Co(II)-Catalyzed Regioselective Pyridine C-H Coupling with Diazoacetates

Article abstract of DOI:10.1021/acs.orglett.9b01196

A Co(II)-catalyzed pyridyl C-H bond carbenoid insertion with α-diazoacetates has been realized. This transformation features a highly regioselective C-C bond formation at the C3-position of pyridines, providing an efficient access to diverse α-aryl-α-pyri

Full text of DOI:10.1021/acs.orglett.9b01196

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Co(II)-Catalyzed Regioselective Pyridine C−H Coupling with
Diazoacetates
Haisheng Xie,†,§ Youxiang Shao,‡,§ Jiao Gui,†,§ Jianyong Lan,† Zhipeng Liu,† Zhuofeng Ke,*,‡
Yuanfu Deng,† Huanfeng Jiang,† and Wei Zeng*,†
†Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou 510641, China
‡School of Materials Science & Engineering, PCFM Lab, Sun Yat-sen University, Guangzhou 510275, China
S
* Supporting Information
ABSTRACT: A Co(II)-catalyzed pyridyl C−H bond carbenoid insertion with α-diazoacetates has been realized. This
transformation features a highly regioselective C−C bond formation at the C3-position of pyridines, providing an efficient
access to diverse α-aryl-α-pyridylacetates.
Scheme 1. Versatile Csp2−H Carbenoid Insertion
yridine nuclei are ubiquitous structural motifs found in
1
Pmany bioactive molecules and pharmaceuticals. There-
fore, the site-selective C−H functionalization at different
position of pyridines is of great importance in synthetic
chemistry.2 To access diversified pyridine skeletons, many
methods have been developed to enable the formation of C2-
and C4-selective C−X bonds (X = C, N, and O, etc.) by taking
advantage of the coordination of active catalyst to pyridine “N”
and directing groups.3 However, the regioselectively introduc-
ing chemical bonds into the C3-position of pyridines without
additional chelation assistance is very difficult to achieve.4 In
this regard, only Yu,5 Shi,6 and Oestreich7 reported the C3-
selective cross-coupling of pyridines with olefins, aryl halides,
insertion has not been achieved, because of its electron-
deficient conjugated system. Nevertheless, our recent work
about C−H metallene insertions20 stimulates us to envision
that efficiently leveraging electronic properties of pyridine ring
would possibly allow for the direct pyridine C−H carbenoid
insertion. To verify our hypothesis, herein we explored a Co-
catalyzed cross-coupling reaction between pyridines and
diazoesters, in which C−H carbenoid insertion high-
regioselectively occurred at the C3-position of pyridines
(Scheme 1b).
We were intrigued to investigate whether modifying the
substituent type and substituent position on the pyridines
could lead to direct pyridyl C−H carbenoid insertion. To test
the feasibility of this strategy, we initially conducted density
functional theory (DFT) calculations on the electron density
of different positions in the pyridine ring of pyridine 1a, 1b, 1c,
1d, and 1e [see Scheme 2 and the Supporting Information (SI)
aldehydes, and hydrosilanes employing metal catalysts. As a
consequence, developing diverse strategies to allow the C3-
coupling of pyridines with different coupling partners is highly
desirable.
Carbene transfer reaction provides a powerful tool to
construct C−C bonds.8 Recently, ligand-directed C−H
carbenoid functionalizations have received intensive interest;
this methodology could regioselectively install C−C bonds
into the particular positions on the target molecules.9 Among
them, ammonium salts,10 indoles,11 ketoimines,12 omines,13
hydroxamic acids,14 sulfoximines,15 and others16 have been
widely utilized as a chelation platform to enable the phenyl
ortho-C−H carbenoid insertion. In comparison, the site-
selective coupling between diazo compounds and arenes
without additional directing groups remains rather challenging.
Yet, significant breakthroughs have been made recently by
Zhou,17 Zhang,18 and Shi,19 to realize noble-metal-catalyzed
direct phenyl Csp2−H carbenoid insertion of electron-rich
benzenes through electrophilic aromatic substitution (SEAr)
(Scheme 1a). However, the direct pyridyl Csp2−H carbenoid
Received: April 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01196
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
pyridine ring to deliver products 3-1e−3-1k in yields of 44%−
79%. In particular, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine is
also tolerable to assemble 3-1l (54%). Subsequently, we
evaluated the substitution effects of the pyridine rings on this
reaction. It was found that electron-donating group (Me,
MeO) and weak electron-withdrawing halides (Cl and Br)
could produce moderate to good yields of the desired products
3-1m−3-1r (53%−62%), regardless of the substitution
position of different substituent. In comparison, the more
electron-deficient 3-cyanopyridine gave an inferior reaction
conversion (3-1s, 44%). Of note, introducing a phenyl, alknyl,
and even alkenyl group to the 3-position of the pyridyl ring
could still lead to acceptable yields of 3-1t−3-1v (39%−46%).
Unfortunately, 5-methyl-2-(N-pyrrolidino)pyridine in which
the 5-position on the pyridine ring was blocked, could not
deliver the corresponding product 3-1w. The single-crystal
data of 3-1x, which was derived from 3-1k through
monodebenzylation (see the SI), directly indicated that the
cross-coupling did occur at the 5-position of pyridines.
