Sequential intermolecular aminopalladation/ortho-arene C-H activation reactions of N-phenylpropiolamides with phthalimide

Article abstract of DOI:10.1021/ol800080w

A novel palladium-catalyzed intermolecular aminopalladation/C-H activation method for selectively synthesizing (E)-(2-oxindolin-3-ylidene)-phthalimides has been developed. In the presence of Pd(OAc)₂ and Phl(OAc) ₂, alkynes were difunctionalized with a phthalimide and an arene sp² C-H bond to selectively synthesize (E)-(2-oxoindolin-3-ylidene) phthalimides, which products are of great potential pharmaceutical value products in many major therapeutic areas, such as oncology, inflammation, neurology, immunology, and endocrinology. To the best of our knowledge, the reaction serves as the first example of intermolecular aminopalladation/C-H activation reactions of alkynes.

Full text of DOI:10.1021/ol800080w

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1179-1182
Sequential Intermolecular
Aminopalladation/ortho-Arene C
Activation Reactions of
−H
N-Phenylpropiolamides with Phthalimide
Shi Tang,†,‡ Peng Peng,† Shao-Feng Pi,† Yun Liang,† Nai-Xing Wang,*,‡ and
Jin-Heng Li*,†
Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing
100080, China, Graduate School of Chinese Academy of Sciences, Beijing, China, and
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research,
Hunan Normal UniVersity, Changsha 410081, China
jhli@hunnu.edu.cn
Received January 13, 2008
ABSTRACT
A novel palladium-catalyzed intermolecular aminopalladation/C
phthalimides has been developed. In the presence of Pd(OAc)2 and PhI(OAc)2, alkynes were difunctionalized with a phthalimide and an arene
sp2
H bond to selectively synthesize (E)-(2-oxoindolin-3-ylidene)phthalimides, which products are of great potential pharmaceutical value
products in many major therapeutic areas, such as oncology, inflammation, neurology, immunology, and endocrinology. To the best of our
knowledge, the reaction serves as the first example of intermolecular aminopalladation/C H activation reactions of alkynes.
−H activation method for selectively synthesizing (E)-(2-oxindolin-3-ylidene)-
C−
−
Aminopalladation of an alkyne with an amine or an amide
provides a convenient route to the prevalent Pd(II) σ-vinyl
intermediates, which are frequently utilized in the synthesis
of a variety of biologically active and natural N-containing
compounds.1-3 Despite significant efforts that have been
devoted to this area, only two papers have been reported on
intermolecular aminopalladation of alkynes (eq 1).3
ladation process, creates a substantial hindrance for the
second functionalization of the alkynes, which limits their
application in organic synthesis.1-3 Thus, our aim is to utilize
the Pd(II) σ-vinyl intermediate A for a new C-C bond (eq
2). After a series of trials, we developed a mild method for
achieving this goal based on some recent reports showing
that Pd-C σ-bonds are readily oxidized by iodine(III)-based
Moreover, rapid protonolysis of these Pd(II) σ-vinyl
intermediates, particularly in the intermolecular aminopal-
(2) For very recent papers on the intramolecular aminopalladation
reactions of alkynes, see: (a) Liu, J.; Shen, M.; Zhang, Y.; Li, G.;
Khodabocus, A.; Rodriguez, S.; Qu, B.; Farina, V.; Senanayake, C. H.;
Lu, B. Z. Org. Lett. 2006, 8, 3573. (b) Ambrogio, I.; Cacchi, S.; Fabrizi,
G. Org. Lett. 2006, 8, 2083. (c) Lu, B. Z.; Zhao, W.; Wei, H.-X.; Dufour,
M.; Farina, V.; Senanayake, C. H. Org. Lett. 2006, 8, 3271. (d) Shen, Z.;
Lu, X. Tetrahedron 2006, 62, 10896. (e) Tang, Z.-Y.; Hu, Q.-S. AdV. Synth.
Catal. 2006, 348, 846. (f) Sanz, R.; Castroviejo, M. P.; Guilarte, V.; Perez,
A.; Fananas, F. J. J. Org. Chem. 2007, 72, 5113. (g) Tang, S.; Xie, Y.-X.;
Li, J.-H.; Wang, N.-X. Synthesis 2007, 1841.
† Hunan Normal University.
‡ Technical Institute of Physics and Chemistry.
(1) (a) For reviews, see: (a) Negishi, E. Handbook of Organopalladium
Chemistry for Organic Synthesis, Wiley-Interscience: New York, 2002.
