Oxidative Prins and Prins/Friedel-Crafts cyclizations for the stereoselective synthesis of dioxabicycles and hexahydro-1H-benzo[f]isochromenes via the benzylic C-H activation

Article abstract of DOI:10.1039/c1ob06489d

1-Benzyl ethers of (E)- and (Z)-hex-3-en-1,6-diols and hept-3-en-1,7-diols undergo a smooth oxidative cyclization with DDQ in the presence of In(OTf) ₃ through a sequential C-H bond activation and an intramolecular Prins cyclization to afford t

Full text of DOI:10.1039/c1ob06489d

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Oxidative Prins and Prins/Friedel–Crafts cyclizations for the stereoselective
synthesis of dioxabicycles and hexahydro-1H-benzo[f ]isochromenes via the
benzylic C–H activation†
B. V. Subba Reddy,*a Prashant Borkar,a J. S. Yadav,*a P. Purushotham Reddy,b A. C. Kunwar,b B. Sridharc and
Rene´ Gre´ed
Received 30th August 2011, Accepted 3rd November 2011
DOI: 10.1039/c1ob06489d
1-Benzyl ethers of (E)- and (Z)-hex-3-en-1,6-diols and hept-3-en-1,7-diols undergo a smooth
oxidative cyclization with DDQ in the presence of In(OTf)3 through a sequential C–H bond activation
and an intramolecular Prins cyclization to afford the corresponding trans- and cis-fused
hexahydro-2H-furo[3,2-c]pyrans and octahydropyrano[4,3-b]pyrans respectively in good yields with an
excellent stereoselectivity. Aryl tethered homoallylbenzyl ethers such as benzyl ethers of (E)- and
(Z)-6-arylhex-3-enyl alcohols undergo a tandem Prins/Friedel–Crafts cyclization in the presence of
stoichiometric amounts of DDQ and SnCl4 via the benzylic C–H bond activation to furnish the
corresponding trans- and cis-fused hexahydro-1H-benzo[f ]isochromenes in good yields with complete
stereoselectivity.
oxygen in ethers is a more challenging task than the activation
of a C–H bond of nitrogen in amines due to the former’s higher
The Prins cyclization has emerged as a powerful synthetic tool for
oxidation potential.
Introduction
the synthesis of substituted tetrahydropyran scaffolds,1,2 whereas
In some instances, the use of a Lewis acid is necessary to further
increase the oxidative potential of DDQ.6 However, to the best of
our knowledge, there have been no reports on intramolecular Prins
and Prins/Friedel–Crafts cyclizations via C–H bond activation of
benzyl ethers.
The furo[3,2-c]pyran skeleton is frequently found in various
natural products such as flavonoids, catechins and pterocarpans
(Fig. 1, a).7,8 In addition, the pyrano[4,3-b]pyran moiety is also a
core structure in some biologically active natural products such
as Blepharocalyxin D (Fig. 1, b).9 Blepharocalyxin D is a unique
member of dimeric diarylheptanoid natural products isolated from
the seeds of Alpinia blepharocalyx. It acts as an antiproliferative
agent (ED50 3.61 mM) against murine colon 26-L5 carcinoma cells.
its intramolecular version is very useful for the stereoselective
synthesis of angularly fused oxa-bicycles and tricycles through
an internal attack of tethered nucleophile to the resulting oxo-
carbenium ion.3 The selective functionalization of sp3 C–H bond
of ethers by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) has
received considerable attention in organic synthesis.4 It was
reported that DDQ can oxidize benzyl ethers to generate oxocar-
benium ions.5 In particular, DDQ-mediated oxidative cyclizations
reported by Floreancig’s group are attractive for the construction
of macrocycles via the chemo- and regioselective activation of
benzylic as well as allylic sp3 C–H bonds.5 Mechanistically,
the reaction was proposed to proceed through an oxidative
cleavage of a carbon–hydrogen bond in benzylic ether to generate
an oxocarbenium ion which in turn reacts with an appended
nucleophile.5h However, the activation of a C–H bond of the
aDivision of Organic Chemistry-1, Indian Institute of Chemical Technology,
Uppal Road, Tarnaka, Hyderabad, 500670, India. E-mail: basireddy@
iict.res.in, yadavpub@iict.res.in; Fax: (+)91 40 27160512
bCentre for Nuclear Magnetic Resonance, Indian Institute of Chemical
Technology, Uppal Road, Tarnaka, Hyderabad, India
cLaboratory of X-ray Crystallography, Indian Institute of Chemical Tech-
nology, Uppal Road, Tarnaka, Hyderabad, India
dUniversite´ de Rennes 1, Laboratoire SCR, CNRS UMR 6226, Avenue du
Ge´ne´ral Leclerc, 35042, Rennes Cedex, France
† Electronic supplementary information (ESI) available: Preparation of
starting materials and copies of 1H and 13C NMR spectrum of products..
CCDC reference number 833511. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c1ob06489d
Fig.
1 Examples of some natural products bearing furo[3,2-
c]pyran, pyrano[4,3-b]pyran and the saturated form of hexahydro-
1H-benzo[f ]isochromene motifs.
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The saturated form of hexahydro-1H-benzo[f ]isochromene motif
is present in labdane diterpene glycosides such as alpindenosides C,
D and curcumanggoside (Fig. 1, c).10 Alpindenosides C and D are
isolated from the stems of Alpinia densespicata and are known to
exhibit NO inhibitory activities. However, they are non-cytotoxic
at 20 mM concentrations against several human tumor cell lines.
In continuation of our research on Prins type cyclizations and its
application to the total synthesis of natural products,11 we herein
report a novel and versatile method for the stereoselective synthesis
of bicyclic and tricyclic tetrahydropyran derivatives through a
sequential benzylic C–H bond activation and an intramolecular
Prins cyclization using a combination of DDQ and Lewis acid.
Fig. 2 Diagnostic coupling constants and chemical structure of 2a.
are in axial orientations. Thus the fusion between the two rings is
trans as shown in Fig. 2.
However, the cyclization of (Z)-6-(4-methoxybenzyloxy)hex-3-
en-1-ol in the presence of DDQ and In(OTf)3 in dichloromethane
at room temperature gave the product 2b in 76% yield with cis-
selectivity (Scheme 1, Table 2, entry b).
Results and discussion
We first attempted an intramolecular Prins type cyclization of (E)-
6-(4-methoxybenzyloxy)hex-3-en-1-ol (1a) using DDQ through
a benzylic C–H activation. To our surprise, no cyclization was
observed in the absence of a Lewis acid. The Prins cyclization
was successful in the presence of both DDQ and a Lewis acid.
Therefore, to optimize the reaction conditions, several Lewis acids
were screened using an equimolar amount of DDQ and the results
are presented in Table 1. Of various Lewis acids probed, 1.1 equiv.
of In(OTf)3 was found to be most effective for the intramolecular
Prins type cyclization. Under optimized conditions, the reaction
requires 1.1 equivalents of both DDQ and In(OTf)3 in CH2Cl2
at room temperature. Under the above conditions, the desired
product 2a was obtained in 75% yield with trans stereoselectivity
(Table 1, entry d). Other Lewis acids such as InBr3 and SnCl4 also
induced the cyclization of 1a in the presence of DDQ to give the
desired product 2a in 40% and 56% yields respectively (Table 1,
entries f and g). The use of 4 A molecular sieves was necessary to
avoid the hydrolysis of oxocarbenium ion which was assumed to
be an active intermediate in the Prins cyclization.
The structure and stereochemistry of product 2a were char-
acterized by double quantum filtered correlation spectroscopy
(DQFCOSY). The proton 4-H shows a large coupling of 9.4 Hz
with 3a-H indicating axial orientation of 4-H. 3a-H also shows a
large coupling (J = 10.0 Hz) with 7a-H which in turn shows a large
coupling (J = 12.0 Hz) with 7-H indicates that 3a-H and 7a-H
Scheme 1 Oxidative cyclization of (Z)-6-(4-methoxybenzyloxy)hex-3-
en-1-ol with DDQ/In(OTf)3.
Similarly, (Z)-6-(3-methoxybenzyloxy)hex-3-en-1-ol (1g) also
gave the corresponding furo[3,2-c]pyran 2g in 72% yield with
a complete cis-selectivity (Table 2, entry g). The structure and
stereochemistry of product 2g were characterized by double
quantum filtered correlation spectroscopy (DQFCOSY). The
coupling between 4-H and 3a-H protons is 3.1 Hz, which indicates
that 3a-H is in an equatorial position. This is further confirmed
by a small coupling between 3a-H and 7a-H (J = 6.6 Hz). 7a-H is
in an axial position as it shows a large coupling (J = 10.0 Hz) with
7-H. From these observations it was confirmed that the fusion
between the two rings is cis as shown in Fig. 3.
