Cobalt-Catalyzed, Imine-Directed Olefin Hydroarylation under Grignard-Free Conditions

Article abstract of DOI:10.1002/adsc.201600403

We report here that a cobalt catalyst generated from a cobalt(II) salt and a ligand using magnesium metal is capable of promoting hydroarylation reactions through chelation-assisted C?H activation. With the appropriate choice of the ligand and other react

Full text of DOI:10.1002/adsc.201600403

UPDATES
DOI: 10.1002/adsc.201600403
Cobalt-Catalyzed, Imine-Directed Olefin Hydroarylation under
Grignard-Free Conditions
Wengang Xu,a Jie Hui Pek,a and Naohiko Yoshikaia,*
a
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371, Singapore
Fax : +(65)-6791-1961; e-mail: nyoshikai@ntu.edu.sg
Received: April 16, 2016; Revised: May 17, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600403.
Abstract: We report here that a cobalt catalyst gen-
erated from a cobalt(II) salt and a ligand using
magnesium metal is capable of promoting hydroary-
cobalt-catalyzed hydroarylation of olefins using sp2 ni-
trogen directing groups.[11,12] For example, we have
demonstrated that addition reactions of aryl keti-
mines or aldimines to styrene or vinylsilane proceed
smoothly using cobalt catalysts generated in situ from
appropriately selected cobalt(II) salts, phosphine or
nitrogen ligands, and Grignard reagents,[8c–e] which
À
lation reactions through chelation-assisted C H ac-
tivation. With the appropriate choice of the ligand
and other reaction conditions, ketimine- or aldi-
mine-directed branched selective hydroarylations of
styrenes and ketimine-directed hydroarylations of
vinylsilane have been achieved. The reported cata-
lytic systems may serve as more convenient alterna-
tives to previously developed catalytic systems em-
ploying Grignard reagents as reducing agents.
À
represent notable examples of C H activation at mild
temperatures (Scheme 1).[13] The hydroarylation reac-
tions to styrene are also notable for being among the
limited examples of branched-selective hydroarylation
(Scheme 1a, b).[4b,7b,d–f,14]
Despite the notable features, the requirement for
a substoichiometric amount of Grignard reagents, in-
cluding less common ones (e.g., t-BuCH2MgBr and
Me3SiCH2MgCl), as reductants reduces the practicali-
ty and functional group compatibility of these cobalt-
catalyzed hydroarylation reactions. To address this
problem, we became interested in the search for
À
À
Keywords: alkenes; C C bond formation; C H ac-
tivation; cobalt; hydroarylation
The regioselective introduction of an alkyl group to
an aromatic compound is among the most fundamen-
tal tasks in synthetic organic chemistry. The transition
metal-catalyzed hydroarylation reaction of olefins
À
through chelation-assisted C H bond activation offers
a step- and atom-economical solution to this task,[1]
which complements conventional alkylation reactions
such as the Friedel–Crafts reaction and cross-coupling
between aryl (or alkyl) halides and alkyl (or aryl)
metal reagents. Since the seminal work of Lewis and
Smith on ruthenium-catalyzed ortho-ethylation of
phenol with ethylene[2] and the ground breaking dis-
covery of ruthenium-catalyzed ortho-alkylation of
aryl ketones with olefins by Murai and co-workers,[3]
various catalytic systems using late transition metals
such as ruthenium,[4] rhodium,[5] rhenium,[6] iridium,[7]
cobalt,[8] and iron[9] have been developed for the hy-
droarylation of olefins assisted by oxygen- and nitro-
À
gen-based directing groups. In pursuit of C H activa-
Scheme 1. Imine-directed hydroarylation reactions using ter-
nary catalytic systems comprising cobalt salt, ligand, and
tion with earth-abundant transition metal catalysts,[10]
our group has been committed to the development of Grignard reagent (PMP=p-methoxyphenyl).
