Synthesis of β-arylated alkylamides via Pd-catalyzed one-pot installation of a directing group and C(sp3)-H arylation

Article abstract of DOI:10.3762/bjoc.12.108

The synthesis of β-arylated alkylamides via alkyl C-H bond arylation has been realized by means of direct one-pot reactions of acyl chlorides, aryl iodides and 8-aminoquinoline. Depending on the structure of the starting materials, both single and double β-arylated alkylamides could be accessed.

Full text of DOI:10.3762/bjoc.12.108

Synthesis of β-arylated alkylamides via Pd-catalyzed one-pot
installation of a directing group and C(sp3)–H arylation
Yunyun Liu*1, Yi Zhang1, Xiaoji Cao2 and Jie-Ping Wan1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 1122–1126.
1College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang 330022 P. R. China and 2Research Center of
Analysis and Measurement, Zhejiang University of Technology, 18
Chaowang Road, Hangzhou, Zhejiang 310014, P.R. China
doi:10.3762/bjoc.12.108
Received: 06 April 2016
Accepted: 25 May 2016
Published: 03 June 2016
Email:
Yunyun Liu* - chemliuyunyun@jxnu.edu.cn
Associate Editor: K. Itami
* Corresponding author
© 2016 Liu et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
alkylamides; C–H arylation; directing group; in situ installation;
one-pot
Abstract
The synthesis of β-arylated alkylamides via alkyl C–H bond arylation has been realized by means of direct one-pot reactions of acyl
chlorides, aryl iodides and 8-aminoquinoline. Depending on the structure of the starting materials, both single and double β-arylated
alkylamides could be accessed.
Introduction
The elaboration of inert C–H bonds is regarded as the long- reactants is required in most of presently known DG-assisted
standing aim of modern organic synthesis. Upon the extensive reactions. For example, in the widely studied reactions employ-
efforts during the past decades, the exploration and application ing AQ (8-aminoquinoline) as DG, the prior reaction (including
of C–H activation/functionalization has won splendid success isolation) of the corresponding acyl chlorides and AQ is gener-
[1-6]. Among the numerous elegant examples of C–H activa- ally the mandatory procedure before conducting subsequent
tion reactions, the DG (directing group) assisted C–H activa- C–H transformation [10-12]. The additional time in running the
tion is obviously the most generally applicable tactic because of DG installation reaction and purification as well as related
the irreplaceable function of the DG in facilitating the incorpo- consumption of chemicals substantially undermine the effi-
ration of a metal catalyst and controlling the site selectivity ciency of the C–H activation-based synthesis, which is against
[7-9]. While benefiting the advantage of straightforward trans- the principle of step economy [13,14]. In this context, devel-
formation from the C–H activation strategy, the utilization of a oping alternative strategies which are able to skip the
DG also brings unfavorable defection of step economics DG-installing procedure is of high emergence in the chemistry
because an additional operation step in installing the DG to of DG-based C–H activation.
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Beilstein J. Org. Chem. 2016, 12, 1122–1126.
To solve the problem of additional cost resulted from the DG known examples, including C(sp3)–H alkylation, arylation or
installation, the concept of domino reaction in which the oxygenation employing different transition metal catalysts such
multiple chemical bond transformations complete in one-step as palladium, nickel, and iron have provided enriched routes for
operation is theoretically the best option [15-20]. On the other the synthesis of structurally diverse amides, a two step process
hand, owing to their close relevance to biological processes and involving the operation in installing the AQ to the substrate has
clinical pharmaceuticals [21-23], the amides constitute a class been required [41-50]. Herein, we report our results in the
of most important targets of organic synthesis [24-27]. As a rep- establishment of a complementary one-pot domino approach
resentative protocol for the synthesis of C–H elaborated alkyl/ without prior DG installation for the synthesis of diverse
arylamides, the AQ-assisted C–H functionalization reactions arylated alkylamides.
have been broadly investigated and applied [28-34]. Since the
prior preparation and purification of N-AQ amides have been Results and Discussion
required in all these known syntheses, a domino process by To start the exploration, the reaction of AQ 1, butyryl chloride
which the AQ can be linked directly to the raw substrates to (2a) and iodobenzene (3a) was selected as a model reaction.
enable the subsequent arylation transformation in one pot would The primary reaction in the presence of Pd(OAc)2 provided
be highly favorable for enhancing step economy.
smoothly the target product 4a (entry 1, Table 1). The variation
