2-[Anilino(di­phenyl­phosphoryl)methyl]phenol from a three-component Kabachnik–Fields reaction

The title compound, C₂₅H₂₂NO₂P, was synthesized in high yield by a three-component Kabachnik–Fields reaction of di­phenyl­phosphine oxide, salicyl­aldehyde and aniline in dry toluene at room temperature. It precipitates as racemic crystals, in which strong hydrogen bonds between the hy­droxy group and the P=O group of a neighbouring mol­ecule form one-dimensional heterochiral chains along the crystallographic a axis, with an O...O separation of 2.568 (2) Å. The pseudo-tetra­hedral environment of the P atom is distorted, with O—P—C bond angles significantly larger than the C—P—C angles.

S1. Introduction

Chiral phospho­rus-containing compounds such as α-amino phospho­nic acids and their derivatives have attracted considerable attention due to their promising biological properties (Romanenko & Kukhar, 2006; Haynes et al., 1989, 1991; Shi et al., 2000; Kafarski & Lejczak, 2001). They have found application as anti­bacterials (Pratt, 1989), anti­viral agents (Huang & Chen, 2000) and enzyme inhibitors (Smith et al., 1989; Kafarski & Lejczak, 1991). The absolute configuration of phospho­nyl compounds strongly influences their biological properties (Patel et al., 1995). Various synthetic methods for α-amino­phospho­nic acids and α-amino­phospho­nates have therefore been reported (Moore et al., 2002; Demmer et al., 2011; Bálint et al., 2013; Wu et al., 2013). However, other α-amino phospho­rus derivatives such as α-amino­phosphine oxides have received much less attention for their biological properties due to the lack of direct synthetic access. We report herein a convenient one-pot three-component method through a Kabachnik–Fields reaction for the synthesis of 2-[anilino(di­phenyl­phospho­ryl)methyl]­phenol, (I), using di­phenyl­phosphine oxide, salicyl­aldehyde and aniline as starting materials (see scheme). The notable advantages of this methodology are operational simplicity, mild reaction conditions, higher yields, a reasonable reaction time and ease of isolation of the pure products. In order to further confirm the stereostructure and structure–activity relationship of α-amino­phosphine oxides potentially helpful for practical applications, we established the crystal structure of (I).

S2. Experimental

S2.1. Synthesis and crystallization

A solution of di­phenyl­phosphine oxide (1.01 g, 5 mmol, 1 equivalent) in dry toluene (10 ml) was added to a 50 ml dry flask equipped with a CaCl₂ tube and which contained a solution of aniline (1.8 ml, 20 mmol, 4 equivalents) and salicyl­aldehyde (0.61 g, 5 mmol, 1 equivalent) in dry toluene (20 ml). After stirring for 4 h at room temperature, the reaction was complete; the precipitate was filtered off, washed with cold toluene (10 ml) and then dried under vacuum to afford the pure title product, (I) (yield 1.8 g, 90%), as a colourless solid. Single crystals of (I) suitable for X-ray diffraction were obtained by recrystallization from di­ethyl ether. Spectroscopic analysis: ¹H NMR (400 MHz, CDCl₃, 298 K, δ, p.p.m.): 9.82 (s, 1H, OH), 7.81–6.62 (m, 19H, Ar-H), 5.46 (d, ²J_P—H = 8.5 Hz, 1H, C—H), 3.73 (br s, 1H, NH); ¹³C NMR (100 MHz, CDCl₃, 298 K, δ, p.p.m.): 155.9, 145.8, 132.7, 129.3, 129.7, 129.2, 128.8, 128.6, 128.4, 128.3, 122.4, 120.4, 119.2, 114.4, 56.9 (d, ¹J_P—C = 39.9 Hz); ³¹P NMR (162 MHz, CDCl₃, 298 K, δ, p.p.m.): 38.4; IR (KBr, ν, cm^-1): 3430 (NH), 3228 (OH), 3303 (NH), 3138, 3062, 2969, 2916, 2884, 2827, 1591, 1553, 1485, 1438, 1171 (P═O), 1122, 1096 (P—O), 1070, 1037, 855, 743, 726, 693, 561, 542, 525, 439. Analysis, found for C₂₅H₂₂NO₂P: C 75.19, H 5.43, N 3.55%; calculated: C 75.18, H 5.55, N 3.51%.

