Deformylation of indole and azaindole-3-carboxaldehydes using anthranilamide and solid acid heterogeneous catalyst via quinazolinone intermediate

Article abstract of DOI:10.1016/j.tetlet.2012.02.079

The deformylation of indole and azaindole-3-carboxaldehydes was achieved in the presence of anthranilamide and a solid acid heterogeneous catalyst under reflux conditions in 25-90% yield. The reaction proceeds via quinazolinone intermediate, which undergoes acid catalyzed cleavage to form deformylated product.

Full text of DOI:10.1016/j.tetlet.2012.02.079

Tetrahedron Letters 53 (2012) 2222–2225
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Deformylation of indole and azaindole-3-carboxaldehydes using
anthranilamide and solid acid heterogeneous catalyst via quinazolinone
q
intermediate
Rammohan R. Yadav, Narsaiah Battini, Ramesh Mudududdla, Jaideep B. Bharate, Nagaraju Muparappu,
⇑
⇑
Sandip B. Bharate , Ram A. Vishwakarma
Medicinal Chemistry Division, Indian Institute of Integrative Medicine (Council of Scientific and Industrial Research), Canal Road, Jammu 180001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The deformylation of indole and azaindole-3-carboxaldehydes was achieved in the presence of anthra-
nilamide and a solid acid heterogeneous catalyst under reflux conditions in 25–90% yield. The reaction
proceeds via quinazolinone intermediate, which undergoes acid catalyzed cleavage to form deformylated
product.
Received 5 January 2012
Revised 13 February 2012
Accepted 16 February 2012
Available online 23 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Azaindole
Deformylation
Heterogeneous catalyst
Indole
Indole aldehyde
Quinazolinone
7
Methods for the removal of functional groups from organic mol-
ecules are immensely important in organic synthesis and biological
systems. In organic chemistry, the utility of functional groups is
mainly due to their ability to act as directing groups as well as their
high reactivity and selectivity in a wide variety of transformations.
Formyl group is one of the very important and widely used func-
tionality in organic synthesis. With extensive amount of literature
available on the introduction of this functionality on a variety of
olefinic and aromatic compounds, significant number of reports
also exists for the removal of this moiety. The process of deformy-
lation involves the removal of carbon monoxide and was first dis-
natural products. Position 3 of the indole is highly reactive toward
8
electrophilic substitution. Thus, the formylation of indoles is well
known and has been widely used in medicinal chemistry as a key
step toward the synthesis of several synthetic as well as natural
compounds. However, only two earlier reports exist on the
deformylation of indole-3-carboxaldehydes. Hazra et al.9 while
preparing unsymmetrical and symmetrical triindolylmethanes
using molecular iodine, observed the formation of deformylated
1
0
product indole in 5% yield. Chikvaidze et al.
reported the
deformylation of 2-substituted indole-3-carboxaldehydes using
diethylene glycol, ethylene glycol or glycerin under reflux
conditions in 30–60% yields. Deformylation of N-formyl indole
(of tryptophan) was reported using N,N -dimethylethylenediamine
(DMEDA) in water. In the present Letter, we report a new method
1
2
covered by Tsuji and Ohno using palladium, and rhodium metal
catalysts. These earlier discoveries were later followed with a num-
0
3
4
11
ber of reports using various rhodium, as well as palladium cata-
lysts. Deformylation reaction has also been known to occur in
biological systems, for example, biosynthesis of alkanes and al-
for the deformylation of indole and azaindole-3-carboxaldehydes.
kenes from cyanobacteria has been recently suggested to occur
through deformylation as one of the key steps.5
O
6
Indole is a very important and widely investigated heterocycle
CHO
O
HN
Amberlyst-15
(50% w/w)
ACN, 80 °C, 1 h
NH
and has been a part of several potent therapeutic agents. Further-
more, this heterocycle has been encountered in a large number of
NH2
+
+
N
N
H
H
NH2
N
H
q
IIIM Publication number IIIM/1467/2012.
1a
2a
3a (50%)
4a (25%)
⇑
Corresponding authors. Tel.: +91 191 2569111; fax: +91 191 2563333.
E-mail addresses: sbharate@iiim.ac.in (S.B. Bharate), ram@iiim.ac.in
Scheme 1. Amberlyst-15 catalyzed formation of quinazolinone 3a and indole 4a
from condensation reaction between 1a and 2a.
