(1R,3S)-Methyl 6,7-dimeth­oxy-1-(4-meth­oxy­phen­yl)-1,2,3,4-tetra­hydro­isoquinoline-3-carboxyl­ate

The title compound, C₂₀H₂₃NO₅, is the third in a series of tetra­hydoisoquinoline (TIQ) compounds that are precursors to novel chiral catalysts. The N-containing six-membered ring assumes a half-boat conformation. No hydrogen bonding is observed in the crystal structure.

Key indicators

• Single-crystal X-ray study
• T = 173 K
• Mean [sigma](C-C) = 0.002 Å
• R factor = 0.036
• wR factor = 0.090
• Data-to-parameter ratio = 12.0

checkCIF/PLATON results

No syntax errors found



Alert level A
DIFF019_ALERT_1_A  _diffrn_standards_number is missing
            Number of standards used in measurement.
DIFF020_ALERT_1_A  _diffrn_standards_interval_count and
            _diffrn_standards_interval_time are missing. Number of measurements
            between standards or time (min) between standards.

Alert level C
PLAT910_ALERT_3_C Missing # of FCF Reflections Below Th(Min) .....          2

Alert level G
REFLT03_ALERT_4_G Please check that the estimate of the number of Friedel pairs is
            correct. If it is not, please give the correct count in the
            _publ_section_exptl_refinement section of the submitted CIF.
           From the CIF: _diffrn_reflns_theta_max           29.57
           From the CIF: _reflns_number_total               2878
           Count of symmetry unique reflns         2880
           Completeness (_total/calc)             99.93%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured         0
           Fraction of Friedel pairs measured     0.000
           Are heavy atom types Z>Si present         no
PLAT720_ALERT_4_G Number of Unusual/Non-Standard Labels ..........         30
PLAT791_ALERT_4_G Note: The Model has Chirality at C7     (Verify)          S
PLAT791_ALERT_4_G Note: The Model has Chirality at C9     (Verify)          R
PLAT981_ALERT_1_G No non-zero f" Anomalous Scattering Values Found          ?

   2 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   1 ALERT level C = Check and explain
   5 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
   1 ALERT type 3 Indicator that the structure quality may be low
   4 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

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S1. Comment

The title compound was derived from commercially available L-DOPA and anisaldehyde. Diastereomers formed during the first step of the synthesis were separated to yield subsequent derivatives and the title compound with the stereochemistry as illustrated in Fig. 1. The title compound is the third report in a series of molecules containing a tetrahydroisoquinoline backbone and is a precursor to one of the molecules that we previously reported ((1R,3S)-methyl 2-benzyl-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate), (Naicker et al., 2009). The molecule has been reported previously and the absolute stereochemistry of the diastereomer was confirmed to be R,S at C4 and C2 positions respectively by proton NMR (Aubry et al., 2006).

There are a number of common features found in this structure and that of the the unprotected secondary amine system. First, the N-containing six membered ring assumes a half boat conformation. This differs from last report for the (1R,3S)-2-benzyl-6,7-dimethoxy-1-phenyl-1,2,3,4 tetrahydroisoquinolin-3-yl diphenylmethanol structure (Naicker et al., 2010) and previous reports by Alberach et al. (2004) and Aubry et al. (2006) where the heteroatomic ring adopted a half chair conformation. Second, given the presence of the secondary amine, ether and in this example ester functional groups, no hydrogen bonding is observed in any of the structures of this series, (see Fig. 2).

Related literature

For related crystallographic structures, see: Naicker et al. (2009, 2010); Alberach et al. (2004). For synthesis of the title compound, see: Aubry et al. (2006).

S2. Experimental

A solution of the Cbz protected trans-6,7-dimethoxy-1-(4-methoxyphenyl)-TIQ methyl ester (1.0 g, 0.21 mmol) in THF (20 ml) was added to a suspension of activated 10 wt% Pd/C (500 mg) in dry MeOH (20 ml). The mixture was connected to a hydrogen source at one atmosphere and stirred at room temperature for 1 h. Completion of the reaction was monitored through TLC in hexane/ethyl acetate (50/50, R_f = 0.6). The Pd/C was filtered through a Celite pad and washed with methanol (20 ml). The filtrate was evaporated under reduced pressure affording the crude amino ester, which was purified by column chromatography using ethyl acetate/hexane (50:50) as the eluent to yield pure title compound (0.70 g, 93%) as a yellow solid. m.p. = 392–393 K. Crystals suitable for X-ray diffraction were obtained by slow evaporation of the title compound in MeOH at room temperature.

