Palladium-catalyzed oxidative carboacetoxylation of activated alkynes with amino acids

Article abstract of DOI:10.1080/00397911.2013.835422

A palladium-catalyzed intramolecular oxidative carboacetoxylation reaction of alkynes with various amino acids has been demonstrated for the first time, forming pharmaceutically important 3-methyleneindolin-2-one. In the presence of Pd(OAc)₂ and ArI(OAc)₂, N-arylpropiolamides underwent tandem acetoxypalladation/C-H functionalization reactions with various Boc-amino acids to form corresponding methyleneindolin-2-ones bearing amino acid motifs in moderate to excellent yields. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.] Copyright

Full text of DOI:10.1080/00397911.2013.835422

Synthetic Communications1, 44: 689–696, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.835422
PALLADIUM-CATALYZED OXIDATIVE
CARBOACETOXYLATION OF ACTIVATED ALKYNES
WITH AMINO ACIDS
Shi Tang, Qing-Lan Li, Dong Zhou, Xin-Mei Tang, and
Shu-Hua Li
College of Chemistry and Chemical Engineering, Jishou University,
Jishou, China
GRAPHICAL ABSTRACT
Abstract A palladium-catalyzed intramolecular oxidative carboacetoxylation reaction of
alkynes with various amino acids has been demonstrated for the first time, forming
pharmaceutically important 3-methyleneindolin-2-one. In the presence of Pd(OAc)2 and
ArI(OAc)2, N-arylpropiolamides underwent tandem acetoxypalladation/C-H functionali-
zation reactions with various Boc-amino acids to form corresponding methyleneindolin-2-
ones bearing amino acid motifs in moderate to excellent yields.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Acetoxypalladation; amino acids; C-H activation; methyleneindolin-2-one;
tandem reaction
INTRODUCTION
3-Methyleneindolin-2-ones, especially the ones bearing hetero atoms on the
side chain, are pharmaceutically interesting compounds that display great potential
utilizations in many major therapeutic areas, such as oncology, inflammation, the
Received July 2, 2013.
Address correspondence to Shi Tang, College of Chemistry and Chemical Engineering, Jishou
University, Jishou 416000, China. E-mail: shitang@126.com
689

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S. TANG ET AL.
central nervous system, immunology, and endocrinology.[1] For example, sunitinib,
BIBF1120, and tenidip were recently commercialized by Plifzer to treat gastrointes-
tinal stromal tumor and inflammation (Fig. 1).
The traditional synthetic method for these compounds is via the intermolecular
condensation of an oxindole with a diaryl ketone.[1,2] However, the methodology is
limited to some extent because of its low selectivity and tedious steps. Considerable
efforts have been devoted to develop the metal-catalyzed domino reactions for the
synthesis of 3-methyleneindolin-2-ones to solve these drawbacks.[3] We recently
developed several oxidative Pd-catalyzed tandem heteropalladation=C-H activation
reactions to prepare a wide variety of 3-heteromethyleneindolin-2-ones.[4] Note that
a wide variety of carboxylic acids including aliphalic and aryl acids could, among
those tandem acetoxypalladation=C-H activation reactions, involved the smooth
acetoxypalladation of actived alkynes (Scheme 1). However, little progess has been
achieved toward acetoxypalladation invoving amino acids. Given the biological
and medicinal importance of amino acid motifs, the by introducing amino acid
Figure 1. Three commercial medicines.
Scheme 1. Oxidative carboacetoxylation of alkynes.

OXIDATIVE CARBOACETOXYLATION OF ALKYNES
691
motifs into the 3-methyleneindolin-2-one skeleton is possible to find some pharme-
ceutically important 3-methyleneindolin-2-ones.[5] With our continuing interest in
tandem reactions combining heteropalladation and C-H activation, we herein dem-
onstrate a tandem acetoxypalladation=C-H activation of activated alkynes and
amino acids to introduce amino acid motifs into 3-methyleneindolin-2-ones.
RESULTS AND DISCUSSION
In the course of our research project aiming at Pd-catalyzed carboacetoxyla-
tion of N-arylpropiolamide and amino acids, N-methyl-N,3-diphenylpropiolamide
(1a) was employed as the starting substrate to explore the optimal conditions
(Table 1). Initially, glycine (NH2CH2CO2H) was used as the nucleophile, and none
Table 1. Screening of conditionsa
Entry
Oxidant
PhI(OAc)2
PhI(OAc)2
Solvent
Yield of 3a (%)b
1c
2d
3
4e
5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Dioxane
THF
0
35
PhI(OAc)2
PhI(OAc)2
55
52
MesI(OAc)2
PhI(OCOCF3)2
PhI(OCOtBu)2
Cu(OAc)2
71
43
6
7
56
11
6
7
Cu(OAc)2=O2
Cu(OAc)2=AgOAc
K2S2O8
13
17
8
9
<10
<10
21
10
11
12
13
14
15f
16g
17h
O2
MesI(OAc)2
MesI(OAc)2
MesI(OAc)2
MesI(OAc)2
MesI(OAc)2
MesI(OAc)2
MesI(OAc)2
15
DMF
<10
23
Toluene
CH3CN
CH3CN
CH3CN
63
12
56
aReaction conditions: 1a (0.3 mmol), 2a (1.5 mmol), Pd(OAc)2 (5 mol%), oxidant
(1.3 eq) in CH3CN (2 mL) at 80 ꢀC for 10 h.
bDetermined by GC with a dodecane as internal standard.
cGlycine (5 equiv) instead of 2a.
d3 equiv of 2a.
e8 equiv of 2a.
f3 mol% of Pd(OAc)2 for 24 h.
gAt rt.
hAt 100 ꢀC.

