Selective Functionalization of Achmatowicz Rearrangement Products by Reactions with Potassium Organotrifluoroborates under Transition-Metal-Free Conditions

Article abstract of DOI:10.1021/acs.joc.8b01643

The repertoire of synthetic transformations of the products of the Achmatowicz rearrangement has been expanded by exploring their reactivity with potassium organotrifluoroborates in the absence of transition metals. Depending on the reaction conditions and the substitution pattern of the starting material, the reaction may lead to the stereoselective synthesis of dihydropyranones (2,6-trans), tetrahydropyranones (2,3-cis-2,6-cis) or functionalized 1,4-dicarbonyl compounds. The method has also been adapted for the one-pot synthesis of functionalized pyrroles.

Full text of DOI:10.1021/acs.joc.8b01643

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Note
Selective Functionalization of Achmatowicz
Rearrangement Products by Reactions with Potassium
Organotrifluoroborates under Transition-Metal-Free Conditions
Silvia Roscales, Victor Ortega, and Aurelio Garcia Csaky
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01643 • Publication Date (Web): 23 Jul 2018
Downloaded from http://pubs.acs.org on July 24, 2018
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The Journal of Organic Chemistry
Selective Functionalization of Achmatowicz Rearrangement Prod-
ucts by Reactions with Potassium Organotrifluoroborates under
Transition-Metal-Free Conditions
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Silvia Roscales, Víctor Ortega, and Aurelio G. Csákÿ*
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Instituto Pluridisciplinar, Universidad Complutense, Campus de Excelencia Internacional Moncloa, Paseo de Juan XXIII, 1,
28040 Madrid, Spain
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Supporting Information
ABSTRACT: The repertoire of synthetic transformations of the products of the Achmatowicz rearꢀ
rangement has been expanded by exploring their reactivity with potassium organotrifluoroborates in the
absence of transitionꢀmetals. Depending on the reaction conditions and the substitution pattern of the
starting material, the reaction may lead to the stereoselective synthesis of dihydropyranones (2,6ꢀtrans),
tetrahydropyranones (2,3ꢀcisꢀ2,6ꢀcis) or functionalized 1,4ꢀdicarbonyl compounds. The method has also
been adapted for the oneꢀpot synthesis of functionalized pyrroles.
The Achmatowicz rearrangement (AR) consists of an oxidative ringꢀexpansion rearrangement of readily
available 2ꢀfurfuryl alcohols 1 to 6ꢀhydroxyꢀ3ꢀpyranones 2 (also known as pyranuloses) (Scheme 1).1,2
Due to their dense functionalization, the AR products 2 constitute useful starting materials for the prepaꢀ
ration of an ample variety of molecules with dihydropyran or tetrahydropyran core, such as dihydropyꢀ
ranones, oxidopyryliums, δꢀlactones, or pyranoses.3
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Scheme 1. Previous Work: Synthesis and Transformations of AR Products.
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Thus for example, AR products participate as glycosyl donors in Pdꢀcatalyzed glycosylation reactions (2
ꢀ 3, FeringaꢀO’Doherty Oꢀglycosylation),4 in bicycloketalization reactions (2 ꢀ 4),5 as 1,3ꢀdipoles in
[5+2]ꢀcycloadditions with alkenes under basic conditions (2 ꢀ 5),6 as 2π components in phosphineꢀ
catalyzed [3+2]ꢀcycloaddition reactions with allenoates (2 ꢀ 6),7 as 2π components in Pdꢀcatalyzed
oxaꢀ[3+2]ꢀcycloaddition reactions with 1,3ꢀdicarbonyl compounds (2 ꢀ 7),8 or in the Kishi reduction,
which leads to cisꢀ2,6ꢀdihydropyranones 8.9 Additionally, by means of a twoꢀstep sequence consisting of
elimination (2 ꢀ 9) followed by HeckꢀMatsuda arylation (Pdꢀcatalyzed coupling with aryldiazonium
salts), they may also give rise to transꢀ2,6ꢀdihydropyranones 10.10 Many of these transformations have
been used in the synthesis of natural products, bioactive carbohydrates, and advanced pharmaceutical
ingredients.
However, taking into consideration the simultaneous presence of the hemiacetal and α,βꢀunsaturated
ketone moieties, the synthetic potential of these densely functionalized compounds as pluripotent moꢀ
lecular platforms for diversity oriented synthesis (DOS) is still poorly developed.11 In this context, we
were interested in finding new transformations of the AR products 2 using aryl, alkenyl and alkynyl
potassium organotrifluoroborates 11 as reagents. The interest of these reagents in synthesis is due to the
fact that they are benchꢀstable reagents that can be used without the need for protection from humidity,
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and are compatible with unprotected functional groups, such as OH.12 In particular, we have focused our
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attention on finding selective reaction conditions for the stereoselective replacement of the γCꢀO bond
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in 2 by a γCꢀC bond, and on stereoselective conjugate addition reactions to OHꢀunprotected 2, both of
them under transitionꢀmetalꢀfree conditions (Scheme 2).13,14 Depending on the reactants and reaction
conditions, these transformations will lead selectively to dihydropyranones 10, tetrahydropyranones
12,1,3 or 1,4ꢀdicarbonyl compounds 13.15 In addition, we will consider the application of these findings
to the oneꢀpot synthesis of highly functionalized pyrroles (14, 15).16
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Scheme 2. This Paper: Reactions of AR Products with Organotrifluoroborates under Transition-
Metal-Free Conditions.
With regard to literature precedents for the replacement of the γCꢀO bond in AR products 2 with a γCꢀ
C(sp) bond, alkynylation reactions have only been carried out in connection with the synthesis of spiroꢀ
cyclic pyrans and macrocyclic lactones by the Lewisꢀacid catalyzed addition of alkynylsilanes.17 Conꢀ
cerning γCꢀC(sp2) bonds, the direct arylation has been reported as a lowꢀyielding process, and the synꢀ
thesis of 10 has only been previously achieved by a sequence of elimination – HeckꢀMatsuda reaction.10
To the best of our knowledge, the direct vinylation reaction is unprecedented.
With respect to literature precedents for conjugate addition reactions to AR products 2, the addition of
alkyl groups using organometallic nucleophiles18 or radicals19 has only been carried out on Oꢀprotected
derivatives of the AR products 2, and is amply precedented. However, the addition of vinyl or aryl
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groups is underdeveloped, and has only been carried out on Oꢀprotected AR products 2.20,21 To the best
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of our knowledge, the conjugate addition of C(sp)ꢀnucleophiles has not been previously reported.
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We started our investigations by considering the selective replacement of the γCꢀO bond in Oꢀ
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unprotected 2 with a γCꢀC(sp2) bond (Scheme 3) toward the synthesis of 10.22 The first challenge of this
transformation was finding reaction conditions devoid of competence with conjugate addition to the
α,βꢀunsaturated ketone moiety of the AR starting materials 2, which would lead to 12.23 In addition, we
were concerned about the sterochemical outcome of the transformation, which could lead to the dihyꢀ
dropyranones 10 either in 2,6ꢀcis or 2,6ꢀtrans relative configuration. In particular, the diastereoselective
obtention of 2,6ꢀtransꢀdihydropyranones is challenging.10 After some experimentation using 2a as startꢀ
ing material, we were pleased to find that the reaction with potassium (E)ꢀphenylvinyl trifluoroborate
11a gave rise to the selective formation of 10a either when promoted by trifluoroacetic anhydride
(TFAA, Scheme 3, conditions A) or by HBF4 (Scheme 3, conditions B). Under both reaction conditions,
10a was obtained as a single 2,6ꢀtrans diastereomer.24
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Scheme 3. Reactions of 2a with 11a
Complementarily, we looked for reaction conditions that could selectively afford the conjugate addition
products 12 without formation of 10. Again using 2a as starting material, we found that the reaction
with (E)ꢀphenylvinyl potassium trifluoroborate 11a promoted by Bu4NHSO4 (Scheme 3, conditions C)
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produced selectively the conjugate addition product 12a. However, since 12a was unstable to purificaꢀ
tion by silica gel chromatography, the crude reaction product was acetylated in situ to 16a. Under both
reaction conditions, 16a was obtained with high 2,3ꢀcisꢀ2,6ꢀcis diastereoselectivity.24,25
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Under the optimum reaction conditions for the formation of 10a (TFAA promotion, ꢀ15 ºC to rt), we
extended our observations to other AR products 2 for the synthesis of various 2,6ꢀtransꢀ
dihydropyranones 10 (Scheme 4).24,26 We found that the additions of arylvinyltrifluoroborates and alꢀ
kylvinyltrifluoroborates to 2a took place smoothly to give the corresponding dihydropyranones 10b –
10e in good yields and with trans : cis dr > 98:02. Similar results were obtained for the reactions of 2a
with potassium aryltrifluoroborates (10f – 10h). However, an erosion of the diastereoselectivity was
observed in the addition of potassium alkynyltrifluoroborates (10i, 10j). In these cases, we observed that
lowering the reaction temperature to ꢀ40 ºC afforded compounds 10i and 10j with increased trans : cis
dr. Good yields and trans : cis dr > 98:02 were also obtained when starting from the AR products 2b and
2c (synthesis of 10k – 10n). We were also glad to observe that the vinylation and arylation reactions of
compound 2d, with a quaternary carbon center, also took place in good yield and full 2,6ꢀtrans diastereꢀ
oselectivity (synthesis of 10o, 10p), although the alkynylation reaction (synthesis of 10q), as well as the
reactions of 2e (synthesis of 10r, 10s), were less stereoselective. In these cases, we were not able to
improve the diastereoselectivity by diminishing the reaction temperature.
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Scheme 4. Diastereoselective synthesis of dihydropyranones 10b-s
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O
F
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Ph
10f (85%)
Cl
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Ph
10e (93 %)
F
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OMe
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10c (65%)
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Ph
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OMe
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10m (69%)
10h (55%)
10i
dr = 72:28 (83%)
dr = 91:09 (81%)*
10j
dr = 85:15 (77%)
dr = 100:0 (72%)*
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10s
dr = 75:25 (56%)
Ph
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10n (62%)
Ph
10o (85%)
Ph
Ph
10q
dr= 85:15 (82%)
* Reactions carried out at -40 ºC. Unless otherwise stated, dr > 98:02
10r
dr= 78:22 (71%)
In a similar fashion, under the optimum reaction conditions for the formation of 16a (promotion with
Bu4NHSO4, rt), we extended our observations to other representative examples of potassium organotriꢀ
fluoroborates 11 in their reactions with 2a for the synthesis of various tetrahydropyranones 16 (Scheme
5). The new compounds 16bꢀe have been also obtained with high 2,3ꢀcisꢀ2,6ꢀcis diasereoselectivity.
Scheme 5. Diastereoselective synthesis of tetrahydropyranones 16b-e
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However, when the γꢀcarbon of the AR product 2 was fully substituted (Scheme 6, 2f – 2i, R2 ≠ H), the
outcome of the reaction with potassium organotrifluoroborates 11 changed drastically. Instead of the
expected dihydropyranones 10 or tetrahydropyranones 12, the reaction gave rise to the 1,4ꢀdicarbonyl
compounds 13.15 The reaction was selective for αꢀfunctionalization adjacent to the hydroxymethylcarꢀ
bonyl group. As observed for 13a, this result was independent of the method of activation (13a: TFAA,
80%; HBF4, 62%; Bu4NHSO4, 75%). Under the best conditions found for 13a (TFAA activation) the
reaction was extended to several other examples (Scheme 6).
