Exploring allene chemistry using phosphorus-based allenes as scaffolds

Synthetic routes to phosphorus-based allenes – isolation of some unusual products

The general method for the synthesis of this class of allenes is well-known and involves the reaction of a precursor possessing a P(III)–Cl bond with a propargylic alcohol [23]. There are other catalytic routes using H-phosphonates [28], [29], but in our reactions we have used P(III)–Cl precursors. One example of such a system using pentaerythritol based P–Cl precursor is shown in Scheme 1a [23]. In contrast to this, facile formation of phosphono-benzazepine 10 by using a nitro-functionalized propargyl alcohol and (OCH₂CMe₂CH₂O)₂PCl (8) via the intermediate 9 has been discovered in our laboratory (Scheme 1b) [30]. An intramolecular cyclization followed by CO₂ elimination is probably involved in this process as evidenced by the X-ray structure determination of 11 that is analogous to 10. In addition to these, when the cyclohexenyl group in the propargylic alcohol is replaced by a phenyl group, N-hydroxy-indolinones of type 12 are formed. Since products 11–12 arise from similar reactions, a common pathway involving an allene intermediate at least in the initial steps is indicated, but the reaction pathway is too complex to be discussed here. Variations of this interesting transformation have been reported from our group recently [31], [32]. As an example, when the monochloro-cyclodiphosphazane precursor 13 was treated with the o-nitro-substituted propargyl alcohol 14, two products (15–16) were obtained. We believe that the oxa-aza-benzocycloheptenone 15 arises from a path only slightly different from that of 10–11. Indolinone 16 must have arisen in a route similar to 12 involving an allene intermediate, but with subsequent rearrangement and phosphorylation of the N–OH group followed by dephosphonylation/partial hydrolysis [32]. What is perhaps more interesting is that hydrolysis of the P–N bond in 15 led to 2-phenyl indole 17 (Scheme 2). The molecular structures of 5, 9 and 15 are shown in Fig. 1.

Scheme 1:

Formation of phosphorus based allenes 5–7 and phosphonobenzazepine 10.

Scheme 2:

Formation of oxa-aza-benzocycloheptenone 15, indolinone 16 and 2-phenyl-indole 17.

Fig. 1:

Molecular structures of allene 5 (left, coordinates from ref. 23), intermediate 9 (center, coordinates from ref. 5) and cyclophosphazane based oxaza-heterocycle 15 (right, coordinates from ref. 32). Selected bond parameters [Å, °] with esds in parentheses. Compound 5: P C4 1.777(4) C4 C5 1.306(6), C5 C6 1.307(6) C4 C5 C6 178.7(5)°. Compound 9: P1 C6 1.822(4), C6 C20 1.318(5), C15 C20 1.533(5), N1 C15 1.478(5), O4 N1 1.475(5), O4 C14 1.362(5), C7 C14 1.522(7), C6 C7 1.549(5). Compound 15: P1 N4 1.697(3), N4 C13 1.428(5), O2 N4 1.447(4), C13 C18 1.424(6), C18 C19 1.449(6), C20 C19 1.340(6), C21 C20 1.484(6), O2 C21 1.370(5).

In a reaction similar to the above, when the propargyl alcohol 18 was treated with two mole equivalents of Ph₂PCl in the presence of a base, one of the allenic CH protons could be substituted from the intermediate 19 to give rise to allenyl-bisphosphine oxide 20 after air oxidation (Scheme 3) [33]. It is likely that the o-nitro group enhances the acidity of the proximal allenyl CH proton. What is perhaps interesting is that small quantities of both the enantiomers of this allene 20 could be isolated. This result represents the first case of spontaneous resolution upon crystallization in allene chemistry.

Scheme 3:

Formation of allenyl-bis(phosphine) oxide 20.

One of the reasons for utilizing the o-nitro-functionalized propargylic alcohols in the above reactions was to use this group for further transformations. Taking a cue from this, we wanted to have functionalized allenes that could be used as precursors for cyclization reactions. In one such study, we synthesized allene precursors of the types 21 and 24. While allene 21 underwent facile hydrolysis using conc. HCl and subsequent cyclization using Et₃N to lead to the phosphinoyl-benzofuran 23via intermediate 22, the other precursor 24 underwent direct cyclization in the presence of ZrCl₄ to afford the phosphinoyl-isochromene 25 (Scheme 4) [31]. Several examples in which the terminal hydrogen atoms of the =CH₂ group of the allene are replaced by other groups also smoothly underwent this cyclization.

