Ethyl 6-acetylamino-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-6-carboxylate

The title compound, C₂₀H₂₁NO₃, is a derivative of Aib (α-­aminoisobutyric acid) and is cyclized at the C^α position by bi­phenyl rings. The seven-membered ring possesses C2 symmetry. The C^α cyclization causes the backbone to assume a helical conformation in the crystal structure. The packing of the mol­ecules is stabilized by intermolecular C—H...O, C—H...π and N—H...O hydrogen bonds.

S1. Comment

In recent years, the synthesis and structural analysis of peptide fragments incorporating α,α-disubstituted glycines have attracted considerable attention (Heimgartner, 1991; Toniolo et al., 1993; Smythe et al., 1995; Crisma et al., 1991; Prasad et al., 1994; Valle et al., 1991), and α-aminoisobutyric acid (Aib or α-methyl alanine) is the best studied member of this family. However, its analogue, α,α-dibenzylglycine (Dbzg), has not been studied extensively (Kotha et al., 2002). We believe that the main reason for this is the non-availablity of simple preparative methods for these α,α-disubstituted aminoacid derivatives (Kotha et al., 2001, 2000; Formaggio et al., 2000; Ridvan et al., 1999). The unique stereochemistry of peptides containing these conformationally restricted amino acids provides a useful spectroscopic probe for the study of conformation-activity relationships (Karle & Balaram, 1990; Polese et al., 1996; Kotha & Brahmachary, 2000). Here, we present the crystal structure of the title compound, (I), a derivative of Aib. \sch

The structure of (I) is shown in Fig. 1. The bond distances and angles are close to the reported values (Allen et al., 1979). Atoms C20 and C7 are coplanar with rings A and C, respectively. The angle between the biphenyl rings A and C is 49.2 (2)°. The seven-membered ring B has C2 symmetry, and the symmetry axis passes through atom C6 and the C13—C14 bond. The amide unit is planar and the backbone torsion angles ϕ and ψ (C22—N21—C6—C4 and N21—C6—C4—O3) are 48.0 (4) and 44.6 (4)°, respectively, indicating a near α-helical conformation (Ramesh & Balaram, 1999).

The packing in (I) is stabilized by intermolecular C—H···O, N—H···O and C—H···π (Desiraju, 1989) hydrogen bonds, shown in Fig. 2 and Table 1. The carbonyl atom O23 forms a bifurcated hydrogen bond with atoms N21 and C24 (Fig. 2).

S2. Experimental

The Scheme above shows the synthesis of (I) under phase-transfer conditions (PTC), using ethyl isocyanoacetate as a glycine equivalent. Thus, treatment of 2,2'-bis(bromomethyl)-1,1'-biphenyl, (1), with ethyl isocyanoacetate in acetonitrile in the presence of K₂CO₃ and tetrabutylammonium hydrogen sulfate at room temperature gave the isonitrile compound, (2). Hydrolysis of the coupling product was achieved by treating (2) in ethanolic HCl at room temperature for a few hours. The free amino group in (3) was protected with acetic anhydride in dichloromethane in the presence of a catalytic amount of 4-(dimethylamino)pyridine, to give (I) (m.p. 431–433 K).

S3. Refinement

H atoms were fixed geometrically at calculated positions, with C—H = 0.93–0.96 Å and N—H = 0.86 Å, and treated as riding, with U_iso(H) = 1.2U_eq(C). Are these the correct constraints?

Computing details

Data collection: CAD-4 EXPRESS (Enraf-Nonius, 1994); cell refinement: CAD-4 EXPRESS; data reduction: XCAD4 (Harms & Wocadlo, 1995); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 (Farrugia, 1997).

Figures

	Fig. 1. The molecular structure of (I) with the atomic numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 2. A stereoview of the packing of the molecules in (I), showing the C—H···O and N—H···O interactions.

