Practical and highly selective C-H functionalization of structurally diverse ethers

Article abstract of DOI:10.1002/anie.201407083

A trityl ion mediated C-H functionalization of ethers with a wide range of nucleophiles at ambient temperature has been developed. The reaction displays high chemo-selectivity and good functional group tolerance. The protocol also exhibits excellent regio- and diastereoselectivities for the unsymmetric ethers, thus stereoselectively generating highly functionalized disubstituted 2,5-trans tetrahydrofurans (THF), 2,6-trans tetrahydropyrans (THP), 2,6-trans dihydropyrans (DHP), and 1,3-trans isochromans, and highlighting the capacity of the protocol in complex molecule synthesis.

Full text of DOI:10.1002/anie.201407083

Angewandte
Chemie
DOI: 10.1002/anie.201407083
À
C H functionalization
Hot Paper
À
Practical and Highly Selective C H Functionalization of Structurally
Diverse Ethers**
Miao Wan, Zhilin Meng, Hongxiang Lou, and Lei Liu*
À
Abstract: A trityl ion mediated C H functionalization of
ethers with a wide range of nucleophiles at ambient temper-
ature has been developed. The reaction displays high chemo-
selectivity and good functional group tolerance. The protocol
also exhibits excellent regio- and diastereoselectivities for the
unsymmetric ethers, thus stereoselectively generating highly
functionalized disubstituted 2,5-trans tetrahydrofurans (THF),
2,6-trans tetrahydropyrans (THP), 2,6-trans dihydropyrans
(DHP), and 1,3-trans isochromans, and highlighting the
capacity of the protocol in complex molecule synthesis.
a-Substituted ether synthesis typically relies on the trans-
formation of pre-existing functional groups such as hetero-
atoms and unsaturation in Williamson ether synthesis, hydro-
alkoxylation, Lewis acid mediated nucleophilic substituent of
acetals, etc.[2] While the traditional methods are efficient,
multiple and unproductive steps are usually involved for
reactive functionality incorporation.[3] Moreover, the a-sub-
stituent is customarily installed early in the synthesis, and thus
the starting materials are often dissimilar from the targets.
Therefore, during the preparation of a series of compounds,
multiple and distinct de novo sequences are required for each
3
À
E
thers are one of the most common structural motifs spread
derivative. In contrast, selective and direct C(sp ) H func-
across bioactive natural products and synthetic pharmaceut-
tionalization of ethers with different carbon nucleophiles
provides a straightforward approach to access multiple
analogues from a common structural precursor by a struc-
icals (Figure 1).[1] Over 20% of the top 200 small-molecule
tural-core diversification strategy.[4] The C H functionaliza-
À
tion of ethers has attracted great interest since the pioneering
studies of Li and co-workers, and a number of oxidation
systems have been developed.[5] However, the approaches
lack broad generality. The scope is narrow, with the substrate
largely restricted to activated benzyl ethers like isochroman
derivatives. The functionalization of saturated ethers proved
to be much more challenging, which might be ascribed to their
inherent low reactivity.[6,7] The existing oxidation systems
typically required high temperature, neat conditions, and long
reaction times. Therefore, poor regio- and diastereoselectivity
are always observed during the oxidation of unsymmetric
ethers. The neat conditions call for a large excess of ether
substrates as the solvent, lacks atom-economy, and limits the
application in the late-stage synthesis of complex molecules
because of the inaccessibility to solvent-scaled advanced
ether intermediates. Moreover, each known method only
focused on a single class of the nucleophile, and therefore, the
integrated pattern of functionalities in the a-position is
narrow. Therefore, the development of a mild and selective
Figure 1. Representative bioactive molecules containing a-functional-
ized ethers.
pharmaceuticals and 75% of new chemical entities contain at
least one a-substituted ether moiety.[1c] Therefore, the avail-
ability of efficient methods for the synthesis of structurally
diverse a-substituted ethers is vital to the discovery of
biologically interesting agents.
À
approach for direct C H functionalization of a variety of
[*] M. Wan,[+] Z. Meng,[+] Prof. H. Lou, Prof. L. Liu
Key Lab of Chemical Biology of Ministry of Education
School of Pharmaceutical Sciences
Shandong University, Jinan 250012 (China)
E-mail: leiliu@sdu.edu.cn
[+] These authors contributed equally to this work.
ethers with a wide range of nucleophiles is highly desired.
