Cyclic oxyphosphoranes in synthesis. A novel synthesis of oxathiaphospholenes, fused pyrimidines, and aminooxyphosphoranes

Trialkyl phosphites induced the condensation of one molecule of 3,5-di-tert -butyl-1,2-benzoquinone ( 1 ) with two molecules of methyl-, ethyl-, phenyl-and hexyl iso thiocyanates ( 6a-6d ) leading to the formation of quinazoline-2,4-dithione derivatives ( 12a, 12b, 14, and 15 ) and trialkyl phosphates. Three steps were involved, and the intermediates could, but need not, be isolated. In the second step, the intermediates, new six-membered phosphorus heterocycles 8a-8d were isolated and identified. In contrast, condensation of 4,6-di-tert -butylbenzo-2-methoxy-2- oxo-1,3,2-dioxaphosphole ( 19 ) with one molecule of 6a-6d afforded the corresponding aminooxyphosphoranes 22a-22d . Allyl iso thiocyanate ( 16 ), on the other hand, reacted with 2,2,2-trialkoxy-1,3,2-dioxaphospholenes 3a and 3b to give the phosphates 18a and 18b whereas with 19 spirocyclic oxaphosphole 24 was isolated.


Introduction
Cyclic pentacoordinate phosphoranes are compounds possessing a phosphorus atom to which five ligands are covalently bonded.They are useful models for intermediates in phosphate ester hydrolysis. 1 The inclusion of five-membered cyclic substituents in phosphoranes has aided the interpretation of the great acceleration in hydrolysis of similarly constructed cyclic phosphole esters, which is of importance in biological mechanisms.The latter interpretation has been summarized in Westheimer model.1b Although there exists a wealth of studies on the synthesis, structure 1,2 , and synthetic potential 3,4 of phosphoranes containing five-membered rings, little is known about the six-membered rings. 5he latter, which, are present in trigonal bipyramidal arrangements are expected to exert less ring strain than the five-membered rings. 5n the present work, it is intended to investigate the electrophilic addition reactions of some isothiocyanates 6a-6d and 16 to 2,2,2-trialkoxy 4,6-di-tert-butylbenzo-1,3,2-dioxaphospholenes 3a and 3b, attempting not only to study the regioselectivity of the reactions but also to isolate oxathiaphosphoranes containing six-membered rings and biologically active pyrimidine derivatives.Pyrimidines were originally synthesized as compounds bearing structure kinship to many potent chemotherapeutic agents. 6Condensation of the relevant cyclic enediol methylphosphate 19 with 6a-6d and 16 was also studied.The result is the formation of aminooxyphosphoranes 22a-22d and cyclic spiro oxaphospholes 24, respectively.
In one of our previous studies 7,8 on the reactivity of P(III) and P(V) reagents toward 3,5-ditert-butylbenzoquinones, we reported 7 that o-quinone 1 reacted with trialkyl phosphites 2a and 2b to give pentaoxyphosphoranes 3a and 3b, as presumably observed with o-quinones, whereas when reacting with dialkyl phosphonates an anomalous behavior was shown, whereupon a ring attack occurred to give phosphonate adducts 5a and 5b.It has been also pointed out that when 3a and 3b were treated with dry HCl gas in ether, o-quinol monophosphates 4a and 4b were produced (Scheme 1).The latter observation was attributed to the substitution pattern in 1, which would obstruct (for steric reasons 9 ) a nucleophilic approach by the phosphorus moiety to C-2(O); i.e. the effect of the neighboring t-Bu moiety on the C-2(O) group would be quite unfavorable.

