A new strategy for the synthesis of pyridines from: N -propargylic β-enaminothiones

Article abstract of DOI:10.1039/c8ob03180k

A new method for the synthesis of 2,4,5-trisubstituted pyridines from N-propargylic β-enaminothiones is reported. β-Enaminothiones were prepared by thionation of the corresponding β-enaminones with Lawesson's reagent. When treated with diisopropylamine in DMF at room temperature, N-propargylic β-enaminothiones yielded 2,4,5-trisubstituted pyridines in moderate to high yields, along with small amounts of 2-methylene-2,3-dihydro-1,4-thiazepines. The reaction was found to be general for a broad range of N-propargylic β-enaminothiones and tolerated the presence of aromatic, heteroaromatic and aliphatic groups with electron-withdrawing and electron-donating substituents. The method could be widened to the internal alkyne-tethered N-propargylic β-enaminothiones. This operationally simple method may provide rapid access to a library of functionalized pyridines of pharmacological interest.

Full text of DOI:10.1039/c8ob03180k

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A new strategy for the synthesis of pyridines from N-propargylic
β-enaminothiones
Received 00th January 20xx,
Accepted 00th January 20xx
Yilmaz Kelgokmen and Metin Zora *
DOI: 10.1039/x0xx00000x
A new method for the synthesis of 2,4,5-trisubstituted pyridines from N-propargylic β-enaminothiones is reported. β-
Enaminothiones were prepared by thionation of the corresponding β-enaminones with Lawesson’s reagent. When treated
with diisopropylamine in DMF at room temperature, N-propargylic β-enaminothiones yielded 2,4,5-trisubstituted
pyridines in moderate to high yields, along with the small amount of 2-methylene-2,3-dihydro-1,4-thiazepines. The
reaction was found to be general for a broad range of N-propargylic β-enaminothiones and tolerated the presence of
aromatic, heteroaromatic and aliphatic groups with electron-withdrawing and electron-donating substituents. The method
could be widened to the internal alkyne-tethered N-propargylic β-enaminothiones. This operationally simple method may
provide rapid access to a library of functionalized pyridines of pharmacological interest.
www.rsc.org/
continue to emerge since they have a remarkable impact as
intermediates in the synthesis of various drugs and natural
products.22
Introduction
Pyridines are popular targets for medicinal and synthetic chemists
primarily because of their diverse and potent biological properties.1
In fact, pyridines have been extensively studied in the last decades
as a prominent class of heterocycles and still continue to receive
noteworthy interest for the broad range of biological and material
properties they hold.2 Pyridines are often employed as building
blocks and scaffolds for pharmaceutical research as well since they
are present in the structures of a wide range of leading drugs,
including HIV antiviral Atazanavir,3 hipnotic and sedative
Eszopiclone,4 antineoplastic and anticancer Imatinib,5 cholesterol
and triglyceride regulator Niacin,6 bone calcium regulator
Recently, cyclization of functionally-substituted alkynes has
been recognized as a valuable tool to generate a variety of
important heterocycles.23 Among them, N-propargylic β-
enaminones have proven useful since, when treated with proper
agents, they furnish a diverse range of heterocyclic compounds,24
including pyrroles, pyridines, 1,2-dihydropyridines and 1,4-
oxazepines.25 In this regard, we have recently described the
synthesis of 1,4-oxazepines 2 from N-propargylic β-enaminones 1 in
the presence of zinc chloride (Scheme 1, upper left).26 When the
zinc chloride-mediated cyclization of N-propargylic β-enaminones 1
was performed in the presence of molecular iodine, it afforded 2-
Risedronate,7
Pioglitazone,9 and antiulcerants Esomeprazole,10 Pantoprazole,11
Dexlansoprazole,12 Lansoprazole,13 Omeprazole14
and
antihistaminic
Desloratadine,8
antidiabetic
(iodomethylene)-2,3-dihydro-1,4-oxazepines
3 in good to high
yields (Scheme 1, upper right).27 Importantly, the presence of an
iodine atom in the structures of 1,4-oxazepines 3 may offer
opportunities for building more complex frameworks.
Subsequently, treatment of N-propargylic β-enaminones 1 with
Lawesson’s reagent28 provided N-propargylic β-enaminothiones 4
(thio-β-enaminones) in good to high yields (Scheme 1, middle).29
Interestingly, when treated with zinc chloride, N-propargylic β-
enaminothiones 4 mimicked the chemistry of N-propargylic β-
enaminones and yielded 2-methylene-2,3-dihydro-1,4-thiazepines 5
with high efficiency and large functional group tolerance (Scheme 1,
lower left).29 As a further study, we wanted to study the reactions
of internal alkyne-tethered N-propargylic β-enaminothiones, such
as 6. So, for the synthesis of N-propargylic β-enaminothione 6a, we
subjected N-propargylic β-enaminothione 4a to a coupling protocol
with iodobenzene (Scheme 1, lower right). Surprisingly, β-
enaminothione 4a did not produce the expected coupling product
6a; instead, in the presence of diisopropylamine (DIPA), it possibly
Rapeprazole.15 Pyridines are also found in structurally diverse
natural products like Diploclidine and Nakinadine A.16 Notably, most
of pyridine-based alkaloid natural products are derivatives of
nicotinic acid (known also as vitamin B3 and Niacin).17 Pyridines are
also employed in the preparation of conjugated polymers and
functional materials, which are utilized in light-emitting devices
(LEDs).18 Notably, most syntheses of pyridine rings rely upon one of
two approaches; condensation of carbonyl compounds with
amines,19 and cycloaddition of azadienes and nitriles with alkenes
and alkynes.20 In fact over the years, many fruitful methods have
been developed for the synthesis of pyridines,21 and new strategies
Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey.
Phone: (+90)-312-2103213; fax: (+90)-312-2103200; e-mail: zora@metu.edu.tr
† Electronic Supplementary Information (ESI) available: Copies of 1H and 13C NMR
spectra for all new compounds (PDF). See DOI: 10.1039/x0xx00000x
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R2
I
R2
R2
O
O
H
ZnCl2
ZnCl2, I2
O
R2
DCM, 40 oC, or
DCM, 40 o
C
R1
NH
N
N
CHCl3, 61 o
C
S
R1
R1
R1
NH
2
1
3
R3
Lawesson's Reagent
Benzene, 60 °C
6 (R2 = Ar)
6a (R3 = Ph)
(not observed)
R2
1.5 equiv. R3-I
2 mol% PdCl2(PPh2)2
2 mol% CuI
R2
R2
R2
S
S
ZnCl2
S
CH3
+
R1
NH
CHCl3, 61 o
C
(i-Pr)2NH, DMF
R1
N
N
N
R1
R1
5 (R2 = Ar)
5a (6%)
5
7 (R2 = Ar)
7a (67%)
4
4a (R1 = R2 = Ph)
Scheme 1 Strategies for the synthesis of 1,4-oxazepines, 1,4-thiazepines and pyridines.
Ar
Ar
NH2
Lawesson's
O
9
Reagent
S
underwent a base-mediated reaction to afford 2,4,5-trisubstituted
pyridine 7a and 2-methylene-2,3-dihydro-1,4-thiazepine 5a in 67
and 6% yields, respectively. Notably, the presence of the base has
created a new pathway for the synthesis of pyridine derivatives 7
from N-propargylic β-enaminothiones 4. Our interest in novel
heterocyclic molecules as potential pharmaceuticals and scaffolds
has prompted us to explore base-mediated reactions of β-
enaminothiones 4 as well. Herein, we report the full details of this
unprecedented methodology.
O
Ar
Benzene, 60 °
C
R
NH
R
NH
CH3OH, 65 °C
R
8
1
4
Scheme 2 Synthesis of N-propargylic β-enaminothiones 4.
With N-propargylic β-enaminothiones 4 in hand, we next
investigated their cyclization under basic conditions as
illustrated in Table 1. To test pyridine formation and optimize
its conditions, we first studied the cyclization of N-propargylic
β-enaminothione 4a. Initially, we carried out the reaction with
0.1 mL of diisopropylamine (DIPA) in DMF at room
temperature and 50 oC, which produced 2,4,5-trisubtituted
pyridine derivative 7a in 75 and 67% yields, respectively (Table
1, Entries 1 and 2). Since the former reaction gave a higher
yield of 7a, we continued optimization studies at room
temperature. It should be noted that from these reactions, a
side product, 2-methylene-2,3-dihydro-1,4-thiazepine 5a, was
also isolated in 4 and 5% yields, respectively (Table 1, Entries 1
and 2). Subsequently, we tried the same reaction with
different amounts of DIPA (0.2-1.0 mL) in DMF, ACN and
DMSO (Table 1, Entries 3-9). These reactions afforded 5-
methylpyridine 7a in good to high yields (61-85%), along with
small amount (5%) of 2-methylene-2,3-dihydro-1,4-thiazepine
5a. Notably, the reaction times in ACN and DMSO were longer
Results and discussion
First, we prepared the requisite N-propargylic β-
enaminothiones 4 according to our recent studies (Scheme
2).26,29,30 Conjugate addition of propargylamine (9) to α,β-
alkynic ketones 8 in refluxing methanol afforded N-propargylic
β-enaminones 1,26,30 which upon thionation with Lawesson’s
reagent28 in benzene at room temperature produced N-
propargylic β-enaminothiones 4 in good to high yields.29 By
employing these reactions, we synthesized 20 derivatives of N-
propargylic β-enaminothiones including alkyl, thiophenyl and
aryl groups with electron-donating and electron-withdrawing
substituents (For the structures and yields of the synthesized
N-propargylic
β-enaminothiones
4,
see
Supporting
Information).
