Asymmetric Prins Cyclizations of O-Prenylated Salicylaldehydes

Dedication

Dedicated to Professor Paul Knochel on the occasion of his 70th birthday.

Abstract

We report the asymmetric intramolecular Prins cyclization reactions of O-prenylated salicylaldehydes to 4-chromanols. Excellent efficiencies and selectivities were herein obtained using a highly fluorinated imino-imidodiphosphate (iIDP) Brønsted acid catalyst. The presented method tolerates substrates bearing both electron-donating and electron-withdrawing groups.

 

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Keywords

Asymmetric organocatalysis - Imino-imidodiphosphate (iIDP) - Prins cyclization - 4-chromanols - O-prenylated salicylaldehydes

Chiral and strongly acidic binaphthol-based organocatalysts, such as imino-imidodiphosphates (iIDPs), have demonstrated great utility in various enantioselective C–C bond formations involving carbonyl functionalities and alkenes.[1] Remarkable selectivities and efficiencies have been achieved across a broad spectrum of substrates due to the chiral reaction volume they confine with the 3,3′-substituents of their BINOL scaffold. Building upon our previous studies on intramolecular Prins cyclization reactions of α,β-unsaturated alkenyl aldehydes using a highly fluorinated iIDP[1c] ([Scheme 1A]), we sought to explore its generality and performance in further Prins cyclization reactions. The utilization of O-prenylated salicylaldehydes 1 for the synthesis of annulated ring systems, such as chromanols, has been previously examined by the Simpson group in the context of biosynthesis studies of xanthones.[2] Initial investigations on organocatalytic variants by the Kotsuki group used trityl bromide[3] as achiral Lewis acid catalyst and recently the Jacobsen group reported the first enantioselective method for this transformation ([Scheme 1A]).[4] The Jacobsen group employed enantioselective cooperative hydrogen-bond donor (HBD) catalysis to furnish 4-chromanols 2 in high yields and selectivities.[4] Their approach required the utilization of electron-withdrawing group substituted salicylaldehyde derivatives 1, and an expansion of the accessible substrate scope therefore occurred to be interesting. Here, we report highly enantioselective intramolecular Prins cyclizations of O-prenylated salicylaldehydes 1 to 4-chromanols 2, using the confined and highly fluorinated iIDP catalyst 3 ([Scheme 1B]).

Scheme 1 (A) Previous work on the asymmetric synthesis of 4-chromanols via intramolecular Prins cyclization and (B) this work on iIDP-catalyzed Prins cyclizations.

We started our exploration by using O-prenylated salicylaldehyde 1a as model substrate. To our delight, the previously established reaction conditions[1c] also provided remarkable reactivity in this reaction and the corresponding unsubstituted 4-chromanol 2a was isolated in excellent yield and selectivities (94% yield, d.r. >20:1, e.r. = 99.5:0.5) ([Scheme 2]). The absolute configuration of 4-chromanol 2a was determined to be (3R, 4S)-2a by comparing its optical rotation to the precedent literature value.[4] Next, we turned our attention to the exploration of the substrate scope. Methyl substitution at the 3-, 4-, or 5-position of the aryl ring is well tolerated (2b–d). Increasing the steric bulk at the 3- and 5-positions exemplarily shown by 4-chromanol 2e maintains excellent levels of efficiency and selectivity (89% yield, d.r. >20:1, e.r. = 99:1). Introduction of a substituent at the 6-position, vicinal to the aldehyde functionality, reduces the enantioselectivity of the desired cyclized product 2f however while retaining excellent levels of diastereoselectivity. The lower enantioselectivity of product 2f can be explained by steric interactions of the methyl group with the 3,3′-substituents within the confined iIDP reaction space. Other functional groups such as an aldehyde (2g), an ester (2h), and a methyl-protected phenol functionality (2i) are well tolerated. Upon introduction of an electron-withdrawing group at the para position to the aldehyde functionality (2k), the reaction was performed at a higher temperature while using a lower catalyst loading of 0.5 mol% to guarantee high yield with still excellent selectivity.

Scheme 2 Asymmetric catalytic Prins cyclizations of o-prenylated salicylaldehydes to 4-chromanols. The reactions were carried out on a 0.25-mmol scale of substrates 1a–k. Isolated yields are reported. The diastereomeric ratios were determined using ¹H NMR spectroscopy. The enantiomeric excesses were determined by GC or HPLC on a chiral stationary phase. Reported enantiomeric ratios (e.r.) refer to the major trans-products depicted. ^a Reaction was performed at r.t. using 0.5 mol% iIDP 3.

This work expands the substrate scope of such Prins cyclizations and now enables the inclusion of substrates with electron-donating groups, while maintaining excellent levels of efficiency and selectivity.

Analytical instrumentation and general methods are described in the Supporting Information.

 

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O-Prenylated Salicylaldehydes 1a–k; General Procedure

The O-prenylated salicylaldehydes 1a–k were synthesized according to the following procedure, adapted from the literature.[4] In a flame-dried flask under argon, K₂CO₃ (1.5 equiv) and the corresponding α-hydroxy aldehyde (1.0 equiv) were suspended in anhydrous DMF (0.45 M), followed by the addition of 1-bromo-3-methyl-2-butene (1.2–1.3 equiv). The reaction was stirred at room temperature until full conversion (1–2 d). Upon completion of the reaction, brine was added, and the aqueous layer was extracted with Et₂O. The combined organic layers were dried with MgSO₄, filtered, and concentrated under reduced pressure. The obtained crude material was purified by automated column chromatography. The conditions are individually given for each compound.

