Oxidative coupling of alkenes with aldehydes and hydroperoxides: One-pot synthesis of 2,3-epoxy Ketones

Article abstract of DOI:10.1002/adsc.201400629

A new transition metal-free oxidative coupling of unactivated terminal alkenes with aldehydes and hydroperoxides in the presence of 10 mol% potassium tert-butanolate (t-BuOK) is described thereby realizing trifunctionalization of alkenes toward 2,3-epoxy ketones. This method is applicable to a wide range of aldehydes, including aryl and alkyl aldehydes, with excellent functional group tolerance, and provides for the one-step assembly of 2,3-epoxy ketones.

Full text of DOI:10.1002/adsc.201400629

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DOI: 10.1002/adsc.201400629
Oxidative Coupling of Alkenes with Aldehydes and
Hydroperoxides: One-Pot Synthesis of 2,3-Epoxy Ketones
Wen-Ting Wei,a Xu-Heng Yang,a Hai-Bing Li,a and Jin-Heng Lia,*
a
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan
University, Changsha 410082, Peopleꢀs Republic of China
Fax : (+86)-731-8871-3642; phone: (+86)-731-8871-3642; e-mail: jhli@hnu.edu.cn
Received: June 27, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400629.
Abstract: A new transition metal-free oxidative
coupling of unactivated terminal alkenes with alde-
hydes and hydroperoxides in the presence of
10 mol% potassium tert-butanolate (t-BuOK) is de-
scribed thereby realizing trifunctionalization of alk-
proaches for the coupling of alkenes, particularly un-
2
À
activated alkenes, with the carbonyl C(sp ) H bonds
are rare and limited.[3–5] These oxidative transforma-
tions focused on the coupling with the aldehyde
2
À
C(sp ) H bonds (Scheme 1a), including (i) the cou-
ACHTUNGTRENNUNGenes toward 2,3-epoxy ketones. This method is ap-
plicable to a wide range of aldehydes, including aryl
and alkyl aldehydes, with excellent functional group
tolerance, and provides for the one-step assembly
of 2,3-epoxy ketones.
Keywords: aldehydes; alkenes; 2,3-epoxy ketones;
oxidative coupling
Alkenes are abundant organic molecules and useful
chemical feedstock, and methods for their direct, se-
lective functionalization are attractive as an important
means to assemble more complex molecular entities.
The transition metal-catalyzed Heck couplings of alk-
ACHTUNGTRENNUNGenes with organic electrophiles have become one of
the most efficient and common methods for alkene
functionalization due to operational simplicity, com-
Scheme 1. Oxidative coupling of alkenes with aldehydes.
mercially available starting materials and the versatili- pling of electron-deficient alkenes with aldehydes
ty of the resulting alkenes in synthesis.[1] Despite their (often alkyl aldehydes) initiated by air or N-hydroxy-
widespread applications, the Heck coupling routes are
ACHTUNGTRENpNGNU hthalimide (NHPI) combined with dibenzoyl perox-
typically protracted by the need to pre-functionalize ide (BPO) leading to saturated ketones,[3] (ii) the
À
À
the C H bond toward the C X bond (X=halides and Heck-type coupling of unactivated alkenes with aryl
pseudohalides). Therefore, an attractive alternative aldehydes using the [(Cp*RhCl2)2]/C5H2Ph4/Cu(OAc)2
À
would involve a C H functionalization that directly or the CuCl2/tert-butyl hydroperoxide (TBHP) system
couples unactivated alkenes to a broad diversification for synthesizing a,b-unsaturated ketones,[4] and (iii)
of functional groups with excellent selectivity control. the difunctionalization of arylalkenes with aldehydes
À
The oxidative coupling methodology involving C
and TBHP catalyzed by FeCl2 so accessing b-peroxy
H functionalization has attracted much attention for ketones.[5] Herein, we report a new transition metal-
replacing the conventional cross-coupling procedures, free oxidative coupling of terminal alkenes with alde-
in part due to its step-economy by the avoidance of hydes and hydroperoxides using base catalysis
the pre-functionalization process.[2–5] Despite remark- (Scheme 1b). In the presence of a catalytic amount of
able advances in the oxidative coupling field, ap- t-BuOK, a variety of terminal alkenes successfully un-
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Table 1. Screening for optimal reaction conditions.[a]
ides revealed that only hydroperoxides, TBHP, TAHP
(tert-amyl hydroperoxide) and CHP (cumene hydro-
peroxide), could initiate the coupling (entries 2 and
8–10), and other peroxides without a hydroxy group,
DTBP and BPO, had no activity at all (entries 11 and
12). However, product 3aa was not observed without
oxidants (entry 13). The effect of solvents was also
evaluated, and the results showed that the other sol-
vents, including 1,4-dioxane, toluene and DMSO, are
less effective than MeCN (entry 2 vs. entries 14–16).
