Chemoselective Activation of Diethyl Phosphonates: Modular Synthesis of Biologically Relevant Phosphonylated Scaffolds

Abstract Phosphonates have garnered considerable attention for years owing to both their singular biological properties and their synthetic potential. State‐of‐the‐art methods for the preparation of mixed phosphonates, phosphonamidates, phosphonothioates, and phosphinates rely on harsh and poorly selective reaction conditions. We report herein a mild method for the modular preparation of phosphonylated derivatives, several of which exhibit interesting biological activities, that is based on chemoselective activation with triflic anhydride. This procedure enables flexible and even iterative substitution with a broad range of O, S, N, and C nucleophiles.

The phosphonate functional group remains acornerstone of modern organic chemistry.I ndeed, phosphonic acids and derivatives thereof can be found in the scaffolds of arange of bioactive products (Scheme 1). [1] Among them, aminophosphonates are commonly used as analogues of amino acids. [2] As phosphonates present enhanced resistance towards hydrolysis,t he phosphonate moiety has proven very useful in the development of potential drugs and agrochemicals. [3] Thesynthesis of phosphonates classically relies mainly on two different strategies,n amely on either the action of at rialkyl phosphite on an alkyl halide (Michaelis-Arbuzov reaction) [4] or am etal-mediated coupling with dialkyl phosphite. [5] Although these methods are efficient, they only lead to symmetric phosphonates (i.e., phosphonates of the form RP(O)(OR') 2 ). To access mixed phosphonates,ag eneral method consists of preforming either ad ichloro-or am onochlorophosphonyl derivative from ar eadily available symmetric phosphonate with astrong chlorinating agent, or from ap hosphonic acid ester with classical acid activation. These intermediates can then be substituted by different nucleophiles as shown in Scheme 2a. [1e,6] Depending on the chlorinating agent used, some lack of selectivity between monoand disubstitution was observed when phosphorus pentachloride was used. [7] Moreover,t hese are somewhat harsh reagents with low functional group tolerance.H owever, milder chlorinating agents,s uch as oxalyl chloride,c an be used to efficiently yield the monochlorinated product. [8] An elegant approach employing copper catalysis and diaryliodonium reagents has been developed to substitute phosphonates,b ut it is limited to aryloxy modifications. [9] Selective reductions [10,11] or arylations [12] of aryl phosphine oxides or phosphonates have been achieved with different activating agents.T he Atherton-Todd reaction is also an elegant approach for the synthesis of phosphonamidates and phosphoramidates with global inversion of configuration. [13] Scheme 1. Selected examples of phosphonate-containingb iologically active compounds.
Herein, we present an approach to the substitution of phosphonates.T his strategy relies on electrophilic activation with triflic anhydride followed by the addition of ac hloride source to selectively and transiently yield amonochlorophosphonyl species.I nsitu attack by an ucleophile then provides asimple and versatile approach for the synthesis of arange of not only phosphonates,but also phosphonamidates,phosphonothioates,and phosphinates (Scheme 2a). [14] Phosphonates can be activated with triflic anhydride to give phosphonium ion I.Then, an Arbuzov reaction can occur promoted by triflate and 2-iodopyridine (see the Supporting Information for details) to yield the mixed phosphonate II. Simple substitution with achloride forms III,which ultimately generates the expected product after addition of the deprotonated nucleophile (Scheme 2b). In contrast to ar eport by Kang and co-workers, [14] the replacement of the triflate by the pyridine on intermediate II was not observed.
Our investigations started with phosphonate 2a as the substrate and sodium isopropoxide as the nucleophile (Table 1; for full optimization details and mechanistic investigations by 31 PNMR spectroscopy,s ee the Supporting Information). We found that reproducibly high yields of product were obtained when 2-iodopyridine was employed as the base (entry 1) instead of pyridine (entry 2). Using tetraethylammonium chloride as the chloride source (entry 3) avoided the formation of unidentified side products. Theu se of trifluoromethanesulfonyl chloride did not lead to any conversion (entry 4). Ultimately,t he optimized conditions allowed full conversion into the desired product (entry 5), which was isolated in 60 %yield.
