Copper-catalyzed tandem C-C/C-O bond-forming reactions of ortho-halo-β-chlorostyrenes with ketones: Synthesis of 4- trifluoromethylbenzoxepines

Article abstract of DOI:10.1002/adsc.201200784

A copper-catalyzed cyclization reaction of trifluoromethyl-containing ortho-halo-β-chlorostyrenes with ketones has been developed. Using a combination of copper(I) bromide, 2,2,6,6-tetramethylheptane-3,5-dione and sodium tert-butoxide, a variety of 4-trifluoromethylbenzoxepines was prepared in moderate to good yields by the tandem a-alkenylation of ketones with subsequent O-arylation.

Full text of DOI:10.1002/adsc.201200784

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DOI: 10.1002/adsc.201200784
À
À
Copper-Catalyzed Tandem C C/C O Bond-Forming Reactions
of ortho-Halo-b-chlorostyrenes with Ketones: Synthesis of
4-Trifluoromethylbenzoxepines
Lei-Lei Sun,a Bo-Lun Hu,a Ri-Yuan Tang,a Chen-Liang Deng,a
and Xing-Guo Zhanga,*
a
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, Peopleꢀs Republic of China
Fax : (+86)-577-8668-9615; phone: (+86)-577-8668-9615; e-mail: zxg@wzu.edu.cn
Received: August 30, 2012; Revised: November 5, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200784.
Abstract: A copper-catalyzed cyclization reaction of
trifluoromethyl-containing ortho-halo-b-chlorostyr-
enes with ketones has been developed. Using a com-
bination of copper(I) bromide, 2,2,6,6-tetramethyl-
heptane-3,5-dione and sodium tert-butoxide, a varie-
ty of 4-trifluoromethylbenzoxepines was prepared
in moderate to good yields by the tandem a-alkeny-
lation of ketones with subsequent O-arylation.
Recently, reports in the literature have highlighted
the copper-catalyzed carbon-oxygen bond forming re-
actions.[9] The palladium-catalyzed direct a-arylation
of ketones has also become a general methodology
for the synthesis of a-aryl ketones.[10] A copper-cata-
lyzed a-arylation of activated methylene compounds,
including malonates[11] and b-keto esters[12] has also
been developed. To the best of our knowledge, how-
ever, the copper-catalyzed a-arylation or alkenylation
of simple ketones still remains a challenging area for
exploration. As part of our ongoing studies towards
the synthesis of trifluoromethylated aromatic com-
pounds,[13] we have been investigating the preparation
of CF3-contanning benzoxepines from our previously
Keywords: benzoxepines; copper; ortho-halo-b-
chlorostyrenes; ketones; tandem reactions
À
À
reported building blocks via a tandem C C/C O
Benzoxepines are an important class of heterocyclic bond-forming reaction. Herein, we report a simple
compounds and widely represented in a variety of dif- and efficient protocol for the synthesis of 4-trifluoro-
ferent biologically active molecules,[1] including natu- methylbenzo[b]oxepines by the copper-catalyzed
ral products,[2] and natural herbicides.[3] Consequently, tandem a-alkenylation of ketones with a subsequent
extensive research efforts have been focused on the O-arylation reaction (Scheme 1).
development of methods for constructing the benzox-
The reaction of 1-bromo-2-(2-chloro-3,3,3-trifluoro-
epine ring.[4] The majority of the traditional ap- prop-1-en-1-yl)benzene (1a)[14] with acetophenone
proaches available for the assembly of these mole- (2a) was used as a model reaction to screen for the
cules involve multistep transformations and harsh re- optimal reaction conditions, and the results are sum-
action conditions.[5] In contrast, transition metal-cata- marized in Table 1. Initially, treatment of substrate 1a
lyzed cyclization reactions provide a straightforward with acetophenone (2a), CuI (10 mol%), and t-
access to these benzoxepines. For example, Lu[6] re- BuONa (3 equiv.) in DMF at 1008C afforded the de-
ported the synthesis of 1-benzoxepines by two cation- sired product 3 in 56% yield (entry 1). The structure
ic palladium-catalyzed [5+2]annulation reactions.[6] of product 3 was confirmed by an X-ray single-crystal
Ramachary et al.[7] also developed a ruthenium-cata- diffraction analysis (Figure 1).[15] Inspired by some of
À
lyzed ring closing metathesis (RCM) reaction for the the ligand-accelerated C O bond-forming reactions
synthesis of highly substituted benzo[b]oxepines. Al-
though the incorporation of a CF3 group into aromat-
ics often enhances their biological activity and has
come to represent a powerful and widely used strat-
egy in the process of drug design, to date, no synthetic
methods have been reported for the synthesis of tri-
fluoromethylated benzoxepines.[8]
Scheme 1. Synthesis of 4-trifluoromethylbenzoxepines.