After varying the temperature, the reaction at 1008C
provided the best results (entry 2 vs. entries 17 and
18). Notably, the reaction of alkene 1a was successful-
ly performed on a 1-gram scale, delivering 2,3-epoxy
ketone 3aa in high yield (entry 19). The structure of
2,3-epoxy ketone 3aa was assigned as the trans-isomer
according to the chemical shift of the hydrogen atom
on the epoxide ring by comparison with the known
1H NMR spectral data of 2,3-epoxy ketones.[5,6]
With the optimal conditions in hand, we next
turned our attention to investigate the scope of this
oxidative coupling procedure by testing various termi-
nal alkenes 1 and aldehydes 2 (Table 2). In the pres-
ence of 4-methylbenzaldehyde (2a), TBHP and t-
BuOK, the successful process was consistent with
a wide range of alkenes 1 involving arylalkenes, a het-
eroarylalkene, an alkylalkene and 1,1-disubstituted al-
kenes, and also readily accommodated several sub-
stituents such as Me, MeO and Br on the aromatic
ring (2,3-epoxy ketones 3ba–la). Also styrene (1b) or
1-methyl-4-vinylbenzene (1c) reacted with aldehyde
2a, giving 2,3-epoxy ketones 3ba and 3ca in 77% and
91% yields, respectively. The MeO-substituted alk-
Entry [O] (equiv.) Base (mol%) Solvent
Yield [%]
1
2
3
4
5
6
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TAHP (2)
CHP (2)
DTBP (2)
BPO (2)
–
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
–
MeCN
MeCN
0
48
84
83
78
64
37
79
52
31
trace
trace
0
5
10
trace
26
82
t-BuOK (5)
t-BuOK (10) MeCN
t-BuOK (20) MeCN
K2CO3 (10)
DBU (10)
MeCN
MeCN
7
DABCO (10) MeCN
t-BuOK (10) MeCN
t-BuOK (10) MeCN
t-BuOK (10) MeCN
t-BuOK (10) MeCN
t-BuOK (10) MeCN
t-BuOK (10) MeCN
t-BuOK (10) 1,4-dioxane
t-BuOK (10) tolune
t-BuOK (10) DMSO
t-BuOK (10) MeCN
t-BuOK (10) MeCN
t-BuOK (10) MeCN
8[b]
9
10
11
12
13
14
15
16
17[c]
18[d]
19[e]
83
[a]
Reaction conditions: 1a (0.4 mmol), 2a (0.8 mmol), [O]
(2 equiv.), base and solvent (2 mL) at 1008C for 12 h.
TBHP (5M in decane).
TBHP (70% in water).
At 808C.
At 1208C.
1a (1 g, 7.22 mmol) for 48 h.
[b]
[c]
[d]
[e]
AHCTUNGTREGeNNNU nes 1-methoxy-4-vinylbenzene (1d), 1-methoxy-3-vi-
nylbenzene (1f) or 1-methoxy-2-vinylbenzene (1g)
were also examined, and the order of their reactivity
is as follows: para>meta>ortho (2,3-epoxy ketones
3da, 3fa and 3ga). Importantly, the optimal conditions
derwent the trifunctionalization reaction with a wide were consistent with 1-bromo-4-vinylbenzene (1e),
range of aldehydes and hydroperoxides, giving in one- thereby enabling subsequent modifications at the
step 2,3-epoxy ketones in high yields.[6] Notably, the halogenated positions (86% yield; 2,3-epoxy ketone
oxygen atoms in the new formed 2,3-epoxy moiety 3ea). We were pleased to find that 2-vinylnaphthalene
are from hydroperoxides.
