PTABS: Low-Temperature Thioetherification of Chloro(hetero

Article Cite This: J. Org. Chem. 2019, 84, 8921−8940

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Pd/PTABS: Low-Temperature Thioetherification of Chloro(hetero)arenes Siva Sankar Murthy Bandaru,§ Shatrughn Bhilare,† Jesvita Cardozo,† Nicolas Chrysochos,§ Carola Schulzke,*,§ Yogesh S. Sanghvi,∥ Krishna Chaitanya Gunturu,⊥ and Anant R. Kapdi*,†,‡ †

Department of Chemistry, Institute of Chemical Technology, Nathalal Parekh Road, Matunga, Mumbai 400019, India Institute of Chemical Technology, Indian Oil Odisha Campus, IIT Kharagpur Extension Centre, Mouza Samantpuri, Bhubaneswar, Odisha 751013, India § Institut für Biochemie, Universität Greifswald, Felix-Hausdorff-Straße 4, Greifswald D-17487, Germany ∥ Rasayan Inc., 2802 Crystal Ridge Road, Encinitas, California 92024-6615, United States ⊥ School of Chemical Sciences, SRTM University, Nanded 431606, India

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‡

S Supporting Information *

ABSTRACT: The thioetherification of heteroaryl chlorides is an essential synthetic methodology that provides access to bioactive drugs and agrochemicals. Due to their (actual or potential) industrial importance, the development of efficient and lowtemperature protocols for accessing these compounds is a requirement for economic and ecologic reasons. A particular highly effective catalytic protocol using the Pd/ PTABS system at only 50 °C was developed accordingly. The coupling between chloroheteroarenes and a variety of less reactive arylthiols and alkylthiols was carried out with a high efficiency. Heteroarenes of commercial relevance such as purines and pyrimidines were also found to be useful substrates for the reported transformation. The commercial drug Imuran (azathioprine) was synthesized as an example, and its preparation could be optimized. DFT studies were performed to understand the electronic effects of the tested ligands on the catalytic reaction. ment as coupling partners.27,28 The poor compatibility of the available catalytic protocols with different functional groups and competing for disulfide formation represent further problems, which have plagued the synthesis of thioether in the past.29 Even though modified transition-metal-based catalytic systems have been tested for carrying out such synthetic transformation,30 no fully satisfying solution to the existing problems could be reached as of yet. The functionalization of chloroheteroarenes31,32 is one crucial aspect that has been mostly unexplored with only a very few examples for respective thioetherification available in literature.33−35 Very recently, Hierso and co-workers36 significantly advanced this field when they reported an excellent protocol utilizing their previously developed ferrocene-based phosphines in combination with a Pd-precursor for the thioetherification of chloroheteroarenes. The high efficiency of the developed catalytic protocol accomplished the thioetherification at a low catalyst concentration with consequently rather good turnover numbers. However, upon closer inspection of the published protocol, it is evident that the substrates scope is very limited and the required high reaction temperature (115 °C) was economically and ecologically unfavorable. The operating temperature might also be detrimental to temperature-sensitive functional groups

1. INTRODUCTION The formation of a C−S bond is a synthetically challenging reaction1 that has commercial relevance due to the occurrence of thioethers as important structural motifs in pharmaceutical drugs,2 insecticides,3 and generally bioactive molecules.4 Derivatives of thioethers, namely, sulfones5,6 and sulfoximines,7,8 which can be easily accessed from thioethers, also find a wide variety of applications as cell proliferation inhibitors,9 insecticides,10 ATR kinase inhibitors,11 prostacydin receptor agonists,12,13 etc. (Figure 1). Traditional synthetic approaches to prepare thioethers14 are numerous but suffer from drawbacks such as long reaction times, moderate reactivities, and poor results with aryl thiols synthons.15−18 One of the earliest examples addressing these issues was provided by Migita and co-workers who introduced the first respective transition-metal-catalyzed C−S bond formation reaction.19,20 The employment of [Pd(PPh3)4] by Migita laid the foundation for a plethora of palladium-based catalytic systems to be explored for such a synthetically valuable transformation.21 Many research groups, which are active in this research area, have focused on the coupling of aryl chlorides as the electrophilic coupling partners with aryl or alkyl thiols.22−24 Reports using aryl thiols with chloro(hetero)arenes have various limitations in reactivity.25,26 The ability of thiols and sulfur-containing compounds to act as catalyst poison by actively coordinating the catalyst metal center constitutes a significant problem associated with their employ© 2019 American Chemical Society

Received: March 26, 2019 Published: June 10, 2019 8921

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

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The Journal of Organic Chemistry

Figure 1. (A) Bioactive molecules and commercial drugs having a C−S bond on heteroarenes. (B) Previous reports of C−S bond formation processes using Pd or other transition metals and limitations. (C) Current work.

chloroheteroarene amination,40 or etherification,41 as well as oxadiazole C−H bond functionalization.42 The success of all these protocols is based on the discovery and development of the highly efficient Pd/PTABS catalytic system by the Kapdi group, which was found to promote various reactions under (relatively) mild conditions. To provide a catalytically efficient solution to the problems associated with thioetherification, the exceptionally successful Pd/PTABS catalytic system was now investigated in the context of these challenging transformations. At first, as a standard transformation, the thioetherification of 2-chloropyrazine43 was performed with thiophenol as a coupling partner and different catalyst systems including the Pd/PTABS system were assessed (Table 1). Screening studies were carried out at a relatively lower temperature (50 °C) compared to what is specified in the available literature reports.44 Initially, a background reaction was performed in DMF at 50 °C in the absence of any Pd-precursor or ligand using only the base K3PO4 (entry 1, Table 1). No reaction was observed under these conditions. Next, the feasibility of employing Pd(OAc)2 on its own under ligand-free conditions was tested (entry 2, Table 1). As the desired product was formed in only 38% yield, it was then investigated whether the incorporation of an activating ligand could improve the outcome. Previously, we have reported on the application of triazaphosphaadamantane (PTA, I) and its derivatives (PTABS, II and PTAPS, III) as ligands in a variety of catalytic processes.39−41,45 As expected, the addition of PTA as an activating ligand supported product formation and raised the yield to 62%

of the reactants. These disadvantages of the known procedures provided the incentive to develop a milder, hence better, protocol for thioetherification reactions. In the following, we report the catalytic thioetherification of a variety of chloroheteroarenes using the Pd/PTABS catalyst system, which is highly efficient even at a low temperature.37 The employment of both aryl as well as alkylthiols provided good to excellent yields of the targeted thioethers, while a wide variety of chloroheteroarenes could be utilized. Even purine and pyrimidine structural motifs bearing temperature-sensitive ribose and deoxyribose sugars were well-tolerated and gave good yields of the desired products. Commercially useful sulfones and sulfoximine analogues of selected thioether derivatives were prepared from those to highlight further the endless potential and significance of the reported approach as thioethers constitute not only targets but also valuable synthons in industrial synthesis. The unique reactivity of the PTABS system in this context was explored by density functional theory (DFT) methods, and a catalytic mechanism is proposed based on the respective computational results.

2. RESULTS AND DISCUSSION The significance of thioetherification reactions relates to the occurrence of the particularstructural C−S−C motif in commercially relevant compounds motivating researchers to develop sustainable solutions for accessing these moieties.38 Our research groups have been interested in the development of efficient, ambient to low-temperature palladium-catalyzed protocols for a variety of synthetically challenging substrates, e.g., nucleoside modification via cross-coupling processes,39 8922

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

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The Journal of Organic Chemistry Table 1. Screening Studies for Low-Temperature Thioetherification of Chloroheteroarenes

entry

catalyst (1.0 mol %)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 PdCl2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2

ligand (2.0 mol %)

base (equiv)

solvent

temperature (°C)

yieldb (%)

PTA PTABS PTAPS PTABI PTABBr PTABCl PTABBn XPhos SPhos Xantphos PTABS PTABS PTABS PTABS PTABS PTABS PTABS PTABS PTABS PTABS

K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 Na2CO3 Cs2CO3 KOtBu K3PO4 K3PO4 K3PO4

DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF CH3CN dioxane THF DMF DMF DMF DMF DMF DMF

50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 50 rt (25 °C) 60 80

NR 38 62 91 85 85 80 76 82 53 62 68 85 42 68 27 22 68 54 25 88 73

a

Reaction conditions: 1.0 mmol of 1a, 1.5 mmol of 2a, 1.0 mol % Pd(OAC)2 or PdCl2, 2.0 mol % PTABS/ligand, 3.0 mL of solvent, DMF stirring at 50 °C for 2 h. bIsolated yields.

activating ligands effectively. Considering their role in the aryl halides (including chlorides), bulky phosphines such as XPhos, SPhos, and Xantphos were employed to obtain a better yield of the desired product (entries 10−12, Table 1). Lower yields as compared to PTABS in all of the cases further confirmed our initial findings of the product yield enhancing capabilities of PTABS. Change in the palladium precursor from Pd(OAc)2 to PdCl2 also failed to bring about any improvement in the product yield (entry 13, Table 1). Furthermore, solvent and base studies performed provided conclusive evidence supporting the employment of K3PO4 as the base in DMF as a solvent (entries 14−19, Table 1). Optimization of conditions for the thioetherification of chloroheteroarenes provides us with a mild and low-temperature protocol as any further reduction in temperature (rt or 25 °C) was found to be less effective (entry 20, Table 1). The same was the case with any further increase in the reaction temperature proving detrimental for the thioetherification to proceed (entries 21− 22, Table 1).

(entry 3, Table 1), while the sulfonated PTA derivatives, PTABS and PTAPS, even reached 91% and 85% product yields, respectively (entries 4 and 5, Table 1). As it was observed that the utilized PTA-derived ligand had at least a small impact on the resulting quantity of product, further derivatives were prepared by synthetically convenient alkylations of the PTA ligand. The change from covalently attached SO3− to unbound counterion X− (X = I, Br, or Cl) results in a minor decrease in catalytic efficiency under the tested/optimized conditions (entries 6−8, Table 1). The alternative introduction of a benzyl moiety on the PTA ligand led to similarly decent yields of the thioether product (82%, entry 9, Table 1). Among all seven tested PTA-based derivatives, however, PTABS constitutes the ligand of choice as was observed previously for other transformations. Highly electron-rich phosphines46,47 and N-heterocyclic carbenes48,49 have in the past found broad applications in the thioetherification of aryl halides with the groups of Hartwig,50 Itoh,51 and Nolan,52 utilizing sterically bulky 8923

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

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The Journal of Organic Chemistry Scheme 1. Scope for Thioetherification of Chloroheteroarenes with Thiophenolsa

a

Reaction conditions: 1.0 mmol of chloroheteroarene, 1.5 mmol of thiol, 1.0 mol % Pd(OAc)2, 2.0 mol % PTABS ligand, 3.0 mL of solvent, DMF, stirred at 50 °C for 2 h. b2.2 equiv of thiol used. c3.2 equiv of thiol used. Isolated yields.

With 2-chlorobenzothiazole as the substrate, a similar catalytic reactivity was observed and good to excellent yields of the desired thioethers were obtained (3o−t, Scheme 1). It has to be emphasized though that, with the high efficiency of the catalytic system toward etherification (reported earlier)50−52 as well as thioetherification, the reactions exhibit comparably poorer (or) no respective chemo-selectivity (example 3r, Scheme 1). In the case of the thioetherification of 2,6-dichloropyrimidine, as another example for the occasional disadvantages of high reactivity, the formation of doubly thioetherified product highlights the loss of regioselectivity (3u, Scheme 1). 2,4,6-Trichloropyrimidine underwent efficient triple thioetherification with phenylthiol or 4-fluorophenylthiol to provide the respective products (3w or 3x, Scheme 1) in excellent yields. All available Cl substituent of the precursors are similarly activated in the course of the coupling reactions without any discrimination. As the pentafluorophenyl substituent is known to enhance the bioactivity of drug molecules, pentafluorophenylthiol was coupled with heteroarenes showing an excellent reactivity, which further confirms the exceptional synthetic utility of the developed protocol (3y and 3z, Scheme 1). A couple of the synthesized thioetherified products (3i and 3u) could be isolated as crystalline solids and were

With a highly efficient thioetherification protocol in hand, the substrate scope for the reaction of different chloroheteroarenes with arylthiols was undertaken (Scheme 1). 2Chloropyrazine was the first to be coupled with a sterically hindered 2,6-dimethyl thiophenol, providing a good yield of the coupled product (72%, 3b, Scheme 1). Presence of electron-deficient substituents such as 4-Cl or 4-F or 4-CO2Me was found to have a negligible impact on the reactivity as good to excellent yields were obtained (3c 88%, 3d 84%, 3e 88%, respectively). Free-amine groups present in the 2- or 4-position of the thiophenol moiety were also well-tolerated, giving 92% (3f) and 87% (3g) of the thioether products, respectively. The introduction of heteroaryl thiols (pyridine-2-thiol) was also found to be compatible with the developed protocol providing the coupled product in 76% yield (3h, Scheme 1). Next, 2-chloroquinoxaline was coupled with different aryl and heteroaryl thiols under the optimized conditions. In most cases, good to excellent yields of the targeted quinoxalinederived thioethers were obtained (entries 3i−l, Scheme 1). An electron-poor arylthiol bearing an ester functionality as well as a heteroarylthiol (benzothiazole-2-thiol), presumed to be challenging synthons, were successfully employed as reactants without any noticeable reduction in the yield of the coupled products (3m−n, Scheme 1). 8924

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

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The Journal of Organic Chemistry Scheme 2. Scope for Thioetherification of Chloroheteroarenes with Alkanethiolsa

a Reaction conditions: 1.0 mmol of chloroheteroarene, 1.5 mmol of thiol, 1.0 mol % Pd(OAc)2, 2.0 mol % PTABS ligand, 3.0 mL of solvent, DMF stirred at 50 °C for 2 h. Isolated yields.

