Synthesis of reaction-ready 6,6′-biindole and 6,6′-biisatin via palladium(ii)-catalysed intramolecular C-H functionalisation

Article abstract of DOI:10.1039/c002098b

The first synthesis of a 6,6′-biindole and 6,6′-biisatin scaffold is reported with the penultimate step being the formation of the di-heterocyclic ring by Pd(ii)-catalysed intramolecular C-H functionalisation and Sandmeyer cyclisation, respectively.

Full text of DOI:10.1039/c002098b

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Synthesis of reaction-ready 6,60-biindole and 6,60-biisatin via
palladium(II)-catalysed intramolecular C–H functionalisationw
Allan B. Gamble and Paul A. Keller*
Received (in Cambridge, UK) 1st February 2010, Accepted 4th March 2010
First published as an Advance Article on the web 23rd March 2010
DOI: 10.1039/c002098b
The first synthesis of a 6,60-biindole and 6,60-biisatin scaffold is
reported with the penultimate step being the formation of the
di-heterocyclic ring by Pd(II)-catalysed intramolecular C–H
functionalisation and Sandmeyer cyclisation, respectively.
provide 7, which was further reduced under ultrasound in the
presence of iron11 to afford bianiline 8.
Transition-metal-catalysed direct arylation via C–H insertion
has undergone rapid development, and is still receiving
significant attention.12 A recent report12d outlined the synthesis
of indoles from simple anilines and alkynes via a Pd(II)-
catalysed C–H activation using dioxygen, however, at the
outset of our work, the only reports of a 2,3-disubstituted
methyl ester indole via Pd(II)-catalysis involved an excess of
Pd(OAc)2 (2 equiv.).13 For cyclisation of 8 to biindole 1, a
catalytic method tolerating an aryl bromide substituent was
required. Thus, the synthesis of enaminone 10 via Michael
addition of dimethyl acetylenedicarboxylate to aniline 7
allowed for the optimisation of Pd(II)-catalysed C–H insertion
and intramolecular cyclisation via indole 11 (Scheme 2).14
Intriguingly, solvent plays an important role in the mechan-
ism for reaction. In the case of the Pd(II)-cyclisation of
enaminones, it has not been discussed in detail, however,
compounds of similar structure to 10 are capable of forming
Nature provides a rich source of biaryl compounds with
significant biological activity1 and numerous methods exist
for the synthesis of structurally diverse biaryls e.g. by
transition-metal catalysis2,3 or oxidative coupling.3 As part
of our ongoing investigations into the biological activities of
homo- and hetero-dimeric aromatic systems,4,5 we have been
investigating biindoles as bioisosteres of binaphthyl units. In
particular we are interested in privileged heterocyclic scaffolds
having the potential for multiple functionalisations in often
unreactive positions. Although the synthesis of symmetrical
biindoles has been reported,6 symmetrical 6,60-biindoles and
6,60-biisatins have no literature precedence. Herein we report
the first synthesis of the symmetrical 6,60-biindole 1 and
6,60-biisatin 2 biaryl scaffolds with strategically positioned
‘reaction-ready’ functional groups in the 2-, 3- and usually
unreactive 4-positions, upon which chemical libraries can be
built in search of bioactive compounds (Fig. 1).
a
stable six-membered intramolecular hydrogen bond
(Scheme 3),15 preventing the orientation required for intra-
molecular cyclisation to indole 11. Proton transfer can occur,
allowing for both an enaminone 10A and imino–enol 10B
tautomer, with equilibrium shifted to favour 10A as solvent
polarity increases.15 On the basis of the previous experiments
(Scheme 2)14 we postulate that both DMA and acetonitrile can
competitively H-bond to the N–H enaminone proton, disrupting
the stable six-membered ring conformer 10A and establishing
an equilibrium with the desired 10AA enaminone intermediate.
However, DMA participates more aggressively in H-bonding
(Scheme 3),16 and thus, 10AA is expected to predominate
in DMA.
