Note pubs.acs.org/joc
Organocatalytic Enantioselective Michael−Acetalization−Henry Reaction Cascade of 2‑Hydroxynitrostyrene and 5‑Oxohexanal for the Entry to the Hexahydro‑6H‑benzo[c]chromenones with Four Consecutive Stereogenic Centers and an Approach to Aflatoxin Analogues Yu-You Hsieh,† Arun Raja,† Bor-Cherng Hong,*,† Prakash Kotame,† Wan-Chen Chang,† and Gene-Hsiang Lee‡ †
Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi 621, Taiwan, R.O.C. Instrumentation Center, National Taiwan University, Taipei 106, Taiwan, R.O.C.
‡
S Supporting Information *
ABSTRACT: A domino reaction with the organocatalytic enantioselective Michael−acetalization−Henry reaction of 2hydroxynitrostyrene and 5-oxohexanal was developed for the synthesis of hexahydro-6H-benzo[c]chromenones with four consecutive stereogenic centers and high enantioselectivity (up to >99% ee). The transformation of a NaBH4-reduced adduct to the aflatoxin system via the Nef-cyclization process was achieved by the assistant of ZnBr2.
T
sclerosis (Figure 1). Moreover, several intricate total syntheses of the naturally occurring hexahydro-6H-benzo[c]chromene have been revealed. For example, a short and divergent total synthesis of (+)-machaeriol B, (+)-machaeriol D, and (+)-Δ8THC has been developed by Studer and co-workers, with the key step being the stereospecific palladium-catalyzed decarboxylative arylation.3 Moreover, a tandem 5-exo, 6-exo radical cyclization was introduced by Parker et al. as the pivotal step in the total synthesis of (±)-bisabosqual A.4 Since the turn of this century, many domino organic reactions with the organocatalyts have been developed and have enriched the synthetic methodologies. In 2011, Gong and co-workers reported an asymmetric organocatalytic tandem Michael−hemiacetalization for the synthesis of chiral dihydrocoumarins, chromanes, and 4H-chromenes (Scheme 1).5 Coincidentally and almost concurrently, an asymmetric synthesis of cis-3,4-disubstituted chromans and dihydrocoumarins by the aid of an organocatalytic Michael−hemiacetalization reaction was developed by Enders et al. (Scheme 1).6 Compellingly, within 6 weeks after Gong’s publication, our group revealed a related organocatalytic Michael−hemiacetalization reaction “on water”, where the reactions were dramatically accelerated, and with the extension of the domino Michael−acetalization−Henry reactions of 2hydroxynitrostyrenes and glutaraldehyde for the preparation of hexahydro-6H-benzo[c]chromenones, with the tricyclic chromane scaffold (Scheme 1).7 Despite the aforementioned advances in the synthesis of chromanes, a few extensions of the synthetic methods are as yet required in terms of substrate
he chroman motif is an important scaffold found in natural products which widely occur in natural resources and have a broad spectrum of biological activities. Among them, hexahydro-6H-benzo[c]chromene emerges as a peculiar representative in this family. Many chromans have attracted considerable attention owing to their promising pharmacological activities (Figure 1).1 As the result, the total syntheses of the natural products of this family as well as their derivatives have garnered significant research interest.2 One of the investigations successfully delivered an FDA approved therapeutic drug, nabilone, which was used as an antiemetic and as an adjunct analgesic in the treatment of neuropathic pain, for example, the symptoms caused by fibromyalgia and multiple
Figure 1. Naturally occurring and synthetic bioactive hexahydro-6Hbenzo[c]chromenes. © 2017 American Chemical Society
Received: September 6, 2017 Published: October 25, 2017 12840
DOI: 10.1021/acs.joc.7b02178 J. Org. Chem. 2017, 82, 12840−12848
Note
The Journal of Organic Chemistry
CH2Cl2 somewhat expedited the process and afforded higher yields (Table 1, entries 6−7). Encouragingly and as expected, the reaction of hydroxynitrostyrene 1a and 6 equiv of 5oxohexanal (2) “on water”9 not only facilitated the reaction, which was completed in 28 h, but also furnished a higher yield of the domino Michael−acetalization−Henry product (74% yield, Table 1, entry 8). With the optimized reaction conditions in hand, the transformation was studied with a series of hydroxynitrostyrenes 1 and 5-oxohexanal (2), followed by the oxidation with PCC to give the lactone derivatives 4 and 5 (Table 2). For example, to a solution of catalyst I (20 mol %) and HOAc (20 mol %) in water was added nitrostyrene 1a and ketoaldehyde 2, and the solution was stirred at ambient temperature (∼25 °C) for 28 h, until the completion of the reaction, followed by dilution with CH2Cl2. To this reaction mixture was added PCC (3 equiv), and the solution was stirred at room temperature for 12 h. After the regular extraction-concentration work up, the diastereomeric ratio of the product was determined by the crude 1H NMR spectrum of the residue and was found to have a ratio of 79:21. The crude product was purified by silica-gel chromatography to give lactones 4a and 5a in a total yield of 59% (Table 2, entry 1). As shown in Table 2, the reaction was quite general with respect to the various hydroxynitrostyrene derivatives and gave good yields. The enantioselectivities of the major diastereomeric products were high with up to 99% ee, (Table 2, entries 1 and 2). In addition, the first step the Michael−acetalization−Henry reaction was slightly faster and was completed in 18 h when the hydroxynitrostyrene 1 bore an electron-withdrawing substituent on the aromatic ring, e.g., NO2 group (Table 2, entry 5), whereas the reaction was slightly slower when the electron-donating groups were presented on the aromatic ring, e.g., OMe, OBn group (Table 2, entries 4, 7, 8, and 11). The structures and the absolute configurations of the products (+)-4b and (−)-4c were unambiguously characterized by single-crystal X-ray analysis (Figure 2).10 Consequently, in the attempt to expand the structural diversity of the prepared product and to broaden the synthetic applications, we envisaged that the nitroalkane 6, which could be generated from the reduction of lactol 3a, could be transformed to the tetrahydrofuro[2,3-b]benzofuran systems 8, i.e., the aflatoxin skeleton, since the nitro group could serve as the carbonyl equivalent by the Nef reaction,11 and with the intramolecular acetalization−cyclization, Scheme 2.12 In this context, treatment of nitroalkene 1l13 and 5oxohexanal (2) with the preceding Michael−acetalization− Henry reaction, followed by the reduction of the acetal intermediate with NaBH4 in MeOH at 0 °C for 30 min gave the triol 9 in 55% yield (Scheme 3). During this process, in addition to the reduction of the acetal group on intermediate 3l, the ring opening and reduction of the cyclic tert-βnitroalcohol group was observed in the NaBH4 reduction reaction.14,15 Zinc-catalyzed organic reactions have been applied in many organic syntheses.16 Among them, ZnBr2 has been used for many synthetic transformations.17 Owing to its Lewis-acid property, we suspect that the Nef reaction of 9 could be achieved by the ZnBr2-mediated process, which will be a process with less basic or acidic reaction conditions than the traditional Nef process conditions, e.g., KOH, HCl, TiCl4, SnCl4, etc. To our delight, treatment of 9 with 1.5 equiv of ZnBr2 in CH2Cl2 for 30 h gave the expected tetrahydrofuro[2,3-b]benzofuran 10 in 61% yield. Oxidation of 10 with PCC afforded a 78% yield of ketone 11, which was analyzed by
Scheme 1. Selected Examples of the Synthesis of the Chromanes by the Aid of Asymmetric Organocatalysis Cascade
