Dedication
Special Topic Dedicated to Prof. Paul Knochel.
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.
O-Prenylated Salicylaldehydes 1a–k; General Procedure
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.
2-((3-Methylbut-2-en-1-yl)oxy)benzaldehyde (1a)
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]
3-Methyl-2-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (1b)
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; Rf
= 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.
4-Methyl-2-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (1c)
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; Rf
= 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.
5-Methyl-2-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (1d)
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; Rf
= 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.
3,5-Di-tert-butyl-2-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (1e)
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; Rf
= 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.
3,6-Dimethyl-2-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (1f)
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; Rf
= 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.
5-Methyl-2-((3-methylbut-2-en-1-yl)oxy)isophthalaldehyde (1g)
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; Rf
= 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.
Ethyl 3-Formyl-4-((3-methylbut-2-en-1-yl)oxy)benzoate (1h)
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; Rf
= 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.
3-Methoxy-2-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (1i)
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; Rf
= 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]
4-Chloro-2-((3-methylbut-2-en-1-yl)oxy)benzaldehyde (1k)
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; Rf
= 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.
Asymmetric Prins Cyclization Reactions of O-Prenylated Salicylaldehydes 1 to 4-Chromanols 2; General Procedure
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.
3-(Prop-1-en-2-yl)chroman-4-ol (2a)
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]
8-Methyl-3-(prop-1-en-2-yl)chroman-4-ol (2b)
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); Rf
= 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.
7-Methyl-3-(prop-1-en-2-yl)chroman-4-ol (2c)
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); Rf
= 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 df, 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.
6-Methyl-3-(prop-1-en-2-yl)chroman-4-ol (2d)
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); Rf
= 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 df, 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.
6,8-Di-tert-butyl-3-(prop-1-en-2-yl)chroman-4-ol (2e)
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); Rf
= 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.
5,8-Dimethyl-3-(prop-1-en-2-yl)chroman-4-ol (2f)
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); Rf
= 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.
4-Hydroxy-6-methyl-3-(prop-1-en-2-yl)chromane-8-carbaldehyde (2g)
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); Rf
= 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.
Ethyl 4-Hydroxy-3-(prop-1-en-2-yl)chromane-6-carboxylate (2h)
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); Rf
= 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.
8-Methoxy-3-(prop-1-en-2-yl)chroman-4-ol (2i)
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); Rf
= 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 df, 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.
7-Chloro-3-(prop-1-en-2-yl)chroman-4-ol (2k)
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); Rf
= 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.