6-Acetylamino-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-6-carboxylic acid ethyl ester

Crystal data

C20H21NO3	F(000) = 688
Mr = 323.38	Dx = 1.224 Mg m^−3
Monoclinic, P21/c	Cu Kα radiation, λ = 1.5418 Å
a = 7.837 (2) Å	Cell parameters from 25 reflections
b = 24.074 (9) Å	θ = 7.6–28.4°
c = 9.543 (2) Å	µ = 0.66 mm^−1
β = 102.87 (2)°	T = 293 K
V = 1755.2 (9) Å^3	Rectangular block, colourless
Z = 4	0.35 × 0.13 × 0.10 mm

Data collection

Enraf-Nonius CAD-4 diffractometer	1976 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.047
Graphite monochromator	θmax = 71.9°, θmin = 3.7°
non–profiled ω/2θ scans	h = −9→9
Absorption correction: ψ-scan (North et al., 1968)	k = 0→29
Tmin = 0.802, Tmax = 0.922	l = −11→10
3522 measured reflections	3 standard reflections every 120 min
3312 independent reflections	intensity decay: 16%

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)] = 0.080	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.262	H-atom parameters constrained
S = 1.05	w = 1/[σ^2(Fo^2) + (0.1621P)^2 + 0.167P] where P = (Fo^2 + 2Fc^2)/3
3312 reflections	(Δ/σ)max = 0.046
219 parameters	Δρmax = 0.24 e Å^−3
0 restraints	Δρmin = −0.28 e Å^−3

Special details

Experimental. For the absorption correction: Number of psi-scan sets used was 3 Theta correction was applied. Averaged transmission function was used. No Fourier smoothing was applied.

