Catalytic oxidation/C-H functionalization of N-arylpropiolamides by means of gold carbenoids: Concise route to 3-acyloxindoles

Article abstract of DOI:10.1039/c2cc31972a

An efficient catalytic C-H functionalization by means of gold carbenoids for the one-step synthesis of 3-acyloxindole derivatives has been developed. The reaction proceeds efficiently with extremely good substrate scope and significant opportunities for s

Full text of DOI:10.1039/c2cc31972a

View Online / Journal Homepage
ChemComm
Accepted Manuscript
This is an Accepted Manuscript, which has been through the RSC Publishing peer
review process and has been accepted for publication.
Accepted Manuscripts are published online shortly after acceptance, which is prior
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
Chemical Communications
www.rsc.org/chemcomm
Volume 46
| Number 32 | 28 August 2010 | Pages 5813–5976
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
ISSN 1359-7345
COMMUNICATION
FEATURE ARTICLE
J. Fraser Stoddart et al.
Directed self-assembly of
ring-in-ring complex
Wenbin Lin et al.
a
Hybrid nanomaterials for biomedical
applications
1359-7345(2010)46:32;1-H
www.rsc.org/chemcomm
Registered Charity Number 207890

ChemComm
Page 1 of 4ChemComm
Dynamic Article Links ►
View Online
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
COMMUNICATION
Catalytic Oxidation/C–H Functionalization of N-Arylpropiolamides by
Means of Gold Carbenoid: Concise Route to 3-Acyloxindoles†
Deyun Qiana and Junliang Zhang,*a,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
R3
O
An efficient catalytic C–H functionalization by means of gold
carbenoids for one-step synthesis of 3-acyloxindole
derivatives has been developed. The reaction proceeds
efficiently with extremely good substrate scope and
R3
O
N2
O
1-2 steps
TsN3
O
R3 = Me
a
N
R1
R2
N
R1
R2
10 significant opportunities for structural diversification.
[M] = [Rh], [Ag]
Oxindoles are important units in natural products, biologically
active molecules, and drug candidates (Scheme 1).1-2 In this
context, 3-acyloxindoles are striking molecular frames,2 and they
serve as useful precursors for a variety of functional group
15 transformations.3 Consequently, the privileged structure has been
constructed by the acylation of the oxindoles with acyl chlorides
and condensation of the oxindoles with esters,4 transition-metal-
catalyzed intramolecular cyclization of β-keto amides,2a and other
methods.5 Despite enormous efforts has been made, the develop-
20 ment of mild, efficient, and economic methods is still desired: 1)
Precursors should be easily prepared or handled; 2) The synthesis
should be ‘ideal’ as far as possible;6 3) The application of new
strategies as enabling technologies for drug discovery and
synthesis should be highlighted.7 As an alternative approach,
25 recent research has focused on catalytic C–H functionalizations
by means of metal carbenoids.7 Rh- or Ag-catalyzed C–H
functionalization has emerged for the synthesis of 3-acyloxindole
motifs, wherein metal carbenes traditionally formed in situ
through dediazotization (Scheme 2, a).8 However, this method
30 suffers from drawbacks such as tedious steps, relatively limited
R3
R3
R1
OH
HN
[Au
], [O
]
1-2 steps
RT
O
RT
N
N
R1
O
R2
R2
R2
R1
Structural diversification
mild conditions; high efficiency; good substrate scope
This work:
Scheme 2. Methods for the synthesis of 3-acyloxindoles.
