B(C6F5)3-catalyzed Prins/Ritter reaction: A novel synthesis of hexahydro-1H-furo[3,4-c]pyranyl amide derivatives

Article abstract of DOI:10.1016/j.tetlet.2014.05.115

The coupling of aldehydes or ketones with (2-(4-methoxyphenyl)-4- methylenetetrahydrofuran-3-yl)methanol in the presence of nitriles under the influence of 5 mol % tris(pentaflourophenyl)borane at room temperature afforded a novel series of cis-fused hexahydro-1H-furo[3,4-c]pyran derivatives in good yields with high selectivity. This is the first report on the synthesis of hexahydro-1H-furo[3,4-c]pyranyl amide through a sequential Prins/Ritter reactions using B(C₆F₅)₃ as a mild Lewis acid.

Full text of DOI:10.1016/j.tetlet.2014.05.115

Tetrahedron Letters 55 (2014) 4298–4301
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Tetrahedron Letters
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B(C6F5)3-catalyzed Prins/Ritter reaction: a novel synthesis
of hexahydro-1H-furo[3,4-c]pyranyl amide derivatives
B. V. Subba Reddy a, , Supriya Ghanty a,c, Ch. Kishore a, B. Sridhar b
⇑
a Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
c An Associate Institution of University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The coupling of aldehydes or ketones with (2-(4-methoxyphenyl)-4-methylenetetrahydrofuran-3-
yl)methanol in the presence of nitriles under the influence of 5 mol % tris(pentaflourophenyl)borane at
room temperature afforded a novel series of cis-fused hexahydro-1H-furo[3,4-c]pyran derivatives in good
yields with high selectivity. This is the first report on the synthesis of hexahydro-1H-furo[3,4-c]pyranyl
amide through a sequential Prins/Ritter reactions using B(C6F5)3 as a mild Lewis acid.
Ó 2014 Published by Elsevier Ltd.
Received 11 December 2013
Revised 28 May 2014
Accepted 29 May 2014
Available online 14 June 2014
Keywords:
Prins/Ritter cascade process
Tris (petaflourophenyl)borane
cis-Fused furopyranylamide derivatives
Oxygen containing bicycles such as furo[3,2-c]pyrans are often
found in various natural products such as cordigol, triFA1, flavo-
noids, catechins and pterocarpans.1 In particular, 4-amino tetrahy-
dropyran ring is a core structure of various natural products such
as ambruticins VS3, dysiherbaine, glycamino acid and others
(Fig. 1).2 Of various methods, Prins cyclization is one of the most
elegant approaches for the synthesis of tetrahydropyran deriva-
tives.3 Consequently, a few acid catalysts are reported for the syn-
thesis of tetrahydropyranyl amide derivatives through a Prins/
Ritter cascade process. However, the generation of tert-amide
functionality into a bicyclic system through a Prins/Ritter cascade
process is still unexplored.
Recently, tris(pentafluorophenyl)borane [B(C6F5)3] has attracted
considerable attention because of its high reactivity, stability,
non-toxicity and ability to tolerate moisture or water.4 It is a
non-conventional acid catalyst and its Lewis acidity is comparable
to BF3ꢀOEt2 but without the problems associated with reactive B–F
bonds. Consequently, various research groups were engaged in
exploring the potential utility of B(C6F5)3 for various organic
transformations.5 To the best of our knowledge, there are no
reports on the use of B(C6F5)3 for the Prins type cyclization.
Following our interest on Prins/Ritter reaction,6 we herein
report a simple and efficient strategy for the synthesis of a novel
class of cis-fused 7a,3,6-trisubstituted hexahydro-1H-furo[3,4-c]
pyranyl amide derivatives through a sequential Prins and Ritter
OMe
H
HO
HO
HO
H
OH
O
H
O
H
HO2C
O
O
HO
H
O
O
OH
H
OMe
OH
HO
OMe
Cordigol
triFA1
HO
O
O
O
OH
N
Ambruticin VS3
Figure 1. Representative examples of cordigol, triFA1 and ambruticin VS3.
reactions. The desired starting material, (2-(4-methoxyphenyl)-4-
methylenetetrahydrofuran-3-yl)methanol (1) was prepared from
anisaldehyde in four steps. Accordingly, the synthesis of 1 involves
the Wittig olefination of an aldehyde and the bromoalkoxylation of
the olefin followed by a radical cyclization to afford the exo-cyclic
olefinic ester.7 Reduction of the ester using LAH in THF afforded the
required exo-cyclic hydroxy olefin (1) (Scheme 1).
⇑
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
http://dx.doi.org/10.1016/j.tetlet.2014.05.115
0040-4039/Ó 2014 Published by Elsevier Ltd.

