Intramolecular Diels-Alder reactions of 1,2,4-triazines. Synthesis of 3-alkylpyridines via Raney nickel desulfurization of thieno[2,3-b]pyridines

Article abstract of DOI:10.1016/j.tet.2021.132158

2-Aryl-2,3-dihydrothieno[2,3-b]pyridines have been prepared via intramolecular Diels-Alder reactions of suitably 3-substituted 1,2,4-triazine intermediates, followed by their reductive desulfurization with Raney Nickel to form 3-substituted pyridines. A o

Full text of DOI:10.1016/j.tet.2021.132158

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Intramolecular Diels-Alder reactions of 1,2,4-triazines. Synthesis of 3-
alkylpyridines via Raney nickel desulfurization of thieno[2,3-b]
pyridines
,
Maria V. Papadopoulou* 1, Edward C. Taylor 2
Department of Chemistry, Princeton University, Princeton, NJ, 08544, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Aryl-2,3-dihydrothieno[2,3-b]pyridines have been prepared via intramolecular Diels-Alder reactions of
suitably 3-substituted 1,2,4-triazine intermediates, followed by their reductive desulfurization with
Raney Nickel to form 3-substituted pyridines. A one-pot synthesis of 2-aryl-2,3-dihydrothieno[2,3-b]-
pyridines from thiosemicarbazide is described as well.
Received 2 March 2021
Received in revised form
7 April 2021
Accepted 9 April 2021
Available online xxx
© 2021 Elsevier Ltd. All rights reserved.
Keywords:
Intramolecular Diels-Alder reactions
Triazines
Pyridines
Desulfurization
1. Introduction
2. Results and discussion
The versatility displayed with 1,2,4-triazines possessing suitable
dienophilic appendages in their 3- or 6-position for obtaining
various fused heterocycles via intramolecular Diels-Alder reactions
has been previously demonstrated [1e16]. The mode of cycload-
dition in these reactions involves addition across C3 and C6 of the
1,2,4-triazine nucleus with subsequent aromatization of the inter-
mediate cycloadduct by extrusion of molecular nitrogen, affording
fused heterocyclic species, often under extremely mild conditions
[1e15]. The usual need for an electron-rich dienophile is overcome
due to the intramolecular process. We have now extended this
methodology to form 2-aryl-2,3-dihydrothieno[2,3-b]pyridines
through 3-appropriately substituted 1,2,4-triazines. These, in turn,
can undergo reductive desulfurization with Raney Nickel to give 3-
substituted pyridines. Such functionalized pyridines are of interest,
since they may serve as potential intermediates for ultimately
obtaining various analogues of tetrahydrofolic acid.
The first approach attempted for obtaining 2-aryl-2,3-
dihydrothieno[2,3-b]pyridines 7, was via the 3-(arylmethyleno-
thio)-1,2,4-triazines 3, which by alkylation on the active benzylic
position with propargyl bromide could give the desired triazines 5
followed by an intramolecular Diels-Alder reaction to give the 2-
aryl-2,3-dihydrothieno[2,3-b]pyridines 7 (Scheme 1).
Unfortunately this attempted alkylation proved fruitless, even in
the case of the sulfoxide 4, in which the benzylic position is even
more active. No significant influence in the reactivity of the
benzylic position could be achieved by varying the electron with-
drawing substituents Y in the para-position of the phenyl group of
3. We therefore decided that preparation of the requisite cycload-
dition precursors 5 might be achieved by incorporating the dien-
ophilic sidechain into the active methylene group of compound 2
prior to the condensation reaction with the 1,2-dicarbonyl com-
pounds 1. For this purpose, S-(1-aryl-3-butynyl-) thio-
semicarbazide hydrogen bromides or iodides 13 were synthesized
through bromides [17] 11 or iodides [17] 12 (Scheme 2).
During the alkylation of thiosemicarbazide to give 13, an elim-
ination process was observed to occur as well, leading to the 4-aryl-
3-buten-1-yne 14. The elimination process was expected to some
extent since heating was required during the alkylation, but it was
substantial when substituent Y was a strong electron withdrawing
* Corresponding author.
E-mail address: mvpapadopoulou@gmail.com (M.V. Papadopoulou).
Recently retired from NorthShore University HealthSystem, 2650 Ridge Ave,
1
Evanston, IL 60201. Home address: 5337 Lunt Ave, Skokie, IL, 60077.
2
This manuscript is dedicated to the memory of Professor EC Taylor.
https://doi.org/10.1016/j.tet.2021.132158
0040-4020/© 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: M.V. Papadopoulou and E.C. Taylor, Intramolecular Diels-Alder reactions of 1,2,4-triazines. Synthesis of 3-
alkylpyridines via Raney nickel desulfurization of thieno[2,3-b]pyridines, Tetrahedron, https://doi.org/10.1016/j.tet.2021.132158

Scheme 1. Procedures attempted for the synthesis of compounds 7
Scheme 2. Synthetic procedures for compounds 13
2

M.V. Papadopoulou and E.C. Taylor
Tetrahedron xxx (xxxx) xxx
group (e.g., carbomethoxy-group), limiting therefore the yield of
13. A similar type of elimination reaction takes place also during the
heating required for the condensation reaction of 13 with 1,2-
dicarbonyl compounds 1, diminishing thus the yield of 5 (Proced-
ure B, Scheme 3).
yield and temperature. This buttressing effect [7] of the a-substit-
uent in the tethered chain is presumably a consequence of
“entropic assistance” provided by the aryl group, which facilitates
orientation of the side chain into a preferred conformation for
cycloaddition (Thorpe-Ingold effect).