S2.2. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. H atoms bound to C or N atoms were positioned geometrically and refined using a riding model, with aryl C—H = 0.93 Å, methine C—H = 0.98 Å and N—H = 0.86 Å, with U_iso(H) = 1.2U_eq(C,N). The hy­droxy H atom was located from a difference Fourier map and the O—H distance was constrained to 0.82 Å, with U_iso(H) = 1.5U_eq(O).

S3. Results and discussion

In compound (I), the formation of P—C bonds between the P atom of di­phenyl­phosphine oxide and the carbonyl C atom of salicyl­aldehyde results in the formation of a stereocentre at atom C7 (Fig. 1). The space group Pbca was identified with the help of the program PLATON (Spek, 2009). Not surprisingly, (I) forms racemic crystals with one molecule in the asymmetric unit. A displacement ellipsoid plot of the S enanti­omer is shown in Fig. 1. The O—P—C bond angles are significantly larger than the C—P—C angles (Table 2), indicating that the P atom adopts a distorted tetra­hedral configuration with sp³-hybridization.

An inter­molecular O1—H1···O2ⁱ hydrogen bond (details in Table 3, including symmetry code) between the O1—H1 hy­droxy group and the P-bonded atom O2 links neighbouring molecules into heterochiral chains along the crystallographic a axis. The hydrogen bonds are shown in a packing diagram (Fig. 2).

Related literature

For related literature, see: Bálint et al. (2013); Demmer et al. (2011); Haynes et al. (1989, 1991); Huang & Chen (2000); Kafarski & Lejczak (1991, 2001); Moore et al. (2002); Patel et al. (1995); Pratt (1989); Romanenko & Kukhar (2006); Shi (2000); Smith (1989); Spek (2009); Wu et al. (2013).

Computing details

Data collection: CrysAlis PRO (Agilent, 2012); cell refinement: CrysAlis PRO (Agilent, 2012); data reduction: CrysAlis PRO (Agilent, 2012); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

Figures

Fig. 1. The molecular structure of (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.

Fig. 2. A packing diagram for (I), showing the intermolecular hydrogen-bonding interactions (dashed lines) between atoms H1B and O2ⁱ of neighbouring S and R enantiomers. [Symmetry code: (i) x - 1/2, y, -z + 3/2.]

2-[Anilino(diphenylphosphoryl)methyl]phenol

Crystal data

C25H22NO2P	Dx = 1.226 Mg m^−3
Mr = 399.41	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, Pbca	Cell parameters from 3813 reflections
a = 12.5489 (4) Å	θ = 2.3–29.7°
b = 16.4560 (5) Å	µ = 0.15 mm^−1
c = 20.9643 (6) Å	T = 293 K
V = 4329.2 (2) Å^3	Prism, colourless
Z = 8	0.1 × 0.1 × 0.1 mm
F(000) = 1680

Data collection

Agilent Xcalibur (Atlas, Gemini ultra) diffractometer	4429 independent reflections
Radiation source: fine-focus sealed tube	2951 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.039
ω scans	θmax = 26.4°, θmin = 2.3°
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2012)	h = −14→15
Tmin = 0.774, Tmax = 1.000	k = −20→16
14390 measured reflections	l = −26→25

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.048	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.122	H-atom parameters constrained
S = 1.02	w = 1/[σ^2(Fo^2) + (0.0503P)^2 + 0.6207P] where P = (Fo^2 + 2Fc^2)/3
4429 reflections	(Δ/σ)max < 0.001
263 parameters	Δρmax = 0.29 e Å^−3
0 restraints	Δρmin = −0.27 e Å^−3

