Oxidative dimerization of N-protected and free indole derivatives toward 3,3′-biindoles via Pd-catalyzed direct C-H transformations

Article abstract of DOI:10.1039/c0cc00486c

An oxidative homo dimerization of N-protected and free indole derivatives toward bioactive 3,3′-linked biindolyl scaffolds via Pd-catalyzed direct C-H transformations was first successfully demonstrated.

Full text of DOI:10.1039/c0cc00486c

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Oxidative dimerization of N-protected and free indole derivatives toward
3,30-biindoles via Pd-catalyzed direct C–H transformationsw
Yang Li,ab Wen-Hua Wang,ab Shang-Dong Yang,ab Bi-Jie Li,ab Chun Fengab and
Zhang-Jie Shi*ab
Received 19th March 2010, Accepted 23rd April 2010
First published as an Advance Article on the web 19th May 2010
DOI: 10.1039/c0cc00486c
An oxidative homo dimerization of N-protected and free indole
derivatives toward bioactive 3,30-linked biindolyl scaffolds via
Pd-catalyzed direct C–H transformations was first successfully
demonstrated.
presence of catalytic Pd(OTFA)2 at 90 1C in DMSO, and its
structure was further confirmed by X-ray crystallography.
Direct functionalization of the indole derivatives has attracted
great attention since the indole skeletons widely exist
in bioactive synthetic and natural products and possess a
privileged structure in drug discovery.1 C-arylation of
indole derivatives is particularly challenging because of both
the chemo- and regio-selectivities. Elegant methodologies for
the direct C-2 and C-3 arylation of indole derivatives have
already been reported with different aryl organohalides and
organometallic reagents.2 Recent advances also showed
that the most efficient transformation to approach those goals
was through the cross dehydrogenative arylation with general
arenes.3
3,30-Biindole scaffolds are important motifs in many natural
products and the synthetic world.4 Many methods have
already been developed to construct biindolyl scaffolds.5 In
recent years, some progress on construction of the 2,30-linked
and 3,30-linked biindolyl scaffolds was made, including the
enzymatic method,5f the palladium catalyzed cross coupling
of the indolyl halides with boronic compounds5g and the
Sonogashira coupling of the indolyl halides with terminal aryl
alkynes, followed by the further indole formation.5i When we
prepared for this manuscript, Zhang and co-workers first
reported the oxidative cross dimerization of N-protected
indole derivatives to give 2,30-linked products.6 However, the
3,30-linked homo dimerization of indoles still remained
elusive. In this communication, we report the first successful
example of oxidative dimerization of N-protected and free
indole derivatives toward 3,30-linked biindolyl scaffolds via Pd
catalyzed direct C–H transformations.
As reported, C-3 palladation of indole derivatives was
proposed by the electrophilic substitution due to the high
nucleophilicity of C-3 position in indolyl derivatives.2b,j
Starting from this point, we envisioned that such a cross
dimerization might go through the same intermediate 2
(Scheme 1). In the previous studies, different additives and
oxidants were found to effect the regioselectivity in direct
functionalization of indole derivatives.2,3 For example, the
silver salts showed the great potential in this aspect.2d,3b,d
This idea might also work for tuning the selectivity of the
dimerization of indole derivatives to approach the 3,30-linked
indole derivatives. Thus, we further started searching for
an extended pathway to construct 3,30-linked biindolyl
derivatives through Pd-catalyzed direct C–H transformations.
After systematic screening, to our satisfaction, AgNO3
seemed to play a key role in tuning the coupling pathway
and the 3,30-dimer 4a was obtained in 72% isolated yield
(entry 1, Table 1). N-Protected indoles with different substituents
were further investigated. With electron donating groups, such
as methoxy and methyl, the oxidative coupling products were
formed in good yields (entries 5, 7 and 8). Notably, the
5-methoxy group in substrate 1d accelerated the rate of the
3,30-dimerization (entry 4), however, the isolated yield was
obviously decreased, probably due to the poorer stability of
both starting material and product. Substrates with a strong
electron withdrawing group, such as an ester group (entry 3
and 10) were also suitable. Moreover, C–X (X = Cl, Br)
bonds (entries 2 and 6) survived well, which could be further
N-Methylindole 1a was selected for our initial studies.
Similarly as in Zhang’s report, a new cross dimerized product
3a with the unique 2,30-linkage was obtained when 1a was
treated with a stoichiometric amount of Cu(OAc)2 in the
a Beijing National Laboratory of Molecular Sciences (BNLMS) and
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, College of Chemistry, Peking University,
Beijing 10087, China
b State Key Laboratory of Organometallic Chemistry, SIOC, CAS,
Shanghai 200032, China. E-mail: zshi@pku.edu.cn
w Electronic supplementary information (ESI) available: Experimental
details. CCDC 715135 and 755576. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c0cc00486c
Scheme 1 Rational design to construct biindolyl scaffolds with
different linkage fashions via Pd catalysis.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 4553–4555 | 4553

