Aluminum Chloride Promoted Hantzsch Reaction of N -Tosylhydrazones

Article abstract of DOI:10.1055/s-0036-1588496

An aluminum chloride promoted Hantzsch reaction of N -tosylhydrazones has been developed. The reaction is general for a wide range of N -tosylhydrazones, and a series of 1,4-dihydropyridines (1,4-DHPs) were prepared in moderate to excellent yields.

Full text of DOI:10.1055/s-0036-1588496

SYNTHESIS
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1
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7
-
2
1
0
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–F
paper
A
en
H. Wang, M. Tang
Paper
Synthesis
Aluminum Chloride Promoted Hantzsch Reaction of N-Tosylhydra-
zones
R1
Hu Wang
R2
R3O2C
Me
CO2R3
Me
Meng Tang*
O
O
NNTs
AlCl3, CHCl3
r.t.
+
Me
OR3
R1
H
School of Pharmacy, Lanzhou University,
Lanzhou 730000, P. R. of China
tangmeng@lzu.edu.cn
N
N
R2
Ts
22 examples and 24–96% yield
Received: 19.04.2017
Accepted after revision: 09.06.2017
Published online: 25.07.2017
useful reagent,15–17 N-tosylhydrazones have not been used
in the Hantzsch reaction. Recently, Wu and Jiang et al. re-
ported a copper-mediated [3+2] oxidative cyclization reac-
tion of N-tosylhydrazones with β-keto esters to synthesize
2,3,5-trisubstituted furans.18 In continuation of our ongoing
interest in the synthesis of pyrazoles19–22 and indazoles23
DOI: 10.1055/s-0036-1588496; Art ID: ss-2017-h0263-op
Abstract An aluminum chloride promoted Hantzsch reaction of N-to-
sylhydrazones has been developed. The reaction is general for a wide
range of N-tosylhydrazones, and a series of 1,4-dihydropyridines (1,4-
DHPs) were prepared in moderate to excellent yields.
Table 1 Screening of the Reaction Conditionsa
Key words synthetic method, aluminum chloride, Hantzsch reaction,
N-tosylhydrazones, 1,4-dihydropyridines
Ph
EtO2C
Me
CO2Et
Me
O
O
acid (0.5 equiv)
solvent
NNHTs
H
Since Hantzsch’s seminal report, the Hantzsch reaction,
which incorporates two dicarbonyl compounds, an amine,
and an aldehyde into a 1,4-dihydropyridine (1,4-DHP), has
been used extensively in different settings.1–5 1,4-DHPs and
their derivatives represent an important class of pharmaco-
logically active compounds;6,7 and some of them have been
commercialized, such as nifedipine and felodipine, which
are marketed drugs used as therapeutic for the treatment of
cardiovascular diseases (Figure 1). 1,4-DHPs are also useful
building blocks in organic chemistry and usually serve as
selective reducing agents.8–10
+
Me
OEt
Ph
r.t.
N
HN
3a
Ts
1a
2a
Entry
Acid
Solvent
Time (h)
Yield (%)b
1
2
none
AlCl3
H2SO4
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCE
4
–
1.5
4
74
–
3
4
HCl (concd)
BF3·OEt2
ZnBr2
TiCl4
4
trace
–
5
4
Cl
6
4
–
7
4
–
NO2
Cl
8
PTS
4
–
MeO2C
Me
CO2Me
MeO2C
Me
CO2Et
9
AlCl3
4
63
66
60
trace
trace
–
N
H
Me
N
H
Me
10
11
12
13
14
AlCl3
CH2Cl2
CCl4
2
nifedipine
felodipine
AlCl3
8
Figure 1 Some drugs containing 1,4-DHP structure
AlCl3
toluene
MeCN
THF
8
AlCl3
8
Literature survey revealed that inorganic ammonium
salts, organic amines, imines, enamines, ureas, and
thioureas have been employed as the source of nitrogen in
the Hantzsch reaction.11–14 But as a readily accessible and
AlCl3
8
a Reactions were performed with N-tosylhydrazone 1a (0.3 mmol), ethyl ac-
etoacetate (2a; 0.75 mmol) in 3 mL of solvent.
b Isolated yields.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

B
H. Wang, M. Tang
Paper
Synthesis
from N-tosylhydrazones, herein, we present the results of
our investigations on the Hantzsch reaction of N-tosylhy-
drazones.
