A novel pyrimidine forming cyclization

Journal Pre-proofs A novel pyrimidine forming cyclization Ruben Leenders, Marc van de Sande, Jean-François Bonfanti PII: DOI: Reference:

S0040-4039(19)31160-8 https://doi.org/10.1016/j.tetlet.2019.151369 TETL 151369

To appear in:

Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

2 September 2019 24 October 2019 5 November 2019

Please cite this article as: Leenders, R., van de Sande, M., Bonfanti, J-F., A novel pyrimidine forming cyclization, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151369

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Graphical abstract:

A novel pyrimidine forming cyclization Ruben Leenders, Marc van de Sande, Jean-François Bonfanti R2

R2 Br R1

Br N

N

R3

R1

R2 Br NH

O H2N

3

R

R1

O

A novel pyrimidine forming cyclization Ruben Leenders,*a Marc van de Sande,a Jean-François Bonfantib aMercachem bJanssen

BV, Kerkenbos 10-13, 6546 BB Nijmegen, The Netherlands

Research and Development, Medicinal Chemistry Infectious Diseases,

Campus de Maigremont BP315, F-27106 Val de Reuil Cedex, France

Abstract— A novel reaction giving easy access to 5-bromopyrimidines via the cyclization of 1,2dibromoenones and amidines is described. Keywords: Heterocyclic chemistry; pyrimidines; cyclisation; 5-bromopyrimidines The pyrimidine core is very common in medicinal chemistry,1 and as a result, it is present in a large number of marketed drugs.2 In continuation of our research towards new drug candidates, we have devised a novel cyclization reaction towards the 5-bromopyrimidine core, which is outlined in the present Letter. 5-Bromopyrimidines B (Scheme 1) are conventionally prepared by electrophilic bromination of the pyrimidine ring. As the pyrimidine ring is electron-poor, bromination of A is possible provided there is at least one strongly electron-donating group at the 2-, 3- or 6-position. R2 "Br "

1

R

N

3

A

R

Br

N

R1

N

R3

B

R1 or R2 or R3 = OR, SR, NR2

Scheme 1. Electrophilic bromination of the pyrimidine core.

In cases where there is no strong activator present on the pyrimidine ring, bromination is typically unfeasible.3 We have therefore devised a strategy wherein the bromine atom is already present in the starting material. Retrosynthetically disconnecting target pyrimidine B along the indicated positions gives dibromide 1 and amidine 2. E-1,2-Dibromoalkenes 1 can be further disconnected to ynones 3 (Scheme 2). R2 Br

R2 Br

N

R1

N B

R3

Boc

N

TMS

4

Boc

N

Boc

Br

N

H

5

Br

Br H N 2 HCl

py-HBr-Br2, CH2Cl2, r.t.

O

NH

O

N

7

N N

N DIPEA, Boc EtOH, r.t., 88% calculated from (E)-6

(E)-6 (Z)-6

N

8

Scaffold 10 was prepared from acrylic dibromide 96,7 in 38% isolated yield.8 Theoretically, both compounds could also be prepared from the corresponding 5H-pyrimidines by bromination. In this respect, a number of bromination reactions for testing the synthesis of 10 from 11 were attempted,9 but none gave the desired product. This further underlines the significance of the present novel 5bromopyrimidine-forming reaction. NH

O

R3

Scheme 2. Retrosynthetic analysis of pyrimidine B.

* Corresponding author: [email protected]

Br 7

N

N

HO

DIPEA, EtOH r.t. 38%

N 10

N

N

3 R1

H 2N HCl

9 Br

HO

Br

Br

EtO

R2

R1 O 1 + NH 2 H 2N

NaOAc, MeOH, 0 °C

O

Scheme 3. Synthesis of scaffold 8.

R2 N

This synthetic route was exemplified with two fundamentally different pyrimidine scaffolds (Scheme 3): dibromide 6 is prepared from the corresponding known ynone 4 as an E/Z-mixture in a ratio of 6:5.4 This E/Z-mixture is reacted with amidine 7 giving the desired pyrimidine scaffold 8 in 88% yield calculated from (E)-6,5 while (Z)-6 did not contribute to product formation.

