SNAr Reactions of 2-Methylthio-4-pyrimidinones in Pivalic Acid: Access to Functionalized Pyrimidinones and Pyrimidines

PAPER 1109

SNAr Reactions of 2-Methylthio-4-pyrimidinones in Pivalic Acid: Access to Functionalized Pyrimidinones and PyrimidinesSNAr Reactions of 2-Methylthio-4-pyrimidinones in Pivalic AcidMatthew L. Maddess,* Rhiannon CarterDepartment of Discovery Process Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USAFax +1(617)9922403; E-mail: [email protected] 19 December 2011; revised 3 February 2012

SYNTHESIS 2012, 44, 1109–1118xx.xx.2012Advanced online publication: 15.03.2012DOI: 10.1055/s-0031-1289744; Art ID: M116611SS© Georg Thieme Verlag Stuttgart · New York

Abstract: Pivalic acid is a useful medium to effect the direct SNArdisplacement of 2-methylthio-4-pyrimidinones with a variety ofanilines. Products are easily isolated in good to excellent yields, andfollowing chlorination, provide an opportunity to rapidly querystructure–activity relationships at the 4-position of functionalizedpyrimidines.

Key words: heterocycles, nucleophilic aromatic, solvent effects,medicinal chemistry, regioselectivity

2-Anilinopyrimidinones and particularly pyrimidineshave historically enjoyed strong popularity as core scaf-folds in drug discovery programs that target the treatmentof a variety of human malignancies.1–8 In large part, theirsuccess can be attributed to an ability to form a bidentatehydrogen bonding interaction with hinge amino acids in awide range of kinases.7 This promiscuous activity canthen be fine tuned by sequential modification of the pe-ripheral substituents leading to various useful kinase se-lectivity profiles.

Investigation of structure–activity relationships (SAR)about the pyrimidine nucleus is most often performed byexploitation of the differential reactivity of halopyrim-idines, for example, 1.2–4 Specifically, the 4-position isconsiderably more reactive towards both nucleophilicaromatic substitution (C–X) and metal-mediated (C–X/C–C) bond-forming processes.2–4,9–12 Although mixturesof regioisomers are often formed to some extent,13–15 con-ditions can at times be optimized to greatly favor the de-sired 4-regioisomer16 readily providing scaffolds 2 toexplore the effects of functionalization at C2 (Scheme 1,approach 1).

The complementary approach wherein substituents at C4could be varied post C2 derivatization is of value to a ro-bust medicinal chemistry effort in this area (3, Scheme 1,

approach 2). Surprisingly such a strategy has seen rela-tively limited application,17–20 presumably because chlo-ropyrimidines such as 3 are less readily accessed than the2-regioisomer 2. Commercially available 2-methylthio-4-pyrimidinone21 (4) appears to provide a most straightfor-ward entry to scaffolds of this type. However, standardconditions22 for displacement at C2 with a variety ofanilines require extended reaction times in refluxing di-glyme.23 This low reactivity is further exacerbated withelectron-deficient nucleophiles, which often afford pooryields24 or utilize an excess of the aniline in a fusion pro-cedure.25

With the goal of developing a general, scalable, and effi-cient protocol for direct SNAr displacement at C2 of 2-methylthio-4-pyrimidinones with anilines, we explored avariety of additives and modified conditions in a represen-tative system.26 Selected results are displayed inScheme 2 for reaction of 3-bromoaniline (5) with 4 inwhich conversion into pyrimidinone 6 relative to the start-ing material 4 was followed by HPLC as a function oftime.

SNAr displacement under standard conditions in diglymewithout additive was, as expected, sluggish at 130 °C withonly 8% conversion being achieved after 24 hours. Addi-tion of organic bases yielded at best no benefit (Hünig’sbase) or inhibited the reaction (DABCO). In contrast,acidic additives [AcOH, pivalic acid (PivOH), or MSA]provided markedly improved results with regards to con-version in a trend roughly correlated with the strength ofthe acid. Running the reaction in neat AcOH was superiorto that where it was used as an additive; however, the re-action was observed to stall due to unproductive con-sumption of the aniline via acylation by the solvent.27

Switching to pivalic acid resolved this issue and full con-version was achieved in less than six hours with an overall

Scheme 1 SAR approaches to 2,4-disubstituted pyrimidines

N

N

Cl

Cl

CX or CCcoupling

4-selective

N

N

R

ClN

N

Cl

NHN

NH

O

SMeAr

1. HNAr

2. POCl3

convenientSAR

approach 1 approach 2

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1110 M. L. Maddess, R. Carter PAPER

Synthesis 2012, 44, 1109–1118 © Thieme Stuttgart · New York

very clean reaction profile.28 On the whole, either neatPivOH or MSA (1 equiv) in diglyme appear to be practicalsystems to effect the desired transformation. Ultimately,the former was chosen for further exploration of the reac-tion scope given the improved impurity profile observed(Table 1).

According to the optimized procedure,29 2-methylthio-4-pyrimidinone (4) was mixed with the appropriate aniline(1.2 equiv) and diluted with 9 volumes (relative to 4) ofpivalic acid.30 The resulting mixture was heated to an in-ternal temperature of 130 °C and followed by HPLC untilthe pyrimidinone starting material was consumed. Uponcooling and addition of hexanes, the desired 2-substitutedproducts were obtained by simple filtration in sufficientpurity to use directly in subsequent transformations. Gen-erally, yields were found to be good to excellent for avariety of anilines tested including those containingelectron-withdrawing and/or reactive functional groups aswell as heterocyclic systems (Table 1, entries 13–17). Inmost cases reaction times were conveniently short (6 h or

less); although slower rates were observed for electroni-cally deactivated nucleophiles (Table 1, entries 13 to 16)or sterically encumbered anilines (Table 1, entry 6). In allcases, treatment of the isolated solids with phosphorusoxychloride afforded the desired activated pyrimidinescaffolds in good yield poised for derivatization at C4(Table 1).

