Metal-free synthesis of ortho -CHO diaryl ethers by a three-component sequential coupling

Article abstract of DOI:10.1021/ol503224u

A practical, metal-free, and highly chemoselective approach was developed for the synthesis of ortho-CHO diaryl ethers by a three-component sequential coupling of arynes, N,N-dimethylformamide (DMF), and diaryliodonium salts. Diverse functional groups including halo, nitryl, and bulky substituents and heteroaromatics are well tolerated. Mechanistically, isotopic tracer experiments reveal that the diaryliodonium salt serves as an electrophile to trap the transient intermediates generated from the [2 + 2] cyclization of an aryne and DMF.

Full text of DOI:10.1021/ol503224u

Letter
pubs.acs.org/OrgLett
Metal-Free Synthesis of ortho-CHO Diaryl Ethers by a Three-
Component Sequential Coupling
Fangliang Liu,† Huameng Yang,‡ Xinquan Hu,†,‡ and Gaoxi Jiang*,‡,§
†College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, P. R. China
‡State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, P. R. China
§Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, P. R. China
S
* Supporting Information
ABSTRACT: A practical, metal-free, and highly chemo-
selective approach was developed for the synthesis of ortho-
CHO diaryl ethers by a three-component sequential coupling
of arynes, N,N-dimethylformamide (DMF), and diaryliodo-
nium salts. Diverse functional groups including halo, nitryl, and
bulky substituents and heteroaromatics are well tolerated. Mechanistically, isotopic tracer experiments reveal that the
diaryliodonium salt serves as an electrophile to trap the transient intermediates generated from the [2 + 2] cyclization of an aryne
and DMF.
iaryl ethers are prominent structural motifs found in
numerous natural products with vital biological activities,
limited to the coupling of electron-rich/neutral phenols with
highly activated aryl fluorides.6 Recently, Olofsson and co-
workers described an elegant protocol, wherein 1 equiv of a
strong base, such as NaH, t-BuOK, and NaOH, is essential to
deprotonate phenols followed by O-arylation with diary-
liodonium salts (Scheme 1, eq 2).7 Despite these important
advances, the development of a practical methodology for the
synthesis of ortho substituted and sterically hindered diaryl
ethers remains a challenge. Particularly, exploration for a mild
synthesis of ortho-CHO diaryl ethers is of great interest and
significance because such ethers are very useful to making
diverse interesting compounds.8 Herein, we report a practical
and highly chemoselective approach for the synthesis of ortho-
CHO diaryl ethers by a novel three-component sequential
coupling of arynes,9 DMF,10 and diaryliodonium salts (Scheme
1, eq 3).
D
drug candidates, high-selling medicines, and relevant materials
used in life science and industry.1 Consequently, for more than
a century continuous endeavors have been made toward the
efficient synthesis of the unique unit. Ullmann-type diaryl
synthesis represents a classical method although stoichiometric
amounts of copper reagents and harsh conditions are often
required.1b,2 In recent decades, significant progress has been
achieved by Cu-3 and Pd-catalyzed4 cross-coupling reactions of
phenols with aryl halides or arylboronic acids (Scheme 1, eq 1).
Scheme 1. Profile for the Synthesis of Diaryl Ethers
Inspired by the pioneering results from the Miyabe group, in
which highly reactive intermediates benzoxetene A and its
isomer ortho-quinone methide B might form by [2 + 2] π-bond
cyclization of an aryne with DMF,11 we speculate that an extra
electrophile (E+) could trap A/B at the oxygen position to
furnish C involving formation of a new O−E bond and an
ortho-imine group that leads to an ortho-CHO group formation
on the aryl ring after simple workup (Scheme 2). Importantly,
the process avoids the use of stoichiometric amounts of
dangerous strong bases or Lewis acids that is necessary for
CHO group introduction by traditional approaches.12 Reason-
ably, diaryliodonium salts (E+ = Ar+, herein) that have been
widely utilized as excellent electrophilic arylation reagents7
were selected for the hypothesis.
