Cu-Catalyzed Direct C-P Bond Formation through Dehydrogenative

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Cu-Catalyzed Direct C-P Bond Formation through Dehydrogenative Cross-Coupling Reactions between Azoles and Dialkyl Phosphites Soumyadip Hore, Abhijeet Srivastava, and Ravi P Singh J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00670 • Publication Date (Web): 10 May 2019 Downloaded from http://pubs.acs.org on May 10, 2019

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The Journal of Organic Chemistry

Cu-Catalyzed

Direct

C-P

Bond

Formation

through

Dehydrogenative Cross-Coupling Reactions between Azoles and Dialkyl Phosphites Soumyadip Hore,† Abhijeet Srivastava,† and Ravi P. Singh†,* †,

*Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi

ABSTRACT: A direct dehydrogenative cross-coupling of azoles [C(sp2)-H] with dialkyl phosphites [P(O)-H] to access 2-phosphonated azoles using Cu(I)/Cu(II) as catalysts and K2S2O8/DTBP as oxidants have been achieved. A remarkable advantage over reported procedures includes that oxazoles, imidazoles, benz(ox/othi/imid)azoles and indole are found to react under optimized reaction conditions to provide corresponding adducts in high yields. The mechanistic insight of cross-coupling was obtained by deuterium kinetic isotope effect studies. INTRODUCTION C–H functionalization processes including intermolecular and intramolecular cross-couplings have already been recognized as a powerful method for obtaining complex scaffolds by conserving the number of synthetic steps involved.1a-d Generally, noble transition metals such as Pd, Rh, or Ir are being used as catalysts.1e-j As an advancement of the strategy, while, many

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efforts have been focused on the formation of carbon-heteroatoms (N, O and S) bonds,2 limited protocols for direct formation of C-P bonds have been realized.3-7 These coupling reactions have been limited to various pre-functionalized precursors (e.g., aryl halides,3 triflates,4 boronic acids,5 aryl sulfonates6 and triaryl bismuths7) and usually generate large quantities of wastes, thus leading to low atom and step economy. Phosphorus containing organics, although synthetically challenging, have garnered huge interest as catalyst, medicine and functional material owing to their valuable chemical and biological activity.8 Various phosphorous sources like dialkyl/diaryl phosphites, H-phosphonates or secondary phosphine oxides have been used for C-P bond constructions; however, along with the requirement of large excess of the catalyst/oxidants, ligands or the source in these transformations limits their wide applicability.9,12-15 Since the onset of development of Jason and Fields’ novel approach on radical phosphonation of aromatic compounds,10 this area has significantly attracted synthetic organic chemists. Later, Ishii and co-workers11a developed phosphonation of arenes with dialkyl phosphites by Mn(II)/Co(II)/O2 redox couple, while Zou and Zhang11b has reported Mn(OAc)2-promoted regioselective phosphonation of heteroaryl compounds. Both methodologies had suffered drawbacks and the major concern was use of aliphatic acid as solvent, which is not suitable for acid sensitive substrates. Notably, in search of more convenient and diversified approaches for construction of C-P bonds, Huang,12a Yang,12b Duan,12c and Wen12d in their individual attempts have explored Ag catalyst in catalytic to equivalent amounts. However, use of equivalent amount of Ag and selected substrate scopes limits its wide applicability. Recently, Li et al.13 reported Pdcatalyzed direct phosphonation of azoles with H-phosphonates. In this work, they have shown


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that 30 mol % proline or 2,2’-bipyridine as ligand and 3.0 equiv. of K2S2O8 as oxidant was necessary.

Fig. 1. Previous Contributions and Current Approach for Phosphonation of Heteroarenes For metal-free alternatives, Qu and co-workers14a utilized peroxide like DTBP for generation of DTBP-triggered phosphorous-centered phosphonate radical to synthesize benzothiazol-2ylphosphonates. Cai and co-workers14b has made an attempt to phosphonate benzoxazoles and



benzothiazoles with I2 and K2S2O8. When he tried dialkylphosphite instead of triethylphosphite, no reaction was happened. On the other hand, Lei15a has demonstrated visible-light mediated aerobic radical C-H phosphorization of benzothiazoles with diarylphosphine oxides. Similarly, Köning15b has utilized Rhodamine 6G as visible light photocatalyst for Photo-Arbuzov reaction between aryl bromides and trialkyl phosphites for the synthesis of aryl phosphonates. Although these metal- and metal-free synthetic methodologies demonstrate efficient direct C-H phosphorylation, the reports were limited to few azole substrates and surprisingly, none of them have explored C2 phosphorylation of imidazoles or benzimidazoles. Thus, development of a method to obtain synthetically relevant scaffolds via C-H functionalization using an economical metal catalyst, such as Cu, would be significant. Cu catalysts can be attractive alternative owing to their low cost, low toxicity and ease of isolation but their low reactivity towards the direct functionalization of C-H bonds limits their applications and examples of copper-mediated carbon−phosphorus bond formation are rather rare.16 In view of the need, herein, we report a ligand-free, Cu-catalyzed, C-P bond formation of heteroarenes via cross dehydrogenative coupling of C-H and P-H bonds (Fig. 1c). This methodology, to the best of our knowledge is the first strategy for achieving direct C-P bond construction on azoles with Cu as catalyst. Remarkably, various azole substrates like benzothiazoles, oxazoles, benzoxazoles, imidazoles and benzimidazoles could be successfully coupled with H-phosphonates in this C-H phosphorylation reaction, which could be utilized for post synthesis functionalization of complex bioactive small molecules. RESULTS AND DISCUSSION Initial examination, which was aimed at identifying optimum reaction conditions include 1a, 5a and 6c as prototypical reaction partners. The optimization results revealed that 10 mol % of


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Cu(OH)2 can affect the transformation of benzothiazole 1a into diisopropyl benzothiazole-2phosphonate 7c. Thus, the reaction was performed using 1.0 equiv of 1a, 2.0 equiv of 6c with 10 mol % of Cu(OH)2 and 3.0 equiv of K2S2O8 as oxidant in CH3CN solvent at 120 °C (Table 1, entry 1). Increasing catalyst loading up to 20 mol % resulted in decreased yield of 7c to 57% (Table 1, entry 2). In the absence of Cu(OH)2 the yield was 35% while removing the oxidant K2S2O8 from optimum conditions did not yield the desired product at all (Table 1, entries 3 and 4, respectively). These observations suggested that oxidant is necessary for this transformation. To identify the best oxidant, the reaction was carried with Ag2CO3, TBHP, and I2 (Table 1, entries 5-7) but the best yield was obtained with K2S2O8. To identify a better solvent, the reaction was carried out in propionitrile, DMA and toluene (Table 1, entries 8-10) but no improvement was observed and CH3CN was the best solvent. Table 1.a Optimization of Reaction Conditions for the Phosphonation of Benzothiazole 1



a

Reaction Conditions 1a:6c = 1:2, for 0.2 mmol scale, solvent 2mL. bentry 3-16, run for 24 h.

c

Isolated yield. TBHP = tert-Butylhydrogenperoxide, DMA = N,N-Dimethylacetamide. ND = not

detected. Finally, Cu salts other than Cu(OH)2 were investigated. Cu(II) salts like Cu(OAc)2 and Cu(OTf)2 yielded 7c in 23 and 30%, respectively (Table 1, entries 11, 12). Interestingly, use of CuBr2 instead of Cu(OH)2 did not give 7c at all (Table 1, entry 13). On the other hand, Cu(I) salts like CuCl, CuOAc and CuI produced moderate results. While CuOAc gave 44% yield, incorporation of CuCl gave only 40% yield of 7c. In case of CuI, 7c was undetected even in trace amounts (Table 1, entry 14-16). The optimized reaction condition was implemented on various benzothiazoles, oxazoles and benzoxazoles (Table 2) giving access to dimethyl, dibutyl and diisopropyl benzothiazole-2phosphonates in good yields of 63%-65% (Table 2, 7a-7c). It was observed that electron donating groups like 6-ethyl and 3,4,5-trimethoxy on benzothiazoles were excellently tolerated to give the desired phosphonated product in moderate yields of 44%-51% (Table 2, 7d and 7e). Unfortunately, electron withdrawing group like 6-NO2 did not produce even a trace amount of phosphonated product (Table 2, 7f). Further it was observed that 4-carboxymethyl-5-(2fluorophenyl) oxazole 2 could be coupled with dimethyl and diisopropyl phosphites to afford desired products 8a and 8b in 46% and 43% isolated yields, respectively (Table 2). Next, the variations on the substituents of benzoxazoles (Table 2) were studied. It was found that unsubstituted benzoxazole 3a provided phosphonated products with diisopropyl and dibutyl phosphonates 6b and 6c in 66% and 67% yields, respectively (Table 2, 9a and 9b). Electron donating and electron withdrawing substituents on benzoxazoles were well tolerated too under these reaction conditions.


