Crystal structure of (R)-6-fluoro-2-[(S)-oxiran-2-yl]chroman.

The title compound, C11H11FO2, is a building block in the synthesis of the active pharmaceutical ingredient dl-nebivolol. The synthesis starting from the enanti-omerically pure (R)-6-fluoro-4-oxo-3,4-di-hydro-2H-chromene-2-carb-oxy-lic acid resulted in a mixture of two stereoisomers, namely (R)-6-fluoro-2-[(S)-oxiran-2-yl]chroman and (R)-6-fluoro-2-[(R)-oxiran-2-yl]chroman. The mixture was separated by column chromatography but only one stereoisomer crystallized. The X-ray structure analysis revealed that the solid consisted of the R,S isomer. A similar procedure was repeated for (S)-6-fluoro-4-oxo-3,4-di-hydro-2H-chromene-2-carb-oxy-lic acid and, in this case, the S,R isomer was produced as a crystalline solid. Thus, all four stereoisomers of the title epoxide were obtained and their absolute configuration was assigned. The crystal studied was refined as an inversion twin.

Related literature

For the synthesis of the enanti­opure title product, see: Jas et al. (2011 ▸). For pharmacological properties of nebivolol, see: Van Lommen et al. (1990 ▸). For a study of related isomers, see: Horiguchi et al. (1997 ▸). For the determination of absolute structure, see: Flack (2003 ▸).

Experimental

Crystal data

C11H11FO2

M = 194.20

Monoclinic,

a = 9.3742 (3) Å

b = 4.76845 (12) Å

c = 11.0212 (3) Å

β = 114.202 (4)°

V = 449.35 (3) Å3

Z = 2

Cu Kα radiation

μ = 0.94 mm−1

T = 100 K

0.05 × 0.05 × 0.02 mm

Data collection

Agilent SuperNova Dual Source diffractometer with an Atlas detector

Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2012 ▸) T min = 0.64, T max = 1

14207 measured reflections

1847 independent reflections

1820 reflections with I > 2σ(I)

R int = 0.050

Refinement

R[F 2 > 2σ(F 2)] = 0.032

wR(F 2) = 0.092

S = 1.10

1847 reflections

128 parameters

1 restraint

H-atom parameters constrained

Δρmax = 0.20 e Å−3

Δρmin = −0.16 e Å−3

Absolute structure: crystal refined as an inversion twin (Flack, 2003 ▸)

Absolute structure parameter: 0.0 (2)

Data collection: CrysAlis PRO (Agilent, 2012 ▸); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▸); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015 ▸); molecular graphics: OLEX2 (Dolomanov et al., 2009 ▸); software used to prepare material for publication: OLEX2.

Crystal structure: contains datablock(s) I, New_Global_Publ_Block. DOI: 10.1107/S205698901501261X/gk2636sup1.cif

Structure factors: contains datablock(s) I. DOI: 10.1107/S205698901501261X/gk2636Isup2.hkl

Click here for additional data file.

Supporting information file. DOI: 10.1107/S205698901501261X/gk2636Isup3.mol

Click here for additional data file.

Supporting information file. DOI: 10.1107/S205698901501261X/gk2636Isup4.cml

Click here for additional data file.

. DOI: 10.1107/S205698901501261X/gk2636fig1.tif

View of the mol­ecular structure of the title compound with 50% probability displacement ellipsoids for the non-hydrogen atoms.

Click here for additional data file.

