Synthesis of bis-Quaternary Centers at the α-Positions of Cyclohexanones via Copper(I)-Catalyzed Claisen Rearrangement: The Substituent Effect from the Opposing α-Quaternary Center on Diastereoselectivity

Abstract

We report the synthesis of bis-quaternary centers at the α-positions of cyclohexanones. In this chemistry, ionization of an α-hydroxy allyl vinyl ether with Cu(MeCN)4BF4 catalyst at room temperature formed an allyloxy allyl cation that was captured by indole in a regioselective manner to create an α-quaternary center. Upon heating, the Claisen rearrangement occurred in situ to produce a second quaternary center at the opposing α’-position, thereby furnishing the targeted bis-quaternary center motif. Studies in this article examined the alkyl substituents at the α-carbon and their effect on diastereoselectivity of the Claisen rearrangement. Interestingly, the copper catalyst enhanced the trans delivery of the allyl group with respect to the indole versus the background diastereoselectivity of the uncatalyzed reaction.

Graphical Abstract

1. Introduction

Quaternary stereocenters are carbon atoms that contain four different carbon substituents at the sp³ tetrahedral vertices. Despite their prevalence in numerous bioactive compounds,¹ broader applications of quaternary stereocenters in drug discovery have been hindered by synthetic challenges that must overcome steric congestion associated with the formation of these carbon atoms.² A particularly powerful C-C bond-forming reaction to construct quaternary stereocenters is the Claisen rearrangement.³ Proceeding via the [3,3]-sigmatropic rearrangement,⁴ the Claisen rearrangement readily transforms substituted allyl vinyl ethers under thermal or Lewis acid activation to assemble quaternary centers in the form of α-allyl carbonyl compounds.⁵ Empowered by asymmetric catalysis, elegant methods have been developed to produce enantiomerically enriched quaternary centers via the Claisen rearrangement.⁶

The Claisen rearrangement for the diastereoselective synthesis of quaternary centers from chiral allyl vinyl ether precursors, particularly in monocyclic systems, is similarly challenging.⁷ Scheme 1 depicts some examples. Kanai and Shibasaki showcased that [3,3]-sigmatropic rearrangement of stereochemically rich substrate 1a under high heat produced quaternary center 1b as a single diastereomer in 96% yield.^7a Nevertheless, this substrate-directed approach did not always result in effective diastereocontrol. For instance, Soós^7b and Lei^7c reported that the Claisen rearrangement of allyl vinyl ethers 2a and 3a afforded the respective quaternary centers in ketones 2b and 3b as a mixture of diastereomers despite the presence of stereocenters embedded in the substrates.

Scheme 1.

Diastereoselectivity in the Quaternary Center Formation via the Claisen Rearrangement

We recently investigated new chemistries that capitalized on the versatility of the Claisen rearrangement to create quaternary centers. Our unique approach unmasked the reactivity of prochiral allyloxy electrophile 4a toward cascade reactions that commenced with regioselective nucleophilic addition to form allyl vinyl ether intermediate 4b with a fully substituted α-carbon atom. This stereocenter was subsequently harnessed to govern diastereoselectivity in the ensuing Claisen rearrangement, thereby creating a quaternary center at the opposing α’-position. Our findings are summarized in Scheme 2.⁸ We discovered that the reaction of allyloxy ketone 5a with the Grignard reagents in dichloromethane, followed by extended mixing of the reaction mixture at room temperature, resulted in ketone 5b in which the nucleophilic addition and the allyl migration occurred with the cis relative stereochemistry.^8a This selectivity was proposed to originate from an intramolecular binding of the magnesium metal to the alkoxide and allyloxy groups in chelate model 5c that ultimately triggered the [3,3]-sigmatropic rearrangement. To establish the trans delivery between the allyl group and the nucleophile, we subjected α-hydroxy allyl vinyl ether 6a to nucleophilic addition in the presence of Cu(MeCN)₄BF₄ catalyst in 1,2-dichloroethane at room temperature. The ensuing warming of the reaction mixture to 83 °C then initiated the Claisen rearrangement to afford the trans delivery product 6b.^8b

Scheme 2.

Diastereocomplementary Synthesis of Fully Substituted Cyclic Ketones at the Opposing α-Positions

The origin of the observed trans diastereoselectivity remains unclear, thus prompting us to launch further investigations into this copper-catalyzed chemistry. In the previous report,^8b we described the facile reaction of α-methyl substrate motif 7a and various substituted indoles as the nucleophile, which yielded a broad scope of α,α’-bis-quaternary centers 7b (Scheme 3). Remarkably, ketone products 7b were isolated as a single regio- and diastereomer with the trans relative stereochemistry between the allyl and the indole groups. The mechanism of this reaction was proposed to involve ionization of the α-hydroxy group in substrate 8a by the mildly Lewis acidic Cu(MeCN)₄BF₄ catalyst.⁹ The ensuing indole addition to the emerging allyloxy allyl cation 8b then transpired regioselectively at the α-carbon bearing the methyl group to form quaternary center 8c.¹⁰ Facilitated by heat, the copper catalyst then prompted the Claisen rearrangement to forge the second quaternary center at the opposing α’-position, thereby furnishing fully substituted ketone 8d.

Scheme 3.

Copper(I)-Catalyzed Claisen Rearrangement

[a] The ellipsoid contour was set at a 50% probability level.

Our data from the crossover and isotope labeling experiments suggested that the allyl migration appeared to have occurred via a concerted, intramolecular mechanism.^8b Based on the X-ray crystal structure of the bis-quaternary centers, such as in α’-phenyl-α-indole ketone trans-13a,¹¹ and assuming that the Claisen rearrangement in this copper-catalyzed reaction proceeded via the chair-like transition state,¹² we envisioned that the observed trans diastereorelationship between the indole ring and the allyl group in the resulting product 8d might have been produced from a possible pre-organized transition structure 8e. This hypothetical model would implicate the orientation of both aromatic rings in the axial directions,¹³ thereby allowing for a favorable spatial interaction between the copper catalyst and the small methyl substituent.

In this study, we examined the potential significance of this steric effect imposed by the α-methyl group by replacing it with various alkyl substituents. Two related substrates were subjected in this endeavor: α-hydroxy allyl vinyl ether 11 and allyl vinyl ether 12 bearing an α-indole quaternary center. Treatment of substrate 11 under the catalysis conditions would deduce the role of copper in biasing diastereoselectivity of the Claisen rearrangement. To measure the background diastereoselectivity, substrate 12 would be subjected to the uncatalyzed conditions, i.e., DCE at 83 °C. These two substrates were prepared from phenyl-substituted allyloxy enone 10. The reaction of this compound with the Grignard reagents furnished substrate 11.¹⁴ The α-indole quaternary center in substrate 12 was then installed by exposing substrate 11 to catalytic Cu(MeCN)₄BF₄ and indole at room temperature. Our ability to isolate compound 12 is a testament that the Claisen rearrangement required heat to proceed even in the presence of the copper catalyst.

2. Result and Discussion

Our results are compiled in Table 1. The benchmark for diastereoselectivity was established with the α-methyl group (entry 1). Treatment of substrate 11a under the catalysis conditions furnished ketone trans-13a with >20:1 dr. Meanwhile, the inherent diastereoselectivity from the background Claisen rearrangement of substrate 12a in DCE at 83 °C was found to be 5.4:1, also favoring the trans-13a. As shown in entries 2 and 3, the methyl group was then replaced with ethyl and n-propyl in the form of α-hydroxy allyl vinyl ethers 11b and 11c, respectively. This seemingly minor steric modulation drastically rendered the copper-catalyzed Claisen rearrangement non-diastereoselective, with a slight bias toward the cis-13b diastereomer for the ethyl substrate. These results were then compared to the background diastereoselectivity from the thermal rearrangement of the respective α-indolyl quaternary center in allyl vinyl ethers 12b and 12c. Surprisingly, these uncatalyzed conditions favored the cis-13b and cis-13c diastereomers by a substantial margin.

Table 1.

Catalysis versus Background Diastereoselectivity

entry	substrate	trans : cis crude ratio[a] trans + cis yield [b]	products	trans : cis crude ratio[a] trans + cis yield [b]	substrate
1		>20 : 1 94% + 0%		5.4 : 1 79% + 12%
2		1 : 1.2 33% + 32%		1 : 1.7 37% + 63%
3		1 : 1.0 38% + 41%		1 : 2.0 25% + 56%
4		2.7 : 1 49% + 23% [c]		1 : 1.8 30% + 56%
5		nd [d] 28% + 53%		1 :1.8 28% + 57%
6		1 : 1.9 13% + 42%		1 : 2.5 19% + 56%
7		nd [d] 49% + 24%		3.3 : 1 59% + 20%
8		1.0 : 1 40% + 36%		1.0 : 1 47% + 41%

^[a]The diastereomeric ratio was determined by ¹H NMR analyses of the crude reaction mixture.

^[b]Isolated yield after column chromatography.

^[c]Two equivalents of indole were used to improve the product yields. The use of 1.5 equivalents of indole formed trans-13d and cis-13d products in 37% and 17% yields, respectively.

^[d]Diastereomeric ratio could not be determined from the crude reaction mixture by ¹H NMR due to overlapping signals.

Another unexpected outcome was noted with substrates bearing an allyl substituent at the α-carbon (entry 4). While the background Claisen rearrangement of compound 12d similarly favored cis-13d diastereomer, the copper-catalyzed conditions reversed diastereoselectivity to furnish the trans-13d isomer as the major product with 2.7:1 dr. As the steric size was further increased to the n-octyl and benzyl groups (entries 5–6), both the respective catalyzed and uncatalyzed reactions resulted in essentially comparable stereochemical outcomes, favoring the cis-13e and cis-13f diastereomers. We observed a similar behavior with cyclopropyl-bearing substrates 11g and 12g. As shown in entry 7, the catalysis and background conditions both generated a mixture of diastereomers, interestingly favoring the trans-13g stereoisomer. The role of the α-alkyl group as a structural feature that introduced diastereoselective bias in the Claisen rearrangement was supported by our findings as depicted in entry 8, in which the aromatic α,α’-diphenyl substrates 11h and 12h produced the trans-13h and cis-13h diastereomers interestingly as a 1:1 mixture under their respective catalysis and background conditions.