Ther eaction displays excellent functional group tolerance.I ndeed, reactive functional groups such as ap hthalimide-protected amine (2j), an ester (2k), or an itrile (2n) were all well-tolerated. This unique chemoselectivity is all the more noteworthy as even ap rimary alkyl bromide (2m)i s tolerated without competing S N 2s ubstitution taking place. Theu se of vinyl, phenyl, or alkynyl phosphonates was also possible (2o-2q). Finally,t his method was applied on 15 mmol scale to prepare 2.2 go ft he phosphonate 2r in av ery good 82 %yield.
ar ange of thiols,i ncluding decanethiol (3a), benzyl mercaptan (3b), and the bulkier cyclohexanethiol (3c)a nd tertbutylthiol (3d), were all competent nucleophiles for this process.F inally,s ubstitution with aryl thiols allowed us to prepare 3e and 3f. Eager to access phosphonamidates by as imilar process, we decided to study the addition of nitrogen nucleophiles (Scheme 4). We found that upon deprotonation with NaH, sulfonamides are competent partners in this reaction. Thus the nosyl phosphonamidate 4a and the tosyl phosphonamidates 4b and 4c were readily accessed, the latter carrying aprotected glycine moiety.V aluable amines,such as morpholine,piperazine,and difluoropyrrolidine,were added as their lithium amides to prepare 4d, 4e,and 4f,respectively,invery good yields.T he acyclic substrates methylallylamine and dimethylamine were also viable nucleophiles,d elivering the corresponding phosphonamidates 4g and 4i in lower yields whilst benzylamine afforded 4h in good yield.
At this point, we envisioned that alkynes could be attractive nucleophiles for the preparation of phosphinates. Theterminal alkynes were deprotonated with n-butyllithium prior to addition (Scheme 4). Theu se of ab enzyl-protected propargyl alcohol led to the formation of 5a in good yield. Tr iisopropylsilylacetylene could also be used to generate phosphinate 5b in an excellent yield of 90 %, and athiophene ring was also tolerated (5c). Phosphinates bearing alkyl chains such as cyclopropyl (5d), decyl (5e), or phenylpropyl (5g)were efficiently prepared. Phenylacetylene could also be used to form 5f.
Having demonstrated that abroad range of nucleophiles, including heteroatom nucleophiles,p erform competently in this substitution reaction, we were intrigued by the possibility of achieving sequential double substitution. Indeed, as the products still carry one OEt moiety,w eh ypothesized that renewed activation and substitution would lead to an iterative procedure for decorating ap hosphorus center in af lexible manner.I ndeed, starting from phosphonate 1l,afirst substitution with phenol yielded the mixed phosphonate 2s in high yield. Renewed activation of 2s enabled displacement with morpholine to form the modularly assembled phosphonamidate 6a in moderate yield (Scheme 5a). An iterative substitution was also possible on phosphinate 5b with propargyl alcohol, affording product 6b in moderate yield.
As mentioned in the introduction, phosphonylated compounds exhibit aw ide range of biological activities.W e therefore envisaged the preparation of various bioactive targets using this method (Scheme 5b). Fori nstance,t he mixed phosphonate 7 presents antituberculosis properties. [1f,g] This compound was readily prepared using the novel method reported herein in as ingle step from commercially available diethyl butylphosphonate (1n)a nd the commercially available benzylic alcohol derivative in 55 %y ield. Thei ncorporation of phosphonamidates into peptide chains is particularly interesting. In particular, phosphonamide surrogates of glycine-proline are appealing for their singular stability and reactivity,w hich are due to the slightly pyramidal nitrogen atom. [15] In this context, we decided to investigate the use of proline as an ucleophile.P hosphonamidate 8 was indeed accessed in moderate yield. After preparation of phosphonothioate 3g from phosphonate 1k,d isplacement of the bromide with N-phenylpiperazine yielded 9,acompound exhibiting hypotensive activity. [16] Furthermore,w ep repared phosphinate 5h as ap atented precursor to ap hosphate transport inhibitor. [17] Finally,the nosyl group on phosphonamidate 4a could be efficiently cleaved under classical conditions to yield the deprotected compound 10 (Scheme 5c).
In conclusion, we have developed am ild electrophilic activation method that enables the chemoselective substitution of phosphonates in the presence of arange of functional groups such as esters,n itriles,o rh alides.B yf ollowing this procedure,aplethora of O, N, S, and Cnucleophiles can be added to efficiently prepare mixed phosphonates,phosphonamidates,p hosphonothioates,a nd phosphinates,r espectively (several of them are bioactive substances). We believe that the mild conditions and high functional group tolerance of this procedure are well suited for late-stage functionalization Scheme 4. Scope with amine and alkyne nucleophiles. Yields refer to isolated, pure compounds.S ee the Supporting Information for the reaction conditions. 2-Iodopyridine (1.5 equiv) and triflic anhydride (2 equiv) were added to asolution of the phosphonate (0.2 mmol) in CH 2 Cl 2 (4 mL) at 0 8 8C. After 30 min, TEAC (2.5 equiv) was added at 0 8 8C. After another 15 min, asolution of deprotonated nucleophile (4 equiv) in THF (2 mL) was added, and the reaction mixture was stirred at room temperaturef or 18 h. *NaH used for the deprotonation. ** Tetrabutylammonium chloride was used instead of TEAC. Bn = benzyl, TIPS = triisopropylsilyl. and the modular decoration of phosphorus centers in medicinal and agricultural chemistry.