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Scheme 6. Regioselective synthesis of 1,4-dicarbonyl compounds 13a-h
The reactions of potassium organotrifluoroborates 11 with the AR products 2 can be understood
(Scheme 7) by considering the direct conjugate addition to the enone moiety versus addition to the oxoꢀ
nium I that results from dehydroxylation.22
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Scheme 7. Proposed Reaction Course.
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In the presence of TFAA or HBF4, formation of the oxonium I is expected to be easy. Direct addition of
11 to the electrophilic γꢀcarbon in I accounts for the formation of dihydropyranones 10.27 The relative
stereochemistry of the final products 10 is governed by trans addition to the most bulky group (L) on
the starting material. This type of reaction would be hindered for R1 ≠ H. On the other hand, organotriꢀ
fluoroborates are known to be in equilibrium with organodifluoroboranes under a variety of circumꢀ
stances.28,29 Thus, under reaction conditions that do not favor formation of I (Bu4NHSO4), coordination
of a trivalent boron species to the OH group in 2 may trigger the conjugate addition reaction that leads
to tetrahydropyranones 12. This type of addition is presumed to take place from the βꢀface on a reactive
conformation with the most bulky group (L) at a pseudoequatorial position.30 The formation of the 1,4ꢀ
dicarbonyl compounds 13 can be understood by an OHꢀtriggered conjugate addition to the open chain
intermediates II, which may be in equilibrium with 2 (R1 ≠ H).31
Finally, we have considered the application of this methodology to the oneꢀpot synthesis of highly funcꢀ
tionalized pyrroles (Scheme 8).16 Thus, reaction of 2a or 2j with compounds 11 in the presence of
Bu4NHSO4 followed by the addition of benzylamine gave rise to pyrroles 14, whereas reaction of 2f or
2g with compounds 11 in the presence of TFAA followed by the addition of benzylamine gave rise to
pyrroles 15 in good yields. Both types of transformations were tolerant with the presence of a free OH
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group. It is worth mentioning the complementary relative disposition of the βꢀsubstituent and the αꢀ
hydroxyalkyl chain in pyrroles 14 (2,4ꢀrelative disposition) and 15 (2,3ꢀrelative disposition).
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Scheme 8. Synthesis of pyrroles 14 and 15
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In conclusion, the results presented in this paper put forward new valorizations of Achmatowicz rearꢀ
rangement products 2 using potassium organotrifluoroborates 11 as reagents in the absence of transitionꢀ
metals. The substitution pattern at position γ of the starting material 2 is crucial in determining the
course of the reaction. When the γꢀcarbon is fully substituted, the reaction leads to 1,4ꢀdicarbonyl comꢀ
pounds 13 independently of the reaction conditions. Compounds 13 show the particular feature of funcꢀ
tionalization in αꢀposition to the carbonyl group of a hydroxymethylcarbonyl group. When the γꢀcarbon
of 2 is tertiary, the reaction can be controlled to obtain selectively the dihydropyranones 10 (TFAAꢀ
promotion, 2,6ꢀtrans) or the tetrahydropyranones 12 (Bu4NHSO4ꢀpromotion, 2,3ꢀcisꢀ2,6ꢀcis). Comꢀ
pounds 10, 12 and 13 are useful intermediates for the synthesis of an ample diversity of products. As an
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example, crude 12 and 13 have been transformed into functionalized pyrroles 14 and 15 bearing αꢀ
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hydroxyalkyl chains in a oneꢀpot operation.
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EXPERIMENTAL SECTION
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General information. Unless otherwise stated, all starting materials acids were commercially
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available researchꢀgrade chemicals and were used without further purification. Silica gel 60 F254 was
used for TLC, and the spots were detected with UV light (254 and/or 366 nm) and/or vanillin solution.
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Flash column chromatography was carried out on silica gel 60. HꢀNMR spectra were recorded at 300
or 500 MHz, 13CꢀNMR spectra were recorded at 75 or 125 MHz, and 19FꢀNMR spectra were recorded at
282 MHz, all of them in CDCl3, or acetoneꢀd6 solution.
Synthesis of 1aꢀg, 1i and 1j. 1ꢀ(Furanꢀ2ꢀyl)ethanol (1a),32 furanꢀ2ꢀyl(phenyl)methanol (1b),33 1ꢀ
(furanꢀ2ꢀyl)ꢀ2ꢀmethylpropanꢀ1ꢀol (1c),34 2ꢀ(furanꢀ2ꢀyl)ꢀ3ꢀmethylbutanꢀ2ꢀol (1d),35 1ꢀ(furanꢀ2ꢀyl)ꢀ1ꢀ
phenylethanol (1e),36 (5ꢀmethylfuranꢀ2ꢀyl)methanol (1f),37 (5ꢀphenylfuranꢀ2ꢀyl)methanol (1g),34 1ꢀ(5ꢀ
methylfuranꢀ2ꢀyl)ethanol (1i),38 and furanꢀ2ꢀylmethanol (1j)39 were synthetized following previous litꢀ
erature procedures.
(4,5-Dimethylfuran-2-yl)methanol (1h): 4,5ꢀDimethylfurfural (300 mg, 2.2 mmol) was disꢀ
solved in anhydrous methanol (1.3 mL) and sodium borohydride (163.4 mg, 4.5 mmol) was added at
0ºC. The mixture was stirred for 1 h at room temperature, water was then added, and the aqueous phase
was extracted with dichloromethane. The combined organic layers were dried over MgSO4 and filtered.
The solvent was evaporated and the crude product was purified via flash column chromatography on
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silica gel eluting with hexane:AcOEt 8:2 (260.6 mg, 94% yield). Yellow oil. H NMR (300 MHz,
13
CDCl3) δ: 6.05 (S, 1H), 4.50 (S, 2H), 2.19 (s, 3H), 1.91 (s, 3H), 1.76 (bs, 1H) ppm; C NMR (75 MHz,
CDCl3) δ 151.1, 147.7, 114.8, 111.4, 57.7, 11.5, 9.91 ppm. Anal. calcd. for C7H10O2: C, 66.65; H, 7.99.
Found: C, 66.69; H, 7.98.
Synthesis of 2aꢀc, 2f, 2g, 2i, and 2j. 6ꢀHydroxyꢀ2ꢀmethylꢀ2Hꢀpyranꢀ3(6H)ꢀone (2a),40 6ꢀ
hydroxyꢀ2ꢀphenylꢀ2Hꢀpyranꢀ3(6H)ꢀone (2b),41 6ꢀhydroxyꢀ2ꢀisopropylꢀ2Hꢀpyranꢀ3(6H)ꢀone (2c),41 6ꢀ
hydroxyꢀ6ꢀmethylꢀ2Hꢀpyranꢀ3(6H)ꢀone (2f),31 6ꢀhydroxyꢀ6ꢀphenylꢀ2Hꢀpyranꢀ3(6H)ꢀone (2g),41 6ꢀ
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hydroxyꢀ2,6ꢀdimethylꢀ2Hꢀpyranꢀ3(6H)ꢀone (2i),42 and 6ꢀhydroxyꢀ2Hꢀpyranꢀ3(6H)ꢀone (2j)43 were synꢀ
thetized following previous literature procedures.
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General procedure for the synthesis of 2d, 2e, and 2h. To a stirred solution of the furfuryl alcoꢀ
hol 1 (1 mmol) in DCM (8 mL) was added mꢀchloroperbenzoic acid (mCPBA, 1.5 mmol) at 0 °C. After
completion of the addition, the reaction was allowed to stir at 0 °C for 1 h. Evaporation of the solvent
gave the crude product which was purified via flash column chromatography on silica gel.
6-Hydroxy-2-isopropyl-2-methyl-2H-pyran-3(6H)-one (2d): Colorless oil. Major diastereomer.
1H NMR (300 MHz, CDCl3) δ: 6.83 (d, J = 10.3 Hz, 1H), 6.05 (d, J = 10.3 Hz, 1H), 5.70ꢀ5.69 (m, 1H),
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4.55 (bs, 1H), 2.15ꢀ2.06 (m, 1H), 1.34 (s, 3H), 0.90ꢀ0.83 (m, 6H) ppm. C NMR (75 MHz, CDCl3) δ:
1
200.0, 145.3, 126.9, 87.6, 84.3, 33.5, 21.9, 17.3, 16.3 ppm. Minor diastereomer. H NMR (300 MHz,
CDCl3) δ: 6.84 (d, J = 10.3 Hz, 1H), 6.03 (d, J = 10.3 Hz, 1H), 5.68ꢀ5.67 (m, 1H), 4.55 (bs, 1H), 2.28ꢀ
13
2.21 (m, 1H), 1.25 (s, 3H), 0.90ꢀ0.83 (m, 6H) ppm C NMR (75 MHz, CDCl3) δ: 200.1, 146.7, 127.4,
87.7, 83.8, 34.5, 18.9, 17.2, 16.1 ppm. Anal. calcd. for C9H14O3: C, 63.51; H, 8.29. Found: C, 63.58; H,
8.30.
6-Hydroxy-2-methyl-2-phenyl-2H-pyran-3(6H)-one (2e): White solid (m.p: 77ꢀ79ºC). Major
diastereomer. 1H NMR (300 MHz, CDCl3) δ: 7.36ꢀ7.33 (m, 5H), 6.79 (d, J = 10.3 Hz, J = 1.3 Hz, 1H),
6.20 (d, J = 10.3 Hz, J = 1.7 Hz, 1H), 5.42 (s, 1H), 3.24 (bs, 1H), 1.67 (s, 3H) ppm. 13C NMR (750
MHz, CDCl3) δ: 196.2, 147.4, 138.5, 128.9 (2C), 128.5, 128.4, 125.5 (2C), 88.6, 83.6, 27.8 ppm. Anal.
calcd. for C12H12O3: C, 70.57; H, 5.92. Found: C, 70.61; H, 5.92.
6-Hydroxy-5,6-dimethyl-2H-pyran-3(6H)-one (2h): Colorless oil. 1H NMR (300 MHz, CDCl3):
δ 5.90 (s, 1H), 4.48 (d, J = 16.9 Hz, 1H), 4.08 (d, J = 16.9 Hz, 1H ), 3.51 (bs, 1H), 2.04ꢀ2.03 (m, 3H),
1.61 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 195.5, 161.0, 124.4, 95.4, 66.6, 25.9, 19.9 ppm. Anal.
calcd. for C7H10O3: C, 59.14; H, 7.09. Found: C, 59.08; H, 7.08.
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General Procedure for the Synthesis of compounds 10 and 13, Conditions A: A stirred soluꢀ
tion of compound 2 (0.23 mmol, 1.0 equiv) and the corresponding potassium trifluoroborate 11 (0.28
mmol, 1.2 equiv) in DCM (1.4 mL, 6 mL/mmol) was cooled to ꢀ15ºC. After stirring for 5 min, TFAA
(0.23ꢀ0.52 mmol, 1.0 ꢀ 2.2 equiv) was added and the reaction mixture was allowed to warm to rt. Then,
the solvent was removed in vacuo and the crude product was purified by flash column chromatography
on silica gel.
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General Procedure for the Synthesis of compounds 10, Conditions B. A stirred solution of
compound 2 (0.23 mmol, 1.0 equiv) and the corresponding potassium transꢀstyryltrifluoroborate 11
(0.35 mmol, 1.5 equiv) in MeCN (2.3 mL, 10 mL/mmol) was cooled to 0ºC. After stirring for 5 min,
HBF4·OEt2 (0.35 mmol, 1.5 equiv) was added, and the solution was stirred at 0 ºC for 15 min. The reacꢀ
tion was quenched with water (15 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer
was dried with MgSO4 and concentrated. The crude product was purified by flash column chromatogꢀ
raphy on silica gel.
