Synthesis of new class of alkyl azarene pyridinium zwitterions via iodine mediated sp3 c-h bond activation

Article abstract of DOI:10.1021/ol202654j

An efficient and conceptually different approach toward C-H bond activation by using iodine mediated sp³ C-H functionalization for the synthesis of alkyl azaarene pyridinium zwitterions is described. This work has the interesting distinction of

Full text of DOI:10.1021/ol202654j

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6366–6369
Synthesis of New Class of Alkyl Azarene
Pyridinium Zwitterions via Iodine
Mediated sp3 CꢀH Bond Activation
Atul Kumar,* Garima Gupta, and Suman Srivastava
Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR,
Lucknow, India
dratulsax@gmail.com
Received October 2, 2011
ABSTRACT
An efficient and conceptually different approach toward CꢀH bond activation by using iodine mediated sp3 CꢀH functionalization for the
synthesis of alkyl azaarene pyridinium zwitterions is described. This work has the interesting distinction of being the first synthesis of a new class
of alkyl azaarene pyridinium zwitterion via transition-metal-free sp3 CꢀH bond activation of an alkyl azaarene.
CꢀH bond activation has revalorized the science of
synthesis by its ingenious contribution to synthetic organic
chemistry.1,2 CꢀH activation generally involves synthetic
methodologies that make use of metal catalyzed activation
and successivefunctionalizationofsp2 and sp3 CꢀH bonds
which directly install important functional groups to build
complex structures.3 With increasing environmental concerns
and waste management, especially in the area of pharma-
ceuticals, identification of methods that do not require
transition metal catalysts are very important because the
removal of metallic impurities from final pharmaceutical
entities increases the cost considerably. The development
of an efficient and transition-metal-free protocol will
significantly change synthetic applications of direct CꢀH
functionalization. Recently some efficient transition-me-
tal-free sp2 CꢀH bond activations have been reported.2e,4
Inspired by these we describe a remarkable result from our
laboratory which demonstrates a new transition-metal-
free strategy for achieving sp3 CꢀH activation. This first
iodine mediated synthesis of an alkyl azaarene pyridinium
(AAP) zwitterion is an efficient strategy for sp3 CꢀH bond
activation in a multicomponent protocol.
A zwitterion is a neutral molecule with a positive and
negative electrical charge at different locations within that
molecule. Zwitterions are widely used in organic synthesis5
and can be trapped by a series of electrophiles and proton
donors to give a variety of heterocyclic compounds.6 To
the best of our knowledge zwitterions have not yet been
formed from an inactivated CꢀH bond. The direct and
simple approach for the synthesis of zwitterions via CꢀH
activation of alkyl azaarene remains a challenging task.
(1) (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094–5115. (b) Ackermann, L.; Vicente, R.;
Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792–9826. (c) Sun, C.-L.;
Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677–685.
(2) (a) Ackermann, L.; Mulzer, M. Org. Lett. 2008, 10, 5043–5045.
(b) Jin, W.; Yu, Z.; He, W.; Ye, W.; Xiao, W.-J. Org. Lett. 2009, 11,
1317–1320. (c) Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2010, 49,
8181–8184. (d) Cui, S.; Wojtas, L.; Antilla, J. C. Org. Lett. 2011, 13,
5040–5043. (e) Lamani, M.; Prabhu, K. R. J. Org. Chem. 2011, 76, 7938–
7944. (f) Ranjit, S.; Lee, R.; Heryadi, D.; Shen, C.; Wu, J.; Zhang, P.;
Huang, K.-W.; Liu, X. J. Org. Chem. 2011, 76, 8999–9007.
(3) (a) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698–1712.
(b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110,
624–655. (c) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102,
1731–1770. (d) Zhang, G.; Luo, Y.; Wang, Y.; Zhang, L. Angew. Chem.,
Int. Ed. 2011, 50, 4450–4454.
(4) (a) Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett.
2008, 10, 4673–4676. (b) Bajracharya, G. B.; Daugulis, O. Org. Lett.
2008, 10, 4625–4628. (c) Sun, C.-L.; Li, H.; Yu, D.-G.; Yu, M.; Zhou, X.;
Lu, X.-Y.; Huang, K.; Zheng, S.-F.; Li, B.-J.; Shi, Z.-J. Nat. Chem. 2010,
2, 1044–1049. (d) Chudasama, V.; Fitzmaurice, R. J.; Caddick, S. Nat.
Chem. 2010, 2, 592–596. (e) Shirakawa, E.; Itoh, K.; Higashino, T.;
Hayashi, T. J. Am. Chem. Soc. 2010, 132, 15537–15539. (f) Liu, W.; et al.
J. Am. Chem. Soc. 2010, 132, 16737–16740.
r
10.1021/ol202654j
Published on Web 11/22/2011
2011 American Chemical Society

