CC BY ND NC 4.0 · SynOpen 2017; 01(01): 0045-0049
DOI: 10.1055/s-0036-1588456
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Copyright with the author

l-Proline-Catalysed One-Pot Regio- and Diastereoselective Synthesis of Spiro[pyrido[2,3-d]pyrimidin-2-amine-6,5′-pyrimidines] in Water

Subarna Jyoti Kalita, Bidyut Das, Dibakar Chandra Deka*
  • Department of Chemistry, University of Gauhati, G. B. Nagar, Guwahati 781014, Assam, India   Email: dcdeka@rediffmail.com
Further Information

Publication History

Received: 29 March 2017

Accepted after revision: 21 May 2017

Publication Date:
29 June 2017 (online)

 

Abstract

A simple l-proline-catalysed regio- and diastereoselective synthesis of spiro[pyrido[2,3-d]pyrimidin-2-amine-6,5′-pyrimidines] in water through a strategy of one-pot multicomponent domino reaction of 2,6-diaminopyrimidin-4-one, aldehydes and barbituric acids is described. The notable advantages of the protocol are operational simplicity, mild reaction conditions, simple purification process involving no chromatographic techniques, wide substrate scope, and high yields. The method delivers the desired product within short reaction time and with a diastereoselectivity of 61:39 to 100:0, which makes the protocol highly attractive.


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The development of simple, efficient, environmentally benign and economically viable reaction protocols with high regio- and diastereoselectivity continues to be an important area of research. In this context, development of multicomponent domino reactions have become an increasingly powerful tool in organic synthesis because the protocol allows flexible, convergent, atom- and step-economic­ synthesis.[1] Furthermore, due to the adverse implications of organic solvents, efforts to design efficient synthetic methodology in aqueous medium are of interest. Water can also regulate the course of a reaction by its unique physiochemical properties; polarity, hydrogen bonding, hydrophobic effect and trans-phase interactions.[2]

In this area, organocatalysis has emerged as a powerful strategy, whereby chemical reactions are accelerated by the application of small organic molecules in substoichiometric amounts. Ideal organocatalysts are easy to handle, air- and water-stable, relatively non-toxic, work under mild conditions, are easily separated from the crude reaction mixture and overcome the major drawbacks of heterogeneous catalysts, such as metal-leaching, long reaction times and structural stability.[3]

Pyrido[2,3-d]pyrimidines and their spiro analogues exhibit a wide range of biological activities such as antibacterial,[4] antitumor,[5] antihypertensive,[6] cardiotonic,[7] antiproliferative,[8] vasodilator,[9] antifolating,[10] antimalarial,[11] analgesic[12] and antifungal[13] properties. Furthermore, the presence of the spiro-carbon atom provides structural rigidity, can induce steric strain and helps the parent molecule to undergo thermal, base- or acid-promoted rearrangements, often resulting in new and unexpected products.[14]

Quiroga et al. reported a triethylamine-catalysed synthesis of pyridopyrimidin-spirocyclohexanotriones from 6-aminopyrimidines, dimedone and formaldehyde under microwave irradiation but with no diastereoselectivity.[15] Barua and Bhuyan developed a two-step procedure for the synthesis of spiro-substituted pyrido[2,3-d]pyrimidines. However, the use of organic solvents and piperidine and diisopropylethylamine (DIPEA) as catalysts reduce its green credentials.[16] In 2009, Jiang et al. developed an elegant procedure for the synthesis of 6-spiro-substituted pyrido[2,3-d]pyrimidines from 2,6-diaminopyrimidin-4-one, aldehydes and barbituric acids under microwave irradiation. However, this procedure is compatible only with aryl aldehydes.[17] Herein, we report a new and simple l-proline-catalysed regio- and diastereoselective synthesis of spiro[pyrido[2,3-d]pyrimidin-2-amine-6,5′-pyrimidines] by one-pot multicomponent domino reaction of 2,6-diaminopyrimidine-4-one, aldehydes and barbituric acids in water with diastereoselectivity from 61:39 to 100:0 under mild reaction conditions (Scheme [1]).[18]

Zoom Image
Scheme 1 Synthesis of spiro[pyrido[2,3-d]pyrimidin-2-amine-6,5′-pyrimidines]

