Electrophile induced branching cascade: A powerful approach to access various molecular scaffolds and their exploration as novel anti-mycobacterial agents

Article abstract of DOI:10.1039/c3cc45289a

Herein we report on the Electrophile Induced Branching Cascade (EIBC), a new technique to produce a variety of biologically important molecular scaffolds. Some compounds exhibit excellent activities against Mycobacterium smegmatis. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc45289a

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Electrophile induced branching cascade: a powerful
approach to access various molecular scaffolds and
their exploration as novel anti-mycobacterial agents†
Cite this: Chem. Commun., 2013,
49, 10109
Received 16th July 2013,
Nitin T. Patil,z*a Ashok Konala,a Sudha Sravanti,b Ashita Singh,b
Accepted 30th August 2013
Ramesh Ummannib and Balasubramanian Sridharc
DOI: 10.1039/c3cc45289a
www.rsc.org/chemcomm
Herein we report on the Electrophile Induced Branching Cascade
(EIBC), a new technique to produce a variety of biologically important
molecular scaffolds. Some compounds exhibit excellent activities
against Mycobacterium smegmatis.
In the recent times, a ‘‘branching cascade’’1 has been proposed as a
new technique of ‘‘Diversity Oriented synthesis’’2 for the systematic
exploration of chemical space.3 Recently, we introduced the relay
catalytic branching cascade (RCBC) as a new technique for accessing
a series of multifunctional polyheterocyclic scaffolds4 in an efficient
manner.5 In this communication, we report an entirely novel
technique; namely, an ‘‘electrophile induced branching cascade’’
(EIBC) to access various molecular scaffolds which have potential
for further diversification.
Fig. 1 Concept of electrophile induced branching cascade (EIBC). X = common type
of starting material, SBA = scaffold building agent, P = product, E+ = electrophile.
As part of our ongoing interest in DOS, we assumed that a
common type of starting material (X) would react with several and appropriate reaction conditions which should only give the
variables (scaffold building agents, SBAs) in the presence of a desired product.
suitable electrophile (E+) leading to the formation of various
To the best of our knowledge, there have been no reports on
molecular scaffolds (Fig. 1). Such an EIBC technique would be such an EIBC approach leading to diverse electrophile incorpo-
synthetically valuable as it would incorporate an electrophile into rated molecular scaffolds in one-pot operation. Keeping in the
the polyheterocyclic scaffold and therefore offer clear-cut potential mind that the scaffolds of known bioactive small molecules
for introduction of further diversity.6 Unlike our previous report,5 a play a key role in guiding the chemist’s navigation of bio-
major concern was that E+ would react with the electron rich SBAs logically relevant chemical space, the strategy was designed in
leading to the formation of electrophile incorporated SBAs which such a way that the accessed compounds would (1) be a hybrid
may further react with X creating a mixture of products. The of privileged scaffolds, (2) satisfy the Lipinski ‘‘rule of five’’,
products formed have propensity to react again with electrophiles (3) have at least one sp3 carbon to attribute the 3D character,
and therefore the overall process can be considered as complicated (4) have smaller molecular weights, and (5) have the possibility
as it would be difficult to obtain any of the products in good yields. for incorporation of more polar functionalities.
The challenge, therefore, was to search for a suitable E+ source
We began to test our hypothesis using 2-(alkynyl)benzaldehydes
(X) as a common type of starting materials. The SBAs (1–11, Fig. 2)
were either prepared in the laboratory or purchased from commer-
cial sources.7 Iodonium ions were considered as a source of electro-
philes due to the low electrophilicity of molecular iodine, compared
a CSIR – Indian Institute of Chemical Technology, Hyderabad – 500 007, India
b Centre for Chemical Biology, CSIR – Indian Institute of Chemical Technology,
Hyderabad – 500 007, India
c Laboratory of X-Ray Crystallography CSIR –Indian Institute of Chemical Technology, to that of molecular chlorine and bromine, which would enable
Hyderabad – 500 007, India
obtaining the desired product suppressing the formation of
side products.8 The hypothesis, in part, was also based on the
† Electronic supplementary information (ESI) available. CCDC 928899, 928900
and 929085. For ESI and crystallographic data in CIF or other electronic format
fact that I+ is well suited for electrophilic cyclization of alkynes9
see DOI: 10.1039/c3cc45289a
and especially due to the excellent ability of the iodo-group
containing product to cross-couple with various nucleophiles
‡ Present address: CSIR-National Chemical Laboratory, Dr Homi Bhabha Road,
Pune – 411 008, India. E-mail: n.patil@ncl.res.in.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 10109--10111 10109

