One-Pot Synthesis of Hantzsch Pyridines via NH4I Promoted Condensation of 1,3-Dicarbonyl Compounds with DMSO and NH4OAc

Article abstract of DOI:10.1002/cjoc.201600255

A one-pot synthesis of Hantzsch pyridines was achieved through NH₄I-promoted condensation of 1,3-dicarbonyl compounds with DMSO and NH₄OAc, in which the C4 of the pyridine rings was derived from DMSO and the nitrogen atom resulted from NH₄OAc and NH₄I. The target product could be obtained in moderate to excellent yields.

Full text of DOI:10.1002/cjoc.201600255

FULL PAPER
DOI: 10.1002/cjoc.201600255
One-Pot Synthesis of Hantzsch Pyridines via NH4I Promoted
Condensation of 1,3-Dicarbonyl Compounds with
DMSO and NH4OAc
Liming Chang, Junyi Lai, and Gaoqing Yuan*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, Guangdong 510640, China
A one-pot synthesis of Hantzsch pyridines was achieved through NH4I-promoted condensation of 1,3-di-
carbonyl compounds with DMSO and NH4OAc, in which the C4 of the pyridine rings was derived from DMSO and
the nitrogen atom resulted from NH4OAc and NH4I. The target product could be obtained in moderate to excellent
yields.
Keywords pyridines, 1,3-dicarbonyl compounds, dimethyl sulfoxide, ammonium iodide
source of methylene units (Scheme 1c).[16] Based on the
important roles that DMSO is playing in organic syn-
thesis, we tried to achieve a one-pot synthesis of
Hantzsch symmetrical pyridines via ammonium iodide-
promoted condensation of 1,3-dicarbonyl compounds
with DMSO and ammonium acetate (Scheme 1d). The
present work is different from Wu’s work. The reaction
could be smoothly performed to afford the target prod-
ucts in good to excellent yields without copper salts.
Compared with the two-step process (Scheme 1a), the
present synthetic route is more facile and convenient for
the synthesis of Hantzsch symmetrical pyridines.
Introduction
Pyridines are an important class of hererocycles,
which have been widely used as functional materials,
farm chemicals, pharmaceutical drugs, important lig-
ands, organic bases and catalysts.[1,2] As a consequence,
the synthesis of pyridine and its derivatives has been a
quite interesting research topic.[3,4]
Hantzsch pyridines, as the classic symmetrical pyri-
dines, have attracted considerable attention. The
Hantzsch pyridines synthesis[5] is mainly based on con-
densation of amines and carbonyl compounds, in which
dihydropyridine was first formed, followed by oxidation
to generate pyridines (Scheme 1a). In addition, oxida-
tive aromatization of Hantzsch 1,4-dihydropyridines as
a common route was used to prepare Hantzsch pyri-
dines.[6-12] For example, Wen and co-workers have
demonstrated the synthesis of Hantzsch pyridines using
Na2S2O4 and TBHP as a new oxidation system to the
oxidative aromatization of 1,4-DHPs (Scheme 1b).[7] It
should be noted that most of the reported oxidation
procedures suffer from the use of complicated oxidants
or transition metal catalysts, such as RuCl3,[8]
Mn(OAc)3,[9] Zr(NO3)4,[10] FeCl3•6H2O,[11] and MnO2.[12]
Therefore, to develop a new and efficient metal-free
catalytic method for the synthesis of Hantzsch pyridines
is still necessary.
Experimental
General
1H and 13C NMR spectra were determined on a
1
Bruker Advance 400 spectrometer (400 MHz for H,
100 MHz for 13C NMR spectroscopy) in CDCl3. Proton
coupling patterns were described as singlet (s), doublet
(d), triplet (t), quartet (q) and multiplet (m). MS anal-
yses were performed on a Shimadzu GCMS-QP5050A
spectrometer. The new compounds were characterized
by a high resolution mass spectrometer (MAT95XP).
TLC was performed using commercially prepared
100－400 mesh silica gel plates (GF254), and visualiza-
tion was effected at 254 nm. All reagents and solvents
were purchased from commercial suppliers and used
without further purification.
DMSO, a cheap and popular polar solvent, has been
widely used in organic synthesis. Moreover, DMSO can
be used as a useful precursor to afford Me,[13] SO2Me[14]
and CHO synthons.[15] For instance, Wu and co-workers
reported an iodine promoted cyclization of ketones with
DMSO for the synthesis of polysubstituted pyridines in
the presence of Cu(NO3)2•3H2O, in which DMSO was a
A typical procedure for the synthesis of Hantzsch
pyridines
The mixture of ammonium iodide (0.5 mmol),
*
E-mail: gqyuan@scut.edu.cn
Received April 30, 2016; accepted June 14, 2016; published online XXXX, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600255 or from the author.
Chin. J. Chem. 2016, XX, 1—8
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Chang, Lai & Yuan
FULL PAPER
Scheme 1 Different methods for the synthesis of Hantzsch pyr-
idines
1.78－1.71 (m, 4H), 1.50－1.42 (m, 4H), 0.97 (t, J＝7.4
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ: 165.9, 162.2,
140.9, 123.0, 65.2, 30.6, 24.8, 19.2, 13.6.