Scheme 2 Additive effects: SNAr reaction of pyrimidinone 4 with 5

Scheme 3 PivOH SNAr reactions of 5-halopyrimidinone 41

N

NBr

NH

X

O

ON

NHBr

SMe

O

H2N

O

O

41 X = OH, 43

X = Cl, 44POCl3, 70 °C

1 h, 85%

PivOH130 °C, 6 h

96%

N

NBr

NH

X

Cl

N

NHBr

SMe

O

H2N

Cl

41 X = OH, 46

X = Cl, 47POCl3, 70 °C

1 h, 88%

PivOH130 °C, 6 h

89%

42(1.2 equiv)

45(1.2 equiv)

Me

Me

Me

Me

+

+

Table 1 PivOH Scope of SNAr Reactions of 4 with Anilinesa

Entry Product A Yield (%)b

B Yield (%)c

1 8 82 9 98

2 10 89 11 95

3 12 89 13 99

4 14 85 15 99

5 6 95 7 97

6 16 67 17 70

7 18 91 19 99

8 20 81 21 95

4

N

NH

O

SMe

H2N

N

N

NH

XPivOH

(9 volumes)R R

130 °C3–24 h

(1.2 equiv) X = OH, A

X = Cl, B

POCl370 °C, 1 h

+

N

N

NH

Br

X

N

N

NH

Cl

X

N

N

NH

X

F

N

N

NH

X

F

N

N

NH

X

Br

N

N

NH

X

Br

N

N

NH

X

N

N

NH

X

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PAPER SNAr Reactions of 2-Methylthio-4-pyrimidinones in Pivalic Acid 1111

© Thieme Stuttgart · New York Synthesis 2012, 44, 1109–1118

In an attempt to gain access to pyrimidines that would per-mit exploration at C5 as well as C4, the known 5-iodo (40,91%; I2, aq 1 N NaOH)31 and 5-bromo (41, 72%; NBS,DMF)32 derivatives of 4 were prepared and subjected tothe pivalic acid SNAr conditions. Whilst the former suf-fered from decomposition during the reaction conditionsgiving rise to a complex mixture of products, the latterbromide derivative 41 was found to provide satisfactoryresults similar to those previously observed with 4(Scheme 3).

As an alternative entry to scaffolds such as 43, which per-mits construction of the 5-iodo products, 2-anilinopyrim-idinones can be efficiently halogenated after SNArdisplacement (Scheme 4). These sorts of multi-halogenat-ed products provide interesting opportunities for selectivepost-functionalization at multiple positions on the anili-nopyrimidine core.

Scheme 4 Alternative entry to C5-halogenated pyrimidinones

In addition to the substrate scope presented above, thePivOH SNAr displacement conditions discussed thus farhave proven useful in a number of other contexts usingcommercially available electrophiles (Scheme 5).

For example, both C6-substituted trifluoromethyl 54 andhydroxypyrimidinones 61 underwent successful displace-ment at C2 with aniline nucleophiles to afford, after chlo-rination, scaffolds 57 and 60, respectively. For the former54, both extended reaction times and slightly larger equiv-alents of the aniline were required to obtain satisfactoryyields of the SNAr products 56 and 59. In contrast, 4,6-di-hydroxy-2-methylthiopyrimidine (61) required only twohours to reach full conversion, although in this case by-product formation limited the isolated yield to 75%.

The non-pyrimidinone starting materials 2-chloro-4-methylpyrimidine (64) and 6,8-dibromoimidazo[1,2-a]pyrazine (67) were both found to be viable substrates.

9 22 79 23 98

10 24 81 25 83

11 26 94 27 93

12 28 92 29 88

13 30 91 31 90

14 32 78 33 70

15 34 80 35 89

16 36 67 37 97

17 38 99 39 81

a Reactions performed on 7 to 270 mmol scale of 4. b Isolated yields corrected for weight percent as determined by 1H NMR and HPLC.c Isolated yields.

Table 1 PivOH Scope of SNAr Reactions of 4 with Anilinesa

(continued)

Entry Product A Yield (%)b

B Yield (%)c

4

N

NH

O

SMe

H2N

N

N

NH

XPivOH

(9 volumes)R R

130 °C3–24 h

(1.2 equiv) X = OH, A

X = Cl, B

POCl370 °C, 1 h

+

N

N

NH

X

Br

F

N

N

NH

X Br

N

N

NH

X I

N

N

NH

OMe

OMe

X

N

N

NH

X O

OMe

N

N

NH

X

CF3

N

N

NH

CN

X

N

N

NH

N

F

X

N

N

NH

X

N

Br

N

NH

O

NH

Br

N

NI

NH

X

6 X = OH, 48

X = Cl, 49POCl3, 70 °C

1 h, 96%

97%

NIS, DMF, 70 °C

Br

N

NH

O

NH

Br

N

NBr

NH

X

6 X = OH, 50

X = Cl, 51POCl3, 70 °C

1 h, 86%

73%

NBS, DMF, 70 °C

Br

N

NH

O

NH

Br

N

NCl

NH

X

6 X = OH, 52

X = Cl, 53POCl3, 70 °C

1 h, 89%

82%

NCS, AcOH, 90 °C

Br

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SNAr displacement on the former 64 with 3-bromo-5-methylaniline was complete in less than two hours, gavean excellent yield of the desired product, and was easilyscaled to 1.17 mol (66). The latter 67 when reacted with3,4-dimethoxyaniline afforded a single regioisomer of thedesired product 68 in yields and reaction times superior tothose reported in the literature (74%, >14 h).33

In conclusion, SNAr reaction of a variety of anilines with2-methylthio-4-pyrimidinones in pivalic acid provides aconvenient entry to pharmaceutically relevant 2-anilino-pyrimidinones and pyrimidines. This methodology is sim-ple, scalable, high-yielding, tolerant of functional groups,and should be of interest to medicinal chemistry programstargeting kinase inhibitors.

Unless otherwise noted all reactions were performed in air-driedglassware under a N2 atmosphere. HPLC grade solvents were usedwith no additional purification or drying and all anilines and pyrim-idinones were obtained either from commercial sources or preparedby straightforward literature procedures. Reactions were monitoredby HPLC [C-18 column, 4.6 × 100 mm, 2.7 mm particle column;40 °C; mobile phase: (A) 0.1% H3PO4–H2O; (B) MeCN, gradient10–95% B in 6 min and hold at 95% B for 2 min; flow rate, 1.8 mL/min (UV = 220 and 254 nm)], and/or TLC (0.25 mm silica gel

plates with UV indicator), and/or LC/MS [(30 mm × 2 mm, 2.0 mmparticle column; 2 mL injection; 3% to 98% MeCN–H2O + 0.05%TFA gradient over 2.3 min; 0.9 mL/min flow; APCI; positive ionmode; UV detection at 254 nm). Compounds were purified by crys-tallization or forced flow column chromatography using silica gel(230–400 mesh) and EtOAc–hexanes or MeOH–CH2Cl2 solventsystems. Reported yields are based upon isolated mass of the de-sired product and corrected for purity by weight percent as deter-mined by 1H NMR or HPLC using purified standards whenappropriate. 1H and 13C NMR were recorded on a 500 or 600 MHzspectrometer and are internally referenced to residual protio solventsignals. Data for 1H NMR are reported as follows: chemical shift (dppm), multiplicity (standard abbreviations), integration and cou-pling constant (Hz). Data for 13C NMR are reported in terms ofchemical shift (d ppm) and multiplicity as before when appropriate.HRMS data was obtained from an LC/MSD TOF spectrometer.Melting points were determined by differential scanning calorime-try (heating rate: 10 °C/min, temperature range: 25 to 350 °C) usinga DSC Q200 from TA Instruments.

