Iron(II) chloride catalyzed alkylation of propargyl ethers: Direct functionalization of an sp3 C-H bond adjacent to oxygen

Article abstract of DOI:10.1055/s-0030-1260131

Iron(II) chloride catalyzed direct alkylation of sp³ C-H bond adjacent to oxygen in propargyl ethers has been accomplished by the use of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as oxidant under mild reaction conditions. The reaction proceeded smoothly with a variety of 1,3-diketones leading to -dicarbonyl ether in moderate yields. In the absence of 1,3-diketones, ynenones were produced by the use of iron(III) chloride and DDQ. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260131

PAPER
2803
Iron(II) Chloride Catalyzed Alkylation of Propargyl Ethers: Direct
Functionalization of an sp3 C–H Bond Adjacent to Oxygen
Functionalization
o
o
f
an sp3 C–Hn
B
ond
A
dja
c
ent to
O
xyg
j
en u Xie,a Ming Yu,a Yuhong Zhang*a,b
a
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87953244; E-mail: yhzhang@ zju.edu.cn
b
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Received 10 May 2011; revised 9 June 2011
cules.11 To our surprise, there is no report about the C–H
functionalization of propargyl ether. Herein, we report a
direct alkylation of propargyl sp3 C–H using iron(II) chlo-
ride catalyst in the presence of 2,3-dichloro-5,6-dicyano-
Abstract: Iron(II) chloride catalyzed direct alkylation of sp3 C–H
bond adjacent to oxygen in propargyl ethers has been accomplished
by the use of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as
oxidant under mild reaction conditions. The reaction proceeded
smoothly with a variety of 1,3-diketones leading to b-dicarbonyl 1,4-benzoquinone (DDQ) under mild reaction conditions.
ether in moderate yields. In the absence of 1,3-diketones, ynenones
were produced by the use of iron(III) chloride and DDQ.
It was found that ynenones resulted only when propargyl
ether was used as the substrates in the presence of iron(III)
Key words: alkylation, iron-catalyzed, propargyl ether, C–H func-
tionalization, C–C bond formation
chloride and 1.2 equivalents of DDQ.
Initially (3-methoxyprop-1-ynyl)benzene (1a) and 3-meth-
ylpentane-2,4-dione (2a) were chosen as the standard sub-
strates to search for suitable reaction conditions. The
copper(I) bromide and tert-butyl hydroperoxide catalytic
system used in our previous addition reaction was tried
first.4d,10c Unfortunately, no desired C–H functionalized
product was observed. Considering that iron is an inex-
pensive and environmentally benign catalyst and has been
widely studied in C–H activation reactions,12 we studied
the efficiency of iron catalysts. To our delight, the treat-
ment of 1a and 2a with 20 mol% Fe(acac)3 catalysts
afforded 15% of the alkylated product 3-(1-methoxy-
3-phenylprop-2-ynyl)-3-methylpentane-2,4-dione (3a)
(Table 1, entry 2) together with much of the by-products
3-phenylpropiolaldehyde and methyl 3-phenylpropiolate
resulting from the oxidation of 1a by DDQ. The yield was
increased to 48% by the use of iron(III) chloride as the cat-
alyst (entry 3), but the yield was difficult to improve fur-
ther due to the formation of the by-product (E)-2-
(methoxymethyl)-1,5-diphenylpent-2-en-4-yn-1-one (4a)
in 21% yield. A more promising result was obtained when
iron(II) chloride was used as the catalyst to give a 63%
yield (entry 4) and the formation of by-product 4a was al-
most suppressed. No reaction was observed in the absence
of metal catalyst (entry 1). The solvents are crucial to the
reaction. No reaction was observed in 1,4-dioxane, aceto-
nitrile, tetrahydrofuran, toluene, nitromethane, and di-
methyl sulfoxide (entries 6–11). Low yield was observed
in 1,2-dichloroethane (DCE) (entry 12). Oxidants such as
tert-butyl hydroperoxide (TBHP), azobisisobutyronitrile
(AIBN), and oxygen showed poor effect (entries 13–15).
No reaction occurred in the absence of the oxidant (entry
16). A yield of 42% of 3a was obtained when the reaction
was carried out in the presence of N2 (entry 17).
Transition-metal-catalyzed C–H bond functionalization
has attracted much interest in recent years1 because it of-
fers highly efficient and atom-economic organic transfor-
mations for the construction of complex molecules.
