Transition-metal-free hydroamination/defluorination/cyclization of perfluoroalkyl alkynes with amidines

Li-Wen Sun a, Zi-Lun Yu a, Xin-Long Luo a, Mengtao Ma b, Zhi-Liang Shen *a and Xue-Qiang Chu *a
aInstitute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816, China. E-mail: ias_zlshen@njtech.edu.cn; xueqiangchu@njtech.edu.cn
bDepartment of Chemistry and Materials Science, College of Science, Nanjing Forestry University, Nanjing 210037, China

Received 24th September 2021 , Accepted 16th November 2021

First published on 16th November 2021


Abstract

An efficient defluorinative net-[3 + 3]-cyclization strategy for the construction of perfluoroalkyl-substituted pyrimidine derivatives by using a series of perfluoroalkyl alkynes and amidines as starting materials was developed. The present reaction proceeded successfully under transition-metal-free conditions to form two new C–N bonds and a new heterocyclic ring through a sequence of hydroamination, defluorination, and annulation. The desired pyrimidines could be obtained with good functional group tolerance and moderate to good yields. Moreover, the distinctive fluorine effects of perfluoroalkyl substituents are vital for tuning the reactivity of alkynes for the anticipated defluorinative annulation. The pendant π system would lower associated bond dissociation energy significantly compared to that of a nonactivated C(sp3)–F bond.


Introduction

Organofluorine compounds are of special importance in fields ranging from modern agrochemistry, drug discovery, clinical medicines, and materials science to organic synthesis due to the unique properties of fluorine.1 It has been well recognized that the introduction of fluorine atoms or higher homologue fluoroalkyl groups (Rf) into organic molecules can lead to dramatic changes in physical and chemical properties.2 During the past decades, considerable progress has been accomplished in trifluoromethylation using various CF3 reagents. However, its bulkier analogue, the perfluoroalkyl (Rf) group, has attracted vastly less attention, although many biologically and pharmaceutically active molecules, such as anticancer drug (Faslodex), fungicide (ZJ5337), and fungicide (Nicofluprole), contain this privileged subunit (Fig. 1).3 Additionally, highly substituted pyrimidines represent one of the most varied and largest families of N-heterocycles, which are associated with interesting activities such as PI3K inhibitor (NVP-BKM 120), antidiabetic activity (Gemigliptin), and fungicide (Fluoxastrobin).4 In this context, the development of practical and reliable approaches for the facile incorporation of both perfluoroalkyl group and pyrimidine structural motif in one molecule is urgently demanded, especially starting from readily available starting materials under mild reaction conditions.
image file: d1qo01439k-f1.tif
Fig. 1 Representative biologically active perfluoroalkylated molecules and pyrimidines.

Amidine, as a dual nucleophile bearing two nitrogen atoms, has been extensively used as a versatile building block in the preparation of diversified N-heterocyclic compounds.5 Considerable advancements pertaining to transition metal-catalyzed or metal-free condensation/oxidation cascade of amidines with 1,3-dicarbonyl derivatives,6 α,β-unsaturated ketones/aldehyde,7 propiophenones,8 allylbenzene,9 propargylic alcohols,10 or propargylic amines,11 have been made (Scheme 1, 1). Alternatively, lots of efforts have been spent on the late-stage modification of pre-existing pyrimidine counterparts through direct C–H bond functionalization by employing extra Rf-source (Scheme 1, 2a).12 However, these transformations generally suffered from the requirement of heterocyclic precursors, expensive metal catalysts, and harsh reaction conditions. In particular, the site-selectivity of perfluoroalkylation is predominantly dictated by the innate reactivity of the substrate. Recently, we found that multi-component cyclization through sequential fluoroalkylation, defluorination, and heteroannulation could provide chemists an efficient strategy to prepare perfluoroalkyl substituted pyrimidines (Scheme 1, 2b).13 In these cases, the in situ formed α-perfluoroalkylated ketones served as the key intermediates. However, transition metal-catalyst or photocatalyst were essential for the success.


image file: d1qo01439k-s1.tif
Scheme 1 Amidine as a versatile building block in the preparation of diversified N-heterocyclic compounds and related approaches for the synthesis of functionalized pyrimidines.

The introduction of fluorine atoms adjacent to the alkyne moiety can tune the reactivity of the triple C–C bonds.14 Diverse reaction modes involving one or two folds C–F bond cleavage and transformation of alkynyl functionality have been realized by the research groups of Loh,14a Feng,14a,b Wang,14c Yi,14d,e Fan,14f and Rovis14g (Scheme 1, 3). Nevertheless, the utilities of costly metal catalysts, extra additives, and harsh reaction conditions were necessary. While research interest had also been directed towards the exploration of oxidative cyclization of simple alkynes with amidines for the synthesis of imidazoles (Scheme 1, 4),15 as far as we know, the direct exploitation of perfluorinated internal alkynes via two-fold C–F bond functionalization for rapidly accessing six-membered heterocycles with spatially defined perfluoroalkyl substituent has never been reported till now. The transition-metal-free net-[3 + 3]-condensation of perfluoroalkyl alkynes and amidines has the potential to advance green and sustainable chemistry.

