Nucleophilic substitution of hydrogen–the Boger reaction sequence as an approach towards 8-(pyridin-2-yl)coumarins

Article abstract of DOI:10.1016/j.mencom.2019.05.019

5,7-Dimethoxy-8-(3,6-diphenylpyridin-2-yl)coumarins were obtained from 5,7-dimethoxycoumarins and 3,6-diphenyl-1,2,4-triazines via the protocol comprising aromatic S_N^H substitution in the triazine ring followed by the Boger transform

Full text of DOI:10.1016/j.mencom.2019.05.019

Mendeleev
Communications
Mendeleev Commun., 2019, 29, 299–300
Nucleophilic substitution of hydrogen–the Boger reaction
sequence as an approach towards 8-(pyridin-2-yl)coumarins
Ramil F. Fatykhov,a Maria I. Savchuk,a Ekaterina S. Starnovskaya,a Maria V. Bobkina,a
Dmitry S. Kopchuk,*a,b Emiliya V. Nosova,a,b Grigory V. Zyryanov,a,b Igor A. Khalymbadzha,a,b
Oleg N. Chupakhin,a,b Valery N. Charushina,b and Viktor G. Kartsevc
a Institute of Chemical Engineering, Ural Federal University, 620002 Ekaterinburg, Russian Federation.
Fax: +7 343 374 1189; e-mail: dkopchuk@mail.ru
b I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
620990 Ekaterinburg, Russian Federation
c InterBioScreen Ltd., 142432 Chernogolovka, Moscow Region, Russian Federation
DOI: 10.1016/j.mencom.2019.05.019
OMe R2
5,7-Dimethoxy-8-(3,6-diphenylpyridin-2-yl)coumarins were
obtained from 5,7-dimethoxycoumarins and 3,6-diphenyl-
1,2,4-triazines via the protocol comprising aromatic SHN sub-
stitution in the triazine ring followed by the Boger transforma-
tion of formed triazine moiety into the pyridine one. The
advantages of the suggested method are simple procedures,
high yields, and the absence of transition-metal catalysts.
R1
O
OMe R2
OMe R2
R1
O
R1
O
Boger
reaction
MeO
O
+
SHN
MeO
Ph
O
MeO
Ph
O
Ph
Ph
Ph
N
N
N
N
N
N
N
Ph
Coumarin derivatives bearing pyridine fragments are of particular
interest due to their wide spectrum of physiological activity.1 The
reported synthetic approaches include multistep reaction sequences
involving acylation of coumarins, halogenation of the acyl
derivatives, halogen substitution and the Kröhnke ring formation.2
Noteworthy that aromatic nucleophilic substitution of hydrogen
(SNH)3 is a versatile tool for the single-step modification of
various p-deficient heterocycles, in particular, 1,2,4-triazines,4
by the incorporation of electron-rich residues. Unfortunately,
the reactivity of pyridine ring is generally insufficient for its
modification by direct substitution of hydrogen. At the same
time, the Boger pyridine synthesis5 involving hetero-Diels–Alder
reaction of 1,2,4-triazines followed by extrusion of N2 provides
simple conversion of triazines into pyridines. This protocol is widely
used, e.g., for the synthesis of (bi)pyridines with such substituents
as (het)aryl, alkylthio, ester and chloromethyl groups.6 Therefore,
SNH reaction of 1,2,4-triazines or its activated forms (1,2,4-triazine
4-oxides) followed by the Boger reaction represent an effective
strategy for the synthesis of substituted pyridines. In this way,
various 2,2'-bi- and 2,2':6',2''-terpyridines were obtained via ring
The C–C coupling of 5,7-dimethoxycoumarins 1a–c at the
5-position of 3,6-diphenyl-1,2,4-triazine17 was processed via
aromatic nucleophilic addition followed by oxidation of initially
formed dihydroadducts 2a–c.† We have found that the earlier
described conditions18 for the addition of 1,2,4-triazines to
5,7-dihydroxycoumarins (3 equiv. MsOH, 24 h, ambient tem-
perature) could be successfully applied to methoxy derivatives
Ph
OMe R2
OH R2
N
R1
O
R1
O
N
Ph
N
i
ii
85–94%
MeO
O
HO
O
1a–c
OMe R2
OMe R2
R1
O
R1
MeO
O
MeO
Ph
O
O
iii
Ph
Ph
63–74%
(2 steps)
iv
N
N
77–80%
N
N
N
Ph
N
transformation of the corresponding 5-Nu-1,2,4-triazine precursors
.