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Table 2.a Scope of Cu(OH)2-Catalyzed Phosphonation of Benzothiazoles 1, Oxazoles 2, and Benzoxazoles 3.



a

Reaction conditions: Azoles (1.0 equiv), dialkyl phosphites (2.0 equiv), Cu(OH)2 (10 mol %),

K2S2O8 (3.0 equiv), 4Å MS in CH3CN (2 mL) at 120 °C for 2 h. bIsolated yields in %. ND = not detected. For example, benzoxazoles with electron donating substituents like 5-Me (3b), 5-tert-butyl (3c) and 5-(4-OMePh) (3d) were successfully coupled with diisopropyl phosphites in the isolated yields of 36% to 68% (Table 2, 9c-9e). Whereas electron withdrawing substituents like 5-Ph (3e), 5-Br (3f), 5-Cl (3g), 6-Cl (3h), 5-F (3i), and 5-CO2Me (3j) were coupled with same phosphites 6c in 42% to 49% isolated yields (Table 2, 9f-9k). Unfortunately, with NO2 substituted benzoxazoles, the dehydrogenative cross-coupling with phosphite to produce desired product could not proceed (Table 2, entry 9l). Phosphorylation of 4,5-dimethylthiazole under the optimized reaction conditions did not yield desired product (Table 2, entry 9m). Similarly, these optimized reaction conditions, when used for a benzimidazole and phosphite to cross-couple, did not proceed as expected and an alternative reaction conditions had to be sought. Interestingly, when 20 mol % of CuBr was used in combination with 3.0 equiv of DTBP as an oxidant in DCE at 120 °C, diisopropylphosphite 6c could be successfully coupled with N(pyrimidin-2-yl)benzimidazole 5a in 1:3 equivalent ratio within 6 h to yield 11a in 67% yield (Table 3, entry 1). In an attempt to minimize catalyst loading of CuBr at 10 mol %, the reaction yielded 11a in only 30% of isolated yield (Table 3, entry 2). When the reaction was carried out in absence of either CuBr or DTBP, no progress in the reaction was observed (Table 3, entries 3 and 4). These findings revealed that both catalyst CuBr and oxidant DTBP were necessary for this transformation. These findings revealed that both the catalyst CuBr and oxidant DTBP were necessary for this transformation. Further, other oxidants like K2S2O8, Oxone®, TBHP, Ag2O and Ag2CO3. K2S2O8 and Oxone® did not give desired phosphonated product 11a (Table 3,


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entries 5 and 6). TBHP, Ag2O and Ag2CO3 give 12, 19 and 52% of isolated yield of 11a respectively (Table 3, entries 7-9). We also tried solvents other than DCE like toluene, DMF, 1,4-dioxane, EtOAc and chlorobenzene but no except last two gives 11a in 15 and 22% of isolated yields (Table 3, entries 10-15). As for benzothiazole, here we also evaluated other copper salts. Table 3.a Optimization of Reaction Conditions for the Phosphonation of N-Pyrimidine Protected Benzimidazole 5



a

Reaction Conditions: 5a:6c = 1:3, for 0.2 mmol scale, solvent 2mL. bIsolated yield. DCE = 1,2-

Dichloroethane. DMF = N,N-Dimethylformamide. DTBP = Di-tert-butylperoxide. ND = not detected. Next, we used Cu(I) salts e.g. CuCl, CuI and CuOAc. In which except CuOAc, others did not produce desired result (Table 3, entries 16-18). Among Cu(II) salts, we screened CuBr2, Cu(OTf)2, Cu(OH)2 and Cu(OAc)2 (Table 3, entries 19-23). Here, only CuBr2 and Cu(OAc)2 gave 11a in 41 and 15% yields, respectively, while others were not even promoted this transformation. In a separate experiment when we took CuBr2 and Ag2CO3 instead of CuBr and DTBP, 48% yield of 11a was observed (Table 3, entry 20). Gratifyingly, with the optimized reaction conditions for the synthesis of phosphonated benzimidazoles in hand, these reaction conditions were successfully extended to various functionally rich N-pyrimidine-protected imidazoles and benzimidazoles (Table 4). Further examination revealed that various imidazoles 4 and benzimidazoles 5 reacted well with dialkyl phosphites (6b and 6c) in the 1:3 ratio to yield corresponding adducts up to 68% (Table 4). Imidazoles and benzimidazoles precursors bearing other directing groups like tosyl or acetyl were not viable for these cross-coupling reactions (see SI). Unsubstituted N-pyrimidine-protected imidazole (4a), 4,5-diphenyl substituted (4b), substitution on N-pyrimidine-protected imidazoles with sensitive functional groups like 4,5-dicarboxyethyl (4c), and 4,5-dicyano (4d) were well tolerated under present protocol and afforded 24% to 49% isolated yields of desired phosphonated products (Table 4, 10a-10d). On the other hand, unsubstituted N-pyrimidineprotected benzimidazole (5a), and substitution on same precursor with electron donating substituents like 5,6-dimethyl (5b), 5-methoxy (5c), and 5,6-di(4-methoxyphenyl) (5d), yielded phosphonated coupled products in 38% to 67% isolated yields (Table 4, 11a-11e). Electron


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withdrawing substituent like 5,6-di(4-fluorophenyl) (5e) provided phosphonated N-pyrimidineprotected benzimidazole 11f in 41% isolated yields (Table 4). N-pyrimidine-protected benzimidazole with other electron withdrawing substituents like 5,6-dicarboxyethyl (5f) produced 11g in 35% yield (Table 4). Table 4.a Scope of CuBr-Catalyzed Phosphonation of Imidazoles 4, and Benzimidazoles 5

a

Reaction conditions: Azoles (1.0 equiv), dialkyl phosphites (3.0 equiv), CuBr (10 mol%), DTBP

(3.0 equiv) in DCE (2 mL) at 120 °C for 6 h. bN-(Tosyl) or N-(Acetyl) or N-(Phenyl) substituted



imidazoles/benzimidazoles did not yield corresponding phosphonated product. cIsolated yields in %. dEtOAc is used as solvent. eAg2CO3 is used as oxidant. fDCE:Chlorobenzene (1:1) is used as solvent. ND = not detected. Intriguingly, we presumed to further extend this Cu-catalyzed phosphorylation over other heterocycles like indole, pyrazole and 1,2,4-triazole. We summarized results into Table 5 which includes various reaction conditions of Cu-salts/oxidants/solvents operated over these heterocycles and isolated yields in these conditions. Table 5. Scope of Cu-catalyzed Phosphonation of N-Pyrimidine Protected Indole, Pyrazole and 1,2,4-Triazole

Among these heterocycles, only indole reacted under the optimized reaction condition of Cusalts/oxidants for phosphorylation and Cu(OH)2/K2S2O8, CuBr/Ag2CO3 and CuBr/DTBP


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catalytic systems gave 57%, 51% and 46% isolated yields respectively. These catalytic systems did not work either on pyrazole or on 1,2,4-triazole. To demonstrate the practical utility of the optimized method, a gram-scale synthesis was performed. When 3.0 mmol of 1a was reacted with 6.0 mmol of 6c under the optimized reaction conditions, it gave 56% of 2-phosphonated benzothiazole 7c (Scheme 1). Scheme 1. Gram Scale Synthesis

To demonstrate the synthetic power of developed methodology, the phosphoester 7c was further transformed into corresponding phosphoric acid 14 (Scheme 2). Scheme 2. Transformation of Phosphonated Benzothiazole into its Phosphoric Acid Analogue

To understand the reaction mechanism, control experiments depicted in Scheme 3 and 4 were carried out. The optimized reaction was performed for the phosphonation of benzothiazole 1a in the presence of radical scavengers such as TEMPO and BHT. It was found that no trace of phosphite coupled benzothiazole was found with BHT, but 29% isolated yield of 7c was observed with TEMPO. Notably, in the case of N-pyrimidine-protected benzimidazole 5a when



employed under the standard reaction conditions with TEMPO or BHT (each 1.0 equiv), no reaction occurred. The above observations concluded that radical species might be involved in these cross-coupling reactions between azoles and dialkyl phosphites. Intermolecular deuterium kinetic isotope effects (KIE)17 have been determined for the cross-coupling reactions between 1a, 1a-d, 5a, 5a-d and diisopropyl phosphite 6c. Benzothiazole-d (kH/kD = 1.84) and Npyrimidine-protected benzimidazole-d (kH/kD = 6.99) show large intermolecular primary isotope effects, suggesting that the breaking of the C−H(D) bonds are the RDS in these transformations (Scheme 2) [see SI]. Scheme 3. Control Experiments with Radical Scavengers TEMPO and BHT.


