Palladium-catalyzed intermolecular C-H amidation of indoles with sulfonyl azides

Article abstract of DOI:10.1007/s11426-015-5369-y

A new kind of intermolecular indole C-H amidation reaction catalyzed by the most frequently used palladium catalyst has been developed. Sulfonyl azide was employed as an innovative nitrogen source and environmentally benign nitrogen was produced as the on

Full text of DOI:10.1007/s11426-015-5369-y

SCIENCE CHINA
Chemistry
June 2015 Vol.58 No.6: 1–5
doi: 10.1007/s11426-015-5369-y
• ARTICLES •
· SPECIAL ISSUE · CH bond activation
doi: 10.1007/s11426-015-5369-y
Palladium-catalyzed intermolecular C–H amidation of indoles with
sulfonyl azides
Ziwei Hu, Shuang Luo* & Qiang Zhu*
State Key Laboratory of Respiratory Disease; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,
Guangzhou 510530, China
Received November 26, 2014; December 29, 2014
A new kind of intermolecular indole C–H amidation reaction catalyzed by the most frequently used palladium catalyst has
been developed. Sulfonyl azide was employed as an innovative nitrogen source and environmentally benign nitrogen was pro-
duced as the only byproduct.
C–H amidation, indole, palladium, sulfonyl azide
tions have appeared in literatures [9,10]. Typically, these
1 Introduction
reactions are catalyzed by Rh, Ru and Ir using various di-
recting groups. Palladium, the most frequently used
transition-metal in C–H activation, has been absent from the
feast.
Methods of C–N bond formation have attracted particular
attention of organic chemists due to the fact that nitrogen-
containing molecules are ubiquitous in pharmaceuticals,
agricultural chemicals, natural products and synthetic mate-
rials [1]. Among them, Ullmann reaction [2] and Buchwald-
Hartwig amination [3] have been extensively investigated as
efficient strategies using readily available pre-functionalized
haloarenes. In recent years, transition metal-catalyzed direct
amination of C–H bonds has emerged as a powerful tool
without the need for pre-functionalized arenes [4,5]. How-
ever, this process usually requires external oxidants to com-
plete the catalytic cycles [6]. Alternatively, electrophilic
aminating agents [7], such as halogenated amines, have
been successfully employed in C–H amination of arenes.
However, generation of stoichiometric halogenated waste
cannot be avoided. Recently, Chang’s group [8] has demon-
strated that sulfonyl azides could be used as novel ami-
dation agents with environment benign N2 as the sole by-
product in the absence of additional oxidants. After that, a
surge of sulfonyl azide participated C–H amidation reac-
Indole and its derivatives are always hot topics because
of their wide existence in biologically relevant compounds
[11]. As a result, much effort has been made to synthesis of
indole through either construction or decoration of the in-
dole cores [12]. The electron-rich character of indoles al-
lows them to undertake direct C–H bond functionalization
resulting in the formation of carbon-carbon or carbon-
heteroatom bonds at C2 or C3 position. Previously, we have
reported palladium-catalyzed C–H functionalization of in-
doles followed by isocyanide insertion [13]. Considering the
electronic similarity between carbene and nitrene, we envi-
sioned that C–H amidation of indoles with sulfonyl azide
might take place using palladium catalyst (Scheme 1) [14].
2 Results and discussion
To test our hypothesis, we initiated the study by investigat-
ing the reaction of 2-phenylindole 1a with p-methylbenzen-
*Corresponding authors (email: luo_shuang@gibh.ac.cn; zhu_qiang@gibh.ac.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2015
chem.scichina.com link.springer.com

2
Hu et al. Sci China Chem June (2015) Vol.58 No.6
esulfonyl azide (TsN3) 2a in the presence of Pd(TFA)2 in
THF at 80 °C and found no desired product appeared (En-
try1, Table 1). Intriguingly, the target product 3a was gen-
erated in 32% yield by addition of PPh3 (Entry 2). Screen-
ing of solvents indicated that non-polar solvents were more
suitable than polar ones and m-xylene was the optimal sol-
vent of choice (Entries 3–8). Other tested palladium salts
including PdCl2, Pd(OAc)2, Pd(PPh3)2Cl2 and Pd(acac)2
were obviously less effective than Pd(TFA)2 (Entries 9–12).
