Benzyl-N-[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]carbamate

Abstract

Heterocycles—cyclic compounds containing at least one non-carbon heteroatom (e.g., N, O, S)—are fundamental in medicinal chemistry due to their influence on a drug’s physicochemical and biological properties. They improve solubility, bioavailability, and facilitate molecular recognition through their electronic and hydrogen-bonding features. These properties make them indispensable in drug design. This study focuses on the synthesis of a key heterocyclic intermediate: benzyl-N-[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]carbamate. This molecule incorporates a thiazole ring, known for its rigidity and electronic properties, that enhances target interactions. The 2-position bears a Cbz-protected amine, enabling orthogonal deprotection, while the 4-position features a hydroxyethyl side chain, providing a handle for further chemical modifications via nucleophilic substitution. Herein, we report the successful synthesis of this intermediate along with its full ¹H and ¹³C NMR spectra, melting point, and crystal structure, confirming its identity and purity.

1. Introduction

Heterocyclic compounds, so defined since they contain at least one heteroatom—such as nitrogen, oxygen, sulfur—in a cyclic structure, are derived from natural products or obtained by chemical synthesis in the laboratory [1,2,3]. The non-carbon atoms profoundly influence the physical, chemical, and biological properties of these compounds, which are particularly important when they are used as drugs. Heterocycles typically give the molecule better solubility and salt-forming propensity, which enhances the pharmacokinetic properties, including oral absorption and bioavailability [4]. Thus, by incorporating heterocycles, medicinal chemists can tune lipophilicity, polarity, solubility, and metabolic stability. Finally, heterocycles play a crucial role in target binding and molecular recognition by exploiting their unique electronic structures and hydrogen-bonding capabilities. For these reasons, synthetically accessible and pharmacologically relevant heterocycle intermediates are extremely useful in medicinal chemistry for designing and developing novel therapeutic agents. One such molecule is benzyl-N-[4-(2-hydroxyethyl)-1,3-thiazol-2-yl]carbamate (Figure 1), a highly versatile compound that combines multiple functional elements critical for drug synthesis. Structurally, this intermediate features a thiazole ring substituted at the 2-position by a benzyloxycarbonyl (Cbz)-protected amine and at the 4-position by an ethyl chain bearing an alcoholic function.

The thiazole moiety is a well-established, privileged structure in medicinal chemistry due to its rigid planarity, electronic properties, and hydrogen-bonding potential, all of which contribute to favorable interactions with biological targets. The Cbz-protected amine allows orthogonal deprotection and further derivatization, while the alcoholic function can be transformed to facilitate nucleophilic substitution, enabling the rapid construction of more complex, bioactive molecules. This combination makes the compound exceptionally valuable in combinatorial synthesis, fragment-based drug discovery, and late-stage functionalization—core strategies in the pharmaceutical industry, as demonstrated by the presence of the 2-amino-thiazol-4-yl-ethyl substructure in several classes of clinically important drugs (Figure 2) [5,6,7,8,9].

Herein, we report the synthesis of this key synthetic building block along with its ¹H and ¹³C NMR spectra, melting point, and crystal structure.

2. Results and Discussion

To synthesize benzyl-(4-(2-hydroxyethyl)thiazol-2-yl)carbamate (Scheme 1), we slightly modified the procedure reported by Inoue et al. [10]. We began by dissolving methyl 2-(2-(((benzyloxy)carbonyl)amino)thiazol-4-yl)acetate in tetrahydrofuran (THF), followed by the portionwise addition of lithium borohydride (LiBH₄) at −10 °C. The reaction mixture was gently warmed to room temperature and stirred until the ester was completely reduced. The reduction was monitored by thin-layer chromatography (TLC) using cyclohexane/ethyl acetate 7:3 as the mobile phase (Rf 1 = 0.6, Rf 2 = 0.2, see Supplementary Materials).

The achievement of the title compound (2) was confirmed by ¹H and ¹³C NMR.

Looking at ¹H NMR, the methylene protons attached to the thiazole ring resonate at 2.81 as a triplet of doublets (td, J = 6.7, 0.9 Hz, 2H), while the methylene adjacent to the oxygen appears at 3.80 ppm as a triplet (t, J = 6.7 Hz, 2H). The unique proton of the thiazole moiety resonates as a triplet at 6.69 ppm (t, J = 0.9 Hz, 1H). Additionally, the aromatic region of the spectrum presents a multiplet in the range 7.46–7.26 ppm, which corresponds to protons belonging to the benzyloxycarbonyl (Cbz) protection (m, 5H).

