Oxidative coupling of alkenes with amides using peroxides: Selective amide C(sp3)-H versus C(sp2)-H functionalization

Article abstract of DOI:10.1039/c4cc05051g

A new oxidative coupling of unactivated terminal alkenes with amides using peroxides is described, in which mono- and difunctionalization of alkenes are selectively achieved. In this reaction with amides, the chemoselectivity toward the functionalization of the C(sp³)-H bonds adjacent to the nitrogen atom or the functionalization of the carbonyl C(sp²)-H bonds across alkenes relies on the reaction conditions. This journal is

Full text of DOI:10.1039/c4cc05051g

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Oxidative coupling of alkenes with amides using
peroxides: selective amide C(sp3)–H versus
C(sp2)–H functionalization†
Cite this: Chem. Commun., 2014,
50, 12867
Received 2nd July 2014,
Accepted 13th August 2014
Xu-Heng Yang,a Wen-Ting Wei,a Hai-Bing Li,a Ren-Jie Songa and Jin-Heng Li*ab
DOI: 10.1039/c4cc05051g
www.rsc.org/chemcomm
A new oxidative coupling of unactivated terminal alkenes with
amides using peroxides is described, in which mono- and difunc-
tionalization of alkenes are selectively achieved. In this reaction
with amides, the chemoselectivity toward the functionalization of
the C(sp3)–H bonds adjacent to the nitrogen atom or the function-
alization of the carbonyl C(sp2)–H bonds across alkenes relies on
the reaction conditions.
Alkenes are abundant organic molecules and simple chemical
feedstock, and methods for their direct, selective functionaliza-
tion are attractive as an important means to assemble more
complex molecular entities. The transition-metal-catalyzed Heck
couplings of alkenes with organic electrophiles have become
Scheme 1 Oxidative coupling of alkenes with carbonyl compounds.
some of the most efficient and common methods for the alkene C(sp2)–H bonds (Scheme 1a, including 1) the coupling of electron-
functionalization due to their operational simplicity, the use of deficient alkenes with aldehydes (often alkyl aldehydes) initiated
commercially available starting materials and the versatility of by air or N-hydroxyphthalimide (NHPI) combined with dibenzoyl
the resulting alkenes in synthesis.1 Despite their widespread peroxide (BPO) leading to saturated ketones,3 (2) the Heck-type
applications, the Heck coupling routes are typically protracted coupling of unactivated alkenes with aryl aldehydes by using the
by the need to pre-functionalize the C–H bond toward the C–X [(Cp*RhCl2)2]/C5H2Ph4/Cu(OAc)2 or CuCl2/tert-butyl hydroperoxide
bond (X = halides and pseudohalides). Therefore, an attractive (TBHP) system for synthesizing a,b-unsaturated ketones,4 and (3)
alternative would involve a C–H functionalization that directly the difunctionalization of arylalkenes with aldehydes and TBHP
couples unactivated alkenes with broad diversification of func- catalyzed by FeCl2 accessing b-peroxy ketones.5 However, methods
tional groups and excellent selectivity control.
for the oxidative coupling of alkenes with the formyl C(sp2)–H
The oxidative coupling methodology involving the C–H func- bonds of formamides have not been reported.6 Herein, we report a
tionalization has attracted much attention for replacing the new oxidative coupling of terminal alkenes with amides using
conventional cross-coupling procedures, in part due to its step- peroxides and a catalytic amount of bases (Scheme 1b); the
economy by the avoidance of the pre-functionalization process.2–5 chemoselectivity of this method can be controlled by changing
t
Despite remarkable advances in the field, approaches for the the reaction conditions: while a catalytic amount of BuOK com-
coupling of alkenes, particularly unactivated alkenes, with the bined with TBHP delivers b-amino ketones5 from alkenes and
carbonyl C(sp2)–H bonds are rare and limited.2–5 Generally, these the C(sp3)–H bonds adjacent to the nitrogen atom of amides, the
oxidative transformations focus on the coupling with the aldehyde FeCl3/DABCO/di-tert-butyl peroxide (DTBP) system assembles
a,b-unsaturated amides by using alkenes to react with the carbonyl
a State Key Laboratory of Chemo/Biosensing and Chemometrics, College of
Chemistry and Chemical Engineering, Hunan University, Changsha 410082,
China. E-mail: jhli@hnu.edu.cn; Fax: +86 731 8871 3642; Tel: +86 731 8882 2286
b State Key Laboratory of Applied Organic Chemistry Lanzhou University,
Lanzhou 730000, China
C(sp2)–H bonds of formamides. Notably, the oxygen atoms in the
new formed carbonyl groups are from hydroperoxides.