(
R.A. Vishwakarma).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.079

R. R. Yadav et al. / Tetrahedron Letters 53 (2012) 2222–2225
2223
8
). Later, we investigated other heterogeneous solid acid catalyst
O
1
2
silica-HClO
4
with acetonitrile as a reaction medium under reflux
O
H N
2
conditions. This catalyst was found to be superior to amberlyst-15
and acetic acid, and produced deformylated product in 80% yield
after 12 h reflux (Table 1, entry 12).
Next, we studied the scope of this new deformylation reaction
for different substituted indoles (Table 2). Different 5-substituted
indoles and N-methyl indoles were chosen and their 3-formyl
H N
2
CHO
HN
2
a
NH
Amberlyst-15
ACN, 80 C, 1 h
°
N
H
N
H
1a
Amberlyst-15
ACN, 80
3a
Amberlyst-15
ACN, 80 C,
13
products 1a–1h were prepared using Vilsmeier-Haack proce-
dure. Like unsubstituted indole 1a (entry 1), 5-methyl and 5-
°
14
°
C,1 h
1
h
methoxy indole-3-carboxaldehydes 1b and 1c (entries 2–3) pro-
duced good yields of the corresponding deformylated products.
Similarly, 5-halo indole-3-carboxaldehydes 1f and 1g participated
well in this reaction and desired deformylated products were
formed in 65–70% yield after refluxing for 6 h (Table 2, entries 9
and 10). Interestingly, the 5-carboxymethyl ester of indole-3-car-
boxaldehyde 1d did not undergo deformylation reaction, even after
refluxing for 24 h (Table 2, entries 4 and 5). Similarly N-methyl in-
dole-3-carboxaldehyde 1h has not participated in the deformyla-
tion reaction (Table 2, entry 11), indicating the necessity of free
indolic NH for deformylation process. It is noteworthy to mention
that, in the case of 5-nitro-indole-3-carboxaldehyde (1e), the
deformylation reaction went on so smoothly that even after stir-
ring at room temperature for 6 h, 65% of deformylated product
was formed (Table 2, entry 7). Under reflux condition, 1e produced
the corresponding deformylated product in 90% yield (Table 2, en-
try 8).
2
a
ACN, 80
°
C,1 h
N
H
4
a
Scheme 2. Investigation of deformylation mechanism.
As a part of our medicinal chemistry program involving the syn-
thesis of indole based heterocyclic compounds as potential thera-
peutic agents, interestingly we observed the solid-acid catalyst
catalyzed deformylation of indole aldehyde. Reaction between in-
dole-3-carboxaldehyde (1a) and anthranilamide (2a) in acetoni-
trile in the presence of amberlyst-15 at 80 °C for 1 h (Scheme 1),
resulted in the formation of the expected quinazolinone product
a (50%) along with non-polar side products (25%); which after
spectral characterization and matching with the commercial refer-
ence standard turned out to be indole (4a).
3
Further, in order to check the mechanism for the formation of
this deformylated product, a reaction of indole-3-carboxaldehyde
The scope of this deformylation process was also investigated
for 7-azaindole-3-carboxaldehyde (6). As shown in Scheme 3, the
(
1a) with amberlyst-15 in the absence of anthranilamide (2a)
was performed under similar reaction conditions and surprisingly
a was not formed. Similarly, reaction of 1a with 2a in the absence
4
treatment of 6 with silica-HClO under reflux, led to the formation
of deformylated product 5 in 25% yield. The scope of this reaction
for other representative heterocyclic aldehydes viz. quinoline-3-
carboxaldehyde, pyridine-4-carboxaldehyde, and benzofuran-2-
carboxaldehyde was also investigated under similar conditions;
however none of them underwent deformylation. Similarly, this
methodology was not applicable to aromatic aldehydes (e.g. 3,4-
dihydroxy benzaldehyde).
4
of amberlyst-15 also did not produce 4a. Lastly, the isolated qui-
nazolinone 3a was refluxed in ACN in the presence of amberlyst-
1
5, which led to the formation of indole 4a and anthranilamide
a in 80% and 10% yields respectively. These observations led to
2
the conclusion that deformylation of indole-3-carboxaldehyde
1a) proceeds via quinazolinone intermediate 3a as depicted in
Scheme 2.
