Scope of regioselective Suzuki reactions in the synthesis of arylpyridines and benzylpyridines and subsequent intramolecular cyclizations to azafluorenes and azafluorenones

Article abstract of DOI:10.1039/C8NJ02734J

The current investigation on regioselective Suzuki reactions of 2,3-dihalopyridines and 2-halo-3-halomethylpyridines yielded the unexplored synthesis of arylpyridines and benzylpyridines bearing synthetic handles for further functionalization. Indeed, the scope of intramolecular cyclizations of arylpyridines and benzylpyridines prepared in this study for the synthesis of azafluorenes and azafluorenones has been investigated.

Full text of DOI:10.1039/C8NJ02734J

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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Scope of regioselective Suzuki reactions in the synthesis of
arylpyridines and benzylpyridines and subsequent intramolecular
cyclizations to azafluorenes and azafluorenones
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Joydev K. Laha,* Ketul V. Patel, Saima, Surabhi Pandey, Ganesh Solanke and Vanya
Vashisht
www.rsc.org/
The current investigation on regioselective Suzuki reactions of 2,3-dihalopyridines and 2-halo-3-halomethylpyridines
yielded unexplored synthesis of arylpyridines and benzylpyridines bearing synthetic handles for further functionalizations.
Indeed, the scope of intramolecular cyclizations of arylpyridines and benzylpyridines prepared in this study for the
synthesis of azafluorenes and azafluorenones has been investigated.
chemists. Our previous contributions on understanding the
reactivity of halopyridines11 and subsequent development to the
synthesis of pyridine-fused heterocycles fuelled to embark us on
Introduction
Among many other C-C bond formation at the frontier of organic
chemistry, Suzuki reaction has become a fundamental tool for C-C
bond forming reactions, largely practiced both in academia and
industry.1 Often, regioselective Suzuki reactions have been
developed delivering biaryls that are otherwise difficult to obtain by
direct arylation2 or oxidative coupling.3
exploratory investigation on this issue. Herein, we describe our
investigational findings on regioselective Suzuki reactions of
pyridines that led to the unexplored synthesis of arylpyridines and
benzylpyridines, which could be used as advanced intermediates in
the synthesis of pyridine-fused heterocycles. Indeed, arylpyridines
and benzylpyridines are demonstrated to undergo palladium-
catalyzed intramolecular cyclization to the synthesis of azafluorenes
and azafluorenones in the current study. The regioselective Suzuki
reactions on pyridines and subsequent intramolecular cyclizations
of the compounds described in this study may fall under preliminary
investigation. Taken together, the current study should merit as
further advancement on pyridine chemistry.
Arylpyridines and benzylpyridines represent important
structural motifs ubiquitously found in natural products, fine
chemicals, and functional materials.4 In addition, they have been
demonstrated as building blocks for the preparation various
pyridine-fused heterocycles.5
2-Arylpyridines have been
functionalized at the ortho-position of aryl ring wherein pyridine
acts as the directing group.6 Despite all these documented utilities,
their synthesis endorses only a limited success. The palladium-
catalyzed direct arylation7 or arylation via oxidative coupling8 of
pyridines is a commonly recognized synthetic challenge. In addition,
high Lewis basicity of the sp2-nitrogen in pyridine often results in
catalyst coordination and/or poisoning of the catalyst. In this
regard, Suzuki reaction on pyridines has been demonstrated an
alternative beneficial approach for the synthesis of arylpyridines
and benzylpyridines.9 However, regioselectivity could be an issue in
Suzuki reactions of dihalopyridines.10 An exploratory investigation
on this issue appears to be a reasonable task for the synthetic
Result and discussion
Synthesis of Arylpyridines
Our initial investigation was largely focused on regioselective Suzuki
reactions on 2,3-diahlopyridines and 2-halo-3-halomethylpyridines.