Scheme 3. Thioetherification of Synthons with Chloropyrimidine Structural Motifsa

a Reaction conditions: 1.0 mmol of chloroheteroarene, 1.5 mmol of thiol, 1.0 mol % Pd(OAc)2, 2.0 mol % PTABS ligand, 3.0 mL of solvent, DMF stirred at 50 °C for 2 h. Isolated yields.

partners, resulting in >80% yield (5i−j, Scheme 2). The alkylthiols, despite their inherent higher reactivity, behave just as well as coupling partners under the optimized conditions as the initially investigated arylthiols. The pyrimidine structural motif is a feature in a large number of bioactive molecules most prominently in nucleosides such as uracil and cytidine.45,54 Chemical modifications of these molecules are highly desirable as these could lead to the development of fluorescent DNA/RNA probes and useful drug candidates.55 Subjecting 6-chlorouracil to thioetherification under optimized conditions with 4-methoxyphenylthiol or 2-chlorobenzylthiol as coupling partners gave the respective products 7a and 7b in excellent yields (Scheme 3). Protecting the uracil-based precursor did not impair the coupling reactions as was shown by the thioetherification of Nmethyl-protected 6-chlorouracil with similarly high yields (7c, Scheme 3). The important antidiabetic drug Alogliptin,56 which is marketed by Takeda Pharmaceuticals, constitutes a 3fold substituted uracil nucleobase, and reasonable modifications of its molecular structure might help enhance its biological activity necessarily. The thioetherification of 2-((6-

characterized with single-crystal X-ray diffraction (see Supporting Information for detailed X-ray crystallography data). The coupling of arylthiols is synthetically challenging for their comparably lower activity as coupling partners.53 The developed protocol has shown exceptional reactivity toward the thioetherification of chloroheteroarenes with a variety of arylthiols in easily controllable reactions. Encouraged by these results, it was further envisaged to employ the alkylthiols as coupling partners in order to test whether they would also lead to well-defined products despite their higher reactivity. Notably, only a somewhat limited number of reports are available, which detail examples of alkylthiol coupling. 2Chloropyrazine was first coupled under the optimized conditions to a variety of alkylthiols such as ethylthiol, dodecanethiol, adamantanethiol, 2-butanethiol, and 2-chlorobenzylthiol, resulting in excellent yields of the thioetherified products in all investigated cases (5a−e, Scheme 2). Next, 2chloroquinoxaline was similarly employed as chloroheteroarenes to quantitative yields of the products (5f−h, Scheme 2). Finally, benzothiazole was chosen to couple with dodecanethiol and tert-butyl(2-mercaptoethyl)carbamate as coupling 8925

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

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The Journal of Organic Chemistry Scheme 4. Scope for Thioetherification of Purines and Ribonucleosidesa

a

Reaction conditions: 1.0 mmol of chloroheteroarene, 1.5 mmol of thiol, 1.0 mol % Pd(OAc)2, 2.0 mol % PTABS ligand, 3.0 mL of solvent, DMF stirred at 50 °C for 2 h. Isolated yields.

chloroguanine with pyridine-2-thiol, dodecanethiol, and 4chlorophenylthiol as coupling partners furnishing the desired products in good to excellent yields (9a−c, Scheme 4). Similarly, 6-chloroguanosine (ribose) reacted efficiently to give the thioether product without any deglycosylation observed (9d, Scheme 4). The second purine nucleobase was similarly subjected to the optimized reaction conditions employing 6chloroadenine, which was thioetherified with a variety of thiols, namely, ethanethiol, dodecanethiol, thiobenzene, pyridine-2thiol, 4-chlorophenylthiol, and adamantanethiol (9f−j, Scheme 4). The reactivity, though, was found to be slightly lower than with the guanine analogue, which was also observed when 6chloroadenosine (ribose, 9m, and 9o) and 6-chloroadenosine were employed as coupling partners (9k−p, Scheme 4). Deazapurine is a related structural motif, which comprises a common feature of a wide variety of drugs and bioactive molecules such as tubercidin,62 toyocamycin,63 and sangivamycin.64 As a respective example, 6-chloro-7-deazapurine was tested and shown to be efficiently coupled to dodecanethiol

chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl)methyl)benzonitrile with phenylthiol or 2-butanethiol yields derivatives of Alogliptin, in which the amino-piperidinyl substituent on the ene carbon atom is replaced by an RS substituent in good yields (7d,e, Scheme 3). It shows that several modifications can be facilitated by the optimized protocol very conveniently. Determining whether the novel compounds do indeed have an improved biological reactivity is out of the scope of this study but shall be investigated in future experiments. Synthetically challenging substrates, which have found full applications as fluorescent probes,57 anticancer,58 and antiviral59,60 drugs are the purines bases (adenine and guanine) in nucleobase and nucleoside forms, i.e., with or without the respective sugars (ribose and deoxyribose).59 A thiomethylation of purines was recently reported by Jiang and coworkers.61 However, the operating high-temperature conditions of the developed protocol render it synthetically less attractive. The thioetherification with the Pd/PTABS catalytic system at a moderate temperature was first applied to 68926

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

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inhibitor BAY1000394 from Bayer74 and the ATR inhibitor AZD673875,76 from Astra-Zeneca underlines the importance of the developed thioetherifcation protocol, as a wide variety of respective precursor compounds is now easily accessible. As a proof of principle, a one-pot N- and O-transfer reaction for the formation of NH-sulfoximines from thioethersas earlier reported by Bull and Luisi73 was employed to obtain good to excellent yields of the sulfoximine products (12a−d, Scheme 5). The immediate synthetic utility of the developed thioetherification protocol with the Pd/PTABS catalytic system was, last, demonstrated with the efficient synthesis of an important immunosuppressant: Imuran (azathioprine).77 Azathioprine is a purine-based drug bearing a thioether linkage, which exhibits excellent immunosuppressant properties. It is administered commonly to patients undergoing kidney or liver transplantation as it helps to decrease the body immunity, which subsequently leads to a better acceptance of the transplanted organ.78 Using the Pd/PTABS-derived catalytic system, we envisaged the synthesis of azathioprine via the coupling of 5chloro-4-nitro-N-methylimidazole and 7-H purine-6-thiol, resulting in the formation of the desired product in a good yield (Scheme 6).

with the optimized protocol, resulting in good yields of the product (9e, Scheme 4). The thioetherification of purine derivatives provided crystalline material for 9h, which could be analyzed using single-crystal X-ray diffraction confirming the proposed molecular structure (see Supporting Information for detailed X-ray crystallography data). With a large variety of thioethers successfully synthesized, the question was raised whether it was possible to convert these coupled products into molecules of even further synthetic significance. Sulfones are important synthetic intermediates65 readily made available from thioethers via simple oxidation.66 A structural feature having commonly been found in a variety of drugs and, at the same time, providing easy access to a large number of chemically and biologically active molecules increases the appeal of sulfones.67,68 A few selected synthesized thioethers were subsequently converted into their sulfones in good yields by oxidation with meta-chloroperbenzoicacid (mCPBA)44 in dichloromethane as a solvent (11a−e, Scheme 5). As derivatives of sulfones, sulfoximines69,70 constitute another class of compounds obtained from thioethers. They are commonly found as critical structural motifs in medicinal71 and pharmaceutical chemistry.72,73 Their occurrence in commercially relevant anticancer drugs such as the pan-CDK

Scheme 6. Synthesis of Imuran (Azathioprine 15)a

Scheme 5. Conversion of Sulfides to Sulfones and Sulfoximinesa

a

Reaction conditions: 1.0 mmol of chloroheteroarene, 1.5 mmol of thiol, 1.0 mol % Pd(OAc)2, 2.0 mol % PTABS ligand, 3.0 mL of solvent, DMF stirred at 50 °C for 2 h. Isolated yield.

3. DENSITY FUNCTIONAL THEORY STUDIES In order to understand the mechanistic aspects of the present work, density functional theory (DFT) studies were carried out, and the relevant results are presented in Table 2. A total of seven P-ligand derivatives including PTA, PTABS, PTAPS, ionic derivatives like PTAB (representing PTABBr, PTABCl, and PTABI), and PTABBn were computationally investigated along with XPhos and SPhos to correlate the respective structures to the observed experimental reactivity. The effect of the halogen counterion X− (Cl−, Br−, and I−) was not addressed when the ionic PTABX and PTABBn derivatives were analyzed. Instead, these were considered as cationic species. The geometry optimizations for all derivatives were carried out at the B3LYP/6-31G(d,p) level of theory using the Gaussian16 program suit,79 and all positive second-order energy gradients confirmed the resulting structures as minima on the potential energy surfaces. The optimized geometries were further treated for natural population analysis (NPA) and the obtained molecular electrostatic potential (MEP) mapped to the total electronic density of the same. The calculated NPA charges on the phosphorus centers of the derivatives reveal the electropositivity of the P atom to be lowest of all derivatives in PTA. The respective charge, for instance, is 0.715 e in PTA, while ca. 0.822 e is found for PTABS and PTAPS derivatives

a

Reaction conditions for sulfone synthesis: 1.0 mmol of thioether, 2.5 mmol of mCPBA, 0 °C, 5.0 mL of DCM. Isolated yields. Reaction conditions for sulfoximines synthesis: 1.0 mmol of thioether, 3.0 mmol of PhI(OAc)2, 2.0 mmol of ammonium acetate, 4 mL of MeOH, room temperature. 8927

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

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Table 2. Computational Data Derived from the DFT Study Analyzing the Electronic Structures of the Phosphorus Ligands

a The MEP plotting ranges from −0.028 to 0.028 for PTA, XPhos, and SPhos, 0 to 0.160 for PTAB and PTABBn, −0.128 to 0.128 for PTAB,S and −0.114 to 0.114 for PTAPS. In the MEP drawing,s red indicates an electronegative and blue an electropositive nature.

Figure 2. Correlation between electronic on the phosphorus atom and catalytic reactivity.

and the ionic derivatives PTAB and PTABBn exhibit a charge of ca. 0.837 e on P. The most substantial positive charges were obtained for XPhos and SPhos with 0.864 and 0.874 e, respectively. With PTA and SPhos at both ends of the range but an equal catalytic efficiency, the charge on P cannot be directly related to the catalytic performance observed in the experimental thioether-

ifications. The computational study was therefore extended beyond the phosphorus atom. In order to explain the better performance (higher yields) in the C−S coupling reactions of PTA derivatives compared to PTA, XPhos, and SPhos, the MEPs were plotted. Notably, a small electronegative center (−0.028 au) is located around the phosphorus atom in PTA, whereas for all of the PTA derivatives this region is 8928

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

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Figure 3. Effect of phosphine electronics on the thioetherification of chloroheteroarenes.

results in either a weak or negligible reactivity, highlighting the crucial role of the directing group effect of the heteroatom in such catalytic reactions.

electropositive, i.e., 0.026, 0.015, 0.027, and 0.080 au for PTABS, PTAPS, PTAB and PTABBn, respectively. This can be attributed to the presence of the positive charge introduced to the PTA scaffold by substituting one of its nitrogen atoms (countered by halogen ions Cl−, Br−, I−, or the SO3− substituent) in the PTA derivatives. This marked difference suggests better π-accepting abilities of the phosphorus atom in the PTA derivatives, while in the case of the parent PTA, phosphorus and its vicinity are found to be electron-richer (i.e., P a better donor of electron density). This subtle change in the electronic structure around the phosphorus atom is hypothesized to have a profound effect on the coordination properties with the palladium center, which invariably affects the catalytic activity. Similarly to PTA, in the case of XPhos and SPhos, a small negative potential of −0.035 au was observed around the Pcenter, which is by the relatively lower yields in the catalyzed reaction. Thus, not only the charge directly at the phosphorus P-center but also the electrostatic potentials around it influence the interaction between the P-ligand and Pd precatalyst. These relations as depicted in Figure 2 provide an insight into the subtle effects of the ligand’s electronic structure on the catalytic activity where it involves the phosphorus donor atom. A derived model of the potential coordination characteristics of the various phosphines with the palladium center80,81 and the respective effect on the catalytic activity is represented in Figure 3. We propose that the more electron-rich phosphines (PTA, XPhos, and SPhos), in which the phosphorus atoms possess more electron density, would further enhance the nucleophilicity of the palladium center. Rather than insertion into the C−Cl bond of the chloroheteroarene reactants, the nucleophilic palladium might become stably coordinated by the heteroatoms of electron-poor heteroarenes (pyrazines, pyrimidines, and others), which is in accordance with the observed lower reactivity exhibited by these ligands. The electron-poorer phosphines (PTABS, PTAPS, PTABBn, and PTABX), on the other hand, in which phosphorus possesses less electron density, could act as stronger π-accepting ligands decreasing the nucleophilic character of the palladium center. With a slightly less nucleophilic palladium, the consequently weaker coordination by the heteroatom cannot compete permanently with the insertion into the C−Cl bond, which now takes place more efficiently, providing the desired products. The heteroatom, in this case, acts as a directing group providing the required weak coordination site to attract palladium, eventually allowing the oxidative addition to taking place via C−Cl bond cleavage. Such a proposition is particularly relevant in the case of heteroarenes bearing the C−Cl bond next to the heteroatom (2nd position relative to heteroatom). Any change in the position of the C−Cl bond

4. CONCLUSION In conclusion, we have developed a highly efficient catalytic protocol involving the Pd/PTABS system for the very reliable coupling of a wide variety of chloroheteroarenes to less reactive arylthiols and more reactive alkylthiols. It is possible to couple substrates even bearing labile functional groups as the reaction temperature could be kept much lower (50 °C) than in previously reported related reactions. The novel protocol facilitates access to a considerable variety of thioethers including the thioether analogue of the commercially available Alogliptin. The mild reaction conditions further allow the employment of temperature labile substrates such as purine and pyrimidines (as nucleobases and nucleosides) to be modified with high yields and without any deglycosylation observed. To demonstrate the synthetic utility of the developed catalytic protocol, Imuran (azathioprine), an immunosuppressive agent was synthesized in good yields. Some of the synthesized thiols were also converted into sulfones, and sulfoximines as their frequent occurrence in bioactive molecules emphasize the importance of respective reliable synthetic routes. The developed procedures expected to permit mild syntheses resulting in various target compounds and the assembly of respective libraries for combinatorial medicinal chemistry screening programs. Finally, to ascertain the influence of the ligand’s electronic structures on the palladium-catalyzed coupling process, DFT studies were performed on different ligands with the most reactive PTABS and related ionic ligands distinguishing themselves with a comparably more electropositive character by providing better reactivity than the electron-richer PTA, XPhos and SPhos. 5. EXPERIMENTAL SECTION 5.1. General. All of the reactions were performed under a nitrogen atmosphere using oven-dried standard Schlenk glassware. The completely dried N,N-dimethylformamide (DMF, 99.8%, extra dry, stored over molecular sieves) was purchased from Acros organics and used as received for all air- or moisture-sensitive reactions. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded either on an NMR EMAU Avance II-300 spectrometer or Agilent-400 MHz spectrometer. Chemical shifts δ are given in ppm, and the solvent residual peak (CDCl3 1H, δ = 7.27; 13C, δ = 77.0 and DMSO-d6 1H, δ = 2.50; 13C, δ = 40) was used as an internal standard. Peak multiplicities are specified as followed: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. APCI-MS (m/z) spectra were recorded on an Advion MS. Macherey-Nagel silica gel 60 F-254 plates were used for thin-layer chromatography (TLC), and detection was achieved by UV light. Column chromatography was performed on silica gel 60 (40−63 μm) or Acros Organics silica gel 60 (35−70 μm). 8929

