DBU-Mediated Cyclization of Acylcyclopropanecarboxylates with

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DBU-Mediated Cyclization of Acylcyclopropanecarboxylates with Amidines: Access to Polysubstituted Pyrimidines Shan Wang,† Naili Luo,† Yan Li,‡ and Cunde Wang*,† †

School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, P. R. China School of Pharmacy, Taizhou Polytechnic College, Taizhou 225300, P. R. China

‡

Downloaded by UNIV AUTONOMA DE COAHUILA at 10:15:44:935 on June 04, 2019 from https://pubs.acs.org/doi/10.1021/acs.orglett.9b01436.

S Supporting Information *

ABSTRACT: DBU-mediated cyclization of 2-acyl-1-cyanocyclopropanecarboxylates with amidines for the synthesis of multisubstituted pyrimidine derivatives is described. This reaction gives a practical method for producing a diverse set of pyrimidines, having simple experimentation, readily available starting materials, a wide substrate scope, and very good yields.

P

yrimidine is a distinctive scaffold in numerous natural bioactive compounds and synthetic pharmaceuticals.1 Many pyrimidine-containing compounds are used widely in clinical medicine, for example, vitamin B1, Imatinib, HIV drug zidovudine, ceritinib, trimethoprim, iclaprim, sodium thiopental, barbituric acid, Veronal, and Crestor.2 Pyrimidine has been accepted as a special pharmacophore in pharmaceutical investigations. Recently, the functionalized pyrimidines have shown important biological activities such as acting as antitubercular agents,3 exhibiting antimicrobial,4 antibacterial,5 antiviral,6 anticancer,7 anti-HIV,8 and antimalarial properties,9 and acting as phosphodiesterase 10A (PDE10A) inhibitors10 and antifungal protein kinase inhibitors.11 In addition, pyrimidine derivatives can be used in photophysical materials as molecular devices,12 especially light-emitting devices,13 and functional materials.14 Because of the inherent biological activity of pyrimidine derivatives, the construction of the pyrimidine motif has attracted a great deal of attention over the years.15 A number of means for the synthesis of multisubstituted pyrimidine have been investigated, such as the annulation of carbamidine and 1,3-dicarbonyl compounds,16 the cyclization reaction between α,β-unsaturated ketones and amidines (Figure 1A),17 the domino reaction of acyl chlorides and 1,3-diazabutadienes,18 the cyclization reaction of amides and β-enaminone derivatives,19 the one-pot reaction of iminoureas, aldehydes, and α-cyanoketones,20 the condensation of amidines with two components such as N,Ndimethylformamide and styrene,21 aldehydes and aryl alkynes (Figure 1B),22 and the precursors of carbonyl compounds like alcohols (Figure 1C).23 In addition, pyrimidine derivatives were also synthesized via the annulation reaction of amidines with propargylic alcohols promoted by microwave irradiation24 and with saturated ketones catalyzed by transition metals.25 Despite numerous reported studies of the synthesis of pyrimidine derivatives, these methods still have many shortcomings such as the use of expensive and water-sensitive transition metal catalysts,25 the use of multistep reactions,18 © XXXX American Chemical Society

Figure 1. Reported reactions for the formation of multisubstituted pyrimidines (A−C) and our attempts (D).

the use of microwave irradiation,24 and unavailable substrates and/or reagents.19 Therefore, the exploration of novel reactions for the preparation of multisubstituted pyrimidines from simple, readily available starting materials by using the mild reaction condition is quite a challenge. To develop an efficient synthesis of polysubstituted pyrimidines, we focused our attention on atom-efficient and sustainable reactions. However, the most common approach for the preparation of polysubstituted pyrimidines still employs the cyclization reaction between carbonyls and amidines, which are more atom-economical and durable than their classical counterparts, wherein 2-acyl-1-cyanocyclopropanecarboxylates react as synthetic equivalents of β-diketones; like the synthesis of pyridimines with benzyl substituents (Figure 1D), common Received: April 24, 2019

A

DOI: 10.1021/acs.orglett.9b01436 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Table 1. Reaction Conditions for the Synthesis of 3aa

