Palladium(0)-catalyzed dearomative arylation of indoles: Convenient access to spiroindolenine derivatives

Article abstract of DOI:10.1021/ol301663h

Dearomatization of an indole via palladium(0)-catalyzed cross-coupling reaction has been realized. With readily available triphenylphosphine as ligand, various spiroindolenine derivatives have been obtained in good to excellent yields, and enantioselectiv

Full text of DOI:10.1021/ol301663h

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3772–3775
Palladium(0)-Catalyzed Dearomative
Arylation of Indoles: Convenient Access
to Spiroindolenine Derivatives
Ke-Jia Wu, Li-Xin Dai, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
slyou@sioc.ac.cn
Received June 17, 2012
ABSTRACT
Dearomatization of an indole via palladium(0)-catalyzed cross-coupling reaction has been realized. With readily available triphenylphosphine as ligand,
various spiroindolenine derivatives have been obtained in good to excellent yields, and enantioselective control is also feasible with chiral ligands.
Dearomatization1 of arenes and heteroarenes has been
widely utilized in the synthesis of complex naturally oc-
curring bioactive compounds and pharmaceuticals.2 In
addition to methods such as metal-mediated alkylation
through metalÀarene complexation,3 hypervalent iodine-
mediated oxidation,4 and reductive alkylation under Birch
conditions,5 where a stoichiometric amount of metal re-
agents or oxidants in general is required, transition-metal-
catalyzed dearomatization6 of aromatic compounds has
made significant progress in recent years. Particularly, the
Pd-catalyzed cross-coupling reaction,7 one of the most
important reaction types in organic synthesis, was recently
also demonstrated successfully in a dearomatization re-
action. With an intramolecular design, Buchwald and
co-workers recently realized dearomative arylation of ani-
linederivativesand phenols.8 On the other hand, indole and
its derivatives represent one aspect of the most important
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r
10.1021/ol301663h
Published on Web 07/12/2012
2012 American Chemical Society

