Three component reaction of aryl diazonium salt with sulfonamide & actonitrile to synthesize N-sulfonyl amidine

Article abstract of DOI:10.1016/j.tetlet.2018.10.027

A new method was developed to prepare N-sulfonyl amidine compounds through three-component reaction of aryl diazonium salts with sulfonamides and acetonitrile, in which, nitrilium ion intermediate, generated from the reaction of aryldiazonium salt with nitrile, was subsequently trapped by sulfonamides. A series of N-sulfonyl amidine derivatives were synthesized by using various types of aryl diazonium salts, sulfonamides and nitriles. In addition, indolyl imine products could also be prepared by using indole as the nucleophile to trap nitrilium ion intermediate.

Full text of DOI:10.1016/j.tetlet.2018.10.027

Accepted Manuscript
Three Component Reaction of Aryl Diazonium Salt with Sulfonamide & Ac-
tonitrile to Synthesize N-sulfonyl Amidine
Yuan Zhang, Zili Chen
PII:
S0040-4039(18)31234-6
https://doi.org/10.1016/j.tetlet.2018.10.027
TETL 50337
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 August 2018
9 October 2018
15 October 2018
Please cite this article as: Zhang, Y., Chen, Z., Three Component Reaction of Aryl Diazonium Salt with Sulfonamide
& Actonitrile to Synthesize N-sulfonyl Amidine, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.10.027
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Three Component Reaction of Aryl
Diazonium Salt with Sulfonamide &
Actonitrile to Synthesize N-sulfonyl Amidine
Yuan Zhang, Zili Chen*
Department of Chemistry, Renmin University of China, Beijing 100872, China
A new method was developed to prepare N-sulfonyl amidine compounds through three-component reaction of aryl
diazonium salts with sulfonamides and acetonitrile
Three Component Reaction of Aryl Diazonium Salt with
Sulfonamide & Actonitrile to Synthesize N-sulfonyl Amidine
Yuan Zhang, Zili Chen*
Department of Chemistry, Renmin University of China, Beijing 100872, China
Abstract—© 2018 Elsevier Science. A new method was developed to prepare N-sulfonyl amidine compounds through three-component
reaction of aryl diazonium salts with sulfonamides and acetonitrile, in which, nitrilium ion intermediate, generated from the reaction of
aryldiazonium salt with nitrile, was subsequently trapped by sulfonamides. A series of N-sulfonyl amidine derivatives were synthesized by
using various types of aryl diazonium salts, sulfonamides and nitriles. In addition, indolyl imine products could also be prepared by using
indole as the nucleophile to trap nitrilium ion intermediate.
Keywords: Amidine, Nitrilium ion, Indolyl imine compound, Three component reaction
Introduction: Amidines are important functional groups in organic chemistry. These structural subunits could be found in
numerous natural products1 and biologically active molecules2, and have been widely utilized as building blocks for the
preparation of heterocyclic compounds,3 or as ligands for the transition metal complexation.4
In this field, numerous efforts have been made by organic chemists for the synthesis of amidine derivatives. As shown in
scheme 1A, there are two major approaches for the construction of amidine molecules. The first major synthetic route
resorted to the nucleophilic addition of amines onto the activated nitrile,5 amides,6 ketenimines,7
———