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
C1	0.0342 (7)	0.2792 (2)	0.2297 (5)	0.1071 (16)
H1A	−0.0641	0.2791	0.1490	0.161*
H1B	0.0629	0.2418	0.2604	0.161*
H1C	0.1328	0.2961	0.2022	0.161*
C2	−0.0099 (6)	0.31073 (18)	0.3473 (4)	0.0854 (12)
H2A	−0.0400	0.3485	0.3157	0.103*
H2B	−0.1114	0.2941	0.3732	0.103*
O3	0.1349 (3)	0.31184 (10)	0.4732 (3)	0.0763 (7)
C4	0.2659 (5)	0.34668 (12)	0.4701 (3)	0.0649 (9)
O5	0.2660 (4)	0.37839 (10)	0.3734 (3)	0.0898 (9)
C6	0.4073 (4)	0.34408 (11)	0.6100 (3)	0.0559 (8)
C7	0.3318 (5)	0.37216 (12)	0.7286 (3)	0.0588 (8)
H7A	0.2139	0.3585	0.7222	0.071*
H7B	0.4019	0.3613	0.8216	0.071*
C8	0.3268 (5)	0.43492 (12)	0.7200 (3)	0.0588 (8)
C9	0.1709 (5)	0.46296 (14)	0.6760 (4)	0.0681 (9)
H9	0.0673	0.4429	0.6497	0.082*
C10	0.1654 (6)	0.52047 (16)	0.6702 (4)	0.0794 (11)
H10	0.0591	0.5389	0.6408	0.095*
C11	0.3183 (6)	0.54984 (14)	0.7084 (4)	0.0809 (11)
H11	0.3160	0.5884	0.7032	0.097*
C12	0.4741 (6)	0.52298 (15)	0.7540 (4)	0.0771 (11)
H12	0.5765	0.5436	0.7809	0.093*
C13	0.4827 (5)	0.46519 (13)	0.7611 (3)	0.0649 (9)
C14	0.6512 (5)	0.43511 (14)	0.8114 (3)	0.0655 (9)
C15	0.7659 (6)	0.45047 (17)	0.9383 (4)	0.0828 (11)
H15	0.7396	0.4808	0.9902	0.099*
C16	0.9189 (6)	0.4210 (2)	0.9882 (5)	0.1008 (15)
H16	0.9945	0.4311	1.0741	0.121*
C17	0.9584 (6)	0.3767 (3)	0.9101 (5)	0.1005 (15)
H17	1.0609	0.3566	0.9433	0.121*
C18	0.8454 (5)	0.36200 (18)	0.7817 (4)	0.0827 (11)
H18	0.8742	0.3322	0.7293	0.099*
C19	0.6924 (5)	0.39033 (14)	0.7304 (4)	0.0638 (8)
C20	0.5712 (5)	0.37480 (14)	0.5902 (3)	0.0642 (9)
H20A	0.6340	0.3514	0.5358	0.077*
H20B	0.5361	0.4083	0.5347	0.077*
N21	0.4457 (4)	0.28618 (9)	0.6532 (3)	0.0562 (7)
H21	0.4491	0.2771	0.7409	0.067*
C22	0.4756 (4)	0.24690 (13)	0.5636 (3)	0.0603 (8)
O23	0.4738 (4)	0.25799 (9)	0.4360 (2)	0.0772 (8)
C24	0.5110 (5)	0.18948 (13)	0.6230 (4)	0.0716 (10)
H24A	0.5037	0.1892	0.7221	0.107*
H24B	0.6260	0.1781	0.6155	0.107*
H24C	0.4258	0.1643	0.5694	0.107*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.113 (4)	0.104 (3)	0.090 (3)	−0.006 (3)	−0.007 (3)	−0.021 (3)
C2	0.079 (2)	0.092 (3)	0.072 (3)	0.006 (2)	−0.0121 (19)	−0.005 (2)
O3	0.0830 (17)	0.0788 (15)	0.0571 (15)	−0.0112 (13)	−0.0059 (12)	0.0090 (11)
C4	0.092 (2)	0.0485 (15)	0.0475 (18)	−0.0008 (16)	0.0006 (16)	0.0014 (13)
O5	0.133 (2)	0.0707 (15)	0.0520 (14)	−0.0151 (15)	−0.0085 (14)	0.0189 (12)
C6	0.078 (2)	0.0504 (15)	0.0366 (16)	−0.0041 (14)	0.0079 (13)	0.0005 (12)
C7	0.078 (2)	0.0533 (15)	0.0445 (17)	−0.0041 (15)	0.0112 (14)	0.0003 (13)
C8	0.080 (2)	0.0530 (16)	0.0407 (16)	−0.0033 (15)	0.0085 (14)	−0.0010 (12)
C9	0.084 (2)	0.066 (2)	0.0497 (19)	0.0014 (17)	0.0070 (16)	−0.0010 (14)
C10	0.111 (3)	0.067 (2)	0.054 (2)	0.019 (2)	0.0058 (19)	0.0044 (16)
C11	0.124 (3)	0.0502 (17)	0.067 (2)	0.003 (2)	0.017 (2)	0.0025 (15)
C12	0.109 (3)	0.0605 (19)	0.062 (2)	−0.018 (2)	0.018 (2)	−0.0051 (16)
C13	0.092 (2)	0.0594 (17)	0.0435 (18)	−0.0079 (17)	0.0158 (16)	−0.0030 (13)
C14	0.076 (2)	0.070 (2)	0.0487 (19)	−0.0156 (16)	0.0098 (15)	−0.0021 (15)
C15	0.092 (3)	0.096 (3)	0.056 (2)	−0.020 (2)	0.0064 (19)	−0.0113 (19)
C16	0.081 (3)	0.151 (4)	0.063 (3)	−0.014 (3)	0.001 (2)	−0.002 (3)
C17	0.071 (3)	0.149 (4)	0.076 (3)	0.009 (3)	0.007 (2)	0.011 (3)
C18	0.084 (3)	0.102 (3)	0.064 (2)	−0.002 (2)	0.022 (2)	−0.001 (2)
C19	0.071 (2)	0.071 (2)	0.0499 (19)	−0.0112 (16)	0.0137 (15)	0.0022 (15)
C20	0.088 (2)	0.0616 (17)	0.0451 (18)	−0.0061 (16)	0.0181 (16)	0.0009 (14)
N21	0.0837 (18)	0.0496 (13)	0.0328 (13)	−0.0017 (12)	0.0074 (11)	0.0007 (9)
C22	0.073 (2)	0.0610 (17)	0.0413 (19)	−0.0011 (15)	0.0017 (14)	−0.0006 (13)
O23	0.126 (2)	0.0673 (14)	0.0379 (14)	0.0049 (13)	0.0179 (12)	0.0022 (10)
C24	0.102 (3)	0.0578 (18)	0.051 (2)	0.0161 (17)	0.0069 (17)	0.0008 (14)

