Copper-promoted direct C-H alkoxylation of: S, S -functionalized internal olefins with alcohols

Article abstract of DOI:10.1039/c7ob01234a

Copper-promoted direct C-H alkoxylation of S,S-functionalized internal olefins, that is, α-oxo ketene dithioacetals, was efficiently achieved with alcohols as the alkoxylating agents, (diacetoxyiodo)benzene (PhI(OAc)₂) as the oxidant, and benzoquinone (BQ) as the co-oxidant. The alkoxylated olefins were thus constructed and applied for the synthesis of alkoxylated N-heterocycles. The polarization of the olefinic carbon-carbon double bond by the electron-donating dialkylthio and electron-withdrawing α-oxo functionalities plays a crucial role in making such C-H alkoxylation reactions to occur under mild conditions. Mechanistic studies implicate a single-electron-transfer (SET) reaction pathway involved in the overall catalytic cycle.

Full text of DOI:10.1039/c7ob01234a

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DOI: 10.1039/C7OB01234A
Organic &
Biomolecular Chemistry
PAPER
Copper-Promoted Direct CH Alkoxylation of S,S-Functionalized
Internal Olefins with Alcohols
Zhuqing Liu,a,b Fei Huang,a,b Jiang Lou,a,b Quannan Wanga,b and Zhengkun Yu*a
Received 00th January 20xx,
Accepted 00th January 20xx
Copper-promoted direct CH alkoxylation of S,S-functionalized internal olefins, that is, α-oxo ketene dithioacetals, was
efficiently achieved with alcohols as the alkoxylating agents, (diacetoxyiodo)benzene (PhI(OAc)2) as the oxidant, and
benzoquinone (BQ) as the co-oxidant. The alkoxylated olefins were thus constructed and applied for the synthesis of
alkoxylated Nheterocycles. Polarization of the olefinic carbon-carbon double bond by the electron-donating dialkylthio
and electron-withdrawing α-oxo functionalities plays a crucial role in rendering such CH alkoxylation reactions to undergo
under mild conditions. Mechanistic studies implicate a single-electron-transfer (SET) reaction pathway involved in the
overall catalytic cycle.
DOI: 10.1039/x0xx00000x
www.rsc.org/
number of examples have been illustrated in cobalt-catalyzed
C

H alkoxylation of olefinic carboxamides with ethanol and
Introduction
methanol (Scheme 1a),8b and palladium-catalyzed
CH
Carbon-oxygen bond is one of the most important chemical
bonds and it is abundant in many synthetic and natural
products. Various synthetic methods have been developed to
alkoxylation of α,β-unsaturated carbonyls with alcohols
(Scheme 1b).11 Very recently, photocatalytic dehydrogenative
construct a C
direct C H functionalization has been paid more and more

O bond.1 Recently, transition metal-catalyzed

attention for the formation of different chemical bonds in
diverse organic transformations due to the high atom
economy and simplicity of the synthetic C

H activation
protocols.2 In this regard, C
H alkoxylation has aroused much
interests3 although aryl ethers can be traditionally synthesized
from the reactions of aryl halides with alkali metallic
alkoxides,4 pseudo-halides such as aryl boronic esters5 and
hypervalent iodine derivatives6 with alcohols, or by other
methods.7 Direct arene C(sp2)
H alkoxylation has been
extensively investigated with alcohols as the alkoxylating
agents to access aryl alkyl ethers by means of various
transition metal catalysts.8 Plenty of examples of aliphatic
C(sp3)

H
alkoxylation with alcohols have also been
documented to prepare dialkyl ethers.8d,9 Unfortunately, direct
olefinic C(sp2)
H alkoxylation with alcohols has been rarely
Scheme 1 CH alkoxylation of olefins with alcohols.
cross-coupling of olefins with alcohols was reported.12
However, in the three above-mentioned cases only the β-CH
bond of an α,β-unsaturated carbonyl compound or indene
substrate could undergo the alkoxylation reaction with an

reported although enol ethers can be used as useful synthetic
building blocks in organic synthesis and enol ether motifs exist
in many biologically active molecules.10 To date, only a limited
alcohol, which suggests that olefinic α-C
such functionalized olefins is very challenging because the in
situ generated alkoxy metal intermediates in the catalytic
cycle prefer to undergo reductive β-elimination to form the β-
alkoxylated products and the alkanol substrates tend to be
oxidized to their corresponding aldehydes or ketones under
the oxidative reaction conditions.4b,8b,13
H alkoxylation of
a.Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan

Road, Dalian, Liaoning 116023, Peoples Republic of China.
b.University of Chinese Academy of Sciences, Beijing 100049, People
China.
s Republic of
Fax: +86-411-8437-9227; e-mail: zkyu@dicp.ac.cn
† Electronic Supplementary Information (ES(I) available: Experimental details,
compound characterization, NMR and HRMS See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Cu(OH)2 and PhI(OAc)2 (1.5 equiv), 1a was reacted with EtOH
in air at ambient temperature for 24 h. The target α-CH
We recently became interested in the direct
functionalization of internal olefins.14 In order to enhance the
reactivity of an internal olefinic C H bond, two electron
CH
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DOI: 10.1039/C7OB01234A
alkoxylation product 3a was formed in 35% yield (Table 1,
entry 1). Addition of 50 mol% benzoquinone (BQ) obviously
improved the reaction efficiency (Table 1, entries 2-5), while
an oxygen atmosphere deteriorated the yield to 11% (Table 1,
entry 6). Elevating the reaction temperature to 50 oC with
increasing the loading of PhI(OAc)2 to two equivalents
remarkably enhanced the product yield, leading to 3a in 71%
isolated yield (Table 1, entry 8). Use of temperature at 80-100
oC lowered the product yield (53-63%). Applying 10 equiv of
EtOH in a solvent such as THF, DMF, 1,2-dichloroethane (DCE),
or DMSO lessoned the reaction efficiency, and only in the case


donating alkylthio moieties and one electron-withdrawing
carbonyl group are introduced to the two ends of an olefinic
C=C bond to construct polarized olefin substrates, that is, α-
oxo ketene dithioacetals, which were readily prepared from
various methyl ketones by the reported methods.14a,15 On the
basis of the electronic and structural features, α-benzoyl
ketene di(methylthio)acetal (1a) was tentatively reacted with
ethanol (2a) under copper catalysis. To our delight, the desired
α-C
alkoxylated olefin product. Herein, we report efficient copper-
promoted direct C H alkoxylation of S,S-functionalized internal
H alkoxylation reaction occurred to form the target
Table 2 Scope of α-oxo ketene dithioacetals 1a,b

