Functionalized orthoesters as powerful building blocks for the efficient preparation of heteroaromatic bicycles

Article abstract of DOI:10.1021/ol301472a

By combining substituted anilines with functionalized orthoesters, an efficient and connective methodology for the preparation of benzoxazole, benzothiazole, and benzimidazole derivatives has been established. The versatility of this approach enables the development of new libraries of heterocycles containing multifunctional sites.

Full text of DOI:10.1021/ol301472a

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Functionalized Orthoesters as Powerful
Building Blocks for the Efficient
Preparation of Heteroaromatic Bicycles
ꢀ
Gulluzar Bastug, Christophe Eviolitte, and Istvan E. Marko*
ꢀ
ꢀ
Laboratory of Organic and Medicinal Chemistry, Universite Catholique de Louvain,
Batiment Lavoisier, Place Louis Pasteur 1 bte L4.01.02., B-1348 Louvain-la-Neuve,
^
Belgium
istvan.marko@uclouvain.be
Received May 29, 2012
ABSTRACT
By combining substituted anilines with functionalized orthoesters, an efficient and connective methodology for the preparation of benzoxazole,
benzothiazole, and benzimidazole derivatives has been established. The versatility of this approach enables the development of new libraries of
heterocycles containing multifunctional sites.
Benzoxazoles, benzothiazoles, and benzimidazoles are im-
portant fragments in medicinal chemistry because of their
wide range of biological activities. For example, mibefradil
(1),1 developed by Merck healthcare, contains a benzimida-
zole core and is active against hypertension. Zopalrestat (2),2
a good representative of benzothiazole-containing drugs, is
used for the treatment of diabetic complications and is
commercialized by the Takeda Pharmaceutical Co. Calcimy-
cin (3),3 a benzoxazole derivative produced by combinatorx,
is employed as an ionophore antibiotic (Figure 1).
(1) Moreira de Almeida, I. Patent WO2007/93021 A1, 2007.
(2) Murata, T.; Makino, S. Patent EP1876179 A1, 2008.
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WO2008/133884 A2, 2008.
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Z.; Zhang, W. Eur. J. Med. Chem. 2011, 46, 1706.
(6) Fukuda, S.; Nakamura, A.; Shimizu, M.; Okada, T.; Oohida, S.;
Figure 1. Example of drugs containing heteroaromatic bicycles.
Asahara, T. Patent US2004/14977 A1, 2004.
(7) (a) Khaksar, S.; Heydari, A.; Tajbakhsh, M.; Vahdat, S. M.
J. Fluorine Chem. 2010, 131, 1377. (b) Zhang, Z. H.; Li, T. S.; Li, J. J.
Monatsh. Chem. 2007, 138, 89. (c) Sanjeeva Reddy, C.; Nagaraj, A.
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Several methods have been reported for the preparation
of these benzofused heterocyclic structures. A general route
consists of the condensation of anilines with carboxylic
acids,4 esters,5 or acid chlorides6 under strongly acidic con-
ditions, at high temperatures, or under pressure. In a similar
r
10.1021/ol301472a
XXXX American Chemical Society