The preferred experimental apparatus for standard reaction scales(~1 g) was 40 mL Chemglass disposable pressure release vials (CG-4912-06) and 1–1/2 × 5/16 disposable stirbars from Fisher(1451395). For large-scale reactions an overhead stirrer is recom-mended.

SNAr Reactions of 2-Methylthio-4-pyrimidinones in Pivalic Acid; General Procedure A A mixture of the respective 2-methylthio-4-pyrimidinone and thedesired aniline (1.2 equiv) in PivOH (9 volumes) was heated to aninternal temperature of 130 °C.29,30 Stirring was maintained at thistemperature until the pyrimidinone was fully consumed or untilconversion was observed to stall. Heating was then discontinuedand the internal temperature slowly allowed too decrease. Uponreaching 70 °C, hexanes (18 volumes) were added over 3 to 15 min.The slurry was further cooled to r.t. where it was stirred for 30 minprior to filtration through a medium glass frit. The filter cake wassubsequently washed with hexanes (2 × 3 to 5 volumes each), thendried, to afford the desired 2-anilinopyrimidinones in suitablepurity34 for direct use in subsequent transformations. Compounds10,22a 18,22a 28,35 and 3422a showed satisfactory spectroscopic datain agreement with those reported in the literature.

Chlorination of Pyrimidinone-4(3H)-ones with POCl3; General Procedure B A suspension of the respective 2-anilinopyrimidinone in POCl3 (12equiv) was heated to an internal temperature of 70 °C. After ~ 1 h,full conversion into the desired 4-chloropyrimidine was achievedand heating was discontinued. The reaction mixture was cooled tor.t. and the excess POCl3 removed by concentration in vacuo (careto ensure proper ventilation during removal and disposal of thePOCl3 waste should be implemented). The residue was then dilutedwith CH2Cl2 (20 volumes), and stirred with an equal volume of sat.aq NaHCO3 until the evolution of CO2 ceased. The layers were thenseparated; the aqueous extracted a second time with CH2Cl2 (20 vol-umes), the combined organics dried (MgSO4), filtered, and concen-trated in vacuo. Unless otherwise noted, purification by flashchromatography (0 to 100% EtOAc–hexanes or 0 to 10% MeOH–CH2Cl2) was used to afford analytically pure products. Compound2935 showed satisfactory spectroscopic data in agreement with thatreported in the literature.

2-[(3-Bromophenyl)amino]pyrimidin-4(3H)-one (6) Procedure A; yield: 8.1 g (99 wt%, 30.0 mmol, 95%); white solid;mp 267 °C. 1H NMR (600 MHz, DMSO-d6): d = 11.04 (br s, 1 H), 9.12 (br s, 1H), 8.02 (s, 1 H), 7.82 (s, 1 H), 7.46 (d, J = 7.5 Hz, 1 H), 7.21 (t,J = 8.0 Hz, 1 H), 7.14 (d, J = 7.9 Hz, 1 H), 5.87 (s, 1 H).

Scheme 5 Expanded scope of PivOH SNAr reactions

N

N

NH

X

N

NH

SMe

O

H2N

54 X = OH, 56

X = Cl, 57POCl3, 70 °C

1 h, 89%

PivOH135 °C, 44 h

71%F3C F3C

N

N

NH

X

F

N

NH

SMe

O

H2N

F

54 X = OH, 59

X = Cl, 60POCl3, 70 °C

1 h, 79%

PivOH135 °C, 44 h

85%F3C F3C

N

N

NH

X

N

NH

SMe

O

H2N

61 X = OH, 62

X = Cl, 63POCl3, 100 °C

1 h, 78%

PivOH130 °C, 2 h

75%HO X

N

N

Cl

Br

H2N

PivOH130 °C, 1.5 h

89% N

N

NH

Br

64 66

N

N

Br

Br

N O

OMeMe

NH2

N

N

NH

Br

N

OMe

OMePivOH

100 °C, 1 h

99%

67 68

55(1.8 equiv)

58(1.8 equiv)

55(1.2 equiv)

65(1.1 equiv)

42(1.2 equiv)

+

+

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HRMS (EI): m/z calcd for C10H9BrN3O: 265.9924; found: 265.9921(M + H).

N-(3-Bromophenyl)-4-chloropyrimidin-2-amine (7) Procedure B; yield: 1.98 g (6.96 mmol, 97%); white solid; mp 103°C. 1H NMR (600 MHz, CDCl3): d = 8.29 (s, 1 H), 7.87 (s, 1 H), 7.65(s, 1 H), 7.43 (s, 1 H), 7.17 (s, 2 H), 6.77 (d, J = 4.2 Hz, 1 H). 13C NMR (150 MHz, CDCl3): d = 161.7, 159.6, 159.1, 140.1, 130.4,126.4, 122.9, 122.6, 118.3, 113.0.

HRMS (EI): m/z calcd for C10H8BrClN3: 283.9585; found:283.9581 (M + H).

2-[(4-Bromophenyl)amino]pyrimidin-4(3H)-one (8) Procedure A; yield: 1.58 g (97 wt%, 5.76 mmol, 82%); white solid;mp 243 °C. 1H NMR (600 MHz, DMSO-d6): d = 10.89 (br s, 1 H), 9.02 (br s, 1H), 7.76 (s, 1 H), 7.57 (d, J = 7.4 Hz, 2 H), 7.43 (d, J = 8.2 Hz, 2 H),5.83 (s, 1 H).

HRMS (EI): m/z calcd for C10H9BrN3O: 265.9924; found: 265.9919(M + H).

N-(4-Bromophenyl)-4-chloropyrimidin-2-amine (9) Procedure B; yield: 1.52 g (5.34 mmol, 98%); white solid; mp 126°C. 1H NMR (600 MHz, CDCl3): d = 8.26 (d, J = 5.2 Hz, 1 H), 7.48 (m,3 H), 7.42 (d, J = 8.8 Hz, 2 H), 6.76 (d, J = 5.2 Hz, 1 H). 13C NMR (150 MHz, CDCl3): d = 162.0, 159.4, 158.6, 137.7, 132.2,121.5, 116.2, 112.7.


4-Chloro-N-(4-chlorophenyl)pyrimidin-2-amine (11)36 Procedure B; yield: 1.25 g (5.21 mmol, 95%); white solid; mp 126°C. 1H NMR (600 MHz, CDCl3): d = 8.25 (d, J = 5.2 Hz, 1 H), 7.71 (brs, 1 H), 7.51 (d, J = 8.8 Hz, 2 H), 7.27 (d, J = 8.8 Hz, 2 H), 6.74 (d,J = 5.2 Hz, 1 H). 13C NMR (150 MHz, CDCl3): d = 161.7, 159.8, 159.1, 137.3, 129.2,128.5, 121.2, 112.7.

HRMS (EI): m/z calcd for C10H8Cl2N3: 240.0090; found: 240.0086(M + H).