We commenced our investigations by optimizing the reaction
conditions for the oxidative coupling of 4-vinyltoluene (1a) with
N,N-dimethylformamide (DMF; 2a) (Table 1).7 Initially, alkene 1a
was treated with DMF 2a and TBHP at 110 1C for 24 h, but no
† Electronic Supplementary Information (ESI) available. See DOI: 10.1039/
c4cc05051g
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t
Table 1 Screening optimal conditionsa
Table 2 Coupling of alkenes (1) with amides (2), TBHP and BuOKa
Isolated
yield (%)
Entry [O] (equiv.) Base (mol%) Solvent T (1C) 3aa
4aa
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)
—
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
DMF
DMF
DMF
DMF
DMF
110
110
110
110
110
110
110
110
110
110
110
110
110
80
120
110
110
110
110
110
110
0
26
70
69
65
46
19
66
61
28
Trace
Trace
0
10
69
70
8
Trace
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
5
tBuOK (5)
tBuOK (10)
tBuOK (20)
K2CO3 (10)
DBU (10)
7
DABCO (10)
tBuOK (10)
tBuOK (10)
tBuOK (10)
tBuOK (10)
tBuOK (10)
tBuOK (10)
tBuOK (10)
tBuOK (10)
tBuOK (10)
tBuOK (10)
DABCO (10)
DABCO (10)
DABCO (30)
DABCO (30)
8b
9
10
11
12
13
14
15
16c
17d
18d
19d
20d
21e
a
t
—
Reaction conditions: 1 (0.4 mmol), 2 (4 mmol), BuOK (10 mol%),
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
DTBP (2)
DTBP (5)
DTBP (5)
TBHP (2 equiv.; 5 M in decane) and MeCN (2 mL) at 110 1C for 24 h.
in 56% yield from styrene (1b) and DMF 2a. Interestingly, a
variety of substituted arylalkenes were also compatible with the
optimal conditions, and substituents, including Cl, Br, MeO
and CN, on the aromatic ring were well-tolerated (3ca–ge). Treat-
ment of Cl- and Br-substituted alkenes 1c and 1d with DMF 2a,
TBHP and tBuOK successfully afforded 3ca and 3da in 62 and 61%
yields, respectively. ortho-MeO-substituted alkene 1e also delivered
3ea in moderate yield. Unfortunately, oct-1-ene (1f), an alkylalkene,
9
43
85
53
0
0
a
Reaction conditions: 1a (0.4 mmol), 2a, [O] (2 equiv.), base and solvent
b
c
(2 mL) for 24 h. TBHP (5 M in decane). TBHP (70% in water). DMF
(4 mmol). FeCl3 (30 mol%) was added for 48 h. FeCl2 (30 mol%) was
added for 48 h.
d
e
coupled products were observed (entry 1). Gratifyingly, we found was not a suitable substrate (3fa). The optimal conditions were
that a catalytic amount of tBuOK could trigger the reaction, and applicable to various amides 2b–2e (3ab–ae), but failed to an
t
10 mol% BuOK was preferred to form b-amino ketone 3aa in amine 2f (3af). Two cycloalkylamines, piperidine-1-carbaldehyde
70% yield (entries 2–4). Other bases, including K2CO3, DBU and (2b) and morpholine-4-carbaldehyde (2c), could couple with alkene 1a,
t
DABCO, could effect the reaction, but they were less efficient than TBHP and BuOK, providing 3ab and 3ac in moderate yields.
tBuOK (entries 4–7). Screening of peroxides revealed that only hydro- 1-Methylpyrrolidin-2-one (2d) was also a viable substrate, generat-
peroxides, TBHP, TAHP (tert-amyl hydroperoxide) and CHP (cumene ing 3ad in 63% yield, in which alkene 1a regiospecifically attacked
hydroperoxide), could initiate the coupling (entries 2 and 8–10), and the 5 position (the methylene group), and not the 1-methyl group.
other peroxides without hydroxyl groups, DTBP and BPO, have no Moreover, the reaction of N,N-dimethylacetamide (2e) with various
t
activities at all (entries 11 and 12). However, no product 3aa was arylalkenes 1a–c or 1g, TBHP and BuOK was successfully per-
observed without oxidants (entry 13). After varying the temperatures, formed, furnishing 3ae, 3ce and 3ge in good yields.
