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

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ISSN: 2056-9890

3-Ethyl-2-methyl-5-methyl­ene-6,7-di­hydroindol-4(5H)-one

aDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington KY 40536, USA, and bDepartment of Chemistry, University of Kentucky, Lexington KY 40536, USA
*Correspondence e-mail: pcrooks@email.uky.edu

(Received 19 November 2007; accepted 25 November 2007; online 6 December 2007)

The title compound, C12H15NO, a degradation product of molindone hydro­chloride, was prepared by the reaction of molindone with methyl iodide and subsequent reaction of the resulting quaternary ammonium salt with 2N aqueous sodium hydroxide. The newly formed double bond is exocyclic in nature and the carbonyl group is conjugated with the π-electrons of the pyrrole ring. The six-membered ring is in the half-chair conformation. The H atom attached to the N atom is involved in an inter­molecular hydrogen bond with the O atom of a screw-related mol­ecule, thus forming a continuous chain.

Related literature

For related literature, see: Dudzinski et al. (1973[Dudzinski, J., Lachman, L., Shami, E. & Tingstad, J. (1973). J. Pharm. Sci. 62, 622-624.]).

[Scheme 1]

Experimental

Crystal data
  • C12H15NO

  • Mr = 189.25

  • Monoclinic, P 21 /n

  • a = 9.0451 (3) Å

  • b = 8.5840 (3) Å

  • c = 14.3557 (5) Å

  • β = 107.355 (1)°

  • V = 1063.88 (6) Å3

  • Z = 4

  • Cu Kα radiation

  • μ = 0.59 mm−1

  • T = 90.0 (2) K

  • 0.15 × 0.12 × 0.10 mm

Data collection
  • Bruker X8 Proteum diffractometer

  • Absorption correction: multi-scan (SADABS in APEX2; Bruker, 2006[Bruker (2006). APEX2. Bruker AXS Inc., Madison, Wisconcin, USA.]) Tmin = 0.837, Tmax = 0.944

  • 15160 measured reflections

  • 1972 independent reflections

  • 1893 reflections with I > 2σ(I)

  • Rint = 0.039

Refinement
  • R[F2 > 2σ(F2)] = 0.038

  • wR(F2) = 0.097

  • S = 1.05

  • 1972 reflections

  • 129 parameters

  • H-atom parameters constrained

  • Δρmax = 0.24 e Å−3

  • Δρmin = −0.20 e Å−3

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
N1—H1⋯O1i 0.88 1.91 2.7749 (12) 169
Symmetry code: (i) [x-{\script{1\over 2}}, -y+{\script{1\over 2}}, z-{\script{1\over 2}}].

Data collection: APEX2 (Bruker, 2006[Bruker (2006). APEX2. Bruker AXS Inc., Madison, Wisconcin, USA.]); cell refinement: APEX2; data reduction: APEX2; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997[Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of Göttingen, Germany.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997[Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of Göttingen, Germany.]); molecular graphics: XP in SHELXTL (Sheldrick, 1995[Sheldrick, G. M. (1995). XP in SHELXTL/PC. Siemens Analytical Instruments Inc., Madison, Wisconsin, USA.]); software used to prepare material for publication: SHELX97 and local procedures.

Supporting information


Comment top

The Mannich condensation reaction is frequently used in the synthesis of pharmaceutical compounds. One such example is the synthesis of molindone, an antipsychotic agent. During stability studies and development of an assay for molindone hydrochloride, a degradation product was identified as 3-ethyl-2-methyl-5-methylene-6,7-dihydro-5H-indol-4-one (Dudzinski et al., 1973). Molindone has UV absorption peaks at 255 nm and 299 nm; these UV wavelengths can be used quantitatively for quantifying the drug substance. However, preliminary studies indicated that chemical degradation (as evidenced by color and precipitate formation) was not accompanied by a decrease in UV absorption, suggesting that the degradation product had a similar chromophore to molindone. The title compound was prepared by the reaction of molindone free base with methyl iodide and subsequent reaction of the resulting quaternary ammonium salt with 2 N aqueous sodium hydroxide. The structure of the resulting compound, 3-ethyl-2-methyl-5-methylene-6,7-dihydro-5H-indol-4-one, was initially characterized by NMR spectroscopy and shown to be identical to the degradation product of molindone hydrochloride. To confirm the exocyclic nature of newly formed double bond and to identify chromophoric group in the molecule responsible for its UV absorption profile, its crystal structure was determined by X-ray analysis.