Currently, the activation of sp2 C–H bond has achieved
significant success and has been applied in the organic
synthesis.2 However, the activation of sp3 C–H bond is be-
lieved to be more difficult because the cleavage of sp3 C–
H bond is kinetically and thermodynamically unfavor-
able. Recent researches established that sp3 C–H bonds
adjacent to a heteroatom such as N,3 O,4 and S5 were more
reactive than those surrounded by carbon atoms, and some
promising catalytic systems have been developed for the
cleavage of sp3 C–H bonds. For example, Murahashi and
co-workers reported the cyanation of RuCl3-catalyzed ox-
idation of C–H bonds of tertiary amines.6 Murai and co-
workers reported the ruthenium-catalyzed addition reac-
tion of sp3 C–H bonds adjacent to a nitrogen atom in alkyl-
amines with alkenes.7 Li and co-workers reported the
copper-catalyzed conversion of sp3 C–H bonds adjacent
to heteroatoms into C–C bonds via the cross-dehydroge-
native coupling (CDC) process.8 The addition of a C–H
bond adjacent to an oxygen atom in 1,2-dimethoxyethane
across alkenes was achieved via an Ir-catalyzed reaction.9
In our ongoing research program towards the develop-
ment of catalytic systems for the direct functionalization
of C–H bonds,10 we have studied the copper-catalyzed ad-
dition of sp3 C–H bond adjacent to oxygen atom into
alkynes 4d and copper-catalyzed regioselective oxyalkyla-
tion of vinylarenes through the cleavage of sp3 C–H bond
adjacent to oxygen atom.4g Propargyl compounds are im-
portant structural motifs and biologically active mole-
With the optimized reaction condition in hand, the gener-
ality of the reaction was then evaluated with a variety of
aryl propargyl ethers and b-dicarbonyl compounds as
shown in Table 2. The electron-donating substituents in
SYNTHESIS 2011, No. 17, pp 2803–2809
x
x.
x
x
.
2
0
1
1
Advanced online publication: 21.07.2011
DOI: 10.1055/s-0030-1260131; Art ID: H48311SS
© Georg Thieme Verlag Stuttgart · New York

2804
Y. Xie et al.
PAPER
Table 1 Optimization of Reaction Conditionsa
O
O
O
O
catalyst (20 mol%), oxidant
solvent
OMe
+
Ph
OMe
Ph
2a
3a
1a
Entry
1
Catalyst
none
Solvent
Oxidant
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
TBHP
AIBN
O2
Yield (%)b
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1.4-dioxane
MeCN
THF
n.r.
2
Fe(acac)3
FeCl3
15
3
48 (21)c
63
4
FeCl2
5
FeCl2·4H2O
FeCl2
39
6
trace
trace
trace
trace
trace
trace
35
7
FeCl2
8
FeCl2
9
FeCl2
toluene
MeNO2
DMSO
DCE
10
11
12
13
14
15
16
17
FeCl2
FeCl2
FeCl2
FeCl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
trace
trace
n.r.
FeCl2
FeCl2
FeCl2
none
n.r.
FeCl2
DDQ
42d
a Reaction conditions: 1a (0.3 mmol, 1.0 equiv), 2a (0.36 mmol, 1.2 equiv), catalyst (20 mol%), oxidant (1.2 equiv), solvent (1.5 mL), 30 °C,
15 h.
b Isolated yields based on 1a.
c By-product 4a was obtained in 21% yield.
d The reaction was carried out under N2 atmosphere.
the aryl ring of propargyl ether were tolerated to give rea- conditions (entries 13–15) and gave the two diastereo-
sonable yields (Table 2, entries 2–5). It is noteworthy that mers.
the presence of C–X bond (X = F, Cl, and Br) in the aryl
During the optimization of reaction conditions for this
propargyl ethers did not alter the reaction pathway (entries
alkylation reaction using iron(III) chloride as catalyst,
6–9), and the produced halogen containing propargyl de-
(E)-2-(methoxymethyl)-1,5-diphenylpent-2-en-4-yn-1-
one (4a) was isolated in 21% yield (Table 1, entry 3).
