Highly effective Pd-catalyzed ortho olefination of acetanilides: Broad substrate scope and high tolerability

Article abstract of DOI:10.1002/asia.201000613

Bring it on! An effective Pd-catalyzed ortho olefination of various acetanilides has been developed. This transformation has a broad substrate scope and wide functional-group tolerability, regardless of the electronic and steric properties of acetanilide substrates, providing a straightforward access to highly functionalized arenes.

Full text of DOI:10.1002/asia.201000613

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DOI: 10.1002/asia.201000613
Highly Effective Pd-Catalyzed ortho Olefination of Acetanilides: Broad
Substrate Scope and High Tolerability
Byung Seok Kim,[a] Chungsik Jang,[b] Dong Jin Lee,[a] and So Won Youn*[a]
À
In recent years, direct functionalization of C H bonds in
organic compounds has emerged as an efficient, atom-eco-
nomical, and environmentally friendly synthetic tool, with
widespread applications in the preparation of natural prod-
ucts, pharmaceuticals, and organic materials. In particular,
the presence of an electrophile [Eq. (2)]. More specifically,
in the presence of an a,b-unsaturated substrate as a coupling
partner (e.g., E=acrylate), we anticipated the formation of
the corresponding 2’-alkenyl-2-arylanilines as the Fujiwara–
Moritani product.
À
direct activation/functionalization of C H bonds in aromatic
compounds has attracted the most attention[1] and is note-
worthy for its application in industrial settings.[2] As a repre-
sentative example in this context, oxidative cross-coupling
reaction between arenes and olefins, commonly known as
the Fujiwara–Moritani reaction,[1c,g,3] is a powerful variant of
the classical Mizoroki–Heck reaction[4] which circumvents
the use of preformed or less readily accessible aryl halides.
In general, regioselectivity in Fujiwara–Moritani reactions
can be achieved either through the coordinative nature of a
directing group that resides in the aromatic system,[5] or
through the use of external ligands.[6] While significant ad-
vances have been made since the discovery of the Fujiwara–
Moritani reaction with greatly improved efficiency and less
drastic reaction conditions,[7–8] broad substrate scope and
wide functional group compatibility are yet to be realized.
Herein, we report the discovery of a highly effective proto-
col for the Pd-catalyzed Fujiwara–Moritani reaction of sub-
stituted acetanilides with unprecedented substrate scope.[7i]
Along this line of thought, as illustrated in Scheme 1, we
began our investigations using 2-phenylacetanilide (1a) and
methyl acrylate as the test substrates. Much to our surprise,
when a solution of 1a in TFA (0.1m) was treated with Pd-
À
In view of the recent reports on the C H activation of 2-
arylanilines under palladium catalysis [Eq. (1)],[9] we specu-
lated that these substrates could partake in an analogous
mechanistic pathway to afford 2’-substitued 2-arylanilnes in
ACHTNUGRTNE(NUNG OAc)2 (5 mol%), K2S2O8 (1.0 equiv), and methyl acrylate
(2.0 equiv) at room temperature,[10] none of the expected
C2’-substituted Fujiwara–Moritani product 2a’ nor its cy-
clized heterocyclic derivative 2a’’ was detected. Instead, the
C2-substituted Fujiwara–Moritani product 2a was observed
[a] B. S. Kim, D. J. Lee, Prof. Dr. S. W. Youn
Department of Chemistry
1
as the sole product (by H NMR analysis). This unexpected
finding is of great interest since it is well documented that
Hanyang University
Seongdong-Gu, Seoul 133-791 (Korea)
Fax : (+82)2-2299-0762
À
Pd-catalyzed C H functionalizations of ortho-substituted
acetanilides, such as o-methylacetanilide, o-methoxyacetani-
lide, o-trifluoromethylacetanilide, and N-Ac-1-naphthyl-
amine are drastically impeded by the ortho substituents, re-
sulting in very low or no conversion even at elevated tem-
perature.[7b–e,8]
E-mail: sowony73@hanyang.ac.kr
[b] C. Jang
Department of Chemistry
Pukyong National University
Nam-Gu, Busan 608-737ACTHNUTRGNEU(GN Korea)
Based on this serendipitous finding, we subsequently
channeled our efforts to elucidate the possible contributors
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000613.