scope and reaction selectivities, and consequently, the development of related studies for easy access to other derivatives is still a compelling subject. Herein, we report the details of our extension works, the various domino Michael−acetalization− Henry reactions of 5-oxohexanal and 2-hydroxynitrostyrenes, which afford the hexahydro-6H-benzo[c]chromenones with four consecutive stereogenic centers, and also an approach to the aflatoxin system via a sequence of reduction−Nef− acetalization reactions. At the outset, a solution of hydroxynitrostyrene 1a and 5oxohexanal (2) in 95% ethanol was employed with Jørgensen− Hayashi catalyst I−PhCO2H (20 mol %) for 96 h, providing 43% yield of the Michael−acetalization−Henry product 3a (Table 1, entry 1).8 In order to find the best reaction media providing the highest yield, the reaction was screened in a series of solvents (Table 1, entries 2−8). The reactions conducted in THF, toluene, DMF, and CH3CN were sluggish, giving lesser yields (22−32%) after a 7-day reaction period (Table 1, entries 2−5). Additionally, the reaction performed in CHCl3 and Table 1. Screening of Additives and Solvents for the Domino Reactiona
entry 1 2 3 4 5 6 7 8c
solvent d
EtOH THF toluene DMF CH3CN CHCl3 CH2Cl2 H2O
additive (20 mol %)
time (h)
yieldb (%)
PhCO2H PhCO2H PhCO2H PhCO2H PhCO2H PhCO2H PhCO2H AcOH
96 168 168 168 168 68 68 28
43 22 24 30 32 54 59 74
a
Unless otherwise noted, the reaction was performed on a 0.6 M scale of 1a and 2 with the addition of 0.2 equiv of 2 in a 24 h interval. b Yields of 3a isolated. cKetoaldehyde 2 (6 equiv) was added at once in the beginning of the reaction. d95% EtOH was used. 12841
DOI: 10.1021/acs.joc.7b02178 J. Org. Chem. 2017, 82, 12840−12848
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The Journal of Organic Chemistry Table 2. Examples of the One-Pot Michael−Acetalization−Henry Reaction of 1 and 2
entry
product
time (h)b
yield (%)c
drd (4:5)
ee (%)e
1 2 3 4 5 6 7 8 9 10 11
a. R1H, R2H, R3H b. R1Br, R2H, R3H c. R1Cl, R2H, R3H d. R1=OMe, R2H, R3H e. R1= NO2, R2H, R3H f. R1=CH3, R2H, R3H g. R1H, R2=OMe, R3H h. R1=OBn, R2H, R3H i. R1H, R2H, R3Br j. R1H, R2H, R3Cl k. R1H, R2H, R3=OMe
28/12 20/12 22/16 28/16 18/13 24/15 26/17 30/15 26/18 26/19 28/18
59f 61 59 61 52 64 63 54 54 51 55
79:21 88:12 79:21 94:6 90:10 92:8 87:13 90:10 79:21 80:20 96:4
99 99 99 (96)g 99 99 99 (99) 99 (97)g 99 99 (92)g 99 (94)g 99
The reaction was performed on a 0.6 M scale of 1 and 2 (6 equiv) “on H2O” at ambient temperature (∼25 °C). bReaction time for the Michael− acetalization−Henry reaction/reaction time for the PCC oxidation. cYield of the product 4 and 5 isolated. dDetermined by 1H NMR of the crude product of 4 and 5. eUnless otherwise noted, ee was determined by HPLC with a chiral column (Chiralpak IA); ee of the minor products 5 in parentheses. fIsolated yields for the cascade reaction and oxidation were found to be 74% and 86%, respectively. gee was determined by HPLC with a chiral column (Chiralpak IC). a
cyclization via G to afford tetrahydrofuro[2,3-b]furan 10. An observation supports the intramolecular hydroxy-assisted ZnBr2-mediated Nef-cyclization reaction: the same reaction conditions applied to alcohol 9 analog, 12a, and 12b, which lacked the additional hydroxy group on the tether, gave a tiny amount of the product (Figure 3). In addition, the reaction of 12c led to the formation of tiny amounts of products, with recovery of most of the starting compound. Thus, the two alkoxy groups on the benzene moiety increased the nucleophilicity of phenolic hydroxyl groups and, hence, triggered the reaction. In summary, a domino Michael−acetalization−Henry reaction of 5-oxohexanal and 2-hydroxynitrostyrenes has been developed for the synthesis of the hexahydro-6H-benzo[c]chromenones with four consecutive stereogenic centers and high enantioselectivity (up to >99% ee). The structures and absolute configurations of the products (+)-4b, (−)-4c, and (−)-10, have been unambiguously confirmed by single-crystal X-ray crystallographic analyses. Transformation of alcohol 9 to an aflatoxin system via the key step of the Nef-cyclization process was achieved with the mild Lewis acid, ZnBr2. Given the widespread occurrence in nature and the intriguing biological activities of the chromanes and the aflatoxins, these adequate asymmetric processes could become a conventional means to the synthesis of related compounds.
Figure 2. Stereo plots of the X-ray crystal structures of (+)-4b,(−)-4c and (−)-10: C, gray; O, red; N, blue; Br, purple; Cl, green.
HPLC with a chiral column, affording 99% ee. It is noteworthy that the mild Lewis acid ZnBr2 was first successfully applied in the Nef-acetalization reactions, without the need of treatment with strong base and acid conditions.18 The structure and the absolute configuration of 10 was revealed by X-ray diffraction analysis of its single crystal (Figure 2). To account for the retroHenry−reduction process as well as the ZnBr2-mediated Nefcyclization reaction, a plausible mechanism has been proposed as depicted in Scheme 4. Initial treatment of intermediate 3l with NaBH4 would lead to the formation of ketone B intermediate via the retro-Henry−reduction of A, followed by the reduction of ketone and acetal to give triol 9. Reaction of 9 with ZnBr2 would promote the formation of nitronate D, via the neighboring group participation of ZnBr2 with the hydroxyl group on the tether, followed by cyclization of phenol to give dihydroxyamine E. After dehydration, dihydroxyamine E would be transformed to nitroso intermediate F, and the subsequent
Scheme 2. Retrosynthetic Analysis of the Tetrahydrofuro[2,3-b]benzofurans with Nef-Acetalization Transformation
12842
DOI: 10.1021/acs.joc.7b02178 J. Org. Chem. 2017, 82, 12840−12848
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The Journal of Organic Chemistry Scheme 3. Expanded Application of the Reaction Sequence
Scheme 4. Proposed Reaction Mechanism
General Procedure for the Synthesis of Products 4 and 5. To a solution of catalyst I (19.5 mg, 0.06 mmol, 0.2 equiv) and acetic acid (3.6 mg, 0.06 mmol, 0.2 equiv) in H2O (0.5 mL) was added (E)-2-(2nitrovinyl)phenol (1a, 50 mg, 0.30 mmol, 1.0 equiv) and 5-oxohexanal (205.5 mg, 1.8 mmol, 6.0 equiv). The resulting solution was stirred at room temperature (∼25 °C) for 28 h until the completion of the reaction, monitored by TLC. The resulting mixture was extracted with EtOAc (15 mL × 3), washed with brine (10 mL), dried over MgSO4, and concentrated in vacuo to give the crude product. A solution of the crude product in CH2Cl2 (15 mL) and PCC (194.0 mg, 0.9 mmol, 3.0 equiv) and Celite 545 (400 mg) was stirred at ambient temperature for 12 h until the completion of the reaction, monitored by TLC. The reaction mixture was diluted with EtOAc (50 mL) and filtered through Celite 545. The filtrate was concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography with 15% EtOAc−hexane (Rf = 0.46 for 4a and Rf = 0.41 for 5a in 30% EtOAc−hexane) to give 4a (43.9 mg, 47% yield) and 5a (11.7 mg, 12% yield) as white solids. (6aR,9R,10S,10aS)-9-Hydroxy-9-methyl-10-nitro-6a,7,8,9,10,10ahexahydro-6H-benzo[c]chromen-6-one (4a). Mp 198−200 °C; [α]26 D −56.9 (c 1, CHCl3); IR (neat): 3540, 1767, 1545, 1362 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.31 (dd, J = 8.0, 7.5 Hz, 1 H), 7.10−7.00 (m, 3 H), 4.39 (d, J = 12.0 Hz, 1 H), 3.96 (dd, J = 12.0, 6.0 Hz, 1 H), 3.12 (s, 1 H), 2.92 (s, 1 H), 2.32 (dd, J = 14.0, 2.0 Hz, 1 H), 2.20−2.11 (m, 1 H), 1.89 (d, J = 14.0 Hz, 1 H), 1.70−1.60 (m, 1 H), 1.27 (s, 3
Figure 3. Alcohol 9 analogs.
