Completely OH-selective FeCl3-catalyzed prins cyclization: Highly stereoselective synthesis of 4-OH-tetrahydropyrans

Article abstract of DOI:10.1021/ja3062002

The completely OH-selective Prins cyclization has been realized from the enantioselective ene reaction product. A variety of 4-hydroxyl-tetrahydropyrans were exclusively generated via FeCl₃-catalyzed Prins reaction. Excellent stereoselectivitie

Full text of DOI:10.1021/ja3062002

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Article
Completely OH-Selective FeCl3-Catalyzed Prins Cyclization:
Highly Stereoselective Synthesis of 4-OH-Tetrahydropyrans
Ke Zheng, Xiaohua Liu, Song Qin, Mingsheng Xie, Lili Lin, Changwei Hu, and Xiaoming Feng
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 02 Oct 2012
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Completely OH-Selective FeCl3-Catalyzed Prins Cyclization:
Highly Stereoselective Synthesis of 4-OH-Tetrahydropyrans
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Ke Zheng, Xiaohua Liu, Song Qin, Mingsheng Xie, Lili Lin, Changwei Hu and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China.
Supporting Information Placeholder
ABSTRACT: The completely OHꢀselective Prins cyclization has been realized from the enantioselective ene reaction product. A
variety of 4ꢀhydroxylꢀtetrahydropyrans were exclusively generated via FeCl3 catalyzed Prins reaction. Excellent stereoselectivities
(up to >99:1 dr and >99.5:0.5 er) were obtained for a remarkably broad substrates under mild reaction conditions. The control
experiments, including NOE effects and 18Oꢀlabeling studies, as well as DFT calculations were conducted to provide fundamental
insights into the mechanism of the reaction. A different [2+2] cycloaddition process was suggested to rationalize the observed OHꢀ
selectivity.
INTRODUCTION
Substituted tetrahydropyrans represent a common structural
motif featured in a large number of natural products and
biologically active compounds.1 In particular, chiral 4ꢀ
hydroxyl substituted tetrahydropyran derivatives play an
important role in therapeutic area. In virtue of the varied and
significant biological activities2ꢀ4 observed for such a class of
compounds, the development of catalytic asymmetric
synthesis of 4ꢀhydroxyl tetrahydropyrans is highly valuable.
Therefore, a number of reactions have been developed to
approach to this target.5 Among existing approaches, the Prins
affording a mixture of products in some case.10 Thus, the
cyclization, a coupling of a homoallylic alcohol with a
development of catalytic methods that selectively produce
optically active 4ꢀhydroxylꢀtetrahydropyrans would be
particularly valuable.
carbonyl compound in the presence of an acid catalyst, stood
out as one of the most attractive.6–11 However, the
enantioselective access to substituted tetrahydropyrans via the
Prins cyclization was restricted to two of the problems
common to the typical Prins cyclization protocols: sideꢀchain
exchange and partial racemization by reversible 2ꢀoxonia
Cope rearrangement and solvolysis effect, which has been
demonstrated as a competitive process in Prins cyclization by
Rychnovsky and Willis (Scheme 1).8 On the other hand, in
previous works, the halogenated Lewis acidꢀpromoted (such as
MXn and TMSX) Prins cyclizations usually gave the haloꢀ
substituted tetrahydropyrans as products, which formed as the
result of intermediateꢀtrapping by halogen ion (most
commonly from the original acid MXn and TMSX). And
hydroxylꢀsubstituted products were only obtained as the
byproducts.9 Although hydroxylꢀadded products could be
achieved as the main products in the presence of TFA or
M(OTf)n (a Lewis acid with a nonꢀnucleophilic anion), more
generally, strongly acidic conditions and stoichiometric
amounts of catalyst were required,
The design of practically simple and efficient organic
transformations is one of the main challenges of current
organic synthesis. The formation of multiple bonds through
sequential reactions constitutes one approach to achieving this
goal.12 Considering the fact that homoallylic alcohols achieved
by ene reaction are pivotal substrates for the Prins cyclization,
we envisioned that a stepwise catalytic asymmetric ene
reaction, followed by an intermolecular Prins cyclization
would produce optically active substituted tetrahydropyrans
(Scheme 2). Herein, we report our investigations on
stereoselective synthesis of 4ꢀhydroxyl tetrahydropyrans by
sequential ene/Prins cyclization reactions. Chiral Ni(II)–N,N'ꢀ
dioxide complex13,14 and FeCl3 were used for the two processes,
respectively. None of 2ꢀoxoniaꢀCope
Scheme 2. Lewis acid catalyzed ene-Prins cyclizations
Scheme 1. OH-Selective FeCl3-catalyzed Prins cyclization
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x
t
yield of
entry additive
er of 5nc
(mol %)
(h) 5n/7n (%)b
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1
2
TMSCl
TESCl
TBSCl
Ph3SiCl
TBSOTf
TMSOTf
TBSCl
TBSCl
TBSCl
NEt3
20
6
<5/68
18/62
92/<5
84/10
12/65
<5/72
90/<5
92/<5
89/<5
ꢀ
ꢀ
20
6
99:1
99:1
99:1
ꢀ
3
20
20
12
24
0.5
0.5
12
12
12
48
32
64
48
4
rearrangement was observed in the reaction. This new
approach permitted an easy and straight route to a range of
optically active 4ꢀhydroxylꢀtetrahydropyrans with excellent
outcomes (up to 92% yield, >99:1 dr, >99:1 er) under mild
conditions. We also detailed mechanistic studies such as
control experiments, NOE effects, and Oxygenꢀ18 labeling
studies, as well as computational calculation.
5
20
6
20
ꢀ
7
10
99:1
99:1
99:1
ꢀ
8
50
9
120
20
10
11
12
13d
RESULTS AND DISCUSSION
Reaction Optimization.
H2O
120
500
20
89/<5
82/<5
ꢀ
99:1
99:1
ꢀ
H2O
Table 1. Examination of Lewis acid in the Prins
cyclizationa
TBSCl
a
Unless otherwise noted, the crude product 4a (0.2 mmol) of
carbonylꢀene reaction was added to test tube with 2ꢀ
naphthaldehyde 3n (0.24 mmol), FeCl3 (20 mol %) and additive
(x mol %) in CH2Cl2 (1.0 mL) at 10 °C. Isolated yield.
Determined by chiral HPLC.
a
b
c
d
The reaction was performed
without FeCl3. TBS = tertꢀbutyldimethylsilyl, TES = triethylsilyl.
