An efficient prins cyclization for stereoselective synthesis of tetrahydropyran from imines and homoallyl alcohols

Article abstract of DOI:10.1002/cjoc.201400450

An unprecedented protocol has been developed for the efficient synthesis of substituted tetrahydropyrans via a bismuth-promoted Prins cyclization of imines with homoallyl alcohols. In the presence of 40 mol% BiCl₃, a wide variety of imines react smoothly with homoallyl alcohols at room temperature to give the corresponding 4-chlorotetrahydropyran derivatives in good to excellent yields.

Full text of DOI:10.1002/cjoc.201400450

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DOI: 10.1002/cjoc.201400450
An Efficient Prins Cyclization for Stereoselective Synthesis
of Tetrahydropyran from Imines and Homoallyl Alcohols
Congrong Liu,*,a,b Daojuan Cheng,b and Fulai Yangb
a School of Environment Engineering, Nanjing Institute of Technology, Nanjing, Jiangsu 211167, China
b Joint Laboratory of Green Synthetic Chemistry, Department of Chemistry, University of Science and
Technology of China, Hefei, Anhui 230026, China
An unprecedented protocol has been developed for the efficient synthesis of substituted tetrahydropyrans via a
bismuth-promoted Prins cyclization of imines with homoallyl alcohols. In the presence of 40 mol% BiCl3, a wide
variety of imines react smoothly with homoallyl alcohols at room temperature to give the corresponding
4-chlorotetrahydropyran derivatives in good to excellent yields.
Keywords Prins cyclization, tetrahydropyrans, imine, homoallyl alcohol, Lewis acid
pyrans with excellent stereoselectivity.[4] Substituted
tetrahydropyran ring system is an important unit be-
cause of its presence in many biologically active natural
products,[5] such as acutiphycins, oscillatoxins, aplysia-
toxins, avermectins, talaromycins and latrunculins.
These heterocycles are also frequently utilized in me-
dicinal chemistry.[6] Generally, they are prepared from
the Prins cyclization of aldehydes and homoallyl alco-
hols under Brønsted or Lewis acid promoted condi-
tions.[7] However, many of these classical methods often
involve the use of stoichiometric amounts of Lewis acid
and poor tolerance of substrates. Our goal was to de-
crease the amount of Lewis acid and extend the scope of
substrates.
Introduction
Various nucleophiles undergo additions to imines by
breaking the C－N π bonds but delivering the stronger
C－N σ bonds to the final products.[1] In comparison,
the transformation of imines has rarely been reported
through the complete cleavage of C＝N bonds. In the
presence of carbon or heteroatom nucleophiles, the C＝
N bonds of imines can be converted into two σ bonds.[2]
Recently, we reported a biarylation of imines or car-
bonyl compounds with arenes,[2,3] wherein the reactions
of imines only need a catalytic amount of Lewis acid
(TMSCl), but carbonyl compounds need two-equivalent
Lewis acid (TMSCl). Inspired by this study, we inves-
tigated the Prins cyclization of imines with homoallyl
alcohols for the formation of substituted tetrahydro-
pyrans and developed an efficient synthesis of tetrahy-
dropyrans with a catalytic amount of Lewis acid
(Scheme 1).
Results and Discussion
The Prins cyclization of N-tosyl imine (1a) with
homoallyl alcohol (2a) was selected as a model reaction
to evaluate the catalytic activity of chlorinated Lewis
acid at room temperature. As summarized in Table 1, a
number of Lewis acids (40 mol%) were examined in
dichloromethane, and to our delight, the best catalytic
activity was observed with BiCl3, an inexpensive and
environmentally benign Lewis acid,[8] which promoted
the reaction to afford tetrahydropyran 3a in 98% yield.
Further efforts to decrease the amount of BiCl3 resulted
in a lower yield (Table 1, Entry 7). Moreover, the reac-
tion gave a lower yield when replacing the p-toluene-
sulfonyl group in imine (1a) with a phenyl group, a sul-
famido group, an acyl group or a sulfinyl group (Table 1,
Entries 8－11).
Scheme 1 Breaking the C＝N bonds of imines
O
0.20 equiv. TMSCl
2.0 equiv. TMSCl
Ar
previous work
ref.[3]
previous work
ref.[2]
X
R
H
R
Ar
N
R
H
R'
O
R
this work
Nu
It is well known that the Prins cyclization is a pow-
erful method to generate polysubstituted tetrahydro-
*
E-mail: congrong@njit.edu.cn; Tel.: 0086-025-86118974
Received July 4, 2014; accepted August 29, 2014; published online October 8, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400450 or from the author.
