Copper Difluorocarbene Involved Catalytic gem-Difluoropropargylation

doi:10.21203/rs.3.rs-5324940/v1

The use of metal for catalytic difluorocarbene transfer reactions has long been hindered by the lack of understanding of metal difluorocarbene chemistry, despite the prospect of a new dimension to create novel fluorine structures for medicinal chemistry and advanced materials science. Here, we report a new mode of copper catalyzed difluorocarbene transfer reaction via 1,2-migration of copper difluorocarbene, in sharp contrast to the previous nucleophilic addition of copper difluorocarbene pathway. This innovative reaction enables the development of a modular catalytic gem-difluoropropargylation reaction using a variety of simple and widely available potassium propiolates, terminal alkynes, and allyl/propargyl electrophiles to couple difluorocarbene, opening a new avenue to precise synthesis of organofluorine compounds without tedious synthetic procedure. The impact of this protocol has been demonstrated by the efficient synthesis of complex fluorinated skeletons and the rapid synthesis of the key intermediates of pheromone derivative and PGF_2a agonist. Mechanistic studies reveal that the migratory insertion of difluorocarbene into the C-Cu bond of the alkynylcopper species is involved in the reaction.

Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology

Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology

The precise fluorine editing of organic molecules has emerged as a powerful tool in modern drug discovery due to the beneficial effect of fluorine atom(s) that can significantly improve the metabolic stability, lipophilicity, and binding affinity of bioactive compounds.^1-4 Consequently, impressive achievements have been made in the fluoroalkylation reactions over the past decades.^5-9 However, most developed methods focus on the transformations of fluorinated carbanions, carbocations, and carbon-centered radicals.^5-9 Compared to these three active intermediates, difluorocarbene, the smallest fluorocarbon unit, has the advantage of forming two chemical bonds,^10-12 providing a new dimension to expand the chemical space and create new fluorine structures for medicinal chemistry. Ideally, coupling difluorocarbene with two simple and readily available feedstocks would enable more efficient access to organofluorine compounds without the tedious synthesis of fluoroalkylating reagents (Fig. 1a). Nevertheless, this straightforward synthetic route is regulated by the high reactivity of difluorocarbene. As a result, only limited reaction types of difluorocarbene transfer reactions have been reported so far.^13-16 To overcome this limitation, the complexation of difluorocarbene with metal would be an attractive strategy, as the reactivity of difluorocarbene can be modulated by metal (Fig. 1b). However, due to the lack of catalytic activity in those isolated metal difluorocarbene complexes, the metal-catalyzed difluorocarbene transfer reaction remains a substantial challenge,¹⁷ in sharp contrast to the classic metal catalyzed carbene transfer reactions that have been proven to be a powerful transformation in organic synthesis.^18-20 This problem is further underscored by the lack of understanding of metal difluorocarbene chemistry, though investigating metal difluorocarbene complexes has been around for over 40 years.²¹

We recently isolated palladium(0) (ref 22) and copper(I) (ref 23) difluorocarbene complexes ([Pd⁰]=CF₂ and [Cu^I]=CF₂) and found they possess opposite reactivities ([Pd⁰]=CF₂, nucleophilic; [Cu^I]=CF₂, electrophilic), though Pd⁰ and Cu^I have the same d electron count. These findings have been applied in catalytic organic synthesis.^24-27 However, the initial step of these catalytic difluorocarbene transfer reactions requires the formation of the low valent metal difluorocarbene ([M]=CF₂, M = Pd⁰, Cu^I) intermediates, followed by attacking the carbene carbon center with an electrophile or a nucleophile to generate a difluoroalkyl metal species ([M]-CF₂R) (Fig. 1c).^{22, 23} We envision that the formation of the M-CF₂R species by migratory insertion of difluorocarbene into the C-M bond would open a new dimension to harness metal difluorocarbene chemistry for catalytic synthesis of organofluorine compounds, as the C-M bond can be easily constructed by transmetalation or oxidative addition,²⁸ which would provide a more general pathway for catalytic difluorocarbene transfer reactions (Fig. 1d). To realize this hypothesis, one critical factor is the rapid formation of a metal difluorocarbene complex C-[M]=CF₂, followed by a facile migratory insertion pathway without the influence of coupling [M]-C with an electrophile or a nucleophile. Since copper is low-cost, earth-abundant, and easy to form a [Cu^I]-C species via transmetalation between [Cu^I] and a nucleophile,²⁹ we assume that using copper as a catalyst under suitable conditions may address the above crucial issue and provide a cost-efficient route for modular construction of fluorinated structures (Fig. 1e), thus expanding copper difluorocarbene chemistry and opening a new avenue to efficient, precise synthesis of organofluorine compounds.

