Facile P,N-heterocycle synthesis via tandem aminomethylation–cyclization of H-phosphinate building blocks

Abstract

Various heterocycles containing phosphorus and nitrogen are easily synthesized from readily available H-phosphinate building blocks. Aminomethylation of these H-phosphinates is followed by in situ cyclization through substitution or cross-coupling to produce novel heterocycles in moderate to good yields.

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Introduction

Perhaps surprisingly, few phosphorus–nitrogen heterocycles have been synthesized previously.¹ In recent work, we reported the formation of such heterocycles starting from ω-amino-H-phosphinates (eqn (1)) through condensation with carbonyl compounds.² The method was made possible by synthetic methodologies we developed to access the starting materials.³ Herein, we shifted the focus to precursors which do not contain an amino group, but instead possess a reactive halide.

With the exception of our previous report (eqn (1)),²P,N-containing phosphinic heterocycles are rare in the literature. Since heterocycles have shown a variety of biological activities, and since cyclic P,N-phosphinates can be considered analogs of amino acids, we set out to expand the range of compounds accessible from simple building blocks. Below, we describe a general approach to P,N-heterocycles based on the Kabachnick–Fields aminomethylation⁴ of precursors, followed by in situ cyclization of the resulting amines (Scheme 1). Over the past several years, our laboratory has reported several general methods to prepare functionalized H-phosphinates.³ In the present work, such intermediates are prepared and their use in the synthesis of P,N-heterocycles is investigated.

Scheme 1 Strategy for the synthesis of P,N-heterocycles

Results and discussion

Precursor synthesis

Several synthons were prepared through established reactions.³ Compounds 1, 2 and 5 were prepared via hydrophosphinylation,^3d–j compound 3via Pd-catalyzed cross-coupling,^3k and compound 4via base-promoted alkylation.^3r The detailed conditions are shown in Schemes 2–4, and eqn (2) and (3). Synthon 1 (Scheme 2) was synthesized through our radical hydrophosphinylation using Et₃B as the initiator, as reported previously.^3h The resulting intermediate 6 was esterified⁵ directly to produce ester 1. The low yield of compound 1 was attributed to difficulties during the purification of this polar compound using chromatography on silica gel. Nonetheless, the preparation of 1 was easily accomplished.

Scheme 2 Synthesis of ethyl (3-chloropropyl)-H-phosphinate 1. (a) NaH₂PO₂, Et₃B, rt, 2 h, 71%; (b) (EtO)₄Si, toluene, reflux, 24 h, 40%.

Homolog 2 was prepared in a single step through palladium-catalyzed hydrophosphinylation^3d of 4-bromo-1-butene (eqn (2)). Synthon 2 was obtained in 67% yield. A similar reaction was used to prepare 5 from commercially available 2-bromostyrene (eqn (3)) in 64% yield.

Synthon 3 required the use of our palladium-catalyzed cross-coupling of anilinium hypophosphite^3k with 1-bromo-2-iodobenzene. Esterification then proceeded in reasonable yield to form 3 (Scheme 3).

Scheme 3 Synthesis of ethyl (2-bromophenyl)-H-phosphinate 3. (a) 1-bromo-2-iodobenzene, anilinium hypophosphite (3 equiv.), Pd(OAc)₂ (2 mol%), dppp (2.2 mol%), CH₃CN, reflux, 16 h, 65%; (b) (EtO)₄Si, toluene, reflux, 24 h, 64%.

Finally, synthon 4 was synthesized through the LiHMDS-promoted alkylation^3r of 2-bromobenzyl bromide followed by deprotection of the acetal using TMSCl.⁶ The sequence produced 4 in 60% overall yield (Scheme 4).

Scheme 4 Synthesis of ethyl (2-bromobenzyl)-H-phosphinate 4. (a) 2-bromobenzyl bromide, LiHMDS, THF, −78 °C to rt, 3 h, 61%; (b) TMSCl, CH₂Cl₂, EtOH, rt, 16 h, 99%.

Reactivity and cyclization

With the above precursors in hand, their reactions with imines were investigated. Table 1 shows the results obtained with synthons 1 and 2. Reaction of the H-phosphinates with imines proceeded smoothly and cyclization then took place uneventfully.

Table 1 P,N-heterocycle formation from 1 and 2

Entry	Synthon	Imine^a	Product	Isolated yield (%)^b
a Conditions: N-benzylideneaniline, toluene, reflux, 16 h; or 1,3,5-tribenzylhexahydro-1,3,5-triazine, toluene, reflux, 16 h.b Yield of pure compound after column chromatography.
1	1	PhCH=NPh		61
2	1	H2C=NBn		58
3	2	PhCH=NPh		76
4	2	H2C=NBn		45

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The reactions of 2-bromophenyl-substituted H-phosphinate esters were investigated next (Table 2). Compounds 3 and 4 were subjected to similar reaction conditions, except that a base (Cs₂CO₃, 1.5 equiv.) and a palladium catalyst (Pd(PPh₃)₄, 2 mol%) were also added to the reaction mixtures. As expected, the aminomethylation took place easily, but, perhaps more surprisingly, the simplest Pd-catalyst delivered C–N bond formation in good yield, without the need for more sophisticated Buchwald–Hartwig-type cross-coupling catalysts.⁷ Thus, 5- and 6-membered P,N-heterocycles were obtained in a one-pot procedure (Table 2). Compound 3 reacted with a variety of imines (Table 2, entries 1–6). Interestingly, a reaction (entry 3) conducted with in situ formation of the imine (from paraformaldehyde and benzylamine) gave the expected product in only slightly lower yield than with the triazine precursor (entry 2). Compound 4 provided the 6-membered heterocycle in comparable yields (entries 7 and 8). Again, Pd(PPh₃)₄ successfully catalyzed the cross-coupling step.

