Letter pubs.acs.org/OrgLett
Dearomatization Approach to 2‑Trifluoromethylated Benzofuran and Dihydrobenzofuran Products David T. Smith, Edon Vitaku, and Jon T. Njardarson* Department of Chemistry and Biochemistry, University of Arizona, 1306 East University Boulevard, Tucson, Arizona 85721, United States S Supporting Information *
ABSTRACT: A mild dearomatization enabled ortho-selective replacement of an aromatic C−H bond with a hexafluoroacetylacetone (hfacac) substituent has been developed. This reaction is dependent on a hypervalent iodine generated phenoxonium intermediate, a critical choice of solvent, and reagent addition order. The fluorinated dihydrobenzofuran product can be transformed into dihydrobenzofuran and benzofuran products decorated with a 2-trifluoromethyl group. The 3trifluoromethylacyl substituted benzofurans rapidly form hydrates, which can be reduced to the corresponding alcohols.
B
This is evident from the rapid increase in recent years of fluorinated drugs, which currently compose over 10% of US FDA small-molecule drugs and around 20% of drugs approved in the current decade.2 We proposed that highly functionalized fluorinated benzofuran architectures could be assembled in one pot from readily available monoalkylated hydroquinones (Scheme 1). The proposed cascade would be initiated with a
enzofurans along with their dihydro- and oxidized variants are an important heterocyclic family. These heterocycles are found in many natural products and pharmaceuticals.1 Shown in Figure 1 are 11 such structures, all of which have
Scheme 1. Proposed Dearomatization−Rearomatization to Fluorinated Benzofurans and Dihydrobenzofurans
dearomatization step (DeA), which would result in the formation of a highly reactive oxonium ion that would be suitable for selective capture by weak nucleophiles such as hexafluoroacetylacetone (hfacac). The resulting conjugated addition adduct would then spontaneously rearomatize (ReA) to regenerate a phenol moiety, which would be expected to immediately engage the reactive trifluoroacetyl groups to result in the formation of a dihydrobenzofuran. This product has two differentiated trifluoromethyl groups in the 2- and 3-positions of the benzofuran. The net outcome of this overall cascade is replacement of a relatively unreactive aromatic C−H bond with a highly decorated sp3-hybrized carbon substituent without the
Figure 1. Benzofuran and dihydrobenzofuran drugs.
been approved by regulatory agencies for a variety of disease conditions. Interestingly, four of these pharmaceuticals are natural products (morphine, methoxsalen, griseofulvin, and galantamine). One of the more common later stage structural fine-tunings of the architectures of promising drug candidates involve the addition of fluorine or fluorinated substituents. © 2017 American Chemical Society
Received: May 16, 2017 Published: June 9, 2017 3508
DOI: 10.1021/acs.orglett.7b01479 Org. Lett. 2017, 19, 3508−3511
Letter
Organic Letters
while reducing the necessary equivalents of hfacac by half (entry 9). The optimized addition order and speed presumably increase the yield of 6 by maximizing the amount of hfacac relative to the phenol as it is oxidized.
