Palladium-catalyzed tandem allenyl and aryl C-N bond formation: Efficient access to N-functionalized multisubstituted indoles

Article abstract of DOI:10.1021/ol3018775

An efficient palladium-catalyzed synthesis of N-functionalized multisubstituted indoles from easily accessible ortho-haloarylallenes and primary amines has been developed. A wide range of electronically and structurally varied nitrogen fragments could be introduced through this tandem C-N bond-forming process by tuning the reaction conditions.

Full text of DOI:10.1021/ol3018775

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4398–4401
Palladium-Catalyzed Tandem Allenyl
and Aryl CꢀN Bond Formation:
Efficient Access to N‑Functionalized
Multisubstituted Indoles
Bingxin Liu,† Xiaohu Hong,† Dong Yan,† Shuguang Xu,† Xiaomei Huang,† and
Bin Xu*,‡,§
Department of Chemistry, Shanghai University, Shanghai 200444, China, and State Key
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China, and Shanghai Key Laboratory
of Green Chemistry and Chemical Processes, Department of Chemistry, East China
Normal University, Shanghai 200062, China
xubin@shu.edu.cn
Received July 9, 2012
ABSTRACT
An efficient palladium-catalyzed synthesis of N-functionalized multisubstituted indoles from easily accessible ortho-haloarylallenes and primary
amines has been developed. A wide range of electronically and structurally varied nitrogen fragments could be introduced through this tandem
CꢀN bond-forming process by tuning the reaction conditions.
The indole skeleton is one of the most attractive frame-
works with a wide range of biological and pharmacolo-
gical activities, which has been generally recognized as a
privileged structure in medicinal chemistry.1 The preva-
lence of this physiologically important nucleus, found in
therapeutic agents as well as in natural products,2 has
prompted the development of many useful methods for
their preparation.3,4 Recently, Jiao et al.5 demonstrated a
direct approach for constructing indoles from anilines and
alkynes by CꢀH activation. However, much less attention
has been paid for the assembly of N-functionalized multi-
substituted indole frameworks.6
† Shanghai University
‡ Chinese Academy of Sciences
Allenes are uniquely versatile intermediates in organic
synthesis because of their structural and reactiveproperties
§ East China Normal University
(1) Ishikura, M.; Yamada, K.; Abe, T. Nat. Prod. Rep. 2010, 27,
1630–1680.
(2) Bandgar, B. P.; Sarangdhar, R. J.; Viswakarma, S.; Ahamed,
F. A. J. Med. Chem. 2011, 54, 1191–1201.
(5) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N.
Angew. Chem., Int. Ed. 2009, 48, 4572–4576 and references cited therein.
(6) For recent selective examples on synthesis of N-functionalized
multifunctionalized indoles, see: (a) Fang, Y.-Q.; Lautens, M. J. Org.
Chem. 2008, 73, 538–549. (b) Stuart, D. R.; Bertrand-Laperle, M. G.;
Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474–
16475. (c) Barluenga, J.; Jimenez-Aquino, A. N.; Aznar, F.; Valdes, C.
J. Am. Chem. Soc. 2009, 131, 4031–4041. (d) Denmark, S. E.; Baird, J. D.
Tetrahedron 2009, 65, 3120–3129. (e) Monguchi, Y.; Mori, S.; Aoyagi,
S.; Tsutsui, A.; Maegawa, T.; Sajiki, H. Org. Biomol. Chem. 2010, 8,
3338–3342.
(3) For recent selective reviews on indole synthesis, see: (a) Cacchi, S.;
Fabrizi, G.; Goggiamani, A. Org. Biomol. Chem. 2011, 9, 641–652.
(b) Taber, D. F.; Tirunahari, P. K. Tetrahedron 2011, 67, 7195–7210.
(c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215–PR283.
(4) For recent examples on indole synthesis, see: (a) Guan, Z.-H.;
Yan, Z.-Y.; Ren, Z.-H.; Liu, X.-Y.; Liang, Y.-M. Chem. Commun. 2010,
46, 2823–2825. (b) Han, X.; Lu, X. Org. Lett. 2010, 12, 3336–3339.
