Lactic acid-mediated tandem one-pot synthesis of 2-aminothiazole derivatives: A rapid, scalable, and sustainable process

Abstract

Environmentally benign and biodegradable lactic acid is identified as alternative solvent and catalyst for the tandem one-pot synthesis of Hantzsch 2-aminothiazole derivatives (4) from readily available aralkyl ketones (1) through in situ regioselective α-bromination using N-bromosuccinimide (2) followed by heterocyclization using thiourea (3) at 90–100°C. The major advantages of the present method include short reaction times (10–15 min), practical, simple to perform, easy work-up, good yield of products (up to 96%), productive for large-scale applications, free from apply of α-bromoketones (lachrymator) as substrates, avoids column purification. Hence, the present method meets with the concepts of both Wender’s “ideal synthesis” and sustainable chemical process.

Keywords:

• 2-aminothiazole
• lactic acid
• NBS
• thiourea, α-bromination
• scale-up process

Public Interest Statement

The reported method provides wide scope and quick access to Hantzsch 2-aminothiazole derivatives in good to excellent isolated yields within a short period of time from readily available aralkyl ketones through in situ regioselective α-bromination using NBS and subsequent heterocyclization using thiourea in presence of environmentally benign and biodegradable lactic acid at 90–100°C in a single step operation. Major advantages of the present method include scale-up process, non-explosive, easy to perform, simple work-up, easy isolation of products, improved worker safety and use of environmentally benign, non-volatile and biodegradable lactic acid as an alternative solvent and catalyst. Further, the present protocol is free from (i) column purification, (ii) the use of hazardous solvents and (iii) the isolation of lachrymatory α-bromoketones. Hence, the present method meets the concept of Wender’s “ideal synthesis”. Finally, it is concluded that the present method is an attractive addition to the sustainable chemical processes.

1. Introduction

The growing interest in developing simple, more convenient methods for the synthesis of medicinally important thiazole moiety has great demand both in academic, chemical, and pharmaceutical domains (Dondoni, 1985). Consequently, extensive use of conventional solvents and hazardous catalysts became mandatory for their preparation which is leading to environmental pollution. Besides, these are mostly prepared from α-bromoketones that are difficult to store and not easily accessible. Further, these α-bromoketones are lachrymatory and cause other severe health hazards to the operating chemists. As a result, the growing interest in developing simple, safe, more convenient, and sustainable scale-up methods for the synthesis of these thiazole synthetic precursors from readily available ketones has great demand in academic, chemical, and pharmaceutical domains. The Hantzsch thiazole synthesis (Hantzsch & Weber, 1887) is a powerful synthetic tool for the construction of the five-membered 2-aminothiazole derivatives. Even though it was introduced more than one century ago, still the development of new Hantzsch-based methods is warranted. As a result, numerous methods have been reported with the improvement of many aspects of the original synthetic protocol for their syntheses from either ketones or α-brominated ketones or other key starting materials (Jacques & Vernin, 2008). 2-aminothiazole derivatives possess broad range of pharmacological activities (Biagetti et al., 2010; González Cabrera et al., 2011; Jaen et al., 1990; Parekh, Juddhawala, & Rawal, 2013; Patt et al., 1992; Shah, Shah, Patel, & Patel, 2012; Shao et al., 2013; Singh et al., 2014; Spector, Liang, Giordano, Sivaraja, & Peterson, 1998; Yang et al., 2010) and plant growth activities (An Tran, Anil Kumar, Jung-Ae, Lee, & Park, 2015). Recently, 2-aminothiazole derivatives are identified as a prodrug for the treatment of type 2 diabetes (I and II) (Erion et al., 2005), anti-tuberculosis agent (III) (Makam & Kannan, 2014), and anti-Parkinsonian agent-pramipexole (IV) (Chau, Cooper, & Schapira, 2013) as shown in Figure 1. Consequently, thiazole moiety is considered as “Important Structural motif” and the desirable properties of 2-amino thiazole derivatives render them attractive targets for new drug discovery. There are many reports on the synthesis of thiazole derivatives from ketones or their derivatives (Kumar, Minh An, Lee, Park, & Lee, 2015; Heravi, Poormohammad, Beheshtiha, & Baghernejad, 2011; Huang, Zhu, & Zhang, 2002; Janardhan, Krishnaiah, Rajitha, & Crooks, 2014; Kidwai, Chauhan, & Bhatnagar, 2011; Meshram, Thakur, Madhu Babu, & Bangade, 2012; Nitta et al., 2012; Potewar, Ingale, & Srinivasan, 2008; Zhuravel, Kovalenko, Vlasov, & Chernykh, 2005; Zhu et al., 2012) and thiourea or substituted thiourea. However, most of the reported methods suffer from one or more disadvantages including use of hazardous and toxic reagents, long reaction times, low selectivity of the products, use of toxic and volatile solvents as well as catalysts, environmentally hazardous processes, low yields and difficulties in work-up and isolation of products and oppressive operational procedures.