General Procedure for the Synthesis of compounds 16, Conditions C: A solution of comꢀ
pound 2 (0.23 mmol, 1.0 equiv), the corresponding potassium trifluoroborate 11 (0.35 mmol, 1.5 equiv)
and tetrabutylammonium hydrogenosulfate (0.12 mmol, 0.5 equiv) in DCM (4.6 mL, 20 mL/mmol) was
allowed to stir at rt for 24ꢀ48h. After reaction completion as determined by TLC analysis, the crude
mixture was cooled to 0ºC, and Ac2O (0.23 mmol, 1.0 equiv), DMAP (0.012 mmol, 5% mol) and Et3N
(0.47 mmol, 2.0 equiv) were added, and the reaction mixture was stirred at 0ºC for 1 h. Then, the mixꢀ
ture was concentrated and purified via flash column chromatography on silica gel.
General Procedure for the one-pot Synthesis of pyrroles 14: A solution of compound 2 (0.23
mmol, 1.0 equiv), the corresponding potassium trifluoroborate 11 (0.35 mmol, 1.5 equiv) and tetrabuꢀ
tylammonium hydrogenosulfate (0.12 mmol, 0.5 equiv) in DCM anh. (4.6 mL, 20 mL/mmol) was alꢀ
lowed to stir at rt for 24ꢀ48h. After reaction completion as determined by TLC analysis, the solvent was
removed in vacuo and the residue was redissolved in toluene (1.1 mL, 5 mL/mmol). Benzylamine (0.23
mmol, 1 equiv) and pꢀtoluenesulfonic acid (0.023 mmol, 0.1 equiv) were added and the mixture was
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stirred at rt. Then, the mixture was concentrated and purified via flash column chromatography on silica
gel.
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General Procedure for the one-pot Synthesis of pyrroles 15: A stirred solution of compound 2
(0.23 mmol, 1.0 equiv) and the corresponding potassium trifluoroborate 11 (0.28 mmol, 1.2 equiv) in
DCM (1.4 mL, 6 mL/mmol) was cooled to ꢀ15ºC. After stirring for 5 min, TFAA (0.23ꢀ0.52 mmol, 1.0 ꢀ
2.2 equiv) was added and the reaction mixture was allowed to warm to rt. Then, the solvent was reꢀ
moved in vacuo and the residue was redissolved in toluene (1.1 mL, 5 mL/mmol). Benzylamine (0.23
mmol, 1 equiv) and pꢀtoluenesulfonic acid (0.023 mmol, 0.1 equiv) were added and the mixture was
stirred at rt. Then, the mixture was concentrated and purified via flash column chromatography on silica
gel.
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(2R,6R)-2-Methyl-6-((E)-styryl)-2H-pyran-3(6H)-one (10a): Following general procedure for
the synthesis of compounds 10, Conditions A, starting from 2a (30.1 mg, 0.23 mmol, 1.0 equiv), potasꢀ
sium transꢀstyryltrifluoroborate 11a (59.0 mg, 0.28 mmol, 1.2 equiv) and TFAA (33 ꢀL, 0.23 mmol, 1.0
equiv) in DCM anh. (1.4 mL) for 1 h. The crude product was purified by flash column chromatography
on silica gel eluting with Hexane:AcOEt 8:2 to afford a colorless oil (45.1 mg, 90% yield). Following
general procedure for the synthesis of compounds 10, Conditions B, starting from 2a (30.3 mg, 0.23
mmol, 1.0 equiv), potassium transꢀstyryltrifluoroborate 11a (73.8 mg, 0.35 mmol, 1.5 equiv) and
HBF4·OEt2 (48ꢀL, 0.35 mmol, 1.5 equiv.) in MeCN anh. (2.3 mL). The crude product was purified by
flash column chromatography on silica gel eluting with Hexane:AcOEt 8:2 to afford a colorless oil (37.6
1
mg, 75% yield). H NMR (300 MHz, CDCl3): δ 7.17ꢀ7.39 (m, 5H), 7.00 (dd, J = 10.4 Hz, J = 3.5 Hz,
1H), 7.60 (d, J = 16.1 Hz, 1H), 6.24 (dd, J = 16.1 Hz, J = 6.2 Hz, 1H), 6.10 (dd, J = 10.4 Hz, J = 1.7 Hz,
13
1H), 5.01ꢀ5.08 (m, 1H), 4.34 (c. J = 6.8 Hz, 1H), 1.34 (d, J = 6.8 Hz, 3H) ppm. CꢀNMR (75 MHz,
CDCl3): δ 196.9, 148.9, 135.9, 134.6, 128.9, 128.6, 126.8, 126.3, 124.0, 72.8, 71.6, 15.6 ppm. Anal.
calcd. for C14H14O2: C, 78.48; H, 6.59. Found: C, 78.55; H, 6.58.
(2R,6R)-6-((E)-4-Fluorostyryl)-2-methyl-2H-pyran-3(6H)-one (10b): Following general proꢀ
cedure for the synthesis of compounds 10, Conditions A, starting from 2a (29.7 mg, 0.23 mmol, 1.0
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equiv), potassium 2ꢀ(4ꢀfluorophenyl)vinyltrifluoroborate 11b (64.1 mg, 0.28 mmol, 1.2 equiv) and
TFAA (33 ꢀL, 0.23 mmol, 1.0 equiv) in DCM anh. (1.4 mL) for 2 h. The crude product was purified by
flash column chromatography on silica gel eluting with Hexane:AcOEt 8:2 to afford a yellow oil (51.6
mg, 95% yield). 1H NMR (300 MHz, CDCl3): δ 7.34ꢀ7.42 (m, 2H), 6.97ꢀ7.09 (m, 3H), 6.63 (d, J = 16.1
Hz, 1H), 6.23 (dd, J = 16.1 Hz, J = 6.0 Hz, 1H), 6.16 (dd, J = 10.4 Hz, J = 1.8 Hz, 1H), 5.06ꢀ5.13 (m,
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1H), 4.40 (c. J = 6.8 Hz, 1H), 1.41 (d, J = 6.8 Hz, 3H) ppm. CꢀNMR (75 MHz, CDCl3): δ 196.8,
164.6, 161.3, 148.8, 133.4, 132.1, 132.0, 128.5, 128.4, 126.3, 123.8, 123.7, 116.0, 115.7, 72.9, 71.5,
15.6 ppm. Anal. calcd. for C14H13FO2: C, 72.40; H, 5.64. Found: C, 72.49; H, 5.62.
(2R,6R)-6-((E)-4-Methoxystyryl)-2-methyl-2H-pyran-3(6H)-one (10c): Following general proꢀ
cedure for the synthesis of compounds 10, Conditions A, starting from 2a (29.7 mg, 0.23 mmol, 1.0
equiv), potassium 2ꢀ(4ꢀmethoxyphenyl)vinyltrifluoroborate 11c (67.4 mg, 0.28 mmol, 1.2 equiv) and
TFAA (33 ꢀL, 0.23 mmol, 1.0 equiv) in DCM anh. (1.4 mL) for 2 h. The crude product was purified by
flash column chromatography on silica gel eluting with Hexane:AcOEt 8:2 to afford a yellow oil (37.2
mg, 65% yield). 1H NMR (500 MHz, CDCl3): δ 7.34 (d, J = 8.7 Hz, 2H), 7.06 (dd, J = 10.8 Hz, J = 4.3
Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.14ꢀ6.20 (m, 2H), 5.06ꢀ5.11 (m, 1H), 4.40
(c. J = 6.8 Hz, 1H), 3.82 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H) ppm. 13CꢀNMR (125 MHz, CDCl3): δ 197.0,
160.0, 149.2, 134.3, 128.7, 128.1, 126.2, 121.6, 114.3, 72.7, 71.8, 55.5, 15.6 ppm. Anal. calcd. for
C15H16O3: C, 73.75; H, 6.60. Found: C, 73.64; H, 6.58.
(2R,6S)-6-((E)-3-Chloroprop-1-en-1-yl)-2-methyl-2H-pyran-3(6H)-one (10d): Following genꢀ
eral procedure for the synthesis of compounds 10, Conditions A, starting from 2a (30.1 mg, 0.23 mmol,
1.0 equiv), potassium transꢀ2ꢀchloromethylvinyltrifluoroborate 11d (51.2 mg, 0.28 mmol, 1.2 equiv)
and TFAA (39 ꢀL, 0.28 mmol, 1.2 equiv) in DCM anh. (1.4 mL) for 2 h. The crude product was puriꢀ
fied by flash column chromatography on silica gel eluting with Hexane:AcOEt 8:2 to afford a colorless
1
oil (40.2 mg, 92% yield). H NMR (300 MHz, CDCl3): δ 6.96 (dd, J = 10.4 Hz, J = 3.4 Hz, 1H), 6.12
(dd, J = 10.4 Hz, J = 1.7 Hz, 1H), 5.86ꢀ6.01 (m, 2H), 4.93ꢀ5.00 (m, 1H), 4.32 (c. J = 6.8 Hz, 1H), 4.00ꢀ
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4.16 (m, 2H), 1.38 (d, J = 6.8 Hz, 3H) ppm. 13CꢀNMR (75 MHz, CDCl3): δ 196.5, 148.1, 130.7, 129.4,
126.3, 73.0, 70.4, 43.8, 15.4 ppm. Anal. calcd. for C9H11ClO2: C, 57.92; H, 5.94. Found: C, 57.99; H,
5.92.
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(2R,6R)-2-Methyl-6-((E)-3-phenylprop-1-en-1-yl)-2H-pyran-3(6H)-one (10e): Following genꢀ
eral procedure for the synthesis of compounds 10, Conditions A, starting from 2a (30.0 mg, 0.23 mmol,
1.0 equiv), potassium transꢀ3ꢀphenylꢀ1ꢀpropenꢀ1ꢀyltrifluoroborate 11e (63.0 mg, 0.28 mmol, 1.2 equiv)
and TFAA (39 ꢀL, 0.28 mmol, 1.2 equiv) in DCM anh. (1.4 mL) for 2 h. The crude product was puriꢀ
fied by flash column chromatography on silica gel eluting with Hexane:AcOEt 8:2 to afford a colorless
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oil (49.7 mg, 93% yield). H NMR (300 MHz, CDCl3): δ 7.05ꢀ7.31 (m, 5H), 6.89 (dd, J = 10.2 Hz, J =
3.4 Hz, 1H), 6.00 (dd, J = 10.2 Hz, J = 1.3 Hz, 1H), 5.87 (dt, J = 15.5 Hz, J = 16.7 Hz, 1H), 5.59 (dd, J
= 15.5 Hz, J = 6.7 Hz, 1H), 4.82ꢀ4.90 (m, 1H), 4.26 (c. J = 6.8 Hz, 1H), 3.37 (d, J = 6.7 Hz, 2H), 1.31
(d, J = 6.8 Hz, 3H) ppm. 13CꢀNMR (75 MHz, CDCl3): δ 197.0, 149.4, 139.3, 135.3, 128.7, 128.6, 126.5,
126.2, 125.9, 72.7, 71.3, 38.9, 15.5 ppm. Anal. calcd. for C15H16O2: C, 78.92; H, 7.06. Found: C, 78.90;
H, 7.07.
