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

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

doi:10.1107/S1600536804013984

organic compounds

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 60| Part 7| July 2004| Pages o1188-o1190

https://doi.org/10.1107/S1600536804013984

Ethyl 2-amino-4-isopropyl-1,3-thiazole-5-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, 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 26 May 2004; accepted 9 June 2004; online 19 June 2004)

Both the molecular and the crystal structures of the title compound, C₉H₁₄N₂O₂S, are similar to those of its 4-phenyl analogue. The supramolecular network is based upon N—H⋯N hydrogen-bonded centrosymmetric dimers linked by N—H⋯O contacts.

Comment

The quest for bioactive compounds led us to the synthesis of a variety of heterocylic compounds, among them the title compound, (I). There are many compounds in nature incorporating the thiazole moiety in their structure (Ikemoto et al., 2003 ; Kumar et al., 2002 ; El-Meligie & El-Awady, 2002 ), that have useful bioactivities. For example, Leucamide A was first extracted from the Australian marine sponge Leucetta microraphis and showed cytotoxicity toward several tumour cell lines (Wang & Nan, 2003 ). Thiazoles containing an isopropyl group were recently incorporated in the synthesis of minor-groove binders and this has led to a new class of potent antibacterial and antifungal compounds (Khalaf et al., 2004 ; Antony et al., 2004 ).

The molecular structure of (I) 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 angles C2—C3—C4 and C3—C2—C7 to 133.90 (14) and 127.20 (14)°, respectively. However, all geometric parameters are in excellent agreement with those found for the 4-phenyl analogue of (I) (Lynch & McClenaghan, 2000 ). Indeed, the similarity of these two structures extends to their hydrogen-bonding motifs. Compound (I) mimics its analogue in forming hydrogen-bonded centrosymmetric dimers via near-linear N—H⋯N contacts (Table 2), the supramolecular network being completed by N—H⋯O contacts.

Figure 1
The molecular structure of (I

), with 50% probability displacement ellipsoids.

Experimental

Bromine (10.5 g, 65.3 mmol) was added to a stirred suspension of ethyl 4-methyl-3-oxopentanoate (10.0 g, 63.2 mmol) in water (50 ml) at 273 K over a period of 45 min. After a further 30 min at 273 K, the reaction mixture was extracted with diethyl ether (150 ml). The organic layer was then dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure to give ethyl 2-bromo-4-methyl-3-oxopentanoate as an oil (14.6 g, 61.1 mmol). This oil was added to a solution of thiourea (4.7 g, 61.1 mmol) in ethanol (50 ml). The reaction mixture was kept under reflux for 1 h. Ice-water (250 ml) was added and the mixture was basified with 18 M aqueous ammonia with vigorous stirring. The insoluble material was filtered off, washed with water and dried under reduced pressure at 303 K overnight. This gave the desired product as a pale-yellow crystalline material [6.7 g, 49% yield; m.p. 449–451 K, literature m.p. 449–451 K (Barton et al., 1982 )]. ¹H NMR (CDCl₃): 1.25 (6H, d, J = 8.0 Hz), 1.33 (3H, t, J = 7.1 Hz), 3.88 (1H, hept, J = 6.9 Hz), 4.27 (2H, q, J = 7.1 Hz), 5.41 (2H, s). IR (KBr): 3393, 3112, 1665, 1531, 1509, 1466, 1307, 1134, 1034 cm⁻¹.

Crystal data

C₉H₁₄N₂O₂S
M_r = 214.28
Monoclinic, P2₁/n
a = 7.8757 (10) Å
b = 9.1080 (11) Å
c = 15.8434 (12) Å
β = 100.853 (9)°
V = 1116.1 (2) Å³
Z = 4
D_x = 1.275 Mg m⁻³
Mo Kα radiation
Cell parameters from 24 reflections
θ = 18.7–19.8°
μ = 0.27 mm⁻¹
T = 295 (2) K
Plate, colourless
0.65 × 0.40 × 0.18 mm

Data collection

Rigaku AFC-7S diffractometer
ω/2θ scans
Absorption correction: ψ scan (North et al., 1968 ) T_min = 0.760, T_max = 0.950
2849 measured reflections
2674 independent reflections
2119 reflections with I > 2σ(I)
R_int = 0.023
θ_max = 28.0°
h = 0 → 10
k = 0 → 11
l = −20 → 19
3 standard reflections every 150 reflections intensity decay: none