Initially, the chiral homoallylic alcohol 4a (99:1 er), generated
from chiral N,N'ꢀdioxide L–Ni(II) complex catalyzed ene
reaction, was used for the Prins reaction with 2ꢀ
naphthaldehyde 3n. Various acidic catalysts, generally used in
Prins cyclization,9ꢀ10 were examined. To our surprise, 4ꢀ
hydroxy tetrahydropyran 5n was exclusively obtained no
matter what kind of Lewis acid was used. As shown in Table
1, with 3.0 equivalences of TFA, the Prins cyclization
proceeded at 10 °C to afford 4ꢀhydroxylꢀtetrahydropyran 5n in
36% yield with 98:2 er, and a 42% yield of dihydroꢀ2Hꢀpyran
derivatives 7n15 (Table 1, entry 1). In the presence of 20
mol % catalyst of Sc(OTf)3 or In(OTf)3 (the Lewis acid with a
nonꢀnucleophilic anion), the reactivity was slightly improved,
and the product 5n was obtained in 52% yield and 46% yield,
respectively (Table 1, entries 2–3). Interestingly, when
halogenated Lewis acids, which generally afforded 4ꢀhaloꢀ
substituted products in previously related work, were tested in
the reaction, 4ꢀhydroxy tetrahydropyran 5n rather than 4ꢀhalo
tetrahydropyran 6n was generated.9 In the presence of 20
mol % of FeCl3, the unexpected hydroxylꢀadded product 5n
was generated in 72% yield and 99:1 er within 24 hours (Table
1, entry 8). Moreover, no competitive 2ꢀoxonia Cope
yield of
Lewis
acid
catalyst
loading
er of 5n
entry
t (h)
5n/7n
c
(%)b
1
2
3
4
5
6
7
8
9
TFA
300 mol %
20 mol %
20 mol %
20 mol %
20 mol %
20 mol %
20 mol %
20 mol %
20 mol %
24
24
24
48
48
48
48
24
24
36/42
98:2
In(OTf)3
Sc(OTf)3
AlCl3
52/32
99:1
46/35
99:1
ꢀ
ꢀ
SnCl4
ꢀ
ꢀ
InCl3
ꢀ
ꢀ
InBr3
ꢀ
ꢀ
FeCl3
72/12
63/22
99:1
FeBr3
98.5:1.5
anhydrous
HCl
10
ꢀ
6
ꢀ
ꢀ
a
Unless otherwise noted, the crude product 4a (0.2 mmol)
obtained from asymmetric catalytic carbonylꢀene reaction was
added to a test tube with 2ꢀnaphthaldehyde 3n (0.24 mmol), acid
catalyst in CH2Cl2 (1.0 mL) at 10 °C.
Determined by chiral HPLC.
b
c
Isolated yield.
rearrangement
Contrastingly, other
Table 3. Optimization of other reaction conditionsa
and
sideꢀchain
exchange
occurred.
Table 2. Examination of additives in the Prins cyclizationa
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accelerated the generation of the byproduct 7n (Table 2,
entries 5–6). Moreover, varying the amount of TBSCl (0.1–1.2
equiv) had no obvious effect upon the outcomes (Table 2,
entries 7–9). The use of base additive NEt3 inhibited the
occurrence of Prins cyclization (Table 2, entry 10). The
reaction time prolonged with an increase of the amount of H2O,
but the elimination product somewhat decreased (Table 2,
entries 11–12 vs Table 1, entry 8).18 Additionally, in the
absence of FeCl3, no reaction was observed using TBSCl
alone (Table 2, entry 13).
yield of
5n/7n
(%)c
x
t
er of 5n
entry Conc.b
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d
(mol %) (h)
1
2
0.05 M
0.1 M
0.2 M
0.5 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
20
20
20
20
10
50
100
20
20
20
32
24
12
10
24
4
89/<5
99:1
99:1
99:1
99:1
99:1
ꢀ
With FeCl3 and TBSCl identified as the optimized catalyst
system for the Prins cyclization, effects related to reaction
concentration, temperature and catalyst loading were next
examined. As shown in Table 3, a slight enhancement in
reactivity was observed when the concentration was increased
(Table 3, entries 1–4). It is worth pointing out that decreasing
the catalyst loading to 10 mol % resulted in a slightly reduced
yield of 5n (Table 3, entry 5). While, when large quantities of
FeCl3 were present, the elimination product 7n was obtained
as the major product (Table 3, entries 6–7). Additionally,
decreasing the reaction temperature to 0 °C or −20 °C led to
no improvements (Table 3, entries 8–9). High temperature was
favorable for the formation of the product 7n, and only trace
of product 5n was obtained at 35 °C (Table 3, entry 10).
90/<5
92/<5
90/<5
89/<5
<5/73
<5/80
87/<5
92/<5
<5/75
3
4
5
6
7
1
ꢀ
8e
9f
10g
48
24
4
99:1
99:1
ꢀ
a
Unless otherwise noted, the crude product 4a (0.2 mmol) of
carbonylꢀene reaction was added to test tube with 2ꢀ
a
naphthaldehyde 3n (0.24 mmol), FeCl3 (x mol %) and additive
Substrate Scope. With the optimal reaction conditions estabꢀ
lished, the substrate scope was extended. As summarized in
Table 4, the reaction displayed a broad scope for aldehydes,
and excellent levels of chemoꢀ and stereoselectivity were
achieved. Aromatic aldehydes with either electron donating or
withdrawing substituents at the ortho-, meta-, or para- posiꢀ
tions all performed well, furnishing the corresponding prodꢀ
ucts with 68–90% yields, 80:20–>95:5 dr, and 98:2–>99:1 er
(Table 4, entries 2–12). In general, the reaction rate of the
Prins cyclization was higher with electronꢀrich aldehydes. For
example, methylbenzaldehydes and methoxylbenzaldehydes
underwent the reaction within 4–6 hours (Table 4, entries 2–
7), whereas chloroꢀ, fluoroꢀ, and trifluoromethylꢀsubstituted
benzaldehydes required 12–36 hours (Table 4, entries 8–12). It
was noteworthy that the naphthaldehydes 3m, 3n, and the
heteroaromatic aldehydes 3o, 3p also well tolerated, giving the
corresponding products in high yields with excellent stereoseꢀ
lectivities (Table 4, entries 13–16). Some representative aliꢀ
phatic aldehydes were also evaluated. Excitingly, linear aldeꢀ
hydes, such as nꢀpropanal, nꢀbutanal, nꢀhexanal, 3ꢀ
phenylpropanal, cinnamaldehyde, and (E)ꢀbutꢀ2ꢀenal gave the
corresponding products with high yields within 3–8 hours
(Table 4, entries 17–18, 21, and 24–26). Comparatively, steric
bulkier aldehydes gave moderate yields with somewhat longer
reaction time (Table 4, entries 19–20 and 22–23). It suggested
that for the cyclization of aliphatic aldehydes, smaller steric
hindrance significantly benefited the reactivity.
(20 mol %) in CH2Cl2 at 10 °C. b With respect to 4a. Isolated
c
d
e
yield.
Determined by chiral HPLC.
The reaction was
performed at −20 °C. f The reaction was performed at 0 °C. g The
reaction was performed at 35 °C.
Lewis acids such as AlCl3, SnCl4, InCl3, and InBr3 afforded no
products, reflecting the importance and particular
characteristic of metal iron (Table 1, entries 4–7 vs 8).
Changing the counterion of the iron(III) salt provided no
improvement in the reaction efficiency (Table 1, entry 9). The
anhydrous HCl was also used in the reaction, but no desired
product 5n was obtained, and the reaction only gave some
impurity with the same Rf value, which were difficult to
separate via flash chromatography (Table 1, entry 10).
