sign in sign up
<<
Home , Phenyl group, Transalkylation

Ester Dance Reaction on the Aromatic Ring Kaoru Matsushita, Ryosuke Takise, Kei Muto, and Junichiro Yamaguchi*

Department of Applied Chemistry, Waseda University, 3-4-1, Ohkubo, Shinjuku, Tokyo, 169-8555, Japan ABSTRACT: Aromatic rearrangement reactions are useful tools in the organic chemist’s toolbox when generating uncommon substitution patterns. However, it is difficult to precisely translocate a in (hetero)arene systems, with the exception of halogen atoms in a halogen dance reaction. Herein, we describe an unprecedented “ dance” reaction: a predictable translocation of an ester group from one atom to another on an aromatic ring. Specifically, a phenyl carboxylate can be shifted from one carbon to an adjacent carbon on a (hetero)aromatic ring under palladium catalysis to often give a thermodynamically favored, regioisomeric product with modest to good conversions. The obtained ester moiety can be further converted to various aromatic derivatives through the use of classic as well as state-of- the-art transformations including an amidation, acylations and decarbonylative couplings.

Dedicated to Professor Kuniaki Tatsuta on his 80th birthday.

Substitution reactions on (hetero)aromatic substrates are some of there are currently no reports of a catalytic rear- the most important reactions in organic chemistry. However, some rangement. Much like the halogen dance reaction wherein a func- substitution patterns can be more difficult to forge than others based tional group is translocated from one ring carbon to another, we de- on the propensity of the positions on the (hetero)arene to engage in scribe a palladium-catalyzed translocation of an ester group on the electrophilic, nucleophilic or -based substitution. In such aromatic ring, coined herein as an “ester dance” reaction. cases, aromatic rearrangement reactions can help access ring posi- During our recent efforts in the development of decarbonylative tions that are difficult to functionalize otherwise. Although there are transformations of aromatic (9–13), we found that a phenyl many well-known aromatic rearrangements such as the Smiles, carboxylate at the C1-position of phenyl 1-naphthoate (1a) mi- Claisen, and Bamberger rearrangements, these transformations grated to the C2-position, affording phenyl 2-naphthoate (2a) un- leave behind a functional group at the carbon atom that was origi- der palladium catalysis, albeit with low conversion (18% yield of 2a, nally substituted in the starting material (Fig 1A). A more rare type Fig. D). We hypothesize that product 2a can potentially arise from a of aromatic rearrangement involves translocation of a functional formal 1,2-rearrangement of the ester (phenyl carboxylate) in 1a, in- group, in which the carbon atom bearing the functional group in the volving: (1) oxidative addition of palladium into the ester C(O)–O starting material loses the group entirely, and the same group is bond; (2) deprotonation (ortho C–H bond activation of complex brought back to another carbon atom on the aromatic ring. One ex- A) followed by decarbonylation (14), producing an aryne-palladium ample of this type of aromatic translocation is , which complex (or a h2-arene–palladium complex; complex B) (15–18); is a disproportionation of an group under Friedel–Crafts alkyl- (3) protonation and carbonylation; and (4) reductive elimination. ation conditions, also known as a carbon-substituent rearrangement The product 2a is thermodynamically more stable than reactant 1a (Fig. 1B) (2–4). This reaction can translocate an alkyl substituent to (3.7 kcal/mol lower in energy, Figs. S6 and S7), and it is likely that another position on the same aromatic ring or onto another aromatic this is a reversible reaction that thermally converges to 2a. The prod- ring, allowing for several compounds including to form from uct in this experiment is an ester that can be reacted with nucleo- a single starting material; therefore, it is utilized mainly in the petro- philes using versatile reactions such as metal-catalyzed decarbonyla- chemical industry. However, this reaction requires extremely harsh tive coupling reactions (10–13,19–24), amidation (25) and conditions and unpredictably generates a mixture of products. formation (26,27) (see Fig. S1, more details). Therefore, we began An intriguing example utilized in the synthesis of fine chemicals is to examine to develop this unprecedented reaction. called the “halogen dance” reaction of haloarenes (Fig. 1C) (5–7). After extensive investigation, we found the optimal conditions: This reaction is a translocation induced by a strong base, and pro- when the reaction was conducted with 10 mol% PdCl2, 20 mol% vides a regioisomeric product via a sequence of halogen-metal ex- dcypt [3,4-bis(dicyclohexylphosphino)thiophene](28), and K2CO3 change processes on the aromatic ring. The net effect is a removal of (0.5 equiv) in m- at 150 ºC for 24 h, 1a was converted to 2a in a halogen atom from one ring carbon, and placement onto another 85% yield along with recovered 1a (7% yield) (Table 1, standard ring carbon. Due to its practical and predictable nature, this reaction conditions; also, see Tables S1–S9).Without PdCl2, dcypt, or K2CO3, is often exploited even in the total synthesis of complex natural prod- the reaction completely shut down (Entries 1–3). Other palladium ucts (7). In an example of a simultaneous, multiple rearrangement salts also worked, albeit with a lower yield of 2a; other metal salts on an aromatic ring, Scott and coworkers observed a rearrangement such as NiCl2 were ineffective (Entries 4 and 5). Other electron-rich of boron in an iridium-catalyzed borylation with cata- bidentate ligands such as dcype and dcypbz were also effective, but lytic potassium tert-butoxide (8). To the best of our knowledge, the yields were slightly lower (Entries 6 and 7). Further

