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. 2020 Oct 29;5(44):28712–28721. doi: 10.1021/acsomega.0c03987

Production of Amidinyl Radicals via UV–Vis-Light Promoted Reduction of N-Arylthiophene-2-carboxamidoximes and Application to the Preparation of Some New N-Arylthiophene-2-carboxamidines

Islam M A Mekhemer 1, Abdel-Aal M Gaber 1,*, Morsy M M Aly 1
PMCID: PMC7659145  PMID: 33195924

Abstract

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A modern method for the preparation of some new N-arylthiophene-2-carboxamidines via amidinyl radicals generated using UV–vis-light promoting the reduction of N-arylthiophene-2-carboxamidoximes without any catalyst in a short amount of time, highly straight forward, and in an efficient manner is described. This method defeats the flaws of the conventional methods for the reduction of amidoxime derivatives to amidine derivatives, which require harsh conditions such as using a strong acid, high temperature, and expensive catalysts. Benzo[d]imidazoles, benzo[d]oxazoles, and amides can also be synthesized by applying this method. The photoproducts were analyzed by various spectroscopic and analytical techniques, including thin-layer chromatography, column chromatography, high-performance liquid chromatography, gas chromatography/mass spectrometry, IR, 1H NMR, 13C NMR, and MS. Notably, the chromatographic analyses proved that the best time for the production of N-arylthiophene-2-carboxamidines is 20 min. The reaction mechanism comprising pathways and intermediates was also suggested via the homolysis of N–O and C–N bonds.

1. Introduction

Amidines are a ubiquitous class of pharmaceutical organic compounds, and they are used as important building blocks for many heteroarenes in addition to having several invaluable applications in materials chemistry.1−5 Amidine derivatives own various biological activity, including antiparasitic and antimicrobial agents, and have been used for the treatment of a variety of diseases, such as human African trypanosomiasis antimony, pneumocystis pneumonia, and resistant leishmaniasis.6−10 Owing to the biological significance of the metabolic cyclic reduction of amidoxime compounds to amidine compounds, this reduction has been studied through the use of mitochondrial enzymes, microsomal fractions, hepatocytes, and reconstituted enzyme systems from human as well as pig liver and kidney.11 Amidines are compounds closely related to amidoximes in terms of their in vivo conversion to one another.

Chemically, approaches in regard of amidines founded the reduction of amidoximes, either through catalytic hydrogenation with palladium over charcoal in the presence of acetic acid12 or reduction with Zn in acetic acid13 or transition-metal catalysis in general.14 Dormoy et al.(15) mentioned that the reduction of benzamidoxime with sodium amalgam yields ammonia and benzaldoxime; most of the amidoxime remains unchanged. Cesar et al.(13) reported the reduction of solid-supported amidoximes with SnCl2·H2O, which led to amidines in high yield. Additionally, a direct conversion of amidoximes to amidines has been described using a transfer hydrogenation approach.16 The conversion proceeded after the addition of formic acid salt and Pd/C in to the corresponding amidoxime.5 The Pd-catalyzed regioselective cleavage of O-benzyl-N-aryl amidoximes affords to the production of N-aryl amidines.17 In the current year, Perontsis et al.(18) have prepared the pyridine-2-carboxamidine Cu(II) complex through the reduction of N-(4-nitrophenyl sulfonyloxy)-pyridine-2-carboxamidoxime in the presence of Cu(NO3)2·3H2O. Also, N-tosylindole-3-formamidoximes were reduced to N-tosylindole-3-formamidines using the Rany Nickle catalyst and hydrogen atmosphere.19

Recent developments revealed enzymatic reductions of N-hydroxylated compounds, including amidoximes, that should predominate in vivo compared to the reverse metabolic pathway, the oxidation of their corresponding amidines.20,21 Specifically, the reduction of benzamidoxime to benzamidine was the main pathway in human hepatocytes, being in the order of 98%. All previous methods usually require harsh conditions such as using a strong acid, high temperatures, expensive catalysts, stoichiometric oxidants, and unfriendly materials for the environment; besides, it takes a long time for the preparation of corresponding amidines. Thus, a moderate, environmentally friendly procedure for the preparation of amidines remains to be developed. In the past forty years, the photochemistry of organic compounds has developed rapidly and led to a wealth of novel reactions and applications of great significance.22−24

The production of N-centered radicals such as iminyl and amidinyl was carried out using the cleavage of N–H, N–X, N–S, N–N, and N–O bonds (direct method) or reaction of another radical with a cyano group (indirect method).25 Especially the cleavage of the N–O bond has been widely used in the formation of iminyl and amidinyl radicals via oxime and amidoxime derivatives as precursors for these radicals, according to the facility of cleavage for this bond comparatively respect with other bonds.26,27 Zard28 and Wang29 reported that the amidinyl radicals are very important intermediates for the synthesis of imidazole and imidazoline derivatives. These versatile radicals can be generated via visible-light-promoted or electrochemistry to give several heterocycle compounds, which has many important biological applications.9,30

Herein, we introduce an unprecedented method for the preparation of some new N-arylthiophene-2-carboxamidines by the irradiation of N-arylthiophene-2-carboxamidoximes using UV–vis-light without any catalyst. Besides, this study represents a facile method to produce hydroxyl radicals from the non-O-substituted amidoximes. The final products for these reactions are analyzed by various spectroscopic and chromatographic techniques. The free radical mechanism was the predominant route for this conversion via the homolysis of N–O and C–N bonds.