These results promoted us to carry out an exhaustive study to
find the optimal conditions for the formation of optically
active 4ꢀhydroxy tetrahydropyran derivative 5n. Silicon Lewis
acids is an useful mediator in carbonꢀcarbon bond forming
reactions.16 Inspired by previous works,9 some acidic
compounds such as the TMSCl, TESCl, TMSOTf as additives
were examined to further improved the selectivity and activity
of reaction.17 As shown in Table 2, it was found that the
additives had a significant effect on the outcome of the ratio
between 5n and elimination product 7n. Excitingly, TBSCl
was found as the most effective additive, affording the product
5n/7n in 92% and <5% yield, respectively (Table 2, entries 1–
6). The enantiomeric excess of the product 5n was maintained.
However, when TMSCl or TESCl was used, the amount of
byproduct 7n exceeded that of 5n (Table 2, entries 1–2).
TBSOTf and TMSOTf shorten the reaction time, but
Additionally, a series of alkenes were proven suitable for this
reaction as highlighted in Table 5. For the first step, the
asymmetric ene reaction of various alkenes (2b–2i)
Table 4. Substrate scope of aldehydes in the synthesis of 4-hydroxyl tetrahydropyransa
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3, R3
x (mol %)
t (h)b
yield (%)c
drd
er e,g
entry
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3a, C6H5
1
20
10
10
10
10
10
10
20
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20
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5a, 74
5b, 85
5c, 83
5d, 88
5e, 72
5f, 82
5g, 90
5h, 82
5i, 81
5j, 70
5k, 90
5l, 68
5m, 87
5n, 92
5o, 58
5p, 80
5q, 88
5r, 85
5s, 84
5t, 75
5u, 88
5v, 73
90:10
85:15
90:10
80:20
90:10
85:15
80:20
80:20
80:20
>95:5
>95:5
>95:5
85:15
>95:5
80:20
90:10
99:1
99:1
99:1
3b, 2ꢀCH3C6H4
3c, 3ꢀCH3C6H4
3d, 4ꢀCH3C6H4
3e, 2ꢀCH3OC6H4
3f, 3ꢀCH3OC6H4
3g, 4ꢀCH3OC6H4
3h, 4ꢀFC6H4
3i, 4ꢀClC6H4
3j, 3ꢀBrC6H4
3k, 4ꢀBrC6H4
3l, 4ꢀCF3C6H4
3m, 1ꢀnaphthyl
3n, 2ꢀnaphthyl
3o, 2ꢀfuryl
2
3
6
98.5:1.5
99:1
4
6
5
4
99:1
6
4
99:1
7
4
98:2
8
24
24
24
12
36
16
12
12
12
6
99:1
9
99:1
10
11f
12
13
14
15
16
17
18
19
20
21
22
99.5:0.5
99.5:0.5
99:1
97.5:2.5
99:1
99:1
3p, 2ꢀthienyl
3q, Et
99:1
99:1
3r, nꢀPr
8
99:1
99.5:0.5
98:2
3s, iꢀPr
12
24
8
99:1
3t, tꢀBu
>99:1
>99:1
99:1
97.5:2.5
99:1
3u, nꢀpentyl
3v, cꢀhexyl
24
99.5:0.5
23
24
20
20
24
6
5w, 68
5x, 80
99:1
98.5:1.5
99:1
3w,
3x,
>95:5
25
26
10
20
3
8
5y, 92
5z, 76
90:10
99:1
99:1
3y,
3z,
98.5:1.5
a Unless otherwise noted, the reaction was carried out with ethyl glyoxylate 1a (0.2 mmol), 2ꢀphenylpropene 2a (2.0 equiv) and 10 mol %
of Ni(II)–L in CH2Cl2 (1.0 mL) at 35 °C for 48 hours. After flash column chromatography, the crude product 4a was added to a test tube
with aldehyde 3 (0.24 mmol), FeCl3 1and TBSCl in CH2Cl2 (1.0 mL) at 10 °C. b The reaction time of the Prins cyclization. c Isolated yield
on the basis of 1a. d Determined by H NMR spectroscopy of the crude product and chiral HPLC analysis. e Determined by chiral HPLC
analysis. f The absolute configuration of the product 5k was determined to be (2S, 4S, 6R) by Xꢀray diffraction analysis.19 g For most
products the stereochemistry of the minor diastereomer were the same to the major diastereomer.20
Table 5. Substrate scope of alkenes in the synthesis of 4-hydroxyl tetrahydropyransa
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Product 4
Product 5
9
entry
2
3
yield (%)b
er d
yield (%)b
dr (%)c
er d,e
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2b, R2 = 2ꢀCH3C6H4
2c, R2 = 4ꢀCH3C6H4
2d, R2 = 4ꢀFC6H4
2e, R2 = 4ꢀClC6H4
2f, R2 = 4ꢀBrC6H4
2c, R2 = 4ꢀCH3C6H4
2d, R2 = 4ꢀFC6H4
2e, R2 = 4ꢀClC6H4
2f, R2 = 4ꢀBrC6H4
2g, R2 = 4ꢀCH3OC6H4
R3 = 4ꢀBrC6H4
R3 = 4ꢀBrC6H4
R3 = 4ꢀBrC6H4
R3 = 4ꢀBrC6H4
R3 = 4ꢀBrC6H4
R3 = Et
1
2
3
4
5
6
7
8
77
95
94
82
90
95
94
82
90
95
99.5:0.5
99:1
98.5:0.5
99:1
99:1
99:1
98.5:0.5
99:1
98.5:0.5
99:1
5aa, 50
5ab, 58
5ac, 58
5ad, 62
5ae, 52
5af, 63
5ag, 76
5ah, 72
5ai, 75
ꢀ
99:1
99:1
90:10
80:20
99:1
99:1
99:1
99:1
99:1
ꢀ
98.5:1.5
99:1
98:2
99:1
99:1
99:1
98.5:1.5
99:1
98.5:1.5
ꢀ
R3 = Et
R3 = Et
R3 = Et
9
10
R3 = Et
R3 = Et
11
96
92
99.5:0.5
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2h,
R3 = Et
12
99.5:0.5
ꢀ
2i,
a
b
c
1
The procedure was similar to that in Table 4. Isolated yield on the basis of 1a. Determined by H NMR spectroscopy of the crude
product and chiral HPLC analysis. d Determined by chiral HPLC analysis. e The stereochemistry of the minor diastereomer is unknown.