A. Aromatic rearragement and translocation

Y X X Y X X Table 1. Selected optimizations of reaction conditions. Rearrangement Y or O OPh 10 mol% PdCl O OPh Ar Ar’ Ar’ and/or Ar’ 2 O 20 mol% dcypt many reports 1 1 2 K CO (0.5 equiv) Y 2 3 + OPh e.g. Smiles e.g. Claisen e.g. Bamberger m-xylene (0.5 M) X 150 °C, 24 h 1a 1a: 7% recovered 2a: 85% yield Translocation X Standard conditionsa Ar Ar or Ar or Ar few reports X X GC yield (%)b deviation from S entrya the standard conditions 1a 2a B. Transalkylation OH 1 without PdCl2 74 0 P P Me OH Me 2 without dcypt 73 0 Me H+ dcypt cat. Me 3 without K2CO3 86 0 + Me 4 PdBr2 15 51 5 NiCl2 55 1 6 dcype 14 72 Me Me Me Me 7 dcypbz 23 67 8 dppe 78 0 9 dppf 78 0 P P C. Halogen dance reaction Br Li 10 BINAP 79 0 dcype 11 PCy3 86 0 Br Br Br Br H 12 ICy 67 0 H Li Ar Ar 13 Xphos 66 0 LDA + SM H O Br c 2 14 Na2CO3 79 6 Ar Ar Ar c 15 Cs2CO3 0 0 Li Br c 16 K3PO4 65 16 SM H H 17 58 28 P P Ar Ar 18 1,4-dioxane 42 44 dcypbz 19 DMF 6 5

