Boric Ester and Thiourea as Coupling Partners in a Copper-Mediated

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Boric Ester and Thiourea as Coupling Partners in a Copper-Mediated Oxidative Dehydrosulfurative Carbon−Oxygen Cross-Coupling Reaction Hyeji Kim,† Jihong Lee,† Hyunik Shin,‡ and Jeong-Hun Sohn*,† †

Department of Chemistry, College of Natural Sciences, Chungnam National University, Dajeon 305-706, Korea Yonsung Fine Chemicals R&D Center, 602 Innoplex 2, 306 Sinwon-ro, Yeongtong-gu, Suwon 443-380 Korea

‡

S Supporting Information *

ABSTRACT: A copper-mediated oxidative dehydrosulfurative carbon−oxygen cross-coupling reaction with boric ester and sixmembered cyclic thiourea for single-step production of densely substituted 2-alkoxypyrimidines incorporated in a privileged scaffold is described. This is the first demonstration of boric ester acting as an alkoxy donor in a metal-catalyzed coupling reaction to produce ether. The reaction method offers a shortcut for producing 2-alkoxypyrimidine derivatives with rapid diversification and expands the utility of boric ester and the scope of Liebeskind−Srogl-type reactions.

T

hydride elimination side-reactions for aliphatic 1° or 2° alcohols as well as the steric bulkiness of 3° alcohols.8 Transition-metal-catalyzed cross-coupling reactions with organoboron compounds have been a popular approach for the synthesis of target molecules.9 These reactions mostly employ boronic acids, boronic esters, boronates, borate salts, and boronamides as coupling partners. Despite their versatility, the organoboron compounds have rarely been used in C−O cross-couplings. Only boronic acids or esters and borate salts have been used in the reactions (Scheme 1).10−14 Herein, we report a novel copper-mediated oxidative dehydrosulfurative C−O cross-coupling reaction between DHPM and boric ester

he pyrimidine moiety has been of long-standing interest in organic and medicinal chemistry because of its role as a critical substructure in many drugs and natural products.1 The extensive research into this highly versatile template has resulted in several drugs being introduced onto the market, such as the hypocholesterolemic agent rosuvastatin (Crestor) and the potent anticancer drug imatinib (Gleevec).2 In addition to the privileged scaffold, which acts as a key binding fragment to their biological targets, the pyrimidine motifs have been used as molecular probes in studies of chemical/biological interfaces.3 Despite their high importance to these research areas, strategies for synthesizing the various pyrimidine derivatives are limited in terms of their scope and generality with respect to the functionalization of densely substituted varieties. For the shortcut access to pyrimidine derivatives, we have focused on the 6-membered thiourea compounds as electrophilic partners in transition-metal-catalyzed cross-coupling reactions. Since Kappe’s pioneering work,4 much attention has been paid to thiourea, thioamide, and thiourethane fragments bearing latent free-thiol functionalities as coupling partners in Pd-catalyzed/Cu-mediated dehydrosulfurative C−C cross-couplings,5 as a notable extension of the Liebeskind− Srogl reaction.6 We have recently developed a cascade reaction method for the oxidative dehydrosulfurative C−C or C−N cross-coupling of 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) with boronic acids or amines under a Pd/Cu catalytic system to synthesize diverse C2-arylated or -aminated pyrimidines.7 The success of these reaction protocols inspired us to explore oxidative dehydrosulfurative C−O cross-couplings to produce 2-alkoxypyrimidines with rapid diversification. Despite the existence of versatile reactions to form C−C and C−N bonds, methodologies for the metal-catalyzed C−O coupling reactions usually with aryl halides or related leaving groups and alcohols are still limited due to competing β© XXXX American Chemical Society

Scheme 1. C−O Cross-Coupling with Organoboron Compounds

Received: February 11, 2018

A

DOI: 10.1021/acs.orglett.8b00502 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

needed to facilitate desulfuration via Cu coordination to S for facile ligand exchange in desulfurative C−C cross-coupling with a thioamide fragment.4b This led us to test the reaction with three equivalent Cu sources. There was no increase in the reaction yield when a CuTC/Cu(OTf)2 (2/1) mixture was used, but the yield from the reaction with CuTC/CuSCN (2/ 1) mixture increased slightly, compared with the case of Cu(OTf)2 or CuSCN alone (entries 4 and 5). These results encouraged us to optimize the reaction further by varying the reaction parameters under the CuTC/CuSCN system. We observed that Cs2CO3 was superior to other bases examined in the studies, such as K2CO3, LDA, t-BuOK, CsF2, and K3PO4 (entries 6−10). A lower amount of Cs2CO3 reduced the yield of the reaction with the remaining starting material (entry 11). When the solvent effect was investigated, DMF was better than DMA or PhMe (entries 12 and 13). Next, we varied the CuTC/CuSCN ratios in 3.0 equiv of Cu, which did not improve the reaction yield (entries 14−16). However, we observed that the yield of the desired product could be increased to 71% or 79% by increasing the amount of either CuSCN or CuTC by 0.5 or 1.0 equiv, respectively (entries 17 and 18). Based on these results, we proceeded to test the reaction with a CuTC/CuSCN (3.0/1.5) mixture and obtained an 87% yield (entry 19). When the reaction was conducted under oxygen, which enabled for a catalytic process in the Chan−Evans−Lam reaction,10c the results of the reaction were messy (entry 20). Under the optimal reaction conditions, we assessed the scope of this reaction with various commercially available trialkylborates (Figure 1). When the reactions of DHPM 1a with 1°

