7,8,9,10-Tetra­hydro-2-methyl­cyclo­hepta­[b]indol-6(5H)-one

Makuteswaran Sridharan; Karnam J Rajendra Prasad; Aimable Ngendahimana; Matthias Zeller

doi:10.1107/S1600536808016498

. 2008 Jun 7;64(Pt 7):o1207. doi: 10.1107/S1600536808016498

7,8,9,10-Tetrahydro-2-methylcyclohepta[b]indol-6(5H)-one

Makuteswaran Sridharan ^a, Karnam J Rajendra Prasad ^a, Aimable Ngendahimana ^b, Matthias Zeller ^b,^*

PMCID: PMC2961774 PMID: 21202846

Abstract

The title compound, C₁₄H₁₅NO, was synthesized from 2-hydroxymethylenecycloheptanone via a Japp–Klingemann acid-catalyzed cyclization. The seven-membered ring exhibits a slightly distorted envelope conformation. N—H⋯O hydrogen bonds form a centrosymmetric dimer; C—H⋯O hydrogen bonds and π–π stacking interactions (the centers of the atoms involved in the stacking interaction are separated by 3.504 Å) give rise to another type of centrosymmetric dimer. In combination, these interactions create a stair-like chain of molecules that interacts only loosely with neighboring chains via van der Waals interactions and weak C—H⋯π contacts.

Related literature

For related literature on the synthesis, structure, anticancer and antidepressant activities, and toxicity of functionalized cyclohept[b]indoles, see: Cornec et al. (1998 ▶); Joseph et al. (1999 ▶); Kinnick et al. (2006 ▶); Humphrey & Kuethe (2006 ▶, and references therein); Benoit et al. (2000 ▶); Kavitha & Rajendra Prasad (1999 ▶, and references therein). Brameld et al. (2008 ▶) describe small-molecule conformational preferences derived from crystal structure data. Bernstein et al. (1995 ▶) present the use of the versatile graph-set analysis for the description of hydrogen bonds.

Experimental

Crystal data

C₁₄H₁₅NO
M _r = 213.27
Monoclinic,
a = 11.461 (3) Å
b = 6.5062 (19) Å
c = 14.459 (4) Å
β = 92.310 (4)°
V = 1077.3 (6) Å³
Z = 4
Mo Kα radiation
μ = 0.08 mm⁻¹
T = 100 (2) K
0.48 × 0.10 × 0.08 mm

Data collection

Bruker SMART APEX CCD diffractometer
Absorption correction: multi-scan (SADABS as implemented in APEX2; Bruker, 2008 ▶) T _min = 0.731, T _max = 0.993
9984 measured reflections
2652 independent reflections
1581 reflections with I > 2σ(I)
R _int = 0.081

Refinement

R[F ² > 2σ(F ²)] = 0.056
wR(F ²) = 0.135
S = 1.00
2652 reflections
146 parameters
H-atom parameters constrained
Δρ_max = 0.19 e Å⁻³
Δρ_min = −0.28 e Å⁻³

Data collection: APEX2 (Bruker, 2008 ▶); cell refinement: APEX2; data reduction: APEX2; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL and Mercury (Macrae et al., 2006 ▶); software used to prepare material for publication: SHELXTL and Mercury.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536808016498/fl2202sup1.cif

e-64-o1207-sup1.cif^{(17.4KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808016498/fl2202Isup2.hkl

e-64-o1207-Isup2.hkl^{(130.3KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯O1ⁱ	0.88	2.09	2.890 (2)	150
C4—H4a⋯O1ⁱⁱ	0.99	2.59	3.211 (3)	121
C2—H2B⋯Cg1ⁱⁱⁱ	0.99	2.88	3.740 (2)	146
C5—H5b⋯C10^iv	0.99	2.90	3.794 (2)	151

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) . Cg1 is the centroid of the C8–C13 ring.