(c) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676–3677.
(d) Gehrmann, T.; Lloret Fillol, J.; Scholl, S. A.; Wadepohl, H.; Gade,
L. H. Angew. Chem., Int. Ed. 2011, 50, 5757–5761. (e) Wetzel, A.; Gagosz,
F. Angew. Chem., Int. Ed. 2011, 50, 7354–7358. (f) Lavery, C. B.;
McDonald, R.; Stradiotto, M. Chem. Commun. 2012, 48, 7277–7279.
(g) Wei, Y.; Deb, I.; Yoshikai, N. J. Am. Chem. Soc. 2012, 134, 9098–9101.
(h) Ackermann, L.; Lygin, A. V. Org. Lett. 2012, 14, 764–767.
ꢀ
ꢀ
(7) For recent monographs, see: (a) Ma, S. Palladium-catalyzed two-
or three-componentcyclization of functionalized allenes. In Palladium in
Organic Synthesis; Tsuji, J., Ed.; Springer: Berlin, 2005; p 183. (b) Science
of Synthesis; Krause, N., Ed.;Thieme: Stuttgart, 2007; Vol. 44.
r
10.1021/ol3018775
Published on Web 08/15/2012
2012 American Chemical Society

and have proven themselves to be powerful C3 building
blocks toward a variety of desirable highly functionalized
heterocycles.7,8 For example, indole and its annelated
derivatives could be synthesized through intra- or inter-
molecular cyclization of allenylanilines,9a,b,g allenyl azides,9c,d,f
aminoallenes,9e or allenylbromide.9h
corresponding de-esterification product of 3aa, 2-(1-phe-
nyl-1H-indol-2-yl)-propanoic acid (3aa0).11
Table 1. Selected Conditions for Optimization of Indole
Synthesisa
Among those reactions on indole synthesis with allenes,
most of them involve only one intramolecular CꢀN bond
formation to construct the pyrrole nucleus of indole.9aꢀg
Herein, we describe a palladium-catalyzed tandem reaction,
whereby a sequential double CꢀN bond was formed from
easily accessible ortho-halo substituted arylallenes and pri-
mary amines to give multisubstituted indoles (Scheme 1). To
our knowledge, the given approach represents the first report
for the synthesis of N-functionalized multisubstituted in-
doles from easily available haloallenes and primary amines.
time
(h)
yield
(%)b
entry Pd source
ligand
PPh3
base
solvent
1
2
3
4
5
6
7
8
9
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
4
9
3
9
3
6
47
tBu3P
40
40
49
19
40
PCy3
JohnPhos Cs2CO3 toluene
TFP
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
BINAP
DPPP
4.5 62
Scheme 1. New Synthetic Strategy on Indole Ring Synthesis
Xantphos Cs2CO3 toluene
Xantphos Cs2CO3 DMF
Xantphos Cs2CO3 DMSO
Xantphos Cs2CO3 dioxane
2
77
24
24
24
2
<5c
<5c
<5
10 Pd(dba)2
11 Pd(dba)2
12 Pd(OAc)2 Xantphos Cs2CO3 toluene
13 Pd(OAc)2 Xantphos K2CO3 toluene
14 Pd(OAc)2 Xantphos K2CO3 toluene
15 Pd(OAc)2 Xantphos K2CO3 toluene
80
5
84
5
82d (90)
75e
Preliminary investigation was started by examining
the reaction of 1a10 with aniline (Table 1). An extensive
screening of monodentate (Table 1, entries 1ꢀ5) and
bidentate ligands (entries 6ꢀ8) revealed that the employ-
ment of Xantphos was proven to be the most favorable
ligand and afforded product 3aa in 77% yield in the
presence of 5 mol % Pd(dba)2 using Cs2CO3 as base
(entry 8). Switching the solvent from toluene to DMF,
DMSO or dioxane gave trace amount of product (entries
9ꢀ11). Improved yield could be achieved using 5 mol % of
Pd(OAc)2 with K2CO3 as base (entry 13). Decreasing the
loading of Pd(OAc)2 to 2 mol % gave satisfactory result
(entry 14), and the yield was dropped to 75% with further
decreased loading of palladium to 1 mol % (entry 15).
