Synthesis and Evaluation of Biological Activities of Thieno-[2,3-d]-pyrimidine Derivatives

Abstract

A series of novel thieno[2,3-d]pyrimidine derivatives were designed, synthesized and evaluated for their biological ability. 2-Amino-4,7-dihydro-5H-thieno[2,3-d]pyrano-3-cyanonitrile was synthesized by Gewald reaction using pyranone as substrate, malonitrile and sulfur powder as raw materials and triethylamine as base at room temperature. Subsequent amination with N,N-dimethylformamide dimethyl acetal (DMF-DMA) gave N'-(3-cyano-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-N,N-dimethylmethanimidamide. In this article, the 23 thieno[2,3-d] pyrimidines were obtained by Dimroth rearrangement condensation with different anilines, 16 of them being new compounds. Meanwhile, all compounds were assessed for breast cancer MDA-MB-231 cell line bioactivity with paclitaxel (PTX) as the positive control, and all compounds in the series showed inhibitory effects on breast cancer cell MDA-MB-231. The IC₅₀ of compound l against MDA-MB-231 is 27.6 μM, which is similar to that of PTX with an IC₅₀ of 29.3 μM. This means that compound l exhibits comparable inhibitory activity to PTX in MDA-MB-231 cells and may be considered as a potential anti-MDA-MB-231 inhibitor.

Keywords:
thieno[2,3-d]pyrimidine derivatives; Dimroth rearrangement; Gewald reaction; antitumor; microwave synthesis

Introduction

Cancer is an enemy of human health, and the enormous disease burden caused by cancer is not only among the vital causes of death globally but also a major impediment to increasing human life expectancy.¹ 2.26 million new cases regarding breast cancer were reported worldwide in 2020.² There are many ways to classify breast cancer based on immunohistochemistry into three receptors: estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2).³ Breast cancer is broadly categorized into Luminal A,⁴ Luminal B,⁵ triple-negative types, as well as HER2 overexpression. The triple-negativity with regards to breast cancer is demonstrated by the fact that all three receptors, ER, PR, and HER2, are negative in cancerous tissues,⁶ which is one of the most important diseases in gynecological clinics due to its close association with malignant tumors of the female reproductive tract. Triple-negative breast cancer denotes pathologic subtype of breast cancer, having the highest lethality and recurrence rates of all breast cancer pathologic subtypes. This makes it a very challenging disease.

Thieno[2,3-d]pyrimidine allows the design of biotargeted agents that inhibit triple-negative breast cancer cells, including epidermal growth factor receptor suppression (EGFR), tyrosine kinase (TKI), as well as vascular endothelial growth factor suppression (VEGF).⁷

At present, the EGFR tyrosine kinase small molecule inhibitors that have been listed and entered clinical trials are mainly I (gefitinib), II (erlotinib) and III (lapatinib), IV (CI1033), V (EKB-2569) and VI (PKI-66) (Figure 1).⁸ They have a pyrimidine nucleus of the quinazoline nucleus and can therefore be considered bioisomers of the quinazoline nucleus.

Figure 1
Chemical structure for anticancer biological evaluation drugs with quinazoline.

Thieno[2,3-d]pyrimidine derivatives can be regarded as bioelectronic equivalents of quinazoline due to their unique ring structure. Thieno[2,3-d]pyrimidine derivatives have pyrimidine rings in their structure, which refers to the building blocks of RNA as well as DNA.⁹ These compounds can be served as highly active drug targets with significant pharmacological activity and can be utilized in the development of targeted antitumor therapies,¹⁰ antidiabetic,¹¹ antimicrobial,¹² and anti-inflammatory drugs.¹³ In 2017, Saddik et al.¹⁴ synthesized a series of 5-amino-2-ethylthio-4-phenyl-6-substituted thieno[2,3-d]pyrimidine derivatives, and cell activity assay was carried out, finding that the synthesized compounds VII could effectively inhibit the activity of tumor cells. In 2018, Yong et al.¹⁵ synthesized a series of thieno[2,3-d]pyrimidine derivatives by reacting 5-substituted-4-chlorothienopyrimidine and (3-(substituted-phenyl)-isoxazole-5-yl)-methanol in dried isopropyl alcohol with triethylamine as catalyst. Among them, 6-methyl-4-{[3-(4-chlorophenyl)-isoxazol-5-yl-]-methoxy-}-thieno[2,3-d]pyrimidine (VIII) was the most potent inhibitors of tumor cells. In 2022, Elmongy et al.¹⁶ synthesized a series of thieno[2,3-d]pyrimidine derivatives, and monitored the inhibitory activity of the compound IX against breast cancer cells and non-small cell lung cancer, with inhibitory activity ranging from 43 to 87% (Figure 2).

Figure 2
Thieno[2,3-d]pyrimidine derivatives in the literature.

A series of thieno[2,3-d]pyrimidine derivatives were synthesized in consideration of the important cytotoxic activity of thieno[2,3-d]pyrimidine skeleton compounds.

In this study, we are interested in the cytotoxic activity of the widely reported thieno[2,3-d]pyrimidine derivatives via different synthetic methods. There are two main synthesis routes of thieno[2,3-d]pyrimidine derivatives reported in the literature: (i) first, construct the thiophene ring, and then synthesize starting from the thiophene ring; (ii) synthesis from pyrimidine ring.¹⁷,¹⁸,¹⁹,²⁰,²¹ There are more research on the former, but relatively few on the latter. The first synthetic route was found: Tolan et al.²² showed that the reaction of substituted 2-aminothiophene-3-carbonitrile (X) and substituted acetic acid (RCOOH) in 1,4-dioxane and phosphoryl trichloride afforded the corresponding scaffold XI (Figure 3). Isakhanyan et al.²³ introduced the synthesis of thieno[2,3-d] pyrimidine-4-one derivatives (XIII) using a cyclization reaction between 2-aminothiophene-3-carbonitrile (XII) and acyl chloride in 1,4-dioxane by refluxing in the presence of concentrated HCl in ethanol (Figure 4). The second synthetic route was found: Brough et al.²⁴ prepared 2-amino-4-chloro-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (XIV) with 2-amino-4,6-dichloro-5-pyrimidine carbaldehyde (XV) and ethyl-2-mercaptoacetate as raw materials under alkaline conditions (Figure 5). Eissa et al.²⁵ reacted ethyl chloroacetate with 4-mercapto-2-methyl-sulfanyl-6-naphthalen-1-yl-pyrimidine-5-carbonitrile (XVI) to obtain an intermediate compound XVII, and 5-amino-thieno[2,3-d]pyrimidine (XVIII) was obtained by intramolecular rearrangement under alkaline conditions (Figure 6).

