Rh(II)-Catalyzed Ring Expansion of Pyrazoles with Diazocarbonyl

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Rh(II)-Catalyzed Ring Expansion of Pyrazoles with Diazocarbonyl Compounds as a Method for the Preparation of 1,2-Dihydropyrimidines Alexander N. Koronatov, Nikolai V. Rostovskii, Alexander F. Khlebnikov, and Mikhail Sergeevich Novikov J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01228 • Publication Date (Web): 19 Jun 2018 Downloaded from http://pubs.acs.org on June 20, 2018

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The Journal of Organic Chemistry

Rh(II)-Catalyzed Ring Expansion of Pyrazoles with Diazocarbonyl Compounds as a Method for the Preparation of 1,2-Dihydropyrimidines Alexander N. Koronatov, Nikolai V. Rostovskii, Alexander F. Khlebnikov, Mikhail S. Novikov* St. Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab., St. Petersburg, 199034 Russia

Graphical abstract

ABSTRACT: High yield synthesis of 1,2-dihydropyrimidines by Rh(II)-catalyzed reaction of diazocarbonyl compounds with 1,4-di- and 1,4,5-trisubstituted pyrazoles is reported. This reaction represents the first example of a carbenoid insertion into an NN bond and provides a novel approach to 4-unsubstituted 1,2-dihydropyrimidines with a broad range of functional group tolerance. According to DFT calculations the pyrazole ring expansion proceeds via the sequential formation of the metal-bound pyrazolium ylide, metal-free pyrazolium ylide and 1,5diazahexatriene followed by 1,6-cyclization.

INTRODUCTION The dihydropyrimidine ring is an important structural unit contained in many biologically active compounds displaying antiviral,1 anticancer,2 antibacterial,3 antihypertensive4 and other kinds of activity. Of the partially saturated pyrimidines, 1,2-dihydro derivatives are the least accessible. There are two different strategies for the synthesis of these compounds, the first of

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which involves the preparation or generation in situ of 1,5-diazahexa-1,3,5-trienes from acyclic precursors and their subsequent 1,6-cyclization.5 The second approach is based on ringexpansion reactions of strained heterocycles and heterocycles containing a weak heteroatomheteroatom bond. Thus, the 1,2-dihydropyrimidine derivative, containing an ester group at C2, was synthesized by one-atom ring expansion of an N-vinylpyrazolium salt.6 2-Мonosubstituted 1,2-dihydropyrimidines can be prepared in moderate to good yields by base-induced rearrangement of pyrazolium halides (Scheme 1, reaction 1).7 For the preparation of 1,2dihydropyrimidines having two electron-withdrawing substituents at C2 the three-atom ring expansion of the azirine ring of 2H-azirine-2-carbaldimines by rhodium carbenoids has recently been used (Scheme 1, reaction 2).8 This reaction can be used to prepare pyrimidine derivatives, which are able to undergo reversible isomerization to 1,5-diazahexatrienes, which are attractive reactive intermediates for heterocyclic synthesis. The limitation of the method is the low stability and poor availability of some azirine-2-carbaldimines. In particular, this procedure cannot be applied for the preparation of 4-unsubstituted 1,2-dihydropyrimidines due to the inaccessibility of

thermally

unstable

3-unsubstituted

2H-azirine

derivatives.9

In

the

meantime

dihydropyrimidines containing an unsubstituted endocyclic C=N bond could be most suitable for further modification of the ring via the Ugi reaction, the Staudinger reaction and also by other methods.10


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Scheme 1. Approaches for the synthesis of 1,2-Dihydropyrimidines

We hypothesized that this problem could be solved by using pyrazole derivatives which can be hypothetically converted into 4-unsubstituted 1,2-dihydropyrimidines by carbenoid insertion into the NN bond. (Scheme 1, reaction 3). Substituted pyrazoles including those bearing functional substituents are synthetically accessible compounds, and this makes them very attractive substrates for the design of new molecular systems.11 α-Diazocarbonyl compounds are the best source of the carbenoids that are capable of being inserted into various single bonds.12 At the same time, all the known reactions of pyrazoles with diazo compounds proceed with retention of the 5-membered ring. A pyrazole ring attached at its N1 position to an aromatic system is usually used as a directing group for the Cp*Rh(III)-catalyzed ortho-arylation13 and ortho-alkylation under Cp*Rh(III)14 or Cp*Co(III) catalysis.15 Diazo carbonyl compounds were also used as ketene sources for the α-ketoacylation of pyrazoles via CH-insertion under microwave activation.16 The same reaction conditions were applied for the annulation of 2-



aminopyrazole17

or

2-(alkylideneamino)pyrazoles18

with

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cyclic

2-diazo-1,3-dicarbonyl

compounds. Recently, the Ni(II)-catalyzed reaction of α-diazo pyrazoleamides with sulfides proceeding with the retention of the pyrazole system was reported.19 Two reactions of Rh(II) carbenoids with pyrazole-containing compounds are also known but they do not affect the pyrazole system.20 In this communication we report a simple and high-yield method for the synthesis of 1,2dihydropyrimidines using a one-atom ring expansion of 1,4-di- and 1,4,5-trisubstituted pyrazoles by NN insertion of rhodium(II) carbenoids generated from diazo carbonyl compounds. The synthesis is supplemented by a theoretical study of the reaction mechanism.

RESULTS AND DISCUSSION Recently it was found that isoxazoles and their oxo derivatives can smoothly undergo ring opening across the NO bond by the insertion of rhodium carbenoids generated from diazo carbonyl compounds21 or 1,2,3-triazoles22 under catalysis by rhodium(II) carboxylates. Taking this into account, three rhodium carboxylates, namely Rh2(esp)2, Rh2(Piv)4, and Rh2(OAc)4, were tested as catalysts for our initial experiments on the reaction of pyrazoles 1a,b with diazo ester 2a (Scheme 2, Table 1). Pyrazole 1а having the phenyl substituent at the C3 position, irrespective of the Rh(II) catalyst used, was found to be inactive towards diazo compound 2a over a wide range of temperatures. In contrast, the 3-unsubstituted pyrazole 1b readily reacted with 2a in boiling 1,2-dichloroethane (DCE) to give pyrimidine 3b in good to high yield for the tested catalysts (Table 1, entries 13). In the case of Rh2(esp)2 (1 mol%) the yield of 3b became


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nearly quantitative when the temperature was increased to 115 C (entry 6). These conditions were used in further experiments.

Scheme 2. Synthesis of Dihydropyrimidines 3a,b

Table 1. Optimization of Pyrimidine 3b Synthesisa

a

entry catalystb

equiv of 2ac

T, C

time

yield of 3b (%)d

1 2 3 4 5 6 7 8

2.0 2.0 2.0 2.0 1.6 1.5 2.0 2.0f

84 84 84 115 115 115 20 84

15 min 25 min 120 min 5 min 3 min 3 min 1d 120 min

83 60 58 38 88 96 traces traces

Rh2(esp)2 Rh2(Piv)4 Rh2(OAc)4e Rh2(OAc)4e Rh2(Piv)4 Rh2(esp)2 Rh2(esp)2 Rh2(esp)2

Compounds 1b and 2a, solvent and catalyst (1 mol%) were heated in a screw-cap tube. bPiv =

pivalate, esp = α,α,α’,α’-tetramethyl-1,3-benzenedipropanoate.

c

Amount required for full

conversion of 1b. dYields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard. e5 mol % of catalyst.

f

Diazo compound 2a was added dropwise to a refluxing

solution of 1b and Rh2(esp)2 in DCE within 2 h.



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Having come to the conclusion that the absence of a substituent at the C3 of the pyrazole is a mandatory requirement for the reaction to occur, we explored the scope of 3-unsubstituted pyrazoles, which could be suitable for the preparation of dihydropyrimidines 3. For this purpose, 1,4-di- and 1,4,5-trisubstituted pyrazoles 1cza were synthesized and their reactions with diazo compound 2a were carried out (Scheme 3). Changes in the aryl group (R3 substituent) had no noticeable effect on the product yield (compounds 3b3i). The heteroaryl substituent and benzoyl group in this position also tolerated the reaction conditions (compounds 3j,k). Dihydropyrimidines 3lv were obtained in good yields from N-alkyl-, N-aryl- and Ntosylpyrazoles. The greatest decrease in yield was observed for dihydropyrimidine 3n obtained from pyrazole 1n with bulky isopropyl group at the N1 position. 1,4,5-Trisubstituted pyrazoles with various substituents also gave dihydropyrimidines 3wza in good yields. It is noteworthy that strong electron-withdrawing substituents R2, reducing the reactivity of the pyrazole towards the electrophilic carbenoid, only slightly affect the yields of the dihydropyrimidines (compounds 3xz). It is known that 1-sulfonyl-1,2,3-triazoles are sensitive toward Rh(II) carboxylates.22, 23 The same goes for isoxazoles,24 which, in addition, can easily undergo ring opening induced by Rh(II) carbenoids.21,

22

We were pleased to find that 1,2,3-triazole- and isoxazole-containing

pyrazoles 3p,u are compatible with the reaction conditions and gave pyrimidines in good yields.