2. Results and Discussion

N-(p-Methoxyphenyl)thiophene-2-carboxamidoxime (IV) was chosen as a model compound for experiments to optimize the best condition for the production of amidine derivatives (Table 1) in this study. To our delight, we prepared some new N-arylthiophene-2-carboxamidines (2I–V) in high % yield reaches 80% (entry II) via the irradiation of starting materials (I–V) using UV–vis-light for 20 min at room temperature in acetonitrile as a solvent as shown in Table 2. While the period of the reaction increased, the number of amidines decreased, and the amount of benzo[d]imidazoles (1I–IV) increased. This may be attributed to that the amidine derivatives (2I–V) underwent intramolecular cyclization over time therein process.31 When the starting compounds (I–V)were irradiated by UV–vis-light at different time intervals (5,10, 15, 20, 25, 35, 40, 55, and 60 min, respectively), they were completely consumed at 20 min. At this point, the results proved that the amidine derivatives (2I–V) represent the predominate products in the reaction. The reaction time was extended to 60 min to allow an opportunity for studying and explanation the free radical pathways mechanism through the formation of more photoproducts as outlined in Schemes 1–7. To our surprise, extending the reaction to 60 min increased the amount of benzo[d]imdazoles (1I–V) relative to N-arylthiophene-2-carboxamidines (2I–V) reaches 35% (entry V) as outlined in Table 2. Also, the radiation of starting compounds (I–V) lead to other products besides N-arylthiophene-2-carboxamidines (2I–V) and benzo[d]imdazoles (1I–V), including N-arylthiophene-2-carboxamides (3I–V), 2-(thiophene-2-yl)benzo[d]oxazoles (4I–V), 2-hydroxythiophene (5), N-aryl formamides (6I–V), phenyl isocyanates (7I–V), thiophene-2-carboxamide (8), anilines (9-I–V), thiophene-2-carbonitrile (10), and 9H-carbazole (11–I). Notably, what we believe is novel and unusual gain of the release of hydroxyl radicals, meaning the facile homolysis of the OH group from the non-O-substituted amidoxime, as shown in Scheme 1. Besides, the modern synthesis of the important class of amidines (Scheme 2), this photolysis may receive significant biological applications such as the photo-dynamic therapy and photo-inactivation of bacteria.32 Additionally, the reactive hydroxyl radicals and derived amidines are usually antimicrobial, and thus this methodology may offer synergistic therapeutic applications.33,34 All of the previous products encouraged us to design and explain the proposed mechanism for this process via the homolysis of N–O and C–N bonds for the starting material (I–V). As well as some products exist in small quantities because of the decaying rate of free radical intermediates, their presence is of great importance to mechanistic interpretation. The qualitative and quantitative [thin layer hromatography (TLC), MP, column chromatography (CC), high-performance liquid chromatography (HPLC), gas chromatography/mass spectrometry (GC/MS), Fourier transform infrared (FT-IR), 1H NMR, 13C NMR, MS] aspects were accomplished in our study for the analysis of the photoproducts.

Table 1. Optimization of Conditions for the Preparation of N-(p-Methoxyphenyl)thiophene-2-carboxamidine (2–IV) Using N-(p-Methoxyphenyl)thiophene-2-carboxamidinyl Radicals.

2.

time (min) 5 10 15 20 25 35 45 55 60
% yielda 47 65 67 73 63 66 69 37 35
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a

The yield is isolated yield by column chromatography.

Table 2. Study of the Time Effect on the Percent Yield of Some Photolysis Products of N-Arylthiophene-2-carboxamidoximes (I–V).

entries I II III IV V reaction time (min)
benz[d]imidazoles (1I–V)a 11.8 9.5 13 5 31 60
  1 2.5 1.5 2 11 20
N-arylthiophene-2-carboxamidines (2I–V)a 44.5 52 42 35 2.1 60
  70 80 65 73 60 20
thiophene-2-carbonitrile 10b 0.1 0.7 0.3 0.33 18 60
arylamines (9I–V)b 2.2 1.5 1.6 2.4 14 60
anilides (3I–V)a 28 16 22 37.5 2.1 60
benzo[d]oxazoles (4I–V)b 1 0.6 1 1 4.5 60
thiophene-2-carboxamide 8b 1.4 0.8 0.8 2.54 4.1 60
carbazoles (11I–V)b 1         60
N-arylformamides (6I–IV)b 1.4 0.6 1 traces 2.6 60
phenylisocyanates (7I-IV)b 1.3 0.5 0.4 1 8 60
2-hydroxythiophene 5b traces traces     traces 60
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a

The yield is isolated yield by column chromatography.

b

The yield is GC/MS yield.

