Thioacetamide as an ammonium source for multicomponent synthesis of pyridines from aldehydes and electron-deficient enamines or alkynes

Article abstract of DOI:10.1055/s-0034-1378635

A generally applicable multicomponent method has been established for the synthesis of pyridines. In the reactions, thioacetamide is used as a cheap and efficient ammonium source in a multicomponent reaction with aldehydes and electron-deficient enamines

Full text of DOI:10.1055/s-0034-1378635

3256▌
PAPER
paper
Thioacetamide as an Ammonium Source for Multicomponent Synthesis of
Pyridines from Aldehydes and Electron-Deficient Enamines or Alkynes
Multicomponent Synthesis of Pyridines
Jie-Ping Wan,*a Youyi Zhou,a Kezhi Jiang,b Hongyan Yea
a
Key Laboratory of Functional Small Organic Molecule, Ministry of Education, and College of Chemistry and Chemical Engineering, Jiangxi
Normal University, Nanchang 330022, P. R. of China
b
Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, Hangzhou
310012, P. R. of China
Fax +86(791)88120380; E-mail: wanjieping@jxnu.edu.cn
Received: 13.06.2014; Accepted after revision: 17.07.2014
tion patterns have also been developed to provide pyridine
Abstract: A generally applicable multicomponent method has been
derivatives with an extended range of structural diversity.8
established for the synthesis of pyridines. In the reactions, thioacet-
amide is used as a cheap and efficient ammonium source in a mul-
ticomponent reaction with aldehydes and electron-deficient
enamines or alkynes to give 3,4,5-trisubstituted pyridines in moder-
ate to good yields and with a high product diversity.
The main advantage of conventional methods, such as the
Hantzsch and similar reactions,9 is the ready availability
of the starting materials. However, the requirement for an
additional oxidation operation and the presence of 1,4-di-
hydropyridine byproducts have hindered the widespread
application of these methods. In this context, the design of
simpler routes that combine the advantages of readily
available starting materials, one-pot operation, and high
selectivity to give target pyridines is highly desirable. In
continuation of our longstanding interest in exploring
enaminone-based multicomponent reactions (MCRs) for
synthesis of structurally diverse heterocycles,10 we dis-
covered an unexpected multicomponent protocol in which
thioacetamide (ethanethioamide) acts as an ammonium
source to permit direct one-step synthesis of pyridines
from enaminones and aldehydes in the presence of ceri-
um(IV) ammonium nitrate (CAN).11 To the best of our
knowledge, this is the first example of the use of thioacet-
amide as a source of ammonium for multicomponent pyr-
idine synthesis.
Key words: multicomponent reactions, ring closure, pyridines, al-
dehydes, enamines, alkynes
The pyridine ring is a fundamental fragment of numerous
organic molecules. This moiety is widely present as a cen-
tral structure in many natural products, pharmaceuticals,
pesticides, and functional materials.1 As the most widely
available heterocyclic compounds, pyridines have a rich
and versatile synthetic utility. For example, pyridines are
frequently used as alkali catalysts or additives in many or-
ganic reactions, and they are also important ligands in co-
ordination chemistry.2 More notably, as easily available
starting materials, pyridines have been used as central
building blocks in syntheses of numerous nitrogen-con-
taining organic molecules.3 As a result, the synthesis of
pyridines has received a great deal of attention during re-
cent decades.
Initially, we surmised that a three-component reaction of
enaminone 1a, 4-chlorobenzaldehyde (2a), and thioacet-
amide (3a) might give the 1,3-thiazine 4a by making use
of both the nucleophilic nitrogen and sulfur sites in thio-
acetamide (3a). Unexpectedly, however, when we per-
formed the reaction in dimethyl sulfoxide in the presence
of CAN at 90 °C, we did not obtain the expected product;
instead, pyridine 5a was the only isolable product
(Scheme 1). This unprecedented result inspired us to in-
vestigate this reaction in more detail, not only for its po-
tential use in the synthesis of pyridines, but also because
of the significance of discovering alternative nitrogen
sources with novel functions for the construction of nitro-
gen-containing molecules.12
The Hantzsch reaction, which involves the condensation
and stepwise oxidation of aldehydes, 1,3-dicarbonyl
methylene compounds, and ammonia, was one of the ear-
liest methods used for the synthesis of pyridines.4 Subse-
quently, a variety of other methods were devised to
increase the synthetic efficiency and diversity of pyridine
products. Typical examples of these methods include tran-
sition-metal-catalyzed [2+2+2] cycloaddition reactions
involving two alkynes and one nitrile;5 condensation reac-
tions of enaminones, 1,3-dicarbonyl compounds, and am-
monium ions;6 and the Kröhnke two-step procedure using
