From Anilines to Aryl Ethers: A Facile, Efficient, and Versatile Synthetic Method Employing Mild Conditions

Article abstract of DOI:10.1002/anie.201712618

We have developed a simple and direct method for the synthesis of aryl ethers by reacting alcohols/phenols (ROH) with aryl ammonium salts (ArNMe₃⁺), which are readily prepared from anilines (ArNR′₂, R′=H or Me). This reaction proceeds smoothly and rapidly (within a few hours) at room temperature in the presence of a commercially available base, such as KO^tBu or KHMDS, and has a broad substrate scope with respect to both ROH and ArNR′₂. It is scalable and compatible with a wide range of functional groups.

Full text of DOI:10.1002/anie.201712618

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: From Aniline to Aryl Ether: A Facile, Efficient and Versatile
Synthetic Protocol Employing Mild Conditions
Authors: Dong-Yu Wang, Ze-Kun Yang, Chao Wang, Ao Zhang, and
Masanobu Uchiyama
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712618
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10.1002/anie.201712618
Angewandte Chemie International Edition
COMMUNICATION
From Aniline to Aryl Ether: A Facile, Efficient and Versatile
Synthetic Protocol Employing Mild Conditions
Dong-Yu Wang,[ab] Ze-Kun Yang,[cd] Chao Wang,*[cd] Ao Zhang,*[abe] and Masanobu Uchiyama*[cd]
In memory of Professor Keiji Morokuma
Abstract: We have developed a simple and direct protocol for
utility that a suitable protocol would have. Interestingly, ether
formation by reaction of alcohol (used as EtONa) with ArNMe3
+
synthesis of aryl ethers by reaction of alcohols/phenols (ROH) with
+
aryl ammonium salts (ArNMe3 ), which are readily prepared from
salts via cleavage of the aryl C–N bond, leading to ArOEt, was
+
anilines (ArNR´2, R’ = H or Me). This reaction proceeds smoothly
and rapidly (within a few hours) at room temperature in the presence
of a commercially available base, such as KOtBu or KHMDS, and
first observed as a side reaction of demethylation of ArNMe3 as
early as in 1942.[6] However, this etherification reaction has
since been largely neglected, probably because many other
has a broad substrate scope for both ROH and ArNR´2. It is scalable, methods for the formation of (aryl) ethers have been
and compatible with a wide range of functional groups.
developed.[7] Nevertheless, many of these existing methods
require harsh conditions, such as a large excess of ROH, high
reaction temperature, or undesirable solvent, and hence there is
still a requirement for novel, efficient protocols. Herein, we report
an efficient, selective and easy-handling method for conversion
of anilines (via their ammonium salts) to aryl ethers by reaction
with alcohols/phenols in the presence of a base at room
temperature, without the need for any TM catalyst.
Amino groups are present in an enormous variety of natural
products, as well as in pharmaceuticals, dyes, and many
functional molecules. In addition, various amines are produced
on an industrial scale and are available at reasonable cost.
Therefore, efficient and selective C–N bond transformation
protocols are of great interest.[1] However, the C–N bonds of
amines are generally very stable, and direct transformation of
the amino group is difficult even in the presence of transition-
metal (TM) catalysts under severe conditions.[2] One approach to
overcome this issue is pre-activation of the C–N bond. For
example, quaternary organo-ammonium salts can be prepared
easily from various amines in high/quantitative yield, and are
extremely stable. In 1988, Wenkert et al. pioneered the protocol
for TM-catalysed cross-coupling of ammonium salts via C–N
bond cleavage,[3] and it is now well established that ammonium
salts show diverse reactivity and synthetic utility as efficient
substitutes for halides.[4] Besides TM-catalysed C–C bond-
forming reactions, fluorination of aryl C–N bonds in ammonium
salts via the SNAr mechanism has also been reported,[5] and is
now used for labeling bio-active molecules with 18F.
Aryltrimethylammonium salts 1 were readily synthesised
from various anilines bearing a NH2, NHMe, or NMe2 group[4,8]
(for details, see Supporting Information). We initially examined
the reaction of 1a as a model compound with various alcohols
and/or phenols
2
(Scheme 1). Optimization of reaction
conditions showed that the counterion of the base (e.g., Na+, K+,
Cs+, etc.) and 1a (e.g., TfO–, I–, BF4 , etc.), and the solvent
–
critically influenced this transformation (Table S1, Supporting
Information). Under the optimized conditions (KOtBu or KHMDS
as a base, DMF solvent, room temperature,[9] within 3 hours), we
found that most of the reactions proceeded smoothly to give the
desired ether products 3 in good to excellent yields without
detectable formation of a demethylation by-product (Scheme 1).