olefins α-oxo ketene dithioacetals (Scheme 1c).
Results and discussion
Table 1 Screening of the reaction conditionsa
Entr
y
PhI(OAc)2
(equiv)
Additive
(equiv)
Temp
(oC)
Yieldb of
3a
Solvent
1
2
1.5
1.5
1.5
1.5
1.5
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
EtOH
EtOH
25
25
25
25
25
25
25
50
50
50
50
50
50
50
50
35
40
BQ (0.2)
BQ (0.5)
BQ (1.0)
BQ (2.0)
O2 (1 atm)
BQ (0.5)
BQ (0.5)
BQ (0.5)
BQ (0.5)
BQ (0.5)
BQ (0.5)
BQ (0.5)
BQ (0.5)
BQ (0.5)
3
EtOH
50
4
EtOH
44
5
EtOH
43
6
EtOH
11
7
EtOH
56
79 (71)c
8
EtOH
THFd
9
34
10
11
12
13
14
15
DMFd
DCEd
DMSOd
toluened
toluenee
toluenef
36
56
23
63
50
36
a
b
Conditions: 1a (0.3 mmol), Cu(OH)2 (0.06 mmol), solvent (3 mL), air, 24 h.
Determined by 1H NMR analysis using 1,3,5-trimethoxylbenzene as the
c
d
internal standard. Isolated yield given in parentheses. Using 10 equiv
EtOH. e Using 5 equiv EtOH. f Using 2 equiv EtOH.
a
Conditions: 1 (0.5 mmol), Cu(O(H)2 (0.1 mmol), PhI(OAc)2 (1.0 mmol), BQ (0.25
mmol), EtOH (5 mL), 50 oC, air, 24 h. b Yields refer to the isolated products.
of using toluene as the solvent 3a could be formed in a comparative
yield (Table 1, entries 9-13). It was noted that large excess of
ethanol facilitated the desired reaction in toluene solvent more
effectively (Table 1, entries 13-15). Various copper sources, e. g.,
CuCl2, CuBr2, CuI, CuOAc, and Cu(OTf)2, did not efficiently promote
the reaction (see the Supporting Information for details). Other
hypervalent iodine reagents were also tested as the oxidants
(Scheme 2). 1-Acetoxy-1,2-benziodoxol-3-(1H)-one and (dibenzoxy-
iodo)benzene (PhI(OCOPh)2) promoted the reaction to form 3a (12-
Scheme 2 Effect of the I(III) reagents.
Initially, the reaction of α-benzoyl ketene di(methylthio)-
acetal (1a) with ethanol (2a) was conducted to screen the
reaction conditions (Table 1). In the presence of 20 mol %
2 | J. Name., 2012, 00, 1-3
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reaction of 1a with EtOH (2a) afforded 3a in 71% isolated yield.
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DOI: 10.1039/C7OB01234A
Electron-donating methyl group on the α-aroyl moiety of 1 had no
obvious impact on the product yields of 3b-d. Both 2-methoxyl and
2-fluoro substituents did not exhibit obvious steric and electronic
effects, and the corresponding reactions gave 3e (74%) and 3f (72%)
in good yields. In the cases of using bromo-substituted substrates a
steric effect was observed, leading to 3i-k in 72-81% yields. The
bulkyl α-naphthoyl substrate reacted with ethanol less efficiently,
yielding 3l in a moderate yield (64%). α-Furoyl and α-thienoyl
ketene dithioacetals exhibited different reactivities, affording the
target products 3m (71%) and 3n (60%), respectively, which is
presumably attributed to the possible interaction of the thienyl
sulfur atom with the catalytically active copper species during the
reaction. Unexpectedly, α-alkenoyl ketene dithioacetals underwent
the reactions to regioselectively form 3o-r in 60-67% yields. α-
Acetyl ketene dithioacetal and its alkyl analogs also reacted to give
ethoxylated products 3s-u (56-63%). Variation of the alkylthio
groups from methylthio (MeS) to ethylthio (EtS) did not affect
formation of the target products, i. e., 3v-x (70-75%), whereas
replacement of the alkylthio by benzylthio resulted in yield
decrease of product 3y (67%). In a similar fashion, cyclic α-aroyl
ketene dithioacetals reacted with ethanol to form the target
product 3z-z2 in 53-56% yields, exhibiting an obvious negative steric
effect from the cyclic alkylthio functionality. Reactions of the olefin
substrates bearing other electron-withdrawing groups such as CN
could not form the target products under the stated conditions. The
α-oxo functionality may help to stabilize species B as shown in the
mechanism scheme via an intramolecular OHhydrogen bond.
42%) less efficiently than PhI(OAc)2, while both bis(trifluoroacetoxy-
)iodobenzene (PhI(OCOCF3)2) and iodosylbenzene (PhIO) rendered