The molecular structure and the atom-numbering scheme are shown in Fig. 1. The bond length C4—C5 [1.5115 (16) Å] indicates that the newly formed double bond is exocyclic in nature. Further, it is evident from the bond lengths of C5—C6 and C6—C7 [1.5058 (15) and 1.4327 (15) Å, respectively] that the carbonyl group is conjugated with the π-electrons of pyrrole ring and not π-electrons of the exocyclic double. This explains why molindone and its degradation product, the title compound exhibit similar UV absorption. The mode of packing along the b direction is illustrated in Fig. 2. The H atom attached to atom N1 is involved in an intermolecular hydrogen bond [2.7749 (12) Å] with atom O1 of an inversion-related molecule, thus forming a continuous chain.

Related literature top

For related literature, see: Dudzinski et al. (1973).

Experimental top

A mixture of molindone (0.276 g, 1 mmol) and excess methyl iodide (2 ml) was stirred at ambient temperature. After completion of the reaction, unreacted methyl iodide was evaporated, and the crude quaternary ammonium salt was then mixed with 2 N aqueous sodium hydroxide (10 ml) and stirred for 1 h at ambient temperature. The resulting precipitate was collected by filtration and washed with water. Recrystallization from ethanol afforded the title compound as colorless crystalline product, which was suitable for X-ray analysis. Compound I: 1H NMR (400 MHz, CDCl3, p.p.m): δ 1.15 (t, J = 7.6 Hz, 3H), 2.16 (s, 3H), 2.70 (q, J = 7.6 Hz, 2H), 2.83 (s, 4H), 5.29 (d, J = 1.6 Hz, 1H), 6.03 (d, J = 1.6 Hz, 1H), 8.43 (sb, 1H); 13C NMR (75 MHz, CDCl3, p.p.m.): δ 10.68, 15.83, 18.41, 23.65, 32.13, 118.66, 119.16, 121.58, 124.74, 142.28, 144.84, 184.13.

Refinement top

All H atoms were found in difference Fourier maps and but were subsequently placed in idealized positions with constrained distances of 0.98 Å (RCH3), 0.99 Å (R2CH2), 0.95 Å (RCsp2H2) and 0.88 Å (NH). Uiso(H) values were set to either 1.2Ueq or 1.5Ueq (RCH3 only) of the attached atom.

Structure description top

The Mannich condensation reaction is frequently used in the synthesis of pharmaceutical compounds. One such example is the synthesis of molindone, an antipsychotic agent. During stability studies and development of an assay for molindone hydrochloride, a degradation product was identified as 3-ethyl-2-methyl-5-methylene-6,7-dihydro-5H-indol-4-one (Dudzinski et al., 1973). Molindone has UV absorption peaks at 255 nm and 299 nm; these UV wavelengths can be used quantitatively for quantifying the drug substance. However, preliminary studies indicated that chemical degradation (as evidenced by color and precipitate formation) was not accompanied by a decrease in UV absorption, suggesting that the degradation product had a similar chromophore to molindone. The title compound was prepared by the reaction of molindone free base with methyl iodide and subsequent reaction of the resulting quaternary ammonium salt with 2 N aqueous sodium hydroxide. The structure of the resulting compound, 3-ethyl-2-methyl-5-methylene-6,7-dihydro-5H-indol-4-one, was initially characterized by NMR spectroscopy and shown to be identical to the degradation product of molindone hydrochloride. To confirm the exocyclic nature of newly formed double bond and to identify chromophoric group in the molecule responsible for its UV absorption profile, its crystal structure was determined by X-ray analysis.

The molecular structure and the atom-numbering scheme are shown in Fig. 1. The bond length C4—C5 [1.5115 (16) Å] indicates that the newly formed double bond is exocyclic in nature. Further, it is evident from the bond lengths of C5—C6 and C6—C7 [1.5058 (15) and 1.4327 (15) Å, respectively] that the carbonyl group is conjugated with the π-electrons of pyrrole ring and not π-electrons of the exocyclic double. This explains why molindone and its degradation product, the title compound exhibit similar UV absorption. The mode of packing along the b direction is illustrated in Fig. 2. The H atom attached to atom N1 is involved in an intermolecular hydrogen bond [2.7749 (12) Å] with atom O1 of an inversion-related molecule, thus forming a continuous chain.

