Cycloaddition Reaction of α-Diazoacetates and β-Trifluoromethyl

Letter Cite This: Org. Lett. 2018, 20, 6444−6448

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Phosphine-Catalyzed [3 + 2] Cycloaddition Reaction of α‑Diazoacetates and β‑Trifluoromethyl Enones: A Facile Access to Multisubstituted 4‑(Trifluoromethyl)pyrazolines Yongfeng Li, Huamin Wang, Yuwei Su, Runchen Li, Cao Li, Lu Liu,* and Junliang Zhang* School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, P. R. China

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ABSTRACT: A novel phosphine-catalyzed [3 + 2] cycloaddition of α-diazoacetates and β-trifluoromethyl enones has been developed that provides facile access to multisubstituted 4-(trifluoromethyl)pyrazolines in good to excellent yields at room temperature. In addition, a tandem [3 + 2] cycloaddition/Michael addition is also presented.

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ver the past decade, the introduction of fluorine atoms or fluoroalkylated groups into organic molecules has received increasing attention and has become a hot topic recently because fluorine-containing compounds play significant roles in pharmaceutical chemistry, agrochemistry, and materials science.1 For example, the motifs of CF3-substituted pyrazolines and pyazoles wildly exist in many bioactive molecules and pharmaceuticals (some examples are depicted in Figure 1).2 Thus, the development of more efficient

Scheme 1. Synthesis of CF3-Substituted Pyrazolines and Pyrazoles via [3 + 2] Cycloaddition

Figure 1. Trifluoromethylated pyrazoline- and pyrazole-containing bioactive molecules.

limited substrate scope. Recently, some progress was successfully achieved by the groups of Ma 5c−e and Mykhailiuk,5a,b providing facile access to 3-(trifluoromethyl)pyrazolines and -pyazoles by using a “one-pot” approach.5 Nonetheless, the development of new methods to broaden the diversity of pyrazolines and pyrazoles with CF3 at different positions especially in large-scale is still highly desirable. In addition, good substrate scope, mild conditions and readily available starting materials are also important. Herein, we wish

synthetic methods to construct these heterocyclic skeletons with various substituents is of great significance in organic and medicinal chemistry.3 The [3 + 2] cycloaddition of 2,2,2-trifluorodiazoethane (CF3CHN2) with an electron-deficient carbon multiple bond,4 such as alkenes, alkynes, and allenes, represents a straightforward strategy to access CF3-substituted pyrazolines and pyazoles (Scheme 1a). However, these transformations usually suffer from challenges such as operation, harsh conditions, and © 2018 American Chemical Society

Received: August 28, 2018 Published: October 2, 2018 6444

DOI: 10.1021/acs.orglett.8b02757 Org. Lett. 2018, 20, 6444−6448

Letter

Organic Letters

Scheme 2. Synthesis of 3,4,5-Trisubstituted Pyrazolinesa,b

to present our progress on phosphine-catalyzed6 the [3 + 2] cycloaddition of diazoacetate7 and β-trifluoromethyl enones,8 affording the multisubstituted pyrazolines with CF3 at the 4position and the corresponding pyrazoles upon further oxidation. We embarked on our inverstigations by probing the reaction of (E)-1-(4-chlorophenyl)-4,4,4-trifluorobut-2-en-1-one (1a) with ethyl diazoacetate (EDA, 2a) under the catalysis of different phosphine catalysts. To our delight, the desired product 4-trifluoromethylated 3,4,5-trisubstituted pyrazoline 3aa was isolated in 72% yield under the catalysis of 10 mol % of CH3PPh2 in touluene at room temperature for 48 h (Table 1, entry 1). Notably, the structure and the relative Table 1. Optimization of Reaction Conditionsa

entry

cat.

solvent

time (h)

yieldb (%)

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

MePPh2 PPh3 (2-MeC6H4)3P DPPB DPPE DPPM PPh3 PPh3 PPh3 PPh3 PPh3 PPh3

toluene toluene toluene toluene toluene toluene DCE THF CH3CN CHCl3 toluene toluene toluene

48 48 48 40 40 40 48 36 36 48 36 48 76

72 89 54 73 71 68 85 60 68 65 80 86 36

a

A solution of EDA 2a (0.8 mmol) in 1 mL of toluene was introduced to the mixture of 1 (0.4 mmol) and PPh3 (0.4 mmol) in toluene (1 mL) by syringe in 2 min, and the reaction mixture stirred for 36−72 h. bIsolated yield.