2-[(4-Fluorophenyl)amino]pyrimidin-4(3H)-one (12) Procedure A; yield: 1.84 g (70 wt%, 6.28 mmol, 89%); white solid;mp 262 °C. 1H NMR (600 MHz, DMSO-d6): d = 11.30 (br s, 1 H), 8.91 (br s, 1H), 7.70 (s, 1 H), 7.57 (s, 2 H), 7.11 (t, J = 8.5 Hz, 2 H), 5.78 (s, 1H).

HRMS (EI): m/z calcd for C10H9FN3O: 206.0724; found: 206.0725(M + H).

4-Chloro-N-(4-fluorophenyl)pyrimidin-2-amine (13) Procedure B; yield: 1.35 g (6.04 mmol, 99%); white solid; mp 175°C. 1H NMR (600 MHz, CDCl3): d = 8.25 (s, 1 H), 7.56–7.46 (m, 2 H),7.35 (s, 1 H), 7.03 (t, J = 8.6 Hz, 2 H), 6.73 (d, J = 5.1 Hz, 1 H). 13C NMR (150 MHz, CDCl3): d = 161.9, 159.9, 159.1 (d, J = 242.0Hz), 158.8, 134.5 (d, J = 2.8 Hz), 122.1 (d, J = 8.0 Hz), 115.8 (d,J = 21.9 Hz), 112.4.

HRMS (EI): m/z calcd for C10H8ClFN3: 224.0385; found: 224.0386(M + H).

2-[(3-Fluorophenyl)amino]pyrimidin-4(3H)-one (14) Procedure A; yield: 30.8 g (99 wt%, 150 mmol, 85%); white solid;mp 258 °C. 1H NMR (600 MHz, DMSO-d6): d = 10.91 (br s, 1 H), 9.11 (br s, 1H), 7.82 (s, 1 H), 7.72 (d, J = 11.7 Hz, 1 H), 7.39–7.13 (m, 2 H),6.77 (t, J = 7.6 Hz, 1 H), 5.87 (s, 1 H).


4-Chloro-N-(3-fluorophenyl)pyrimidin-2-amine (15) Procedure B; yield: 1.40 g (6.26 mmol, 99%); white solid; mp 110°C. 1H NMR (600 MHz, DMSO-d6): d = 10.22 (s, 1 H), 8.41 (d, J = 5.2Hz, 1 H), 7.69 (d, J = 12.2 Hz, 1 H), 7.42 (dd, J = 8.2, 0.9 Hz, 1 H),7.26 (dd, J = 15.3, 8.1 Hz, 1 H), 6.93 (d, J = 5.2 Hz, 1 H), 6.74 (td,J = 8.4, 2.2 Hz, 1 H). 13C NMR (150 MHz, DMSO-d6): d = 162.9 (d, J = 240.9 Hz),160.6, 160.5, 160.1, 142.1 (d, J = 11.3 Hz), 130.6 (d, J = 9.7 Hz),115.6 (d, J = 2.3 Hz), 112.7, 109.0 (d, J = 21.2 Hz), 106.4 (d,J = 26.6 Hz).


2-[(2-Bromophenyl)amino]pyrimidin-4(3H)-one (16) Procedure A; yield: 1.31 g (96 wt%, 4.73 mmol, 67%); white solid;mp 198 °C. 1H NMR (600 MHz, DMSO-d6): d = 11.38 (br s, 1 H), 8.27 (br s, 1H), 7.97 (s, 1 H), 7.61 (d, J = 7.8 Hz, 2 H), 7.33 (s, 1 H), 7.03 (s, 1H), 5.75 (s, 1 H).

HRMS (EI): m/z calcd for C10H9BrN3O 265.9924; found: 265.9920(M + H).

N-(2-Bromophenyl)-4-chloropyrimidin-2-amine (17) Procedure B; yield: 0.9 g (3.16 mmol, 70%); white solid; mp 59 °C. 1H NMR (600 MHz, CDCl3): d = 8.40 (dd, J = 8.3, 1.4 Hz, 1 H),8.29 (d, J = 5.2 Hz, 1 H), 7.65 (s, 1 H), 7.54 (dd, J = 8.0, 1.4 Hz, 1H), 7.36–7.28 (m, 1 H), 6.92 (td, J = 7.9, 1.5 Hz, 1 H), 6.79 (d,J = 5.2 Hz, 1 H). 13C NMR (150 MHz, CDCl3): d = 161.6, 159.7, 159.1, 136.6, 132.7,128.3, 124.4, 121.4, 114.0, 113.2.


4-Chloro-N-(4-methylphenyl)pyrimidin-2-amine (19)37 Procedure B; yield: 1.35 g (6.15 mmol, 99%); yellow solid; mp 113°C. 1H NMR (600 MHz, CDCl3): d = 8.22 (s, 1 H), 7.72 (s, 1 H), 7.43(d, J = 7.5 Hz, 2 H), 7.13 (d, J = 7.5 Hz, 2 H), 6.69 (d, J = 3.7 Hz, 1H), 2.31 (s, 3 H). 13C NMR (150 MHz, CDCl3): d = 161.7, 160.1, 158.8, 136.0, 133.5,129.7, 120.6, 111.9, 21.1.

HRMS (EI): m/z calcd for C11H11ClN3: 220.0636; found: 220.0637(M + H).

2-[(2,4-Dimethylphenyl)amino]pyrimidin-4(3H)-one (20) Procedure A; yield: 1.82 g (68 wt%, 5.72 mmol, 81%); white solid;mp 244 °C.

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1H NMR (600 MHz, DMSO-d6): d = 11.33 (br s, 1 H), 8.01 (br s, 1H), 7.65–7.41 (m, 2 H), 7.10–6.78 (m, 2 H), 5.65 (d, J = 5.7 Hz, 1H), 2.21 (s, 3 H), 2.13 (s, 3 H).

HRMS (EI): m/z calcd for C12H14N3O: 216.1131; found: 216.1131(M + H).

4-Chloro-N-(2,4-dimethylphenyl)pyrimidin-2-amine (21) Procedure B; yield: 1.24 g (5.31 mmol, 95%); yellow solid; mp 61°C. 1H NMR (600 MHz, CDCl3): d = 8.18 (d, J = 5.2 Hz, 1 H), 7.57 (d,J = 8.7 Hz, 1 H), 7.54 (s, 1 H), 7.06 (s, 2 H), 6.64 (d, J = 5.2 Hz, 1H), 2.33 (s, 3 H), 2.26 (s, 3 H). 13C NMR (150 MHz, CDCl3): d = 161.6, 161.3, 159.5, 135.2, 134.0,131.6, 131.6, 127.5, 124.5, 111.5, 21.2, 18.3.