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Scheme 3. Scope of Pyrazoles 1a

a

Reaction conditions: 1 (0.5 mmol), 2a (0.75–1.6 mmol), Rh2(esp)2 (1 mol%), DCE (5 mL),

115 °C, 15 min.

A number of donor/acceptor and acceptor/acceptor diazo compounds were tested in the reaction with pyrazole 1b under the standard conditions (Scheme 4). With all aryldiazoacetic ACS Paragon Plus Environment


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esters 2be as well as phenyl diazo acetone (2f) the reaction proceeds smoothly to give high yields of dihydropyrimidines 3zbzf. Dimethyl diazomalonate (2g) also gave dihydropyrimidine 3zg but in lower yield. Another acceptor/acceptor diazo compound, ethyl 2-cyano-2diazoacetate, failed to give the corresponding dihydropyrimidine. In this case, the reaction proceeded with the formation of an inseparable mixture of products, which is most likely due to the side reactions of the dihydropyrimidine with the carbenoid. A complex mixture of products was also obtained from such a donor/acceptor diazo compound as methyl (E)-4-phenyl-2-diazo3-butenoate and pyrazole 1b under the standard reaction conditions. The structures of compounds 3b−z,3za−zg were verified by 1H and 13C NMR spectroscopy, HRMS and the structure of 3s was confirmed by X-ray analysis.25

Scheme 4. Scope of Diazo Compounds 2a


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a

Reaction conditions: 1b (0.5 mmol), 2 (0.751.1 mmol), Rh2(esp)2 (1 mol%), DCE (5 mL),

115 °C, 125 min.

The pathways for the formation of 1,2-dihydropyrimidines by carbenoid-mediated one-atom ring expansion of pyrazoles, which can involve the formation of several reactive intermediates, are presented for the model reaction of pyrazole 1b with diazo compound 2h under Rh2(OAc)4 catalysis leading to dihydropyrimidine 3zh (Scheme 5). The most intriguing question is whether the formation of metal-free pyrazolium ylide 5 precedes the five-membered ring opening or the cleavage of the NN bond occurs in the metal-bound ylide 4. Whereas the formation of metalfree pyridinium,26 quinolinium27 and benzoxazolium ylides26f was reported in some metalcatalyzed reactions of diazo compounds with the corresponding N-heterocycles, the generation of pyrazolium ylides by the addition of carbenoids to pyrazoles has not previously been studied. Scheme 5. Theoretical Investigation of the Reaction Mechanism



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We carried out a DFT investigation of this reaction by use of B3LYP/6-31+G(d,p)/Stuttgart RSC 1997 ECP level of theory. Scanning of the PES for the formation of complex 4 from carbenoid 7 and pyrazole 1b did not reveal the presence of an activation barrier (Figure S1, Supporting Information). Energy profiles for possible pathways of the transformation of complex 4 to dihydropyrimidine 3zh are depicted in Figure 1. Complex 4 is kinetically unstable intermediate, which rapidly undergoes Rh2(OAc)4 extrusion (TS1, G‡ 1.9 kcal/mol) to give pyrazolium ylide 5. According to the calculations, ylide 5 has nonplanar geometry, which is close to that for the stable α,α-bis(trifluoroacetyl)-substituted pyridinium ylides in the crystal.28 The recyclization of ylide 5 to dihydropyrimidine 3zh proceeds via the intermediate formation of diazahexatriene 6 which is less stable than both 3zh and 5. An alternative one-step pathway for the formation of diazahexatriene 6 via simultaneous cleavage of NN and СRh bonds in complex 4 has a significantly higher activation barrier (TS4, G‡ 35.8 kcal/mol). From the relatively low values of energy barriers on the way from dihydropyrimidine 3zh to ylide 5 and back it follows that at moderately elevated temperatures dihydropyrimidines 3 can exist in an equilibrium both with 1,5-diazahexatrienes 68 and pyrazolium ylides 5. The analysis of the computed structure of complex 4 revealed that the introduction of any substituent into the C3 position of the pyrazole must completely block the formation of the metal-bound pyrazolium ylide because of the steric hindrance for an approach of the carbenoid. Obviously, it is this reason why 1-methyl-3-phenylpyrazole (1a) is inactive in the reaction with diazo compound 2a (Scheme 2). For the same reason, the known reactions of Rh(II)-carbenoids with pyrazoles mentioned in the introduction occur with the retention of the 5-membered ring.20 ACS Paragon Plus Environment

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Figure 1. Energy profiles (Gibbs free energies, DFT B3LYP/6-31+G (d,p)/Stuttgart RSC 1997 ECP, kcal/mol, 357K, 1,2-dichloroethane) for transformations of metal-bound pyrazolium ylide 4 to 1,2-dihydropyrimidine 3zh.

CONCLUSION In conclusion, an efficient method for the preparation of 1,2-dihydropyrimidines from 1,4di- and 1,4,5-trisubstituted pyrazoles and diazocarbonyl compounds under Rh(II) catalysis has been developed. The reaction works with 3-unsubstituted pyrazoles and allows the introduction of various substituents in positions 1, 2, 5 and 6 of the 1,2-dihydropyrimidine ring. According to DFT calculations the reaction proceeds via the sequential formation of extremely unstable metalbound pyrazolium ylide, metal-free pyrazolium ylide and 1,5-diazahexatriene, followed by 1,6cyclization. The disclosed one-atom pyrazole ring expansion is the first example of carbenoid insertion into the NN bond.



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EXPERIMENTAL SECTION General Methods. Melting points were determined on a melting point apparatus and are uncorrected. All solvents were distilled and dried prior to use. 1,2-Dichloroethane was washed with concentrated H2SO4, water, then distilled from P2O5 and stored over anhydrous K2CO3. 1H (400 MHz) and

13

C (100 MHz) NMR spectra are reported in parts per million downfield from

tetramethylsilane in CDCl3. High-resolution mass spectra were recorded on an HRMS-ESIQTOF instrument, electrospray ionization, positive mode. Thin-layer chromatography (TLC) was conducted on aluminum sheets precoated with SiO2 ALUGRAM SIL G/UV254. Column chromatography was performed on silica gel 60 M (0.04–0.063 mm). Pyrazoles 1a–i,l,m,29 1k,30 1n,31 1o,32 1q,33 1r34, 1s,t,35 1x36, 1y37 and diazo compounds 2a,38 2be,39 2f,40 2g41 are known compounds and were prepared by the reported procedures.

Synthetic procedures for the preparation of pyrazoles 1j,p,u,v,w,z, 1za, 1zz. 1-Methyl-4-(1-methylindol-3-yl)-1H-pyrazole (1j). Sodium hydride (60% suspension in mineral oil, 280 mg, 7 mmol) was washed with hexane (3×2 mL), and THF (24 mL) was added. The suspension was cooled to 0 °С under argon atmosphere, and 4-indol-3-yl-1H-pyrazole42 (549 mg, 3 mmol) was added in one portion. The mixture was stirred for 30 min at 0 °С, and methyl iodide (1.87 g, 6.6 mmol) was added. After overnight stirring the mixture was diluted with EtOAc (30 mL) and workup was done with water (20 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4. After the solvent evaporation product was purified by column chromatography on silica gel (eluent – CH2Cl2–EtOAc 8:1). Beige solid (494 mg, yield 78%). Mp: 133−137 °C (CHCl3). 1H NMR (400 MHz, CDCl3) δ 3.83 (s, 3H), 4.00 (s, 3H), 7.17 (s, 1H), 7.18–7.24 (m, 1H), 7.27–7.33 (m, 1H), 7.35–7.39 (m, 1H), 7.65 (s, 1H), 7.77– 7.82 (m, 2H);

13

C NMR (100 MHz, CDCl3) δ 32.7, 38.9, 107.5, 109.4, 116.2, 119.5, 119.6,

121.9, 125.4, 126.4, 126.6, 137.1, 137.3. HRMS−ESI [M + H]+ calcd for C13H14N3+ 212.1182; found 212.1180. ACS Paragon Plus Environment

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1-(4-Methylphenylsulfonyl)-4-[(4-phenyl-1H-pyrazol-1-yl)methyl]-1H-1,2,3-triazole (1p). To a stirred solution of 4-phenyl-1-(prop-2-yn-1-yl)-1H-pyrazole (182 mg, 1 mmol), tosyl azide (217 mg, 1.1 mmol) and 2-aminophenol (6 mg, 0.05 mmol) in acetonitrile (0.6 mL) Cu(OAc)2·H2O (20 mg, 0.01 mmol) was added. After 10 min of stirring at room temperature the solvent was evaporated in vacuo. The crude product was purified by column chromatography on silica gel (eluent hexane–EtOAc 4:1) followed by recrystallization from Et2O–hexane mixture (2:1). Orange solid (322 mg, yield 85%). Mp: 160−162 °C (CHCl 3). 1