approach, orthoesters can also be used as annelating agents
(scheme 1). As reported in the literature, benzimidazoles7
were prepared from orthoesters in the presence of hexa-
fluoroisopropyl alcohol, aminosulfonic acid, or zirconium
oxychloride as catalysts. For the benzothiazoles,8 silica-
supported fluoroboric acid or Bi(OTf)3 can be used in the
condensation reaction with orthoesters. Polyphosphoric acid
(PPA) and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH)
are also interesting agents for the preparation of benzoxaz-
oles.9 The main shortcoming of this methodology resides in
the limited diversity of the orthoesters employed. Indeed,
only three or four commercially available orthoesters are rou-
tinely screened.
functionalities suitable for the preparation of libraries in
medicinal chemistry oriented synthesis.12 At the onset of
our study, the chlorine-containing orthoesters 10 and 11
and their unsaturated analogues 14 and 15 were prepared
Table 1. Condensation of Anilines and Chlorinated Orthoesters
Scheme 1. Preparation of Heteroaromatic Bicycles
The pharmacological potential of these heterocycles,
combined with the limited access to high structural
complexity, due to the paucity of orthoesters available
(typically R1 = H, Me, Et, Ph), and the harsh conditions
used in previously reported condensation reactions,
incited us to revisit this ring-forming process.
Overtheyears, ourlaboratoryhasprepareda widerange
of functionalized orthoesters using the modified Pinner
sequence described in Scheme 2.10 In this method, an
imidate salt11 formed from a nitrile such as 7 is subse-
quently converted into the corresponding orthoester 8.
Scheme 2. Modified Pinner Sequence
These orthoesters are particulary interesting since
their substituents can be converted into a wide variety of
(8) (a) Patil, A. V.; Lee, S. H.; Bandgar, B. P. Bull. Korean Chem. Soc.
2010, 31, 1719. (b) Mohammadpoor-Baltork, I.; Khosropour, A. R.;
Hojati, S. F. Monatsh. Chem. 2007, 138, 663. (c) Mohammadpoor-
Baltork, I.; Khosropour, A. R.; Hojati, S. F. Catal. Commun. 2007, 8,
1865.
(9) (a) Jared, F. M.; Andrew, J. M.; El-Malika, J. Org. Lett. 2008, 10,
4915. (b) Hojati, S. F.; Maleki, B.; Beykzadeh, Z. Monatsh. Chem. 2011,
142, 87. (c) Mylari, B. L.; Scott, P. J.; Zembrowski, W. J. Synth.
Commun. 1989, 19, 2921. (d) Mohammadpoor-Baltork, I.; Moghadam,
M.; Tangestaninejad, S.; Mirkhani, V.; Zolfigol, M. A.; Hojati, S. F.
J. Iran Chem. Soc. 2008, 5, S65.
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(10) (a) Marko, I. E.; Ates, A. Synlett 1999, 1033. (b) Marko, I. E.;
Vanherck, J.-C.; Ates, A.; Tinant, B.; Declercq, J.-P. Tetrahedron Lett.
a Isolated yields after column chromatography on silica gel or
recrystallization.
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2003, 44, 3333. (c) Maulide, N.; Vanherck, J.-C.; Marko, I. E. Eur. J.
Org. Chem. 2004, 3962. (d) Maulide, N.; Marko, I. E. Chem. Commun.
2006, 11, 1200. (e) Maulide, N.; Marko, I. E. Org. Lett. 2006, 8, 3705.
(f) Maulide, N.; Marko, I. E. Org. Lett. 2007, 19, 3757. (g) De Bo, G.;
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Marko, I. E. Eur. J. Org. Chem. 2011, 1859.
(12) Wermuth, C. G. The practice of medicinal chemistry, Elsevier,
(11) Yadav, V. K.; Babu, K. G. Eur. J. Org. Chem. 2005, 452.
2008.
B
Org. Lett., Vol. XX, No. XX, XXXX