. DOI: 10.1107/S205698901501261X/gk2636fig2.tif

Reaction scheme for the synthesis of nebivolol

CCDC reference: 1409735

Additional supporting information: crystallographic information; 3D view; checkCIF report

C11H11FO2	F(000) = 204
Mr = 194.20	Dx = 1.435 Mg m−3
Monoclinic, P21	Cu Kα radiation, λ = 1.54184 Å
a = 9.3742 (3) Å	Cell parameters from 7897 reflections
b = 4.76845 (12) Å	θ = 4.4–76.3°
c = 11.0212 (3) Å	µ = 0.94 mm−1
β = 114.202 (4)°	T = 100 K
V = 449.35 (3) Å3	Needle, colourless
Z = 2	0.05 × 0.05 × 0.02 mm

Agilent SuperNova Dual Source diffractometer with an Atlas detector	1847 independent reflections
Radiation source: SuperNova (Cu) X-ray Source	1820 reflections with I > 2σ(I)
Mirror monochromator	Rint = 0.050
Detector resolution: 5.2474 pixels mm-1	θmax = 76.5°, θmin = 4.4°
CCD rotation images, thick slices scans	h = −11→11
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2012)	k = −5→5
Tmin = 0.64, Tmax = 1	l = −13→13
14207 measured reflections

Refinement on F2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.032	H-atom parameters constrained
wR(F2) = 0.092	w = 1/[σ2(Fo2) + (0.0529P)2 + 0.0952P] where P = (Fo2 + 2Fc2)/3
S = 1.10	(Δ/σ)max < 0.001
1847 reflections	Δρmax = 0.20 e Å−3
128 parameters	Δρmin = −0.16 e Å−3
1 restraint	Absolute structure: crystal refined as an inversion twin (Flack, 2003)
0 constraints	Absolute structure parameter: 0.0 (2)

Experimental. Analyzes were recorded in the "Pole Chimie Moleculaire", the technological platform for chemical analysis and molecular synthesis (http://www.wpcm.fr) which relies on the Institute of the Molecular Chemistry of University of Burgundy and Welience"TM", a Burgundy University private subsidiary.1H and 13C NMR measurements were performed in deuterated methanol on Bruker Avance III, recorded at 500 MHz and 125 MHz, respectively. Chemical shifts (δ) and coupling constants are reported respectively in p.p.m. and hertz (Hz). The optical rotation was measured using a UV Visible Perkin Elmer Lambda 12, polarimeter at 589 nm. High-resolution mass spectrometry (HRMS) was performed in ESI a positive mode. The infrared spectrum (IR) was generated by ATR using a Spectrometer Infrared Avatar 370. A scan range of 4000 - 400 cm-1 was used.(2S,2R)-(6-fluoro-2-chromanyl)oxirane:δ(1H, DMSO-d6, 300 MHz, ppm): 1.72 (1H, m); 2.00 (1H, m); 2.74 (2H, m); 2.82 (2H, m); 3.17 (1H, ddd); 3.94 (1H, ddd); 6.77 (1H, dd); 6.92 (2H, m).δ(13C DMSO-d6, 75.47MHz, ppm): 23.4, 23.7, 44.5, 52.3, 75.3, 113.7 (d, 23.2 Hz), 115.2 (d, 22.3 Hz), 117.2 (d, 8.2 Hz), 123.5(d, 7.5 Hz), 150.1 (d, 1.5 Hz), 156.0(d, 234.8 Hz).[α]29D +67.5o (c =1.0 in CHCl3)HRMS (ESI) for C18H21FNO2[M+H]+ m/z = 195.08158, found m/z = 195.08120.IR (cm-1) 3050, 3001, 2951, 1492, 1220Data CCDC-1407326 contains the enantiomer structure of (S)-6-Fluoro-2-[(R)-oxiran-2-yl]chroman. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif

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. Refined as a 2-component inversion twin.