(1i) and 4-vinylpyridine (1j) were viable substrates for
We began our investigations by exploiting the oxi- the reaction with aldehyde 2a, TBHP and t-BuOK,
dative coupling of 1-chloro-4-vinylbenzene (1a) with providing 2,3-epoxy ketones 3ia and 3ja in moderate
4-methylbenzaldehyde (2a) for optimization of the re- yields. Remarkably, alkylakene 1h reacted with alde-
action conditions (Table 1). Initially, alkene 1a was hyde 2a, TBHP and t-BuOK to afford 1-para-tolyl-
treated with aldehyde 2a and TBHP in MeCN at nonan-1-one (3ha), not the 2,3-epoxy ketone. It was
1008C for 24 h, but no coupled products were ob- noted that 1,1-disubstituted alkenes, 1,1-diphenylethy-
served (entry 1). Gratifyingly, we found that a catalytic lene (1k) and 1-methyl-1-phenylethylene (1l), reacted
amount of t-BuOK could trigger the reaction, and successfully to access 2,3-epoxy ketones 3ka and 3la
10 mol% t-BuOK was preferred leading to the desired in 81 and 71% yield, respectively.
2,3-epoxy ketone 3aa in 84% yield (entries 2–4). Sub-
The optimal conditions were found to be applicable
sequently, a series of other bases, including K2CO3, to a wide range of other aldehydes, including aryl al-
DBU and DABCO, was examined: they could pro- dehydes 2b–h and alkyl aldehydes 2i and 2j, furnish-
mote the reaction, but they were less efficient than t- ing 2,3-epoxy ketones 3ab–3aj, 3cb and 3cc in good to
BuOK (entry 3 vs. entries 5–7). Screening of perox- excellent yield. Moreover, this coupling allows several
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Oxidative Coupling of Alkenes with Aldehydes and Hydroperoxides
Table 2. Oxidative coupling of alkenes (1) with aldehydes (2), TBHP and t-BuOK.[a]
[a]
Reaction conditions: 1 (0.4 mmol), 2 (0.8 mmol), t-BuOK (10 mol%), TBHP (2 equiv.; 5M in decane) and MeCN (2 mL)
at 1008C for 12 h.
substituents including MeO, Cl, Me and Br on the stituted aldehyde 2h was viable for the reaction, deliv-
aryl ring to be readily accommodated (2,3-epoxy ke- ering 2,3-epoxy ketone 3ah in 46% yield. Reaction of
tones 3ab–3ah). For example, treatment of benzalde- alkyl aldehydes 2i or 2j with alkene 1a, TBHP and t-
hyde (2b) with alkene 1a, TBHP and t-BuOK afford- BuOK successfully generated 2,3-epoxy ketones 3ai
ed the desired 2,3-epoxy ketone 3ab in 80% yield. and 3aj in moderate yields. The reactions of 1-methyl-
Gratifyingly, p-MeO- or p-Cl-substituted aryl alde- 4-vinylbenzene (1c) with two aldehydes, benzaldehyde
hydes 2c and 2d were converted into the correspond- (2b) and 4-methoxybenzaldehyde (2c), are successful-
ing 2,3-epoxy ketones 3ac and 3ad in high yields. Al- ly performed, giving 2,3-epoxy ketones 3cb and 3cc in
though the reactivity of ortho-substituted aldehydes 72% and 71% yields, respectively.
2e–2g was lower, 2,3-epoxy ketones 3ae–3ag were
As illustrated in Scheme 2, the absence of bases re-
also constructed in good yields. Naphthalen-1-yl-sub- sulted in the selectivity toward 3-(tert-butylperoxy)-3-
Scheme 2. Control experiments.
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Scheme 3. Possible mechanism.
À
(4-chlorophenyl)-1-para-tolylpropan-1-one (4aa), not proceeds via a new tandem C H/alkene functionaliza-
2,3-epoxy ketone 3aa, in 45% yield [Eq. (1)]. Interest- tion step that occurs through an oxidative radical
ingly, product 4aa could be readily converted into 2,3- pathway with a broad substrate scope and excellent
epoxy ketone 3aa in 95% yield using 10 mol% t- selectivity control.
