Pd-Catalyzed ortho Selective C–H Acyloxylation and Hydroxylation of Pyridotriazoles

Article abstract of DOI:10.1002/ejoc.201901748

An efficient protocol for the palladium-catalyzed direct ortho C–H acyloxylation of 3-phenyl-pyridotriazoles is described. The reaction was facilitated by PhI(OAc)₂ (PIDA) as an oxidant and with carboxylic acids as acyloxylation reagents. The reaction is highly selective for mono acyloxylation of pyridotriazoles with various acids such as aliphatic, branched, and cyclic including adamantane carboxylic acids. When acetic anhydride was employed as acylation reagent, interesting 2-oxo-1-phenyl-1-(pyridin-2-yl)propyl acetates were obtained through the ring opening of pyridotriazoles. The key strategy is the employment of pyridotriazoles as a modifiable heterocycle; acyloxylation followed by the hydrolysis in one pot to yield the potential drug intermediates [(2-hydroxyphenyl)pyridin-2-yl]methanone in good yields.

Full text of DOI:10.1002/ejoc.201901748

A Journal of
Accepted Article
Title: Pd-Catalyzed ortho Selective C–H Acyloxylation and
Hydroxylation of Pyridotriazoles
Authors: Deepa Rawat, Rahul Kumar, and Subbarayappa Adimurthy
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901748
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901748
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10.1002/ejoc.201901748
European Journal of Organic Chemistry
COMMUNICATION
Pd-Catalyzed ortho Selective C–H Acyloxylation and
Hydroxylation of Pyridotriazoles
Deepa Rawat,[a] Rahul Kumar[a] and Subbarayappa Adimurthy*[a]
Abstract. An efficient protocol for the palladium-catalyzed direct as acylation reagent, an interesting product 2-oxo-1-phenyl-1-
ortho C−H acyloxylation of 3-phenyl-pyridotriazoles is described. (pyridin-2-yl)propyl acetates were obtained through the ring
The reaction was facilitated by PhI(OAc)2 (PIDA) as an oxidant opening of pyridotriazoles. The key strategy is the employment of
and with carboxylic acids as acyloxylation reagents. The reaction pyridotriazoles as a modifiable heterocycle; acyloxylation followed
is highly selective for mono acyloxylation of pyridotriazoles with by the hydrolysis in one pot to yield the potential drug
various acids such as aliphatic, branched, cyclic including intermediates (2-hydroxyphenyl)pyridin-2-yl)methanone in good
adamantine carboxylic acids. When acetic anhydride employed
yields.
as a reliable and valuable tool for the synthesis of various
ketones.
Introduction
Selective C–H functionalization heterocycles represents
a
Although a number of approaches for the acyloxylation of 2-
arylpyridines[5] and other directing groups[6,7] have been
developed (Scheme 1 a-d), the acyloxylation of pyridotriazoles
have never been attempted. Transition-metal-catalyzed
denitrogenative transannulation of pyridotriazole is one of the
most significant achievements in synthetic chemistry.[8] Because,
triazole derivatives are well-known precursors to generate metal
carbenoid species. These metal carbenoids react with various
nucleophiles to generate corresponding fused heterocycles.[8,9]
As a part of our program on the development of denitrogenative
transannulation of pyridotriazoles,[10] we envisioned that, aliphatic
carboxylic acids may serve as better acyloxylation reagents to
obtain acyloxy substituted pyridotriazoles and their subsequent
conversion to 2-([1,2,3]triazolo[1,5-a]pyridin-3-yl)phenol (Scheme
1e).
