Metal-Free Synthesis of 2,4,6-Trisubstituted Pyridines via Iodine-Initiated Reaction of Methyl Aryl Ketones with Amines under Neat Heating

Article abstract of DOI:10.1055/s-0036-1588380

A neat heating protocol has been developed for metal-free synthesis of various 2,4,6-trisubstituted pyridines via iodine-initiated (in situ generated HI-catalyzed) condensation of methyl aryl ketones with amines and the following cyclization-aerobic oxidation. Large-scale synthesis and mechanistic investigation were also performed.

Full text of DOI:10.1055/s-0036-1588380

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–E
paper
A
H. Xu et al.
Paper
Synthesis
Metal-Free Synthesis of 2,4,6-Trisubstituted Pyridines via Iodine-
Initiated Reaction of Methyl Aryl Ketones with Amines under Neat
Heating
Hui Xu
I2
Ji-Chao Zeng
Fang-Jian Wang
Ze Zhang*
(1.0 mol%)
R
O
cat. [HI]
+
R
NH2
Ar
neat, 140 °C, 10 h
Ar
N
Ar
School of Biological and Chemical Engineering,
Anhui Polytechnic University, Wuhu 241000,
P. R. of China
• Metal-free
• Readily available starting materials
• Easy workup • Feasible for large-scale synthesis
18 examples
52–94% yield
zhangze@ustc.edu.cn
Received: 06.10.2016
Accepted after revision: 29.11.2016
Published online: 15.12.2016
acids with ketones,11 TfOH- or Cu(OTf)2-catalyzed cycliza-
tion of amines with ketones,12,13 and photoredox catalysis
of aryl ketones with benzyl amines.14
DOI: 10.1055/s-0036-1588380; Art ID: ss-2016-h0701-op
During our investigation on iodine-mediated cascade
condensation-cyclization of aryl methyl ketones with ani-
lines for straightforward synthesis of 1,2,4-triarylpyrroles,15
Abstract A neat heating protocol has been developed for metal-free
synthesis of various 2,4,6-trisubstituted pyridines via iodine-initiated (in
situ generated HI-catalyzed) condensation of methyl aryl ketones with
amines and the following cyclization-aerobic oxidation. Large-scale syn-
thesis and mechanistic investigation were also performed.
Table 1 Optimization of the Reaction Conditions for the Synthesis of
2,4,6-Triphenylpyridine (3a)a
Key words 2,4,6-trisubstituted pyridine, molecular iodine, metal-
free, neat heating, methyl aryl ketone
O
Multi-substituted pyridines, especially 2,4,6-trisubsti-
tuted pyridines (Kröhnke pyridines),1 have been broadly
applied for chemosensors,2 asymmetric catalysis,3 and as
photosensitizers.4 Such moieties are also very important
building blocks in supramolecular chemistry due to their π-
stacking ability along with directional H-bonding capacity.5
In addition, the outstanding thermal stabilities of these
pyridines have attracted growing interests for their use as
monomeric building blocks in thin films and organometal-
lic polymers.6 Hence their synthesis has drawn a great deal
of attention. Since Kröhnke’s original report on the synthe-
sis of 2,4,6-trisubstituted pyridines, there has been a pleth-
ora of research targeting their synthesis, and enormous
number of preparative approaches have been developed,
most of which are summarized by Katritzky.7 In contrast,
the most commonly used approaches to 2,4,6-trisubstitut-
ed pyridines involve cyclocondensation reaction of ace-
tophenones and benzaldehydes with ammonium acetate;
and various new catalysts or conditions have been report-
ed.8 Recently, some new methods were developed by em-
ploying other starting materials, including solvent-free
heating of acetophenone oximes with aldehydes or ace-
tophenones with benzyl halides,9,10 I2-mediated process
based on catabolism and reconstruction behaviors of amino
I2
NH2
+
N
1a
2a
3a
Entry
Ratio (1a/2a/I2)
Solvent
Temp (°C)
Yield (%)b
1
2
2:2:1
PhCl
PhCl
PhCl
PhCl
PhCl
neat
neat
neat
neat
neat
neat
140
140
140
140
140
140
120
100
140
140
140
89
90
90
90
10
94
63
47
93
93
65
2:2:0.2
2:2:0.1
2:2:0.01
2:2:0
3
4
5
6
2:2:0.01
2:2:0.01
2:2:0.01
2:1.5:0.01
2:1:0.01
2:1:0.01
7
8
9
10
11c
a A mixture of acetophenone (1a; 2 mmol), benzylamine (2a), I2, and sol-
vent (entries 1–5, 5 mL) was stirred for 10 h in a 25 mL sealed Schlenk tube
full of air and opened to air for further 1 h stirring.
