An unprecedented Pd-catalyzed trans-addition of boronic acids to ynamides

Article abstract of DOI:10.1039/c3cc49069f

An unprecedented Pd-catalyzed trans-addition of boronic acids to ynamides has been reported, giving α,β-disubstituted enamides in high yields with excellent regio- and stereoselectivity. A possible mechanism involving the palladium carbene intermediate has been proposed to account for the unusual trans-addition. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3cc49069f

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An unprecedented Pd-catalyzed trans-addition of
boronic acids to ynamides†
Yuanfa Yang,a Lina Wang,a Jieni Zhang,b Yali Jinb and Gangguo Zhu*ab
Cite this: Chem. Commun., 2014,
50, 2347
Received 28th November 2013,
Accepted 6th January 2014
DOI: 10.1039/c3cc49069f
www.rsc.org/chemcomm
Table 1 Screening of the reaction conditionsa
An unprecedented Pd-catalyzed trans-addition of boronic acids to
ynamides has been reported, giving a,b-disubstituted enamides in
high yields with excellent regio- and stereoselectivity. A possible
mechanism involving the palladium carbene intermediate has been
proposed to account for the unusual trans-addition.
Entry
Ligand
Solvent
E/Zb
Yieldc (%)
1d
2d
3
4
5
6
7
8
9
10
11
12
13e
PPh3
Dioxane
Dioxane
Dioxane
DMF
80 : 20
86 : 14
85 : 15
95 : 5
89 : 11
95 : 5
67
71
75
82
78
88
91
93
62
76
56
87
85
Enamides are remarkably versatile building blocks in organic
chemistry because they participate in a wide selection of chemical
transformations.1 Consequently, the interest in enamides has been
long standing and the effective synthesis of these motifs, especially
the stereocontrolled version, is still in urgent need. So far, enamides
can be assembled by the isomerization of N-allylamides,2 hydro-
amination of alkynes or alkenes,3 methylenation of amides,4 amida-
tion of alkenyl halides or equivalents,5 and the C–H activation
strategy.6 The functionalization of ynamides, including silabora-
tion,7a hydroboration,7b hydrophosphorylation,7c hydroacyloxyla-
tion,7d hydroamination,7e hydrohalogenation,8 carbometallation,9
cycloaddition,10 and other reactions,11 stands out as an attractive
alternative protocol for accessing highly substituted enamides.
In continuation of our program geared towards the functionalization
of ynamides,12 we describe here a Pd-catalyzed stereospecific trans-
P(3-tol)3
P(3-tol)3
P(3-tol)3
P(3-tol)3
P(3-tol)3
P(3-tol)3
P(3-tol)3
PPh3
PCy3
dppe
P(4-tol)3
P(3-tol)3
THF
MeOH
Toluene
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
98 : 2
>98 : 2
75 : 25
78 : 22
38 : 62
96 : 4
92 : 8
a
Reaction conditions: 1a (0.30 mmol), 2a (0.45 mmol), Pd(OAc)2
b
(5 mol%), ligand (10 mol%), under N2, 70 1C, 5 h. Determined by GC.
c
Isolated yield. d
2
equiv. of Na2CO3 was added. e Under an air
atomosphere.
addition of boronic acids to ynamides, providing stereodefined 10 mol% of PPh3, and 2 equiv. of Na2CO3 in dioxane at 70 1C under
a,b-disubstituted enamides in high yields with excellent regio- a nitrogen atmosphere for 5 h, a mixture of 80 : 20 E/Z isomers of 3aa
and stereoselectivity. It should be noted that, although transition- was obtained (Table 1, entry 1). Interestingly, the base was found to
metal-catalyzed addition of boronic acids to alkynes has become a be unnecessary for the addition (Table 1, entries 2 and 3). A survey of
powerful method for the assembly of multifunctional alkenes,13 the solvents utilizing P(3-tol)3 as the ligand revealed that the readily
Pd-catalyzed trans-hydroarylation of C–C triple bonds with boronic accessible and environmentally friendly EtOH was the most effective,
acids has not been reported before.14
affording 3aa as a single (E)-isomer in 93% yield (Table 1, entry 8).
The initial investigation began by screening the reaction The regio- and stereochemistry of this reaction was unambiguously
conditions for hydroarylation of ynamide 1a with PhB(OH)2 (2a). determined by the NOE and HMBC measurements (see ESI†). Other
When the reaction was conducted with 5 mol% of Pd(OAc)2, ligands such as PPh3, PCy3, dppe, and P(4-tol)3 provided inferior
results (Table 1, entries 9–12). Therefore, the best reaction condi-
a Key Laboratory of the Ministry of Education for Advanced Catalysis Materials,
Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, China.
E-mail: gangguo@zjnu.cn
tions for trans-addition of boronic acids to ynamides were affirmed
as follows: 5 mol% of Pd(OAc)2 and 10 mol% of P(3-tol)3 in EtOH
under a nitrogen atmosphere at 70 1C for 5 h.
Then, the scope of this trans-hydroarylation reaction was
investigated by using different types of organoboron reagents
(Table 2). Arylboronic acids possessing both electron-withdrawing
b Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road,
Jinhua 321004, China
† Electronic supplementary information (ESI) available: Experimental details and
characterization of compounds 3 and 4. See DOI: 10.1039/c3cc49069f
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Table 2 Scope of boronic acidsa
Table 3 Scope of ynamidesa,b
Entry
2
Yieldb (%)
1
2
3
4
5
6
7
8
4-F-C6H4 (2b)
90 (3ab)
89 (3ac)
84 (3ad)
82 (3ae)
85 (3af)
91 (3ag)
91 (3ah)
89 (3ai)
84 (3aj)
88 (3ak)
92 (3al)
87 (3am)
83 (3an)
88 (3ao)
85 (3ap)
86 (3aq)
79 (3ar)
70 (3as)
82 (3at)
77 (3au)
76 (3aa)
NR
2,4-F2-C6H3 (2c)
4-CF3-C6H4 (2d)
3-NO2-C6H4 (2e)
4-Cl-C6H4 (2f)
4-Me-C6H4 (2g)
3-Me-C6H4 (2h)
2-Me-C6H4 (2i)
4-OMe-C6H4 (2j)
3,4-(OMe)2-C6H3 (2k)
3,4-Methylenedioxyphenyl (2l)
4-CHO-C6H4 (2m)
4-MeCO-C6H4 (2n)
4-CN-C6H4 (2o)
4-Ph-C6H4 (2p)
2-Naphthyl (2q)
(E)-1-Pentenyl (2r)
(E)-Styryl (2s)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
a
b
c
Reaction conditions: see Table 1, 5–12 h. Isolated yield. Deter-
mined by GC.
2-Thienyl (2t)
2-Benzothiazolyl (2u)
PhBpin (2v)
Next, we turned our attention to explore the synthetic utility
of this protocol. When compound 3ag was treated with 1 mol%
of I2 and 5 mol% of CuCl2 in MeOH at 50 1C for 24 h,12b
a phenanthrene derivative 4 was obtained in 70% yield upon
isolation (eqn (1)).
Me (2w)
a
b
Reaction conditions: see Table 1. Isolated yield.
and electron-donating substituents served as the good coupling
partners in this process. Of note, the steric hindrance of 2
seemed to have no significant influence on the yield (Table 2,
entries 1, 2, and 6–8). Gratifyingly, various functional groups
such as F, CF3, NO2, Cl, OMe, CHO, Ac, CN, alkyl and aryl
substituents were found to be compatible (Table 2, entries 1–16).
Alkenyl boronic acids 2r and 2s furnished the 1,3-dienyl amides
3ar and 3as in good yields with excellent regio- and stereo-
selectivity (Table 2, entries 17 and 18). Moreover, the reaction
was applicable to heteroarylboronic acids, as demonstrated by
the reaction of 2t and 2u (Table 2, entries 19 and 20). Reaction of
PhBpin (2v) performed well to generate 3aa in satisfactory yield,
(1)
(2)
Meanwhile, the deuteration experiments were conducted by
while MeB(OH)2 (2w) did not yield the desired product (Table 2, reacting 1a with (PhBO)3 in CD3OD at reflux for 5 h, and
entries 21 and 22). consequently, 3aa-d was isolated in 87% yield with 95% deuter-
On the other hand, a variety of ynamides were successfully ium incorporation (eqn (2)). Although the detailed mechanism
applied to the present trans-hydroarylation reaction. As shown for this unexpected trans-addition of boronic acids to ynamides
in Table 3, both electron-poor and electron-rich ynamides is still unclear at the current stage, a plausible mechanism is
1b–g reacted well to produce the corresponding enamides in proposed in Scheme 1. Initially, an intermediate A, generated
excellent yields (Table 3, 3ba–ga). Vinylic ynamide 1i furnished from transmetallation of Pd(II) with boronic acids 2, undergoes
dienyl enamide 3ia in 76% yield, and substrate 1j, with an alkyl the cis-carbopalladation with 1 to afford the species B. The
chain, was also found to be well tolerated (Table 3, 3ia and 3ja). highly polarized C–C triple bond of 1, resulted from the electron
The N-Me and N-Bn substrates 1l and 1m provided 3lj and donation by the nitrogen atom, may be responsible for controlling the
3mj in high yields, while the N-Cy counterpart 1n failed to regioselectivity of carbopalladation. Then, the E–Z isomerization15,16
produce the expected product, implying that the steric effects of can take place via the palladium carbene species C, leading to the
N-substituents of ynamides had some influence on this reaction production of D. Finally, the protonolysis of the alkenyl C–Pd bond17
(Table 3, 3lj–nj). In contrast, ynamide 1o provided the trans- of D provides 3 and regenerates the Pd(II) catalyst (Scheme 1).
addition product 3oj in reduced stereoselectivity (Table 3, 3oj).
In summary, we have achieved a Pd-catalyzed stereospecific
Additionally, when 3-(2-phenylethynyl)-2-oxazolidinone (1p) was trans-addition of boronic acids to ynamides for the first time,
subjected to the standard reaction conditions, only low conversion furnishing a,b-disubstituted enamides in high yields with excellent
(o15%) was observed.
regio- and stereoselectivity. The reaction operates under mild
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This work was supported by Natural Science Foundation of
Zhejiang Province (LR12B02001), National Natural Science
Foundation of China (No. 20902084 and 21172199), and Open
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Chem. Commun., 2014, 50, 2347--2349 | 2349