rivatives could be further functionalized to construct more
complex structures. ortho-Substituted aryl propargyl
ethers delivered lower yield compared with its meta or
para analogues (entries 2, 9). Stronger electron-donating
Since ynenones are versatile scaffolds in organic synthe-
sis,13 the reaction for the formation of ynenones was in-
vestigated as shown in Table 3. It was found that ynenone
products could be obtained by the combination of iron(III)
substituent (OMe) at the para-position of the phenyl ring
gave the product in lower yield (entry 5). It was important
chloride and 1.2 equivalents of DDQ when only aryl pro-
that the heterocycle thiophene was well tolerated to this
pargyl ether was used as the substrate (27% of 4a was sep-
arated when 20% of iron(III) chloride was used). Thus, a
reaction (entry 10). Propargyl allyl ether and propargyl
benzyl ether could also be used in this novel iron-cata-
variety of ynenones could be prepared by the use of di-
lyzed C–H transformation under the standard reaction
verse aryl propargyl ethers. 1H NMR indicates the ob-
conditions (entries 11, 12). The cyclic dicarbonyl deriva-
tained ynenones are E/Z mixtures and the major isomer is
the E-isomer (confirmed by nuclear Overhauser effect
tives, like the linear dicarbonyl compounds, were also
found to undergo smoothly under the standard reaction
Synthesis 2011, No. 17, 2803–2809 © Thieme Stuttgart · New York

PAPER
Functionalization of an sp3 C–H Bond Adjacent to Oxygen
2805
Table 2 Iron(II) Chloride Catalyzed Direct Functionalization of
Propargyl Ethers with b-Dicarbonyl Compoundsa
Table 3 Ynenone Formation through Arylpropargyl Methyl Ethera
OMe
FeCl3, DDQ (1.2 equiv)
Ar
OMe
R3
CH2Cl2, 30 °C, air, 15 h
Ar
O
O
Ar
R2
O
O
FeCl2 (20 mol%), DDQ
CH2Cl2, 30 °C, air
O
H
O
+
Ar
O
1
4
R3
Ar
R2
Entry
1
Product Yield (%)b
1
2
3
Entry
1
1
Product Yield (%)b
1
2
3
4
5
6
7
1a
1b
1c
1d
1f
Ar = Ph
4a
4b
4c
4d
4e
4f
57 (93:7)
38 (82:18)
51 (92:8)
45 (60:40)
35 (93:7)
43 (91:9)
51 (86:14)
1a
1b
1c
1d
1e
1f
Ar = Ph
R2 = Me
3a
3b
3c
3d
3e
3f
63
45
64
52
37
47
56
35
41
61
40
46
Ar = 2-MeC6H4
Ar = 3-MeC6H4
Ar = 4-MeC6H4
Ar = 4-ClC6H4
Ar = 4-BrC6H4
Ar = 4-FC6H4
2
3
Ar = 2-MeC6H4
R2 = Me
Ar = 3-MeC6H4
R2 = Me
1g
1h
4
Ar = 4-MeC6H4
R2 = Me
4g
a Reaction conditions: propargyl ether (0.3 mmol, 1.0 equiv), FeCl3
(0.3 mmol), DDQ (1.2 equiv), CH2Cl2 (1.5 mL), 30 °C, 15 h.
b Isolated yields. The E/Z ratios showed in the parentheses were deter-
mined by 1H NMR of the crude products.
5
Ar = 4-MeOC6H4
R2 = Me
6
Ar = 4-ClC6H4
R2 = Me
7
1g
1h
1i
Ar = 4-BrC6H4
R2 = Me
3g
3h
3i
ride catalyzed this C–H bond functionalization reaction,
and less yields were obtained by the use of iron(III) chlo-
ride due to the formation of ynenones. Therefore, we sup-
posed that the iron salts mainly played the role of Lewis
acid to activate the 1,3-diketones.4b,12a,15 Based on the pre-
vious studies and our results, a plausible mechanism ac-
counting for the alkylation reaction is depicted in
Scheme 1. The oxidation of propargyl ether via a single
electron transfer process by DDQ generates the interme-
diate I. The reaction of b-dicarbonyl compound 2 activat-
ed by iron salt with the intermediate I proceeds to give the
alkylated product 3. However, the iron(II)-catalyzed oxi-
dative radical processes can not be excluded.14,16
8
Ar = 4-FC6H4
R2 = Me
9
Ar = 2-BrC6H4
R2 = Me
10
11
12
1j
Ar = 2-thienyl
R2 = Me
3j
1k
1l
Ar = Ph
3k
3l
R2 = CH2CH=CH2
Ar = Ph
R2 = Bn
62 (1:1)c
43 (1:1)c
49 (1.8:1)c
The formation of ynenones in the presence of iron(III)
chloride and DDQ is proposed as shown in Scheme 2.
Treatment of 1a with iron(III) chloride/DDQ affords the
intermediate A, which undergoes electrophilic reaction
with propargyl methyl ethers to give the cationic interme-
diate B. The intermediate B is trapped by water to give in-
termediate C, which generates the intermediate D after the
deprotonation. The final desired product enynone 4a is
produced by the enolization and elimination of water. Pro-
pynal 1a¢ was detected when propargyl ether 1a was treat-
ed with DDQ, which partially supports the proposed
mechanism.
13
14
15
1a
1b
1a
3m
3n
3o
a Reaction conditions: propargyl ether (0.3 mmol, 1.0 equiv), b-dicar-
bonyl compound (0.36 mmol, 1.2 equiv), FeCl2 (20 mol%), DDQ (1.2
equiv), CH2Cl2 (1.5 mL), 30 °C, 15 h.
b Isolated yields.
c The ratio was determined by 1H NMR spectroscopy.
spectroscopy for 4a and 4e, see Supporting Information).
Aryl propargyl methyl ethers bearing both electron-donat-
ing and electron-withdrawing substituents in the aryl ring
such as methyl, F, Cl, and Br tolerated the reaction condi-
tions to afford the diverse ynenones smoothly (Table 3,
entries 1–7).
