Direct Oxidative Cross-Coupling of Toluene Derivatives and N-Acyl-2-aminoacetophenones

Article abstract of DOI:10.1002/adsc.201600712

The direct oxidative cross-coupling between N-acyl-2-aminoacetophenones and toluene derivatives was developed with a new C–C bond being formed under metal-free and environmentally friendly conditions with excellent atom economy. A possible reaction pathway for the formation of the products is also discussed in this paper. (Figure presented.).

Full text of DOI:10.1002/adsc.201600712

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DOI: 10.1002/adsc.201600712
Direct Oxidative Cross-Coupling of Toluene Derivatives and N-
Acyl-2-aminoacetophenones
Hui Yu,a,* Yilan Xu,a Rui Dong,a and Yan Fanga
a
Department of Chemistry, Tongji University, 1239 Siping Road, Shanghai 200092, Peopleꢀs Republic of China
E-mail: yuhui@tongji.edu.cn
Received: July 6, 2016; Revised: October 19, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600712.
Abstract: The direct oxidative cross-coupling be-
tween N-acyl-2-aminoacetophenones and toluene
derivatives was developed with a new C–C bond
being formed under metal-free and environmentally
friendly conditions with excellent atom economy. A
possible reaction pathway for the formation of the
products is also discussed in this paper.
zation of a C–H bond adjacent to the nitrogen atom
of an amide is of great value in organic synthesis and
has attracted much interest in recent years.[6] N-Acyl
a-amino carbonyl compounds were also proved to be
suitable substrates for such transformations. In 2008,
Li reported an efficient coupling reaction between
malonates and N-acylglycine esters and C–C bonds
were formed by using Cu(OAc)2 as a stoichiometric
oxidant.[7] With zhe N-2-pyridinecarbonyl group as an
auxiliary group and catalyzed by FeCl3, amino acid
esters could also be attacked by C-nucleophilic re-
agents to establish a-quaternary carbon atom cen-
ters.[8] Moreover, Nachtsheim and co-workers report-
ed an iodide-catalyzed oxidative cross-coupling be-
tween phenols and N-acyl-2-aminoacetophenones to
Keywords: benzylation; C–C bond formation; di-
tert-butyl peroxide; oxidative coupling; toluene de-
rivatives
As a novel and powerful approach to the synthesis of form C–O bonds.[9] To the best of our knowledge, the
nitrogen-containing compounds, direct functionaliza- cross-coupling between C(sp3)–H and N-acyl-2-ami-
tion reactions of C–H bonds adjacent to a nitrogen noacetophenones to form C–C bond has not been re-
atom have received considerable attention in recent ported before. Herein, as a continuation of our efforts
decades, and noticeable progress has been made in on the oxidative synthesis of amide derivatives,[10] we
this area.[1] N-Aryl-substituted amines, including describe our work on the direct benzylation of amides
N,N-dialkylanilines,[2] N-aryltetrahydroisoquinolines under mild and metal-free conditions and its applica-
(THIQ),[3] N-arylglycine derivatives,[4] and N-arylami- tion in organic synthesis.
no ketones[5] are potential substrates for the investiga-
Initially, N-benzoyl-2-aminoacetophenone 1a was
tion of such reactions. In most cases, these reactions chosen as the model substrate to optimize the reac-
are believed to proceed with the in situ generated imi- tion conditions including the temperature, oxidant
nium ion or imine as the key intermediate, which is and catalyst. As shown in Table 1, the reaction of 1a
subsequently attacked by a nucleophile to form with 4.0 equiv. of di-tert-butyl peroxide (DTBP) was
carbon–carbon or carbon–heteroatom bonds in an examined in 2 mL toluene at 1108C for 24 h, and the
economically favourable way by using environmental- desired product 3a was isolated in 54% yield with
ly friendly processes. Although reasonable amounts of 20% of 3a recovered (Table 1, entry 1). When the re-
synthetically meaningful compounds have been pre- action temperature was increased to 1208C, all the
pared under mild conditions by such a strategy, one starting material was nearly consumed in 24 h and the
drawback still exists in that it is difficult to remove yield of 3a was increased to 82%, but higher tempera-
the aryl group from the obtained products,which has tures of 1308C or 1408C caused lower yields (Table 1,
limited the application of this methodology in organic entries 2–4). When the amount of DTBP was de-
synthesis.
