Stereoselective Synthesis of Unsymmetrical 4-Aryltetrahydropyrans
4.3. Results and Discussion
In our previous chapter we had described a methodology for the synthesis of 4-aryl- tetrahydropyran by using Sakurai-Hosomi-Prins-Friedel-Crafts reaction. Although the Sakurai-Hosomi-Prins-Friedel-Crafts reaction provides symmetrical 4-aryl tetrahydropyran with excellent stereochemistry, but it fails to afford unsymmetrical 2,6- disubstituted 4-aryl-tetrahydropyran. Here we report an efficient method for the synthesis of unsymmetrical 2,6-disubstituted 4-aryl tetrahydropyran from carbonyl compound, homoallyl alcohol and arene mediated by boron trifluoride etherate in excellent yield and stereochemistry.
Initially benzaldehyde was reacted with homoallyl alcohol in the presence of boron trifluoride etherate in benzene at rt. The product 2,4,-diphenyltetrahydropyran was obtained with 75% yield in 6 h. The reaction is stereoselectve and both the substituents are in cis position. BF3.
OEt2 was found to be the most effective Lewis acid for the reaction as several other non-halogenated Lewis acids such as TMSOTf, In(OTf)3,
Scheme 4.3.1. Synthesis of 2,6-disubstituted 4-phenyl tetrahydropyran
O OH
OTES
OMe MeO
O OH
MeO
OMe
i) BiBr3, Et3SiH MeCN, rt ii) NaOtBu, MeOH
0 oC
(-)-Sugiresinol, 34 33 99%
H O
+ OH
BF3.Et2O O
Ar R1 R1
R
arene 0 oC - rt
R
where R = R1 = H, Alkyl, Aryl, Heterocyclic
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Chapter 4 Unsymmetrical 4-Aryltetrahydropyrans
105 Table 4.3.1. Synthesis of 2,6-disubstituted 4-aryl tetrahydropyran
CHO
CHO O2N
CHO
NO2
OH
OH
O
Ph O
NO2
Ph
OH O NO2
Ph
CHO Cl
OH O
Cl
Ph CHO
Cl
OH O Cl
Ph CHO
Br
OH O
Ph
Br CHO
F
OH O
F
Ph
CHO
CF3 OH O
CF3
Ph CHO
MeOOC
OH O
COOMe
Ph OH
CHO
O
Ph Aldehyde (a)
Sl No. Homoallyl
alcohol Product (b)
1
2
Time /h Yielda (%)
8
9
6
3
4
5
6
7
10
4
4
4
4
4
4
4
4
9
75
90
90
95
88
92
80
93
90
60
continue...
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Chapter 4 Unsymmetrical 4-Aryltetrahydropyrans
106
CHO
MeO OH
O
OMe
Ph
CHO OH O
Ph
OH
O
Ph CHO
OH O
Ph
OH
O
Ph H
5O
H O
OH O O
Ph H
O O
O
NO2
Ph H
O
O
NO2
Ph H
O
OH NO2
OH NO2
OH O
Ph CHO
OH NO2 CHO
O2N
O
NO2
Ph O2N
O
NO2
OH Ph NO2
CHO
5 Aldehyde (a)
Sl No. Homoallyl
alcohol Time / h Product (b) Yielda (%)
11 9 70
12 10 65
13 4 80
14 4 85
15 5 70
6 63
6 65
18 3
19 3 85
21 3 92
16
17
20 3 90
75
aYields refers to isolated yield.
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Chapter 4 Unsymmetrical 4-Aryltetrahydropyrans
107 Bi(OTf)3 and Sc(OTf)3 were found to be either less effective or not effective at all. The reaction can be generalized as shown in scheme 4.3.1.
In order to prove its general applicability, aliphatic, aromatic, unsaturated, and hetrerocyclic aldehydes were examined and found that all types of aldehydes give good yields and stereochemistry (Table 4.3.1)
In all the cases studied, 4-aryl tetrahydropyran 1b-21b (Table 4.3.1) could be obtained in high purity without any side products. Both aliphatic and aromatic aldehydes give good yield with high degree of diastereoselectivity as determined from the 1H and 13C NMR spectrum of the crude product. The substituent on the aromatic ring has promising effect on this reaction. The electron-withdrawing and simple benzaldehydes gave good yields compared to electron donating groups. Aliphatic aldehydes are found to be better substituents for this reaction.