As summarized in Table 2, we sought to better understand the effect of the alkyl substituents by examining the difference in diastereomeric excess of product trans-13 (Δde) obtained from the catalysis and the background conditions. In this effort, two sets of data points were calculated: one from the isolated product yields and the other from the diastereomeric excess of the crude reaction mixtures if they could be determined by ¹H NMR. The following trends were illuminated: 1) Without the copper catalyst, the background Claisen rearrangement favored the cis diastereoselectivity with the larger alkyl substituents. The cyclopropyl group is a surprising exception. 2) The copper catalyst enhanced the trans delivery of the allyl group. A profound catalyst effect was noted with the α-allyl substrate. 3) The copper catalyst appeared to become ineffective with the presence of a sterically more imposing substituents, such as those of octyl, benzyl, and cyclopropyl. Considering the negligible Δde, the observed diastereoselectivity in the catalysis conditions could have resulted from the background reaction. 4) As evidenced in the methyl and cyclopropyl substrates versus those of ethyl, propyl, octyl, allyl, and benzyl counterparts, the trans and cis diastereochemical preference from the background Claisen rearrangement could not be readily anticipated. 5) Unlike the α,α’-dimethyl variant that exhibited profound trans diastereoselectivity as a response to the catalyst effect,^8b,13 the Claisen rearrangement of the α,α’-diphenyl variant did not produce any diastereoselection either under the catalytic or background conditions.

Table 2.

Trends in Diastereoselectivity

Entry	alkyl group	catalysis trans da (%)[a]	background trans de (%)[a]	trans Δdc (%)[a]
1	methyl	100 (>95)	74 (69)	26 (26)
2	ethyl	2 (−9)	−26 (−26)	28 (17)
3	propyl	−4 (0)	−38 (−33)	34 (33)
4	allyl	36 (46)	−30 (−29)	66 (75)
5[b]	octyl	−31 (nd)	−34 (−29)	3 (nd)
6	benzyl	−53 (−31)	−49 (−43)	−4 (12)
7 [b]	cyclopropyl	34 (nd)	49 (53)	−15 (nd)
8	phenyl	5 (0)	7 (0)	−2 (0)

^[a]Diastereomeric excess in the parenthesis was determined by ¹H NMR of the crude reaction mixtures.

^[b]Diastereomeric excess could not be determined from the crude reaction mixture by ¹H NMR due to overlapping signals.

3. Conclusion

Our data suggested that the interaction between the Claisen rearrangement precursor and the copper catalyst appeared to be rather labile under the reaction conditions. Such complexation was readily disturbed by simple steric modulation in the α-alkyl region, therefore allowing competition from the background reaction to occur. Nevertheless, when effectively interacting to the allyl vinyl ether substrate, the catalyst could provide a considerable induction to augment the trans diastereoselectivity between the allyl and the indole groups compared to that generated by the uncatalyzed Claisen rearrangement. The α-alkyl substituent also contributed to affecting diastereoselectivity in the Claisen rearrangement, thus underscoring its critical role in the reaction.

4. Experimental Section

Unless otherwise noted, all materials were used as received from commercial suppliers without further purification. All anhydrous reactions were performed using oven-dried glassware, which was then cooled under vacuum and purged with nitrogen gas. Reaction solvents were filtered through activated silica or 3Å molecular sieves under argon contained in a Solvent Purification System. All reactions were monitored by analytical thin layer chromatography (TLC Silica Gel 60 F₂₅₄, Glass Plates) and analyzed with 254 nm UV light and / or anisaldehyde – sulfuric acid or potassium permanganate treatment. Column chromatography was completed using silica gel (32–63 μ). The ¹H and ¹³C NMR spectra were recorded in CDCl₃ using a Bruker Ascend 400 spectrometer operating at 400 MHz for ¹H and 100 MHz for ¹³C or Bruker Ascend 500 spectrometer operating at 500 MHz for ¹H and 125 MHz for ¹³C. Chemical shifts (δ) are reported in ppm relative to residual CHCl₃ as an internal reference (¹H: 7.26 ppm, ¹³C: 77.00 ppm). Coupling constants (J) are reported in Hertz (Hz). Peak multiplicity is indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), (septet), h (heptet), b (broad), and m (multiplet). FT-IR spectra were recorded on Bruker Tensor 27 spectrometer and OPUS 6.5 Data Collection Program, and absorption frequencies were reported in reciprocal centimeters (cm⁻¹). High Resolution Mass Spectrometry (HRMS) analyses were performed by the Louisiana State University Mass Spectrometry Facility. X-ray structure analyses were performed by the Louisiana State University X-ray Structure Facility.

Compound 11a.

Ketone 10 (1.54 g, 6.75 mmol) was dissolved in CH₂Cl₂ (33 mL). After cooling the solution to −78 °C, methylmagnesium bromide (2.9 mL, 8.8 mmol, 3.0 M in Et₂O) was added dropwise. The solution was then warmed to room temperature and stirred for 30 minutes. Upon consumption of the starting material as monitored by TLC, the reaction mixture was cooled to 0 °C, quenched with a saturated NH₄Cl solution (15 mL), and then diluted with DI water (15 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were then washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The crude material was purified by column chromatography using 100% hexanes to 90:10 hexanes : EtOAc to afford compound 11a in 81% yield (1.34 g, 5.46 mmol) as a yellow oil.

Rf: 0.5 in 80:20 hexanes : EtOAc

¹H NMR: (500 MHz, CDCl₃) δ = 7.37 – 7.31 (m, 4H), 7.24 – 7.22 (m, 1H), 5.77 – 5.70 (m, 1H), 5.12 – 5.03 (m, 2H), 3.88 – 3.85 (m, 2H), 2.50 – 2.44 (m, 1H), 2.34 – 2.26 (m, 1H), 2.26 (s, 1H), 1.93 – 1.89 (m, 1H), 1.84 – 1.80 (m, 2H), 1.76 – 1.67 (m, 1H), 1.46 (s, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 153.6, 140.1, 134.5, 128.3, 128.1, 126.7, 121.2, 116.6, 74.2, 71.3, 38.1, 31.3, 27.4, 19.9.

IR: f (cm⁻¹) = 3446, 3078, 3055, 2934, 2866, 1709, 1646, 1444, 1386, 1267, 1130, 1040, 985.

HRMS (ESI-TOF): m/z [M-OH]⁺ = 227.1430 calculated for C₁₆H₁₉O; found 227.1426.

Compound 11b.

Ketone 10 (503 mg, 2.20 mmol) was dissolved in CH₂Cl₂ (11 mL). After cooling the solution to −78 °C, ethylmagnesium bromide (1.1 mL, 3.3 mmol, 3.0 M in Et₂O) was added dropwise. The solution was then warmed to room temperature and stirred for 1 hour. Upon consumption of the starting material as monitored by TLC, the reaction mixture was cooled to 0 °C, quenched with a saturated NH4Cl solution (10 mL), and then diluted with water (10 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were then washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The crude material was purified by column chromatography using 100% hexanes to 90:10 hexanes : EtOAc to afford compound 11b in 87% yield (495 mg, 1.92 mmol) as a colorless oil.

Rf: 0.7 in 90:10 hexanes : EtOAc

¹H NMR: (500 MHz, CDCl₃) δ = 7.36 – 7.29 (m, 4H), 7.22 (tt, J = 6.5, 1.6 Hz, 1H), 5.77 – 5.68 (m, 1H), 5.09 (dq, J = 17.2, 1.6 Hz, 1H), 5.04 (dq, J = 10.4, 1.2 Hz, 1H), 3.86 (d, J = 1.3 Hz, 1H), 3.85 (d, J = 1.4 Hz, 1H), 2.53 – 2.47 (m, 1H), 2.29 – 2.22 (m, 1H), 2.03 (br s, 1H), 1.88 – 1.67 (m, 6H), 0.97 (t, J = 7.5 Hz, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 153.6, 140.3, 134.7, 128.4, 128.2, 126.7, 122.1, 116.4, 74.1, 73.8, 33.9, 32.3, 31.4, 19.4, 8.5.

IR: f (cm⁻¹) = 3456, 3079, 3055, 2965, 2935, 2867, 1645, 1292, 1442, 1336, 1260, 1127, 978.

HRMS (ESI-TOF): m/z [M-OH]⁺ = 241.1587 calculated for C₁₇H₂₁O; found 241.1586.

Compound 11c.

Ketone 10 (484 mg, 2.12 mmol) was dissolved in CH₂Cl₂ (10 mL). After cooling the solution to −78 °C, n-propylmagnesium bromide (1.4 mL, 2.76 mmol, 2.0 M in Et₂O) was added dropwise. The solution was then warmed to room temperature and stirred for 1 hour. Upon consumption of the starting material as monitored by TLC, the reaction mixture was cooled to 0 °C, quenched with a saturated NH₄Cl solution (10 mL), and then diluted with water (10 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were then washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The crude material was purified by column chromatography using 100% hexanes to 95:5 hexanes : EtOAc to afford compound 11c in 88% yield (509 mg, 1.87 mmol) as a colorless oil.

Rf: 0.4 in 80:20 hexanes : EtOAc

¹H NMR: (500 MHz, CDCl₃) δ = 7.35 – 7.29 (m, 4H), 7.23 – 7.20 (m, 1H), 5.73 (ddt, J = 16.0, 10.7, 5.6 Hz, 1H), 5.09 (dq, J = 17.2, 1.6 Hz, 1H), 5.04 (dq, J = 10.4, 1.2 Hz, 1H), 3.89 – 3.82 (m, 2H), 2.54 – 2.46 (m, 1H), 2.28 – 2.20 (m, 1H), 2.03 (s, 1H), 1.86 – 1.75 (m, 4H), 1.74 – 1.67 (m, 2H), 1.49 – 1.38 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 153. 8, 140.3, 134.7, 128.4, 128.2, 126.7, 121.9, 116.4, 74.2, 73.5, 42.3, 34.7, 31.4, 19.5, 17.5, 14.7.

IR: f (cm⁻¹) = 3470, 3081, 3056, 2934, 2870, 1734, 1647, 1492, 1443, 1331, 1132, 978, 923.

HRMS (ESI-TOF): m/z [M-OH]⁺ = 255.1743 calculated for C₁₈H₂₃O; found 255.1730.

Compound 11d.