Scheme 2. Optimization of the Reaction Parameters
a
All the reactions were performed using pyridines 1a−1e (0.10
mmol) and α-diazoester 2a (0.30 mmol) with CoBr2 (5 mol %) in the
presence of Cu(OAc)2 (5 mol %) in TFE (0.5 mL) at 80 °C for 12 h
under an argon atmosphere in a sealed tube, followed by flash
b
chromatography on SiO2. Isolated yield.
for more computational details]. The DFT results indicated
that 1c and 1e possess stronger nucleophilic reactivity (see
Figure S-9 in the SI), and could possibly couple with metal
carbenes regioselectively at the C-3/C-5 position. Encouraged
by these computational results, we proceeded to perform
experimental studies with these substrates to explore the
feasibility of the desired pyridyl C−H carbenoid functionaliza-
tion. As expected, when these pyridines were employed as
templates to couple with α-phenyl-α-diazoester (2a) in the
presence of Co(acac)2 catalysts, we soon found that the
Co(II)-catalyzed C3-selective C−H carbenoid functionaliza-
tion of pyridine occurred regioselectively by using 1e as a
substrate in 2,2,2-trifluoro ethanol (TFE) under an argon
atmosphere at 80 °C for 12 h, and provided 75% yield of α-
phenyl-α-(5-pyridyl) ester 3-1e (see the SI for screening
conditions).
The scope of the present procedure, with regard to different
diazoesters, has also been established systematically (Scheme
4). 4-Alkylphenyl- and halophenyl-substituted donor/acceptor
a b
,
Scheme 4. Diazo Compound Scope
With the optimized reaction conditions in hand, we then
evaluated the regioselectivity and the substrate scope of this
transformation with a variety of 2-aminopyridines. As
summarized in Scheme 3, the carbene transfer reaction of 2a
with 2-cyclic and 2-acyclic secondary amine-substituted
pyridines could proceed smoothly at the 5-position of the
a b
,
a
Scheme 3. Pyridine Scope
Unless otherwise noted, all the reactions were performed using
pyridines (1e) (0.10 mmol) and α-diazoester (2) (0.3 mmol) with
CoBr2 (5.0 mol %) in the presence of Cu(OAc)2 (5 mol %) in TFE
(0.5 mL) at 80 °C for 12 h under an argon atmosphere in a sealed
b
reaction tube, followed by flash chromatography on SiO2. Isolated
yield. 0.5 mmol of diazo compound was used.
c
diazoesters could be transferred to α-phenyl-α-(5-pyridyl)-
esters (3-2a−3-2g) with good efficiency (60%−78%). Among
them, ortho-, meta-, and para-bromophenyl-substitution effect
did not significantly affect the reaction conversions (3-2e, 3-2f,
and 3-2g). Meanwhile, electron-deficient diazoester also gave
good yield of the product 3-2h (61%). In contrast, α-(3,4-
dimethylphenyl)-α-diazoester, α-(3,4-dichlorophenyl)-α-diazo-
ester, and α-(3,4-alkoxyphenyl)-α-diazoester produced lower
yields of 3-2i, 3-2j, and 3-2k (48%−50%). It is gratifying that
the carbene transfer reaction could be further extended to α-
(2-naphthyl)-α-diazoester and α-(3-thienyl)-α-diazoeste, af-
fording good yields of the desired products 3-2l (56%) and 3-
2m (60%), respectively. Compared with the α-methoxycarbo-
nyldiazo compound 2a, α-ethoxycarbonyl and α-isoproxycar-
bonyl diazo compounds made the reaction somewhat sluggish,
possibly because of the steric hindrance (3-1e vs 3-2n and 3-
2o). Note that acceptor/acceptor diazoesters such as α-diazo-
a
Unless otherwise noted, all the reactions were performed using
pyridines (1) (0.10 mmol) and α-diazoester (2a) (0.3 mmol) with
CoBr2 (5.0 mol %) in the presence of Cu(OAc)2 (5 mol %) in TFE
(0.5 mL) at 80 °C for 12 h under an argon atmosphere in a sealed
b
reaction tube, followed by flash chromatography on SiO2. Isolated
yield. 1.0 mmol of pyridine 1e was employed. 0.5 mmol of diazo
compound was used.
c
d
B
DOI: 10.1021/acs.orglett.9b01196
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Organic Letters
Letter
β-ketoesters did not allow this reaction to give the desired
products (3-2p).
6c). These two control experiments demonstrated that metal
protonation instead of enol isomerization led to the H/D
exchange at the α-position of acetate ester 3-1e. Moreover,
cobalt-catalyzed cross-coupling between d1-1e (90% D) with
2a resulted in the loss of 50% deuterium atoms in the product
d-3-1e, indicating that a stepwise 1,2-H shift17 was possibly
involved in the carbene transfer process (Scheme 6d).
