Methyl 2-amino-5-iso­propyl-1,3-thia­zole-4-carboxyl­ate

Kennedy, A.R.; Khalaf, A.I.; Suckling, C.J.; Waigh, R.D.

doi:10.1107/S1600536804019282

organic compounds

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 60| Part 9| September 2004| Pages o1510-o1512

https://doi.org/10.1107/S1600536804019282

Methyl 2-amino-5-isopropyl-1,3-thiazole-4-carboxylate

Alan R. Kennedy,^a ^* Abedawn I. Khalaf,^a Colin J. Suckling ^a and Roger D. Waigh ^b

^aDepartment of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, Scotland, and ^bDepartment of Pharmaceutical Sciences, University of Strathclyde, Glasgow G4 0NR, Scotland
^*Correspondence e-mail: a.r.kennedy@strath.ac.uk

(Received 2 August 2004; accepted 5 August 2004; online 13 August 2004)

The title compound, C₈H₁₂N₂O₂S, forms a supramolecular network based on N—H⋯N hydrogen-bonded centrosymmetric dimers that are linked in turn by N—H⋯O contacts.

Comment

To improve the sequence selectivity of the DNA-binding drugs distamycin and netropsin (lexitropsins), a variety of heterocyclic compounds were used in replacing N-methyl pyrroles, the main components of the natural products (Khalaf et al., 2000 ; Khalaf et al., 2002 ). The title compound, (I), was chosen among others to improve the binding of these compounds to the wall of the minor groove by forming hydrophobic bonds as well as selecting guanine/cytosine over adenine/thiamine base pairs. Thiazoles containing the isopropyl group were recently incorporated in the synthesis of minor groove binders and this process has led to a new class of potent antibacterial and antifungal compounds (Khalaf et al., 2004 ; Anthony et al., 2004 ).

The molecular structure of (I) (Fig. 1) is unexceptional, with all ring bond lengths and angles (Table 1) close to the mean values obtained from 22 related fragments in the Cambridge Structural Database (Version 5.25 with updates to April 2004; Allen, 2002 ). Steric repulsion between the adjacent isopropyl and ester groups causes the main deviation from ideal geometry, widening the C2—C3—C6 and C3—C2—C4 angles to 130.7 (2) and 124.07 (18)°, respectively. However, these deviations are smaller than those found in an analogue with the positions of the isopropyl and ester groups reversed [133.90 (14) and 127.20 (14)° in ethyl 2-amino-4-isopropyl-1,3-thiazole-5-carboxylate, (II) (Kennedy et al., 2004 )]. This alleviation of steric strain is connected to a rotation of the ester group so that in (I) the smaller C=O group contacts the isopropyl group, rather than the OR group as in (II). Detailed comparison of (I) and (II) also shows that (I) has a more exaggerated diene conformation of short and long bonds. This difference is attributed to the effect of removing the ester group from resonance with the NCN fragment. Despite these differences, (I) retains a similar supramolecular network to that observed in (II) and other 5-carboxylate species (Lynch & McClenaghan, 2000 ). This is based on forming hydrogen-bonded centrosymmetric dimers via N—H⋯N contacts (Table 2), the network being completed by N—H⋯O contacts. In (I), these contacts are longer and thus presumably weaker than in (II).

Figure 1
Molecular structure of (I

), with 50% probability displacement ellipsoids.

Experimental

A solution prepared from Na (3.0 g, 0.130 mol) and dry methanol (50 ml) was added over a 45 min period to a solution of methyl dichloroacetate (20.0 g, 0.139 mol) and isobutyraldehyde (14 ml, 0.194 mol) in dry ether (50 ml). The resulting mixture was stirred vigorously at 273 K. After 1 h, diethyl ether (50 ml) and brine were added, and the layers were separated. The ether solution was dried and evaporated to give 16.2 g of material, which was dissolved in dry methanol (60 ml) containing thiourea (8.5 g, 0.112 mol). The solution was boiled under reflux for 4 h, concentrated under reduced pressure and neutralized with 18 M aqueous ammonia. Extraction with dichloromethane gave the title compound as pale-yellow crystals after recrystallization from ethanol–water (16.1 g, 41% yield). M.p. 424–425 K [literature m.p. 423–424 K (Barton et al., 1982 )]. ¹H NMR (CDCl₃): δ 1.27 (6H, d, J = 6.8 Hz), 3.87 (3H, s), 4.05 (1H, hept, J = 6.8 Hz), 5.15 (2H, s). IR (KBr): 3432, 3275, 3136, 2961, 1694, 1627, 1555, 1446, 1338, 1223, 1060, 987 cm⁻¹.