2-[(4-Bromo-3-fluorophenyl)amino]pyrimidin-4(3H)-one (22) Procedure A; yield: 1.58 g (99 wt%, 5.55 mmol, 79%); white solid;mp 297 °C. 1H NMR (600 MHz, DMSO-d6): d = 11.08 (br s, 1 H), 9.33 (br s, 1H), 8.09–7.71 (m, 2 H), 7.53 (t, J = 8.4 Hz, 1 H), 7.28 (d, J = 7.3 Hz,1 H), 5.94 (s, 1 H).

HRMS (EI): m/z calcd for C10H8BrFN3O: 283.9829; found:283.9826 (M + H).

N-(4-Bromo-3-fluorophenyl)-4-chloropyrimidin-2-amine (23) Procedure B; yield: 1.56 g (5.16 mmol, 98%); white solid; mp 148°C. 1H NMR (600 MHz, CDCl3): d = 8.29 (d, J = 4.7 Hz, 1 H), 7.73 (d,J = 10.6 Hz, 1 H), 7.69 (s, 1 H), 7.41 (t, J = 8.0 Hz, 1 H), 7.06 (d,J = 8.1 Hz, 1 H), 6.80 (d, J = 4.8 Hz, 1 H). 13C NMR (150 MHz, CDCl3): d = 161.8, 159.3, 159.3 (d, J = 245.1Hz), 159.0, 139.6 (d, J = 10.2 Hz), 133.4 (d, J = 1.6 Hz), 116.1 (d,J = 3.2 Hz), 113.3, 107.9 (d, J = 27.7 Hz), 102.0 (d, J = 21.4 Hz).

HRMS (EI): m/z calcd for C10H7BrClFN3: 301.9490; found:301.9489 (M + H).

2-[(3-Bromo-5-methylphenyl)amino]pyrimidin-4(3H)-one (24) Procedure A; yield: 62.0 g (99 wt%, 218 mmol, 81%); beige solid;mp 304 °C. 1H NMR (600 MHz, DMSO-d6): d = 10.94 (br s, 1 H), 8.94 (br s, 1H), 7.81 (s, 2 H), 7.25 (s, 1 H), 6.99 (s, 1 H), 5.85 (s, 1 H), 2.23 (s,3 H).

HRMS (EI): m/z calcd for C11H11BrN3O: 280.0086; found:280.0096 (M + H).

N-(3-Bromo-5-methylphenyl)-4-chloropyrimidin-2-amine (25) Procedure B; yield: 55 g (184 mmol, 83%); white solid; mp 102 °C. 1H NMR (600 MHz, CDCl3): d = 8.26 (d, J = 5.2 Hz, 1 H), 7.78 (s,1 H), 7.69 (s, 1 H), 7.19 (s, 1 H), 6.99 (s, 1 H), 6.74 (d, J = 5.2 Hz,1 H), 2.28 (s, 3 H). 13C NMR (150 MHz, CDCl3): d = 161.6, 159.8, 159.1, 140.7, 139.9,127.1, 122.6, 119.9, 119.1, 112.8, 21.6.


2-[(3-Iodo-5-methylphenyl)amino]pyrimidin-4(3H)-one (26) Procedure A; yield: 8.83 g (99 wt%, 27.0 mmol, 94%); light pinksolid; mp 322 °C.

1H NMR (600 MHz, DMSO-d6): d = 10.93 (br s, 1 H), 8.88 (br s, 1H), 7.91 (s, 1 H), 7.78 (s, 1H), 7.29 (s, 1 H), 7.17 (s, 1 H), 5.83 (s, 1H), 2.20 (s, 3 H).

HRMS (EI): m/z calcd for C11H11IN3O: 327.9941; found: 327.9936(M + H).

4-Chloro-N-(3-iodo-5-methylphenyl)pyrimidin-2-amine (27) Procedure B; yield: 1.85 g (5.35 mmol, 93%); white solid; mp 101°C. 1H NMR (600 MHz, CDCl3): d = 8.25 (d, J = 4.7 Hz, 1 H), 7.81 (s,1 H), 7.78 (s, 1 H), 7.26 (s, 1 H), 7.21 (s, 1 H), 6.73 (d, J = 4.8 Hz,1 H), 2.26 (s, 3 H). 13C NMR (150 MHz, CDCl3): d = 161.7, 159.6, 159.0, 140.8, 139.7,133.2, 125.8, 120.0, 112.7, 94.5, 21.4.

HRMS (EI): m/z calcd for C11H10ClIN3: 345.9602; found: 345.9598(M + H).

Methyl 4-[(6-Oxo-1,6-dihydropyrimidin-2-yl)amino]benzoate (30)19 Procedure A; yield: 1.69 g (93 wt%, 6.41 mmol, 91%); yellow solid;mp 258 °C. 1H NMR (600 MHz, DMSO-d6): d = 11.05 (br s, 1 H), 9.34 (br s, 1H), 7.92–7.80 (m, 3 H), 7.76 (d, J = 8.4 Hz, 2 H), 5.93 (s, 1 H), 3.77(s, 3 H).

HRMS (EI): m/z calcd for C12H12N3O3: 246.0873; found: 246.0869(M + H).

Methyl 4-[(4-Chloropyrimidin-2-yl)amino]benzoate (31) Procedure B; yield: 1.47 g (5.57 mmol, 90%); white solid; mp 172°C. 1H NMR (600 MHz, CDCl3): d = 8.32 (d, J = 5.2 Hz, 1 H), 8.00 (d,J = 8.7 Hz, 2 H), 7.68 (d, J = 8.7 Hz, 2 H), 7.59 (s, 1 H), 6.81 (d,J = 5.2 Hz, 1 H), 3.88 (s, 3 H). 13C NMR (150 MHz, CDCl3): d = 166.9, 161.7, 159.4, 159.0, 143.0,131.1, 124.6, 118.4, 113.4, 52.2.

HRMS (EI): m/z calcd for C12H11ClN3O2: 264.0534; found:264.0530 (M + H).

2-{[4-(Trifluoromethyl)phenyl]amino}pyrimidin-4(3H)-one (32) Procedure A; yield: 1.67 g (75 wt%, 4.91 mmol, 78%); white solid;mp 239 °C. 1H NMR (600 MHz, DMSO-d6): d = 11.60 (br s, 1 H), 9.45 (br s, 1H), 8.07–7.45 (m, 5 H), 5.91 (s, 1 H).

HRMS (EI): m/z calcd for C11H9F3N3O: 256.0692; found: 256.0688(M + H).

4-Chloro-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine (33) Procedure B; yield: 0.90 g (3.29 mmol); white solid; mp 148 °C. 1H NMR (600 MHz, CDCl3): d = 8.31 (d, J = 5.1 Hz, 1 H), 7.71 (d,J = 8.5 Hz, 2 H), 7.63 (s, 1 H), 7.57 (d, J = 8.5 Hz, 2 H), 6.82 (d,J = 5.2 Hz, 1 H). 13C NMR (150 MHz, CDCl3): d = 161.7, 159.5, 159.1, 141.9, 126.5(q, J = 3.8 Hz), 125.0 (q, J = 32.8 Hz), 124.4 (q, J = 269.4 Hz),119.0, 113.4.

