Co(OAc)2-Catalyzed Trifluoromethylation and C(3)-Selective Arylation of 2-(Propargylamino)pyridines via a 6-Endo-Dig Cyclization

Article abstract of DOI:10.1021/acs.orglett.7b02759

A Co(OAc)₂-catalyzed trifluoromethylation and subsequent C(3)-selective arylation of 2-(propargylamino)pyridines has been developed. A new 6-endo-dig cyclization involving an unprecedented C(3) selective arylation of the pyridines instead of a commonly observed 5-exo-dig cyclization with "N" is realized. Moreover, the study presents the first case of the installation of a trifluoromethyl group into electron-deficient azaarenes. The process delivers an efficient cascade approach to new trifluoromethylated 1,8-naphthyridine structures with a broad substrate scope.

Full text of DOI:10.1021/acs.orglett.7b02759

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Co(OAc)2‑Catalyzed Trifluoromethylation and C(3)-Selective
Arylation of 2‑(Propargylamino)pyridines via a 6-Endo-Dig
Cyclization
Jianjun Li,† Yifan Lei,† Yang Yu,† Cong Qin,† Yiwei Fu,† Hao Li,*,† and Wei Wang*,†,‡
†State Key Laboratory of Bioengineering Reactor, Shanghai Key Laboratory of New Drug Design, and School of Pharmacy, East
China University of Science and Technology, 130 Mei-long Road, Shanghai 200237, China
‡Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, New Mexico 87131-0001, United States
S
* Supporting Information
ABSTRACT: A Co(OAc)2-catalyzed trifluoromethylation and
subsequent C(3)-selective arylation of 2-(propargylamino)-
pyridines has been developed. A new 6-endo-dig cyclization
involving an unprecedented C(3) selective arylation of the
pyridines instead of a commonly observed 5-exo-dig cyclization
with “N” is realized. Moreover, the study presents the first case
of the installation of a trifluoromethyl group into electron-
deficient azaarenes. The process delivers an efficient cascade
approach to new trifluoromethylated 1,8-naphthyridine structures with a broad substrate scope.
yridines are “privileged” structures that are widely featured
in many pharmaceuticals, natural products, and catalyst
the more nucleophilic nitrogen in the electron-deficient
heteroaromatic dictates the cyclization. A similar observation
was also seen in C−H amination with pyridine by Zhu and Liang
(Scheme 1, eq 2).6 Although C(3)-selective functionalization
could provide valuable methods for the construction of new
pyridine structures, the electron-poor C(3) site in pyridine
renders this difficult. As far as we are aware, such a process has
not been reported.
Herein, we disclose an unprecedented Co(OAc)2-promoted
C(3)-selective arylation of pyridines7 with alkynes in an unusual
6-endo-dig fashion. The process creates a distinct C−C bond
connection. 6-Membered 1,8-naphthyridine molecular architec-
tures are an important class of heteroaromatics widely used as
ligands in catalysis and as quinoline bioisosteres in drug
discovery; they can now be synthesized according to eq 3.8 A
new reactivity, harnessed by Co(OAc)2-promoted selective
activation of C(3) in pyridine, has been implemented for
reaction with electrophilic CF3• radical, which is produced from
TMSCF3 in the presence of phenyliodonium diacetate (PIDA)
as oxidant. The study offers the first example of installation of a
trifluoromethyl group, a preeminent moiety prevalent in
pharmaceuticals, agrochemicals, and materials,9 into electron-
deficient azaarenes in an efficient, regio- and chemoselective
cascade manner. It is noteworthy that carbotrifluoromethylation
of CC10,11 and CC12 bonds and subsequent arylation has
been elegantly realized. Nonetheless, electron-rich aromatic
systems are essentially used in these reactions.
P
ligands.1 Therefore, the functionalization of pyridines has been of
long-standing interest in organic and medicinal chemistry.