In conclusion, we have developed a new iron-catalyzed
protocol for the oxidative dehydrogenative coupling of
propargyl ethers with b-dicarbonyl compounds. The reac-
tion provides a convenient way for the alkylation of prop-
argyl ethers through the cleavage of sp3 C–H bond
adjacent to oxygen atom. Furthermore, ynenones were
prepared under very mild reaction conditions.
DDQ is a well-known oxidant and has been applied in
transition-metal-catalyzed C–H cleavage reactions.4b,14 In
our experiment, both iron(II) chloride and iron(III) chlo-
Synthesis 2011, No. 17, 2803–2809 © Thieme Stuttgart · New York

2806
Y. Xie et al.
PAPER
O
O
Cl
Cl
CN
CN
R2
O
O
H
R3
Fe
Ln
O
R2
Ar
O
OH
O
I
Ar
1
Cl
Cl
CN
CN
O
O
R3
R3
OH
OH
2
O
O
R2
Cl
Cl
CN
CN
[Fe]
+
O
Ar
3
Scheme 1 A plausible mechanism for the alkylation reaction
OMe
DDQ
1a
O
OMe
OH
H
FeCl3
1a
1a'
A
H
OH
H
OH
O
H
H
O
OMe
OMe
O
B
C
H
OH OH
– H+
– H2O
OMe
OMe
4a
D
Scheme 2 A plausible mechanism for the ynenone (formation of the minor Z-isomer is omitted for clarity)
3-(1-Methoxy-3-phenylprop-2-ynyl)-3-methylpentane-2,4-di-
one (3a); Typical Procedure
Starting materials and solvents were purchased from common com-
mercial sources and were used without additional purification. All
reagents were weighed and handled in air at r.t. H NMR spectra
1
To a mixture of FeCl2 (8 mg, 0.06 mmol, 20 mol%) and DDQ (82
mg, 0.36 mmol, 1.2 equiv) were added (3-methoxyprop-1-
ynyl)benzene (1a; 44 mg, 0.3 mmol, 1.0 equiv), 3-methylpentane-
2,4-dione (2a; 41 mg, 0.36 mmol, 1.2 equiv) and CH2Cl2 (1.5 mL)
was added at r.t. Then the reaction vessel was capped and the reac-
tion temperature was raised to 30 °C for 15 h. The solvent was then
removed and the residue was purified by flash column chromatog-
raphy on silica gel (eluent: PE–EtOAc, 20:1) to give 3a; yield: 49
mg (63%) (Table 2).
1H NMR (400 MHz, CDCl3): d = 7.41 (d, J = 8.0 Hz, 2 H), 7.29–
7.33 (m, 3 H), 5.00 (s, 1 H), 3.48 (s, 3 H), 2.22 (s, 3 H), 2.20 (s, 3
H), 1.59 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 14.7, 26.9, 27.2, 57.2, 71.3, 73.9,
84.2, 88.2, 121.9, 128.3, 128.8, 131.8, 204.2, 204.3.
were recorded on Bruker Avance DMX 400 MHz spectrometers
and the chemical shifts were reported in parts per million (d) rela-
tive to internal standard TMS (0 ppm) for CDCl3. The coupling con-
stants, J, are reported in hertz (Hz). 13C NMR spectra were obtained
at 75 MHz spectrometers and referenced to the internal solvent sig-
nals (central peak is 77.0 ppm in CDCl3). Column chromatographic
purification was carried out on silica gel (300–400 mesh) purchased
from Yinlong Company. The eluent was a mixture of petroleum
ether (PE) and EtOAc, unless otherwise mentioned. PE used refers
to the fraction boiling in the range 60–90 °C. Mass spectrometry
data of the product of the reaction was collected on a HRMS-EI in-
strument.
Synthesis 2011, No. 17, 2803–2809 © Thieme Stuttgart · New York

PAPER
Functionalization of an sp3 C–H Bond Adjacent to Oxygen
2807
HRMS (EI): m/z [M]+ calcd for C16H18O3: 258.1256; found:
3-[3-(4-Fluorophenyl)-1-methoxyprop-2-ynyl]-3-methylpen-
258.1246.
tane-2,4-dione (3h)
1H NMR (400 MHz, CDCl3): d = 7.40 (dd, J = 8.4, 5.6 Hz, 2 H),
7.00 (t, J = 8.4 Hz, 2 H), 4.99 (s, 1 H), 3.47 (s, 3 H), 2.22 (s, 3 H),
2.19 (s, 3 H), 1.58 (s, 3 H).
