Metal free coupling of heteroaryl N-tosylhydrazones and thiols: Efficient synthesis of sulfides

Article abstract of DOI:10.1016/j.tetlet.2017.04.021

A metal free coupling of heteroaromatic N-tosylhydrazones with thiols is presented. A convenient synthetic route to synthesize heteroaryl N-tosylhydrazones is also showed. Valuable thioethers with pyrroles, pyridines, thieno[2,3-b]pyridines, imidazo[1,2-a]pyridines, and 6H-thieno[2,3-b]pyrroles derivatives were synthesized in good yields. This coupling reaction can be carried out in a one-pot fashion and scaled up to the gram scale by using heteroaryl aldehydes, without the need to isolate the N-tosylhydrazone.

Full text of DOI:10.1016/j.tetlet.2017.04.021

Accepted Manuscript
Metal free coupling of Heteroaryl N-Tosylhydrazones and Thiols: efficient syn-
thesis of Sulfides
Mario Alfredo Garcia-Carrillo, Angel Guzman, Eduardo Diaz
PII:
S0040-4039(17)30438-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.021
TETL 48813
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 February 2017
31 March 2017
4 April 2017
Please cite this article as: Garcia-Carrillo, M.A., Guzman, A., Diaz, E., Metal free coupling of Heteroaryl N-
Tosylhydrazones and Thiols: efficient synthesis of Sulfides, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.04.021
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Metal Free Coupling of Heteroaryl N-Tosylhydrazones and Thiols: Efficient Synthesis of Sulfides
Mario Alfredo Garcia-Carrillo,* Angel Guzman, Eduardo Diaz*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Metal free coupling of Heteroaryl N-Tosylhydrazones and Thiols: efficient synthesis
of Sulfides
Mario Alfredo Garcia-Carrilloa, ∗ Angel Guzmana and Eduardo Diaza, *
a Instituto de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 México, Ciudad de México, México
ARTICLE INFO
ABSTRACT
Article history:
Received
A metal free coupling of heteroaromatic N-tosylhydrazones with thiols is presented. A
convenient synthetic route to synthesize heteroaryl N-tosylhydrazones is also showed. Valuable
thioethers with pyrroles, pyridines, thieno[2,3-b]pyridines, imidazo[1,2-a]pyridines, and 6H-
thieno[2,3-b]pyrroles derivatives were synthesized in good yields. This coupling reaction can be
carried out in a one-pot fashion and scaled up to the gram scale by using heteroaryl aldehydes,
without the need to isolate the N-tosylhydrazone.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
In memory of Prof. Dr. José Barluenga
N-Tosylhydrazones
Heteroaromatic sulfides
Diazocompounds
Imidazo[1,2-a]pyridines
thieno[2,3-b]pyridines
Introduction
of boronic acids, phenols, and alcohols with N-tosylhydrazones.11
The group of Wang also reported a metal-free reaction to convert
N-tosylhydrazones into pinacol boronates.12 In addition, the
formation of C-C,13 C–O,14 C–N,15 C–P,16 C–S,17 N–N,18 and C-
Sn21 has been described. Ding and co-workers reported two
synthesis of thioethers via metal-free reductive coupling of
tosylhydrazones with thiols; nevertheless, they did not use N-
heteroarylhydrazones in their experiments, only N-
arylhydrazones were tested17. In a more recent study, Han and co-
workers reported the synthesis of alkyl 1H-tetrazol-5-yl
thioethers via a one-pot reaction of aldehydes and 1H-tetrazole-5-
thiols mediated by N-tosylhydrazones.17e In Han´s report the
reactivity between aliphatic and aromatic N-tosylhydrazones was
discussed, but no mention about the reactivity of N-
heteroarylhydrazones was made.
Heteroaryl thioethers are versatile molecules due to their
importance and applications as antiviral agents,
antiinflammatories, analgesics, antiepileptics, antiulcer agents,
material sciences, antifungals, and antibacterials.1 For example,
imidazo[1,2-a]pyridine derivative (I) is an antiviral agent with
pronounced activity against varicella-zoster virus,2 L-708,714
showed photoaffinity labeling of the active site of 5-
lipoxygenase,3 and 3-phenylthio-3-nicotinyl propionic acid
fragment (II) is a αvβ3 antagonist with nanomolar activity in the
biochemical assay and able to efficiently inhibit cell adhesion
mediated by vitronectin4 (Figure 1). Furthermore, aliphatic,
aromatic, and heteroaromatic thioethers can be considered as key
precursors for the corresponding sulfoxides, sulfones, and
sulfoximines which also exhibit a broad spectrum of therapeutic
activities.5 Therefore, the development of efficient strategies for
the synthesis of sulfides has attracted much attention. Thiol
alkylation and alkene addition normally require harsh reaction
conditions which are not compatible with sensitive functional
groups.6 Transition metal-catalyzed C–S cross coupling reaction
between thiols and halides has been previously reported,7
however the strong coordination nature8 of organic sulfur
compounds and their tendency to oxidize to disulfides are
substantial difficulties that are needed to be overcome.
N
N
N
N
N
N
N
N
N
N
Metal-free coupling reactions of diazo compounds generated
in situ from N-tosylhydrazones under basic reaction conditions
(Bamford–Stevens reaction)9 have recently found broad synthetic
applications.10 In pioneering studies, Barluenga, Valdés, and co-
Figure 1. Representative heteroaryl thioethers with biological
properties.
Stimulated by these previous reports, we became interested in
the application of a metal-free cross-coupling reaction of
workers discovered a metal-free reductive cross-coupling process
———
∗ Corresponding author. e-mail: marioagc@comunidad.unam.mx (M.A. Garcia-Carrillo), maudiaz@unam.mx (E. Diaz).

