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Aromatization-Driven Cascade [1, 5]-Hydride Transfer/ Spirocyclization Promoted by Fluorinated Alcohols Xintong Lv, Fangzhi Hu, Kang Duan, Shuai-Shuai Li, Qing Liu, and Jian Xiao J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02754 • Publication Date (Web): 04 Jan 2019 Downloaded from http://pubs.acs.org on January 5, 2019

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The Journal of Organic Chemistry

Aromatization-Driven

Cascade

[1,

5]-Hydride

Transfer/Spirocyclization Promoted by Fluorinated Alcohols †〢

†〢

Xintong Lv, , Fangzhi Hu, , Kang Duan,† Shuai-Shuai Li,*,† Qing Liu,§ Jian Xiao*,†,‡ †

Shandong Province Key Laboratory of Applied Mycology, College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, China ‡ College

of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China.

§College

of Chemical and Environmental Engineering, Shandong University of Science and Technology, Qingdao 266590, China

Corresponding author: Shuai-Shuai Li; Jian Xiao E-mail address: [email protected]; [email protected]

Graphic Abstract

Abstract: The aromatization-driven redox-neutral cascade [1,5]-hydride transfer/spirocyclization and cascade [1,5]-hydride transfer/hydrolysis from para-quinone methide in HFIP were developed. These protocols enabled the synthesis of azaspirocyclohexadienones and ortho-benzylated anilines in good to high yields under mild conditions, featuring room temperature, additive-free and good functional group tolerance. INTRODUCTION Spirocyclohexadienones are widely distributed as privileged structures in a range of natural products and pharmaceutical molecules with unique biological activities.1 Moreover, they have also been extensively utilized as synthetically important building blocks in organic synthesis and material chemistry.2 As such, the development of powerful methodologies to construct these frameworks has received considerable attention in the synthetic community.3 Among the various methods, the employment of para-quinone methide (p-QM) as a synthon via intermolecular [2+n]

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cycloadditions to construct spirocyclohexadienones have made a significant progress. For instance, the strategies to construct spiro[2.5]octa-4,7-dien-6-one unit have been established by Yao, Fan and Waser groups through 1,6-addition-mediated [2+1] annulation of p-QMs with bromomalonates4, sulfur ylides5 and ammonium ylides6 (Scheme 1, eq 1). In addition, the transition metal-catalyzed 1,6-addition-invovled

[3+2]

annulations

of

p-QMs

with

propargyl

malonates

and

vinylcyclopropanes to synthesize spiro[4.5]deca-6,9-dien-8-one skeleton have been achieved by Lin and Zhao groups, respectively (Scheme 1, eq 2).7 Recently, Yao group successfully accomplished the construction of 2-oxaspiro[5.5]undeca-7,10-dien-9-ones by reaction of p-QMs with allyl carbonates through palladium-catalyzed oxa-[4+2] annulation (Scheme 1, eq 3).8 Despite these advances with p-QMs-involved [2+n] cycloadditions, it is still highly desirable to explore a novel methodology to access spirocyclohexadienones from p-QMs. Redox-neutral cascade [1,5]-hydride transfer/cyclization has attracted intense interest as an efficient strategy for direct functionalization of C(sp3)-H bonds.9 As is well-known, this reaction relies on the transfer of α-H adjacent to heteroatom, induced by electron-deficient hydride acceptors, such as electron-poor alkenes,10 alkynes,11 carbonyl derivatives,12 and so on.13 Given the inherent reactivity of p-QMs,14 we wondered whether the propensity for aromatization could serve as a powerful driving force to initiate the intramolecular hydride transfer, producing active iminium Scheme 1. p-QMs-Involved Methods for Synthesis of Spirocyclohexadienones


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intermediates, then it can be further elaborated in miscellaneous means. As our continuing interest in one-step assembly of molecular complexity via hydride transfer,15 herein, we report p-QMs initiated cascade [1,5]-hydride transfer/cyclization and cascade [1,5]hydride transfer/hydrolysis reaction in hexafluoroisopropanol (HFIP), allowing the generation of azaspirocyclohexadienones and ortho-benzylated anilines in high efficiency (Scheme 1, eq 4). RESULTS AND DISCUSSION Table 1. Optimization of the Reaction Conditionsa

entry

catalyst

solvent

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

(-)-CSA PhCO2H Cu(OTf)2 Sc(OTf)3 Mg(OTf)2 ------

DCE DCE DCE DCE DCE TFE HFIP i-PrOH H2O HFIP

concentration (mol/L) 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.10

time (h) 24 24 24 24 48 24 10 min 24 24 10 min


yield (%)b 32 20 42 40 50 39 90 0 0 85


aReaction bIsolated

11e -HFIP 0.025 10 min 89 conditions: 1a (0.05 mmol), catalyst (10 mol%), in 1 mL of solvent at room temperature under air.

yield after column chromatography. cAt 100 C. d0.5 mL of HFIP. e2 mL of HFIP.

Initially, p-QM 1a carrying pyrrolidine at the ortho-position was designed as the model substrate to validate our hypothesis (Table 1). At first, various Brønsted acids and Lewis acids catalysts were employed in DCE to examine their catalytic activity at room temperature. Satisfyingly, the expected reaction exactly occurred in the presence of acid catalysts, albeit affording 2a in low yields (Table 1, entries 1-5). Obviously, the triflate salts exhibited slightly higher catalytic performance than Brønsted acids, and a moderate yield was observed in the presence of 10 mol % Mg(OTf)2 after 48 h (Table 1, entry 5). With the low yields of acids catalysts, we noticed that fluorinated alcohols were extraordinary solvents with unique properties, which could promote a great deal of chemical processes through hydrogen bonding activation.16 Inspired by the outstanding performance of fluorinated alcohols and our previous success with these solvents,17 then fluorinated alcohols were examined as reaction solvents and promoters. To our delight, trifluoroethanol (TFE) could promote this transformation to deliver 2a in 39% yield after 24 h (Table 1, entry 6). Surprisingly, when HFIP was employed as a solvent, both the yield and reaction rate was significantly enhanced, affording 2a in 90% yield within 10 mins (Table 1, entry 7). However, neither i-PrOH nor H2O took effect in Table 2. The Scope of [1,5]-Hydride Transfer/Cyclizationa


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aReaction

conditions: 1 (0.1 mmol) in 2 mL of HFIP at room temperature under air, isolated yield after column

chromatography. b1a (2.2 mmol) in 44 mL of HFIP. cAt 100 C. dIn 4 mL of HFIP.

this reaction, even heating at 100 °C, which might be ascribed to their weak hydrogen bond donor ability (Table 1, entries 8-9). Further increasing or decreasing the reaction concentration lowered the yields (Table 1, entries 10-11). Therefore, the use of HFIP as a solvent with 0.05 mol/L was finally selected as the best reaction conditions. With the optimized conditions in hand, various p-QMs were subjected to HFIP to evaluate the generality of this process. As shown in Table 2, a range of substrates were tolerable in HFIP,



affording various functionalized 2-azaspiro[5.5]undeca-7,10-dien-9-ones 2a-s in high yields. The substitution effect on the phenyl ring was firstly checked. Pleasingly, both electron-donating and electron-withdrawing groups worked very well in this system (2a-k). In addition, conducting the reaction on a larger scale (2.2 mmol) almost had no effect on the efficiency which demonstrated the practical utility of the method as a synthetic tool. And the structure of 2c was unambiguously confirmed by X-ray crystallographic analysis (see the Supporting Information). Further varying the position of substituents on the phenyl ring indicated that the chlorine substituent at the ortho-, metaand para-position of alkene group were fully compatible, delivering the desired products in high yields (2f-h). In particular, the substrate bearing strong electron-withdrawing nitro group also exhibited good compatibility, furnishing the corresponding product 2k in quantitative yield (99%), which was conducive for further application. Afterwards, different functional groups were installed on phenyl ring to further test the applicability of this protocol. Fortunately, in addition to the halide and trifluoromethyl groups, a wide range of functional groups survived in this reaction, including cyano, alkenyl ester, and acetyl groups, affording the corresponding products (2l-o) in excellent yields. The good functional group tolerance demonstrated the robust capacity of this strategy in preparing diversely functionalized azaspiro-cyclohexadienones-based molecules. Particularly, the replacement of the phenyl ring with electron-poor quinoline and naphthyl moiety was also amenable for this intramolecular redox reaction, affording the corresponding products 2p and 2q in 95% and 98% yields, respectively. Satisfyingly, the p-QMs carrying ortho-acyclic amines, such as N, Ndimethyl group, were also good candidates, furnishing the desired products (2r and 2s) in moderate to good yields. Surprisingly, in addition to N,N-dimethyl group, the substrates incorporating other acyclic amines including N,N-dibenzyl, N-methyl-N-benzyl and N,N-diethyl groups were inapplicable for this cyclization process, producing the ortho-benzylated anilines 3a-c in high yields (Table 3). Undoubtedly, for these substrates, the [1, 5]-hydride transfer reactions occurred to generate the iminium ions successfully. However, these iminium ions underwent hydrolysis rather than intramolecular cyclization, which might be ascribed to the relative instability of iminium ions. In addition, in case of product 3b, the hydrolysis priority of benzyl group over methyl group implied that formaldehyde was an undesired hydrolysate, which was consistent with the fact that N, N-


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dimethyl group succeeded in the cyclization process (2r-s). On the other hand, the substituents on the phenyl ring had significant influence on the reaction efficiency. Various electron-withdrawing groups were fully compatible in this reaction, affording the corresponding products 3d-g in good yields. Nevertheless, the substrates incorporating electron-donating substituents such as methyl and methoxyl groups produced complex mixtures, which were difficult to isolate. It is noteworthy that the diarylmethane products were structural hybrids of benzylated phenols and benzylated anilines, which constituted core structures of natural products, medicines and materials.18 This transformation also provided an alternative way for debenzylation and deethylation processes. Table 3. Substrate-Controlled Cascade [1,5]-Hydride Transfer/Hydrolysisa

aReaction

conditions: 1 (0.1 mmol) in 2 mL of HFIP at room temperature under air, isolated yield after column

chromatography.

