Name Reactions in Heterocyclic Chemistry II

Edited by Jie Jack Li

Copyright 2011 John Wiley & Sons, Inc.

PART 3 SIX-MEMBERED HETEROCYCLES 337

Chapter 6 Pyridines 337

6.1 Baeyer Pyridine Synthesis 338

6.2 Katrizky Pyridine Synthesis 347
338 Name Reactions in Heterocyclic Chemistry-II

6.1 Baeyer Pyridine Synthesis

David A. Conlon

6.1.1 Description

0 OCH3 OCH 3

A
II
(H 3 CO) 2 S0 2 (NH 4 ) 2 C0 3
* ^-
R' ^R 20% HCI0 4
CIO4
1 2 3

The reaction of pyrylium salts 2 with ammonia or ammonium salts to

produce pyridine derivatives 3 is referred to as the Baeyer pyridine
synthesis. There are several methods available for the preparation of
pyrylium salts, the alkylation of pyran-4-one derivatives 1 with
dimethylsulfate to generate the prerequisite pyrylium salts was reported by
Baeyer in his 1910 paper.
Addition of an ammonia source to pyrylium salts readily affords
pyridine derivatives and provides a good method for the preparation of the
pyridine moiety if the corresponding pyrylium salt is accessible. The carbon
oxygen double bond present in the pyrylium salt is an oxonium ion however,
owing to aromatic stabilization they are easily formed by a variety of
methods. The reactivity of pyrylium salts toward nucleophiles makes them
useful reagents for the preparation of structurally diverse heterocyclic
compounds. Thus pyrylium salts afford pyridines by reaction with ammonia,
pyridine-JV-oxides by reaction with hydroxylamine and pyridinium salts by
reaction with primary amines.

6.1.2 Historical Perspective

3 QCH3
/
(H3CO)2S02 (NH4)2C03

H 3 C " ^CH 3 2 0 % HCI

4 3 " "CH 3 3 " ' "CH 3
CIQ4
4 5 6
 Chapter 6 Pyridines 339

In 1910, Adolf von Baeyer at the University of Munich reported that the
product from the reaction of dimethylsulfate and 2,6-dimethyl-4#-pyran-4-
one 4 at 50 C formed an insoluble pyrylium salt 5 when treated with
perchloric acid. Treatment of the isolated solid with aqueous ammonium
carbonate generated 4-methoxy-2,6-dimethylpyridine (6).
In 1912, Baeyer and Picard reported that 2,4,6-trimethylpyrylium
perchlorate (7) could be prepared by reacting 2,6-dimethylpyrone (4) with
methylmagnesium iodide followed by treatment of the reaction mixture with
perchloric acid.2 2,4,6-Trimethypyridine (8) was readily formed upon
treatment of 7 with ammonia.

CH,
CH3Mgl

2 0 % HCI
HgC'Sr^CHa 4 ^^
CI4
4 7

2,6-Dimethyl-4-phenylpyridine was produced using an analogous

sequence and this process has expanded the access to a variety of 2,4,6-
substituted pyridines. This synthetic sequence had limited utility however,
due to the reactivity of the intermediate pyrylium ions with residual
organomagnesium reagents during the quench.
Two efficient procedures for synthesizing the requisite pyrylium salts
were reported by Dilthey and Balaban. Symmetrical pyrylium salts with
aromatic substituents such 2,4,6-triphenylpyrylium ferrochloride were
prepared by Dilthey from 2 mol of acetophenone and 1 mol of benzaldehyde
in the presence of acetic anhydride and ferric chloride.3 By preforming the
intermediate chalcone 11 it is also possible to prepare unsymmetrically
substituted 2,4,6-triarylpyrylium salts 14.4 Once again, these pyrylium salts
are readily converted to the corresponding triarylpyridines 15 following
treatment with ammonium acetate under mild conditions.5 In 2005, Wang
reported the preparation and subsequent conversion to of a series of pyrylium
salts to 2,4,6-triarylpyridines with diverse aryl ring substituents.6 The
conversion of the pyrylium salts to pyridines was performed under
microwave irradiation in aqueous ammonia using PEG-400 as a phase
transfer catalyst.


II ^ II 10 7
1
Ar CHO + ^2 A^^^^Ar2 "
9 10 11
340 Name Reactions in Heterocyclic Chemistry-II

Ari H

HoO -H

In 1959, Balaban and Nenitzescu reported their work on the

preparation of pyrylium salts that followed an earlier report by Praill.7 This
process is often referred to as the Balaban-Nenitzescu-Praill synthesis and is
an efficient method for the preparation of alkyl substituted pyrylium salts and
therefore alkyl substituted pyridines. The process involves the diacylation of
olefins and has become a common method for the synthesis of 2,4,6-
trialkylsubstituted pyrylium salts with identical substituents in the 2- and 6-
positions.8 Stang reported an improved procedure to prepare 2,6-di-tert-
butyl-4-methylpyridine (17) from the corresponding 2,6-di-fer/-butyl-4-
methyl-pyrylium triflate salt (16) in 1976.

