organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

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ISSN: 2056-9890

(5-Bromo-2-methyl­phen­yl)(4-eth­­oxy­phen­yl)methanone

aTianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, People's Republic of China, and bSchool of Pharmacy, Tianjin Medical University, Tianjin 300070, People's Republic of China
*Correspondence e-mail: weirun_xu@yahoo.cn

(Received 7 July 2010; accepted 9 July 2010; online 17 July 2010)

In the title compound, C16H15BrO2, the dihedral angle between the benzene rings is 68.5 (2)°. In the crystal structure, mol­ecules are linked by weak C—H⋯O hydrogen bonds into chains parallel to the b axis.

Related literature

For details of the biological activity of SGLT2 inhibitors, see: Meng et al. (2008[Meng, M., Ellsworth, B. A., Nirschl, A. A., McCann, P. J., Patel, M., Girotra, R. N., Wu, G., Sher, P. M., Morrison, E. P., Biller, S. A., Zahler, R., Deshpande, P. P., Pullockaran, A., Hagan, D. L., Morgan, N., Taylor, J. R., Obermeier, M. T., Humphreys, W. G., Khanna, A., Discenza, L., Robertson, J. M., Wang, A., Han, S., Wetterau, J. R., Janovitz, E. B., Flint, O. P., Whaley, J. M. & Washburn, W. N. (2008). J. Med. Chem. 51, 1145-1149.]). For bond-length data, see: Allen et al. (1987[Allen, F. H., Kennard, O., Watson, D. G., Brammer, L., Orpen, A. G. & Taylor, R. (1987). J. Chem. Soc. Perkin Trans. 2, pp. S1-19.]).

[Scheme 1]

Experimental

Crystal data
  • C16H15BrO2

  • Mr = 319.19

  • Orthorhombic, P b c a

  • a = 9.5730 (19) Å

  • b = 13.188 (3) Å

  • c = 22.205 (4) Å

  • V = 2803.4 (10) Å3

  • Z = 8

  • Mo Kα radiation

  • μ = 2.93 mm−1

  • T = 113 K

  • 0.30 × 0.20 × 0.16 mm

Data collection
  • Rigaku Saturn CCD area-detector diffractometer

  • Absorption correction: multi-scan (CrystalClear; Rigaku, 2005[Rigaku. (2005). CrystalClear. Rigaku Corporation, Tokyo, Japan.]) Tmin = 0.474, Tmax = 0.652

  • 17506 measured reflections

  • 2479 independent reflections

  • 2133 reflections with I > 2σ(I)

  • Rint = 0.044

Refinement
  • R[F2 > 2σ(F2)] = 0.041

  • wR(F2) = 0.107

  • S = 1.10

  • 2479 reflections

  • 175 parameters

  • H-atom parameters constrained

  • Δρmax = 0.84 e Å−3

  • Δρmin = −0.57 e Å−3

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
C11—H11⋯O1i 0.95 2.42 3.313 (3) 156
Symmetry code: (i) [-x+{\script{1\over 2}}, y+{\script{1\over 2}}, z].

Data collection: CrystalClear (Rigaku, 2005[Rigaku. (2005). CrystalClear. Rigaku Corporation, Tokyo, Japan.]); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Supporting information


Comment top

Dapagliflozin is an anti-diabetic agent through the inhibition of renal SGLT2, which was developed by Bristol-Myers Squibb Company and is now in the phase III clinical trial (Meng et al., 2008). During the discovery of our own SGLT2 inhibitors as anti-diabetic agents, we prepared the derivatives of dapagliflozin (Meng et al., 2008) for biological evaluation, and the title compound, (5-bromo-2-methylphenyl)(4-ethoxyphenyl)methanone, was prepared as an important intermediate.

In title compound, C16H15BrO2, bond lengths are normal (Allen et al., 1987)). The dihedral angle between the benzene rings (C2—C7 and C9—C14) is 68.5 (2)°. In the crystal structure, molecules interact through weak C—H···O hydrogen bonds to form chains parallel to the b axis.

Related literature top

For details of the biological activity of SGLT2 inhibitors, see: Meng et al. (2008). For bond-length data, see: Allen et al. (1987).