(borate) to produce 2-alkoxypyrimidine derivatives in a single step. Boric esters are usually used as reagents in the preparation of the organoboron coupling partners mentioned above.15,16 Implementation of this reaction can offer very rapid diversification of 2-alkoxypyrimidine derivatives because the well-known Biginelli three-component reaction allows us to easily prepare readily available DHPMs with diverse C4−C6 substituents.17 Our initial studies were performed with DHPM 1a and (nPrO)3B (1.5 equiv) in the presence of Pd(PPh3)4 (15 mol %), Cu(I)-thiophene-2-carboxylate (CuTC, 3.0 equiv) and K2CO3 (3.0 equiv) in DMF at 100 °C under Ar to produce a 19% yield of the desired product 2a. We proceeded to conduct subsequent optimization studies, which afforded a maximum product yield of 39%. Over the course of our studies, we discovered the interesting result that the desired product could be obtained without Pd. After this discovery, we directed our efforts toward establishing the optimal reaction conditions in the absence of Pd (Table 1). Instead of CuTC, which gave a Table 1. Optimization of Reaction Conditionsa

entry

Cu (equiv)

base

solvent

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11c 12 13 14 15 16 17 18 19 20d

CuTC (3.0) Cu(OTf)2 (3.0) CuSCN (3.0) CuTC/Cu(OTf)2 (2.0/1.0) CuTC/CuSCN (2.0/1.0) CuTC/CuSCN (2.0/1.0) CuTC/CuSCN (2.0/1.0) CuTC/CuSCN (2.0/1.0) CuTC/CuSCN (2.0/1.0) CuTC/CuSCN (2.0/1.0) CuTC/CuSCN (3.0/1.5) CuTC/CuSCN (2.0/1.0) CuTC/CuSCN (2.0/1.0) CuTC/CuSCN (1.5/1.5) CuTC/CuSCN (1.0/2.0) CuTC/CuSCN (1.0/1.5) CuTC/CuSCN (2.0/1.5) CuTC/CuSCN (3.0/1.0) CuTC/CuSCN (3.0/1.5) CuTC/CuSCN (3.0/1.5)

Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 K2CO3 LDA t-BuOK CsF2 K3PO4 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3

DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMA PhMe DMF DMF DMF DMF DMF DMF DMF

16 51 63 50 67 56 0 14 60 42 69 31 trace 47 45 41 71 79 87 messy

Figure 1. Scope of the reaction with respect to trialkylborate. Reaction conditions: 1a, (RO)3B (1.5 equiv), CuTC (3.0 equiv), CuSCN (1.5 equiv), Cs2CO3 (3.0 equiv), DMF at 100 °C for 9−12 h under Ar. Yields are isolated yields. (a) (MeOBpin) instead of (MeO)3B was used.

a

Reaction conditions: 1a, (n-PrO)3B (1.5 equiv), base (3.0 equiv) at 100 °C for 9−12 h under Ar. bIsolated yield. cWith 2.0 equiv of Cs2CO3. dUnder O2.

16% yield of the desired product (entry 1), we investigated other Cu sources. From the alternative Cu sources, Cu(OTf)2 and CuSCN significantly increased the reaction yields, to 51% and 63%, respectively (entries 2 and 3). We then investigated whether the reaction yield could be increased further, using mixtures of each of these two and CuTC. CuTC has been the representative reagent for desulfurative C−C cross-coupling reactions since the development of the Liebeskind−Srogl reaction and gave the best results in our previous oxidative dehydrosulfurative C−C and C−N cross-couplings.7 According to the proposition by the Kappe group, 2−3 equiv of CuTC is

alkylborates were accomplished, ethoxy- (2c, 71%), n-butoxy(2d, 87%), and n-hexoxypyrimidine (2e, 81%) were obtained in good yields. In the case of trimethylborate, the desired product 2b was produced in low yield (26%), which is presumably due to the low boiling point of the borate. However, this could be overcome by using 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (MeOBpin), instead of trimethylborate, which afforded 75% yield of the product. The 2° alkylborate, (iPrO)3B, gave pyrimidine 2f in 67% yield. We did not observe the carbonyl compound corresponding to the competing side B

