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Acta Cryst. (2012). E68, o3252    [ doi:10.1107/S1600536812044261 ]

10'-Chloro-3',4'-dihydro-2'H-spiro[cyclopropane-1,7'(6'H)-pyrimido[2,1-a]isoquinolin]-6'-one

K. Okuda, T. Hirota, Y. Nishina and H. Ishida

Abstract top

In the title compound, C14H13ClN2O, the fused hydropyrimidine ring adopts an envelope conformation with one of the methylene C atoms at the flap. The three-membered ring is approximately perpendicular to the attached isoquinoline ring system, with a dihedral angle of 89.44 (11)°. In the crystal, molecules are linked by a weak C-H...[pi] interaction, forming a helical chain along the c axis.

Comment top

As an extension of our work to develop complex heterocyclic skeletons as leads for potential pharmaceutical agents (Okuda et al., 2011), we found that tricyclic 5-amino-1,2-dihydrofuro[2,3-c]isoquinolines (Okuda et al., 2010), easily accessible by a one step base-induced Truce-Smiles rearrangement of 2-(3-cyanopropoxy)benzonitriles, showed bronchodilator activity (unpublished results). In the pursuit of more potent analogs, we have explored preparation of additional new ring-fused tetracyclic heterocycles. Herein we report that reaction of 5-amino-7-chloro-1,2-dihydrofuro[2,3-c]isoquinoline with 1,3-dibromopropane in the presence of calcium oxide afforded the title compound (Okuda et al., 2012) via rearrangement instead of the anticipated 10-chloro-2,3,6,7-tetrahydrofuro[2,3-c]imidazo[2,1-a]isoquinoline.

In the title compound, the fused hydropyrimidine N1/C1/N2/C12–C14 ring adopts an envelope conformation with atom C13 at the flap. The isoquinoline C1/N1/C2–C9 ring system is planar with an r.m.s. deviation of 0.044 (1) Å. The three-membered C3/C10/C11 ring is approximately perpendicular to the attached isoquinoline ring system with a dihedral angle of 89.44 (11)°. In the crystal, molecules are linked by a weak C—H···π interaction (Table 1), forming a helical chain along the c axis.

Related literature top

For recent reports on the development of complex heterocyclic skeletons for potential pharmaceutics in one step using the Truce–Smiles rearrangement, see: Okuda et al. (2010, 2011). For the synthesis of the title compound, see: Okuda et al. (2012).

Experimental top

The detailed experimental procedure for the synthesis of 10'-chloro-3',4'-dihydro-2'H-spiro[cyclopropane-1,7'(6'H)-pyrimido[2,1-a]isoquinolin]-6'-one (m.p. 424–425 K from n-hexane) from 5-amino-7-chloro-1,2-dihydrofuro[2,3-c]isoquinoline was described in our previous paper (Okuda et al., 2012). Single crystals suitable for X-ray diffraction were obtained from an acetonitrile/water solution. The title compound was dissolved in hot acetonitrile, then water was added dropwise until the solution became turbid. Slow evaporation at room temperature gave the colourless crystals

Refinement top

H atoms were located in a difference Fourier map and then were positioned geometrically (C—H = 0.95 or 0.99 Å) and refined as riding, with Uiso(H) = 1.2Ueq(C).

Computing details top

Data collection: PROCESS-AUTO (Rigaku/MSC, 2004); cell refinement: PROCESS-AUTO (Rigaku/MSC, 2004); data reduction: CrystalStructure (Rigaku/MSC, 2004); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 (Farrugia, 1997); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).

