Condensation of anthranilic acids with pyridines to furnish pyridoquinazolones via pyridine dearomatization

Article abstract of DOI:10.1039/c6cc07365d

The unprecedented carbodiimide-mediated condensation between pyridines and anthranilic acids via pyridine dearomatization at room temperature has been developed to provide a straightforward approach to pyridoquinazolones. The value of this approach has further been demonstrated by its application to one-step, gram-scale syntheses of a series of pyridoquinazolone-based natural products and their analogues from readily available starting materials.

Full text of DOI:10.1039/c6cc07365d

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Condensation of Anthranilic Acids with Pyridines to
Pyridoquinazolones via Pyridines Dearomatization†
Yajun Yang,‡a Cuiju Zhu,‡b Min Zhang,b Shijun Huang,b Jingjing Lin,a Xiandao Pan,*a and Weiping
Received 00th January 20xx,
Accepted 00th January 20xx
Su*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
The unprecedented carbodiimide-mediated condensation
between pyridines and anthranilic acids via pyridines
dearomatization at room temperature has been developed to
provide a straightforward approach to pyridoquinazolones. The
value of this approach has further demonstrated by its application
to one-step, gram-scale syntheses of
a
series of
pyridoquinazolone-based natural products and their analogues
from readily available starting materials.
Pyridine moieties are ubiquitous structural units in natural
products, pharmaceuticals, bioactive compounds, ligands and
functional materials. Thus, the development of synthetic
methods for the functionalizations of pyridines has been and
continues to be of intensive interest.1 In general, the
functionalizations of pyridines are achieved by way of the
nucleophilic addition to the activated pyridines such as
the direct functionalization of nonactivated pyridines is still in
high demand. Herein, we report mild, metal-free
carbodiimide-mediated condensation of nonactivated
a
pyridines with anthranilic acids to furnish pyridoquinazolones
via pyridines dearomatization in generally good yields (Scheme
1).
2
pyridine N-oxides, N-acyl, N-alkyl pyridinium intermediates
and pyridine-Lewis acid adducts.3 These transformations of
pyridines generally occur via either pyridine dearomatization
or pyridine dearomatization/oxidation sequence. Recently, the
pyridine dearomatization has successfully been applied to
enantioselective syntheses of chiral nitrogen-containing
heterocycles.4 From the viewpoints of atom- and step-
Quinazolinone derivatives represent a class of the privileged
structural motifs present in a broad range of natural products,
pharmceuticals and bioactive compounds.8 For example,
Febrifugine, 9 Rutaecarpine and Evodiamine are all effective
ingredients of Chinese herbal medicines, and Methaqualone is
a quinazolinone-based synthetic medicine for sedative and
hypnotic medication.
economy, the metal-catalyzed direct C-H functionalization of
5, 6
pyridines
provides an ideal approach to decorate pyridine
without the need for preactivation of pyridines. Considering
that the costly and difficult removal of metal contamination is
often required in the metal-catalyzed processes, especially for
the pharmaceutical productions,7 the metal-free method for
Numerous methods for the syntheses of quinazolinones
have been developed so far.10 However, the syntheses of
pyridoquinazolones are still very limited.11-13 Previously, the
synthesis of pyridoquinazolones was achieved by means of the
reactions of substituted anthranilic acids with electron-
deficient 2-cholorpyridines, which is usually conducted at high
temperature in the presence of strong acids.11 Recently, the
Pd-catalyzed carbonylation reactions have been developed for
the synthesis of pyridoquinazolones,12 such as the
carbonylative coupling of 2-aminopyridines with 2-
bromofluorobenzenes, and C-H carbonylation of N-aryl-2-
aminopyridines. Because the previously established methods
for the synthesis of pyridoquinazolones have been limited to
specific starting materials such as such as C2-halogenated
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pyridines bearing electron-withdrawing groups, the multistep dimerization of 2-aminobenzoic acid and give higher yield of
synthesis routes are often taken for the preparation of 3a (entry 4). Increasing the amount of EDCI led to further
pyridoquinazolones.13
improvement of yield of the desired product (entries 5 and 6).