Scheme 3. Successful synthetic procedures for compounds 7a-g
To overcome this problem, Procedure A was used (Scheme 3).
This strategy, which has been successfully applied before in similar
reactions [7], explored the one-pot synthesis of 2-aryl-2,3-
dihydrothieno[2,3-b]pyridines 7, starting from the condensation
of 1,2-dicarbonyl compounds 1 with thiosemicarbazide to provide
the hydrazones 16. Deprotonation of 16 with one equivalent of NaH
gave the delocalized anion 17. This upon alkylation with 4-aryl-4-
bromo (or iodo-)-1-butyne 11/(12), led directly to the triazines 5,
which was not isolated, avoiding thus its further conversion to the
elimination products 14 and 15. Changing the solvent at this point
to chlorobenzene, followed by refluxing for 6 h, resulted in the
formation of 2-aryl-2,3-dihydrothieno[2,3-b]pyridines 7. The yields
of 7 shown in Table 1 are based on the 1,2-dicarbonyl compounds 1
and therefore are relatively low (except for 7a in which the yield is
based on the corresponding triazine 5a, where Procedure B was
followed). On the other hand, the competitive elimination reaction
giving 1,2,4-triazin-3-thione 15 and 4-aryl-3-buten-1-yne 14
(Scheme 3) could not be avoided, due to heating during the Diels-
Alder reaction, thus decreasing the yields of 7 to a significant de-
gree. This competitive reaction did not occur when the substituent
Y was hydrogen. Since the duration of the Diels-Alder reaction was
kept constant (6 h), we cannot compare the effect of the sub-
stituents R1 and R2 of the triazines 5 on the rate of the condensation
We modified the previous methodology to obtain the fused
pyridine 18, derived from diethylketomalonate, which permits the
continuation towards the 6,7-annulated-5-deazapterine [18] 19, a
precursor of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid, DDATHF 20
(Scheme 4). 2-Amino-5-deaza-pterines 19 can be obtained by
reacting compounds 18 with guanidine hydrochloride in N-methyl-
2-pyrrolidinone. In fact, we have successfully synthesized such a
compound (Y ¼ CN), in 40% yield (data not included). Compounds
19 can then be hydrolyzed to their carboxylic acids and coupled
with diethyl L-glutamate. Desulfurization, hydrolysis of the ethyl
esters and reduction of the pyridinic ring could lead to the desired
compound 20.
The modification of the procedure consisted of the formation of
Table 1
R1
R2
X
Y
7
Yield %
Procedure
H
H
H
H
Ph
Ph
Ph
4-ClC6H4
Br
I
H
CN
CO2Me
CN
CN
a
b
c
d
e
f
78
29
trace
30
15
B
A
B
A
A
A
A
Br
Br
Br
Br
Br
(CH2)4<
Me
H
Me
4-MeOC6H4
CN
CN
30
23
g
reaction. However, the substituent in the
a-position of the tethered
chain seems to facilitate the Diels-Alder reaction, in terms of time,
3

M.V. Papadopoulou and E.C. Taylor
Tetrahedron xxx (xxxx) xxx
Scheme 4. Potential synthetic scheme for 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF) 20
Scheme 5. Synthetic procedure for compounds 18a-c
the thione [19] 21, which upon treatment with NaH gave the anion
22. Alkylation of 22 with 11/12 provided the intermediate tri-
azinone 23, which was refluxed in POCl3 to give directly the 2-aryl-
Finally, reductive desulfurization of 7 was undertaken, to form their
corresponding 3-substituted pyridines. This desulfurization with
Raney Nickel worked sufficiently well as depicted in Scheme 6, and
5-carboethoxy-6-chloro-2,3-dihydrothieno[2,3-b]pyridine
18
(Scheme 5) and Table 2.
Table 3
Y
R1
R2
7
24
Yield %
Reflux time (h)
Table 2
H
H
H
H
Ph
Ph
p-ClC6H4
a
b
d
e
f
aa
bb
bb
c
d
e
86
96
91
98
95
93
5
5
5
5
Y
23
18
Yield %
mp oC
CN
CN
CN
CN
CN
H
CN
CO2Me
a
a
b
c
48
15
35
88e89
144e145
132e134
ba
ca
(CH2)4<
Me
H
Me
p-MeOC6H4
5
g
48RT þ 2c
a
23b,c were not isolated to avoid decomposition via elimination.
a
24a is a phenyl-ethyl pyridine, since Y ¼ H in 7a.
b
During desulfurization of 7d, chlorine was cleaved. Therefore, the desulfuriza-
tion product of 7d is identical with the desulfurization product of 7b, characterized
as 24b.
c
48RT þ 2: 24 h strirring under room temperature and 2 h refluxing in chloro-
benzene (132 ꢀC).
Scheme 6. Desulfurization of compounds 7 to obtain compounds 24a-e
4

M.V. Papadopoulou and E.C. Taylor
Tetrahedron xxx (xxxx) xxx
Table 3, but with some restrictions regarding substituents.