The present work is the result of our continuous efforts on the development of new protocols involving greener methodologies for the synthesis of biologically active heterocyclic molecules.[19] l-Proline is the catalyst of choice because it is not only a mild and readily available bifunctional organocatalyst but it also catalyses a range of reactions by its different activation modes such as by enamine and iminium cation formation. Moreover, it has been described as the simplest molecule that can facilitate chemical transformations similar to those catalysed by complex enzymes and has shown remarkable efficiency in promoting diverse synthetic transformations including enantio- and diastereoselective aldol, Mannich, and Michael reactions.[20]

Table 1 Optimization of the Reactiona

Entry

Catalyst (mol%)

Solventb

Time (min)

Yield (%)c

cis/trans d

RT

Reflux

1

H2O

720

0

0

2

H2O

30

150

70

84:16

3

l-Proline (10)

H2O

20

70

80

90:10

4

l-Proline (20)

H2O

15

30

95

97:3

5

l-Proline (30)

H2O

15

30

95

97:3

6

l-Proline (20)

EtOH

15

30

80

93:7

7

l-Proline (20)

MeOH

15

30

82

91:9

a Reaction scale: 1 (1 mmol), 2a (2 mmol) and 3a (1 mmol).

b Solvent (5 mL) used.

c Isolated yield.

d Based on 1H NMR spectroscopic analysis.

Initially, a mixture of 2,6-diaminopyrimidin-4-one (1, 1 mmol), benzaldehyde (2a, 2 mmol) and 1,3-dimethylbarbituric acid (3a, 1 mmol) was stirred at room temperature and only 5-benzylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione was isolated along with the unreacted starting materials (Table [1], entry 1). With this observation, we stirred a mixture of 1,3-dimethylbarbituric acid (3, 1 mmol) and benzaldehyde (2a, 1 mmol) at room temperature until the generation of 5-benzylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione was indicated by TLC. Next, another 1 mmol of benzaldehyde (2a) followed by 1 mmol of 2,6-diaminopyrimidin-4-one (1) were added to the reaction mixture and the reaction was heated to reflux, which resulted in the formation of 2-amino-1′,3′-dimethyl-5,7-diphenyl-7,8-dihydro-1′H,3H-spiro[pyrido[2,3-d]pyrimidine-6,5′-pyrimidine]-2′,4,4′,6′(3′H,5H)-tetraone (4aa) in 70% yield in 3 h, with 84:16 diastereoselectivity (entry 2). However, when the same reaction was carried out using 10 mol% l-proline, the yield of 4aa increased to 80% and diastereoselectivity increased to 90:10 in 1.5 h (entry 3). Further increasing the catalyst load to 20 mol% led to 4aa being isolated in 95% yield within 45 min with 97:3 diastereoselectivity (entry 4). No further improvement in yield or diastereoselectivity was observed when the catalyst load was increased to 30 mol% (entry 5). To assess the effect of solvent, when the reaction was executed in EtOH and MeOH the desired product was obtained in 80 and 82% yield, respectively (entries 6 and 7). Thus, the above studies led to the conclusion that 20 mol% l-proline in water under room temperature to reflux are the optimum conditions in terms of yield and diastereoselectivity. It may be noted that simultaneous mixing of 1 (1 mmol), 2a (2 mmol) and 3a (1 mmol) using 20 mol% l-proline also yielded the desired product in 95% yield in 45 min under reflux conditions, but the two-step procedure reduces the required reflux time.

Table 2 Scope of the Synthesisa

Entry

R1

R2

R3

4

Time (min)