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

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The Journal of Organic Chemistry

and 2,6-dimethylbenzenethiol (0.2 mL, 1.5 mmol, 1.5 equiv) to obtain the desired 2-(2,6-dimethylphenylthio)pyrazine (156 mg, 0.72 mmol, 72%) as a pale yellow oil. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 2.44 (s, 6H), 7.17−7.24 (m, 2H), 7.24−7.31 (m, 1H), 7.98 (d, J = 1.56 Hz, 1H), 8.18 (d, J = 2.57 Hz, 1H), 8.27−8.34 (m, 1H). 13C{1H} NMR (75 MHz, chloroform-d): δ 21.7 (s, 2C), 127.1 (s, 1C), 128.6 (s, 2C), 130.0 (s, 1C), 139.5 (s, 2C), 141.3 (s, 1C), 143.6 (s, 1C), 143.8 (s, 1C), 158.0 (s, 1C). (+)APCI-MS: m/z calcd for C12H12N2S [M], 216.07; found, 217.82 [M + H]. The compound exhibited identical 1H and 13C NMR data to the previous reports.83 2-(4-Chlorophenylthio)pyrazine (3c). A general procedure (GP1) was followed by using 2-chloropyrazine (2 mmol, 1 equiv) and 4chlorothiophenol (2.4 mmol, 1.2 equiv) to obtain the desired product (392 mg, 88%) as a pale colorless liquid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 8.32−8.28 (m, 1H), 8.23 (ddd, J = 5.9, 3.4, 2.1 Hz, 2H), 7.51−7.47 (m, 2H), 7.40−7.35 (m, 2H). 13C{1H} NMR (126 MHz, CDCl3): δ 157.6 (s), 143.9 (s), 142.8 (s), 140.5 (s), 136.2 (s), 135.9 (s), 130.0 (s), 127.4 (s). ESI-MS: m/z calcd for C10H7ClN2S [M], 222.69; found, 223.71 [M + H]. The compound exhibited identical 1H and 13C NMR data to the previous reports.84 2-(4-Fluorophenylthio)pyrazine (3d). A general procedure (GP1) was followed by using 2-chloropyrazine (2 mmol, 1 equiv) and 4fluorothiophenol (2.4 mmol, 1.2 equiv) to obtain the desired product (346 mg, 84%) as a colorless liquid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 8.29 (dd, J = 2.6, 1.6 Hz, 1H), 8.21 (d, J = 2.6 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 7.58−7.55 (m, 2H), 7.13−7.10 (m, 2H). 13C{1H} NMR (126 MHz, CDCl3): δ 163.7 (d, J = 240.8 Hz), 158.3 (s), 143.9 (s), 142.8 (s), 140.2 (s), 137.4 (d, J = 8.5 Hz), 123.9 (s), 117.0 (d, J = 24.0 Hz). ESI-MS: m/z calcd for C10H7FN2S [M], 206.24; found, 207.20 [M + H]. Methyl 2-(Pyrazin-2-ylthio)benzoate (3e). A general procedure (GP1) was followed by using 2-chloropyrazine (2 mmol, 1 equiv) and methyl-2-thiosalicylate (2.4 mmol, 1.2 equiv) to obtain the desired product (433 mg, 88%) as a colorless liquid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 8.44 (d, J = 3.4 Hz, 1H), 8.40 (dd, J = 2.4, 1.5 Hz, 1H), 8.32 (dd, J = 4.2, 2.9 Hz, 1H), 7.96−7.91 (m, 1H), 7.45−7.37 (m, 3H), 3.84 (d, J = 1.4 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 166.7 (s), 156.5 (s), 145.4 (s), 144.3 (s), 141.3 (s), 133.8 (s), 132.8 (d, J = 16.0 Hz), 132.3 (s), 131.0 (s), 128.1 (s), 52.4 (s). ESI-MS: m/z calcd for C12H10N2O2S [M], 246.05; found, 246.05 [M + H]. Anal. Calcd for C12H10N2O2S: C, 58.52; H, 4.09; N, 11.37; S, 13.02. Found: C, 58.62; H, 4.25; N, 11.25; S, 13.20. 2-(Pyrazin-2-ylthio)benzenamine (3f). A general procedure (GP1) was followed by using 2-chloropyrazine (0.89 mL, 1 mmol) and 2-aminobenzenethiol (0.160 mL, 1.5 mmol, 1.5 equiv) to obtain the desired 2-(pyrazin-2-ylthio)benzenamine (186 mg, 0.92 mmol, 92%) as a pale yellow oil. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 4.38 (br s, 2H), 6.72−6.90 (m, 2H), 7.23−7.34 (m, 1H), 7.49 (dd, J = 7.70, 1.56 Hz, 1H), 8.08 (d, J = 1.56 Hz, 1H), 8.23 (d, J = 2.57 Hz, 1H), 8.34 (dd, J = 2.57, 1.56 Hz, 1H). 13C{1H} NMR (75 MHz, chloroform-d): δ 115.6 (s, 1C), 119 (s, 2C), 132.2 (s, 2C), 137.5 (s, 1C), 140.0 (s, 1C), 141.9 (s, 1C), 143.7 (s, 1C), 149.2 (s, 1C). (+)APCI-MS: m/z calcd for C10H9N3S [M], 203.05; found, 204.1 [M + H]. The compound exhibited identical 1H and 13C NMR data to previous reports.85 4-(Pyrazin-2-ylthio)benzenamine (3g). A general procedure (GP1) was followed by using 2-chloropyrazine (2 mmol, 1 equiv) and 4-aminothiophenol (2.4 mmol, 1.2 equiv) to obtain a desired product (353 mg, 87%) as a pale yellow solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 8.31−8.28 (m, 1H), 8.16 (d, J = 2.6 Hz, 1H), 8.08 (d, J = 1.3 Hz, 1H), 7.38−7.35 (m, 2H), 6.71 (dd, J = 8.9, 2.2 Hz, 2H), 3.99 (s, 2H). 13C{1H} NMR (126 MHz, CDCl3): δ 160.5 (s), 148.3 (s), 143.5 (s), 141.9 (s), 139.4 (s), 137.2 (s), 116.0

The single X-ray crystal structure experiments were conducted by using “STOE IPDS2T” and a diffraction source with a fine-focus sealed molybdenum tube. An ElementarVario MICRO cube was used for the experimental determination of elemental configurations of final pure products. HRMS was performed using a Q-TOF mass analyzer and by using the Supporting Information method. 5.2. Crystal Structures and Crystallographic Information. Suitable single crystals of 3i, 3u, and 9h were mounted on a thin glass fiber coated with paraffin oil. X-ray single-crystal structural data were collected at a low temperature (170 K) equipped with a normal-focus, 2.4 kW, sealed-tube X-ray source with graphite-monochromatic Mo Kα radiation (λ = 0.71073 Å). The program X-Area was used for integration of diffraction profiles; the numerical absorption correction was made with the programs X-shape and X-red;31 the structures were solved by SIR929 and refined by full-matrix least-squares methods using SHELXL-2013.29 All other hydrogen atoms were refined with a constraint on the displacement parameter but freely concerning the position. All calculations were carried out using SHELXL-201329 and WinGX GUI, Ver 2013.2.30 Crystallographic data are summarized in the Supporting Information. 5.3. General Procedure (GP1). To a 25 mL oven-dried Schlenk tube were added 1 mol % Pd(OAc)2, 2 mol % PTABS (ligand, phosphoadamantinebutylsaltone), and 1 mmol of a chloroheteroarene derivative under a N2 atmosphere, and the resultant mixture was dissolved in 3 mL of dry DMF. The reaction mixture was stirred for 5 min, and 1.2−1.5 equiv of the corresponding thiophenol and 2.0−2.5 equiv of K3PO4 were added followed by stirring at 50 °C for 1−2 h. After consumption of the starting material (monitored by TLC/TLCMS), the solvent was removed in a vacuum, and the resultant residue obtained was purified by column chromatography in the hexane/ethyl acetate (10−50%) solvent system to afford the desired product. In the case of nucleoside derivatives of purine and pyrimidine substrates (7a−e and 9a−9p), CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 5.4. General Procedure for Thioether Oxidation to Sulfones (GP2). In a clean and dry Schlenk tube, thioether (1 mmol) was dissolved in DCM (5 mL). The solution cooled to 0 °C, and then mCPBA (2.5 equiv in 3 mL of DCM) was added dropwise at 0 °C. The reaction was then stirred at room temperature until the complete conversion is reached (progress checked by TLC). The mixture was washed with a saturated aqueous solution of Na2S2O3 (3 × 10 mL). After separation, the organic layers were washed with a saturated aqueous solution of sodium bicarbonate (3 × 5 mL). The organic phase was dried over Na2SO4. The organic solvent was evaporated to get the corresponding sulfones. 5.5. General Procedure for Thioether Oxidation to Sulfoximine (GP3). In a clean Schlenk tube, thioether (1 mmol), PhI(OAc)2 (3 mmol), and ammonium acetate (2 mmol) were diluted in MeOH (4 mL) at room temperature. The mixture was stirred until complete conversion was reached (progress checked by TLC). The solvent was evaporated under reduced pressure by using a rota evaporator. The residue was then purified by silica gel column chromatography to get the corresponding sulfoximine. 5.6. Substrate Scope for Palladium-Catalyzed Thioetherification of Chloroheteroarenes. 2-(Phenylthio)pyrazine (3a). A general procedure (GP1) was followed by using 2-chloropyrazine (0.89 mL, 1 mmol) and thiophenol (0.123 mL, 1.2 mmol, 1.2 equiv) to obtain the desired 2-(phenylthio)pyrazine (165 mg, 0.88 mmol, 88%) as a pale pink oil. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 7.37−7.50 (m, 3H), 7.56−7.66 (m, 2H), 8.21 (dd, J = 5.96, 2.02 Hz, 2H), 8.29−8.36 (m, 1H). 13C{1H} NMR (75 MHz, chloroform-d): δ 129.3 (s, 1C), 129.9 (s, 1C), 130.1 (s, 2C), 135.3 (s, 2C), 140.4 (s, 1C), 143.0 (s, 1C), 144.1 (s, 1C), 158.9 (s, 1C). APCIMS: m/z calcd for C10H8N2S [M] 188.04; found, 189.12 [M + H]. The compound exhibited identical 1H and 13C NMR data to the previous reports.82 2-(2,6-Dimethylphenylthio)pyrazine (3b). A general procedure (GP1) was followed by using 2-chloropyrazine (0.89 mL, 1 mmol) 8930

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

Article

The Journal of Organic Chemistry (s), 115.1 (s). ESI-MS: m/z calcd for C10H9N3S [M], 203.26; found, 204.25 [M + H]. HRMS: m/z calcd for C10H10N3S [M + H], 204.0589; found, 204.0589. 2-(Pyridin-2-ylthio)pyrazine (3h). A general procedure (GP1) was followed by using 2-chloropyrazine (2 mmol, 1 equiv) and 2thiopyridine (2.4 mmol, 1.2 equiv) to obtain a desired product (287 mg, 76%) as a solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 8.58 (d, J = 1.5 Hz, 1H), 8.46−8.43 (m, 1H), 8.39 (dd, J = 3.7, 2.1 Hz, 1H), 8.33−8.29 (m, 1H), 7.59 (tdd, J = 6.5, 4.2, 2.3 Hz, 1H), 7.43−7.39 (m, 1H), 7.15−7.11 (m, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 154.6 (s), 154.5 (s), 150.4 (s), 146.3 (s), 144.3 (s), 141.8 (s), 137.3 (s), 126.2 (s), 122.4 (s). ESI-MS: m/z calcd for C9H7N3S [M], 189.04; found, 190.06 [M + H]. The compound exhibited identical 1H and 13C NMR data to previous reports.86 2-(Phenylthio)quinoxaline (3i). A general procedure (GP1) was followed by using 2-chloroquinoxaline (146 mg, 1 mmol) and thiophenol (0.154 mL, 1.5 mmol, 1.5 equiv) to obtain the desired 2(phenylthio)quinoxaline (222 mg, 0.93 mmol, 93%) as colorless needles. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 7.45−7.51 (m, 3H), 7.63−7.73 (m, 4H), 7.88−7.92 (m, 1H), 7.97− 8.03 (m, 1H), 8.44 (s, 1H). 13C{1H} NMR (75 MHz, chloroform-d): δ 128.2 (s, 1C), 128.7 (s, 2C), 128.9 (s, 1C), 129.1 (s, 1C), 129.6 (s, 2C), 129.7 (s, 1C), 130.4 (s, 1C), 134.9 (s, 1C), 139.83 (s, 1C), 142.1 (s, 1C), 143.4 (s, 1C), 157.1 (s, 1C). (+)APCI-MS: m/z calcd for C14H10N2S [M], 238.06; found, 239.09 [M + H]. Anal. Calcd for C14H10N2S: C, 70.56; H, 4.23; N, 11.76; S, 13.46. Found: C, 70.51; H, 4.19; N, 11.71, S, 13.41. The X-ray single-crystal structure was measured. The compound exhibited identical 1H and 13C NMR data to previous reports.87 2-(2,6-Dimethylphenylthio)quinoxaline (3j). A general procedure (GP1) was followed by using 2-chloroquinoxaline (146 mg, 1 mmol) and 2,6-dimethylbenzenethiol (0.2 mL, 1.5 mmol, 1.5 equiv) to obtain the desired 2-(2,6-dimethylphenylthio)quinoxaline (234 mg, 0.88 mmol, 88%) as a colorless solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 2.49 (s, 6H), 7.23−7.28 (m, 2H), 7.30−7.36 (m, 1H), 7.68 (dd, J = 8.21, 1.70 Hz, 1H), 7.64 (dd, J = 8.12, 1.60 Hz, 1H), 7.88−7.92 (m, 1H), 7.97−8.03 (m, 1H), 8.26 (s, 1H). 13C{1H} NMR (75 MHz, chloroform-d): δ 21.9 (s, 2C), 127.1 (s, 1 C), 128 (s, 2C), 128.2 (s, 1C), 128.6 (s, 1C), 129.0 (s, 2C), 130.1 (s, 1C), 130.3 (s, 1C), 139.6 (s, 1C), 142.2 (s, 1C), 142.3 (s, 1C), 143.8 (s, 1C), 156.7 (s, 1C). (+)APCI-MS: m/z calcd for C16H14N2S [M], 266.09; found, 267.1 [M + H]. Anal. Calcd for C16H14N2S: C, 72.15; H, 5.30; N, 10.52; S, 12.04. Found: C, 72.09; H, 5.26; N, 10.59; S, 12.34. 4-(Quinoxalin-2-ylthio)benzenamine (3k). A general procedure (GP1) was followed by using 2-chloroquinoxaline (2 mmol, 1 equiv) and 4-aminothiophenol (2.4 mmol, 1.2 equiv) to obtain the desired product (461 mg, 91%) as a pale yellow solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 8.36 (d, J = 1.4 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.90 (dd, J = 8.4, 1.4 Hz, 1H), 7.70−7.66 (m, 1H), 7.63− 7.60 (m, 1H), 7.47−7.45 (m, 1H), 7.44 (t, J = 1.7 Hz, 1H), 6.77− 6.76 (m, 1H), 6.75 (t, J = 1.7 Hz, 1H), 3.96 (s, 2H). 13C{1H} NMR (126 MHz, CDCl3): δ 159.0 (s), 148.2 (s), 142.8 (s), 142.0 (s), 139.5 (s), 137.1 (s), 130.3 (s), 129.1 (s), 128.2 (s), 128.0 (s), 116.0 (s), 115.3 (s). (+)APCI-MS: m/z calcd for C14H11N3S [M], 253.07; found, 254.2 [M + H]. Anal. Calcd for C14H11N3S: C, 66.38; H, 4.38; N, 16.59; S, 12.66. Found: C, 66.44; H, 4.30; N, 16.50; S, 12.51. 2-(Quinoxalin-2-ylthio)benzenamine (3l). A general procedure (GP1) was followed by using 2-chloroquinoxaline (146 mg, 1 mmol) and 2-aminobenzenethiol (0.160 mL, 1.5 mmol, 1.5 equiv) to obtain the desired 2-(quinoxalin-2-ylthio)benzenamine (212.5 mg, 0.84 mmol, 84%) as a yellow oil. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 4.46 (s, 2H), 6.62−6.71 (m, 1H), 6.74−6.86 (m, 2H), 7.18−7.35 (m, 1H), 7.56−7.71 (m, 2H), 7.86−7.93 (m, 1H), 7.94−7.99 (m, 1H), 8.27−8.35 (m, 1H). 13C{1H} NMR (75 MHz, DMSO-d6): δ 115.5 (s, 1C), 117.8 (s, 1C), 118.7 (s, 1C), 127.8 (s,