Dipentyl-2,6-dimethylpyridine-3,5-dicarboxylate
(2f)[18] Pale yellow liquid. 1H NMR (400 MHz, CDCl3)
δ: 8.69 (s, 1H), 4.33 (t, J＝6.8 Hz, 4H), 2.85 (s, 6H),
1.81－1.76 (m, 4H), 1.42－1.38 (m, 8H), 0.94 (t, J＝6.8
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ: 165.9, 162.2,
140.9, 123.0, 65.5, 28.2, 28.1, 24.9, 22.2, 13.9.
(a)
2
Hantzsch's work:
R1
O
R3
C
O
O
O
(1) EtOH
(2) [O]
+
+
NH3
R2O
OR2
R3
H
O
R2O
R1
N
R1
(b) Wen's work:
O
R2
O
O
R2
O
Diallyl-2,6-dimethylpyridine-3,5-dicarboxylate
Na2S2O4, TBHP
EtOAc, air, r.t.
R1O
OR1
(2g)[17] White solid. m.p. 62－65 ℃ (lit., 64－
R1O
OR1
1
66 ℃); H NMR (400 MHz, CDCl3) δ: 8.74 (s, 1H),
N
N
H
6.10－6.00 (m, 2H), 5.45－5.40 (m, 2H), 5.32 (d, J＝
10.4 Hz, 2H), 4.84 (d, J＝5.7 Hz, 4H), 2.86 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ: 165.5, 162.6, 141.0, 131.8,
122.7, 118.8, 66.0, 25.0.
H
C
(c) Wu's work:
O
R1
R1
Ar
NH4OAc, I2, [Cu]
DMSO, 130 °C
R1
Ar
Ar
N
Bis(2-methoxyethyl)-2,6-dimethylpyridine-3,5-
1
dicarboxylate (2h) Orange yellow liquid. H NMR
(d)
This work:
O
H
C
O
(400 MHz, CDCl3) δ: 8.71 (s, 1H), 4.46 (t, J＝4.8 Hz,
4H), 3.72 (t, J＝4.6 Hz, 4H), 3.42 (s, 6H), 2.84 (s, 6H);
13C NMR (100 MHz, CDCl3) δ: 165.8, 162.4, 141.1,
NH4OAc, NH4I
R2
DMSO, 115 °C
O
O
2
R1
R2
R2
R1
N
R1
122.7, 70.3, 64.3, 58.9, 24.8; HRMS (ESI) m/z: calcd
＋
for C15H21NNaO6 [M ＋ Na] , 334.1264; found
334.1261.
DMSO (2 mL), ammonium acetate (1 mmol) and
1,3-dicarbonyl compound (1 mmol) was stirred at
115 ℃ for 10 h in a 15 mL sealed tube successively.
After cooling down, the reaction mixture was diluted
with ethyl acetate and washed with Na2S2O3 solutions
and water three times. The obtained top organic layer
was dried with anhydrous MgSO4. After drying, the
mixture was concentrated under vacuum, and the crude
product was purified by silica gel column chromatog-
raphy.
Dibenzyl-2,6-dimethylpyridine-3,5-dicarboxylate
(2i)[17] White solid. m.p. 79－80 ℃ (not reported);
1H NMR (400 MHz, CDCl3) δ: 8.75 (s, 1H), 7.43－7.36
(m, 10H), 5.35 (s, 4H), 2.84 (s, 6H); 13C NMR (100
MHz, CDCl3) δ: 165.6, 162.6, 141.1, 135.5, 128.7,
128.4, 128.2, 122.7, 67.1, 25.0.
1,1'-(2,6-Dimethylpyridine-3,5-diyl)bis(3-methyl-
butan-1-one) (2j) Yellow liquid. 1H NMR (400 MHz,
CDCl3) δ: 8.01 (s, 1H), 2.74 (d, J＝6.9 Hz, 4H), 2.68 (s,
6H), 2.27－2.17 (m, 2H), 0.97 (d, J＝6.7 Hz, 12H); 13C
NMR (100 MHz, CDCl3) δ: 202.2, 159.1, 135.8, 130.8,
50.4, 25.1, 24.4, 22.5; HRMS (ESI) m/z: calcd for
C17H26NO2 [M＋H]＋, 276.1957; found 276.1958.
(2,6-Dimethylpyridine-3,5-diyl)bis(phenylmethan-
1,1'-(2,6-Dimethylpyridine-3,5-diyl)diethanone
(2a)[17] White solid. m.p. 64－66 ℃ (lit., 65－
1
67 ℃); H NMR (400 MHz, CDCl3) δ: 8.25 (s, 1H),
2.77 (s, 6H), 2.64 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ: 199.2, 160.2, 137.7, 130.1, 29.3, 24.9.
1
Dimethyl-2,6-dimethylpyridine-3,5-dicarboxylate
one) (2k) Yellow liquid. H NMR (400 MHz, CDCl3)
(2b)[17] White solid. m.p. 100－103 ℃ (lit., 98－
δ: 7.79 (d, J＝7.5 Hz, 4H), 7.62－7.58 (m, 3H), 7.47 (t,
J＝7.7 Hz, 4H), 2.61 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ: 196.1, 158.0, 136.8, 136.5, 133.8, 130.5,
129.9, 128.7, 23.5; HRMS (ESI) m/z: calcd for
C21H18NO2 [M＋H]＋, 316.1335; found 316.1332.
