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

Sonar, V.N.; Parkin, S.; Crooks, P.A.

doi:10.1107/S1600536807063076

organic compounds

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Volume 64| Part 1| January 2008| Page o158

https://doi.org/10.1107/S1600536807063076

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

Vijayakumar N. Sonar,^a Sean Parkin ^b and Peter A. Crooks ^a ^*

^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 ).

Experimental

Crystal data

C₁₂H₁₅NO
M_r = 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 ) T_min = 0.837, T_max = 0.944
15160 measured reflections
1972 independent reflections
1893 reflections with I > 2σ(I)
R_int = 0.039

Refinement

R[F² > 2σ(F²)] = 0.038
wR(F²) = 0.097
S = 1.05
1972 reflections
129 parameters
H-atom parameters constrained
Δρ_max = 0.24 e Å⁻³
Δρ_min = −0.20 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	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); cell refinement: APEX2; data reduction: APEX2; 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 and local procedures.

Supporting information

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S1600536807063076/om2194sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S1600536807063076/om2194Isup2.hkl

checkCIF report

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.

Structure description top

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

	Fig. 1. A view of the title compound I showing atom numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
	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.
	Fig. 3. Compounds (I) and (II).

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

Crystal data top

C₁₂H₁₅NO	F(000) = 408
M_r = 189.25	D_x = 1.182 Mg m⁻³
Monoclinic, P2₁/n	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: -P 2yn	Cell parameters from 9990 reflections
a = 9.0451 (3) Å	θ = 3.2–69.4°
b = 8.5840 (3) Å	µ = 0.59 mm⁻¹
c = 14.3557 (5) Å	T = 90 K
β = 107.355 (1)°	Block, colourless
V = 1063.88 (6) Å³	0.15 × 0.12 × 0.10 mm
Z = 4

Data collection top

Bruker X8 Proteum diffractometer	1972 independent reflections
Radiation source: fine-focus rotating anode	1893 reflections with I > 2σ(I)
Graded multilayer optics monochromator	R_int = 0.039
Detector resolution: 18 pixels mm^-1	θ_max = 69.4°, θ_min = 5.2°
φ and ω scans	h = −10→10
Absorption correction: multi-scan (SADABS in APEX2; Bruker, 2006)	k = −10→10
T_min = 0.837, T_max = 0.944	l = −17→17
15160 measured reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.038	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.097	H-atom parameters constrained
S = 1.05	w = 1/[σ²(F_o²) + (0.0464P)² + 0.432P] where P = (F_o² + 2F_c²)/3
1972 reflections	(Δ/σ)_max < 0.001
129 parameters	Δρ_max = 0.24 e Å⁻³
0 restraints	Δρ_min = −0.20 e Å⁻³

Crystal data top

C₁₂H₁₅NO	V = 1063.88 (6) Å³
M_r = 189.25	Z = 4
Monoclinic, P2₁/n	Cu Kα radiation
a = 9.0451 (3) Å	µ = 0.59 mm⁻¹
b = 8.5840 (3) Å	T = 90 K
c = 14.3557 (5) Å	0.15 × 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)
T_min = 0.837, T_max = 0.944	R_int = 0.039
15160 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.038	0 restraints
wR(F²) = 0.097	H-atom parameters constrained
S = 1.05	Δρ_max = 0.24 e Å⁻³
1972 reflections	Δρ_min = −0.20 e Å⁻³
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