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Table 1 Optimization studies for the cyclization of N-propargylic β-enaminothiones in basic conditions.a
Ph
Ph
Ph
Ph
CH3
S
S
CH3
Base
S
+
Ph
NH
Solvent, Temperature
Time
N
N
Ph
N
Ph
Ph
7a
5a
10a
(not observed)
4a
Entry
Base (amt. or equiv.)
DIPA (0.1 mL)
DIPA (0.1 mL)
DIPA (0.2 mL)
DIPA (0.2 mL)
DIPA (0.2 mL)
DIPA (0.2 mL)
DIPA (0.3 mL)
DIPA (0.5 mL)
DIPA (1.0 mL)
DIPA (1.0 mL)
Solvent
Temp. (oC)
r.t.
Time (h)
Product(s) (% Yield)b
7a (75) + 5a (4)
7a (67) + 5a (5)
7a (61) + 5a (5)c
7a (79) + 5a (5)
7a (79) + 5a (5)
7a (69) + 5a (5)
7a (80) + 5a (5)
7a (85) + 5a (5)
7a (85) + 5a (5)
N.R.d,e
1
DMF
DMF
DMF
DMF
ACN
DMSO
DMF
DMF
DMF

40.0
1.0
50
2
r.t.
3
4.5
r.t.
4
16.0
20.0
20.0
5.0
r.t.
5
r.t.
6
r.t.
7
r.t.
8
2.0
r.t.
9
2.0
r.t.
10
11
12
13
14
15
16
17
18
19
20
21
3.0
r.t.
7a (62) + 5a (8)f
7a (77) + 5a (9)
7a (51) + 5a (5)g
7a (69)
TEA (0.2 mL)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
ACN
DMF
DMF
DMF
20.0
48.0
20.0
3.0
TEA (0.2 mL)
r.t.
DBU (0.2 equiv.)
DBU (0.4 equiv.)
DBU (1.0 equiv.)
DBU (2.0 equiv.)
DBU (2.0 equiv.)
DBU (2.0 equiv.)
r.t.
r.t.
r.t.
7a (72)
3.0
r.t.
7a (59)
3.0
0 to r.t.
r.t.
7a (63)
3.0
7a (68)
3.0
r.t.
7a (27) + 5a (10)
7a (45)
Cs2CO3 (1.0 equiv.)
NaH (1.0 equiv.)
NaH (2.0 equiv.)
3.0
r.t.
3.0
r.t.
7a (45)
3.0
aReactions were carried out on a 0.30 mmol scale of N-propargylic β-enaminothione 4a in 0.5 mL solvent under indicated conditions.
bIsolated yield. cThe starting β-enaminothione 4a was recovered in 18% yield as well. dN.R. = No Reaction. eThe starting β-
f
enaminothione 4a was recovered in 97% yield. The starting β-enaminothione 4a was recovered in 16% yield as well. gThe starting β-
enaminothione 4a was recovered in 10% yield as well.
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and the yields of 7a were the same or lower (Table 1, Entries 5 drugs and drug candidates in clinical development contain
and 6), as compared to that in DMF using the same amount of halogens in their structures. The formation of halogen bonds
DIPA (Table 1, Entry 4). Importantly, the use of relatively in ligand-target complexes is recognized as
a kind of
higher amounts of DIPA such as 0.3-1.0 mL increased the yield intermolecular interaction that favorably contributes to the
of 7a significantly (80-85%) and shortened the reaction times stability of protein-ligand complexes.32 Thus nine derivatives of
considerably (2-5 h) (Table 1, Entries 7 and 9). The best yield halogen-containing pyridines, 7g-7i and 7l-7q, were
(85%) of pyridine 7a was obtained by using 0.5 and 1.0 mL of synthesized in 49-71% yields (Table 2). In particular, five of
DIPA (Table 1, Entries 8 and 9). Clearly, the excess amount of them bear fluorine functionality in their composition, 7h, 7i,
DIPA (1.0 mL) did not improve the yield of 7a. So we preferred 7n, 7o and 7q, since the existence of fluorine in organic
to use 0.5 mL of DIPA. When the reaction was performed in structures may lead to improvements in their pharmacological
neat conditions without the solvent, no reaction was occurred properties.33 Briefly, this cyclization was found to be general
and the most of the starting β-enaminothione 4a was for a diverse array of N-propargylic β-enaminothiones 4 and
recovered (Table 1, Entry 10). The reaction was also tested demonstrated good tolerance to a variety of substituents,
with triethylamine (TEA), but 5-methylpyridine 7a was isolated including electron-donating and electron-withdrawing groups.
in relatively lower yields (62-77%) with longer reaction times Overall, 20 derivatives of 2,4,5-trisubstituted pyridines 7 were
(20-48 h) (Table 1, Entries 11 and 12), as compared to that in prepared, 18 of which were synthesized for the first time
DMF with the same amount of DIPA (Table 1, Entry 4). (Table 2). It should be mentioned that along with pyridines 7,
Subsequently, the cyclization of N-propargylic β- 2-methylene-2,3-dihydro-1,4-thiazepine derivatives
5 were
enaminothione 4a was tested with varying amount of 1,8- also isolated from these reactions as side products in 2-13%
diazabicyclo(5.4.0)undec-7-ene (DBU) (0.2-2.0 equiv.) in DMF yields, full structures of which are given in Fig. S1 in ESI.
or ACN (Table 1, Entries 13-18). However, these reactions Importantly, from the reaction of β-enaminothione 4k, a new
afforded 5-methylpyridine 7a in 51-72% yields. Lastly, the type of pyrrole derivative, 11k, was obtained as the major
reaction of β-enaminothione 4a was performed in the product (27%), along with 5-methylpyridine 7k (13%) and 2,3-
presence of equimolar amounts of Cs2CO3 and NaH, which dihydro-1,4-thiazepine 5k (2%). The structure of pyrrole 11k is
yielded pyridine 7a in 27 and 45% yields, respectively (Table 1, given in Fig. S1 in ESI as well. To the best of our knowledge,
Entries 19 and 20). Noticeably, a twofold increase in NaH (2.0 formation of such a pyrrole derivative with a new substitution
equiv.) did not enhance the yield (45%) of 7a (Table 1, Entry pattern was never observed before from the reactions of N-
21). It should be mentioned that in many cases, 2-methylene- propargylic β-enaminones and β-enaminothiones. Notably,
2,3-dihydro-1,4-thiazepine 5a was isolated as the side product during derivatization studies, formation of the corresponding
(4-10%) from these reactions along with 5-methylpyridine 7a. fully unsaturated 1,4-thiazepines 10 was not observed at all.
The fully unsaturated 1,4-thiazepine 10a was not observed at
all in these reactions. In summary, the generality of the of 2-methylene-2,3-dihydro-1,4-thiazepines
We have also investigated the possibility of the conversion
to 5-
5
reaction and the scope of the substrates were explored under methylpyridines 7 as depicted in Table 3. For this reason, 1,4-
the optimized conditions present in entry 8 of Table 1, i.e. with thiazepine 5a was treated with DIPA in DMF at room
0.5 mL of DIPA for 0.30 mmol of N-propargylic β- temperature, which afforded 5-methylpyridine 7a in very low
enaminothione 4 in 0.5 mL DMF at room temperature, which yield (7%) after 4 days (Table 3, Entry 1). When the same
o
gave the highest yield of pyridine 7a (85%). The results from a reaction was carried out at 60 C, it yielded 7a in 11% yield
systematic study are depicted in Table 2.
(Table 3, Entry 2). After these two results, we have concluded
As illustrated in Table 2, we synthesized a diverse range of that 5-methylpyridine 7a is not a secondary product of the
2,4,5-trisubstituted pyridines 7 by employing a variety of N- reaction and does not form from 1,4-thiazepine 5a during the
propargylic β-enaminothiones 4. Under optimized conditions, course of the reaction. We have also examined this conversion
pyridines were obtained in moderate to high yields (46-85%), in the presence of a stronger base, NaH. At room temperature,
except that 2-butyl-substituted pyridine derivative 7k was this reaction produced 5-methylpyridine 7a in 10% yield (Table
o
isolated in low yield (13%). It is well known that thiophenes are 3, Entry 3). When the same reaction was repeated at 60 C, it
commonly utilized as building blocks and scaffolds in a provided 7a in 37% yield (Table 3, Entry 4). Finally, we
diversity of pharmaceuticals, agrochemicals and materials performed the same reaction with 2 equiv. of NaH, which
science.31 So we synthesized two derivatives of 2-(thiophen-3- afforded pyridine 7a in slightly higher yield (41%) (Table 3,
yl)-substituted pyridines, 7j and 7s, in 69 and 77% yields, Entry 5). It should be noted that 2-methyl-1,4-thiazepine 10a
respectively (Table 2). Notably, a considerable number of was never isolated from these reactions. To sum up, the yields
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Table 2 Synthesis of 2,4,5-trisubstituted pyridine derivatives 7.a,b,c
Ar
Ar
Ar
S
Ar
CH3
(i-Pr)2NH
S
CH3
+
+
R
N
H
DMF, r.t.