Initially, we conducted the reaction of the N-tosylhydra-
zone 1a with ethyl acetoacetate (2a) in the presence of vari-
ous Brønsted acids and Lewis acids in CHCl3 at room tem-
perature (Table 1, entries 2–8), but most of the acids gave
disappointing results. Fortunately, the use of AlCl3 resulted
in a good yield of 3a and the reaction could reach comple-
tion within 1.5 hours (entry 2). Of the solvents screened
(entries 9–14), DCE, CH2Cl2, and CCl4 gave moderate yields
but the reactions required longer times (entries 9–11).
Under the above optimized conditions, we then at-
tempted to synthesize a variety of 1,4-DHPs to test the gen-
erality and scope of the method (Scheme 1). First, the scope
of the reaction was evaluated with regard to the structure
of the substituent R1. N-Tosylhydrazones derived from
benzaldehyde featuring electron-donating (3b and 3c) or
electron-withdrawing (3d, 3e, 3f, and 3g) substituents in
aromatic ring all gave the corresponding 1,4-DHP deriva-
tives. However, lower yields were observed with electron-
R1
R2
R3O2C
Me
CO2R3
Me
O
O
NNTs
AlCl3, CHCl3
r.t.
+
Me
OR3
R1
H
N
N
1
2
R2
Ts
3
OMe
Me
NO2
Cl
Cl
Br
Cl
EtO2C
Me
CO2Et
Me
EtO2C
Me
CO2Et
EtO2C
Me
CO2Et
Me
EtO2C
Me
CO2Et
EtO2C
Me
CO2Et
EtO2C
Me
CO2Et
N
N
Me
N
HN
N
Me
N
Me
Ph
N
Me
HN
HN
HN
HN
HN
Ts
Ts
Ts
Ts
Ts
Ts
3c
3b
3d
3f
3g
3e
82%
79%
43%
44%
50%
24%
Ph
Ph
Ph
Ph
EtO2C
Me
CO2Et
Me
EtO2C
Me
CO2Et
Me
EtO2C
CO2Et
EtO2C
Me
CO2Et
Me
EtO2C
Me
CO2Et
EtO2C
Me
CO2Et
N
N
N
N
Me
N
Me
N
N
N
N
Me
N
N
Me
HN
Ts
Me
Ts
Ts
Ts
Me
Ts
Me
Ts
3h
3i
3j
3k
3l
3m
64%
68%
78%
68%
95%
53%
OMe
O
O
O
S
Ph
MeO2C
CO2Me
Me
MeO2C
Me
CO2Me
Me
MeO2C
CO2Me
Me
EtO2C
CO2Et
Me
EtO2C
CO2Et
Me
MeO2C
CO2Me
Me
Me
N
N
N
Me
N
Me
N
Me
N
Me
N
HN
HN
HN
N
HN
Me
Ts
Ts
Ts
Me
Ts
Ts
Ts
3n
3o
57%
3p
3r
64%
3q
3s
79%
84%
87%
96%
S
S
S
EtO2C
Me
CO2Et
Me
MeO2C
Me
CO2Me
EtO2C
CO2Et
Me
N
N
N
N
Me
Me
N
HN
Me
Ts
Me
Ts
Ts
3u
3v
3t
56%
85%
60%
Scheme 1 Synthesis of 1,4-DHPs. Reagents and conditions: Reactions were performed with N-tosylhydrazone 1 (0.3 mmol), 2 (0.75 mmol), and AlCl3
(0.15 mmol) in CHCl3 (3 mL). Isolated yields are shown.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

C
H. Wang, M. Tang
Paper
Synthesis
withdrawing substituents; N-tosylhydrazone derived from
2-nitrobenzaldehyde was also tested, but no product could
be isolated. And the reaction was also general for aliphatic
aldehyde tosylhydrazone 3h. Additionally, some N-alkylat-
ed tosylhydrazones were employed in the reaction. As
shown in Scheme 1, methyl (3i, 3j and 3k), allyl (3l), and
propargyl (3m) were all suitable for R2 and gave the corre-
sponding 1,4-DHP derivatives in good to high yields. Other
dicarbonyl compounds were also investigated. Methyl ace-
toacetate was suitable for the reaction (3n and 3o), but eth-
yl benzoylacetate, 2,4-pentanedione, and diethyl malonate
resulted in complex products. Furthermore, tosylhydra-
zones derived from 2-furaldehyde and 2-thiophenaldehyde
were also appropriate for the reaction, and products 3p–v
were obtained in good yields.
hydrazone iminium salt 4 resulting in intermediate 5, and
then a H-elimination gives p-toluenesulfonyl hydrazide an-
ion 6 and α,β-unsaturated carbonyl compound 7. Conden-
sation of 6 with another equivalent of dicarbonyl com-
pound affords 8. Subsequently, the Michael addition of 8 to
the α,β-unsaturated carbonyl compound 7 produces the in-
termediate 9, which undergoes an intramolecular conden-
sation and elimination to form 1,4-DHPs 3.