1
100 ℃); H NMR (400 MHz, CDCl3) δ: 8.70 (s, 1H),
3.93 (s, 6H), 2.85 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ: 166.2, 162.6, 141.0, 122.6, 52.3, 24.9.
Diethyl-2,6-dimethylpyridine-3,5-dicarboxylate
(2c)[17] White solid. m.p. 67－69 ℃ (lit., 69－71 ℃);
1H NMR (400 MHz, CDCl3) δ: 8.67 (s, 1H), 4.40 (q,
J＝7.1 Hz, 4H), 2.85 (s, 6H), 1.42 (t, J＝7.1 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ: 165.9, 162.2, 140.9,
123.1, 61.4, 24.9, 14.2.
1,1'-(2,6-Diethylpyridine-3,5-diyl)bis(propan-1-
1
one) (2l) Orange yellow liquid. H NMR (400 MHz,
CDCl3) δ: 7.99 (s, 1H), 3.00 (q, J＝7.4 Hz, 4H), 2.92 (q,
J＝7.1 Hz, 4H), 1.29 (t, J＝7.4 Hz, 6H), 1.22 (t, J＝7.0
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ: 203.4, 163.9,
135.5, 130.3, 35.1, 30.0, 13.9, 8.2; HRMS (ESI) m/z:
calcd for C15H22NO2 [M ＋ H] ＋ , 248.1649; found
248.1645.
Dipropyl-2,6-dimethylpyridine-3,5-dicarboxylate
1
(2d)[18] Orange yellow liquid. H NMR (400 MHz,
CDCl3) δ: 8.70 (s, 1H), 4.31 (t, J＝6.6 Hz, 4H), 2.85 (s,
6H), 1.86－1.77 (m, 4H), 1.04 (t, J＝7.4 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ: 165.9, 162.2, 140.9, 123.0,
66.9, 24.9, 22.0, 10.5.
Dimethyl-2,6-diethylpyridine-3,5-dicarboxylate
(2m)[17] White solid. m.p. 49－51 ℃ (lit., 50－
1
52 ℃); H NMR (400 MHz, CDCl3) δ: 8.64 (s, 1H),
Dibutyl-2,6-dimethylpyridine-3,5-dicarboxylate-
(2e)[18] Pale yellow liquid. 1H NMR (400 MHz, CDCl3)
δ: 8.66 (s, 1H), 4.32 (t, J＝6.6 Hz, 4H), 2.83 (s, 6H),
3.93 (s, 6H), 3.20 (q, J＝7.5 Hz, 4H), 1.31 (t, J＝7.5 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ: 167.2, 166.3,
141.2, 122.0, 52.3, 30.3, 13.7.
2
www.cjc.wiley-vch.de
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, XX, 1—8

One-Pot Synthesis of Hantzsch Pyridines via NH4I Promoted Condensation
1
Diethyl-2,6-dipropylpyridine-3,5-dicarboxylate
(2o) White solid. m.p. 55－58 ℃ (not reported); H
noline-3-carboxylate (3b) Orange yellow liquid; H
1
NMR (400 MHz, CDCl3) δ: 8.78 (s, 1H), 6.08－6.02 (m,
1H), 5.46－5.32 (m, 2H), 4.86－4.83 (m, 2H), 3.05 (s,
2H), 2.90 (s, 3H), 2.58 (s, 2H), 1.13 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ: 197.1, 165.4, 164.8, 164.5, 137.1,
131.7, 124.9, 124.2, 119.1, 66.1, 51.9, 46.5, 32.9, 28.3,
25.2; HRMS (ESI) m/z: calcd for C16H20NO3 [M＋H]＋,
274.1439; found 274.1438.
Ethyl-2-cyclopropyl-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydroquinoline-3-carboxylate (3c) Orange yel-
low liquid. 1H NMR (400 MHz, CDCl3) δ: 8.64 (s, 1H),
4.41 (q, J＝7.1 Hz, 2H), 3.17－3.13 (m, 1H), 2.94 (s,
2H), 2.53 (s, 2H), 1.44 (t, J＝7.1 Hz, 3H), 1.30－1.26
(m, 4H), 1.10 (s, 6H); 13C NMR (100 MHz, CDCl3) δ:
197.2, 168.8, 166.5, 164.5, 136.5, 124.2, 123.5, 61.4,
51.9, 46.5, 32.8, 28.3, 15.0, 14.3, 12.6; HRMS (ESI) m/z:
calcd for C17H22NO3 [M ＋ H] ＋ , 288.1591; found
288.1594.
