Copper-catalyzed dehydrogenative cross-coupling reaction between unactivated ethers and simple ketones mediated by pyrrolidine

Article abstract of DOI:10.1016/j.tet.2013.07.085

A copper-catalyzed dehydrogenative cross-coupling reaction between unactivated ethers and simple ketones mediated by pyrrolidine has been developed. Under the catalysis of CuBr₂ and in the presence of pyrrolidine, either tetrahydrofuran 2a or tetrahydropyran 2b can react smoothly with a series of methyl aryl ketones 1a-m to give desired coupling products 3aa-mb using TBHP as an oxidant. The advantages of the dehydrogenative cross-coupling reaction are adoption of unmodified ethers as substrates, good tolerance of many functional groups and use of cheap copper salt as a catalyst. A plausible radical mechanism through enamine attack is proposed.

Full text of DOI:10.1016/j.tet.2013.07.085

Tetrahedron 69 (2013) 8579e8582
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper-catalyzed dehydrogenative cross-coupling reaction between
unactivated ethers and simple ketones mediated by pyrrolidine
,b,
Xing-Fen Huang a, Zhi-Qiang Zhu a, Zhi-Zhen Huang a
*
a Department of Chemistry, Zhejiang University, Hangzhou 310028, PR China
b State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 May 2013
Received in revised form 16 July 2013
Accepted 25 July 2013
Available online 1 August 2013
A copper-catalyzed dehydrogenative cross-coupling reaction between unactivated ethers and simple
ketones mediated by pyrrolidine has been developed. Under the catalysis of CuBr2 and in the presence of
pyrrolidine, either tetrahydrofuran 2a or tetrahydropyran 2b can react smoothly with a series of methyl
aryl ketones 1aem to give desired coupling products 3aaemb using TBHP as an oxidant. The advantages
of the dehydrogenative cross-coupling reaction are adoption of unmodified ethers as substrates, good
tolerance of many functional groups and use of cheap copper salt as a catalyst. A plausible radical
mechanism through enamine attack is proposed.
Keywords:
CeH functionalization
Dehydrogenative cross-coupling
Copper-catalysis
Ether
Ó 2013 Elsevier Ltd. All rights reserved.
Ketone
1. Introduction
manganese dioxideemethanesulfonic acid oxidation system.1n In
order to challenge the dehydrogenative cross-coupling reaction of
With the rapid advancement in CeH transformations, direct
-CeH functionalizations of ethers have received considerable
unactivated ethers with simple ketones, which have no aryl or other
functional group in -position of ethers, we envisioned to use amine
to promote the reactivity of ketone with unmodified ether. Herein,
we wish to report a copper-catalyzed dehydrogenative cross-
coupling reaction between tetrahydrofuran or tetrahydropyran
with methyl ketones mediated by pyrrolidine synergistically.
a
a
attention.1aen Recently, the use of only CeH bonds to undergo
dehydrogenative cross-coupling was considered as a new generation
of CeC bond formations because dehydrogenative cross-coupling
reactions avoid prefunctionalization of substrates and are more
atom economic and environmentally friendly.2 Among the
a-CeH
functionalizations of ethers, there have been a few literature on
dehydrogenative cross-coupling reactions of ethers with simple ke-
2. Results and discussion
tones, but all these ethers bear phenyl group in
a-position to activate
Initially, acetophenone 1a and THF 2a were chosen as model
substrates to explore and optimize the dehydrogenative cross-
coupling reaction (Table 1). When CuCl2 and pyrrolidine were
employed in catalytic and stoichiometric amount, respectively, we
were pleased to find that the dehydrogenative cross-coupling re-
action between acetophenone 1a and THF 2a could occur at reflux
using t-BuOOH (TBHP) as an oxidant, affording the coupling product
