Directed CâH Bond Functionalization: A Unified Approach to Formal

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Directed C–H Bond Functionalization: A Unified Approach to Formal Syntheses of Amorfrutin A, Cajaninstilbene Acid, Hydrangenol and Macrophyllol Gowri Sankar Grandhi, Jayaraman Selvakumar, Suman Dana, and Mahiuddin Baidya J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02116 • Publication Date (Web): 13 Sep 2018 Downloaded from http://pubs.acs.org on September 13, 2018

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The Journal of Organic Chemistry

Directed C–H Bond Functionalization: A Unified Approach to Formal Syntheses of Amorfrutin A, Cajaninstilbene Acid, Hydrangenol and Macrophyllol Gowri Sankar Grandhi, Jayaraman Selvakumar, Suman Dana, and Mahiuddin Baidya* Department of Chemistry, Indian Institute of Technology Madras, Chennai – 600 036, India. Supporting Information Placeholder

ABSTRACT: Formal syntheses of natural products amorfrutin A, cajaninstilbene acid, hydrangenol and macrophyllol have been accomplished based on successive C–H bond functionalization of ready-stock benzoic acids. This concise strategy involves transition metal catalyzed directed C–H olefination, C–H hydroxylation, and acid mediated C–H prenylation as key steps.

α-Hydroxy benzoic acid decorated bibenzyls and stilbenes constitute a very rapidly developing field of research as molecules possessing such frameworks are ubiquitous in myriad natural products with diverse biological activities.1,2 Pivotal examples include prenylated compound amorfrutin A (1), which has been isolated from the two dietary legumes Glycyrrhiza foetida and Amorpha fruticosa (Figure 1).1a It exhibits profound activation of PPARγ and is also a lead compound in type II diabetes drug discovery.1c The unsaturated analogue cajaninstilbene acid (2) displays anti-inflammatory,2g antioxidant,2a-c and anti-tumor activities.2d-f Other cyclic analogues, such as hydrangenol (3) and macrophyllol (4), members of dihydroisocoumarine family of natural products, are known to suppress T-lymphocyte proliferation and inhibit histamine release.3 These extraordinary bioactivities fuel on the pursuit of synthetic strategies en route to these natural products. However, efficient synthetic protocols to access these molecules are limited. In general, their syntheses have been addressed through the construction of aromatic ring with desired substitutions from prefunctionalized linear molecules4 or olefination of protected salicyclic acid derivatives.2h,5 Syntheses of macrophyllol and hydrangenol primarily rely on strategic ortho- and lateral-lithiation processes using salicylic acid derivatives.6 Over the past decades, transition metal catalyzed reactions have shaped the contemporary organic synthesis by enabling direct functionalization of unreactive C–H bond and successfully been executed in the synthesis and late-stage functionalization of various natural products.7-9 We envisioned that implementation of this step- and atom-economic technology for syntheses of aforementioned molecules would be very effective. Accordingly, a retrosynthetic plan was conceived (Figure 1). A threefold C–H bond functionalization consists of C–H homobenzylation (C–H styrylation/reduction or hydroarylation), hydroxylation, and prenylation of ready-stock aromatic

acid would deliver the Amorfrutin A (1). Cajaninstilbene acid (2) can be prepared following C–H styrylation, hydroxylation, and prenylation as key steps. Similarly, a twofold regioselective C–H bond functionalization such as C–H styrylation with readily available styrene derivatives and hydroxylation of benzoic acid, and subsequent cyclization would result in natural products hydrangenol (3) and macrophyllol (4). Herein, we report the development of this approach for the formal syntheses of Amorfrutin A, cajaninstilbene acid, hydrangenol and macrophyllol.

Figure 1. Natural products 1–4 and retrosynthetic analysis Synthesis of amorfrutin A (1) started with the installation of homobenzyl group at the ortho-position of commercially available para-anisic acid (Scheme 1a). Recently, we have developed weak coordination directed ortho C–H styrylation

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of benzoic acids using Ru(II)-catalyst under mild conditions.10 Adaptation of this strategy in the coupling reaction of paraanisic acid (5a) with commercially available styrene 6a produced the styrylated ester 7 in 56% yield. Hydrogenation of the double bond with H2 and Pd/carbon followed by hydrolysis of the ester group quantitatively delivered the acid 8. Alternatively, the ruthenium catalyzed C–H hydroarylation reaction of 4-acetylanisole 9 with styrene 6a followed by manganese catalyzed oxidation furnished the desired acid 8 in 76% isolated yield (in two steps).11 To execute inexpensive copper-mediated C–H hydroxylation reaction, acid 8 was converted to the corresponding acid chloride, which was then coupled with 2aminophenylpyrazole (2-APP, 10), a directing group independently introduced by us and Li group for C–H bond activation strategy.12,13 Treatment of 2-APP directing group coupled amide 11 with copper acetate (1.5 equiv) and K2CO3 (1.5

equiv) in DMSO solvent at 80 oC produced the ortho C−H hydroxylated compound 12 in 84% yield. The 2-APP directing group was removed via Lewis acid mediated methanolysis to get ortho-hydroxyl ester 13.12,14 To install the prenyl functionality on the aromatic ring, previously reported rearrangement of O-prenyl ether to C-prenyl aromatic alcohol was implemented.15 For that purpose, the hydroxyl group was prenylated with prenyl bromide in the presence of sodium hydride to provide compound 14. Exposure of O-prenylated ether 14 to montmorillonite K10 (1 wt equiv) offered the methyl ester of amorfrutin A (1a) in 38% yield along with deprenylated precursor 13 in 56% yield. It is worth noting that compound 13 can be utilized in prenylation followed by O-prenyl ether rearrangement sequence, mitigating the loss of material during synthesis.