Bromide was selected for the reactive handles in the
normally deactivated 4,40-positions, thus, the key intermediate
was bianiline 8,7 which allowed for a convergent synthesis to
both targets. A 2,3-dicarboxylate substituent pattern on the
indole nucleus8 also allowed for future derivatisation, while
reducing the reactivity of these positions during subsequent
aryl bromide reactions. Thus, 8 was synthesised via a modified
procedure in six steps from commercially available 2,20-
biphenol 3, without the need for column chromatography in
an overall yield of 52% (Scheme 1).9,10 Key was the selective
nitration of 6, followed by protection of the phenolic groups to
Thus, we postulate a similar mechanism to Jiao and
co-workers,12d with an emphasis on the importance of a strong
H-bond acceptor solvent such as DMA (Scheme 3). Acting as
a Lewis-base donor,16 coordination of DMA sets up an
equilibrium thought to favour the conformation of 10AA,
and increases the nucleophilicity of the a-carbon and arene
through weakening of the N–H bond. C–H insertion via
electrophilic palladation12d of 10AA and reconjugation of
the DMA stabilised cationic imine intermediate affords
10AB, with subsequent electrophilic aromatic substitution
and re-aromatisation providing palladacycle 10AC. Reductive
elimination of 10AC gives the desired indole 11, with the Pd(0)
generated reoxidized by a Cu(II) salt. Alternatively, CꢀH
activation via an electrophilic aromatic substitution reaction
could precede enaminone CꢀH insertion, especially in an
electron-rich arene such as 10. However, in less electrophilic
arenes, previous intramolecular isotope effect studies for
Fig. 1 Reaction ready 6,60-biindole 1 and 6,60-biisatin 2 target
scaffolds.
School of Chemistry, University of Wollongong, 2522, Wollongong,
Australia. E-mail: keller@uow.edu.au; Fax: +61 2 4221 4287;
Tel: +61 2 4221 4692
w Electronic supplementary information (ESI) available: Details of
experimental procedures, optimisation details and discussion for
cyclisation to indole monomers, 1H and 13C NMR spectra for biindole
1 and biisatin 2. See DOI: 10.1039/c002098b
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Scheme 1 The synthesis of substituted bianiline 8.
Scheme 2 Investigation into the Pd(II)-catalysed CꢀH activation of enaminone 10, affording 2,3-disubstituted indole 11.
groups have been reported.12d Therefore we examined the
tolerance of our optimised conditions14b using two electron-
deficient arenes (Scheme 4). Indole 11 was isolated in modest
yield (35%) and 5-bromo indole 15 in a poorer yield (18%). A
higher catalyst loading and 50 mol% Cu(OAc)2ꢂH2O as
co-oxidant marginally increased the yield of indole 15 to
22%. Although not optimised, these indolisation conditions
tolerate electron-deficient and aryl bromide functional groups,
and could be utilised in the synthesis of the 6,60-biindole 1.
Reaction of dimethyl acetylenedicarboxylate with bianiline
8 provided di-enaminone 16 in 71% yield. Cyclisation via
Pd(II)-catalysed oxidative coupling yielded 6,60-biindole 1 in
22% yield (Table 1, entry 1). The higher catalyst and oxidant
loading of 30 mol% (15 mol%/enaminone) and 100 mol%
(50 mol%/enaminone), respectively, was used to promote
more efficient oxidation of generated Pd(0). Further optimisation
through catalyst and oxidant loading (Table 1, entries 2 and 3)
did not improve the yield of 1. Excess Pd(OAc)2 in air resulted
in complete consumption of 16, however, 1 could only be
isolated in 8% yield with multiple by-products formed. The
observed product distribution was presumably a consequence
Scheme
3
Proposed mechanism for 2,3-dicarboxylate indole
synthesis via Pd(II)-catalysed CꢀH functionalisation in DMA.
oxidative Pd(II)-catalysed conditions12d support the formation
of an enaminone intermediate analogous to 10AB.
