacy of Ni catalysts. While Ni
complexes are less prolific than their Pd counterparts in terms of
alkene π-activation, important precedents in the arena of Heck
Organoboron compounds are broadly useful reagents in organic
chemistry. From the standpoint of enantioselective synthesis,
considerable recent research has focused on the development
of processes for the construction of chiral non-racemic
organoboronic esters, in particular pinacol boronates. These
reagents have the attractive features that they are chemically
and configurationally stable – indeed, pinacol boronic esters are
often isolable, storable materials – and they engage in a broad
]
range of chemical transformations.[1 However, less common
trialkylborane reagents hold two distinct advantages relative to
their alkyl boronic ester counterparts. First, trialkylboranes are
readily available by hydroboration of alkenes. Second, the
enhanced electrophilicity of trialkylboranes relative to boronic
esters allows the former to engage in reactions that are
unavailable to the latter. Especially powerful reactions that
apply to 9-BBN derivatives include an inexpensive CO-based
]
]
11
reactions[ ], olefin polymerization[
and oligomerization[
,
9
10
suggested that Ni(II) complexes might be effective for
conjunctive coupling.
Table 1. Catalyst Studies in 9-BBN Borate Conjunctive Coupling
]
]
homologation[2 , homologations with α-haloacetate derivatives[3 ,
9-BBN
(1.2 equiv)
THF
and O'Donnell catalytic asymmetric amino acid syntheses.[ 4
]
5% catalyst
Li
OH
PhX (1 equiv)
hexyl
Despite this synthesis utility, there is a lack of methods available
for the asymmetric synthesis of 9-BBN derivatives. Indeed, as
far as we are aware, the powerful Aggarwal homologation is the
only method for the direct preparation of nonracemic 9-BBN
1-octene
Ph
B
hexyl
then
THF, 60 °C, 12 h;
NaOH, H2O2
(1.2 equiv)
Li
1
(1.1 equiv)
Entry
MX
Ligand
PhX
Yielda
e.r.
]
reagents.[5 In this report, we address this short-coming through
1b
2
Pd(OAc)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
MandyPhos (L1)
none
PhOTf
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
50
<5
70
24
<5
<5
<5
87
60
58
50:50
the development of a Ni-catalyzed conjunctive-cross-coupling
with 9-BBN-derived boron ate complexes.
–
–
3
bipyridine
DMEDA
TMEDA
i-PrPybox (L2)
t-BuBox (L3)
L4
4
–
via:
5
–
C(sp2) MLn
catalyst
C(sp2)
RM
M
6
–
H
M
RM BL2
X
BL2
7
–
C(sp2)
BL2
RM
RM
BL2
8
79:21
93:7
95:5
metal-induced
metallate shift
9
L5
"ate" complex
10
L6
[a] Yield is after isolation and purification by silica gel chromatography. [b]
Scheme 1. Catalytic Conjunctive Cross-Coupling Reaction.
Experiment employed 1-hexene and PhOTf as substrates.
Me Me
O
O
Ph
Ar2P
Ph
Fe
N
N
Recently, our laboratory developed
conjunctive cross-coupling reaction (Scheme 1) that merges
a
Pd-catalyzed
MeHN
Ph
NHMe
Ph
O
O
NMe2
N
L5
L6
L3
t-Bu
t-Bu
N
N
PAr2
O
L2
i-Pr
NMe2
i-Pr
L1
MeHN
NHMe
N
N
t-Bu
[a]
M. Chierchia, C. Law, Prof. J. P. Morken
Department of Chemistry
Boston College
2609 Beacon Street, Chestnut Hill, MA 02467, USA
E-mail: morken@bc.edu
L4
Initial studies with Ni catalysts employed aryl halide
electrophiles and simple achiral Ni complexes. Of note, while
the reaction in the absence of ligand provides <5% yield (entry
2), when the bipyridine-derived catalyst was employed with
iodobenzene electrophile (entry 3), the coupling product was
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201706719
Angewandte Chemie International Edition
COMMUNICATION
isolated in 70% yield. In addition to bipyridine, N,N'-dimethyl-
1,2-ethylene diamine was also mildly effective (entry 4). With
these promising observations, several chiral ligands bearing sp2-
Table 2. Scope of Ni-Catalyzed Enantioselective Conjunctive Coupling[a]
5% Ni(acac)2
6% L6
Ar-I (1 equiv)
Li
9-BBN
THF
Ph
Ph
OH
R
hybridized
N
donors were examined for stereoselective
R
Ar
B
then
MeHN
NHMe
THF, 60 °C
12 h;
NaOH, H2O2
conjunctive cross-coupling reactions. While elevated levels of
selectivity were observed with pyridyl oxazoline ligands L4,
much higher levels of selectivity were observed when chiral
aliphatic diamines were employed (see Supplementary Material
for complete ligand survey), with N,N'-dimethyl-1,2-stilbene
R
Li
L6
1.1 equiv
1: (R = H): 80%, 95:5
1: (R = H): 70%, 94:6 (1 gram scale)
1: (R = H): 63%, 95:5 (from PhBr+NaI)
2: (R = OMe): 43%, 95:5
R
OH
]
diamine (L6) proving most selective.[
A survey of Ni
12
3[b]: (R = CF3): 70%, 93:7
4[c]: (R = Br): 80%, 93:7
n-octyl
precatalysts revealed that Ni(acac)2 was the most effective and
the most convenient catalyst precursor.