Table 6. Substrate scope of glyoxal derivatives in the synthesis of 4-hydroxyl tetrahydropyransa
Product 4
yield (%)b
Product 5
entry
R1
R3
er d
yield (%)b
dr (%)c
er d,e
Ph
4ꢀBrC6H4
4ꢀBrC6H4
4ꢀBrC6H4
2ꢀnaphthyl
1
2
3
4
5
6
7
8
98
97
88
98
98
97
99
92
88
95
93
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
>99.5:0.5
99.5:0.5
>99.5:0.5
>99.5:0.5
99.5:0.5
5aj, 65
5ak, 42
5al, 48
5am, 56
5an, 76
5ao, 52
5ap, 50
5aq, 58
5ar, 56
5as, 62
99:1
99:1
99:1
99:1
99:1
99:1
99:1
>95:5
99:1
>95:5
99:1
>99.5:0.5
>99.5:0.5
99.5:0.5
98.5:1.5
98.5:1.5
>99.5:0.5
98.5:1.5
98.5:1.5
99:1
4ꢀCH3C6H4
4ꢀClC6H4
Ph
Ph
Et
Et
Et
Et
Et
Et
Et
4ꢀCH3C6H4
4ꢀCH3OC6H4
4ꢀFC6H4
4ꢀClC6H4
4ꢀBrC6H4
2ꢀnaphthyl
9
10
98.5:1.5
97.5:2.5
11
99.5:0.5
5at, 58
a
b
c
1
The procedure was similar to that in Table 4. Isolated yield on the basis of 1. Determined by H NMR spectroscopy of the crude
product and chiral HPLC analysis. d Determined by chiral HPLC analysis. e The stereochemistry of the minor diastereomer is unknown.
with ethyl glyoxylate could afford the corresponding
homoallylic alcohols in high yields with excellent
enantioselectivities (in the range of 98.5:0.5–99.5:0.5 er). As
expected, for the following Prins cyclization, both aromatic
4
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aldehyde and aliphatic aldehyde reacted well with the
of the glyoxal derivatives had little effect on the reaction
intermediate 4, affording the corresponding 4ꢀhydroxyl
tetrahydropyrans with moderate to high yields, and excellent
stereoselectivities (50–76% yields, 80:20–99:1 dr, 98:2–99:1
er; Table 5, entries 1–9). The electronic nature of the aromatic
alkenes had little effect on the yields and stereoselectivities
except 4ꢀMeOꢀsubstituted one (Table 5, entry 10). Both the
electronꢀdonating substituted alkenes and the electronꢀ
withdrawing substituted alkenes gave the desired products
with moderate yields and excellent stereoselectivities (Table 5,
entries 1–5). nꢀPropanal gave slightly higher yield compared
with the aromatic aldehyde (Table 5, entries 6–9 vs entries 1–
5). It is worth pointing out that although the ene reaction could
activity and stereoselectivity (Table 6, entries 6–10). The
condensedꢀring glyoxal also performed well, giving the
corresponding product in moderate yield with excellent er
ratio (Table 6, entry 11).
3
4
5
6
7
8
9
To further investigate potential utility of the reaction, we
chose different homoallylic alcohols as the substrates under
the standard Prins reaction conditions. The cyclization of
alkylꢀsubstituted olefin was investigated. After optimizing the
conditions, the cinnamaldehyde 3y was used to react with
alkylꢀsubstituted olefin 4u and 4v, and the corresponding
products with aliphatic group at the C4 of the THP were
obtained with 35–38% yields within 48 hours (Scheme 3, eq.
1–2). Besides, the elimination products accompanied in the
reaction.21 In addition, when the multisubstituted olefin 8–10
were treated with 2ꢀnaphthaldehyde 3n or nꢀpropanal 3q under
the standard reaction conditions, the corresponding
tetrahydropyrans 11–13 with methyl substitutents at 3ꢀ or 5ꢀ
positions were obtained in 63–72% yields (Scheme 3, eq. 3–5).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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give the intermediates
4 with excellent outcomes, no
cyclization products were detected if the alkene 2g with a
methoxy group on the aromatic ring or benzocyclic alkenes 2h
and 2i was used as the starting materials (Table 5, entries 10–
12).
Following the studies of asymmetric ene/Prins cyclization
with various alkenes, we next examined the scope of the
glyoxal derivatives. Unfortunately, the reaction proceeded
sluggishly with aromatic aldehydes, and the desired 4ꢀ
hydroxyl tetrahydropyrans 5aj–5am were obtained in
moderate yields (Table 6, entries 1–4). We considered that the
steric hindrance effect between the aryl group of glyoxal
derivative 1 and the aryl group of the aldehyde 3 increased in
the Prins cyclization
Scheme 4. Asymmetric ene/Prins cyclization on a gram
scale
Scheme 3. Substrate scope of ene/Prins cyclization in the
synthesis of multi-substituted tetrahydropyrans
For the purpose of examining the potential utility of this
methodology, a model reaction was carried out on a gram
scale. As shown in Scheme 4, the reaction took place smoothly
in the presence of 10 mol % of Ni(II)–L and 10 mol % of
FeCl3/TBSCl, affording a slightly better yield of the product
5q (90%) without any loss of the enantiomeric excess.
Stereochemical Assignment. It is worth pointing out that in
most cases high diastereoselective products were obtained,
even single diastereomer for most substrates. The
stereochemistry of substituted tetrahydropyrans 5q, 5m, 5r
and 5u was confirmed by NOE studies,20 which clearly
revealed that three bulky substituents at Cꢀ2, Cꢀ4 and Cꢀ6 on
the tetrahydropyranyl ring occupied equatorial positions. In
each case, an excellent degree of selectivity was observed for
the newly formed stereogenic centers at the 4ꢀ, and 6ꢀpositions
of the tetrahydropyran ring. These results were consistent with
Alder’s computational calculation and the previous works.8,22
Furthermore, the absolute configuration of the product 5k was
determined as (2S, 4S, 6R) by Xꢀray
process, and thus lowered the yield. Accordingly, nꢀpropanal
was used to minimize this adverse effect. To our delight, the
corresponding product 5an was performed with 76% yield and
excellent enantiomeric excess (99:1 dr, 98.5:1.5 er; Table 6,
entry 5). Next, the substrate scope of glyoxal derivatives was
briefly examined. As shown in Table 6, the electronic nature
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Figure 1. The Xꢀray crystallographic structure of the product
5k. The thermal ellipsoids’ level is 30% for the above crystal
14
15
16
17
18
19
20
21
22
23
24
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structure.
Figure 3. Reaction profile of FeCl3ꢀcatalyzed Prins
cyclization, picturing the formation and elimination of the
product 5q.
Scheme 5. Elimination reactions from the product 5q
Figure 2. The selected CD (circular dichroism) spectra of a
part of the products.
crystallographic analysis (Figure 1).19 The CD (circular
dichroism) spectra of products were measured in ethanol.
These of 4ꢀhydroxyl tetrahydropyrans exhibited a similar (+)
Cotton effect in their CD spectra (as shown in Figure 2).
Mechanism Study. The unique chemoselectivity (completely
OHꢀselective) in the FeCl3ꢀcatalyzed Prins cyclization of
aldehydes encouraged us to investigate the reaction
mechanism. Firstly, in order to verify whether the elimination
products 7 arose solely through eliminating water from
compounds 5 or they formed via eliminating hydrogen ion
eq. 2). The elimination reaction were effectively suppressed
(65% yield of 7q in 1 h) when 20 mol % of TBSCl was added
in the reaction (eq. 3 vs. eq. 2). Expectedly, 5q was slowly
transformed into 7q under the standard reaction conditions
(eq. 4). These results indicated that FeCl3 mediated both the
formation and elimination of the product 5q, and the formation
of the product 5q was prior to the elimination.23
directly from the carbocation intermediate.
