Tandem Prins/friedel-crafts cyclization for stereoselective synthesis of heterotricyclic systems

Article abstract of DOI:10.1021/jo201027u

Homoallylic substrates such as (E)-6-arylhex-3-enyl alcohols, N-tosylamides, and thiols undergo smooth cross-coupling with various aldehydes in the presence of 10 mol % Sc(OTf)₃ and 30 mol % TsOH to afford the trans-fused hexahydro-1H-benzo [f]isochromenes, N-tosyloctahydrobenzo [f] -isoquinolines, and hexahydro-lH-benzo [f]isothiochromenes, respectively. However, the cross-coupling of (Z)-olefins such as 6-arylhex-3-enyl alcohols, N-tosylamides, and thiols with aldehydes affords the corresponding hexahydro-1H-benzo-[f]isochromenes, N-tosyloctahydrobenzo [f]isoquinolines, and hexahydro-1H-benzo[f] isothiochromenes with complete cis selectivity via intramolecular Prins-, aza-Prins-, and thia-Prins/(Figure presented) Friedel - Crafts cyclizations, respectively. Though the Prins cyclization proceeds smoothly under the influence of Sc(OTf)₃, high conversions and enhanced reaction rates are achieved using a mixture of Sc(OTf)₃ and TsOH (1:3).

Full text of DOI:10.1021/jo201027u

ARTICLE
pubs.acs.org/joc
Tandem Prins/FriedelꢀCrafts Cyclization for Stereoselective Synthesis
of Heterotricyclic Systems
B. V. Subba Reddy,*,† Prashant Borkar,† J. S. Yadav,*,† B. Sridhar,‡ and Renꢀe Grꢀee§
†Division of Organic Chemistry and ‡Laboratory of X-ray Crystallography, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
§Universitꢀe de Rennes 1, Laboratoire SCR, CNRS UMR 6226, Avenue du Gꢀenꢀeral Leclerc, 35042 Rennes Cedex, France
S Supporting Information
b
ABSTRACT: Homoallylic substrates such as (E)-6-arylhex-3-
enyl alcohols, N-tosylamides, and thiols undergo smooth cross-
coupling with various aldehydes in the presence of 10 mol %
Sc(OTf)3 and 30 mol % TsOH to afford the trans-fused
hexahydro-1H-benzo[f]isochromenes, N-tosyloctahydrobenzo[f]-
isoquinolines, and hexahydro-1H-benzo[f]isothiochromenes,
respectively. However, the cross-coupling of (Z)-olefins such
as 6-arylhex-3-enyl alcohols, N-tosylamides, and thiols with
aldehydes affords the corresponding hexahydro-1H-benzo-
[f]isochromenes, N-tosyloctahydrobenzo[f]isoquinolines, and
hexahydro-1H-benzo[f]isothiochromenes with complete cis
selectivity via intramolecular Prins-, aza-Prins-, and thia-Prins/
FriedelꢀCrafts cyclizations, respectively. Though the Prins cyclization proceeds smoothly under the influence of Sc(OTf)3, high
conversions and enhanced reaction rates are achieved using a mixture of Sc(OTf)3 and TsOH (1:3).
’ INTRODUCTION
The coupling of an olefin with a carbonyl compound in the
presence of an acid catalyst is known as the ‘Prins reaction’, which
normally provides a mixture of 1,3-diols, 1,3-dioxanes, and allylic
alcohols.1ꢀ4 In particular, the coupling of a homoallylic alcohol
with a carbonyl compound in the presence of an acid catalyst is
Figure 1. Examples of bioactive octahydrobenzo[f]isoquinoline analogues.
known as the ‘Prins cyclization’, which is a powerful synthetic
tool for the stereoselective synthesis of tetrahydropyran scaffolds.5
The saturated form of the hexahydro-1H-benzo[f]isochromene
On the other hand, aza-Prins cyclization of homoallylic amides
skeleton is typically found in some biologically active natural pro-
ducts such as alpindenosides C and D and curcumanggoside.25,26
with carbonyl compounds is one of the most elegant approaches
for the synthesis of piperidine derivatives.5ꢀ8 In the same way,
thia-Prins cyclization of homoallylic mercaptans with aldehydes
Alpindenosides C and D are a novel class of labdane diterpene
glycosides isolated from the stems of Alpinia densespicata which
under the influence of an acid catalyst provides the correspond-
ing thia-tetrahydropyrans with high selectivity.9,10 Subsequently,
tandem Prins cyclizations, such as Prins/Ritter and Prins/Friedelꢀ
Crafts, have also been reported to produce 4-amido- and 4-aryltetra-
hydropyran derivatives, respectively.5,11ꢀ18 Recently, a tandem
ene/Prins cyclization has been reported to furnish annulated
tetrahydropyran scaffolds.19 Therefore, the Prins cyclization has
emerged as a powerful method for stereoselective synthesis of a
wide range of heterocycles such as tetrahydropyrans, thiapyrans,
and piperidine scaffolds. In spite of its potential application in
natural products synthesis,20 the intramolecular versions of Prins
and aza-Prins cyclizations are still unexplored.5,14,21ꢀ24 To the
best of our knowledge, until now, there have been no reports
on the intramolecular versions of aza- and thia-Prins/Friedelꢀ
Crafts cyclizations.
exhibit moderate NO inhibitory activities, whereas they are
noncytotoxic at 20 μM against several human tumor cell lines.
Curcumanggoside is also a labdane diterpene glycoside isolated
from the rhizomes of Curcuma mangga. Some of the trans- and
cis-fused octahydrobenzo[f]isoquinoline analogues (Figure 1)
show a high affinity toward σ receptors with regard to psycho-
tomimetic effects27ꢀ29 or as potential calcium channel blockers.30
Thiapyrans are rarely available in Nature. The thiapyran motif
occupies a key role in a number of pharmaceutical agents such as
cephalosporins and dithiathromboxane A2.31,32 Furthermore,
thiacyclohexane derivatives can be transformed into a variety of
Received: January 28, 2011
Published: August 15, 2011
r
2011 American Chemical Society
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Table 1. Catalyst Optimization for Intramolecular Prins/FriedelꢀCrafts Cyclization of (E)-6-Phenylhex-3-en-1-ol with
4-Bromobenzaldehydea
entry
Sc(OTf)3(mol %)
TsOH(mol %)
TfOH(mol %)
time (h)
yield (%)b
a
b
c
d
e
f
10
30
30
24
36
30
16
18
11
7
75
80
49
57
84
80
85
92
65
86
10
30
10
10
20
30
30
10
10
10
g
h
i
30
30
24
8
j
10
a Reaction was performed at 0.5 mmol scale with respect to olefin in dichloromethane at room temperature. b Combined yield of trans- and cis-fused
product (diastereomeric ratio = 9:1) after column chromatography.
explained by means of a cooperative catalysis38 between Sc(OTf)3
and an organic cocatalyst (TsOH) or by in situ formation of
Sc(OTs)3. However, no Sc(OTs)3 was formed in situ from
Sc(OTf)3 and TsOH, which was later confirmed by running a
simple 1H NMR experiment of the catalyst. Indeed, no significant
change in chemical shift (δ) values of the p-tolyl group of TsOH
was observed in the 1H NMR spectrum. Formation of Sc(OTs)3
may be ruled out further as there was no characteristic m/z peak
for Sc(OTs)3 in the mass spetrum. Moreover, it was supported
by performing the reaction in the presence of Sc(OTf)3 and
TfOH wherein similar enhanced catalytic activity was observed
(entry j, Table 1).
Figure 2. Characteristic NOEs and chemical structure of (4S*,4aS*,10bR*)-4-
(4-bromophenyl)-2,4,4a,5,6,10b-hexahydro-1H-benzo[f]isochromene (3a).
structures through simple reactions such as hydrogenolysis,
oxidation, and olefination.33,34
The structure and stereochemistry of (4S*,4aS*,10bR*)-4-(4-
bromophenyl)-2,4,4a,5,6,10b-hexahydro-1H-benzo[f]isochromene
3a was established by NOE experiments. The proton 4-H shows
a large coupling of 9.8 Hz with 4a-H indicating the axial orienta-
tion of 4-H. Also, 4a-H shows a large coupling (12.1 Hz) with
10b-H, which further shows a large coupling with one of the 1-H
protons, indicating that 4a-H and 10b-H are in axial positions. In
addition to the couplings, the presence of NOE cross-peaks
between 4-H, 10b-H, and 2-H as well as cross-peaks between 4a-
H and 1-H confirmed that the fusion between the two rings is
trans (Figure 2). The double-edged arrows show characteristic
NOE correlations. Furthermore, the structure of 3a was con-
firmed by X-ray crystallography.39
However, the cross-coupling of (Z)-6-phenylhex-3-en-1-ol
with 4-bromobenzaldehyde in the presence of 10 mol % Sc-
(OTf)3 and 30 mol % TsOH in dichloromethane at room
temperature gave the product 3b in 88% yield with complete
cis selectivity (Scheme 1, Table 2, entry b). The above results
provided a gateway to extend this process to a variety of other
interesting substrates like (E)- and (Z)-6-(3-methoxyphenyl)hex-
3-en-1-ol and (E)- and (Z)-6-p-tolylhex-3-en-1-ol. The scope of
the reaction is illustrated with respect to various aldehydes like
’ RESULTS AND DISCUSSION
In a continuation of our research program on Prins-type
cyclizations and its application to the total synthesis of natural
products,35ꢀ37 we herein report a versatile method for stereo-
selective synthesis of heterotricycles, namely, hexahydro-1H-
benzo[f]isochromene, octahydrobenzo[f]isoquinoline, and
hexahydro-1H-benzo[f]isothiochromene, via intramolecular Prins-,
aza-Prins-, and thia-Prins/FriedelꢀCrafts cyclizations, respectively.
As a model reaction, we first attempted the cross-coupling of
4-bromobenzaldehyde (2) with (E)-6-phenylhex-3-en-1-ol (1)
in the presence of 10 mol % Sc(OTf)3 and 30 mol % TsOH in
dichloromethane. The reaction proceeded smoothly at room
temperature to furnish the corresponding product 3a in 92%
yield with a high trans selectivity (90:10, Table 1, entry h). The
ratio of trans/cis isomers was determined by 1H NMR spectra of
a crude product. The two diastereomers could easily be separated
by silica gel column chromatography. The combination of Sc(OTf)3
and TsOH (1:3) works more effective than either Sc(OTf)3
or TsOH alone in terms of reaction time and yield (Table 1).
The high catalytic activity of the above reagent system may be
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Scheme 1. Reaction of (Z)-6-Phenylhex-3-en-1-ol with 4-Bromobenzaldehyde
cyclohexanecarboxaldehyde, thiophene-2-carbaldehyde, 3-methyl-
butanal, 4-nitrobenzaldehyde, and cinnamaldehyde, and the
results are presented in Table 2 (entries cꢀh, kꢀn). In all cases,
the corresponding hexahydro-1H-benzo[f]isochromenes (entriesg,
h, kꢀn, Table 2) were obtained in good yields with high selectivity.
The geometry of the olefin controls the stereoselectivity of the
reaction. It is known that cis olefin gives cis-fused product exclu-
sively, whereas trans olefin provides trans-fused product predomi-
nantly. This method works well not only with aldehydes but also
with ketones. For instance, cyclohexanone affords the spiropyrans
under identical conditions (entries i and j). In the case of the meta-
substituted aryl group, for example, 6-(3-methoxyphenyl)hex-3-en-
1-ol, the corresponding product was obtained as a 3:1 mixture of
para/ortho isomers (entries gꢀj, Table 2). The ratio of para/ortho
isomers was determined by 1H NMR spectra of the crude product.
The two regioisomers could easily be separated by silica gel column
chromatography. In the case of entry a, formation of minor cis-fused
product (10%) may be due to some nonconcertedness during the
process of cyclization with 4-bromobenzaldehyde in which a minor
amount of trapping of the secondary carbenium ion may occur from
the same face as the dihydrostyryl substituent.
Figure 3. Coupling constants and characteristic NOEs of (4S*,4aR*,10bR*)-
4-isobutyl-3-tosyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]isoquinoline (5f).
Figure 4. Characteristic NOEs and chemical structure of (4S*,4aS*,
10bR*)-4-(2-fluorophenyl)-2,4,4a,5,6,10b-hexahydro-1H-benzo[f]iso-
thiochromene (7a).