To check whether this deformylation is limited to amberlyst-15,
(
Further, it is noteworthy to mention that both solid acid cata-
lysts (amberlyst-15 and silica-HClO
used several times without significant loss of activity.
4
) are recyclable and can be re-
16
we investigated other acid catalysts. Initially, two most commonly
used homogeneous acid catalysts viz. p-TSA and glacial acetic acid
were investigated. Both catalysts were found to be capable of
deformylation when refluxed for 24 h, with varying yields. The
pTSA catalyzed reaction produced only 20% yield of deformylated
product (Table 1, entry 5); however acetic acid catalyzed reaction
led to the formation of 75% deformylated product (Table 1, entry
Next, we sought to determine the mechanism of deformylation
of indole aldehydes. It is evident from Scheme 2 that, the presence
of anthranilamide as well as acidic condition is essential for the
deformylation of indole 3-carboxaldehydes, and quinazolinone 3a
is the key intermediate in this process. Further to unravel the
mechanism of quinazolinone (3a) cleavage, firstly the possible role
of CN nucleophile (from acetonitrile solvent) in this process was
Table 1
a
Optimization of reaction conditions for deformylation of 1a
Entry
Catalyst
Solvent
Temp. (°C)
Time (h)
Deformylation yield (%)b
1
2
3
4
5
6
7
8
9
Amberlyst-15c
Amberlyst-15c
Amberlyst-15c
ACN
ACN
ACN
ACN
80
80
80
80
1
3
6
12
24
3
12
24
1
25
40
60
60
20
30
50
75
35
48
74
80
c
Amberlyst-15
pTSAc
ACN
80
Acetic acid
Acetic acid
Acetic acid
Acetic acid
Acetic acid
ACN
ACN
ACN
120
120
120
80
80
80
Acetic acid
c
Silica-HClO
Silica-HClO
Silica-HClO
Silica-HClO
4
4
4
4
c
c
c
1
1
1
0
1
2
3
6
12
ACN
80
a
b
c
Indole-3-carboxaldehyde (1a, 1 mmol) and anthranilamide (2a, 1 mmol).
The isolated yield after silica gel column chromatography.
5
0% w/w of catalyst with respect to indole-3-carboxaldehyde 1a.

2
224
R. R. Yadav et al. / Tetrahedron Letters 53 (2012) 2222–2225
Table 2
4a was formed in good yield (ꢀ80%), however the mass balance for
a, 15
Scope of the deformylation reaction
anthranilamide portion of 3a was not observed, as only 10% yield
of 2a was obtained. The probable mechanism for the cleavage of
quinazolinone intermediate 3a leading to the formation of indole
O
CHO
NH2
NH2
Silica-HClO4
ACN
R
R
+
4
a and anthranilamide 2a is depicted in Figure 1.
N
H
N
In conclusion, we have established a novel, wide applicability,
R1
1
2a
4
eco-friendly, and mild conditioned deformylation of indole and
azaindole-3-carboxaldehydes using reusable heterogeneous cata-
lysts. Conceptually, the work described provides a useful strategy
in multi-step synthetic protocols, wherein an aldehyde acts as an
activating/directing group and is subsequently removed or excised.
When this concept has been used previously the excisable groups
were limited to heteroatom-based systems, such as sulfones or
nitroalkanes. The deformylation strategy we have described may
have additional useful applications in indole/azaindole based
chemistry. Furthermore, the present Letter adds the new use of
Yield (%)b
Entry
Indole aldehyde
1a: R = H, R = H
1b: R = 5-Me, R
1c: R = 5-OMe, R
1d: R = 5-CO
1d: R = 5-CO
1e: R= 5-NO
1e: R= 5-NO
1e: R= 5-NO
1f: R = 5-Br, R
1g: R = 5-I, R
1h: R = H, R
Temp (°C)
Time (h)
1
2
3
4
5
6
7
8
9
1
80
80
80
80
80
rt
6
6
6
6
24
3
6
6
6
6
6
80
80
74
0
1
= H
= H
1
2
Me, R
Me, R
1
= H
= H
2
1
0
2
, R
, R
, R
1
1
1
= H
= H
= H
50
65
90
65
70
0
2
2
rt
80
80
80
80
1
= H
= H
= Me
1
1
0
1
1
4
the heterogeneous solid acid catalysts silica-HClO and amber-
1
lyst-15.
a
Indole-3-carboxaldehyde (1 mmol), anthranilamide (1 mmol), and silica-HClO
4
Acknowledgements
(
50% w/w) in acetonitrile were heated at 80 °C for 3 h.