A careful
monitoring of the reaction under the standard conditions was
investigated. The reaction profile in Figure 3 clearly showed
the formation of the product 7q during the reaction course.
The amount of elimination products 7q increased sharply after
six hours along with the diminution of the product 5q. It
indicated that the product 7 formed more likely through
eliminating water from the precursor 5. In order to find out the
linchpin subject of the elimination process, the catalyst
components of Prins reaction were introduced to the isolated
product 5q (Scheme 5). In the presence of 1.2 equivalences of
TBSCl at 35 °C, 5q could not transform into 7q after 24 hours
(Scheme 5, eq. 1). However, the addition of 1.2 equivalences
of FeCl3 led to a full conversion of 5q into 7q within 1 hour
(Scheme 5,
We next tried to rationalize the phenomenon of excellent
stereoselectivity of the highly substituted tetrahydropyran
products.8 Relative rates of Prins cyclization versus competing
oxoniaꢀCope rearrangement had a dramatic effect upon the
stereoselectivity. Stabilizing the tetrahydropyranyl cation
intermediate raised the transition state energy for ringꢀopening
and effectively eliminates oxoniaꢀCope rearrangement.8d
Alder’s model had shown that
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Scheme 7. Oxygen-18 labeling studies of the FeCl3-
mediated Prins cyclizations and 13C NMR spectra of the
corresponding product
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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34
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. Stabilization of tetrahydropyranyl cation.
Scheme 6. Control Experiments
b) The Prins cyclization with additional H218O
Ph
18OH
1.2 equiv H218O
O
OH
CO2Et
FeCl3/TBSCl
Ph
H
Ph
(1:1, 20 mol %)
Ph
O
CO2Et
CH2Cl2, 10 o
C
4a
3a
5a
, 70%
ca. 29% 18O
oxocarbenium ion 14 is 13.4 kJ/mol stable than
tetrahydropyranyl cation 15. The activation barrier for the ring
opening of cation 15 to oxocarbenium ion 14 is only 1.9
kJ/mol.22 Thus, the oxoniaꢀCope rearrangements were rapid
for monosubstituted olefins.
To provide insight into the tetrahydropyranyl cation stability
in this case, DFT (B3LYP/6ꢀ31G*) calculations were
performed (Figure 4). In contrast, tetrahydropyran cation 21
was stabilized due to the delocalization of the phenyl group at
4ꢀposition, which is 85.0 kJ/mol lower in energy than
oxocarbenium ion 19. In addition, the oxocarbenium ion
resulting from the hypothetical rearrangement was also
destablized. The results were similar to Rychnovsky’s report,
in which the tetrahydropyranyl cation with a methyl group at
4ꢀposition 18 is 40.9 kJ/mol lower in energy than
oxocarbenium ion 17.8d Therefore, cyclization was irreversible,
and the 2ꢀoxonia Cope rearrangement was disfavored than the
nucleophilic capture. As a result, oxonia Cope rearrangement
mediated racemization was ruled out.
With an initial survey of reaction stereoselectivity, our
attention turned to the chemoselectivity of the reaction that 4ꢀ
hydroxylꢀtetrahydropyran 5 rather than 4ꢀchloroꢀsubstituted
one was observed in the FeCl3ꢀcatalyzed Prins cyclization. The
monosubstituted olefin 22 was used as the substrate to react
with 2ꢀnaphthaldehyde 3n under the FeCl3/TBSCl conditions,
but no cyclization
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product was observed with the starting materials being
apparently a small upfield shift (ca. δ 0.02 ppm) of the signal,
recovered quantitatively after 48 hours (Scheme 6, eq. 1). The
results indicated that the substituent at the C4 position played
an important role for the formation of the 4ꢀhydroxyl
tetrahydropyran. Whereas, for the initial substrate 4a, no trace
of chloroꢀadded product was detected even the amount of
TBSCl was increased to five equivalences. Interestingly, the 4ꢀ
hydroxylꢀtetrahydropyran 5n was obtained in 82% yield
within 1 hour (Scheme 6, eq. 2). These results indicated that
the nucleophile concentration (Cl− or OH−) did not affect the
selectivity of the reaction. TBSCl might assist the FeCl3ꢀ
mediated Prins reaction.
assigning to Cꢀ4 in each case as a result of the αꢀisotope effect
(Scheme 7, a). The result indicated that the oxygen atom of the
hydroxy at C4 position of products was transformed from the
aldehyde 3a. In contrast, when the 1.2 equivalences of H218O
were added under the standard conditions, the 4ꢀhydroxylꢀ
tetrahydropyran 5a was formed with ca. 29% 18Oꢀlabeled
(Scheme 7, b). We also found that the 18Oꢀlabeled product 5n
was observed excepted for the 18Oꢀlabeled product 5a, when
olefin 4a was added to the mixture of the 18Oꢀlabeled
benzaldehyde 3a and 16Oꢀlabeled naphthaldehyde 3n with the
catalyst FeCl3/TBSCl (Scheme 7, c).24 Moreover, the 18Oꢀ
labeled product 5a (50% 18Oꢀlabeled) was also observed when
the product 5a was treated with the 1.2 equivalences of H218O
under the standard reaction conditions (Scheme 7, d). These
results suggested that the products 5 were more likely to be
formed through an intramolecular way. The hydroxyl group at
C4 position might exchange with the OHꢀ from the reaction
system under the standard reaction conditions via carbonium
ion intermediate.
3
4
5
6
7
8
9
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60
To further verify the generation of the reactive hydroxyl
nucleophile, as well as the OHꢀtrapped product 5 via solely a
direct intramolecular or an intermolecular process, the isotopic
labeling experiments were performed. As shown in Scheme 7,
the 18Oꢀlabeled aldehyde 3a was used under the standard
cyclization conditions, and the product was analyzed by 13C
NMR spectroscopy and ESIꢀMS. It was found that 18Oꢀlabeled
product 5a was formed with ca. 72% 18Oꢀlabeled solely at 4ꢀ
position. The corresponding 13C NMR spectrum illustrated
Figure 5. Gibbs free energy diagram and the proposed entire reaction mechanism of the FeCl3ꢀcatalyzed Prins cyclization
of –OH in 5q comes from acetaldehyde and H from 4a,
respectively. It also showed that the release of FeCl3,
corresponding to IM4 to FeCl3+5q, must over a significant
large energy barrier of ca. 140 kJ/mol, which is comparable to
the barrier of RDS. This means that the catalytic cycle would
be hindered in the step of recovery of FeCl3 if no other
auxiliary reagent is involved.