1C), 128.4 (s, 1C), 129 (s, 1C), 130.2 (s, 1C), 131.3 (s, 1C), 132 (s, 1C), 139.6 (s, 1C), 142.3 (s, 1C), 149.3 (s, 1C), 156.3 (s, 1C). (+)APCI-MS: calcd for C14H11N3S [M], 253.07; found, 254.62 [M + H]. Anal. Calcd for C14H11N3S: C, 66.38; H, 4.38; N, 16.59; S, 12.66. Found: C, 66.42; H, 4.28; N, 16.45; S, 12.66. Methyl 2-(Quinoxalin-2-ylthio)benzoate (3m). A general procedure (GP1) was followed by using 2-chloroquinoxaline (2 mmol, 1 equiv) and methyl-2-thiosalicylate (2.4 mmol, 1.2 equiv) to obtain the desired product (515 mg, 87%) as a pale colorless liquid. Hexane/ ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 8.59 (d, J = 1.6 Hz, 1H), 8.02−7.97 (m, 2H), 7.91−7.89 (m, 1H), 7.71−7.64 (m, 2H), 7.59−7.56 (m, 1H), 7.49−7.42 (m, 2H), 3.80 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 166.8 (s), 155.6 (s), 145.1 (s), 142.2 (s), 140.1 (s), 134.3 (s), 133.2 (s), 132.3 (s), 131.9 (s), 131.1 (s), 130.5 (s), 129.1 (s), 129.2 (s), 128.4 (s), 128.5 (s), 52.41 (s). ESI-MS: m/z calcd for C16H12N2O2S [M], 296.34; found, 297.38 [M + H]. HRMS: calcd for C16H12N2NaO2S [M + Na], 319.0511; found, 319.0514. 2-(Benzo[d]thiazol-2-ylthio)quinoxaline (3n). A general procedure (GP1) was followed by using 2-chloroquinoxaline (2 mmol, 1 equiv) and 2-mercapto benzothiazole (2.4 mmol, 1.2 equiv) to obtain the desired product (443 mg, 75%) as a pale yellow solid. Hexane/ ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 8.93−8.90 (m, 1H), 8.13−8.10 (m, 2H), 8.04−8.01 (m, 1H), 7.90 (ddd, J = 4.1, 2.7, 2.1 Hz, 1H), 7.79 (ddd, J = 9.3, 8.6, 5.1 Hz, 2H), 7.51 (tdd, J = 4.9, 4.3, 1.2 Hz, 1H), 7.45−7.41 (m, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 159.7 (s), 152.2 (s), 151.3 (s), 144.6 (s), 142.1 (s), 140.7 (s), 136.1 (s), 130.9 (s), 130.0 (s), 129.4 (s), 128.4 (s), 126.4 (s), 125.4 (s), 122.7 (s), 121.1 (s). Anal. Calcd for C15H9N3S2: C, 60.99; H, 3.07; N, 14.23; S, 21.71. Found: C, 60.74; H, 3.06; N, 14.44; S, 21.53. 2-(4-Chlorophenylthio)benzo[d]thiazole (3o). A general procedure (GP1) was followed by using 2-chlorobenzothiazole (2 mmol, 1 equiv) and 4-chlorothiophenol (2.4 mmol, 1.2 equiv) to obtain a desired product (472 mg, 85%) as a colorless liquid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1 H NMR (500 MHz, CDCl3): δ 7.90−7.87 (m, 1H), 7.67−7.63 (m, 3H), 7.44 (m, 1H), 7.43−7.38 (m, 2H), 7.30−7.26 (m, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 168.4 (s), 153.8 (s), 136.9 (s), 136.4 (s), 135.5 (s), 130.2 (s), 128.3 (s), 126.3 (s), 124.5 (s), 122.0 (s), 120.9 (s). ESI-MS: m/z calcd for C13H8ClNS2 [M], 276.98; found, 279.1[M + H]. The compound exhibited identical 1H and 13C NMR data to previous reports.88 2-(4-Methoxyphenylthio)benzo[d]thiazole (3p). A general procedure (GP1) was followed by using 2-chlorobenzothiazole (2 mmol, 1 equiv) and 4-methoxythiophenol (2.4 mmol, 1.2 equiv) to obtain the desired product (481 mg, 88%) as a pale yellow solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1 H NMR (500 MHz, CDCl3): δ 7.86−7.83 (m, 1H), 7.65 (dd, J = 4.2, 1.0 Hz, 1H), 7.64−7.63 (m, 1H), 7.62−7.60 (m, 1H), 7.40−7.35 (m, 1H), 7.22 (ddd, J = 7.4, 6.4, 1.1 Hz, 1H), 7.00−6.99 (m, 1H), 6.98− 6.96 (m, 1H), 3.85 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 172.0 (s), 161.7 (s), 154.2 (s), 137.6 (s), 135.4 (s), 126.1 (s), 124.1 (s), 121.7 (s), 120.8 (s), 120.1 (s), 115.5 (s), 55.5 (s). ESI-MS: m/z calcd for C14H11NOS2 [M], 273.03; found, 274.01 [M + H]. The compound exhibited identical 1H and 13C NMR data to previous reports.89 2-(Naphthalen-1-ylthio)benzo[d]thiazole (3q). A general procedure (GP1) was followed by using 2-chloro benzothiazole (2 mmol, 1 equiv) and 1-naphthylthiol (2.4 mmol, 1.2 equiv) to obtain the desired product (521 mg, 89%) as a white solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 8.53−8.47 (m, 1H), 8.09−8.05 (m, 2H), 7.94 (dq, J = 7.0, 3.5 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.59−7.55 (m, 3H), 7.52 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 11.4, 4.0 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 170.1 (s), 153.9 (s), 136.4 (s), 135.5 (s), 134.5 (s), 134.3 (s), 132.2 (s), 128.7 (s), 127.9 (s), 126.9 (s), 126.8 (s), 126.1 (s), 125.9 (s), 125.5 (s), 124.1 (s), 121.8 (s), 120.7 (s). ESI-MS: m/z 293.40 calcd for 8931

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

Article

The Journal of Organic Chemistry

chloroform-d): δ 13.9 (s, 1C), 22.4 (s, 1C), 27.9 (s, 1C), 28.1 (s, 1C), 68.4 (s, 1C), 123.1 (s, 1C), 125.6 (s, 1C), 125.9 (s, 1C), 126.4 (s, 1C), 126.8 (s, 1C), 127.7 (s, 1C), 128.8 (s, 1C), 131.3 (s, 1C), 134.3 (s, 1C), 134.5 (s, 1C), 135.5 (s, 1C), 149.2 (s, 1C), 152.7 (s, 1C), 154.6 (s, 1C), 160.6 (s, 1C), 166.9 (s, 1 C). Anal. Calcd for C21H21N5OS: C, 64.43; H, 5.41; N, 17.89; S, 8.19. Found: C, 64.55; H, 5.60; N, 17.95; S, 8.33. 2,4,6-Tris(phenylthio)-1,3,5-triazine (3w). A general procedure (GP1) was followed by using 2,4,6-trichloro-1,3,5-triazine (185 mg, 1 mmol) and thiophenol (0.310 mL, 3.2 mmol, 3.2 equiv) to obtain the desired 2,4,6-tris(phenylthio)-1,3,5-triazine (388 mg, 0.96 mmol, 96%) as a low melting solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 7.16−7.25 (m, 6H), 7.26−7.40 (m, 9H); 13C{1H} NMR (75 MHz, chloroform-d): δ 126.9 (s, 1C), 128.9 (s, 1C), 129.3 (s, 1C), 134.8 (s, 1C), 180.2 (s, 1C). (+)APCI-MS: m/z calcd for C21H15N3S3 [M], 405.04; found, 406.2 [M + H]. Anal. Calcd for C21H15N3S3: C, 62.19; H, 3.73; N, 10.36; S, 23.72. Found: C, 62.14; H, 3.69; N, 10.35; S, 23.75. 2,4,6-Tris((4-fluorophenyl)thio)-1,3,5-triazine (3x). A general procedure (GP1) was followed by using 2,4,6-trichloro-1,3,5-triazine (1 mmol, 1 equiv) and 4-fluorothiophenol (3.2 mmol, 3.2 equiv) to obtain the desired product (418 mg, 91%) as a white solid. Hexane/ ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, chloroform-d): δ 6.94−7.05 (m, 6H), 7.31−7.37 (m, 4H), 7.37−7.42 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d): δ 116.9−116.7 (d, J = 22.7 Hz), 122.5 (d, J = 2.5 Hz), 137.8 (d, J = 7.6 Hz), 164.7−162.7 (d, J = 253.3 Hz), 171.7 (s). Anal. Calcd for C21H12F3N3S3: C, 54.89; H, 2.63; N, 9.14; S, 20.93. Found: C, 54.64; H, 2.88; N, 9.06; S, 20.71. 2-(Pentafluorophenylthio)benzo[d]thiazole (3y). A general procedure (GP1) was followed by using 2-chlorobenzothiazole (2 mmol, 1 equiv) and pentafluorothiophenol (2.4 mmol, 1.2 equiv) to obtain the desired product (566 mg, 85%) as a pale yellow solid. Hexane/ ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 7.87 (dd, J = 8.2, 2.9 Hz, 1H), 7.75 (t, J = 7.0 Hz, 1H), 7.46−7.42 (m, 1H), 7.37−7.33 (m, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 162 (s), 161.1 (s), 153.2−152.9 (m), 148.9−148.3 (m), 148.1 (m), 147.9−147.5 (m), 146.9−146.6 (m), 146.6−146 (m), 145.8−145.4 (m), 144.5 (m), 143.9−143.6 (m), 142.4 (m), 141.9−141.5 (m), 137.2−136.8 (m), 135.8 (m), 126.6−126.4 (m), 125.4−125.1 (m), 122.5 (m), 121.1 (m), 104.4 (m), 104.3−104.3 (m). Anal. Calcd for C13H4F5NS2: C, 46.85; H, 1.21; N, 4.20; S, 19.24. Found: C, 46.75; H, 1.29; N, 4.40; S, 19.50. 2-(Pentafluorophenylthio)pyrazine (3z). A general procedure (GP1) was followed by using 2-chloropyrazine (2 mmol, 1 equiv) and pentafluorothiophenol (2.4 mmol, 1.2 equiv) to obtain the desired product (451 mg, 81%) as a pale yellow solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1 H NMR (500 MHz, CDCl3): δ 8.57 (t, J = 3.2 Hz, 1H), 8.34 (dd, J = 7.3, 2.5 Hz, 1H), 8.30−8.27 (m, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 161.9 (s), 161.0 (s), 153.0 (d), 148.9−148.2 (m), 148.2− 147.8 (m), 147.8−147.4 (m), 146.9−146.2 (m), 146.2−145.8 (m), 145.8−145.3 (m), 144.7−144.2 (m), 142.6−142.2 (m), 139.2−138.7 (m), 137.2−136.7 (m), 135.7 (d), 126.5 (d), 125.4−125.0 (m), 122.5 (d), 121.0 (d); Anal. Calcd for C10H3F5N2S: C, 43.17; H, 1.09; N, 10.07; S, 11.52. Found: C, 43.21; H, 1.11; N, 10.19; S, 11.66. 2-(Ethylthio)pyrazine (5a). A general procedure (GP1) was followed by using 2-chloropyrazine (0.89 mL, 1 mmol) and ethanethiol (0.110 mL, 1.5 mmol, 1.5 equiv) to obtain the desired 2-(ethylthio)pyrazine (125 mg, 0.89 mmol, 89%) as a colorless oil. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 1.33 (t, J = 7.34 Hz, 3H), 3.13 (q, J = 7.37 Hz, 2H), 8.13 (d, J = 2.66 Hz, 1H), 8.29 (dd, J = 2.61, 1.60 Hz, 1H), 8.38 (d, J = 1.56 Hz, 1H). 13C{1H} NMR (75 MHz, chloroform-d): δ 14.31 (s, 1C), 23.8 (s, 1C), 139.0 (s, 1C), 143.6 (s, 1C), 143.7 (s, 1C), 157.1 (s, 1C). (+)APCI-MS: m/ z calcd for C6H8N2S [M], 140.04; found, 141.19 [M + H]. The

C17H11NS2 [M], 293.40; found, 294.45 [M + H]. The compound exhibited identical 1H and 13C NMR data to previous reports.90 2-(4-(Benzo[d]thiazol-2-ylthio)phenoxy)benzo[d]thiazole (3r). A general procedure (GP1) was followed by using 4-hydroxy-1thiophenol (1.2 mmol, 0.55 equiv) and 2-chlorobenzothiazole (2 mmol, 1 equiv) to obtain the desired product (689 mg, 88%) as a white solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 7.83 (d, J = 8.1 Hz, 1H), 7.77−7.73 (m, 2H), 7.72−7.69 (m, 1H), 7.67−7.61 (m, 2H), 7.48−7.45 (m, 2H), 7.36 (dd, J = 7.9, 7.5 Hz, 2H), 7.27− 7.21 (m, 2H). 13C{1H} NMR (126 MHz, CDCl3): δ 170.5 (s), 156.1 (s), 153.8 (s), 148.7 (s), 137.0 (s), 135.5 (s), 132.3 (s), 127.0 (s), 126.4 (s), 126.2 (s), 125.9 (s), 124.4 (s), 122.0 (s), 121.9 (s), 121.73 (s), 121.4 (s), 120.8 (s), 120.6 (s). ESI-MS: m/z calcd for C20H12N2OS3 [M], 392.01; found, 393.12 [M + H]. Anal. Calcd for C20H12N2OS3: C, 61.20; H, 3.08; N, 7.14; S, 24.51. Found: C, 61.17; H, 3.01; N, 7.19; S, 24.47. 4-(Benzo[d]thiazol-2-ylthio)benzenamine (3s). A general procedure (GP1) was followed by using 2-chlorobenzothiazole (2 mmol, 1 equiv) and 4-aminothiophenol (2.4 mmol, 1.2 equiv) to obtain the desired product (439 mg, 85%) as a pale yellow solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1 H NMR (500 MHz, CDCl3): δ 7.87−7.80 (m, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.53−7.44 (m, 2H), 7.37 (ddd, J = 11.2, 4.1, 3.0 Hz, 1H), 7.25−7.19 (m, 1H), 6.75−6.69 (m, 2H), 4.06 (s, 2H). 13C{1H} NMR (126 MHz, CDCl3): δ 173.5 (s), 154.3 (s), 149.1 (s), 137.6 (s), 135.3 (s), 126.0 (s), 123.8 (s), 121.5 (s), 120.7 (s), 116.3 (s), 115.9 (s). ESI-MS: m/z calcd for C13H10N2S2 [M], 258.36; found, 259.35 [M + H]. The compound exhibited identical 1H and 13C NMR data to previous reports.91,92 2-(4-Fluorophenylthio)benzo[d]thiazole (3t). A general procedure (GP1) was followed by using 2-chlorobenzothiazole (2 mmol, 1 equiv) and 4-fluoro thiophenol (2.4 mmol, 1.2 equiv) to obtain the desired product (391 mg, 75%) as a colorless liquid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1 H NMR (500 MHz, CDCl3): δ 7.87 (m, 1H), 7.77−7.71 (m, 2H), 7.69−7.65 (m, 1H), 7.44−7.39 (m, 1H), 7.31−7.26 (m, 1H), 7.22− 7.16 (m, 2H). 13C{1H} NMR (126 MHz, CDCl3): δ 169.6 (s), 165.2 (d, J = 252 Hz), 153.9 (s), 137.8 (d, J = 8.8 Hz), 135.4 (s), 126.2 (s), 125.0 (d, J = 3.5 Hz), 124.4 (s), 121.9 (s), 120.8 (s), 117.3 (s), 117.2 (s). The compound exhibited identical 1H and 13C NMR data to previous reports.93 ESI-MS: m/z calcd for C13H8FNS2 [M], 261.33; found, 262.21 [M + H]. The compound exhibited identical 1H and 13 C NMR data to previous reports.94 2,4-Bis(phenylthio)pyrimidine (3u). A general procedure (GP1) was followed by using 2,4-dichloropyrimidine (149 mg, 1 mmol) and thiophenol (0.225 mL, 2.2 mmol, 2.2 equiv) to obtain the desired 2,4bis(phenylthio)pyrimidine (275 mg, 0.93 mmol, 93%) as colorless cubes. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 6.45 (d, J = 5.41 Hz, 1H), 7.33−7.50 (m, 6H), 7.50−7.60 (m, 4H), 8.08 (d, J = 5.41 Hz, 1H). 13C{1H} NMR (75 MHz, chloroform-d): δ 112.5 (s, 1C), 127.2 (s, 1C), 128.6 (s, 1C), 128.6 (s, 1C), 128.8 (s, 1C), 129.3 (s, 1C), 129.5 (s, 1C), 134.6 (s, 1C), 135.1 (s, 1C), 155.5 (s, 1C), 171.5 (s, 1C), 172.7 (s, 1C). (+)APCI-MS: m/z calcd for C16H12N2S2 [M], 296.04; found, 297.10 [M + H]. Anal. Calcd for C16H12N2S2: C, 64.83; H, 4.08; N, 9.45; S, 21.64. Found: C, 64.78; H, 4.04; N, 9.41, S, 21.59. The X-ray single-crystal structure was confirmed. The compound exhibited identical 1H and 13C NMR data to previous reports.95 7-(Naphthalen-1-ylthio)-4-(pentyloxy)pteridin-2-amine (3v). A general procedure (GP1) was followed by using chloropterin (2 mmol, 1 equiv) and 1-naphthylthiol (2.4 mmol, 1.2 equiv) to obtain the desired product (633 mg, 81%) as a yellow solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1 H NMR (500 MHz, chloroform-d): δ 0.93−0.98 (m, 3H), 1.39−1.44 (m, 4H), 1.86−1.92 (m, 2H), 4.53 (t, J = 6.97 Hz, 2H), 5.35 (br s, 2H), 7.51−7.58 (m, 3H), 7.91−7.96 (m, 1H), 7.97−8.03 (m, 2H), 8.10 (s, 1H), 8.36 (d, J = 7.76 Hz, 1H). 13C{1H} NMR (126 MHz, 8932

