5,8-Di­methoxy-3-methyl­isochroman

The crystal structure of the title compound, C₁₂H₁₆O₃, an analogue of the naturally occurring 1,3-di­methyl­isochromans or the related naphtho­[2,3-c]­pyrans, confirms that the C-3 methyl substituent adopts an equatorial position in the solid state.

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.003 Å
• R factor = 0.056
• wR factor = 0.179
• Data-to-parameter ratio = 15.9

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry

---

S1. Comment

The synthesis of substituted 1,3-dimethylisochromans or the related naphtho[2,3-c]pyrans is important as a result of the biological activities of both these classes of compounds (Thomson, 1987). For example, the recently isolated bioxanthracenes, such as compound (1), show promising antimalarial activity (Isaka et al., 2001). A large number of these types of compounds have been synthesized by several research groups but only a few X-ray crystallographic studies have been carried out (Cook et al., 2002; Zhang et al., 1997; Giles et al., 1988; Zhengxiong et al., 1986; Egert et al., 1983; Cooke et al., 1980; Cameron et al., 1977). From these X-ray crystallographic studies, it is clear that the C-1 methyl group of the fused pyran ring adopts a pseudo-axial position, while the C-3 methyl substituent adopts an equatorial position.

As part of our ongoing research programme on the syntheses of substituted isochromans, we needed to synthesize compounds lacking the C-1 methyl substituent. The synthesis of 3-methylisochromane, (2), was therefore pursued. This was achieved by reacting the benzylic alcohol (3) with potassium t-butoxide in DMF, as previously described (Green et al., 1995), or by the reduction of the corresponding isochromene (4), as detailed in the Experimental and shown in the Scheme. A single-crystal X-ray structure determination on the product, (2), confirmed that the heterocyclic ring adopts a half-chair conformation, with the C-3 methyl substituent in an equatorial position (Figs. 1 and 2).

S2. Experimental

10% Pd/C (24 mg) and 1 drop of concentrated hydrochloric acid were added to ethyl acetate (6.3 ml) in a two-necked 50 ml flask. The system was purged for 15 min by exposing the suspension to hydrogen gas before isochromene (4) (99.8 mg) was introduced. The reaction mixture was then stirred under a hydrogen gas pressure of 2.5 atm for 24 h. The reaction mixture was filtered through a silica gel plug, followed by removal of solvent in vacuo. The crude material was purified by silica-gel column chromatography (20% ethyl acetate/hexane) to afford (±)-5,8-dimethoxy-3-methylisochromane, (2) (90.7 mg), in 90% yield. The compound was recrystallized from CH₂Cl₂ by slow evaporation, to afford colourless block-like crystals [m.p. 346–347 K, literature 347–348 K (Green et al., 1995)].

S3. Refinement

H atoms were positioned geometrically and allowed to ride on their respective parent atoms, with U_iso(H) = 1.2U_eq(C) [1.5U_eq(C) for methyl groups].

Computing details

Data collection: SMART-NT (Bruker, 1998); cell refinement: SAINT (Bruker, 1999); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Bruker, 1999); program(s) used to refine structure: SHELXTL; molecular graphics: PLATON (Spek, 1990); software used to prepare material for publication: SHELXTL.

Figures

	Fig. 1. A view of (2) with the atomic numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 2. A side view of (2), showing the equatorial C-3 methyl group.

5,8-Dimethoxy-3-methyl-1H-isochroman

Crystal data

C12H16O3	F(000) = 448
Mr = 208.25	Dx = 1.220 Mg m^−3
Monoclinic, P21/c	Melting point = 346–347 K
Hall symbol: -P 2ybc	Mo Kα radiation, λ = 0.71073 Å
a = 13.2543 (15) Å	Cell parameters from 701 reflections
b = 5.9923 (7) Å	θ = 3.1–23.2°
c = 14.5744 (17) Å	µ = 0.09 mm^−1
β = 101.633 (2)°	T = 293 K
V = 1133.8 (2) Å^3	Block, colourless
Z = 4	0.30 × 0.26 × 0.17 mm

Data collection

Bruker SMART CCD area-detector diffractometer	2219 independent reflections
Radiation source: fine-focus sealed tube	1431 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.049
ϕ and ω scans	θmax = 26.0°, θmin = 1.6°
Absorption correction: multi-scan (SADABS; Bruker, 1999)	h = −16→16
Tmin = 0.975, Tmax = 0.985	k = −7→7
6472 measured reflections	l = −17→15

Refinement

Refinement on F^2	H-atom parameters constrained
Least-squares matrix: full	w = 1/[σ^2(Fo^2) + (0.1085P)^2] where P = (Fo^2 + 2Fc^2)/3
R[F^2 > 2σ(F^2)] = 0.056	(Δ/σ)max = 0.001
wR(F^2) = 0.179	Δρmax = 0.17 e Å^−3
S = 1.03	Δρmin = −0.21 e Å^−3
2219 reflections	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
140 parameters	Extinction coefficient: 0.028 (7)
0 restraints

