English

• 1.   Introduction

  Thienopyrimidine nucleus has received considerable attention over the past years due to their wide ranging pharmacological and biological activities.^[1~3] Among them, thieno[2, 3-d]pyrimidin-4-amine derivatives are useful as fungicides and as antiviral, anti-inflammatory, antipyretic, antibacterial agents^[4~8]. In particular, they are potent and highly selective inhibitors of hepatitis C virus, ^[9] interleukin-1 receptor-associated kinase, ^[10] fms-like tyrosine kinase^[11] and phosphdiesteraase 7B.^[12] Furthermore, it was documented that fusion of the thieno[2, 3-d]pyrimidine core with five-, six- or seven-membered cycloalkyl lipophilic moieties conserved the antitumor activity^[13~19] as revealed by 4-substituted-6, 7-dihydro-5H-cyclopenta[4, 5]thieno[2, 3-d]pyrimidine (Ⅰ and Ⅱ) and 4-substituted-5, 6, 7, 8-tetra- hydrobenzo[4, 5]thieno[2, 3-d]pyrimidine (Ⅲ) which was described to exert high anticancer activity. Moreover, Song et al.^[20] reported that the presence of trifluoromethyl moiety at position 2 in VI showed excellent antitumor activity against MCF-7 and HepG2. There has been lots of literatures reported the synthetic route of six or four-membered thieno[2, 3-d]pyrimidine, but studies related to the five- membered are scarce.^{[21, 22]} Therefore, our research herein focused on the synthesis a novel series 4-substituted-6, 7- dihydro-5H-cyclopenta[4, 5]thieno[2, 3-d]pyrimidine hoping to obtain new derivatives with good antitumor activities.

  Figure 1

  

  Figure 1.  Examples of pharmaceutically thieno[2, 3-d]pyrimidine core with five-, six-membered cycloalkyl lipophilic moieties

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  Traditional preparation of thieno[2, 3-d]pyrimidin-4- amine derivatives involves the reaction of amines and 4-chlorothieno[2, 3-d]pyrimidine. The 4-chlorothieno[2, 3-d]pyrimidine were synthesized by chlorination of the corresponding thieno[2, 3-d]-pyrimidin-4(3H)-one that were in turn prepared by heating N-formyl derivatives with formic acid, triethyl orthoformate or formamide (Scheme 1).^{[13, 22~25]} Overall, this multi-step synthetic route is fairly labor intensive, requires several intermediate purifications, as well as a relatively high temperature reaction. In our view, access to the target compounds would require an alternate synthetic route to be effectively accessed via library synthesis.

  Scheme 1

  

  Scheme 1.  Traditional preparation of thieno[2, 3-d]pyrimidin-4-amine

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  Looking for an efficient method allowing incorporation of the 4-anilino group during ring cyclisation, Zhan et al.^[26] have reported the synthesis of thieno[2, 3-d]-pyrimidin- 4-amines performed in only two steps via condensation of anilines with an intermediate (E)-N-(5-bromo-3-cyano- thiophen-2-yl)-N, N-dimethylformimidamide, which was obtained by reaction of 2-amino-5-bromothiophene-3-car- bonitrile with N, N-dimethylformamide dimethyl acetal (DMF-DMA). In 2004, Han and co-workers^[27] described a microwave approach for the second step performed in a parallel format. As the same time, microwave assisted organic synthesis (MAOS) is also a powerful tool, because it can decrease reaction times, improve yields and purity of the final compounds.^[28~32] Based on the above information, we were able to construct a series of substituted thieno[2, 3-d]-pyrimidine analogs by employing the similar method under microwave irradiation. A new method for the synthesis of substituted thieno[2, 3-d]pyrimidines was studied 3a~3y (Scheme 2).

  Scheme 2

  

  Scheme 2.  Synthesis of compounds 3a~3y

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  2.   Results and discussion

  The starting materials 2-amino-5, 6-dihydro-4H-cyclo- penta[b]thiophene-3-carbonitrile (1) was prepared following the method of Gewald^[33] via the reaction of cyclopentanone, malononitrile and elemental sulfur in the presence of 4-methylpiperidine as catalyst. Applying methods from the literature, ^{[20, 30~32]} we found 4-methyl-piperidine as an inexpensive, highly efficient catalyst that can produce 2-amino-5, 6-dihydro-4H-cyclopenta[b]thiophene-3-carbo- nitrile (1) in short time and favorable yield. What's more, this reaction was studied under microwave irradiation. After various trials to optimize reaction time, temperature, microwave power and the amount of catalyst, we were able to obtain 1 at 60 ℃ in only 5 min of irradiation in quantitative yields (95% after purification). To show the merits of the present work, we compared results obtained from 4-methylpiperidine with those previously reported (Table 1).

  Table 1

  

  Table 1.  Comparison of different methods for the synthesis of 1

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  Entry	Catalyst	Condition	Time	Yielda/%	Ref.
  1	NaAlO2	Ethanol, 60 ℃	10 h	62	[34]
  2	L-Proline	DMF, 60 ℃	10 h	79	[35]
  3	Bovine serum albumin	DMF, 50 ℃	4 h	65	[36]
  4	KF-alumina	Ethanol, MWb	8 min	57	[37]
  5	KF-alumina	Ethanol, reflux	5.5 h	55	[37]
  6	Nano ZnO	Solvent free, 100 ℃	6 h	49	[38]
  7	KG-60-piperazine	Ethanol, reflux	4 h	47	[39]
  8	Morpholine	Ethanol, r.t.	20 h	46	[40]
  9	K2CO3	Ethanol, reflux	3 h	81	[20]
  10	4-Methylpiperidinec	Ethanol, 60 ℃	4 h	95	This work
  11	4-Methylpiperidinec	Ethanol, MWb	5 min	95	This work
  a Isolated yield. b Microwave irritation(150 W). c conditions: cyclopentanone (0.84 g, 10 mmol), malononitrile (0.66g, 10mmol), elemental sulfur (0.35 g, 11.0 mmol), 4-methylpiperidine (0.1 g, 1.0 mmol), ethanol (5 mL).

  The intermediate N-(3-cyano-5, 6-dihydro-4H-cyclo- penta[b]-thien-2-yl)-N, N-dimethylmethanimidamide (2) was obtained by reaction of DMF-DMA with 2-amino-5, 6- dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile (3). After optimization of the microwave conditions by varying microwave power, solvent, amount of DMF-DMA, tem- perature and reaction time (Table 2), the expected product 2 was obtained at 200 W, 70 ℃ in only 5 min of irradiation in quantitative yields (96% after purification).

