Synthesis of Symmetrical N-Aryl-C-phosphonoacetamidines

Abstract

An efficient synthesis of a series of novel symmetrical N-aryl-C-phosphonoacetamidines through reaction of diisopropyl (chloroethynyl)phosphonate with primary aryl amines was developed. This procedure tolerates a wide range of functional groups and has a good atom economy. The (E)-isomer was the major product that crystallized preferentially over the (Z)-isomer.

The amidine motif is present in many naturally occurring compounds and biologically active synthetic compounds.[1] Amidine derivatives have been exploited as useful substrates for the synthesis of valuable organic compounds,[1] [2] ligands,[3] and organic bases.[4] Furthermore, due to their unique structural properties amidines exhibit a ­variety of biological activities that make them potential candidates for drug-discovery programs.[5] The introduction of an aryl or heteroaryl group at a nitrogen atom of an ­amidine attenuates the basic properties of the core, permitting various lipophilic groups to be appended and, in turn, opening the way to the creation of novel compounds with diverse biological activities.[6] Compounds containing the N-arylamidine moiety have shown promise as treatments for inflammation[7] and pain.[8] N-Arylamidines can serve as precursors for the synthesis of biologically important hetero­cycles such as imidazoles,[9] benzimidazoles,[10] quinazolinones,[11] or quinazolines.[12] This clearly identifies N-arylamidines as emerging privileged structures.

Phosphonates and their derivatives are useful in biochemistry,[13] in organic synthesis,[14] and in medicinal[15] and agricultural chemistry.[16] As a result of these diverse applications, the development of efficient approaches to the ­synthesis of new types of organophosphorus compounds has become an promising challenge in organic synthesis. Combinations of phosphonate moieties and nitrogen atoms in multifunctional compounds might result in improved synthetic and biological potentials.[17] Amidines bearing a phosphoryl group have been reported over several decades;[18] [19] however, reports on the synthesis of symmetrical phosphonoamidines are rare.[20–22] Sinitsa and co-workers[20] reported the synthesis of N-alkylated symmetrical amidines by treating a (gem-dichlorovinyl)phosphonate with primary amines. An alternative preparation of symmetrical phosphonoamidines starting from a phosphorylated ketenimine had been reported by Motoyoshiya et al.[22]

Phosphonoketenimines and -ynamines, which are ­highly reactive species and useful synthetic intermediates, are suitable sources for obtaining phosphorylated amidines. Recently, an efficient approach to the synthesis of non­symmetrical C-phosphonoacetamidines through the reaction of ynaminephosphonates[19] or keteniminephosphonates[23] with primary aromatic amines or NH-tetrazoles has been described. Depending on the basicity and nature of the amine, direct amination of (chloroethynyl)phosphonates ­affords amidines or enediamines through formation of an intermediate ynamine.[19]

A possibility of synthesizing symmetrical C-phosphonoamidines through the reaction of a (chloroethynyl)phosphonate with primary aromatic amines such as aniline or p-anisidine has been reported.[24] However, neither the structure of the resulting compounds nor the scope and limitations of the conversion were studied in detail.

Because of the importance of amidines, and in continuation of our studies on the chemistry of functionalized amino­phosphorus compounds,[23] [25] we report a simple synthesis of novel symmetrical N-aryl-C-phosphonоaсetamidines 3a–r by treating a (chloroethynyl)phosphonate with primary aryl amines.

In our first attempt, we reacted diisopropyl (chloroethynyl)phosphonate (1) with aniline (2a) in absolute ­diethyl ether without any additive. A two-fold excess of ­aniline was used as the hydrogen chloride acceptor. After stirring the reaction mixture at 0 °C for 16 hours, the ­amidine 3a was isolated in 68% yield (Table [1], entry 1).