Experimental top

A round-bottomed flask was charged with 2.15 g (10 mmol) of 5-bromo-2-methylbenoic acid, 1 drop of DMF, 1.27 g (10 mmol) of oxalyl chloride and 3 ml of dried dichloromethane, and the mixture was stirred at room temperature over night until a clear solution formed. The reaction mixture was evaporated on a rotary evaporator to give crude 5-bromo-2-chlorobenzoyl chloride, which was dissolved in 15 ml of dried dichloromethane. The solution thus obtained was stirred while being cooled with an ice-salt bath, and 1.22 g (10 mmol) of phenetole was added followed by the addition of 1.60 g (12 mmol) of anhydrous aluminium chloride in a portionwise manner. The resulting mixture was stirred at this temperature for 1 h and poured into 150 ml of ice-water. The mixture formed was extracted with three 50 ml portions of dichloromethane, and the combined extracts were washed with saturated brine, dried over sodium sulfate and evaporated on a rotary evaporator to afford the crude title compound. Pure title compound was obtained by column chromatography. Crystals suitable for X-ray diffraction were obtained through slow evaporation of a solution of the pure title compound in ethyl acetate/petroleum ether (1/5 v/v).

Refinement top

All H atoms were found on difference Fourier maps, and included in the final cycles of refinement using a riding model, with C—H = 0.95–0.99 Å and with Uiso(H) = 1.2Ueq(C) for aryl and methylene H atoms and 1.5Ueq(C) for the methyl H atoms.

Structure description top

Dapagliflozin is an anti-diabetic agent through the inhibition of renal SGLT2, which was developed by Bristol-Myers Squibb Company and is now in the phase III clinical trial (Meng et al., 2008). During the discovery of our own SGLT2 inhibitors as anti-diabetic agents, we prepared the derivatives of dapagliflozin (Meng et al., 2008) for biological evaluation, and the title compound, (5-bromo-2-methylphenyl)(4-ethoxyphenyl)methanone, was prepared as an important intermediate.

In title compound, C16H15BrO2, bond lengths are normal (Allen et al., 1987)). The dihedral angle between the benzene rings (C2—C7 and C9—C14) is 68.5 (2)°. In the crystal structure, molecules interact through weak C—H···O hydrogen bonds to form chains parallel to the b axis.

For details of the biological activity of SGLT2 inhibitors, see: Meng et al. (2008). For bond-length data, see: Allen et al. (1987).