 

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2-((3-Methylbut-2-en-1-yl)oxy)benzaldehyde (1a)

Scale: salicylaldehyde (0.9 mL, 8.45 mmol), K₂CO₃ (1.7 g, 12 mmol), 1-bromo-3-methyl-2-butene (1.4 mL, 11 mmol); purification: automated FCC [spherical silica gel; pentane–CH₂Cl₂, 5% CH₂Cl₂ (1 CV), 5–10% (1 CV), 10% (10 CV), 10–15% (1 CV), 15% (16 CV)].

Yield: 970 mg (60%); colorless oil.

¹H NMR (501 MHz, CDCl₃): δ = 10.49 (s, 1 H), 7.83 (dd, J = 7.7, 1.8 Hz, 1 H), 7.52 (ddd, J = 8.9, 7.3, 1.9 Hz, 1 H), 7.03–6.97 (m, 2 H), 5.52–5.47 (m, 1 H), 4.63 (d, J = 6.7 Hz, 2 H), 1.80 (s, 3 H), 1.75 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 190.1, 161.5, 138.8, 135.9, 128.4, 125.3, 120.7, 119.1, 113.1, 65.6, 25.9, 18.4.

HRMS (GC-EI): m/z calcd for C₁₂H₁₄O₂ [M]^+•: 190.098830; found: 190.098700.

The analytical data are in agreement with the literature.[4]

 

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3-Methyl-2-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (1b)

Scale: 2-hydroxy-3-methylbenzaldehyde (1.0 mL, 8.2 mmol), K₂CO₃ (1.7 g, 12 mmol), 1-bromo-3-methyl-2-butene (1.4 mL, 11 mmol); purification: automated FCC [spherical silica gel; pentane–CH₂Cl₂, 5–25% (8 CV), 25% (20 CV)].

Yield: 1.2 g (73%); colorless oil; R_f = 0.35 (hexane–Et₂O, 10:1).

¹H NMR (501 MHz, CD₂Cl₂): δ = 10.34 (d, J = 0.8 Hz, 1 H), 7.64 (dd, J = 7.7, 1.8 Hz, 1 H), 7.46 (ddd, J = 7.6, 1.9, 1.0 Hz, 1 H), 7.13 (t, J = 7.6 Hz, 1 H), 5.55 (tdt, J = 7.4, 3.0, 1.5 Hz, 1 H), 4.48 (d, J = 7.4 Hz, 2 H), 2.35 (s, 3 H), 1.77 (s, 3 H), 1.59 (s, 3 H).

¹³C NMR (126 MHz, CD₂Cl₂): δ = 190.6, 160.9, 140.2, 137.7, 133.2, 130.4, 126.1, 124.5, 119.6, 72.4, 25.9, 18.1, 16.1.

HRMS (GC-EI): m/z calcd for C₁₃H₁₆O₂ [M]^+•: 204.114480; found: 204.114500.

 

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4-Methyl-2-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (1c)

Scale: 2-hydroxy-4-methylbenzaldehyde (1.03 g, 7.6 mmol), K₂CO₃ (1.8 g, 13 mmol), 1-bromo-3-methyl-2-butene (1.3 mL, 10 mmol); purification: automated FCC [spherical silica gel; hexane–Et₂O, 10% (7 CV)].

Yield: 1.19 g (77%); colorless oil; R_f = 0.39 (hexane–EtOAc, 10:1).

¹H NMR (501 MHz, CDCl₃): δ = 10.41 (s, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 6.82–6.79 (m, 1 H), 6.77 (s, 1 H), 5.49 (tdd, J = 6.6, 2.9, 1.4 Hz, 1 H), 4.60 (d, J = 6.7 Hz, 2 H), 2.38 (s, 3 H), 1.80 (s, 3 H), 1.75 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 189.7, 161.5, 147.3, 138.7, 128.3, 123.0, 121.7, 119.2, 113.6, 65.5, 25.9, 22.4, 18.4.

HRMS (GC-EI): m/z calcd for C₁₃H₁₆O₂ [M]^+•: 204.114480; found: 204.114380.

 

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5-Methyl-2-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (1d)

Scale: 2-hydroxy-5-methylbenzaldehyde (1.12 g, 8.2 mmol), K₂CO₃ (1.7 g, 12 mmol), 1-bromo-3-methyl-2-butene (1.4 mL, 11 mmol); purification: automated FCC [spherical silica gel; pentane–CH₂Cl₂, 10% (7 CV), 10–15% (1 CV), 15% (17 CV), 20–50% (10 CV)].

Yield: 1.24 g (74%); colorless oil; R_f = 0.42 (hexane–EtOAc, 10:1).

¹H NMR (501 MHz, CDCl₃): δ = 10.46 (s, 1 H), 7.62 (d, J = 2.4 Hz, 1 H), 7.32 (dd, J = 8.5, 2.4 Hz, 1 H), 6.89 (d, J = 8.5 Hz, 1 H), 5.48 (ddt, J = 6.6, 5.1, 1.4 Hz, 1 H), 4.60 (d, J = 6.7 Hz, 2 H), 2.30 (s, 3 H), 1.79 (s, 3 H), 1.74 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 190.3, 159.6, 138.7, 136.6, 130.1, 128.4, 125.0, 119.3, 113.2, 65.8, 25.9, 20.4, 18.4.