promising approach for the synthesis of complex molecules as
they play a crucial role in various fields including pharmaceuticals,
agrochemicals and material science.[1] The rapid and efficient
synthesis of such complex molecules has been a long-standing
interest and challenging in organic chemistry. Particularly,
pyridine-fused heterocycles such as imidazo[1,2-a]pyridines,
imidazo[1,5-a]pyridines, imidazo[1,2-a]pyrazines, indolizines,
imidazo[2,1-a]isoquinolines,
pyrazolo[1,5-a]pyridines
and
pyrido[1,2-a]indoles are important intermediates in both medicinal
chemistry and drug development.[2] Despite the wide range of
biological activity of such complex molecules,[2h-j] it is important to
note that, the hydrophilic groups (such as sulphonyl,
sulphonamide, acyloxy and hydroxy groups) present in such
molecules enhance the drug discovery due to the fact that, they
act rapidly and with site selective to treat diseases.[3] Therefore,
the concept of introducing a functional handle onto heterocyclic
system is considered to be a powerful tool for accessing such
molecules with increased biological activity or suitable for
subsequent derivatization.[4]
In this context, the selective acyloxylation of 2-arylpyridines
have witnessed the efforts made by various groups with transition
metal catalysts including palladium, ruthenium and rhodium.[5] In
addition, ortho sp2(C-H) acyloxylation and acylation of arenes with
various directing groups have been also reported.[6,7] In the last
few decades, transition-metal-catalyzed direct C−H bond
acylation under the assistance of a directing group has emerged
[a] Academy of Scientific & Innovative Research, CSIR–Central Salt &
Marine Chemicals Research Institute, G.B. Marg, Bhavnagar-364 002.
Gujarat (INDIA)
E-mail: adimurthy@csmcri.res.in
http://adimurthy.wix.com/drsadimurthygroup
Supporting information and ORCID(s) from the authors for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901748.
Scheme 1. ortho-Acyloxylation of arenes with directing groups.
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10.1002/ejoc.201901748
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The reaction of 3-phenyl[1,2,3]triazolo[1,5-a]pyridine (1a) with
a various carboxylic acids, such as long chain, branched,
secondary, tertiary and cyclic including adamantane-1-carboxylic
acid, reacted smoothly and gave good yields (63−83%) of the
desired products 3a−3j. One of the product 3d was further
confirmed by single-crystal XRD. The reaction of 3-(4-
chlorophenyl)-[1,2,3]triazolo[1,5-a]pyridine 1b was reacted with
the above carboxylic acid derivatives and afforded the desired
products (3k−3s) in good to excellent yields (71−86%) under the
optimised conditions. It may be noted that chloro substituted
pyridotriazole derivatives 3k−3s were well tolerated, and these
products could be further useful in traditional cross-coupling
reactions.
Results and Discussion
Initially, we examined the optimization of conditions for the
selective acyloxylation of pyridotriazole 1a with propionic acid 2a
in the presence of 3 mol % of Pd(OAc)2 at 120°C temperature in
a sealed tube, and no reaction was observed up to 24 h (Table
1, entry 1). When the same reaction was performed with the
Table 1. Screening of conditions
Table 2. Substrate scope for acyloxylation pyridotriazolesa
Reaction condition: 1a (0.2 mmol), 2a (0.6 mmol), Pd(PPh3)4 (3 mol %),
PhI(OAc)2 (1.5 eqiv.), solvent (1mL), 120°C, sealed tube, isolated
yields.aPhI(OAc)2, 1.0 eqiv. bPd(PPh3)4 1 mol %.
aReaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), Pd(PPh3)4 (3 mol %), 24.0 h,
DCE (1.0 mL), isolated yields.
Addition of PhI(OAc)2 (PIDA) as oxidant[11] the desired product 3a
was isolated in 24% yield (Table 1, entry 2). Performing the
reaction in dichlorobenzene (DCB) as solvent, the yield of 3a was
increased to 33% (Table 1, entry 3). Screening of different
solvents showed that, dichloroethane is the best among the
(CH3CN, THF, Toluene, DMSO, and H2O) solvents for the
reaction (Table 1, entries 4-9). Different catalysts were also
considered and the results showed that [Pd(PPh3)4] was more
effective than the other catalysts (Table 1, entries 10–13). The
yield of the desired product 3a was increased to 81%, when 3.0
equivalents of 2a was employed (w.r.t. 1a) (entry 14). While
decreasing the amount of oxidant, catalyst and temperature, the
yield of the desired product was also reduced (Table 1, entries
15-18), and no reaction was observed without catalyst (Table 1,
entry19). Further, no improvement in yield was observed, while
increasing the reaction temperature to 140 ℃ (Table 1, entry 20).
The best yield of 3a was obtained under the conditions of entry
14; these parameters were set as optimal for further acyloxylation
of pyridotriazole with different carboxylic acids (Table 2).
For our curiosity, we hypothesized to employ acetic anhydride
in place of carboxylic acid it may serve as both solvent as well as
acylation reagent. Accordingly 1a was subjected to the optimised
conditions without external solvent (Table 3).