Table 2 P,N-heterocycle formation from 3 and 4

Entry	Synthon	Imine^a	Product	Isolated yield (%)^b
a Conditions: imine or triazine (1 equiv.), Cs2CO3 (1.5 equiv.), Pd(PPh3)4 (2 mol%), toluene, reflux, 24 h.b Yield of pure compound after column chromatography.c 1,3,5-tribenzylhexahydro-1,3,5-triazine was used.
1	3	PhCH=NPh		61
2	3	H2C=NBn^c		63
3	3	(CH2O)n + BnNH2		53
4	3	PhCH=NBn		74
5	3	PhCH=N-tBu		44
6	3	PhCH=NMe		62
7	4	PhCH=NPh		76
8	4	H2C=NBn^c		41

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However, with synthon 5, although the Kabachnik–Fields reaction took place in good yield, the resulting intermediates did not cyclize to give the 7-membered ring under otherwise identical conditions. The aminomethylated products were obtained with N-benzylideneaniline or 1,3,5-tribenzylhexahydro-1,3,5-triazine in 51 and 67% isolated yields, respectively.

In a different (but related) approach, the heterocyclization of unsaturated ethyl cinnamyl-H-phosphinate was investigated through a tandem aminomethylation–Heck cyclization process (Scheme 5). Readily available cinnamyl-H-phosphinic acid⁸7 was esterified⁵ to 8 using our typical conditions. Ester 8 was then reacted with 2-iodoaniline and paraformaldehyde to form aminomethylated iodide 9 in moderate isolated yield. Compound 9 was subjected to Heck-type⁹ reaction conditions (Pd/dppf, 2 mol%) in DMF to produce the desired 7-membered ring heterocycle 10 in 35% isolated yield. We have not optimized this reaction, other than the use of dppf¹⁰ instead of PPh₃. While more work would be required to fully explore this strategy, Scheme 5 provides an interesting “proof of concept”, and the basis for future experiments.

Scheme 5 Tandem aminomethylation–Heck cyclization. (a) (EtO)₄Si, toluene, reflux, 24 h, 92%; (b) 2-iodoaniline (1.2 equiv.), paraformaldehyde (1.2 equiv.), toluene, reflux, 16 h, 46%; (c) Pd(OAc)₂ (2 mol%), dppf (2.2 mol%), i-Pr₂NEt (2 equiv.), DMF, 110 °C, 35%.

Along similar lines, we briefly attempted the Wacker-type cyclization¹¹ of unsaturated amino-H-phosphinate 12 (Scheme 6). Unfortunately, attempts on 12a and 12b were unsuccessful. The use of ethyl cinnamyl-H-phosphinate 8via sulfonamide 13 similarly failed, although Liu and Stahl reported the successful cyclization of the all-carbon analog 14.^11c

Scheme 6 Attempted Pd(II)-catalyzed cyclization. (a) 1,3,5-tribenzylhexahydro-1,3,5-triazine (0.4 equiv.), toluene, reflux, 16 h, 12a 57%; 12b 83%. (b) Pd(OAc)₂ (5 mol%), AcONa (2 equiv.), DMSO, O₂, 80 °C, 60 h.

Admittedly, we have not fully investigated the palladium-catalyzed heterocyclizations of precursors 9, 12 and 13. In spite of the above failed experiments, tremendous flexibility remains available to synthesize phosphorus heterocycles from simple precursors. For example, Wolfe-type carboaminations¹² could also be tried on aminophosphinate precursors 12 and 13. Similarly, the use of allyl amine in the place of 2-iodoaniline (Scheme 5) could lead to a ring-closing metathesis precursor (the reaction of 8 with paraformaldehyde and allyl amine gives the corresponding diene in 53% yield). Our methodologies have made available a wide range of compounds through hydrophosphinylation, cross-coupling (halides, carboxylates, alcohols), alkylation, etc.,³ so that novel P-containing precursors could lead to facile syntheses of heterocyclic products. The preparation of P,O-heterocycles through the well-known addition of H-phosphinates to carbonyl compounds, using the precursors described in the present work, was not investigated because P,N-heterocycles are likely to be more interesting as amino acid analogs.¹³

Conclusions

The facile synthesis of P,N-heterocycles (substituted 3-hydroxy-1,3-azaphospholane and 3-hydroxy-1,3-azaphosphorinane-3-oxides) is described. With aryl bromide precursors, the cyclization proceeded well using Pd(PPh₃)₄ (2 mol%) as the cross-coupling catalyst. The availability of simple H-phosphinate building blocks opens up the possibility for the synthesis of various phosphorus heterocycles. Catalytic methods for the cyclization of other phosphinate precursors for the preparation of P,N- as well as other P-heterocycles will be the object of future studies.