the reaction to produce the diethoxylation product 3a (10-32%),
and 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one could not
promote the reaction. It is noteworthy that α-oxo ketene
monothioacetal 1a, 1,3,3-triphenylpropenone (1a),16 and acetal
1a’ did not react with ethanol under the stated conditions (eqn
(1)), suggesting that the dialkylthio functionalities are indispensable
in the olefin substrates. Interaction between the two alkylthio
functionalities and the olefinic C=C bond via p π conjugation thus
activates the internal olefinic CH bond, which makes the a-CH
vicinal to the electron-withdrawing carbonyl more reactive towards
electrophiles as compared to ethylene.14a,15
Table 3 Scope of alcohols 2a
Next, the protocol generality was explored by carrying out
the reactions of α-aroyl ketene dithioacetals with various
alcohols (Table 3). α-Benzoyl ketene dithioacetal (1a) reacted
with methanol to afford methoxylated product 4a in 72% yield.
Other substituted α-benzoyl ketene dithioacetals also
smoothly reacted in methanol to give the corresponding
products 4b-e (62-74%), demonstrating diverse substituent
effects. Moderate chain alcohol, that is, n-butanol, and
secondary alcohol 2-propanol, underwent the reactions with
1a to form 4f (62%) and 4g (67%), respectively. However, allyl
alcohol reacted with 1a under the stated conditions to afford
diketone 4h (53%) as the major product (eqn (2)). The process
may follow a two-step sequence, that is, C-H alloxylation/
Claisen rearrangement, to generate 4h. Sterically bulky tert-
a
Conditions: 1 (0.5 mmol), Cu(O(H)2 (0.1 mmol), PhI(OAc)2 (1.0 mmol), BQ (0.25
butyl alcohol did not react with 1. Although benzyl alcohol
mmol), 50 oC, air, 24 h. Yields refer to the isolated products. In ROH (5 mL).
b
c
exhibited a lower reactivity to 1a to form 4i in 63% yield,
methyl-substituted benzyl alcohols efficiently underwent the
reactions with 1a in toluene, affording the target benzylation
products 4j-l (70-76%). A negative electronic effect was
observed for 2-flourobenzyl alcohol, while 2-, 3-, and 4-
Using 10 equiv ROH in toluene (5 mL).
Under the optimal conditions, the scope of α-oxo ketene
dithioacetals 1 was investigated on a 0.5 mmol scale (Table 2). The
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chlorobenzyl alcohols showed a positive electronic effect to as 2,2,6,6-tetramethyl-1-piperdinyloxy (TEMPO) or 2,6-di-tert-butyl-
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produce 4m-p
in 70-76% yields. 4-Bromobenzyl alcohol also 4-methylphenol (BHT) to the reaction ofDO1Ia: 10a.n10d39e/Cth7aOnBo0l12(324aA)
efficiently reacted to give the corresponding product 4q (70%). completely inhibited the reaction under the standard conditions
However, 2-naphthylmethyl alcohol demonstrated a negative (eqn (4)), revealing a radical reaction mechanism involving a single-
steric effect on the product yield, leading to 4r in 64% yield. 3- electron-transfer (SET) process.14c The kinetic isotope effect (KIE)
Bromo and 2-fluoro-substituted benzoyl ketene dithioacetals experiments were carried out by means of the reactions of 1a and
reacted with 4-chlorobenzyl alcohol to form products 4s (76%) its deuterated form 1a[D] with ethanol (eqn (5)), respectively. A
and 4t (70%), respectively, while the 4-F substituted analog kH/kD = 1.0 value was observed, suggesting that cleavage of the
underwent the reaction less efficiently to produce 4u (65%). internal olefinic CH bond in α-oxo ketene dithioacetals 1 was not
The di(ethylthio)acetal substrate also efficiently reacted with involved in the rate-determining step of the overall catalytic cycle.
4-methylbenzyl alcohol to generate 4v (79%). Under the same
conditions ketene dithioacetals
1 did not underwent the CH
phenoxylation reactions with phenols. It should be noted that
α-oxo ketene dithioacetals reacted with benzyl alcohols to
form the C
The molecular structures of the C
and were further confirmed by the X-ray single crystal

