A metal-free tandem demethylenation/C(sp2)-H cycloamination process of N -Benzyl-2-aminopyridines via C-C and C-N bond cleavage

Article abstract of DOI:10.1021/ol4015656

A mild, metal-free synthesis of pyrido[1,2-a]benzimidazoles starting with N-benzyl-2-aminopyridines, which employs PhI(OPiv)₂ as a stoichiometric oxidant, has been developed. The process is initiated by an unusual PhI(OPiv)₂-mediated ipso S_EAr reaction, followed by solvent-assisted C-C and C-N bond cleavage.

Full text of DOI:10.1021/ol4015656

ORGANIC
LETTERS
2013
Vol. 15, No. 13
3476–3479
A Metal-Free Tandem Demethylenation/
C(sp2)ꢀH Cycloamination Process of
N‑Benzyl-2-aminopyridines via CꢀC and
CꢀN Bond Cleavage
Dongdong Liang, Yimiao He, Lanying Liu, and Qiang Zhu*
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,
190 Kaiyuan Avenue, Guangzhou 510530, China
zhu_qiang@gibh.ac.cn
Received June 4, 2013
ABSTRACT
A mild, metal-free synthesis of pyrido[1,2-a]benzimidazoles starting with N-benzyl-2-aminopyridines, which employs PhI(OPiv)2 as a stoichiometric
oxidant, has been developed. The process is initiated by an unusual PhI(OPiv)2-mediated ipso SEAr reaction, followed by solvent-assisted CꢀC and
CꢀN bond cleavage.
Tandem reactions, in which multiple chemical bonds are
formed in one-pot processes, are highly useful for creating
molecular complexity.1 Transition-metal-triggered tandem
processes are typically initiated by oxidative addition
of a carbonꢀ(pseudo)halogen bond to a transition metal
species in its lower oxidation state followed by diverse
transformations of the resulting reactive intermediates.2
Alternatively, similar types of reactive intermediates can
be generated by employing transition-metal-catalyzed
CꢀC and/or CꢀO bond cleavage reactions of carbonyl
containing starting materials, which frequently are more
readily available than the corresponding organohalides.
Representatives of this approach are decarboxylative
and decarbonylative tandem reactions, in which CO2
and CO are respectively excised from substrates in initial
steps via CꢀC and CꢀX (X = O, H, C) bond cleavage
(eqs 1 and 2).3,4 However, a tandem reaction of a non-
carbonyl substrate, driven by an analogous demethylena-
tion process involving consecutive CꢀC and CꢀN bond
cleavage, is unprecedented (eq 3).5 In a recent study, de-
scribed below, we developed a new hypervalent iodine(III)-
promoted tandem reaction of N-benzyl-2-aminopyridines,
which is initiated by oxidative demethylenation followed
by intramolecular aromatic CꢀH amination. This process
occurs under mild and transition-metal-free conditions to
form pyrido[1,2-a]benzimidazoles in high yields.
(3) For select reports, see: (a) Zhang, C.; Seidel, D. J. Am. Chem. Soc.
2010, 132, 1798. (b) Weaver, J. D.; Ka, B. J.; Morris, D. K.; Thompson,
W.; Tunge, J. A. J. Am. Chem. Soc. 2010, 132, 12179. (c) Zhang, F.;
Greaney, M. F. Angew. Chem., Int. Ed. 2010, 49, 2768. (d) Trost, B. M.;
€
Schaffner, B.; Osipov, M.; Wilton, D. A. A. Angew. Chem., Int. Ed. 2011,
50, 3548. (e) Hu, P.; Zhang, M.; Jie, X.; Su, W. Angew. Chem., Int. Ed.
2012, 51, 227. (f) Shang, R.; Ji, D.-S.; Chu, L.; Fu, Y.; Liu, L. Angew.
Chem., Int. Ed. 2011, 50, 4470. (g) Cornella, J.; Righi, M.; Larrosa, I.
Angew. Chem., Int. Ed. 2011, 50, 9429.
(1) For recent reviews, see: (a) Vlaar, T.; RuiJter, E.; Orru, R. V. A.