To provide further insight into the observed OHꢀselective
process of 4ꢀphenyl tetrahydropyran catalyzed by FeCl3, DFT
(B3LYP(PCM,CH2Cl2)//B3LYP/6ꢀ31G**) calculations were
performed.20 A different Prins cyclization mechanism was
suggested. The results of calculations related to the entire
reaction mechanism were illustrated in Figure 5. It shown that
the entire catalytic cycle contains three successive stages: (1)
stepwise [2+2] cycloaddition reaction via TS1 and TS2; (2)
migration of O atom of acetaldehyde to 4a with the cleavage
of C–O bond of the carbonyl group via TS3; (3) migration of
H of ꢀOH in 4a via TS4, leading to the formation of 5q. PCM
calculation placed the largest barrier in Gibbs free energy to be
112.0 kJ/mol, which corresponds to the step from IM2 to TS3
in stage 2. This step is rateꢀdetermining in the entire reaction
process. Moreover, the calculation predicted that the O atom
However, when TBSCl is considered, DFT calculation
predicted that TBSCl might coordinate to the FeCl3 with the
formation of TBSClꢀFeCl3 species form IM4, resulting the
yield of 5q with a smaller energy barrier of 70.0 kJ/mol.
Therefore, the existence of TBSCl might facilitate the
formation of 5q and exert positive effect on the present FeCl3
catalytic systems.23 This theoretical prediction is in agreement
with the present experimental observation. In previous works,
the general mechanism of Lewis acid catalyzed Prins
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cyclization is that the key intermediate is an oxocarbenium ion,
The paper is dedicated to Professor Michael P. Doyle on the
which generated from a hemiacetal. Then the oxoꢀcarbenium
ion could be captured with a large array of nucleophiles to
afford substituted tetrahydropyrans. The nature of such a
difference between the two mechanisms is not yet clear at
present. It might be due to the variation of catalysts as well as
the homoallylic alcohols used in the reactions.
occasion of his 70th birthday.
REFERENCES
(1) For a general review on the synthesis of tetrahydropyrans, see: (a)
Muzart, J. J. Mol. Catal. A: Chem. 2010, 319, 1. (b) Boivin, T.
L. B. Tetrahedron 1987, 43, 3309. (c) Clarke, P. A.; Santos, S.
Eur. J. Org. Chem. 2006, 2045. (d) Larrosa, I.; Romea, P.; Urpí,
F. Tetrahedron 2008, 64, 2683.
9
CONCLUSION
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In conclusion, we have established a general method for the
completely OHꢀselective sequential ene/Prins cyclization by
using Ni(II)–N,N'ꢀdioxide complex and FeCl3 as the catalysts,
respectively. The method enabled an efficient access to
optically pure 4ꢀhydroxylꢀtetrahydropyran derivatives. The
extremely high enantiomeric excess, broad substrate scope,
facile procedure, and mild reaction conditions showed the
potential of the catalytic system for practical synthesis. This
method will be a valuable complement to the existing arsenal
(2) (a) Lin, Y. ꢀY.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J.;
Golik, J.; James, J. C.; Nakanishi, K. J. Am. Chem. Soc. 1981,
103, 6773. (b) Kunze, B.; Jansen, R.; Sasse, F.; Höfle, G.;
Reichenbach, H. J. Antibiot. 1998, 51, 1075. (c) Ali, M. S.;
Tezuka, Y.; Banskota, A. H.; Kadota, S. J. Nat. Prod. 2001, 64,
491. (d) Corminboeuf, O.; Overman, L. E.; Pennington, L. D. J.
Am. Chem. Soc. 2003, 125, 6650. (e) Cossey, K. N.; Funk, R. L.
J. Am. Chem. Soc. 2004, 126, 12216. (f) Bahnck, K. B.;
Rychnovsky, S. D. Chem. Commun. 2006, 2388. (g) Bahnck, K.
B.; Rychnovsky, S. D. J. Am. Chem. Soc. 2008, 130, 13177. (h)
Wang, X.; Zheng, J.; Chen, Q.; Zheng, H.; He, Y.; Yang, J.; She,
X. J. Org. Chem. 2010, 75, 5392.
of
the
enantioselective
synthesis
of
4ꢀhydroxyl
tetrahydropyrans via Prins cyclization. Moreover, mechanistic
investigations including control experiments, NOE effects,
Oxygenꢀ18 labeling studies, DFT calculations were also
investigated to gain insights into the mechanism of the
reaction. Additional investigations aimed at expanding the
scope of the application are underway.
(3) (a) Paterson, I.; Anderson, E. A. Science 2005, 310, 451. (b)
Wender, P. A.; Schrier, A. J. J. Am. Chem. Soc. 2011, 133, 9228.
For reviews, see: (c) Benson, S.; Collin, M. P.; Arlt, A.; Gabor,
B.; Goddard, R.; Fürstner, A. Angew. Chem., Int. Ed. 2011, 50,
8739. (d) Hale, K. J.; Manaviazar, S. Chem. Asian J. 2010, 5,
704. and references therein.
EXPERIMENTAL SECTION
(4) (a) Singh, P.; Bhardwaj, A. J. Med. Chem. 2010, 53, 3707. (b)
Rao, P. N. P.; Uddin, M. J.; Knaus, E. E. J. Med. Chem. 2004,
47, 3972. (c) Delorme, D.; Ducharme, Y.; Brideau, C.; Chan, C.;
Chauret, N.; Desmarais, S.; Dubé, D.; Falgueyret, J.; Fortin, R.;
Guay, J.; Hamel, P.; Jones, T.; Lépine, C.; Li, C.; McAuliffe,
M.; McFarlane, C. S.; NicollꢀGriffith, D. A.; Riendeau, D.;
Yergey, J. A.; Girard, Y. J. Med. Chem. 1996, 39, 3951. and
references therein.
Typical experimental procedure for the sequential
ene/Prins reaction: The mixture of N,N'ꢀdioxide L (12.8 mg,
0.02 mmol) and Ni(BF4)2ꢁ6H2O (6.8 mg, 0.02 mmol) in
CH2Cl2 (1.0 mL) were stirred at 30 °C for 30 min. Then, the
ethyl glyoxylate 1a (0.2 mmol) and 2.0 equiv of 2ꢀ
phenylpropene 2a was added at 35 °C and being stirred for 48
hours. After flash column chromatography, the crude product
of the carbonylꢀene reaction was added into the test tube with
1.2 equiv of 2ꢀnaphthaldehyde 3n (0.24 mmol), 20 mol % of
FeCl3 and 20 mol % of TBSCl in CH2Cl2 (1.0 mL) at 10 °C.
After being stirred at 10 °C for 12 hours, the reaction mixture
was directly purified by column chromatography on silica gel
(ethyl acetate : petroleum ether = 1 : 8) to afford the
corresponding product 5n in 92% yield as a colourless liquid.
The enantiomeric excess of 5n was determined by using chiral
HPLC analysis.
(5) For selected examples, see: (a) Micalizio, G. C.; Pinchuk, A. N.;
Roush, W. R. J. Org. Chem. 2000, 65, 8730. (b) Smith, A. B., III;
Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M. J. Am. Chem.