  Table 2

  

  Table 2.  Optimization of the reaction conditions for the synthesis of 2^a

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  Entry	Microwave power	Solvent	DMF-DMA/equiv.	Temperature/℃	Time/min	Yieldb/%
  1	100	Toluene	2.5	50	10	50
  2	150	Toluene	2.5	50	10	58
  3	200	Toluene	2.5	50	10	67
  4	250	Toluene	2.5	50	10	67
  5	200	THF	2.5	50	10	76
  6	200	CH3CN	2.5	50	10	70
  7	200	CH3OH	2.5	50	10	88
  8	200	H2O	2.5	50	10	93
  9	200	—	2.5	50	10	85
  10	200	H2O	2	50	10	93
  11	200	H2O	1.5	50	10	90
  12	200	H2O	1	50	10	85
  13	200	H2O	2.5	70	10	96
  14	200	H2O	2.5	30	10	64
  15	200	H2O	2.5	70	6	96
  16	200	H2O	2.5	70	3	96
  a Reaction conditions: 1a (3 mmol), solvent (2 mL) and microwave irradiation. b Isolated yield.

  It was found that microwave irradiation power had little influence on this reaction (Table 2, Entries 1~4). As shown in Table 2, the yield of 2 reached 50% when the microwave irradiation power was 100 W, increasing to 67% when the microwave irradiation power was increased to 200 W. However, if the power was higher than 200 W the yield of product 3p is invariant.

  In order to check the effect of the solvent on the reaction, various solvents were also evaluated (Table 2, Entries 5~8). As shown in Table 2, aprotic organic solvents including toluene, acetonitrile and THF afforded 67%~76% yields of the product 2, whereas reaction in polar protic solvents, such as methanol, provided 88% yield of product 2. Notably, when the reaction was carried out in water, the yield of the desired product increasing to 95%. Water is economical and environmentally friendly compared with other organic solvents.

  Furthermore, the amount of DMF-DMA was also important. The yields of product 2 decreased when the amount of DMF-DMA was decreased to 2, 1.5 and 1 equiv., respectively (Entries 10, 11 and 12). Next, the reac- tion temperature was explored. It suggested that 70 ℃ was optimal (Table 2, Entries 8, 13 and 14). The irradiation time is another important parameter in reaction optimization. The effects of three different reaction times on the yield were tested and the results showed that the ideal microwave irradiation time was 3 min. This reaction under traditional thermal heating was also proceeded in heated oil bath with above optimized condition, but the reaction time is longer (90 min) and the yield is 87%.

  Similar optimization reactions were explored for the last step which consists in heating different anilines with 2 in the presence of acetic acid under microwave irradiation (Table 3). The choice of AcOH was guided by the fact that this carboxylic acid is a good solvent for heating under microwaves (tan d＝0.174 at 2.45 GHz).^[41] The model reactions were conducted using 2 with 1.2 equiv. of nucleophilic anilines substituted by m-methoxy groups. After various trials to optimize reaction parameters (microwave power, amount of aniline, time, and temperature), the expected N-(3-methoxyphenyl)-6, 7-dihydro-5H-cyclopenta- [4, 5]thieno[2, 3-d]pyrimidin-4-amine was obtained at 200 W, 140 ℃ in only 3 min of irradiation in quantitative yields (91% after purification).

  Table 3

  

  Table 3.  Optimization of the reaction conditions for the synthesis of 3f^a

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  Entry	Microwave power/W	Aniline/ equiv.	Temp./℃	Time/min	Yieldb/%
  1	100	1	120	9	70
  2	150	1	120	9	74
  3	200	1	120	9	82
  4	250	1	120	9	82
  5	200	1.1	120	9	85
  6	200	1.2	120	9	89
  7	200	1.2	140	9	91
  8	200	1.2	100	9	86
  9	200	1.2	140	6	91
  10	200	1.2	140	3	91
  a Reaction conditions: compound 2 (2 mmol), 3-methoxyaniline, solvent: acetic acid (5 mL) and microwave irradiation. b Isolated yield.

  After the establishment of the optimal reaction conditions, a variety of aromatic amines were tested for this cyclization and then Dimroth rearrangement reaction with N-(3-cyano-2-pyridinyl)-N, N-dimethylformimidamide (2) (Table 4). It seems obvious that the result of the reaction depends on the nucleophilicity of the aniline and its accessibility in connection with the steric hindrance of the substituents. The presence of large atoms or groups on the para-position of the aromatic amine involved an increase of reaction time and slight decrease of the yields (e.g., 3i, 3m, 3t, 3w). The reaction time of the aniline in the para-position is slightly longer and the yield is not high (e.g., 3c and 3d, 3f and 3g, 3h and 3i, 3l and 3m). For the halogen atom, the greater the electronegativity reaction is easier to proceed and the higher the yield (e.g., 3h, 3k, 3l, 3i and 3m).

  Table 4

  

  Table 4.  Effect of microwave irradiation and traditional refluxing on the compounds 3a~3y

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  Compd.	R	Conventional methoda			Microwave methodb
  		t/min	Yieldb/%		t/min	Yieldc/%
  3a	Ph	90	75		6	81
  3b	2-MeC6H4	90	81		6	84
  3c	3-MeC6H4	60	86		3	92
  3d	4-MeC6H4	90	71		6	87
  3e	2-MeOC6H4	90	80		6	85
  3f	3-MeOC6H4	60	79		3	91
  3g	4-MeOC6H4	120	87		30	90
  3h	3-FC6H4	60	84		3	95
  3i	4-FC6H4	90	90		6	93
  3j	2-ClC6H4	150	78		42	79
  3k	3-ClC6H4	90	87		6	90
  3l	3-BrC6H4	30	83		3	87
  3m	4-BrC6H4	90	75		6	82
  3n	3, 4-F2C6H3	60	81		6	83
  3o	3, 5-F2C6H3	90	80		30	82
  3p	3, 4-Cl2C6H3	60	76		6	80
  3q	3, 5-Cl2C6H3	90	77		12	82
  3r	3, 5-(CH3)2C6H3	90	74		6	76
  3s	3-Cl-4-FC6H3	120	79		9	80
  3t	4-NCC6H4	240	69		42	74
  3u	3-CF3C6H4	90	66		9	70
  3v	3-HC≡CC6H4	90	71		12	73
  3w	4-NO2C6H4	300	64		45	71
  3x	4-(CH3)3CC6H4	60	70		6	75
  3y	CH3(CH2)3	60	90		9	95
  a Reaction conditions: 2 (2.5 mmol), amine (3 mmol), acetic acid (5 mL) and oil bath reflux (140 ℃). b Reaction conditions: 2 (2.5 mmol), amine (3 mmol), acetic acid (5 mL), 140 ℃ and irradiation at 200 W. c Isolated yield.