H NMR (400 MHz, (CD 3)2SO–CDCl3 mixture) δ 2.30 (s, 3H), 5.46 (s, 2H), 7.13–7.24 (m,

3H), 7.32–7.35 (m, 2H), 7.53–7.56 (m, 4H), 7.85–7.88 (m, 2H), 8.22 (s, 1H);

13

C NMR (100

MHz, (CD3)2SO–CDCl3 mixture) δ 20.8, 46.4, 122.2, 125.0, 125.5, 126.0, 127.1, 128.2, 128.7, 129.1, 132.3, 136.4, 138.1, 141.9. HRMS−ESI [M + Na] + calcd for C 19H17N5NaO2S+ 402.0995; found 402.1007. 3-Phenyl-5-(4-phenyl-1H-pyrazol-1-yl)isoxazole (1u). A mixture of pyrazole 1b (498 mg, 3.15 mmol), 5-chloro-3-phenylisoxazole 43 (535 mg, 3 mmol), and K 2CO3 (1.2 g, 9 mmol) in anhydrous DMF (5 mL) was stirred at 160 °C for 5 h. The mixture was poured into water (10 mL), and the product was filtered off, washed with water and MeOH –H2O (1:1), and dried in air. White solid (560 mg, yield 65%). Mp: 163−164 °C (CHCl 3). 1H NMR (400 MHz, CDCl 3) δ 6.69 (s, 1H), 7.33–7.36 (m, 1H), 7.43–7.46 (m, 2H), 7.50–7.52 (m, 3H), 7.57–7.59 (m, 2H), 7.86–7.88 (m, 2H), 8.11 (s, 1H), 8.32 (s, 1H);

13

C NMR (100

MHz, CDCl3) δ 86.8, 124.1, 125.9, 126.0, 126.7, 127.6, 128.4, 128.9, 129.0, 130.5, 130.6, 141.4, 161.9, 164.0. HRMS−ESI [M + H] + calcd for C 18H14N3O+ 288.1131; found 288.1144. 4-(4-Methoxyphenyl)-1-(4-methylphenylsulfonyl)-1H-pyrazole (1v). To a stirred solution of 4-(4-methoxyphenyl)-1H-pyrazole (522 mg, 3 mmol) and pyridine (0.7 mL, 9 mmol) in dichloromethane (DCM) (20 mL) was added tosyl chloride (857 mg, 4.5 mmol). The resulting mixture was stirred for 1 d, then poured into water (10 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with concentrated aquous NH 3



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(3×5 mL), 1M HCl (3×5 mL) and saturated NaHCO 3 (5 mL) and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and the residue was purified by column chromatography on silica gel (eluent hexane–EtOAc 10:1) to give compound 1v. White solid (876 mg, yield 89%). Mp: 121−122 °C (CHCl 3). 1H NMR (400 MHz, CDCl 3) δ 2.43 (s, 3H), 3.84 (s, 3H), 6.93–6.95 (m, 2H), 7.34–7.36 (m, 2H), 7.40–7.43 (m, 2H), 7.93–7.95 (m, 3H), 8.25 (s, 1H);

13

C NMR (100 MHz, CDCl 3) δ 21.7, 55.3, 114.5, 122.7, 125.6, 126.1,

127.2, 128.1, 130.0, 134.0, 143.1, 145.8, 159.3. HRMS−ESI [M + Na] + calcd for C17H16N2NaO3S+ 351.0774; found 351.0782. 5-Benzyl-1-methyl-4-phenyl-1H-pyrazole (1w). To a stirred solution of pyrazole 1b (1.42 g, 9 mmol) in THF (15 mL) a 2.5 M solution of n-BuLi (4.5 mL, 11.25 mmol) in hexane was slowly added with a syringe at –86 °C. The mixture was allowed to warm to –20 °C and stirred at this temperature for 3 h. Then, the reaction mixture was cooled to –86 °C, and benzyl bromide (1.92 g, 11.25 mmol) was slowly added over 30 min. The resulting mixture was stirred at –86 °C for 1 h and at room temperature overnight. The mixture was poured into water (30 mL) and extracted with EtOAc (3×45 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na 2 SO4. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent benzene–EtOAc 4:1) to give compound 1w. Yellow oil (162 mg, yield 7%). 1H NMR (400 MHz, CDCl 3) δ 3.71 (s, 3H), 4.20 (s, 2H), 7.09–7.11 (m, 2H), 7.24–7.30 (m, 2H), 7.32–7.37 (m, 6H), 7.69 (s, 1H);

13

C NMR (100 MHz, CDCl 3) δ 29.9, 36.8, 122.3,

126.5, 126.7, 127.7, 127.8, 128.7, 128.9, 133.6, 136.8, 137.4, 137.5. HRMS−ESI [M + H] + calcd for C 17H17N2+ 249.1386; found 249.1389. N,N,1-trimethyl-4-phenyl-1H-pyrazole-5-carboxamide (1z). To a stirred solution of pyrazole 1b (474 mg, 3 mmol) in THF (5 mL) a 2.5 M solution of n-BuLi (1.5 mL, 3.75 mmol) in hexane was slowly added with a syringe at –86 °C. The mixture was allowed to warm to –20 °C and stirred at this temperature for 3 h. Then, the reaction mixture was


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cooled to –86 °C and N,N-dimethyl-1,1,1-trifluoroacetamide (1.27 g, 9 mmol) was slowly added over 30 min. The resulting mixture was stirred at –86 °C for 1 h and at room temperature overnight. The mixture was poured into water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent EtOAc) to give compound 1z. Colorless oil (315 mg, yield 46%). 1H NMR (400 MHz, CDCl 3) δ 2.61 (s, 3H), 3.08 (s, 3H), 3.93 (s, 3H), 7.25–7.31 (m, 1H), 7.34–7.39 (m, 4H), 7.64 (s, 1H);

13

C

NMR (100 MHz, CDCl 3) δ 34.8, 37.56, 37.62, 121.7, 126.6, 127.0, 128.9, 132.0, 133.3, 136.6, 163.0. HRMS−ESI [M + H] + calcd for C 13H16N3O+ 230.1288; found 230.1294. 5-Iodo-1-methyl-4-phenyl-1H-pyrazole (1zz). To a stirred solution of pyrazole 1b (474 mg, 3 mmol) in THF (5 mL) a 2.5 M solution of n-BuLi (1.5 mL, 3.75 mmol) in hexane was slowly added with a syringe at –86 °C. The mixture was allowed to warm to –20 °C and stirred at this temperature for 3 h. Then, the reaction mixture was cooled to –86 °C and solution of iodine (2.29 g, 9 mmol) in THF (7 mL) was slowly added over 30 mi n. The resulting mixture was stirred at –86 °C for 1 h and at room temperature overnight. The mixture was poured into water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with Na 2S2O3 solution, then with brine (5 mL) and dried over anhydrous Na 2SO4. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent benzene–EtOAc 4:1) followed by recrystallization from Et 2O–hexane mixture (1:1) to give compound 1zz. White solid (648 mg, yield 76%). Mp: 109−111 °C (CHCl 3). 1H NMR (400 MHz, CDCl 3) δ 4.04 (s, 3H), 7.33–7.37 (m, 1H), 7.42–7.46 (m, 2H), 7.54–7.56 (m, 2H), 7.69 (s, 1H);

13

C NMR

(100 MHz, CDCl 3) δ 40.3, 82.6, 127.1, 127.9, 128.0, 128.5, 132.7, 139.2. HRMS−ESI [M + H]+ calcd for C 10H10IN2 + 284.9883; found 284.9878.



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5-(4-Chlorophenyl)-1-methyl-4-phenyl-1H-pyrazole (1za). Pyrazole (1zz) (284 mg, 1 mmol), (4-chlorophenyl)boronic acid (172 mg, 1.1 mmol), K2CO3 (1.38 g), THF (5 mL) and water (1.2 mL) were placed in a seal-tube and through resulting mixture argon was bubled for 2 min. After that in current of argon Pd 2(dba)3 (52 mg, 0.05 mmol) was added and the reaction mixture was stirred at 80 °C (oil bath temperature) for 3 h. The mixture was poured into water (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na 2SO4. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent hexane–EtOAc 1:1) followed by recrystallization from Et 2O–hexane mixture (1:1). White solid (264 mg, yield 98%). Mp: 108−110 °C (CHCl 3). 1H NMR (400 MHz, CDCl3) δ 3.80 (s, 3H), 7.17–7.21 (m, 3H), 7.24–7.28 (m, 4H), 7.44–7.46 (m, 2H), 7.75 (s, 1H);

13

C NMR (100 MHz, CDCl 3) δ 37.3, 121.4, 126.3, 127.4, 128.5, 128.9, 129.2,

131.5, 132.8, 135.0, 137.7 138.7. HRMS−ESI [M + H] + calcd for C 16H1435ClN2+ 269.0840; found 269.0835.