It is remarkable that the cyano-group was converted all the way
to the methyl-group, presumably via the formation of a primary
benzylic amine [20]. Thus, in the case that we need to retain a
functional group for its eventual conversion to a carboxyl group,
instead of a cyano group, we should use a carboalkoxy group which
is not affected [21] by Raney Nickel, or we should attempt the hy-
drolysis of the nitrile group before the desulfurization. We also
observed that the chloro-substituent in 7d was cleaved during
desulfurization [22]. We are not sure if the chlorine in the 6-
position of 18 would behave in the same way during desulfuriza-
tion. In this case, the condensation with guanidine should precede
the desulfurization of 18.
4.2. Procedure B
To a stirred mixture of the phenyl glyoxal hydrate (10.0 mmol)
and sodium bicarbonate (10.0 mmol) in ethanol (10 mL) at 0 ꢀC was
added dropwise
a
solution of S-(1-aryl-3-butynyl)thio-
semicarbazide (10.0 mmol) in water (10 mL). After the addition the
reaction mixture was stirred at room temperature for 4 h. Ethanol
was removed from the resulting reaction mixture by evaporation
under reduced pressure, and the residual aqueous mixture was
extracted with methylene chloride (3 ꢁ 20 mL). The methylene
chloride extracts were combined, dried (anhy. Na2SO4), and evap-
orated under reduced pressure. The residual oil was purified by
silica gel (~50 g) column chromatography with methylene chloride
as eluting solvent. The 5-phenyl-S-(1-aryl-3-butynylthio)-1,2,4-
triazine 5 was isolated as an oil and was refluxed in chloroben-
zene for 6 h, giving the corresponding fused pyridine 7.
3. Conclusions
Using two alternative routes, we have synthesized a series of 2-
aryl-2,3-dihydrothieno[2,3-b]pyridines (7a-g and 18a-c) via intra-
molecular Diels-Alder reactions of suitably 3-substituted 1,2,4-
triazine intermediates. Reaction conditions (e.g. solvent, tempera-
ture, reaction time, substitution) could be optimized for improving
the yields of these compounds in the future. The reductive desul-
furization of 7a-g with Raney nickel led to the formation of 3-
substituted pyridines (24a-e) in good yields. Compounds such as
18a-c can serve as precursors of 5,10-dideaza-5,6,7,8-
tetrahydrofolic acid (DDATHF 20) analogues, known to exhibit
anticancer therapeutic properties [23].
4.3. 2,6-Diphenyl-2,3-dihydrothieno[2,3-b]pyridine (7a)
Following Procedure
B with 3-(1-phenyl-3-butynylthio)-5-
phenyl-triazine (5a). Yield: 78%. Obtained as a white solid, mp
130e132 ꢀC; following recrystallization from 50 : 50 ether/petro-
leum ether. 1H NMR (CDCl3)
d
3.46 (dd, J1 ¼ 15 Hz, J2 ¼ 6 Hz, 1H);
3.68 (dd, J1 ¼15 Hz, J2 ¼ 9 Hz, 1H); 5.13 (t, J ¼ 7.5 Hz, 1H); 7.27e7.49
(m, 10H); 7.98 (d, J ¼ 6 Hz, 2H). HRMS: Calcd for C19H15NS: m/z
289.0925. Found m/z 289.0919. Anal. Calcd for C19H15NS: C, 78.86;
H, 5.22; N, 4.87. Found: C, 77.43; H, 5.07; N, 5.37.
4.4. 2-(p-Cyanophenyl)-6-phenyl-2,3-dihydrothieno[2,3-b]pyridine
(7b)
4. Experimental section
Melting points were determined on a Thomas-Hoover open
capillary melting point apparatus and are uncorrected. Infrared
spectra were obtained on a PerkinElmer 1320 Infrared Spectro-
photometer, and NMR spectra were determined on a Nicolet QE300
(300 MHz) spectrometer. Mass spectra were determined on a AEI
MS-9 instrument, and elemental analyses were carried out by Eli
Lilly & Co., Indianapolis, Indiana. Commercial reagents were uti-
lized without further purification.
Following Procedure A with phenyl glyoxal monohydrate. Yield:
29%. Obtained as a white solid, mp 137e138 ꢀC. 1H NMR (CDCl3)
d
3.40 (dd, J1 ¼ 15 Hz, J2 ¼ 6 Hz, 1H); 3.75 (dd, J1 ¼ 18 Hz, J2 ¼ 9 Hz,
1H); 5.09 (t, J ¼ 7.5 Hz, 1H); 7.40e7.57 (m, 5H); 7.62 (dd, J1 ¼ 6 Hz,
J2 ¼ 3 Hz, 4H); 7.98 (dd, J1 ¼ 3 Hz, J2 ¼ 1.5 Hz, 2H). HRMS: Calcd for
C
C
20H14N2S: m/z 314.0878. Found m/z 314.0868. Anal. Calcd for
20H14N2S: C, 76.40; H, 4.49; N, 8.91; S, 10.20. Found: C, 76.14; H,
4.70; N, 8.74; S, 10.05.