Scheme 1. Formal Synthesis of Amorfrutin A (1) and Cajaninstilbene Acid (2)

Cajaninstilbene acid (2) structurally resembles amorfrutin A (1), where the homobenzyl group is replaced with a styryl group. Thus, tactically the synthesis of cajaninstilbene can be accomplished in a similar fashion as described in the preceding section, excluding the step that was involved in the hydrogenation of alkene functionality. Accordingly, the compound 7, obtained via Ru-catalyzed styrylation of para-anisic acid (5a), was hydrolyzed to afford styrylated aromatic acid 15 in 98% yield (Scheme 1b). The 2-APP directing group was installed to give stilbene-substituted benzamide 16. Satisfyingly,

when the compound 16 was exposed to hydroxylation conditions described above, the desired C–H hydroxylated compound 17 was isolated in 81% yield. While direct C–H hydroxylation of various benzoic acid derivatives has been intensively investigated using transition metal catalysts,16 utilization of challenging ortho-styrylated benzoic acid derivatives for such purpose is elusive, signifying the importance of our findings and the effectiveness of 2-APP directing group in C–H bond activation. The execution of prior established sequence, removal of the directing group, formation of O-prenyl

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The Journal of Organic Chemistry ether 19 and its rearrangement under montmorillonite K10, produced the desired methyl ester of cajaninstilbene acid 2a. Simple hydrolysis of the esters 1a and 2a to forge natural products amorfrutin A (1) and cajaninstilbene acid (2), respectively, was previously reported.5d Scheme 2. Formal Synthesis of Hydrangenol (3) and Macrophyllol (4) H

styrenes 6b-c [Ru(p-cymene)Cl2]2 (5 mol %) K2HPO4 (1 equiv ) CuO (2 equiv), MeOH, 85 oC

O OH 5b

then K2CO3, MeI, CH3CN, rt MeO

MeO

(6c)

MeO

(6b)

OMe (44% yield, 48 h)

(58% yield, 24 h)

OMe

OMe

MeO

OMe

O

O OMe

OMe 25

20 a

(95% yield)

a) NaOH, H2O/EtOH (5:1) reflux, 3 h

a

(94% yield)

OMe

OMe MeO

OMe

O

O OH

OH

21

26 (96% yield, 2 steps)

b

b) 1. (COCl)2, cat. DMF 0 oC - rt, 3 h 2. 2-APP (10), Et3N 0 oC - rt, 6 h

OMe

(98% yield, 2 steps)

b

OMe

O PP

N H

H 27

Cu(OAc)2 K2CO3, DMSO air, 80 oC, 5 h

c)

c

(88% yield)

c

(85% yield)

OMe

OMe MeO

OMe

O

O

N H OH

PP

d)

23 d

N H OH

BF3.OEt2, MeOH 100 oC, 36 h

PP

28 d

(92% yield)

(92% yield)

OMe

OMe OH

MeO

OMe MeO

OMe

OMe

O

O ref. 6b,d OMe

OH 24

PP

H

22

O

ref. 6b

O O

OH hydrangenol (3)

To accomplish the formal synthesis of macrophyllol (4), C–H styrylation of benzoic acid 5b was performed with electron-rich styrene 6c (Scheme 2, right). This coupling process was relatively slow and the desired product 25 was isolated in 44% yield after prolonging the reaction time. Nevertheless, compound 25 was transformed to amide 27 in a similar manner and then subjected to C–H hydroxylation with Cu(OAc)2 to furnish compound 28. Removal of directing group delivered the hydroxylated ester 29 from which the synthesis of macrophyllol (4) is a known process.6b-c,17 In conclusion, we have devised a succinct and unified route for formal syntheses of four natural products, amorfrutin A, cajaninstilbene acid, hydrangenol and macrophyllol. This strategy uses otherwise unactivated C–H bonds of benzoic acids as a pivotal synthetic handle to install styryl, hydroxyl, and prenyl functionalities. Further applications of direct activation/functionalization of ubiquitous C–H bonds towards natural products syntheses are ongoing in our laboratory.

OMe MeO

O N H

For the synthesis of cyclic dihydroisocoumarine natural product hydrangenol (3), parent benzoic acid (5b) was reacted with 4-methoxystyrene (6b) under chelation-assisted Ru(II)catalyzed ortho-styrylation conditions to prepare key building block 20 (58% yield, Scheme 2, left).10 Then, it was utilized to hinge 2-APP (10) directing group following ester hydrolysis/acid chloride formation/amidation sequences, delivering compound 22 in high yield. Copper-mediated hydroxylation followed by the removal of the 2-APP directing group via methanolysis resulted in compound 24 in excellent yield. Synthesis of natural product hydrangenol (3) from compound 24 via cyclization is known in literature.6b,d

OMe O

OH macrophyllol (4)