The identity of 3aa was determined by spectral analysis
and further confirmed by X-ray crystallography from
23
a Reaction conditions: 1a (0.355 mmol), aniline (1.5 equiv), [Pd]
(5 mol %), ligand (10 mol %), base (2.0 equiv), solvent (1.5 mL),
under nitrogen. BINAP = 2,20-bis(diphenylphosphino)-1,10-binaphthyl.
DPPP = 1,3-Bis(diphenylphosphino)propane. JohnPhos = 2-(Di-t-butyl-
phosphino)biphenyl. PCy3 = tricyclohexylphosphine. TFP = Trifuran-
2-ylphosphine. Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethyl-
xanthene. b Isolated yield. NMR yield was given in brackets. c At 120 °C.
d Pd(OAc)2 (2 mol %), Xantphos (4 mol %) were used. e Pd(OAc)2
(1 mol %), Xantphos (2 mol %) were used.
Having developed conditions for the catalytic forma-
tion of indoles, we then extended the reaction to a range of
commercially available primary amines. A wide variety of
substitution patterns and functionalities were tolerated, as
shown in Scheme 2. Substrates containing both electron-
donating (3ab, 3ac and 3ag) and electron-withdrawing
groups (3adꢀ3af, and 3ah), or bearing para- (3abꢀ3af)
and meta- groups (3agꢀ3ah) proceeded efficiently with
good to excellent yields. However, anilines with a methyl
or chloro substitution at ortho- position afforded 3ai
and 3aj with atropisomeric structures,12 which indicated
that the indole derivatives possessing a steric bulky group
on the nitrogen atom have a high rotational energy barrier
around the NꢀAr bond and significantly affect the reac-
tivity. When pyridin-2-amine (2k) was used as the sub-
strate, the corresponding amidated product 3ak was
obtained in 43% yield, and pyrimidin-5-amine (2l) could
transform into3al in70% yield. Intriguingly, n-butylamine
and benzylamine can also be transformed into products in
91 and 73% yield, respectively (3am and 3an).
(8) For recent selective reviews, see: (a) Ma, S. Chem. Rev. 2005, 105,
2829–2872. (b) Ma, S. Top. Organomet. Chem. 2005, 14, 155–173.
(c) Ma, S. Aldrichimica Acta 2007, 40, 91–102. (d) Brasholz, M.; Reissig,
H. U.; Zimmer, R. Acc. Chem. Res. 2009, 42, 45–56. (e) Ma, S. Acc.
Chem. Res. 2009, 42, 1679–1688. (f) Deagostino, A.; Prandi, C.; Tabasso,
S.; Venturello, P. Molecules 2010, 15, 2667–2685.
(9) (a) Mukai, C.; Takahashi, Y. Org. Lett. 2005, 7, 5793–5796.
(b) Kuroda, N.; Takahashi, Y.; Yoshinaga, K.; Mukai, C. Org. Lett. 2006,
8, 1843–1845. (c) Feldman, K. S.; Iyer, M. R.; Hester, D. K. Org. Lett.
2006, 8, 3113–3116. (d) Feldman, K. S.; Hester, D. K.; Lopez, C. S.;
Faza, O. N. Org. Lett. 2008, 10, 1665–1668. (e) Inuki, S.; Oishi, S.; Fujii,
N.; Ohno, H. Org. Lett. 2008, 10, 5239–5242. (f) Feldman, K. S.; Hester,
ꢀ
D. K.; Iyer, M. R.; Munson, P. J.; Silva Lopez, C.; Faza, O. N. J. Org.
Chem. 2009, 74, 4958–4974. (g) Mohamed, Y. A. M.; Inagaki, F.;
Takahashi, R.; Mukai, C. Tetrahedron 2011, 67, 5133–5141. (h) Masters,
€
K.-S.; Wallesch, M.; Brase, S. J. Org. Chem. 2011, 76, 9060–9067.
