2-Ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexa­hydro-1H-isoindole-4-carboxylic acid

Mutikainen, I.; Kiriazis, A.; Leikoski, T.; Yli-Kauhaluoma, J.

doi:10.1107/S1600536807027900

2-Ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-4-carboxylic acid

I. Mutikainen, A. Kiriazis, T. Leikoski and J. Yli-Kauhaluoma

The Diels-Alder cycloaddition reactions between deactivated dienes and electron-deficient dienophiles are generally known to be thermodynamically disfavoured but when low solvent volumes were used for the reaction, the cycloaddition of 4-(bromomethyl)phenoxymethyl polystyrene-bound (E)-1,3-butadiene-1-carboxylic acid with N-ethylmaleimide gave the title compound, C₁₁H₁₃NO₄, in good yield. The molecules are connected through hydrogen bonds between the carboxyl group and one exocyclic carbonyl oxygen. The title compound is interesting in medicinal chemistry since related compounds are known to increase the blood platelet count in thrombocytopenia and to possess anticonvulsant activity.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536807027900/bg2064sup1.cif Contains datablocks I, global
	Structure factor file (CIF format) https://doi.org/10.1107/S1600536807027900/bg2064Isup2.hkl Contains datablock I

CCDC reference: 654980

checkCIF report

Key indicators

Single-crystal X-ray study
T = 173 K
Mean (C-C) = 0.003 Å
R factor = 0.056
wR factor = 0.130
Data-to-parameter ratio = 15.8

checkCIF/PLATON results

No syntax errors found



Datablock: I


Alert level G
PLAT793_ALERT_1_G Check the Absolute Configuration of C2     = ...          S
PLAT793_ALERT_1_G Check the Absolute Configuration of C6     = ...          R
PLAT793_ALERT_1_G Check the Absolute Configuration of C7     = ...          R

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   0 ALERT level C = Check and explain
   3 ALERT level G = General alerts; check

   3 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   0 ALERT type 2 Indicator that the structure model may be wrong or deficient
   0 ALERT type 3 Indicator that the structure quality may be low
   0 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

Comment top

The Diels-Alder cycloaddition reactions between deactivated dienes and electron-deficient dienophiles are generally known to be thermodynamically disfavoured. We have recently found that when low solvent volumes (Morphy et al., 2002) were used for the reaction, the disfavoured cycloaddition of the 4-(bromomethyl)-phenoxymethyl polystyrene-bound (E)-1,3-butadiene-1-carboxylic acid with N-ethylmaleimide (PhMe, rt, 2 d) gave the endo cycloadduct in 40% yield (Kiriazis et al., 2004). The hexahydro-1,3-dioxoisoindole structure of the cycloadduct is very interesting in medicinal chemistry. For example, the related compounds are known to increase the blood platelet count in thrombocytopenia (Kanai et al., 2000) and to possess anticonvulsant activity (Bailleux et al., 1994).

Related literature top

For related literature, see: Bailleux et al. (1994); Kanai et al. (2000); Kiriazis et al. (2004); Morphy et al. (2002).

Experimental top

Polystyrene-bound 1,3-butadiene-1-carboxylic acid (1.4 mmol/g, 600 mg) was treated with N-ethylmaleimide (8.4 mmol, 1.05 g) in toluene (1.0 ml) at room temperature for 48 h. Cleavage with TFA-CH₂Cl₂ 1:4 (8 ml) over 2 h at room temperature and purification by successive trituration with hexane, Et₂O and EtOAc gave the endo cycloadduct (75 mg, 40%) as white crystals, mp 156–158 °C.

Structure description top

For related literature, see: Bailleux et al. (1994); Kanai et al. (2000); Kiriazis et al. (2004); Morphy et al. (2002).

Computing details top

Data collection: COLLECT (Nonius, 2002); cell refinement: DIRAX (Duisenberg, 1992); data reduction: EVAL (Nonius, 2002); program(s) used to solve structure: SIR2002 (Burla et al., 2003); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Sheldrick, 1990); software used to prepare material for publication: SHELXTL.

Figures top

Fig. 1. View of the molecule. Thermal ellipsoids are drawn at 30% probability.