Figure 1. Representative examples of biologically active 2-aminothiazole derivatives.

On the other hand, now-a-days, recycle and reduce of solvent usage or change to other solvents with better environmental profiles (Jessop, 2011; Kerton, 2009) become prominent. Accordingly, we found that environmentally benign lactic acid (Yang, Tan, & Gu, 2012) can act as catalyst cum solvent for in situ regioselective α-bromination and subsequent heterocyclization in the synthesis of pharmacologically active 2-aminothiazole derivatives. The present method is scale-up process and also meets the concept of “ideal synthesis” as described by Wender, Handy, and Wright (1997).

Herein, we report a simple, more convenient, practical method in which lactic acid acts as green catalyst and solvent for the one-pot synthesis of Hantzsch 2-aminothiazole derivatives (4) within 10–15 min from readily available aralkyl ketones (1) through in situ regioselective α-bromination using N-bromosuccinimide (2) followed by heterocyclization using thiourea (3) at 90–100°C (Scheme 1).

Scheme 1. Lactic acid as catalyst and solvent for the one-pot synthesis of Hantzsch 2-aminothiazole derivatives.

2. Results and discussion

It is planned to develop a simple, more convinient method for the preparation of Hantzsch 2-amino thiazole derivatives (4). For this purpose, initially we have choosen to synthesize the 4-(4-bromophenyl)thiazol-2-amine (4a) using 4′-bromoacetophenone (1a). It is used as model substrate for the optimization of reaction conditions as discusssed below.

2.1. Selection of suitable catalyst and solvent

For the success of the present hypothesis, an acidic organic liquid which can function as a catalyst and solvent is needed to identify for the accomplishment of both in situ regioselective α-bromination and heterocyclization in a single step operation, as the solubility of key reactants and their α-bromination and subsequent heterocyclization become easy in the presence of acidic organic liquid compared to solid catalysts alone. At the same time, it is evident that both the α-bromination and hetrocyclization processes proceed in the presence of acidic catalysts.

Toward this direction, a reaction is carried out using 4′-bromoacetophenone (1a) and N-bromosuccinimide (2) followed by addition of thiourea (3) in the presence of acetic acid (entry 1, Table 1) and the isolated yield of desired product (4a) is 30% at RT (entry 1, Table 1) and 58% at 90–100°C. To increase the yield of 4a, the same reaction is carried out in lactic acid and the obtained yield of product (4a) is increased to 45% at RT (entry 3). The same reaction at 90–100°C provided 96% yield (entry 4, Table 1). It may be due to more acidic nature of lactic acid compared to acetic acid. The evaluation of suitable acidic organic liquid which acts both as catalyst and solvent disclosed that lactic acid is the best option to obtain maximum yield (96%) of the desired product (4a) (entry 4, Table 1) compared to acetic acid (entry 2, Table 1).

Table 1. Screening of suitable acidic organic liquid (act as catalyst and solvent) for the synthesis of 4-(4-bromophenyl)thiazol-2-amine (4a)^a

Entry	Catalyst^b	Temperature	Time (min)	Product	Yield^c (%)
1	Acetic acid	RT	7 h	4a	30
2		90–100°C	90 min		58
3	Lactic acid	RT	1.2 h	4a	45
4		90–100°C	13 min		96

^a Reaction conditions: 4′-bromoacetophenone (1a) (25.0 mmol), N-bromosuccinimide (2) [(30.0 mmol) is added in 4 portions], thiourea (3) (30.0 mmol) and dual functional weak organic acid (20 mL) at 90–100°C.

^b Act as catalyst and solvent.

^c Isolated yield.