On the basis of the above experimental studies, a plausible reaction mechanism was proposed in Scheme 2. Firstly, p-QMs 1 are activated by hydrogen bonding clusters of HFIP to form complex I,19-20 in which HFIP acts as a netted charge template to decrease the electron density of conjugate p-QM. Consequently, the strong propensity for aromatization of p-QMs initiated the intramolecular [1,5]-hydride transfer, generating the rearomatic complex II with iminium ion. Subsequently, two competitive reaction pathways, i.e. hydrolysis and dearomatization/nucleophilic addition might operate for zwitterionic intermediate II. The followed dearomatization/nucleophilic addition



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process produces the dearomatic azaspiro-cyclohexadienones 2 (path A), and the hydrolysis process will give the ortho-benzylated anilines 3, alternatively (path B, R1 = Me or Ph). It is the substituents installed on nitrogen atom that determine which way would go. We reason that the tert-butyl groups on the quinone moiety play an important role on the difference between the HFIP promoted reaction and Lewis-acid catalyzed reactions. HFIP is relatively small molecule, thus it is easy to activate the carbonyl moiety with the vicinal and sterically hindered tert-butyl groups. Nevertheless, it is much more difficult to activate the carbonyl moiety with the bulky Lewis-acid catalysts.

Scheme 2. Proposed Reaction Mechanism

CONCLUSION In

conclusion,

we

have

developed

p-QMs-triggered

cascade

[1,5]-hydride

transfer/Spirocyclizations and cascade [1,5]-hydride transfer/hydrolysis reactions in HFIP. These protocols enabled the synthesis of 2-azaspiro[5.5]undeca-7,10-dien-9-one and ortho-benzylated anilines in good to high yields under mild conditions, featuring room temperature, additive-free, and good functional group tolerance. This work integrates and greatly pushes forward the chemistry of hydride transfer and p-QMs, two important areas in organic chemistry. Moreover, these protocols demonstrated that aromatization could serve as a powerful driving force to trigger hydride transferinvolved cascade reactions for construction of architecturally complex molecules, which opens a new avenue for C(sp3)-H functionalization. Further investigations to develop new reactions by exploiting aromatization-driven hydride transfer are underway in our laboratory.


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Experimental Section All the reactions were performed in sealed tube and monitored by TLC (0.2 mm silica gel-coated HSGF 254 plates). The products were purified by flash column chromatography (200-300 mesh silica gel) eluted with the gradient of petroleum ether and ethyl acetate. Proton nuclear magnetic resonance spectra (1H NMR) were recorded on a Bruker 500 MHz NMR spectrometer (CDCl3 solvent). The chemical shifts were reported in parts per million (ppm), downfield from SiMe4 (δ 0.0) and relative to the signal of chloroform-d (δ 7.26, singlet) or dimethyl sulfoxide-d6 (δ 2.54, singlet). Multiplicities were given as: s (singlet); d (doublet); t (triplet); q (quartet); dd (doublets of doublet) or m (multiplets). The number of protons for a given resonance is indicated by nH. Coupling constants are reported as a J value in Hz. Carbon nuclear magnetic resonance spectra (13C NMR) were reported in ppm using solvent CDCl3 (δ (ppm) = 77.16 ppm) as an internal standard. HRMS analyses were performed on a Waters XEVO QTOF mass spectrometer. All substituted 2fluorobenzaldehydes, and 2,6-di-tert-butylphenol were purchased from adamas-beta. General Procedure for the Preparation of para-Quinone methides Carrying Pyrrolidine at the ortho-Position A round bottom flask was charged with 2,6-di-tert-butylphenol S-1 (5.2 mmol), oaminobenzaldehyde S-2 (4 mmol), piperidine (8 mmol) and toluene (40 mL). The mixture was stirred at 120 C in oil bath under an air atmosphere for 12 h until S-2 was consumed up. The mixture was concentrated in vacuum and the residue was directly purified by alkaline aluminum oxide column chromatography (eluent: petroleum ether) to afford the desired para-quinone methides 1. General Procedure for the Synthesis of Spiro-cyclohexadienones A reaction tube was charged with para-quinone methide 1 (0.1 mmol) and HFIP (2.0 mL). The mixture was stirred at room temperature under an air atmosphere. Upon completion of the reaction as indicated by TLC analysis, the mixture was concentrated in vacuum at room temperature and the



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residue was directly purified by flash column chromatography on neutral alumina (eluent: ethyl acetate/petroleum ether, 1:200) to afford the desired spiro-cyclohexadienones 2.

General Procedure for the Synthesis of 2a on a Larger Scale

A reaction tube was charged with para-quinone methide 1a (2.2 mmol) and HFIP (44.0 mL). The mixture was stirred at room temperature under an air atmosphere. Upon completion of the reaction as indicated by TLC analysis, the mixture was concentrated in vacuum at room temperature and the residue was directly purified by flash column chromatography on neutral alumina (eluent: ethyl acetate/petroleum ether, 1:200) to afford the desired spiro-cyclohexadienones 2a in 80% yield (638 mg). 2,6-di-tert-butyl-4-(2-(pyrrolidin-1-yl)benzylidene)cyclohexa-2,5-dien-1-one (1a). Red solid, 1.09 g, 75% yield; 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 1.9 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 7.3 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.90 – 6.84 (m, 2H), 3.29 (t, J = 6.4 Hz, 4H), 1.94 (t, J = 6.4 Hz, 4H), 1.34 (s, 9H), 1.30 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.6, 150.5, 148.4, 147.0, 144.4, 135.1, 133.2, 129.9, 128.9, 128.7, 124.5, 118.5, 114.7, 52.4, 35.4, 34.9, 29.6, 29.6, 25.7 ppm. HRMS (ESI): calcd. for C25H34NO [M+H]+: 364.2635, found: 364.2640. 2,6-di-tert-butyl-4-(4-methoxy-2-(pyrrolidin-1-yl)benzylidene)cyclohexa-2,5-dien-1-one (1b). Yellow solid, 1.24 g, 79% yield; 1H NMR (500 MHz, CDCl3) δ 7.53 (s, 1H), 7.23 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 6.46 (d, J = 8.5 Hz, 1H), 6.40 (s, 1H), 3.85 (s, 3H), 3.31 (s, 4H), 1.94 (s, 4H), 1.34 (s, 9H), 1.31 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.5, 161.5, 152.0, 148.0, 146.4, 144.5, 135.2, 134.8, 128.7, 127.7, 118.0, 104.0, 100.8, 55.2, 52.5, 35.3, 34.9, 29.6, 29.5, 25.6 ppm. HRMS (ESI): calcd. for C26H36NO2 [M+H]+: 394.2741, found: 394.2748. 2,6-di-tert-butyl-4-(4-methyl-2-(pyrrolidin-1-yl)benzylidene)cyclohexa-2,5-dien-1-one

(1c).

Red

solid, 1.14 g, 76% yield; 1H NMR (500 MHz, CDCl3) δ 7.54 (s, 1H), 7.25 (s, 1H), 7.15 (d, J = 7.9 Hz, 1H), 7.02 (s, 1H), 6.70 (s, 2H), 3.29 (s, 4H), 2.36 (s, 3H), 1.93 (s, 4H), 1.34 (s, 9H), 1.30 (s, 9H); 13C{1H}


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NMR (126 MHz, CDCl3) δ 186.6, 150.6, 148.2, 146.7, 144.7, 140.4, 135.3, 133.3, 128.8, 128.5, 122.0, 119.7, 115.5, 52.5, 35.4, 34.9, 29.6, 29.6, 25.6, 21.8 ppm. HRMS (ESI): calcd. for C26H36NO [M+H]+: 378.2791, found: 378.2799. 2,6-di-tert-butyl-4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzylidene)cyclohexa-2,5-dien-1-one (1d). Yellow solid, 1.33 g, 77% yield; 1H NMR (500 MHz, CDCl3) δ 7.41 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 7.06 (d, J = 11.2 Hz, 2H), 7.02 (s, 1H), 3.34 (s, 4H), 1.97 (s, 4H), 1.34 (s, 9H), 1.29 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.6, 150.0, 149.1, 147.7, 142.3, 134.6, 133.4, 131.3 (q, J = 31.5 Hz), 130.2, 128.0, 126.8, 124.2 (q, J = 272.2 Hz), 120.9 (s), 114.4 (d, J = 3.7 Hz), 111.1 (d, J = 3.8 Hz), 52.3, 35.4, 35.1, 29.6, 29.5, 25.8 ppm. HRMS (ESI): calcd. for C26H33F3NO [M+H]+: 432.2509, found: 432.2511. 4-(4-bromo-2-(pyrrolidin-1-yl)benzylidene)-2,6-di-tert-butylcyclohexa-2,5-dien-1-one

(1e).