Nevertheless, such transition-metal catalyses always rely on the
use of noncommercially available or expensive ligands and
generally suffer from the use of excess amounts of reagents,
limited substrate tolerance, high temperatures, and long
reaction times, which severely restrict application in organic
and pharmaceutical synthesis. Therefore, considerable effort has
been directed toward the discovery of a metal-free strategy.5
Among these attempts, the SNAr reaction is useful but mostly
Received: November 6, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol503224u | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Hypothetical Reaction Pathway
Table 2. Substrate Scope of Arynes
Indeed, this hypothesis guided our initial screening experi-
ments (Table 1). To our delight, the treatment of the readily
a
Table 1. Optimization of Reaction Conditions
entry
Ph2I+ X−
[F−] (equiv)
solvent
yield (%)
−
1
2
3
4
Ph2I+ OTf 2a
TBAF (3.0)
CsF (3.0)
KF (3.0)
KF (4.0)
KF (4.0)
KF (4.0)
KF (4.0)
KF (4.0)
KF (4.0)
KF (4.0)
KF (4.0)
KF (4.0)
KF (4.0)
KF (4.0)
DMF
DMF
DMF
DMF
DMF
THF
70
73
79
87
61
2a
2a
2a
2a
2a
2a
2a
2a
b
5
a
Reaction conditions: 1b−f (0.15 mmol), 2a (1.2 equiv), KF (4.0
equiv), DMF (1.0 mL), 60 °C, 3 h; all yields are isolated.
c
d
6
N.R.
c
d
7
CH2Cl2
toluene
CH3CN
DMF
DMF
DMF
DMF
DMF
N.R.
c
8
15
66
83
69
71
80
50
c
to 1a, symmetric ortho-silyl aryl triflates 1b and 1c were well
tolerated and provided adducts 3ba and 3ca in 91% and 82%
yields, respectively (entries 1 and 2). Notably, asymmetric
ortho-silyl aryl triflates 1d and 1e gave exclusively 3da and 3ea
in 78% and 84% yields that exhibit excellent regioselectivity
(entries 3−4).13 In contrast to 1d−e, the aryne procurers 1f
and 1g decreased regioselectivity, leading to regioisomers 3fa/
3fa′ and 3ga/3ga′ in 90% and 96% yields with ratios of 1.2:1
and 1:1, respectively (entries 5−6). It is noteworthy that both
mixtures of 3fa/3fa′ and 3ga/3ga′ can be facilely separated by
single flash column chromatography. Importantly, for an aryne
precursor having electron-withdrawing groups, 4,5-difluoro-
substituted 2-(trimethylsilyl)phenyl triflate 1h is also tolerated
in the reaction to afford the desired product 3ha in 72% yield
smoothly (entry 7).
Next, a wide range of diaryliodonium salts was employed
under the standard reaction conditions. Remarkably, we were
pleased to find that a large variety of diaryliodonium salts are
quite applicable to the three-component coupling reaction. As
demonstrated in Table 3, using 1b as the aryne precursor,
diverse diaryliodonium salts gave the desired products in good
yields. Symmetric diaryliodonium salts 2g−i bearing a halogen
(Cl and Br) and tert-butyl substituted at the para position
furnished 3bg−bi in 78−83% yields (entries 1−3). Encouraged
by Olofsson’s arylation with unsymmetrical diaryliodonium
salts, in which an interesting result of “dummy groups”-
controlled chemoselectivity was confirmed,7d a series of
asymmetric diaryliodonium salts 2j−u with one para-
CH3OC6H4 as the “dummy group” were prepared and reacted
with 1b under the standard reaction conditions (entries 4−15).
Remarkably, excellent chemoselectivity was observed regardless
of the electronic and steric properties of the other aryl group.
For instance, triflate salts 2k−m having a para-halogen (F, Cl,
and Br) and even strong electron-withdrawing substituents CF3
(2n) and NO2 (2o) are all suitable for the three-component
9
Ph2I+ PF6 2b
−
10
d
−
11
Ph2I+ AsF6 2c
12e
13
14
Ph2I+ NO3 2d
−
Ph2I+ Cl− 2e
Ph2I+ Br− 2f
a
Reaction conditions: 1a (0.15 mmol), 2 (1.2 equiv), [F−] (3.0−4.0
b
equiv), solvent (1.0 mL), 60 °C, 3 h; all yields are isolated. At 50 °C.
c
d
DMF (10.0 equiv). N.R. means no reaction.
accessible aryne precursor 2-(trimethylsilyl)aryl triflate 1a with
diphenyliodonium triflate Ph2I+OTf− 2a (1.2 equiv) and
tetrabutylammonium fluoride (TBAF) (3.0 equiv) in DMF at
60 °C for 3 h facilitated the desired product 2-phenoxybenz-
aldehyde 3aa in 70% yield predominantly (entry 1). Stimulated
by the preliminary result, further optimization to improve the
chemical yield was conducted. Using CsF and KF instead of
TBAF improved the yield of 3aa to 73% and 79%, respectively
(entries 2 and 3). Gratifyingly, enlarging the loading of KF to
4.0 equiv gave the best result and afforded 3aa in 87% yield
(entry 4). Lowering the temperature to 50 °C decreased the
yield somewhat (entry 5). A brief screening of solvents revealed
that DMF is optimal (entries 4, 6−9). The reactions were
completely suppressed in THF and CH2Cl2 due to the
substrate insolubility (entries 6 and 7). Changing the solvent
to toluene and acetonitrile (CH3CN) lowered the yield of 3aa
to 15% and 66%, respectively (entries 8 and 9). The anion
effect of diphenyliodonium salts has also been investigated.