˚
Table 1 Effect of various Lewis acids in the Prins cyclization of (E)-6-(4-
methoxybenzyloxy)hex-3-en-1-ola
Fig. 3 Diagnostic coupling constants and chemical structure of 2g.
The scope of the reaction is illustrated in Table 2. A variety
of other substrates such as (E)-6-(3,4-dimethoxybenzyloxy)hex-
3-en-1-ol (1c), (Z)-6-(benzyloxy)hex-3-en-1-ol (1d), (E)-6-(3,4,5-
trimethoxybenzyloxy)hex-3-en-1-ol (1e), (E)-6-(naphthalen-2yl-
methoxy)hex-3-en-1-ol (1f) and (Z)-6-(4-methylbenzyloxy)hex-3-
en-1-ol (1h) participated well to furnish the corresponding trans-
or cis-fused hexahydro-2H-furo[3,2-c]pyrans in moderate to good
yields (entries c, d, e, f and h, Table 2). As seen from Table 2,
the electronic factors of the benzyl ring did show some effect
on the conversion. In general, electron-rich benzyl ethers gave
Entry
Lewis Acid
Equiv.
T (◦C)
Time (h)
Yield (%)b
a
b
c
d
e
f
no acid
Sc(OTf)3
ln(0Tf)3
ln(OTf)3
ln(OTf)3
lnBr3
—
rt
rt
0 to rt
rt
rt
0 to rt
-10 to rt
24
24
10
18
18
24
18
0
1.1
0.1
1.1
1.5
1.1
1.1
trace
10
75
75
40
56
g
SnCI4
a The reaction was performed on a 0.5 mmol scale. b Isolated yield.
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Table 2 Synthesis of trans- and cis-fused hexahydro-2H-furo[3,2-c]pyran
Next, we studied the reactivity of 1-benzylhept-3-en-1,7-
diol in intramolecular Prins cyclization. Thus, treatment
of (E)-7-(benzyloxy)hept-4-en-1-ol (3a) with stoichiometric
amounts of DDQ and In(OTf)3 in the presence of molecular
sieves in dichloromethane gave the corresponding trans-fused
octahydropyrano[4,3-b]pyran 4a as a major product along with
5a in a 9 : 1 ratio with 75% overall yield (Scheme 2; R = phenyl),
Table 3, entry a). These two isomeric products were inseparable by
silica gel column chromatography therefore the ratio of products
4a : 5a was determined by HPLC.
scaffoldsa
Entry Substrate (1)
Product (2)b
Time (h) Yield (%)c
a
18
18
16
75
76
78
b
c
d
e
24
16
65
80
Scheme 2 Oxidative Prins cyclization of olefin (E)-3.
Likewise, the reaction of (E)-7-(4-methylbenzyloxy)hept-4-en-
1-ol (3c) with DDQ under identical conditions afforded the
corresponding products 4c and 5c in a 9 : 1 ratio with 80% overall
yield (Scheme 2; R = p-tolyl; Table 3, entry c). The structure and
stereochemistry of product 4c were characterized by extensive
NMR experiments including 2-D Nuclear Overhauser Effect
spectroscopy (NOESY) and double quantum filtered correlation
spectroscopy (DQFCOSY). The assignments were made with the
help of a DQFCOSY experiment using a doublet assigned to
5-H at about 4.00 ppm. The NOE correlations, 5-H/8a-H, 5-
H/7-H, 8a-H/7-H, 8a-H/4-H, 8a-H/2-H, 4-H/2-H, 5-H/4-H,
4a-H/3-H and 4a-H/8-H provide emphatic support for the energy
minimized structure shown in Fig. 4. The structure clearly brings
out the trans (disposition of 4a-H and 8a-H) fusion of the two
six membered rings which take 5C8 and 2C4a chair conformations.
The assigned structure is very well supported by di-axial vicinal
coupling constants, 3J5-H/4a-H = 9.8, 3J4a-H/8a-H = 9.8, 3J4-H/3-H = 12.5,
f
22
19
22
70
72
68
g
h
3
3J3-H/2-H = 12.5 and J8-H/7-H = 11.6 Hz as well as axial/equatorial
3
and equatorial/equatorial vicinal coupling constants, J4-H/3-H¢
=
4.4, 3J3-H¢/2-H¢ = 2.6, 3J8a-H/8-H¢ = 5.6, 3J8-H¢/7-H = 3.3, 3J8-H/7-H¢ = 4.4 and
3J8-H¢/7-H¢ = 1.9 Hz.
i
24
65
a The reactions were performed on a 0.5 mmol scale. b All the products were
characterized by 1H and 13C NMR, IR and mass spectroscopy. c Yield refers
to pure products after column chromatography.
higher yields in shorter reaction times compared to simple benzyl
ethers. This may be attributed to the lower oxidation potential and
the greater stabilizing ability of oxocarbenium ions derived from
electron-rich benzyl ethers. Notably, (E)-6-(cinnamyloxy)hex-3-
en-1-ol (1i) also participated well in this reaction to furnish the
desired product 2i in good yield. However, the cyclization was
sluggish with the mono-allyl ether of hex-3-en-1-diol and also the
desired product was obtained in a low yield. The geometry of the
olefin controls the stereoselectivity of the reaction. It is known that
cis-olefins give the cis-fused product whereas trans-olefins provide
the trans-fused product exclusively.3d–3f
Fig. 4 Characteristic NOE’s and energy minimized structure of 4c.
As expected, the cyclization of (Z)-7-(benzyloxy)hept-4-
en-1-ol (3b) under similar conditions gave the cis-fused
octahydropyrano[4,3-b]pyran 4b in 65% yield as a major product
(Scheme 3; R = phenyl; Table 3, entry b). The minor product 5b
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Table 3 Synthesis of trans- and cis-fused octahydropyrano[4,3-b]pyran
(NOESY) and double quantum filtered correlation spectroscopy
(DQFCOSY). For product 4d, a small value of 2.8 Hz for 3J5-H/4a-H
reflects a distinct change to the cis fusion of the two six membered
rings. The NOE correlations, 5-H/8a-H, 5-H/7-H, 8a-H/7-H,
4a-H/3-H, 4-H/2-H and 4-H/8-H are consistent with energy
scaffoldsa
Time Yield 4 : 5 ratio
Entry Substrate (3)
Product (4)b
(h)
(%)c
75e
(%)d
5
minimized structure shown in the Fig. 2 which has C8 and 4aC2
a
18
90 : 10
chair conformation of the two six membered rings. The large di-
3
3
axial vicinal coupling constants, J4a-H/4-H = 12.4, J4-H/3-H = 12.4,
3J3-H/2-H = 11.6, J8a-H/8-H = 12.7 and J8-H/7-H = 12.7 Hz as well as
3
3
b
c
18
17
65
85 : 15
90 : 10
3
3
other couplings (small couplings, J4a-H/8a-H = 5.1, J4a-H/4-H¢ = 4.1,
3J3-H/2-H¢ = 4.0, 3J8a-H/8-H¢ = 5.1, 3J8-H/7-H¢ = 5.4, 3J8-H¢/7-H = 2.0, 3J8-H¢/7-H¢
=
1.2 Hz) strongly support the structure as shown in Fig. 5.
80e
d
e
16
15
60
75 : 25
85 : 15
84e
f
18
15
65
66
80 : 20
75 : 25
g
Fig. 5 Characteristic NOE’s and energy minimized structure of 4d.
In the case of 5d, the trans orientation of 2-H with respect to
3
3
5-H and 3-H is supported by J2-H/5-H = 8.8 and J2-H/3-H = 10.9
Hz. This implies that 5-H and 3-H will be proximal. Indeed the
NOE correlation, 5-H/3-H bears testimony to this. The NOE
correlations, 2-H/6-H¢, 2-H/4-H¢, 6-H¢/3-H¢, 6-H/3-H and 5-
H/7-H are consistent with the energy minimized structure shown
in Fig. 6.
a The reactions were performed on a 0.5 mmol scale. b All the products
were characterized by 1H and 13C NMR, IR and mass spectroscopy. c Yield
refers to pure products after column chromatography. d Ratio of 4 : 5 was
determined by 1H NMR spectra of the crude product. e The two isomers
were inseparable by silica gel column chromatography and the ratio was
determined by HPLC.