D. Ester dance reaction (This work) a 1a (0.4 mmol), PdCl2 (10 mol%), dcypt (20 mol%), K2CO3 (0.2 b O OPh O OPh mmol), m-xylene (0.8 mL), 150 ºC, 24 h GC yield was determined by O c 1 cat. Pd 1 2 using n-decane as an internal standard. Base (1.5 equiv) was added. base + OPh 150 °C, 24 h 1a 1a: 60% recovered 2a: 18% yield Generally, this reaction formed the corresponding product 2 (42– 71% yields) along with small amounts of recovered starting material (5–20% yields), as well as hydrolyzed benzoic derivatives (5– Complex A Complex B 10% yields). Starting materials with benzo[d][1,3]dioxol-5-yl (1k), Oxidative Deprotonation Protonation addition Decarbonylation Carbonylation; naphthyl (1l) and pyridyl groups (1m) were tolerated under these Reductive elimination reaction conditions, producing the corresponding regioisomers 2k– Complex A Complex B L 2m. Pd L L O OPh Next, we examined this translocation reaction on heteroarene Pd Pd H CO CO cores under the optimized conditions. To this end, isonicotinates or HOPh HOPh (C4-carboxylated ) were found to be applicable in this re- ortho C–H bond activation aryne-Pd η2-arene Pd action, with the ester substituents migrating from the C4- to the C3- position of the , giving nicotinate products. The use of phe- Fig. 1. (A) Aromatic rearrangement and translocation. (B) Transal- nyl (1n), p-methoxyphenyl (1o) and p-fluorophenyl (1p) isonico- kylation of aromatics. (C) Halogen dance reaction of (hetero)aromatics. tinates afforded the corresponding nicotinates 2n–2p with moder- (D) Discovery of an “ester dance” reaction of aromatic esters, and a ate conversions. When an electron-donating group was present, the plausible mechanism. direction of the isomerization interestingly changed: 2-methoxy- isonicotinate (2q) and 2-ethoxyisonicotinate (2r) were obtained in 61% and 47% isolated yields from the corresponding nicotinates via nearly shut down completely when the base was changed from this translocation reaction. p-Anisyl 2-methoxynicotinate (1s) also K2CO3 (Entries 14–16); assisted deprotonation during the ortho C– gave the C4- 2s in good yield. With benzo-fused heteroarenes, H bond activation of complex A is likely to be important. When us- phenyl quinoline-4-carboxylate (1t) gave C3-isomer 2t in good ing other solvents, toluene or 1,4-dioxane showed successful reac- yield, and phenyl benzo[b]thiophene-2-carboxylate (1u) was also tions but the yields were diminished (Entries 17–19). converted into C3-isomer 2u, albeit with reduced yield (27%). It is With the optimized conditions in hand, the scope of this “ester worth noting that 1u, generated from the corresponding carboxylic dance” was explored (Fig. 2; also see Supplementary information re- acid (costing $20/g, Sigma-Aldrich), can be transformed into a garding the yields of recovered starting materials). In the first series much more precious derivative (the acid derivative of experiments, the naphthoate portion of phenyl 1-naphthoate (1a) of 2u costs $13,300/g). was kept constant, but the was modified. Various We also investigated other aromatic esters such as phenyl benzo- groups such as p-tolyl, m-tolyl and o-tolyl (1b–1d), p-anisyl and m- ates (1v–1aa). Phenyl benzoates, in which the para position of the anisyl (1e and 1f), p-fluorophenyl and m-fluorophenyl (1g and 1h), benzoate was substituted by trifluoromethyl (1v), sulfonamide (1w), p- and m-biphenyl (1i and 1j) gave the corresponding aryl- methyl ester (1x), or methyl (1y), formed products 2v–2y under the 2-naphthoates in moderate yields (2b–2j).

O OAr’ 10 mol% PdCl 2 O 20 mol% dcypt S K2CO3 (0.5 equiv) OAr’ Ar Ar P P m-xylene (0.5 M) 150 °C, 24 h dcypt 1 2 31 examples 2-Naphthoate O O O O O O 2b (p-Me) : 50% 1 2c (m-Me) : 71% N 2 O O O O O O 2d (o-Me) : 42% R 2e (p-OMe) : 45% 2f (m-OMe) : 66%a 2g (p-F) : 76% b 2a: 86% 2k: 70% 2l: 64% 2m: 33% 2h (m-F) : 66% 2i (p-Ph) : 51% 2j (m-Ph) : 47% Heteroaryl R OMe O O O O O 4 4 3 R MeO 3 3 O O O O O N N S N N 2 b, c 2n (R = H) : 54%b 2q (R = OMe) : 61%b 2s : 74% 2t : 60%b 2u: 27% b 2o (R = OMe) : 62% 2r (R = OEt) : 47% from benzothiophene-2-CO H ($20/g) a 2 2p (R = F) : 40% to 2-benzothiophene-3-CO2H ($13,300/g)