Control experiments showed the palladium catalyst was
required for the transformation (Entry 13). Only trace or
even no product was detected by replacing PPh3 with other
phosphine or nitrogen ligands (Entries 14–19). Both acid
and base additives inhibited the reaction apparently (Entries
20, 21). To our delight, the addition of 10 equivalent of wa-
ter increased the yield to 95% (Entry 22). In particular, ar-
gon atmosphere didn’t change the yield obviously, which
suggested that no external oxidant was involved.
With the optimized conditions in hand, we next explored
the generality of this transformation using a variety of in-
doles with 2a (Scheme 2). Both electron-donating (CH3,
OMe) (3b, 3c) and withdrawing (F, Cl) (3d, 3e) substituents
on the indole core were compatible with the newly estab-
lished protocol. Indoles bearing different tolyl groups (3g,
3h) at C2 position were amidated efficiently. The yield of 3f
was relatively low probably due to steric hindrance. Sub-
strates with electron-withdrawing para-fluorophenyl group
(3i), para-chlorophenyl group (3j), para-trifluoromethyl-
phenyl (3k) and meta-methoxylcarbonylphenyl group (3l) at
C2 position of indole afforded the corresponding products
in good to excellent yields. Satisfyingly, we found that the
amidation reaction of C2 cyclohexyl substituted substrate
(3m) proceeded smoothly as well. However, C2 unsubsti-
tuted indole (3n) did not react under the developed condi-
tions and the starting material was completely recovered.
The scope of different sulfonyl azides with 1a was inves-
tigated subsequently. Electron-donating and electron-with-
drawing substituted arylsulfonyl azides reacted efficiently,
generating the corresponding products (3o–3s) in good
yields. To our delight, aliphatic sulfonyl azide also gave
good yield of the desired product (3t).
In order to evaluate the function of PPh3, we conducted
the reaction under the identical conditions by omitting PPh3
and found no product was detected (Scheme 3(a)). As the
Staudinger reaction might take place between TsN3 and
PPh3, reactions were operated by replacing PPh3 with
OPPh3 (Scheme 3(b)) and TsNH2 (Scheme 3(c)) respec-
tively. No desired product was detected in both cases. Alt-
hough the true function was not clear at the present stage,
these results indicated that PPh3 played a requisite role in
the transformation.
Scheme 1 Reaction between indole and carbene or nitrene.
Table 1 Optimization of the reaction conditions a)
Entry
1
Pd
Ligand Additive
Solvent Yield (%) b)
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
PdCl2
–
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PCy3
dppm
dppf
–
THF
THF
nd
32
2
–
3
–
Toluene
DCE
71
4
–
68
5
–
CH3CN
trace
trace
76
6
–
DMF
7
–
m-xylene
mesitylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
8
–
73
9
–
nd
10
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(acac)2
–
–
14
11
–
trace
14
12
–
13
14
–
nd
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
–
nd
15
–
nd
16
–
nd
17 c)
18 c)
19 c)
20 d)
21 e)
22 f)
23 f, g)
TMEDA
Phen
L-proline
PPh3
PPh3
PPh3
PPh3
–
nd
A possible mechanism was proposed on the basis of
these experimental results and relative literatures (Scheme
4). Ligand chelated Pd(II) species facilitates C–H bond ac-
tivation to give intermediate A. Coordination of azide to A
leads to B, followed by the subsequent insertion of a sul-
fonamido moiety into the C–Pd bond through concerted
migratory insertion driven by releasing of N2 to genernate
intermediate C. Stepwise intrenoid path involving Pd(IV)
species is also possible. Protonolysis of C delivers the final
product 3 and dissociates Pd(II) for the next catalytic cycle.
