octanes from Ketones and Acetylene - ACS Publications - American

Jul 20, 2018 - Dienyl 6,8-Dioxabicyclo[3.2.1]octanes from Ketones and Acetylenes. Elena Y. Schmidt, Inna V. Tatarinova, Nadezhda V. Semenova, Nadezhda...
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Article Cite This: J. Org. Chem. 2018, 83, 10272−10280

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Exploring Acetylene Chemistry: A Transition Metal-Free Route to Dienyl 6,8-Dioxabicyclo[3.2.1]octanes from Ketones and Acetylenes Elena Y. Schmidt, Inna V. Tatarinova, Nadezhda V. Semenova, Nadezhda I. Protsuk, Igor’ A. Ushakov, and Boris A. Trofimov* A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Street, 664033 Irkutsk, Russia J. Org. Chem. 2018.83:10272-10280. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 09/08/18. For personal use only.

S Supporting Information *

ABSTRACT: Dienyl derivatives of 6,8-dioxabicyclo[3.2.1]octanes, closely related to naturally abundant molecules, have been synthesized from 2-acetyl-3,4-dihydropyrans (readily available from ketones and acetylene in two steps), which further add to aryl(hetaryl)acetylenes in the KOBut/DMSO superbase system (105 °C, 1.5 h) to stereoselectively give the corresponding Estyryl adducts. The latter undergo ring closure (NH4Cl/H2O, acetonitrile, reflux, 8 h) to form the 6,8-dioxabicyclo[3.2.1]octane core decorated with the (1Z,3E)-diene substituent.

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INTRODUCTION The bridgehead bicyclic acetal architectures 6,8dioxabicyclo[3.2.1]octanes (commonly abbreviated as 6,8DOBCOs), represent a naturally abundant scaffold met in the molecules of insect pheromones (frontalin,1 brevicomin,1a,2 multistriatin1a,2b,3), mammal hormones,4 and marine toxins.5 Some 6,8-DOBCOs are found to possess anticancer6 and antiviral7 activity. Therefore, the interest in this class of compounds keeps steadily growing, and novel approaches to their synthesis warranting structural diversity are in demand. However, the existing protocols are mostly multistep, transition-metal-catalyzed and require hardly accessible polyfunctional starting materials, e.g., δ-keto diols, δ-keto epoxides, diazo ketones, and so forth (see, for example, the recent review8). Thus, the search for simpler, more expedient, and transition-metal-free strategies for the design of 6,8-DOBCOs remains a challenge. Recently, we have discovered the superbase-catalyzed onepot diastereoselective self-organization of two molecules of ketones with two molecules of acetylene to 7-methylene-6,8DOBCOs 1 (Scheme 1, eq 1),9 thereby opening up fresh opportunities for further development of these bicyclic acetals chemistry. Compounds 1 appear to be quantitatively isomerized under the action of an acid catalyst to 2-acetyl3,4-dihydropyrans 2 (Scheme 1, eq 2).10 Furthermore, the dehydrative rearrangement of 6,8-DOBCOs 1 to acylcyclopentadienes (Scheme 1, eq 2)11 and the click thiol addition12 to their double bond have been realized. In turn, 2-acetyl-3,4dihydropyrans 2 are transformed into 1,6-dioximes,13 and their deacetylation to another series of dihydropyrans14 is implemented (Scheme 1, eq 3). Here, we report acetylene-based two-step stereoselective synthesis of dienyl derivatives of 6,8-DOBCOs 5 that includes © 2018 American Chemical Society

the superbase-promoted C-vinylation of 2-acetyl-3,4-dihydropyrans 2 with aryl(hetaryl)acetylenes 3 and acid-catalyzed ring closure of adducts 4 to form the bicyclic acetals 5 (Scheme 1, eq 4).

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RESULTS AND DISCUSSION The C-vinylation of dihydropyrans 2 with aryl(hetaryl)acetylenes 3 proceeds upon their heating in the KOBut/ DMSO superbase system to afford the E-styryl derivatives 4 in 72−83% yields (Table 1). The narrow range of yields shows a weak dependence of the reaction efficiency on the reactant structure of both dihydropyrans 2 and acetylenes 3. The reaction conditions can be considered as provisionally optimum because they have been selected from a series of experiments carried out at various temperatures, reactant/ catalyst ratios, and process durations. Typical features of the optimization process conducted for the reaction 2a + 3a to give dihydropyran 4a are shown in Table 2. Astonishingly, in contrast to KOBut, KOH appears to be absolutely inactive as a catalyst in this reaction (entry 1). The best acetylenic substrates for the vinylation of acetyldihydropyrans 2 are alkynylarenes 3 (Table 1), whereas aliphatic acetylenes appeared to be unsuitable for this reaction because under strongly basic conditions they readily undergo acetylene-allene prototropic isomerization or are not electrophilic enough (e.g., tert-butylacetylene) toward carbanions of ketones 2. At the same time, the reactant scope is obviously not extendable over some strongly electrophilic acetylenes such as propiolates and the like due to the side transformations of the functional groups or their anionic oligomerization. Received: June 7, 2018 Published: July 20, 2018 10272

DOI: 10.1021/acs.joc.8b01449 J. Org. Chem. 2018, 83, 10272−10280

Article

The Journal of Organic Chemistry Scheme 1. Previous and Present Works

cyclization, the most selective and efficient catalyst proved to be aqueous NH4Cl, which is rationalized below. Structures of compounds 5 have been unambiguously established by NMR spectra using COSY, NOESY, 1H−13C HSQC, and 1H−13C HMBC experiments (Figure 1, see Supporting Information (SI) for details). The isomerization of dihydropyrans 4 into isomers 5 apparently starts with their enolization (Scheme 4). Enol B undergoes intramolecular addition to the dihydropyran double bond through carbocation C, which, after the ring closure (involving the OH group) and release of the proton, delivers the final product 5. The diastereoselectivity of closing bicycle 5 is predetermined by the cyclic structure of the starting dihydropyran 4 in which the hydroxyl group can attack position 6 only from axial direction that leads to just a single configuration of carbon-6. Apparently, NH4Cl plays the role of bifunctional catalyst, not only protonating the carbonyl function but also facilitating the proton elimination from the neighboring CH2 group of cation C. A striking feature of this isomerization is that it is the reverse reaction relative to 1 → 2 rearrangement (Scheme 1, eq 2), which very rapidly and completely occurs in the presence of trace acids.10 Evidently, this unexpected transformation is due to energy gain in the extended conjugation system (het)aryl− CHCH−CHC−O that is absent in DOBCOs 1. In summary, we have developed an acetylene-based facile transition-metal-free route to previously inaccessible diversely substituted dienyl derivatives of 6,8-dioxabicyclo[3.2.1]octanes (6,8-DOBCOs). The synthesis involves the following two steps: (i) base-catalyzed addition of 2-acetyl-3,4-dihydropyrans (readily available from ketones and acetylene) to aryl(hetaryl)acetylenes and (ii) ring closure of the formed E-styryl derivatives under mild conditions. Simple precursors (ketones and acetylenes) and the simple protocol developed herein

The structure variation of acetyldihydropyrans 2 are represented by aromatic and tert-alkyl groups, which cover a large range of organic substituents though there are no obvious fundamental obstacles for primary and secondary alkyls to be involved in this reaction. The C-vinylation represents a nucleophilic addition of the carbon-centered nucleophiles to the acetylenic moiety: the carbanions A generated by deprotonation of the acetyl group under the action of superbase (KOBut/DMSO) regio- and stereoselectively attack the triple bond (Scheme 2).15 Commonly, such nucleophilic addition to acetylenes stereoselectively leads to the Z-adducts (trans-addition rule).16 The inversion of the stereoselectivity in this case is evidently due to a steric repulsion between the densely substituted 3,4dihydropyran moiety and aryl group of acetylene. The E configuration of adducts 4 has been unambiguously established by 3JH−H values (15.8−16.1 Hz) between protons at the double bond in the 1H NMR spectra (see Experimental Section). In the case of bulky substituents (e.g., 4-PhC6H4, 2naphthyl) adjacent to the acetyl group, the vinylation does not occur (Table 1, substrates 2e,f), obviously due to the steric shielding of the reacting carbanion. Here, instead of Cvinylation, the loss of the acetyl group with release of dihydropyrans 6a,b is observed. This side reaction and its tentative mechanism were considered previously.14 When dihydropyrans 4 are refluxed in the presence of 1.5 equiv of NH4Cl in aqueous acetonitrile, the ring closure takes place to form dienyl derivatives 5 (Scheme 3). This rearrangement also occurs in anhydrous acidic conditions but not as clean as with the system NH4Cl/H2O/MeCN (small amounts of side products are detectable in 1H NMR spectra). A general impression about the influence of the reaction conditions on dihydropyran 4a cyclization can be drawn from Table 3. As mentioned above, although some acids catalyze the 10273

DOI: 10.1021/acs.joc.8b01449 J. Org. Chem. 2018, 83, 10272−10280

Article

The Journal of Organic Chemistry Table 1. Substrate Scope of C-Vinylation of 3,4-Dihydropyrans 2 with Acetylenes 3a

a

Reaction conditions: 2 (2 mmol), 3 (2 mmol), KOBut (2 mmol, 224 mg), DMSO (10 mL). bYields after column chromatography (Al2O3, hexane) are given. cDiastereomeric ratio = dr.

blocks for the design of naturally related molecular architectures.