Scheme 3 Oxidative Prins cyclization of olefin (Z)-3.
was obtained in 12% yield. These two isomeric products could be
easily separated by silica gel column chromatography.
Similarly, the reaction of (Z)-7-(naphthalen-2yl-methoxy)hept-
4-en-1-ol (3d) afforded the respective cis-fused octahydropy-
rano[4,3-b]pyran 4d in 60% yield as a major product. The
minor product, i.e. 2-(2-(naphthalen-2-yl)-tetrahydrofuran-3-yl)-
tetrahydrofuran 5d was obtained in 20% yield (Scheme 3; R = 2-
naphthyl; Table 3, entry d). The structures and stereochemistry
of products 4d and 5d were characterized by extensive NMR
experiments including 2-D nuclear Overhauser effect spectroscopy
Fig. 6 Characteristic NOE’s and energy minimized structure of 5d.
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Table 4 Synthesis
of
trans-
and
cis-fused
hexahydro-1H-
The scope of the reaction with other 1-benzylhept-3-en-1,7-
diols is illustrated in Table 3. Other substrates like (E)-7-(4-
methoxybenzyloxy)hept-4-en-1-ol (3e), (Z)-7-(cinnamyloxy)hept-
4-en-1-ol (3f) and (E)-7-(2,5-dimethoxybenzyloxy)hept-4-en-1-
ol (3g) participated well to furnish the corresponding trans-
or cis-fused pyrano[4,3-b]pyrans as major products along with
3-(tetrahydrofuran-2-yl)tetrahydrofurans as minor products in
moderate to good yields (entries e–g, Table 3). The electronic effect
of the benzyl ring shows some effect on the conversion as discussed
earlier.
benzo[f ]isochromene scaffolds via the Prins/Friedel–Crafts cyclizationa
Entry Substrate (6)
Product (7)b
Time (h) Yield (%)c
a
14
78
b
14
80
Encouraged by the results obtained from mono-benzyl ethers
of hex-3-en-1,6-diol (1) and hept-3-en-1,7-diol (3), we extended
our efforts to study the Prins/Friedel–Crafts cyclization with
aryl tethered homoallyl benzyl ethers. Accordingly, we attempted
the oxidative cyclization of (E)-1-(6-(4-methoxybenzyloxy)hex-3-
enyl)benzene (6a) using stoichiometric amounts of DDQ and
SnCl4 in the presence of molecular sieves in dichloromethane.
Interestingly, the cyclization proceeded smoothly at room tem-
perature to afford the corresponding trans-fused hexahydro-1H-
benzo[f ]isochromene 7a as the sole product in 78% yield (Scheme
4, Table 4, entry a). However, the Prins/Friedel–Crafts cyclization
was very sluggish when In(OTf)3 was used.
c
11
12
82
d
58d
e
14
55d
f
14
14
75
74
g
Scheme 4 Oxidative cyclization of (E)-1-(6-(4-methoxybenzyloxy)hex-
3-enyl)benzene (6a).
h
15
70
The structure and stereochemistry of product 7a were estab-
lished by DQFCOSY. A large coupling (J = 12.6 Hz) between 4a-
H and 10b-H confirms that 4a-H is in an axial position and also
a large coupling (J = 12.5 Hz) between 10b-H and 1-H further
confirms that the 10b-H is in an axial position and hence the
fusion is in trans orientation. Similarly, a large coupling (J = 9.7
Hz) between 4-H and 4a-H confirms the axial orientation of 4-H
(Fig. 7).
a The reactions were performed on a 0.5 mmol scale. b All the products
were characterized by 1H and 13C NMR, IR and mass spectroscopy. c Yield
refers to pure products after column chromatography. d Yield of the major
regioisomer (regioisomeric ratio = 3 : 1).
Scheme 5 Oxidative cyclization of (Z)-1-(6-(4-methoxybenzyloxy)hex-
3-enyl)benzene (6b).
Fig. 7 Characteristic coupling constants and chemical structure of 7a.
From these observations, it was confirmed that the fusion between
the two rings is cis as shown in Fig. 8.
However, an oxidative cyclization of (Z)-1-(6-(4-methoxy-
benzyloxy)hex-3-enyl)benzene (6b) under similar conditions af-
forded the cis-fused hexahydro-1H-benzo[f ]isochromene 7b ex-
clusively in 80% yield (Scheme 5, Table 4, entry b).
The structure and the stereochemistry of product 7b were also
established by DQFCOSY. The coupling between 4-H and 4a-H
protons is 2.8 Hz indicating that 4-H and 4a-H are in equatorial
positions. This is further confirmed by a small coupling between
4a-H and 10b-H (J = 4.7 Hz). Therefore, 10b-H is in an axial
position since it shows a large coupling (J = 12.8 Hz) with 1-H.
Furthermore, the structure of 7b was confirmed by X-ray
crystallography (Fig. 9).12
The scope of the methodology is illustrated in Table 4 with
respect to other benzyl ethers of E/Z-6-arylhex-3-en-1-ol (entries
c–g). Various benzyl ethers such as simple benzyl ether (6e),
methylenedioxybenzyl-, methoxy- and methyl-substituted benzyl
ethers (6c, 6b, 6d and 6g) and also 1-naphthylmethyl ether (6f)
underwent smooth cyclization to provide the corresponding trans-
or cis-fused hexahydro-1H-benzo[f ]isochromenes in moderate to
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the olefin on the benzoxy cation generates the carbocation, which
could be trapped with a tethered nucleophile to give the desired
dioxa-bicycles and oxa-tricycles. The role of In(OTf)3 or SnCl4 is
most likely to activate the DDQ to further increase its oxidative
potential.
Conclusions
In summary, we have demonstrated a versatile approach for the
stereoselective synthesis of a novel class of dioxa-bicycles and oxa-
tricycles in a single step operation. This transformation proceeds
through benzylic C–H bond activation via DDQ oxidation fol-
lowed by the intramolecular Prins cyclization. This is the first
report on intramolecular Prins cyclization through C–H activation
by DDQ. Our approach is highly stereoselective to provide cis- and
trans-fused bicyclic and tricyclic tetrahydropyran scaffolds.
Fig. 8 Characteristic coupling constants and chemical structure of 7b.
Experimental
General
Fig. 9 ORTEP diagram of 7b.
The solvent dichloromethane was dried according to a standard
literature procedure. The reactions were performed in oven-dried
two necked round bottom flasks under an argon atmosphere. Glass
syringes were used to transfer the solvent. The products were
purified by column chromatography on silica gel of 60–120 or
100–200 mesh. Thin layer chromatography plates were visualized
by ultraviolet light and/or by exposure to iodine vapours and/or
by exposure to methanolic acidic solution of p-◦anisaldehyde
followed by heating (<1 min) on a hot plate (~250 C). Organic
solutions were concentrated on a rotary evaporator at 35–40 ◦C. IR
spectra were recorded on FT-IR spectrometer. 1H and 13C NMR
spectra were recorded in CDCl3 using 300, 400, 500 or 600 MHz
NMR spectrometers. Chemical shifts (d) are reported in parts
per million (ppm) with respect to TMS as an internal standard.
Coupling constants (J) are quoted in hertz (Hz). Mass spectra were
recorded on a mass spectrometer by Electrospray ionization (ESI)
or Atmospheric pressure chemical ionization (APCI) technique.
good yields. These results clearly indicate that the electronic effect
of benzyl ring shows some effect on the conversion. In addition
to benzyl ethers, 1-((Z)-6-(cinnamyloxy)hex-3-enyl)benzene (6h)
also participated well in this cyclization to afford product 7h
in 70% yield. In the case of meta-substituted aryl groups, for
example, the benzyl ether of 6-(3-methoxyphenyl)hex-3-en-1-ol,
the products were obtained as a 3 : 1 mixture of para-/ortho-
substituted products (entries d–e, Table 4). The ratio of the
1
para-/ortho-substituted products was determined by H NMR
spectra of the crude product. The two regioisomers could be easily
separated by silica gel column chromatography.
Of the various Lewis acids studied for this conversion (Table
1), In(OTf)3 was found to give the best results in Prins cyclization
(Table 1), whereas SnCl4 gave excellent results in Prins/Friedel–
Crafts cyclization in terms of conversion. Next, we examined
the effect of various solvents, such as dichloromethane, 1,2-
dichloroethane and toluene. Of these, dichloromethane appeared
to give the best results. This method is simple and convenient and
also provides the desired products in good yields with an excellent
stereoselectivity.