H
Such nucleophiles as cyanide anion,7 resorcinol, thiophene, lithium
acetylides,8 lithiocarboranes,8,9 lithium salts of polynuclear aromatic
compounds10 and C–H-active compounds11 were successfully
employed in this strategy. Moreover, the possibility of combina-
tion of SNH, SNipso and the Boger reactions for the preparation of
2,2'-bipyridines bearing aniline,12 amine or alcohol13 functional
groups should be noted. Recently, this strategy has been extended
onto in situ generated aryne intermediates as dienophiles.14
The aim of this communication is to describe a convenient
synthetic approach towards 8-(pyridin-2-yl)coumarin derivatives
comprising SNH reaction at the first step and Boger reaction at the
second step (Scheme 1).
2a–c
3a–c
OMe R2
OMe R2
R1
O
R1
MeO
O
MeO
Ph
O
O
– N2
Ph
Ph
N
N
N
–
N
Ph
4a–c
a R1 = H, R2 = Me
b R1 = H, R2 = Ph
c R1 = Bn, R2 = Me
5,7-Dimethoxycoumarins 1 were synthesized by methylation
of the corresponding known15 5,7-dihydroxy precursors according
to the procedure reported for other analogous compounds.16
Scheme 1 Reagents and conditions: i, Me2SO4, K2CO3, acetone, reflux, 8 h;
ii, MsOH, CH2Cl2, room temperature, 24 h; iii, DDQ, C2H2Cl2, reflux, 6 h;
iv, 1,2-Cl2C6H4, 215°C (autoclave), 20 h.
© 2019 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2019, 29, 299–300
1a–c. Adducts 2 can be readily isolated (e.g. 2a can be easily
Online Supplementary Materials
purified by single recrystallization from benzene) and subjected
to the aromatization.
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2019.05.019.
Although coumarins 1a–c contain two nucleophilic centres (C6
and C8 carbon atoms), they add 3,6-diphenyltriazine exclusively
at the 8-position. This was based on 2D HMBC experiment data
for adduct 2a revealing cross-peaks between C6 hydrogen and the
C5 and C7 carbon atoms (see Online Supplementary Materials),
which was in good agreement with published data.18,19
References
1 (a) A. K. Patel, N. H. Patel, M. A. Patel and D. I. Brahmbhatt, Arkivoc, 2010,
(xi), 28;(b)R. B. Moffett, J. Med. Chem., 1964, 7, 446;(c)B. Sreenivasulu,
V. Sundaramurthy and N. V. Subba Rao, Proc.-Indian Acad. Sci., Sect. A,
1974, 79, 41.
2 (a) H. B. Lad, R. R. Giri, Y. L. Chovatiya and D. I. Brahmbhatt, J. Serb.
Chem. Soc., 2015, 80, 739; (b) D. I. Brahmbhatt, J. M. Gajera, V. P. Pandya
and M. A. Patel, Indian J. Chem., Sect. B, 2007, 46, 869; (c) D. I.
Brahmbhatt and V. P. Pandya, Indian J. Chem., Sect. B, 2001, 40, 419.
3 (a) V. N. Charushin and O. N. Chupakhin, Metal Free C–H Func-
tionalization of Aromatics, Nucleophilic Displacement of Hydrogen, in
Topics in Heterocyclic Chemistry, eds. V. Charushin and O. Chupakhin,
Springer, 2014, vol. 37, pp. 1–50, 2014; (b) O. N. Chupakhin and
I. Ya. Postovskii, Russ. Chem. Rev., 1976, 45, 454 (Usp. Khim., 1976,
45, 908).
To restore aromaticity of 1,2,4-triazine ring, dihydroadducts
2a–c were oxidized by refluxing with 1.5 equiv. DDQ in 1,2-di-
chloroethane thus yielding triazines 3a–c (see Scheme 1).
According to our strategy, the last step of the pyridine ring
synthesis is the replacement of N=N fragment in 1,2,4-triazines
3a–c with the CH=CH moiety originating from 2,5-norbornadiene
as a dienophile (see Scheme 1). However, attempts to conduct
this reaction in high-boiling solvents such as toluene, o-xylene
or 1,2-dichlorobenzene failed, and only starting materials were
recovered. It worth noting that carrying out such a reaction under
elevated pressure and temperature was described.20 For example,
5-aryl-2,2'-bipyridines bearing alcohol or amine moiety at the
C6 position were obtained via the reaction of the 1,2,4-triazine
precursors with 2,5-norbornadiene in an autoclave at 215°C in
1,2-dichlorobenzene.13 This procedure proved to be applicable to
the preparation of coumarins 4a–c containing pyridine residues,
and after carrying out the reaction for 20 h the complete conver-
sion of the starting 1,2,4-triazines 3 into the products did occur.‡
NMR spectra provide evidence of replacing the N=N fragment
with the CH=CH one when two characteristic pyridine doublets
were observed. Other proton signals underwent noticeable upfield
shift (see Online Supplementary Materials).