2-Ethyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-4-carboxylic acid top

Crystal data top

C₁₁H₁₃NO₄	F(000) = 472
M_r = 223.22	D_x = 1.431 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 257 reflections
a = 8.432 (1) Å	θ = 2.2–17.9°
b = 8.588 (1) Å	µ = 0.11 mm⁻¹
c = 14.342 (2) Å	T = 173 K
β = 94.07 (2)°	Needle, colorless
V = 1035.9 (2) Å³	0.25 × 0.11 × 0.10 mm
Z = 4

Data collection top

Nonius Kappa CCD diffractometer	2350 independent reflections
Radiation source: fine-focus sealed tube	1345 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.078
ω scans	θ_max = 27.5°, θ_min = 5.3°
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	h = −9→10
T_min = 0.97, T_max = 0.99	k = −11→11
7378 measured reflections	l = −18→12

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)] = 0.056	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.130	H atoms treated by a mixture of independent and constrained refinement
S = 1.00	w = 1/[σ²(F_o²) + (0.0571P)²] where P = (F_o² + 2F_c²)/3
2350 reflections	(Δ/σ)_max < 0.001
149 parameters	Δρ_max = 0.41 e Å⁻³
0 restraints	Δρ_min = −0.25 e Å⁻³

Crystal data top

C₁₁H₁₃NO₄	V = 1035.9 (2) Å³
M_r = 223.22	Z = 4
Monoclinic, P2₁/c	Mo Kα radiation
a = 8.432 (1) Å	µ = 0.11 mm⁻¹
b = 8.588 (1) Å	T = 173 K
c = 14.342 (2) Å	0.25 × 0.11 × 0.10 mm
β = 94.07 (2)°

Data collection top

Nonius Kappa CCD diffractometer	2350 independent reflections
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	1345 reflections with I > 2σ(I)
T_min = 0.97, T_max = 0.99	R_int = 0.078
7378 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.056	0 restraints
wR(F²) = 0.130	H atoms treated by a mixture of independent and constrained refinement
S = 1.00	Δρ_max = 0.41 e Å⁻³
2350 reflections	Δρ_min = −0.25 e Å⁻³
149 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

