I2-DMSO promoted metal free oxidative cyclization for the synthesis of substituted Indoles and pyrroles

Article abstract of DOI:10.1016/j.tetlet.2016.05.025

A series of di substituted indole and tri substituted pyrrole derivatives were synthesized efficiently by using I₂/K₂CO₃ in DMSO. The novel synthesis method offers the advantage of mild reaction conditions, operational simplicity, higher yields. The method is functional group tolerant and provides quick access to medicinally significant compounds in moderate to high yields.

Full text of DOI:10.1016/j.tetlet.2016.05.025

Accepted Manuscript
I2-DMSO Promoted metal free Oxidative Cyclizationfor the Synthesis of Sub-
stituted Indoles and Pyrroles
A. Ramakrishnam Raju, R. Venkata Reddy, V. Mallikarjuna Rao, V. Venkata
Naresh, A. Venkateswara Rao
PII:
S0040-4039(16)30539-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.025
TETL 47644
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 March 2016
3 May 2016
6 May 2016
Please cite this article as: Ramakrishnam Raju, A., Venkata Reddy, R., Mallikarjuna Rao, V., Venkata Naresh, V.,
Venkateswara Rao, A., I2-DMSO Promoted metal free Oxidative Cyclizationfor the Synthesis of Substituted Indoles
and Pyrroles, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.05.025
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Graphical Abstract
I2-DMSO Promoted metal free Oxidative
Cyclization for the Synthesis of Substituted
Indoles and Pyrroles
A. Ramakrishnam Raju,a,b R. Venkata Reddy,b V. Mallikarjuna Rao,b V. Venkata Naresh,b and A. Venkateswara Rao*a

1
Tetrahedron Letters
I2-DMSO Promoted metal free Oxidative Cyclization for the Synthesis of Substituted
Indoles and Pyrroles
A. Ramakrishnam Raju,a,b R. Venkata Reddy,b V. Mallikarjuna Rao,b V. Venkata Naresh,b and A. Venkateswara Rao*a
aDepartment of Chemistry, K L University, Vaddeswaram, Guntur (Dist), A.P, India; b GVK Biosciences Private Limited, Medicinal Chemistry Divison 28 A,
IDA ,Nacharam, Hyderabad-500076, TS.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of di substituted indole and tri substituted pyrrole derivatives were synthesized
efficiently by using I2/K2CO3 in DMSO. The novel synthesis method offers the advantage
of mild reaction conditions, operational simplicity, higher yields. The method is functional
group tolerant and provides quick access to medicinally significant compounds in moderate
to high yields.
Available online
Keywords:
Heterocycles
Iodine
DMSO
Indoles
2009 Elsevier Ltd. All rights reserved.
Pyrroles
The indole nucleus is a key shape in numerous natural
products, pharmaceutical agents, and functional materials.1
The gathering of indole derivatives have attracted great
interest.2 Amongst the family of indoles, 2,3-disubstituted
indoles are an significant class of heterocycles because of
their biological activities and medicinal applications.3 They
are being documented as privileged structures in medicinal
chemistry because of their attraction to bind with various
receptors. Various drugs and a large number of natural
products bearing an indole moiety are known, e.g.,
fascaplysin, homofascaplysin A, B and C (Figure 1).4-6
atorvastatin calcium (Lipitor), one of the top-selling drugs
worldwide (Fig. 1).9
Figure 1: Biologically active molecules
In other hand, pyrroles represent an important class of
heterocycles in organic chemistry. They are structural units in
many natural products and pharmaceuticals and are key
intermediates for the synthesis of a variety of biologically
active molecules and functional materials.7 It is the key
structural fragment of heme and chlorophyll, two pigments
essential for life.8 As examples of pyrrole derived drugs, non-
steroidal antiinflamatory compound tolmetin, the anticancer
drug candidate tallimustine and the cholesterol-lowering agent
Therefore, new methods for the synthesis of di-substituted
indoles are an important and popular topic of research,
particularly for acyl indole preparation due to wide
applications of its carbonyl group as a versatile intermediate
in the syntheses of a broad range of indole derivatives.
Traditionally, Friedel−Crafts acylations,10 Vilsmeier−Haack
acylations,11 and the reactions of indole salts with acyl
chlorides12 are usually employed for the synthesis of acyl
indoles. However, some of these methods suffer from the
requirement of stoichiometric metal Lewis acids, harsh