R
NH
N
R
N
S
R
7
5
11
4
CH3
CH3
CH3
CH3
CH3
OCH3
H3C
N
N
N
N
N
H3C
H3CO
7a (85%), 2.0 h
[5a (5%)]
7b (66%), 3.5 h
[5b (5%)]
7c (74%), 3.0 h
[5c (8%)]
7d (46%), 3.0 h
[5d (8%)]
7e (76%), 3.0 h
[5e (9%)]
CH3
CH3
CH3
CH3
CH3
Br
F
N
N
N
N
N
S
F3C
(H3C)3C
7f (68%), 3.0 h
[5f (5%)]
7g (60%), 2.0 h
[5g (13%)]
7h (67%), 4.0 h
[5h (5%)]
7i (56%), 3.0 h
[5i (5%)]
7j (69%), 3.0 h
[5j (6%)]
Br
Br
Br
Br
CH3
CH3
CH3
CH3
CH3
H3C
F
N
N
N
N
N
F3C
CH3
7k (13%), 4.0 h
[5k (2%)]
7l (53%), 2.0 h
[5l (10%)]
7m (49%), 2.0 h
[5m (7%)]
7n (51%), 2.0 h
[5n (9%)]
7o (54%), 2.0 h
[5o (10%)]
{11k (27%)}
Cl
Cl
CH3
CH3
OCH3
CH3
CH3
CH3
CH3
CH3
F
N
N
N
N
N
S
7p (67%), 2.0 h
[5p (4%)]
7q (71%), 2.0 h
[5q (7%)]
7r (83%), 4.0 h
[5r (7%)]
7s (77%), 3.0 h
[5s (10%)]
7t (53%), 2.0 h
[5t (7%)]
aReaction conditions: N-propargylic β-enaminothione 4 (0.30 mmol), DIPA (0.5 mL) and DMF (0.5 mL) at room
temperature. For the full procedure including work-up and purification, see Experimental Section. bIsolated yields.
cCompound numbers and yields for 2-methylene-2,3-dihydro-1,4-thiazepines 5 are depicted in square brackets while
those for 2-ethanethioyl-1H-pyrrole 11k is given in curly braces. For their full structures, see Fig. S1 in ESI.
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Table 3 Conversion of 2-methylene-2,3-dihydro-1,4-thiazepine 5a to 5-methylpyridine 7a.a
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DOI: 10.1039/C8OB03180K
Ph
Ph
Ph
CH3
S
S
Base
CH3
Solvent, Temperature
Time
N
N
Ph
N
Ph
Ph
5a
7a
10a
(not observed)
Entry
Base (amt. or equiv.)
DIPA (0.2 mL)
Solvent
Temp. (oC)
Time (h)
Product(s) (% Yield)b
r.t.
60
r.t.
60
60
7a (7)c
1
2
3
4
5
DMF
DMF
DMF
DMF
DMF
96.0
9.0
DIPA (0.2 mL)
7a (11)d
7a (10)e
7a (37)
7a (41)
NaH (1.0 equiv.)
NaH (1.0 equiv.)
NaH (2.0 equiv.)
96.0
5.0
0.5
aReactions were performed on a scale of 0.30 mmol of 1,4-thiazepine 5a in 0.5 mL solvent under indicated conditions. bIsolated yield.
cThe starting 1,4-thiazepine 5a was recovered in 59% yield as well. dThe starting 1,4-thiazepine 5a was recovered in 58% yield as well.
eThe starting 1,4-thiazepine 5a was recovered in 21% yield as well.
(7-41%) for the conversion of 2-methylene-2,3-dihydro-1,4- base (DIPA) might be the reason that both propargylic and
thiazepine 5a to 5-methylpyridine 7a are far from that (85%) amine hydrogens are deprotonated with base during the
obtained from N-propargylic β-enaminothione 4a. These course of the reaction. On the other hand, 1,4-thiazepines 5
cumulative results clearly imply that 5-methylpyridines 7 form form via
a different mechanism. Abstraction of amine
via a different mechanism from β-enaminothiones 4, not hydrogen of 4 with base, followed by vinylogous amido-imido
through the intermediacy of 1,4-thiazepines 5, as it will be tautomerization, starts the cyclization to furnish vinyl anion 16,
discussed in the mechanism.
which upon protonation produces 2-methylene-2,3-dihydro-
The mechanism proposed for the formation of 5- 1,4-thiazepines 5 (Scheme 3).
methylpyridines 7 and 1,4-thiazepines 5 in the presence of
The mechanism proposed for the occurrence of pyrrole 11k
DIPA is outlined in Scheme 3. First, in the presence of base, is illustrated in Scheme 4. First, conjugate addition of water to
propargyl-to-allene isomerization (4  12  13) occurs via the vinylogous imine functionality of 5k produces intermediate
intermediacy of allenyl anion 12. As shown by the Balci 17k, ring opening of which generates thioenol-enol
research group using similar systems, activation barrier for intermediate 18k. Afterward, 18k converts into more stable
such isomerizations is approximately 9.0 kcal/mol.34 Then thioenol-enol intermediate 19k. Notably, 19k can also be
abstraction of amine hydrogen of 13 with base initiates produced from fully unsaturated 1,4-thiazepine 10k, if formed,
cyclization through vinylogous amido-imido tautomerization to by a similar mechanism via intermediacy of 20k. Subsequently,
afford carbanion 14, which upon protonation yields fully keto-enol tautomerization of 19k provides thioenol-keto
unsaturated 1,4-thiazepine 10. Due to its anti-aromatic intermediate 21k, which undergoes an aldol-type cyclization to
character to some extent, 1,4-thiazepine 10 should be very form 1-pyrroline 22k. Then formation of thioenol 23k,
reactive and immediately undergoes 6πe electrocyclic ring followed by the removal of hydroxyl group, produces 3H-
closure to generate bicyclic intermediate 15. This could be the pyrrole 24k. Finally, isomerization affords pyrrole 11k (Scheme
reason why 1,4-thiazepine 10 was never observed during these 4).
reactions. Lastly, sulfur extrusion from 15 affords 5-
During our studies, we have also examined one example of
methylpyridines 7 (Scheme 3). Importantly, amine hydrogen (- the cyclization of β-enaminothione that contains internal
NH-CH2-) of propargylamine moiety is more acidic than alkyne functionality, namely 6a (Table 4). β-Enaminothione 6a
propargylic hydrogen (-NH-CH2-), but in basic medium, was prepared from its β-enaminone analog by thionation with
propargyl moiety can be easily converted into allene unit since Lawesson’s reagent28 in 80% yield, according to our previous
the process is also governed by the relative stability of the study.29 First, β-enaminothione 6a was treated with 0.5 mL of
anions formed.34,35 Moreover, in heteropropargyl systems, DIPA in DMF at room temperature, which afforded the
allene isomers can be more stable than the propargyl expected 5-benzyl-substituted pyridine derivative 25a in 35%
isomers.34,36 For the formation of pyridines 7, both propargylic yield, along with 2-benzylidene-2,3-dihydro-1,4-thiazepine 26a
and amine hydrogens are deprotonated with base during the in 15% yield (Table 4, Entry 1). On the other hand, the reaction
course of the reaction; however, to the best of our knowledge, of β-enaminothione 6a with 1.0 equiv. of DBU in ACN at room
formation of allene unit from propargyl moiety should be the temperature gave 5-benzyl-substituted pyridine derivative 25a
first as depicted in Scheme 3. In addition, the use of excess in 32% yield (Table 4, Entry 2). Finally, the reaction with DIPA
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C8OB03180K
Organic & Biomolecular Chemistry
ARTICLE
Ar
Ar
Ar
S
S
S
BaseH+
-Base
C
C
-BaseH+
N
H
N
H
N
H
R
H
R
R
Base
Base
4
12
13
-BaseH+
S
Ar
Ar
CH3
Ar
CH2
S
S
Ar
CH3
sulfur
BaseH+
-Base
CH3
N
N
extrusion
N
R
N
R
R
R
7
15
10
14
Ar
S
Ar
Ar
S
S
BaseH+
-Base
-BaseH+
N
N
N
H
R
R
R
Base
4
16
5
Scheme 3 Proposed mechanism for the formation of 5-methylpyridines 7 and 1,4-thiazepines 5 in the presence of DIPA.
H2O
Ph
HO
OH HS
OH HS
S
S
Ph
Ph
CH3
Ph
N
N
N
N
19k
Bu
Bu
H
Bu
Bu
5k
17k
18k
H2O
Ph
HO
Bu
O
HS
CH3
CH3
S
S
Ph
CH3
Ph
N
N
N
Bu
Bu
H
10k
20k
21k
OH
OH
Ph
Ph
Ph
Ph
CH3
CH3
CH3
CH3
Bu
Bu
Bu
Bu
N
H
N
N
N
-H2O
S
S
SH
S
11k
24k
23k
22k
Scheme 4 Proposed mechanism for the formation of pyrrole 11k.