Typical procedure for the Prins cyclization of substrate 1 via C–H
activation
A plausible mechanism for the coupling is proposed in Scheme
6. The reaction was assumed to proceed via a single-electron
transfer from the benzyl ether to DDQ which generates a radical
cation and a DDQ radical anion. The radical oxygen of the DDQ
radical anion then abstracts the H-atom from the radical cation
and generates a benzoxy cation. Finally, nucleophilic attack of
˚
To a 25 mL two neck round bottom flask containing dried 4 A
molecular sieves (300 mg) was added a solution of homoallylic
ether 1 (0.5 mmol) in dry dichloromethane (10 mL) under an
argon atmosphere. Then DDQ (1.1 equiv.) and In(OTf)3 (1.1
equiv.) were added sequentially at 0 ◦C. The resulting mixture
was stirred at room temperature for the specified time (Table 2).
After completion of the reaction as indicated by TLC, the mixture
was quenched with saturated aqueous NaHCO3 solution and
then extracted with Et2O (2 ¥ 20 mL). The organic extracts were
washed with brine (2 ¥ 5 mL), dried over anhydrous Na2SO4 and
concentrated in vacuo. The resulting crude product was purified by
column chromatography (silica gel, 60–120 mesh) using a gradient
mixture of ethyl acetate/hexane to afford the pure product 2
(Table 2).
(3aR*,4R*,7aS*)-4-(4-Methoxyphenyl)-hexahydro-2H-furo[3,
2-c]pyran (2a; Table 2; Entry a). Yield, 88 mg, 75%; Liquid; 1H
NMR (600 MHz, CDCl3): d 7.30–7.27 (m, 2H), 6.90–6.87 (m,
Scheme
cyclization.
6
A plausible reaction pathway for intramolecular Prins
1354 | Org. Biomol. Chem., 2012, 10, 1349–1358
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2H), 4.23 (ddd, J = 12.0, 4.7 and 2.0 Hz, 1H), 4.15 (d, J = 9.4 Hz,
1H), 3.92 (ddd, J = 9.7, 8.5 and 2.7 Hz, 1H), 3.86 (ddd, J = 9.7,
8.5 and 7.5 Hz, 1H), 3.55 (dt, J = 12.0 and 2.0 Hz, 1H), 3.35 (ddd,
J = 12.0, 10.0 and 4.0 Hz, 1H), 2.12 (tdd, J = 12.0, 4.0 and 2.0 Hz,
1H), 1.82 (dq, J = 12.0 and 4.7 Hz, 1H), 1.75–1.56 (m, 3H);13C
NMR (75 MHz, CDCl3): d 159.2, 132.6, 127.5, 113.7, 82.8, 80.9,
66.3, 65.8, 55.1, 50.2, 32.6, 27.3; IR (neat): n 2928, 2849, 1513,
1247, 1169, 1057, 826 cm-1; MS (APCI): m/z 235 (M + H)+;
HRMS (APCI) calculated for C14H19O3 (M + H)+: 235.1334,
found 235.1342.
12.0 and 3.0 Hz, 1H), 2.69–2.55 (m, 1H), 2.04–1.86 (m, 1H), 1.85–
1.63 (m, 2H), 1.38–1.21 (m, 1H);13C NMR (75 MHz, CDCl3): d
138.9, 133.2, 132.5, 127.9, 127.8, 127.5, 125.9, 125.5, 123.4, 123.3,
77.1, 74.8, 66.3, 65.6, 44.2, 28.3, 23.9; IR (neat): n 2924, 2852,
1061, 754 cm-1; MS (APCI): m/z 255 (M + H)+; HRMS (APCI)
calculated for C17H19O2 (M + H)+: 255.1385, found 255.1385.
(3aS*,4R*,7aS*)-4-(3-Methoxyphenyl)-hexahydro-2H-furo[3,
2-c]pyran (2g; Table 2; Entry g). Yield, 84 mg, 72%; Liquid; 1H
NMR (600 MHz, CDCl3): d 7.24 (t, J = 7.9 Hz, 1H), 6.92–6.87
(m, 2H), 6.79 (dd, J = 8.3 and 2.4 Hz, 1H), 4.74 (d, J = 3.1 Hz,
1H), 4.30 (td, J = 10.0 and 6.6 Hz, 1H), 4.13 (ddd, J = 12.4, 5.0
and 2.2 Hz, 1H), 3.97 (ddd, J = 9.6, 8.5 and 2.4 Hz, 1H), 3.81 (s,
3H), 3.76 (ddd, J = 9.6, 8.5 and 7.7 Hz, 1H), 3.50 (dt, J = 12.4 and
2.2 Hz, 1H), 2.52 (dddd, J = 12.2, 7.7, 6.6 and 3.1 Hz, 1H), 1.96 (tt,
J = 12.2 and 9.6 Hz, 1H), 1.77 (tdd, J = 13.3, 6.6 and 2.2 Hz, 1H),
1.70 (dddd, J = 13.3, 12.4, 10.0 and 6.6 Hz, 1H), 1.37 (dtd, J =
12.2, 7.7 and 2.4 Hz, 1H);13C NMR (75 MHz, CDCl3): d 159.5,
143.1, 129.1, 117.3, 112.3, 110.6, 77.0, 74.8, 66.3, 65.5, 55.0, 44.3,
28.3, 23.8; IR (neat): n 2953, 2843, 1600, 1458, 1259, 1151, 1056,
855, 727 cm-1; MS (APCI): m/z 235 (M + H)+; HRMS (APCI)
calculated for C14H19O3 (M + H)+: 235.1334, found 235.1328.
(3aS*,4R*,7aS*)-4-(4-Methoxyphenyl)-hexahydro-2H-furo[3,
2-c]pyran (2b; Table 2; Entry b). Yield, 89 mg, 76%; Liquid; 1H
NMR (500 MHz, CDCl3): d 7.32–7.27 (m, 2H), 6.89–6.84 (m, 2H),
4.72 (d, J = 3.1 Hz, 1H), 4.32–4.25 (m, 1H), 4.12 (ddd, J = 12.0,
5.0 and 2.0 Hz, 1H), 4.00–3.95 (m, 1H), 3.80 (s, 3H), 3.79–3.73 (m,
1H), 3.50 (dt, J = 12.0 and 2.0 Hz, 1H), 2.53–2.44 (m, 1H), 1.99–
1.91 (m, 1H), 1.80–1.67 (m, 2H), 1.43–1.35 (m, 1H);13C NMR (75
MHz, CDCl3): d 159.6, 133.7, 126.2, 113.5, 77.0, 74.9, 66.4, 65.7,
55.2, 44.6, 28.4, 23.9; IR (neat): n 2935, 2837, 1500, 1253, 1152,
1036, 823 cm-1; MS (APCI): m/z 235 (M + H)+; HRMS (APCI)
calculated for C14H19O3 (M + H)+: 235.1334, found 235.1345.
(3aS*,4R*,7aS*)-4-p-Tolyl-hexahydro-2H-furo[3,2-c]pyran (2h;
Table 2; Entry h). Yield, 74 mg, 68%; Liquid; H NMR (300
(3aR*,4R*,7aS*)-4-(3,4-Dimethoxyphenyl)-hexahydro-2H-furo-
[3,2-c]pyran (2c; Table 2; Entry c). Yield, 103 mg, 78%; Liquid;
1H NMR (500 MHz, CDCl3): d 6.97–6.80 (m, 3H), 4.29–4.20
(m, 1H), 4.15 (d, J = 8.8 Hz, 1H), 3.98–3.80 (m, 8H), 3.61–3.52
(m, 1H), 3.40–3.31 (m, 1H), 2.18–2.09 (m, 1H), 1.90–1.78 (m,
1H), 1.77–1.51 (m, 3H);13C NMR (75 MHz, CDCl3): d 149.0,
148.7, 133.2, 118.6, 110.9, 109.4, 83.1, 80.9, 66.3, 65.9, 55.8, 50.4,
32.7, 27.4; IR (neat): n 2928, 2850, 1514, 1262, 1156, 1028, 806
cm-1; ESI-MS: m/z 265 (M + H)+; HRMS (ESI) calculated for
C15H21O4 (M + H)+: 265.1440, found 265.1451.