HRMS (EI): m/z calcd for C11H8ClF3N3: 274.0353; found: 274.0349(M + H).

4-[(4-Chloropyrimidin-2-yl)amino]benzonitrile (35)17

Procedure B; yield: 1.04 g (4.51 mmol, 89%); yellow solid; mp 211°C.

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1H NMR (600 MHz, DMSO-d6): d = 10.52 (s, 1 H), 8.48 (d, J = 5.2Hz, 1 H), 7.87 (d, J = 8.8 Hz, 2 H), 7.71 (d, J = 8.8 Hz, 2 H), 7.06(d, J = 5.2 Hz, 1 H). 13C NMR (150 MHz, DMSO-d6): d = 160.7, 160.7, 159.8, 144.7,133.7, 120.0, 119.3, 113.7, 104.0.


2-[(5-Fluoro-4-methylpyridin-2-yl)amino]pyrimidin-4(3H)-one (36) Procedure A; yield: 1.53 g (68 wt%, 4.72 mmol, 67%); white solid;mp 264 °C. 1H NMR (600 MHz, DMSO-d6): d = 12.67 (br s, 1 H), 11.29 (br s,1 H), 8.22 (s, 1 H), 7.72 (d, J = 6.0 Hz, 1 H), 7.18 (d, J = 4.1 Hz, 1H), 5.78 (d, J = 6.5 Hz, 1 H), 2.24 (s, 3 H).


4-Chloro-N-(5-fluoro-4-methylpyridin-2-yl)pyrimidin-2-amine (37) Procedure B; yield: 1.06 g (4.44 mmol, 97%); purified by crystalli-zation (EtOAc–hexanes); white solid; mp 206 °C. 1H NMR (600 MHz, CDCl3): d = 9.14 (s, 1 H), 8.40 (d, J = 5.2 Hz,1 H), 8.30 (d, J = 5.8 Hz, 1 H), 8.14 (s, 1 H), 6.84 (d, J = 5.2 Hz, 1H), 2.38 (s, 3 H). 13C NMR (150 MHz, CDCl3): d = 161.6, 159.2, 158.8, 155.1 (d,J = 247 Hz), 148.1 (d, J = 2.5 Hz), 133.5, 115.5 (d, J = 1.8 Hz),113.6, 105.0, 15.4 (d, J = 2.9 Hz).


2-[(3-Bromo-8-methylquinolin-6-yl)amino]pyrimidin-4(3H)-one (38) Procedure A; yield: 11.2 g (95 wt%, 32.1 mmol, 99%); pink solid;mp 299 °C. 1H NMR (600 MHz, DMSO-d6): d = 11.00 (br s, 1 H), 9.44 (br s, 1H), 8.70 (d, J = 2.2 Hz, 1 H), 8.43 (d, J = 2.1 Hz, 1 H), 8.13 (s, 1 H),7.83 (d, J = 6.0 Hz, 1 H), 7.64 (s, 1 H), 5.89 (d, J = 6.3 Hz, 1 H),2.60 (s, 3 H).

HRMS (EI): m/z calcd for C14H12BrN4O: 331.0189; found:331.0186 (M + H).

3-Bromo-N-(4-chloropyrimidin-2-yl)-8-methylquinolin-6-amine (39) Procedure B; yield: 1.63 g (4.66 mmol, 84%); purified by crystalli-zation (EtOAc–hexanes); beige solid; mp 209 °C. 1H NMR (600 MHz, DMSO-d6): d = 10.34 (s, 1 H), 8.71 (d, J = 1.5Hz, 1 H), 8.47 (d, J = 5.1 Hz, 1 H), 8.44 (d, J = 1.3 Hz, 1 H), 8.21(s, 1 H), 7.75 (s, 1 H), 7.00 (d, J = 5.1 Hz, 1 H), 2.60 (s, 3 H). 13C NMR (150 MHz, DMSO-d6): d = 160.6, 160.2, 148.3, 142.2,139.0, 137.6, 137.2, 130.4, 124.8, 117.9, 113.1, 111.9, 105.0, 18.4.


5-Bromo-2-[(3,4-dimethoxyphenyl)amino]pyrimidin-4(3H)-one (43) Procedure A; yield: 1.54 g (92 wt%, 4.34 mmol, 96%); grey solid;mp 228 °C. 1H NMR (600 MHz, DMSO-d6): d = 11.24 (br s, 1 H), 8.68 (br s, 1H), 7.95 (s, 1 H), 7.10 (d, J = 2.2 Hz, 1 H), 6.98 (dd, J = 8.6, 2.2 Hz,1 H), 6.87 (d, J = 8.7 Hz, 1 H), 3.70 (s, 3 H), 3.69 (s, 3 H).

HRMS (EI): m/z calcd for C12H13BrN3O3: 326.0135; found:326.0130 (M + H).

5-Bromo-4-chloro-N-(3,4-dimethoxyphenyl)pyrimidin-2-amine (44) Procedure B; yield: 1.24 g (3.60 mmol, 85%); yellow solid; mp 130°C. 1H NMR (600 MHz, CDCl3): d = 8.35 (s, 1 H), 7.31 (s, 1 H), 7.21(s, 1 H), 6.93 (dd, J = 8.6, 2.3 Hz, 1 H), 6.81 (d, J = 8.6 Hz, 1 H),3.86 (s, 3 H), 3.84 (s, 3 H). 13C NMR (150 MHz, CDCl3): d = 160.5, 159.9, 158.6, 149.3, 146.0,131.8, 112.7, 111.7, 106.7, 105.5, 56.4, 56.1.

HRMS (EI): m/z calcd for C12H12BrClN3O2: 343.9796; found:343.9795 (M + H).

5-Bromo-2-[(4-chlorophenyl)amino]pyrimidin-4(3H)-one (46) Procedure A; yield: 1.42 g (85 wt%, 4.03 mmol, 89%); yellow solid;mp 253 °C. 1H NMR (600 MHz, DMSO-d6): d = 11.39 (br s, 1 H), 9.02 (br s, 1H), 8.02 (s, 1 H), 7.55 (d, J = 8.7 Hz, 2 H), 7.34 (d, J = 8.9 Hz, 2 H).

HRMS (EI): m/z calcd for C10H8BrClN3O: 299.9534; found:299.9530 (M + H).

5-Bromo-4-chloro-N-(4-chlorophenyl)pyrimidin-2-amine (47) Procedure B; yield: 1.70 g (5.33 mmol, 88%); white solid; mp 166°C. 1H NMR (600 MHz, DMSO-d6): d = 10.29 (s, 1 H), 8.63 (s, 1 H),7.64 (d, J = 8.9 Hz, 2 H), 7.31 (d, J = 8.9 Hz, 2 H). 13C NMR (150 MHz, DMSO-d6): d = 161.4, 159.0, 158.6, 138.9,129.1, 126.9, 121.5, 106.6.