scope, and hazardous precursors (potentially expensive α-
diazocarbonyl substrates), which impede the development of its
35 corresponding application. Lately gold-catalyzed alkyne
oxidations using pyridine/quinoline N-oxides as oxidants for the
generation of gold-carbenoid intermediates has presented a
promising alternative to the generation of α-oxo metal carbenes
from α-diazo ketones.9-11 Herein, we describe a concise route to
40 3-acyloxindoles: gold-catalyzed oxidation/C–H functionalization
reaction12 of electron-deficient N-arylpropiolamides; the reaction
proceeds efficiently with extremely good substrate scope and
mild conditions to give 3-acyloxindole derivatives with
significant opportunities for structural diversification.13
45
The groups of Zhang and Liu have done seminal
contribution for the generation of gold carbenes from alkynes.10
However, among these transformations, electron-rich terminal
alkynes are commonly used, while the corresponding electron-
deficient internal alkynes remain rarely reported.11 Recently, we
50 have demonstrated a gold–catalyzed tandem oxidation/
cyclopropanation of electron-deficient 1,6-enynes, leading to
various [n.1.0]bicycloalkanes in good to high yields.11 During
this study, we interestingly found that the reaction of N-phenyl-N-
allylpropiolamide 1a afforded an unexpected 3-acyloxindole 3a
55 in 89% isolated yield rather than the corresponding cyclopropana-
tion product 2a under the catalysis of IPrAuCl/AgNTf2 (eqn (1)).
Encouraged by this result, the readily available N-methyl-N,3-
diphenylpropiolamide 1b was chosen as the model substrate for
optimization of the reaction conditions (see ESI†, Table S1). The
60 reaction of 1b in the presence of various gold catalysts and 2-
Scheme 1. Biologically active molecules
a Shanghai Key Laboratory of Green Chemistry and Chemical Processes,
Department of Chemistry, East China Normal University, 3663 N,
Zhongshan Road, Shanghai 200062 (P. R. China), Fax: (+86) 21-6223-
5039; E-mail: jlzhang@chem.ecnu.edu.cn
b State key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences.
†Electronic Supplementary Information (ESI) available: Representative
experimental procedure and characterization of reaction products See
DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

ChemComm
Page 2 of 4
View Online
Table 1. Scope of the reaction a
bromopydine /8-methylquinoline N-oxide 4a /4b (1.3 equiv) were
investigated. To our delight, the desired 3-acyloxindole 3b was
obtained in the best yield (94%), when [(2,4-tBu2PhO)3P
AuCl]/AgNTf2 was employed as the catalyst and the N-oxide 4a
as the oxidant (Table S1, entry 3).
5
PMP
Ph
Ph
Ph
OH
OH
O
OH
O
OH
O
O
N
N
N
N
Allyl
Bn
3c (90%)
Ac
3a (95%)
3b (91%)
3d (0%)
With the optimized reaction conditions, the substrate scope
was then investigated as shown in Table 1. The effect of the
protecting group on the nitrogen atom was firstly probed. For
Ar
S
OH
O
Ar = 4-MeOC6H4 3e (90%)
Ar = 4-MeC6H4 3f (90%)
Ar = 4-FC6H4
Ar = 4-ClC6H4 3h (86%)
OH
Cl
3g (85%)
10 substrates bearing an N-allyl, alkyl or benzyl group, the reactions
proceeded smoothly to provide products 3a-3c in excellent yields.
In contrast, the substrate with an electron-withdrawing group on
N atom did not yield the desired product 3d. Satisfactory yields
(83-90%) of the 3-acyloxindoles 3e-3h could be obtained,
15 indicating the electron nature of aryl group on the alkyne moiety
has no significant influence on the reaction efficiency. This
oxidative intramolucalar C–H functionalization worked also well
with substrate bearing a thienyl group, thus affording the exciting
product 3i in good yield (87%), the structure of which is core
20 backbone to Tendiap.2 These results illustrate the potential
application of our method in medicinal chemistry. Furthermore,
substituents at different positions on the N-aryl ring (para, meta,
and ortho positions) were readily tolerated and furnished the
corresponding 3-acyloxindole structural motifs 3i-3r and 3w in
25 50-94% yields. Gratifyingly, the substrates having two
substituents on the N-aryl ring were still good for this
transformation (3n-3o, 3q). Notably, several functional groups,
such as methoxy, -Cl and -Br, are compatible with this catalytic
system. It is remarkable that the reaction afforded 3o with
30 excellent regioselectivity. In addition, this new transformation is
applicable to those substrates bearing functionalized alkenyl and
alkyl substituents, including an alkenyl group (3r, 3s), a
cyclopropyl group (3t), an acid-labile group THP (3v), and a
chloroalkyl (3w). These functional groups provide significant
35 opportunities for further structural diversification.
