Lewis acid-catalyzed Friedel-Crafts alkylations of 3-hydroxy-2-oxindole: An efficient approach to the core structure of azonazine

Article abstract of DOI:10.1039/c2cc35283d

A Lewis acid catalyzed Friedel-Crafts reaction of electron rich aromatics with 3-alkyl-3-hydroxy-2-oxindole (5) has been developed. The methodology provides a straightforward access to the core of azonazine (2) sharing an all-carbon quaternary stereocenter at the tetracyclic ring junction. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc35283d

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Lewis acid-catalyzed Friedel–Crafts alkylations of 3-hydroxy-2-oxindole:
an efficient approach to the core structure of azonazinew
Santanu Ghosh, Lakshmana K. Kinthada, Subhajit Bhunia and Alakesh Bisai*
Received 22nd July 2012, Accepted 19th August 2012
DOI: 10.1039/c2cc35283d
A Lewis acid catalyzed Friedel–Crafts reaction of electron rich
aromatics with 3-alkyl-3-hydroxy-2-oxindole (5) has been developed.
The methodology provides a straightforward access to the core of
azonazine (2) sharing an all-carbon quaternary stereocenter at the
tetracyclic ring junction.
8.37 mM) and nitrite production (IC50 13.70 mM) but was less
potent than the standard celastrol (IC50 0.3 mM).7 The biosynthesis
of azonazine (2) has been proposed through a condensation of
D-tyrosine (Tyr) and D-tryptophan (Trp) generating a diketo-
piperazine (DKP) moiety followed by additional functionali-
zation viz. oxidative cyclization, N-acetylation of the indoline
unit followed by mono N-methylation of DKP. To the best of
our knowledge, no total synthesis of azonazine (2) has yet been
reported, despite interesting biological properties and intriguing
architecture. Herein, we delineate our efforts towards the synthesis
of a tetracyclic core of azonazine (2) via Lewis acid-catalyzed
Friedel–Crafts alkylation of 4-substituted phenol8 with 3-hydroxy-
2-oxindoles (5) to synthesize intermediate 4 having all-carbon
stereogenic at the pseudobenzylic position.
The Friedel–Crafts alkylations of electron rich aromatics with
electron-deficient species is one of the most powerful methods for
the formation of a new C–C bond.1 Since years, this process has
extensively been exploited in organic synthesis from small scale
experiments to industrial processes and is mostly facilitated by
protic acid or Lewis acids.2 In this regard, the total synthesis of
diazonamide A,3 by Nicolaou et al., beautifully indicates the
application of this strategy where 3-hydroxy-2-oxindole (5) com-
pound could be activated under the influence of trifluoromethane
sulfonic acid leading to the formation of an all-carbon quaternary
center at the pseudobenzylic (3a)-position of the 2-oxindole deriva-
tive (4). Their pioneering work led to the efficient total synthesis of
diazonamide A4 (1) and related structures. Recently, an
architecturally interesting indole alkaloid, azonazine5 (2) (Fig. 1),
has been isolated from a Hawaiian marine sediment-derived
fungus Aspergillus insulicola, having a unique dipeptide structure
with a similar tetracyclic core as present in diazonamide A.