Chin. J. Chem. 2014, 32, 1095—1098
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Table
1
Survey of the Lewis acid (MCln) and imine
Table 2 Synthesis of 4-chlorotetrahydropyrans from imines,
homoallyl alcohols and BiCl3
a
N-substituents a
X
N
Ph
R'
Ts
R
R'
O
O
MCln (0.4 equiv.)
CH2Cl2, r.t.
N
BiCl3 (0.4 equiv.)
CH2Cl2, r.t.
+
+
HO
HO
Ph
H
R
H
2
2a
1
Cl
1a 1ae
Cl
3a
3
Entry MCln
1a－1ae, X
1a, Ts
Time/h
Yieldd/%
87
Entry 1, R
2, R'
3
Time/h Yieldb/%
1
FeCl3
BiCl3
InCl3
SnCl3
2
1
1a, Ph
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
3a 1.0
3b 2.0
3c 1.5
3d 1.0
3e 1.5
3f 2.0
3g 1.5
3h 3.0
3i 1.0
3j 1.0
3k 1.5
3l 2.0
3m 2.0
3n 1.0
3o 1.5
3p 2.0
3q 1.0
98
77
85
95
92
88
93
98
99
99
68
73
85
92
99
91
93
85
87
96
92
2
1a, Ts
1
98
2
1b, 2-NO2C6H4
1c, 2-ClC6H4
1d, 2-MeOC6H4
1e, 3-NO2C6H4
1f, 4-NO2C6H4
1g, 4-ClC6H4
1h, 4-CNC6H4
1i, 4-MeC6H4
1j, 4-MeOC6H4
1k, PhCH2
3
1a, Ts
24
24
24
24
24
8
54
3
4
1a, Ts
67
4
5 b
ZnCl2 1a, Ts
80
5
6
AlCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
1a, Ts
30
6
7c
8
1a, Ts
81
7
1ab, Ph
46
8
9
1ac, NHTs
1ad, COPh
1ae, SOtBu
8
53
9
10
5
68
10
11
12
13
14
15
16
17
18
19
20
21
11
2
47
a
Reaction conditions: imines 1a－1ae (0.2 mmol), homoallyl
alcohol 2a (0.24 mmol), Lewis acid (0.080 mmol), dichloro-
methane (1.0 mL), room temperature. b ZnCl2: 0.60 equiv. (0.12
mmol). c BiCl3: 0.34 equiv. (0.068 mmol). d Isolated yield.
1l, cyclohexyl
1m, Me2CH
1n, (E)-PhCH＝CH 2a, H
1a, Ph
1a, Ph
2b,Ph
2c, Me2CH
Encouraged by our preliminary findings, we inves-
tigated the substrate scope for the Prins cyclization of
imines and homoallyl alcohols. In the presence of 40
mol% BiCl3, a number of aromatic imines bearing either
electron-withdrawing groups (Cl, NO2 and CN) or elec-
tron-donating groups (Me and OMe) on the ortho-,
meta- or para-positions of the aromatic rings, and ali-
phatic imines, were transformed into their correspond-
ing 4-chlorotetrahydropyrans at room temperature in
good to excellent yields (Table 2, Entries 1－13 and 20).
α,β-Unsaturated imine (1n) was also found to be able to
serve as a suitable substrate for the Prins cyclization
(Table 2, Entries 14 and 17). Next, we examined the
reactivity of various homoallyl alcohols toward imines
(Table 2, Entries 14－21). A variety of homoallyl alco-
hols reacted smoothly and produced the corresponding
4-chlorotetrahydropyrans in excellent yields. All the
reactions are clean and only cis-isomer was obtained in
each reaction, its structure being confirmed by contrast
with the reported 1H NMR spectra.
1n, (E)-PhCH＝CH 2b, Ph
1d, 2-MeOC6H4
1k, cyclohexy
1n, 1-naphthyl
1l, Me2CH
2d, cyclohexyl 3r 2.5
2d, cyclohexyl 3s 4.0
2d, cyclohexyl 3t 3.0
2c, Me2CH
3u 4.0
a Reaction conditions: imine 1 (0.2 mmol), homoallyl alcohol 2
(0.24 mmol), BiCl3 (0.08 mmol), dichloromethane (1.0 mL),
room temperature. b Isolated yield.
On the basis of our results and previous relevant
mechanistic studies,[9] we proposed the reaction path-
way depicted in Scheme 2. We reasoned that a plausible
catalytic pathway could be readily initiated via an acti-
vation of the imine 1 with the bismuth salt. Its reaction
with the homoallyl alcohol 2 affords the intermediate (6,
7, 8). Intermediate (6, 7, 8) undergoes cyclization to
give tetrahydropyranyl cation 9 that can easily be
trapped by nucleophile (Cl−) to give the final product
4-chlorotetrahydropyran 3.