3-(1-Methoxy-3-o-tolylprop-2-ynyl)-3-methylpentane-2,4-di-
one (3b)
1H NMR (400 MHz, CDCl3): d = 7.38 (d, J = 7.2 Hz, 1 H), 7.18–
7.25 (m, 2 H), 7.12 (t, J = 7.2 Hz, 1 H), 5.06 (s, 1 H), 3.49 (s, 3 H),
2.39 (s, 3 H), 2.23 (s, 3 H), 2.20 (s, 3 H), 1.59 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 14.6, 26.7, 27.1, 57.1, 71.2, 73.8,
83.9, 87.0, 115.5 (d, JC,F = 21.3 Hz), 118.0 (d, JC,F = 3.8 Hz), 133.7
(d, JC,F = 8.4 Hz), 162.6 (d, JC,F = 249.0 Hz), 204.0, 204.1.
HRMS (EI): m/z [M]+ calcd for C16H17FO3: 276.1162; found:
276.1164.
13C NMR (100 MHz, CDCl3): d = 14.8, 20.7, 26.9, 27.3, 57.2, 71.3,
74.0, 87.1, 88.0, 121.8, 125.5, 128.8, 129.5, 132.2, 140.3, 204.3.
HRMS (EI): m/z [M]+ calcd for C17H20O3: 272.1412; found:
272.1428.
3-[3-(2-Bromophenyl)-1-methoxyprop-2-ynyl]-3-methylpen-
tane-2,4-dione (3i)
3-(1-Methoxy-3-m-tolylprop-2-ynyl)-3-methylpentane-2,4-di-
one (3c)
1H NMR (400 MHz, CDCl3): d = 7.57 (d, J = 7.6 Hz, 1 H), 7.45 (dd,
J = 8.0, 1.6 Hz, 1 H), 7.26 (t, J = 7.2 Hz, 1 H), 7.16 (td, J = 8.0, 1.6
Hz, 1 H), 5.01 (s, 1 H), 3.52 (s, 3 H), 2.24 (s, 3 H), 2.22 (s, 3 H),
1.63 (s, 3 H).
1H NMR (400 MHz, CDCl3): d = 7.11–7.21 (m, 4 H), 4.98 (s, 1 H),
3.46 (s, 3 H), 2.30 (s, 3 H), 2.21 (s, 3 H), 2.18 (s, 3 H), 1.56 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 14.7, 21.1, 26.9, 27.2, 57.2, 71.3,
73.9, 83.7, 88.4, 121.7, 128.2, 128.9, 129.7, 132.3, 138.0, 204.3,
204.3.
13C NMR (100 MHz, CDCl3): d = 14.8, 27.0, 27.2, 57.3, 71.3, 73.9,
86.5, 88.9, 124.2, 125.5, 127.0, 130.0, 132.4, 133.6, 204.1, 204.2.
HRMS (EI): m/z [M]+ calcd for C16H17BrO3: 336.0361; found:
336.0354.
HRMS (EI): m/z [M]+ calcd for C17H20O3: 272.1412; found:
272.1422.
3-(1-Methoxy-3-thiophen-2-ylprop-2-ynyl)-3-methylpentane-
2,4-dione (3j)
3-(1-Methoxy-3-p-tolylprop-2-ynyl)-3-methylpentane-2,4-di-
one (3d)
1H NMR (400 MHz, CDCl3): d = 7.28 (s, 1 H), 7.21 (d, J = 3.6 Hz,
1 H), 6.97 (t, J = 4.2 Hz, 1 H), 5.02 (s, 1 H), 3.46 (s, 3 H), 2.21 (s,
3 H), 2.18 (s, 3 H), 1.58 (s, 3 H).
1H NMR (400 MHz, CDCl3): d = 7.30 (d, J = 8.0 Hz, 2 H), 7.11 (d,
J = 7.6 Hz, 2 H), 4.99 (s, 1 H), 3.47 (s, 3 H), 2.34 (s, 3 H), 2.22 (s,
3 H), 2.20 (s, 3 H), 1.58 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 14.7, 26.8, 27.1, 57.2, 71.2, 74.0,
81.4, 88.2, 121.7, 126.9, 127.7, 132.7, 204.0, 204.1.
HRMS (EI): m/z [M]+ calcd for C14H16O3S: 221.0636 [M – 43];
found: 221.0626 [M – 43].
13C NMR (100 MHz, CDCl3): d = 14.7, 21.5, 26.9, 27.3, 57.2, 71.3,
73.9, 83.4, 88.3, 118.8, 129.0, 131.7, 139.0, 204.4.
HRMS (EI): m/z [M]+ calcd for C17H20O3: 272.1412; found:
272.1419.