Yellow solid, 1.43 g, 81% yield; 1H NMR (500 MHz, CDCl3) δ 7.41 (s, 1H), 7.15 (s, 1H), 7.04 (d, J = 8.1 Hz, 1H), 7.02 – 6.93 (m, 3H), 3.29 (s, 4H), 1.94 (s, 4H), 1.33 (s, 9H), 1.29 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.6, 151.0, 148.8, 147.3, 142.9, 134.8, 134.3, 129.4, 128.2, 124.3, 122.8, 121.2, 117.6, 52.3, 35.4, 35.0, 29.6, 29.5, 25.7 ppm. HRMS (ESI): calcd. for C25H33BrNO [M+H]+: 442.1740, found: 442.1744. 2,6-di-tert-butyl-4-(4-chloro-2-(pyrrolidin-1-yl)benzylidene)cyclohexa-2,5-dien-1-one (1f). Yellow solid, 1.20 g, 76% yield; 1H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 1.9 Hz, 1H), 7.17 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 9.1 Hz, 2H), 3.30 (t, J = 6.4 Hz, 4H), 1.94 (t, J = 6.4 Hz, 4H), 1.33 (s, 9H), 1.29 (s, 9H);

C{1H} NMR (126 MHz, CDCl3) δ 186.6, 150.9, 148.7, 147.3,

13

143.0, 135.9, 134.8, 134.1, 129.3, 128.2, 122.4, 118.3, 114.7, 52.3, 35.4, 35.0, 29.6, 29.5, 25.8 ppm. HRMS (ESI): calcd. for C25H33ClNO [M+H]+: 398.2245, found: 398.2246. 2,6-di-tert-butyl-4-(5-chloro-2-(pyrrolidin-1-yl)benzylidene)cyclohexa-2,5-dien-1-one

(1g).

Red

solid, 1.11 g, 70% yield; 1H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 1.7 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.15 (s, 1H), 6.99 (d, J = 1.8 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 3.25 (t, J = 6.3 Hz, 4H), 1.94 (t, J = 6.4 Hz, 4H), 1.33 (s, 9H), 1.30 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.5, 148.9, 148.8, 147.5, 142.2, 134.7, 132.2, 129.8, 129.4, 128.1, 125.3, 123.3, 115.9, 52.4, 35.4, 35.0, 29.6, 29.5, 25.7 ppm. HRMS (ESI): calcd. for C25H33ClNO [M+H]+: 398.2245, found: 398.2246. 2,6-di-tert-butyl-4-(2-chloro-6-(pyrrolidin-1-yl)benzylidene)cyclohexa-2,5-dien-1-one

(1h).

Red

solid, 1.29 g, 81% yield; 1H NMR (500 MHz, CDCl3) δ 7.25 (s, 1H), 7.16 (t, J = 8.1 Hz, 1H), 7.04 (d, J



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= 1.6 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.84 (s, 1H), 6.78 (d, J = 8.5 Hz, 1H), 3.03 (s, 4H), 1.83 (d, J = 97.1 Hz, 4H), 1.34 (s, 9H), 1.18 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.7, 149.8, 148.1, 147.5, 140.4, 135.7, 134.2, 131.3, 129.7, 128.6, 120.0, 118.8, 112.7, 51.6, 35.1, 35.0, 29.6, 29.5, 25.9 ppm. HRMS (ESI): calcd. for C25H33ClNO [M+H]+: 398.2245, found: 398.2247. 2,6-di-tert-butyl-4-(2-fluoro-6-(pyrrolidin-1-yl)benzylidene)cyclohexa-2,5-dienone (1i). Red solid, 1.22 g, 80% yield; 1H NMR (500 MHz, CDCl3) δ 7.20 (dd, J = 15.0, 7.8 Hz, 1H), 7.04 (d, J = 13.9 Hz, 3H), 6.64 (d, J = 8.4 Hz, 1H), 6.56 (t, J = 8.9 Hz, 1H), 3.16 (s, 4H), 1.89 (s, 4H), 1.33 (s, 9H), 1.23 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.6, 161.1 (d, J = 246.3 Hz), 150.5 (d, J = 5.1 Hz), 147.9, 147.2, 136.4, 134.4, 131.8, 130.3 (d, J = 11.3 Hz), 128.9, 111.1 (d, J = 16.4 Hz), 109.9, 104.5 (d, J = 23.5 Hz), 51.9, 35.2, 35.0, 29.6, 29.5, 25.8 ppm. HRMS (ESI): calcd. for C25H33FNO [M+H]+: 382.2541, found: 382.2544. 4-(2-bromo-6-(pyrrolidin-1-yl)benzylidene)-2,6-di-tert-butylcyclohexa-2,5-dien-1-one

(1j).

Red

solid, 1.38 g, 78% yield; 1H NMR (500 MHz, CDCl3) δ 7.21 (s, 1H), 7.08 (d, J = 7.7 Hz, 2H), 7.04 (s, 1H), 6.84 – 6.78 (m, 2H), 3.14 – 2.90 (m, 4H), 1.94 (s, 2H), 1.71 (s, 2H), 1.34 (s, 9H), 1.17 (s, 9H); 13

C{1H} NMR (126 MHz, CDCl3) δ 186.7, 149.7, 148.1, 147.6, 142.5, 134.0, 131.0, 129.9, 128.6, 126.2,

122.0, 121.3, 113.3, 51.5, 35.1, 35.1, 29.6, 29.5, 25.9 ppm. HRMS (ESI): calcd. for C25H33BrNO [M+H]+: 442.1740, found: 442.1744. 2,6-di-tert-butyl-4-(5-nitro-2-(pyrrolidin-1-yl)benzylidene)cyclohexa-2,5-dien-1-one (1k). Red solid, 1.27 g, 78% yield; 1H NMR (500 MHz, CDCl3) δ 8.10 (dd, J = 7.7, 2.4 Hz, 2H), 7.32 (d, J = 2.3 Hz, 1H), 7.22 (s, 1H), 6.98 (d, J = 2.3 Hz, 1H), 6.76 – 6.71 (m, 1H), 3.49 (t, J = 6.5 Hz, 4H), 2.03 – 1.97 (m, 4H), 1.35 (d, J = 8.9 Hz, 9H), 1.28 (d, J = 3.5 Hz, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.4, 153.3, 149.5, 148.0, 141.2, 137.6, 134.1, 130.6, 129.8, 127.4, 125.6, 120.7, 113.1, 52.3, 35.5, 35.1, 29.5, 26.0 ppm. HRMS (ESI): calcd. for C25H33N2O3 [M+H]+: 409.2486, found: 409.2492. 3-((3,5-di-tert-butyl-4-oxocyclohexa-2,5-dien-1-ylidene)methyl)-4-(pyrrolidin-1-yl)benzonitrile (1l). Red solid, 1.27 g, 82% yield; 1H NMR (500 MHz, CDCl3) δ 7.45 (dd, J = 8.8, 2.0 Hz, 1H), 7.39 (d, J = 1.7 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.16 (s, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 3.40 (t, J = 6.5 Hz, 4H), 2.03 – 1.92 (m, 4H), 1.33 (s, 9H), 1.28 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.4, 151.7, 149.4, 147.9, 141.4, 137.0, 134.2, 133.1, 130.3, 127.4, 122.2, 119.7, 114.2, 99.2, 52.0, 35.4, 35.0, 29.5, 25.9 ppm. HRMS (ESI): calcd. for C26H33N2O [M+H]+: 389.2587, found: 389.2593.