EtOH
-60 C
95%

6.1.3 Mechanism

The initial nucleophilic attack of ammonia on a 2,4,6-trisubstituted pyrylium

cation 18 occurs at the at -oxonium carbon that has the smaller substituent.
This is followed by deprotonation with a second equivalent of ammonia and
 Chapter 6 Pyridines 341

an electrocyclic ring opening to produce a vinylogous amide 20 and an

ammonium salt. The vinylogous amide is converted to the product pyridine 6
with the loss of a mole of water.

OCH, OCH

NH,
NH,
NH4X ,^-^2
x" 19
18

OCH, OCH,

H3C N CH 3

6.1.4 Variations

The reaction of pyrylium salts with hydroxylamines and primary amines

produces pyridine TV-oxides and pyridinium salts, respectively. These
pyridine derivatives have interesting properties and are also useful
intermediates for the preparation of a variety of new materials. For example,
nucleophilic substitution on the pyridine ring is facilitated by the formation
of an /V-oxide or pyridinium salt.
It was reported in the late 1950s, that the reaction of pyrylium salts
with hydroxylamine produces pyridine /V-oxides. This procedure has been
used to prepare 2,6-disubstituted pyridine TV-oxides in better yield than
obtained from the oxidative procedure.11

CH, CH,
NH2OH
AcOH
H,C , H,C N CH,
NaOAc I
reflux O"
21

The reactions of primary amines with pyrylium salts produce

pyridinium salts. Pyridinium salts like 23 are useful intermediates that have
342 Name Reactions in Heterocyclic Chemistry-II

been used to prepare a diverse array of compounds by nucleophilic

displacement of the pyridine.12 Pyridinium salts such as 25 have found use as
carbonic anhydrase activators13 and derivatives like 26 exhibit anti-
cholinesterase activity.14

NH,

0 ^ph 1.Et3N, CH2CI2

2. HOAc
BF 4 " 90%
22

H2NCH2CH2OH

EtOH
45-50 C
67%

H
CH, HoN-
N "

J H,C - N
HOAc CIO.
CI0 4

The Baeyer pyridine procedure has been extended to the preparation

of other six-membered heterocycles, such as quinolines, isoquinolines, and
acridines which are obtained by the reactions of the corresponding pyrylium
salts with ammonia derivatives. For example, benzopyrylium salt 27 is
converted to isoquinoline 28 as shown below.
 Chapter 6 Pyridines 343

/OCH3 3
EtC^C^'N*^ HC^C^4
^il
^ ^
H3co H3CO JL 1
OCH 3 3

H3C0
<^ 4 NH4OH H3CO
CH3 , 43% 3

27 28

6.1.5 Synthetic Utility

The pyridine ring is ubiquitous in compounds of pharmaceutical and

agrochemical interest. Six-membered heterocycles such as pyridines,
quinolines, isoquinolines, and acridines can also be obtained by the reactions
of the pyrylium salts with ammonia derivatives.
-Carbolines are a class of indole alkaloids, which are structurally
similar to the amino acid L-tryptophan and have a diverse biological activity.
Several clinical investigations have indicated that -carboline derivatives are
potentially useful for a variety of neuroscience applications.16 The Baeyer
pyridine synthesis procedure was used during the preparation of the novel -
carboline derivative, ambocarb (30), as shown below. 7

NH4OH
EtOH

H CH 3
ambocarb 30

Pyrylium salts have been shown to be versatile synthetic

intermediates for the preparation of many novel and naturally occurring
1 R

heterocyclic ring systems.

6.1.6 Experimental

0CH3 OCH,
(H 3 C) 2 S0 4 (NH 4 ) 2 C0 3
A 2 0 % HCI
H,C 0 CH, 4 HoC 0 CH3 H3C" N CHo
4
5 6
344 Name Reactions in Heterocyclic Chemistry-II

2,4-Dimethy-4-methoypyridine (6)
Dry dimethylpyrone (50 g) and dimethylsulfate (80 g) are mixed with
methanol (5 g) and heated to 50 C to give a solution. Treatment of the
cooled solution with 20% aqueous 4 (190 g) and aging for 2 h produced
2,6-dimethyl-4-methoxypyrylium perchlorate as a crystalline solid. [NOTE:
Pyrylium perchlorate salts are known to be explosive]. 2,6-Dimethyl-4-
methoxypyrylium perchlorate is instantly converted into 2,6-dimethyl-4-
methoxypyridine by the action of aqueous ammonium carbonate.

