Aminopalladation-triggered carbene insertion reaction: Synthesis of 2-(1H-indol-3-yl)acetates

Article abstract of DOI:10.1002/adsc.201400799

The first example of a nucleopalladation-triggered carbene insertion reaction for the synthesis of C-3 alkylated indole derivatives from ortho-alkynyltrifluoroacetanilides and α-diazoacetates is presented; it involves a palladium catalyst and a weak base in the open air. Yields range from 49-88% with excellent functional group tolerance. The reaction proceeds through intramolecular aminopalladation of alkynes followed by carbene insertion. Migratory insertion of the carbene into the σ-indolylpalladium intermediate was favored over N-H insertion.

Full text of DOI:10.1002/adsc.201400799

UPDATES
DOI: 10.1002/adsc.201400799
Aminopalladation-Triggered Carbene Insertion Reaction:
Synthesis of 2-(1H-Indol-3-yl)acetates
Ziwei Hu,a Shuang Luo,a,* and Qiang Zhua,*
a
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of
Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, Peopleꢀs Republic of China
Fax : (+86)-20-3201-5299; phone: (+86)-20-3201-5287; e-mail: luo_shuang@gibh.ac.cn or zhu_qiang@gibh.ac.cn
Received: August 12, 2014; Revised: January 6, 2015; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400799.
À
Abstract: The first example of a nucleopalladation-
triggered carbene insertion reaction for the synthe-
sis of C-3 alkylated indole derivatives from ortho-
alkynyltrifluoroacetanilides and a-diazoacetates is
presented; it involves a palladium catalyst and
a weak base in the open air. Yields range from 49–
88% with excellent functional group tolerance. The
reaction proceeds through intramolecular aminopal-
ladation of alkynes followed by carbene insertion.
Migratory insertion of the carbene into the s-indo-
mations, such as X H (X=C or heteroatom) inser-
tion, cyclopropanation, ylide formation, and others
useful reactions.[7] The RPdX species used for carbene
complex formation can be generated mainly through
two pathways including oxidative addition of aryl, al-
kenyl, benzyl or allylic halides to Pd(0),[8] and ligand
exchange or transmetallation of terminal alkynes or
arylboronic acids with Pd(II).[9] On the other hand,
nucleopalladation of alkynes activated by Pd(II) spe-
cies is a well-established strategy for alkyne difunc-
tionalization, which is particularly useful in heterocy-
cle synthesis.[10] Very recently, intramolecular carbo-
palladation of alkynes followed by carbene insertion
reactions have been reported for the synthesis of
3-vinylindoles and 3-vinylbenzofurans [Eq. (1),
Scheme 1].[11] Herein we report an aminopalladation-
triggered carbene insertion reaction for the synthesis
of 2-(1H-indol-3-yl)acetates under mild conditions
[Eq. (2), Scheme 1].
À
lylpalladium intermediate was favored over N H
insertion.
