Synthesis of Dihydro- and Tetrahydropyrans via Oxonium-ene Cyclization Reaction
3.2. Literature Methods for the Synthesis of Dihydro- and Tetrahydropyrans
Over the years many strategies have been developed for the synthesis of dihydro- and tetrahydropyrans, which include Prins cyclization, intramolecular silyl-modified Sakurai reaction (ISMS), oxonium-ene cyclization, ring closing metathesis and Wittig reaction.
Semeyn et al. had investigated the effect of geometry of (Z)-vinylsilanes 6 and (E)- vinylsilanes 7 on the cis/trans diastereoselectivity of 2, 6-disubstituted-3, 4-dihydropyrans products (Scheme 3.2.1). The (Z)-vinylsilane on treatment with boron trifluoride etherate produces cis diastereomer 8 as a major isomer. Whereas, the (E)-vinyl silane on reaction with aldehyde gives trans diastereomer 9 as a major isomer.8
Scheme 3.2.1.
In a similar approach Dobbs and coworkers showed the effective use of stoichiometric amount of InCl3 as a Lewis acid catalyst to promote the cyclization of aldehydes 11 with (Z)-vinylsilanes 10 to 3,4-dihydropyrans 12 in good yields with excellent diastereoselectivity (Scheme 3.2.2).9
Scheme 3.2.2.
Panek and coworkers demonstrated a method for the synthesis cis-2,6- and trans-2,6- dihydropyrans by the reaction of β-hydroxyallylsilanes with aldehydes in the presence of TMSOTf (Scheme 3.2.3). This raction first generates an oxocarbenium ion intermediate, followed by intramolecular sillyl Prins cyclization reaction. The cyclization of syn-silane 13 with
aldehyde 14 gave the cis-2,6-trans-5,6-trisubstituted dihydropyran 15 as the major product and trans-2,6-trans-5,6-trisubstituted dihydropyran 16 as minor product. Whereas, the cyclization of anti-silane 17 with aldehyde 14 provided trans-2,6-trans-5,6-trisubstituted dihydropyran 18 as the major isomer with all cis dihydropyran 19 as minor isomer.10
SiMe2Ph OTMS
CO2Me TMSOTf
O
MeO2C MeO2C O
Syn-Silane13
CHO
cis-transisomer trans-transisomer 25:1
30:1 87%
CH2Cl2-20 °C
SiMe2Ph OTMS
CO2Me TMSOTf
Anti-Silane17
CHO
CH2Cl2-20 °C
O
MeO2C MeO2C O
allcis isomer 19
tr ans-transisomer 18
14 85%
15 16
14
Scheme 3.2.3.
Hinkle has reported a Bi(OTf)3 catalyzed cascade reaction, involving rearrangement of epoxides 21 to aldehyde electrophiles, which subsequently undergo cyclization with (Z)-δ- hydroxyalkenylsilane 20 via intramolecular silyl-modified Sakurai reaction (ISMS) to afford 2,6- disubstituted 3,6-dihydro-2H-pyrans 22 in moderate yields (Scheme 3.2.4).11
Scheme 3.2.4.
Schmidt et al. have implemented ring-closing metathesis for the synthesis of dihydropyrans. The ring-closing metathesis of allyl homoallyl ether 23 having two adjacent protected hydroxymethyl side chains catalysed by Grubbs 1st generation catalyst 25, afforded the dihydropyran 24 in excellent yield (Scheme 3.2.5).12
Ru CHPh Cl
Cl P(Cy)3
P(Cy)3 O
OTBDMS
OBn O
OBn OTBDMS
23 24 25
25(3mol%) CH2Cl2
97%
Scheme 3.2.5.
Epoxides 27 which function as an aldehyde equivalent, undergo cyclization with homopropargylic alcohols 26 in the presence of zirconium tetrachloride under mild conditions to afford the corresponding dihydropyran derivatives 28 in excellent yields under mild conditions (Scheme 3.2.6).13
Scheme 3.2.6.
Recently, Martin has also explored the synthetic potential of cyclizations involving homopropargylic alcohol.14 Reactions of homopropagylic alcohols 29 and aldehydes 30 mediated by anhydrous FeCl3 or FeBr3 gave 4-halo-2-alkyl-5,6-dihydro-2H- pyrans 31 in yields ranging from 30 to 98% (Scheme 3.2.7).