heterocyclic compounds in nature and their transformation
has attracted much attention. The 3-substituted indoles
have also been reported to be compatible with dearomatiza-
tion procedures such as iminium catalysis,1e,f,iÀk cycloaddi-
tion,1h,6m and the allylic alkylation reaction.6bÀd,i However,
the dearomative arylation of 3-substituted indole via the
Pd-catalyzed cross-coupling reaction has been rarely
explored9,10 despite the significant importance of the target
spirocycles. Given our interest in developing dearomatiza-
tion reactions of indole,6i,l we recently found that indol-
3-yl aryl bromide could be subjected to Pd-catalyzed
dearomative arylation reaction (Scheme 1). This intramo-
lecular cross-coupling type dearomatization of indol-3-yl
aryl bromides provides spiroindolenine derivatives,11,12
and the utilization of readily available phosphine ligands
potentially allows an asymmetric version of this reaction.
Herein we report our preliminary results on this subject.
summarized in Table 1. With the catalyst generated from
[Pd(C3H5)Cl]2 (2.5 mol %) and PPh3 (7.5 mol %), the
dearomatization reaction of 1a in the presence of K2CO3
(1.5 equiv) in refluxed dioxane (0.2 M) could proceed
smoothly, affording desired product 2a in 85% yield
(entry 1). Further screening of various ligands such
as P(nBu)3, SIPr HBF4, phosphoramidite L1, XPhos,
3
XPhos(tBu), QPhos, and P1 revealed that phosphora-
midite L113 gave a slightly higher yield (88%, entry 4). It
was worth mentioning that bidentate ligands such as
Phox, dppp, and dppf did not lead to the formation of
desired product but complete recovery of the starting
material (entries 9À11).
Table 1. Screening of Ligandsa
Scheme 1. Dearomative Arylation of 3-Substituted Indoles
We began our work by testing 3-(3-(2-bromophenyl)-
propyl)-1H-indole 1a as the model substrate with readily
available palladium precursors and ligands. The results are
(5) For a review: (a) Schultz, A. G. Chem. Commun. 1999, 1263. (b)
Subba Rao, G. S. R. Pure Appl. Chem. 2003, 75, 1443. For a recent
example: (c) Melero, C.; Herrera, R. P.; Guijarro, A.; Yus, M. Chem.;
Eur. J. 2007, 13, 10096.
entry
L
yield (%)b
entry
L
yield (%)b
(6) For Pd-catalyzed dearomatization procedures: (a) Wiegand, S.;
€
Schafer, H. J. Tetrahedron 1995, 51, 5341. (b) Kimura, M.; Futamata,
M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127, 4592. (c) Trost,
B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314. (d) Kagawa, N.;
Malerich, J. P.; Rawal, V. H. Org. Lett. 2008, 10, 2381. (e) Bedford,
R. B.; Butts, C. P.; Haddow, M. F.; Osborne, R.; Sankey, R. F. Chem.
Commun. 2009, 4832. (f) Nemoto, T.; Ishige, Y.; Yoshida, M.; Kohno,
Y.; Kanematsu, M.; Hamada, Y. Org. Lett. 2010, 12, 5020. (g) Wang,
D.-S.; Ye, Z.-S.; Chen, Q.-A.; Zhou, Y.-G.; Yu, C.-B.; Fan, H.-J.; Duan,
Y. J. Am. Chem. Soc. 2011, 133, 8866. For Ir-catalyzed dearomatization
procedures: (h) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005,
127, 8966. (i) Wu, Q.-F.; He, H.; Liu, W.-B.; You, S.-L. J. Am. Chem.
Soc. 2010, 132, 11418. (j) Wu, Q.-F.; Liu, W.-B.; Zhuo, C.-X.; Rong,
Z.-Q.; Ye, K.-Y.; You, S.-L. Angew. Chem., Int. Ed. 2011, 50, 4455. (k)
Zhuo, C.-X.; Liu, W.-B.; Wu, Q.-F.; You, S.-L. Chem. Sci. 2012, 3, 205.
(l) Wu, Q.-F.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51,
1680. For Rh-catalyzed dearomatization procedures: (m) Reddy, R. P.;
Davies, H. M. L. J. Am. Chem. Soc. 2007, 129, 10312. (n) Lian, Y.;
Davies, H. M. L. J. Am. Chem. Soc. 2010, 132, 440. For Au(I)-catalyzed
dearomatization procedure: (o) Cera, G.; Chiarucci, M.; Mazzanti, A.;
Mancinelli, M.; Bandini, M. Org. Lett. 2012, 14, 1350.
(7) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805. (b) Dounay, A. B.; Overman, L. E. Chem. Rev.
2003, 103, 2945. (c) Negishi, E. J. Organomet. Chem. 1999, 576, 179. (d)
Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036. (e) Martin, R.;
Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461. (f) Kambe, N.;
Iwasakia, T.; Teraob, J. Chem. Soc. Rev. 2011, 40, 4937.
(8) (a) Garcıa-Fortanet, J.; Kessler, F.; Buchwald, S. L. J. Am. Chem.
Soc. 2009, 131, 6676. (b) Rousseaux, S.; Garcıa-Fortanet, J.; Del Aguila
Sanchez, M. A.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 9282.
(9) Bedford, R. B.; Fey, N.; Haddow, M. F.; Sankey, R. F. Chem.
Commun. 2011, 47, 3649.
1
PPh3
85
7
QPhos
P1
63
2c
3
P(nBu)3
N. D.
55
8
complex
N. D.
N. D.
N. D.
SIPr HBF4
9c
10c
11c
Phox
dppp
dppf
3
4
L1
88
5
6c
XPhos
XPhos(tBu)
61
N. D.
a Reaction conditions: [Pd(C3H5)Cl]2 (2.5 mol %), L (7.5 mol %),
K2CO3 (1.5 equiv), and 1a (0.2 mmol) in dioxane (1.0 mL, 0.2 M), reflux.
b Isolated yields. c Conversions determined by 1H NMR.
(11) For a book: (a) Rahman, A. U.; Basha, A. Indole Alkaloids;
Hawood Academic Publishers: Amsterdam, 1997. For examples: (b) Chou,
T. Q. Chin. J. Physiol. 1931, 5, 345. (c) Liu, C.-T.; Wang, Q.-W.; Wang,
C.-H. J. Am. Chem. Soc. 1981, 103, 4634. (d) Verbitski, S. M.; Mayne,
C. L.; Davis, R. A.; Concepcion, G. P.; Ireland, C. M. J. Org. Chem.
2002, 67, 7124. (e) Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.;
Kawai, K.; Usami, Y.; Matsumura, E.; Imachi, M.; Ito, T.; Hasegawa,
T. Tetrahedron Lett. 1993, 34, 2355. (f) Jadulco, R.; Edrada, R. A.; Ebel,
R.; Berg, A.; Schaumann, K.; Wray, V.; Steube, K.; Proksch, P. J. Nat.
Prod. 2004, 67, 78. (g) Somei, M. S.; Yamada, F. Y. Nat. Prod. Rep. 2005,
22, 73.
(12) Notably, intermolecular reaction of 3-subsituted indole with
ArÀX with palladium catalyst generally afford indole 2-arylation
product. For selected examples: (a) Wang, X.; Gribkov, D. V.; Sames,
D. J. Org. Chem. 2007, 72, 1476. (b) Ruiz-Rodrıguez, J.; Albericio, F.;
Lavilla, R. Chem.;Eur. J. 2010, 16, 1124.
(10) During the preparation of this manuscript, Zhu and Rawal
reported a Pd-catalyzed benzylation reaction of indoles:Zhu, Y.; Rawal,
V. H. J. Am. Chem. Soc. 2012, 134, 111.
(13) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2374.
Org. Lett., Vol. 14, No. 14, 2012
3773

