A highly efficient, metal-free and convenient diarylallyl ether/ thioether formation via oxidative c-h activation

Article abstract of DOI:10.1002/adsc.200800810

A metal free highly efficient and concise oxidative-coupling ether formation between 1,3-diarylallylic sp³ C-H and aliphatic alcohols promoted by 2,3-dichloro-5,6-dicyanoquinone (DDQ) is reported. This system is also applied to form C-S bonds f

Full text of DOI:10.1002/adsc.200800810

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DOI: 10.1002/adsc.200800810
A Highly Efficient, Metal-Free and Convenient Diarylallyl Ether/
Thioether Formation via Oxidative C-H Activation
Yan Lia and Weiliang Baoa,*
a
Department of Chemistry, Xixi Campus, Zhejiang University, Hangzhou 310028, Peopleꢀs Republic of China
Fax : (+86)-571-8827-3814; phone: (+86)-571-8827-3814; e-mail: wlbao@css.zju.edu.cn
Received: December 26, 2008; Revised: March 21, 2009; Published online: April 6, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800810.
Abstract: A metal free highly efficient and concise
PhIACTHUNGETRNNUG
(OAc)2 was developed.[6a] Although great progress
has been made in generating C O bonds through C
H activation, examples of the reactions without any
metal have rarely been reported.
À
À
oxidative-coupling ether formation between 1,3-di-
ACHTUNGTRENNUNG
arylallylic sp3 C-H and aliphatic alcohols promoted
by 2,3-dichloro-5,6-dicyanoquinone (DDQ) is re-
À
ported. This system is also applied to form C S
Allylic acetate or its derivatives were employed for
[9,10]
À
bonds from 1,3-diarylpropylene and thiols/thiophe-
nols. The corresponding diarylallyl ethers/thioethers
are obtained in good yields.
the construction of C X (X=C/N/O, etc.) bonds.
3
À
Alkylation directly from the allylic sp C H bond was
also reported.[11] Recently, we have developed a new
oxidative coupling reaction between diarylallylic sp3
3
À
À
À
À
À
Keywords: alcohols; C H activation; C O, C S
bond formation; cross-coupling; 1,3-diarylpropy-
lenes; 2,3-dichloro-5,6-dicyanoquinone (DDQ)
C H and active methylenic sp C H bonds mediated
by DDQ.[12] It is worthy of note that alkoxylation di-
3
À
rectly from allylic sp C H bonds without a metal cat-
alyst has been only studied sporadically.
Herein, we report a highly efficient and concise
metal-free oxidative coupling reaction promoted by
2,3-dichloro-5,6-dicyanoquinone (DDQ) between 1,3-
À
The formation of carbon-heteroatom bonds from a diarylallylic sp3 C H bonds and alcohols/thiols to
À
À
common intermediate is of great significance to the form C O/C S bonds.
drug discovery process.[1] In particular, the construc-
DDQ is a well-known oxidation reagent for organic
tion of an ether linkage adjacent to a sterically hin- synthesis.[13] In our study, we first examined the oxida-
dered carbon centre is important for the synthesis of tive coupling between 1a and 2b with DDQ in CH2Cl2
many biologically active compounds.[2] The conven- at room temperature. After a few minutes, the desired
tional method for ether synthesis is the direct SN2- product 3b was obtained in 75% yield (Table 1,
type O-alkylation (Williamson ether synthesis). How- entry 5). We then set the temperature to 08C in order
ever, this protocol is sometimes synthetically impracti- to slow down the reaction. However, the yield did not
cal owing to the strong basicity of the alkoxide anion, alter obviously. Then several solvents were screened.
which may be incompatible with other functional The reaction can proceed in all the solvents tested
groups presented in the system.[3] Therefore some (Table 1). The product yield declined to 67% without
modified methods were developed,[4,5,6] for example, any solvent (Table 1, entry 6). Some undesired prod-
transition metal-catalyzed cross-coupling of aryl hal- ucts were observed when the reaction was carried out
ides with phenols or alcohols.[4b,c,e,f,l] However, transi- in THF, CH3CN or dioxane. When CH3NO2 was used
tion metal-based protocols, although successful, usual- as solvent, the reaction was slower and the yield was
ly have some inherent limitations such as moisture decreased. The yield was improved when the reaction
sensitivity, costly metal catalysts and environmental was performed in CHCl3. As for the effect of the
toxicity.[4c] With the prevalence of “atom economy”[7] DDQ dosage, it was found that decreasing the
and “green chemistry”,[8] the cross-coupling reaction amount of DDQ resulted in reduced yields while with
À
for constructing C O bonds via transition metal-cata- 1.5 equiv. DDQ added, the yield was not improved
lyzed direct C H functionalization has attracted great obviously. Therefore, the optimized condition was 1a
À
interest for its atom economy. Recently, a method to (0.6 mmol)/2b (0.5 mmol)/DDQ (0.6 mmol)/CHCl3
form C O bonds using relatively cheap CuCl and (2 mL) at room temperature. Then, a scale-up experi-
À
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865