BuOK [Eq. (1)].[5,6] However, 3 equiv. of 2,2,6,6-tetra-
methylpiperidinyloxyl (TEMPO) completely sup-
pressed the coupling of alkene 1a with aldehyde 2c Experimental Section
and TBHP by forming product 5 from aldehyde 2c
and TEMPO [Eq. (2)]. Moreover, other radical inhib- Typical Experimental Procedure for the the Coupling
itors, hydroquinone and BHT, also resulted in no de- of Alkenes 1 with Aldehydes 2, TBHP and t-BuOK
tectable product 3ac. These findings imply that the re-
action involves a radical process.
To a Schlenk tube were added alkenes 1 (0.4 mmol), alde-
hydes 2 (0.8 mmol), TBHP (0.8 mmol, 5M in decane), t-
BuOK (10 mol%), and CH3CN (2 mL). Then the tube was
The results of entries 3 and 8–12 in Table 1 demon-
strated that only hydroperoxides could trigger the re-
action, suggesting that the oxygen atoms in the new
formed 2,3-epoxy group of products 3 might be from
hydroperoxides. To verify this, a control experiment
between alkene 1a and aldehyde 2a using 4 equiv.
H218O was performed: product 3aa did not include
the 18O atom, ruling out the oxygen atom from H2O.
Notably, the results of Table 1 and Table 2 indicated
that the peroxy esters were not observed from the re-
actions of aldehydes and hydroperoxide, and only
some acids were detected by GC-MS analysis.
stirred at 1008C for the indicated time until complete con-
sumption of starting material as monitored by TLC and/or
GC-MS analysis. After the reaction was finished, the reac-
tion mixture was washed with brine. The aqueous phase was
re-extracted with ethyl acetate. The combined organic ex-
tracts were dried over Na2SO4, concentrated under vacuum,
and the resulting residue was purified by silica gel column
chromatography (hexane/ethyl acetate) to afford the desired
product 3.
[3-(4-Chlorophenyl)oxiran-2-yl](para-tolyl)methanone
(3aa):[7] 1H NMR (400 MHz, CDCl3): d=7.90 (d, J=7.2 Hz,
2H), 7.36 (d, J=7.2 Hz, 2H), 7.29 (d, J=6.8 Hz, 4H), 4.23
(s, 1H), 4.05 (s, 1H), 2.42 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=192.2, 145.2, 134.8, 134.1, 132.9, 129.5, 128.9,
128.4, 127.1, 60.7, 58.5, 21.7.
A possible mechanism as outlined in Scheme 3 was
proposed for this current oxidative coupling.[2–6] Ini-
tially, TBHP is split into t-BuOC radical and COH radi-
cal under heating, and the COH radical can react with
TBHP to afford a t-BuOOC radical and H2O.[2] Alkyl
radical A is readily formed from aldehyde 1 with t-
BuOOC, followed by addition with alkene 1 which af-
Acknowledgements
fords the other alkyl radical B. Intermediate C, gener- We thank the Natural Science Foundation of China (No.
21172060), the Specialized Research Fund for the Doctoral
Program of Higher Education (No. 20120161110041), and
the Hunan Provincial Natural Science Foundation of China
(No. 13JJ2018) for financial support.
ated from alkyl radical B and t-BuOOC, is not stable
and is converted into product 3 and t-BuOH by a cata-
lytic amount of t-BuOK.[5,6] This is because the hydro-
gen atom (H+ cation) from the deprotonation process
is consumed to form t-BuOH, thus making the reac-
tion system alkaline to initiate the conversion of inter-
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In summary, we have developed a new oxidative
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hydes and hydroperoxides using base catalysis for the
selective synthesis of 2,3-epoxy ketones. This method
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6 Oxidative Coupling of Alkenes with Aldehydes and
Hydroperoxides: One-Pot Synthesis of 2,3-Epoxy Ketones
Adv. Synth. Catal. 2014, 356, 1 – 6
Wen-Ting Wei, Xu-Heng Yang, Hai-Bing Li, Jin-Heng Li*
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