Table 2. Optimization of the Reaction Conditionsa
Table 3. Substrate Scope of Dearomative Arylationa,b
entry
[Pd]
base
solvent
yield (%)b
1
[Pd(C3H5)Cl]2
Pd(OAc)2
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
Li2CO3
NaOAc
KOtBu
NaHCO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
o-xylene
NMP
85
52
<5
65
62
57
<5
<5
N. D.
8
2
3c
4d
5
Pd2(dba)3
Pd(PPh3)4
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
[Pd(C3H5)Cl]2
6c
7c
8c
9c
10
11
12
13
14
15
16
54
67
55
88
77
82
diglyme
toluene
DMF
DMAc
a Reaction conditions: Pd source (5.0 mol %), PPh3 (7.5 mol %), base
(1.5 equiv), and 1a (0.2 mmol) in solvent (1.0 mL, 0.2 M), heated at
120 °C, reflux for dioxane. b Isolated yields. c Conversions determined by
1H NMR. d In the absence of PPh3.
a Reaction conditions: [Pd(C3H5)Cl]2 (2.5 mol %), PPh3 (7.5 mol %),
K2CO3 (1.5 equiv), and 1a (0.2 mmol) in toluene (1.0 mL, 0.2 M), reflux.
b Isolated yields. c [Pd(C3H5)Cl]2 (1.0 mol %), PPh3 (3.0 mol %) were
employed. d XPhos was used instead of PPh3.
PPh3 was chosen as the ligand for further optimization
given its ready availability and low cost. As summarized in
Table 2, after examining different palladium precursors
(entries 2À4) and bases (entries 5À10), the original condi-
tions, [Pd(C3H5)Cl]2 (2.5 mol %), PPh3 (7.5 mol %), and
K2CO3 (1.5 equiv), were found to be optimal. We then
tested the effects of various solvents including o-xylene,
NMP, diglyme, toluene, DMF, and DMAc (entries 11À16).
All the tested solvents could be tolerated, and the reaction in
toluene gave the highest yield (88%, entry 14).
Scheme 2. Formation of Five-Membered Ring
Under the optimal reaction conditions (2.5 mol % of
[Pd(C3H5)Cl]2, 7.5 mol % of PPh3, 1.5 equiv of K2CO3,
toluene (0.2 M) at reflux; Table 2, entry 14), different
substrates varying substituents and tethers were investi-
gated to evaluate the generality of the reaction. The results
are summarized in Table 3. The substrates bearing either
an electron-donating group (5-MeO, 4-Me, 7-Me, 2bÀ2d)
or an electron-withdrawing group (5-Cl, 6-F, 2e, 2f) on the
indole ring were all well-tolerated under the optimized
reaction conditions. In general, good to excellent yields
could be obtained for the desired dearomatization pro-
ducts. The 2-substituted indolyl products 2g and 2h were
also compatible to afford dearomatization products in
moderate yields. In the case of product 2g, XPhos14 was
found to be a better ligand than PPh3.
Substituents on the benzene ring including the electron-
donating group (2i, 2j) and the electron-withdrawing one
(2k, 2l) were all tolerated and led to dearomatization
products in 72À87% yields. When the naphthyl substrate
was employed, XPhos performed better to afford the
corresponding product 2m in 89% yield. Notably, the thienyl
substrate was found to be applicable in this protocol,
giving 2n in 61% yield. Moreover, tethers could also be
(14) For a review: (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2,
27. For the synthesis of XPhos: (b) Huang, X.-H.; Anderson, K. W.;
Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 6653.
3774
Org. Lett., Vol. 14, No. 14, 2012