Later, other reaction conditions such as effect of brominating agent and mode of addition of brominating agent on the course of in situ regioselective α-bromination and also the effect of temperature both on in situ regioselective α-bromination and subsequent heterocyclization is investigated and the results obtained are discussed below.

In the present method, the in situ α-bromination reaction plays a vital role as the yield of target 2-aminothiazoles (4) is directly proportional to the yield of in situ generated α-brominated ketone (5). For this reason, various brominating agents and their mode of addition are studied. In particular, greater attention has been paid to improve the efficiency of α-bromination of ketones in terms of regioselectivity to generate α-monobrominated ketones exclusively compared to α-dibrominated ketones and also to achieve maximum conversion. The results obtained are presented in Tables 2 and 3.

Table 2. Effect of brominating agent on the course of in situ α-bromination reaction^a

Entry	Brominating agent	Time (min)	Temperature (°C)	Product (5a)	Yield^b (%)	Selectivity (%) (5a:6a)^c
1	Br2	25	10–15	5a	55	55:16
2	HBr-H2O2	31	RT	5a	60	60:13
3	Dioxane dibromide	20	90–100	5a	76	76:12
4	N-bromosuccinimide	12	90–100	5a	97	97:02
5	CuBr2	25	90–100	5a	81	81:10

^a Reaction conditions: 4′-bromoacetophenone (1a) (25.0 mmol), brominating agent (2) [(30.0 mmol) is added in 4 portions] and lactic acid (20 mL) at 90–100°C.

^b Isolated yield.

^c Unreacted substrate.

Table 3. Effect of mode of addition of N-bromosuccinimide (NBS) on course of in situ α-bromination reaction^a

Entry	Mode of NBS addition (Portions)	Time (min)	Product	Yield^b (%)	Selectivity (%) (5a:6a)^c
1	Once	7	5a	67	67:16
2	Two	9	5a	76	76:14
3	Four	12	5a	97	97:02

^a Reaction conditions: 4′-bromoacetophenone (1a) (25.0 mmol), N-bromosuccinimide (2) (30.0 mmol) is added in 4 portions and lactic acid (20 mL) at 90–100°C.

^b Isolated yield.

^c Unreacted substrate.

2.2. Screening of suitable brominating agent

The effect of brominating agent is studied on the course of in situ regioselective α-bromination and the results obtained are presented in Table 2. Accordingly, a reaction is carried out using molecular bromine and obtained lower yield (55%) of product 5a (entry 1, Table 2). The toxicity, difficulties in handling and low selectivity of molecular bromine encouraged us to use other user-friendly and readily available brominating agents such as HBr-H₂O₂, dioxane dibromide, N-bromosuccinimide (NBS) and CuBr₂ which provided 60, 76, 97, and 81% yields of product 5a, respectively (entries 2–5, Table 2).

The study revealed that NBS is the best brominating agent as it gave maximum yield (97%) of product 5a when added in 4 portions (entry 3, Table 3).

2.3. Effect of temperature

In general, the solubility of reactants and products, rate of reaction, efficiency and selectivity of catalyst are highly dependent on operating temperature of the reaction. Hence, we desired to study the effect of temperature on the course of both in situ α-bromination (A) and subsequent heterocyclization (B) process. Accordingly, reactions are conducted at various ranges of temperature and the results obtained are presented in Table 4.

Table 4. Effect of temperature on in situ regioselective α-bromination and subsequent heterocyclization^a

Entry	Type of reactionα-bromination (A)^bHeterocyclization (B)^c	Temperature (°C)	Time	Product	Yield^d (%)	Selectivity (%) (5a:6a)^e
1	A	RT	4 h	5a	53	53:18
	B		30 min	4a	40	–
2	A	40–50	3 h	5a	65	65:15
	B		15 min	4a	58	–
3	A	50–60	70 min	5a	69	69:13
	B		6 min	4a	62	–
4	A	70–80	50 min	5a	75	75:10
	B		4 min	4a	71	–
5	A	80–90	45 min	5a	84	84:6
	B		5 min	4a	82	–
6	A	90–100	12 min	5a	97	97:2
	B		1 min	4a	96	–

^a Reaction conditions: 4′-bromoacetophenone (1a) (25.0 mmol), N-bromosuccinimide (2) (30.0 mmol) is added in 4 portions), thiourea (3) (30.0 mmol) and lactic acid (20 mL) at specified temperature.