use of transition metals or directing groups. The majority of routes to 2-trifluoromethyl benzofurans rely on trifluoromethylation of existing benzofurans.3 Only a few known methods allow for benzofuran or dihydrobenzofuran synthesis with direct incorporation of a 2-trifluoromethyl group.4 Inspired by our recent success in forming C−C bonds with oxidative dearomatization5 and more specifically, constructing fluorinated indoles using a DeA/ReA approach,6 we set out to identify the optimal conditions for selectively substituting the ortho-phenol C−H bond of 4-methoxyphenol (1, Table 1) with Table 1. 2-CF3 Dihydrobenzofuran Optimizations
We postulate two possible mechanisms for the sodium hydroxide mediated deacylation step as shown in Scheme 2. In
a
Scheme 2. Proposed Mechanism for Loss of CF3CO
entry
R
hfacac (equiv)
PIDA (equiv)
addition time (min)
solvent
yield (%)a
1 2 3 4 5 6 7 8 9 10
H H H H H H Cl Cl Cl H
3 10 10 10 10 5 10 10 5 5
2 2 1 1.5 1.5 1.5 1.5 1.5 1.5 1.5
0b 0b 0b 0b 0b 0b 0b 30c 60c 60c
TFE TFE TFE TFE HFIP HFIP HFIP HFIP HFIP HFIP
47 67 66 61 97 47 36 77 89 93
the first pathway, hydration under basic conditions generates 7 which undergoes trifluoroacetate release7 to form 9, which then engages the nearby trifluoromethyl ketone to form hemiketal 5. Alternatively, deprotonation of the hemiacetal hydroxyl group of 3 is followed by a C−C bond cleavage to form 8, which contains a labile trifluoroacyl protected phenol. Hydrolysis of this acyl group liberates phenol 9. We applied our optimized reaction conditions to the nine substrates shown in Table 2, which contain five ortho-, two meta-, and two alkyl ether substrates. Yields are good to excellent, and in all cases the hfacac nucleophile adds selectively away from substituents. Because of their importance as substituents and as functional group handles for crosscouplings, radical and other later stage synthetic approaches, we opted to closely evaluate halogenated substrates (2, 12, 18, and 20). Substituting with bromine at the 3-position (R2) gave dihydrobenzofuran 13 in 60% yield; however, 3-iodo-4methoxyphenol was insoluble in HFIP and 3-chloro-4methoxyphenol gave a mixture of products, which proved unstable to purification. Halogens were tolerated better at the 2-position, with 2-chloro-4-methoxyphenol (2) giving the best yield of dihydrobenzofuran 6 (89%, entry 6). Interestingly, the presence of large phenyl groups in the 2- (16) and 3-positions (10) did not impede this new reaction affording dihydrobenzofuran products 17 and 11 in 95% and 93% yield, respectively. We next turned our attention to the original task of a one-pot synthesis of 3-trifluoroacetyl benzofurans (Scheme 3). Dehydration of 3 proved much more challenging than expected. In our indole series, the dehydration was accomplished by treatment of the aminal with trifluoroacetic acid (TFA) at room temperature. For phenol ketals such as 3, it was eventually determined that heating in a pressure tube at 75 °C with TFA and trifluoroacetic anhydride (TFAA) resulted in good conversion of 3 to benzofuran 24. Unlike its indole counterpart, this product (24) started to immediately form a hydrate at room temperature with the product commonly being isolated as a 3:1 mixture of hydrate 25 and 24. Crystal structure analysis enabled unambiguous confirmation of the structure of hydrate 25. The crystal packing is most noteworthy for its
a
Yields shown are of isolated product 5 or 6. bSolution of 5 or 6 and hfacac in solvent added to stirred solution of PIDA in solvent. c Separate solutions of 1 or 2 in solvent and PIDA in solvent added simultaneously to hfacac by syringe pump over the time indicated.
hfacac. Dearomatization proceeded rapidly with phenyl iodine diacetate (PIDA) as oxidant, but trapping efficiently with hfacac turned out to be more challenging than we had anticipated. Furthermore, the relative instability of the product (3) coupled with its partial degradation upon exposure to silica purification presented us with additional unforeseen obstacles. In an attempt to form a more stable product and to probe the necessity of the two trifluoromethyl groups, the reaction was attempted with a series of 1,3-diketones. Dimethyl malonate, methyl acetoacetate, acetylacetone, and trifluoroacetylacetone all failed to react. In order to gain better insight into the key dearomatization step we opted to treat the crude reaction mixture with sodium hydroxide and drive the reaction to dihydrobenzofuran 5, which we were gratified to learn was stable and easily purified. The structure of 5 was unambiguously confirmed by an X-ray crystal structure. The reaction conditions we had used for indoles (entry 1, Table 1) afforded the product in poor yield. This problem could be partially solved by increasing the equivalents of hfacac employed (entries 2−4). The real breakthrough came when we substituted trifluoroethanol (TFE) with hexafluoroisopropanol (HFIP) as solvent (entry 5), which afforded 5 in outstanding 97% yield. When the conditions were applied to 2-chloro-4methoxyphenol (2), low yields prompted investigation of the effect of addition time. Simultaneous addition of separate solutions of 2 in HFIP and PIDA in HFIP to neat hfacac over 30 min led to a substantial improvement in yield of 6 (entry 8). Slowing the addition time to 60 min further increased the yield 3509
DOI: 10.1021/acs.orglett.7b01479 Org. Lett. 2017, 19, 3508−3511
Letter
Organic Letters
hydrogen bonding networks with the hydrate engaging another hydrate as well as the lone pairs of the methyl ether. Purification of the benzofuran products proved challenging due to the reactivity of the trifluoroacetyl group,8 especially the tendency to hydrate. To address this purification challenge we decided to add a third reagent to the reaction mixture in hopes of obtaining a product that would be easier to purify. We argued that a hydride addition would fit our goals well, while also affording a product that could be converted back the acyl group if needed. Toward that end, reduction of the crude material with sodium borohydride enabled full conversion to the corresponding alcohol which was found to be stable to silica purification. The scope of this three-step one-pot transformation procedure consisting of hfacac addition, dehydration, and reduction was investigated with a variety of substrates as demonstrated in Figure 2.