4.1. Formation of 2-aryl-2,3-Dihydrothieno[2,3-b]pyridines (7).
Procedure A
4.5. 2-(p-Carbomethoxyphenyl)-6-phenyl-2,3-dihydrothieno[2,3-b]
pyridine (7c)
A mixture of the 1,2-dicarbonyl compound (10 mmol) and thi-
osemicarbazide (10.0 mmol) in 30 mL of absolute ethanol was
heated at reflux for 20 min. The resulting solution was then cooled
in an ice bath, and sodium hydride (80% in mineral oil, 10 mmol)
was cautiously added to the mixture, which was then stirred at
room temperature with exclusion of water for 15 min. This was
followed by the dropwise addition of 4-aryl-4-bromo-(or iodo-)
butyne (10.0 mmol), and the resulting reaction mixture was heated
at reflux with exclusion of water for 1 h. Ethanol was removed from
the reaction mixture by evaporation under reduced pressure, and
the residual oily solid was redissolved in chlorobenzene (10 mL).
This mixture was refluxed (132 ꢀC) with exclusion of moisture for
6 h. A saturated solution of sodium bicarbonate (20 mL) was added
to the resultant reaction solution, and this aqueous mixture was
extracted with methylene chloride (3 ꢁ 20 mL). The methylene
chloride extracts were combined, dried (anhy. Na2SO4), and evap-
orated under reduced pressure to yield an oil which was chroma-
tographed over silica gel (~60 g); elution with methylene chloride-
ether (90:10) yielded the desired 2-aryl-2,3-dihydrothieno[2,3-b]
pyridines (7) plus a variable amount of the 5,6-substituted-1,2,4-
triazine-3-thiones (15) and the corresponding trans 4-aryl -3-
buten-1-ynes (14) [elimination products].
Following Procedure B with the corresponding triazine 5c. Iso-
lated by preparative TLC in trace quantity. 1H NMR (CDCl3)
d 3.40
(dd, J1 ¼ 15 Hz, J2 ¼ 6 Hz, 1H); 3.75 (dd, J1 ¼ 18 Hz, J2 ¼ 9 Hz, 1H);
3.92 (s, 3H); 5.15 (t, J ¼ 9 Hz, 1H); 7.40e8.06 (m, 11H). HRMS: Calcd
for C21H17NO2S: m/z 347.0990. Found m/z 347.0980.
4.6. 2-(p-Cyanophenyl)-6-(p-chlorophenyl)-2,3-dihydrothieno[2,3-
b]pyridine (7d)
Following Procedure A with p-chlorophenyl glyoxal mono-
hydrate. Yield ¼ 30%. Obtained as a white solid, mp 158e160 ꢀC. 1H
NMR (CDCl3)
d
3.40 (dd, J1 ¼ 15 Hz, J2 ¼ 6 Hz, 1H); 3.75 (dd,
J1 ¼ 15 Hz, J2 ¼ 6 Hz, 1H); 5.09 (t, J ¼ 6 Hz, 1H); 7.39e7.63 (m, 8H);
7.92 (d, J ¼ 9 Hz, 2H). HRMS: Calcd for C20H13N2SCl: m/z 348.0488.
Found m/z 348.0472. Anal. Calcd for C20H13N2SCl: C, 68.86; H, 3.76;
N, 8.03; S, 9.19; Cl,10.16. Found: C, 68.64; H, 3.69; N, 7.93; S, 8.96; Cl,
9.90.
4.7. 2-(p-Cyanophenyl)-2,3,5,6,7,8-hexahydrothieno[2,3-b]
quinoline (7e)
Following Procedure A with 1,2-cyclohexanedione. Yield: 15%.
5

M.V. Papadopoulou and E.C. Taylor
Tetrahedron xxx (xxxx) xxx
Obtained as a white solid, mp 134e135 ꢀC; following recrystalli-
mixture was extracted with methylene chloride (3 ꢁ 15 mL), dried
over anhydrous sodium sulfate and evaporated under reduced
pressure. The residue was heated with 20.0 mL of phosphorus
oxychloride at reflux for 6 h. The excess of phosphorus oxychloride
was evaporated under reduced pressure and the residue was dis-
solved in a small amount of methylene chloride and filtered
through a silica gel pad with 50:50 hexane/ethyl acetate as eluant.
Evaporation under reduced pressure gave 0.26 g (15%) of a white
zation from 50 : 50 ether/petroleum ether. 1H NMR (CDCl3)
d
1.76e1.90 (m, 4H); 2.68 (t, J ¼ 6 Hz, 2H); 2.83 (t, J ¼ 6 Hz, 2H); 3.30
(dd, J1 ¼ 18 Hz, J2 ¼ 9 Hz, 1H); 3.65 (dd, J1 ¼ 15 Hz, J2 ¼ 6 Hz, 1H);