Unlike Suzuki reactions of haloarenes with aryl boronic acids or
boronates, halopyridines could feature distinct reactivity depending
upon the position of the halogen on the pyridine ring. Suzuki
reaction of substituted 2- or 3-bromopyridine and 2-substituted
phenylboronic acids in the presence of Pd2(dba)3, X-Phos and
K3PO4.H2O in 1,4 dioxane:H2O (3:1) at 100 °C for 16 h gave the
corresponding 2- and 3-arylpyridines 3a-3e in 77-89% yields
(Scheme 1). In addition, 4-substituted boronic acids also underwent
Suzuki coupling with halopyridines to successfully form the
corresponding products 3f-3h in good yields. Apparently, 2-
bromopyridine parallels the reactivity of 3-bromopyridine under
this condition. Similarly, substituted 2-chloropyridines react with
phenylboronic acid affording 2-arylpyridines 3i and 3j in 76% and
*Department of Pharmaceutical Technology (Process Chemistry)
National Institute of Pharmaceutical Education and Research
S. A. S. Nagar, Punjab 160062, India; E-mail: jlaha@niper.ac.in
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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71% yields, respectively. While a direct comparison of the reactivity should be mentioned that the starting material remain unreacted in
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DOI: 10.1039/C8NJ02734J
of 2-bromopyridine and 2-chloropyridine is difficult from these case of 2,3 dibromo pyridine with formation of one side (3k) and
studies, both of them react under Suzuki condition to give the two side Suzuki product (3k’) (see S.I. for NMR) due to the equal
corresponding arylated products. The question remains whether reactivity of both bromo substituents on pyridine ring.
both 2- and 3-halogen in 2,3-dihalopyridine would react similarly
Moreover, another comparable study was performed wherein
under Suzuki condition to yield a double arylated product, or a substituted boronic acid reacted with 2,3-dibromopyridine and 2-
regioselective Suzuki reaction of 2,3-dihalopyridine would be chloro-3-bromopyridine yielding the products 3r and 3s in 82% and
possible to develop.
33% yields, respectively.
Similarly, reaction of 3-bromo-2-chloropyridine and 2-
methylphenylboronic acid resulted in the formation of 3l under the
similar condition. Furthermore, investigation of the reactions of
substituted 3-bromo-2-chloropyridine and 2-methylphenylboronic
acid under the similar condition resulted in the preparation of
substituted 3-arylpyridines containing the 2-chloro group. Perhaps
most importantly, the current investigation unveiled that 2-halo
and 3-halo present in 2,3-dihalopyridines could exhibit different
reactivity profile towards arylboronic acid. It is important to note
here that the arylpyridines bearing a halogen could potentially be
used as building blocks for the preparation of pyridine fused
heterocycles.
Further synthetic manipulations provided arylpyridines
containing a halomethyl group poised for intramolecular cyclization
(Scheme 3). Thus, halogenations of arylpyridine 3a with NBS or NCS
in the presence of
a catalytic amount of AIBN produced
arylpyridines 3aa-3ab (Path A) containing a haolmethyl group.
These arylpyridines 3aa-3ab were also prepared from the
arylpyridines containing an ester group via reduction followed by
halogenations of the hydroxymethyl group (Path B).
Scheme 1 Suzuki reactions on 2- or 3-bromo/chloropyridines.
Indeed,
reaction
of
2,3-dibromopyridine
and
2-
methylphenylboronic acid in the presence of Pd2(dba)3, X-Phos and
K3PO4.H2O in dioxane:H2O (3:1) at 100 °C for 16 h gave only 3-
arylpyridine 3k in 27% yield (Scheme 2).
Scheme 3 Synthetic manipulations on arylpyridines.
Synthesis of Benzylpyridines: While Suzuki reactions of
halopyridines have been well investigated, reactions of halomethyl
pyridines with arylboronic acids under Suzuki conditions remain
underdeveloped, however in some cases with other heteroarenes
are known.12 Unlike oxidative addition of palladium (0) into the C-Br
bond of pyridine, the oxidative addition of palladium (0) into the
benzylic ˗CH2-Br bond of pyridine would seem difficult to achieve.13
More precisely, regioselectivity in Suzuki reactions of pyridines
Scheme 2 Regioselective Suzuki reactions on 2,3-dihalopyridines.
Importantly, Suzuki reaction occurred selectively at the 3-
position of 2,3-dibromopyridine affording 3-arylpyridine 3k. It
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containing both halogen and halomethyl group has been a rare this privileged scaffold.18f Although fluorenes are structurally similar
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investigation. Considering these cumulative limitations, exploration to azafluorenes, many synthetic approaches dealing with the
of regioselective Suzuki reactions on 2-halo-3-halomethylpyridines, synthesis of fluorenes have been found incompatible for
which could provide arylpyridines containing a halomethyl group, or azafluorene synthesis.19 Moreover, arylpyridines or benzylpyridines
benzylpyridines containing a halogen group was the focus of our have never been demonstrated to the synthesis of azafluorenes.
subsequent
investigation.