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Table 1. Screening or the reaction conditions.[a]
Entry [Cu]
Ligand Base
Solvent Temp. Yield
[oC]
[%][b]
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr L2
CuCl L2
Cu2O L2
–
t-BuONa DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
56
57
78
68
71
67
65
80
58
64
30
40
Figure 1. X-ray crystallographic structure of compound 3
L1
L2
L3
L4
L5
L6
t-BuONa DMF
t-BuONa DMF
t-BuONa DMF
t-BuONa DMF
t-BuONa DMF
t-BuONa DMF
t-BuONa DMF
t-BuONa DMF
t-BuONa DMF
t-BuONa DMF
ganic bases were evaluated. The use of other strong
bases, such as KOH and Cs2CO3, also worked well
and provided the product in moderate yields (en-
tries 12 and 13). The use of weaker bases, however,
such as K3PO4 and K2CO3 (entries 14 and 15) resulted
only in the isolation of trace amounts of the product.
Finally, the effect of the solvent was examined (en-
tries 16–18). DMSO provided the best results, with
the product being obtained in 82% yield (entry 16).
Lower yields were observed when the reaction was
conducted at 80 or 1208C (entries 19 and 20). It is
noteworthy that the trifluoromethyl group played an
important role in this annulation reaction, in that only
a trace amount of the product was detected when 1-
bromo-2-(2-chlorovinyl)benzene was used as the sub-
strate (entry 21). In addition, the yield of product 3
was independent of the E/Z ratio of 1a, with the same
9
10
11
12
13
14
15
16
17
18
19
20
21[c]
–
L2
CuBr L2
CuBr L2
CuBr L2
CuBr L2
CuBr L2
CuBr L2
CuBr L2
CuBr L2
CuBr L2
CuBr L2
KOH
DMF
DMF
DMF
DMF
Cs2CO3
K3PO4
K2CO3
54
trace
trace
82
<5
0
51
70
trace
t-BuONa DMSO 100
t-BuONa NMP 100
t-BuONa toluene 100
t-BuONa DMSO 80
t-BuONa DMSO 120
t-BuONa DMSO 100
[a]
Reaction conditions: 1a (0.2 mmol), 2a (0.22 mmol), [Cu]
(10 mol%), ligand (20 mol%) and base (3 equiv.) in sol- yield being observed when either mixtures of 1a (Z/
E=82:18)[14c] or 1a (Z/E=95:5)[14d] were used.
To explore the substrate scope of this tandem reac-
tion in greater detail, a variety of different o-bromo-
vent (2 mL) under an N2 atmosphere for 4 h.
Isolated yield.
1-bromo-2-(2-chlorovinyl)benzene was used as substrate.
[b]
[c]
b-chlorostyrenes and ketones was examined under the
standard reaction conditions (Table 2). Firstly, the re-
reported in the literature,[16] we proceeded to investi- actions between ketones and substrate 1a were evalu-
gate some bidentate ligands with the aim of increasing ated in the presence of CuBr, TMHD and t-BuONa.