5.01 (t, J ¼ 6 Hz, 1H); 7.09 (s, 1H); 7.51 (d, J ¼ 6 Hz, 2H); 7.58 (d,
J2 ¼ 6 Hz, 2H). HRMS: Calcd for C18H16N2S: m/z 292.1034. Found m/z
292.1023. Anal. Calcd for C18H16N2S: C, 73.94; H, 5.52; N, 9.58; S,
10.96. Found: C, 73.66; H, 5.45; N, 9.72; S, 11.11.
solid, mp 144e145 ꢀC. 1H NMR (CDCl3)
d
1.39 (t, J ¼ 7.5 Hz, 3H); 3.40
4.8. 2-(p-Cyanophenyl)-5,6-dimethyl-2,3-dihydrothieno[2,3-b]
pyridine (7f)
(dd, J1 ¼ 15 Hz, J2 ¼ 6 Hz, 1H); 3.75 (dd, J1 ¼ 18 Hz, J2 ¼ 9 Hz, 1H);
4.38 (q, J ¼ 7.5 Hz, 2H); 5.16 (t, J ¼ 7.5 Hz, 1H); 7.51 (d, J ¼ 9 Hz, 2H);
7.63 (d, J ¼ 9 Hz, 2H); 7.88 (s, 1H). HRMS: Calcd for C17H13N2O2SCl:
m/z 344.0386. Found m/z 344.0393. Anal. Calcd for C17H13ClN2O2S:
C, 59.21; H, 3.80; N, 8.12; S, 9.30; Cl, 10.28. Found: C, 58.96; H, 3.74;
N, 7.89; S, 9.09; Cl, 10.46.
Following Procedure A with 2,3-butanedione. Yield: 30%. Ob-
tained as a white solid, mp 115e117 ꢀC; following recrystallization
from 50 : 50 ether/petroleum ether. 1H NMR (CDCl3)
d 2.21 (s, 3H);
2.43 (s, 3H); 3.30 (dd, J1 ¼ 15.9 Hz, J2 ¼ 6.8 Hz, 1H); 3.65 (dd,
J1 ¼15.9 Hz, J2 ¼ 8.4 Hz, 1H); 5.02 (t, J ¼ 7.7 Hz, 1H); 7.15 (s, 1H); 7.52
(d, J ¼ 6 Hz, 2H); 7.60 (d, J ¼ 6 Hz, 2H). HRMS: Calcd for C16H14N2S:
m/z 266.0878. Found m/z 266.0866. Anal. Calcd for C16H14N2S: C,
72.15; H, 5.30; N,10.52; S,12.04. Found: C, 71.94; H, 5.33; N,10.31; S,
11.97.
4.12. 2-(4-Carbomethoxyphenyl)-5-carboethoxy-6-chloro-2,3-
dihydrothieno[2,3-b] pyridine (18c)
6-Carboethoxy-4,5-dihydro-5-oxo-1,2,4-triazine-3-thione (21)
(1.35 g, 6.72 mmol) was stirred for 10 min at 0 ꢀC in N-methyl-2-
pyrrolidinone (12 mL) and NaH (0.16 g, 6.67 mmol) was added
carefully. After a while the suspension became a deep red solution
and the stirring was continued for another 15 min at 0 ꢀC. 4-Bromo-
4-(4-carbomethoxyphenyl)-1-butyne (1.27 g, 4.76 mmol) in N-
methyl-2-pyrrolidinone (4 mL) was added dropwise and the stir-
ring at 0 ꢀC was continued for an additional 15 min before heating
for 2 h at 78e80 ꢀC in an oil bath. The reaction mixture was then
cooled, sat. NH4Cl solution (24 mL) was added, followed by
extraction with CH2Cl2 (3 ꢁ 24 mL). The organic layer was dried
with Na2SO4, filtered and evaporated under reduced pressure. N-
methyl-2-pyrrolidinone was removed by distillation, using an oil
pump. Phosphorous oxychloride (20 mL) was added to the residue
followed by refluxing for 3 h under a nitrogen atmosphere. The
excess of phosphorus oxychloride was evaporated under reduced
pressure and the residue was dissolved in a small amount of
methylene chloride and filtered through a silica gel pad with 60:40
hexane/ethyl acetate as eluant. Evaporation under reduced pres-
sure provided pale yellow crystals which were further purified by
trituration with ether (0.63 g, 35%, based on the bromide). mp
4.9. 2-(p-Cyanophenyl)-6-(p-methoxyphenyl)-2,3-dihydrothieno
[2,3-b]pyridine (7g)
Following Procedure A with p-methoxyphenyl glyoxal mono-
hydrate. Yield: 23%. Obtained as a white solid, mp 143e145 ꢀC;
following recrystallization from 50 : 50 methylene chloride/pe-
troleum ether. 1H NMR (CDCl3)