  With the optimized conditions, we also compared our microwave experiment with traditional thermal heating in heated oil bath. The results showed that the method of microwave irradiation for the preparation of thieno[2, 3-d]- pyrimidin-4-amine was time-saving and high yield (Table 4).

  3.   Conclusions

  In summary, a simple, highly efficient, and facile procedure for the synthesis of 6, 7-dihydro-5H-cyclopenta- [4, 5]thieno[2, 3-d]pyrimidin-4-amine was described by Gewald reaction, condensation, cyclization and then Dimroth rearrangement reaction under microwave irradiation. The advantages of the methods are a short synthetic route, short reaction time, low cost and efficient yield, and work-up easily.

  4.   Experimental section

  4.1   Instruments and reagents

  Unless specified otherwise, all starting materials and reagents were obtained from commercial suppliers without further purification. All melting points were taken on a METTLEE TOLEDO MP90 melting point apparatus and were uncorrected. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker AVANCE Ⅲ HD 400 MHz instrument using TMS as the internal standard. Due to solubility problem, NMR spectra of compounds 3a~3y were tested in DMSO-d₆. IR spectra were recorded as KBr pellets on a VERTEX 80/Raman Ⅱ FTIR spectrometer. Mass spectra were recorded on a Triple TOF^TM 5600⁺(AB SCIEX USA). The microwave assisted reactions have been carried out in a CEM Explorer Hybrid instrument. The reactions were monitored by thin layer chromatography (TLC) using silica gel GF254.

  4.2   Synthesis of 2-amino-5, 6-dihydro-4H-cyclopen- ta[b]thiophene-3-carbonitrile 1

  Traditional preparation: A mixture of cyclopentanone (0.84 g, 10 mmol), malononitrile (0.66 g, 10 mmol), elemental sulfur (0.35 g, 11.0 mmol), 4-methylpiperidine (0.1 g, 1.0 mmol) and ethanol (5 mL) in a 25 mL of round bottom flask was stirred at 60 ℃ for 4 h. After reaction, the insoluble material was filtered off and the solvent was removed by evaporation under reduced pressure. The crude product was washed with water and recrystallized from ethanol to give brown crystals with 95% yield. m.p. 152~153 ℃ (Lit.^[20] 152~153℃); ¹H NMR (400 MHz, CDCl₃) δ: 4.74 (s, 2H), 2.84~2.59 (m, 4H), 2.35 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.5, 141.9, 125.1, 115.7, 84.3, 29.3, 28.4, 27.4; IR (KBr) ν: 3421, 3332, 3223, 2916, 2854, 2199, 1622, 1510 cm^-1; HRMS (ESI) calcd for C₈H₉N₂S [M+H]⁺ 165.0486, found 165.0485.

  Microwave irradiation: Cyclopentanone (0.84 g, 10 mmol), malononitrile (0.66 g, 10mmol), elemental sulfur (0.35 g, 11.0 mmol), 4-methylpiperidine (0.1 g, 1.0 mmol) were suspended in ethanol (5 mL) was irradiated at 60 ℃ (power input: 150 W) for 5 min. The insoluble material was filtered off, and the solvent was removed by evaporation under reduced pressure. The crude product was washed with water and recrystallized from ethanol to give brown crystals with yield 95%. m.p. 152~153 ℃ (Lit.^[20] 152~153 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 4.74 (s, 2H), 2.84~2.59 (m, 4H), 2.35 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.5, 141.9, 125.1, 115.7, 84.33, 29.3, 28.4, 27.4; IR (KBr) ν: 3421, 3332, 3223, 2916, 2854, 2199, 1622, 1510 cm^-1; HRMS (ESI) calcd for C₈H₉N₂S [M+H]⁺ 165.0486, found 165.0485.

  4.3   Synthesis of N-(3-cyano-5, 6-dihydro-4H-cyclo- penta[b]thien-2-yl)-N, N-dimethylmethanimidamide (2)

  Traditional preparation:^[41] 2-Amino-5, 6-dihydro-4H- cyclopenta[b]thiophene-3-carbonitrile (1) (0.493 g, 3 mmol) and DMF-DMA (1 mL, 6 mmol) were suspended in H₂O (2 mL), and then heated to reflux for 90 min. The resulting mixture was cooled to room temperature, poured onto ice cold water. The precipitate was filtered off, washed with water, and then dried to afford N-(3-cyano- 5, 6-dihydro-4H-cyclopenta[b]thien-2-yl)-N, N-dimethylme- thanimidamide (2), dark brown crystal, 83% yield. m.p. 147~149 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.93 (s, 1H), 3.10 (s, 3H), 2.99 (s, 3H), 2.81~2.73 (m, 2H), 2.71~2.62 (m, 2H), 2.37~2.24 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.5, 155.0, 142.0, 128.2, 116.7, 91.5, 40.5, 35.0, 29.9, 28.4, 27.0; IR (KBr) ν: 2916, 2204, 1620, 1553, 1501, 1110 cm^-1; HRMS (ESI) calcd for C₁₁H₁₄N₃S [M+H]⁺ 220.0908, found 220.0910.

  Microwave irradiation: 2-Amino-5, 6-dihydro-4H-cy- clopenta[b]thiophene-3-carbonitrile (1) (0.493g, 3 mmol) and DMF-DMA (1 mL, 6 mmol) were suspended in H₂O (2mL) was irradiated at 70 ℃ (power input: 200 W) for 3 min. The resulting mixture was cooled to room temperature, poured onto ice cold water. The precipitate was filtered off, washed with water, and then dried to afford N-(3-cyano-5, 6-dihydro-4H-cyclopenta[b]thien-2-yl)-N, N- dimethyl-methanimidamide (2), dark brown crystal, 91% yield. m.p. 147~149 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 7.93 (s, 1H), 3.10 (s, 3H), 2.99 (s, 3H), 2.81~2.73 (m, 2H), 2.71~2.62 (m, 2H), 2.37~2.24 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.5, 155.0, 142.0, 128.2, 116.7, 91.5, 40.5, 35.0, 29.9, 28.4, 27.0; IR (KBr) ν: 2916, 2204, 1620, 1553, 1501, 1110 cm^-1; HRMS (ESI) calcd for C₁₁H₁₄N₃S [M+H]⁺ 220.0908, found 220.0910.

