Highly linear selective cobalt-catalyzed addition of aryl imines to styrenes: Reversing intrinsic regioselectivity by ligand elaboration

Article abstract of DOI:10.1002/anie.201408028

Highly linear selective, imine-directed hydroarylation of styrene has been achieved with cobalt-based catalytic systems featuring bis(2,4-dimethoxyphenyl)(phenyl)phosphine and either 2-methoxypyridine or DBU as a ligand and a Lewis base additive, respectively, thus affording a variety of 1,2-diarylethanes (bibenzyls) in good yields under mild reaction conditions. The triarylphosphine controls the regioselectivity, while the Lewis base significantly accelerates the reaction. Ligand screening and deuterium-labeling studies provide implications about the roles of the ligand and the Lewis base in the crucial C-C reductive elimination step.

Full text of DOI:10.1002/anie.201408028

Angewandte
Chemie
DOI: 10.1002/anie.201408028
À
C H Activation
Highly Linear Selective Cobalt-Catalyzed Addition of Aryl Imines to
Styrenes: Reversing Intrinsic Regioselectivity by Ligand Elaboration**
Wengang Xu and Naohiko Yoshikai*
Abstract: Highly linear selective, imine-directed hydroaryla-
tion of styrene has been achieved with cobalt-based catalytic
systems featuring bis(2,4-dimethoxyphenyl)(phenyl)phos-
phine and either 2-methoxypyridine or DBU as a ligand and
a Lewis base additive, respectively, thus affording a variety of
1,2-diarylethanes (bibenzyls) in good yields under mild
reaction conditions. The triarylphosphine controls the regiose-
lectivity, while the Lewis base significantly accelerates the
reaction. Ligand screening and deuterium-labeling studies
provide implications about the roles of the ligand and the
À
Lewis base in the crucial C C reductive elimination step.
C
ontrol of regioselectivity in olefin functionalization reac-
tions has been a subject of fundamental and practical interest
in homogeneous catalysis.[1,2] Among such reactions is tran-
À
sition-metal-catalyzed addition of an arene C H bond across
styrene (hydroarylation), which can lead to branched or linear
adducts. Besides Friedel–Crafts-type hydroarylation reactions
which invariably lead to branched adducts,[3] various exam-
ples of styrene hydroarylation by transition-metal-mediated
À
arene C H activation, which selectively affords either linear
or branched adducts, have been reported.[4,5] Nevertheless,
the ability to achieve regiodivergence in this class of reaction,
that is, to transform the same arene substrate into either of the
two regioisomers by subtle modification of the catalyst or
ligand structure, has been relatively limited,[5d,6,7] regardless
of the presence of both 1,1-diarylethane and 1,2-diarylethane
in bioactive molecules.
As one of the rare examples of regiodivergent styrene
hydroarylation, we previously reported branched- and linear-
selective addition of 2-arylpyridine to styrene using cobalt/
phosphine (PCy3) and cobalt/N-heterocyclic carbene (IMes)
catalysts, respectively (Scheme 1a).[8a] To rationalize the
regiodivergence, a common catalytic cycle involving rever-
Scheme 1. Cobalt-catalyzed, nitrogen-directed hydroarylation of styr-
enes. PMP=para-methoxyphenyl, THF=tetrahydrofuran.
selectivity with the Co/PCy3 catalyst was ascribed to h3-benzyl
coordination in the branched pathway,[9] while the sterically
shielding nature of the IMes ligand was speculated to be the
origin of the linear selectivity. A recent computational study
by Fu et al. supported these speculations and suggested
intrinsic preference of cobalt catalysts toward the branched
selectivity.[10] Indeed, the scope of the branched-selective
addition has been extended to aryl aldimines and ketimines
by simple modification of the cobalt/phosphine system.[8b,c]
Herein, we report on our effort to push the limit of
regiodivergence in cobalt catalysis, which has led to a signifi-
cant expansion of the scope of linear-selective styrene hydro-
arylation. Thus, with the carefully optimized ligand [bis(2,4-
dimethoxyphenyl)(phenyl)phosphine] and Lewis base addi-
tive (2-methoxypyridine or DBU), highly linear selective
addition of aryl ketimines to styrenes is achieved at a mild
temperature (Scheme 1b).
The addition of the acetophenone imine 1a to styrene
(2a) was studied as a model reaction for ligand screening
(Scheme 2). As reported previously, by using CoBr2
(5 mol%), para-substituted triarylphosphine (10 mol%),
and CyMgBr (50 mol%), this reaction gives the branched
adduct 3aa’ at room temperature with high regioselectivity.[8c]
Contrary to our expectation, sterically crowded tris(2,6-
diethylphenyl)phosphine (L1) and tri(2-ethylphenyl)phos-
À
sible C H oxidative addition, reversible and competitive
styrene insertion leading to the branched and linear inter-
mediates A and B, respectively, and regioselectivity-deter-
mining reductive elimination was proposed. The branched
[*] W. Xu, Prof. N. Yoshikai
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637371 (Singapore)
E-mail: nyoshikai@ntu.edu.sg
Homepage: http://www3.ntu.edu.sg/home/nyoshikai/yoshi-
kai_group/Home.html
[**] This work was supported by the Singapore National Research
Foundation (NRF-RF2009-05), Nanyang Technological University,
and JST, CREST.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408028.