Corresponding author. Tel/Fax: 0086-10-62516660; E-mail: zilichen@ruc.edu.cn

Scheme 1. Different approaches for the preparation of Amidines.
etc. The second route involved the dipolar cycloaddtion of azide compounds with alkynes (via metal keteiminium
intermediate),8 vinyl amines,9 vinyl amine intermediates10 and thioamides,11 followed by the intermediate trapping and
subsequent derivation process. Despite these achievements,12 there is still no general method for the synthesis of amidine
derivatives in the mild condition, which could accommodate a broad range of structure and substitution diversity. Developing
new approach of amidine synthetic method, especially from the simple starting materials, can enhance the flexibility to
construct these important structural entities, and therefore broaden their application in medicinal chemistry and biological
chemistry.
On the other hand, nitrilium ion,13 as shown in scheme 1B, could be in situ generated from the reaction of aryldiazonium
salt with nitrile. As a very reactive electrophilic intermediate, nitrilium ion could be trapped by various type of nucleophiles, and
has been widely utilized as the synthons to prepare a large spectrum of heterocycles, such as: quinoline,14 quinazoline,15
phenanthridine16 and N-arylbenzimidazole,17 etc (Scheme 1B). In the course of this research, Liu and his colleagues reported the
synthesis of ketimine compounds by using electro-rich arenes as nitrilium ion trapping nucleophiles.18 In this paper, we want
to report a simple method to construct N-sulfonyl amidines from the reaction of aryl diazonium salts with acetonitrile and
sulfoamides, in which, a process of trapping the aryl nitrilium ion with sulfonamide was involved. In addition, indolyl imine
derivatives were also synthesized by using indole as the nitrilium ion trapper.
Our initial research started from the reaction of 0.1 mmol of phenyl diazonium salt 1a with toluene sulfonamide 2a
Table 1. Optimization upon three component reaction of aryl diazonium salt 1a with tosyl amine 2a in dry acetonitrile a,b
2a(eq.)/
3a(eq.)
a Unless otherwise noted, all the reactions were carried out with 1a (0.1 mmol),
2a (0.1-0.3 mmol), 3a (20-50 equiv.) in solvent (2 mL) under argon atmosphere.
b Yield of the isolated product. c 100 mg molecular sieves was added.
entry
T(oC)
Solvent
Yield(4aa/5a)
1
1/ND
1/20
1/20
1/20
1/20
1/20
1/30
1/50
2/50
3/50
1/50
1/50
60
CH3CN
DCM
DCE
0/52
22/41
27/35
0
2
reflux
60
3
4
60
DMF
1,4-dioxane
DCE
5
60
0
6 c
60
25/32
43/28
76/17
73/16
76/16
48/24
78/12
Figure 1. ORTEP picture of compound 4aa with the displacement ellipsoid
drawn at 50% probability with hydrogen atoms omitted for clarity
7
60
DCE
8
60
DCE
(1 equivalent) in dry acetonitrile at 60 °C (Table 1, entry 1). To
our disappointment, only N-Acetylaniline 5a was obtained in
52% yield. No amidine product could be detected in the reaction
mixture. When dry dichloromethane (DCM) was utilized as the
solvent with the addition of acetonitrile (20 equivalent), the
desired amidine product 4aa could be separated in 22% yield
(Table 1, entry 2).19
9
60
DCE
10
11
12
60
DCE
40
DCE
80
DCE

1
Compound 4aa’s was fully characterized by H and 13C NMR spectroscopy and HRMS analysis. Its structure was
determined by single-crystal X-ray diffraction after crystallization by slow diffusion of Et2O into a concentrated solution of
(R)-7a in CH2Cl2 (Figure 1).
Further solvent screening was performed, in which, 1,2-dichloroethane was found to be the best reaction media (Table 1,
entry 3). No reactions were found in DMF and 1,4-dioxane (Table 1, entry 4-5). Attempt to remove water from the reaction
mixture by using molecular sieves was not helpful (Table 1, entry 6).
Table 2. Three component reactions of various diazonium salts with tosyl amine 2a in dry acetonitrile
a Unless otherwise noted, all the reactions were carried out with 1 (0.1 mmol), 2a (0.1 mmol), 3a (50 mol equiv.) in DCE (2 mL) under argon atmosphere.
b Yield of the isolated product. c side product 6-methyl phenanthridine was obtained in 30% yield.
Improving acetonitrile 3a to 30 or 50 mol equivalent could enhance 4aa’s yield (Table 1, entry 7-8), while improving tosyl
amine’s equivalence didn’t affect the reaction yield (Table 1, entry 9-10). Further optimization upon the reaction temperature
proved that 80 °C was the optimal reaction temperature (Table 1, entry 12).
With the optimized reaction condition in hand, various substrate scopes were then explored. As shown in table 2, a series
of aryl diazonium salts were evaluated by using toluene sulfonamide 2a and acetonitrile 3a as the trapping partner. Different
phenyl substitution patterns were investigated, in which, substrates bearing with electro-rich substituents (Table 2, 4aa-ba)
performed better than their electro-poor analogues (Table 2, 4ca-da). The reaction of p-methylphenyl diazonium salt 1b
provided the highest reaction yield (Table 2, 4ba), while p-fluoro substituted amidine product 4ca was obtained in a
relatively low yield (Table 2). m-Iodophenyl diazonium salt 1f gave 4fa in 65%
Table 3. Three component reactions of phenyl diazonium salt 1a with various sulfonamides in dry acetonitrile
a
b
Unless otherwise noted, all the reactions were carried out with 1a (1 mmol), 2 (0.1 mmol), 3a (50 equiv.) in DCE (2 mL) under argon atmosphere.
Yield of the isolated product. c The reaction temperature was 60 °C.
yield, which is lower than that of p-iodophenyl diazonium salt 1e. The bulky 2-naphthalenyl diazonium salt 1g was also
tested, providing the desired bulky amidine product 4ga in a moderate yield (Table 2). The reaction of biphenyl-2-diazonium
salt 1h afforded amidine 4ha in 23% yield (Table 2, 4ha), together with the formation of 6-methylphenanthridine side
product.16
Then, various sulfonamide substrates were explored by using phenyl diazonium salt 1a and acetonitrile 3a as the reaction
partners. As shown in table 2, three benzene sulfonamide substrates 2b-d, bearing no substituent or different substitution
groups, behave similarly in this three component reaction, giving the desired sulfonyl amidine product in moderate yields