Reactions with simple alcohols such as methanol 2a, ethanol 2b,
and iso-propanol 2c quantitatively afforded ethers 3aa-3ac.
Importantly, even bulky tertiary alcohols including tert-butanol 2d,
tert-amyl alcohol 2e, as well as 1-adamantanol 2f reacted with
1a to form the corresponding products 3ad-3af in high yields.
Alcohols bearing a terminal alkynyl moiety 2g or (free) amino
groups 2h-i, as well as allyl or benzyl alcohols 2j-k, and diol 2m,
also reacted without difficulty, generating the desired etheric
products 3ag-3am in 70–96% isolated yields. It is noteworthy
that fluorinated alcohols 2n-r were highly reactive towards 1a
under the same conditions, affording fluoroalkyl ethers 3an-3ar
in good to quantitative yields. Such results indicate broad
applicability of the current protocol as a method for introducing
fluorine-containing functional groups during development of
pharmaceuticals and functional materials. Finally, phenols 2s-w
and polyphenol 2x also afforded the diaryl ethers 3as-3ax in 64–
81% isolated yields. It is noteworthy that bromine, iodine, and
even boronate were compatible with the reaction conditions,
which would facilitate diverse functionalization of the products.
However, although oxygen is an electronegative element,
like fluorine, there are few reports on the reaction of ammonium
salts with alcohol or phenol to afford ethers, despite the great
[a]
Dr. D.-Y. Wang, Prof. Dr. A. Zhang
CAS Key Laboratory of Receptor Research and the State Key
Laboratory of Drug Research, Shanghai Institute of Materia Medica
(SIMM), Chinese Academy of Sciences
Shanghai 201203, China
E-mail: aozhang@simm.ac.cn (A.Z.)
[b]
[c]
Dr. D.-Y. Wang, Prof. Dr. A. Zhang
University of Chinese Academy of Sciences.
Shanghai 201203, China
Z.-K. Yang, Prof. Dr. C. Wang, Prof. Dr. M. Uchiyama
Graduate School of Pharmaceutical Sciences, University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
E-mail: chaowang@mol.f.u-tokyo.ac.jp (C.W.)
E-mail: uchiyama@mol.f.u-tokyo.ac.jp (M.U.)
Z.-K. Yang, Prof. Dr. C. Wang, Prof. Dr. M. Uchiyama
Elements Chemistry Laboratory, RIKEN
[d]
[e]
2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
Prof. Dr. A. Zhang
To further investigate the synthetic applicability of this
protocol, we examined the reactions of 1a with various
pharmaceuticals, bio-active molecules, natural products, or their
derivatives containing an OH moiety (Scheme 2). Despite their
ShanghaiTech University, Shanghai 201203, China
Supporting information for this article is given via a link at the end of
the document. ((Please delete this text if not appropriate))
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10.1002/anie.201712618
Angewandte Chemie International Edition
COMMUNICATION
2a
2b
2c
OiPr
2d
OtBu
KOtBu or KHMDS (1.4 eq.)
DMF, r.t., 3 h
Ar
NC
NMe3 • OTf
1a
+
HO––R
Ar
OMe
Ar
OEt
Ar
Ar
2
(1.5 eq.)
3aa: >99%
3ab: >99%
3ac: >99%
3ad: 95%
(1.0 eq.)
(91%)
(94%)
(92%)
(90%)
2e
2f
2g
2h
2i
Ar
O
Ar
O
Ar
O
Ar
O
NH2
Ar
O
Me
Me
NMe2
Me
3ae:
3af:
92% (90%)
3ag: 95%
3ah: 92%
3ai: 96%
84% (80%)
(90%)
(88%)
(91%)
Br
2j
2k
Ph
2l
2m
2n
Ar
Ar
O
Ar
O
Ar
O
Ar
O
Ar
O
O
Ar
Ar
F
3aj: >99%
3ak: >99%
3al: 95%
3am: 78%
3an: >99%
(94%)
(92%)
(96%)
(93%)
(70%)
F
2o
2p
2q
2r
nC7F15
2s
OPh
2t
O
Ar
O
CF3
Ar
O
C2F5
Ar
O
Ar
O
OCF3
F
3ao: >99%
3ap: >99%
3aq: 94%
3ar: 84%
3as: 82%
3at: 77%
(97%)
(95%)
(89%)
(77%)
(78%)
(73%)
Me
Me
O
O
Me
Me
2u
2v
2w
2x
Ar
O
Br
Ar
O
I
Ar
O
B
Ar
O
O
Ar
3aw: 82%
3ax: 85%
3av: 82%
3au: 79%
(64%)
(81%)
(80%)
(74%)
Scheme 1. Scope of the reactions of 1a as a model arylammonium compound with various alcohols 2a-r or phenols 2s-x. Yields were calculated based on NMR
(bold) and isolation (in parentheses). For 2a-b and 2d-e, the corresponding commercially available potassium alkoxides were directly used.