Scheme 1. Proposed Mechanism for the Preparation of benzo[d]imidazole Derivatives (1I–IV).

Scheme 1

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Scheme 7. Proposed Mechanism for the Formation of Thiophene-2-carbonitrile 10 and α-naphthylamine (9-V).

Scheme 7

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Scheme 2. Mechanistic Pathways for the Formation of N-Aryllthiophene-2-carboxamidines (2I–IV).

Scheme 2

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2.1. Photolysis of N-Arylthiophene-2-carboxamidoxime (I–IV): Products, Intermediates, and Pathways

Based on the above-described experiments, we propose possible reaction mechanisms for the formation of these products. The photoproducts can be revealed to follow the series of reactions as shown in Scheme 1, which suggests the preliminary homolysis of the N–O bond (route i)35 to produce N-arylthiophene-2-carboxamidinyl derivatives and hydroxyl radicals. The N-aryl-thiophene-2-carboxamidinyl derivatives radical may typically undergo intramolecular cyclization followed by dehydrogenation to afford 2-(thiophene-2-yl)benzo[d]imidazoles (1I–IV), m/e 200, 234, 214, and 230, respectively.31,36 The hydroxyl radical may be consumed in other processes which will be shown in the next Schemes. Interestingly, this photolysis proved the facility of homolytic fission of the N–O bond for non-O-substituted amidoximes. Also, it can be utilized as a potential source of hydroxyl radicals in living organisms for many pharmaceutical areas such as antibacterial, antioxidant, and anticancer.37

It is noteworthy that some new N-aryllthiophene-2-carboxamidines (2I–IV), m/e 202, 236, 216, 232, and 252, respectively, were formed with a high-yield reaches 80%. This may be according to the formation of the tautomeric form of N-arylthiophene-2-carboxamidoxime derivatives (I–IV) as reported by Tiemann and Krüger.38 The tautomeric form of these compounds readily gives the N-arylthiophene-2-carboxamidinyl or N-arylthiophene-2-carboximidinyl radical, and then the high reactivity of amidinyl or imidinyl radicals39,40 makes the abstraction of hydrogen from the reaction mixture more preferable. In contrast, the amidinyl radicals need high energy and longer time in the case of the formation of 2-(thiophene-2-yl)benzo[d]imidazoles (1I–IV) via the intermolecular cyclization process41 (Scheme 1 and Table 2). All of the aforementioned reasons give us strong evidence for a high-yield of the target compounds (2I–IV) when irradiated the N-arylthiophene-2-carboxamidoximes (I–IV).

Scheme 3 depicts the homolysis of C–N bond (route ii) for the tautomeric form of heading compounds (I–IV), which produce N-arylthiophene-2-iminyl and hydroxyaminyl radicals. N-Arylthiophene-2-carboxamides (3I–IV), m/e 203, 237, 217, and 233, respectively, were formed through the interaction between N-arylthiophene-2-iminyl and hydroxyl radical.42 A possible pathway for the formation of 2-(thiophene-2-yl)benzo[d]oxazoles (4I–IV), m/e 201, 235, 215, and 231, respectively, in low yield, through a process of keto–enol tautomerism followed by the intramolecular cyclization of N-arylthiophene-2-carboxamidyl.43 The evidence for the presence of 2-(thiophene-2-yl)benzo[d]oxazoles (4I–IV) in the reaction mixture was detected by TLC, GC/MS, and photolysis of N-arylthiophene-2-carboxamides (3I–IV) under the same conditions of target compounds (I–IV). The hydroxyaminyl radical may abstract hydrogen radical from the reaction medium and afford hydroxylamine which subsequently undergoes fragmentation to ammonia, nitrogen gas, and water,44 as outlined in Scheme 3.

Scheme 3. Proposed Mechanism for the Formation of N-Arylthiophene-2-carboxamides (3I–IV) and 2-(Thiophene-2-yl)benzo[d]oxazoles (4I–IV).

Scheme 3

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Scheme 4 explains further fragmentation of N-arylthiophene-2-carboxamide (3I–IV) under the same conditions through the homolysis of the C–N bond (route ii) to produce 2-thienoyl and anilino radical pairs. A new route for photofragmentation of N-arylthiophene-2-carboxamide (3I–IV) is the homolysis of the C–C bond (route iii) via the α-cleavage “Norrish type I reaction” which lead to N-aryl formamidyl and 2-thienyl radicals.45,46 The N-arylformamidyl radicals may couple with hydrogen radical in the reaction medium to afford N-aryl formamides (6I–IV), m/e 121, 155, 135, and 151, respectively,47 which follow by oxidative dehydrogenation to form phenyl isocyanates (7I–IV), m/e 119, 153, 133, and 149, respectively.48,49 2-Hydroxythiophene 5 was formed by the interaction of 2-thienyl radical with hydroxyl radical, which was readily available in the reaction medium.50 Besides, thiophene-2-carboxamide 8, m/e 127, and aniline (9I–IV), m/e 93, 127, 107, and 123, respectively, were afforded through the interaction of former radicals with ammonia, which was abundant in the reaction medium.51

Scheme 4. Suggested Mechanism for the Formation of 2-Hydroxythiophene 5, N-Arylformamides (6I–IV), Phenyl Isocyanates (7I–IV), Thiophene-2-carboxamide 8, and Aniline Derivatives (9I–IV).