Special details

Experimental. CrysAlisPro, Agilent Technologies, Version 1.171.36.21 (release 14-08-2012 CrysAlis171 .NET) (compiled Sep 14 2012,17:21:16) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
P1	0.68854 (4)	0.10727 (3)	0.67088 (2)	0.03680 (16)
O1	0.43871 (13)	0.17634 (11)	0.75461 (7)	0.0704 (5)
H1B	0.3989	0.1774	0.7856	0.106*
O2	0.79368 (10)	0.14729 (9)	0.66206 (6)	0.0484 (4)
N1	0.59018 (14)	0.21014 (10)	0.59205 (7)	0.0476 (4)
H1	0.6477	0.2017	0.5708	0.057*
C1	0.65930 (19)	0.30369 (13)	0.71138 (11)	0.0559 (6)
H1A	0.7084	0.3083	0.6784	0.067*
C2	0.6630 (2)	0.35799 (15)	0.76194 (13)	0.0732 (7)
H2	0.7144	0.3987	0.7629	0.088*
C3	0.5904 (2)	0.35127 (16)	0.81021 (12)	0.0693 (7)
H3	0.5931	0.3876	0.8442	0.083*
C4	0.5139 (2)	0.29207 (15)	0.80944 (10)	0.0603 (6)
H4	0.4646	0.2885	0.8424	0.072*
C5	0.51038 (17)	0.23744 (13)	0.75920 (9)	0.0466 (5)
C6	0.58356 (16)	0.24296 (11)	0.70957 (9)	0.0392 (5)
C7	0.58122 (15)	0.17948 (12)	0.65686 (8)	0.0384 (5)
H7	0.5136	0.1500	0.6602	0.046*
C8	0.41040 (18)	0.26471 (13)	0.59454 (10)	0.0514 (6)
H8	0.3999	0.2444	0.6355	0.062*
C9	0.3292 (2)	0.30678 (15)	0.56417 (12)	0.0668 (7)
H9	0.2646	0.3146	0.5850	0.080*
C10	0.3430 (3)	0.33700 (16)	0.50364 (14)	0.0758 (8)
H10	0.2881	0.3651	0.4836	0.091*
C11	0.4382 (3)	0.32536 (16)	0.47317 (12)	0.0740 (8)
H11	0.4478	0.3458	0.4322	0.089*
C12	0.5201 (2)	0.28378 (13)	0.50237 (10)	0.0561 (6)
H12	0.5843	0.2763	0.4810	0.067*
C13	0.50706 (18)	0.25279 (11)	0.56411 (9)	0.0433 (5)
C14	0.5774 (2)	−0.00203 (15)	0.59125 (10)	0.0621 (6)
H14	0.5149	0.0253	0.6019	0.075*
C15	0.5736 (3)	−0.06854 (17)	0.55043 (12)	0.0788 (8)
H15	0.5086	−0.0861	0.5342	0.095*
C16	0.6647 (3)	−0.10775 (17)	0.53429 (13)	0.0860 (10)
H16	0.6619	−0.1523	0.5071	0.103*
C17	0.7601 (3)	−0.08252 (17)	0.55751 (14)	0.0857 (9)
H17	0.8221	−0.1096	0.5458	0.103*
C18	0.7655 (2)	−0.01646 (14)	0.59873 (11)	0.0640 (7)
H18	0.8310	0.0006	0.6145	0.077*
C19	0.67364 (17)	0.02364 (12)	0.61607 (9)	0.0428 (5)
C20	0.7151 (2)	0.10357 (17)	0.80119 (10)	0.0719 (8)
H20	0.7624	0.1463	0.7948	0.086*
C21	0.6948 (3)	0.0757 (2)	0.86265 (12)	0.0975 (11)
H21	0.7280	0.1003	0.8973	0.117*
C22	0.6265 (3)	0.0125 (2)	0.87217 (12)	0.0874 (9)
H22	0.6143	−0.0067	0.9133	0.105*
C23	0.5764 (2)	−0.02250 (17)	0.82197 (13)	0.0783 (8)
H23	0.5290	−0.0651	0.8287	0.094*
C24	0.5956 (2)	0.00505 (14)	0.76081 (10)	0.0609 (6)