–
–
nd
nd
PivOH
53
Na2CO3 m-xylene
24
H2O
H2O
m-xylene
m-xylene
95
95
a) All reactions were carried out at 0.2 mmol scale, with Pd catalyst (5
mol%), ligand (10 mol%), in solvent (1 mL), at 80 C, in air; b) isolated
yield; c) 5 mol% ligand was used; d) 1.0 equiv. of PivOH was added; e) 1.0
equiv. of Na2CO3 was added; f) 10 equiv. of H2O was added; g) in argon
atmosphere.

Hu et al. Sci China Chem June (2015) Vol.58 No.6
3
Scheme 4 Proposed reaction mechanism of the intermolecular indole
C–H amidation reaction.
3 Conclusions
In summary, we have developed a new kind of intermolec-
ular indole C–H amidation reaction. The reaction, which is
catalyzed by the most frequently used palladium catalyst, is
different from the published reactions [14] using sulfonyl
azides as amidating reagents. Sulfonyl azide was employed
as an innovative nitrogen source and environmentally be-
nign nitrogen was produced as the only byproduct.
Scheme 2 Scope of the catalytic intermolecular C–H amidation. Condi-
tions: 1 (0.2 mmol), sulfonyl azide 2 (0.3 mmol), Pd(TFA)2 (5 mol%), PPh3
(10 mol%), H2O (10 equiv.), in m-Xylene (1 mL), 80 C, 5 h, isolated yield
of 3; a) 8 h.
Supporting information
The supporting information is available online at chem.scichina.com and
link.springer.com/journal/11426. The supporting materials are published as
submitted, without typesetting or editing. The responsibility for scientific
accuracy and content remains entirely with the authors.
This work was financially supported by the National Natural Science
Foundation of China (21272233, 21472190, 21402203).
1
2
a) Hili R, Yudin AK. Making carbon-nitrogen bonds in biological
and chemical synthesis. Nat Chem Biol, 2006, 2: 284–287; b) Ricci A.
Amino Group Chemistry. Weinheim: Wiley-VCH, 2008
a) Evano G, Blanchard N, Toumi M. Copper-mediated coupling reac-
tions and their applications in natural products and designed biomol-
ecules synthesis. Chem Rev, 2008, 108: 3054–3131; b) Rao H, Fu H.
Copper-catalyzed coupling reactions. Synlett, 2011, 6: 745–769
a) Tye JW, Weng Z, Johns AM, Incarvito CD, Hartwig JF. Copper
complexes of anionic nitrogen ligands in the amidation and imidation
of aryl halides. J Am Chem Soc, 2008, 130: 9971–9983; b) Hartwig
3
Scheme 3 Evaluation of the function played by PPh3.

4
Hu et al. Sci China Chem June (2015) Vol.58 No.6
JF. Evolution of a fourth generation catalyst for the amination and
amination of azoles with chloroamines at room temperature. J Am
Chem Soc, 2010, 132: 6900–6901; b) Sun K, Li Y, Xiong T, Zhang J,
Zhang Q. Palladium-catalyzed C−H aminations of anilides with N-
fluorobenzenesulfonimide. J Am Chem Soc, 2011, 133: 1694–1697;
c) Yoo EJ, Ma S, Mei TS, Chan KSL, Yu JQ. Pd-catalyzed intermo-
lecular C–H amination with alkylamines. J Am Chem Soc, 2011, 133:
7652–7655; d) Ng KH, Zhou Z, Yu WY. Rhodium(III)-catalyzed in-
termolecular direct amination of aromatic C–H bonds with N-chlo-
roamines. Org Lett, 2012, 14: 272–275; e) Grohmann C, Wang H,
Glorius F. Rh[III]-catalyzed direct C–H amination using N-chloroa-
mines at room temperature. Org Lett, 2012, 14: 656–659
thioetherification of aryl halides. Acc Chem Res, 2008, 41: 1534–
1544; c) Wolfe JP, Wagam S, Marcoux JF, Buchwald SL. Rational
development of practical catalysts for aromatic carbon-nitrogen bond
formation. Acc Chem Res, 1998, 31: 805–818; d) Paul F, Patt J,
Hartwig JF. Palladium-catalyzed formation of carbon-nitrogen bonds.