Scheme 3. Asymmetric Dearomatization Reaction
Scheme 4. Proposed Reaction Mechanism
moderate ees could be obtained in the presence of chiral
spiro phosphoramidate16 L2 (58% ee) and L3 (61% ee)
(Scheme 3).
varied in the substrates. The O-linked product 2o was ob-
tained in 68% yield with XPhos. The malonate diester
linked substrates exhibited higher reactivity, affording
products (2pÀ2r) in excellent yields (89À93%).
A plausible mechanism for Pd-catalyzed dearomative
arylation is depicted in Scheme 4. With in situ generated
Pd(0) catalyst, 1a proceeds oxidative addition to form
Pd(II) intermediate I. Assisted by base, indole acts as
nucleophile through C-3 position to attack palladium
center, leading to seven-membered ring intermediate II.
Then intermediate II undergoes reductive elimination to
affordproduct 2a, meanwhile regenerating Pd(0) species to
complete the catalytic cycle.
In summary, we have developed an intramolecular Pd-
catalyzed dearomative arylation of 3-substituted indoles,
which provides a novel synthetic route of spiroindolenines
by generation of a quaternary center at the C-3 position.
The preliminary studies also show that the catalytic asym-
metric dearomative arylation is feasible. Further extension
of the reaction scope and improvement of enantioselec-
tivity are currently ongoing in our laboratory.
In addition to the six-membered ring formation men-
tioned above, the five-membered ring formation was also
attempted. Substrate 3 by shortening one carbon linkage
was tested, as shown in Scheme 2. The five-membered ring
dearomatization product was found unstable during the
silica gel column chromatography purification. To address
this problem, in situ reduction of the dearomatization
product with sodium borohydride was carried out, and
the desired product 4a could be obtained in 29% yield.
Further optimization of the reaction conditions by chang-
ing the solvents (toluene for dearomatization and THF for
reduction) could improve the yield of 4a to 58% by
suppressing the formation of compound 4b. The isolation
of products 4a and 4b indicated the formation of inter-
mediate 4c in a dearomatization process and the transfor-
mation of 4c to 4b via a migration process.12,15
Acknowledgment. The National Basic Research Pro-
gram of China (973 Program 2009CB825300) and the
National Natural Science Foundation of China (20923005,
20932008, 21025209, 21121062) are acknowledged for gener-
ous financial support.
The asymmetric version of the current dearomative
arylation reaction was also examined. Indeed, screening
of commercially available chiral ligands disclosed that
(15) However, the mechanism of direct C2 arylation via CÀH
activation can not be ruled out; see: (a) Campeau, L.; Parisien, M.;
Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. (b) Bellina, F.;
Cauteruccio, S.; Rossi, R. Eur. J. Org. Chem. 2006, 1379.
(16) For a review: (a) Xie, J.-H.; Zhou, Q.-L. Acc. Chem. Res. 2008,
41, 581. For the synthesis of chiral spiro phosphoramidites: (b) Zhou,
H.; Wang, W.-H.; Fu, Y.; Xie, J.-H.; Shi, W.-J.; Wang, L.-X.; Zhou,
Q.-L. J. Org. Chem. 2003, 68, 1582. For the results of other chiral
ligands, see Table S1 of the Supporting Information.
Supporting Information Available. Experimental pro-
cedures and analysis data for all new compounds. 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. 14, 2012
3775