Figure 3
Route for synthesizing compound XI containing thieno[2,3-d]pyrimidine.

Figure 4
Route for synthesizing compound XIII containing thieno[2,3-d]pyrimidine.

Figure 5
Route for synthesizing compound XV containing thieno[2,3-d]pyrimidine.

Figure 6
Route for synthesizing compound XVIII containing thieno[2,3-d]pyrimidine.

In recent years, microwave-assisted organic synthesis has received increasing attention as an efficient and portable tool for drug synthesis. Microwave synthesis is suitable for a wide range of reactions, greatly reducing the reaction time, improving the reaction efficiency, and reducing the synthesis of by-products. Microwave irradiation technique can be used for the synthesis of thieno[2,3-d]pyrimidine derivatives.

Interestingly, a compound with a similar structure (Figure 7, compound XIX) was developed as a novel anticancer drug with VEGFR-2 kinase inhibitory activity,²⁶ this compound is a pyridino[2,3-d]thieno pyrimidine scaffold, which is not extensively reported as anti-triple-negative breast cancer compounds. In this paper, a series of thieno[2,3-d]pyrimidine derivatives were designed and synthesized as potential anti-triple-negative breast cancer compounds based on bioisosteric modification strategy with the major aim to improve and enhance the drug activation properties by introducing highly polar groups.

Figure 7
Compound XIX.²⁶

Benzothieno[2,3-d]pyrimidine derivative (XIX, a novel VEGFR-2 inhibitor) was the lead compound. This series was designed to bear the essential pharmacodynamic fragments for anticancer activity, aiming at maintaining the same binding interaction between the N-1 nitrogen of the fused pyrimidine scaffolds and the hinge region NH. The structure (Figure 7) was modified: the five membered ring was replaced by hexatomic ring, and the nonpolar cyclohexyl moiety was replaced by its oxygenated isostere congener derivative. The substituted aromatic group was replaced by various substituting groups, which were either electron-withdrawing or electron-donating, resulting in compounds a-w (Scheme 1).

Two problems were solved in this study: (i) a series of thieno[2,3-d]pyrimidine derivatives a-w obtained by microwave irradiation technology (Figure 8); (ii) to evaluate the cytotoxic activity of the synthesized compounds against MDA-MB-231 cell.

Scheme 1
Synthetic route of target compounds a-w. Reagents and conditions: (a) aldehyde (i, 10 mmol), nitrile (ii, 10 mmol), sulfur (10 mmol), triethylamine (10 mmol), ethyl alcohol 10 mL, room temperature, 5 h (yield 75%); (b) iii (10 mmol), DMF-DMA (25 mmol), 70 °C and irradiation at 200 W, 20 min (yield 95%); (c) iv (4.25 mmol), amine (5.1 mmol), acetic acid (10 mL), 120 °C and irradiation at 200 W, 1 h.

Figure 8
Main structure of synthesized compounds (for example: new compound g).

Results and Discussion

Scheme 1 summarizes the synthesis strategy used in this study. 2-Amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carbonitrile was synthesized by a modified Gewald method using the alkali catalyst triethylamine (TEA) as a catalyst and pyranone, malononitrile, and sulfur in ethanol. In order to show the advantages of the current work, we will use triethylamine as base catalyst. Compared to other base catalysts, this method is inexpensive and environmentally friendly, no heating is required, and the reaction can be carried out at room temperature. The product precipitates naturally without the need to pass through the column due to the high polarity of the medium.

Regarding the synthesis of the intermediate compound iv (N'-(3-cyano-4,5,6,1-tetrahydrobenzo[b]thiophene-2-yl) N,N-dimethylmethanimidamide), Zhan et al.²⁷ reported that the reaction of 2-amino-5-bromothiophene-3-carbonitrile and N,N-dimethylformamide dimethyl acetal (DMF-DMA) were reacted to obtain (E)-N'-(5-bromo-3-cyanothiophen-2-yl)-N,N-dimethylformimidamide. In 2004, Yoon et al.²⁸ explored a parallel reaction under microwave conditions. Based on the above information, we can react 2-amino-4,1-dihydro-5H-thieno[2,3-c]pyran-3-carbonitrile with DMF-DMA under microwave irradiation to obtain compound iv in 95% yield. This method has short reaction time, high yield and simple post-treatment.

Compounds a-w (Table 1) were synthesized by acid-catalyzed Dimroth rearrangement between compound iv and a suitable aromatic amine under microwave radiation. The results showed that p-substituted aromatic amines reacted with compound iv in high yields. However, under the same reaction condition, o-substituted aromatic amines and compound iv could only form trace amounts of the desired compounds. The reaction yield of mesoaniline was slightly lower for halogen atoms (e.g., g, h, i). The weaker the electronegativity the easier the reaction is to carry out and the higher the yield (e.g., g, h, i). This new synthetic route involves only three steps, making the process simple and efficient. Therefore, the preparation of thieno[2,3-d] pyrimidine-4-amine by microwave reaction is convenient and in high yield. The proposed mechanism for this rearrangement l is described in Scheme 2.