O
N
N
Bn
3i (87%)
Ar
Ph
Ph
OH
O
OH
O
OH
MeO
Cl
Br
O
N
N
N
3j (85%)
3k (89%)
Ar = 4-ClC6H4 3l (70%)
Ph
Ph
O
Ph
OH
OH
OH
R'
O
O
O
O
O
+
N
N
O
N
R
3o'
3o
R = Me, R' = H 3m (78%)
R = R' = Me
94% (<1:20)b
OH
3n (75%)
Ph
Ar
OH
O
OH
OH
O
Cl
O
O
N
N
N
N
Ar = 4-FC6H4
3q (85%)
3p (50%)
3r (91%)
3s (88%)
Bu
R
R
OH
OH
OH
O
OH
Cl
O
O
O
N
N
N
N
R = (CH2)2OTHP
R = (CH2)4Cl
3w (88%)
3t (89%)
3u (85%)
3v (72%)
a
To probe the mechanism of the oxidation/Csp2–H functiona-
lization reaction, deuterium-labeled substrates [D1]-1b and [D5]-
1b were synthesized. [D1]-1b was subjected to the standard
reaction conditions to determine the intramolecular isotope effect
40 (kH/kD = 1.0, eqn (2)), and the mixture of substrates 1b and [D5]-
1b (1:1 ratio) was used to probe the intermolecular isotope effect
Reactions were conducted at 0.2 mmol scale of 1. Yields are those of
the isolated product. b The ratio of 3o and 3o’ was determined by 1H NMR
spectroscopy. PMP = 4-meo-thoxyphenyl, Bn = benzyl, THP = 2-
tetrahydropyranyl.
45 (kH/kD = 1.0, eqn (3)). The absence of an intramolecular isotope
effect suggests that the reaction is most likely to involve an
electrophilic aromatic substitution process.14 We postulated that
the α-oxo Au carbenoid generated in this reaction can efficiently
undergo electrophilic aromatic substitution, yielding the observed
50 3-acyloxindoles.9-12, 14-15
Apart from their biological importance, 3-acyloxindoles are
also significant building blocks and synthons for assembling
challenging molecules. For example, compound 3b was
transformed into triflate 5, which affords the opportunity to form
55 even more sophisticated products via cross coupling reaction (eqn
(4)). Furthermore, synthon 3, which possesses multiple
nucleophlic and electrophilic attacking sites, was applied to
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 4
ChemComm
View Online
T. E. Liston, D.Malloy, J. J. Martin, D. Y. Mitchell, F. W. Rusek, S.
45
establish five or six-membered spirooxindole scaffold (eqns (5)
L. Shamblin and C. F. Wright, J. Med. Chem., 1996, 39, 10; (d) S.
Golding, P. Emery and S. P. Young, J. Immunol., 1995, 154, 5384;
(e) K. E. B. Parkes, P. Ermert, J. Fassler, J. Ives, J. A. Martin, J. H.
Merrett, D. Obrecht, G. Williams and K. Klumpp, J. Med. Chem.,
2003, 46,1153.
and (6)). The spirocyclic oxindole core is featured in a number of
natural products as well as medicinally relevant compounds
(Scheme 1), but its stereocontrolled synthesis, particularly
installing the challenging spiro-quaternary stereocenter, poses a
great synthetic problem.16 As shown in eqn (5), six-membered
5
50
55
60
65
70
75
80
85
3
For selected examples, see: (a) L.-L. Wang, L. Peng, J.F. Bai, Q.-
C.Huang, X.-Y. Xu and L.-X. Wang, Chem. Commun., 2010, 46,
8064; (b) F. X. Smith, E. Williams Gelsleichter, J. A. Podcasy, J. T.