N-phenylacylpyridinium salts, enones, and ammonium
ions.7 In the wake of the rapid advance in new synthetic
strategies, various novel protocols involving transforma-
Guided by our primary result (Table 1, entry 1), we per-
formed a control experiment to confirm that thioacet-
amide (3a) was indeed the source of ammonium. In the
absence of thioacetamide (3a) (entry 2), no target product
5a was obtained, clearly suggesting that 3a was the source
of ammonium for the formation of 5a. Subsequently, we
SYNTHESIS 2014, 46, 3256–3262
Advanced online publication: 20.08.2014
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7
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1
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DOI: 10.1055/s-0034-1378635; Art ID: ss-2014-h0367-op
© Georg Thieme Verlag Stuttgart · New York

PAPER
Multicomponent Synthesis of Pyridines
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Table 1 Optimization of Reaction Conditionsa
Cl
Entry
Catalyst
Solvent
T (°C)
Yieldb (%)
58
O
1
2
CAN
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
120
O
Ph
Ph
N
Me
c
120
–
N
1a
S
4a
Me
3
FeCl3
AlCl3
TsOH
morpholine
CAN
CAN
CAN
CAN
CAN
CAN
CAN
CAN
CAN
CAN
CeCl3
120
15
Cl
CAN
DMSO, 90 °C
+
4
120
11
Cl
NH2
5
120
21
S
3a
CHO
2a
6
120
trace
55
O
O
7d
8e
9
120
Ph
Ph
120
24
N
5a
110
67
Scheme 1 Unexpected synthesis of pyridines
10
11
12
13
14
15
16
17
100
27
110
21
systematically screened various reaction parameters, in-
cluding the catalyst, the solvent, and the temperature. Var-
ious Lewis and Brønsted acids and basic morpholine all
displayed poor activities in catalyzing the reaction (entries
3–6). The uniquely catalytic efficiency of CAN in this re-
action might be attributed to the polyfunctional behavior
of CAN as a Lewis acid, a Brønsted acid, and an oxidant.11
Having established that CAN is the optimal catalyst, we
studied the effects of various amounts of CAN and found
that a 50 mol% loading was optimal (entries 7 and 8). A
subsequent study on the effects of the reaction tempera-
ture showed that a temperature at 110 °C gave a slightly
better yield of pyridine 5a (entry 9); further lowering of
the temperature to 100 °C, however, led to a sharp de-
crease in the yield (entry 10). Finally, studies with N,N-di-
methylformamide, benzyl alcohol, 1,4-dioxane, toluene,
acetonitrile, or ethanol as the solvent confirmed that di-
methyl sulfoxide is the best solvent for the reaction (en-
tries 11–16). Additionally, replacement of CAN by
cerium(III) chloride gave a 12% yield of 5a, suggesting
that CAN is a particularly effective cerium catalyst for the
reaction (entry 17).
BnOH
110
24
1,4-dioxane
toluene
MeCN
EtOH
reflux
110
45
37
reflux
reflux
110
trace
trace
12
DMSO
a Reaction conditions: enamine 1a (0.5 mmol), aldehyde 2a (0.3
mmol), thioacetamide (3a; 0.3 mmol), catalyst (50 mol%), solvent (2
mL), 12 h, stirring (unless otherwise specified).
b Yield of isolated product based on enamine 1a.
c No reaction.
d CAN (70 mol%).
e CAN (30 mol%).
idines (5i–n) efficiently and in moderate to good yields
(Table 2, entries 9–14).
The general applicability of the electron-deficient enam-
ine-based pyridine synthesis inspired us to further expand
the synthetic application of the catalytic method by em-
ploying electron-deficient alkynes directly as alternative
building blocks. Our previous experience suggested that
electron-deficient alkynes might be efficiently activated
by a secondary amine through rapid formation of electron-
deficient enamine intermediate.13 Piperazine was there-
fore used to promote the reaction. To our delight, the con-
ditions smoothly gave the pyridines 7, as expected (Table
3). Electron-deficient alkynes 6 reacted with a variety of
aldehydes 2 and thioacetamide (3a) to give the corre-
sponding pyridines containing 3,5-dicarboxylate frag-
ments (Table 3, entries 1–13). The yields of the products
were determined mainly by the electronic properties of the
aldehyde component. Aryl aldehydes containing electron-
withdrawing groups generally gave higher yields than
those containing electron-donating groups (entries 1–5,
8–11). The alkyne-based synthesis of pyridines, in combi-
nation with the enaminone/enaminonitrile-based synthe-
By using the optimized protocol, we examined the reac-
tions of various aldehydes with enaminones or enamino-
nitriles. The reaction showed a broad scope in the
synthesis of 3,4,5-trisubstituted pyridines and tolerated a
variety of substrates bearing diverse functional groups, in-
cluding alkyl, alkoxy, halo, cyano, and hetaryl groups
(Table 1, entries 1–13). The electronic properties of the
enamine 1 or aldehyde 2 displayed no obvious effects on
the yield of the corresponding product. However, some al-
dehydes containing an electron-withdrawing group under-
went the transformation more smoothly and gave the
corresponding pyridines 5j, 5m, and 5n in relatively high-
er yields (Table 2, entries 10, 13, and 14, respectively).