the yield of the reaction (entries 2–7). Pleasingly, all The results indicated that both aromatic and aliphatic
of the ligands promoted the tandem reaction, with ketones were suitable substrates for the tandem reac-
2,2,6,6-tetramethylheptane-3,5-dione (TMHD) L2 tions and could be converted successfully to the corre-
providing the best result with a yield of 78% sponding products in moderate to good yields. In gen-
(entry 3). Subsequently, we proceeded to evaluate eral, aromatic ketones bearing electron-donation
a variety of different copper catalysts to optimize the groups, such as methyl and methoxy groups, provided
reaction conditions. CuBr was found to be superior to higher yields than those bearing electron-withdrawing
CuI and the other copper salts tested, including CuCl group, such as CF3, nitro and cyano groups. For exam-
and Cu2O (entries 8–10). It is noteworthy that a 30% ple, substrates bearing a 4-methoxyphenyl or 4-nitro-
yield of product was still obtained in the absence of phenyl group underwent the tandem reaction with
a copper catalyst, which suggested that the t-BuONa substrate 1a to afford the corresponding products 6
probably played a key role in the transformation and 13 in 83 and 57% yields, respectively. In contrast,
(entry 11). With this in mind, several different inor- products 5 and 7 were obtained in lower yields (53
2
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Copper-Catalyzed Tandem C C/C O Bond-Forming Reactions of ortho-Halo-b-chlorostyrenes
Table 2. CuBr-catalyzed tandem reaction of o-bromo-b-
and 56%), presumably as a consequence of the steric
hindrance provided by the ortho-methyl and methoxy
groups. Cyclization of the para-halogenated acetophe-
nones proceeded smoothly to give the corresponding
products in 55–81% yields (8–11). 1-(1H-Pyrrol-2-
yl)ethanone, which contained a heterocycle moiety,
was well tolerated under the standard reaction condi-
tions and provided product 15 in 70% yield. Similarly,
aliphatic ketones were successfully subjected to the
reaction conditions to provide the corresponding
products 16–19 in moderate yields. For example, cy-
clohexanone reacted with 1a under the standard con-
ditions to provide the corresponding product 19 in
70% yield. Based on these results, we proceeded to
examine a variety of ortho-(2-chlorovinyl)bromobenz-
chlorostyrenes with ketones.[a]
AHCTUNGTREGeNNUN nes bearing different functional groups on their aryl
moieties. The results demonstrated that several sub-
stituents, including methyl, methoxy, chloro, fluoro,
and trifluoromethyl groups, were compatible with the
standard reaction conditions. For example, methyl-
substituted bromobenzene was treated with acetophe-
none (2a), CuBr, TMHD and t-BuONa to afford the
desired product 20 in 61% yield. Interestingly, a sub-
strate bearing a fluoro group also smoothly under-
went the tandem reaction with acetophenone (2a) to
give product 23 in 79% yield.
Pleasingly, the o-chloro-b-chlorostyrenes 1g–1i were
successfully subjected to this tandem reaction under
Table 3. CuBr-catalyzed tandem reaction of o-chloro-b-
chlorostyrenes with ketones.[a]
[a]
Reaction conditions: 1 (0.2 mmol), 2 (0.22 mmol), CuBr
(10 mol%), L2 (20 mol%), and t-BuONa (3 equiv.) in
DMSO (2 mL) at 1008C under an N2 atmosphere for 4 h.
Isolated yield.
[b]
[a]
Reaction conditions: 1 (0.2 mmol), 2 (0.22 mmol), CuBr
(10 mol%), L2 (20 mol%), and t-BuONa (3 equiv.) in
DMSO (2 mL) at 1008C under an N2 atmosphere for 4 h.
Isolated yield.
[b]
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Scheme 2. Control experiments.
Scheme 3. Possible mechanism.
the standard reaction conditions (Table 3). The results sequent treatment of compound 27 with t-BuONa,
demonstrated that the reaction between substrate 1g CuBr and L2 under the standard conditions provided
and aromatic ketones containing either electron-with- the target product 3 in a 52% yield. In contrast, only
drawing or electron-donating groups proceeded 16% yield was obtained in the absence of copper cat-
smoothly to give the corresponding products in 43– alyst and ligand [Eq. (2)].
68% yields. For example, acetophenones bearing a 4-
Based on the present results and another mecha-
methylphenyl or 4-cyanophenyl group were well toler- nism reported in the literature,[10b,17] we have proposed
ated to provide the desired products in 68 and 61% a possible mechanism, as outlined in Scheme 3. Oxi-
yields. As expected, the aliphatic ketone pentan-2-one dative addition of CuX to substrate 1 would afford in-
was also well tolerated by the reaction conditions and termediate A, which could be converted to intermedi-
was transformed to the desired product 18 in 43% ate B following a ligand exchange process with the
yield. Moreover, several trisubstituted chlorobenzenes ketone enolate. Following a reductive elimination
were also compatible with the standard tandem reac- process, intermediate C could be formed with the con-
tion conditions. For instance, dimethoxy-substituted comitant regeneration of CuX. Subsequent keto-enol
chlorobenzene reacted with acetophenone (2a) to tautomerism could then occur in the presence of t-
afford the corresponding product 25 in 61% yield.