Scheme 4:

Synthesis of phosphinoyl-benzofuran 23 and phosphinoyl-isochromene 25via allenylphosphine oxides.

Cycloaddition reactions

With two cumulative and reactive double bonds, allenes are wonderful partners in cycloaddition reactions. They can undergo self [2+2] cycloaddition reaction, and it appears that cycloaddition involving [β, γ] double bonds is generally favored as shown by the formation of [2+2] adduct 27 from allene 26 (Scheme 5) [23]. However, cycloaddition reactions of allenylphosphonates/allenylphosphine oxides with 1,3-diphenylisobenzofuran (DPBF) are perhaps more interesting [34]. When a cyclohexenyl group is present on the α-carbon (e.g. 28), initially the expected [4+2]-[α, β]-cycloadduct 29 is formed, but upon increasing the temperature, retro-Diels-Alder reaction, followed by a novel [4+2+2] cycloaddition takes place leading to the adduct 30 (Scheme 6). To our knowledge, such a cycloaddition was not reported prior to our work. When the allene 26 with =CMe₂ group at the γ-position was utilized, the [β, γ]-cycloadduct 31 was the product which suggested that moderate changes in the substituents had significant impact on the cycloaddition. Taking this as a hint, we have performed the reaction of sulfur based allene 32 with DPBF. Indeed, the [α, β]-cycloadduct 33 that is similar to compound 29 was readily obtained in decent yields (Scheme 6b and Fig. 2 [35], [36], [37], [38]). It can be noted that there are three chiral centers (cf. 29) generated during this process. Thus if the ring bearing phosphorus in the allene has chiral centers, several diastereomeric cycloadducts (either exo or endo) may be generated and in favorable cases, individual diastereomers may be isolated [39]. We had been partially successful in isolating some of these using the allenes 34–35 wherein racemic diols/diamine was used to begin with, but this part requires a more detailed examination.

Scheme 5:

Self [2+2] cycloaddition reaction of allene 26.

Scheme 6:

Cycloaddition reactions of phosphorylated allenes and a sulfonyl allene with DPBF.

Fig. 2:

Molecular structure of compound 33. Selected bond parameters: S1–C21 1.8697(16), C21–C22 1.528(2), C22–C23 1.306(2), C22–C1 1.544(2), O1 C1 1.4448(19), O1 C4 1.4403(19), C2 C3 1.386(2), C2 C1 1.521(2), C4 C3 1.528(2) (Å).

Dimethyl acetylenedicarboxylate (DMAD) is a good dienophile and can react with allenes in many different ways. One such interesting reaction is shown in Scheme 7 [34]. All the phosphono-naphthalenes 37a–c thus obtained are [α, β]-cycloadducts in which the allene with α-phenyl group acts as the diene. It can also be noted that while 37b is a 1:2 adduct, 37c is a 2:1 adduct.

Scheme 7:

Cycloaddition reaction of allenylphosphonate 36 with DMAD.

Nucleophilic addition/cyclization reactions

In several reports, we have elaborated on the synthesis of various phosphono/phosphinoyl-heterocycles by treating allenes with suitably positioned double functional reactants (Scheme 8) [22], [24], [25], [26], [40]. In the first reaction, thiosalicylaldehyde reacts with the allene to give thiochroman 38 [40]. Formation of stereoisomers may be explained by the prevalence of intermediates like I/I′ and II/II′ (Scheme 9). In the corresponding reaction with salicylaldehydes, the initial product in most cases is a similar chroman which undergoes dehydration to give the chromene 39 [22]. In a recent work, when we used dialkyl 2-(2-formylphenyl)malonates in place of salicylaldehyde, phosphononaphthalenes were formed by elimination of one of the carboxylate groups [27]. In a reaction analogous to these, if we use N-protected o-amino benzaldehyde/acetophenone, we obtain phosphono-quinolines of type 40 readily [26]. Interestingly, though, compound 40 readily undergoes thermal phosphono-phosphate rearrangement to lead to the quinoline-phosphate ester 41. In another variation, reaction of allene 36 with 2-formylindole led to phosphono-pyrroloindole 42 [41], in which a new five-membered pyrrole ring is formed as a result of the presence of only one intervening carbon between the NH and CHO groups.

Scheme 8:

Base-catalyzed cyclization reaction of allenes with o-functionalized aldehydes leading to heterocycles.

Scheme 9:

Possible rationalization for the formation of isomeric thiochromans 38.