(trifluoromethyl)-4,5-dihydro-1H-pyrazoles in good to excellent yields (60−97%). The steric hindrance had no obvious effect on this cycloaddition because good yields were achieved for ortho-substituted substrates (3oa,pa). The meta- and multiple-substituted aryl enones were also suitable for this system (3qa−sa). This transformation could be carried out with β-trifluoromethyl enones containing a polycycle (3ta) and heterocycle (3ua), affording the desired products in 84% and 90% yields, respectively. It was noteworthy that alkylsubstituted β-trifluoromethyl enone was also proven to be a good substrate under the optimal conditions (3va−xa). In addition, the (difluoromethyl)pyrazoline9 3ya can also be obtained via this approach from β-difluoromethyl enone 1y. Having successfully realized the [3 + 2] cycloaddition of EDA, we wondered if α-substituted α-diazoacetates were applicable substrates or not. To our delight, the reaction of ethyl α-methyl α-diazoacetate 2b and β-trifluoromethyl enones 1d proceeded smoothly, affording the corresponding pyrazoline 3db in 90% isolated yield with a diastereoisomer ratio (Scheme 3). It must be noted that the steric effect of diazoacetate is important to control the diastereoselectivity in this reaction. Compared to ethyl α-methyl α-diazoacetate, both larger alkyl group and ester group can improve the diastereoselectivity up to 10:1 (3db−fe). All reactions of βtrifluoromethyl enones containing various substitutes on phenyl or heterocycle with isopropyl α-methyl α-diazoacetate 2e proceeded smoothly, affording desired pyrazoline 3de−wb in excellent yields with high diastereoselectivity. Unfortunately, the reaction of α-aryl α-diazoesters with enones did not occur in this system. To further showcase the application of this transformation in organic synthesis, we then turned our attention to the threecomponent cascade [3 + 2] cycloaddition/Michael addition reaction. However, phosphine cannot catalyze this cascade

a

Unless otherwise stated, all reactions were carried out with 1a (0.1 mmol), 2a (0.2 mmol), and catalyst (10 mol %) in solvent (2 mL) at room temperature. bIsolated yield. cMethyl acrylate (0.5 equiv) was added. dH2O (1 equiv) was added.

configuration of product 3aa were confirmed by single-crystal X-ray diffraction. Because of this promising result, we then investigated various phosphine catalysts including monophosphine and bisphosphines (Table 1, entries 2−6), among which PPh3 was found to be the best catalyst, delivering 89% yield. Further solvent screening showed that DCE, THF, acetonitrile, etc. cannot further improve the yield (Table 1, entries 7−10). The addition of methyl acrylate decreased the yield, indicating that the in situ generated organic base was not efficient (Table 1, entry 11). This transformation is not sensitive to water because the addition of water has little effect on the result (Table 1, entry 12). Control experiments showed that the phosphine catalyst could accelerate this transformation (Table 1, entry 13). Having the optimal reaction conditions for this [3 + 2] cycloaddition reaction, we then investigated the substrate scope of various β-trifluoromethyl enones 1 with ethyl diazoacetate 2a. As shown in Scheme 2, in the case of enones, this transformation tolerated diverse substituents on the phenyl ring such as electron-withdrawing halo (3aa−ca), cyano (3da), trifluoromethyl (3ea), nitro (3fa), ester (3ga), and electrondonating alkyl (3ja,ka), phenyl (3la), methoxy (3ma) and so on at the para position, delivering the corresponding 46445

