Functionalization of the Benzylic C-H Bonds in Azaarenes by Cobalt-Catalyzed 1,4-Addition to Enones

Article abstract of DOI:10.1002/ejoc.201403203

Functionalization of the C(sp³)-H bonds in azaarenes was catalyzed by CoCl₂ as an inexpensive Lewis acid catalyst. Enones were demonstrated to be good C=C electrophilic acceptors for the construction of various azaarene-containing 1,4-addition products in yields of up to 95 %. Functionalization of the C(sp³)-H bonds in azaarenes catalyzed by CoCl₂ as an inexpensive Lewis acid catalyst is reported. Enones are demonstrated to be good C=C electrophilic acceptors for the construction of various azaarene-containing 1,4-addition products in yields up to 95 %.

Full text of DOI:10.1002/ejoc.201403203

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403203
Functionalization of the Benzylic C–H Bonds in Azaarenes by
Cobalt-Catalyzed 1,4-Addition to Enones
Zaini Jamal,[a] Yong-Chua Teo,*[a] and Ling-Keong Wong[a]
Keywords: C–H activation / Cobalt / Enones / Heterocycles / Lewis acids
Functionalization of the C(sp3)–H bonds in azaarenes was
catalyzed by CoCl2 as an inexpensive Lewis acid catalyst.
Enones were demonstrated to be good C=C electrophilic
acceptors for the construction of various azaarene-containing
1,4-addition products in yields of up to 95%.
Introduction
Results and Discussion
At the onset of our initiative, we were interested in the
Co-catalyzed benzylic C–H 1,4-addition of 1a to enones as
a convenient C=C electrophilic acceptor. Kanai and Mat-
sunaga demonstrated the benzylic addition to chalcones by
using Sc(OTf)3 and Y(OTf)3 as the catalysts of choice.[3f] In
a related study by Huang, the lanthanide salt Yb(OTf)3·
xH2O was employed to catalyze the C(sp3)–H addition to
the C=C bonds of methylenemalononitriles.[3b] However,
the catalytic capabilities of simple Co salts to promote the
direct C(sp3)–H addition to C=C bonds were overlooked
despite their known Lewis acidic character.[7]
Research endeavors towards the direct utilization of
C–H bonds have resulted in the development of ingenious
approaches for organic synthesis.[1] One of the strategies for
this realization is the C–H addition to polar multiple
bonds.[2] Through this approach, several classes of Lewis
acids have been shown to promote the direct functionaliza-
tion of C(sp3)–H bonds in alkyl-substituted azaarenes.
Notable classes of these Lewis acids predominantly include
expensive or rare metal salts.[3] Therefore, considering the
value of azaarene-containing compounds,[4] it is inevitable
that further studies in the search for new and simple metal-
based catalysts are highly desirable.
Therefore, considering the development of a Co-cata-
lyzed methodology as one of the approaches towards sus-
Continuing our interest in the development of cheap and tainable catalysis,[8] we initiated our endeavor by performing
sustainable protocols for organic synthesis, herein we wish the reaction between 1a and 2a in the presence of CoCl2
to report the utilization of a simple Co-catalyzed protocol (10 mol-%) in H2O (Table 1, Entry 1). After 24 h of stirring
for the direct functionalization of C–H bonds. The pre- at 140 °C, only a modest 34% yield of 3aa was obtained.
cedent for this work emerged from the cobalt-catalyzed ac- However, a further survey of different solvents largely
tivation of the benzylic C–H bond of 2-methylquinoline culminated in improved yields, whereby 3aa was isolated in
(1a). By means of deuterium-exchange experiments, the 73% yield upon performing the reaction in THF (Table 1,
presence of CoCl2 as a Lewis acid catalyst was observed to Entry 7).
be essential in enhancing the acidity of the C(sp3)–H bond
Hence, delighted with the potential of CoCl2 in promot-
to affect a rapid exchange reaction.[5] The activation of a ing the reaction, our attention was next focused on the reac-
molecule has the consequence of increasing its reactivity tivity of several other Co salts, whereby a comparable yield
towards a reagent.[6] Similarly, the acidity enhancement of of 74% was obtained with a catalytic loading of CoBr2
1a has the effect of promoting the benzylic addition of 1a (Table 1, Entry 13). Nonetheless, as we embarked on fur-
to an electrophile. Therefore, on this basis we started to ther studies, less-expensive CoCl2 was undoubtedly chosen
foresee the development of a simple protocol for the benz- for subsequent optimizations, which eventually led to the
ylic C–H addition of azaarenes to polar C=C bonds, which isolation of 3aa in an excellent yield of 95% (Table 1, En-
remains an approach with limited literature examples.
try 18).
Guided by the optimized reaction conditions, the scope
of our newly established Co-catalyzed protocol was next
tested with respect to various enones (Table 2).
A sizeable number of halogen-substituted enones were
proven to be good C=C electrophilic acceptors, whereby the
desired addition adducts were isolated in yields ranging
from 78 to 87% (Table 2, Entries 1–6). An excellent yield
[a] Natural Sciences and Science Education, National Institute of
Education, Nanyang Technological University
1 Nanyang Walk, 637616 Singapore
E-mail: yongchua.teo@nie.edu.sg
http://www.nie.edu.sg/profile/teo-yong-chua
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403203.