Accordingly, the replacement of 2a by 2b−2f decreased the
yield of 3aa to 83−50% (entries 10−14).
Under the optimized reaction conditions, we next examined
the substrate scope with respect to both aryne precursors and
diaryliodonium salts to the novel sequential coupling reaction.
First, several ortho-silyl aryl triflates were employed and the
representative results were summarized in Table 2. In addition
B
dx.doi.org/10.1021/ol503224u | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
in which the diaryliodonium salt acts as an electrophile to trap
the transient intermediates generated from the [2 + 2] π-bond
cyclization of aryne and DMF.
Table 3. Substrate Scope of Diaryliodonium Salts
In summary, we have realized a useful approach for the
synthesis of ortho-CHO diaryl ethers by a three-component
sequential coupling reaction of arynes, DMF, and diary-
liodonium salts. Remarkably, a C−C bond and two new C−
O bonds simultaneously formed in the transformation.
Mechanistically, isotope experiments disclose that the diary-
liodonium salt functions as an electrophile to trap the active
intermediates generated from the [2 + 2] cyclization of an
aryne and DMF. Further applications of the practical method to
some interesting natural products and diaryl ether materials are
under investigation in our laboratory and will be reported in
due course.
entry
diaryliodonium salts
product
yield (%)
1
2
R = Cl, Ar = p-ClC6H4 2g
R = Br, Ar = p-BrC6H4 2h
R = Bu, Ar = p-t‑BuC6H4 2i
3bg
3bh
3bi
78
81
83
84
61
65
83
88
65
84
56
85
72
76
68
t‑
3
4
R = OMe, Ar = C6H5 2j
3ba
3bk
3bg
3bh
3bn
3bo
3bp
3bq
3br
3bs
3bt
5
R = OMe, Ar = p-FC6H4 2k
R = OMe, Ar = p-ClC6H4 2l
R = OMe, Ar = p-BrC6H4 2m
R = OMe, Ar = p-CF3C6H4 2n
R = OMe, Ar = p-NO2C6H4 2o
R = OMe, Ar = o-MeC6H4 2p
R = OMe, Ar = m-MeC6H4 2q
R = OMe, Ar = p-MeC6H4 2r
R = OMe, Ar = 2,4,6-Me3C6H2 2s
R = OMe, Ar = 3-pyridyl 2t
R = OMe, Ar = 2-(6-Cl)pyridyl 2u
6
7
8
9
10
ASSOCIATED CONTENT
* Supporting Information
b
■
11
b
S
12
13
14
15
Complete experimental details and characterization data for the
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
3bu
a
Reaction conditions: 1b (0.15 mmol), 2 (1.2 equiv), KF (4.0 equiv),
b
AUTHOR INFORMATION
Corresponding Author
DMF (1.0 mL), 60 °C, 3 h; all yields are isolated. Reaction time was
■
prolonged to 8 h.
*E-mail: gxjiang2012@sinano.ac.cn.
Notes
coupling reaction and provided 3bk−bo in 61−88% yields
(entries 5−9). In contrast to 2p with an ortho-methyl group
(entry 10), 2q and 2r containing a methyl group at the meta-
and para-position that seem less reactive proceeded in the
reaction with a prolonged reaction time of up to 8 h, affording
3bq and 3br in 56% and 85% yields, respectively (entries 11
and 12). Significantly, highly substituted salt 2s is also
compatible with this transformation, and the reaction enabled
the formation of 3bs in 72% yield smoothly (entry 13).
Importantly, ortho-CHO pyridyl ethers 3bt and 3bu can be
isolated in 76% and 68% yields with pyridyliodonium salts 2t
and 2u as electrophiles (entries 14 and 15).
In order to explore the reaction mechanism, isotopic tracer
experiments were executed. As shown in Scheme 3, the
reactions proceeded in D-DMF (eq 1), 13C-DMF (eq 2), and
18O-DMF (eq 3), delivering the corresponding isotope labeled
products 3ba-D, 3ba-13C, and 3ba-18O in high yields,
respectively. Reasonably, these observations reveal that such a
three-component sequential coupling reaction should go
through the postulated pathway demonstrated at Scheme 2,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from Hundred Talent Program of Chinese
Academy of Sciences (CAS) is gratefully acknowledged.
■
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