1
MHz, CDCl3): d 7.20–7.02 (m,4H), 4.66 (broad s, 1H), 4.27–4.14
(m, 1H), 4.13–4.02 (m, 1H), 3.95–3.85 (m, 1H), 3.76–3.63 (m,
1H), 3.51–3.37 (m, 1H), 2.54–2.38 (m, 1H), 2.31 (s, 3H), 1.98–
1.79 (m, 1H), 1.78–1.51 (m, 2H), 1.38–1.23 (m, 1H);13C NMR (75
MHz, CDCl3): d 138.4, 136.3, 128.7, 124.8, 77.1, 74.8, 66.3, 65.5,
44.4, 28.3, 23.8, 21.0; IR (neat): n 2953, 2877, 1362, 1148, 1094,
1062, 732 cm-1; MS (APCI): m/z 219 (M + H)+; HRMS (APCI)
calculated for C14H19O2 (M + H)+: 219.1385, found 219.1378.
(3aR*,4S*,7aS*,E)-4-Styryl-hexahydro-2H-furo[3,2-c]pyran (2i;
Table 2; Entry i). Yield, 75 mg, 65%; Liquid; 1H NMR (500 MHz,
CDCl3): d 7.51–7.16 (m, 5H), 6.64 (d, J = 15.6 Hz, 1H), 6.22 (dd,
J = 15.6 and 6.8 Hz, 1H), 4.26–4.14 (m, 1H), 4.00–3.82 (m, 3H),
3.55–3.44 (m, 1H), 3.32–3.22 (m, 1H), 2.14–1.93 (m, 2H), 1.83–
1.70 (m, 1H), 1.69–1.43 (m, 2H);13C NMR (75 MHz, CDCl3): d
136.6, 131.4, 128.5, 128.1, 127.8, 126.5, 81.7, 80.8, 66.5, 65.5, 49.3,
32.6, 27.2; IR (neat): n 2928, 2853, 1162, 1072, 967, 749, 695 cm-1;
MS (APCI): m/z 231 (M + H)+; HRMS (APCI) calculated for
C15H19O2 (M + H)+: 231.1385, found 231.1378.
(3aS*,4R*,7aS*)-4-Phenylhexahydro-2H-furo[3,2-c]pyran (2d;
Table 2; Entry d). Yield, 66 mg, 65%; Liquid; H NMR (300
1
MHz, CDCl3): d 7.34–7.15 (m, 5H), 4.72 (d, J = 3.0 Hz, 1H), 4.30–
4.19 (m, 1H), 4.12 (ddd, J = 12.1, 4.5 and 2.3 Hz, 1H), 3.98–3.88 (m,
1H), 3.78–3.66 (m, 1H), 3.48 (dt, J = 12.1 and 3.0 Hz, 1H), 2.56–
2.44 (m, 1H), 2.00–1.82 (m, 1H), 1.80–1.59 (m, 2H), 1.39–1.26
(m, 1H);13C NMR (75 MHz, CDCl3): d 141.4, 128.2, 126.9, 125.0,
77.3, 74.9, 66.4, 65.6, 44.4, 28.4, 23.9; IR (neat): n 2926, 2847,
1061, 771 cm-1; MS (APCI): m/z 205 (M + H)+; HRMS (APCI)
calculated for C13H17O2 (M + H)+: 205.1229, found 205.1232.
Typical procedure for the Prins cyclization of substrate 3 via C–H
activation
(3aR*,4R*,7aS*)-4-(3,4,5-Trimethoxyphenyl)-hexahydro-2H-
furo[3,2-c]pyran (2e; Table 2; Entry e). Yield, 118 mg, 80%;
Liquid; H NMR (300 MHz, CDCl3): d 6.58 (s, 2H), 4.31–4.21
(m, 1H), 4.14 (d, J = 8.9 Hz, 1H), 4.01–3.85 (m, 8H), 3.83 (s, 3H),
3.57 (dt, J = 12.1 and 2.3 Hz, 1H), 3.42–3.30 (m, 1H), 2.19–2.09
(m, 1H), 1.93–1.56 (m, 4H);13C NMR (75 MHz, CDCl3): d 153.1,
137.4, 136.1, 103.1, 83.3, 80.8, 66.3, 65.8, 60.7, 56.0, 50.3, 32.6,
27.3; IR (neat): n 2934, 2849, 1591, 1459, 1234, 1124, 1067 cm-1;
ESI-MS: m/z 295 (M + H)+; HRMS (ESI) calculated for C16H23O5
(M + H)+: 295.1545, found 295.1554.
1
˚
To a 25 mL two neck round bottom flask containing dried 4 A
molecular sieves (300 mg) was added a solution of homoallylic
ether 3 (0.5 mmol) in anhydrous dichloromethane (10 mL) under
an argon atmosphere. Then DDQ (1.1 equiv.) and In(OTf)3 (1.1
equiv.) were added sequentially at 0 ◦C. The resulting mixture
was stirred at room temperature for the specified time (Table 3).
After completion of the reaction as indicated by TLC, the mixture
was quenched with saturated aqueous NaHCO3 solution and
then extracted with Et2O (2 ¥ 20 mL). The organic extracts were
washed with brine (2 ¥ 5 mL), dried over anhydrous Na2SO4 and
concentrated in vacuo. The resulting crude product was purified
by column chromatography (silica gel, 100–200 mesh) using ethyl
acetate/hexane mixture to afford products 4/5 (Table 3).
(3aS*, 4R*, 7aS*)-4-(Naphthalene-2-yl)hexahydro-2H-furo[3,2-
1
c]pyran (2f; Table 2; Entry f). Yield, 90 mg, 70%; Liquid; H
NMR (300 MHz, CDCl3): d 7.82–7.73 (m, 4H), 7.47–7.33 (m, 3H),
4.89 (d, J = 3.0 Hz, 1H), 4.35–4.25 (m, 1H), 4.23–4.14 (m, 1H),
3.93 (dt, J = 9.8 and 3.0 Hz, 1H), 3.77–3.66 (m, 1H), 3.55 (dt, J =
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(4aR*,5R*,8aS*)-5-Phenyl-octahydropyrano[4,3-b]pyran (4a;
Table 3; Entry a). The reaction afforded a 9 : 1 mixture of two
products 4a and 5a. The two regioisomers were inseparable by
silica gel column chromatography and 4a:5a ratio was determined
by HPLC. Yield, 82 mg, 75%; Liquid; 1H NMR (500 MHz,
CDCl3): d 7.37–7.22 (m, 5H), 4.20–4.15 (m, 1H), 4.01–3.95 (m,
1H), 3.92 (d, J = 10.0 Hz, 1H), 3.73–3.65 (m, 1H), 3.52–3.45
(m, 1H), 3.34–3.25 (m, 1H), 1.92–1.84 (m, 2H), 1.67–1.49 (m,
3H), 1.27–1.20 (m, 1H), 1.12–1.02 (m, 1H);13C NMR (75 MHz,
CDCl3): d 139.5, 128.3, 127.9, 127.1, 83.6, 79.5, 68.2, 66.7, 47.3,
32.8, 26.1, 25.1; IR (neat): n 2934, 2849, 1094, 758, 701 cm-1;
MS (APCI): m/z 219 (M + H)+; HRMS (APCI) calculated for
C14H19O2 (M + H)+: 219.1385, found 219.1388.
(2R*,3R*)-2-(Naphthalen-2-yl)-3-((S*)-tetrahydrofuran-2-yl)-
tetrahydrofuran (minor product 5d; Table 3; Entry d). Yield,
27 mg, 20%; Liquid; 1H NMR (600 MHz, CDCl3): d 7.85–7.80 (m,
2H), 7.79–7.76 (m, 2H), 7.50 (dd, J = 8.4 and 1.2 Hz, 1H), 7.48–
7.42 (m, 2H), 5.37 (d, J = 7.5 Hz, 1H), 4.39 (dt, J = 8.4 and 2.1 Hz,
1H), 4.01 (ddd, J = 10.2, 8.4 and 6.8 Hz, 1H), 3.84 (dt, J = 8.2 and
6.0 Hz, 1H), 3.54 (dt, J = 8.2 and 5.5 Hz, 1H), 3.14 (dt, J = 8.8 and
5.4 Hz, 1H), 2.69 (dddd, J = 10.9, 8.8, 7.5 and 6.8 Hz, 1H), 1.94
(dtd, J = 12.3, 6.8 and 2.1 Hz, 1H), 1.90–1.78 (m, 2H), 1.70–1.62
(m, 2H), 1.50–1.41 (m, 1H);13C NMR (75 MHz, CDCl3): d 138.5,
133.1, 132.6, 128.0, 127.5, 127.1, 125.7, 125.4, 125.2, 82.2, 78.5,
68.3, 67.4, 49.1, 30.1, 27.1, 25.5; IR (neat): n 2928, 2868, 1059,
820, 755 cm-1; MS (APCI): m/z 269 (M + H)+; HRMS (APCI)
calculated for C18H21O2 (M + H)+: 269.3581, found 269.3570.