Trityl ions have long been known to mediate the oxidation
of oxygen-containing substrates.[8] For example, Ph3CBF4 was
used to promote the deprotection of benzyl ethers,[8a] and
induce the oxidation of trimethylsilyl ethers to ketones.[8b]
À
Ph3CBF4 can also facilitate the C H functionalization of
[**] We are grateful to Dr. Paul E. Floreancig (University of Pittsburgh)
and Dr. Armin R. Ofial (University of Munich) for helpful suggestion
on the mechanism. This work was supported by the National
Science Foundation of China (21202093, 21472112, and 21432003),
the Program for New Century Excellent Talents in University (NCET-
13-0346), and the Fundamental Research Funds of Shandong
University (2014JC005).
acetal 1,3-dioxolane with MeLi or TMSCN in two steps, with
the formation of the isolable 1,3-dioxolan-2-ylium cation as
the first step.[8c,d] However, to the best of our knowledge, trityl
ions have not been used to initiate the oxidative coupling of
ethers with carbon nucleophiles to date.
Inspired by the predictable reactivity patterns and func-
tional diversity of organoboranes, the coupling of the
tetrahydrofuran (THF; 1a) with the potassium trifluorobo-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407083.
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Table 1: The exploration of trityl ion source.[a]
Entry
Trityl ion
Time [h]
Yield [%][b]
1
2
3
4
Ph3CBF4
1
1
1
1
1
31
42
<20
20
Ph3CClO4
Ph3CX[c]
Ph3CCl/TMSOTf
Ph3CCl/FeCl3
5
50
6
7
8
9
10
11
12
13
14
Ph3CCl/InBr3
1
1
1
24
1
1
1
1
24
75
<40
92
0
43
76
81
21
0
Ph3CCl/LA[d]
Scheme 1. Scope of organoboranes. Reaction conditions: 1a (4 mmol),
2 (0.2 mmol), Ph3CCl (0.1 mmol), and GaCl3 (0.1 mmol) in CH2Cl2
(1.0 mL) at RT in 2 h. [a] (Phenylethynyl)boronic acid used. [b] Diethyl
(phenylethynyl)boronate used. [c] (p-MeO)Ph3CCl and GaCl3 used.
[d] Ph3CClO4 in CH3CN at 608C. [e] Ph3CClO4 in CH3CN at 808C.
[f] Ph3CClO4 without solvent at 1008C.
Ph3CCl/GaCl3
GaCl3 or Ph3CCl
Ph3CClO4/GaCl3
(m-F)Ph3CCl/GaCl3
(p-Me)Ph3CCl/GaCl3
(p-OMe)Ph3CCl/GaCl3
Ph2CHCl/GaCl3
[a] The reaction was conducted with 1a (4 mmol), 2a (0.2 mmol), and
oxidant (0.1 mmol) in CH2Cl2 (1.0 mL) at RT. [b] Yield of isolated
product. [c] Ph3COTf, Ph3CSbCl6, and Ph3CPF6 used. [d] Other Lewis
acids: TiCl4, AlCl3, InCl3, Yb(OTf)3, Sc(OTf)3, Cu(OTf)2, and BF3·OEt2.
LA=Lewis acid, Tf=trifluoromethanesulfonyl, TMS=trimethylsilyl.
rate 2a was selected as a model reaction for the optimiza-
tion.[9] Initially, several commonly employed pre-prepared
trityl salts were examined in CH2Cl2 at room temperature
(Table 1, entries 1–3). The different efficiency observed for
these oxidants prompted us to further explore the counter-ion
effect on the coupling. Accordingly, a number of trityl salts
were examined by mixing Ph3CCl (1.0 equiv) with a variety of
Lewis acids (1.0 equiv) in CH2Cl2 (entries 4–8; see also
Table S1 in the Supporting Information). Delightedly, GaCl3
was finally found to be the optimal choice, with the desired 3a
isolated in 92% yield (entry 8). No reaction took place if
GaCl3 or Ph3CCl alone was used (entry 9). The combination
of Ph3CClO4 with GaCl3 did not give any improvement
(entries 2 and 10). Then electronically varied trityl chlorides
together with benzhydrylium ion were studied, and Ph3CCl
proved to be the best candidate (entries 10–14).
The reaction proved general for a broad range of
structurally and electronically varied potassium alkynyltri-
fluoroborates in high efficiency (3a and 3d–k; Scheme 1).
