Arylation, Vinylation, and Alkynylation of Electron-Deficient (Hetero)arenes Using Iodonium Salts

Article abstract of DOI:10.1021/acs.orglett.6b02550

Arylation, vinylation, and alkynylation of electron-deficient arenes and heteroarenes have been achieved by chemoselective C-H zincation followed by copper-catalyzed coupling reactions using iodonium salts. This approach offers a direct and general access to a wide scope of (hetero)biaryls as well as alkenylated and alkynylated heteroarenes under mild conditions. It is particularly useful and valuable for the rapid and modular synthesis of diverse (hetero)aryl compounds, as demonstrated in the synthesis of transient receptor potential vanilloid 1 (TRPV1) antagonists and angiotensin II receptor type 1 (AT1 receptor) antagonists.

Full text of DOI:10.1021/acs.orglett.6b02550

Letter
pubs.acs.org/OrgLett
Arylation, Vinylation, and Alkynylation of Electron-Deficient
(Hetero)arenes Using Iodonium Salts
Chuan Liu and Qiu Wang*
Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
S
* Supporting Information
ABSTRACT: Arylation, vinylation, and alkynylation of
electron-deficient arenes and heteroarenes have been achieved
by chemoselective C−H zincation followed by copper-
catalyzed coupling reactions using iodonium salts. This
approach offers a direct and general access to a wide scope
of (hetero)biaryls as well as alkenylated and alkynylated heteroarenes under mild conditions. It is particularly useful and valuable
for the rapid and modular synthesis of diverse (hetero)aryl compounds, as demonstrated in the synthesis of transient receptor
potential vanilloid 1 (TRPV1) antagonists and angiotensin II receptor type 1 (AT1 receptor) antagonists.
eveloping rapid and efficient access to diverse electron-
deficient biaryl motifs is highly valuable, as they have a
ubiquitous presence and indispensable role in natural
products,1a pharmaceutically important compounds,1b,c and
functional materials1d (Figure 1). Complementary to traditional
1a),7a phenols, and anilines (Scheme 1b).7b,c Yet, arylation of
electron-deficient arenes using iodonium salts has not been
reported, likely due to their weaker nucleophilicity.
1
D
Scheme 1. Arylation of Arenes with Iodonium Salts
Figure 1. Electron-deficient biaryl motifs in natural products, bioactive
compounds, and functional molecules.
Along with our research interests in direct functionalization
of arenes,8 we envisioned that arylation of electron-deficient
arenes could be achieved in one pot by selective zincation for
the formation of more nucleophilic organozinc intermediates9
followed by copper-catalyzed arylation with iodonium salts
(Scheme 1c). This approach of preparing (hetero)biaryls
features a broad scope of arenes, superior functional group
tolerance, and mild reaction conditions. In this letter, we report
the development of such an arene arylation method using
iodonium salts and its application in the synthesis of bioactive
biaryl compounds. We also demonstrate such a strategy is
effective for arene vinylation and alkynylation.
metal catalyzed cross-coupling reactions which require multi-
step preparation of organometallic reagents,2,3 direct arylation
of arenes offers an attractive and rapid strategy for the synthesis
of biaryls.4 Despite remarkable advancement in arene arylation,
current methods often suffer from the limited scope of arenes
bearing specific directing groups, the use of strong oxidants, and
harsh reaction conditions. Thus, it is desirable to develop a
general and mild arene arylation approach to diverse electron-
deficient biaryl compounds.
Recently, iodonium salts have emerged as a powerful and
attractive electrophilic arylation reagent alternative to aryl
halides in cross-coupling reactions,5 due to their favorable
properties such as high reactivity, air and moisture stability, and
convenient preparation without the need for chromatography
purification.6 For example, they have been used in the direct
arylation of electron-rich aromatic compounds to directly
access electron-rich biaryl compounds, such as indoles (Scheme
Our studies began with model substrates 3-cyanopyridine
(nicotinonitrile) 1a and diphenyliodonium salt 2a (Table 1).