	x	y	z	U_iso*/U_eq
O1	0.68573 (9)	0.20035 (10)	0.42456 (6)	0.0247 (2)
N1	0.35484 (10)	0.23361 (11)	0.11591 (6)	0.0186 (2)
H1	0.3128	0.2575	0.0540	0.022*
C2	0.49707 (13)	0.27649 (13)	0.17035 (8)	0.0181 (2)
C3	0.60968 (13)	0.37109 (14)	0.13708 (8)	0.0232 (3)
H3A	0.5914	0.4835	0.1445	0.028*
H3B	0.5977	0.3499	0.0674	0.028*
C4	0.77279 (13)	0.32599 (14)	0.20002 (8)	0.0239 (3)
H4A	0.7983	0.2212	0.1805	0.029*
H4B	0.8484	0.4006	0.1879	0.029*
C5	0.78799 (13)	0.32500 (13)	0.30777 (8)	0.0212 (3)
C6	0.66379 (13)	0.24233 (12)	0.33901 (8)	0.0184 (2)
C7	0.52110 (12)	0.21662 (12)	0.26362 (8)	0.0168 (2)
C8	0.38323 (12)	0.13283 (12)	0.26393 (8)	0.0179 (3)
C9	0.28372 (13)	0.14590 (12)	0.17184 (8)	0.0190 (3)
C10	0.12335 (13)	0.08583 (15)	0.12770 (9)	0.0270 (3)
H10A	0.1004	0.0069	0.1708	0.041*
H10B	0.1149	0.0391	0.0640	0.041*
H10C	0.0494	0.1719	0.1193	0.041*
C11	0.35382 (13)	0.04614 (13)	0.34712 (8)	0.0224 (3)
H11A	0.4509	−0.0057	0.3850	0.027*
H11B	0.2761	−0.0362	0.3205	0.027*
C12	0.29655 (17)	0.14824 (17)	0.41558 (10)	0.0342 (3)
H12A	0.3746	0.2276	0.4444	0.051*
H12B	0.2784	0.0839	0.4675	0.051*
H12C	0.1996	0.1991	0.3790	0.051*
C13	0.90486 (14)	0.39164 (15)	0.37417 (9)	0.0283 (3)
H13A	0.9101	0.3872	0.4412	0.034*
H13B	0.9835	0.4439	0.3548	0.034*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0246 (4)	0.0296 (5)	0.0160 (4)	−0.0050 (3)	0.0003 (3)	0.0018 (3)
N1	0.0188 (5)	0.0208 (5)	0.0137 (4)	0.0021 (4)	0.0010 (4)	−0.0001 (3)
C2	0.0186 (5)	0.0177 (5)	0.0177 (5)	0.0014 (4)	0.0046 (4)	−0.0012 (4)
C3	0.0249 (6)	0.0265 (6)	0.0184 (5)	−0.0025 (5)	0.0070 (5)	0.0024 (4)
C4	0.0204 (6)	0.0266 (6)	0.0260 (6)	−0.0032 (5)	0.0091 (5)	0.0003 (5)
C5	0.0180 (5)	0.0193 (5)	0.0245 (6)	0.0003 (4)	0.0040 (4)	0.0025 (4)
C6	0.0198 (6)	0.0166 (5)	0.0174 (5)	0.0004 (4)	0.0033 (4)	−0.0008 (4)
C7	0.0172 (5)	0.0165 (5)	0.0158 (5)	0.0003 (4)	0.0037 (4)	−0.0009 (4)
C8	0.0176 (5)	0.0163 (5)	0.0194 (5)	0.0001 (4)	0.0049 (4)	−0.0012 (4)
C9	0.0178 (5)	0.0169 (5)	0.0212 (6)	0.0005 (4)	0.0043 (4)	−0.0018 (4)
C10	0.0189 (6)	0.0272 (6)	0.0304 (6)	−0.0025 (5)	0.0002 (5)	−0.0010 (5)
C11	0.0221 (6)	0.0218 (6)	0.0233 (6)	−0.0024 (4)	0.0067 (4)	0.0028 (4)
C12	0.0415 (8)	0.0368 (7)	0.0303 (7)	0.0054 (6)	0.0200 (6)	0.0059 (5)
C13	0.0245 (6)	0.0282 (6)	0.0280 (6)	−0.0066 (5)	0.0011 (5)	0.0058 (5)

Geometric parameters (Å, º) top

O1—C6	1.2377 (14)	C7—C8	1.4407 (15)
N1—C2	1.3423 (14)	C8—C9	1.3640 (15)
N1—C9	1.3905 (14)	C8—C11	1.4968 (15)
N1—H1	0.8800	C9—C10	1.4911 (15)
C2—C7	1.3894 (15)	C10—H10A	0.9800
C2—C3	1.4883 (15)	C10—H10B	0.9800
C3—C4	1.5322 (16)	C10—H10C	0.9800
C3—H3A	0.9900	C11—C12	1.5185 (17)
C3—H3B	0.9900	C11—H11A	0.9900
C4—C5	1.5115 (16)	C11—H11B	0.9900
C4—H4A	0.9900	C12—H12A	0.9800
C4—H4B	0.9900	C12—H12B	0.9800
C5—C13	1.3237 (17)	C12—H12C	0.9800
C5—C6	1.5058 (15)	C13—H13A	0.9500
C6—C7	1.4327 (15)	C13—H13B	0.9500