Another noteworthy point was that enaminonitriles, as al-
ternative building blocks, also reacted with aldehydes and
thioacetamide, to give the corresponding 3,5-dicyanopyr-
© Georg Thieme Verlag Stuttgart · New York
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J.-P. Wan et al.
PAPER
Table 2 Electron-Deficient Enamine-Based Multicomponent Syn-
Table 3 Electron-Deficient Alkyne-Based Synthesis of Pyridinesa
thesis of Pyridinesa
CO2R1
R1
Me
CO2R1
N
R1
CAN (50 mol%)
6
1
piperazine (50 mol%)
CAN (50 mol%)
DMSO, 110 °C
Me
S
R2
S
N
+
R2
+
N
R2
R2
DMSO, 110 °C
CHO
NH2
CO2R1
R1
CHO
NH2
3a
2
7
3a
2
5
Entry
R1
R2
Product
Yieldb (%)
Entry
R1
R2
Product Yieldb (%)
1
2
Me
Me
Me
Me
Me
Me
Me
Et
4-ClC6H4
4-Tol
7a
7b
7c
7d
7e
7f
57
48
55
51
58
51
46
66
52
53
65
61
52
1
2
PhCO
4-ClC6H4
5a
5b
5c
5d
5e
5f
67
57
65
63
57
53
67
56
63
71
69
67
88
73
PhCO
2-ClC6H4
2-furyl
3
4-BrC6H4
3-MeOC6H4
4-O2NC6H4
2,4-Cl2C6H3
2-ClC6H4
4-ClC6H4
4-Tol
3
PhCO
4
4
4-TolCO
4-TolCO
4-BrC6H4CO
3-MeOC6H4CO
4-F3CC6H4CO
CN
2-BrC6H4
5
5
3-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
3-MeOC6H4
4-ClC6H4
4-Tol
6
6
7
7g
7h
7i
7
5g
5h
5i
8
8
9
Et
9
10
11
12
13
Et
4-BrC6H4
4-O2NC6H4
3-O2NC6H4
Ph
7j
10
11
12
13
14
CN
5j
Et
7k
7l
CN
5k
5l
Et
CN
4-MeOC6H4
2-ClC6H4
4-BrC6H4
Et
7m
CN
5m
5n
a Reaction conditions: alkynoate 6 (0.5 mmol), aldehyde 2 (0.3 mmol),
thioacetamide (3a; 0.3 mmol), CAN (50 mol%), piperazine (50
mol%), DMSO (2 mL), 110 °C, 12 h, stirring.
CN
a Reaction conditions: enamine 1 (0.5 mmol), aldehyde 2 (0.3 mmol),
thioacetamide (3a; 0.3 mmol), CAN (50 mol%), DMSO (2 mL),
110 °C, 12 h, stirring.
b Yield of isolated product based on alkynoate 6.
b Yield of isolated products based on enamine 1.
secondary amine and/or water, present in the reaction sys-
tem, to give the pyridine 5 or 7.
sis of pyridines 5, demonstrated the genuinely broad range
of applicability of our thioacetamide-initiated multicom-
ponent method for pyridine synthesis. However, when an
aliphatic aldehyde such as propanal was used as the alde-
hyde component, no product 7 containing a 4-alkyl sub-
stituent was obtained.
In conclusion, by employing conventional aldehydes and
electron-deficient enamines or alkynes as the main build-
ing blocks, we have, for the first time, achieved a direct
one-step synthesis of pyridines by using thioacetamide as
an ammonium source and CAN as a catalyst. Compared
with known two-step methods that use other ammonium
sources such as ammonium acetate, our protocol has the
advantages of a simpler one-step operation and a much
broader tolerance to various substrates. Our reaction
therefore provides a new route for the synthesis of struc-
turally diverse pyridines.
On the basis of the results from the synthesis of pyridines
with thioacetamide, we propose the plausible reaction
mechanism shown in Scheme 2. The reaction proceeds by
a domino transformation consisting of enamine-based ho-
mocondensation, thioacetamide-initiated transamination,
and cerium-promoted elimination–aromatization. First,
the electron-deficient enamine 1 or 8, as either a starting
material or an intermediate formed in situ,13 reacts with
the aldehyde to give complex 9. The cerium ion promotes
transamination of 9 with thioacetamide to give the inter-
mediate 10. Intramolecular transamination of 10 gives the
N-protected 1,4-dihydropyridine 11. In the presence of
CAN as an oxidant, 11 undergoes oxidative aromatization
to form the thioacetylpyridinium salt 12. Finally, the thio-
acetyl cation in 12 is removed by rapid incorporation of a
All chemicals were purchased from J & K or Energy Chemical Co.,
Ltd. and used directly. Enaminones 1 were synthesized following a
literature procedure.14 Melting points were determined on an X-4A
apparatus and are uncorrected. IR spectra were recorded on a Nicolet
1
6700 spectrometer. H and 13C NMR spectra were recorded on a
Bruker Avance 400 spectrometer at 400 and 100 MHz, respectively.