HRMS (GC-EI): m/z calcd for C₁₃H₁₆O₂ [M]^+•: 204.114480; found: 204.114400.

 

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3,5-Di-tert-butyl-2-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (1e)

Scale: 3,5-di-tert-butyl-2-hydroxybenzaldehyde (500 mg, 2.1 mmol), K₂CO₃ (446 mg, 3.22 mmol), 1-bromo-3-methyl-2-butene (0.35 mL, 2.7 mmol); purification: automated FCC [spherical silica gel; hexane–CH₂Cl₂, 5–7% (4 CV), 7% (12 CV), 7–10% (1 CV), 10% (15 CV), 10–15% (1 CV), 15% (15 CV)].

Yield: 559 mg (87%); colorless solid; R_f = 0.52 (hexane–Et₂O, 10:1).

¹H NMR (501 MHz, CDCl₃): δ = 10.32 (s, 1 H), 7.71 (d, J = 2.6 Hz, 1 H), 7.62 (d, J = 2.7 Hz, 1 H), 5.61 (ddq, J = 8.2, 5.7, 1.4 Hz, 1 H), 4.48 (d, J = 6.8 Hz, 2 H), 1.81 (d, J = 1.5 Hz, 3 H), 1.66 (s, 3 H), 1.44 (s, 9 H), 1.32 (s, 9 H).

¹³C NMR (126 MHz, CDCl₃): δ = 191.1, 160.3, 146.4, 143.2, 138.2, 131.0, 129.7, 123.8, 119.9, 76.3, 35.5, 34.8, 31.5, 31.1, 26.0, 18.5.

HRMS (GC-EI): m/z calcd for C₂₀H₃₀O₂ [M]^+•: 302.224030; found: 302.224200.

 

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3,6-Dimethyl-2-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (1f)

Scale: 2-hydroxy-3,6-dimethylbenzaldehyde (500 mg, 3.32 mmol), K₂CO₃ (690 mg, 5.00 mmol), 1-bromo-3-methyl-2-butene (0.51 mL, 4.0 mmol); purification: automated FCC [spherical silica gel; hexane–EtOAc, 2% (10 CV)].

Yield: 258 mg (36%); colorless liquid; R_f = 0.43 (hexane–Et₂O, 10:1).

¹H NMR (501 MHz, CD₂Cl₂): δ = 10.53–10.48 (m, 1 H), 7.30 (d, J = 7.8 Hz, 1 H), 6.91 (d, J = 7.7 Hz, 1 H), 5.55 (tdt, J = 7.3, 2.9, 1.4 Hz, 1 H), 4.42 (d, J = 7.2 Hz, 2 H), 2.51 (s, 3 H), 2.30 (s, 3 H), 1.78 (d, J = 1.3 Hz, 3 H), 1.62 (d, J = 1.4 Hz, 3 H).

¹³C NMR (126 MHz, CD₂Cl₂): δ = 193.2, 162.2, 139.7, 139.3, 136.5, 130.1, 128.6, 127.5, 119.8, 72.5, 25.9, 21.1, 18.1, 15.9.

HRMS (GC-EI): m/z calcd for C₁₄H₁₈O₂ [M]^+•: 218.130130; found: 218.130410.

 

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5-Methyl-2-((3-methylbut-2-en-1-yl)oxy)isophthalaldehyde (1g)

Scale: 2-hydroxy-5-methylisophthalaldehyde (500 mg, 3.0 mmol), K₂CO₃ (631 mg, 4.57 mmol), 1-bromo-3-methyl-2-butene (0.50 mL, 4.0 mmol); purification: automated FCC [spherical silica gel; hexane–EtOAc, 5% (4 CV), 5–10% (1 CV), 10% (7 CV)].

Yield: 404 mg (57%); colorless solid; R_f = 0.34 (hexane–EtOAc, 10:1).

¹H NMR (501 MHz, CDCl₃): δ = 10.35 (s, 2 H), 7.89 (s, 2 H), 5.55–5.45 (m, 1 H), 4.62 (d, J = 7.7 Hz, 2 H), 2.40 (s, 3 H), 1.74 (s, 3 H), 1.50 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 189.1, 162.3, 142.5, 135.0, 134.9, 130.6, 118.0, 75.8, 25.9, 20.7, 18.1.

HRMS (GC-EI): m/z calcd for C₁₄H₁₆O₃ [M]^+•: 232.109395; found: 232.109480.

 

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Ethyl 3-Formyl-4-((3-methylbut-2-en-1-yl)oxy)benzoate (1h)

Scale: ethyl 3-formyl-4-hydroxybenzoate (500 mg, 2.58 mmol), K₂CO₃ (533 mg, 3.86 mmol), 1-bromo-3-methyl-2-butene (0.4 mL, 3.1 mmol); purification: automated FCC [spherical silica gel; hexane–CH₂Cl₂, 20% (5 CV), 20–78% (21 CV), 78–100% (5 CV)].

Yield: 631 mg (93%); colorless solid; R_f = 0.27 (hexane–EtOAc, 10:1).