Table 1
Preparation of the compounds a-w

Compound	R	mp / °C	Yielda/ %
a	Ph	157.0-158.0	50
b	2-MeC6H4	188.2-189.7	47
c b	3-MeC6H4	172.0-173.0	79
d	4-MeC6H4	174.2-175.5	62
eb	2-MeOC6H4	205.3-206.8	70
fb	3-MeOC6H4	130.0-131.2	83
gb	4-MeOC6H4	170.0-171.3	59
hb	2-FC6H4	219.8-221.4	73
i	3-FC6H4	162.2-163.1	41
j	4-FC6H4	190.6-191.9	84
kb	2-ClC6H4	170.9-171.7	29
lb	3-ClC6H4	168.5-169.7	59
mb	3-BrC6H4	186.6-188.1	70
nb	4-BrC6H4	188.9-190.0	58
ob	3-NCC6H4	233.3-234.7	23
pb	3-CH≡CC6H4	212.2-213.9	76
qb	3-F3CC6H4	185.0-186.0	18
rb	3-(CH3)3CC6H4	182.6-184.0	18
s	3,4-Cl2C6H3	183.5-184.7	63
tb	3,4-F2C6H3	186.3-187.8	74
ub	3,5-F2C6H3	197.6-199.0	34
v	3-Cl-4-FC6H3	219.9-221.5	75
wb	2-Me-3-ClC6H3	205.3-206.8	75

• ^aIsolated yield; ^bnew compounds. mp: melting point.

Scheme 2
Proposed mechanism for the Dimroth rearrangement.

The inhibitory effect of thienopyrimidine derivatives on different cancer cells was detected using the MTT method.²⁹ The MTT method can be referred to as the MTT colorimetric method, and its range of applications can be used to detect cell survival and growth. Once the cellular activity evaluation of 23 synthesized thienopyrimidine analogs was done, antitumor cellular activity tests of new compounds were performed to screen compounds with good targeting drug activity against triple-negative breast cancer cells (Table 2). Correspondingly, it was initially screened at a compound concentration of 50 μmol L^-1 using paclitaxel (PTX) as a positive control, and compounds with similar or stronger results than PTX were further tested for their half maximal inhibitory concentration (IC₅₀).

Table 2
Results of in vitro antitumor activity of compounds a-w

Compound	R	Inhibition rate (at 50 μM) / %
		MDA-MB-231	PTXa
a	Ph	23.1	56.4
b	2-MeC6H4	57.0	59.0
c	3-MeC6H4	38.7	59.0
d	4-MeC6H4	24.9	59.0
e	2-MeOC6H4	33.0	54.3
f	3-MeOC6H4	37.3	54.3
g	4-MeOC6H4	33.7	54.3
h	2-FC6H4	44.7	54.3
i	3-FC6H4	25.1	59.0
j	4-FC6H4	41.5	59.0
k	2-ClC6H4	41.5	54.3
l	3-ClC6H4	58.3	54.3
m	3-BrC6H4	32.7	54.3
n	4-BrC6H4	34.5	59.0
o	3-NCC6H4	43.3	56.6
p	3-CH≡CC6H4	43.1	56.6
q	3-F3CC6H4	40.4	54.3
r	3-(CH3)3CC6H4	20.8	54.3
s	3,4-Cl2C6H3	30.7	54.3
t	3,4-F2C6H3	54.0	55.3
u	3,5-F2C6H3	11.2	54.3
v	3-Cl-4-FC6H3	45.4	54.3
w	2-Me-3-ClC6H3	47.3	55.3

• ^aUsed as a positive control (standard PTX). MDA-MB-231: human breast cancer cells. PTX: paclitaxel.

By calculating and organizing the obtained data, compounds a-w were tested for biological activity against MDA-MB-231 at a concentration of 50 μmol L^-1, and it was found that all compounds of the series had different degrees of inhibitory effects on MDA-MB-231. Note that compounds with different substituents attached at different positions on the benzene ring resulted in significantly different rates of inhibition of cancer cells, suggesting that the same substituents will have different activities depending on their position on the R benzene ring. Different substituents attached at the identical position pertaining to the R benzene ring exhibited a great difference in the inhibition rate of cancer cells. This indicates that different atoms attached at the same position pertaining to the R benzene ring possessed distinct inhibitory effects on MDA-MB-231. The anticancer activity of compound l was slightly higher than that of PTX, which is meso-substituted and carries substituents that are more polar halogens. It is hypothesized that its spatial configuration, as well as the substituents it carries, affect the inhibition rate of the compounds against MDA-MB-231 to some extent. Here, the compound l was measured for its IC₅₀ value and calculated. The IC50 of l against MDA-MB-231 was obtained as 27.6 μM, while that of PTX against MDA-MB-231 was 29.3 μM, which was observed to be lower than that of PTX for l against MDA-MB-231.

The cytotoxic activity of MDA-MB-231 was assessed for 23 synthesized compounds, leading to the derivation of the following preliminary structure-activity relationships:

• (i) Compound l had the strongest cytotoxic activity against MDA-MB-231 cell line (IC₅₀ = 21.6 μM). The cytotoxic activity of the compounds replaced by electron-withdrawing group (l, Ar = m-ClPh) is higher than that of the other compounds (IC₅₀ = 29.3 μM), which may be due to the presence of p-π conjugation effect (l, Ar = m-ClPh).

• (ii) All the synthesized compounds exhibited cytotoxic activity against MDA-MB-231 cell line at the drug concentration of 50 μM. Moreover, all the synthesized compounds showed significant selective cytotoxicity effects on MDA-MB-231.