Experimental

For general chemistry information, and additional details on the synthesis of precursors and intermediates, spectral data, and a copy of the ³¹P, ¹H and ¹³C NMR spectra, see the ESI.†

Ethyl (3-chloropropyl)-H-phosphinate (Scheme 2, compound 1)

To (3-chloropropyl)-H-phosphinic acid^3g (2.56 g, 18 mmol) in toluene (60 mL) was added tetraethyl orthosilicate (1.5 equiv., 5.63 g) under N₂, and the mixture was refluxed for 24 h. The solvent was removed in vacuo and the resulting oil was purified by column chromatography (silica, EtOAc 100%) to afford the desired product as a yellow oil (1.22 g, 40%): ¹H NMR (CDCl₃, 300 MHz) δ 7.17 (d, J = 533 Hz, 1H, H–P), 4.00-4.30 (m, 2H, –CH₂–O–), 3.64 (t, J = 5 Hz, 2H, –CH₂–Cl), 1.85-2.10 (m, 4H, 2 x –CH₂–), 1.39 (t, J = 7 Hz, 3H, CH₃–); ¹³C NMR (CDCl₃, 75.45 MHz) δ 62.8 (d, J_POC = 6 Hz), 44.9 (d, J_PCCCCl = 17 Hz), 26.3 (d, J_PC = 95 Hz), 24.2 (d, J_PCC = 2 Hz), 16.4 (d, J_POCC = 6 Hz); ³¹P NMR (CDCl₃, 121.47 MHz) δ 37.7 (d, J = 533 Hz); HRMS (EI⁺) calc. for C₅H₁₂ClO₂P 171.0342, found 171.0346.

Ethyl (3-bromobutyl)-H-phosphinate (eqn (2), compound 2)^3e

To a solution of EtOP(O)H₂ in CH₃CN (2 equiv., 60 mmol, 120 mL) and 4-bromo-1-butene (30 mmol, 4.05 g, 3 mL) were added Pd₂dba₃ (0.5 mol%, 137 mg) and xantphos (1.1 mol%, 191 mg). After 16 h of reflux, the mixture was concentrated and the resulting oil was diluted in EtOAc (60 mL) and washed with brine (1 × 20 mL). The organic layer was dried and concentrated. The resulting oil was purified by column chromatography (silica, EtOAc 100%) to afford the desired product as a yellow oil (4.6 g, 67%): ¹H NMR (CDCl₃, 300 MHz) δ 7.13 (d, J = 530 Hz, 1H, H–P), 4.00-4.35 (m, 2H, –CH₂–O), 3.43 (t, J = 7 Hz, 2H, –CH₂–Br), 1.95-2.10 (m, 2H, –CH₂–), 1.65-1.90 (m, 4H, 2 x –CH₂–), 1.37 (t, J = 7 Hz, 3H, CH₃–); ¹³C NMR (CDCl₃, 75.45 MHz) δ 62.6 (d, J_POC = 7 Hz), 33.1 (d, J_PCC = 15 Hz), 32.7, 27.9 (d, J_PC = 94 Hz), 19.6, 16.4 (d, J_POCC = 6 Hz); ³¹P NMR (CDCl₃, 121.47 MHz) δ 38.8 (d, J = 530 Hz); HRMS (EI⁺) calc. for C₆H₁₄BrO₂P 228.9993, found 228.9990.

Ethyl 2-(2-bromophenyl)ethyl-H-phosphinate (eqn (3), compound 5)

To a solution of EtOP(O)H₂ in CH₃CN (1.6 equiv., 32 mmol, 64 mL) and 2-bromostyrene (20 mmol, 3.66 g) were added Pd₂dba₃ (0.75 mol%, 137 mg) and xantphos (1.6 mol%, 185 mg). After 16 h of reflux, the mixture was concentrated and the resulting oil was diluted in EtOAc (30 mL) and washed with brine (1 × 10 mL). The organic layer was dried and concentrated. The resulting oil was purified by column chromatography (silica, EtOAc–hexanes 7 : 3, v/v) to afford the desired product as a yellow oil (3.56 g, 64%): ¹H NMR (CDCl₃, 300 MHz) δ 7.53 (d, J = 8 Hz, 1H, aro CH), 7.20-7.35 (m, 2H, aro CH), 7.14 (d, J = 532 Hz, 1H, H–P), 7.00-7.15 (m, 1H, aro CH), 4.00-4.25 (m, 2H, –CH₂–O–), 2.90-3.10 (m, 2H, –CH₂–P), 2.00-2.20 (m, 2H, –C–CH₂–), 1.37 (t, J = 14, 7 Hz, 3H, CH₃–); ¹³C NMR (CDCl₃, 75.45 MHz) δ 139.6 (d, J_PCCC = 16 Hz), 133.2, 130.5, 128.6, 127.9, 124.3, 62.7 (d, J_POC = 7 Hz), 28.9 (d, J_PC = 92 Hz), 27.9, 16.5 (d, J_POCC = 6 Hz); ³¹P NMR (CDCl₃, 121.47 MHz) δ 37.4 (d, J = 532 Hz).

Ethyl (2-bromobenzyl)-H-phosphinate (Scheme 4, compound 4)

To ethyl (1,1-diethoxyethyl)-(2-bromobenzyl)phosphinate (3.03 g, 8 mmol) in 20 mL of 10% ethanol in dichloromethane was added chlorotrimethylsilane (1.5 equiv., 12 mmol, 1.3 mL) under N₂ and the clear solution was stirred for 16 h at room temperature.⁶ The solvent was removed in vacuo and the resulting oil was purified by column chromatography (silica, EtOAc–hexanes 3 : 7, v/v) to afford the desired product as a yellow oil (2.1 g, 99%): ¹H NMR (CDCl₃, 300 MHz) δ 7.58 (d, J = 8 Hz, 1H, aro CH), 7.20-7.40 (m, 2H, aro CH), 7.10-7.20 (m, 1H, aro CH), 7.16 (d, J = 544 Hz, 1H, H–P), 4.00-4.25 (m, 2H, –CH₂–O–), 3.35-3.55 (m, 2H, C–CH₂–P), 1.32 (t, J = 14, 7 Hz, 3H, CH₃–); ¹³C NMR (CDCl₃, 75.45 MHz) δ 133.2 (d, J = 2 Hz), 132.1 (d, J = 6 Hz), 130.7 (d, J = 7 Hz), 129.2 (d, J = 4 Hz), 128.1 (d, J = 4 Hz), 124.8 (d, J = 7 Hz), 63.0 (d, J_POC = 6 Hz), 37.3 (d, J_PC = 89 Hz), 16.4 (d, J_POCC = 6 Hz); ³¹P NMR (CDCl₃, 121.47 MHz) δ 34.3 (d, J = 544 Hz); HRMS (EI⁺) calc. for C₉H₁₂BrO₂P 262.9837, found 262.9835.