Learning from Knochel’s seminal work9 and our recent
Received: August 27, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02550
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Organic Letters
Letter
a
a
Table 1. Condition Optimization for Arylation of 1a
Scheme 2. Scope of Iodonium Salts
temp
time
b
2a
3aa
b
c
entry
catalyst
X
(°C)
(h)
(equiv) (yield, %)
1
−
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
BF4
AsF6
SbF6
OTf
−
rt
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
1.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.0
2.0
2.0
2.0
2.0
2.0
2.0
trace
22
5
2
Cu(OTf)2
Cu(OAc)2
Cu(acac)2
CuCl
rt
3
rt
4
rt
28
34
22
53
65
79
65
79
74
82
0
5
rt
6
CuBr
rt
d
7
CuOTf
rt
d
8
CuOTf
50
50
50
50
50
50
50
50
d
9
CuOTf
d
10
11
12
13
CuOTf
d
CuOTf
d
CuOTf
d
CuOTf
e
d
14
CuOTf
1.0
f
d
15
CuOTf
−
1.0
0
a
Reactions conditions: 1a (0.3 mmol), Zn(tmp)Cl·LiCl (0.6 mmol);
a
b
Reaction conditions: 1a (0.3 mmol), Zn(tmp)Cl·LiCl (0.6 mmol), 50
°C, 1 h; 2 (0.6 mmol), CuOTf·1/2PhMe (0.03 mmol), 8 h.
then catalyst (0.03 mmol), THF (3 mL). Deprotonation temperature
and time. Isolated yield. CuOTf·1/2PhMe. PhI was used instead of
2a. PhOTf was used instead of 2a.
c
d
e
f
Scheme 3. Scope of Electron-Deficient Hetereoarene and
a
Arene Substrates
experience,8 we chose Zn(tmp)Cl·LiCl as an effective base to
promote selective H−Zn exchange for the formation of arylzinc
intermediate. Upon the direct treatment of diphenyliodonium
salt 2a, desired product 3aa was observed only in trace amounts
(entry 1). To our delight, the formation of 3aa was successful
with the presence of a copper catalyst (entries 2−7). Among
different copper salts, CuOTf·1/2PhMe was the most effective
(entry 7). We next surveyed the conditions for generating the
organozinc intermediate; elevated temperature resulted in a
better yield of 3aa (entry 8). Increasing the loading of 2a
improved the formation of 3aa to 79% yield (entry 9). The use
of other common counterions of iodonium salts such as BF4,
AsF6, and SbF6 did not give better results (entries 10−12).
Finally, extending the deprotonation time further increased the
formation of 3aa to 82% yield, which was chosen as the
standard reaction conditions (entry 13). When iodonium salt
was replaced with either PhI or PhOTf under the optimized
reaction conditions, no desired product 3aa was observed
(entries 14−15), indicating the superior reactivity of
diphenyliodonium salt in this reaction.
a
Reaction conditions: 1 (0.3 mmol), Zn(tmp)Cl·LiCl (0.6 mmol); 2a
With arylation conditions established, we examined the scope
of iodonium salts in their reactions with 1a (Scheme 2).
Various substituents on the iodonium salts were found to be
well tolerated. For example, desired products 3aa−3ai,
containing either an electron-donating group (Me, MeO) or
an electron-withdrawing group (F, Cl, Br, COOEt, NO2, CF3)
at the 4-position, all readily formed in 58−84% yields. Likewise,
substituents at the C-2 and C-3 positions of iodonium aryl salts
were also examined with desired products 3aj−3al formed
smoothly. In addition, heteroarene-derived iodonium salts, such
as pyridine and thiophene, were also effective in the arylation
reactions and formed 3am−3an in moderate yields.
(0.6 mmol), CuOTf·1/2PhMe (0.03 mmol), THF (3 mL).
b
c
Deprotonation step run at room temperature. Reaction run in
CH2Cl2 because of the poor solubility of caffeine in THF.
successfully arylated under standard conditions (3ba and 3ca).