(2R,6S)-2-Methyl-6-phenyl-2H-pyran-3(6H)-one (10f): Following general procedure for the
synthesis of compounds 10, Conditions A, starting from 2a (29.5 mg, 0.23 mmol, 1.0 equiv), potassium
phenyltrifluoroborate 11f (51.7 mg, 0.28 mmol, 1.2 equiv) and TFAA (39 ꢀL, 0.28 mmol, 1.2 equiv) in
DCM anh. (1.4 mL) for 2 h. Then, a second equivalent of TFAA (33 ꢀL, 0.23 mmol, 1.0 equiv) was
added and the reaction mixture was allowed to warm to room temperature for 4 h. The crude product
was purified by flash column chromatography on silica gel eluting with Hexane:AcOEt 8:2 to afford a
colorless oil (37.4 mg, 85% yield). 1H NMR (300 MHz, CDCl3): δ 7.37ꢀ7.43 (m, 5H), 7.16 (dd, J = 10.4
Hz, J = 3.1 Hz, 1H), 6.23 (dd, J = 10.4 Hz, J = 1.9 Hz, 1H), 5.48ꢀ5.54 (m, 1H), 4.26 (c. J = 6.9 Hz, 1H),
13
1.40 (d, J = 6.9 Hz, 3H) ppm. CꢀNMR (75 MHz, CDCl3): δ 197.0, 149.3, 136.9, 129.0, 128.9, 128.2,
126.2, 73.3, 72.8, 15.4 ppm. Anal. calcd. for C12H12O2: C, 76.57; H, 6.43. Found: C, 76.62; H, 6.42.
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(2R,6S)-6-(4-Fluorophenyl)-2-methyl-2H-pyran-3(6H)-one (10g): Following general proceꢀ
dure for the synthesis of compounds 10, Conditions A, starting from 2a (29.9 mg, 0.23 mmol, 1.0
equiv), potassium 4ꢀfluorophenyltrifluoroborate 11g (56.8 mg, 0.28 mmol, 1.2 equiv) and TFAA (39
ꢀL, 0.28 mmol, 1.2 equiv) in DCM anh. (1.4 mL) for 2 h. Then, the mixture was cooled at 0ºC and a
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second equivalent of TFAA (33 ꢀL, 0.23 mmol, 1.0 equiv) was added and the reaction mixture was alꢀ
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lowed to warm to room temperature for 4 h. The crude product was purified by flash column chromaꢀ
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tography on silica gel eluting with Hexane:AcOEt 8:2 to afford a colorless oil (44.9 mg, 93% yield). H
NMR (300 MHz, CDCl3): δ 7.34ꢀ7.44 (m, 2H), 7.04ꢀ7.17 (m, 3H), 6.23 (dd, J = 10.4 Hz, J = 1.9 Hz,
13
1H), 5.46ꢀ5.50 (m, 1H), 4.23 (c. J = 6.8 Hz, 1H), 1.40 (d, J = 6.8 Hz, 3H) ppm. CꢀNMR (75 MHz,
CDCl3): δ 196.8, 164.7, 161.4, 148.9, 132.9, 132.8, 130.0, 129.9, 126.3, 116.0, 115.8, 73.3, 72.0, 15.4
ppm. Anal. calcd. for C12H11FO2: C, 69.89; H, 5.38. Found: C, 69.85; H, 5.37.
(2R,6S)-6-(2-Methoxyphenyl)-2-methyl-2H-pyran-3(6H)-one (10h): Following general proceꢀ
dure for the synthesis of compounds 10, Conditions A, starting from 2a (30.1 mg, 0.23 mmol, 1.0
equiv), potassium 2ꢀmehtoxyphenyltrifluoroborate 11h (60.1 mg, 0.28 mmol, 1.2 equiv) and TFAA (33
ꢀL, 0.23 mmol, 1.0 equiv) in DCM anh. (1.4 mL) for 3 h. The crude product was purified by flash colꢀ
umn chromatography on silica gel eluting with Hexane:AcOEt 8:2 to afford a yellow oil (28.1 mg, 55%
yield). 1H NMR (300 MHz, CDCl3): δ 7.30ꢀ7.40 (m, 2H), 7.08 (dd, J = 10.3 Hz, J = 2.8 Hz, 1H), 6.92ꢀ
7.01 (m, 2H), 6.17 (dd, J = 10.4 Hz, J = 2.2 Hz, 1H), 5.88ꢀ5.94 (m, 1H), 4.38 (c. J = 7.0 Hz, 1H), 3.89
(s, 3H), 1.43 (d, J = 7.0 Hz, 3H) ppm. 13CꢀNMR (75 MHz, CDCl3): δ 197.5, 157.1, 150.2, 130.0, 128.3,
125.5, 125.2, 120.7, 111.1, 74.1, 66.8, 55.8, 15.4 ppm. Anal. calcd. for C13H14O3: C, 71.54; H, 6.47.
Found: C, 71.61; H, 6.45.
(2R,6S)-2-Methyl-6-(phenylethynyl)-2H-pyran-3(6H)-one (10i): Following general procedure
for the synthesis of compounds 10, Conditions A, starting from 2a (30.1 mg, 0.23 mmol, 1.0 equiv),
potassium phenylethylnyltrifluoroborate 11i (58.5 mg, 0.28 mmol, 1.2 equiv) and TFAA (33 ꢀL, 0.23
mmol, 1.0 equiv) in DCM anh. (1.4 mL) at ꢀ40ºC for 3 h. The crude product was purified by flash colꢀ
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umn chromatography on silica gel eluting with Hexane:AcOEt 8:2 to afford a colorless oil (40.2 mg,
81% yield, dr 91:09). 1H NMR (300 MHz, CDCl3): δ 7.43ꢀ7.50 (m, 2H), 7.32ꢀ7.38 (m, 3H), 7.03 (dd, J
= 10.2 Hz, J = 4.2 Hz, 1H), 6.11 (dd, J = 10.2 Hz, J = 1.5 Hz, 1H), 5.37 (dd, J = 4.2 Hz, J = 1.5 Hz,
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1H), 4.67 (c. J = 6.7 Hz, 1H), 1.44 (d, J = 6.7 Hz, 3H) ppm. CꢀNMR (75 MHz, CDCl3): δ 196.4,
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146.3, 132.1, 129.2, 128.5, 125.8, 121.8, 87.9, 81.8, 73.3, 63.4, 15.4 ppm. Anal. calcd. for C14H12O2: C,
79.22; H, 5.70. Found: C, 79.29; H, 5.69.
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(2R,6S)-6-(Cyclohexylethynyl)-2-methyl-2H-pyran-3(6H)-one (10j): Following general proceꢀ
dure for the synthesis of compounds 10, Conditions A, starting from 2a (30.4 mg, 0.23 mmol, 1.0
equiv), potassium cyclohexylethylnyltrifluoroborate 11j (60.1 mg, 0.28 mmol, 1.2 equiv) and TFAA (33
ꢀL, 0.23 mmol, 1.0 equiv) in DCM anh. (1.4 mL) at ꢀ40ºC for 3 h. The crude product was purified by
flash column chromatography on silica gel eluting with Hexane:AcOEt 8:2 to afford a colorless oil (37.3
1
mg, 72% yield). H NMR (300 MHz, CDCl3): δ 6.92 (dd, J = 10.1 Hz, J = 4.2 Hz, 1H), 6.00 (dd, J =
10.1 Hz, J = 1.4 Hz, 1H), 5.09ꢀ5.17 (m, 1H), 4.56 (c. J = 6.7 Hz, 1H), 2.36ꢀ2.47 (m, 1H), 1.40 (d, J =
13
6.7 Hz, 3H), 1.18ꢀ1.84 (m, 10H) ppm. CꢀNMR (75 MHz, CDCl3): δ 196.7, 147.4, 125.1, 93.2, 72.9,
63.1, 32.5, 32.4, 29.2, 25.9, 24.9, 15.3 ppm. Anal. calcd. for C14H18O2: C, 77.03; H, 8.31. Found: C,
77.00; H, 8.25.
(2S,6S)-2-Phenyl-6-((E)-styryl)-2H-pyran-3(6H)-one (10k): Following general procedure for
the synthesis of compounds 10, Conditions A, starting from 2b (30.0 mg, 0.16 mmol, 1.0 equiv), potasꢀ
sium transꢀstyryltrifluoroborate 11a (39.9 mg, 0.19 mmol, 1.2 equiv) and TFAA (23 ꢀL, 0.16 mmol, 1.0
equiv) in DCM anh. (1.0 mL) for 1 h. The crude product was purified by flash column chromatography
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on silica gel eluting with Hexane:AcOEt 8:2 to afford a colorless oil (28.7 mg, 65% yield). H NMR
(300 MHz, CDCl3): δ 7.43ꢀ7.31 (m, 10H), 7.07 (dd, J = 10.4 Hz, J = 2.8 Hz, 1H), 6.73 (d, J = 16.0 Hz,
1H), 6.28ꢀ6.36 (m, 2H), 5.34 (s, 1H), 5.04ꢀ5.06 (m, 1H) ppm. 13CꢀNMR (75 MHz, CDCl3): δ 194.4,
149.5, 136.0, 134.8, 134.4, 128.9 (2C), 128.7 (3C), 128.6, 127.7 (2C), 127.0, 126.9 (2C), 124.6, 79.4,
71.1 ppm. Anal. calcd. for C19H16O2: C, 82.58; H, 5.84. Found: C, 82.51; H, 5.86.
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(2S,6R)-2,6-Diphenyl-2H-pyran-3(6H)-one (10l): Following general procedure for the synthesis
of compounds 10, Conditions A, starting from 2b (30.0 mg, 0.16 mmol, 1.0 equiv), potassium phenyltriꢀ
fluoroborate 11f (35.0 mg, 0.19 mmol, 1.2 equiv) and TFAA (23 ꢀL, 0.16 mmol, 1.0 equiv) in DCM
anh. (1.0 mL) for 24 h. The crude product was purified by flash column chromatography on silica gel
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eluting with Hexane:AcOEt 8:2 to afford a colorless oil (22.8 mg, 57% yield). H NMR (300 MHz,
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CDCl3): δ 7.41ꢀ7.39 (m, 10H), 7.10 (dd, J = 10.4 Hz, J = 2.4 Hz, 1H), 6.37 (dd, J = 10.4 Hz, J = 2.4 Hz,
13
1H), 5.35 (t, J = 2.4 Hz, 1H), 5.31 (s, 1H) ppm. CꢀNMR (75 MHz, CDCl3): δ 194.5, 150.3, 137.8,
134.4, 129.1 (2C), 129.0, 128.8 (2C), 128.7, 127.9 (2C), 127.6 (2C), 126.8, 79.9, 72.3 ppm. Anal. calcd.
for C17H14O2: C, 81.58; H, 5.64. Found: C, 81.55; H, 5.71.
(2S,6S)-2-Isopropyl-6-((E)-styryl)-2H-pyran-3(6H)-one (10m): Following general procedure
for the synthesis of compounds 10, Conditions A, starting from 2c (29.4 mg, 0.19 mmol, 1.0 equiv),
potassium transꢀstyryltrifluoroborate 11a (47.5 mg, 0.23 mmol, 1.2 equiv) and TFAA (26 ꢀL, 0.19
mmol, 1.0 equiv) in DCM anh. (1.1 mL) for 1 h. The crude product was purified by flash column chroꢀ
matography on silica gel eluting with Hexane:AcOEt 8:2 to afford a colorless oil (31.7 mg, 69% yield).