General procedure for the cyclization from compound 1 or 2

To the compound 1 or 2 (1 mmol) in toluene (10 mL) was added N-benzylideneaniline (1.2 equiv.) or 1,3,5-tribenzylhexahydro-1,3,5-triazine (0.4 equiv) and the mixture was refluxed for 16 h. The solvent was removed in vacuo, and the resulting oil was diluted in EtOAc (30 mL) and washed with brine (1 × 10 mL). The organic layer was dried and concentrated. The resulting oil was purified by column chromatography (silica, EtOAc–hexanes 3 : 7, v/v) to afford the desired product.

1,2-Diphenyl-3-ethoxy-1,3-azaphosphorinane-3-oxide (Table 1, entry 1). Yellow oil, yield: 61%. ¹H NMR (CDCl₃, 300 MHz) δ 7.00-7.50 (m, 7H, aro CH), 6.50-6.80 (m, 3H, aro CH), 4.80-5.00 (m, 1H, –CH₂–), 4.55-4.75 (m, 1H, –P–CH–N–), 4.00-4.25 (m, 2H, –CH₂–O–)_a, 3.20-3.40 and 3.65-3.85 (m, 2H, –CH₂–O–)_b, 3.55-3.60 (m, 1H, –CH₂–), 3.40-3.50 (m, 1H, –CH₂–), 2.00-2.20 (m, 1H, –CH₂–), 1.60-2.00 (m, 2H, –CH₂–), 1.20-1.40 (m, 3H, CH₃–)_a, 1.03 (t, J = 14, 7 Hz, 3H, CH₃–)_b; ¹³C NMR (CDCl₃, 75.45 MHz) δ 146.4, 146.2, 135.9, 135.5, 129.5, 129.2, 128.9, 128.3, 128.2 (d, J = 4 Hz), 127.8 (d, J = 4 Hz), 118.8, 114.3 (d, J = 6 Hz), 62.4 (d, J_POC = 7 Hz)_a, 62.1 (d, J_POC = 7 Hz)_b, 57.9 (d, J_PC = 93 Hz)_b, 57.7 (d, J_PC = 96 Hz)_a, 45.4 (d, J_PCC = 5 Hz)_a, 45.1 (d, J_PCC = 6 Hz)_b, 25.4 (d, J_PC = 92 Hz)_a, 25.2, 24.3 (d, J_PC = 95 Hz)_b, 16.9 (d, J_POCC = 5 Hz)_a, 16.6 (d, J_POCC = 6 Hz)_b; ³¹P NMR (CDCl₃, 121.47 MHz) δ 50.6 (s), 51.6 (s); HRMS (EI⁺) calc for C₁₈H₂₂NO₂P 315.1388, found 315.1388.

1-Benzyl-3-ethoxy-1,3-azaphosphorinane-3-oxide (Table 1, entry 2). Yellow oil, yield: 58%. ¹H NMR (CDCl₃, 300 MHz) δ 7.25-7.35 (m, 5H, aro CH), 3.90-4.20 (m, 2H, –CH₂–O–), 3.71 (dd, J = 12, 2 Hz, 1H, –CH₂–), 3.49 (dd, J = 13, 2 Hz, 1H, –CH₂–), 2.96 (t, J = 15 Hz, 1H, –CH₂–), 2.79 (d, J = 12 Hz, 1H, –CH₂–), 2.45 (d, J = 15 Hz, 1H, –CH₂–), 2.20-2.35 (m, 1H, –CH₂–), 1.85-2.10 (m, 3H, –CH₂–CH₂–), 1.60-1.80 (m, 1H, –CH₂–), 1.33 (t, J = 14, 7 Hz, 3H, CH₃–); ¹³C NMR (CDCl₃, 75.45 MHz) δ 137.4, 129.2 (2C), 128.5 (2C), 127.6, 64.4 (d, J_PCNC = 15 Hz), 60.4 (d, J_POC = 7 Hz), 54.2 (d, J_PCCC = 5 Hz), 52.2 (d, J_PC = 98 Hz), 25.6 (d, J_PC = 89 Hz), 23.4 (d, J_PCC = 6 Hz), 16.7 (d, J_POCC = 6 Hz); ³¹P NMR (CDCl₃, 121.47 MHz) δ 44.2 (s); HRMS (EI⁺) calc. for C₁₃H₂₀NO₂P 253.1232, found 253.1230.