3aa albeit in a low yield (entry 1, Table 1). Then, other transition-
metal catalysts were tried in the reaction as well (For details, see
Supplementary data). CuBr2 was proved to be most effective to give
3aa in 59% yields (entry 14, Table 1). Increase or decrease of the
amount of CuBr2 resulted in the reductions of coupling yields (entry
2, 12, 13, Table 1). Among secondary amines examined, pyrrolidine
was best in yield. Using small amounts of pyrrolidine led to poor
efficiency (entry 17, Table 1), and at least 70 mol % of pyrrolidine had
to be employed in the reaction. Except TBHP, many oxidants, such as
the
a
-CeH bond.1a,1e,1j,1n In 2006, Li et al. revealed an efficient
dehydrogenative cross-coupling reaction between benzyl ethers and
simple ketones mediated by 2, 3-dichloro-5, 6-dicyanobenzoquinone
(DDQ).1a Later, theyalsodeveloped a dehydrogenative cross-coupling
reaction of benzyl ethers with methyl ketones under the catalysis of
Cu(OTf)2, InCl3 and N-hydroxyphthalimide using oxygen as a termi-
nal oxidant.1e Recently, Mancheno’s group found that using N-
~
oxoammonium salt as oxidant, benzyl ethers performed coupling
reactions with aldehydes or ketones smoothly under the catalysis of
Cu(OTf)2.1j In 2013, Lou et al. developed a dehydrogenative cross-
coupling reaction of benzyl ethers with simple ketones by
* Corresponding author. Tel.: þ86 0571 87951352; fax: þ86 0571 87951895;
e-mail addresses: huangzhizhen@zju.edu.cn, huangzz@nju.edu.cn (Z.-Z. Huang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.085

8580
X.-F. Huang et al. / Tetrahedron 69 (2013) 8579e8582
Table 1
O
CuBr2 (10 mol%)
O
n
n
Optimization of dehydrogenative cross-coupling reaction between acetophenone 1a
pyrrolidine (70 mol%)
H
and tetrahydrofuran 2aa
+
H
Ar
Ar
O
O
TBHP (3 eq) / AcOH (3 eq)
reflux, 6 h
3aa-mb
1a-l
2a: n=1
2b: n=2
O
O
O
O
O
O
Entry
[M] (mol %)
Oxidant (equiv)
Amine (equiv)
Yield (%)b
1
2
3
4
5
6
7
8
CuCl2(10)
CuBr2(10)
CuBr2(10)
d
TBHP(2)
TBHP(2)
d
Pyrrolidine(1)
Pyrrolidine(1)
Pyrrolidine(1)
Pyrrolidine(1)
d
15
30
Nd
Nd
Nd
0
0
10
0
3aa (75%)
3ba (64%)
3ca (62%)
O
O
O
TBHP(2)
TBHP(2)
DDQ(1)
O2 (1)
O
O
O
CuBr2(10)
CuBr2(10)
CuBr2(10)
CuBr2(10)
CuBr2(10)
CuBr2(10)
CuBr2(10)
CuBr2(5)
CuBr2(20)
CuBr2(10)
CuBr2(10)
CuBr2(10)
CuBr2(10)
t-Bu
F
MeO
Pyrrolidine(1)
Pyrrolidine(1)
Pyrrolidine(1)
Pyrrolidine(1)
Pyrrolidine(1)
Pyrrolidine(1)
Pyrrolidine(1)
Pyrrolidine(1)
Pyrrolidine(1)
Pyrrolidine(1)
Pyrrolidine(0.7)
Pyrrolidine(0.3)
3fa (55%)
O
3da (51%)
3ea (69%)
(tBuO)2(3)
AIBN (1)
NMO(1)
mCPBA(1)
TBHP(2)
TBHP(2)
TBHP(3)
TBHP(3)
TBHP(3)
TBHP(3)
O
O
9
O
O
O
O
O
10
11
12
13
14
15c
16c
17c,d
5
21
15
13
59
70
75
32
NC
Cl
F
3ia (53%)
O
3ha (52%)
3ga (72%)
O
O
O
O
I
Br
3la (61%)
O
3ja (55%)
3ka (54%)
a
Reaction conditions: 1a (0.5 mmol), 2a (2 ml), reflux 6 h under aerobic condi-
O
O
tion, unless otherwise noted.
O
O
b
Yield of isolated product.
3 equiv of AcOH was added.
c
d
12 h.
3ma (70%)
3bb (60%)
3ab (58%)
O
O
O
O
DDQ, dioxygen, tert-butyl peroxide, 2, 20-azobisisobutyronitrile
(AIBN), N-Methylmorpholine-N-Oxide (NMO), 3-Chloroperbenzoic
acid (mCPBA) were less effective for this reaction (entry 6e11,
Table 1). The addition of 3 equiv of acetic acid promoted the reaction
remarkably (Entry 14, 15, Table 1). It is noteworthy that if either
CuBr2 or pyrrolidine was not employed, no desired product 3aa was
observed (entry 4, 5, Table 1).
Cl
3mb (49%)
3jb (43%)
Scheme 1. Dehydrogenative cross-coupling reaction between methyl aryl ketones
1aem and tetrahydrofuran 2a or tetrahydropyran 2b. Reaction conditions: acetophe-
none (0.5 mmol), CuBr2 (0.05 mmol), TBHP (3 equiv, 5e6 M in decane), pyrrolidine
(0.35 mmol), AcOH (1.5 mmol), THF (2 ml)/THP (0.5 ml), 110 ꢀC, reflux 6 h under
aerobic condition. Isolated yields.