¹H NMR (600 MHz, CdCl₃, d, p.p.m.): 1.58 (broad s, 1H), 2.99 (dd, 1H), 3.09 (dd, 1H), 3.60 (s, 3H), 3.66 (s, 3H) 3.67(s, 3H), 3.78 (m, 1H), 3.88 (s, 3H), 5.23 (s, 1H), 6.30(s, 1H), 6.61 (s, 1H), 6.82 (d, 2H), 7.09 (d, 2H).

IR: 2946 (w), 1700 (w), 1507 (s), 1223 (vs), 832 (s), 563 (w)

S3. Refinement

All H atoms, except H1N, were positioned geometrically with C—H distances ranging from 0.95 Å to 1.00 Å and refined as riding on their parent atoms, with U_iso (H) = 1.2–1.5U_eq (C).

Computing details

Data collection: APEX2 (Bruker, 2006); cell refinement: SAINT (Bruker, 2006); data reduction: SAINT (Bruker, 2006); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Figures

	Fig. 1. The title compound (all H atoms omitted for clarity). All non-H atoms are shown as ellipsoids with probability level of 50%.
	Fig. 2. Projection viewed along [010].

(1R,3S)-Methyl 6,7-dimethoxy-1-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate

Crystal data

C20H23NO5	F(000) = 760
Mr = 357.39	Dx = 1.344 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 13619 reflections
a = 5.3719 (7) Å	θ = 2.3–29.6°
b = 12.1726 (14) Å	µ = 0.10 mm^−1
c = 27.021 (3) Å	T = 173 K
V = 1766.9 (4) Å^3	Needle, colourless
Z = 4	0.20 × 0.12 × 0.12 mm

Data collection

Bruker Kappa DUO APEXII diffractometer	2538 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.032
Graphite monochromator	θmax = 29.6°, θmin = 2.3°
0.5° φ scans and ω scans	h = −7→7
13619 measured reflections	k = −16→16
2878 independent reflections	l = −26→37

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.036	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.090	H atoms treated by a mixture of independent and constrained refinement
S = 1.04	w = 1/[σ^2(Fo^2) + (0.0435P)^2 + 0.3587P] where P = (Fo^2 + 2Fc^2)/3
2878 reflections	(Δ/σ)max = 0.001
239 parameters	Δρmax = 0.26 e Å^−3
1 restraint	Δρmin = −0.18 e Å^−3