Geometric parameters (Å, º)

C1—C2	1.459 (6)	C12—C13	1.394 (5)
C1—H1A	0.9600	C12—H12	0.9300
C1—H1B	0.9600	C13—C14	1.489 (5)
C1—H1C	0.9600	C14—C15	1.388 (5)
C2—O3	1.458 (4)	C14—C19	1.405 (5)
C2—H2A	0.9700	C15—C16	1.383 (6)
C2—H2B	0.9700	C15—H15	0.9300
O3—C4	1.331 (4)	C16—C17	1.375 (7)
C4—O5	1.198 (4)	C16—H16	0.9300
C4—C6	1.534 (4)	C17—C18	1.389 (6)
C6—N21	1.466 (4)	C17—H17	0.9300
C6—C20	1.530 (5)	C18—C19	1.372 (5)
C6—C7	1.545 (4)	C18—H18	0.9300
C7—C8	1.513 (4)	C19—C20	1.505 (5)
C7—H7A	0.9700	C20—H20A	0.9700
C7—H7B	0.9700	C20—H20B	0.9700
C8—C9	1.376 (5)	N21—C22	1.330 (4)
C8—C13	1.401 (5)	N21—H21	0.8600
C9—C10	1.386 (5)	C22—O23	1.244 (4)
C9—H9	0.9300	C22—C24	1.496 (4)
C10—C11	1.369 (6)	C24—H24A	0.9600
C10—H10	0.9300	C24—H24B	0.9600
C11—C12	1.364 (6)	C24—H24C	0.9600
C11—H11	0.9300
C2—C1—H1A	109.5	C11—C12—H12	119.4
C2—C1—H1B	109.5	C13—C12—H12	119.4
H1A—C1—H1B	109.5	C12—C13—C8	118.4 (4)
C2—C1—H1C	109.5	C12—C13—C14	122.0 (3)
H1A—C1—H1C	109.5	C8—C13—C14	119.5 (3)
H1B—C1—H1C	109.5	C15—C14—C19	120.1 (4)
O3—C2—C1	111.7 (4)	C15—C14—C13	120.5 (3)
O3—C2—H2A	109.3	C19—C14—C13	119.5 (3)
C1—C2—H2A	109.3	C16—C15—C14	120.5 (4)
O3—C2—H2B	109.3	C16—C15—H15	119.8
C1—C2—H2B	109.3	C14—C15—H15	119.8
H2A—C2—H2B	107.9	C17—C16—C15	119.6 (4)
C4—O3—C2	117.2 (3)	C17—C16—H16	120.2
O5—C4—O3	123.5 (3)	C15—C16—H16	120.2
O5—C4—C6	124.9 (3)	C16—C17—C18	120.0 (4)
O3—C4—C6	111.5 (3)	C16—C17—H17	120.0
N21—C6—C20	111.7 (3)	C18—C17—H17	120.0
N21—C6—C4	110.3 (2)	C19—C18—C17	121.6 (4)
C20—C6—C4	109.7 (3)	C19—C18—H18	119.2
N21—C6—C7	107.3 (2)	C17—C18—H18	119.2
C20—C6—C7	110.4 (2)	C18—C19—C14	118.3 (3)
C4—C6—C7	107.4 (3)	C18—C19—C20	121.5 (3)
C8—C7—C6	114.0 (3)	C14—C19—C20	120.2 (3)
C8—C7—H7A	108.8	C19—C20—C6	113.0 (3)
C6—C7—H7A	108.8	C19—C20—H20A	109.0
C8—C7—H7B	108.7	C6—C20—H20A	109.0
C6—C7—H7B	108.7	C19—C20—H20B	109.0
H7A—C7—H7B	107.6	C6—C20—H20B	109.0
C9—C8—C13	119.3 (3)	H20A—C20—H20B	107.8
C9—C8—C7	121.1 (3)	C22—N21—C6	123.4 (3)