H alkylation products under Lewis acid catalysis.17

H alkoxylation products 3
4
structural determination of compound 4i (Figure 1).
In order to further verify the reaction mechanism, PhI(OEt)2 and
PhI(OEt)(OAc) were tentatively prepared from the reaction of
PhI(OAc)2 with EtOH (2a) using a literature method.18 Unfortunately,
both PhI(OEt)2 and PhI(OEt)(OAc) could not be successfully obtained
due to their high susceptibility to thermal and moisture conditions.
Alternatively, stable cyclic methoxyiodo(III) compound, that is, 1-
methoxy-1,2-benziodoxol-3-(1H)-one (6)19 was prepared and
applied to react with 1a in both methanol and toluene solvents
under the standard conditions, forming 4a in 59% and 15% yields
Figure 1 Molecular structure of compound 4i.
Scheme 3 Scale-up reactions of 1a with alcohols.
o
(eqn (6)), respectively. By elevating the temperature to 110 C in a
sealed tube the yield could be improved to 71% and 19%,
respectively. These results have implicated the involvement of
alkoxyiodo(III) species in the CH alkoxylation of 1 with alcohols.
The synthetic protocol was then tested for its applicability in
organic synthesis. The scaling-up reactions of α-benzoyl ketene
dithioacetal (1a) with ethanol (2a) and 4-chlorobenzyl alcohol on a
5 mmol scale were conducted, affording the corresponding target
products 3a (71%) and 4p (76%), respectively (Scheme 3).Treatment
of the CH alkoxylation products 3a, 4i, and 4v with hydroxylamine
in refluxing ethanol afforded the desulfurative condensation
products, that is, fully substituted oxazoles 5a-c (53-62%) (eqn (3)),
illustrating a potential application of the alkoxylated tetrasubsti-
tuted olefins.
To probe into the reaction mechanism, control experiments were
performed. Addition of two equivalents of a radical scavenger such
Scheme 4 Proposed mechanism.
4 | J. Name., 2012, 00, 1-3
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PAPER
Chem. Rev., 2011, 111, 1315; (g) C. S. Yeung and V. M. Dong,
A plausible mechanism is proposed in Scheme 4. Interaction
of Cu(OH)2 with α-oxo ketene dithioacetal 1a generates Cu(II)
View Article Online
Chem. Rev., 2011, 111, 1215; (h) D. A. Colby, R. G. Bergman
DOI: 10.1039/C7OB01234A
and J. A. Ellman, Chem. Rev., 2010, 110, 624.
species
process occurs between species
iodine intermediate or formed in situ from the reaction of
PhI(OAc)2 and ethanol (2a), yielding cationic radical species
B with release of water. A single-electron-transfer (SET)
3
4
B. Liu and B.–F. Shi. Tetrahedron Lett., 2015, 56, 15.
(a) X. X. Wu, B. P. Fors and S. L. Buchwald, Angew. Chem. Int.
Ed., 2011, 50, 9943; (b) S. Gowrisankar, A. G. Sergeev, P.
Anbarasan, A. Spannenberg, H. Neumann and M. Beller, J.
Am. Chem. Soc., 2010, 132, 11592.
B
and the ethoxy hypervalent
C
C
D
,
which then transforms to the target product 3a and cationic
copper hydroxy radical. A second SET process occurs to
regenerate Cu(OH)2. Other in situ formed copper species may
also promote the desired C-H alkoxylation reaction. In the
overall reaction cycle, benzoquinone (BQ) facilitates the
regeneration of catalytically active Cu(OH)2, and both
PhI(OAc)2 and air promote oxidation of the reduced form of
BQ, that is, hydrobenzoquinone (H2BQ), to BQ, suggesting a
cooperative effect between PhI(OAc)2 and BQ.20
5
6
A. E. King, T. C. Brunold and S. S. Stahl, J. Am. Chem. Soc.,
2009, 131, 5044.
(a) E. Lindstedt, E. Stridfeldt and B. Olofsson, Org. Lett.,
2016, 18, 4234; (b) E. Lindstedt, R. Ghosh and B. Olofsson,
Org. Lett., 2013, 15, 6070.
7
8
S. Bhadra, W. I. Dzik and L. J. Goossen, J. Am. Chem. Soc.,
2012, 134, 9938.