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

Article

The Journal of Organic Chemistry compound exhibited identical 1H and 13C NMR data to previous reports.96 2-(Dodecylthio)pyrazine (5b). A general procedure (GP1) was followed by using 2-chloropyrazine (2 mmol, 1 equiv) and 1dodecylthiol (2.4 mmol, 1.2 equiv) to obtain the desired product (493 mg, 88%) as a solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 8.42 (d, J = 1.5 Hz, 1H), 8.33 (dd, J = 2.6, 1.5 Hz, 1H), 8.16 (d, J = 2.6 Hz, 1H), 3.16−3.13 (m, 2H), 1.69 (dt, J = 15.0, 7.5 Hz, 2H), 1.42 (dd, J = 15.0, 7.4 Hz, 2H), 1.34−1.22 (m, 16H), 0.86 (t, J = 6.9 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 157.5 (s), 143.9 (s), 143.8 (s), 139.1 (s), 31.9 (s), 29.7 (s), 29.6 (s), 29.5 (s), 29.5 (s), 29.4 (s), 29.3 (s), 29.1 (d), 28.8 (s), 22.7 (s), 14.1 (s). ESI-MS: m/z calcd for C16H28N2S [M], 280.47; found, 281.45 [M + H]. The compound exhibited identical 1H and 13C NMR data to previous reports.97 2-Admantanethiopyrazine (5c). A general procedure (GP1) was followed by using 2-chloropyrazine (0.89 mL, 1 mmol) and admantanethiol (0.202 mg, 1.2 mmol, 1.2 equiv) to obtain the desired 2-admantanethiopyrazine (237 mg, 0.91 mmol, 91%) as a colorless solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 1.69 (t, J = 2.98 Hz, 6H), 1.98−2.17 (m, 10 H), 8.30 (d, J = 2.48 Hz, 1H), 8.43 (dd, J = 2.57, 1.56 Hz, 1H), 8.51 (d, J = 1.47 Hz, 1H). 13 C{1H} NMR (75 MHz, chloroform-d): δ 30.4 (s, 1C), 36.5 (s, 1C), 43.7 (s, 1C), 51.4 (s, 1C), 77.4 (s, 1C), 77.8 (s, 1C), 141.5 (s, 1C), 144.3 (s, 1C), 148.4 (s, 1C), 155.7 (s, 1C). (+)APCI-MS: m/z calcd for C14H18N2S [M], 246.12; found, 247.21 [M + H]. Anal. Calcd for C14H18N2S: C, 68.25; H, 7.36; N, 11.37; S, 13.01. Found: C, 68.21; H, 7.32; N, 11.34; S, 12.97. 2,4-Bis(sec-butylthio)pyrimidine (5d). A general procedure (GP1) was followed by using 2,4-dichloropyrimidine (0.149 mg, 1 mmol) and 2-butanethiol (0.269.3 mL, 2.5 mmol, 2.5 equiv) to obtain the desired 2,4-bis(sec-butylthio)pyrimidine (230.8 mg, 0.90 mmol, 90%) as a pale yellow low melting solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 0.92−1.10 (m, 6H), 1.33−1.45 (m, 6H), 1.57−1.84 (m, 4H), 3.77 (qd, J = 6.79, 1.93 Hz, 1H), 3.92 (qd, J = 6.76, 2.11 Hz, 1H), 6.71 (d, J = 5.41 Hz, 1H), 8.04 (d, J = 5.41 Hz, 1H). 13C{1H} NMR (75 MHz, chloroform-d): δ 10.8 (s, 1C), 10.9 (s, 1C), 19.9 (s, 1C), 19.9 (s, 1C), 20.0 (s, 1C), 20.03 (s, 1C), 28.8 (s, 1C), 28.8 (s, 1C), 28.8 (s, 1 C),40.1 (s, 1C), 40.1 (s, 1C), 41.3 (s, 1C), 41.3 (s, 1C), 113.8 (s, 1C), 153.7 (s, 1C), 169.8 (s, 1C), 171.4 (s, 1C). (+)APCI-MS: m/z calcd for C12H20N2S2 [M], 256.11; found, 257.43 [M + H]. Anal. Calcd for C12H20N2S2: C, 56.21; H, 7.86; N, 10.92; S, 25.01. Found: C, 56.08; H, 7.56; N, 10.63; S, 25.21. 2-(2-Chlorobenzylthio)pyrazine (5e). A general procedure (GP1) was followed by using 2-chloropyrazine (2 mmol, 1 equiv) and 2chlorobenzylthiol (2.4 mmol, 1.2 equiv) to obtain the desired product (397 mg, 84%) as a white solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 8.43 (d, J = 1.5 Hz, 1H), 8.39 (dd, J = 2.6, 1.6 Hz, 1H), 8.21 (d, J = 2.7 Hz, 1H), 7.50 (dd, J = 7.1, 2.2 Hz, 1H), 7.38 (dd, J = 7.5, 1.7 Hz, 1H), 7.18 (ddd, J = 6.7, 5.6, 1.8 Hz, 2H), 4.54 (s, 2H). 13 C{1H} NMR (126 MHz, CDCl3): δ 156.2 (s), 143.8 (s), 143.7 (s), 139.6 (s), 135.1 (s), 134.3 (s), 131.0 (s), 129.6 (s), 128.8 (s), 126.8 (s), 31.4 (s). Anal. Calcd for C11H9ClN2S: C, 55.81; H, 3.83; N, 11.83; S, 13.54. Found: C, 55.48; H, 3.76; N, 12.01; S, 13.31. Admantanethio 2-Quinoxaline (5f). A general procedure (GP1) was followed by using 2-chloro quinoxaline (164 mg, 1 mmol) and 2butanethiol (0.38 mL, 2.5 mmol, 2.5 equiv) to obtain the desired 2adamantan-1-yl)thio)quinoxaline (266 mg, 0.90 mmol, 90%) as a white amorphous solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 1.71−1.88 (m, 6H), 2.12 (br s, 3H), 2.35 (d, J = 2.75 Hz, 6H), 7.60−7.76 (m, 2H), 7.91−8.06 (m, 2H), 8.57 (s, 1H). 13 C{1H} NMR (75 MHz, chloroform-d): δ 30.0 (s, 1C), 36.3 (s, 1C), 42.7 (s, 1C), 51.9 (s, 1 C),128.3 (s, 1C), 128.4 (s, 1C), 129.2 (s, 1C), 129.9 (s, 1C), 139.7 (s, 1C), 142.4 (s, 1C), 146.7 (s, 1C), 156.3 (s, 1C). (+)APCI-MS: m/z calcd for C18H20N2S [M], 296.13; found,

297.22 [M + H]. Anal. Calcd for C18H20N2S: C,72.93; H, 6.80; N, 9.45; S, 10.82. Found: C, 72.89; H, 6.75; N, 9.41; S, 10.80. 2-(Benzylthio)quinoxaline (5g). A general procedure (GP1) was followed by using 2-chloroquinoxaline (164 mg, 1 mmol) and benzylthiol (150 mg, 1.2 mmol, 1.2 equiv) to obtain the desired 2(benzylthio)quinoxaline (231 mg, 0.92 mmol, 92%) as a semisolid sticky material. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroformd): δ 4.58 (s, 2H), 7.20−7.34 (m, 3H), 7.44−7.50 (m, 2H), 7.57− 7.65 (m, 1H), 7.65−7.73 (m, 1H), 7.93−8.05 (m, 2H), 8.57 (s, 1H). 13 C{1H} NMR (75 MHz, chloroform-d): δ 33.6 (s, 1C), 76.6 (s, 1C), 127.3 (s, 1C), 127.7 (s, 1C), 128.0 (s, 1C), 128.5 (s, 1C), 129.1 (s, 1C), 129.2 (s, 1C), 130.1 (s, 1C), 137.3 (s, 1C), 139.9 (s, 1C), 142.6 (s, 1C), 144.5 (s, 1C), 155.6 (s, 1C). (+)APCI-MS: m/z calcd for C15H12N2S [M], 252.07; found, 253.1 [M + H]. Anal. calcd for C15H12N2S: C, 71.40; H, 4.79; N, 11.10; S, 12.71. Found: C, 71.38; H, 4.77; N, 11.07; S, 12.69. The compound exhibited identical 1H and 13 C NMR data to previous reports.98 2-(sec-Butylthio)quinoxaline (5h). A general procedure (GP1) was followed by using 2-chloroquinoxaline (82 mg, 0.5 mmol) and 2butanethiol (0.081 mL, 0.75 mmol, 1.5 equiv) to obtain the desired 2(sec-butylthio)quinoxaline (104 mg, 0.475 mmol, 95%) as a pale yellow solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 1.07 (t, J = 7.43 Hz, 3H), 1.47 (d, J = 6.88 Hz, 3H), 1.68−1.94 (m, 2H), 4.04−4.20 (m, 1H), 7.53−7.71 (m, 2H), 7.86−7.94 (m, 1H), 7.95−8.04 (m, 1H), 8.54 (s, 1H). 13C{1H} NMR (75 MHz, chloroform-d): δ 11.3 (s, 1C), 20.4 (s, 1C), 29.3 (s, 1C), 41.1 (s, 1C), 127.7 (s, 1C), 127.7 (s, 1C), 129.1 (s, 1C), 129.8 (s, 1C), 139.6 (s, 1C), 142.7 (s, 1C), 145.0 (s, 1C), 156.6 (s, 1C). (+)APCI-MS: m/ z calcd for C12H14N2S [M], 218.09; found: 219.17 [M + H]. Anal. calcd for C12H14N2S: C, 66.02; H, 6.46; N, 12.83; S, 14.69. Found: C, 65.97; H, 6.33; N, 12.96; S, 14.79. 2-(Dodecylthio)benzo[d]thiazole (5i). A general procedure (GP1) was followed by using 2-chlorobenzothizole (2 mmol, 1 equiv) and 1dodecylthiol (2.4 mmol, 1.2 equiv) to obtain the desired product (577 mg, 86%) as a white solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, chloroform-d): δ 0.88−0.91 (m, 3H), 1.25−1.31 (m, 16 H), 1.45− 1.51 (m, 2H), 1.79−1.85 (m, 3H), 3.34 (t, J = 7.58 Hz, 2H), 7.23− 7.32 (m, 1H), 7.39−7.45 (m, 1H), 7.75 (d, J = 7.83 Hz, 1H), 7.87 (d, J = 8.31 Hz, 1H). 13C{1H} NMR (126 MHz, chloroform-d): δ 14.3 (s, 1C), 22.9 (s, 1C), 28.9 (s, 1C), 29.2 (s, 1C), 29.3 (s, 1C), 29.3 (s, 1C), 29.5 (s, 1C), 29.5 (s, 1C), 29.6 (s, 1C), 29.7 (s, 1C), 29.7 (s, 1C), 29.8 (s, 1C), 29.8 (s, 1C), 32.1 (s, 1C), 33.8 (s, 1C), 77.2 (s, 1C), 77.5 (s, 1C), 121.0 (s, 1C), 121.2 (s, 1C), 121.6 (s, 1C), 124.2 (s, 1C), 126.1 (s, 1C), 135.3 (s, 1C), 153.5 (s, 1C), 167.6 (s, 1C). ESI-MS: m/z calcd for C19H29NS2 [M], 335.57; found, 336.60 [M + H]. The compound exhibited identical 1H and 13C NMR data to previous reports.99 tert-Butyl 2-(Benzo[d]thiazol-2-ylthio)ethylcarbamate (5j). A general procedure (GP1) was followed by using 2-chlorobenzothiazole (2 mmol, 1 equiv) and tert-butyl (2-mercaptoethyl)carbamate (2.4 mmol, 1.2 equiv) to obtain the desired product (527 mg, 85%) as a white solid. Hexane/ethyl acetate (7:3) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 7.85 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.43−7.40 (m, 1H), 7.32− 7.28 (m, 1H), 3.58 (dd, J = 11.9, 5.9 Hz, 2H), 3.48 (t, J = 6.1 Hz, 2H), 1.64 (d, J = 18.9 Hz, 1H), 1.42 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3): δ 166.2 (s), 155.8 (s), 153.0 (s), 135.3 (s), 126.0 (s), 124.3 (s), 121.4 (s), 120.9 (s), 79.4 (s), 40.3 (s), 33.5 (s), 28.3 (s). ESI-MS: m/z calcd for C14H18N2O2S2 [M], 310.43; found, 311.08 [M + H]. The compound exhibited identical 1H and 13C NMR data to previous reports.100 6-(4-Methoxyphenylthio)pyrimidine-2,4(1H,3H)-dione (7a). A general procedure (GP1) was followed by using 6-chloro uracil (2 mmol, 1 equiv) and 4-methoxy thiophenol (2.4 mmol, 1.2 equiv) to obtain the desired product (430 mg, 86%) as a white solid. CHCl3/ MeOH (9:1) was used as a mobile phase for column chromatography. 1 H NMR (500 MHz, DMSO-d6): δ 11.54 (s, 1H), 10.93 (s, 1H), 7.53 8933