Figures top
[Figure 1] Fig. 1. The molecular structure of the title compound, with the atom-labeling. Displacement ellipsoids of non-H atoms are drawn at the 50% probability level.
[Figure 2] Fig. 2. A packing diagram of the title compound, showing a chain structure formed by C—H···π interactions (dashed lines).
10'-Chloro-3',4'-dihydro-2'H-spiro[cyclopropane- 1,7'(6'H)-pyrimido[2,1-a]isoquinolin]-6'-one top
Crystal data top
C14H13ClN2OF(000) = 544.00
Mr = 260.72Dx = 1.489 Mg m−3
Orthorhombic, Pca21Mo Kα radiation, λ = 0.71075 Å
Hall symbol: P 2c -2acCell parameters from 15021 reflections
a = 8.8746 (5) Åθ = 3.1–30.0°
b = 13.3273 (7) ŵ = 0.32 mm−1
c = 9.8331 (6) ÅT = 180 K
V = 1163.01 (11) Å3Platelet, colourless
Z = 40.25 × 0.21 × 0.03 mm
Data collection top
Rigaku R-AXIS RAPIDII
diffractometer		3095 reflections with I > 2σ(I)
Detector resolution: 10.00 pixels mm-1Rint = 0.027
ω scansθmax = 30.0°
Absorption correction: numerical
(NUMABS; Higashi, 1999)		h = −12→12
Tmin = 0.931, Tmax = 0.991k = −18→18
17373 measured reflectionsl = −13→13
3359 independent 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)] = 0.031H-atom parameters constrained
wR(F2) = 0.079 w = 1/[σ2(Fo2) + (0.0483P)2 + 0.1225P]
where P = (Fo2 + 2Fc2)/3
S = 1.05(Δ/σ)max = 0.001
3359 reflectionsΔρmax = 0.32 e Å−3
163 parametersΔρmin = −0.15 e Å−3
1 restraintAbsolute structure: Flack (1983), 1571 Friedel pairs
Primary atom site location: structure-invariant direct methodsFlack parameter: 0.01 (5)
Crystal data top
C14H13ClN2OV = 1163.01 (11) Å3
Mr = 260.72Z = 4
Orthorhombic, Pca21Mo Kα radiation
a = 8.8746 (5) ŵ = 0.32 mm−1
b = 13.3273 (7) ÅT = 180 K
c = 9.8331 (6) Å0.25 × 0.21 × 0.03 mm
Data collection top
Rigaku R-AXIS RAPIDII
diffractometer		3359 independent reflections
Absorption correction: numerical
(NUMABS; Higashi, 1999)		3095 reflections with I > 2σ(I)
Tmin = 0.931, Tmax = 0.991Rint = 0.027
17373 measured reflectionsθmax = 30.0°
Refinement top
R[F2 > 2σ(F2)] = 0.031H-atom parameters constrained
wR(F2) = 0.079Δρmax = 0.32 e Å−3
S = 1.05Δρmin = −0.15 e Å−3
3359 reflectionsAbsolute structure: Flack (1983), 1571 Friedel pairs
163 parametersFlack parameter: 0.01 (5)
1 restraint
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
Cl10.55266 (4)0.63700 (2)0.30542 (5)0.03531 (10)
O10.57503 (12)0.04186 (7)0.43848 (12)0.0307 (2)
N10.45976 (11)0.15982 (7)0.31067 (13)0.01989 (19)
N20.36794 (13)0.28236 (8)0.15502 (12)0.0249 (2)
C10.44659 (13)0.25802 (10)0.25827 (13)0.0189 (2)
C20.56200 (15)0.13087 (10)0.40789 (14)0.0211 (2)
C30.65462 (14)0.20982 (9)0.47518 (13)0.0205 (2)
C40.63116 (14)0.31618 (9)0.43507 (12)0.0191 (2)
C50.70816 (15)0.39510 (11)0.49866 (14)0.0259 (3)
H50.77740.38060.56970.031*
C60.68510 (16)0.49385 (10)0.45973 (15)0.0260 (3)
H60.73720.54700.50380.031*
C70.58418 (16)0.51363 (10)0.35496 (15)0.0242 (3)
C80.50749 (14)0.43794 (9)0.28990 (14)0.0226 (2)