Chemical shifts (δ) are reported relative to TMS as an internal stan-
dard. Mass spectra were recorded on a Bruker micrOTOF-QII
QTOF mass spectrometer operated in the ESI mode.
Synthesis 2014, 46, 3256–3262
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Multicomponent Synthesis of Pyridines
3259
ESI-HRMS: m/z [M + H]+ calcd for C25H17ClNO2: 398.0948;
found: 398.0949.
EWG
H
N
+
[4-(2-Furyl)pyridine-3,5-diyl]bis(phenylmethanone) (5c)
Brown solid; yield: 57 mg (65%); mp 138–139 °C.
6
IR (KBr): 3035, 3021, 1670, 1392, 720 cm–1.
S
Ar
EWG
1H NMR (400 MHz, CDCl3): δ = 8.79 (s, 2 H), 7.71 (d, J = 7.6 Hz,
4 H), 7.52 (d, J = 7.2 Hz, 2 H), 7.37 (t, J = 7.6 Hz, 4 H), 7.05 (s, 1
H), 6.39 (d, J = 3.2 Hz, 1 H), 6.05 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 195.6, 150.0, 146.3, 144.5, 136.2,
134.1, 133.8, 132.5, 129.5, 128.6, 115.2, 112.2.
EWG
N
EWG
N
NH2
ArCHO
H2O
N
Ce4+
1 or 8
H
N
9
ESI-MS: m/z = 354 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C23H16NO3: 354.1130; found:
354.1125.
Ar
Ar
Ar
N
H
EWG
EWG
EWG
EWG
EWG
EWG
[4-(2-Bromophenyl)pyridine-3,5-diyl]bis[(4-tolyl)methanone]
(5d)
Pale-yellow solid; yield: 74 mg (63%); mp 161–164 °C.
IR (KBr): 3035, 3021, 1661, 720, 550 cm–1.
1H NMR (400 MHz, CDCl3) δ = 8.80 (s, 2 H), 7.59 (d, J = 7.6 Hz,
4 H), 7.19 (d, J = 7.2 Hz, 1 H), 7.13–7.06 (m, 6 H), 6.91 (t, J = 7.6
Hz, 1 H), 2.31 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 194.0, 150.7, 147.0, 144.7, 135.7,
135.4, 133.9, 132.4, 131.6, 130.3, 129.9, 129.1, 126.9, 122.1, 21.6.
NH
N
oxidation
N
Ce4+
S
Ce4+
10
S
S
H
11
N
12
Ar
EWG
EWG
S
S
+
and/or
N
OH
N
5 or 7
H
ESI-MS: m/z = 470 [M + H]+.
N
and/or H2O
ESI-HRMS: m/z [M + H]+ calcd for C27H21BrNO2: 470.0756;
found: 470.0744.
Scheme 2 Proposed reaction mechanism
[4-(3-Methoxyphenyl)pyridine-3,5-diyl]bis[(4-tolyl)meth-
anone] (5e)
White solid; yield: 60 mg (57%); mp 163–165 °C.
IR (KBr): 3038, 3027, 1661, 1185, 720 cm–1.
3,4,5-Trisubstituted Pyridines 5; General Procedure
A 10 mL flask equipped with a stirrer bar was charged with enamine
1 (0.5 mmol), aldehyde 2 (0.3 mmol), thioacetamide (3a; 0.3
mmol), CAN (0.125 mmol), and DMSO (2 mL). The mixture was
then stirred at 110 °C for 12 h. When the reaction was complete
(TLC), H2O (5 mL) was added and the mixture was extracted with
EtOAc (3 × 10 mL). The organic phases were combined, dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
residue was subjected to preparative TLC (EtOAc–PE, 1:4).
1H NMR (400 MHz, CDCl3): δ = 8.79 (s, 2 H), 7.54 (d, J = 7.6 Hz,
4 H), 7.11 (d, J = 8.0 Hz, 4 H), 6.92 (t, J = 8.0 Hz, 1 H), 6.66 (d, J =
7.6 Hz, 1 H), 6.62 (s, 1 H), 6.55 (d, J = 8.8 Hz, 1 H), 3.53 (s, 3 H),
2.34 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 195.3, 159.0, 149.3, 146.4, 144.8,
136.1, 135.6, 134.1, 130.0, 129.4, 129.1, 121.8, 115.2, 114.3, 55.1,
21.7.
ESI-MS: m/z = 422 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C28H24NO3: 422.1756; found:
[4-(4-Chlorophenyl)pyridine-3,5-diyl]bis(phenylmethanone)
(5a)
White solid; yield: 66 mg (67%); mp 131–133 °C.
422.1768.