Adv. Synth. Catal. 2011, 353, 809. (b) Zhu, C.; Wang, R.; Falck, J. R.
Chem.;Asian J. 2012, 7, 1502. (c) Millemaggi, A.; Taylor, R. J. K. Eur.
J. Org. Chem. 2010, 4527. (d) Foster, R. A. A.; Willis, M. C. Chem. Soc.
Rev. 2013, 42, 63. (e) Eilbracht, P.; Barfacker, L.; Buss, C.; Hollmann,
C.; Kitsos-Rzychon, B. E.; Kranemann, C. L.; Rische, T.; Roggenbuck,
R.; Schmidt, A. Chem. Rev. 1999, 99, 3329.
(4) (a) Fristrup, P.; Kreis, M.; Palmelund, A.; Norrby, P.; Madsen, R.
J. Am. Chem. Soc. 2008, 130, 5206. (b) Murakami, M.; Amii, H.;
Shigeto, K.; Ito, Y. J. Am. Chem. Soc. 1996, 118, 8285. (c) Roa, A. E.;
ꢀ
~
Salazar, V.; Lopez-Serrano, J.; Onate, E.; Paneque, M.; Poveda, M. L.
€
ꢀ
Organometallics 2012, 31, 716. (d) Roa, A. E.; Salazar, V.; Lopez-
~
Serrano, J.; Onate, E.; Alvarado-Rodrıguez, J. G.; Paneque, M.; Poveda,
M. L. Organometallics 2012, 31, 3185.
ꢀ
(2) (a) Barluenga, J.; Valdes, C. Angew. Chem., Int. Ed. 2011, 50,
7486. (b) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem.
2003, 4101.
(5) For a recent example of demethylenation via CꢀC and CꢀO
bond cleavage, see: Liu, H.; Dong, C.; Zhang, Z.; Wu, P.; Jiang, X.
Angew. Chem., Int. Ed. 2012, 51, 12570.
r
10.1021/ol4015656
Published on Web 06/26/2013
2013 American Chemical Society

Scheme 1. Formation of Pyrido[1,2-a]benzimidazoles
Compared with those containing transition metals, hy-
pervalent iodine(III) reagents in many cases serve as
complementary and even superior promoters of CꢀC6
and Cꢀheteroatom7 bond forming reactions. For instance,
Antonchick8a and Chang8b et al. independently developed
rt hypervalent iodine(III)-mediated intramolecular CꢀH
amidationreactionsfortheefficientsynthesisofcarbazoles.
In addition, it has been shown that hypervalent iodine
reagents are powerful oxidants in CꢀC bond cleavage of
O-containing substances, such as glycols,9 epoxides,10 and
olefins.11 Despite these successes, hypervalent iodine(III)
reagent promoted demethylenation reactions, involving
CꢀC and CꢀN bond cleavage followed by intramolecular
CꢀN bond formation, remain undocumented.
Owing to their remarkable biological activities, includ-
ing antibacterial,12 antitumor,13 and antiviral,14 many
methods15ꢀ17 have been developed for the preparation of
multisubstituted pyrido[1,2-a]benzimidazoles. Among the
approaches devised, Pd-catalyzed intramolecular CꢀN
coupling reactions of N-ortho-bromophenyl-2-aminopyr-
idines in refluxing DMF are the premier methods used to
construct this scaffold (Scheme 1).16 Independently, we17a
and Maes et al.17b also developed improved methods
through intramolecular CꢀH amination. However, both
of these processes need to be performed at temperatures
over 120 °C and their substrate scope is limited in that
substrates bearing electron-withdrawing substituents on
the pyridine ring are far less reactive.
In continuing studies, we envisaged that hypervalent
iodine(III)-promoted intramolecularCꢀH amination reac-
tions18 could be employed to prepare 6H-pyrido[1,2-a]-
quinazolines starting with readily accessible N-benzyl-2-
aminopyridines.19 In fact, utilizing N-benzyl-2-aminopyridine
1a as the substrate in the presence of 2.2 equiv of phenyliodine
diacetate (PIDA) in HFIP at rt, this reaction leads to the
formation of pyrido[1,2-a]benzimidazole 2a in 85% yield. To
further improve the yield of 2a, the reaction conditions were
optimized by screening additives, solvents, and other hyper-
valent iodines (see Supporting Information (SI) for details).
