A facile access to: N -sulfonylthioimidates and their use for the transformation to 3,4-dihydroquinazolines

Article abstract of DOI:10.1039/d0ob01963a

N-Sulfonylthioimidates can be efficiently synthesized through one-pot three-component coupling of terminal alkynes, sulfonyl azides, and thiols by using a copper(i) catalyst in the presence of 4-dimethylaminopyridine. The proposed reaction is characterized by mild reaction conditions and tolerance of diverse functional groups. Additionally, the crucial pharmacophore of 3,4-dihydroquinazolines was synthesized using a one-pot synthetic strategy from N-sulfonylthioimidates. This journal is

Full text of DOI:10.1039/d0ob01963a

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DOI: 10.1039/D0OB01963A
ARTICLE
A Facile Access to N-Sulfonylthioimidates and Their Use for the
Transformation to 3,4-Dihydroquinazolines
Jia-Yu Wu, a Wei-Jr Liao, a Xiu-Yi Lin, a and Chien-Fu Liang*c
Received 00th January 20xx,
Accepted 00th January 20xx
N-sulfonylthioimidates can be efficiently synthesized through one-pot three-component coupling of terminal alkynes, sulfonyl
azides, and thiols by using a copper(I) catalyst in the presence of 4-dimethylaminopyridine. The proposed reaction is
characterized by mild reaction conditions and tolerance of diverse functional groups. Additionally, the crucial pharmacophore
of 3,4-dihydroquinazolines was synthesized using a one-pot synthetic strategy from N-sulfonylthioimidates.
DOI: 10.1039/x0xx00000x
Recently, the modified copper-catalyzed alkyne-azide
cycloaddition (CuAAc) of a highly reactive ketenimine
intermediate for the preparation of various molecules,14 such as
Introduction
Thioimidate derivatives are crucial building blocks in organic
synthesis1 and intermediates in medical compounds.2 Moreover,
a thioimidate moiety is present in heterocycles, including
benzothiazoles and thiazoles.3 In addition, an aryl thioimidate
scaffold regioselectively reacts with alkynes to form aryl thio
azadienes.4 Therefore, the development of novel methods for
thioimidate synthesis remains desirable. Conventional methods
for thioimidate synthesis involve thioamide alkylation to yield
alkyl thioimidates.5 However, a major limitation of the
aforementioned method is the preparation of thioamide, which is
synthesized directly by treating amide groups with P4S10, B2S3,
or Lawesson’s reagent. These methods require the use of highly
toxic reagents or are applied under harsh conditions. To
overcome these problems, more recently, numerous synthetic
strategies for the organic synthesis of thioimidates have been
developed. Examples include copper- or palladium-catalyzed
iminothiolation of isocyanides,1g,6 organoaluminium-promoted
Beckmann rearrangement of oxime sulfonates,7 combination of
nitriles with thiols,8 palladium-catalyzed coupling between aryl
halide, thioalkoxide, and isocyanide,9 radical alkylation of α-
amides,15 amidines,16 imidates,17 coumarins,18 quinolines,19
thiophenes,20 dihydropyrimidin-4-ones,21 oxindoles,21 4-
substituted pyridines,22 and cyclohexadienones,23 has received
research attention. The reaction mechanism proceeds through the
formation of sulfonyl copper triazole, which can be formed
through the CuAAc pathway.14 Subsequently, the Dimroth
rearrangement leads to the formation of a diazoimino copper
intermediate, which is converted to the ketenimine intermediate
through the Wolff rearrangement. A nucleophilic group can be
employed to attack the electrophilic ketenimine intermediate to
obtain corresponding products (Scheme 1a). However, Wang’s
group found that the reaction of aryl thiol molecules through a
CuAAc strategy yields a disulfide byproduct (Scheme 1b);
although they reported that the reaction could be performed to
produce aryl thioimidates by using potassium aryl thiolate
derivatives.24 They proposed that sulfonyl azide might be
reduced to sulfonyl amide and nitrogen gas by thiols in the
presence of triethylamine (TEA), and thiols were oxidized to
disulfide derivatives.24-25 Thus, we developed a novel synthetic
strategy for thioimidate synthesis with the use of mild and
feasible reaction conditions. In this paper, the synthesis of N-
nitro
thiophenol
compounds,10
combination
of
hexamethyldisilazane-promoted thiols with nitroalkanes,11
palladium-catalyzed insertion of isocyanides into the C–S bonds
of heteroaryl sulfides,12 and reaction of secondary thioamides
with diaryliodonium salts under metal-free conditions.13
Although thioimidates can be efficiently synthesized using
numerous methods, each of these synthetic protocols has distinct
disadvantages. The development of an ideal reaction condition
that can be applied feasibly and is scalable for industrial
applications is required.