Page 13 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


4-((3,5-di-tert-butyl-4-oxocyclohexa-2,5-dien-1-ylidene)methyl)-3-(pyrrolidin-1-yl)benzonitrile (1m). Yellow solid, 1.21 g, 78% yield; 1H NMR (500 MHz, CDCl3) δ 7.33 (d, J = 1.9 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.15 (s, 1H), 7.08 (d, J = 8.1 Hz, 1H), 7.06 (s, 1H), 7.00 (d, J = 2.0 Hz, 1H), 3.31 (t, J = 6.3 Hz, 4H), 1.97 (t, J = 6.4 Hz, 4H), 1.33 (s, 9H), 1.28 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.5, 149.8, 149.5, 148.1, 141.4, 134.4, 133.5, 130.8, 127.8, 127.7, 120.8, 119.2, 117.6, 112.8, 52.1, 35.5, 35.1, 29.5, 29.5, 25.8 ppm. HRMS (ESI): calcd. for C26H33N2O [M+H]+: 389.2587, found: 389.2585. methyl(E)-3-(4-((3,5-di-tert-butyl-4-oxocyclohexa-2,5-dien-1-ylidene)methyl)-3-(pyrrolidin-1yl)phenyl)acrylate (1n). Yellow solid, 1.16 g, 65% yield; 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 15.9 Hz, 1H), 7.47 (s, 1H), 7.25 (d, J = 9.2 Hz, 1H), 7.21 (s, 1H), 7.05 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 18.6 Hz, 2H), 6.47 (d, J = 15.9 Hz, 1H), 3.82 (s, 3H), 3.32 (s, 4H), 1.96 (s, 4H), 1.34 (s, 9H), 1.30 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.5, 167.4, 150.5, 148.8, 147.4, 144.9, 143.1, 135.6, 134.9, 133.6, 129.7, 128.3, 126.3, 118.4, 117.7, 114.4, 52.3, 51.8, 35.4, 35.0, 29.6, 29.6, 25.7 ppm. HRMS (ESI): calcd. for C29H38NO3 [M+H]+: 448.2846, found: 448.2850. 4-((4'-acetyl-3-(pyrrolidin-1-yl)-[1,1'-biphenyl]-4-yl)methylene)-2,6-di-tert-butylcyclohexa-2,5dien-1-one (1o). Red solid, 1.52 g, 79% yield; 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz, 2H), 7.73 (d, J = 7.6 Hz, 2H), 7.56 (s, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.28 (s, 1H), 7.13 (d, J = 7.9 Hz, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 3.38 (s, 4H), 2.65 (s, 3H), 1.98 (s, 4H), 1.35 (s, 9H), 1.32 (s, 9H);

13

C{1H}

NMR (126 MHz, CDCl3) δ 197.7, 186.6, 150.8, 148.7, 147.2, 145.6, 143.5, 141.4, 136.2, 135.0, 133.9, 129.4, 128.9, 128.5, 127.3, 124.4, 117.5, 113.4, 52.5, 35.5, 35.0, 29.6, 29.6, 26.7, 25.7 ppm. HRMS (ESI): calcd. for C33H40NO2 [M+H]+: 482.3054, found: 482.3058. 2,6-di-tert-butyl-4-((2-(pyrrolidin-1-yl)quinolin-3-yl)methylene)cyclohexa-2,5-dien-1-one

(1p).

Yellow solid, 1.29 g, 78% yield; 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.50 (s, 1H), 7.27 (d, J = 3.4 Hz, 2H), 7.05 (s, 1H), 3.67 (s, 4H), 1.95 (s, 4H), 1.35 (s, 9H), 1.30 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.6, 156.6, 149.3, 147.9, 147.7, 141.7, 140.9, 134.3, 130.9, 130.6, 127.7, 126.5, 123.2, 122.7, 120.6, 50.7, 35.5, 35.1, 29.6, 29.5, 25.8 ppm. HRMS (ESI): calcd. for C28H35N2O [M+H]+: 415.2744, found: 415.2748. 2,6-di-tert-butyl-4-((2-(pyrrolidin-1-yl)naphthalen-1-yl)methylene)cyclohexa-2,5-dien-1-one (1q). Red solid, 1.16 g, 70% yield; 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.5 Hz, 1H), 7.74 (t, J = 7.3 Hz, 2H), 7.69 (s, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 8.7 Hz, 2H), 7.16 (s, 1H), 6.92 (s, 1H), 3.21 (s,



Page 14 of 30

4H), 1.88 (d, J = 60.2 Hz, 4H), 1.38 (s, 9H), 1.14 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.8, 147.9, 147.0, 146.9, 142.3, 134.5, 133.9, 131.4, 130.1, 129.1, 128.2, 127.5, 126.8, 122.6, 122.5, 116.6, 113.3, 52.1, 35.1, 35.1, 29.7, 29.5, 26.1 ppm. HRMS (ESI): calcd. for C29H36NO [M+H]+: 414.2791, found: 414.2795. 2,6-di-tert-butyl-4-(2-(dimethylamino)benzylidene)cyclohexa-2,5-dien-1-one (1r). Orange solid, 0.91 g, 68% yield; 1H NMR (500 MHz, CDCl3) δ 7.57 (s, 1H), 7.35 (dd, J = 17.2, 8.0 Hz, 3H), 7.14 – 7.01 (m, 3H), 2.79 (s, 6H), 1.36 (s, 9H), 1.32 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.6, 154.2, 148.8, 147.2, 142.3, 135.4, 132.8, 130.2, 130.1, 128.7, 128.6, 121.5, 117.8, 44.9, 35.4, 35.0, 29.7, 29.6, 29.5 ppm. HRMS (ESI): calcd. for C23H32NO [M+H]+: 338.2478, found: 338.2480. 2,6-di-tert-butyl-4-(2-(dimethylamino)-4-(trifluoromethyl)benzylidene)cyclohexa-2,5-dien-1-one (1s). Yellow solid, 1.13 g, 70% yield; 1H NMR (500 MHz, CDCl3) δ 7.46 (s, 1H), 7.43 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 9.7 Hz, 2H), 7.20 (s, 1H), 7.09 (s, 1H), 2.84 (s, 6H), 1.35 (s, 9H), 1.31 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.5, 154.0, 149.6, 147.9, 140.1, 134.9, 132.9, 131.6, 131.5 (d, J = 25.2 Hz), 131.4, 127.9, 124.0 (q, J = 273.4 Hz), 117.7 (d, J = 3.8 Hz), 114.5 (d, J = 3.7 Hz), 44.5, 35.5, 35.1, 29.6, 29.5 ppm. HRMS (ESI): calcd. for C24H31F3NO [M+H]+: 406.2352, found: 406.2355. 4-(2-(benzyl(methyl)amino)benzylidene)-2,6-di-tert-butylcyclohexa-2,5-dien-1-one

(1t).

Yellow

solid, 1.19 g, 72% yield; 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 3.2 Hz, 1H), 7.42 (dd, J = 16.1, 5.8 Hz, 2H), 7.38 – 7.21 (m, 6H), 7.14 – 7.05 (m, 2H), 6.96 (d, J = 3.0 Hz, 1H), 4.16 (d, J = 5.0 Hz, 2H), 2.74 (d, J = 5.1 Hz, 3H), 1.31 (d, J = 5.3 Hz, 18H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.6, 153.4, 148.9, 147.3, 142.0, 138.1, 135.3, 132.6, 130.3, 130.1, 129.1, 128.4, 128.1, 127.3, 121.8, 119.1, 61.8, 40.8, 35.4, 35.0, 29.6, 29.5 ppm. HRMS (ESI): calcd. for C29H36NO [M+H]+: 414.2791, found: 414.2796. 2,6-di-tert-butyl-4-(2-(diethylamino)benzylidene)cyclohexa-2,5-dien-1-one (1u). Yellow solid, 1.07 g, 73% yield; 1H NMR (500 MHz, CDCl3) δ 7.54 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.38 – 7.32 (m, 2H), 7.09 (dd, J = 17.4, 7.7 Hz, 3H), 3.12 (qd, J = 7.0, 2.2 Hz, 4H), 1.35 (d, J = 2.3 Hz, 9H), 1.32 (d, J = 2.3 Hz, 9H), 1.06 (td, J = 7.0, 2.3 Hz, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.6, 151.9, 148.6, 147.1, 142.4, 135.4, 132.7, 130.9, 130.1, 129.5, 128.6, 121.8, 121.0, 47.4, 35.4, 35.0, 29.6, 29.5, 12.3 ppm. HRMS (ESI): calcd. for C25H36NO [M+H]+: 366.2791, found: 366.2799. 2,6-di-tert-butyl-4-(4-chloro-2-(diethylamino)benzylidene)cyclohexa-2,5-dien-1-one (1v). Yellow solid, 1.12 g, 70% yield; 1H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 1.8 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.20 (s, 1H), 7.09 – 7.01 (m, 3H), 3.12 (q, J = 7.0 Hz, 4H), 1.34 (s, 9H), 1.31 (s, 9H), 1.07 (t, J =