Computing details top

Data collection: CrystalClear (Rigaku, 2005); cell refinement: CrystalClear (Rigaku, 2005); data reduction: CrystalClear (Rigaku, 2005); program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures top
[Figure 1] Fig. 1. The molecular structure of the title compound, with displacement ellipsoids drawn at the 40% probability level.
(5-Bromo-2-methylphenyl)(4-ethoxyphenyl)methanone top
Crystal data top
C16H15BrO2F(000) = 1296
Mr = 319.19Dx = 1.513 Mg m3
Orthorhombic, PbcaMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ac 2abCell parameters from 6268 reflections
a = 9.5730 (19) Åθ = 2.1–27.9°
b = 13.188 (3) ŵ = 2.93 mm1
c = 22.205 (4) ÅT = 113 K
V = 2803.4 (10) Å3Block, colorless
Z = 80.30 × 0.20 × 0.16 mm
Data collection top
Rigaku Saturn CCD area-detector
diffractometer
2479 independent reflections
Radiation source: rotating anode2133 reflections with I > 2σ(I)
Confocal monochromatorRint = 0.044
Detector resolution: 7.31 pixels mm-1θmax = 25.0°, θmin = 1.8°
ω and φ scansh = 1110
Absorption correction: multi-scan
(CrystalClear; Rigaku, 2005)
k = 1515
Tmin = 0.474, Tmax = 0.652l = 2619
17506 measured reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.041H-atom parameters constrained
wR(F2) = 0.107 w = 1/[σ2(Fo2) + (0.0598P)2 + 1.3319P]
where P = (Fo2 + 2Fc2)/3
S = 1.10(Δ/σ)max = 0.004
2479 reflectionsΔρmax = 0.84 e Å3
175 parametersΔρmin = 0.57 e Å3
0 restraintsExtinction correction: SHELXTL (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.0120 (8)
Crystal data top
C16H15BrO2V = 2803.4 (10) Å3
Mr = 319.19Z = 8
Orthorhombic, PbcaMo Kα radiation
a = 9.5730 (19) ŵ = 2.93 mm1
b = 13.188 (3) ÅT = 113 K
c = 22.205 (4) Å0.30 × 0.20 × 0.16 mm
Data collection top
Rigaku Saturn CCD area-detector
diffractometer
2479 independent reflections
Absorption correction: multi-scan
(CrystalClear; Rigaku, 2005)
2133 reflections with I > 2σ(I)
Tmin = 0.474, Tmax = 0.652Rint = 0.044
17506 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0410 restraints
wR(F2) = 0.107H-atom parameters constrained
S = 1.10Δρmax = 0.84 e Å3
2479 reflectionsΔρmin = 0.57 e Å3
175 parameters
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 > 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 (Å2) top
xyzUiso*/Ueq
Br10.00393 (3)0.34535 (2)0.307507 (13)0.03274 (18)
O10.0807 (2)0.03567 (15)0.10091 (9)0.0353 (5)
O20.1222 (2)0.43270 (15)0.05895 (8)0.0322 (5)
C10.3438 (3)0.0117 (2)0.18087 (13)0.0354 (7)
H1A0.43510.01040.20090.053*
H1B0.35620.02990.13840.053*
H1C0.30050.05550.18360.053*
C20.2512 (3)0.08893 (19)0.21113 (13)0.0259 (6)
C30.2670 (3)0.1078 (2)0.27228 (13)0.0286 (6)
H30.33280.06910.29460.034*
C40.1895 (3)0.1816 (2)0.30181 (12)0.0303 (7)
H40.19990.19210.34390.036*
C50.0968 (3)0.2395 (2)0.26867 (11)0.0269 (6)
C60.0771 (3)0.2229 (2)0.20780 (12)0.0264 (6)
H60.01290.26330.18570.032*
C70.1528 (3)0.1459 (2)0.17905 (12)0.0255 (6)
C80.1169 (3)0.1222 (2)0.11452 (12)0.0267 (6)
C90.1212 (3)0.2048 (2)0.06972 (11)0.0246 (6)
C100.2006 (3)0.2915 (2)0.07938 (11)0.0256 (6)
H100.25180.29790.11580.031*
C110.2069 (3)0.3687 (2)0.03726 (11)0.0250 (6)
H110.26340.42680.04420.030*
C120.1289 (3)0.3597 (2)0.01543 (12)0.0267 (6)
C130.0496 (3)0.2727 (2)0.02606 (12)0.0308 (7)
H130.00320.26680.06210.037*
C140.0480 (3)0.1956 (2)0.01559 (12)0.0294 (6)
H140.00340.13560.00750.035*
C150.2006 (3)0.5248 (2)0.04965 (13)0.0334 (7)
H15A0.30200.51020.04970.040*
H15B0.17560.55570.01050.040*
C160.1645 (3)0.5955 (2)0.10032 (13)0.0364 (7)
H16A0.19060.56440.13880.055*
H16B0.21540.65940.09520.055*
H16C0.06380.60900.10000.055*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Br10.0346 (3)0.0327 (3)0.0309 (3)0.00282 (11)0.01170 (11)0.00058 (11)