Other aromatics

O O O O O O 4 1 1 3 F 2 2 O O O O O O R

CF3 R Me

b b, c b a a 2ad (R = H) : 71% 2v (R = CF3) : 46% 2z: 30% 2aa: 23% 2ab: 36% 2ac: 41% b from 4-Me-naphth-1-CO2H ($8/g) 2w (R = SO2NPr2) : 28% from pyrene-1-CO2H ($55/g) ® to pyrene-2-CO H ($454/g) to 1-Me-naphth-3-CO2H ($2,998/g) from Probenecid 2 2ae (R = Me) : 44% b 2x (R = CO2Me) : 42% 2y (R = Me) : 30%d Fig. 2. Substrate scope. a The reaction was conducted at 160 ºC. b The reaction was conducted at 140 ºC. c The reaction was conducted for 36 h. d The reaction was conducted at 170 ºC. standard reaction conditions. Notably, 1w, which is derivatized from decarbonylative C–H coupling under the same catalytic conditions Probenecid® (a well-known drug for the treatment of gout), can be (13). As already mentioned for Fig. 2., phenyl 4-pyridine carboxylate transformed directly to its C3-isomer 2w. o-Fluoro- (1z) and m-tri- (1n) rearranges to phenyl nicotinate (2n). Curiously, however, in fluoromethyl- (1z) benzoates also allowed the ester substituent to the presence of a sterically hindered diphenyl (4B), the ester migrate and gave the corresponding products 2z and 2aa, albeit with dance reaction occurred in reversed fashion (from 2n to 1n), fol- low conversions. Additionally, this translocation reaction enabled lowed by decarbonylative amination to afford the corresponding the synthesis of products that are otherwise difficult to make. For ex- coupling product 3B in 62% yield (Fig. 3B). Additionally, when 2t ample, phenyl ester 1ac derivatized from pyrene-1-carboxylic acid was treated under modified standard conditions, diaryl 3C was ($55/g) gave a derivative of pyrene-2-carboxylic acid ($454/g), obtained in 43% yield (Fig. 3C). Although the possible intermediate which is useful for pyrene-labeled fluorescent biosensors(29,30). 1t is thermodynamically unstable compared with 2t, the decarbonyl- Additionally, the corresponding carboxylic acid of aryl 4-methyl-1- ative etherification occurs only at the C4-position on the quinoline naphthoates (1ad and 1ae) is an inexpensive compound ($8/g), but ring, and therefore 3C was obtained with virtually complete regiose- can be reacted under the standard conditions to afford the C2 iso- lectivity (15). Finally, we successfully achieved a 1,3-translocation mers 2ad and 2ae (an ester derivative of an expensive carboxylic acid, product (i.e., two sequential translocations) from 1n to 3n through $2,998/g). Although the reaction mechanism remains unclear, we 2n, when we attempted to react 1n for a longer time from 24 to 48 h investigated 1) the reversibility of both isomers using 1v and 2v (Fig. (Fig. 3D). In fact, 2n is thermodynamically more stable than 1n (by S3), 2) the electronic and steric effects of aromatic rings (Tables S24 0.5 kcal/mol), with 3n bearing the highest G (1.08 kcal/mol). and S25), and 3) a deuterium labeling experiment (Figs. S4 and S5). However, the decarbonylative etherification proceeds only from the These experiments confirmed that this reaction is reversible, and C2 position of azine carboxylates (12), and therefore 3D was ob- deprotonation of the ortho- atom occurs. tained as the major isomer (see Tables S10–S23 and Figs. S8–S12 Furthermore, we demonstrated a combination of the ester dance for more details). Overall, the present ester dance reaction can fur- reaction and decarbonylative coupling (Fig. 3). Phenyl 3-thiocar- nish not only thermodynamically stable regioisomers at the adjacent boxylate (1af) was reacted with benzothiazole (4A) under the opti- carbon atom, but also other substitution patterns when combined mized conditions to give 3A in 60% yield as the major isomer (Fig. with further ester-transforming reactions. We believe that this trans- 4A). This reaction takes place because the ester dance reaction of 1af location will help the organic chemist synthesize (hetero)aromatic occurs first to give phenyl 2-thiocarboxylate, followed by compounds that are difficult or expensive to access, by providing an unconventional yet predictable synthetic approach.