EXPERIMENTAL SECTION: General Information: All anhydrous solvents were dried by standard techniques and freshly distilled prior to use. Column chromatography was carried out using dry packed Finar silica gel 100-200µm and thin layer chromatography was carried out in WhatmanPartisil® K6F TLC plates (silica gel 60 Å, 0.25 mm thickness). Visualisation was accomplished using ultra violet light (366 or 254 nm) and chemical staining with basic potassium permanganate solution. 13C and 1H NMR spectra were recorded on a Bruker 400 or Bruker 500 MHz spectrometers. Chemical shift values (δ) are reported in ppm and calibrated to the residual solvent peak CDCl3 δ = 7.260 ppm for 1H, δ = 77.160 for 13C or calibrated to tetramethylsilane (δ = 0.00). All NMR spectra were recorded at ambient temperature (290 K) unless otherwise noted. 1H NMR spectra are reported as follows: chemical shift (multiplicity, coupling constant, integration). The following abbreviations are used to indicate multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublet; dt, doublet of triplet; dq, doublet of quartet; br, broad. Mass spectra were recorded by electrospray ionization (ESI) method on a Q-TOF Micro with lock spray source.

OH 29

Synthesis of compounds 7, 20, and 25 via Ru(ll)-catalyzed C–H styrylation of benzoic acids: To an oven dried 50 mL round bottom flask, para-anisic acid 5a (3.2 mmol, 1 equiv), styrene 6a (1.5 equiv), [Ru(p-cymene)Cl2]2 (5 mol %), K2HPO4 (1 equiv), and CuO (2 equiv) were taken and 10 mL

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methanol solvent was added. The round bottom flask was then sealed with a glass stopper. The reaction mixture was stirred at 85 oC for 24 h under air. After completion (monitored by TLC), the solvent was evaporated under reduced pressure. Then K2CO3 (2 equiv) and MeI (3 equiv) were added to the crude reaction mixture in the presence of acetonitrile solvent (10 mL) and the reaction mixture was stirred for 4 hours at room temperature. After completion (monitored by TLC), the crude reaction mixture was diluted with ethyl acetate and filtered through a celite pad. Next, the solvent was evaporated under reduced pressure. In order to get pure 2-styrylbenzoic acid methyl ester 7, the resulting residue was purified through column chromatography on silica gel with a gradient eluent of hexane and ethyl acetate (2-5% ethyl acetate in hexane). Compounds 20 and 25 were synthesized following the same synthetic procedure from the benzoic acid 5b using styrene 6b and 6c, respectively. (E)-Methyl 4-methoxy-2-styrylbenzoate (7): Liquid, yield 56% (465 mg); 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 16.2 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.55-7.53 (m, 2H), 7.36-7.32 (m, 2H), 7.27-7.23 (m, 1H), 7.17 (d, J = 2.6 Hz, 1H), 6.986.94 (m, J = 16.2 Hz, 1H), 6.82 (dd, J = 8.8, 2.6 Hz, 1H), 3.87 (s, 3H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 167.5, 162.6, 142.1, 137.5, 133.2, 131.6, 128.8, 128.1, 128.0, 127.0, 120.9, 112.8, 112.2, 55.6, 51.9. HRMS (ESI/TOF-Q) m/z: [M+Na]+ Calcd for C17H16O3Na+ 291.0990; Found 291.0997. (E)-Methyl 2-(4-methoxystyryl)benzoate (20): White solid; yield 58% (490 mg); mp 125-127 oC; 1H NMR (400 MHz, CDCl3): δ 7.91-7.83 (m, 2H), 7.70-7.68 (m, 1H), 7.49-7.46 (m, 3H), 7.27 (t, J = 7.5 Hz, 1H), 6.98-6.94 (m, 1H), 6.89-6.87 (m, 2H), 3.91 (s, 3H), 3.81 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 168.1, 159.6, 139.6, 132.2, 131.1, 130.8, 130.4, 128.4, 128.2, 126.88, 126.85, 125.3, 114.2, 55.5, 52.2; HRMS (ESI/TOF-Q) m/z: [M+Na]+ Calcd for C17H16O3Na+ 291.0997; Found 291.0992. (E)-Methyl 2-(3,4,5-trimethoxystyryl)benzoate (25): White solid, yield 44% (460 mg); mp 119-121 oC; 1H NMR (400 MHz, CDCl3): δ 7.95-7.87 (m, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.54-7.48 (m, 1H), 7.33 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 16.2 Hz, 1H), 6.78 (s, 2H), 3.92 (s, 9H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.0, 153.5, 139.4, 133.4, 132.3, 131.6, 130.9, 128.6, 127.3, 127.21, 127.15, 105.7, 104.2, 61.1, 56.3, 56.2, 52.2; HRMS (ESI/TOF-Q) m/z: [M+K]+ Calcd for C19H20O5K+ 367.0948; Found 367.0941. Synthesis of compound 8 from compound 7: To an oven dried 25 ml round-bottom flask, styrylated product 7 (1.4 mmol, 1 equiv) and 10% Pd/C (10 mol %) were taken and 10 mL dry methanol was added. The reaction mixture was stirred overnight at room temperature under H2 balloon pressure. After completion (monitored by TLC), the reaction mixture was filtered through a Celite pad. Then the solvent was evaporated under reduced pressure and resulting residue was transferred to a 25 mL round bottom flask and KOH (2 equiv) was taken in it. Next, 8 mL mixture of H2O and ethanol (5:1, v/v) was added in the flask and the mixture was refluxed for 3 hours. After completion (monitored by TLC), the ethanol was evaporated under reduced pressure. The reaction mixture was neutralized with 1N HCl and then crude carboxylic acid was ob-