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Table 4. Reaction of internal alkyne containing β-enaminothione 6a under basic conditions.a
View Article Online
DOI: 10.1039/C8OB03180K
Ph
Ph
Ph
Ph
S
Base
S
Ph
+
Ph
NH
Solvent, Temperature
Time
N
Ph
N
Ph
25a
26a
Ph
6a
Entry
Base (amt. or equiv.)
DIPA (0.5 mL)
Solvent
Temp. (oC)
Time (h)
Product(s) (% Yield)b
r.t.
r.t.
60
25a (35) + 26a (15)
25a (32)
1
2
3
DMF
ACN
DMF
3.0
3.0
3.0
DBU (1.0 equiv.)
DIPA (0.5 mL)
25a (24) + 26a (5)
aReactions were performed on a scale of 0.30 mmol of β-enaminothione 6a in 0.5 mL solvent under indicated conditions. bIsolated yield.
was carried out at 60 oC as well (Table 4, Entry 3), which
produced the expected pyridine derivative 25a (24%) and 1,4-
thiazepine 26a (5%) in relatively lower yields. In summary, the
reactions of internal alkyne-tethered N-propargylic β-
Experimental section
General information
1H and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively. Chemical shifts are given in parts per million
(ppm) relative to CDCl3 (7.26 and 77.16 ppm in 1H and 13C
NMR, respectively). Coupling constants (J) are reported in
hertz (Hz), and spin multiplicities are presented by the
following symbols: s (singlet), br s (broad singlet), d (doublet), t
(triplet), q (quartet), p (pentet), m (multiplet). DEPT 13C NMR
information is given in parentheses as C, CH, CH2 and CH3.
Infrared spectra (IR) were recorded by using attenuated total
reflection (ATR). Band positions are reported in reciprocal
centimeters (cm-1). Mass spectra (MS) were obtained by using
Electrospray Ionization (ESI) with Micro-Tof; m/z values are
reported (For each measurement, the mass scale was
recalibrated with sodium formate clusters, and samples were
dissolved and measured in acetonitrile or MeOH). High
resolution mass spectra (HRMS) were also obtained by using
Electrospray Ionization (ESI) with Micro-Tof. Flash
chromatography was performed using thick-walled glass
columns and “flash grade” silica (230-400 mesh). Thin layer
chromatography (TLC) analysis was performed by using
commercially prepared 0.25 mm silica gel plates and
visualization was effected with short wavelength UV lamp (254
nm). The relative proportions of solvents in chromatography
solvent mixtures refer to the volume:volume ratio. All
commercially available reagents were used directly without
purification unless otherwise stated. All the solvents used in
reactions and chromatography were distilled for purity.
Tetrahydrofuran (THF) was distilled from sodium
metal/benzophenone in glass kettle. Triethylamine and N,N-
dimethylformamide (DMF) were purified through vacuum
distillation. The inert atmosphere was created by slight
positive pressure (ca. 0.1 psi) of argon. All glassware was dried
in oven prior to use. Note that characterization data and NMR
spectra for 1,4-thiazepines 5 and 26a were fully reported in
our previous study.29
enaminothiones
6
require
further
investigation.
Reoptimization of the reaction conditions may provide higher
yields of pyridine derivatives 25.
Conclusions
In summary, we have prepared N-propargylic β-
enaminothiones and investigated their cyclizations under basic
conditions. N-Propargylic β-enaminothiones were synthesized
from the corresponding β-enaminones in good to high yields
by thionation with Lawesson’s reagent. Treatment of N-
propargylic β-enaminothiones with DIPA in DMF at room
temperature afforded 2,4,5-trisubstituted pyridines in
moderate to high yields, along with the small amount of 2-
methylene-2,3-dihydro-1,4-thiazepines. The reaction has been
found to be general for a variety of N-propargylic β-
enaminothiones and tolerated a wide range of functional
groups with electron-donating and electron-withdrawing
substituents. Furthermore, this process is applicable to the
cyclization of internal alkyne-tethered N-propargylic β-
enaminothiones. The reaction involves in situ formation of the
fully unsaturated 1,4-thiazepines, which upon electrocyclic ring
closure and sulfur extrusion afford 2,4,5-trisubstituted pyridine
derivative. We anticipate that high reaction efficiency and
wide reaction scope could make the method particularly
attractive in the area of pharmaceuticals for the building of
pyridine libraries. Also, the synthesized pyridines are of
potential utility as new pharmacophores and scaffolds for drug
discovery.
8 | J. Name., 2012, 00, 1-3
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3H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.4 (C), 151.2 (CH),
View Article Online
DOI: 10.1039/C8OB03180K
General Procedure for the synthesis of 5-methylpyridines 7 150.0 (C), 139.6 (C), 138.7 (C), 136.6 (C), 129.5 (CH), 128.9 (C), 128.7
(Table 2).
(CH), 128.6 (CH), 128.0 (CH), 126.7 (CH), 120.7 (CH), 21.3 (CH3), 17.1
To a stirred solution of the corresponding β-enaminothione 4 (CH3); IR (neat): 3024, 2919, 1592, 1574, 1542, 1494, 1473, 1442,
(0.30 mmol) in DMF (0.50 mL) at room temperature under 1369, 1179, 1111, 1042, 1018, 889, 822, 772, 754, 738, 702, 627,
argon was added (i-Pr)2NH (0.50 mL), and the resulting mixture 564 cm-1; MS (ESI, m/z): 260.14 [M+H]+; HRMS (ESI) calcd. for
was stirred at room temperature. (Note that stirring was C19H18N: 260.1434 [M+H]+, found: 260.1442.
continued until β-enaminothione 4 was completely consumed
2-(2-Methoxyphenyl)-5-methyl-4-phenylpyridine (7d). 3-(2-
as monitored by routine TLC analysis). After the reaction was Methoxyphenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-ene-1-
over, ethyl acetate (40 mL) was added, and the resulting thione (4d) (110.7 mg, 0.36 mmol), (i-Pr)2NH (0.60 mL, 4.27 mmol)
solution was washed with a saturated NH4Cl solution (15 mL) and DMF (0.60 mL) were employed to afford 45.4 mg (46%) of the
in a separatory funnel. After the layers were separated, the indicated product as a yellowish brown solid (mp 105.3-106.6 oC)
aqueous layer was extracted with ethyl acetate (2 x 30 mL). and 8.9 mg (8%) of 5-(2-methoxyphenyl)-2-methylene-7-phenyl-2,3-
Then, organic phase was dried over MgSO4 and evaporated on dihydro-1,4-thiazepine (5d)29 in 3.0 h.
a rotary evaporator to give the crude product, which was
7d: 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.79 (dd, J = 7.6, 1.8
purified by flash chromatography on silica gel using Hz, 1H), 7.71 (s, 1H), 7.51-7.34 (m, 6H), 7.09 (td, J = 7.5, 1.0 Hz, 1H),
hexane/ethyl acetate (15:1 followed by 9:1) as the eluent to 7.00 (d, J = 8.3 Hz, 1H), 3.84 (s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz,
afford 5-methylpyridine derivative 7.
CDCl3) δ 157.0 (C), 154.0 (C), 150.9 (CH), 149.0 (C), 139.7 (C), 131.2
5-Methyl-2,4-diphenylpyridine (7a). 1,3-Diphenyl-3-(prop-2-yn- (CH), 129.8 (CH), 129.1 (C), 128.82 (CH), 128.78 (C), 128.5 (CH),
1-ylamino)prop-2-ene-1-thione (4a) (83.2 mg, 0.30 mmol), (i-Pr)2NH 127.9 (CH), 125.4 (CH), 121.1 (CH), 111.4 (CH), 55.7 (OCH3), 17.2
(0.50 mL, 3.56 mmol) and DMF (0.50 mL) were employed to afford (CH3); IR (neat): 2995, 2954, 2930, 2834, 1593, 1578, 1540, 1495,
62.4 mg (85%) of the indicated product as a dark brown solid (mp 1465, 1435, 1367, 1277, 1240, 1177, 1121, 1058, 1024, 897, 852,
74.1-75.1 oC) and 4.2 mg (5%) of 2-methylene-5,7-diphenyl-2,3- 795, 772, 752, 703, 633, 601 cm-1; MS (ESI, m/z): 276.14 [M+H]+;
dihydro-1,4-thiazepine (5a)29 in 2.0 h.
HRMS (ESI) calcd. for C19H18NO: 276.1383 [M+H]+, found: 276.1390.
1
7a: H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.03 (d, J = 7.5 Hz,
2-(4-Methoxyphenyl)-5-methyl-4-phenylpyridine (7e). 3-(4-
2H), 7.63 (s, 1H), 7.53-7.37 (m, 8H), 2.32 (s, 3H); 13C NMR (100 MHz, Methoxyphenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-ene-1-
CDCl3) δ 155.4 (C), 151.3 (CH), 150.0 (C), 139.5 (C), 139.4 (C), 129.2 thione (4e) (104.5 mg, 0.34 mmol), (i-Pr)2NH (0.57 mL, 4.03 mmol)
(C), 128.8 (CH), 128.74 (CH), 128.65 (CH), 128.6 (CH), 128.1 (CH), and DMF (0.57 mL) were employed to afford 71.1 mg (76%) of the
126.8 (CH), 121.0 (CH), 17.0 (CH3); IR (neat): 3056, 2999, 2921, indicated product as an orangish brown solid (mp 92.0-93.1 oC) and
1735, 1591, 1574, 1541, 1495, 1474, 1442, 1370, 1241, 1229, 1075, 9.4 mg (9%) of 5-(4-methoxyphenyl)-2-methylene-7-phenyl-2,3-
1025, 1000, 918, 892, 850, 775, 746, 715, 696, 632, 597, 536 cm-1. dihydro-1,4-thiazepine (5e)29 in 3.0 h.