Page 15 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


7.0 Hz, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.5, 152.8, 149.0, 147.4, 140.8, 135.6, 135.1, 133.4, 130.4, 128.9, 128.1, 121.8, 121.1, 47.2, 35.4, 35.0, 29.6, 29.5, 12.2 ppm. HRMS (ESI): calcd. for C25H35ClNO [M+H]+: 400.2402, found: 400.2404. 4-(4-bromo-2-(diethylamino)benzylidene)-2,6-di-tert-butylcyclohexa-2,5-dien-1-one (1w). Yellow solid, 1.27 g, 72% yield; 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 2.2 Hz, 1H), 7.25 – 7.17 (m, 4H), 7.07 (d, J = 2.2 Hz, 1H), 3.11 (q, J = 7.0 Hz, 4H), 1.35 (d, J = 10.3 Hz, 9H), 1.31 (s, 9H), 1.07 (t, J = 7.0 Hz, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.5, 152.9, 149.0, 147.4, 140.8, 135.1, 133.6, 130.4, 129.4, 128.1, 124.8, 124.2, 123.9, 47.2, 35.4, 35.0, 29.6, 29.5, 12.2 ppm. HRMS (ESI): calcd. for C25H35BrNO [M+H]+: 444.1897, found: 444.1899. 4-((3,5-di-tert-butyl-4-oxocyclohexa-2,5-dien-1-ylidene)methyl)-3-(diethylamino)benzonitrile (1x). Yellow solid, 1.17 g, 75% yield; 1H NMR (500 MHz, CDCl3) δ 7.43 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.31 (d, J = 6.5 Hz, 2H), 7.16 (s, 1H), 7.06 (d, J = 2.2 Hz, 1H), 3.14 (q, J = 7.0 Hz, 4H), 1.34 (s, 9H), 1.30 (s, 9H), 1.08 (t, J = 7.0 Hz, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.4, 151.9, 149.7, 148.2, 139.3, 135.0, 134.7, 133.1, 131.8, 127.5, 124.5, 123.9, 118.9, 112.5, 46.9, 35.5, 35.1, 29.6, 29.5, 12.2 ppm. HRMS (ESI): calcd. for C26H35N2O [M+H]+: 391.2744, found: 391.2748. 2,6-di-tert-butyl-4-(5-chloro-2-(diethylamino)benzylidene)cyclohexa-2,5-dien-1-one (1y). Yellow solid, 1.12 g, 70% yield; 1H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 1.7 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.23 (s, 1H), 7.07 (d, J = 1.9 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 3.09 (q, J = 7.0 Hz, 4H), 1.34 (s, 9H), 1.33 (s, 9H), 1.04 (t, J = 7.0 Hz, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.5, 150.2, 149.2, 147.6, 140.1, 135.0, 132.3, 132.0, 130.9, 129.2, 127.9, 126.9, 122.2, 47.4, 35.4, 35.0, 29.6, 29.5, 12.2 ppm. HRMS (ESI): calcd. for C25H35ClNO [M+H]+: 400.2402, found: 400.2404. 3,5-di-tert-butyl-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'-pyrrolo[1,2-a]quinoline]-2,5dien-4-one (2a). Yellow solid, 32.7 mg, 90% yield; 1H NMR (500 MHz, CDCl3) δ 7.14 (t, J = 7.7 Hz, 1H), 6.99 (d, J = 7.4 Hz, 1H), 6.62 (t, J = 7.3 Hz, 1H), 6.51 (d, J = 8.1 Hz, 1H), 6.35 (d, J = 2.9 Hz, 1H), 6.33 (d, J = 2.8 Hz, 1H), 3.63 (dd, J = 9.2, 6.2 Hz, 1H), 3.45 (td, J = 8.6, 3.6 Hz, 1H), 3.24 (dd, J = 16.5, 8.2 Hz, 1H), 3.18 (d, J = 15.8 Hz, 1H), 2.55 (d, J = 15.8 Hz, 1H), 1.91 (ddd, J = 15.2, 9.0, 5.7 Hz, 2H), 1.79 (ddd, J = 12.5, 6.3, 3.0 Hz, 1H), 1.27 (s, 9H), 1.13 (s, 9H);

C{1H} NMR (126 MHz, CDCl3) δ

13

186.8, 149.1, 148.2, 144.3, 143.5, 139.5, 129.0, 127.7, 118.6, 115.9, 110.6, 64.3, 47.5, 39.9, 38.4, 34.9, 34.9, 30.4, 29.5, 27.7, 23.3 ppm. HRMS (ESI): calcd. for C25H34NO [M+H]+: 364.2635, found: 364.2640. 3,5-di-tert-butyl-8'-methoxy-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'-pyrrolo[1,2-



a]quinoline]-2,5-dien-4-one (2b). Yellow solid, 24.3 mg, 62% yield; 1H NMR (500 MHz, CDCl3) δ 6.89 (d, J = 8.1 Hz, 1H), 6.33 (d, J = 13.6 Hz, 2H), 6.19 (d, J = 8.1 Hz, 1H), 6.07 (s, 1H), 3.81 (s, 3H), 3.65 – 3.57 (m, 1H), 3.43 (t, J = 7.3 Hz, 1H), 3.22 (q, J = 8.2 Hz, 1H), 3.10 (d, J = 15.4 Hz, 1H), 2.50 (d, J = 15.4 Hz, 1H), 1.88 (dd, J = 19.1, 8.7 Hz, 2H), 1.81 – 1.72 (m, 1H), 1.32 – 1.20 (m, 10H), 1.13 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.8, 159.6, 149.0, 148.2, 144.4, 144.3, 139.5, 129.5, 111.4, 100.4, 97.1, 64.2, 55.1, 47.5, 39.3, 38.6, 34.9, 34.8, 29.5, 27.8, 23.3 ppm. HRMS (ESI): calcd. for C26H36NO2 [M+H]+: 394.2741, found: 394.2746. 3,5-di-tert-butyl-8'-methyl-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'-pyrrolo[1,2a]quinoline]-2,5-dien-4-one (2c). Yellow solid, 34.3 mg, 91% yield; 1H NMR (500 MHz, CDCl3) δ 6.88 (d, J = 7.5 Hz, 1H), 6.45 (d, J = 7.4 Hz, 1H), 6.34 (d, J = 11.1 Hz, 3H), 3.59 (dd, J = 9.0, 6.3 Hz, 1H), 3.43 (td, J = 8.7, 3.5 Hz, 1H), 3.24 (q, J = 8.1 Hz, 1H), 3.13 (d, J = 15.7 Hz, 1H), 2.52 (d, J = 15.7 Hz, 1H), 2.31 (s, 3H), 1.95 – 1.83 (m, 2H), 1.77 (dtd, J = 9.6, 6.5, 3.0 Hz, 1H), 1.31 – 1.21 (m, 10H), 1.13 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.9, 148.9, 148.1, 144.4, 143.3, 139.7, 137.3, 128.8, 116.7, 115.7, 111.4, 64.3, 47.4, 39.6, 38.7, 34.9, 34.8, 29.6, 29.5, 27.7, 23.3, 21.6 ppm. HRMS (ESI): calcd. for C26H36NO [M+H]+: 378.2791, found: 378.2792. 3,5-di-tert-butyl-8'-(trifluoromethyl)-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'pyrrolo[1,2-a]quinoline]-2,5-dien-4-one (2d). Yellow solid, 41.4 mg, 96% yield; 1H NMR (500 MHz, CDCl3) δ 7.06 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.67 (s, 1H), 6.34 (s, 1H), 6.24 (s, 1H), 3.71 – 3.61 (m, 1H), 3.49 (t, J = 8.4 Hz, 1H), 3.26 (q, J = 8.2 Hz, 1H), 3.17 (d, J = 16.0 Hz, 1H), 2.60 (d, J = 16.1 Hz, 1H), 2.02 – 1.88 (m, 2H), 1.82 (dd, J = 12.1, 5.9 Hz, 1H), 1.34 – 1.22 (m, 10H), 1.13 (s, 9H); C{1H} NMR (126 MHz, CDCl3) δ 186.6, 149.6, 148.7, 143.5, 138.5, 130.3 (q, J = 31.5 Hz ), 129.9,

13

129.6, 129.1, 129.6 (q, J = 273.4 Hz), 122.2, 112.3 (q, J = 3.8 Hz), 106.7 (q, J = 3.8 Hz), 64.3, 47.5, 39.8, 37.8, 35.0, 34.9, 29.5, 27.8, 23.3 ppm. HRMS (ESI): calcd. for C26H33F3NO [M+H]+: 432.2509, found: 432.2517. 8'-bromo-3,5-di-tert-butyl-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'-pyrrolo[1,2a]quinoline]-2,5-dien-4-one (2e). Yellow solid, 41.0 mg, 93% yield; 1H NMR (500 MHz, CDCl3) δ 6.83 (d, J = 7.8 Hz, 1H), 6.72 (dd, J = 7.9, 1.9 Hz, 1H), 6.61 (d, J = 1.9 Hz, 1H), 6.33 (d, J = 2.9 Hz, 1H), 6.24 (d, J = 2.9 Hz, 1H), 3.61 (dd, J = 9.5, 6.0 Hz, 1H), 3.43 (td, J = 8.8, 3.2 Hz, 1H), 3.20 (dd, J = 16.4,