Next, we examined the aza-Prins/FriedelꢀCrafts cyclization
of 4-methyl-N-(6-arylhex-3-enyl)benzenesulfonamide (4) with
aldehydes. Accordingly, 3-methylbutanal was treated with (E)-4-
methyl-N-(6-phenylhex-3-enyl)benzenesulfonamide (4) in the
presence of 10 mol % Sc(OTf)3 in 1,2-dichloroethane. To our
surprize, aza-Prins cyclization proceeded at 80 °C to afford
the corresponding trans-fused N-tosyl-octahydrobenzo[f]iso-
quinoline 5e in 78% yield as a sole product (Table 3, entry e).
Likewise, coupling of (Z)-4-methyl-N-(6-phenylhex-3-enyl)benzene-
sulfonamide with 3-methylbutanal gave the cis-fused N-tosyl-
octahydrobenzo[f]isoquinoline 5f in 80% yield exclusively
(Table 3, entry f). The structure and stereochemistry of
(4S*,4aR*,10bR*)-4-isobutyl-3-tosyl-1,2,3,4,4a,5,6,10b-octahydro-
benzo[f]isoquinoline 5f was established by NOE experiments.
The coupling between 4-H and 4a-H protons is 1 Hz. This indi-
cates that 4-H and 4a-H are in equatorial positions. This is further
confirmed by a small coupling between 4a-H and 10b-H (4.9 Hz)
and absence of NOE cross-peaks between 4-H/10b-H, 4-H/2-H,
4a-H/1-H. The proton 10b-H is in the axial position since it
shows a large coupling (11.7 Hz) with one of the 1-H protons
and NOE with one of the 2-H protons. From these observations,
it is confirmed that the cis fusion takes place between the two
rings (Figure 3). The coupling values and NOEs are consistent
with the structure as shown in Figure 3. The double-edged arrows
show characteristic NOEcorrelations. Furthermore, the structure of
5f was confirmed by X-ray crystallography.39
participated well in this cyclization (entries g and h, Table 3). As
shown in Table 3, aromatic aldehydes gave slightly lower yields
than aliphatic counterparts (entries c, d, m and n). In the case of
4-methyl-N-(6-(3-methoxyphenyl)hex-3-enyl)benzenesulfonamide,
products 5iꢀl were obtained as a 2:1 mixture of para/ortho-
substituted products (entries iꢀl, Table 3). The two regioisomers
could easily be separated by silica gel column chromatography.
Encouraged by the results obtained with aryl-tethered homo-
allylic alcohols (1) and tosylamides (4), we turned our attention
to extend this process for the thia-Prins/FriedelꢀCrafts cycliza-
tion. Accordingly, 2-fluorobenzaldehyde was treated with (E)-6-
phenylhex-3-ene-1-thiol (6) in the presence of 10 mol % Sc(OTf)3
in dichloromethane. Interestingly, thia-Prins cyclization proceeded
smoothly at room temperature to afford the respective trans-fused
hexahydro-1H-benzo[f]isothiochromene 7a as a sole product in
86% yield (Table 4, entry a). The structure and stereochemistry
of (4S*,4aS*,10bR*)-4-(2-fluorophenyl)-2,4,4a,5,6,10b-hexahydro-
1H-benzo[f]isothiochromene 7a was characterized by NOE
experiments. The proton 4-H shows a large coupling of 10.6
Hz with 4a-H, indicating axial orientation of 4-H. Also, 4a-H
shows a large coupling (J = 10.6 Hz) with 10b-H, which further
shows a large coupling with one of the 1-H protons, indicating
that 4a-H and 10b-H are in axial positions. It is further confirmed
by the presence of NOE cross-peaks between 4-H, 10b-H, and
2-H as well as cross-peaks between 4a-H and 1-H. From the above
observations, it is confirmed that the fusion between the two rings
is trans as shown in Figure 4. The thiapyran ring in the mole-
cule adopts the chair form, which is in agreement with the ob-
served couplings and NOE cross-peaks. The double-edged arrows
show characteristic NOE correlations. Furthermore, the structure of
7a was confirmed by X-ray crystallography.39
The scope of the reaction is illustrated with regard to substrates
such as (E)- and (Z)-4-methyl-N-(6-(3-methoxyphenyl)hex-3-en-
yl)benzenesulfonamide and (E)- and (Z)-4-methyl-N-(6-p-tolylhex-
3-enyl)benzenesulfonamide and various aldehydes, and the results
are summarized in Table 3. Notably, paraformaldehyde40 also
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Table 2. Synthesis of Hexahydro-1H-benzo[f]isochromene Scaffolds via Intramolecular Prins/FriedelꢀCrafts Cyclizationsa
a Reaction was performed with 0.5 mmol of olefin, 0.6 mmol of aldehyde, and 10 mol % Sc(OTf)3 + 30 mol % TsOH in dichloromethane at room
temperature. b All products were characterized by 1H and 13C NMR, IR, and mass spectroscopy. c Yield refers to pure product after column
chromatography. d Yield of major regioisomer (regioisomeric ratio = 3:1).
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Table 3. Sc(OTf)3-Catalyzed Synthesis of N-Tosyl-octahydrobenzo[f]isoquinolinesa
a Reaction was performed with 0.5 mmol of olefin, 0.6 mmol of aldehyde, and 10 mol % Sc(OTf)3 in 1,2-dichloroethane at 80 °C. b,c,d Same as in Table 2.
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Table 4. Synthesis of Hexahydro-1H-benzo[f]isothiochromene Scaffolds via Intramolecular Thia-Prins/FriedelꢀCrafts
Cyclizationa
a Reaction was performed with 0.5 mmol of olefin, 0.6 mmol of aldehyde, and 10 mol % Sc(OTf)3 in dichloromethane at room temperature.
b All products were characterized by 1H and 13C NMR, IR, and mass spectroscopy. c Yield refers to pure product after column chromatography.
d Yield of major regioisomer (regioisomeric ratio = 3:1).
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Scheme 2. Plausible Reaction Pathway for Prins/FriedelꢀCrafts Cyclization
As expected, coupling of (Z)-6-phenylhex-3-ene-1-thiol with
2-fluorobenzaldehyde under similar conditions afforded the
corresponding cis-fused hexahydro-1H-benzo[f]isothiochromene
7b exclusively in 84% yield (Table 4, entry b). The scope of the
reaction with other aldehydes like thiophene-2-carbaldehyde and
cinnamaldehyde is illustrated in Table 4 (entries cꢀf). Similarly,
other aryl-tethered homoallylic mercaptans such as (E)- and (Z)-
6-(3-methoxyphenyl)hex-3-ene-1-thiol and (E)- and (Z)-6-p-
tolylhex-3-ene-1-thiol also underwent smooth intramolecular
thia-Prins/FriedelꢀCrafts cyclization with different aldehydes
such as naphthalene-2-carbaldehyde, n-butyraldehyde, and 2-ni-
trobenzaldehyde to afford the respective trans/cis-fused hexahy-
dro-1H-benzo[f]isothiochromenes 7 (entries gꢀl, Table 4). In
the case of 6-(3-methoxyphenyl)hex-3-ene-1-thiol, the product
was obtained as a 3:1 mixture (determined by 1H NMR spectra of
the crude product) of para/ortho-substituted products (entries
gꢀj, Table 4). These two regioisomers could easily be separated
by silica gel column chromatography.
Besides aldehydes, we found that epoxides are also equally
effective in Prins- and aza-Prins/FriedelꢀCrafts cyclizations in
the presence of an acid catalyst. It is well known that epoxides
undergo a facile rearrangement to aldehydes or ketones in the
presence of an acid catalyst.23,41 In the present study, styrene oxide
underwent smooth rearrangement when exposed to 10 mol %
Sc(OTf)3 to give the phenylacetaldehyde, which subsequently
reacted with (Z)-4-methyl-N-(6-phenylhex-3-enyl)benzenesulfon-
amide (4) at ambient temperature to furnish the cis-fused N-tosyl-
octahydrobenzo[f]isoquinoline 8d as a sole product in 70% yield
(entry g, Table 5). However, the product 8d was obtained in 78%
yield when the reaction was performed with phenylacetaldehyde
directly at 80 °C (entry h, Table 5). The above experiments
proved that phenylacetaldehyde is a superior substrate to styrene
oxide. Other homoallylic substrates such as (E)-4-methyl-N-
(6-p-tolylhex-3-enyl)benzenesulfonamide, (Z)-6-phenylhex-3-
en-1-ol, and (E)-6-(3-methoxyphenyl)hex-3-en-1-ol were trea-
ted with both styrene oxide and phenylacetaldehyde, and the
results are summarized in Table 5.
dichloromethane, 1,2-dichloroethane, toluene, andtetrahydrofuran.
Among them, dichloromethane and 1,2-dichloroethane gave
the best results.
Mechanistically, the reaction is expected to proceed via
formation of oxocarbenium ion from hemiacetal which is formed
in situ from an aldehyde and a homoallylic alcohol, likely after activa-
tion through Sc(III). This is followed by attack of an internal olefin,
resulting in formation of carbocation, which is simultaneously
trapped by an aryl group, leading to formation of hexahydro-1H-
benzo[f]isochromene as depicted in Scheme 2.
’ CONCLUSION
In summary, we demonstrated a versatile approach for stereo-
selective synthesis of a novel class of heterotricycles in a single-
step operation. This is the first report on intramolecular aza- and
thia-Prins/FriedelꢀCrafts cyclizations. Our approach is highly
stereoselective to provide cis- and trans-fused tricyclic systems.
This method provides direct access to the synthesis of biologi-
cally active octahydrobenzo[f]isoquinolines which are reported
as potent σ receptors with regard to psychotomimetic effects.
These new products are under biological screening, in particular
for CNS activity. We found that the combination of Sc(OTf)3
and TsOH (cocatalysis) works more effectively than either Sc(OTf)3
or TsOH alone in terms of reaction time and yields.
’ EXPERIMENTAL SECTION
General. All solvents were dried according to standard literature
procedures. Reactions were performed in oven-dried round-bottom
flask, the flasks were fitted with rubber septa, and reactions were con-
ducted under a nitrogen atmosphere. Glass syringes were used to tran-
sfer solvent. Crude products were purified by column chromatography
on silica gel of 60ꢀ120 or 100ꢀ200 mesh. Thin layer chromatography
plates were visualized by exposure to ultraviolet light, exposure to iodine
vapors, and/or exposure to methanolic acidic solution of p-anisaldehyde
(anis) followed by heating (<1 min) on a hot plate (∼250 °C). Organic
solutions were concentrated on a rotary evaporator at 35ꢀ40 °C. IR spectra
Other Brønsted acids such as trifluoromethanesulfonic acid
(TfOH) and camphorsulfonic acid (CSA) as well as Lewis acids
such as In(OTf)3, La(OTf)3, and InBr3 were screened for this
conversion. Of these, the combination of Sc(OTf)3 and TsOH
(1:3) was found to give the best results in Prins/FriedelꢀCrafts
cyclization (Table 1), whereas Sc(OTf)3 gave excellent results in
aza-Prins and thia-Prins/FriedelꢀCrafts cyclizations (Table 6).
Next, we examined the effect of various solvents such as
1
were recorded on FT-IR spectrometer. H and 13C NMR (proton-
decoupled) spectra were recorded in CDCl3 solvent on a 200, 300, 400,
or 500 MHz NMR spectrometer. Chemical shifts (δ) were 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 the electrospray ionization (ESI) or
atmospheric pressure chemical ionization (APCI) technique.
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Table 5. Comparative Study of Prins- and Aza-Prins/FriedelꢀCrafts Cyclizations with Phenyl Acetaldehyde and Styrene Oxidea
a Reaction was performed with 0.5 mmol of olefin, 0.75 mmol of styrene oxide, or 0.6 mmol of phenylacetaldehyde and 10 mol % Sc(OTf)3 at room
temperature. b Isolated yield after column chromatography. c Reaction afforded a 3:1 ratio of para/ortho-substituted products; yield of major isomer.
d Reaction was performed at 80 °C.