Keywords: acetates; carbene insertion; indoles; nu-
cleopalladation; palladium
To some extent, the versatility of palladium chemistry
The indole scaffold exists ubiquitously in natural
relies on the fact that unsaturated small molecules, products, biologically active molecules, pharmaceuti-
such as alkenes,[1] alkynes,[2] CO,[3] and isocyanides[4] cals, and agrochemicals.[12] As a result, developing
À
can insert into X Pd bonds (X=C or heteroatom), practical methods for the synthesis of indole deriva-
À
À
generating X C and C Pd bonds for further transfor- tives has been a long-lasting interest. In recent years,
mations. During the past decade, diazo compounds palladium-catalyzed tandem processes for indole syn-
have been recognized as another class of small mole- thesis have attracted great attention.[13] Among them,
cules applicable in these migratory insertion reactions intramolecular aminopalladation of ortho-alkynylani-
which were first developed by Van Vranken[5] and lides followed by trapping with various nucleophiles is
then systematically investigated by Wang and a prominent approach for the construction of substi-
others.[6] The key palladium carbene intermediates tuted indole derivatives. According to our recent re-
can be generated by Pd(II)-facilitated decomposition ports on the synthesis of 2-substituted 1H-indole-3-
of stabilized diazo compounds, or transformation of carboxamides[14] and 2-substituted 1H-indole-3-car-
N-tosylhydrazones as precursors of non-stabilized boxamidines[15] through isocyanide insertion, we envi-
diazo compounds. Subsequently, migratory insertion sioned that indole derivatives containing a C-3 alkyl-
À
of the carbene moiety into R Pd bond would create substituted acetate moiety could be obtained through
a new C Pd s-bond which can be utilized for further palladium-catalyzed intramolecular aminopalladation
À
transformations including b-H elimination, protona- of ortho-alkynylanilides followed by carbene inser-
tion, or cross-coupling.[6] This novel C C bond-form- tion, although competitive N H insertion is a foresee-
ing strategy greatly expands the synthetic application able side reaction in this process. Furthermore, it is
of diazo compounds to many conventional transfor-
À
À
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

UPDATES
Ziwei Hu et al.
Scheme 1. Nucleopalladation-triggered carbene insertion reactions.
Table 1. Optimization of the reaction conditions.[a]
Scheme 2. Natural products containing the 2-(indol-3-yl)ace-
tate moiety.
Entry Pd
Base/equiv. Solvent
Yield [%][b]
worthy of note that the skeleton of the resulting prod-
ucts can be found in natural products (Scheme 2).
To test the hypothesis, we initiated the study by re-
acting ortho-(phenylethynyl)trifluoroacetanilide 1a
and methyl a-phenyldiazoacetate 2a in the presence
of PdCl2 (5 mol%) and Na2CO3 (1.0 equiv.) at 808C in
DMSO in the open air (Table 1). Gratifyingly, the ex-
pected product, methyl 2-phenyl-2-(2-phenyl-1H-
indol-3-yl)acetate 3a, was isolated in 54% yield
(entry 1). DMF was found to be the most suitable sol-
vent for the reaction after extensive screening (en-
1
PdCl2
Na2CO3/1.0 DMSO
Na2CO3/1.0 toluene
54
trace
2
PdCl2
3
PdCl2
Na2CO3/1.0 dioxane trace
Na2CO3/1.0 DCE trace
Na2CO3/1.0 CH3CN 50
Na2CO3/1.0 DMF 79
Na2CO3/1.0 C2H5OH 37
K2CO3/1.0 DMF
4
PdCl2
5
PdCl2
6
PdCl2
7
PdCl2
8
PdCl2
38
68
57
75
88
88
trace
72
78
78
87
nr
9
PdCl2
Cs2CO3/1.0 DMF
NaOAc/1.0 DMF
10
PdCl2
11
PdCl2
K3PO4/1.0
DMF
tries 1–7). A screen of bases was also conducted, and 12
PdCl2
PdCl2
Na2CO3/1.2 DMF
Na2CO3/1.2 DMF
13[c]
Na2CO3 gave better results than K2CO3, Cs2CO3,
NaOAc and K3PO4 (entries 8–11). Increasing the
amount of Na2CO3 to 1.2 equivalents afforded the
target compound 3a in an improved 88% yield, and
no reaction occurred in the absence of base (en-
tries 12 and 14). A control reaction under argon sug-
gested that dioxygen was unnecessary for this reaction
(entry 13). Other palladium catalysts gave inferior or
comparative results to PdCl2 (entries 15–18). Howev-
er, no product was detected in the absence of a palla-
dium catalyst (entry 19).
14
15
16
17
18
19
PdCl2
–
DMF
Pd(OAc)2
Pd(TFA)2
Pd(acac)2
Na2CO3/1.2 DMF
Na2CO3/1.2 DMF
Na2CO3/1.2 DMF
Pd(MeCN)Cl2 Na2CO3/1.2 DMF
Na2CO3/1.2 DMF
–
[a]
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol,
1.5 equiv.), Pd catalyst (5 mol%), base, solvent (1 mL),
air, 3 h, 808C.