2
Tetrahedron
reaction conditions (often strict exclusion of moisture) and
unsatisfactory selectivity. Thus, the development of new,
catalytic routes to selectively accessing 3-acylindoles using
readily available starting materials is highly desirable.
Inspired by previous literature,13 herein we report a novel,
efficient, and green procedure for the synthesis of 2,3-
disubstituted indoles by using I2/K2CO3 in DMSO (Scheme
1). To the best of our knowledge, this methodology has not
been reported in the literature.
Initially, the condensation reaction of 2-amino acetophenone
and phenyl acetylene in the presence of I2 (30 mol%), K2CO3
o
(1 equiv) in DMSO at 70 C was employed to prepare the
desired compound 3a. To our surprise, this condensation
afford the cyclization product 3a in 45% yield.
Lower yield was obtained when the reaction was conducted
under an argon or N2 atmosphere. After several experimental
optimizations, we found best optimization conditions were I2
Scheme 1: Synthesis of 2,3-disubstituted indoles from 2-
amino acetophenone and phenyl acetylene
o
(1.5 equiv) and K2CO3 (1 equiv) in DMSO at 100 C for 6 h
in open air (Scheme 2).
Scheme 2: Synthesis of 2,3-disubstituted indoles from 2-
amino acetophenone and phenyl acetylene
Next, we performed reactions for improving the yield of the
product, various catalysts were investigated in further detail in
DMSO. Our surprise, the reaction could not perform without
I2/K2CO3. Therefore, the next reaction was performed with
1.5 equiv of I2. In fact, improvement in the yield from 45% to
70% was observed by increasing the amount of I2 from 30
mol% to 1.5 equiv. To further optimize the reaction
conditions, we investigated the effect of temperature on
reaction rate as well as on yields of products. It showed that
no product could be detected at room temperature even after
12 h (Table 1, entry a). The yield of product 3a was improved
and the reaction time was shortened as the temperature was
With optimized reaction conditions in our hand, next
we extended this method to other acetophenones such as 3-
methyl, 4-methyl and 3,4,5-trimethoxy substituted phenyl
acetylenes. In all cases, the corresponding indole derivatives
were obtained in good yields, furthermore, we examined the
reactivity of different 2-amino acetophenones. Interestingly,
other 2-amino acetophenones such as 4,5-dimethoxy, 5-chloro
and 2-amino benzophenones afforded the corresponding
indoles in good yields. In case of halogen containing phenyl
ketones, the corresponding indole was obtained relatively in
lower yields (Table 2, entry 3f) than other counterpart. In all
the cases, the reactions proceeded efficiently in DMSO at 100
oC and the products were obtained in good yields.
o
o
increased from 70 C to 100 C (Table 1, entry d, 6 hrs), so
the most appropriate reaction temperature is 100 oC. When we
employ the same reaction condition in the usual solvents
(DMF, Toluene, CH3CN and DCE) and eco-friendly solvent
(PEG), product 3a was formed in low yields after long time
(Table 1, entries e–i).
Table 1. Effect of catalyst and solvent in the formation of 3a

3
Table 2. Reaction screening with different phenyl acetylenes
acetylene in similar conditions. Surprisingly, the product
and 2-amino acetophenones.
was obtained in 75% yield. The scope of the reaction is
investigated to other β-enamino ketones and substituted
phenyl acetylenes. In all cases, the corresponding pyrrole
derivatives were obtained in good yields (Table 3). This
method also works well with β-enamino esters to furnish the
respective pyrrole carboxylates (Table 3, entries d, f, and g).
A few controlled experiments (Scheme 4) were performed in
order to support our proposed mechanism.
When
phenylacetylene was treated with I2 in presence of DMSO,
the reaction exclusively produced phenylglyoxal (Scheme 4a).
Phenylglyoxal (E) reacted with β-enaminoketone in presence
of I2/K2CO3 and DMSO to form pyrrole (5a) absolutely
(Scheme 4d). Furthermore, in the similar conditions
Phenylglyoxal (B) did not react with 2-amino acetophenone
(Scheme 4b). Therefore, Scheme 4b, 4c and 4d reveals that
the intermediates in the pyrrole and indole formation were
different.
The above results provided a gateway to extend this
process to other substrate like β-enamino ketones. Firstly, we
performed the reaction β-enamino ketone (4) with phenyl
Table 3. Reaction screening with different enamines and
phenyl acetylenes.
Scheme 4: Control experiments.
Based on the experimental results, we proposed a plausible
mechanism of the Iodine/K2CO3 condensation for the
formation of derivatives 3 as shown in Scheme 5. Firstly,
phenyl acetylene attack on keto group on 2-amino
acetophenone would give A, then Iodine/DMSO activates the
alkyne group forms intermediate B.13b,14 Then, displacement
of iodine would furnish cyclized product C, which underwent
dehydration to give the product 3.
Scheme 5: A possible mechanism for the formation of 3.