Crystal data

C₈H₁₂N₂O₂S
M_r = 200.26
Monoclinic, P2₁/n
a = 8.4219 (13) Å
b = 9.9620 (12) Å
c = 12.4307 (15) Å
β = 90.916 (11)°
V = 1042.8 (2) Å³
Z = 4
D_x = 1.276 Mg m⁻³
Mo Kα radiation
Cell parameters from 25 reflections
θ = 13.7–20.1°
μ = 0.28 mm⁻¹
T = 295 (2) K
Plate, colourless
0.55 × 0.55 × 0.05 mm

Data collection

Rigaku AFC-7S diffractometer
ω/2θ scans
Absorption correction: ψ scan (North et al., 1968 ) T_min = 0.806, T_max = 0.986
2552 measured reflections
2395 independent reflections
1423 reflections with I > 2σ(I)
R_int = 0.040
θ_max = 27.5°
h = 0 → 10
k = 0 → 12
l = −16 → 16
3 standard reflections every 150 reflections intensity decay: none

Refinement

Refinement on F²
R[F² > 2σ(F²)] = 0.041
wR(F²) = 0.125
S = 1.01
2395 reflections
129 parameters
H atoms treated by a mixture of independent and constrained refinement
w = 1/[σ²(F_o²) + (0.053P)² + 0.0985P] where P = (F_o² + 2F_c²)/3
(Δ/σ)_max < 0.001
Δρ_max = 0.18 e Å⁻³
Δρ_min = −0.17 e Å⁻³

Table 1
Selected geometric parameters (Å, °)

S1—C3	1.739 (2)
S1—C1	1.748 (2)
O1—C4	1.203 (2)
O2—C4	1.322 (3)
N1—C1	1.300 (3)
N1—C2	1.389 (2)
N2—C1	1.342 (3)
C2—C3	1.358 (3)
C2—C4	1.472 (3)

C3—S1—C1	89.68 (10)
C1—N1—C2	110.21 (17)
N1—C1—N2	124.6 (2)
N1—C1—S1	114.50 (15)
N2—C1—S1	120.93 (18)
C3—C2—N1	117.19 (18)
C3—C2—C4	124.07 (18)
N1—C2—C4	118.63 (17)
C2—C3—C6	130.7 (2)
C2—C3—S1	108.41 (15)
C6—C3—S1	120.60 (18)

Table 2
Hydrogen-bonding geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2—H1⋯O1ⁱ	0.82 (3)	2.21 (3)	2.975 (3)	155 (2)
N2—H2⋯N1ⁱⁱ	0.83 (3)	2.20 (3)	3.020 (3)	171 (3)
Symmetry codes: (i) $[x-{\script{1\over 2}},{\script{1\over 2}}-y,z-{\script{1\over 2}}]$ ; (ii) 1-x,1-y,-z.

The amine H atoms were located in a difference map and refined freely. All other H atoms were included in the riding-model approximation, with C—H distances of 0.96 (CH₃) and 0.98 Å (CH), and with U_iso(H) = 1.5U_eq(C).

Data collection: MSC/AFC Diffractometer Control Software (Molecular Structure Corporation, 1988 $[Molecular Structure Corporation (1988). MSC/AFC Diffractometer Control Software. MSC, 3200 Research Forest Drive, The Woodlands, TX 77381, USA.]$ ); cell refinement: MSC/AFC Diffractometer Control Software; data reduction: TEXSAN (Molecular Structure Corporation, 1992 ); program(s) used to solve structure: SIR92 (Altomare et al., 1994 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997 ); molecular graphics: ORTEPII (Johnson, 1976 ); software used to prepare material for publication: SHELXL97.