Refinement

Refinement on F²
R[F² > 2σ(F²)] = 0.038
wR(F²) = 0.109
S = 1.03
2674 reflections
138 parameters
H atoms treated by a mixture of independent and constrained refinement
w = 1/[σ²(F_o²) + (0.0493P)² + 0.2832P] where P = (F_o² + 2F_c²)/3
(Δ/σ)_max < 0.001
Δρ_max = 0.23 e Å⁻³
Δρ_min = −0.26 e Å⁻³

Table 1
Selected geometric parameters (Å, °)

S1—C1	1.7350 (15)
S1—C3	1.7468 (15)
O1—C4	1.2149 (19)
O2—C4	1.3357 (19)
N1—C1	1.3226 (18)
N1—C2	1.371 (2)
N2—C1	1.331 (2)
C2—C3	1.3707 (19)

C1—S1—C3	88.68 (7)
C1—N1—C2	111.26 (12)
N1—C1—N2	123.58 (14)
N1—C1—S1	114.78 (12)
N2—C1—S1	121.64 (12)
C3—C2—N1	115.18 (13)
C3—C2—C7	127.20 (14)
N1—C2—C7	117.60 (12)
C2—C3—C4	133.90 (14)
C2—C3—S1	110.09 (12)
C4—C3—S1	116.01 (11)

C2—N1—C1—S1	−1.08 (18)
C3—S1—C1—N1	1.13 (13)
C1—N1—C2—C3	0.4 (2)
N1—C2—C3—S1	0.45 (18)
C1—S1—C3—C2	−0.85 (12)

Table 2
Hydrogen-bonding geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2—H1⋯O1ⁱ	0.85 (2)	2.08 (2)	2.902 (2)	163 (2)
N2—H2⋯N1ⁱⁱ	0.86 (2)	2.15 (2)	3.006 (2)	177 (2)
Symmetry codes: (i) $[{\script{1\over 2}}-x,{\script{1\over 2}}+y,{\script{1\over 2}}-z]$ ; (ii) 1-x,1-y,1-z.

The amine H atoms were located in a difference map and refined isotropically; all other H atoms were constrained to idealized geometry with a riding model, with U_iso(H) = 1.5U_eq(C). C—H distances: CH₃ = 0.96 Å, CH₂ = 0.97 Å and CH = 0.98 Å.

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/S1600536804013984/cf6356sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S1600536804013984/cf6356Isup2.hkl

Computing details top

Data collection: MSC/AFC Diffractometer Control Software (Molecular Structure Corporation, 1988); cell refinement: MSC 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.

(I) top

Crystal data top

C₉H₁₄N₂O₂S	F(000) = 456
M_r = 214.28	D_x = 1.275 Mg m⁻³
Monoclinic, P2₁/n	Mo Kα radiation, λ = 0.71069 Å
a = 7.8757 (10) Å	Cell parameters from 24 reflections
b = 9.1080 (11) Å	θ = 18.7–19.8°
c = 15.8434 (12) Å	µ = 0.27 mm⁻¹
β = 100.853 (9)°	T = 295 K
V = 1116.1 (2) Å³	Plate, colourless
Z = 4	0.65 × 0.40 × 0.18 mm

