Efficient synthesis of novel furo[2,3-d]pyrimidine derivatives under catalyst-free conditions

Accepted Manuscript Efficient Synthesis of Novel Furo[2,3-d]pyrimidine Derivatives under Catalystfree Conditions Chunmei Li, Furen Zhang PII: DOI: Reference:

S0040-4039(17)30305-2 http://dx.doi.org/10.1016/j.tetlet.2017.03.019 TETL 48720

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Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

5 January 2017 3 March 2017 7 March 2017

Please cite this article as: Li, C., Zhang, F., Efficient Synthesis of Novel Furo[2,3-d]pyrimidine Derivatives under Catalyst-free Conditions, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.03.019

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Efficient Synthesis of Novel Furo[2,3d]pyrimidine Derivatives under Catalyst-free Conditions Chunmei Li, Furen Zhang*

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1

Tetrahedron Letters j o ur n al h o m e p a g e : w w w . e l s e v i e r . c o m

Efficient Synthesis of Novel Furo[2,3-d]pyrimidine Derivatives under Catalyst-free Conditions Chunmei Li, Furen Zhang* School of Chemistry and Chemical Engineering, Zhejiang Key Laboratory of Alternative Technologies for Fine Chemicals Process, Shaoxing University, Shaoxing, Zhejiang Province 312000, China

A R T IC LE IN F O

A B S TR A C T

Article history: Received Received in revised form Accepted Available online

A series of furo[2,3-d]pyrimidine derivatives were synthesized via the [3+2] cyclization of pyrimidine-4,6-diol and a variety of nitroolefins at catalyst-free conditions. The reaction is easy to perform simply mixing inexpensive starting materials in water under conventional heating at 90 o C. The reaction proceeds at a fast speed within 1.5-2 hours and gives the high biological and pharmacological active substituent furo[2,3-d]pyrimidine derivatives with good to high yields. Mechanism of formation of these furo[2,3-d]pyrimidine derivatives are also proposed.

Keywords: Synthesis Nitroolefins Water Catalyst-free Furo[2,3-d]pyrimidine

2009 Elsevier Ltd. All rights reserved.

1. Introduction Pyrimidine derivatives usually existing in natural and unnatural products,1 play an crucial role in human life. 1 Pyrimidine activated sugars are also serve essential functions in phospholipid and polysaccharide synthesis, glucuronidation in detoxification processes, glycosylation of proteins and lipids.2 In addition, pyrimidines can be salvaged by human cells for the synthesis of deoxyribonucleotides that are used for DNA synthesis, and pyrimidine derivatives commonly display remarkable biological and pharmacological activity for human diseases, such as cancer,3 varicella-zoster virus,4 malaria,5 tumor of L1210 and P388 leukemias6 and so on7. Study indicates that the fusion of pyrimidine moiety with different heterocycle scaffolds gives rise to a new class of hybrid heterocycles with improved biological activity. 8 Various fivemembered heteroaromatic ring fused-pyrimidines, furopyrimidines in particular, were studied and found to possess remarkable pharmacological properties.9 Furo[2,3-d]pyrimidine derivatives represent an entirely new class of pyrimidine derivatives with unprecedented biological activities for many diseases.3b,10-12 Of particular interest in Figure 1, synthetic furo[2, 3-d]pyrimidine derivative (type I) has served as valid glycinamide ribonucleotide formyltransferase (GARFTase) inhibitors,10 type II been against tested fungi and bacteria,11 type III has been used in vitro inhibits HUVEC cell line proliferation, using doxorubicin as control,3b and type IV has exhibited the most pronounced cytostatic acitivities against hepatocellular carcinoma (HepG2) and cervical carcinoma (HeLa) cells.12

In view of the biological importance of furo[2,3-d]pyrimidine derivatives, many efforts have been devoted to efficient synthetic methods toward furo[2,3-d]pyrimidine derivatives.13,14 However, the synthetic methodology used for such bicyclic furo[2,3d]pyrimidines process is limited. A survey of the literature method indicates that one general strategy have been developed, which is the cyclization between 2-aminopyrimidine-4,6-diol and aryl-substituted-(Z)-(2-chloro-2-nitrovinyl)benzenes in reflux ethanol and butanone using DBU as catalyst. 14 However, this method involves drastic condition, expensive metal catalysts, and complex laborious procedure. Therefore, the exploration of a versatile and efficient strategy for synthesis of furo[2,3d]pyrimidine derivatives from readily available starting material is highly valuable.