Table 6. Catalyst Screening for Intramolecular Aza-Prins-
(1; 0.50 mmol) and aldehyde (0.60 mmol) in anhydrous dichloro-
methane (5 mL) was added Sc(OTf)3 (10 mol %) and p-TsOH (30 mol
%), and this was stirred at room temperature under a nitrogen atmo-
sphere for the specified time (Table 2). After completion of the reaction
as indicated by TLC, the mixture was quenched with saturated NaHCO3
solution (0.5 mL) and extracted with dichloromethane (2 ꢁ 5 mL). The
organic phases were combined, washed with brine (3 ꢁ 2 mL), dried
over anhydrous Na2SO4, and concentrated in vacuo. The resulting crude
product was purified by silica gel column chromatography (100ꢀ200 mesh)
using ethyl acetate/hexane gradients to afford pure product 3 (Table 2).
(4S*,4aS*,10bR*)-4-(4-Bromophenyl)-2,4,4a,5,6,10b-hex-
ahydro-1H-benzo[f]isochromene (3a; Table 2; Entry a). The
reaction afforded a 90:10 mixture of trans:cis-fused products. The two
isomers could be easily separated by silica gel column chromatography.
Crystals for XRD were obtained by dissolving the compound in 3 mL of
ethanol, followed by slow evaporation of solvent over 4 days. Yield, 158
and Thia-Prins/FriedelꢀCrafts Cyclizationsa
entry
X
R
catalyst
product time (h) yield (%)b
a
b
c
d
e
f
NTs cyclohexyl Sc(OTf)3
5a
7
76
70
50
55
58
80
86
75
In(OTf)3
La(OTf)3
TsOH
7
12
12
12
6
S
o-F-phenyl InBr3
In(OTf)3
7a
g
h
Sc(OTf)3
La(OTf)3
6
1
mg, 92%; white solid, mp 98ꢀ100 °C; H NMR (300 MHz, CDCl3)
6
δ 7.47, 7.44 (AA0, 2H), 7.21, 7.18 (BB0, 2H), 7.20ꢀ7.16 (m, 1H),
7.15ꢀ7.03 (m, 2H), 7.02ꢀ6.96 (m, 1H), 4.28 (ddd, J= 11.3, 4.5, and 1.5 Hz,
1H), 4.02 (d, J = 9.8 Hz, 1H), 3.77 (dt, J = 12.1 and 2.3 Hz, 1H),
2.83ꢀ2.61 (m, 3H), 2.41ꢀ2.30 (m, 1H), 1.85ꢀ1.68 (m, 1H), 1.64ꢀ
1.50 (m, 1H), 1.49ꢀ1.29 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 139.8,
138.7, 136.3, 131.4, 129.1, 128.9, 126.0, 125.8, 124.7, 121.6, 84.8, 68.5,
a Reaction was performed with 0.5 mmol of olefin, 0.6 mmol of aldehyde, and
10 mol % catalyst. b Yield refers to pure product after column chromatography.
Typical Procedure for Intramolecular Prins/Friedelꢀ
Crafts Cyclization. To a stirred solution of 6-arylhex-3-en-1-ol
7684
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The Journal of Organic Chemistry
ARTICLE
44.7, 41.4, 30.7, 28.6, 24.5; IR (KBr) νmax 2925, 2846, 1485, 1069, 820,
746 cmꢀ1; ESI-MS m/z 343 (M + H)+; HRMS (ESI) calcd for
C19H20BrO, 343.0692 (M + H)+; found, 343.0706.
6.63 (dd, J = 8.5 and 2.6 Hz, 1H), 6.55 (d, J = 2.6 Hz, 1H), 4.12 (ddd, J =
11.3, 4.5, and 1.5 Hz, 1H), 3.74 (s, 3H), 3.55 (dt, J = 12.3 and 2.3 Hz,
1H), 3.18ꢀ3.07 (m, 1H), 2.91ꢀ2.72 (m, 2H), 2.51ꢀ2.38 (m, 1H), 2.25ꢀ
2.13 (m, 1H), 1.98ꢀ1.80 (m, 2H), 1.65ꢀ1.48 (m, 1H), 1.47ꢀ1.12
(m, 4H), 0.98ꢀ0.85 (m, 6H); 13C NMR (75 MHz, CDCl3): δ 157.7,
137.7, 131.9, 125.6, 113.6, 111.5, 79.6, 67.8, 55.2, 44.2, 42.3, 40.7, 30.9,
29.2, 24.6, 24.2, 24.0, 21.5; IR (KBr) νmax 2950, 2834, 1609, 1502, 1462,
1238, 1094, 1037, 819 cmꢀ1; MS (APCI) m/z 275 (M + H)+; HRMS
(APCI) calcd for C18H27O2, 275.2006 (M + H)+; found, 275.2005.
(4R*,4aR*,10bR*)-4-Isobutyl-8-methoxy-2,4,4a,5,6,10b-
hexahydro-1H-benzo[f]isochromene (3h; Table 2; Entry h).
The reaction 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, 79 mg, 58%; viscous liquid;
1H NMR (300 MHz, CDCl3) δ 6.90 (d, J = 8.3 Hz, 1H), 6.61 (dd, J = 8.3
and 2.4 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 4.01ꢀ3.90 (m, 1H), 3.75
(s, 3H), 3.57ꢀ3.41 (m, 2H), 2.91ꢀ2.64 (m, 3H), 1.91ꢀ1.46 (m, 6H),
1.35ꢀ1.09 (m, 2H), 0.99ꢀ0.81 (m, 6H); 13C NMR (75 MHz, CDCl3):
δ 157.6, 137.3, 133.5, 129.5, 113.2, 112.2, 78.2, 68.6, 55.2, 42.0, 38.8,
37.9, 31.9, 29.7, 24.7, 23.2, 22.6, 16.8; IR (KBr) νmax 2949, 2865, 1610,
1500, 1461, 1266, 1090, 1040, 820 cmꢀ1; MS (APCI) m/z 275 (M + H)+;
HRMS (APCI) calcd for C18H27O2, 275.2006 (M + H)+; found, 275.2011.
Compound 3i (Table 2; Entry i). Reaction 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 regioi-
(4S*,4aR*,10bR*)-4-(4-Bromophenyl)-2,4,4a,5,6,10b-hex-
ahydro-1H-benzo[f]isochromene (3b; Table 2; Entry b). Yield,
1
151 mg, 88%; white solid, mp 117ꢀ119 °C; H NMR (500 MHz,
CDCl3) δ 7.45, 7.43 (AA0, 2H), 7.17, 7.15 (BB0, 2H), 7.10ꢀ6.95 (m,
4H), 4.62 (broad s, 1H), 4.22ꢀ4.15 (m, 1H), 3.76ꢀ3.67 (m, 1H), 3.10
(td, J = 11.7, 4.9 Hz, 1H), 2.81ꢀ2.71 (m, 1H), 2.66ꢀ2.55 (m, 1H),
2.11ꢀ2.01 (m, 1H), 1.95ꢀ1.83 (m, 1H), 1.82ꢀ1.72 (m, 1H),
1.71ꢀ1.64 (m, 1H), 1.31ꢀ1.19 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 140.6, 140.4, 135.9, 131.1, 129.0, 128.6, 127.3, 126.0, 125.7, 120.4,
81.0, 68.8, 39.5, 39.4, 31.3, 29.1, 16.6; IR (KBr) νmax 2942, 2843, 1487,
1093, 744 cmꢀ1; ESI-MS m/z 343 (M + H)+; HRMS (ESI) calcd for
C19H20BrO, 343.0692 (M + H)+; found, 343.0685.
(4R*,4aS*,10bR*)-4-Cyclohexyl-2,4,4a,5,6,10b-hexahydro-
1H-benzo[f]isochromene (3c; Table 2; Entry c). Yield, 116 mg,
86%; white solid, mp 88ꢀ90 °C; 1H NMR (300 MHz, CDCl3)
δ 7.20ꢀ6.96 (m, 4H), 4.15 (ddd, J = 11.3, 4.5, and 1.5 Hz, 1H), 3.55
(dt, J = 12.1 and 2.3 Hz, 1H), 3.01ꢀ2.93 (m, 1H), 2.90ꢀ2.76 (m, 2H),
2.57ꢀ2.44 (m, 1H), 2.27ꢀ2.16 (m, 1H), 1.96ꢀ1.40 (m, 10H), 1.39ꢀ
1.07 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 139.7, 136.3, 128.7, 125.9,
125.7, 124.7, 85.9, 68.3, 41.4, 39.9, 38.7, 31.0, 30.8, 28.9, 27.1, 26.8, 26.7,
25.1, 24.0; IR (KBr) νmax 2925, 2848, 1453, 1089, 741 cmꢀ1; ESI-MS
m/z 271 (M + H)+; HRMS (ESI) calcd for C19H27O, 271.2056
(M + H)+; found, 271.2060.
(4R*,4aR*,10bR*)-4-Cyclohexyl-2,4,4a,5,6,10b-hexahydro-
1H-benzo[f]isochromene (3d; Table 2; Entry d). Yield, 114 mg,
84%; white solid, mp 98ꢀ100 °C; 1H NMR (300 MHz, CDCl3)
δ 7.08ꢀ6.94 (m, 4H), 4.06ꢀ3.97 (m, 1H), 3.56ꢀ3.42 (m, 1H), 3.08ꢀ
2.99 (m, 1H), 2.95ꢀ2.69 (m, 3H), 2.21ꢀ2.08 (m, 1H), 1.99ꢀ1.44
(m, 10H), 1.36ꢀ1.07 (m, 3H), 0.98ꢀ0.76 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 141.3, 136.1, 129.0, 128.6, 125.8, 125.6, 84.7, 68.8, 39.6, 38.8,
34.6, 32.0, 30.7, 29.3, 27.9, 26.6, 26.0, 25.8, 16.8; IR (KBr) νmax 2925,
2840, 1443, 1093, 745 cmꢀ1; ESI-MS m/z 271 (M + H)+; HRMS (ESI)
calcd for C19H27O, 271.2056 (M + H)+; found, 271.2046.
1
somer, 81 mg, 56%; solid, mp 118ꢀ120 °C; H NMR (300 MHz,
CDCl3) δ 7.07 (d, J = 8.6 Hz, 1H), 6.63 (dd, J = 8.6 and 2.6 Hz, 1H), 6.52
(d, J = 2.6 Hz, 1H), 3.87ꢀ3.63 (m, 5H), 2.92ꢀ2.65 (m, 3H), 2.25ꢀ2.07
(m, 2H), 1.94ꢀ1.61 (m, 4H), 1.60ꢀ1.30 (m, 8H), 1.20ꢀ1.00 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 157.5, 137.7, 132.2, 126.6, 113.5, 111.8,
74.8, 60.2, 55.2, 48.6, 36.6, 34.9, 31.9, 30.6, 26.3, 24.7, 24.3, 21.3, 20.5; IR
(KBr) νmax 2933, 2853, 1502, 1234, 1092, 1035, 843 cmꢀ1; MS (APCI)
m/z 287 (M + H)+; HRMS (APCI) calcd for C19H27O2, 287.2006
(M + H)+; found, 287.1996.
Compound 3j (Table 2; Entry j). Reaction 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
(4S*,4aS*,10bR*)-4-(Thiophen-2-yl)-2,4,4a,5,6,10b-hexa-
hydro-1H-benzo[f]isochromene (3e; Table 2; Entry e). Yield,
1
regioisomer, 80 mg, 56%; semisolid; H NMR (300 MHz, CDCl3)
1
δ 6.90 (d, J = 8.3 Hz, 1H), 6.61 (dd, J = 8.3 and 2.4 Hz, 1H), 6.52 (broad
s, 1H), 3.82ꢀ3.59 (m, 5H), 3.17ꢀ3.04 (m, 1H), 2.91ꢀ2.63 (m, 2H),
2.39ꢀ2.20 (m, 1H), 1.95ꢀ1.18 (m, 14H); 13C NMR (75 MHz, CDCl3)
δ 157.5, 137.1, 133.6, 129.7, 113.0, 112.2, 73.5, 60.2, 55.1, 39.6, 35.8,
33.3, 31.6, 31.0, 29.8, 26.1, 21.7, 21.6, 17.1; IR (KBr) νmax 2929, 2854,
1501, 1267, 1086, 1042, 819 cmꢀ1;MS(APCI) m/z 287 (M + H)+; HRMS
(APCI) calcd for C19H27O2, 287.2006 (M + H)+; found, 287.2015.
(4S*,4aS*,10bR*)-9-Methyl-4-(4-nitrophenyl)-2,4,4a,5,6,10b-
hexahydro-1H-benzo[f]isochromene (3k; Table 2; Entry k).
