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Acta Cryst. (2007). E63, o3703-o3704    [ doi:10.1107/S160053680703749X ]

2-{5-Chloro-2-[(4-methoxybenzyl)amino]phenyl}-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol

R. J. Butcher, J. P. Jasinski, A. N. Mayekar, H. S. Yathirajan and B. Narayana

Abstract top

In the title molecule, C21H19ClF3NO2, the 5-chlorophenyl and 4-methoxybenzyl groups are twisted slightly with respect to the amine group [dihedral angles = -8.4 (2) and 13.6 (2)°] and with respect to each other [6.2 (7)°], forming a nearly planar arrangement. The crystal packing is stabilized by intramolecular N-H...O hydrogen bonding between the amine H atom and the hydroxyl O atom. In addition, intermolecular hydrogen bonding between the same amine H atom and an F atom, N-H...F, and between the methoxy O atom and the hydroxyl H atom, O-H...O, adds to this stability.

Comment top

The title compound is an intermediate in the preparation of efavirenz, an anti HIV drug. Efavirenz is also used in combination with other antiretroviral agents as part of an expanded postexposure prophylaxis regime to prevent HIV transmission for those exposed to materials associated with a high risk for HIV transmission. Efavirenz was approved by the Food and Drug Administration (FDA) in 1998, making it the 14t h approved antiretroviral drug. In recent years fluorinated compounds find much importance in the pharmaceutical field. Fluorinated compounds in general, fluorinated heterocycles in particular, are those focused on much in modern-day medicinal chemistry. Incorporation of a fluorine atom instead of hydrogen one can alter the course of the reaction as well as its biological activities. Further introduction of a fluorine atom as the CF3 group provides a more lipophilically and pharmacologically interesting compound compared to their non fluorinated analogues. The trifluoromethyl substituted compounds have been reported to possess biological activities as herbicides, fungicides and inhibitors for platelet aggregation. In view of the importance of the fluro derivatives, a crystal structure of the title compound, (I), is reported.

The mean planes of the 5-chlorophenyl and 4-methoxybenzyl groups are twisted slightly with the amine group [dihedral angles: N—C7—C8—C13 = −8.4 (2)°; C7—N—C6—C5 = 13.6 (2)°] and 6.2 (7)° with each other forming a nearly planar arrangement (Fig. 1).

Intramolecular hydrogen bonding occurs between the amine hydrogen, and the hydroxyl oxygen, N—H0A···O2, of the title molecule. In addition, intermolecular hydrogen bonding between the the same amine hydrogen and a fluorine atom, N—H0A···F2, as well as between the methoxy oxygen atom and hydroxyl hydrogen atom, O2—H2B···O1, adds to crystal packing stability (Fig. 2).

Related literature top

For related structures, see: Yathirajan, Sarojini et al. (2007); Yathirajan, Sreevidya et al. (2007). For related literature, see: Whittle et al. (1994); Ren et al. (2002); Jung et al. (2002); Küçükgüzel et al. (2000).

Experimental top

A pure sample of the title compound was obtained as a gift sample from Sequent Scientific Ltd., India and was crystallized from a mixture of (1:1) ethylacetate and toluene (m.p.: 427–429 K).

Refinement top

The H atoms were included in the riding model approximation with O—H = 0.83 Å, N—H = 0.87 Å and C—H = 0.94–0.98 Å, and with Uiso(H) = 1.19–1.49Ueq(C, O, N).

Computing details top

Data collection: CrysAlisPro (Oxford Diffraction, 2007); cell refinement: CrysAlisPro; data reduction: CrysAlisPro; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Bruker, 2000); software used to prepare material for publication: SHELXTL.