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Scheme 4. Kinetic Isotope Effecta

a

Studied by intermolecular competitive reaction. Azoles conversions were determined based on

the 1H NMR after isolation and purification. Based on above results and literature report,18 we propose the following reaction mechanisms which may include two individual plausible pathways for these transformations (Scheme 3 and 4). In Scheme 3, benzothiazole 1a, could co-ordinate with Cu(OH)2 to produce A, and through concomitant dehydration, which undergoes carbometalation, may give transient intermediate B. Scheme 5. Plausible Mechanism for the Synthesis of Phosphonated Benzothiazoles



The oxidative addition of dehydrogenated diisopropyl phosphonate radical 6’ to this transient intermediate B may give C. Later, C may experience reductive elimination to give the phosphonated product 7c and CuOH. Then Cu(OH)2 was regenerated upon the oxidation by K2S2O8. A plausible mechanistic pathway for the formation of phosphonated benzimidazole is depicted in Scheme 4. It was assumed that N-pyrimidine-protected benzimidazole 5a may coordinate with Cu(II)-complex D through nitrogen of pyrimidine, and can form a transient structure E, then, after carbometalation to C(2)-H bond of benzimidazole it may give another transient intermediate F. Oxidative addition of dehydrogenated diisopropyl phosphonate radical 6c’ to this transient intermediate F may produce G and reductive elimination of G may generate phosphonated benzimidazole 11a and regenerate CuBr, which further participate in next catalytic cycle. Scheme 6. Plausible mechanism for the synthesis of phosphonated N-pyrimidine-protected benzimidazoles


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CONCLUSION In conclusion, an efficient copper-catalyzed, ligand-free carbon−phosphorus bond-forming methodology for synthesizing phosphonated azoles under relatively mild conditions has been developed. Apart from being economical, this reaction offers an extremely simple and quite a broad functional group tolerant method for directly installing C-P bond in various heteroaromatic scaffolds. EXPERIMENTAL SECTION General Information. All the reactions were carried out in a flame or oven-dried glass wares under an argon or nitrogen atmosphere with freshly distilled dry solvents under anhydrous conditions unless otherwise indicated. Chromatograms were visualized by fluorescence quenching with UV light at 254 nm. Nuclear magnetic resonance (NMR) spectra were recorded in deuterated solvents with residual protonated solvent signal as internal reference on a Brücker Ava-300 or JNM-ECA 400. Chemical shifts are reported in parts per million using the solvent resonance internal standard (chloroform, 7.26 and 77.0 ppm or DMSO, 2.50 and 40.0 ppm). Data is reported as follows: chemical shift  in ppm, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, bs =broad singlet), coupling constant J, and integration. Electrospray and electron impact high resolution mass spectrometry was performed by Brücker mass spectrometer. The data is recorded as the ionization method followed by the calculated and measured masses. Solvents for starting material preparation and coupling reactions were dried before use. General Method for the Synthesis of Starting Materials 1-5. a. Synthesis of Benzothiazoles 1b-1c19



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Synthesis of benzothiazoles involves two steps, where first step is the synthesis of 2aminobenzothiazoles from corresponding anilines and, second step is deamination of 2aminobenzothiazoles which generates benzothiazoles. The details of these steps are as follows Step 1: Synthesis of 2-Aminobenzothiazole - A mixture of aniline (1.0 equiv) and ammonium thiocyanate (2 equiv) in glacial acetic acid (20 mL) was cooled to 10 °C and stirred. A solution of bromine (1 equiv) in glacial acetic acid (3 mL) was added drop wise at such a rate to keep the temperature below 10 °C throughout the addition. Stirring was continued for an additional 12 h; then the reaction mixture was poured into ice-cold water, and an aqueous solution of ammonium hydroxide (25%) was added to reach pH of solution at ∼ 9. The precipitate was filtered, washed with water, dried, and recrystallized from ethanol to obtain 2-aminobenzothiazoles. If necessary, column chromatography was performed. Step 2: Deamination of 2-Aminobenzothiazoles - To a stirred solution of 2aminobenzothiazoles (1.0 mmol) and NaNO2 (1.5 mmol) in DMF (6 mL) was added drop wise BF3.OEt2 (2.0 mmol) at room temperature and reaction was continued for 1 h. On completion of the reaction was diluted with H2O (15 mL) and extracted with EtOAc (3 X 20 mL). The pooled organic phase was dried over anhydrous Na2SO4 and concentrated in vacuum to obtain a residue which after purification over silica gel column with hexanes/ EtOAc (9.5:0.5, v/v) as eluent gave hydrodeaminated benzothiazoles 1b-1c as a colorless oil. All 1H and

13

C spectra were matched

with reported literatures and found same. b. Synthesis of Oxazole 220 A solution of methyl isocyanoacetate (1.5 g, 13 mmol, 1.0 equiv) in anhydrous THF (8 mL) was added drop wise to a stirred ice-cooled solution of potassium tert-butoxide (1.5 g, 13 mmol, 1.0


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equiv) in dry THF (15 mL) under argon. Afterward a solution of acyl chloride (13 mmol, 1.0 equiv) in THF (6 mL) was added drop wise by maintaining the temperature below 0 °C. The resulting mixture was stirred at room temperature for 3 h. An aqueous solution of acetic acid (0.4 mL, 6.5 mmol, 0.5 equiv) was added and the mixture was extracted with Et 2O. The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (6%-7% EtOAc:Hexane) to afford methyl 5-(2fluorophenyl)oxazole-4-carboxylate 2. c. Synthesis of Benzoxazoles 3a-3j21 In a 100 mL flask, 2-aminophenol derivative (20 mmol) was added to triethyl orthoformate (30 mL) under an argon atmosphere; the resulting mixture was refluxed for 5-8 h and monitored by TLC. After cooling to room temperature, triethyl orthoformate was removed under reduced pressure at 70-80 °C; the residue was purified by column chromatography afforded to the desired products. All 1H and 13C spectra were matched with reported literatures and found same. d. Imidazoles 4a-4d Unprotected imidazoles 4a, 4b and 4d were purchased. Unprotected imidazole 4c was esterified from its commercially available carboxylic acid precursor. Pyrimidine protection of all imidazoles were done according to literature procedure as same for benzimidazoles (step 3). e. Benzimidazoles 5a-5i Unprotected benzimidazoles 5a, 5b, 5c, 5f and 5g were purchased while 5h was esterified from its commercially available carboxylic acid precursor. e_1: Synthesis of Benzimidazoles 5d and 5e22a,b



Step 1: Synthesis of Respective o-Phenylenediamines - Into a solution of 4,5-dibromo-1,2phenylenediamine (4.0 mmol), phenyl boronic acids (1.22 g, 10 mmol) and Pd(PPh3)4 (0.12 g, 0.1mmol) in 60 mL toluene was added 15 mL 2 M K2CO3 aqueous solution. Then the mixture was degassed and stirred for 24 h at 85 °C in oil bath. The mixture was cooled to room temperature, poured into a large amount of water, and extracted with ethyl acetate. The organic layer was washed with water three times and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel with petroleum ether:ethyl acetate (4:1) as the eluent to afford compound 5d and 5e as a white solids. Step 2: Synthesis of Benzimidazoles from corresponding o-Phenylenediamines - oPhenylenediamines of first step were refluxed at 105 °C in oil bath with the excess amount (30 equiv) of formic acid under nitrogen atmosphere. After 4 h, remaining acid was evaporated, and aqueous work up was done to exclude last amount of acid. Organic phase (generally ethyl acetate) was dried over Na2SO4 and then concentrated to get final products which were used as obtained. Step 3: All imidazoles, benzimidazoles and indole were pyrimidine protected as followed.22c Method for Pyrimidine Protection - An oven dried 2-neck round bottom flask was charged with NaH (2.5 equiv) and rinsed with n-hexane (2mL x 1 mmol) under nitrogen atmosphere for 10 min. 1.0 equiv. of DMF solution of imidazole or benzimidazole was added drop wise followed by drop wise addition of DMF solution of 2-chloropyridine. Whole solution was stirred overnight. After completion of reaction, monitored by TLC, reaction mixture was poured into either ethyl acetate or ice-cold water. Aqueous work up was done, and organic phase was dried over anhydrous Na2SO4. Final solution was concentrated and column over silica gel to get pure N-pyrimidine protected imidazole or benzimidazole.