1,2-Diphenyl-3-ethoxy-1,3-azaphosphepane-3-oxide (Table 1, entry 3). Yellow oil, yield: 76%. ¹H NMR (CDCl₃, 300 MHz) δ 6.50-7.60 (m, 10H, aro CH), 4.69 (d, J = 17 Hz, 1H, –P–CH–N–)_a, 4.61 (d, J = 16 Hz, 1H, –P–CH–N–)_b, 3.70-3.85 and 4.00-4.30 (m, 2H, –CH₂–O–), 3.39 (t, J = 13, 6 Hz, 1H, –CH₂–), 3.29 (t, J = 13, 7 Hz, 1H, –CH₂–), 1.70-2.00 (m, 4H, –CH₂–CH₂–), 1.50-1.65 (m, 2H, –CH₂–), 1.28 (t, J = 14, 7 Hz, 3H, –CH₃–)_a, 1.02 (t, J = 14, 7 Hz, 3H, –CH₃–)_b; ¹³C NMR (CDCl₃, 75.45 MHz) δ 146.3, 136.1, 135.6, 133.2, 132.1, 129.4, 129.1 (d, J = 2 Hz), 128.9 (d, J = 2 Hz), 128.3 (d, J = 4 Hz)_a, 127.8 (d, J = 4 Hz)_b, 118.9, 114.4, 111.8, 62.3 (d, J_POC = 7 Hz)_a, 61.9 (d, J_POC = 7 Hz)_b, 57.9 (d, J_PC = 91 Hz)_a, 57.6 (d, J_PC = 95 Hz)_b, 33.6 (d, J_PCC = 3 Hz)_a, 33.4 (d, J_PCC = 3 Hz)_b, 33.0, 32.9, 26.9 (d, J_PC = 78 Hz)_a, 25.7 (d, J_PC = 80 Hz)_b, 20.7 (d, J_PCCC = 5 Hz)_a, 20.3 (d, J_PCCC = 4 Hz)_b, 16.9 (d, J_POCC = 5 Hz)_a, 16.7 (d, J_POCC = 5 Hz)_b; ³¹P NMR (CDCl₃, 121.47 MHz) δ 51.8 (s), 50.9 (s); HRMS (EI⁺) calc. for C₁₉H₂₄NO₂P 329.1544, found 329.1545.

1-Benzyl-3-ethoxy-1,3-azaphosphepane-3-oxide (Table 1, entry 4). Yellow oil, yield: 45%. ¹H NMR (CDCl₃, 300 MHz) δ 7.25-7.35 (m, 5H, aro CH), 3.90-4.00 (m, 1H, –N–CH₂–P), 3.60-3.80 (m, 3H, –N–CH₂–P and –CH₂–O), 2.90-3.10 (m, 2H, –N–CH₂–P), 2.80-2.90 (m, 1H, –CH₂–), 2.60-2.70 (m, 1H, –CH₂–), 2.00-2.20 (m, 3H, –CH₂–CH₂–), 1.55-1.90 (m, 3H, –CH₂–CH₂–), 1.23 (t, J = 14, 7 Hz, 3H, –CH₃–); ¹³C NMR (CDCl₃, 75.45 MHz) δ 138.7, 129.2 (2C), 128.5 (2C), 127.5, 64.2 (d, J_PCNC = 16 Hz), 60.0 (d, J_POC = 7 Hz), 58.3, 54.5 (d, J_PCC = 105 Hz), 30.2, 29.1 (d, J_PC = 88 Hz), 19.9 (d, J_PCC = 2 Hz), 16.7 (d, J_POCC = 6 Hz); ³¹P NMR (CDCl₃, 121.47 MHz) δ 63.1 (s); HRMS (EI⁺) calc. for C₁₄H₂₂NO₂P 267.1388, found 267.1389.

General procedure for the cyclization from compound 3 or 4

To compound 3 or 4 (5 mmol) in toluene (50 mL) was added the corresponding imine (1.2 equiv.) and the mixture was refluxed for 16 h. Then, caesium carbonate (1.2 equiv.) and Pd(PPh₃)₄ (2 mol%) were added, and the mixture was refluxed for 24 h. The solvent was removed in vacuo, and the resulting oil was diluted in EtOAc (30 mL) and washed with brine (1 × 10 mL). The organic layer was dried and concentrated. The resulting oil was purified by column chromatography (silica, EtOAc–hexanes 3 : 7, v/v) to afford the desired product.

1,2-Diphenyl-3-ethoxy-1,2-dihydro-benzo[1,3]azaphosphole-3-oxide (Table 2, entry 1). Yellow oil, yield: 61%. ¹H NMR (CDCl₃, 300 MHz) δ 6.80-7.70 (m, 14H, aro CH), 5.13 (d, J = 15 Hz, 1H, –N–CH–P–)_b, 4.79 (d, J = 17 Hz, 1H, –N–CH–P–)_a, 4.20-4.30 (m, 2H, –CH₂–O–)_a, 3.85-3.95 and 3.20-3.30 (m, 2H, –CH₂–O–)_b, 1.38 (t, J = 14, 7 Hz, 3H, CH₃–)_a, 0.95 (t, J = 14 Hz, 3H, CH₃–)_b; ¹³C NMR (CDCl₃, 75.45 MHz) δ 154.7 (d, J = 22 Hz)_b, 152.9 (d, J = 22 Hz)_a, 143.2 (d, J = 8 Hz)_a, 142.3 (d, J = 10 Hz)_b, 134.8 (d, J = 2 Hz)_b, 134.6 (d, J = 2 Hz)_a, 134.1 (d, J = 7 Hz), 129.8, 129.7, 129.5 (d, J = 6 Hz), 129.1 (d, J = 2 Hz), 128.9 (d, J = 6 Hz), 128.8 (d, J = 2 Hz), 128.2 (d, J = 3 Hz), 128.18, 128.12, 127.6 (d, J = 5 Hz), 126.1, 125.6 (d, J = 83 Hz), 123.2, 120.3, 120.1, 119.9, 112.8 (d, J = 10 Hz)_a, 112.1 (d, J = 11 Hz)_b, 65.6 (d, J_PC = 96 Hz)_b, 64.8 (d, J_PC = 99 Hz)_a, 62.6 (d, J_POC = 7 Hz)_b, 62.1 (d, J_POC = 7 Hz)_a, 16.9 (d, J_POCC = 6 Hz)_a, 16.4 (d, J_POCC = 6 Hz)_b; ³¹P NMR (CDCl₃, 121.47 MHz) δ 50.6 (s), 49.4 (s); HRMS (EI⁺) calc. for C₂₁H₂₀NO₂P 349.1232, found 349.1237.