Soc. 2001, 123, 10942. (c) Paterson, I.; Chen, D. Y. ꢀK.; Coster,
M. J.; Aceña, J. L.; Bach, J.; Gibson, K. R.; Keown, L. E.;
Oballa, R. M.; Trieselmann, T.; Wallace, D. J.; Hodgson, A. P.;
Norcross, R. D. Angew. Chem., Int. Ed. 2001, 40, 4055. (d) Hilli,
F.; White, J. M.; Rizzacasa, M. A. Org. Lett. 2004, 6, 1289. (e)
Smith, A. B., III; Fox, R. J. Org. Lett. 2004, 6, 1477. (f) Ding,
F.; Jennings, M. P. Org. Lett. 2005, 7, 2321. (g) Boulard, L.;
BouzBouz, S.; Cossy, J.; Franck, X.; Figadère, B. Tetrahedron
Lett. 2004, 45, 6603. (h) Pellissier, H. Tetrahedron 2009, 65,
2839. (i) Sabitha, G.; Rao, A. S.; Yadav, J. S. Synthesis 2010,
505. (j) Yadav, J. S.; Ather, H.; Rao, N. V.; Reddy, M. S.;
Prasad, A. R. Synlett 2010, 1205. and references therein.
ASSOCIATED CONTENT
Supporting Information. Experimental details and analytic data
(NMR, HPLC and ESIꢀHRMS). This material is available free of
charge via the Internet at http://pubs.acs.org.
(6) For a general review of the Prins cyclization reactions, see: (a)
Arundale, E.; Mikeska, L. A. Chem. Rev. 1952, 51, 505. (b)
Pastor, I. M.; Yus, M. Curr. Org. Chem. 2007, 11, 925. (c) Olier,
C.; Kaafarani, M.; Gastaldi, S.; Bertrand, M. P. Tetrahedron
2010, 66, 413. (d) Crane, E. A.; Scheidt, K. A. Angew. Chem.,
Int. Ed. 2010, 49, 8316. (e) Overman, L. E.; Pennington, L. D. J.
Org. Chem. 2003, 68, 7143.
AUTHOR INFORMATION
Corresponding Author
xmfeng@scu.edu.cn
ACKNOWLEDGMENT
(7) For recently examples of Prins cyclizations (a) Crane, E. A.;
Zabawa, T. P.; Farmer, R. L.; Scheidt, K. A. Angew. Chem., Int.
Ed. 2011, 50, 9112. (b) Ramachandran, P. V.; Gagare, P. D.
Tetrahedron Lett. 2011, 52, 4378. (c) Ghosh, A. K.; Nicponski,
D. R. Org. Lett. 2011, 13, 4328. (d) Reddy, B. V. S.; Borkar, P.;
Yadav, J. S.; Sridhar, B.; Grée, R. J. Org. Chem. 2011, 76, 7677.
(e) Reddy, B. V. S.; Ganesh, A. V.; Krishna, A. S.; Kumar, G. G.
K. S. N.; Yadav, J. S. Tetrahedron Lett. 2011, 52, 3342. (f) Chio,
We appreciate the National Natural Science Foundation of China
(Nos. 21021001 and 21172151) and National Basic Research
Program of China (973 Program: No. 2010CB833300) for
financial support and Sichuan University Analytical & Testing
Centre for NMR and Xꢀray diffraction analysis.
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F. K.; Warne, J.; Gough, D.; Penny, M.; Green, S.; Coles, S. J.;
74, 2605. (k) Overman, L. E.; Velthuisen, E. J. J. Org. Chem.
2006, 71, 1581. (l) Van Orden, L. J.; Patterson, B. D.;
Rychnovsky, S. D. J. Org. Chem. 2007, 72, 5784. (m) Yu, B.;
Jiang, T.; Li, J.; Su, Y.; Pan, X.; She, X. Org. Lett. 2009, 11,
3442. (n) Woo, S. K.; Lee, E. J. Am. Chem. Soc. 2010, 132, 4564.
(o) Bondalapati, S.; Reddy, U. C.; Kundu, D. S.; Saikia, A. K. J.
Fluorine Chem. 2010, 131, 320. (p) Miranda, P. O.; Carballo, R.
M.; Mart n, V. S.; Padr n J. I. Org. Lett. 2009, 11, 357. and
more examples see the review ref. 6b
Hursthouse, M. B.; Jones, P.; Hassall, L.; McGuire, T. M.;
Dobbs, A. P. Tetrahedron 2011, 67, 5107. (g) Chen, Z. H.; Tu,
Y. Q.; Zhang, S. Y.; Zhang, F. M. Org. Lett. 2011, 13, 724 (h)
Karmakar, R.; Mal, D. Tetrahedron Lett. 2011, 52, 6098. (i)
Jacolot, M.; Jean, M.; Levoin, N.; Weghe, P. Org. Lett. 2012, 14,
58.
8
9
(8) (a) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.;
Willis, C. L. Org. Lett. 2002, 4, 577. (b) Barry, C. S.; Bushby,
N.; Harding, J. R.; Hughes, R. A.; Parker, G. D.; Roe, R.; Willis,
C. L. Chem. Commun. 2005, 3727. (c) Marumoto, S.; Jaber, J. J.;
Vitale, J. P.; Rychnovsky, S. D. Org. Lett. 2002, 4, 3919. (d)
Jasti, R.; Rychnovsky, S. D. J. Am. Chem. Soc. 2006, 128, 13640.
(12) For selected reviews, see: (a) Tietze, L. F. Chem. Rev. 1996,
96, 115. (b) Tietze, L. F.; Haunert, F. Stimulating Concepts
in Chemistry, WileyꢀVCH, Weinheim, 2000, 39. (c) Trost, B.
M. Acc. Chem. Res. 2002, 35, 695. (d) Nicolaou, K. C.; Chen,
J. S. Chem. Soc. Rev. 2009, 38, 2993.
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(9) For selected examples for synthesis of 4ꢀhaloꢀtetrahydropyrans,
see: 4ꢀF: (a) Kishi, Y.; Nagura, H.; Inagi, S.; Fuchigami, T.
Chem. Commun. 2008, 3876. (b) Kishi, Y.; Inagi, S.; Fuchigami,
T. Eur. J. Org. Chem. 2009, 103. 4ꢀCl: (c) Miranda, P. O.; Díaz,
D. D.; Padrón, J. I.; Bermejo, J.; Martín, V. S. Org. Lett. 2003, 5,
1979. (d) Biermann, U.; Lützen, A.; Metzger, J. O. Eur. J. Org.
Chem. 2006, 2631. (e) Dobbs, A. P.; Pivnevi, L.; Penny, M. J.;
Martinović, S.; Iley, J. N.; Stephenson, P. T. Chem. Commun.
2006, 3134. (f) Lee, C. H. A.; Loh, T. P. Tetrahedron Lett. 2006,
47, 1641. (g) Miranda, P. O.; Ramirez, M. A.; Martin, V. S.;
Padron, J. I. Org. Lett. 2006, 8, 1633. 4ꢀBr: (h) Vitale, J. P.;
Wolckenhauer, S. A.; Do, N. M.; Rychnovsky, S. D. Org. Lett.