General procedure for the preparation of 1,2-dihydropyrimidines 3. 1Hpyrazole 1 (0.5 mmol, 1 equiv), diazo compound 2 (1.5–3.2 equiv) and 1,2-dichloroethane (5 mL) were placed in a screw-cap tube. After the addition of Rh 2(esp)2 (3.8 mg, 0.01 equiv), cap was rapidly screwed and the tube was placed into oil bath preheated to 115 °C. The reaction mixture was heated at this temperature under stirring until full decomposition of diazo compound (1–25 min). Full consumption of reagents was controlled by TLC in eluent indicated below. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel unless otherwise stated to give 1,2-dihydropyrimidine 3bz, 3zazg. Ethyl 1-methyl-5-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-carboxylate (3b). Obtained according to the general procedure from 1-methyl-4-phenyl-1H-pyrazole (1b) and diazo compound 2a (0.75 mmol, 1.5 equiv), 3 min, eluent for chromatography hexane–


Page 17 of 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


EtOAc 4:1. Yellow oil (150 mg, yield 96%). 1H NMR (400 MHz, CDCl 3) δ 1.37 (t, J = 7.1 Hz, 3H), 3.18 (q, J = 1.3 Hz, 3H), 4.33–4.42 (m, 2H), 6.85 (d, J = 1.8 Hz, 1H), 7.20–7.24 (m, 1H), 7.26–7.28 (m, 2H), 7.33–7.37 (m, 2H), 8.16 (d, J = 1.8 Hz, 1H);

13

C NMR (100

MHz, CDCl3) δ 13.9, 40.2 (q, J = 2.2 Hz), 63.0, 81.7 (q, J = 28.4 Hz), 107.5, 122.8 (q, J = 291 Hz), 123.6, 125.9, 128.9, 135.1, 143.3, 159.0, 165.2. HRMS−ESI [M + H] + calcd for C15H16F3N2O2+ 313.1158; found 313.1172. Ethyl

1-methyl-5-(4-methylphenyl)-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-

carboxylate (3c). Obtained according to the general procedure from 1-methyl-4-(4methylphenyl)-1H-pyrazole (1c) and diazo compound 2a (0.8 mmol, 1.6 equiv), 4 min, eluent for chromatography benzene–EtOAc 10:1. Yellow solid (137 mg, yield 84%). Mp: 83−85 °C (CHCl 3). 1H NMR (400 MHz, CDCl 3) δ 1.36 (t, J = 7.1 Hz, 3H), 2.35 (s, 3H), 3.17 (s, 3H), 4.31–4.42 (m, 2H), 6.80 (d, J = 1.5 Hz, 1H), 7.16 (s, 4H), 8.13 (s, 1H);

13

C

NMR (100 MHz, CDCl 3) δ 13.9, 20.9, 40.1 (q, J = 2.3 Hz), 62.9, 81.7 (q, J = 28.5 Hz), 107.6, 122.8 (q, J = 291.1 Hz), 123.6, 129.5, 132.2, 135.6, 142.8, 159.1, 165.3. HRMS−ESI [M + H] + calcd for C 16H18F3N2O2+ 327.1315; found 327.1300. Ethyl

5-(4-chlorophenyl)-1-methyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-

carboxylate (3d). Obtained according to the general procedure from 4-(4-chlorophenyl)-1methyl-1H-pyrazole (1d) and diazo compound 2a (0.8 mmol, 1.6 equiv), 3 min, eluent for chromatography benzene–EtOAc 8:1. Yellow solid (166 mg, yield 96%). Mp: 97−99 °C (CHCl3). 1H NMR (400 MHz, CDCl 3) δ 1.36 (t, J = 7.1 Hz, 3H), 3.16 (s, 3H), 4.32–4.41 (m, 2H), 6.83 (d, J = 1.8 Hz, 1H), 7.16–7.19 (m, 2H), 7.28–7.31 (m, 2H), 8.10 (s, 1H);

13

C

NMR (100 MHz, CDCl 3) δ 13.9, 40.3 (q, J = 2.5 Hz), 63.0, 81.7 (q, J = 28.6 Hz), 106.3, 122.7 (q, J = 291 Hz), 124.7, 128.9, 131.5, 133.6, 143.5, 158.5, 165.0. HRMS−ESI [M + H]+ calcd for C 15H1535ClF3N2O2+ 347.0769; found 347.0760. Ethyl

5-(4-bromophenyl)-1-methyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-

carboxylate (3e). Obtained according to the general procedure from 4-(4-bromophenyl)-1-



Page 18 of 36

methyl-1H-pyrazole (1e) and diazo compound 2a (0.8 mmol, 1.6 equiv), 3 min, eluent for chromatography benzene–EtOAc 8:1. Yellow solid (186 mg, yield 95%). Mp: 106−108 °C (CHCl3). 1H NMR (400 MHz, CDCl 3) δ 1.36 (t, J = 7.1 Hz, 3H), 3.16 (q, J = 1.4 Hz, 3H), 4.02–4.42 (m, 2H), 6.84 (d, J = 1.9 Hz, 1H), 7.10–7.13 (m, 2H), 7.43–7.45 (m, 2H), 8.09 (d, J = 1.9 Hz, 1H);

13

C NMR (100 MHz, CDCl 3) δ 13.9, 40.3 (q, J = 2.4 Hz), 63.0, 81.7 (q, J =

28.5 Hz), 106.2, 122.7 (q, J = 291.1 Hz), 125.0, 127.0 131.9, 134.1, 143.5, 158.4, 164.9. HRMS−ESI [M + H] + calcd for C 15H1579BrF3N2O2+ 391.0264; found 391.0267. Ethyl

5-(4-methoxyphenyl)-1-methyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-

carboxylate (3f). Obtained according to the general procedure from 4-(4-methoxyphenyl)-1methyl-1H-pyrazole (1f) and diazo compound 2a (0.8 mmol, 1.6 equiv), 3 min, eluent for chromatography benzene–EtOAc 8:1. Yellow solid (149 mg, yield 87%). Mp: 67−69 °C (CHCl3). 1H NMR (400 MHz, CDCl 3) δ 1.36 (t, J = 7.1 Hz, 3H), 3.15 (s, 3H), 3.81 (s, 3H), 4.30–4.42 (m, 2H), 6.73 (d, J = 1.1 Hz, 1H), 6.88–6.90 (m, 2H), 7.16–7.18 (m, 2H), 8.09 (s, 1H);

13

C NMR (100 MHz, CDCl 3) δ 13.9, 40.1 (q, J = 2.4 Hz), 55.3, 62.9, 81.6 (q, J = 28.3

Hz), 107.4, 114.3, 122.8 (q, J = 291 Hz), 125.0, 127.8, 142.4, 158.1, 159.2, 165.3. HRMS−ESI [M + H] + calcd for C 16H18F3N2O3+ 343.1264; found 343.1267. Ethyl

1-methyl-5-(4-nitrophenyl)-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-

carboxylate (3g). Obtained according to the general procedure from 1-methyl-4-(4nitrophenyl)-1H-pyrazole (1g) and diazo compound 2a (0.8 mmol, 1.6 equiv), 4 min, eluent for chromatography benzene–EtOAc 8:1. Yellow solid (157 mg, yield 88%). Mp: 110−112 °C (CHCl3). 1H NMR (400 MHz, CDCl 3) δ 1.37 (t, J = 7.1 Hz, 3H), 3.23 (q, J = 1.4 Hz, 3H), 4.32–4.44 (m, 2H), 7.11 (d, J = 2.0 Hz, 1H), 7.37–7.39 (m, 2H), 8.17–8.19 (m, 2H), 8.22 (d, J = 2.0 Hz, 1H);

13

C NMR (100 MHz, CDCl 3) δ 13.9, 40.8 (q, J = 2.4 Hz), 63.3,

81.9 (q, J = 28.8 Hz), 104.7, 122.5 (q, J = 290.8 Hz), 122.6, 124.5, 141.7, 145.3, 145.5, 157.5, 164.4. HRMS−ESI [M + H] + calcd for C 15H15F3N3O4+ 358.1009; found 358.0999.