Table 2. Optimization of the Reaction Conditions for the Synthesis of Dihydropyran 4aa

entry

base

temp (°C)

time (h)

2a:4ab

yield of 4a (%)c

1 2 3 4

KOH KOBut KOBut KOBut

100 100 100 105

1.5 1.0 1.5 1.5

1:0 1:4 1:10 0:1

0 51 65 76

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EXPERIMENTAL SECTION

General Remarks. 1H (400.1 MHz) and 13C (100.6 MHz) NMR spectra were recorded in C6D6 (for 4a−l) or in CDCl3 (for 5a−l, 6a,b) with hexamethyldisiloxane (HMDS) as an internal standard. Chemical shifts (δ) are given in ppm, and coupling constants (J) are given in Hz. The 1H and 13C chemical shifts (δ) were referenced to HMDS (0.05 and 2.0 ppm, respectively). The assignment of signals in the 1H NMR spectra was made using COSY and NOESY experiments. Resonance signals of carbon atoms were assigned based on 1H−13C HSQC and 1H−13C HMBC experiments. Coupling constants (J) were measured from one-dimensional spectra, and multiplicities were abbreviated as follows: s (singlet), d (doublet), dd (doublet of doublets), dt (doublet of triplets), m (multiplet). IR spectra were taken with FT-IR. Melting points (uncorrected) were measured on a Kofler micro hot-stage apparatus. The microanalyses were performed on a Flash EA 1112 Series elemental analyzer. Thin layer chromatography was carried out on Merck silica gel 60 F254 precoated aluminum foil sheets (eluent: Et2O/hexane = 1:3) and were visualized using UV light (254 nm). Column chromatography was carried out using basic Al2O3 (eluent: hexane).

a Reaction conditions: 2a (2 mmol, 585 mg), 3a (2 mmol, 204 mg), base (2 mmol), DMSO (10 mL). bMolar ratio according to 1H NMR spectra of the crude product. cAfter column chromatography (Al2O3, hexane).

make the methodology practically feasible for the synthesis of previously unknown congeners of insect pheromones, mammal hormones, and marine toxins as well as attractive building 10274

DOI: 10.1021/acs.joc.8b01449 J. Org. Chem. 2018, 83, 10272−10280

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The Journal of Organic Chemistry Scheme 2. C-Vinylation of 2-Acetyl-3,4-Dihydropyrans 2

Scheme 3. Cyclization of Dihydropyrans 4 to DOBCOs 5a

a

Reaction conditions: 4 (1 mmol), NH4Cl (1.5 mmol, 80 mg), H2O (1.5 mL), MeCN (7.5 mL). Yields after column chromatography (Al2O3, hexane) are given.

Starting Materials. 6,8-DOBCOs 1 were synthesized by published procedures from ketones and acetylene in the KOH/ DMSO system.9 2-Acetyl-3,4-dihydropyrans 2 were prepared by the TFA-catalyzed rearrangement of the 6,8-DOBCO 1 according to the literature procedure. 10 All other chemicals and solvents are commercially available and were used without further purification. General Procedure for the Synthesis of Dihydropyrans 4 and 6. A mixture of 2-acetyl-3,4-dihydropyran 2 (2 mmol), arylacetylene 3 (2 mmol), and KOBut (2 mmol, 224 mg) in DMSO (10 mL) was stirred at 105 °C for 1.5 h. The reaction mixture, after cooling (rt), was diluted with H2O (15 mL) and extracted with Et2O (7 mL × 4). The organic extract was washed with H2O (5 mL × 3) and dried (K2CO3). Et2O was evaporated in a vacuum, and the

residue was purified by column chromatography (basic Al2O3, eluent: hexane). (E)-1-((2S*,4S*)-4-Methyl-2,6-diphenyl-3,4-dihydro-2H-pyran-2yl)-4-phenylbut-3-en-1-one (4a). Following the general procedure, 4a was prepared from dihydropyran 2a (585 mg, 2 mmol) and acetylene 3a (204 mg, 2 mmol); 4a was isolated as a yellow oil (600 mg, 76% yield). Anal. Calcd for C28H26O2: C, 85.25; H, 6.64. Found: C, 85.27; H, 6.63. IR (film): ν 3032, 1954, 1886, 1807, 1718, 1654, 1105, 965. 1H NMR (C6D6): δ 7.76−7.70 (m, 2H, Ho), 7.69−7.64 (m, 2H, Ho), 7.25−7.15 (m, 2H), 7.15−7.06 (m, 4H), 7.05−6.99 (m, 3H), 6.95−6.85 (m, 2H) [HPh], 6.14 (dt, 3J = 15.9 Hz, 3J = 8.0 Hz, 1H, Hβ), 5.90 (d, 3J = 15.9 Hz, 1H, Hγ), 5.19−5.17 (m, 1H, H5), 3.36 (d, 3J = 8.0 Hz, 2H, Hα), 2.86 (dd, 2J = 13.4 Hz, 3J = 6.5 Hz, 1H, 310275