(10) Nanayakkara, P.; Alper, H. J. Org. Chem. 2004, 69, 4686–4691.
(11) Crystallographic data for 3aa0: C17H15NO2, M = 265.30, mono-
˚
clinic, C2/c (No. 15), a = 12.391(5) A, b = 11.044 (5) A, c = 20.158
˚
o
3
˚
˚
(5) A, β = 100.261 (5) , V = 2714.4 (18) A , Z = 8, Crystal size: 0.30 ꢁ
(12) (a) Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPlante, S. R.
Angew. Chem., Int. Ed. 2009, 48, 6398–6401. (b) Ototake, N.; Morimoto,
Y.; Mokuya, A.; Fukaya, H.; Shida, Y.; Kitagawa, O. Chem.;Eur. J.
2010, 16, 6752–6755.
0.25 ꢁ 0.20 mm, T= 295 K, Fcalcd =1.298g cmꢀ3, R1 =0.0645(I>4σ(I)),
3
wR2 = 0.1911 (all data), GOF = 1.048, reflections collected/unique:
6427/2379 (Rint = 0.0499), Data: 2379, restraints: 0, parameters: 182.
Org. Lett., Vol. 14, No. 17, 2012
4399

Scheme 2. Palladium-Catalyzed Reaction of 1a with Primary
Aminesa,b
Scheme 3. Allene Scope in the Palladium Catalyzed Indole
Synthesisa,b
a Reaction conditions: allene (1.0 equiv), aniline (1.5 equiv), Pd(OAc)2
(2 mol %), Xantphos (4 mol %), K2CO3 (2 equiv), toluene (1.5 mL),
reflux, under nitrogen. X = Br. b Isolated yield. c Pd(OAc)2 (5 mol %),
Xantphos (10 mol %), Cs2CO3 (2 equiv), xylene (1.5 mL), reflux, under
nitrogen. d 4-(2-Chloro-phenyl)-2-methyl-buta-2,3-dienoic acid ethyl
ester (1j) was used, X = Cl.
a Reaction conditions: 1a (0.355 mmol), amine (1.5 equiv), Pd(OAc)2
(2 mol %), Xantphos (4 mol %), K2CO3 (2 equiv), toluene (1.5 mL),
reflux, under nitrogen. b Isolated yield. c The ratio of atropisomeric
product is 1:1. d The ratio of atropisomeric product is 1.8:1. e Pyridin-
2-amine (4 equiv) was used.
To study the effects of the electronic properties of
substituents on this tandem process, cyclization of a series
of substituted allenes 1bꢀk were investigated, which could
bereadilyobtainedthroughtheWittigꢀHornerreaction.10
As shown in Scheme 3, allenes bearing both electron-
donating and electron-withdrawing group on the aryl
ring could afford indole products 3baꢀ3da efficiently,
and electron-withdrawing substituent had more effect on
the yield (3da). Changing the methyl substitution to benzyl
group in 1a, the indole 3ea could be obtained in good yield.
For multisubstituted allenes (3fa, 3ga) or allenamide (3ha),
better results could be achieved using Cs2CO3 as base
under refluxedxylene. It should be noted that phenylamine
substituted 1H-indene 4 could be isolated in 13% yield
together with 63% yield of corresponding indole 3ga. To
further expand the scope of the reaction, substrate 1i with
quinoxaline moiety was investigated under standard con-
ditions. Gratifyingly, the corresponding indole product 3ia
could also be well achieved in 94% yields. Furthermore,
the less reactive chloro-substituted substrate 1j gave
trace amount of product 3aa, while 60% yield of indole
could be achieved using Cs2CO3 as base. However, when
1-bromo-2-(propa-1,2-dienyl)benzene (1k) was used under
optimized reactions, no desired product (3ka) could be
generated.
and JohnPhos using 3.0 equiv of tBuOK as base in
toluene.13,14 The strong base tBuOK is essential to process
this reaction; other bases such as K2CO3, Cs2CO3 and
tBuONa gave only trace amount of indole product. Under
the optimized conditions, the reaction proceeded very fast,
and a series of aryl or heteroaryl amines could be tolerated
in this tandem reaction as shown in Scheme 4. All of those
substrates can react smoothly to provide the correspond-
ing indoles in moderate to good yield. Aryl amines having
substituents at ortho-, meta- or para- position gave
2-methyl substituted indoles in high yields (3kaꢀ3ko).