(4aS*,5R*,8aS*)-5-Phenyl-octahydropyrano[4,3-b]pyran (4b;
Table 3; Entry b). The reaction afforded a 85 : 15 mixture of
two products 4b and 5b. The two regioisomers could be easily
separated by silica gel column chromatography. Yield of major
isomer, 71 mg, 65%; Liquid; 1H NMR (500 MHz, CDCl3): d
7.32–7.23 (m, 2H), 7.22–7.14 (m, 3H), 4.42 (d, J = 1.9 Hz, 1H),
4.24–4.17 (m, 1H), 4.16–4.08 (m, 1H), 3.67–3.57 (m, 2H), 3.53
(dt, J = 12.1 and 1.9 Hz, 1H), 2.49–2.38 (m, 1H), 2.11–2.03 (m,
1H), 1.61–1.43 (m, 4H), 1.05–0.97 (m, 1H);13C NMR (75 MHz,
CDCl3): d 140.1, 128.0, 126.8, 125.4, 81.0, 72.8, 66.7, 60.5, 41.4,
25.8, 23.9, 17.2; IR (neat): n 2925, 2852, 1098, 772, 702 cm-1;
MS (APCI): m/z 219 (M + H)+; HRMS (APCI) calculated for
C14H19O2 (M + H)+: 219.1385, found 219.1376.
(4aR*,5R*,8aS*)-5-(4-Methoxyphenyl)-octahydropyrano[4,3-
b]pyran (4e; Table 3; Entry e). The reaction afforded a 85 : 15
mixture of two products 4e and 5e. The two regioisomers were
inseparable by silica gel column chromatography and 4e : 5e ratio
1
was determined by HPLC. Yield, 104 mg, 84%; Semi-solid; H
NMR (300 MHz, CDCl3): d 7.19–7.11 (m, 2H), 6.85–6.76 (m, 2H),
4.17–4.07 (m, 1H), 3.98–3.88 (m, 1H), 3.80 (d, J = 10.1 Hz, 1H),
3.78 (s, 3H), 3.69–3.56 (m, 1H), 3.42 (dt, J = 11.5 and 3.0 Hz, 1H),
3.28–3.15 (m, 1H), 1.91–1.72 (m, 2H), 1.68–1.32 (m, 3H), 1.31–
1.18 (m, 1H), 1.08–0.90 (m, 1H);13C NMR (75 MHz, CDCl3): d
159.3, 132.0, 128.4, 113.7, 83.3, 79.8, 68.2, 66.7, 55.1, 47.5, 33.0,
26.3, 25.4; IR (neat): n 2932, 2860, 1497, 1261, 1093, 835, 741
cm-1; MS (APCI): m/z 249 (M + H)+; HRMS (APCI) calculated
for C15H21O3 (M + H)+: 249.1491, found 249.1480.
(4aR*,5R*,8aS*)-5-p-Tolyl-octahydropyrano[4,3-b]pyran (4c;
Table 3; Entry c). The reaction afforded a 90 : 10 mixture of two
products 4c and 5c. The two regioisomers were inseparable by
silica gel column chromatography and 4c : 5c ratio was determined
by HPLC. Yield, 124 mg, 80%; Liquid; 1H NMR (600 MHz,
CDCl3): d 7.20–7.12 (m,4H), 4.15 (ddd, J = 11.6, 4.4 and 1.9 Hz,
1H), 3.97 (tdd, J = 11.6, 4.4 and 1.6 Hz, 1H), 3.88 (d, J = 9.8 Hz,
1H), 3.67 (dt, J = 11.6 and 3.3 Hz, 1H), 3.47 (dt, J = 11.6 and
2.6 Hz, 1H), 3.28 (dt, J = 9.8 and 5.6 Hz, 1H), 2.33 (s, 3H),
1.90–1.82 (m, 2H), 1.64–1.49 (m, 3H), 1.27–1.22 (m, 1H), 1.04
(dq, J = 12.5 and 4.4 Hz, 1H);13C NMR (75 MHz, CDCl3): d
137.4, 136.5, 128.9, 127.0, 83.4, 79.6, 68.1, 66.6, 47.2, 32.8, 26.1,
25.1, 21.1; IR (neat): n 2924, 2852, 1095, 811 cm-1; MS (APCI):
m/z 233 (M + H)+; HRMS (APCI) calculated for C15H21O2 (M +
H)+: 233.1542, found 233.1532.
(4aS*,5S*,8aS*,E)-5-Styryl-octahydropyrano[4,3-b]pyran (4f;
Table 3; Entry f). The reaction afforded a 80 : 20 mixture of
two products 4f and 5f. The two regioisomers could be easily
separated by silica gel column chromatography. Yield of major
isomer, 79 mg, 65%; Liquid; 1H NMR (500 MHz, CDCl3): d 7.37–
7.32 (m, 2H), 7.29–7.25 (m, 2H), 7.22–7.17 (m, 1H), 6.60 (d, J =
16.0 Hz, 1H), 6.09 (dd, J = 16.0 and 7.6 Hz, 1H), 4.42–4.36 (m,
1H), 4.09–4.02(m, 1H), 3.85–3.74 (m, 2H), 3.72–3.67 (m, 1H), 3.48
(dt, J = 12.0 and 2.2 Hz, 1H), 1.92–1.82 (m, 2H), 1.81–1.65 (m,
2H), 1.61–1.46 (m, 2H), 1.33–1.27 (m, 1H); 13C NMR (75 MHz,
CDCl3): d 136.7, 133.0, 128.8, 128.5, 127.7, 126.5, 75.9, 72.8, 68.8,
62.8, 39.2, 32.5, 25.0, 21.3; IR (neat): n 2926, 2855, 1455, 1088, 748
cm-1; MS (APCI): m/z 245 (M + H)+; HRMS (APCI) calculated
for C16H21O2, 245.1542 (M + H)+; Found, 245.1532.
(4aS*,5R*,8aS*)-5-(Naphthalen-2-yl)-octahydropyrano[4,3-b]-
pyran (4d; Table 3; Entry d). The reaction afforded a 75 : 25
mixture of two products 4d and 5d. The two regioisomers could
be easily separated by silica gel column chromatography. Yield
(4aR*,5R*,8aS*)-5-(2,5-Dimethoxyphenyl)-octahydropyrano[4,
3-b]pyran (4g; Table 3; Entry g). The reaction afforded a 75 : 25
mixture of two products 4g and 5g. The two regioisomers could
be easily separated by silica gel column chromatography. Yield
of major isomer, 92 mg, 66%; Liquid; 1H NMR (500 MHz,
CDCl3): d 7.00–6.97 (m, 1H), 6.82–.6.75 (m, 2H), 4.52 (d, J =
10.1 Hz, 1H), 4.18–4.12 (m, 1H), 4.00–3.94 (m, 1H), 3.78 (s, 3H),
3.76 (s, 3H), 3.73–3.66 (m, 1H), 3.49 (dt, J = 12.0 and 3.0 Hz,
1H), 3.38–3.31 (m, 1H), 1.91–1.79 (m, 2H), 1.68–1.45 (m, 4H),
1.24–1.12 (m, 1H);13C NMR (75 MHz, CDCl3): d 154.0, 151.0,
129.4, 113.6, 112.9, 111.7, 79.6, 75.5, 68.3, 66.8, 56.1, 55.7, 47.9,
32.9, 26.3, 24.5; IR (neat): n 2940, 2849, 1495, 1212, 1054, 810,
748 cm-1; ESI-MS: m/z 279 (M + H)+; HRMS (ESI) calculated
for C16H23O4 (M + H)+: 279.3514, found 279.3526.