Scheme 4

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It is worth mentioning that another pathway involves the homolysis of the C–N bond (route ii) via a tautomeric form of target compounds (I–IV) as reported by Tiemann and Krüger52 to form thiophene-2-iminoxyl and anilino radicals. Thiophene-2-carbonitrile 10, m/e 109, was formed through further photofragmentation thiophene-2-iminoxyl, whereas the aniline derivatives (9I–IV), m/e 93, 127, 107, and 133, respectively, were formed by the abstraction of hydrogen radical from a suitable source in the reaction medium.53 Thiophene-2-carbonitrile 10 may undergo hydrolysis by the presence of water available in the reaction medium to give thiophene-2-carboxamide 8, m/e 127;54Scheme 5.

Scheme 5. Suggested Mechanism for the Formation of Thiophene-2-carbonitrile 10, Thiophene-2-carboxamide 8, and Arylamines (9I–IV).

Scheme 5

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A plausible mechanism for the formation of 9H-carbazole (11-I), m/e 167 is through dimerization of anilino radical followed by the loss of ammonia. 9H-carbazole easily identified from the GC/MS and fragmentation pattern55 as shown in Scheme 6.

Scheme 6. Proposed Mechanism for the Formation of 9H-Carbazole (11-I).

Scheme 6

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2.2. Photolysis of N-α-Naphthylthiophene-2-carboxamidoxime (V)

A solution of N-α-naphthylthiophene-2-carboxamidoxime (e) in acetonitrile was irradiated under the same conditions of the target compounds (I–IV) for 60 min, leads to the formation of 2-(thiophene-2-yl)naphtho[d]imidazole (1-V), thiophene-2-carbonitrile 10 and α-naphthylamine (9-V) as the major products. Besides, N-α-naphthylthiophene-2-carboxamidine (2-V), N-α-naphthylthiophene-2-carboxamide (3-V), thiophene-2-carboxamide 8, 2-(thiophene-2-yl)naphtha [d]oxazole (4-V), N-α-naphthylformamide (6-V), α-naphthyl isocyanate (7-V), and 2-hydroxythiophene 5 as the minor products (Table 2). In contrast, N-α-naphthylthiophene-2-carboxamidine (2-V) was predominant at 20 min. All of the pervious compounds were identified as mentioned before in Section 2.1.

The formation of these products can be revealed to follow the series of reactions as mentioned before in Schemes 1–6.

It is worth mentioning that the appearance of a high-yield of α-naphthylamine (9-V) and thiophene-2-carbonitrile 10 in this process was attributed to further degradation of the N-α-naphthylthiophene-2-carboxamidinyl radical. The N-α-naphthylthiophene-2-carboxamidinyl decomposed via homolysis the C–N bond route (ii) to give thiophene-2-carbonitrile 10 and α-naphthylaminyl radical, which reacts with hydrogen radical as shown in Scheme 7.

2.3. Photolysis of N-Phenylthiophene-2-carboxamidoxime I in the Presence of Tetralin as a Radical Scavenger

The photolysis of N-phenylthiophene-2-carboxamidoxime I under the nitrogen atmosphere in the presence of tetralin as a radical scavenger gave α-tetralol 12, α-tetralone 13, naphthalene 14 thiophene-2-carboxamide 8, and N-α-naphthylthiophene-2-carboxamide 3-I in addition to the previously photolysis products as shown in Schemes 1–6 (Table 3). The α-tetrayl radical is formed through hydrogen abstraction from solvent nuclei (tetralin). It may undergo coupling with hydroxyl radical which is readily available in the reaction medium followed by oxidative dehydrogenation to form α-tetralol 12 and α-tetralone 13, respectively.56 The presence of compounds (12 and 13) in the photolysate confirmed that the homolysis of non-O-substituted amidoximes give hydroxyl radicals is very easy and available. The final fate for α-tetralyl radical was oxidative dehydrogenation,57 then reacts with thiophene-2-carboxamide 8 which is readily available in the reaction medium to produce naphthalene 14 and N-α-naphthylthiophene-2-carboxamide (3-I),58 respectively, as shown in Scheme 8.