BuONa and the occurrence of another oxidative addi-
To elucidate the mechanism of the transformation, tion of CuX to bromobenzene or chlorobenzene
a control reaction was conducted between substrate would give intermediate D. Following the E/Z-isomer-
1g and acetophenone (2a) in the presence of CuBr, ization of complex D at high temperature, an intra-
TMHD and t-BuONa at room temperature for 10 min molecular ligand exchange could occur to provide
[Scheme 2, Eq. (1)]. The a-alkenylation product 27 copper complex E. Finally, reductive elimination of E
was isolated in 65% yield. This result indicated that would afford product 3–26 and regenerate the active
À
the a-alkenylation occurred prior to the C O bond CuX. A detailed study of this mechanism is in cur-
forming reaction under the standard conditions. Sub- rently in progress.
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References
In conclusion, we have successfully developed
À
À
a copper-catalyzed tandem C C/C O bond forming
reaction. In the presence of CuBr, TMHD, and t-
BuONa, a broad range of trifluoromethyl-containing
ortho-halo-b-chlorostyrenes underwent the cyclization
reaction with ketones to give the corresponding ben-
zo[b]oxepines in moderate to good yields. The annu-
lation involved the direct a-alkenylation of ketones
with a subsequent intramolecular O-arylation process.
This protocol could be used for the synthesis of tri-
fluoromethyl-containing building blocks, and could
also provide a new strategy for the construction of
benzo[b]oxepine rings.
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General Procedure for the Copper-Catalyzed Tandem
À
À
C C/C O Bond-Forming Reaction
A flask containing a mixture of ortho-halo-b-chlorostyrene
1
(0.2 mmol), ketone
2
(0.22 mmol), CuBr (2.9 mg,
10 mol%), TMHD (7.4 mg, 20 mol%), t-BuONa (57.6 mg,
3 equiv.), in DMSO (2 mL) was evacuated and backfilled
with nitrogen (3 cycles) and then the mixture was stirred at
1008C for 4 h or until complete consumption of starting ma-
terial was indicated by TLC or GC-MS analysis. After the
reaction was completed, the mixture was filtered through
a glass filter and washed with ethyl acetate. The mixture was
washed with brine and extracted with ethyl acetate. The or-
ganic layers were dried with anhydrous Na2SO4 and evapo-
rated under vacuum, and the residue was purified by flash
column chromatography (hexane/ethyl acetate) to give
products 3–26.
2-Phenyl-4-(trifluoromethyl)benzo[b]oxepine (3): Yellow
solid; yield: 47.1 mg (82%); mp 55.3–56.78C; 1H NMR
(500 MHz, CDCl3): d=7.85–7.83 (m, 2H), 7.44–7.37 (m,
4H), 7.27–7.26 (m, 2H), 7.20–7.17 (m, 1H), 7.11 (d, J=
8.0 Hz, 1H), 6.33 (s, 1H); 13C NMR (125 MHz, CDCl3): d=
157.2, 155.4, 134.0, 132.3, 131.2 (q, JC,F =5.8 Hz), 130.1,
129.6, 129.3, 128.9 (q, JC,F =30.1 Hz), 128.7, 125.8, 125.3,
123.4 (q, JC,F =271.6 Hz), 121.5, 105.1 (q, JC,F =2.3 Hz);
19F NMR (470 MHz, CDCl3): d= À66.8 (s, 3F); IR (neat):
n=3080, 1646, 1588, 1494, 1394, 753 cmÀ1; LR-MS (EI,
70 eV): m/z (%)=288 (M+, 88), 105 (100), 186 (22), 165 (7),
77 (29); HR-MS (ESI): m/z=289.0829, calcd. for
C17H12F3O+ ([M+H]+): 289.0835.
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We thank the National Natural Science Foundation of China
(No. 21002070 and 21102104) and Zhejiang Provincial Natu-
ral Science Foundation of China (No. Y4100307) for finan-
cial support.
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Copper-Catalyzed Tandem C C/C O Bond-Forming
Reactions of ortho-Halo-b-chlorostyrenes with Ketones:
Synthesis of 4-Trifluoromethylbenzoxepines
7
Adv. Synth. Catal. 2013, 355, 1 – 7
Lei-Lei Sun, Bo-Lun Hu, Ri-Yuan Tang, Chen-Liang Deng,
Xing-Guo Zhang*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!