View Article Online
Table 1 Homocoupling of various indole derivatives to construct
3,30-biindole scaffoldsa
Entry
Condition
R
R0
Yield (%)
1
2
3
4
5
6
7
8
9
10
A
A
A
B
B
A
B
B
C
C
Me
Me
Me
Me
Me
Me
Me
Me
Bn
H (1a)
5-Br (1b)
5-CO2Me (1c)
5-OMe (1d)
5-Me (1e)
6-Cl (1f)
7-OMe (1g)
7-Me (1h)
H (1i)
4a (72)
4b (79)
4c (80)
4d (20)
4e (61)
4f (73)
4g (72)
4h (72)
4i (69)
4j (79)
Scheme 2 Proposed catalytic pathway toward 3,30-linked biindoles.
Bn
5-COOMe (1j)
such transformations (entries 3, 4, 7 and 8). Since the reaction
condition was mild and neutral, the aldehyde group also
survived (entries 2 and 6). Obviously, this study provides a
direct and novel route to construct such unique 3,30-biindole
scaffolds.
Conditions: A: Pd(OTFA)2 (10 mol%), AgNO3 (1.2 equiv.), HOAc
(2.0 equiv.), DMSO (2.0 mL), 30 1C, 10 h; B: Pd(OTFA)2 (10 mol%),
AgNO3 (1.2 equiv.), DMSO (7.0 mL), 30 1C, 3–20 h; C: Pd(OTFA)2
(10 mol%), AgNO3 (2.0 equiv.), DMSO (1.0 mL), 60 1C, 4.5–10 h.
All the reactions were carried out on the scale of 0.5 mmol
(condition A)/0.25 mmol (condition B and C) and the average isolated
yields of two runs were reported.
a
With this developed method, the proposed structure of a
phenolic antioxidant found in beetroot (Beta vulgaris) (5) was
synthesized from commercial available starting material 1s in
two steps in an 80% yield.7 This approach also afforded a
high potential to make the diversified compounds with such
scaffolds, which could be further evaluated in biosystems.
transformed into different functionalities. Interestingly, the
slight change of the reaction conditions, for example,
concentration of the substrate, reaction temperature and the
presence or absence of HOAc, was necessary to pursue high
efficiency for different substrates.
In a previous report, magnesium slats were considered to
tune the reactivity of free indole.2b In our studies we
found that, the free indole could also undergo the similar
dimerization to produce 3,30-linked dimer 4k in 54% yield in
the presence of MgSO4 (entry 1, Table 2). With different
electron donating or electron withdrawing substituents
(entries 5, 9 and 10), the yields of desired products were even
higher. Similarly, the compatibility of halides group extended
The plausible pathway was proposed as Scheme 2.
Compound 4 was obtained from key intermediate 2, which
was produced from 1 via electrophilic substitution. The second
molecule of indole 1 was attacked by intermediate 2 via the
second electrophilic substitution to form intermediate 6, which
produced 3,30-linked oxidative coupling product 4 by the
release of a proton and reductive elimination.
Table 2 Homocoupling of various indole derivatives to construct
3,30-biindole scaffoldsa
In conclusion, we first demonstrated the oxidative homo
dimerization of N-protected and free indole derivatives toward
3,30-linked biindolyl scaffolds via Pd catalysis. The broad
group tolerance made this method useful to construct such
unique scaffolds from commercially available indole and its
derivatives. This homocoupling was also successfully applied
to construct biological active molecule. Further efforts to
understand such transformations are under way.
Entry
R0
Yield (%)
1
2
3
4
5
6
7
8
9
10
H (1k)
4k (54)
4l (84)
4m (78)
4n (82)
4o (50)b
4p (87)
4q (69)
4r (78)
4s (80)c
4t (72)
We are grateful to the NSFC (No. 20542001, 20521202,
20672006).
4-CHO (1l)
5-Br (1m)
5-Cl (1n)
5-CO2Me (1o)
5-CHO (1p)
6-Br (1q)
6-Cl (1r)
5,6-OAc (1s)
7-OMe (1t)
Notes and references
1 S. Cacchi and G. Fabrizi, Chem. Rev., 2005, 105, 2873.
2 (a) X. Wang, B. S. Lane and D. Sames, J. Am. Chem. Soc., 2005,
127, 4996; (b) B. S. Lane, M. A. Brown and D. Sames, J. Am. Chem.
Soc., 2005, 127, 8050; (c) N. R. Deprez, D. Kalyani, A. Krause and
M. S. Sanford, J. Am. Chem. Soc., 2006, 128, 4972;
(d) S. Yanagisawa, T. Sudo, R. Noyori and K. Itami, J. Am. Chem.
Soc., 2006, 128, 11748; (e) B. B. Toure, B. S. Lane and D. Sames,
Org. Lett., 2006, 8, 1979; (f) X. Wang, D. V. Gribkov and D. Sames,
J. Org. Chem., 2007, 72, 1476; (g) S. D. Yang, C. L. Sun, Z. Fang,
a
All the reactions were carried out on the scale of 0.5 mmol and the
b
average isolated yields of two runs were reported. The reactions was
c
carried out at 40 1C. The reaction was carried out in 30.0 mL/1.5 mmol.
ꢀc
This journal is The Royal Society of Chemistry 2010
4554 | Chem. Commun., 2010, 46, 4553–4555