Supporting information

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S1600536804019282/tk6182sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S1600536804019282/tk6182Isup2.hkl

Computing details top

Data collection: MSC/AFC Diffractometer Control Software (Molecular Structure Corporation, 1988); cell refinement: MSC/AFC Diffractometer Control Software; data reduction: TEXSAN (Molecular Structure Corporation, 1992); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPII (Johnson, 1976); software used to prepare material for publication: SHELXL97.

Methyl 2-amino-5-isopropyl-1,3-thiazole-4-carboxylate top

Crystal data top

C₈H₁₂N₂O₂S	F(000) = 424
M_r = 200.26	D_x = 1.276 Mg m⁻³
Monoclinic, P2₁/n	Mo Kα radiation, λ = 0.71069 Å
Hall symbol: P 2yn	Cell parameters from 25 reflections
a = 8.4219 (13) Å	θ = 13.7–20.1°
b = 9.9620 (12) Å	µ = 0.28 mm⁻¹
c = 12.4307 (15) Å	T = 295 K
β = 90.916 (11)°	Plate, colourless
V = 1042.8 (2) Å³	0.55 × 0.55 × 0.05 mm
Z = 4

Data collection top

Rigaku AFC-7S diffractometer	1423 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	R_int = 0.040
Graphite monochromator	θ_max = 27.5°, θ_min = 2.6°
ω/2θ scans	h = 0→10
Absorption correction: ψ scan (North et al., 1968)	k = 0→12
T_min = 0.806, T_max = 0.986	l = −16→16
2552 measured reflections	3 standard reflections every 150 reflections
2395 independent reflections	intensity decay: none

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.041	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.125	H atoms treated by a mixture of independent and constrained refinement
S = 1.01	w = 1/[σ²(F_o²) + (0.053P)² + 0.0985P] where P = (F_o² + 2F_c²)/3
2395 reflections	(Δ/σ)_max < 0.001
129 parameters	Δρ_max = 0.18 e Å⁻³
0 restraints	Δρ_min = −0.17 e Å⁻³

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

	x	y	z	U_iso*/U_eq
S1	0.35650 (8)	0.16130 (6)	0.11493 (5)	0.0623 (2)
O1	0.6386 (3)	0.36598 (18)	0.39165 (14)	0.0830 (6)
O2	0.5943 (2)	0.54159 (15)	0.28610 (12)	0.0640 (5)
N1	0.4959 (2)	0.39136 (17)	0.12017 (13)	0.0480 (4)
N2	0.3785 (3)	0.3405 (3)	−0.04668 (16)	0.0706 (6)
H1	0.328 (3)	0.285 (3)	−0.082 (2)	0.061 (7)*
H2	0.409 (3)	0.411 (3)	−0.074 (2)	0.083 (9)*
C1	0.4155 (3)	0.3124 (2)	0.05626 (17)	0.0507 (5)
C2	0.5124 (2)	0.3334 (2)	0.22139 (15)	0.0458 (5)
C3	0.4476 (3)	0.2099 (2)	0.23525 (18)	0.0539 (5)
C4	0.5890 (2)	0.4118 (2)	0.30810 (16)	0.0492 (5)
C5	0.6541 (4)	0.6271 (3)	0.3716 (2)	0.0780 (8)
H5A	0.5852	0.6213	0.4322	0.117*
H5B	0.6578	0.7183	0.3467	0.117*
H5C	0.7590	0.5986	0.3926	0.117*
C6	0.4336 (3)	0.1245 (3)	0.3346 (2)	0.0743 (8)
H6	0.5219	0.1476	0.3835	0.111*
C7	0.2811 (4)	0.1554 (3)	0.3910 (2)	0.0929 (10)
H7A	0.2762	0.2498	0.4064	0.139*
H7B	0.2772	0.1056	0.4570	0.139*
H7C	0.1927	0.1307	0.3455	0.139*
C8	0.4451 (5)	−0.0257 (3)	0.3091 (4)	0.1255 (15)
H8A	0.3580	−0.0513	0.2627	0.188*
H8B	0.4411	−0.0763	0.3747	0.188*
H8C	0.5434	−0.0436	0.2738	0.188*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
S1	0.0743 (4)	0.0500 (3)	0.0620 (4)	−0.0169 (3)	−0.0118 (3)	0.0068 (3)
O1	0.1178 (16)	0.0670 (11)	0.0628 (10)	0.0064 (10)	−0.0404 (10)	0.0097 (9)
O2	0.0920 (12)	0.0486 (9)	0.0509 (9)	−0.0089 (8)	−0.0167 (8)	0.0020 (7)
N1	0.0591 (10)	0.0429 (9)	0.0418 (8)	−0.0042 (8)	−0.0052 (7)	0.0030 (7)
N2	0.1028 (18)	0.0646 (13)	0.0438 (10)	−0.0314 (13)	−0.0160 (11)	0.0056 (10)
C1	0.0606 (13)	0.0454 (11)	0.0462 (11)	−0.0051 (9)	−0.0021 (9)	0.0052 (9)
C2	0.0490 (11)	0.0449 (10)	0.0434 (10)	0.0021 (9)	−0.0030 (9)	0.0058 (9)
C3	0.0530 (12)	0.0521 (11)	0.0564 (12)	−0.0030 (10)	−0.0059 (10)	0.0111 (10)
C4	0.0504 (12)	0.0520 (12)	0.0451 (11)	0.0042 (10)	−0.0037 (9)	0.0047 (9)
C5	0.103 (2)	0.0658 (16)	0.0646 (16)	−0.0156 (14)	−0.0106 (15)	−0.0136 (13)
C6	0.0773 (17)	0.0737 (17)	0.0712 (16)	−0.0209 (13)	−0.0172 (13)	0.0336 (14)
C7	0.126 (3)	0.089 (2)	0.0648 (16)	−0.0303 (19)	0.0139 (17)	0.0062 (16)
C8	0.149 (3)	0.076 (2)	0.153 (4)	0.019 (2)	0.035 (3)	0.064 (2)