DOI: 10.1021/acs.joc.8b01449 J. Org. Chem. 2018, 83, 10272−10280

Article

The Journal of Organic Chemistry

(dd, 2J = 13.6 Hz, 3J = 11.3 Hz, 1H, 3-CH2), 0.80 (d, 3J = 7.0 Hz, 3H, 4-Me). 13C{1H} NMR (C6D6): δ 208.7 (CO), 149.4 (C6), 140.4, 136.8, 135.8, 134.9, 133.5, 129.3, 129.1, 129.0, 128.8, 128.7, 128.5, 125.2, 124.8 (18CPh), 126.5 (Cβ), 121.5 (Cγ), 105.7 (C5), 87.6 (C2), 40.9 (Cα), 40.0 (C3), 25.4 (C4), 21.1 (Me, 4-Me). (E)-4-([1,1′-Biphenyl]-4-yl)-1-((2S*,4S*)-4-methyl-2,6-diphenyl3,4-dihydro-2H-pyran-2-yl)but-3-en-1-one (4c). Following the general procedure, 4c was prepared from dihydropyran 2a (585 mg, 2 mmol) and acetylene 3c (356 mg, 2 mmol); 4c was isolated as a yellow oil (678 mg, 72% yield). Anal. Calcd for C34H30O2: C, 86.77; H, 6.43. Found: C, 86.31; H, 6.43. IR (film): ν 3031, 1900, 1716, 1652, 1100, 974. 1H NMR (C6D6): δ 7.75−7.70 (m, 2H, Ho), 7.69− 7.64 (m, 2H; Ho), 7.38−7.31 (m, 2H), 7.27−7.21 (m, 2H), 7.20− 7.15 (m, 2H), 7.15−6.96 (m, 9H) [HPh], 6.19 (dt, 3J = 16.1 Hz, 3J = 7.0 Hz, 1H, Hβ), 5.93 (d, 3J = 16.1 Hz, 1H, Hγ), 5.18−5.17 (m, 1H, H5), 3.39 (d, 3J = 7.0 Hz, 2H, Hα), 2.87 (dd, 2J = 13.4 Hz, 3J = 6.5 Hz 1H, 3-CH2), 2.59−2.49 (m, 1H; H4), 1.27 (dd, 2J = 13.4 Hz, 3J = 11.1 Hz, 1H, 3-CH2), 0.77 (d, 3J = 7.0 Hz, 3H, Me). 13C{1H} NMR (C6D6): δ 208.6 (CO), 149.4 (C6), 141.3, 140.4, 136.5, 135.8, 133.1, 130.0, 129.3, 129.0, 128.9, 128.8, 128.6, 127.4, 127.3, 127.2, 127.1, 125.4, 125.2, 124.8 (24CPh), 127.0 (Cβ), 122.7 (Cγ), 105.7 (C5), 87.7 (C2), 41.0 (Cα), 40.0 (C3), 25.4 (C4), 21.1 (Me). (E)-4-(3-Methoxyphenyl)-1-((2S*,4S*)-(4-methyl-2,6-diphenyl3,4-dihydro-2H-pyran-2-yl)but-3-en-1-one (4d). Following the general procedure, 4d was prepared from dihydropyran 2a (585 mg, 2 mmol) and acetylene 3d (264 mg, 2 mmol); 4d was isolated as a yellow oil (671 mg, 79% yield). Anal. Calcd for C29H28O3: C, 82.05; H, 6.65. Found: C, 82.02; H, 6.61. IR (film): ν 3033, 1955, 1891, 1808, 1717, 1653, 1104, 964. 1H NMR (C6D6): δ 7.77−7.75 (m, 2H, Ho), 7.71−7.69 (m, 2H, Ho), 7.23−7.14 (m, 2H), 7.11−7.06 (m, 2H), 7.04−7.00 (m, 1H), 6.99−6.91 (m, 2H), 6.70−6.59 (m, 3H) [HPh], 6.21 (dt, 3J = 15.9 Hz, 3J = 7.3 Hz, 1H, Hβ), 5.92 (d, 3J = 15.9 Hz, 1H, Hγ), 5.20−5.18 (m, 1H, H5), 3.39 (d, 3J = 7.3 Hz, 2H, Hα), 3.20 (s, 3H, OMe), 2.89 (dd, 2J = 13.3 Hz, 3J = 6.5 Hz 1H, 3-CH2), 2.60−2.52 (m, 1H; H4), 1.29 (dd, 2J = 13.3 Hz, 3J = 11.4 Hz, 1H, 3CH2), 0.80 (d, 3J = 6.9 Hz, 3H, Me). 13C{1H} NMR (C6D6): δ 208.6 (CO), 160.3 (C-OMe), 149.4 (C6), 140.3, 139.0, 135.8, 133.6, 129.6, 129.0, 128.7, 128.6, 127.4, 125.4, 124.8 (14CPh), 125.2 (Cβ), 122.7 (Cγ), 119.2, 113.6, 111.7 (3CPhOMe), 105.7 (C5), 87.6 (C2), 54.6 (OMe), 40.9 (Cα), 40.0 (C3), 25.4 (C4), 21.1 (Me). (E)-4-(4-Fluorophenyl)-1-((2S*,4S*)-(4-methyl-2,6-diphenyl-3,4dihydro-2H-pyran-2-yl)but-3-en-1-on (4e). Following the general procedure, 4e was prepared from dihydropyran 2a (585 mg, 2 mmol) and acetylene 3e (240 mg, 2 mmol); 4e was isolated as a yellow oil (677 mg, 82% yield). Anal. Calcd for C28H25FO2: C, 81.53; H, 6.11; F, 4.61. Found: C, 81.50; H, 6.03; F, 4.49. IR (film): ν 3040, 1957, 1889, 1719, 1654, 1102, 967. 1H NMR (C6D6): δ 7.76−7.70 (m, 2H, Ho), 7.69−7.64 (m, 2H; Ho), 7.25−7.15 (m, 2H), 7.15−7.06 (m, 4H), 6.75−6.66 (m, 2H), 6.63−6.57 (m, 2H) [HPh], 5.97 (dt, 3J = 15.8 Hz, 3J = 7.0 Hz, 1H, Hβ), 5.74 (d, 3J = 15.8 Hz, 1H, Hγ), 5.18− 5.17 (m, 1H, H5), 3.34 (d, 3J = 7.0 Hz, 2H, Hα), 2.87 (dd, 2J = 13.4 Hz, 3J = 6.4 Hz 1H, 3-CH2), 2.60−2.50 (m, 1H, H4), 1.28 (dd, 2J = 13.4 Hz, 3J = 11.1 Hz, 1H, 3-CH2), 0.80 (d, 3J = 7.0 Hz, 3H, Me). 13 C{1H} NMR (C6D6): δ 208.6 (CO), 162.5 (d, 1J = 246.1 Hz, C− F), 149.4 (C6), 140.3, 135.8, 133.6, 132.2, 129.0, 128.7, 128.6, 125.4, 125.2, 124.8 (13CPh), 124.8 (Cβ), 122.3 (Cγ), 115.3 (d, 2J = 21.6 Hz, CmPhF), 105.7 (C5), 87.6 (C2), 40.8 (Cα), 39.9 (C3), 25.4 (C4), 21.1 (Me). (E)-1-((2S*,4S*)-(4-Methyl-2,6-diphenyl-3,4-dihydro-2H-pyran-2yl)-4-(thiophen-3-yl)but-3-en-1-one (4f). Following the general procedure, 4f was prepared from dihydropyran 2a (585 mg, 2 mmol) and acetylene 3f (216 mg, 2 mmol); 4f was isolated as a beige oil (593 mg, 74% yield). Anal. Calcd for C26H24O2S: C, 77.97; H, 6.04; S, 8.00. Found: C, 77.94; H, 6.00; S, 7.97. IR (film): ν 3059, 1955, 1889, 1806, 1718, 1653, 1105, 963. 1H NMR (C6D6): δ 7.76− 7.70 (m, 2H, Ho), 7.69−7.64 (m, 2H, Ho), 7.25−7.15 (m, 2H), 7.13−7.06 (m, 3H), 7.05−6.99 (m, 1H) [HPh], 6.75 (d, 3J = 5.0 Hz, 1H, H5Thioph), 6.67 (dd, 3J = 5.0 Hz, 3J = 3.1 Hz, 1H, H4Thioph), 6.48 (d, 3J = 3.1 Hz, 1H, H2Thioph), 5.97 (dt, 3J = 16.0 Hz, 3J = 7.1 Hz, 1H, Hβ), 5.82 (d, 3J = 16.0 Hz, 1H, Hγ), 5.19−5.18 (m, 1H, H5), 3.32 (d,

Table 3. Influence of the Reaction Conditions on Cyclization of Dihydropyran 4a to DOBCO 5aa

entry 1 2 3 4 5 6

acid c

HCl MeCOOH CF3COOH CF3COOH CF3COOH NH4Cl/H2Oe

4a:acid molar ratio

time (h)

4a:5a molar ratiob

1:1 1:1 2:1 1:1 1:1 1:1.5

8 6 8 2 8 8

1.5:1 1:0 5:1 3:1 3:1d 0:1 (71%)f

a

Reaction conditions: 4a (1 mmol, 395 mg), acid, MeCN (7.5 mL). According to 1H NMR spectra of crude product. cUsing 0.36 mL of 10% aqueous HCl. dResinification of the reaction mixture was observed. eNH4Cl (1.5 mmol, 80 mg), H2O (1.5 mL). fYield of 5a after column chromatography (Al2O3, hexane). b

Figure 1. Main NOESY correlations for compound 5k.

Scheme 4. Plausible Mechanism of the Isomerization

CH2), 2.61−2.48 (m, 1H, H4), 1.26 (dd, 2J = 13.4 Hz, 3J = 11.1 Hz, 1H, 3-CH2), 0.78 (d, 3J = 6.9 Hz, 3H, Me). 13C{1H} NMR (C6D6): δ 208.6 (CO), 149.4 (C6), 140.3, 137.5, 135.8, 133.5, 129.0, 128.7, 128.6, 127.4, 125.4, 125.2, 124.8 (18CPh), 126.5 (Cβ), 122.6 (Cγ), 105.7 (C5), 87.6 (C2), 40.8 (Cα), 40.0 (C3), 25.4 (C4), 21.1 (Me). (E)-1-((2S*,4S*)-4-Methyl-2,6-diphenyl-3,4-dihydro-2H-pyran-2yl)-4-(p-tolyl)but-3-en-1-one (4b). Following the general procedure, 4b was prepared from dihydropyran 2a (585 mg, 2 mmol) and acetylene 3b (232 mg, 2 mmol); 4b was isolated as a yellow oil (597 mg, 73% yield). Anal. Calcd for C29H28O2: C, 85.26; H, 6.91. Found: C, 85.29; H, 6.99. IR (film): ν 3029, 1955, 1897, 1718, 1653, 1106, 966. 1H NMR(C6D6): δ 7.76−7.70 (m, 2H, Ho), 7.69−7.64 (m, 2H; Ho), 7.25−7.15 (m, 2H), 7.14−7.09 (m, 3H), 7.05−6.99 (m, 1H), 6.95−6.89 (m, 2H), 6.83−6.76 (m, 2H) [HPh], 6.15 (dt, 3J = 15.9 Hz, 3 J = 7.0 Hz, 1H, Hβ), 5.93 (d, 3J = 15.9 Hz, 1H, Hγ), 5.19−5.16 (m, 1H, H5), 3.38 (d, 3J = 7.0 Hz, 2H, Hα), 2.87 (dd, 2J = 13.6 Hz, 3J = 6.6 Hz 1H, 3-CH2), 2.59−2.49 (m, 1H; H4), 1.98 (s, 3H, Me), 1.28 10276

