Metal-free oxidative direct C(sp3)-H bond functionalization of ethers with α,α-diaryl allylic alcohols

Article abstract of DOI:10.1039/c4cc04282d

A metal-free method for direct C(sp³)-H bond functionalization of simple ethers with α,α-diaryl allylic alcohols is described. The established protocol provides facile access to α-aryl-β-oxyalkylated carbonyl ketones via radical addition and a

Full text of DOI:10.1039/c4cc04282d

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Metal-free oxidative direct C(sp3)–H bond
functionalization of ethers with a,a-diaryl allylic
alcohols†
Cite this: Chem. Commun., 2014,
50, 9718
Received 4th June 2014,
Accepted 26th June 2014
Xue-Qiang Chu, Hua Meng, You Zi, Xiao-Ping Xu* and Shun-Jun Ji*
DOI: 10.1039/c4cc04282d
www.rsc.org/chemcomm
A metal-free method for direct C(sp3)–H bond functionalization of
Although these type of reactions, using ethers as reactants,
simple ethers with a,a-diaryl allylic alcohols is described. The established have considerably improved, more versatile C–C formation for
protocol provides facile access to a-aryl-b-oxyalkylated carbonyl the synthesis of pharmaceuticals and biologically active molecules is
ketones via radical addition and a 1,2-aryl migration cascade process. still highly desirable. To the best of our knowledge, a neophyl-type
An application of the product has been demonstrated in the synthesis rearrangement16,17e driven by an a-carbon-centered radical adjacent
of a serotonin antagonist.
to a heteroatom addition to allylic alcohols 1, leading to a variety of
a-aryl-b-oxyalkylated carbonyl ketones, has never been previously
Direct C–H functionalization has emerged as an attractive protocol reported (Scheme 1, eqn (5)). As a continuation of our interest in
to construct C–C and C–X bonds, as it reduces prefunctionalization the radical pathway transformations,17 herein, we developed a
while improving atom-economy and environmental sustainability.1–4 novel reaction of a,a-diaryl allylic alcohols with ethers under
In the past decades, remarkable advances have been achieved on mild metal-free conditions.
the activation of an inert C(sp3)–H bond.3,4 Recently, much attention
Previous studies5–14 revealed that the a-H of an ether can be
has been paid to the free-radical-initiated direct a-C(sp3)–H bond oxidized with peroxide for the generation of radicals. Based on this
functionalization of ethers.5–14 In particular, substituted ether assumption, initial studies were focused on the model reaction of
derivatives are featured in the synthesis of various pharmaceuticals allylic alcohol 1a and 1,4-dioxane 2a in the presence of various
and biologically active molecules.15 However, the cleavage of these catalysts and oxidants under air (Table 1, entries 1–9). It was found
stable bonds is still a challenging task for chemists. Several groups that direct alkylation with concomitant 1,2-migration of a phenyl
have disclosed a variety of novel C–C,6 C–O,7 C–N,8 C–S9 bond group was achieved with catalytic amounts of Cu2O, TBAI or AgNO3,
formations of ethers with different nucleophiles via Cross- and the targeted carbonyl compound 3aa was obtained in 71–83%
Dehydrogenative-Coupling (CDC) reactions. Zhang et al.10 and GC-yield after 24 h (Table 1, entries 1–3). To our delight, the GC-yield
Wang et al.11 reported oxyalkylation reactions of vinylarenes with of 3aa could be increased to 91%, when 3 equiv. of di-tert-butyl
cyclic ethers under homogeneous and heterogeneous systems,
respectively (Scheme 1, eqn (1)). Recently, Li and coworkers
investigated iron-catalyzed 1,2-alkylarylation of activated alkenes via
a tandem radical addition/homolytic aromatic substitution process
(Scheme 1, eqn (2)).12 Later, Lei’s group developed copper-catalyzed
oxidative C–H/C–H coupling between olefins and simple ethers
(Scheme 1, eqn (3)).13 Similarly, we also described an efficient
pathway leading to 6-alkyl phenanthridine, involving C(sp3)–H/
C(sp2)–H bond cleavage (Scheme 1, eqn (4)).14
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science & Collaborative Innovation Center of
Suzhou Nano Science and Technology, Soochow University, Suzhou, 215123,
People’s Republic of China. E-mail: xuxp@suda.edu.cn, shunjun@suda.edu.cn;
Fax: +86-512-65880307; Tel: +86-512-65880307
† Electronic supplementary information (ESI) available. CCDC 1006442. For ESI
Scheme 1 Transformations based on C–H bond functionalization of
ethers.