Conclusions

Gewald, amination, and Dimroth rearrangement reactions were utilized in the synthesis of 23 thieno[2,3-d] pyrimidin-4-amines. Moreover, the effect of antitumor activity on breast cancer cell MDA-MB-231 was detected, and it was concluded that all compounds of the series had an inhibitory effect. Compound l was screened for stronger inhibition of breast cancer cell MDA-MB-231 than the positive control, and the series of derivatives can be further structurally optimized as well as investigated for mechanism of action to obtain potential anti-breast cancer cellular drugs for clinical studies.

Experimental

Every reagent as well as starting materials, except if noted otherwise, were purchased from MACKLIN unpurified (MACKLIN, Shanghai, China). All reported yields are the maximum observed, they can be up to 8% lower given slight variation in weighing reagents, solvent quality, and manipulation losses. Each melting points were measured using an uncorrected METTLER TOLEDO MP90 (Mettler Toledo, Zurich, Switzerland) melting point apparatus. Using tetramethylsilane (TMS) as the internal standard, ¹H nuclear magnetic resonance (NMR) as well as ¹³C NMR spectra were documented on a Bruker AVANCE II HD 400 MHz (Bruker, Billerica, USA). Mass spectrometry (MS) was performed in an LCMS-2020 with electrospray ionization (ESI, Shimadzu, Kyoto, Japan). Additionally, via KBr pellets, infrared (IR) spectra were captured using a VERTEX 80/Raman II FTIR (Bruker, Karlsruhe, Germany) spectrometer. Meanwhile, a Triple TOF™ 5600+ (AB SCIEX, California, USA) was utilized to record the mass spectra. Next, the Anton Paar Microwave

Synthesizer (Anton Paar, Shanghai, China) has been utilized to conduct the microwave-assisted reactions. By employing silica gel GF254 (HAIYANG, Qingdao, China), thin layer chromatography (TLC) was utilized to track the reactions. Further details are available in the Supplementary Information (SI) section.

Experimental data

Synthesis of 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carbonitrile (iii)

Pyrantel (1.00 g, 10 mmol), sulfur (0.32 g, 10 mmol), malononitrile (0.66 g, 10 mmol), as well as ethanol (10 mL) were incorporated into a 50 mL round-bottom flask. Triethylamine (1.01 g, 10 mmol) was then slowly introduced. Next, the reaction was mixed for 5 h at room temperature with TLC observation. It was filtered after the reaction. The filter cake was then washed with ethanol to obtain a crude product, which was recrystallized with ethanol to obtain the light pink product iii. After drying, it was weighed to be 1.35 g with a yield of 15%.

Synthesis of N'-(3-cyano-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-N,N-dimethylmethanimidamide (iv)

Compound 2-amino-4,1-dihydro-5H-thieno[2,3-c] pyran-3-carbonitrile iii (1.80 g, 10 mmol), N,N-dimethylformamide dimethyl acetal DMF-DMA (4.11 mL, 25 mmol), and magnets were incorporated to a 30 mL microwave tube. Afterward, the reaction temperature was set to 10 °C. Note that the reaction time was set to 10 min as well as the microwave power was modified to 200 W. Once the reaction was concluded, the temperature was brought down to room level. Subsequently, it was streamed into 20 mL of ice water and filtered. Then, ice water was utilized to wash the filter cake to give the yellow solid iv. After drying, it was weighed to give 2.35 g in 95% yield.

Synthesis of thieno[2,3-d]pyrimidin-4-amine derivatives (a-w)

The yellow solid compound N'-(3-cyano-4,1-di-hydro-5H-thieno[2,3-c]pyran-2-yl)-N,N-dimethyl-methanimidamide iv (1.00 g, 4.25 mmol), aniline with different substituent groups (5.1 mmol) and 10 mL of acetic acid as well as magnets were added in a 30 mL microwave tube. Next, they were all mixed well. The tube was put into a microwave synthesizer and set aside to react for 1 h. TLC was used to track the completion of the reaction. The majority of the acetic acid evaporated under lower pressure at the final stage of the reaction. They were then left to stand overnight in a refrigerator. The target compounds a-w were filtered and washed with ether.

Structural characterization of compounds a-w

N-Phenyl-5,8-dihydro-6H-pyrano[4',3':4,5]thieno[2,3-d] pyrimidin-4-amine (a)

White solid, 0.60 g, 50%, mp 157.0-158.0 °C; IR (KBr) ν / cm^-1 3434, 3059, 2982, 2838, 1598, 1563, 1497, 1445, 1355, 977, 781, 756, 692; ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (s, 1H), 8.20 (s, 1H), 7.66 (d, J 7.5 Hz, 2H), 7.36 (t, J 8.0 Hz, 2H), 7.10 (t, J 7.3 Hz, 1H), 4.83 (s, 2H), 3.97 (t, J 5.48 Hz, 2H), 3.23 (t, J 5.63 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.3, 155.0, 152.4, 139.1, 130.6, 128.4, 124.6, 123.4, 122.2, 116.2, 64.7, 63.9, 25.9.

N-(o-Tolyl)-5,8-dihydro-6H-pyrano[4',3':4,5]thieno[2,3-d] pyrimidin-4-amine (b)

White solid, 0.59 g, 48%, mp 188.2-189.7 °C; IR (KBr) ν / cm^-1 3403, 2987, 2826,1557, 1511, 1470, 1419, 1303, 977, 874, 754; ¹H NMR (400 MHz, chloroform-d) δ 8.48 (s, 1H), 7.89 (d, J 8.0 Hz, 1H), 7.29 (t, J 7.9 Hz, 2H), 7.16 (t, J 7.3 Hz, 2H), 6.82 (s, 1H), 4.90 (t, J 2.0 Hz, 2H), 4.13 (t, J 5.5 Hz, 2H), 3.13-3.17 (m, 2H), 2.33 (s, 3H); ¹³CNMR (100 MHz, DMSO-d₆) δ 166.4, 154.6, 152.2, 131.1, 124.4, 118.6, 118.5, 118.4, 117.0, 116.8, 116.2, 111.4, 111.1, 64.7, 63.8, 25.8; MS (ESI) m/z, calcd. for C₁₆H₁₆N₃OS [M + H]+: 298, found: 298.