After screening of reaction conditions, it can be concluded that
the optimized reaction should be performed by using 10 mol % of
CuBr2, 70 mol % of pyrrolidine, 3 equiv of TBHP, and 3 equiv of
acetic acid (entry 17, Table 1). Under the optimized conditions, we
examined the scope of the copper-catalyzed dehydrogenative
cross-coupling reaction. It was found that methyl aryl ketones
1ael, which bearing either electron-rich or electron-deficient
groups on the benzene rings could undergo the dehydrogenative
cross-coupling reaction smoothly with THF to give desired prod-
ucts 3aaela in the yields of 51e75% (Scheme 1). Naphthyl group
instead of phenyl group also performed the coupling reaction to
N
6
.
t-BuO
H2O
Ar
N
.
3aa
O
O
O
5
CuI
CuII
Ar
O
2a
7
4
.
t-BuOOH
t-BuO + OH
Scheme 2. Plausible mechanism of dehydrogenative cross-coupling reaction of tet-
rahydrofuran 2a with methyl aryl ketone 1a.
give
a-CeH functionalized product 3ma of tetrahydrofuran in
a satisfactory yield. The coupling reaction tolerated many func-
tions, such as methoxyl, fluoro, chloro, bromo, iodo and cyano
group. When methyl alkyl ketone or ethyl ketone was employed,
no coupling product was obtained under the optimized condi-
tions. Using this strategy, tetrahydropyran 2b can also perform
the dehydrogenative cross-coupling reaction with methyl aryl
ketone 1a, 1b, 1j, 1m expediently (3abemb, Scheme 1). However,
acyclic ethers, such as diethyl ether did not undergo the coupling
reaction.
from methyl aryl ketone 1a with pyrrolidine 2a in situ attacks
nucleophilically on 5 to form ammonium 7. Finally, hydrolysis of 7
generates coupling product 3aa.
3. Conclusion
In summary, we have developed a copper-catalyzed dehydro-
genative cross-coupling reaction between unactivated ethers and
simple ketones mediated by pyrrolidine synergistically. Under the
catalysis of CuBr2 and in the presence of pyrrolidine, either tetra-
hydrofuran 2a or tetrahydropyran 2b can react smoothly with
many methyl aryl ketones 1aem to give the desired coupling
products 3aaemb using TBHP as an oxidant. The advantages of the
dehydrogenative cross-coupling reaction are adoption of un-
modified ethers as substrates, good tolerance of many functional
groups and use of cheap copper salt as a catalyst. A plausible radical
mechanism through enamine attack is proposed.
Further investigation demonstrated that if 2, 6-di-tert-butyl-4-
methyl phenol (BHT), a radical inhibitor, was added into the re-
action system, the yield of coupling product 3a was decreased
dramatically from 75% to less than 5%. Thus, the mechanism of the
dehydrogenative cross-coupling reaction may undergo a radical
pathway, which is depicted in Scheme 2. Initially, a tert-butoxyl
radical generated by the dissociation of t-BuOOH3 may abstract
a-
hydrogen of 2a to form radical 4. A single electron transfer (SET)
from 4 leads to oxonium species 5. Then, the enamine 6 resulted

X.-F. Huang et al. / Tetrahedron 69 (2013) 8579e8582
8581
4. Experimental section
d
7.96 (d, J¼8.8 Hz, 2H), 6.94 (d, J¼9.2 Hz, 2H), 4.42e4.39 (m, 1H),
3.91 (q, J¼7.2 Hz, 1H), 3.89 (s, 3H), 3.77 (q, J¼7.6 Hz, 1H), 3.36 (dd,
J1¼6.4 Hz, J2¼16.0 Hz, 1H), 3.02 (dd, J1¼6.8 Hz, J2¼16.0 Hz, 1H),
2.23e2.16 (m, 1H), 1.98e1.91 (m, 2H), 1.63e1.56 (m, 1H); 13C NMR
4.1. General procedure for the dehydrogenative cross-
coupling reaction of tetrahydrofuran 2a with methyl aryl
ketone 1aem
(100 MHz, CDCl3/TMS)
d 196.9, 163.4, 130.4, 130.1, 113.6, 75.5, 67.7,
55.4, 44.2, 31.5, 25.6; MS (EI) m/z (%) 220, 177, 150, 135 (100%), 107,
The mixture of CuBr2 (11.1 mg, 0.05 mmol), AcOH (90.8 mg,
3 equiv), acetophenone (60.0 mg, 0.5 mmol), pyrrolidine (24.9 mg,
70 mol %) and THF (2 ml) was stirred for a couple of minutes at
110 ꢀC. tert-Butyl hydroperoxide (0.28 ml, 3 equiv, 5e6 M in dec-
ane) was added to the mixture, and the reaction mixture was
stirred for 6 h at this temperature. After reaction, the mixture was
filtered. The filtrate was evaporated under reduced pressure, and
the residue was purified by column chromatography (silica gel,
ethyl acetate/petroleum ether¼1:40 as eluent) to give the desired
product 3aaema.
92, 77, 71, 43.