Results and Discussion
The 2,2,2-trialkoxy-1,3,2-dioxaphospholenes (DOP) 3a and 3b, prepared from o-quinone 1 and trialkyl phosphites 2a and 2b, 7 reacted smoothly with methyl-6a and ethyl isothiocyanates (6b) in methylene chloride at 25 o C and yielded, in each case, only one regioisomer of structure 8. Oxathiaphospholenes 8a-8d are quite stable and will remain intact for months if stored frozen under argon.The assigned structure was determined to be 8 rather than 9 or 10 based on the following: (a) Compatible elementary analyses and molecular weight determinations (MS) were gained for all adducts.(b) Compounds 8a-8d had 31 P NMR (CDCl 3 ) chemical shifts around δp -66 ppm vs. H 3 PO 4 , which are within the range expected for oxathiaphosphoranes, and can readily eliminate a structure like 9, which would predict a chemical shift in the range δp -30 to -40 ppm in their 31 P NMR spectra.(c) The IR (KBr) spectrum of 8a, taken as an example, revealed the presence of absorption bands at 3450 (OH), 1672 (= NMe), and at 1030 cm -1 (P-O-Me).(d) The 1 H NMR (CDCl 3 ) spectrum of 8a had two 9 1 H singlets at δ 1.25 and 1.34 that correspond to the protons of the tert-butyl groups.The 3 1 H singlet at 3.18 was assigned to N-CH 3 .The 9 1 H of the three-methoxy groups attached to the phosphorus atom gave rise to one doublet ( 3 J PH = 12.5 Hz) at δ 3.69 ppm.Moreover, the two doublets (2 x 1H, J HH = 4 Hz)) at δ H 6.23 and 6.99 assignable to protons on C-7 and C-5 in the 1 H NMR spectrum of 3a 7 were absent in the PMR spectrum of the adduct 8a.Instead, a singlet at δ H 6.98 accounted for the proton on C-6 in PMR of 8a, while the broad signal present around δ 8.76 ppm was assigned for the phenolic OH group.The more plausible depiction suggested by the editor, of the electrophilic aromatic substitution of an iso thiocyanates is outlined in Scheme 2. Accordingly, the formation of 8a-8d involves the initial electrophilic aromatic substitution in which the highly activated aromatic ring (contains two OR groups, cf Scheme 1-ii) 7,9 suffers an electrophilic attack by the weak electrophile 6 to give the zwitterionic intermediate 7A.Rearrangement of 7A to 7D via the intermediates 7B and 7C, and subsequent aromatization with concomitant proton-shift then leads directly to 8. The ring attack of iso thiocyanates to dioxaphospholenes has been previously reported by Neidlein and Mosebach 10a for the reaction of 2,2,2-trimethoxy cyclohexane-1,3,2dioxaphospholene.Furthermore, the formation of the six-membered phosphorus heterocycles 8 instead of the aminotetraoxyphosphoranes 9 is consistent with the reports 4,11 on the relative stabilities of these ring systems.It is pointed out that the alternate cyclization of 7 to 9 would give a phosphorane with one N and four O attached to phosphorus.Due to the larger steric requirements associated with the azaphosphorane vs. oxathiaphosphorane, the former are favored over the latter, i. e. 8 should be formed.However, the formation of 8 in one concerted step that requires little or no charge separation, i.e. without the transient state such as 7, was also reported.11a,b Furthermore, a structural isomer of the spiro-1,3,2-oxathiaphospholene 10, which would arose 4 by the nucleophilic addition of a carbon atom of the phospholene 3 to the carbon of iso thiocyanate, could not be isolated.The loss of aromaticity is most likely the reason 10 is not formed.
The phospholenes 8a-8d were further allowed to react with a second molecule of alkyl isothiocyanates 6a and 6b in methylene chloride.The reaction had a 1:1 stoichiometry and produced trialkyl phosphates 13a and 13b together with 5,7-di-tert-butyl-8-hydroxy-1,3dialkylquinazoline-2,4(1H,3H)-dithiones 12a and 12b in good yields.The rates of the reactions of alkyl iso thiocyanates with the phospholenes 3 and with the phospholenes 8 were very similar.Therefore, the best procedure to make 8 involved slow addition of 6a (and 6b) to 3a (or 3b) in CH 2 Cl 2 at -5 → 0 o C. On the other hand, compounds 12a and 12b were isolated in ~80% yields when 2.2 mol of iso thiocyanates 6a (or 6b) and 1mol of the phospholenes 3a (or 3b) were allowed to react in boiling CH 2 Cl 2 solution.Small amounts of a second substance 8 could not be detected in this reaction.Compounds 12a and 12b had infrared bands at υ ≈ 3450, 1185 and 1190 cm -1 attributed to the phenolic OH and the two-thione groups.The 1 H NMR spectrum of 12a had the expected 18 1 H tert-butyl singlets at δ1.23 and 1.46 along with two 3 1 H signals at δ 3.21 and 3.26 ppm due to the two N-Me groups.Carbon atoms of the N-Me groups in the 13 C NMR spectrum of 12a appeared at δ 39.7 and 42.5 ppm.
When phenyl-6c and cyclohexyl isothiocyanates 6d were caused to react with equivocal amount of phospholenes 3a (or 3b), the starting P(V) 3 was not totally consumed until the second equivalent of isothiocyanate was added.The pyrimidinedithiones: 14 (80% yield) and 15 (82% yield) were the reaction products whereas thiaphospholene analogs of 8 could not be isolated from these latter reactions.Obviously, the formation of 14 and 15 involved the transformation of the initially formed 7 to 8 analogs.However, these very sterically hindered molecules apparently underwent a fast follow up reaction with 6c (or 6d to form 14 (or 15).Since the latter reaction is faster than the initial reaction of 3 with 6c (or 6d), 7 (or 8) are not fully consumed.In contrast to the findings obtained from the reactions of 3a and 3b with 6a-6d, protonation of the iso thiocyanate occurred when 3a and 3b were allowed to react with allyl isothiocyanate 16 and gave 1:1 adducts formulated as thiocarbamyl phosphates 18a and 18b.A possible mechanism for this reaction is illustrated in Scheme 4. At the stage of the formation of the dipolar ion 17, the proton can shift from C-6 to nitrogen instead of C-2 (O) (cf.Scheme 2) with considerable resonance stabilization to give 17.Dealkylation of 17 with adventitious moisture yielded the final products 18a (or 18b).Compounds 18a (or 18b) was isolated as a sole reaction product whether one or two moles of 16 were used in the above reaction.Furthermore, no reaction was observed when 18 was caused to react with a second mole of 16.
Next, the cyclic enediol phosphate-iso thiocyanate condensation was investigated.The required phosphate 19 was readily obtained in 74% yield by O-acylation of the oxaphospholene 3a, using freshly distilled acetyl chloride as an acylating agent and acetonitrile as a solvent.The ester 19 reacted with isothiocyanates 6a-6d and gave the corresponding aminooxyphosphorane derivatives 22a-22d, according to Scheme 5. Isomerization of 21 to 22 is not surprising as it is known that the iminophosphoranes like 21, rapidly rearrange and/or dealkylate to the aminooxyphosphoranes. 13 Products 22a-22d had singlets around δ 19 ppm in their 31 P NMR spectra, 14 while their IR spectra revealed a strong absorption band at υ ≈ 1237 cm -1 (P=O).The 1 H NMR spectrum of 22a showed the presence of a doublet ( 3 J PH = 10.8Hz, 6H, N(CH 3 ) 2 ) at δ 3.18, whereas the aromatic protons gave two doublets (each with J HH = 4.0 Hz) at 6.23 (7-C-H) and 6.99 (5-CH).Its 13 C NMR spectrum displayed carbon resonance of dimethylamine at δ 36.3 ppm.