¹H NMR (501 MHz, CD₂Cl₂): δ = 10.45 (s, 1 H), 8.41 (d, J = 2.4 Hz, 1 H), 8.20 (dd, J = 8.8, 2.3 Hz, 1 H), 7.07 (d, J = 8.8 Hz, 1 H), 5.51 (tdq, J = 6.7, 2.8, 1.4 Hz, 1 H), 4.72 (d, J = 6.7 Hz, 2 H), 4.34 (q, J = 7.1 Hz, 2 H), 1.82–1.80 (m, 3 H), 1.78–1.77 (m, 3 H), 1.37 (t, J = 7.1 Hz, 3 H).

¹³C NMR (126 MHz, CD₂Cl₂): δ = 189.3, 165.8, 164.7, 140.0, 137.1, 130.3, 125.1, 123.5, 118.7, 113.3, 66.4, 61.4, 25.9, 18.5, 14.5.

HRMS (GC-EI): m/z calcd for C₁₅H₁₈O₄ [M]^+•: 262.119950; found: 262.119960.

 

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3-Methoxy-2-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (1i)

Scale: 2-hydroxy-3-methoxybenzaldehyde (1.0 g, 6.6 mmol), K₂CO₃ (1.4 g, 9.9 mmol), 1-bromo-3-methyl-2-butene (1.0 mL, 7.9 mmol); purification: automated FCC [spherical silica gel; hexane–Et₂O, 5–10% (4 CV), 10% (4 CV)].

Yield: 802 mg (55%); pale-yellow liquid; R_f = 0.19 (hexane–EtOAc, 10:1).

¹H NMR (501 MHz, CDCl₃): δ = 10.38 (d, J = 0.7 Hz, 1 H), 7.39 (dd, J = 6.9, 2.5 Hz, 1 H), 7.16–7.07 (m, 2 H), 5.49 (tp, J = 7.5, 1.4 Hz, 1 H), 4.64 (d, J = 7.5 Hz, 2 H), 3.90 (s, 3 H), 1.73 (s, 3 H), 1.59 (d, J = 0.8 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 190.7, 153.4, 151.5, 140.4, 130.7, 124.2, 119.4, 119.0, 117.9, 70.6, 56.2, 25.9, 18.0.

HRMS (GC-EI): m/z calcd for C₁₃H₁₆O₃ [M]^+•: 220.109395; found: 220.109450.

The analytical data are in agreement with the literature.[5]

 

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4-Chloro-2-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (1k)

Scale: 4-chloro-2-hydroxybenzaldehyde (1.0 g, 6.4 mmol), K₂CO₃ (1.3 g, 9.6 mmol), 1-bromo-3-methyl-2-butene (1.0 mL, 7.7 mmol); purification: automated FCC [spherical silica gel; hexane–CH₂Cl₂, 5% (4 CV), 5–8% (3 CV), 8% (4 CV), 8–10% (1 CV), 10% (11 CV), 10–15% (1 CV), 15% (7 CV)].

Yield: 1.23 g (86%); colorless solid; R_f = 0.49 (hexane–EtOAc, 10:1).

¹H NMR (501 MHz, CDCl₃): δ = 10.40 (s, 1 H), 7.79–7.72 (m, 1 H), 7.00–6.97 (m, 2 H), 5.48 (ddq, J = 8.1, 5.3, 1.4 Hz, 1 H), 4.62 (d, J = 6.7 Hz, 2 H), 1.84–1.79 (m, 3 H), 1.76 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ = 188.9, 161.8, 141.9, 139.6, 129.6, 123.8, 121.2, 118.4, 113.7, 66.0, 25.9, 18.5.

HRMS (GC-EI): m/z calcd for C₁₂H₁₃O₂Cl [M]^+•: 224.059858; found: 224.059870.

 

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Asymmetric Prins Cyclization Reactions of O-Prenylated Salicylaldehydes 1 to 4-Chromanols 2; General Procedure

Into a flame-dried flask/vial equipped with a magnetic stirring bar was weighed the corresponding O-prenylated salicylaldehyde 1 (1.0 equiv) and dissolved in dry toluene (0.1 M). In a separate flame-dried flask/vial iIDP 3 (2.5 mol%) was dissolved in dry toluene (0.1 M). Both flasks/vials were cooled to the desired temperature. After 10 min, the solution containing the iIDP catalyst was added to the vial/flask containing the O-prenylated salicylaldehyde. The reaction was stirred for 24 h and was then quenched by the addition of a few drops of Et₃N. The reaction mixture was warmed to room temperature and the solvent was evaporated. The obtained crude reaction mixture was purified by column chromatography and the conditions are individually given for each compound.

The corresponding racemates were prepared according to the general procedure by using a racemic mixture of (R,R)- and (S,S)-iIDP catalyst.

 

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3-(Prop-1-en-2-yl)chroman-4-ol (2a)

The reaction was performed according to the general procedure with aldehyde 1a (52.5 mg, 0.276 mmol). Purification by FCC (silica gel; hexane–EtOAc, 10:1) furnished the desired product as a colorless solid (49.1 mg, 0.258 mmol, 94% yield) and as mixtures of diastereoisomers; d.r. (trans/cis) >20:1.

[α]_D ²⁵ –22.7 (c 0.16, CH₂Cl₂) [Lit.[[4] ((3S,4R)-2a): [α]_D ²² +17.0 (c 1.0, CH₂ Cl₂)].