b Isolated yield based on 1a.
c Reaction was carried out open to air.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

B
H. Xu et al.
Paper
Synthesis
it was unexpectedly found that 2,4,6-triphenylpyridine but
not 1,2,4-triphenylpyrrole was obtained when benzyl-
amine (2a) was employed instead of anilines to react with
acetophenone (1a) in PhCl by heating at 140 °C for 10 hours
in the presence of 50 mol% iodine (Table 1, entry 1). To the
best of our knowledge, this iodine-promoted transforma-
tion is a new alternative for the construction of 2,4,6-tri-
substitutted pyridine. In view of green synthesis, we want-
ed to optimize the reaction with more efficient and milder
conditions to further increase the yield and simplify the
workup (Table 1).
Since usage of excess of iodine often leads to tedious ex-
traction and washing operation with aqueous sodium thio-
sulfate, we therefore attempted to reduce the amount of io-
dine (Table 1, entries 2–4). To our delight, decreasing the
usage of iodine has no significant effect on the reaction effi-
ciency, and even only 1.0 mol% iodine can still afford 90%
yield. However, only minor amount of the product was gen-
erated in the absence of I2 (entry 5). To avoid the use of high
boiling PhCl as solvent, this reaction was performed direct-
ly under neat heating. Surprisingly and gratifyingly, this
protocol exhibited obviously higher efficiency (entry 6), in
which acetophenone (1a) was completely consumed. In
contrast, there was more or less residual acetophenone (1a)
left in all experiments with PhCl as solvent. When the reac-
tion temperature was lowered with fixed molar ratio of
acetophenone (1a), benzylamine (2a), and I2 at 2:2:0.01 un-
der neat heating for 10 hours, large amounts of starting ma-
terials remained, thus decreasing the yield significantly
(entries 7, 8). Based on the fact that the stoichiometric ratio
of acetophenone (1a) to benzylamine (2a) is 2:1, we further
attempted to reduce the usage amount of benzylamine (2a)
R
O
I2 (1.0 mol%)
neat, 140 °C
+
R
NH2
Ar
Ar
N
3
Ar
1
2
N
N
N
N
O
O
Ph
Ph
3a, 93%
3b, 94%
3c, 81%
3d, 76%
Cl
Cl
N
N
N
N
Cl
Cl
Br
Br
F
F
3e, 88%
3f, 77%
3g, 76%
3h, 80%
Br
Br
O
Cl
Cl
N
N
3j, 72%
O
N
N
O
O
Cl
Cl
3l, 90%
3k, 71%
3i, 77%
Cl
O
O
N
N
N
N
N
N
S
S
3m, 68%
3n, 92%
3p, 83%
3o, 57%
3q, 52%
3r, 73%
Scheme 1 I2-initiated reaction of methyl aryl ketones 1 with amines 2 for the synthesis of 2,4,6-trisubstituted pyridines (3) under neat heating. Reac-
tion conditions: a mixture containing 1 (2.0 mmol), 2 (1.0 mmol), and I2 (0.01 mmol) was stirred in a 25 mL sealed Schlenk tube full of air under neat
heating (140 °C) for 10 h. Isolated yields after short flash column chromatography are shown.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