+
complex structures and variety of functional groups, most
reactions involving these functional molecules proceeded
smoothly and chemoselectively under the same reaction
conditions. Not only primary (2A-D) and secondary alcohols (2E-
L), but also sterically congested tertiary ones (2M-N) reacted
with 1a to give the corresponding etheric derivatives 3aA-3aN in
good to excellent yields. Further, several functionalized phenols
(2O-T) underwent this reaction, affording 3aO-3aT with high
efficiency, albeit that the yield was significantly reduced when
sterically bulky propofol 2S was used.
NMe3 , R = Me, MeO, etc.) showed little or no reactivity toward
alcohols/phenols; 2) electron-withdrawing groups at the ortho-
position of anilines (1b) had little effect on the reactivity or
selectivity, whereas the reactions of meta-substituted anilines
+
were very sluggish (m-R–C6H4–NMe3 , R = CN, COOEt, etc.); 3)
while bulky alcohols/phenols could participate in the reactions
(e.g., 3aM, 3aN, 3Ad, 3Bd, 3Cd), they were much less reactive
than sterically unhindered ROH compounds.[10]
As regards the mechanism, ICP-MS analysis of the reaction
mixture of 3ad showed that Fe, Co, Ni, Cu, Ru, Rh, Pd, Ag, Os,
Ir, Pt, or Au were below the detection limit (1 ppb), so it is very
unlikely that TM catalysis plays a significant role. In addition,
when the reaction of 1a and 2d was performed in the dark or in
the presence of TEMPO as a radical scavenger (see Supporting
Information Table S1), the yield of 3ad hardly changed,
excluding radical involvement.[11] Overall, our findings suggest
that the current reaction occurs via an SNAr mechanism,[12]
rather than via TM catalysis or a radical process. Detailed
mechanistic studies of this reaction are in progress, using both
experimental and theoretical methods.[13]
Next, we investigated the substrate scope for anilines in this
reaction (Scheme 3) using commercially available KOR as
representative alcohol partners of 2a, 2b and 2d. Ammonium
salts 1 from a variety of anilines reacted smoothly to give the
desired ether products 3. Firstly, electron-deficient anilines
showed excellent reactivity and chemoselectivity, establishing
compatibility of the reaction conditions with a wide range of
functional moieties, including nitrile (1a-b), ester (1c), ketone
(1d-f), nitro (1g), and sulfone (1h), affording the corresponding
aromatic ethers in good to quantitative yields. Secondly,
ammonium salts bearing halogen (Cl, Br, I) on the phenyl ring
(1i-n) could also be used for the reaction, albeit with lower yield
in some cases. Thirdly, anilines with an extended π-system,
such as 1o-q, reacted without difficulty, affording etheric
products in 75–90% yield. More importantly, ammonium salts
prepared from dye, bio-active compound, and pharmaceuticals
(1A-D) also afforded the etheric derivatives without difficulty,
suggesting the potential of this reaction for efficient late-stage
derivatization of functional molecules.
Additional reactions were performed to further examine the
scope of this etherification protocol. Compounds with multiple
OH groups (2y and 2z) reacted smoothly with 1a at the less
hindered position to give 3ay and 3az, respectively, in high yield
as the sole etherified products (Scheme 4-A). Further, substrate
1f with two ammonium moieties could react with two different
alcohols, 2p and 2a, to afford hybrid etherified product 3f-pa as
the main product (B). Finally, we examined the applicability of
this reaction for synthesis of pharmaceutical or bio-active
molecules. We obtained nitrofen 3ga´ (a herbicide) directly from
ammonium compound 1g and phenol 2a´ in high yield on a gram
Limitations and features of this reaction include: 1)
ammonium salts derived from electron-rich anilines (p-R–C6H4–
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10.1002/anie.201712618
Angewandte Chemie International Edition
COMMUNICATION
NO2
N
2A: β-Citronellol
2B: Metronidazole
KOtBu or KHMDS (1.4 eq.)