N-(m-Tolyl)-5,8-dihydro-6H-pyrano[4',3':4,5]thieno[2,3-d] pyrimidin-4-amine (c)

White solid, 1.00 g, 79%, mp 172.0-173.0 °C; IR (KBr) ν / cm^-1 3457, 2978, 2846, 2822, 1617, 1573, 1514, 1485, 1375, 973, 886, 781, 690; ¹H NMR (400 MHz, chloroform-d) δ 8.52 (s, 1H), 7.46 (d, J 7.4 Hz, 1H), 7.42 (s, 1H), 7.28 (t, J 7.7 Hz, 1H), 6.97 (t, J 7.6 Hz, 2H), 4.89 (t, J 2.0 Hz, 2H), 4.12 (t, J 5.5 Hz, 2H), 3.16-3.24 (m, 2H), 2.39 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.2, 155.0, 152.4, 139.0, 137.7, 130.6, 128.3, 124.6, 124.2, 122.6, 119.2, 116.2, 64.7, 63.9, 25.9, 21.2; MS (ESI) m/z, calcd. for C₁₆H₁₆N₃OS [M + H]+: 298, found: 298.

N-(p-Tolyl)-5,8-dihydro-6H-pyrano[4',3':4,5]thieno[2,3-d] pyrimidin-4-amine (d)

White solid, 0.78 g, 62%, mp 174.2-175.5 °C; IR (KBr) ν / cm^-1 3445, 2974, 2861, 2844, 1608, 1565, 1507, 1439, 973, 872, 812, 783, 690; ¹H NMR (400 MHz, chloroform-d) δ 8.48 (s, 1H), 7.48 (d, J 8.3 Hz, 2H), 7.19 (d, J 8.7 Hz, 2H), 6.90 (s, 1H), 4.84 (t, J 1.8 Hz, 1H), 4.10 (t, J 5.5 Hz, 2H), 3.13 (t, J 5.3 Hz, 2H), 2.35 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.1, 155.2, 152.4, 136.4, 132.6, 130.4, 128.8, 124.6, 122.4, 116.0, 64.7, 63.9, 26.0, 20.5; MS (ESI) m/z, calcd. for C₁₆H₁₆N₃OS [M + H]+: 298, found: 298.

N-(2-Methoxyphenyl)-5,8-dihydro-6H-pyrano[4',3':4,5] thieno[2,3-d]pyrimidin-4-amine (e)

White solid, 1.10 g, 83%, mp 205.3-206.8 °C; IR (KBr) ν / cm^-1 3445, 2974, 2861, 2844, 1608, 1565, 1507, 1439, 973, 872, 812, 783, 690; ¹³C NMR (100 MHz, DMSO-d₆) ò 165.5, 154.4, 152.6, 149.0, 131.1, 128.1, 123.8, 123.4, 120.8, 120.5, 116.0, 110.9, 64.6, 63.8, 56.2, 25.8; MS (ESI) m/z, calcd. for C16H16N3O2S [M + H]⁺: 314, found: 314.

N-(3-Methoxyphenyl)-5,8-dihydro-6H-pyrano[4',3':4,5] thieno[2,3-d]pyrimidin-4-amine (f)

Yellow solid, 0.78 g, 59%, mp 130.0-131.2 °C; IR (KBr) ν / cm^-1 3447, 2995, 2978, 2870, 2832, 1602, 1563, 1516, 1454, 1280, 998, 876, 748; ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (s, 1H), 8.16 (s, 1H), 7.32-7.35 (m, 1H), 7.26 (d, J 5.5 Hz, 2H), 6.64-6.71 (m, 1H), 4.84 (s, 2H), 3.98 (t, J 5.6 Hz, 2H), 3.76 (s, 3H), 3.20-3.27 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.7, 159.9, 155.4, 152.8, 140.7, 131.2, 129.6, 125.0, 116.8, 114.6, 109.1, 108.2, 65.2, 64.3, 55.5, 26.3; MS (ESI) m/z, calcd. for C₁₆H₁₆N₃O₂S [M + H]+: 314, found: 314.

N-(4-Methoxyphenyl)-5,8-dihydro-6H-pyrano[4',3':4,5] thieno[2,3-d]pyrimidin-4-amine (g)

White solid, 0.94 g, 71%, mp 170.0-171.3 °C; IR (KBr) ν / cm^-1 3459, 2984, 2921, 2828, 1598, 1561, 1501, 1443, 1256, 977, 874, 824, 775, 701; ¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (s, 1H), 8.07 (s, 1H), 7.50 (d, J 9.0 Hz, 2H), 6.94 (d, J 9.2 Hz, 2H), 4.83 (s, 2H), 3.97 (t, J 4.0 Hz, 2H), 3.76 (s, 3H), 3.21 (t, J 5.7 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.4, 156.4, 155.8, 153.0, 132.2, 130.6, 125.2, 125.0, 116.1, 114.0, 65.2, 64.3, 55.6, 26.4; MS (ESI) m/z, calcd. for C₁₆H₁₆N₃O₂S [M + H]+: 314, found: 314.

N-(2-Fluorophenyl)-5,8-dihydro-6H-pyrano[4',3':4,5] thieno[2,3-d]pyrimidin-4-amine (h)

Yellow solid, 0.53 g, 41%, mp 219.8-221.4 °C; IR (KBr) ν / cm^-1 3436, 2980, 2910, 2824, 1596, 1559, 1501, 1435, 1346, 1235, 975, 827, 746, 697; ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (s, 1H), 8.21 (s, 1H), 7.80-7.88 (m, 1H), 7.31-7.39 (m, 3H), 4.84 (s, 2H), 4.00 (t, J 5.5 Hz, 2H), 3.19 (t, J 5.6 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.2, 155.2, 152.5, 130.8, 127.0, 126.6, 126.2, 124.4, 124.3, 116.0, 115.6, 115.4, 64.6, 63.8, 26.0; MS (ESI) m/z, calcd. for C₁₅H₁₃FN₃OS [M + H]+: 302, found: 302.