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Chem. Asian J. 2010, 5, 2336 – 2340

Encouraged by the success in
the Pd-catalyzed ortho func-
tionalization of 2-arylacetani-
lides, we turned our attention
to simple acetanilides as shown
in Table 2. Employing our es-
tablished protocol, oxidative
cross-coupling reactions be-
tween unsubstituted acetanilide
and activated alkenes proceed-
ed smoothly to afford the corre-
sponding 2-alkenylacetanilides
in moderate to good yields
À
Scheme 1. Unexpected C H activation at the C2 position instead of the anticipated C2’ position.
Table 1. Pd-catalyzed oxidative cross-coupling between 2-arylacetanilides
and activated olefins.
to the success of this unexpected oxidative cross-coupling re-
action. First, among a variety of nitrogen protecting groups
examined, the acetyl group was found as the protecting
group of choice (for details, see the Supporting Informa-
tion). Second, Pd
ladium catalyst for this cross-coupling reaction, and no reac-
tion was observed in the absence of Pd(OAc)2. The unique
combination of solvent system [TFA/CH2Cl2 (4:1)], high
concentration (0.5m), and the choice of oxidant (K2S2O8)
was also key to the optimized reaction conditions (for de-
tails, see the Supporting Information). TFA as the source of
acid proved superior among all the acids examined, either
as a solvent/cosolvent or as an additive.
ACHTUNGTRENNUNG(OAc)2 proved to be the most effective pal-
Product
Yield [%][e]
AHCTUNGTRENNUNG
2a: R=CO2Me
2b: R=CO2Et
2c: R=CO2nBu
2d: R=CONMe2
72[a]
64[a] (72)[a,b]
77
59
With the optimized reaction conditions in hand, we set
out to explore the substrate scope of this process and the re-
sults are shown in Table 1. In all cases, reactions between 2-
arylacetanilide 1a and activated olefins proceeded smoothly
to afford 2-alkenyl-6-phenylacetanilides with exclusive E
stereoselectivities in moderate to good yields (Table 1, 2a–
d). Double bond isomerized product 2e was obtained when
methyl methacrylate was employed as the activated olefin,
albeit in a lower yield. Acetanilides bearing strongly elec-
tron-withdrawing groups (e.g., 4-nitro or 5-nitro) required
more forcing conditions (608C) for the cross-coupling reac-
tions to take place, and resulted in the preferential forma-
tion of C2’-functionalized products presumably because the
anilide aromatic system is strongly deactivated (Table 1,
2g,h). Acetanilides with substitution on the 2-aryl domain
also displayed good reactivity, where both electron-donating
and electron-withdrawing substituents were well tolerated
(Table 1, 2i–p). The structure of cross-coupling product 2p
was unambiguously confirmed by X-ray crystallographic
analysis.[11] Equally noteworthy is the fact that this process
can tolerate a variety of functionalities including methoxy,
halogen, ketone, and nitro groups (Table 1, 2g–p). In the
case of halogenated substrates, only C2-alkenylation prod-
ucts were observed (Table 1, 2n,o), uncomplicated by deha-
logenation or Heck-type processes which could potentially
take place at the halogenated positions. As such, this func-
tional group tolerance should permit further elaboration of
the cross-coupling products, and enable greater structural di-
versity.