————

Figure 1. Bioactive furo[2,3-d]pyrimidine derivatives.

∗ Corresponding author. Tel.: +86 575 88345682; fax: +86 575 88345682; e-mail: [email protected].

During our continuous efforts on the development synthetic methods for various heterocyclic compounds using nitroolefin as

2

Tetrahedron Letters

original substrate,15 here we would like to report an efficient, and green synthetic strategy for the preparation of furo[2,3d]pyrimidine derivatives. This reaction was achieved by using readily available 2-aminopyrimidine-4,6-diol (1a) or 2methylpyrimidine-4,6-diol (1b) and nitroolefins (2) under catalyst-free conditions in water.

Table 1 Optimization of solvents and temperature for the synthesis of 3aa

2. Results and discussion We started this study by mixing 2-aminopyrimidine-4,6-diol (1a) and (E)-(2-nitroprop-1-en-1-yl)benzene (2a) at 90 oC using different solvents, including protic solvents such as ethanol (EtOH), isopropanol (iPrOH), glycol, and water and non-protic solvents such as acetonitrile (CH3CN), tetrahydrofuran (THF), chloroform (CHCl 3), N, N-dimethylformamide (DMF), and toluene. The results were summarized in Table 1. The use of protic solvents as reaction medium at 90 o C allowed the direct conversion of starting materials to corresponding 2-amino-6methyl-5-phenylfuro[2,3-d]pyrimidin-4-ol (3a) with isolated yields of 52-92% (Table 1, entries 1-4). Of these protic medium, the water gave the highest yield of goal product (Table 1, entry 4). However, only 32-50% yields of desired products (3a) were obtained when the non-protic solvents were used as reaction medium at the same reaction temperature. Under the aqueous condition, the model reaction resulted in 2-amino-6-methyl-5phenylfuro[2,3-d]pyrimidin-4-ol with a yield of 92% and the reaction proceeded rapidly to completion at 90 oC within 2 hours. However, the yields of desired product decreased obviously when the temperature was reduced to 70 oC with a decreasement of 10 oC (Table 1, entries4, 10-11). In addition, increasing reaction temperature to 100 oC did not improve the yield of product 3a obviously (Table 1, entry 12).

Entry

Solvent

T (oC)

Time (h)

Yield (%)b

1

EtOH

reflux

5

65

2

i

PrOH

reflux

5

52

3

Glycol

90

2

90

4

H2 O

90

2

92

5

CH3 CN

reflux

5

34

6

THF

reflux

5

40

7

CHCl3

reflux

5

33

8

DMF

90

5

50

9

Toluene

90

5

32

10

H2 O

80

2

81

11

H2 O

70

2

56

12

H2 O

100

2

93

a

Reaction conditions: 1a (0.50 mmol), 2a (0.50 mmol), and solvent (2.5 mL), in given time. b

Isolated yields.