With the 1,4-DHPs 3 in hand, the N–N bond cleavage re-
actions and detosylations of these products were investigat-
ed to demonstrate their utility. 1,4-DHPs 3 could be trans-
formed to pyridine derivatives 10 by N–N bond cleavage
and aromatization with silver nitrate in DMSO;24 thus prod-
ucts 10a and 10b were prepared in good yields (Scheme 4).
Some common conditions for detosylation were then
screened, such as TBAF in THF, Mg(OMe)2 in MeOH, NaOEt
in EtOH, and NaOH in EtOH, but no reactions were ob-
served, even at higher temperature.
We also tried to use benzaldehyde and p-toluenesulfo-
nyl hydrazide instead of N-tosylhydrazone 1a to carry out
the Hantzsch reaction. However, to ensure the consumption
of the in situ formed N-tosylhydrazone more than 1.0
equivalent of AlCl3 was needed and the yield of 3a was 66%
(Scheme 2).
R1
R1
R3O2C
Me
CO2R3
Me
R3O2C
Me
CO2R3
Me
AgNO3, DMSO
100 °C
N
N
AlCl3 (1.0 equiv)
HN
3
Ph CHO
TsNHNH2
+
2a
3a
+
Ts
10
CHCl3, r.t.
66%
Scheme 2 Using benzaldehyde and p-toluenesulfonyl hydrazide in-
stead of N-tosylhydrazone
EtO2C
CO2Et
EtO2C
CO2Et
Me
Me
N
Me
According to the classical mechanism of the Hantzsch
reaction, we propose a plausible pathway for the transfor-
mation. As shown in Scheme 3, the reaction is initiated by
the nucleophilic addition of dicarbonyl compounds to tosyl-
Me
N
10a 75%
10b 38%
Scheme 4 N–N Bond cleavage reactions of 1,4-DHPs 3
In summary, we have reported the AlCl3-promoted
Hantzsch reaction of N-tosylhydrazones. The protocol was
applied to a wide range of N-tosylhydrazones and demon-
strated excellent tolerance to a variety of substituents, and
a series of 1,4-DHPs were prepared in moderate to excellent
yields. A plausible pathway for the transformation was pro-
posed.
R2
N
O
O
H
Cl3Al
OH
O
Me
O
OEt
NR2Ts
N
Ts
Me
OEt
Me
R1
N
R1
H
AlCl3
5
4
O
AlCl3
Ts
N
OEt
R2
+
HN
R1
6
7
O
O
For product purification by flash column chromatography, silica gel
(200–300 mesh) and light petroleum ether (bp 30–60 °C) were used.
1H and 13C NMR spectra were recorded on a Varian Mercury 300 MHz
or Bruker Avance III 400 MHz spectrometer. The HRMS data were de-
termined on a Bruker Daltonics APEXII 47e FT-ICR spectrometer.
Melting points are uncorrected.
Me
OEt
O
R1
N
R2
TsN
EtO2C
O
CO2Et
O
NH
O
Me
OEt
OEt
Me
Me
R2
Me
R1
N
9
R1
Ts
8
7
N-Tosylhydrazones 1 were prepared according to our reported proce-
R1
dure.20,25
H
H
EtO2C
HO
CO2Et
Me
EtO2C
Me
CO2Et
Me
1,4-DHPs 3; General Procedure
N
N
N
Me
Under an argon atmosphere, a mixture of N-tosylhydrazone 1 (0.3
mmol), dicarbonyl compound 2 (0.75 mmol), and AlCl3 (0.15 mmol)
in CHCl3 (3 mL) was stirred at r.t. for 1–10 h. After quenching with
H2O, the product was extracted with EtOAc and the organic layer was
N
3
R2
Ts
R2
Ts
Scheme 3 Proposed pathway for 1,4-DHPs formation
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

D
H. Wang, M. Tang
Paper
Synthesis
washed with sat. aq Na2CO3 and brine, dried (anhyd MgSO4), filtered,
and concentrated in vacuo. Purification by chromatography on silica
gel using PE/EtOAc as eluent afforded the desired product 3.