C
H. Xu et al.
Paper
Synthesis
up to 0.5 equivalent. To our delight, the reaction still pro-
ceeded completely with no decrease in the yield (entries 9,
10). Therefore, the best reaction condition for this iodine-
promoted transformation of acetophenone (1a) and benzyl-
amine (2a) to 2,4,6-triphenylpyridine is neat heating at 140
°C with a 2:1:0.01 molar ratio of acetophenone (1a), ben-
zylamine (2a), and I2 (entry 10). It is worth mentioning that
a reduced yield of 65% was achieved when the reaction was
carried out opened to air (entry 11). This result may be as-
cribed to the possible sublimation of some iodine, and it
can be further understood from the possible reaction
mechanism in which some in situ generated ammonia may
escape (see Scheme 3, vide infra). In sealed Schlenk tube,
these problems were avoided, and the filled air accompa-
nied with further stirring in open air ensured complete aro-
matization of the in situ generated 1,4-dihydropyridine
into the final product.
Therefore, a plausible reaction mechanism is proposed as
shown in Scheme 3. First, I2-initiated oxidation of benzyl-
amine provides the corresponding imine and afterward
benzaldehyde via hydrolysis. The in situ generated HI fur-
ther transforms benzylamine into its ammonium iodide,
which is oxidized to imine via dehydration in the presence
of oxygen. Benzaldehyde and NH3 are formed through hy-
drolysis of the imine, and HI gets regenerated for next cy-
cles. Then the reaction may undergo the following steps for
the formation of the product, in which HI may still be in-
volved in catalysis: aldol condensation of acetophenone
(1a) with the in situ generated benzaldehyde from benzyl-
amine (2a) to afford chalcone (4); afterward Michael addi-
tion to accomplish the 1,5-diketone 5; further cyclization
with in situ generated NH3 to form the precursor 1,4-dihy-
dropyridine 6, and aromatization to the final product 3a.
This mechanism is somewhat similar to what have been re-
ported,8b,16 and is further confirmed by several other con-
trolled experiments as shown in Scheme 2, B–D. A stirred
mixture containing benzylamine (2a), acetophenone (1a; 5
mol%), and I2 (1 mol%) was heated at 140 °C for 2 hours, af-
fording majority of benzaldehyde (>90% yield), and a trace
of product 3a; intermediates 4–6 were also detected
(Scheme 2, B). On the other hand, a three-component reac-
tion of PhCH2NH2, PhCHO, and PhCOMe (1:1:2) under the
standard condition afforded 2,4,6-triphenylpyridine in
comparable yield (87%), but some PhCHO remained and mi-
nor side products were generated (Scheme 2, C). Further-
more, a comparative reaction of PhCHO (1.0 mmol),
PhCOMe (2.0 mmol), NH4I (2.5 mmol), and HI (5.0 mol%)
was performed by neat heating at 140 °C for 3 hours
(Scheme 2, D). As expected, the corresponding 2,4,6-tri-
phenylpyridine was obtained in 90% yield, and the forma-
tion of the aldol/chalcone adduct and the Michael adduct
1,5-diketone was also detected during the reaction process.
Then the optimized reaction condition was applied to
various methyl aryl ketones and amines, and a series of
2,4,6-trisubstituted pyridines were obtained in moderate to
good yields. The results are summarized as outlined in
Scheme 1.
First, various methyl aryl ketones were employed to re-
act with benzylamine, including substituted acetophenones
3a–k and heterocyclic aryl ketones 3l, m. Then some other
substituted benzylamines 3n–p, 2-furanmethylamine (3q),
and long-chain aliphatic amine 3r were chosen to react
with acetophenone. In these cases, substrates bearing ei-
ther electron-donating or electron-withdrawing group all
can afford the corresponding products efficiently, showing
no obvious difference from substituent effect. Thus, this
protocol exhibited a broad scope of substrates and high
substituent compatibility. The reaction was performed un-
der neat heating and just a trace of iodine was involved, and
the resulting reaction mixture was directly subjected to a
very short column chromatography, accomplishing facile
isolation of the desired products without extractive work-
up. Furthermore, a large scale synthesis of 3a has also been
attempted under the standard condition. A mixture of ace-
tophenone (1a; 40 mmol), benzylamine (2a; 20 mmol), and
iodine (0.2 mmol) was stirred for 24 hours in a 25 mL
sealed Schlenk tube under constant bubbling of O2. Then
cold water containing EtOH (10 mL, v/v = 1:1) was added to
the cooled reaction mixture under stirring, and the desired
product 3a was simply obtained just by filtration, washing,
and desiccation (82% yield, >96% purity).