The optimized conditions involving the use of 2.2 equiv of
PhI(OPiv)2 in HFIP at rt in air were identified (Scheme 2).
Substrates containing a variety of para-substituents,
regardless of their electron-donating (Me and OMe) or
electron-withdrawing (F, Cl, Br, and I) properties, under-
go efficient (84%ꢀ96%) reactions that generate the
(6) (a) Samanta, R.; Lategahn, J.; Antonchick, A. P. Chem. Commun.
2012, 48, 3194. (b) Wang, J.; Yuan, Y.; Xiong, R.; Zhang-Negrerie, D.;
Du, Y.; Zhao, K. Org. Lett. 2012, 14, 2210. (c) Kita, Y.; Morimoto, K.;
Ito, M.; Ogawa, C.; Goto, A.; Dohi, T. J. Am. Chem. Soc. 2009, 131,
1668. (d) Dohi, T.; Ito, M.; Morimoto, K.; Iwata, M.; Kita, Y. Angew.
Chem., Int. Ed. 2008, 47, 1301. (e) Dohi, T.; Morimoto, K.; Maruyama,
A.; Kita, Y. Org. Lett. 2006, 8, 2007. (f) Dohi, T.; Morimoto, K.;
Kiyono, Y.; Maruyama, A.; Tohma, H.; Kita, Y. Chem. Commun. 2005,
41, 2930. (g) Node, M.; Kodama, S.; Hamashima, Y.; Baba, T.;
Hamamichi, N.; Nishide, K. Angew. Chem., Int. Ed. 2001, 40, 3060.
(7) For recent examples, see: (a) Souto, J. A.; Martınez, C.; Velilla, I.;
~
Muniz, K. Angew. Chem., Int. Ed. 2013, 52, 1324. (b) Farid, U.; Wirth, T.
~
Angew. Chem., Int. Ed. 2012, 51, 3462. (c) Souto, J. A.; Zian, D.; Muniz,
K. J. Am. Chem. Soc. 2012, 134, 7242. (d) Souto, J. A.; Becker, P.;
~
Iglesias, A.; Muniz, K. J. Am. Chem. Soc. 2012, 134, 15505. (e) Samanta,
R.; Bauer, J. O.; Strohmann, C.; Antonchick, A. P. Org. Lett. 2012, 14,
5518. (f) Ban, X.; Pan, Y.; Lin, Y.; Wang, S.; Du, Y.; Zhao, K. Org.
~
Biomol. Chem. 2012, 10, 3606. (g) Lishchynskyi, A.; Muniz, K. Chem.;
ꢀ
Eur. J. 2012, 18, 2212. (h) Souto, J. A.; Gonzalez, Y.; Iglesias, A.; Zian,
~
D.; Lishchynskyi, A.; Muniz, K. Chem.;Asian J. 2012, 7, 1103.
(8) (a) Antonchick, A. P.; Samanta, R.; Kulikov, K.; Lategahn, J.
Angew. Chem., Int. Ed. 2011, 50, 8605. (b) Cho, S. H.; Yoon, J.; Chang,
S. J. Am. Chem. Soc. 2011, 133, 5996.
(9) (a) Angyal, S. J.; Young, R. J. J. Am. Chem. Soc. 1959, 81, 5467.
(b) Pausacker, K. H. J. Chem. Soc. 1953, 107.
(10) Spyroudis, S.; Varvoglis, A. J. Org. Chem. 1981, 46, 5231.
(11) (a) Miyamoto, K.; Sei, Y.; Yamaguchi, K.; Ochiai, M. J. Am.
Chem. Soc. 2009, 131, 1382. (b) Miyamoto, K.; Tada, N.; Ochiai, M.