In the formation of compound 38, it may be noted that the thiol end is bonded to the β-carbon of the allene. In fact, an apparently straightforward reaction of allene 26 with 4-chlorothiophenol under neat conditions leads to the thiolate 43 (Scheme 10) [42]. One should be cautious with respect to precursor 26 since this compound exposed to air for a long time, leads to the peroxo compound 44 and alkynol 45, albeit in small quantities. The latter two compounds were characterized by single crystal X-ray crystallography.

Scheme 10:

Formation of the thiolate 43, peroxo compound 44 and alkynol 45 from the allene 26.

In the reaction cited in Scheme 8 above, it can be noted that the β-carbon of the allene is being attacked by the nitrogen of the amide or indole. In general, it has been noticed that the initial attack of a nucleophile takes place at this carbon, consistent with the greater s-character at this carbon. Several nucleobase appended phosphonates were thus prepared by us earlier; one such products, the cytosine adduct 47 of the allene 46 is shown in Scheme 11a [43]. In the present work, we wanted to use an external nucleophile for cyclization of allenylphosphonate bearing an o-functionality like CO₂Me. For this reason, we treated allenylphosphine oxide 48 with diethylamine (Scheme 11b). Interestingly, this reaction led to the phosphinoylnaphthol 49. Although this reaction needs generalization, it does pave the way for further work in this area. Single crystal X-ray data confirmed the enol-form for compound 49 (Fig. 3) [39].

Scheme 11:

Reaction of allenes with nucleobases and amines – a new cyclization reaction.

Fig. 3:

Molecular structures of compounds 47 (left, coordinates from ref. 43) and 49·1/2 H₃CC(O)OC₂H₅ (right, coordinates from ref. 39). Selected bond parameters follow. Compound 47: P C24 1.778(3), C24 C25 1.338(5), C25 C26 1.430(7), N1 C25 1.446(4) (Å). Compound 49: P1–C1 1.788(5), C1–C10 1.394(7), C10–N1 1.412(7), C10–C9 1.416(7), C9–C8 1.353(7), C8–O2 1.347(6) (Å).

Transition-metal mediated cyclization, in particular [Pd]-catalyzed Heck-type reaction can also be performed on allenes [44], [45], [46]. An interesting case is that by using 2-iodophenol as the reacting partner. By using phosphorus-based allenes, and by the combined use of ³¹P NMR spectroscopy and X-ray crystallography, we have demonstrated that cyclization could be effected via reactions at any of three carbon atoms of the allenes. Two examples of such cyclization involving allenes 26 and 50 that provide the phosphonobenzofurans 51–53 are shown in Scheme 12a. Later, a possible way of maximizing the yields of some of the products by using PEG-400 as the solvent has also been illustrated [45]. The reaction could be extended to include 2-iodobenzyl alcohols also (Scheme 12b), wherein phosphonobenzopyrans (e.g. 54) are the products. Use of 3-iodo-indole-2-carboxylic acid in place of iodophenol results in the formation of indolopyranones (e.g. 55; Scheme 12c) [46]. Thus it is possible to have several variations of this Heck-type of reaction in allene chemistry.

Scheme 12:

[Pd]-catalyzed reaction of allenylphosphonates with 2-iodophenol, 2-iodobenzyl alcohol and 3-iodo-indole-2-carboxylic acid.

The reaction of allenes (e.g. 50, 56) with Me₃SiN₃ (source of HN₃) generates synthetically useful vinyl azides (e.g. 57–58) [47]. It can be noted again that the azide group is on the β-carbon of the phosphonate. These azides undergo thermolysis upon melting to lead to pyrazines 59–60 (Scheme 13a). This kind of reaction does not have precedence in the literature. The vinyl azides (e.g. 58) thus generated can also be utilized in other reactions like that with ethyl acetoacetate to lead to a new class of phosphono pyrazoles (e.g. 61; Scheme 13b). A direct one-pot route to 61 using the allene 56 has also been developed [47].

Scheme 13:

Pyrazine and pyrrole formation via vinyl azides generated from allenylphosphonates.

Phosphonylation of allenylphosphonates leads to phosphonates containing more than one phosphorus atom per molecule [48], [49]. One example of phosphonylation of allene 36 using tetrabutyl ammonium fluoride in ionic liquid that leads to the bisphosphonate 62 is shown in Scheme 14 [48]. This reaction takes place through the intermediacy of pentacoordinate phosphorus intermediate in which the phosphorus is directly connected to the fluoride as evidenced by the combined use of ¹H, ¹⁹F and ³¹P NMR spectroscopic techniques. These products may be of use as ligands if a suitable procedure for the P=O bond reduction can be developed.

Scheme 14:

TBAF mediated phosphonylation of allene 36.