DOI: 10.1021/acs.joc.8b01449 J. Org. Chem. 2018, 83, 10272−10280

Article

The Journal of Organic Chemistry

H5), 3.42−3.35 (m, 2H, Hα), 2.90 (dd, 2J = 13.3 Hz, 3J = 6.7 Hz 1H, 3-CH2), 2.62−2.51 (m, 1H, H4), 2.08 (s, 3H, Me), 2.00 (s, 3H, Me), 1.35 (dd, 2J = 13.3 Hz, 3J = 11.3 Hz, 1H, 3-CH2), 0.80 (d, 3J = 6.9 Hz, 3H, 4-Me). 13C{1H} NMR (C6D6): δ 208.8 (CO), 149.6 (C6), 140.1 (C3Thioph), 138.2, 137.8, 137.7, 133.2, 129.7, 129.6, 125.2, 124.8 (10CPh), 125.6 (Cβ), 125.2 (C2Thioph), 125.0 (C5Thioph), 122.5 (Cγ), 121.6 (C4Thioph), 104.9 (C5), 87.6 (C2), 40.7 (Cα), 40.1 (C3), 25.5 (C4), 21.2 (4-Me), 20.1, 20.9 (Me). (E)-1-((2S*,4S*)-(2,6-Bis(4-fluorophenyl)-4-methyl-3,4-dihydro2H-pyran-2-yl)-4-phenylbut-3-en-1-one (4k). Following the general procedure, 4k was prepared from dihydropyran 2c (763 mg, 2 mmol) and acetylene 3a (204 mg, 2 mmol); 4k was isolated as a yellow oil (1047 mg, 76% yield). Anal. Calcd for C28H24F2O2: C, 78.12; H, 5.62; F, 8.83. Found: C, 78.21; H, 5.59; F, 8.85. IR (film): ν 3041, 1895, 1719, 1655, 1096, 965. 1H NMR (C6D6): δ 7.50−7.39 (m, 4H), 7.12−6.90 (m, 5H), 6.89−6.75 (m, 4H) [HPh], 6.16 (dt, 3J = 15.9 Hz, 3 J = 7.0 Hz, 1H, Hβ), 5.96 (d, 3J = 15.9 Hz, 1H, Hγ), 5.01−4.98 (m, 1H, H5), 3.27 (d, 3J = 7.0 Hz, 2H, Hα), 2.77 (dd, 2J = 13.6 Hz, 3J = 6.5 Hz 1H, 3-CH2), 2.52−2.43 (m, 1H, H4), 1.16 (dd, 2J = 13.6 Hz, 3J = 11.3 Hz, 1H, 3-CH2), 0.80 (d, 3J = 6.9 Hz, 3H, Me). 13C{1H} NMR (C6D6): δ 208.3 (CO), 163.3 (d, 1JCF = 247.6 Hz, C−F), 162.9 (d, 1 JCF = 247.6 Hz, C−F), 148.5 (C6), 137.3, 135.8, 133.5, 129.0, 128.7, 128.6, 127.4, 125.4, 125.2, 124.8 (12CPh), 126.5 (Cβ), 122.2 (Cγ), 115.9, 115.8 (CPhF), 105.4 (C5), 87.2 (C2), 40.7 (Cα), 39.8.0 (C3), 25.3 (C4), 21.0 (Me). (E)-4-([1,1′-Biphenyl]-4-yl)-1-((2S*,4S*)-(2,6-di-tert-butyl-4methyl-3,4-dihydro-2H-pyran-2-yl)but-3-en-1-one (5l). Following the general procedure, 4l was prepared from dihydropyran 2d (505 mg, 2 mmol) and acetylene 3c (356 mg, 2 mmol); 4l was isolated as a yellow oil (629 mg, 73% yield). Anal. Calcd for C30H38O2: C, 83.67; H, 8.89. Found: C, 83.47; H, 8.74. IR (film): ν 3031, 1903, 1709, 1072, 967. 1H NMR (C6D6): δ 7.42−7.40 (m, 2H), 7.39−7.35 (m, 2H), 7.32−7.27 (m, 2H), 7.21−7.15 (m, 2H), 7.11−7.05 (m, 1H) [HPh], 6.59 (ddd, 3J = 16.1 Hz, 3J = 7.4 Hz, 3J = 6.4 Hz, 1H, Hβ), 5.39 (d, 3J = 16.1 Hz, 1H, Hγ), 4.39−4.35 (m, 1H, H5), 3.76 (dd, 2J = 19.3 Hz, 3J = 7.4 Hz, 1H, Hα), 3.34 (dd, 2J = 19.3 Hz, 3J = 6.4 Hz, 1H, Hα), 2.40 (dd, 2J = 12.5 Hz, 3J = 5.1 Hz, 1H, 3-CH2), 2.05−1.95 (m, 1H, H4), 1.15 (s, 9H, But), 1.00 (s, 10H, 3-CH2, But), 0.79 (d, 3J = 6.7 Hz, 3H, Me). 13C{1H} NMR (C6D6): δ 213.3 (CO), 159.4 (C6), 141.3, 140.5, 136.7, 132.7, 129.1, 129.0, 128.9, 128.1, 128.6, 127.9, 127.3 (12CPh), 127.1 (Cβ), 123.5 (Cγ), 99.4 (C5), 90.2 (C2), 45.0 (CMe3), 38.3 (Cα), 35.4 (C3), 33.3, 28.7, 25.6 (3C, But), 24.1 (C4), 22.0 (Me). 2,6-Di[1,1′-biphenyl]-4-yl-4-methyl-3,4-dihydro-2H-pyran (6a). Following the general procedure, 6a was prepared from dihydropyran 2e (889 mg, 2 mmol) and acetylene 3a (204 mg, 2 mmol); 6a was isolated as a mixture of two diastereomers in a 2:1 molar ratio; yield 636 mg (79%); white solid; mp 108−110 °C. Anal. Calcd for C30H26O: C, 89.51; H, 6.51. Found: C, 89.75; H, 6.46. IR (film): ν 3032, 1949, 1913, 1801, 1647, 1109. (2S*,4R*)-2,6-Di([1,1′biphenyl]-4-yl)-4-methyl-3,4-dihydro-2H-pyran (major isomer): 1H NMR (CDCl3) δ 7.72−7.69 (m, 2H, Ho), 7.62−7.30 (m, 16H, HPh), 5.48 (d, 3J = 4.4 Hz, 1H, H5), 5.11 (d, 3J = 9.8 Hz, 1H, H2), 2.47−2.43 (m, 1H, H4), 2.19−2.14 (m, 1H, H3), 1.87−1.84 (m, 1H, H3), 1.20 (d, 3J = 7.1 Hz, 3H, Me). 13C{1H} NMR (CDCl3) δ 150.5 (C6), 141.4 (Ci), 141.0−140.5 (4CPh), 135.0 (Ci), 128.9−126.9 (14CPh), 126.4, 125.1 (2Co), 103.8 (C5), 74.1 (C2), 37.3 (C3), 25.5 (C4), 22.8 (Me). (2S*,4S*)-2,6-Di([1,1′-biphenyl]-4-yl)-4-methyl-3,4dihydro-2H-pyran (minor isomer): 1H NMR (CDCl3) δ 7.71−7.69 (m, 2H, Ho), 7.62−7.30 (m, 16H, HPh), 5.35 (s, 1H, H5), 5.08 (d, 3J = 11.7 Hz, 1H, H2), 2.78−2.75 (m, 1H, H4), 2.21−2.19 (m, 1H, H3), 1.65−1.62 (m, 1H, H3), 1.14 (d, 3J = 7.0 Hz, 3H, Me). 13C{1H} NMR (CDCl3) δ 150.8 (C6), 141.3 (Ci), 141.0−140.5 (4CPh), 134.9 (Ci), 128.9−126.9 (14CPh), 126.6 (2Co), 125.1 (2Co), 104.1 (C5), 78.1 (C2), 40.0 (C3), 28.5 (C4), 21.6 (Me). 4-Methyl-2,6-di(2-naphthyl)-3,4-dihydro-2H-pyran (6b). Following the general procedure, 6b was prepared from dihydropyran 2f (785 mg, 2 mmol) and acetylene 3a (204 mg, 2 mmol); 6b was isolated as a mixture of two diastereomers in a 2:1 molar ratio; yield 568 mg (81%); white solid; mp 81−83 °C. Anal. Calcd for C26H22O:

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J = 7.1 Hz, 2H, Hα), 2.87 (dd, 2J = 13.8 Hz, 3J = 6.5 Hz, 1H, 3-CH2), 2.58−2.50 (m, 1H, H4), 1.27 (dd, 2J = 13.8 Hz, 3J = 11.0 Hz, 1H, 3CH2), 0.80 (d, 3J = 7.0 Hz, 3H, 4-Me). 13C{1H} NMR (C6D6): δ 208.7 (CO), 149.6 (C6), 140.4, 140.1 (C3Thioph), 135.8, 129.0, 128.7, 128.6, 128.5, 125.4 (10CPh), 125.7 (Cβ), 125.2 (C2Thioph), 125.0 (C5Thioph), 122.2 (Cγ), 121.6 (C4Thioph), 105.7 (C5), 87.6 (C2), 40.7 (Cα), 40.0 (C3), 25.4 (C4), 21.1 (Me). (E)-1-((2S*,4S*)-(4-Methyl-2,6-di-p-tolyl-3,4-dihydro-2H-pyran2-yl)-4-phenylbut-3-en-1-one (4g). Following the general procedure, 4g was prepared from dihydropyran 2b (641 mg, 2 mmol) and acetylene 3a (204 mg, 2 mmol); 4g was isolated as a yellow oil (693 mg, 82% yield). Anal. Calcd for C30H30O2: C, 85.27; H, 7.16. Found: C, 85.29; H, 7.21. IR (film): ν 3029, 1945, 1908, 1798, 1717, 1652, 1099, 964. 1H NMR (C6D6): δ 7.73−7.71 (m, 2H, Ho), 7.65−7.53 (m, 2H, Ho), 7.05−6.98 (m, 2H), 6.97−6.80 (m, 7H) [HPh], 6.18 (dt, 3J = 15.8 Hz, 3J = 7.0 Hz, 1H, Hβ), 5.91 (d, 3J = 15.8 Hz, 1H, Hγ), 5.20−5.18 (m, 1H, H5), 3.50−3.33 (m, 2H, Hα), 2.90 (dd, 2J = 13.5 Hz, 3J = 6.8 Hz, 1H, 3-CH2), 2.62−2.47 (m, 1H, H4), 2.08 (s, 3H, Me), 2.00 (s, 3H, Me), 1.31 (dd, 2J = 13.5 Hz, 3J = 11.1 Hz, 1H, 3CH2), 0.81 (d, 3J = 6.9 Hz, 3H, 4-Me). 13C{1H} NMR (C6D6): δ 208.8 (CO), 149.6 (C6), 138.2, 137.8, 137.6, 135.5, 133.4, 133.2, 129.7, 129.5, 129.3, 129.0, 128.6, 127.3, 125.2, 124.8 (18CPh), 126.5 (Cβ), 122.8 (Cγ), 104.9 (C5), 87.6 (C2), 40.8 (Cα), 40.1 (C3), 25.4 (C4), 21.2 (4-Me), 21.0 (2C, Me). (E)-4-([1,1′-Biphenyl]-4-yl)-1-((2S*,4S*)-(4-methyl-2,6-di-p-tolyl3,4-dihydro-2H-pyran-2-yl)but-3-en-1-one (4h). Following the general procedure, 4h was prepared from dihydropyran 2b (641 mg, 2 mmol) and acetylene 3c (356 mg, 2 mmol); 4h was isolated as a yellow oil (788 mg, 79% yield). Anal. Calcd for C36H34O2: C, 86.71; H, 6.87. Found: C, 86.58; H, 6.92. IR (film): ν 3030, 1906, 1798, 1717, 1653, 1099, 965. 1H NMR (C6D6): δ 7.92−7.90 (m, 2H, Ho), 7.83−7.81 (m, 2H, Ho), 7.54−7.52 (m, 2H, Ho), 7.44−7.42 (m, 2H, Ho), 7.30−7.15 (m, 9H, HPh), 6.42 (dt, 2J = 15.4, 3J = 7.6 Hz, 1H, Hβ), 6.17 (d, 2J = 15.9 Hz, 1H, Hγ), 5.38 (m, 1H, H5), 3.72−3.60 (m, 2H, Hα), 3.14−3.09 (m, 1H, 3-CH2), 2.82−2.75 (m, 1H, H4), 2.28, 2.20 (s, 6H, 2Me), 1.57−1.50 (m, 1H, 3-CH2), 1.00 (d, 2J = 6.9 Hz, 3H, 4-Me). 13C{1H} NMR (C6D6): δ 208.5 (CO), 149.3 (C6), 141.0, 140.0, 137.9, 137.5, 137.3, 136.3, 132.9, 132.8, 129.4, 129.2, 128.7, 127.0, 127.0, 126.9, 126.7, 124.6 (24C, Ph), 124.9 (Cβ), 122.6 (Cγ), 104.6 (C5), 87.3 (C2), 40.6 (Cα), 39.8 (C3), 25.2 (C4), 20.9, 20.9, 20.7 (3C, Me). (E)-4-(3-Methoxyphenyl)-1-((2S*,4S*)-(4-methyl-2,6-di-p-tolyl3,4-dihydro-2H-pyran-2-yl)but-3-en-1-one (4i). Following the general procedure, 4i was prepared from dihydropyran 2b (641 mg, 2 mmol) and acetylene 3d (264 mg, 2 mmol); 4i was isolated as a yellow oil (751 mg, 83% yield). Anal. Calcd for C31H32O3: C, 82.27; H, 7.13. Found: C, 82.30; H, 7.16. IR (film): ν 3029, 1914, 1713, 1654, 1097, 965. 1H NMR (C6D6): δ 7.73−7.65 (m, 2H, Ho), 7.64− 7.58 (m, 2H, Ho), 7.09−7.01 (m, 2H), 7.00−6.95 (m, 2H), 6.94− 6.87 (m, 2H, H), 6.70−6.64 (m, 1H), 6.62−6.56 (m, 1H) [HPh], 6.25 (dt, 3J = 15.9 Hz, 3J = 6.9 Hz, 1H, Hβ), 5.96 (d, 3J = 15.9 Hz, 1H, Hγ), 5.19 (m, 1H, H5), 3.50−3.41 (m, 2H, Hα), 2.93 (dd, 2J = 13.3 Hz, 3J = 6.3 Hz, 1H, 3-CH2), 2.67−2.50 (m, 1H, H4), 2.09 (s, 3H, Me), 2.01 (s, 3H, Me), 1.35 (dd, 2J = 13.3 Hz, 3J = 11.3 Hz, 1H, 3-CH2), 0.81 (d, 3J = 6.8 Hz, 3H, 4-Me). 13C{1H} NMR (C6D6): δ 208.8 (CO), 160.3 (C-OMe), 149.6 (C6), 139.0, 138.2, 137.8, 137.6, 133.6, 133.2, 129.7, 129.5, 125.2, 124.8 (14CPh), 125.2 (Cβ), 123.0 (Cγ), 119.2, 113.6, 111.7 (3CPh), 104.9 (C5), 87.6 (C2), 54.6 (OMe), 40.9 (Cα), 40.1 (C3), 25.5 (C4), 21.2 (4-Me), 20.9 (2C, Me). (E)-1-((2S*,4S*)-(4-Methyl-2,6-di-p-tolyl-3,4-dihydro-2H-pyran2-yl)-4-(thiophen-3-yl)but-3-en-1-one (4j). Following the general procedure, 4j was prepared from dihydropyran 2b (641 mg, 2 mmol) and acetylene 3f (216 mg, 2 mmol); 4j was isolated as a yellow oil (660 mg, 77% yield). Anal. Calcd for C28H28O2S: C, 78.47; H, 6.59; S, 7.48. Found: C, 78.41; H, 6.61; S, 7.50. IR (film): ν 3028, 1909, 1717, 1656, 1094, 962. 1H NMR (C6D6): δ 7.71−7.66 (m, 2H, Ho), 7.63− 7.58 (m, 2H, Ho), 7.04−7.00 (m, 2H), 6.98−6.93 (m, 2H) [HPh], 6.73 (d, 3J = 5.0 Hz, 1H, H5Thioph), 6.64 (dd, 3J = 5.0 Hz, 3J = 3.1 Hz, 1H, H4Thioph), 6.46 (d, 3J = 3.1 Hz, 1H, H2Thioph), 6.00 (dt, 3J = 15.9 Hz, 3J = 7.0 Hz, 1H, Hβ), 5.85 (d, 3J = 15.9 Hz, 1H, Hγ), 5.18 (m, 1H, 10277