DMF, r.t., 3 h
Ar
O
Me
Ar
O
Ar
NC
NMe3 • OTf
1a
+
HO––R
N
3aA: 98%
3aB: 82%
(75%) Me
2
(1.5 eq.)
Me
Me
(1.0 eq.)
(91%)
2C: Lamivudine
Cl
2D: Perphenazine
2E: Carvedilol
S
Ar
O
N
Ar
O
Ar
O
NH2
OMe
O
NH
O
N
S
N
O
O
N
N
N
H
3aC: 88%
3aD: 92%
3aE:
(82%)
(84%)
78% (71%)
Me
Me
Ar
O
O
2F: Epiandrosterone
2G: Testosterone
2H: Dihydrocholesterol
2I: α-D-allofuranose
Me
Me
(protected)
O
O
Me
Me
Me
H
Me
H
H
Me
O
O
Me
Me
Me
Me
H
H
H
H
O
Ar
O
Ar
O
O
Ar
O
3aF: 97%
(92%)
3aG: 86%
3aH: 92%
3aI: 98%
(78%)
(88%)
(93%)
BnO
BnO
2J: D-glucopyranose
2K: Galanthamine
2L: Quinine
2M: Nerolidol
(protected)
Me
O
Ar
O
Ar
O
Ar
O
Me
N
N
O
Ar
MeO
Me
Me
Me
BnO
OBn
3aJ: 90% (83%)
3aK:
87% (81%)
3aL:
3aM: 93%
(88%)
O
85% (77%)
N
MeO
O
2N: Venlafaxine
2O: Estrone
2P: Paracetamol
2Q: L-Tyrosine (protected)
H
Ar
O
NH
Ar
O
O
Ar
Ar
O
OMe
Me
H
H
O
HN
OMe
Ar
O
3aN:
3aP: 85%
3aQ: 93%
NMe2
Boc
75% (66%)
3aO: 85% (80%)
(91%)
(84%)
iPr
iPr
O
Me
Et
2R: Capsaicin
2S: Propofol
2T: Diethylstilbestrol
Ar
HN
Me
Ar
O
O
Ar
O
O
Et
3aR: 88%
3aS:
3aT: 95%
MeO
(83%)
36% (30%)
(90%)
Scheme 2. Scope of the reactions of 1a as a model arylammonium compound with various pharmaceuticals, bio-active molecules, natural products, or their
derivatives 2A-T containing an OH moiety. Yields were calculated based on NMR (bold) and isolation (in parentheses)
scale (C). Clorgyline (D, a monoamine oxidase inhibitor) and
triparanol (E, a cholesterol-lowering drug) were also synthesized
Acknowledgements
in satisfactory yields by simple transformations of the ethereal
products 3jb´ and 3rc´, which were readily prepared from 1j/2b´
and 1r/2c´, respectively.
This work was supported by grants (to A. Z. and D-Y. W.) from
the Chinese NSF (81373277, 81430080, 21702216), the
National Program on Key Basic Research Project of China
(2015CB910603), the International Cooperative Program
(GJHZ1622) and the Key Program of Frontier Science (160621)
of the Chinese Academy of Sciences, the Shanghai Commission
of Science and Technology (16XD1404600, 14431905300,
14431900400). D-Y.W. gratefully acknowledges the support of
SA-SIBS Scholarship Program and China Postdoctoral Science
Foundation. This work was also supported by a JSPS Grant-in-
Aid for Scientific Research on Innovative Areas (No. 17H05430),
and JSPS KAKENHI (S) (No. 17H06173) (to M. U.), and
bygrants from Kobayashi International Scholarship Foundation
(to M. U. and C. W.), and YakuGaku ShinKoKai Foundation (to
C. W.). Z.-K.Y. is grateful for the Junior Research Associate
fellowship provided by RIKEN.
In summary, we have developed
a direct C–O bond
formation protocol through reaction of alcohols/phenols with aryl
ammonium salts, which are easily prepared from anilines. This
reaction proceeds efficiently and selectively at room temperature
within a few hours in the absence of any TM catalyst. A great
variety of functional molecules containing NR2 or OH moieties,
including natural products, pharmaceuticals, and dyes, afforded
the corresponding ethers in high yields, and the reaction was
also applied to synthesize several molecules of pharmaceutical
interest. We believe this protocol will be useful for preparation
and/or late-stage derivatization of a wide variety of functional
molecules. Mechanistic studies are in progress, as well as
further synthetic applications.
