Directed C–H Alkenylation of Aryl Imines with Alkenyl Phosphates Promoted by a Cobalt–N-Heterocyclic Carbene Catalyst

Article abstract of DOI:10.1002/adsc.201701105

We report herein an ortho-C–H alkenylation reaction of aryl imines with alkenyl phosphates promoted by a cobalt–N-heterocyclic carbene (NHC) catalytic system. While commercially available bulky NHC ligands exhibited only modest catalytic activity, elaboration of the nitrogen substituents and backbone of the NHC enabled the desired transformation to proceed in high yield at a mild temperature. The new Co–NHC system proved applicable to a variety of aryl imines and alkenyl phosphates to afford ortho-alkenylated aryl imines, which serve as precursors to benzofulvene derivatives. (Figure presented.).

Full text of DOI:10.1002/adsc.201701105

Title: Directed C–H Alkenylation of Aryl Imines with Alkenyl Phosphates
Promoted by a Cobalt–N-Heterocyclic Carbene Catalyst
Authors: Pin-Sheng Lee, Wengang Xu, and Naohiko Yoshikai
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10.1002/adsc.201701105
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Directed C–H Alkenylation of Aryl Imines with Alkenyl
Phosphates Promoted by a Cobalt–N-Heterocyclic Carbene
Catalyst
Pin-Sheng Lee,a† Wengang Xu,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: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. We report herein an ortho-C–H alkenylation The new Co–NHC system proved applicable to a variety of
reaction of aryl imines with alkenyl phosphates promoted by aryl imines and alkenyl phosphates to afford ortho-
a cobalt–N-heterocyclic carbene (NHC) catalytic system. alkenylated aryl imines, which serve as precursors to
While commercially available bulky NHC ligands exhibited benzofulvene derivatives.
only modest catalytic activity, elaboration of the N-
substituents and the backbone of NHC enabled the desired
transformation in high yield at a mild temperature.
Keywords: C–H functionalization; C–C bond formation;
homogeneous catalysis; cobalt; N-heterocyclic carbenes
available bulky NHCs such as IMes (1,3-bis(2,4,6-
trimethylphenyl)imidazole-2-ylidene) and IPr (1,3-
bis(2,6-diisopropylphenyl)imidazole-2-ylidene) have
often showed optimal performance for various
Introduction
Transition metal-catalyzed, directing group-assisted
arene C–H bond activation has evolved as an atom-
and step-economical approach to the synthesis of
functionalized arenes.[1] This approach is not just
useful for the high efficiency and predictable
regioselectivity of C–H activation. The product of the
directed C–H activation reaction would serve as an
intermediate for the synthesis of carbo- and
heterocycles through simultaneous utilization of the
directing group and the newly introduced functional
group. In this context, the introduction of alkenyl
groups into the ortho position of functionalized
arenes, which has been most commonly achieved by
way of dehydrogenative Heck-type process,[2] is
particularly attractive because of the versatility of
alkenyl groups.
Over the last years, low-valent cobalt-catalyzed
directed ortho-C–H functionalization of arenes using
organic electrophiles have been achieved by
Nakamura,[3] Ackermann,[4] and our group[5] using a
catalyst generated from a cobalt(II) or cobalt(III)
precatalyst, a supporting ligand, and a Grignard
reagent, where the Grignard reagent serves as a
reductant for the cobalt precatalyst and also as a base
to remove the ortho C–H proton.[6,7] In particular, the
Ackermann group and our group have independently
demonstrated the utility of N-heterocyclic carbenes
(NHCs) as supporting ligands for such
transformations (Scheme 1a). Like many transition
metal–NHC complex-catalyzed reactions,[8] readily
electrophiles
including
aryl
carbamates/sulfamates/chlorides,[4a,b,5b]
alkyl
halides,[4b] aldimines,[5a] and aziridines.[5d] Along this
line, Ackermann recently achieved mild and efficient
cobalt-catalyzed C–H alkenylation of N-pyrimidyl
indoles and pyrroles with alkenyl acetates using IPr
as the supporting ligand (Scheme 1b).[4c] The same
catalytic system also allowed the use of alkenyl
carbamates, carbonates, and phosphates as
alkenylating agents. The reaction is particularly
attractive as it complements other types of C–H
alkenylation such as dehydrogenative Heck reaction[9]
and hydroarylation of alkynes,[10-12] while the scope
of the aromatic substrates remains to be extended.[13]
As a part of our exploration of cobalt-catalyzed
arene C–H functionalization with versatile imine
directing groups,[5,11b,14] we have developed an ortho
C–H alkenylation reaction of aryl imines with alkenyl
phosphates, which is described herein (Scheme 1c).