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Table 1: Effect of additives.[a]
Entry
Additive (mol%)
Yield [%][b]
l/b[c]
92:8
1
2
3
4
5
6
none
pyridine (80)
DMAP (80)
2-methoxypyridine (80)
2-methoxypyridine (200)
2-methoxypyridine (400)
2-methoxypyridine (80)
DBU (80)
40
54
32
70
80
91[d]
70
91
63
38
93:7
89:11
95:5
94:6
97:3
4:96
93:7
97:3
88:12
7[e]
8
9
10
DMPU (80)
TMEDA (80)
[a] The reaction was performed on a 0.3 mmol scale. [b] Determined by
1H NMR spectroscopy or GC. [c] Linear-to-branched ratio determined by
1H NMR spectroscopy or GC. [d] Yield of isolated product. [e] L9 was
omitted. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DMAP=4-(N,N-
dimethyl)pyridine, DMPU=1,3-dimethyltetrahydro-2-pyrimidinone,
TMEDA=N,N,N’,N’-tetramethylethylenediamine.
obtained in 91% yield upon isolation, with an l/b ratio of
97:3 (entry 6). The use of 2-methoxypyridine in the absence
of L9 resulted in high branched selectivity (entry 7), thus
demonstrating that L9 plays a decisive role in the linear
selectivity. Examination of other Lewis bases identified
DBU as another effective additive (91% yield, l/b = 93:7;
entry 8).
Scheme 2. Ligand screening. The reaction was performed on a 0.3 mmol
scale. The yield was determined by GC using n-tridecane as an internal
standard.
phine (L2) did not alter the regioselectivity, while maintaining
modest catalytic activity. Notably, triarylphosphines bearing
different numbers of 2,6-dimethoxyphenyl groups (L3–L5)
significantly reduced the catalytic activity but reversed the
regioselectivity (l/b = 83:17–61:39). Upon examination of
several triarylphosphines bearing 2-methoxyaryl groups
(L6–L10), an l/b ratio exceeding 90:10 was achieved with L8
and L9 bearing three and two, respectively, 2,4-dimethoxy-
phenyl groups. Subsequent screening experiments revealed
significant influence of subtle changes in the ligand structure.
The 2,5-dimethoxyphenyl analogues of L8 and L9 (L11 and
L12), the ethoxy analogue of L9 (L13), and the 4-dimethy-
lamino analogue of L9 (L14) all exhibited branched selectiv-
ity. Even changing the phenyl group of L9 to the 4-meth-
oxyphenyl or 4-fluorophenyl group reversed the regioselec-
tivity (see L15 and L16). Among other ligands examined, only
2-dimethylaminophenyl(diphenyl)phosphine L18 exhibited
linear selectivity close to 9:1. As expected, the IMes ligand
showed high linear selectivity but with very low catalytic
activity. Note also that the reaction proceeded even without
a ligand with an l/b ratio of 11:89.
By using the Co/L9/2-methoxypyridine catalytic
system, the reaction of imines derived from substituted
acetophenones, except for some meta-substituted derivatives
(see below), with styrene afforded the corresponding 1,2-
diarylethanes 3aa–ga in moderate to good yields with l/b
ratios of 90:10 or greater (Figure 1). The imine derived from
Upon further optimization using L9, we found that the
addition of an appropriate Lewis base significantly enhances
the reaction efficiency without deteriorating the linear
selectivity (Table 1). Among pyridine derivatives, 2-methoxy-
pyridine was particularly effective (entries 1–4). Using
4 equivalents of 2-methoxypyridine, the product 3aa was
Figure 1. 1,2-Diarylethanes obtained from various imines and styrene
under the reaction conditions in Table 1, entry 6. The linear-to-
branched ratio is shown within parentheses. [a] The reaction time was
48 h. [b] DBU (80 mol%) was used instead of 2-methoxypyridine.
2
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3’-methylacetophenone reacted exclusively at the less hin-
dered position (3ga). Imines prepared from tetralone deriv-
atives and 4-chromanone also afforded the desired 1,2-
diarylethanes 3ha–ka. While the performance of the Co/L9/
2-methoxypyridine system was moderate for a propiophe-
none-derived imine (72% yield, l/b = 81:19), the Co/L9/DBU
system (Table 1, entry 8) significantly improved the reaction
(3la). The reaction of 3-iminoindole was smooth but poorly
regioselective, regardless of the catalytic system used (3ma;
Figure 1).
Imines bearing a meta-alkoxy or meta-fluoro substituent
(1n–p) behaved very differently (Figure 2). These imines
À
underwent regioselective C H activation at the position
proximal to the alkoxy group or the fluorine atom, as
Figure 3. 1,2-Diarylethanes obtained from 1a and various styrenes
under the reaction conditions in Table 1, entry 6. The linear-to-
branched ratio is shown within parentheses. [a] DBU (80 mol%) was
used instead of 2-methoxypyridine. The reaction time was 48 h.