IR (KBr): 3050, 3030, 1665, 750, 730 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.84 (s, 2 H), 7.61 (d, J = 7.6 Hz,
4 H), 7.50 (t, J = 7.2 Hz, 2 H), 7.34 (t, J = 7.6 Hz, 4 H), 7.00 (s, 4 H).
[4-(4-Chlorophenyl)pyridine-3,5-diyl]bis[(4-bromophe-
nyl)methanone] (5f)
Orange solid; yield: 73 mg (53%); mp 188–191 °C.
13C NMR (100 MHz, CDCl3): δ = 195.4, 149.9, 145.6, 136.5, 135.3,
135.0, 133.9, 133.2, 130.5, 129.7, 128.6, 128.5.
ESI-MS: m/z = 398 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C25H17ClNO2: 398.0948;
found: 398.0950.
IR (KBr): 3038, 3027, 1670, 723, 565 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.83 (s, 2 H), 7.50–7.45 (m, 8 H),
7.05 (d, J = 8.0 Hz, 2 H), 6.98 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 194.4, 150.0, 145.3, 135.5, 135.0,
134.8, 132.9, 132.0, 131.1, 130.4, 129.6, 128.9.
ESI-MS: m/z = 554 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C25H15Br2ClNO2: 553.9153;
[4-(2-Chlorophenyl)pyridine-3,5-diyl]bis(phenylmethanone)
(5b)
White solid; yield: 57 mg (57%); mp 182–183 °C.
found: 553.9150.
IR (KBr): 3045, 3031, 1667, 745, 720 cm–1.
[4-(4-Chlorophenyl)pyridine-3,5-diyl]bis[(3-methoxyphe-
nyl)methanone] (5g)
Orange solid; yield: 77 mg (67%); mp 118–121 °C.
IR (KBr): 3041, 3021, 1657, 1225, 724 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.82 (s, 2 H), 7.25 (t, J = 8.0 Hz,
4 H), 7.13 (d, J = 7.6 Hz, 2 H), 7.08–7.03 (m, 6 H), 3.79 (s, 6 H).
1H NMR (400 MHz, CDCl3): δ = 8.85 (s, 2 H), 7.63 (d, J = 7.2 Hz,
4 H), 7.44 (t, J = 7.2 Hz, 2 H), 7.30 (t, J = 7.6 Hz, 4 H), 7.08 (d, J =
7.6 Hz, 1 H), 7.01–6.94 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 194.7, 150.9, 145.4, 136.4, 135.3,
133.8, 133.6, 131.9, 131.5, 130.0, 129.8, 129.3, 128.4, 126.6.
ESI-MS: m/z = 398 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York
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J.-P. Wan et al.
PAPER
13C NMR (100 MHz, CDCl3): δ = 195.2, 159.7, 149.8, 145.7, 137.9,
135.3, 135.0, 133.3, 130.5, 129.6, 128.6, 123.1, 120.1, 113.4, 55.5.
ESI-MS: m/z = 458 [M + H]+.
ESI-MS: m/z = 236 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C14H10N3O: 236.0824; found:
236.0824.
ESI-HRMS: m/z [M + H]+ calcd for C27H21ClNO4: 458.1159;
found: 458.1161.
4-(2-Chlorophenyl)pyridine-3,5-dicarbonitrile (5m)
Pale-yellow solid; yield: 53 mg (88%); mp 119–122 °C.
IR (KBr): 3029, 3014, 2243, 730, 716 cm–1.
[4-(4-Chlorophenyl)pyridine-3,5-diyl]bis{[4-(trifluorometh-
yl)phenyl]methanone} (5h)
1H NMR (400 MHz, CDCl3): δ = 9.14 (s, 2 H), 7.64 (d, J = 8.0 Hz,
1 H) 7.58 (t, J = 7.6 Hz, 1 H), 7.51 (t, J = 7.2 Hz, 1 H), 7.36 (d, J =
7.6 Hz, 1 H).
Pale-yellow solid; yield: 75 mg (56%); mp 125–129 °C.
IR (KBr): 3033, 3018, 1660, 1395, 724 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.90 (s, 2 H), 7.69 (d, J = 8.4 Hz,
4 H), 7.59 (d, J = 8.0 Hz, 4 H), 7.02 (d, J = 8.4 Hz, 2 H), 6.95 (d, J =
8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 194.4, 150.4, 145.7, 139.0, 135.8,
135.2, 134.6, 132.7, 130.5, 129.9, 128.9, 125.6 (d, J = 3.6 Hz),
121.9.
13C NMR (100 MHz, CDCl3): δ = 155.5, 153.7, 132.6, 132.3, 131.2,
130.7, 130.0, 127.8, 113.9, 112.0.
ESI-MS: m/z = 240 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C13H7ClN3: 240.0328; found:
240.0323.
ESI-MS: m/z = 534 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C27H15ClF6NO2: 534.0696;
4-(4-Bromophenyl)pyridine-3,5-dicarbonitrile (5n)
Pale-yellow solid; yield: 52 mg (73%); mp 153–156 °C.