Yan Li and Weiliang Bao
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Table 1. Screening of reaction conditions.[a]
the substituents on the aromatic ring of 1 was exam-
ined. Substrates bearing an electron-withdrawing
group on the aromatic ring resulted in good yields
and a rapid reaction rate (Table 2, entries 11, 12, and
13). When an electron-donating group was intro-
duced, the result was the opposite (Table 2, entry 10).
Encouraged by the above results, we further inves-
tigated the similar reactions between 1,3-diarylpropy-
lenes and thiols. To our delight, the corresponding thi-
oethers could be successfully formed at low tempera-
ture (À108C). And further oxidation did not occur.
Various substituted thiophenols were also found to be
reactive. All the thioethers were produced in good
yields. However, as for the phenol, although the aryl
ether can be formed, the product decomposed easily
owing to the leaving group ability of the phenolate
anion.
Entry
Solvent
T [oC]
Yield [%][b]
1
2
3
4
5
6
7
8
CH3CN
THF
CH3NO2
dioxane
CH2Cl2
neat
CHCl3
CH2Cl2
CHCl3
CHCl3
CHCl3
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
50
63
37
55
75
67[c]
87
74
9
10
11
r.t.
r.t.
r.t.
81[d]
88[e]
86[f]
As indicated in Table 2, when ethane-1,2-diol (2i)
was used as the substrate, both dioxolane (3i) and di-
ether (3j) were obtained ACTHNUTRGENUGN(Scheme 1). On changing the
[a]
0.6 mmol of 1a, 0.5 mmol of 2b, 2 mL of solvent,
0.6 mmol of DDQ, 15 min.
Isolated yield.
0.5 mmol of 1a, 2 mL of 2b, 0.6 mmol of DDQ.
0.5 mmol of DDQ.
0.75 mmol of DDQ.
[b]
[c]
[d]
[e]
[f]
ratios of 1a and 2i, 3i or 3j was obtained separately as
the main product. When 1a:2i was 2.2:1, 3j was the
main product (3j 85%, 3i:3j=1:8.1), whereas,
when1a:2i was 1:1.5, 3i was the main product (3i 89%,
3i: 3j=10:1).
According to the literature and the observations in
our reactions, a possible mechanism was proposed
(Scheme 2). The formation of product may follow two
8 mmol of 1a, 6.67 mmol of 2b, 30 mL of CHCl3, 8 mmol
of DDQ. Yield was determined by GC.
ment was carried out: 8 mmol of 1a, 6.67 mmol of 2b, pathways, hydride transferred directly from allylic po-
30 mL of CHCl3, 8 mmol of DDQ, and the yield was sition and/or proton abstraction after an electron was
86% (Table 1, entry 11).
transferred from the allylic double bond to
Based on the above study, various substrates were DDQ.[13a,14] In our experiment, we observed the self-
subjected to the reaction under the optimized condi- coupling product of 1,3-diarylpropylene. This coupling
tions (Table 2). An effect of steric hindrance of the al- reaction may indicate a single-electron transfer in the
cohols in the reaction was observed. Primary alcohol process. However, compounds 1b, 1c and 1d reacted
can proceed smoothly. The bulkier the R3 group, the with ethanol to give the corresponding a- and g-ether
lower the products yields. The use of secondary or ter- products 3k, 3l and 3m. The allylic cation is more
tiary alcohols as the substrate resulted in a decrease likely to be rearranged between the a- and g-posi-
in the yields of the desired ether and formation of the tions. The incoming nucleophile attacked at the orgi-
self-coupling product of 1,3-diarylpropylene. In order nal allylic or g-position to form the isomerized prod-
to avoid the generation of the by-product, the ratio of ucts. When 1b and 1d were used as the substrates, the