1-Benzyl-3-ethoxy-1,2-dihydro-benzo[1,3]azaphosphole-3-oxide (Table 2, entry 2). Yellow oil, yield: 63%: ¹H NMR (CDCl₃, 300 MHz) δ 7.20-7.80 (m, 7H, aro CH), 6.75-6.85 (m, 2H, aro CH), 4.52 (q, J = 16 Hz, 2H, –N–CH₂–P–), 4.10-4.20 (m, 2H, –CH₂–O–), 3.37 (dd, J = 13, 5 Hz, 2H, –N–CH₂–Ph), 1.34 (t, J = 14, 7 Hz, 3H, CH₃–); ¹³C NMR (CDCl₃, 75.45 MHz) δ 155.3 (d, J = 23 Hz), 136.8, 135.0 (d, J = 2 Hz), 132.3 (d, J = 16 Hz), 129.1, 128.8, 128.7 (d, J = 5 Hz), 127.9, 127.4, 117.9 (d, J = 12 Hz), 113.2 (d, J = 131 Hz), 109.9 (d, J = 12 Hz), 61.9 (d, J_POC = 6 Hz), 52.5 (d, J_PCNC = 6 Hz), 47.6 (d, J_PC = 102 Hz), 16.8 (d, J_POCC = 6 Hz); ³¹P NMR (CDCl₃, 121.47 MHz) δ 52.4 (s); HRMS (EI⁺) calc. for C₁₆H₁₈NO₂P 287.1075, found 287.1080.

1-Benzyl-3-ethoxy-2-phenyl-1,2-dihydro-benzo[1,3]azaphosphole-3-oxide (Table 2, entry 4). Yellow oil, yield: 74%. ¹H NMR (CDCl₃, 300 MHz) δ 6.65-7.70 (m, 14H, aro CH), 4.75 (d, J = 16 Hz, 2H, –N–CH–Ph), 4.61 (d, J = 14 Hz, 1H, –N–CH–P–)_b, 4.41 (d, J = 16 Hz, 1H, –N–CH₂–P–)_a, 4.00-4.25 (m, 2H, –CH₂–O–)_a, 3.15-3.35 and 3.75-3.95 (m, 2H, –CH₂–O–)_b, 1.32 (t, J = 14, 7 Hz, 3H, CH₃–)_a, 0.91 (t, J = 14 Hz, 3H, CH₃–)_b; ¹³C NMR (CDCl₃, 75.45 MHz) δ 155.2 (d, J = 23 Hz)_b, 154.6 (d, J = 23 Hz)_a, 137.0, 136.4, 135.21, 135.18, 133.87, 133.82, 133.74, 132.3 (d, J = 10 Hz), 129.5 (d, J = 5 Hz), 129.2 (d, J = 2 Hz)_a, 129.1 (d, J = 2 Hz)_b, 129.0, 128.5 (d, J = 2 Hz), 128.3 (d, J = 4 Hz), 127.73, 127.69, 127.63, 127.3, 118.7 (d, J = 12 Hz)_b, 118.2 (d, J = 12 Hz)_a, 113.5, 113.1, 111.7, 111.4, 110.7 (d, J = 11 Hz)_a, 109.4 (d, J = 11 Hz)_b, 63.4 (d, J_PC = 98 Hz)_b, 62.5 (d, J_POC = 7 Hz)_b, 61.95 (d, J_PC = 101 Hz)_a, 61.93 (d, J_POC = 7 Hz)_a, 49.1 (d, J_PCNC = 8 Hz)_b, 48.9 (d, J_PCNC = 8 Hz)_a, 17.0 (d, J_POCC = 6 Hz)_a, 16.4 (d, J_POCC = 6 Hz)_b; ³¹P NMR (CDCl₃, 121.47 MHz) δ 51.1 (s), 49.8 (s); HRMS (EI⁺) calc. for C₂₂H₂₂NO₂P 363.1388, found 363.1395.