Figures top
[Figure 1] Fig. 1. Molecular structure of the title compound (I), showing atom labelling and 50% probability displacement ellipsoids. Dashed lines indicate N—H···O intramolecular hydrogen bonds.
[Figure 2] Fig. 2. Packing diagram of (I), viewed down the a axis. Dashed lines indicate O—H···O, and N—H···F intermolecular and N—H···O intramolecular hydrogen bonds.
2-{5-Chloro-2-[(4-methoxybenzyl)amino]phenyl}-4-cyclopropyl- 1,1,1-trifluorobut-3-yn-2-ol top
Crystal data top
C21H19ClF3NO2F000 = 848
Mr = 409.82Dx = 1.450 Mg m−3
Orthorhombic, P212121Mo Kα radiation
λ = 0.71073 Å
Hall symbol: P 2ac 2abCell parameters from 4798 reflections
a = 8.6400 (19) Åθ = 4.6–32.6º
b = 9.7671 (9) ŵ = 0.25 mm−1
c = 22.240 (5) ÅT = 203 K
V = 1876.8 (6) Å3Plate, colourless
Z = 40.43 × 0.37 × 0.14 mm
Data collection top
Oxford Diffraction Gemini R
diffractometer		Rint = 0.050
Radiation source: fine-focus sealed tubeθmax = 32.7º
Monochromator: graphiteθmin = 4.8º
T = 203 Kh = −12→12
φ and ω scansk = −13→14
Absorption correction: multi-scan
(CrysAlis RED; Oxford Diffraction, 2007)		l = −32→32
Tmin = 0.906, Tmax = 1.0002 standard reflections
18057 measured reflections every 50 reflections
6220 independent reflections intensity decay: none
2640 reflections with I > 2σ(I)
Refinement top
Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullH-atom parameters constrained
R[F2 > 2σ(F2)] = 0.032  w = 1/[σ2(Fo2) + (0.0312P)2]
where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.069(Δ/σ)max = 0.016
S = 0.76Δρmax = 0.21 e Å−3
6220 reflectionsΔρmin = −0.22 e Å−3
254 parametersExtinction correction: none
Primary atom site location: structure-invariant direct methodsAbsolute structure: Flack (1983), with 3628 Friedel pairs
Secondary atom site location: difference Fourier mapFlack parameter: 0.02 (4)
Crystal data top
C21H19ClF3NO2V = 1876.8 (6) Å3
Mr = 409.82Z = 4
Orthorhombic, P212121Mo Kα
a = 8.6400 (19) ŵ = 0.25 mm−1
b = 9.7671 (9) ÅT = 203 K
c = 22.240 (5) Å0.43 × 0.37 × 0.14 mm
Data collection top
Oxford Diffraction Gemini R
diffractometer		2640 reflections with I > 2σ(I)
Absorption correction: multi-scan
(CrysAlis RED; Oxford Diffraction, 2007)		Rint = 0.050
Tmin = 0.906, Tmax = 1.0002 standard reflections
18057 measured reflections every 50 reflections
6220 independent reflections intensity decay: none
Refinement top
R[F2 > 2σ(F2)] = 0.032H-atom parameters constrained
wR(F2) = 0.069Δρmax = 0.21 e Å−3
S = 0.76Δρmin = −0.22 e Å−3
6220 reflectionsAbsolute structure: Flack (1983), with 3628 Friedel pairs
254 parametersFlack parameter: 0.02 (4)
Special details top