The isolated yield after silica gel column chromatography.
b
R.R.Y., R.M. and N.M. are thankful to the CSIR and N.B. is thank-
ful to the UGC for award of Junior Research Fellowship. Authors
thank the analytical department, IIIM for NMR and MS analysis
of our compounds.
POCl /DMF
C, 12 h, 70% yield
3
100
°
CHO
References and notes
N
N
H
N
N
H
2a
6
5
1.
(a) Tsuji, J.; Ohno, K. Tetrahedron Lett. 1965, 6, 3969–3971; (b) Tsuji, J.; Ohno, K.;
Kajimoto, T. Tetrahedron Lett. 1965, 6, 4565–4568.
Silica-HClO
4
ACN, 80
°C, 12 h, 25% yield
2
3
.
.
Ohno, K.; Tsuji, J. J. Am. Chem. Soc. 1968, 90, 99–107.
(a) Fristrup, P.; Kreis, M.; Palmelund, A.; Norrby, P. O.; Madsen, R. J. Am. Chem.
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Motoyoshi, H.; Carreira, E. M. Angew. Chem. Int. Ed. 2007, 46, 9331–9334; (d)
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Kreis, M.; Palmelund, A.; Bunch, L.; Madsen, R. Adv. Synth. Catal. 2006, 348,
Scheme 3. Formylation and deformylation of 7-azaindole.
investigated. The reaction of 1e with 2a in the presence of silica-
HClO in other solvents such as dioxane, methanol, and THF was
performed under optimized reaction conditions. The desired
4
2148–2154; (h) Doughty, D. H.; Pignolet, L. H. J. Am. Chem. Soc. 1978, 100,
deformylated product 4e was formed in all three solvents in 20%,
7083–7085.
5
5% and 35% yields respectively. These results ruled out the role
of CN nucleophile in the mechanism. As depicted in Figure 1, we
speculated that under acidic environment, indolic C -position gets
4.
Konopka, J. Senior Thesis 2011, Salve Regina University.
5. (a) Schirmer, A.; Rude, M. A.; Li, X. Z.; Popova, E.; del Cardayre, S. B. Science
2
2
010, 329, 559–562; (b) Patra, T.; Manna, S.; Maiti, D. Angew. Chem., Int. Ed.
011, 50, 12140–12142.
3
protonated resulting in the formation of iminium ion intermediate
I with disrupted aromaticity.1 Iminium form of indole is highly
unstable; thus the intermediate I gets cleaved leading to the for-
mation of indole 4a. The expected side product of this cleavage,
quinazolinone II was not detected; however we observed the
formation of anthranilamide (2a) in the reaction mixture. This
indicates that quinazolinone II can be further cleaved to anthra-
nilamide 2a under acidic condition as reported earlier.18 The indole
6
.
.
(a) Poulsen, T. B.; Jorgensen, K. A. Chem. Rev. 2008, 108, 2903–2915; (b) Sun, K.;
Liu, S.; Bec, P. M.; Driver, T. G. Angew. Chem., Int. Ed. 2011, 50, 1702–1706; (c)
You, S. L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38, 2190–2201; (d) Bartoli, G.;
Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39, 4449–4465.
7,8
7
(a) Casapullo, A.; Bifulco, G.; Bruno, I.; Riccio, R. J. Nat. Prod. 2000, 63, 447–451;
(
b) Endo, T.; Tsuda, M.; Fromont, J.; Kobayashi, J. J. Nat. Prod. 2007, 70, 423–424;
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J. A. J. Nat. Prod. 1998, 61, 1130–1132; (d) Kobayashi, J.; Murayama, T.;
Ishibashi, M.; Kosuge, S.; Takamatsu, M.; Ohizumi, Y.; Kobayashi, H.; Ohta, T.;
Nozoe, S.; Sasaki, T. Tetrahedron 1990, 46, 7699–7702; (e) Seldes, A. M.; Brasco,
M. F.; Franco, L. H.; Palermo, J. A. Nat. Prod. Res. 2007, 21, 555–563; (f) Walker, S.
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Yamashita, T.; Imoto, M.; Sawa, T.; Naganawa, H.; Kurasawa, S.; Zhu, B.-Q.;
Umezawa, K. J. Nat. Prod. 1988, 51, 1184–1187.