3-[1-(Allyloxy)-3-phenylprop-2-ynyl]-3-methylpentane-2,4-di-
one (3k)
3-[1-Methoxy-3-(4-methoxyphenyl)prop-2-ynyl]-3-methylpen-
tane-2,4-dione (3e)
1H NMR (400 MHz, CDCl3): d = 7.40–7.42 (m, 2 H), 7.29–7.34 (m,
3 H), 5.87–5.93 (m, 1 H), 5.32 (dd, J = 17.2, 2 Hz, 1 H), 5.23 (d,
J = 10.4 Hz, 1 H), 5.15 (s, 1 H), 4.33–4.37 (m, 1 H), 4.02–4.06 (m,
1 H), 2.24 (s, 3 H), 2.20 (s, 3 H), 1.61 (s, 3 H).
1H NMR (400 MHz, CDCl3): d = 7.35 (d, J = 8.4 Hz, 2 H), 6.83 (d,
J = 8.4 Hz, 2 H), 4.99 (s, 1 H), 3.81 (s, 3 H), 3.47 (s, 3 H), 2.22 (s,
3 H), 2.20 (s, 3 H), 1.58 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 204.5, 159.9, 133.3, 114.0, 113.9,
88.2, 82.7, 73.9, 71.3, 57.2, 55.3, 27.3, 26.9, 14.8.
13C NMR (100 MHz, CDCl3): d = 14.9, 26.9, 27.3, 70.2, 71.2, 71.4,
84.4, 88.1, 117.9, 122.0, 128.3, 128.8, 131.8, 133.5, 204.3, 204.4.
HRMS (EI): m/z [M]+ calcd for C17H20O4: 288.1362; found:
HRMS (EI): m/z [M]+ calcd for C18H20O3: 284.1412; found:
288.1366.
284.1404.
3-[3-(4-Chlorophenyl)-1-methoxyprop-2-ynyl]-3-methylpen-
tane-2,4-dione (3f)
3-(1-(Benzyloxy)-3-phenylprop-2-ynyl)-3-methylpentane-2,4-
dione (3l)
1H NMR (400 MHz, CDCl3): d = 7.34 (d, J = 8.4 Hz, 2 H), 7.28 (d,
J = 8.4 Hz, 2 H), 4.99 (s, 1 H), 3.47 (s, 3 H), 2.22 (s, 3 H), 2.19 (s,
3 H), 1.58 (s, 3 H).
1H NMR (400 MHz, CDCl3): d = 7.41–7.43 (m, 2 H), 7.30–7.35 (m,
8 H), 5.15 (s, 1 H), 4.88 (d, J = 11.6 Hz, 1 H), 4.58 (d, J = 12.0 Hz,
1 H), 2.172 (s, 3 H), 2.168 (s, 3 H), 1.62 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 14.7, 26.8, 27.2, 57.3, 71.2, 73.8,
13C NMR (100 MHz, CDCl3): d = 15.0, 26.9, 27.2, 71.2, 71.2, 71.5,
84.3, 84.4, 122.0, 128.0, 128.1, 128.3, 128.4, 128.8, 131.8, 137.0,
204.2, 204.5.
85.2, 87.0, 120.4, 128.7, 133.0, 134.9, 204.0, 204.2.
HRMS (EI): m/z [M[+ calcd for C16H17ClO3: 292.0866; found:
292.0854.
HRMS (EI): m/z [M]+ calcd for C22H22O3: 334.1569; found:
334.1556.
3-[3-(4-Bromophenyl)-1-methoxyprop-2-ynyl]-3-methylpen-
tane-2,4-dione (3g)
2-Acetyl-2-(1-methoxy-3-phenylprop-2-ynyl)cyclopentanone
(3m)
1H NMR (400 MHz, CDCl3): d = 7.45 (d, J = 8.4 Hz, 2 H), 7.27 (d,
J = 8.4 Hz, 2 H), 5.00 (s, 1 H), 3.47 (s, 3 H), 2.22 (s, 3 H), 2.19 (s,
3 H), 1.58 (s, 3 H).
1H NMR (400 MHz, CDCl3): d = 7.38–7.41 (m, 2 H), 7.29–7.34 (m,
3 H), 4.92 (s, 1 H), 3.44 (s, 3 H), 2.71–2.77 (m, 1 H), 2.28–2.36 (m,
6 H), 1.96–2.06 (m, 1 H), 1.81–1.91 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.6, 26.7, 27.1, 57.2, 71.2, 73.8,
85.4, 87.0, 120.8, 123.0, 131.5, 133.1, 203.9, 204.1.
HRMS (EI): m/z [M]+ calcd for C16H17BrO3: 336.0361; found:
336.0208.
13C NMR (100 MHz, CDCl3): d = 19.7, 26.1, 26.8, 39.4, 57.4, 73.3,
73.5, 84.1, 87.6, 121.8, 128.3, 128.8, 131.8, 200.4, 212.6.
HRMS (EI): m/z [M]+ calcd for C17H18O3: 270.1256; found:
270.1269.