NH2
OH
Ph
NH2
OH
OH
n-octyl
To survey the substrate scope, a range of 9-BBN-derived
borate complexes was prepared from appropriate alkenes
(hydroboration with 9-BBN in THF, followed by addition of
vinyllithium[13]) and employed in a one-pot fashion. Treatment of
the ate complex with pre-mixed Ni(acac)2 and ligand L6 in the
presence of aryl halide electrophiles, followed by heating for 12
h at 60 °C and subsequent oxidative work-up afforded the
derived alcohols. As noted in Table 2, good yield and selectivity
can be obtained for many substrates. For the coupling with
phenyl iodide, 80% yield is obtained on small scale (0.2 mmol),
with a slight erosion of efficiency on gram scale. Bromobenzene
could also be employed as long as an equivalent of sodium
iodide is included. Both electron-poor (3, 4, 11) and electron-
rich arenes (2, 5) can serve as competent electrophiles,
although the reaction is more efficient with electron-withdrawing
groups attached to the electrophilic substrate (cf. 3 and 2).
Notably, electrophiles with sensitive functionality, such as
ketones (11), halides (4) and even free amines (5-7) are
tolerated in the reaction. Although Lewis basic functional groups
are tolerated, electrophiles with an ability to coordinate to a
linked transition metal center (2-pyridyl and ortho-anilido; 6 and
13) react with diminished selectivity. Migrating groups with
different substitution patterns were also tolerated in the reaction.
Interestingly, products derived from migration of the bicyclooctyl
group of the 9-BBN ligand were not observed as a byproduct,
even when secondary borane ligands (i.e. cyclohexyl) were
employed as a migrating group (substrate 19).[14] In addition,
substrates bearing appended arenes (5, 15, 16), silyl ethers (14),
alkenes (21), acetals (13, 17), silanes (22), and ferrocenyl
groups (25) are processed effectively in these reactions. Lastly,
catalyst control operates with chiral substrates furnishing
compounds 23, 26, and 27 with useful levels of
diastereoselection.
n-octyl
NH2
5: 54%
95:5 er
6: 62%
75:25 er
7: 80%
97:3 er
Boc
N
OH
OH
OH
S
n-octyl
n-octyl
n-octyl
8[d]: 55%
95:5 er
9: 50%
95:5 er
10: 55%
95:5 er
O
O
Ph
Cy
(BN)
B
O
N
O
O
OH
Me
OH
2
n-octyl
n-octyl
11: 78%
95:5 er
12: 65%
93:7 er
13[e]: 73%
52:48 er
Ph
Ph
O
TBDPSO
OH
OH
OH
OH
Ph
Ph
O
Ph
Ph
10
14[b]: 74%
94:6 er
15: 50%
95:5 er
16: 50%
94:6 er
17: 63%
93:7 er
Me
OH
OH
OH
Ph
OH
Ph
Cy
Ph
Cy
18: 58%
94:6 er
19: 50%
60:40 er
20: 75%
88:12 er
21: 38%
91:9 er
Me
Ph
Me
OH
Me
Ph
Me
Me3Si
Ph
O
OH
OH
OH
Ph
Fe
4
H
22[b]: 55%
94:6 er
23: 59%
84:16 dr
24: 73%
95:5 er
25: 54%
95:5 er
TBDPSO
Me
OH
Ph
TBDPSO
Me
OH
Ph
26: 74%
93:7 dr
27: 74%
95:5 dr
[a] See text and Supporting Information details. Vinyllithium prepared from n-
BuLi and tetravinyl stannane. Yields are of purified material and represent the
average value for two experiments. [b] Vinyllithium prepared from n-BuLi and
vinyl iodide. [c] Reaction conducted at room temperature. [d] Substrate was
(4-iodophenyl)triethylsilyl acetylene, which undergoes desilylation during
oxidation. [e] Product difficult to oxidize; isolated as the borane after silica gel
chromatography.