Ketone 10 (149 mg, 0.657 mmol) was dissolved in CH₂Cl₂ (3.3 mL). After cooling the solution to −78 °C, allylmagnesium bromide (0.85 mL, 0.85 mmol, 1.0 M in Et₂O) was added dropwise. The solution was then warmed to room temperature and stirred for 2 hours. Upon consumption of the starting material as monitored by TLC, the reaction mixture was cooled to 0 °C, quenched with a saturated NH₄Cl solution (5 mL), and then diluted with water (10 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were then washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The crude material was purified by column chromatography using 100% hexanes to 90:10 hexanes : EtOAc to afford compound 11d in 68% yield (120 mg, 0.443 mmol) as a yellow oil.

Rf: 0.4 in 80:20 hexanes : EtOAc

¹H NMR: (500 MHz, CDCl₃) δ = 7.37 – 7.30 (m, 4H), 7.25 – 7.20 (m, 1H), 5.96 – 5.88 (m, 1H), 5.77 – 5.69 (m, 1H), 5.17 – 5.03 (m, 4H), 3.87 (dt, J = 5.6, 1.5 Hz, 2H), 2.55 (d, J = 7.4 Hz, 2H), 2.54 – 2.47 (m, 1H), 2.30 – 2.14 (m, 2H), 1.92 – 1.67 (m, 4H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 153.1, 140.1, 134.6, 134.2, 128.4, 128.2, 126.8, 122.3, 118.1, 116.5, 74.1, 72.9, 44.4, 34.9, 31.3, 19.3.

IR: f (cm⁻¹) = 3445, 3079, 2926, 2865, 2925, 1640, 1492, 1443, 1135, 980.

HRMS (ESI-TOF): m/z [M-OH]⁺ = 253.1587 calculated for C₁₈H₂₁O; found 253.1583.

Compound 11e.

Ketone 10 (1.06 g, 4.64 mmol) was dissolved in CH₂Cl₂ (23 mL). After cooling the solution to −78 °C, n-octylmagnesium bromide (3.5 mL, 7.0 mmol, 2.0 M in Et₂O) was added dropwise. The solution was then warmed to room temperature and stirred for 2 hours. Upon consumption of the starting material as monitored by TLC, the reaction mixture was cooled to 0 °C, quenched with a saturated NH₄Cl solution (20 mL), and then diluted with water (10 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were then washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The crude material was purified by column chromatography using 100% hexanes to 90:10 hexanes : EtOAc to afford compound 11e in 63% yield (1.00 g, 2.93 mmol) as a yellow oil.

Rf: 0.4 in 80:20 hexanes : EtOAc

¹H NMR: (500 MHz, CDCl₃) δ = 7.37 – 7.30 (m, 4H), 7.25 – 7.20 (m, 1H), 5.96 – 5.88 (m, 1H), 5.77 – 5.69 (m, 1H), 5.17 – 5.03 (m, 4H), 3.87 (dt, J = 5.6, 1.5 Hz, 2H), 2.55 (d, J = 7.4 Hz, 2H), 2.54 – 2.47 (m, 1H), 2.30 – 2.14 (m, 2H), 1.92 – 1.67 (m, 4H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 153.1, 140.1, 134.6, 134.2, 128.4, 128.2, 126.8, 122.3, 118.1, 116.5, 74.1, 72.9, 44.4, 34.9, 31.3, 19.3.

IR: f (cm⁻¹) = 3445, 3079, 2926, 2865, 2925, 1640, 1492, 1443, 1135, 980.

HRMS (ESI-TOF): m/z [M-OH]⁺ = 253.1587 calculated for C₁₈H₂₁O; found 253.1583.

Compound 11f.

Ketone 10 (242 mg, 1.06 mmol) was dissolved in CH₂Cl₂ (5.3 mL). After cooling the solution to −78 °C, benzylmagnesium chloride (1.6 mL, 1.6 mmol, 1.0 M in Et₂O) was added dropwise. The solution was then warmed to room temperature and stirred for 5 hours. Upon consumption of the starting material as monitored by TLC, the reaction mixture was cooled to 0 °C, quenched with a saturated NH₄Cl solution (20 mL), and then diluted with water (10 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were then washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The crude material was purified by column chromatography using 90:10 hexanes : EtOAc to afford compound 11f in 43% yield (147 mg, 0.460 mmol) as a colorless oil.

Rf: 0.5 in 80:20 hexanes : EtOAc

¹H NMR: (400 MHz, CDCl₃) δ = 7.38 – 7.29 (m, 8H), 7.27 –7.21 (m, 2H), 5.78 (ddt, J = 17.2, 10.6, 5.5 Hz, 1H), 5.13 (dq, J = 17.2, 1.7 Hz, 1H), 5.07 (dq, J = 10.5, 1.4 Hz, 1H), 3.94 (dt, J = 5.4, 1.5 Hz, 2H), 3.17 (d, J = 13.2 Hz, 1H), 3.06 (d, J = 13.2 Hz, 1H), 2.47 (ddd, J = 17.6, 5.6, 3.8 Hz, 1H), 2.21 (s, 1H), 2.18 – 2.09 (m, 1H), 1.83 – 1.60 (m, 4H).

¹³C{¹H} NMR: (100 MHz, CDCl₃) δ = 152.8, 140.2, 137.5, 134.7, 130.7, 128.3, 128.2, 128.0, 126.8, 126.4, 122.7, 116.4, 74.3, 73.9, 45.6, 34.7, 31.3, 19.2.

IR: f (cm⁻¹) = 3421, 3056, 3025, 2928, 2865, 1642, 1455, 1416, 1337, 1261, 1015, 982.

HRMS (ESI-TOF): m/z [M-OH]⁺ = 303.1754 calculated for C₂₂H₂₃O; found 303.1755.

Compound 11g.

Bromocyclopropane (1.0 mL, 8.3 mmol) was dissolved in THF (10 mL). After cooling to −78 °C, n-BuLi (3.3 mL, 8.3 mmol, 2.5 M in hexanes) was added dropwise. After stirring for 30 minutes, a solution of ketone 10 (633 mg, 2.77 mmol) in THF (4.0 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Upon consumption of the starting material as monitored by TLC, the reaction mixture was cooled to 0 °C, quenched with a saturated NH₄Cl solution (10 mL), and then diluted with water (10 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were then washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The crude material was purified by column chromatography using 100% hexanes to 80:20 hexanes : EtOAc to afford compound 11g in 88% yield (663 mg, 2.45 mmol) as a colorless oil.

Rf: 0.6 in in 90:10 hexanes : EtOAc

¹H NMR: (500 MHz, CDCl₃) δ = 7.38 (d, J = 7.3 Hz, 2H), 7.32 (t, J = 7.7 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 5.72 (ddt, J = 16.1, 10.9, 5.6 Hz, 1H), 5.07 (dd, J = 17.2, 1.6 Hz, 1H), 5.05 – 5.02 (m, 1H), 3.94 (dd, J = 12.3, 5.5 Hz, 1H), 3.80 (dd, J = 12.3, 5.7 Hz, 1H), 2.53 – 2.44 (m, 1H), 2.38 – 2.31 (m, 1H), 2.29 – 2.25 (m, 1H), 1.91 – 1.79 (m, 2H), 1.19 – 1.17 (m, 1H), 0.61 – 0.55 (m, 1H), 0.54 – 0.49 (m, 1H), 0.49 – 0.47 (m, 1H), 0.35 – 0.33 (m, 1H)

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 153.2, 140.0, 134.4, 128.2, 128.1, 126.7, 121.9, 116.6, 73.9, 71.2, 36.5, 31.1, 19.9, 19.5, 2.1, −0.4.

IR: f (cm⁻¹) = 3466, 3079, 3007, 2934, 2868, 1645, 1492, 1443, 1329, 1163, 1020, 973.

HRMS (ESI-TOF): m/z [M-OH]⁺ = 253.1587 calculated for C₁₈H₂₁O; found 253.1582.

Compound 11h.

Ketone 10 (750 mg, 3.29 mmol) was dissolved in CH₂Cl₂ (16 mL). After cooling the solution to −78 °C, phenylmagnesium bromide (1.4 mL, 4.3 mmol, 3.0 M in Et₂O) was added dropwise. The solution was then warmed to room temperature and stirred for 5 hours. Upon consumption of the starting material as monitored by TLC, the reaction mixture was cooled to 0 °C, quenched with a saturated NH₄Cl solution (20 mL), and then diluted with water (10 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were then washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The crude material was purified by column chromatography using 90:10 hexanes : EtOAc to afford compound 11h in 57% yield (577 mg, 2.93 mmol) as a colorless oil.

Rf: 0.3 in 90:10 hexanes : EtOAc

¹H NMR: (400 MHz, CDCl₃) δ = 7.57 – 7.49 (m, 2H), 7.42 – 7.35 (m, 2H), 7.33 – 7.42 (m, 4H), 7.23 – 7.13 (m, 2H), 5.46 (ddt, J = 17.1, 10.2, 5.6 Hz, 1H), 4.89 – 4.79 (m, 2H), 3.80 – 3.65 (m, 2H), 2.82 (s, 1H), 2.56 (ddd, J = 17.1, 8.1, 5.6 Hz, 1H), 2.35 (dt, J = 17.0, 5.4 Hz, 1H), 2.08 (ddd, J = 13.3, 10.4, 3.2 Hz, 1H), 1.93 (ddd, J = 13.2, 7.7, 3.1 Hz, 1H), 1.76 – 1.66 (m, 1H), 1.62 – 1.51 (m, 1H).

¹³C{¹H} NMR: (100 MHz, CDCl₃) δ = 151.9, 147.1, 140.1, 134.4, 128.3, 128.3, 128.0, 127.0, 126.9, 126.2, 122.8, 116.7, 76.0, 74.1, 40.1, 31.2, 19.2.

IR: f (cm⁻¹) = 3457, 3080, 3057, 3024, 2935, 2867, 1646, 1599, 1446, 1329, 1264, 1126, 982.

HRMS (ESI-TOF): m/z [M-OH]⁺ = 289.1598 calculated for C₂₁H₂₁O; found 289.1596.

Compound 12a.

α-Hydroxy allyl vinyl ether 11a (103 mg, 0.422 mmol) was dissolved in DCE (2.1 mL). Indole (74 mg, 0.63 mmol) was then added, followed by Cu(MeCN)₄BF₄ (27 mg, 0.084 mmol). The reaction mixture was stirred at room temperature for 16 hours. Upon consumption of the starting material as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 60:40 hexanes : CH₂Cl₂ to afford compound 12a in 93% yield (134 mg, 0391 mmol) as a yellow oil.