¹H NMR (501 MHz, CDCl₃): δ (major trans-diastereoisomer) = 7.46 (d, J = 7.6 Hz, 1 H), 7.19 (ddd, J = 8.5, 7.5, 1.7 Hz, 1 H), 6.95 (td, J = 7.5, 1.2 Hz, 1 H), 6.82 (dd, J = 8.2, 1.2 Hz, 1 H), 5.02–5.00 (m, 1 H), 4.86 (s, 1 H), 4.83 (d, J = 7.7 Hz, 1 H), 4.27 (dd, J = 11.2, 3.5 Hz, 1 H), 4.09 (dd, J = 11.2, 8.8 Hz, 1 H), 2.59 (td, J = 8.2, 3.5 Hz, 1 H), 1.85 (br s, OH), 1.84 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃)>: δ (major trans-diastereoisomer) = 154.2, 142.2, 129.4, 128.4, 124.7, 121.0, 116.6, 113.9, 67.2, 66.7, 48.0, 21.7.

GC (EI): m/z calcd for C₁₂H₁₄O₂ [M]+•: 190.098830; found: 190.098960.

Chiral HPLC (OJ-3R, 4.6 mm i.d., 3 μm, MeOH–H₂O, 70–90 gradient, 1.0 mL/min, 298 K, 220 nm): t _R (trans, major) = 6.33 (96.06%), t _R (cis, major) = 7.08 (2.88%), t _R (cis, minor) = 7.71 (0.54%), t _R (trans, minor) = 8.38 (0.37%) min; e.r. (trans) = 99.5:0.5, e.r. (cis) = 84:16.

The analytical data are in agreement with the literature.[4]

 

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8-Methyl-3-(prop-1-en-2-yl)chroman-4-ol (2b)

The reaction was performed according to the general procedure with aldehyde 1b (58.0 mg, 0.284 mmol). Purification by FCC (silica gel; hexane–EtOAc, 10:1) furnished the desired product as a colorless solid (48.9 mg, 0.239 mmol, 84% yield) and as mixtures of diastereoisomers; d.r. (trans/cis) >20:1.

[α]_D ²⁵ –16.52 (c 0.14, CHCl₃); R_f = 0.25 (hexane–EtOAc, 10:1).

¹H NMR (501 MHz, CDCl₃): δ (major trans-diastereoisomer) = 7.30 (d, J = 7.7 Hz, 1 H), 7.06 (d, J = 7.3 Hz, 1 H), 6.86 (t, J = 7.5 Hz, 1 H), 5.02–4.97 (m, 1 H), 4.88–4.84 (m, 1 H), 4.82 (d, J = 7.7 Hz, 1 H), 4.30 (dd, J = 11.2, 3.5 Hz, 1 H), 4.10 (dd, J = 11.2, 8.7 Hz, 1 H), 2.57 (td, J = 8.2, 3.5 Hz, 1 H), 2.19 (s, 3 H), 1.89 (br s, OH), 1.83 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃): δ (major trans-diastereoisomer) = 152.3, 142.4, 130.4, 125.9, 125.8, 124.1, 120.3, 113.7, 67.5, 66.7, 47.9, 21.7, 16.1.

HRMS (EI): m/z calcd for C₁₃H₁₆O₂ [M]+•: 204.114480; found: 204.114650.

Chiral HPLC (OJ-3R, H₂O–MeCN, 60:40, 1.0 mL/min, 298 K, 220 nm): t _R (trans, major) = 8.97 (96.77%), t _R (cis, major) = 9.85 (2.25%), t _R (trans, minor) = 10.90 (0.59%), t _R (cis, minor) = 12.59 (0.40%) min; e.r. (trans) = 99.5:0.5, e.r. (cis) = 85:15.

 

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7-Methyl-3-(prop-1-en-2-yl)chroman-4-ol (2c)

The reaction was performed according to the general procedure with aldehyde 1c (52.6 mg, 0.258 mmol). Purification by FCC (silica gel; hexane–EtOAc, 10:1) furnished the desired product as a colorless solid (45.7 mg, 0.224 mmol, 87% yield) and as mixtures of diastereoisomers; d.r. (trans/cis) >20:1.

[α]_D ²⁵ –10.8 (c 0.37, CHCl₃); R_f = 0.43 (hexane–EtOAc, 4:1).

¹H NMR (501 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 7.30 (d, J = 7.9 Hz, 1 H), 6.76 (dd, J = 8.0, 1.7 Hz, 1 H), 6.61 (d, J = 1.7 Hz, 1 H), 4.97 (p, J = 1.6 Hz, 1 H), 4.84–4.81 (m, 1 H), 4.76 (d, J = 7.3 Hz, 1 H), 4.23 (dd, J = 11.2, 3.5 Hz, 1 H), 4.07 (dd, J = 11.2, 8.3 Hz, 1 H), 2.52 (dddd, J = 8.4, 7.3, 3.5, 0.9 Hz, 1 H), 2.28 (s, 3 H), 2.06 (s, 1 H), 1.82 (s, 3 H).

¹³C NMR (126 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 154.4, 143.0, 139.7, 128.6, 122.3, 122.0, 116.9, 113.5, 67.2, 66.9, 48.3, 21.8, 21.3.

HRMS (GC-EI): m/z calcd for C₁₃H₁₆O₂ [M]^+•: 204.114480; found: 204.114440.

Chiral GC (BGB-174/BGB-1701 0.25/0.25 d_f, temp: 220/140, 112 min iso 8/min 240/350, gas: 0.6 bar H₂): t _R (cis, major) = 73.39 (0.66%), t _R (trans, minor) = 76.59 (0.22%), t _R (cis, minor) = 91.63 (0.24%), t _R (trans, major) = 101.52 (98.88%) min; e.r. (trans) = 99.8:0.2, e.r. (cis) = 73:27.