Geometric parameters (Å, º) top

S1—C3	1.739 (2)	C5—H5A	0.9600
S1—C1	1.748 (2)	C5—H5B	0.9600
O1—C4	1.203 (2)	C5—H5C	0.9600
O2—C4	1.322 (3)	C6—C7	1.505 (4)
O2—C5	1.446 (3)	C6—C8	1.533 (5)
N1—C1	1.300 (3)	C6—H6	0.9800
N1—C2	1.389 (2)	C7—H7A	0.9600
N2—C1	1.342 (3)	C7—H7B	0.9600
N2—H1	0.82 (3)	C7—H7C	0.9600
N2—H2	0.83 (3)	C8—H8A	0.9600
C2—C3	1.358 (3)	C8—H8B	0.9600
C2—C4	1.472 (3)	C8—H8C	0.9600
C3—C6	1.506 (3)

C3—S1—C1	89.68 (10)	O2—C5—H5C	109.5
C4—O2—C5	115.89 (18)	H5A—C5—H5C	109.5
C1—N1—C2	110.21 (17)	H5B—C5—H5C	109.5
C1—N2—H1	118.6 (18)	C7—C6—C3	110.1 (2)
C1—N2—H2	120 (2)	C7—C6—C8	110.7 (2)
H1—N2—H2	121 (3)	C3—C6—C8	112.0 (3)
N1—C1—N2	124.6 (2)	C7—C6—H6	107.9
N1—C1—S1	114.50 (15)	C3—C6—H6	107.9
N2—C1—S1	120.93 (18)	C8—C6—H6	107.9
C3—C2—N1	117.19 (18)	C6—C7—H7A	109.5
C3—C2—C4	124.07 (18)	C6—C7—H7B	109.5
N1—C2—C4	118.63 (17)	H7A—C7—H7B	109.5
C2—C3—C6	130.7 (2)	C6—C7—H7C	109.5
C2—C3—S1	108.41 (15)	H7A—C7—H7C	109.5
C6—C3—S1	120.60 (18)	H7B—C7—H7C	109.5
O1—C4—O2	122.5 (2)	C6—C8—H8A	109.5
O1—C4—C2	125.0 (2)	C6—C8—H8B	109.5
O2—C4—C2	112.52 (17)	H8A—C8—H8B	109.5
O2—C5—H5A	109.5	C6—C8—H8C	109.5
O2—C5—H5B	109.5	H8A—C8—H8C	109.5
H5A—C5—H5B	109.5	H8B—C8—H8C	109.5