Yield, 145 mg, 90%; white solid, mp 109ꢀ111 °C; 1H NMR (300 MHz,
CDCl3) δ 8.21, 8.18 (AA0, 2H), 7.50, 7.47 (BB0, 2H), 7.01 (m, 1H),
6.98ꢀ6.84 (m, 2H), 4.43ꢀ4.26 (m, 1H), 4.17 (d, J = 9.8 Hz, 1H), 3.88ꢀ
3.72 (m, 1H), 2.85ꢀ2.53 (m, 3H), 2.50ꢀ2.25 (m, 4H), 1.90ꢀ1.69
(m, 1H), 1.66ꢀ1.22 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 148.1,
147.5, 138.1, 135.3, 132.9, 128.9, 128.3, 126.9, 125.4, 123.5, 84.4, 68.6,
45.1, 41.3, 30.6, 28.2, 24.5, 21.2; IR (KBr) νmax 2919, 2842, 1518, 1346,
1083, 847 cmꢀ1; ESI-MS m/z 324 (M + H)+; HRMS (ESI) calcd for
C20H22NO3, 324.1594 (M + H)+; found, 324.1602.
(4S*,4aR*,10bR*)-9-Methyl-4-(4-nitrophenyl)-2,4,4a,5,6,10b-
hexahydro-1H-benzo[f]isochromene (3l; Table 2; Entry l).
Yield, 137 mg, 85%; white solid, mp 156ꢀ158 °C; 1H NMR (300 MHz,
CDCl3) δ 8.22, 8.19 (AA0, 2H), 7.48, 7.45 (BB0, 2H), 6.94ꢀ6.82 (m, 3H),
4.75 (d, J = 1.9 Hz, 1H), 4.28ꢀ4.18 (m, 1H), 3.80ꢀ3.67 (m, 1H),
3.14ꢀ3.00 (m, 1H), 2.80ꢀ2.65 (m, 1H), 2.63ꢀ2.45 (m, 1H), 2.30 (s, 3H),
2.19ꢀ2.06 (m, 1H), 1.99ꢀ1.64 (m, 3H), 1.17ꢀ1.03 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 149.1, 146.9, 140.1, 135.3, 132.5, 129.1, 128.9,
116 mg, 86%; solid, mp 64ꢀ66 °C; H NMR (300 MHz, CDCl3)
δ 7.31ꢀ7.20 (m, 2H), 7.19ꢀ6.93 (m, 5H), 4.42 (d, J = 9.8 Hz, 1H),
4.36ꢀ4.26 (m, 1H), 3.82 (dt, J = 12.1 and 2.3 Hz, 1H), 2.86ꢀ2.65
(m, 3H), 2.40ꢀ2.30 (m, 1H), 1.90ꢀ1.56 (m, 3H), 1.49ꢀ1.29 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 143.9, 138.7, 136.5, 128.9, 126.2, 126.0,
125.8, 125.6, 125.1, 124.7, 80.5, 68.6, 45.8, 41.5, 30.5, 28.7, 24.8; IR
(KBr) νmax 2919, 2844, 1091, 743, 702 cmꢀ1; MS (APCI) m/z 271
(M + H)+; HRMS (APCI) calcd for C17H19OS, 271.1157 (M + H)+;
found, 271.1150.
(4S*,4aR*,10bR*)-4-(Thiophen-2-yl)-2,4,4a,5,6,10b-hexa-
hydro-1H-benzo[f]isochromene (3f; Table 2; Entry f). Yield,
108 mg, 80%; semisolid; 1H NMR (300 MHz, CDCl3) δ 7.21ꢀ7.15 (m,
1H), 7.11ꢀ6.93 (m, 5H), 6.87ꢀ6.81 (m, 1H), 4.91 (broad s, 1H), 4.23ꢀ
4.13 (m, 1H), 3.82ꢀ3.69 (m, 1H), 3.13ꢀ3.01 (m, 1H), 2.89ꢀ2.62
(m, 2H), 2.22ꢀ2.11 (m, 1H), 2.04ꢀ1.76 (m, 2H), 1.73ꢀ1.62 (m, 1H),
1.61ꢀ1.49 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 144.8, 140.6, 136.1,
129.1, 128.6, 126.6, 126.1, 125.7, 123.5, 122.0, 79.3, 69.1, 40.3, 39.1, 31.3,
29.2, 17.0; IR (neat) νmax 2925, 2852, 1091, 702 cmꢀ1; MS (APCI)
m/z 271 (M + H)+; HRMS (APCI) calcd for C17H19OS, 271.1157
(M + H)+; found, 271.1164.
(4R*,4aS*,10bR*)-4-Isobutyl-8-methoxy-2,4,4a,5,6,10b-
hexahydro-1H-benzo[f]isochromene (3g; Table 2; Entry g).
The reaction 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, 82 mg, 60%; white solid,
mp 60ꢀ62 °C; 1H NMR (300 MHz, CDCl3) δ 7.05 (d, J = 8.5 Hz, 1H),
7685
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The Journal of Organic Chemistry
ARTICLE
127.1, 126.3, 123.3, 80.9, 68.8, 39.6, 39.4, 31.2, 28.6, 20.9, 16.9; IR (KBr)
νmax 2926, 2850, 1516, 1343, 1090, 710 cmꢀ1; ESI-MS m/z 324
(M + H)+; HRMS (ESI) calcd for C20H22NO3, 324.1594 (M + H)+;
found, 324.1588.
(4R*,4aS*,10bR*)-4-(4-Chlorophenyl)-3-tosyl-1,2,3,4,4a,5,6,-
10b-octahydrobenzo[f]isoquinoline (5c; Table 3; Entry c). Yield,
147 mg, 65%; solid, mp 110ꢀ112 °C; 1H NMR (500 MHz, CDCl3) δ
7.31ꢀ6.92 (m, 12H), 5.17 (d, J = 5.9 Hz, 1H), 4.13ꢀ4.06 (m, 1H), 3.41
(dt, J = 12.8 and 3.0 Hz, 1H), 2.96ꢀ2.80 (m, 2H), 2.79ꢀ2.64 (m, 1H),
2.59ꢀ2.51 (m, 1H), 2.35 (s, 3H), 2.13ꢀ2.04(m, 1H), 1.74ꢀ1.62 (m, 2H),
1.07ꢀ0.95 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 142.7, 137.7, 136.6,
136.3, 136.2, 133.4, 130.4, 129.2, 129.0, 128.0, 126.8, 126.1, 125.9, 60.8,
43.1, 42.8, 34.1, 30.9, 29.5, 26.6, 21.3; IR (KBr) νmax 2924, 1337, 1158,
1094 cmꢀ1; ESI-MS m/z 452 (M + H)+; HRMS (ESI) calcd for
C26H27NO2SCl, 452.1451 (M + H)+; found, 452.1459.
(4R*,4aR*,10bR*)-4-(4-Chlorophenyl)-3-tosyl-1,2,3,4,4a,5,6,-
10b-octahydrobenzo[f]isoquinoline (5d; Table 3; Entry d).
Yield, 153 mg, 68%; white solid, mp 122ꢀ124 °C; 1H NMR (300 MHz,
CDCl3) δ 7.71, 7.69 (AA0, 2H), 7.29ꢀ7.19 (m, 6H), 7.08ꢀ6.96
(m, 3H), 6.89ꢀ6.83 (m, 1H), 5.22 (broad s, 1H), 3.84ꢀ3.73
(m, 1H), 3.07 (dt, J = 13.6 and 3.0 Hz, 1H), 3.01ꢀ2.79 (m, 2H), 2.74
(td, J = 12.1 and 4.5 Hz, 1H), 2.64ꢀ2.53 (m, 1H), 2.44 (s, 3H),
1.98ꢀ1.58 (m, 3H), 1.57ꢀ1.45 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 143.1, 139.9, 138.4, 137.4, 135.3, 132.8, 129.6, 129.1, 128.8, 128.7,
128.5, 126.9, 126.3, 125.8, 60.7, 41.4, 36.6, 34.1, 30.0, 29.3, 23.7, 21.5; IR
(KBr) νmax 2925, 1491, 1342, 1156, 1092, 710 cmꢀ1; ESI-MS m/z 474
(M+Na)+; HRMS (ESI) calcd for C26H27NO2SCl, 452.1451 (M + H)+;
found, 452.1433.
(4S*,4aS*,10bR*)-4-Isobutyl-3-tosyl-1,2,3,4,4a,5,6,10b-
octahydrobenzo[f]isoquinoline (5e; Table 3; Entry e). Yield,
155 mg, 78%; solid, mp 125ꢀ127 °C; 1H NMR (500 MHz, CDCl3) δ
7.72, 7.70 (AA0, 2H), 7.23, 7.21 (BB0, 2H), 7.13ꢀ6.97 (m, 4H), 4.22ꢀ
4.15 (m, 1H), 3.92ꢀ3.84 (m, 1H), 3.27ꢀ3.17 (m, 1H), 2.84ꢀ2.69
(m, 3H), 2.38 (s, 3H), 2.17ꢀ2.08 (m, 1H), 1.80ꢀ1.40 (m, 5H), 1.25ꢀ
1.04 (m, 2H), 1.02ꢀ0.82 (m, 6H); 13C NMR (75 MHz, CDCl3)
δ 142.9, 138.8, 138.7, 136.5, 129.6, 129.1, 126.9, 125.8, 55.8, 42.0,
40.8, 35.4, 34.2, 30.1, 24.2, 24.1, 21.5, 21.4; IR (KBr) νmax 2925, 2864,
1336, 1156, 1092, 744 cmꢀ1; ESI-MS m/z 398 (M + H)+; HRMS (ESI)
calcd for C24H32NO2S, 398.2153 (M + H)+; found, 398.2145.
(4S*,4aR*,10bR*)-4-Isobutyl-3-tosyl-1,2,3,4,4a,5,6,10b-
octahydrobenzo[f]isoquinoline (5f; Table 3; Entry f). Crystals
for XRD were obtained by dissolving compound in 4 mL of ethanol,
followed by slow evaporation of solvent over 4 days. Yield, 159 mg, 80%;
white solid, mp 116ꢀ118 °C; 1H NMR (500 MHz, CDCl3) δ 7.70, 7.68
(AA0, 2H), 7.25, 7.23 (BB0, 2H), 7.09ꢀ6.96 (m, 4H), 4.03 (dt, J = 6.8
and 1.0 Hz, 1H), 3.72ꢀ3.64 (m, 1H), 3.06 (dt, J = 12.7 and 3.0 Hz, 1H),
2.95 (td, J = 11.7 and 4.9 Hz, 1H), 2.88ꢀ2.75 (m, 2H), 2.41 (s, 3H),
1.98ꢀ1.81 (m, 2H), 1.71ꢀ1.48 (m, 5H), 1.44ꢀ1.33 (m, 1H), 0.96ꢀ
0.85 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 142.7, 140.2, 138.6, 135.8,
129.4, 129.1, 128.9, 127.0, 126.1, 125.6, 56.8, 40.4, 39.0, 36.3, 33.9, 30.4,
29.3, 25.2, 23.7, 23.0, 22.3, 21.4; IR (KBr) νmax 2927, 2869, 1329, 1156,
1093, 744 cmꢀ1; ESI-MS m/z 420 (M+Na)+; HRMS (ESI) calcd for
C24H32NO2S, 398.2153 (M + H)+; found, 398.2140.
(4R*,4aS*,10bR,*E)-9-Methyl-4-styryl-2,4,4a,5,6,10b-hexahydro-
1H-benzo[f]isochromene (3m; Table 2; Entry m). Yield, 128 mg,
84%; solid, mp 100ꢀ102 °C; 1H NMR (300 MHz, CDCl3) δ 7.43ꢀ7.33
(m, 2H), 7.32ꢀ7.15 (m, 3H), 6.99 (s, 1H), 6.96ꢀ6.85 (m, 2H), 6.61 (d, J=
15.9 Hz, 1H), 6.17 (dd, J = 15.9 and 7.6 Hz, 1H), 4.28ꢀ4.18 (m, 1H),
3.79ꢀ3.64 (m, 2H), 2.85ꢀ2.73 (m, 2H), 2.65ꢀ2.51 (m, 1H), 2.35ꢀ2.23
(m, 4H), 1.98ꢀ1.86 (m, 1H), 1.76ꢀ1.58 (m, 1H), 1.52ꢀ1.31 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 138.7, 136.7, 135.1, 133.3, 133.1, 128.9,
128.6, 128.5, 127.7, 126.8, 126.5, 125.4, 83.4, 68.0, 43.7, 41.1, 30.6, 28.4,
24.9, 21.2; IR (KBr) νmax 2921, 2838, 1494, 1442, 1088, 967, 750, 693 cmꢀ1
;
MS (APCI) m/z 305 (M + H)+; HRMS (APCI) calcd for C22H25O,
305.1900 (M + H)+; found, 305.1905.