  4.4   Synthesis of 6, 7-dihydro-5H-cyclopenta[4, 5]- thieno[2, 3-d]pyrimidin-4-amine (3a~3y)

  Traditional preparation: A mixture of N-(3-cyano- 5, 6-dihydro-4H-cyclopenta[b]thien-2-yl)-N, N-dimethyl-methanimidamide (2) (0.44 g, 2.5 mmol) and appropriate amine (3 mmol) in acetic acid (5 mL) was heated to reflux for different time (140 ℃). On completion, the reaction was cooled to ambient temperature. The resulting mixture was evaporated to dryness and crude product was obtained. The crude product was filtered, washed with little acetic acid and then dried to afford the target compound.

  Microwave irradiation: A mixture of N-(3-cyano-5, 6- dihydro-4H-cyclopenta[b]thien-2-yl)-N, N-dimethyl-metha- ni mi damide (2) (0.44 g, 2.5 mmol) and appropriate amine (3 mmol) in acetic acid (5 mL) was irradiated at 140 ℃ (power input: 200 W) for different time. On completion, the reaction was cooled to ambient temperature. The resulting mixture was evaporated to dryness and crude product was obtained. The crude product was filtered, washed with little acetic acid and then dried to afford the target compound.

  N-Phenyl-6, 7-dihydro-5H-cyclopenta[4, 5]thieno[2, 3-d]-pyrimidin-4-amine (3a)^[12]: brown solid, 74% yield. m.p. 165~167 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.38 (s, 1H), 8.22 (s, 1H), 7.68 (d, J＝8.6 Hz, 2H), 7.35 (t, J＝7.9 Hz, 2H), 7.09 (t, J＝7.4 Hz, 1H), 3.20 (t, J＝7.2 Hz, 2H), 2.98 (t, J＝7.3 Hz, 2H), 2.44 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.6, 154.8, 152.5, 139.5, 138.7, 136.0, 128.9, 123.8, 122.5, 114.4, 29.7, 29.2, 27.8; IR (KBr) ν: 3396, 2961, 2914, 2853, 1574, 1451, 1305, 974, 894, 776, 749 cm^-1; HRMS (ESI) calcd for C₁₅H₁₄N₃S [M+H]⁺ 268.0908, found 268.0901.

  N-(o-Tolyl)-6, 7-dihydro-5H-cyclopenta[4, 5]thieno[2, 3-d]- pyrimidin-4-amine (3b)^[12]: gray solid, 77% yield. m.p. 203~204 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.27 (s, 1H), 8.07 (s, 1H), 7.61 (d, J＝7.1 Hz, 1H), 7.33~7.21 (m, 2H), 7.17 (td, J＝7.4, 1.2 Hz, 1H), 3.16 (t, J＝7.2 Hz, 2H), 2.99 (t, J＝7.3 Hz, 2H), 2.50~2.41 (m, 2H), 2.23 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.3, 155.6, 152.8, 138.2, 137.8, 136.1, 133.7, 130.7, 126.6, 126.5, 125.9, 113.7, 29.6, 29.3, 27.9, 18.3; IR (KBr) ν: 3448, 3375, 2949, 2911, 2851, 1571, 1501, 1390, 1307, 975, 760 cm^-1; HRMS (ESI) calcd for C₁₆H₁₆N₃S [M+H]⁺ 282.1065, found 282.1062.

  N-(m-Tolyl)-6, 7-dihydro-5H-cyclopenta[4, 5]thieno[2, 3-d]pyrimidin-4-amine (3c): brown solid, 84% yield. m.p. 153~155 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.38 (s, 1H), 8.13 (s, 1H), 7.58~7.44 (m, 2H), 7.23 (t, J＝7.8 Hz, 1H), 6.91 (d, J＝7.5 Hz, 1H), 3.20 (t, J＝7.2 Hz, 2H), 2.98 (t, J＝7.3 Hz, 2H), 2.48~2.39 (m, 2H), 2.31 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.5, 154.8, 152.6, 139.5, 138.7, 138.1, 136.0, 128.7, 124.5, 122.9, 119.6, 114.3, 29.7, 29.2, 27.8, 21.6; IR (KBr) ν: 3411, 2968, 2912, 2855, 1669, 1489, 1306, 973, 893, 852, 779 cm^-1; HRMS (ESI) calcd for C₁₆H₁₆N₃S [M+H]⁺ 282.1065, found 282.1063.

  N-(p-Tolyl)-6, 7-dihydro-5H-cyclopenta[4, 5]thieno[2, 3-d]pyrimidin-4-amine:^[12] dark brown solid, 79% yield. m.p. 183~184 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.34 (s, 1H), 8.12 (s, 1H), 7.58~7.50 (m, 2H), 7.15 (d, J＝8.2 Hz, 2H), 3.19 (t, J＝7.2 Hz, 2H), 2.96 (t, J＝7.3 Hz, 2H), 2.44 (m, 2H), 2.29 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.4, 154.9, 152.6, 138.5, 136.9, 136.0, 132.9, 129.3, 122.8, 114.1, 29.7, 29.2, 27.8, 20.9; IR (KBr) ν: 3433, 3297, 3028, 2914, 2851, 1607, 1501, 1307, 976, 810, 782 cm^-1; HRMS (ESI) calcd for C₁₆H₁₆N₃S [M+H]⁺ 282.1065, found 282.1059.

  N-(2-Methoxyphenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]thieno[2, 3-d]pyrimidin-4-amine (3e)^[42]: light brown gray solid, 78% yield. m.p. 194~196 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.77 (dd, J＝7.3, 2.3 Hz, 1H), 8.53 (s, 1H), 7.88 (s, 1H), 7.10~6.97 (m, 2H), 6.95~6.87 (m, 1H), 3.94 (s, 3H), 3.16 (t, J＝7.1 Hz, 2H), 3.03 (t, J＝7.3 Hz, 2H), 2.59 (p, J＝7.3 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 171.1, 154.0, 152.6, 147.9, 139.6, 134.1, 128.7, 122.4, 121.2, 119.5, 114.7, 109.9, 56.0, 29.6, 29.0, 28.0; IR (KBr) ν: 3402, 2905, 2842, 1610, 1520, 1451, 1152, 1113, 1025, 981, 780, 753 cm^-1; HRMS (ESI) calcd for C₁₆H₁₆N₃OS [M+H]⁺ 298.1014, found 298.1006.