2
Tetrahedron
heteroaryl N-tosylhydrazones with thiols, since this process
would provide a convenient entry to heteroaromatic sulfides.
seemed to exert an important effect on the reactivity. The
reaction conditions have revealed that K2CO3 is more effective
than other bases, such as NaH, NaOH, and KOH (Table 1, entries
4–6). Interestingly, treatment of 1and 2 in the presence of KI as
additive and KOH or K2CO3 afforded the expected heteroaryl
sulfide 3a in only 49% and 75% yield, respectively (Table 1,
entries 7 and 8). These results indicate that the use of an additive
as some jobs suggest is not necessary.17e Raising or decreasing
the loading of K2CO3 did not report an improvement in the yields
of product 3a (Table 1, entry 9-10). When the molar ratio of 1 to
2 was changed from 1:1.5 to 1.5: 1 the yield of 3a decreased
considerably (Table 1, entry 11). Finally, an increment in the
amount of 2 under the same reaction conditions resulted in a
slight decrease in the reaction yield (Table 1, entry 12). In
summary, combination of 1 (1.0 mmol), thiol 2 (1.5 equivalents),
Results and discussion
According to our literature search, a few examples of N-
tosylhydrazones derived from aliphatic aldehydes and ketones
have been reported, which were much less reactive with poor
yields. On the other hand, moderate to high yields were reported
for a wide range of N-tosylhydrazones derived from different
aromatic aldehydes and ketones.11,14-17 To our surprise, we also
noted that only a few examples of heteroaryl N-tosylhydrazones
have been used in a metal-free cross-coupling process, with very
good reaction yields, nevertheless no explanation was offered
about this reactivity.11,16b,17a,d,e Even though the heteroaromatic
aldehydes and heteroaromatic ketones are abundant in nature,
their use in synthesis is relatively unusual because they are
commercially scarce, and thus they have to be prepared in the
laboratory.
Table 1. Optimization of the reaction conditions.a
Entry
1
Base
Solvent
Dioxane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Temperature (°C)
Yield (%)b
79
90
K2CO3
K2CO3
K2CO3
NaH
100
100
65
2
3
71
83
4
100
100
100
100
100
100
100
100
100
5
6
NaOH
KOH
KOH
40
59
7
49c
75c
90d
54e
56f
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
9
10
11
12
88g
aReaction conditions: 1, (1.0 mmol); 2, (1.5 mmol, 1.5 equiv.), base (2.5
equiv.), solvent 4 mL.
b Isolated yield.
c1 equiv. of KI as additive was used.
d3 equiv. of base was used.
e2 equiv. of base was used.
f The molar ratio of 1:2 was 1.5:1.
g The molar ratio of 1:2 was 1:2.
To verify our hypothesis on the reactivity and versatility of the
heteroaryl N-tosylhydrazones, we began the study of the reaction
between the N-tosylhydrazone pyrrole derivative 1 and the thiol 2
(table 1).22 The decision to use 1 was based on the high reactivity
offered by an electron-rich system such as the pyrrole.19 Besides,
according to the proposed mechanism in the previous report,11a
we reasoned that an aromatic electron-rich system will help in the
stability of the intermediate carbene present, which would
improve its reactivity in the coupling process. As depicted in
Table 1 and for our delight, when the reaction was carried out
with K2CO3 as a base in the presence of dioxane or toluene at 100
°C the corresponding product 3a was obtained in very good yield
(Table 1, entries 1–2). Therefore we decided to use toluene as the
solvent because of the higher reaction rate. A decrease yield was
observed when the reaction temperature was dropped to 65 °C
(Table 1, entry 3), which indicated that the reaction temperature
Scheme 1. Heteroaryl aldehydes and heteroaryl ketones.
K2CO3 (2.5 equivalents) at 100 °C in toluene (4 mL) were found
to be the optimal reaction conditions.
With the optimized reaction conditions in hand and motivated
by the results, we prepared a series of heteroaryl aldehydes and
ketones (Scheme 1), in order to prepare the corresponding
heteroaryl N-tosylhydrazones and test the versatility of this
protocol. Synthesis of imidazo[1,2-a]pyridine derivatives were
prepared through the reaction of 2-aminopyridine with
bromoacetone or 1,1,1-trifluoro-3-bromoacetone in an ethanol-
dioxane solution, followed by a Vilsmeier-Haack formilation,
then methyl magnesium iodide addition, and finally Dess-Martin
oxidation (Scheme 1a). The Diels-Alder reaction of 3,5-dichloro-
6-(chloromethyl)-2H-1,4-oxazin-2-one with 3-bromopropyne
showed to be a versatile method for the generation of substituted