CH3Mgl

20% 1
^'^ 4 -^^
10"4
4 7

2,4,6-Trimethypyridine (8)
The addition of methylmagnesium iodide to dimethylpyrone in a mixture of
ethyl ether and anisole followed by treatment with 20% aqueous HCIO4
generated 2,4,6-trimethylpyrylium perchlorate. Treatment of the pyrylium
salt with ammonia gave 2,4,6-trimethylpyridine.

, /^ ^ \ 70% 4
4 (CH 3 CO) 2 0 + 3 ^ S-
3

2,4,6-Trimethylpyrylium perchlorate (7)

Anhydrous /-butyl alcohol (148 g, 2.0 mol) and acetic anhydride (1020 g,
945 mL, 10.0 mol) are combined and cooled to -10 C. 70% Aqueous
perchloric acid (250 g, 150 mL, 1.75 moles) was rapidly added to the mixture
of/-butyl alcohol and acetic anhydride. When the temperature of the reaction
mixture reaches 40-50 C, crystals of 2,4,6-trimethylpyrylium perchlorate
should begin to form. [NOTE: Pyrylium perchlorate salts are known to be
explosive.] The temperature is allowed to rise to 100 C. The rate of
perchloric acid introduction and the use of the cooling bath are adjusted to
control the temperature of the reaction mixture between 100 and 105 C.
After all the perchloric acid has been added, the cooling bath is removed and
stirring of the mixture is continued. The temperature remains at about 90
for 10 or 15 min and then cools to about 75 C after 30 min. The dark brown
 Chapter 6 Pyridines 345

stirred mixture is cooled to 15 C. The crystalline 2,4,6-trimethylpyrylium

perchlorate, which has precipitated, is collected on a Bchner funnel and is
washed with a 1:1 mixture of acetic acid and ethyl ether and then washed
twice with ethyl ether. Suction is stopped before the crystals are dry. The
product can be air dried to give 195-210 g (50-54%) of yellow crystals.

H3C
CF3SQ3H
4H 3 C 3-)- -
CI
H3C 3 85
54%

2,6-Di-tri-butyl-4-methylpyrylium Triflate (16)

Pivaloyl chloride (24.2 g, 0.2 mol) and tert-hutyi alcohol (3.7 g, 0.05 mol)
were combined and the mixture was heated to 85 C. Triflic acid (15 g, 0.1
mol) was added over a period of 15 min. After the triflic acid addition was
completed the mixture was stirred for an additional 10 min at 85 C. The
light brown reaction mixture was then cooled in an ice bath and poured into
100 mL of cold ethyl ether. The light tan precipitate was collected by
filtration and air dried to give 9.6 g (54%) of pyrylium salt that was used
without further purification in the next step. [Note: The pyrylium
trifluoromethanesulfonate salt does not have the explosive hazard of the
corresponding perchlorate]

NH4OH
EtOH H3C
H 3 C^ "
-60 C H3C
CH3 CH3 95%
CF3S3
16 17

2,6-Di- tert-butyl-4-methylpyridine (17)

A slurry of crude pyrylium salt 16 (10 g, 0.028 mol) in 200 mL of 95%
ethanol was cooled to -60 C and added to concentrated ammonium
hydroxide (100 mL) at -60 C. The yellow reaction mixture was held at -60
C for 30 min., then maintained at -40 for 2 h, during which time the
slurry dissolved. The reaction mixture was then allowed to slowly warm up
to room temperature. The reaction mixture was poured into 500 mL of a 2%
346 Name Reactions in Heterocyclic Chemistry-II

NaOH solution, and the resulting emulsion was extracted with four 100-mL
portions of pentane; the combined extracts were washed with 25 mL of
saturated NaCl, and the pentane was removed on a rotary evaporator. The
residual light yellow oil was purified by column chromatography on a 50
0.5-cm activated alumina column using pentane as the eluent. The pentane
was removed on a rotary evaporator to yield 5.46 g (95%) of a colorless oil
that solidifies on cooling or standing.