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EXPERIMENTAL SECTION
General Information. All solvents were reagent grade. Reactions were normally carried out under nitrogen atmosphere in glassware. Merck silica gel 60 (particle size 0.04−0.063 mm) was employed for flash chromatography. Melting points are uncorrected. 1H NMR spectra were obtained in CDCl3 unless otherwise noted at 400 MHz (Bruker DPX-400) or 500 MHz (Varian-Unity INOVA-500). 13C NMR spectra were obtained at 100 or 125 MHz. The ee values were measured by HPLC on a chiral column (chiralpak IC, IA, or IB, 0.46 cm ID × 25 cm, particle size 5 μ) by elution with IPA−hexane or EtOAc−hexane. The flow rate of the indicated elution solvent is maintained at 1 mL/min, and the retention time of a compound is recorded accordingly. HPLC was equipped with the ultraviolet and refractive index detectors. The melting point was recorded on a melting point apparatus (MPA100 − automated melting point system, Stanford Research Systems, Inc.) and is uncorrected. The optical rotation values were recorded with a Jasco-P-2000 digital polarimeter. 12843
DOI: 10.1021/acs.joc.7b02178 J. Org. Chem. 2017, 82, 12840−12848
Note
The Journal of Organic Chemistry H); 13C NMR (125 MHz, CDCl3): δ 168.4 (C), 151.1 (C), 130.2 (CH), 128.3 (CH), 125.2 (CH), 121.1 (C), 117.3 (CH), 94.2 (CH), 70.1 (C), 38.8 (CH), 37.2 (CH), 33.8 (CH2), 27.1 (CH3), 19.5 (CH2); MS (m/z, relative intensity): 277 (M+, 14), 230 (21), 215 (100); exact mass calculated for C14H15NO5 (M+): 277.0950; found: 277.0951. HPLC (Chiralcel IA, 8% i-PrOH/hexane, 1.0 mL/min, UV λ = 254 nm) tR(major) = 8.51 min, tR(minor) = 11.84 min. (6aS,9R,10S,10aS)-9-Hydroxy-9-methyl-10-nitro-6a,7,8,9,10,10ahexahydro-6H-benzo[c]chromen-6-one (5a). Mp: 139−140 °C; 1 [α]26 D −31.4 (c 1, CHCl3); H NMR (500 MHz, CDCl3): δ 7.32− 7.28 (m, 1 H), 7.11−7.07 (m, 2 H), 7.00 (dd, J = 7.0, 1.0 Hz, 1 H), 4.76 (d, J = 11.0 Hz, 1 H), 3.95 (dd, J = 13.5, 11.5 Hz, 1 H), 2.41−2.34 (m, 1 H), 2.21−2.09 (m, 4 H), 1.60−1.48 (m, 1 H), 1.41 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 169.0 (C), 150.9 (C), 129.2 (CH), 125.1 (CH), 124.8 (C), 122.9 (CH), 117.6 (CH), 93.8 (CH), 70.0 (C), 40.7 (CH), 36.4 (CH2), 34.9 (CH), 27.5 (CH3), 20.1 (CH2). (6aS,9R,10S,10aS)-2-Bromo-9-hydroxy-9-methyl-10-nitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (4b). White solid. Yield: 57.9 mg (54%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.35 developed twice in 20% EtOAc− hexane). Mp 213-214 °C; [α]26 D +18.8 (c 1.0, CHCl3); IR (neat): 3552, 1760, 1548, 1362 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.43 (dd, J = 9.0, 2.5 Hz, 1 H), 7.17 (d, J = 2.5 Hz, 1 H), 6.95 (d, J = 8.5 Hz, 1 H), 4.36 (d, J = 12 Hz, 1 H), 3.94 (dd, J = 12, 6 Hz, 1 H), 3.09−3.07 (m, 1 H), 2.81(d, J = 2.5 Hz, 1 H), 2.34−2.29 (m, 1 H), 2.19−2.11 (m, 1 H), 1.92−1.89 (m, 1 H), 1.69−1.62 (m, 1 H), 1.28 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 167.7 (C), 150.2 (C), 133.3 (CH), 131.1(CH), 123.1 (C), 119.0 (CH), 117.7 (C), 93.8 (CH), 70.2 (C), 38.5 (CH), 36.9 (CH), 33.8 (CH2), 27.1 (CH3), 19.4 (CH2); MS (m/z, relative intensity): 357 (M+ + 2, 38), 355 (M+, 39), 310 (24), 308 (24), 295 (95), 293 (100); exact mass calculated for C14H14BrNO5 (M+): 355.0055; found: 355.0058. HPLC (Chiralcel IA, 16% i-PrOH/hexane, 1.0 mL/min, UV λ = 254 nm) tR(major) = 10.67 min, tR(minor) = 30.83 min. (6aS,9R,10S,10aS)-2-Bromo-9-hydroxy-9-methyl-10-nitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (5b). White solid. Yield: 7.9 mg, (7%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.32 developed twice in 20% EtOAc− 1 hexane). Mp 149−150 °C; [α]24 D −36.2 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3): δ 7.42 (dd, J = 8.5, 2.0 Hz, 1 H), 7.11 (d, J = 1.0 Hz, 1 H), 6.98 (d, J = 8.5 Hz, 1 H), 4.74 (d, J = 11.0 Hz, 1 H), 3.95 (dd, J = 14.0., 110 Hz, 1 H), 2.37−2.31 (m, 1 H), 2.19−2.05 (m, 4 H), 1.42 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 168.4 (C), 149.9 (C), 132.3 (CH), 127.0 (C), 126.1 (CH), 119.3 (CH), 117.9 (C), 93.4 (CH), 70.0 (C), 40.3 (CH), 36.3 (CH2), 34.8 (CH), 27.5 (CH3), 20.0 (CH2). (6aS,9R,10S,10aS)-2-Chloro-9-hydroxy-9-methyl-10-nitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (4c). White solids. Yield: 40.6 mg (43%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.50 developed twice in 20% EtOAc− hexane). Mp 206−207 °C; [α]27 D −6.1 (c 1, CHCl3); IR (neat): 3550, 1762, 1542, 1362 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.28 (dd, J = 9.0, 2.5 Hz, 1 H), 7.02 (d, J = 2.5 Hz, 1 H), 7.00 (d, J = 9.0 Hz, 1 H), 4.38 (d, J = 12.5 Hz, 1 H), 3.94 (dd, J = 11.8, 6.0 Hz, 1 H), 3.09−3.07 (m, 1 H), 2.82 (d, J = 2.0 Hz, 1 H), 2.33−2.29 (m, 1 H), 2.19−2.10 (m, 1 H), 1.91−1.88 (m, 1 H), 1.69−1.63 (m, 1 H), 1.28 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 167.8 (C), 149.7 (C), 130.30 (CH), 130.28 (C), 128.2 (CH), 122.7 (C), 118.7 (CH), 93.8 (CH), 70.2 (C), 38.5 (CH), 37.0 (CH), 33.7 (CH2), 27.1 (CH3), 19.4 (CH2); MS (m/z, relative intensity): 313 (M+ + 2, 1.1), 311 (M+, 3.2), 264 (2), 251 (3), 58 (100); Exact mass calculated for C14H14ClNO5 (M+): 311.0561; found: 311.0559. HPLC (Chiralcel IA, 16% i-PrOH/hexane, 1.0 mL/min, UV λ = 254 nm) tR(major) = 10.92 min, tR(minor) = 37.79 min. (6aS,9R,10S,10aS)-2-Chloro-9-hydroxy-9-methyl-10-nitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (5c). White solid. Yield: 15.0 mg (16%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.45 developed twice in 20% EtOAc− hexane). Mp 120−121 °C; [α]D27 −49.7 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.27 (dd, J = 9.0, 2.0 Hz, 1 H), 7.04 (d, J = 9.0