Herein, wedemonstratethe first iodine promoted sp3 CꢀH
bond activation for the efficient and direct synthesis of
AAP zwitterions via a new multicomponent reaction in the
presence of triethylamine without the use of any transition
metal.
solvent. Initial trials using metal triflates Sc(OTf)3, Zn(OTf)2,
Fe(OTf)3 and Lewis acids like AlCl3, ScBr3, BF3(OEt)2 did
not promote the desired reaction at all. Only Cu(OTf)2 and
CuCl2 promoted the reaction in very low yield (10%). To
our surprise when iodine was used as a Lewis acid in the
reaction for the synthesis of an AAP zwitterion, the results
obtained were interesting. The reaction proceeded to form
the desired zwitterion in low yield (35%) with 40 mol %
iodine. Furtherwetried tooptimizethe reactionconditions
with iodine to get improved results. The reaction pro-
gressed in improved yield (45%) with 70 mol % of iodine.
At room temperature with 100 mol % iodine, the reaction
was complete after 36 h and we obtained a 55% reaction
yield. Encouraged by these results we adopted a sequential
addition methodology to form zwitterions with the above-
mentioned standardized reaction conditions to further im-
prove the reaction yield. We added quinaldine, pyridine,
and iodine and stirred the reaction for 2 h at 100 °C,
followed by the addition of benzaldehyde, meldrum acid,
and triethylamine at room temperature in acetonitrile as
solvent. To our delight the reaction was complete in 24 h
and a 70% reaction yield was obtained. However any
further increase in the iodine amount (150 mol %) did
not improve the yield (Table 1). At higher temperatures
(70ꢀ80 °C), a complex mixture of products resulted which
were difficult to identify. These zwitterions are usually very
reactive species, which should be kept at low temperature
and in an inert atmosphere.
Scheme 1. Synthesis of AAP Zwitterions from Quinaldine,
Pyridine, Aromatic Aldehydes, and Meldrum Acid
Our strategy for the synthesis of unusual charge sepa-
rated AAP-meldrum acid zwitterionic salts involve a one-
pot multicomponent reaction of quinaldine, pyridine, aro-
matic aldehydes, and meldrum acid in the presence of iodine
and triethylamine. We started our exploration by taking
quinaldine as an alkyl azaarene, pyridine, benzaldehyde,
and meldrum acid as model substrates for the reaction.
Based on precedent in the Lewis acid catalyzed intramole-
cular C(sp3)ꢀH functionalization7 and Lewis acid suppor-
ted C(sp2)ꢀH activation of pyridines and/or quinolines,8
we envisioned the use of different Lewis acids9 for the func-
tionalization of quinaldine under proton-transfer condi-
tions (Table 1).
Table 1. Optimization with Different Lewis Acids
To test the feasibility of our hypothesis, we screened
various Lewis acids using quinaldine, pyridine, benzaldehyde,
and meldrum acid with triethylamine in acetonitrile as
Lewis acid
time
(h)
yield
(%)c
entry
(x mol %)
1a
Sc(OTf)3 (40 mol %)
Zn(OTf)2 (40 mol %)
Fe(OTf)3 (40 mol %)
Cu(OTf)2 (40 mol %)
AlCl3 (40 mol %)
ScBr3 (40 mol %)
CuCl2 (40 mol %)
BF3(OEt)2 (40 mol %)
I2 (40 mol %)
36
36
36
36
36
36
36
36
36
36
36
24
48
0
0
(5) (a) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.;
Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899–907. (b) Nair,
V.; Biju, A. T.; Vinod, A. U.; Suresh, E. Org. Lett. 2005, 7, 5139–5142.
(c) Nair, V.; Menon, R. S.; Sreekanth, A. R.;Abhilash, N.; Biju, A. T. Acc.
Chem. Res. 2006, 39, 520–530. (d) Nair, V.; Deepthi, A.; Poonoth, M.;
Santhamma, B.; Vellalath, S.; Babu, B. P.; Mohan, R.; Suresh, E. J. Org.
Chem. 2006, 71, 2313–2319.
(6) (a) Yan, C. G.; Cai, X. M.; Wang, Q. F.; Wang, T. Y.; Zheng, M.
Org. Biomol. Chem. 2007, 5, 945–951. (b) Yan, C. G.; Song, X. K.; Wang,
Q. F.; Sun, J.; Siemeling, U.; Bruhn, C. Chem. Commun. 2008, 1440–
1442. (c) Wang, Q. F.; Hou, H.; Hui, L.; Yan, C.-G. J. Org. Chem. 2009,
74, 7403–7406. (d) Wang, Q. F.; Song, X. K.; Chen, J.; Yan, C. G. J.
Comb. Chem. 2009, 11, 1007–1010. (e) Yan, C. G.; Wang, Q. F.; Song,
X. K.; Sun, J. J. Org. Chem. 2009, 74, 710–718.
(7) (a) MacQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2009, 131,
402–403. (b) MacQuaid, K. M.; Long, J. Z.; Sames, D. Org. Lett. 2009,
11, 2972–2975. (c) Murarka, S.; Zhang, C.; Konieczynska, M. D.; Seidel,
D. Org. Lett. 2009, 11, 129–132. (d) Shikanai, D.; Murase, H.; Hata, T.;
Urabe, H. J. Am. Chem. Soc. 2009, 131, 3166–3167. (e) Komai, H.;
Yoshino, T.; Matsunaga, S.; Kanai, M. Org. Lett. 2011, 13, 1706–1709.
(f) Song, G.; Su, Y.; Gong, X.; Han, K.; Li, X. Org. Lett. 2011, 13, 1968–
1971.
2a
3a
0
4a
10
0
5a
6a
0
7a
10
0
8a
9a
35
45
55
70
70
10a
11a
12b
13b
I2 (70 mol %)
I2 (100 mol %)
I2 (100 mol %)
I2 (150 mol %)
a Reaction conditions: 1 (1.0 mmol), 2 (2.5 mmol), 3 (benzaldehyde)
(1.0 mmol), 4 (1.0 mmol), Lewis acid, NEt3 (1.5 mmol), CH3CN (5.0 mL).
b Reaction conditions: 1 (1.0 mmol), 2 (2.5 mmol), I2 heated at 100 °C
for 2 h then added 3 (benzaldehyde) (1.0 mmol), 4 (1.0 mmol), NEt3
(1.5 mmol) at room temperature in CH3CN (5.0 mL). c Isolated yield
after column chromatography.
(8) (a) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. A. J. Am. Chem. Soc.
2008, 130, 2448–2449. (b) Deng, G.; Li, C.-J. Org. Lett. 2009, 11, 1171–
1174. (c) Nakao, Y.; Yamada, Y.; Kashihara, N.; Hiyama, T. J. Am.
Chem. Soc. 2010, 132, 13666–13668. (d) Tsai, C.-C.; Shih, W.-C.; Fang,
C.-H.; Li, C.-Y.; Ong, T.-G.; Yap, G. P. A. J. Am. Chem. Soc. 2010, 132,
11887–11889. (e) Huang, G.; Sun, H.; Qiu, X.; Jin, C.; Lin, C.; Shen, Y.;
Jiang, J.; Wang, L. Org. Lett. 2011, 13, 5224–5227. (f) Zhao, Y.; Chen, G.
Org. Lett. 2011, 13, 4850–4853. (g) Li, W.; Yin, Z.; Jiang, X.; Sun, P. J.
Org. Chem. 2011, 76, 8543–8548.
Thus we developed a one pot multicomponent protocol
via reaction of quinaldine, pyridine, aromatic aldehyde
and meldrum acid in the presence of iodine as Lewis acid
and triethylamine as base resulting in the formation of the
1-(2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-aryl-
1-(quinolin-2-yl)ethyl)pyridinium (Scheme 1). The reac-
tion occurs via sp3 CꢀH bond activation of methyl of
(9) (a) Qian, B.; Guo, S.; Xia, C.; Huang, H. Adv. Synth. Catal. 2010,
352, 3195–3200. (b) Rueping, M.; Tolstoluzhsky, N. Org. Lett. 2011, 13,
1095–1097.
Org. Lett., Vol. 13, No. 24, 2011
6367