R3
N
Previous Work
H
N
(a)
R4
R4
R3
R1
R1
O
R2
O
NSO2R2
cat. Cu(I)
R2 SO2N3
S
[Cu]
R1
R1
C
N
R3 OH
O
R3
NSO2R2
(b)
R1
OHC
HS
CHO
cat. CuI
+
PhSO2N3
NEt3, rt or reflux
S
2
This work
NTs
S
1. cat. Cu(I), base, rt
R1
(c)
+
R1
R2
TsN3
a. Department of Chemistry, National Chung Hsing University, Taichung, 402,
Taiwan. E-mail: lcf0201@dragon.nchu.edu.tw; Tel: +886-4-22840411.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
R2 SH, rt
2.
Scheme 1. Copper-catalyzed multicomponent reaction of alkyne, sulfonyl azide,
and diverse nucleophiles.
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ARTICLE
Journal Name
sulfonylthioimidates through a new multicomponent reaction, formation.27 Inspired by the use of aryl thiolates aVsieaw AsrutibclsetOitnulintee
tosyl triazole–mediated denitrogenative thiolation, is proposed. for thiols in thiochromene synthesis,24 we considered the base
DOI: 10.1039/D0OB01963A
Recently, our group developed a method for thiol group used in this reaction to be a potentially crucial factor. To
formation that involves the lanthanide(III)-catalyzed S- determine the optimal base, reaction conditions were set
deacetylation of thioacetates.26 We now report the successful according to the use of aromatic bases, including imidazole
preparation of N-sulfonylthioimidates through a one-pot two- (entry 9), pyridine (entry 10), 2,6-lutidine (entry 11), and 4-
step reaction, in which freshly prepared thiols are directly reacted dimethylaminopyridine (DMAP, entry 12). We found that the
with ketenimine intermediates, which are formed using alkyne reaction could proceed favorably in the presence of the CuI
and tosyl azide under copper (I) catalyst conditions (Scheme 1c). catalyst with 1 equivalent of DMAP and 3 equivalents of the
thiol molecule 2a at room temperature to obtain a satisfactory
yield of the desired N-sulfonylthioimidate 3a (80%). Therefore,
DMAP was selected as the base for optimal reactivity.
Results and discussion
To extend the scope of thioimidate formation, the
aforementioned optimization conditions of the one-pot three-
component reaction were used to synthesize several
functionalized thioimidates by treating organic alkynes with
The model of the one-pot three-component reaction of
thioimidate synthesis was optimized using phenylacetylene 1a,
tosyl azide (TsN3), and thiol molecule 2a by employing a
copper(I) catalyst under different base and solvent conditions
tosyl azide, thiol molecules, and DMAP in the copper(I) iodide
(Table 1). Initially, to prevent the reduction of tosyl azide to tosyl
amide (TsNH2) by thiol molecule,24 alkyne 1a with tosyl azide
was reacted in a copper(I) iodide catalytic system for 1 h to
produce ketenimine intermediates, and the freshly prepared thiol
molecule 2a was subsequently added to the reaction mixture. The
reactivity of the one-pot two-step reaction was assessed using the
reported reaction conditions,14 including bases, (triethylamine
and potassium carbonate), solvents (tetrahydrofuran,
acetonitrile, dimethylformamide, and dichloromethane), and
copper(I) sources (CuI and CuCl) (Table 1, entries 1–8). The
results revealed that the reaction proceeds unfavorably, and the
major product is disulfide. Chang et al. reported a range of base
additives suitable for accelerating ketenimine intermediate
catalytic system. Various structurally and electronically tuned
organic thiol molecules were investigated under these optimized
conditions (Table 2). Benzylic thiol molecules with electron-
Table 2. Thioimidate formation by using various organic thiol molecules.a
NTs
1. TsN3, CuI, DMAP, DCM, rt, 1 h
Ph
Ph
S
R1
1a
2.