Hz, 1 H), 6.98 (s, 1 H), 4.74 (d, J = 11.0 Hz, 1H), 3.94 (dd, J = 14.0, 11.5 Hz, 1H), 2.39−2.31 (m, 1 H), 2.20−2.05 (m, 5 H), 1.42 (s, 3 H); 13 C NMR (125 MHz, CDCl3): δ 168.4 (C), 149.4 (C), 130.5 (C), 129.2 (CH), 126.6 (C), 123.3 (CH), 118.9 (CH), 93.4 (CH), 70.0 (C), 40.3 (CH), 36.3 (CH2), 34.9 (CH), 27.5 (CH3), 20.0 (CH2). HPLC (Chiralcel IC, 14% EtOAc/hexane, 1.0 mL/min, UV λ = 280 nm) tR(major) = 11.26 min, tR(minor) = 14.37 min. (6aS,9R,10S,10aS)-9-Hydroxy-2-methoxy-9-methyl-10-nitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (4d). White solids. Yield: 55.9 mg (61%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.34 developed in 30% EtOAc−hexane). Mp 178−179 °C; [α]D27 −14.4 (c 1, CHCl3); IR (neat): 3552, 1760, 1542, 1369 cm−1; 1H NMR (500 MHz, CDCl3): δ 6.98 (d, J = 9.0 Hz, 1 H), 6.82 (dd, J = 9.0, 3.0 Hz, 1 H), 6.53 (d, J = 3.0 Hz, 1 H), 4.38 (d, J = 12.0 Hz, 1 H), 3.90 (dd, J = 12.0, 6.0 Hz, 1 H), 3.73 (s, 3 H), 3.09−3.07 (m, 1 H), 2.87 (d, J = 3.0 Hz, 1 H), 2.34−2.29 (m, 1 H), 2.17−2.10 (m, 1 H), 1.91−1.87 (m, 1 H), 1.70−1.62 (m, 1 H), 1.27 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 168.5 (C), 156.5 (C), 144.9 (C), 121.9 (C), 118.1 (CH), 115.4 (CH), 113.1 (CH), 94.1 (CH), 70.1 (C), 55.7 (CH3), 38.7 (CH), 37.5 (CH), 33.8 (CH2), 27.1 (CH3), 19.5 (CH2); MS (m/z, relative intensity): 308 (M+ + 1, 18), 307 (M+, 100), 260 (17); Exact mass calculated for C15H17NO6 (M+): 307.1056; found: 307.1055. HPLC (Chiralcel IA, 16% i-PrOH/hexane, 1.0 mL/min, UV λ = 254 nm) tR(major) = 11.08 min, tR(minor) = 28.97 min. (6aS,9R,10S,10aS)-9-Hydroxy-9-methyl-2,10-dinitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (4e). White solids. Yield: 50 mg (52%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.50 developed three times in 20% EtOAc−hexane). Mp 207−208 °C; [α]26 D +68.2 (c 1, CHCl3); IR (neat): 3552, 1760, 1542, 1369 cm−1; 1H NMR (500 MHz, CDCl3): δ 8.23 (d, J = 9.0, 2.5 Hz, 1 H), 7.97 (d, J = 2.5 Hz, 1 H), 7.22 (d, J = 9.0 Hz, 1 H), 4.38 (d, J = 12.0 Hz, 1 H), 4.12 (dd, J = 12.0, 6.0 Hz, 1 H), 3.17−3.14 (m, 1 H), 2.79 (d, J = 3.0 Hz, 1 H), 2.36−2.31 (m, 1 H), 2.25−2.16 (m, 1 H), 1.96−1.92 (m, 1 H), 1.71−1.64 (m, 1 H), 1.31 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 166.7 (C), 155.5 (C), 144.5 (C), 126.1 (CH), 124.3 (CH), 122.3 (C), 118.3 (CH), 93.6 (CH), 70.2 (C), 38.3 (CH), 37.0 (CH), 33.8 (CH2), 27.0 (CH3), 19.3 (CH2); MS (m/z, relative intensity): 322 (M+, 3), 307 (11), 59 (100); exact mass calculated for C14H14N2O7 (M+): 322.0801; found: 322.0800. HPLC (Chiralcel IA, 25% i-PrOH/hexane, 1.0 mL/min, UV λ = 280 nm) tR(major) = 9.03 min, tR(minor) = 63.01 min. (6aS,9R,10S,10aS)-9-Hydroxy-2,9-dimethyl-10-nitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (4f). White solids. Yield: 51.2 mg (59%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.45 developed three times in 20% EtOAc−hexane). Mp 218−219; [α]26 D −23.8 (c 1, CHCl3); IR (neat): 3543, 1757, 1548, 1367 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.10 (dd, J = 8.5, 2.0 Hz, 1 H), 6.94 (d, J = 8.5 Hz, 1 H), 6.80 (d, J = 2.0 Hz, 1 H), 4.37 (d, J = 12.5 Hz, 1 H), 3.89 (dd, J = 12.0, 5.5 Hz, 1 H), 3.09−3.06 (m, 1 H), 2.92 (d, J = 3.0 Hz, 1 H), 2.33−2.28 (m, 1 H), 2.26 (s, 3 H), 2.17−2.09 (m, 1 H), 1.91−1.86 (m, 1 H), 1.70−1.62 (m, 1 H), 1.27 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 168.6 (C), 149.0 (C), 134.9 (C), 130.7 (CH), 128.5 (CH), 120.7 (C), 117.0 (CH), 94.2 (CH), 70.1 (C), 38.8 (CH), 37.2 (CH), 33.8 (CH2), 27.1 (CH3), 20.7 (CH3), 19.5 (CH2); MS (m/z, relative intensity): 291 (M+, 35), 244 (15), 229 (100); exact mass calculated for C15H17NO5 (M+): 291.1107; found: 291.1110. HPLC (Chiralcel IA, 16% i-PrOH/ hexane, 1.0 mL/min, UV λ = 254 nm) tR(major) = 9.55 min, tR(minor) = 23.04 min. (6aS,9R,10S,10aS)-9-Hydroxy-2,9-dimethyl-10-nitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (5f). White solids. Yield: 4.5 mg (5%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.38 developed three times in 20% 1 EtOAc−hexane). Mp 144−145 °C; [α]26 D −59.5 (c 0.5, CHCl3); H NMR (500 MHz, CDCl3): δ 7.08 (d, J = 8.5 Hz, 1 H), 6.98 (d, J = 8.5 Hz, 1 H), 6.79 (s, 1 H), 4.75 (d, J = 11.5 Hz, 1 H), 3.92 (dd, J = 13.5, 11.5 Hz, 1H), 2.37−2.31 (m, 1 H), 2.27 (s, 3 H), 2.20−2.07 (m, 4 H), 1.41 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 169.3 (C), 148.7 (C), 134.8 (C), 129.6 (CH), 124.5 (C), 123.2 (CH), 117.4 (CH), 93.8 12844
DOI: 10.1021/acs.joc.7b02178 J. Org. Chem. 2017, 82, 12840−12848
Note
The Journal of Organic Chemistry
1.0 mL/min, UV λ = 238 nm) tR(major) = 9.21 min, tR(minor) = 30.59 min. (6aS,9R,10S,10aS)-4-Bromo-9-hydroxy-9-methyl-10-nitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (5i). White solids. Yield: 12.1 mg (11%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.46 developed three times in 20% 1 EtOAc−hexane). Mp 166−167 °C; [α]26 D −56.5 (c 0.4, CHCl3); H NMR (500 MHz, CDCl3): δ 7.53 (dd, J = 7.5, 2.0 Hz, 1 H), 6.99−6.94 (m, 2 H), 4.75 (d, J = 11.0 Hz, 1 H), 3.98 (dd, J = 13.5, 11.0 Hz, 1 H), 2.41−2.35 (m, 1 H), 2.24−2.09 (m, 4 H), 1.42 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 167.8 (C), 147.9 (C), 133.1 (CH), 126.8 (C), 125.7 (CH), 121.9 (CH), 111.8 (C), 93.6 (CH), 70.0 (C), 40.4 (CH), 36.3 (CH2), 35.3 (CH), 27.5 (CH3), 20.0 (CH2). HPLC (Chiralcel IC, 15% EtOAc/hexane, 1.0 mL/min, UV λ = 254 nm) tR(major) = 11.43 min, tR(minor) = 14.46 min. (6aS,9R,10S,10aS)-4-Chloro-9-hydroxy-9-methyl-10-nitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (4j). White solids. Yield: 37.9 mg (41%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.48 developed three times in 20% EtOAc−hexane). Mp 205−206 °C; [α]26 D −86.4 (c 1, CHCl3); IR (neat): 3742, 1757, 1548, 1368 