For related literature, see: Dudzinski et al. (1973).

Computing details top

Data collection: APEX2 (Bruker, 2006); cell refinement: APEX2 (Bruker, 2006); data reduction: APEX2 (Bruker, 2006); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: XP in SHELXTL (Sheldrick, 1995); software used to prepare material for publication: SHELX97 (Sheldrick, 1997) and local procedures.

Figures top
[Figure 1] Fig. 1. A view of the title compound I showing atom numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
[Figure 2] Fig. 2. A packing diagram viewed down the b axis, showing hydrogen bonding interactions (dashed lines). For clarity, only those H atoms involved in hydrogen bonding are shown.
[Figure 3] Fig. 3. Compounds (I) and (II).
3-Ethyl-2-methyl-5-methylene-6,7-dihydroindol-4(5H)-one top
Crystal data top
C12H15NOF(000) = 408
Mr = 189.25Dx = 1.182 Mg m3
Monoclinic, P21/nCu Kα radiation, λ = 1.54178 Å
Hall symbol: -P 2ynCell parameters from 9990 reflections
a = 9.0451 (3) Åθ = 3.2–69.4°
b = 8.5840 (3) ŵ = 0.59 mm1
c = 14.3557 (5) ÅT = 90 K
β = 107.355 (1)°Block, colourless
V = 1063.88 (6) Å30.15 × 0.12 × 0.10 mm
Z = 4
Data collection top
Bruker X8 Proteum
diffractometer
1972 independent reflections
Radiation source: fine-focus rotating anode1893 reflections with I > 2σ(I)
Graded multilayer optics monochromatorRint = 0.039
Detector resolution: 18 pixels mm-1θmax = 69.4°, θmin = 5.2°
φ and ω scansh = 1010
Absorption correction: multi-scan
(SADABS in APEX2; Bruker, 2006)
k = 1010
Tmin = 0.837, Tmax = 0.944l = 1717
15160 measured reflections
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.038Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.097H-atom parameters constrained
S = 1.05 w = 1/[σ2(Fo2) + (0.0464P)2 + 0.432P]
where P = (Fo2 + 2Fc2)/3
1972 reflections(Δ/σ)max < 0.001
129 parametersΔρmax = 0.24 e Å3
0 restraintsΔρmin = 0.20 e Å3
Crystal data top
C12H15NOV = 1063.88 (6) Å3
Mr = 189.25Z = 4
Monoclinic, P21/nCu Kα radiation
a = 9.0451 (3) ŵ = 0.59 mm1
b = 8.5840 (3) ÅT = 90 K
c = 14.3557 (5) Å0.15 × 0.12 × 0.10 mm
β = 107.355 (1)°
Data collection top
Bruker X8 Proteum
diffractometer
1972 independent reflections
Absorption correction: multi-scan
(SADABS in APEX2; Bruker, 2006)
1893 reflections with I > 2σ(I)
Tmin = 0.837, Tmax = 0.944Rint = 0.039
15160 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0380 restraints
wR(F2) = 0.097H-atom parameters constrained
S = 1.05Δρmax = 0.24 e Å3
1972 reflectionsΔρmin = 0.20 e Å3
129 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 > 2σ(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
O10.68573 (9)0.20035 (10)0.42456 (6)0.0247 (2)
N10.35484 (10)0.23361 (11)0.11591 (6)0.0186 (2)
H10.31280.25750.05400.022*
C20.49707 (13)0.27649 (13)0.17035 (8)0.0181 (2)
C30.60968 (13)0.37109 (14)0.13708 (8)0.0232 (3)
H3A0.59140.48350.14450.028*
H3B0.59770.34990.06740.028*
C40.77279 (13)0.32599 (14)0.20002 (8)0.0239 (3)
H4A0.79830.22120.18050.029*
H4B0.84840.40060.18790.029*
C50.78799 (13)0.32500 (13)0.30777 (8)0.0212 (3)
C60.66379 (13)0.24233 (12)0.33901 (8)0.0184 (2)
C70.52110 (12)0.21662 (12)0.26362 (8)0.0168 (2)
C80.38323 (12)0.13283 (12)0.26393 (8)0.0179 (3)
C90.28372 (13)0.14590 (12)0.17184 (8)0.0190 (3)
C100.12335 (13)0.08583 (15)0.12770 (9)0.0270 (3)
H10A0.10040.00690.17080.041*
H10B0.11490.03910.06400.041*
H10C0.04940.17190.11930.041*
C110.35382 (13)0.04614 (13)0.34712 (8)0.0224 (3)
H11A0.45090.00570.38500.027*