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc04282d
9718 | Chem. Commun., 2014, 50, 9718--9721
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Table 1 Optimization of the reaction conditionsa
Table 2 Reaction of 1 with ethersa
Entry Catalyst (mol%) Oxidant (equiv.) Time (h) GC yieldb (%)
1
2
3
4
5
6
7
8
Cu2O(5)
TBAI(5)
AgNO3(5)
DTBP (3)
DTBP(3)
DTBP(3)
DTBP(3)
TBHP(3)
TBPB(3)
CHP(3)
PhI(OAc)2(3)
K2S2O8(3)
—
TBPB(2)
TBPB(2)
TBPB(2)
TBPB(2)
TBPB(1)
24
24
24
24
24
24
24
24
24
24
24
12
83
71
82
91
51
92
48
64
—
—
—
—
—
—
—
—
—
9
0
10
11
12
13
14
15
Trace
92
95(95c)
—
—
—
12
3
24
47d
64
72
a
Reaction conditions: 1a (0.3 mmol), 2a (1 mL), catalyst (5 mol%) and
oxidant (1–3 equiv.) (DTBP = di-tert-butyl peroxide, TBHP = tert-butyl hydro-
peroxide (70% in aqueous solution), TBPB = tert-butylperoxybenzoate, CHP =
cumyl hydroperoxide) at 120 1C under air. b Yields were determined by GC
with an internal standard. c Isolated yields. d At 100 1C.
a
All reactions are carried out under the optimal conditions; yields of
isolated products. Determined by 1H NMR of the isolated product.
b
c
peroxide (DTBP) was used without any catalysts (Table 1, entry 4).
Furthermore, other radical initiators besides DTBP were examined,
and tert-butylperoxybenzoate was demonstrated to be the best one
At 150 1C for 11 h.
(Table 1, entries 5–9). In the absence of an oxidant, no reaction took 80% and 89% yields, respectively. Although the electronic effect on
place, which suggested the crucial importance of peroxide in this the aryl ring reduced the yields to some extent, good yields of 3da,
transformation (Table 1, entry 10). Further screening of the amount 3ea and 3fa were still obtained. Meanwhile, a meta-substituted aryl
of TBPB, the reaction temperature and reaction time established the group also worked well as a migrating group and the product 3ga
optimized conditions as follows: a,a-diphenyl allylic alcohol 1a and was isolated in 76% yield. In addition, benzo[d][1,3]dioxole could be
1,4-dioxane 2a in the presence of 2.0 equiv. TBPB at 120 1C for 12 h. tolerated (Table 2, 3ci).
The desired 3aa could be obtained in 95% GC-yield, along with an
isolated yield of 95% (Table 1, entry 12).
To further expand the scope of this particular metal-free oxidative
alkylation reaction and to obtain information on the selectivity of the
With the optimal conditions in hand, the generality and substrate aryl migration, we turned our attention to allylic alcohols bearing two
scope of this radical rearrangement reaction were investigated using different aryl groups (Table 3). To our delight, 1h ran smoothly to
various readily available ether derivatives and symmetrical a,a-diaryl afford ketone 3hi and its isomer in an inseparable mixture of 49%
allylic alcohols (Table 2). Tetrahydro-2H-pyran was first employed yield, and the ratio was determined by 1H NMR (4 : 1). Although the
to react with a,a-diphenyl allylic alcohol 1a, smoothly rendering procedure was not sensitive to the nature of the substituted group,
the target alkylation product in 63% yield (Table 2, 3ab). The five- the electronic properties of the aryl ring affect the migration rate.
membered cyclic ethers, such as THF, 2-ethyl-2-methyl-1,3-dioxolane For substrates 1i–k and heterocyclic 1m, preferential migration of the
and 1,3-dioxolane, were also suitable under the optimal conditions more electron-poor aryl groups was detected. This chemoselective
(Table 2, 3ac–3ae). It was noted that the cleavage of the C–H bond at manner suggested that the reaction might involve a radical
the 2-position of 1,3-dioxolane was preferential and the a-aryl-b- (‘‘neophyl’’) rearrangement process.16 The structure of 3mi was
oxyalkylated ketone 3ae was isolated as the major product. confirmed by X-ray single crystal diffraction.18 On the other
Open-chain diethyl ethers were also good candidates, affording hand, ortho-substituted aryl rings (1l) migrated less effectively,
4-ethoxy-1,2-diphenylpentan-1-one 3af in 45% yield. The regio- indicating that steric hindrance had a detrimental effect on the
selectivity of direct oxidative functionalization of glycol dimethyl rearrangement. However, pentafluorophenyl 1n was almost inert
ether 2g was observed. The reaction was more prone to occur at under our conditions.