N-(3-Fluorophenyl)-5,8-dihydro-6H-pyrano[4',3':4,5] thieno[2,3-d]pyrimidin-4-amine (i)

Yellow solid, 1.08 g, 84%, mp 162.2-163.1 °C; IR (KBr) ν / cm^-1 3445, 2972, 2879, 2844, 1606, 1582, 1505, 1448, 1280, 979, 864, 680; ¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.34 (s, 1H), 7.67 (dt, J 11.9, 2.4 Hz, 1H), 7.46 (d, J 9.2 Hz, 1H), 7.38-7.46 (m, 1H), 6.90 (td, J 8.5, 2.7 Hz, 1H), 4.84 (s, 2H), 4.04 (q, J 8.2 Hz, 2H), 3.23 (t, J 5.6 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.6, 154.6, 152.2, 141.1, 141.0, 131.2, 130.0, 124.6, 117.4, 116.6, 109.6, 108.2, 64.8, 63.9, 25.8; MS (ESI) m/z, calcd. for C₁₅H₁₃FN₃OS [M + H]+: 302, found: 302.

N-(4-Fluorophenyl)-5,8-dihydro-6H-pyrano[4',3':4,5] thieno[2,3-d]pyrimidin-4-amine (j)

White solid, 0.39 g, 31%, mp 190.6-191.9 °C; IR (KBr) ν / cm^-1 3409, 3067, 2925, 2840, 1611, 1561, 1503, 1441, 1282, 977, 876, 833, 777, 692; ¹H NMR (400 MHz, chloroform-d) δ 8.49 (s, 1H), 7.52-7.56 (m, 2H), 7.09-7.17 (m, 2H), 6.92 (s, 1H), 4.88 (t, J 2.0 Hz, 2H), 4.11 (t, J 5.5 Hz, 2H), 3.14-3.22 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.2, 159.7, 157.3, 155.0, 152.4, 135.2, 130.6, 124.6, 116.0, 115.1, 64.7, 63.8, 26.0; MS (ESI) m/z, calcd. for C₁₅H₁₃FN₃OS [M + H]+: 302, found: 302.

N-(2-Chlorophenyl)-5,8-dihydro-6H-pyrano[4',3':4,5] thieno[2,3-d]pyrimidin-4-amine (k)

White solid, 0.80 g, 59%, mp 170.9-171.7 °C; IR (KBr) ν / cm^-1 3428, 3048, 3007, 2844, 1594, 1565, 1499, 1445, 1297, 1086, 990, 789, 738, 684; ¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (s, 1H), 8.20 (s, 1H), 8.07 (dd, J 8.1, 1.6 Hz, 1H), 7.55 (dd, J 8.0, 1.5 Hz, 1H), 7.40 (td, J 7.7, 1.5 Hz, 1H), 7.23 (td, J 7.7, 1.6 Hz, 1H), 4.84 (t, J 1.9 Hz, 2H), 4.01 (t, J 5.5 Hz, 2H), 3.22-3.30 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.2, 155.0, 152.4, 135.8, 131.0, 129.4, 127.6, 127.5, 126.2, 126.0, 124.2, 116.0, 64.6, 63.8, 26.2; MS (ESI) m/z, calcd. for C15H13ClN3OS [M + H]⁺: 318, found: 318.

N-(3-Chlorophenyl)-5,8-dihydro-6H-pyrano[4,,3':4,5] thieno[2,3-d]pyrimidin-4-amine (l)

Yellow solid, 1.08 g, 80%, mp 168.5-169.7 °C; IR (KBr) ν / cm^-1 3416, 2987, 2933, 2838, 1600, 1557, 1503, 1478, 1095, 979, 876, 864, 682; ¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.33 (s, 1H), 7.84 (t, J 2.1 Hz, 1H), 7.64 (d, J 8.1 Hz, 1H), 7.37 (t, J 8.1 Hz, 1H), 7.13 (d, J 8.5 Hz, 1H), 4.84 (t, J 2.1 Hz, 2H), 3.98 (t, J 5.5 Hz, 2H), 3.23-3.31 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.5, 154.6, 152.2, 140.7, 132.7, 131.2, 130.0, 124.6, 122.8, 121.1, 120.2, 116.5, 64.7, 63.8, 25.8; MS (ESI) m/z, calcd. for C₁₅H₁₃ClN₃OS [M + H]+: 318, found: 318.

N-(3-Bromophenyl)-5,8-dihydro-6H-pyrano[4,,3':4,5] thieno[2,3-d]pyrimidin-4-amine (m)

Yellow solid, 0.90 g, 58%, mp 186.6-188.1 °C; IR (KBr) ν / cm^-1 3418, 2991, 2927, 2832, 1600, 1555, 1505, 1445, 1268, 1091, 992, 874, 857, 682; ¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.31 (s, 1H), 7.96 (t, J 1.9 Hz, 1H), 7.69 (d, J 8.1 Hz, 1H), 7.31 (t, J 8.0 Hz, 1H), 7.26 (d, J 8.0 Hz, 1H), 4.84 (s, 2H), 3.98 (t, J 5.5 Hz, 2H), 3.24 (d, J 5.4 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.5, 154.5, 152.2, 140.8, 131.2, 130.3, 125.7, 124.5, 124.0, 121.2, 120.6, 116.5, 64.7, 63.8, 25.8; MS (ESI) m/z, calcd. for C₁₅H₁₃BrN₃OS [M + H]+: 362; 364, found: 362; 364.