(4R*,4aR*,10bR,*E)-9-Methyl-4-styryl-2,4,4a,5,6,10b-hexa-
hydro-1H-benzo[f]isochromene (3n; Table 2; Entry n). Yield,
1
131 mg, 86%; white solid, mp 112ꢀ114 °C; H NMR (300 MHz,
CDCl3) δ 7.40ꢀ7.32 (m, 2H), 7.31ꢀ7.23 (m, 2H), 7.21ꢀ7.14 (m, 1H),
6.95ꢀ6.80 (m, 3H), 6.60 (dd, J = 15.9 and 1.5 Hz, 1H), 6.19 (dd, J = 15.9
and 5.2 Hz, 1H), 4.28ꢀ4.22 (m, 1H), 4.16ꢀ4.07 (m, 1H), 3.71ꢀ3.59
(m, 1H), 2.98ꢀ2.61 (m, 3H), 2.29 (s, 3H), 2.00ꢀ1.73 (m, 4H), 1.69ꢀ
1.57 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 140.6, 137.0, 135.1,
132.9, 129.7, 129.2, 129.1, 128.9, 128.5, 127.3, 126.9, 126.3, 80.2, 68.5,
39.1, 38.9, 31.5, 28.9, 21.0, 17.5; IR (KBr) νmax 2925, 2848, 1493, 1441,
1142, 1089, 974, 813, 751, 694 cmꢀ1; MS (APCI) m/z 305 (M + H)+;
HRMS (APCI) calcd for C22H25O, 305.1900 (M + H)+; found,
305.1917.
Typical Procedure for Intramolecular Aza-Prins/Friedelꢀ
Crafts Cyclization. To a stirred solution of 4-methyl-N-(6-arylhex-3-
enyl)benzenesulfonamide (4; 0.50 mmol) and aldehyde (0.60 mmol) in
anhydrous 1,2-dichloroethane (4 mL) was added Sc(OTf)3 (10 mol %),
and this was heated at 80 °C under a nitrogen atmosphere for the
specified time (Table 3). After completion of the reaction as indicated by
TLC, the mixture was quenched with saturated NaHCO3 solution
(0.5 mL) and extracted with dichloromethane (2 ꢁ 5 mL). The organic
phases were combined, washed with brine (3 ꢁ 2 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The resulting crude pro-
duct was purified by silica gel column chromatography (60ꢀ120 mesh)
using ethyl acetate/hexane gradients to afford pure product 5 (Table 3).
(4S*,4aS*,10bR*)-4-Cyclohexyl-3-tosyl-1,2,3,4,4a,5,6,10b-
octahydrobenzo[f]isoquinoline (5a; Table 3; Entry a). Yield,
1
161 mg, 76%; white solid, mp 124ꢀ126 °C; H NMR (200 MHz,
CDCl3) δ 7.73, 7.69 (AA0, 2H), 7.23, 7.19 (BB0, 2H), 7.18ꢀ6.95 (m, 4H),
4.06ꢀ3.84 (m, 2H), 3.30ꢀ3.09 (m, 1H), 3.01ꢀ2.48 (m, 3H), 2.36
(s, 3H), 2.18ꢀ2.02 (m, 1H), 2.01ꢀ1.43 (m, 10H), 1.36ꢀ0.92 (m, 5H);
13C NMR (75 MHz, CDCl3) δ 142.7, 139.1, 138.5, 136.4, 129.6, 129.1,
126.6, 126.4, 125.9, 125.8, 62.2, 44.1, 43.0, 36.5, 35.9, 33.4, 31.1, 30.8,
30.2, 27.7, 26.7, 26.5, 26.1, 21.4; IR (KBr) νmax 2925, 2853, 1334, 1157,
752 cmꢀ1; ESI-MS m/z 424 (M + H)+; HRMS (ESI) calcd for
C26H34NO2S, 424.2310 (M + H)+; found, 424.2291.
(4aS*,10bR*)-3-Tosyl-1,2,3,4,4a,5,6,10b-octahydrobenzo-
[f]isoquinoline (5g; Table 3, Entry g). Yield, 140 mg, 82%; solid,
mp 142ꢀ144 °C; 1H NMR (500 MHz, CDCl3) δ 7.66, 7.64 (AA0, 2H),
7.32, 7.30 (BB0, 2H), 7.14ꢀ6.99 (m, 4H), 4.03ꢀ3.96 (m, 1H), 3.86ꢀ
3.80 (m, 1H), 2.97ꢀ2.78 (m, 2H), 2.45 (s, 3H), 2.42ꢀ2.30 (m, 2H),
2.20ꢀ2.12 (m, 1H), 2.02 (t, J = 11.0 Hz, 1H), 1.87ꢀ1.56 (m, 3H),
1.45ꢀ1.34 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 143.4, 137.8, 136.3,
133.2, 129.6, 129.1, 127.6, 126.1, 125.8, 124.9, 52.0, 46.8, 41.5, 38.4, 29.4,
28.9, 26.7, 21.5; IR (KBr) νmax 2921, 2836, 1339, 1164, 1092, 925, 812,
754, 733, 656 cmꢀ1; ESI-MS m/z 342 (M + H)+; HRMS (ESI) calcd for
C20H24NO2S, 342.1528 (M + H)+; found, 342.1519.
(4S*,4aR*,10bR*)-4-Cyclohexyl-3-tosyl-1,2,3,4,4a,5,6,10b-
octahydrobenzo[f]isoquinoline (5b; Table 3; Entry b). Yield,
1
157 mg, 74%; white solid, mp 162ꢀ164 °C; H NMR (300 MHz,
CDCl3) δ 7.70, 7.67 (AA0, 2H), 7.23, 7.20 (BB0, 2H), 7.08ꢀ6.89
(m, 4H), 3.73ꢀ3.56 (m, 2H), 3.08ꢀ2.65 (m, 4H), 2.41 (s, 3H), 2.17ꢀ
2.04 (m, 1H), 1.92ꢀ1.41 (m, 10H), 1.32ꢀ0.92 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 142.4, 140.3, 139.0, 135.8, 129.2, 129.0, 128.8,
126.9, 126.0, 125.6, 64.2, 40.9, 36.1, 34.3, 33.4, 31.4, 29.9, 29.6, 29.5,
26.3, 26.2, 24.1, 21.4; IR (KBr) νmax 2928, 2847, 1321, 1151, 1089, 809,
739 cmꢀ1; ESI-MS m/z 424 (M + H)+; HRMS (ESI) calcd for
C26H34NO2S, 424.2310 (M + H)+; found, 424.2319.
(4aR*,10bR*)-3-Tosyl-1,2,3,4,4a,5,6,10b-octahydrobenzo-
[f]isoquinoline (5h; Table 3, Entry h). Yield, 136 mg, 80%; solid,
1
mp 167ꢀ169 °C; H NMR (500 MHz, CDCl3) δ 7.63, 7.61 (AA0,
2H), 7.31, 7.29 (BB0, 2H), 7.08ꢀ6.99 (m, 3H), 6.94ꢀ6.90 (m, 1H),
7686
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The Journal of Organic Chemistry
ARTICLE
3.75ꢀ3.70 (m, 1H), 3.69ꢀ3.64 (m, 1H), 2.94ꢀ2.79 (m, 2H), 2.63ꢀ2.52
(m, 2H), 2.45 (s, 3H), 2.35 (dt, J = 12.0 and 3.0 Hz, 1H), 2.25ꢀ2.14
(m, 1H), 2.07ꢀ1.99 (m, 1H), 1.97ꢀ1.87 (m, 1H), 1.81ꢀ1.72 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 143.3, 139.7, 135.8, 133.1, 129.5, 129.2,
128.5, 127.7, 126.1, 125.7, 51.4, 46.6, 37.8, 33.5, 30.7, 29.1, 22.4, 21.5; IR
(KBr) νmax 2926, 2856, 1336, 1159, 1093, 954, 719, 668 cmꢀ1; ESI-MS
m/z 342 (M + H)+; HRMS (ESI) calcd for C20H24NO2S, 342.1528
(M + H)+; found, 342.1540.
(4S*,4aS*,10bR*)-4-Ethyl-8-methoxy-3-tosyl-1,2,3,4,4a,5,6,-
10b-octahydrobenzo[f]isoquinoline (5i; Table 3; Entry i). Reac-
tion afforded a 2:1 mixture of para/ortho-substituted products. The two
regioisomers could be easily separated by silica gel column chromatogra-
phy. Yield of major regioisomer, 100 mg, 50%; solid, mp 119ꢀ121 °C; 1H
NMR (300 MHz, CDCl3) δ 7.74, 7.71 (AA0, 2H), 7.24, 7.21 (BB0, 2H),
7.06 (d, J = 8.7 Hz, 1H), 6.68 (dd, J = 8.7 and 2.6 Hz, 1H) 6.57 (d, J = 2.6
Hz, 1H), 4.08ꢀ3.98 (m, 1H), 3.97ꢀ3.85 (m, 1H), 3.75 (s, 3H), 3.23ꢀ3.09
(m, 1H), 2.81ꢀ2.58 (m, 3H), 2.38 (s, 3H), 2.17ꢀ2.05 (m, 1H), 1.74ꢀ1.38
(m, 5H), 1.19ꢀ1.02 (m, 1H), 0.96 (t, J= 7.3 Hz, 3H); 13C NMR(75 MHz,
CDCl3) δ 157.5, 142.8, 138.9, 137.7, 130.8, 129.6, 126.8, 113.6, 111.9, 59.3,
55.1, 42.3, 40.6, 34.8, 30.3, 26.6, 21.5, 17.9, 11.1; IR (KBr) νmax 2922, 2853,
1490, 1230, 752 cmꢀ1; ESI-MS m/z 400 (M + H)+; HRMS (ESI) calcd for
C23H30NO3S, 400.1946 (M + H)+; found, 400.1953.
1H), 3.79ꢀ3.65 (m, 4H), 3.13ꢀ2.97 (m, 1H), 2.96ꢀ2.84 (m, 1H),
2.83ꢀ2.69 (m, 2H), 2.68ꢀ2.48 (m, 2H), 2.42 (s, 3H), 1.96ꢀ1.74
(m, 4H), 1.68ꢀ1.46 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 157.8,
142.8, 141.5, 138.6, 137.0, 132.4, 129.8, 129.5, 128.4, 128.3, 126.9,
125.9, 113.3, 112.3, 58.6, 55.2, 40.4, 36.5, 33.4, 33.3, 32.3, 30.6,
29.7, 23.6, 21.5; IR (KBr) νmax 2940, 1607, 1501, 1320, 1152, 1098,
963, 921, 711, 670 cmꢀ1; ESI-MS m/z 476 (M + H)+; HRMS (ESI)
calcd for C29H34NO3S, 476.2259 (M + H)+; found, 476.2236.
(4R*,4aS*,10bR*)-4-(4-Bromophenyl)-9-methyl-3-tosyl-1,2,
3,4,4a,5,6,10b-octahydrobenzo[f]isoquinoline (5m; Table 3;
Entry m). Yield, 166 mg, 65%; white solid, mp 190ꢀ192 °C; 1H NMR
(300 MHz, CDCl3) δ 7.30ꢀ7.16 (m, 4H), 7.10ꢀ6.95 (m, 5H), 6.85
(s, 2H), 5.13 (d, J = 5.7 Hz, 1H), 4.17ꢀ4.04 (m, 1H), 3.39 (dt, J = 12.8
and 3.2 Hz, 1H), 2.92ꢀ2.72 (m, 2H), 2.71ꢀ2.48 (m, 2H), 2.36 (s, 3H),
2.27 (s, 3H), 2.13ꢀ1.98 (m, 1H), 1.75ꢀ1.56 (m, 2H), 1.06ꢀ0.82 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 142.7, 137.4, 137.1, 136.3, 135.4, 133.1,
131.0, 130.7, 129.1, 129.0, 127.0, 126.8, 126.6, 121.5, 61.0, 43.2, 42.8,
34.0, 31.0, 29.2, 26.7, 21.4, 21.1; IR (KBr) νmax 2921, 2858, 1334, 1154,
1106, 1001, 809, 583 cmꢀ1; ESI-MS m/z 510 (M + H)+; HRMS (ESI)
calcd for C27H29NO2SBr, 510.1102 (M + H)+; found, 510.1084.