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For pyrimidine protection of pyrazole and 1,2,4-triazole, we follow literature report.22d,e General Method for the Synthesis of 7, 8, 9, 13. Step 1. In a sealed tube 10 mol % of Cu(OH)2, benzothiazole 1, or oxazoles 2, or benzoxazoles 3 (1.0 equiv, 0.2 mmol), oxidant K2S2O8 (3.0 equiv, 0.6 mmol), phosphite 6 (2.0 equiv, 0.4 mmol) and 4Å MS (3-4 medium size beads) were taken with 2.0 mL of dry acetonitrile. Step 2. Sealed tube was purged with N2 gas and screwed tight and transferred to pre-heated oil bath at 120 °C for stipulated period of time. Pause. After 2 h, color changed from dark brown to reddish-yellow. TLC pattern and Rf value: In 40% EtOAc in hexane, Rf values were 0.4-0.6. Purification: After completion of reaction, reaction mixture was passed through celite pad with ethyl acetate and then concentrated. Reaction mixture was then chromatographed on 100-200 mesh Silica-Gel with 18-24 % ethyl acetate in hexane as eluent. General Method for the synthesis of 10 and 11. Step 1. In a sealed tube 20 mol % of CuBr, oxidant DTBP (3.0 equiv, 0.6 mmol), phosphite 6 (2.0 equiv, 0.4 mmol) were taken with 1.0 mL of dry dichloroethane and stirred in air for 30 minutes. Pause 1. A white turbid solution was obtained. Step 2. Sealed tube was purged with N2 gas and screwed tight, and transferred to preheated oil bath at 120 °C. Pause 2. Wait for 30 minutes or till the solution become clear. Step 3. Imidazole 4, or benzimidazole 5 (1.0 equiv, 0.2 mmol) in 1 mL DCE was added after step 2. (Cooled the solution of step 2, open sealed cap and then transfer solution of step 3 (i.e. 4 or 5 in DCE), again purge the final solution (step 2 + step 3) with N2 gas and transferred it to pre-heated oil bath). Pause 3. Color changed from transparent to pale yellow. Step 4. Reaction mixture was again heated at 120 °C for stipulated period. Pause 4. After approximately 6 h, in general no color change was found except darkening of yellow color of step 4, but light brown color precipitates were obtained for 10c, 10d, 11g and 11h. TLC pattern and Rf value: In EtOAc, Rf



values were 0.4-0.6. Purification: After completion of reaction, reaction mixture was passed through celite pad with ethyl acetate and then concentrated over rotatory evaporator. Reaction mixture was then chromatographed on 230-400 mesh Silica-Gel with 80-90% ethyl acetate in hexane as eluent. The spectral and analytical data of all the compounds are given as follows: Methyl 5-(2-fluorophenyl)oxazole-4-carboxylate (2): White gummy solid, mp = 43-45 ˚C; 1H NMR (300 MHz, CDCl3):  7.93 (s, 1H), 7.59 (t, J = 8.2 Hz, 1H), 7.41 (dddd, J1 = 8.4, J2 = 7.1, J3 = 5.2, J4 = 1.8 Hz, 1H), 7.24-7.06 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3):  161.6, 156.0 (d, J = 253.9 Hz), 150.4, 150.3, 134.9 (d, J = 9.1 Hz), 132.5 (d, J = 8.5 Hz), 132.0, 131.2 (d, J = 1.5 Hz), 128.8, 123.9 (d, J = 3.7 Hz), 116.9 (d, J = 22.5 Hz), 116.1 (d, J = 21.4 Hz), 115.2 (d, J = 13.6 Hz), 52.2. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C11H8FNNaO3, 244.0380; Found: 244.0381. 2-(4,5-Diphenyl-1H-imidazol-1-yl)pyrimidine (4b): White solid, mp = 120-122 ˚C; 1H NMR (400 MHz, CDCl3):  8.46 (d, J = 4.7 Hz, 3H), 7.42 (d, J = 6.6 Hz, 2H), 7.27 (dd, J1 = 10.4, J2 = 7.8 Hz, 5H), 7.20-7.08 (m, 3H), 7.05 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3):  158.3, 155.6, 140.4, 137.6, 134.0, 131.6, 130.9, 128.2, 128.0, 128.0, 127.4, 126.8, 118.9. HRMS (ESI/QTOF), m/z: [M+H]+ Calcd. for C19H15N4, 299.1291; Found: 299.1279. Diethyl 1-(pyrimidin-2-yl)-1H-imidazole-4,5-dicarboxylate (4c): White solid, mp = 60-62 ˚C; 1H NMR (400 MHz, CDCl3):  8.65 (d, J = 4.80 Hz, 2H), 8.49 (s, 1H), 7.27-7.21 (m, 1H), 4.464.30 (m, 4H), 1.36-1.30 (m, 6H).

13C{1H}

NMR (100 MHz, CDCl3):  161.5, 161.4, 158.7,

153.7, 136.1, 133.3, 128.0, 120.0, 62.4, 61.2, 14.2, 13.8. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C13H14N4NaO4, 313.0907; Found: 313.0913.


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1-(Pyrimidin-2-yl)-1H-imidazole-4,5-dicarbonitrile (4d): White solid, mp = 136-138 ˚C; 1H NMR (400 MHz, CDCl3):  8.82 (d, J = 4.2 Hz, 2H), 8.74 (s, 1H), 7.45 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3):  159.4, 152.8, 140.0 126.4, 121.6, 111.2, 110.3, 108.1. HRMS (ESI/QTOF), m/z: [M+H]+ Calcd. for C9H5N6, 197.0570; Found: 197.0576. 5,6-bis(4-methoxyphenyl)-1-(pyrimidin-2-yl)-1H-benzo[d]imidazole (5d): Pink Solid, mp = 145147 ˚C; 1H NMR (300 MHz, CDCl3):  9.10 (s, 1H), 8.72 (d, J = 4.8 Hz, 2H), 8.60 (s, 1H), 7.84 (s, 1H), 7.14 (t, J = 8.4 Hz, 4H), 6.79 (dd, J1 = 8.0, J2 = 5.1 Hz, 4H), 3.79 (s, 6H). 13C{1H} NMR (75 MHz, CDCl3):  158.5, 158.1, 158.1, 156.2, 144.3, 142.4, 137.5, 136.7, 134.7, 134.3, 131.3, 131.2, 131.1, 121.6, 118.0, 117.2, 113.3, 113.3, 55.2, 55.2. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C25H20N4NaO2, 431.1478; Found: 431.1476. 5,6-Bis(4-fluorophenyl)-1-(pyrimidin-2-yl)-1H-benzo[d]imidazole (5e): Pink solid, mp = 188190 ˚C; 1H NMR (300 MHz, CDCl3):  9.14 (s, 1H), 8.75 (d, J = 4.8 Hz, 2H), 8.61 (s, 1H), 7.84 (s, 1H), 7.33-7.08 (m, 5H), 6.94 (dd, J1 = 13.7, J2 = 8.5 Hz, 3H).

13C{1H}

NMR (75 MHz,

CDCl3):  161.7 (d, J = 245.9 Hz), 161.6 (d, J = 245.9 Hz), 158.6, 156.1, 144.5, 142.8, 137.9 (d, J = 3.3 Hz), 137.5 (d, J = 3.3 Hz), 136.8, 136.0, 131.7 (dd, J1 = 9.9, J2 = 8.0 Hz), 131.3, 121.8, 118.2, 117.3, 114.8 (dd, J1 = 21.30, J2 = 2.40 Hz). 19F NMR (282 Hz, CDCl3):  -116.1, -116.2. HRMS (ESI/QTOF), m/z: [M+H]+ Calcd. for C23H15F2N4, 385.1259; Found: 385.1256. Dimethoxy benzo[d]thiazol-2-ylphosphonate (7a):14b (yield 65%, weight 31.6 mg); pale yellow liquid; 1H NMR (400 MHz, CDCl3):  8.26 (d, J = 7.16 Hz, 1H), 8.03 (d, J = 7.49 Hz, 1H), 7.63 – 7.51 (m, 2H), 3.98 (s, 3H), 3.95 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):  157.6 (d, J = 240.42 Hz), 153.5 (d, J = 28.36 Hz), 135.3 (d, J = 1.64 Hz), 126.1, 125.9 (d, J = 0.49 Hz), 123.9, 120.9 (d, J = 1.65 Hz), 53.2, 53.2. 31P NMR (162 MHz, CDCl3):  6.69 (s).