4.1.7. 4-(2-(Tetrahydrofuran-2-yl) acetyl) benzonitrile 3ga.4 Yield
72%; yellow solid; mp 55e57 ꢀC; 1H NMR (400 MHz, CDCl3/TMS)
d
8.04 (d, J¼8.4 Hz, 2H), 7.75 (d, J¼8.8 Hz, 2H), 4.39e4.32 (m, 1H),
3.86 (q, J¼7.2 Hz, 1H), 3.74 (q, J¼7.3 Hz, 1H), 3.34 (dd, J1¼6.4 Hz,
J2¼16.0 Hz, 1H), 3.05 (dd, J1¼6.0 Hz, J2¼16.4 Hz, 1H), 2.21e2.16 (m,
1H), 1.96e1.89 (m, 2H), 1.59e1.54 (m, 1H); 13C NMR (100 MHz,
CDCl3/TMS)
d 197.2, 139.9, 132.4, 128.6, 117.8, 116.2, 75.0, 67.9,
44.8, 31.5, 25.5; MS (EI) m/z (%) 215, 187, 172, 145, 130 (100%), 102,
71, 43.
4.1.1. 1-Phenyl-2-(tetrahydrofuran-2-yl) ethanone 3aa.4 Yield 75%;
light yellow oil; 1H NMR (400 MHz, CDCl3/TMS)
d
7.98 (d, J¼7.8 Hz,
4.1.8. 1-(4-Fluorophenyl)-2-(tetrahydrofuran-2-yl) ethanone 3ha.4 Yield
2H), 7.58 (t, J¼7.6 Hz, 1H), 7.48 (t, J¼7.6 Hz, 2H), 4.46e4.40 (m, 1H),
3.92 (q, J¼7.2 Hz, 1H), 3.77 (q, J¼7.2 Hz, 1H), 3.42 (dd, J1¼6.4 Hz,
J2¼16.4 Hz, 1H), 3.08 (dd, J1¼6.4 Hz, J2¼16.0 Hz, 1H), 2.23e2.20 (m,
1H), 1.99e1.91 (m, 2H), 1.61e1.56 (m, 1H); 13C NMR (100 MHz,
52%; light yellow oil; 1H NMR (400 MHz, CDCl3/TMS)
d 7.99 (t,
J¼8.5 Hz, 2H), 7.13 (t, J¼8.4 Hz, 2H), 4.41e4.37 (m, 1H), 3.89 (q,
J¼7.2 Hz, 1H), 3.75 (q, J¼7.2 Hz, 1H), 3.35 (dd, J1¼6.0 Hz, J2¼16.0 Hz,
1H), 3.02 (dd, J1¼6.4 Hz, J2¼16.0 Hz, 1H), 2.22e2.16 (m, 1H), 1.97e1.90
CDCl3/TMS)
d 198.4, 136.9, 133.0, 128.5, 128.1, 75.3, 67.7, 44.6, 31.5,
(m, 2H), 1.62e1.55 (m, 1H); 13C NMR (100 MHz, CDCl3/TMS)
d 196.8,
25.6; MS (EI) m/z (%) 190, 162, 147, 120, 105 (100%), 91, 77, 51, 43.
165.7 (d, J¼253.2 Hz), 133.4, 130.8 (d, J¼9.3 Hz), 115.6 (d, J¼21.7 Hz),
75.3, 67.8, 44.5, 31.5, 25.5; MS (EI) m/z (%) 208, 180, 165, 138, 123
(100%), 95, 71, 43.
4.1.2. 2-(Tetrahydrofuran-2-yl)-1-p-tolylethanone 3ba.4 Yield 64%;
light yellow oil; 1H NMR (400 MHz, CDCl3/TMS)
d
7.88 (d, J¼8.4 Hz,
2H), 7.27 (d, J¼6.8 Hz, 2H), 4.43e4.38 (m, 1H), 3.90 (q, J¼7.2 Hz, 1H),
3.76 (q, J¼7.2 Hz, 1H), 3.38 (dd, J1¼6.0 Hz, J2¼16.0 Hz, 1H), 3.04 (dd,
J1¼6.8 Hz, J2¼16.0 Hz, 1H), 2.42 (s, 3H), 2.23e2.20 (m, 1H),
1.96e1.92 (m, 2H), 1.62e1.55 (m, 1H); 13C NMR (100 MHz, CDCl3/
4.1.9. 1-(3-Fluorophenyl)-2-(tetrahydrofuran-2-yl) ethanone 3ia.4 Yield
53%; light yellow oil; 1H NMR (400 MHz, CDCl3/TMS)
d
7.75 (d, J¼7.6 Hz,
1H), 7.64 (d, J¼9.2 Hz, 1H), 7.45(q, J¼7.2 Hz, 1H), 7.26 (t, J¼7.6 Hz, 1H),
4.42e4.38 (m,1H), 3.89 (q, J¼7.2 Hz,1H), 3.76 (q, J¼7.2 Hz,1H), 3.35 (dd,
J1¼6.4 Hz, J2¼16.4 Hz, 1H), 3.04 (dd, J1¼6.4 Hz, J2¼16.4 Hz, 1H),
2.24e2.16 (m, 1H), 1.97e1.90 (m, 2H), 1.62e1.53 (m, 1H); 13C NMR
TMS)
d 198.0, 143.8, 134.5, 129.2, 128.2, 75.4, 67.7, 44.5, 31.5, 25.6,
21.6; MS (EI) m/z (%) 204, 161, 134, 119 (100%), 91, 71, 65, 43.