In 2010, Crews et al.5 reported that azonazine (2) was
inactive at 1 mg mLÀ1 in the disk diffusion assay and it was
inactive using an MTT screen6 at 100 mM against human prostate
(PC3), human breast adenocarcinoma (MCF-7), and murine
macrophage (RAW 264.7) cells. Alternatively, azonazine exhibited
anti-inflammatory activity by inhibiting NF-kB luciferase (IC50
At the outset, the optimization studies for the Friedel–
Crafts alkylation were performed using p-cresol and 3-methyl-3-
hydroxy-2-oxindole (5a) using BF3ÁOEt2 in different solvents. It
was observed that 50 mol% of BF3ÁOEt2 in dichloromethane
under reflux was the optimum condition to afford 4a (in 90%
yield, 6 h). On decreasing the catalyst loading, the reaction becomes
sluggish [25 and 10 mol% of BF3ÁOEt2 provided 62% (16 h) and
38% (24 h) yields, respectively]. The F–C alkylation proceeds
through a 2H-indol-2-one ring system (7)9 (Scheme 1), which could
easily be generated from 3-hydroxy-2-oxindole derivatives (5) in the
presence of BF3ÁOEt2. Further, in pursuit of the catalytic version,
we looked forward for Lewis acid-catalyzed Friedel–Crafts alkyla-
tions of cresol with 3-hydroxy-2-oxindoles (5a) in the presence of
various metal triflates (Table 1). It was found that the reaction was
sluggish despite higher catalyst loadings (entries 1–3) at room
temperature. After extensive optimization (Table 1), we found that
10 mol% of In(OTf)3 (condition A), Cu(OTf)2 (condition B), and
Bi(OTf)3 (condition C) provided Friedel–Crafts alkylation products
(4a) in 92% (entry 10), 91% (entry 17), and 94% (entry 20),
respectively. Although, under the similar conditions, 25–50 mol%
of Ce(OTf)3 and Sn(OTf)2 provided high yields of products
(79–90%, entries 13, 14, 21, and 22), but 10 mol% of these catalysts
afforded only 53% (entry 23) and 65% yields (entry 24),
Fig. 1 Diazonamide A (1), azonazine (2) and their tetracyclic core (3).
Department of Chemistry, Indian Institute of Science Education and
Research Bhopal, Bhopal, MP 460 023, India.
E-mail: alakesh@iiserb.ac.in
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, NMR spectra. See DOI: 10.1039/
c2cc35283d
Scheme 1 Retrosynthetic plan and working hypothesis.
c
10132 Chem. Commun., 2012, 48, 10132–10134
This journal is The Royal Society of Chemistry 2012

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Table 1 Optimization with Lewis acids as catalyst
Entry
Lewis acid
Equiv.a
Temp.
Time
Yieldb
1
2
3
4
5
6
7
8
Sc(OTf)3
In(OTf)3
Zn(OTf)2
Zn(OTf)2
Cu(OTf)2
Sn(OTf)2
FeCl3
In(OTf)3
In(OTf)3
In(OTf)3
FeCl3
Ce(OTf)3
Ce(OTf)3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Sn(OTf)2
Sn(OTf)2
Ce(OTf)3
Sn(OTf)2
50 mol%
50 mol%
50 mol%
25 mol%
50 mol%
50 mol%
50 mol%
50 mol%
25 mol%
10 mol%
50 mol%
50 mol%
25 mol%
50 mol%
25 mol%
10 mol%
50 mol%
25 mol%
10 mol%
50 mol%
25 mol%
10 mol%
10 mol%
25 1C
25 1C
25 1C
45 1C
25 1C
25 1C
25 1C
45 1C
45 C
45 8C
45 1C
45 1C
45 1C
45 1C
45 1C
45 8C
25 1C
45 1C
45 8C
45 1C
45 1C
45 1C
45 1C
24 h
24 h
24 h
12 h
24 h
18 h
24 h
4 h
5 h
7 h
18h
12h
12 h
12 h
14 h
12 h
12 h
12 h
10 h
14 h
14 h
16 h
15 h
10%
46%
Traces
Traces
24%
42%
40%
95%
92%
92%
56%
90%
82%
92%
91%
91%
94%
93%
94%
86%
79%
53%
65%
Fig. 3 Further substrates scope.
cases where catalyst loadings were in the range of 25–40 mol%
(Fig. 3). Next, we set forth for a generalized method for the
reaction of phenol with 3-hydroxy-2-oxindole (5) substrates in
the presence of a catalytic amount of Lewis acids. It was found
that, in all cases the yields were moderate to good (Fig. 4), and that
the phenol had reacted at the p-position to yield compound 6.