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.39 (dd, J = 8.0, 1.5 Hz, 1 H), 7.02 (dd, J = 8.0, 7.5 Hz, 1 H), 6.93 (dd, J = 8.0, 1.5 Hz, 1 H), 4.38 (d, J = 12.0 Hz, 1 H), 3.99 (dd, J = 12.5, 6.0 Hz, 1 H), 3.13 (dd, J = 4.5, 4.0 Hz, 1 H), 2.86 (d, J = 2.5 Hz, 1 H), 2.36−2.31 (m, 1 H), 2.21−2.13 (m, 1 H), 1.93−1.89 (m, 1 H), 1.71−1.63 (m, 1 H), 1.28 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 167.1 (C), 147.1(C), 131.0 (CH), 126.6 (CH), 125.4 (CH), 122.8 (C), 122.4 (C), 93.9 (CH), 70.1 (C), 38.6 (CH), 37.5 (CH), 33.7 (CH2), 27.1 (CH3), 19.4 (CH2); MS (m/z, relative intensity): MS (m/z, relative intensity): 313 (M+ + 2, 6), 311 (M+, 20), 264 (11), 251 (28), 249 (100); exact mass calculated for C14H14ClNO5 (M+): 311.0561; found: 311.0563. HPLC (Chiralcel IA, 16% i-PrOH/hexane, 1.0 mL/min, UV λ = 238 nm) tR(major) = 9.00 min, tR(minor) = 34.26 min. (6aS,9R,10S,10aS)-4-Chloro-9-hydroxy-9-methyl-10-nitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (5j). White solids. Yield: 9.5 mg (10%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.40 developed three times in 20% 1 EtOAc−hexane). Mp 173−174 °C; [α]26 D −74.3 (c 0.3, CHCl3); H NMR (500 MHz, CDCl3): δ 7.37 (d, J = 8.0 Hz, 1 H), 7.04 (dd, J = 8.0, 8.0 Hz, 1 H), 6.91 (d, J = 7.5 Hz, 1 H), 4.75 (d, J = 11.5 Hz, 1 H), 3.97 (dd, J = 13.0, 12.5 Hz, 1 H), 2.42−2.35 (m, 1 H), 2.21−2.11 (m, 4 H), 1.42 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 167.7 (C), 146.9 (C), 130.1 (CH), 126.8 (C), 125.3 (CH), 123.0 (C), 121.1 (CH), 93.6 (CH), 70.0 (C), 40.3 (CH), 36.3 (CH2), 35.3 (CH), 27.5 (CH3), 20.0 (CH2). HPLC (Chiralcel IC, 15% EtOAc/hexane, 1.0 mL/min, UV λ = 254 nm) tR(major) = 10.65 min, tR(minor) = 10.34 min. (6aS,9R,10S,10aS)-9-Hydroxy-4-methoxy-9-methyl-10-nitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (4k). White solids. Yield: 50.3 mg (55%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.32 developed in 30% EtOAc−hexane). Mp 183−184 °C; [α]26 D −63.6 (c 1, CHCl3); IR (neat): 3528, 1759, 1549, 1368 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.03 (dd, J = 8.0, 8.0 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 1 H), 6.59 (d, J = 7.5 Hz, 1 H), 4.38 (d, J = 12.0 Hz, 1 H), 3.94 (dd, J = 12.0, 6.0 Hz, 1 H), 3.87 (s, 3 H), 3.12 (s, 1 H), 2.93 (d, J = 2.0 Hz, 1 H), 2.32 (d, J = 14.5 Hz, 1 H), 2.19−2.11 (m, 1 H), 1.89 (d, J = 14.5 Hz, 1 H), 1.69−1.63 (m, 1 H), 1.27 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 167.8 (C), 147.7(C), 140.3(C), 125.2 (CH), 122.0 (C), 119.5 (CH), 112.7 (CH), 94.1 (CH), 70.1 (C), 56.1 (CH3), 38.6 (CH), 37.4 (CH), 33.8 (CH2), 27.1 (CH3), 19.5 (CH2); MS (m/z, relative intensity): 308 (M+ + 1, 17), 307 (M+, 100); exact mass calculated for C15H17NO6 (M+): 307.1056; found: 307.1057. HPLC (Chiralcel IA, 32% i-PrOH/hexane, 1.0 mL/ min, UV λ = 238 nm) tR(major) = 7.53 min, tR(minor) = 29.33 min. (R)-2-((S)-1-(2-Hydroxy-4,6-bis(methoxymethoxy)phenyl)-2nitroethyl)hexane-1,5-diol (9). Colorless oil. Yield: 66.6 mg (55%). Column chromatography eluents: 70% EtOAc−hexane (TLC: Rf = 0.21 developed in 70% EtOAc−hexane). IR (neat): 3332, 1549, 1378 cm−1; 1H NMR (500 MHz, CDCl3, * denotes the isomeric peak): δ 6.34 (s, 1 H), 6.19 (s, 1 H), 5.11 (s, 2 H), 5.06 (s, 2 H), 4.91−4.85 (m,
(CH), 70.0 (C), 40.7 (CH), 36.4 (CH2), 34.8 (CH), 27.6 (CH3), 21.1 (CH3), 20.0 (CH2). HPLC (Chiralcel IA, 16% i-PrOH/hexane, 1.0 mL/min, UV λ = 238 nm) tR(major) = 11.17 min, tR(minor) = 21.21 min. (6aS,9R,10S,10aS)-9-Hydroxy-3-methoxy-9-methyl-10-nitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (4g). White solids. Yield: 50.7 mg (55%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.42 developed three times in 20% EtOAc−hexane). Mp 224−225 °C; [α]26 D −54.7 (c 0.5, CHCl3); IR (neat): 3567, 1766, 1546, 1361 cm−1; 1H NMR (500 MHz, CDCl3): δ 6.91 (d, J = 8.5 Hz, 1 H), 6.62 (d, J = 2.5 Hz, 1 H), 6.60 (s, 1 H), 4.34 (d, J = 12.0 Hz, 1 H), 3.90 (dd, J = 12.0, 6.0 Hz, 1 H), 3.76 (s, 3 H), 3.10−3.09 (m, 1 H), 2.89 (s, 1 H), 2.33−2.28 (m, 1 H), 2.20−2.10 (m, 1 H), 1.88 (d, J = 14.5 Hz, 1 H), 1.68−1.60 (m, 1 H), 1.26 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 168.4 (C), 161.0 (C), 152.0 (C), 128.8 (CH), 112.8 (C), 111.0 (CH), 102.9 (CH), 94.6 (CH), 70.1 (C), 55.5 (CH3), 39.0 (CH), 36.7 (CH), 33.8 (CH2), 27.1 (CH3), 19.5 (CH2); MS (m/z, relative intensity): 307 (M+, 16), 260 (18), 245 (100); exact mass calculated for C15H17NO6 (M+): 307.1056; found: 307.1056. HPLC (Chiralcel IA, 16% i-PrOH/hexane, 1.0 mL/min, UV λ = 280 nm) tR(major) = 8.66 min, tR(minor) = 20.34 min. (6aS,9R,10S,10aS)-9-Hydroxy-3-methoxy-9-methyl-10-nitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (5g). White solids. Yield: 7.6 mg (8%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.35 developed three times in 20% 1 EtOAc−hexane). Mp 117−118 °C; [α]27 D −90.5 (c 1, CHCl3); H NMR (500 MHz, CDCl3): δ 6.89 (d, J = 8.5 Hz, 1 H), 6.65 (d, J = 2.5 Hz, 1 H), 6.62 (dd, J = 8.5, 2.5 Hz, 1 H), 4.71 (d, J = 11.0 Hz, 1 H), 3.88 (dd, J = 13.5, 11.5 Hz, 1 H), 3.76 (s, 3 H), 2.37−2.31 (m, 1 H), 2.22−2.08 (m, 4 H), 1.39 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 169.0 (C), 160.1 (C), 151.7 (C), 123.5 (CH), 116.5 (C), 110.5 (CH), 103.5 (CH), 94.2 (CH), 70.0 (C), 55.6 (CH3), 41.1 (CH), 36.4 (CH2), 34.5 (CH), 27.5 (CH3), 20.0 (CH2). HPLC (Chiralcel IC, 20% EtOAc/hexane, 1.0 mL/min, UV λ = 280 nm) tR(major) = 9.41 min, tR(minor) = 13.55 min. (6aS,9R,10S,10aS)-2-(Benzyloxy)-9-hydroxy-9-methyl-10-nitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (4h). White solids. Yield: 62.7 mg (54%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.55 developed three times in 20% EtOAc−hexane). Mp 163−164 °C; [α]25 D +8.6 (c 