4.1.3. 2-(Tetrahydrofuran-2-yl)-1-m-tolylethanone 3ca.4 Yield 62%;
(100 MHz, CDCl3/TMS)
d
197.1,162.7(d, J¼246.3 Hz),139.0 (d, J¼6.1 Hz),
light yellow oil; 1H NMR (400 MHz, CDCl3/TMS)
d
7.75 (d, J¼9.6 Hz,
130.2 (d, J¼7.5 Hz), 123.9 (d, J¼2.7 Hz), 120.0 (d, J¼21.3 Hz), 114.8 (d,
J¼22.1 Hz),75.2, 67.8, 44.7, 31.5, 25.5; MS (EI) m/z (%) 208 (Mþ),180,165,
138, 123 (100%), 95, 71, 43.
2H), 7.34 (q, J¼7.6 Hz, 2H), 4.42e4.38 (m, 1H), 3.89 (q, J¼7.6 Hz, 1H),
3.75 (q, J¼7.2 Hz, 1H), 3.38 (dd, J1¼6.0 Hz, J2¼16.4 Hz, 1H), 3.04 (dd,
J1¼6.8 Hz, J2¼16.4 Hz, 1H), 2.40 (s, 3H), 2.21e2.16 (m, 1H), 1.96e1.88
4.1.10. 1-(4-Chlorophenyl)-2-(tetrahydrofuran-2-yl) ethanone 3ja.4 Yield
(m, 2H), 1.60e1.53 (m, 1H); 13C NMR (100 MHz, CDCl3/TMS)
d 198.6,
55%; light yellow oil; 1H NMR (400 MHz, CDCl3/TMS)
d 7.93 (d,
138.3, 137.0, 133.8, 128.6, 128.4, 125.3, 75.3, 67.7, 44.6, 31.5, 25.6,
J¼8.4 Hz, 2H), 7.46 (d, J¼8.8 Hz, 2H), 4.42e4.39 (m, 1H), 3.91 (q,
J¼7.2 Hz, 1H), 3.77 (q, J¼7.6 Hz, 1H), 3.36 (dd, J1¼6.4 Hz, J2¼16.4 Hz,
1H), 3.05 (dd, J1¼6.4 Hz, J2¼16.0 Hz, 1H), 2.24e2.19 (m, 1H), 1.99e1.93
21.3; MS (EI) m/z (%) 204, 161, 134, 119 (100%), 91, 71, 65, 43.
4.1.4. 2-(Tetrahydrofuran-2-yl)-1-o-tolylethanone 3da.4 Yield 51%;
(m, 2H), 1.61e1.56 (m, 1H); 13C NMR (100 MHz, CDCl3/TMS)
d 197.2,
light yellow oil; 1H NMR (400 MHz, CDCl3/TMS)
d
7.66 (d, J¼7.6 Hz,
139.5, 135.3, 129.6, 128.8, 75.2, 67.8, 44.5, 31.5, 25.5; MS (EI) m/z (%) 224
1H), 7.37 (t, J¼7.6 Hz, 1H), 7.28e7.24 (m, 2H), 4.38e4.35 (m, 1H),
3.89 (q, J¼7.2 Hz, 1H), 3.75 (q, J¼7.2 Hz, 1H), 3.29 (dd, J1¼6.8 Hz,
J2¼16.0 Hz, 1H), 3.01 (dd, J1¼6.4 Hz, J2¼16.0 Hz, 1H), 2.51 (s, 3H),
2.19e2.14 (m, 1H), 1.96e1.90 (m, 2H), 1.60e1.53 (m, 1H); 13C NMR
(Mþ), 196, 181, 154, 139 (100%), 111, 71, 43.
4.1.11. 1-(4-Bromophenyl)-2-(tetrahydrofuran-2-yl) ethanone 3ka.4 Yield
54%; yellow solid; mp 39e42 ꢀC; 1H NMR (400 MHz, CDCl3/TMS)
(100 MHz, CDCl3/TMS) d 202.4, 138.1, 137.9, 131.8, 131.2128.5, 125.5,
d
7.82 (d, J¼8.4 Hz, 2H), 7.59 (d, J¼8.8 Hz, 2H), 4.39e4.36 (m, 1H), 3.88
75.4, 67.7, 47.5, 31.5, 25.5, 21.2; MS (EI) m/z (%) 204, 145, 119 (100%),
91, 71, 65, 43.