1
The spectral data are in agreement with those reported previously
for this compound.37
7e: H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.99-7.94 (m, 2H),
7.55 (s, 1H), 7.50-7.36 (m, 5H), 7.03-6.95 (m, 2H), 3.85 (s, 3H), 2.29
5-Methyl-4-phenyl-2-(m-tolyl)pyridine (7b). 1-Phenyl-3-(prop- (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.3 (C), 155.0 (C), 151.1 (CH),
2-yn-1-ylamino)-3-(m-tolyl)prop-2-ene-1-thione (4b) (99.1 mg, 0.34 150.0 (C), 139.6 (C), 132.0 (C), 128.7 (CH), 128.54 (CH), 128.49 (C),
mmol), (i-Pr)2NH (0.57 mL, 4.03 mmol) and DMF (0.57 mL) were 128.04 (CH), 128.01 (CH), 120.3 (CH), 114.2 (CH), 55.4 (OCH3), 17.0
employed to afford 58.5 mg (66%) of the indicated product as a (CH3); IR (neat): 2991, 2956, 2931, 2835, 1606, 1592, 1542, 1513,
dark brown solid (mp 68.9-70.4 oC) and 5.0 mg (5%) of 2-methylene- 1494, 1472, 1441, 1416, 1369, 1305, 1239, 1171, 1110, 1028, 896,
7-phenyl-5-(m-tolyl)-2,3-dihydro-1,4-thiazepine (5b)29 in 3.5 h.
854, 826, 786, 775, 757, 742, 712, 704, 679, 657, 626, 568 cm-1; MS
1
7b: H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.91-7.74 (m, 2H), (ESI, m/z): 276.14 [M+H]+; HRMS (ESI) calcd. for C19H18NO: 276.1383
7.64 (s, 1H), 7.54-7.35 (m, 6H), 7.25 (d, J = 7.3 Hz, 1H), 2.47 (s, 3H), [M+H]+, found: 276.1393.
2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.5 (C), 151.2 (CH),
2-(4-(tert-Butyl)phenyl)-5-methyl-4-phenylpyridine (7f). 3-(4-
150.0 (C), 139.6 (C), 139.4 (C), 138.4 (C), 129.5 (CH), 129.2 (C), 128.7 (tert-Butyl)phenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-ene-1-
(2xCH), 128.6 (CH), 128.1 (CH), 127.6 (CH), 123.9 (CH), 121.1 (CH), thione (4f) (116.7 mg, 0.35 mmol), (i-Pr)2NH (0.58 mL, 4.15 mmol)
21.6 (CH3), 17.1 (CH3); IR (neat): 3060, 2989, 2918, 1590, 1542, and DMF (0.58 mL) were employed to afford 71.2 mg (68%) of the
1495, 1471, 1451, 1440, 1383, 1358, 1229, 1061, 1040, 888, 816, indicated product as a dark brown oil and 5.8 mg (5%) of 5-(4-(tert-
799, 770, 757, 740, 632, 601, 553 cm-1; MS (ESI, m/z): 260.14 butyl)phenyl)-2-methylene-7-phenyl-2,3-dihydro-1,4-thiazepine
[M+H]+; HRMS (ESI) calcd. for C19H18N: 260.1434 [M+H]+, found: (5f)29 in 3.0 h.
260.1446.
7f: 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 7.98-7.94 (m, 2H),
5-Methyl-4-phenyl-2-(p-tolyl)pyridine (7c). 1-Phenyl-3-(prop-2- 7.61 (s, 1H), 7.50 (ddd, J = 8.2, 5.1, 1.6 Hz, 4H), 7.46-7.43 (m, 1H),
yn-1-ylamino)-3-(p-tolyl)prop-2-ene-1-thione (4c) (99.1 mg, 0.34 7.41-7.37 (m, 2H), 2.32 (s, 3H), 1.38 (s, 9H); 13C NMR (100 MHz,
mmol), (i-Pr)2NH (0.57 mL, 4.03 mmol) and DMF (0.57 mL) were CDCl3) δ 155.4 (C), 151.9 (C), 151.3 (CH), 149.9 (C), 139.6 (C), 136.6
employed to afford 65.4 mg (74%) of the indicated product as a (C), 128.9 (C), 128.7 (CH), 128.6 (CH), 128.0 (CH), 126.5 (CH), 125.8
brown oil and 7.9 mg (8%) of 2-methylene-7-phenyl-5-(p-tolyl)-2,3- (CH), 120.8 (CH), 34.8 (C), 31.4 (CH3), 17.1 (CH3); IR (neat): 2960,
dihydro-1,4-thiazepine (5c)29 in 3.0 h.
2903, 2865, 1592, 1541, 1494, 1474, 1369, 1268, 1112, 1022, 1013,
1
7c: H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.95 (d, J = 8.2 Hz, 889, 839, 772, 734, 701, 657, 625 cm-1; MS (ESI, m/z): 302.19
2H), 7.62 (s, 1H), 7.54-7.39 (m, 5H), 7.31 (d, J = 8.0 Hz, 2H), 2.44 (s,
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
[M+H]+; HRMS (ESI) calcd. for C22H24N: 302.1916 [M+H]+, found:
302.1903.
5-Methyl-4-phenyl-2-(thiophen-3-yl)pyridine (7j). 1-Phenyl-3-
View Article Online
DOI: 10.1039/C8OB03180K
(prop-2-yn-1-ylamino)-3-(thiophen-3-yl)prop-2-ene-1-thione
(4j)
2-(2-Bromophenyl)-5-methyl-4-phenylpyridine
(7g).
3-(2- (90.7 mg, 0.32 mmol), (i-Pr)2NH (0.53 mL, 3.79 mmol) and DMF
Bromophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-ene-1-
(0.53 mL) were employed to afford 55.3 mg (69%) of the indicated
thione (4g) (89.1 mg, 0.25 mmol), (i-Pr)2NH (0.42 mL, 2.96 mmol) product as a dark brown solid (mp 62.6-64.4 oC) and 5.4 mg (6%) of
and DMF (0.42 mL) were employed to afford 49.0 mg (60%) of the 2-methylene-7-phenyl-5-(thiophen-3-yl)-2,3-dihydro-1,4-thiazepine
indicated product as an orangish brown oil and 11.6 mg (13%) of 5- (5j)29 in 3.0 h.
(2-bromophenyl)-2-methylene-7-phenyl-2,3-dihydro-1,4-thiazepine
(5g)29 in 2.0 h.
7j: 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.88 (dd, J = 3.0, 1.2
Hz, 1H), 7.66 (dd, J = 5.0, 1.2 Hz, 1H), 7.53-7.35 (m, 7H), 2.28 (s, 3H).
7g: 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.70 (dd, J = 8.0, 1.1 13C NMR (100 MHz, CDCl3) δ 151.6 (C), 151.2 (CH), 150.0 (C), 142.2
Hz, 1H), 7.61 (dd, J = 7.7, 1.7 Hz, 1H), 7.53 (s, 1H), 7.52-7.40 (m, 6H), (C), 139.4 (C), 129.0 (C), 128.63 (CH), 128.59 (CH), 128.1 (CH), 126.3
7.29-7.23 (m, 1H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.10 (CH), 123.0 (CH), 120.8 (CH), 17.1 (CH3). (Note that two CH peaks
(C), 151.1 (CH), 149.1 (C), 141.2 (C), 139.2 (C), 133.4 (CH), 131.6 overlap on each other); IR (neat): 3089, 3059, 2918, 1592, 1535,
(CH), 129.7 (CH), 129.6 (C), 128.8 (CH), 128.6 (CH), 128.2 (CH), 127.6 1495, 1473, 1441, 1377, 1334, 1272, 1226, 1200, 1074, 1043, 1022,
(CH), 125.2 (CH), 122.1 (CBr), 17.2 (CH3); IR (neat): 3055, 3024, 1000, 916, 891, 863, 838, 798, 771, 751, 738, 703, 677, 628, 595 cm-
2997, 2956, 2923, 1594, 1562, 1538, 1493, 1461, 1440, 1427, 1368, 1; MS (ESI, m/z): 252.08 [M+H]+; HRMS (ESI) calcd. for C16H14NS:
1256, 1075, 1046, 1024, 1001, 896, 852, 772, 751, 701, 655, 631 cm- 252.0842 [M+H]+, found: 252.0839.
1; MS (ESI, m/z): 324.04 [M+H]+; HRMS (ESI) calcd. for C18H1579BrN:
324.0382 [M+H]+, found: 324.0392.
