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Synlett 2010(17): 2611-2616  
DOI: 10.1055/s-0030-1258803
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Easy and Efficient Copper-Catalyzed Synthesis of Bicyclic Pyrimidinones under Mild Conditions

Qi Guoa, Haijun Yanga, Hongxia Liub, Yuyang Jiangb, Hua Fu*a
a Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, P. R. of China
b Key Laboratory of Chemical Biology, Guangdong Province, College of Shenzhen, Tsinghua University, Shenzhen 518057, P. R. of China
Fax: +86(10)62781695; e-Mail: fuhua@mail.tsinghua.edu.cn;

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Publication History

Received 22 July 2010
Publication Date:
30 September 2010 (online)

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Abstract

A simple and efficient copper-catalyzed method has been developed for synthesis of bicyclic pyrimidinones containing six-, seven-, eight-membered rings under mild conditions. The protocol uses readily available 2-bromocycloalk-1-enecarboxylic acids, amidines, and guanidines as the starting materials, copper-catalyzed cascade couplings provide the corresponding bicyclic ­pyrimidinones without addition of any ligand or additive, and the method is of economical and practical advantages.

Key words

copper - cascade reaction - bicyclic pyrimidinone - nitrogen heterocycle - synthetic method

The pyrimidinones and their derivatives are ubiquitous in natural products, pharmaceuticals, and functional materials. [¹] For example, research at Merck has led to the identification of raltegravir potassium (A in Figure  [¹] ), [²] a potent and well-tolerated HIV-1 integrase inhibitor that targets strand transfer, the second of two catalytic cycles mediated by the integrase enzyme. [³] Bicyclic pyrimidones have been identified as potent HIV integrase inhibitors endowed with desirable preclinical features, and amongst them hexahydropyrimido[1,2-a]azepine-2-carboxamide derivative proved particularly interesting. [4] Very recently, Muraglia and co-workers have developed a new kind of bicyclic pyrimidinones as potent and orally bioavailable HIV-1 integrase inhibitors (IC50 = 12 nM for compound B in Figure  [¹] ). [5] 5,8-Dideaza-5,6,7,8-tetrahydrofolic acid (C in Figure  [¹] ) and 2-substituted tetrahydroquinazolinones have attracted considerable attention in chemistry [6] and biology. [7] A wide range of biological activities have been discovered for such compounds, such as anticancer activity, antimicrobial activity against Streptococcus faecium, inhibition of dihydrofolate reductase and thymidilate synthase, [8] as well as an ability to be good substrates for partially purified mouse liver folylpolyglutamate synthetase. [9] Compound D in Figure  [¹] was found to be a highly potent inhibitor of poly(ADP-ribose) polymerase-1 (PARP-1). [¹0] On the other hand, the substituted 4(3H)-pyrimidinones are the key intermediates to the preparation of the bioactive pyrimidines that are of wide biological or medicinal activities. [¹] Therefore, it is very desirable to develop readily preparation of pyrimidinone derivatives.

Figure 1 Examples of biologically or medicinally active pyrimi­dones

There are several known preparative routes to pyrimidone dervatives. [9-¹¹] For example, de Meijere and co-workers have developed an approach to such compounds by way of Michael addition of amidines to methyl 2-chloro-2-­cyclopropylideneacetate, [¹²a] with ring-enlarging rearrangement to yield cyclobutene-annelated pyrimidinones, which subsequently undergo thermal cyclobutene ring opening followed by Diels-Alder reaction. [¹²b] Thermal ­cyclobutene ring opening of the latter at 175 ˚C followed by regioselective Diels-Alder cycloaddition with phenyl vinyl sulfone gives the 2-aryl-6-(phenylsulfonyl)-5,6,7,8-tetrahydroquinazolinone derivatives. [¹²c] However, the substrate scope is very limited for the construction of ­bicyclic pyrimidinones by the above method. The wide applications of bicyclic pyrimidinone derivatives as biological and medicinal active molecules have stimulated our research into the development of new strategy for their synthesis. Recently, copper-catalyzed Ullmann N-arylations have made great progress, [¹³] and the N-arylation strategy has been used to make N-heterocycles. [¹4] Unfortunately, these methods sometimes cannot be used to construct functionalized molecules because the reaction temperature is still too high, so it is highly desirable to develop milder copper-catalyzed methods. Recently, we [¹5] and other groups [¹6] have developed copper-catalyzed N-arylations at room temperature, and the results showed that efficiency of the copper-catalyzed coupling reactions highly depended on the involvement of the suitable ligands. In continuation of our endeavors to develop copper-catalyzed cross-couplings [¹7] and synthesis of N-heterocycles, [¹8] herein, we report an easy and efficient copper-catalyzed synthesis of bicyclic pyrimidinones without addition of any ligand or additive under mild conditions.