HRMS (ESI): m/z calcd for C26H29ClN2O6SNa [M + Na]+: 555.133;
found: 555.134.
Compound 3f
Compound 3a
Yellow oil; yield: 86.4 mg (50%).
Yellow oil; yield: 110.6 mg (74%).
1H NMR (400 MHz, CDCl3): δ = 1.23 (t, J = 7.2 Hz, 6 H), 2.09 (s, 6 H),
2.40 (s, 3 H), 4.08–4.19 (m, 4 H), 5.40 (s, 1 H), 7.06 (td, J = 7.2, 1.6 Hz, 1
H), 7.25–7.39 (m, 4 H), 7.48 (dd, J = 8.0, 1.2 Hz, 1 H), 7.66 (d, J = 8.4 Hz,
2 H), 7.81 (dd, J = 8.0, 1.6 Hz, 1 H).
1H NMR (400 MHz, DMSO-d6): δ = 1.16 (t, J = 7.2 Hz, 6 H), 2.05 (s, 6 H),
2.35 (s, 3 H), 4.01–4.13 (m, 4 H), 5.02 (s, 1 H), 7.22–7.26 (m, 7 H),
7.33–7.36 (m, 2 H), 10.92 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 14.0, 14.8, 20.9, 37.7, 59.8, 106.1,
126.4, 127.0, 128.0, 129.8, 135.6, 144.1, 144.6, 149.8, 166.5.
HRMS (ESI): m/z calcd for C26H31N2O6S [M + H]+: 499.1897; found:
499.1892.
13C NMR (100 MHz, CDCl3): δ = 14.3, 15.2, 21.6, 39.2, 60.5, 108.6,
122.6, 127.7, 128.0, 128.2, 130.2, 130.7, 132.8, 135.3, 144.8, 145.2,
147.5, 167.5.
HRMS (ESI): m/z calcd for C26H29BrN2O6SNa [M + Na]+: 599.0822;
found: 599.0831.
Compound 3b
Compound 3g
Yellow oil; yield: 126.0 mg (82%).
Yellow oil; yield: 61.5 mg (24%).
1H NMR (400 MHz, DMSO-d6): δ = 1.16 (t, J = 7.2 Hz, 6 H), 2.04 (s, 6 H),
2.29 (s, 3 H), 2.36 (s, 3 H), 4.00–4.10 (m, 4 H), 4.96 (s, 1 H), 7.14 (s, 4
H), 7.27–7.32 (m, 4 H), 10.87 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 14.5, 15.3, 21.1, 21.5, 37.9, 60.3,
106.8, 127.5, 127.6, 129.1, 130.4, 135.9, 136.2, 142.2, 144.7, 150.0,
167.1.
1H NMR (300 MHz, DMSO-d6): δ = 0.97 (t, J = 6.6 Hz, 6 H), 1.87 (s, 6 H),
2.24 (s, 3 H), 3.84–3.91 (m, 4 H), 5.25 (s, 1 H), 7.26–7.38 (m, 4 H),
7.49–7.53 (m, 3 H), 10.80 (br s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 14.5, 15.5, 21.6, 37.9, 60.5, 106.9,
127.6, 128.9, 129.1, 129.5, 130.0, 130.7, 132.2, 136.7, 145.0, 146.4,
149.2, 167.0.
HRMS (ESI): m/z calcd for C27H32N2O6SNa [M + Na]+: 535.1873; found:
535.1879.
HRMS (ESI): m/z calcd for C26H28Cl2N2O6SNa [M + Na]+: 589.0937;
found: 589.0941.
Compound 3c
Compound 3h
Yellow oil; yield: 125.2 mg (79%).
Yellow oil; yield: 101.0 mg (64%).
1H NMR (400 MHz, CDCl3): δ = 1.26 (t, J = 7.2 Hz, 6 H), 2.15 (s, 6 H),
2.37 (s, 3 H), 3.80 (s, 3 H), 4.13–4.19 (m, 4 H), 5.11 (s, 1 H), 6.88–6.90
(m, 2 H), 7.09 (d, J = 8.4 Hz, 2 H), 7.22–7.26 (m, 2 H), 7.29–7.33 (m, 3
H).
13C NMR (100 MHz, CDCl3): δ = 14.2, 15.1, 21.6, 37.2, 55.3, 60.3, 107.9,
113.5, 127.8, 128.5, 129.9, 134.6, 136.7, 144.8, 149.4, 158.3, 167.4.