Table 3. Photolysis Products of N-Phenylthiophene-2-carboxamidoxime I in the Presence of Tetralin.

entries % yielda
(2-thiophen-2-yl)benzo[d]imidazole (1-I) 10.5
thiophene-2-carbonitrile 10 2.4
aniline (9-I) 3
N-phenylthiophen-2-carboxamidine (2-I) 52
N-phenylthiophen-2-carboxamide (3-I) 22.5
2-(thiophen-2-yl)benzo[d]oxazole (4-I) 0.3
Α-tetralol 12 1.5
Α-tetrlone 13 2
naphthalene 14 2.4
N-α-naphthylthiophene-2-carboxamide (3-V) 2.1
unreacted tetralin (mg) 15
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a

The yield is GC/MS yield.

Scheme 8. Proposed Mechanism for the Formation of α-tetralol (12), α-tetralone (13), Naphthalene (14), N-α-Naphthylthiophene-2-carboxamide (3–I), and Andthiophene-2-carboxamide 8.

Scheme 8

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Ultimately, the absence of UV–vis-light (entries I–V) caused no reaction to occur, which indicated that the presence of light was indispensable for the completion of all of the above transformation.

3. Conclusions

In the culmination of the above discussion, it is quite clear that the new N-arylthiophene-2-carboxamidines (2I–V) were synthesized using irradiation of N-arylthiophene-2-carboxamidoximes (I–V) via UV–vis-light with high percent yield, reaching 80% in the absence of any catalyst at quite a short time (20 min). This is the first and facile method reported to produce amidine derivatives from amidoxime derivatives through the production of amidinyl radicals in the presence of light. The novelty of this work comes from the facile releasing of hydroxyl radicals by homolysis of the N–O bond from non-O-substituted N-arylthiophene-2-carboxamidoximes, detecting this through tetralin as the radical scavenger. In this photolysis, the production of amidines and hydroxyl radicals may have critical therapeutic applications such as photodynamic therapy and photoinactivation of bacteria. Also, this method could produce benzo[d]imidazoles with percent yield reaching 35%, when the time of reaction is extended to 60 min and identification of other photolysis products including, amides, benzo[d]oxazoles, carbazoles, and phenyl isocyanates at this time. All photoproducts were analyzed by qualitative and quantitative techniques such as TLC, MP, CC, HPLC, GC/MS, FT-IR, 1H NMR, 13C NMR, and MS. The mechanistic study of this process was attempted via two competitive pathways, homolysis of N–O and C–N bonds. Many parameters were studied for the percent yield of photoproducts such as time effect and addition of the radical scavenger (tetralin).

4. Experimental Section

4.1. Materials

Thiophene-2-carbonitrile (Alfa Aeser, 98%), thiophene-2-carbaldehyde (Merck, 93%), N-chlorosuccinimide (Alfa Aeser, 98%), p-anisidine (Alfa Aeser, 99%), aluminum chloride anhydrous (Fluka, 98%), p-toluidine (Adwic, Egypt), hydroxylamine hydrochloride (Oxford, 98%), aniline (Adwic, Egypt), O-phenylenediamine (Sigma-Aldrich, 98%), α-naphthylamine (Adwic, Egypt), tetralin (Alfa Aser, 97%), 2-amino-5-chlorophenol (Sigma-Aldrich, 97%), acetonitrile (Sigma-Aldrich, HPLC grade), 2-amino-5-methylphenol (Sigma-Aldrich, 98%), phenyl isocyanate (Sigma-Aldrich, 98%), 4-methoxyphenyl isocyanate (Sigma-Aldrich, 98%), 4-methylphenyl isocyanate (Sigma-Aldrich, 98%), and 1,1,2,2-tetrachloroethane (Fluka, 95%) were used. Other reagents and solvents were purchased and used as received unless otherwise listed.

4.2. Instrumentation

Melting points were determined in open capillary tubes, using a Stuart SMP10 digital melting point apparatus. FT-IR spectra were recorded on Nicolet 6700 Thermo Fisher Scientific, using the KBr pellet technique. 1H NMR spectra were recorded on Bruker A V500 at 500 MHz (Shanghai University, China) and Varian-Mercury-300BB at 300 MHz (Cairo University, Egypt), and 1H NMR and 13C NMR spectra were recorded on Bruker A V500 at 400 MHz and 101 MHz (Cairo University, Egypt), respectively, using CDCl3 and DMSO-d6 as solvents at room temperature and TMS as an internal standard. GC/MS was recorded on a Jeol JMS-600 mass spectrometer. GC/MS analyses were carried out using PerkinElmer Clarus 500 provided with a PerkinElmer Clarus 500 MS detector using the following capillary column: DB-5 with a length of 30 m, internal diameter of 0.25 mm, film thickness of 0.25 μm with carrier gas helium, and the temperature programming (40 °C for 5 min, 5 °C/min up to 150 °C, hold time for 5 min, 5 °C/min up to 280 °C, hold time for 15 min). HPLC separation was carried out with the column Luna 5u C18 with a diameter of 250 × 4.6 mm. The mobile phase was acetonitrile: water (1:1 v/v) with a flow rate of 0.5 mL/min. The injection volume for the selected sample and the standard solution was 20 μL. The pH was carefully adjusted to 5. The detection occurred at UV light at 305 nm wavelength. Absorption spectra were recorded in ethanol within the range of 200–800 nm for amidoxime derivatives with a Shimadzu 2110 PC scanning spectrophotometer (Assiut University). UV–vis photolysis reactions were carried out in a Pyrex immersion well-equipped with a reflux condenser. Using a 450 W medium pressure mercury lamp [ACE glass Inc., USA, maximum emission at 296.7–578 nm (4.18-2.15 eV)] and cooled by water circulation. The system was covered with aluminum foil to decrease light loss, as shown in Figure 1.