Mechanistically, the reaction can proceed through 2H-indol-2-
one (7) (Scheme 2) formed upon treatment of 3-hydroxy-2-oxindole
(5) in the presence of a Lewis acid. The electron-rich p-position of
phenol derivatives can easily add to the intermediate (7) to afford
products with excellent regioselectivity. Alternatively, it can also
follow a path where intermediate 7 forms twice during the course of
the reaction, initially from the starting 3-hydroxy-2-oxindole (5) in
the presence of Lewis acid and at a later stage from 3-O-aryloxy-2-
oxindoles (8) via a C–O bond breaking through a dissociated ion
pair as shown in Scheme 2. In the latter case one would expect a
regioisomeric (para:ortho) mixture of products. However, the
exclusive formation of p-substituted products (6) (Fig. 4), together
with the literature report on the thermal and acid-catalyzed
rearrangement of 3-N-aryl-2-oxindoles and 3-O-aryloxy-2-oxindoles
(8) into 3-(p-aminoaryl)-2-oxindoles and 3-(p-hydroxyaryl)-2-
oxindoles (6), respectively,11 following a Hofmann–Martius
rearrangement, supports the attack of the p-position of electron-
rich phenols to 2H-indol-2-one (7) (Scheme 2) leading to the final
products.
9
10
11
13
14
15
16
17
18
19
20
21
22
23
24
a
Reactions were carried out in 0.50 mmol of 5a with 1.50 mmol of
b
p-cresol in 6 mL of CH2Cl2, unless noted otherwise. Isolated yields.
respectively. So, in general, 10–25 mol% of these catalysts were
good enough for an efficient reaction.
The reaction was later on extended to a variety of 3-hydroxy-2-
oxindole derivatives (5) as shown in Fig. 2. p-Cresol and 4-tert-butyl
phenol were efficiently added to 3-methyl-3-hydroxy-2-oxindoles (5)
to provide products with good-to-excellent yields (Fig. 2).
In the case of halogen substituted 3-hydroxy-2-oxindoles, the
reaction rate was slower than the one with no substitution.
Evidently, the electron-withdrawing halogen substituent hampers
the formation of the electron-deficient 2H-indol-2-one ring system
(7).10 The reactions of p-cresol and 4-tert-butyl phenol with halogen
substituted substrates also work without event, except in some
Further, we looked forward to employ the Friedel–Crafts
alkylation strategy in the construction of a tetracyclic core of
Fig. 4 Substrates scope using phenol.a
Fig. 2 Substrates scope.a,b
Scheme 2 Plausible mechanism for Friedel–Crafts alkylation.
Chem. Commun., 2012, 48, 10132–10134 10133
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Scheme 3 Reductive cyclization approach.
3 For isolation of diazonamide A, see: (a) N. Lindquist, W. Van Duyne,
G. D. Fenical and J. Clardy, J. Am. Chem. Soc., 1991, 113, 2303; (b) For
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M. A. Ciufolini, Org. Lett., 2011, 13, 390 and references cited therein.
5 For isolation of azonazine (2), see; Q.-X. Wu, M. S. Crew,
M. Draskovic, J. Sohn, T. A. Johnson, K. Tenney, F. A. Valeriote,
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8 (a) Z. Rappoport, The chemistry of phenols; John Wiley and Sons,
New York, 2003; (b) H. Heaney, in Comprehensive Organic Synthesis,
ed. B. M. Trost and I. Fleming, Pergamon Press, Oxford, UK, 1991,
vol. 2, pp. 733–752.
9 (a) For BF3ÁOEt2 and p-TsOH-catalyzed formation of 2H-indol-2-one
ring system (7), see; D. B. England, G. Merey and A. Padwa, Org.