(Table 3, 4ab-ad). The reaction of heterocyclic thiophene-2-sulfonamide 2e provided the coupling adduct 4ae in a relatively
low yield, while ethyl sulfonamide 2f afforded 4af in a moderate yield (Table 3, 4ae-4af). N-alkyl or phenyl substituted
sulphonamides were also tested. N-methyl sulfonyl amidine 4ag could be obtained in 71% yield (Table 3, 4ag), while N-
phenyl sulfonylamidine 4ah’s yield was very low, possibly because of inefficient trapping reaction of the nitrilium ion
intermediate with bulky N-phenyl toluenesulphonamide substrate (Table 3, 4ah). 20
Scheme 2. The reaction of phenyl diazonium salt 1a, toluene sulfonamide 2a by using allylnitrile 3b and benzonitrile 3c.
Next, other nitrile substrates were examined. As shown in Scheme 2, phenyl diazonium salt 1a and toluene sulfonamide 2a
were treated with allylnitrile 3b in DCE at 60 °C, allyl substituted amidine product 6b could be synthesized in 38% yield,
together with the formation of N-phenylbut-3-enamide 5b in 11% yield (Scheme 2). However, in the reaction of benzonitrile
3c, only trace amount of amidine product could be detected (Scheme 2), while N-phenylbenzamide 5c was obtained in 36 %
yield.
A plausible simple reaction mechanism, as shown in Scheme 1B, has been proposed. According to this mechanism, a
nitrilium ion intermediate was in-situ generated from the reaction of aryl diazonium salt with nitrile, which could be trapped
by different types of nucleophiles (Scheme 1B).14-18 The corresponding amidine product could be obtained by using
sulfonamide as the nitrilium ion trapper in this work. We considered that the indole compounds would be another suitable
nucleophile to trap the nitrilium ion intermediate.
Scheme 3. Three component reactions of phenyl diazonium salt 1a with indole in dry acetonitrile
As shown in scheme 3, the reaction of indole 7a with 1a and 3a in DCE could provide N-phenyl indolyl imine 8a in 64%
yield. Similarly, N-methyl indole 7b afforded indolyl imine 8b in 56% yield.
Scheme 4. Scale-up experiments
Scale up reactions were performed to prepare N-sulfonyl amidine 4aa. As shown in Scheme 4, a 1 mmol scale and a 10
mmol scale reaction were performed, the desired amidine product 4aa was obtained in 74% yield and 69% yield.
In summary, a new method was developed to synthesize N-sulfonyl amidine product through the reaction of aryl
diazonium salts with sulfonamides and acetonitrile, in which, a process of trapping nitrilium ion intermediate with
sulfonamides was involved. Various types of aryl diazonium salts, sulfonamides were investigated to provide a series of N-
sulfonyl amidine product. Other nitrile substrates, such as: allylnitrile, was also examined to give the desired amidine
product. Two indolyl imine products were synthesized by using indole as the nucleophile to trap nitrilium ion intermediate.
Acknowledgments
Financial support of this work by the grant from National Sciences Foundation of China (Nos. 21472237) is gratefully
acknowledged.
Supplementary data
Supplementary data associated with this article include: a brief experimental details, and spectral data for all new products is
available free of charge via the Internet.
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19. It was reported that diarylamidine intermediate could be in-situ generated from the reaction of arenediazonium salt, nitrile, and free
anilines. See ref. 17 for the details.
20. Other types of amide substrates, such as: acetamide, benzamide, were also investigated, in which, no desired nitrilium ion trapping
reaction was observed.
21. General procedure for the three component reaction of phenyl diazonium salt with toluene sulfonamide and acetonitrile: To a solution
of phenyl diazonium salt 1a (19 mg, 0.1 mmol) and toluene sulfonamide 2a (17 mg, 0.1 mmol, 1 equiv) in dry DCE (2 mL), was
added acetonitrile 3a (260 uL, 5 mmol, 50 equiv) via syringe. The reaction was stirred at 80 °C until complete consumption of the
starting material 1a with TLC monitoring (3 h). Then, the reaction mixture was concentrated in vacuum, and the residue was purified
by flash chromatography over silica gel column using hexane/EtOAc (5:1) as the eluent to afford 3a in 78% yield as a white solid.
Obtained as a white solid in 76% yield. The spectral data of (Z)-N'-phenyl-N-tosyl acetimidamide 4aa: M.p. 84.5-86.2; 1H NMR (400
MHz, DMSO-d6): δ 10.35 (s, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.35-7.27 (m, 4H), 7.11 (t, 1H), 2.48 (s, 3H),
2.32 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 163.65, 142.00, 140.64, 137.91, 129.40, 128.70, 125.95, 125.04, 121.74, 20.92, 20.85;
HR-MS (ESI) m/z calcd for C15H17N2O2S [M+H]+: 289.1005, Found: 289.0999.

Highlights:




Three-component reaction of aryl diazonium salt with sulfonamide and acetonitrile
Nitrilium ion intermediate generates in reaction of aryldiazonium salt with nitrile
Trapping nitrilium ion by sulfonamide to give N-sulfonyl amidine
Trapping nitrilium ion by indole to give indolyl imine