Acknowledgments

We acknowledge UGC, New Delhi, India, for the award of Major Research Project grant No. F. 31–122/2005. MS thanks UGC, New Delhi, for the award of a research fellowship. The diffractometer was funded by NSF grant 0087210, by Ohio Board of Regents grant CAP-491, and by YSU.

supplementary crystallographic information

Comment

Development of new methods towards the synthesis of functionalized cyclohept[b]indoles is currently attractive to organic chemists due to the discovery of anti-cancer and anti-depressant activities associated with this system (Cornec et al., 1998; Joseph et al. 1999). Synthetic studies on the large family of indoles have been documented extensively because of their structural diversity and association with their wide spectrum of pharmacological potential. Synthetic approaches to prepare cyclohept[b]indoles have been described in the literature and examined for central nervous system activity and reported to be active as antidepressants (Kinnick et al., 2006; Humphrey & Kuethe, 2006, and references therein). The design of molecules that spontaneously organize into a helical architecture is of considerable interest because of their fascinating structural features as well as their potential applications. Benoit et al. (2000) have reported the toxicity and structure activity relationship of benzocyclohept[b]indoles and these were found to be potent anti-inflammatory and anti-cancer agents. Therefore, much effort has been directed towards the development of efficient methodologies for the construction of heterocyclo-fused cyclohept[b]indoles. Based on the interesting features of these compounds we reported the synthesis and utility of cyclohept[b]indoles and their substituted analogs (Kavitha & Rajendra Prasad 1999, and references therein).

Cyclization of 2-hydroxymethylenecycloheptanone under Japp-Klingemann conditions using acetic acid and HCl in a 4:1 ratio (Kent's reagent) as the catalyst furnished the title compound (Fig. 1). Details of the synthesis of the title compound were reported by Kavitha & Rajendra Prasad (1999). An ORTEP style representation of the title compound is given in Fig 2.

The sp² hybridized section of the molecule is essentially planar with an r.m.s. deviation from the mean plane of only 0.052 Å. Of the methylene carbon atoms C3 is deviates the most (0.786 (3) Å ) from this plane. Deviations for C2 and C4 are 0.252 (2) and -0.157 (3) Å, respectively. The seven membered ring thus is best described as having a slightly distorted envelope conformation (Brameld et al. 2008). All bond distances and angles in the structure of the title compound are in the expected ranges.

Via a pair of N—H···O hydrogen bonds the molecules form centrosymmetric dimers with an R²₂(10) graph set motif (Bernstein et al., 1995) in the solid state (Table 1, Fig. 3). The keto oxygen atom also acts as acceptor for a weaker C—H···O hydrogen bond from another neighboring molecule. The same neighboring molecule also acts as a partner for a π-π stacking interaction across an inversion center. The π moieties of these thus formed π-stacked dimers are slipped against each other and only the atoms C1, C6, C7 and C13 and their inversion symmetry related counterparts in the neighboring molecule are involved in the interaction of the π systems with a distance of about 3.5 Å between the planes (Fig. 3). Distances between the slipped centroids of the pyrrole rings are given in table 1. The main planes of the molecules are connected via the N—H···O and C—H···O hydrogen bonds and the π-π stacking interactions are all aligned roughly in parallel to each other. The two types of dimers created by the N—H···O and C—H···O interactions do each share one molecule, which extends the molecules held together via these strong to medium interactions into a flight of stairs like chain of molecules. Neighboring chains are only loosly connected via van der Waals interactions and weak C—H···π contacts (Table 1, Fig. 4).

Experimental

A solution of 2-(2-(4-methylphenyl)hydrazono)cycloheptanone (0.230 g, 0.001 mol) in a mixture of acetic acid (20 ml) and concentrated hydrochloric acid (5 ml) was heated to reflux on an oil bath pre-heated to 398–403 K for 2 h. The reaction was monitored by TLC. After completion of the reaction the contents were cooled and poured into icewater with stirring. The separated brown solid was filtered and purified by passing through a column of silica gel and eluting with a petroleum ether-ethyl acetate mixture (95:5) to yieldthe title compound (171 mg, 80%). The product thus obtained was recrystallized using ethanol, m.p. 451–453 K.