^b The yields of α-brominated product (5a) increases with increase of No. of portions of NBS and temperature.

^c Isolated yield of final product (4a) depends on yield of in situ generated regioselective α-brominated product (5a).

^d Isolated yield.

^e Regioselectivity of in situ α-bromination [Unreacted substrate (1a)].

For instance, when the reaction is carried out at room temperature, the rate of α-bromination (A) process is slow (3 h) and provided lower yield (53%) of product 5a (entry 1, Table 4) and subsequent heterocyclization (B) using thiourea (3) provided only 40% yield of final product 4a (entry 1). This may be due to partial solubility of the reactants. To improve the solubility of reactants and yield of α-bromoketone (5a) further, the reaction is conducted at different temperatures, for example at 40–50, 50–60, 70–80, 80–90, and 90–100°C provided 65, 69, 75, 84, and 97% isolated yield of α-bromoketone (5a) (entries 2–6).

While we consider heterocyclization (B) step alone, this stage is also slightly influenced by the operating temperature. For example, at room temperature, the yield of product 4a (40%) is decreased (entry 1, Table 4) significantly due to the partial solubility of thiourea (3) in lactic acid. When the same reaction is conducted at 40–50°C, improved yield (58%) of product 4a is obtained compared to RT (entry 2). But, when the reaction is operated at 50–60, 70–80, 80–90, and 90–100°C provided yields of 62, 71, 82, and 96% of product 4a, respectively (entries 3–6, Table 4).

These results indicate that the isolated yield of product 4a is directly proportional to the percentage of formation of in situ regioselective α-bromoketone 5a (entries 2–6, Table 4).

When we consider the overall reaction i.e. both in situ regioselective α-bromination (A) and heterocyclization (B), the optimum operating temperature is 90–100°C for maximum conversion and isolated yield (96%) of target product 4a (entry 7, Table 4). Based on our present study, we found that in case of laboratory scale, the optimum temperature is 90–100°C for the synthesis of 2-aminothiazoles (4).

2.4. Scope of the method

The substrate scope of the present method is studied with the help of above optimized reaction conditions using different types of aralkyl ketones (1a-o) as key starting substrates and the results obtained are presented in Table 5. The study disclosed that the substrate with fluoro, chloro, and bromo groups at para-position provided excellent yields (90–96%) of the products 4a, 4c, 4d (entries 1, 3, and 4, Table 5), but meta monohalogenated substrate, for example 1-(3-bromophenyl)ethanone (1b) provided good yield (85%)of the product 4b (entry 2, Table 5). Whereas the dihalogenated substrates, 1-(2,4-dichlorophenyl)ethanone (1e) and 1-(3,4-dichlorophenyl) ethanone (1f) provided moderate yields of products 4e and 4f in 74% and 78%, respectively (entries 5 and 6, Table 5). It is found that the isolated yield of the respective products depends on the position of halogen(s) on aromatic ring of aralkyl ketone (entries 1–6, Table 5).

Table 5. Tandem one-pot synthesis of 2-amino thiazole derivatives (4a-o) from readily available aralkyl ketones (1a-o)^a

Entry	Substrate (1)	Product (4)	Time (min)	Yield^b (%)
1	1a	4a	13	96
2	1b	4b	14	85
3	1c	4c	13	95
4	1d	4d	14	94
5	1e	4e	15	74
6	1f	4f	15	78
7^c	1g	4g	14	53
8^c	1h	4h	14	46
9	1i	4i	15	92
10	1j	4j	15	84
11	1k	4k	15	77
12	1l	4l	14	79
13	1m	4m	13	88
14	1n	4n	15	81
15	1o	4o	14	90

^a Reaction conditions: Aralkyl ketone (1a-o) (25.0 mmol), N-bromosuccinimide (2) [(30.0 mmol) is added in 4 portions], thiourea (3) (30.0 mmol) and lactic acid (20 mL) at 90–100°C.

^b Isolated yield.

^c 45.0 mmol of N-bromosuccinimide is used.