  N-(3-Methoxyphenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]-thieno[2, 3-d]pyrimidin-4-amine (3f): brown solid, 83% yield. m.p. 130~131 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.40 (s, 1H), 8.15 (s, 1H), 7.37 (t, J＝2.2 Hz, 1H), 7.29 (dt, J＝8.1, 1.3 Hz, 1H), 7.24 (t, J＝8.0 Hz, 1H), 6.67 (ddd, J＝7.9, 2.5, 1.2 Hz, 1H), 3.75 (s, 3H), 3.20 (t, J＝7.2 Hz, 2H), 2.97 (t, J＝7.3 Hz, 2H), 2.44 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.6, 159.9, 154.6, 152.5, 140.7, 138.8, 136.0, 129.6, 114.5, 114.5, 109.0, 108.1, 55.5, 29.7, 29.2, 27.8; IR (KBr) ν: 3434, 2956, 2910, 2856, 1610, 1490, 1261, 1157, 822, 778 cm^-1; HRMS (ESI) calcd for C₁₆H₁₆N₃OS [M+H]⁺ 298.1014, found 298.1011.

  N-(4-Methoxyphenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]-thieno[2, 3-d]pyrimidin-4-amine (3g): brown solid, 82% yield. m.p. 131~133 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.28 (s, 1H), 8.10 (s, 1H), 7.58~7.41 (m, 2H), 7.01~6.84 (m, 2H), 3.74 (s, 3H), 3.16 (t, J＝7.2 Hz, 2H), 2.95 (t, J＝7.3 Hz, 2H), 2.42 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.3, 156.3, 155.2, 152.6, 138.2, 136.0, 132.2, 125.0, 114.1, 113.8, 55.7, 29.6, 29.3, 27.9; IR (KBr) ν: 3392, 2952, 2915, 2842, 1691, 1605, 1502, 1231, 1028, 881, 834, 778 cm^-1; HRMS (ESI) calcd for C₁₆H₁₆N₃OS [M+H]⁺ 298.1014, found 298.1008.

  N-(3-Fluorophenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]-thieno[2, 3-d]pyrimidin-4-amine (3h): brown gray solid, 87% yield. m.p. 174~175 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.47 (s, 1H), 8.37 (s, 1H), 7.74 (dt, J＝11.8, 2.3 Hz, 1H), 7.52 (ddd, J＝8.2, 1.9, 0.8 Hz, 1H), 7.39 (td, J＝8.2, 6.9 Hz, 1H), 7.01~6.83 (m, 1H), 3.23 (t, J＝7.2 Hz, 2H), 3.01 (t, J＝7.3 Hz, 2H), 2.50~2.41 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 162.5 (d, ¹J_C—F＝240.3 Hz), 154.3, 152.3, 141.4, 139.3, 135.9, 130.4, 130.3, 117.7 (d, ³J_C—F＝3.0 Hz), 114.7, 109.9 (d, ²J_C—F＝21.5 Hz), 108.7 (d, ²J_C—F＝25.0 Hz), 29.7, 29.1, 27.8; IR (KBr) ν: 3393, 3061, 2958, 2913, 2853, 1609, 1556, 1503, 1391, 987, 854, 777 cm^-1; HRMS (ESI) calcd for C₁₅H₁₃FN₃S [M+H]⁺ 286.0814, found 286.0809.

  N-(4-Fluorophenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]-thieno-[2, 3-d]pyrimidin-4-amine (3i): dark brown solid, 85% yield. m.p. 159~160 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.36 (s, 1H), 8.27 (s, 1H), 7.72~7.64 (m, 2H), 7.25~7.16 (m, 2H), 3.26~3.16 (m, 2H), 2.99 (t, J＝7.3 Hz, 2H), 2.49~2.39 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 158.9 (d, ¹J_C—F＝239.5 Hz), 154.8, 152.5, 138.7, 136.0, 135.8, 135.7, 124.9 (d, ³J_C—F＝8.0 Hz), 115.4 (d, ²J_C—F＝22.3 Hz), 114.1, 29.7, 29.2, 27.8; IR (KBr) ν: 3433, 2059, 2953, 2912, 2851, 1581, 1497, 1388, 977, 833, 784 cm^-1; HRMS (ESI) calcd for C₁₅H₁₃FN₃S [M+H]⁺ 286.0814, found 286.0810.

  N-(2-Chlorophenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]-thieno[2, 3-d]pyrimidin-4-amine (3j): dark brown black solid, 72% yield. m.p. 157~158 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.40 (s, 1H), 8.26~8.11 (m, 2H), 7.57 (dd, J＝8.0, 1.4 Hz, 1H), 7.42 (td, J＝7.8, 1.5 Hz, 1H), 7.23 (td, J＝7.7, 1.6 Hz, 1H), 3.21 (t, J＝7.2 Hz, 2H), 3.01 (t, J＝7.4 Hz, 2H), 2.49 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.5, 154.6, 152.6, 139.3, 136.1, 135.5, 129.8, 128.1, 127.2, 126.1, 125.9, 114.2, 29.7, 29.3, 27.9; IR (KBr) ν: 3405, 2952, 2905, 2851, 1602, 1502, 1446, 1392, 1309, 980, 780, 754 cm^-1; HRMS (ESI) calcd for C₁₅H₁₃ClN₃S [M+H]⁺ 302.0519, found 302.0511.

  N-(3-Chlorophenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]-thieno[2, 3-d]pyrimidin-4-amine (3k): brown black solid, 82% yield. m.p. 153~155 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.47 (s, 1H), 8.36 (s, 1H), 7.91 (t, J＝2.0 Hz, 1H), 7.68 (ddd, J＝8.2, 2.0, 0.8 Hz, 1H), 7.39 (t, J＝8.1 Hz, 1H), 7.14 (ddd, J＝8.0, 2.0, 0.8 Hz, 1H), 3.23 (t, J＝7.2 Hz, 2H), 3.01 (t, J＝7.3 Hz, 2H), 2.50~2.43 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.8, 154.3, 152.4, 141.2, 139.3, 135.9, 133.2, 130.5, 123.2, 121.4, 120.5, 114.6, 29.7, 29.1, 27.8; IR (KBr) ν: 3389, 3062, 2960, 2917, 2857, 1604, 1500, 1306, 980, 870, 775 cm^-1; HRMS (ESI) calcd for C₁₅H₁₃ClN₃S [M+H]⁺ 302.0519, found 302.0513.