Table 2. Dihydrobenzofuran Substrate Scope
Scheme 3. Synthesis of Hydrated 2-CF3 Benzofuran
Figure 2. Reduced 2-CF3 benzofuran substrate scope. Yields shown are of isolated product over three steps.
The unsubstituted 4-methoxyphenol gave the best yield, affording benzofuran 26 in 68% yield overall (88% average per transformation, Figure 2). As was observed in Table 2, arylsubstituted phenol substrates performed well furnishing benzofuran products 28, 32, and 32−36 in good overall yields. Substituting with a chlorine at the 2-position led to a minor reduction in yield. Interestingly, bromo (29) and allyl (27 and 30) substituents were not as well tolerated. Comparing with the results in Table 1, it can be deduced that any drops in yield are primarily due to the dehydration step with TFA and TFAA. In summary, we report a new, dearomatization enabled synthesis of 2-trifluoromethyl dihydrobenzofurans from 4alkoxyphenols and hfacac. This method was further extended to prepare 2-trifluoromethyl-3-trifluoroacetyl benzofurans, obtained as their reduced analogues to allow for efficient 3510
DOI: 10.1021/acs.orglett.7b01479 Org. Lett. 2017, 19, 3508−3511
Letter
Organic Letters
U.; Poll, W.; Rickerich, L. Chem. Ber. 1988, 121, 1841−1845. (c) Rozhkov, V. V.; Kuvshinov, A. M.; Shevelev, S. A. Russ. Chem. Bull. 2000, 49, 573−574. (d) Kuethe, J. T.; Wong, A.; Journet, M.; Davies, I. W. J. Org. Chem. 2005, 70, 3727−3729. (e) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 14570−14571. (f) Zhou, H.; Niu, J.-J.; Xu, J.-W.; Hu, S.-J. Synth. Commun. 2009, 39, 716−732. (5) (a) Vitaku, E.; Njardarson, J. T. Tetrahedron Lett. 2015, 56, 3550−3552. (b) Vitaku, E.; Njardarson, J. T. Eur. J. Org. Chem. 2016, 2016, 3679−3683. (6) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Angew. Chem., Int. Ed. 2016, 55, 2243−2247. (7) (a) Han, C.; Kim, E. H.; Colby, D. A. J. Am. Chem. Soc. 2011, 133, 5802−5805. (b) John, J. P.; Colby, D. A. J. Org. Chem. 2011, 76, 9163−9168. (c) Riofski, M. V.; Hart, A. D.; Colby, D. A. Org. Lett. 2013, 15, 208−211. (d) Zhang, P.; Wolf, C. J. Org. Chem. 2012, 77, 8840−8844. (8) Kelly, C. B.; Mercadante, M. A.; Leadbeater, N. E. Chem. Commun. 2013, 49, 11133−11148.
purification. Alkyl, aryl, and halide substituted phenols work well with the reaction.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01479. Crystallographic data for 5 (CCDC 1549515) (CIF) Crystallographic data for 25 (CCDC 1549517) (CIF) Crystallographic data for 26 (CCDC 1549516) (CIF) Experimental procedures and characterization data for new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jon T. Njardarson: 0000-0003-2268-1479 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We would like to thank Dr. Andrei Astachkine and Pradipta Das from the University of Arizona for help with securing X-ray structures. Acknowledgment is made to the donors of the American Chemical Society Petroleum Research Fund for partial support of this research.
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REFERENCES
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