Table 3. Conversion of pyridotriazoles to 2-oxo-1-aryl-1-(pyridinyl)propyl
acetates
Reaction conditions: 1a (0.2 mmol), Ac2O, (5.0 mmol), Pd(PPh3)4 (3 mol %),
PIDA (1.5 eqiv.), 24 .0 h, isolated yields.
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10.1002/ejoc.201901748
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COMMUNICATION
Surprisingly we observed the formation of interesting product
2-oxo-1-phenyl-1-(pyridin-2-yl)propyl acetate 4a in 70% isolated
yield. This reaction may proceeds through the formation of
intermediate 2-(diazo(phenyl)methyl)pyridine 4, by ring opening
of 1 under these conditions. With the encouraging result of 4a,
and the importance of substituted pyridines in chemo sensor
applications[12] we further subjected various aryl and naphthyl
substituted pyridotriazoles to the same conditions, and obtained
the corresponding products 4b−4f in good yields.
yl)methyl)phenol 7a in one pot procedure. The structure of the
product 7a was further confirmed by single-crystal XRD
analysis.[18] Other substituents such as meta-tolyl, 3-Br-phenyl,
naphthyl, and phenyl on the pyridotriazole also afforded the
corresponding products 7b−7f in moderate to good yields (60-
81%) under the optimised conditions (Table 4, conditions B).
For the conditions B; no external solvent was used, instead,
5.0 mmol of acetic anhydride was employed. Development of
direct methods for the synthesis of desired products by reducing
the number of steps is of prime importance in synthetic chemistry,
as these molecules are useful for industrial applications. By this
method not only reduces the cost of the process, but also it is step
economical. To see the feasibility of the process two products 5a
and 7a were performed at a gram scale under the optimized
conditions (Scheme 4). Although this route to the formation of
hydroxy derivatives was only realized for a particular class of
substrates, pyridotriazoles, it represents a major developmental
strategy to obtain hydroxy derivatives of pyridines via
acyloxylation of pyridotriazoles followed by hydrolysis.
Further we observed that, the direct access to the
hydroxylated pyridines and pyridotriazole derivatives were not
available in the literature, however, they have been isolated from
natural products through multistep procedure.[13] In this context,
we subjected the products 3j and 3k to the hydrolysis using
potassium carbonate in methanol as solvent[14] and obtained 2-
([1,2,3]triazolo[1,5-a]pyridin-3-yl)phenol
5a
and
2-
([1,2,3]triazolo[1,5-a]pyridin-3-yl)-5-chlorophenol 5b in 83% and
75% yield respectively (Scheme 2).
Table 4. Direct conversion of pyridotriazoles to 5 and 7 via hydrolysisa
Scheme 2
Based on our previous understanding on the ring opening of
pyridotriazoles under Lewis acid catalysis,[10b,c] we further
subjected the product 3i and 3k using trifluoro acetic acid (TFA)
and 1,2-dichlorobenzene as solvent to get the 2-picolinoylphenyl
acetates 6, instead, we observed the formation of pyridotriazole
ring opening and simultaneous hydrolysed products (2-
hydroxyphenyl)(pyridin-2-yl)methanone 6a and (4-chloro-2-
hydroxyphenyl)(pyridin-2-yl)methanone 6b in 80% and 64%
yields respectively (Scheme 3).
aReaction conditions A: 1 (0.2 mmol), 2 (RCOOH, 0.6 mmol), Pd(PPh3)4 (3
mol %), PhI(OAc)2 (1.5 eqiv.), DCE (1 mL), 24 h, followed by the addition of
K2CO3 (2.0 eqiv.), MeOH (1 mL), isolated yields.
aReaction conditions B: 1 (0.2 mmol), Ac2O (5.0 mmol), Pd(PPh3)4 (3 mol %),
PhI(OAc)2 (1.5 eqiv.), 24 h, followed by the addition of K2CO3 (2 eqiv.), MeOH
(1 mL), isolated yields.
Scheme 3.