I2 (1 mol%)
(A) PhCH2NH2
PhCHO
95%
neat
140 °C, 2 h
under air
--------------------------------------------------------------------------
1a (5 mol%)
I2 (1 mol%)
(B) PhCH2NH2
PhCHO + 3a + 4 + 5 + 6
neat
>90%
trace
140 °C, 2 h
under air
--------------------------------------------------------------------------
standard
conditions
(C) PhCH2NH2 + PhCHO + 1a
3a
87%
During the reaction, we found that the deep purple col-
or of iodine disappeared rapidly, which implies that herein
employed I2 was consumed and acted as initiator but not as
catalyst. On the other hand, controlled experiment showed
that benzylamine (2a) was efficiently transferred into benz-
aldehyde and ammonia in the presence of a catalytic
amount of iodine by neat heating under air (Scheme 2, A).
--------------------------------------------------------------------------
NH4I (2.5 equiv)
HI (5 mol%)
3a
(D) PhCHO + 1a
neat
140 °C, 3 h
under air
90%
Scheme 2 Controlled experiments
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

D
H. Xu et al.
Paper
Synthesis
2,4,6-Trisubstituted Pyridines; General Procedure
Initiation:
I2
H2O
A mixture of methyl aryl ketone 1 (2.0 mmol), amine 2 (1.0 mmol),
and molecular I2 (2.5 mg, 0.01 mmol) was stirred at 140 °C for 10 h in
a 25 mL sealed Schlenk tube, followed by further 1 h stirring in open
air. After completion, the reaction mixture was directly subjected to a
short silica gel column chromatography with PE–EtOAc as the eluent,
affording the desired product 3 as a white solid.
PhCH2NH2
PhCH=NH
PhCH=O
_
HI
2a
Catalysis:
PhCH2NH2
HI
Ph
N
3a
Details of all the products are given in the Supporting Information;
analytical and spectral data for some selected new compounds are
given below.
Ph
Ph
PhCH2NH3
O2
I
heating
under air
Aromatization
2,6-Bis(3-chlorophenyl)-4-phenylpyridine (3g)
Ph
White solid; yield: 285.1 mg (76%); mp 151–153 °C.
1H NMR (400 MHz, CDCl3): δ = 8.18–8.15 (m, 2 H), 8.05 (dt, J = 6.9, 1.9
Hz, 2 H), 7.86 (s, 2 H), 7.74–7.70 (m, 2 H), 7.56–7.40 (m, 7 H).
13C NMR (100 MHz, CDCl3): δ = 156.19 (2 C), 150.65, 141.10 (2 C),
138.50, 134.87 (2 C), 130.02 (2 C), 129.30, 129.24 (2 C), 129.20 (2 C),
127.26 (2 C), 127.19 (2 C), 125.23 (2 C), 117.68 (2 C).
PhCH=NH
H2O
Ph
N
H
Ph
6
PhCH=O
NH3
HRMS (ESI-TOF): m/z calcd for C23H16Cl2N [M + H]+: 376.0660; found:
376.0667.
PhCOMe 1a
Aldol
Ph
condensation
2,6-Bis(3-bromophenyl)-4-phenylpyridine (3i)
1a
O
White solid; yield: 356.4 mg (77%); mp 172–174 °C.