B. V. Subba Reddy et al. / Tetrahedron Letters 55 (2014) 4298–4301
CO2Et
4299
At first, we attempted the coupling of the exo-cyclic hydroxy
olefin (1) with benzaldehyde (2) using catalytic amount of
B(C6F5)3 in acetonitrile at room temperature. The reaction was
complete within 20 min affording the corresponding cis-fused 6-
(phenyl)-3-(4-methoxyphenyl)hexahydro-1H-furo[3,4-c]pyran-7-
yl)acetamide 4a in 80% yield (Scheme 2).
CHO
OH
Ph3PCH2CO2Et
benzene, reflux
85%
MeO
MeO
O
Cp2TiCl2
CO2Et
Zn, THF,
80%
Unlike classical Prins/Ritter reaction, the formation of undesired
side products such as 4-halo- or 4-hydroxy tetrahydropyrans was
not observed when a catalytic amount tris(pentafluorophenyl)
borane was employed. Inspired by the unique catalytic properties
of [B(C6F5)3], we extended this protocol for other substrates. Inter-
estingly, the coupling of aliphatic aldehydes such as propanal and
butanal with [2-aryl-4-methylene-tetrahydrofuran-3-yl]methanol
in acetonitrile gave the corresponding bicyclic acetamide deriva-
tives in good yields (entries b and c, Table 1). Our next attempt
was made to explore the feasibility of this protocol with ketones.
Interestingly, the cyclic ketones such as cyclohexanone and
cyclopentanone participated well in this reaction to provide the
corresponding spirotricyclic amides (entries d and g, Table 1).
For instance, the reaction of (2-(4-methoxyphenyl)-4-methylene-
tetrahydrofuran-3-yl)methanol with cyclohexanone in acetonitrile
under the influence of 5 mol % [B(C6F5)3] furnished the spiro-
3-(4-methoxyphenyl)hexahydro-1H-furo[3,4-c]pyran-7a-yl)acet-
amide in 80% yield (entry d, Table 1). The reaction proceeded
LiBr, CAN, CH3CN
70%
Br
MeO
O
O
LAH, THF
0-rt, 80%
CO2Et
OH
MeO
MeO
1
Scheme 1. Preparation of exo-cyclic hydroxyl olefin (1).
CH3
N
NHCOCH3
Ph
O
H
O
3
H
H
5 mol% B(C6F5)3
0 oC- r.t.
+
O
Ph
O
H
OH
MeO
MeO
4a
1
2
Scheme 2. A sequential Prins/Ritter reaction.
Table 1
B(C6F5)3-catalyzed synthesis of hexahydro-1H-furo[3,4-c]pyran-7a-yl amide derivatives.a
Entry
a
Carbonyl compounds
Nitrile
Product (4)b
Time (min)
20
Yieldc (%)
80
NHCOMe
Ph
O
H
PhCHO
MeCN
H
O
O
H
O
O
NHCOMe
H
b
c
MeCN
MeCN
MeCN
20
20
25
85
85
80
H
O
O
H
O
O
NHCOMe
H
H
O
O
H
O
O
NHCOMe
H
d
H
O
O
O
H
N
CN
O
H
H
O
e
f
20
20
25
85
90
O
H
O
CHO
H
CN
CN
N
O
H
H
O
Cl
O
Cl
H
O
O
H
N
O
H
O
g
80
85
H
O
O
O
O
NHCOEt
CN
H
h
i
25
25
H
O
O
O
CHO
NHCOPh
H
PhCN
90
O2N
H
O
NO2
H
O
(continued on next page)