C2—N1—C9	109.90 (9)	C9—C8—C7	106.11 (9)
C2—N1—H1	125.1	C9—C8—C11	126.25 (10)
C9—N1—H1	125.1	C7—C8—C11	127.64 (10)
N1—C2—C7	107.88 (10)	C8—C9—N1	108.61 (9)
N1—C2—C3	126.27 (10)	C8—C9—C10	131.34 (11)
C7—C2—C3	125.85 (10)	N1—C9—C10	120.05 (10)
C2—C3—C4	107.68 (9)	C9—C10—H10A	109.5
C2—C3—H3A	110.2	C9—C10—H10B	109.5
C4—C3—H3A	110.2	H10A—C10—H10B	109.5
C2—C3—H3B	110.2	C9—C10—H10C	109.5
C4—C3—H3B	110.2	H10A—C10—H10C	109.5
H3A—C3—H3B	108.5	H10B—C10—H10C	109.5
C5—C4—C3	112.49 (9)	C8—C11—C12	113.92 (10)
C5—C4—H4A	109.1	C8—C11—H11A	108.8
C3—C4—H4A	109.1	C12—C11—H11A	108.8
C5—C4—H4B	109.1	C8—C11—H11B	108.8
C3—C4—H4B	109.1	C12—C11—H11B	108.8
H4A—C4—H4B	107.8	H11A—C11—H11B	107.7
C13—C5—C6	119.71 (11)	C11—C12—H12A	109.5
C13—C5—C4	122.95 (11)	C11—C12—H12B	109.5
C6—C5—C4	117.34 (10)	H12A—C12—H12B	109.5
O1—C6—C7	123.12 (10)	C11—C12—H12C	109.5
O1—C6—C5	121.31 (10)	H12A—C12—H12C	109.5
C7—C6—C5	115.57 (9)	H12B—C12—H12C	109.5
C2—C7—C6	121.18 (10)	C5—C13—H13A	120.0
C2—C7—C8	107.51 (9)	C5—C13—H13B	120.0
C6—C7—C8	131.31 (10)	H13A—C13—H13B	120.0

C9—N1—C2—C7	0.04 (12)	C5—C6—C7—C2	−5.13 (15)
C9—N1—C2—C3	179.92 (10)	O1—C6—C7—C8	−5.42 (19)
N1—C2—C3—C4	−152.52 (11)	C5—C6—C7—C8	174.62 (10)
C7—C2—C3—C4	27.34 (15)	C2—C7—C8—C9	0.04 (12)
C2—C3—C4—C5	−48.30 (13)	C6—C7—C8—C9	−179.74 (11)
C3—C4—C5—C13	−133.03 (12)	C2—C7—C8—C11	179.14 (10)
C3—C4—C5—C6	47.57 (14)	C6—C7—C8—C11	−0.63 (19)
C13—C5—C6—O1	−18.54 (17)	C7—C8—C9—N1	−0.02 (12)
C4—C5—C6—O1	160.88 (10)	C11—C8—C9—N1	−179.14 (10)
C13—C5—C6—C7	161.42 (11)	C7—C8—C9—C10	−179.29 (11)
C4—C5—C6—C7	−19.16 (14)	C11—C8—C9—C10	1.6 (2)
N1—C2—C7—C6	179.76 (9)	C2—N1—C9—C8	−0.01 (12)
C3—C2—C7—C6	−0.13 (17)	C2—N1—C9—C10	179.35 (10)
N1—C2—C7—C8	−0.05 (12)	C9—C8—C11—C12	−96.71 (14)
C3—C2—C7—C8	−179.93 (10)	C7—C8—C11—C12	84.36 (14)
O1—C6—C7—C2	174.83 (10)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O1ⁱ	0.88	1.91	2.7749 (12)	169

Symmetry code: (i) x−1/2, −y+1/2, z−1/2.

Experimental details

Crystal data
Chemical formula	C₁₂H₁₅NO
M_r	189.25
Crystal system, space group	Monoclinic, P2₁/n
Temperature (K)	90
a, b, c (Å)	9.0451 (3), 8.5840 (3), 14.3557 (5)
β (°)	107.355 (1)
V (Å³)	1063.88 (6)
Z	4
Radiation type	Cu Kα
µ (mm⁻¹)	0.59
Crystal size (mm)	0.15 × 0.12 × 0.10

Data collection
Diffractometer	Bruker X8 Proteum diffractometer
Absorption correction	Multi-scan (SADABS in APEX2; Bruker, 2006)
T_min, T_max	0.837, 0.944
No. of measured, independent and observed [I > 2σ(I)] reflections	15160, 1972, 1893
R_int	0.039
(sin θ/λ)_max (Å⁻¹)	0.607

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.038, 0.097, 1.05
No. of reflections	1972
No. of parameters	129
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	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···A	D—H	H···A	D···A	D—H···A
N1—H1···O1ⁱ	0.88	1.91	2.7749 (12)	169.1

Symmetry code: (i) x−1/2, −y+1/2, z−1/2.

References

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

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