Selected recent reports on arene C(sp2)–H alkoxylation with
alcohols, see: (a) J. Alvarado, J. Fournier and A. Zakarian,
Angew. Chem. Int. Ed., 2016, 55, 11625; (b) L. B. Zhang, X. Q.
Hao, S. K. Zhang, Z. J. Liu, X. X. Zheng, J. F. Gong, J. L. Niu and
M. P. Song, Angew. Chem. Int. Ed., 2015, 54, 272; (c) F. Pron,
C. Fossey, J. O. Santos, T. Cailly and F. Fabis, Chem. Eur.–J.,
2014, 20, 7507; (d) F.–J. Chen, S. Zhao, F. Hu, K. Chen, Q.
Conclusions
In summary, copper(II)-promoted direct α-CH alkoxylation of S,S-
functionalized α-oxo internal olefins with alcohols was efficiently
achieved by means of a combination of PhI(OAc)2 and benzo-
quinone as the oxidants. Polarization of the olefinic C=C bond is
crucial to render the olefinic CH alkoxylation reactions to undergo
under mild conditions. The present protocol provides a concise
route to alkoxylated olefins and the related alkoxylated N-
heterocycles.
Zhang, S.–Q. Zhang and B.–F. Shi, Chem. Sci., 2013, 4, 4187;
(e) S. Bhadra, C. Matheis, D. Katayev and L. J. Gooßen,
Angew. Chem. Int. Ed., 2013, 52, 9279; (f) A. M. Suess, M. Z.
Ertem, C. J. Cramer and S. S. Stahl, J. Am. Chem. Soc., 2013,
135, 9797; (g) J. Roane and O. Daugulis, Org. Lett., 2013, 15
,
5842; (h) S. Bhadra, W. I. Dzik and L. J. Gooßen, Angew.
Chem. Int. Ed., 2013, 52, 2959; (i) M. Anand and R. B. Sunoj,
Org. Lett., 2011, 13, 4802.
9
Selected recent examples of C(sp3)–H alkoxylation with
alcohols, see: (a) S. J. Thompson, D. Q. Thach and G. Dong. J.
Am. Chem. Soc., 2015, 137, 11586; (b) G. Shan, X.–L. Yang, Y.
Zong and Y. Rao, Angew. Chem. Int. Ed., 2013, 52, 13606; (c)
M. O. Ratnikov, X. F. Xu and M. P. Doyle, J. Am. Chem. Soc.,
2013, 135, 9475; (d) S.-Y. Zhang, G. He, Y.–S. Zhao, K. Wright,
W. A. Nack and G. Chen, J. Am. Chem. Soc., 2012, 134, 7313.
Experimental Section
Typical Procedure for the CH Alkoxylation Reactions of 1 with 2:
Synthesis of 3a
10 (a) Y. J. Xie, J. H. Hu, P. Xie, B. Qian and H. M. Huang, J. Am.
Chem. Soc., 2013, 135, 18327; (b) P. K. Prasad, R. N. Reddi
and A. Sudalai, Org. Lett., 2016, 18, 500; (c) J. M. Eagan, M.
Hori, J. Wu, K. S. Kanyiva and S. A. Snyder, Angew. Chem. Int.
Ed., 2015, 54, 7842; (d) B. S. Wu, G. C. Feast, A. L. Thompson
and J. Robertson, J. Org. Chem., 2012, 77, 10623.
A mixture of α-benzoyl ketene di(methylthio)acetal (1a) (112 mg,
0.5 mmol), Cu(OH)2 (10 mg, 0.1 mmol), PhI(OAc)2 (322 mg, 1.0
mmol), and BQ (27 mg, 0.25 mmol) in 5 mL EtOH (2a) was stirred at
50 oC for 24 h. After cooled to ambient temperature, all the
volatiles were evaporated under reduced pressure. The resultant
mixture was subject to purification by column chromatography on
11 Y. Monguchi, K. Kunishima, T. Hattori, T. Takahashi, Y.
Shishido, Y. Sawama and H. Sajiki, ACS Catal., 2016, 6, 3994.
o
silica gel (eluent: petroleum ether (60-90 C)/ethyl acetate = 200:1,
12 H. Yi, L. B. Niu, C. L. Song, Y. Y. Li, B. W. Dou, A. K. Singh and A.
W. Lei, Angew. Chem. Int. Ed., 2017, 56, 1120.
v/v), affording 3a as a yellow liquid (95 mg, 71%).
13 (a) J. M. Hoover, B. L. Ryland and S. S. Stahl, J. Am. Chem.
Soc., 2013, 135, 2357; (b) K. E. Torraca, X. Huang, C. A.
Parrish, S. L. Buchwald, J. Am. Chem. Soc., 2001, 123, 10770.
Acknowledgements
14 (a) L. D. Wang, W. He and Z. K. Yu, Chem. Soc. Rev., 2013, 42
,
We are grateful to the National Natural Science Foundation of China
(21472185) and National Basic Research Program of China
(2015CB856600).
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Table of contents:
Efficient copper−promoted direct C−H alkoxylation of internal olefins α-oxo ketene
dithioacetals was achieved with alcohols as the alkoxylating reagents.