Intensive attention has been paid to developing methods capable
of diversifying the structure.2 Among them, 2-aminopyridines
serve as a versatile handle for the synthesis of new pyridine-
derived structures.3 For instance, Lewis acid catalyzed cyclization
of 2-(propargylamino)pyridines delivers medicinally useful
imidazo[1,2-a]pyridine frameworks.4 The Gevorgyan, Lin, Lei,
and Zeng groups, respectively, reported efficient π-philic metal-
catalyzed cyclization processes (Scheme 1, eq 1).5 It is noted that
these reactions proceed in a 5-exo-dig closure fashion. Moreover,
Scheme 1. Arylation of Pyridines with Alkynes
Our investigation began with a reaction of N-(1,3-
diphenylprop-2-ynyl)pyridin-2-amine (1a) in the presence of
Received: September 4, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02759
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Letter
10 mol % of Cu(OAc)2, CsF (4 equiv), and TMSCF3 (4 equiv) in
toluene (1.5 mL) at 80 °C for 12 h (Table 1, entry 1).
(entries 18 and 19). Finally, different ligands were also examined
and gave inferior outcomes.14 These investigations revealed the
ligand sensitivity of the coordination of the pyridine “N” with
Co(OAc)2.15
a
Table 1. Optimization of Reaction Conditions
With the optimized reaction conditions in hand, the substrate
scope of this new cascade reaction was investigated (Scheme 2).
a
Scheme 2. Scope of Pyridines
b
b
entry
c
cat.
[O]
PIDA
2a, yield (%) 3a, yield (%)
1
2
3
4
5
6
7
8
9
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
50
c
trace
41
trace
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PhI(OPiv)2
PIFA
18
Pd(OAc)2
Fe(OAc)2
Ni(OAc)2
Zn(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
30
<10
21
26
46
d
10
11
12
13
14
15
16
17
18
19
50
d
d
d
d
d
d
d
d
d
25
<10
<10
47
a
O2
Unless otherwise specified, 1 (0.15 mmol), Co(OAc)2 (20 mol %),
,
,
,
,
,
,
e
f
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
45
43
59
70
20
30
PIDA (0.75 mmol), CsF (0.6 mmol), and TMSCF3 (0.6 mmol) in 1.5
mL of DCM was stirred for 12 h at rt. Isolated yields.
g
g
g
g
,
,
,
h
h
h
,
,
i
j
Alternation of substituents on the pyridine ring was first probed.
The results show that the process serves as a general approach to
1,8-naphthyridines. It appears that the electronic effect has
impact on the reaction. The pyridine rings bearing an electron-
donating group afforded the desired products (2b and 2c) with
lower yields, while electron-withdrawing groups delivered the
corresponding naphthyridine products (2d−g) with higher
efficiency. Pyrazine 1h worked smoothly with the protocol as
well (2h). The structure of the products was determined by the
single-crystal X-ray diffraction analysis of 2a (Figure S1).16
Next, the structural variation of the alkyne components (e.g.,
R′ and R′′, respectively) was examined according to Scheme 3.
Probing R1 revealed that a wide range of structures tolerated the
protocol. They include aryl (2i−o), heteroaromatic (2p), and
alkyl (2q) structures. Furthermore, arene rings bearing electron-
neutral (2a), -donating (2i and 2j), and -withdrawing (2k−o)
groups have limited influence on the reaction. Finally, we
examined the R′′ component. Similarly, both electron-donating
(4-Me) and electron-withdrawing groups (3-Br and 2-Cl)
worked smoothly to give the desired products (2r−2t).
1,2,3,4-Tetrahydronaphthyridines (THNADs) are an impor-
tant class of framework, exhibiting diversely attractive biological
activities.17 In addition, they are also versatile building blocks in
synthesis.18 The 1,8-naphthyridine products 2 could serve as the
precursors for the synthesis of unique trifluoromethylated
THNADs. We identified the reaction conditions with 10 mol
% of PtO2 under 1 atm of H2 pressure at rt for 24 h, enabling
selective reduction of the unsubstituted pyridine ring to deliver
THNAD 4 in 71% yield (Scheme 4).
a
Unless specified, 1a (0.15 mmol), cat. (10 mol %), oxidant (0.75
mmol), CsF (0.6 mmol), and TMSCF3 (0.6 mmol) in 1.5 mL of
b
c
CH3CN was stirred at 80 °C for 12 h. Isolated yield. Toluene was
used as solvent. Lewis acid (20 mol %) was used. PIDA (4 equiv)
was used. PIDA (6 equiv) was used. The reaction was performed at
d
e
f
g
h
i
rt. DCM was used as solvent. KF (4 equiv) instead of CsF was used.
j
AgF (4 equiv) instead of CsF was used.