2-Butyl-5-methyl-4-phenylpyridine (7k). 1-Phenyl-3-(prop-2-yn-
1-ylamino)hept-2-ene-1-thione (4k) (87.5 mg, 0.34 mmol), (i-Pr)2NH
2-(3-Fluorophenyl)-5-methyl-4-phenylpyridine
Fluorophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-ene-1-
thione (4h) (97.5 mg, 0.33 mmol), (i-Pr)2NH (0.55 mL, 3.91 mmol) 5-butyl-2-methylene-7-phenyl-2,3-dihydro-1,4-thiazepine (5k)29 and
and DMF (0.55 mL) were employed to afford 58.5 mg (67%) of the 23.6 mg (27%) of 1-(5-butyl-3-phenyl-1H-pyrrol-2-yl)ethanethione
(7h).
3-(3- (0.57 mL, 4.03 mmol) and DMF (0.57 mL) were employed to afford
9.6 mg (13%) of the indicated product as a brown oil, 1.8 mg (2%) of
o
indicated product as a light yellow solid (mp 43.9-45.3 C) and 4.9 (11k) as a greenish brown oil in 4.0 h.
1
mg (5%) of 5-(3-fluorophenyl)-2-methylene-7-phenyl-2,3-dihydro-
1,4-thiazepine (5h)29 in 4.0 h.
7k: H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.48-7.37 (m, 3H),
7.35-7.30 (m, 2H), 7.03 (s, 1H), 2.84-2.77 (m, 2H), 2.24 (s, 3H), 1.72
7h: 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.81-7.73 (m, 2H), (tt, J = 7.8, 6.7 Hz, 2H), 1.40 (sextet, J = 7.4 Hz, 3H), 0.94 (t, J = 7.3
7.59 (s, 1H), 7.52-7.36 (m, 6H), 7.08 (td, J = 8.2, 2.5 Hz, 1H), 2.32 (s, Hz, 3H); IR (neat): 2954, 2926, 2857, 1618, 1595, 1543, 1480, 1407,
1
3H); 13C NMR (100 MHz, CDCl3) δ 163.5 (d, J = 245.3 Hz, CF), 154.0 1385, 1274, 1196, 1074, 1046, 881, 774, 736, 701, 630 cm-1; MS
4
3
(d, J = 2.5 Hz, C), 151.4 (CH), 150.2 (C), 141.7 (d, J = 7.5 Hz, C), (ESI, m/z): 226.16 [M+H]+; HRMS (ESI) calcd. for C16H20N: 226.1590
139.3 (C), 130.3 (d, 3J = 8.3 Hz, CH), 130.0 (C), 128.7 (CH), 128.2 [M+H]+, found: 226.1596.
4
2
1
(CH), 122.3 (d, J = 2.5 Hz, CH), 121.1 (CH), 115.6 (d, J = 21.2 Hz,
11k: H NMR (400 MHz, CDCl3) δ 9.67 (br s, 1H), 7.43-7.34 (m,
2
CH), 113.8 (d, J = 22.8 Hz, CH), 17.1 (CH3) (Note that two CH peaks 5H), 6.11 (d, J = 2.9 Hz, 1H), 2.65-2.60 (m, 2H), 2.50 (s, 3H), 1.68
overlap on each other); IR (neat): 3063, 3026, 1612, 1582, 1545, (ddd, J = 15.4, 8.6, 6.5 Hz, 2H), 1.43 (sextet, J = 7.3 Hz, 2H), 0.96 (t, J
1494, 1465, 1440, 1359, 1253, 1198, 1170, 1150, 1072, 1051, 991, = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 214.7 (C=S), 145.8 (C),
900, 880, 822, 787, 771, 755, 737, 690, 632, 597 cm-1; MS (ESI, m/z): 137.8 (C), 137.2 (C), 133.4 (C), 129.5 (CH), 128.4 (CH), 127.8 (CH),
264.12 [M+H]+; HRMS (ESI) calcd. for C18H15FN: 264.1183 [M+H]+, 114.6 (CH), 35.8 (CH2), 30.9 (CH2), 27.8 (CH3), 22.5 (CH2), 13.9 (CH3);
found: 264.1195.
5-Methyl-4-phenyl-2-(4-(trifluoromethyl)phenyl)pyridine (7i). 1181, 1136, 1071, 1003, 846, 763, 700 cm-1; MS (ESI, m/z): 258.13
1-Phenyl-3-(prop-2-yn-1-ylamino)-3-(4-
[M+H]+; HRMS (ESI) calcd. for C16H20NS: 258.1311 [M+H]+, found:
(trifluoromethyl)phenyl)prop-2-ene-1-thione (4i) (86.3 mg, 0.25 258.1323.
mmol), (i-Pr)2NH (0.42 mL, 2.96 mmol) and DMF (0.42 mL) were 4-(2-Bromophenyl)-5-methyl-2-phenylpyridine
employed to afford 44.0 mg (56%) of the indicated product as a Bromophenyl)-3-phenyl-3-(prop-2-yn-1-ylamino)prop-2-ene-1-
light yellow solid (mp 65.3-66.3 oC) and 4.3 mg (5%) of 2-methylene- thione (4l) (60.6 mg, 0.17 mmol), (i-Pr)2NH (0.28 mL, 2.02 mmol)
IR (neat): 3287, 2954, 2927, 2858, 1618, 1550, 1469, 1391, 1270,
(7l).
1-(2-
7-phenyl-5-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1,4-thiazepine
and DMF (0.28 mL) were employed to afford 29.1 mg (53%) of the
indicated product as an orange oil and 6.1 mg (10%) of 7-(2-
(5i)29 in 3.0 h.
1
7i: H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.13 (d, J = 8.1 Hz, bromophenyl)-2-methylene-5-phenyl-2,3-dihydro-1,4-thiazepine
2H), 7.72 (d, J = 8.3 Hz, 2H), 7.64 (s, 1H), 7.53-7.43 (m, 3H), 7.41- (5l)29 in 2.0 h.
7.36 (m, 2H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.8 (C),
7l: 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.92 (d, J = 7.2 Hz,
151.6 (CH), 150.4 (C), 142.8 (C), 139.3 (C), 130.7 (q, 2J = 32.4 Hz, C), 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.38 (t, J = 7.3 Hz, 2H),
130.4 (C), 128.73 (CH), 128.67 (CH), 128.3 (CH), 127.1 (CH) 125.8 (q, 7.34-7.27 (m, 2H), 7.21 (td, J = 7.9, 1.6 Hz, 1H), 7.14 (dd, J = 7.5, 1.5
3J = 3.7 Hz, CH), 124.2 (q, 1J = 272.2 Hz, CF3), 121.4 (CH), 17.2 (CH3); Hz, 1H), 2.07 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.1 (C), 150.8
IR (neat): 2994, 1617, 1594, 1577, 1542, 1493, 1475, 1411, 1326, (CH), 149.6 (C), 140.3 (C), 139.1 (C), 133.0 (CH), 130.1 (C), 130.1
1153, 1117, 1102, 1069, 1013, 999, 893, 847, 775, 758, 734, 703, (CH), 129.7 (CH), 128.91 (CH), 128.85 (CH), 127.6 (CH), 126.9 (CH),
653, 640, 618, 590 cm-1; MS (ESI, m/z): 314.12 [M+H]+; HRMS (ESI) 122.6 (CBr), 120.9 (CH), 16.6 (CH3); IR (neat): 3051, 2919, 1600,
calcd. for C19H15F3N: 314.1151 [M+H]+, found: 314.1163.
1561, 1544, 1483, 1464, 1431, 1381, 1368, 1257, 1225, 1065, 1016,
996, 887, 850, 777, 765, 745, 732, 693, 666 cm-1; MS (ESI, m/z):
10 | J. Name., 2012, 00, 1-3
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324.04 [M+H]+; HRMS (ESI) calcd. for C18H1579BrN: 324.0382 [M+H]+, 1321, 1257, 1158, 1117, 1068, 1013, 891, 847, 835, 767, 746, 727,
View Article Online
-1
+
DOI: 10.1039/C8OB03180K
found: 324.0399.
4-(2-Bromophenyl)-5-methyl-2-(m-tolyl)pyridine (7m). 1-(2- calcd. for C19H1479BrF3N: 392.0256 [M+H]+, found: 392.0271.
Bromophenyl)-3-(prop-2-yn-1-ylamino)-3-(m-tolyl)prop-2-ene-1- 4-(4-Chlorophenyl)-5-methyl-2-phenylpyridine (7p).
thione (4m) (66.7 mg, 0.18 mmol), (i-Pr)2NH (0.30 mL, 2.13 mmol) Chlorophenyl)-3-phenyl-3-(prop-2-yn-1-ylamino)prop-2-ene-1-
706, 658, 629, 618 cm ; MS (ESI, m/z): 392.03 [M+H] ; HRMS (ESI)
1-(4-
and DMF (0.30 mL) were employed to afford 30.0 mg (49%) of the thione (4p) (109.1 mg, 0.35 mmol), (i-Pr)2NH (0.58 mL, 4.15 mmol)
indicated product as a yellowish brown oil and 4.7 mg (7%) of 7-(2- and DMF (0.58 mL) were employed to afford 65.5 mg (67%) of the
bromophenyl)-2-methylene-5-(m-tolyl)-2,3-dihydro-1,4-thiazepine
(5m)29 in 2.0 h.
indicated product as a brown solid (mp 81.6-83.4 oC) and 4.4 mg
(4%) of 7-(4-chlorophenyl)-2-methylene-5-phenyl-2,3-dihydro-1,4-
7m: 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.85 (s, 1H), 7.78 thiazepine (5p)29 in 2.0 h.
