Palladium-catalyzed regioselective γ-mono- and diarylation of acrylamide derivatives with aryl halides

Article abstract of DOI:10.1002/adsc.201100373

Palladium-catalyzed direct mono- and diarylations involving C(sp ³)-H cleavage at the γ-position of acrylamides are described. The monoarylation products can be obtained with ortho-substituted aryl halides. Single crystal X-ray diffraction has

Full text of DOI:10.1002/adsc.201100373

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DOI: 10.1002/adsc.201100373
Palladium-Catalyzed Regioselective g-Mono- and Diarylation of
Acrylamide Derivatives with Aryl Halides
Ming Yu,a Yongju Xie,a Jinheng Li,b,* and Yuhong Zhanga,c,*
a
Department of Chemistry, Zhejiang University, Hangzhou 310027, Peopleꢀs Republic of China
Fax : (+86)-571-8795-3244; e-mail: yhzhang@zju.edu.cn
College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, Peopleꢀs Republic of China
b
Fax : (+86)-577-8836-8607; e-mail: jhli@hunnu.edu.cn
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, Peopleꢀs Republic of China
c
Received: May 12, 2011; Published online: November 7, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100373.
Abstract: Palladium-catalyzed direct mono- and di-
philic than the enolate. In fact, the g-arylation of a,b-
unsaturated ketones and related carbonyl functional
groups is still rare.[6] To overcome these problems, ac-
tivated a,b-unsaturated esters instead of simple a,b-
unsaturated esters have been employed for the prepa-
ration of g-arylated a,b-unsaturated esters.[7] Herein,
we report the new Pd(0)-catalyzed intermolecular ar-
ylation of acrylamide derivatives with aryl iodides and
aryl bromides. It is found that arylation at the g-posi-
3
À
arylations involving C
N
sition of acrylamides are described. The monoaryla-
tion products can be obtained with ortho-substitut-
ed aryl halides. Single crystal X-ray diffraction has
shown that the double bond has shifted towards the
introduced aryl group to afford the g-arylated b,g-
unsaturated amide products. A second arylation
occurs when less sterically hindered aryl halides are
employed. This chemistry offers a novel disconnec-
tion for the synthesis of g-arylated compounds.
À
tion to the C H bond of the acrylamides can be
smoothly achieved and the subsequent double bond
shift leads to the formation of b,g-unsaturated amide
products. The a- and/or b-regioisomeric arylation
products are not detected in this transformation. This
chemistry will offer a novel disconnection for the syn-
thesis of arylated compounds.
Keywords: acrylamides; allylic compounds; amides;
À
g-arylation; aryl halides; C C bond formation; pal-
ladium catalysis
Initially, we examined the reaction of substrate 1a
and iodobenzene 2a in the presence of 10 mol%
PdACTHNUTRGEN(NUG OAc)2 and 3 equiv. t-BuONa at 1108C for 1 h,
The transition metal-catalyzed coupling of enolates which afforded arylated product 3a in 9% yield
with aryl and vinyl electrophiles has attracted signifi- (Table 1). The result of heteronuclear multiple-bond
cant research efforts due to its importance in organic coherence (HMBC) experiments of the product dem-
synthesis and the chemical industry.[1] In particular, onstrated that the CH2 groups had correlations with
the palladium-catalyzed direct a-arylation of ketones carbonyl groups, revealing that double bond was shift-
and related carbonyl functional groups has emerged ed towards the aryl group. The most valuable infor-
as a powerful and versatile tool for the generation of mation regarding the constitution of the arylated
a-aryl ketones from ketones and aryl halides via an product was unambiguously established by X-ray
enolate mechanism.[2] Recently, some examples of the analysis of the related derivative 4e (CCDC 825218)
b-arylation reaction of ketones and related carbonyl (Figure 1), which clearly indicated the double bond
functional groups were reported.[3] However, the ex- shift towards the aryl group to give the b,g-unsaturat-
tension of this reaction to a,b-unsaturated carbonyl ed amides. The 1,3-hydrogen shift in the absence of
compounds by the dienolate mechanism has been aryl iodide was not observed under the reaction con-
much less developed.[4] A key factor that contributes ditions, showing that the 1,3-hydrogen shift took place
to the difficulty of developing such a process is the after the arylation. The effects of palladium catalysts
poor regioselectivity: there is the potential for the and phosphine ligands toward the reaction were ex-
generation of a-, b-, and g-regioisomeric products.[5] amined (Table 1). The ligand has a significant impact
In addition, the reactivity of the dienolate is reduced on the reactivity. The reaction of substrate 1a with io-
compared to that of the enolate for it is less nucleo- dobenzene 2a in the absence of the ligand or in the
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Table 1. The effect of palladium-catalysts and ligands.[a]
combination of 10 mol% PdCl2 and 20 mol% PPh3 re-
sulted in a mixture of 3a and the single arylated prod-
uct (Table 1, entry 9). The choice of palladium cata-
lyst was important: Pd
result in comparison
Pd(CH3CN)2Cl2. There was no reaction when EtONa
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
or Cs2CO3 was used as base (see Supporting Informa-
tion).