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

Article

The Journal of Organic Chemistry (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 4.41 (d, J = 1.6 Hz, 1H), 3.80 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6): δ 162.6 (s), 161.7 (s), 158.5 (s), 151.2 (s), 138.1 (s), 116.3 (s), 116.2 (s), 95.2 (s), 55.9 (s). (+)APCI-MS: m/z calcd for C11H10N2O3S [M], 250.04; found, 251.22 [M + H]. Anal. Calcd for C11H10N2O3S: C, 52.79; H, 4.03; N, 11.19; S, 12.81. Found: C, 52.72; H, 4.09; N, 11.11; S, 12.76. 6-(2-Chlorobenzylthio)pyrimidine-2,4(1H,3H)-dione (7b). A general procedure (GP1) was followed by using 6-chlorouracil (2 mmol, 1 equiv) and 2-chlorobenzylthiol (2.4 mmol, 1.2 equiv) to obtain the desired product (439 mg, 82%) as a pale yellow solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, DMSO-d6): δ 4.36 (s, 2H), 5.53 (d, J = 1.47 Hz, 1H), 7.33−7.39 (m, 2H), 7.48−7.53 (m, 1H), 7.54−7.59 (m, 1H), 10.98 (s, 1H), 11.34 (s, 1H). 13C{1H} NMR (126 MHz, DMSO-d6): δ 32.8 (s, 1C), 96.4 (s, 1C), 127.8 (s, 1C), 129.9 (s, 1C), 130.1 (s, 1C), 131.6 (s, 1C), 132.9 (s, 1C), 133.5 (s, 1C), 150.9 (s, 1C), 154.2 (s, 1C), 162.6 (s, 1C). (+)APCI-MS: m/z calcd for C11H9ClN2O2S [M], 268.01; found, 269.18 [M + H]. Anal. Calcd for C11H9ClN2O2S: C, 49.17; H, 3.38; N, 10.42; S, 11.93. Found: C, 49.15; H, 3.34; N, 10.49; S, 11.99. 3-Methyl-6-(phenylthio)pyrimidine-2,4(1H,3H)-dione (7c). A general procedure (GP1) was followed by using 6-chloro-3-methylpyrimidine-2,4(1H,3H)-dione (160.6 mg, 1 mmol) and thiophenol (0.154 mL, 1.5 mmol, 1.5 equiv) to obtain the desired 3-methyl-6(phenylthio)pyrimidine-2,4(1H,3H)-dione (168 mg, 0.72 mmol, 72%) as a colorless solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, DMSO-d6): δ 3.05 (s, 3H), 4.69 (s, 1H), 7.46−7.68 (m, 5H), 11.84 (br s, 1H). 13 C{1H} NMR (75 MHz, DMSO-d6): δ 26.9 (s, 1C), 39.2 (s, 1C), 39.8 (s, 1 C), 96.0 (s, 1C), 126.7 (s, 1C), 130.8 (s, 1C), 131.3 (s, 1C), 136 (s, 1C), 151.5 (s, 1C), 155.2 (s, 1C), 161.9 (s, 1C). (+)APCIMS: m/z calcd for C11H10N2O2S [M], 234.05; found, 234.05 [M + H]. Anal. Calcd for C11H10N2O2S: C, 56.39; H, 4.30; N, 11.96; S, 13.69. Found: C, 56.35; H, 4.26; N, 11.90; S, 13.66. 2-((3-Methyl-2,4-dioxo-6-(phenylthio)-3,4-dihydropyrimidin1(2H)-yl)methyl)benzonitrile (7d). A general procedure (GP1) was followed by using 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (137.5 mg, 0.5 mmol) and thiophenol (0.077 mL, 0.75 mmol, 1.5 equiv) to obtain the desired 2-((3-methyl-2,4-dioxo-6-(phenylthio)-3,4-dihydropyrimidin-1(2H)yl)methyl)benzonitrile (140 mg, 0.78 mmol, 78%) as a white solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 3.31 (s, 3H), 5.10 (s, 1H), 5.52 (s, 2H), 7.19−7.26 (m, 1H), 7.37−7.52 (m, 6H), 7.56−7.64 (m, 1H), 7.69 (dd, J = 7.70, 1.01 Hz, 1H). 13C{1H} NMR (75 MHz, chloroform-d): δ 28 (s, 1C), 47 (s, 1C), 98.5 (s, 1C), 110.8 (s, 1C), 116.7 (s, 1C), 125.6 (s, 1C), 126.0 (s, 1C), 128.1 (s, 1C), 130.4 (s, 1C), 131.2 (s, 1C), 133.1 (s, 1C), 133.2 (s, 1C), 135.8 (s, 1C), 139.2 (s, 1C), 151.7 (s, 1C), 157.1 (s, 1C), 160.7 (s, 1C). (+)APCI-MS: m/z calcd for C19H15N3O2S [M], 349.09; found, 350.2 [M + H]. Anal. Calcd for C19H15N3O2S: C, 65.31; H, 4.33; N, 12.03; S, 9.18. Found: C, 65.29; H, 4.28; N, 12.00; S, 9.15. 2-((6-(sec-Butylthio)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin1(2H)-yl)methyl)benzonitrile (7e). A general procedure (GP1) was followed by using 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (137.5 mg, 0.5 mmol) and 2butanethiol (0.081 mL, 0.75 mmol, 1.5 equiv) to obtain the desired 2((6-(sec-butylthio)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl)methyl)benzonitrile (250 mg, 0.76 mmol, 76%) as a colorless solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 0.87−1.01 (m, 3H), 1.33 (d, J = 6.69 Hz, 3H), 1.45−1.78 (m, 2H), 3.13−3.26 (m, 1H), 3.33 (s, 3H), 5.42 (s, 2H), 5.66 (s, 1H), 7.11 (d, J = 7.98 Hz, 1H), 7.32−7.41 (m, 1H), 7.49−7.58 (m, 1H), 7.65 (dd, J = 7.70, 1.01 Hz, 1H). 13C{1H} NMR (75 MHz, chloroform-d): δ 11.00 (s, 1C), 19.5 (s, 1C), 28.5 (s, 1C), 32.8 (s, 1C), 36.3 (s, 1C), 44.9 (s, 1C), 97.8 (s, 1C), 110.8 (s, 1C), 116.7 (s, 1C), 125.8 (s, 1C), 127.8 (s, 1C), 133 (s, 1C), 133 (s, 1C), 139.4 (s, 1C), 151.8 (s, 1C), 155.1 (s, 1C), 160.7 (s, 1C). (+)APCI-MS: m/z calcd for C17H19N3O2S [M], 329.12; found, 330.19 [M + H]. Anal. Calcd for C17H19N3O2S:

C, 61.98; H, 5.81; N, 12.76; S, 9.73. Found: C, 61.92; H, 5.80; N, 12.80; S, 9.71. 6-(Pyridin-2-ylthio)-9H-purin-2-amine (9a). A general procedure (GP1) was followed by using 2-amino-6-chloropurine (2 mmol, 1 equiv) and 2-thiopyridine (2.4 mmol, 1.2 equiv) to obtain the desired product (405 mg, 83%) as a white solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, DMSO-d6): δ 6.41 (br s, 2H), 7.29−7.38 (m, 1H), 7.74−7.87 (m, 2H), 7.96 (s, 1H), 8.50 (d, J = 4.16 Hz, 1H), 12.66 (br s, 1H). 13 C{1H} NMR (126 MHz, DMSO-d6): δ 122.8 (s, 1C), 124.7 (s, 1C), 128.3 (s, 1C), 137.3 (s, 1C), 140.1 (s, 1C), 149.9 (s, 1C), 153.1 (s, 1C), 153.9 (s, 1C), 156.1 (s, 1C), 160 (s, 1C). ESI-MS: m/z 244.05 m/z calcd for C10H8N6S [M]; found, 245.08 [M + H]. The compound exhibited identical 1H and 13C NMR data to previous reports.101 6-(Dodecylthio)-9H-purin-2-amine (9b). A general procedure (GP1) was followed by using 2-amino-6-chloro purine (2 mmol, 1 equiv) and 1-dodecylthiol (2.4 mmol, 1.2 equiv) to obtain the desired product (570 mg, 85%) as a white solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, DMSO-d6): δ 12.48 (s, 3H), 7.85 (s, 3H), 6.27 (s, 6H), 3.22 (t, J = 7.2 Hz, 6H), 1.64−1.58 (m, 7H), 1.39−1.33 (m, 7H), 1.26−1.18 (m, 48H), 0.81 (t, J = 6.9 Hz, 9H). 13C{1H} NMR (126 MHz, DMSO-d6): δ 164.7 (s), 164.1 (s), 156.7 (s), 143.8 (s), 129.1 (s), 36.5 (s), 34.5 (s), 34.3−34.1 (4C), 33.9 (2C), 33.4 (s), 32.5 (s), 27.3 (s), 19.1 (s). Anal. Calcd for C17H29N5S: C, 60.86; H, 8.71; N, 20.87; S, 9.56. Found: C, 60.75; H, 8.79; N, 20.76; S, 9.24. The compound exhibited identical 1H and 13C NMR data to previous reports.102,103 6-(4-Chlorophenylthio)-9H-purin-2-amine (9c). A general procedure (GP1) was followed by using 2-amino-6-chloro purine (2 mmol, 1 equiv) and 4-chlorothiophenol (2.4 mmol, 1.2 equiv) to obtain the desired product (511 mg, 92%) as a white solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, DMSO-d6): δ 12.60 (s, 1H), 7.93 (s, 1H), 7.60 (ddd, J = 5.6, 3.4, 1.8 Hz, 2H), 7.48 (ddd, J = 6.6, 3.5, 1.8 Hz, 2H), 6.25 (s, 2H). 13C{1H} NMR (126 MHz, DMSO-d6): δ 160.1 (s), 157.5 (s), 152.7 (s), 139.9 (s), 136.90 (s), 134.2 (s), 129.5 (s), 127.5 (s), 123.8 (s). ESI-MS: m/z calcd for C11H8ClN5S [M], 277.73; found, 278.70 [M + H]. The compound exhibited identical 1H and 13C NMR data to previous reports.104 2-(2-Amino-6-(dodecylthio)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (9d). A general procedure (GP1) was followed by using 2-amino-6-chloro purine riboside (2 mmol, 1 equiv) and 1-dodecylthiol (2.4 mmol, 1.2 equiv) to obtain the desired product (739 mg, 79%) as a pale yellow solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, DMSO-d6): δ 8.16 (s, 1H), 6.47 (s, 2H), 5.77 (d, J = 5.9 Hz, 1H), 5.41 (d, J = 6.0 Hz, 1H), 5.14 (d, J = 4.8 Hz, 1H), 5.08 (t, J = 5.6 Hz, 1H), 4.45 (dd, J = 11.0, 5.9 Hz, 1H), 4.09 (dd, J = 8.4, 4.8 Hz, 1H), 3.88 (q, J = 3.8 Hz, 1H), 3.64−3.60 (m, 1H), 3.52 (ddd, J = 11.9, 5.8, 4.0 Hz, 1H), 3.24 (t, J = 7.0 Hz, 2H), 1.63 (dt, J = 14.8, 7.3 Hz, 2H), 1.40−1.34 (m, 2H), 1.27−1.19 (m, 15H), 0.82 (t, J = 6.9 Hz, 3H). 13C{1H} NMR (126 MHz, DMSO-d6): δ 160.3 (s), 159.9 (s), 151.2 (s), 139.1 (s), 124.6 (s), 86.9 (s), 85.7 (s), 73.9 (s), 70.7 (s), 61.7 (s), 31.7 (s), 29.7 (s), 29.63−29.36 (4C), 29.2 (s), 29.1 (s), 28.7 (s), 27.8 (s), 22.5 (s), 14.4 (s). Anal. Calcd for C22H37N5O4S: C, 56.51; H, 7.98; N, 14.98; S, 6.86. Found: C, 56.37; H, 7.99; N, 14.70; S, 6.50. 4-(Dodecylthio)-7H-pyrrolo[2,3-d]pyrimidine (9e). A general procedure (GP1) was followed by using 6-chloro-7-deazapurine (1 mmol, 1 equiv) and 1-dodecylthiol (1.2 mmol, 1.2 equiv) to obtain the desired product (267 mg, 85%) as pale yellow solid. CHCl3/ MeOH (9:1) was used as a mobile phase for column chromatography. 1 H NMR (500 MHz, DMSO-d6): δ 12.11 (s, 1H), 8.53 (s, 1H), 7.43 (dd, J = 3.3, 2.5 Hz, 1H), 6.42 (dd, J = 3.5, 1.8 Hz, 1H), 3.28 (t, J = 7.3 Hz, 2H), 1.69−1.63 (m, 2H), 1.41−1.35 (m, 2H), 1.22 (d, J = 16.1 Hz, 15H), 0.82 (t, J = 6.9 Hz, 3H). 13C{1H} NMR (126 MHz, DMSO-d6): δ 159.8 (s), 150.7 (s), 149.2 (s), 126.0 (s), 115.5 (s), 98.7 (s), 31.7 (s), 29.6 (s), 29.4 (d), 29.3 (s), 29.3 (s), 29.1 (s), 28.9 (s), 28.6 (s), 28.2 (s), 22.5 (s), 14.4 (s). Anal. Calcd for C18H29N3S: 8934