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 > 2sigma(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 (Å2) top
xyzUiso*/Ueq
Cl0.82991 (6)0.66081 (4)0.14333 (2)0.05311 (14)
F10.90703 (12)0.15349 (10)0.23407 (4)0.0495 (3)
F20.85448 (12)0.01133 (9)0.16359 (4)0.0507 (3)
F31.06136 (12)−0.01341 (9)0.21520 (4)0.0485 (3)
O10.89852 (13)−0.45246 (10)−0.11680 (5)0.0395 (3)
O21.12304 (12)0.08094 (11)0.10175 (4)0.0355 (3)
H2B1.20160.04390.11580.053*
N0.86626 (16)0.10757 (13)0.03665 (5)0.0332 (3)
H0A0.90880.04110.05680.040*
C10.94820 (17)0.26983 (14)0.11402 (6)0.0260 (3)
C20.93451 (18)0.40036 (16)0.13820 (7)0.0306 (4)
H2A0.99130.42300.17290.037*
C30.8395 (2)0.49753 (14)0.11254 (7)0.0339 (4)
C40.7563 (2)0.46620 (17)0.06224 (8)0.0398 (4)
H4A0.69190.53250.04460.048*
C50.76666 (19)0.33727 (17)0.03738 (7)0.0360 (4)
H5A0.70830.31680.00290.043*
C60.86196 (18)0.23591 (15)0.06223 (6)0.0282 (4)
C70.8037 (2)0.07891 (15)−0.02165 (7)0.0364 (4)
H7A0.85170.1405−0.05100.044*
H7B0.69240.0981−0.02120.044*
C80.82856 (19)−0.06668 (15)−0.04160 (7)0.0306 (4)
C90.7601 (2)−0.10854 (17)−0.09471 (8)0.0424 (4)
H9A0.6951−0.0473−0.11530.051*
C100.7839 (2)−0.23590 (17)−0.11818 (8)0.0434 (4)
H10A0.7357−0.2614−0.15440.052*
C110.87869 (18)−0.32664 (16)−0.08862 (7)0.0311 (4)
C120.9456 (2)−0.29100 (16)−0.03566 (8)0.0392 (4)
H12A1.0091−0.3535−0.01500.047*
C130.9191 (2)−0.16095 (17)−0.01221 (7)0.0390 (4)
H13A0.9643−0.13700.02480.047*
C141.0172 (2)−0.54038 (17)−0.09373 (9)0.0514 (5)
H14A1.0199−0.6244−0.11700.077*
H14B0.9956−0.5617−0.05200.077*
H14C1.1166−0.4946−0.09660.077*
C151.05879 (17)0.16978 (15)0.14503 (6)0.0274 (3)
C160.9694 (2)0.07957 (17)0.18995 (8)0.0345 (4)
C171.18271 (19)0.23895 (15)0.17881 (7)0.0311 (4)
C181.28762 (19)0.28546 (15)0.20665 (7)0.0342 (4)
C191.4148 (2)0.34007 (18)0.24111 (8)0.0411 (4)
H19A1.42280.30490.28270.049*
C201.4705 (3)0.4811 (2)0.23272 (10)0.0676 (7)
H20A1.41820.53780.20260.081*
H20B1.50660.53080.26830.081*
C211.5639 (3)0.3671 (2)0.21144 (10)0.0727 (7)
H21A1.65860.34530.23370.087*
H21B1.57030.35230.16790.087*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Cl0.0663 (3)0.0375 (2)0.0555 (3)0.0118 (2)−0.0040 (3)−0.0080 (2)
F10.0513 (6)0.0649 (6)0.0323 (5)0.0004 (6)0.0132 (5)0.0022 (5)
F20.0472 (6)0.0591 (6)0.0459 (6)−0.0258 (5)−0.0090 (5)0.0130 (5)
F30.0560 (6)0.0459 (5)0.0435 (6)0.0030 (5)−0.0096 (5)0.0180 (5)
O10.0334 (7)0.0377 (6)0.0475 (7)0.0026 (5)−0.0007 (6)−0.0050 (5)
O20.0313 (7)0.0436 (6)0.0318 (6)0.0099 (5)−0.0045 (6)−0.0058 (5)
N0.0399 (8)0.0319 (7)0.0279 (7)0.0000 (6)−0.0098 (7)0.0025 (6)
C10.0241 (8)0.0308 (8)0.0231 (8)−0.0018 (7)0.0014 (7)0.0032 (7)
C20.0271 (8)0.0395 (9)0.0253 (8)−0.0024 (7)0.0023 (8)0.0011 (7)