View Article Online
B. J. Li, Y. Z. Li and Z. J. Shi, Angew. Chem., Int. Ed., 2008, 47,
1473; (h) F. Bellina, F. Benelli and R. Rossi, J. Org. Chem., 2008, 73,
5529; (i) N. Lebrasseur and I. Larrosa, J. Am. Chem. Soc., 2008,
130, 2926; (j) R. J. Phipps, N. P. Grimster and M. J. Gaunt, J. Am.
Chem. Soc., 2008, 130, 8172; (k) I. Ban, T. Sudo, T. Taniguchi and
K. Itami, Org. Lett., 2008, 10, 3607; (l) L. Joucla and L. Djakovitch,
Adv. Synth. Catal., 2009, 351, 673.
3 (a) D. R. Stuart and K. Fagnou, Science, 2007, 316, 1172;
(b) D. R. Stuart, E. Villemure and K. Fagnou, J. Am. Chem. Soc.,
2007, 129, 12072; (c) T. A. Dwight, N. R. Rue, D. Charyk,
R. Josselyn and B. DeBoef, Org. Lett., 2007, 9, 3137;
(d) S. Potavathri, A. S. Dumas, T. A. Dwight, G. R.
Naumiec, J. M. Hammann and B. DeBoef, Tetrahedron Lett.,
2008, 49, 4050.
4 (a) C.-L. Fang, S. Horne, N. Taylor and R. Rodrigo, J. Am. Chem.
Soc., 1994, 116, 9480; (b) E. Desarbre and J. Bergman, J. Chem.
Soc., Perkin Trans. 1, 1998, 2009; (c) L. E. Overman, J. F. Larrow,
B. A. Stearns and J. M. Vance, Angew. Chem., Int. Ed., 2000, 39,
213; (d) T. Janosik, J. Bergman, B. Stensland and C. Stalhandske,
J. Chem. Soc., Perkin Trans. 1, 2002, 330; (e) A. Pezzella,
L. Panzella, A. Natangelo, M. Arzillo, A. Napolitano and
M. d’Ischia, J. Org. Chem., 2007, 72, 9225; (f) M. Movassaghi
and M. A. Schmidt, Angew. Chem., Int. Ed., 2007, 46, 3725;
(g) T. Qi, W. Qiu, Y. Liu, H. Zhang, X. Gao, Y. Liu, K. Lu,
C. Du, G. Yu and D. Zhu, J. Org. Chem., 2008, 73, 4638;
(h) M. d’Ischia, A. Napolitano, A. Pezzella, P. Meredith and
T. Sarna, Angew. Chem., Int. Ed., 2009, 48, 3914.
5 (a) O. Schmitz-Dumont and B. Nicolojannis, Chem. Ber., 1930, 63,
323; (b) T. E. Young, J. Org. Chem., 1962, 27, 507; (c) U. Berensa,
J. M. Brown, J. Long and R. Seike, Tetrahedron: Asymmetry, 1996,
7, 285; (d) J. T. Kuethe, A. Wong and I. W. Davies, Org. Lett., 2003,
5, 3721; (e) G. Abbiati, A. Arcadi, E. Beccalli, G. Bianchi,
F. Marinelli and E. Rossi, Tetrahedron, 2006, 62, 3033;
(f) L. Panzella, A. Pezzella, A. Napolitano and M. d’lschia, Org.
Lett., 2007, 9, 1411; (g) H. A. Duong, S. Chua, P. B. Huleatt and
C. L. L. Chai, J. Org. Chem., 2008, 73, 9177; (h) P. A. Keller,
N. R. Yepuri, M. J. Kelso, M. Mariani, B. W. Skelton and
A. H. White, Tetrahedron, 2008, 64, 7787; (i) L. Capelli,
P. Manini, A. Pezzella, A. Napolitano and M. d’Ischia, J. Org.
Chem., 2009, 74, 7191; (j) N. R. Yepuri, R. Haritakul, P. A. Keller,
B. W. Skelton and A. H. White, Tetrahedron Lett., 2009, 50, 2501;
(k) J. Cornella, P. Lu and I. Larrosa, Org. Lett., 2009, 11, 5506.
6 During our preparation of manuscript, we found very similar
research for the synthesis of 2,30-linked biindolyl scaffolds via
Pd catalysis was reported: Z. Liang, J. Zhao and Y. Zhang,
J. Org. Chem., 2010, 75, 170.
7 S. P. H. Mee, V. Lee, J. E. Baldwin and A. Cowley, Tetrahedron,
2004, 60, 3695.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 4553–4555 | 4555