Figure 1.

Figure 1

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Schematic diagram for the ACE lamp photoreactor (taken by Mekhemer, Islam).

4.3. Starting Materials

N-Arylthiophene-2-carboxamidoximes (I–V) were prepared by two different methods according to our previous work.59

4.3.1. N-Phenylthiophene-2-carboxamidoxime I

The product was obtained as needle white crystals, in 45% yield, mp 88–92 °C (lit60 mp 90–93 °C). The IR spectrum showed characteristic absorption at 3367 (NH), 3212 (OH), 3095 (CH aromatic), 1626 (C=N), 1592 (C=C), 1378 (C–N), and 1090 for (C–O) cm–1; 1H NMR (500 MHz, CDCl3): spectrum showed signals at δ 8.73 (s, 1H, NH), 7.32 (d, J = 5.0 Hz, 1H), 7.23 (s, 1H, OH), 7.21 (d, J = 7.7 Hz, 2H), 7.05 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 3.5 Hz, 2H), 6.97–6.94 (m, 1H), 6.88 (d, J = 8.0 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 147.63, 139.37, 131.96, 129.28, 128.84, 127.54, 127.15, 123.89, 122.69; MS (EI, 200 °C), m/e (%): 218 (46), 201 (100), 186 (20), 169 (4), 125 (2), 109 (13), 93 (61), 77 (16), 65 (18).

4.3.2. N-(p-Chlorophenyl)thiophene-2-carboxamidoxime II

The product was obtained as peel white crystals in 60% yield; mp 179–180 °C. The IR spectrum showed characteristic absorption at 3404 (NH), 3213 (OH), 3113 (CH aromatic), 1645 (C=N), 1599 (C=C), 1371 (C–N), and 1090 cm–1 for (C–O); 1H NMR (500 MHz, CDCl3): spectrum showed signals at δ 8.5 (s, 1H, NH), 7.34 (dd, J = 4.6, 1.6 Hz, 1H), 7.18 (s, 1H, OH), 7.16 (t, J = 2.5 Hz, 2H), 6.99–6.96 (m, 2H), 6.80 (d, J = 8.8 Hz, 2H);13 C NMR (101 MHz, CDCl3): δ 147.36, 137.77, 131.12, 129.62, 128.97, 128.12, 127.32, 123.86; MS (EI, 200 °C), m/e (%): 254 (M + 2, 34), 252 (M + , 100), 235 (56), 220 (19), 200 (8), 186 (4), 127 (44), 109 (13), 97 (7).

4.3.3. N-p-Tolylthiophene-2-carboxamidoxime III

The product was obtained as off-white crystals in 50% yield, mp 169–170 °C (lit60 mp 170 °C). The IR spectrum showed characteristic absorption at 3355 (NH), 3206 (OH), 3098 (CH aromatic), 2914 (CH aliphatic), 1626 (C=N), 1592 (C=C), 1365 (C–N), and 1063 cm–1 for (C–O); the 1H NMR (500 MHz, CDCl3): spectrum showed signals at δ 9.12 (s, br, 1H, NH), 7.32–7.29 (m, 1H), 7.19 (s, 1H, OH), 7.02 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 4.7 Hz, 1H), 6.94 (d, J = 4.9 Hz, 1H), 6.80 (d, J = 8.3 Hz, 2H), 3.29 (s, 3H, CH3);13 C NMR (101 MHz, CDCl3): δ 147.86, 136.82, 133.71, 132.21, 129.41, 129.14, 127.29, 127.06, 123.11, 20.74; MS (EI, 200 °C), m/e (%): 232 (M+, 91), 215 (100), 200 (42), 186 (7), 107 (14), 91 (8), 77 (5), 65 (3).