methods for pyrimidine synthesis are usually inefficient for the preparation of such compounds. Donor−acceptor cyclopropane (D-A cyclopropane) chemistry has advanced considerably in recent years.26 D−A cyclopropanes as C3 synthons were used widely for the total synthesis of natural compounds and important bioactive compounds.27 The diversifying ring-opening reactions rely heavily on the diversified polar C−C bonds of the cyclopropane ring under different conditions,26,27 to yield multifarious 1,3-dipoles that afford the diversified cyclization reactions and different reacting partners, offering effective ways to prepare the diverse and valuable compounds.28 Among D−A cyclopropanes, 2-acyl-1-cyanocyclopropane-1-carboxylates and 2-acylcyclopropane-1,1-dicarbonitriles are readily available from acylmethylpyridinium salt with 2-cyano-3-aryl acrylates or 2-benzylidenemalononitriles.29 The numerous very fruitful studies of D−A cyclopropanes with a carbonyl in this field have recently attracted considerable attention, leading to multifarious 1,3-dipoles in combination with a carbonyl via regioselective C−C cleavages enabling the synthesis of products with increased structural diversity and complexity.30 On the basis of our previous studies employing D−A cyclopropanes with a carbonyl in cycloadditions,30 we speculated that improving the nucleophilic condition to a carbonyl would lead to highly regioselective C−C cleavages to yield diverse processes. Motivated by the therapeutic potential of biologically active pyrimidine products, we strategically chose 2-acyl-1-cyanocyclopropane-1-carboxylates as our synthons.31 To the best of our knowledge, the cyclization reactions of 2-acyl-1-cyanocyclopropane-1-carboxylates with amidines are not reported. In this communication, we contribute the stereocontrolled preparation of diversified pyrimidine derivatives through a tandem nucleophilic addition/regioselective ring opening/intramolecular cycloaddition of 2-acyl-1-cyanocyclopropanecarboxylates with amidines (Figure 1D). Herein, as part of our ongoing research based on acylcyclopropanes for the new cyclization reactions to synthesize the important bioactive heterocycles, we envisioned that D−A acylcyclopropanes should be used as efficient electron-deficient-like enone motifs to trap the amidines through annulation reaction to form easily the pyrimidine skeleton. After preliminary experiments, the envisioned synthetic plan was demonstrated as feasible, and further extensive optimization followed. First, the different reaction conditions were used for the cyclization reaction of amidine 2a and acylcyclopropane 1a. The results are listed in Table 1. Among the basic reagents employed (Table 1, entries 1−6), in acetonitrile, under refluxing, DBU provided the best yield, 75% (Table 1, entry 2), when compared to those of the other bases (Table 1, entries 1 and 3−6). Surprisingly, only Et3N does not work (Table 1, entry 1). A number of inorganic bases are effective for this transformation (Table 1, entries 4−6). However, NaOH was used for the reaction to afford a black messy mixture, and product 3a was obtained in an only 47% yield. The reason is the strongly basic nature of NaOH, and the cyano, ester groups, and cyclopropane unit are easily destroyed to afford unpredictable side reactions. Next, different amounts of DBU were evaluated (Table 1, entries 7 and 8), but all performed less efficiently than the previous amount of 1 equiv (Table 1, entry 2). Obviously, while 0.5 equiv of DBU was used, the intermediate amidine

entry

base (equiv)

solvent

temp (°C)

time (h)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15c

Et3N (1.0) DBU (1.0) DABCO (1.0) K2CO3 (1.0) Cs2CO3 (1.0) NaOH (1.0) DBU (0.5) DBU (1.5) DBU (1.0) DBU (1.0) DBU (1.0) DBU (1.0) DBU (1.0) DBU (1.0) DBU (1.0)

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN DMF EtOH THF toluene cyclohexane CH3CN CH3CN

reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux 70 90

16 10 14 10 10 12 10 10 10 18 18 18 18 12 10

trace 75 32 54 59 47 54 45 62 0 trace 0 0 67 54

a

Reaction conditions: cyclopropanes 1a (1.0 mmol), 1/1 1a/2a molar ratio, solvent (15 mL). bIsolated yields. cSealed tube.

formed incompletely from amidine salt, thus affording also a low yield for this transformation (Table 1, entry 7). In contrast, when the amount of DBU increased to 1.5 equiv, the product yield of 3a did not display an improvement, and the excess DBU is highly susceptible to an opening ring reaction of partially substituted cyclopropane first. Various common solvents, including DMF, EtOH, THF, toluene, and cyclohexane, were further utilized in the reaction. However, our results showed that the most effective solvent was CH3CN (Table 1, entries 2 and 9−13). When the temperature was decreased to 70 °C, the yield of 3a decreased rapidly (Table 1, entry 14). Furthermore, an only 54% yield of 3a was obtained when the temperature was increased to 90 °C in sealed tube (Table 1, entry 15), because a ring opening reaction of partially substituted cyclopropane occurred first at 90 °C to add a side reaction.31a The optimization revealed that the best reaction conditions were followed by using DBU (1.0 equiv) in CH3CN under reflux for 10 h (Table 1, entry 2). Next, the optimal reaction conditions were used (Table 1, entry 2), we have studied various acylcyclopropane carboxylates and various amidine hydrochlorides to furnish the corresponding pyrimidine derivatives as shown in Table 2. The scope of the acylcyclopropanecarboxylate component was briefly investigated first. The cyclization reaction of amidine with various acylcyclopropanecarboxylates in aromatic rings containing OMe, Me, OPh, Cl, and Br furnished the corresponding substituted compound in good yields (Table 2). The results indicated that the electron-donating group or electron-withdrawing group substitution on the aryl ring has no significant effect on the outcome of the cyclization. Additionally, we also used the starting material with the pNO2 substituent on Ar1 for the cyclization reaction with amidine, but the expected product was not obtained; we thought that because the p-NO2 substituent of reactants possesses the special conjugate effect and electronic effect to lead to an unusual reaction, and our previous reports have B

DOI: 10.1021/acs.orglett.9b01436 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 2. Synthesis of Substituted 4-Benzyl-2-alkyl-6arylpyrimidines 3a−3aaa

entry

R1

R2

Ar(R)

time (h)