O10.0412 (13)0.0268 (11)0.0379 (11)0.0026 (9)0.0050 (9)0.0040 (8)
O20.0373 (12)0.0317 (12)0.0276 (10)0.0050 (9)0.0020 (8)0.0032 (8)
C10.0350 (17)0.0322 (18)0.0390 (16)0.0046 (14)0.0043 (13)0.0038 (13)
C20.0237 (15)0.0226 (15)0.0314 (15)0.0026 (12)0.0001 (11)0.0005 (11)
C30.0281 (16)0.0264 (16)0.0314 (15)0.0010 (12)0.0050 (11)0.0036 (11)
C40.0317 (16)0.0343 (16)0.0248 (14)0.0063 (13)0.0020 (11)0.0019 (11)
C50.0265 (15)0.0269 (15)0.0273 (14)0.0050 (12)0.0061 (11)0.0013 (11)
C60.0209 (14)0.0275 (15)0.0307 (14)0.0008 (11)0.0022 (11)0.0026 (11)
C70.0225 (15)0.0246 (16)0.0293 (14)0.0032 (11)0.0001 (11)0.0010 (10)
C80.0180 (14)0.0304 (16)0.0318 (15)0.0022 (11)0.0000 (10)0.0044 (13)
C90.0207 (14)0.0278 (15)0.0254 (14)0.0031 (11)0.0018 (10)0.0037 (11)
C100.0197 (14)0.0326 (16)0.0245 (13)0.0032 (12)0.0018 (10)0.0054 (11)
C110.0199 (14)0.0273 (14)0.0278 (14)0.0022 (11)0.0023 (10)0.0060 (11)
C120.0245 (15)0.0302 (16)0.0254 (14)0.0011 (12)0.0029 (11)0.0004 (11)
C130.0298 (16)0.0361 (18)0.0266 (15)0.0041 (13)0.0052 (12)0.0055 (12)
C140.0253 (15)0.0309 (16)0.0321 (16)0.0037 (13)0.0017 (12)0.0033 (12)
C150.0311 (16)0.0324 (17)0.0367 (16)0.0045 (13)0.0001 (12)0.0007 (12)
C160.0335 (17)0.0361 (18)0.0397 (16)0.0011 (13)0.0051 (13)0.0063 (13)
Geometric parameters (Å, º) top
Br1—C51.903 (3)C8—C91.475 (4)
O1—C81.230 (3)C9—C101.389 (4)
O2—C121.365 (3)C9—C141.397 (4)
O2—C151.442 (3)C10—C111.385 (4)
C1—C21.509 (4)C10—H100.9500
C1—H1A0.9800C11—C121.393 (4)
C1—H1B0.9800C11—H110.9500
C1—H1C0.9800C12—C131.396 (4)
C2—C31.389 (4)C13—C141.374 (4)
C2—C71.400 (4)C13—H130.9500
C3—C41.388 (4)C14—H140.9500
C3—H30.9500C15—C161.502 (4)
C4—C51.382 (4)C15—H15A0.9900
C4—H40.9500C15—H15B0.9900
C5—C61.382 (4)C16—H16A0.9800
C6—C71.401 (4)C16—H16B0.9800
C6—H60.9500C16—H16C0.9800
C7—C81.506 (4)
C12—O2—C15117.9 (2)C10—C9—C8121.2 (2)
C2—C1—H1A109.5C14—C9—C8120.2 (2)
C2—C1—H1B109.5C11—C10—C9121.7 (2)
H1A—C1—H1B109.5C11—C10—H10119.2
C2—C1—H1C109.5C9—C10—H10119.2
H1A—C1—H1C109.5C10—C11—C12118.8 (3)
H1B—C1—H1C109.5C10—C11—H11120.6
C3—C2—C7118.3 (2)C12—C11—H11120.6
C3—C2—C1119.5 (2)O2—C12—C11124.0 (2)
C7—C2—C1122.1 (3)O2—C12—C13115.7 (2)
C2—C3—C4122.0 (3)C11—C12—C13120.2 (2)
C2—C3—H3119.0C14—C13—C12120.0 (3)
C4—C3—H3119.0C14—C13—H13120.0
C5—C4—C3118.6 (2)C12—C13—H13120.0
C5—C4—H4120.7C13—C14—C9120.6 (3)
C3—C4—H4120.7C13—C14—H14119.7
C6—C5—C4121.4 (3)C9—C14—H14119.7
C6—C5—Br1119.3 (2)O2—C15—C16107.2 (2)
C4—C5—Br1119.3 (2)O2—C15—H15A110.3
C5—C6—C7119.3 (3)C16—C15—H15A110.3
C5—C6—H6120.4O2—C15—H15B110.3
C7—C6—H6120.4C16—C15—H15B110.3
C2—C7—C6120.4 (3)H15A—C15—H15B108.5
C2—C7—C8121.7 (2)C15—C16—H16A109.5
C6—C7—C8117.8 (2)C15—C16—H16B109.5
O1—C8—C9121.8 (2)H16A—C16—H16B109.5
O1—C8—C7119.4 (2)C15—C16—H16C109.5
C9—C8—C7118.8 (2)H16A—C16—H16C109.5
C10—C9—C14118.6 (3)H16B—C16—H16C109.5
C7—C2—C3—C40.7 (4)O1—C8—C9—C10159.8 (3)
C1—C2—C3—C4176.7 (3)C7—C8—C9—C1022.6 (4)
C2—C3—C4—C51.8 (4)O1—C8—C9—C1418.3 (4)
C3—C4—C5—C62.2 (4)C7—C8—C9—C14159.3 (3)
C3—C4—C5—Br1177.0 (2)C14—C9—C10—C110.9 (4)
C4—C5—C6—C70.1 (4)C8—C9—C10—C11179.0 (2)
Br1—C5—C6—C7179.1 (2)C9—C10—C11—C121.5 (4)
C3—C2—C7—C62.8 (4)C15—O2—C12—C110.1 (4)
C1—C2—C7—C6174.6 (3)C15—O2—C12—C13179.1 (2)
C3—C2—C7—C8172.7 (2)C10—C11—C12—O2177.1 (2)
C1—C2—C7—C810.0 (4)C10—C11—C12—C132.0 (4)
C5—C6—C7—C22.4 (4)O2—C12—C13—C14179.0 (3)
C5—C6—C7—C8173.2 (2)C11—C12—C13—C140.2 (4)
C2—C7—C8—O153.5 (4)C12—C13—C14—C92.2 (4)
C6—C7—C8—O1122.1 (3)C10—C9—C14—C132.8 (4)
C2—C7—C8—C9128.8 (3)C8—C9—C14—C13179.1 (3)
C6—C7—C8—C955.6 (3)C12—O2—C15—C16174.5 (2)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
C11—H11···O1i0.952.423.313 (3)156
Symmetry code: (i) x+1/2, y+1/2, z.