Interestingly, substrates, 1-(4-nitrophenyl)ethanone (1g) and 1-(3-nitrophenyl)ethanone (1h) with high deactivating groups (-NO₂) provided lower yields of product 4g (53%) and 4h (46%) (entries 7 and 8, Table 5) compared to all other substrates used in the present study. This may be due to the presence of strong electron withdrawing groups on the aromatic ring cause to reduce the percentage of formation of in situ α-brominated ketones which play vital role on yield of final product. Simple aralkyl ketones, for instance acetophenone (1i) and propiophenone (1l) provided good yields of the products 4i (92%) and 4l (84%) (entries 9 and 12, Table 5) and the substrates with moderate activating groups, for example 1-(p-tolyl)ethanone (1j), 1-(4-ethylphenyl)ethanone (1k) provided acceptable yields (79–84%) of respective products (4j and 4k) (entries 10–11, Table 5). But, the substrate with high activating group, for example 1-(4-methoxyphenyl)ethanone (1m) provided good yield (88%) of the product 4m (entry 13, Table 5). Interestingly, in case of acenaphthanones (1n and 1o), the 1-acetyl naphthalene (1n) gave lower yield (81%) of product 4n when compared to 2-acetyl naphthalene (1o) which afforded higher yield (90%) of product 4o (entries 14 and 15, Table 5). It may be due to steric effects.

3. Conclusions

In summary, the developed method provides wide scope and quick access to Hantzsch 2-aminothiazole derivatives (4) in good yields within 10–15 min from readily available aralkyl ketones (1) through in situ regioselective α-bromination using NBS (2) and subsequent heterocyclization using thiourea (3) in the presence of lactic acid at 90–100°C in a single step operation when compared to an alternative two-step procedures or other reported one-step methods. Major advantages of the present method include scale-up process, non-explosive, easy to perform, simple work-up, easy isolation of products, improved worker safety and use of environmentally benign, non-volatile and biodegradable lactic acid as alternative solvent and catalyst. Further, the current protocol is free from (i) column purification, (ii) the use of hazardous solvents, and (iii) the isolation of lachrymatory α-bromoketones. Finally, it is concluded that the present method is an attractive addition to the sustainable chemical processes.

4. Materials and method

4.1. Materials

Melting points of various obtained products are determined and uncorrected. ¹H NMR spectra are recorded on a Varian 400 MHz and ¹³C NMR spectra on a Jeol/AL-100 MHz. Chemical shifts were expressed in parts per million (ppm), coupling constants are expressed in Hertz (Hz). Splitting patterns describe apparent multiplicities and were designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). High-resolution mass spectra (HRMS) and compound purity data are acquired on a Exactive Orbitrap Mass Spectrometer (ThermoScientific, Waltham, MA, USA) equipped with electro spray ionization (ESI) source. Thin-layer chromatography is performed on 0.25 mm Merck silica gel plates and visualized with UV light. Column chromatography is performed on silica gel. Chemicals and solvents are purchased from Sigma Aldrich and Merck. Isolated compounds are identified on the basis of spectroscopic data (¹H & ¹³C NMR, Mass and HRMS).

4.2. Method for the synthesis of 2-aminothiazole derivatives (4a-o)

In a 100-mL 3 necked round bottom flask, aralkyl ketone (1) (25.0 mmole) and lactic acid (20 mL) are taken. The substrate (1) is partially soluble in lactic acid at room temperature. The temperature of the reaction mass is raised to 90–100°C. At this temperature, the reaction mass became homogeneous and N-bromosuccinimide (2) (30.0 mmol) is added in 4 portions (7.5 × 4 = 30 mmol). On addition of each portion of NBS (3.0 mmol), the color of the reaction mass is changed from colorless to orange red. This indicates that the bromonium ion is released from NBS (2). Later, within few minutes, the disappearance of the orange red color is observed. The same situation is observed when another 3 portions of NBS (2) is added. After the completion of α-bromination as per TLC, thiourea (3) (30.0 mmol) is added and stirred at the same temperature for 1 min. Then, the reaction mass is slowly cooled down to RT. As the temperature of the reaction mass is below 80°C, the final product (4) is slowly thrown out from the lactic acid. At room temperature, 20 mL of water is added for the precipitation of product (4). Then, it is filtered-off and washed with 10 mL of water. The crude solid product (4) is collected and to this 100 mL of cold water is added and quenched with NaHCO₃.¹ Again, it is filtered-off and washed twice with water (2 × 25 mL) for the removal of by-product and inorganic salts.² The pure solid product (4) is collected and dried in vacuum oven at ambient temperature and the isolated yields of respective products are presented in Table 5. All the prepared products (4a-o) are characterized by physical and spectroscopic data (¹H &¹³C NMR, Mass, and HRMS).