1H NMR (300 MHz, CDCl3): δ 7.41ꢀ7.28 (m, 5H), 7.03 (dd, J = 10.4 Hz, J = 3.4 Hz, 1H), 6.66 (d, J =
16.2 Hz, 1H), 6.26 (dd, J = 16.2 Hz, J = 6.0 Hz, 1H), 6.14 (dd, J = 10.4 Hz, J = 1.9 Hz, 1H), 5.10ꢀ5.12
(m, 1H), 4.00 (d, J = 5.3 Hz, 1H), 2.41ꢀ2.30 (m, 1H), 1.01 (d, J = 6.9 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H)
13
ppm. CꢀNMR (75 MHz, CDCl3): δ 196.4, 148.6, 136.0, 134.2, 128.8 (2C), 128.5, 126.9, 126.8 (2C),
124.5, 81.4, 71.5, 28.4, 19.0, 17.7 ppm. Anal. calcd. for C16H18O2: C, 79.31; H, 7.49. Found: C, 79.20;
H, 7.37.
(2S,6R)-2-Isopropyl-6-phenyl-2H-pyran-3(6H)-one (10n): Following general procedure for the
synthesis of compounds 10, Conditions A, starting from 2c (29.1 mg, 0.19 mmol, 1.0 equiv), potassium
phenyltrifluoroborate 11f (41.2 mg, 0.22 mmol, 1.2 equiv) and TFAA (26 ꢀL, 0.19 mmol, 1.0 equiv) in
DCM anh. (1.1 mL) for 24 h. The crude product was purified by flash column chromatography on silica
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gel eluting with Hexane:AcOEt 8:2 to afford a colorless oil (25.5 mg, 62% yield). H NMR (300 MHz,
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CDCl3): δ 7.40ꢀ7.39 (m, 5H), 7.13 (dd, J = 10.4 Hz, J = 3.1 Hz, 1H), 6.20 (dd, J = 10.4 Hz, J = 2.1 Hz,
1H), 5.51ꢀ5.49 (m, 1H), 3.80 (d, J = 6.4 Hz, 1H), 2.38ꢀ2.27 (m, 1H), 1.03 (d, J = 6.7 Hz, 3H), 0.94 (d, J
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= 6.9 Hz, 3H) ppm. CꢀNMR (75 MHz, CDCl3): δ 196.4, 149.0, 137.6, 128.9 (2C), 128.8, 128.0 (2C),
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126.7, 82.1, 72.6, 28.1, 18.8, 18.2 ppm. Anal. calcd. for C14H16O2: C, 77.75; H, 7.46. Found: C, 77.73;
H, 7.58.
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(2S,6S)-2-Isopropyl-2-methyl-6-((E)-styryl)-2H-pyran-3(6H)-one (10o): Following general
procedure for the synthesis of compounds 10, Conditions A, starting from 2d (29.9 mg, 0.18 mmol, 1.0
equiv), potassium transꢀstyryltrifluoroborate 11a (44.3 mg, 0.21 mmol, 1.2 equiv) and TFAA (25 ꢀL,
0.18 mmol, 1.0 equiv) in DCM anh. (1.1 mL) for 1 h. The crude product was purified by flash column
chromatography on silica gel eluting with Hexane:AcOEt 8:2 to afford a colorless oil (39.2 mg, 85%
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yield). H NMR (300 MHz, CDCl3): δ 7.42ꢀ7.28 (m, 5H), 6.84 (dd, J = 10.3 Hz, J = 1.5 Hz, 1H), 6.72
(d, J = 15.9 Hz, 1H), 6.20 (dd, J = 15.9 Hz, J = 7.0 Hz, 1H), 6.00 (dd, J = 10.3 Hz, J = 2.5 Hz, 1H),
5.03ꢀ5.06 (m, 1H), 2.32ꢀ2.23 (m, 1H), 1.26 (s, 3H), 1.07 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H)
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ppm. CꢀNMR (75 MHz, CDCl3): δ 198.7, 148.2, 136.2, 133.1, 128.7 (2C), 128.3, 126.8 (3C), 124.7,
83.6, 70.1, 29.4, 17.3, 17.0, 16.3 ppm. Anal. calcd. for C17H20O2: C, 79.65; H, 7.86. Found: C, 79.74; H,
7.76.
(2S,6R)-2-Isopropyl-2-methyl-6-phenyl-2H-pyran-3(6H)-one (10p): Following general proceꢀ
dure for the synthesis of compounds 10, Conditions A, starting from 2d (29.5 mg, 0.17 mmol, 1.0
equiv), potassium phenyltrifluoroborate 11f (38.3 mg, 0.21 mmol, 1.2 equiv) and TFAA (24 ꢀL, 0.17
mmol, 1.0 equiv) in DCM anh. (1.0 mL) for 24 h. The crude product was purified by flash column
chromatography on silica gel eluting with Hexane:AcOEt 8:2 to afford a colorless oil (22.7 mg, 58%
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yield). H NMR (300 MHz, CDCl3): δ 7.40ꢀ7.36 (m, 5H), 6.87 (dd, J = 10.3 Hz, J = 1.7 Hz, 1H), 6.04
(dd, J = 10.3 Hz, J = 2.6 Hz, 1H), 5.40ꢀ5.42 (m, 1H), 2.42ꢀ2.32 (m, 1H), 1.25 (s, 3H), 1.09 (d, J = 6.8
Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H) ppm. 13CꢀNMR (75 MHz, CDCl3): δ 198.7, 149.2, 139.5, 129.0 (2C),
128.7, 127.5 (2C), 124.3, 84.0, 71.6, 29.2, 17.4, 17.0, 16.0 ppm. Anal. calcd. for C15H18O2: C, 78.23; H,
7.88. Found: C, 78.15; H, 7.93.
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(2S,6R)-2-Isopropyl-2-methyl-6-(phenylethynyl)-2H-pyran-3(6H)-one (10q): Following genꢀ
eral procedure for the synthesis of compounds 10, Conditions A, starting from 2d (30.1 mg, 0.18 mmol,
1.0 equiv), potassium phenylethylnyltrifluoroborate 11i (44.2 mg, 0.28 mmol, 1.2 equiv) and TFAA (25
ꢀL, 0.18 mmol, 1.0 equiv) in DCM anh. (1.1 mL) at ꢀ40ºC for 3 h. The crude product was purified by
flash column chromatography on silica gel eluting with Hexane:AcOEt 8:2 to afford a colorless oil (37.5
mg, 82% yield, dr = 85:15). 1H NMR (300 MHz, CDCl3): δ 7.48ꢀ7.46 (m, 2H), 7.33ꢀ7.31 (m, 3H), 6.93
(dd, J = 10.2 Hz, J = 2.4 Hz, 1H), 6.05 (dd, J = 10.2 Hz, J = 2.5 Hz, 1H), 5.45 (t, J = 2.5Hz, 1H), 2.22
(heptet, J = 6.8Hz, 1H), 1.37 (s, 3H), 1.03 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H) ppm. 13CꢀNMR
(75 MHz, CDCl3): δ 198.1, 145.7, 132.0 (2C), 129.0, 128.4 (2C), 125.1, 122.1, 86.4, 85.0, 84.4, 60.6,
30.6, 17.9, 17.2, 16.8 ppm. Anal. calcd. for C17H18O2: C, 80.28; H, 7.13. Found: C, 80.30; H, 7.24.
(2S,6S)-2-Methyl-2-phenyl-6-((E)-styryl)-2H-pyran-3(6H)-one (10r): Following general proꢀ
cedure for the synthesis of compounds 10, Conditions A, starting from 2e (30.0 mg, 0.15 mmol, 1.0
equiv), potassium transꢀstyryltrifluoroborate 11a (37.1 mg, 0.18 mmol, 1.2 equiv) and TFAA (21 ꢀL,
0.15 mmol, 1.0 equiv) in DCM anh. (0.9 mL) for 1 h. The crude product was purified by flash column
chromatography on silica gel eluting with Hexane:AcOEt 8:2 to afford the desired compound as a sepaꢀ
rable mixture of diastereomers (30.9 mg, 72% yield, dr = 78:22).
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(2S,6S)-2-Methyl-2-phenyl-6-((E)-styryl)-2H-pyran-3(6H)-one. Mayor diastereomer. Colorless
oil. 1H NMR (300 MHz, CDCl3): δ 7.43ꢀ7.30 (m, 10H), 6.80ꢀ6.71 (m, 2H), 6.28ꢀ6.17 (m, 2H), 4.80ꢀ4.77
(m, 1H), 1.66 (s, 3H) ppm. 13CꢀNMR (75 MHz, CDCl3): δ 196.4, 149.4, 138.6, 136.2, 133.3, 128.8
(2C), 128.7 (2C), 128.4, 128.3, 126.8 (2C), 126.2, 126.0, 125.8 (2C), 83.1, 71.0, 27.5 ppm. Anal. calcd.
for C20H18O2: C, 82.73; H, 6.25. Found: C, 82.86; H, 6.18.
(2R,6S)-2-Methyl-2-phenyl-6-((E)-styryl)-2H-pyran-3(6H)-one. Minor diastereomer. Colorless
oil. 1H NMR (300 MHz, CDCl3): δ 7.57 (d, J = 8.0 Hz, 2H), 7.38ꢀ7.29 (m, 8H), 7.00 (dd, J = 10.3 Hz, J
= 1.9 Hz, 1H), 6.73 (d, J = 16.0 Hz, 1H), 6.21ꢀ6.10 (m, 2H), 5.25 (d, J = 7.1 Hz, 1H), 1.80 (s, 3H) ppm.
13CꢀNMR (75 MHz, CDCl3): δ 196.8, 148.9, 141.7, 136.2, 133.3, 128.7 (2C), 128.3, 128.1 (2C), 127.9,
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126.8 (2C), 126.6 (2C), 126.4, 125.6, 81.9, 71.2, 22.5 ppm. Anal. calcd. for C20H18O2: C, 82.73; H,
6.25. Found: C, 82.80; H, 6.17.
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(2S,6R)-2-Methyl-2,6-diphenyl-2H-pyran-3(6H)-one (10s): Following general procedure for
the synthesis of compounds 10, Conditions A, starting from 2e (30.0 mg, 0.15 mmol, 1.0 equiv), potasꢀ
sium phenyltrifluoroborate 11f (33.1 mg, 0.18 mmol, 1.2 equiv) and TFAA (21 ꢀL, 0.15 mmol, 1.0
equiv) in DCM anh. (0.9 mL) for 24 h. The crude product was purified by flash column chromatography
on silica gel eluting with Hexane:AcOEt 8:2 to afford the desired compound as a separable mixture of
diastereomers (22.2 mg, 56% yield, dr = 75:25).
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(2S,6R)-2-Methyl-2,6-diphenyl-2H-pyran-3(6H)-one. Colorless oil Mayor diastereomer. H
NMR (300 MHz, CDCl3): δ 7.40ꢀ7.38 (m, 10H), 6.82 (dd, J = 10.3 Hz, J = 1.6 Hz, 1H), 6.22 (dd, J =
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10.4 Hz, J = 2.7 Hz, 1H), 5.14ꢀ5.13 (m, 1H), 1.67 (s, 3H) ppm. CꢀNMR (75 MHz, CDCl3): δ 196.4,
150.3, 139.1, 138.6, 129.0 (2C), 128.8 (2C), 128.7, 128.3, 127.5 (2C), 125.9 (2C), 125.8, 83.4, 72.9,
27.6 ppm. Anal. calcd. for C18H16O2: C, 81.79; H, 6.10. Found: C, 81.64; H, 6.02.