The key to the success of this reaction was an NHC
ligand CyIEt,[15] which evolved through elaboration of
the N-substituents and the backbone of NHC. The
present Co–NHC system was applicable to a variety
of aryl imines and alkenyl phosphates, and proved to
be complementary to Ackermann's alkenylation
system.
1
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10.1002/adsc.201701105
Advanced Synthesis & Catalysis
(entries 7 and 8). Using CyIEt•HBr, the amount of the
Grignard reagent could be reduced to 2 equiv without
notable decrease in the product yield (entry 9). While
TMEDA did not improve the reaction using IMes
(entries 1 and 4), it clearly exhibited a beneficial
effect when combined with the modified NHC
(entries 9 and 10). While the origin of this effect is
not clear, we suspect that TMEDA acts as a Lewis
base to magnesium rather than as a ligand to cobalt,
thus affecting the aggregation state of the Grignard
reagent and its transmetalation with cobalt species.
As was the case with other C–H/electrophile coupling
reactions developed by our group,5 the use of t-
BuCH2MgBr was crucial, as other Grignard reagents
such as i-PrMgBr and CyMgCl shut down the desired
alkenylation (entries 11 and 12). Note that attempts to
use cyclohexenyl acetate or carbamate in place of 2a
did not afford 4aa under any of the examined
conditions.
Table 1. Screening of reaction conditions.[a]
Scheme 1. Cobalt–NHC catalysis for directed C–H
functionalization with electrophiles (PMP
methoxyphenyl).
=
p-
Results and Discussion
The present study commenced with a screening of
conditions for the reaction of imine 1a derived from
tetralone and p-anisidine with cyclohexenyl
phosphate 2a (Table 1). We initially tested catalytic
systems comprising CoBr2 (10 mol%), IMes•HCl or
IPr•HCl (10 mol%), and t-BuCH2MgBr (2.5 equiv),
which were previously developed for the ortho C–H
functionalization of aryl imines with aryl chlorides,
aldimines, and aziridines.[5a,b,d] However, these
systems afforded, upon acidic hydrolysis, the desired
ortho-cyclohexenylated ketone 4aa only in modest
yields (entries 1 and 2). In addition, Ackermann's
catalytic system for the alkenylation of N-
pyrimidylindole (Scheme 1b)[4c] failed to promote the
present reaction (entry 3).