1H NMR (400 MHz, DMSO-d6): δ = 1.17 (t, J = 7.2 Hz, 6 H), 1.63–1.69
(m, 2 H), 2.02 (s, 6 H), 2.40 (s, 3 H), 2.47–2.51 (m, 2 H), 3.86 (t, J = 7.2
Hz, 1 H), 4.04–4.12 (m, 4 H), 7.17–7.21 (m, 3 H), 7.29–7.33 (m, 2 H),
7.38 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.4 Hz, 2 H), 10.95 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 14.5, 15.1, 21.5, 31.9, 32.9, 36.7,
60.2, 107.2, 126.1, 127.5, 128.4, 128.8, 130.4, 136.5, 142.5, 144.8,
150.0, 167.0.
HRMS (ESI): m/z calcd for C27H32N2O7SNa [M + Na]+: 551.1822; found:
551.1831.
HRMS (ESI): m/z calcd for C28H34N2O6SNa [M + Na]+: 549.2030; found:
549.2037.
Compound 3d
Yellow oil; yield: 70.1 mg (43%).
Compound 3i
1H NMR (400 MHz, CDCl3): δ = 1.18 (t, J = 7.2 Hz, 6 H), 2.12 (s, 6 H),
2.30 (s, 3 H), 4.06–4.13 (m, 4 H), 5.13 (s, 1 H), 7.06 (d, J = 8.0 Hz, 2 H),
7.20–7.23 (m, 2 H), 7.54 (d, J = 8.8 Hz, 2 H), 7.82 (s, 1 H), 8.12 (d, J = 8.8
Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.1, 15.2, 21.5, 38.6, 60.7, 106.5,
123.3, 127.4, 128.6, 130.0, 134.7, 145.2, 146.6, 150.7, 152.4, 166.8.
Yellow oil, yield: 104.5 mg (68%).
1H NMR (400 MHz, CDCl3): δ = 1.24 (t, J = 7.2 Hz, 6 H), 2.10 (s, 6 H),
2.39 (s, 3 H), 3.35 (s, 3 H), 4.13 (q, J = 7.2 Hz, 4 H), 5.02 (s, 1 H), 7.17–
7.24 (m, 3 H), 7.32–7.40 (m, 4 H), 7.51 (d, J = 7.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.2, 15.2, 21.6, 38.6, 41.8, 60.2, 107.5,
126.4, 127.3, 128.0, 128.1, 130.1, 135.3, 144.5, 145.6, 149.3, 167.3.
HRMS (ESI): m/z calcd for C27H32N2O6SNa [M + Na]+: 535.1873; found:
HRMS (ESI): m/z calcd for C26H29N3O8SNa [M + Na]+: 566.1568; found:
566.1595.
535.1882.
Compound 3e
Compound 3j
Yellow oil; yield: 70.3 mg (44%).
Yellow oil; yield: 111.9 mg (78%).
1H NMR (400 MHz, CDCl3): δ = 1.23 (t, J = 7.2 Hz, 6 H), 2.11 (s, 6 H),
2.40 (s, 3 H), 4.05–4.19 (m, 4 H), 5.46 (s, 1 H), 7.13–7.17 (m, 1 H),
7.22–7.26 (m, 3 H), 7.29–7.33 (m, 2 H), 7.60 (d, J = 8.4 Hz, 2 H), 7.77
(dd, J = 8.0, 1.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.1, 15.1, 21.6, 36.7, 60.5, 108.2,
127.2, 127.7, 127.9, 129.4, 130.2, 130.5, 132.4, 135.2, 142.7, 145.1,
148.0, 167.4.
1H NMR (400 MHz, CDCl3): δ = 0.96 (t, J = 7.2 Hz, 3 H), 1.27–1.35 (m, 8
H), 1.50–1.56 (m, 2 H), 2.03 (s, 6 H), 2.45 (s, 3 H), 3.35 (s, 3 H), 3.81 (t,
J = 7.2 Hz, 1 H), 4.11–4.24 (m, 4 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.68 (d, J =
8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.2, 14.8, 18.7, 21.6, 32.2, 39.2, 42.0,
60.0, 108.4, 127.2, 130.0, 135.5, 144.6, 149.1, 167.5.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

E
H. Wang, M. Tang
Paper
Synthesis
HRMS (ESI): m/z calcd for C24H34N2O6SNa [M + Na]+: 501.2030; found:
13C NMR (100 MHz, CDCl3): δ = 15.2, 21.5, 38.1, 41.9, 51.4, 107.1,
501.2050.