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
O9	0.50285 (10)	0.2117 (2)	0.89740 (10)	0.0679 (5)
O2	0.73492 (9)	0.6133 (2)	1.03766 (9)	0.0624 (4)
C4A	0.76055 (13)	0.3825 (3)	0.87837 (13)	0.0536 (5)
C8A	0.66753 (13)	0.3635 (3)	0.90751 (12)	0.0509 (5)
C8	0.59316 (13)	0.2098 (3)	0.86396 (13)	0.0539 (5)
O11	0.87556 (11)	0.2677 (3)	0.78487 (11)	0.0810 (5)
C5	0.78005 (15)	0.2404 (3)	0.80701 (14)	0.0593 (5)
C7	0.61220 (14)	0.0759 (3)	0.79265 (14)	0.0589 (5)
H7	0.5625	−0.0250	0.7637	0.071*
C1	0.64551 (13)	0.5085 (4)	0.98574 (13)	0.0591 (5)
H1A	0.5960	0.6223	0.9595	0.071*
H1B	0.6146	0.4177	1.0278	0.071*
C4	0.83867 (14)	0.5537 (4)	0.92275 (14)	0.0635 (6)
H4A	0.8664	0.6285	0.8742	0.076*
H4B	0.8951	0.4791	0.9641	0.076*
C6	0.70626 (14)	0.0916 (3)	0.76381 (14)	0.0611 (6)
H6	0.7191	0.0016	0.7154	0.073*
C3	0.79179 (15)	0.7250 (3)	0.97790 (15)	0.0615 (6)
H3	0.7443	0.8186	0.9339	0.074*
C10	0.42779 (15)	0.0477 (4)	0.86299 (17)	0.0736 (7)
H10A	0.4048	0.0664	0.7966	0.110*
H10B	0.3703	0.0637	0.8934	0.110*
H10C	0.4573	−0.0981	0.8756	0.110*
C13	0.87016 (18)	0.8737 (4)	1.03799 (19)	0.0865 (7)
H13A	0.8361	0.9707	1.0745	0.130*
H13B	0.9048	0.9615	0.9987	0.130*
H13C	0.9196	0.7835	1.0791	0.130*
C12	0.90347 (19)	0.1157 (5)	0.7204 (2)	0.0936 (8)
H12A	0.8996	−0.0338	0.7431	0.140*
H12B	0.9726	0.1462	0.7133	0.140*
H12C	0.8572	0.1313	0.6609	0.140*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O9	0.0473 (7)	0.0815 (10)	0.0778 (10)	−0.0147 (6)	0.0191 (7)	−0.0171 (7)
O2	0.0530 (8)	0.0737 (9)	0.0608 (8)	−0.0128 (6)	0.0124 (7)	−0.0086 (6)
C4A	0.0422 (9)	0.0647 (11)	0.0537 (10)	0.0021 (8)	0.0089 (8)	0.0040 (9)
C8A	0.0429 (9)	0.0589 (10)	0.0498 (9)	0.0010 (8)	0.0067 (8)	0.0052 (9)
C8	0.0412 (9)	0.0627 (11)	0.0573 (10)	0.0008 (8)	0.0090 (8)	0.0028 (9)
O11	0.0545 (9)	0.1081 (13)	0.0876 (10)	−0.0065 (8)	0.0316 (8)	−0.0250 (9)
C5	0.0446 (10)	0.0742 (13)	0.0604 (11)	0.0048 (9)	0.0133 (9)	−0.0002 (10)
C7	0.0492 (10)	0.0625 (12)	0.0622 (11)	−0.0005 (9)	0.0047 (9)	−0.0037 (10)
C1	0.0461 (10)	0.0710 (12)	0.0621 (11)	−0.0078 (9)	0.0153 (9)	−0.0068 (10)
C4	0.0460 (10)	0.0787 (14)	0.0676 (12)	−0.0084 (9)	0.0154 (10)	−0.0014 (11)
C6	0.0559 (11)	0.0693 (13)	0.0577 (11)	0.0080 (9)	0.0102 (9)	−0.0064 (9)
C3	0.0489 (10)	0.0644 (12)	0.0712 (12)	−0.0069 (9)	0.0117 (10)	0.0035 (10)
C10	0.0515 (11)	0.0740 (14)	0.0980 (16)	−0.0162 (10)	0.0215 (11)	−0.0105 (12)
C13	0.0726 (14)	0.0857 (16)	0.1034 (18)	−0.0254 (12)	0.0231 (14)	−0.0207 (14)
C12	0.0727 (15)	0.111 (2)	0.1086 (18)	0.0032 (14)	0.0459 (14)	−0.0255 (16)

Geometric parameters (Å, º)