, t (h), yield (%)b
3
R1
SH
Ph
2
NTs
NTs
NTs
Ph
Ph
S
S
S
3c
3a
9 h, 80%
3b
OMe
5 h, 74%(77%)c
5 h, 66%
OMe
NTs
OMe
NTs
NTs
S
Ph
Ph
Ph
S
S
3d
7 h, 78%
3e
3f
Table 1. Optimization of the reaction conditions
10 h, 81%
8 h, 77%
NTs
1. Cu(I), base, solvent, 1 h
NTs
NTs
NTs
Ph
1a
Ph
Ph
Ph
Ph
Ph
Ph
S
2.
2a
SH
+
S
S
3i
3 h, 75%
S
MeO
r.t., t (h), yield (%)
3a
3g
TsN3
3h
5 h, 75%
OMe
yield (%)e
Cl
Br
F
3 h, 88%
NTs
entry
NTs Ph
solvent
THF
base
Et3N
t (h)
4
NTs
Ph
Ph
1a
2a
4
S
Ph
S
S
3j
3l
7 h, 76%
3k
4
2
NO2
ACN
Et3N
Et3N
5
10 h, 66%
7 h, 66%
3a
NTs
NTs
N.D.
DMF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Ph
S
S
4a
5a
6b
6
10
Et3N
K2CO3
Et3N
3
4
8
6
8
3n
8 h, 51%
3m
7 h, 76%
N.D.
NTs
O
6
Ph
S
OCH3
Boc
7c
8d
Et3N
Et3N
3o
3 h, 75%
3b
X-ray of
CCDC No: 2004076
8
HN
N.R.
4
9c
Imidazole
Pyridine
8
9
9
9
a
Conditions: Phenylacetylene 1a (1.0 equiv), TsN3 (1.2 equiv), CuI (0.2 equiv),
DMAP (1.0 equiv) and thiol (3.0 equiv) in DCM under nitrogen atmosphere.
Isolated yield. c Gram scale (1a, 9.79 mmol)
10c
18
b
11c
12c
DCM
DCM
2,6-Lutidine
DMAPf
15
80 (39)g
donating groups, such as p-OMe (2a), m-OMe (2c), o-OMe(2d),
p-Me (2e), and naphthalene (2f) derivatives, formed the desired
thioimidate products (3a–3f) with satisfactory yields (66%–
81%). Moreover, a reaction with an electron-withdrawing group
of benzylic thiol molecules, such as p-F (2g), p-Cl (2h), p-Br
(2i), and p-NO2 (2j), produced satisfactory yields (66%–88%).
a Conditions: phenylacetylene (1.0 equiv), TsN3 (1.2 equiv), CuI (0.1 equiv), base
(1.0 equiv), and thiol (1.5 equiv) under nitrogen atmosphere. b Thiol (3.0 equiv). c
d
e
CuI (0.2 equiv), and thiol (3.0 equiv). CuCl (0.2 equiv), and thiol (3.0 equiv).
Isolated yield. f When DMAP was used 0.3 equiv, the reaction yield was only 25%
g When thiol 2a was used 1.5 equiv. N.D. = not detected. N.R. = no reaction.
2 | J. Name., 2012, 00, 1-3
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Additionally, reactions involving branched chain thiol molecules glycosyl acceptors.29 Thus, we conducted the reacVtiieownArbtiycleuOsnilninge
DOI: 10.1039/D0OB01963A
(2k and 2l), medium-length alkyl chain thiol molecules (2m and phenylacetylene 1a, tosyl azide, and β-1-mercapto glycosides
2n), and the biological molecules of cysteine derivatives 2o (2p–2r). Scheme 2 displays the results. With the use of 3
achieved favorable results, and the obtained yield of equivalents of thiol molecules, the yield of the desirable products
corresponding products (3k–3o) was 51%–76%. Moreover, we of the reaction decreased and disulfide byproducts were obtained
applied these reaction conditions to gram-scale procedures and in major yields. To suppress byproduct formation, we used 1.5
achieved a satisfactory yield of desired thioimidate 3b. The equivalents of 2p–2r, which led to the formation of the desired
structure and (E)-geometry of thioimidate 3b was confirmed glycosyl 1-thioimidate 3p–3r with satisfactory yields (60%-–
using X-ray crystal analysis (Table 2).28 Based on the successful 66%). Notably, the configuration of newly formed glycosyl
results presented in Table 2, we used aromatic thiol molecules thioimidates was determined using nuclear magnetic resonance
with electron-donating (2e) and electron-withdrawing (2g) spectroscopy, and no α-anomer was obtained under these
groups and treated these molecules with diverse organic alkynes reaction conditions.