Table 1 Optimization the Synthesis of N-Aryl Phosphonoaceta­midines^a

Entry	Amine (equiv)	K2CO3 (equiv)	Solvent	Temp (°C)	Time (h)	Yield (%)b
1	4	0	Et2O	0	16	68
2	2	1	Et2O	20	10	74
3	4	0	CH2Cl2	40	9	72
4	2	1	CH2Cl2	40	7	75
5	4	0	CCl4	80	6	75
6	2	1	CCl4	80	4	89
7	4	0	MeCN	82	6	73
8	2	1	MeCN	82	5	87
9	4	0	toluene	110	5	75
10	2	1	toluene	110	3.5	85

^a Reaction conditions: 1a (1 mmol), PhNH₂ (2a; 2–4 equiv), K₂CO₃ (0–1 equiv), solvent (10 mL).

^b Yield of isolated pure compound after crystallization from hexane.

It is known that amines of moderate or low basicity are incapable of rapidly trapping the evolved hydrogen chloride, whereupon hydrochlorination of the intermediate ynamine across the triple bond can occur, decreasing the reaction rate.[19] For this reason, we examined the use of ­potassium carbonate as the HCl acceptor. In the presence of one equivalent of K₂CO₃, the reaction proceeded at room temperature within ten hours to give the desired amidine 3a in 74% yield (Table [1], entry 2). The use of one equivalent of K₂CO₃ in refluxing anhydrous carbon tetrachloride required a shorter reaction time of four hours to convert phosphonate 1a completely into amidine 3a in 89% yield (Table [1], entry 6). Changing the solvent to higher-boiling toluene or polar acetonitrile did not have a marked effect on the outcome of the reaction (Table [1], entries 8 and 10). However, because of the toxicity of carbon tetrachloride, the use of acetonitrile as the solvent is far preferable in our opinion.

A series of symmetrical N-aryl amidines 3a–r was prepared from various primary aryl amines 2a–r and diiso­propyl (chloroethynyl)phosphonate (1) under the optimized reaction conditions (Table [2]).[26] The scope of the primary aryl amine was tested. Anilines substituted by an electron-donating group such as 4-methoxy (Table [2], entry 3) or 4-methyl (Table [2], entry 2) showed an increased reactivity. Note that 4-aminophenol (2d) (Table [2], entry 4) led to the formation ofgave only a trace of the target product as a result of the involvement of the hydroxy group in the reaction (Table [2], entry 4). With halo-substituted substrates, the highest yield (82%) was obtained from 4-chloroaniline 2f (Table [2], entry 6). The trend in the reactivity of 4-halo­anilines was F > Cl > Br > I. Substrates with an electron-withdrawing nitro, trifluoromethyl, or acetyl group were tolerated under the reaction conditions, giving moderate yields of the corresponding symmetrical arylamidines (­Table [2], entries 9–11). In the case of 1-(4-amino­phenyl)ethanone (2k), toluene was used as the solvent (Table [2], entry 11).

Table 2 Synthesis of Symmetrical Phosphonoacetamidines 3a–r

Entry	Adduct	R1	R2	Time (h)	Yield (%)a
1	3a	H	H	5	87
2	3b	4-Me	H	6.5	88
3	3c	4-OMe	H	5	93
4	3d	4-OH	H	20	trace
5	3e	4-F	H	5	81
6	3f	4-Cl	H	6	82
7	3g	4-Br	H	6.5	78
8	3h	4-I	H	21	72
9	3i	4-CF3	H	8	81
10	3j	4-NO2	H	21	43
11b	3k	4-Ac	H	15	65
12	3l	2-OMe	5-Me	14	88
13	3m	2-Me	4-Me	16	81
14	3n	2-OMe	4-NO2	25	45
15	3o	2-Cl	4-Cl	18	85
16	3p	2-F	4-Br	20	72
17	3q	3-F	4-F	8.5	93
18	3r	3-CF3	5-CF3	17	69

^a Yields of isolated pure compounds after crystallization from hexane.

^b Toluene was used as the solvent.