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8.7 Hz, 1H), 3.08 (dd, J = 15.8, 0.8 Hz, 1H), 2.51 (d, J = 15.8 Hz, 1H), 1.98 – 1.84 (m, 2H), 1.79 (dtd, J = 10.0, 6.4, 3.2 Hz, 1H), 1.29 – 1.23 (m, 10H), 1.13 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.7, 149.4, 148.5, 144.5, 143.7, 138.7, 130.2, 121.3, 118.5, 117.5, 113.1, 77.3, 77.0, 76.8, 64.1, 47.5, 39.5, 38.0, 35.0, 34.9, 29.5, 29.5, 27.7, 23.3 ppm. HRMS (ESI): calcd. for C25H33BrNO [M+H]+: 442.1740, found: 442.1746. 3,5-di-tert-butyl-8'-chloro-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'-pyrrolo[1,2a]quinoline]-2,5-dien-4-one (2f). Yellow solid, 37.3 mg, 94% yield; 1H NMR (500 MHz, CDCl3) δ 6.89 (d, J = 7.9 Hz, 1H), 6.57 (d, J = 7.9 Hz, 1H), 6.46 (s, 1H), 6.33 (s, 1H), 6.25 (s, 1H), 3.67 – 3.57 (m, 1H), 3.43 (t, J = 8.4 Hz, 1H), 3.20 (d, J = 8.3 Hz, 1H), 3.09 (d, J = 15.7 Hz, 1H), 2.52 (d, J = 15.8 Hz, 1H), 1.91 (dd, J = 17.1, 8.1 Hz, 2H), 1.83 – 1.74 (m, 1H), 1.26 (s, 10H), 1.13 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.7, 149.4, 148.5, 144.3, 143.7, 138.8, 133.1, 129.8, 117.0, 115.6, 110.2, 64.2, 47.5, 39.5, 38.0, 35.0, 34.9, 29.5, 29.5, 27.8, 23.3 ppm. HRMS (ESI): calcd. for C25H33ClNO [M+H]+: 398.2245, found: 398.2248. 3,5-di-tert-butyl-7'-chloro-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'-pyrrolo[1,2a]quinoline]-2,5-dien-4-one (2g). Yellow solid, 32.1 mg, 85% yield; 1H NMR (500 MHz, CDCl3) δ 7.08 (d, J = 8.6 Hz, 1H), 6.95 (s, 1H), 6.41 (d, J = 8.6 Hz, 1H), 6.32 (d, J = 1.7 Hz, 1H), 6.25 (s, 1H), 3.60 (dd, J = 9.0, 6.3 Hz, 1H), 3.50 – 3.39 (m, 1H), 3.20 (d, J = 8.2 Hz, 1H), 3.12 (d, J = 15.9 Hz, 1H), 2.51 (d, J = 15.9 Hz, 1H), 1.90 (dd, J = 17.2, 9.0 Hz, 2H), 1.79 (dd, J = 7.4, 4.5 Hz, 1H), 1.34 – 1.23 (m, 10H), 1.13 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.7, 149.4, 148.5, 143.7, 142.1, 138.8, 128.6, 127.5, 120.3, 120.1, 111.6, 64.3, 47.6, 39.7, 38.1, 35.0, 34.9, 29.5, 27.7, 23.3 ppm. HRMS (ESI): calcd. for C25H33ClNO [M+H]+: 398.2245, found: 398.2253. 3,5-di-tert-butyl-6'-chloro-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'-pyrrolo[1,2a]quinoline]-2,5-dien-4-one (2h). Yellow solid, 38.5 mg, 97% yield; 1H NMR (500 MHz, CDCl3) δ 7.06 (t, J = 8.0 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1H), 6.42 (d, J = 8.2 Hz, 1H), 6.35 (d, J = 2.2 Hz, 1H), 6.28 (s, 1H), 3.55 (t, J = 7.2 Hz, 1H), 3.43 (td, J = 8.5, 3.9 Hz, 1H), 3.27 (q, J = 8.1 Hz, 1H), 2.95 – 2.83 (m, 2H), 1.97 – 1.85 (m, 2H), 1.84 – 1.76 (m, 1H), 1.33 – 1.24 (m, 11H), 1.14 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.7, 149.3, 148.6, 144.8, 143.7, 138.9, 134.6, 128.0, 116.7, 116.6, 109.2, 63.6, 47.7, 38.5, 37.2, 35.0, 34.9, 29.5, 27.6, 23.4 ppm. HRMS (ESI): calcd. for C25H33ClNO [M+H]+: 398.2245, found: 398.2251.



3,5-di-tert-butyl-6'-fluoro-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'-pyrrolo[1,2a]quinoline]-2,5-dien-4-one (2i). Yellow solid, 31.6 mg, 83% yield; 1H NMR (500 MHz, CDCl3) δ 7.08 (dd, J = 15.0, 7.8 Hz, 1H), 6.37 (dd, J = 16.6, 5.6 Hz, 2H), 6.28 (dd, J = 9.5, 5.4 Hz, 2H), 3.58 (dd, J = 8.9, 6.4 Hz, 1H), 3.45 (td, J = 8.6, 3.4 Hz, 1H), 3.26 (q, J = 8.1 Hz, 1H), 2.83 (dd, J = 39.7, 16.4 Hz, 2H), 1.88 (dt, J = 21.9, 5.8 Hz, 2H), 1.84 – 1.77 (m, 1H), 1.28 (d, J = 10.6 Hz, 10H), 1.14 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.6, 161.5 (d, J = 239.7 Hz), 148.9 (d, J = 92.0 Hz),144.9 (d, J = 7.8 Hz), 143.8, 138.8, 128.0 (d, J = 10.8 Hz), 106.3, 105.7 (d, J = 20.0 Hz), 102.6 (d, J = 22.7 Hz), 63.7, 47.7, 37.7, 34.9, 34.9, 32.4, 32.4, 29.5, 27.6, 26.9, 23.3 ppm. HRMS (ESI): calcd. for C25H33FNO [M+H]+: 382.2546, found: 382.2552. 6'-bromo-3,5-di-tert-butyl-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'-pyrrolo[1,2a]quinoline]-2,5-dien-4-one (2j). Yellow solid, 43.7 mg, 99% yield; 1H NMR (500 MHz, CDCl3) δ 6.99 (t, J = 7.9 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 6.46 (d, J = 8.1 Hz, 1H), 6.35 (s, 1H), 6.27 (s, 1H), 3.61 – 3.50 (m, 1H), 3.43 (d, J = 3.0 Hz, 1H), 3.27 (d, J = 8.2 Hz, 1H), 2.92 (d, J = 16.7 Hz, 1H), 2.84 (d, J = 16.7 Hz, 1H), 1.98 – 1.84 (m, 2H), 1.81 (dd, J = 9.8, 6.3 Hz, 1H), 1.31 (d, J = 11.7 Hz, 1H), 1.28 (s, 9H), 1.15 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.7, 149.3, 148.6, 144.9, 143.6, 138.8, 128.4, 125.5, 119.9, 118.2, 109.9, 63.7, 47.7, 40.2, 38.9, 35.0, 34.9, 29.5, 29.5, 27.5, 23.4 ppm. HRMS (ESI): calcd. for C25H33BrNO [M+H]+: 442.1740, found: 442.1746. 3,5-di-tert-butyl-7'-nitro-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'-pyrrolo[1,2a]quinoline]-2,5-dien-4-one (2k). Yellow solid, 40.6 mg, 99% yield; 1H NMR (500 MHz, CDCl3) δ 8.08 (dd, J = 9.0, 1.7 Hz, 1H), 7.95 (s, 1H), 6.45 (d, J = 9.1 Hz, 1H), 6.34 (d, J = 2.6 Hz, 1H), 6.12 (d, J = 2.6 Hz, 1H), 3.75 (dd, J = 10.0, 5.9 Hz, 1H), 3.62 (t, J = 8.9 Hz, 1H), 3.32 (d, J = 7.9 Hz, 1H), 3.17 (d, J = 15.8 Hz, 1H), 2.64 (d, J = 15.8 Hz, 1H), 2.03 (dd, J = 13.5, 6.5 Hz, 1H), 1.96 (d, J = 8.3 Hz, 1H), 1.90 – 1.81 (m, 1H), 1.33 – 1.23 (m, 10H), 1.12 (s, 9H);

C{1H} NMR (126 MHz, CDCl3) δ 186.2, 150.3,

13

149.3, 148.2, 142.4, 137.0, 136.9, 125.4, 125.3, 118.1, 109.1, 64.8, 47.9, 39.6, 37.5, 35.1, 35.0, 29.5, 29.4, 27.7, 23.1 ppm. HRMS (ESI): calcd. for C25H33N2O3 [M+H]+: 409.2486, found: 409.2488. 3,5-di-tert-butyl-4-oxo-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'-pyrrolo[1,2a]quinoline]-2,5-diene-7'-carbonitrile (2l). Yellow solid, 35.3 mg, 91% yield; 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 6.47 (d, J = 8.5 Hz, 1H), 6.33 (d, J = 2.3 Hz, 1H), 6.14 (d, J = 2.3 Hz, 1H), 3.70 (dd, J = 9.8, 6.0 Hz, 1H), 3.54 (t, J = 8.9 Hz, 1H), 3.25 (dd, J = 17.0, 9.0 Hz, 1H), 3.13 (d, J = 15.8 Hz, 1H), 2.56 (d, J = 15.8 Hz, 1H), 2.04 – 1.89 (m, 2H), 1.84 (dt, J = 12.2, 6.1 Hz,