Here, we disclose a copper catalyzed gem-difluoropropargylation reaction via 1,2-migration of copper difluorocarbene (Fig. 1e). This innovative reaction uses inexpensive and industrial feedstock potassium bromodifluoroacetate (BrCF₂CO₂K) as the difluorocarbene precursor,^{30, 31} allowing various widely available potassium propiolates, terminal alkynes, and allyl/propargyl electrophiles to couple difluorocarbene, providing a facile route to accessing synthetically valuable gem-difluoropropargylated compounds. The distinct feature of this approach is the synthetic simplicity without the tedious synthesis of fluoroalklyating reagents or moisture-sensitive organometallic reagents. The diverse transformations of the resulting products and the applications of the current protocol in the rapid synthesis of the key intermediates of bioactive molecules demonstrate the synthetic utility of this new mode of catalytic difluorocarbene transfer reaction, showing the prospective in modern drug discovery. Mechanistic studies reveal that the fast migratory insertion of difluorocarbene into the C-Cu bond of alkynylcopper(I) species is the key step for the catalytic difluorocarbene transfer.

To test our hypothesis, we chose terminal alkynes as the nucleophiles, as the resulting gem-difluoropropargyl structure is a synthetically versatile synthon for diverse transformations. Notably, it has been widely used in copper-free click chemistry^{32, 33} because of the unique properties of the difluoromethylene (CF₂) group that can lower the lowest unoccupied molecular orbital (LUMO) of the alkynes.^{32, 34} Furthermore, the CF₂ group is a bioisostere of the oxygen atom and the carbonyl group (Fig. 1f).^{2, 35} Incorporating the CF₂ group at the metabolic liable position can increase the metabolic stability of bioactive molecules.^1-4 It has been one of the valuable strategies for discovering new bioactive molecules by tactically site-selective difluoromethylenation (Fig. 1f).^{1-4, 35, 36} However, efficient methods for such a gem-difluoropropargyl structure are limited. The developed methods either rely on the deoxyfluorination of alkynyl ketones with sulfur fluorides³⁷ or coupling gem-difluoropropargyl bromides with organometallic reagents,^{38, 39} aldehydes,⁴⁰ or imines⁴¹. However, the requirement of multiple steps to prepare the substrates, such as alkynyl ketones and organometallic reagents, as well as the poor functional group of sulfur fluorides and of using strong base n-butyllithium to prepare gem-difluoropropargyl bromides⁴² regulate the widespread applications of these methods. Yet, the current catalytic modular synthesis harnessing copper difluorocarbene chemistry would overcome these limitations and provide straightforward access to the gem-difluoropropargyl structure.

Initially, to ascertain the feasibility of the migratory insertion of difluorocarbene into the C-Cu bond, we prepared the 1,10-phenanthroline-supported alkynyl complex A1.⁴³ Unexpectedly, treatment of A1 with inexpensive and widely available difluorocarbene precursor BrCF₂CO₂K 1 in CH₃CN at 50 ^oC afforded a trifluoroalkene 3 instead of gem-difluoropropargyl copper complex C1 (Fig. 2a). A similar result was also observed in DMF. Although low yields of 3 were obtained due to the decomposition of A1, these results demonstrate the feasibility of the migratory insertion pathway. Once C1 was formed via the copper difluorocarbene complex B1, it underwent another difluorocarbene insertion to generate a tetrafluoroalkylcopper E1 (ref 23). Finally, b-fluoride (b-F) elimination of E1 produced 3. This possible pathway indicates that the difluorocarbene elongation in the alkynyl copper complex C1 is thermodynamically favorable, and the tetrafluoroalkyl copper E1 is prone to b-F elimination due to its instability. Complex A1 could also be used as a nucleophile to react with 1 and allyl chloride 2a in CH₃CN, providing the three-component coupling product 4 in 38% yield along with a side product 5 (13%) generated between A1 and 2a (Fig. 2b). Replacing CH₃CN with DMF led to a lower yield of 4. No 4 was observed using DMSO. These results suggest that the formation of C1 via an alkynylcopper difluorocarbene complex B1 through 1,2-migration is reasonable, which should be faster than the cross-coupling of A1 with 2a in a suitable reaction media, such as CH₃CN and DMF, thereby facilitating the formation of gem-difluoropropargyl structure in the catalytic reaction. Given the difficulty in obtaining C1 through the current difluorocarbene pathway, we prepared gem-difluoropropargyl cadmium species F1 and F2 by reaction of gem-difluoropropargyl bromide 6 with cadmium in DMF.⁴⁴ These two organocadmium reagents were assigned according to the literature.⁴⁵ Transmetalation of the mixture of F1 and F2 with CuI at -40 ^oC afforded the gem-difluoropropargyl copper C2 and bis(gem-difluoropropargyl)copper species C3 in 41% yield and 8% yield, respectively. Since it is hard to isolate these two species, they were directly used to react with allyl chloride 2a, providing 7 in 95% yield, thus demonstrating the feasibility of coupling gem-difluoroproparyl copper with an electrophile (Fig. 2c). To investigate the possibility of nucleophilic addition of alkynyl species to the carbene carbon center, we prepared copper difluorocarbene complex G.²³ However, no desired product 4 was obtained when G was treated with 2a and alkynyl nucleophiles, including alkynyl lithium/zinc reagents (8a, 8b) and potassium propiolate 9a (Fig. 2d). Thus, the pathway beginning with the formation of [Cu^I]=CF₂, followed by a reaction with an alkynyl nucleophile, is less likely.