Methyl-2-ethyl-7,7-dimethyl-5-oxo-5,6,7,8-tetra-
hydroquinoline-3-carboxylate (3d) Orange yellow
liquid. 1H NMR (400 MHz, CDCl3) δ: 8.72 (s, 1H), 3.94
(s, 3H), 3.23 (q, J＝7.5 Hz, 2H), 3.06 (s, 2H), 2.57 (s,
2H), 1.33 (t, J＝7.6 Hz, 3H), 1.13 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ: 197.2, 169.4, 166.3, 164.5, 137.2,
124.7, 123.8, 52.3, 51.9, 46.5, 32.9, 30.6, 28.3, 13.8;
HRMS (ESI) m/z: calcd for C15H20NO3 [M＋H]＋ ,
262.1436; found 262.1438.
NMR (400 MHz, CDCl3) δ: 8.60 (s, 1H), 4.39 (q, J＝
7.0 Hz, 4H), 3.14 (t, J＝7.6 Hz, 4H), 1.78－1.69 (m,
4H), 1.41 (t, J＝7.0 Hz, 6H), 1.00 (t, J＝7.2 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ: 166.2, 165.5, 141.0,
122.9, 61.4, 39.0, 23.2, 14.2, 14.1; HRMS (ESI) m/z:
calcd for C17H26NO4 [M ＋ H] ＋ , 308.1862; found
308.1856.
Diethyl-2,6-dicyclopropylpyridine-3,5-dicarboxyl-
ate (2p) Pale yellow solid. m.p. 101－103 ℃ (not
reported); 1H NMR (400 MHz, CDCl3) δ: 8.54 (s, 1H),
4.39 (q, J＝7.1 Hz, 4H), 3.13－3.07 (m, 2H), 1.41 (t,
J＝7.1 Hz, 6H), 1.13 (d, J＝3.2 Hz, 4H), 1.00 (q, J＝
3.3 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ: 166.5,
166.1, 140.4, 121.1, 61.2, 14.5, 14.3, 11.9; HRMS (ESI)
m/z: calcd for C17H21NNaO4 [M＋Na]＋, 326.1370;
found 326.1363.
Diethyl-2,6-diisopropylpyridine-3,5-dicarboxylate
1
(2q) Pale yellow liquid. H NMR (400 MHz, CDCl3)
δ: 8.46 (s, 1H), 4.40 (q, J＝7.1 Hz, 4H), 3.92－3.85 (m,
2H), 1.42 (t, J＝7.1 Hz, 6H), 1.31 (d, J＝6.7 Hz, 12H);
13C NMR (100 MHz, CDCl3) δ: 169.3, 166.6, 140.2,
122.0, 61.3, 32.8, 22.1, 14.2; HRMS (ESI) m/z: calcd
＋
for C17H25NNaO4 [M ＋ Na] , 330.1674; found
330.1676.
Diethyl-2,6-diphenylpyridine-3,5-dicarboxylate
(2r) White solid. m.p. 50－53 ℃ (lit., 52－55 ℃);
1H NMR (400 MHz, CDCl3) δ: 8.57 (s, 1H), 7.67－7.64
(m, 4H), 7.47－7.45 (m, 6H), 4.23 (q, J＝7.1 Hz, 4H),
1.12 (t, J＝7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ:
167.4, 159.8, 140.3, 139.4, 129.2, 128.9, 128.1, 124.8,
61.7, 13.7; HRMS (ESI) m/z: calcd for C23H22NO4 [M
＋H]＋, 376.1543; found 376.1543.
Diethyl-2,6-dimethylpyridine-4-D-3,5-dicarboxyl-
ate (2c') Orange yellow liquid. H NMR (400 MHz,
CDCl3) δ: 4.40 (q, J＝6.9 Hz, 4H), 2.85 (s, 6H), 1.42 (t,
J＝7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ: 165.9,
162.2, 123.0, 61.4, 24.9, 14.2; HRMS (ESI) m/z: calcd
for C13H17DNO4 [M＋H]＋, 253.1294; found 253.1309.
1
3,3,6,6-Tetramethyl-3,4,6,7-tetrahydroacridine-1,
8(2H,5H)-dione (2s) Pale yellow solid. m.p. 144－
145 ℃ (not reported); H NMR (400 MHz, CDCl3) δ:
Results and Discussion
1
Ethyl acetoacetate (1a) as a simple model substrate
was investigated to establish the feasibility of the strat-
egy and to screen the reaction conditions. Initially, sev-
eral nitrogen sources were examined, including
(NH4)2CO3, NH4HCO3, NH4Cl, CO(NH2)2, NH3•H2O
and NH4OAc (Table 1, Entries 1－6). Among these
nitrogen sources, NH4OAc exhibited the best result and
the yield of target product 2c could reach 94% (Table 1,
Entry 6). In the absence of NH4I or NH4OAc, the reac-
tion at the same conditions could afford 2c only in low
yields (Table 1, Entries 7 and 8), indicating that the
combination of NH4I and NH4OAc is important for this
transformation. In addition, the yield of the target prod-
uct decreased to 86% when the temperature was elevat-
ed to 130 ℃ from 115 ℃ (Table 1, Entry 9). Notably,
the desired product was obtained only in 9% yield when
the reaction was carried out at 100 ℃ (Table 1, Entry
10 and Eq. 1). The reason may be that the decomposi-
tion of DMSO to form HCHO needs higher reaction
temperature. In the present system, HCHO generated
from DMSO could act as C1 synthon. The effect of sol-
vents was further evaluated for this reaction. The results
8.81 (s, 1H), 3.06 (s, 4H), 2.57 (s, 4H), 1.13 (s, 12H);
13C NMR (100 MHz, CDCl3) δ: 196.8, 166.3, 133.5,
126.2, 51.9, 46.8, 32.7, 28.2. HRMS (ESI) m/z: calcd
for C17H22NO2 [M＋H]＋ , 272.1642; found 272.1645.