for thioimidate synthesis (Table 3). A wide range of alkynes was
easily converted into the corresponding thioimidate adducts (4b–
4o), and for most of them (4b–4f and 4h–4l), satisfactory
1. CuI (20 mol%)
DMAP(1 equiv),
DCM, rt, 1 h
O
Ph
TsN3
+
S
AcO
(1.2 equiv)
reaction yields (61%–76%) were obtained. Therefore, this aryl
system exhibited high functional group tolerance, and aromatic
alkynes with electron-donating (1b–1d) and electron-
withdrawing (1e–1f) groups were successfully employed in this
synthetic strategy. In contrast to the aryl alkynes, the aliphatic 1-
hexyne (1g) was treated with thiol molecules 2e and 2g, which
resulted in the formation of the desired products 4g and 4m with
yields of 37% and 31%, respectively. However, treatment of the
stereo-hindered aliphatic alkyne (1h) with 2e and 2g led to the
formation of 4n with a low reaction yield (21%) and traces of 4o.
Ph
1a
(1 equiv)
O
3p 3r
-
2.
NTs
AcO
SH
(1.5 equiv)
t (min)
AcO
AcO
OAc
OAc
O
AcO
AcO
AcO
AcO
AcO
AcO
O
O
S
S
S
Ph
Ph
Ph
OAc
3q
(t = 40 min, 66%)
OAc
3r
NTs
NTs
NTs
3p
(t = 90 min, 63%)
(t = 30 min, 60%)
Scheme 2. Thioimidates formation by using β-1-mercapto glycosides.
Subsequently, the practical potential of thioimidates for the
synthesis of heterocycles was investigated.
dihydroquinazoline core is biologically
A
3,4-
crucial
Table 3. Thioimidates formation by using various organic alkyne molecules.a
a
NTs
pharmacophore, and various derivatives with the key moiety
exhibit anticancer,30 antidepressant,31 and trypanothione
reductase inhibition32 activities. Therefore, several synthetic
methods for pharmacophore synthesis have been developed.33
Because we considered that the key molecular skeleton of C2-
substituted 3,4-dihydroquinazolines could be synthesized
through the intramolecular cyclization of precursors obtained
using the sequential N-functionalization of 2-aminobenzylamine
with thioimidates, we developed a one-pot two-step route for the
synthesis of crucial pharmacophores (Table 4). The
intramolecular cyclization of 2-aminobenzyl amidines (5a–5f),
which were obtained using 2-aminobenzyl amine and
thioimidates, was readily achieved by employing p-
toluenesulfonic acid. Under the proposed conditions, C2-
substituted 3,4-dihydroquinazolines were obtained in
satisfactory to excellent yields (52%–94%). We purified
compound 5a after the first step, and the results revealed that
regioselective amidine formation was observed for benzylic
amine over phenyl amine, leading to a 95% yield of 2-
aminobenzyl amidines 5a. Because thioimidates were employed
in 3,4-dihydroquinazoline synthesis, we conducted C2-
substituted quinazoline synthesis by using one-pot three-step
reaction. After the sequential two-step reaction, an acid agent
was removed, and then oxidation was induced through the
addition of iodobenzenediacetate (PIDA) in tetrahydrofuran. The
one-pot operation was successfully applied for three procedures
to obtain a satisfactory yield of the desired C2-substituted
quinazoline 7.
1. TsN3, CuI, DMAP, DCM, rt, 1 h
2e: R1 = p-MeC6H4
R1 2g: R1 = p-FC6H4
R2
R2
S
(2e 2g), t (h), yield (%)b
or
2.