Based on the above results, a new mode of copper catalyzed difluorocarbene transfer reaction should be feasible for the catalytic modular synthesis of gem-difluoropropargylated compounds. In this copper catalyzed process, the reaction is initiated by the formation of an alkynylcopper species A, which subsequently undergoes complexation with a difluorocarbene to generate an alkynylcopper difluorocarbene intermediate B. This key intermediate undergoes 1,2-difluorocarbene migratory insertion to produce the gem-difluoropropargyl copper species C. Finally, C reacts with an electrophile to produce the gem-difluoropropargylated compound and releases copper catalyst simultaneously (Fig. 2e).

Inspired by the above observations and the possible pathway illustrated in Fig. 1e, we explored catalytic coupling reaction between terminal alkyne 8c and allyl chloride 2a to couple with difluorocarbene (Table 1). When 8c (1.0 equiv) was treated with 2a (1.5 equiv) and difluorocarbene precursor 1 (2.0 equiv) in the presence of CuCl (10 mol%) and 1,10-phenanthroline L1 (10 mol%) in CH₃CN at 50 ^oC using K₂CO₃ as the base, 10% yield of the desired product 4 was obtained along with 5% yield of side product 5 (entry 1). A survey of the ligands showed that ligand L4 could suppress the generation of 5 and increase the yield of 4 to 34% (entries 2-4, supplementary Table 2). Replacing K₂CO₃ with Na₂CO₃ slightly improved the reaction efficiency (entry 5, supplementary Table 3). However, the undesired defluorination of 8c and the sensitivity of [Cu^I]=CF₂ to the base make it difficult to increase the yield further. To circumvent these limitations, we chose readily available potassium propiolate 9b as the alternative substrate. We envisioned that the relatively faster release of alkynyl nucleophile through decarboxylation of 9b without needing a base would benefit the reaction efficiency. Similar to terminal alkyne 8c, the ligand is critical for the reaction (entries 6-8, supplementary Table 5), and L4 remained the optimal ligand, providing 7 in 73% yield at 80 ^oC (entry 6). Decreasing the reaction temperature to 70 ^oC increased the yield to 85% (entry 9). To optimize the reaction conditions further, we examined a series of reaction parameters, including copper catalysts, solvents, the loading amount of the catalyst, the ratio of the reactants, and the reaction time (entries 10, 11, supplementary Tables 6-11). Finally, the optimized reaction conditions were identified by shortening the reaction time to 30 min with 7.5% mol CuCl/L4 as the catalyst (entry 12). Under these conditions, 1.5 equiv of 1 and 1.2 equiv of 2a could provide 7 in 80% isolated yield. Notably, this reaction proceeded smoothly, even shortening the reaction time to 10 min (entry 13). This distinct feature is in sharp contrast to the conventional copper-catalyzed fluoroalkylation reactions that usually take a long time, thus underscoring the advance of the current copper catalyzed difluorocarbene transfer reaction and providing a potential opportunity to prepare ¹⁸F-labeling difluoromethylenation tracers for positron emission tomography (PET).⁴⁶ No product was observed without copper salt or ligand (entries 14, 15), demonstrating the essential role of Cu/L in promoting the reaction.