creased to 3.0 equiv. and 2.0 equiv., the yield of 3a
Compared with the aryl group, the acyl group is was decreased to 70% and 52%, respectively (Table 1,
a more frequently used protective group for the syn- entry 5). The reaction was also examined in other sol-
thesis of amine derivatives allowing the convenient vents such as CH3CN and DCE with 2.0 equiv. of 2a,
preparation and cleavage of amides. Thus, functionali- but the yield was quite low (Table 1, entry 6). Other
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Table 1. Optimization of the reaction conditions for ketone
3a.[a]
Table 2. Reaction of 1a with toluene derivatives.[a,b]
Entry
Catalyst
Oxidant
Temp. [8C]
Yield[b] [%]
1
2
3
4
5
6
7
8
–
–
–
–
–
–
–
–
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBHP
CHP
TBPB
DCP
BPO
DTBP
DTBP
DTBP
110
120
130
140
120
120
120
120
120
120
120
120
120
120
54
82
76
65
70,[c] 52[d]
49,[e] 32[f]
60
25
32
40
28
20
18
10
9
–
–
–
I2
CuBr
FeCl2
10
11
12
13
14
[a]
Reaction conditions: 1a (0.2 mmol), oxidant (4.0 equiv.)
in 2a (2 mL) in a sealed tube at the indicated tempera-
ture in air, 24 h. DTBP=tert-butyl peroxide, TBHP=
tert-butyl hydroperoxide, CHP=cumene hydroperoxide,
TBPB=tert-butyl perbenzoate, DCP=dicumyl peroxide,
BPO=benzoyl peroxide.
Isolated yield.
With 3.0 equiv. of DTBP.
With 2.0 equiv. of DTBP.
With 2.0 equiv. of 2a and CH3CN (2 mL) as the solvent.
With 2.0 equiv. of 2a and DCE (2 mL) as the solvent.
[b]
[c]
[d]
[e]
[f]
[a]
Reaction conditions: 1a (0.2 mmol), DTBP (4 equiv.) in 2
(2 mL) in a sealed tube at 120 C, 24 h.
Isolated yields reported.
[b]
commercially available oxidants including TBHP,
CHP, TBPB, DCP and BPO were also tested and
DTBP remained as the best one (Table 1, entries 7–
11). To promote the reaction, catalytic amounts a smooth reaction to give the product in 63% yields
[13]
(20 mol%) of I2,[11] CuCl,[12] and FeCl2 were added (Table 2, 3l). 4-Nitrotoluene and methylheteroarenes
to the reaction but led to poor yields (Table 1, en- including 2-methylfuran, 4-methylpyridine, and 1-
tries 12–14). On the basis of these results, entry 2 rep- methylimidazole were also tested under the optimized
resents the best conditions.
reaction conditions but no desired products were
Once the optimized reaction conditions were estab- found (Table 2, 3k, 3m).
lished, the effect of the substrate was examined, with
For substrates with the methyl group substituted at
the results being summarized in Table 2. Firstly, a vari- different positions on the benzoyl group of 1a, no sig-
ety of differently substituted toluenes was investigat- nificant steric hindrance was observed (Table 3, 4a–c).