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tained through work up with ethyl acetate. The solvent was evaporated under reduced pressure and, to obtain pure compound 8, the resulting residue was purified through column chromatography on silica gel with a gradient eluent of hexane and ethyl acetate. (E)-4-methoxy-2-styrylbenzoic acid (8): Solid, yield 99% (250 mg); mp 116-118 oC; 1H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 8.7 Hz, 1H), 7.27-7.18 (m, 5H), 6.81-6.68 (m, 2H), 3.81 (s, 3H), 3.35- 3.31 (m, 2H), 2.96-2.92 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 172.2, 163.2, 147.9, 142.2, 134.6, 128.8, 128.5, 126.0, 120.2, 116.8, 111.7, 55.5, 38.1, 37.7; HRMS (ESI/TOF-Q) m/z: [M+H]+ Calcd for C16H16O3H+ 257.1178; Found 257.1188. Procedure for the hydrolysis of esters 7, 20, and 25: To an oven dried 25 ml round-bottom flask, ester compound 7 (1 mmol, 1 equiv) and KOH (2 equiv) were taken and 8 mL mixture of H2O and ethanol (5:1, v/v) was added. The reaction mixture was refluxed for 3 hours. After completion (monitored by TLC), the ethanol was evaporated under reduced pressure. The reaction mixture was neutralized with 1N HCl and then crude carboxylic acid was obtained through work up with ethyl acetate. The solvent was evaporated under reduced pressure and, to obtain pure compound 15, the resulting residue was purified through column chromatography on silica gel with a gradient eluent of hexane and ethyl acetate. Compound 21 and 26 were prepared following the same procedure from the corresponding esters 20 and 25, respectively. (E)-4-methoxy-2-styrylbenzoic acid (15): White solid; yield 98% (250 mg); mp 152-154 oC; 1H NMR (400 MHz, CDCl3): δ 8.14-8.06 (m, 2H), 7.57-7.55 (m, 2H), 7.38-7.19 (m, 4H), 7.01-6.93 (m, 1H), 6.87 (d, J = 9.1 Hz, 1H), 3.91 (s, 3H); 13 CNMR (101 MHz, CDCl3): δ 172.9, 163.4, 143.0, 137.4, 134.4, 131.8, 128.8, 128.2, 128.1, 127.1, 119.8, 112.9, 112.6, 55.6; HRMS (ESI/TOF-Q) m/z: [M+H]+ Calcd for C16H14O3H+ 255.1021; Found 255.1025. (E)-2-(4-methoxystyryl)benzoic acid (21): White solid; yield 95% (360 mg); mp 177-179 oC; 1H NMR (400 MHz, CDCl3): δ 8.08-8.06 (m, 1H), 7.96-7.92 (m, 1H), 7.74-7.72 (m, 1H), 7.57-7.49 (m, 3H), 7.34 (t, J = 7.1 Hz, 1H), 7.02-6.98 (m, 1H), 6.92-6.90 (m, 2H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 172.2, 159.7, 140.6, 133.2, 131.7, 131.5, 130.4, 129.6, 128.4, 127.2, 127.0, 125.5, 114.3, 55.5; HRMS (ESI/TOF-Q) m/z: [M+Na]+ Calcd for C16H14O3Na+ 277.0841; Found 277.0857. (E)-2-(3,4,5-trimethoxystyryl)benzoic acid (26): White solid, yield 94% (295 mg); mp 120-122 oC; 1H NMR (400 MHz, CDCl3): δ 8.07-7.93 (m, 2H), 7.72-7.70 (m, 1H), 7.56-7.47 (m, 1H), 7.35-7.20 (m, 1H), 6.94 (d, J = 16.1 Hz, 1H), 6.78 (s, 2H), 3.88 (s, 6H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 172.8, 153.5, 140.2, 138.4, 133.3, 133.2, 131.8, 131.7, 127.42, 127.37, 126.4, 105.6, 104.2, 61.1, 56.2 (C×2). HRMS (ESI/TOF-Q) m/z: [M+H]+ Calcd for C18H18O5H+ 315.1232; Found 315.1262. Synthesis of compound 8 from 4-acetylanisole 9: To an oven dried 15 ml Schlenk tube, 4-acetylanisole 9 (4 mmol, 1 equiv), styrene 6a (2 equiv), [Ru(p-cymene)Cl2]2 (2.5 mol %), sodium formate (HCO2Na) (30 mol %), and PPh3 (15 mol %) were taken under N2 atmosphere. Dry toluene (5 mL) was injected and the reaction mixture was stirred at 140 oC for 36