Data collection top

Rigaku AFC-7S diffractometer	2119 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	R_int = 0.023
Graphite monochromator	θ_max = 28.0°, θ_min = 2.6°
ω/2θ scans	h = 0→10
Absorption correction: ψ scan (North et al., 1968)	k = 0→11
T_min = 0.760, T_max = 0.950	l = −20→19
2849 measured reflections	3 standard reflections every 150 reflections
2674 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)] = 0.038	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.109	H atoms treated by a mixture of independent and constrained refinement
S = 1.03	w = 1/[σ²(F_o²) + (0.0493P)² + 0.2832P] where P = (F_o² + 2F_c²)/3
2674 reflections	(Δ/σ)_max < 0.001
138 parameters	Δρ_max = 0.23 e Å⁻³
0 restraints	Δρ_min = −0.26 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	0.35390 (5)	0.22977 (5)	0.31256 (2)	0.04375 (14)
O1	0.47481 (17)	−0.03494 (16)	0.23705 (8)	0.0606 (4)
O2	0.70278 (16)	−0.08324 (14)	0.34096 (8)	0.0531 (3)
N1	0.55929 (16)	0.32156 (15)	0.44919 (8)	0.0420 (3)
N2	0.3123 (2)	0.46619 (18)	0.40776 (11)	0.0540 (4)
H1	0.222 (3)	0.483 (2)	0.3702 (13)	0.056 (6)*
H2	0.345 (3)	0.526 (2)	0.4493 (14)	0.061 (6)*
C1	0.41151 (19)	0.35188 (17)	0.39715 (10)	0.0402 (3)
C2	0.63246 (18)	0.19615 (17)	0.42422 (9)	0.0370 (3)
C3	0.54117 (18)	0.12966 (17)	0.35213 (9)	0.0379 (3)
C4	0.5675 (2)	−0.00187 (19)	0.30463 (10)	0.0421 (3)
C5	0.7327 (3)	−0.2197 (2)	0.29860 (13)	0.0588 (5)
H5A	0.8551	−0.2427	0.3109	0.088*
H5B	0.6975	−0.2083	0.2369	0.088*
C6	0.6343 (4)	−0.3418 (3)	0.3283 (2)	0.0880 (8)
H6A	0.6587	−0.3454	0.3900	0.132*
H6B	0.6678	−0.4329	0.3057	0.132*
H6C	0.5128	−0.3261	0.3085	0.132*
C7	0.8035 (2)	0.14796 (19)	0.47675 (10)	0.0446 (4)
H7	0.8388	0.0574	0.4514	0.067*
C8	0.9424 (2)	0.2634 (3)	0.47442 (16)	0.0726 (6)
H8A	0.9522	0.2819	0.4159	0.109*
H8B	1.0511	0.2284	0.5058	0.109*
H8C	0.9115	0.3525	0.5001	0.109*
C9	0.7856 (3)	0.1150 (3)	0.56843 (13)	0.0739 (7)
H9A	0.7498	0.2021	0.5943	0.111*
H9B	0.8949	0.0826	0.6006	0.111*
H9C	0.7008	0.0393	0.5685	0.111*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
S1	0.0385 (2)	0.0470 (2)	0.0396 (2)	0.00162 (16)	−0.00809 (15)	−0.00464 (16)
O1	0.0576 (7)	0.0646 (8)	0.0504 (7)	0.0054 (6)	−0.0135 (6)	−0.0192 (6)
O2	0.0550 (7)	0.0518 (7)	0.0471 (6)	0.0117 (6)	−0.0041 (5)	−0.0141 (5)
N1	0.0384 (6)	0.0419 (7)	0.0405 (7)	0.0034 (5)	−0.0062 (5)	−0.0049 (5)
N2	0.0453 (8)	0.0508 (9)	0.0565 (9)	0.0124 (6)	−0.0141 (7)	−0.0123 (7)
C1	0.0366 (7)	0.0402 (8)	0.0402 (8)	−0.0005 (6)	−0.0021 (6)	−0.0012 (6)
C2	0.0340 (7)	0.0391 (7)	0.0355 (7)	−0.0006 (6)	0.0006 (5)	−0.0009 (6)
C3	0.0348 (7)	0.0413 (8)	0.0350 (7)	−0.0008 (6)	0.0004 (5)	−0.0003 (6)
C4	0.0401 (7)	0.0461 (8)	0.0386 (7)	−0.0031 (6)	0.0031 (6)	−0.0049 (6)
C5	0.0586 (11)	0.0555 (11)	0.0601 (11)	0.0114 (9)	0.0052 (9)	−0.0196 (9)
C6	0.0876 (17)	0.0597 (14)	0.118 (2)	−0.0006 (13)	0.0237 (16)	−0.0137 (14)
C7	0.0382 (8)	0.0476 (9)	0.0429 (8)	0.0063 (6)	−0.0055 (6)	−0.0062 (7)
C8	0.0383 (9)	0.0989 (17)	0.0746 (14)	−0.0089 (10)	−0.0046 (9)	0.0152 (12)
C9	0.0611 (12)	0.0956 (17)	0.0594 (12)	0.0074 (12)	−0.0033 (9)	0.0329 (12)