A marked decrease in reactivity (43% yield) was observed when 4-nitroaniline (2j) was used as the reactant (Table [2], entry 10). Disubstituted anilines 2l–r provided moderate to high yields of the target products. 2,4-Dichloro­aniline (2o) and 3,4-difluoroaniline (2q) gave the highest yields of the corresponding symmetrical amidines (85 and 93%, respectively).

The structures of amidines 3a–r were confirmed by IR and ¹Н, ¹³C, ¹⁹F and ³¹P NMR spectroscopy. The ¹Н NMR spectra of the symmetrical phosphonoacetamidines 3a–r contained a characteristic doublet signal for the methylene PCН₂ protons in the range δ = 2.82–3.08 with a spin–spin coupling constant (² J _HP) of 19.3–24.1 Hz. The signal for the NH proton was observed at δ = 7.74–9.76 ppm. In the ¹³C NMR spectra, the signal for the carbon atom adjacent to the phosphorus atom appeared as a doublet at δ_C = 29.13–30.95, with coupling constants of ¹ J _CP = 129.1–136.2 Hz, typical of phosphonates with an sp³-hybridized carbon ­atom. The azomethyne carbon resonated at a lower field at δ_C = 146.47–150.23 with a spin–spin coupling constant of ² J _CP = 5.1–7.3 Hz. The chemical shifts of the phosphorus ­nuclei in adducts 3a–r appeared in the range δ_P = 19–23 ppm. The IR spectra of compounds 3a–r contained strong absorption bands at 1500–1657 cm^–1, assigned to the C=N bond stretching.

The structures of compounds 3b, 3k, and 3l [27] were confirmed by X-ray single-crystal studies (Figures [1] and 2, and Supplementary Information Figure S1). These compounds crystallized in a monoclinic space group (P2₁/c or P2₁/n) with one molecule in the asymmetric unit cell. The bond lengths and angles coincided with those typically found in similar compounds, and the molecules were not sterically strained. It is likely that only the (E)-isomer crystallized, due to the steric hindrance imparted by the diisopropylphosphoryl fragment. In the crystal, the (E)-configuration of the amidine fragment is stabilized by intramolecular hydrogen bonding between the phosphoryl oxygen, imine, and aryl ortho-CH moieties. For ­example, in the crystal of 3l, the following intramolecular interactions were observed: N²–H···O¹–P¹ 2.480 Å, C¹=N¹···H–C¹², C⁶–H···O³=P¹ 2.478 Å, C¹=N¹···H–C¹² 2.326 Å (Figure [2]).

To evaluate the configuration of the symmetrical N-aryl-C-phosphonoacetamidines 3a–r in solution, we performed 2D NOESY experiments for all the compounds obtained, with CDCl₃ and DMSO-d ₆ as solvents. In the spectra of the 4-methoxyarylamidine 3c and 4-haloarylamidines 3e–g in CDCl₃, cross-peaks between the diisopropylphosphoryl moiety and the protons of the imino­aryl ring were observed, indicating an (E)-configuration of the C=N double bond. These interactions were not observed when polar DMSO-d ₆ was used as a solvent. Another trend was observed in the case of the 4-iodoaryl derivative 3h, where cross-peaks between the methyl protons of the isopropyl group (δ = 1.21 ppm) and the ortho-protons of the imino­aryl ring (δ = 7.72 ppm) were observed in DMSO-d ₆ solution, but no cross-peaks were observed in CDCl₃ solution. The NOESY results therefore showed that for N-arylamidines 3i–l and 3n, the (E)-isomer is predominant in both CDCl₃ and DMSO-d ₆ solutions. In contrast, for the phenyl derivative 3a and the 4-tolyl derivative 3b, no correlation between the signals of the diisopropylphosphoryl and imino­aryl moieties was found in either CDCl₃ or DMSO-d ₆. Identical results were obtained in the case of disubstituted N-aryl amidine 3r. For compounds 3m, 3o, and 3p, NOESY experiments showed a correlation between the signals of the methyl protons of the isopropyl group and the ortho-­protons of the iminoaryl ring only when nonpolar CDCl₃ was used as the solvent, indicating the presence of the (E)-isomer.