1, CHCl3); IR (neat): 3540, 1759, 1549, 1375 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.38−7.31 (m, 5 H), 6.98 (d, J = 9.0 Hz, 1 H), 6.89 (dd, J = 8.5, 2.5 Hz, 1 H), 6.61 (d, J = 2.5 Hz, 1 H), 4.97 (s, 2 H), 4.38 (d, J = 11.5 Hz, 1 H), 3.89 (dd, J = 12.0, 6.0 Hz, 1 H), 3.07 (s, 1 H), 2.86 (d, J = 2.5 Hz, 1 H), 2.35−2.28 (m, 1 H), 2.18−2.10 (m, 1 H), 1.90−1.85 (m, 1 H), 1.70−1.60 (m, 1 H), 1.23 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 168.5 (C), 155.6 (C), 145.1 (C), 136.3 (C), 128.7 (2CH), 128.1 (CH), 127.5 (2CH), 121.9 (C), 118.2 (CH), 116.5 (CH), 114.1 (CH), 94.1 (CH), 70.6 (CH2), 70.2 (C), 38.7 (CH), 37.5 (CH), 33.8 (CH2), 27.1 (CH3), 19.5 (CH2); MS (m/z, relative intensity): 384 (M+ + 1, 3), 383 (M+, 11), 91 (100) exact mass calculated for C21H21NO6 (M+): 383.1369; found: 383.1367. HPLC (Chiralcel IA, 16% i-PrOH/hexane, 1.0 mL/min, UV λ = 254 nm) tR(major) = 17.33 min, tR(minor) = 38.37 min. (6aS,9R,10S,10aS)-4-Bromo-9-hydroxy-9-methyl-10-nitro6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-6-one (4i). White solids. Yield: 45.6 mg (43%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.50 developed three times in 20% EtOAc−hexane). Mp 206−207 °C; [α]26 D −97.5 (c 1, CHCl3); IR (neat): 3531, 1769, 1549, 1368 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.55 (dd, J = 7.5, 2.5 Hz, 1 H), 6.99−6.93 (m, 2 H), 4.38 (d, J = 12.0 Hz, 1 H), 3.98 (dd, J = 12.0, 6.0 Hz, 1 H), 3.13 (dd, J = 5.5, 4.0 Hz, 1 H), 2.87 (d, J = 3.0 Hz, 1 H), 2.36−2.30 (m, 1 H), 2.21−2.13 (m, 1 H), 1.93−1.88 (m, 1 H), 1.70−1.66 (m, 1 H), 1.28 (s, 3 H); 13C NMR (125 MHz, CDCl3): δ 167.2 (C), 148.2 (C), 134.1 (CH), 127.4 (CH), 125.9 (CH), 122.8 (C), 111.1 (C), 93.9 (CH), 70.1 (C), 38.6 (CH), 37.6 (CH), 33.7 (CH2), 27.1 (CH3), 19.3 (CH2); MS (m/z, relative intensity): 357 (M+ + 2, 32), 355 (M+, 32), 310 (16), 308 (17), 295 (91), 293 (100); exact mass calculated for C14H14O5NBr (M+): 355.0055; found: 355.0057. HPLC (Chiralcel IA, 16% i-PrOH/hexane, 12845
DOI: 10.1021/acs.joc.7b02178 J. Org. Chem. 2017, 82, 12840−12848
Note
The Journal of Organic Chemistry 1 H), 4.21−4.15 (m, 1 H), 3.73−3.64 (m, 2 H), 3.60−3.58 (m, 1 H), 3.47 (s, 3 H), 3.44 (s, 3 H), 2.18−2.02 (m, 1 H), 1.52−1.30 (m, 4 H), 1.09 (d, J = 6 Hz, 3 H)*, 1.06 (d, J = 6.5 Hz, 3 H)*; 13C NMR (125 MHz, CDCl3, * denotes the isomeric peak): δ 157.6 (C)*, 157.5 (C)*, 156.4 (C), 107.5 (C), 97.9 (CH)*, 97.8 (CH)*, 95.9 (CH)*, 95.8 (CH)*, 94.8 (CH2)*, 94.3 (CH2)*, 77.6 (CH2), 68.4 (CH)*, 68.3 (CH)*, 68.0 (CH), 63.3 (CH2)*, 62.7 (CH2)*, 56.4 (CH3)*, 56.1 (CH3)*, 41.9 (CH), 36.0 (CH2)*, 35.8 (CH)*, 24.5 (CH2), 23.4 (CH3)*, 23.1 (CH3)*; MS (m/z, relative intensity): 403 (M+, 3), 385 (7), 267 (9), 354 (100); exact mass calculated for C18H29NO9 (M+): 403.1842; found: 403.1849. 4-[(2S,3R,6R)-10,12-Bis(methoxymethoxy)-5,7-dioxatricyclo[6.4.0.02,6]dodeca-1(12),8,10-trien-3-yl]butan-2-ol (10). To a solution of alcohol 9 (15 mg, 0.037 mmol) in dry CH2Cl2 (4 mL) was added ZnBr2 (12.6 mg, 0.056 mmol, 1.5 equiv) at ambient temperature. The resulting solution was stirred at room temperature for 30 h until the completion of the reaction, monitored by TLC. The reaction was quenched by the addition of aqueous NaHCO3 solution (3 mL). The reaction mixture was extracted with EtOAc (20 mL × 2), washed with brine (10 mL), dried over MgSO4, and concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography with 30% EtOAc−hexane (Rf = 0.65 in 70% EtOAc−hexane), to give alcohol 10 (8 mg, 61%) as a white solid. Select data for 10: Mp 74−75 °C; [α]26 D −22.5 (c 1, CHCl3); IR (neat): 3421, 1609, 1143, 1049 cm−1; 1H NMR (500 MHz, CDCl3, * denotes the isomeric peak): δ 6.29−6.27 (m, 2 H), 6.22 (s, 1 H), 5.18−5.13 (m, 2 H), 5.08 (s, 2 H), 3.86−3.84 (m, 1 H), 3.78 (d, J = 3.0 Hz, 2 H), 3.63 (dd, J = 6.0, 3.0 Hz, 1 H), 3.47 (s, 3 H), 3.46 (s, 3 H), 3.44 (s, 6 H), 2.35−2.32 (m, 1 H), 1.63−1.49 (m, 4 H), 1.23 (d, J = 3.5 Hz, 3 H)*, 1.21 (d, J = 3.5 Hz, 3H)*; 13C NMR (125 MHz, CDCl3 * denotes the isomeric peak): δ 160.81 (C)*, 160.79 (C),* 159.2 (C), 153.92 (C)*, 153.88 (C),* 111.7 (CH),* 111.6 (CH),* 108.7 (C)*, 108.6 (C),* 95.69 (CH)*, 95.68 (CH),* 94.7 (CH2), 94.2 (CH2),* 94.1 (CH2)*, 91.95 (CH)*, 91.92 (CH),* 71.96 (CH2)*, 71.88 (CH2),* 67.96 (CH)*, 67.84 (CH), 56.3 (CH3),* 56.2 (CH3),* 56.1 (CH3), 50.43 (CH)*, 50.41 (CH),* 44.9 (CH)*, 44.8 (CH),* 37.0 (CH2), 30.1 (CH2)*, 30.0 (CH2),* 23.8 (CH3)*, 23.6 (CH3)*; MS (m/z, relative intensity): 355 (M+ + 1, 20), 354 (M+, 100), 322 (19), 292 (53); exact mass calculated for C18H26O7 (M+): 354.1679; found: 354.1672. 4-[(2S,3R,6R)-10,12-Bis(methoxymethoxy)-5,7-dioxatricyclo[6.4.0.02,6]dodeca-1(12),8,10-trien-3-yl]butan-2-one (11). To a solution of alcohol 10 (8.4 mg, 0.024 mmol) in CH2Cl2 (5 mL) was added pyridinium chlorochromate (15.5 mg, 0.072 mmol, 3 equiv) and Celite 545 (31 mg) at ambient temperature. The resulting solution was stirred at room temperature for 2 h until the completion of the reaction, monitored by TLC. The reaction mixture was diluted with EtOAc (25 mL) and filtered through Celite 545. The filtrate was concentrated in vacuo to give the crude product. The residue was purified by flash column chromatography with 15% EtOAc−hexane (Rf = 0.55 in 30% EtOAc−hexane), to give 11 (6.5 mg, 78%) as a colorless oil. Select data for 11: [α]26 D −26.6 (c 0.54, CHCl3); IR (neat): 1712, 1612, 1219, 1014 cm−1; 1H NMR (500 MHz, CDCl3): δ 6.29 (d, J = 2.0 Hz, 1 H), 6.28 (d, J = 6.0 Hz, 1 H), 6.22 (d, J = 2.0 Hz, 1 H), 5.14 (dd, J = 13.5, 6.5 Hz, 2 H), 5.07 (s, 2 H), 3.77 (d, J = 3.5 Hz, 2 H), 3.60 (d, J = 6.0 Hz, 1 H), 3.46 (s, 3 H), 3.44 (s, 3 H), 2.62− 2.53 (m, 2 H), 2.35−2.32 (m, 1 H), 2.17 (s, 3 H), 1.78−1.73 (m, 2 H); 13C NMR (125 MHz, CDCl3): δ 208.0 (C), 160.8 (C), 159.3 (C), 153.9 (C), 111.6 (CH), 108.3 (C), 95.7 (CH), 94.7 (CH2), 94.2 (CH2), 91.9 (CH), 71.7 (CH2), 56.3 (CH3), 56.1 (CH3), 50.2 (CH), 44.2 (CH), 41.3 (CH2), 30.0 (CH3), 27.5 (CH2); MS (m/z, relative intensity): 353 (M+ + 1, 20), 352 (M+, 100), 307 (12), 294 (44); exact mass calculated for C18H24O7 (M+): 352.1522; found: 352.1524. HPLC (Chiralcel IB, 10% i-PrOH/hexane, 1.0 mL/min, UV λ = 238 nm) tR(major) = 10.39 min, tR(minor) = 12.22 min. General Procedure for the Synthesis of Nitroalkene 1. A solution of 5-bromo-2-hydroxybenzaldehyde (201 mg, 1.0 mmol) and ammonium acetate (115.7 mg, 1.5 mmol, 1.5 equiv) in nitromethane (5 mL) was heated to reflux for 12 h until the completion of reaction, as monitored by TLC. Then the reaction mixture was directly