Given these unsatisfactory preliminary results, we
turned to modification of the NHC ligand and search
for additives to improve the reaction. Throughout this
effort, we noted substantial effects of the N-
substituent and backbone of NHC on the catalytic
activity, and also beneficial influence of N,N,N',N'-
tetramethylethylenediamine (TMEDA, 7 equiv) as an
additive (entries 4–10). The use of an imidazolium
salt bearing 2,6-diethylphenyl groups (IEt•HCl) as
the NHC precursor and TMEDA as the additive
improved the yield of 4aa to 62% (entry 5). The
reaction was further improved by installation of
methyl groups on the 4,5-positions of the NHC
precursor (MeIEt•HCl; entry 6). Finally, NHC
precursors CyIEt•HBr and CyhIEt•HBr featuring N,N'-
bis(2,6-diethylphenyl) groups and cyclohexane- or
Entry NHC RMgX
Additive Yield
[%][b]
1
IMes t-BuCH2MgBr
None
None
None
39
28
< 1
2
IPr
IPr
t-BuCH2MgBr
CyMgCl
3[c]
4
IMes t-BuCH2MgBr
IEt t-BuCH2MgBr
TMEDA 24
TMEDA 62
TMEDA 69
TMEDA 94 (90)
TMEDA 96 (90)
TMEDA (90)
5
6
7
8
MeIEt t-BuCH2MgBr
CyIEt t-BuCH2MgBr
CyhIEt t-BuCH2MgBr
CyIEt t-BuCH2MgBr
CyIEt t-BuCH2MgBr
CyIEt i-PrMgBr
9[d]
10
11
None
TMEDA
TMEDA
65
2
4
12
CyIEt CyMgCl
[a]
Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol),
CoBr2 (10 mol%), NHC•HX (10 mol%), t-BuCH2MgBr
(0.75 mmol), TMEDA (0 or 2 mmol) in THF, 40 °C, 12 h.
[b]
Determined by GC using n-tridecane as an internal
[c]
standard. Isolated yield is shown in parentheses.
Ackermann's system (CoI2, IPr•HCl, DMPU) was used.
0.6 mmol of the Grignard reagent was used.
[d]
With the Co–CyIEt catalytic system in hand, we
explored the scope of the ortho C–H alkenylation
reaction. First, various aryl ketimines were subjected
to the reaction with cyclohexenyl phosphate 2a
(Table 2). As expected, the imines derived from
substituted tetralones or chromanone smoothly
participated in the reaction to afford, upon acidic
cycloheptane-fused
backbone
promoted
the
alkenylation to afford 4aa in more than 90% yield
2
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10.1002/adsc.201701105
Advanced Synthesis & Catalysis
hydrolysis, the desired alkenylated ketones 4ba–4da
in good yields. The imines derived from
acetophenone and propiophenone derivatives were
also amenable to the present C–H alkenylation. For
such imines, the alkenylation products were subjected
to reduction with NaBH3CN and then isolated in the
form of benzylic amine 5, while their treatment under
acidic hydrolysis conditions caused intramolecular
cyclization (vide infra). The imines bearing two
equivalent ortho C–H bonds exclusively afforded
monoalkenylation products 5ea–5ga, 5ia, and 5ja in
moderate to good yields, except for the one derived
from 4-fluoroacetophenone, which underwent
twofold alkenylation to afford the dialkenylated
imine 3ha in 54% yield. The reaction proved to be
In light of our previous studies on cobalt-catalyzed
C–H functionalization,[6] it was not surprising that the
unsymmetrical imines bearing 3-fluoro, 3-chloro, 3,4-
methylenedioxy, and 3,4-difluoro groups underwent
regioselective C–H activation at the more hindered
ortho position (see 5ka–5na), which could be
ascribed to the secondary directing effect of the lone
pair of these substituents. On the other hand, it was
unusual that the imine bearing 3,4-dimethoxy groups
also exhibited the same regioselectivity (see 5na),
because the buttressing effect of the adjacent
methoxy groups is expected to make the 3-methoxy
group act as a steric bulk rather than a secondary
directing group (Scheme 2).[16] Another peculiar
observation was that the imine bearing a 3-methyl
sensitive to a highly electron-withdrawing substituent, group afforded a ca. 1:1 mixture of two regioisomers
as acetophenone imine bearing a para-CF3 group
failed to produce the desired alkenylation product in
an appreciable yield.
5pa and 5pa', while the one bearing a 3-phenyl group
underwent exclusive alkenylation at the less hindered
position (see 5qa). Imine derived from 2-
acetylnaphthalene was alkenylated at the 1-position
(see 5ra). C2-alkenylation of 3-iminoindole was also
achieved in high yield (see 3sa).