At first, 2-bromocyclohex-1-enecarboxylic acid and butyramidine hydrochloride were used as the model substrates to optimize reaction conditions including the catalysts, bases, and solvents under nitrogen atmosphere. As shown in Table  [¹] , four copper catalysts were screened at room temperature in the presence of two equivalents of Cs2CO3 (relative to amount of 2-bromocyclohex-1-enecarboxylic acid) in DMF (entries 1-4), and CuI showed the best activity (entry 2). No target product was obtained in the absence of copper catalyst (entry 5). Other bases, K2CO3 and K3PO4, were tested, and Cs2CO3 was the most effective base (compare entries 2, 6, and 7). The cascade coupling yield decreased as amount of base reduced (compare entries 2 and 8), and the reaction did not work in the absence of base (entry 9). The effect of solvents was also investigated (compare entries 2, 10-15), and DMF provided the highest yield (entry 2). Only trace amount of pyrimidinone 3a was observed under air (entry 16).

Table 1 Copper-Catalyzed Synthesis of 2-Propyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one via Cascade Coupling of 2-Bromocyclohex-1-enecarboxylic Acid with Butyramidine Hydrochloridea

Entry Catalyst Base Solvent Yield (%)b
 1 CuSO4 Cs2CO3 DMF  8
 2 CuI Cs2CO3 DMF 65
 3 CuBr Cs2CO3 DMF 42
 4 Cu2O Cs2CO3 DMF 63
 5 - Cs2CO3 DMF tracec
 6 CuI K2CO3 DMF 53
 7 CuI K3PO4 DMF trace
 8 CuI Cs2CO3 DMF 47d
 9 CuI - DMF trace
10 CuI Cs2CO3 MeCN 46
11 CuI Cs2CO3 dioxane trace
12 CuI Cs2CO3 DMSO 40
13 CuI Cs2CO3 EtOAc  0
14 CuI Cs2CO3 toluene  0
15 CuI Cs2CO3 H2O 25
16 CuI Cs2CO3 DMF tracee
a Reaction conditions: 2-bromocyclohex-1-enecarboxylic acid (0.5 mmol), butyramidine hydrochloride (0.6 mmol), catalyst (0.025 mmol for Cu2O; 0.05 mmol for the others), base (1 mmol), solvent (1 mL) at r.t. (ca. 25 ˚C) under a nitrogen atmosphere.
b Isolated yield.
c No addition of catalyst.
d Base (0.5 mmol).
e Under air.

We investigated the scope of copper-catalyzed cascade reactions of 2-bromocycloalk-1-enecarboxylic acids with amidines and guanidines under our optimized conditions (10 mol% CuI as the catalyst, 2 equiv of Cs2CO3 as the base, and DMF as the solvent). [¹9] As shown in Table  [²] , the amidines were converted into the products in good yields at room temperature, and cyclopropanecarboxamidine and isonicotinamidine exhibited higher reactivity than other amidines. Guanidines also provided the corresponding bicyclic pyrimidinones in moderate to good yields when temperature was raised to 40 or 50 ˚C (entries 6, 7 13, and 19). For the 2-bromocycloalk-1-enecarboxylic acids containing six-, seven-, and eight-membered rings, their reactive activity did not show any notable difference.