1
of major isomer, 81 mg, 60%; Semi-solid; H NMR (600 MHz,
CDCl3): d 7.84–7.79 (m, 3H), 7.75 (s, 1H), 7.48–7.42 (m, 2H), 7.34
(dd, J = 8.4 and 1.1 Hz, 1H), 4.64 (d, J = 2.8, 1H), 4.30 (ddd, J =
11.7, 5.4, and 1.2 Hz, 1H), 4.24 (td, J = 12.7 and 5.1 Hz, 1H), 3.72–
3.61 (m, 3H), 2.52 (dq, J = 12.7 and 5.4 Hz, 1H), 2.22 (dddd, =
12.4, 5.1, 4.1 and 2.8 Hz, 1H), 1.66–1.44 (m, 4H), 1.00 (qd, J =
12.6 and 4.1 Hz, 1H);13C NMR (75 MHz, CDCl3): d 137.6, 133.1,
132.5, 127.9, 127.6, 127.5, 126.0, 125.5, 124.0, 123.6, 81.0, 72.9,
66.8, 60.6, 41.3, 25.8, 24.0, 17.3; IR (neat): n 2937, 2851, 1094, 741
cm-1; MS (APCI): m/z 269 (M + H)+; HRMS (APCI) calculated
for C18H21O2 (M + H)+: 269.3581, found 269.3585.
1356 | Org. Biomol. Chem., 2012, 10, 1349–1358
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((2R*,3R*)-2-(2,5-Dimethoxyphenyl)-3-((R*)-tetrahydrofuran-
2-yl)-tetrahydrofuran (minor product 5g; Table 3; Entry g). Yield,
30 mg, 22%; Liquid; H NMR (400 MHz, CDCl3): d 7.04–7.00
125.9, 125.6, 113.4, 81.3, 68.8, 55.2, 39.8, 39.5, 31.4, 29.2, 16.7; IR
(KBr): n 2931, 2837, 1509, 1246, 1090, 1023, 742 cm-1; ESI-MS:
m/z 317 (M + Na)+; HRMS calculated for C20H23O2 (M + H):
295.1698, found 295.1690.
1
(m, 1H), 6.72–6.65 (m, 2H), 5.02 (d, J = 5.9 Hz, 1H), 4.18–4.09
(m, 1H), 3.88–3.79 (m, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 3.72–3.64
(m, 1H), 3.49–3.40 (m, 1H), 3.34–3.24 (m, 1H), 2.57–2.44 (m,
1H), 2.34–2.21 (m, 1H), 2.20–2.07 (m, 1H), 1.77–1.52 (m, 2H),
1.12–0.95 (m, 2H);13C NMR (75 MHz, CDCl3): d 153.5, 150.5,
129.5, 112.9, 112.7, 110.5, 78.5, 77.2, 67.0, 66.8, 55.8, 55.6, 47.1,
30.2, 29.3, 26.0; IR (neat): n 2944, 2869, 1497, 1217, 1058, 806
cm-1; ESI-MS: m/z 279 (M + H)+; HRMS (ESI) calculated for
C16H23O4 (M + H)+: 279.3514, found 279.3507.
(4R*,4aR*,10bS*)-4-(Benzo[d][1,3]dioxol-5-yl)-2,4,4a,5,6,10b-
hexahydro-1H-benzo[f ]isochro◦mene (7c; Table 4; Entry c). Yield,
126 mg, 82%; Solid, mp 84–86 C; 1H NMR (300 MHz, CDCl3): d
7.24–7.16 (m, 1H), 7.15–6.96 (m, 3H), 6.84–80 (m, 1H), 6.78–6.69
(m, 2H), 5.93 (s, 2H), 4.26 (ddd, J = 11.5, 4.3 and 1.3 Hz, 1H),
3.97 (d, J = 9.6 Hz, 1H), 3.76 (dt, J = 12.3 and 2.3 Hz, 1H), 2.82–
2.60 (m, 3H), 2.39–2.26 (m, 1H), 1.83–1.66 (m, 1H), 1.65–1.27 (m,
3H); 13C NMR (75 MHz, CDCl3): d 147.7, 147.1, 138.9, 136.4,
134.7, 128.9, 125.9, 125.7, 124.7, 121.1, 107.8, 107.5, 100.9, 85.2,
68.5, 44.6, 41.4, 30.7, 28.7, 24.6; IR (KBr): n 2919, 2846, 1490,
1443, 1248, 1092, 1038, 744 cm-1; MS (APCI): m/z 309 (M +
H)+; HRMS (APCI) calculated for C20H21O3 (M + H)+: 309.1491,
found 309.1502.
Typical procedure for the intramolecular Prins/Friedel–Crafts
cyclization via C–H activation
˚
To a 25 mL two neck round bottom flask containing dried 4 A
molecular sieves (400 mg) was added a solution of homoallylic
ether substrate 6 (0.5 mmol) in anhydrous dichloromethane
(10 mL) under an argon atmosphere. Then DDQ (1.1 equiv.)
and SnCl4 (1.1 equiv., 1 M in DCM) were added sequentially
at -10 ◦C. The resulting mixture was stirred at room temperature
for the specified time (Table 4). After completion of the reaction
as indicated by TLC, it was quenched with saturated aqueous
NaHCO3 solution and then extracted with Et2O (2 ¥ 20 mL).
The organic extracts were washed with brine (2 ¥ 5 mL), dried
over anhydrous Na2SO4 and concentrated in vacuo. The resulting
crude product was purified by column chromatography (silica gel,
100–200 mesh) using a gradient mixture of ethyl acetate/hexane
to afford pure product 7 (Table 4).
(4R*,4aR*,10bS*)-8-Methoxy-4-(3-methoxyphenyl)-2,4,4a,5,6,
10b-hexahydro-1H-benzo[f ]isochromene (7d; Table 4; Entry d).
The reaction afforded a 3 : 1 mixture of para-/ortho-substituted
products. The two regioisomers could be easily separated by silica
gel column chromatography. Y◦ield of major regioisomer, 94 mg,
58%; White solid, mp 108–110 C; 1H NMR (300 MHz, CDCl3):
d 7.24–7.17 (m, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.90–6.75 (m,
3H), 6.66 (dd, J = 8.3 and 2.3 Hz, 1H), 6.52 (d, J = 2.3 Hz, 1H),
4.28 (ddd, J = 11.3, 4.5 and 1.5 Hz, 1H), 4.02 (d, J = 9.8 Hz,
1H), 3.83–3.72 (m, 7H), 2.78–2.58 (m, 3H), 2.37–2.26 (m, 1H),
1.84–1.67 (m, 1H), 1.66–1.23 (m, 3H); 13C NMR (75 MHz,
CDCl3): d 159.6, 157.7, 142.3, 137.8, 131.2, 129.3, 125.8, 120.0,
113.6, 113.5, 112.7, 111.7, 85.4, 68.5, 55.2, 44.9, 41.0, 30.9, 29.0,
24.6; IR (KBr): n 2942, 2843, 1588, 1455, 1259, 1084, 1040, 786
cm-1; MS (APCI): m/z 325 (M + H)+; HRMS (APCI) calculated
for C21H25O3 (M + H)+: 325.1804, found 325.1806.
(4R*,4aR*,10bS*)-4-(4-Methoxyphenyl)-2,4,4a,5,6,10b-hexa-
hydro-1H-benzo[f ]isochromene (7a; Table 4; Entry a). Yield,
1
115 mg, 78%; Semi-solid; H NMR (600 MHz, CDCl3): d 7.30–
7.26 (m, 3H), 7.20–7.16 (m, 1H), 7.15–7.12 (m, 1H), 7.08–7.04 (m,
1H), 6.91–6.87 (m, 2H), 4.31 (ddd, J = 11.5, 4.5 and 1.5 Hz, 1H),
4.06 (d, J = 9.7 Hz, 1H), 3.85–3.79 (m, 4H), 2.81–2.68 (m, 3H),
2.36 (tdd, J = 12.5, 4.5 and 2.0 Hz, 1H), 1.79 (dq, J = 12.5 and
4.5 Hz, 1H), 1.67 (dddd, J = 12.6, 11.2, 9.7 and 3.1 Hz, 1H), 1.45
(tdd, J = 12.6, 6.7 and 3.1 Hz, 1H), 1.36 (dtd, J = 12.6, 11.2 and
6.7 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 159.2, 139.0, 136.5,
133.0, 128.9, 128.6, 125.9, 125.7, 124.7, 113.7, 85.0, 68.5, 55.2,
44.6, 41.5, 30.7, 28.7, 24.6; IR (KBr): n 2922, 2840, 1513, 1249,
1092, 828, 743 cm-1; ESI-MS: m/z 295 (M + H); HRMS calculated
for C20H23O2 (M + H)+: 295.1698, found 295.1699.
(4R*,4aS*,10bS*)-8-Methoxy-4-phenyl-2,4,4a,5,6,10b-hexa-
hydro-1H-benzo[f ]isochromene (7e; Table 4; Entry e). The reac-
tion afforded a 3 : 1 mixture of para-/ortho-substituted products.