Rf: 0.4 in 50:50 hexanes : CH₂Cl₂

¹H NMR: (500 MHz, CDCl₃) δ = 7.91 (bs, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 6.9 Hz, 2H), 7.36 – 7.30 (m, 3H), 7.24 – 7.21 (m, 1H), 7.20 – 7.16 (m, 1H), 7.13 – 7.08 (m, 2H), 5.38 (ddt, J = 16.1, 10.7, 5.4 Hz, 1H), 4.79 – 4.77 (m, 1H), 4.77 – 4.74 (m, 1H), 3.66 – 3.63 (m, 1H), 3.59 – 3.57 (m, 1H), 2.59 (t, J = 6.2 Hz, 2H), 2.50 – 2.42 (m, 1H), 1.81 – 1.79 (m, 3H), 1.78 (s, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 156.9, 141.6, 137.0, 134.7, 128.5, 128.1, 126.2, 123.0, 123.6, 122.1, 121.5, 120.8, 120.0, 118.9, 115.4, 111.3, 73.8, 40.5, 38.8, 31.7, 25.1, 20.2.

IR: f (cm⁻¹) = 3414, 3078, 3055, 2932, 2866, 2833, 1643, 1491,1457, 1268, 1131, 990.

HRMS (ESI-TOF): m/z [M+K]⁺ = 382.1568 calculated for C₂₄H₂₅NOK; found 382.1566.

Compound 12b.

α-Hydroxy allyl vinyl ether 11b (130 mg, 0.503 mmol) was dissolved in DCE (2.5 mL). Indole (88 mg, 0.75 mmol) was then added, followed by Cu(MeCN)₄BF₄ (31 mg, 0.10 mmol). The reaction mixture was stirred at room temperature for 16 hours. Upon consumption of the starting material as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 60:40 hexanes : CH₂Cl₂ to afford compound 12b in 56% yield (101 mg, 0.282 mmol) as a purple oil.

Rf: 0.5 in 50:50 hexanes : CH₂Cl₂

¹H NMR: (500 MHz, CDCl₃) δ = 7.93 (s, 1H), 7.89 (d, J = 8.1Hz, 1H), 7.45 – 7.42 (m, 2H), 7.36 – 7.31 (m, 3H), 7.24 – 7.20 (m, 1H), 7.18 – 7.14 (m, 1H), 7.12 – 7.06 (m, 2H), 5.43 – 5.35 (m, 1H), 4.82 – 4.75 (m, 2H), 3.72 (ddt, J = 12.8, 5.6, 1.5 Hz, 1H), 3.61 (ddt, J = 12.8, 5.2, 1.6 Hz, 1H), 2.61 – 2.53 (m, 1H), 2.50 – 2.43 (m, 1H), 2.32 – 2.19 (m, 3H), 2.05 – 1.99 (m, 1H), 1.76 – 1.70 (m, 2H), 1.12 (t, J = 7.4 Hz, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 155.6, 142.0, 136.9, 134.8, 128.6, 128.1, 126.2, 123.2, 122.7, 121.3, 120.7, 118.8, 115.3, 111.2, 73.6, 44.5, 34.6, 31.8, 30.6, 20.1, 10.0.

IR: f (cm⁻¹) = 3415, 3054, 3021, 2932, 2870, 1643, 1456, 1336, 1129, 921.

HRMS (ESI-TOF): m/z [M+H]⁺ = 358.2165 calculated for C₂₅H₂₈NO; found 358.2161.

Compound 12c.

α-Hydroxy allyl vinyl ether 11c (130 mg, 0.477 mmol) was dissolved in DCE (2.3 mL). Indole (83 mg, 0.71 mmol) was then added, followed by Cu(MeCN)₄BF₄ (30 mg, 0.095 mmol). The reaction mixture was stirred at room temperature for 16 hours. Upon consumption of the starting material as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 50:50 hexanes : CH₂Cl₂ to afford compound 12c in 94% yield (166 mg, 0.447 mmol) as a purple oil.

Rf: 0.5 in 50:50 hexanes : CH₂Cl₂

¹H NMR: (500 MHz, CDCl₃) δ = 7.94 (bs, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 7.7 Hz, 2H), 7.36 – 7.31 (m, 3H), 7.21 (t, J = 7.3 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.11 – 7.06 (m, 2H), 5.38 (ddt, J = 16.3, 10.7, 5.4 Hz, 1H), 4.80 – 4.77 (m, 2H), 3.69 (dd, J = 12.8, 5.7 Hz, 1H), 3.60 (dd, J = 12.9, 5.1 Hz, 1H), 2.56 (dt, J = 16.8, 5.5 Hz, 1H), 2.47 (dt, J = 16.9, 6.8 Hz, 1H), 2.30 – 2.25 (m, 1H), 2.22 – 2.17 (m, 2H), 2.04 – 1.99 (m, 1H), 1.74 – 1.71 (m, 2H), 1.66 – 1.53 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 155.9, 142.0, 136.9, 134.8, 128.6, 128.1, 126.2, 126.2, 123.3, 122.6, 121.31, 121.28, 120.3, 118.8, 115.3, 111.2, 73.5, 44.3, 40.8, 35.2, 31.8, 20.2, 18.7, 15.1.

IR: f (cm⁻¹) = 3415, 3055, 3020, 2955, 2929, 2868, 1643, 1489, 1417, 1243, 1130, 908.

HRMS (ESI-TOF): m/z [M+H]⁺ = 372.2322 calculated for C₂₆H₂₉NO; Found 372.2318.

Compound 12d.

α-Hydroxy allyl vinyl ether 11d (120 mg, 0.444 mmol) was dissolved in DCE (2.2 mL). Indole (78 mg, 0.67 mmol) was then added, followed by Cu(MeCN)₄BF₄ (28 mg, 0.089 mmol). The reaction mixture was stirred at room temperature for 72 hours. Upon consumption of the starting material as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 75:25 hexanes : CH₂Cl₂ to afford compound 12d in 91% yield (149 mg, 0.403 mmol) as a colorless oil.

Rf: 0.6 in 50:50 hexanes : CH₂Cl₂

¹H NMR: (500 MHz, CDCl₃) δ = 7.96 (bs, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.46 – 7.41 (m, 2H), 7.37 – 7.31 (m, 3H), 7.22 (t, J = 7.4 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.13 – 7.07 (m, 2H), 6.13 – 6.05 (m, 1H), 5.38 (ddt, J = 16.3, 10.7, 5.3 Hz, 1H), 5.27 – 5.19 (m, 1H), 5.13 (dd, J = 10.1, 2.1 Hz, 1H), 4.83 – 4.76 (m, 2H), 3.72 (ddt, J = 12.8, 5.6, 1.6 Hz, 1H), 3.59 (ddt, J = 12.8, 5.2, 1.7 Hz, 1H), 3.11 – 3.07 (m, 1H), 2.97 (dd, J = 14.0, 8.1 Hz, 1H), 2.60 – 2.55 (m, 1H), 2.51 – 2.46 (m, 1H), 2.28 – 2.25 (m, 1H), 2.08 – 2.03 (m, 1H), 1.75 – 1.72 (m, 2H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 155.2, 141.7, 136.9, 136.7, 134.7, 128.5, 128.1, 126.3, 126.1, 122.7, 122.6, 121.4, 121.2, 120.7, 118.9, 116.6, 115.3, 111.3, 73.5, 44.0, 42.6, 35.0, 31.7, 19.9.

IR: f (cm⁻¹) = 3411, 3071, 3058, 2925, 2857, 1719, 1617, 1458, 1132.

HRMS (ESI-TOF): m/z [M+H]⁺ = 370.2165 calculated for C₂₆H₂₈NO; found 370.2174.

Compound 12e.

α-Hydroxy allyl vinyl ether 11e (164 mg, 0.479 mmol) was dissolved in DCE (2.3 mL). Indole (84 mg, 0.72 mmol) was then added, followed by Cu(MeCN)₄BF₄ (30 mg, 0.095 mmol). The reaction mixture was stirred at room temperature for 16 hours. Upon consumption of the starting material as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 60:40 hexanes : CH₂Cl₂ to afford compound 12e in 95% yield (200 mg, 0.453 mmol) as a brown oil.

Rf: 0.6 in in 50:50 hexanes : CH₂Cl₂

¹H NMR: (500 MHz, CDCl₃) δ = 7.98 – 7.92 (m, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.46 – 7.42 (m, 2H), 7.34 (t, J = 7.9 Hz, 3H), 7.22 (t, J = 7.4 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.12 – 7.05 (m, 2H), 5.43 – 5.35 (m, 1H), 4.82 – 4.77 (m, 2H), 3.73 – 3.69 (m, 1H), 3.63 – 3.59 (m, 1H), 2.59 – 2.54 (m, 1H), 2.52– 2.46 (m, 1H), 2.34 – 2.25 (m, 1H), 2.24 – 2.18 (m, 2H), 2.06 – 2.00 (m, 1H), 1.73 (p, J = 6.3 Hz, 2H), 1.67 – 1.49 (m, 2H), 1.42 – 1.28 (m, 10H), 0.93 – 0.90 (m, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 155.9, 142.0, 136.9, 134.8, 128.5, 128.1, 126.2, 126.2, 123.3, 122.6, 121.3, 120.2, 118.8, 115.2, 111.2, 73.5, 44.3, 38.4, 35.1, 31.9, 31.8, 30.7, 29.7, 29.4, 25.4, 22.7, 20.2, 14.1.

IR: f (cm⁻¹) = 3415, 3056, 3019, 2924, 2954, 1699, 1457, 1132.

HRMS (ESI-TOF): m/z [M+H]⁺ = 442.3104 calculated for C₃₁H₄₀NO; found 442.3100.

Compound 12f.

α-Hydroxy allyl vinyl ether 11f (126 mg, 0.394 mmol) was dissolved in DCE (2.0 mL). Indole (69 mg, 1.5 mmol) was then added, followed by Cu(MeCN)₄BF₄ (25 mg, 0.079 mmol). The reaction mixture was stirred at room temperature for 16 hours. Upon consumption of the starting material as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 30:70 hexanes : CH₂Cl₂ to afford compound 12f in 65% yield (107 mg, 0.256 mmol) as a white solid.