O

N 11

bromination N

Scheme 4. Synthesis of scaffold 10.

Further decoration of the versatile scaffolds 8 and 10 was accomplished in two independent positions as exemplified in Scheme 5.10

Br

1) HCl, 1,4-dioxane, 2) (CH3)3CCOCl, Et3N, CH2Cl2, 0 °C

N N

Boc

8

N

N

Ar-B(OH)2, Na2CO3,

3) AlH3-Me2NEt, toluene, THF, 0 °C to r.t. 45-55%

N

HO

N

13

Ph-3-OCH3-B(OH)2, Na2CO3,

N

O HO

N 10

(PPh3)2PdCl2 (5 mol%), N 1,2-DME, H2O, 65 °C 1) oxalyl chloride, O DMF (cat.), CH2Cl2, r.t. 2) R1-NH-R2, DIPEA, THF, 65 °C

N 14

N R2

N 15

N

Examples of 15 R1-NH-R2 (yield) = a: HN O

N R1

N

Examples of 13 Ar (yield) = a: Ph (99%) b: Ph-3-CN (75%) c: Ph-3-NMe2 (73%) d: 4-pyridyl (60%) e: Ph-2-Me (100%)

N N

N

N N 12

N

Ar

(PPh3)2PdCl2 (5 mol%), 1,2-DME, H2O 65 °C

Br

Br

b: N

N H

OPh

(57%)

HN N

(56%)

Scheme 5. Decoration of scaffolds 8 and 10.

  

Facile synthesis of 5-bromopyridines Bromine atom already present in building block Cyclisation of guanidines with dibromo enones

Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

References and notes 1. Modi, V. S.; Basuri, T. S. Int. J. Pharm. Pharm. Sci. 2011, 3, 13. 2. Selvam, T. P.; James, C. R.; Dniandev, P. V.; Valzita, S. K. Res. Pharm. 2012, 2, 1.