The two regioisomers could be easily separated by silica gel column
chromatography. Yield of major regioisomer, 81 mg, 55%; Semi-
solid; 1H NMR (300 MHz, CDCl3): d 7.35–7.13 (m, 5H), 6.98–6.89
(m, 1H), 6.69–6.56 (m, 1H), 6.53–6.46 (m, 1H), 4.64 (br s, 1H),
4.22–4.10 (m, 1H), 3.83–3.61 (m, 4H), 3.07–2.95 (m, 1H), 2.78–
2.48 (m, 2H), 2.12–1.97 (m, 1H), 1.96–1.53 (m, 3H), 1.32–1.17 (m,
1H); 13C NMR (75 MHz, CDCl3): d 157.6, 141.3, 137.2, 133.2,
129.4, 128.0, 126.6, 125.5, 113.2, 112.2, 81.7, 68.7, 55.1, 39.9, 38.8,
31.5, 29.5, 16.6; IR (KBr): n 2932, 2845, 1500, 1265, 1097, 703
cm-1; MS (APCI): m/z 295 (M + H); HRMS (APCI) calculated
for C20H23O2 (M + H): 295.1698, found 295.1705.
(4R*,4aS*,10bS*)-4-(4-Methoxyphenyl)-2,4,4a,5,6,10b-hexa-
hydro-1H-benzo[f ]isochromene (7b; Table 4; Entry b). Crystals
for XRD were obtained by dissolving compound in 4–5 mL
ethanol, followed by slow evaporation of◦solvent over 4 days. Yield,
118 mg, 80%; White solid, mp 118–120 C; 1H NMR (600 MHz,
CDCl3): d 7.25–7.22 (m, 2H), 7.16–7.09 (m, 3H), 7.08–7.04 (m,
1H), 6.92–6.88 (m, 2H), 4.68 (d, J = 2.8 Hz, 1H), 4.21 (ddd, J =
11.5, 4.7 and 1.2 Hz, 1H), 3.81 (s, 3H), 3.76 (ddd, J = 12.7, 11.5
and 2.3 Hz, 1H), 3.12 (td, J = 12.8 and 4.7 Hz, 1H), 2.78 (ddd, J =
17.0, 5.8 and 1.7 Hz, 1H), 2.62 (ddd, J = 17.0, 12.8 and 6.3 Hz,
1H), 2.06 (tdd, J = 13.0, 4.7 and 2.8 Hz, 1H), 1.92 (dq, J = 12.8
and 4.7 Hz, 1H), 1.81 (dq, J = 13.0 and 5.8 Hz, 1H), 1.73–1.67 (m,
1H), 1.35 (tddd, J = 13.0, 6.3, 2.8 and 1.7 Hz, 1H); 13C NMR (75
MHz, CDCl3): d 158.3, 140.9, 136.1, 133.5, 129.0, 128.6, 126.6,
(4R*,4aR*,10bS*)-9-Methyl-4-(naphthalen-2-yl)-2,4,4a,5,6,
10b-hexahydro-1H-benzo[f ]isochromene ◦(7f; Table 4; Entry f).
Yield, 123 mg, 75%; Solid, mp 102–104 C; 1H NMR (300 MHz,
CDCl3): d 7.84–7.72 (m, 4H), 7.50–7.38 (m, 3H), 7.06–7.02 (m,
1H), 6.92–6.84 (m, 2H), 4.34 (ddd, J = 11.3, 4.5 and 1.5 Hz, 1H),
4.23 (d, J = 9.8 Hz, 1H), 3.84 (dt, J = 12.1 and 2.3 Hz, 1H), 2.80–
2.59 (m, 3H), 2.45–2.35 (m, 1H), 2.32 (s, 1H), 1.92–1.66 (m, 2H),
1.50–1.31 (m, 2H); 13C NMR (75 MHz, CDCl3): d 138.7, 138.3,
135.1, 133.3, 133.2, 128.9, 128.1, 128.0, 127.6, 126.8, 126.7, 126.0,
125.8, 125.4, 125.2, 85.7, 68.7, 44.8, 41.6, 30.9, 28.4, 24.8, 21.2; IR
This journal is
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Org. Biomol. Chem., 2012, 10, 1349–1358 | 1357
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(KBr): n 2943, 2833, 1080, 818, 744 cm-1; MS (APCI): m/z 329 (M
+ H); HRMS (APCI) calculated for C24H25O (M + H): 329.1905,
found 329.1912.
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(4R*,4aS*,10bS*)-9-Methyl-4-p-tolyl-2,4,4a,5,6,10b-hexahy-
dro-1H-benzo[f ]isochromene (7g; Table 4; Entry g). Yield,
108 mg, 74%; Solid, mp 92–94 ◦C; 1H NMR (300 MHz, CDCl3):
d 7.18–7.06 (m, 4H), 6.92–6.81 (m, 3H), 4.63 (d, J = 1.9 Hz, 1H),
4.24–1.14 (m, 1H), 3.77–3.65 (m, 1H), 3.08–2.97 (m, 1H), 2.77–
2.64 (m, 1H), 2.63–2.46 (m, 1H), 2.34 (s, 3H), 2.29 (s, 3H), 2.10–
1.98 (m, 1H), 1.97–1.59 (m, 3H), 1.33–1.22 (m, 1H); 13C NMR (75
MHz, CDCl3): d 140.8, 138.3, 136.1, 135.0, 133.0, 129.1, 128.9,
128.7, 126.9, 125.4, 81.7, 68.8, 39.8, 39.6, 31.5, 28.9, 21.1, 21.0,
16.8; IR (KBr): n 2925, 2834, 1088, 820 cm-1; MS (APCI): m/z
293 (M + H); HRMS (APCI) calculated for C21H25O (M + H)+:
293.1905, found 293.1898.
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(4S*,4aS*,10bS*,E)-4-Styryl-2,4,4a,5,6,10b-hexahydro-1H -
benzo[f ]isochromene (7h; Table 4; Entry h). Yield, 102 mg, 70%;
White solid, mp 96–98 ◦C; 1H NMR (300 MHz, CDCl3): d 7.40–
7.33 (m, 2H), 7.32–7.14 (m, 3H), 7.11–6.98 (m, 4H), 6.60 (dd, J =
16.6 and 1.5 Hz, 1H), 6.19 (dd, J = 15.9 and 4.5 Hz, 1H), 4.29–
4.22 (m, 1H), 4.17–4.07 (m, 1H), 3.73–3.60 (m, 1H), 3.04–2.68 (m,
3H), 2.03–1.75 (m, 4H), 1.70–1.59 (m, 1H); 13C NMR (75 MHz,
CDCl3): d 140.8, 137.0, 136.0, 129.7, 129.1, 129.0, 128.6, 128.5,
127.3, 126.3, 126.0, 125.7, 80.1, 68.4, 39.1, 38.8, 31.4, 29.3, 17.3; IR
(KBr): n 2930, 2832, 1143, 1079, 972, 756, 698 cm-1; MS (APCI):
m/z 291 (M + H); HRMS (APCI) calculated for C21H23O (M +
H)+: 291.1749, found 291.1738.
Acknowledgements
This research has been performed as part of the Indo-French
“Joint Laboratory for Sustainable Chemistry at Interfaces”. We
thank CSIR and CNRS for support. PB thanks CSIR, New Delhi
for the award of a fellowship.
Notes and references
1 For an excellent recent review on Prins reactions see: (a) C. Olier, M.
Kaafarani, S. S. Gastaldi and M. P. Bertrand, Tetrahedron, 2010, 66,
413 and references cited therein; (b) D. R. Adams and S. R. Bhatnagar,
Synthesis, 1977, 661; (c) E. Arundale and L. A. Mikeska, Chem. Rev.,
1952, 51, 505; (d) I. M. Pastor and M. Yus, Curr. Org. Chem., 2007, 11,
925; (e) E. A. Crane and K. A. Scheidt, Angew. Chem., Int. Ed., 2010,
49, 8316–8326.
2 (a) O. L. Epstein and T. Rovis, J. Am. Chem. Soc., 2006, 128, 16480;
(b) L. E. Overman and E. J. Velthuisen, J. Org. Chem., 2006, 71, 1581;
(c) J. S. Yadav, B. V. S. Reddy, T. Maity and G. G. K. S. Narayana
12 CCDC-833511 (7b) contains the supplementary crystallographic data
for this paper †.
1358 | Org. Biomol. Chem., 2012, 10, 1349–1358
This journal is
The Royal Society of Chemistry 2012
©