N-(4-Bromophenyl)-5,8-dihydro-6H-pyrano[4,,3':4,5] thieno[2,3-d]pyrimidin-4-amine (n)

Yellow solid, 0.27 g, 18%, mp 188.9-190.0 °C; IR (KBr) ν / cm^-1 3459, 2976, 2877, 2838, 1604, 1557, 1503, 1437, 1070, 971, 880, 822, 777, 690; ¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (s, 1H), 8.29 (s, 1H), 7.65 (d, J 9.0 Hz, 2H), 7.53 (d, J 8.7 Hz, 2H), 4.84 (s, 2H), 3.97 (t, J 5.6 Hz, 2H), 3.19-3.25 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.4, 154.6, 152.2, 138.6, 131.2, 131.0, 124.6, 123.8, 116.4, 115.0, 64.7, 63.8, 25.8; MS (ESI) m/z, calcd. for C₁₅H₁₃BrN₃OS [M + H]+: 362; 364, found: 362; 364.

3-((5,8-Dihydro-6H-pyrano[4;3':4,5]thieno[2,3-d]pyrimidin-4-yl)amino)-benzonitrile (o)

Yellow solid, 1.00 g, 76%, mp 233.3-234.7 °C; IR (KBr) ν / cm^-1 3436, 2976, 2939, 2836, 2225, 1613, 1559, 1511, 1485, 1303, 983, 862, 672; ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 7.98 (d, J 7.7 Hz, 1H), 7.47-7.60 (m, 2H), 4.84 (s, 2H), 3.98 (t, J 5.5 Hz, 2H), 3.23 (t, J 5.6 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.7, 154.4, 152.2, 140.2, 131.4, 129.8, 126.6, 126.4, 124.6, 124.5, 118.8, 116.6, 111.2, 64.7, 63.8, 25.8; MS (ESI) m/z, calcd. for C₁₆H₁₂N₄OS [M + H]+: 309.05, found: 309.08.

N-(3-Ethynylphenyl)-5,8-dihydro-6H-pyrano[4,,3':4,5] thieno[2,3-d]pyrimidin-4-amine (p)

Yellow solid, 0.25 g, 19%, mp 212.2-213.9 °C; IR (KBr) ν / cm^-1 3453, 3277, 3053, 2978, 2840, 1604, 1553, 1499, 1470, 1448, 977, 876, 789, 680; ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (s, 1H), 8.26 (s, 1H), 7.83 (s, 1H), 7.73 (d, J 8.2 Hz, 1H), 7.36 (t, J 7.9 Hz, 1H), 7.19 (d, J 7.7 Hz, 1H), 4.83 (s, 2H), 4.20 (s, 1H), 3.97 (t, J 5.6 Hz, 2H), 3.3 (t, J 5.6 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.0, 155.8, 152.7, 137.4, 133.7, 130.3, 130.0, 126.4, 126.1, 125.6, 124.6, 115.6, 64.7, 64.0, 63.8, 26.2, 18.0; MS (ESI) m/z, calcd. for C17H14N3OS [M + H]⁺: 308.05, found: 308.09.

N-(3-(Trifluoromethyl)phenyl)-5,8-dihydro-6H-pyrano[4',3':4,5]thieno[2,3-d]pyrimidin-4-amine (q)

Yellow solid, 0.54 g, 36%, mp 185-186 °C; IR (KBr) ν / cm^-1 3430, 3011, 2984, 2869, 1598, 1563, 1518, 1450, 1328, 1120, 965, 800, 662; ¹HNMR (400 MHz, DMSO-d₆) δ 8.48 (s, 2H), 8.01 (s, 1H), 8.00 (d, J 8.1 Hz, 1H), 1.58 (t, J 1.9 Hz, 1H), 1.42 (d, J 1.8 Hz, 1H), 4.84 (s, 2H), 3.98 (t, J 5.6 Hz, 2H), 3.25 (t, J 5.6 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.6, 154.6, 152.2, 140.0, 131.2, 129.5, 129.1, 125.6, 124.6, 122.8, 119.4, 111.9, 116.6, 64.8, 63.9, 25.8; MS (ESI) m/z, calcd. for C₁₆H₁₃F₃N₃OS [M + H]+: 352.00, found: 352.01.

N-(3-(tert-Butyl)phenyl)-5,8-dihydro-6H-pyrano[4;3':4,5] thieno[2,3-d]pyrimidin-4-amine (r)

White solid, 0.94 g, 65%, mp 182.6-184 °C; IR (KBr) ν / cm^-1 3451, 3024, 2980, 2958, 2852, 1611, 1559, 1489, 1439, 1301, 948, 855, 196, 690; ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 8.11 (s, 1H), 1.59 (t, J 2.0 Hz, 1H), 1.54 (d, J 1.9 Hz, 1H), 1.28 (t, J 1.9 Hz, 1H), 1.13 (d, J 1.8 Hz, 1H), 4.83 s, 2H), 3.98 (t, J 5.5 Hz, 2H), 3.24 (t, J 5.6 Hz, 2H), 1.30 (s, 9H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.2, 155.2, 152.4, 151.1, 138.1, 130.5, 128.0, 124.6, 120.5, 119.8, 119.2, 116.2, 64.1, 63.9, 34.4, 31.2, 25.9; MS (ESI) m/z, calcd. for C₁₉H₂₂N₃OS [M + H]+: 340.10, found: 340.15.