Yield (%)b

cis/trans c

RT

Reflux

1

C6H5

CH3

CH3

4aa

15

30

95

97:3

2

2-O2NC6H4

CH3

CH3

4bb

10

25

93

100:0

3

2-BrC6H4

CH3

CH3

4cc

15

30

90

84:16

4

3-FC6H4

CH3

CH3

4dd

15

30

91

92:8

5

4-ClC6H4

CH3

CH3

4ee

15

25

96

100:0

6

4-MeOC6H4

CH3

CH3

4ff

10

30

94

92:8

7

2-Thienyl

CH3

CH3

4gg

15

30

90

61:39

8

4-Pyridyl

CH3

CH3

4hh

15

30

94

98:2

9

2-ClC6H4

H

CH3

4ii

15

30

91

71:29

10

3-BrC6H4

H

CH3

4jj

15

35

94

93:7

11

4-MeOC6H4

H

CH3

4fk

10

30

91

100:0

12

4-MeC6H4

H

CH3

4kl

15

25

93

100:0

13

3,5-(MeO)2C6H3

H

H

4lm

10

25

90

98:2

14

3-MeC6H4

H

H

4mn

15

30

91

100:0

15

4-MeOC6H4

H

H

4fo

10

25

93

100:0

a Reaction scale: 1 (1 mmol), 2 (2 mmol), 3 (1 mmol).

b Isolated yield.

c Based on 1H NMR spectroscopic analysis.

Having established the optimised reaction conditions, the scope of the reaction was explored by reacting 2,6-diaminopyrimidin-4-one (1) with various aldehydes 2 and barbituric acids 3; the results are presented in Table [2]. Various aromatic aldehydes participated well in the reaction and the target products were obtained in good to excellent yields. The electronic and steric effects from the substituents on the benzene ring have no significant impact on the course of the reaction, as is evident from the fact that benzaldehydes with electron-withdrawing and -donating groups in ortho-, meta- and para-positions reacted efficiently (Table [2]). Much to our satisfaction, heteroaromatic aldehydes such as thiophene-2-carboxaldehyde and pyridine-4-carboxaldehyde also reacted efficiently to give their corresponding products 4gg and 4hh in 90% and 94% yields, respectively (entries 7 and 8). The generality of the protocol was further expanded when 1-methylbarbituric acid (3b) and barbituric acid (3c) were reacted with 2,6-diaminopyrimidin-4-one and various aldehydes under the same reaction conditions, and their corresponding products were obtained in high yields (entries 9–15).

Assessment of the 1H NMR spectra revealed that the reaction is highly diastereoselective and the products 4bb, 4ee, 4fk, 4kl, 4mn and 4fo were obtained in 100:0 diastereoselectivity. A comparison of the diastereoselectivity and product yields of the present methodology with the reported procedures for the synthesis of spiro[pyrido[2,3-d]pyrimidin-2-amine-6,5′-pyrimidines] is shown in Table [3]. Interestingly, the use of l-proline increases the diastereoselectivity and the product yield significantly. However, all products were racemic.

Table 3 Comparison of Present Methodology with Reported Methodology

Entry

4

Yield (%)a

cis/trans b

This work

Ref.[17]

This work

Ref.[17]

1

4aa

95

85

97:3

94:6

2

4ee

96

83

100:0

80:20

3

4ff

94

88

92:8

86:14

4

4fk

91

88

100:0

96:4

5

4kl

93

82

100:0

96:4

6

4fo

93

89

100:0

93:7

7

4gg

90

No reaction

61:39

8

4hh

94

No reaction

98:2

a Isolated yield.

b Based on 1H NMR spectroscopic analysis.

All products synthesised were characterised by 1H and 13C NMR, IR spectroscopy, mass spectrometry and elemental analysis. Known compounds were further authenticated by comparison with analytical data from previous reports.

In summary, we have developed a straightforward synthesis of spiro[pyrido[2,3-d]pyrimidin-2-amine-6,5′-pyrimidines] by l-proline-catalysed one-pot multicomponent domino reaction of 2,6-diaminopyrimidin-4-one, aldehydes and barbituric acids in water. The protocol is highly regio- and diastereoselective and works under mild reaction conditions. The use of water as reaction medium and l-proline as organocatalyst has expanded the scope of aqueous medium organocatalysed reactions. Operational simplicity, high yields, shorter reaction time, wide substrate scope, simple purification process and diastereoselectivity from 61:39 to 100:0 make this protocol highly attractive.


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Acknowledgment

The authors thank UGC, Govt. of India for the financial assistance. The authors also thank SAIF-NEHU, GU, IIT Guwahati, IIT Ropar and TU for sample analyses.