d
3.38 (dd, J1 ¼ 16.1 Hz, J2 ¼ 6.9 Hz,
1H); 3.73 (dd, J1 ¼ 16.2 Hz, J2 ¼ 8.5 Hz, 1H); 3.86 (s, 3H); 5.08 (t,
J ¼ 8.1 Hz, 1H); 6.97 (d, J ¼ 9 Hz, 2H); 7.35 (d, J ¼ 6 Hz, 1H); 7.43 (d,
J ¼ 6 Hz, 1H); 7.55 (d, J ¼ 9 Hz, 2H); 7.62 (J ¼ 6 Hz, 2H); 7.93 (d,
J ¼ 9 Hz, 2H). HRMS: Calcd for C21H16N2OS: m/z 344.0983. Found m/
z 344.0972. Anal. Calcd for C21H16N2OS: C, 73.23; H, 4.68; N, 8.13; S,
9.31. Found: C, 72.98; H, 4.56; N, 7.98; S, 9.12.
4.10. 2-Phenyl-5-carboethoxy-6-chloro-2,3-dihydrothieno[2,3-b]
pyridine (18a)
A
suspension of 3-(1-phenyl-3-butynylthio)-6-carboethoxy-
1,2,4-triazine-5(2H)-one (23a) (0.13 g, 0.395 mmol) in 2.63 mL of
phosphorous oxychloride was heated at reflux for 10 h. After this
period, the volatiles of the reaction mixture were evaporated under
reduced pressure and the residual black gum was taken up in
methylene chloride and filtered through a silica gel pad, eluting
with 1:1 hexane/ethyl acetate. The filtrate was evaporated under
reduced pressure to yield 0.06 g (48%) of a white solid, mp
132e134 ꢀC. 1H NMR (CDCl3)
d
1.39 (t, J ¼ 7.5 Hz, 3H); 3.43 (dd,
J1 ¼15 Hz, J2 ¼ 6 Hz, 1H); 3.72 (dd, J1 ¼18 Hz, J2 ¼ 9 Hz, 1H); 3.91 (s,
3H); 4.38 (q, J ¼ 7.5 Hz, 2H); 5.18 (t, J ¼ 7.5 Hz, 1H); 7.47 (d, J ¼ 6 Hz,
2H); 7.87 (s, 1H); 8.00 (d, J ¼ 6 Hz, 2H). HRMS: Calcd for
C
18H16ClNO4S: m/z 377.0488. Found m/z 377.0478.
4.13. 3-(1-Phenyl-3-butynylthio)-5-phenyl-1,2,4-triazine (5a)
88e89 ꢀC. 1H NMR (CDCl3)
d
1.39 (t, J ¼ 7.5 Hz, 3H); 3.44 (dd,
J1 ¼18 Hz, J2 ¼ 9 Hz, 1H); 3.68 (dd, J1 ¼18 Hz, J2 ¼ 9 Hz, 1H); 4.39 (q,
J ¼ 7.5 Hz, 2H); 5.17 (t, J ¼ 7.5 Hz, 1H); 7.30e7.42 (m, 5H); 7.92 (s,
1H). HRMS: Calcd for C16H14NO2SCl: m/z 319.0434. Found m/z
319.0430. Anal. Calcd for C16H14NO2SCl: C, 60.09; H, 4.41; N, 4.38.
Found: C, 59.88; H, 4.40; N, 4.36.
Following Procedure B: Yield: 62%. Obtained as a pale yellow oil.
1H NMR (CDCl3)
d
2.05 (s, 1H); 3.07e3.14 (m, 2H); 5.31 (t, J ¼ 6 Hz,
1H); 7.27e8.12 (m, 10H); 9.35 (s, 1H). HRMS: Calcd for C19H15N3S:
m/z 317.0987. Found m/z 317.0987.
4.14. 3-[1-(p-Carbomethoxyphenyl)-3-butynylthio]-5-phenyl-
1,2,4-triazine (5c)
4.11. 2-(p-Cyanophenyl)-5-carboethoxy-6-chloro-2,3-
dihydrothieno[2,3-b]pyridine (18b)
Following Procedure B: Obtained in trace quantity as a yellow
To
a
mixture of 6-carboethoxy-4,5-dihydro-5-oxo-1,2,4-
oil. 1H NMR (CDCl3)
3.90 (s, 3H); 5.34 (t, J ¼ 6 Hz, 1H); 7.53e8.17 (m, 9H); 9.37 (s, 1H).
HRMS: Calcd for C21H17N3O2S: m/z 375.1041. Found m/z 375.1034.
d
2.05 (d, J ¼ 2.5 Hz, 1H); 3.05e3.12 (m, 2H);
triazine-3-thione (21) (1.0 g, 4.98 mmol) and sodium hydride
(0.15 g, 5.0 mmol, 80% dispersion in mineral oil) in 7.0 mL of ab-
solute ethanol cooled to 0 ꢀC, a solution of 4-(p-cyanophenyl)-4-
bromo-1-butyne 11 (1.16 g, 4.96 mmol) in 6.0 mL of ethanol was
added dropwise. After the addition, the mixture was stirred at 0 ꢀC
for 15 min and then heated at reflux for 1 h. To the cooled solution
was added 14.0 mL of saturated ammonium chloride solution. The
4.15. 3-(1-Phenyl-3-butynylthio)-6-carboethoxy-1,2,4-triazin-
5(2H)-one (23a)
A
solution of S-(1-phenyl-3-butynyl)isothiosemicarbazide
6

M.V. Papadopoulou and E.C. Taylor
Tetrahedron xxx (xxxx) xxx
hydrobromide (13a) (0.42 g, 1.4 mmol), diethylketomalonate
(0.25 g, 1.4 mmol) and sodium bicarbonate (0.12 g, 1.4 mmol) in
3 mL of ethanol was heated at reflux for 6 h and stirred at room
temperature overnight. The white precipitate was collected by
filtration and washed with water and ether. Recrystallization from
ethanol/water gave 0.33 g (70%) of a white solid, mp 188e190 ꢀC. 1H
(s, 4H); 2.89 (t, J ¼ 6 Hz, 2H); 7.09 (m, 4H); 7.15 (s, 1H); 8.17 (s, 1H).
HRMS: Calcd for C18H21N: m/z 251.1674. Found m/z 251.1685.