(q, J¼8.4 Hz, 1H), 3.74 (q, J¼8.0 Hz, 1H), 3.33 (dd, J1¼6.4 Hz,
J2¼16.4 Hz, 1H), 3.01 (dd, J1¼6.4 Hz, J2¼16.0 Hz, 1H), 2.21e2.16 (m, 1H),
1.94e1.90 (m, 2H), 1.60e1.53 (m, 1H); 13C NMR (100 MHz, CDCl3/TMS)
4.1.5. 1-(4-tert-Butylphenyl)-2-(tetrahydrofuran-2-yl)ethanone
3ea.4 Yield 69%; light yellow oil; 1H NMR (400 MHz, CDCl3/TMS)
d
197.3, 135.7, 131.8, 129.7, 128.2, 75.2, 67.8, 44.5, 31.5, 25.5; MS (EI) m/z
(%) 268 (Mþ), 227, 198, 185 (100%), 155, 71, 43.
d
7.92 (d, J¼8.4 Hz, 2H), 7.48 (d, J¼8.4 Hz, 2H), 4.42e4.39 (m, 1H),
3.90 (q, J¼7.2 Hz, 1H), 3.75 (q, J¼7.6 Hz, 1H), 3.39 (dd, J1¼6.0 Hz,
J2¼16.0 Hz, 1H), 3.04 (dd, J1¼6.8 Hz, J2¼16.0 Hz, 1H), 2.23e2.16 (m,
1H), 1.97e1.89 (m, 2H), 1.61e1.34 (m, 1H), 1.34 (s, 9H); 13C NMR
4.1.12. 1-(4-Iodophenyl)-2-(tetrahydrofuran-2-yl) ethanone 3la. Yield
61%; yellow solid; mp 63e65 ꢀC; 1H NMR (400 MHz, CDCl3/TMS)
d
7.83 (d, J¼8.4 Hz, 2H), 7.68 (d, J¼8.4 Hz, 2H), 4.40e4.37 (m, 1H),
(100 MHz, CDCl3/TMS)
44.5, 35.0, 31.5, 31.0, 25.6; MS (EI) m/z (%) 246, 203, 161 (100%), 146,
119, 105, 91, 71, 43.
d 198.0, 156.8, 134.4, 128.1, 125.4, 75.5, 67.7,
3.88 (q, J¼8.4 Hz, 1H), 3.74 (q, J¼8.0 Hz, 1H), 3.33 (dd, J1¼6.0 Hz,
J2¼16.0 Hz, 1H), 3.02 (dd, J1¼6.4 Hz, J2¼16.4 Hz, 1H), 2.22e2.17 (m,
1H), 1.95e1.91 (m, 2H), 1.59e1.54 (m, 1H); 13C NMR (100 MHz,
CDCl3/TMS)
d 197.7, 137.8, 136.2, 129.5, 101.3, 75.2, 67.8, 44.4, 31.5,
4.1.6. 1-(4-Methoxyphenyl)-2-(tetrahydrofuran-2-yl)
ethanone
25.5; MS (EI) m/z (%) 316 (Mþ), 288, 273, 246, 231 (100%), 203, 189,
3fa.4 Yield 55%; light yellow oil; 1H NMR (400 MHz, CDCl3/TMS)

8582
X.-F. Huang et al. / Tetrahedron 69 (2013) 8579e8582
104, 71, 43. HRMS (EI-TOF) [M]þ calculated for C12H13O2I 315.9960,
found 315.9951.
J1¼5.2, J2¼16.0, 1H), 1.85 (q, J¼6.0, 1H), 1.73 (d, J¼13.2, 1H),
1.57e1.52 (m, 3H), 1.39e1.35 (m, 1H); 13C NMR (100 MHz, CDCl3/
TMS)
d 198.0, 140.1, 136.3, 130.4, 129.5, 75.0, 69.3, 46.0, 32.7, 26.5,
4.1.13. 1-(Naphthalen-2-yl)-2-(tetrahydrofuran-2-yl)
ethanone
24.0; MS (EI) m/z (%) 238 (Mþ), 196, 181, 154, 139 (100%), 111, 85, 75,
55, 41. HRMS (EI-TOF) [M]þ calculated for C13H15O2Cl 238.0761,
found 238.0760.