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S. TANG ET AL.
of the desired product was observed, owing to possible unproductive binding of the
basic amino group (-NH2) to the Pd catalyst. The next screening discovered less
nucleophlic Boc-glycine afforded the desired 3-methyleneindolin-2-one in 35% yield.
Encouraged by this improvement, we then examined the impact of the amount of
Boc-glycine, and the results showed that the amount of Boc-glycine has considerable
influence on the reaction in view of yield and rate (Table 1, entries 2–4). In the pres-
ence of 5 equiv of Boc-NHCH2CO2H (2a), the reaction of amide 1a with Pd(OAc)2
and PhI(OAc)2 in MeCN proceeded smoothly and afforded the product 3a in a yield
of 55% (entry 2). It is worth mentioning that side-product 3-(diphenyl-methylene)-
1-methylindolin-2-one originating from carbopalladation of PhI(OAc)2 was detected
along with the desired product 3a. [3d]. Further screening of oxidants discovered that
bulk MesI(OAc)2 could suppress the mentioned side reaction to enhance the yield to
71% and other typical oxidants regenenated Pd(II) and=or Pd(IV) specices, such as
PhI(OCOCF3)2 (PIFA), PhI(OCOtBu), Cu(OAc)2, and Cu(OAc)2=O2. Cu(OAc)2=
AgOAc and K2S2O8 afforded 3a in unparallel yield (enties 6–10). Solvent screening
revealed CH3CN as the best choice. The reaction can be conducted in good yields
even at a loading of 3 mol% Pd after prolonging the reaction time (entry 15). How-
ever, no reaction was observed without Pd(OAc)2 (entry 8). Finally, the temperature
effect was investigated, and greater temperature favored the reaction (entries
16 and 17).
With optimal carboacetoxylation conditions of N-arylpropiolamide in hand,
we then investigated substrate scope of the reaction shown in Scheme 2. Expectedly,
N-methyl-N,3-diphenylpropiolamide (1a) with various Boc-amino acids could
undergo tandem aetoxypalladation=C-H activation to form corresponding 3-
methyleneindolin-2-ones in moderate to good yield. Note that various Boc-amino
acids can involve the carboacetoxylation smoothly with N-arylpropiolamide irres-
pective of steric and electronic character of the substituent groups. Noteworthy is
that ester and methyl groups on the aromatic ring of amide were successfully toler-
ated and afforded the target product 3b and 3c in 57% and 78% yield respectively.
Boc-alanine and Boc-phenylanine could also involve the carboacetoxylation to
give the desired oxindoles. Unexpectedly, treatment of the steric Boc-proline with
N-methyl-N,3-diphenylpropiolamide
(1a)
underwent
the
tandem
acetoxlpalladation=C-H activation to yield the desired 3-methyleneindolin-2-ones
in a moderate yield (49%). Unfortunately, the N-a-Boc-arginine proved to be inef-
ficient for this transformation owing to the existance of a basic guanidyl group in
N-a-Boc-arginine with which to bind the Pd catalyst unproductively. Expectedly,
the optimization conditions aslo allowed the amide 1d bearing other heterocyclic
motif (thienyl ring) and HOAc to undergo the carboacetoxylation to give the corre-
sponding product 3h.
Subsequently, we treated optical pure Boc-L-proline with N-methyl-N,3-
diphenylpropiolamide (1a) under standard conditions [Pd(OAc)2 (5 mol%) and
MesI(OAc)2(1.3 eq eq) in MeCN] to investigate the racemization of chiral amino
acid in this transformation. We were happy to find that Boc-L-proline underwent
the tandem acetoxylation=C-H activation process with good chirality retention
and gave the desired 3-methyleneindolin-2-one 3f in 95% ee (Scheme 3).
The efficient carboacetoxylation of N-arylpropiolamide with Boc-amino acid is
understood in terms of the catalytic cycles shown in Scheme 4.[4–8] First, PdII with