N-(3,4-Dichlorophenyl)-5,8-dihydro-6H-pyrano[4;3':4,5] thieno[2,3-d]pyrimidin-4-amine (s)

Yellow solid, 1.01 g, 61%, mp 183.5-184.1 °C; IR (KBr) ν / cm^-1 3451, 3010, 2912, 2850, 1594, 1555, 1495, 1445, 919, 1093, 808, 185, 138, 691; ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.38 (s, 1H), 8.02 (d, J 2.6 Hz, 1H), 1.69 (dd, J 8.8, 2.6 Hz, 1H), 1.58 (d, J 8.8 Hz, 1H), 4.84 (s, 2H), 3.91 (t, J 5.6 Hz, 2H), 3.25 (t, J 5.6 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.6, 154.2, 152.2, 139.4, 131.4, 130.6, 130.2, 124.5, 124.4, 122.8, 121.8, 116.6, 64.1, 63.8, 25.8; MS (ESI) m/z, calcd. for C₁₅H₁₂Cl₂N₃OS [M + H]+: 351.95, found: 352.00.

N-(3,4-Difluorophenyl)-5,8-dihydro-6H-pyrano[4;3':4,5] thieno[2,3-d]pyrimidin-4-amine (t)

Yellow solid, 0.45 g, 33%, mp 186.3-181.8 °C; IR (KBr) ν / cm^-1 3440, 3063, 2910, 2828, 1631,1580, 1514, 1443, 1218, 1151, 981, 864, 802, 115, 692; ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (s, 1H), 8.04 (s, 1H), 1.54 (d, J 6.4 Hz, 1H), 1.28 (d, J 1.3 Hz, 1H), 1.24 (t, J 1.4 Hz, 1H), 1.16 (t, J 1.3 Hz, 1H), 4.83 (s, 2H), 3.99 (t, J 5.5 Hz, 1H), 3.20 (t, J 3.2 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.0, 155.8, 152.1, 131.4, 133.1, 130.3, 130.0, 126.4, 125.6, 124.6, 115.6, 64.1, 64.0, 26.2, 18.0; MS (ESI) m/z, calcd. for C₁₅H₁₂F₂N₃OS [M + H]+: 320.05, found: 320.01.

N-(3,5-Difluorophenyl)-5,8-dihydro-6H-pyrano[4;3':4,5] thieno[2,3-d]pyrimidin-4-amine (u)

White solid, 1.01 g, 19%, mp 191.6-199 °C; IR (KBr) ν / cm^-1 3453, 3119, 2914, 2894, 1606, 1511, 1565, 1414, 1318, 1151, 990, 822, 659; ¹H NMR (400 MHz, DMSO-d₆) δ 8.53 (s, 1H), 8.46 (s, 1H), 1.50 (dd, J 9.9, 2.3 Hz, 2H), 6.89 (t, J 9.3 Hz, 1H), 4.84 (s, 2H), 3.91 (t, J 5.6 Hz, 2H), 3.22 (t, J 5.5 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.8, 163.6, 161.2, 154.1, 152.1, 142.0, 131.1, 124.4, 116.8, 104.0, 103.8, 91.8, 64.8, 63.8, 25.8; MS (ESI) m/z, calcd. for C₁₅H₁₂F₂N₃OS [M + H]+: 320.05, found: 320.01.

N-(3-Chloro-4-fluorophenyl)-5,8-dihydro-6H-pyrano[4',3':4,5] thieno[2,3-d]pyrimidin-4-amine (v)

Yellow solid, 0.11 g, 54%, mp 219.9-221.5 °C; IR (KBr) ν / cm^-1 3385, 3055, 2914, 2834, 1598, 1511, 1495, 1441, 1266, 1202, 1091, 994, 816, 843, 181, 101, 686; ¹H NMR (400 MHz, chloroform-d) δ 8.53 (s, 1H), 1.84 (dd, J 6.4, 2.1 Hz, 1H), 1.45 (ddd, J 8.9, 4.1, 2.1 Hz, 1H), 1.15 (t, J 8.1 Hz, 1H), 6.89 (s, 1H), 4.89 (t, J 2.0 Hz, 2H), 4.13 (t, J 5.5 Hz, 2H), 3.14-3.22 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.4, 154.6, 152.2, 136.3, 131.0, 124.5, 123.8, 122.8, 118.8, 118.1, 116.6, 116.2, 64.1, 63.8, 25.9; MS (ESI) m/z, calcd. for C15H12ClFN3OS [M + H]⁺: 336, found: 336.

N-(3-Chloro-2-methylphenyl)-5,8-dihydro-6H-pyrano[4',3:4,5]thieno[2,3-d]pynmidin-4-amine (w)

Yellow solid, 0.93 g, 66%, mp 205.3-206.8 °C; IR (KBr) ν / cm^-1 3461, 3110, 3081, 2966, 2850, 1639, 1580, 1501, 1443, 1285, 1016, 911, 822, 146, 101; ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (s, 2H), 1.39 (dd, J 11.0, 1.9 Hz, 2H), 1.26 (t, J 1.9 Hz, 1H), 4.83 (s, 2H), 3.99 (t, J 5.6 Hz, 2H), 3.20 (t, J 5.6 Hz, 2H), 2.19 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 166.4, 159.4, 156.0, 152.8, 139.4, 133.9, 133.0, 130.5, 121.2, 126.3, 124.9, 115.8, 64.9, 64.1, 26.4, 15.6; MS (ESI) m/z, calcd. for C₁₆H₁₅ClN₃OS [M + H]+: 332.00, found: 332.06.

Supplementary Information

Supplementary information is available free of charge at http://jbcs.sbq.org.br as PDF file.https://minio.scielo.br/documentstore/1678-4790/RXBkmPcxK53C7jqGj4rz6Gr/07cb4609a38545e9cb9ad6397ffc0bcc6ffce878.pdf

Acknowledgments

This work was supported by the National Natural Science Foundation of China (grant No. 82103995) and Yancheng City Basic Research Guidance Project (YCBK2023054).

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Edited by

• Editor handled this article: Brenno A. D. Neto

Publication Dates

• Publication in this collection
  02 Nov 2024
• Date of issue
  2025

History

• Received
  19 June 2024
• Accepted
  11 Oct 2024