Special details

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds 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
O1	0.6521 (3)	0.82927 (10)	0.91879 (5)	0.0334 (3)
O2	0.3315 (3)	0.91415 (10)	0.85890 (5)	0.0351 (3)
O3	0.3734 (3)	0.44954 (13)	0.76583 (6)	0.0498 (4)
O4	0.2473 (3)	0.28121 (11)	0.78678 (5)	0.0378 (3)
O5	0.4011 (3)	0.34146 (11)	1.09674 (5)	0.0307 (3)
N1	0.0808 (3)	0.40422 (12)	0.87542 (5)	0.0253 (3)
H1N	0.078 (4)	0.3258 (5)	0.8806 (7)	0.031 (5)*
C1	0.3147 (3)	0.45361 (13)	0.89317 (6)	0.0224 (3)
H1	0.4574	0.4190	0.8752	0.027*
C2	0.3126 (3)	0.57639 (13)	0.88213 (6)	0.0211 (3)
C3	0.4841 (3)	0.64470 (14)	0.90671 (6)	0.0229 (3)
H3	0.5967	0.6136	0.9299	0.027*
C4	0.4912 (3)	0.75648 (14)	0.89759 (6)	0.0242 (3)
C5	0.3187 (4)	0.80245 (13)	0.86413 (6)	0.0250 (3)
C6	0.1543 (3)	0.73469 (14)	0.83937 (6)	0.0253 (3)
H6	0.0407	0.7657	0.8164	0.030*
C7	0.1519 (3)	0.62062 (14)	0.84759 (6)	0.0231 (3)
C8	−0.0280 (3)	0.55050 (15)	0.81826 (7)	0.0269 (4)
H8A	−0.0184	0.5713	0.7829	0.032*
H8B	−0.1997	0.5652	0.8298	0.032*
C9	0.0265 (3)	0.42813 (14)	0.82338 (6)	0.0264 (4)
H9	−0.1279	0.3871	0.8141	0.032*
C10	0.2348 (4)	0.39131 (15)	0.78851 (6)	0.0276 (4)
C11	0.4358 (4)	0.23681 (18)	0.75419 (8)	0.0383 (5)
H11A	0.4304	0.1564	0.7553	0.057*
H11B	0.6003	0.2623	0.7649	0.057*
H11C	0.4044	0.2617	0.7203	0.057*
C12	0.3392 (3)	0.42874 (12)	0.94812 (6)	0.0216 (3)
C13	0.5433 (3)	0.37117 (13)	0.96620 (6)	0.0239 (3)
H13	0.6727	0.3501	0.9442	0.029*
C14	0.5606 (3)	0.34403 (14)	1.01604 (7)	0.0256 (3)
H14	0.7007	0.3045	1.0280	0.031*
C15	0.3716 (3)	0.37499 (13)	1.04827 (6)	0.0238 (3)
C16	0.1682 (3)	0.43478 (13)	1.03116 (6)	0.0250 (3)
H16	0.0406	0.4574	1.0533	0.030*
C17	0.1551 (3)	0.46090 (13)	0.98113 (6)	0.0245 (3)
H17	0.0167	0.5017	0.9692	0.029*
C18	0.1949 (4)	0.35863 (18)	1.12932 (7)	0.0399 (5)
H18A	0.2374	0.3319	1.1625	0.060*
H18B	0.0496	0.3185	1.1169	0.060*
H18C	0.1563	0.4372	1.1309	0.060*
C19	0.8323 (4)	0.78695 (16)	0.95244 (7)	0.0317 (4)
H19A	0.9354	0.8473	0.9650	0.047*
H19B	0.9380	0.7334	0.9353	0.047*
H19C	0.7474	0.7510	0.9802	0.047*
C20	0.1569 (4)	0.96322 (17)	0.82600 (8)	0.0419 (5)
H20A	0.1835	1.0429	0.8252	0.063*
H20B	−0.0125	0.9477	0.8375	0.063*
H20C	0.1797	0.9329	0.7927	0.063*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0349 (7)	0.0253 (6)	0.0399 (7)	−0.0042 (6)	−0.0127 (6)	−0.0019 (5)
O2	0.0433 (8)	0.0212 (6)	0.0409 (8)	−0.0014 (6)	−0.0095 (7)	0.0042 (5)
O3	0.0537 (10)	0.0375 (8)	0.0581 (10)	−0.0089 (8)	0.0274 (9)	−0.0036 (7)
O4	0.0463 (8)	0.0301 (7)	0.0370 (7)	−0.0025 (6)	0.0121 (7)	−0.0065 (6)
O5	0.0360 (7)	0.0309 (6)	0.0252 (6)	0.0054 (6)	0.0012 (5)	0.0018 (5)
N1	0.0265 (7)	0.0241 (7)	0.0253 (7)	−0.0065 (6)	0.0018 (6)	−0.0012 (6)
C1	0.0226 (7)	0.0205 (7)	0.0242 (7)	−0.0020 (6)	0.0033 (6)	−0.0014 (6)
C2	0.0214 (7)	0.0201 (7)	0.0218 (7)	−0.0015 (6)	0.0032 (6)	−0.0004 (6)
C3	0.0221 (7)	0.0237 (7)	0.0229 (7)	0.0002 (6)	−0.0005 (6)	0.0009 (6)
C4	0.0246 (8)	0.0236 (7)	0.0246 (8)	−0.0022 (7)	−0.0007 (7)	−0.0023 (6)
C5	0.0292 (8)	0.0207 (7)	0.0252 (8)	−0.0003 (7)	0.0020 (7)	0.0014 (6)
C6	0.0256 (8)	0.0268 (8)	0.0235 (8)	0.0008 (7)	−0.0023 (7)	0.0023 (6)
C7	0.0229 (7)	0.0254 (7)	0.0211 (7)	−0.0019 (7)	0.0015 (7)	−0.0027 (6)
C8	0.0242 (8)	0.0296 (8)	0.0269 (8)	−0.0021 (7)	−0.0041 (7)	−0.0024 (7)
C9	0.0256 (8)	0.0276 (8)	0.0261 (8)	−0.0063 (7)	0.0012 (7)	−0.0034 (7)
C10	0.0302 (9)	0.0302 (9)	0.0223 (8)	−0.0047 (7)	−0.0004 (7)	−0.0057 (7)
C11	0.0400 (11)	0.0407 (11)	0.0342 (10)	0.0036 (9)	0.0033 (9)	−0.0115 (9)
C12	0.0226 (7)	0.0175 (7)	0.0248 (8)	−0.0022 (6)	0.0006 (7)	−0.0006 (6)
C13	0.0198 (7)	0.0214 (7)	0.0304 (8)	0.0000 (6)	0.0042 (7)	−0.0027 (6)
C14	0.0214 (7)	0.0225 (7)	0.0329 (9)	0.0021 (6)	−0.0017 (7)	0.0004 (7)
C15	0.0281 (8)	0.0185 (7)	0.0247 (8)	−0.0027 (6)	−0.0004 (7)	−0.0006 (6)
C16	0.0252 (7)	0.0220 (7)	0.0278 (8)	0.0027 (7)	0.0041 (7)	−0.0028 (6)
C17	0.0235 (7)	0.0211 (7)	0.0289 (8)	0.0036 (7)	0.0012 (7)	0.0006 (6)
C18	0.0469 (12)	0.0432 (11)	0.0296 (9)	0.0033 (10)	0.0082 (9)	0.0042 (8)
C19	0.0302 (9)	0.0348 (9)	0.0300 (9)	−0.0043 (8)	−0.0062 (8)	−0.0030 (7)
C20	0.0488 (12)	0.0272 (9)	0.0498 (12)	0.0069 (10)	−0.0084 (11)	0.0058 (8)