126.5, 127.3, 127.7, 128.1, 130.0, 135.2, 144.5, 145.2, 149.8, 167.7.
HRMS (ESI): m/z calcd for C25H28N2O6SNa [M + Na]+: 507.1560, found:
507.1570.
Compound 3k
Yellow oil; yield: 110.2 mg (68%).
1H NMR (400 MHz, CDCl3): δ = 1.28 (t, J = 7.2 Hz, 6 H), 1.85–1.91 (m, 2
H), 2.07 (s, 6 H), 2.43 (s, 3 H), 2.62–2.68 (m, 2 H), 3.36 (s, 3 H), 3.91 (t,
J = 7.2 Hz, 1 H), 4.13–4.21 (m, 4 H), 7.13–7.17 (m, 1 H), 7.26–7.30 (m,
6 H), 7.64 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.2, 14.9, 21.6, 31.9, 32.7, 38.0, 42.0,
60.1, 107.9, 125.4, 127.2, 128.1, 128.2, 130.1, 135.5, 142.8, 144.6,
149.4, 167.4.
Compound 3p
Yellow oil; yield: 115.9 mg (84%).
1H NMR (400 MHz, CDCl3): δ = 2.15 (s, 6 H), 2.39 (s, 3 H), 3.75 (s, 6 H),
5.27 (s, 1 H), 6.14 (d, J = 3.2 Hz, 1 H), 6.36 (dd, J = 3.2, 2.0 Hz, 1 H), 7.13
(d, J = 8.0 Hz, 2 H), 7.27–7.31 (m, 2 H), 7.40 (s, 1 H), 7.64 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.9, 21.6, 32.8, 51.7, 104.5, 105.4,
110.2, 127.8, 129.9, 134.3, 141.4, 145.0, 151.2, 156.3, 167.3.
HRMS (ESI): m/z calcd for C29H36N2O6SNa [M + Na]+: 563.2186; found:
563.2195.
HRMS (ESI): m/z calcd for C22H24N2O7SNa [M + Na]+: 483.1196; found:
483.1208.
Compound 3l
Compound 3q
Yellow oil; yield: 161.3 mg (95%).
Yellow oil; yield: 127.4 mg (87%).
1H NMR (400 MHz, DMSO-d6): δ = 1.18 (t, J = 7.2 Hz, 6 H), 1.74–1.80
(m, 2 H), 2.01 (s, 6 H), 2.42 (s, 3 H), 2.53–2.57 (m, 2 H), 3.80 (t, J = 6.8
Hz, 1 H), 4.06–4.13 (m, 4 H), 4.41 (d, J = 6.8 Hz, 2 H), 5.29–5.32 (m, 1
H), 5.39–5.44 (m, 1 H), 5.98–6.08 (m, 1 H), 7.15–7.22 (m, 3 H), 7.27–
7.31 (m, 2 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.63 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 14.1, 15.5, 21.0, 31.2, 32.4, 38.2,
58.6, 59.7, 106.9, 120.9, 125.6, 127.1, 127.9, 128.3, 130.1, 132.2, 135.4,
142.1, 144.8, 149.0, 166.7.
1H NMR (400 MHz, CDCl3): δ = 1.28 (t, J = 7.2 Hz, 6 H), 2.14 (s, 6 H),
2.40 (s, 3 H), 4.17–4.25 (m, 4 H), 5.29 (s, 1 H), 6.15 (d, J = 3.2 Hz, 1 H),
6.36 (dd, J = 3.2, 2.0 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 2 H), 7.22 (s, 1 H), 7.33
(d, J = 8.4 Hz, 2 H), 7.40 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.2, 15.0, 21.6, 33.0, 60.4, 105.0,
105.3, 110.2, 127.9, 129.9, 134.4, 141.2, 144.9, 150.6, 156.5, 166.9.
HRMS (ESI): m/z calcd for C24H28N2O7SNa [M + Na]+: 511.1509; found:
511.1518.
HRMS (ESI): m/z calcd for C31H38N2O6SNa [M + Na]+: 589.2343; found:
589.2355.
Compound 3r
Yellow oil; yield: 96.4 mg (64%).