4.3. Characterization data of the corresponding compounds are as follows

4.3.1. 4-(4-bromophenyl) thiazol-2-amine (4a)

Off-white solid, yield: 96%; m.p. 180–181°C; ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 7.73 (2H, dd, J = 6.8 Hz, J = 2.0 Hz, arom H), 7.69 (2H, br s, -NH₂), 7.61 (2H, dd, J = 6.8 Hz, J = 2.0 Hz, arom H), 7.16 (1H, s, thiazole H); ¹³C NMR (100 MHz, DMSO-d₆, δ/ppm): 169.12, 144.39, 131.59 (3C), 127.61 (2C), 121.09, 102.91; HRMS (ESI): calcd for C₉H₈BrN₂S [M + H]⁺254.9586, found 254.9596;[M + H + 2]⁺256.9572.

4.3.2. 4-(3-bromophenyl) thiazol-2-amine (4b)

Yellow solid, yield: 85%; m.p. 162–163°C; ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 7.98 (1H, s, arom H), 7.79 (1H, d, J = 7.6 Hz, arom H), 7.44 (1H, d, J = 6.8 Hz, arom H), 7.32 (1H, t, J = 8.0 Hz, arom H), 7.16 (1H, s, thiazole H), 7.15 (2H, br s, -NH₂); ¹³C NMR (100 MHz, DMSO-d₆, δ/ppm): 168.35, 148.06, 137.11, 130.62, 129.73, 128.15, 124.32, 121.99, 103.10; HRMS (ESI): calcd for C₉H₈BrN₂S [M + H]⁺ 254.9507, found 254.9596; [M + H + 2]⁺ 256.9550.

4.3.3. 4-(4-chlorophenyl) thiazol-2-amine (4c)

Off-white solid, yield: 95%; m.p. 166–167°C; ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 7.80 (2H, d, J = 8.4 Hz, arom H), 7.41 (2H, d, J = 8.8 Hz, arom H), 7.09 (2H, s, -NH₂), 7.07(1H, s, thiazole H); ¹³C NMR (100 MHz, DMSO-d₆, δ/ppm): 168.39, 148.56, 133.71, 131.57, 128.45 (2C), 127.20(2C), 102.28; HRMS (ESI): calcd for C₉H₈N₂ClS [M + H]⁺ 211.0091, found 211.0082.

4.3.4. 4-(4-fluorophenyl) thiazol-2-amine (4d)

Off-white solid, yield: 94%; m.p. 101–102°C; ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 8.8 (2H, br s, -NH₂), 7.82 (2H, m, arom H), 7.34 (2H, t, J = 6.8 Hz, arom H), 7.21 (1H, s, thiazole H); ¹³C NMR (100 MHz, DMSO-d₆, δ/ppm): 170.33, 162.51(1C, d, ¹J_C-F=246.2 Hz), 137.66, 128.17, (2C, d, ³J_C-F = 8.3 Hz), 125.20 (1C, d, ⁴J_C-F = 3.3 Hz), 116.08 (2C, d,²J_C-F = 21.4 Hz), 102.82; HRMS (ESI): calcd for C₉H₈N₂FS [M + H]⁺ 195. 0387, found 195. 0377.

4.3.5. 4-(2, 4-dichlorophenyl) thiazol-2-amine (4e)

Off-white solid, yield: 74%; m.p. 189–191°C; ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 8.6 (2H, Br s, -NH₂), 7.79 (1H, d, J = 2.4 Hz, arom H), 7.71 (1H, d, J = 8.4 Hz, arom H), 7.57 (1H, dd, J = 8.4 Hz, J = 2.0 Hz, arom H), 7.14 (1H, s, thiazole H); ¹³C NMR (100 MHz, DMSO-d₆, δ/ppm): 169.21, 135.40, 134.92, 132.87 (2C), 129.65, 127.81, 127.58, 108.13; MS (ESI) m/z: [M + H]⁺ 245.00, [M + H + 2]⁺ 247.00.