Reaction intermediates and catalyst improvements in the hetero
cross-coupling of aryl halides and tin amides. J Am Chem Soc, 1994,
116: 5969–5970; e) Guram AS, Buchwald SL. Palladium-catalyzed
aromatic aminations with in situ generated aminostannanes. J Am
Chem Soc, 1994, 116: 7901–7902
4
For recent reviews on direct C–H amination: a) Wencel-Delord J,
Droge T, Liu F, Glorius F. Towards mild metal-catalyzed C–H bond
activation. Chem Soc Rev, 2011, 40: 4740–4761; b) Cho SH, Kim JY,
Kwak J, Chang S. Recent advances in the transition metal-catalyzed
twofold oxidative C–H bond activation strategy for C–C and C–N
bond formation. Chem Soc Rev, 2011, 40: 5068–5083; c) Song G,
Wang F, Li X. C–C, C–O and C–N bond formation via rhodium(III)-
catalyzed oxidative C–H activation. Chem Soc Rev, 2012, 41: 3651–
3678; d) Stokes BJ, Driver TG. Transition metal-catalyzed formation
of N-heterocycles via aryl- or vinyl- C–H bond amination. Eur J Org
Chem, 2011: 4071–4088; e) Lu H, Zhang XP. Catalytic C–H func-
tionalization by metalloporphyrins: recent developments and future
directions. Chem Soc Rev, 2011, 40: 1899–1909; f) Collet F, Lescot
C, Dauban P. Catalytic C–H amination: the stereoselectivity issue.
Chem Soc Rev, 2011, 40: 1926–1936; g) Roizen JL, Harvey ME, Du
Bios J. Metal-catalyzed nitrogen-atom transfer methods for the oxi-
dation of aliphatic C–H bonds. Acc Chem Res, 2012, 45: 911–922
For recent reviews on C–H activation, see: a) Rouquet G, Chatani N.
Catalytic functionalization of C(sp2)–H and C(sp3)–H bonds by using
bidentate directing groups. Angew Chem Int Ed, 2013, 52: 11726–
11743; b) Li BJ, Shi ZJ. From C(sp2)–H to C(sp3)–H: systematic
studies on transition metal-catalyzed oxidative C–C formation. Chem
Soc Rev, 2012, 41: 5588–5598; c) Kuhl N, Hopkinson MN, Wencel-
Delord J, Glorius F. Beyond directing groups: transition-metal-
catalyzed C–H activation of simple arenes. Angew Chem Int Ed, 2012,
51: 10236–10254; d) Ackermann L, Kapdi AR, Potukuchi HK, Ko-
zhushkov SI. Synthesis via C–H bond functionalizations. In: Li CJ,
Ed. Handbook of Green Chemistry. Weinheim: Wiley-VCH, 2012.