alcohol to the 1,3-diarylpropylene was changed to 5:1 a-ethers were more stable than the g-ethers. As for
or more. For tert-butyl alcohol, the solvent CHCl3 was 1c, the g-ether was the main product. These results
not needed (Table 2, entry 4). The electronic effect of may support our proposed mechanism.
Scheme 1.
866
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A Highly Efficient, Metal-Free and Convenient Diarylallyl Ether/Thioether Formation
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Table 2. Formation of ethers and thioethers.[a]
Entry
R1,R2
R3
X
Time [min]
T [oC]
Product
Yield [%][b]
1
2
3
4
5
6
7
8
H, H 1a
1a
1a
1a
1a
1a
1a
1a
CH3 2a
CH3CH2 2b
T
N
cyclohexyl 2e
CH2=CHCH2 2f
4-CH3OC6H4CH2 2g
4-ClC6H4CH2 2h
HOCH2CH2 2i
2b
O
O
O
O
O
O
O
O
O
O
O
O
O
S
12
10
30
40
30
11
12
15
10
20
12
15
12
10
15
10
10
10
25
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
3a
3b
3c
3d
3e
3f
3g
3h
3i, 3j
3k[e]
3l[e]
3m[e]
3n
3o
3p
3q
3r
3s
3t
90
87
85[c]
50[d]
88[c]
95
85
90
40, 37
55
89
85
90
89
80
92
90
90
70
9
1a
10
11
12
13
14
15
16
17
18
19
H, CH3 1b
H, Cl 1c
Cl, H 1d
Cl, Cl 1e
1a
1a
1a
1a
1a
1a
2b
2b
2b
r.t.
CH3CH2 2j
C6H5 2k
4-CH3C6H4 2l
2-CH3C6H4 2m
C6H5CH2 2n
3,5-dimethylpyrimidinyl 2o
À10
À10
À10
À10
À10
À10
S
S
S
S
S
[a]
0.6 mmol of 1, 0.5 mmol of 2, 2 mL of CHCl3, 0.6 mmol of DDQ unless noted.
Isolated yield.
0.5 mmol of 1, 2.5 mmol of 2, 2 mL of CHCl3, 0.6 mmol of DDQ.
0.5 mmol of 1, 2 mL of 2, 0.6 mmol of DDQ.
For all of these substrates both a- and g-ethers were formed. For 3k, 3l and 3m, the ratios of the a- and g-ethers were
separately 2:1, 1:2, 1.6:1, determined by the synthesis of pure a-ether of 3m and g-ether of 3k.
[b]
[c]
[d]
[e]
Scheme 2. A possible mechanism.
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Yan Li and Weiliang Bao
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In conclusion, we have developed a highly efficient
oxidative coupling reaction between 1,3-diarylallylic
compounds and aliphatic alcohols, thiols or thiophe-
nols promoted by DDQ. It provides a highly efficient,
fast and convenient approach to synthesize diarylallyl
ethers/thioethers.
Experimental Section
General Procedures
Formation of ethers: A 25-mL round-bottom flask was
charged with ethanol (0.5 mmol) and 1,3-diarylpropene
(0.6 mmol) in 2 mL CHCl3 and DDQ (0.6 mmol) was added.
The mixture was stirred at room temperature and monitored
by TLC. Purification was done by column chromatography
on silica gel (200–300 mesh) with petroleum ether and ethyl
acetate (30:1) as the eluent to give the pure product.
Formation of thioethers: A 25-mL round-bottom flask was
charged with ethanethiol (0.5 mmol) and 1,3-diarylpropene
(0.6 mmol) in 2 mL CHCl3 and DDQ (0.6 mmol) was added.
The mixture was stirred at À108C and monitored by TLC.
Purification was done by column chromatography on silica
gel (200–300 mesh) with petroleum ether and ethyl acetate
(30:1) as the eluent to give the pure product.
[5] For metal-free ether formation, see: a) A. Patra, A. K.
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Albini, J. Am. Chem. Soc. 2006, 128, 10670–10671.
À
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À
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Acknowledgements
[8] N. Winterton, Green Chem. 2001, 3, G73.
This work was financially supported by the Specialized Re-
search Fund for the Doctoral Program of Higher Education
of China (20060335036).
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