	x	y	z	U_iso*/U_eq
O1	1.20615 (19)	0.12766 (19)	0.18956 (12)	0.0291 (5)
H1A	1.305 (3)	0.108 (3)	0.2114 (19)	0.040 (8)*
O2	1.20296 (19)	−0.1224 (2)	0.14398 (13)	0.0344 (5)
O3	1.01229 (17)	−0.02571 (19)	0.33666 (12)	0.0275 (4)
O4	0.48321 (17)	0.0661 (2)	0.28732 (12)	0.0337 (5)
N1	0.74206 (19)	0.0088 (2)	0.33060 (13)	0.0191 (5)
C1	1.1350 (3)	0.0004 (3)	0.15529 (17)	0.0230 (6)
C2	0.9591 (2)	0.0274 (3)	0.12836 (17)	0.0208 (5)
H2A	0.9518	0.0958	0.0718	0.025*
C3	0.8682 (3)	−0.1201 (3)	0.10316 (16)	0.0244 (6)
H3A	0.9225	−0.2159	0.0965	0.029*
C4	0.7109 (3)	−0.1129 (3)	0.09050 (17)	0.0271 (6)
H4A	0.6509	−0.2048	0.0771	0.032*
C5	0.6282 (3)	0.0415 (3)	0.09743 (17)	0.0272 (6)
H5A	0.5127	0.0242	0.1009	0.033*
H5B	0.6436	0.1039	0.0408	0.033*
C6	0.6941 (2)	0.1316 (3)	0.18465 (16)	0.0208 (5)
H6A	0.6670	0.2445	0.1772	0.025*
C7	0.8756 (2)	0.1135 (3)	0.20590 (15)	0.0184 (5)
H7A	0.9244	0.2190	0.2154	0.022*
C8	0.8919 (2)	0.0247 (3)	0.29702 (16)	0.0187 (5)
C9	0.6239 (2)	0.0690 (3)	0.27090 (16)	0.0216 (5)
C10	0.7154 (3)	−0.0611 (3)	0.42150 (17)	0.0251 (6)
H10A	0.8034	−0.1338	0.4396	0.030*
H10B	0.6151	−0.1214	0.4164	0.030*
C11	0.7061 (3)	0.0629 (3)	0.49656 (18)	0.0313 (6)
H11A	0.6884	0.0130	0.5564	0.047*
H11B	0.6180	0.1340	0.4793	0.047*
H11C	0.8061	0.1215	0.5024	0.047*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0200 (8)	0.0271 (9)	0.0400 (12)	−0.0019 (8)	0.0004 (7)	0.0025 (9)
O2	0.0329 (9)	0.0281 (10)	0.0428 (12)	0.0084 (8)	0.0069 (8)	−0.0017 (9)
O3	0.0229 (8)	0.0337 (10)	0.0256 (10)	0.0041 (7)	−0.0020 (7)	0.0018 (8)
O4	0.0199 (8)	0.0499 (12)	0.0315 (11)	0.0012 (8)	0.0033 (7)	0.0026 (9)
N1	0.0222 (9)	0.0199 (11)	0.0154 (11)	−0.0004 (8)	0.0033 (8)	0.0012 (8)
C1	0.0276 (12)	0.0247 (13)	0.0173 (13)	−0.0012 (11)	0.0065 (10)	0.0037 (11)
C2	0.0249 (11)	0.0215 (13)	0.0165 (13)	0.0021 (10)	0.0035 (9)	0.0024 (10)
C3	0.0329 (13)	0.0208 (12)	0.0195 (14)	0.0024 (11)	0.0011 (10)	−0.0047 (11)
C4	0.0347 (13)	0.0241 (13)	0.0221 (14)	−0.0067 (11)	0.0004 (10)	−0.0058 (11)
C5	0.0259 (12)	0.0341 (15)	0.0210 (14)	−0.0010 (11)	−0.0028 (10)	−0.0003 (12)
C6	0.0215 (11)	0.0191 (11)	0.0214 (13)	0.0027 (10)	−0.0017 (9)	−0.0013 (11)
C7	0.0201 (11)	0.0158 (11)	0.0192 (13)	−0.0024 (9)	0.0011 (9)	−0.0010 (10)
C8	0.0203 (11)	0.0162 (12)	0.0191 (13)	0.0006 (10)	−0.0013 (9)	−0.0054 (10)
C9	0.0216 (11)	0.0220 (13)	0.0209 (14)	0.0018 (10)	−0.0006 (10)	−0.0041 (11)
C10	0.0307 (12)	0.0260 (13)	0.0193 (14)	0.0005 (11)	0.0057 (10)	0.0025 (11)
C11	0.0345 (13)	0.0380 (15)	0.0215 (15)	−0.0024 (12)	0.0020 (11)	−0.0011 (12)

Geometric parameters (Å, º) top

O1—C1	1.325 (3)	C4—H4A	0.9500
O1—H1A	0.89 (3)	C5—C6	1.541 (3)
O2—C1	1.217 (3)	C5—H5A	0.9900
O3—C8	1.208 (3)	C5—H5B	0.9900
O4—C9	1.226 (2)	C6—C9	1.508 (3)
N1—C9	1.368 (3)	C6—C7	1.547 (3)
N1—C8	1.391 (3)	C6—H6A	1.0000
N1—C10	1.467 (3)	C7—C8	1.511 (3)
C1—C2	1.523 (3)	C7—H7A	1.0000
C2—C3	1.511 (3)	C10—C11	1.520 (3)
C2—C7	1.546 (3)	C10—H10A	0.9900
C2—H2A	1.0000	C10—H10B	0.9900
C3—C4	1.327 (3)	C11—H11A	0.9800
C3—H3A	0.9500	C11—H11B	0.9800
C4—C5	1.505 (3)	C11—H11C	0.9800