Geometric parameters (Å, º) top

S1—C1	1.7350 (15)	C5—H5A	0.970
S1—C3	1.7468 (15)	C5—H5B	0.970
O1—C4	1.2149 (19)	C6—H6A	0.960
O2—C4	1.3357 (19)	C6—H6B	0.960
O2—C5	1.453 (2)	C6—H6C	0.960
N1—C1	1.3226 (18)	C7—C9	1.516 (3)
N1—C2	1.371 (2)	C7—C8	1.522 (3)
N2—C1	1.331 (2)	C7—H7	0.980
N2—H1	0.85 (2)	C8—H8A	0.960
N2—H2	0.86 (2)	C8—H8B	0.960
C2—C3	1.3707 (19)	C8—H8C	0.960
C2—C7	1.5093 (19)	C9—H9A	0.960
C3—C4	1.450 (2)	C9—H9B	0.960
C5—C6	1.482 (3)	C9—H9C	0.960

C1—S1—C3	88.68 (7)	C5—C6—H6A	109.5
C4—O2—C5	117.46 (13)	C5—C6—H6B	109.5
C1—N1—C2	111.26 (12)	H6A—C6—H6B	109.5
C1—N2—H1	118.9 (14)	C5—C6—H6C	109.5
C1—N2—H2	119.7 (14)	H6A—C6—H6C	109.5
H1—N2—H2	121 (2)	H6B—C6—H6C	109.5
N1—C1—N2	123.58 (14)	C2—C7—C9	110.59 (14)
N1—C1—S1	114.78 (12)	C2—C7—C8	110.90 (15)
N2—C1—S1	121.64 (12)	C9—C7—C8	110.91 (17)
C3—C2—N1	115.18 (13)	C2—C7—H7	108.1
C3—C2—C7	127.20 (14)	C9—C7—H7	108.1
N1—C2—C7	117.60 (12)	C8—C7—H7	108.1
C2—C3—C4	133.90 (14)	C7—C8—H8A	109.5
C2—C3—S1	110.09 (12)	C7—C8—H8B	109.5
C4—C3—S1	116.01 (11)	H8A—C8—H8B	109.5
O1—C4—O2	122.72 (16)	C7—C8—H8C	109.5
O1—C4—C3	122.75 (15)	H8A—C8—H8C	109.5
O2—C4—C3	114.53 (13)	H8B—C8—H8C	109.5
O2—C5—C6	110.80 (18)	C7—C9—H9A	109.5
O2—C5—H5A	109.5	C7—C9—H9B	109.5
C6—C5—H5A	109.5	H9A—C9—H9B	109.5
O2—C5—H5B	109.5	C7—C9—H9C	109.5
C6—C5—H5B	109.5	H9A—C9—H9C	109.5
H5A—C5—H5B	108.1	H9B—C9—H9C	109.5

C2—N1—C1—N2	178.68 (16)	C5—O2—C4—O1	−2.8 (3)
C2—N1—C1—S1	−1.08 (18)	C5—O2—C4—C3	177.58 (15)
C3—S1—C1—N1	1.13 (13)	C2—C3—C4—O1	−174.00 (18)
C3—S1—C1—N2	−178.64 (16)	S1—C3—C4—O1	6.4 (2)
C1—N1—C2—C3	0.4 (2)	C2—C3—C4—O2	5.6 (3)
C1—N1—C2—C7	179.22 (14)	S1—C3—C4—O2	−173.96 (11)
N1—C2—C3—C4	−179.14 (16)	C4—O2—C5—C6	−87.8 (2)
C7—C2—C3—C4	2.2 (3)	C3—C2—C7—C9	−119.71 (19)
N1—C2—C3—S1	0.45 (18)	N1—C2—C7—C9	61.6 (2)
C7—C2—C3—S1	−178.24 (13)	C3—C2—C7—C8	116.8 (2)
C1—S1—C3—C2	−0.85 (12)	N1—C2—C7—C8	−61.8 (2)
C1—S1—C3—C4	178.82 (13)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N2—H1···O1ⁱ	0.85 (2)	2.08 (2)	2.902 (2)	163 (2)
N2—H2···N1ⁱⁱ	0.86 (2)	2.15 (2)	3.006 (2)	177 (2)

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

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