Table 2. Reaction of various aryl imines with
cyclohexenyl phosphate 2a.[a]
Scheme 2. Expected effect of 3,4-dimethoxy groups.
We performed several reference experiments to
gain insight into the origin of the counterintuitive
regioselectivity observed for the 3,4-dimethoxy-
substituted imine 1o (Scheme 3). First, the use of
IMes instead of CyIEt in the alkenylation reaction of
1o with 2a resulted in a near equimolar mixture of
two regioisomeric products (Scheme 3a). Second,
cobalt-catalyzed ortho C–H functionalization of 1o
with cyclohexyl bromide,[5c] vinyltrimethylsilane,[14a]
or styrene[14b] under previously developed catalytic
systems uniformly resulted in the exclusive
functionalization of the less hindered ortho C–H bond
to afford the respective products 6–8 (Scheme 3b–3d),
regardless of the secondary directing effect of
substituents such as 3-fluoro and 3,4-methylenedioxy
groups observed in these catalytic systems. On the
basis of these results, we suspect that the steric and
electronic nature of the CyIEt ligand is primarily
responsible for the unique regioselectivity, where the
interaction between the cobalt center and the 3-
methoxy group would override the unfavorable
repulsion between the methoxy groups (Scheme 2).
[a]
The reaction was performed on a 0.3 mmol scale
[b]
according to the standard conditions in Table 1, entry 7.
Isolated in the form of imine without hydrolysis and
reduction.
3
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10.1002/adsc.201701105
Advanced Synthesis & Catalysis
[a]
The reaction was performed on a 0.3 mmol scale
according to the standard conditions described in Table 1,
entry 7. Unless otherwise noted, the configuration of the
alkenyl phosphate was E. [b] A mixture of E -and Z-alkenyl
[c]
phosphate (ratio = ca. 1:1) was used.
Z-rich alkenyl
phosphate (Z/E = ca. 9:1) was converted to a ca. 2:1
Scheme 3. Reference experiments using 3,4-dimethoxy-
substituted imine 1o.
[d]
mixture of E- and Z-isomers.
E-rich alkenyl phosphate
(E/Z = ca. 3:1) was converted to a mixture of E- and Z-
isomers (ratio = ca. 2:1).
We next examined C–H alkenylation of tetralone
imine 1a with a series of alkenyl phosphates (Table
3). As expected, 4-substituted cyclohexenyl
phosphates smoothly participated in the reaction,
affording the desired products 4ab–4ad in good
yields. The reaction of a cyclohexenyl phosphate
having a 6-methyl substituent was less efficient (see
4ae), presumably because of the steric hindrance.
While cyclopentenyl phosphate reacted rather
sluggishly (see 4af), other cycloalkenyl phosphates
with larger ring sizes afforded the desired products
4ag–4ai in good yields. Notable among these
examples are the reactions of cyclodecenyl- and
cyclododecenyl phosphates. The former reaction
involved conversion of an E/Z mixture of the alkenyl
phosphate into the single E-product 4ai. On the other
hand, in the latter reaction, Z-rich alkenyl phosphate
(Z/E = ca. 9:1) ended up in the alkenylated product
4aj as a ca. 2:1 mixture of the E- and Z-isomers.
Likewise, the reaction of E-rich alkenyl phosphate
(E/Z = ca. 3:1) derived from 4-heptanone resulted in
the product 4ak as a mixture of the E- and Z-isomers
with a moderate ratio (ca. 2:1).