4.3.6. 4-(3, 4-dichlorophenyl) thiazol-2-amine (4f)

Off-white solid, yield: 78%; m.p. 193–194°C; ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 8.016 (1H, d, J = 2.0 Hz, arom H), 7.78 (1H, dd, J = 8.8 Hz, J = 1.6 Hz, arom H), 7.61 (1H, d, J = 8.4 Hz, arom H), 7.23 (1H, s, arom H), 7.16 (2H, br s, -NH₂); ¹³C NMR (100 MHz, DMSO-d₆, δ/ppm): 168.58, 146.95, 135.18, 131.38, 130.59, 129.44, 127.19, 125.44, 103.76; HRMS (ESI): calcd for C₉H₇N₂Cl₂S [M + H]⁺ 244.9702, found 244. 9691;[M + H + 2]⁺246.9658.

4.3.7. 4-(4-nitrophenyl) thiazol-2-amine (4g)

Orange solid, yield: 53%; m.p. 285–286°C; ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 8.23 (2H, d, J = 8.8 Hz, arom H), 8.04 (2H, d, J = 8.8 Hz, arom H), 7.42 (1H, s, thiazole H), 7.25 (2H, br s, -NH₂); ¹³C NMR (100 MHz, DMSO-d₆, δ/ppm): 168.79, 146.85, 146.02, 140.28, 126.32 (2C), 124.00 (2C), 106.67; HRMS (ESI): calcd for C₉H₈O₂N₃S [M + H] ⁺ 222.0332, found 222.0341.

4.3.8. 4-(3-nitrophenyl) thiazol-2-amine (4h)

Yellow solid, yield: 46%; m.p. 282–283°C; ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 8.60 (1H, s, arom H), 8.23 (1H, d, J = 7.6 Hz, arom H), 8.14 (1H, d, J = 8.0 Hz, arom H), 7.69 (1H, t, J = 8.0 Hz, arom H), 7.38 (1H, s, thiazole H);¹³C NMR (100 MHz, DMSO-d₆, δ/ppm): 169.03, 148.19, 144.93, 134.93, 131.69, 130.19, 122.19, 120.05, 104.65; MS (ESI) m/z:[M + H]⁺ 222.00.

4.3.9. 4-phenylthiazol-2-amine (4i)

Off-white solid, yield: 92%, m.p. 149–151°C; ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 8.6 (2H, br s, -NH₂), 7.73 (2H, d, J = 7.6 Hz, arom H), 7.48 (2H, t, J = 8.0 Hz, arom H), 7.41 (1H, d, J = 7.6 Hz, arom H), 7.21 (1H, s, thiazole H); ¹³C NMR (100 MHz, DMSO-d₆, δ/ppm): 170.30, 138.53, 129.54, 129.10 (2C), 128.46, 125.80 (2C), 103.06; HRMS (ESI): calcd for C₉H₉N₂S [M + H]⁺ 177.0481, found 177.0486.

4.3.10. 2-Amino-4-(4-methylphenyl) thiazole (4j)

Off-white solid, yield: 84%; m.p. 136–137°C; ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 8.7 (2H, br s, -NH₂), 7.62 (2H, d, J = 8.4 Hz, arom H), 7.29 (2H, d, J = 8.0 Hz, arom H), 7.15 (1H, s, thiazole H), 2.34 (3H, s, -CH₃); ¹³C NMR (100 MHz, DMSO-d₆, δ/ppm): 170.27, 139.28, 138.46, 129.61 (2C), 125.66 (3C), 102.05, 20.88; HRMS (ESI): calcd for C₁₀H₁₁N₂S [M + H]⁺ 191.0637, found 191.0644.

4.3.11. 4-(4-ethylphenyl) thiazol-2-amine (4k)

Off-white solid, yield: 77%; m.p. 140–141°C; ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 8.75 (2H, br s, -NH₂), 7.67 (2H, d, J = 8.4 Hz, arom H), 7.32 (2H, d, J = 8.6 Hz, arom H), 7.14 (1H, s, thiazole H), 2.64 (2H, q, J = 7.6 Hz, -CH₂-), 1.19 (3H, t, J = 7.6 Hz, -CH₃); ¹³C NMR (100 MHz, DMSO-d₆, δ/ppm): 168.14, 149.97, 142.71, 132.57, 127.82 (2C), 125.56 (2C), 100.58, 27.92, 15.50; HRMS (ESI): calcd for C₁₁H₁₃N₂S [M + H]⁺ 205.07940, found 205.07976.