concentrated in vacuo to give the crude residue. The crude product was purified by flash column chromatography with 20% EtOAc-hexane (Rf = 0.5 for 1b in 30% EtOAc-hexane) to afford product 1b (214.5 mg, 88% yield) as a yellow solid. (E)-4-Bromo-2-(2-nitrovinyl)phenol (1b). Yellow solids. Yield: 214.5 mg (88%). Column chromatography eluents: 20% EtOAc− hexane (TLC: Rf = 0.5 in 30% EtOAc−hexane). Mp 117−118 °C; IR (neat): 3324, 1620, 1554, 1334 cm−1; 1H NMR (500 MHz, acetoned6): δ 10.02 (brs, 1 H), 8.14 (d, J = 14 Hz, 1 H), 8.09 (d, J = 14 Hz, 1 H), 7.84 (d, J = 2.5 Hz, 1 H), 7.48 (dd, J = 9.0, 2.5 Hz, 1 H), 7.01 (d, J = 9.0 Hz, 1 H);19 13C NMR (125 MHz, acetone-d6): δ 157.8 (C), 139.8 (CH), 136.5 (CH), 134.7 (CH), 134.5 (CH), 120.6 (C), 119.2 (CH), 112.5 (C); EI-MS (m/z, relative intensity): 245 (M++3, 21), 243 (M+ + 1, 22), 198 (100), 196 (100); exact mass calculated for C8H6O3NBr (M+): 242.9531; found: 242.9536. (E)-4-Chloro-2-(2-nitrovinyl)phenol (1c). Yellow-orange solid. Yield: 171.6 mg (86%). Column chromatography eluents: 20% EtOAc−hexane (TLC: Rf = 0.50 in 30% EtOAc−hexane). Mp 162− 163 °C; IR (neat): 3514, 1622, 1487, 1337 cm−1; 1H NMR (500 MHz, acetone-d6): δ 10.00 (brs, 1 H), 8.16 (d, J = 14 Hz, 1 H), 8.10 (d, J = 14 Hz, 1 H), 7.73 (d, J = 2.5 Hz, 1 H), 7.36 (dd, J = 8.5, 2.5 Hz, 1 H), 7.06 (d, J = 8.5 Hz, 1 H);19 13C NMR (125 MHz, acetone-d6): δ 157.4 (C), 139.9 (CH), 134.6 (CH), 133.6 (CH), 131.7 (CH), 125.5 (C), 120.0 (C), 118.8 (CH); EI-MS (m/z, relative intensity): 201 (M+ + 2, 4), 199 (M+, 13), 154 (26), 153 (6), 152 (100); exact mass calculated for C8H6O3NCl (M+): 199.0036; found: 199.0037. (E)-4-Methoxy-2-(2-nitrovinyl)phenol (1d). Yellow solids. Yield: 173.5 mg (89%). Column chromatography eluents: 20% EtOAc− hexane (TLC: Rf = 0.45 in 30% EtOAc−hexane). Mp 152−153 °C; IR (neat): 3148, 1612, 1495, 1347 cm−1; 1H NMR (500 MHz, acetoned6): δ 9.29 (brs, 1 H), 8.22 (d, J = 13.5 Hz, 1 H), 8.07 (d, J = 13.5 Hz, 1 H), 7.24 (s, 1 H), 7.00−6.96 (m, 2 H), 3.79 (s, 3 H);5 13C NMR (125 MHz, acetone-d6): δ 154.2 (C), 153.0 (C), 138.9 (CH), 136.0 (CH), 121.5 (CH), 118.4 (C), 118.2 (CH), 115.2 (CH), 56.1 (CH3); EI-MS (m/z, relative intensity): 196 (M+ + 1, 4), 195 (M+, 39), 149 (16), 148 (100); exact mass calculated for C9H9O4N (M+): 195.0532; found: 195.0533. (E)-4-Nitro-2-(2-nitrovinyl)phenol (1e). Yellow solids. Yield: 147.2 mg (70%). Column chromatography eluents: 30% EtOAc−hexane (TLC: Rf = 0.2 in 30% EtOAc−hexane). Mp 181−182 °C; IR (neat): 2900−3300, 1617, 1518, 1341 cm−1; 1H NMR (500 MHz, acetoned6): δ 8.54 (d, J = 3.0 Hz, 1H), 8.20−8.13 (m, 3 H), 7.18 (d, J = 9.0 Hz, 1 H);20 13C NMR (125 MHz, acetone-d6): δ 163.5 (C), 141.9 (C), 140.8 (CH), 133.9 (CH), 128.9 (CH), 128.7 (CH), 119.0 (C), 117.7 (CH); EI-MS (m/z, relative intensity): 211 (M+ + 1, 1), 210 (M+, 12), 182 (12), 165 (15), 163 (100); exact mass calculated for C8H6O5N2 (M+): 210.0277; found: 210.0279. (E)-4-Methyl-2-(2-nitrovinyl)phenol (1f). Yellow solids. Yield: 150.1 mg (84%). Column chromatography eluents: 20% EtOAc− hexane (TLC: Rf = 0.55 in 30% EtOAc−hexane). Mp 164−165 °C; IR (neat): 3407, 1627, 1586, 1330 cm−1; 1H NMR (500 MHz, acetoned6): δ 9.52 (brs, 1 H), 8.17 (d, J = 13.5 Hz, 1H), 8.04 (d, J = 13.5 Hz, 1 H), 7.46 (d, J = 1.0 Hz, 1 H), 7.19 (dd, J = 8.5, 1.5 Hz, 1 H), 6.94 (d, J = 8.5 Hz, 1 H), 2.26 (s, 3 H);21 13C NMR (125 MHz, acetone-d6): δ 156.8 (C), 138.6 (CH), 136.2 (CH), 135.1 (CH), 132.9 (CH), 130.4 (C), 118.1 (C), 117.2 (CH), 20.3 (CH3); EI-MS (m/z, relative intensity): 179 (M+, 31), 132 (100), 131 (42); exact mass calculated for C9H9O3N (M+): 179.0582; found: 179.0585. (E)-5-Methoxy-2-(2-nitrovinyl)phenol (1g). Yellow solids. Yield: 153.8 mg (79%). Column chromatography eluents: 30% EtOAc− hexane (TLC: Rf = 0.35 in 30% EtOAc−hexane). Mp 146−147 °C; IR (neat): 3334, 1609, 1338, 1099 cm−1; 1H NMR (500 MHz, acetoned6): δ 8.15 (d, J = 13.5 Hz, 1 H), 7.95 (d, J = 13.5 Hz, 1 H), 7.56 (dd, J = 7.5, 2.5 Hz, 1 H), 6.58−6.55 (m, 2 H), 3.82 (s, 3 H);22 13C NMR (125 MHz, acetone-d6): δ 165.3 (C), 160.6 (C), 136.43 (CH), 136.38 (CH), 134.7 (CH), 111.6 (C), 108.0 (CH), 102.4 (CH), 55.9 (CH3); EI-MS (m/z, relative intensity): 195 (M+, 24), 178 (8), 149 (15), 148 (100); exact mass calculated for C9H9O4N (M+): 195.0532; found: 195.0531. 12846
DOI: 10.1021/acs.joc.7b02178 J. Org. Chem. 2017, 82, 12840−12848
Note