Synthesis 2011, No. 17, 2803–2809 © Thieme Stuttgart · New York

2808
Y. Xie et al.
PAPER
2-Acetyl-2-(1-methoxy-3-o-tolylprop-2-ynyl)cyclopentanone
(3n)
1H NMR (400 MHz, CDCl3): d = 7.58 (d, J = 9.2 Hz, 2 H), 7.36 (t,
J = 7.2 Hz, 2 H), 7.31 (d, J = 7.6 Hz, 2 H), 7.26 (t, J = 7.2 Hz, 1 H),
7.20 (d, J = 7.2 Hz, 1 H), 6.52 (s, 1 H), 4.61 (s, 2 H), 3.46 (s, 3 H),
2.42 (s, 3 H), 2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 21.2, 21.3, 58.9, 68.5, 84.5, 103.7,
122.1, 123.7, 126.7, 128.2, 128.4, 128.9, 129.9, 130.3, 132.3, 133.2,
137.4, 138.3, 138.3, 146.2, 196.2.
1H NMR (400 MHz, CDCl3): d = 7.36 (d, J = 8.0 Hz, 1 H), 7.23 (d,
J = 7.2 Hz, 1 H), 7.19 (d, J = 7.2 Hz, 1 H), 7.13 (t, J = 7.2 Hz, 1 H),
4.97 (s, 1 H), 3.46 (s, 3 H), 2.73–2.79 (m, 1 H), 2.37 (s, 3 H), 2.33
(s, 3 H), 2.28–2.35 (m, 3 H), 1.96–2.06 (m, 1 H), 1.81–1.93 (m, 1
H).
13C NMR (100 MHz, CDCl3): d = 19.7, 20.6, 26.1, 26.8, 39.4, 57.3,
73.4, 73.6, 86.5, 88.0, 121.6, 125.5, 128.8, 129.5, 132.2, 140.4,
200.2, 212.6.
HRMS (EI): m/z [M]+ calcd for C21H20O2: 304.1463; found:
304.1465.
HRMS (EI): m/z [M]+ calcd for C18H20O3: 284.1412; found:
284.1408.
(E)-2-(Methoxymethyl)-1,5-di-p-tolylpent-2-en-4-yn-1-one (4d)
E/Z = 60:40.
1H NMR (400 MHz, CDCl3): d = 7.71 (d, J = 8.0 Hz, 2 H), 7.39 (d,
J = 8.0 Hz, 2 H), 7.26 (d, J = 8.0 Hz, 2 H), 7.17 (d, J = 8.0 Hz, 2 H),
6.50 (s, 1 H), 4.60 (s, 2 H), 3.45 (s, 3 H), 2.42 (s, 3 H), 2.38 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 21.6, 21.6, 58.8, 68.7, 84.4, 103.5,
119.3, 123.2, 129.0, 129.3, 129.7, 131.7, 134.7, 139.8, 143.3, 146.1,
195.7.
2-Acetyl-2-(1-methoxy-3-phenylprop-2-ynyl)cyclohexanone
(3o)
1H NMR (400 MHz, CDCl3): d = 7.43–7.45 (m, 2 H), 7.30–7.34 (m,
3 H), 5.03 (s, 1 H), 3.45 (s, 3 H), 2.62–2.68 (m, 1 H), 2.46–2.51 (m,
1 H), 2.26–2.29 (m, 1 H), 2.24 (s, 3 H), 1.96–2.07 (m, 2 H), 1.80–
1.89 (m, 2 H), 1.67–1.73 (m, 1 H).
HRMS (EI): m/z [M]+ calcd for C21H20O2: 304.1463; found:
304.1466.
13C NMR (100 MHz, CDCl3): d = 22.2, 26.3, 26.8, 30.2, 41.5, 57.2,
71.6, 73.9, 84.6, 88.5, 122.2, 128.3, 128.7, 131.8, 203.5, 206.9.
HRMS (EI): m/z [M]+ calcd for C18H20O3: 284.1412; found:
284.1413.
(E)-1,5-Bis(4-chlorophenyl)-2-(methoxymethyl)pent -2-en-4-
yn-1-one (4e)
E/Z = 93:7.
Compounds 4; General Procedure
1H NMR (400 MHz, CDCl3): d = 7.75 (d, J = 8.4 Hz, 2 H), 7.42–
7.46 (m, 4 H), 7.35 (d, J = 8.8 Hz, 2 H), 6.46 (s, 1 H), 4.57 (s, 2 H),
3.44 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 59.0, 68.6, 85.4, 102.3, 120.6,
122.9, 128.8, 129.0, 130.9, 133.0, 135.5, 135.7, 139.9, 146.4, 194.6.
HRMS (EI): m/z [M]+ calcd for C19H14Cl2O2: 344.0371; found:
344.0378.
To a mixture of FeCl3 (49 mg, 0.3 mmol), DDQ (82 mg, 0.36 mmol,
1.2 equiv) in a 35 mL reaction tube were added (3-alkoxyprop-1-
ynyl)benzene 1 (0.3 mmol, 1.0 equiv) and CH2Cl2 (1.5 mL) at r.t.