DOI: 10.1021/acs.joc.8b01449 J. Org. Chem. 2018, 83, 10272−10280

Article

The Journal of Organic Chemistry C, 89.11; H, 6.33. Found: C, 89.21; H, 6.28. IR (film): ν 3055, 1919, 1644, 1071. (2S*,4R*)-4-Methyl-2,6-di(naphthalen-2-yl)-3,4-dihydro2H-pyran (major isomer): 1H NMR (CDCl3) δ 8.15 (s, 1H), 7.90 (s, 1H), 7.74−7.76 (m, 1H), 7.55−7.54 (m, 1H), 7.94−7.39 (m, 10H) [HNaphth], 5.58 (d, 3J = 4.2 Hz, 1H, H5), 5.27 (d, 3J = 9.8 Hz, 1H, H2), 2.47−2.44 (m, 1H, H4), 2.20−2.18 (m, 1H, H3), 1.91−1.89 (m, 1H, H3), 1.22 (d, 3J = 7.1 Hz, 3H, Me). 13C{1H} NMR (CDCl3) δ 150.7 (C 6 ), 139.7 (C2 Naphth ), 133.4−133.1, 128.4−125.8 (14CNaphth), 132.9 (C2Naphth), 124.6 (C1Naphth), 124.2 (C3Naphth), 123.4 (C1Naphth), 122.8 (C3Naphth), 104.5 (C5), 74.5 (C2), 37.3 (C3), 25.6 (C4), 22.8 (Me). (2S*,4S*)-4-Methyl-2,6-di(naphthalen-2-yl)-3,4dihydro-2H-pyran (minor isomer): 1H NMR (CDCl3) δ 8.11 (s, 1H), 7.94 (s, 1H), 7.72−7.70 (m, 1H), 7.59−7.58 (m, 1H), 7.94−7.39 (m, 10H) [HNaphth], 5.46 (s, 1H, H5), 5.21 (d, 3J = 11.1 Hz, 1H, H2), 2.79−2.78 (m, 1H, H4), 2.25−2.21 (m, 1H, H3), 1.73 (m, 1H, H3), 1.17 (d, 3J = 6.9 Hz, 3H, Me). 13C{1H} NMR (CDCl3) δ 151.0 (C6), 139.6, 133.0 (2C2Naphth), 128.4−124.8 (14CNaphth), 124.9 (C1Naphth), 124.4 (C3Naphth), 123.5 (C1Naphth), 122.8 (C3Naphth), 104.7 (C5), 78.4 (C2), 39.9 (C3), 28.6 (C4), 21.5 (Me). General Procedure for the Rearrangement of Dihydropyrans 4 to DOBCOs 5. A mixture of dihydropyran 4 (1 mmol), NH4Cl (1.5 mmol, 80 mg), and H2O (1.5 mL) was refluxed in MeCN (7.5 mL) for 8 h. The reaction mixture, after cooling (rt), was diluted with Et2O and dried (K2CO3). Et2O and MeCN was evaporated in a vacuum, and the residue was purified by column chromatography (basic Al2O3, eluent: hexane). (1R*,3R*,5S*,Z)-3-Methyl-1,5-diphenyl-7-((E)-3-phenylallylidene)-6,8-dioxabicyclo[3.2.1]octane (5a). Following the general procedure, 5a was prepared from dihydropyran 4a (395 mg, 1 mmol); 5a was isolated as a colorless oil (281 g, 71% yield). Anal. Calcd for C28H26O2: C, 85.25; H, 6.64. Found: C, 85.31; H, 6.61. IR (film): ν 3033, 1953, 1895, 1799, 1667, 1610, 1565, 1506, 1087, 945. 1 H NMR (CDCl3): δ 7.77−7.74 (m, 2H, Ho′), 7.64−7.63 (m, 2H, Ho), 7.48−7.35 (m, 10H, HPh), 7.17−7.13 (m, 1H, Hp″), 7.10 (dd, 3J = 15.9 Hz, 3J = 11.0 Hz, 1H, Hβ), 6.28 (d, 3J = 15.9 Hz, 1H, Hγ), 4.82 (d, 3J = 11.0 Hz, 1H, Hα), 2.42 (m, 3H, H2eq, H3, H4eq), 1.82 (dd, 2J = 11.8 Hz, 3J = 11.3 Hz, 1H, H2ax), 1.74 (dd, 2J = 14.4, 3J = 12.1 Hz, 1H, H4ax), 1.12 (d, 3J = 5.9 Hz, 3H, Me). 13C{1H} NMR (CDCl3): δ 158.1 (C7), 139.4, 139.3, 138.1 (Ci, Ci′, Ci″), 128.9 (Cγ), 128.4, 128.3, 128.3, 127.9, 127.9, 126.6, 126.2, 125.90, 125.5 (15CPh), 123.5 (Cβ), 110.8 (C5), 96.5 (Cα), 85.8 (C1), 42.0 (C4), 41.0 (C2), 25.3 (C3), 21.3 (3-Me). (1R*,3R*,5S*,Z)-3-Methyl-1,5-diphenyl-7-((E)-3-(p-tolyl)allylidene)-6,8-dioxabicyclo[3.2.1]octane (5b). Following the general procedure, 5b was prepared from dihydropyran 4b (409 mg, 1 mmol); 5b was isolated as a white oil (278 mg, 68% yield). Anal. Calcd for C29H28O2: C, 85.26; H, 6.91. Found: C, 85.48; H, 6.78. IR (film): ν 3033, 1953, 1895, 1798, 1667, 1610, 1565, 1506, 1087, 945. 1 H NMR (CDCl3): δ 7.75−7.73 (m, 2H, Ho′), 7.63−7.60 (m, 2H, Ho), 7.47−7.36 (m, 6H, HPh), 7.26−7.24 (m, 2H, Ho″), 7.08−7.06 (m, 2H, Hm″), 7.03 (dd, 3J = 15.7 Hz, 3J = 10.8 Hz, 1H, Hβ), 6.24 (d, 3 J = 15.7 Hz, 1H, Hγ), 4.80 (d, 3J = 10.8 Hz, 1H, Hα), 2.45−2.36 (m, 3H, H2eq, H3, H4eq), 2.31 (s, 3H, Me), 1.81 (dd, 2J = 11.5 Hz, 3J = 11.3 Hz, 1H, H2ax), 1.73 (dd, 2J = 14.4 Hz, 3J = 12.0 Hz, 1H, H4ax), 1.11 (d, 3J = 5.9 Hz, 3H, 3-Me). 13C{1H} NMR (CDCl3): δ 157.8 (C7), 139.5, 139.4, 136.5, 135.4, 129.2, 129.0, 128.4, 128.4 (11CPh), 128.3 (Cγ), 128.0 (Cp′), 126.3, 126.0, 125.6 (6CPh), 122.4 (Cβ), 109.8 (C5), 96.70 (Cα), 85.9 (C1), 42.1 (C4), 40.8 (C2), 25.5 (C3), 21.4 (3-Me), 21.3 (Me). (1R*,3R*,5S*,Z)-7-((E)-3-([1,1′-Biphenyl]-4-yl)allylidene)-3-methyl-1,5-diphenyl-6,8-dioxabicyclo[3.2.1]octane (5c). Following the general procedure, 5c was prepared from dihydropyran 4c (470 mg, 1 mmol); 5c was isolated as a yellow oil (310 mg, 66% yield). Anal. Calcd for C34H30O2: C, 86.77; H, 6.43. Found: C, 86.88; H, 6.38. IR (film): ν 3032, 1953, 1894, 1807, 1666, 1602, 1488, 1087, 945. 1H NMR (CDCl3): δ 7.78−7.75 (m, 2H, Ho), 7.63−7.58 (m, 6H), 7.46− 7.36 (m, 11H) [HPh], 7.14 (dd, 3J = 15.8 Hz, 3J = 10.9 Hz, 1H, Hβ), 6.31 (d, 3J = 15.8 Hz, 1H, Hγ), 4.85 (d, 3J = 10.9 Hz, 1H, Hα), 2.46− 2.41 (m, 3H; H2eq, H3, H4eq), 1.83 (dd, 2J = 11.9 Hz, 3J = 11.2 Hz, 1H, H2ax), 1.75 (dd, 2J = 14.3 Hz, 3J = 12.0 Hz, 1H, H4ax), 1.13 (d, 3J