Rf: 0.6 in in 50:50 hexanes : CH₂Cl₂

¹H NMR: (400 MHz, CDCl₃) δ = 7.99 (s, 1H), 7.92 (d, J = 7.96 Hz, 1H), 7.46 (dd, J = 8.4, 1.7 Hz, 2H), 7.39 (dt, J = 8.4, 1.7 Hz, 3H), 7.36 – 7.30 (m, 4H), 7.27 – 7.09 (m, 4H), 5.34 (dtt, J = 17.2, 5.2, 5.2 Hz, 1H), 4.84 – 4.75 (m, 2H), 3.83 (d, J = 12.8 Hz, 1H), 3.71 (ddt, J = 12.9, 5.4, 1.5 Hz, 1H), 2.33 (ddd, J = 13.1, 9.2, 3.4 Hz, 1H), 3.32 (d, J = 12.8 Hz, 1H), 2.57 (dt, J = 16.7, 6.1 Hz, 1H), 2.33 (ddd, J = 13.1, 9.2, 3.4 Hz, 1H), 2.08 (dt, J = 16.7, 6.2 Hz, 1H), 1.99 (ddd, J = 13.5, 8.5, 3.2 Hz, 1H), 1.57 – 1.44 (m, 2H), 1.13 – 1.01 (m, 1H).

¹³C{¹H} NMR: (100 MHz, CDCl₃) δ = 153.5, 142.0, 139.3, 136.9, 134.9, 131.1, 128.3, 128.0, 127.7, 126.2, 126.1, 126.1, 123.5, 122.5, 121.7, 121.5, 121.2, 119.0, 115.1, 111.3, 73.5, 45.0, 43.8, 35.2, 31.8, 19.9.

IR: f (cm⁻¹) = 3420, 3056, 3025, 2928, 2865, 1642, 1455, 1337, 1261, 924.

HRMS (ESI-TOF): m/z [M+H]⁺ = 420.2322 calculated for C₃₀H₃₀NO; found 420.2318.

Compound 12g.

α-Hydroxy allyl vinyl ether 11g (120 mg, 0.444 mmol) was dissolved in DCE (2.4 mL). Indole (84 mg, 0.721 mmol) was then added, followed by Cu(MeCN)₄BF₄ (30 mg, 0.096 mmol). The reaction mixture was stirred at room temperature for 3 hours. Upon consumption of the starting material as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 60:40 hexanes : CH₂Cl₂ to afford compound 12g in 86% yield (142 mg, 0.384 mmol) as a white solid.

Rf: 0.6 in in 50:50 hexanes : CH₂Cl₂

¹H NMR: (500 MHz, CDCl₃) δ = 7.97 (d, J = 8.1 Hz, 1H), 7.96 (bs, 1H), 7.51 – 7.46 (m, 2H), 7.40 – 7.34 (m, 3H), 7.32 (d, J = 2.4 Hz, 1H), 7.25 – 7.21 (m, 1H), 7.18 (t, J = 6.9 Hz, 1H), 7.12 (t, J = 6.9 Hz, 1H), 5.36 – 5.33 (m, 1H), 4.78 – 4.74 (m, 2H), 3.80 (ddt, J = 12.7, 5.5, 1.5 Hz, 1H), 3.62 (ddt, J = 12.7, 5.2, 1.6 Hz, 1H), 2.53 – 2.48 (m, 2H), 2.20 – 2.13 (m, 1H), 1.85 – 1.76 (m, 1H), 1.76 – 1.66 (m, 1H), 1.60 – 1.53 (m, 1H), 1.53 – 1.46 (m, 1H), 0.95 – 0.88 (m, 1H), 0.83 – 0.76 (m, 1H), 0.68 – 0.62 (m, 1H), 0.60 – 0.52 (m, 1H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 155.4, 141.9, 136.9, 134.8, 128.3, 128.1, 126.2, 126.2, 123.6, 123.5, 121.3, 121.2, 121.0, 118.8, 115.2, 111.2, 73.6, 43.1, 32.9, 31.5, 19.6, 18.8, 3.8, 1.8.

IR: f (cm⁻¹) = 3412, 3055, 3017, 2930, 2865, 2865, 1643, 1455, 1490, 1417, 1335, 1265, 1123.

HRMS (ESI-TOF): m/z [M+H]⁺ = 370.2165 calculated for C₂₆H₂₈NO; found 370.2162.

Compound 12h.

α-Hydroxy allyl vinyl ether 11h (102 mg, 0.251 mmol) was dissolved in DCE (1.3 mL). Indole (44 mg, 0.38 mmol) was then added, followed by Cu(MeCN)₄BF₄ (16 mg, 0.050 mmol). The reaction mixture was stirred at room temperature for 120 hours. Upon consumption of the starting material as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 50:50 hexanes : CH₂Cl₂ to afford compound 12h in 38% yield (38 mg, 0.099 mmol) as a white solid.

Rf: 0.4 in in 50:50 hexanes : CH₂Cl₂

¹H NMR: (400 MHz, CDCl₃) δ = 7.87 (s, 1H), 7.47 – 7.40 (m, 4H), 7.27 – 7.16 (m, 4H), 7.16 – 7.09 (m, 3H), 7.02 (dddd, J = 9.5, 8.2, 1.1 Hz, 2H), 6.79 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 4.81 (ddt, J = 17.1, 10.2, 6.0 Hz, 1H), 4.48 (dp, J = 10.3, 1.1 Hz, 1H), 4.33 (dq, J = 17.1, 1.6 Hz, 1H), 3.12 – 3.01 (m, 2H), 2.66 (ddd, J = 12.6, 8.1, 4.0 Hz, 1H), 2.50 – 2.35 (m, 3H), 1.61 – 1.44 (m, 2H).

¹³C{¹H} NMR: (100 MHz, CDCl₃) δ = 154.4, 145.9, 141.6, 137.0, 134.2, 129.2, 128.1, 128.1, 127.6, 126.8, 126.3, 126.0, 124.3, 122.5, 122.3, 121.7, 121.4, 118.7, 116.2, 110.9, 73.8, 49.8, 37.6, 31.5, 19.4.

IR: f (cm⁻¹) = 3418, 3078, 3055, 2935, 2866, 1643, 1491, 1338, 927.

HRMS (ESI-TOF): m/z [M+H]⁺ = 406.2165 calculated for C₂₉H₂₈O; found 406.2165.

Catalysis:

α-Hydroxy allyl vinyl ether 11a (100 mg, 0.409 mmol) was dissolved in DCE (2.0 mL). Indole (72 mg, 0.61 mmol) was then added, followed by Cu(MeCN)₄BF₄ (26 mg, 0.082 mmol). The reaction mixture was stirred at room temperature for 24 hours. Upon consumption of the starting material as monitored by TLC, the solution was heated to 83 °C in an oil bath for 16 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 90:10 hexanes : CH₂Cl₂ to afford compound trans-13a in 94% yield (132 mg, 0.384 mmol) as a white solid. ¹H NMR analysis of the crude reaction mixture indicated the ratio of trans-13a : cis-13a to be >20:1 dr.

Background:

Allyl vinyl ether 12a (140 mg, 0.408 mmol) was dissolved in DCE (2.0 mL). The solution was heated to 83 °C in an oil bath for 112 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 50:50 hexanes : CH₂Cl₂ to afford compound trans-13a in 79% yield (111 mg, 0.323 mmol) as a white solid and cis-13a in 12% yield (17 mg, 0.049 mmol) as a colorless oil. ¹H NMR analysis of the crude reaction mixture indicated the ratio of trans-13a : cis-13a to be 5.4:1 dr.

Diastereomer trans-13a

Rf: 0.6 Rf in 50:50 hexanes : CH₂Cl₂

¹H NMR: (500 MHz, CDCl₃) δ = 7.70 (d, J = 7.7 Hz, 1H), 7.47 (bs, 1H), 7.10 – 7.03 (m, 3H), 6.83 (d, J = 8.5 Hz, 2H), 6.69 – 6.67 (m, 2H), 6.59 (t, J = 7.7 Hz, 2H), 5.34 – 5.26 (m, 1H), 4.89 – 4.85 (m, 2H), 2.63 – 2.59 (m, 3H), 2.58 – 2.43 (m, 2H), 1.92 – 1.89 (m, 1H), 1.88 – 1.79 (m, 2H), 1.55 (s, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 212.6, 139.6, 136.4, 134.8, 126.7, 126.2, 125.7, 125.3, 121.6, 121.3, 120.8, 119.1, 118.3, 117.4, 110.6, 55.2, 49.0, 46.7, 39.2, 33.5, 27.4, 18.7.

IR: f (cm⁻¹) = 3373, 2955, 2861, 1681, 1460, 1421, 1343, 1245, 1105, 917.

HRMS (ESI-TOF): m/z [M+H]⁺ = 344.2009 calculated for C₂₄H₂₆NO; found 344.2018.

X-Ray Structure: CCDC 2072233. The ellipsoid contour was set at a 50% probability level.

Diastereomer cis-13a

Rf: 0.3 Rf in 20:40 hexanes : CH₂Cl₂

¹H NMR (400 MHz, CDCl₃) δ = 7.98 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.42 – 7.32 (m, 5H), 7.30 – 7.26 (m, 1H), 7.19 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.11 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 6.95 (d, J = 2.2 Hz, 1H), 5.51– 5.40 (m, 1H), 4.96 – 4.89 (m, 2H), 2.65 – 2.46 (m, 4H), 2.10 – 2.00 (m, 2H), 1.87 – 1.77 (m, 1H), 1.76 – 1.68 (m, 1H), 1.26 (s, 3H).

¹³C{1H} NMR: (125 MHz, CDCl₃) δ = 213.6, 140.8, 137.1, 134.5, 128.6, 126.7, 126.2, 125.5, 121.8, 121.1, 121.1, 120.9, 119.2, 117.8, 111.4, 55.1, 49.6, 47.0, 36.9, 30.3, 26.1, 17.7.

IR: f (cm⁻¹) = 3374, 2957, 2924, 2860, 1681, 1421, 1343, 1245, 1120, 1011, 917.

HRMS (ESI-TOF): m/z [M+H]⁺ = 344.2009 calculated for C₂₄H₂₆NO; found 344.2018.