To extend the utility of this method various arens, as nucleophile, were systematically investigated under these reaction conditions. It was observed that methyl and methoxy substituted benzene reacts faster than benzene. Thus the reaction with toluene gave 22 as an inseparable regioisomers with a ratio of 4.7:1 and 97% overall yield. Similarly ortho and meta- xylene gave products 23 (85% yield) and 24 (80% yield) as mixture of two regioisomers with a ratio of 2:1 and 80% overall yield (Table 4.3.2). On the other hand 1-methoxy-4-methyl benzene gave single isomer 27 with 82% yield. But fused ring aromatic compounds, for example, naphthalene, 2-methoxy naphthalene and deactivated aromatic compounds were remained uncreative.
The conformation of the compounds is in the chair form and all the three substituents are in equatorial position. The substituent’s at the 2-, 4-, and 6-positions of the tetrahydropyran ring are in a cis relationship and are equatorial. This is revealed from the two inseparable regioisomers with a ratio of 1:1.2 and 1:2.7, respectively. On the other hand para xylene gave 25 as a single isomer with 88% yield. Anisole gave 26 as ortho/para coupling constants of the 2-H (J = 10.8 and 1.6 Hz), 6-H (J = 11.6 and 2.8 Hz) and the 4-H (J = 12.4 and 3.6 Hz) hydrogen atoms of compound 2b (Figure 4.3.1).
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108 Table 4.3.2. Reaction of 3-buten-1-ol and m-nitro-benzaldehyde with other nucleophiles
(Arenes)
Me O NO2
Me Me
O NO2
Me
Me
O NO2
O NO2
Me Me Me
Me
O NO2
OMe
O NO2
Me
OMe Me
OMe
Me
Me
Me Me Me
OMe
S.No. Arene Time (/h) Product %Yielda
3
4
5
1 1.5 90
2 1 85
1 88
1 80
6 80
6 6 82
(22)
(23)
(24)
(25)
(26)
(27)
aYields refer to isolated yield
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Chapter 4 Unsymmetrical 4-Aryltetrahydropyrans
109 This was confirmed by NOE experiment and single-crystal X-ray analysis of 2-(4-Nitro- phenyl)-4-phenyl-tetrahydropyran (Figure 4.3.2).16
Figure 4.3.1. Coupling constants and NOE of Compound (2b)
Figure 4.3.2. ORTEP diagram of 2-(4-Nitro-phenyl)-4-phenyl-tetrahydropyran (2b)
We were naturally tempted to gauge the efficacy of the above protocol for the construction of tetrahydropyran ring, and thus we attempted the reaction with ketones as well (Scheme 4.3.2). The reactions proceeded smoothly to generate the desired products in good yields (Table 4.3.3). But, the reaction requires high temperature (40 oC) and takes longer reaction time. Thus, the reaction with cyclohexanone and 1,4-cyclohexanedione gave spirocyclic product 28 and 29 with 46% and 30% respectively at 40 oC. On the other hand symmetrical dichloroacetone gave 2,2-bis-chloromethyl-4-phenyl-tetrahydropyran
O
H H
Ph Ar NOE
(J = 10.8, 1.6 Hz) (J = 12.4, 3.6 Hz)
H H
(J = 11.6, 2.8 Hz)
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Chapter 4 Unsymmetrical 4-Aryltetrahydropyrans
110 30 with 40% yield. Thus, it is evident that this reaction has widespread application for the synthesis of novel bicyclic heterocycles.
Scheme 4.3.2 Reaction of 3-buten-1-ol with ketone Table 4.3.3. Reaction with Ketones
The major advantage of this reaction is that in a single step, two reactions primarily Prins cyclisation and Friedel-Crafts reaction can be performed without any difficulties.
The mechanism of the reaction can be explained as follows (Scheme 4.3.3). In the presence of Lewis acid homoallyl alcohol 31 reacts with aldehyde to afford oxocarbenium ion 32. The intermediate 32 undergoes Prins cyclization to give tetrahydropyranyl cation 33, which in the presence of aryl neucleophile, gives
R
O + OH BF3.Et2O
Benzene 40 oC
O R
R ketone
R
O O
O Cl
Cl O
O
O O
Cl Cl
O
Ketone Time /h Product Yielda
46
30
40 8
24
8
(28)
(29)
(30)
aYields refers to isolated yield
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Chapter 4 Unsymmetrical 4-Aryltetrahydropyrans
111 intermediate 34. The species 34 after deprotonation gives the 2,6-disubstituted-4- aryltetrahydropyran 35.
Scheme 4.3.3 Mechanism of the reaction
Conclusion:
An efficient, highly diastereoselective one-pot method has been developed for the synthesis of unsymmetrical 2,6-disubstituted 4-aryl tetrahydropyran. The same method can be used for the synthesis of spirocyclic compound in good yields. This method holds good for aldehydes, ketones and will be of immense importance in natural product synthesis.