H80.43910.45310.21850.027*
C90.53128 (13)0.33791 (9)0.33006 (13)0.0187 (2)
C100.81354 (17)0.17547 (12)0.51350 (16)0.0301 (3)
H10A0.84430.10690.48650.036*
H10B0.89520.22600.51080.036*
C110.69779 (19)0.18535 (11)0.62195 (15)0.0293 (3)
H11A0.70790.24200.68640.035*
H11B0.65700.12290.66210.035*
C120.27594 (16)0.20671 (11)0.08694 (15)0.0297 (3)
H12A0.33280.17940.00860.036*
H12B0.18360.23900.05130.036*
C130.23159 (15)0.12115 (11)0.17992 (16)0.0289 (3)
H13A0.16100.14560.25050.035*
H13B0.18020.06810.12680.035*
C140.37139 (16)0.07873 (10)0.24647 (16)0.0267 (3)
H14A0.34210.02880.31620.032*
H14B0.43380.04430.17730.032*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Cl10.04450 (18)0.01793 (13)0.0435 (2)−0.00198 (13)0.00151 (18)0.00384 (15)
O10.0391 (5)0.0195 (5)0.0334 (6)−0.0010 (4)−0.0080 (5)0.0010 (4)
N10.0222 (4)0.0189 (4)0.0186 (5)−0.0024 (3)−0.0003 (4)−0.0022 (5)
N20.0257 (5)0.0269 (5)0.0221 (5)−0.0025 (4)−0.0051 (4)0.0002 (4)
C10.0193 (5)0.0197 (5)0.0177 (5)0.0001 (4)0.0020 (4)−0.0015 (4)
C20.0244 (5)0.0197 (6)0.0190 (6)−0.0007 (4)0.0012 (4)0.0000 (4)
C30.0227 (5)0.0201 (5)0.0187 (5)−0.0006 (4)−0.0026 (4)−0.0005 (4)
C40.0205 (5)0.0185 (5)0.0184 (5)−0.0011 (4)0.0005 (4)−0.0012 (4)
C50.0280 (6)0.0252 (6)0.0245 (6)−0.0031 (5)−0.0051 (5)−0.0013 (5)
C60.0295 (6)0.0215 (6)0.0270 (7)−0.0065 (5)0.0022 (5)−0.0046 (5)
C70.0279 (6)0.0176 (5)0.0272 (6)−0.0009 (5)0.0069 (5)0.0009 (5)
C80.0239 (5)0.0209 (5)0.0231 (6)0.0005 (4)0.0005 (5)0.0008 (5)
C90.0193 (5)0.0194 (5)0.0174 (6)−0.0005 (4)0.0020 (4)−0.0013 (4)
C100.0273 (7)0.0278 (7)0.0351 (8)0.0024 (6)−0.0106 (6)−0.0001 (6)
C110.0407 (8)0.0257 (6)0.0214 (6)−0.0004 (6)−0.0089 (6)0.0032 (5)
C120.0302 (7)0.0331 (7)0.0259 (7)−0.0057 (6)−0.0092 (6)−0.0028 (5)
C130.0256 (6)0.0330 (7)0.0281 (7)−0.0072 (5)−0.0040 (5)−0.0051 (6)
C140.0321 (6)0.0200 (6)0.0282 (6)−0.0051 (5)−0.0052 (5)−0.0039 (5)
Geometric parameters (Å, º) top
Cl1—C71.7376 (14)C6—H60.9500
O1—C21.2292 (16)C7—C81.3748 (19)
N1—C21.3733 (17)C8—C91.4063 (17)
N1—C11.4113 (16)C8—H80.9500
N1—C141.4769 (16)C10—C111.486 (2)
N2—C11.2740 (17)C10—H10A0.9900
N2—C121.4599 (17)C10—H10B0.9900
C1—C91.4822 (17)C11—H11A0.9900
C2—C31.4902 (18)C11—H11B0.9900
C3—C41.4859 (17)C12—C131.514 (2)
C3—C111.5284 (19)C12—H12A0.9900
C3—C101.5299 (19)C12—H12B0.9900
C4—C91.3913 (17)C13—C141.512 (2)
C4—C51.4015 (18)C13—H13A0.9900
C5—C61.3859 (19)C13—H13B0.9900
C5—H50.9500C14—H14A0.9900
C6—C71.390 (2)C14—H14B0.9900
C2—N1—C1124.71 (10)C4—C9—C1121.81 (11)
C2—N1—C14116.28 (10)C8—C9—C1118.10 (11)
C1—N1—C14118.59 (11)C11—C10—C360.87 (9)
C1—N2—C12119.73 (12)C11—C10—H10A117.7
N2—C1—N1124.92 (12)C3—C10—H10A117.7
N2—C1—C9118.32 (12)C11—C10—H10B117.7
N1—C1—C9116.76 (11)C3—C10—H10B117.7
O1—C2—N1120.24 (12)H10A—C10—H10B114.8
O1—C2—C3121.39 (12)C10—C11—C360.97 (9)
N1—C2—C3118.37 (11)C10—C11—H11A117.7
C4—C3—C2118.58 (11)C3—C11—H11A117.7