3
2,6-dichloropyridines, which was treated with sodium to obtain
the corresponding dicarbaldehyde (Scheme 1b). Reduction of
benzyl succinimide with sodium borohydride followed by a
formylation with DMF and phosphorus oxychloride afforded the
corresponding pyrrole depicted in Scheme 1c. On the other hand,
N-benzylation and oxidation with meta-chloroperoxybenzoic acid
furnished the pyrrole derivative presented in Scheme 1d. At the
end, to prepare the thieno[2,3-b]pyridine scaffold, we employed
2-nitrothiophene or an acetyl derivative which were submitted to
a reduction reaction with the concomitant cyclization using
different acetals (Scheme 1e, 1f, and 1g).
Imidazo[1,2-a]pyridine N-tosylhydrazones bearing methyl and
trifluoro methyl groups could also be used in the reaction, the
corresponding sulfides were obtained in 84% and 77% yields,
respectively (Table 2, 3g and 3h). This result can be rationalized
by the electron-withdrawing group nature of the trifluoro methyl
involved.
We then turned our attention towards the incorporation of
heteroaromatic bis-tosylhydrazones. The reaction with heteroaryl
bis-tosylhydrazones gave the corresponding products with a
slightly diminished yield (Table 2, 3j-3m). The reaction might be
marginally influenced by the steric effect. Again the pyrrole ring
(Table 2, 3j-3k) was more reactive, than the pyridine ring (Table
2, 3l). Next, 6H-thieno[2,3-b]pyrrole bis-tosylhydrazone was
chosen as an example of bis-tosylhydrazone containing aldehyde
and ketone derivatives of sulfonyl hydrazones groups inside the
structure. As shown in Table 2, the reaction was found to be not
significantly affected by the nature of the hydrazones and the
desired product 3m was isolated in 63% yield (Table 2, 3m).
Finally, we also used an example of acetyl naphthalene
derivative, tosylhydrazide, because their wide use in medicinal
chemistry.20
The corresponding sulfonyl hydrazones were prepared using
p-toluenesulfonhydrazide with the heteroaryl aldehydes and
ketones synthetized in an acidic methanol solution.23 With theese
substrates in hand, the generality of N-tosylhydrazones was
examined. The results are summarized in Table 2.
Table 2: Synthesis of various heteroaryl sulfides.a,b
aReaction conditions: 1, (1.0 mmol); 2, (1.5 mmol, 1.5 equiv.), K2CO3 (2.5
NN
K
R
R
A twostep, one-pot conversion of heteroaryl aldehydes to
thioethers was demonstrated to provide the product in
comparable yields to that found in Table 2 (Table 3).
Table 3: One-Pot Conversion of heteroaryl aldehydes to
sulfidesa,b
aReaction conditions: Heteroaryl aldehyde, (1.0 mmol); TsNHNH2, (1.1
mmol, 1.1 equiv.), toluene 4 mL, thiol (1.5 mmol, 1.5 equiv.), K2CO3 (2.5
equiv.).
bIsolated yield.
c2.2 equiv. of TsNHNH2, 3 equiv. of thiol, and 5 equiv. of K2CO3 were used.
The synthetic utility of this cross-coupling reaction was then
explored. Gram-scale synthesis was conducted at a 5 mmol scale,
and as expected, the corresponding product 3a was obtained in
83% yield. Therefore, the scale-up of the procedure did result in a
reduction of the yield (Scheme 2).
equiv.), Toluene 4 mL.
bIsolated yield.
c3 equiv. of 2 and 5 equiv. of K2CO3 were used.
Satisfyingly pyrrolyl-, thieno[2,3-b]pyrrolyl-, thieno[2,3-
b]pyridyl-, imidazo[1,2-a]pyridyl-, and pyridyl-bearing N-
tosylhydrazones all reacted successfully to give the condensation
adducts 3a-3i in good to excellent yields (Table 2). N-
tosylhydrazone of thieno[2,3-b]pyridine aldehyde afforded better
yield than N-tosylhydrazones of thieno[2,3-b]pyridine ketones
(Table 2, 3c-3f). The low solubility of the thiol such as that
derived from pyridine could provide a significantly moderate
yield in the sulfide (Table 2, 3e). We could observed that the
reactivity changes in the thieno[2,3-b]pyridine system, being
more reactive in position two than in position five (80% and 76%
respectively, Table 2, 3d and 3f). One explanation for the low
yield in position five could be a disruption of the aromaticity,
being more difficult in pyridine ring than in thiophene ring.19a
Scheme 2. Gram-Scale Synthesis of 3a.
Conclusions
We have developed a method for the synthesis of
heteroaromatic sulfides from heteroaryl N-tosylhydrazones and
thiols in good to high yields under mild reaction conditions. The

