Allenylphosphine oxides as simple scaffolds for phosphinoylindoles and phosphinoylisocoumarins

Summary A range of phosphinoylindoles was prepared in one-pot from functionalized propargyl alcohols and a suitable P(III) precursor via a base-mediated reaction. The reaction proceeds via the intermediacy of allenylphosphine oxides. Similarly, phosphinoylisocoumarins were prepared from allenylphosphine oxides in a trifluoroacetic acid-mediated reaction; the latter also acts as a solvent. Interestingly, in the presence of wet trifluoroacetic acid, in addition to phosphinoylisocoumarins, phosphorus-free isocoumarins were also obtained. Key products were characterized by single crystal X-ray crystallography.

It may also be noted that organophosphonates in addition have wide applications in medicinal chemistry [3,18,19] and as reagents in organic synthesis [20]. In our previous reports, we described the utility of phosphorus-based allenes in various cyclization reactions involving heteroatoms that could lead to phosphono/phosphinoyl hetero-/carbocycles [21][22][23][24][25][26][27][28][29][30]. The reported series include phosphonobenzofurans/indenones [21,22], -pyrazoles [23], -chromenes/thiochromenes [24,25], -pyrroles [26], multiply substituted furans [27], indolopyran-1ones [28], N-hydroxyindolinones [29], and oxindoles [30]. In the reaction shown in Scheme 1a, for the formation of the phosphinoylindolinone, one of the oxygen atoms of the nitro group has been moved to a carbon [29]. The reaction shown in Scheme 1b led to rather previously unsuspected and unexpected benzazepines as products. After the elimination of a CO 2 molecule, this reaction also features an unprecedented rearrangement involving the interemdiate allene [29]. Many other unusual transformations have also been reported recently [31]. In another reaction leading to phosphinoylindenone depicted in Scheme 1c, an intramolecular ene-reaction is possibly involved and in Scheme 1d the reaction led to phosphinoylisochromenes via deprotection of an allene intermediate under Lewis acid mediation [22]. In this context it was of interest to see, in a reaction like that shown in Scheme 1c, whether the introduction of an amide or a carboxylate ester in place of the -CHO group could lead to phosphinoyl-subtstituted indoles/isocoumarins via allenic intermediates or not. It is pertinent to note that indoles and isocoumarins are core structures found in many natural and pharmacological products [32][33][34]. Thus in this paper, we wish to report simple synthetic routes to phosphinoylindoles, and -isocoumarins utilizing functionalized allenylphosphine oxides/allenylphosphonates.
After having several functionalized allenes in hand, initially we chose allenes 3a and 3m to achieve intramolecular cyclization. These were treated with 0.5 mol equivalents of base (K 3 PO 4 ) since the substrates contain active hydrogen. This reaction afforded the N-substituted phosphinoylindoles 5 and 7, 8. Essentially a single isomer 5 (a dihydroindole), in which the  yields of the isolated products were excellent in both cases. The structure of compound 7 was further confirmed by X-ray crystallography ( Figure 2). The C=CHMe distance of 1.317(2) Å clearly indicates a double bond between these two carbon atoms. The other stereoisomer in which the methyl group is trans to the nitrogen was not observed. Interestingly though, the removal of the acyl/benzoyl group on the nitrogen in compounds 5 or 7, 8 in aq NaOH afforded the 2,3-disubstituted NH-indoles 6 or 9, respectively, in excellent yields. The NH band (3156 cm −1 ) in the IR spectrum and a doublet for PC carbon at δ 98.4 ( 1 J(PC) = 128.0 Hz) reveal the identity of compound 9. Its structure was further confirmed by X-ray crystallography ( Figure 3).
Subsequently, we used aq sodium hydroxide as the base instead of K 3 PO 4 (cf. conditions (ii) in Scheme 3) to perform the reaction on allene 3a. To our delight, only phosphinoyl-NH-indole 6 was the sole product with not even traces of 5 (Scheme 4). This shows that a strong base like sodium hydroxide effectively performs both deprotection and cyclization in a single step.