= 6.0 Hz, 3H, 3-Me). 13C{1H} NMR (CDCl3): δ 158.3 (C7), 140.9, 139.4, 139.3, 137.3, 129.1, 128.8, 128.5 (8CPh), 128.45 (Cγ), 128.40, 127.46, 127.19, 127.17, 126.89, 126.43, 126.29, 125.57 (16CPh), 123.5 (Cβ), 109.9 (C5), 96.7 (Cα), 86.0 (C1), 42.1 (C4), 40.8 (C2), 25.5 (C3), 21.4 (3-Me). (1R*,3R*,5S*,Z)-7-((E)-3-(3-Methoxyphenyl)allylidene)-3-methyl1,5-diphenyl-6,8-dioxa-bicyclo[3.2.1]octane (5d). Following the general procedure, 5d was prepared from dihydropyran 4d (425 mg, 1 mmol); 5d was isolated as a colorless oil (281 mg, 66% yield). Anal. Calcd for C29H28O3: C, 82.05; H, 6.65. Found: C, 81.98; H, 6.68. IR (film): ν 3033, 1666, 1596, 1488, 1088, 949. 1H NMR (CDCl3): δ 7.76−7.73 (m, 2H, Ho′), 7.63−7.60 (m, 2H, Ho), 7.47− 7.37 (m, 6H, HPh), 7.19−7.14 (m, 1H, Hm″), 7.07 (dd, 3J = 15.8 Hz, 3 J = 11.0 Hz, 1H, Hβ), 6.95 (d, 3J = 7.7 Hz, 1H, Ho″), 6.89 (s, 1H, Ho″), 6.72 (d, 3J = 8.3 Hz, 1H, Hp″), 6.24 (d, 3J = 15.8 Hz, 1H, Hγ), 4.80 (d, 3J = 11.0 Hz, 1H, Hα), 2.45−2.37 (m, 3H, H2eq, H3, H4eq), 1.81 (dd, 2J = 10.0 Hz, 3J = 9.8 Hz, 1H, H2ax), 1.73 (dd, 2J = 14.3 Hz, 3 J = 12.8 Hz, 1H, H4ax), 1.11 (d, 3J = 5.9 Hz, 3H, 3-Me). 13C{1H} NMR (CDCl3): δ 159.8 (C-OMe), 158.3 (C7), 139.7 (Ci″), 139.4 (Ci, Ci′), 129.4 (Cp′), 129.1 (Cp), 128.4 (Cm, Cm′), 128.1 (Cγ), 127.9 (Cm″), 126.3 (Co), 125.5 (Co′), 123.7 (Cβ), 118.9 (Co″), 112.4 (Cp″), 111.2 (Co″), 109.9 (C5), 96.5 (Cα), 85.9 (C1), 55.3 (OMe), 42.0 (C4), 40.8 (C2), 25.4 (C3), 21.4 (3-Me). (1R*,3R*,5S*,Z)-7-((E)-3-(4-Fluorophenyl)allylidene)-3-methyl1,5-diphenyl-6,8-dioxa-bicyclo[3.2.1]octane (5e). Following the general procedure, 5e was prepared from dihydropyran 4e (413 mg, 1 mmol); 5e was isolated as a yellow oil (231 mg, 56% yield). Anal. Calcd for C28H25FO2: C, 81.53; H, 6.11; F, 4.61. Found: C, 81.49; H, 6.05; F, 4.63. IR (film): ν 3040, 1954, 1888, 1814, 1667, 1601, 1505, 1089, 945. 1H NMR (CDCl3): δ 7.78−7.75 (m, 2H, Ho), 7.65−7.62 (m, 2H, Ho), 7.47−7.36 (m, 6H), 7.32−7.31 (m, 2H) [HPh], 7.03 (dd, 3J = 15.8 Hz, 3J = 11.0 Hz, 1H, Hβ), 6.97 (m, 2H, HPhF), 6.24 (d, 3 J = 15.8 Hz, 1H, Hγ), 4.82 (d, 3J = 11.0 Hz, 1H, Hα), 2.43 (m, 3H; H2eq, H3, H4eq), 1.84 (dd, 2J = 12.0 Hz, 3J = 11.8 Hz, 1H, H2ax), 1.76 (dd, 2J = 15.4 Hz, 3J = 12.8 Hz, 1H, H4ax), 1.13 (d, 3J = 5.6 Hz, 3H, 3Me). 13C{1H} NMR (CDCl3): δ 162.3 (d, 1JCF = 246.7 Hz, C−F), 158.2 (C7), 139.4, 139.3, (Ci, Ci′), 134.4 (CPhF), 129.0 (Cγ), 128.4, 127.3, 126.7, 126.3, 125.5 (2CPhF, 10CPh), 123.1 (Cβ), 115.4 (d, 3JCF = 21.0 Hz, 2CPhF), 109.9 (C5), 96.4 (Cα), 85.9 (C1), 42.0 (C4), 40.7 (C2), 25.4 (C3), 21.4 (3-Me). (1R*,3R*,5S*,Z)-3-Methyl-1,5-diphenyl-7-((E)-3-(thiophen-3-yl)allylidene)-6,8-dioxa-bicyclo[3.2.1]octane (5f). Following the general procedure, 5f was prepared from dihydropyran 4f (401 mg, 1 mmol); 5f was isolated as a yellow oil (213 mg, 53% yield). Anal. Calcd for C26H24O2S: C, 77.97; H, 6.04; S, 8.01. Found: C, 77.89; H, 5.99; S, 7.95. IR (film): ν 3037, 1955, 1887, 1810, 1668, 1607, 1598, 1088, 952. 1H NMR (CDCl3): δ 7.80−7.77 (m, 2H, Ho), 7.68−7.65 (m, 2H, Ho), 7.52−7.43 (m, 7H, HPh, HThioph), 7.30−7.27 (m, 1H), 7.09−7.06 (m, 1H) [HThioph], 6.97 (dd, 3J = 15.7 Hz, 3J = 10.9 Hz, 1H, Hβ), 6.34 (d, 3J = 15.7 Hz, 1H, Hγ), 4.81 (d, 3J = 10.9 Hz, 1H, Hα), 2.50−2.41 (m, 3H, H2eq, H3, H4eq), 1.81 (dd, 2J = 11.7 Hz, 3J = 10.5 Hz, 1H, H2ax), 1.73 (dd, 2J = 14.6 Hz, 3J = 12.3 Hz, 1H, H4ax), 1.16 (d, 3J = 5.9 Hz, 3H, 3-Me). 13C{1H} NMR (CDCl3): δ 157.8 (C7), 140.9 (C3Thioph), 139.5 (Ci″), 139.4 (Ci′), 129.0 (Cp′), 128.4, 128.4 (4C, Cm, Cm′), 128.3 (Cp), 126.3 (2C, Co), 125.7 (C5Thioph), 125.5 (2C, Co′), 125.1 (C4Thioph), 123.4 (Cβ), 122.3 (Cγ), 120.4 (C2Thioph), 109.8 (C5), 96.4 (Cα), 85.8 (C1), 42.0 (C4), 40.8 (C2), 25.4 (C3), 21.4 (3-Me). (1R*,3R*,5S*,Z)-3-Methyl-7-((E)-3-phenylallylidene)-1,5-di-ptolyl-6,8-dioxabicyclo[3.2.1]octane (5g). Following the general procedure, 5g was prepared from dihydropyran 4g (423 mg, 1 mmol); 5g was isolated as a white solid (317 mg, 75% yield); mp 79− 81 °C. Anal. Calcd for C30H30O2: C, 85.27; H, 7.16. Found: C, 85.33; H, 7.11. IR (film): ν 3028, 1907, 1803, 1667, 1616, 1598, 1513, 1072, 945. 1H NMR (C6D6): δ 7.86−7.83 (m, 2H, Ho′), 7.67−7.64 (m, 2H, Ho), 7.59 (dd, 3J = 16.1 Hz, 3J = 10.8 Hz, 1H, Hβ), 7.36−7.34 (m, 2H, Ho″), 7.19−7.14, (m, 6H, Hm, Hm′, Hm″), 7.08−7.04, (m, 1H, Hp″), 6.30 (d, 3J = 16.1 Hz, 1H, Hγ), 5.10 (d, 3J = 10.8 Hz, 1H, Hα), 2.40−2.36 (m, 1H, H3), 2.28−2.24 (m, 2H, H2eq, H4eq), 2.23 (s, 3H, Me), 2.21 (s, 3H, Me), 1.75 (dd, 2J = 12.3 Hz, 3J = 12.2 Hz, 1H, 10278