The desired product was not detected when either the boronic
acid 2b or boronate ester 2c was used, and might be ascribed
to their reduced nucleophilicity compared with 2a or the
incompatibility towards the reaction conditions.[2d,9] Alkenyl
trifluoroborate salts (2l and 2m) are suitable coupling
partners to deliver the desired vinyl THFs in good yields
with olefin geometry highly conserved. The arylation of 1a
also proceeded smoothly when Ph3CClO4 was used as the
oxidant. The reaction is efficient not only for the p-rich aryl
(3n and 3o) and heteroaryl borates (3r), but also for p-
neutral (3p) and p-deficient (3q) arylboranes, though elec-
tron-poor 2-pyridinyl borate (3s) failed to give any desired
product. The mild reaction possesses excellent functional-
group compatibility, with halogens (3d and 3e) and benzyl
ether (3k) well-tolerated for further manipulations.
Scheme 2. Scope of heteroatom-containing components. Reaction con-
ditions: 4 (0.1 mmol), 2 (0.2 mmol), Ph3CCl (0.1 mmol), and GaCl3
(0.1 mmol) in CH2Cl2 (1.0 mL) at 08C or RT in 1 h. [a] 5–20 equiv of
ether employed. [b] Ph3CClO4 as oxidant. [c] Ph3CBF4 as oxidant.
[d] (m-F)2Ph3CCl and GaCl3 as oxidant.
With the expansive scope of organoboranes in hand, we
next explored the scope with respect to the ether (Scheme 2).
Besides THF, commonly encountered saturated cyclic ethers
including tetrahydrothiophene (5b), THP (5c), oxepane (5d),
and 2,2-disubstituted THF (5e) were well compatible with the
reaction. Cyclic benzyl ethers like isochroman (5 f), phthalan
(5g), and benzoxathiole (5h) reacted smoothly with 2a. The
reaction of cyclic allyl ether 2H-chromene (5i) was highly
regioselective, thus delivering predominantly the C2-addition
products, and no C4 addition or double addition was
observed. Acyclic ethers also proved to be competent
substrates, with Et2O (5j) and nBu2O (5k) well tolerated.
Alkoxy aryl ethers, the core scaffold of a large number of
synthetic drugs like Duloxetine and Atomoxetine,[1c] were
also explored. While anisole failed to yield 5l, ethoxybenzene
delivered 5m in modest yield. Acyclic benzyl ether (5n) was
not compatible with the reaction. Besides the ether candi-
dates, the scope was expanded to amines (5o–q) and
saturated carbamates (5r–s).
À
Selective functionalization of non-equivalent C H bonds
in saturated ethers with high regio- and diastereoselectivity by
À
bimolecular C C bond formation has not been well estab-
lished probably because of the harsh reaction conditions.[10]
2
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a single diastereomer. Such structure was routinely accessed
through Ferrier reaction employing an allylic acetate or
tosylate as the nucleofuge, whose synthesis usually suffered
from extra steps.[11] Considering that trans-2,6-disubstituted
THP or DHP is the core unit within a multitude of
biologically active natural products, DHPs bearing commonly
encountered functional groups like the aryl ring 6i, acid-
sensitive silyl ether 6j, and electrophilic acetate 6k were
studied to demonstrate the synthetic potential of the practical
method. Notably, allyl trimethylsilane proved to be compat-
ible with the system to give the trans-DHPs 7i–k as the single
diastereomer, thus highlighting the capacity of the protocol in
creating unique and useful chemoselectivity patterns in highly
functionalized molecules. Indeed 7j is the real synthetic
intermediate leading to the synthesis of natural products
swinholide A.[11b] The efficiency dropped for the substrates
bearing electron-withdrawing moieties, probably because of
the inductive deactivation effect on the cation intermediates.
Such excellent trans selectivity was also observed for 3-methyl
isochroman (6l) when Ph3CClO4 was employed.[5l] While no
single set of trityl ion was applicable to all of the substrates
studied, an optimal set could be identified for each substrate
according to an understanding of the reactivities of substrates
and trityl ions. Equivalents of unsaturated substrates sufficed
for the reaction, but excess of saturated ones were always
required. While the origin of the difference has not been
elucidated, the volatility and reactivity of the substrate
together with the stability of the formed carbocation inter-
mediate might contribute to the observation.[12f,13c]
Scheme 3. Studies on the regio- and diastereoselectivity. Reaction
conditions: ether 6d–l (0.1 mmol), nucleophile (0.2 mmol), and oxi-
dant (0.1 mmol) in CH2Cl2 (1.0 mL) in 1 h. 6a–c (20 equiv). TBS=tert-
butyldimethylsilyl.