Table 1. Representative Results for the Optimization of the Reaction Conditions^a

entry	[Cu]	L	base	temp (^oC)	4 or 7, yield (%)^b	5 or 10, yield (%)^b
1^c	CuCl	L1	K₂CO₃	50	4, 10	5, 5
2^c	CuCl	L2	K₂CO₃	50	4, 25	5, 30
3^c	CuCl	L3	K₂CO₃	50	4, 2	5, 37
4^c	CuCl	L4	K₂CO₃	50	4, 34	5, nd
5^c	CuCl	L4	Na₂CO₃	50	4, 38	5, nd
6^d	CuCl	L4	--	80	7, 73	10, --
7^d	CuCl	L5	--	80	7, 48	10, --
8^d	CuCl	L6	--	80	7, 27	10, --
9^d	CuCl	L4	--	70	7, 85	10, --
10^d	CuBr	L4	--	70	7, 80	10, --
11^d	CuI	L4	--	70	7, 55	10, --
12^d,e	CuCl	L4	--	70	7, 82 (80)	10, --
13^d,e,f	CuCl	L4	--	70	7, 83	10, --
14^d	none	L4	--	70	7, nd	10, --
15^d	CuCl	none	--	80	7, 3	10, --

^aReaction conditions (unless otherwise specified): 8c or 9a (0.2 mmol, 1.0 equiv), 1 (2.0 equiv), 2a (1.5 equiv), MeCN (2 mL), 6 h. ^bDetermined by ¹⁹F-NMR using fluorobenzene as an internal standard; nd, not detected. ^cUsing 8c as the substrate. ^dUsing 9b as the substrate. ^e9b (0.5 mmol, 1.0 equiv), 1 (1.5 equiv), 2a (1.2 equiv), CuCl/L4 (7.5 mol%), 30 min. The data in the parenthesis is the isolated yield. ^fThe reaction was run in 10 min.

With the viable reaction conditions in hand, we examined the scope of this copper difluorocarbene involved catalytic gem-difluoroproparylation reaction (Fig. 3). Various potassium arylpropiolates were applied to this transformation (Fig. 3a), providing the corresponding gem-difluoropropargylated products efficiently (4, 7, 12-32). Generally, aromatic propiolates bearing an electron-donating substituent provided higher yields than electron-deficient substrates. The reaction exhibited high functional group tolerance. Base and nucleophile sensitive functional groups, such as ketone (13), ester (14), and nitrile (16), were compatible with the reaction; aryl fluoride (4), chloride (21), bromide (17, 19-21), and iodide (18) moieties underwent the current copper-catalyzed process smoothly. Additionally, the position of bromide in the aromatic ring did not affect the reaction efficiency. Para-, meta-, and ortho-aryl bromides efficiently delivered the corresponding gem-difluoropropargylated products (17, 19, 20). The high compatibility of chlorobromoaryl moiety (21) offers a good opportunity for diversified transformations by sequential aryl bromide and chloride functionalization. Ferrocene- and thiophene-containing substrates were also applied to the reaction, with moderate to good yields obtained (22-24). The reaction was not restricted to allyl chloride 2a, as substituted allyl chlorides, including linear, branched, and cyclic allyl chlorides (25-32), underwent smooth coupling. Even highly reactive allyl chlorides bearing vinyl chloride (30) or unsaturated ester (31) were still amenable to the reaction. In the case of linear allyl chloride (25), no branched product was observed. In addition to arylpropiolates, alkyl- and silyl-substituted propiolates were competent coupling partners (33-38), and the aliphatic side chain bearing benzyloxy (34), chloride (35), sulfamide (36), or cyclopropyl (37) did not interfere with the reaction efficiency. This approach could also be extended to propargyl electrophiles (Fig. 3b). One problem with this type of substrate is forming a copper-allenylidene complex between the copper catalyst and propargyl electrophile.⁴⁷ This competitive side reaction significantly influences the current copper catalyzed difluorocarbene transfer process. After extensive efforts (supplementary Table 12), we found that using propargyl sulfonates as the limiting substrates could suppress this undesired side reaction, producing various gem-difluoropropargylated allenes with high efficiency. Although the synthesis of allenes has been well-established,^48-51 efficient methods for such fluoroalkylated allenes have yet to be reported. Given the synthetic versatility of allene and alkyne, the resulting gem-difluoroporpargylated allenes should be a valuable structure for diverse transformations. As depicted in Fig. 3b, arylpropiolates underwent smooth coupling with good functional group tolerance (39-43). Versatile synthetic handles, such as nitrile (40), thiophene (41), aryl bromide (43), and alkyl chloride (42) moieties, tolerate the reaction well. In contrast to the allyl electrophiles, arylpropiolate bearing an electron-withdrawing group provided a higher yield (40). However, alkylpropiolates led to low yields (20-30%). Of note, for all the coupling reactions described above, no [2+1] cycloaddition side products generated between difluorocarbene and the unsaturated carbon-carbon bond were observed,¹⁵ thus demonstrating the advance of this copper catalytic system further.