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The Journal of Organic Chemistry h. After completion (monitored by TLC), the reaction mixture was diluted with DCM and filtered through a celite pad. The volatiles were evaporated under reduced pressure. To the resulting residue was transferred to a 25 mL round bottom flask and Mn(OAc)24H2O (1 mol %) was added. Next, acetic acid (4.0 mL) was injected in the reaction mixture and the flask was equipped with a balloon filled with O2. The mixture was then stirred at 100 oC for 15 hours. After completion, the reaction mixture was cooled to room temperature and extracted with NaHCO3 solution followed by work-up with 1N HCl to give acid 8 (778.5 mg, 76% yield). Installation of 2-APP directing group to prepare compound 11, 16, 22, and 27: To an oven dried 50 ml roundbottom flask (with suitable gas outlet), acid 8 (0.9 mmol, 1 equiv) was dissolved in 10 mL dichloromethane and oxalyl chloride (2 equiv) was added under N2 atmosphere. The reaction mixture was cooled to 0 oC and then, one drop of DMF was added. The reaction mixture was stirred at 0 oC for 1 hour and further stirred for 3 hours at room temperature. Afterwards, the volatiles were evaporated under reduced pressure. The resulting residue was dissolved in 10 mL dichloromethane and (2-aminophenyl)pyrazole (2-APP) 10 (1.1 equiv) and triethyl amine (2 equiv) were added at 0 oC under inert atmosphere. The mixture was stirred at room temperature for overnight. After the completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure and the resulting residue was purified by column chromatography on silica gel with a gradient eluent of hexane and ethyl acetate. Amides 16, 22, and 27 were also prepared following the abovementioned procedure from acids 15, 21, and 26, respectively. N-(2-(1H-pyrazol-1-yl)phenyl)-4-methoxy-2phenethylbenzamide (11): Liquid, yield 99% (350 mg); mp 92-94 oC; 1H NMR (400 MHz, CDCl3): δ 10.56 (s, 1H), 8.65 (dd, J = 8.3, 1.2 Hz, 1H), 7.80 (dd, J = 2.5, 0.5 Hz, 1H), 7.737.72 (m, 1H), 7.45-7.38 (m, 2H), 7.35-7.32 (m, 1H), 7.21-7.18 (m, 3H), 7.16-7.08 (m, 3H), 6.77-6.74 (m, 1H), 6.68-6.67 (m, 1H), 6.46-6.45 (m, 1H), 3.77 (s, 3H), 3.18-3.14 (m, 2H), 2.942.90 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 167.6, 161.0, 143.8, 141.9, 141.2, 132.2, 130.3, 129.3, 129.0, 128.8, 128.7, 128.3, 128.2, 125.9, 124.1, 123.0, 122.6, 116.5, 111.5, 107.2, 55.4, 37.9, 35.9; HRMS (ESI/TOF-Q) m/z: [M+H]+ Calcd for C25H23N3O2H+ 398.1869; Found 398.1857. (E)-N-(2-(1H-pyrazol-1-yl)phenyl)-4-methoxy-2styrylbenzamide (16): Liquid; yield 99% (350 mg); mp 93-95 o C; 1H NMR (400 MHz, CDCl3): δ 10.70 (s, 1H), 8.71-8.69 (m, 1H), 7.71-7.56 (m, 4H), 7.45-7.38 (m, 3H), 7.30-7.16 (m, 6H), 7.00 (d, J = 16.7 Hz, 1H), 6.86-6.84 (m, 1H), 6.33 (s, 1H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 167.1, 161.3, 141.1, 138.9, 137.2, 132.1, 131.4, 130.0, 129.7, 129.2, 128.5, 128.1, 127.8, 126.9, 126.4, 124.0, 122.8, 122.5, 113.9, 113.0, 111.8, 107.1, 55.4; HRMS (ESI/TOF- Q) m/z: [M+Na]+ Calcd for C25H21N3O2Na+ 418.1531; Found 418.1537. (E)-N-(2-(1H-pyrazol-1-yl)phenyl)-2-(4methoxystyryl)benzamide (22): Liquid; yield 96% (340 mg); mp 98-100 oC; 1H NMR (400 MHz, CDCl3): δ 10.72 (s, 1H), 8.74 (d, J = 7.4 Hz, 1H), 7.71-7.69 (m, 2H), 7.61-7.54 (m, 2H), 7.45-7.39 (m, 3H), 7.37-7.35 (m, 2H), 7.32-7.27 (m, 2H), 7.19 (t, J = 7.8 Hz, 1H), 7.00-6.96 (m, 1H), 6.84-6.81 (m, 2H),

6.32 (s, 1H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.8, 159.6, 141.2, 136.8, 135.4, 131.9, 131.0, 130.7, 130.2, 130.1, 129.2, 128.3, 128.2, 127.9, 127.2, 126.4, 124.3, 123.9, 122.9, 122.6, 114.1, 107.2, 55.4; HRMS (ESI/TOF-Q) m/z: [M+Na]+ Calcd for C25H21N3O2Na+ 418.1531; Found 418.1525.