	x	y	z	Uiso*/Ueq
C1	0.7376 (2)	0.5622 (5)	0.50701 (19)	0.0255 (4)
C6	0.8296 (2)	0.4711 (5)	0.4448 (2)	0.0254 (4)
H6	0.9095	0.3366	0.4870	0.030*
C5	0.8061 (2)	0.5754 (4)	0.32005 (19)	0.0226 (4)
C4	0.6872 (2)	0.7732 (4)	0.26151 (18)	0.0214 (4)
C3	0.5962 (2)	0.8655 (5)	0.3267 (2)	0.0255 (4)
H3	0.5165	1.0009	0.2857	0.031*
C2	0.6216 (2)	0.7604 (5)	0.4512 (2)	0.0261 (4)
H2	0.5608	0.8231	0.4968	0.031*
C7	0.9061 (2)	0.4801 (4)	0.24929 (19)	0.0253 (4)
H7A	0.8759	0.2868	0.2157	0.030*
H7B	1.0172	0.4770	0.3132	0.030*
C8	0.8876 (2)	0.6721 (5)	0.13380 (19)	0.0240 (4)
H8A	0.9306	0.5803	0.0755	0.029*
H8B	0.9458	0.8488	0.1678	0.029*
C9	0.7148 (2)	0.7350 (5)	0.05528 (19)	0.0235 (4)
H9	0.6568	0.5539	0.0267	0.028*
C10	0.6765 (2)	0.9185 (5)	−0.0645 (2)	0.0271 (4)
H10	0.5651	0.9814	−0.1082	0.033*
C11	0.7573 (2)	0.8967 (5)	−0.1530 (2)	0.0286 (5)
H11A	0.8377	0.7487	−0.1340	0.034*
H11B	0.6968	0.9384	−0.2485	0.034*
O1	0.65326 (15)	0.8871 (3)	0.13795 (13)	0.0246 (3)
O2	0.79031 (19)	1.1254 (4)	−0.06003 (15)	0.0329 (4)
F1	0.76157 (14)	0.4549 (3)	0.62882 (12)	0.0333 (3)

	U11	U22	U33	U12	U13	U23
C1	0.0249 (9)	0.0259 (10)	0.0236 (9)	−0.0037 (8)	0.0079 (7)	−0.0017 (8)
C6	0.0206 (8)	0.0216 (10)	0.0299 (10)	0.0010 (7)	0.0064 (7)	0.0003 (8)
C5	0.0191 (8)	0.0202 (10)	0.0261 (9)	−0.0036 (8)	0.0070 (7)	−0.0049 (8)
C4	0.0185 (8)	0.0201 (10)	0.0238 (9)	−0.0035 (8)	0.0070 (7)	−0.0029 (8)
C3	0.0214 (9)	0.0265 (11)	0.0276 (9)	0.0035 (7)	0.0090 (7)	−0.0011 (8)
C2	0.0245 (9)	0.0274 (11)	0.0282 (10)	−0.0013 (8)	0.0128 (8)	−0.0051 (8)
C7	0.0224 (8)	0.0220 (10)	0.0303 (9)	0.0040 (8)	0.0097 (8)	−0.0013 (8)
C8	0.0180 (8)	0.0252 (10)	0.0288 (9)	0.0010 (7)	0.0096 (7)	−0.0042 (8)
C9	0.0201 (8)	0.0252 (11)	0.0266 (9)	0.0009 (7)	0.0109 (7)	−0.0042 (8)
C10	0.0225 (9)	0.0309 (11)	0.0273 (9)	0.0016 (8)	0.0096 (7)	−0.0015 (9)
C11	0.0272 (9)	0.0315 (11)	0.0286 (9)	−0.0033 (9)	0.0130 (8)	−0.0049 (9)
O1	0.0224 (6)	0.0275 (8)	0.0247 (6)	0.0066 (6)	0.0106 (5)	0.0019 (6)
O2	0.0442 (9)	0.0260 (9)	0.0323 (7)	−0.0047 (7)	0.0195 (6)	−0.0041 (6)
F1	0.0343 (6)	0.0384 (8)	0.0268 (6)	0.0030 (6)	0.0121 (5)	0.0062 (6)