4.22. 2,3-Dimethyl-5-[2-(p-tolyl)ethyl]pyridine (24d)
Yield: 95%. Obtained as a white solid, mp 30e32 ꢀC. 1H NMR
NMR (CDCl3)
d
1.44 (t, J ¼ 7.5 Hz, 3H); 2.03 (d, J ¼ 2.5 Hz, 1H); 3.03
(CDCl3) d 2.24 (s, 3H); 2.33 (s, 3H); 2.47 (s, 3H); 2.84 (s, 4H); 7.08 (m,
4H); 7.20 (s, 1H); 8.14 (s, 1H). HRMS: Calcd for C16H19N: m/z
225.1517. Found m/z 225.1518.
(m, 2H); 4.48 (q, J ¼ 6 Hz, 2H); 5.27 (t, J ¼ 6 Hz, 1H); 7.31e7.48 (m,
5H). HRMS: Calcd for C16H15N3O3S: m/z 329.0834. Found m/z
329.0829.
4.23. 2-(p-Methoxyphenyl)-5-[2-(p-tolyl)ethyl]pyridine (24e)
4.16. S-(1-phenyl-3-butynyl)isothiosemicarbazide hydrobromide
(13a)
Yield: 93%. Obtained as a white solid, mp 106e108 ꢀC. 1H NMR
(CDCl3)
d
2.32 (s, 3H); 2.92 (s, 4H); 3.86 (s, 3H); 7.04 (d, J ¼ 23 Hz,
A mixture of 4-bromo-4-phenyl-1-butyne (2.0 g, 9.5 mmol) and
thiosemicarbazide (0.87 g, 9.5 mmol) in 20 mL of ethanol was
heated at reflux for 2 h. The solution was evaporated under reduced
pressure and the residue filtered through a silica gel pad. The silica
gel pad was eluted first with methylene chloride to remove the
unreacted starting materials and then eluted with ethanol. Evap-
oration of the ethanol gave 0.97 g (34%) of a white solid, mp
2H); 7.10 (m, 4H); 7.54 (dd, J1 ¼ 21, J2 ¼ 9 Hz, 2H); 7.93 (d, J ¼ 6 Hz,
2H); 8.45 (s, 1H). HRMS: Calcd for C21H21NO: m/z 303.1623. Found
m/z 303.1623. Anal. Calcd for C21H21NO: C, 83.13; H, 6.98; N, 4.62.
Found: C, 83.11; H, 6.95; N, 4.84.
4.24. Preparation of bromides 11, iodides 12 and carbinols 9
137e138 ꢀC. 1H NMR (DMSO‑d6)
d 2.41e2.55 (m, 1H); 2.80e2.99 (m,
Bromides 11 or iodides 12 were prepared from their corre-
sponding carbinols 9, with pyridine and phosphorus tribromide or
with o-phenylene phosphorochloridite, pyridine and iodine
respectively, as previously described [17], and purified by distilla-
tion or column chromatography. Carbinols 9 were obtained by a
modified Reformatsky reaction [17,25,26], in which the catalyst was
zinc-copper couple instead of zinc, from the corresponding p-
substituted benzaldehydes and propargyl bromide. Their purifica-
tion was achieved by column chromatography (silica gel,
CH2Cl2eEt2O, 90/10).
2H); 3.29e3.42 (m, 2H); 5.16 (t, J ¼ 7.5 Hz, 1H); 7.14e7.48 (m, 5H);
9.30 (bs, 1H). HRMS: Calcd for C11H13N3S: m/z 219.0830. Found m/z
219.0835.
4.17. S-[1-(p-carbomethoxyphenyl)-3-butynyl]isothiosemicarbizide
hydrobromide (13c)
Following the procedure described for 13a: Yield: 21%. Obtained
as a pale yellow solid, mp 169e170 ꢀC. 1H NMR (DMSO‑d6)
d 2.07 (s,
2H); 2.13 (s, 2H); 2.29 (s, 1H); 2.91e2.97 (m, 2H); 3.91 (s, 3H); 5.38
(t, J ¼ 7.5 Hz, 1H); 7.70e8.05 (dd, J1 ¼ 9 Hz, J2 ¼ 9 Hz, 4H); 9.52 (bs,
1H). HRMS: Calcd for C13H15N3O2S: m/z 277.0885. Found m/z
277.0880.
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
4.18. Reductive desulfurization of 7a-b and 7d-g with Raney Nickel.
General Procedure [24]
Acknowledgements
A mixture of 7 (90 mg) and Raney Nickel (ca. 1.0 g, Aldrich,
washed with water, then ethanol) in 20 mL ethanol was refluxed for
5 h (except of the case of 7g, see Table 3). The mixture was filtered
through Celite, which was washed well with ethanol. Evaporation
of the ethanol gave compounds 24a-e which were recrystallized
from 50:50 methylene chloride/hexanes.
This work was performed about 30 years ago, while M.V.
Papadopoulou was doing postdoctoral research under the super-
vision of Professor E.C. Taylor (to whom this paper is dedicated) at
Princeton University.
Appendix A. Supplementary data
4.19. 2-Phenyl-5-(2-phenylethyl)pyridine (24a)
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132158.
Yield: 86%. Obtained as a white solid, mp 80e82 ꢀC. 1H NMR
(CDCl3)
d
2.98 (s, 4H); 7.17e7.67 (m, 10H); 7.99 (dd, J1 ¼ 9 Hz,
J2 ¼ 6 Hz, 2H), 8.52 (s, 1H). HRMS: Calcd for C19H17N: m/z 259.1361.
References
Found m/z 259.1366.