Michael
addition
Ph
Ph
O O
Ph
Ph
1H NMR (500 MHz, CDCl3): δ = 8.33 (s, 2 H), 8.12 (d, J = 7.8 Hz, 2 H),
7.86 (s, 2 H), 7.76–7.72 (m, 2 H), 7.60 (d, J = 7.9 Hz, 2 H), 7.56 (t, J = 7.3
Hz, 2 H), 7.53–7.49 (m, 1 H), 7.40 (t, J = 7.9 Hz, 2 H).
5
4
Scheme 3 Proposed reaction mechanism
13C NMR (125 MHz, CDCl3): δ = 156.09 (2 C), 150.63, 141.36 (2 C),
138.48, 132.10 (2 C), 130.27 (2 C), 130.16 (2 C), 129.28, 129.22 (2 C),
127.17 (2 C), 125.72 (2 C), 123.05 (2 C), 117.66 (2 C).
HRMS (ESI-TOF): m/z calcd for C23H16Br2N [M + H]+: 463.9649; found:
463.9656.
In summary, a simple and efficient method has been
successfully developed for the metal-free synthesis of vari-
ous 2,4,6-trisubstituted pyridines starting from methyl aryl
ketones and amines via cascade condensation-cyclization-
aromatization process. The transformation was accom-
plished in moderate to excellent yield in the presence of
catalytic (1.0 mol%) molecular iodine acting as an initiator
to generate HI in situ as the actual catalyst, followed by aer-
obic oxidation under neat heating conditions. This expedi-
tious protocol exhibits several advantages such as employ-
ment of readily accessible and easily handled starting mate-
rials, no use of any metal catalyst or additional oxidant,
broad scope of substrates and high functional group com-
patibility, great potential for large scale synthesis, and no
tedious extractive workup. These merits make the present
method a concise and low-cost access to construct 2,4,6-
trisubstituted pyridines.
2,6-Bis(3,4-dichlorophenyl)-4-phenylpyridine (3j)
White solid; yield: 319.0 mg (72%); mp 194–196 °C.
1H NMR (500 MHz, CDCl3): δ = 8.26 (d, J = 1.8 Hz, 2 H), 8.00 (dd, J = 8.3,
1.8 Hz, 2 H), 7.83 (s, 2 H), 7.72 (d, J = 7.1 Hz, 2 H), 7.60–7.50 (m, 5 H).
13C NMR (125 MHz, CDCl3): δ = 155.23 (2 C), 150.94, 139.03 (2 C),
138.22, 133.50 (2 C), 133.12 (2 C), 130.73 (2 C), 129.46, 129.29 (2 C),
128.92 (2 C), 127.15 (2 C), 126.18 (2 C), 117.54 (2 C).
HRMS (ESI-TOF): m/z calcd for C23H14Cl4N [M + H]+: 443.9880; found:
443.9892.
4-Pentyl-2,6-diphenylpyridine (3r)
Colorless oil; yield: 219.8 mg (73%).
1H NMR (500 MHz, CDCl3): δ = 8.19–8.15 (m, 4 H), 7.54 (s, 2 H), 7.51
(t, J = 7.5 Hz, 4 H), 7.44 (t, J = 7.3 Hz, 2 H), 2.77–2.72 (m, 2 H), 1.79–
1.72 (m, 2 H), 1.44–1.37 (m, 4 H), 0.94 (t, J = 7.1 Hz, 3 H).
NMR spectra were recorded on a Bruker AV400 or AV500 NMR instru-
ment in CDCl3. All melting points were determined on a XT-4 binocu-
lar microscope (Beijing Tech Instrument Co., China) and are not cor-
rected. High-resolution mass spectra (HRMS) were recorded on a
Bruker MicroTOF-QII mass instrument (ESI). TLC was performed on
precoated glass plates and visualized with UV light at 254 nm. Flash
column chromatography was performed on silica gel with PE–EtOAc
as the eluent.
13C NMR (125 MHz, CDCl3): δ = 156.91 (2 C), 153.17, 139.82 (2 C),
128.81 (2 C), 128.63 (4 C), 127.09 (4 C), 119.09 (2 C), 35.78, 31.50,
30.28, 22.53, 14.00.