3. In a few isolated instances bromination was accomplished, but benzylic bromination competes in cases where alkyl substituents are present. See for example: Wang, Z.; Chi, Y.; Harris, A. R.; Gray, D.; Davoren, J. E. Synthesis 2011, 1529. 4. t-Butyl-4-propioloylpiperidine-1-carboxylate (5) At 0 °C, NaOAc (1.4 g, 16.9 mmol) was added to a solution of t-butyl 4-[3-(trimethylsilyl)propioloyl]piperidine-1-carboxylate 4 (5.2 g, 16.9 mmol) in MeOH (60 mL). After stirring for 45 min. at 0 °C, TLC (heptane/EtOAc, 1:1) showed complete conversion. The solvent was removed in vacuo at 20 °C. After co-evaporation with CH2Cl2 the residue was triturated with CH2Cl2 (50 mL). Solids were filtered off and washed with CH2Cl2. The filtrate was used as such in the following step. For analysis, a sample was evaporated and purified by flash column chromatography (heptane, 15% EtOAc). 1H-NMR (400 MHz, CDCl )  4.30 – 3.87 (m, 2H), 3.39 (s, 3 1H), 3.03 – 2.76 (m, 2H), 2.68 – 2.52 (m, 1H), 2.06 – 1.82 (m, 2H), 1.67 – 1.56 (m, 2H), 1.46 (s, 9H); MW[C13H19NO3] = 237.29 g/mol; MS (ESI) m/z = 182 (M-C4H8+H)+. E- and Z-t-Butyl 4-(2,3-dibromoacryloyl)piperidine-1carboxylate, (E-6 and Z-6) A solution of crude t-butyl 4-propioloylpiperidine-1carboxylate (obtained as described above) in CH2Cl2 (60 mL) was added to a suspension of pyridinium tribromide (6.7 g, 21.0 mmol) in CH2Cl2 (100 mL). After stirring at room temperature for 15 min., all the solids had dissolved. Stirring was continued overnight. Aqueous Na2S2O5 (5%, 30 mL) was added and the mixture was stirred until the orange color had disappeared. The aqueous layer was extracted with CH2Cl2 (2 x 15 mL) and the combined organic layers washed with H2O (30 mL) and dried over Na2SO4. The solvents were removed in vacuo to give 6.1 g (15.3 mmol, 91% over two steps) of a yellow oil. 1H-NMR analysis was in agreement with a mixture of E- and Z-t-butyl 4-(2,3dibromoacryloyl)piperidine-1-carboxylate in the ratio 6:5. The mixture was used as such in the following step. 1H-NMR (400 MHz, CDCl )  8.13 (s, 0.46H), 6.86 (s, 3 0.54H), 4.24 – 3.98 (m, 2H), 3.30 – 3.23 (m, 0.46H), 3.18 – 3.11 (m, 0.54H), 2.99 – 2.70 (m, 2H), 1.96 – 1.90 (m, 1H), 1.88 – 1.76 (m, 1H), 1.68 – 1.54 (m, 2H), 1.46 (s, 9H); MW[C13H19Br2NO3] = 397.10 g/mol; MS (ESI) m/z = 418/420/422 (M+Na)+. 5. t-Butyl 4-[5-bromo-2-(pyridin-4-yl)pyrimidin-4yl]piperidine-1-carboxylate (8) DIPEA (0.7 mL, 4.1 mmol) was added to a solution of a mixture of (E)-6 and (Z)-6 (0.78 g, 1.95 mmol) and 7 (0.32 g, 2.0 mmol) in EtOH (30 mL) at room temperature. The reaction mixture was stirred overnight and the solvent was removed in vacuo. Purification by flash column chromatography (heptane, 8-20% EtOAc) afforded 510 mg (1.2 mmol, 48%; 88% calculated from (E)-6; (Z)-6 did not contribute to product formation) of 8 as a yellow solid, purity 98%. 1H-NMR (400 MHz, CDCl )  8.83 (s, 1H), 8.77 (d, J = 3 6.1 Hz, 2H), 8.27 (d, J = 6.1 Hz, 2H), 4.50 – 4.13 (m, 2H), 3.39 – 3.26 (m, 1H), 3.04 – 2.77 (m, 2H), 2.00-1.83 (m, 4H), 1.51 (s, 9H); MW[C19H23BrN4O2] = 419.32 g/mol; MS (ESI) m/z = 419/421 (M+H)+. 6. Myers, A. G.; Alauddin, M. M.; Fuhry, M-A. M.; Dragovich, P. S.; Finney, N. S.; Harrington, P. M. Tetrahedron Lett. 1989, 30, 6997. 7. Bellina, F.; Carpita, A.; De Santis, M.; Rossi, R.; Tetrahedron Lett. 1994, 35, 6913. 8. 5-Bromo-2-(pyridin-4-yl)pyrimidin-4-ol (10) At room temperature DIPEA (7.0 mL, 40.7 mmol) was added to a suspension of E-ethyl 2,3-dibromoacrylate 6 (3.5 g, 13.6 mmol) and 7 (3.2 g, 20.4 mmol) in EtOH (150 mL). The mixture was stirred at 40 ºC for 18 h. and was allowed to cool to room temperature. The solvents were removed in vacuo. The solid residue was first triturated with H2O (50 mL) over 48 h. and subsequently in i-Pr2O (30 mL) for 18 h. The solids were filtered off, washed with i-Pr2O and dried in vacuo at room temperature to give 1.3 g (5.2 mmol, 38%) of 5-bromo2-(pyridin-4-yl)pyrimidin-4-ol. 1NMR (400 MHz, CDCl )  8.85 – 8.69 (m, 2H), 8.37 (s, 3 1H), 8.08 (d, J = 6.0 Hz, 2H); MW[C9H6BrN3O] = 252.07 g/mol; MS (ESI) m/z = 252/254 (M+H)+. 9. Brominaton was attempted with pyr-HBr-Br2/CH2Cl2/r.t., Br2/NaOAc/AcOH/r.t., and NBS/AcOH/90 °C, but the

desired product was not obtained under any of these conditions. 10.Bonfanti, J.F.; Muller P. ; Doublet, F. ; Fortin, J. ; Lounis, N. WO2013164337