This article is protected by copyright. All rights reserved.

10.1002/anie.201712618
Angewandte Chemie International Edition
COMMUNICATION
CN
2a: KO–Me
O
O
OtBu
OtBu
1b
1c
1d
Ar
+
2b: KO–Et
NMe3 • OTf
1
OMe
DMF, r.t., 3 h
2d: KO–tBu
EtO
Me
3bd: 50%
3cd: 80%
3da: >99%
(1.0 eq.)
(1.5 eq.)
(38%)
(70%)
(92%)
O
C
O
S
O
O
OtBu
OtBu
1h
1e
1e
1g
1f
1f
OMe
MeO
OMe O2N
Me
OMe
Ph
Ph
O
3ea: >99%
3ed: 92%
3f-aa: 93% (90%)
3gd: 95%
3ha: >99%
(94%)
(90%)
(90%)
(91%)
Cl
Cl
Br
Br
1i
1j
1k
1l
1m
1m
Cl
OMe
Cl
OMe
Br
OMe
Br
OMe
OMe
OEt
3ia: 60%
3ja: 80%
3ka: 70%
3la: 90%
3ma: 90%
3mb: 70%
(58%)
(75%)
(65%)
(85%)
(84%)
(61%)
Methyl yellow
Methyl yellow
OtBu
1A
1n
1o
1p
1q
1A
N
I
OMe
OMe
OMe
OMe
N
OMe
Ph
N
Ph
N
3na: 85%
3oa: 75%
(72%)
3pa: 52%
(50%)
3qa: 90%
3Aa: 98%
3Ad: 54%
(81%)
(85%)
(92%)
(52%)
N-Methyl-Sulfadiazine
N-Methyl-Sulfadiazine
Avlosulfon
Padimate A
O
O
O
S
O
Me
Me
OtBu
N
N
S
OMe
OtBu
MeO
OMe
1B
N
N
S
1C
1D
1D
1C
O
N
N
O
O
O
3Bd: 70%
3Ca: >99%
(92%)
3Cd: 93%
3D-aa: 93%
Me
(65%)
(88%)
(90%)
Me
Scheme 3. Scope of the reactions of various arylammoniums 1 with 2a, 2b and 2d as representative alcohol partners (directly used as corresponding potassium
alkoxides). Yields were calculated based on NMR (bold) and isolation (in parentheses).
D.-Y. Wang, H. Minami, H. Ogawa, T. Ozaki, T. Saito, K. Miyamoto, C.
Keywords: Ether • Amine • C–N bond Cleavage • C–O bond
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Formation • Late-Stage Functionalization
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Org. Chem. 2016,81, 14; h) T. Moragas, M. Gaydou, R. Martin, R.
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5053; i) Uemura, T.; Yamaguchi, M.; Chatani, N. Angew. Chem. 2016,
128, 3214; Angew. Chem. Int. Ed. 2016, 55, 3162; j) D.-Y. Wang, M.
Kawahata, Z.-K. Yang, K.Miyamoto, S. Komagawa, K. Yamaguchi, C.
Wang, M. Uchiyama, Nature Commun. 2016, 7, 12937; k) Z.-K. Yang,
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10.1002/anie.201712618
Angewandte Chemie International Edition
COMMUNICATION
2y
O
2z
KHMDS (3.0 eq.)
Me
Me
O
Ar
Ar
Ar
HO
OH
OH
NC
NMe3 • OTf
1a
+
DMF/THF, r.t., 3 h
Me
OH
2
(1.5 eq.)
3ay: 95%
3az: 94%
(1.0 eq.)
Me
Me
(90%)
(91%)
(A)
HOCH2CF3 (2p) (1.0 eq.)
O
C
2p
O
2a
O
C
KOMe (2a) (2.0 eq.)
KHMDS (1.0 eq.)
1f
1f
F3C
OMe
TfO • Me3N
(B)
NMe3 • OTf
DMF/THF, r.t., 3 h
DMF/THF, r.t., 3 h
3f-pa: 70% (65%)
1f (1.0 eq.)
Cl
Cl
KHMDS (1.4 eq.)
DMF/THF, r.t., 3 h
1g
2a′
O2N
(C)
NMe3 • OTf
+
HO
Cl
O2N
O
Cl
Nitrofen
1g (1.0 eq.)
2a′ (1.5 eq.)