Trityl ion mediated cross-dehydrogenative coupling
À
(CDC) with C H reagents was next explored (Scheme 4).
The mild reaction conditions prompted us to evaluate the
regio- and diastereoselectivity for unsymmetric ethers
(Scheme 3). 2-Methyl THF (6a) reacted smoothly with 2a
to yield 7a in 73% yield with overwhelming selectivity at the
À
less sterically hindered secondary C H bond. With (p-
Me)2Ph3CCl as the trityl ion source the best diastereocontrol
(3:1) was obtained. The similar site selectivity was also
observed for the 2-alkyl THP 6b, thus affording trans-7b as
the single diastereomer. The chemoselectivity advantages for
Scheme 4. The CDC reaction of THF and phenylacetylene.
À
secondary C H bond oxidation might be ascribed to the
À
increased steric accessibility compared to tertiary C H bonds.
While acetophenone (9a) only afforded trace amounts of the
desired 10a, the alkyne 9b proved to be a good partner, thus
giving desired 3a and hydrated 10a in a total yield of 81%.
Accordingly, 10a was uniquely achieved in 75% yield through
CDC and a simple hydration process in one pot.
À
The site-selectivity between primary and secondary C H
bonds was also evaluated, as demonstrated by the reaction of
methyl butyl ether (6c), and 7c was isolated as a single
regioisomer. Such selectivity for the secondary C H bond
À
oxidation might arise from the greater electron-rich character
The trityl ion is typically recognized to act as a hydride
À
À
compared to primary C H bonds. Another possibility which
cannot be excluded is that the carbocation 8 formed by
acceptor or one-electron oxidant in the C H oxidation
process (Figure 2).[12] Given the different oxidation potentials,
the mechanisms for saturated and unsaturated ethers will be
discussed independently. With respect to the saturated ether,
THF showed an intermolecular KIE of 2.9, thus suggesting
À
primary C H bond oxidation might collapse before the
addition of 2a.
The electronic effect on the site-selectivity is also obvious,
with excellent selectivity at the electron-rich allyl methylene
site (Scheme 3). 3,6-dihydropyran (3,6-DHP; 6d) and 2,3,4,7-
tetrahydrooxepine (6e) participated in the coupling effi-
ciently, thus yielding the corresponding products 7d–g as
a single regioisomer. The reaction of 6h displayed excellent
yields, thus affording the trans-2,6-disubstituted DHP 7h as
À
the C H cleavage involved in the rate-determining step.
Judging from the oxidation potential of THF (E8ox > 2.5 V vs
SCE)[13] and the reduction potential of Ph3C+ (E8red = 0.19 V
vs SCE),[14] single-electron transfer (SET) from THF to Ph3C+
is highly endergonic, with a minimum barrier of 222 kJmolÀ1
at 258C, and a maximum second-order rate constant of 5.3 ꢀ
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to series of multiple compounds by a structural-core diversi-
fication strategy to discover novel biologically interesting
agents.
Received: July 10, 2014
Revised: August 31, 2014
Published online: && &&, &&&&
À
Keywords: boron · C H functionalization · ethers · Lewis acid ·
regioselectivity
.
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À
implying that a reactive intermediate is formed prior to C H
cleavage, and its formation is not rapidly reversible.[16,17]
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molecular KIE than the less reactive one (2.8 for 4t versus 4.4
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À
opposite to DDQ-induced C H cleavage initiated by an SET
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the protocol with excellent regio- and diastereoselectivity for
the unsymmetric ethers, thus stereoselectively yielding highly
functionalized disubstituted 2,5-trans THF, 2,6-trans THP and
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
À
C H functionalization
M. Wan, Z. Meng, H. Lou,
L. Liu*
&&&& — &&&&
À
À
Practical and Highly Selective C H
Functionalization of Structurally Diverse
Ethers
A practical trityl ion mediated C H
diastereoselectivities for unsymmetric
ethers, thus stereoselectively yielding
highly functionalized trans-disubstituted
tetrahydrofuran, tetrahydropyran, dihy-
dropyran, and isochroman moieties.
functionalization of ethers has been dis-
closed. The reaction proceeds at ambient
temperature with high chemoselectivity
and good functional-group tolerance. The
protocol displays excellent regio- and
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!