H11B0.27610.03620.32050.027*
C120.29655 (17)0.14824 (17)0.41558 (10)0.0342 (3)
H12A0.37460.22760.44440.051*
H12B0.27840.08390.46750.051*
H12C0.19960.19910.37900.051*
C130.90486 (14)0.39164 (15)0.37417 (9)0.0283 (3)
H13A0.91010.38720.44120.034*
H13B0.98350.44390.35480.034*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0246 (4)0.0296 (5)0.0160 (4)0.0050 (3)0.0003 (3)0.0018 (3)
N10.0188 (5)0.0208 (5)0.0137 (4)0.0021 (4)0.0010 (4)0.0001 (3)
C20.0186 (5)0.0177 (5)0.0177 (5)0.0014 (4)0.0046 (4)0.0012 (4)
C30.0249 (6)0.0265 (6)0.0184 (5)0.0025 (5)0.0070 (5)0.0024 (4)
C40.0204 (6)0.0266 (6)0.0260 (6)0.0032 (5)0.0091 (5)0.0003 (5)
C50.0180 (5)0.0193 (5)0.0245 (6)0.0003 (4)0.0040 (4)0.0025 (4)
C60.0198 (6)0.0166 (5)0.0174 (5)0.0004 (4)0.0033 (4)0.0008 (4)
C70.0172 (5)0.0165 (5)0.0158 (5)0.0003 (4)0.0037 (4)0.0009 (4)
C80.0176 (5)0.0163 (5)0.0194 (5)0.0001 (4)0.0049 (4)0.0012 (4)
C90.0178 (5)0.0169 (5)0.0212 (6)0.0005 (4)0.0043 (4)0.0018 (4)
C100.0189 (6)0.0272 (6)0.0304 (6)0.0025 (5)0.0002 (5)0.0010 (5)
C110.0221 (6)0.0218 (6)0.0233 (6)0.0024 (4)0.0067 (4)0.0028 (4)
C120.0415 (8)0.0368 (7)0.0303 (7)0.0054 (6)0.0200 (6)0.0059 (5)
C130.0245 (6)0.0282 (6)0.0280 (6)0.0066 (5)0.0011 (5)0.0058 (5)
Geometric parameters (Å, º) top
O1—C61.2377 (14)C7—C81.4407 (15)
N1—C21.3423 (14)C8—C91.3640 (15)
N1—C91.3905 (14)C8—C111.4968 (15)
N1—H10.8800C9—C101.4911 (15)
C2—C71.3894 (15)C10—H10A0.9800
C2—C31.4883 (15)C10—H10B0.9800
C3—C41.5322 (16)C10—H10C0.9800
C3—H3A0.9900C11—C121.5185 (17)
C3—H3B0.9900C11—H11A0.9900
C4—C51.5115 (16)C11—H11B0.9900
C4—H4A0.9900C12—H12A0.9800
C4—H4B0.9900C12—H12B0.9800
C5—C131.3237 (17)C12—H12C0.9800
C5—C61.5058 (15)C13—H13A0.9500
C6—C71.4327 (15)C13—H13B0.9500
C2—N1—C9109.90 (9)C9—C8—C7106.11 (9)
C2—N1—H1125.1C9—C8—C11126.25 (10)
C9—N1—H1125.1C7—C8—C11127.64 (10)
N1—C2—C7107.88 (10)C8—C9—N1108.61 (9)
N1—C2—C3126.27 (10)C8—C9—C10131.34 (11)
C7—C2—C3125.85 (10)N1—C9—C10120.05 (10)
C2—C3—C4107.68 (9)C9—C10—H10A109.5
C2—C3—H3A110.2C9—C10—H10B109.5
C4—C3—H3A110.2H10A—C10—H10B109.5
C2—C3—H3B110.2C9—C10—H10C109.5
C4—C3—H3B110.2H10A—C10—H10C109.5
H3A—C3—H3B108.5H10B—C10—H10C109.5
C5—C4—C3112.49 (9)C8—C11—C12113.92 (10)
C5—C4—H4A109.1C8—C11—H11A108.8
C3—C4—H4A109.1C12—C11—H11A108.8
C5—C4—H4B109.1C8—C11—H11B108.8
C3—C4—H4B109.1C12—C11—H11B108.8
H4A—C4—H4B107.8H11A—C11—H11B107.7
C13—C5—C6119.71 (11)C11—C12—H12A109.5
C13—C5—C4122.95 (11)C11—C12—H12B109.5
C6—C5—C4117.34 (10)H12A—C12—H12B109.5
O1—C6—C7123.12 (10)C11—C12—H12C109.5
O1—C6—C5121.31 (10)H12A—C12—H12C109.5
C7—C6—C5115.57 (9)H12B—C12—H12C109.5
C2—C7—C6121.18 (10)C5—C13—H13A120.0
C2—C7—C8107.51 (9)C5—C13—H13B120.0
C6—C7—C8131.31 (10)H13A—C13—H13B120.0
C9—N1—C2—C70.04 (12)C5—C6—C7—C25.13 (15)
C9—N1—C2—C3179.92 (10)O1—C6—C7—C85.42 (19)
N1—C2—C3—C4152.52 (11)C5—C6—C7—C8174.62 (10)
C7—C2—C3—C427.34 (15)C2—C7—C8—C90.04 (12)
C2—C3—C4—C548.30 (13)C6—C7—C8—C9179.74 (11)
C3—C4—C5—C13133.03 (12)C2—C7—C8—C11179.14 (10)
C3—C4—C5—C647.57 (14)C6—C7—C8—C110.63 (19)
C13—C5—C6—O118.54 (17)C7—C8—C9—N10.02 (12)
C4—C5—C6—O1160.88 (10)C11—C8—C9—N1179.14 (10)
C13—C5—C6—C7161.42 (11)C7—C8—C9—C10179.29 (11)
C4—C5—C6—C719.16 (14)C11—C8—C9—C101.6 (2)
N1—C2—C7—C6179.76 (9)C2—N1—C9—C80.01 (12)
C3—C2—C7—C60.13 (17)C2—N1—C9—C10179.35 (10)
N1—C2—C7—C80.05 (12)C9—C8—C11—C1296.71 (14)
C3—C2—C7—C8179.93 (10)C7—C8—C11—C1284.36 (14)
O1—C6—C7—C2174.83 (10)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1···O1i0.881.912.7749 (12)169
Symmetry code: (i) x1/2, y+1/2, z1/2.