C30.0369 (9)0.0301 (8)0.0346 (9)0.0007 (8)0.0026 (9)−0.0014 (7)
C40.0395 (10)0.0391 (10)0.0408 (10)0.0071 (8)−0.0050 (9)0.0071 (8)
C50.0354 (9)0.0442 (10)0.0283 (8)0.0001 (9)−0.0076 (8)0.0031 (8)
C60.0253 (9)0.0327 (9)0.0267 (8)−0.0027 (7)0.0000 (8)0.0040 (7)
C70.0432 (11)0.0394 (9)0.0267 (9)−0.0005 (8)−0.0059 (8)0.0035 (7)
C80.0297 (9)0.0359 (9)0.0263 (8)−0.0044 (8)0.0014 (8)0.0011 (7)
C90.0461 (11)0.0441 (10)0.0370 (10)0.0112 (8)−0.0180 (9)−0.0045 (8)
C100.0467 (11)0.0488 (11)0.0347 (10)0.0033 (9)−0.0119 (9)−0.0059 (9)
C110.0258 (9)0.0333 (9)0.0342 (9)−0.0062 (8)0.0019 (8)−0.0013 (8)
C120.0432 (11)0.0382 (10)0.0361 (10)−0.0038 (8)−0.0113 (9)0.0066 (8)
C130.0497 (11)0.0368 (9)0.0306 (9)−0.0082 (9)−0.0137 (9)0.0004 (8)
C140.0415 (11)0.0500 (11)0.0628 (13)0.0093 (9)−0.0033 (10)−0.0051 (10)
C150.0267 (8)0.0306 (7)0.0248 (8)0.0001 (8)0.0003 (8)−0.0030 (7)
C160.0368 (10)0.0356 (9)0.0312 (9)−0.0032 (9)−0.0025 (9)0.0044 (8)
C170.0275 (9)0.0320 (8)0.0337 (9)−0.0003 (8)−0.0023 (8)0.0037 (7)
C180.0304 (10)0.0337 (9)0.0386 (10)0.0016 (8)0.0010 (8)−0.0005 (7)
C190.0359 (10)0.0465 (10)0.0408 (10)−0.0044 (9)−0.0069 (9)0.0017 (9)
C200.0816 (17)0.0393 (11)0.0818 (15)−0.0179 (12)−0.0386 (14)0.0011 (11)
C210.0464 (12)0.0994 (18)0.0723 (15)−0.0318 (13)0.0111 (13)−0.0185 (13)
Geometric parameters (Å, °) top
Cl—C31.7375 (15)C8—C91.383 (2)
F1—C161.3321 (18)C9—C101.365 (2)
F2—C161.3317 (19)C9—H9A0.9400
F3—C161.3311 (18)C10—C111.374 (2)
O1—C111.3901 (18)C10—H10A0.9400
O1—C141.4327 (19)C11—C121.357 (2)
O2—C151.4097 (16)C12—C131.392 (2)
O2—H2B0.8300C12—H12A0.9400
N—C61.3771 (18)C13—H13A0.9400
N—C71.4323 (18)C14—H14A0.9700
N—H0A0.8700C14—H14B0.9700
C1—C21.389 (2)C14—H14C0.9700
C1—C61.411 (2)C15—C171.472 (2)
C1—C151.531 (2)C15—C161.540 (2)
C2—C31.379 (2)C17—C181.188 (2)
C2—H2A0.9400C18—C191.442 (2)
C3—C41.365 (2)C19—C201.471 (3)
C4—C51.378 (2)C19—C211.471 (3)
C4—H4A0.9400C19—H19A0.9900
C5—C61.401 (2)C20—C211.454 (3)
C5—H5A0.9400C20—H20A0.9800
C7—C81.505 (2)C20—H20B0.9800
C7—H7A0.9800C21—H21A0.9800
C7—H7B0.9800C21—H21B0.9800
C8—C131.373 (2)
C11—O1—C14117.17 (13)C13—C12—H12A120.4
C15—O2—H2B109.5C8—C13—C12121.81 (15)
C6—N—C7122.80 (12)C8—C13—H13A119.1
C6—N—H0A118.6C12—C13—H13A119.1
C7—N—H0A118.6O1—C14—H14A109.5
C2—C1—C6119.12 (14)O1—C14—H14B109.5
C2—C1—C15117.70 (13)H14A—C14—H14B109.5
C6—C1—C15123.18 (13)O1—C14—H14C109.5
C3—C2—C1121.49 (14)H14A—C14—H14C109.5
C3—C2—H2A119.3H14B—C14—H14C109.5
C1—C2—H2A119.3O2—C15—C17110.16 (12)
C4—C3—C2119.92 (14)O2—C15—C1109.34 (11)
C4—C3—Cl120.25 (13)C17—C15—C1113.01 (12)
C2—C3—Cl119.81 (12)O2—C15—C16106.76 (12)
C3—C4—C5119.96 (15)C17—C15—C16107.23 (12)
C3—C4—H4A120.0C1—C15—C16110.14 (12)
C5—C4—H4A120.0F2—C16—F3106.82 (13)
C4—C5—C6121.71 (15)F2—C16—F1107.11 (14)