Compound 3m
1H NMR (400 MHz, CDCl3): δ = 1.27 (t, J = 7.2 Hz, 6 H), 2.07 (s, 6 H),
2.40 (s, 3 H), 3.36 (s, 3 H), 4.15–4.23 (m, 4 H), 5.19 (s, 1 H), 6.22 (dd, J =
2.4, 0.8 Hz, 1 H), 6.35 (dd, J = 3.2, 1.6 Hz, 1 H), 7.19 (d, J = 8.4 Hz, 2 H),
7.38–7.42 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 14.2, 15.0, 21.6, 32.8, 42.2, 60.3, 104.7,
105.5, 110.3, 127.4, 130.0, 135.2, 141.0, 144.5, 150.5, 157.4, 166.9.
Yellow oil: yield: 89.7 mg (53%).
1H NMR (400 MHz, DMSO-d6): δ = 1.18 (t, J = 7.2 Hz, 6 H), 1.71–1.77
(m, 2 H), 2.04 (s, 6 H), 2.42 (s, 3 H), 2.51–2.56 (m, 2 H), 3.56 (t, J = 2.4
Hz, 1 H), 3.81 (t, J = 7.2 Hz, 1 H), 4.08–4.12 (m, 4 H), 4.75 (d, J = 2.0 Hz,
2 H), 7.16–7.22 (m, 3 H), 7.28–7.32 (m, 2 H), 7.41 (d, J = 8.4 Hz, 2 H),
7.69 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 14.1, 15.1, 21.0, 31.3, 32.4, 37.8,
45.0, 59.8, 77.3, 78.1, 107.0, 125.6, 127.3, 127.9, 128.3, 129.9, 135.1,
142.0, 145.1, 149.4, 166.7.
HRMS (ESI): m/z calcd for C25H30N2O7SNa [M + Na]+: 525.1666; found:
525.1678.
Compound 3s
HRMS (ESI): m/z calcd for C31H36N2O6SNa [M + Na]+: 587.2186; found:
587.2198.
Yellow oil; yield: 137.1 mg (96%).
1H NMR (400 MHz, CDCl3): δ = 2.17 (s, 6 H), 2.37 (s, 3 H), 3.76 (m, 6 H),
5.34 (s, 1 H), 6.94–6.95 (m, 1 H), 6.98–7.00 (m, 1 H), 7.08 (q, J = 17.2,
8.2 Hz, 4 H), 7.23–7.24 (m, 1 H), 7.45 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.9, 21.6, 33.9, 51.6, 106.8, 123.9,
124.1, 126.3, 127.7, 129.9, 134.1, 144.9, 148.0, 151.1, 167.2.
Compound 3n
Yellow oil: yield: 118.5 mg (79%).
1H NMR (400 MHz, CDCl3): δ = 2.16 (s, 6 H), 2.36 (s, 3 H), 3.72 (s, 6 H),
3.80 (s, 3 H), 5.11 (s, 1 H), 6.88–6.91 (m, 2 H), 7.07 (d, J = 8.0 Hz, 2 H),
7.17 (d, J = 8.4 Hz, 2 H), 7.26–7.30 (m, 2 H), 7.42 (s, 1 H).
HRMS (ESI): m/z calcd for C22H24N2O6S2Na [M + Na]+: 499.0968;
found: 499.0977.
13C NMR (100 MHz, CDCl3): δ = 15.0, 21.6, 36.8, 51.6, 55.3, 107.5,
113.6, 127.7, 128.3, 129.9, 134.4, 136.3, 144.9, 150.1, 158.4, 167.8.
HRMS (ESI): m/z calcd for C25H28N2O7SNa [M + Na]+: 523.1509; found:
523.1518.
Compound 3t
Yellow oil; yield: 99.2 mg (56%).
1H NMRd (400 MHz, CDCl3): δ = 2.10 (s, 6 H), 2.37 (s, 3 H), 3.36 (s, 3
H), 3.74 (s, 6 H), 5.26 (s, 1 H), 6.97–7.03 (m, 2 H), 7.12 (d, J = 8.4 Hz, 2
H), 7.20–7.27 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 15.0, 21.5, 33.7, 42.1, 51.5, 106.5,
124.0, 124.2, 126.4, 127.3, 130.0, 135.0, 144.5, 148.8, 150.8, 167.1.
Compound 3o
Yellow oil; yield: 82.8 mg (57%).