OH +
H O
O X FeX3
CH2Cl2, rt
X = Cl, 24 h 80%
X = Br, 2 h 73%
29 30
31
Scheme 3.2.7.
More recently, Saikia and coworkers have developed an efficient method for the synthesis of 4- aryldihydropyrans 34 from carbonyl compounds 32, homopropargylic alcohols, and arenes mediated by boron trifluoride etherate via Prins-Friedal-Crafts reaction (Scheme3.2.8).
Furthermore, the method has also been extended to terminal epoxides 33, which gives dihydropyrans 35.15
OH +
R H
O
BF3.Et2O Arene
r.t. to 40 C O
where R = alkyl, aryl R1= H, alkyl Ar or
R1
R O R1
R 32
33
35 O
Ar R 34
45-95%
Scheme 3.2.8.
A number of procedures in the literature for the preparation of tetrahydropyrans with an exomethylene double bond. Some of these introduce the exomethylene moiety on to a preformed tetrahydropyran ring. For example, Kabata et al. in their preparation of a precursor of α-2,5- dihydroxy-vitamin D3 used Wittig methodology to produce the exomethylene tetrahydropyrans 36 (Scheme 3.2.9).16
Scheme 3.2.9
Schiff et al. have reported a facile enantioselective synthesis of cis-2,6-disubstituted 4-methylene tetrahydropyran derivatives through a two-step process (Scheme 3.2.10).17 The first step is asymmetric allylation of an aldehyde 38 with allyl stannane 37 in the presence of a BINOL titanium isopropoxide catalyst to generate the enantiopure hydroxyl allylsilane 39. The second step, trimethylsillyltriflate promoted annulation of the allyl silane with a second aldehyde 40, to afford the cis-2,6-tetrahydropyran 41 containing an exo-methylene in the 4th position.
Scheme 3.2.10.
Rychnovsky has developed tandem Mukaiyama aldol-Prins (MAP) cyclization reaction using allylsilane derivatives and aldehydes for the synthesis of 4-methylene tetrahydropyrans (Scheme 3.2.11).18 The cascade reaction involves the Mukaiyama aldol condensation of an aldehyde 43
and an alkyl enol ether 42 to generate an intermediate oxocarbenium ion 44. This oxocarbenium ion is then trapped with an allylsilane to produce tetrahydropyran 45.
Scheme 3.2.11.
Minehan and coworkers developed an environmentally benign method for the synthesis of cis- 2,6-disubstituted-4-methylene tetrahydropyran systems through an one-pot, two-step process (Scheme 3.2.12),19 in which allylation of aldehyde 47 occurs with sillyl substituted allyl iodide 46 in the presence of indium metal to generate substituted homoallylalcohol 48, followed by annulation of homoallylalcohol with a second aldehyde 49 to give cis-2,6-disubstituted-4- methylenetetrahydropyran 50.
Me3Si I In(0)
H2O:i-PrOH 10h
C5H11 OH
SiMe3
O C5H11CHO
C5H11
Cl CHO
2 eqiv Cl
14h Overall
yield 68%
H2O:i-PrOH
46 47
48
49
50
Scheme 3.2.12.
Loh and coworkers20 described a two component reaction between homoallylalcohol 52 and aldehyde 51 catalyzed by In(OTf)3 for the synthesis of 4-methylene tetrahydropyrans, which proceeds through intramolecular (2,5)-oxonium-ene cyclization reaction. This method gave both syn and anti diastereomers 53, 54 in the ratio ranging from 56:44 to 95:5 (Scheme 3.2.13).
Hoveyda and coworkers reported an highly stereoselective method for the synthesis of cis-2,6- disubstituted-4-methylene tetrahydropyrans using a Brønsted acid-catalysed reaction of
Scheme 3.2.13.
homoallyl enol ethers.21 An enol ether 55 was reacted with a catalytic (0.01 mol%) amount of TfOH to afford the desired tetrahydropyran 56 and its regioisomers 57, 58 (Scheme 3.2.14).
Scheme 3.2.14.