Sisko and D. M. Hrubowchak, Synth. Commun., 2006, 36, 765; (c)
E. M. Beccalli, F. Clerici and A. Marchesini, Tetrahedron, 2001, 57,
4787. (d) E. M. Beccalli, A. Marchesini and T. Pilati, Tetrahedron,
1994, 50, 12697; (e) T. Kosuge, H. Ishida, A. Inaba and H. Nukaya,
Chem. Pharm. Bull., 1985, 33, 1414.
spirocyclic oxindole
6
was readily prepared through
organocatalytic enantioselective domino Michael addition/ ketone
aldol/dehydration reaction,3a bearing contiguous stereogenic
10 centres, with high diastereomeric ratio and excellent optical
purity. In addition, the allylation reaction of 3r with allylic
bromide provided compound 7 in 92% yield under mild
conditions and subsequent RCM reaction led to spirooxindole 8
in high yield.
4
(a) M. Porcs-Makkay and G. Simig, Org. Proc. Res. Dev., 2000, 4,
10; (b) M. Sechi, L. Sannia, F. Carta, M. Palomba, R. Dallocchio, A.
Dessi, M. Derudas, Z. Zawahir and N. Neamati, Antiviral Chem.
Chemother., 2005, 16, 41; (c) M. Treu, U. Guertler, T. Karner, O.
Kraemer, J. J. Quant and S. K. Zahn, WO2008152013 A1,
Boehringer Ingelheim Int., Dec 18, 2008.
5
6
(a) Z. Yu, L. Ma and W. Yu, Synlett, 2010, 17, 2607; (b) see ref. 2b,
and references therein.
The ‘ideal‘ synthesis encompasses the ideas of atom, step, and redox
economy, see: (a) T. Gaich and P. S. Baran, J. Org. Chem., 2010, 75,
4657; (b) J. B. Hendrickson, J. Am. Chem. Soc., 1975, 97, 5784.
For a recent review, see: H. M. L. Davies and J. R. Manning, Nature,
2008, 451, 417.
7
8
For Rhodium carbenoid, see: (a) M. P. Doyle, M. S. Shanklin, H. Q.
Pho and S. N. Mahapatro, J. Org. Chem., 1988, 53, 1017; (b) N.
Etkin, S. D. Babu, C. J. Fooks and T. Durst, J. Org. Chem., 1990, 55,
1093; for Silver carbenoid, see ref. 2b.
9
For a recent review on α-carbonyl gold carbenoids, see: (a) J. Xiao
and X. Li, Angew. Chem. Int. Ed., 2011, 50, 7226; for selected
reviews on gold catalysts, see: (b) Z. Li, C. Brouwer and C. He,
Chem. Rev., 2008, 108, 3239; (c) A. Arcadi, Chem. Rev., 2008, 108,
3266; (d) D. J. Gorin, B. D. Sherry, F. D. Toste, Chem. Rev. 2008,
108, 3351; (e) A. S. K. Hashmi, Chem. Rev., 2007, 107, 3180.
15
In conclusion, we have established that an efficient catalytic
10 (a) L. Ye, L. Cui, G. Zhang and L. Zhang, J. Am. Chem. Soc., 2010,
132, 3258; (b) B. Lu, C. Li and L. Zhang, J. Am. Chem. Soc., 2010,
132, 14070; (c) W. He, C. Li, L. Zhang, J. Am. Chem. Soc. 2011,
133, 8482; (d) L. Ye,W. He, L. Zhang, Angew. Chem. Int. Ed. 2011,
50, 3236; (e) D. Vasu, H.-H. Hung, S. Bhunia, S. A. Gawade, A.
Das and R.-S. Liu, Angew. Chem. Int. Ed., 2011, 50, 6911; (f) A.
Mukherjee, R. B. Dateer, R. Chaudhuri, S. Bhunia, S. N. Karad
and R.-S. Liu, J. Am. Chem. Soc., 2011, 133, 15372; (g) Y. Wang, K.
Ji, S. Lan and L. Zhang, Angew.Chem. Int. Ed., 2012, 51, 1915; (h)
S. Bhunia, S. Ghorade, D. B. Huple and R.-S. Liu, Angew.Chem. Int.
Ed., 2012, 51, 2939; (i) P. W. Davies, A. Cremonesi and N. Martin,
Chem. Commun., 2011, 47, 379.