HRMS (ESI-TOF): m/z calcd for C22H24N [M + H]+: 302.1909; found:
302.1901.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E

E
H. Xu et al.
Paper
Synthesis
Acknowledgment
(6) Lohmeijer, B. G. G.; Schubert, U. S. J. Polym. Sci., A: Polym. Chem.
2003, 41, 1413.
We are grateful for the financial support from National Natural Sci-
ence Foundation of China (21242013) and Key Projects for Outstand-
ing Young Talents in Colleges and Universities of Anhui Province (No.
gxyqZD2016121).
(7) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Tymoshenko, D. O.;
Essawy, S. A. Synthesis 1999, 2114.
(8) For some selected examples in recent years, see: (a) Moosavi-
Zare, A. R.; Zolfigol, M. A.; Rezanejad, Z. Can. J. Chem. 2016, 94,
626. (b) Tabrizian, E.; Amoozadeh, A.; Rahmani, S.; Imanifar, E.;
Azhari, S.; Malmir, M. Chin. Chem. Lett. 2015, 26, 1278.
(c) Zarnegar, Z.; Safari, J.; Borjian-borujeni, M. Chem. Heterocycl.
Compd. 2015, 50, 1683. (d) Maleki, B. Org. Prep. Proced. Int. 2015,
47, 173. (e) Alinezhad, H.; Tajbakhsh, M.; Ghobadi, N. Synth.
Commun. 2015, 45, 1964. (f) Moosavi-Zare, A. R.; Zolfigol, M. A.;
Farahmand, S.; Zare, A.; Pourali, A. R. Synlett 2014, 25, 193.
(9) Mahernia, S.; Mahdavi, M.; Adib, M. Synlett 2014, 25, 1299.
(10) Adib, M.; Ayashi, N.; Mirzaei, P. Synlett 2016, 27, 417.
(11) Xiang, J.-C.; Wang, M.; Cheng, Y.; Wu, A.-X. Org. Lett. 2016, 18,
24.
(12) Zhang, X.; Wang, Z.-Q.; Xu, K.; Feng, Y.-Q.; Zhao, W.; Xu, X.-F.;
Yan, Y.-L.; Yi, W. Green Chem. 2016, 18, 2313.
(13) Huang, H.-W.; Ji, X.-C.; Wu, W.-Q.; Huang, L.-B.; Jian, H.-F. J. Org.
Chem. 2013, 78, 3774.
(14) Rohokale, R. S.; Koenig, B.; Dhavale, D. D. J. Org. Chem. 2016, 81,
7121.
(15) Xu, H.; Wang, F.-J.; Xin, M.; Zhang, Z. Eur. J. Org. Chem. 2016,
925.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588380.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
References
(1) Kröhnke, F. Synthesis 1976, 1.
(2) Fang, A. G.; Mello, J. V.; Finney, N. S. Tetrahedron 2004, 60,
11075.
(3) Chelucci, G.; Thummel, R. P. Chem. Rev. 2002, 102, 3129.
(4) Islam, A.; Sugihara, H.; Arakawa, H. J. Photochem. Photobiol., A
2003, 158, 131.
(5) (a) Newkome, G. R.; Wang, P. C.; Moorefield, N.; Cho, T. J.;
Mohapatra, P. P.; Li, S.; Hwang, S. H.; Lukoyanova, O.;
Echegoyen, L.; Palagallo, J. A.; Iancu, V.; Hla, S. W. Science 2006,
312, 1782. (b) Constable, E. C.; Dunphy, E. L.; Housecroft, C. E.;
Kylberg, W.; Neuberger, M.; Schaffner, S.; Schofield, E. R.; Smith,
C. B. Chem. Eur. J. 2006, 12, 4600. (c) Wang, P.; Moorefield, C. N.;
Newkome, G. R. Angew. Chem. Int. Ed. 2005, 44, 1679.
(16) Amoros-Marin, L.; Carlin, R. B. J. Am. Chem. Soc. 1959, 81, 733.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–E