Lett., 2007, 9, 3805; (b) For a recent report on Friedel–Crafts
alkylations of 3-hydroxy-2-oxindoles with electron-rich aromatics
catalyzed by Hg(ClO4)2ÁH2O, see; F. Zhou, Z.-Y. Cao, J. Zhang,
H.-B. Yang and J. Zhou, Chem.–Asian J., 2012, 7, 233.
10 For a Cs2CO3-mediated formation of 7 for the synthesis of
pyrroloindolines, see; C. Menozzi, P. I. Dalko and J. Cossy, Chem.
Commun., 2006, 4638.
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Scheme 4 Crafting the tetracyclic core via oxidative coupling.
azonazine (2) through a reductive cyclization approach
(Scheme 3). Efforts in this direction either led to multitude of
products or over reduced product to 11 which on acetylation
afforded bis acetylated product 12 in 72% yield (Scheme 3).
Ultimately, we thought to exploit intramolecular oxidative
coupling to craft the tetracyclic core (3) as originally reported
by Nicolaou for diazonamide A.12 As shown in Scheme 4,
when compound 11 was treated with MnO2 in refluxing
benzene, it led to the formation of a tetracyclic core 3a in
72% yield. Mechanistically, a-elimination of intermediate
Mn(IV)-complex 13 under an oxidative environment forms
an iminium intermediate 15 via the intermediacy of 14. The
phenoxide of 15 then reacts with iminium ion intramolecularly
to afford the tetracyclic core (3a), which on subsequent
acetylation provides compound 3b in 85% yield (Scheme 4).
In conclusion, we have developed Lewis acid catalyzed
Friedel–Crafts alkylation of phenol derivatives with a variety
of 3-hydroxy-2-oxindoles. The strategy has been applied in the
synthesis of the tetracyclic core (3) of azonazine (2) through late-
stage intramolecular oxidative coupling. The depicted Friedel–
Crafts alkylation relies on the utility of the 2H-indol-2-one
system (7), formed in the presence of Lewis acids, to afford
oxindole derivatives (4) possessing an all-carbon quaternary
stereocenter at the C(3a)-position.13 We believe that nucleophilic
addition to the 2H-indol-2-one ring system (7) using a chiral
Lewis acid-complex14 could be one of the promising platforms
to accomplish this target in an enantioenriched form. Further
exploratory studies towards this direction are currently under
progress and will be reported in due course.
12 For MnO2-mediated cyclization, see; K. C. Nicolaou, J. Hao,
M. V. Reddy, P. Bheema Rao, G. Rassias, S. A. Snyder, X. Huang,
D. Y. -K. Chen, W. E. Brenzovich, N. Guiseppone, P. Giannakakou
and A. O’Brate, J. Am. Chem. Soc., 2004, 126, 12897.
We sincerely thank Professor Vinod K. Singh, the Director,
IISER Bhopal, for research facilities. A.B. thanks the BRNS,
DAE, India, for a Young Scientist Research Award and the
CSIR, New Delhi, for a research grant. S.G., L.K.K., and S.B.
thank the CSIR, New Delhi, for JRFs.
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Notes and References
1 (a) G. A. Olah, Friedel–Crafts and Related Reactions, Wiley-Inter-
science, New York, 1963; (b) G. A. Olah, R. Krishnamurti and G. K.
S. Prakash, In Comprehensive Organic Synthesis, ed. B. M. Trost and
I. Fleming, Pergamon Press, Oxford, 1991, vol. 3, ch. 1.8, pp. 293–339;
(c) G. R. Meima, G. S. Lee and J. M. Garces, in Friedel–Crafts
Alkylation, ed. R. A. Sheldon and H. Bekkum, Wiley-VCH,
14 For enantioselective alkylation to 3-halo-2-oxindole see; S. Ma,
X. Han, S. Krishnan, S. C. Virgil and B. M. Stoltz, Angew. Chem.,
Int. Ed., 2009, 48, 8037.
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10134 Chem. Commun., 2012, 48, 10132–10134
This journal is The Royal Society of Chemistry 2012