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(2R,6R)-2-Methyl-2,6-diphenyl-2H-pyran-3(6H)-one. Colorless oil. Minor diastereomer. H
NMR (300 MHz, CDCl3): δ 7.60 (d, J = 7.6 Hz, 2H), 7.49ꢀ7.29 (m, 8H), 7.03 (dd, J = 10.3 Hz, J = 1.6
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Hz, 1H), 6.20 (dd, J = 10.3 Hz, J = 2.4 Hz, 1H), 5.65 (s, 1H), 1.87 (s, 3H) ppm. CꢀNMR (75 MHz,
CDCl3): δ 196.8, 149.9, 141.3, 139.3, 129.1 (2C), 128.7, 128.1 (2C), 127.8, 127.5 (2C), 126.7 (2C),
125.4, 82.2, 72.2, 21.5 ppm. Anal. calcd. for C18H16O2: C, 81.79; H, 6.10. Found: C, 81.85; H, 6.00.
(E)-1-Hydroxy-3-styrylhexane-2,5-dione (13a): Following general procedure for the synthesis
of compounds 13, Conditions A, starting from 2f (30.0 mg, 0.23 mmol, 1.0 equiv), potassium transꢀ
styryltrifluoroborate 11a (59.1 mg, 0.28 mmol, 1.2 equiv) and TFAA (32 ꢀL, 0.23 mmol, 1.0 equiv) in
DCM anh. (1.4 mL) for 1 h. The crude product was purified by flash column chromatography on silica
gel eluting with Hexane:AcOEt 8:2 (42.7 mg, 80% yield). 1H NMR (300 MHz, CDCl3): δ 7.33ꢀ7.27 (m,
5H), 6.56 (d, J = 15.8 Hz, 1H), 6.00 (dd, J = 15.8 Hz, J = 9.3 Hz, 1H), 4.48 (s, 2H), 3.75 (td, J = 9.5 Hz,
J = 3.8 Hz, 1H), 3.29 (dd, J = 18.3 Hz, J = 9.8 Hz, 1H), 2.92 (bs, 1H), 2.74 (dd, J = 18.3 Hz, J = 3.8 Hz,
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1H), 2.17 (s, 3H) ppm. CꢀNMR (75 MHz, CDCl3): δ 209.5, 206.3, 136.1, 134.7, 128.8 (2C), 128.4,
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126.5 (2C), 124.7, 67.6, 47.4, 45.5, 29.8 ppm. Anal. calcd. for C14H16O3: C, 72.39; H, 6.94. Found: C,
72.33; H, 6.80.
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1-Hydroxy-3-phenylhexane-2,5-dione (13b): Following general procedure for the synthesis of
compounds 13, Conditions A, starting from 2f (30.0 mg, 0.23 mmol, 1.0 equiv), potassium phenyltriꢀ
fluoroborate 11f (51.5 mg, 0.28 mmol, 1.2 equiv) and TFAA (32 ꢀL, 0.23 mmol, 1.0 equiv) in DCM
anh. (1.4 mL) for 1 h. The crude product was purified by flash column chromatography on silica gel
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eluting with Hexane:AcOEt 8:2 (21.3 mg, 45% yield). H NMR (300 MHz, CDCl3): δ 7.33ꢀ7.28 (m,
3H), 7.21ꢀ7.18 (m 2H), 4.42 (d, J = 18.9 Hz, 1H), 4.23 (d, J = 18.9 Hz, 1H), 4.17 (dd, J = 10.7 Hz, J =
3.6 Hz, 1H), 3.55 (dd, J = 18.3 Hz, J = 10.7 Hz, 1H), 2.86 (bs, 1H), 2.74 (dd, J = 18.3 Hz, J = 3.6 Hz,
1H), 2.17 (s, 3H) ppm. 13CꢀNMR (75 MHz, CDCl3): δ 208.9, 206.6, 136.7, 129.4 (2C), 128.2 (2C),
128.1, 67.4, 49.3, 46.9, 29.8 ppm. Anal. calcd. for C12H14O3: C, 69.88; H, 6.84. Found: C, 69.99; H,
6.95.
(E)-5-Hydroxy-1-phenyl-3-styrylpentane-1,4-dione (13c): Following general procedure for the
synthesis of compounds 13, Conditions A, starting from 2g (29.7 mg, 0.16 mmol, 1.0 equiv), potassium
transꢀstyryltrifluoroborate 11a (39.4 mg, 0.19 mmol, 1.2 equiv) and TFAA (22 ꢀL, 0.16 mmol, 1.0
equiv) in DCM anh. (1.0 mL) 1 h. The crude product was purified by flash column chromatography on
silica gel eluting with Hexane:AcOEt 8:2 (38.6 mg, 82% yield). 1H NMR (500 MHz, CDCl3): δ 7.96 (d,
J = 8.6 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.9 Hz, 2H), 7.36ꢀ7.28 (m, 5H), 6.63 (d, J = 15.8
Hz, 1H), 6.12 (dd, J = 15.8 Hz, J = 9.0 Hz, 1H), 4.59 (q, J = 19.0 Hz, 2H), 3.95 (td, J = 9.5 Hz, J = 3.4
Hz, 1H), 3.86 (dd, J = 17.8 Hz, J = 9.5 Hz, 1H), 3.31 (dd, J = 17.8 Hz, J = 3.4 Hz, 1H), 3.00 (bs, 1H),
ppm. 13CꢀNMR (125 MHz, CDCl3): δ 209.6, 197.7, 136.2, 136.1 134.7, 133.7, 128.9 (4C), 128.4, 128.3
(2C); 126.6 (2C); 125.1, 67.7, 47.5, 41.3 ppm. Anal. calcd. for C19H18O3: C, 77.53; H, 6.16. Found: C,
77.67; H, 6.02.
5-Hydroxy-1,3-diphenylpentane-1,4-dione (13d): Following general procedure for the synthesis
of compounds 13, Conditions A, starting from 2g (29.9 mg, 0.16 mmol, 1.0 equiv), potassium phenyltriꢀ
fluoroborate 11f (34.8 mg, 0.19 mmol, 1.2 equiv) and TFAA (22 ꢀL, 0.16 mmol, 1.0 equiv) in DCM
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anh. (1.0 mL) 1 h. The crude product was purified by flash column chromatography on silica gel eluting
with Hexane:AcOEt 8:2 (34.7 mg, 81% yield). 1H NMR (300 MHz, CDCl3): δ 7.95 (d, J = 8.1 Hz, 2H),
7.58 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.36ꢀ7.27 (m, 5H), 4.58 (d, J = 18.8 Hz, 1H), 4.40ꢀ4.30
(m, 2H), 4.11 (dd, J = 18.0 Hz, J = 10.6 Hz, 1H), 3.32 (dd, J = 18.0 Hz, J = 3.4 Hz, 1H), 3.17 (bs, 1H)
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ppm. CꢀNMR (75 MHz, CDCl3): δ 209.0, 197.9, 136.9, 136.1, 133.7, 129.5 (2C), 128.8 (2C), 128.3
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(2C), 128.2 (2C); 128.1, 67.5, 49.4, 42.8 ppm. Anal. calcd. for C17H16O3: C, 76.10; H, 6.01. Found: C,
75.93; H, 5.86.
(E)-6-Hydroxy-4-styrylheptane-2,5-dione (13e): Following general procedure for the synthesis
of compounds 13, Conditions A, starting from 2i (29.8 mg, 0.21 mmol, 1.0 equiv), potassium transꢀ
styryltrifluoroborate 11a (52.9 mg, 0.25 mmol, 1.2 equiv) and TFAA (29 ꢀL, 0.21 mmol, 1.0 equiv) in
DCM anh. (1.3 mL) for 1 h. The crude product was purified by flash column chromatography on silica
gel eluting with Hexane:AcOEt 8:2 to afford the desired compound as a mixture of diastereomers (66:
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33 mixture, 34.1 mg, 66% yield). Mayor diastereomer. Colorless oil H NMR (300 MHz, CDCl3): δ
7.32ꢀ7.28 (m, 5H), 6.56 (d, J = 15.9 Hz, 1H), 5.98 (dd, J = 15.9 Hz, J = 9.4 Hz, 1H), 4.50 (q, J = 7.1,
1H), 3.75 (td, J = 9.7 Hz, J = 4.0 Hz, 1H), 3.40 (bs, 1H), 3.30 (dd, J = 18.3 Hz, J = 10.0 Hz, 1H), 2.66
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(dd, J = 18.3 Hz, J = 3.8 Hz, 1H), 2.18 (s, 3H), 1.50 (d, J = 7.1 Hz, 3H) ppm. CꢀNMR (75 MHz,
CDCl3): δ 212.3, 206.6, 136.1, 134.7, 128.8 (2C), 128.3, 126.5 (2C), 125.2, 71.8, 45.9, 45.3, 29.9, 20.3
ppm. Anal. calcd. for C15H18O3: C, 73.15; H, 7.37. Found: C, 73.22; H, 7.39.
(E)-1-Hydroxy-4-methyl-3-styrylhexane-2,5-dione (13f): Following general procedure for the
synthesis of compounds 13, Conditions A, starting from 2h (30.0 mg, 0.21 mmol, 1.0 equiv), potassium
transꢀstyryltrifluoroborate 11a (53.3 mg, 0.25 mmol, 1.2 equiv) and TFAA (29 ꢀL, 0.21 mmol, 1.0
equiv) in DCM anh. (1.3 mL) 1 h. The crude product was purified by flash column chromatography on
silica gel eluting with Hexane:AcOEt 8:2 to afford the desired compound as a mixture of diastereomers
(90: 10 mixture, 41.3 mg, 80% yield). Mayor diastereomer. Colorless oil. 1H NMR (300 MHz, CDCl3):
δ 7.34ꢀ7.29 (m, 5H), 6.60 (d, J = 15.7 Hz, 1H), 6.00 (dd, J = 15.7 Hz, J = 10.0 Hz, 1H), 4.43 (s, 2H),
3.52 (t, J = 10.0 Hz, 1H), 3.28ꢀ3.17 (m, 1H), 2.86 (bs, 1H), 2.22 (s, 3H), 1.16 (d, J = 7.5 Hz, 3H) ppm.
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13CꢀNMR (75 MHz, CDCl3): δ 211.4, 210.2, 136.2, 136.1, 128.9 (2C), 128.4, 126.6 (2C), 124.4, 67.5,
54.9, 48.5, 28.7, 14.9 ppm. Anal. calcd. for C15H18O3: C, 73.15; H, 7.37. Found: C, 73.19; H, 7.21.
5-Hydroxy-3-(4-methoxyphenyl)-1-phenylpentane-1,4-dione (13g): Following general proceꢀ
dure for the synthesis of compounds 13, Conditions A, starting from 2g (30.1 mg, 0.16 mmol, 1.0
equiv), potassium 4ꢀmehtoxyphenyltrifluoroborate 11m (40.7 mg, 0.19 mmol, 1.2 equiv) and TFAA (22
ꢀL, 0.16 mmol, 1.0 equiv) in DCM anh. (1.0 mL) for 3 h. The crude product was purified by flash colꢀ
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umn chromatography on silica gel eluting with Hexane:AcOEt 8:2 (36.3 mg, 76% yield). H NMR (300
MHz, CDCl3): δ 7.96ꢀ7.93 (m, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.20 (d, J = 8.7
Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.55 (d, J = 18.7 Hz, 1H), 4.36ꢀ4.29 (m, 2H), 4.07 (dd, J = 18.2 Hz, J
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= 10.5 Hz, 1H), 3.80 (s, 3H), 3.28 (dd, J = 18.2 Hz, J = 3.5 Hz, 1H), 2.86 (bs, 1H) ppm. CꢀNMR (75
MHz, CDCl3): δ 209.2, 198.0, 159.5, 136.2, 133.6, 129.4 (2C), 128.8 (3C), 128.2 (2C), 114.8, 67.3,
55.5, 48.5, 42.8 ppm. Anal. calcd. for C18H18O4: C, 72.47; H, 6.08. Found: C, 72.61; H, 6.20.