259; e) Neufeldt SR, Sanford MS. Controlling site selectivity in pal-
ladium-catalyzed C–H bond functionalization. Acc Chem Res, 2012,
45: 936–946; f) Colby DA, Tsai AS, Bergman RG, Ellman JA. Rho-
dium catalyzed chelation-assisted C–H bond functionalization reac-
tion. Acc Chem Res, 2012, 45: 814–825; g) Engle KM, Mei TS, Wasa
M, Yu JQ. Weak coordination as a powerful means for developing
broadly useful C–H functionalization reactions. Acc Chem Res, 2012,
45: 788–802; h) Arockiam PB, Bruneau C, Dixueuf PH. Rutheni-
um(II)-catalyzed C–H bond activation and functionalization. Chem
Rev, 2012, 112: 5879–5918; i) Ackermann L. Carboxylate-assisted
transition-metal-catalyzed C−H bond functionalizations: mechanism
and scope. Chem Rev, 2011, 111: 1315–1345; j) Xu LM, Li BJ, Yang
Z, Shi ZJ. Organopalladium(IV) chemistry. Chem Soc Rev, 2010, 39:
712–733
8
9
Kim JY, Park SH, Ryu J, Cho SH, Kim SH, Chang S. Rhodium-
catalyzed intermolecular amidation of arenes with sulfonyl azides via
chelation-assisted C–H bond activation. J Am Chem Soc, 2012, 134:
9110–9113
For recent transition-metal catalyzed amidation reaction with sulfonyl
azide as nitrogen source, see: a) Zheng QZ, Liang YF, Qin C, Jiao N.
Ru(II)-catalyzed intermolecular C–H amidation of weakly coordinat-
ing ketones. Chem Commun, 2013, 49: 5654–5656; b) Yu DG, Suri
M, Glorius F. Rh(III)/Cu(II)-cocatalyzed synthesis of 1H-indazoles
through C–H amidation and N–N bond formation. J Am Chem Soc,
2013, 135: 8802–8805; c) Thirunavukkarasu VS, Raghuvanshi K,
Ackermann L. Expedient C–H amidations of heteroaryl arenes cata-
lyzed by versatile ruthenium(II) catalysts. Org Lett, 2013, 15: 3286–
3289; d) Kim J, Kim J, Chang S. Ruthenium-catalyzed direct C–H
amidation of arenes including weakly coordinating aromatic ketones.
Chem Eur J, 2013, 19: 7328–7333; e) Bhanuchandra M, Yadav MR,
Rit RK, Kuram MR, Sahoo AK. Ru(II)-catalyzed intermolecular
ortho-C–H amidation of aromatic ketones with sulfonyl azides. Chem
Commun, 2013, 49: 5225–5227; f) Shi J, Zhou B, Yang Y, Li Y.
Rhodium-catalyzed regioselective amidation of indoles with sulfonyl
azides via C–H bond activation. Org Biomol Chem, 2012, 10: 8953–
8955; g) Yadav MR, Rit RJ, Sahoo AK. Sulfoximine directed inter-
molecular o-C–H amidation of arenes with sulfonyl azides. Org Lett,
2013, 15: 1638–1641; h) Lee D, Kim Y, Chang S. Iridium-catalyzed
direct arene C–H bond amidation with sulfonyl- and aryl- azides. J
Org Chem, 2013, 78: 11102–11109
5
10 For recent transition-metal catalyzed amination reaction with other
types of azide as nitrogen source, see: a) Ryu J, Kwak J, Shin K, Lee
D, Chang S. Ir(III)-catalyzed mild C–H amidation of arenes and al-
kenes: an efficient usage of acyl azides as the nitrogen source. J Am
Chem Soc, 2013, 135: 12861–12868; b) Lian Y, Hummel JR, Berg-
man RG, Ellman JA. Facile synthesis of unsymmetrical acridines and
phenazines by a Rh(III)-catalyzed amination/cyclization/aromatiza-
tion cascade. J Am Chem Soc, 2013, 135: 12548–12551; c) Ryu J,
Shin K, Park SH, Kim JY, Chang S. Rhodium-catalyzed direct C–H
amination of benzamides with aryl azides: a synthetic route to dia-
rylamines. Angew Chem Int Ed, 2012, 51: 9904–9908; d) Shin K,
Baek Y, Chang S. Direct C–H amination of arenes with alkyl azides