Unfortunately, only the commonly observed imidazopyridine
product 3a was obtained. However, to our delight, in the
presence of oxidant PIDA (5 equiv), the reaction course was
altered (entry 2). A new, major, 1,8-naphthyridine product 2a
was detected with a trace amount of 3a. When the reaction
medium was changed to MeCN, 2a was isolated in 41% yield
(entry 3). Importantly, the production of 3a was completely
suppressed. The yield decreased sharply (18%) when Cu(OAc)2
was removed, indicative of the indispensable role of Lewis acid in
the 6-membered cyclization (entry 4). More commonly used
Lewis acids, such as Pd(OAc)2, Fe(OAc)2, Ni(OAc)2, and
Zn(OAc)2 were probed but resulted in lower yields (entries 5−
8). Encouragingly, the isolated yield could be elevated to 46% by
use of Co(OAc)2 (entry 9). Elevating the catalyst loading to 20
mol % led to a slight growth in the yield to 50% (entry 10).
Various oxidants were examined subsequently. PhI(OPiv)2
delivered a lower yield of 25% (entry 11). The stronger oxidant
PIFA only generated a trace amount of 2a along with 3a (entry
12). The combination of O2 and Co(OAc)2 failed to promote the
cyclization (entry 13). Neither reducing nor increasing amount
of the PIDA was beneficial (entries 14 and 15). The reaction
carried out at room temperature resulted in marginal improve-
ment (59%, entry 16). Moreover, our screening of solvents
including EtOAc, toluene, CHCl3, THF, and DMF led to DCM
being selected as the best choice (70% yield, entry 17).13
Substitution of CsF by KF and AgF afforded 2a in lower yields
To gain a preliminary understanding of the mechanistic aspect
of the new reaction, several experiments were carried out
(Scheme 5). In the presence of 2,2,6,6-tetramethyl-1-piperidi-
nyloxy (TEMPO, 1.5 equiv), the formation of product 2a was
suppressed along with a trace amount of 3a detected (Scheme 5,
eq 1). A new TEMPO−CF3 adduct 5 was observed in 29% yield
by NMR analysis. In addition, the reactions of TEMPO carried
B
DOI: 10.1021/acs.orglett.7b02759
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Letter
a
reaction proceeds via a plausible radical process initiated by
Scheme 3. Scope of Substituents on Alkynes
•
CF3 radical produced from the combination of PIDA, TMSCF3,
and CsF.10,11 To understand the fact that the reaction takes
places at C(3) rather than on the often observed N of the
pyridine ring, 1H NMR studies were performed in DMSO-d6 by
using 2-(methylamino)pyridine 6 as substrate and HOTf instead
of Co(OAc)2 due to its electron paramagnetic effect. As shown in
Figure 1, C(3) in 6 has higher electron density than that of
Figure 1. 1H NMR studies of different related species in DMSO-d6: (a)
spectrum of pyridine in DMSO-d6; (b) spectrum of 2-(methylamino)-
pyridine in DMSO-d6; (c) spectrum of a mixture of 2-(methylamino)-
pyridine and 1 equiv of HOTf for 30 min in DMSO-d6; (d) spectrum of
phenol acetate in DMSO-d6.
a
Unless otherwise specified,1 (0.15 mmol), Co(OAc)2 (20 mol %),
PIDA (0.75 mmol), CsF (0.6 mmol), and TMSCF3 (0.6 mmol) in 1.5
mL of DCM were stirred at room temperature for 12 h. Isolated yields.
b
The reaction mixture was stirred for 4 d.