HRMS (EI): m/z calcd for C10H7BrCl2N3: 317.9200; found:317.9224 (M + H).

2-[(3-Bromophenyl)amino]-5-iodopyrimidin-4(3H)-one (48) To a suspension of 6 (1.0 g, 3.71 mmol) in DMF (7 mL) was addedNIS (0.92 g, 4.08 mmol). After 1 h, H2O (10 mL) containingNa2SO3 (200 mg) was added dropwise resulting in decolorizationand the formation of a gum. The mixture was heated to 70 °C for 1h, the resulting slurry cooled to r.t., filtered and washed with H2O(2 × 10 mL) to afford the desired product; yield: 1.41 g (3.60 mmol,97%); white solid; mp 244 °C. 1H NMR (600 MHz, DMSO-d6): d = 11.37 (br s, 1 H), 9.06 (br s, 1H), 8.16 (s, 1 H), 7.91 (s, 1 H), 7.41 (d, J = 7.7 Hz, 1 H), 7.23 (t,J = 8.0 Hz, 1 H), 7.18 (d, J = 7.8 Hz, 1 H).

HRMS (EI): m/z calcd for C10H8BrIN3O: 391.8890; found:391.8884 (M + H).

N-(3-Bromophenyl)-4-chloro-5-iodopyrimidin-2-amine (49) Procedure B; yield: 1.30 g (3.16 mmol, 96%); white solid; mp 130°C. 1H NMR (600 MHz, CDCl3): d = 8.57 (s, 1 H), 7.82 (d, J = 1.8 Hz,1 H), 7.40 (dt, J = 6.8, 2.1 Hz, 1 H), 7.30 (s, 1 H), 7.22–7.14 (m, 2H). 13C NMR (150 MHz, CDCl3): d = 166.0, 163.7, 158.6, 139.7, 130.5,126.7, 123.0, 122.5, 118.2, 80.4.

HRMS (EI): m/z calcd for C10H7BrClIN3: 409.8551; found:409.8547 (M + H).

5-Bromo-2-[(3-bromophenyl)amino]pyrimidin-4(3H)-one (50) To a suspension of 6 (1.0 g, 3.71 mmol) in DMF (7 mL) was addedNBS (0.727 g, 4.08 mmol). After 1 h, H2O (10 mL) containingNa2SO3 (200 mg) was added. Additional H2O (30 mL) was added,

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the mixture extracted with 5% MeOH–EtOAc (2 × 30 mL), and thecombined organics were dried (MgSO4), filtered, and concentratedin vacuo. The crude residue was taken up in i-PrOH (7 mL) and hex-anes (21 mL) was added dropwise. After stirring for 1 h, this wasfiltered and washed with hexanes (15 mL) to afford the desiredproduct; yield: 1.16 g (81 wt%, 2.72 mmol, 73%); white solid; mp145 °C. 1H NMR (600 MHz, DMSO-d6): d = 11.51 (br s, 1 H), 9.12 (br s, 1H), 8.07 (s, 1 H), 7.92 (s, 1 H), 7.41 (d, J = 7.6 Hz, 1 H), 7.23 (t,J = 8.0 Hz, 1 H), 7.19 (d, J = 7.9 Hz, 1 H).

HRMS (EI): m/z calcd for C10H8BrIN3O: 391.8890; found:391.8884 (M + H).

5-Bromo-N-(3-bromophenyl)-4-chloropyrimidin-2-amine (51) Procedure B; yield: 0.81 g (2.22 mmol, 86%); white solid; mp 128°C. 1H NMR (600 MHz, CDCl3): d = 8.43 (s, 1 H), 7.82 (s, 1 H), 7.40(d, J = 7.1 Hz, 1 H), 7.31 (s, 1 H), 7.22–7.13 (m, 2 H). 13C NMR (150 MHz, CDCl3): d = 160.5, 160.1, 157.9, 139.7, 130.5,126.7, 123.0, 122.4, 118.1, 108.2.

HRMS (EI): m/z calcd for C10H7Br2ClN3: 361.8690; found:361.8687 (M + H).

2-[(3-Bromophenyl)amino]-5-chloropyrimidin-4(3H)-one (52) To a suspension of 6 (1.0 g, 3.71 mmol) in AcOH (7 mL) was addedNCS (0.727 g, 4.08 mmol). The mixture was heated to 90 °C for 4h, cooled to r.t. and H2O was added (21 mL) dropwise. The slurrywas stirred for 1 h at r.t., filtered, and washed with H2O (2 × 10 mL)to afford the desired product; yield: 0.98 g (95 wt%, 3.10 mmol,82%); yellow solid; mp 254 °C. 1H NMR (600 MHz, DMSO-d6): d = 11.56 (br s, 1 H), 9.04 (br s, 1H), 7.97 (s, 1 H), 7.92 (s, 1 H), 7.40 (d, J = 7.6 Hz, 1 H), 7.23 (t,J = 8.0 Hz, 1 H), 7.19 (d, J = 7.9 Hz, 1 H).

HRMS (EI): m/z calcd for C10H8BrClN3O: 299.9539; found:299.9551 (M + H).

N-(3-Bromophenyl)-4,5-dichloropyrimidin-2-amine (53) Procedure B; yield: 0.85 g (2.66 mmol, 89%); white solid; mp 120°C. 1H NMR (600 MHz, CDCl3): d = 8.33 (s, 1H), 7.81 (s, 1H), 7.46–7.33 (m, 2H), 7.22 – 7.10 (m, 2H). 13C NMR (150 MHz, CDCl3): d = 158.5, 157.8, 157.4, 139.8, 130.5,126.6, 123.0, 122.4, 119.5, 118.0.

HRMS (EI): m/z calcd for C10H7BrCl2N3: 317.9200; found:317.9229 (M + H).

2-[(4-Methylphenyl)amino]-6-(trifluoromethyl)pyrimidin-4(3H)-one (56) Procedure A, using p-toluidine (1.8 equiv); yield: 0.91 g (99 wt%,3.38 mmol, 71%); beige solid; mp 231 °C. 1H NMR (600 MHz, DMSO-d6): d = 11.16 (br s, 1 H), 9.06 (br s, 1H), 7.41 (s, 2 H), 7.11 (d, J = 8.2 Hz, 2 H), 6.20 (s, 1 H), 2.23 (s, 3H).

HRMS (EI): m/z calcd for C12H11F3N3O: 270.0854; found:270.0866 (M + H).