View Article Online
Communication
ChemComm
delivered the required products 2a and 2b in 72 and 68% yields
(branch-2). Fluorine substituted SBA-2(I) also worked well with
Xa under the same reaction conditions to get product 2c in 65%
yield. It should be noted that the protection of one of the amine
nitrogens on 1,2-diaminobenzene proved to be essential. As
shown in branch-3, the substrate, 2-alkynylbenzaldehydes Xa,
Xb and Xc reacted well with 2-(aminophenyl)benzimdazole (3)
under the reaction condition-6 to give desired benzoimadazo-
quinazolines 3a, 3b and 3c in 75, 71 and 62% yields, respec-
tively. The excellent reaction profiles observed with the SBA
2-aminobenzenesulphonamide (4) and 2-alkynylbenzaldehydes
Xa, Xd and Xc affording the cyclization products 4a, 4b and 4c
in 80%, 87% and 78% yields, respectively (branch-4). The
SBA-5, 2-(aminophenyl)imadazole found to be react efficiently
under the reaction condition-6 with Xa, Xb and Xc to produce
imadazoquinazolines 5a, 5b and 5c in 84%, 62% and 75%
yields, respectively (branch-5). The SBA-6 afforded the expected
quinazolines 6a and 6b in moderate yields after reaction with
Xa and Xc under the reaction condition-1 (branch-6). Gratify-
ingly, the pyrrole based SBA derivatives 7, 7(I) and 7(II) also
worked well with Xa under the reaction condition-5 to afford
the fused ring products 7a, 7b and 7c; albeit, in low yields
(branch-7). To further explore the generality and scope of EIBC,
indole based SBAs were examined to deliver the indole fused
heterocyclic scaffolds. For instance the desired indoloquinazo-
lines 8a, 8b and 8c were obtained in 48–64% yields from SBA-8
and 2-alkynylbenzaldehydes Xa, Xb and Xc under the reaction
condition-4 (branch-8). The other indole based SBA, 2-amino-N-
Fig. 2 Structure of SBAs and common types of starting materials.
much easier than other halo groups. Our preliminary study phenylindole (9) reacted with 2-alkynylbenzaldehydes Xa and
revealed very discouraging results; as envisioned, a number of Xb under the reaction condition-2 to deliver the products 9a
products formed in most of the ‘‘X-SBAs combinations’’ when and 9b in moderate yields (branch-9). The SBA, 2-aminobenzyl-
iodine alone was used as the source of iodonium ions. A mere alcohol (10) when treated with Xa and Xb under the reaction
change in the reaction conditions such as temperature and condition-3 to afford the desired oxazinoisoquinolines 10a and
solvents did not give the anticipated products in reasonable yields. 10b in 74% and 63% yields (branch-10). The methyl derivative
Moreover, it was found that the reaction conditions suitable for of SBA 10(I) afforded the product 10c in 66% yield after reaction
certain kinds of SBAs did not work well for others. We, therefore, with Xa. The tetrazoquinazolines 11a and 11b were obtained in
carried out detailed investigations and looked for variation in the 64% and 62% yields; respectively, when 5-(2-aminophenyl)-
iodonium ion source, solvents, bases, time, temperature...etc. for tetrazole (11) reacted with Xa and Xd under the reaction
each and every SBA. Careful optimization studies led us to establish condition-6 (branch-11). The structure of products 1b, 1e and
six reaction conditions; those are: (1) I2, DCE, rt, 3 hours (2) I2, 5c was unequivocally confirmed by using X-ray crystallography.7
CH3CN, rt, 8 hours (3) I2, K2CO3, CH3CN, rt, 5 hours (4) I2, K2CO3, A product accessed through one of the branches was transformed
DCE, 75 1C, 5 hours (5) p-TSA, DCE, rt, 3 hours then K2CO3, I2, rt, to more functionalised scaffolds by metal catalysed cross-coupling
2 hours and (6) p-TSA, DCM, rt, 6 hours then ICl, 0 1C, 2 hours. reactions.7 It should be noted that each scaffold has several
With the optimized reaction conditions in hand, the scope of the privileged structures embedded within it.7 One of the branches
EIBC was then investigated.
of present EIBC (branch 1) has been made enantioselective
As shown in Fig. 3, a wide array of SBAs (amino-aromatics, (90% ee) under the catalysis of chiral Brønsted acid under the
amino-alcohols, diamines, etc.) participated smoothly in the realm of iodine induced cyclization.7 Some of the compounds
reaction leading to a powerful EIBC approach for the synthesis accessed through EIBC; especially, 7a, 7b, and 8a showed excellent
of the iodo-group containing polyheterocyclic scaffolds in moderate activity against Mycobacterium smegmatis (MIC = 11.15, 6.14 and
to good yields. The reaction of 2-(phenylethynyl)benzaldehyde (Xa) 7.70, respectively) in a reference to isoniazid (MIC = 15.25) and
with 2-aminobenzamide (1) and its derivatives 1(I), 1(II), 1(III), 1(IV) rifampicin (MIC = 1.87) with minimum cytotoxicity.7
under the reaction condition-1 afforded cyclization products 1a, 1b,
In summary, we have developed electrophile induced branching
1c, 1d and 1e in 92%, 89%, 84%, 84% and 83% yields, respectively cascade (EIBC) as an interesting and a very direct approach for the
(branch-1). Similar results were observed with the substrate Xc efficient generation of a library of drug-like polyheterocycles. One of
and 2-aminobenzamide derivative 1(III) to get the product 1f in the branches of the present EIBC has been made enantioselective
81% yield. The SBA, monoprotected 1,2-diamino benzene 2, indicating the possibility of enantioselective EIBC. The screening
when treated with Xa and Xc under the reaction condition-1, results are found to be very promising as some compounds are
c
10110 Chem. Commun., 2013, 49, 10109--10111
This journal is The Royal Society of Chemistry 2013