the reaction at 110 1C provided the best results (entry 3 vs. entries 14
and 15). Notably, the reaction was successfully performed in MeCN, a,b-unsaturated amides 4 from alkenes 1 and formamides 2 in the
delivering 3aa in 70% yield (entry 16). presence of FeCl3, DTBP and DABCO. Arylalkenes 1b–c and 1h–i even
As shown in Table 3, we turned our attention to assemble
Interestingly, addition of FeCl3 could shift the chemoselectivity: with Br, NO2 and Cl groups on the aryl ring successfully underwent
b-amino ketone 3aa and (E)-N,N-dimethyl-3-p-tolylacrylamide the coupling with DMF 2a, giving 4ba–ca and 4ha–ia in 53–77%
(4aa)5 were obtained in 5 and 8% yields, respectively (entry 17). yields, and the order of their reactivity is as follows: electron-rich 4
Evaluation of various reaction parameters revealed that 30 mol% electron-deficient. However, alkylalkene 1f had a relatively low reac-
FeCl3, 30 mol% DABCO and 5 equiv. of DTBP at 110 1C for 48 h tivity (4fa). Gratifyingly, 1,1-diphenylethylene (1j) and (E)-phenylbuta-
gave the best results: product 4aa was obtained exclusively in 85% 1,3-diene (1k) delivered 4ja and 4ka smoothly in 55% and 50% yields,
yield (entries 17–19 and 21 vs. entry 20). It should be noted that respectively. It is important to note that this coupling generally
FeCl2 can effect the reaction, ableit lowering the yield to 53% proceeds in moderate to good yields with an extensive range of other
(entry 21).
formamides, including N,N-dialkylformamides 1b–c and 1g,
With the optimal reaction conditions in hand, we first N-methyl-N-phenylformamide (1h), N,N-diphenylformamide (1i)
sought to coupling of various terminal alkenes 1 with amides and N-phenylformamide (1j) (4bb–bc and 4bg–bj).
2 to synthesize diverse b-amino ketones 3 (Table 2). In the
The results of entries 3 and 9–13 in Table 1 showed that only
presence of TBHP and tBuOK, b-amino ketone 3ba was formed hydroperoxides could trigger the reaction, suggesting that the
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Table 3 Fe-catalyzed coupling of alkenes (1) with formamides (2)a
t
species and BuOÀ. Finally, b-H elimination of alkyl cation F
with BuOÀ by using the DABCO base gives 4 and BuOH.
The presence of FeCl3 lowered the reactivity of alkenes 1 for
reacting with the C(sp3)–H bonds of amines, this is because
ꢀOH radical is consumed to form the Fen+(OH) species, com-
t
t
t
pressing the generation of BuOOꢀ radical.
In summary, we have developed the first oxidative coupling
of unactivated terminal alkenes with amides using peroxides
for selective synthesis of b-amino ketones and a,b-unsaturated
amides. This method proceeds via a tandem C–H/alkene func-
tionalization step that occurs through an oxidative radical
pathway with a broad substrate scope and excellent selectivity
control.
This research was supported by the NSFC (No. 21172060)
and the Hunan Provincial Natural Science Foundation of China
(No. 13JJ2018).
a
Reaction conditions: 1 (0.4 mmol), 2 (2 mL), FeCl3 (30 mol%), DBACO
Notes and references
(30 mol%) and DTBP (5 equiv.) at 110 1C for 48 h.
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may be from hydroperoxides. To verify this, a control experi-
ment between alkene 1a and DMF 2a using 4 equiv. of H218O
was performed: product 3aa did not include the 18O atom,
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between alkenes and formamides, only the corresponding hydroamidation
a radical process.
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for the oxidative coupling.2–5,8 Initially, alkyl radical A is formed
by abstracting the a-H-atom alpha to the N-atom of DMF 1a
products were obtained. Moreover, these transition-metal-catalyzed meth-
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7 The detail data of screening optimal conditions are summarized in
Table S1 of ESI†.
t
with BuOOꢀ, which is generated from TBHP under heating
with the aid of bases.2,8 Addition of alkyl radical A to alkene 1
affords the other alkyl radical B. The reaction of alkyl radical B
t
and BuOOꢀ occurs to afford intermediate C. Finally, the O–O
bond of intermediate C cleaved by tBuOK, followed by oxidation
t
with TBHP produces 3 and BuOH.
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and the BuOꢀ radical.2–5 Hydrogen-abstraction of DMF 2a by 8 (a) A. Studer, Chem. – Eur. J., 2001, 7, 1159; (b) A. Studer, Chem. Soc.
t
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between alkyl radical E and Fe3+(OtBu) gives alkyl cation F, Fe2+
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Chem. Commun., 2014, 50, 12867--12869 | 12869