Page 19 of 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Ethyl

1-methyl-5-(naphthalen-1-yl)-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-

carboxylate (3h). Obtained according to the general procedure from) 1-methyl-4(naphthalen-1-yl)-1H-pyrazole (1h) and diazo compound 2a (0.75 mmol, 1.5 equiv), 4 min, eluent for chromatography hexane–EtOAc 9:1. Yellow oil (152 mg, yield 84%). 1H NMR (400 MHz, CDCl 3) δ 1.43 (t, J = 7.1 Hz, 3H), 3.20 (q, J = 1.4 Hz, 3H), 4.43 (qd, J = 7.1, 0.8 Hz, 2H), 6.75 (d, J = 1.8 Hz, 1H), 7.32–7.34 (m, 1H), 7.45–7.48 (m, 1H), 7.50–7.54 (m, 2H), 7.79–7.81 (m, 1H), 7.87–7.89 (m, 1H), 7.95–7.97 (m, 1H), 7.99 (d, J = 1.8 Hz, 1H); 13

C NMR (100 MHz, CDCl 3) δ 14.0, 40.0 (q, J = 2.3 Hz), 63.0, 81.5 (q, J = 28.3 Hz), 106.7,

123.0 (q, J = 291 Hz), 124.9, 125.5, 125.6, 125.9, 126.2, 127.5, 128.4, 132.1, 133.2, 133.9, 145.4, 160.9, 165.4. HRMS−ESI [M + H] + calcd for C 19H18F3N2O2+ 363.1315; found 363.1310. Ethyl

1-methyl-5-(naphthalen-2-yl)-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-

carboxylate (3i). Obtained according to the general procedure from 1-methyl-4-(naphthalen2-yl)-1H-pyrazole (1i) and diazo compound 2a (0.8 mmol, 1.6 equiv), 3 min, eluent for chromatography benzene–EtOAc 8:1. Yellow solid (163 mg, yield 90%). Mp: 103−105 °C (CHCl3). 1H NMR (400 MHz, CDCl 3) δ 1.39 (t, J = 7.1 Hz, 3H), 3.21 (s, 3H), 4.36–4.42 (m, 2H), 6.98 (s, 1H), 7.40–7.50 (m, 3H), 7.68 (s, 1H), 7.81–7.83 (m, 3H), 8.31 (s, 1H);

13

C

NMR (100 MHz, CDCl 3) δ 13.9, 40.3 (q, J = 2.5 Hz), 63.0, 81.8 (q, J = 28.5 Hz), 107.3, 122.1, 122.5, 122.8 (q, J = 291 Hz), 125.3, 126.4, 127.5, 127.6, 128.6, 131.8, 132.5, 133.7, 143.6, 159.0, 165.1. HRMS−ESI [M + H] + calcd for C 19H18F3N2O2+

363.1315; found

363.1302. Ethyl

1-methyl-5-(1-methyl-1H-indol-3-yl)-2-(trifluoromethyl)-1,2-dihydropyrimidine-

2-carboxylate (3j). Obtained according to the general procedure from 1-methyl-4-(1methylindol-3-yl)-1H-pyrazole (1j) and diazo compound 2a (0.8 mmol, 1.6 equiv), 4 min, eluent for chromatography benzene–EtOAc 5:1. Yellow oil (144 mg, yield 79%). 1H NMR (400 MHz, CDCl 3) δ 1.39 (t, J = 7.1 Hz, 3H), 3.17 (q, J = 1.5 Hz, 3H), 3.80 (s, 3H), 4.35–



Page 20 of 36

4.42 (m, 2H), 6.79 (d, J = 1.8 Hz, 1H), 6.98 (s, 1H), 7.15–7.18 (m, 1H), 7.26–7.30 (m, 1H), 7.33–7.35 (m, 1H), 7.62–7.64 (m, 1H), 8.07 (d, J = 1.8 Hz, 1H);

13

C NMR (100 MHz,

CDCl3) δ 14.0, 32.7, 40.0 (q, J = 2.4 Hz), 62.8, 81.5 (q, J = 28.2 Hz), 101.9, 109.4, 110.2, 119.2, 122.0, 123.0 (q, J = 291 Hz), 124.6, 126.3, 137.0, 142.6, 160.6, 165.6. HRMS−ESI [M + H] + calcd for C 18H19F3N3O2+ 366.1424; found 366.1441. Ethyl 5-benzoyl-1-methyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-carboxylate (3k). Obtained

according

to

the

general

procedure

from

(1-methyl-1H-pyrazol-4-

yl)(phenyl)methanone (1k) and diazo compound 2a (0.8 mmol, 1.6 equiv), 3 min, eluent for chromatography benzene–EtOAc 4:1. Yellow solid (160 mg, yield 94%). Mp: 88−90 °C (CHCl3). 1H NMR (400 MHz, CDCl3) δ 1.37 (t, J = 7.1 Hz, 3H), 3.21 (q, J = 1.3 Hz, 3H), 4.33–4.45 (m, 2H), 7.44–7.47 (m, 2H), 7.51–7.58 (m, 4H), 8.41 (d, J = 1.8 Hz, 1H);

13

C

NMR (100 MHz, CDCl 3) δ 13.9, 41.5 (q, J = 2.4 Hz), 63.6, 82.4 (q, J = 28.7 Hz), 106.6, 122.8 (q, J = 291 Hz), 128.4, 128.5, 131.5, 138.0, 155.2, 158.7, 163.4, 189.5. HRMS−ESI [M + Na] + calcd for C 16H15F3N2NaO3+ 363.0927; found 363.0925. Ethyl

1-ethyl-5-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-carboxylate (3l).

Obtained according to the general procedure from 1-ethyl-4-phenyl-1H-pyrazole (1l) and diazo compound 2a (0.9 mmol, 1.8 equiv), 2 min, eluent for chromatography hexane–EtOAc 6:1. Yellow oil (132 mg, yield 81%). 1H NMR (400 MHz, CDCl 3) δ 1.36 (t, J = 7.2 Hz, 3H), 1.38 (t, J = 7.1 Hz, 3H), 3.34 (q, J = 7.2 Hz, 2H), 4.38 (qd, J = 7.1, 1.5 Hz, 2H), 6.94 (d, J = 1.6 Hz, 1H), 7.21–7.25 (m, 1H), 7.27–7.29 (m, 2H), 7.34–7.38 (m, 2H), 8.17 (d, J = 1.6 Hz, 1H);

13

C NMR (100 MHz, CDCl 3) δ 13.9, 14.7, 46.2, 63.0, 82.3 (q, J = 28.1 Hz), 107.3,

123.0 (q, J = 292.3 Hz), 123.6, 125.9, 128.9, 135.4, 140.4, 159.2, 165.5. HRMS−ESI [M + H]+ calcd for C 16H18F3N2O2+ 327.1315; found 327.1325. Ethyl 1-benzyl-5-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-carboxylate (3m). Obtained according to the general procedure from 1-benzyl-4-phenyl-1H-pyrazole (1m) and diazo compound 2a (0.9 mmol, 1.8 equiv), 2 min, eluent for chromatography hexane–EtOAc


Page 21 of 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


4:1. Yellow oil (155 mg, yield 80%). 1H NMR (400 MHz, CDCl 3) δ 1.21 (t, J = 7.2 Hz, 3H), 4.10–4.28 (m, 2H), 4.38 (s, 2H), 6.64 (d, J = 1.9 Hz, 1H), 7.04–7.09 (m, 3H), 7.16–7.20 (m, 2H), 7.23–7.30 (m, 5H), 8.12 (d, J = 1.9 Hz, 1H);

13

C NMR (100 MHz, CDCl 3) δ 13.8, 54.7

(q, J = 2.2 Hz), 63.1, 82.0 (q, J = 28.0 Hz), 107.9, 123.3 (q, J = 293.3 Hz), 123.7, 126.0, 128.3 (2C), 128.8, 129.0, 135.1, 135.2, 140.6, 159.5, 165.3. HRMS−ESI [M + H] + calcd for C21H20F3N2O2+ 389.1471; found 389.1476. Ethyl

1-isopropyl-5-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-carboxylate

(3n). Obtained according to the general procedure from 1-isopropyl-4-phenyl-1H-pyrazole (1n) and diazo compound 2a (1 mmol, 2 equiv), 2 min, eluent for chromatography benzene– EtOAc 9:1. Yellow oil (77 mg, yield 45%). 1H NMR (400 MHz, CDCl 3) δ 1.38–1.42 (m, 9H), 3.42 (sep, J = 6.5 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 6.99 (d, J = 1.7 Hz, 1H), 7.21– 7.24 (m, 1H), 7.27–7.28 (m, 2H), 7.34–7.38 (m, 2H), 8.16 (d, J = 1.7 Hz, 1H);

13

C NMR

(100 MHz, CDCl 3) δ 13.9, 22.1, 23.3, 52.1, 63.0, 82.8 (q, J = 28.0 Hz), 106.8, 123.1 (q, J = 293.3 Hz), 123.6, 125.9, 128.9, 135.7, 137.2, 159.4, 165.2. HRMS−ESI [M + Na] + calcd for C17H19F3N2NaO2+ 363.1291; found 363.1281. Ethyl 1-(2-methoxy-2-oxoethyl)-5-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2carboxylate (3o). Obtained according to the general procedure from methyl 2-(4-phenyl-1Hpyrazol-1-yl)acetate (1o) and diazo compound 2a (0.75 mmol, 1.5 equiv), 2 min, eluent for chromatography benzene–EtOAc 9:1. Yellow oil (146 mg, yield 79%). 1H NMR (400 MHz, CDCl3) δ 1.37 (t, J = 7.1 Hz, 3H), 3.81 (s, 3H), 3.99 and 4.13 (AB-q, J = 18.1 Hz, 2H), 4.30–4.37 (m, 2H), 6.84 (d, J = 1.8 Hz, 1H), 7.23–7.26 (m, 1H), 7.29–7.31 (m, 2H), 7.34– 7.38 (m, 2H), 8.22 (d, J = 1.8 Hz, 1H);

13

C NMR (100 MHz, CDCl 3) δ 13.8, 52.3, 52.6,

63.4, 81.5 (q, J = 28.7 Hz), 107.9, 122.8 (q, J = 292.5 Hz), 124.0, 126.3, 128.9, 134.9, 141.9, 159.6, 164.9, 168.9. HRMS−ESI [M + H] + calcd for C 17H18F3N2O4+ 371.1213; found 371.1222.