1-tert-Butyl-3-ethoxy-2-phenyl-1,2-dihydro-benzo[1,3]azaphosphole-3-oxide (Table 2, entry 5). Yellow oil, yield: 44%. ¹H NMR (CDCl₃, 300 MHz) δ 6.70-7.80 (m, 9H, aro CH), 4.84 (d, J = 20 Hz, 1H, –N–CH–P–)_b, 4.66 (d, J = 20 Hz, 1H, –N–CH–P–)_a, 4.00-4.25 (m, 2H, –CH₂–O–)_a, 3.15-3.35 and 3.75-3.95 (m, 2H, –CH₂–O–)_b, 1.43 (s, 9H, –N–C(CH₃)₃)_a, 1.41 (s, 9H, –N–C(CH₃)₃)_b, 1.33 (t, J = 14, 7 Hz, 3H, CH₃–)_a, 0.80 (t, J = 14 Hz, 3H, CH₃–)_b; ¹³C NMR (CDCl₃, 75.45 MHz) δ 154.7 (d, J = 25 Hz)_b, 154.1 (d, J = 24 Hz)_a, 139.1 (d, J = 4 Hz), 137.1, 134.18, 134.15, 134.13, 132.3 (d, J = 10 Hz), 130.1 (d, J = 6 Hz)_a, 129.3 (d, J = 5 Hz)_b, 129.04, 129.01, 128.97, 127.8 (d, J = 3 Hz)_a, 127.6 (d, J = 3 Hz)_b, 126.9 (d, J = 4 Hz)_a, 126.8 (d, J = 4 Hz)_b, 118.1 (d, J = 12 Hz)_b, 117.7 (d, J = 12 Hz)_a, 115.5, 114.8 (d, J = 11 Hz)_b, 114.1 (d, J = 10 Hz)_b, 113.8, 62.7 (d, J_POC = 7 Hz)_b, 61.9 (d, J_PC = 93 Hz)_b, 61.6 (d, J_POC = 7 Hz)_a, 60.3 (d, J_PC = 100 Hz)_a, 57.7 (d, J_PCNC = 6 Hz)_b, 56.8 (d, J_PCNC = 6 Hz)_a, 29.6 (3C)_b, 29.5 (3C)_a,16.9 (d, J_POCC = 6 Hz)_a, 16.2 (d, J_POCC = 6 Hz)_b; ³¹P NMR (CDCl₃, 121.47 MHz) δ 52.3 (s), 51.3 (s); HRMS (EI⁺) calc. for C₁₉H₂₄NO₂P 329.1545, found 329.1546.

3-Ethoxy-1-methyl-2-phenyl-1,2-dihydro-benzo[1,3]azaphosphole-3-oxide (Table 2, entry 6). White solid mp 114–116 °C, yield: 62%. ¹H NMR (CDCl₃, 300 MHz) δ 6.70-7.70 (m, 9H, aro CH), 4.45 (d, J = 15 Hz, 1H, –N–CH–P–)_b, 4.32 (d, J = 15 Hz, 1H, –N–CH–P–)_a, 4.15-4.25 (m, 2H, –CH₂–O–)_a, 3.10-3.30 and 3.75-3.95 (m, 2H, –CH₂–O–)_b, 2.84 (s, 3H, –N–CH₃)_b, 2.83 (s, 3H, –N–CH₃)_a, 1.37 (t, J = 14, 7 Hz, 3H, CH₃–)_a, 0.89 (t, J = 14 Hz, 3H, CH₃–)_b; ¹³C NMR (CDCl₃, 75.45 MHz) δ 156.2 (d, J = 23 Hz)_a, 155.4 (d, J = 23 Hz)_b, 135.17, 135.15, 135.12, 135.09, 134.0 (d, J = 7 Hz), 133.9 (d, J = 4 Hz), 129.19, 129.17, 129.10, 129.07, 128.8 (d, J = 5 Hz), 128.47, 128.43, 128.39, 128.1 (d, J = 5 Hz), 127.8 (d, J = 4 Hz), 118.8 (d, J = 12 Hz)_b, 117.9 (d, J = 12 Hz)_a, 113.3 (d, J = 20 Hz), 111.7 (d, J = 17 Hz), 110.3 (d, J = 11 Hz)_b, 109.1 (d, J = 11 Hz)_a, 66.5 (d, J_PC = 98 Hz)_b, 64.8 (d, J_PC = 101 Hz)_a, 62.4 (d, J_POC = 7 Hz)_a, 61.9 (d, J_POC = 7 Hz)_b, 34.2 (d, J_PCNC = 11 Hz)_a, 33.5 (d, J_PCNC = 10 Hz)_b, 16.9 (d, J_POCC = 6 Hz)_a, 16.4 (d, J_POCC = 6 Hz)_b; ³¹P NMR (CDCl₃, 121.47 MHz) δ 50.5 (s), 49.1 (s); HRMS (EI⁺) calc. for C₁₆H₁₈NO₂P 287.1075, found 287.1073.

1,2-Diphenyl-3-ethoxy-1,2,3,4-tetrahydro-benzo[d][1,3]azaphosphinine (Table 2, entry 7). Yellow oil, yield: 76%: ¹H NMR (CDCl₃, 300 MHz) δ 6.80-7.60 (m, 14H, aro CH), 5.26 (d, J = 22 Hz, 1H, –N–CH–P–)_b, 5.06 (d, J = 25 Hz, 1H, –N–CH–P–)_a, 4.10-4.30 (m, 2H, –CH₂–O–)_a, 3.95-4.10 (m, 1H, –CH₂–O–)_b, 3.60-3.75 (m, 1H, -CH₂–O–)_b, 3.00-3.30 (m, 2H, –C–CH₂–P–), 1.28 (t, J = 14, 7 Hz, 3H, CH₃-)_a, 0.76 (t, J = 14, 7 Hz, 1H, CH₃–)_b; ¹³C NMR (CDCl₃, 75.45 MHz) δ 149.2 (d, J = 4 Hz)_a, 148.5 (d, J = 4 Hz)_b, 143.2 (d, J = 9 Hz)_a, 142.8 (d, J = 9 Hz)_b, 138.4, 136.6 (d, J = 6 Hz), 132.3 (d, J = 12 Hz)_a, 130.9 (d, J = 7 Hz)_b, 129.7, 129.2, 129.17, 129.15, 128.9 (d, J = 2 Hz), 128.5 (d, J = 2 Hz), 128.2, 127.87, 127.84, 127.3 (d, J = 4 Hz), 126.8 (d, J = 4 Hz), 126.6 (d, J = 10 Hz), 125.7 (d, J = 2 Hz), 125.1, 123.9, 122.2 (d, J = 9 Hz)_a, 121.9, 121.6 (d, J = 7 Hz)_b, 120.9, 117.3, 63.2 (d, J_PC = 95 Hz)_b, 62.8 (d, J_PC = 91 Hz)_a, 61.7 (d, J_POC = 7 Hz)_b, 61.6 (d, J_POC = 7 Hz)_a, 31.5 (d, J_PC = 84 Hz)_b, 28.6 (d, J_PC = 86 Hz)_a, 16.7 (d, J_POCC = 6 Hz)_a, 16.4 (d, J_POCC = 6 Hz)_b; ³¹P NMR (CDCl₃, 121.47 MHz) δ 43.0 (s), 54.4 (s); HRMS (EI⁺) calc. for C₂₂H₂₂NO₂P 363.1388, found 363.1382.