IR (KBr): 3031, 3023, 2233, 720, 570 cm–1.
found: 534.0699.
1H NMR (400 MHz, CDCl3): δ = 9.11 (s, 2 H), 7.77 (d, J = 7.6 Hz,
2 H), 7.47 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 156.1, 154.3, 132.9, 130.4, 130.3,
126.8, 114.5, 110.5.
ESI-MS: m/z = 284 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C13H7BrN3: 283.9823; found:
4-(3-Methoxyphenyl)pyridine-3,5-dicarbonitrile (5i)
Pale-yellow solid; yield: 37 mg (63%); mp 173–174 °C.
IR (KBr): 3033, 3018, 2230, 1215, 731 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.09 (s, 2 H), 7.52 (t, J = 8.0 Hz,
1 H), 7.15 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 2 H), 7.09–7.08 (m, 1 H),
3.89 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 160.0, 156.0, 155.3, 132.8, 130.8,
121.0, 117.5, 114.7, 114.1, 110.7, 55.2.
283.9818.
4-Substituted Pyridine-3,5-dicarboxylates 7; General Proce-
dure
ESI-MS: m/z = 236 [M + H]+.
A 10 mL flask equipped with a stirrer bar was charged with alky-
noate 6 (0.5 mmol), aldehyde 2 (0.3 mmol), thioacetamide (3; 0.3
mmol), CAN (0.125 mmol), piperazine (0.125 mmol), and DMSO
(2 mL). The mixture was stirred at 110 °C for 12 h until the reaction
was complete (TLC). Workup was identical to that for the 3,4,5-tri-
substituted pyridines 5.
ESI-HRMS: m/z [M + H]+ calcd for C14H10N3O: 236.0824; found:
236.0825.
4-(4-Chlorophenyl)pyridine-3,5-dicarbonitrile (5j)
Pale-yellow solid; yield: 42 mg (71%); mp 157–160 °C.
IR (KBr): 3039, 3022, 2238, 755, 726 cm–1.
Dimethyl 4-(4-Chlorophenyl)pyridine-3,5-dicarboxylate (7a)
1H NMR (400 MHz, CDCl3): δ = 9.11 (s, 2 H), 7.61 (d, J = 8.8 Hz,
2 H), 7.55 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 156.1, 154.2, 138.4, 130.2, 129.9,
129.8, 114.5, 110.6.
ESI-MS: m/z = 240 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C13H7ClN3: 240.0328; found:
Orange solid; yield: 43 mg (57%); mp 107–109 °C.
IR (KBr): 3061, 1730, 880, 810, 750 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.12 (s, 2 H), 7.39 (d, J = 8.4 Hz,
2 H), 7.13 (d, J = 8.4 Hz, 2 H), 3.70 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 165.9, 152.8, 148.8, 134.9, 134.6,
129.0, 128.1, 127.6, 52.5.
ESI-MS: m/z = 306 [M + H]+.
240.0332.
4-(4-Tolyl)pyridine-3,5-dicarbonitrile (5k)
Pale-yellow solid; yield: 38 mg (69%); mp 129–132 °C.
IR (KBr): 3029, 3018, 2870, 2218, 715 cm–1.
ESI-HRMS: m/z [M + H]+ calcd for C15H13ClNO4: 306.0533;
found: 306.0528.
Dimethyl 4-(4-Tolyl)pyridine-3,5-dicarboxylate (7b)
1H NMR (400 MHz, CDCl3): δ = 9.07 (s, 2 H), 7.51 (d, J = 8.4 Hz,
2 H), 7.42 (d, J = 8.4 Hz, 2 H), 2.47 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 156.1, 155.6, 142.4, 130.1, 128.8,
114.9, 110.6, 21.6.
ESI-MS: m/z = 220 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C14H10N3: 220.0875; found:
Orange solid; yield: 34 mg (48%); mp 121–122 °C.
IR (KBr): 3051, 2915, 1719, 860, 735 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.06 (s, 2 H), 7.21 (d, J = 8.0 Hz,
2 H), 7.08 (d, J = 7.6 Hz, 2 H), 3.66 (s, 6 H), 2.40 (s, 3 H)
13C NMR (100 MHz, CDCl3): δ = 166.4, 152.1, 150.0, 138.3, 133.3,
128.7, 128.2, 127.5, 52.5, 21.4.
ESI-MS: m/z = 286 [M + H]+.
220.0879.
4-(4-Methoxyphenyl)pyridine-3,5-dicarbonitrile (5l)
Pale-yellow solid; yield: 39 mg (67%); mp 168–170 °C.
IR (KBr): 3035, 3028, 2875, 1218, 735 cm–1.
ESI-HRMS: m/z [M + H]+ calcd for C16H16NO4: 286.1079; found:
286.1080.