Experimental details

Crystal data
Chemical formulaC12H15NO
Mr189.25
Crystal system, space groupMonoclinic, P21/n
Temperature (K)90
a, b, c (Å)9.0451 (3), 8.5840 (3), 14.3557 (5)
β (°) 107.355 (1)
V3)1063.88 (6)
Z4
Radiation typeCu Kα
µ (mm1)0.59
Crystal size (mm)0.15 × 0.12 × 0.10
Data collection
DiffractometerBruker X8 Proteum
diffractometer
Absorption correctionMulti-scan
(SADABS in APEX2; Bruker, 2006)
Tmin, Tmax0.837, 0.944
No. of measured, independent and
observed [I > 2σ(I)] reflections
15160, 1972, 1893
Rint0.039
(sin θ/λ)max1)0.607
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.038, 0.097, 1.05
No. of reflections1972
No. of parameters129
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.24, 0.20

Computer programs: APEX2 (Bruker, 2006), SHELXS97 (Sheldrick, 1997), SHELXL97 (Sheldrick, 1997), XP in SHELXTL (Sheldrick, 1995), SHELX97 (Sheldrick, 1997) and local procedures.

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1···O1i0.881.912.7749 (12)169.1
Symmetry code: (i) x1/2, y+1/2, z1/2.
 

References

First citationBruker (2006). APEX2. Bruker AXS Inc., Madison, Wisconcin, USA.  Google Scholar
First citationDudzinski, J., Lachman, L., Shami, E. & Tingstad, J. (1973). J. Pharm. Sci. 62, 622–624.  CrossRef CAS PubMed Web of Science Google Scholar
First citationSheldrick, G. M. (1995). XP in SHELXTL/PC. Siemens Analytical Instruments Inc., Madison, Wisconsin, USA.  Google Scholar
First citationSheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of Göttingen, Germany.  Google Scholar

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.

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ISSN: 2056-9890
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