Dibutyl benzo[d]thiazol-2-ylphosphonate(7b):14b (yield 63%, weight 45.3 mg); pale yellow liquid; 1H NMR (400 MHz, CDCl3):  8.24 (d, J = 7.72 Hz, 1H), 8.01 (d, J = 7.84 Hz, 1H), 7.59-7.51 (m, 2H), 4.30-4.22 (m, 4H), 1.74-1.70 (m, 4H), 1.43-1.39 (m, 4H), 0.91 (t, J = 7.34 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3):  159.9 (d, J = 238.9 Hz), 154.5 (d, J = 28.30 Hz), 136.3 (d, J = 1.33 Hz), 126.8 (d, J = 16.10 Hz), 124.9, 121.9 (d, J = 1.42 Hz), 67.7 (d, J = 6.16 Hz), 32.3 (d, J = 6.28 Hz), 18.6, 13.5. 31P NMR (162 MHz, CDCl3):  4.14 (s). Diisopropyl benzo[d]thiazol-2-ylphosphonate (7c): (yield 64%, weight 38.3 mg); pale yellow liquid; 1H NMR (300 MHz, CDCl3):  8.24 (d, J = 8.52 Hz, 1H), 8.00 (d, J = 7.77 Hz, 1H), 7.59-7.51 (m, 2H), 4.98-4.87 (m, 2H), 1.43 (d, J = 6.15 Hz, 6H), 1.34 (d, J = 6.18 Hz, 6H). 13C{1H}

NMR (100 MHz, CDCl3):  161.4 (d, J = 239.28 Hz), 154.5 (d, J = 37.78 Hz), 136.4,

126.7 (d, J = 13.87 Hz), 124.8, 121.8, 121.8, 73.2 (d, J = 7.90 Hz), 24.0 (d, J = 5.44 Hz), 23.7 (d, J = 6.53 Hz).

31P

NMR (162 MHz, CDCl3):  1.91 (s). HRMS (ESI/QTOF), m/z: [M+Na]+

Calcd. for C13H18NNaO3PS, 322.0637; Found: 322.0643. Diisopropyl (5,6,7-trimethoxybenzo[d]thiazol-2-yl)phosphonate (7d): (yield 51%, weight 33.4 mg); pale yellow liquid; 1H NMR (400 MHz, CDCl3):  7.44 (s, 1H), 4.92-4.81 (m, 2H), 4.07 (s, 3H), 3.93 (s, 3H), 3.92 (s, 3H), 1.39 (d, J = 6.15 Hz, 6H), 1.31 (d, J = 6.15 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3):  160.8 (d, J = 239.43 Hz)., 154.6, 151.2 (d, J = 29.33 Hz), 146.6, 141.1, 122.7, 101.5, 73.1, 61.5, 60.7, 56.3, 24.1 (d, J = 3.61 Hz), 23.8 (d, J = 4.60 Hz). 31P NMR (162 MHz, CDCl3):  1.96 (s). HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C16H24NNaO6PS, 412.0954; Found: 412.0968. Diisopropyl (6-ethylbenzo[d]thiazol-2-yl)phosphonate (7e): (yield 44%, weight 34.3 mg); yellow liquid; 1H NMR (400 MHz, CDCl3):  8.13 (d, J = 8.00 Hz, 1H), 7.79 (s, 1H), 7.40 (d, J = 7.72


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Hz, 1H), 4.93-4.85 (m, 2H), 2.81 (q, J = 7.54 Hz, 2H), 1.41 (d, J = 6.04 Hz, 6H), 1.33-1.24 (m, 9H).

13C{1H}

NMR (100 MHz, CDCl3):  160.3 (d, J = 241.60 Hz), 153.1 (d, J = 26.5 Hz),

143.8, 137.0, 127.6, 124.6, 120.3, 73.2 (d, J = 5.85 Hz), 29.17, 24.1 (d, J = 4.03 Hz), 23.9 (d, J = 4.84), 15.8.

31P

NMR (162 MHz, CDCl3):  2.26 (s). HRMS (ESI/QTOF), m/z: [M+Na]+

Calcd. for C15H22NNaO3PS, 350.0950; Found: 350.0950. Methyl 2-(dimethoxyphosphoryl)-5-(2-fluorophenyl)oxazole-4-carboxylate (8a): (yield 46%, weight 30.3 mg); pale yellow liquid; 1H NMR (300 MHz, CDCl3):  7.64-7.59 (m, 1H), 7.497.41 (m, 1H), 7.23-7.20 (m, 1H), 7.18-7.10 (m, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.81 (s, 3H). 13C{1H}

NMR (75 MHz, CDCl3):  165.8 (d, J = 240.96 Hz), 161.7, 161.2, 160.7, 158.3, 156.1,

153.0 (d, J = 4.63 Hz), 152.5, 135.1 (d, J = 9.12 Hz), 133.2 (d, J = 8.61 Hz), 132.7, 131.2, 130.2 (d, J = 14.34 Hz), 124.2 (d, J = 3.70 Hz), 124.1 (d, J = 3.97 Hz), 118.1 (d, J = 9.30 Hz), 117.1 (d, J = 22.37 Hz), 116.3 (d, J = 21.27 Hz), 114.7 (d, J = 13.45 Hz), 54.8, 52.5. 19F NMR (282 MHz, CDCl3):  - 110.50 (s). 31P NMR (121.5 MHz, CDCl3):  - 1.38 (s). HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C13H13FNNaO6P, 352.0357; Found: 352.0357. Methyl 2-(diisopropoxyphosphoryl)-5-(2-fluorophenyl)oxazole-4-carboxylate (8b): (yield 43%, weight 33.1 mg); pale yellow liquid; 1H NMR (300 MHz, CDCl3):  7.63-7.58 (m, 1H), 7.487.41 (m, 1H), 7.23-7.19 (m, 1H), 7.18-7.10 (m, 1H), 4.93-4.78 (m, 2H), 3.80 (s, 3H), 1.35 (d, J = 6.21 Hz, 6H), 1.32 (d, J = 6.18 Hz, 6H).

13C{1H}

NMR (75 MHz, CDCl3):  160.6, 160.4,

157.2, 155.2 (d, J = 267.46 Hz), 151.4 (d, J = 4.25 Hz), 131.9 (d, J = 8.56 Hz), 130.2, 129.0 (d, J = 14.44 Hz), 123.0 (d, J = 3.67 Hz), 115.1 (d, J = 21.33 Hz), 113.9 (d, J = 13.40 Hz), 73.0 (d, J = 5.98 Hz), 51.2, 22.9 (d, J = 4.11 Hz), 22.6 (d, J = 5.04 Hz).


19F

NMR (376 MHz, CDCl3):  -


110.48 (s).

31P

NMR (121.5 MHz, CDCl3):  - 6.17 (s). HRMS (ESI/QTOF), m/z: [M+Na]+

Calcd. for C17H21FNNaO6P, 408.0983; Found: 408.0962. Diisopropyl benzo[d]oxazol-2-ylphosphonate (9a):13 (yield 67%, weight 38.0 mg); pale yellow liquid; 1H NMR (400 MHz, CDCl3):  7.84 (d, J = 7.21 Hz, 1H), 7.62 (d, J = 7.68 Hz, 1H), 7.46 (t, J = 6.97 Hz, 1H), 7.40 (t, J = 7.02 Hz, 1H), 5.03-4.87 (m, 2H), 1.43 (d, J = 5.92 Hz, 6H), 1.38 (d, J = 5.89 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3):  157.7 (d, J = 267.45 Hz), 151.0 (d, J = 5.71 Hz), 140.3 (d, J = 16.43 Hz), 127.2, 125.1, 121.6, 111.4, 73.8 (d, J = 5.94 Hz), 24.0 (d, J = 4.14 Hz), 23.6 (d, J = 5.02 Hz). 31P NMR (162 MHz, CDCl3):  - 4.35 (s). Dibutyl benzo[d]oxazol-2-ylphosphonate (9b):14b (yield 66%, weight 41.1 mg); pale yellow liquid; 1H NMR (400 MHz, CDCl3):  7.87 (d, J = 7.55 Hz, 1H), 7.65 (d, J = 7.91 Hz, 1H), 7.49 (t, J = 7.29 Hz, 1H), 7.43 (t, J = 7.07 Hz, 1H), 4.33 (dd, J1 = 13.95, J2 = 7.05 Hz, 4H), 1.88-1.62 (m, 5H), 1.45 (dd, J1 = 14.75, J2 = 7.37 Hz, 5H), 0.94 (t, J = 7.31 Hz, 7H). 13C{1H} NMR (100 MHz, CDCl3):  156.7 (d, J = 267.04 Hz), 151.0 (d, J = 5.74 Hz), 140.2 (d, J = 16.39 Hz), 127.3, 125.3 (d, J = 0.93 Hz), 121.6, 111.5, 68.2 (d, J = 6.19 Hz), 32.3 (d, J = 6.26 Hz), 18.5, 13.5. 31P NMR (162 MHz, CDCl3):  - 1.97 (s). Diisopropyl (5-methylbenzo[d]oxazol-2-yl)phosphonate (9c):13 (yield 54%, weight 32.1 mg); pale yellow liquid; 1H NMR (400 MHz, CDCl3):  7.63 (s, 1H), 7.50 (d, J = 8.32 Hz, 1H), 7.28 (d, J = 7.88 Hz, 1H), 4.89-4.85 (m, 2H), 2.49 (s, 3H), 1.44 (d, J = 5.92 Hz, 6H), 1.38 (d, J = 5.92Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3):  156.6 (d, J = 267.71 Hz), 148.4 (d, J = 5.80 Hz), 139.6 (d, J = 16.29 Hz), 134.2, 127.5, 120.2, 109.8, 72.8 (d, J = 5.92 Hz), 23.0 (d, J = 4.12 Hz), 22.6 (d, J = 4.97 Hz), 20.4. 31P NMR (162 MHz, CDCl3):  - 4.16 (s).