and provided the desired zwitterionic compounds in mod-
erate to good yields (60ꢀ80%) (Table 2, entries 1ꢀ17). The
structures of the products were fully characterized by mass
spectroscopy, 1H, 13C NMR, and elemental analysis.
Based on these studies, it is clear that the formed zwitter-
ionic salt came from all four components of the reaction.
The pyridyl group and meldrum acid moiety were present
on the same side of the molecule which causes the positive
and negative charge in the shortest distance. The quinal-
dine and phenyl group exist on the other side. The methy-
lene carbon atom in the meldrum acid unit adopts an sp2
hybrid, and the negative charge is delocalized to two
Table 2. Synthesis of Various Zwitterions with Iodine As Lewis
Acid
1
carbonyl groups. In H NMR spectra the methylene
group connected with the unit of meldrum acid usually
shows one doublet at about δ 5.00ꢀ6.00 ppm with the
vicinal coupling constant J = 12.0 Hz. Due to the con-
nection with the strongly electron-withdrawing pyridinium
group, the absorption peak of another methylene group
greatly shifts to the range of δ 7ꢀ8 ppm and overlaps
1
with signals of aromatic protons. 1Hꢀ H COSY, HMBC,
and HSQC spectra of 5l supported the formation of the
AAP zwitterion.
In order to examine the substrate scope and limitation of
this multicomponent reaction, aliphatic aldehydes were
also tested under the above-mentioned reaction condi-
tions. Aliphatic aldehydes such as butyraldehyde and iso-
butyraldehyde reacted similarly, and new substituted AAP
zwitterions were obtained in moderate yields (Scheme 2)
(Table 2, entries 18ꢀ19). The structures of zwitterions were
fully characterized by 1H, 13C NMR, mass spectroscopy,
and elemental analysis performed for 6a and 6b. These
results demonstrated that this reaction has great general-
ity, and a library of AAP zwitterions could be efficiently
synthesized.
Scheme 2. Synthesis of AAP Zwitterions from Quinaldine,
Pyridine, Aliphatic Aldehydes, and Meldrum Acid
a Reaction conditions: 1 or 10 (1.0 mmol), 2 (2.5 mmol), I2 (1.0 mmol)
heated at 100 °C for 2 h then added 3 (1.0 mmol), 4 (1.0 mmol), and NEt3
(1.5 mmol) at room temperature in CH3CN (5.0 mL) and stirred for
additional 22 h. b Reaction conditions: 1(1.0mmol),2(2.5mmol),I2 (1.0mmol)
heated at 100 °C for 2 h then added 30 (1.0 mmol), 4 (1.0 mmol), andNEt3
(1.5 mmol) at room temperature in CH3CN (5.0 mL) and stirred for
additional 28 h. c Isolated yield after column chromatography.
To further evaluate the scope of this CꢀH activation
methodology, another methyl azaarene that is 4-amino
quinaldine was also tested. The reaction of 4-amino qui-
naldine, pyridine, aromatic aldehydes, and meldrum acid
in acetonitrile with iodine and triethylamine went smoothly
(Scheme 3). These 1-(1-(4-aminoquinolin-2-yl)-2-(2,
2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-arylethyl) pyridiniums
were obtained in low yields (Table 2, entries 20ꢀ21). It
should be mentioned that the yields of the 4-amino quina-
ldine derived AAP zwitterion salts (7a, 7b) are lesser than
those of the zwitterionic salts synthesized from quinaldine
(5aꢀ5q). The structures of the prepared 1-(1-(4-aminoqui-
nolin-2-yl)-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2
quinaldine by the coordination to Lewis acid that would
increase the acidity of benzylic CꢀH bonds.
With the optimized conditions in hand, the scope of the
reaction with regard to the structure of various aromatic
aldehydes was investigated. The reaction of quinaldine
with various aromatic aldehydes bearing electron-donating
or -withdrawing aryl substituents proceeded smoothly
6368
Org. Lett., Vol. 13, No. 24, 2011