Catalysis:

α-Hydroxy allyl vinyl ether 11b (146 mg, 0.565 mmol) was dissolved in DCE (2.8 mL). Indole (99 mg, 0.85 mmol) was then added, followed by Cu(MeCN)₄BF₄ (35 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 20 hours. Upon consumption of the starting material as monitored by TLC, the solution was heated to 83 °C in an oil bath for 42 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 50:50 hexanes : CH₂Cl₂ to afford compound trans-13b in 33% yield (66 mg, 0.18 mmol) as a white solid and cis-13b in 32% yield (64 mg, 0.18 mmol) as a colorless oil. ¹H NMR analysis of the crude reaction mixture indicated the ratio of trans-13b : cis-13b to be 1:1.2 dr.

Background:

Allyl vinyl ether 12b (78 mg, 0.22 mmol) was dissolved in DCE (1.1 mL). The solution was heated to 83 °C in an oil bath for 114 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 50:50 hexanes : CH₂Cl₂ to afford compound trans-13b in 37% yield (29 mg, 0.081 mmol) as a white solid and cis-13b in 63% yield (49 mg, 0.14 mmol) as a colorless oil. ¹H NMR analysis of the crude reaction mixture indicated the ratio of trans-13b : cis-13b to be 1:1.7 dr.

Diastereomer trans-13b

Rf: 0.5 in 50:50 hexanes : CH₂Cl₂

¹H NMR: (500 MHz, CDCl₃) δ = 7.75 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.09 – 7.02 (m, 3H), 6.80 (d, J = 8.2 Hz, 2H), 6.70 – 6.64 (m, 2H), 6.57 (t, J = 7.7 Hz, 2H), 5.36 – 5.26 (m, 1H), 4.89 (bs, 1H), 4.88 – 4.84 (m, 1H), 2.64 – 2.40 (m, 6H), 1.90 – 1.74 (m, 4H), 0.56 (t, J = 7.5 Hz, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 212.3, 139.9, 136.5, 134.8, 126.6, 126.2, 125.6, 125.2, 122.4, 121.5, 121.4, 119.1, 117.3, 115.8, 110.5, 55.3, 52.5, 46.8, 34.8, 33.1, 30.6, 18.5, 7.9.

IR: f (cm⁻¹) = 3393, 3041, 3022, 2944, 2879, 1683, 1457, 944.

HRMS (ESI-TOF): m/z [M+H]⁺ = 358.2165 calculated for C₂₅H₂₈NO; Found 358.2169.

X-Ray Structure: CCDC 2072242. The ellipsoid contour was set at a 50% probability level.

Diastereomer cis-13b

Rf: 0.2 in 50:50 hexanes : CH₂Cl₂

¹H NMR: (500 MHz, CDCl₃) δ = 8.10 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.43 – 7.34 (m, 5H), 7.30 – 7.26 (m, 1H), 7.19 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.11 (td, J = 7.5, 6.9, 1.1 Hz, 1H), 6.98 (d, J = 2.3 Hz, 1H), 5.39 – 5.30 (m, 1H), 4.88 – 4.79 (m, 2H), 2.63 (ddt, J = 13.9, 6.9, 1.4 Hz, 1H), 2.50 (dd, J = 13.9, 7.7 Hz, 1H), 2.41 – 2.30 (m, 2H), 2.04 – 1.92 (m, 2H), 1.90 – 1.82 (m, 2H), 1.80 – 1.69 (m, 2H), 0.57 (t, J = 7.4 Hz, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 213.2, 140.3, 136.9, 134.5, 128.5, 126.6, 126.3, 126.0, 122.1, 121.8, 121.3, 119.4, 117.6, 117.3, 111.3, 54.8, 52.9, 46.6, 31.2, 29.2, 28.0, 16.9, 8.8.

IR: f (cm⁻¹) = 3403, 3056, 2944, 2875, 1690, 1457, 1378, 1104, 998, 907.

HRMS (ESI-TOF): m/z [M+H]⁺ = 358.2165 calculated for C₂₅H₂₈NO; Found 358.2169

Catalysis:

α-Hydroxy allyl vinyl ether 11c (155 mg, 0.569 mmol) was dissolved in DCE (2.8 mL). Indole (100 mg, 0.854 mmol) was then added, followed by Cu(MeCN)₄BF₄ (35 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 16 hours. Upon consumption of the starting material as monitored by TLC, the solution was heated to 83 °C in an oil bath for 48 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 50:50 hexanes : CH₂Cl₂ to afford compound trans-13c in 38% yield (80 mg, 0.22 mmol) as a white solid and cis-13c in 41% yield (86 mg, 0.24 mmol) as a colorless oil. ¹H NMR analysis of the crude reaction mixture indicated the ratio of trans-13c : cis-13c to be 1:1.0 dr.

Background:

Allyl vinyl ether 12c (104 mg, 0.280 mmol) was dissolved in DCE (1.4 mL). The solution was heated to 83 °C in an oil bath for 114 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 50:50 hexanes : CH₂Cl₂ to afford compound trans-13c in 25% yield (26 mg, 0.070 mmol) as a white solid and cis-13c in 56% yield (59 mg, 0.16 mmol) as a colorless oil. ¹H NMR analysis of the crude reaction mixture indicated the ratio of trans-13c : cis-13c to be 1:2.0 dr.

Diastereomer trans-13c

Rf: 0.5 in 40:20 hexanes : CH₂Cl₂ (TLC was run twice)

¹H NMR: (500 MHz, CDCl₃) δ = 7.77 (d, J = 7.8 Hz, 1H), 7.47 (bs, 1H), 7.10 – 7.03 (m, 3H), 6.79 (d, J = 8.4 Hz, 2H), 6.68 (t, J = 7.3 Hz, 1H), 6.64 (d, J = 2.9 Hz, 1H), 6.57 (t, J = 7.6 Hz, 2H), 5.35 – 5.27 (m, 1H), 4.89 (bs, 1H), 4.86 (d, J = 6.0 Hz, 1H), 2.63 – 2.53 (m, 3H), 2.49 – 2.39 (m, 3H), 1.89 – 1.82 (m, 2H), 1.81 – 1.70 (m, 2H), 1.13 – 1.07 (m, 1H), 0.81 – 0.71 (m, 4H).

¹³C{1H} NMR: (125 MHz, CDCl3) δ = 212.1, 139.9, 136.5, 134.9, 126.7, 126.3, 125.6, 125.2, 122.1, 121.5, 121.5, 119.1, 117.3, 116.3, 110.5, 55.2, 52.4, 46.9, 40.5, 35.5, 33.0, 18.6, 16.7, 14.7.

IR: f (cm⁻¹) = 3345, 3059, 2952, 2927, 2856, 1678, 1572, 1427, 1241, 1014, 995.

HRMS (ESI-TOF): m/z [M+H]⁺ = 372.2322 calculated for C₂₆H₃₀NO; found 372.2321.

Diastereomer cis-13c

Rf: 0.3 in 40:20 hexanes : CH₂Cl₂ (TLC was run twice)

¹H NMR: (500 MHz, CDCl₃) δ = 8.03 (bs, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.41 – 7.35 (m, 5H), 7.28 – 7.26 (m, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 2.8 Hz, 1H), 5.39 – 5.27 (m, 1H), 4.84 – 4.83 (m, 1H), 4.81 (bs, 1H), 2.61 (dd, J = 13.9, 6.9 Hz, 1H), 2.48 (dd, J = 13.9, 7.8 Hz, 1H), 2.40 – 2.31 (m, 2H), 1.99 – 1.78 (m, 4H), 1.74 – 1.63 (m, 2H), 1.10 – 1.02 (m, 1H), 0.89 – 0.80 (m, 1H), 0.64 (t, J = 7.2 Hz, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 213.0, 140.4, 136.9, 134.5, 128.5, 126.6, 126.3, 126.0, 121.9, 121.8, 121.3, 119.5, 117.7, 117.6, 111.2, 54.8, 52.7, 46.6, 41.3, 29.7, 27.7, 17.5, 16.9, 14.4.

IR: f (cm⁻¹) = 3323, 3084, 3053, 2960, 2921, 2858, 1681, 1572, 1430, 1244, 1032, 905.

HRMS (ESI-TOF): m/z [M+H]⁺ = 372.2322 calculated for C₂₆H₃₀NO; found 372.2324.

Catalysis:

α-Hydroxy allyl vinyl ether 11d (150 mg, 0.555 mmol) was dissolved in DCE (2.8 mL). Indole (129 mg, 1.10 mmol) was then added, followed by Cu(MeCN)₄BF₄ (35 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 40 hours. Upon consumption of the starting material as monitored by TLC, the solution was heated to 83 °C in an oil bath for 72 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 60:40 hexanes : CH₂Cl₂ to afford compound trans-13d in 49% yield (100 mg, 0.270 mmol) as a white solid as a white solid and cis-13d in 23% yield (47 mg, 0.13 mmol) as a colorless oil. ¹H NMR analysis of the crude reaction mixture indicated the ratio of trans-13d : cis-13d to be 2.7:1 dr.

Background:

Allyl vinyl ether 12d (50 mg, 0.14 mmol) was dissolved in DCE (0.7 mL). The solution was heated to 83 °C in an oil bath for 144 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 50:50 hexanes : CH₂Cl₂ to afford compound trans-13d in 30% yield (15 mg, 0.041 mmol) as a white solid and cis-13c in 56% yield (28 mg, 0.076 mmol) as a colorless oil. ¹H NMR analysis of the crude reaction mixture indicated the ratio of trans-13d : cis-13d to be 1:1.8 dr.

Diastereomer trans-13d

Rf: 0.7 in 40:20 hexanes : CH₂Cl₂ (TLC was run three times)

¹H NMR: (500 MHz, CDCl₃) δ = 7.77 (d, J = 7.0 Hz, 1H), 7.49 (bs, 1H), 7.12 – 7.03 (m, 3H), 6.80 – 6.77 (m, 2H), 6.70 – 6.65 (m, 2H), 6.56 (t, J = 7.7 Hz, 2H), 5.44 – 5.26 (m, 2H), 4.95 – 4.84 (m, 4H), 3.16 (ddt, J = 14.0, 6.4, 1.5 Hz, 1H), 2.66 – 2.55 (m, 3H), 2.52 – 2.39 (m, 3H), 1.95 – 1.75 (m, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 211.5, 139.7, 136.5, 135.2, 134.7, 126.7, 126.1, 125.6, 125.3, 122.0, 121.6, 121.4, 119.3, 117.4, 117.0, 115.9, 110.6, 55.3, 51.8, 46.8, 43.0, 35.7, 33.3, 18.5.