4 D. N. Kozhevnikov, V. L. Rusinov and O. N. Chupakhin, Adv. Heterocycl.
Chem., 2002, 82, 261.
5 (a) J. J. Li, Name Reactions, Springer, 2014, p. 64; (b) G. R. Pabst,
O. C. Pfüller and J. Sauer, Tetrahedron, 1999, 55, 8045; (c)A. Rykowski,
D. Branowska and J. Kielak, Tetrahedron Lett., 2000, 41, 3657; (d) D. S.
Kopchuk, I. S. Kovalev, A. F. Khasanov, G. V. Zyryanov, P. A. Slepukhin,
V. L. Rusinov and O. N. Chupakhin, Mendeleev Commun., 2013, 23, 142.
6 A. M. Prokhorov and D. N. Kozhevnikov, Chem. Heterocycl. Compd.,
2012, 48, 1153 (Khim. Geterotskl. Soedin., 2012, 1237).
7 V. N. Kozhevnikov, D. N. Kozhevnikov, T. V. Nikitina, V. L. Rusinov,
O. N. Chupakhin, M. Zabel and B. König, J. Org. Chem., 2003, 68, 2882.
8 D. N. Kozhevnikov, V. N. Kozhevnikov, A. M. Prokhorov, M. M. Ustinova,
V. L. Rusinov, O. N. Chupakhin, G. G. Aleksandrov and B. König,
Tetrahedron Lett., 2006, 47, 869.
9 A. M. Prokhorov, D. N. Kozhevnikov, V. L. Rusinov, O. N. Chupakhin,
I. V. Glukhov, M. Yu. Antipin, O. N. Kazheva, A. N. Chekhlov and
O. A. Dyachenko, Organometallics, 2006, 25, 2972.
10 I. S. Kovalev, D. S. Kopchuk,A. F. Khasanov, G.V. Zyryanov,V. L. Rusinov
and O. N. Chupakhin, Mendeleev Commun., 2014, 24, 117.
11 Y. K. Shtaitz, M. I. Savchuk, E. S. Starnovskaya, A. P. Krinochkin, D. S.
Kopchuk, S. Santra, G.V. Zyryanov,V. L. Rusinov and O. N. Chupakhin,
AIP Conf. Proc., 2019, 2063, 040050.
In conclusion, the suggested SHN substitution–the Boger
reaction sequence is a simple and useful tool to access pyridine-
containing coumarins. This protocol provides wide diversity
within the chemotype of such compounds.
This work was supported by the Russian Science Foundation
(grant no. 18-73-10119) and the State Contract of the RF Ministry
of Education and Science (ref. no. 4.6351.2017/8.9).
12 (a)D. S. Kopchuk, N.V. Chepchugov, I. S. Kovalev, S. Santra, M. Rahman,
K. Giri, G.V. Zyryanov,A. Majee,V. N. Charushin and O. N. Chupakhin,
RSC Adv., 2017, 7, 9610; (b) D. S. Kopchuk, A. P. Krinochkin, E. S.
Starnovskaya,Y. K. Shtaitz, A. F. Khasanov, O. S. Taniya, S. Santra, G. V.
Zyryanov, A. Majee, V. L. Rusinov and O. N. Chupakhin, ChemistrySelect,
2018, 3, 4141.
13 M. I. Savchuk, E. S. Starnovskaya, Y. K. Shtaitz, D. S. Kopchuk, E. V.
Nosova, G. V. Zyryanov, V. L. Rusinov and O. N. Chupakhin, Russ.
J. Gen. Chem., 2018, 88, 2213 (Zh. Obshch. Khim., 2018, 88, 1728).
14 D. S. Kopchuk, I. L. Nikonov, A. F. Khasanov, K. Giri, S. Santra, I. S.
Kovalev, E. V. Nosova, S. Gundala, P. Venkatapuram, G. V. Zyryanov,
A. Majee and O. N. Chupakhin, Org. Biomol. Chem., 2018, 16, 5119.
15 (a) H. Sharghi and M. Jokar, Heterocycles, 2007, 71, 2721; (b) M. Iinuma,
T. Tanaka, K. Hamada, M. Mizuno and F. Asai, Chem. Pharm. Bull.,
1987, 35, 3909.