The reaction is readily scalable, as demonstrated by the gram-scale synthesis of 7 with a high yield (Fig. 4a). The resulting gem-difluoropropargyl products can be elaborated through a myriad of transformations to create a diversity of new organofluorine compounds. Selective oxidative cleavage of the carbon-carbon double bond of 7 with ozone, followed by reduction with NaBH₄, afforded alcohol 44 efficiently. Cyclization of 37 with phenidone 45 via rhodium catalysis produced difluoroalkylated indole 46 with high efficiency (Fig. 4b).⁵² The gem-difluoropropargyl structure could also be used to construct the difluoroalkylated pyrrole 49 through deprotection of 38, followed by silver-catalyzed [3+2] reaction with ethyl isocyanoacetate 49 (Fig. 4c).⁵³ Given the unique properties of the CF₂ group and critical applications of indole and pyrrole in medicinal chemistry, the rapid access to these complex fluorinated molecules that otherwise require tedious steps to prepare through conventional methods provides a good opportunity to discover new interesting bioactive molecules. Remarkably, this copper catalyzed difluorocarbene transfer reaction could be used as a key step to introduce the CF₂ group at the metabolic liable allylic position of bioactive molecules. As shown in Fig. 4d, pheromone derivative 52, a probe used to study hydrophobic interaction in pheromone reception, was rapidly accessed from 50 via two steps, followed by a reported procedure.⁵⁴ Since the Z-difluoroalkylated alkenes have been found in a series of pheromone analogs,⁵⁴ this copper difluorocarbene involved catalytic gem-difluoropropargylation should have applications in such a kind of compounds. Furthermore, using (-)-corey lactone diol derived terminal alkyne 8d as the substrate could directly afford 53 by harnessing the current copper difluorocarbene chemistry (Fig. 4e). Although a 42% yield of 53 was obtained, 46% of 8d could be recovered. Notably, compound 53 could be used as a potential key intermediate for synthesizing tafluprost 54, a PGF₂_a agonist for treating glaucoma,³⁶ thus underscoring the synthetic utility of this transformation.

In summary, a new mode of copper difluorocarbene involved catalytic coupling reaction has been developed. The stoichiometric reactions reveal that a difluorocarbene migratory insertion into the C-Cu bond is involved in the catalytic cycle. This innovative approach allows a wide range of readily available simple components, including potassium propiolates, terminal alkynes, and allyl/propargyl electrophiles, for the rapid modular synthesis of valuable gem-difluoropropargyl structure, opening a new avenue to the efficient, precise synthesis of organofluorine compounds. We anticipate that this copper difluorocarbene chemistry will be attractive to creating novel fluorinated structures of interest in medicinal chemistry and ¹⁸F PET-CT for diagnosis. Most importantly, this work should also prompt the development of new metal difluorocarbene involved catalytic coupling reactions in methodology development.

Data availability

Experimental procedures, characterization of new compounds, and all other data supporting the findings are available in the Supplementary Information.

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (21931013, 22193072, 22301307), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0590000), the Science and Technology Commission of Shanghai Municipality (22JC1403500), and the Shanghai Pujiang Program (23PJ1415900).

Author contributions

X. Zhang and X. Zeng conceived the research concept. X. Zhang directed the project. X. Zeng conducted the experiments. S.-P. S. examined some substrates. X. Zeng and H.-Y. Z. analyzed the data. X. Zhang wrote the manuscript. All authors reviewed and edited the manuscript.

Competing interests

The authors declare that they have no competing interests.

Additional information

Supplementary information The online version contains supplementary material.

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Copper Difluorocarbene Involved Catalytic gem-Difluoropropargylation

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