3,4,6,7-Tetrahydroacridine-1,8(2H,5H)-dione (2t)
Pale yellow solid. m.p. 161－163 ℃ (not reported); 1H
NMR (400 MHz, CDCl3) δ: 8.85 (s, 1H), 3.17 (t, J＝5.7
Hz, 4H), 2.71 (t, J＝6.0 Hz, 4H), 2.24－2.19 (m, 4H);
13C NMR (100 MHz, CDCl3) δ: 196.7, 167.2, 134.7,
127.3, 38.4, 32.9, 21.4. HRMS (ESI) m/z: calcd for
C13H13NNaO2 [M＋Na]＋, 238.0841; found 238.0838.
Ethyl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydro-
quinoline-3-carboxylate (3a) Yellow liquid. 1H NMR
(400 MHz, CDCl3) δ: 8.73 (s, 1H), 4.39 (q, J＝7.1 Hz,
2H), 3.03 (s, 2H), 2.88 (s, 3H), 2.56 (s, 2H), 1.40 (t, J＝
7.1 Hz, 3H), 1.12 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ: 197.1, 165.8, 164.6, 164.2, 137.0, 124.9, 124.5, 61.4,
51.9, 46.4, 32.9, 28.2, 25.1, 14.2; HRMS (ESI) m/z:
calcd for C15H20NO3 [M ＋ H] ＋ , 262.1438; found
262.1438.
Alyl-2,7,7-trimethyl-5-oxo-5,6,7,8-tetrahydroqui-
Chin. J. Chem. 2016, XX, 1—8
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
3

Chang, Lai & Yuan
FULL PAPER
demonstrated that only a trace amount of target product
2c was detected in toluene solvent (Table 1, Entry 11).
Especially, no expected product 2c was observed in
DMF, DMA and CH3CN (Table 1, Entries 12－14).
These results showed that DMSO solvent participated in
the reaction. In the present system, DMSO could act not
only as a solvent but also as a reactant. Compared with
NH4I, NH4Cl or NH4Br and KI resulted in a lower yield
(Table 1, Entries 15－17). Also, the results were unsat-
isfactory when I2 or HI instead of NH4I was used to fa-
cilitate this reaction (Table 1, Entries 18 and 19). Di-
rectly using I2 as the promoter, we observed the for-
mation of a lot of unknown by-products. By contrast,
NH4I as the promoter seems to be more suitable to this
reaction.
and practical.
NH2
O
O
O
NH4OAc, NH4I
DMSO, 100 °C
+
OEt
OEt
O
78%
O
EtO
OEt
(1)
(2)
N
2c, 9%
O
O
O
O
NH4OAc, NH4I
EtO
OEt
OEt
DMSO, 115 °C
15.0 mmol scale
N
2c, 86%
With the optimal conditions in hand, commercially
available 1,3-dicarbonyl compounds were employed to
examine the scope of this reaction. As shown in Table 2,
the reaction could be successfully extended to acetoace-
tates under the optimum conditions and provide the
corresponding products in relatively high isolated yields
(Table 2, Entries 2－8). However, possibly due to the
effects of steric hindrance, the yield of the target prod-
uct decreased for those 1,3-dicarbonyl compounds with
substituted benzene ring (Table 2, Entries 9, 11 and 18),
and the similar result was also observed with cyclopro-
pane as R1 group (Table 2, Entry 16). Generally, elec-
tron-donating groups have a positive effect on the reac-
tion. For example, the ideal yields were obtained when
the R1 group was replaced by electron-rich alkane (Ta-
ble 2, Entries 13, 15 and 17). In the absence of ester
groups, the yield of the target product decreased (Table
2, Entries 1, 10 and 12). Nevertheless, dimethyl malo-
nate failed to give the corresponding product (Table 2,
Entry 14), it showed that the reaction was facilitated by
mono-ester instead of diester groups. In addition, the
six-member ring diketone showed a good reactivity in
this system. Unfortunately, no desired product was de-
tected with cyclopentane-1,3-dione as the substrate (Ta-
ble 2, Entry 21).
Interestingly, when the linear and cyclic 1,3-di-
arbonyl compounds were simultaneously applied as the
substrates, three different target products were obtained
in moderate to good yields (Table 3), through the self-
coupling and cross-coupling reactions. For instance, the
reactions utilizing 5,5-dimethylcyclohexane-1,3-dione
and ethyl acetoacetate as the substrates gave a mixture
of three desired products (2c, 3a and 2s) in a ratio of
1∶4.09∶1.56 (Table 3, Entry 1). The product 3a cor-
responding to the cross-coupling reaction is main (about
61% isolated yield). Expectedly, the reaction of 5,5-di-
methylcyclohexane-1,3-dione with other open 1,3-di-
carbonyl compounds could also afford the correspond-
ing products in acceptable yields (Table 3, Entries 2－4).