(E)-5-Hydroxy-1-phenyl-3-(3-phenylprop-1-en-1-yl)pentane-1,4-dione (13h): Following genꢀ
eral procedure for the synthesis of compounds 13, Conditions A, starting from 2g (29.8 mg, 0.16 mmol,
1.0 equiv), potassium transꢀ3ꢀPhenylꢀ1ꢀpropenꢀ1ꢀyltrifluoroborate 11e (42.6 mg, 0.19 mmol, 1.2 equiv)
and TFAA (22 ꢀL, 0.16 mmol, 1.0 equiv) in DCM anh. (1.0 mL) for 3 h. The crude product was puriꢀ
fied by flash column chromatography on silica gel eluting with Hexane:AcOEt 8:2 (38.0 mg, 77%
yield). 1H NMR (300 MHz, CDCl3): δ 7.93 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.6
Hz, 2H),7.32ꢀ7.21 (m, 3H), 7.14 (d, J = 7.4 Hz, 2H), 5.94ꢀ5.84 (m, 1H), 5.46 (dd, J = 15.3 Hz, J = 7.8
Hz, 1H), 4.59 (s, 2H), 3.81ꢀ3.70 (m, 2H), 3.37 (d, J = 6.6 Hz, 2H), 3.25ꢀ3.16 (m, 1H), 2.98 (bs, 1H),
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ppm. CꢀNMR (75 MHz, CDCl3): δ 209.8, 197.8, 139.4, 136.2, 134.9, 133.7, 128.8 (2C), 128.7 (2C),
128.6 (2C), 128.2 (2C), 127.0, 126.5, 67.5, 47.2, 41.1, 39.0 ppm. Anal. calcd. for C20H20O3: C, 77.90;
H, 6.54. Found: C, 78.03; H, 6.49.
(E)-(1-Benzyl-4-styryl-1H-pyrrol-2-yl)methanol (14a): Following general procedure for the
synthesis of pyrroles 14, starting from 2j (35.0 mg, 0.31 mmol, 1.0 equiv), potassium transꢀ
styryltrifluoroborate 11a (96.8 mg, 0.46 mmol, 1.5 equiv), tetrabutylammonium hydrogenosulfate (52.6
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mg, 0.16 mmol, 0.5 equiv) in DCM anh. (6.2 mL) at rt for 48h. Then, benzylamine (34 ꢀL, 0.31 mmol,
1.0 equiv) and pꢀtoluenesulfonic acid (5.9 mg, 0.03 mmol, 0.1 equiv) in toluene (1.6 mL) at rt for 12 h.
The crude product was purified via flash column chromatography on silica gel eluting with Hexꢀ
ane:AcOEt 8:2 (67.3 mg, 75% yield). 1H NMR (500 MHz, acetoneꢀd6): δ 7.44 (d, J = 8.2 Hz, 2H), 7.33
(t, J = 7.6 Hz, 2H), 7.29 (t, J = 8.1 Hz, 3H), 7.18 (d, J = 7.8 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 7.05 (d, J
= 16.3 Hz, 1H), 6.92 (d, J = 1.8 Hz, 1H), 6.76 (d, J = 16.3 Hz, 1H), 6.36 (d, J = 1.8 Hz, 1H), 5.23 (s,
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2H), 4.47 (s, 2H), 2.81 (bs, 1H) ppm. CꢀNMR (125 MHz, acetoneꢀd6): δ 139.8, 139.6, 135.2, 129.4
(2C), 129.3 (2C), 128.1, 127.8 (2C), 127.0, 126.4 (2C), 124.1, 123.7, 123.4, 122.6, 106.5, 56.7, 50.9
ppm. Anal. calcd. for C20H19NO: C, 83.01; H, 6.62. Found: C, 82.90; H, 6.74.
(E)-1-(1-Benzyl-4-styryl-1H-pyrrol-2-yl)ethanol (14b): Following general procedure for the
synthesis of pyrroles 14, starting from 2a (29.7 mg, 0.23 mmol, 1.0 equiv), potassium transꢀ
styryltrifluoroborate 11a (73.8 mg, 0.35 mmol, 1.5 equiv) and tetrabutylammonium hydrogenosulfate
(39.7 mg, 0.12 mmol, 0.5 equiv) in DCM anh. (4.6 mL) at rt for 48h. Then, benzyl amine (26 ꢀL, 0.23
mmol, 1.0 equiv) and pꢀtoluenesulfonic acid (4.4 mg, 0.02 mmol, 0.1 equiv) in toluene (1.2 mL) at rt for
1 h. The crude product was purified via flash column chromatography on silica gel eluting with Hexꢀ
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ane:AcOEt 8:2 to afford a yellow oil (57.5 mg, 81% yield). H NMR (300 MHz, acetoneꢀd6): δ 7.42ꢀ
7.47 (m, 2H), 7.22ꢀ7.37 (m, 6H), 7.12ꢀ7.18 (m, 2H), 7.06 (d, J = 16.2 Hz, 1H), 6.88 (d, J = 1.7 Hz, 1H),
6.77 (d, J = 16.2 Hz, 1H), 6.40 (d, J = 1.7 Hz, 1H), 5.36 (d, J = 16.0 Hz, 1H), 5.20 (d, J = 16.0 Hz, 1H),
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4.70 (q. J = 6.3 Hz, 1H), 3.91 (d, J = 6.3 Hz, 1H), 1.48 (d, J = 6.3 Hz, 3H) ppm. CꢀNMR (75 MHz,
CDCl3): δ 140.0, 139.6, 139.0, 129.4, 129.3, 128.0, 127.7, 126.9, 126.3, 124.0, 123.8, 123.2, 122.3,
103.6, 62.2, 50.9, 22.9 ppm. Anal. calcd. for C21H21NO: C, 83.13; H, 6.98. Found: C, 83.09; H, 6.99.
(E)-1-(1-Benzyl-4-(3-phenylprop-1-en-1-yl)-1H-pyrrol-2-yl)ethanol (14c): Following general
procedure for the synthesis of pyrroles 14, starting from 2a (30.3 mg, 0.23 mmol, 1.0 equiv), transꢀ3ꢀ
phenylꢀ1ꢀpropenꢀ1ꢀyltrifluoroborate 11e (78.5 mg, 0.35 mmol, 1.5 equiv) and tetrabutylammonium hyꢀ
drogenosulfate (39.7 mg, 0.12 mmol, 0.5 equiv) in DCM anh. (4.6 mL) rt for 48h. Then, benzyl amine
(26 ꢀL, 0.23 mmol, 1.0 equiv) and pꢀtoluenesulfonic acid (4.4 mg, 0.02 mmol, 0.1 equiv) in toluene (1.2
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mL) at rt for 12 h. The crude product was purified via flash column chromatography on silica gel eluting
with Hexane:AcOEt 8:2 to afford a yellow oil (57.9 mg, 78% yield). 1H NMR (300 MHz, acetoneꢀd6): δ
7.06ꢀ7.38 (m, 10H), 6.69 (d, J = 1.9 Hz, 1H), 6.30 (d, J = 15.5 Hz, 1H), 6.21 (d, J = 1.9 Hz, 1H), 5.94
(dt, J = 15.5 Hz, J = 7.1 Hz, 1H), 5.32 (d, J = 16.1 Hz, 1H), 5.14 (d, J = 16.1 Hz, 1H), 4.68 (q. J = 6.5
Hz, 1H), 3.83 (d, J = 6.8 Hz, 1H), 3.44 (d, J = 6.8 Hz, 2H),1.43 (d, J = 6.5 Hz, 3H) ppm. 13CꢀNMR (75
MHz, CDCl3): δ 142.3, 140.2, 138.5, 129.4, 129.2, 128.0, 127.7, 126.7, 125.6, 124.3, 122.2, 121.8,
103.6, 62.3, 50.8, 40.0, 23.0 ppm. Anal. calcd. for C22H23NO: C, 83.24; H, 7.30. Found: C, 83.31; H,
7.28.
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(1-Benzyl-4-(phenylethynyl)-1H-pyrrol-2-yl)methanol (14d): Following general procedure for
the synthesis of pyrroles 14, starting from 2j (36.0 mg, 0.31 mmol, 1.0 equiv), potassium pheꢀ
nylethynyltrifluoroborate 11i (95.7 mg, 0.46 mmol, 1.5 equiv) and tetrabutylammonium hydrogenosulꢀ
fate (52.6 mg, 0.16 mmol, 0.5 equiv) in DCM anh. (6.2 mL) at rt for 48h. Then, benzylamine (34 ꢀL,
0.31 mmol, 1.0 equiv) and pꢀtoluenesulfonic acid (5.9 mg, 0.03 mmol, 0.1 equiv) in toluene (1.6 mL) at
rt for 12 h. The crude product was purified via flash column chromatography on silica gel eluting with
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Hexane:AcOEt 8:2 (57.0 mg, 64% yield). H NMR (300 MHz, acetoneꢀd6): δ 7.45ꢀ7.29 (m, 8H), 7.20
(d, J = 7.5 Hz, 2H), 7.09 (d, J = 1.8 Hz, 1H), 6.22 (d, J = 1.8 Hz, 1H), 5.28 (s, 2H), 4.48ꢀ4.47 (m, 2H),
4.08 (bs, 1H) ppm. 13CꢀNMR (75 MHz, acetoneꢀd6): δ 139.2, 134.4, 131.7 (2C), 129.4 (2C), 129.2 (2C),
128.3, 128.2, 127.8 (2C), 127.5, 125.4, 112.2, 103.6, 87.9, 86.5, 56.3, 51.0 ppm. Anal. calcd. for
C20H17NO: C, 83.59; H, 5.96. Found: C, 83.76; H, 6.08.