4
Tetrahedron
2009, 4, 1036−1048. (c) Kruger, K.; Tillack, A.; Beller, M.
Adv. Synth. Catal. 2008, 350, 2153−2167.
3.
(a) Jennings, L. D.; Foreman, K. W.; Rush, T. S., III;
Tsao, D. H. H.; Mosyak, L.; Kincaid, S. L.; Sukhdeo, M.
N.; Sutherland, A. G.; Ding, W.; Kenny, C. H.; Sabus, C.
L.; Liu, H.; Dushin, E. G.; Moghazeh, S. L.; Labthavikul,
P.; Petersen, P. J.; Tuckman, M.; Ruzin, A. V. Bioorg.
Med. Chem. 2004, 12, 5115− 5131. (b) Matter, H.;
Defossa, E.; Heinelt, U.; Blohm, P. M.; Schneider, D.;
Muller, A.; Herok, S.; Schreuder, H.; Liesum, A.;
Brachvogel, V.; Lonze, P.; Walser, A.; Al-Obeidi, F.;
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Tarzia, G.; Diamantini, G.; Giacomo, B. D.; Spadoni, G. J.
Med. Chem. 1997, 40, 2003−2010.
In case of pyrroles initially, the phenyl acetylene was α-
iodination followed by Kornblum oxidize to (E), which could
further imine formation to F. Then,
F
underwent
cyclization/dehydration to form H. Which further
aromatisation to 5 (Scheme 6).
Scheme 6: A possible mechanism for the formation of 5.
4.
5.
Roll, D. M.; Ireland, C. M.; Lu, H. S.; Clardy, J. J. Org.
Chem. 1988, 53, 3276–3278.
(a) Segraves, N. L.; Lopez, S.; Johnson, T. A.; Said, S. A.;
Fu, X.; Schmitz, F. J.; Pietraszkiewicz, H.; Valeriotec, F.
A.; Crewsa, P. Tetrahedron Lett. 2003, 44, 3471e3475; (b)
Schmidt, E. W.; Faulkner, D. J. Tetrahedron Lett. 1996,
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In conclusion, an efficient and simple procedure to
the synthesis of di substituted indoles and tri substituted
pyrroles is reported. The mild reaction conditions, operational
simplicity, higher yields (65–80%), short reaction time, cheap
starting materials and environmental friendliness are notable
features of this procedure. With no doubt, this reaction should
be useful to invent a simple oxidative cyclization reaction for
the synthesis of indole and pyrrole derivatives.
6.
7.
8.
Supplementary data
1
Experimental details, characterization data, copies of H and 13C
NMR spectrum of products can be found, in the online version, at
http:// dx.doi.org/
9.
(a) Zeng, L.; Miller, E. W.; Pralle, A.; Isacoff E. Y.;
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Novellino, E.; Befani, O.; Turini. P.; Agostinelli, E. J.
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2.
selected For reviews on indole synthesis, see: (a) Taber, D.
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Barluenga, J.; Rodriguez, F.; Fananas, F. J. Chem. Asian J.

5
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15. General experimental procedure: A mixture of 2-amino
acetophenone (1 or 4) (1 mmol, 1 eq.), phenyl acetylene
(2) (1 mmol, 1 eq.), I2 (1.5 eq.) and K2CO3 (1 eq.) in
DMSO (4mL) was stirred at 100 ˚C for 6hrs in open air.
After completion of the reaction, as indicated by TLC, the
solvent was diluted with water and extracted with ethyl
acetate (10 x 3 times). After solvent was removed in
vacuo. The resulting residue was subjected to column
chromatography on silica gel using petroleum ether/ethyl
acetate as eluent to afford the product 3 or 5.13b
Highlights
1. Synthesis of indole and pyrrole derivatives
through oxidative cyclization process.
2. A metal free approach for oxidative cyclization
process,
3. Iodine/DMSO has successfully been utilized to
oxidize phenyl acetylene group.
4. Efficient and regieoselective construction of
pyrrole and indole derivatives.