in the effect of catalyst loading proved that 5 mol % was proper
Upon this assumption as well as our interest in both domino (entries 2 and 3, Table 1). Further investigations using different
reactions and C–H functionalization chemistry [35-40], we have palladium catalysts such as PdCl2, Pd/C, Pd(PPh3)4 did not
executed efforts to the AQ-assisted β-C–H functionalization show better results (entries 4–6, Table 1). The screening on the
reactions of alkylamides via activation of the C(sp3)–H bond, a effect of base and solvent species demonstrated that K2CO3 and
classical protocol toward β-arylamide synthesis. While the p-xylene were the best base additive and reaction medium, re-
Table 1: Optimization of reaction conditions.a
Entry
Catalyst
Base
Solvent
Yield (%)b
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
NaHCO3
Cs2CO3
KOH
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
1,4-dioxane
CH3CN
75
2c
3d
4
74
51
52
5
Pd(PPh3)4
Pd/C
44
6
trace
trace
trace
63
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
8
9
10
11
12
13
14
15
16e
17f
trace
26
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
trace
43
toluene
DMF
trace
trace
72
DMSO
p-xylene
p-xylene
55
aGeneral conditions: 1a (0.2 mmol), 2a (0.2 mmol), 3a (0.3 mmol), catalyst (5 mol %), base (0.4 mmol), solvent (2 mL), stirred at 120 °C or reflux (for
solvents with lower bp) for 12 h. bIsolated yield. cPd(OAc)2 (10 mol %). dPd(OAc)2 (3 mol %). eThe temperature was 130 °C. fThe temperature was
110 °C.
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Beilstein J. Org. Chem. 2016, 12, 1122–1126.
spectively (entries 7–15, Table 1). On the other hand, final opti- stituent. A notable point was that the selective formation of
mization on the reaction temperature indicated that 120 °C was single arylated products was kept even though diiodobenzenes
the favorable temperature (entries 16 and 17, Table 1).
were employed (4f and 4s, Table 2). When 2-iodopyridine was
employed, the expected reaction was not observed (entry 25,
Following the above optimization experiments, the scope of this Table 2). Additionally, the reaction of 3-methylbutanoyl chlo-
one-pot approach in the synthesis of arylated amides was then ride, a secondary alkyl chloride, with iodobenzene was also
examined by subjecting different aryl iodides and acyl chlo- found not practical, indicating the evident effect of steric
rides. According to the acquired results (Table 2), the acyl chlo- hindrance to the reaction. Finally, the entry employing
rides bearing chains of different length such as butanoyl, hexa- bromobenzene as reaction partner of 1 and 2a provided only
noyl, octanoyl and dodecanoyl all exhibited good tolerance to trace amounts of target product 4a.
the synthesis of the corresponding β-arylated products. Simi-
larly, good compatibility was also observed in the component of Interestingly, when less steric propionyl chloride 2e was em-
aryl iodides. Functional groups of different features including ployed in the reactions with AQ and aryl iodides, the in situ
alkyl, alkoxyl, halogen, nitro etc. were all well tolerated in the generated propionamide intermedidates underwent selectively
reaction, and the products were generally provided with good to double β-C–H arylation to provide the corresponding 3,3-diaryl-
excellent yields regardless of the different property of the sub- amides 5 (Scheme 1).
Table 2: Scope of the single β-arylation of alkylamides.a
Entry
R
Ar
Product
Yield (%)b
1
CH3
Ph
4a
4b
4c
4d
4e
4f
72
65
77
76
75
78
86
72
74
80
84
85
76
80
78
65
82
79
67
85
78
75
70
71
–
2
CH3
4-MeC6H4
4-OMeC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
3
CH3
4
CH3
5
CH3
6
CH3
7
CH3
4-NO2C6H4
4-COMeC6H4
Ph
4g
4h
4i
8
CH3
9
n-C3H7
n-C3H7
n-C3H7
n-C3H7
n-C3H7
n-C3H7
CH3(CH2)4
CH3(CH2)4
CH3(CH2)4
CH3(CH2)4
CH3(CH2)4
CH3(CH2)8
CH3(CH2)8
CH3(CH2)8
CH3(CH2)8
CH3(CH2)8
CH3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4-MeC6H4
4-OMeC6H4
4-ClC6H4
4-NO2C6H4
3-MeC6H4
Ph
4j
4k
4l
4m
4n
4o
4p
4q
4r
4-MeC6H4
4-OMeC6H4
4-BrC6H4
3-IC6H4
4s
4t
Ph
4-OMeC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
pyridine-2-yl
4u
4v
4w
4x
–
aGeneral conditions: 1a (0.3 mmol), 2 (0.3 mmol), 3 (0.45 mmol), Pd(OAc)2 (5 mol %), K2CO3 (0.6 mmol), p-xylene (2 mL), stirred at 120 °C for 12 h.
bIsolated yield.
1124

Beilstein J. Org. Chem. 2016, 12, 1122–1126.
Scheme 1: Double C–H arylation of N-AQ acetamide.
What’s more, when cyclohexylformic acid (2f) was subjected Acknowledgements
with AQ and aryl iodides, the C–H bonds at the two identical The authors are grateful for the financial support from the
β-carbon atoms were simultaneously arylated to yield 2,6- National Natural Science Foundation of China (21562024)
diarylcyclohexylformamides 6 (Scheme 2). The results in the and the Natural Science Foundation of Jiangxi Province
production of all these single and double arylated products indi- (20142BAB213007).
cated the broad application scope of the present one-pot C–H
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