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Diisopropyl (5-(tert-butyl)benzo[d]oxazol-2-yl)phosphonate (9d):13 (yield 68%, weight 46.2 mg); pale yellow liquid; 1H NMR (300 MHz, CDCl3):  7.87 (s, 1H), 7.56 (s, 2H), 5.05-4.83 (m, 2H), 1.46-1.40 (m, 21H). 13C{1H} NMR (75 MHz, CDCl3):  159.5, 155.9, 149.1 (d, J = 6.1 Hz), 148.8, 140.3 (d, J = 15.9 Hz), 125.2, 117.8, 110.6, 73.8 (d, J = 5.9 Hz), 35.0, 31.6, 24.0 (d, J = 4.1 Hz), 23.7 (d, J = 5.0 Hz). 31P NMR (121.5 MHz, CDCl3):  - 4.21 (s). Diisopropyl (5-(4-methoxyphenyl)benzo[d]oxazol-2-yl)phosphonate (9e): (yield 36%, weight 28.0 mg); pale yellow liquid; 1H NMR (400 MHz, CDCl3):  7.98 (s, 1H), 7.65 (s, 1H), 7.54 (d, J = 8.44 Hz, 2H), 7.00 (d, J = 8.00 Hz, 2H), 5.00-4.95 (m, 2H), 3.88 (s, 3H), 1.46 (d, J = 5.80 Hz, 6H), 1.41 (d, J = 5.80Hz, 6H).

13C{1H}

NMR (100 MHz, CDCl3):  159.3, 158.2 (d, J =

265.57 Hz), 150.2 (d, J = 5.65 Hz), 141.0 (d, J = 16.24 Hz), 138.9, 133.0, 131.0, 128.5, 128.1, 126.6, 119.3, 114.4, 112.7, 111.4, 74.0 (d, J = 5.96 Hz), 55.3, 24.0 (d, J = 4.07 Hz), 23.7 (d, J = 5.00 Hz).

31P

NMR (162 MHz, CDCl3):  - 4.43 (s). HRMS (ESI/QTOF), m/z: [M+Na]+

Calcd. for C20H24NNaO5P, 412.1284; Found: 412.1272. Diisopropyl (5-phenylbenzo[d]oxazol-2-yl)phosphonate (9f): (yield 43%, weight 30.9 mg); pale yellow liquid; 1H NMR (400 MHz, CDCl3):  7.95 (s, 1H), 7.61 (s, 2H), 7.52 (d, J = 6.92 Hz, 2H), 7.38-7.37 (m, 2H), 7.31-7.29 (m, 1H), 4.91-4.88 (m, 2H), 1.38 (d, J = 5.44 Hz, 6H), 1.33 (d, J = 5.44Hz, 6H).

13C{1H}

NMR (100 MHz, CDCl3):  157.3 (d, J = 266.88 Hz), 149.5 (d, J =

5.74 Hz), 140.0 (d, J = 16.39 Hz), 139.5, 138.2, 127.9, 126.5 (d, J = 3.39 Hz), 125.9, 118.8, 110.5, 72.9 (d, J = 5.96 Hz), 23.0 (d, J = 4.11 Hz), 22.7 (d, J = 5.00 Hz). 31P NMR (162 MHz, CDCl3):  - 4.48 (s). HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C19H22NNaO4P, 382.1179; Found: 382.1179.



Diisopropyl (5-bromobenzo[d]oxazol-2-yl)phosphonate (9g): (yield 49%, weight 35.5 mg); brown liquid; 1H NMR (400 MHz, CDCl3):  7.84 (s, 1H), 7.56 (d, J = 8.64 Hz, 1H), 7.45 (d, J = 7.52 Hz, 1H), 4.97-4.94 (m, 2H), 1.45 (d, J = 5.68 Hz, 6H), 1.40 (d, J = 5.68 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3):  159.2 (d, J = 265.61 Hz), 149.6 (d, J = 5.89 Hz), 141.4 (d, J = 16.53 Hz), 130.8, 127.7, 121.4, 112.2, 74.1 (d, J = 6.02 Hz), 24.0 (d, J = 4.11 Hz), 23.6 (d, J = 5.04 Hz).

31P


Calcd. for C13H17BrNNaO4P, 383.9971; Found: 383.9961. Diisopropyl (5-chlorobenzo[d]oxazol-2-yl)phosphonate (9h): (yield 47%, weight 29.9 mg); yellow liquid; 1H NMR (400 MHz, CDCl3):  7.77 (d, J = 8.40 Hz, 1H), 7.65 (s, 1H), 7.40 (d, J = 7.00 Hz, 1H), 4.97-4.92 (m, 2H), 1.45 (d, J = 5.76 Hz, 6H), 1.40 (d, J = 5.80 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3):  158.4 (d, J = 266.24 Hz), 151.3, 139.1 (d, J = 16.64 Hz), 133.2, 126.1, 124.0, 122.1, 112.0, 74.1 (d, J = 6.02 Hz), 24.0 (d, J = 4.13 Hz), 23.7 (d, J = 5.04 Hz). 31P NMR (162 MHz, CDCl3):  - 4.98 (s). HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C13H17ClNNaO4P, 340.0476; Found: 340.0506. Diisopropyl (6-chlorobenzo[d]oxazol-2-yl)phosphonate (9i): (yield 46%, weight 29.2 mg); yellow liquid; 1H NMR (400 MHz, CDCl3):  8.00 (s, 1H), 7.59 (d, J = 8.16 Hz, 1H), 7.51 (d, J = 8.52 Hz, 1H), 4.99-4.94 (m, 2H), 1.45 (d, J = 5.72 Hz, 6H), 1.39 (d, J = 5.68 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3):  159.0 (d, J = 265.49 Hz), 150.0 (d, J = 5.87 Hz), 141.9 (d, J = 16.50 Hz), 130.4, 124.5, 118.0, 112.7, 74.2 (d, J = 6.01 Hz), 24.0 (d, J = 4.13 Hz), 23.6 (d, J = 5.02 Hz).

31P


Calcd. for C13H17ClNNaO4P, 340.0476; Found: 340.0494.


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Diisopropyl (5-fluorobenzo[d]oxazol-2-yl)phosphonate (9j): (yield 42%, weight 25.3 mg); pale yellow liquid; 1H NMR (300 MHz, CDCl3):  7.53-7.44 (m, 2H), 7.20-7.12 (m, 1H), 4.95-4.84 (m, 4H), 1.37 (d, J = 6.18 Hz, 6H), 1.33 (d, J = 6.18 Hz, 6H). 13C{1H} NMR (75 MHz, CDCl3):

 159.3 (d, J = 242.47 Hz), 158.6 (d, J = 266.20 Hz), 146.4 (d, J = 5.88 Hz), 140.2 (d, J = 13.21 Hz), 140.0 (d, J = 13.32 Hz), 114.4 (d, J = 26.70 Hz), 110.9 (d, J = 9.96 Hz), 106.6 (d, J = 25.44 Hz), 73.1 (d, J = 6.00 Hz), 23.0 (d, J = 4.11 Hz), 22.6 (d, J = 5.03 Hz).

19F

NMR (282 Hz,

CDCl3):  -116.4 (s). 31P NMR (121.5 MHz, CDCl3):  - 4.98 (s). HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C13H17FNNaO4P, 324.0771; Found: 324.0776. Methyl 2-(diisopropoxyphosphoryl)benzo[d]oxazole-5-carboxylate (9k): (yield 49%, weight 33.4 mg); pale yellow liquid; 1H NMR (400 MHz, CDCl3):  8.32 (s, 1H), 8.14 (d, J = 7.12 Hz, 1H), 7.89 (d, J = 8.36 Hz, 1H), 5.01-4.97 (m, 2H), 3.97 (s, 3H), 1.46 (d, J = 5.96 Hz, 6H), 1.41 (d, J = 5.92 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3):  166.2, 160.4 (d, J = 264.18 Hz), 150.7 (d, J = 5.70 Hz), 143.9 (d, J = 16.16 Hz), 129.3, 126.6, 121.3, 113.2, 74.3 (d, J = 6.05 Hz), 52.5, 24.0 (d, J = 4.10 Hz), 23.7 (d, J = 5.04 Hz).