J. Am. Chem. Soc. 2007, 129, 2772. (c) Ochiai, M.; Miyamoto, K.;
Yokota, Y.; Suefuji, T.; Shiro, M. Angew. Chem., Int. Ed. 2005, 44, 75.
(d) Ochiai, M.; Miyamoto, K.; Shiro, M.; Tomoyuki, O.; Yamaguchi, K.
J. Am. Chem. Soc. 2003, 125, 13006. (e) Koser, G. F.; Wettach, R. H.;
Troup, J. M.; Frenz, B. A. J. Org. Chem. 1976, 41, 3609.
(12) Hammad, M.; Mequid, A.; Ananni, M. E.; Shafik, N. Egypt. J.
Chem. 1987, 29, 5401.
(16) Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin
Trans. 1 1999, 1505.
(17) (a) Wang, H.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. J. Am.
Chem. Soc. 2010, 132, 13217. (b) Masters, K.-S.; Rauws, T. R. M.;
Yadav, A. K.; Herrebout, W. A.; Van der Veken, B.; Maes, B. U. W.
Chem.;Eur. J. 2011, 17, 6315.
(18) (a) Huang, J.; He, Y.; Wang, Y.; Zhu, Q. Chem.;Eur. J. 2012,
18, 13964. (b) Alla, S. K.; Kumar, R. K.; Sadhu, P.; Punniyamurthy, T.
Org. Lett. 2013, 15, 1334. (c) Qu, G.-R.; Liang, L.; Niu, H.-Y.; Rao,
W.-H.; Guo, H.-M.; Fossey, J. S. Org. Lett. 2012, 14, 4494.
(19) (a) Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.;
Buchwald, S. L. Chem. Sci. 2011, 2, 57. (b) Rodriguez, S.; Qu, B.;
Haddad, N.; Reeves, D. C.; Tang, W.; Lee, H.; Krishnamurthy, D.;
Senanayake, C. H. Adv. Synth. Catal. 2011, 353, 533. (c) Huang, M.; Lin,
X.; Zhu, X.; Peng, W.; Xie, J.; Wan, Y. Eur. J. Org. Chem. 2011, 4523. (d)
Lundgren, R. J.; Sappong-Kumankumah, A.; Stradiotto, M. Chem.;
Eur. J. 2010, 16, 1983. (e) Liu, Z.-J.; Vors, J.-P.; Gesing, E. R. F.; Bolm,
C. Adv. Synth. Catal. 2010, 352, 3158.
(13) (a) Badaway, E.; Kappe, T. Eur. J. Med. Chem. 1995, 30, 327.
ꢁ
(b) Hranjec, M.; Piantanida, I.; Kralj, M.; Suman, L.; Pavelı, K.;
Karminski-Zamola, G. J. Med. Chem. 2008, 51, 4899. (c) Hranjec, M.;
ꢁ
Kralj, M.; Piantanida, I.; Sedı, M.; Suman, L.; Pavelı, K.; Karminski-
Zamola, G. J. Med. Chem. 2007, 50, 5696.
(14) Kotovskaya, S. K.; Baskakova, Z. M.; Charushin, V. N.;
Chupakhin, O. N.; Belanov, E. F.; Bormotov, N. I.; Balakhnin, S. M.;
Serova, O. A. Pharm. Chem. J. 2005, 39, 574.
(15) (a) Liubchak, K.; Nazarenko, K.; Tolmachev, A. Tetrahedron
2012, 68, 2993. (b) Wu, Z.; Huang, Q.; Zhou, X.; Yu, L.; Li, Z.; Wu, D.
Eur. J. Org. Chem. 2011, 27, 5242. (c) Zhao, D.; Hu, J.; Wu, N.; Huang,
X.; Qin, X.; Lan, J.; You, J. Org. Lett. 2011, 13, 6516. (d) Venkatesh, C.;
Sundaram, G. S. M.; Ila, H.; Junjappa, H. J. Org. Chem. 2006, 71, 1280.
(d) Kutsumura, N.; Kunimatsu, S.; Kagawa, K.; Otani, T.; Saito, T.
Synthesis 2011, 3235.