(4R*,4aR*,10bR*)-4-(4-Bromophenyl)-9-methyl-3-tosyl-1,2,
3,4,4a,5,6,10b-octahydrobenzo[f]isoquinoline (5n; Table 3;
Entry n). Yield, 168 mg, 66%; white solid, mp 158ꢀ160 °C; 1H NMR
(4S*,4aR*,10bR*)-4-Ethyl-8-methoxy-3-tosyl-1,2,3,4,4a,5,6,
10b-octahydrobenzo[f]isoquinoline (5j; Table 3; Entry j).
Reaction afforded a 2:1 mixture of para/ortho-substituted products.
The two regioisomers could be easily separated by silica gel column
chromatography. Yield of major regioisomer, 96 mg, 48%; white
0
(300 MHz, CDCl3) δ 7.71, 7.690(AA0, 2H), 7.41, 7.38 (A1A1 , 2H), 7.26,
7.24 (BB0, 2H), 7.17, 7.14 (B1B1 , 2H), 6.95ꢀ6.80 (m, 2H), 6.67 (s, 1H),
5.19 (broad s, 1H), 3.86ꢀ3.72 (m, 1H), 3.13ꢀ2.97 (m, 1H), 2.96ꢀ2.62
(m, 3H), 2.61ꢀ2.50 (m, 1H), 2.44 (s, 3H), 2.21 (s, 3H), 1.96ꢀ1.43
(m, 4H); 13C NMR (75 MHz, CDCl3) δ 143.1, 139.7, 138.3, 138.0, 135.3,
132.1, 131.7, 129.5, 129.3, 128.9, 128.8, 127.2, 126.9, 120.9, 60.8, 41.5,
36.6, 34.1, 29.9, 28.9, 23.8, 21.5, 20.8; IR (KBr) νmax 2916, 2863, 1334,
1156, 1092, 947, 812, 546 cmꢀ1; ESI-MS m/z 510 (M + H)+; HRMS
(ESI) calcd for C27H29NO2SBr, 510.1102 (M + H)+; found, 510.1114.
(4S*,4aS*,10bR*,E)-9-Methyl-4-styryl-3-tosyl-1,2,3,4,4a,5,6,
10b-octahydrobenzo[f]isoquinoline (5o; Table 3; Entry o).
Yield, 169 mg, 74%; white solid, mp 190ꢀ192 °C; 1H NMR (500 MHz,
CDCl3) δ 7.62, 7.60 (AA0, 2H), 7.22, 7.20 (BB0, 2H), 7.19ꢀ7.13 (m, 1H),
7.11ꢀ7.03 (m, 4H), 6.94 (s, 1H), 6.90ꢀ6.83 (m, 2H), 6.46 (d, J = 15.8 Hz,
1H), 5.90 (dd, J = 15.8 and 7.9 Hz, 1H), 4.74ꢀ4.69 (m, 1H), 4.02ꢀ3.95
(m, 1H), 3.15 (dt, J = 12.8 and 3.0 Hz, 1H), 2.89ꢀ2.78 (m, 1H), 2.77ꢀ
2.69 (m, 1H), 2.66ꢀ2.57 (m, 1H), 2.44ꢀ2.36 (m, 1H), 2.27 (s, 6H),
1.95ꢀ1.86 (m, 1H), 1.79ꢀ1.72 (m, 1H), 1.64ꢀ1.52 (m, 1H), 1.51ꢀ
1.39 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 142.9, 137.8, 136.9, 136.3,
135.3, 134.8, 133.3, 129.3, 129.1, 128.3, 127.7, 127.5, 126.9, 126.3, 120.8,
60.5, 43.3, 42.1, 36.1, 31.0, 29.2, 26.7, 21.3, 21.1; IR (KBr) νmax 2923,
1337, 1155, 660 cmꢀ1; ESI-MS m/z 458 (M + H)+; HRMS (ESI) calcd
for C29H32NO2S, 458.2153 (M + H)+; found, 458.2144.
(4S*,4aR*,10bR*,E)-9-Methyl-4-styryl-3-tosyl-1,2,3,4,4a,5,6,
10b-octahydrobenzo[f]isoquinoline (5p; Table 3; Entry p).
Yield, 172 mg, 75%; white solid, mp 184ꢀ186 °C; 1H NMR (300 MHz,
CDCl3) δ 7.70, 7.68 (AA0, 2H), 7.33ꢀ7.16 (m, 5H), 7.11 (m, 2H), 7.04ꢀ
6.89 (m, 2H), 6.82 (s, 1H), 6.39 (d, J = 15.9 Hz, 1H), 6.04 (dd, J = 15.9
and 6.0 Hz, 1H), 4.72 (dd, J = 6.0 and 1.0 Hz, 1H), 3.89ꢀ3.77 (m, 1H),
3.12 (dt, J = 12.8 and 3.0 Hz, 1H), 2.98ꢀ2.74 (m, 3H), 2.34 (s, 3H), 2.26
(s, 3H), 2.19ꢀ2.01 (m, 2H), 1.93ꢀ1.65 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 142.9, 139.9, 137.6, 136.5, 135.2, 132.5, 129.4, 129.3, 129.0,
128.4, 127.6, 127.4, 127.2, 126.2, 126.0, 60.4, 41.4, 39.1, 34.4, 30.7, 28.8,
23.3, 21.4, 20.9; IR (KBr) νmax 2929, 2858, 1333, 1154, 1094, 974,
746, 677 cmꢀ1; ESI-MS m/z 458 (M + H)+; HRMS (ESI) calcd for
C29H32NO2S, 458.2153 (M + H)+; found, 458.2147.
1
solid, mp 110ꢀ112 °C; H NMR (300 MHz, CDCl3) δ 7.69, 7.66
(AA0, 2H), 7.25, 7.22 (BB0, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.59 (dd, J =
8.3 and 2.3 Hz, 1H) 6.50 (d, J = 2.3 Hz, 1H), 3.86 (dt, J = 7.6 and
1.0 Hz, 1H), 3.72 (s, 3H), 3.70ꢀ3.59 (m, 1H), 3.09ꢀ2.94 (m, 1H),
2.92ꢀ2.66 (m, 3H), 2.41 (s, 3H), 1.94ꢀ1.76 (m, 2H), 1.75ꢀ1.46
(m, 5H), 0.90 (t, J = 7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 157.7, 142.6, 138.7, 137.0, 132.5, 129.7, 129.4, 126.9, 113.3, 112.2,
60.4, 55.1, 40.3, 35.9, 33.2, 30.5, 29.7, 23.7, 23.0, 21.4, 11.4; IR (KBr)
νmax 2929, 2873, 1608, 1499, 1328, 1156, 1090, 755, 666 cmꢀ1; ESI-MS
m/z 400 (M + H)+; HRMS (ESI) calcd for C23H30NO3S, 400.1946
(M + H)+; found, 400.1950.
(4S*,4aS*,10bR*)-8-Methoxy-4-phenethyl-3-tosyl-1,2,3,4,
4a,5,6,10b-octahydrobenzo[f]isoquinoline (5k; Table 3;
Entry k). Reaction afforded a 2:1 mixture of para/ortho-substituted
products. The two regioisomers could be easily separated by silica
gel column chromatography. Yield of major regioisomer, 128 mg,
54%; solid, mp 112ꢀ114 °C; 1H NMR (500 MHz, CDCl3) δ 7.72,
7.70 (AA0, 2H), 7.26ꢀ7.18 (m, 4H), 7.17ꢀ7.08 (m, 3H), 6.95 (d, J =
8.9 Hz, 1H), 6.58 (dd, J = 8.9 and 3.0 Hz, 1H), 6.46 (d, J = 3.0 Hz,
1H), 4.17ꢀ4.09 (m, 1H), 3.99ꢀ3.91 (m, 1H), 3.70 (s, 3H),
3.26ꢀ3.16 (m, 1H), 2.76ꢀ2.52 (m, 5H), 2.38 (s, 3H), 2.13ꢀ2.04
(m, 1H), 1.93ꢀ1.81 (m, 1H), 1.74ꢀ1.58 (m, 2H), 1.54ꢀ1.39 (m, 2H),
1.16ꢀ1.05 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 157.5, 142.9,
142.1, 138.8, 137.6, 130.6, 129.7, 128.3, 126.8, 125.8, 113.6, 111.9,
57.7, 55.1, 42.1, 40.9, 34.8, 32.9, 30.3, 30.2, 27.5, 26.5, 21.4; IR (KBr)
νmax 2925, 2861, 1499, 1332, 1155, 754, 707 cmꢀ1; ESI-MS m/z 476
(M + H)+; HRMS (ESI) calcd for C29H34NO3S, 476.2259 (M + H)+;
found, 476.2269.
(4S*,4aR*,10bR*)-8-Methoxy-4-phenethyl-3-tosyl-1,2,3,4,
4a,5,6,10b-octahydrobenzo[f]isoquinoline (5l; Table 3;
Entry l). Reaction afforded a 2:1 mixture of para/ortho-substi-
tuted products. The two regioisomers could be easily separated by
silica gel column chromatography. Yield of major regioisomer, 124 mg,
Typical Procedure for Intramolecular Thia-Prins/Friedelꢀ
Crafts Cyclization. To a stirred solution of 6-arylhex-3-ene-1-thiol
(6; 0.50 mmol) and aldehyde (0.60 mmol) in anhydrous dichloro-
methane (5 mL) was added Sc(OTf)3 (10 mol %), and this was stirred at
room temperature under a nitrogen atmosphere for the specified time
1
52%; white solid, mp 128ꢀ130 °C; H NMR (300 MHz, CDCl3)
δ 7.67, 7.65 (AA0, 2H), 7.28ꢀ7.18 (m, 4H), 7.17ꢀ7.10 (m, 1H),
7.09ꢀ7.03 (m, 2H), 6.86 (d, J = 8.3 Hz, 1H), 6.60 (dd, J = 8.3 and
2.3 Hz, 1H), 6.50 (d, J = 2.3 Hz, 1H), 4.00 (dt, J = 7.6 and 0.9 Hz,
7687
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The Journal of Organic Chemistry
ARTICLE
(Table 4). After completion of the reaction as indicated by TLC, the
mixture was quenched with saturated NaHCO3 solution (0.5 mL) and
extracted with dichloromethane (2 ꢁ 5 mL). The organic phases were
combined, washed with brine (3 ꢁ 2 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The resulting crude product was
purified by silica gel column chromatography (100ꢀ200 mesh) using
ethyl acetate/hexane gradients to afford pure product 7 (Table 4).
1.62 (m, 2H), 1.46ꢀ1.26 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 138.9, 137.1, 136.6, 133.1, 129.0, 128.9, 128.5, 127.6, 126.3, 125.8,
50.3, 46.5, 43.2, 33.0, 29.8, 27.5,; IR (KBr) νmax 2922, 2853, 1489, 1445,
966, 740, 693 cmꢀ1; MS (APCI) m/z 307 (M + H)+; HRMS (APCI)
calcd for C21H23S, 307.1515 (M + H)+; found, 307.1510.
(4R*,4aR*,10bR*,E)-4-Styryl-2,4,4a,5,6,10b-hexahydro-1H-
benzo[f]isothiochromene (7f; Table 4; Entry f). Yield, 130 mg,
1
85%; solid, mp 84ꢀ86 °C; H NMR (300 MHz, CDCl3) δ 7.38ꢀ
(4S*,4aS*,10bR*)-4-(2-Fluorophenyl)-2,4,4a,5,6,10b-hexa-
hydro-1H-benzo[f]isothiochromene (7a; Table 4; Entry a).