1
4
MeO
NTs
NTs
NTs
S
S
4d
17 h, 66%
S
4c
4b
17 h, 63%
8 h, 61%
O
O2N
NTs
S
NTs
NTs
S
4f
S
4g
10 h, 37%
4e
7 h, 73%
9 h, 65%
MeO
NTs
S
NTs
NTs
S
4j
16 h, 70%
S
4i
8 h, 65%
4h
F
F
F
7 h, 64%
O
O2N
NTs
S
NTs
S
NTs
S
4k
4l
4m
8 h, 31%
F
F
F
8 h, 76%
8 h, 73%
NTs
NTs
S
S
4n
4o
8 h, trace
F
9 h, 21%
a
Conditions: Alkyne (1.0 equiv), TsN3 (1.2 equiv), CuI (0.2 equiv), DMAP (1.0
equiv) and thiol (3.0 equiv) in DCM under nitrogen atmosphere. b Isolated yield.
Furthermore, to determine the applicability of the one-pot
three-component reaction, we explored the possibility of
conducting this reaction with carbohydrates. In particular,
glycosyl thioimidates were selected as the anomeric leaving
group of glycosyl donors and temporary masking group of
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Journal Name
Conflicts of interest
View Article Online
DOI: 10.1039/D0OB01963A
Table 4. Synthesis of C2-substituted 3,4-dihydroquinazolines.
NTs
There are no conflicts of interest to declare.
PTSA
NH
R1
NH2
NH2
Thioimidates
THF, rt, 2~3 h
N
H
NH2
R1
rt, 2~3 h
N
5a-5f
6a-6f
Acknowledgements
OMe
NH
NH
NH
This work is supported by grants from the Ministry of Science
and Technology, Taiwan (Grant MOST 108-2113-M-005-019-
and 109-2113-M-005-004-). We also acknowledge the support
from the National Chung Hsing University.
N
N
N
a,b
a,b
a,b
6a
6b
6c
, 94%
, 90%
, 88%
NH
O
NH
NH
N
N
N
a,b
a,b
a,b
6e
, 94%
6d
6f
, 52%
, 93%
Notes and references
1
For a review, see: T. S. Jagodzinski, Chem. Rev., 2003, 103,
197. For some recent paper, see: (a) J. Schleiss, P. Rollin, A.
Tatibouet, Angew. Chem. Int. Ed., 2010, 49, 577; (b) N. R. Perl,
N. D. Ide, S. Prajapati, H. H. Perfect, S. G. Duron, D. Y. Gin,
J. Am. Chem. Soc., 2010, 132, 1802; (c) Y. Karibe, H. Kusama,
N. Iwasawa, Angew. Chem. Int. Ed., 2012, 51, 6214; (d) A. F.
G. Goldberg, N. R. O’Connor, R. A. Craig II, B. M. Stoltz,
Org. Lett., 2012, 14, 5314; (e) Z. Guan, M. Nieger, A. Schmidt,
Eur. J. Org. Chem., 2015, 4710; (f) K. Shvydenko, K.
Nazarenko, T. Shvydenko, Y. Vlasenko, A. Tolmachev, A.
Kostyuk, Tetrahedron, 2015, 71, 7567; (g) A. H. Vahabi, A.
Alizadeh, H. R. Khavasi, A. Bazgir, Eur. J. Org. Chem., 2017,
5347; (h) M. Feng, P. Yang, G. Yang, W. Chen, Z. Chai, J.
Org. Chem., 2018, 83, 174; (i) P. D. Parker, B. C. Lemercier,
J. G. Pierce, J. Org. Chem., 2018, 83, 12.
(a) F. Thuanu, S. Kojima, G. Hirai, K. Oonuma, A. Tsuchiya,
T. Uchida, T. Tsuchimoto, M. Sodeoka, Bioorg. Med. Chem.,
2014, 22, 2771; (b) M. Feng, B. Tang, S. H. Liang, X. Jiang,
Curr. Top. Med. Chem., 2016, 16, 1200.
For a review, see: (a) W.-S. Guo, L.-R. Wen, M. Li, Org.
Biomol. Chem., 2015, 13, 1942; (b) H. Liu, X. Jiang, Chem.