arylethyl)pyridinium were fully characterized by spectro-
scopicmethodsandelemental analysis. Theseresultsclearly
demonstrated that this multicomponent reaction has great
generality and can be developed for other inactivated
methylene compounds.
Scheme 3. Synthesis of AAP Zwitterions from 4-Amino Qui-
naldine, Pyridine, Aromatic Aldehydes, and Meldrum Acid
Figure 1. Plausible mechanism for the formation of AAP
zwitterions.
salts were prepared in moderate to good yields in a very
convenient manner. Prominent among the advantages of
this new methodology are operational simplicity, novelty,
and good yields. Further extension of the reaction scope
and synthetic applications of this methodology are in
progress in our laboratory.
Our working hypothesis is shown in Figure 1. Activation
of methyl azaarenes by coordination to a Lewis acid iodine
would increase the acidity of the benzylic CꢀH bonds.
Cleavage of the CꢀH bond by either counterions of the
Lewis acid would generate a 1-iodo-2-methylene-1,2-
dihydroquinoline species (2). Pyridine as a nucleophile
attacks 2 to form 1-(quinolin-2-ylmethyl)pyridinium iodide
(3). Thisiodidesaltattacksanarylidenedione (anaromatic
aldehyde meldrum acid adduct obtained via Knoevenagel
condensation) to form AAP zwitterions.
Acknowledgment. Authors (G.G. and S.S.) are thank-
ful to CSIR-UGC New Delhi for the award of a senior
research fellowship. We also gratefully acknowledge SAIF,
CDRI for providing spectral and analytical facilities.
CDRI communication number: 8155.
In conclusion, we described here an interesting transition-
metal-free sp3 CꢀH bond activation of an alkyl azaarene
to form AAP zwitterions in a new multicomponent reaction.
A series of unusual charge separated AAP zwitterionic
Supporting Information Available. Detailed experi-
mental and compound characterization. This material
is available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 24, 2011
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