6.1.7 References
1 Baeyer, A. Ber. 1910, 43, 2337-2343.
2 (a) Baeyer, A.; Piccard, J. Liebigs Ann. Chem. 1912, 384, 208-224. (b) Baeyer, A.; Piccard,
J.; Gruber, W. Liebigs Ann. Chem. 1915, 407, 332-369.
3 Dilthey, W. J. Prakt. Chem. 1916, 94, 53-76.
4 Lin, S. S.; Li, Y.; Wang, X. Chin. Chem. Lett. 2002, 13, 605-606.
5 Simalty-Siemiatycki, M. Bull. Soc. Chim. Fr. 1965, 7, 1944-1950.
6 Huang, X. Q.; Li, H. X.; Wang, J. X.; Jia, X. F. Chin. Chem. Lett. 2005,16, 607-608.
7 (a) Balaban, . .; Nenitzescu, D. Tetrahedron Lett. 1960, /, 7-10. (b) Balaban, . .;
Nenitzescu, D Org. Synth., Coll. Voi 5, 1973, 1106-1110. () Balaban, . .; Nenitzescu,
D. Org. Synth., Coll. Voi 5,1973, 1114-1116.
8 Anderson, A. G.; Stang, P. J. J. Org. Chem. 1976, 41, 3034-3036.
9 Pedersen, C ; Harrit, N.; Buchardt, O. Acta. Chem. Scand 1970, 24, 3435-3443.
10 Uncuta, C ; Cproiu, M. .; Cmpeanu, V.; Petride, A.; Danila, M. G.; Plveti, M.; Balaban,
A. T. Tetrahedron 1998, 54, 94-964.
11 Katritzky, A. R. Tetrahedron 1980, 36, 679-699.
12 Said, S. A; Fiksdahl, A. Tetrahedron: Asymmetry 2001,12, 1947-1951.
13 Hies, M.; Banciu, M. D.; Hies, M. A.; Scozzafava, A.; Caproiu, M. .; Supuran, . . J. Med.
Chem. 2002,45,504-510.
14 Golikov, A. G.; Reshetov, P. V.; Kriven'ko, A. P.; Safonova, A. A. Pharm. Chem. J. 2005,
39, 473^75.
15 Blask, G.; Cordell, G. A. J. Heterocyclic Chem. 1989,26, 1601-1603.
16 Cao, R.; Peng, W.; Wang, Z.; Xu, A. Curr. Med. Chem. 2007,14, 479-500.
17 (a) Luk'yanenko, V. I.; Komissarov, I. V.; Larina, T. F.; Brainina, M. E.; Komissarov, S. I.;
Dulenko, V. I. U.S.S. R., 753093, 30 Nov. 1982. (b) Dulenko, V. I.; Luk'yanenko, V. I.;
Kibal'nii, A. V.; Malienko, A. A.; Nikolyukin, Yu. A. Khimiya Geterotsiklicheskikh
Soedinenii 1985, 3, 363-366.
18 [R] Balaban, . .; Dinculescu, A.; Dorofeenko, G. N.; Fischer, G. W.; Koblik, A. V.;
Mezheritskii, V. V.; Schroth, W. Pyrylium Salts: Syntheses, Reactions, and Physical
Properties. Academic Press: New York, 1982.
 Chapter 6 Pyridines 347

6.2 Katritzky Pyridine Synthesis

David A. Conlon

6.2.1 Description

R2

i
R2 N"N

NH4OAc I^SI
AcOH, reflux - ' . , . ^ 3
k
R3 "R
N
1 2
3

The Katritzky pyridine synthesis is similar to the Krhnke pyridine synthesis,

because both involve the Michael addition of -substituted ketones 2 to ,-
unsaturated carbonyl compounds 1 in the presence of ammonium acetate,
followed by the loss of the -substituent to generate the pyridine 3. The a-
substituent on the ketone in the Krhnke pyridine synthesis is typically a
pyridinium salt. The -substituent on the ketone in the Katritzky pyridine
synthesis is the benzotriazolyl moiety.

6.2.2 Historical Perspective

In 1999, Katritzky reported a novel [3+2+1] synthesis of 2,4,6-trisubstituted

pyridine derivatives that used the Michael addition of ct-benzotriazolyl
ketones to ,-unsaturated carbonyl compounds.1 This reaction resembles the
Krhnke pyridine synthesis and is an extension of Katritzky's earlier studies
with benzotriazolyl derivatives that provided access to pyridones, 2-
thiopyridones, 5-alkyl-2,4-diphenylpyridines and 2-aminopyridines.2-5 This
approach is attractive as both components are readily synthesized or
commercially available. The availability of these starting materials allows
for an efficient access to structurally diverse 2,4,6-triaryl pyridines when
combined with ammonium acetate in acetic acid at reflux. In addition, it is
possible to access fused 2,3,4,6-tetrasubstituted pyridines from the requisite
fused bicyclic ketone starting material. The preparation of the pyridine ring
via benzotriazole methodology has resulted in improved yields for many
compounds and the opportunity to synthesize molecules with a substitution
pattern that would be difficult to prepare by other methods.
348 Name Reactions in Heterocyclic Chemistry-II