C1—O1—H1A	111.1 (18)	C9—C6—H6A	109.5
C9—N1—C8	112.67 (19)	C5—C6—H6A	109.5
C9—N1—C10	124.08 (17)	C7—C6—H6A	109.5
C8—N1—C10	123.24 (18)	C8—C7—C2	111.26 (18)
O2—C1—O1	124.0 (2)	C8—C7—C6	104.42 (17)
O2—C1—C2	123.9 (2)	C2—C7—C6	113.64 (18)
O1—C1—C2	112.1 (2)	C8—C7—H7A	109.1
C3—C2—C1	113.65 (19)	C2—C7—H7A	109.1
C3—C2—C7	108.91 (17)	C6—C7—H7A	109.1
C1—C2—C7	112.04 (18)	O3—C8—N1	123.7 (2)
C3—C2—H2A	107.3	O3—C8—C7	127.59 (19)
C1—C2—H2A	107.3	N1—C8—C7	108.66 (18)
C7—C2—H2A	107.3	O4—C9—N1	122.9 (2)
C4—C3—C2	118.6 (2)	O4—C9—C6	127.3 (2)
C4—C3—H3A	120.7	N1—C9—C6	109.74 (17)
C2—C3—H3A	120.7	N1—C10—C11	111.22 (19)
C3—C4—C5	119.7 (2)	N1—C10—H10A	109.4
C3—C4—H4A	120.2	C11—C10—H10A	109.4
C5—C4—H4A	120.2	N1—C10—H10B	109.4
C4—C5—C6	110.73 (19)	C11—C10—H10B	109.4
C4—C5—H5A	109.5	H10A—C10—H10B	108.0
C6—C5—H5A	109.5	C10—C11—H11A	109.5
C4—C5—H5B	109.5	C10—C11—H11B	109.5
C6—C5—H5B	109.5	H11A—C11—H11B	109.5
H5A—C5—H5B	108.1	C10—C11—H11C	109.5
C9—C6—C5	110.30 (18)	H11A—C11—H11C	109.5
C9—C6—C7	104.05 (18)	H11B—C11—H11C	109.5
C5—C6—C7	113.84 (17)

O2—C1—C2—C3	11.0 (3)	C9—N1—C8—O3	−176.9 (2)
O1—C1—C2—C3	−171.04 (19)	C10—N1—C8—O3	4.7 (3)
O2—C1—C2—C7	135.0 (2)	C9—N1—C8—C7	3.2 (3)
O1—C1—C2—C7	−47.1 (2)	C10—N1—C8—C7	−175.14 (19)
C1—C2—C3—C4	171.3 (2)	C2—C7—C8—O3	51.0 (3)
C7—C2—C3—C4	45.7 (3)	C6—C7—C8—O3	174.0 (2)
C2—C3—C4—C5	2.6 (3)	C2—C7—C8—N1	−129.13 (18)
C3—C4—C5—C6	−46.2 (3)	C6—C7—C8—N1	−6.2 (2)
C4—C5—C6—C9	−78.7 (2)	C8—N1—C9—O4	179.7 (2)
C4—C5—C6—C7	37.8 (3)	C10—N1—C9—O4	−2.0 (3)
C3—C2—C7—C8	68.7 (2)	C8—N1—C9—C6	1.3 (3)
C1—C2—C7—C8	−57.9 (2)	C10—N1—C9—C6	179.67 (19)
C3—C2—C7—C6	−48.8 (2)	C5—C6—C9—O4	−60.9 (3)
C1—C2—C7—C6	−175.39 (19)	C7—C6—C9—O4	176.6 (2)
C9—C6—C7—C8	6.6 (2)	C5—C6—C9—N1	117.4 (2)
C5—C6—C7—C8	−113.5 (2)	C7—C6—C9—N1	−5.1 (2)
C9—C6—C7—C2	128.0 (2)	C9—N1—C10—C11	−82.9 (3)
C5—C6—C7—C2	7.9 (3)	C8—N1—C10—C11	95.3 (2)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1A···O4ⁱ	0.89 (3)	1.83 (3)	2.690 (2)	164 (2)

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

Experimental details

Crystal data
Chemical formula	C₁₁H₁₃NO₄
M_r	223.22
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	173
a, b, c (Å)	8.432 (1), 8.588 (1), 14.342 (2)
β (°)	94.07 (2)
V (Å³)	1035.9 (2)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.11
Crystal size (mm)	0.25 × 0.11 × 0.10

Data collection
Diffractometer	Nonius Kappa CCD
Absorption correction	Multi-scan (SADABS; Sheldrick, 1996)
T_min, T_max	0.97, 0.99
No. of measured, independent and observed [I > 2σ(I)] reflections	7378, 2350, 1345
R_int	0.078
(sin θ/λ)_max (Å⁻¹)	0.650

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.056, 0.130, 1.00
No. of reflections	2350
No. of parameters	149
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.41, −0.25

Computer programs: COLLECT (Nonius, 2002), DIRAX (Duisenberg, 1992), EVAL (Nonius, 2002), SIR2002 (Burla et al., 2003), SHELXL97 (Sheldrick, 1997), SHELXTL (Sheldrick, 1990), SHELXTL.