4.3.4. N-(p-Methoxyphenyl)thiophene-2-carboxamidoxime IV

The product was obtained as white crystals in 50% yield, mp 180–181 °C; the IR spectrum showed characteristic absorption at 3340 (NH), 3203 (OH), 3104 (CH aromatic), 2959 (CH aliphatic), 1626 (C=N), 1506 (C=C), 1378 (C–N), and 1023 cm–1 for (C–O); 1H NMR (500 MHz, CDCl3): spectrum showed signals at δ 8.82 (s, br, 1H, NH), 7.28 (d, J = 1.3 Hz, 1H), 7.13 (s, br, 1H, OH), 6.94–6.87 (m, 4H), 6.80–6.75 (m, 2H), 3.03 (s, 3H, OCH3); 13C NMR (101 MHz, CDCl3): δ 157.03, 132.10, 130.51, 129.44, 127.55, 126.95, 125.72, 115.31, 114.13, 55.42; MS (EI, 200 °C), m/e (%): 248 (M+, 100), 230 (19), 215 (41), 187 (4), 123 (14), 95 (4), 80 (3).

4.3.5. N-α-Naphthylthiophene-2-carboxamidoxime V

The product was obtained as yellow powder in 69% yield, mp 164–165 °C; the IR spectrum showed characteristic absorption at 3349 (NH), 3212 (OH), 3058 (CH aromatic), 1639 (C=N), 1592 (C=C), 1358 (C–N), and 1103 cm–1 for (C–O); 1H NMR (500 MHz, CDCl3): spectrum showed signals at δ 8.78 (s, br, 1H, NH), 8.26 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.58 (dt, J = 21.3, 7.2 Hz, 2H), 7.44 (s, br, 1H, OH), 7.33–7.26 (m, 2H), 7.22 (dd, J = 4.6, 1.4 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.82 (q, J = 3.6 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 149.48, 134.25, 129.58, 129.36, 128.37, 127.82, 127.30, 127.05, 126.66, 126.45, 125.94, 125.30, 122.83, 122.09; MS (EI, 200 °C), m/e (%): 268 (M+, 25), 251 (100), 236 (10), 205 (5), 153 (15), 143 (30), 115 (77), 109 (9).

4.4. General Procedure for Photolysis of N-Arylthiophene-2-carboxamidoxime I–V

A solution of N-arylthiophene-2-carboxamidoxime (I–V) (1.83 mmol) was prepared in dry acetonitrile (350 mL) and transferred to the reaction under a nitrogen atmosphere and irradiated with a 450 W medium pressure mercury vapor lamp (ACE glass, see above Figure 1) for 60 min at different time intervals (5, 10, 15, 20, 25, 35, 45, 55, and 60 min, respectively). The substrates completely disappeared (20 min; according to HPLC and TLC monitoring). The time of the reaction was extended to 60 min to study the effect of time on photoproducts and explanation of the proposed pathway mechanism. The gases evolved were detected by standard chemical methods (NH3 by Nessler’s reagent).61 The acetonitrile was evaporated in vacuo, and the remaining residue (photolysate) was analyzed using TLC, CC, and GC/MS techniques. Chemical yields of all photolysis products were determined by CC and GC/MS analyses. The major products were identified by isolation, comparison of spectral properties (IR, MS, 1H NMR, and 13C NMR) with authentic samples and GC/MS analyses. Minor products were detected by GC/MS analysis via the comparison of mass spectral fragmentation patterns with library standards or authentic samples.

4.5. Photolysis of N-Phenylthiophene-2-carboxamidoxime I in the Presence of Tetralin as the Radical Scavenger

A solution of N-phenylthiophene-2-carboxamidoxime I (0.4 g, 1.83 mmol) was irradiated in acetonitrile under a continuous stream of nitrogen for 60 min with the same manner, as described in Section 4.4 at ambient temperature in the presence of tetralin (25 mg) as the radical scavenger. The gases evolved were detected by standard chemical methods (NH3 by Nessler’s reagent).61 After the disappearance of the starting materials as monitored by the TLC technique, the products were separated as done previously. The acetonitrile was evaporated in vacuo, and the remaining residue was subjected to GC/MS and CC.

4.6. Purification and Identification of Photolysis Products

The purity of isolated end products and irradiation progressing were tested by TLC with mobile phase acetone: petroleum-ether (60–80 °C) (1:4 v/v). All end products were purified and separated using column chromatography by mobile phase acetone: petroleum-ether (60–80 °C) with gradual elution. The separated products were analyzed by IR, GLC, TLC, MS, 1H NMR, 13C NMR, HPLC, and GC/MS. Products were identified either by coinjection with reference samples and/or by comparison with known GC/MS library fragmentation patterns (NIST, Pfleger, and Geopetro).

4.7. Photoproducts

4.7.1. N-Phenylthiophene-2-carboxamidine (2–I)

Chromatography [acetone–petroleum ether (60–80 °C) (1:4 v/v)], pale yellow crystals, 70 mg, yield 70% at 20 min and 44.5 mg, yield 44.5% at 60 min; mp 136–138 °C (lit,62 mp 137–139 °C); FT-IR (KBr): 3243, 3175, 3045, 3004, 2882, 2827, 2780, 1653, 1605 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.45 (t, J = 4.3 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.09 (dt, J = 9.0, 5.8 Hz, 2H), 7.01 (d, J = 7.5 Hz, 2H), 5.09 (s, b, 2NH, 2H);13C NMR (101 MHz, CDCl3): δ 150.18, 148.02, 139.78, 129.48, 129.15, 127.30, 126.58, 123.56, 122.04; MS (EI, 250 °C) m/e (%): 204 (M + 2, 2), 203 (M + 1, 14), 202 (M +, 100), 186 (38), 110 (38), 93 (97), 77 (54), 51 (16).