C4—C3—C11119.30 (11)C10—C11—H11B117.7
C2—C3—C11114.01 (11)C3—C11—H11B117.7
C4—C3—C10118.68 (11)H11A—C11—H11B114.8
C2—C3—C10113.99 (11)N2—C12—C13112.88 (12)
C11—C3—C1058.16 (9)N2—C12—H12A109.0
C9—C4—C5119.05 (11)C13—C12—H12A109.0
C9—C4—C3119.00 (11)N2—C12—H12B109.0
C5—C4—C3121.94 (11)C13—C12—H12B109.0
C6—C5—C4121.16 (12)H12A—C12—H12B107.8
C6—C5—H5119.4C14—C13—C12109.24 (11)
C4—C5—H5119.4C14—C13—H13A109.8
C5—C6—C7118.68 (12)C12—C13—H13A109.8
C5—C6—H6120.7C14—C13—H13B109.8
C7—C6—H6120.7C12—C13—H13B109.8
C8—C7—C6121.64 (12)H13A—C13—H13B108.3
C8—C7—Cl1118.96 (11)N1—C14—C13110.31 (11)
C6—C7—Cl1119.40 (10)N1—C14—H14A109.6
C7—C8—C9119.38 (12)C13—C14—H14A109.6
C7—C8—H8120.3N1—C14—H14B109.6
C9—C8—H8120.3C13—C14—H14B109.6
C4—C9—C8120.09 (11)H14A—C14—H14B108.1
C12—N2—C1—N13.66 (19)C4—C5—C6—C7−0.4 (2)
C12—N2—C1—C9−176.29 (11)C5—C6—C7—C80.0 (2)
C2—N1—C1—N2169.27 (13)C5—C6—C7—Cl1179.55 (11)
C14—N1—C1—N2−2.93 (19)C6—C7—C8—C90.1 (2)
C2—N1—C1—C9−10.78 (18)Cl1—C7—C8—C9−179.46 (10)
C14—N1—C1—C9177.02 (11)C5—C4—C9—C8−0.63 (18)
C1—N1—C2—O1−173.21 (13)C3—C4—C9—C8−179.79 (11)
C14—N1—C2—O1−0.84 (19)C5—C4—C9—C1179.82 (11)
C1—N1—C2—C37.29 (19)C3—C4—C9—C10.66 (17)
C14—N1—C2—C3179.66 (12)C7—C8—C9—C40.24 (18)
O1—C2—C3—C4−178.91 (12)C7—C8—C9—C1179.81 (11)
N1—C2—C3—C40.58 (18)N2—C1—C9—C4−173.56 (12)
O1—C2—C3—C11−30.41 (18)N1—C1—C9—C46.49 (17)
N1—C2—C3—C11149.08 (13)N2—C1—C9—C86.88 (17)
O1—C2—C3—C1033.87 (19)N1—C1—C9—C8−173.07 (11)
N1—C2—C3—C10−146.63 (13)C4—C3—C10—C11108.47 (14)
C2—C3—C4—C9−4.26 (17)C2—C3—C10—C11−104.35 (13)
C11—C3—C4—C9−151.08 (12)C4—C3—C11—C10−107.42 (14)
C10—C3—C4—C9141.41 (12)C2—C3—C11—C10104.32 (13)
C2—C3—C4—C5176.60 (12)C1—N2—C12—C1325.27 (18)
C11—C3—C4—C529.78 (18)N2—C12—C13—C14−52.69 (16)
C10—C3—C4—C5−37.73 (18)C2—N1—C14—C13160.89 (12)
C9—C4—C5—C60.73 (19)C1—N1—C14—C13−26.25 (17)
C3—C4—C5—C6179.87 (13)C12—C13—C14—N151.96 (16)
Hydrogen-bond geometry (Å, º) top
Cg1 is the centroid of the C1/N1/C2–C4/C9 ring.
D—H···AD—HH···AD···AD—H···A
C12—H12B···Cg1i0.992.723.6000 (15)148
Symmetry code: (i) −x+1/2, y, z−1/2.
Hydrogen-bond geometry (Å, º) top
Cg1 is the centroid of the C1/N1/C2–C4/C9 ring.
D—H···AD—HH···AD···AD—H···A
C12—H12B···Cg1i0.992.723.6000 (15)148
Symmetry code: (i) −x+1/2, y, z−1/2.
references
References top

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Flack, H. D. (1983). Acta Cryst. A39, 876–881.

Higashi, T. (1999). NUMABS. Rigaku Corporation, Tokyo, Japan.

Okuda, K., Takechi, H., Hirota, T. & Sasaki, K. (2011). Heterocycles, 83, 1315–1328.

Okuda, K., Yoshida, M., Hirota, T. & Sasaki, K. (2010). Chem. Pharm. Bull. 58, 363–368.

Okuda, K., Yoshida, M., Hirota, T. & Sasaki, K. (2012). Synth. Commun. 42, 865–871.

Rigaku/MSC (2004). PROCESS-AUTO and CrystalStructure. Rigaku/MSC Inc., The Woodlands, Texas, USA.

Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.

Spek, A. L. (2009). Acta Cryst. D65, 148–155.