Reaction
of
2-bromo-3- Leveraging our previous experiences on the synthesis of pyridine
bromomethylpyridine and arylboronic acid under Suzuki conditions fused heterocycles,20 we decided to explore further the palladium-
gave the coupled product 3t corresponding to the reaction at 3- catalyzed intramolecular cyclizations of arylpyridines and
bromomethyl site. The reaction demonstrated
substrate scope including use of 2-methyl, 2-acetyl, and 4-
a
reasonable benzylpyridines prepared in this study.
Intramolecular cyclization reactions of 3l in the presence of a
acetylphenyl boronic acids as the coupling partner. However, 4- palladium-catalyst, ligand, base and solvent were examined (Table
fluorophenyl boronic acid gave a double Suzuki coupled product 3t 1). Thus, heating 3l in the presence of 10 mol% Pd(OAc)2, BINAP,
arising from reactions at both 2-bromo and 3-bromomethyl sites. In and Na2CO3 in DMA for 24 h resulted in the formation of 4a in 34%
this case, attempted isolation of a regioselective Suzuki product was yield (entry 1). Subsequent experimentations revealed that an alkyl
unsuccessful. The use of a seemingly different reaction partner, 2- phosphine has tremendous influence in the reaction affording 4a in
chloro-3-iodomethylpyridine 1h also gave 3x. Further attempt was 87% yield (entries 2-5). The other bases had an adverse effect in the
made
involving
the
reaction
between
o-halo-oˊ- reaction (entries 6-8). Similarly, the other solvents exerted
bromomethylpyridine and 4-cyano-phenylboronic acid. However, deleterious effect in the reaction (entries 9-11). A different
only a poor regioselectivity was observed. Attempted efforts to palladium also did not prove effective (entries 12-13).
improve the regioselectivity by decreasing the amount or changing
Table 1 Intramolecular cyclization of arylpyridines to azafluorenesa
the base were unsuccessful. The current investigation disclosed that
2-halo and 3-halomethyl present in 2-halo-3-halomethylpyridines
could exhibit different reactivity profile towards arylboronic acid.
Notably, regioselective Suzuki reaction at the 2-position in 2-halo-3-
halomethylpyridines could possess significant challenge and is the
subject of further investigation.
a Reaction conditions: 3l (0.25 mmol), Pd-catalyst (5 mol%), ligand (10
mol%), base (1.2 equiv), solvent (1 mL), 24 h. b Isolated yield.
Having optimized condition in hand, we further investigated
intramolecular cyclization of various arylpyridines prepared in
this study to the synthesis of azafluorene (Scheme 5).
Scheme 4 Scope of selective Suzuki coupling on o-halo-oˊ-
halomethylpyridine.
Intramolecular Cyclization of Arylpyridines and Benzylpyridines to
the Synthesis of Azafluorenes: Among various heterocycles
embedded with pyridine nucleus, azafluorenes and azafluorenones
contribute
a
major part.14 Many of them are effective
physiologically active substances with sedative, neuroleptic,
antihistamine, antibacterial, antioxidant, pesticide and adrenolytic
activities.15 Derivatives of azafluorene have been found to produce
marked effects on the CNS disorders.16 They also possess good
emission and absorption properties, which make them useful in the
preparation of dyes and light emitting materials.17 However, a few
literatures are available for the synthesis of azafluorenes.18 Some
reports have used prefunctionalized moieties for the synthesis of
Scheme 5 Substrate scope for azafluorene synthesis.
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A small set of examples to the synthesis of azafluorenes have
been prepared. However, azafluorene4d containing a -OCF3
group was not obtained under the condition. Instead, a
dehalogenated product 4e was obtained in this case.
Having successfully prepared the azafluorenes in two steps,
we further investigated the opportunity of integrating two
steps into a one-pot strategy.
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Scheme 8 Mechanism involves in the synthesis of azafluorene.
Intramolecular Cyclization of Arylpyridines to the
Serendipitous Synthesis of Azafluorenones:
Scheme 6 One-pot synthesis of azafluorene.
As described in the previous section, intramolecular sp3 C-H
arylation of 3-arylpyridines containing an ortho-methyl group
on the phenyl ring gave 1-azafluorene. In contrast, reaction of
3-arylpyridines containing an ortho-methyl group on the
pyridine ring yielded serendipitous formation of 3-
azafluorenone 4j in 42% yield under a slightly modified
condition [Pd(OAc)2 (10 mol%), PCy3 (20 mol%), Na2CO3 (1.2
equiv), DMF (4 mL/mmol), 130°C, 24 h). It is noteworthy that
sp3 C-H functionalization of unactivated pyridine, considered
to be a challenging task, has been achieved in this preliminary
Thus,
a
regioselective Suzuki coupling of 2-chloro-3-
bromopyridine and tolylboronate followed by intramolecular
cyclization of the coupling product, generated in situ, yielded
azafluorene 4a albeit in low yield (Scheme 6).