2e
2 f
37
65[a]
2g: R’=4-NO2
2h: R’=5-NO2
42[b,c]
44[b,c]
2i: R’’=4’-MeO
2j: R’’=3’-MeO
2k: R’’=2’-MeO
2l: R’’=4’-Me
2m: R’’=4’-Ac
2n: R’’=4’-Cl
2o: R’’=4’-F
71
71[b]
70
52 (15)[d]
80
75
66[a]
63
2p: R’’=3’-NO2
Reaction conditions: 1 (1 equiv), olefin (2 equiv), Pd
and K2S2O8 (1 equiv) in TFA/CH2Cl2 (4:1, 0.5m) at 258C for 24–48 h,
unless otherwise noted. [a] With 5 mol% Pd(OAc)2. [b] In TFA (0.5m).
[c] At 608C. [d] Yield of diolefination product at both C2 and C2’ posi-
tions. [e] Yield of isolated product.
ACHTUNGRTEN(NUNG OAc)2 (10 mol%),
AHCTUNGTRENNUNG
(Table 2, 4a–e). Methyl vinyl ketone also proved to be a
suitable substrate, affording the corresponding alkenylated
product 4d. Acrylonitrile, (E)-ethyl crotonate, and styrenes
were less effective substrates for the cross-coupling reac-
1
tions, giving little or no conversions (20–35% by H NMR)
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S. W. Youn et al.
COMMUNICATION
ni reaction;[7b–e,8] therefore, the successful preparation of 4h,
4k, 4p, and 4q is a true testament of the power of this
newly established protocol. Lastly, N-methylacetanilide, a
substrate previously reported to be inert in the Pd-catalyzed
Fujiwara–Moritani reaction[7b–c,e–f] also proceeded unevent-
fully to give product 4r in 52% yield.
Table 2. Pd-catalyzed oxidative cross-coupling between acetanilides and
activated olefins.
Product
Yield [%][f]
The anilide moiety has been demonstrated to be an effec-
4a: R=CO2Me
4b: R=CO2nBu
4c: R=CONMe2
4d: R=COMe
87 (94)[a]
80
[7]
À
tive directing group in C H activation, whereas TFA
67
serves to enhance the electrophilicity of the palladium
71[a,b]
[1c,3f,12]
À
center and its metalation of the aromatic C H bond.
We were delighted to find that, upon treatment of 1a with
4e
43
PdACTHUNTRGENNG(U OAc)2 in TFA, palladacycle I was isolated in 80% yield
[Eq. (3)] and its structure was validated by X-ray crystallo-
graphic analysis (Figure 1).[11] In support of the C H activa-
4 f: R’=4-Me
4g: R’=3-Me
4h: R’=2-Me
4i: R’=4-MeO
4j: R’=3-MeO
4k: R’=2-MeO
4l: R’=4-Cl
4m: R’=3-Cl
4n: R’=4-F
4o: R’=4-NO2
83 (93)[a]
75
À
88[a]
86 (92)[a]
71[c] (81)[a,c]
71 (84)[a]
70
70[a]
76
50[a,d]
4p
82
4q
58[a]
4r
52[a,e]
Figure 1. Molecular structure of I. Thermal ellipsoids are shown at the
30% probability level.
Reaction conditions: 3 (1 equiv), olefin (2 equiv), Pd
and K2S2O8 (1 equiv) in TFA/CH2Cl2 (4:1, 0.5m) at 258C for 20–48 h,
unless otherwise noted. [a] With 10 mol% Pd(OAc)2. [b] In TFA/CH2Cl2
(1:1, 0.5m). [c] In TFA/CH2Cl2 (1:2, 0.5m). [d] At 408C in TFA (0.5m).
Yield was determined by 1H NMR of the crude mixture using trichloro-
ethylene as an internal standard. Isolation failed owing to the nearly
same Rf value as that of starting material. [e] At 608C in TFA (0.5m).
[f] Yield of isolated product.