C1—C6	1.374 (3)	C7—C8	1.519 (3)
C1—C2	1.381 (3)	C8—H8A	0.9900
C1—F1	1.366 (2)	C8—H8B	0.9900
C6—H6	0.9500	C8—C9	1.521 (2)
C6—C5	1.392 (3)	C9—H9	1.0000
C5—C4	1.399 (3)	C9—C10	1.500 (3)
C5—C7	1.514 (2)	C9—O1	1.456 (2)
C4—C3	1.393 (3)	C10—H10	1.0000
C4—O1	1.377 (2)	C10—C11	1.463 (3)
C3—H3	0.9500	C10—O2	1.439 (3)
C3—C2	1.387 (3)	C11—H11A	0.9900
C2—H2	0.9500	C11—H11B	0.9900
C7—H7A	0.9900	C11—O2	1.440 (3)
C7—H7B	0.9900
C6—C1—C2	122.35 (18)	C7—C8—H8B	109.9
F1—C1—C6	119.21 (18)	C7—C8—C9	108.92 (16)
F1—C1—C2	118.43 (17)	H8A—C8—H8B	108.3
C1—C6—H6	119.9	C9—C8—H8A	109.9
C1—C6—C5	120.12 (19)	C9—C8—H8B	109.9
C5—C6—H6	119.9	C8—C9—H9	108.9
C6—C5—C4	118.06 (17)	C10—C9—C8	115.48 (16)
C6—C5—C7	121.35 (18)	C10—C9—H9	108.9
C4—C5—C7	120.59 (17)	O1—C9—C8	110.18 (15)
C3—C4—C5	121.04 (18)	O1—C9—H9	108.9
O1—C4—C5	122.66 (16)	O1—C9—C10	104.31 (16)
O1—C4—C3	116.30 (17)	C9—C10—H10	115.1
C4—C3—H3	119.9	C11—C10—C9	122.88 (19)
C2—C3—C4	120.19 (19)	C11—C10—H10	115.1
C2—C3—H3	119.9	O2—C10—C9	117.62 (16)
C1—C2—C3	118.22 (17)	O2—C10—H10	115.1
C1—C2—H2	120.9	O2—C10—C11	59.51 (13)
C3—C2—H2	120.9	C10—C11—H11A	117.8
C5—C7—H7A	109.3	C10—C11—H11B	117.8
C5—C7—H7B	109.3	H11A—C11—H11B	115.0
C5—C7—C8	111.62 (16)	O2—C11—C10	59.42 (13)
H7A—C7—H7B	108.0	O2—C11—H11A	117.8
C8—C7—H7A	109.3	O2—C11—H11B	117.8
C8—C7—H7B	109.3	C4—O1—C9	115.60 (15)
C7—C8—H8A	109.9	C10—O2—C11	61.08 (13)
C1—C6—C5—C4	0.0 (3)	C7—C5—C4—O1	1.0 (3)
C1—C6—C5—C7	179.71 (17)	C7—C8—C9—C10	−178.77 (17)
C6—C1—C2—C3	1.3 (3)	C7—C8—C9—O1	63.4 (2)
C6—C5—C4—C3	0.7 (3)	C8—C9—C10—C11	38.9 (3)
C6—C5—C4—O1	−179.29 (18)	C8—C9—C10—O2	−31.0 (3)
C6—C5—C7—C8	−165.51 (18)	C8—C9—O1—C4	−49.5 (2)
C5—C4—C3—C2	−0.4 (3)	C9—C10—C11—O2	−105.1 (2)
C5—C4—O1—C9	17.2 (2)	C9—C10—O2—C11	113.8 (2)
C5—C7—C8—C9	−44.7 (2)	C10—C9—O1—C4	−174.00 (14)
C4—C5—C7—C8	14.2 (2)	O1—C4—C3—C2	179.56 (17)
C4—C3—C2—C1	−0.5 (3)	O1—C9—C10—C11	159.93 (19)
C3—C4—O1—C9	−162.78 (17)	O1—C9—C10—O2	90.0 (2)
C2—C1—C6—C5	−1.0 (3)	F1—C1—C6—C5	179.30 (18)
C7—C5—C4—C3	−178.99 (18)	F1—C1—C2—C3	−179.04 (19)