1H NMR (400 MHz, CDCl3): δ = 2.10 (s, 6 H), 2.37 (s, 3 H), 3.35 (s, 3 H),
3.68 (s, 6 H), 5.05 (s, 1 H), 7.15 (d, J = 8.0 Hz, 2 H), 7.21–7.26 (m, 1 H),
7.30–7.36 (m, 4 H), 7.47 (d, J = 7.2 Hz, 2 H).
HRMS (ESI): m/z calcd for C23H26N2O6S2Na [M + Na]+: 513.1124;
found: 513.1135.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

F
H. Wang, M. Tang
Paper
Synthesis
Compound 3u
Supporting Information
Yellow oil; yield: 128.5 mg (85%).
Supporting information for this article is available online at
1H NMR (400 MHz, CDCl3): δ = 1.29 (t, J = 7.2 Hz, 6 H), 2.16 (s, 6 H),
2.37 (s, 3 H), 4.18–4.27 (m, 4 H), 5.36 (s, 1 H), 6.95–6.96 (m, 1 H),
6.98–7.00 (m, 1 H), 7.05–7.07 (m, 2 H), 7.11–7.13 (m, 2 H), 7.23 (dd,
J = 4.8, 0.8 Hz, 1 H), 7.42 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.2, 15.0, 21.6, 33.9, 60.5, 107.1,
123.8, 123.9, 126.2, 127.7, 130.0, 134.2, 144.8, 148.2, 150.7, 166.8.
https://doi.org/10.1055/s-0036-1588496.
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References
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Arulmoli, T.; Isloor, N. A. Eur. J. Med. Chem. 2011, 46, 5591.
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2007, 40, 1327.
HRMS (ESI): m/z calcd for C24H28N2O6S2Na [M + Na]+: 527.1281;
found: 527.1292.
Compound 3v
Yellow oil; yield: 93.3 mg (60%).
1H NMR (400 MHz, CDCl3): δ = 1.29 (t, J = 7.2 Hz, 6 H), 2.10 (s, 6 H),
2.38 (s, 3 H), 3.02 (s, 3 H), 4.16–4.24 (m, 4 H), 5.27 (s, 1 H), 6.96–6.98
(m, 1 H), 7.04–7.06 (m, 1 H), 7.13 (d, J = 8.0 Hz, 2 H), 7.20 (dd, J = 4.8,
1.2 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.2, 15.1, 21.6, 33.9, 42.1, 60.4, 107.0,
123.8, 124.3, 126.3, 127.3, 130.0, 135.1, 144.5, 149.0, 150.3, 166.8.
HRMS (ESI): m/z calcd for C25H30N2O6S2Na [M + Na]+: 541.1437;
found: 541.1447.
(11) Yoo, J. S.; Laughlin, T. J.; Krob, J. J.; Mohan, R. S. Tetrahedron Lett.
2015, 56, 4060.
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926.
Pyridines 10; General Procedure
A mixture of 1,4-DHP 3 (0.1 mmol) and AgNO3 (17 mg, 0.1 mmol) in
DMSO (1.5 mL) was stirred at 100 °C for 3 h. After quenching with
H2O, the product was extracted with EtOAc and the organic layer was
washed with brine, dried (anhyd MgSO4), filtered, and concentrated
in vacuo. Purification by chromatography on silica gel using PE/EtOAc
as eluent afforded the desired product 10.
The spectral data for compounds 10a and 10b are in agreement with
the literature values.26
Compound 10a
Yellow oil; yield: 24.5 mg (75%).
1H NMR (300 MHz, CDCl3): δ = 0.90 (t, J = 9.0 Hz, 6 H), 2.61 (s, 6 H),
4.00 (q, J = 9.0 Hz, 4 H), 7.23–7.27 (m, 2 H), 7.34–7.37 (m, 3 H).
(24) Zhao, Y.-H.; Li, Y.; Luo, M.; Tang, Z.; Deng, K. Synlett 2016, 27,
2597.
(25) Kong, Y.; Zhang, W.; Tang, M.; Wang, H. Tetrahedron 2013, 69,
7487.
(26) Kumar, A.; Maurya, R. A.; Sharma, S. Bioorg. Med. Chem. Lett.
2009, 19, 4432.
Compound 10b
Yellow oil; yield: 13.0 mg (38%).
1H NMR (300 MHz, CDCl3): δ = 0.95 (t, J = 9.0 Hz, 6 H), 2.36 (s, 3 H),
2.60 (s, 6 H), 4.03 (q, J = 9.0 Hz, 4 H), 7.16 (d, J = 3.0 Hz, 4 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F