O9—C8	1.380 (2)	C1—H1B	0.970
O9—C10	1.416 (2)	C4—C3	1.513 (3)
O2—C1	1.418 (2)	C4—H4A	0.970
O2—C3	1.428 (2)	C4—H4B	0.970
C4A—C8A	1.387 (2)	C6—H6	0.930
C4A—C5	1.408 (3)	C3—C13	1.508 (3)
C4A—C4	1.507 (3)	C3—H3	0.980
C8A—C8	1.404 (3)	C10—H10A	0.960
C8A—C1	1.508 (3)	C10—H10B	0.960
C8—C7	1.376 (3)	C10—H10C	0.960
O11—C5	1.378 (2)	C13—H13A	0.960
O11—C12	1.411 (3)	C13—H13B	0.960
C5—C6	1.379 (3)	C13—H13C	0.960
C7—C6	1.397 (3)	C12—H12A	0.960
C7—H7	0.930	C12—H12B	0.960
C1—H1A	0.970	C12—H12C	0.960
C8—O9—C10	117.80 (15)	H4A—C4—H4B	107.9
C1—O2—C3	111.68 (14)	C5—C6—C7	120.01 (18)
C8A—C4A—C5	118.89 (17)	C5—C6—H6	120.0
C8A—C4A—C4	120.05 (16)	C7—C6—H6	120.0
C5—C4A—C4	121.06 (16)	O2—C3—C13	108.02 (18)
C4A—C8A—C8	120.14 (17)	O2—C3—C4	109.25 (15)
C4A—C8A—C1	120.22 (16)	C13—C3—C4	113.64 (17)
C8—C8A—C1	119.64 (15)	O2—C3—H3	108.6
O9—C8—C7	125.14 (16)	C13—C3—H3	108.6
O9—C8—C8A	114.51 (16)	C4—C3—H3	108.6
C7—C8—C8A	120.33 (17)	O9—C10—H10A	109.5
C5—O11—C12	117.13 (17)	O9—C10—H10B	109.5
O11—C5—C6	124.80 (18)	H10A—C10—H10B	109.5
O11—C5—C4A	114.55 (17)	O9—C10—H10C	109.5
C6—C5—C4A	120.65 (17)	H10A—C10—H10C	109.5
C8—C7—C6	119.93 (18)	H10B—C10—H10C	109.5
C8—C7—H7	120.0	C3—C13—H13A	109.5
C6—C7—H7	120.0	C3—C13—H13B	109.5
O2—C1—C8A	112.98 (14)	H13A—C13—H13B	109.5
O2—C1—H1A	109.0	C3—C13—H13C	109.5
C8A—C1—H1A	109.0	H13A—C13—H13C	109.5
O2—C1—H1B	109.0	H13B—C13—H13C	109.5
C8A—C1—H1B	109.0	O11—C12—H12A	109.5
H1A—C1—H1B	107.8	O11—C12—H12B	109.5
C4A—C4—C3	111.69 (15)	H12A—C12—H12B	109.5
C4A—C4—H4A	109.3	O11—C12—H12C	109.5
C3—C4—H4A	109.3	H12A—C12—H12C	109.5
C4A—C4—H4B	109.3	H12B—C12—H12C	109.5
C3—C4—H4B	109.3
C5—C4A—C8A—C8	−2.1 (3)	C4—C4A—C5—C6	−176.95 (17)
C4—C4A—C8A—C8	177.68 (16)	O9—C8—C7—C6	178.96 (17)
C5—C4A—C8A—C1	178.19 (17)	C8A—C8—C7—C6	0.5 (3)
C4—C4A—C8A—C1	−2.0 (3)	C3—O2—C1—C8A	50.7 (2)
C10—O9—C8—C7	7.0 (3)	C4A—C8A—C1—O2	−15.0 (3)
C10—O9—C8—C8A	−174.38 (16)	C8—C8A—C1—O2	165.36 (16)
C4A—C8A—C8—O9	−178.14 (16)	C8A—C4A—C4—C3	−14.8 (2)
C1—C8A—C8—O9	1.5 (2)	C5—C4A—C4—C3	164.98 (17)
C4A—C8A—C8—C7	0.5 (3)	O11—C5—C6—C7	179.27 (19)
C1—C8A—C8—C7	−179.82 (18)	C4A—C5—C6—C7	−1.9 (3)
C12—O11—C5—C6	−7.1 (3)	C8—C7—C6—C5	0.3 (3)
C12—O11—C5—C4A	174.0 (2)	C1—O2—C3—C13	167.14 (17)
C8A—C4A—C5—O11	−178.22 (16)	C1—O2—C3—C4	−68.79 (19)
C4—C4A—C5—O11	2.0 (3)	C4A—C4—C3—O2	48.6 (2)
C8A—C4A—C5—C6	2.9 (3)	C4A—C4—C3—C13	169.26 (19)