Org. Lett., Vol. 15, No. 13, 2013
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analyzed by using MS. An intense peak at 349 (m/z) was
seen in the mass spectrum, corresponding to the proto-
nated form of the bis((1,1,1,3,3,3-hexafluoropropan-2-yl)-
oxy)methane acetal of formaldehyde. Moreover, mass
spectrometric analysis of the crude product mixture arising
from the reaction of substrate 3a (41%, eq 4, Scheme 3)
demonstrates that HFIP acetal of acetaldehyde is also
produced (see SI). For the purpose of demonstrating the
excision of the methylene group in this reaction in the form
of an aldehyde, the bicyclic substrate 3b was subjected to
the reaction conditions. This process leads to the forma-
tion of 2y, which contains a linked formyl group (eq 5).
Additional information about the nature of the oxidative
demethylenation reaction comes from the finding that
substrate 3c, possessing an extra CH2 group between the
amine nitrogen and benzylic carbon, also reacts to produce
2a, while 3d containing a longer linker does not undergo
this reaction (eq 6).
Scheme 2. Substrate Scopea
Scheme 3. Substrate Extension
a Reaction conditions: 1 (0.2 mmol), HFIP (1.5 mL) at rt (25 °C) in air
for 5ꢀ24 h; isolated yields.
corresponding products (2bꢀ2g). However, the presence
of the strong electron-withdrawing CF3 group causes a
significant reduction in the reaction yield (2h, 30%).
Additional observations show that an alkynyl group sur-
vives the reaction conditions (2i, 65%). Then we observed
that reactions of substrates containing meta-Me and -Cl
substituents take place with no regioselectivity (2j and 2j0,
and 2k and 2k0 are produced in near 1:1 ratios). Substi-
tuents located at ortho-benzyl positions do not hamper the
demethylenation/annulation process (e.g., 96% for 2l and
75% for 2m). Substrates with methyl groups at each of
the pyridine ring centers react to give the corresponding
methyl-substituted pyrido[1,2-a]benzimidazoles (2oꢀ2r)
in excellent yields. It is noteworthy that, in Cu-mediated
CꢀH cycloamination reactions of N-p-toluyl-6-methyl-2-
aminopyridine, harsh reaction conditions (1.0 equiv of
Cu(OAc)2, 5.0 equiv of PivOH, 130 °C, 46 h) were required
and the reaction yield was quite low (24%).17a In addition,
substrates with electron-withdrawing groups (e.g., F, Cl,
CN, and CF3) on the pyridine ring undergo smooth
(81ꢀ91%) demethylenative annulation to generate the
corresponding products 2sꢀ2w. This is an advantageous
feature of the new methodology because these types of
electron-deficient pyrido[1,2-a]benzimidazoles cannot be
prepared in acceptable yields by using Cu-mediated CꢀH
cycloamination.17 It is worth mentioning again that these
reactions are performed at ambient temperature in good to
excellent yields under metal- and additive-free conditions.
To gain information on how the methylene group is
lost, the crude mixture arising from the reaction of 1a was
In further studies aimed at exploring the mechanism of
the tandem process, a crossover reaction was tested using
the mixture of 1a and 1z (see SI). The absence of crossover
products shows that demethylenation and the following
CꢀN bond formation steptake placeintramolecularly. We
also prepared imine 4 and amide 5, two possible oxidized
intermediates in the reaction pathway. However, imine 4
decomposed and amide 5 remained unreacted when the
respective substances were exposed to the reaction condi-
tions. Two potential intermediates, diazaphenanthridone6
and diazaphenthridine 7, in which the CꢀN bond between
the pyridine nitrogen and the ortho phenyl carbon in
substrate 1a were formed before demethylenation, were
also synthesized. Surprisingly, neither 6 nor 7 reacts under
the optimized conditions to produce 2a, suggesting that
the CꢀN bond between the amino nitrogen and the ipso
aromatic carbon is likely formed first.