IR: f (cm⁻¹) = 3412, 3069, 2924, 2857, 1690, 1459.

HRMS (ESI-TOF): m/z [M+H]⁺ = 370.2165 calculated for C₂₆H₂₈NO; found 370.2166.

X-Ray Structure: CCDC 2072243. The ellipsoid contour was set at a 50% probability level.

Diastereomer cis-13d

Rf: 0.3 in 40:20 hexanes : CH₂Cl₂ (TLC was run three times)

¹H NMR: (500 MHz, CDCl₃) δ = 8.08 (bs, 1H), 7.81 (dd, J = 8.1, 1.0 Hz, 1H), 7.43 – 7.34 (m, 5H), 7.30 – 7.24 (m, 1H), 7.22 – 7.17 (m, 1H), 7.14 – 7.09 (m, 1H), 7.02 (d, J = 2.4 Hz, 1H), 5.43 – 5.27 (m, 2H), 4.85 – 4.77 (m, 4H), 2.79 – 2.72 (m, 1H), 2.60 – 2.54 (m, 1H), 2.51 – 2.43 (m, 2H), 2.38 – 2.29 (m, 2H), 1.97 – 1.80 (m, 3H), 1.73 – 1.64 (m, 1H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 212.4, 140.2, 136.9, 134.8, 134.4, 128.5, 126.7, 126.4, 125.9, 122.1, 121.9, 121.4, 119.6, 117.6, 117.2, 116.9, 111.3, 54.9, 52.1, 46.4, 43.3, 29.2, 27.8, 16.8.

IR: f (cm⁻¹) = 3406, 3072, 2949, 2927, 2872, 1697, 1458.

HRMS (ESI-TOF): m/z [M+H]⁺ = 370.2165 calculated for C₂₆H₂₈NO; Found 370.2162.

Catalysis:

α-Hydroxy allyl vinyl ether 11e (154 mg, 0.450 mmol) was dissolved in DCE (2.2 mL). Indole (86 mg, 0.74 mmol) was then added, followed by Cu(MeCN)₄BF₄ (31 mg, 0.099 mmol). The reaction mixture was stirred at room temperature for 6 hours. Upon consumption of the starting material as monitored by TLC, the solution was heated to 83 °C in an oil bath for 24 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 60:40 hexanes : CH₂Cl₂ to afford compound trans-13e in 28% yield (55 mg, 0.125 mmol) as an off-white solid as a white solid and cis-13e in 53% yield (105 mg, 0.238 mmol) as a yellow oil. Diastereomeric ratio could not be determined from the crude reaction mixture by ¹H NMR due to overlapping signals.

Background:

Allyl vinyl ether 12e (40 mg, 0.091 mmol) was dissolved in DCE (0.6 mL). The solution was heated to 83 °C in an oil bath for 90 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 50:50 hexanes : CH₂Cl₂ to afford compound trans-13e in 28% yield (11 mg, 0.025 mmol) and cis-13e in 57% yield (23 mg, 0.052 mmol) as pink solid. ¹H NMR analysis of the crude reaction mixture indicated the ratio of trans-13e : cis-13e to be 1:1.8 dr.

Diastereomer trans-13e

Rf: 0.6 in 40:20 hexanes : CH₂Cl₂

¹H NMR: (400 MHz, CDCl₃) δ = 7.76 (d, J = 7.8 Hz, 1H), 7.47 (bs, 1H), 7.09 – 7.02 (m, 3H), 6.79 (d, J = 7.5 Hz, 2H), 6.68 (t, J = 7.2 Hz, 1H), 6.64 (d, J = 2.6 Hz, 1H), 6.57 (t, J = 7.8 Hz, 2H), 5.31 (ddt, J = 15.0, 11.2, 7.8 Hz, 1H), 4.89 (s, 1H), 4.86 (d, J = 5.0 Hz, 1H), 2.63 – 2.52 (m, 3H), 2.51 – 2.38 (m, 3H), 1.88 – 1.73 (m, 4H), 1.23 – 1.05 (m, 12H), 0.82 (t, J = 7.3 Hz, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 212.2, 139.9, 136.5, 134.9, 126.7, 126.2, 125.6, 125.2, 122.1, 121.5, 119.1, 117.3, 116.3, 110.5, 55.2, 52.3, 46.9, 38.1, 35.5, 31.8, 30.2, 29.5, 29.3, 23.5, 22.6, 18.6, 14.1.

IR: f (cm⁻¹) = 3406, 3055, 3033, 2960, 2926, 2860, 1685, 1459.

HRMS (ESI-TOF): m/z [M+H]⁺ = 442.3104 calculated for C₃₁H₄₀NO; found 442.3107.

X-Ray Structure: CCDC 2072244. The ellipsoid contour was set at a 50% probability level.

Diastereomer cis-13e

Rf: 0.3 in 40:20 hexanes : CH₂Cl₂

¹H NMR: (500 MHz, CDCl₃) δ = 8.05 (bs, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.42 – 7.34 (m, 5H), 7.28 (d, J = 6.8 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 2.6 Hz, 1H), 5.39 – 5.29 (m, 1H), 4.85 (d, J = 3.5 Hz, 1H), 4.82 (s, 1H), 2.64 (dd, J = 13.9, 6.9 Hz, 1H), 2.49 (dd, J = 14.0, 7.9 Hz, 1H), 2.40 – 2.31 (m, 2H), 2.00 – 1.79 (m, 4H), 1.77 – 1.60 (m, 2H), 1.27 – 1.00 (m, 12H), 0.83 (t, J = 7.2 Hz, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 213.0, 140.3, 136.9, 134.5, 128.5, 126.6, 126.3, 126.0, 121.9, 121.8, 121.3, 119.4, 117.8, 117.6, 111.2, 54.8, 52.8, 46.7, 38.6, 31.8, 30.1, 29.9, 29.3, 29.2, 28.1, 24.1, 22.6, 17.0, 14.1.

IR: f (cm⁻¹) = 3394, 3088, 3057, 2925, 2854, 1694, 1459.

HRMS (ESI-TOF): m/z [M+H]⁺ = 442.3104 calculated for C₃₁H₄₀NO; found 442.3104.

Catalysis:

α-Hydroxy allyl vinyl ether 11f (95 mg, 0.30 mmol) was dissolved in DCE (1.5 mL). Indole (52 mg, 0.44 mmol) was then added, followed by Cu(MeCN)₄BF₄ (19 mg, 0.059 mmol). The reaction mixture was stirred at room temperature for 21 hours. Upon consumption of the starting material as monitored by TLC, the solution was heated to 83 °C in an oil bath for 136 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 70:30 hexanes : CH₂Cl₂ to 30:70 hexanes : CH₂Cl₂ to afford compound trans-13f in 13% yield (16 mg, 0.037 mmol) as a white solid and cis-13f in 42% yield (52 mg, 0.12 mmol) as a white solid. ¹H NMR analysis of the crude reaction mixture indicated the ratio of trans-13f : cis-13f to be 1:1.9 dr.

Background:

Allyl vinyl ether 12f (93 mg, 0.22 mmol) was dissolved in DCE (1.0 mL). The solution was heated to 83 °C in an oil bath for 34 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 70:30 hexanes : CH₂Cl₂ to 30:70 hexanes : CH₂Cl₂ to afford compound trans-13f in 19% yield (17 mg, 0.041 mmol) as a white solid and cis-13f in 56% yield (52 mg, 0.12 mmol) as a white solid. ¹H NMR analysis of the crude reaction mixture indicated the ratio of trans-13f : cis-13f to be 1:2.5 dr.

Diastereomer trans-13f

Rf: 0.7 in 50:50 hexanes : CH₂Cl₂

¹H NMR: (400 MHz, CDCl₃) δ = 7.90 – 7.85 (m, 1H), 7.45 (s, 1H), 7.16 – 7.07 (m, 3H), 7.00 (dtt, J = 20.8, 8.7, 1.4 Hz, 3H), 6.82 (dt, J = 8.2, 1.1 Hz, 2H), 6.64 (tt, J = 6.5, 1.2 Hz, 1H), 6.54 (td, J = 6.4, 1.7, 4H), 6.40 (d, J = 2.6 Hz, 1H), 5.78 (ddt, J = 17.2, 10.6, 5.5 Hz, 1H), 4.92 – 4.85, (m, 2H), 3.90 (d, J = 13.4 Hz, 1H), 3.01 (d, J = 13.4 Hz, 1H), 2.69 – 2.55 (m, 2H), 2.50 (ddt, J = 14.0, 8.0, 1.1 Hz, 1H), 2.45 – 2.32 (m, 1H), 2.13 (dq, J = 14.3, 3.3 Hz, 1H), 1.93 – 1.73 (m, 3H).

¹³C{¹H} NMR: (100 MHz, CDCl₃) δ = 211.7, 139.5, 138.3, 136.4, 134.7, 130.5, 127.1, 126.6, 126.5, 125.7, 125.7, 125.2, 122.7, 121.7, 121.5, 119.5, 117.4, 115.0, 110.7, 55.5, 52.9, 46.9, 43.9, 36.0, 33.6, 18.4.

IR: f (cm⁻¹) = 3424, 3058, 3027, 2924, 2858, 1690, 1451, 916.

HRMS (ESI-TOF): m/z [M+H]⁺ = 420.2322 calculated for C₃₀H₃₀NO; found 420.2324.

X-Ray Structure: CCDC 2405594. The ellipsoid contour was set at a 50% probability level.

Diastereomer cis-13f

Rf: 0.5 in 50:50 hexanes : CH₂Cl₂

¹H NMR: (500 MHz, CDCl₃) δ = 8.06 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.39 (dt, J = 8.1, 0.9 Hz, 1H), 7.31 – 7.19 (m, 7H), 7.12 (ddd, J = 8.2, 7.0, 1.2, Hz, 1H), 7.05 (tt, J = 5.9, 1.7 Hz, 1H), 7.00 (tt, J = 5.8, 1.6 Hz, 2H), 6.85 (d, J = 2.6 Hz, 1H), 6.62 (dd, J = 6.8, 1.6 Hz, 2H), 5.29 (ddt, J = 16.8, 10.4, 7.3 Hz, 1H), 4.78 (dp, J = 9.4, 1.3 Hz, 1H), 4.75 (td, J = 1.8, 0.6 Hz, 1H), 3.49 (d, J = 13.3 Hz, 1H), 2.96 (d, J = 13.3 Hz, 1H), 2.49 (dt, J = 7.2, 1.2 Hz, 2H), 2.25 – 2.12 (m, 2H), 1.88 −1.76 (m, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 212.4, 140.4, 137.8, 136.9, 134.4, 130.8, 128.4, 127.2, 126.5, 126.2, 126.1, 125.9, 122.4, 122.0, 121.6, 119.8, 117.5, 115.8, 111.2, 55.1, 53.0, 46.0, 45.0, 27.7, 27.1, 16.6.