Ethyl

Page 22 of 36

1-((1-(4-methylphenylsulfonyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-2-

(trifluoromethyl)-1,2-dihydropyrimidine-2-carboxylate (3p). Obtained according to the general procedure from 1-(4-methylphenylsulfonyl)-4-[(4-phenyl-1H-pyrazol-1-yl)methyl]1H-1,2,3-triazole (1p) and diazo compound 2a (0.95 mmol, 1.9 equiv), 2 min, after the reaction completion pyridine (20 mg) was added to the reaction mixture, eluent for chromatography hexane–EtOAc 5:1. Yellow solid (189 mg, yield 71%). Mp: 43−45 °C (CHCl3). 1H NMR (400 MHz, CDCl 3) δ 1.35 (t, J = 7.1 Hz, 3H), 2.46 (s, 3H), 4.26–4.43 (m, 2H), 4.57 (s, 2H), 7.01 (d, J = 1.8 Hz, 1H), 7.20–7.24 (m, 3H), 7.30–7.34 (m, 2H) , 7.39– 7.41 (m, 2H) , 8.01–8.03 (m, 2H), 8.17 (d, J = 1.8 Hz, 1H), 8.24 (s, 1H);

13

C NMR (100

MHz, CDCl3) δ 13.9, 21.8, 45.9, 63.4, 82.0 (q, J = 28.5 Hz), 108.4, 122.9 (q, J = 292.3 Hz), 122.9, 123.8, 126.3, 128.8, 128.9, 130.5, 132.7, 134.6, 140.5, 143.2, 147.6, 159.5, 165.4. HRMS−ESI [M + H] + calcd for C 24H23F3N5O4S+ 534.1417; found 534.1409. Ethyl

1-(2-bromoethyl)-5-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-

carboxylate (3q). Obtained according to the general procedure from 1-(2-bromoethyl)-4phenyl-1H-pyrazole (1q) and diazo compound 2a (1.3 mmol, 2.6 equiv), 2 min, eluent for chromatography hexane–EtOAc 4:1. Yellow oil (174 mg, yield 86%). 1 H NMR (400 MHz, CDCl3) δ 1.38 (t, J = 7.1 Hz, 3H), 3.54–3.64 (m, 2H), 3.72 (t, J = 7.4 Hz, 2H), 4.32–4.45 (m, 2H), 6.96 (d, J = 1.7 Hz, 1H), 7.24–7.30 (m, 3H), 7.35–7.39 (m, 2H), 8.19 (d, J = 1.7 Hz, 1H);

13

C NMR (100 MHz, CDCl3) δ 13.9, 29.1, 53.1 (q, J = 1.3 Hz), 63.4, 81.6 (q, J =

28.4 Hz), 109.1, 122.8 (q, J = 290.8 Hz), 123.9, 126.4, 128.9, 134.7, 140.8, 159.2, 165.6. HRMS−ESI [M + H] + calcd for C 16H1779BrF3N2O2+ 405.0420; found 405.0424. Ethyl

1-(2-bromobenzyl)-5-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-

carboxylate (3r). Obtained according to the general procedure from 1-(2-bromobenzyl)-4phenyl-1H-pyrazole (1r) and diazo compound 2a (0.95 mmol, 1.9 equiv), 2 min, eluent for chromatography hexane–EtOAc 4:1. Yellow oil (180 mg, yield 77%). 1 H NMR (400 MHz, CDCl3) δ 1.29 (t, J = 7.1 Hz, 3H), 4.22–4.36 (m, 2H), 4.64 and 4.66 (AB-q, J = 16.8 Hz,


Page 23 of 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2H), 6.73 (d, J = 1.7 Hz, 1H), 7.21–7.24 (m, 4H), 7.31–7.40 (m, 3H), 7.49–7.51 (m, 1H), 7.61–7.63 (m, 1H), 8.29 (d, J = 1.7 Hz, 1H);

13

C NMR (100 MHz, CDCl 3) δ 13.8, 54.6 (q, J

= 2.2 Hz), 63.2, 81.7 (q, J = 28.2 Hz), 108.8, 123.1 (q, J = 292.8 Hz), 123.4, 123.7, 126.2, 128.0, 128.9, 129.4, 129.6, 133.0, 134.8, 134.9, 140.8, 159.4, 165.2. HRMS−ESI [M + H] + calcd for C 21H1979BrF3N2O2+ 467.0577; found 467.0592. Ethyl

1,5-diphenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-carboxylate

(3s).

Obtained according to the general procedure from 1,4-diphenyl-1H-pyrazole (1s) and diazo compound 2a (0.75 mmol, 1.5 equiv), 1 min, eluent for chromatography hexane–EtOAc 8:1, after the chromatography product was recrystallized from Et 2O–hexane mixture 1:1. Yellow solid (92 mg, yield 49%). Mp: 101−103 °C (CHCl 3). 1H NMR (400 MHz, CDCl 3) δ 0.98 (t, J = 7.1 Hz, 3H), 4.06 (q, J = 7.1 Hz, 2H), 6.98 (s, 1H), 7.26–7.30 (m, 1H), 7.38–7.42 (m, 9H), 8.42 (s, 1H);

13

C NMR (100 MHz, CDCl 3) δ 13.3, 62.8, 82.1 (q, J = 28.1 Hz), 112.3,

123.1 (q, J = 291.7 Hz), 124.1, 126.6, 126.8 (q, J = 1.9 Hz), 127.7, 129.0, 129.3, 134.8, 138.9, 143.0, 159.0, 164.5. HRMS−ESI [M + H] + calcd for C 20H18F3N2O2+ 375.1315; found 375.1313. Ethyl

1-(2-methylphenyl)-5-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-

carboxylate (3t). Obtained according to the general procedure from 1-(2-methylphenyl)-4phenyl-1H-pyrazole (1t) and diazo compound 2a (0.95 mmol, 1.9 equiv), 4 min, eluent for chromatography hexane–EtOAc 12:1. Yellow liquid (140 mg, yield 72%), mixture of two atropoisomers in 1:1.3 ratio. 1H NMR (400 MHz, CDCl 3) δ 0.93 (br t, J = 6.9 Hz, 1.3H), 1.34 (t, J = 6.9 Hz, 1.9H), 2.18 (s, 1.8H), 2.30 (s, 1.3H), 3.91–3.93 (br m, 0.85H), 4.33–4.37 (br m, 1.15H), 6.81 (s, 0.42H), 6.88 (s, 0.58H), 7.26–7.36 (m, 8H), 7.59 (br d, J = 7.5 Hz, 0.44H), 7.92 (br d, J = 7.5 Hz, 0.58H), 8.38 (s, 0.59H), 8.49 (s, 0.42H);

13

C NMR (100

MHz, CDCl3) δ 13.1, 13.9, 17.4, 18.1, 62.6, 63.1, 81.6 (q, J = 28.9 Hz), 82.1 (q, J = 28.9 Hz), 113.0, 113.4, 122.0 (q, J = 285.5 Hz), 123.4 (q, J = 294.8 Hz), 123.8, 123.9, 126.3, 126.4, 126.6, 128.9, 129.1, 129.4, 130.2, 131.1, 131.6, 134.5, 134.8, 138.3, 138.6, 139.4,