As mentioned above, 9-BBN derivatives are not commonly
generated as products of asymmetric processes. Thus, it was of
interest to examine transformations that might apply to Ni-
catalyzed conjunctive coupling products. As depicted in Figure
15
]
2, while well-established oxidation[
delivers alcohol 1
effectively, C-C bond-forming cyanomethylation[3c] was also
found to apply in a one pot protocol, directly with the 9-BBN
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10.1002/anie.201706719
Angewandte Chemie International Edition
COMMUNICATION
derivative, delivering 28 with excellent stereospecificity. In
connection to other reactions, important studies by Aggarwal[14a]
revealed a strong migratory aptitude of the 9-BBN bicyclooctane
ring that often outcompetes migration of other alkyl substituents.
To avoid this, we considered that the derived borinic ester,
readily obtained by monooxidation with trimethylamine N-oxide
(TMANO) as described by Soderquist[ 16 ], might provide a
solution. The Soderquist oxidation applied directly on product
mixtures and the resulting secondary borinic ester 29 was found
to be stable in the open atmosphere and may be purified by
column chromatography (83% isolated yield). Of note, the
inexpensive hydrated form of TMANO proved equally effective
(82% yield 29). Also of note, the borinic ester is a useful
intermediate and can be employed directly, without isolation,
allowing the alkene starting material to be converted directly, in
a one-pot fashion, to the derived stereospecific amination[17] (30)
or vinylation[18] (31) products in good yield and selectivity. The
enhanced electrophilicity of borane derivatives can also be used
to advantage in the selective functionalization of polyboryl
species as demonstrated in Figure 1b.
stereospecifically by overall anti addition across the alkene and
delivers 34; this outcome is consistent with a catalyst-promoted
metallate shift as opposed to radical-based addition reactions
that appear to operate in processes recently developed by
Studer[7h] and Aggarwal.[7i] Stoichiometric experiments with
plausible catalytic intermediates were also undertaken. For the
reaction with Ni/bipyridine, it was considered that oxidative
addition adduct 35 (eq. 2) might be a catalytic intermediate. To
investigate this, compound 35 was prepared by reacting
iodobenzene with bipyridine•Ni(cod)2 complex in pentane and
then triturating the resulting precipitate to remove unreacted
electrophile.[20] To confirm the structure, Ni(II)(aryl)iodide adduct
35 was recrystallized and its structure determined by X-ray
crystallography (inset, Figure 2).[ 21 ] Importantly, the solid
obtained from the oxidative addition reaction, when treated with
one equivalent of the octene-derived borate complex, furnished
the conjunctive coupling product in 45% yield (eq. 3). This
observation suggests that oxidative addition takes place before
the 1,2-metallate shift, a feature consistent with the observed
dependence of enantioselectivity on the structure of the aryl
iodide. It also suggests that a Ni(0)-Ni(II) redox cycle may
operate although it remains to be determined whether this
species dissociates iodide prior to "ate" complex binding or
whether five-coordinate complexes may be reactive species.
a:
5% Ni(acac)2
Ph
Ph
6%
MeHN
NHMe
Li
B(BN)
Ph
OH
Ph
(PhI 1.2 equiv)
octyl
B
octyl
octyl
5% Ni(II)/L
Ph-I
THF, 60 °C, 12 h
THF, 60 °C
15 h
OH
Li
1: 75%
95:5 er
9-BBN
Ph
hexyl B(BN)
hexyl
butyl
(1)
then
then NaOH
H2O2
D
a. Me3NO
b. MeONH2
tBuOK
Li
34: 63%
10:1 dr, 95:5 er
a. Me3NO
b. vinyllithium
c. I2, NaOMe
ClCH2CN
t-BuOK
(tBu)2phenol
D
D
Me3NO
L
c. Boc2O
Ph Ni
H
L
CN
Ph
NHBoc
O
D
H
B
Ph
Ph
B
octyl
octyl
octyl
Ph
octyl
Li
RM
28: 57%
95:5 er
30: 59%
95:5 er
31: 82%
95:5 er
29: 83%
bipyridine
THF, 3 h
N
Ph
b:
(2)
Ni(cod)2
OH
Ni
NaOH
H2O2
OH
then PhI
22 °C, pentane
2 h
I
N
5% Ni(acac)2
n-octyl
6% L6
x-ray of 35
32: 75%
96:4 er
9-BBN
THF
35: 43%
I
B(pin)
hexyl
then
THF, 60 °C
12 h
Li
N
N
CN
B(pin)
OH
octyl
Ph
+
I
mix
Li
Ni
octyl B(BN)
(3)
Cl
CN
Ph
then NaOH
H2O2
n-octyl
t-BuOK
1: 45%
35
33: 47%
95:5 er
(tBu)2phenol
Figure 2. Mechanistic experiments on Ni-catalyzed conjunctive coupling.
Figure 1. a: Direct transformation of conjunctive coupling intermediate to chiral
alcohol, amine, nitrile, and alkene products. b: Conjunctive coupling followed
by selective functionalization of the borane in preference to the B(pin) group.