Page 18 of 30

Page 19 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1H), 1.33 – 1.23 (m, 10H), 1.12 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.4, 149.9, 149.0, 146.3, 142.8, 137.5, 132.5, 132.5, 120.7, 118.9, 110.2, 97.4, 64.5, 47.5, 39.5, 37.4, 35.1, 34.9, 29.5, 29.5, 27.8, 23.2 ppm. HRMS (ESI): calcd. for C26H33N2O [M+H]+: 389.2587, found: 389.2588. 3,5-di-tert-butyl-4-oxo-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'-pyrrolo[1,2a]quinoline]-2,5-diene-8'-carbonitrile (2m). Yellow solid, 38.1 mg, 98% yield; 1H NMR (500 MHz, CDCl3) δ 7.04 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.68 (s, 1H), 6.33 (s, 1H), 6.16 (s, 1H), 3.66 (dd, J = 9.2, 6.2 Hz, 1H), 3.47 (t, J = 8.5 Hz, 1H), 3.27 – 3.12 (m, 2H), 2.59 (d, J = 16.2 Hz, 1H), 1.95 (dt, J = 17.3, 8.0 Hz, 2H), 1.83 (dt, J = 11.9, 5.8 Hz, 1H), 1.34 – 1.22 (m, 10H), 1.12 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.5, 149.8, 148.9, 143.6, 143.0, 137.9, 129.5, 123.8, 119.8, 119.4, 112.8, 111.3, 64.3, 47.5, 40.1, 37.5, 35.0, 34.9, 29.5, 27.8, 23.3 ppm. HRMS (ESI): calcd. for C26H32NaN2O [M+Na]+: 411.2412, found: 411.2417. methyl(E)-3-(3,5-di-tert-butyl-4-oxo-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'pyrrolo[1,2-a]quinoline]-2,5-dien-8'-yl)acrylate (2n). Yellow solid, 39.4 mg, 88% yield; 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 16.0 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.62 (s, 1H), 6.41 (d, J = 15.9 Hz, 1H), 6.34 (s, 1H), 6.27 (s, 1H), 3.81 (s, 3H), 3.68 – 3.59 (m, 1H), 3.48 (t, J = 8.5 Hz, 1H), 3.26 (d, J = 8.2 Hz, 1H), 3.16 (d, J = 16.1 Hz, 1H), 2.58 (d, J = 16.1 Hz, 1H), 1.93 (dd, J = 16.7, 7.8 Hz, 2H), 1.80 (dd, J = 7.7, 4.4 Hz, 1H), 1.31 (s, 1H), 1.26 (s, 9H), 1.12 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.7, 167.7, 149.4, 148.5, 145.8, 143.7, 143.7, 138.9, 133.8, 129.4, 121.6, 116.6, 116.3, 109.5, 64.3, 51.6, 47.5, 40.0, 38.2, 35.0, 34.9, 29.5, 27.8, 23.3 ppm. HRMS (ESI): calcd. for C29H38NO3 [M+H]+: 448.2846, found: 448.2848. 8'-(4-acetylphenyl)-3,5-di-tert-butyl-1',2',3',3a'-tetrahydro-5'H-spiro[cyclohexane-1,4'pyrrolo[1,2-a]quinoline]-2,5-dien-4-one (2o). Yellow solid, 40.9 mg, 85% yield; 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 7.4 Hz, 2H), 7.72 (d, J = 7.4 Hz, 2H), 7.09 (d, J = 7.3 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H), 6.72 (s, 1H), 6.48 – 6.31 (m, 2H), 3.67 (t, J = 6.8 Hz, 1H), 3.54 (t, J = 8.3 Hz, 1H), 3.33 (d, J = 8.1 Hz, 1H), 3.21 (d, J = 15.9 Hz, 1H), 2.63 (s, 3H), 2.60 (s, 1H), 2.02 – 1.87 (m, 2H), 1.82 (d, J = 2.9 Hz, 1H), 1.33 (s, 1H), 1.30 (s, 9H), 1.15 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 197.8, 186.7, 149.3, 148.4, 146.5, 143.9, 143.8, 139.4, 139.1, 135.6, 129.5, 128.8, 127.1, 119.0, 115.0, 109.1, 64.3, 47.5, 39.7, 38.4, 35.0, 34.9, 29.5, 29.5, 27.7, 26.6, 23.3 ppm. HRMS (ESI): calcd. for C33H40NO2 [M+H]+: 482.3054, found: 482.3053.



3',5'-di-tert-butyl-1,2,3,3a-tetrahydro-5H-spiro[benzo[g]pyrrolo[1,2-a][1,8]naphthyridine-4,1'cyclohexane]-2',5'-dien-4'-one (2p). Yellow solid, 39.4 mg, 95% yield; 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 1H), 7.60 – 7.47 (m, 3H), 7.19 (t, J = 7.4 Hz, 1H), 6.39 (d, J = 2.8 Hz, 1H), 6.29 (d, J = 2.8 Hz, 1H), 3.98 – 3.91 (m, 1H), 3.86 (dd, J = 9.6, 5.8 Hz, 1H), 3.71 (dt, J = 11.3, 8.1 Hz, 1H), 3.25 (d, J = 15.7 Hz, 1H), 2.72 (d, J = 15.7 Hz, 1H), 2.01 – 1.81 (m, 3H), 1.38 – 1.24 (m, 10H), 1.11 (s, 9H); C{1H} NMR (126 MHz, CDCl3) δ 186.6, 152.9, 150.1, 149.1, 147.9, 142.8, 137.7, 134.7, 128.9, 126.9,

13

125.9, 123.2, 121.7, 117.5, 64.5, 46.9, 40.2, 38.5, 35.1, 34.9, 29.5, 28.3, 23.1 ppm. HRMS (ESI): calcd. for C28H35N2O [M+H]+: 415.2744, found: 415.2745. 3',5'-di-tert-butyl-1,2,3,12a-tetrahydro-11H-spiro[benzo[f]pyrrolo[1,2-a]quinoline-12,1'cyclohexane]-2',5'-dien-4'-one (2q). Yellow solid, 40.5 mg, 98% yield; 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 8.3, 3.7 Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 6.48 – 6.38 (m, 2H), 3.60 (d, J = 6.5 Hz, 2H), 3.42 (q, J = 7.7 Hz, 1H), 3.19 (d, J = 16.3 Hz, 1H), 3.04 (d, J = 16.3 Hz, 1H), 1.87 (ddd, J = 18.0, 13.6, 6.3 Hz, 3H), 1.40 – 1.28 (m, 10H), 1.10 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.8, 148.9, 148.4, 144.6, 141.1, 139.8, 133.2, 128.6, 128.0, 126.8, 126.5, 121.4, 121.4, 115.0, 108.9, 63.6, 47.9, 38.8, 35.6, 34.9, 34.9, 29.6, 29.5, 27.5, 26.9, 23.6 ppm. HRMS (ESI): calcd. for C29H36NO [M+H]+: 414.2791, found: 414.2795. 3,5-di-tert-butyl-1'-methyl-1',4'-dihydro-2'H-spiro[cyclohexane-1,3'-quinoline]-2,5-dien-4-one (2r). Yellow solid, 17.5 mg, 52% yield; 1H NMR (500 MHz, CDCl3) δ 7.16 (t, J = 7.7 Hz, 1H), 6.97 (d, J = 7.3 Hz, 1H), 6.69 (dd, J = 14.1, 7.6 Hz, 2H), 6.55 (s, 2H), 3.11 (s, 2H), 2.95 (s, 3H), 2.79 (s, 2H), 1.21 (s, 18H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.6, 147.3, 145.0, 143.1, 129.4, 127.6, 119.5, 116.9, 111.1, 59.6, 39.2, 38.6, 36.7, 34.8, 29.5 ppm. HRMS (ESI): calcd. for C23H32NO [M+H]+: 338.2478, found: 338.2477. 3,5-di-tert-butyl-1'-methyl-7'-(trifluoromethyl)-1',4'-dihydro-2'H-spiro[cyclohexane-1,3'quinoline]-2,5-dien-4-one (2s). Yellow solid, 29.8 mg, 72% yield; 1H NMR (500 MHz, CDCl3) δ 7.04 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.86 (s, 1H), 6.49 (s, 2H), 3.17 (s, 2H), 2.99 (s, 3H), 2.81 (s, 2H), 1.21 (s, 18H); 13C{1H} NMR (126 MHz, CDCl3) δ 186.4, 147.7, 144.9, 142.2, 130.0 (d, J = 31.3 Hz), 129.5, 124.5 (q, J = 273.4 Hz), 122.9, 113.3 (d, J = 3.8 Hz), 107.3 (d, J = 3.8 Hz), 59.4, 39.1, 38.6, 36.2, 34.8, 29.5 ppm. HRMS (ESI): calcd. for C24H31F3NO [M+H]+: 406.2352, found: 406.2355. 4-(2-(benzylamino)benzyl)-2,6-di-tert-butylphenol (3a). Pale yellow solid, 39.3 mg, 92% yield; 1H NMR (500 MHz, CDCl3) δ 7.30 – 7.21 (m, 3H), 7.18 – 7.10 (m, 3H), 7.07 (d, J = 7.1 Hz, 1H), 6.96 (s,