Hydroxypyridine derivatives are important precursors[15] for
the drug 5-aminolevulinic acid that is used in cancer therapy.[16]
Due to the biological importance of these hydroxylated pyridine
derivatives,[17] and based on the encouraging results of scheme 2
and 3, we prepared some of the pyridine derivatives directly from
pyridotriazoles with the above optimized conditions followed by
hydrolysis in one pot procedure (Table 4), rather than subjecting
the isolated products 3 and 4 separately. As can be seen from the
products of table 4 (conditions A), the best yields (82% and 73%)
of hydrolysed products 5a and 5b were obtained when propionic
acid and acetic acid were used as acyloxylation reagents
compared to other carboxylic acid derivatives. Under the
conditions of B, table 4, the unsubstituted pyridotriazoles provided
good yield (81%) of hydrolysis product 2-(methoxy(pyridin-2-
To gain insights into the reaction mechanism of present
transformation, some experiments were performed (Scheme 5).
Initially 2-benzoylpyridine
8 and 2-benzylpyridine 9 were
subjected to the optimized conditions in place of 1a, but these
reaction fail to afford desire product 3a (eq. a). These two
reactions indicate that the nitrogen atom of triazole ring is
essential for the regioselective acyloxylation.[5-7]
Further to check the regioselectivity, one of the substrate 2-
([1,2,3]triazolo[1,5-a]pyridine-3-yl)phenyl pivalate 3d was
subjected to the same reaction conditions, the formation of
desired product 10 was not observed (Scheme 5, eq. b). This
experiment indicates that, the present transformation is highly
desirable for selective mono acyloxylation of pyridotriazoles.
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10.1002/ejoc.201901748
European Journal of Organic Chemistry
COMMUNICATION
coordination of nitrogen atom of 1a with Pd(II) species affords an
intermediate A. Subsequently, the cleavage of the ortho C−H
bond smoothly proceeds and generates a five-membered
cyclopalladated(II) intermediate B,[7c-e] which undergoes oxidative
addition with PhI(OAc)2 to deliver the Pd(IV) intermediate C.
Followed by its reductive elimination leads the formation of the
desired product 3a with the regeneration of the Pd(II)-catalyst.
Scheme 4. Gram scale reactions
To see the effect of carboxylic acid, upon subjecting 1a with
the optimised conditions without any carboxylic acid, we obtained
83% yield of product 3j (Scheme 5, eq. c). It indicate that, the acyl
group contributes from PhI(OAc)2 (PIDA) in absence of external
carboxylic acid. Further to confirm the source of acyloxylation, 1a
was reacted with PhI(OCOtBu)2 and the mixture of PhI(OCOtBu)2
and butanoic acid separately in place of PhI(OAc)2 under the
optimized conditions; the desired products 3d and 3b were
obtained in 71% and 52% yields respectively (Scheme 5, eqs. d
& e). In the latter case along with major product 3b, small amount
of 3d was also observed, it may be due to the stability of
carboxylate (tBuCOO-) ion. The reaction of 1a under the optimized
conditions without PIDA, no product formation was observed
(Scheme 5, eq. f). The reactions of equations c - f (Scheme 5)
suggest that, PIDA is essential for present transformation and
also indicates the exchange of ligand with PIDA (carboxylate
derivative), such exchange of ligands were known in the
literature.[19] To confirm the source of methoxy group, 4a was
reacted with deuterated methanol (CD3OD) under the optimized
conditions and observed the formation of 2-((methoxy-d3)pyridin-
2-yl)methyl)phenol 7g in 57% yield (Scheme 5 eq. g). This
reaction indicates that, the methoxy group comes from the
methanol during hydrolysis.
Scheme 6. Plausible reaction mechanism for 3a
Similar reaction mechanism is applicable for the 2-oxo-1-
phenyl-1-(pyridin-2-yl)propyl acetate (4a) under the present
conditions (Scheme 7). Denitrogenation of 1a with Pd(PPh3)4 may
generate the metallocarbene intermediate A.10a The insertion of
Ac2O to the intermediate A may generates metalated intermediate
B. Which upon elimination of (Pd(PPh3)2 generates another
intermediate C. Due to the positive charge on oxygen of Ac2O, the
negative charge present on the central carbon may attack on
electrophilic carbonyl carbon and deliver the desired product 4a.
Scheme 5. Control experiments
Scheme 7. Proposed mechanism for 4a
Based on previous literature and our experiments, a plausible
reaction mechanism has been proposed (Scheme 6). Initially
Pd(PPh3)4 oxidized to Pd(II) species by PhI(OAc)2 and
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10.1002/ejoc.201901748
European Journal of Organic Chemistry
COMMUNICATION
CSIR-CSMCRI Communication No. 128/2019. We are thankful to
“Analytical Discipline and Centralized Instrumental Facilities” for
providing instrumentation facilities. Our special thanks to Dr. E.