A possible formation mechanism of bicyclic pyrimidinones was proposed in Scheme  [¹] . Coordination of 2-bromocycloalk-1-enecarboxylic acid with CuI first forms I in the presence of base (Cs2CO3). Oxidative addition of I yields II, and complexation of II with amidine or guanidine gives coordinate III, and reductive elimination of III provides N-arylation product IV releasing copper catalyst. The ortho substituent effect were found in copper-catalyzed Ullmann-type couplings by us [¹8] and other groups. [²0] Finally, coupling of the carboxyl and amino of amidino in IV affords the target product 3. [²¹]

In summary, we have developed a simple and efficient copper-catalyzed method for the synthesis of bicyclic pyrimidinones containing six-, seven-, and eight-membered rings. The cascade reactions of 2-bromocycloalk-1-enecarboxylic acids with amidines or guanidines were performed well under very mild conditions (r.t. to 50 ˚C) without addition of any ligand or additive, and the target products were obtained in good yields. The present method provides opportunity for screening of diverse and useful biological and medicinal molecules.

Scheme 1 Possible formation mechanism of bicyclic pyrimidinones

Table 2 Copper-Catalyzed Synthesis of Bicyclic Pyrimidinonesa (continued)

Entry 2 Time (h) Product (3) Yield (%)b
1

2a 		2

3a 		80
2

2b 		2

3b 		66
3

2c 		1

3c 		65
4

2d 		2

3d 		62
5

2e 		3

3e 		84
 6

2f 		2

3f 		60c
 7

2g 		6

3g 		45d
 8 2a 0.5

3h 		71
 9 2b 2

3i 		72
10 2c 2

3j 		67
11 2d 2

3k 		75
12 2e 3

3l 		80
13 2f 2

3m 		65c
14 2a 0.5

3n 		82
15 2b 2

3o 		73
16 2c 2

3p 		63
17 2d 1

3q 		78
18 2e 3

3r 		82
19 2f 2

3s 		76c
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), CuI (0.05 mmol), Cs2CO3 (1 mmol), DMF (3 mL) at r.t. (ca. 25 ˚C) under a nitrogen atmosphere.
b Isolated yield.
c Reaction temperature (40 ˚C).
d Conditions: 2g (0.35 mmol), reaction temperature 50 ˚C.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.

Acknowledgment

This work was supported by the National Natural Science Foundation of China (Grant No. 20972083), Chinese 863 Project (Grant No. 2007AA02Z160) and the Key Subject Foundation from Beijing Department of Education (XK100030514).

2

Raltegravir has been approved by the FDA for the treatment of HIV/AIDS under the trademark ISENTRESS.

19

General Procedure for the Synthesis of Compounds 3a-s A two-neck round-bottom flask was charged with a magnetic stirrer, evacuated and backfilled with nitrogen. Amidine hydrochloride or guanidine hydrochloride 2a-f (0.6 mmol) or bis(guanidine)sulfate (2g, 0.35 mmol), CuI (0.05 mmol, 9.5 mg), Cs2CO3 (1 mmol, 326 mg), and DMF (1 mL) were added under nitrogen atmosphere. After a 15 min stirring, 2-bromocycloalk-1-enecarboxylic acid (1, 0.5 mmol) was added to the flask. The mixture was allowed to stir under nitrogen atmosphere at the shown temperature for some time (see Table  [²] ). After completion of the reaction, the mixture was concentrated with the aid of a rotary evaporator. The residue was purified by column chroma-tography on silica gel using PE-EtOAc or CH2Cl2-MeOH as eluent to provide the desired product.

2

Raltegravir has been approved by the FDA for the treatment of HIV/AIDS under the trademark ISENTRESS.

19

General Procedure for the Synthesis of Compounds 3a-s A two-neck round-bottom flask was charged with a magnetic stirrer, evacuated and backfilled with nitrogen. Amidine hydrochloride or guanidine hydrochloride 2a-f (0.6 mmol) or bis(guanidine)sulfate (2g, 0.35 mmol), CuI (0.05 mmol, 9.5 mg), Cs2CO3 (1 mmol, 326 mg), and DMF (1 mL) were added under nitrogen atmosphere. After a 15 min stirring, 2-bromocycloalk-1-enecarboxylic acid (1, 0.5 mmol) was added to the flask. The mixture was allowed to stir under nitrogen atmosphere at the shown temperature for some time (see Table  [²] ). After completion of the reaction, the mixture was concentrated with the aid of a rotary evaporator. The residue was purified by column chroma-tography on silica gel using PE-EtOAc or CH2Cl2-MeOH as eluent to provide the desired product.

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Figure 1 Examples of biologically or medicinally active pyrimi­dones

Scheme 1 Possible formation mechanism of bicyclic pyrimidinones