Isolated yield. nr=no reaction.
Argon atmosphere.
[b]
[c]
With the optimized conditions in hand, the sub-
strate scope was then investigated (Scheme 3). Un-
fortunately, no desired product was detected when
AHCTUNGTREGeNNNU thynyl)acetanilide was used as substrate, which indi-
ortho-(phenylethynyl)aniline
or
ortho-(phenyl- cated the necessity of the trifluoroacetamide group in
2
asc.wiley-vch.de
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

UPDATES
Aminopalladation-Triggered Carbene Insertion Reaction
the substrates. ortho-(Phenylethynyl)trifluoroacetani-
lides with electron-donating substituents (Me,
1
OMe) or electron-withdrawing substituents (F, Br,
CF3) on the anilinic ring were tested, and the corre-
sponding products were obtained in moderate to good
yields (3b–3f, 3s). A range of functional groups on the
arylalkynyl moiety, including p-Me, p-OMe, p-Br, and
o-Cl was tolerated under the reaction condition (3g–
3j). In addition, 2-alkenyl- and 2-heteroaryl-substitut-
ed products (3k and 3l) can also be obtained with
moderate yields by following the current procedure.
The structure of 3l was confirmed by X-ray diffrac-
tion.[16] Fortunately, an alkylsubstituted substrate
could also survive the reaction conditions and afford-
ed the 2-alkyl-subsituted product (3r) in moderate
yield.
Then, a variety of a-aryldiazoacetates with p-MeO,
p-Cl, m-MeO, or o-Br substituents was explored.
These functional groups were compatible with the re-
action conditions, and afforded the corresponding
aryl-substituted methyl 2-(2-phenyl-1H-indol-3-yl)ace-
tates 3m–3p in 57–69% yields. When unsubstituted
ethyl diazoacetate was used, the corresponding alky-
lated indole derivative, ethyl 2-(2-phenyl-1H-indol-3-
yl)acetate 3q, was isolated in 59% yield under slightly
modified conditions. It is notable that in all of the
cases, no side product derived from carbene insertion
À
to the N H bond was formed. On the contrary, car-
bene insertion to the N H bond occurred exclusively
À
when N-tosylhydrazone was used as the carbene pre-
cursor.
In order to probe the reaction mechanism, 2-phe-
nylindole 4 and a-phenyldiazoacetate 2a were subject-
ed to the standard reaction conditions. 2-Phenylindole
was completely recovered, while a-phenyldiazoace-
tate 2a decomposed. The result ruled out the possibil-
ity of 2-phenylindole being a reaction intermediate.
Based on the above experiments, a plausible mech-
anism is proposed (Scheme 4). First, substrate depro-
tonation by Na2CO3 and the alkyne moiety activation
by PdCl2 generate a palladium complex A. Then, in-
tramolecular aminopalladation of A forms the key s-
indolylpalladium intermediate B. Decomposition of
a-phenyldiazoacetate 2a by B leads to a palladium
carbene species C with concomitant release of gas-
eous nitrogen. Migratory insertion of the carbene
À
moiety into the C Pd bond of s-indolylpalladium in-
termediate C generates a new C Pd bond in inter-
À
mediate D, which tautomerizes to a more stabilized
enol E. Ligand exchange of E with chloride anion de-
livers the final product 3a after protonation and de-
protection during work-up.
In summary, we have developed an efficient
method for the construction of 2-(1H-indol-3-yl)ace-
tate derivatives through a Pd-catalyzed carbene mi-
gratory insertion reaction in air. This is the first exam-
ple of a nucleopalladation-triggered carbene insertion
Scheme 3. Substrate
scope.
Reaction
conditions:
1
(0.2 mmol), 2 (0.3 mmol, 1.5 equiv.), PdCl2 (1.8 mg,
0.01 mmol, 5 mol%), Na2CO3 (25 mg, 0.24 mmol, 1.2 equiv.),
DMF (1 mL), air, 808C.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

UPDATES
Ziwei Hu et al.