Besides the aryl imines, substrates bearing a
pyridyl directing group were also amenable to the
present alkenylation reaction. Thus, the reaction of 2-
phenylpyridine (9a) with 2a exclusively afforded the
monoalkenylation product 10a in 82% yield (Scheme
4a). By contrast, 2-ferrocenylpyridine (9b) afforded a
mixture of mono- and di-alkenylation products under
the standard conditions using 1.5 equiv of 2a,
indicating high reactivity of the ferrocenyl C–H
bonds. Indeed, the reaction of 9b with 2 equiv of 2a
furnished the dialkenylation product 10b in good
yield (Scheme 4b). This observation is notable
because Ackermann's catalytic system promoted
exclusive mono-alkenylation of the same ferrocene
substrate.[4c]
Table 3. Reaction of imine 1a with various alkenyl
phosphates.[a]
4
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10.1002/adsc.201701105
Advanced Synthesis & Catalysis
Scheme 4. C–H alkenylations directed by a 2-pyridyl
group.
In order to gain insight into the nature of the C–H
activation step in the present reaction, we performed
kinetic isotope effect (KIE) experiments using a
pentadeuterated imine 1e-d5 (Scheme 5). Prior to the
KIE experiments, we confirmed that the reaction of
1e-d5 with 2a under the standard conditions afforded
the alkenylation product 3ea-d4 in a moderate yield
(68%), without any loss of the remaining deuterium
atoms on the aromatic ring. An intermolecular
competition reaction of 1e and 1e-d5 quenched at a
reaction time of 10 min resulted in predominant
alkenylation of the former, corresponding to a KIE
value of 5.9 (Scheme 5a). Comparison of parallel
independent reactions of 1e and 1e-d5 also gave a
smaller but substantial KIE value of 2.9 (Scheme 5b).
While the KIE observed in the intermolecular
competition would directly reflect the nature of C–H
activation as the first irreversible step, the KIE
determined by the parallel reactions would indicate
that C–H activation is a major rate-controlling step of
the present reaction.[17]
Scheme 5. Kinetic isotope effect experiments.
The C–H alkenylation products obtained from
acetophenone-derived imines serve as unique
precursors to benzofulvene derivatives, which have
attracted much interest as synthetic intermediates for
indene derivatives, precursors to metallocene
complexes, and organic materials.[19] Thus, treatment
of the ortho-cyclohexenylated imines 3 with aqueous
HCl at room temperature caused intramolecular
deaminative cyclization, thus affording tricyclic
benzofulvenes 11a–11c in respectable yields (Scheme
6a). Besides the acid-mediated intramolecular
cyclization, one can also utilize the alkenyl and the
imine groups of the alkenylation products in a
different manner. To illustrate this point, two-step
conversion of the alkenylated imine 3ea to a fused
carbazole derivative 13 was achieved through Pd-
catalyzed aerobic dehydrogenative cyclization of the
imine moiety to the indole 12[20] followed by acid-
mediated intramolecular Friedel–Crafts cyclization
and subsequent aromatization (Scheme 6b).
We assume that the present C–H alkenylation
reaction shares some of key mechanistic features with
other previously developed C–H/electrophile
coupling reactions. First, an alkylcobalt species
generated from the precatalyst and the Grignard
reagent
would
undergo
C–H
metalation
(cyclometalation) of the imine.[18] The resulting
cobaltacycle intermediate would be intercepted by the
alkenyl phosphate to afford the alkenylation product
and a cobalt phosphate species. Transmetalation of
the cobalt phosphate with the Grignard reagent would
regenerate the alkylcobalt species. In Ackermann's
alkenylation system, alkenyl acetate, which has
higher C–O dissociation energy than alkenyl
phosphate, behaved as a more reactive alkenylating
agent.[4c] With this reactivity order and other
observations, they proposed that the alkenylation
would take place through migratory insertion of the
alkenyl C=C bond to a cobaltacycle species followed
by β-acetoxy elimination. Because our catalytic
system was not effective for alkenyl acetates, we
consider that the cobaltacycle intermediate in the
present reaction would behave differently. Given the
lack of stereochemical integrity with respect to the
alkenyl phosphate (cf. 4ai–4ak in Table 3), we
suspect that the reaction may involve an electron
transfer from the cobaltacycle intermediate to the
alkenyl phosphate to form a radical species.