4.3.12. 5-methyl-4-phenylthiazol-2-amine (4l)

Off-white solid, yield: 79%, m.p. 118–120°C; ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 8.96 (2H, br s, -NH₂), 7.57–7.48 (5H, m, arom H), 2.28 (3H, s, -CH₃); ¹³C NMR (100 MHz, DMSO-d₆, δ/ppm): 179.46, 167.66, 133.12, 129.43, 128.95 (2C), 128.45 (2C), 114.83, 11.70; HRMS (ESI): calcd for C₁₀H₁₁N₂S [M + H]⁺191.0637, found 191.0642.

4.3.13. 4-(4-methoxyphenyl) thiazol-2-amine (4m)

Off-white solid, yield: 88%; m.p. 205–206°C; ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 8.9 (2H, br s, -NH₂) 7.71 (2H, d, J = 8.8 Hz, arom H), 7.085 (1H, s, thiazole H), 7.05 (H, d, J = 8.8 Hz, arom H), 3.81 (3H, s, -OCH₃); ¹³C NMR (100 MHz, DMSO-d₆, δ/ppm): 170.38, 160.12, 138.14, 127.26 (2C), 120.91, 114.49 (2C), 100.49, 55.42; HRMS (ESI): calcd for C₁₀H₁₁ON₂S [M + H]⁺ 207.0587, found 207.0593.

4.3.14. 4-(naphthalen-1-yl) thiazol-2-amine (4n)

Brown solid, yield: 81%; m.p. 164–165°C; ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 9.06 (2H, br s, -NH₂), 8.10–8.02 (4H, m, arom H), 7.69 -7.60 (3H, m, arom H), 7.07 (1H, s, arom H); ¹³C NMR (100 MHz, DMSO-d₆, δ/ppm): 168.05, 149.86, 133.48, 133.39, 130.74, 128.13, 127.96, 126.61, 126.23, 125.89, 125.79, 125.41, 104.99; HRMS (ESI): calcd for C₁₃H₁₁N₂S [M + H]⁺ 227.06375, found 227.06416.

4.3.15. 4-(naphthalen-2-yl) thiazol-2-amine (4o)

Brown solid, yield: 90%; m.p. 151–152°C; ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 8.32 (1H, s, arom H), 7.96–7.87 (4H, m, arom H), 7.52–7.47 (2H, m, arom H), 7.17 (1H, s, arom H), 7.13 (2H, br s, -NH₂); ¹³C NMR (100 MHz, DMSO-d₆, δ/ppm): 169.44, 153.37, 133.01, 132.74, 132.36, 128.36, 127.80, 127.49, 126.58, 126.42, 125.66, 123.53, 103.63; HRMS (ESI): calcd for C₁₃H₁₁N₂S [M + H]⁺ 227.0637, found 227.0645.

4.3.16. 2-bromo-1-(4-bromophenyl)ethanone (5a)

Off-white solid, yield: 97%; m.p. 108–110°C; ¹H NMR (400 MHz, CDCl₃): δ = 7.53 (d, J = 8.8 Hz, 2H, arom H), 7.64 (d, J = 8.4 Hz, 2H, arom H), 4.39 (s, 2 H, -CH₂-).

Additional information

Funding

The authors acknowledge the financial support provided by the Department of Atomic Energy-Board of Research in Nuclear Sciences (DAE-BRNS) (Bhabha Atomic Research Centre), Mumbai, India through a major research project (grant number 2011/37C/52/BRNS/2264).

Notes on contributors

N.C. Gangi Reddy

N.C. Gangi Reddy was born in 1981 in Naravakati Palle village, Kadapa, Andhra Pradesh, INDIA. He has been awarded the PhD degree from Sri Venkateswara University, Tirupati, INDIA in April 2007. Later, he joined as an assistant professor in the Department of Chemistry, Yogi Vemana University, Kadapa in June 2007. His research interests are design and synthesis of medicinally valuable organic compounds and development of catalyst-based synthetic methodologies. He published more than 25 research papers in journals of international repute. He completed two major research projects as principal investigator.

Notes

1. NaHCO₃ is added slowly, because of rapid effervescences.

2. If the reaction mass contains unreacted substrate (1), after water wash, it is to be washed again with petroleum ether.