1-Benzyl-3-ethoxy-1,2,3,4-tetrahydro-benzo[d][1,3]azaphosphinine (Table 2, entry 8). Yellow oil, yield: 41%. ¹H NMR (CDCl₃, 300 MHz) δ 7.10-7.80 (m, 7H, aro CH), 6.80-7.00 (m, 2H, aro CH), 4.35 (dd, J = 5, 2 Hz, 2H, –N–CH₂–P–), 3.85-4.20 (m, 2H, –CH₂–O–), 3.05-3.25 (m, 4H, –C–CH₂–P– and –N–CH₂–Ph), 1.24 (t, J = 14, 7 Hz, 3H, CH₃–); ¹³C NMR (CDCl₃, 75.45 MHz) δ 148.3 (d, J = 4 Hz), 137.3, 132.3 (d, J = 10 Hz), 132.2, 131.0 (d, J = 10 Hz), 128.76 (d, J = 12 Hz), 128.72 (d, J = 35 Hz), 128.4 (d, J = 2 Hz), 127.9, 123.0 (d, J = 7 Hz), 122.9, 115.9 (d, J = 2 Hz), 61.0 (d, J_POC = 7 Hz), 57.2 (d, J_PCNC = 12 Hz), 48.3 (d, J_PC = 111 Hz), 31.6 (d, J_PC = 87 Hz), 16.7 (d, J_POCC = 6 Hz); ³¹P NMR (CDCl₃, 121.47 MHz) δ 57.2 (s); HRMS (EI⁺) calc. for C₁₇H₂₀NO₂P 301.1232, found 301.1227.

Formation in situ of the imine from an aldehyde (Table 2, entry 3)

To the compound 3 (5 mmol) in toluene (50 mL) were added benzylamine (1.2 equiv., 0.65 mL) and paraformaldehyde (1.2 equiv., 198 mg), and the mixture was refluxed for 16 h. Then, caesium carbonate (1.2 equiv.) and Pd(PPh₃)₄ (2 mol%) were added and the mixture was refluxed for 24 h. The solvent was removed in vacuo, and the resulting oil was diluted in EtOAc (30 mL) and washed with brine (1 × 10 mL). The organic layer was dried and concentrated. The resulting oil was purified by column chromatography (silica, EtOAc–hexanes 3 : 7, v/v) to afford the desired product as a yellow oil (760 mg, 53%).

Heck product (Scheme 5, compound 10)

To compound 9 (0.5 mmol, 221 mg) in DMF (2.5 mL) was added N,N-diisopropylethylamine (2 equiv., 1 mmol, 0.2 mL), 1,1′-bis(diphenylphosphino)ferrocene (2.2 mol%, 6.1 mg) and Pd(OAc)₂ (2 mol%, 2.2 mg). After 40 h of reflux, the solvent was removed in vacuo, and the resulting oil was diluted in EtOAc (10 mL) and washed with brine (1 × 20 mL). The organic layer was dried and concentrated. The resulting oil was purified by column chromatography (silica, EtOAc 100%) to afford the desired product as a pink oil (54.7 mg, 35%): ¹H NMR (CDCl₃, 300 MHz) δ 7.20-7.60 (m, 6H, aro CH), 7.13 (t, J = 15, 7 Hz, 1H, aro CH), 6.94 (d, J = 5 Hz, 1H, aro CH), 6.85 (t, J = 14, 7 Hz, 1H, aro CH), 6.67 (d, J = 8 Hz, 1H, –C=CH–Ph), 4.00-4.25 (m, 1H, –NH–), 3.90-4.00 (m, 1H, –CH₂–O–), 3.45-3.70 (m, 3H, P–CH₂–N– and P–CH₂–C–), 3.35-3.45 (m, 1H, –CH₂–O–), 3.15-3.25 (m, 1H, P–CH₂–C–), 1.09 (t, J = 14, 7 Hz, 3H, CH₃–); ¹³C NMR (CDCl₃, 75.45 MHz) δ 145.5 (d, J = 2 Hz), 137.5 (d, J = 3 Hz), 133.0 (d, J = 7 Hz), 131.9 (d, J = 11 Hz), 131.56, 131.54, 129.6, 128.9 (d, J = 2 Hz), 128.88, 128.81, 128.5 (d, J = 2 Hz), 127.3, 119.9, 118.3, 60.9 (d, J_POC = 7 Hz), 44.3 (d, J_PC = 119 Hz), 31.4 (d, J_PC = 78 Hz), 16.6 (d, J_POCC = 6 Hz); ³¹P NMR (CDCl₃, 121.47 MHz) δ 54.2 (s); HRMS (EI⁺) calc. for C₁₈H₂₀NO₂P 313.1232, found 313.1230.

Acknowledgements

We thank the National Institute of General Medical Sciences/NIH (1R01 GM067610) for the financial support of this research.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Additional procedures and spectral data. See DOI: 10.1039/b917428a

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