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

Article

The Journal of Organic Chemistry

3.97 (d, J = 3.61 Hz, 1H), 4.14−4.22 (m, 1H), 4.59 (d, J = 5.26 Hz, 1H), 5.13 (t, J = 5.53 Hz, 1H), 5.24 (d, J = 4.95 Hz, 1H), 5.53 (d, J = 5.93 Hz, 1H), 5.99 (d, J = 5.56 Hz, 1H), 8.70 (s, 1H), 8.71−8.74 (m, 1H). 13C{1H} NMR (126 MHz, DMSO-d6): δ 14.1 (s, 1C), 22.2 (s, 1C), 27.9 (s, 1C), 28.3 (s, 1C), 28.7 (s, 1C), 28.9 (s, 1C), 29.1 (s, 1C), 29.1 (s, 1C), 29.1 (s, 1C), 29.2 (s, 1C), 29.2 (s, 1C), 31.4 (s, 1C), 61.4 (s, 1C), 70.4 (s, 1C), 73.9 (s, 1C), 85.8 (s, 1C), 87.9 (s, 1C), 131.3 (s, 1C), 143.3 (s, 1C), 148.2 (s, 1C), 151.6 (s, 1C), 160.2 (s, 1C). Anal. Calcd for C22H36N4O4S: C, 58.38; H, 8.02; N, 12.38; S, 7.08. Found: C, 58.31; H, 8.20; N, 12.22; S, 7.21. (2R,3S,4R,5R)-2-(6-(Cyclohexylthio)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol (9l). A general procedure (GP1) was followed by using 6-chloropurine riboside (2 mmol, 1 equiv) and cyclohexanethiol (2.4 mmol, 1.2 equiv) to obtain the desired product (578 mg, 79%) as a pale yellow solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, DMSO-d6): δ 1.23−1.34 (m, 1H), 1.38−1.62 (m, 5H), 1.66−1.77 (m, 2H), 2.01−2.11 (m, 2H), 3.53−3.63 (m, 1H), 3.70 (dt, J = 11.65, 4.17 Hz, 1H), 3.98 (d, J = 3.48 Hz, 1H), 4.12−4.24 (m, 2H), 4.60 (q, J = 5.36 Hz, 1H), 5.15 (t, J = 5.35 Hz, 1H), 5.25 (d, J = 4.77 Hz, 1H), 5.55 (d, J = 5.81 Hz, 1H), 6.00 (d, J = 5.50 Hz, 1H), 8.70 (s, 1H), 8.72 (s, 1H). 13C{1H} NMR (126 MHz, DMSO-d6): δ 25.0 (s, 1C), 25.3 (s, 1C), 32.5 (s, 1C), 32.6 (s, 1C), 61.1 (s, 1C), 70.1 (s, 1C), 73.7 (s, 1C), 85.5 (s, 1C), 87.7 (s, 1C), 130.9 (s, 1C), 143.0 (s, 1C), 148.0 (s, 1C), 151.4 (s, 1C), 159.8 (s, 1C). Anal. Calcd for C16H22N4O4S: C, 52.44; H, 6.05; N, 15.29; S, 8.75. Found: C, 52.48; H, 5.91; N, 15.45; S, 8.55. (2R,3R,4S,5R)-2-(Hydroxymethyl)-5-(6-(phenylthio)-9H-purin-9yl)-tetrahydrofuran-3,4-diol (9m). A general procedure (GP1) was followed by using 6-chloropurinriboside (287 mg, 1 mmol) and thiophenol (0.154 mL, 1.5 mmol, 1.5 equiv) to obtain the desired (2R,3R,4S,5R)-2-(hydroxymethyl)-5-(6-(phenylthio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol (237 mg, 0.69 mmol, 69%) as a fluffy white solid. CHCl/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, DMSO-d6): δ 3.58 (s, 1H), 3.67 (br s, 1H), 3.98 (d, J = 3.85 Hz, 1H), 4.18 (br s, 1H), 4.56−4.65 (m, 1H), 5.15 (br s, 1H), 5.27 (br s, 1H), 5.55 (br s, 1H), 5.99 (d, J = 5.59 Hz, 1H), 7.46−7.55 (m, 3H), 7.60−7.70 (m, 2H), 8.58 (s, 1H), 8.76 (s, 1H). 13C{1H} NMR (75 MHz, DMSO-d6): δ 61.0 (s, 1C), 70.0 (s, 1C), 73.6 (s, 1C), 85.5 (s, 1C), 87.7 (s, 1C), 126.4 (s, 1C), 129.39 (s, 1C), 129.5 (s, 1C), 130.4 (s, 1C), 135.3 (s, 1C), 143.5 (s, 1C), 148.4 (s, 1C), 151.5 (s, 1C), 158.9 (s, 1C). (+)APCI-MS: m/z calcd for C16H16N4O3S [M], 360.09; found, 361.19 [M + H], 227.1 [M-sugar]. C16H16N4O4S: C, 53.32; H, 4.47; N, 15.55; S, 8.90 Found: C, 53.29; H, 4.41; N, 15.59; S, 8.93. (2R,3S,4R,5R)-2-(2-Amino-6-(ethylthio)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol (9n). A general procedure (GP1) was followed by using 6-chloro purine riboside (2 mmol, 1 equiv) and ethylthiol (2.4 mmol, 1.2 equiv) to obtain the desired product (509 mg, 86%) as a white solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, DMSO-d6): δ 8.72 (s, 1H), 8.69 (s, 1H), 5.97 (d, J = 5.6 Hz, 1H), 5.53 (d, J = 6.0 Hz, 1H), 5.24 (d, J = 5.0 Hz, 1H), 5.12 (t, J = 5.6 Hz, 1H), 4.58 (dd, J = 10.9, 5.6 Hz, 1H), 4.16 (dd, J = 8.7, 4.8 Hz, 1H), 3.95 (q, J = 3.8 Hz, 1H), 3.69−3.64 (m, 1H), 3.55 (ddd, J = 11.9, 6.0, 4.0 Hz, 1H), 3.34−3.30 (m, 2H), 1.33 (d, J = 7.3 Hz, 3H). 13 C{1H} NMR (126 MHz, DMSO-d6): δ 160.3 (s), 151.9 (s), 148.5 (s), 143.6 (s), 131.6 (s), 88.1 (s), 86.1 (s), 74.1 (s), 70.6 (s), 61.6 (s), 22.8 (s), 15.3 (s). ESI-MS: m/z calcd for C12H16N4O4S [M], 312.09; found, 313.21 [M + H]. The compound exhibited identical 1H and 13 C NMR data to previous reports.107 (2R,3S,4R,5R)-2-(6-(sec-Butylthio)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol (9o). A general procedure (GP1) was followed by using 6-chloropurinriboside (287 mg, 1 mmol) and 2-butanethiol (0.162 mL, 1.5 mmol, 1.5 equiv) to obtain the desired (2R,3S,4R,5R)-2-(6-(sec-butylthio)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol (224 mg, 0.66 mmol, 66%) as a colorless oil. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, chloroform-d): δ 0.64 (td, J = 7.36, 1.70 Hz, 3H), 1.05 (d, J = 6.79 Hz, 3H), 1.23−1.50 (m, 2H),

C, 67.67; H, 9.15; N, 13.15; S, 10.03. Found: C, 67.66; H, 9.20; N, 13.11; S, 10.20. 6-(Ethylthio)-9H-purine (9f). A general procedure (GP1) was followed by using 6-chloro purine (2 mmol, 1 equiv) and ethylthiol (2.4 mmol, 1.2 equiv) to obtain the desired product (121 mg, 67%) as a white solid.CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.41 (s, 1H), 3.31 (q, J = 7.3 Hz, 2H), 1.34 (t, J = 7.3 Hz, 3H). 13 C{1H} NMR (126 MHz, DMSO-d6): δ 158.5 (s), 151.9 (s), 150.6 (s), 143.7 (s), 130.1 (s), 22.8 (s), 15.4 (s). ESI-MS: m/z calcd for C7H8N4S [M], 180.23; found, 181.20 [M + H]. The compound exhibited identical 1H and 13C NMR data to previous reports.102 6-(Dodecylthio)-9H-purine (9g). A general procedure (GP1) was followed by using 6-chloro purine (2 mmol, 1 equiv) and 1dodecylthiol (2.4 mmol, 1.2 equiv) to obtain the desired product (416 mg, 65%) as a white solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, DMSO-d6): δ 13.45 (s, 1H), 8.63 (s, 1H), 8.38 (s, 1H), 3.31 (d, J = 8.0 Hz, 3H), 1.68−1.64 (m, 2H), 1.39−1.35 (m, 2H), 1.18 (s, 15H), 0.80 (t, J = 6.6 Hz, 3H). 13C{1H} NMR (126 MHz, DMSO-d6): δ 159.4 (s), 151.8 (s), 149.5 (s), 143.1 (s), 130.8 (s), 31.7 (s), 29.74−29.28 (5C), 29.1 (s), 29.0 (s), 28.6 (s), 28.1 (s), 22.5 (s), 14.3 (s). ESI-MS: m/z calcd for C17H28N4S [M], 320.50; found, 321.49 [M + H]. The compound exhibited identical 1H and 13C NMR data to previous reports.103 6-(Phenylthio)-9H-purine (9h). A general procedure (GP1) was followed by using 6-chloropurine (155 mg, 1 mmol) and thiophenol (0.154 mL, 1.5 mmol, 1.5 equiv) to obtain the desired 6-(phenylthio)9H-purine (203 mg, 0.89 mmol, 89%) as a white needle. CHCl3/ MeOH (9:1) was used as a mobile phase for column chromatography. 1 H NMR (300 MHz, DMSO-d6): δ 7.48−7.55 (m, 3H), 7.61−7.71 (m, 2H), 8.50 (s, 1H), 8.54 (s, 1H). 13C{1H} NMR (75 MHz, DMSO-d6): δ 127.1 (s, 1C), 129.5 (s, 1C), 129.6 (s, 1C), 135.5 (s, 1C), 144 (s, 1C), 151.7 (s, 1C). (+)APCI-MS: m/z calcd for C11H8N4S [M], 228.05; found, 229.31 [M + H]. Anal. Calcd for C11H8N4S: C, 57.88; H, 3.53; N, 24.54; S, 14.05. Found: C, 57.82; H, 3.49; N, 24.50; S, 14. The X-ray crystal structure was confirmed. The compound exhibited identical 1H and 13C NMR data to previous reports.105 6-(Pyridin-2-ylthio)-9H-purine (9i). A general procedure (GP1) was followed by using 6-chloropurine (2 mmol, 1 equiv) and 2thiopyridine (2.4 mmol, 1.2 equiv) to obtain the desired product (393 mg, 86%) as a white solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, DMSO-d6): δ 13.60 (s, 1H), 8.63 (s, 1H), 8.56−8.54 (m, 1H), 8.52 (s, 1H), 7.84 (ddd, J = 7.4, 1.9, 0.9 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.40 (ddd, J = 7.3, 4.8, 1.0 Hz, 1H). 13C{1H} NMR (126 MHz, DMSO-d6): δ 157.0 (s), 152.4 (s), 152.0 (s), 150.8 (s), 150.6 (s), 144.3 (s), 137.9 (s), 130.9 (s), 130.1 (s), 123.8 (s). ESI-MS: m/z calcd for C10H7N5S [M], 229.26; found, 230.20 [M + H]. The compound exhibited identical 1H and 13C NMR data to previous reports.101 6-(4-Chlorophenylthio)-9H-purine (9j). A general procedure (GP1) was followed by using 6-chloro purine (2 mmol, 1 equiv) and 4-chlorothiophenol (2.4 mmol, 1.2 equiv) to obtain the desired product (462 mg, 88%) as a white solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, DMSO-d6): δ 8.52 (s, 1H), 8.47 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H). 13C{1H} NMR (126 MHz, DMSO-d6): δ 157.5 (s), 156.8 (s), 156.7 (s), 156.0 (s), 149.0 (s), 142.3 (s), 139.7 (s), 134.5 (s), 131.2 (s). ESI-MS: m/z calcd for C11H7ClN4S [M], 262.72; found, 263.70 [M + H]. The compound exhibited identical 1 H and 13C NMR data to previous reports.106 2-(6-(Dodecylthio)-9H-purin-9-yl)-5-(hydroxymethyl)-tetrahydrofuran-3,4-diol (9k). A general procedure (GP1) was followed by using 6-chloropurine riboside (2 mmol, 1 equiv) and 1-dodecylthiol (2.4 mmol, 1.2 equiv) to obtain the desired product (687 mg, 76%) as a pale yellow solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, DMSO-d6): δ 0.83 (t, J = 6.60 Hz, 3H), 1.18−1.28 (m, 18 H) 1.40 (d, J = 6.85 Hz, 2H), 1.69 (t, J = 7.24 Hz, 2H), 3.53−3.60 (m, 1H), 3.65−3.72 (m, 1H), 8935

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

Article

The Journal of Organic Chemistry

1H), 9.12−9.31 (m, 1H). 13C{1H} NMR (126 MHz, chloroform-d): δ 116.7 (d, J = 25.2 Hz), 127.1 (d, J = 10.0 Hz), 140.8 (s), 143.8 (s), 143.9 (s), 145.8 (s), 161.3 (s), 164.6 (d, J = 253.2 Hz). Anal. Calcd for C10H7FN2O2S: C, 50.42; H, 2.96; N, 11.76; S, 13.46. Found: C, 50.31; H, 2.88; N, 11.50; S, 13.70. tert-Butyl 2-(Benzo[d]thiazol-2-ylsulfonyl)ethylcarbamate (11e). A general procedure (GP2) was followed by using tert-butyl (2(benzo[d]thiazol-2-ylsulfonyl)ethyl)carbamate (0.5 mmol, 1 equiv) and mCPBA (1.5 mmol, 3 equiv) to obtain the desired product (143 mg, 84%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (d, J = 8.0 Hz, 1H), 8.03 (dd, J = 8.0, 0.7 Hz, 1H), 7.63 (dtd, J = 15.1, 7.3, 1.2 Hz, 2H), 5.24 (s, 1H), 3.73 (d, J = 2.3 Hz, 4H), 1.33 (s, 9H). 13 C{1H} NMR (126 MHz, CDCl3): δ 165.6 (s), 155.4 (s), 152.6 (s), 136.7 (s), 128.2 (s), 127.7 (s), 125.5 (s), 122.3 (s), 79.9 (s), 55.0 (s), 34.7 (s), 28.1 (s). Anal. Calcd for C14H18N2O4S2: C, 49.11; H, 5.30; N, 8.18; S, 18.73. Found: C, 49.10; H, 5.20; N, 8.20; S, 18.50. Imino(phenyl)(quinoxalin-2-yl)-sulfanone (12a). A general procedure (GP3) was followed by using 2-(phenylthio)quinoxaline (0.5 mmol, 1 equiv) to obtain the desired product (115 mg, 85%) as a pale yellow solid. Hexane/ethyl acetate (5:5) was used as a mobile phase for column chromatography. 1H NMR (400 MHz, chloroform-d): δ 3.71 (br s, 1H), 7.52−7.65 (m, 3H), 7.83−7.91 (m, 2H), 8.14−8.27 (m, 4H), 9.58 (s, 1H). 13C{1H} NMR (101 MHz, chloroform-d): δ 129.6 (s, 1C), 129.63 (s, 1C), 130.4 (s, 1C), 131.8 (s, 1C), 132.9 (s, 1C), 133.9 (s, 1C), 140.2 (s, 1C), 141.2 (s, 1C), 142.5 (s, 1C), 143.2 (s, 1C), 154.8 (s, 1C). (+)APCI-MS: m/z calcd for C14H11N3OS [M], 269.32; found, 270.39 [M + H]. Anal. Calcd for C14H11N3OS:C, 62.43; H, 4.12; N, 15.60; S, 11.91. Found: C, 62.39; H, 4.19; N, 15.51; S, 11.97. Benzo[d]thiazol-2-yl(imino)(naphthalen-1-yl)-sulfanone (12b). A general procedure (GP3) was followed by using 2-(naphthalen-1ylthio)benzo[d]thiazole (0.5 mmol, 1 equiv) to obtain the desired product (137 mg, 85%) as a white solid. Hexane/ethyl acetate (5:5) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 9.15 (d, J = 8.7 Hz, 1H), 8.65 (d, J = 7.5 Hz, 1H), 8.06−8.02 (m, 2H), 7.81 (dd, J = 10.7, 8.4 Hz, 2H), 7.57 (t, J = 7.8 Hz, 2H), 7.49−7.37 (m, 3H), 3.97 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 170.0 (s), 152.5 (s), 137.7 (s), 135.8 (s), 134.8 (s), 134.4 (s), 131.2 (s), 129.0 (s), 128.9 (s), 128.3 (s), 127.4 (s), 127.1 (s), 126.9 (s), 125.4 (s), 125.3 (s), 124.4 (s), 122.0 (s). Anal. Calcd for C17H12N2OS2: C, 62.94; H, 3.73; N, 8.64; S, 19.76. Found: C, 62.84; H, 3.88; N, 8.60; S, 19.50. 2-(Dodecylsulfoimidolyl)pyrazine (12c). A general procedure (GP3) was followed by using 2-(dodecylthio)pyrazine (0.5 mmol, 1 equiv) to obtain the desired product (141 mg, 91%) as a white solid. Hexane/ethyl acetate (5:5) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 9.27 (d, J = 1.3 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.66 (dd, J = 2.3, 1.5 Hz, 1H), 3.33 (m, 3H), 2.93 (s, 1H), 1.77−1.73 (m, 1H), 1.66−1.61 (m, 1H), 1.32− 1.28 (m, 2H), 1.20 (m, 15H), 0.81 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 155.5 (s), 147.5 (s), 144.3 (s), 143.4 (s), 54.0 (s), 31.8 (s), 29.6 (s), 29.5 (d), 29.4 (s), 29.3 (s), 29.2 (s), 28.9 (s), 28.2 (s), 22.6 (s), 22.3 (s), 14.1 (s). Anal. Calcd for C16H29N3OS: C, 61.70; H, 9.38; N, 13.49; S, 10.29. Found: C, 61.87; H, 9.24; N, 13.44; S, 10.38. 2-(4-Chloropehylsulfoimidolyl)benzothiazole (12d). A general procedure (GP3) was followed by using 2-((4-chlorophenyl)thio)benzo[d]thiazole (0.5 mmol, 1 equiv) to obtain the desired product (121 mg, 79%) as a white solid. Hexane/ethyl acetate (5:5) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, CDCl3): δ 8.20−8.17 (m, 2H), 8.13 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.51 (dd, J = 7.2, 4.9 Hz, 3H), 3.77 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 170.0 (s), 152.9 (s), 140.7 (s), 137.92 (s), 137.8 (s), 130.6 (s), 129.6 (s), 127.6 (s), 127.4 (s), 125.3 (s), 122.1 (s). Anal. Calcd for C13H9ClN2OS2: C, 50.56; H, 2.94; N, 9.07; S, 20.76. Found: C, 50.40; H, 2.82; N, 9.11; S, 20.55. Azathiopurine (15). A general procedure (GP1) was followed by using 5-chloro-1-methyl-4-nitro-1H-imidazole (2 mmol, 1 equiv) and 6-thiopurine (2.4 mmol, 1.2 equiv) to obtain the desired product (470