The biologically interesting activities of pyridoquinazolones A 92% yield was obtained when 2.0 equiv of EDCI was added to
aroused our interest in exploring the new reactivity of the reaction system (entry 6). When the reaction system was
pyridines and therefore developing the efficient method for open to air through a glass tube filled with dry CaCl2, an 83%
the facile synthesis of structurally diverse pyridoquinazolones yield was obtained (entry 7). With 2.0 equiv of EDCI, 3 equiv of
starting from readily available pyridines. Inspired by the pyridine gave a synthetically usful yield. (entry 10). In the
carbodiimide-mediated condensation of carboxylic acids with absence of oxidant, the reaction of 1a with pyridine, which
amines to form amides, we questioned whether carbodiimide was conducted under argon atmosphere, produced
is able to promote condensation between pyridines and dihydropyridoquinazolone (3aa) rather than 3a. Exposed to air,
anthranilic acids to pyridoquinazolones via N-benzoylation of 3aa underwent quick oxidation to 3a, indicating that 3aa is a
pyridine with benzoic acid to generate pyridinium possible reaction intermediate in the course of condensation
intermediate and therefore activate pyridine. To answer this of 1a with pyridine to generate 3a.
question, we initiated our investigation by checking the
reaction of 2-amino-6-methylbenzoic acid (1a) with equimolar examined using the reaction conditions of entry 6 in Table 1.
pyridine 2a), which was conducted in CH2Cl2 at room Meanwhile, the reactions of anthranilic acids with 3 equiv of
temperature under 1 atm dioxygen atmosphere with varying pyridine under otherwise identical conditions were also
reaction parameters. (Table 1). checked for comparison, which, in many cases, gave
As shown in Table 2, a series of anthranilic acids were
(
Although DCC (N,N'-dicyclohexylcarbodiimide) and DIPC synthetically useful yields. The anthranilic acids containing
14
(N,N'-diisopropylcarbodiimide) are reagents commonly used electron-donating groups on the positions ortho or meta to
to effect the condensation of carboxylic acids with amines to carboxyl, such as methyl and methoxy groups, were efficiently
amides, we found that neither DCC nor DIPC gave the coupled with pyridine (3a
expected results (entries 1 and 2). Gratifyingly, less sterically the position ortho to amino group of anthranilic acids resulted
hindered EDCI (1-ethyl-3-(3-dimethylaminopropyl) in a slightly lower yield (3d). The latter probably stemmed
, 3b, 3e, 3f) while the substituents on
carbodiimide hydrochloride) as an additive enabled the from the steric factor that influences the nucleophilic attack of
expected reaction to occur in a 30% yield (entry 3). In this case, amino group to the activated pyridine. Notably, the anthranilic
a
large amount of the unwanted by-product from the acids bearing electron-withdrawing groups such as F, Br, Cl, CF3
dimerization of 1a was also observed. The use of excessive also worked well and furnished good yields (3h, 3i, 3j, 3k, 3l,
amount of pyridine (9 equiv.) was observed to suppress the 3m), in which the tolerance of halide substituents provides a
handle for further transformation of pyridoquinazolone
products. Other 2-amino aromatic acids including naphthoic
acid and thiophenecarboxylic acid participated in this reaction
with reasonable yields obtained
(3g, 3n). However, the
2 | J. Name., 2012, 00, 1-3
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electron-deficient 2-amino 3-pyridinecarboxylic acid or 3- applied to one-step efficient syntheses of a series of natural
amino 2-pyridinecarboxylic acid did not react with pyridine, products containing pyridoquinazolone core structure and
which might result from the diminished nucleophilicity of their
analogues,
including
Rutaecarpine
(
5a),15-16
amino group.