4300
B. V. Subba Reddy et al. / Tetrahedron Letters 55 (2014) 4298–4301
Table 1 (continued)
Entry
Carbonyl compounds
Nitrile
PhCN
Product (4)b
Time (min)
20
Yieldc (%)
85
CHO
NHCOPh
Ph
O
H
H
j
O
H
O
a
Reaction was performed with 0.5 mmol olefin, 0.75 mmol aldehyde/ketone using 5 mol % of B(C6F5)3 in nitrile solvent.
All products were characterized by NMR, IR mass spectroscopy.
Yield refers to pure products after chromatography.
b
c
efficiently not only with cyclic ketones but also with acetone (entry
h, Table 1).
Other aromatic aldehydes such as p-chloro-, and p-nitrobenzal-
The structure of 4e was established by single crystal X-ray crys-
tallography (Fig. 3).9
However, no reaction was observed in the absence of the cata-
lyst. To compare the efficiency of B(C6F5)3, we performed the reac-
tion with commonly used acid catalysts. As shown in Table 2, in
most cases, the Prins/Ritter amidation was associated with other
side products such as hydroxy or halo adducts along with the
desired amide derivatives. For instance, the reaction of 1 with
benzaldehyde in acetonitrile in the presence of MX3 gave the halo
substituted tetrahydropyran along with the required 4-acetamido-
tetrahydropyran derivative 4a. In case of metal triflates, the forma-
tion of hydroxytetrahydropyran was observed together with the
desired amide 4a. Unlike BF3ꢀOEt2 catalyst, B(C6F5)3 is a stable
and highly reactive due to the presence of strong electron-with-
drawing pentafluorophenyl groups. Furthermore, the counter ion
C6F(5ꢁ) is non-nucleophilic. Therefore, B(C6F5)3 is a much superior
catalyst for the Prins/Ritter reaction than a commonly used
BF3ꢀOEt2.
dehydes also reacted well with exo-cyclic hydroxy olefin 1 in the
presence of nitriles to yield the corresponding bicyclic amide
derivatives (entries f and i, Table 1). Next, we examined the reac-
tivity of different nitriles. Remarkably, the reaction was successful
with different nitriles such as acrylonitrile, propionitrile and ben-
zonitrile to afford the corresponding acrylamide, propionamide
and benzamide derivatives (entries e–j, Table 1). In all cases, the
products were obtained in good yields with cis-selectivity. A single
product was formed in each reaction, the structure of which was
confirmed by the NMR spectrum.
The relative stereochemistry of 4f was established by using
detailed 1D and 2D NMR experiments.8 The scalar coupling
3
3
3
0
constants JH2-H3(ax) = 11.4 Hz, JH2-H3 (eq) = 3.5 Hz, JH5(ax)-H6(ax)
=
9.9 Hz along with the appearance of NOE cross peaks between
H2-H6(ax), H3(ax)-H5(ax) support the existence of six-membered
ring in 4C1 chair conformation, while the chlorophenyl substitution
at C2 occupies equatorial position. The stereochemistry at the
fusion of two rings was determined by the observation of NOE
cross peaks H9-H2, NH-H5, H7-H6(ax), H7-H6(eq) as cis fusion at
C4–C5 bond as represented in Figure 2.
The reaction is proposed to proceed via the formation of
oxocarbenium ion from hemi-acetal which is formed in situ from
exo-cyclic hydroxy olefin 1 and aldehyde 2. Thus formed oxocarbe-
nium ion may undergo smooth cyclization with an internal olefin
to generate the carbocation which is subsequently trapped with
a nitrile leading to the formation of hexahydro-1H-furo[3,4-c]pyr-
anyl amide 4 as depicted in Scheme 3.
The scope of the tris(pentafluorophenyl)borane catalyzed Prins/
Ritter reaction is illustrated with various aldehydes and ketones in
the presence of different nitriles and the results are presented in
Table 1.10
H
H
H
H
O
O
NHCOR
H
Cl
Table 2
H
Screening of various acid catalysts in the formation of 4a
H
Entry
Acid catalysta
Amide (4a)b (%)
a
b
c
d
e
f
g
h
i
BF3ꢀOEt2 (0.1 equiv)
InBr3 (1 equiv)
60
<35
15
<30
20
35
<25
80
<45
CeCl3ꢀ7H2O(1 equiv)
OMe
TFA (1 equiv)
InCl3 (1 equiv)
TMS(OTf) (1 equiv)
GaCl3 (1 equiv)
B(C6F5)3 (0.05 equiv)
Sc(OTf)3 (0.1 equiv)
Figure 2. Characteristic nOes of 4f.
a
The reactions were performed in 20 min.
Yield refers to pure products after chromatography.
b
OH
+
O
Ar
B(C6F5)3
r.t
R2
R1
O
Ar
R1
R2
O
O
NC-R
R2
R1
NHCOR
R2
O
Ar
O
Ar
O
O
R1
Figure 3. ORTEP diagram of 4e.
Scheme 3. A plausible reaction pathway.

B. V. Subba Reddy et al. / Tetrahedron Letters 55 (2014) 4298–4301
4301
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amide derivatives using tris(pentafluorophenyl)borane as a mild
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Acknowledgments
S.G. thanks CSIR and C.K. thanks UGC-New Delhi for the
award of fellowships. B.V.S. thanks CSIR, New Delhi for financial
support as a part of XII five year plan program under title ORIGIN
(CSC-0108).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.05.
115.
References and notes
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10. General experimental procedure: To a mixture of aldehyde/ketone (0.75 mmol)
and B(C6F5)3 (5 mmol %) in nitrile (4 mL) was added exo-cyclic hydroxy olefin
(0.5 mmol). The resulting mixture was stirred at room temperature (27 °C) for
the specified time. After completion, as indicated by TLC, the reaction mixture
was quenched with saturated NaHCO3 and extracted with ethyl acetate
(2 ꢂ 15 mL). The combined organic layers were washed with brine followed by
water, dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting
crude mass was subjected to flash column chromatography using 1:3 mixture
of n-hexane and ethyl acetate as eluent to afford the pure compound. The
products thus obtained were characterized by IR, NMR and mass spectroscopy.