Scheme 4. Selective Reduction of Pyridine Rings
pyridine due to the resonance effect of aminopyridine by
comparison of their 1H chemical shifts (panel a vs b).19
Treatment of 6 with 1 equiv of HOTf in DMSO-d6 led to a
decrease of the C(3) electron density (panel b vs c). However, its
electron density was still higher that of phenol acetate 8, which
has been used to construct trifluoromethylcoumarin via a similar
radical mechanism (panel c vs d).12a Furthermore, it is believed
that the complexation of the N of pyridine with Lewis acids can
activate C−H bond and facilitates C−H bond cleavage.19,20
A plausible reaction mechanism is proposed (Scheme 6). An
initial trifluoromethylated hypervalent iodine(III) species A was
formed from the reaction of PIDA, TMSCF3, and CsF, and this
Scheme 5. Control Experiments with TEMPO
•
delivered an electrophilic CF3 radical via homolytic cleav-
Scheme 6. Proposed Mechanism
out under the standard conditions with and without Co(OAc)2,
respectively, led to 49% and 71% yields of TEMPO−CF3 adduct
5 (Scheme 5, eqs 2 and 3). When other radical scavengers
(butylated hydroxytoluene (BHT) and galvinyoxy) were added
into the reaction mixture under the standard conditions, the
formation of product 2a was suppressed completely as well
(Supporting Information). These results suggest that the
C
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age.10,11,21 β-Selective addition of the radical to the Co(II)
coordinated CC in intermediate B, generated from complex-
ation of Co(OAc)2 with the pyridine “N” and CC in 1a, gave
an electrophilic radical intermediate C. It is believed that the
Co(II) chelation with “N” rendered the “N” electron deficient. A
new 6-endo-dig pathway with the relatively electron-rich C(3)
carbon then led to radical C. Two possible paths may account for
the formation of the terminal product 2a.12a In path a, cyclization
of the radical with C(3) carbon gives the radical intermediate D.
Alternatively (path b), the intermediate C undergoes a PIDA-
mediated single-electron transfer (SET) oxidation to generate a
cation E, followed by a Friedel−Crafts type reaction to deliver an
intermediate F. Finally, under the influence of the Co(II)
promoted C−H cleavage, the product 2a is produced by PIDA
oxidation and concurrent release of catalyst Co(II).
In summary, we have developed an unprecedented Co(OAc)2-
catalyzed trimethylation and subsequent C(3)-selective func-
tionalization of pyridine derivatives. The process creates a
distinct C−C bond-forming process for the assembly of the new
pyridine frameworks of trifluoromethylated 1,8-naphthyridines
instead of the well-documented imidazo[1,2-a]pyridines. The
combination of Co(OAc)2 as catalyst, PIDA as oxidant, and
presence of TMSCF3 and CsF changes the reaction course from a
commonly observed 5-exo-dig cyclization involving “N” to an
unusual 6-endo-dig with “C” atom of pyridines. The mild reaction
conditions enable a broad scope of N-(prop-2-ynyl)pyridin-2-
amine substrates to work smoothly in the protocol. Further
exploration of this catalytic system in new organic trans-
formations and studies into understanding its mechanistic
aspects are being conducted in our laboratories.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02759.
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Lett. 2014, 16, 504.
Experimental procedures, characterization, and spectral
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(13) The details of other screened solvents are provided in the
Supporting Information.
(14) The details of screening of ligands are provided in the Supporting
Information.
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Accession Codes
CCDC 1529108 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: hli77@ecust.edu.cn.
*E-mail: wwang@unm.edu.
ORCID
Wei Wang: 0000-0001-6043-0860
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support of this research from the program for the
National Science Foundation of China (21738002, 21372073,
21572054, and 21572055), the Fundamental Research Funds for
the Central Universities is gratefully acknowledged.
D
DOI: 10.1021/acs.orglett.7b02759
Org. Lett. XXXX, XXX, XXX−XXX