C2—N1—C1—N2	179.4 (2)	C1—S1—C3—C6	175.3 (2)
C2—N1—C1—S1	−0.7 (2)	C5—O2—C4—O1	−3.9 (3)
C3—S1—C1—N1	0.20 (18)	C5—O2—C4—C2	174.3 (2)
C3—S1—C1—N2	−179.9 (2)	C3—C2—C4—O1	19.6 (4)
C1—N1—C2—C3	1.0 (3)	N1—C2—C4—O1	−164.5 (2)
C1—N1—C2—C4	−175.22 (18)	C3—C2—C4—O2	−158.6 (2)
N1—C2—C3—C6	−175.0 (2)	N1—C2—C4—O2	17.4 (3)
C4—C2—C3—C6	1.0 (4)	C2—C3—C6—C7	89.7 (3)
N1—C2—C3—S1	−0.9 (3)	S1—C3—C6—C7	−83.9 (3)
C4—C2—C3—S1	175.16 (16)	C2—C3—C6—C8	−146.6 (3)
C1—S1—C3—C2	0.36 (18)	S1—C3—C6—C8	39.8 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N2—H1···O1ⁱ	0.82 (3)	2.21 (3)	2.975 (3)	155 (2)
N2—H2···N1ⁱⁱ	0.83 (3)	2.20 (3)	3.020 (3)	171 (3)

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

References

Allen, F. A. (2002). Acta Cryst. B58, 380–388. Web of Science CrossRef CAS IUCr Journals Google Scholar
Altomare, A., Cascarano, G., Giacovazzo, C., Guagliardi, A.,Burla, M. C., Polidori, G. & Camalli, M. (1994). J. Appl. Cryst. 27, 435. CrossRef Web of Science IUCr Journals Google Scholar
Anthony, N. G., Fox, K. R., Johnston, B. F., Khalaf, A. I., Mackay, S. P., McGroarty, I. S., Parkinson, J. A., Skellern, G. G., Suckling, C. J. & Waigh, R. D. (2004). Bioorg. Med. Chem. Lett. 14, 1353–1356. Web of Science CrossRef PubMed CAS Google Scholar
Barton, A., Breukelman, S. P., Kaye, P. T., Meakins, G. D. & Morgan, D. J. (1982). J. Chem. Soc. Perkin Trans. 1, pp. 159–164. Google Scholar
Johnson, C. K. (1976). ORTEPII. Report ORNL-5138. Oak Ridge National Laboratory, Tennessee, USA. Google Scholar
Kennedy, A. R., Khalaf, A. I., Suckling, C. J. & Waigh, R. D. (2004). Acta Cryst. E60, o1188–o1190. Web of Science CSD CrossRef IUCr Journals Google Scholar
Khalaf, A. I., Pitt, A. R., Scobie, M., Suckling, C. J., Urwin, J., Waigh, R. D., Fishleigh, R. V., Young, S. C. & Wylie, W. A. (2000). Tetrahedron, 46, 5225–5239. Web of Science CrossRef Google Scholar
Khalaf, A. I., Suckling, C. J. & Waigh, R. D. (2002). British Patent Application PCT GB02 05916. Google Scholar
Khalaf, A. I., Waigh, R. D., Drummond, A. J., Pringle, B., McGroarty, I., Skellern, G. G. & Suckling, C. J. (2004). J. Med. Chem. 47, 2133–2156. Web of Science CrossRef PubMed CAS Google Scholar
Lynch, D. E. & McClenaghan, I. (2000). Acta Cryst. C56, e586. Web of Science CSD CrossRef IUCr Journals Google Scholar
Molecular Structure Corporation (1988). MSC/AFC Diffractometer Control Software. MSC, 3200 Research Forest Drive, The Woodlands, TX 77381, USA. Google Scholar
Molecular Structure Corporation (1992). TEXSAN. MSC, 3200 Research Forest Drive, The Woodlands, TX 77381, USA. Google Scholar
North, A. C. T., Phillips, D. C. & Mathews, F. S. (1968). Acta Cryst. A24, 351–359. CrossRef IUCr Journals Web of Science Google Scholar
Sheldrick, G. M. (1997). SHELXL97. University of Göttingen, Germany. Google Scholar

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