1-(1-Benzyl-4-(phenylethynyl)-1H-pyrrol-2-yl)ethanol (14e): Following general procedure for
the synthesis of pyrroles 14, starting from 2a (30.3 mg, 0.23 mmol, 1.0 equiv), potassium pheꢀ
nylethynyltrifluoroborate 11i (73.1 mg, 0.35 mmol, 1.5 equiv) and tetrabutylammonium hydrogenosulꢀ
fate (39.7 mg, 0.12 mmol, 0.5 equiv) in DCM anh. (4.6 mL) at rt for 48h. Then, benzyl amine (26 ꢀL,
0.23 mmol, 1.0 equiv) and pꢀtoluenesulfonic acid (4.4 mg, 0.02 mmol, 0.1 equiv) in toluene (1.2 mL) at
rt for 12 h. The crude product was purified via flash column chromatography on silica gel eluting with
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Hexane:AcOEt 8:2 to afford a yellow oil (57.2 mg, 81% yield). H NMR (300 MHz, acetoneꢀd6): δ
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7.25ꢀ7.46 (m, 8H), 7.17 (d, J = 7.4 Hz, 2H), 7.05 (d, J = 1.7 Hz, 1H), 6.23 (d, J = 1.0 Hz, 1H), 5.41 (d, J
= 15.8 Hz, 1H), 5.25 (d, J = 15.8 Hz, 1H), 4.73 (q. J = 6.5 Hz, 1H), 4.04 (d, J = 6.5 Hz, 1H), 1.43 (d, J =
6.5 Hz, 3H) ppm. 13CꢀNMR (75 MHz, CDCl3): δ 139.4, 138.2, 131.7, 129.4, 129.3, 128.2, 128.1, 127.7,
127.2, 125.4, 109.6, 103.4, 87.9, 86.6, 62.0, 51.1.22.8 ppm. Anal. calcd. for C21H19NO: C, 83.69; H,
6.35. Found: C, 83.60; H, 6.34.
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(E)-(1-Benzyl-5-phenyl-3-styryl-1H-pyrrol-2-yl)methanol (15a): Following general procedure
for the synthesis of pyrroles 15, starting from 2g (29.7 mg, 0.16 mmol, 1.0 equiv), potassium transꢀ
styryltrifluoroborate 11a (39.4 mg, 0.19 mmol, 1.2 equiv) and TFAA (22 ꢀL, 0.16 mmol, 1.0 equiv) in
DCM anh. (1.0 mL) for 1 h. Then, benzylamine (17 ꢀL, 0.16 mmol, 1.0 equiv) and pꢀtoluenesulfonic
acid (3.0 mg, 0.02 mmol, 0.1 equiv) in toluene (0.8 mL) at rt for 12 h. The crude product was purified
via flash column chromatography on silica gel eluting with Hexane:AcOEt 8:2 (42.1 mg, 72% yield). 1H
NMR (300 MHz, acetoneꢀd6): δ 7.55ꢀ7.53 (m, 2H), 7.35ꢀ7.26 (m, 12H), 6.98ꢀ6.96 (m, 3H), 6.61 (s,
1H), 5.41 (s, 2H), 4.62 (s, 2H), 4.07 (bs, 1H) ppm. 13CꢀNMR (75 MHz, acetoneꢀd6): δ 140.3, 139.6,
137.1, 134.0, 133.7, 129.6 (2C), 129.5 (2C), 129.4 (2C), 129.3 (2C), 128.2, 127.8, 127.2, 126.6 (2C),
126.4 (2C), 125.4, 122.2, 122.0, 106.1, 53.8, 48.2 ppm. Anal. calcd. for C26H23NO: C, 85.45; H, 6.34.
Found: C, 85.35; H, 6.48.
(E)-(1-Benzyl-5-phenyl-3-(3-phenylprop-1-en-1-yl)-1H-pyrrol-2-yl)methanol (15b): Followꢀ
ing general procedure for the synthesis of pyrroles 15, starting from 2g (29.8 mg, 0.16 mmol, 1.0 equiv),
potassium transꢀ3ꢀphenylꢀ1ꢀpropenꢀ1ꢀyltrifluoroborate 11e (42.6 mg, 0.19 mmol, 1.2 equiv) and TFAA
(22 ꢀL, 0.16 mmol, 1.0 equiv) in DCM anh. (1.0 mL) for 3 h. Then, benzylamine (17 ꢀL, 0.16 mmol,
1.0 equiv) and pꢀtoluenesulfonic acid (3.0 mg, 0.02 mmol, 0.1 equiv) in toluene (0.8 mL) at rt for 12 h.
The crude product was purified via flash column chromatography on silica gel eluting with Hexꢀ
ane:AcOEt 8:2 (46.7 mg, 77% yield). 1H NMR (500 MHz, acetoneꢀd6): δ 7.32ꢀ7.26 (m, 11H), 7.22ꢀ7.19
(m, 2H), 6.92 (d, J = 7.3 Hz, 2H), 6.56 (d, J = 15.6 Hz, 1H), 6.40 (s, 1H), 6.11 (dt, J = 15.6, Hz, J = 7.1
Hz, 1H), 5.36 (s, 2H), 4.49 (d, J = 5.3 Hz, 2H), 3.93 (t, J = 5.3 Hz, 1H), 3.52 (d, J = 7.1 Hz, 2H) ppm.
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13CꢀNMR (125 MHz, acetoneꢀd6): δ 142.1, 140.5, 136.6, 134.2, 132.1, 129.6 (2C), 129.5 (2C), 129.4
(2C), 129.3 (2C), 129.2 (2C), 128.0, 127.7, 126.7, 126.4 (2C), 125.9, 124.0, 122.1, 106.3, 53.9, 48.1,
40.2 ppm. Anal. calcd. for C27H25NO: C, 85.45; H, 6.64. Found: C, 85.31; H, 6.75.
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(E)-(1-Benzyl-5-methyl-3-styryl-1H-pyrrol-2-yl)methanol (15c): Following general procedure
for the synthesis of pyrroles 15, starting from 2f (30.5 mg, 0.24 mmol, 1.0 equiv), potassium transꢀ
styryltrifluoroborate 11a (65.0 mg, 0.29 mmol, 1.2 equiv) and TFAA (33 ꢀL, 0.24 mmol, 1.0 equiv) in
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DCM anh. (1.4 mL) for 1 h. Then, benzylamine (26 ꢀL, 0.24 mmol, 1.0 equiv) and pꢀtoluenesulfonic
acid (4.6 mg, 0.02 mmol, 0.1 equiv) in toluene (1.2 mL) at rt for 12 h. The crude product was purified
via flash column chromatography on silica gel eluting with Hexane:AcOEt 8:2 (36.4 mg, 50% yield). 1H
NMR (300 MHz, acetoneꢀd6): δ 7.50 (d, J = 7.6 Hz, 2H), 7.34ꢀ7.13 (m, 8H), 7.01 (d, J = 7.5 Hz, 2H),
6.78 (d, J = 16.1 Hz, 1H), 6.23 (s, 1H), 5.28 (s, 2H), 4.62ꢀ4.61 (m, 2H), 3.92 (t, J = 5.4 Hz, 1H), 2.11 (s,
3H) ppm. 13CꢀNMR (75 MHz, acetoneꢀd6): δ 139.9, 139.8, 132.2, 131.2, 129.4 (2C), 129.3 (2C), 127.8,
126.9, 126.7 (2C), 126.4 (2C), 124.2, 122.5, 120.9, 104.0, 53.5, 47.4, 12.3 ppm. Anal. calcd. for
C21H21NO: C, 83.13; H, 6.98. Found: C, 83.29; H, 6.90.
(1-Benzyl-3,5-diphenyl-1H-pyrrol-2-yl)methanol (15d): Following general procedure for the
synthesis of pyrroles 15, starting from 2g (30.3 mg, 0.16 mmol, 1.0 equiv), potassium phenyltrifluorobꢀ
orate 11f (34.8 mg, 0.19 mmol, 1.2 equiv) and TFAA (22 ꢀL, 0.16 mmol, 1.0 equiv) in DCM anh. (1.0
mL) for 1 h. Then, benzylamine (17 ꢀL, 0.16 mmol, 1.0 equiv) and pꢀtoluenesulfonic acid (3.0 mg, 0.02
mmol, 0.1 equiv) in toluene (0.8 mL) at rt for 12 h. The crude product was purified via flash column
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chromatography on silica gel eluting with Hexane:AcOEt 8:2 (38.0 mg, 70% yield). H NMR (300
MHz, acetoneꢀd6): δ 7.62ꢀ7.58 (m, 2H), 7.42ꢀ7.22 (m, 11H), 6.98 (d, J = 7.1 Hz, 2H), 6.44 (s, 1H), 5.47
(s, 2H), 4.55ꢀ4.53 (m, 2H), 4.07 (t, J = 4.8 Hz, 1H) ppm. 13CꢀNMR (75 MHz, acetoneꢀd6): δ 140.4,
137.5, 136.1, 134.2, 130.8 129.6 (2C), 129.5 (2C), 129.3 (2C), 129.2 (2C), 129.0 (2C), 128.1, 127.8,
126.5, 126.4 (2C), 125.8, 109.4, 54.7, 48.3 ppm. Anal. calcd. for C24H21NO: C, 84.92; H, 6.24. Found:
C, 85.11; H, 6.15.
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(1-Benzyl-3-(4-methoxyphenyl)-5-phenyl-1H-pyrrol-2-yl)methanol (15e): Following general
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1.0 equiv) in DCM anh. (1.0 mL) for 3 h. Then, benzylamine (17 ꢀL, 0.16 mmol, 1.0 equiv) and pꢀ
toluenesulfonic acid (3.0 mg, 0.02 mmol, 0.1 equiv) in toluene (0.8 mL) at rt for 12 h. The crude prodꢀ
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52
53
54
55
56
57
58
59
60
1
mg, 81% yield). H NMR (300 MHz, acetoneꢀd6): δ 7.52 (d, J = 8.9 Hz, 2H), 7.37ꢀ7.22 (m, 8H), 6.99ꢀ
6.96 (m, 4H), 6.39 (s, 1H), 5.44 (s, 2H), 4.51 (s, 2H), 4.06 (bs, 1H), 3.81 (s, 3H) ppm. 13CꢀNMR (75
MHz, acetoneꢀd6): 159.1, 140.5, 139.5, 134.3, 130.4, 130.0 (2C), 129.9, 129.6 (2C), 129.4 (2C), 129.3
(2C), 128.0, 127.8, 126.4 (2C), 125.6, 114.7 (2C), 109.3, 55.5, 54.9, 48.3 δ ppm. Anal. calcd. for
C25H23NO2: C, 81.27; H, 6.27. Found: C, 81.22; H, 6.38.
(2S,3R,6R)-6-Methyl-5-oxo-3-((E)-styryl)tetrahydro-2H-pyran-2-yl acetate (16a): Following
general procedure for the synthesis of compounds 16, Conditions C, starting from 2a (29.4 mg, 0.23
mmol, 1.0 equiv), potassium transꢀstyryltrifluoroborate 11a (73.8 mg, 0.35 mmol, 1.5 equiv) and
tetrabutylammonium hydrogenosulfate (39.7 mg, 0.12 mmol, 0.5 equiv) in DCM anh. (4.6 mL) at rt for
48h. Then, Ac2O (22 ꢀL, 0.23 mmol, 1.0 equiv), DMAP (1.4 mg, 0.012 mmol, 5% mmol) and Et3N (65
ꢀL, 0.47 mmol, 2.0 equiv) at 0ºC for 1 h. The crude product was purified via flash column chromatogꢀ
raphy on silica gel eluting with Hexane:AcOEt 8:2 to afford a yellow oil (52.6 mg, 82% yield, dr
1
90:10). H NMR (300 MHz, CDCl3): δ 7.14ꢀ7.34 (m, 5H), 6.42 (d, J = 15.8 Hz, 1H), 6.09 (d, J = 5.4
Hz, 1H), 6.03 (dd, J = 15.8 Hz, J = 7.7 Hz, 1H), 4.31 (q. J = 6.8 Hz, 1H), 2.93ꢀ3.06 (m, 1H), 2.51ꢀ2.69
(m, 2H), 2.08 (s, 3H), 1.27 (d, J = 6.8 Hz, 3H) ppm. 13CꢀNMR (75 MHz, CDCl3): δ 208.9, 169.9, 136.4,
133.0, 128.8, 128.2, 126.6, 126.5, 94.4, 73.2, 42.2, 39.5, 21.3, 15.1 ppm. Anal. calcd. for C16H18O4: C,
70.06; H, 6.61. Found: C, 70.14; H, 6.59.
(2S,3R,6R)-6-Methyl-3-(2-methylprop-1-en-1-yl)-5-oxotetrahydro-2H-pyran-2-yl
acetate
(16b): Following general procedure for the synthesis of compounds 16, Conditions C, starting from 2a
29
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