Conclusions
A comparison of the behavior of 1,3,2-dioxaphospholenes 3a, 3b and the enediol cyclophosphole 19 toward iso thiocyanates 6a-6d is instructive.The key intermediate in the dioxyphosphoraneiso thiocyanates condensation is the iminothiaphospholenes 8a-8d, which is derived from the ring attack.These intermediates were, in turn capable of nucleophilic addition by nitrogen to iso thiocyanates yielding the 1:2 adducts 12a, 12b, 14 and 15.In the second step, the driving force is the ejection of trialkyl phosphate.On the other hand, nucleophilic addition of phosphoryl group in the phosphole 19 to the isothiocyanates was observed in the second reaction and afforded aminooxyphosphoranes 22a-22d.Finally, although the first step in the two reactions of allyl isothiocyanate 16 with either 3a, 3b or 19 is the same as other iso thiocyanates, the consequences of the initial step varied markedly and yielded the phosphates 18a, 18b or spiro compound 24, respectively.Finally, it is note worthy that the two novel systems studied: 1,3-substituted quinazoline-2,4 (1H, 3H)-dithiones 12a, 12b, 14 and 15 and spiro[benzo-1,2-dioxaphosphole-2,2'-pyrrole] 24 have not been described in the literature (Beilstein research) and that the described method in this work is a reasonable way of making them.