in large scale (>10 g) and in high yield by the modified
Pinner sequence.
The starting materials 10 and 11 were condensed with a
variety of substituted anilines (Table 1), leading to the
corresponding fused heterocycles in good to excellent
yields. The condensations were carried out at room tem-
of the alkyl side chain and the alkoxy groups. Gratifyingly,
these modifications do not affect the results of the annelat-
ing reaction. As can be seen in Table 3, the desired adducts
are obtained in good to excellent yields. It should be noted
that the β,γ-unsaturated orthoester 18 undergoes migra-
tion of the alkene moiety during the condensation reac-
tion, affording solely the R,β-unsaturated benzoxazole 21
(Table 3, entry 1). Moreover, it is important to highlight
that neither 18 nor 19 could be prepared via the Pinner
methodology.14
perature in the presence of 1 equiv of BF3 OEt2 and were
3
complete within 3 h. As can be seen in Table 1, the reaction
occurs efficiently with both electron-donating and elec-
tron-withdrawing groups on the aromatic ring (entries
1ꢀ12). Benzoxazoles, benzothiazoles, and benzimidazoles,
bearing a functionalized alkyl side chain, can thus be
generated efficiently.
Table 3. Condensation of Anilines and Functionalized
Orthoesters
Orthoesters 14 and 15, interesting annelating agents
possessing a terminal alkene, were coupled with various
aniline derivatives under identical conditions. Again, the
desired compounds could be isolated in high yields (Table 2).
It is noteworthy that the substituents on the aromatic ring
have little or no effect on the outcome of this reaction
(entries 1ꢀ3). Moreover, the presence of the alkene moiety
enables an even wider range of modifications to be per-
formed on adducts 16 and 17 (vide infra).
Table 2. Condensation of Anilines and γ,δ-Unsaturated
Orthoesters
a Isolated yields after column chromatography on silica gel or
recrystallization.
To illustrate the synthetic potential of these easily
assembled and functionalized heteroaromatic rings, we
prepared some tricyclic compounds. Indeed, simple treat-
ment of the chlorinated heterocycle 12d with NaH in THF
affordedthe desiredproduct 26a in93% yield (scheme3).15
When benzimidazole 13d was used in the cyclization
reaction, the 4,5,5-tricycle was generated in 95% of yield.
With the substituted benzimidazole 12h, the two regioisomers
(13) Recently, our laboratory has developed a novel method for the
synthesis of orthoesters that cannot be obtained by the Pinner protocol.
It involves the electrolysis of the bis-ammonium salt derived from the
corresponding diacid 31. An example is decribed in the Supporting
ꢀ
Information.Mathot, C.; Lam, K.; Lucaccioni F.; Marko, I. E. Unpub-
lished work.
a Isolated yields after column chromatography on silica gel or
recrystallization.
At this stage, several new orthoesters were prepared by
electrochemistryand submittedtotheconditions described
above, providing a wide variety of fused hetero aromatic
bicycles (table 3).13 These orthoesters differ by the nature
(14) In the case of the orthoester 19, it is likely that the starting
material (propane-1,3-dinitrile) will undergo a double Pinner reaction.
This example highlights the complementarity between our novel elec-
trochemically based synthesis of orthoesters and the Pinner protocol.
(15) Haque, R.; Rasmussen, M. Tetrahedron 1997, 53, 6937.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Cyclization Reactions
Scheme 5. Synthesis of Procodazole 29
Scheme 6. Lactam Formation
Scheme 4. Alkylation of Chlorinated Heterocycle
Futhermore, procodazole (29) can undergo a subse-
quent ring closure by treatment with acetic anhydride to
ꢁ
provide the tricyclic lactam 30, as described by Stanek and
Wollrab, in 79% yield (Scheme 6).18
In summary, our methodology enables the convenient,
flexible, connective, and efficient preparation of function-
alized benzoxazole, benzothiazole, and benzimidazole de-
rivatives in good to excellent yields under mild conditions.
The rapid and easy access to a large variety of sub-
stituted orthoesters enabled us to widen the scope of this
condensation, hence opening new avenues for its applica-
tion in medicinal chemistry.
26c and 26c0 were obtained in a 1:1 ratio. Unfortunatly, they
could not be separated.
To illustrate further the potential of the products synthe-
sized through our method, the substituted benzothiazole
25 was coupled with the phthalhydrazide 27 to afford
compound 28 (Scheme 4).16 This adduct is an advanced
intermediate for the synthesis of zopalrestat analogues.
Oxidation of the alkene moiety present in imidazole 16d
enables the preparation of the corresponding acid, proco-
dazole (29) (Scheme 5). Starting from orthoester 14 and
phenyldiamine 9d, procodazole (29) could thus be assem-
bled in three steps (condensation, ozonolysis and oxidation)
in 39% overall yield and under mild conditions.17
Acknowledgment. Financial support of this work by the
ꢂ
Fonds pour la Formation a la Recherche dans l’Industrie
et l’Agriculture (F.R.I.A., studentships to G.B. and C.E.),
ꢀ
the Universite Catholique de Louvain, and the Action de
Recherche Concertees (ARC 08/13-012) is gratefully
ꢀ
acknowledged.
Supporting Information Available. Full experimental
and characterization details for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Kotani, T.; Nagaki, Y.; Ishii, A.; Konishi, Y.; Yago, H.; Suehiro,
S.; Okukado, N.; Okamoto, K. J. Med. Chem. 1997, 40, 684.
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(b) Chatterjee, B. J. Chem. Soc. 1929, 2967. (c) Guenes, H. S.; Cosar,
G. Arzneim.-Forsch. 1992, 42, 1045. (d) Tewari, A. K; Mishra, A. Indian
J. Chem. Sect. B 2006, 45, 489. (e) Yao, M.-X.; Zeng, M.-H.; Zou, H.-H.;
Zhou, Y.-L.; Liang, H. Dalton Trans. 2008, 18, 2428. (f) Maras, M.;
Kocevar, M. Helv. Chim. Acta 2011, 94, 1860. (g) Phillips, M. A.
J. Chem. Soc. 1928, 2395.
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(18) Stanek, J.; Wollrab, V. Monatsh. Chem. 1960, 91, 1064.
The authors declare no competing financial interest.
D
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