The ¹³C spectrum shows all the expected carbons. The carbonyl carbon of the Cbz group appears at 173.79 ppm, while the signals corresponding to the thiazole ring are observed at 160.02, 148.75, and 107.78 ppm. Chemical shifts for the CH carbons of the phenyl ring appear at 128.17 ppm, 127.99 ppm, and 127.82 ppm, the quaternary carbon adjacent to the benzylic group at 135.92, and the benzylic CH₂ at 67.21 ppm, while the carbonyl carbon is observed at 154.00 ppm. The signal at 60.65 ppm corresponds to the aliphatic CH₂ attached to the hydroxyl group, while the central CH₂ appears at 34.02 ppm. Thus, both the spectra are consistent with the structure of compound 2.

Additionally, compound 2 was analyzed by single-crystal X-ray diffraction to further confirm the success of the reduction and study the structural features of this class. The compound crystallized in the monoclinic system with the space group P2₁/c. The asymmetric unit, shown as an ellipsoid diagram in Figure 3, contains one molecule of compound 2. The terminal C-OH of the flexible hydroxyethyl side chain is disordered over two positions, with a refined occupancy of 7:3; atoms corresponding to the minor component (30%) are labeled with the suffix A (Figure 3).

The molecule features a planar core, composed of the thiazole and carbamate moieties. The phenyl ring of the Cbz group is inclined at 76.0° relative to the main plane, forming a torsional angle of −83.4 (6)° for C8-C7-O3-C6. The disordered hydroxyethyl chain adopts two distinct torsional angles: −74.0 (1)° for C1-C4-C5-O1 and −169.0 (1)° for C1-C4-C5A-O1A. The crystal packing is dominated by hydrogen bonding (Figure 4). The carbamate NH forms intermolecular hydrogen bonds with the thiazole nitrogen, resulting in centrosymmetric dimers extending along the c axis. This interaction appears to influence the geometry of the thiazole ring, reducing the C1–N1–N3 angle to 109.6 (5)°, which is statistically smaller than that observed in most thiazole-containing structures [11]. This effect has also been reported in other similar structures from the literature [12]. Additionally, the hydroxyl groups engage in hydrogen bonding with neighboring molecules, generating zipper-like chains that propagate along the b axis. This geometry implies a possible disorder of the hydroxyl hydrogen over two equivalent sites. However, the electron density is not sufficiently clear to model the atom with confidence, likely due to the modest resolution and local disorder. Interestingly, the A-labeled component exhibits less favorable hydrogen-bonding geometry compared to the major conformer, which is consistent with its lower refined occupancy. The absence of a Cπ–H···O interaction in this minor conformer further contributes to its reduced stability. A full account of the hydrogen bonds is shown in

Table 1. Hydrogen bond geometry (D: Donor, A: Acceptor) in the crystal structure of compound 2.

	D-H/Å	H∙∙∙A/Å	D∙∙∙A/Å	D-H∙∙∙A/°
N2-H2···N1 I	0.92 (5)	2.09 (5)	3.012 (6)	177 (5)
O1A-H1A···O1 II	0.82 (2)	2.23 (1)	2.79 (2)	125 (1)
C13-H13···O1 III	0.93 (1)	2.76 (1)	3.52 (1)	139.8 (5)
O1-H1···O1A IV	0.82 (1)	1.92 (2)	2.73 (2)	167.9 (8)
O1-H1···O1 IV	0.82 (1)	2.29 (1)	3.02 (2)	148.7 (7)

Equivalent positions: ^I 1-x, 1-y, 1-z; ^II 2-x, -y, 1-z; ^III x-1, y+1, z; ^IV 2-x, 1-y, 1-z.

. π-π stacking interactions also play a role in the stabilization of the packing (Figure 4). In detail, the phenyl rings of the Cbz moieties of adjacent molecules form an offset parallel stacking interaction with a centroid–centroid distance of 4.92 Å, as well as a T-shaped interaction with a centroid–centroid distance of 5.53 Å. Moreover, the thiazole cores also engage in offset parallel heteroaromatic stacking interactions, with a centroid–centroid distance of 4.92 Å. Finally, a geometry check of the molecule was performed using the Mogul routine [11], which compares molecular geometries to empirical distributions from the Cambridge Structural Database, providing valuable insight into structural features, as demonstrated in our previous study [13]. The analysis showed that most bond lengths and angles fall within typical ranges, except for the previously mentioned C1–N1–N3 angle and the disordered region, which is expected due to the flexibility of the side chain.

3. Materials and Methods

All reagents, chemicals, and solvents were purchased from commercial suppliers (Merck KGaA, Darmstadt, Germany; TCI Europe N.V.) and used as received. Anhydrous solvents were used as provided by the suppliers. Aluminum foil-backed silica gel 60 matrix with fluorescent indicator was used for thin-layer chromatography to follow the course of the reaction (visualization at 254 nm). A Stuart SMP 30 Mp Apparatus (Cole-Parmer Stuart, Stone, UK) was employed to measure the melting point. ¹H NMR and ¹³C NMR spectra were recorded at room temperature with a Varian Oxford 300 MHz instrument (Varian, Palo Alto, CA, USA) operating at 300 MHz for ¹H and 75 MHz for ¹³C.