(E)-N-(2-(1H-pyrazol-1-yl)phenyl)-2-(3,4,5trimethoxystyryl)benzamide (27): Yellow solid,

yield 98% (380 mg); 1H NMR (400 MHz, CDCl3): δ 10.82 (s, 1H), 8.73 (d, J = 7.1 Hz, 1H), 7.75- 7.69 (m, 2H), 7.63 (s, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.57-7.41 (m, 3H), 7.33 (d, J = 6.5 Hz, 2H), 7.20 (d, J = 6.9 Hz, 1H), 6.95 (d, J = 16.0 Hz, 1H), 6.67 (s, 2H), 6.37-6.35 (m, 1H), 3.84 (s,9H); 13C NMR (100 MHz, CDCl3): δ 167.7, 153.4, 141.3, 136.5, 135.5, 133.2, 131.9, 131.5, 130.8, 130.0, 129.2, 128.2, 127.9, 127.6, 126.7, 125.9, 124.4, 122.9, 122.5, 107.3, 104.2, 61.1, 56.2(C×2); HRMS (ESI/TOF-Q) m/z: [M+Na]+ Calcd for C27H25N3O4Na+ 478.1743; Found 478.1740. Synthesis of compounds 12, 17, 23, and 28 via directed C– H hydroxylation using Cu(OAc)2: A mixture of amide 11 (0.75 mmol, 1.0 equiv), anhydrous copper acetate (1.5 equiv), and K2CO3 (1.5 equiv) in DMSO (6 mL) was taken in a 25 mL round-bottom flask under open air conditions. The mixture was stirred at 80 oC for 5 h. After the completion of the reaction (monitored by TLC), the crude mixture was then transferred to a 125 mL separating funnel and 25 ml brine solution was added. It was extracted with ethyl acetate (3×20) and volatiles were removed under reduced pressure. Then, the resulting residue was purified by column chromatography on silica gel with a gradient eluent of hexane and ethyl acetate. The same copper-mediated directed C–H hydroxylation procedure was followed for the syntheses of compounds 17, 23, and 28 from 16, 22, and 27, respectively. N-(2-(1H-pyrazol-1-yl)phenyl)-2-hydroxy-4-methoxy-6phenethylbenzamide (12): White solid, yield 84% (250 mg); mp 130-132 oC; 1H NMR (400 MHz, CDCl3): δ 10.64 (s, 1H), 10.28 (s, 1H), 8.43 (dd, J = 8.3, 1.2 Hz, 1H), 7.74 (dd, J = 2.5, 0.5 Hz, 1H), 7.67-7.66 (m, 1H), 7.43-7.39 (m, 1H), 7.35- 7.33 (m, 1H), 7.25-7.12 (m, 4H), 7.06-7.03 (m, 2H), 6.40-6.39 (m, 1H), 6.36 (s, 2H), 3.77 (s, 3H), 3.16-3.12 (m, 2H), 2.93-2.89 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 168.8, 162.8, 161.7, 142.0, 141.5, 141.2, 130.8, 130.1, 129.9, 128.5(2×C), 128.1, 126.1, 125.0, 124.0, 122.9, 111.8, 109.7, 107.5, 99.7, 55.4, 37.5, 36.7; HRMS (ESI/TOF-Q) m/z: [M+H]+ Calcd for C25H23N3O3H+ 414.1818; Found 414.1802. (E)-N-(2-(1H-pyrazol-1-yl)phenyl)-2-hydroxy-4-methoxy-6styrylbenzamide (17): Solid; yield 81% (251 mg); mp 145-147 o C; 1HNMR (400 MHz, CDCl3): δ 11.58 (s, 1H), 10.58 (s, 1H), 8.50 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.417.32 (m, 5H), 7.28-7.15 (m, 5H), 7.02-6.98 (m, 1H), 6.61 (d, J = 2.5 Hz, 1H), 6.43 (d, J = 2.5 Hz, 1H), 6.10 (t, J = 2.2 Hz, 1H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.9, 163.4, 163.2, 141.0, 139.6, 136.8, 133.7, 130.9, 130.1, 129.4, 128.6, 128.2, 127.7, 127.1, 126.5, 124.9, 124.2, 122.9, 109.2, 107.4, 107.2, 100.9, 55.5; HRMS (ESI/TOF-Q) m/z: [M+H]+ Calcd for C25H21N3O3H+ 412.1661; Found 412.1682. (E)-N-(2-(1H-pyrazol-1-yl)phenyl)-2-hydroxy-6-(4methoxystyryl)benzamide (23): White solid; yield 88% (250