View Article Online
ChemComm
Communication
Fig. 3 Generation of focused library via electrophile induced branching cascade. Reaction conditions: SBA (1 eq.), 2-alkynylbenzaldehyde (1 eq.) Condition 1: I2
(3 eq.), DCE, rt, 3 hours (for N1, N2, N4, N6). Condition 2: I2 (3 eq.), CH3CN, 8 hours (for N9). Condition 3: I2 (1.8 eq.), K2CO3 (2 eq.), CH3CN, rt, 5 hours (for N10). Condition 4: I2
(1.8 eq.), K2CO3 (2 eq.), DCE, 75 1C, 5 hours (for N8). Condition 5: p-TSA (0.05 eq.), DCE, rt, 3 hours the K2CO3 (1.2 eq.), I2 (1.1 eq.), 2 hours (for N7). Condition 6: p-TSA
(0.05 eq.), DCM, rt, 6 hours then ICl (1.1 eq.), 0 1C, 2 hours (for N3, N5, N11). Note: N1,2. . .11 represents the branch number generated from corresponding SBAs.
4269–4270; (d) S. Ohwa and S. B. Park, Chem. Commun., 2011, 47,
12754–12761; (e) T. W. J. Cooper, I. B. Campbell and S. J. F.
Macdonald, Angew. Chem., Int. Ed., 2010, 49, 8082–8091; ( f ) W. R. J. D.
Galloway, A. Isidro-Llobet and D. R. Spring, Nat. Commun., 2010,
1, 80; (g) K. Grabowski, K.-H. Baringhaus and G. Schneider, Nat. Prod.
Rep., 2008, 25, 892–904.
4 (a) D. Morton, S. Leach, C. Cordier, S. Warriner and A. Nelson, Angew.
Chem., Int. Ed., 2009, 48, 104–109; (b) G. L. Thomas, R. J. Spandl,
F. G. Glansdorp, M. Welch, A. Bender, J. Cockfield, J. A. Lindsay,
C. Bryant, D. F. J. Brown, O. Loiseleur, H. Rudyk, M. Ladlow and
D. R. Spring, Angew. Chem., Int. Ed., 2008, 47, 2808–2812.
5 N. T. Patil, V. S. Shinde and B. Sridhar, Angew. Chem., Int. Ed., 2013,
52, 2251–2255.
6 Y. Yamamoto, G. Ilya, N. T. Patil and T. Jin, Chem. Commun., 2009,
5075–5087.
7 See ESI† for details.
8 (a) A. C. Legon, Chem. Commun., 1998, 2585–2586; (b) P. Perez,
A. Aizman and R. Contreras, J. Phys. Chem. A, 2002, 106, 3964–3966;
(c) Z. Jia, M. G. Salaita and D. W. Margerum, Inorg. Chem., 2000, 39,
1974–1978.
9 Reviews on electrophilic cyclization of alkynes: (a) A. Palisse and
S. F. Kirsch, Org. Biomol. Chem., 2012, 10, 8041–8047; (b) B. Godoi,
R. F. Schumacher and G. Zeni, Chem. Rev., 2011, 111, 2937–2980.
highly selective against Mycobacterium smegmatis. Further efforts
to test these compounds against Mycobacterium tuberculosis and
SAR studies are currently underway in our laboratories.
NTP and RU gratefully acknowledge financial support from
MoES, ORGIN, OSDD and SMILE projects.
Notes and references
1 For reports on branching cascades, see: (a) W. Liu, V. Khedkar,
B. Baskar, M. Schu¨mann and K. Kumar, Angew. Chem., Int. Ed.,
2011, 50, 6900–6905; (b) D. Robbins, A. F. Newton, C. Gignoux,
J.-C. Legeay, A. Sinclair, M. Rejzek, C. A. Laxon, S. K. Yalamanchili,
W. Lewis, M. A. O’Connell and R. A. Stockman, Chem. Sci., 2011, 2,
2232–2235; (c) E. E. Wyatt, S. Fergus, W. R. J. D. Galloway, A. Bender,
D. J. Fox, A. T. Plowright, A. S. Jessiman and D. R. Spring, Chem.
Commun., 2006, 3296–3298; (d) O. Kwon, S. B. Park and S. L.
Schreiber, J. Am. Chem. Soc., 2002, 124, 13402–13404.
2 S. L. Schreiber, Science, 2000, 287, 1964–1969.
3 Reviews: (a) C. J. O’Connor, H. S. G. Beckmann and D. R. Spring,
Chem. Soc. Rev., 2012, 4444–4456; (b) L. Q. Lu, J. R. Chen and
W. J. Xiao, Acc. Chem. Res., 2012, 45, 1278–1293; (c) A. Tavassoli,
A. D. Hamilton and D. R. Spring, Chem. Soc. Rev., 2011, 40,
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 10109--10111 10111