31P

NMR (121.5 MHz, CDCl3):  - 5.16 (s). HRMS

(ESI/QTOF), m/z: [M+Na]+ Calcd. for C15H20NNaO6P, 364.0920; Found: 364.0922. Diisopropyl (1-(pyrimidin-2-yl)-1H-imidazol-2-yl)phosphonate (10a): (yield 49%, weight 30.4 mg); pale yellow liquid; 1H NMR (400 MHz, CDCl3):  8.70 (d, J = 4.8 Hz, 2H), 8.64 (d, J = 4.8 Hz, 1H), 7.93-7.92 (m, 1H), 7.21-7.20 (m, 1H), 4.87-4.76 (m, 2H), 1.33 (s, 6H), 1.31 (s, 6H). 13C{1H}

NMR (100 MHz, CDCl3):  157.7, 157.3, 153.8, 138.5 (d, J = 264.00 Hz), 129.4 (d, J =

20.92 Hz), 120.9 (d, J = 3.43 Hz), 118.6, 117.9, 71.2 (d, J = 6.14 Hz), 23.1 (d, J = 3.42 Hz), 22.5 (d, J = 6.23 Hz). 31P NMR (162 MHz, CDCl3):  1.21 (s). HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C13H19N4NaO3P, 333.1087; Found: 333.1066.



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Diisopropyl (4,5-diphenyl-1-(pyrimidin-2-yl)-1H-imidazol-2-yl)phosphonate (10b): (yield 36%, weight 33.3 mg); yellow liquid; 1H NMR (400 MHz, CDCl3):  8.70 (d, J = 4.65 Hz, 1H), 7.55 (d, J = 6.37 Hz, 1H), 7.25 (d, J = 11.94 Hz, 5H), 5.01-4.51 (m, 1H), 1.39 (d, J = 5.62 Hz, 4H), 1.36 (d, J = 6.03 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3):  158.2, 156.3, 139.8 (d, J = 87.81 Hz), 138.6 (d, J = 189.32 Hz), 133.6, 132.2 (d, J = 4.03 Hz), 130.5, 129.6, 128.4, 128.1, 127.5, 127.0, 120.6, 72.3 (d, J = 5.84 Hz), 24.0 (d, J = 3.75 Hz), 23.6 (d, J = 5.61 Hz). 31P NMR (162 MHz, CDCl3):  0.14 (s). HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C25H27N4NaO3P, 485.1713; Found: 485.1724. Diethyl 2-(diisopropoxyphosphoryl)-1-(pyrimidin-2-yl)-1H-imidazole-4,5-dicarboxylate (10c): (yield 37%, weight 33.6 mg); yellow liquid; 1H NMR (400 MHz, CDCl3):  8.80 (d, J = 4.60 Hz, 2H), 7.41-7.40 (m, 1H), 4.80-4.77 (m, 2H), 4.39 (q, J = 6.86 Hz, 2H), 4.29 (q, J = 7.00 Hz, 2H), 1.38-1.34 (m, 12H), 1.24 (t, J = 6.94 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3):  160.6 (d, J = 192.59 Hz), 158.3, 154.9, 141.1 (d, J = 252.02 Hz), 135.0 (d, J = 18.19 Hz), 129.9 (d, J = 3.92 Hz), 121.1, 73.1 (d, J = 6.01 Hz), 62.2, 61.4, 24.0 (d, J = 3.62 Hz), 23.4 (d, J = 5.90 Hz), 14.1, 13.8.

31P


Calcd. for C19H27N4NaO7P, 477.1510; Found: 477.1511. Diisopropyl (4,5-dicyano-1-(pyrimidin-2-yl)-1H-imidazol-2-yl)phosphonate (10d): (yield 24%, weight 17.3 mg); yellow liquid; 1H NMR (400 MHz, CDCl3):  8.92 (d, J = 4.84 Hz, 2H), 7.56 (dd, J1 = 4.88 Hz, J2 = 4.86 Hz, 1H), 4.88-4.80 (m, 2H), 1.39 (br, 6H), 1.37 (br, 6H).

13C{1H}

NMR (100 MHz, CDCl3):  159.1, 153.1, 145.5 (d, J = 247.24 Hz), 124.2 (d, J = 21.30 Hz), 122.3, 114.3 (d, J = 5.15 Hz), 110.8, 107.4, 74.2 (d, J = 6.42 Hz), 24.0 (d, J = 3.46 Hz), 23.5 (d,


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J = 6.19 Hz). 31P NMR (162 MHz, CDCl3):  - 5.01 (s). HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C15H17N6NaO3P, 383.0992; Found: 383.0997. Diisopropyl (1-(pyrimidin-2-yl)-1H-benzo[d]imidazol-2-yl)phosphonate (11a): (yield 67%, weight 48.3 mg); pale yellow liquid; 1H NMR (400 MHz, CDCl3):  8.86 (d, J = 3.60 Hz, 2H), 8.22 (d, J = 7.80 Hz, 1H), 7.92 (d, J = 7.56 Hz, 1H), 7.45-7.32 (m, 1H), 7.26 (s, 1H), 4.92-4.89 (m, 2H), 1.41-1.40 (m, 12H).

13C{1H}

NMR (100 MHz, CDCl3):  158.2, 155.9, 145.3 (d, J =

255.00 Hz), 143.2 (d, J = 21.73 Hz), 134.2 (d, J = 4.54 Hz), 126.2, 124.1, 121.5, 119.2, 114.2, 72.7 (d, J = 6.20 Hz), 24.1 (d, J = 3.44 Hz), 23.6 (d, J = 6.08 Hz). 31P NMR (162 MHz, CDCl3):

 0.92 (s). HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C17H21N4NaO3P, 383.1243; Found: 383.1234. Diisopropyl

(5,6-dimethyl-1-(pyrimidin-2-yl)-1H-benzo[d]imidazol-2-yl)phosphonate

(11b):

(yield 59%, weight 45.8 mg); pale yellow liquid; 1H NMR (400 MHz, CDCl3):  8.85 (s, 2H), 7.99 (s, 1H), 7.70 (s, 1H), 7.31 (s, 1H), 4.91-4.90 (m, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 1.41 (br, 12H). 13C{1H} NMR (100 MHz, CDCl3):  158.2, 155.9, 144.0 (d, J = 254.65 Hz), 141.3 (d, J = 21.30 Hz), 136.0, 133.5, 132.6 (d, J = 4.76 Hz), 121.0, 119.1, 114.1, 72.7 (d, J = 6.19 Hz), 24.1 (d, J = 3.54 Hz), 23.6 (d, J = 6.04 Hz), 20.8, 20.2.

31P

NMR (162 MHz, CDCl3):  0.88 (s).

HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C19H25N4NaO3P, 411.1556; Found: 411.1557. Dibutyl (5,6-dimethyl-1-(pyrimidin-2-yl)-1H-benzo[d]imidazol-2-yl)phosphonate (11c): (yield 54%, weight 44.9 mg); pale yellow liquid; 1H NMR (400 MHz, CDCl3):  8.77 (d, J = 4.49 Hz, 2H), 8.01 (s, 1H), 7.59 (s, 1H), 7.21 (d, J = 4.65 Hz, 1H), 4.21 (d, J = 6.45 Hz, 4H), 2.35 (s, 3H), 2.32 (s, 3H), 1.66 (s, 4H), 1.40-1.32 (m, 4H), 0.85 (t, J = 7.21 Hz, 6H).

13C{1H}

NMR (100

MHz, CDCl3):  157.1, 154.8, 143.6, 141.1 (d, J = 2.6 Hz), 140.8, 135.0, 132.4, 131.6 (d, J = 4.6



Page 32 of 42

Hz), 120.2, 117.8, 113.5, 66.5 (d, J = 6.6 Hz), 31.4 (d, J = 6.4 Hz), 19.8, 19.2, 17.7, 12.6.

31P

NMR (162 MHz, CDCl3):  3.29 (s). HRMS (ESI/QTOF), m/z: [M+H]+ Calcd. for C21H30N4O3P, 417.2050; Found: 417.2067. Diisopropyl (5-methoxy-1-(pyrimidin-2-yl)-1H-benzo[d]imidazol-2-yl)phosphonate (11d): (yield 51%, weight 39.8 mg); reddish yellow liquid; 1H NMR (400 MHz, CDCl3):  8.88-8.85 (m, 4H), 8.16 (d, J = 8.20 Hz, 1H), 7.81-7.74 (m, 2H), 7.36-7.32 (m, 3H), 7.07 (dd, J1 = 8.28 Hz, J2 = 25.78 Hz, 2H), 4.92-4.91 (m, 4H), 3.91 (s, 6H), 1.43-1.42 (m, 24H). 13C{1H} NMR (100 MHz, CDCl3):  158.32, 158.30, 122.1, 119.2, 116.8, 115.1, 114.2, 102.7, 97.2, 72.7 (d, J = 6.12 Hz), 72.6 (d, J = 6.10 Hz), 55.9, 55.8, 24.2, 23.8 (d, J = 5.58 Hz), 23.7 (d, J = 5.84 Hz).