C13—C8—C7	119.6 (3)	C22—N21—H21	118.3
C8—C9—C10	121.3 (4)	C6—N21—H21	118.3
C8—C9—H9	119.3	O23—C22—N21	120.8 (3)
C10—C9—H9	119.3	O23—C22—C24	122.0 (3)
C11—C10—C9	119.2 (4)	N21—C22—C24	117.3 (3)
C11—C10—H10	120.4	C22—C24—H24A	109.5
C9—C10—H10	120.4	C22—C24—H24B	109.5
C12—C11—C10	120.5 (3)	H24A—C24—H24B	109.5
C12—C11—H11	119.7	C22—C24—H24C	109.5
C10—C11—H11	119.7	H24A—C24—H24C	109.5
C11—C12—C13	121.2 (4)	H24B—C24—H24C	109.5
C1—C2—O3—C4	77.9 (5)	C12—C13—C14—C15	49.2 (5)
C2—O3—C4—O5	3.6 (5)	C8—C13—C14—C15	−130.5 (4)
C2—O3—C4—C6	179.2 (3)	C12—C13—C14—C19	−131.9 (4)
O5—C4—C6—N21	−139.9 (4)	C8—C13—C14—C19	48.4 (4)
O3—C4—C6—N21	44.6 (4)	C19—C14—C15—C16	−1.8 (6)
O5—C4—C6—C20	−16.6 (5)	C13—C14—C15—C16	177.2 (4)
O3—C4—C6—C20	167.9 (3)	C14—C15—C16—C17	1.0 (7)
O5—C4—C6—C7	103.4 (4)	C15—C16—C17—C18	0.3 (7)
O3—C4—C6—C7	−72.1 (3)	C16—C17—C18—C19	−0.7 (7)
N21—C6—C7—C8	165.7 (3)	C17—C18—C19—C14	−0.1 (6)
C20—C6—C7—C8	43.8 (4)	C17—C18—C19—C20	179.1 (4)
C4—C6—C7—C8	−75.8 (3)	C15—C14—C19—C18	1.3 (5)
C6—C7—C8—C9	107.8 (4)	C13—C14—C19—C18	−177.6 (3)
C6—C7—C8—C13	−73.9 (4)	C15—C14—C19—C20	−177.9 (3)
C13—C8—C9—C10	0.7 (5)	C13—C14—C19—C20	3.1 (5)
C7—C8—C9—C10	178.9 (3)	C18—C19—C20—C6	105.0 (4)
C8—C9—C10—C11	0.3 (5)	C14—C19—C20—C6	−75.8 (4)
C9—C10—C11—C12	−1.1 (6)	N21—C6—C20—C19	−76.0 (3)
C10—C11—C12—C13	1.0 (6)	C4—C6—C20—C19	161.5 (3)
C11—C12—C13—C8	0.0 (5)	C7—C6—C20—C19	43.4 (4)
C11—C12—C13—C14	−179.6 (3)	C20—C6—N21—C22	−74.2 (4)
C9—C8—C13—C12	−0.8 (5)	C4—C6—N21—C22	48.0 (4)
C7—C8—C13—C12	−179.1 (3)	C7—C6—N21—C22	164.7 (3)
C9—C8—C13—C14	178.8 (3)	C6—N21—C22—O23	0.6 (5)
C7—C8—C13—C14	0.5 (4)	C6—N21—C22—C24	−179.3 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N21—H21···O23^i	0.86	2.01	2.863 (3)	169
C24—H24A···O23^i	0.96	2.46	3.316 (4)	148
C9—H9···Cg2^ii	0.93	3.30	3.926 (4)	127
C15—H15···Cg1^iii	0.93	3.03	3.785 (4)	140

Symmetry codes: (i) x, −y+1/2, z+1/2; (ii) x−1, y, z; (iii) −x+1, −y, −z+1.