OXIDATIVE CARBOACETOXYLATION OF ALKYNES
693
Scheme 2. Carboacetoxylation of 1 with Boc-amino acids: (a) reaction conditions: 1 (0.3 mmol), 2
(1.5 mmol), Pd(OAc)2 (5 mol%), MesI(OAc)2 (1.3 eq) in CH3CN (2 mL) at 80 ꢀC for 10–24 h: (b) Isolated
yield.
alkyne and Boc-amino acid readily occurred to afford intermediate A via a acetox-
ypalladation process. The PdII intermediate B is then oxidized by MesI(OAc)2 to give
a PdIV intermediate C. The PdIV intermediate C is formed by activation of ortho-C-H
bond of intermediate B. The reductive elimination of intermediate C occurs readily
to yield the desired 3-methyleneindolin-2-ones and the active PdII species. However,
we cannot rule out the possibility of a PdII=Pd0 mechanism because the target
product could be obtained in the presence of Cu(OAc)2, a traditional PdII=Pd0
oxidant.[9]

694
S. TANG ET AL.
Scheme 3. Carboacetoxylation of 1a with Boc-L-proline.
Scheme 4. Proposed reaction mechanism process. (Figure is provided in color online.)
CONCLUSIONS
In summary, we have developed an efficient carboacetoxylation reaction of
activated alkynes with amino acid through an oxidative tandem acetoxypalladation=
C-H activation process for the first time. It opens a door for constructing pharme-
ceuticallly important 3-methyleneindolin-2-ones bearing amino acid motifs. The
detailed mechanism and application of the novel reaction to more complex targets
are currently under study in our laboratory.
EXPERIMENTAL
All reactions were carried out under an argon atmosphere in flame-dried glass-
ware. Syringes used to transfer anhydrous solvents or reagents were purged with

OXIDATIVE CARBOACETOXYLATION OF ALKYNES
695
argon prior to use. NMR spectra were recorded on solutions in deuterated chloro-
1
form (CDCl3) with residual chloroform (d 7.26 ppm for H NMR and d 77.0 ppm
for 13C NMR). Abbreviations for signal coupling are as follows: s, singlet; d, doub-
let; t, triplet; q, quartet; m, multiplet, br, broad. Column chromatographical purifica-
tions were performed using SiO2(0.040ꢁ0.063 mm, 230ꢁ400 mesh ASTM) from
Merck. Unless otherwise noted, commercial available starting materials and solvents
were purchased from commercial sources and used without further purification. N-
Arylpropiolamides were prepared according to literature procedures.[3d,6] Pd(OAc)2
was purchased from Strem and used without further purification.
A mixture of N-methyl-N,3-diphenylpropiolamide 1a (0.3 mmol), Boc-
NHCH2CO2H 2a (1.5 mmol), Pd(OAc)2 (5 mol%), and MesI(OAc)2 (0.39 mmol) in
CH3CN (2 mL) was stirred at 80 ꢀC for the indicated time until complete consump-
tion of starting material as monitored by thin-layer chromatography (TLC). After
the reaction was finished, the mixture was poured into ethyl acetate, which was
washed with brine. The aqueous layer was further extracted with ethyl acetate.
The combined organic layers was dried over anhydrous Na2SO4 and evaporated
under vacuum. The residue was purified by flash column chromatography (hexane =
ethyl acetate 5:1) to afford the desired product 3a (a yellowish oil, 80 mg, 65%),
1
Rf ¼ 0.31. H NMR (500 MHz, CDCl3) d: 7.67 (d, J ¼ 8.4 Hz, 2H), 7.59 (d, J ¼
7.6 Hz, 1H), 7.46–7.41 (m, 3H), 7.32–7.27 (m, 1H), 7.10–7.05 (m. 1H), 6.81 (d, J ¼
6.8 Hz, 1H), 5.10 (br, 1H), 4.24 (s, 2H), 3.19 (S, 3H), 1.45 (S, 9H). 13C NMR
(125 MHz, CDCl3) d: 167.6, 166.6, 155.9, 142.5, 133.2, 130.7, 129.9, 127.9, 126.3,
117.4, 123.6, 122.2, 121.5, 108.0, 80.4, 42.9, 28.2, 25.9. IR (KBr, cmꢁ1) n 1753.4,
1705.8, 1696.4, 1605.4. MS (EI, 70 eV): m=z (%) ¼ 251 [Mþ þ 1-COCH2NHBoc]
(100), 173 (65). HRMS (EI): calcd. for C23H24N2O5: 408.1685. Found: 408.1683.
ACKNOWLEDGMENTS
We thank the Scientific Research Fund of Hunan Provincial Education
Department (No. 13B094) and Research-Based Learning and Innovative Experiment
Project of Jishou University (No. JSU-CX-2013-03) for financial support.
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