mg); mp 126-128 oC; 1H NMR (400 MHz, CDCl3) δ 10.77 (s, 1H), 10.75 (s, 1H), 8.61 (d, J = 8.2 Hz, 1H), 7.56 (s, 1H), 7.43 – 7.40 (m, 1H), 7.36 – 7.30 (m, 4H), 7.26 – 7.17 (m, 3H), 7.07 (d, J = 7.7 Hz, 1H), 6.98 – 6.94 (m, 1H), 6.90 – 6.88 (m, 1H), 6.81 (d, J = 8.3 Hz, 2H), 6.13 (s, 1H), 3.79 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.9, 160.3, 159.7, 141.2, 138.1, 133.1, 132.9, 130.9, 130.1, 129.8, 129.5, 128.4, 127.9, 125.1, 124.2, 123.9, 122.9, 119.4, 116.7, 116.6, 114.1, 107.3, 55.4; HRMS (ESI/TOF-Q) m/z: [M+H]+ Calcd for C25H21N3O3H+ 412.1661; Found 412.1659. (E)-N-(2-(1H-pyrazol-1-yl)phenyl)-2-hydroxy6(3,4,5trimethoxystyryl)benzamide (28): White solid, yield 85% (280 mg); mp 176-178 oC; 1H NMR (400 MHz, CDCl3): δ 10.85 (s, 1H), 10.48 (s, 1H), 8.59 (d, J = 6.3 Hz, 1H), 7.61 (s, 1H), 7.43-7.39 (m, 2H), 7.35 (t, J = 7.9 Hz, 1H), 7.28-7.23 (m, 3H), 7.10-7.09 (m, 1H), 6.97-6.90 (m, 2H), 6.61 (s, 2H), 6.20 (s, 1H), 3.83 (s, 3H), 3.74 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 168.6, 159.9, 153.2, 141.0, 138.2, 137.4, 132.9, 132.81, 132.78, 130.6, 129.8, 129.3, 127.8, 126.1, 125.1, 123.7, 122.5, 119.1, 116.8, 107.2, 104.1, 60.9, 56.0 (2×C); HRMS (ESI/TOF-Q) m/z: [M+H]+ Calcd for C27H25N3O5H+ 472.1872; Found 472.1876. Synthesis of compounds 13, 18, 24, and 29 via removal of the 2-APP directing group: In a 30 mL pressure tube equipped with a magnetic stir bar, compound 12 and dry methanol (8 mL) were added. Then, BF3.Et2O (6 equiv) was added drop wise to the stirred solution at room temperature. The resulting mixture was stirred at 100 °C for 36 h. After cooling to room temperature, Et3N (10 equiv) was added drop wise to the reaction mixture. The volatile components were removed under reduced pressure and the crude reaction mixture was directly loaded onto silica gel column and purified through gradient eluent of hexane and ethyl acetate mixture to obtain the pure product 13. The removal of directing group from compounds 17, 23, 28 to prepare hydroxyl compounds 18, 24, and 29, respectively, was also accomplished following this procedure. Methyl 2-hydroxy-4-methoxy-6-phenethylbenzoate (13): Oil, yield 95% (65 mg); 1H NMR (400 MHz, CDCl3): δ 11.75 (s, 1H), 7.31-7.17 (m, 5H), 6.36-6.28 (m, 2H), 3.95 (s, 3H), 3.78 (s, 3H), 3.18-3.14 (m, 2H), 2.85-2.81 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 171.9, 165.8, 164.2, 146.8, 142.0, 128.55, 128.46, 126.1, 111.0, 104.8, 99.3, 55.4, 52.1, 39.0, 38.4; HRMS (ESI/TOF-Q) m/z: [M+Na]+ Calcd for C17H18O4Na+ 309.1103; Found 309.1124. Methyl (E)-2-hydroxy-4-methoxy-6-styrylbenzoate (18): Oil; yield 95% (64 mg); 1H NMR (400 MHz, CDCl3): δ 11.67 (s, 1H), 7.70-7.66 (m, 1H), 7.49-7.47 (m, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.29-7.24 (m, 1H), 6.81-6.77 (m, 1H), 6.63 (d, J = 2.5 Hz, 1H), 6.44 (d, J = 2.6 Hz, 1H), 3.94 (s, 3H), 3.84 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 171.8, 165.3, 164.3, 143.0, 137.6, 131.0, 129.9, 128.9, 127.9, 126.8, 108.1, 104.1, 100.4, 55.6, 52.4; HRMS (ESI/TOF-Q) m/z: [M+Na]+ Calcd for C17H16O4Na+ 307.0946; Found 307.0964. (E)-Methyl 2-hydroxy-6-(4-methoxystyryl)benzoate (24): Oil, yield 92% (60 mg); 1H NMR (400 MHz, CDCl3) δ 11.16 (s, 1H), 7.57 (d, J = 16.0 Hz, 1H), 7.45 – 7.43 (m, 2H), 7.39 (t, J = 8.0 Hz, 1H), 7.09 – 7.07 (m, 1H), 6.92 – 6.90 (m, 3H), 6.80