3.1. Synthesis and Characterization of Benzyl-(4-(2-hydroxyethyl)thiazol-2-yl)carbamate

To a suspension of LiBH₄ (85.2 mg, 3.92 mmol) in anhydrous THF (2 mL) at −10 °C, a solution of compound 1 (200.0 mg, 0.6527 mmol) in anhydrous THF (2.5 mL) was added dropwise under a nitrogen atmosphere. The reaction mixture was allowed to gently warm up at room temperature and was stirred until TLC confirmed the disappearance of compound 1 (mobile phase cyclohexane/ethyl acetate; 7:3), which was complete after 4 h. Afterwards, water (1 mL) was slowly added, the solvent was removed, and the residue was taken up with ethyl acetate (10 mL). The organic phase was extracted with brine (2 mL), dried over Na₂SO₄, and concentrated to obtain compound 2 as a white solid (167.3 mg, 0.6012 mmol); m.p: 115.8 °C; yield: 92.5%. ¹H NMR (300 MHz, CD₃OD) δ 7.46–7.26 (m, 5H), 6.69 (t, J = 0.9 Hz, 1H), 5.24 (s, 2H), 3.80 (t, J = 6.7 Hz, 2H), 2.81 (td, J = 6.7, 0.9 Hz, 2H). ¹³C NMR (75 MHz, CD₃OD) δ 160.02, 154.00, 148.75, 135.92, 128.17, 127.99, 127.82, 107.78, 67.21, 60.65, 34.02.

3.2. Single-Crystal X-Ray Diffraction

Benzyl-(4-(2-hydroxyethyl)thiazol-2-yl)carbamate (2) was crystallized by layering isopropyl ether on a solution of the compound in methanol. Colorless plates grew within one week and were harvested for single-crystal X-ray diffraction analysis. Intensity data were collected at 293 K using an Oxford Diffraction Xcalibur diffractometer (Oxford Diffraction Ltd., Abingdon, UK), equipped with a Sapphire2 CCD detector and graphite monochromator, operating at 50 kV and 40 mA with MoKα radiation. Data collection was performed using 1° φ and ω scans, with exposure times of 40 s per frame for φ scans and 60 s per frame for ω scans, up to a maximum 2θ of 23°. The crystal was determined to be metrically monoclinic, and systematic absences were compatible with space group P2₁/c. Lorentz-polarization and analytical absorption corrections were applied using CrysAlisPro (Oxford Diffraction). The structure was solved by direct methods using SIR-2019/3 and completed by iterative cycles of full-matrix least-squares refinement on F_o² and ΔF [14] synthesis using SHELXL-2019/3 [15] within the WinGX suite (WinGX v.2023.1) [16]. Hydrogen atoms were introduced at calculated positions in their described geometries and were allowed to ride on the attached atom with fixed isotropic thermal parameters (1.2 Ueq of the parent atom for aromatic and methylene H). The carbamate hydrogen was refined freely, with an isotropic displacement parameter. Conversely, the hydroxyl hydrogens were refined in their calculated position with fixed isotropic thermal parameters (1.5 Ueq of the parent atom) due to the disorder in the side chain. The structure was analyzed with PARST [17], Mercury 2025.1.1 [18], and Mogul [11]; graphical representations were rendered with Mercury. Data collection and refinement statistics are reported in

Table 2. Crystal data and structure refinement statistics for compound 2.

Identification Code	2
Empirical formula	C13H14N2O3S
Formula weight	278.32
Temperature (K)	293(2)
Wavelength (Å)	0.71073
Crystal system	Monoclinic
Space group	P21/c
Unit cell dimensions (Å/°)	a = 11.0837 (11)
	b = 4.9184 (5)	β = 101.858 (10)
	c = 24.941 (3)
Volume (Å3)	1330.6 (2)
Z	4
Density calcd. (Mg/m3)	1.389
Abs. coefficient (mm−1)	0.249
F(000)	584
Crystal size (mm3)	0.12 × 0.05 × 0.01
θ range data collection (°)	2.757 to 23.257
Index ranges	−12 ≤ h ≤ 12, −5 ≤ k ≤ 5, −27 ≤ l ≤ 27
Reflections collected	20,820
Independent reflections	1910 [Rint = 0.0698]
Completeness to θmax (%)	99.4%
Refinement method	Full-matrix least-squares on F2
Data/restraints/parameters	1910/2/195
Goodness-of-fit on F2	1.090
Final R indices [I > 2σ(I)]	R1 = 0.0738, wR2 = 0.1421
R indices (all data)	R1 = 0.1142, wR2 = 0.1587
Extinction coefficient	0.0040 (7)
Largest diff. peak/hole (e·Å−3)	0.199 and −0.214
CCDC deposition number	2467715

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