Page 24 of 36

140.4, 140.7, 141.0, 157.3, 159.3, 163.7, 167.4. HRMS−ESI [M + Na] + calcd for C21H19F3N2NaO2+ 411.1291; found 411.1276. Ethyl 5-phenyl-1-(3-phenylisoxazol-5-yl)-2-(trifluoromethyl)-1,2-dihydropyrimidine-2carboxylate (3u). Obtained according to the general procedure from 3-phenyl-5-(4-phenyl1H-pyrazol-1-yl)isoxazole (1u) and diazo compound 2a (1.15 mmol, 2.3 equiv), 2 min, eluent for chromatography hexane–EtOAc 15:1. Yellow solid (146 mg, yield 66%). Mp: 152−154 °C (CHCl 3). 1H NMR (400 MHz, CDCl 3) δ 1.21 (t, J = 7.1 Hz, 3H), 4.24–4.36 (m, 2H), 6.10 (s, 1H), 7.33 (d, J = 1.7 Hz, 1H), 7.36–7.50 (m, 8H), 7.77–7.79 (m, 2H), 8.41 (d, J = 1.7 Hz, 1H);

13

C NMR (100 MHz, CDCl 3) δ 13.6, 63.6, 80.4 (q, J = 29 Hz), 87.3 (q, J =

2.9 Hz), 112.6, 122.9 (q, J = 292.2 Hz), 124.9, 126.6, 127.8, 128.4, 129.0, 129.2, 130.5, 131.5, 133.6, 159.6, 162.9, 163.6, 163.9. HRMS−ESI [M + H] + calcd for C 23H19F3N3O3+ 442.1373; found 442.1371. Ethyl

5-(4-methoxyphenyl)-1-(4-methylphenylsulfonyl)-2-(trifluoromethyl)-1,2-

dihydropyrimidine-2-carboxylate (3v). Obtained according to the general procedure from 4(4-methoxyphenyl)-1-(4-methylphenylsulfonyl)-1H-pyrazole (1v) and diazo compound 2a (1.6 mmol, 3.2 equiv), 5 min, eluent for chromatography benzene–EtOAc 100:1. Pale yellow solid (186 mg, yield 77%). Mp: 142−144 °C (CHCl 3). 1H NMR (400 MHz, CDCl 3) δ 1.43 (t, J = 7.2 Hz, 3H), 2.46 (s, 3H), 3.83 (s, 3H), 4.42–4.54 (m, 2H), 6.91–6.94 (m, 2H), 7.02 (d, J = 1.6 Hz, 1H), 7.18–7.20 (m, 2H), 7.37–7.39 (m, 2H), 7.89–7.91 (m, 2H), 8.20 (d, J = 1.6 Hz, 1H);

13

C NMR (100 MHz, CDCl 3) δ 13.7, 21.6, 55.3, 63.6, 79.3 (q, J = 29.2 Hz),

113.4, 114.5, 122.4 (q, J = 291.7 Hz), 125.8, 126.4, 128.2, 129.4, 130.0, 135.2, 145.5, 159.1, 159.6, 164.3. HRMS−ESI [M + Na] + calcd for C 22H21F3N2NaO5S + 505.1015; found 505.1030. Ethyl

6-benzyl-1-methyl-5-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-

carboxylate (3w). Obtained according to the general procedure from 5-benzyl-1-methyl-4phenyl-1H-pyrazole (1w) and diazo compound 2a (0.85 mmol, 1.7 equiv), 3 min, eluent for


Page 25 of 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


chromatography benzene–EtOAc 12:1. Yellow solid (123 mg, yield 61%). Mp: 105−107 °C (CHCl3). 1H NMR (400 MHz, CDCl3) δ 1.38 (t, J = 7.1 Hz, 3H), 2.86 (q, J = 1.4 Hz, 3H), 3.78 and 3.84 (AB-q, J = 16.7 Hz, 2H), 4.33–4.44 (m, 2H), 7.19–7.22 (m, 2H), 7.24–7.31 (m, 6H), 7.36–7.40 (m, 2H), 7.89 (s, 1H);

13

C NMR (100 MHz, CDCl 3) δ 14.0, 35.0 (q, J =

2.2 Hz), 35.1, 62.8, 83.5 (q, J = 27.6 Hz), 110.2, 123.5 (q, J = 293.2 Hz), 126.8, 126.9, 127.5, 128.6, 128.8, 129.1, 136.3, 136.8, 150.5, 161.3, 165.6. HRMS−ESI [M + H] + calcd for C22H22F3N2O2+ 403.1628; found 403.1615. Ethyl

6-benzoyl-1-methyl-5-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine-2-

carboxylate (3x). Obtained according to the general procedure from (1-methyl-4-phenyl-1Hpyrazol-5-yl)(phenyl)methanone (1x) and diazo compound 2a (0.85 mmol, 1.7 equiv), 3 min, eluent for chromatography hexane–EtOAc 4:1. Yellow solid (173 mg, yield 83%). Mp: 77−79 °C (CHCl 3). 1H NMR (400 MHz, CDCl 3) δ 1.42 (t, J = 7.1 Hz, 3H), 2.89 (s, 3H), 4.44 (q, J = 7.1 Hz, 2H), 7.06–7.10 (m, 3H), 7.12–7.16 (m, 2H), 7.40–7.44 (m, 2H), 7.54– 7.58 (m, 1H), 7.91–7.93 (m, 2H), 8.04 (s, 1H);

13

C NMR (100 MHz, CDCl 3) δ 14.0, 36.3 (q,

J = 2.3 Hz), 63.2, 82.4 (q, J = 28.2 Hz), 107.3, 123.1 (q, J = 291.8 Hz), 127.0, 128.3, 128.4, 129.0, 129.3, 134.0, 134.8, 134.9, 148.4, 161.1, 164.9, 191.2. HRMS−ESI [M + H] + calcd for C22H20F3N2O3+ 417.1421; found 417.1402. Diethyl 3-methyl-5-phenyl-2-(trifluoromethyl)-2,3-dihydropyrimidine-2,4-dicarboxylate (3y). Obtained according to the general procedure from ethyl 1-methyl-4-phenyl-1Hpyrazole-5-carboxylate (1y) and diazo compound 2a (0.85 mmol, 1.7 equiv), 2 min, eluent for chromatography hexane–EtOAc 12:1. Yellow oil (184 mg, yield 96%). 1H NMR (400 MHz, CDCl3) δ 1.00 (t, J = 7.1 Hz, 3H), δ 1.38 (t, J = 7.1 Hz, 3H), 3.03 (q, J = 0.7 Hz, 3H), 4.07–4.15 (m, 2H), 4.35–4.43 (m, 2H), 7.18–7.20 (m, 2H), 7.25–7.35 (m, 3H), 8.00 (s, 1H); 13

C NMR (100 MHz, CDCl 3) δ 13.4, 13.9, 36.2 (q, J = 2.4 Hz), 62.3, 63.1, 81.5 (q, J = 28.4

Hz), 109.0, 123.0 (q, J = 291.5 Hz), 127.2, 127.6, 128.5, 134.5, 143.9, 160.7, 162.7, 165.0. HRMS−ESI [M + Na] + calcd for C18H19F3N2NaO4+ 407.1189; found 407.1183.



Ethyl

Page 26 of 36

6-(dimethylcarbamoyl)-1-methyl-5-phenyl-2-(trifluoromethyl)-1,2-

dihydropyrimidine-2-carboxylate (3z). Obtained according to the general procedure from N,N,1-trimethyl-4-phenyl-1H-pyrazole-5-carboxamide (1z) and diazo compound 2a (1 mmol, 2 equiv), 3 min, eluent for chromatography hexane–EtOAc 3:2. Yellow solid (138 mg, yield 72%), mixture of two atropoisomers in 1:1 ratio. Mp: 102−104 °C (CHCl 3). 1H NMR (400 MHz, CDCl 3) δ 1.39 (t, J = 7.1 Hz, 3H), 2.73 (s, 1.5H), 2.75 (s, 1.5H), 2.80 (s, 1.5H), 2.82 (s, 1.5H), 2.99 (s, 3H), 4.39 (q, J = 7.1 Hz, 2H), 7.22–7.34 (m, 5H), 7.92 (s, 0.5H), 7.94 (s, 0.5H);

13

C NMR (100 MHz, CDCl 3) δ 13.9, 34.05, 34.08, 35.7 (q, J = 2.4

Hz), 35.8 (q, J = 2.1 Hz), 36.8, 37.0, 63.06, 63.11, 81.8 (q, J = 27.4 Hz), 82.5 (q, J = 28.6 Hz), 105.1, 105.7, 122.7 (q, J = 291.3 Hz), 123.3 (q, J = 292.5 Hz), 126.9, 127.0, 127.25, 127.32, 128.5, 128.6, 134.3, 134.4, 145.9, 147.0, 160.6, 160.9, 162.8, 162.9, 164.6, 165.4. HRMS−ESI [M + H] + calcd for C 18H21F3N3O3+ 384.1530; found 384.1538. Ethyl 6-(4-chlorophenyl)-1-methyl-5-phenyl-2-(trifluoromethyl)-1,2-dihydropyrimidine2-carboxylate (3za). Obtained according to the general procedure from 5-(4-chlorophenyl)1-methyl-4-phenyl-1H-pyrazole (1za) and diazo compound 2a (0.9 mmol, 1.8 equiv), 4 min, eluent for chromatography benzene–EtOAc 10:1. Yellow solid (207 mg, yield 98%). Mp: 76−77 °C (CHCl 3). 1H NMR (400 MHz, CDCl 3) δ 1.31 (t, J = 7.1 Hz, 3H), 2.88 (s, 3H), 4.28–4.40 (m, 2H), 6.90–6.91 (m, 2H), 7.06–7.15 (m, 3H), 7.21–7.23 (m, 2H), 7.26–7.28 (m, 2H), 8.15 (s, 1H);