ACKNOWLEDGMENT O OAr’ cat. Pd/ dcypt O We thank Prof. Kenichiro Itami, Dr. Eisuke Ota, Toshimasa Okita, and K2CO3 Nu (4) Nu OAr’ Dr. Yoshihiro Ishihara (Vertex Pharmaceuticals) for fruitful discussion Ar Ester Dance Ar Decarbonylative Ar Coupling and critical comments. The Materials Characterization Central Labora- 1 2 3 tory in Waseda University is acknowledged for the support of HRMS

A measurement. We also would like to thank National Institute of Health O OPh cat. Pd/ Sciences in Japan for the support of NMR measurement. Funding: This dcypt 3 N 3 2 N K3PO4 2 + work was supported by JSPS KAKENHI Grant Number H S S S Ester Dance S JP19H02726,JP18H04272 (to J.Y.), JP18H04661 (Hybrid Catalysis), Decarbonylative 1af 4A C–H aryaltion 3A: 60% and JP19K15573 (to K.M.). Author contributions: J.Y. directed the projects and designed the experiments. K.M. and R.T. performed exper- B O OPh cat. Pd/ iments. All authors contributed to data analysis. J.Y. wrote the manu- dcypt Ph 3 Ph 3 script with feedback from the other authors. Data and materials availa- 4 K3PO4 4 N + H N Ph bility: Experimental procedures, extensive optimization data, 1H NMR N Ph Ester Dance N 13 Decarbonylative spectra, C NMR spectra, and MS data are available in the supplemen- Amination 2n 4B 3B: 62% tary materials.