References
[1] a) T. E. Muller, M. Beller, Chem. Rev. 1998, 98, 675;
b) J. L. Bras, J. Muzart, Chem. Rev. 2011, 111, 1170.
[2] R. Chinchilla, C. Nꢃjera, Chem. Rev. 2014, 114, 1783.
[3] a) A. Brennfuhrer, H. Neumann, M. Beller, Angew.
Chem. 2009, 121, 4176; Angew. Chem. Int. Ed. 2009, 48,
4114; b) A. Brennfuhrer, H. Neumann, M. Beller,
ChemCatChem 2009, 1, 28; c) M. Beller, Carbonylation
of Benzyl and Aryl-X Compounds, in: Applied Homo-
geneous Catalysis with Organometallic Compounds, 2nd
edn., (Eds.: B. Cornils, W. A. Herrmann), Wiley-VCH,
Weinheim, 2002, pp 145–156; d) X.-F. Wu, H. Neu-
mann, M. Beller, Chem. Soc. Rev. 2011, 40, 4986; e) X.-
F. Wu, H. Neumann, M. Beller, Chem. Rev. 2013, 113,
1; f) Q. Liu, H. Zhang, A. Lei, Angew. Chem. 2011,
123, 10978; Angew. Chem. Int. Ed. 2011, 50, 10788.
[4] a) T. B. Vlaar, W. Maes, E. Ruijter, R. V. A. Orru,
Angew. Chem. 2013, 125, 7222; Angew. Chem. Int. Ed.
2013, 52, 7084; b) S. Lang, Chem. Soc. Rev. 2013, 42,
4867; c) G. Qiu, Q. Ding, J. Wu, Chem. Soc. Rev. 2013,
42, 5257.
Scheme 4. Plausible reaction mechanism.
[5] a) K. L. Greenman, D. S. Carter, D. L. Van Vranken,
Tetrahedron 2001, 57, 5219; b) K. L. Greenman, D. L.
Van Vranken, Tetrahedron 2005, 61, 6438; c) S. K. J.
Devine, D. L.Van Vranken, Org. Lett. 2007, 9, 2047;
d) S. K. J. Devine, D. L.Van Vranken, Org. Lett. 2008,
10, 1909; e) R. Kudirka, D. L.Van Vranken, J. Org.
Chem. 2008, 73, 3585; f) R. Kudirka, S. K. J. Devine,
C. S. Adams, D. L. Van Vranken, Angew. Chem. 2009,
121, 3731; Angew. Chem. Int. Ed. 2009, 48, 3677; g) A.
Khanna, C. Maung, K. R. Johnson, T. T. Luong, D. L.
Van Vranken, Org. Lett. 2012, 14, 3233.
reaction for the synthesis of C-3 alkylated indole de-
rivatives. The current reaction would expand the ap-
plication of the migratory insertion of palladium car-
bene in C C bond formation. No N H insertion reac-
tion was observed under our reaction conditions.
À
À
Experimental Section
[6] a) Q. Xiao, Y. Zhang, J. Wang, Acc. Chem. Res. 2013,
46, 236; b) Y. Zhang, J. Wang, Eur. J. Org. Chem. 2011,
1015; c) J. Barluenga, C. Valdꢄs, Angew. Chem. 2011,
123, 7626; Angew. Chem. Int. Ed. 2011, 50, 7486; d) Z.
Shao, H. Zhang, Chem. Soc. Rev. 2012, 41, 560; e) Z.