DOI: 10.1021/acs.orglett.8b02757 Org. Lett. 2018, 20, 6444−6448

Letter

Organic Letters Scheme 3. Synthesis of 3,4,5,5-Tetrasubstituted Pyrazolinesa,b

Scheme 4. Tandem [3 + 2] cycloaddition/Michael Additiona,b

a

A solution of 2 (0.8 mmol) in 1 mL of toluene was introduced to the mixture of 1 (0.4 mmol) and PPh3 (0.04 mmol) in toluene (1 mL) by a syringe in 2 min, and the reaction mixture was stirred for 36−72 h. b Total isolated yield of two isomers.

reaction of 1a and 2a. After screening of various conditions, 3 equiv of CsF proved the best to afford 4a in 69% yield (Scheme 4, for screening of conditions, see Table S4). With the optimal conditions in hand, we then explored the substrate scope. As summarized in Scheme 4, the reaction of various βtrifluoromethyl enones 1 and α-diazoacetate 2 proceeded smoothly, affording the corresponding pyrazolines 4b−j in moderate yield as single diastereoselective ([3 + 2] cycloaddition) and regioselective10 (Michael addition) isomers (Scheme 4). It was noteworthy that the yield of the yields of this cascade [3 + 2] cycloaddition/Michael addition were higher than those of the two-step reaction. The structure of 4ba was verified by means of single-crystal X-ray diffraction, and all other adducts 4 were assigned by analogy. It should be noted that this phosphine-catalyzed [3 + 2] cycloaddition of β-trifluoromethyl enones with diazoacetate is easy to scale up. A gram-scale reaction of 4 mmol of 1d and 8 mmol of 2a was carried out under the standard conditions, furnishing 1.2842 g of 3da in 92% isolated yield (Scheme 5). In addition, to exhibit the synthetic value of this protocol, we also explored several transformations of 3 in Scheme 5. DMAP-promoted protection of 3da could be effected, delivering the N-Boc substituted product 5 in 99% yield. The transesterification could easily occur when 3da was exposed to HCl in methanol. The 4-(trifluoromethyl)pyrazole 7 was obtained by the oxidation of 3ka. To our surprise, the ester group could be selectively reduced to hydroxyl by NaBH4, whereas the ketone group was still present. A preliminary asymmetric catalysis of this [3 + 2] cycloaddition reaction was carried out. The applications of chiral (R)-BINAP resulted in good yield (83%) but low enantioselectivity (15% ee, eq 1). This result indicates that the asymmetric version is promising and the phosphine is the catalytic species in this transformation. To our delight, this cycloaddition can be carried out in an open f lask, furnishing the

a

A solution of 2 (0.8 mmol) in 1 mL of toluene was introduced to the mixture of 1 (0.4 mmol) and CsF (1.2 mmol) in toluene (1 mL) by a syringe in 2 min, and the reaction mixture stirred for 36−72 h. b Isolated yield.

Scheme 5. Gram Scale-up and Transformation of Products

desired product 3ca in a yield (88%) similar to that in a Schlenk tube (eq 2). 6446

DOI: 10.1021/acs.orglett.8b02757 Org. Lett. 2018, 20, 6444−6448

Letter

Organic Letters On the basis of this result and our preliminary mechanistic study (see the SI for details of the mechanistic study), a plausible reaction pathway for this phosphine-catalyzed [3 + 2] cycloaddition is depicted in Scheme 6. There are two resonant

ORCID

Scheme 6. Proposed Mechanism

The authors declare no competing financial interest.

Lu Liu: 0000-0003-2151-891X Junliang Zhang: 0000-0002-4636-2846 Notes

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (Nos. 21772042, 21572065, 21425205), the Science and Technology Commission of Shanghai Municipality (18JC1412300), and the Changjiang Scholars and Innovative Research Team in University (IRT_16R25) for financial support.