3ma.4 Yield 70%; light yellow oil; 1H NMR (400 MHz, CDCl3/TMS)
d
8.49 (s, 1H), 8.04 (d, J¼8.8 Hz, 1H), 7.97 (d, J¼8.0 Hz, 1H), 7.88 (t,
J¼8.4 Hz, 2H), 7.62e7.53 (m, 2H), 4.50e4.47 (m, 1H), 3.92 (q,
J¼7.2 Hz, 1H), 3.78 (q, J¼7.6 Hz, 1H), 3.54 (dd, J1¼6.0 Hz, J2¼16.0 Hz,
1H), 3.19 (dd, J1¼6.8 Hz, J2¼16.4 Hz, 1H), 2.26e2.19 (m, 1H),
2.00e1.93 (m, 2H), 1.66e1.61 (m, 1H); 13C NMR (100 MHz, CDCl3/
4.2.4. 1-Naphthalen-2-yl-2-(tetrahydro-pyran-2-yl)-ethanone
3mb.5 Yield 49%; light yellow oil; 1H NMR (400 MHz, CDCl3/TMS)
d
8.50 (s, 1H), 8.05 (d, J¼8.4, 1H), 7.98 (d, J¼8.0, 1H), 7.89 (t, J¼8.0,
TMS)
d
198.3, 135.5, 134.3, 132.4, 129.9, 129.5, 128.4, 128.3, 127.7,
2H), 7.62e7.54 (m, 2H), 4.06e3.96 (m, 2H), 3.51e3.42 (m, 2H), 3.05
(dd, J1¼5.6, J2¼16.0, 1H), 1.87 (q, J¼4.2, 1H), 1.80 (d, J¼12.8, 1H),
1.62e1.54 (m, 3H), 1.48e1.41 (m, 1H); 13C NMR (100 MHz, CDCl3/
126.7, 123.8, 75.5, 67.8, 44.6, 31.6, 25.6; MS (EI) m/z (%) 240 (Mþ),
197, 170, 155 (100%), 127, 71, 43.
TMS)
d 199.0, 136.3, 135.3, 133.2, 130.8, 130.3, 129.1, 129.0, 128.4,
4.2. General procedure for the dehydrogenative cross-
coupling reaction of tetrahydropyran 2b with acetophenones
1a, b, j, m
127.4, 124.6, 75.2, 69.3, 46.1, 32.7, 26.5, 24.1; MS (EI) m/z (%) 254
(Mþ), 170, 155 (100%), 127, 77, 41.
Acknowledgements
The mixture of CuBr2 (11.1 mg, 0.05 mmol), AcOH (90.8 mg,
3 equiv), methyl aryl ketone (60.0 mg, 0.5 mmol), pyrrolidine
(24.9 mg, 70 mol %) and THP (0.5 ml) was stirred for a couple of
minutes at 120 ꢀC. tert-butyl hydroperoxide (0.28 ml, 3 equiv,
5e6 M in decane) was added to the mixture, and the reaction
mixture was stirred for 6 h at this temperature. After reaction, the
mixture was filtered. The filtrate was evaporated under reduced
pressure, and the residue was purified by column chromatography
(silica gel, ethyl acetate/petroleum ether¼1:50 as eluent) to give
the desired product 3abemb.
Financial supports from MOST of China (973 program
2011CB808600) and National Natural Science Foundation of China
(No. 21072091) are gratefully acknowledged.
Supplementary data
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.07.085.
References and notes
4.2.1. 1-Phenyl-2-(tetrahydro-pyran-2-yl)-ethanone
58%; light yellow oil; 1H NMR (400 MHz, CDCl3/TMS)
3ab.4 Yield
7.98 (d,
1. For a-functionalizations of ethers, see: (a) Zhang, Y.; Li, C.-J. J. Am. Chem. Soc.
d
2006, 128, 4242e4243; (b) Zhang, Y.-H.; Li, C.-J. Angew. Chem., Int. Ed. 2006, 45,
1949e1952; (c) Tu, W. Y.; Liu, L.; Floreancig, P. E. Angew. Chem., Int. Ed. 2008, 47,
4184e4187; (d) Li’s group reported a CDC reaction of unactivated ethers with
active methylene compounds: Li, Z.; Yu, R.; Li, H. Angew. Chem. 2008, 120,
7607e7610; (e) Yoo, W. J.; Correia, C. A.; Zhang, Y.; Li, C.-J. Synlett 2009, 138e142;
(f) Liu, L.; Floreancig, P. E. Angew. Chem., Int. Ed. 2010, 49, 3069e3072; (g) Liu, L.;
Floreancig, P. E. Angew. Chem., Int. Ed. 2010, 49, 5894e5897; (h) Ghobrial, M.;
Harhammer, K.; Mihovilovic, M. D.; Schnurch, M. Chem. Commun. 2010,
8836e8838; (i) Richter, H.; Mancheno, O. G. Eur. J. Org. Chem. 2010, 23,
4460e4467; (j) Richter, H.; Rohlmann, R.; Mancheno, O. G. Chem.dEur. J. 2011,
17, 11622e11627; (k) Ghobrial, M.; Schnurch, M.; Mihovilovic, M. D. J. Org. Chem.