16 H. Wulff, H. Rauer, T. Düring, C. Hanselmann, K. Ruff, A. Wrisch,
S. Grissmer and W. Hänsel, J. Med. Chem., 1998, 41, 4542.
17 T. V. Saraswathi and V. R. Srinivasan, Tetrahedron, 1977, 33, 1043.
18 I. A. Khalymbadzha, O. N. Chupakhin, R. F. Fatykhov, V. N. Charushin,
A. V. Schepochkin and V. G. Kartsev, Synlett, 2016, 27, 2606.
19 I. A. Khalymbadzha, R. F. Fatykhov, O. N. Chupakhin, V. N. Charushin,
T. A. Tseitler, A. D. Sharapov, A. K. Inytina andV. G. Kartsev, Synthesis,
2018, 50, 2423.
20 (a) N. S. S. Kumar, M. Z. Shafikov, A. C. Whitwood, B. Donnio, P. B.
Karadakov, V. N. Kozhevnikov and D. W. Bruce, Chem. Eur. J., 2016,
22, 8215; (b) M. Z. Shafikov, D. N. Kozhevnikov, M. Bodensteiner, F.
Brandl and R. Czerwieniec, Inorg. Chem., 2016, 55, 7457; (c) M. M.
†
MsOH (195 ml, 3 mmol) was added to a solution of the corresponding
coumarin 1 (1 mmol) and 3,6-diphenyltriazine (233 mg, 1 mmol) in
CH2Cl2 (7 ml). The mixture was left at room temperature for 24 h, then
diluted with CH2Cl2 (10 ml), basified with saturated solution of Na2CO3,
the organic layer was separated, and the solvent was removed under
reduced pressure to leave product 2.
8-(3,6-Diphenyl-2,5-dihydro-1,2,4-triazin-5-yl)-5,7-dimethoxy-4-methyl-
2H-chromen-2-one 2a. Mp 238–240°C (benzene). 1H NMR (DMSO-d6)
d: 2.43 (s, 3H, Me), 3.86 (s, 3H, OMe), 3.93 (s, 3H, OMe), 5.99 (s, 1H,
H-3), 6.40 [s, 1H, H-5(triazine)], 6.58 (s, 1H, H-6), 7.20–7.30 (m, 3H, Ph),
7.36–7.46 (m, 3H, Ph), 7.61–7.63 (m, 2H, Ph), 7.80–7.82 (m, 2H, Ph).
13C NMR (DMSO-d6) d: 23.8, 45.8, 56.2, 56.4, 92.6, 103.6, 110.5, 111.3,
124.9, 126.2, 128.2, 128.7, 130.2, 133.2, 135.9, 139.4, 149.4, 153.4, 154.4,
158.6, 159.0, 160.7. Found (%): C, 71.45; H, 5.15; N, 9.18. Calc. for
C27H21N3O4 (%): C, 71.51; H, 5.11; N, 9.27.
‡
The mixture of the corresponding triazine 3 (0.3 mmol), 2,5-norborna-
diene (325 ml, 3.2 mmol) and 1,2-dichlorobenzene (25 ml) was stirred
in autoclave under argon atmosphere at 215°C for 20 h. The solvent
was removed under reduced pressure, the residue was purified by flash
chromatography (chloroform as eluent).
8-(3,6-Diphenylpyridin-2-yl)-5,7-dimethoxy-4-methyl-2H-chromen-2-one
4a. Mp 209–211°C. 1H NMR (CDCl3) d: 2.38 (s, 3H, Me), 3.52 (s, 3H,
OMe), 3.73 (s, 3H, OMe), 5.76 (s, 1H, H-3), 6.11 (s, 1H, H-6), 7.05–7.14 (m,
5H, Ph), 7.26–7.27 (m, 1H, Ph), 7.32–7.34 (m, 2H, Ph), 7.65 and 7.68
Krayushkin, I. P. Sedishev,V. N.Yarovenko, I.V. Zavarzin, S. K. Kotovskaya
,
D. N. Kozhevnikov andV. N. Charushin, Russ. J. Org. Chem., 2008, 44, 407
(Zh. Org. Khim., 2008, 44, 411); (d) V. N. Kozhevnikov, M. M. Ustinova,
P. A. Slepukhin, A. Santoro, D. W. Bruce and D. N. Kozhevnikov,
Tetrahedron Lett., 2008, 49, 4096.
3
[both d, 1H, J 8.0 Hz, H-3,4 (Py)], 7.90–7.92 (m, 2H, Ph). 13C NMR
(CDCl3) d: 24.4, 55.7, 55.8, 91.1, 104.6, 111.5, 111.6, 119.9, 127.1, 127.4,
127.7, 128.4, 128.5, 128.6, 137.5, 138.0, 139.6, 139.7, 150.3, 153.9, 154.2,
156.5, 159.2, 160.2, 160.7. Found (%): C, 77.33; H, 4.97; N, 3.44. Calc.
for C29H23NO4 (%): C, 77.49; H, 5.16; N, 3.12.
Received: 16th October 2018; Com. 18/5720
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