To gain more insight into the mechanism, intramolecu-
lar competition reactions were explored using benzhydryl
substrates 8, bearing both a phenyl and an electronically
biased aryl ring at the benzylic carbon (see SI). Reactions
at the electron-donating p-anisyl (in 8a) and p-tolyl (in 8b)
groups were observed to occur 5ꢀ20 times faster than
3478
Org. Lett., Vol. 15, No. 13, 2013

Scheme 4. Proposed Reaction Mechanism
those at the unsubstituted phenyl ring. In sharp contrast,
the para-CF3-phenyl in 8e was 20 times less reactive that
the electron-neutral phenyl. Finally, the results of com-
petition reactions showed that the p-chloro- (in 8c) and
p-fluoro-phenyl (in 8d) moieties are only ∼10ꢀ20% less
reactive than their neutral counterpart, a result that is in
accord with the competing electron-donating conjugative
and electron-withdrawing inductive effects of the halo-
gens. Finally, a F-value of ꢀ3.39 was obtained from a
Hammett plot, indicating that a positive charge develops
on the arene ring in a rate-limiting mechanistic step (see
SI). Further support for this proposal comes from intra-
molecular competition reactions of the meta-Cl and -OMe
benzhydryl substrates 9a and 9b, respectively (see SI).
Compared to that of 8c, reaction at the nonsubstituted
phenyl moiety in 9a takes place ∼9 times faster than at the
meta-Cl-phenyl ring. It is interesting that when the OMe is
moved from the para-position in 8a to the meta-position
in 9b, the reactivity of the OMe-containing phenyl ring
changes from being 20 times more favorable to 2 times less
favorable compared to the nonsubstituted phenyl ring.
Both the meta-OMe and -Cl groups are inductively elec-
tron-withdrawing and, as a result, destabilize the cationic
intermediate in the mechanistic pathway (see SI).
Based on the results of these studies, the plausible
mechanistic pathway, shown in Scheme 4 using 1a as an
example, is proposed for the oxidative, tandem demethyla-
tion CꢀH cycloamination reaction. In the route, initial
coordination of PhI(OPiv)2 with 1a gives the electrophilic
N-iodo species A, which following ipso SEAr on the phenyl
ring generates the delocalized carbocation B (Wheland
intermediate).20 HFIP then participates in nucleophilic
addition to the benzylic carbon in B causing CꢀC bond
cleavage to give intermediate C, which reacts with another
equivalent of PhI(OPiv)2 to form the active complex D.
Unfortunately, the attempt to synthesize intermediate C
failed. CꢀN bond cleavage in D occurs upon another
nucleophilic substitution by HFIP, releasing the methylene
group in the form of an acetal. Subsequent electrophilic
annulation on the pyridine nitrogen, activated by the
electrophilic iodo species, generates intermediate F which
upon deprotonation forms 2a.
In conclusion, the results described above led to an
unexpected, yet highly efficient method for the synthesis
of pyrido[1,2-a]benzimidazoles starting from readily avail-
able N-benzyl-2-aminopyridines at ambient temperature
inthe absenceof metal catalystsandadditives. Mechanistic
studies reveal that the reaction is initiated by an unusual
PhI(OPiv)2-mediated ipso SEAr process followed by sol-
vent-assisted CꢀC bond cleavage. Sequential annulation is
promoted by a second equivalent of PhI(OPiv)2. Finally,
the methylene group isoxidatively cleaved and leavesin the
form of an acetal. The new method serves not only as an
efficient approach to pyrido[1,2-a]benzimidazoles but also
as a rare example of a hypervalent iodine(III) reagent-
mediated tandem CꢀC bond activation and CꢀN bond
formation process.
Acknowledgment. We are grateful for financial sup-
port from the National Science Foundation of China
(21072190, and 21272233).
Supporting Information Available. Experimental pro-
cedure, and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) (a) Rathore, R.; Hecht, J.; Kochi, J. K. J. Am. Chem. Soc. 1998,
120, 13278. (b) Hubig, S. M.; Kochi, J. K. J. Am. Chem. Soc. 2000, 122,
8279. (c) Hadaic, M.; Braıda, B.; Volatron, F. Org. Lett. 2011, 13, 1960.
The authors declare no competing financial interest.
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