6.2.3 Mechanism

The first step in the Katritzky pyridine synthesis is believed to be the Michael
addition of a ct-benzotriazolyl ketone 2 to the ,-unsaturated carbonyl
compound 1 to generate a 1,5-diketone derivative 4. The 1,5-diketone is not
typically isolated although its formation has been confirmed via preparation
under typical Michael reaction conditions in the absence of ammonium
acetate. 1,5-Diketone derivatives are known intermediates in the synthesis of
pyridines and undergo condensation with ammonia or its equivalent followed
by cyclization to form dihydropyridine 5. Elimination of benzotriazole
completes the aromatization process and generates the pyridine ring.

N NH4 Ac
\L/
AcOH,
O'
reflux

T
N-N

6.2.4 Variations and Improvements

Fused 2,3,4,6-tetrasubstituted pyridines 7, 9 and 10 can be prepared by two

complimentary procedures from fused bicyclic ketones.1 In the first synthetic
approach it is the ,-unsaturated ketone 6 that is part of the fused ring
system.

R^ N- \ Rz
NH4OAc^
AcOH, reflux
R3 ''
 Chapter 6 Pyridines 349

In the second approach, the a-benzotriazolyl ketone 8 coupling

partner is part of the fused ring system. This approach was demonstrated for
the preparation of the dihydrobenzoquinoline ring system (9, n = 2) and the
indenopyridine ring (10, n = 1).

NH4OAC
AcOH, reflux
n = 1 or 2
9 or 10

In 1997 Katritzky reported that the Michael addition of a-

benzotriazole nitrile 12 to ,-unsaturated ketones 11 in the presence of a
secondary amine generated 2-aminopyridines, 13.4 This innovative [3+3]
strategy provides an alternative to the typical method of preparing 2-
aminopyridines by reacting 2-halopyridines with aliphatic amines. Following
the initial Michael addition reaction, nucleophilic attack by the secondary
amine on the nitrile moiety initiates the cyclization. This is followed by loss
of benzotriazole and water to generate the 2-aminopyridine 13.

N-N
2D3
NHR^R
2D3
NR^R
N
12

6.2.5 Synthetic Utility

The pyridine moiety is found in many biologically active compounds that

have demonstrated activity in a wide range of pharmaceutical applications.
Pyridines are also important intermediates for the construction of a diverse
array of novel and natural molecules with pharmacologically important
activity.
2-Amino-4,6-diarylpyridines have been reported to exhibit activity as
estrogen receptors.5 The synthesis of 16 uses a variation of the methodology
developed by Katritzky. Addition of a-benzotriazole nitrile 12 to the enone
14 in the presence of secondary amine 15 resulted in the formation of 16.
350 Name Reactions in Heterocyclic Chemistry-II

H,4
N-N N
CH 3 15

1., reflux
N 2. AcOH, 60 C
12

6.2.6 Experimental

N"N R2

NH4QAc
AcOH, reflux
R3 'N' R3
3

Synthesis of 2,4,6-Triarylpyridines 3
A solution the a-(benzotriazol-l-yl) ketone 2, chalcone 1 and ammonium
acetate in glacial acetic acid was refluxed for 30 h. Addition of ice-water
resulted in the precipitation of pyridine 3 which was purified by column
chromatography or by recrystallization from hexanes.

6.2.7 References
1. Katritzky, A. R.; Abdel-Fattah, A. A. A.; Tymoshenko, D. O.; Essawy, S. A. Synthesis 1999,
2114-2118.
2. Katritzky, A. R.; Mazurkiewicz, R.; Stevens, V.; Goordeev, M. F. J. Org. Chem. 1994, 59,
2740-2742.
3. Katritzky, A. R.; Sheherbakove, I. V. J. Heterocyclic Chem. 1996, 33, 2031-2036.
4. Katritzky, A. R.; Belyakov, S. A.; Sorochinsky, A. E. Henderson, S. A. J. Org. Chem. 1997,
62,6210-6214.
5. [R] Katritzky, A R; Rachwal, S. Chem. Rev. 2010,110, 1564-1610.
6. (a) Henke, B. R. ; Drewry, D. H.; Jones, S. A.; Stewart, E. L; Weaver, S. L.; Wiethe, R. W.
Bioorg. Med. Chem. Lett. 2001, / / , 1939-1942. (b) Drewry, D. H.; Henke, B. R. US Pat.
7, 276,523 Oct. 2, 2007.