  N-(3-Bromophenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]-thieno[2, 3-d]pyrimidin-4-amine (3l): black solid, 78% yield. m.p. 190~191 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.44 (s, 1H), 8.32 (s, 1H), 8.01 (t, J＝1.9 Hz, 1H), 7.76~7.68 (m, 1H), 7.31 (t, J＝8.0 Hz, 1H), 7.25 (dt, J＝7.9, 1.2 Hz, 1H), 3.21 (t, J＝7.2 Hz, 2H), 2.98 (t, J＝7.3 Hz, 2H), 2.48~2.40 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.8, 154.3, 152.3, 141.3, 139.3, 135.9, 130.7, 126.1, 124.2, 121.6, 120.9, 114.6, 29.7, 29.1, 27.8; IR (KBr) ν: 3422, 3054, 2959, 2852, 1604, 1551, 1476, 1307, 990, 854, 770 cm^-1; HRMS (ESI) calcd for C₁₅H₁₃BrN₃S [M+H]⁺ 346.0014, found 346.0011.

  N-(4-Bromophenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]-thieno[2, 3-d]pyrimidin-4-amine (3m): light brown solid, 82% yield. m.p. 170~171 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (s, 1H), 8.26 (s, 1H), 7.66 (d, J＝8.8 Hz, 2H), 7.49 (d, J＝8.8 Hz, 2H), 3.17 (t, J＝7.1 Hz, 2H), 2.94 (t, J＝7.2 Hz, 2H), 2.41 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.7, 154.3, 152.3, 139.1, 139.0, 135.9, 131.6, 124.1, 115.3, 114.5, 29.7, 29.2, 27.8; IR (KBr) ν: 3436, 2949, 2906, 2851, 1605, 1509, 1309, 977, 826, 777 cm^-1; HRMS (ESI) calcd for C₁₅H₁₃BrN₃S [M+H]⁺ 346.0014, found 346.0011.

  N-(3, 4-Difluorophenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]-thieno[2, 3-d]pyrimidin-4-amine (3n):^[41] brown gray solid, 76% yield. m.p. 164~165 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.44 (s, 1H), 8.37 (s, 1H), 7.89 (ddd, J＝13.2, 7.4, 2.5 Hz, 1H), 7.53~7.47 (m, 1H), 7.43 (dt, J＝10.5, 8.9 Hz, 1H), 3.22 (t, J＝7.2 Hz, 2H), 3.01 (t, J＝7.3 Hz, 2H), 2.50~2.41 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 154.4, 152.3, 147.1 (dd, J_C—F＝3.5 Hz, 10.7 Hz), 139.2, 136.6 (dd, J_C—F＝3.7 Hz, 9.3 Hz), 135.9, 118.9 (dd, J_C—F＝4.5 Hz, 6.0 Hz), 117.5, 117.3, 114.4, 111.6, 111.4, 29.7, 29.2, 27.8; IR (KBr) ν: 3433, 3282, 3046, 2913, 2852, 1559, 1265, 985, 871, 791 cm^-1; HRMS (ESI) calcd for C₁₅H₁₂F₂N₃S [M+H]⁺ 304.0720, found 304.0714.

  N-(3, 5-Difluorophenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]-thieno[2, 3-d]pyrimidin-4-amine (3o): dark brown solid, 75% yield. m.p. 150~152 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.51 (s, 1H), 8.47 (s, 1H), 7.61~7.50 (m, 2H), 6.88 (tt, J＝9.4, 2.3 Hz, 1H), 3.21 (t, J＝7.2 Hz, 2H), 2.99 (t, J＝7.3 Hz, 2H), 2.48~2.40 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 172.1, 164.0, 161.4, 153.9, 152.2, 142.4, 139.8, 135.8, 114.9, 104.4, 29.8, 29.1, 27.8; IR (KBr) ν: 3435, 3388, 3066, 2911, 2855, 1613, 1477, 1306, 992, 830 cm^-1; HRMS (ESI) calcd for C₁₅H₁₂F₂N₃S [M+H]⁺ 304.0720, found 304.0718

  N-(3, 4-Dichlorophenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]- thieno[2, 3-d] pyrimidin-4-amine (3p):^[12] brown gray solid, 73% yield. m.p. 202~203 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.47 (s, 1H), 8.40 (s, 1H), 8.10 (d, J＝2.5 Hz, 1H), 7.75 (dd, J＝8.8, 2.5 Hz, 1H), 7.59 (d, J＝8.8 Hz, 1H), 3.22 (t, J＝7.2 Hz, 2H), 3.00 (t, J＝7.3 Hz, 2H), 2.46 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 164.0, 163.8, 161.6, 161.4, 153.9, 152.2, 142.3 (dd, J_C—F＝14.3 Hz, 28.0 Hz), 139.8, 135.8, 114.9, 104.2 (dd, J_C—F＝8.5 Hz, 21.7 Hz), 98.2 (dd, J_C—F＝26.0 Hz, 52.5 Hz), 29.8, 29.1, 27.8; IR (KBr) ν: 3431, 3117, 2957, 2898, 2850, 1605, 1503, 1449, 1378, 985, 880, 815, 779 cm^-1; HRMS (ESI) calcd for C₁₅H₁₂Cl₂N₃S [M+H]⁺ 336.0129, found 336.0120.

  N-(3, 5-Dichlorophenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]- thieno[2, 3-d]pyrimidin-4-amine (3q): light brown gray solid, 75% yield. m.p. 210~213 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.50 (s, 1H), 8.39 (s, 1H), 7.88 (d, J＝1.9 Hz, 2H), 7.23 (t, J＝1.8 Hz, 1H), 3.21 (t, J＝7.2 Hz, 2H), 2.99 (t, J＝7.3 Hz, 2H), 2.44 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 172.1, 153.8, 152.2, 142.2, 139.8, 135.8, 134.1, 122.3, 119.7, 114.8, 29.7, 29.1, 27.8; IR (KBr) ν: 3432, 3093, 2912, 2852, 1608, 1551, 1498, 1307, 878, 809, 778 cm^-1; HRMS (ESI) calcd for C₁₅H₁₂Cl₂N₃S [M+H]⁺ 336.0129, found 336.0122.

  N-(3, 5-Dimethylphenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]- thieno[2, 3-d]pyrimidin-4-amine (3r): drak brown solid, 69% yield. m.p. 216~218 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.48 (s, 1H), 6.79 (s, 1H), 6.75 (s, 1H), 3.09 (t, J＝7.2 Hz, 2H), 3.04~2.96 (m, 2H), 2.56 (p, J＝7.3 Hz, 2H), 2.32 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 171.4, 154.4, 152.7, 139.8, 138.8, 138.2, 133.7, 125.8, 118.6, 114.0, 29.6, 29.3, 28.0, 21.4; IR (KBr) ν: 3407, 2913, 2853, 1553, 1307, 980, 885, 840, 780 cm^-1; HRMS (ESI) calcd for C₁₇H₁₈N₃S [M+H]⁺ 296.1221, found 296.1219.