O
O
8.
Loh, C. C. J.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 46–48.
HN
Protonation
of indolic C3
9. Hazra, A.; Paira, P.; Sahu, K. B.; Banerjee, S.; Mondal, N. B. Catal. Commun. 2008,
9, 1681–1684.
10. Chikvaidze, I. S.; Samsoniya, S. A.; Narindoshvili, T. G.; Kobakhidze, N. V. Chem.
Heterocycl. Comp. 2000, 36, 1346.
11. Odagami, T.; Tsuda, T.; Kogami, Y.; Kouji, H.; Okada, Y. Chem. Pharm. Bull. 2009,
57, 211–213.
4
12. Silica-HClO catalyst was prepared from silica gel (#230–400) and perchloric
NH
HN
H
NH
3
H
O
O
N
S
N
H
O
H
3
a
Amberlyst-15
I
acid. For detailed procedure, see: Chakraborti, A. K.; Gulhane, R. Chem.
Commun. 2003, 1896–1897.
H+
H
13. General procedure for the formylation of indoles 4a–4h or azaindole 5:
O
O
Phosphorous
oxychloride
(2 mmol)
was
added
dropwise
to
Amberlyst-15
+
dimethylformamide (3 mL) cooled under ice-bath and allowed to stir for
+
N
H
2
N
H / H O
HN
2
30 min. A solution of indoles 4a–4h or azaindole 5 (1 mmol) in DMF (5 mL) was
H
2
N
N
H
o
added dropwise for 5 min at 0 C. The mixture was further allowed to stir for
II
4a
3
h at 90–100 C. Reaction mixture was cooled to room temperature and
o
2a
poured into crushed ice. Excess POCl
3
was quenched with 1 N NaOH and left
Figure 1. Probable mechanism for the formation of indole (4a) from 3a.
overnight at room temperature. Ice-cold reaction mixture was then extracted

R. R. Yadav et al. / Tetrahedron Letters 53 (2012) 2222–2225
2225
(
50 mL ꢁ 3) with EtOAc. Combined organic layer was concentrated on rotary
16. Catalysts were recovered from the reaction mixture by simple filtration
o
evaporator and crude products were purified by silica gel (#100–200) column
chromatography to get indole-3-carboxaldehydes 1a–1h or 6 in 60–80% yield.
4. Jiang, B.; Smallheer, J. M.; AmaralLy, C.; Wuonola, M. A. J. Org. Chem. 1994, 59,
followed by activation in oven (100 C) for 4–5 h. Treatment of indole-3-
carboxaldehyde (1a, 1 mmol) with anthranilamide (2a, 1 mmol) in the
presence of amberlyst-15 for 6 h at reflux condition led to the formation of
deformylated product 4a in 60%, 55%, 50%, and 42% yield over four cycles
1
1
6
823–6827.
5. Typical procedure for the deformylation of indole and azaindole-
-carboxaldehydes: Solid acid catalyst (50% w/w) was added to the solution
of indole-3-carboxaldehydes 1a–1h or azaindole-3-carboxaldehyde
1 mmol) and anthranilamide 2a (1 mmol) in acetonitrile (6 mL). The
4
respectively. Under similar conditions, silica-HClO produced 80%, 74%, 64%,
3
and 58% yields over four cycles respectively.
6
17. (a) Chen, C. B.; Wang, X. F.; Cao, Y. J.; Cheng, H. G.; Xiao, W. J. J. Org. Chem. 2009,
74, 3532–3535; (b) Kulkarni, A.; Zhou, W.; Torok, B. Org. Lett. 2011, 13,
5124–5127.
18. (a) Asano, T.; Yoshikawa, T.; Nakamura, H.; Uehara, Y.; Yamamoto, Y. Bioorg.
Med. Chem. Lett. 2004, 14, 2299–2302; (b) Shemchuk, L. A.; Chernykh, V. P.;
Levashov, D. V.; Sytnik, K. M. Russ. J. Org. Chem. 2010, 46, 1243–1245.
(
reaction mixture was allowed to stir for 6–24 h at room temperature or at
reflux temperature. The progress of the reaction was monitored by TLC. After
completion of the reaction, it was allowed to cool and catalyst was recovered
by filtration. The filtrate was concentrated to get crude products which after
silica gel (#100–200) column chromatography gave deformylated products
4
a–4h or 5 in 25–90% yield.