These results indicated that this synthetic route is appli-
cable to both linear and cyclic 1,3-dicarbonyl com-
pounds.
Table 1 Optimization of reaction conditionsa
Nitrogen
Entry Promoter (equiv.)
Solvent Yieldb/%
source
1
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
－
(NH4)2CO3
NH4HCO3
NH4Cl
DMSO 76
DMSO 41
DMSO Trace
2
3
4
CO(NH2)2
NH3•H2O
NH4OAc
NH4OAc
－
DMSO
0
5
DMSO 60
DMSO 94
DMSO 12
DMSO 21
DMSO 86
6
7
8
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4Cl (0.5)
NH4Br (0.5)
KI (0.5)
9c
10d
11
12
13
14
15
16
17
18
19
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
DMSO
9
Toluene Trace
DMF
0
0
0
DMA
CH3CN
DMSO 80
DMSO 66
DMSO 62
DMSO 31
DMSO 52
I2 (0.5)
HI (0.5)
a Reaction conditions: 1a (1 mmol), nitrogen source (1 equiv.),
solvent (2.0 mL) and 10 h under air in a sealed tube. b GC yield
based on 1a. c Reaction temperature 130 ℃. d Reaction tempera-
ture 100 ℃.
Moreover, 2c could be obtained in a high yield (86%)
when the reaction was carried out on a 15.0 mmol scale
(Eq. 2), indicating that the reaction could be scalable
4
www.cjc.wiley-vch.de
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, XX, 1—8

One-Pot Synthesis of Hantzsch Pyridines via NH4I Promoted Condensation
Table 2 Synthesis of symmetrical pyridines from linear or cyclic 1,3-dicarbonyl compoundsa,b
Substrate
R2
Entry
Product
Yield/%
R1
Me
2a, 82
2b, 84
2c, 90
2d, 80
2e, 85
2f, 84
2
3
4
5
6
OMe
OEt
Me
OPro
OBu-t
OPentyl
7
8
9
Me
Me
Me
2g, 81
2h, 80
2i, 73
O
O
Ph
O
O
Ph
N
10
Me
2j, 79
11
12
13
14
15
Me
Et
2k, 71
2l, 60
2m, 89
2n, 0
Et
Et
OMe
OMe
OEt
OMe
Pro
2o, 83
16
OEt
2p, 76
Chin. J. Chem. 2016, XX, 1—8
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
5

Chang, Lai & Yuan
Continued
FULL PAPER
Substrate
Entry
R1
Product
Yield/%
R2
17
18
19
OEt
, 83
2q
OEt
, 66
2r
2s
O
, 88
O
20
21
, 82
2t
, 0
2u
a Reaction conditions: 1 (1 mmol), NH4I (0.5 equiv.), H4OAc (1 equiv.), DMSO (2.0 mL), 115 ℃ and 10 h. b Isolated yield.
Table 3 Synthesis of symmetrical and unsymmetrical pyridines from linear and cyclic 1,3-dicarbonyl compoundsa,b
Substrate
Entry
1
Product
Yield/%
R1
R2
Me
OEt
3a, 61
2
3
4
Me
3b, 32
3c, 40
3d, 48
O
O
O
OEt
N
(2p : 3c : 2s = 1: 3.56: 3.04)
O
O
O
Et
OMe
N
(2m : 3d : 2s = 1: 3.22: 2.49)
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), NH4I (0.5 equiv.), NH4OAc (1 equiv.), DMSO (2.0 mL), 115 ℃ and 10 h. b Isolated
yield.
6
www.cjc.wiley-vch.de
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, XX, 1—8

One-Pot Synthesis of Hantzsch Pyridines via NH4I Promoted Condensation
Scheme 2 Control experiments
1,4-dihydropyridine might be the intermediate products
and the formation of the target product probably under-
went a Hantzsch-type reaction process. The reaction
was carried out under N2 to afford the corresponding
product in 84% yield (Scheme 2c). Also, 1,4-dihydro-
pyridine could be successfully oxidized into the corre-
sponding pyridine under N2 protection (Scheme 2d).
These results indicate that oxygen is not responsible for
this oxidation in this reaction system. The reaction of
ethyl acetoacetate with NH4OAc and I2 in DMSO did
not give a satisfactory result (Table 1, Entry 18). This
result indirectly showed that in situ generated I2 from
NH4I was more favorable for this reaction. In the pre-
sent system, I2 from NH4I could acts as an oxidant.
Based on the above experimental results and the re-
lated literatures,[5,19b] plausible reaction mechanism has
been depicted in Scheme 3. First, 1,3-dicarbonyl com-
pound 1 reacts with NH4OAc to result in imine interme-
diate 2, which could be easily isomerized into interme-
diate 3. Meanwhile, the decomposition of DMSO gen-
erates formaldehyde (Scheme 3, Eq. 3).[14c,19b,20] Subse-
quently, the addition of formaldehyde to 1 affords in-
termediate 4, which further reacted with 3 to produce
intermediate 5. The unstable intermediate 5 could be
easily isomerized to 6, followed by an intramolecular
condensation to generate intermediate 7. Finally inter-
mediate 7 is oxidized to the target product 8 by I2 that is
generated through the reaction of DMSO with HI
(Scheme 3, Eq. 5).