3.29−3.44 (m, 1H), 3.46−3.56 (m, 1H), 3.80−3.91 (m, 2H), 3.99− 4.09 (m, 1H), 4.44 (t, J = 5.78 Hz, 2H), 5.00 (br s, 1H), 5.29 (d, J = 8.16 Hz, 1H), 5.62 (d, J = 6.69 Hz, 1H), 7.93 (s, 1H), 8.21 (s, 1H). 13 C{1H} NMR (75 MHz, chloroform-d): δ 10.3 (s, 1C), 10.4 (s, 1C), 19.9 (s, 1C), 28.5 (s, 1C), 28.6 (s, 1C), 39.4 (s, 1C), 39.4 (s, 1C), 61.8 (s, 1C), 70.8 (s, 1C), 73.4 (s, 1C), 86.4 (s, 1C), 89.5 (s, 1C), 131.5 (s, 1C), 142.1 (s, 1C), 146.6 (s, 1C), 150.1 (s, 1C). (+)APCIMS: m/z calcd for C14H20N4O4S [M], 340.12; found, 341.32 [M + H], 207.19 [M-ribose]. The compound exhibited identical 1H and 13 C NMR data to previous reports.107 (2R,3R,4S,5R)-2-(6-(Adamantan-1-ylthio)-9H-purin-9-yl)-5(hydroxymethyl)tetrahydrofuran-3,4-diol (9p). A general procedure (GP1) was followed by using 6-chloropurinriboside (287 mg, 1 mmol) and admantanethiol (300 mg, 1.8 mmol, 1.8 equiv) to obtain a desired purinribosidethio derivative (297 mg, 0.71 mmol, 71%) as a white solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (300 MHz, DMSO-d6): δ 1.54− 1.65 (m, 2H), 1.65−2.02 (m, 10H), 2.06 (br s, 3H), 3.53−3.63 (m, 1H), 3.66−3.76 (m, 1H), 3.93−4.04 (m, 1H), 4.19 (br s, 1H), 4.54− 4.67 (m, 1H), 5.11 (t, J = 5.46 Hz, 1H), 5.21 (br s, 1H), 5.44−5.59 (m, 1H), 5.99 (d, J = 5.50 Hz, 1H), 8.67 (d, J = 4.77 Hz, 2 H); 13 C{1H} NMR (75 MHz, DMSO-d6): δ 29.4 (s, 1C), 29.5 (s, 1C), 35.3 (s, 1 C), 42.1 (s, 1C), 46.9 (s, 1C), 50.8 (s, 1C), 61.2 (s, 1C), 70.3 (s, 1C), 73.8 (s, 1C), 85.7 (s, 1C), 87.8 (s, 1C), 131.3 (s, 1C), 142.9 (s, 1C), 148.2 (s, 1C), 150.8 (s, 1C), 161 (s, 1C). (+)APCIMS: m/z calcd for C20H26N4O4S [M], 418.17; found, 419.21 [M + H], 285.21 [M-ribose]. Anal. Calcd for C20H26N4O4S: C, 57.40; H, 6.26; N, 13.39; S, 7.66. Found: C, 57.35; H, 6.21; N, 13.33; S, 7.62. 2-(Phenylsulfonyl)quinoxaline (11a). A general procedure (GP2) was followed by using tert-butyl 2-(phenylthio)quinoxaline (0.5 mmol, 1 equiv) and mCPBA (1.5 mmol, 3 equiv) to obtain the desired product (237 mg, 88%) as a white solid. 1H NMR (300 MHz, chloroform-d): δ 7.42−7.52 (m, 3H), 7.78−7.92 (m, 4H), 8.08−8.19 (m, 2H), 9.42 (s, 1H). 13C{1H} NMR (75 MHz, chloroform-d): δ 129.0 (s, 1C), 129.3 (s, 1C), 129.4 (s, 1C), 129.4 (s, 1C), 129.5 (s, 1C), 131.2 (s, 1C), 131.4 (s, 1C), 139.8 (s, 1C), 141.1 (s, 1C), 142.7 (s, 1C), 143.0 (s, 1C), 160.0 (s, 1C). (+)APCI-MS: m/z calcd for C14H10N2O2S [M], 270.05; found, 271.39 [M + H]. Anal. Calcd for C14H10N2O2S: C, 62.21; H, 3.73; N, 10.36; S, 11.86. Found: C, 62.19; H, 3.69; N, 10.31; S, 11.82. The compound exhibited identical 1H and 13 C NMR data to previous reports.108 2-(Dodecylsulfonyl)benzo[d]thiazole (11b). A general procedure (GP2) was followed by using 2-(dodecylthio)benzo[d]thiazole (0.5 mmol, 1 equiv) to obtain the desired product (137 mg, 75%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.05 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.57−7.53 (m, 1H), 7.50−7.46 (m, 1H), 3.26−3.14 (m, 2H), 2.00−1.90 (m, 1H), 1.75−1.65 (m, 1H), 1.48− 1.39 (m, 2H), 1.30−1.21 (m, 16H), 0.86 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 177.8 (s), 153.9 (s), 135.9 (s), 126.8 (s), 126.0 (s), 123.8 (s), 122.2 (s), 56.7 (s), 31.8 (s), 29.6 (s), 29.5 (s), 29.4 (s), 29.3 (s), 29.2 (s), 29.0 (s), 28.5 (s), 22.6 (s), 21.5 (s), 14.1 (s). Anal. Calcd for C19H29NO2S2: C, 62.09; H, 7.95; N, 3.81; S, 17.44. Found: C, 62.15; H, 8.05; N, 3.75; S, 17.55. 2-(4-Fluorophenylsulfonyl)benzo[d]thiazole (11c). A general procedure (GP2) was followed by using 2-((4-fluorophenyl)thio)benzo[d]thiazole (0.5 mmol, 1 equiv) to obtain the desired product (118 mg, 81%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.21−8.16 (m, 2H), 8.15 (dd, J = 7.6, 1.0 Hz, 1H), 7.96 (dd, J = 7.5, 1.2 Hz, 1H), 7.56 (dtd, J = 15.0, 7.2, 1.3 Hz, 2H), 7.28−7.23 (m, 2H). 13 C{1H} NMR (126 MHz, CDCl3) δ 167.4 (s), 166.2 (d, J = 210.4 Hz), 152.8 (s), 136.9 (s), 131.9 (d, J = 10.0 Hz), 127.9 (s), 127.6 (s), 125.5 (s), 122.2 (s), 116.9 (d, J = 22.6 Hz). Anal. Calcd for C13H8FNO2S2: C, 53.23; H, 2.75; N, 6.48; S, 21.86. Found: C, 53.25; H, 2.88; N, 6.50; S, 21.71. 2-(4-Fluorophenylsulfonyl)pyrazine (11d). A general procedure (GP2) was followed by using 2-((4-fluorophenyl)thio)pyrazine (0.5 mmol, 1 equiv) to obtain the desired product (87 mg, 75%) as a pale yellow solid. 1H NMR (500 MHz, chloroform-d): δ 7.11−7.21 (m, 2H), 7.70−7.87 (m, 2H), 8.45−8.56 (m, 1H), 8.64 (d, J = 2.32 Hz, 8936

DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

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The Journal of Organic Chemistry mg, 85%) as a pale yellow solid. CHCl3/MeOH (9:1) was used as a mobile phase for column chromatography. 1H NMR (500 MHz, DMSO-d6): δ 13.76 (s, 1H), 8.56 (s, 1H), 8.54 (s, 1H), 8.23 (s, 1H), 3.68 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6): δ 152.1 (s), 152.9 (s), 150.1 (s), 145.1 (s), 144.9 (s), 139.9 (s), 139.7 (s), 117.6 (s), 33.4 (s). Anal. Calcd for C9H7N7O2S: C, 38.99; H, 2.54; N, 35.36; S, 11.56. Found: C, 39.10; H, 2.64; N, 35.45; S, 11.66. The compound exhibited identical 1H and 13C NMR data to previous reports.109

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(9) Arndt, K. E.; Bland, D. C.; Irvine, N. M.; Powers, S. L.; Martin, T. P.; McConnell, J. R.; Podhorez, D. E.; Renga, J. M.; Ross, R.; Roth, G. A.; et al. Development of a Scalable Process for the Crop Protection Agent Isoclast. Org. Process Res. Dev. 2015, 19, 454−462. (10) Ding, M.; Fan, J.; Zhang, Q.; Wang, X.; Zhao, Y.; Huang, M.; Zhang, Y.; Guo, Y.; Wang, Y. Semisynthesis and Insecticidal Activity of Some Novel Fraxinellone-Based Thioethers Containing 1,3,4Oxadiazole Moiety. R. Soc. Open Sci. 2017, 4, 171053. (11) Vendetti, F. P.; Clump, D. A.; O’Connor, M. J.; Cadogan, E.; Abberbock, S.; Leibowitz, B. J.; Kiesel, B. F.; Beumer, J. H.; Schamus, S.; Barnes, J.; et al. Pharmacologic ATM but Not ATR Kinase Inhibition Abrogates P21-Dependent G1 Arrest and Promotes Gastrointestinal Syndrome after Total Body Irradiation. Sci. Rep. 2017, 7, 1−12. (12) Honorato Pérez, J. Selexipag, a Selective Prostacyclin Receptor Agonist in Pulmonary Arterial Hypertension: A Pharmacology Review. Expert Rev. Clin. Pharmacol. 2017, 10, 753−762. (13) Kuhn, M.; Falk, F. C.; Paradies, J. Palladium-Catalyzed C−S Coupling: Access to Thioethers, Benzo[b]Thiophenes, and Thieno[3,2-b]Thiophenes. Org. Lett. 2011, 13, 4100−4103. (14) Cheng, J. H.; Ramesh, C.; Kao, H. L.; Wang, Y. J.; Chan, C. C.; Lee, C. F. Synthesis of Aryl Thioethers through the N -Chlorosuccinimide-Promoted Cross-Coupling Reaction of Thiols with Grignard Reagents. J. Org. Chem. 2012, 77, 10369−10374. (15) HERRIOTT, A. W.; PICKER, D. The Phase-Transfer Synthesis of Sulfides and Dithioacetals. Synthesis 1975, 1975, 447−448. (16) Feng, J.; Lu, G. P.; Cai, C. Selective Approach to Thioesters and Thioethers via Sp3 C-H Activation of Methylarenes. RSC Adv. 2014, 4, 54409−54415. (17) Nguyen, K. N.; Duus, F.; Luu, T. X. T. Benign and Efficient Preparation of Thioethers by Solvent-Free S-Alkylation of Thiols with Alkyl Halides Catalyzed by Potassium Fluoride on Alumina. J. Sulfur Chem. 2016, 37, 349−360. (18) Santoro, F.; Mariani, M.; Zaccheria, F.; Psaro, R.; Ravasio, N. Selective Synthesis of Thioethers in the Presence of a TransitionMetal-Free Solid Lewis Acid. Beilstein J. Org. Chem. 2016, 12, 2627− 2635. (19) Kosugi, M.; Ogata, T.; Terada, M.; Sano, H.; Migita, T. Palladium-Catalyzed Reaction of Stannyl Sulfide with Aryl Bromide. Preparation of Aryl Sulfide. Bull. Chem. Soc. Jpn. 1985, 58, 3657− 3658. (20) Kosugi, M.; Shimizu, T.; Migita, T. Reactions of Aryl Halides with Thiolate Anions in the Presence of Catalytic Amount of Tetrakis(Triphenylphosphine)Palladium Preperation of Aryl Sulfides. Chem. Lett. 1978, 7, 13−14. (21) Moreau, X.; Campagne, J.-M. Palladium Catalyzed Thiol CrossCoupling of Cystein Derivatives with Aryl and Alkenyl Halides. J. Organomet. Chem. 2003, 687, 322−326. (22) Itoh, T.; Mase, T. A General Palladium-Catalyzed Coupling of Aryl Bromides/Triflates and Thiols. Org. Lett. 2004, 6, 4587−4590. (23) Shah, S. T. A.; Khan, K. M.; Martinez Heinrich, A.; Voelter, W. An Alternative Approach towards the Syntheses of Thioethers and Thioesters Using CsF-Celite in Acetonitrile. Tetrahedron Lett. 2002, 43, 8281−8283. (24) Bandna; Guha, N. R.; Shil, A. K.; Sharma, D.; Das, P. LigandFree Solid Supported Palladium(0) Nano/Microparticles Promoted C−O, C−S, and C−N Cross Coupling Reaction. Tetrahedron Lett. 2012, 53, 5318−5322. (25) Kondo, T.; Mitsudo, T. Metal-Catalyzed Carbon−Sulfur Bond Formation. Chem. Rev. 2000, 100, 3205−3220. (26) Cai, L.; Cuevas, J.; Peng, Y. Y.; Pike, V. W. Rapid PalladiumCatalyzed Cross-Coupling in the Synthesis of Aryl Thioethers under Microwave Conditions. Tetrahedron Lett. 2006, 47, 4449−4452. (27) Dunleav, J. Platinum Met. Rev. 2006, 50, 110−110. (28) Kolpin, A.; Jones, G.; Jones, S.; Zheng, W.; Cookson, J.; York, A. P. E.; Collier, P. J.; Tsang, S. C. E. Quantitative Differences in Sulfur Poisoning Phenomena over Ruthenium and Palladium: An Attempt To Deconvolute Geometric and Electronic Poisoning Effects Using Model Catalysts. ACS Catal. 2017, 7, 592−605.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b00840.

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Crystallographic Crystallographic Crystallographic 1 H, 13C NMR, (PDF)

information for 3i (CIF) information for 3u (CIF) information for 9h (CIF) and HRMS spectra and crystal data

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Anant R. Kapdi: 0000-0001-9710-8146 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.R.K. and C.S. acknowledge The Alexander von Humboldt Foundation for the research cooperation program, which is also thanked for the equipment grant to A.R.K. A.R.K. also would like to thank DST SERB for providing a research grant (EMR/2016/005439). We also thank the University Grants Commission India for a UGC-SAP fellowship for S.B. Support from the state of Mecklenburg-Vorpommern (EFRE GHS-160029) is gratefully acknowledged.

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REFERENCES

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DOI: 10.1021/acs.joc.9b00840 J. Org. Chem. 2019, 84, 8921−8940

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The Journal of Organic Chemistry

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