Ethyl 6-methyl-4-[2-(4,4,5,5-tetra­methyl-1,3,2-dioxaborolan-2-yl)thio­phen-3-yl]-2-thioxo-1,2,3,4-tetra­hydro­pyrimidine-5-carboxyl­ate

Andreas Decken; Matthew T Zamora; Dominique R Duguay; Christopher M Vogels; Stephen A Westcott

doi:10.1107/S1600536808005965

. 2008 Apr 26;64(Pt 5):o929. doi: 10.1107/S1600536808005965

Ethyl 6-methyl-4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl]-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

Andreas Decken ^a,^*, Matthew T Zamora ^b, Dominique R Duguay ^b, Christopher M Vogels ^b, Stephen A Westcott ^b

PMCID: PMC2961284 PMID: 21202410

Abstract

A new Biginelli compound, C₁₈H₂₅BN₂O₄S₂, containing a boronate ester group was synthesized from a lithium bromide-catalysed reaction. The compound crystallizes with two independent molecules in the asymmetric unit that differ mainly in the conformation of the ester functionality. The crystal structure is stabilized by intermolecular N—H⋯O and N—H⋯S hydrogen bonds involving the 3,4-dihydropyrimidine-2(1H)-thione NH groups as donors and the carbonyl O and thiophene S atoms as acceptors.

Related literature

Blacquiere et al. (2005 ▶) report on previously studied boronic acid Ugi compounds. Miyaura & Suzuki (1995 ▶) give an excellent review on the Suzuki–Miyaura cross-coupling reaction of aryl halides with organoboron derivatives. Vogels et al. (2006 ▶) describe the synthesis and characterization of aryl boronate esters derived from aniline. Yang et al. (2003 ▶) highlight recent advances of boron chemistry in medicinal research.

Experimental

Crystal data

C₁₈H₂₅BN₂O₄S₂
M _r = 408.33
Triclinic,
a = 11.9274 (17) Å
b = 13.5021 (19) Å
c = 15.225 (2) Å
α = 112.172 (2)°
β = 93.531 (2)°
γ = 109.706 (2)°
V = 2086.9 (5) Å³
Z = 4
Mo Kα radiation
μ = 0.28 mm⁻¹
T = 173 (1) K
0.6 × 0.6 × 0.4 mm

Data collection

Bruker SMART1000/P4 diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 1997 ▶) T _min = 0.850, T _max = 0.896
14611 measured reflections
9077 independent reflections
7758 reflections with I > 2σ(I)
R _int = 0.017

Refinement

R[F ² > 2σ(F ²)] = 0.040
wR(F ²) = 0.113
S = 1.03
9077 reflections
499 parameters
H-atom parameters constrained
Δρ_max = 0.51 e Å⁻³
Δρ_min = −0.41 e Å⁻³

Data collection: SMART (Bruker, 1999 ▶); cell refinement: SMART; 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: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536808005965/gk2133sup1.cif

e-64-0o929-sup1.cif^{(29.4KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808005965/gk2133Isup2.hkl

e-64-0o929-Isup2.hkl^{(443.9KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N8—H8⋯S3	0.88	2.91	3.7702 (15)	167
N6—H6⋯O49ⁱ	0.88	2.06	2.8666 (17)	152
N36—H36⋯O19ⁱⁱ	0.88	2.14	2.9670 (17)	155
N38—H38⋯S2ⁱⁱⁱ	0.88	2.61	3.4817 (14)	170

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) .

Acknowledgments

This work was funded by the Natural Science and Engineering Research Council and AIF/ACOA (Canada).

supplementary crystallographic information

Comment

Compounds containing boronic acids [RB(OH)₂] or boronate esters [RB(OR')₂] have found remarkable synthetic utility in Suzuki-Miyaura cross coupling reactions (Miyaura and Suzuki, 1995) over the past decade. Interest in these compounds also arises from their diverse and potent biological activities (Yang et al., 2003). Indeed, we have recently shown that dihydropyrimidinones (Biginelli products) containing boronic acids show significant promise for their ability to inhibit the MCF7 breast cancer cell line (Blacquiere et al., 2005). Biginelli compounds containing thiophenes showed the most promise in this study. Some of the biological properties of boron compounds have been attributed to the ability of the three-coordinate boron atom to form bonds with biomolecules, as well as form hydrogen bonds with the adjacent O atoms of the boronic acid or boronate ester group. We are preparing a family of boron-containing Biginelli products in order to understand the mechanism of action of these compounds in an effort to design more potent candidates.

The title compound crystallizes with two independent molecules per asymmetric unit. In one of the independent molecules the ester group is coplanar with the pyrimidine ring [torsion angles: C40—C48—O50—C51 = 177.11 (13)° and C48—O50—C51—C52 = 179.83 (16)°], the second independent molecule shows rotation of the ethyl group of the ester moiety that displaces the methyl group from the pyrimidine ring plane [torsion angles: C10—C18—O20—C21 = -179.33 (13)° and C18—O20—C21—C22 = -81.2 (2)°]. Conversely, the latter molecule displays coplanar dioxaborolane and thiophene rings [torsion angles: C2—C1—B1—O2 = 6.2 (3)° and S1—C1—B1—O1 = 3.4 (2)°], while the former shows rotation about the inter-ring linkage [torsion angles: C32—C31—B31—O32 = 20.9 (2)° and S3—C31—B31—O31 = 24.7 (3)°]. However, these torsion angles allow for orbital overlap between the boron p_z orbital and the aryl π-electron system. The Bpin skeleton displays similar bond lengths and angles as found in related aniline derivatives (Vogels et al., 2006). Although steric crowding at the boron center is not present, the title compound shows no appreciable intra- or intermolecular Lewis acid-base interactions. However, hydrogen bonding is observed for all N—H groups of the 3,4-dihydropyrimidine-2(1H)-thione fragment. Two NH···O bonds are present for H6 and H36 (H6···O49ⁱ= 2.06 Å, (i): x, y - 1, z and H36···O19ⁱⁱ = 2.14 Å. (ii): x - 1, y, z) while two very long NH···S bonds are found for H8 and H38 (H8···S3 = 2.91 Å and H38···S2ⁱⁱⁱ = 2.61 Å, (iii): -x, -y + 1, -z).

Experimental

2-(4,4,5,5-Tetramethyl-1,3,2,-dioxaborolan-3-yl)thiophenecarboxaldehyde (548 mg, 2.30 mmol), ethyl acetoacetate (456 mg, 3.50 mmol) and thiourea (266 mg, 3.49 mmol) were added together with CH₃CN (15 ml) and a catalytic amount of lithium bromide (40 mg, 0.46 mmol). The reaction was heated at reflux for 60 h. The solvent was reduced to 5 ml and allowed to stand at room temperature. The title compound precipitated as colourless crystals. Yield: 740 mg (79%); m.p. 469 – 471 K.