DOI: 10.1021/acs.joc.8b01449 J. Org. Chem. 2018, 83, 10272−10280

Article

The Journal of Organic Chemistry H2ax), 1.65 (dd, 2J = 13.3 Hz, 3J = 11.4 Hz, 1H, H4ax), 0.91 (d, 3J = 6.6 Hz, 3H, 3-Me). 13C{1H} NMR (C6D6): δ 158.9 (C7), 138.7 (Cp′), 138.7 (Ci″), 138.0 (Cp), 137.35 (Ci′), 137.3 (Ci), 129.2 (4C, Cm, Cm′), 128.8 (2C, Cm″), 128.4 (Cγ), 126.8 (3C, Co, Cp″), 126.3 (2C, Co″), 126.0 (2C, Co′), 123.8 (Cβ), 110.2 (C5), 97.2 (Cα), 86.1 (C1), 42.4 (C4), 40.8 (C2), 25.6 (C3), 21.4 (3-Me), 21.1, 21.0 (2C, Me). (1R*,3R*,5S*,Z)-7-((E)-3-([1,1′-Biphenyl]-4-yl)allylidene)-3-methyl-1,5-di-p-tolyl-6,8-dioxabicyclo[3.2.1]octane (5h). Following the general procedure, 5h was prepared from dihydropyran 4h (499 mg, 1 mmol); 5h was isolated as a white solid (354 mg, 71% yield); mp 88− 90 °C. Anal. Calcd for C36H34O2: C, 86.71; H, 6.87. Found: C, 86.63; H, 6.81. IR (film): ν 3038, 1906, 1800, 1665, 1604, 1515, 1074, 943. 1 H NMR (CDCl3): δ 7.68−7.65 (m, 2H, Ho′), 7.62−7.59 (m, 2H, Ho), 7.54−7.48 (m, 4H), 7.37−7.30 (m, 9H) [HPh], 7.15 (dd, 3J = 15.8 Hz, 3J = 11.0 Hz, 1H, Hβ), 6.30 (d, 3J = 15.8 Hz, 1H, Hγ), 4.84 (d, 3J = 11.0 Hz, 1H, Hα), 2.43 (s, 3H, Me), 2.40 (s, 3H, Me), 2.39 (m, 3H, H2eq, H3, H4eq), 1.81 (dd, 2J = 12.1 Hz, 3J = 10.1 Hz, 1H, H2ax), 1.74 (dd, 2J = 13.2 Hz, 3J = 11.1 Hz, 1H, H4ax), 1.12 (d, 3J = 5.9 Hz, 3H, 3-Me). 13C{1H} NMR (CDCl3): δ 158.7 (C7), 140.9, 139.2, 138.9, 138.1, 137.4, 136.6, 129.1, 129.0 (10CPh), 128.8 (Cγ), 127.2, 126.9, 126.4, 126.3, 125.5 (14CPh), 123.7 (Cβ), 109.9 (C5), 96.4 (Cα), 85.9 (C1), 41.8 (C4), 40.7 (C2), 25.4 (C3), 21.5 (3-Me), 21.4, 21.3 (2C, Me). (1R*,3R*,5S*,Z)-7-((E)-3-(3-Methoxyphenyl)allylidene)-3-methyl1,5-di-p-tolyl-6,8-dioxabicyclo[3.2.1]octane (5i). Following the general procedure, 5i was prepared from dihydropyran 4i (453 mg, 1 mmol); 5i was isolated as a yellow oil (285 mg, 63% yield). Anal. Calcd for C31H32O3: C, 82.27; H, 7.13. Found: C, 82.33; H, 7.09. IR (film): ν 3030, 1909, 1796, 1668, 1597, 1578, 1515, 1079, 951. 1H NMR (CDCl3): δ 7.60−7.57 (m, 2H. Ho′), 7.46−7.43 (m, 2H, Ho), 7.25−7.17 (m, 4H, HPh), 7.16−7.13 (m, 1H, Hm″), 7.04 (dd, 3J = 15.8 Hz, 3J = 11.0 Hz, 1H, Hβ), 6.91 (d, 3J = 7.5 Hz, 1H, Ho″), 6.85 (s, 1H, Ho″), 6.67−6.65 (m, 1H, Hp″), 6.19 (d, 3J = 15.8 Hz, 1H, Hγ), 4.75 (d, 3J = 11.0 Hz, 1H, Hα), 3.77 (s, 3H, OMe), 2.40−2.33 (m, 3H, H2eq, H3, H4eq), 2.38 (s, 3H, Me), 2.35 (s, 3H, Me), 1.76 (dd, 2 J = 13.7 Hz, 3J = 12.2 Hz, 1H, H2ax), 1.67 (dd, 2J = 14.4 Hz, 3J = 12.6 Hz, 1H, H4ax), 1.07 (d, 3J = 5.8 Hz, 3H, 3-Me). 13C{1H} NMR (CDCl3): δ 159.84 (C-OMe), 158.7 (C7), 139.8 (Ci″), 138.9 (Ci′), 138.1 (Ci), 136.50 (Cp), 129.40 (Cp′), 129.1, 129.0, (4C, Cm, Cm′), 127.6 (Cγ), 127.7 (Cm″), 126.3 (2C, Co), 125.5 (2C, Co′), 123.8 (Cβ), 118.9 (Cp″), 112.4, 111.1 (2C, Co″), 109.9 (C5), 96.3 (Cα), 85.9 (C1), 55.3 (MeO), 41.8 (C4), 40.7 (C2), 25.4 (C3), 21.4 (3-Me), 21.4, 21.2 (2C, Me). (1R*,3R*,5S*,Z)-3-Methyl-7-((E)-3-(thiophen-3-yl)allylidene)-1,5di-p-tolyl-6,8-dioxabicyclo[3.2.1]octane (5j). Following the general procedure, 5j was prepared from dihydropyran 4j (429 mg, 1 mmol); 5j was isolated as a yellow oil (296 mg, 69% yield). Anal. Calcd for C28H28O2S: C, 78.47; H, 6.59; S, 7.48. Found: C, 78.41; H, 6.61; S, 7.50. IR (film): ν 3033, 1909, 1802, 1742, 1668, 1618, 1515, 1075, 955. 1H NMR (CDCl3): δ 7.55−7.52 (m, 2H, Ho′), 7.39−7.36 (m, 2H, Ho), 7.19−7.14 (m, 3H, HPh, HThioph), 7.12−7.09 (m, 3H, HPh, HThioph), 6.90 (s, 1H, HThioph), 6.79 (dd, 3J = 15.8 Hz, 3J = 11.0 Hz, 1H, Hβ), 6.17 (d, 3J = 15.8 Hz, 1H, Hγ), 4.63 (d, 3J = 11.0 Hz, 1H, Hα), 2.30 (s, 3H, Me), 2.27 (s, 3H, Me), 2.26−2.21 (m, 3H, H2eq, H3, H4eq), 1.67 (dd, 2J = 11.7 Hz, 3J = 10.5 Hz, 1H, H2ax), 1.60 (dd, 2J = 14.6 Hz, 3J = 12.3 Hz, 1H, H4ax), 0.99 (d, 3J = 5.9 Hz, 3H, 3-Me). 13 C{1H} NMR (CDCl3): δ 158.1 (C7), 140.9 (C3Thioph), 138.8 (Ci′), 137.9 (Ci), 136.5 (Cp, Cp′), 129.0, 128.9 (4C, Cm, Cm′), 126.2 (2C, Co), 125.6 (C5Thioph), 125.4 (2C, Co′), 125.0 (C4Thioph), 123.5 (Cβ), 121.9 (Cγ), 120.2 (C2Thioph), 109.6 (C5), 96.0 (Cα), 85.7 (C1), 42.8 (C4), 40.7 (C2), 25.3 (C3), 21.3 (3-Me), 21.3, 21.1 (2C, Me). (1R*,3R*,5S*,Z)-1,5-Bis(4-fluorophenyl)-3-methyl-7-((E)-3-phenylallylidene)-6,8-dioxabicyclo[3.2.1]octane (5k). Following the general procedure, 5k was prepared from dihydropyran 4k (431 mg, 1 mmol); 5k was isolated as a white solid (258 mg, 60% yield); mp 64−66 °C. Anal. Calcd for C28H24F2O2: C, 78.12; H, 5.62; F, 8.83. Found: C, 78.21; H, 5.59; F, 8.85. IR (film): ν 3030, 1894, 1668, 1604, 1515, 1071, 951. 1H NMR (CDCl3): δ 7.72−7.69 (m, 2H, Ho′), 7.59−7.55 (m, 2H, Ho), 7.37−7.32 (m, 2H, Ho″), 7.17−7.19, (m, 7H, HPh), 7.07 (dd, 3J = 15.8 Hz, 3J = 11.3 Hz, 1H, Hβ), 6.29 (d,

3

J = 15.8 Hz, 1H, Hγ), 4.77 (d, 3J = 11.3 Hz, 1H, Hα), 2.38−2.33 (m, 3H, H2eq,H3, H4eq), 1.80 (dd, 2J = 13.2 Hz, 3J = 9.9 Hz, 1H, H2ax), 1.71 (dd, 2J = 13.4 Hz, 3J = 11.1 Hz, 1H, H4ax), 1.12 (d, 3J = 5.9 Hz, 3H, Me). 13C{1H} NMR (CDCl3): δ 163.2 (d, 1JCF = 247.5 Hz, Cp′), 162.8 (d, 1JCF = 247.1 Hz, Cp), 157.8 (C7), 138.0 (Ci″), 135.2 (d, 4 JCF = 3.3 Hz, Ci), 135.1 (d, 4JCF = 3.3 Hz, Ci′), 128.6 (3C, Cγ, Cm″), 128.3 (d, 3JCF = 8.3 Hz, Co), 127.6 (d, 3JCF = 8.3 Hz, Co′), 126.9 (Cp″), 126.1 (2C, Co″), 123.0 (Cβ), 115.4 (d, 2JCF = 21.6 Hz, Cm′), 115.3 (d, 2JCF = 21.6 Hz, Cm), 109.5 (C5), 96.9 (Cα), 85.6 (C1), 41.9 (C4), 40.7 (C2), 25.4 (C3), 21.4 (3-Me). (1R*,3R*,5S*,Z)-7-((E)-3-([1,1′-Biphenyl]-4-yl)allylidene)-1,5-ditert-butyl-3-methyl-6,8-dioxabicyclo[3.2.1]octane (5l). Following the general procedure, 5l was prepared from dihydropyran 4l (430 mg, 1 mmol); 5l was isolated as a white solid (245 mg, 57% yield); mp 57−58 °C. Anal. Calcd for C30H38O2: C, 83.67; H, 8.89. Found: C, 83.51%; H, 8.81. IR (film): ν 3029, 1902, 1796, 1655, 1602, 1515, 1085, 965. 1H NMR (CDCl3): δ 7.59−7.56 (m, 2H), 7.53−7.50 (m, 2H), 7.49−7.43 (m, 4H), 7.31−7.28 (m, 1H) [HPh], 7.16 (dd, 3J = 15.9 Hz, 3J = 10.6 Hz, 1H, Hβ), 6.36 (d, 3J = 15.9 Hz, 1H, Hγ), 5.23 (d, 3J = 10.6 Hz, 1H, Hα), 1.94−1.90 (m, 2H, H2eq, H4eq), 1.73−1.69 (m, 1H, H3), 1.34 (dd, 2J = 11.9 Hz, 3J = 11.3 Hz, 1H, H2ax), 1.23 (dd, 2J = 12.9 Hz, 3J = 11.0 Hz, 1H, H4ax), 1.09 (s, 9H, But), 1.05 (s, 9H, But), 0.93 (d, 3J = 6.4 Hz, 3H, 3-Me). 13C{1H} NMR (CDCl3): δ 157.9 (C7), 141.0, 139.0, 137.8 (3C, Ci, Ci′, Cp), 128.8 (Cγ), 127.2, 127.1 (4C, Cm, Cm′), 127.0 (Cp′), 126.9, 126.3 (4C, Co, Co′), 124.7 (Cβ), 112.7 (C5), 95.6 (Cα), 89.5 (C1), 36.9 (C4), 36.6 (C-But), 35.6 (C2), 35.1 (C-But), 26.1 (3C, But), 25.3 (C3), 25.1 (3C, But), 21.9 (3Me).

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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.8b01449. Copies of 1H and 13C NMR spectra of all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: boris_trofi[email protected]. ORCID

Boris A. Trofimov: 0000-0002-0430-3215 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the Baikal Analytical Center for collective use of the Siberian Branch of the Russian Academy of Sciences for the equipment.

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REFERENCES

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