In conclusion, we have developed an efficient approach for the synthesis of novel symmetrical N-aryl-C-phosphonoacetamidines. This strategy tolerates a variety of aryl amines to furnish N-aryl-C-phosphonoacetamidines that might serve as key intermediates in syntheses of various heterocyclic compounds of interest in medicinal chemistry.

Acknowledgment

This research made use of resources of the Centre for Magnetic Resonance, the Centre for Chemical Analysis and Materials, and the Center for X-ray Diffraction Methods of Saint Petersburg State University.

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• 26 N-Aryl-C-phosphonoacetamidines 3a–s; General Procedure The appropriate aniline 2a–s (2 mmol) was added to a mixture of diisopropyl (chloroethynyl)phosphonate (1; 1 mmol) and K₂CO₃ (1 mmol) in anhyd acetonitrile (10 mL) at r.t., and the mixture was stirred vigorously under reflux for 5–25 h. When the reaction was complete, the mixture was filtered and concentrated, and the residue was crystallized from hexane. Diisopropyl {(2E)-2-[(4-Fluorophenyl)amino]-2-[(4-fluorophenyl)imino]ethyl}phosphonate (3e) White needle crystals; yield: 332 mg (81%); mp 104–106 °C. IR (KBr): 995.27 (P–O–C), 1226.73 (P=O), 1500.62 (C=N) cm^–1. ¹H NMR (400.13 MHz, DMSO-d ₆): δ = 1.16 (d, ³ J _HH = 6.1 Hz, 6 H, CH₃), 1.21 (d, ³ J _HH = 6.2 Hz, 6 H, CH₃), 2.92 (d, ² J _HP = 21.8 Hz, 2 H, CH₂P), 4.53 (m, ³ J _HH = 6.1 Hz, ³ J _HP = 12.4 Hz, 1 H, CHOP), 4.54 (m, ³ J _HH = 6.1 Hz, ³ J _HP = 14.0 Hz, 1 H, CHOP), 6.82 [m, ³ J _HH = 8.8 Hz, 1 H, o-CH, Ar(NH)], 6.83 [m, ³ J _HH = 8.8 Hz, 1 H, o-CH, Ar(NH)], 7.09 (m, ³ J _HH = 9.1 Hz, 4 H, m-CH, Ar), 7.73 [m, ³ J _HH = 9.2 Hz, 1 H, o-CH, Ar(N=)], 7.75 [m, ³ J _HH = 9.2 Hz, 1 H, o-CH, Ar(N=)], 8.66 (s, 1 H, NH). ¹³C NMR (100.61 MHz, DMSO-d ₆): δ = 23.97 (d, ³ J _CP = 4.4 Hz, CH₃), 24.11 (d, ³ J _CP = 4.4 Hz, CH₃), 30.25 (d, ¹ J _CP = 133.5 Hz, CH₂P), 70.98 [d, ² J _CP = 6.6 Hz, (OCH)₂P], 115.38 [d, ² J _CF = 21.3 Hz, m-CH, Ar(NH)], 115.59 [d, ² J _CF = 22.0 Hz, m-CH, Ar(N=)], 121.02 [d, ³ J _CF = 7.3 Hz, o-CH, Ar(NH)], 123.50 [d, ³ J _CF = 8.0 Hz, o-CH, Ar(N=)], 137.57 (d, ⁴ J _CF = 1.5 Hz, C-ipso-N=), 146.67 (d, ⁴ J _CF = 1.5 Hz, C-ipso-NH), 148.09 (d, CH₂ C, ² J _CP = 7.3 Hz), 157.62 [d, ¹ J _CF = 239.1 Hz, CF, Ar(NH)], 158.40 [d, ¹ J _CF = 237.6 Hz, CF, Ar(N=)]. ³¹P NMR (161.98 MHz, DMSO-d ₆): δ = 20.63. ¹⁹F NMR (376.50 MHz, DMSO-d ₆): δ = –122.72 [F, Ar(NH)], –121.19 [F, Ar(N=)]. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₀H₂₆F₂N₂O₃P: 411.1660; found: 411.1644.
• 27 CCDC 1505945 and CCDC 1518068 contain the supplementary crystallographic data for compounds 3k and 3l, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