With the above conditions in hand, we then performed the reaction in one pot starting from propargyl alcohol 1a without  isolating the intermediate allenylphosphine oxide 3a. Gratifyingly, the method furnished the desired product 6 in 80% yield. Inspired by this, functionalized propargyl alcohols 1b-l were also subjected to the same one-pot conditions (Scheme 5). This one-pot strategy furnished the desired phosphinoylindoles 9-19 in good to excellent yields without any difficulty in isolation. Analogous products could also be isolated using the P(III) precursor (OCH 2 CMe 2 CH 2 O)PCl (see Supporting Information File 1 for details). In our attmept to obtain phosphorus-free 2-alkylindole from 17 in the presence of triflic acid (as a solvent; 100 °C) led to a mixture of products in which the benzyl group also was cleaved (NMR evidence). Such a reductive cleavage of the P-C bond from phosphinoyl indoles is a reaction that we are still exploring.
A plausible pathway for the formation of phosphinoylindoles 6 and 9-19 is shown in Scheme 6. As depicted above in Scheme 2, the normal reaction of propargyl alcohol with chlorodiphenylphosphine is expected to lead to the allenylphosphine oxide. We believe that there is a subtle difference between the use of K 3 PO 4 and aq NaOH. K 3 PO 4 abstracts the NH proton from allenylphosphine oxide leading to intermediate I which is followed by attack of the nitrogen lone pair on the β-carbon [24] of the allene forming addition product II or III. This upon treating with aq NaOH leads to the deacylated/debenzoylated phosphinoylindoles. In the one-pot reaction, though, the in situ generated allenylphosphine oxide first undergoes deacylation/debenzoylation with aq NaOH resulting in -NH 2 functionalized allene IV; the lone pair on nitrogen will then attack the β-carbon of the allene intramolecularly leading to phosphinoylindoles 6 or 9-19.
After succeeding in generating phosphinoylindoles, we then concentrated on synthesizing phosphinoylisocoumarins. To achieve this, we treated the functionalized allene precursors 4a-j that are tethered with a methyl ester group, with an excess of trifluoroacetic acid at room temperature for 6 h. Gratifyingly, this readily leds to the phosphinoylisocoumarins 20-29 (Scheme 7) in good yields. In the case of compound 25, as expected, both the E and Z isomers are present in a ratio of 1:0.65 (close R f values). Very subtle energy differences seem to be prevalent between the dihydroisocoumains 22, 24, 25, 28, 29 and the normal isocoumarins 20, 21, 23, 26, 27. The former set shows a doublet in the 1 H NMR spectra at δ ~ 4.78 ( 2 J(P-H) = 18.0 Hz, PCH) which is absent in the latter set; the difference in the value of 1 J(P-C) in the two sets is also consistent with the hybridization at the corresponding α-carbon (to phosphorus). Finally, the X-ray structure was determined for 20 ( Figure 4).
The above reaction is believed to proceed by the initial interaction of H + with the α,β-allenic double bond to lead to V (Scheme 8) which on subsequent attack of oxygen of the ester group onto the β-position of allene forms VI. Intermediate VI on demethylation leads to phosphinoylisocoumarin VII. This product VII further involves the double bond isomerization to  Alternatively, the cyclization may also proceed after the hydrolysis of ester group to -COOH due to the presence of adventitious moisture in trifluoroacetic acid. When the above reaction was performed in wet trifluoroacetic acid (TFA/H 2 O = 20:1) at 70 °C, phosphinoylisocoumarins were formed in all cases, but additionally, phosphorus-free isocoumarins 30-35 (Scheme 9) [37] are also formed in the reaction using terminally substituted allenes 4b-d and 4h-j. We have also determined the X-ray structure of compound 33 ( Figure 5) for final confirmation. It is possible that isocoumarins 30-35 are formed via the intermediates VIII-IX (Scheme 10) [40]. The phosphorus moiety of IX may then be cleaved as Ph 2 POOH to form the phosphorus-free isocoumarins. Since this was not the interest in the present study, we did not proceed further.

Conclusion
A fairly simple route to phosphinoylindoles and phosphinoylisocoumarins starting from functionalized propargyl alcohols via allenyl phosphine oxide is developed. The first reaction involves base-mediated deprotection and cyclization while the latter methodology involves acid mediation in which trifluoroacetic acid acts as the reagent as well as the solvent.