Crystals for XRD were obtained by dissolving compound in 4 mL of
ethanol, followed by slow evaporation of solvent over 4 days. Yield, 128
mg, 86%; solid, mp 100ꢀ102 °C; 1H NMR (300 MHz, CDCl3) δ 7.42
(dt, J = 7.6 and 1.5 Hz, 1H), 7.31ꢀ7.16 (m, 2H), 7.15ꢀ6.95 (m, 5H),
4.16 (d, J = 10.6 Hz, 1H), 3.20ꢀ3.05 (m, 1H), 2.92ꢀ2.78 (m, 2H),
2.77ꢀ2.56 (m, 3H), 2.10ꢀ1.94 (m, 1H), 1.91ꢀ1.73 (m, 1H), 1.68ꢀ
1.55 (m, 1H), 1.42ꢀ1.27 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 160.5
(d, J = 245.9 Hz), 138.9, 137.0, 130.0 (d, J = 26.9 Hz), 129.0, 128.7 (d, J =
8.8 Hz), 125.9, 125.6, 124.6 (d, J = 3.3. Hz), 115.4 (d, J = 23.1 Hz), 46.5,
44.0, 33.1, 30.7, 29.6, 26.6; IR (KBr) νmax 2920, 2852, 1484, 1223, 1087,
751 cmꢀ1; MS (APCI) m/z 299 (M + H)+; HRMS (APCI) calcd for
C19H20FS, 299.1270 (M + H)+; found, 299.1275.
7.31 (m, 2H), 7.31ꢀ7.09 (m, 4H), 7.08ꢀ6.93 (m, 3H), 6.55 (d, J = 15.9
Hz, 1H), 6.22 (dd, J = 15.9 and 6.8 Hz, 1H), 3.89 (d, J = 6.8 Hz, 1H),
2.99ꢀ2.56 (m, 5H), 2.42ꢀ2.14 (m, 3H), 1.98ꢀ1.74 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 141.5, 136.8, 136.0, 131.8, 129.0, 128.9, 128.7, 128.5,
127.5, 126.3, 126.0, 125.6, 49.4, 42.2, 39.5, 31.4, 29.9, 29.1, 17.4; IR (neat) νmax
2923, 2853, 1492, 1449, 963, 745, 696 cmꢀ1;MS(APCI) m/z307 (M + H)+;
HRMS (APCI) calcd for C21H23S, 307.1515 (M + H)+; found, 307.1524.
(4S*,4aS*,10bR*)-8-Methoxy-4-(naphthalen-2-yl)-2,4,4a,5,
6,10b-hexahydro-1H-benzo[f]isothiochromene (7g; Table 4;
Entry g). Reaction 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, 106 mg, 59%;
1
solid, mp 125ꢀ127 °C; H NMR (500 MHz, CDCl3) δ 7.88ꢀ7.76
(m, 4H), 7.55ꢀ7.41 (m, 3H), 7.26 (d, J = 8.8 Hz, 1H), 6.75 (dd, J = 8.8
and 2.0 Hz, 1H), 6.58 (d, J = 2 Hz, 1H), 3.92 (d, J = 9.8 Hz, 1H), 3.76
(s, 3H), 3.20ꢀ3.11 (m, 1H), 2.90ꢀ2.79 (m, 2H), 2.76ꢀ2.56 (m, 3H),
2.20ꢀ2.09 (m, 1H), 1.91ꢀ1.78 (m, 1H), 1.67ꢀ1.57 (m, 1H), 1.37ꢀ
1.24 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 157.6, 138.4, 133.4,
132.9, 131.2, 128.4, 127.8, 127.6, 127.3, 126.8, 126.1, 126.0, 125.8, 113.5,
112.0, 55.2, 52.8, 46.9, 43.5, 33.4, 30.8, 30.0, 27.0; IR (KBr) νmax 2924,
2855, 1498, 1240, 1034, 783 cmꢀ1; MS (APCI) m/z 361 (M + H)+;
HRMS (APCI) calcd for C24H25OS, 361.1621 (M + H)+; found,
361.1630.
(4S*,4aR*,10bR*)-4-(2-Fluorophenyl)-2,4,4a,5,6,10b-hexa-
hydro-1H-benzo[f]isothiochromene (7b; Table 4; Entry b).
Yield, 125 mg, 84%; solid, mp 94ꢀ96 °C; 1H NMR (500 MHz, CDCl3)
δ 7.38ꢀ7.32 (m, 1H), 7.30ꢀ6.99 (m, 7H), 4.72 (d, J = 2.0 Hz, 1H), 3.05
(dt, J = 13.1 and 3.0 Hz, 1H), 2.99ꢀ2.92 (m, 1H), 2.89ꢀ2.76 (m, 2H),
2.70ꢀ2.59 (m, 1H), 2.40ꢀ2.31 (m, 1H), 2.31ꢀ2.21 (m, 1H), 2.04ꢀ
1.97 (m, 1H), 1.96ꢀ1.85 (m, 1H), 1.48ꢀ1.41 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 159.6 (d, J = 245.9 Hz), 141.4, 135.9, 130.5 (d, J =
18.1 Hz), 129.9 (d, J = 3.8 Hz), 129.0, 128.8, 126.0, 125.6, 123.7 (d, J =
3.3. Hz), 115.3 (d, J = 22.0 Hz), 44.9, 42.5, 38.9, 31.4, 30.5, 29.0,16.9; IR
(KBr) νmax 2923, 2855, 1489, 1453, 1228, 759 cmꢀ1; MS (APCI) m/z
299 (M + H)+; HRMS (APCI) calcd for C19H20FS, 299.1270 (M + H)+;
found, 299.1259.
(4S*,4aR*,10bR*)-8-Methoxy-4-(naphthalen-2-yl)-2,4,4a,
5,6,10b-hexahydro-1H-benzo[f]isothiochromene (7h; Table 4;
Entry h). Reaction 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, 108 mg, 60%;
(4S*,4aS*,10bR*)-4-(Thiophen-2-yl)-2,4,4a,5,6,10b-hexa-
hydro-1H-benzo[f]isothiochromene (7c; Table 4; Entry c).
1
solid, mp 142ꢀ144 °C; H NMR (500 MHz, CDCl3) δ 7.82ꢀ7.73
1
Yield, 115 mg, 80%; solid, mp 100ꢀ102 °C; H NMR (500 MHz,
(m, 3H), 7.69 (s, 1H), 7.47ꢀ7.35 (m, 3H), 6.93 (d, J = 7.9 Hz, 1H), 6.63
(dd, J = 7.9 and 2.0 Hz, 1H), 6.49 (d, J = 2 Hz, 1H), 4.45 (d, J = 3.0 Hz,
1H), 3.72 (s, 3H), 2.98 (dt, J = 12.8 and 3.0 Hz, 1H), 2.91ꢀ2.84
(m, 1H), 2.83ꢀ2.73 (m, 2H), 2.62ꢀ2.51 (m, 1H), 2.40ꢀ2.33 (m, 1H),
2.28ꢀ2.17 (m, 1H), 2.02ꢀ1.82 (m, 2H), 1.51ꢀ1.41 (m, 1H); 13C NMR
(75 MHz, CDCl3): δ 157.8, 138.7, 137.2, 133.9, 133.2, 132.4, 129.6,
127.9, 127.8, 127.5, 126.5, 126.2, 126.1, 125.7, 113.2, 112.2, 55.2, 52.3,
42.3, 41.3, 31.7, 30.4, 29.4, 16.6; IR (KBr) νmax 2932, 2845, 1497, 1226,
1156, 1034, 818, 755 cmꢀ1; MS (APCI) m/z 361 (M + H)+; HRMS
(APCI) calcd for C24H25OS, 361.1621 (M + H)+; found, 361.1612.
(4R*,4aS*,10bR*)-8-Methoxy-4-propyl-2,4,4a,5,6,10b-
hexahydro-1H-benzo[f]isothiochromene (7i; Table 4; Entry i).
Reaction afforded a 3:1 mixture of para/ortho-substituted products. The
two regioisomers could be easily separated by silica gel column chroma-
tography. Yield of major regioisomer, 81 mg, 59%; viscous liquid; 1H NMR
(300 MHz, CDCl3) δ 7.18 (d, J = 9.1 Hz, 1H), 6.72 (dd, J = 9.1 and 3.0 Hz,
1H), 6.61 (d, J = 3.0 Hz, 1H), 3.83ꢀ3.75 (m, 4H), 3.01ꢀ2.87 (m, 1H),
2.85ꢀ2.65 (m, 4H), 2.47ꢀ2.34 (m, 1H), 2.26ꢀ2.14 (m, 1H), 1.91ꢀ1.76
(m, 1H), 1.72ꢀ1.23 (m, 6H) 0.94 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 157.4, 138.2, 131.7, 126.9, 113.3, 111.8, 55.1, 47.2, 46.7, 43.3,
34.6, 33.6, 30.1, 29.1, 25.9, 19.6, 14.2; IR (neat) νmax 2925, 2865, 1610,
1501, 1459, 1254, 1043, 777 cmꢀ1;MS(APCI) m/z 277 (M + H)+; HRMS
(APCI) calcd for C17H25OS, 277.1621 (M + H)+; found, 277.1627.
(4R*,4aR*,10bR*)-8-Methoxy-4-propyl-2,4,4a,5,6,10b-
hexahydro-1H-benzo[f]isothiochromene (7j; Table 4; Entry j).
Reaction afforded a 3:1 mixture of para/ortho-substituted products. The
two regioisomers could be easily separated by silica gel column
CDCl3) δ 7.25 (d, J = 7.7 Hz, 1H), 7.18 (d, J = 5.1 Hz, 1H), 7.14ꢀ7.03
(m, 2H), 6.99 (d, J = 7.7 Hz, 1H), 6.96 (d, J = 3.4 Hz, 1H), 6.93ꢀ6.88
(m, 1H), 4.06 (d, J = 10.2 Hz, 1H), 3.12ꢀ3.03 (m, 1H), 2.88ꢀ2.65 (m,
4H), 2.61ꢀ2.52 (m, 1H), 2.00ꢀ1.90 (m, 1H), 1.88ꢀ1.76 (m, 2H),
1.33ꢀ1.20 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 144.2, 138.7, 137.0,
128.9, 126.4, 125.8, 125.7, 125.6, 124.5, 49.0, 47.3, 44.0, 32.9, 30.8, 29.7,
26.8; IR (KBr) νmax 2905, 2852, 743, 695 cmꢀ1; MS (APCI) m/z 287
(M + H)+; HRMS (APCI) calcd for C17H19S2, 287.0928 (M + H)+;
found, 287.0917.
(4S*,4aR*,10bR*)-4-(Thiophen-2-yl)-2,4,4a,5,6,10b-hexa-
hydro-1H-benzo[f]isothiochromene (7d; Table 4; Entry d).
1
Yield, 117 mg, 82%; solid, mp 105ꢀ107 °C; H NMR (500 MHz,
CDCl3) δ 7.15 (d, J = 4.6 Hz, 1H), 7.09ꢀ6.96 (m, 4H), 6.95ꢀ6.88 (m,
2H), 4.52 (d, J = 2.7 Hz, 1H), 2.98 (dt, J = 12.8 and 3.6 Hz, 1H),
2.92ꢀ2.82 (m, 2H), 2.81ꢀ2.68 (m, 2H), 2.45ꢀ2.36 (m, 1H), 2.29ꢀ
2.16(m, 1H), 2.01ꢀ1.85 (m, 2H), 171ꢀ1.62(m, 1H);13CNMR(75MHz,
CDCl3) δ 144.1, 141.3, 136.0, 129.0, 128.7, 126.6, 126.1, 125.6, 124.5,
123.8, 47.2, 42.4, 41.3, 31.4, 30.7, 29.0, 17.3; IR (KBr) νmax 2925, 2855,
1224, 1034, 698 cmꢀ1; MS (APCI) m/z 287 (M + H)+; HRMS (APCI)
calcd for C17H19S2, 287.0928 (M + H)+; found, 287.0929.