31P

NMR

(162 MHz, CDCl3):  1.15 (s), - 9.32 (s). HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C18H23N4NaO4P, 413.1349; Found: 413.1361. Diisopropyl

(5,6-bis(4-methoxyphenyl)-1-(pyrimidin-2-yl)-1H-benzo[d]imidazol-2-

yl)phosphonate(11e): (yield 38%, weight 43.5 mg); yellow liquid; 1H NMR (300 MHz, CDCl3):

 8.85 (d, J = 3.90 Hz, 2H), 8.22 (s, 1H), 7.91 (s, 1H), 7.32-7.29 (m, 1H), 7.26 (s, 1H), 7.12-7.09 (m, 5H), 6.78 (d, J = 8.10 Hz, 2H), 6.78 (d, J = 8.10 Hz, 2H), 4.98-4.88 (m, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 1.43 (d, J = 4.32 Hz, 6H), 1.41 (d, J = 4.29 Hz, 6H).

13C{1H}

NMR (75 MHz,

CDCl3):  158.3, 158.2, 155.9, 147.5, 143.4 (d, J = 115.62 Hz), 138.4 (d, J = 151.04 Hz), 134.4, 134.1, 133.5 (d, J = 4.77 Hz), 131.2 (d, J = 5.53 Hz), 122.5, 119.2, 115.6, 113.3, 72.8 (d, J = 6.26 Hz), 55.1, 24.1 (d, J = 3.47 Hz), 23.6 (d, J = 6.02 Hz). 31P NMR (121.5 MHz, CDCl3):  0.80 (s). HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C31H33N4NaO5P, 595.2081; Found: 595.2090.


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Diisopropyl (4,5-bis(4-fluorophenyl)-1-(pyrimidin-2-yl)-1H-imidazol-2-yl)phosphonate

(11f):

(yield 41%, weight 44.9 mg); yellow liquid; 1H NMR (400 MHz, CDCl3): δ 8.88 (d, J = 4.76 Hz, 2H), 8.26 (s, 1H), 7.93 (s, 1H), 7.37-7.33 (m, 1H), 7.14 (s, 1H), 6.97-6.92 (m, 1H), 5.01-4.90 (m, 1H), 1.52 – 1.39 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3):  163.6, 160.2, 158.4, 156.0, 138.7, 137.7, 137.4, 136.7, 133.8, 131.8, 131.7, 122.9, 119.5, 116.0, 115.1, 114.8, 72.9 (d, J = 4.95 Hz), 24.2, 23.7 (d, J = 5.20 Hz). 19F NMR (376 MHz, CDCl3):  - 115.88 (s), - 116.15 (s). P NMR (162 MHz, CDCl3):  0.58 (s). HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for

31

C29H27F2N4NaO3P, 571.1681; Found: 571.1692. Diethyl 2-(diisopropoxyphosphoryl)-1-(pyrimidin-2-yl)-1H-benzo[d]imidazole-5,6-dicarboxylate (11g): (yield 35%, weight 35.3 mg); pale yellow liquid; 1H NMR (400 MHz, CDCl3):  8.92 (d, J = 3.80 Hz, 1H), 8.61 (s, 1H), 8.35 (s, 1H), 7.41 (s, 1H), 4.95 (dd, J1 = 12.80, J2 = 6.40 Hz, 1H), 4.43 (td, J1 = 7.04, J2 = 5.58 Hz, 2H), 1.54-1.35 (m, 8H). 13C{1H} NMR (100 MHz, CDCl3):  168.1, 167.2, 159.2, 158.5, 130.9, 123.0, 119.9, 115.8, 94.3, 73.2 (d, J = 5.7 Hz), 61.9, 61.7, 24.1 (d, J = 3.3 Hz), 23.5 (d, J = 6.3 Hz), 14.2, 14.1.

31P

NMR (162 MHz, CDCl3):  - 0.37 (s).

HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C23H29N4NaO7P, 527.1666; Found: 527.1667. Dibutyl (1-(pyrimidin-2-yl)-1H-indol-2-yl)phosphonate (13a): (yield 57%, weight 44.2 mg); yellow liquid; 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 4.33 Hz, 1H), 8.60 (d, J = 8.46 Hz, 1H), 7.71 (d, J = 7.77 Hz, 1H), 7.44 (dd, J = 16.16, 6.22 Hz, 1H), 7.35-7.24 (m, 1H), 7.19 (d, J = 4.32 Hz, 1H), 4.18 (dd, J = 11.31, 6.75 Hz, 2H), 1.82-1.63 (m, 2H), 1.45 (dd, J = 14.54, 7.12 Hz, 2H), 0.95 (t, J = 7.34 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 158.3, 157.8, 156.9, 138.5 (d, J = 9.40 Hz), 128.3 (d, J = 15.47 Hz), 126.3, 122.5, 121.9, 121.2 (d, J = 14.21 Hz), 117.5, 115.5,



66.6 (d, J = 6.15 Hz), 32.5 (d, J = 6.82 Hz), 18.8, 13.6. 31P NMR (162 MHz, CDCl3) δ 9.12 (s). HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd. for C20H26N3NaO3P, 410.1604; Found: 410.1620. Synthesis of Benzo[d]thiazol-2-ylphosphonic acid (14). Bromine (319.6 mg, 2.0 mmol) was added to a small excess amount of hexamethyldisilane (300 mg, 2.04 mmol) at 0 ˚C (for 40 minutes) under the inert atmosphere and the mixture was heated to 60-70 ˚C in oil bath for 30 minutes to yield bromotrimethylsilane.23 This in situ generated TMS-Br (214.3 mg, 7.0 equiv.) was added dropwise to a solution of 7c in dry DCM (59.86 mg, 0.1 M) at room temperature and resulting mixture was stirred for 36 h. After completion of reaction, solvent was evaporated, and 2 mL of acetonitrile was added to it to initiate precipitation. White precipitate was filtered off and dried under high vacuum to yield corresponding phosphonic acid. Benzo[d]thiazol-2-ylphosphonic acid (14). (yield 75%, weight 32.3 mg); White solid, mp = 161163 ˚C; 1H NMR (400 MHz, DMSO) δ 8.15 (dd, J = 14.05, 7.87 Hz, 2H), 7.55 (dt, J = 14.51, 6.94 Hz, 2H). 13C NMR (75 MHz, DMSO) δ 168.1, 165.2, 154.5 (d, J = 26.08 Hz), 135.9, 127.0 (d, J = 19.40 Hz), 124.2, 123.0.

31P

NMR (162 MHz, DMSO) δ - 0.90 (s). HRMS

(ESI/QTOF), m/z: [M+H]+ Calcd. for C7H7NO3PS, 215.9879; Found: 215.9889. ASSOCIATED CONTENT Supporting Information Copies of 1H, 13C, 19F, and 31P NMR spectra (PDF). The Supporting Information is available free of charge on the ACS Publications website. AUTHOR INFORMATION Corresponding Author


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*E-mail: [email protected] ORCID ID: Ravi P Singh: 0000-0001-5323-5979 Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS We are grateful for the generous financial support from DST-India (EMR/2017/000319) and DAE-BRNS (2018043702RP04978). S.H. is grateful to MHRD, India and A. S. is highly thankful to CSIR-India for Research Associateship. REFERENCES (1) (a) Wang, C.-S.; Dixneuf, P. H.; Soulé, J.-F. Photoredox Catalysis for Building C–C Bonds from C(sp2)–H Bonds. Chem. Rev. 2018, 118, 7532. (b) Lyons, T. W.; Sanford, M. S. Palladium-Catalyzed Ligand-Directed C−H Functionalization Reactions. Chem. Rev. 2010, 110, 1147. (c) Jagadeesh Kalepu, J.; Gandeepan, P.; Ackermann, L.; Pilarski, L. T. C4–H Indole Functionalisation: Precedent and Prospects. Chem. Sci. 2018, 9, 4203. (d) Gao, K.; Yoshikai, N. Low-Valent Cobalt Catalysis: New Opportunities for C–H Functionalization. Acc. Chem. Res. 2014, 47, 1208. (e) Hartwig, J. F. In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, 2002, pp 1051. (f) Muci, A. R.; Buchwald, S. L. Practical Palladium Catalysts for C-N and C-O Bond Formation. Top. Curr. Chem. 2002, 219, 131. (g) Song, G.; Li, X. Substrate Activation Strategies in Rhodium(III)Catalyzed Selective Functionalization of Arenes. Acc. Chem. Res. 2015, 48, 1007. (h) Gensch,



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