Dimethyl 4-(4-Bromophenyl)pyridine-3,5-dicarboxylate (7c)
1H NMR (400 MHz, CDCl3): δ = 9.05 (s, 2 H), 7.59 (d, J = 8.8 Hz,
2 H), 7.11 (d, J = 8.8 Hz, 2 H), 3.91 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.3, 156.2, 155.1, 130.7, 123.7,
115.1, 114.9, 110.4, 55.6.
Orange solid; yield: 48 mg (55%); mp 113–115 °C.
IR (KBr): 3066, 1719, 855, 745, 588 cm–1.
Synthesis 2014, 46, 3256–3262
© Georg Thieme Verlag Stuttgart · New York

PAPER
Multicomponent Synthesis of Pyridines
3261
1H NMR (400 MHz, CDCl3): δ = 9.13 (s, 2 H), 7.55 (d, J = 8.4 Hz,
2 H), 7.07 (d, J = 8.4 Hz, 2 H), 3.68 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 165.6, 152.6, 148.4, 135.3, 134.4,
129.2, 128.0, 127.9, 61.8, 13.7.
13C NMR (100 MHz, CDCl3): δ = 165.8, 152.6, 149.1, 135.3, 131.1,
129.3, 127.6, 122.8, 52.5.
ESI-MS: m/z = 350 [M + H]+.
ESI-MS: m/z = 334 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C17H17ClNO4: 334.0846;
found: 334.0841.
ESI-HRMS: m/z [M + H]+ calcd for C15H13BrNO4: 350.0028;
found: 350.0026.
Diethyl 4-(4-Tolylpyridine-3,5-dicarboxylate) (7i)
Orange oil; yield: 41 mg (52%).
IR (KBr): 3061, 2911, 1729, 875, 743 cm–1.
Dimethyl 4-(3-Methoxyphenyl)pyridine-3,5-dicarboxylate (7d)
Orange solid; yield: 38 mg (51%); mp 105–107 °C.
1H NMR (400 MHz, CDCl3): δ = 8.97 (s, 2 H), 7.13 (d, J = 8.0 Hz,
2 H), 7.01 (d, J = 8.4 Hz, 2 H), 4.01 (q, J = 7.2 Hz, 4 H), 2.32 (s, 3
H), 0.94 (t, J = 7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 166.1, 151.9, 149.6, 138.1, 133.6,
130.0, 128.5, 127.7, 61.6, 21.3, 13.6.
IR (KBr): 3055, 1728, 1090, 810, 715 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.07 (s, 2 H), 7.33 (t, J = 8.0 Hz,
1 H), 6.95 (d, J = 7.6 Hz, 1 H), 6.78 (d, J = 7.6 Hz, 1 H), 6.74 (s, 1
H), 3.81 (s, 3 H), 3.66 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 166.3, 159.2, 152.2, 149.5, 137.7,
129.1, 127.9, 120.1, 113.9, 113.5, 55.2, 52.3.
ESI-MS: m/z = 302 [M + H]+.
ESI-MS: m/z = 314 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C18H20NO4: 314.1392; found:
314.1389.
ESI-HRMS: m/z [M + H]+ calcd for C16H16NO5: 302.1028; found:
302.1023.
Diethyl 4-(4-Bromophenyl)pyridine-3,5-dicarboxylate (7j)
Orange solid; yield: 50 mg (53%); mp 66–68 °C.
IR (KBr): 3055, 1730, 865, 735, 535 cm–1.
Dimethyl 4-(4-Nitrophenyl)pyridine-3,5-dicarboxylate (7e)
Orange solid; yield: 46 mg (58%); mp 192–194 °C.
1H NMR (400 MHz, CDCl3): δ = 9.12 (s, 2 H), 7.54 (d, J = 8.4 Hz,
2 H), 7.08 (d, J = 8.0 Hz, 2 H), 4.11 (q, J = 7.2 Hz, 4 H), 1.06 (t, J =
7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 165.6, 152.6, 148.6, 135.8, 131.0,
129.5, 127.9, 122.5, 61.8, 13.7.
IR (KBr): 3070, 1730, 1535, 840, 720 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.27 (s, 2 H), 8.29 (d, J = 8.8 Hz,
2 H), 7.36 (d, J = 8.4 Hz, 2 H), 3.70 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 165.1, 153.5, 148.7, 147.5, 143.7,
128.7, 126.7, 123.0, 52.7.
ESI-MS: m/z = 378 [M + H]+.
ESI-MS: m/z = 317 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C15H13N2O6: 317.0774; found:
ESI-HRMS: m/z [M + H]+ calcd for C17H17BrNO4: 378.0341;
found: 378.0338.
317.0771.
Diethyl 4-(4-Nitrophenyl)pyridine-3,5-dicarboxylate (7k)
Orange solid; yield: 60 mg (65%); mp 81–85 °C.
Dimethyl 4-(2,4-Dichlorophenyl)pyridine-3,5-dicarboxylate
(7f)
IR (KBr): 3065, 1721, 1525, 845, 730 cm–1.