Continuing with our recent interests in heterocyclic chemistry,16 herein we describe a transition metal-free method for the synthesis of perfluoroalkylated pyrimidines commencing from perfluoroalkyl alkynes and amidines through a convenient sequence of hydroamination, defluorination, and annulation cascade (Scheme 1, 5). In this newly developed protocol, the perfluoroalkyl alkyne acted as an active unsaturated substrate because it could easily undergo the hydroamination under basic conditions. The success of the intramolecular ring-closure step could be attributed to the activation of C(sp3)–F bonds under the effect of the alkali–metal base.17 Moreover, the perfluoroalkyl substituents are vital for the net-[3 + 3]-heteroannulation due to their distinctive fluorine effects in tuning the reactivity of alkynes. As a result, the perfluoroalkyl group exerts both activating effect and directing effect on the annulation. This method involved new C–N bonds formation and a new six-membered ring construction, which featured broad substrate scope, good functional group tolerance, and synthetic simplicity in an eco-friendly manner.

Results and discussion

There are few examples of the intermolecular hydroamination of fluorine-substituted internal alkynes.18 Initially, we examined the reaction of (perfluorohex-1-yn-1-yl)benzene (1a)19 with benzamidine hydrochloride (2a)20 in the presence of copper catalyst, additive, and different bases in THF at 60 °C for 24 h under air atmosphere (see Table S1 in the ESI for more details). To our delight, the proposed cyclization could be successfully realized by the sole use of Cs2CO3 as the base, leading to the desired functionalized pyrimidine 3aa in 63% NMR yield (Table 1, entry 1). Evaluation of various solvents, including MeCN, DMF, DMSO, tBuOH, DCE, H2O, and toluene, led to the discovery of DMF as the optimal solvent for the aminated reaction (entries 2–8). Of different reaction temperatures examined (entries 9–12), performing the model reaction at 70 °C gave the product 3aa in the highest NMR yield (73% isolated yield; entry 11). Furthermore, DMA was found to be superior to DMF or NMP as the reaction solvent (entries 13 and 14). In addition, shortening reaction time from 24 h to 6 h was unfavorable for the complete conversion of starting material 1a, affording the corresponding product 3aa in slightly decreased yield (entry 15). Finally, the importance of perfluoroalkyl moiety and the unique fluorine effects for the net-[3 + 3]-annulation was clarified by using 1,1-difluoropropyl-, 2-ethoxy-1,1-difluoro-2-oxoethyl-, or trifluoromethyl-substituted alkynes (1a′–1a′′′) in the control experiments, which delivered low yields of the corresponding defluorinative products (entries 16–18).
Table 1 Optimization of reaction conditionsa

image file: d1qo01439k-u1.tif

Entry R Solvent Temp. (°C) Yieldb (%)
a Reaction conditions: 1a–1a′′′ (0.3 mmol), 2a (0.36 mmol), and Cs2CO3 (0.9 mmol) in solvent (1.5 mL) under air for 24 h. b Yields were determined by NMR analysis with 1,4-dimethoxybenzene (0.25 mmol) as an internal standard. c Isolated yield. d 6 h. e At 100 °C.
1 n C3F7 (1a) THF 60 63
2 n C3F7 (1a) MeCN 60 37
3 n C3F7 (1a) DMF 60 67
4 n C3F7 (1a) DMSO 60 50
5 n C3F7 (1a) t BuOH 60 37
6 n C3F7 (1a) DCE 60 33
7 n C3F7 (1a) H2O 100 0
8 n C3F7 (1a) Toluene 60 58
9 n C3F7 (1a) DMF 25 37
10 n C3F7 (1a) DMF 40 54
11 n C3F7 (1a) DMF 70 74 (73)c
12 n C3F7 (1a) DMF 80 70
13 n C3F7 (1a) NMP 70 76
14 n C3F7 (1a) DMA 70 79 (77)
15 n C3F7 (1a) DMA 70 74d (72)c
16 C2H5 (1a′) DMA 70 Trace (<5)e
17 CO2Et (1a′′) DMA 70 <5
18 F (1a′′′) DMA 70 <5 (<5)e