[b] Determined by 1H NMR spectroscopy.
Figure 2. 1,2-Diarylethanes obtained from meta-alkoxy or meta-fluoro
imines and styrene under the reaction conditions in Table 1, entry 6 (2-
methoxypyridine as the additive) or entry 8 (DBU as the additive). The
linear-to-branched ratio is shown within parentheses. [a] The yield was
Table 2: Deuterium-labeling experiments.
1
determined by H NMR spectroscopy.
expected from previous studies by us[8,11,12] and Ackermann
et al.,[13] but afforded the 1,2-diarylethanes 3na–pa as minor
products, with l/b ratios of approximately 2:8 to 3:7. Notably,
the use of DBU instead of 2-methoxypyridine had a sizable
effect on the regioselectivity (l/b ratios = ca. 6:4–9:1).
As summarized in Figure 3, various para, meta, ortho, and
multisubstituted styrenes participated in the reaction with 1a
to afford the corresponding 1,2-diarylethanes 3ab–ap in good
yields with high regioselectivities (90:10 or greater), except
for the case of 4-phenylstyrene (3ag; l/b = 75:25). The
reaction of 2-vinylbenzofuran took place sluggishly with
poor regioselectivity (3aq; 8%, l/b = 39:61). The reaction of
2-vinylnaphthalene was even more sluggish (2%, l/b = 38:62
with the DBU system; data not shown). The reason for such
poor reactivities remains unclear at this moment.
To gain insight into the reaction pathway, the reaction of
the deuterated imine [D]5-1a and 4-methoxystyrene (2e) was
examined (Table 2). The reaction under the standard con-
ditions (6 h) afforded the linear product in 79% yield with
substantial decrease in the deuteration rate of the ortho po-
sition (C1) and significant deuterium incorporation into both
the methylene moieties (C2 and C3; entry 1). Along with this,
substantial H/D scrambling between the ortho positions (C4)
of the recovered imine and the recovered styrene (C5 and C6)
was observed. A similar yield and H/D scrambling patterns
were obtained using DBU as the additive (entry 2). While the
reaction in the absence of additive was sluggish as expected,
the degree of H/D scrambling between the recovered starting
materials was substantial (entry 3). The reaction at 08C
Entry Additive
Yield [%][a]
1H NMR integration[b]
C2 C3 C4 C5
C1
C6
1
2
2-MeOPy
DBU
79
82
19
10
0.41 0.93 0.96 1.26 1.43 0.70
0.36 0.85 0.92 1.11 1.22 0.63
0.32 0.99 0.90 1.06 1.27 0.68
0.48 1.14 0.96 0.62 1.50 0.85
3
none
2-MeOPy
4[c]
[a] Determined by 1H NMR analysis of the crude reaction mixture.
[b] Determined after separation of the crude reaction mixtures on silica
gel. Signals of the methoxy groups were used as references. [c] The
reaction was performed at 08C.
resulted in an apparent decrease in the product yield and the
degree of H/D scrambling (entry 4). These observations
suggest 1) rapid and reversible C H activation and styrene
insertion irrespective of the presence or absence of the
additive and 2) rate- and regioselectivity-determining reduc-
tive elimination. A possible role of the additive is to
accelerate reductive elimination, while an alternative role in
an off-cycle process (e.g., preventing catalyst deactivation)
may not be excluded.
À
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On the basis of the above argument, the ligand L9 is
thought to stabilize the transition state (TS) from the linear
intermediate B and/or destabilize the TS from the branched
intermediate A (Scheme 1a). The results of the ligand
screening (Scheme 2) suggest that the linear selectivity of
L9 cannot be simply ascribed to its steric property (L1 and
L2). We speculate that the 2-methoxy group of L9 serves as
a hemilabile donor to provide the linear TS (TS B) with extra
stabilization (Figure 4). Such stabilization may not be avail-
ketimine to styrene through careful tuning of the triarylphos-
phine ligand and the Lewis base additive, and thus expanded
the scope of regiodivergence of cobalt-catalyzed styrene
hydroarylation. The roles of the ligand and the additive in
regiocontrol and acceleration of the catalysis warrant further
experimental and theoretical studies.
Received: August 7, 2014
Published online: && &&, &&&&
À
Keywords: alkenes · C H activation · cobalt · regioselectivity ·
synthetic methods
.
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Recent developments in oxidation methods enable facile
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a
primary amide (5ac;
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4
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Communications
À
C H Activation
W. Xu, N. Yoshikai*
&&&& — &&&&
Highly Linear Selective Cobalt-Catalyzed
Addition of Aryl Imines to Styrenes:
Reversing Intrinsic Regioselectivity by
Ligand Elaboration
Paired off: The title reaction has been
achieved with cobalt-based catalytic sys-
tems featuring bis(2,4-dimethoxy-
good yields. Ligand screening and deu-
terium-labeling studies show the ligand
and Lewis base to be important in the
À
phenyl)(phenyl)phosphine (L) and either
2-methoxypyridine or DBU (LB), thus
affording a variety of 1,2-diarylethanes in
crucial C C reductive elimination step.
Cy =cyclohexyl, PMP=para-methoxy-
phenyl.
6
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