Experimental Section
General Procedures.Melting points are uncorrected.Infrared spectra were measured with a Perkin-Elmer IR-spectrometer model 597 using KBr discs.The 1 H and 13 C NMR spectra were recorded with a Bruker Model WH-300 MHz spectrometer, using TMS as an internal reference.Chemical shifts are given in the δ-scale (ppm), coupling constants J in Hz.The 31 P NMR spectra were run on a Varian CFT-20 relative to external H 3 PO 4 .Mass spectra were performed at 70 eV on a Schimatzu GCS-QPEX spectrometer provided with a data system.The appropriate precautions in handling moisture-sensitive compounds were observed.Light petroleum refers to the fraction 40-60 o C. o-Quinone 1 and iso thiocyanates 6a-6d and 16 are available from Aldrich Company.

Reaction of dioxaphospholenes 3a and 3b with phenyl-6c and hexyl isothiocyanates (6d)
When a mixture of equimolar amounts of 3a (or 3b) and the appropriate iso thiocyanate 6c (or 6d) in CH 2 Cl 2 whereby the procedure and the workup were the same with 6a (or 6b) (General Procedure).The product was 14 (or 15) in ~ 30% yields along with unchanged 3a (or 3b).There was no experimental indication of the presence of the oxathiaphospholene analogs.The reaction was repeated using one mole equiv of 3a (or 3b) and two equivs of 6c (or 6d) in boiling CH 2 Cl 2 for 8 h; and then the mixture was freed from the solvent and trialkyl phosphate.The residue was crystallized from the appropriate solvent to give 14 (or 15).Yields, physical and spectral data were listed in Tables 1, 2, and 3.
Compounds 14 and 15 could also be obtained in ≈ 55% yields, according to method 3. Reaction of dioxaphospholenes 3a and 3b with allyl iso thiocyanate (16).A solution of 1.45 mmol of the phospholene 3a (or 3b) in 15 mL CH 2 CL 2 was added dropwise at 0 o C to a solution of 145 mg (1.46 mmol) of ally iso thiocyanate (16) in 15 mL of CH 2 Cl 2 .The reaction was mildly exothermic and the solution was stirred for 10 h at 20 o C, and then the volatile materials were removed by distillation at 20 o C/3 mm.The phosphate products 18a (or 18b) was purified by triturating with cold ether, followed by crystallization from acetone.Data were listed in Tables 1,  2, and 3.
The reaction of 3a (or 3b) with 2 molar equiv. of 16 gave the same phosphates 18a and 18b plus unchanged 3a (or 3b).No reaction was occurred when 18a or 18b were allowed to react with a second molecule 16.
Preparation of 4,6-di-tert-butylbenzo-2-methoxy-2-oxo-1,3,2-dioxaphosphole (19).5 g (0.023 mol) of o-quinone 1 in 20 mL CH 2 CL 2 was added dropwise with stirring over 1 h to 2.9 mL (0.023 mol) of freshly distilled trimethyl phosphite in 5 mL CH 2 CL 2 with the temperature kept at 0-5 o C.After 3 h at 25 o C, the reaction mixture was freed from CH 2 CL 2 , and 25 mL of acetonitrile was added to the residue followed by 1.8 g (0.023 mol) of freshly distilled acetyl chloride over 2 h.The reaction was exothermic and the addition was carried out at a rate, which kept the solution at ~ 40 o C.After further 2 h at 25 o C, the solution was evaporated and the residue was triturated with cold ether and purified by crystallization from cyclohexane to give 4.7 g (70% yield) of the phosphole 19, as colorless crystals, m.Reaction of the phosphoryl ester 9 with isothiocyanates 6a-d and 16.General procedure solution of 0.5 g (1.68 mmol) of the ester 19 in 15 mL CH 2 Cl 2 at 0 o C was added dropwise in 30 min to a stirred solution of 1.68 mmol of methyl-6a, ethyl-6b, phenyl-6c, hexyl-6d or allyl iso thiocyanate (16) in 15 mL CH 2 Cl 2 .The solution was stirred for 1 h at 0 o C and 24 h at 25 o C. The solvent was evaporated at 30 o C and 20 mm, and the residue was stirred with cold ether and filtered.The products, aminooxyphosphoranes 22a-22d and 4,6-di-tert-butyl spiro[benzo-1,2dioxaphosphole-2,2'-pyrrole] (24) were purified and identified as in Tables 1, 2, and 3.

Furthermore, the distinguishing
Scheme 2

Table 1 .
Physical Properties, and Analytical Data of the Products 8a

Table 2 .
IR, 1 H-, 31 P NMR and MS Data a for Compounds 8a-

Table 3 .
13C NMR Data a for Compounds 8a