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(d, J = 16.0 Hz, 1H), 3.98 (s, 3H), 3.84 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.9, 162.5, 159.6, 141.6, 134.5, 130.7, 130.4, 128.0, 127.6, 119.6, 116.8, 114.3, 110.9, 55.5, 52.7; HRMS (ESI/TOF- Q) m/z: [M+Na]+ Calcd for C17H16O4Na+ 307.0946; Found 307.0971. (E)-Methyl 2-hydroxy-6-(3,4,5-trimethoxystyryl)benzoate (29): Oil, yield 92% (73 mg); 1H NMR (500 MHz, CDCl3): δ 11.16 (s, 1H), 7.62 – 7.58 (m, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.08 – 7.06 (m, 1H), 6.95 (dd, J = 8.3, 0.9 Hz, 1H), 6.78 (s, 1H), 6.74 – 6.73 (m, 2H), 3.99 (s, 3H), 3.92 (s, 6H), 3.88 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 171.7, 162.5, 153.6, 141.1, 134.6, 133.4, 131.1, 131.0, 119.8, 117.2, 116.8, 106.5, 103.8, 61.1, 56.25(2×C), 52.66; HRMS (ESI/TOF-Q) m/z: [M+Na]+ Calcd for C19H20O6Na+ 367.1158; Found 367.1167. Synthesis compounds 14 and 19 through O-prenylation: To a 10 mL round bottom flask equipped with a magnetic stir bar was added 13 (0.20 mmol, 1 equiv). Then NaH (2 equiv) and prenyl bromide (3 equiv) were added in the presence of DMF (3 ml) solvent and the reaction mixture was stirred overnight under N2 atmosphere. After completion (monitored by TLC), it was extracted with ethyl acetate and purified by column chromatography to isolated compound 14. Compound 19 was also synthesized using the same synthetic procedure from compound 18. Methyl 4-methoxy-2-((3-methylbut-2-en-1-yl)oxy)-6phenethylbenzoate (14): Oil, yield 92% (65 mg); 1H NMR (400 MHz, CDCl3): δ 7.29-7.25 (m, 2H), 7.20-7.16 (m, J = 7.1 Hz, 3H), 6.33-6.24 (m, 2H), 5.42 (s, 1H), 4.52 (d, J = 5.7 Hz, 2H), 3.87 (s, 3H), 3.74 (s, 3H), 2.86-2.85 (m, 4H), 1.76 (s, 3H), 1.71 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.8, 161.2, 157.5, 141.8, 141.6, 137.4, 128.46, 128.37, 125.9, 119.7, 116.8, 106.1, 97.9, 65.9, 55.3, 52.0, 37.6, 36.2, 25.7, 18.2; HRMS (ESI/TOF-Q) m/z: [M+H]+ Calcd for C22H26O4H+ 355.1909; Found 355.1921. (E)-Methyl-4-methoxy-2-((3-methylbut-2-en-1-yl)oxy)-6styrylbenzoate (19): Liquid; yield 94 % (66 mg); 1H NMR (400 MHz, CDCl3): δ 7.48-7.45 (m, 2H), 7.36-7.32 (m, 2H), 7.28- 7.24 (m, 1H), 7.12-7.01 (m, 2H), 6.76 (d, J = 2.1 Hz, 1H), 6.41 (d, J = 2.1 Hz, 1H), 5.44-5.40 (m, 1H), 4.54 (d, J = 6.5 Hz, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 1.76 (s, 3H), 1.72 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.6, 161.4, 157.6, 137.7, 137.5, 136.9, 131.7, 128.8, 128.1, 126.9, 125.5, 119.6, 116.6, 101.7, 99.5, 66.0, 55.5, 52.3, 25.8, 18.4; HRMS (ESI/TOF-Q) m/z: [M+H]+ Calcd for C22H24O4H+ 353.1753; Found 353.1750. Synthesis of amorfrutin A methyl ester (1a) and cajaninstilbene acid methyl ester (2a): The O–prenyl ether 14 (0.16 mmol) was taken into an oven dried 10 ml reaction tube equipped with a magnetic stir. Then, Montmorillonite K10 (1 wt equiv) was added in the presence of dichloromethane (3 mL) solvent and the reaction mixture was stirred at room temperature for 8 h. After completion (monitored by TLC), the crude reaction mixture was diluted with ethyl acetate, filtered through a celite pad, and the solvent was evaporated under reduced pressure. In order to get pure product 1a, the resulting residue was purified by column chromatography on silica gel with a gradient eluent of hexane and ethyl acetate. The compound 2a was prepared following the same synthetic procedure from O–prenyl ether 19.


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The Journal of Organic Chemistry Methyl 2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)-6phenethylbenzoate (1a): Oil; yield 38% (23 mg); 1H NMR (400 MHz, CDCl3): δ 11.75 (s, 1H), 7.32-7.28 (m, 2H), 7.227.18 (m, 3H), 6.21 (s, 1H), 5.22-5.17 (m, 1H), 3.96 (s, 3H), 3.80 (s, 3H), 3.34 (d, J = 7.0 Hz, 2H), 3.19-3.15 (m, 2H), 2.862.82 (m, 2H), 1.78 (s, 3H), 1.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.3, 162.0, 161.3, 144.2, 142.2, 131.8, 128.5 (2×C), 126.1, 122.5, 115.3, 106.0, 105.3, 55.6, 52.2, 39.5, 38.5, 25.9, 22.1, 17.9; HRMS (ESI/TOF-Q) m/z: [M+H]+ Calcd for C22H26O4H+ 355.1909; Found 355.1934. (E)-Methyl 2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)-6styrylbenzoate (2a): White solid; yield 40 % (22 mg); mp 9496 oC; 1H NMR (400 MHz, CDCl3): δ 11.69 (s, 1H), 7.72 (d, J = 15.9 Hz, 1H), 7.51-7.49 (m, 2H), 7.38 (t, J= 7.6 Hz, 2H), 7.30-7.28 (m, 1H), 6.78 (d, J = 15.9 Hz, 1H), 6.61 (s, 1H), 5.22 (t, J = 6.8 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.38 (d, J = 7.1 Hz, 2H), 1.79 (s, 3H), 1.68 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 172.1, 161.6, 161.5, 140.4, 137.6, 132.0, 130.8, 130.2, 128.9, 127.9, 126.7, 122.2, 116.8, 104.6, 103.0, 55.8, 52.4, 25.9, 22.3, 17.9; HRMS (ESI/TOF-Q) m/z: [M+Na]+ Calcd for C22H24O4Na+ 375.1572; Found 375.1591. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1H and 13C NMR spectra of products (PDF). AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We gratefully acknowledge CSIR New Delhi (02(0212)/14/EMR-II) and DST-India (EMR/2014/000225) for the financial support. G.S.G. acknowledges UGC for SRF and S.D. acknowledges IIT-Madras for HTRA fellowship. We also thank the Department of Chemistry, IIT-Madras for instrumental facilities.

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