Euxylophoricine B (5l),15 Euxylophoricine A (5d),17 Evodiamine
18
Next, we evaluated the substrate scope with respect to
(
5j
)
starting from inexpensive and commercially available
pyridines, and also diverse combination between anthranilic materials. The previous preparations of these compounds
acids and substituted pyridines considering that substituents generally involve troublesome preactivation of starting
may exert an effect on the reactivity of both coupling partners. materials and protection/deprotection of functional groups,
In most cases, the amounts of substituted pyridines could be thus leading to low overall yields. For example, a typical
15
reduced to 2 to 4 equiv. to give satisfactory yields with the synthesis
of Rutaecarpine from anthranilic acid and 3,4-
exception of 3-fluoropyridine (4i). Both electron-donating (4a, dihydro-β-carboline requires a lengthy synthetic sequence that
4b, 4c and 4j) and electron-withdrawing (4e 4f 4i, 4m and 4n consists of the protection of amino group of anthranilic acid
,
,
)
substituents on pyridine were tolerated with generally good with tosyl group, the conversion of carboxylic acid to acid
yields obtained. Notably, 4-iodo-pyridine smoothly chloride, the condensation between the resultant anthranilic
participated in this reaction with C-I bond intact (4f), though C- acid derivative and 3,4-dihydro-β-carboline, final deprotection
I bond on the para-position of pyridine is prone to undergo of amino group and oxidation. In contrast, our current method
nucleophilic substitution. The analogs of pyridine, such as allowed for the gram-scale reaction of anthranilic acid with
isoquinoline(4g
, 4o, 4q, 4t, 4u), phthalazine (4k) and equimolar 3,4-dihydro-β-carboline to directly produce
pyridazine (4l), were also suitable substrates. Isoquinoline Rutaecarpine in 85% yield. In addition, 3,4-dihydro-β-carboline
could react with N-methylanthranilic acid to give the could react with salicylic acid, and o-mercaptobenzoic acid, to
corresponding product in 64% yield regardless of N-methyl afford the corresponding Evodiamine analogues 5q and 5r
substituent (4s). respectively. For easily oxidative dehydrogenation and good
Significantly, this newly developed approach could be solubility, the reaction of 9H-pyrido[3,4-b]indole with
anthranilic acids, which led the formation of compounds 5k 5p
,
-
(in higer oxidation state), was more accessible than that of
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4,9-dihydro-3H-pyrido[3,4-b]indole to compounds 5a-5j (in
lower oxidation state).
Although the mechanism of the carbodiimide-mediated
condensation of anthranilic acids with pyridines to
pyridoquinazolones remains to be elusive, a possible reaction
pathway was proposed to rationalize our observations
(Scheme 2). Initially, the reaction of anthranilic acid with
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carbodiimide generates O-acylisourea
anthranilic acid. Then, O-acylisourea reacts with pyridine to
give N-benzoyl pyridinium salt ( ) with urea released, followed
(
A
)
to activate
B
S. Banerjee, and N.B. Mondal, Tetrahedron Lett., 2011, 52
3033.
,
by the nucleophilic addition of amino group of anthranilic acid
to N-benzoyl pyridinium to lead to dearomatization of
9 J.B. Koepfli, J.F. Mead, and J.A. Brockman, J. Am. Chem. Soc.,
1947, 69, 1837.
pyridine. Finally, the adduct (C) of pyridine with anthranilic
acid undergoes oxidative dehydrogenation to afford
pyridoquinazolone product. The last two steps in the proposed
mechanism are supported by the isolation of dihydro-
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,
,
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pyridines under nitrogen atmosphere and its aerobic oxidation
to pyridoquinazolone.
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In conclusion, an efficient, general approach to
pyridoquinazolones has been established via carbodiimide-
mediated condensation of pryridines with anthranilic acids via
pyridines dearomatization at room temperature. Importantly,
this operationally simple and mild approach can be scaled up
without compromise of efficiency, demonstrating the great
11 L. Colis, G. Ernst, S. Sanders, H. Liu, P. Sirajuddin, K.
Peltonen, M. DePasquale, J.C. Barrow, and M. Laiho, J.
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is ascribed to EDCI of choice that promotes N-benzoylation of
pyridine with benzoic acid to activate pyridine. Such a pyridine
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14 L.C. Chan, and B.G. Cox, J. Org. Chem., 2007, 72, 8863.
activation strategy opens
a new way to the direct
functionalization of pyridines and the rapid construction of
diverse pyridine-based complex structures from pyridine,
considering the versatile reactivity of the dihydropyridine
generated from pyridine dearomatization.
Financial supports from the NSFC (21431008, 21332001 and
U1505242) and the CAS/SAFEA International Partnership
Program for Creative Research Teams are greatly appreciated.
15 F. Pin, S. Comesse, and A. Daïch, Tetrahedron, 2011, 67
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,
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