C cat. Pd/ REFERENCES O OPh dcypt O 3 K2CO3 3 3 1. J. Mortier, Ed., Arene Chemistry: Reaction Mechanisms and Methods for 4 4 4 OPh OPh Aromatic Compounds (Wiley, 2015). Ester Dance Decarbonylative N N N Etherification 2. K. Griesbaum et al, Ullmann's Encyclopedia of Industrial Chemistry (Wiley, 2011). 3. T.-C. Tsai, S.-B. Liu, I. Wang, Appl. Catal., A 181, 355–398 (1999). 2t 1t 3C: 43% 4. I. O. Voronin, T. N. Nesterova, B. S. Strelchik, E. A. Zhuravskii, Kinetics and Catalysis, 55, 705–711 (2014). D O OPh cat. Pd/ 5. J. F. Bunnett, Acc. Chem. Res. 5, 139–147 (1972). dcypt 4 4 3 K3PO4 6. M. Schnürch, M. A. F. Spina, Khan, M. D. Mihovilovic, P. Stanetty, Chem. 3 2n 3n 2 Soc. Rev. 36, 1046–1057 (2007). 2 Ester Dance Ester Dance Decarbonylative N OPh N Etherification 7. T. Sammakia, E. L. Stangeland, M. C. Whitcomb, Org. Lett. 4, 2385–2388 (2002). 3D: 25% 1n O 8. M. N. Eliseeva, L. T. Scott, J. Am. Chem. Soc. 134, 15169–15172 (2012). 4 4 3 9. R. Takise, K. Muto, J. Yamaguchi, Chem. Soc. Rev. 46, 5864–5888 (2017). 3 OPh 2 10. K. Amaike, K. Muto, J. Yamaguchi, K. Itami, J. Am. Chem. Soc. 134, OPh N 2 N 13573–13576 (2012). O 11. K. Muto, J. Yamaguchi, D.G. Musaev, K. Itami, Nat. Commun. 6, 7508 2n 3n (2015). 12. R. Takise, R. Isshiki, K. Muto, K. Itami, J. Yamaguchi, J. Am. Chem. Soc. 139, 3340–3343 (2017). 13. K. Matsushita, R. Takise, T. Hisada, S. Suzuki, R. Isshiki, K. Itami, K. 1n 2n 3n Muto, J. Yamaguchi, Chem. Asian. J. 13, 2393–2396 (2018). 14. A. A. Cant, L. Roberts, M. F. Greaney, Chem. Commun. 46, 8671–8673 1.08 (2010). 0.50 [kcal/mol] 15. D. A. Watson, M. Su, G. Teverovskiy, Y. Zhang, J. García- Fortanet, T. ΔG = 0.0 Kinzel, S. L. Buchwald, Science 325, 1661–1664 (2009). 16. P. J. Milner, T. Kinzel, Y. Zhang, S. L. Buchwald, J. Am. Chem. Soc. 136, Fig. 3. Ester dance reaction followed by decarbonylative coupling. 15757–15766 (2014). (A) Ester dance and decarbonylative C–H arylation of benzothiazole 4A. 17. M. Retbøll, A. J. Edwards, A. D. Rae, A. C. Willis, M. A. Bennett, E. (B) Ester dance and decarbonylative amination of 2n. (C) Ester dance Wenger, J. Am. Chem. Soc. 124, 8348–8360 (2002). and decarbonylative etherification of 2t via 1t. (D) Double ester dance 18. Y. Sumida, T. Sumida, D. Hashizume, T. Hosoya, Org. Lett. 18, 5600– then decarbonylative etherification, as well as a comparison of free ener- 5603 (2016). gies between 1n, 2n and 3n. 19. T. Okita, K. Muto, J. Yamaguchi, Org. Lett. 20, 3132–3135 (2018). 20. A. Chatupheeraphat, H.-H. Liao, S.-C. Lee, M. Rueping, Org Lett. 19, ASSOCIATED CONTENT 4255–4258 (2017). 21. R. Issiki, K. Muto, J. Yamaguchi, Org. Lett. 20, 1150–1153 (2018). AUTHOR INFORMATION 22. H. Yue, L. Guo, H.-H. Liao, Y. Cai, C. Zhu, M. Rueping, Angew. Chem., Int. Ed. 56, 4282–4285 (2017). Corresponding Author 23. X. Pu, J. Hu, Y. Zhao, Z. Shi, ACS Catal. 6, 6692–6698 (2016). *[email protected] 24. H. Yue, L. Guo, S.-C. Lee, X. Liu, M. Rueping, Angew. Chem. Int. Ed. 56, 3972–3976 (2017). ORCID 25. S. Shi, M. Szostak, Chem. Commun. 53, 10584–10587 (2017). Kei Muto: 0000-0001-8301-4384 26. A. Chatupheeraphat et al., J. Am. Chem. Soc. 140, 3724–3735 (2018). 27. T. Ben Halima et al., J. Am. Chem. Soc. 139, 1311–1318 (2017). Junichiro Yamaguchi: 0000-0002-3896-5882 28. R. Takise, K. Muto, J. Yamaguchi, K. Itami, Angew. Chem. Int. Ed. 53, 6791–6794 (2014). Notes 29. J. Wu et al., J. Am. Chem. Soc. 134, 1958–1961 (2012). No competing financial interests have been declared.

30. A. C. Benniston, A. Harriman, S. L. Howell, C. A. Sams, Y.-G. Zhi, Chem. Eur. J. 13, 4665–4674 (2007). S

P P O OAr’ dcypt O 1 R1 PdCl R1 2 2 OAr’ Ar Ar 2 4 K2CO3 2 4 R R m-xylene R R R3 150 °C, 24 h R3 31 examples