The Prins cyclization of imines with homoallyl al-
cohols was further extended to other nucleophiles (such
as BiBr3, thiophenol, arenes). In the presence of 40
mol% BiBr3, the Prins cyclization proceeded smoothly
to give the corresponding 4-bromotetrahydropyran (5a)
in 95% yield (Table 3, Entry 1). When treated with 5
mol% BiCl3, thiophenol, benzene and p-xylene all re-
acted well with imine (1a) and homoallyl alcohol (2a)
to afford the corresponding tetrahydropyran derivatives
5 in good to excellent yields (Table 3, Entries 2－4).
Conclusions
In summary, we have developed a highly efficient
synthesis of substituted tetrahydropyrans via a bis-
muth-promoted Prins cyclization of imines with ho-
moallyl alcohols. In the presence of 40 mol% BiCl3, a
wide variety of imines react smoothly with homoallyl
alcohols to give the corresponding tetrahydropyran de-
rivatives in good to excellent yields. Furthermore, other
nucleophiles (such as BiBr3, thiophenol, arenes)
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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An Efficient Prins Cyclization for Stereoselective Synthesis of Tetrahydropyran
Scheme 2 proposed reaction pathway
R'
OH
2
Cl3Bi
BiCl2
NTs
NTs
H
TsN
O
+
BiCl3
-HCl
R
H
R
R'
R
1
6
+ H
1
Cl2
Bi
TsN
Cl
NHTs
TsHNBiCl2
R'
+
Cl
R
H
2
-HCl
O
R
R'
O
R
9
+ H
3
NHTs
BiCl
Bi(NHTs)3
TsN
+ H
(TsNH)2BiCl
R'
O
R
Bi(NHTs)2
1
TsN
7
-HCl
BiCl(NHTs)2
R'
O
8
R
TsN
R
H
2
Table 3 Synthesis of structurally diverse tetrahydropyrans from
imine 1a, homoallyl alcohol 2a and BiBr3 , arenes, phenthiola
are also found to serve as suitable nucleophiles for the
Prins cyclization of imine 3a with homoallyl alcohol 2a.
The attractive features of this protocol to synthesize
substituted tetrahydropyrans include catalytic amount of
chlorinated Lewis acid, high yield, broad substrate
scope, mild reaction conditions, and experimental sim-
plicity.
Ph
O
Ts
BiCl3 (5 mol%)
CH2Cl2, r.t.
N
+ NuX
+
HO
Ph
H
4
2a
1a
Nu
5
4a
4b
4c
4d
BiBr3
PhSH
PhMe
p-Xylene
Experimental
Entry NuX
Product
Time/h Yielde/%
General information
Ph
Ph
Ph
O
1H and 13C NMR spectra were recorded on a Bruker
AC-300 FT spectrometer (300 MHz and 75 MHz, re-
spectively) using tetramethylsilane as internal reference.
IR spectra were recorded on a Perkin-Elmer 2000 FTIR
spectrometer. High resolution mass spectra were re-
corded on a LC-TOF spectrometer (Micromass). the UV
detection was monitored at 254 nm. Compounds 1a－
1n and 2b－2d were prepared according to known pro-
cedures.[10] The rest of chemicals were purchased from
the Sinopharm Chemical Reagent Co., Meryer, Acros,
and Alfa Aesar, and used as received.
1b
1.5
10
24
95
84
66
4a
Br
5a
O
2
4b
4c
SPh
5b
O
3c
General procedure for the Prins cyclization of imine,
homoallyl alcohol and BiCl3
Ph
5c
A mixture of imine 1 (0.20 mmol), homoallyl alco-
hol 2 (0.24 mmol), BiCl3 (25.2 mg, 0.080 mmol) and
CH2Cl2 (1.0 mL) was stirred at room temperature. When
the reaction did not proceed further as indicated by TLC,
the reaction mixture was directly purified by flash col-
umn chromatography on silica gel, eluting with petro-
leum ether/EtOAc (30∶1 to 10∶1, V∶V), to give
product 3 (Table 2).
Me
O
4d
24
60
4d
Ph
Me
5d
a Reaction conditions: imines 1a (0.2 mmol), homoallyl alcohol
2a (0.24 mmol), BiCl3 (0.010 mmol), dichloromethane (1.0 mL),
room temperature. b Without BiCl3, BiBr3 0.08 mmol. c Benzene
1.0 mL, without dichloromethane. d Xylene 1.0 mL, without di-
chloromethane. e Isolated yield.
Acknowledgement
We are grateful for the financial support from the
Chin. J. Chem. 2014, 32, 1095—1098
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Liu, Cheng & Yang
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