C–H functionalization by means of gold carbenoids insertion for
one-step synthesis of 3-acyloxindole derivatives, making use of
simple starting materials and mild conditions. This reaction
20 proceeds smoothly with extremely good substrate scope and
significant opportunities for structural diversification. Preliminary
mechanistic studies indicate that the reaction may involve an
intramolecular electrophilic aromatic substitution process. Finally, 90
we used the diverse 3-acyloxindoles to prepare a series of key
25 building blocks, and accomplished the catalytic enantioselective
transformation yielding spirooxindoles, a molecular framework
11 For a recent work from our group, see: D. Qian and J. Zhang, Chem.
Commun., 2011, 47, 11152.
of biological significance. Further synthetic applications and
mechanistic investigations are in progress. We are grateful to
National Natural Science Foundation of China (20972054), 973
30 program (2011CB808600), Fok Ying Tung Education Foundation
for financial support.
95
12 For reviews on gold-mediated C–H functionalization, see: ref. 9b-c
and (a) R. Skouta and C.-J. Li, Tetrahedron, 2008, 64, 4917; (b) T.-
C. Boorman and I. Larrosa, Chem. Soc. Rev., 2011, 40, 1910; (c) T.
Haro and C. Nevado, Synthesis, 2011, 2530.
100 13 For ‘diversity-oriented synthesis‘ (DOS), see: B. Tan and N. R.
Candeias, C. F. Barbas III, Nat. Chem., 2011, 3, 473.
14 For the corresponding KIE value of electrophilic aromatic
substitution process, see (a) N. D. Shapiro and F. D. Toste, J. Am.
Chem. Soc., 2007, 129, 4160; (b) Z. Shi and C. He, J. Org. Chem.,
Notes and references
1
For recent reviews on oxindoles, see: (a) C. V. Galliford and K. A.
Scheidt, Angew. Chem. Int. Ed., 2007, 46, 8748; (b) C. Marti and E.
M. Carreira, Eur. J. Org. Chem., 2003, 12, 2209; (c) B. M. Trost
and M. K. Brennan, Synthesis, 2009, 3003; (d) F. Zhou, Y.-L. Liu
and J. Zhou, Adv. Synth. Catal., 2010, 352, 1381; (e) J. E. M. N.
Klein and R. J. K. Taylor, Eur. J. Org. Chem., 2011, 34, 6821.
(a) B. Lu and D. Ma, Org. Lett., 2006, 8, 6115; (b) H.-L. Wang, Z.
Li, G.-W. Wang and S.-D. Yang, Chem. Commun., 2011, 47, 11336;
For representative molecules, see: (c) R. P. Robinson, L. A. Reiter,
W. E. Barth, A. M. Campeta, K. Cooper, B. J. Cronin, R. Destito,
Barth, A. M. Campeta, K. Cooper, B. J. Cronin, R. Destito, K. M.
Donahue, F. C. Falkner, E. F. Fiese, D. L. Johnson, A. V. Kuperman,
105
2004, 69, 3669.
35
15 For selected examples see: ref. 10e, ref. 11, ref. 14a and (a) G. T. Li
and L. Zhang, Angew. Chem. Int. Ed., 2007, 46, 5156; (b) L. Cui, G.
Z. Zhang, Y. Peng and L. Zhang, Org. Lett., 2009, 11, 1225.
16 For the spirocyclic oxindole core, see: ref. 1, ref. 3a, ref. 13 and (a)
G. Bencivenni, L.-Y. Wu, A. Mazzanti, B. Giannichi, F. Pesciaioli,
M.-P. Song, G. Bartoli and P. Melchiorre, Angew. Chem. Int. Ed.,
2009, 48, 7200; (b) F. Zhong, X. Han, Y. Wang and Y. Lu, Angew.
Chem. Int. Ed., 2011, 50, 7837.
2
110
40
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

ChemComm
Page 4 of 4
Dynamic Article Links ►
ChemComm
View Online
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
COMMUNICATION
Graphic Abstract
One-step efficient synthesis of 3-acyloxindole derivatives was developed with extremely good substrate scope and significant
opportunities for structural diversification.
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 4