ACHTUNGRTEN(NUNG OAc)2 (5 mol%),
AHCTUNGTRENNUNG
tion mechanism, indeed palladacycle I underwent stoichio-
metric C2-alkenylation with methyl acrylate to give the
cross-coupling product 2a in 65% yield [Eq. (4)]. Palladacy-
cle I could also catalyze the oxidative coupling of 1a with
methyl acrylate to afford 2a in 70% yield [Eq. (4)]. Further-
more, kinetic isotope experiments suggest that cleavage of
À
the C H bond at the ortho position is involved in the rate-
determining step (for details, see the Supporting Informa-
even at elevated temperature (508C). Similar to the 2-aryl-
acetanilides discussed earlier, acetanilides bearing electron-
donating or -withdrawing substituents were once again well
tolerated, giving cross-coupling product 4 f–o in moderate to
good yields. Excellent regioselectivity was observed for
meta-substituted acetanilides with the reaction taking place
tion).[7c]
À
at the sterically less encumbered aryl C H bond (Table 2,
4g, 4j, and 4m). Noteworthy is the remarkable effectiveness
of this developed protocol in the cross-coupling reactions of
electron-deficient substrates (i.e. 3-chloro-, 4-chloro-, 4-
fluoro-, 4-nitroacetanilide), giving the corresponding prod-
ucts (Table 2, 4l–o) which could not be easily obtained
under the reported Pd-catalyzed Fujiwara–Moritani reaction
conditions.[7–8] Furthermore, as mentioned earlier, ortho-sub-
stituted substrates traditionally have been extremely chal-
lenging in the context of the Pd-catalyzed Fujiwara–Morita-
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Chem. Asian J. 2010, 5, 2336 – 2340

Pd-Catalyzed ortho Olefination of Acetanilides
Scheme 2 outlines a plausible mechanism for the Pd-cata-
lyzed oxidative cross-coupling reaction between acetanilide
1a and methyl acrylate. Based on our experimental findings,
Experimental Section
General procedure for Pd-catalyzed oxidative coupling reactions of N-
Ac-2-aminobiaryls with electron-deficient olefins via C H bond activa-
tion: To a solution of N-Ac-2-aminobiaryl (1) in TFA and CH2Cl2 (4:1,
À
0.5m) were added olefin (2 equiv), PdACTHUNRGTNEGN(U OAc)2 (5–10 mol%), and K2S2O8
(1 equiv). The resulting mixture was stirred at room temperature for the
reported time. After the reaction was completed, the reaction mixture
was poured into water and basified with sat. NaHCO3, and then the prod-
uct was extracted with CH2Cl2 (three times), dried over MgSO4, and con-
centrated in vacuo. The residue was purified by column chromatography
on silica gel to afford the corresponding product 2.
Acknowledgements
This work was supported by Mid-career Researcher Program (No. R01-
2009-008-3940) and Basic Science Research Program (Nos. 2010-0017149
and 2010-0007737) through the National Research Foundation of Korea
(NRF) grant funded by the Ministry of Education, Science and Technolo-
gy (MEST). We thank Dr. Ji-Eun Lee (Central Instrument Facility,
Gyeongsang National University) for X-ray crystallographic analysis and
Prof. Won Koo Lee (Department of Chemistry, Sogang University) for
support of HRMS analysis.
À
Keywords: acetanilides · C H activation · olefination ·
palladium
Scheme 2. Proposed mechanism for the Pd-catalyzed ortho olefination of
acetanilides.
À
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In summary, we have developed an effective Pd-catalyzed
ortho olefination of acetanilides and demonstrated unprece-
dented substrate scope. In particular, this newly established
reaction protocol overcame the deficiencies in the previous-
ly reported Pd-catalyzed Fujiwara–Moritani reactions with
regard to ortho-substituted and electron-deficient acetani-
lides. Furthermore, functional group compatibility should
enable further elaboration of the cross-coupling product,
thereby allowing rapid access to highly functionalized
arenes. In view of the privileged aromatic motifs found in a
number of natural and designed compounds with important
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COMMUNICATION
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À
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Received: August 27, 2010
14561; b) W. C. P. Tsang, R. H. Munday, G. Brasche, N. Zheng, S. L.
Published online: October 4, 2010
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Chem. Asian J. 2010, 5, 2336 – 2340