• References and Notes

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• 26 N-Aryl-C-phosphonoacetamidines 3a–s; General Procedure The appropriate aniline 2a–s (2 mmol) was added to a mixture of diisopropyl (chloroethynyl)phosphonate (1; 1 mmol) and K₂CO₃ (1 mmol) in anhyd acetonitrile (10 mL) at r.t., and the mixture was stirred vigorously under reflux for 5–25 h. When the reaction was complete, the mixture was filtered and concentrated, and the residue was crystallized from hexane. Diisopropyl {(2E)-2-[(4-Fluorophenyl)amino]-2-[(4-fluorophenyl)imino]ethyl}phosphonate (3e) White needle crystals; yield: 332 mg (81%); mp 104–106 °C. IR (KBr): 995.27 (P–O–C), 1226.73 (P=O), 1500.62 (C=N) cm^–1. ¹H NMR (400.13 MHz, DMSO-d ₆): δ = 1.16 (d, ³ J _HH = 6.1 Hz, 6 H, CH₃), 1.21 (d, ³ J _HH = 6.2 Hz, 6 H, CH₃), 2.92 (d, ² J _HP = 21.8 Hz, 2 H, CH₂P), 4.53 (m, ³ J _HH = 6.1 Hz, ³ J _HP = 12.4 Hz, 1 H, CHOP), 4.54 (m, ³ J _HH = 6.1 Hz, ³ J _HP = 14.0 Hz, 1 H, CHOP), 6.82 [m, ³ J _HH = 8.8 Hz, 1 H, o-CH, Ar(NH)], 6.83 [m, ³ J _HH = 8.8 Hz, 1 H, o-CH, Ar(NH)], 7.09 (m, ³ J _HH = 9.1 Hz, 4 H, m-CH, Ar), 7.73 [m, ³ J _HH = 9.2 Hz, 1 H, o-CH, Ar(N=)], 7.75 [m, ³ J _HH = 9.2 Hz, 1 H, o-CH, Ar(N=)], 8.66 (s, 1 H, NH). ¹³C NMR (100.61 MHz, DMSO-d ₆): δ = 23.97 (d, ³ J _CP = 4.4 Hz, CH₃), 24.11 (d, ³ J _CP = 4.4 Hz, CH₃), 30.25 (d, ¹ J _CP = 133.5 Hz, CH₂P), 70.98 [d, ² J _CP = 6.6 Hz, (OCH)₂P], 115.38 [d, ² J _CF = 21.3 Hz, m-CH, Ar(NH)], 115.59 [d, ² J _CF = 22.0 Hz, m-CH, Ar(N=)], 121.02 [d, ³ J _CF = 7.3 Hz, o-CH, Ar(NH)], 123.50 [d, ³ J _CF = 8.0 Hz, o-CH, Ar(N=)], 137.57 (d, ⁴ J _CF = 1.5 Hz, C-ipso-N=), 146.67 (d, ⁴ J _CF = 1.5 Hz, C-ipso-NH), 148.09 (d, CH₂ C, ² J _CP = 7.3 Hz), 157.62 [d, ¹ J _CF = 239.1 Hz, CF, Ar(NH)], 158.40 [d, ¹ J _CF = 237.6 Hz, CF, Ar(N=)]. ³¹P NMR (161.98 MHz, DMSO-d ₆): δ = 20.63. ¹⁹F NMR (376.50 MHz, DMSO-d ₆): δ = –122.72 [F, Ar(NH)], –121.19 [F, Ar(N=)]. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₀H₂₆F₂N₂O₃P: 411.1660; found: 411.1644.
• 27 CCDC 1505945 and CCDC 1518068 contain the supplementary crystallographic data for compounds 3k and 3l, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

• Supplementary Material