 

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6-Methyl-3-(prop-1-en-2-yl)chroman-4-ol (2d)

The reaction was performed according to the general procedure with aldehyde 1d (54.1 mg, 0.258 mmol). Purification by FCC (silica gel; hexane–EtOAc, 10:1) furnished the desired product as a colorless solid (51.4 mg, 0.252 mmol, 95% yield) and as mixtures of diastereoisomers; d.r. (trans/cis) >20:1.

[α]₄₅₀ ²⁵ –17.1 (c 0.26, CH₂Cl₂); R_f = 0.49 (hexane–EtOAc, 4:1).

¹H NMR (501 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 7.26–7.22 (m, 1 H), 7.01–6.95 (m, 1 H), 6.68 (d, J = 8.3 Hz, 1 H), 4.98 (p, J = 1.5 Hz, 1 H), 4.85–4.82 (m, 1 H), 4.76 (dd, J = 7.6, 4.9 Hz, 1 H), 4.21 (dd, J = 11.2, 3.5 Hz, 1 H), 4.05 (dd, J = 11.2, 8.6 Hz, 1 H), 2.58–2.49 (m, 1 H), 2.27 (s, 3 H), 2.05 (d, J = 5.1 Hz, 1 H), 1.82 (s, 3 H).

¹³C NMR (126 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 152.3, 143.0, 130.3, 130.1, 128.9, 124.8, 116.4, 113.6, 67.4, 66.9, 48.4, 21.7, 20.7.

HRMS (GC-EI): m/z calcd for C₁₃H₁₆O₂ [M]+•: 204.114480; found: 204.114880.

Chiral GC (BGB-174/BGB-1701 0.25/0.25 d_f, temp: 220/150, 62 min iso 8/min 240, 3 min iso/350, gas: 0.6 bar H₂): t _R (cis, major) = 42.20 (1.10%), t _R (trans, minor) = 43.63 (0.16%), t _R (cis, minor) = 51.31 (0.18%), t _R (trans, major) = 53.97 (98.56%) min; e.r. (trans) = 99.8:0.2, e.r. (cis) = 86:14.

 

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6,8-Di-tert-butyl-3-(prop-1-en-2-yl)chroman-4-ol (2e)

The reaction was performed according to the general procedure with aldehyde 1e (83.1 mg, 0.275 mmol). Purification by FCC (silica gel; hexane–EtOAc, 10:1) furnished the desired product as a colorless solid (73.6 mg, 0.243 mmol, 89% yield) and as mixtures of diastereoisomers; d.r. (trans/cis) >20:1.

[α]_D ²⁵ +8.44 (c 0.11, CHCl₃); R_f = 0.24 (hexane–EtOAc, 10:1).

¹H NMR (501 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 7.30 (dd, J = 2.5, 0.8 Hz, 1 H), 7.24 (d, J = 2.5 Hz, 1 H), 4.96 (p, J = 1.6 Hz, 1 H), 4.88–4.86 (m, 1 H), 4.78 (dd, J = 7.0, 5.2 Hz, 1 H), 4.28 (dd, J = 11.1, 3.6 Hz, 1 H), 4.12 (dd, J = 11.1, 7.9 Hz, 1 H), 2.55 (td, J = 7.4, 3.6 Hz, 1 H), 2.03 (d, J = 5.3 Hz, 1 H), 1.83 (s, 3 H), 1.36 (s, 9 H), 1.30 (s, 9 H).

¹³C NMR (126 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 151.1, 143.4, 142.7, 137.0, 124.5, 123.9, 123.5, 113.2, 68.1, 66.1, 48.1, 35.3, 34.7, 31.7, 29.9, 21.8.

HRMS (GC-EI): m/z calcd for C₂₀H₃₀O₂ [M]+•: 302.224030; found: 302.224360.

Chiral HPLC (IC-3R, MeCN–H₂O, 40:60, 1.0 mL/min, 298 K, 210 nm): t _R (trans, minor) = 33.65 (0.90%), t _R (trans, major) = 35.85 (97.45%), t _R (cis, minor) = 39.02 (0.33%), t _R (cis, major) = 43.83 (1.32%) min; e.r. (trans) = 99:1, e.r. (cis) = 80:20.

 

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5,8-Dimethyl-3-(prop-1-en-2-yl)chroman-4-ol (2f)

The reaction was performed according to the general procedure with aldehyde 1f (59.0 mg, 0.270 mmol). Purification by FCC (silica gel; hexane–EtOAc, 10:1) furnished the desired product as a colorless solid (37.5 mg, 0.172 mmol, 64% yield) and as mixtures of diastereoisomers; d.r. (trans/cis) >20:1.

[α]_D ²⁵ –144.22 (c 0.14, CHCl₃); R_f = 0.15 (hexane–EtOAc, 10:1).

¹H NMR (501 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 6.97 (d, J = 7.4 Hz, 1 H), 6.66 (d, J = 7.4 Hz, 1 H), 5.09–5.07 (m, 1 H), 4.82 (td, J = 3.0, 1.5 Hz, 1 H), 4.75–4.72 (m, 1 H), 4.24 (ddd, J = 10.2, 3.8, 1.5 Hz, 1 H), 4.18 (dd, J = 11.9, 10.3 Hz, 1 H), 2.60–2.52 (m, 1 H), 2.38 (s, 3 H), 2.13 (s, 3 H), 1.92 (s, 3 H), 1.83 (d, J = 3.1 Hz, 1 H).