4
Tetrahedron
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sensitive to steric effects. The mild condition in this protocol are
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thieno[2,3-b]pyrrolyl,
thieno[2,3-b]pyridyl,
imidazo[1,2-
a]pyridyl, and pyridyl ketones and aldehydes. We also report an
appropriate synthetic route to get heteroaryl aldehydes and
ketones. Conveniently, this reaction is also applicable to a gram-
scale reaction. This reaction can be carried out in a one-pot
fashion from aldehydes without the necessity of isolating the
hidrazone.
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Acknowledgments
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The authors would like to thank Dr. Javier Perez, Dra. Carmen
Garcia, Ing. Luis Velasco, Q. Rocio Patiño, Q. Angeles Peña,
MSc Elizabeth Huerta, Dra Beatriz Quiroz, MSc Hector Rios, Dr.
Ruben Gaviño, Dra Isabel Chavez, MSc Simon Hernandez, Q.
Ma Paz Orta and MSc Alejandra Nuñez for their technical
assistance. Mario Alfredo Garcia Carrillo is grateful for the
CONACYT doctoral fellowship.
12. Li H, Wang L, Zhang Y, Wang J, Angew Chem Int Ed. 2012; 51: 2943.
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(4.0 mL) was stirred at 100 °C for 24h under Argon. After completion
of the reaction as indicated by TLC, the mixture was cooled to room
temperature. After adding CH2Cl2 (10 mL), the organic phase was
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23. General Procedure for the Preparation of Aldehyde and Ketone Derived
Sulfonyl Hydrazones. A solution of the p-toluenesulfonhydrazide (5.5
mmol) and the appropriate heterocarbonyl compound (5 mmol) in
MeOH (12 mL) and 10% HCl (0.05 mL) was heated at reflux for 24 h.
The reaction mixture was cooled to room temperature; the final
product was filtered and purified by crystallization

5
Supplementary Material
Supplementary data associated with this article can be found,
in the online version. Supplementary material that may be helpful
in the review process should be prepared and provided as a
separate electronic file. That file can then be transformed into
PDF format and submitted along with the manuscript and graphic
files to the appropriate editorial office. Supplementary data
associated with this article can be found, in the online version

6
Tetrahedron
Metal Free Coupling of Heteroaryl N-
Tosylhydrazones and Thiols: Efficient Synthesis
of Sulfides
Mario Alfredo Garcia-Carrillo,* Angel Guzman,
Eduardo Diaz*
Instituto de Química, Universidad Nacional
Autónoma de México, Ciudad Universitaria, 04510
México, Ciudad de México, México.
E-mail: marioagc@comunidad.unam.mx,
maudiaz@unam.mx
In memory of Prof. Dr. José Barluenga
Highlights
•
•
•
•
A
tosylhydrazones with thiols is presented.
novel
coupling
of
aromatic
N-
Valuable thioethers with heteroaryl frameworks
have been synthesized.
This coupling reaction can be carried out in a
one-pot fashion.
The reaction can be made in a scaled up to the
gram scale.