[1] E.C. Taylor, J.E. Macor, Tetrahedron Lett. 26 (1985) 2419.
[2] E.C. Taylor, J.E. Macor, Abstracts, 10th International Congress of Heterocyclic
Chemistry, University of Waterloo, Waterloo, Ontario Canada; Ainsworth:
Kitchener , Ontario Canada, 1985, pp. G4eG28.
[3] E.C. Taylor, J.E. Macor, Tetrahedron Lett. 27 (1986) 431.
[4] E.C. Taylor, L.G. French, Tetrahedron Lett. 27 (1986) 1967.
[5] E.C. Taylor, J.E. Macor, Tetrahedron Lett. 27 (1986) 2107.
[6] E.C. Taylor, J.L. Pont, Tetrahedron Lett. 28 (1987) 379.
[7] E.C. Taylor, J.E. Macor, J. Org. Chem. 52 (1987) 4280.
[8] E.C. Taylor, J.L. Pont, J.C. Warner, Tetrahedron 43 (1987) 5159.
[9] E.C. Taylor, J.C. Warner, J.L. Pont, J. Org. Chem. 53 (1988) 800.
[10] E.C. Taylor, J.L. Pont, J. Org. Chem. 52 (1987) 4287.
[11] E.C. Taylor, K.F. McDaniel, J.C. Warner, Tetrahedron Lett. 28 (1987) 1977.
[12] E.C. Taylor, J.E. Macor, J. Org. Chem. 54 (1989) 4984.
[13] E.C. Taylor, J.E. Macor, J. Org. Chem. 54 (1989) 1249.
[14] E.C. Taylor, L.G. French, J. Org. Chem. 54 (1989) 1245.
[15] E.C. Taylor, J.E. Macor, L.G. French, J. Org. Chem. 56 (1991) 1807.
4.20. 2-Phenyl-5-[2-(p-tolyl)ethyl]pyridine (24b)
Yield: 96%. Obtained as a white solid, mp 70e72 ꢀC. 1H NMR
(CDCl3)
5H); 8.01 (dd, J1 ¼ 9 Hz, J2 ¼ 6 Hz, 2H); 8.52 (s, 1H). HRMS: Calcd for
20H19N: m/z 273.1517. Found m/z 273.1514. Anal. Calcd for C20H19N:
d 2.35 (s, 3H); 2.95 (s, 4H); 7.10e7.11 (m, 4H); 7.44e7.67 (m,
C
C, 87.87; H, 7.01; N, 5.12. Found: C, 87.61; H, 7.28; N, 5.06.
4.21. 3-[2-(p-Tolyl)ethyl]-5,6,7,8-tetrahydro-quinoline (24c)
Yield: 98%. Obtained as a white solid, mp 42e43 ꢀC. 1H NMR
(CDCl3)
d
1.79e1.89 (m, 4H); 2.32 (s, 3H); 2.73 (t, J ¼ 6 Hz, 2H); 2.83
7

M.V. Papadopoulou and E.C. Taylor
Tetrahedron xxx (xxxx) xxx
[16] G. Seitz, S. Dietrich, L. Gorge, J. Richter, Tetrahedron Lett. 27 (1986) 2747.
[17] M.V. Papadopoulou, Chem. Ber. 122 (1989) 2017 (and references cited
within).
[18] E.C. Taylor, Z.-Y. Chang, P.M. Harrington, J.M. Hamby, M. Papadopoulou,
J.C. Warner, G.S.K. Wong, C.-M. Yoon, C. Shih, H.- Ch, in: S. Ghisla, N. Blau
(Eds.), Chemistry and Biology of Pteridines, Curtius, Walter de Gruyter & Co.,
Berlin, New York, 1989, pp. 987e994.
[19] E.C. Baarlow, A.D. Welch, J. Am. Chem. Soc. 78 (1956) 1258.
[20] The conversion of aromatic and aliphatic nitriles to primary amines is known
in the literature, but there is no report for further conversion of the amino-
methyl group to methyl group:. (a) W.P. Utermohlen Jr., J. Am. Chem. Soc. 67
(1945) 1505;
Wisconsin, 1937, p. 53.
[21] F.F. Blicke, J.A. Faust, J. Am. Chem. Soc. 76 (1954) 3156.
[22] Cases in which m-Cl-phenyl or p-Cl-phenyl substituents have lost chlorine
during the Raney Ni desulfurization of the basic compound are known in the
literature:. (a) W.R. Boon, H.C. Carrington, N. Greenhalgh, C.H. Vasey, J. Chem.
Soc. (1954) 3263;
(b) H. Gilman, D.L. Esmay, J. Am. Chem. Soc. 75 (1953) 2947 (They refer to
cases in which bromo-substituted heterocyclic aromatic compounds lost
bromine after Raney Ni desulfurization).
[23] R.G. Moran, S.W. Baldwin, E.C. Taylor, C. Shih, J. Biol. Chem. 264 (1989) 21047.
[24] J.C. Warner, Princeton University, May (1988) 124. Thesis.
[25] E. Santaniello, A. Manzocchi, Synthesis (1977) 698.
(b) H. Adkins, Reactions of Hydrogen, University of Wisconsin Press, Madison,
[26] H.B. Henbest, E.R.H. Jones, I.M.S. Walls, J. Chem. Soc. (1949) 2696.
8