13

C NMR (100 MHz, CDCl 3) δ 14.0, 35.7 (q, J = 3.0 Hz), 63.0, 81.6

(q, J = 28.1 Hz), 114.8, 123.0 (q, J = 288 Hz), 126.0, 128.26, 128.29, 128.9, 130.9, 131.6, 135.5, 135.6, 150.8, 160.4, 167.4. HRMS−ESI [M + Na] + calcd for C 21H1835ClF3N2NaO2+ 445.0901; found 445.0898. Methyl 1-methyl-2,5-diphenyl-1,2-dihydropyrimidine-2-carboxylate (3zb). Obtained according to the general procedure from 1-methyl-4-phenyl-1H-pyrazole (1b) and diazo compound 2b (0.75 mmol, 1.5 equiv), 2 min, eluent for chromatography hexane–EtOAc 4:1. Yellow solid (145 mg, yield 95%). Mp: 132−134 °C (CHCl 3). 1H NMR (400 MHz, CDCl 3) δ


Page 27 of 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2.84 (s, 3H), 3.80 (s, 3H), 7.03 (d, J = 1.5 Hz, 1H), 7.17–7.21 (m, 1H), 7.34–7.35 (m, 4H), 7.41–7.47 (m, 3H), 7.56–7.58 (m, 2H), 8.28 (d, J = 1.5 Hz, 1H);

13

C NMR (100 MHz,

CDCl3) δ 40.7, 52.4, 82.1, 109.0, 123.2, 125.2, 128.0, 128.3, 128.7, 128.8, 136.0, 138.9, 142.4, 156.4, 172.7. HRMS−ESI [M + H] + calcd for C 19H19N2O2+ 307.1441; found 307.1428. Methyl

2-(4-methoxyphenyl)-1-methyl-5-phenyl-1,2-dihydropyrimidine-2-carboxylate

(3zc). Obtained according to the general procedure from 1-methyl-4-phenyl-1H-pyrazole (1b) and diazo compound 2c (0.8 mmol, 1.6 equiv), 3 min, eluent for chromatography hexane–EtOAc 12:1→4:1. Yellow solid (158 mg, yield 94%). Mp: 138−142 °C (CHCl 3). 1H NMR (400 MHz, CDCl 3) δ 2.83 (s, 3H), 3.77 (s, 3H), 3.85 (s, 3H), 6.95–6.98 (m, 2H), 7.03 (d, J = 1.4 Hz, 1H), 7.16–7.21 (m, 1H), 7.33–7.34 (m, 4H), 7.48–7.50 (m, 2H), 8.26 (d, J = 1.4 Hz, 1H);

13

C NMR (100 MHz, CDCl 3) δ 40.6, 52.4, 55.1, 81.7, 109.1, 113.6, 123.2,

125.2, 128.7, 129.3, 131.0, 136.0, 142.4, 156.3, 159.8, 173.0. HRMS−ESI [M + H] + calcd for C20H21N2O3+ 337.1547; found 337.1534. Methyl

2-(4-chlorophenyl)-1-methyl-5-phenyl-1,2-dihydropyrimidine-2-carboxylate

(3zd). Obtained according to the general procedure from 1-methyl-4-phenyl-1H-pyrazole (1b) and diazo compound 2d (0.8 mmol, 1.6 equiv), 7 min, eluent for chromatography benzene–EtOAc 5:1. Yellow solid (129 mg, yield 76%). Mp: 151−153 °C (CHCl 3). 1H NMR (400 MHz, CDCl 3) δ 2.85 (s, 3H), 3.79 (s, 3H), 7.02 (d, J = 1.5 Hz, 1H), 7.17–7.23 (m, 1H), 7.32–7.37 (m, 4H), 7.42–7.44 (m, 2H), 7.51–7.54 (m, 2H), 8.25 (d, J = 1.5 Hz, 1H);

13

C

NMR (100 MHz, CDCl 3) δ 40.7, 52.6, 81.7, 109.4, 123.3, 125.4, 128.5, 128.8, 129.5, 134.9, 135.8, 137.5, 142.3, 156.6, 172.4. HRMS−ESI [M + H] + calcd for C 19H1835ClN2O2+ 341.1051; found 341.1065. Methyl 1-methyl-2-(4-nitrophenyl)-5-phenyl-1,2-dihydropyrimidine-2-carboxylate (3ze). Obtained according to the general procedure from 1-methyl-4-phenyl-1H-pyrazole (1b) and diazo compound 2e (0.8 mmol, 1.6 equiv), 4 min, eluent for chromatography hexane–EtOAc



Page 28 of 36

1:1. Orange solid (128 mg, yield 73%). Mp: 161−164 °C (CHCl 3). 1 H NMR (400 MHz, CDCl3) δ 2.89 (s, 3H), 3.84 (s, 3H), 7.02 (d, J = 1.1 Hz, 1H), 7.19–7.23 (m, 1H), 7.31–7.37 (m, 4H), 7.77–7.79 (m, 2H), 8.25 (d, J = 1.1 Hz, 1H), 8.29–8.32 (m, 2H);

13

C NMR (100

MHz, CDCl3) δ 40.7, 53.0, 81.7, 109.6, 123.40, 123.43, 125.7, 128.8, 129.2, 135.5, 142.4, 145.7, 148.1, 156.8, 171.6. HRMS−ESI [M + H] + calcd for C 19H18N3O4+ 352.1292; found 352.1285. 1-(1-Methyl-2,5-diphenyl-1,2-dihydropyrimidin-2-yl)ethanone (3zf). Obtained according to the general procedure from 1-methyl-4-phenyl-1H-pyrazole (1b) and diazo compound 2f (1.1 mmol, 2.2 equiv), 1 min, eluent for chromatography hexane–EtOAc 4:1. Orange solid (132 mg, yield 91%). Mp: 121−123 °C (CHCl 3). 1H NMR (400 MHz, CDCl 3) δ 2.15 (s, 3H), 2.75 (s, 3H), 7.04 (d, J = 1.6 Hz, 1H), 7.15–7.19 (m, 1H), 7.29–7.35 (m, 4H), 7.44–7.50 (m, 3H), 7.53–7.56 (m, 2H), 8.30 (d, J = 1.6 Hz, 1H);

13

C NMR (100 MHz, CDCl 3) δ 25.5, 41.3,

85.5, 108.4, 123.1, 125.1, 128.5, 128.6, 128.7, 129.0, 136.1, 137.8, 143.4, 156.9, 206.4. HRMS−ESI [M + H] + calcd for C 19H19N2O+ 291.1492; found 291.1479. Dimethyl

1-methyl-5-phenylpyrimidine-2,2(1H)-dicarboxylate

(3zg).

Obtained

according to the general procedure from 1-methyl-4-phenyl-1H-pyrazole (1b) and diazo compound 2g (0.8 mmol, 1.6 equiv), 25 min, eluent for chromatography hexane–EtOAc 4:1→2:1. Yellow solid (79 mg, yield 55%). Mp: 116−118 °C (CHCl 3). 1H NMR (400 MHz, CDCl3) δ 3.22 (s, 3H), 3.89 (s, 6H), 6.90 (s, 1H), 7.17–7.21 (m, 1H), 7.26–7.28 (m, 2H), 7.31–7.35 (m, 2H), 8.14 (s, 1H);

13

C NMR (100 MHz, CDCl 3) δ 40.3, 53.3, 82.3, 108.8,

123.5, 125.7, 128.8, 135.4, 142.2, 156.9, 168.4. HRMS−ESI [M + H] + calcd for C15H17N2O4+ 289.1183; found 289.1187. ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website at DOI: …..


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1

H and

13

C NMR spectra for all new compounds, X-ray crystallography data for compound

3s, computation details with energies of the reactants, transition states, their Cartesian coordinates, and tube representation of the calculated molecules, Figure S1 (PDF).

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected].

Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS We gratefully acknowledge the financial support of the Russian Science Foundation (Grant No. 17-13-01078). This research used resources of ‘Magnetic Resonance Research Centre’, ‘Chemical Analysis and Materials Research Centre’, ‘Computing Centre’, “Centre for X-ray Diffraction Studies”, and ‘Chemistry Educational Centre’ of the Research Park of St. Petersburg State University.

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Rh(II)-Catalyzed Ring Expansion of Pyrazoles with Diazocarbonyl

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