2005, 7, 3255. (i) Patterson, B.; Rychnovsky, S. D. Synlett 2004,
543. (j) Jasti, R.; Vitale, J.; Rychnovsky, S. D. J. Am. Chem.
Soc. 2004, 126, 9904. (k) Jasti, R.; Anderson, C. D.;
Rychnovsky, S. D. J. Am. Chem. Soc. 2005, 127, 9939. (l) Liu,
F.; Loh, T. P. Org. Lett. 2007, 9, 2063. (m) Li, H.; Loh,T. P.
Org. Lett. 2010, 12, 2679. 4ꢀI: (n) Sabitha, G.; Reddy, K. B.;
Bhikshapathi, M.; Yadav, J. S. Tetrahedron Lett. 2006, 47, 2807.
(o) Yadav, J. S.; Reddy, B. V. S.; Kumar, G. G. K. S. N.; Reddy,
G. M. Chem. Lett. 2007, 36, 426. And more examples see the
review ref. 6b
(13) Zheng, K.; Shi, J.; Liu, X. H.; Feng, X. M. J. Am. Chem. Soc.
2008, 130, 15770.
(14) For selected examples of N,N'ꢀdioxide–metal complexes, see: (a)
Liu, X. H.; Lin, L. L.; Feng, X. M. Acc. Chem. Res. 2011, 44,
574. (b) Zheng, K.; Yang, Y.; Zhao, J. N.; Yin, C, K.; Lin, L. L.;
Liu, X. H.; Feng, X. M. Chem. Eur. J. 2010, 16, 9969. (c) Li, W.;
Wang, J.; Hu, X. L.; Shen, K.; Wang, W. T.; Chu, Y. Y.; Lin, L.
L.; Liu, X. H.; Feng, X. M. J. Am. Chem. Soc. 2010, 132, 8532.
(d) Cai, Y. F.; Liu, X. H.; Jiang, J.; Chen, W. L.; Lin, L. L.; Feng,
X. M. J. Am. Chem. Soc. 2011, 133, 5636. (e) Xie, M. S.; Chen,
X. H.; Zhu, Y.; Gao, B.; Lin, L. L.; Liu, X. H.; Feng, X. M.
Angew. Chem., Int. Ed. 2010, 49, 3799. (f) Zheng, K.; Yin, C. K.;
Liu, X. H.; Lin, L. L.; Feng, X. M. Angew. Chem., Int. Ed. 2011,
50, 2573. (g) Li, W.; Liu, X. H.; Hao, X. Y.; Hu, X. L.; Chu, Y.
Y.; Cao, W. D.; Qin, S.; Hu, C. W.; Lin, L. L.; Feng, X. M. J.
Am. Chem. Soc. 2011, 133, 15268. and references therein.
(15) The product 7n was always obtained as a mixture (1/1) of two
inseparable dihydropyrans, and the combined yield was given.
(10) For selected examples for synthesis of 4ꢀhydroxylꢀ
tetrahydropyrans, see: (a) Kay, I. T.; Bartholomew, D.
Tetrahedron Lett. 1984, 25, 2035. (b) Zhang, W. C.;
Viswanathan, G. S.; Li, C. J. Chem. Commun. 1999, 291. (c)
Zhang, W. C.; Li, C. J. Tetrahedron 2000, 56, 2403. (d) Yadav, J.
S.; Reddy, B. V. S.; Kumar, G. M.; Murthy, C. V. S. R.
Tetrahedron Lett. 2001, 42, 89. (e) Keh, C. C. K.; Namboodiri,
V. V.; Varma, R. S.; Li, C. J. Tetrahedron Lett. 2002, 43, 4993.
(f) Hart, D. J.; Bennett, C. E. Org. Lett. 2003, 5, 1499. (g) Barry,
C. S. J.; Crosby, S. R.; Harding, J. R.; Hughes, R. A.; King, C.
D.; Parker, G. D.; Willis, C. L. Org. Lett. 2003, 5, 2429. (h)
Yadav V. K.; Kumar, N. V. J. Am. Chem. Soc. 2004, 126, 8652.
(i) Yadav, J. S.; Reddy, B. V. S.; Kumar, G. G. K. S. N.;
Aravind, S. Synthesis 2008, 395. (j) Tadpetch, K.; Rychnovsky,
S. D. Org. Lett. 2008, 10, 4839. (k) Reddy, B. V. S.;
Venkateswarlu, A.; Kumar, G. G. K. S. N.; Vinu, A.
Tetrahedron Lett. 2010, 51, 6511.
(16) Dilman, A. D.; Ioffe, S. L. Chem. Rev. 2003, 103, 733.
(17) Other additives such as PhCO2H, PhOH, TMSOH and
TMSH were also examined, but no better results were
obtained.
(18) The clarified reaction solution became turbid, generating
brown viscous compounds on the tube wall when H2O was
added. It might be the hydrolysis of FeCl3.
(19) CCDC 855357 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif
(11) For other selected examples of Prins cyclizations, see: (a)
Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis,
C. L. Org. Lett. 2002, 4, 3407. (b) Dalgard, J. E.; Rychnovsky, S.
D. J. Am. Chem. Soc. 2004, 126, 15662. (c) Yadav, J. S.; Subba
Reddy, B. V.; Reddy, Y. J.; Reddy, N. S. Tetrahedron Lett. 2009,
50, 2877. (d) Matsumoto, K.; Fujie, S.; Ueoka, K.; Suga, S.;
Yoshida, J. Angew. Chem., Int. Ed. 2008, 47, 2506. (e) Epstein,
O. L.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 16480. (f) Sabitha,
G.; Bhikshapathi, M.; Nayak, S.; Yadav, J. S.; Ravi, R.; Kunwar,
A. C. Tetrahedron Lett. 2008, 49, 5727. (g) Reddy, U. C.; Rama
Raju, B.; Pramod Kumar, E. K.; Saikia, A. K. J. Org. Chem.
2008, 73, 1628. (h) Yadav, J. S.; Subba Reddy, B. V.; Maity, T.;
Narayana Kumar, G. G. K. S. Synthesis 2008, 2739. (i) Tian, X.;
Jaber, J. J.; Rychnovsky, S. D. J. Org. Chem. 2006, 71, 3176. (j)
Reddy, U. C.; Bondalapati, S.; Saikia, A. K. J. Org. Chem. 2009,
(20) More data see support information.
(21) The separation of them from the reaction mixture was difficult
via flash chromatography as the elimination products have the
same Rf value with the cinnamaldehyde 3y.
(22) Alder, R. W.; Harvey, J. N.; Oakley, M. T. J. Am. Chem. Soc.
2002, 124, 4960.
(23) The role of TBSCl in suppressing the eliminated products is
uncertain at present. The reactivity of R3SiCl is different by
varying the steric volume of alkyl substituents which might lead
to the contrast results by the use of TMSCl and TESCl.
(24) The separation of pure 5a or 5n from the reaction mixture was
difficult via flash chromatography due to that they have the same
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