Supporting Information

  • References

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    • 1c Brauch S. van Berkela SS. Westermann B. Chem. Soc. Rev. 2013; 42: 4948
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    • 2c Butler RN. Coyne AG. Chem. Rev. 2010; 110: 6302
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    • 2e Simon M.-O. Li C.-J. Chem. Soc. Rev. 2012; 41: 1415
    • 2f Wadhwa P. Kaur T. Singh N. Singh UP. Sharma A. Asian J. Org. Chem. 2016; 5: 120
    • 3a MacMillan DW. C. Nature 2008; 455: 304
    • 3b Marson CM. Chem. Soc. Rev. 2012; 41: 7712
    • 3c Renzi P. Bella M. Chem. Commun. 2012; 6881
    • 3d Mase N. Barbas III CF. Org. Biomol. Chem. 2010; 8: 4043
    • 3e Jimeno C. Org. Biomol. Chem. 2016; 14: 6147
    • 3f Samzadeh-Kermani A. Synlett 2016; 27: 2213
  • 4 Narayana BL. Rao AR. R. Rao PS. Eur. J. Med. Chem. 2009; 44: 1369
  • 5 Gineinah MM. Nasr MN. A. Badr SM. I. El-Husseiny WM. Med. Chem. Res. 2013; 22: 3943
  • 6 Blankley CJ. Bennett LR. Fleming RW. Smith RD. Tessman DK. Kaplan HR. J. Med. Chem. 1983; 26: 403
  • 7 Heber D. Heers C. Ravens U. Pharmazie 1993; 48: 537
  • 8 Yang T. He H. Ang W. Yang Y.-H. Yang J.-Z. Lin Y.-N. Yang H.-C. Pi W.-Y. Li Z.-C. Zhao Y.-L. Luo Y.-F. Wei Y. Molecules 2012; 17: 2351
  • 9 Coates W. Eur. Pat 0 351058 A1, 1990 ; Chem. Abstr. 1990, 113, 40711
  • 10 DeGraw JI. Christie PH. Colwell WT. Sirotnakt FM. J. Med. Chem. 1992; 35: 320
  • 11 Colbry NL. Elslager EF. Werbel LM. J. Med. Chem. 1985; 28: 248
  • 12 El-Gazzar A.-RB. A. Hafez HN. Bioorg. Med. Chem. Lett. 2009; 19: 3392
  • 13 Hanafy FI. Eur. J. Chem. 2011; 2: 65
    • 14a Companyó X. Zea A. Alba A.-NR. Mazzanti A. Moyano A. Rios R. Chem. Commun. 2010; 6953
    • 14b Rios R. Chem. Soc. Rev. 2012; 41: 1060
  • 15 Quiroga J. Cruz S. Insuasty B. Abonía R. Nogueras M. Cobo J. Tetrahedron Lett. 2006; 47: 27
  • 16 Baruah B. Bhuyan PJ. Tetrahedron Lett. 2009; 50: 243
  • 17 Jiang B. Cao L.-J. Tu S.-J. Zheng W.-R. Yu H.-Z. J. Comb. Chem. 2009; 11: 612
  • 18 General procedure for the synthesis of spiro[pyrido[2,3-d]pyrimidin-2-amine-6,5′-pyrimidines] (4aa–o): A mixture of aldehyde 2 (1 mmol) and barbituric acid 3 (1 mmol) was stirred at room temperature in the presence of 20 mol% l-proline as catalyst in water (5 mL) until the generation of 5-arylidenebarbituric acid was indicated by TLC. This was then followed by the addition of another 1 mmol of aldehyde 2 and 1 mmol of 2,6-diaminopyrimidine-4-one 1, then the reaction mixture was heated to reflux for the appropriate time (Table 2). On completion of the reaction, as indicated by TLC, the mixture was cooled and the solid product formed was filtered out and washed with water (3 × 10 mL) to afford pure 4
    • 19a Kalita SJ. Mecadon H. Deka DC. RSC Adv. 2014; 4: 10402
    • 19b Kalita SJ. Mecadon H. Deka DC. RSC Adv. 2014; 4: 32207
    • 19c Kalita SJ. Mecadon H. Deka DC. Tetrahedron Lett. 2015; 56: 731
    • 19d Kalita SJ. Saikia N. Deka DC. Mecadon H. Res. Chem. Intermed. 2016; 42: 6863
    • 19e Kalita SJ. Deka DC. Mecadon H. RSC Adv. 2016; 6: 91320
    • 19f Kalita SJ. Bayan R. Devi J. Brahma S. Mecadon H. Deka DC. Tetrahedron Lett. 2017; 58: 566
    • 20a Gröger H. Wilken J. Angew. Chem. Int. Ed. 2001; 40: 529
    • 20b Northrup AB. MacMillan DW. C. J. Am. Chem. Soc. 2002; 124: 6798
    • 20c List B. Tetrahedron 2002; 58: 5573
    • 20d Liu J. Wang L. Synthesis 2017; 49: 960
    • 20e Liu H. Peng L. Zhang T. Li Y. New J. Chem. 2003; 27: 1159
    • 20f Gunasekaran P. Indumathi S. Perumal S. RSC Adv. 2013; 3: 8318
    • 20g Feng L.-C. Sun Y.-W. Tang W.-J. Xu L.-J. Lam K.-L. Zhou Z. Chan AS. C. Green Chem. 2010; 12: 949
    • 20h Khalafi-Nezhad A. Sarikhani S. Shahidzadeh ES. Panahi F. Green Chem. 2012; 14: 2876
    • 20i Inani H. Jha AK. Easwar S. Synlett 2017; 28: 128