4-Chloro-N-(4-methylphenyl)-6-(trifluoromethyl)pyrimidin-2-amine (57) Procedure B; yield: 0.85 g (2.66 mmol, 89%); yellow solid; mp 116°C. 1H NMR (600 MHz, CDCl3): d = 7.44 (d, J = 8.4 Hz, 2 H), 7.30 (s,1 H), 7.15 (d, J = 8.3 Hz, 2 H), 6.98 (s, 1 H), 2.32 (s, 3 H).

13C NMR (150 MHz, CDCl3): d = 163.4, 160.0, 157.9 (q, J = 36.1Hz), 135.3, 134.0, 129.8, 120.2, 120.1 (q, J = 274.9 Hz), 107.8,21.0.

HRMS (EI): m/z calcd for C12H10ClF3N3: 288.0515; found:288.0513 (M + H).

2-[(4-Fluorophenyl)amino]-6-(trifluoromethyl)pyrimidin-4(3H)-one (59) Procedure A, using 4-fluoroaniline (1.8 equiv); yield: 1.17 g (94wt%, 4.03 mmol, 85%); greyish blue solid; mp 236 °C. 1H NMR (600 MHz, DMSO-d6): d = 11.29 (s, 1 H), 9.27 (s, 1 H),7.56 (s, 2 H), 7.15 (t, J = 8.8 Hz, 2 H), 6.24 (s, 1 H).

HRMS (EI): m/z calcd for C11H8F4N3O: 274.0604; found: 274.0608(M + H).

4-Chloro-N-(4-fluorophenyl)-6-(trifluoromethyl)pyrimidin-2-amine (60) Procedure B; yield: 0.86 g (2.95 mmol, 79%); yellow solid; mp 118°C. 1H NMR (500 MHz, CDCl3): d = 7.58–7.50 (m, 2 H), 7.35 (s, 1 H),7.10–7.02 (m, 3 H). 13C NMR (125 MHz, CDCl3): d = 163.6, 160.5, 159.2 (d, J = 166.8Hz), 157.9 (q, J = 36.2 Hz), 133.9 (d, J = 2.8 Hz), 121.8 (d, J = 7.5Hz), 120.1 (q, J = 275.5 Hz), 116.1 (d, J = 22.6 Hz), 108.3.

HRMS (EI): m/z calcd for C11H7ClF4N3: 292.0265; found: 292.0294(M + H).

6-Hydroxy-2-[(4-methylphenyl)amino]pyrimidin-4(3H)-one (62)38 Procedure A; yield: 1.15 g (90 wt%, 4.76 mmol, 75%); white solid;mp 268 °C. 1H NMR (600 MHz, DMSO-d6): d = 10.63 (br s, 2 H), 8.62 (s, 1 H),7.44 (d, J = 7.8 Hz, 2 H), 7.08 (d, J = 7.7 Hz, 2 H), 4.81 (s, 1 H),2.22 (s, 3 H).

HRMS (EI): m/z calcd for C11H12N3O2 218.0930; found: 218.0914(M + H).

4,6-Dichloro-N-(4-methylphenyl)pyrimidin-2-amine (63) Procedure B; yield: 0.86 g (2.95 mmol, 78%); white solid; mp 115°C. 1H NMR (600 MHz, CDCl3): d = 7.41 (d, J = 8.4 Hz, 2 H), 7.30 (s,1 H), 7.14 (d, J = 8.2 Hz, 2 H), 6.72 (s, 1 H), 2.31 (s, 3 H). 13C NMR (150 MHz, CDCl3): d = 162.0, 159.3, 135.3, 134.0, 129.8,120.4, 111.1, 21.1.

HRMS (EI): m/z calcd for C11H10Cl2N3: 254.0252; found: 254.0255(M + H).

N-(3-Bromo-5-methylphenyl)-4-methylpyrimidin-2-amine (66) In a 3-necked 3 L flask equipped with an overhead stirrer, a mixtureof 64 (150 g, 1.17 mol) and 65 (239 g, 1.28 mol) in PivOH (948 mL)was heated to an internal temperature of 130 °C. After stirring for1.5 h, heating was discontinued and the mixture slowly cooled.When the internal temperature had reached 70 °C, hexanes (1 L)was added over a period of 30 min. The resulting slurry was stirredat r.t. over the weekend, then cooled to –10 °C, and stirred for 1 h.The mixture was filtered, washed with cold (–20 °C) hexanes (2 ×200 mL), then dried to afford the desired product; yield: 364 g (79wt%, 1.03 mol, 89%); brown solid. A small sample was diluted withCH2Cl2, washed with sat. aq NaHCO3, dried (MgSO4), filtered, andconcentrated in vacuo. The resulting residue was purified by flashchromatography to afford an analytical sample of 66; beige solid;mp 76 °C.

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1H NMR (600 MHz, DMSO-d6): d = 9.65 (s, 1 H), 8.32 (d, J = 5.0Hz, 1 H), 7.94 (s, 1 H), 7.49 (s, 1 H), 6.88 (s, 1 H), 6.72 (d, J = 5.0Hz, 1 H), 2.32 (s, 3 H), 2.21 (s, 3 H). 13C NMR (150 MHz, DMSO-d6): d = 168.2, 160.2, 158.1, 142.9,140.6, 124.8, 122.0, 118.6, 118.5, 113.0, 24.3, 21.6.

HRMS (EI): m/z calcd for C12H13BrN3: 278.0293; found: 278.0307(M + H).

6-Bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyrazin-8-amine (68)33 To a round-bottomed flask equipped with a large stir bar was added67 (5 g, 18.1 mmol), 42 (3.32 g, 21.7 mmol), and PivOH (35 mL).The resulting mixture was heated to an internal temperature of100 °C and stirred for 1 h. Heating was discontinued, the reactionmixture cooled to 70 °C, and a mixture of EtOH–hexanes (1:1, 70mL) was added dropwise over 20 min. The slurry was stirred at r.t.for 1 h, then filtered, and the resulting cake washed with EtOH–hexanes (1:1, 35 mL). The dried solid was transferred to a round-bottomed flask, diluted with 5% MeOH–CH2Cl2 (250 mL) andtreated with sat. aq NaHCO3 (250 mL) and stirred until both layerswere clear. The layers were separated, the aqueous portion extracteda second time with 5% MeOH–CH2Cl2 (250 mL), and the combinedorganics were dried (MgSO4), filtered, and concentrated in vacuo.The crude residue was purified by flash chromatography to affordthe desired product; yield: 6.25 g (17.9 mmol, 99%); beige solid;mp 165 °C. Compound 68 showed satisfactory spectroscopic datain agreement with that reported in the literature.

Supporting Information for this article is available online athttp://www.thieme-connect.com/ejournals/toc/synthesis.

Acknowledgment

The authors would like to thank Bridget Becker and Bruce Adamsfor NMR support, and in addition Chuck Ross and Adam Beard forHRMS analysis.

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Documents

SNAr Reactions of 2-Methylthio-4-pyrimidinones in Pivalic Acid: Access to Functionalized Pyrimidinones and Pyrimidines