IR: f (cm⁻¹) = 3414, 3058, 3028, 2950, 2872, 1698, 1456, 917.

HRMS (ESI-TOF): m/z [M+H]⁺ = 420.2322 calculated for C₃₀H₃₀NO; found 420.2323.

X-Ray Structure: CCDC 2405595. The ellipsoid contour was set at a 50% probability level.

Catalysis:

α-Hydroxy allyl vinyl ether 11g (150 mg, 0.555 mmol) was dissolved in DCE (2.8 mL). Indole (97 mg, 0.83 mmol) was then added, followed by Cu(MeCN)₄BF₄ (38 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 2 hours. Upon consumption of the starting material as monitored by TLC, the solution was heated to 83 °C in an oil bath for 24 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 60:40 hexanes : CH₂Cl₂ to afford compound trans-13g in 49% yield (100 mg, 0.270 mmol) as a white solid and cis-13g in 24% yield (50 mg, 0.14 mmol) as a colorless oil. Diastereomeric ratio could not be determined from the crude reaction mixture by ¹H NMR due to overlapping signals.

Background:

Allyl vinyl ether 12g (24 mg, 0.065 mmol) was dissolved in DCE (0.7 mL). The solution was heated to 83 °C in an oil bath for 65 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 100% hexanes to 50:50 hexanes : CH₂Cl₂ to afford compound trans-13g in 59% yield (14 mg, 0.038 mmol) as a white solid and cis-13g in 20% yield (5 mg, 0.013 mmol) as a colorless oil. ¹H NMR analysis of the crude reaction mixture indicated the ratio of trans-13g : cis-13g to be 3.3:1 dr.

Diastereomer trans-13g

Rf: 0.4 in 50:50 hexanes : CH₂Cl₂

¹H NMR: (400 MHz, CDCl₃) δ = 7.67 (d, J = 8.7 Hz, 1H), 7.54 (bs, 1H), 7.05 (d, J = 3.6 Hz, 2H), 7.03 – 6.98 (m, 1H), 6.93 – 6.90 (m, 2H), 6.72 – 6.68 (m, 1H), 6.66 – 6.62 (m, 2H), 6.60 (d, J = 2.6 Hz, 1H), 5.34 – 5.24 (m, 1H), 4.91 – 4.86 (m, 2H), 2.75 – 2.69 (m, 1H), 2.57 – 2.47 (m, 2H), 2.43 – 2.33 (m, 2H), 1.89 – 1.75 (m, 3H), 1.64 (m, 1H), 0.40 – 0.35 (m, 2H), 0.15 – 0.10 (m, 1H), 0.02 – −0.03 (m, 1H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 212.2, 139.6, 136.2, 134.8, 126.7, 126.6, 125.9, 125.3, 122.7, 122.0, 121.5, 119.1, 117.4, 113.9, 110.5, 55.1, 52.5, 46.8, 33.9, 32.9, 19.8, 18.5, 2.8, 0.5.

IR: f (cm⁻¹) = 3401, 3063, 2953, 2867, 1689, 1458, 1429, 1244, 1107, 964.

HRMS (ESI-TOF): m/z [M+H]⁺ = 370.2165 calculated for C₂₆H₂₈NO; found 370.2163.

X-Ray Structure: CCDC 2072245. The ellipsoid contour was set at a 50% probability level.

Diastereomer cis-13g

Rf: 0.2 in 50:50 hexanes : CH₂Cl₂

¹H NMR: (500 MHz, CDCl₃) δ = 8.09 (bs, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.41 – 7.34 (m, 4H), 7.26 (m merged, 2H), 7.17 (t, J = 8.0 Hz, 1H), 7.09 (t, J = 8.1 Hz, 1H), 7.00 (d, J = 2.5 Hz, 1H), 5.44 – 5.35 (m, 1H), 4.88 – 4.81 (m, 2H), 2.57 (dd, J = 13.8, 6.9 Hz, 1H), 2.48 (dd, J = 13.9, 7.8 Hz, 1H), 2.34 – 2.21 (m, 2H), 1.90 – 1.77 (m, 1H), 1.78 – 1.70 (m, 2H), 1.54 – 1.45 (m, 1H), 1.18 (m, 1H), 0.45 – 0.38 (m, 1H), 0.27 – 0.22 (m, 1H), 0.15 – 0.08 (m, 1H), −0.14 – −0.19 (m, 1H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 213.7, 140.4, 136.9, 134.6, 128.5, 126.6, 126.5, 126.3, 123.3, 121.8, 121.4, 119.7, 117.6, 114.4, 111.3, 54.8, 51.9, 46.3, 27.0, 26.2, 20.5, 16.5, 3.0, 0.6.

IR: f (cm⁻¹) = 3409, 3059, 3005, 2948, 2874, 1694, 1459, 1244, 1107.

HRMS (ESI-TOF): m/z [M+H]⁺ = 370.2165 calculated for C₂₆H₂₈NO; found 370.2162.

X-Ray Structure: CCDC 2072246. The ellipsoid contour was set at a 50% probability level.

Catalysis:

α-Hydroxy allyl vinyl ether 11h (123 mg, 0.401 mmol) was dissolved in DCE (2.1 mL). Indole (71 mg, 0.60 mmol) was then added, followed by Cu(MeCN)₄BF₄ (25 mg, 0.082 mmol). The reaction mixture was stirred at room temperature for 120 hours. Upon consumption of the starting material as monitored by TLC, the solution was heated to 83 °C in an oil bath for 36 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 50:50 hexanes : CH₂Cl₂ to afford compound trans-13h in 40% yield (65 mg, 0.16 mmol) as a pink solid and cis-13h in 36% yield (58 mg, 0.14 mmol) as a white solid. ¹H NMR analysis of the crude reaction mixture indicated the ratio of trans-13h : cis-13h to be 1.0:1 dr.

Background:

Allyl vinyl ether 12h (30 mg, 0.065 mmol) was dissolved in DCE (0.4 mL). The solution was heated to 83 °C in an oil bath for 72 hours. Once the Claisen rearrangement was complete as monitored by TLC, the crude reaction mixture was concentrated under vacuum and then purified by column chromatography using 50:50 hexanes : CH₂Cl₂ to afford compound trans-13h in 47% yield (14 mg, 0.035 mmol) as a pink solid and cis-13h in 41% yield (12 mg, 0.023 mmol) as a white solid. ¹H NMR analysis of the crude reaction mixture indicated the ratio of trans-13h : cis-13h to be 1.0:1 dr.

Diastereomer trans-13h

Rf: 0.4 in 50:50 hexanes : CH₂Cl₂

¹H NMR: (500 MHz, CDCl₃) δ = 7.71 (s, 1H), 7.27 (ddt, J = 24.4, 8.4, 1.5 Hz, 3H), 7.21 – 7.16 (m, 3H), 7.11 – 6.96 (m, 7H), 6.87 (ddd, J = 8.0, 7.0, 1.13 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 5.44 (ddt, J = 18, 17.25, 7.25 Hz, 1H), 4.96 – 4.88 (m, 2H), 2.68 – 2.48 (m, 4H), 2.36 – 2.21 (m, 2H), 1.97 – 1.79 (m, 2H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 211.1, 144.1, 140.5, 136.6, 134.5, 128.0, 128.0, 127.7, 126.4, 126.1, 126.1, 125.9, 123.7, 122.1, 121.8, 119.3, 118.6, 117.8, 110.7, 58.3, 55.2, 47.1, 36.3, 29.0, 17.8.

IR: f (cm⁻¹) = 3374, 3067, 3001, 2919, 2873, 2850, 1697, 1574, 1220, 1118, 925.

HRMS (ESI-TOF): m/z [M+H]⁺ = 406.2165 calculated for C₂₉H₂₈O; found 406. 2170.

X-Ray Structure: CCDC 2405596. The ellipsoid contour was set at a 50% probability level.

Diastereomer cis-13h

Rf: 0.3 in 50:50 hexanes : CH₂Cl₂

¹H NMR: (500 MHz, CDCl₃) δ = 8.09 (s, 1H), 7.39 (d, J = 8.15 Hz, 1H), 7.34 – 7.13 (m, 7H), 7.11 – 7.02 (m, 3H), 6.99 (ddd, J = 8.15, 7.05, 1.1 Hz, 1H), 6.97 – 6.90 (m, 2H), 6.80 (d, J = 2.5 Hz, 1H), 5.52 – 5.39 (m, 1H), 4.95 (s, 1H), 4.94 – 4.90 (m, 1H), 2.72 (ddt, J = 13.85, 6.7, 1.3 Hz, 1H), 2.60 – 2.34 (m, 4H), 2.11 – 1.91 (m, 2H), 1.78 – 1.62 (m, 1H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ = 211.6, 142.7, 139.9, 137.1, 134.4, 128.4, 128.0, 127.6, 126.8, 126.5, 126.3, 125.8, 124.1, 122.1, 121.1, 119.6, 118.5, 118.0, 111.4, 57.9, 55.3, 46.8, 31.5, 26.9, 17.1.

IR: f (cm⁻¹) = 3413, 3057, 3020, 2925, 2873, 2854, 1695, 1598, 1246, 1106, 917.

HRMS (ESI-TOF): m/z [M+H]⁺ = 406.2165 calculated for C₂₉H₂₈O; found 406. 2170.

Highlights.

• Treatment of α-hydroxy allyl vinyl ether with Cu(MeCN)₄BF₄ catalyst formed an allyloxy allyl cation.

• The capture of an allyloxy allyl cation with indole created an α-quaternary center in a regioselective manner.

• The Claisen rearrangement occurred upon heating to produce a second quaternary center at the opposing α’-position.

• The alkyl substituent at the α-carbon affects the diastereoselectivity of the Claisen rearrangement.

• The copper catalyst enhanced the trans delivery of the allyl group with respect to the indole group.

Data availability

The data underlying this study are available in the published article, its supplementary material, and the provided accession codes.