Only limited examples of this reaction using substrates with
strongly deactivating and/or potentially labile functional
Scheme 4 Optimisation of C–H Pd insertion reactions to form indole
monomers containing electron withdrawing substituents.
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Table 1 Pd(II)-catalysed synthesis of 6,60-biindole scaffold 1
We thank A/Prof. Renate Griffith (Univ. New South
Wales), Drs John Deadman and David Rhodes (AVEXA)
for financial and project support. ABG thanks the ARC for a
scholarship.
Notes and references
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4 (a) P. A. Keller, C. Birch, S. P. Leach, D. Tyssen and R. Griffith,
J. Mol. Graphics, 2003, 21, 365; (b) J. B. Bremner, J. A. Coates,
D. R. Coghlan, D. M. David, P. A. Keller and S. G. Pyne, New J.
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B. W. Skelton, A. H. White and A. C. Willis, Tetrahedron Lett.,
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6 See ref. 5, and references therein. For further examples, see: (a) S.
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Entry Catalyst (mol%) Oxidant (mol%)
Time/h Yielda (%)
22
7.5
1
Pd(OAc)2 (30)
Pd(OAc)2 (20)
Pd(OAc)2 (30)
Cu(OAc)2ꢂH2O (100) 18
Cu(OAc)2ꢂH2O (20) 29
2b
3
Cu(OTf)2 (100)
24
18
0
8
4
Pd(OAc)2 (400) None
a
b
Isolated yield. An additional 10 mol% Pd(OAc)2 and 10 mol%
Cu(OAc)2 added after 23 h.
7 N. Viswanathan and S. J. Patankar, Indian J. Chem., Sect. B, 1985,
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9 Although there is precedence for direct bromination of 3, reported
yields range from 30%–83%; see ref. 10 for examples. In our
hands, reaction of 3 with Br2 in acetic acid resulted in multiple
products requiring significant efforts to isolate the components.
Our protection/deprotection strategy was high yielding, straight-
forward, and required no chromatography. Using an isopropyl
6,60-Biisatin 2 was realised in high yield over two steps from
bianiline 8 via the robust and well precedented Sandmeyer
method (Scheme 5).18 Isonitrosoacetanilide 17 was prepared in
good yield (74%), and subsequent heating of 17 in concen-
trated sulfuric acid allowed di-cyclisation to occur, with
biisatin 2 isolated in 83% yield after precipitation on crushed
ice, without the requirement for chromatography.
protecting group gave
recrystallisation.
a 94% yield for bromination after
10 For recent high yielding e.g. in chlorinated solvent see:
(a) S. Facchetti, D. Losi and A. Iuliano, Tetrahedron: Asymmetry,
2006, 17, 2993–3003; (b) M. Kesselgruber, M. Lotz, P. Martin,
In conclusion, we have demonstrated the first syntheses of
two novel symmetrical 6,60-biheterocycles from a common
bianiline intermediate. Both the 6,60-biindole 1 and 6,60-
biisatin 2 represent scaffolds which contain ‘reaction-ready’
functionalities in previously unreactive positions of the
benzene ring, while retaining the possibility for subsequent
derivatisations on the heterocyclic ring.
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14 (a) Full details and discussion on the optimisation of this reaction
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15 (a) G. Palmieri and C. Cimarelli, ARKIVOC, 2006, 6, 104–126;
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17 The synthesis of 6,60-biindole under a Bischler-type cyclisation was
unsuccessful. This acid-catalysed cyclisation was more successful
with electron-rich arene such as 3,5-dimethoxyaniline 9.
18 S. Lin, Z.-Q. Yang, B. H. B. Kwok, M. Koldobskiy, C. M.
Crews and S. J. Danishefsky, J. Am. Chem. Soc., 2004, 126,
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Scheme 5 Synthesis of 6,60-biisatin.
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This journal is The Royal Society of Chemistry 2010
4078 | Chem. Commun., 2010, 46, 4076–4078