Geometric parameters (Å, º)

O1—C4	1.364 (2)	C8—H8B	0.9900
O1—C19	1.425 (2)	C9—C10	1.530 (3)
O2—C5	1.369 (2)	C9—H9	1.0000
O2—C20	1.424 (2)	C11—H11A	0.9800
O3—C10	1.197 (2)	C11—H11B	0.9800
O4—C10	1.343 (2)	C11—H11C	0.9800
O4—C11	1.446 (2)	C12—C17	1.388 (2)
O5—C15	1.381 (2)	C12—C13	1.390 (2)
O5—C18	1.430 (2)	C13—C14	1.390 (2)
N1—C9	1.465 (2)	C13—H13	0.9500
N1—C1	1.473 (2)	C14—C15	1.390 (2)
N1—H1N	0.965 (5)	C14—H14	0.9500
C1—C12	1.521 (2)	C15—C16	1.392 (2)
C1—C2	1.524 (2)	C16—C17	1.391 (2)
C1—H1	1.0000	C16—H16	0.9500
C2—C7	1.381 (2)	C17—H17	0.9500
C2—C3	1.407 (2)	C18—H18A	0.9800
C3—C4	1.383 (2)	C18—H18B	0.9800
C3—H3	0.9500	C18—H18C	0.9800
C4—C5	1.410 (2)	C19—H19A	0.9800
C5—C6	1.381 (2)	C19—H19B	0.9800
C6—C7	1.406 (2)	C19—H19C	0.9800
C6—H6	0.9500	C20—H20A	0.9800
C7—C8	1.514 (2)	C20—H20B	0.9800
C8—C9	1.524 (3)	C20—H20C	0.9800
C8—H8A	0.9900
C4—O1—C19	117.63 (14)	O3—C10—C9	126.64 (17)
C5—O2—C20	116.62 (16)	O4—C10—C9	110.53 (15)
C10—O4—C11	115.43 (16)	O4—C11—H11A	109.5
C15—O5—C18	116.85 (15)	O4—C11—H11B	109.5
C9—N1—C1	113.65 (13)	H11A—C11—H11B	109.5
C9—N1—H1N	109.5 (12)	O4—C11—H11C	109.5
C1—N1—H1N	111.7 (13)	H11A—C11—H11C	109.5
N1—C1—C12	108.07 (13)	H11B—C11—H11C	109.5
N1—C1—C2	109.28 (14)	C17—C12—C13	118.58 (15)
C12—C1—C2	112.76 (13)	C17—C12—C1	120.63 (15)
N1—C1—H1	108.9	C13—C12—C1	120.77 (15)
C12—C1—H1	108.9	C14—C13—C12	120.87 (16)
C2—C1—H1	108.9	C14—C13—H13	119.6
C7—C2—C3	119.86 (15)	C12—C13—H13	119.6
C7—C2—C1	121.29 (15)	C15—C14—C13	119.62 (16)
C3—C2—C1	118.82 (15)	C15—C14—H14	120.2
C4—C3—C2	121.00 (16)	C13—C14—H14	120.2
C4—C3—H3	119.5	O5—C15—C14	115.50 (16)
C2—C3—H3	119.5	O5—C15—C16	124.03 (16)
O1—C4—C3	125.56 (16)	C14—C15—C16	120.46 (16)
O1—C4—C5	115.32 (15)	C17—C16—C15	118.84 (16)
C3—C4—C5	119.11 (16)	C17—C16—H16	120.6
O2—C5—C6	125.13 (16)	C15—C16—H16	120.6
O2—C5—C4	115.30 (16)	C12—C17—C16	121.60 (16)
C6—C5—C4	119.57 (15)	C12—C17—H17	119.2
C5—C6—C7	121.27 (16)	C16—C17—H17	119.2
C5—C6—H6	119.4	O5—C18—H18A	109.5