(d, J = 7.7 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.42 (t, J = 7.4
7p: 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.89 (d, J = 7.2 Hz,
Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.29 (td, J = 7.7, 1.5 Hz, 1H), 7.25- 2H), 7.47 (s, 1H), 7.40-7.28 (m, 5H), 7.22 (d, J = 8.4 Hz, 2H), 2.20 (s,
7.20 (m, 2H), 2.43 (s, 3H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 3H); 13C NMR (100 MHz, CDCl3) δ 155.5 (C), 151.4 (CH), 148.8 (C),
155.2 (C), 150.7 (CH), 149.6 (C), 140.3 (C), 139.0 (C), 138.5 (C), 133.0 139.2 (C), 137.9 (C), 134.3 (C), 130.1 (CH), 129.1 (C), 128.90 (CH),
(CH), 130.2 (CH), 130.1 (C), 129.7 (CH), 128.8 (CH), 127.63 (CH), 128.85 (CH), 126.8 (CH), 120.8 (CH), 17.0 (CH3) (Note that two CH
127.62 (CH), 124.0 (CH), 122.6 (CBr), 121.0 (CH), 21.7 (CH3), 16.6 peaks overlap on each other); IR (neat): 3059, 2999, 2961, 1602,
(CH3) (Note that two CH peaks overlap on each other); IR (neat): 1588, 1540, 1491, 1473, 1442, 1384, 1370, 1243, 1228, 1178, 1087,
3049, 2950, 2918, 1599, 1584, 1561, 1543, 1463, 1431, 1380, 1358, 1051, 1036, 1015, 997, 894, 843, 830, 780, 749, 710, 694, 665, 599
1260, 1226, 1092, 1063, 1020, 995, 882, 817, 791, 748, 729, 700, cm-1; MS (ESI, m/z): 280.09 [M+H]+; HRMS (ESI) calcd. for C18H15ClN:
666, 629 cm-1; MS (ESI, m/z): 338.06 [M+H]+; HRMS (ESI) calcd. for 280.0888 [M+H]+, found: 280.0901.
C19H1779BrN: 338.0539 [M+H]+, found: 338.0554.
4-(2-Bromophenyl)-2-(3-fluorophenyl)-5-methylpyridine (7n). 1-(4-Chlorophenyl)-3-(3-fluorophenyl)-3-(prop-2-yn-1-
1-(2-Bromophenyl)-3-(3-fluorophenyl)-3-(prop-2-yn-1- ylamino)prop-2-ene-1-thione (4q) (89.1 mg, 0.27 mmol), (i-Pr)2NH
4-(4-Chlorophenyl)-2-(3-fluorophenyl)-5-methylpyridine (7q).
ylamino)prop-2-ene-1-thione (4n) (116.0 mg, 0.31 mmol), (i-Pr)2NH (0.45 mL, 3.20 mmol) and DMF (0.45 mL) were employed to afford
(0.52 mL, 3.68 mmol) and DMF (0.52 mL) were employed to afford 57.0 mg (71%) of the indicated product as a brown solid (mp 74.9-
54.5 mg (51%) of the indicated product as an orange oil and 10.4 76.3 oC) and 6.2 mg (7%) of 7-(4-chlorophenyl)-5-(3-fluorophenyl)-2-
mg (9%) of 7-(2-bromophenyl)-5-(3-fluorophenyl)-2-methylene-2,3- methylene-2,3-dihydro-1,4-thiazepine (5q)29 in 2.0 h.
dihydro-1,4-thiazepine (5n)29 in 2.0 h.
7q: 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.77-7.71 (m, 2H),
7n: 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.72-7.60 (m, 3H), 7.54 (s, 1H), 7.48-7.44 (m, 2H), 7.41 (dd, J = 10.9, 5.0 Hz, 1H), 7.34-
7.43 (s, 1H), 7.33 (td, J = 7.8, 6.6 Hz, 2H), 7.22 (td, J = 7.8, 1.7 Hz, 7.28 (m, 2H), 7.12-7.05 (m, 1H), 2.30 (s, 3H); 13C NMR (100 MHz,
1
4
1H), 7.15 (dd, J = 7.5, 1.7 Hz, 1H), 7.01 (tdd, J = 8.3, 2.5, 0.8 Hz, 1H), CDCl3) δ 163.4 (d, J = 245.5 Hz, CF), 154.1 (d, J = 2.5 Hz, C), 151.5
3
2.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.5 (d, 1J = 245.4 Hz, CF), (CH), 149.0 (C), 141.5 (d, J = 7.3 Hz, C), 137.7 (C), 134.4 (C), 130.3
4
3
3
4
155.8 (d, J = 2.4 Hz, C), 151.1 (CH), 149.6 (C), 141.7 (d, J = 7.6 Hz, (d, J = 8.2 Hz, CH), 130.0 (CH), 129.8 (C), 128.9 (CH), 122.3 (d, J =
C), 140.1 (C), 133.1 (CH), 130.8 (C), 130.3 (d, J = 8.2 Hz, CH), 130.2 2.8 Hz, CH), 120.9 (CH), 115.7 (d, 2J = 21.4 Hz, CH), 113.8 (d, 2J = 22.8
3
4
(CH), 129.8 (CH), 127.7 (CH), 122.6 (CBr), 122.4 (d, J = 2.8 Hz, CH), Hz, CH), 17.1 (CH3); IR (neat): 3040, 1614, 1584, 1570, 1541, 1496,
2
2
120.9 (CH), 115.7 (d, J = 21.3 Hz, CH), 113.9 (d, J = 22.7 Hz, CH), 1469, 1437, 1377, 1358, 1254, 1197, 1172, 1152, 1092, 1054, 1033,
16.6 (CH3); IR (neat): 2977, 1735, 1601, 1585, 1561, 1544, 1486, 1010, 992, 906, 877, 845, 817, 776, 750, 724, 697, 682, 655, 627 cm-
1461, 1371, 1243, 1201, 1175, 1155, 1046, 1020, 905, 878, 825, 1; MS (ESI, m/z): 298.08 [M+H]+; HRMS (ESI) calcd. for C18H14ClFN:
788, 763, 730, 695, 666, 629 cm-1; MS (ESI, m/z): 342.03 [M+H]+; 298.0793 [M+H]+, found: 298.0793.
HRMS (ESI) calcd. for C18H1479BrFN: 342.0288 [M+H]+, found:
342.0302.
5-Methyl-2-phenyl-4-(p-tolyl)pyridine (7r). 3-Phenyl-3-(prop-2-
yn-1-ylamino)-1-(p-tolyl)prop-2-ene-1-thione (4r) (93.3 mg, 0.32
mmol), (i-Pr)2NH (0.53 mL, 3.79 mmol) and DMF (0.53 mL) were
4-(2-Bromophenyl)-5-methyl-2-(4-
(trifluoromethyl)phenyl)pyridine (7o). 1-(2-Bromophenyl)-3-(prop- employed to afford 69.0 mg (83%) of the indicated product as a
2-yn-1-ylamino)-3-(4-(trifluoromethyl)phenyl)prop-2-ene-1-thione
dark brown oil and 6.5 mg (7%) of 2-methylene-5-phenyl-7-(p-tolyl)-
(4o) (110.3 mg, 0.26 mmol), (i-Pr)2NH (0.43 mL, 3.08 mmol) and 2,3-dihydro-1,4-thiazepine (5r)29 in 4.0 h.
1
DMF (0.43 mL) were employed to afford 55.2 mg (54%) of the
7r: H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.09-8.00 (m, 2H),
indicated product as a dark orange solid (mp 85.6-87.2 oC) and 11.0 7.64 (s, 1H), 7.50 (t, J = 7.4 Hz, 2H), 7.43 (t, J = 7.3 Hz, 1H), 7.32 (s,
mg
(10%)
of
7-(2-bromophenyl)-2-methylene-5-(4- 4H), 2.47 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.3 (C),
(trifluoromethyl)phenyl)-2,3-dihydro-1,4-thiazepine (5o)29 in 2.0 h.
151.2 (CH), 150.1 (C), 139.4 (C), 137.9 (C), 136.5 (C), 129.33 (C),
7o: 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.04 (d, J = 8.1 Hz, 129.26 (CH), 128.8 (CH), 128.7 (CH), 128.6 (CH), 126.8 (CH), 121.1
2H), 7.65-7.59 (m, 3H), 7.47 (s, 1H), 7.34 (td, J = 7.5, 1.2 Hz, 1H), (CH), 21.3 (CH3), 17.2 (CH3); IR (neat): 3025, 2919, 1594, 1542, 1511,
7.22 (td, J = 7.8, 1.7 Hz, 1H), 7.14 (dd, J = 7.5, 1.7 Hz, 1H), 2.08 (s, 1474, 1444, 1381, 1369, 1183, 1111, 1074, 1038, 1024, 889, 853,
3H); 13C NMR (100 MHz, CDCl3) δ 153.6 (C), 151.3 (CH), 149.7 (C), 821, 777, 747, 707, 694, 605 cm-1; MS (ESI, m/z): 260.14 [M+H]+;
142.6 (C), 140.0 (C), 133.1 (CH), 131.2 (C), 130.7 (q, 2J = 32.4 Hz, C), HRMS (ESI) calcd. for C19H18N: 260.1434 [M+H]+, found: 260.1446.