Then the reaction vessel was capped and the reaction temperature
was raised to 30 °C for 15 h. The solvent was then removed and the
residue was purified by flash column chromatography on silica gel
(PE–EtOAc, 20:1) to give the desired product (Table 3). The E/Z-
isomers were difficult to separate; therefore the spectral data of only
the major E-isomer were extracted from the spectra of the E/Z-mix-
ture and are listed below.
(E)-1,5-Bis(4-bromophenyl)-2-(methoxymethyl) pent-2-en-4-
yn-1-one (4f)
E/Z = 91:9.
(E)-2-(Methoxymethyl)-1,5-diphenylpent-2-en-4-yn-1-one (4a)
E/Z = 93:7.
1H NMR (400 MHz, CDCl3): d = 7.80 (d, J = 8.0 Hz, 2 H), 7.57 (d,
J = 7.6 Hz, 1 H), 7.45–7.51 (m, 4 H), 7.36–7.39 (m, 3 H), 6.53 (s, 1
H), 4.61 (s, 2 H), 3.46 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 58.9, 68.5, 84.7, 103.5, 122.2,
123.7, 128.4, 128.5, 129.4, 129.5, 131.8, 132.5, 137.3, 146.2, 196.0.
1H NMR (400 MHz, CDCl3): d = 7.67 (d, J = 8.4 Hz, 2 H), 7.61 (d,
J = 8.0 Hz, 2 H), 7.51 (d, J = 8.0 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H),
6.45 (s, 1 H), 4.56 (s, 2 H), 3.44 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 59.0, 68.6, 85.6, 102.4, 121.0,
123.0, 124.0, 127.7, 131.0, 131.8, 131.9, 133.2, 136.0, 146.4, 194.8.
HRMS (EI): m/z [M]+ calcd for C19H14Br2O2: 431.9361; found:
431.9352.
HRMS (EI): m/z [M]+ calcd for C19H16O2: 276.1150; found:
276.1154.
(E)-1,5-Bis(4-fluorophenyl)-2-(methoxymethyl)pent-2-en-4-yn-
1-one (4g)
E/Z = 86:14.
(E)-2-(Methoxymethyl)-1,5-di-o-tolylpent-2-en-4-yn-1-one (4b)
E/Z = 82:18.
1H NMR (400 MHz, CDCl3): d = 7.83–7.87 (m, 2 H), 7.47–7.50 (m,
2 H), 7.15 (t, J = 8.4 Hz, 2 H), 7.07 (t, J = 8.6 Hz, 2 H), 6.45 (s, 1
H), 4.58 (s, 2 H), 3.45 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 59.0, 68.7, 84.3, 102.2, 115.6 (d,
JC,F = 21.5 Hz), 115.9 (d, JC,F = 22.1 Hz), 118.3 (d, JC,F = 3.5 Hz),
122.7, 132.1 (d, JC,F = 9.2 Hz), 133.5 (d, JC,F = 3.2 Hz), 133.8 (d,
JC,F = 8.6 Hz), 146.3, 163.2 (d, JC,F = 250.4 Hz), 165.4 (d,
1H NMR (400 MHz, CDCl3): d = 7.43 (d, J = 8.0 Hz, 1 H), 7.36 (t,
J = 7.2 Hz, 1 H), 7.31 (t, J = 6.4 Hz, 2H), 7.27 (s, 1 H), 7.23–7.24
(m, 2 H), 7.18 (t, J = 7.2 Hz, 1 H), 6.57 (s, 1 H), 4.58 (s, 2 H), 3.47
(s, 3 H), 2.47 (s, 3 H), 2.35 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 19.7, 20.7, 58.9, 67.1, 88.9, 104.7,
122.0, 125.3, 125.8, 127.4, 128.0, 129.7, 130.0, 130.1, 130.9, 131.4,
132.4, 136.4, 138.2, 140.7, 146.3, 198.4.
JC,F = 252.8 Hz), 194.4.
HRMS (EI): m/z [M]+ calcd for C21H20O2: 304.1463; found:
304.1469.
HRMS (EI): m/z [M]+ calcd for C19H14F2O2: 312.0962; found:
312.0970.
(E)-2-(Methoxymethyl)-1,5-di-m-tolylpent-2-en-4-yn-1-one (4c)
E/Z = 92:8.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Synthesis 2011, No. 17, 2803–2809 © Thieme Stuttgart · New York

PAPER
Functionalization of an sp3 C–H Bond Adjacent to Oxygen
2809
(7) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi,
F.; Murai, S. J. Am. Chem. Soc. 2001, 123, 10935.
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Acknowledgment
Funding from National Basic Research Program of China (No.
2011CB936003) and NSFC (No. 20872126, No. 2107216) is highly
acknowledged.
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Synthesis 2011, No. 17, 2803–2809 © Thieme Stuttgart · New York