(b) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (c) Alonso,
F.; Beletskava, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079. (d) Cacchi, S.;
Fabrizi, G. Chem. ReV. 2005, 105, 2873. (e) Humphrey, G. R.; Kuethe, J.
T. Chem. ReV. 2006, 106, 2875. (f) Zeni, G.; Larock, R. C. Chem. ReV.
2006, 106, 4644. (g) Chinchilla, R.; Najera, C. Chem. ReV. 2007, 107, 874.
(h) Severin, R.; Doye, S. Chem. Soc. ReV. 2007, 36, 1407.
(3) (a) Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12670.
(b) Shimada, T.; Bajracharya, G. B.; Yamamoto, Y. Eur. J. Org. Chem.
2005, 59.
10.1021/ol800080w CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/22/2008

oxidants.4 Here, we report the first examples of intermo-
lecular aminopalladation/C-H activation reactions of alkynes
with a phthalimide and an ortho-arene sp2 C-H bond in the
presence of Pd(OAc)2 and PhI(OAc)2 (eq 3).
together with a 4% yield of an acetoxypalladation product
3a (entry 7). Two other palladium catalysts, PdCl2 and
Pd(CH3CN)2Cl2, were subsequently tested, and the results
showed that their catalytic activities were reduced to some
extent (entries 8 and 9). Note that no reaction takes place
without Pd catalysts (entry 10).
With the standard conditions in hand, a variety of
N-phenylpropiolamides were surveyed to explore scope of
the oxidative carboamination/C-H activation reaction (Table
2).6 We were happy to find that N-benzyl-N,3-diphenylpro-
piolamide (1b) selectively underwent the desired reaction
with phthalimide, Pd(OAc)2 and PhI(OAc)2 in a 51% yield
(entry 1). However, trace amounts of products 2 were
observed from the analogous amides with the benzyl group
replaced by a hydrogen or an acetyl group (entries 2 and 3).
To our delight, a number of N-methyl-N-phenylpropiolamides
1e-l bearing various functional groups, such as methyl,
fluoro, chloro, bromo, and ester, on the N-aryl ring were
tolerated well (entries 4-11). Amide 1k having a 2-bromo
group, for instance, successfully reacted with phthalimide,
Pd(OAc)2, and PhI(OAc)2 to afford the target product 2k in
a 50% yield (entry 10). It is noteworthy that N-(3-substituted
aryl)propiolamide (1f) regioselectively provides the 6-posi-
tion C-H activated product 2f in 50% yield due to its lower
steric hindrance (entry 5). However, the target product 2l
from substrate 1l includes a mixture of (E)- and (Z)-isomers
(entry 11). Gratifyingly, alkynes 1m-o bearing aryl groups,
electron-rich or electron-deficient, at the terminus of the
alkyne also worked with phthalimide smoothly under the
standard conditions, but the steric hindrance and an electron-
withdrawing group reduced the yield to some extent (entries
13 and 14). While 4-methoxyphenylalkyne 1m afforded the
target product 2m in a 77% yield, 2-methoxyphenylalkyne
1n provided only 42% yield of the corresponding product
2n (entries 12 and 13). Unfortunately, N-phenylpropiolamides
1p and 1q bearing a hydrogen or methyl group at the
terminus of the alkyne were not suitable substrates under
the standard conditions (entries 15 and 16).
As demonstrated in Table 1, the reaction of N-methyl-
N,3-diphenylpropiolamide (1a) with phthalimide was chosen
to screen the optimal conditions.5 Initially, a series of
palladium catalysts combined with oxidants were tested in
ClCH2CH2Cl (DCE). Without any oxidants, the reaction of
amide 1a with phthalimide and Pd(OAc)2 did not occur (entry
1). Identical results were also obtained using either 1,4-
benzobenzoquinone (BQ) or O2 as the oxidant (entries 2 and
3). Gratifyingly, a trace amount of the target aminopallada-
tion product 2a could be observed by GC-MS analysis in
the presence of Cu(OAc)2 (entry 4). This prompted us to
evaluate other oxidants, such as K2S2O8, oxone, and PhI-
(OAc)2 (entries 5-7). While 11-14% yield of 2a was
isolated using K2S2O8 or oxone as the oxidant (entries 5 and
6), PhI(OAc)2 enhanced the yield of 2a sharply to 61%
Table 1. Screening Conditionsa
As listed in Scheme 1, the earlier reports on palladium-
catalyzed transformations for the synthesis of 3-(diphenyl-
methylene)oxindoles proceed via (i) the reaction of N-(2-
iodophenylpropiolamides or 2-(alkynyl)phenylisocyanates
with arylboronic acids,7a-d and (ii) the reaction of N-phenyl-
isolated yield
(%)
(4) For selected papers on the PdII/PdIV process in the presence of iodine-
(III)-based oxidants, see: (a) Kotov, V.; Scarborough, C. C.; Stahl, S. S.