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Table 1. Addition of aryl imine 1a to styrene 2a using Mg as
a more convenient reductant. Although the identity
of the active cobalt catalyst in each of the catalytic
systems remains unclear, our previous study on the
imine-directed hydroarylation of alkynes has implied
that the Grignard reagent such as t-BuCH2MgBr is
capable of reducing the Co(II) precatalyst to the oxi-
dation state of Co(0).[15] The ineffectiveness of a mild
reductant such as Zn dust, which is known to reduce
Co(II) to Co(I),[16] has also been demonstrated in our
early exploration of the pyridine-directed hydroaryla-
tion of alkynes.[17] On the other hand, Mg metal is
used as a reductant in the preparation of a well-de-
fined Co(0) complex Co(PMe3)4.[18] Moreover, Petit
and co-workers have recently demonstrated that
Co(PMe3)4 catalyzes the imine-directed hydroaryla-
tion of alkynes.[19] With these empirical observations
and literature knowledge taken together, we reasoned
that magnesium metal could serve as a reductant to
generate a catalytically active cobalt species for the
olefin hydroarylation. We report here that all the hy-
droarylation reactions shown in Scheme 1 can indeed
be promoted using Mg metal in place of the Grignard
reagent, albeit at a higher temperature and with
somewhat narrower scopes.
a reductant.[a]
Entry
Ligand
Solvent
Yield (b/l)[b]
1
2
3
4
5
6
7
8
P(4-FC6H4)3
P(4-MeOC6H4)3
P(3-MeC6H4)3
P(2-MeOC6H4)3
PCy3
THF
THF
THF
THF
THF
THF
THF
Et2O
CPME
Et2O
Et2O
Bu2O
56 (>99/1)
55 (>99/1)
52 (>99/1)
8 (45/55)
35 (>99/1)
3 (>99/1)
0
81 (>99/1)
60 (>99/1)
95 (>99/1)
90 (>99/1)
91 (>99/1)
dppp
none
P(4-FC6H4)3
P(4-FC6H4)3
P(4-FC6H4)3
P(4-FC6H4)3
P(4-FC6H4)3
9
10[c]
11[d]
12[c]
[a]
The reaction was performed using 1a (0.2 mmol) and 2a
(0.3 mmol).
Yield and branched/linear (b/l) selectivity were deter-
mined by GC.
The reaction temperature was 808C.
CoBr2 (5 mol%) and P(4-FC6H4)3 (10 mol%) were used.
[b]
The present study was initially focused on the reac-
tion of acetophenone imine 1a and styrene 2a, which
was previously achieved in a branched-selective
manner using a catalytic system comprising CoBr2,
P(4-FC6H4)3, and CyMgBr in THF at room tempera-
[c]
[d]
ture (Scheme 1a). With CoBr2 (10 mol%), P(4- (CPME) was only marginally effective (entry 7). Fur-
FC6H4)3 (20 mol%), and flame-dried Mg turnings thermore, a near quantitative yield of 3 was obtained
(50 mol%) as catalyst precursors, the reaction took by lowering the reaction temperature to 808C
place at an elevated temperature of 1008C to afford (entry 8). The loadings of CoBr2 and P(4-FC6H4)3
the desired hydroarylation product 3 in a modest could be reduced to 5 mol% and 10 mol%, respective-
yield of 56% with exclusive branched selectivity ly, with a slight decrease in the yield of 3 (entry 9).
(Table 1, entry 1). We noted that the color of the reac- For practicality and safety reasons, one may also per-
tion mixture turned dark brown within 5 min upon form the reaction in Bu2O instead of Et2O without
heating, during which reduction of the Co(II) precata- a significant decrease in the yield (entry 10). We
lyst appeared to take place. Comparable catalytic ac- should also comment on the importance of the cobalt
tivities were observed using other unhindered triaryl- precatalyst. Cobalt salts other than CoBr2 led to di-
phosphine ligands such as P(4-MeOC6H4)3 and P(3- minished yield (CoCl2, 20%; CoI2, 24%) or failed to
MeC6H4)3 (entries 2 and 3), while the use of P(2- undergo reduction to generate catalytically active spe-
MeOC6H4)3 drastically slowed the reaction and affect- cies [Co(OAc)2 and Co(acac)2]. Note also that the use
ed the regioselectivity in slight favor of the linear of Rieke Mg failed to promote the reaction for un-
adduct (entry 4).[8f] The performance of PCy3 was in- known reasons.