DOI: 10.1021/acs.orglett.8b00502 Org. Lett. XXXX, XXX, XXX−XXX

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the halides. When the DHPM possesses a bicycle or heterocycle at the C4, such as 2-naphthyl or 2-thiophenyl groups, the desired product 3f or 3g was obtained in 74% or 55% yield, respectively. In the case of the thiophenyl group, the reaction exhibited a higher yield when the Me group at the C6 position was replaced by the Ph group (3h, 72%). We also investigated the effect of varying the substituent of the aryl at the C4 position when a Ph group was used at the C6 position. In addition to the parent Ph group, which gave 3i in high yield, the substituents at the para position of C4 aryl, such as a NO2, Br, or OMe group, afforded the corresponding products 3j−l in 75−92% yields. For the substituents at the ortho or meta positions of the C4 aryl, the desired products 3m−o were also obtained in 71%−94% yields. The substituent, n-Pr or i-Pr, at the C6 position afforded the desired product 3p or 3q, respectively, in moderate yield in the reaction with (n-PrO)3B. We also investigated the scope of the reaction method with various DHPMs, and 2° and 3° alkylborates. We obtained the desired products 4a−f in moderate to high yields (57−90%) when various DHPMs were reacted with (i-PrO)3B. The above DHPMs and (t-BuO)3B, yielding the corresponding products, 4g−k, in 53%−75% yield, were also compatible as the partners for the new reaction. We also evaluated whether triarylborate is available as a coupling partner for this reaction. When DHPM 1a reacted with triphenylborate under the reaction conditions, the desired product 5 was obtained in 76% yield (Scheme 2). In

product in either case. The sterically bulky (t-BuO)3B, giving the desired product 2g, was also compatible with the reaction, though with lower yields than 1° and 2° borate.18 We assessed the scope of the reaction with respect to the DHPM substrate by varying substituents at the C4−C6 positions (Figure 2). DHPM with no substituents at the C5

Scheme 2. Reaction with Triphenylborate

comparison to the usual multiple steps required to prepare the substituted 2-alkyl(aryl)oxypyrimidines, and with there being no reports on the tertiary alkoxypyrimidines, the current reaction method provides unprecedented efficiency for the synthesis of 1°, 2°, and 3° 2-alkoxypyrimidines and 2aryloxypyrimidines.19 In order to understand the mechanism of the reaction, we carried out the reaction of the DHPM possessing a t-Bu group at the C4 position to yield the debutylated product 7 as the major product (Scheme 3, eq 1). This result suggests that the generation of a radical is involved in the aromatization, as described in previous reports on the oxidative dehydrogenation of 2-alkylthiodihydropyrimidine with a t-Bu group at the C4 position.20 We also observed that the reaction of 2-mercaptopyrimidine 8 gave the corresponding product 9 (eq 2, Scheme 3) and the reaction of substrate 10 proceeded via intermediate 11, prior to the C−O cross-coupling (eq 3), which implies that the reaction proceeds via tautomerization and aromatization of the substrate, followed by C−O cross-coupling. We also observed that 2-thiocyanatopyrimidine 12 was produced in the absence of the boric ester (eq 4), and only a trace amount of the desired product was obtained in the presence of moisture. In addition, the reaction of 12 with (n-BuO)3B produced butoxypyrimidine 2d.21 On the basis of these results, it seems likely that stoichiometric CuSCN is needed to produce 2-thiocyanatopyrimidine as an intermediate that facilitates the reaction due to

Figure 2. Scope of the reaction with respect to DHPM and trialkylborate. Reaction conditions: 1, (RO)3B (1.5 equiv), CuTC (3.0 equiv), CuSCN (1.5 equiv), Cs2CO3 (3.0 equiv), DMF at 100 °C for 9−12 h under Ar. Yields are isolated yields.

and C6 positions resulted in the corresponding product 3a in 86% yield. When the effect of the substituents at the C4 position of DHPM was investigated in the reaction with (nPrO)3B, the aryl moiety possessing halide groups, F and Br, at the para position afforded 3b and 3c in 46% and 50% yields, respectively. Electron-donating methoxy and methyl groups at the para position of C4 aryl gave 3d and 3e in 79% and 67% yields, respectively, which are higher than those in the case of C

DOI: 10.1021/acs.orglett.8b00502 Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 3. Related Reaction Studies

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00502. Detailed experimental procedures and characterization data of compounds and their 1H and 13C NMR spectra (PDF)

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REFERENCES

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enhanced leaving group character of thiocyanato group for the C−O cross-coupling. In summary, we developed a copper-mediated oxidative dehydrosulfurative carbon−oxygen cross-coupling reaction between boric ester and a six-membered cyclic thiourea, DHPM, to produce densely substituted 2-alkoxypyrimidines in a single step. The reaction method proceeded well with a wide range of DHPM and 1°, 2°, and 3° alkylborates as coupling partners. This is the first example showing that boric ester can act as an alkoxy donor in metal-catalyzed coupling reactions to produce ether. The reaction method offers a shortcut for producing 2-alkoxypyrimidine derivatives incorporated in a privileged scaffold with rapid diversification. Furthermore, this chemistry expands the utility of boric ester and the scope of Liebeskind−Srogl-type reactions.

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Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jeong-Hun Sohn: 0000-0001-8800-7941 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the NRF grant (NRF2017R1A2B2003614). D

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