Suresh of this institute for his help to solve the crystal structures.
Conclusions
We have developed an efficient protocol for the palladium-
catalyzed direct ortho C−H acyloxylation of 3-phenyl-
pyridotriazoles with various carboxylic acids as acyloxylation
reagents. The reaction is highly selective for mono acyloxylation
of pyridotriazoles with PhI(OAc)2 (PIDA) as an oxidant and
aliphatic carboxylic acids such as aliphatic, branched, cyclic
including adamantine carboxylic acids. When acetic anhydride
was employed as acylation reagent, an interesting product 2-oxo-
1-phenyl-1-(pyridin-2-yl)propyl acetates were obtained through
the ring opening of pyridotriazoles. We also reported the direct
one pot synthesis of (2-hydroxyphenyl)(pyridin-2-yl)methanones
via acyloxylation followed by basic hydrolysis. It is interesting to
note that, when 2-([1,2,3]triazolo[1,5-a]pyridin-3-yl)phenyl acetate
was subjected to acid hydrolysis 2-([1,2,3]triazolo[1,5-a]pyridin-3-
yl)phenol was obtained. To validate the feasibility of the process
for commercial synthesis, two products were synthesized at gram
scale (5.0 mmol) under the optimized conditions.
We are thankful
to DST,
Government
of
India
(EMR/2016/000010) for the research grants and CSIR-CSMCRI
(MLP-0027) for the partial financial support.
Keywords: Ortho-C-H activation, Pyridotriazole, Pd-catalyzed,
ortho hydroxylation, gram scale.
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Experimental Section
General procedure for the synthesis of 2-([1,2,3]triazolo[1,5-
a]pyridin-3yl)phenyl propionate (3a):
To a reaction tube equipped with a magnetic stir bar, added 3-phenyl-
[1,2,3]triazolo[1,5-a]pyridine (1a)(39.0 mg, 0.2 mmol), propionic acid
(2a)(45 mg, 0.6 mmol), Pd(PPh3)4 (6.7 mg, (3 mol%) , PhI(OAc)2 (97
mg,1.5 eqiv) and 1.0 mL of 1,2-dichloroethane. The mixture was heated in
an oil bath at 120ᵒC in a closed tube for 24 h. Reaction was monitored by
TLC, after completion of the reaction; it was allowed to attain room
temperature. Then the mixture was poured into 30 mL of sodium chloride
solution. The product was extracted with EtOAc (15 mL X 3) and dried with
anhydrous Na2SO4. Removal of the solvent under reduced pressure the
left out residue was purified by column chromatography using silica gel
(20% EtOAc/hexane) to afford 3a(40.7 mg; 81% yield).
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16382;
–
–
–
General procedure for the synthesis of 2-oxo-1-phenyl-1-(pyridin-2-
yl)propyl acetate (4a):
–
–
To a reaction tube equipped with a magnetic stir bar, added 3-phenyl-
[1,2,3]triazolo[1,5-a]pyridine (1a)(39.0 mg, 0.2 mmol), acetic anhydride
(0.5 mL, (5.0 mmol), Pd(PPh3)4 (6.7 mg, (3 mol%) and PhI(OAc)2 (97 mg,
1.5 eqiv). The mixture was heated in an oil bath at 120ᵒC in a closed tube
for 24 h. Reaction was monitored by TLC, after completion of the reaction;
it was allowed to attain room temperature. Then the mixture was poured
into 30 mL of sodium chloride solution. The product was extracted with
EtOAc (15 mL X 3) and dried with anhydrous Na2SO4. Removal of the
solvent under reduced pressure the left out residue was purified by column
chromatography using silica gel (20% EtOAc/hexane) to afford 4a(38 mg;
70% yield).
–
–
–
–
–
–
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CCDC 1955145 [for 3d] and 1958755 [for 7a] contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
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Deepa Rawat, Rahul Kumar and Subbarayappa Adimurthy*
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Pd-Catalyzed ortho Selective C-H Acyloxylation and
Hydroxylation of Pyridotriazoles
Pyridotriazole, Pd-catalyzed, ortho hydroxylation
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