Orange solid; yield: 43 mg (51%); mp 103–106 °C.
1H NMR (400 MHz, CDCl3): δ = 9.17 (s, 2 H), 8.21 (d, J = 8.8 Hz,
2 H), 7.31 (d, J = 8.4 Hz, 2 H), 4.05 (q, J = 7.2 Hz, 4 H), 1.01 (t, J =
7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 164.8, 153.4, 148.1, 147.6, 144.0,
128.9, 126.9, 122.9, 62.0, 13.8.
IR (KBr): 3071, 1725, 890, 790, 725 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.30 (s, 2 H), 7.49 (d, J = 7.6 Hz,
1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.03 (d, J = 8.4 Hz, 1 H), 3.73 (s, 6
H).
13C NMR (100 MHz, CDCl3): δ = 164.9, 153.9, 147.4, 134.8, 134.5,
132.9, 129.5, 128.9, 128.7, 126.8, 52.8.
ESI-MS: m/z = 340 [M + H]+.
ESI-MS: m/z = 345 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C17H17N2O6: 345.1087; found:
345.1089.
ESI-HRMS: m/z [M + H]+ calcd for C15H12Cl2NO4: 340.0143;
found: 340.0142.
Diethyl 4-(3-Nitrophenyl)pyridine-3,5-dicarboxylate (7l)
Orange solid; yield: 52 mg (61%); mp 80–81 °C.
Dimethyl 4-(2-Chlorophenyl)pyridine-3,5-dicarboxylate (7g)
IR (KBr): 3070, 1725, 1515, 850, 725 cm–1.
Orange oil; yield: 35 mg (46%).
1H NMR (400 MHz, CDCl3): δ = 9.14 (s, 2 H), 8.19 (d, J = 8.0 Hz,
1 H), 8.00 (s, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.44 (d, J = 5.6 Hz, 1
H), 4.02 (q, J = 7.2 Hz, 4 H), 0.96 (t, J = 7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 164.8, 153.4, 147.6, 138.6, 133.9,
128.7, 128.6, 127.2, 123.0, 122.9, 61.9, 13.7.
IR (KBr): 3065, 1720, 870, 820, 740 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.29 (s, 2 H), 7.47 (d, J = 7.6 Hz,
1 H), 7.40–7.32 (m, 2 H), 7.10 (d, J = 7.2 Hz, 1 H), 3.70 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 165.2, 153.5, 148.4, 135.9, 132.0,
129.6, 128.9, 128.6, 127.1, 126.3, 52.6.
ESI-MS: m/z = 345 [M + H]+.
ESI-MS: m/z = 306 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C17H17N2O6: 345.1087; found:
ESI-HRMS: m/z [M + H]+ calcd for C15H13ClNO4: 306.0533;
345.1089.
found: 306.0528.
Diethyl 4-Phenylpyridine-3,5-dicarboxylate (7m)
Orange oil; yield: 39 mg (52%).
Diethyl 4-(4-Chlorophenyl)pyridine-3,5-dicarboxylate (7h)
Pale-yellow solid; yield: 55 mg (66%); mp 72–75 °C.
IR (KBr): 3055, 1715, 855 825, 740 cm–1.
IR (KBr): 3055, 1725, 890, 815, 735 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.08 (s, 2 H), 7.41–7.38 (m, 3 H),
1H NMR (400 MHz, CDCl3): δ = 9.11 (s, 2 H), 7.38 (d, J = 8.4 Hz,
2 H), 7.14 (d, J = 8.4 Hz, 2 H), 4.11 (q, J = 7.2 Hz, 4 H), 1.05 (t, J =
7.2 Hz, 6 H).
7.21–7.19 (m, 2 H), 4.07 (q, J = 7.2 Hz, 4 H), 0.97 (t, J = 7.2 Hz, 6
H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3256–3262

3262
J.-P. Wan et al.
PAPER
13C NMR (100 MHz, CDCl3): δ = 166.0, 152.5, 152.2, 152.1, 136.8,
128.3, 127.9, 127.7, 61.6, 13.5.
ESI-MS: m/z = 300 [M + H]+.
13024. (c) Kantevari, S.; Patpi, S. R.; Addla, D.; Putapatri,
S. R.; Sridhar, B.; Yogeeswari, P.; Sriram, D. ACS Comb.
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Ed. Engl. 1962, 1, 626. (b) Kröhnke, F. Synthesis 1976, 1.
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(h) Liéby-Muller, F.; Allais, C.; Constantieux, T.;
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ESI-HRMS: m/z [M + H]+ calcd for C17H18NO4: 300.1236; found:
300.1230.
Acknowledgment
The work was financially supported by NSFC of China (no.
21102059) and a project from the Department of Education of
Jiangxi Province (GJJ13245).
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunpfgIpi
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nr
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Synthesis 2014, 46, 3256–3262
© Georg Thieme Verlag Stuttgart · New York