To aid in the understanding of the stereochemistry of
conjunctive coupling, we prepared a coordination complex from
NiBr2 and ligand L6. The crystal structure[21] is depicted in
Figure 3 where it can be seen that the Ni chelate adopts a non-
planar conformation with the phenyl groups and N-methyl
substituents in equatorial positions. Along with this structure, we
also analysed the stereoselectivity obtained with ligand variants
L7-L11 (Figure 3). On the basis of this data, and noting the
correlation between ligand and product configuration, we
Ni-catalyzed cross coupling reactions can occur by a number
of different mechanisms, in particular those that involve
Ni(I)/Ni(III) and Ni(0)/Ni(II) redox cycles.[19] In addition to probing
these possibilities, it was also of interest to learn about the
overall topology of the Ni-catalyzed process. As depicted in
equation
1 (Figure 2), by employing isotopically labeled
vinyllithium, it was found that the Ni-catalyzed coupling occurs
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10.1002/anie.201706719
Angewandte Chemie International Edition
COMMUNICATION
propose a model (A, Figure 3) where alkene binding occurs with
the large borate group directed outside the cyclic framework of
the catalyst and with the more substituted alkene carbon
positioned away from the pseudoequatorial N-methyl group of
the ligand. With permethylated ligand L7, binding of the alkene
to the Ni complex is blocked, whereas with primary amino ligand
(L8), approach of the olefin to Ni can occur from above or below
This work was supported by the NIH (GM-118641). We thank
Dr. Bo Li (Boston College) for assistance with X-ray structures.
Keywords: Cross Coupling • Boron • Asymmetric Catalysis •
Nickel
the square plane leading to non-selective reaction.
The
stereoselectivity observed with ligands L9 and 10 is consistent
with this model as well. Notably, the high level of selectivity
observed with L11, a compound identical to L6 but with only one
backbone substituent, reveals a likely function of the phenyl
group: rather than gear the orientation of the adjacent N-methyl
group, it more likely establishes the ring conformation such that
both N-methyl groups in L11 occupy pseudoequatorial positions
and a selective reaction results. This latter observation holds
the practical implication that a broad array of readily available α-
amino acid-derived ligands may prove effective in this reaction
and thereby serve as a ligand platform to improve selectivity with
problem substrates.
[1]
[2]
[3]
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Ph
N
Ph
N
Ph
Ph
Ph
Ph
Me
Me
H
N
N
Me
Me
N
N
Me
Me Me
H
Me
H
Me
L7: <5%
L8: 54%
L9 : 52%
[8]
[9]
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43:57 e.r.
96:4 e.r.
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X
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Ph
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Ph
Ph
Ph
N
Ph
N
Me
Me
Me
N
N
Ni
Ni
Me
Ar
Ar
Me
N
H
N
Me
Me
N
H
N Me
H
H
Me
H
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Gutierrez, T. F. Jamison, Angew. Chem. Int. Ed. 2014, 53, 1858. (o) J.-
N. Desrosiers, L. Hie, S. Biswas, O. V. Zatolochnaya, S. Rodriguez, H.
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H
H
H
Li
L
H
H
L
L10: 69%
L11: 39%
L
L
H
B
B
94:6 e.r.
90:10 e.r.
RM
Li
RM
A
favored
disfavored
Figure 3. a. X-ray structure of (L6)2NiBr2. b. Effect of ligand structure on
conjunctive coupling reactions to furnish compound 1 (conditions of Table 2).
Also depicted is a stereochemical model for the reaction (inset).
In conclusion, we have demonstrated the ability of Ni(II)
catalysts to promote conjunctive cross-coupling of alkenyl
borates and aryl halide electrophiles.
suggest that this process operates by a net Ni(0)/Ni(II) redox
cycle similar to Pd-based catalysts. Further studies expanding
the scope of this reaction are under way.
Preliminary studies
Acknowledgements
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[13] On small scale (<200 mg), pure vinyllithium in THF and halide-
containing vinyllithium prepared from lithium-iodine exchange proved
equally efficacious. On larger scale, use of halide free vinyl lithium
(prepared by Li/Sn exchange from tetravinyl tin) provided superior
results.
[20] Compound 34 has been reported with limited characterization data (mp,
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[21] X-ray analysis has been deposited. CCDC-#will be assigned upon
acceptance.
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Entry for the Table of Contents (Please choose one layout)
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Matteo Chierchia, Chunyin Law, and
James P. Morken*
Page No. – Page No.
Ni-Catalyzed Enantioselective
Conjunctive Cross-Coupling of 9-BBN
Borates
Conjunctive Coupling: Ni-Catalyzed conjunctive couplings furnish chiral 9-BBN
derivatives in an enantioselective fashion and these are converted to chiral alcohols
and amines, or they can be engaged in other stereospecific C-C bond forming
reactions.
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