130.2 (CH), 129.9 (CH), 127.7 (CH), 127.1 (CH), 125.8 (q, 3J = 3.7 Hz,
5-Methyl-2-(thiophen-3-yl)-4-(p-tolyl)pyridine (7s). 3-(Prop-2-
CH), 124.4 (q, 1J = 274.0 Hz, CF3), 122.5 (CBr), 121.2 (CH), 16.6 (CH3); yn-1-ylamino)-3-(thiophen-3-yl)-1-(p-tolyl)prop-2-ene-1-thione (4s)
IR (neat): 2926, 1616, 1603, 1562, 1485, 1466, 1433, 1412, 1385, (86.3 mg, 0.29 mmol), (i-Pr)2NH (0.48 mL, 3.44 mmol) and DMF
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(0.48 mL) were employed to afford 59.5 mg (77%) of the indicated (CH), 126.3 (CH), 121.5 (CH), 36.3 (CH2); IR (neat)V:ie3w0A5r7tic,le3O0n2lin5e,
product as a dark brown oil and 8.6 mg (10%) of 2-methylene-5- 1590, 1538, 1493, 1473, 1444, 1373, 11D7O8,I: 1101.15063,91/C087O4B,013018207K,
(thiophen-3-yl)-7-(p-tolyl)-2,3-dihydro-1,4-thiazepine (5s)29 in 3.0 h.
888, 759, 716, 695, 670 cm-1; MS (ESI, m/z): 322.16 [M+H]+;
7s: 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.77 (dd, J = 3.0, 1.3 HRMS (ESI) calcd. for C24H20N: 322.1590 [M+H]+, found:
Hz, 1H), 7.55 (dd, J = 5.1, 1.3 Hz, 1H), 7.39 (s, 1H), 7.28 (dd, J = 5.0, 322.1599. The spectral data are in agreement with those
3.0 Hz, 1H), 7.22-7.16 (m, 4H), 2.34 (s, 3H), 2.19 (s, 3H); 13C NMR reported previously for this compound.39
(100 MHz, CDCl3) δ 151.5 (C), 151.1 (CH), 150.0 (C), 142.2 (C), 138.0
(C), 136.5 (C), 129.3 (CH), 129.0 (C), 128.6 (CH), 126.3 (CH), 122.9
(CH), 120.9 (CH), 21.4 (CH3), 17.2 (CH3) (Note that two CH peaks
Conflicts of interest
overlap on each other); IR (neat): 2919, 1594, 1540, 1511, 1474,
1444, 1419, 1380, 1335, 1184, 1112, 1051, 1037, 868, 843, 821,
794, 751, 727, 713, 677, 605 cm-1; MS (ESI, m/z): 266.10 [M+H]+;
HRMS (ESI) calcd. for C17H16NS: 266.0998 [M+H]+, found: 266.1010.
4-(4-Methoxyphenyl)-5-methyl-2-phenylpyridine (7t). 1-(4-
Methoxyphenyl)-3-phenyl-3-(prop-2-yn-1-ylamino)prop-2-ene-1-
thione (4t) (86.1 mg, 0.28 mmol), (i-Pr)2NH (0.47 mL, 3.32 mmol)
and DMF (0.47 mL) were employed to afford 40.5 mg (53%) of the
indicated product as a light yellow oil and 6.0 mg (7%) of 7-(4-
methoxyphenyl)-2-methylene-5-phenyl-2,3-dihydro-1,4-thiazepine
(5t)29 in 2.0 h.
There are no conflicts to declare.
Acknowledgements
We thank the Scientific and Technological Research Council of
Turkey (TUBITAK, Grant No. 114Z811) and the Research Fund of
Middle East Technical University (METU, Grant No. GAP-103-2018-
2770) for financial support of this research.
Notes and references
1
7t: H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.00 (d, J = 7.2 Hz,
1
(a) J. W. Daly, H. M. Garraffo and T. F. Spande, In Alkaloids:
Chemical and Biological Perspectives; W. W. Pelletier, Ed.;
Elsevier: New York, 1999; Vol. 13, pp 95-104. (b) L. D. Quin, J. A.
Tyrell, Fundamentals of Heterocyclic Chemistry; Wiley:
Hoboken, 2010; Chapter 8.3, pp 204-206.
2H), 7.60 (s, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.40 (t, J = 7.3 Hz, 1H), 7.33
(d, J = 8.7 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 3.88 (s, 3H), 2.33 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 159.6 (C), 155.4 (C), 151.3 (CH), 149.8
(C), 139.5 (C), 131.8 (C), 130.0 (CH), 129.4 (C), 128.83 (CH), 128.78
(CH), 126.9 (CH), 121.2 (CH), 114.1 (CH), 55.5 (OCH3), 17.3 (CH3); IR
(neat): 2928, 2834, 1608, 1594, 1576, 1511, 1474, 1442, 1369,
1295, 1246, 1176, 1109, 1043, 1029, 889, 833, 778, 750, 695, 606
cm-1; MS (ESI, m/z): 276.14 [M+H]+; HRMS (ESI) calcd. for C19H18NO:
276.1383 [M+H]+, found: 276.1396. The spectral data are in
agreement with those reported previously for this compound.38
2
For reviews of pyridines, see: (a) C. D. Johnson, D. L. Comins, S.
P. Joseph, N. Dennis, M. Lounasmaa, A. Tolvanen, G. Jones, M.
Balasubramanian and J. G. Keay, In Comprehensive Heterocyclic
Chemistry II; A. R. Katritzky, C. W. Rees, E. F. V. Scriven and A.
McKillop, Eds.; Pergamon: Oxford, 1996; Vol. 5, Chapters 5.01-
5.06, pp 1-300. (b) J. B. Harper, D. L. Comins, S. O’Connor, R. S.
Al-awar, V. Caprio, D. Barker, P. A. Keller, C. H. McAteer, M.
Balasubramanian and R. Murugan, In Comprehensive
Heterocyclic Chemistry III; A. R. Katritzky, C. A. Ramsden, E. F. V.
Scriven, R. J. K. Taylor and D. Black, Eds.; Pergamon: Oxford,
U.K., 2008; Vol. 7, Chapters 7.01-7.06, pp 1-336. (c) L. D. Quin,
and J. A. Tyrell, Fundamentals of Heterocyclic Chemistry; Wiley:
Hoboken, 2010; Chapter 9.13, pp 246-249. (d) J. A. Joule and K.
Mills, Heterocyclic Chemistry; 5th Ed.; Wiley: Chichester, 2010;
Chapter 8, pp 125-175. (e) C. Gonzales-Bello and B. Castedo, In
Modern Heterocyclic Chemistry; J. Alvaroz-Builla, J. J. Vaquero
and J. Barluenga, Eds.; Wiley: Weinheim, 2011; Chapter 16, pp
1431-1525.
Reaction of N-propargylic β-enaminothione 6a under basic
conditions (Table 4, Entry 1).
To
a stirred solution of 1,3-diphenyl-3-((3-phenylprop-2-yn-1-
yl)amino)prop-2-ene-1-thione (6a) (106.0 mg, 0.30 mmol) in DMF
(0.50 mL) at room temperature under argon was added (i-Pr)2NH
(0.50 mL, 3.56 mmol), and the resulting mixture was stirred at room
temperature (Note that stirring was continued until β-
enaminothione 6a was completely consumed as monitored by
routine TLC analysis). After the reaction was over, ethyl acetate (40
mL) was added, and the resulting solution was washed with a
saturated NH4Cl solution (15 mL) in a separatory funnel. After the
layers were separated, the aqueous layer was extracted with ethyl
acetate (2 x 30 mL). Then, organic phase was dried over MgSO4 and
evaporated on a rotary evaporator to give the crude product, which
was purified by flash chromatography on silica gel using
hexane/ethyl acetate (15:1 followed by 9:1) as the eluent to afford
33.8 mg (35%) of 5-benzyl-2,4-diphenylpyridine (25a) as an orangish
brown oil and 15.9 mg (15%) of (Z)-2-benzylidene-5,7-diphenyl-2,3-
dihydro-1,4-thiazepine (26a) as a light brown solid.29
3
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25a: 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.09-8.03 (m,
2H), 7.67 (s, 1H), 7.53-7.47 (m, 2H), 7.47-7.41 (m, 4H), 7.33-
7.28 (m, 2H), 7.27-7.17 (m, 3H), 7.01 (d, J = 7.2 Hz, 2H), 4.05 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 155.5 (C), 151.6 (CH), 150.6
(C), 140.4 (C), 139.2 (C), 139.1 (C), 132.3 (C), 129.0 (CH), 128.9
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Fustero, V. A. Soloshonok and H. Liu, Chem. Rev., 2014, 114,
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