3ga′: 95% (92%), 28 mmol, 5.2 g
(gram-scale)
HO
NHMe
2b′ (1.5 eq.)
Br
Cl
Cl
Cl
(2.0 eq.)
Clorgyline
K2CO3 (2.0 eq.)
KHMDS (1.4 eq.)
2b′
Me
N
1j
Cl
NMe3 • OTf
Cl
O
NHMe
Cl
O
DMF/THF, r.t.ꢀꢁ3 h
CH2Cl2
0 oC to r.t., 2 h
1j (1.0 eq.)
3jb′: 88% (82%)
86% (81%)
(D)
Me
Me
Ar1 = p-Me–C6H4–
Ar2 = p-Cl–C6H4–
HO
ClMg
NEt2
Cl
2c′ (1.5 eq.)
Ar1
Ar2
Triparanol
KOtBu (1.4 eq.)
(1.5 eq.)
2c′
1r
O
HO
O
NMe3 • OTf
NEt2
NEt2
DMF/THF, r.t., 3 h
THF, r.t., 1 h
then H2O
O
O
1r (1.0 eq.)
3rc′: 97% (92%)
90% (87%)
(E)
Scheme 4. Scope of the reactions of compounds with two hydroxyl or ammonium groups, and applications to synthesis of pharmaceuticals or bio-active
molecules. Yields were calculated based on NMR (bold) and isolation (in parentheses).
Chem. Soc. 1996, 118, 13109; n) J. A. Terrett, J. D. Cuthbertson, V. W
Shurtleff, D. W. C. MacMillan, Nature 2015, 524, 330; o) S.-J. Han, R.
Doi, B. M. Stoltz, Angew. Chem. 2016, 128, 7563; Angew. Chem. Int.
Ed. 2016, 55, 7437.
[8]
Methylation of NH2 or NHMe group readily led to dimethylaniline in
quantitative yield, see: E. W. Baxter, A. B. Reitz, Reductive Aminations
of Carbonyl Compounds with Borohydride and Borane Reducing
Agents, in Organic Reactions, John Wiley & Sons, Inc., 2004.
Room temperature (r.t.) ranged from 22 to 27 oC.
[9]
[10]
For example, when tBuOK was used as the base, no t-butoxidized
products were observed. Further, tBuOK is also less reactive than
MeOK toward ortho-substituted anilines such as 1g, 1l, 1m, etc.
a) A. B. Chopa, M. T. Lockhart, G. Silbestri, Organometallics 2001, 20,
3358; b) A. M. Mfuh, J. D. Doyle, B. Chhetri, H. D. Arman, O. V.
Larionov, J. Am. Chem. Soc. 2016, 138, 2985; c) D.-Y. Wang, K.
Morimoto, Z.-K. Yang, C. Wang, M. Uchiyama, Chem. Asian J. 2017,
12, 2554.
[11]
[12]
[13]
For a recent report on etherification with phosphonium salts, see: M. C.
Hilton, R. D. Dolewski, A. McNally, J. Am. Chem. Soc. 2016, 138,
13806. A plausible mechanism of this reaction involves the SNAr route
or ligand coupling in a 5-coordinated phosphorus intermediate.
Our preliminary DFT calculations suggest that the cation-π interaction
might enhance the interaction between the nucleophile and
electrophile, stabilizing the transition state (TS) and the Meisenheimer
intermediate. However, we are currently examining other possible
pathways/important chemistry, such as counterion-recruited TS, as
well as the critical roles of TfO– and K+.
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10.1002/anie.201712618
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
natural products, pharmaceuticals, bio-active molecules, functional materials
Dong-Yu Wang, Ze-Kun Yang,
Chao Wang,* Ao Zhang,* and
Masanobu Uchiyama*
KOtBu or KHMDS
DMF, r.t., 3 h
FG
FG
FG
FG
Ar
NMe3
HO
R
Ar
O
R
+
Page No. – Page No.
facilely prepared from
anilines
direct utilization of
phenols & alcohols Rbroad scope and wide functional group compatibility
Rmild conditions Rsimple procedure Rhigh yields
From Aniline to Aryl Ether: A Facile,
Efficient and Versatile Synthetic
Protocol Employing Mild Conditions
A simple and direct protocol for synthesis of aryl ethers by reaction of
alcohols/phenols with aryl ammonium salts was developed. This reaction proceeds
smoothly and rapidly at room temperature in the presence of a commercially
available base, and has a broad substrate scope for both reactants including
natural products, pharmaceuticals, dyes, and so on.
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