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Z. Jamal, Y.-C. Teo, L.-K. Wong
SHORT COMMUNICATION
Table 1. Optimization studies.[a]
strongly electron-withdrawing substituents were also con-
ducted, which led to the isolation of 3ai and 3aj in yields
of 84 and 80%, respectively (Table 2, Entries 8 and 9). Elec-
tron-rich enones also underwent the reaction smoothly, al-
beit with lower yields of 61 and 66% corresponding to the
products obtained from methoxy-substituted enones
(Table 2, Entries 10 and 11). Compatibility of the protocol
with enones synthesized from heteroaromatics was also
demonstrated, whereby yields of 93 and 83% were obtained
(Table 2, Entries 16 and 17). In all cases, 1,4-additions were
exclusively observed, and this implies good selectivity of
our Co-catalyzed protocol. This was further demonstrated
by the preference for 1,4-addition over both 1,2- and 1,6-
additions (Table 2, Entry 18). With modifications to the
standard reaction conditions, 3as was isolated as the sole
1,4-addition adduct from corresponding enone 2s.
Entry
[Co][b]
Solvent[c]
Yield [%][d]
1
2
3
CoCl2
CoCl2
CoCl2
H2O
toluene
CH2Cl2
DCE
dioxane
tBuOH
THF
DMF
DMSO
DMA
THF
THF
THF
THF
THF
THF
THF
THF
34
68
50
66
72
65
73
39
28
4
5
CoCl2
CoCl2
6
7
CoCl2
CoCl2
8
9
CoCl2
CoCl2
10
11
12
13
14
15
16
17
18
CoCl2
27
Co(acac)2
Co(acac)3
CoBr2
trace
trace
74
trace
trace
10
Notably, a satisfactory 65% yield of 3at was also
afforded from our first trial with enone 2t. This example
holds promise for the utilization of simple substrates based
on aliphatic starting materials. Therefore, further studies on
this approach are ongoing as a means for tethering the
azaarenes with aliphatic C chains.
Co(ClO4)2·6H2O
CoC2O4·2H2O
Co(OAc)2
–
trace
CoCl2
95[e]
[a] General reaction conditions: 1a (0.5 mmol), 2a (2.0 equiv.), [Co]
(10 mol-%), solvent (0.5 mL), 140 °C, 24 h. [b] acac = acetylacet-
onate. [c] DCE = 1,2-dichloroethane, DMA = N,N-dimethylacet-
amide. [d] Yield of isolated product. [e] 1a (2.5 equiv.), 2a
(0.5 mmol), THF (0.25 mL).
Our attention was next focused on probing the generality
of the Co-catalyzed protocol with respect to the azaarene
substrates (Table 3).
Starting with substituted 2-methylquinolines, both
bromo- and chloro-containing addition products were
efficiently prepared in yields between 76 and 87%. A similar
range in yields was also obtained for fluoro-, methyl-, as
well as methoxy-substituted 2-methylquinolines (60–93%).
This set of results satisfyingly showed the generality of the
Co-catalyzed protocol with respect to its tolerance for both
electron-withdrawing and electron-donating groups on the
2-methylquinolines.
With 2-ethylquinoline, 3ja was afforded as a dia-
stereomeric mixture in an excellent yield of 95%. However,
analysis of the crude mixture by 1H NMR spectroscopy
revealed a poor diastereoselectivity ratio of 3:2.
Further attempts with other classes of heterocycles were
also conducted. Both 1-methylisoquinoline and 2-methyl-
benzothiazole showed some reactivity under the standard
reaction conditions. Therefore, with modifications to the
standard reaction conditions, 1-methylisoquinoline was
found to be practically applicable under the catalytic in-
fluence of CoCl2 (20 mol-%) to give intended product 3ka
in 82% yield after 48 h. With a longer reaction time, 3la
was also prepared for the first time in 35% yield as the
corresponding product from 2-methylbenzothiazole.
However, 2,6-lutidine was unreactive under the standard
reaction conditions. This observation was rationalized by
the unfavorable complete disruption of the single-ringed
aromatic system in 2,6-lutidine en route to cleavage of the
C(sp3)–H bond and formation of a Co–enamide intermedi-
ate.[9] Therefore, more forcing reaction conditions were sub-
sequently envisioned, which ultimately afforded 3ma in only
26% yield.