Amine substrates containing the substructure of pyridine
(3kk) and naphthalene (3kp) also gave the corresponding
indoles in good yield. In particular, when hydroxymethyl
substituted allene 1l was applied in this reaction, the
dehydration reaction took place and gave 3la in 62% yield.
Furthermore, when we used 1a as substrate under this
condition, no product was detected, which implied that
this condition is specifically adaptive to unsubstituted
allene substrates.
To probe the mechanism, reactions were carried out to
define the possible pathways, including (i) under optimized
reaction conditions (Table 1, entry 14), only trace amount
of 3aa was found from chloro-substituted substrates 1j;
(ii) no enamine intermediate, which generated from addi-
tion product of 1a and aniline, could be detected during
the reaction or under refluxed toluene without palladium
catalyst; (iii) when the reaction was conducted under
To settle this question, an extensive screening of palla-
dium catalysts andligandstogetherwithsolventsand bases
was next carried out, and we found that indole product 3ka
could be achieved significantly in the presence of Pd(dba)2
(14) For the coordination chemistry of phosphine ligands, see: (a)
Snelders, D. J. M.; van Koten, G.; Klein Gebbink, R. J. M. Chem.;Eur.
J. 2011, 17, 42–57. (b) van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek,
J. N. H.; Dierkes, P. Chem. Rev. 2000, 100, 2741–2769.
(13) For the conditions optimization for unsubstituted allene 1k, see
Table S1 in the Supporting Information.
4400
Org. Lett., Vol. 14, No. 17, 2012

Scheme 4. Amine Scope in the Palladium Catalyzed Indole
Synthesisa,b
Scheme 5. Plausible Mechanism for Synthesis of 3 from 1
a Reaction conditions: allene (1.0 equiv), amine (1.5 equiv), Pd(dba)2
(5 mol %), JohnPhos (10 mol %), tBuOK (3 equiv) in toluene, reflux,
under nitrogen. R3 = R4 = H, unless otherwise indicated. b Isolated
yield. c 4-(2-Bromophenyl)-2-methylbuta-2,3-dien-1-ol (1l) was used,
R3 = CH2OH, R4 = CH3.
optimized reaction conditions, no direct BuchwaldꢀHartwig
amination product was isolated or could be detected by
LCꢀMS.
The characteristics of excellent functional group tolerance
and synthesis modularity will make the described reaction
a broad utility in organic synthesis. Further insight into the
scope and mechanism are now under investigation in our
laboratory and will be reported in due course.
On the basis of these results, we proposed the plausible
mechanism for the formation of indole 3 and 1H-indene
4 (Scheme 5). This tandem reaction may involve the
oxidative addition of Pd(0) to the CꢀBr bond in 1. The
propadiene moiety in the formed intermediate A could
be activated through coordination to the palladium and
attacked by aniline to form intermediate B. The steric and
electronic effects of ligand14 may affect this activation of
double bond, which will depend on the nature of allenes.
The formation of 3 will go through intermediate C fol-
lowed by reductive elimination of Pd(0).
Acknowledgment. Wethank theNational Natural Science
Foundation of China (No. 20972093) and Science and
Technology Commission of Shanghai Municipality (No.
09ZR1412700) for financial support. The authors thank
Prof. Hongmei Deng (Laboratory for Microstructures,
SHU) for spectral support.
In summary, an efficient palladium-catalyzed synthesis
of N-functionalized multisubstituted indoles was devel-
oped in good to excellent yields from easily accessible
ortho-haloarylallenes and primary amines. A wide range
of electronically and structurally varied nitrogen frag-
ments could be introduced through this tandem CꢀN
bond-forming process by tuning the reaction conditions.
Supporting Information Available. Experimental pro-
cedures and characterization data for all compounds,
X-ray structure of 3aa0 (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4401