¹³C NMR (126 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 152.9, 142.8, 136.9, 130.5, 123.9, 121.9, 121.8, 112.9, 63.4, 61.8, 45.4, 23.2, 18.2, 16.1.

HRMS (EI): m/z calcd for C₁₄H₁₈O₂ [M]+•: 218.130130; found: 218.130190.

Chiral HPLC (IB-N3, 4.6 mm i.d., MeOH–H₂O, 75:25, 1.0 mL/min, 298 K, 220 nm): t _R (trans, minor) = 5.82 (10.65%), t _R (trans, major) = 6.54 (88.20%) min; e.r. (trans) = 89:11.

 

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4-Hydroxy-6-methyl-3-(prop-1-en-2-yl)chromane-8-carbaldehyde (2g)

The reaction was performed according to the general procedure with aldehyde 1g (64.6 mg, 0.278 mmol). Purification by FCC (silica gel; hexane–EtOAc, 4:1) furnished the desired product as a colorless solid (55.1 mg, 0.237 mmol, 85% yield) and as mixtures of diastereoisomers; d.r. (trans/cis) >20:1.

[α]_D25 –5.35 (c 0.19, CHCl₃); R_f = 0.22 (hexane–EtOAc, 4:1).

¹H NMR (501 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 10.32 (s, 1 H), 7.54–7.52 (m, 1 H), 7.51–7.48 (m, 1 H), 5.03 (p, J = 1.6 Hz, 1 H), 4.89–4.86 (m, 1 H), 4.80 (dd, J = 8.0, 4.0 Hz, 1 H), 4.37 (dd, J = 11.2, 3.6 Hz, 1 H), 4.17 (dd, J = 11.2, 8.9 Hz, 1 H), 2.60 (td, J = 8.4, 3.6 Hz, 1 H), 2.36 (d, J = 4.8 Hz, 1 H), 2.30 (s, 3 H), 1.84 (s, 3 H).

¹³C NMR (126 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 189.7, 155.1, 142.3, 135.8, 130.3, 128.2, 126.5, 124.1, 114.2, 67.5, 66.9, 47.8, 21.6, 20.5.

HRMS (GC-EI): m/z calcd for C₁₄H₁₆O₃ [M]+•: 232.109395; found: 232.109520.

Chiral HPLC (IG-3R, MeCN–H₂O, 50:50, 1.0 mL/min, 298 K, 210 nm): t _R (trans, minor) = 6.51 (0.64%), t _R (trans, major) = 7.23 (96.75%), t _R (cis, minor) = 11.89 (0.35%), t _R (cis, major) = 18.84 (2.26%) min; e.r. (trans) = 99.5:0.5, e.r. (cis) = 86.5:13.5.

 

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Ethyl 4-Hydroxy-3-(prop-1-en-2-yl)chromane-6-carboxylate (2h)

The reaction was performed according to the general procedure with aldehyde 1h (71.5 mg, 0.273 mmol). Purification by FCC (silica gel; hexane–EtOAc, 4:1) furnished the desired product as a colorless solid (42.6 mg, 0.162 mmol, 60% yield) and as mixtures of diastereoisomers; d.r. (trans/cis) >20:1.

[α]_D ²⁵ +18.49 (c 0.11, CHCl₃); R_f = 0.27 (hexane–EtOAc, 4:1).

¹H NMR (501 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 8.14 (dd, J = 2.2, 0.9 Hz, 1 H), 7.84 (dd, J = 8.6, 2.2 Hz, 1 H), 6.82 (d, J = 8.6 Hz, 1 H), 5.01 (p, J = 1.5 Hz, 1 H), 4.86–4.84 (m, 1 H), 4.83 (dd, J = 7.7, 4.8 Hz, 1 H), 4.35–4.27 (m, 3 H), 4.16 (dd, J = 11.3, 8.7 Hz, 1 H), 2.58 (dddd, J = 8.6, 7.6, 3.7, 0.9 Hz, 1 H), 2.31 (d, J = 4.9 Hz, 1 H), 1.83 (s, 3 H), 1.36 (t,J = 7.1 Hz, 3 H).

¹³C NMR (126 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 166.5, 158.4, 142.3, 131.0, 130.8, 125.1, 123.4, 116.7, 114.1, 67.4, 67.0, 61.1, 47.7, 21.7, 14.6.

HRMS (GC-EI): m/z calcd for C₁₅H₁₈O₄ [M]+•: 262.119960; found: 262.120160.

Chiral HPLC (OJ-3R, H₂O–MeCN, 55:45, 1.0 mL/min, 298 K, 220 nm): t _R (trans, major) = 7.05 (97.75%), t _R (trans, minor) = 7.36 (1.41%), t _R (cis, major) = 8.17 (0.74%), t _R (cis, minor) = 8.54 (0.11%) min; e.r. (trans) = 98.5:1.5, e.r. (cis) = 87:13.

 

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8-Methoxy-3-(prop-1-en-2-yl)chroman-4-ol (2i)

The reaction was performed according to the general procedure with aldehyde 1i (60.0 mg, 0.272 mmol). Purification by FCC (silica gel; hexane–EtOAc–CH₂Cl₂ gradient from 10:1:1 to 5:1:1) furnished the desired product as a colorless solid (58.9 mg, 0.267 mmol, >95% yield) and as mixtures of diastereoisomers; d.r. (trans/cis) >20:1.