Table 2. Scope of enones.[a]
Entry Enone
R1
R2
Product Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
2b
2c
2d
2e
2f
2g
2h
2i
4-BrC6H4
4-ClC6H4
4-FC6H4
Ph
Ph
Ph
Ph
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
87
78
78
4-BrC6H4
4-ClC6H4
4-FC6H4
Ph
83
Ph
Ph
82, 87[c]
86
4-F3CC6H4
4-NCC6H4
Ph
4-MeOC6H4
Ph
4-MeC6H4
Ph
2-naphthyl
4-PhC6H4
2-furyl
94, 87[c]
84
Ph
2j
2k
2l
4-O2NC6H4
Ph
4-MeOC6H4
Ph
4-MeC6H4
Ph
Ph
Ph
2-thienyl
Ph
Me
3aj
3ak
3al
80
61
66
78
75
85
2m
2n
2o
2p
2q
2r
2s
2t
3am
3an
3ao
3ap
3aq
3ar
3as
3at
85, 85[c]
93
Ph
83
(E)-PhCH=CH
Ph
43[d]
65
[a] General reaction conditions: 1a (2.5 equiv.), enone (0.5 mmol),
CoCl2 (10 mol-%), THF (0.25 mL), 140 °C, 24 h. [b] Yield of iso-
lated product. [c] Reaction was performed in dioxane (0.25 mL).
[d] Reaction was performed with CoCl2 (20 mol-%) for 48 h.
of 94% was also obtained with trifluoromethyl-substituted
No desired product was isolated from an attempt with
enone 2h. Further demonstrations with enones bearing 4-methylquinoline. However, the results of a Co-catalyzed
2
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Functionalization of the Benzylic C–H Bonds in Azaarenes
Table 3. Scope of azaarenes.[a]
Scheme 1. Benzylic C–H functionalization via a cyclic Co-enamide
addition to C=C of enones.
Conclusions
A Co-catalyzed protocol for C(sp3)–H functionalization
through benzylic C–H addition of azaarenes to polar C=C
bonds was successfully demonstrated. Under catalytic load-
ings of inexpensive CoCl2, various enones were utilized to
afford the desired azaarene-containing 1,4-addition prod-
ucts in up to 95% yield. Upon the formation of a Co–en-
amide intermediate, the C–H addition is believed to occur
exclusively via a cyclic transition state. In concert with ex-
panding the substrate scope, studies in our laboratory are
also currently focused on the development of an asymmet-
ric variant of this benzylic C–H addition reaction.
Experimental Section
General Procedure for the Co-Catalyzed Benzylic C–H Addition: An
8 mL reaction vial equipped with a magnetic stir bar was sequen-
tially charged with CoCl2 (6.5 mg, 10 mol-%), azaarene
(1.25 mmol, 2.5 equiv.), enone (0.5 mmol, 1.0 equiv.), and THF
(0.25 mL). The vial was then capped, and it was placed into a pre-
heated oil bath at 140 °C with vigorous stirring. After 24 h, the
mixture was then cooled to room temperature and passed through
a short pad of Celite (CH2Cl2). The crude mixture was then dried
with Na2SO4 and concentrated under reduced pressure. Purifica-
tion by silica gel chromatography (hexane/ethyl acetate) then gave
the desired addition adduct.
[a] General reaction conditions: Azaarene (2.5 equiv.), 2a
(0.5 mmol), CoCl2 (10 mol-%), THF (0.25 mL), 140 °C, 24 h.
[b] 130 °C. [c] CoCl2 (20 mol-%), 48 h. [d] CoCl2 (20 mol-%), 72 h.
[e] CoCl2 (20 mol-%), 160 °C, 72 h.
deuterium-exchange experiment are in agreement with an
enhancement in the acidity of the C(sp3)–H bond in 4-
methylquinoline (pKa = 27.5),[10] whereby 88% deuterium
incorporation was observed (see the Supporting Infor-
mation). This suggests that the acidic nature of the benzylic
C–H bond is not the only factor governing the feasibility
of the direct C(sp3)–H functionalization. Therefore, the Co
catalyst is believed to activate the C(sp3)–H bond in the
azaarene substrates and to enhance the electrophilicity of
the C=C bond in the enones through simultaneous coordi-
nation to the Lewis basic N and O atoms on the respective
substrates.
The aftermath of this project led us to theorize the vital
features of the reaction. These include the formation of the
Co–enamide and the exclusive occurrence of a cyclic transi-
tion state (TS) via which the benzylic C–H addition of
azaarenes to the C=C bonds of enones proceeds
(Scheme 1).
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedures, characterization data, and
NMR (1H and 13C) spectra of all new compounds.
Acknowledgments
We would like to thank the National Institute of Education, Nany-
ang Technological University for funding this work.
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Z. Jamal, Y.-C. Teo, L.-K. Wong
SHORT COMMUNICATION
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Received: September 12, 2014
Published Online: ᭿
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Functionalization of the Benzylic C–H Bonds in Azaarenes
C–H Activation
Z. Jamal, Y.-C. Teo,* L.-K. Wong ... 1–5
Functionalization of the Benzylic C–H
Bonds in Azaarenes by Cobalt-Catalyzed
1,4-Addition to Enones
Functionalization of the C(sp3)–H bonds
in azaarenes catalyzed by CoCl2 as an inex-
pensive Lewis acid catalyst is reported. En-
ones are demonstrated to be good C=C
electrophilic acceptors for the construction
of various azaarene-containing 1,4-ad-
dition products in yields up to 95%.
Keywords: C–H activation
/
Cobalt
/
Enones / Heterocycles / Lewis acids
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