under rhodium catalysis. Angew Chem Int Ed, 2013, 52: 8031–8036;
e) Tang C, Yuan Y, Cui Y, Jiao N. Rh-catalyzed diarylamine synthe-
sis by intermolecular C–H amination of heteroarylarenes. Eur J Org
Chem, 2013, 2013: 7480–7483
6
For examples of oxidative amination of activated arenes: a) Wang Q,
Schreiber SL. Copper-mediated amidation of heterocyclic and aro-
matic C−H bonds. Org Lett, 2009, 11: 5178–5180; b) Monguchi D,
Fujiwara T, Furukawa H, Mori A. Direct amination of azoles via cat-
alytic C−H, N−H coupling. Org Lett, 2009, 11: 1607–1610. For ex-
amples of oxidative direct amination of arenes bearing directing
group: c) Xiao B, Gong TJ, Xu J, Liu ZJ, Liu L. Palladium-catalyzed
intermolecular directed C−H amidation of aromatic ketones. J Am
Chem Soc, 2011, 133: 1466–1474; d) John A, Nicholas KM. Copper-
catalyzed amidation of 2-phenylpyridine with oxygen as the terminal
oxidant. J Org Chem, 2011, 76: 4158–4162
11 a) Sundberg RJ. Indoles. San Diego: Academic Press, 1996; b) Kat-
rizky AR, Ress CW. Comprehensive Heterocyclic Chemistry. 2nd Ed.
Pergamon, 1996. 119
12 For some recent reviews: see a) Humphrey GR, Kuethe JT. Practical
methodologies for the synthesis of indoles. Chem Rev, 2006, 106:
2875–2911; b) Vicente R. Recent advances in indole syntheses: new
routes for a classic target. Org Biomol Chem, 2011, 9: 6469–6480; c)
Cacchi S, Fabrizi G. Synthesis and functionalization of indoles
through palladium-catalyzed reactions. Chem Rev, 2011, 111: 215–
283; d) Oda Y, Matsuyama N, Hirano K, Satoh T, Miura M. Dehy-
drogenative synthesis of C3-azolylindoles via copper-promoted an-
7
a) Kawano T, Hirano K, Satoh T, Miura M. A new entry of amination
reagents for heteroaromatic C−H bonds: copper-catalyzed direct

Hu et al. Sci China Chem June (2015) Vol.58 No.6
5
nulative direct coupling of o-alkynylanilines. Synthesis, 2012: 1515–
1520
N-methylindole. J Org Chem, 1973, 38: 11–16. Two reports involv-
ing the reaction of indole with sulfonyl azides to give 3-amidated in-
dole have been published. However, there are several pivotal differ-
ences between our procedure and the published reports: i) Palladium
catalyst and PPh3 are prerequisite for our procedure; however, cata-
lyst was not nessesary in the published reports; ii) N–H free indoles
were suitable substrates for our procedure; but only N–H alkyl sub-
stituted indoles were applied in the published reports; iii) C3-position
amidated indoles generated directly in our procedure; yet C3-position
amidated indoles generated through indole C2 amidation followed
by C2 C3 transformation in flash column chromatography in Ref.
[14b]
13 a) Peng J, Zhao J, Hu Z, Liang D, Huang J, Zhu Q. Palladium-
catalyzed C(sp2)–H cyanation using tertiary amine derived isocyanide
as a cyano source. Org Lett, 2012, 14: 4966–4969; b) Peng J, Liu L,
Hu Z, Huang J, Zhu Q. Direct carboxamidation of indoles by palla-
dium-catalyzed C–H activation and isocyanide insertion. Chem
Commun, 2012, 48: 3772–3774
14 a) Bahadur GA, Bailey AS, Scott PW, Vandrevala MH. The reactions
of four derivatives of pyrrolo[1,2-a]indole with arene-sulphonyl az-
ides. J Chem Soc, Perkin Trans 1, 1980: 2870–2877; b) Harmon RE,
Wellman G, Gupta SK. Reaction of arylsulfonyl azides with