Table 2 Substrate scope for the synthesis of furo[2,3-d]pyrimidine derivativesa

Entry

3

R1

Ar

R2

Time (h)

Yieldb (%)c

Mp (oC)

1

3a

NH2 (1a)

C6 H5

Me

2

92

>300

2

3b

NH2 (1a)

4-Me-C6 H4

Me

2

85

>300

3

3c

NH2 (1a)

4-OMe-C6H4

Me

2

87

>300

4

3d

NH2 (1a)

4-F-C6H4

Me

2

95

>300

5

3e

NH2 (1a)

4-Cl-C6H4

Me

2

93

>300

6

3f

NH2 (1a)

4-Br-C6H4

Me

2

90

>300

7

3g

NH2 (1a)

4-NO2-C6 H4

Me

2

89

>300

8

3h

NH2 (1a)

2,4-Cl-C6 H3

Me

2

87

>300

9

3i

NH2 (1a)

3-NO2-C6 H4

Me

2

88

>300

10

3j

NH2 (1a)

1-naphthyl

Me

2

86

>300

11

3k

NH2 (1a)

2-thienyl

Me

2

85

>300

12

3l

NH2 (1a)

4-Cl-C6H4

Et

2

79

>300

13

3m

CH3 (1b)

C6 H5

Me

1.5

93

>300

14

3n

CH3 (1b)

4-Me-C6 H4

Me

1.5

90

>300

15

3o

CH3 (1b)

4-F-C6H4

Me

1.5

94

>300

16

3p

CH3 (1b)

4-Cl-C6H4

Me

1.5

95

>300

17

3q

CH3 (1b)

3-NO2-C6 H4

Me

1.5

90

>300

18

3r

CH3 (1b)

2-thienyl

Me

2

89

297-298

a

Reaction conditions: 1 (0.50 mmol), 2 (0.50 mmol), and water (2.5 mL) at 90 oC in 1.5-2 h.

b

Isolated yields.

Using these optimized conditions, the substrates scope was evaluated by employing different pyrimidine-4,6-diol with a

variety of nitroolefins (Table 2). To our delight, under the optimized conditions, the reactions proceeded smoothly to give

3 the desired product 5 could not be given even in long reaction time (10 h) instead the non-cyclic product 6 was obtained with 82% yield. On the basis of above results and references,17 we assumed that under the attack of hydroxyl, the oxime might be formed by proton transfer, however, the oxime decomposed immediately and transformed to Michael addition product (6) under the effect of water at 90 oC.

corresponding 5-arylfuro[2,3-d]pyrimidin-4-ol (3) with good to excellent yields (Table 2). 16 Firstly, we set out to explore the scope of a variety of substituted (E)-(2-nitroprop-1-en-1yl)benzenes using 2-aminopyrimidine-4,6-diol (1a) as model pyrimidine substrate. Fortunately, not only (E)-(2-nitroprop-1-en1-yl)benzenes 2b-c, which possess electron-donating substituents, such as methyl, methoxy groups at the para-position of benzene ring (Table 2, entries 2-3), but also 2d-i bearing electrondeficiency substituents, such as fluoro, chloro, bromo and nitro groups (Table 2, entries 4-9) gave the corresponding 2-amino-6methyl-5-arylfuro[2,3-d]pyrimidin-4-ol 3 with good to high yields, respectively. We also noted that all the nitroolefins with electron-withdrawing groups exhibited higher activities than those bearing electron-donating groups and produced corresponding desired products with higher yields. We assumed that the existing of electron-withdrawing groups bearing benzene ring decreased the electron cloud density of α-position of nitroolefins, which is favor of the occurrence of nucleophilicattracking. In addition, because of the steric hindrance, nitroolefins bearing ortho-position of benzene ring shows lower activity (Table 2, entry 8). It was noting that the fused-cyclic nitroolefin, such as (E)-1-(2-nitroprop-1-en-1-yl)naphthalene (2j), and the heterocyclic one, such as (E)-2-(2-nitroprop-1-en-1yl)thiophene (2k), also exhibited high reaction activities and gave corresponding desired products with 86% and 85% yields respectively. Additionally, to further expand the scope of nitroolefin substrates, (E)-(2-nitroprop-1-en-1-yl)benzene (2a) was replaced with (E)-1-chloro-4-(2-nitrobut-1-en-1-yl)benzene (2l). We found that the latter also tolerated this transformation smoothly and gave corresponding 2-amino-5-(4-chlorophenyl)-6ethylfuro[2,3-d]pyrimidin-4-ol (3l) with 79% yields (Table 2, entry 12). It should be noted that this reaction can be performed on a gram-scale under the above simple conditions. In addition, the same product (3a) with similar yield (86%) was obtained, when Z-(2-nitroprop-1-en-1-yl)benzene was submitted to react with 2-aminopyrimidine-4,6-diol (1a) under the same conditions. Unfortunately, the goal product could not be obtained when (E)5-methyl-2-nitrohex-2-ene was submitted to react with 2aminopyrimidine-4,6-diol (1a) at the same conditions.

