Cu-Catalyzed Direct C-P Bond Formation through Dehydrogenative Cross-Coupling Reactions between Azoles and Dialkyl Phosphites

Article abstract of DOI:10.1021/acs.joc.9b00670

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 catalyst and K₂S₂O₈/di-tert-butylperoxide as oxidant has 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.

Full text of DOI:10.1021/acs.joc.9b00670

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Article
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
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Cu-Catalyzed
Direct
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Dehydrogenative Cross-Coupling Reactions between Azoles and
Dialkyl Phosphites
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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
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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 Pd-
catalyzed 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
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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-2-
ylphosphonates. Cai and co-workers14b has made an attempt to phosphonate benzoxazoles and
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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.
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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-2-
phosphonate 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.
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Table 1.a Optimization of Reaction Conditions for the Phosphonation of Benzothiazole 1
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aReaction Conditions 1a:6c = 1:2, for 0.2 mmol scale, solvent 2mL. entry 3-16, run for 24 h.
cIsolated yield. TBHP = tert-Butylhydrogenperoxide, DMA = N,N-Dimethylacetamide. ND = not
detected.
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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-2-
phosphonates 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-(2-
fluorophenyl) 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.
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aReaction 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.
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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.
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Table 3.a Optimization of Reaction Conditions for the Phosphonation of N-Pyrimidine
Protected Benzimidazole 5
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aReaction Conditions: 5a:6c = 1:3, for 0.2 mmol scale, solvent 2mL. Isolated yield. DCE = 1,2-
Dichloroethane. DMF = N,N-Dimethylformamide. DTBP = Di-tert-butylperoxide. ND = not
detected.
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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-pyrimidine-
protected 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-pyrimidine-
protected 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).
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Table 4.a Scope of CuBr-Catalyzed Phosphonation of Imidazoles 4, and Benzimidazoles 5
aReaction 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
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in %. EtOAc is used as solvent. Ag2CO3 is used as oxidant. DCE:Chlorobenzene (1:1) is used
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as solvent. ND = not detected.
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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 Cu-
salts/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).
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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
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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 N-
pyrimidine-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].
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Scheme 3. Control Experiments with Radical Scavengers TEMPO and BHT.
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Scheme 4. Kinetic Isotope Effecta
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aStudied 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
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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.
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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
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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.
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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 2-
aminobenzothiazoles from corresponding anilines and, second step is deamination of 2-
aminobenzothiazoles which generates benzothiazoles. The details of these steps are as follows -
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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 2-
aminobenzothiazoles (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
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hydrodeaminated benzothiazoles 1b-1c as a colorless oil. All H and 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 Et2O. 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-(2-
fluorophenyl)oxazole-4-carboxylate 2.
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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
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Step 1: Synthesis of Respective o-Phenylenediamines - Into a solution of 4,5-dibromo-1,2-
phenylenediamine (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.
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Step 2: Synthesis of Benzimidazoles from corresponding o-Phenylenediamines - o-
Phenylenediamines 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
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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.
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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 pre-
heated 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
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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.
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The spectral and analytical data of all the compounds are given as follows:
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Methyl 5-(2-fluorophenyl)oxazole-4-carboxylate (2): White gummy solid, mp = 43-45 ˚C; H
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.
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2-(4,5-Diphenyl-1H-imidazol-1-yl)pyrimidine (4b): White solid, mp = 120-122 ˚C; H 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), 4.46-
4.30 (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; H
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.
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5,6-bis(4-methoxyphenyl)-1-(pyrimidin-2-yl)-1H-benzo[d]imidazole (5d): Pink Solid, mp = 145-
147 ˚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 = 188-
190 ˚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
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liquid; H 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).
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Dibutyl benzo[d]thiazol-2-ylphosphonate(7b):14b (yield 63%, weight 45.3 mg); pale yellow
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liquid; H NMR (400 MHz, CDCl3):  8.24 (d, J = 7.72 Hz, 1H), 8.01 (d, J = 7.84 Hz, 1H),
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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).
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Diisopropyl benzo[d]thiazol-2-ylphosphonate (7c): (yield 64%, weight 38.3 mg); pale yellow
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liquid; H 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,
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J = 6.53 Hz). P 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
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mg); pale yellow liquid; H 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,
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9H). C{1H} NMR (100 MHz, CDCl3):  160.3 (d, J = 241.60 Hz), 153.1 (d, J = 26.5 Hz),
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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.
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Methyl 2-(dimethoxyphosphoryl)-5-(2-fluorophenyl)oxazole-4-carboxylate (8a): (yield 46%,
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weight 30.3 mg); pale yellow liquid; H NMR (300 MHz, CDCl3):  7.64-7.59 (m, 1H), 7.49-
7.41 (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%,
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weight 33.1 mg); pale yellow liquid; H NMR (300 MHz, CDCl3):  7.63-7.58 (m, 1H), 7.48-
7.41 (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 =
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5.98 Hz), 51.2, 22.9 (d, J = 4.11 Hz), 22.6 (d, J = 5.04 Hz). F NMR (376 MHz, CDCl3):  -
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110.48 (s). P NMR (121.5 MHz, CDCl3):  - 6.17 (s). HRMS (ESI/QTOF), m/z: [M+Na]+
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Calcd. for C17H21FNNaO6P, 408.0983; Found: 408.0962.
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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).
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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
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(m, 5H), 1.45 (dd, J1 = 14.75, J2 = 7.37 Hz, 5H), 0.94 (t, J = 7.31 Hz, 7H). C{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
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mg); pale yellow liquid; H NMR (300 MHz, CDCl3):  7.87 (s, 1H), 7.56 (s, 2H), 5.05-4.83
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(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).
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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
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Hz, 6H), 1.41 (d, J = 5.80Hz, 6H). C{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
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yellow liquid; H 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,
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J = 5.44Hz, 6H). C{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.
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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 NMR (162 MHz, CDCl3):  - 5.03 (s). HRMS (ESI/QTOF), m/z: [M+Na]+
Calcd. for C13H17BrNNaO4P, 383.9971; Found: 383.9961.
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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 NMR (162 MHz, CDCl3):  - 5.09 (s). HRMS (ESI/QTOF), m/z: [M+Na]+
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
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yellow liquid; H NMR (300 MHz, CDCl3):  7.53-7.44 (m, 2H), 7.20-7.12 (m, 1H), 4.95-4.84
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(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,
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CDCl3):  -116.4 (s). P 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
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(d, J = 4.10 Hz), 23.7 (d, J = 5.04 Hz). P 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
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mg); pale yellow liquid; H 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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