We next examined the generality of this new
tandem arylation reaction. The reaction was found to
be chemoselective, and its wide scope is evident from
the results summarized in Table 2. Both aryl iodides
and aryl bromides reacted smoothly with 1a to afford
the diarylated b,g-unsaturated amides. The electron-
rich aryl iodides participated in the reaction to give
the corresponding arylated products in good yields
(Table 2, entries 1, 4, 6, and 10). Gratifyingly, aryl bro-
mides showed almost the similar reactivity as aryl io-
dides to give the diarylated products in high efficiency
(Table 2, entries 2–11). 4-Bromobiphenyl and 4-
bromo-4’-methylbiphenyl underwent the reaction
smoothly to afford the corresponding products in
good yields (Table, 2, entries 12 and 13). It should be
Entry
Catalyst
Ligand
Yield of 3a [%][b]
1
2
3
4
5
6
7
8
9
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
N
–
9
dppb
PCy3
xantphos
–
Ph3P
Ph3P
–
trace
trace
22
14
40 (24)[c,d]
66
65[c]
PdCl2
Ph3P
32 (29)[d]
[a]
Conditions: 1a (79.5 mg, 0.3 mmol), iodobenzene
(244.8 mg, 1.2 mmol), 10 mol% Pd catalyst, 20 mol%
ligand, 3 equiv. t-BuONa (0.9 mmol, 86.4 mg), 2 mL tolu- noted that electron-deficient aryl halides showed
ene under a nitrogen atmosphere at 1108C for 1 h.
Isolated yield of 3a and 4a.
Run at 808C for 12 h.
equally good reactivity as electron-rich aryl halides
(Table 2, entries 14 and 15). The chemoselectivity of
the reaction is noteworthy, as the presence of two hal-
ides (bromide and chloride) on the aromatic ring fur-
nishes the b,g-unsaturated amide 3j as the sole reac-
tion product. In addition, although the N-arylation
and b-arylation (Heck reaction) could theoretically
proceed under these conditions, the exclusive forma-
tion of products 3 was observed.
[b]
[c]
[d]
The yield of single arylated 4a is given in the parenthesis.
Interestingly, substrates containing ortho-substitu-
ents in the aryl halides participate in the reaction to
give the corresponding single arylated b,g-unsaturated
amides (Table 3, entries 1–6). The X-ray diffraction
analysis of the single crystal of product 4e (CCDC
825218) indicated that the double bond in the acryl-
AHCTUNGTREGUNaNN mides was shifted towards the aryl group and the
amide was in the trans-position with regard to the
aryl group to give an E-isomer (Figure 1). The results
suggest that the direct arylation is predominantly con-
Figure 1. The X-ray crystal structure of product 4e.
presence of alkylphosphine ligands such as dppb and trolled by steric factors in these systems and the
PCy3 showed poor reactivity (Table 1, entries 1–3). second arylation failed to occur.
Better results were obtained with xantphos and the
use of Pd
tries 4 and 5). The combination of 10 mol% Pd
On the basis of the known chemistry of dienolates[6]
À
(PPh3)4 delivered a 14% yield (Table 1, en- and previous work on the Pd-catalyzed C H bond ac-
(OAc)2 tivation,[8] we suggest two possible pathways (Path A
and 20 mol% PPh3 afforded the diarylated product 3a and Path B) to account for the present arylation pro-
in 40% yield and the single arylated product in 24% cess (Scheme 1). In Path A, the Pd(0) initially under-
yield at 808C for 12 h (Table 1, entry 6). The reaction goes the oxidative addition with aryl iodide to form
efficiency was enhanced markedly when the tempera- intermediate I, which reacts with dienolate II to
ture was increased to 1108C to give a 66% yield after afford the intermediate IV and VII. The subsequent
1 h (Table 1, entry 7). Good results were also obtained reductive elimination results in the arylated product
by the use of PdACHTUNGTRENNUNG(PPh3)Cl2 to give a 65% yield at 808C VIII, which undergoes the 1,3-hydrogen shift to give
for 12 h (Table 1, entry 8). In this case, however, the the final g-arylated product. Path B involves the for-
higher temperature did not favor the reaction. The mation of imine intermediate V, which results in the
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Palladium-Catalyzed Regioselective g-Mono- and Diarylation of Acrylamide Derivatives
Table 2. Direct diarylation of acrylamide derivatives.[a]
Entry
1
Ar1-X
3
Yield[b] [%] (Product No.)