the C(sp3)–H bond of the internal methylene moiety than at the
During the course of our studies, other types of allylic alcohol
terminal methyl group, and two isomers 3ag and 3ag0 were obtained substrates were chosen as the reactants (Scheme 2). However, ring
with a ratio of 2 : 1. Unfortunately, when oxybis(methylene)dibenzene expansion did not happened when 9-vinyl-9H-fluoren-9-ol 1o was
was used, only a trace amount of the product was detected (Table 2, introduced to the reaction with 2a. Notably, the mono-aryl-type
3ah). When the current typical method was applied to symmetrical allylic alcohol 1p was almost inert under our conditions. It was
compounds 1 bearing methoxyl (1b) and methyl (1c) groups on the demonstrated that the two aryl groups in the starting material were
aromatic ring, the desired ketones 3ba and 3ca were obtained in necessary for the addition–rearrangement reaction.
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Table 3 Reaction of asymmetrical 1 with 2ia
Scheme 3 Radical-trapping experiment.
a
b
All reactions were carried at 150 1C under air for 12 h. Yields of 3
c
and its isomer. Only major products were shown. Determined by
1H NMR of the isolated products. Major product yields. Determined
d
e
by 1H NMR of the crude products.
Scheme 4 A plausible reaction mechanism.
To gain further insight into the possible radical mechanism,
a control experiment of 1a and 2a in the presence of 2 equiv.
TEMPO was carried out (Scheme 3). As expected, the formation
of the desired product 3aa was suppressed, and only the
TEMPO-1,4-dioxane adduct 4 was observed (determined by
LC-MS analysis). This result indicated that TBPB mediated
reaction of a,a-phenyl allylic alcohol 1a with 1,4-dioxane might
be a radical-initiated route17 to the target product.
Scheme 5 Further application of 3ae.
On the basis of recent publications16,17e and the results above, we
proposed a plausible reaction mechanism in Scheme 4. First, high
temperature results in the homolysis of TBPB, which is decomposed
to the tert-butoxyl radical and the benzoate radical. Then, the C–H
bond adjacent to the oxygen atom of 1,4-dioxane is activated by the
tert-butoxyl radical, providing the active intermediate I, which could
be trapped by TEMPO to give 4. The resulting a-carbon-centered
radical I adds to allylic alcohol and produces an alkyl intermediate II.
Subsequently, an intramolecular radical addition to generate the
spiro[2,5]octadienyl radical III, followed by the migration of the
electron-deficient aryl group preferentially releases IV.16d,17e Note
that ortho-substituted groups are reluctant to migrate owing to a
sterically congested radical III might be not favorable. Finally, the
desired product 3 and benzoate are delivered after further oxidation
and deprotonation.
4-(4-(2-Methoxyphenyl)piperazin-1-yl)-1,2-diphenylbutan-1-one
belongs to a family of arylpiperazines that are well known
serotonin antagonists for the treatment of depression and related
disorders.15f,19 Finally, we demonstrated a representative synthesis
of a known serotonin antagonist 5 starting from ketone 3ae in an
efficient manner (Scheme 5).
In conclusion, we have developed a novel TBPB-promoted
radical alkylation reaction of a,a-diaryl allylic alcohols with
ethers (cyclic and open-chain ethers) that provides straightforward
access to a-aryl-b-akylated carbonyl ketones. Two new C–C bonds
were formed in this reaction via C(sp3)–H bond functionalization
and a 1,2-aryl migration process under metal-free conditions. The
application of product 3ae has been demonstrated in the synthesis
of a serotonin antagonist 5.
We gratefully acknowledge the Natural Science Foundation
of China (no. 21172162 and 21372174), the Young National
Natural Science Foundation of China (no. 21202113), the PhD
Programs Foundation of Ministry of Education of China
(2013201130004), Key Laboratory of Organic Synthesis of
Jiangsu Province (KJS1211), PAPD, and Soochow University for
financial support.
Notes and references
1 (a) Handbook of C–H Transformations, ed. G. Dyker, Wiley-VCH,
Weinheim, 2005; (b) Topics in Current Chemistry: C-H Activation,
Scheme 2 The reaction of 1o–p with 2a.
9720 | Chem. Commun., 2014, 50, 9718--9721
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