C7—C6—H6	119.4	O5—C18—H18B	109.5
C2—C7—C6	119.08 (16)	H18A—C18—H18B	109.5
C2—C7—C8	122.23 (15)	O5—C18—H18C	109.5
C6—C7—C8	118.69 (16)	H18A—C18—H18C	109.5
C7—C8—C9	112.38 (15)	H18B—C18—H18C	109.5
C7—C8—H8A	109.1	O1—C19—H19A	109.5
C9—C8—H8A	109.1	O1—C19—H19B	109.5
C7—C8—H8B	109.1	H19A—C19—H19B	109.5
C9—C8—H8B	109.1	O1—C19—H19C	109.5
H8A—C8—H8B	107.9	H19A—C19—H19C	109.5
N1—C9—C8	108.63 (14)	H19B—C19—H19C	109.5
N1—C9—C10	112.79 (15)	O2—C20—H20A	109.5
C8—C9—C10	111.78 (15)	O2—C20—H20B	109.5
N1—C9—H9	107.8	H20A—C20—H20B	109.5
C8—C9—H9	107.8	O2—C20—H20C	109.5
C10—C9—H9	107.8	H20A—C20—H20C	109.5
O3—C10—O4	122.83 (18)	H20B—C20—H20C	109.5
C9—N1—C1—C12	176.36 (14)	C6—C7—C8—C9	168.41 (16)
C9—N1—C1—C2	53.33 (17)	C1—N1—C9—C8	−67.42 (18)
N1—C1—C2—C7	−18.3 (2)	C1—N1—C9—C10	57.07 (19)
C12—C1—C2—C7	−138.55 (16)	C7—C8—C9—N1	43.2 (2)
N1—C1—C2—C3	163.71 (14)	C7—C8—C9—C10	−81.93 (18)
C12—C1—C2—C3	43.5 (2)	C11—O4—C10—O3	−1.9 (3)
C7—C2—C3—C4	1.4 (2)	C11—O4—C10—C9	179.03 (15)
C1—C2—C3—C4	179.36 (15)	N1—C9—C10—O3	−110.1 (2)
C19—O1—C4—C3	1.4 (3)	C8—C9—C10—O3	12.7 (3)
C19—O1—C4—C5	−179.25 (15)	N1—C9—C10—O4	68.92 (19)
C2—C3—C4—O1	−178.92 (16)	C8—C9—C10—O4	−168.34 (16)
C2—C3—C4—C5	1.8 (3)	N1—C1—C12—C17	−57.33 (19)
C20—O2—C5—C6	1.4 (3)	C2—C1—C12—C17	63.6 (2)
C20—O2—C5—C4	−178.97 (16)	N1—C1—C12—C13	121.18 (16)
O1—C4—C5—O2	−2.1 (2)	C2—C1—C12—C13	−117.93 (17)
C3—C4—C5—O2	177.27 (16)	C17—C12—C13—C14	1.5 (2)
O1—C4—C5—C6	177.55 (16)	C1—C12—C13—C14	−177.06 (15)
C3—C4—C5—C6	−3.1 (3)	C12—C13—C14—C15	−0.1 (3)
O2—C5—C6—C7	−179.09 (17)	C18—O5—C15—C14	−171.63 (16)
C4—C5—C6—C7	1.3 (3)	C18—O5—C15—C16	7.7 (2)
C3—C2—C7—C6	−3.2 (2)	C13—C14—C15—O5	178.05 (15)
C1—C2—C7—C6	178.92 (15)	C13—C14—C15—C16	−1.3 (2)
C3—C2—C7—C8	177.06 (15)	O5—C15—C16—C17	−177.95 (16)
C1—C2—C7—C8	−0.9 (2)	C14—C15—C16—C17	1.3 (2)
C5—C6—C7—C2	1.9 (3)	C13—C12—C17—C16	−1.4 (2)
C5—C6—C7—C8	−178.36 (16)	C1—C12—C17—C16	177.10 (15)
C2—C7—C8—C9	−11.8 (2)	C15—C16—C17—C12	0.0 (3)