ferior to that of P(4-FC6H4)3 (entry 5). The use of a di-
With the optimized catalytic system in hand, we
phosphine ligand such as 1,3-bis(diphenylphosphino)- briefly explored the scope of acetophenone imines
propane (dppp) led to only a trace amount of the and styrene derivatives (Table 2). Imines bearing
product (entry 6), while the reaction was completely a para-phenyl or fluoro group underwent smooth ad-
shut down under ligand-free conditions (entry 7).
dition to styrene, affording the branched adduct 4b
Importantly, we noticed that reduction of the imine and 4c in good yield, while the one bearing a para-
1a competed with the desired hydroarylation in THF methoxy group reacted sluggishly (see 4d). As was
(entries 1–5), affording a substantial amount of the the case with the original catalytic system, 3-fluoro
corresponding amine (ca. 20% yield).[20] The use of and 3,4-methylenedioxy groups acted as secondary di-
Et2O as the solvent completely suppressed this unde- recting groups to assist regioselective alkylation of the
À
sirable by-product and substantially improved the ortho C H bond of their proximity (see 4e and 4f).
yield of 3 (entry 6), while cyclopentyl methyl ether Styrene derivatives with substituents such as methoxy,
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Table 2. Addition of aryl ketimines to styrenes.[a]
Table 3. Addition of aryl aldimines to styrenes.[a]
[a]
The reaction was performed using 0.3 mmol of ketimine
and 0.45 mmol of styrene. The b/l ratio was greater than
99/1 unless otherwise indicated in the parentheses.
THF was used as the solvent.
[a]
The reaction was performed using 0.3 mmol of aldimine
and 0.45 mmol of styrene.
P(4-FC6H4)3 was used instead of P(4-MeC6H4)3.
[b]
[b]
fluoro, boryl, and silyl groups smoothly participated trinsically higher reactivity of the latter C=N bond
in the reaction with 1a to afford the adducts 4g–4k in toward reduction. Note also that the use of Et2O as
good yields with excellent regioselectivity. However, the solvent was not effective for the case of the aldi-
contrary to our expectation, the catalytic system mine because of its poor solubility. The new catalytic
failed to promote the reaction of styrenes bearing system promoted efficient alkylation of ortho-substi-
Grignard-sensitive functional groups such as ester and tuted benzaldimines (6b and 6c), regioselective alky-
cyano groups, although the functional groups them- lation of the less hindered position of meta-methyl-
selves remained intact.
benzaldimine (6d), two-fold alkylation of parent ben-
With the demonstration of the feasibility of the ke- zaldimine with excess (3 equiv.) styrene (6e), and C-2
timine-directed styrene hydroarylation, we next exam- alkylation of indole (6f). A range of para-, meta-, and
ined aldimine-directed hydroarylation of styrenes ortho-substituted styrenes were also amenable to the
using Mg metal as the reductant (Table 3). To our sat- present alkylation (see 6g–6l).
isfaction, the reaction of an aldimine derived from 1-
Finally, we examined ketimine-directed hydroaryla-
naphthaldehyde and styrene could be achieved effi- tion of vinylsilane using Mg metal as the reductant
ciently with minimal modification of the original cata- (Table 4). Building on the previous reaction condi-
lytic system (Scheme 1b), i.e., replacement of tions (Scheme 1c), the reaction of 4-phenylacetophe-
Me3SiCH2MgCl with Mg metal and increase of the re- none imine with vinyltrimethylsilane was achieved
action temperature to 808C, affording the adduct 6a using increased loadings (10 mol% each) of CoBr2
in 77% yield with exclusive branched selectivity. and 1,10-phenanthroline (phen) and Mg metal
Unlike the case of the ketimine-directed reaction (50 mol%) in THF at 808C, affording the expected
(vide supra), we did not observe reduction of the aldi- linear alkylation product 8a in 65% yield. The reac-
mine to the corresponding amine, regardless of the in- tion did not take place at all using Et2O instead of
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Table 4. Addition of aryl ketimines to vinylsilane.[a]
additional slight modification of the reaction condi-
tions (e.g., temperature, solvent, catalyst loading), al-
lowed ketimine- or aldimine-directed branched selec-
tive hydroarylation of styrenes as well as ketimine-di-
rected hydroarylation of vinylsilane, albeit with some-
what narrower scopes. The elevated temperature re-
quired for the present catalytic systems, as compared
with the Grignard-based catalytic systems, may be as-
cribed to heterogeneous nature of the reduction of
the cobalt precatalyst with magnesium, and also to
lower reactivity of the present low-valent cobalt spe-
À
cies toward C H activation. The difference between
the magnesium- and Grignard-based catalytic systems
was manifested in some cases of C=N bond reduction
and moderate regioselectivities. Further studies will
be directed to the exploration of the scope of Co/Mg
À
catalytic systems in other C H activation reactions
and the investigation of the nature of the low-valent
cobalt species.