Experimental details

Crystal data
Chemical formulaC16H15BrO2
Mr319.19
Crystal system, space groupOrthorhombic, Pbca
Temperature (K)113
a, b, c (Å)9.5730 (19), 13.188 (3), 22.205 (4)
V3)2803.4 (10)
Z8
Radiation typeMo Kα
µ (mm1)2.93
Crystal size (mm)0.30 × 0.20 × 0.16
Data collection
DiffractometerRigaku Saturn CCD area-detector
Absorption correctionMulti-scan
(CrystalClear; Rigaku, 2005)
Tmin, Tmax0.474, 0.652
No. of measured, independent and
observed [I > 2σ(I)] reflections
17506, 2479, 2133
Rint0.044
(sin θ/λ)max1)0.595
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.041, 0.107, 1.10
No. of reflections2479
No. of parameters175
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.84, 0.57

Computer programs: CrystalClear (Rigaku, 2005), SHELXTL (Sheldrick, 2008).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
C11—H11···O1i0.952.423.313 (3)155.8
Symmetry code: (i) x+1/2, y+1/2, z.
 

References

First citationAllen, F. H., Kennard, O., Watson, D. G., Brammer, L., Orpen, A. G. & Taylor, R. (1987). J. Chem. Soc. Perkin Trans. 2, pp. S1–19.  CSD CrossRef Web of Science Google Scholar
First citationMeng, M., Ellsworth, B. A., Nirschl, A. A., McCann, P. J., Patel, M., Girotra, R. N., Wu, G., Sher, P. M., Morrison, E. P., Biller, S. A., Zahler, R., Deshpande, P. P., Pullockaran, A., Hagan, D. L., Morgan, N., Taylor, J. R., Obermeier, M. T., Humphreys, W. G., Khanna, A., Discenza, L., Robertson, J. M., Wang, A., Han, S., Wetterau, J. R., Janovitz, E. B., Flint, O. P., Whaley, J. M. & Washburn, W. N. (2008). J. Med. Chem. 51, 1145–1149.  Web of Science CrossRef PubMed CAS Google Scholar
First citationRigaku. (2005). CrystalClear. Rigaku Corporation, Tokyo, Japan.  Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar

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ISSN: 2056-9890
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