  N-(3-Chloro-4-fluorophenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]thieno[2, 3-d]pyrimidin-4-amine (3s): light brown solid, 73% yield. m.p. 162~164 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.44 (s, 1H), 8.36 (s, 1H), 7.99 (dd, J＝6.8, 2.6 Hz, 1H), 7.69 (ddd, J＝9.0, 4.3, 2.7 Hz, 1H), 7.43 (t, J＝9.1 Hz, 1H), 3.23 (t, J＝7.2 Hz, 2H), 3.01 (tt, J＝8.1, 1.9 Hz, 2H), 2.50~2.41 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.8, 153.4 (d, ¹J_C—F＝204.0 Hz), 139.2, 135.9, 124.1, 123.9 (d, ³J_C—F＝6.3 Hz), 119.2 (d, ²J_C—F＝18.5 Hz), 117.0, 116.9 (d, ²J_C—F＝22.7 Hz), 29.7, 29.2, 27.8; IR (KBr) ν: 3432, 2955, 2899, 2852, 1577, 1490, 1384, 983, 882, 778 cm^-1; HRMS (ESI) calcd for C₁₅H₁₂ClFN₃S [M+H]⁺ 320.0424, found 320.0421.

  4-((6, 7-Dihydro-5H-cyclopenta[4, 5]thieno[2, 3-d]pyrimidin-4-yl)amino)benzonitrile (3t): dark brown solid, 67% yield. m.p. 201~203 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.66 (s, 1H), 8.51 (s, 1H), 7.92 (d, J＝8.7 Hz, 2H), 7.78 (d, J＝8.7 Hz, 2H), 3.21 (t, J＝7.0 Hz, 2H), 3.00 (t, J＝7.1 Hz, 2H), 2.48~2.39 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 172.3, 153.7, 152.1, 144.3, 140.0, 135.9, 133.3, 121.1, 119.7, 115.4, 104.5, 29.8, 29.1, 27.8; IR (KBr) ν: 3434, 2958, 2902, 2848, 2216 (CN), 1600, 1499, 1443, 1309, 975, 846, 780 cm^-1; HRMS (ESI) calcd for C₁₆H₁₃N₄S [M+H]⁺ 293.0861, found 293.0852.

  N-(3-(Trifluoromethyl)phenyl)-6, 7-dihydro-5H-cyclope-nta[4, 5]thieno[2, 3-d]pyrimidin-4-amine (3u): light gray solid, 64% yield. m.p. 160~162 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.46 (s, 1H), 8.43 (s, 1H), 8.12 (s, 1H), 8.02 (d, J＝8.2 Hz, 1H), 7.56 (t, J＝8.0 Hz, 1H), 7.40 (d, J＝7.7 Hz, 1H), 3.22 (t, J＝7.2 Hz, 2H), 2.97 (t, J＝7.2 Hz, 2H), 2.43 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 171.9, 154.32, 152.31, 140.53, 139.40, 135.94, 129.9, 129.7 (q, ²J_C—F＝33.5 Hz), 125.8, 124.6 (q, ¹J_C—F＝270.0 Hz), 119.7 (q, ³J_C—F＝4.7 Hz), 118.2 (q, ³J_C—F＝4.3 Hz), 114.66, 29.75, 29.21, 27.85; IR (KBr) ν: 3425, 2960, 2904, 2852, 1609, 1555, 1451, 1335, 982, 895, 792 cm^-1; HRMS (ESI) calcd for C₁₆H₁₃F₃N₃S [M+H]⁺ 336.0782, found 336.0776.

  N-(3-Ethynylphenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]-thieno[2, 3-d]pyrimidin-4-amine (3v): light brown gray solid, 67% yield. m.p. 201~203 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.43 (s, 1H), 8.27 (s, 1H), 7.87 (t, J＝1.8 Hz, 1H), 7.75 (ddd, J＝8.2, 2.1, 0.9 Hz, 1H), 7.36 (t, J＝7.9 Hz, 1H), 7.19 (dt, J＝7.6, 1.1 Hz, 1H), 4.19 (s, 1H), 3.21 (t, J＝7.2 Hz, 2H), 2.98 (t, J＝7.3 Hz, 2H), 2.48~2.39 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.7, 154.4, 152.4, 139.9, 139.1, 136.0, 129.3, 126.8, 125.0, 122.9, 122.2, 114.5, 83.9, 81.0, 29.7, 29.2, 27.8; IR (KBr) ν: 3428, 3273, 2957, 2854, 1609, 1550, 1477, 1382, 1305, 876, 789 cm^-1; HRMS (ESI) calcd for C₁₇H₁₄N₃S [M+ H]⁺ 292.0908, found 292.0912.

  N-(4-Nitrophenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]thieno[2, 3-d]pyrimidin-4-amine (3w): dark green solid, 65% yield. m.p. 148~150 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.89 (s, 1H), 8.56 (s, 1H), 8.22 (d, J＝7.8 Hz, 2H), 7.97 (d, J＝7.6 Hz, 2H), 3.23 (s, 2H), 3.00 (s, 2H), 2.46 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 172.6, 153.5, 152.1, 146.5, 141.8, 140.4, 135.9, 125.1, 120.2, 115.7, 29.8, 29.1, 27.8; IR (KBr) ν: 3419, 2913, 2849, 1582, 1500, 1390, 1334, 975, 855, 777, 748 cm^-1; HRMS (ESI) calcd for C₁₅H₁₃N₄O₂S [M+H]⁺ 313.0759, found 313.0747.

  N-(4-(tert-Butyl)phenyl)-6, 7-dihydro-5H-cyclopenta[4, 5]- thieno[2, 3-d]pyrimidin-4-amine (3x): brown solid, 68% yield. m.p. 140~142 ℃; ¹H NMR(400 MHz, DMSO-d₆) δ: 8.34 (s, 1H), 8.14 (s, 1H), 7.61~7.52 (m, 2H), 7.40~7.33 (m, 2H), 3.18 (t, J＝7.2 Hz, 2H), 2.96 (t, J＝7.3 Hz, 2H), 2.44 (m, 2H), 1.29 (s, 9H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.5, 154.9, 152.6, 146.4, 138.5, 136.8, 136.0, 125.5, 122.6, 114.1, 34.5, 31.7, 29.6, 29.2, 27.8; IR (KBr) ν: 3416, 3029, 2964, 1596, 1500, 1306, 975, 833, 779 cm^-1; HRMS (ESI) calcd for C₁₉H₂₂N₃S [M+H]⁺ 324.1534, found 324.1530.