Subsequent to the intramolecular cyclization of
arylpyridines, we investigated the scope of intramolecular
cyclization of benzylpyridines to the synthesis of azafluorenes
(Scheme 7). Benzylpyridines have been utilized for various
applications including in biological and material chemistry.21
However, their intramolecular cyclizations to the synthesis of
azafluorenes, to the best of our knowledge, remain
unexplored. While the optimized reaction condition that was
successful affecting the intramolecular cyclization of
arylpyridines, further experimentation was required to
showcase an intramolecular cyclization on benzylpyridines.
Thus, heating a solution of benzylpyridines in the presence of
palladium acetate (10 mol%), X-Phos (20 mol%) and K2CO3 in
toluene at 110 °C for 3 h gave the cyclized products 4f-4i in 51-
87% yields. The current investigation pertaining to the
investigation.
Subsequently,
palladium-catalyzed
intramolecular benzylation of 3-pyridylbenzyl chloride 3y was
investigated. After several experimentations, intramolecular
cyclization of 3y produced a mixture of 3-azafluorenone 4j and
1-azafluorenone 4i (Scheme 9) in a combined 57% yield with a
high regioselectivity (9:1). The viability of a complementary
approach was also investigated wherein alkyl halide group is
present on the pyridine ring. Indeed, palladium-catalyzed
intramolecular
benzylation
of
(3-bromomethyl)-2-
phenylpyridine also gave 4-azafluorenone 4k in 84% yield.
intramolecular
cyclization
of
benzylpyridines
could
complement the synthesis of azafluorenes available in
literature.
Scheme 9 Serendipitous synthesis of azafluorenones.
Scheme 7 Substrate scope in the synthesis of azafluorene.
A control experiment to understand the mechanism of the
formation of azafluorenones indicated that azafluorene could
undergo oxidation in the presence of air or oxygen. Thus,
heating 4-azafluorenenes 4f in DMF at 130 °C for 6 h led to the
formation of their corresponding azafluorenones 4l. Further
experiments are required to confirm the formation of
azafluorenones in these intramolecular cyclizations (Scheme
10).
The mechanism for the synthesis of azafluorene is presented in
scheme 8. Initially oxidative insertion of Pd0 to aryl halide could give
intermediate I. Further, nucleophilic displacement could give
intermediate II and then reductive elimination could give
azafluorenone formation.
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L. Harikrishnan, D. S. Taylor, A. Y. A. Chen, X. Yin, R. Seethala,
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Scheme 10 Understanding the mechanism for the synthesis of
azafluorenones.
Conclusion
In conclusion, we have developed regioselective Suzuki
reactions on pyridines that led to the unexplored synthesis of
arylpyridines and benzylpyridines. The arylpyridines and
benzylpyridines prepared in this study were subjected to the
palladium-catalyzed intramolecular cyclizations affording novel
syntheses of azafluorenes and azafluorenones. Although a
preliminary investigation has been described herein, the
current study could reflect further advancement on pyridine
chemistry.
6
7
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
We greatly appreciate the Science & Engineering Research
Board (SERB) of DST, New Delhi, for a research fellowship.
Saima is indebted to DST-SERB for NPDF fellowship under
grant no. PDF/2016/003627.
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6 | J. Name., 2012, 00, 1-3
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New Journal of Chemistry
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DOI: 10.1039/C8NJ02734J
Scope of regioselective Suzuki reactions in the synthesis of arylpyridines and
benzylpyridines and subsequent intramolecular cyclizations to azafluorenes and
azafluorenones
Joydev K. Laha,* Ketul V. Patel, Saima, Surabhi Pandey, Ganesh Solanke and Vanya
Varshisht
The current investigation on regioselective Suzuki reactions of 2,3-dihalopyridines and 2-
halo-3-halomethylpyridines yielded unexplored synthesis of arylpyridines and
benzylpyridines bearing synthetic handles for further functionalizations. Indeed, the scope of
intramolecular cyclizations of arylpyridines and benzylpyridines prepared in this study in the
synthesis of azafluorenes and azafluorenones has been investigated.