Experimental Section
Typical Procedure for Ketimine-Directed
Hydroarylation of Styrene
[a]
The reaction was performed using 0.3 mmol of ketimine
and 0.45 mmol of vinylsilane.
The product was obtained as a mixture (2:1) with an
ortho-alkylation/defluorination product (overall yield is
In
a Schlenk tube were placed Mg turnings (3.6 mg,
[b]
0.15 mmol) and CoBr2 (6.7 mg, 0.030 mmol). The solids
were heated using a heat gun at around 3008C under
vacuum for 5 min. After cooling down under a nitrogen at-
mosphere, P(4-FC6H4)3 (19.2 mg, 0.060 mmol) and THF
(0.20 mL) were added. The resulting mixture was heated at
808C for 5 min, during which the color of the mixture
turned dark brown. The mixture was cooled to room tem-
perature and THF was removed under reduced pressure. To
the residue were added acetophenone imine 1a (68 mg,
0.30 mmol), styrene (53 mL, 0.45 mmol), and Et2O
(0.75 mL), and then the resulting mixture was stirred at
808C for 12 h. The reaction mixture was allowed to cool to
room temperature and filtered through a short pad of silica
gel. The filtrate was hydrolyzed using 3N HCl (1.0 mL) for
1 h, and then extracted with EtOAc (5 mLꢁ3). The organic
layer was dried over MgSO4 and concentrated under re-
duced pressure. The residue was purified on silica gel
(eluent: hexane/EtOAc=20/1) to afford 1-[2-(1-phenyle-
thyl)phenyl]ethanone (4a); yield: 59 mg (87%).
shown).
THF, presumably due to the poor solubility of cobalt-
phenathroline complexes. Unlike the case of the keti-
mine-directed addition to styrene (Table 2), 4-me-
thoxy- and 4-fluoroacetophenone imines afforded the
desired products 8b and 8c, respectively, while the
latter product was accompanied by a substantial
amount of ortho-alkylation/defluorination product. A
3,4-methylenedioxy group again caused a strong sec-
À
ondary directing effect in C H activation (see 8d).
Curiously, the reaction of meta-methylacetophenone
imine and 2-acetonaphthone imine produced regioiso-
meric product mixtures (8e/8e’ and 8f/8f’) in slight
favor of regioisomers produced by activation of the
more hindered C H bonds. This is in sharp contrast
to the performance of the original catalytic system,
À
which exclusively afforded 8e and 8f through regiose-
Acknowledgements
À
lective functionalization of the less hindered C H
bonds.[8c] The peculiar regioselectivity suggests that
the electronic nature of the catalytically active species
This work was supported by Ministry of Education of Singa-
pore, Nanyang Technological University (RG 5/14), and JST,
generated using Mg metal is different from that of the CREST.
one generated using the Grignard reagent.
In summary, we have demonstrated that Mg metal
serves as a convenient reductant for cobalt-catalyzed,
imine-directed hydroarylation of alkenes. Replace-
ment of the Grignard reagents in the original ternary
catalytic systems with magnesium metal, along with
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[20] We do not know the mechanism and the origin of hy-
dride of this reduction at this moment. Control experi-
ments using THF-d8 and pentadeuterated acetophe-
none imine did not result in any deuterium incorpora-
tion into the reduced product.
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6 Cobalt-Catalyzed, Imine-Directed Olefin Hydroarylation
under Grignard-Free Conditions
Adv. Synth. Catal. 2016, 358, 1 – 6
Wengang Xu, Jie Hui Pek, Naohiko Yoshikai*
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