Inorg. Chem. 2007, 46, 1910. (b) Deprez, N. R.; Sanford, M. S. Inorg.
Chem. 2007, 46, 1924. (c) Dick, A. R.; Kampf, J. W.; Sanford, M. S. J.
Am. Chem. Soc. 2005, 127, 12790. (d) Hull, K. L.; Lanni, E. L.; Sanford,
M. S. J. Am. Chem. Soc. 2006, 128, 14047. (e) Liu, G.; Stahl, S. S. J. Am.
Chem. Soc. 2006, 128, 7179. (f) Desai, L. V.; Sanford, M. S. Angew. Chem.,
Int. Ed. 2007, 46, 5737. (g) Dick, A. R.; Remy, M. S.; Kampf, J. W.;
Sanford, M. S. Organometallics 2007, 26, 1365. (h) Whitfield, S. R.;
Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 15142. (i) Tong, X.; Beller,
M.; Tse, M. K. J. Am. Chem. Soc. 2007, 129, 4906. (j) Welbes, L. L.;
Lyons, T. W.; Cychosz, K. A.; Sanford, M. S. J. Am. Chem. Soc. 2007,
129, 5836.
(5) The other three solvents (MeCN, THF, and HOAc) and two additives
(NaOAc and AgBF4) were evaluated, and they disfavored the aminopalla-
dation reaction to some extent. The detailed data were summarized in Table
S1 (Supporting Information).
(6) The products 2 were selectively obtained as (E)-isomers except for
the product 2l. The E-configuration of the tretrasubstituted double bond
was determined according to COSY and NOESY spectroscopy of 2n, and
the authoritative 5-H and/or 8-H shift data of oxindoles in ref 7.
entry
[Pd]/[O]
2a
3a
1
2
3
4
5
6
7
8
9
Pd(OAc)2
0
0
0
0
0
0
0
0
0
4
7
8
0
Pd(OAc)2/BQ
Pd(OAc)2/O2
Pd(OAc)2/Cu(OAc)2
Pd(OAc)2/K2S2O8
Pd(OAc)2/oxone
Pd(OAc)2/PhI(OAc)2
PdCl2/PhI(OAc)2
Pd(CH3CN)2Cl2/PhI(OAc)2
PhI(OAc)2
trace
14
11
61
56
57
0
10
a Reaction conditions: 1a (0.2 mmol), phthalimide (0.6 mmol), [Pd] (10
mol %), [O] (0.4 mmol) and DCE (ClCH2CH2Cl; 3 mL) at 100 °C for 4 h.
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Org. Lett., Vol. 10, No. 6, 2008

Scheme 1
Table 2. Pd(OAc)2-Catalyzed Carboamination/C-H Activation
of N-Phenylpropiolamides 1 with Phthalimidea
To elucidate the present results, a working mechanism as
outlined in Scheme 2 was proposed on the basis of the
Scheme 2. Possible Mechanisms
previously proposed mechanism, in particular the PdII/PIV-
catalyzed amination of olefins mechanism.1-4,7 Complexation
of Pd(II) with both CtC and nitrogen occurs to afford
intermediate C followed by cis-aminopalladation of C with
phthalimide to generate intermediate D. The Pd(II) interme-
diate D can be oxidized readily to generate Pd(IV) interme-
diate E by PhI(OAc)2.4 The ortho-arene sp2 C-H bond on
the N-aromatic ring is then activated by the Pd(IV) species
to form a new C-C bond,4a-d,g,h and regenerate the active
Pd(II) species. The results showed that the traditional Pd-
(0)/Pd(II) oxidants, such as Cu(OAc)2, BQ, and O2, were
ineffective for the present transformation, which ruled out
the Pd(0)/Pd(II) mechanism. Although no arylamine product
was observed in the present transformation,10 we cannot rule
(7) For papers on the synthesis of 3-(diphenylmethylene)oxindoles from
the reactions of N-phenylpropiolamides, see: Pd: (a) Cheung, W. S.; Patch,
R. J.; Player, M. R. J. Org. Chem. 2005, 70, 3741. (b) Yanada, R.; Obika,
S.; Inokuma, T.; Yanada, K.; Yamashita, M.; Ohta, S.; Takemoto, Y. J.