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2H), 6.73 (d, J = 7.0 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 5.07 (s, 1H), 4.26 (s, 2H), 3.97 (s, 1H), 3.82 (s, 2H), 1.36 (s, 18H); 13C{1H} NMR (126 MHz, CDCl3) δ 152.3, 146.0, 139.4, 136.1, 130.3, 129.5, 128.5, 127.5, 127.3, 127.0, 125.5, 125.0, 117.3, 110.7, 48.1, 38.2, 34.3, 30.2 ppm. HRMS (ESI): calcd. for C28H36NO [M+H]+: 402.2791, found: 402.2795. 2,6-di-tert-butyl-4-(2-(methylamino)benzyl)phenol (3b). Pale yellow solid, 30.6 mg, 94% yield; 1H NMR (500 MHz, CDCl3) δ 7.19 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 9.5 Hz, 3H), 6.70 (t, J = 7.3 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.07 (s, 1H), 3.77 (s, 2H), 3.64 (s, 1H), 2.81 (s, 3H), 1.39 (s, 18H);

13

C{1H}

NMR (126 MHz, CDCl3) δ 152.2, 147.2, 136.0, 130.0, 129.4, 127.5, 125.4, 125.2, 117.0, 109.8, 37.4, 34.3, 30.8, 30.3 ppm; HRMS (ESI): calcd. for C22H32NO [M+H]+: 326.2478, found: 326.2485. 2,6-di-tert-butyl-4-(2-(ethylamino)benzyl)phenol (3c). Pale yellow solid, 32.5 mg, 90% yield; 1H NMR (500 MHz, CDCl3) δ 7.15 (t, J = 7.6 Hz, 1H), 7.04 – 6.96 (m, 3H), 6.69 (t, J = 7.2 Hz, 1H), 6.63 (d, J = 7.9 Hz, 1H), 5.07 (s, 1H), 3.77 (s, 2H), 3.48 (s, 1H), 3.08 (q, J = 6.7 Hz, 2H), 1.39 (s, 18H), 1.12 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 152.2, 146.5, 136.0, 130.1, 129.6, 127.4, 125.5, 125.2, 116.9, 110.5, 38.4, 38.1, 34.3, 30.3, 14.8 ppm. HRMS (ESI): calcd. for C23H34NO [M+H]+: 340.2635, found: 340.2636. 2,6-di-tert-butyl-4-(4-chloro-2-(ethylamino)benzyl)phenol (3d). Pale yellow solid, 25.4 mg, 68% yield; 1H NMR (500 MHz, CDCl3) δ 6.95 (s, 2H), 6.92 (d, J = 7.9 Hz, 1H), 6.64 (dd, J = 7.9, 2.1 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H), 5.09 (s, 1H), 3.72 (s, 2H), 3.56 (s, 1H), 3.08 – 2.99 (m, 2H), 1.39 (s, 18H), 1.11 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 152.3, 147.5, 136.2, 133.1, 131.0, 129.0, 125.0, 123.7, 116.4, 110.3, 38.3, 37.6, 34.3, 30.3, 14.5 ppm. HRMS (ESI): calcd. for C23H33ClNO [M+H]+: 374.2245, found: 374.2247. 4-(4-bromo-2-(ethylamino)benzyl)-2,6-di-tert-butylphenol (3e). Pale yellow solid, 30.0 mg, 72% yield; 1H NMR (500 MHz, CDCl3) δ 6.95 (s, 2H), 6.86 (d, J = 7.9 Hz, 1H), 6.79 (dd, J = 7.9, 1.7 Hz, 1H), 6.71 (d, J = 1.4 Hz, 1H), 5.09 (s, 1H), 3.70 (s, 2H), 3.55 (s, 1H), 3.03 (dd, J = 6.9, 5.4 Hz, 2H), 1.39 (s, 18H), 1.11 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 152.4, 147.7, 136.2, 131.3, 128.9, 125.1, 124.2, 121.3, 119.4, 113.2, 38.3, 37.7, 34.3, 34.1, 30.3, 14.6 ppm. HRMS (ESI): calcd. for C23H33BrNO [M+H]+: 418.1740, found: 418.1742. 4-(3,5-di-tert-butyl-4-hydroxybenzyl)-3-(ethylamino)benzonitrile (3f). Pale yellow solid, 29.1 mg, 80% yield; 1H NMR (500 MHz, CDCl3) δ 7.07 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.93 (s, 2H), 6.79 (s, 1H), 5.13 (s, 1H), 3.78 (s, 2H), 3.70 (t, J = 4.7 Hz, 1H), 3.11 – 3.02 (m, 2H), 1.39 (s, 18H), 1.14



(t, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 152.6, 146.7, 136.4, 130.6, 130.5, 127.9, 125.1, 120.6, 120.0, 112.7, 110.9, 38.2, 38.1, 34.3, 30.2, 14.4 ppm. HRMS (ESI): calcd. for C24H33N2O [M+H]+: 365.2587, found: 365.2588. 2,6-di-tert-butyl-4-(5-chloro-2-(ethylamino)benzyl)phenol (3g). Pale yellow solid, 23.9 mg, 64% yield; 1H NMR (500 MHz, CDCl3) δ 7.10 (d, J = 8.6 Hz, 1H), 7.00 (s, 1H), 6.96 (d, J = 1.7 Hz, 2H), 6.52 (dd, J = 8.6, 0.9 Hz, 1H), 5.10 (d, J = 1.6 Hz, 1H), 3.73 (s, 2H), 3.47 (s, 1H), 3.03 (d, J = 6.8 Hz, 2H), 1.40 (d, J = 1.7 Hz, 18H), 1.10 (td, J = 7.1, 1.4 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 152.4, 145.2, 136.2, 129.8, 128.8, 127.1, 125.1, 121.4, 111.5, 38.5, 37.9, 34.3, 30.3, 14.6 ppm. HRMS (ESI): calcd. for C23H33ClNO [M+H]+: 374.2245, found: 374.2248.

ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (21702117, 21878167) and the Natural Science Foundation of Shandong Province (JQ201604, ZR2017BB005) as well as the Key Research and Development Program of Shandong Province (2017GSF218073). Supporting Information NMR spectra of the products, X-ray crystallography data and CIF file of compound 2c. This material is available free of charge via the Internet at http: //pubs.acs.org. ORCID Shuai-Shuai Li: 0000-0001-7279-2885 Jian Xiao: 0000-0003-4272-6865 Author Contributions 〢

These authors contributed equally.

Notes The authors declare no competing financial interest.

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(19) For a mechanistic study with HFIP, see: Berkessel, A.; Adrio, J. A.; Hüttenhain, D.; Neudörfl, J. M. Unveiling the “Booster Effect” of Fluorinated Alcohol Solvents: Aggregation-Induced Conformational Changes and Cooperatively Enhanced H-Bonding. J. Am. Chem. Soc. 2006, 128, 8421. (20) For recent examples of HFIP-promoted reactions, see: (a) DiPoto, M. C.; Hughes, R. P.; Wu, J. Dearomative Indole (3 + 2) Reactions with Azaoxyallyl Cations – New Method for the Synthesis of Pyrroloindolines. J. Am. Chem. Soc. 2015, 137, 14861. (b) Libman, A.; Shalit, H.; Vainer, Y.; Narute, S.; Kozuch, S.; Pappo, D. Synthetic and Predictive Approach to Unsymmetrical Biphenols by Iron-Catalyzed Chelated Radical–Anion Oxidative Coupling. J. Am. Chem. Soc. 2015, 137, 11453. (c) Mfuh, A. M.; Nguyen, V. T.; Chhetri, B. J.; Burch, E.; Doyle, J. D.; Nesterov, V. N.; Arman, H. D.; Larionov, O. V. Additive- and Metal-Free, Predictably 1,2- and 1,3-Regioselective, Photoinduced Dual C–H/C–X Borylation of Haloarenes. J. Am. Chem. Soc. 2016, 138, 8408. (d) Colomer, I.; Batchelor-McAuley, C.;



Odell, B.; Donohoe, T. J.; Compton, R. G. Hydrogen Bonding to Hexafluoroisopropanol Controls the Oxidative Strength of Hypervalent Iodine Reagents. J. Am. Chem. Soc. 2016, 138, 8855. (e) Vukovic, V. D.; Richmond, E.; Wolf, E.; Moran, J. Catalytic Friedel–Crafts Reactions of Highly Electronically Deactivated Benzylic Alcohols. Angew. Chem. Int. Ed. 2017, 56, 3085. (f) Zeng, X.; Li, J.; Ng, C. K.; Hammond, G. B.; Xu, B. Ligands with Dual Vitamin D3-Agonistic and Androgen-Antagonistic Activities. Angew. Chem. Int. Ed. 2018, 57, 2924. (g) Arnold, A. M.; Pöthig, A.; Drees, M.; Gulder, T. NXS, Morpholine and HFIP: The Ideal Combination for Biomimetic Haliranium-Induced Polyene Cyclizations. J. Am. Chem. Soc. 2018, 140, 4344.


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