After obtaining the optimized reaction conditions, we began to evaluate the generality of this defluorinative cyclization with regard to diverse amidines, and the results are summarized in Table 2. First of all, a variety of substituents of varying electronic character and steric hindrance on the phenyl moieties in amidines were investigated (3ab–3al). It was found that substrates containing either electron-donating (e.g., OMe, OEt, Me) or electron-withdrawing (e.g., halogen, NO2, CN) groups could provide the desired pyrimidines 3ab–3al in moderate to good yields (54–84% yields). Notably, the ortho steric hindrance of substrate 2c did not obviously interfere with the reaction outcome (3ac). Functional groups, such as F, Cl, Br, I, NO2, and CN were well tolerated under the mild reaction conditions, which offered good opportunities for the late-stage functionalization (3af–3al). Other heteroaromatic motifs, such as pyridine-3-yl (2m), pyrimidine-2-yl (2n), and thiophen-2-yl (2o), were smoothly incorporated into the pyrimidine-based products 3am–3ao in 35–83% yields. Even alkyl-containing amidines participated well in the present transformation, leading to the corresponding products 3ap and 3aq in 76% and 50% yields, respectively. Additionally, guanidine hydrochloride was also proven to be a good candidate to give the aminated product 3ar in 39% yield. However, dual-nucleophilic 1-(3-methoxyphenyl)guanidine (2s), 1H-benzo[d]imidazol-2-amine (2t), and urea (2u) failed to produce any fluorinated products 3as–3au.

Table 2 Substrate scope of various amidines 2a
a Reaction conditions: 1a (0.3 mmol), 2 (0.36 mmol), Cs2CO3 (0.9 mmol), and DMA (1.5 mL) at 70 °C for 24 h under air; isolated yields. b 2 (0.45 mmol) was used.
image file: d1qo01439k-u2.tif


Encouraged by the above results, the general applicability of the present method for the synthesis of highly functionalized pyrimidines by employing a wide array of perfluorobutyl alkynes 1 as substrates was studied. As outlined in Table 3, not only perfluorobutyl alkynes bearing electron-donating groups but also substrates containing electron-withdrawing substituents in the aryl rings could react well with amidines 2i or 2n in a remarkably regioselective manner to produce trisubstituted products 3bi–3ii in 28–80% yields. Although 2-amidinopyrimidine hydrochloride (2n) was found to be less reactive than 2i, this resulting polycyclic aza-aromatic 3bn could not be easily accessed through traditional synthetic routes.12 Moreover, the mild reaction showed good tolerance to several functional groups, such as methoxy (1b), methyl (1c–1e), tert-butyl (1f), and halogens (1g–1i). However, the presence of a methyl group at the C2-position of phenyl ring in the substrate 1e seemed to have a negative effect on the reaction performance (3ei, 29% yield). Furthermore, alkyne 1j derived from naphthalene was tested, furnishing product 3ji in 33% yield, which is mainly due to the steric effect. Similarly, the reactions worked equally well with heteroaryl perfluorobutylethynes 1k–1l under the standard reaction conditions to give the corresponding heterocyclic variants 3ki–3li in reasonable yields.13 In addition, when (E)-(5,5,6,6,7,7,8,8,8-nonafluorooct-1-en-3-yn-1-yl)benzene (1m) was prepared and subjected to the net-[3 + 3] heteroannulation, the desired product 3mi was obtained in 60% yield. As for alkyl substrate, 5,5,6,6,7,7,8,8,8-nonafluoro-2-methyloct-3-yn-2-ol (1n) could participate into the reaction to produce the desired alkyl-substituted pyrimidine 3ni in 41% yield.

Table 3 Substrate scope of different perfluorobutyl alkynes 1a
a Reaction conditions: 1 (0.3 mmol), 2i or 2n (0.36 mmol), Cs2CO3 (0.9 mmol), and DMA (1.5 mL) at 70 °C for 24 h under air; isolated yields. b 2i (0.45 mmol) was used at 100 °C.
image file: d1qo01439k-u3.tif


Next, we turned our attention to expand the substrate scope of the reaction to encompass a spectrum of fluoroalkyl alkynes 1o–1r (Table 4). We were delighted to find that the substrates possessing different perfluoroalkyl chains (3–10 carbon) worked well to produce the products 3oi–3ri in 75%–79% yields.

Table 4 Substrate scope of different perfluoroalkyl alkynes 1a
a Reaction conditions: 1 (0.3 mmol), 2i (0.36 mmol), Cs2CO3 (0.9 mmol), and DMA (1.5 mL) at 70 °C for 24 h under air; isolated yields.
image file: d1qo01439k-u4.tif


To further demonstrate the procedural simplicity and synthetic practicability of the present method, an efficient procedure was established for the scale-up synthesis of product 3aa (Scheme 2A, 80% yield). In addition, the present method could be applied to the late-stage modification of complex molecules. As shown in Scheme 2B, perfluorobutyl derivatives of Estrone and diacetone-D-glucose could be readily accommodated with the well-established conditions to generate the target heterocycles 3sa and 3ta in 38% and 72% yields, respectively. Meanwhile, palladium-catalyzed coupling reaction of the resulting 3ai with thiophen-2-ylboronic acid (4) provided the heterocycle 5 in 96% yield (Scheme 2C), thereby having a chance for potential applications in materials science.


image file: d1qo01439k-s2.tif
Scheme 2 Scale-up synthesis and further transformations.