5
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10.1002/adsc.201701105
Advanced Synthesis & Catalysis
THF, 0.40 mL, 0.60 mmol) and TMEDA (0.30 mL,
2.0 mmol). After stirring for 30 min, cyclohex-1-en-
1-yl diisopropyl phosphate (2a, 108 µL, 0.45 mmol)
was added. The resulting mixture was stirred at 40 °C
for 12 h. The reaction was then quenched by the
addition of HCl (3 N, 1.0 mL), and stirred for 1 h.
The resulting mixture was extracted with EtOAc (5
mL x 3). The organic layer was dried over MgSO4
and concentrated under reduced pressure. Silica gel
chromatography (eluent: hexane/EtOAc = 50/1) of
the crude product afforded 8-(cyclohex-1-en-1-yl)-
3,4-dihydronaphthalen-1(2H)-one (4aa) as a light
1
yellow oil (61 mg, 90%). H NMR (400 MHz,
CDCl3): δ 7.34 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 7.6 Hz,
1H), 7.01 (d, J = 7.6 Hz, 1H), 5.43–5.41 (m, 1H),
2.95 (t, J = 6.1 Hz, 2H), 2.62 (t, J = 6.8 Hz, 2H),
2.19–2.14 (m, 2H), 2.12–2.06 (m, 4H), 1.84–1.78 (m,
2H), 1.73–1.67 (m, 2H); 13C NMR (100 MHz,
CDCl3):  198.7, 147.2, 145.5, 142.1, 132.5, 130.7,
129.4, 127.7, 122.0, 40.8, 31.0, 30.4, 25.7, 23.4, 23.2,
22.4; HRMS (ESI) Calcd for C16H19O [M + H]+
227.1436, found 227.1441.
Acknowledgements
Scheme 6. Transformation of the alkenylated products.
This work was supported by Ministry of Education (Singapore)
and Nanyang Technological University (RG3/15, RG 114/15, and
MOE2016-T2-2-043), and JST, CREST. PSL and WX contributed
equally.
Conclusion
In conclusion, we have developed a cobalt–NHC-
catalyzed ortho C–H alkenylation reaction of an aryl
imine using an alkenyl phosphate as the alkenylating
agent. The reaction was achieved by the elaboration
of both the N-substituents and the backbone of 1,3-
diarylimidazolium salt; the NHC precursors
CyIEt•HBr and CyhIEt•HBr exhibited much higher
catalytic efficiency than commercially available IMes
and IPr derivatives. The present reaction not only
tolerated a variety of aryl imines and alkenyl
phosphates but also displayed unique regioselectivity
for meta-substituted aryl imines, which would
warrant further investigation. We anticipate that, as
has been amply demonstrated for Pd–NHC
catalysis,[8,21] elaboration of the NHC architecture
would also lead to improvement of other C–H
activation and related transformations promoted by
low-valent cobalt catalysts.[22,23]
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Experimental Section
Typical Procedure for ortho-Alkenylation of Aryl Imine
In
a
Schlenk tube were placed (E)-N-(3,4-
dihydronaphthalen-1(2H)-ylidene)-4-methoxyaniline
(1a, 75 mg, 0.30 mmol), CyIEt•HBr (13.8 mg, 0.030
mmol), a freshly prepared THF solution of CoBr2
(0.30 M, 0.10 mL, 0.030 mmol), and THF (0.25 mL).
The resulting solution was cooled in an ice bath,
followed by the addition of t-BuCH2MgBr (1.5 M in
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Advanced Synthesis & Catalysis
FULL PAPER
Directed C–H Alkenylation of Aryl Imines with
Alkenyl Phosphates Promoted by a Cobalt–N-
Heterocyclic Carbene Catalyst
Adv. Synth. Catal. Year, Volume, Page – Page
Pin-Sheng Lee, Wengang Xu, and Naohiko
Yoshikai*
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