4.7.2. N-p-Chlorophenylthiophene-2-carboxamidine (2–II)63

Chromatography [acetone–petroleum ether (60–80 °C) (1:4 v/v)], yellow crystals, 80 mg, yield 80% at 20 min and 52 mg, yield 52% at 60 min, mp 121–122 °C. FT-IR (KBr): 3342, 3210, 3105, 2999, 2960, 1632, 1510, 1444, 1239, 809 cm–1; 1H NMR (400 MHz, DMSO-d6): δ 8.30 (s, 1H, NH), 8.16 (s, 1H, NH), 7.59 (d, J = 8.2 Hz, 3H), 7.48 (d, J = 7.8 Hz, 3H), 7.32 (d, J = 31.2 Hz, 1H); 13C NMR (101 MHz, DMSO-d6): δ 156.9, 135.3, 134.8, 132.7, 129.8, 128.8, 128.1; MS (EI, 250 °C) m/e (%): 239 (M + 4, 2), 238 (M + 3, 4), 237 (M + 2, 20), 236 (M + 1, 10), 235 (M+, 60), 220 (24), 127 (100), 110 (60), 109 (15), 75 (23), 65 (8).

4.7.3. N-p-Tolylthiophene-2-carboxamidine (2–III)63

Chromatography [acetone–petroleum ether (60–80 °C) (1:4 v/v)], orange crystals, 65 mg, yield 65% at 20 min and 42 mg, yield 42% at 60 min, mp 134 °C. FT-IR (KBr): 3450, 3280, 3150, 3073, 2912, 1631, 1579, 847, 712 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 4.8 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 7.07 (t, J = 4.2 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 5.02 (s, 2H, 2NH), 2.35 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3): δ 150.19, 145.47, 140.11, 132.83, 130.05, 128.93, 127.25, 121.82, 20.84; MS (EI, 250 °C), m/e (%): 218 (M + 2, 2), 217 (M + 1, 12), 216 (M+, 81), 200 (23), 107 (100), 91 (32), 65 (23).

4.7.4. N-4-Methoxyphenylthiophene-2-carboxamidine (2–IV)63

Chromatography [acetone–petroleum ether (60–80 °C) (1:4 v/v)], brown crystals, 73 mg, yield 73% at 20 min and 35 mg, yield 35% at 60 min, mp 134–136 °C. FT-IR (KBr): 3483, 3380, 3045, 1632, 1585, 1496, 1223, 816 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.57–6.79 (m, 7H), 4.85 (s, 2H, 2NH), 3.82 (s, 3H, OCH3); 13C NMR (101 MHz, CDCl3): δ 155.81, 149.91, 141.97, 140.82, 128.72, 127.19, 122.69, 114.83, 55.48; MS (EI, 250 °C) m/e (%): 234 (M + 2, 2), 233 (M + 1, 5), 232 (M+, 42), 217 (15), 123 (31), 110 (72), 108 (100), 80 (15), 64 (8).

4.7.5. N-α-Naphthylthiophene-2-carboxamidine 2–V(63)

Chromatography [acetone–petroleum ether (60–80 °C) (1:4 v/v)], brown crystals, 60 mg, yield 60% at 20 min and 2 mg, yield 2% at 60 min, mp 145–148 °C. FT-IR (KBr): 3667, 3551, 3469, 3421, 3278, 3148, 1626, 1585, 1557 cm–1; 1H NMR (400 MHz, CDCl3): δ 8.04 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.74–7.38 (m, 6H), 7.10 (d, J = 5.5 Hz, 2H), 5.03 (s, 2H);13C NMR (101 MHz, CDCl3): δ 150.13, 144.7, 140.17, 134.6, 129.3, 127.9, 127.5, 126.2, 126, 125.14, 123.8, 123.53, 116.79; MS (EI, 250 °C) m/e (%): 252 (M+, 32), 236 (9), 171 (35), 143 (100), 115 (55), 110 (19), 89 (9).

Phenyl isocyanates, and N-arylfromaides, tetralol, and tetralone (Supporting Information).

Benzo[d]imidazoles, benzo[d]oxazoles, amides, arylamines, thiophene-2-carboxamide, thiophene-2-carbonitrile, and 9H-carbazole were discussed in our previous work.59

Acknowledgments

I gratefully appreciate the funding received toward our paper from the Institutional Review Board (IRB) at the Faculty of Science, Assiut University.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c03987.

  • FT-IR, 1HNMR, 13C NMR, MS, and GC/MS of photoproducts (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao0c03987_si_001.pdf (3.1MB, pdf)

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