J¼7.6 Hz, 2H), 7.57 (t, J¼7.2 Hz, 1H), 7.47 (t, J¼7.6 Hz, 2H), 3.96 (q,
J¼7.2 Hz, 2H), 3.49 (t, J¼11.2 Hz, 1H), 3.30 (dd, J1¼6.8 Hz, J2¼16.4 Hz,
1H), 2.93 (dd, J1¼6.0 Hz, J2¼16.0 Hz, 1H), 1.86 (q, J¼4.0 Hz, 1H), 1.75
(d, J¼12.4 Hz, 1H), 1.59e1.55 (m, 3H), 1.40e1.35 (m, 1H); 13C NMR
(100 MHz, CDCl3/TMS)
d 197.0, 136.7, 133.3, 128.7, 128.1, 71.7, 70.8,
66.8, 66.3, 40.6; MS (EI) m/z (%) 204 (Mþ), 162, 147, 120, 105 (100%),
€
~
85, 77, 51, 41.
~
€
4.2.2. 2-(Tetrahydro-pyran-2-yl)-1-p-tolyl-ethanone
3bb. Yield
7.87 (d,
2011, 76, 8781e8793; (l) Park, S. J.; Price, J. R.; Todd, M. H. J. Org. Chem. 2012, 77,
949e955; (m) Clausen, D. J.; Floreancig, P. E. J. Org. Chem. 2012, 77, 6574e6582;
(n) Liu, X.; Sun, B.; Xie, Z.; Qin, X.; Liu, L.; Lou, H. J. Org. Chem. 2013, 78,
3104e3112.
2. For reviews on dehydrogenative cross-coupling reactions: (a) Li, C. J.; Li, Z. Pure
Appl. Chem. 2006, 78, 935e945; (b) Li, C. J. Acc. Chem. Res. 2009, 42, 335e344; (c)
Scheuermann, C. Chem.dAsian J. 2010, 5, 436e451; (d) Yeung, C. S.; Dong, V. M.
Chem. Rev. 2011, 111, 1215e1292; (e) Li, B.-J.; Shi, Z.-J. Chem. Soc. Rev. 2012, 41,
5588e5598.
3. (a) A tert-butoxyl radical can be generated by a Cu(I)-catalyzed dissociation of
t-BuOOH. A trace amount of Cu(I) can also be formed by the redox reaction of
t-BuOOH with Cu(II). For details, see: Kharaschan, M. S.; Fono, A. J. Org. Chem.
1959, 24, 72e78; (b) A tert-butoxyl radical can also be generated from a homo-
lytic cleavage of t-BuOOH. For an example, see: He, T.; Yu, L.; Zhang, L.; Wang, L.;
Wang, M. Org. Lett. 2011, 19, 5016e5019.
4. Cheng, K.; Huang, L.-H.; Zhang, Y. H. Org. Lett. 2009, 11, 2908e2911.
5. Katritzky, A. R.; Abdel-Fattah, A. A. A.; Idzik, K. R.; Bahaa El-Gendya, E.-D. M.;
Soloducho, J. Tetrahedron 2007, 63, 6477e6484.
60%; light yellow oil; 1H NMR (400 MHz, CDCl3/TMS)
d
J¼8.0, 2H), 7.25 (d, J¼8.0, 2H), 3.95 (d, J¼10.0, 2H), 3.46 (t, J¼11.2,
1H), 3.26 (dd, J1¼6.8, J2¼16.0,1H), 2.90 (dd, J1¼5.6, J2¼16.0,1H), 2,41
(s, 3H), 1.84 (q, J¼4.4, 1H), 1,74 (d, J¼12.8, 1H), 1.59e1.49 (m, 3H),
1.38e1.34 (m, 1H); 13C NMR (100 MHz, CDCl3/TMS)
d 198.6, 144.5,
135.5, 129.9, 129.1, 75.1, 69.3, 45.9, 32.7, 26.5, 24.1, 22.3; MS (EI) m/z
(%) 218 (Mþ), 176, 161, 134, 119 (100%), 91, 65, 41. HRMS (EI-TOF)
[M]þ calculated for C14 H18 O2 218.1307, found 218.1303.
4.2.3. 1-(4-Chloro-phenyl)-2-(tetrahydro-pyran-2-yl)-ethanone
3jb. Yield 43%; white solid; mp 43e45 ꢀC; 1H NMR (400 MHz,
CDCl3/TMS)
d
7.91 (d, J¼7.6, 2H), 7.43 (d, J¼7.6, 2H), 3.94 (d, J¼10.6,
2H), 3.46 (t, J¼10.4, 1H), 3.26 (dd, J1¼6.8, J2¼15.6, 1H), 2.87 (dd,