H24	0.5609	−0.0193	0.7266	0.073*
C25	0.66542 (16)	0.06800 (12)	0.74989 (9)	0.0426 (5)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
P1	0.0374 (3)	0.0433 (3)	0.0297 (3)	−0.0013 (2)	−0.0015 (2)	0.0009 (2)
O1	0.0646 (11)	0.0858 (12)	0.0609 (10)	−0.0245 (10)	0.0271 (8)	−0.0124 (9)
O2	0.0378 (8)	0.0683 (9)	0.0391 (7)	−0.0077 (7)	−0.0011 (6)	−0.0007 (7)
N1	0.0492 (11)	0.0603 (11)	0.0333 (8)	0.0079 (9)	0.0064 (8)	0.0097 (8)
C1	0.0629 (15)	0.0474 (13)	0.0574 (14)	−0.0102 (12)	0.0067 (12)	0.0012 (11)
C2	0.0790 (19)	0.0521 (15)	0.089 (2)	−0.0140 (14)	−0.0039 (16)	−0.0097 (14)
C3	0.084 (2)	0.0586 (16)	0.0657 (16)	0.0075 (15)	−0.0063 (15)	−0.0203 (13)
C4	0.0673 (16)	0.0659 (16)	0.0479 (12)	0.0117 (14)	0.0073 (12)	−0.0074 (11)
C5	0.0465 (12)	0.0501 (12)	0.0430 (11)	0.0012 (11)	0.0035 (10)	0.0010 (10)
C6	0.0421 (12)	0.0384 (11)	0.0370 (10)	0.0008 (9)	0.0000 (9)	0.0045 (9)
C7	0.0390 (11)	0.0429 (11)	0.0332 (10)	−0.0034 (9)	0.0006 (8)	0.0051 (8)
C8	0.0570 (14)	0.0535 (13)	0.0436 (12)	0.0074 (11)	−0.0110 (11)	−0.0036 (10)
C9	0.0662 (17)	0.0640 (16)	0.0702 (16)	0.0141 (13)	−0.0229 (13)	−0.0157 (13)
C10	0.093 (2)	0.0604 (17)	0.0743 (18)	0.0103 (15)	−0.0419 (17)	−0.0013 (14)
C11	0.108 (2)	0.0609 (16)	0.0527 (14)	−0.0108 (16)	−0.0350 (16)	0.0141 (12)
C12	0.0759 (16)	0.0524 (13)	0.0400 (11)	−0.0113 (12)	−0.0120 (11)	0.0062 (10)
C13	0.0567 (14)	0.0371 (11)	0.0362 (10)	−0.0034 (10)	−0.0102 (10)	−0.0019 (9)
C14	0.0703 (17)	0.0622 (15)	0.0539 (13)	−0.0032 (13)	−0.0079 (13)	−0.0116 (12)
C15	0.109 (2)	0.0678 (17)	0.0595 (16)	−0.0205 (18)	−0.0115 (16)	−0.0111 (14)
C16	0.148 (3)	0.0524 (16)	0.0574 (16)	−0.006 (2)	0.0084 (19)	−0.0091 (13)
C17	0.116 (3)	0.0599 (17)	0.081 (2)	0.0229 (18)	0.0206 (19)	−0.0111 (15)
C18	0.0740 (18)	0.0570 (15)	0.0609 (14)	0.0125 (14)	0.0016 (13)	−0.0042 (12)
C19	0.0567 (14)	0.0400 (11)	0.0318 (10)	0.0011 (10)	−0.0007 (10)	0.0016 (9)
C20	0.0852 (19)	0.0932 (19)	0.0372 (12)	−0.0216 (16)	−0.0057 (12)	0.0073 (13)
C21	0.129 (3)	0.128 (3)	0.0357 (14)	−0.021 (2)	−0.0097 (15)	0.0118 (16)
C22	0.125 (3)	0.092 (2)	0.0450 (15)	0.011 (2)	0.0147 (17)	0.0264 (15)
C23	0.100 (2)	0.0636 (17)	0.0714 (18)	−0.0068 (16)	0.0200 (17)	0.0246 (14)
C24	0.0745 (17)	0.0593 (15)	0.0491 (13)	−0.0074 (13)	0.0037 (12)	0.0112 (11)
C25	0.0475 (12)	0.0456 (11)	0.0347 (10)	0.0048 (10)	−0.0008 (9)	0.0043 (9)