Meanwhile, the cross-coupling of 1e and 2a could still
happened in the absence of CoBr2 salts (32% yield), indicating
that Cu(OAc)2 played the similar catalytical role as CoBr2
Methoxycarbonylmethylene could be introduced into 3-1e,
assembling quaternary carbon-containing 1,4-dicarbonate 4
(50% yield); and 3-1e could be also reduced by LiAlH4 to
furnish β-phenyl-β-pyridyl-alcohol 5 in 71% yield. More
importantly, the pyrrole moiety of 3-1e could undergo cross-
coupling with styrene and TsN3 to assemble complex 2-
alkylpyrrole 6 (75%) and N-sulfonyl amidine 7 (46%) under
Ru(II)- and Cu(II)-catalytic systems, respectively. Finally,
when α-phenyl-α-pyridylester 3-1k was subjected to the
(NH4)2Ce(NO3)6 reduction system, the free (N−H) α-(2-
aminopyridyl)ester 8 could be produced in 44% yield (see
Scheme 5).
(Scheme 6e). Finally, the secondary inverse KIE (kH/kD
=
0.89) further confirmed that a C−H (C−D) bond experiences
sp2 → sp3 rehybridization21 in the electrophilic addition of
cobalt carbenoids to pyridines, which possibly occurred in the
rate-determining step (RDS) of this transformation (Scheme
6f) (see the SI for more details).
Plausible mechanisms were proposed based on the above
control experiments and DFT studies (see the SI for more
details). As shown in Pathway 1 of Scheme 7 (Figure S-10 in
Scheme 5. Synthetic Applications
Scheme 7. Proposed Mechanism
Designed control experiments (Scheme 6) were performed
to elucidate the plausible reaction mechanism. The H/D
Scheme 6. Preliminary Mechanism Studies
the SI), the Co(II)-catalyzed denitrogenation of 2a first occurs
to form the Co-carbenoid intermediate via Ts1. This Co-
carbenoid could react as an electrophilic carbocation A to
attack pyridine 1e (Ts2, ΔG⧧ = 22.6 kcal/mol) to produce
pyridinium cation C, which subsequently undergoes aromati-
zation via a 1,2-H shift to assemble 3-1e with the regeneration
of Co(II) catalyst. DFT results suggest a stepwise 1,2-H shift
(Ts3, ΔG⧧ = 17.0 kcal/mol) with the assistance of the
carboxylate ligand is preferred over the concerted 1,2-H shift
mechanism (Ts4, ΔG⧧ = 34.6 kcal/mol). This is in good
agreement with the deuterium-labeled results (Scheme 6d).
Along the overall reaction of Pathway 1, the RDS is found to
be the electrophilic addition of cobalt-carbenoid to pyridine
(Ts2), which is in good accordance with the experimental
observed secondary KIE effect.
Meanwhile, Co(II)-catalyzed C−H functionalization gen-
erally involves irreversible C−H activation process, in which
H/D exchange did not occur.22 A concerted metalation/
deprotonation could also form the Csp2-metal bond at the C3-
position of pyridine.23 Therefore, another mechanistic Pathway
2 was also evaluated (Scheme 7), in which the irreversible
electrophilic C3−H activation of pyridine 1e gave the
pyridinyl-Co(II) species E. The σ-complex E initiates the
denitrogenation of 2a to form Co-carbenoid F. The
subsequent migratory insertion, followed by the protonation
of intermediate G, furnishes the desired product 3-1e.
exchange of 1e with CH3OD (2.0 equiv) was first conducted in
the absence of diazo compound 2a under the standard
conditions, no deuterium incorporation at the 5-position of
pyridine 1e implied that either electrophilic addition of cobalt-
carbenoid or irreversible C−H activation process was possibly
involved in this reaction (Scheme 6a). Subsequently, when the
cross-coupling between 1e and 2a was performed under
CoBr2/Cu(OAc)2/MeOD system, 26% deuterium was found
to be incorporated at the α-position of d-3-1e (Scheme 6b).
Meanwhile, the treatment of 3-1e with MeOD under the same
conditions did not lead to the formation of d-3-1e (Scheme
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01196.
■
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Detailed experimental procedures, characterization data,
single-crystal data of 3-1x, copies of H NMR and 13C
1
NMR spectra for all isolated compounds (PDF)
Accession Codes
CCDC 1876951 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kezhf3@mail.sysu.edu.cn (Z. Ke).
*E-mail: zengwei@scut.edu.cn (W. Zeng).
ORCID
Zhuofeng Ke: 0000-0001-9064-8051
Yuanfu Deng: 0000-0002-2460-7224
Huanfeng Jiang: 0000-0002-4355-0294
Wei Zeng: 0000-0002-6113-2459
Author Contributions
§H.X, Y.S, and J.G. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors thank NKRDPC (No. 2016YFA0602900), the
NSFC (Nos. 21871097, 21673301), GPSF (No.
2017B090903003), and GNSF (No. 2018B030308007,
2015A030306027) for financial support.
(23) Ye, M.; Gao, G.; Edmunds, A. J. F.; Worthington, P. A.; Morris,
J. A.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19090.
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DOI: 10.1021/acs.orglett.9b01196
Org. Lett. XXXX, XXX, XXX−XXX