66 (3a)
2
3
48 (3a)
56 (3b)
4
5
64 (3b)
62 (3c)
6
7
56 (3d)
64 (3d)
8
9
55 (3e)
61 (3f)
10
11
56 (3g)
63 (3g)
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Table 2. (Continued)
Entry
Ar1-X
3
Yield[b] [%] (Product No.)
12
71(3h)[c]
13
14
61 (3i)c)
61 (3j)
63 (3j)
15
[a]
Conditions: 1a (79.5 mg, 0.3 mmol), aryl halide (1.2 mmol), 10 mol% PdACTHUNGTRNEUNG(OAc)2 (6.7 mg, 0.03 mmol), 20 mol% PPh3
(0.06 mmol, 15.7 mg), 3 equiv. t-BuONa (0.9 mmol, 86.4 mg), toluene (2 mL), 1108C under N2 for 1 h.
Isolated yields.
The reaction was performed at 808C under N2 for 12 h in the presence of 10 mol% PdACHTNUGTRNE(UGN Ph3P)2Cl2 (0.03 mmol, 21.1 mg).
[b]
[c]
Scheme 1. The possible mechanism.
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Palladium-Catalyzed Regioselective g-Mono- and Diarylation of Acrylamide Derivatives
Table 3. Direct single arylation of acrylamide derivatives.[a]
Entry
1
Ar2-X
4
Yield[b] [%] (Product No.)
42 (4b)[c]
2
3
37(4b)[c]
70 (4c)
4
5
68 (4d)
65 (4e)[c,d]
61 (4e)[c]
6
[a]
Conditions: 1a (79.5 mg, 0.3 mmol), aryl halide (1.2 mmol), 10 mol% PdACTHUNGTRNEUNG(OAc)2 (6.7 mg, 0.03 mmol), 20 mol% PPh3
(0.06 mmol, 15.7 mg), 3 equiv. t-BuONa (86.4 mg, 0.9 mmol), toluene (2 mL), 1108C under N2 for 1 h.
Isolated yields.
[b]
[c]
[d]
The reaction was performed at 808C under N2 for 12 h in the presence of 10 mol% Pd
1a (0.36 mmol), aryl bromide (0.3 mmol).
ACHTUGNTRENUN(GN Ph3P)2Cl2 (0.03 mmol, 21.1 mg).
intermediate VI after the allylic hydrogen was ab- failed to give the desired g-arylated product under the
stracted by the base. The intramolecular anion ex- identical conditions. This result shows that an acidic
À
change generates the same intermediate VII, which N H bond in the amide directing group is essential
goes on to the product.
for the reactivity. While this result is consistent with
In an effort to gain more evidence about the mech- the mechanism illustrated in Path B, we still cannot
anism, control experiments were performed to study rule out the mechanism shown in Path A.
the catalytic pathways (Scheme 2). Treatment of iodo-
In summary, we have developed a new method for
benzene with (E)-N-perfluorophenylbut-2-enamide 6 achieving palladium-catalyzed direct mono- and di-
Scheme 2. Control experiments.
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Typical Procedure for 3a
A mixture of 3-methyl-N-(perfluorophenyl) but-2-enamide
1a (79.5 mg, 0.3 mmol), iodobenzene (244.8 mg, 1.2 mmol),
Pd (OAc)2 (6.7 mg, 0.03 mmol), PPh3 (15.7 mg, 0.06 mmol)
and t-BuONa (86.4 mg, 0.9 mmol) in toluene (2 mL) was
stirred at room temperature under N2 for 5 min, and then at
1108C for 1 h. Afterward, the reaction mixture was allowed
to cool to room temperature and filtered through a pad of
celite. The solvent was evaporated under reduced pressure
and the residue was subjected to flash column chromatogra-
phy (sila gel, ethyl acetate/petroleum ether=1:10, v/v) to
obtain the desired products in 66% yield.
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Acknowledgements
Funding from National Basic Research Program of China
(No. 2011CB936003) and NSFC(No. 20872126, No. 2107216)
is highly acknowledged.
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