In order to clarify the possible mechanism of this transformation, some control experiments were carried out (Scheme 3). First, free-radical intermediate was not involved in the reaction because the addition of radical inhibitor TEMPO (2.5 equiv.) did not affect the reaction performance (Scheme 3A). Second, the deuterium-labeling experiment resulted in the generation of compound 3aa-D, suggesting that the proton atom of product might originate from water in the hydroamination process (Scheme 3B). Third, (perfluorohex-1-yn-1-yl)benzene (1a) could not be converted to fluoroalkylated ynone 6 under the standard conditions, revealing that defluorination step occurred after the intermolecular interaction of 1a and 2a (Scheme 3C). Fourth, the reaction of pre-synthesized 6 with amidine 2a generated the corresponding product 3aa in 77% yield, which further supported the above conjecture (Scheme 3D).


image file: d1qo01439k-s3.tif
Scheme 3 Mechanistic studies.

On the basis of these mechanistic insights, a plausible mechanism was proposed in Scheme 4.13–18 Initially, selective addition of amidine 2 to the triple bond of perfluoroalkyl alkyne 1 under basic conditions provides the vinyl anion A, which then abstracts a proton from water to give the hydroaminated intermediate B. The related intermediate could be detected by 1H NMR and HRMS analysis of the model reaction mixture.21 Next, an intramolecular nucleophilic substitution via the cleavage of the C(sp3)–F bond affords the ring-closure species C, which further undergoes aromatization through removing a molecule of HF with the assistance of alkali–metal base to produce the final product 3.17 Notably, the existence of the Rf group is essential for the desired net-[3 + 3]-heteroannulation of perfluoroalkyl alkynes with amidines.


image file: d1qo01439k-s4.tif
Scheme 4 Proposed mechanism.

Conclusion

In summary, we have developed an efficient defluorinative reaction of perfluoroalkyl alkynes with amidines for the facile synthesis of potentially biologically and pharmaceutically active perfluoroalkylated pyrimidines through a sequence of hydroamination, defluorination, and annulation. This modular and regioselective C–F bond functionalization, which worked efficiently under transition metal-free conditions, featured broad scope of both coupling partners, excellent functional group tolerance, synthetic simplicity, and scale-up synthesis. In the present reaction, two new C–N bonds and a new six-membered ring were simultaneously constructed in a one-pot manner. The perfluoroalkyl group exerts both activating effect and directing effect on the annulation.

Experimental

General procedures for the synthesis of perfluoroalkylated pyrimidines 3

A solution of perfluoroalkylethyne 1 (0.3 mmol), amidine hydrochloride 2 (0.36–0.45 mmol), and Cs2CO3 (293.2 mg, 0.9 mmol) in DMA (1.5 mL) was stirred at 70 °C under air for 24 h. The reaction was then quenched by saturated NH4Cl solution (20 mL) and extracted with EtOAc (20 mL × 3). The organic layer was washed with saturated brine twice, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (300–400 mesh) using petroleum ether/ethyl acetate as eluent to afford the pure products 3.

General procedure for the scale-up synthesis of product 3aa

A solution of (perfluorohex-1-yn-1-yl)benzene (1.60 g, 5 mmol, 1a), benzamidine hydrochloride (0.94 g, 6 mmol, 2a), and Cs2CO3 (4.89 g, 15 mmol) in DMA (30 mL) was stirred at 70 °C under air for 24 h. The reaction was then quenched by saturated NH4Cl solution (100 mL) and extracted with EtOAc (100 mL × 3). The organic layer was washed with saturated brine twice, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (300–400 mesh) using petroleum ether/ethyl acetate as eluent to afford the pure product 3aa (1.60 g, 80% yield).

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We gratefully acknowledge the financial support from National Natural Science Foundation of China (No. 22001121 and 21772093), Natural Science Foundation of Jiangsu Province (BK20180690), National Students’ Platform for Innovation and Entrepreneurship Training Program (202110291019Z), and Nanjing Tech University (Start-up Grant No. 39837118 and 39837146).

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  21. See the ESI for more details of in situ HRMS and 1H NMR analysis of possible intermediates.

Footnote

Electronic supplementary information (ESI) available: General information, experimental details, mechanistic studies, characterization data for products, 1H, 13C, and 19F spectra of products. See DOI: 10.1039/d1qo01439k

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