  • References

    • 1a Dömling A. Chem. Rev. 2006; 106: 17
    • 1b Guillena G. Ramoú DJ. Yus M. Tetrahedron: Asymmetry 2007; 18: 693
    • 1c Brauch S. van Berkela SS. Westermann B. Chem. Soc. Rev. 2013; 42: 4948
    • 1d Cioc RC. Ruijter E. Orru RV. A. Green Chem. 2014; 16: 2958
    • 1e Rotstein BH. Zaretsky S. Rai V. Yudin AK. Chem. Rev. 2014; 114: 8323
    • 1f Ziarani GM. Nasaba NH. Lashgarib N. RSC Adv. 2016; 6: 38827
    • 1g Sahn JJ. Granger BA. Martin SF. Org. Biomol. Chem. 2014; 12: 7659
    • 1h Ziarani GM. Alealia F. Lashgari N. RSC Adv. 2016; 6: 50895
    • 2a Butler RN. Cunningham WJ. Coyne AG. Burke LA. J. Am. Chem. Soc. 2004; 126: 11923
    • 2b Li C.-J. Chem. Rev. 2005; 105: 3095
    • 2c Butler RN. Coyne AG. Chem. Rev. 2010; 110: 6302
    • 2d Gawande MB. Bonifaćio VD. B. Luque R. Brancoa PS. Varma RS. Chem. Soc. Rev. 2013; 42: 5522
    • 2e Simon M.-O. Li C.-J. Chem. Soc. Rev. 2012; 41: 1415
    • 2f Wadhwa P. Kaur T. Singh N. Singh UP. Sharma A. Asian J. Org. Chem. 2016; 5: 120
    • 3a MacMillan DW. C. Nature 2008; 455: 304
    • 3b Marson CM. Chem. Soc. Rev. 2012; 41: 7712
    • 3c Renzi P. Bella M. Chem. Commun. 2012; 6881
    • 3d Mase N. Barbas III CF. Org. Biomol. Chem. 2010; 8: 4043
    • 3e Jimeno C. Org. Biomol. Chem. 2016; 14: 6147
    • 3f Samzadeh-Kermani A. Synlett 2016; 27: 2213
  • 4 Narayana BL. Rao AR. R. Rao PS. Eur. J. Med. Chem. 2009; 44: 1369
  • 5 Gineinah MM. Nasr MN. A. Badr SM. I. El-Husseiny WM. Med. Chem. Res. 2013; 22: 3943
  • 6 Blankley CJ. Bennett LR. Fleming RW. Smith RD. Tessman DK. Kaplan HR. J. Med. Chem. 1983; 26: 403
  • 7 Heber D. Heers C. Ravens U. Pharmazie 1993; 48: 537
  • 8 Yang T. He H. Ang W. Yang Y.-H. Yang J.-Z. Lin Y.-N. Yang H.-C. Pi W.-Y. Li Z.-C. Zhao Y.-L. Luo Y.-F. Wei Y. Molecules 2012; 17: 2351
  • 9 Coates W. Eur. Pat 0 351058 A1, 1990 ; Chem. Abstr. 1990, 113, 40711
  • 10 DeGraw JI. Christie PH. Colwell WT. Sirotnakt FM. J. Med. Chem. 1992; 35: 320
  • 11 Colbry NL. Elslager EF. Werbel LM. J. Med. Chem. 1985; 28: 248
  • 12 El-Gazzar A.-RB. A. Hafez HN. Bioorg. Med. Chem. Lett. 2009; 19: 3392
  • 13 Hanafy FI. Eur. J. Chem. 2011; 2: 65
    • 14a Companyó X. Zea A. Alba A.-NR. Mazzanti A. Moyano A. Rios R. Chem. Commun. 2010; 6953