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structures 2A and 2B for diazoesters 2. Compound 2B can react with enone 1 via [3 + 2] cycloaddition slowly, affording the desired product 3 after the following tautomerization of the forming N−N double bond. Triphenylphosphine can trap 2B, forming the reactive species IA, which would undergo cyclization, 1,3-H shift,11 and the leaving of PPh3 to afford the corresponding product 3. In summary, we developed a novel phosphine-catalyzed intermolecular [3 + 2] cycloaddition reaction of β-trifluoromethyl enones with diazoacetates. This protocol provides facile access to structurally diverse multisubstituted pyrazolines with CF3 at the 4-position. In addition, a tandem [3 + 2] cycloaddition/Michael addition have been also developed. The salient features of this reaction include easy operation, good diastereoselectivity, mild conditions, broad substrate scope, gram scale, and convenient transformation of the products. Moreover, to the best of our knowledge, this report constitutes the first example of phosphine serving as the catalysts to promote the [3 + 2] cycloaddition reaction of alkenes with diazoacetates. Therefore, we anticipate that our strategy will shine some light on the design of novel pathways for phosphine-catalyzed reactions.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02757. Experimental procedures and characterization data (PDF) Accession Codes

CCDC 1861904−1861905 contain 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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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. 6447

DOI: 10.1021/acs.orglett.8b02757 Org. Lett. 2018, 20, 6444−6448

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Organic Letters Chem. Res. 2016, 49, 1369. (d) Wang, Z.; Xu, X.; Kwon, O. Chem. Soc. Rev. 2014, 43, 2927. (e) Li, W.; Zhang, J. Chem. Soc. Rev. 2016, 45, 1657. (7) For selected reviews, see: (a) Doyle, M. P.; McKervey, M. A. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds; Wiley: New York, 1998. (b) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704. (c) Davies, H. M. L.; Manning, J.-R. Nature 2008, 451, 417. (d) Maas, G. Chem. Soc. Rev. 2004, 33, 183. (e) Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577. (f) Ford, A.; Miel, H.; Ring, A.; Slattery, C. N.; Maguire, A. R.; Mckervey, M. A. Chem. Rev. 2015, 115, 9981. (g) Wei, F.; Song, C.; Ma, Y.; Zhou, L.; Tung, C.-H.; Xu, Z. Sci. Bull. 2015, 60, 1479. (h) Fructos, M. R.; Díaz-Requejo, M. M.; Pérez, P. J. Chem. Commun. 2016, 52, 7326. (i) Liu, L.; Zhang, J. Chem. Soc. Rev. 2016, 45, 506. (8) For selected examples of β-trifluoromethyl enones, see: (a) Huang, B.; Li, C.; Wang, H. M.; Wang, C. H.; Liu, L.; Zhang, J. L. Org. Lett. 2017, 19, 5102. (b) Hu, W. F.; Zhao, J. Q.; Chen, Y. Z.; Yuan, W. C. J. Org. Chem. 2018, 83, 5771. (c) Sanz-Marco, A.; GarcíaOrtiz, A.; Blay, G.; Pedro, J. R. Chem. Commun. 2014, 50, 2275. (d) Bai, D. C.; Wang, X. L.; Zheng, G. F.; Li, X. W. Angew. Chem., Int. Ed. 2018, 57, 6633. (9) (a) Zeng, J. L.; Chen, Z.; Zhang, F. G.; Ma, J. A. Org. Lett. 2018, 20, 4562. (b) Mertens, L.; Hock, K. J.; Koenigs, R. M. Chem. - Eur. J. 2016, 22, 9542. (10) Chen, Z.; Zhang, Y.; Nie, J.; Ma, J. A. Org. Lett. 2018, 20, 2120. (11) The 1,3-H transfers should undergo a stepwise (protonation/ deprotonation) process; see: Wang, Y.; Cai, P.-J.; Yu, Z.-X. J. Org. Chem. 2017, 82, 4604.

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DOI: 10.1021/acs.orglett.8b02757 Org. Lett. 2018, 20, 6444−6448