O
D
C
O
O
O
NH4OAc, NH4I
EtO
O
OEt
(a)
(b)
OEt
OEt
N
d6-DMSO, 115 °C
2c', 85%
O
O
O
NH4OAc
EtO
OEt
+
DMSO, 115 °C
N
2c, 12%
O
O
NH2
O
EtO
OEt
+
OEt
N
50%
H
17%
O
O
O
O
NH4OAc, NH4I
EtO
OEt
(c)
(d)
OEt
DMSO, 115 °C
under N2
N
2c, 84%
O
O
O
O
NH4OAc, NH4I
OEt
EtO
EtO
OEt
DMSO, 115 °C
under N2
N
N
H
2c, 82%
In order to investigate the reaction mechanism, some
control experiments were carried out. The 4-deuterated
pyridine 2c' was obtained in 85% yield when DMSO-d6
was used as the solvent under the standard conditions
(Scheme 2a). This means that C4 in the pyridine ring
besides the target product comes from the methyl group
of DMSO. In addition, besides the target product,
(Z)-ethyl-3-aminobut-2-enoate and 1,4-dihydropyridine
were observed in the absence of NH4I (Scheme 2b),
which indicated that (Z)-ethyl-3-aminobut-2-enoate and
Conclusions
In summary, a convenient and highly efficient
one-pot ammonium iodide-promoted condensation of
1,3-dicarbonyl compounds with DMSO and NH4OAc
Scheme 3 Proposed reaction mechanism
(3)
(4)
CH3SH
NH3 + HI
+
HCHO
(CH3)2SO
NH4I
(CH3)2S +
(5)
I2
(CH3)2SO + 2 HI
+
H2O
O
O
O
O
R2
NH4OAc, NH4I
DMSO, 115
R2
R2
R1
1
8
R1
℃
N
R1
O
H C
NH4OAc
-AcOH
-H2O
2HI
I2
H
-H2O
O
O
O
NH
O
R2
R1
R2
CH2
O
R2
R2
R1
N
R1
7
R1
2
H
4
O
O
-H2O
O
O
R2
R2
NH2
O
R2
R1
R2
R1
R2
R1
R1
R1
NH
5
3
OH
NH2
O
6
Chin. J. Chem. 2016, XX, 1—8
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
7

Chang, Lai & Yuan
FULL PAPER
2013, 15, 318; (b) Zhao, M. N.; Hui, R. R.; Ren, Z. H.; Wang, Y. Y.;
Guan, Z. H. Org. Lett. 2014, 16, 3082; (c) Rycke, N. D.; Berionni, G.;
Couty, F.; Mayr, H.; Goumont, R.; David, O. R. P. Org. Lett. 2011,
13, 530.
for the preparation of 2,3,5,6-tetrasubstituted pyridines
was developed. In this strategy, DMSO serves not only
as an efficient solvent, but also as a source of one-car-
bon synthon to pyridine ring. Moreover, this reaction is
applicable to linear and cyclic 1,3-dicarbonyl com-
pounds and affords highly functionalized pyridines in
good yields without metal catalysts. The present work
has a potential application for the synthesis of valuable
symmetrical pyridines.
[5] (a) Hantzsch, A. R. Chemische Berichte 1881, 14, 1637; (b) Gu, C.
H.; Zhai, J. J.; Jiang, J. N.; Liu, H. W.; Wang, L.; Zhu, D. R.; Ji, Y. F.
Chin. J. Chem. 2014, 32, 179.
[6] (a) Mohsen, H. T. A.; Conrad, J.; Beifuss, U. Green Chem. 2012, 14,
2686; (b) Jia, X. D.; Yu, L. L.; Huo, C. D.; Wang, Y. X.; Liu, J.;
Wang, X. C. Tetrahedron Lett. 2014, 55, 264; (c) Saikh, F.; De, R.;
Ghosh, S. Tetrahedron Lett. 2014, 55, 6171; (d) Amaya, T.; Ito, T.;
Inada, Y.; Saio, D.; Hirao, T. Tetrahedron Lett. 2012, 53, 6144.
[7] Bai, C. B.; Wang, N. X.; Wang, Y. J.; Lan, X. W.; Xing, Y.; Wen, J. L.
RSC Adv. 2015, 5, 100531.
[8] Mashraqui, S. H.; Karnik, M. A. Tetrahedron Lett. 1998, 39, 4895.
[9] Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999, 40, 21.
[10] Sabitha, G.; Kumar Reddy, G. S. K.; Reddy, C. S.; Fatima, N.; Yadav,
J. S. Synthesis 2003, 8, 1267.
[11] Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Li, W. Synth. Commun. 2001, 31,
2625.
[12] Bagley, M. C.; Lubinu, M. C. Synthesis 2006, 8, 1283.
[13] Keddie, D. J.; Johnson, T. E.; Arnold, D. P.; Bottle, S. E. Org. Bio-
mol. Chem. 2005, 3, 2593.