Scheme 2. Proposed mechanism for the formation of furo[2,3d]pyrimidines (3).

With the above mentioned results in hand, we turn our attention to investigating the scope of pyrimidine substrate. The 2-methylpyrimidine-4,6-diol (1b) was choosen as model substrate to react with different nitroolefins. Similarly, 2methylpyrimidine-4,6-diol (1b) was another appropriate partner in this reaction and provided the corresponding 2,6-dimethyl-5arylfuro[2,3-d]pyrimidin-4-ol with 89-95% yields. With no exceptions, the reaction between 1b and a variety of nitroolefins resulted in the formation of 2,6-dimethyl-5-arylfuro[2,3d]pyrimidin-4-ol (3m-3r) with higher yields in even shorter reaction time. The results exhibit the scope and generality of the novel reaction between substituted pyrimidines and a variety of nitroolefins.

In conclusion, we have demonstrated an operationally simple and highly efficient approach for the synthesis of fully substituted 6-methyl-5-arylfuro[2,3-d]pyrimidin-4-ol derivatives 3 from common starting materials. The reaction proceed [3+2] heterocyclization obtaining desired products in good to excellent yields, showing that this method allows us to build blocks of 6methyl-5-arylfuro[2,3-d]pyrimidin-4-ol derivatives with a wide diversity in substituents. Features of this strategy include catalyst-free, water as green solvent, short reaction time, simple operation, and high yields. The method is highly valuable in view of the synthetic and product importance of furo[2,3d]pyrimidines of this type, and its application was in progress in our laboratory.

In all cases, the reaction proceeded at very fast speeds and gave corresponding goal products with good to excellent yields. This reaction procedure is efficient and environmentally friendly in view of the use of green and cheap water as solvent and filtration as simple processing work-up. The structures of the resulting products 3 and 6 have been confirmed by 1H NMR, 13C NMR and HR-MS spectral analysis. On the basis of above experiment results, a reasonable reaction mechanism for this reaction is postulated in Scheme 2. Firstly, nucleophilic addition reaction between pyrimidine 1 and nitroolefin 2 occurs, leading to intermediate A, which undergoes electron transfer to afford active intermediate B, which is further isomerized to D. Intermediate B also can transform intermediate D via nucleophilic attack of oxygen atom of hydroxyl group to carbon atom of C=N double bond. Ultimately, the intermediate D would lead to the desired product 3 after elimination of H2O and HNO under aerial oxidation.

Acknowledgments We are grateful for financial support from the Foundation of Education Department of Zhejiang Province (No. Y201636353), and the Natural Science Foundation of Zhejiang Province (No. LY16B020007).

References and notes Scheme 1. The synthesis of unexpected 2-methyl-5-(2-nitro-1phenylethyl)pyrimidine-4,6-diol (6)

Subsequently, to further expand the scope of this reaction, (E)-(2-nitrovinyl)benzene (4) was choosen as nitroolefin substrate to react with pyrimidines (Scheme 1). Unfortunately,

1.

2. 3.

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5 Highlights The synthesis of furo[2,3-d]pyrimidines under catalyst-free conditions has been reported. The green and high efficiency makes this methodology more meaningful. The present protocol offers direct and facile access to furo[2,3-d]pyrimidine derivatives.