ed. The reactions of 1a with o-, m-, p-xylene or mesi- A substrate with an electron-withdrawing group gave
tylene were examined, and the corresponding prod- a lower yield than those with electron-donating
ucts were obtained in good yields regardless of the groups (Table 3, 4d). The 2-naphthoyl substrate un-
position of the methyl group on the benzene ring derwent a smooth reaction to afford the product in
(Table 2, 3b–e). 4-Methylanisole and p-tert-butyltol- 42% yield (Table 3, 4e). The heterocyclic substrate
ACHTUNGTRENNUNGuene also gave the desired products in 62% and 70% with a 2-pyridinecarbonyl moiety also gave the corre-
yields, respectively (Table 2, 3f, 3g). Halogen atoms sponding product in 56% yield (Table 3, 4f). The 2-
such as fluoro, chloro, and bromo on the benzene ring propionyl substrate is also suitable for this reaction
were tolerated under the present reaction conditions with the desired product being obtained in 88% yield
to afford the corresponding products in 67–70% (Table 3, 4g). To our delight, when a carbamate such
yields, which could allow for further synthetic conver- as N-Cbz- or N-Boc-protected substrate was subjected
sions (Table 2, 3h–j). 2-Methylnaphthalene underwent to the optimized reaction conditions, the correspond-
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Table 3. Reaction of compouds 1 with toluene.[a,b]
Scheme 1. Control experiment and KIE experiment.
Although the detailed reaction mechanism still re-
mains to be clarified, a radical reaction pathway is
proposed as shown in Scheme 2. The tert-butoxyl radi-
cals were generated by homolytic cleavage of
[a]
Reaction conditions: 1 (0.2 mmol), DTBP (4 equiv.) in
toluene (2 mL) in a sealed tube at 1208C, 24 h.
Isolated yields reported.
[b]
ing products could be furnished in 64% and 65%
yields, respectively (Table 3, 4h, 4i). Substrates with
different substituents on the arene moiety of the ace-
Scheme 2. Plausible reaction mechanism.
tophenone part of 1a also gave the desired products DTBP.[14] Then the H atom adjacent to the nitrogen
in moderate yields (Table 3, 4j, 4k). N-Benzoyl-2-ami- atom of 1a was abstracted by a tert-butoxyl radical to
noacetone was also tested but only a trace of the form acylimine A. The tert-butoxy radical could also
product could be found (Table 3, 4l).
abstract hydrogen from the methylarene to produce
To gain insights into the reaction mechanism, a con- a benzyl radical.[15] Addition of a benzyl radical to the
trol experiment was carried out to elucidate the acylimine A gave the intermediate B. Finally, the in-
mechanism. When 1.0 equiv. of TEMPO was added to termediate B abstracted one H from t-BuOH to pro-
the reaction, the yield of 3a decreased significantly to vide the final product and regenerate the tert-butoxyl
15% (Scheme 1a), which indicated the possibility of radical (Scheme 2).
a radical pathway. Furthermore, an intermolecular ki-
To demonstrate the utility of our chemistry, a depro-
netic isotopic effect (KIE) experiment was performed tection reaction of the obtained product was carried
in a mixture of toluene (1 mL) and deuterated tolu- out as shown in Scheme 3. When 4i was treated with
ene (1 mL), and a significant KIE could be observed DCM/CF3COOH at room temperature for 3 hours,
with the resulting product ratio of 3a/3a-d7 =7/1, compound 5 was afforded in high yield (Scheme 3a).
which indicated the involvement of the cleavage of Futhermore, the keto amide structure of the resultant
the benzylic C(sp3)–H bond in the rate-determining compound allows it to serve as a precursor for the
step (Scheme 1b).
synthesis of heterocyclic compounds. When 3a was
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In a 25-mL sealed tube, a mixture of 1a (0.2 mmol), DTBP
(0.8 mmol, 4.0 equiv.), and toluene (2 mL) was stirred at
1208C for 24 hours until the starting material was complete-
ly consumed as monitored by TLC. The reaction mixture
was then evaporated under reduced pressure and the resi-
due purified by flash chromatography on silica gel using pe-
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product 3a as a white solid; yield: 54 mg (82%).
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Acknowledgements
Financial support from Tongji University (20123231) is grate-
fully acknowledged.
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6 Direct Oxidative Cross-Coupling of Toluene Derivatives
and N-Acyl-2-aminoacetophenones
Adv. Synth. Catal. 2017, 359, 1 – 6
Hui Yu,* Yilan Xu, Rui Dong, Yan Fang
Adv. Synth. Catal. 0000, 000, 0 – 0
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