C4—C5—H5A119.1F3—C16—F1107.48 (13)
C6—C5—H5A119.1F2—C16—C15112.00 (13)
N—C6—C5119.73 (14)F3—C16—C15111.38 (14)
N—C6—C1122.46 (14)F1—C16—C15111.76 (13)
C5—C6—C1117.80 (14)C18—C17—C15175.12 (16)
N—C7—C8113.44 (13)C17—C18—C19179.06 (18)
N—C7—H7A108.9C18—C19—C20121.87 (15)
C8—C7—H7A108.9C18—C19—C21119.69 (15)
N—C7—H7B108.9C20—C19—C2159.26 (13)
C8—C7—H7B108.9C18—C19—H19A114.9
H7A—C7—H7B107.7C20—C19—H19A114.9
C13—C8—C9116.86 (14)C21—C19—H19A114.9
C13—C8—C7125.05 (15)C21—C20—C1960.39 (12)
C9—C8—C7118.05 (15)C21—C20—H20A117.7
C10—C9—C8122.13 (16)C19—C20—H20A117.7
C10—C9—H9A118.9C21—C20—H20B117.7
C8—C9—H9A118.9C19—C20—H20B117.7
C9—C10—C11119.65 (16)H20A—C20—H20B114.9
C9—C10—H10A120.2C20—C21—C1960.35 (14)
C11—C10—H10A120.2C20—C21—H21A117.7
C12—C11—C10120.23 (15)C19—C21—H21A117.7
C12—C11—O1124.44 (14)C20—C21—H21B117.7
C10—C11—O1115.33 (14)C19—C21—H21B117.7
C11—C12—C13119.28 (15)H21A—C21—H21B114.9
C11—C12—H12A120.4
C6—C1—C2—C3−0.4 (2)C14—O1—C11—C10168.93 (14)
C15—C1—C2—C3178.93 (13)C10—C11—C12—C13−1.0 (2)
C1—C2—C3—C40.0 (2)O1—C11—C12—C13178.99 (14)
C1—C2—C3—Cl−178.38 (12)C9—C8—C13—C122.2 (2)
C2—C3—C4—C50.4 (2)C7—C8—C13—C12−175.29 (16)
Cl—C3—C4—C5178.77 (13)C11—C12—C13—C8−0.9 (3)
C3—C4—C5—C6−0.3 (2)C2—C1—C15—O2−148.07 (13)
C7—N—C6—C513.6 (2)C6—C1—C15—O231.26 (18)
C7—N—C6—C1−167.77 (15)C2—C1—C15—C17−24.99 (18)
C4—C5—C6—N178.61 (15)C6—C1—C15—C17154.34 (14)
C4—C5—C6—C1−0.1 (2)C2—C1—C15—C1694.91 (16)
C2—C1—C6—N−178.20 (14)C6—C1—C15—C16−85.76 (17)
C15—C1—C6—N2.5 (2)O2—C15—C16—F2−61.54 (16)
C2—C1—C6—C50.4 (2)C17—C15—C16—F2−179.58 (13)
C15—C1—C6—C5−178.89 (13)C1—C15—C16—F257.07 (17)
C6—N—C7—C8177.15 (14)O2—C15—C16—F358.03 (16)
N—C7—C8—C13−8.4 (2)C17—C15—C16—F3−60.02 (16)
N—C7—C8—C9174.05 (15)C1—C15—C16—F3176.64 (12)
C13—C8—C9—C10−1.8 (3)O2—C15—C16—F1178.27 (12)
C7—C8—C9—C10175.92 (16)C17—C15—C16—F160.23 (16)
C8—C9—C10—C110.0 (3)C1—C15—C16—F1−63.12 (16)
C9—C10—C11—C121.5 (2)C18—C19—C20—C21−107.99 (19)
C9—C10—C11—O1−178.54 (15)C18—C19—C21—C20111.60 (19)
C14—O1—C11—C12−11.1 (2)
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
O2—H2B···O1i0.831.922.7114 (15)159
N—H0A···O20.872.142.6620 (17)118
N—H0A···F20.872.442.9773 (16)121
Symmetry codes: (i) x+1/2, −y−1/2, −z.
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
O2—H2B···O1i0.831.922.7114 (15)159
N—H0A···O20.872.142.6620 (17)118
N—H0A···F20.872.442.9773 (16)121
Symmetry codes: (i) x+1/2, −y−1/2, −z.
Acknowledgements top

ANM thanks SeQuent Scientific Ltd, India, for a pure sample of the title compound. RJB acknowledges the NSF MRI program (grant No. CHE-0619278) for funds to purchase the X-ray diffractometer.

references
References top

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