  N-n-Butyl-6, 7-dihydro-5H-cyclopenta[4, 5]thieno[2, 3-d]-pyrimidin-4-amine (3y): brown solid, 82% yield. m.p. 200~202 ℃; ¹H NMR(400 MHz, DMSO-d₆) δ: 7.94 (s, 1H), 6.82 (s, 1H), 3.93 (t, J＝7.2 Hz, 2H), 2.98 (t, J＝7.2 Hz, 2H), 2.86 (t, J＝7.3 Hz, 2H), 2.46~2.34 (m, 2H), 1.72~1.61 (m, 2H), 1.39~1.21 (m, 2H), 0.90 (t, J＝7.4 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 174.8, 161.3, 147.7, 139.3, 137.5, 46.5, 30.1, 29.2, 29.0, 28.1, 26.0, 19.7, 14.1; IR (KBr) ν: 3160, 3052, 2950, 2856, 1564, 1446, 1379, 937, 836, 785 cm^-1; HRMS (ESI) calcd for C₁₃H₁₈N₃S [M+H]⁺ 248.1221, found 248.1223.

  Supporting Information  NMR, IR, HRMS spectra of products 1, 2 and 3a~3y are available free of charge via the Internet at http://sioc-journal.cn/.

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• 

  Figure 1  Examples of pharmaceutically thieno[2, 3-d]pyrimidine core with five-, six-membered cycloalkyl lipophilic moieties

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  Scheme 1  Traditional preparation of thieno[2, 3-d]pyrimidin-4-amine

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  Scheme 2  Synthesis of compounds 3a~3y

  下载: 全尺寸图片 幻灯片

  Table 1.  Comparison of different methods for the synthesis of 1

  Entry	Catalyst	Condition	Time	Yielda/%	Ref.
  1	NaAlO2	Ethanol, 60 ℃	10 h	62	[34]
  2	L-Proline	DMF, 60 ℃	10 h	79	[35]
  3	Bovine serum albumin	DMF, 50 ℃	4 h	65	[36]
  4	KF-alumina	Ethanol, MWb	8 min	57	[37]
  5	KF-alumina	Ethanol, reflux	5.5 h	55	[37]
  6	Nano ZnO	Solvent free, 100 ℃	6 h	49	[38]
  7	KG-60-piperazine	Ethanol, reflux	4 h	47	[39]
  8	Morpholine	Ethanol, r.t.	20 h	46	[40]
  9	K2CO3	Ethanol, reflux	3 h	81	[20]
  10	4-Methylpiperidinec	Ethanol, 60 ℃	4 h	95	This work
  11	4-Methylpiperidinec	Ethanol, MWb	5 min	95	This work
  a Isolated yield. b Microwave irritation(150 W). c conditions: cyclopentanone (0.84 g, 10 mmol), malononitrile (0.66g, 10mmol), elemental sulfur (0.35 g, 11.0 mmol), 4-methylpiperidine (0.1 g, 1.0 mmol), ethanol (5 mL).

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  Table 2.  Optimization of the reaction conditions for the synthesis of 2^a

  Entry	Microwave power	Solvent	DMF-DMA/equiv.	Temperature/℃	Time/min	Yieldb/%
  1	100	Toluene	2.5	50	10	50
  2	150	Toluene	2.5	50	10	58
  3	200	Toluene	2.5	50	10	67
  4	250	Toluene	2.5	50	10	67
  5	200	THF	2.5	50	10	76
  6	200	CH3CN	2.5	50	10	70
  7	200	CH3OH	2.5	50	10	88
  8	200	H2O	2.5	50	10	93
  9	200	—	2.5	50	10	85
  10	200	H2O	2	50	10	93
  11	200	H2O	1.5	50	10	90
  12	200	H2O	1	50	10	85
  13	200	H2O	2.5	70	10	96
  14	200	H2O	2.5	30	10	64
  15	200	H2O	2.5	70	6	96
  16	200	H2O	2.5	70	3	96
  a Reaction conditions: 1a (3 mmol), solvent (2 mL) and microwave irradiation. b Isolated yield.

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  Table 3.  Optimization of the reaction conditions for the synthesis of 3f^a

  Entry	Microwave power/W	Aniline/ equiv.	Temp./℃	Time/min	Yieldb/%
  1	100	1	120	9	70
  2	150	1	120	9	74
  3	200	1	120	9	82
  4	250	1	120	9	82
  5	200	1.1	120	9	85
  6	200	1.2	120	9	89
  7	200	1.2	140	9	91
  8	200	1.2	100	9	86
  9	200	1.2	140	6	91
  10	200	1.2	140	3	91
  a Reaction conditions: compound 2 (2 mmol), 3-methoxyaniline, solvent: acetic acid (5 mL) and microwave irradiation. b Isolated yield.

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  Table 4.  Effect of microwave irradiation and traditional refluxing on the compounds 3a~3y

  Compd.	R	Conventional methoda			Microwave methodb
  		t/min	Yieldb/%		t/min	Yieldc/%
  3a	Ph	90	75		6	81
  3b	2-MeC6H4	90	81		6	84
  3c	3-MeC6H4	60	86		3	92
  3d	4-MeC6H4	90	71		6	87
  3e	2-MeOC6H4	90	80		6	85
  3f	3-MeOC6H4	60	79		3	91
  3g	4-MeOC6H4	120	87		30	90
  3h	3-FC6H4	60	84		3	95
  3i	4-FC6H4	90	90		6	93
  3j	2-ClC6H4	150	78		42	79
  3k	3-ClC6H4	90	87		6	90
  3l	3-BrC6H4	30	83		3	87
  3m	4-BrC6H4	90	75		6	82
  3n	3, 4-F2C6H3	60	81		6	83
  3o	3, 5-F2C6H3	90	80		30	82
  3p	3, 4-Cl2C6H3	60	76		6	80
  3q	3, 5-Cl2C6H3	90	77		12	82
  3r	3, 5-(CH3)2C6H3	90	74		6	76
  3s	3-Cl-4-FC6H3	120	79		9	80
  3t	4-NCC6H4	240	69		42	74
  3u	3-CF3C6H4	90	66		9	70
  3v	3-HC≡CC6H4	90	71		12	73
  3w	4-NO2C6H4	300	64		45	71
  3x	4-(CH3)3CC6H4	60	70		6	75
  3y	CH3(CH2)3	60	90		9	95
  a Reaction conditions: 2 (2.5 mmol), amine (3 mmol), acetic acid (5 mL) and oil bath reflux (140 ℃). b Reaction conditions: 2 (2.5 mmol), amine (3 mmol), acetic acid (5 mL), 140 ℃ and irradiation at 200 W. c Isolated yield.

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•