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

o-Cl p-Cl o-Cl o-Br p-Br p-Cl o-Br m-Cl m-Cl o-Br p-Cl p-Cl p-Me m-Cl o-Cl thiophen-3-yl p-Cl p-Br m-PhO o-Br p-Cl p-Br m-PhO p-Cl p-Cl p-Br p-Cl

p-Me p-Br p-Cl p-Br p-Cl p-Br p-Cl p-Cl H p-MeO p-Me p-MeO H p-Br p-Me p-Cl p-Cl p-Br p-Cl p-Br p-Br p-Cl p-Cl p-Br p-Cl p-Me p-Br

C6H5 C6H5 C6H5 C6H5 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4 p-BrC6H4 p-BrC6H4 p-BrC6H4 p-BrC6H4 p-MeC6H4 p-MeC6H4 Me Me

10 9 8.5 10 11 10 11.5 10.5 10 12 10 10 10.5 10 12 10 11 10 12 8.5 10 9.5 12 9.5 10 12 12

yield (%)b 75 75 71 73 83 85 79 77 75 79 71 72 76 74 77 58 79 76 64 77 78 81 61 73 69 59 58

(3a) (3b) (3c) (3d) (3e) (3f) (3g) (3h) (3i) (3j) (3k) (3l) (3m) (3n) (3o) (3p) (3q) (3r) (3s) (3t) (3u) (3v) (3w) (3x) (3y) (3z) (3aa)

Figure 2. Crystal structure of compound 3e with 30% ellipsoid probability.

Scheme 1. Mechanistic Rationalization for the Synthesis of Substituted 4-Benzyl-2-alkyl-6-arylpyrimidines

carbonyl of substrate 2-acyl-1-cyanocyclopropane-1-carboxylates to give an iminium intermediate [A]. The subsequently selective C−C bond cleavage of 1-cyanocyclopropane-1carboxylate was likely due to its iminium as an electrondeficient unit promoting a selective C−C bond cleavage event, which led to a carbonium ion intermediate [B]. Because intermediate [B] was highly unstable, the easy elimination of the ethoxycarbonyl group as carbon dioxide and chloroethane afforded a conjugate cyanobutadiene intermediate [C]. A subsequent N-but-2-en-1-ylidenebenzimidamide ion [D] with a stable conjugate system was obtained via the formation of an iminium salt, via which intermediate [D] underwent a cyclization step via intermolecular Michael addition to yield a cyanodihydropyrimidine intermediate [E]. Finally, after removal of hydrogen cyanide, the aromatization of intermediate [E] produced the desired products 3a−3aa. In summary, we have presented a new activation mode for acylcyclopropanes resulting in an unprecedented annulation for the preparation of substituted pyrimidine derivatives. This reaction gives a practical method for affording a diverse set of pyrimidines, having simple experimentation, readily available starting materials, a wide substrate scope, and very good yields.

a

Reaction conditions: acylcyclopropanes 1a−1u (1 mmol), amidines 2a−2e (1 mmol), DBU (152 mg, 1 mmol), MeCN (15 mL), reflux, 8.5−12 h. bIsolated yield.

shown the divergence.32 Moreover, steric hindrance has a slight effect on the cyclization reaction; the yields of orthosubstituted acylcyclopropanecarboxylates were slightly lower than those of para- and meta-substituted compounds (Table 2, 3a, 3c, 3d, 3g, and 3o). In addition, a heterocycle-containing acylcyclopropanecarboxylate such as 3-thiophenyl-1-cyanocyclopropane-1-carboxylate also afforded the corresponding pyrimidine derivative (3p) in moderate yield. As both electron-donating groups (Me) and electron-deficient groups (Br and Cl) are present in the aryl amidines, the desired pyrimidine derivatives were obtained in good yields. It is delightful to mention that the aliphatic amidine could also be used in the cyclization reaction to give the corresponding pyrimidine derivatives (3z and 3aa) in 59% and 58% yields, respectively. The structure of 3e (Figure 2) was firmly established by X-ray diffraction analysis, which indicates that there are two aromatic rings, one benzyl group, and a new central pyrimidine ring in 3e. On the basis of the results described above, in ref 18, and in our previous work,30,31 we proposed a possible mechanism for the formation of polysubstituted pyrimidines (Scheme 1). In the presence of DBU, amidine hydrochlorides first formed a free base amidine, which underwent a nucleophilic addition to

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01436. C

DOI: 10.1021/acs.orglett.9b01436 Org. Lett. XXXX, XXX, XXX−XXX

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Detailed experimental procedures of substituted pyrimidines 3a−3aa, crystal structure data of compound 3e, characterization data of compounds, and copies of NMR spectra (PDF) Accession Codes

CCDC 1886517 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Cunde Wang: 0000-0001-5561-979X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (21173181), the Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (PPZY2015B112), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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REFERENCES

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DOI: 10.1021/acs.orglett.9b01436 Org. Lett. XXXX, XXX, XXX−XXX

Letter

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DOI: 10.1021/acs.orglett.9b01436 Org. Lett. XXXX, XXX, XXX−XXX