Liu, J. Wang, J. Org. Chem. 2013, 78, 10024; f) Y. Xia,
Y. Zhang, J. Wang, ACS Catal. 2013, 3, 2586.
[7] a) W. R. Bamford, T. S. Stevens, J. Chem. Soc. 1952,
4735; b) T. Ye, M. A. McKervey, Chem. Rev. 1994, 94,
1091; c) A. Padwa, D. J. Austin, Angew. Chem. 1994,
106, 1881; Angew. Chem. Int. Ed. Engl. 1994, 33, 1797;
d) A. Padwa, M. D. Weingarten, Chem. Rev. 1996, 96,
223; e) M. P. Doyle, M. A. McKervey, T. Ye, Modern
Catalytic Methods for Organic Synthesis with Diazo
Compounds: From Cyclopropanes to Ylides, Wiley,
New York, 1998; f) M. P. Doyle, D. C. Forbes, Chem.
Rev. 1998, 98, 911.
[8] a) J. Barluenga, P. Moriel, C. Valdꢄs, F. Aznar, Angew.
Chem. 2007, 119, 5683; Angew. Chem. Int. Ed. 2007, 46,
5587; b) M. Lawson, A. Hamze, J.-F. Peyrat, J. Bignon,
J. Dubois, J.-D. Brion, M. Alami, Org. Biomol. Chem.
2013, 11, 3664; c) M. Roche, A. Hamze, O. Provot, J.-
D. Brion, M. Alami, J. Org. Chem. 2013, 78, 445; d) Z.
Huang, Y. Yang, Q. Xiao, Y. Zhang, J. Wang, Eur. J.
Org. Chem. 2012, 6586; e) K. Yang, J. Zhang, Y. Li, B.
Cheng, L. Zhao, H. Zhai, Org. Lett. 2013, 15, 808; f) Y.
Xia, F. Hu, Z. Liu, P. Qu, R. Ge, C. Ma, Y. Zhang, J
Wang, Org. Lett. 2013, 15, 1784; g) Q. Xiao, J. Ma, Y.
Yang, Y. Zhang, J. Wang, Org. Lett. 2009, 11, 4732;
Typical Procedure for the Preparation of 3a
A
mixture
of
ortho-ethynyltrifluoroacetanilide
1a
(0.2 mmol), PdCl2 (0.01 mmol, 5.0 mol%, 1.8 mg), Na2CO3
(0.24 mmol, 1.2 equiv., 25 mg) and diazoacetate 2a
(0.3 mmol, 1.5 equiv.) in DMF (1 mL) was stirred at 808C
for 3 h. After complete consumption of 1a as monitored by
TLC analysis, the reaction mixture was diluted with H2O
(20 mL) and extracted with EtOAc (20 mLꢂ3). The com-
bined organic layers were washed with brine and concentrat-
ed. The residue was purified by chromatography on silica
gel using petroleum ether/ethyl acetate as eluent to afford
the product 3a as
a
white solid
;
yield: 60 mg
(88%).1H NMR (400 MHz, DMSO-d6): d=11.51 (br s, 1H),
7.50 (m, 4H), 7.42 (m, 3H), 7.29 (m, 2H), 7.22 (m, 3H),
7.12 (m, 1H), 6.96 (m, 1H), 5.38 (s, 1H), 3.58 (s, 3H);
13C NMR (125 MHz, DMSO-d6): d=173.3, 139.5, 137.0,
136.6, 132.5, 129.2, 128.8, 128.7, 128.6, 128.5, 127.6, 127.1,
122.0, 120.4, 119.7, 111.9, 108.0, 52.4, 48.1; IR (KBr): n=
3387, 1723, 1453 cmÀ1; HR-MS (ESI): m/z=342.1486, calcd.
for C23H20NO2 [M+H]+: 342.1489.
Acknowledgements
We are grateful to the National Science Foundation of China
(21402203, 21472190) for financial support of this work.
4
asc.wiley-vch.de
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

UPDATES
Aminopalladation-Triggered Carbene Insertion Reaction
h) W.-Y. Yu, Y.-T. Tsoi, Z. Zhou, A. S. C. Chan, Org.
Lett. 2009, 11, 469; i) S. Chen, J. Wang, Chem.
Commun. 2008, 4198.