[α]_D ²⁵ –17.5 (c 0.34, CHCl₃); R_f = 0.17 (hexane–EtOAc, 4:1).

¹H NMR (501 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 7.04 (ddd, J = 7.9, 1.6, 0.8 Hz, 1 H), 6.88 (t, J = 7.9 Hz, 1 H), 6.80 (dd, J = 8.0, 1.5 Hz, 1 H), 4.98 (p, J = 1.6 Hz, 1 H), 4.84–4.77 (m, 2 H), 4.30 (dd, J = 11.2, 3.5 Hz, 1 H), 4.12 (dd, J = 11.1, 8.4 Hz, 1 H), 3.81 (s, 3 H), 2.59–2.52 (m, 1 H), 2.07 (d, J = 5.0 Hz, 1 H), 1.83 (s, 3 H).

¹³C NMR (126 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 148.5, 144.1, 142.8, 125.9, 120.5, 120.3, 113.6, 111.3, 67.2, 67.0, 56.2, 48.0, 21.7.

HRMS (GC-EI): m/z calcd for C₁₃H₁₆O₃ [M]+•: 220.109395; found: 220.109800.

Chiral GC (BGB-176/BGB-15 0.25/0.25 d_f, temp: 220/150, 125 min 8/min 240, 3 min iso/350, gas: 0.6 bar H₂): t _R (trans, minor) = 93.12 (0.70%), t _R (trans, major) = 104.34 (95.42%), t _R (cis, minor) = 112.19 (0.55%), t _R (cis, major) = 115.33 (3.33%) min; e.r. (trans) = 99:1, e.r. (cis) = 86:14.

 

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7-Chloro-3-(prop-1-en-2-yl)chroman-4-ol (2k)

The reaction was performed according to general procedure with aldehyde 1k (55.9 mg, 0.249 mmol). Purification by FCC (silica gel; hexane–EtOAc, 10:1) furnished the desired product as a colorless solid (53.5 mg, 0.238 mmol, >95% yield) and as mixtures of diastereoisomers; d.r. (trans/cis) = 16.5:1.

[α]_D25 –8.29 (c 0.11, CHCl₃); R_f = 0.38 (hexane–EtOAc, 4:1).

¹H NMR (501 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 7.39 (d, J = 8.4 Hz, 1 H), 6.92 (dd, J = 8.3, 2.1 Hz, 1 H), 6.81 (d, J = 2.1 Hz, 1 H), 5.01 (p, J = 1.6 Hz, 1 H), 4.85 (m, 1 H), 4.77 (dd, J = 7.9, 4.8 Hz, 1 H), 4.26 (dd, J = 11.2, 3.6 Hz, 1 H), 4.09 (dd, J = 11.3, 8.9 Hz, 1 H), 2.55 (td, J = 8.4, 3.5 Hz, 1 H), 2.12 (d, J = 5.0 Hz, 1 H), 1.82 (s, 3 H).

¹³C NMR (126 MHz, CD₂Cl₂): δ (major trans-diastereoisomer) = 155.2, 142.4, 134.4, 129.9, 124.0, 121.2, 116.7, 114.0, 67.4, 66.9, 48.0, 21.6.

HRMS (EI): m/z calcd for C₁₂H₁₃O₂Cl [M]^+•: 224.059858; found: 224.059860.

Chiral HPLC (Chiralpak IA-3, MeCN–H₂O, 60:40, 1.0 mL/min, 298 K, 220 nm): t _R (trans, major) = 4.87 (91.60%), t _R (trans, minor) = 6.05 (1.52%), t _R (cis, major) = 7.39 (4.16%), t _R (cis, minor) = 10.45 (1.43%) min; e.r. (trans) = 98.5:1.5, e.r. (cis) = 74.5:25.5.

 

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Conflict of Interest

A patent on the synthesis of imino-imidodiphosphate (iIDP) catalysts has been filed (patent no. WO 2017/037141 A1, EP 3138845 A1). Furthermore, a patent on an improved synthesis of imidodiphosphoryl-derived catalysts using hexachlorophosphazonium salts has been filed (patent no. EP 3981775 A1).

Acknowledgement

The authors thank the technicians of the List group and the members of our mass spectrometry (MS) and chromatography (GC & HPLC) service departments for their excellent service.

• References

• 1a Liu L, Kaib PJ. S, Tap A, List B. J. Am. Chem. Soc. 2016; 138: 10822
• 1b Díaz-Oviedo CD, Maji R, List B. J. Am. Chem. Soc. 2021; 143: 20598
• 1c Grimm JA. A, Zhou H, Properzi R, Leutzsch M, Bistoni G, Nienhaus J, List B. Nature 2023; 615: 634
• 2 Ahmed SA, Bardshiri E, McIntyre CR, Simpson TJ. Aust. J. Chem. 1992; 45: 249
• 3 Nomoto Y, Horinouchi R, Nishiyama N, Nakano K, Ichikawa K, Kotsuki H. Synlett 2017; 28: 265
• 4 Kutateladze DA, Jacobsen EN. J. Am. Chem. Soc. 2021; 143: 20077
• 5 Schmidt B, Riemer M. Synthesis 2016; 48: 141

Publication History

Received: 03 March 2025

Accepted: 06 March 2025

Article published online:
08 August 2025