    • 14b Rios R. Chem. Soc. Rev. 2012; 41: 1060
  • 15 Quiroga J. Cruz S. Insuasty B. Abonía R. Nogueras M. Cobo J. Tetrahedron Lett. 2006; 47: 27
  • 16 Baruah B. Bhuyan PJ. Tetrahedron Lett. 2009; 50: 243
  • 17 Jiang B. Cao L.-J. Tu S.-J. Zheng W.-R. Yu H.-Z. J. Comb. Chem. 2009; 11: 612
  • 18 General procedure for the synthesis of spiro[pyrido[2,3-d]pyrimidin-2-amine-6,5′-pyrimidines] (4aa–o): A mixture of aldehyde 2 (1 mmol) and barbituric acid 3 (1 mmol) was stirred at room temperature in the presence of 20 mol% l-proline as catalyst in water (5 mL) until the generation of 5-arylidenebarbituric acid was indicated by TLC. This was then followed by the addition of another 1 mmol of aldehyde 2 and 1 mmol of 2,6-diaminopyrimidine-4-one 1, then the reaction mixture was heated to reflux for the appropriate time (Table 2). On completion of the reaction, as indicated by TLC, the mixture was cooled and the solid product formed was filtered out and washed with water (3 × 10 mL) to afford pure 4
    • 19a Kalita SJ. Mecadon H. Deka DC. RSC Adv. 2014; 4: 10402
    • 19b Kalita SJ. Mecadon H. Deka DC. RSC Adv. 2014; 4: 32207
    • 19c Kalita SJ. Mecadon H. Deka DC. Tetrahedron Lett. 2015; 56: 731
    • 19d Kalita SJ. Saikia N. Deka DC. Mecadon H. Res. Chem. Intermed. 2016; 42: 6863
    • 19e Kalita SJ. Deka DC. Mecadon H. RSC Adv. 2016; 6: 91320
    • 19f Kalita SJ. Bayan R. Devi J. Brahma S. Mecadon H. Deka DC. Tetrahedron Lett. 2017; 58: 566
    • 20a Gröger H. Wilken J. Angew. Chem. Int. Ed. 2001; 40: 529
    • 20b Northrup AB. MacMillan DW. C. J. Am. Chem. Soc. 2002; 124: 6798
    • 20c List B. Tetrahedron 2002; 58: 5573
    • 20d Liu J. Wang L. Synthesis 2017; 49: 960
    • 20e Liu H. Peng L. Zhang T. Li Y. New J. Chem. 2003; 27: 1159
    • 20f Gunasekaran P. Indumathi S. Perumal S. RSC Adv. 2013; 3: 8318
    • 20g Feng L.-C. Sun Y.-W. Tang W.-J. Xu L.-J. Lam K.-L. Zhou Z. Chan AS. C. Green Chem. 2010; 12: 949
    • 20h Khalafi-Nezhad A. Sarikhani S. Shahidzadeh ES. Panahi F. Green Chem. 2012; 14: 2876
    • 20i Inani H. Jha AK. Easwar S. Synlett 2017; 28: 128

Zoom Image
Scheme 1 Synthesis of spiro[pyrido[2,3-d]pyrimidin-2-amine-6,5′-pyrimidines]