[11] a) X. Liu, X. Ma, Y. Huang, Z. Gu, Org. Lett. 2013, 15,
4814; b) Z. Liu, Y. Xia, S. Zhou, L. Wang, Y. Zhang, J.
Wang, Org. Lett. 2013, 15, 5032.
[9] a) L. Zhou, F. Ye, J. Ma, Y. Zhang, J. Wang, Angew.
Chem. 2011, 123, 3572; Angew. Chem. Int. Ed. 2011, 50,
3510; b) C. Peng, Y. Wang, J. Wang, J. Am. Chem. Soc.
2008, 130, 1566; c) X. Zhao, J. Jing, K. Lu, Y. Zhang, J.
Wang, Chem. Commun. 2010, 46, 1724.
[12] a) R. J. Sundberg, Indoles, Academic Press, San Diego,
1996; b) R. J. Sundberg, in: Comprehensive Heterocy-
clic Chemistry, 2nd edn., Vol. 2, (Eds.: A. R. Katritzky,
C. W. Ress), Pergamon, Oxford, 1996, p 119.
[13] a) S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Biomol.
Chem. 2011, 9, 641; b) S. A. Patil, R. Patil, D. D. Miller,
Curr. Med. Chem. 2011, 18, 615; c) R. Vicente, Org.
Biomol. Chem. 2011, 9, 6469; d) S. Cacchi, G. Fabrizi,
Chem. Rev. 2011, 111, PR215; e) G. Palmisano, A.
Penoni, M. Sisti, F. Tibiletti, S. Tollari, K. M. Nicholas,
Curr. Org. Chem. 2010, 14, 2409.
[10] a) Q. Xiao, Y. Luo, Y. Yan, Q. Ding, J. Wu, RSC Adv.
2013, 3, 5779; b) L. Wang, J. Huang, S. Peng, H. Liu, X.
Jiang, J. Wang, Angew. Chem. 2013, 125, 1812; Angew.
Chem. Int. Ed. 2013, 52, 1768; c) X.-F. Xia, L.-L.
Zhang, X.-R. Song, Y.-N. Niu, X.-Y. Liu, Y.-M. Liang,
Chem. Commun. 2013, 49, 1410; d) B. Yao, Q. Wang, J.
Zhu, Angew. Chem. 2012, 124, 5260; Angew. Chem. Int.
Ed. 2012, 51, 5170; e) H. Zhong, D. Yang, S. Wang, J.
Huang, Chem. Commun. 2012, 48, 3236; f) Y. Luo, J.
Wu, Org. Lett. 2011, 13, 5858; g) G. Qiu, Q. Ding, H.
Ren, Y. Peng, J. Wu, Org. Lett. 2010, 12, 3975; h) C.
Wang, S. Rakshit, F. Glorius, J. Am. Chem. Soc. 2010,
132, 14006; i) S. Ding, Z. Shi, N. Jiao, Org. Lett. 2010,
12, 1540; j) M. Yamashita, K. Hirano, T. Satoh, M.
Miura, Org. Lett. 2009, 11, 2337; k) Z. Shi, S. Ding, Y.
Cui, N. Jiao, Angew. Chem. 2009, 121, 8035; Angew.
Chem. Int. Ed. 2009, 48, 7895.
[14] a) Z. Hu, D. Liang, J. Zhao, J. Huang, Q. Zhu, Chem.
Commun. 2012, 48, 7371; b) G. Qiu, C. Chen, L. Yao, J.
Wu, Adv. Synth. Catal. 2013, 355, 1579.
[15] Z. Hu, J. Wang, D. Liang, Q. Zhu, Adv. Synth. Catal.
2013, 355, 3290.
[16] CCDC 1017169 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

UPDATES
6 Aminopalladation-Triggered Carbene Insertion Reaction:
Synthesis of 2-(1H-Indol-3-yl)acetates
Adv. Synth. Catal. 2015, 357, 1 – 6
Ziwei Hu, Shuang Luo,* Qiang Zhu*
6
asc.wiley-vch.de
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!