3-Fluoropyridine was also effective, providing the desired
product 3da in 61% yield. Besides pyridines, 1-methylbenzimi-
dazole, benzoxazole, benzothizole, and caffeine all underwent
arylation to afford 3ea−3ha. Simple oxazole and thiazole also
gave the desired products 3ia and 3ja. Finally, pyrazine, N-
methyl-3-aldehydeindole, and even electron-poor benzo nitrile
were examined and found to be effective substrates under
standard conditions, affording biaryl compounds 3ka, 3la, and
3ma, respectively. The high regioselectivity observed is
presumably derived from the selective zinc metalation step.
We also explored different electron-deficient hetereoarene
and arene substrates using diphenyliodonium salt 2a as the
arylation reagent (Scheme 3). Similar to nicotinonitrile 1a, 6-
fluoronicotinonitrile and 6-trifluoromethylnicotinonitrile were
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DOI: 10.1021/acs.orglett.6b02550
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Letter
The broad scope of this reaction also demonstrates its superior
functional group tolerance.
We next explored this approach for vinylation and
alkynylation of arenes by using phenylvinyl and phenylalynyl
iodoium salts (Scheme 4). Different heteroarenes including
precursors of TRPV1 antagonists,10 3ca, 3cd, and 3ce, were
readily obtained using economical nicotinonitrile 1c by this
one-pot arylation protocol with iodonium salts under standard
conditions. Biaryl 3aq, a key intermediate of AT1 receptor
antagonists,11 was readily prepared from nicotinonitrile 1a in
one step (Scheme 5b).
We also applied this transformation for a rapid synthesis of
compound 5, which has inhibitory activity of histone
deacetylases (HDAC) and antiproliferative effects on cancers12
(Scheme 6). Starting from 6-bromonicotinonitrile 1n, arylation
Scheme 4. Vinylation and Alkynylation of Electron-Deficient
Aromatic Substrates
a
Scheme 6. Rapid Synthesis of HDAC Inhibitor
with iodonium salt 2r afforded 3nr in 57% yield. The
subsequent Suzuki cross-coupling reaction provided diaryl-
nicotinonitrile 4 in 98% yield. Hydrolysis of 4 followed by
amidation with 1,2-diaminobenzene gave target molecule 5 in
89% yield over two steps. This synthesis also highlights the
advantageous compatibility of copper-catalyzed arylation using
iodonium salts with halides for further cross-coupling reactions,
as a valuable strategy complementary to existing cross-coupling
arylation reactions2−4 to access biaryl compounds.
a
Reaction conditions: 1 (0.3 mmol), Zn(tmp)Cl·LiCl (0.6 mmol), 2
(0.6 mmol), CuOTf·1/2PhMe (0.03 mmol), THF (3 mL).
In conclusion, we have developed a general approach for
arylation, vinylation, and alkynylation of electron-deficient
(hetero)arenes by selective C−H deprotonative zincation
followed by copper-catalyzed C−C coupling reactions with
iodonium salts. This approach is valuable and useful for rapid
synthesis of biologically significant biaryl compounds that are
the core framework in natural products, pharmaceuticals, and
functional materials. Our future work will extend such
functionalization strategies to other C−H bonds.
nicotinonitrile, 1-methylbenzimidazole, benzothizole, and ox-
azole, when subjected to standard conditions with phenylvinyl
iodoium salt 2o, readily afforded E-alkenylated heteroarenes
3ao−3io in good yields. Electron-deficient pentafluorobenzene
and benzonitrile also effectively underwent vinylation and
afforded products 3no and 3oo in good yields, respectively.
Similarly, the alkynylation of different arenes were also achieved
by the analogous reactions using phenylalynyl iodoium salt 2p.
We next examined this simple arylation protocol in the
synthesis of biaryl-containing compounds of valuable biological
and pharmacological properties (Scheme 5). For example, key
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02550.
Scheme 5. Rapid Access to TRPV1 Antagonists and AT1
Receptor Antagonists
1
Experimental procedures and H and 13C NMR spectra
for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: qiu.wang@duke.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge Duke University for the financial support to
this work. Q.W. is a fellow of the Alfred P. Sloan Foundation
and a Camille Dreyfus Teacher-Scholar.
C
DOI: 10.1021/acs.orglett.6b02550
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Organic Letters
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