Org. Chem. 2005, 70, 6972. (c) Couty, S.; Lie´gault, B.; Meyer, C.; Cossy,
J. Org. Lett. 2004, 6, 2511. (d) D’Souza, D. M.; Rominger, F.; Mu¨ller, T.
J. J. Angew. Chem., Int. Ed. 2005, 44, 153. (e) Pinto, A.; Neuville, L.;
Retailleau, P.; Zhu, J. Org. Lett. 2006, 8, 4927. (f) Pinto, A.; Neuville, L.;
Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 3291. In/Pd: (g) Yanada, R.;
Obika, S.; Oyama, M.; Takemoto, Y. Org. Lett. 2004, 6, 2825. Rh: (h)
Shintani, R.; Yamagami, T.; Hayashi, T. Org. Lett. 2006, 8, 4799.
(8) For a patent on the synthesis of 3-(aminomethylene)oxindoles, which
also display high pharmaceutical value, see: Burgdorf, L. T.; Bruge, D.;
Greiner, H.; Kordowicz, M.; Sirrenberg, C.; Zenke, F. PCT Int. Appl. WO
2006131186 (CAN 146:62590; AN 2006:1312199), 2006.
(9) For selected papers, see: (a) Mohammadi, M.; McMahon, G.; Sun,
L.; Tang, C.; Hirth, P.; Yeh, B. K.; Hubbard, S. R.; Schlessinger, J. Science
1997, 276, 955. (b) Sun, L.; Tran, N.; Liang, C.; Tang, F.; Rice, A.; Schreck,
R.; Waltz, K.; Shawver, L. K.; McMahon, G.; Tang, C. J. Med. Chem.
1999, 42, 5120. (c) Hare, B. J.; Walters, W. P.; Caron, P. R.; Bemis, G. W.
J. Med. Chem. 2004, 47, 4731. (d) Noble, M. E. M.; Endicott, J. A.; Johnson,
L. N. Science 2004, 203, 1800. (e) Liao, J. J.-L. J. Med. Chem. 2007, 50,
409.
a Reaction conditions: 1 (0.2 mmol), phthalimide (0.6 mmol), Pd(OAc)2
(10 mol %), PdI(OAc)2 (0.4 mmol), and DCE (3 mL) at 100 °C for 3-10
h. b Isolated yield. c The ratio of E:Z is 3:1 as determined by 1H NMR
spectra.
propiolamides with aryl iodides.7e-f Compared with these
reported transformations, the present protocol is clearly dif-
ferent: (i) all these reported transformations worked in the
presence of a Pd(0) catalyst and a base. In contrast, the pres-
ent protocol was conducted with the aid of a Pd(II) catalyst
and an oxidant (PhI(OAc)2), and no bases were required.
(ii) Zhu’s method proceeded via an addition of alkyne with
an electrophilic aryl iodide reagent, whereas the present pro-
tocol is attack of alkyne with a nucleophilic amide reagent.
(10) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560.
Org. Lett., Vol. 10, No. 6, 2008
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out another possible mechanism, which is initiated by arene
C-H bond palladation to yield intermediate F followed by
cis-addition with alkyne to give vinylpalladation intermediate
G. Pd(IV) intermediate H is generated by oxidation of the
Pd(II) intermediate G. Pd(IV) intermediate H undergoes
reductive elimination with PhthNH to generate the product
2 and the active Pd(II) species.
In summary, we have developed a novel palladium-
catalyzed carboamination/C-H activation of the alkyne
method for selectively synthesizing (E)-(2-oxindolin-3-
ylidene)phthalimide. In the presence of Pd(OAc)2 and PhI-
(OAc)2, N-phenylpropiolamides successfully underwent the
difunctionalization reactions with a phthalimide and an aryl
sp2 C-H bond in moderate to good yields. Importantly, we
have developed a novel route to the synthesis of new types
of oxindoles,7,8 and oxindoles are of great potential phar-
maceutical value products in many major therapeutic areas,
such as oncology, inflammation, neurology, immunology,
and endocrinology.8,9 Work to probe the detailed mechanism,
determine the bioactivities of these compounds, and apply
the reaction in pharmaceutical synthesis is underway.
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (Nos. 20572020, 20472090 and
20335020), the Specialized Research Fund for the Doctoral
Program of Higher Education (No. 20060542007), New
Century Excellent Talents in University (No. NCET-06-0711)
and Fok Ying Tung Education Foundation (No. 101012) for
financial support.
Supporting Information Available: Analytical data and
spectra (1H and 13C NMR) for all the products 2 and 3;
typical procedure for the intramolecular electrophilic ipso-
iodocyclization reaction. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL800080W
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Org. Lett., Vol. 10, No. 6, 2008