Asian J., 2013, 8, 2546.
Y. Minami, H. Kuniyasu, A. Sanagawa, N. Kambe, Org. Lett.,
2010, 12, 3744.
R. Roger, D. G. Neilson, Chem. Rev., 1961, 61, 179.
T. Livinghouse, R. Smith, J. Chem. Soc. Chem. Commun.,
1983, 210.
K. Maruoka, T. Miyazaki, M. Ando, Y. Matsumura, S. Sakane,
K. Hattori, H. Yamamoto, J. Am. Chem. Soc., 1983, 105, 283.
A. N. Kolontsova, M. N. Ivantsova, M. I. Tokareva, M. A.
Mironov, Mol. Diversity, 2010, 14, 543.
C. G. Saluste, R. Whitby, M. Furber, Tetrahedron Lett., 2001,
42, 6191.
N
Ph
N
a,b,c
7
(3 steps 56%)
a
Condition: Thioimidates (1.0 equiv) and 2-aminobenzylamine (1.2 equiv) in THF
were stirred under nitrogen atmosphere for 2~3 h, then added p-toluenesulfonic
acid monohydrate (2.0 equiv) to the reaction mixture. Isolated yield. After
getting crude 6a, an acid was removed through extraction, then the crude 6a in
THF was added iodobenzenediacetate (3 equiv) at rt for 3 h.
b
c
On the basis of literature reports,14,15,19,34 a proposed reaction
mechanism is shown in Scheme 3. The reaction can be
rationalized as being initiated by the copper(I)-catalyzed [3+2]
cycloaddition of sulfonyl azide and alkynes 1, followed by the
release of N2 to form the intermediate ketenimine B (via A).
Then, the nucleophilic thiols 2 attacked the electron deficient
central carbon of ketenimine B lead to the construction of N-
sulfonylthioimidates 3 or 4.
2
3
4
Cu
R
Ts
1
R
H
R
Cu(I)
-Cu(I), -N2
N H
C
N
5
6
N
N
+
DMAP
Ts
N
B
N
Ts
N N N
A
R' SH
2
7
8
9
Ts
N
NTs
S
R
R'
R
R'
S
H
C
3
4
or
Scheme 3. Possible mechanism route to N-sulfonylthioimidates.
10 J. Y. Lee, Y.-T. Hong, S. Kim, Angew. Chem. Int. Ed., 2006,
45, 6182.
11 K. Kucinski, G. Hreczycho, Eur. J. Org. Chem., 2016, 4577.
12 S. Otsuka, K. Nogi, H. Yorimitsu, Angew. Chem. Int. Ed.,
2018, 57, 6653.
Conclusions
In summary, N-sulfonylthioimidates can efficiently be prepared
through the one-pot three-component reaction of terminal
alkynes, TsN3, and freshly prepared thiols under the action of a
copper(I) catalyst in the presence of DMAP as the base. The
developed method provides advantages such as efficiency, a
wide substrate scope, considerably mild reaction conditions, and
high tolerance toward diverse functional groups. Moreover, the
method can be manipulated to obtain a satisfactory yield of the
13 P. Villo, G. Kervefors, B. Olofsson, Chem. Commun., 2018,
54, 8810.
14 For some reviews, see: (a) E. J. Yoo, S. Chang, Curr. Org.
Chem., 2009, 13, 1766; (b) S. H. Kim, S. H. Park, J. H. Choi,
S. Chang, Chem. Asian J., 2011, 6, 2618; (c) P. Lu, Y. Wang,
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crucial
pharmacophores
of
C2-substituted
3,4-
dihydroquinazolines by using a range of substrates under
ambient reaction conditions.
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21 For dihydropyrimidin-4-ones: (a) J. Wang, J. Wang, P. Lu, Y.
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28 The X-ray crystallographic data collection of 3b can be
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N-sulfonylthioimidates can be synthesized via terminal alkynes,
sulfonyl azide, and thiols using a copper(I) catalyst in the
presence of 4-dimethylaminopyridine. Subsequently, it can be
View Article Online
DOI: 10.1039/D0OB01963A
transformed
to
crucial
pharmacophores
of
3,4-
dihydroquinazoline.
6 | J. Name., 2012, 00, 1-3
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