Geometric parameters (Å, º)

P1—O2	1.4862 (14)	C11—H11	0.9300
P1—C7	1.820 (2)	C12—C11	1.378 (3)
P1—C19	1.803 (2)	C12—H12	0.9300
P1—C25	1.8015 (19)	C13—C8	1.384 (3)
O1—H1B	0.8200	C13—C12	1.401 (3)
N1—H1	0.8600	C14—H14	0.9300
N1—C13	1.387 (3)	C14—C15	1.390 (3)
C1—H1A	0.9300	C15—H15	0.9300
C1—C2	1.387 (3)	C16—C15	1.356 (4)
C2—H2	0.9300	C16—H16	0.9300
C2—C3	1.366 (4)	C16—C17	1.357 (4)
C3—H3	0.9300	C17—H17	0.9300
C4—C3	1.368 (3)	C18—C17	1.390 (3)
C4—H4	0.9300	C18—H18	0.9300
C5—O1	1.352 (2)	C19—C14	1.382 (3)
C5—C4	1.385 (3)	C19—C18	1.377 (3)
C6—C1	1.380 (3)	C20—H20	0.9300
C6—C5	1.391 (3)	C20—C21	1.391 (3)
C7—N1	1.454 (2)	C21—H21	0.9300
C7—C6	1.521 (3)	C22—C21	1.363 (4)
C7—H7	0.9800	C22—H22	0.9300
C8—H8	0.9300	C23—C22	1.355 (4)
C8—C9	1.387 (3)	C23—H23	0.9300
C9—H9	0.9300	C24—C23	1.381 (3)
C9—C10	1.374 (4)	C24—H24	0.9300
C10—H10	0.9300	C25—C20	1.374 (3)
C11—C10	1.368 (4)	C25—C24	1.376 (3)
O2—P1—C7	110.33 (9)	C10—C11—C12	120.9 (2)
O2—P1—C19	110.55 (9)	C12—C11—H11	119.6
O2—P1—C25	114.61 (9)	C11—C12—H12	119.9
C19—P1—C7	108.59 (9)	C11—C12—C13	120.3 (2)
C25—P1—C7	105.28 (9)	C13—C12—H12	119.9
C25—P1—C19	107.19 (9)	N1—C13—C12	119.1 (2)
C5—O1—H1B	109.5	C8—C13—N1	122.41 (17)
C7—N1—H1	119.6	C8—C13—C12	118.4 (2)
C13—N1—H1	119.6	C15—C14—H14	119.9
C13—N1—C7	120.81 (16)	C19—C14—H14	119.9
C2—C1—H1A	119.6	C19—C14—C15	120.2 (3)
C6—C1—H1A	119.6	C14—C15—H15	120.0
C6—C1—C2	120.7 (2)	C16—C15—C14	120.0 (3)
C1—C2—H2	120.3	C16—C15—H15	120.0
C3—C2—C1	119.5 (2)	C15—C16—H16	119.7
C3—C2—H2	120.3	C15—C16—C17	120.6 (3)
C2—C3—H3	119.4	C17—C16—H16	119.7
C2—C3—C4	121.1 (2)	C16—C17—H17	119.8
C4—C3—H3	119.4	C16—C17—C18	120.3 (3)
C3—C4—H4	120.2	C18—C17—H17	119.8
C3—C4—C5	119.6 (2)	C17—C18—H18	120.1
C5—C4—H4	120.2	C19—C18—C17	119.9 (3)
O1—C5—C4	123.9 (2)	C19—C18—H18	120.1
O1—C5—C6	115.74 (18)	C14—C19—P1	124.35 (17)
C4—C5—C6	120.4 (2)	C18—C19—P1	116.58 (17)
C1—C6—C5	118.79 (19)	C18—C19—C14	119.1 (2)
C1—C6—C7	122.05 (18)	C21—C20—H20	119.9
C5—C6—C7	119.09 (18)	C25—C20—H20	119.9
P1—C7—H7	107.8	C25—C20—C21	120.1 (3)
N1—C7—P1	108.69 (13)	C20—C21—H21	119.9
N1—C7—C6	116.05 (16)	C22—C21—C20	120.2 (3)
N1—C7—H7	107.8	C22—C21—H21	119.9
C6—C7—P1	108.47 (13)	C21—C22—H22	119.9
C6—C7—H7	107.8	C23—C22—C21	120.2 (2)
C9—C8—H8	119.9	C23—C22—H22	119.9
C13—C8—H8	119.9	C22—C23—H23	120.0
C13—C8—C9	120.2 (2)	C22—C23—C24	120.0 (3)
C8—C9—H9	119.6	C24—C23—H23	120.0
C10—C9—C8	120.8 (3)	C23—C24—H24	119.6
C10—C9—H9	119.6	C25—C24—C23	120.8 (2)
C9—C10—H10	120.3	C25—C24—H24	119.6
C11—C10—C9	119.4 (2)	C20—C25—P1	119.59 (17)
C11—C10—H10	120.3	C20—C25—C24	118.65 (19)
C10—C11—H11	119.6	C24—C25—P1	121.71 (16)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1B···O2^i	0.82	1.79	2.5677 (19)	159

Symmetry code: (i) x−1/2, y, −z+3/2.