The Journal of Organic Chemistry (E)-4-(Benzyloxy)-2-(2-nitrovinyl)phenol (1h). Yellow solids. Yield: 217.2 mg (80%). Column chromatography eluents: 20% EtOAc− hexane (TLC: Rf = 0.48 in 30% EtOAc−hexane). Mp 127−128 °C; IR (neat): 3375, 1589, 1498, 1347 cm−1; 1H NMR (500 MHz, acetoned6): δ 9.31 (brs, 1 H), 8.23 (d, J = 14.0 Hz, 1 H), 8.08 (d, J = 14.0 Hz, 1 H), 7.48 (dd, J = 7.5, 1.5 Hz, 2 H), 7.42−7.36 (m, 3 H), 7.35−7.30 (m, 1 H), 7.08 (dd, J = 8.5, 3.0 Hz, 1 H), 6.99 (d, J = 8.5 Hz, 1 H), 5.12 (s, 2 H); 13C NMR (125 MHz, acetone-d6): δ 153.4 (C), 153.2 (C), 138.9 (C), 138.4 (CH), 135.9 (CH), 129.4 (2CH), 128.8 (CH), 128.6 (2CH), 122.5 (CH), 118.6 (C), 118.3 (CH), 116.7 (CH), 71.3 (CH2); EI-MS (m/z, relative intensity): 271 (M+, 4), 92 (5), 91 (100); exact mass calculated for C15H13O4N (M+): 271.0845; found: 271.0844. (E)-2-Bromo-6-(2-nitrovinyl)phenol (1i). Yellow solids. Yield: 185.6 mg (76%). Column chromatography eluents: 20% EtOAc−hexane (TLC: Rf = 0.65 in 30% EtOAc−hexane). Mp 120−121 °C; IR (neat): 3420, 1626, 1510, 1333 cm−1; 1H NMR (500 MHz, acetone-d6): δ 8.23 (d, J = 13.5 Hz, 1 H), 8.03 (d, J = 13.5 Hz, 1 H), 7.73−7.67 (m, 2 H), 6.96 (dd, J = 8.0, 8.0 Hz, 1 H); 13C NMR (125 MHz, acetone-d6): δ 154.5 (C), 139.9 (CH), 137.0 (CH), 135.1 (CH), 131.8 (CH), 122.8 (CH), 120.7 (C), 112.4 (C); EI-MS (m/z, relative intensity): 245 (M++2, 27), 243 (M+, 29), 199 (16), 198 (100), 196 (100); exact mass calculated for C8H6BrNO3 (M+): 242.9531; found: 242.9532. (E)-2-Chloro-6-(2-nitrovinyl)phenol (1j). Yellow solids. Yield: 188.6 mg (74%). Column chromatography eluents: 15% EtOAc−hexane (TLC: Rf = 0.62 in 30% EtOAc−hexane). Mp 126−127 °C; IR (neat): 3460, 1627, 1515, 1335 cm−1; 1H NMR (500 MHz, acetone-d6): δ 8.24 (d, J = 13.5 Hz, 1 H), 8.08 (d, J = 13.5 Hz, 1 H), 7.70 (dd, J = 7.5, 1.5 Hz, 1 H), 7.56 (dd, J = 8.0, 1.5 Hz, 1 H), 7.02 (dd, J = 8.0, 7.5 Hz, 1 H); 13C NMR (125 MHz, acetone-d6): δ 153.9 (C), 139.9 (CH), 135.1 (CH), 133.8 (CH), 131.3 (CH), 122.6 (C), 122.1 (CH), 120.7 (C); EI-MS (m/z, relative intensity): 201 (M+ + 2, 9), 199 (M+, 32), 154 (40), 152 (100); exact mass calculated for C8H6O3NCl (M+): 199.0036; found: 199.0037. (E)-2-Methoxy-6-(2-nitrovinyl)phenol (1k). Yellow solids. Yield: 315.7 mg (82%). Column chromatography eluents: 25% EtOAc− hexane (TLC: Rf = 0.45 in 30% EtOAc−hexane). Mp 129−130 °C; IR (neat): 3409, 1622, 1473, 1335 cm−1; 1H NMR (500 MHz, acetoned6): δ 8.22 (d, J = 13.5 Hz, 1 H), 8.06 (d, J = 13.5 Hz, 1 H), 7.25 (dd, J = 8.0, 1.0 Hz, 1 H), 7.13 (dd, J = 8.0, 1.0 Hz, 1 H), 6.91 (dd, J = 8.0, 8.0 Hz, 1 H), 3.90 (s, 3 H);23 13C NMR (125 MHz, acetone-d6): δ 148.8 (C), 148.5 (C), 139.0 (CH), 135.8 (CH), 123.9 (CH), 120.8 (CH), 117.9 (C), 115.4 (CH), 56.7 (CH3); EI-MS (m/z, relative intensity): 196 (M++1, 5), 195 (M+, 60), 149 (11), 148 (100); exact mass calculated for C9H9O4N (M+): 195.0532; found: 195.0531. Procedure for the Synthesis of Nitroalkene 1l. To a solution of 2,4,6-trihydroxybenzaldehyde (929.6 mg, 6.03 mmol) and N,Ndiiospropylethylamine (DIPEA, 5.3 mL, 30.4 mmol, 5.0 equiv) in CH2Cl2 (20 mL) was added bromoethyl methyl ether (1.46 mL, 17.9 mmol, 3.0 equiv) at 0 °C. The resulting solution was stirred at 0 °C for 3.5 h until the completion of the reaction, as monitored by TLC. The solution was extracted with EtOAc (40 mL × 3), and the combined organic solution was washed with brine, dried over MgSO4, and concentrated in vacuo to give a residue. The crude product was purified by flash column chromatography with 15% EtOAc−hexane (Rf = 0.14 in 10% EtOAc−hexane) to afford 2-hydroxy-4,6bis(methoxymethoxy)benzaldehyde (1110 mg, 76%) as a white solid. Selected data: Mp 68−69 °C; 1H NMR (500 MHz, CDCl3): δ 12.26 (s, 1 H), 10.14 (s, 1 H), 6.23 (d, J = 2.0 Hz, 1 H), 6.20 (d, J = 2.0 Hz, 1 H), 5.21 (s, 2 H), 5.15 (s, 2 H), 3.48 (s, 3 H), 3.45 (s, 3 H); 13 C NMR (125 MHz, CDCl3): δ 192.1 (CH), 165.6 (C), 165.5 (C), 161.2 (C), 106.9 (C), 96.6 (CH), 94.6 (CH2), 94.10 (CH), 94.05 (CH2), 56.6 (CH3), 56.5 (CH3);24 EI-MS (m/z, relative intensity): 243 (M+ + 1, 13), 242 (M+, 100), 229 (9), 214 (16), 197 (55); exact mass calculated for C11H14O6 (M+): 242.0790; found: 242.0796. A solution of ammonium acetate (537 mg, 7.0 mmol, 1.6 equiv) and 2-hydroxy-4,6-bis(methoxymethoxy)benzaldehyde (1026 mg, 4.2 mmol) in MeNO2 (30 mL) was heated to reflux for 24 h. The resulting solution was concentrated in vacuo to give a residue. The crude product was purified by flash column chromatography with 15%
EtOAc−hexane (Rf = 0.41 in 50% EtOAc−hexane) to afford (E)-3,5bis(methoxymethoxy)-2-(2-nitrovinyl)phenol (1l, 723 mg, 60%) as a bright yellow solid.12 Selected data: Mp 109−110 °C; IR (neat): 3329, 1612, 1151 cm−1; 1H NMR (500 MHz, acetone-d6): δ 9.88 (brs, OH), 8.51 (d, J = 13.5 Hz, 1 H), 8.07 (d, J = 13.5 Hz, 1 H), 6.46 (d, J = 2.0 Hz, 1 H), 6.42 (d, J = 2.0 Hz, 1 H), 5.38 (s, 2 H), 5.21 (s, 2 H), 3.51 (s, 3 H), 3.44 (s, 3 H); 13C NMR (125 MHz, acetone-d6): δ 163.3 (C), 161.3 (C), 160.5 (C), 137.3 (CH), 130.9 (CH), 103.2 (C), 97.6 (CH), 96.1 (CH), 95.7 (CH2), 95.1 (CH2), 56.8 (CH3), 56.5 (CH3); MS (m/z, relative intensity): 286 (M+ + 1, 4), 285 (M+, 27), 208 (4), 195 (10), 194 (100); exact mass calculated for C12H15NO7 (M+): 285.0849; found: 285.0843.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02178. 1 H and 13C NMR spectra, HPLC analysis data (PDF) X-ray crystallographic data (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Bor-Cherng Hong: 0000-0002-4623-3366 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge the financial support for this study from the Ministry of Science and Technology (MOST, Taiwan) and thank the instrument center of MOST for analyses of compounds. Thanks to Mr. Wei-Lun Huang (NCCU) for his help in the related work.
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DEDICATION This paper is dedicated to Professor Elias J. Corey on the occasion of his 90th birthday. REFERENCES
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DOI: 10.1021/acs.joc.7b02178 J. Org. Chem. 2017, 82, 12840−12848
Note
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DOI: 10.1021/acs.joc.7b02178 J. Org. Chem. 2017, 82, 12840−12848