[14] (a) Yuan, G. Q.; Zheng, J. H.; Gao, X. F.; Li, X. W.; Huang, L. B.;
Chen, H. J.; Jiang, H. F. Chem. Commun. 2012, 48, 7513; (b) Jiang,
Y. J.; Loh, T. P. Chem. Sci. 2014, 5, 4939; (c) Gao, X. F.; Pan, X. J.;
Gao, J.; Huang, H. W.; Yuan, G. Q.; Li, Y. W. Chem. Commun. 2015,
51, 210.
[15] (a) Cao, H.; Lei, S.; Li, N. Y.; Chen, L. B.; Liu, J. Y.; Cai, H. Y.; Qiu,
S. X.; Tan, J. W. Chem. Commun. 2015, 51, 1823; (b) Zhang, Z. G.;
Tian, Q.; Qian, J. J.; Liu, Q. F.; Liu, T. X.; Shi, L.; Zhang, G. S. J.
Org. Chem. 2014, 79, 8182.
[16] Wu, X.; Zhang, J. J.; Liu, S.; Gao, Q. H.; Wu, A. X. Adv. Synth.
Catal. 2016, 358, 218.
Acknowledgement
We are grateful to the National Natural Science
Foundation of China (Nos. 21572070 and 21172079).
References
[1] (a) Henkel, T.; Brunne, R. M.; Müller, H.; Reichel, F. Angew. Chem.,
Int. Ed. Engl. 1999, 38, 643; (b) Henry, G. D. Tetrahedron 2004, 60,
6043; (c) Chen, M. Z.; Micalizio, G. C. J. Am. Chem. Soc. 2012, 134,
1352; (d) Shi, Z.; Loh, T. P. Angew. Chem., Int. Ed. 2013, 52, 8584;
(e) Alex Raja, V. P.; Tenti, G.; Perumal, S.; Menéndez, J. C. Chem.
Commun. 2014, 50, 12270; (f) Durola, F.; Sauvage, J. P.; Wenger, O.
S. Chem. Commun. 2006, 171.
[2] (a) Evdokimov, N. M.; Kireev, A. S.; Yakovenko, A. A.; Antipin, M.
Y.; Magedov, I. V.; Kornienko, A. J. Org. Chem. 2007, 72, 3443; (b)
Roth, H. J.; Kleemann, A. Pharmaceutical Chemistry, Volume 1,
John Wiley & Sons, New York, 1988; (c) Mitscher, L. A. Chem. Rev.
2005, 105, 559; (d) Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem.
2005, 9, 1757; (e) Michael, J. P. Nat. Prod. Rep. 2005, 104, 3787; (f)
Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451; (g)
Zhang, W.; Wang, Y. J.; Bai, C. B.; Wen, J. L.; Wang, N. X. Chin. J.
Chem. 2015, 33, 401.
[3] (a) Lei, C. H.; Wang, D. X.; Zhao, L.; Zhu, J.; Wang, M. X. J. Am.
Chem. Soc. 2013, 135, 4708; (b) Hyster, T. K.; Rovis, T. Chem.
Commun. 2011, 47, 11846; (c) Kim, D. S.; Park, J. W.; Jun, C. H.
Chem. Commun. 2012, 48, 11334; (d) Sim, Y. K.; Lee, H.; Park, J.
W.; Kim, D. S.; Jun, C. H. Chem. Commun. 2012, 48, 11787; (e)
Khanal, H. D.; Lee, Y. R. Chem. Commun. 2015, 51, 9467; (f) Wei,
Y.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 3756; (g) Zhao, M. N.;
Ren, Z. H.; Yu, L.; Wang, Y. Y.; Guan, Z. H. Org. Lett. 2016, 18,
1194; (h) Li, Z. H.; Yan, N. N.; Xie, J. W.; Liu, P.; Zhang, J.; Dai, B.
Chin. J. Chem. 2015, 33, 589.
[17] Chen, S.; Hossain, M. S.; Fossjr, F. W. ACS Sustainable Chem. Eng.
2013, 1, 1045.
[18] Uldrikjis, J.; Duburs, G.; Dipans, I.; Cekavicius, B. Khimiya Get-
erotsiklicheskikh Soedinenii 1975, 9, 1230.
[19] (a) Muller, F. L.; Allais, C.; Constantieux, T.; Rodriguez, J. Chem.
Commun. 2008, 4207; (b) Gao, X. F.; Pan, X. J.; Gao, J.; Jiang, H. F.;
Yuan, G. Q.; Li, Y. W. Org. Lett. 2015, 17, 1038; (c) Allais, C.; Con-
stantieux, T.; Rodriguez, J. Chem. Eur. J. 2009, 15, 12945; (d) Bai,
Y.; Tang, L. C.; Huang, H. W.; Deng, G. J. Org. Biomol. Chem. 2015,
13, 4404.
[20] Xu, Y. F.; Cong, T. T.; Liu, P.; Sun, P. P. Org. Biomol. Chem. 2015,
13, 9742.
[4] (a) Gholap, S. L.; Hommes, P.; Neuthe, K.; Reissig, H. U. Org. Lett.
(Pan, B.; Qin, X.)
8
www.cjc.wiley-vch.de
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, XX, 1—8