(4R*,4aS*,10bR*,E)-4-Styryl-2,4,4a,5,6,10b-hexahydro-1H-
benzo[f]isothiochromene (7e; Table 4; Entry e). Yield, 135 mg,
88%; solid, mp 96ꢀ98 °C; 1H NMR (300 MHz, CDCl3) δ 7.45ꢀ7.02
(m, 9H), 6.62 (d, J = 15.8 Hz, 1H), 6.10 (dd, J = 15.8 and 9.8 Hz, 1H),
3.49 (t, J = 9.8 Hz, 1H), 3.17ꢀ3.04 (m, 1H), 2.89ꢀ2.62 (m, 3H),
2.59ꢀ2.46 (m, 1H), 2.44ꢀ2.21 (m, 1H), 2.20ꢀ2.07 (m, 1H), 1.85ꢀ
7688
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The Journal of Organic Chemistry
ARTICLE
chromatography. Yield of major regioisomer, 80 mg, 58%; viscous liquid; 1H
NMR (500 MHz, CDCl3) δ 6.86 (d, J = 7.9 Hz, 1H), 6.60 (dd, J = 7.9 and
2.0 Hz, 1H), 6.53 (d, J = 2.0 Hz, 1H), 3.73 (s, 3H), 3.03ꢀ2.95 (m, 1H),
2.93ꢀ2.70 (m, 3H), 2.62ꢀ2.52 (m, 2H), 2.20ꢀ2.07 (m, 1H), 2.06ꢀ1.98
(m, 1H), 1.90ꢀ1.71 (m, 2H) 1.69ꢀ1.61 (m, 1H), 1.60ꢀ1.38 (m, 4H),
0.95 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 157.6, 137.3, 134.3,
129.6, 113.2, 112.0, 55.1, 47.0, 41.9, 38.5, 35.3, 32.2, 29.9, 29.4, 20.4, 16.6,
13.0; IR (neat) νmax 2925, 2860, 1608, 1499, 1460, 1263, 1153, 1043,
776 cmꢀ1; MS (APCI) m/z 277 (M + H)+; HRMS (APCI) calcd for
C17H25OS, 277.1621 (M + H)+; found, 277.1618.
(4R*,4aR*,10bR*)-4-Benzyl-2,4,4a,5,6,10b-hexahydro-1H-
benzo[f]isochromene (8b; Table 5; Entry b). Yield, 117 mg, 84%;
1
viscous liquid; H NMR (500 MHz, CDCl3) δ 7.37ꢀ7.17 (m, 5H),
7.14ꢀ7.00 (m, 4H), 4.06ꢀ3.99 (m, 1H), 3.79ꢀ3.72 (m, 1H), 3.60ꢀ
3.51 (m, 1H), 3.02ꢀ2.89 (m, 2H), 2.88ꢀ2.82 (m, 1H), 2.82ꢀ2.72
(m, 2H), 2.04ꢀ1.92 (m, 2H), 1.91ꢀ1.75 (m, 2H), 1.65ꢀ1.54 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 141.0, 139.2, 136.0, 129.1, 128.9, 128.5,
128.3, 126.1, 125.9, 125.6, 81.3, 68.8, 39.6, 39.2, 36.9, 31.6, 29.1, 16.9;
IR (KBr) νmax 2941, 2844, 1088, 749, 700 cmꢀ1; MS (APCI) m/z 279
(M + H)+; HRMS (APCI) calcd for C20H23O, 279.1743 (M + H)+;
found, 279.1735.
(4S*,4aS*,10bR*)-9-Methyl-4-(2-nitrophenyl)-2,4,4a,5,6,10b-
hexahydro-1H-benzo[f]isothiochromene (7k; Table 4; Entry k).
Yield, 156 mg, 92%; solid, mp 150ꢀ152 °C; 1H NMR (500 MHz, CDCl3)
δ 7.77 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.62ꢀ7.56 (m, 1H),
7.42ꢀ7.37 (m, 1H), 7.14 (s, 1H), 6.98ꢀ6.92 (m, 2H), 4.43 (d, J = 10.9 Hz,
1H), 3.19ꢀ3.09 (m, 1H), 2.93ꢀ2.82 (m, 2H), 2.72ꢀ2.60 (m, 3H), 2.32
(s, 3H), 2.13ꢀ2.02 (m, 1H), 1.88ꢀ1.76 (m, 1H), 1.55ꢀ1.47 (m, 1H),
1.46ꢀ1.35 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 150.2, 138.3, 135.3,
133.6, 132.9, 129.5, 128.9, 128.0, 126.8, 126.3, 124.0, 47.4, 45.3, 43.8, 33.2,
(4S*,4aS*,10bR*)-4-Benzyl-9-methyl-3-tosyl-1,2,3,4,4a,5,
6,10b-octahydrobenzo[f]isoquinoline (8c; Table 5; Entry c).
Yield, 178 mg, 80%; white solid, mp 182ꢀ184 °C; 1H NMR (300 MHz,
CDCl3) δ 7.29ꢀ7.09 (m, 7H), 7.06ꢀ6.95 (m, 3H), 6.94ꢀ6.83 (m, 2H),
4.61ꢀ4.48 (m, 1H), 3.75ꢀ3.62 (m, 1H), 3.29ꢀ3.13 (m, 1H), 2.97ꢀ
2.68 (m, 5H), 2.34 (s, 3H), 2.32ꢀ2.23 (m, 4H), 2.00ꢀ1.86 (m, 1H),
1.85ꢀ1.73 (m, 1H), 1.66ꢀ1.45 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 142.5, 138.8, 138.3, 137.7, 135.3, 133.3, 129.3, 129.2, 129.1, 128.4,
127.1, 126.8, 126.5, 126.2, 59.0, 43.1, 40.9, 35.6, 32.0, 30.5, 29.7, 27.1,
30.9, 29.2, 26.8, 21.3; IR (KBr) νmax 2925, 2846, 1532, 1342, 801, 742 cmꢀ1
;
21.4, 21.2; IR (KBr) νmax 2928, 2871, 1316, 1151, 1011, 749, 703 cmꢀ1
;
MS (APCI) m/z 340 (M + H)+; HRMS (APCI) calcd for C20H22NO2S,
ESI-MS m/z 446 (M + H)+; HRMS (ESI) calcd for C28H32NO2S,
340.1366 (M + H)+; found, 340.1357.
446.2153 (M + H)+; found, 446.2133.
(4S*,4aR*,10bR*)-9-Methyl-4-(2-nitrophenyl)-2,4,4a,5,6,10b-
hexahydro-1H-benzo[f]isothiochromene (7l; Table 4; Entry l).
Yield, 153 mg, 90%; solid, mp 130ꢀ132 °C; 1H NMR (500 MHz, CDCl3)
δ 7.89 (d, J = 8.2 Hz, 1H), 7.60ꢀ7.54 (m, 2H), 7.44ꢀ7.37 (m, 1H),
6.90ꢀ6.81 (m, 3H), 4.89 (d, J = 2.7 Hz, 1H), 3.01 (dt, J = 12.8 and 2.7 Hz,
1H), 2.93ꢀ2.86 (m, 1H), 2.85ꢀ2.73 (m, 2H), 2.68ꢀ2.55 (m, 1H), 2.48ꢀ
2.39 (m, 1H), 2.36ꢀ2.24 (m, 4H), 2.06ꢀ1.95 (m, 1H), 1.95ꢀ1.83 (m, 1H),
1.51ꢀ1.42 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 147.9, 138.7, 135.8,
135.2, 133.1, 132.4, 130.8, 130.5, 128.9, 128.3, 127.5, 124.3, 47.0, 42.5, 38.9,
35.3, 32.6, 29.3, 27.1, 21.0; IR (KBr) νmax 2919, 2847, 1523, 1340, 794,
747 cmꢀ1; MS (APCI) m/z 340 (M + H)+; HRMS (APCI) calcd for
C20H22NO2S, 340.1366 (M + H)+; found, 340.1382.
(4S*,4aR*,10bR*)-4-Benzyl-3-tosyl-1,2,3,4,4a,5,6,10b-
octahydrobenzo[f]isoquinoline (8d; Table 5; Entry d). Yield,
1
168 mg, 78%; white solid, mp 150ꢀ152 °C; H NMR (300 MHz,
CDCl3) δ 7.53, 7.50 (AA0, 2H), 7.29ꢀ7.10 (m, 7H), 7.09ꢀ6.93 (m, 4H),
4.28ꢀ4.18 (m, 1H), 3.73ꢀ3.61 (m, 1H), 3.23ꢀ2.93 (m, 3H), 2.89ꢀ
2.63 (m, 3H), 2.40 (s, 3H), 2.10ꢀ1.57 (m, 4H), 1.55ꢀ1.44 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 142.9, 140.1, 138.5, 138.2, 135.9, 129.5,
129.2, 129.1, 128.9, 128.6, 127.0, 126.4, 126.2, 125.7, 60.2, 40.6, 36.3,
34.2, 33.9, 30.5, 29.1, 23.5, 21.4; IR (KBr) νmax 2926, 1312, 1150, 1092,
952, 751, 694 cmꢀ1; ESI-MS m/z 449 (M+NH4)+; HRMS (ESI) calcd
for C27H30NO2S, 432.1997 (M + H)+; found, 432.1996.
Typical Procedure for Intramolecular Prins- and Aza-Prins/
FriedelꢀCrafts Cyclization with Styrene Oxide. To a stirred
solution of homoallylic substrate (0.50 mmol) and styrene oxide (0.75 mmol)
in anhydrous dichloroethane (5 mL) was added Sc(OTf)3 (10 mol %)
and stirred at room temperature under nitrogen atmosphere for the
specified time (Table 5). After completion of the reaction as indicated
by TLC, the mixture was quenched with saturated NaHCO3 solution
(0.5 mL) and extracted with dichloromethane (2 ꢁ 5 mL). The organic
phases were combined, washed with brine (3 ꢁ 2 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The resulting crude
product was purified by silica gel column chromatography using ethyl
acetate/hexane gradients to afford pure product 8 (Table 5). (Yields are
reported with respect to phenyl acetaldehyde since it afforded higher
yield than styrene oxide).
’ ASSOCIATED CONTENT
Supporting Information. 1Hand13CNMRspectraofpro-
S
b
ducts (3aꢀn, 5aꢀp, 7aꢀl, and 8aꢀd), preparation of starting
materials, and X-ray data of compounds (3a, 5f, and 7a) are pro-
vided in the CIF file. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Authors
*Fax: 0091-40-27160512. E-mail:basireddy@iict.res.in; yadavpub@
iict.res.in.
(4R*,4aS*,10bR*)-4-Benzyl-8-methoxy-2,4,4a,5,6,10b-
hexahydro-1H-benzo[f]isochromene (8a; Table 5; Entry a).
Reaction 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, 94 mg, 61%; white solid,
mp 148ꢀ150 °C; 1H NMR (300 MHz, CDCl3) δ 7.32ꢀ7.09 (m, 5H),
7.04 (d, J = 8.5 Hz, 1H), 6.63 (dd, J = 8.5 and 2.5 Hz, 1H), 6.55 (d, J =
2.5 Hz, 1H), 4.16ꢀ4.04 (m, 1H), 3.74 (s, 3H), 3.58ꢀ3.44 (m, 1H),
3.43ꢀ3.31 (m, 1H), 3.06 (dd, J = 14.3 and 2.3 Hz, 1H), 2.89ꢀ2.78 (m,
2H), 2.74ꢀ2.61 (m, 1H), 2.55ꢀ2.40 (m, 1H), 2.24ꢀ1.99 (m, 2H),
1.65ꢀ1.20 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 157.7, 139,3, 137.6,
131.7, 129.4, 128.1, 125.9, 125.6, 113.5, 111.5, 82.2, 67.9, 55.2, 43.2, 40.6,
39.3, 30.7, 29.1, 24.9; IR (KBr) νmax 2920, 2834, 1605, 1498, 1453, 1236,
1127, 1095, 1026, 743, 697 cmꢀ1; MS (APCI) m/z 309 (M + H)+;
HRMS (APCI) calcd for C21H25O2, 309.1849 (M + H)+; found,
309.1858.
’ ACKNOWLEDGMENT
This research was performed as part of the Indo-French “Joint
Laboratory for Sustainable Chemistry at Interfaces”. We thank
CSIR and CNRS for support. P.B. thanks CSIR, New Delhi for
the award of a fellowship.
’ DEDICATION
Dedicated to Prof. E. J. Corey on the occasion of his 82nd
birthday
’ REFERENCES
(1) Prins, H. J. Chem. Weekbl. 1919, 16, 1072.
(2) Prins, H. J. Chem. Weekbl. 1919, 16, 1510.
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The Journal of Organic Chemistry
ARTICLE
(3) Adams, D. R.; Bhatnagar, S. R. Synthesis 1977, 661–672.
(4) Arundale, E.; Mikeska, L. A. Chem. Rev. 1952, 51, 505–555.
(5) Reviews on Prins reactions, see: (a) Olier, C.; Kaafarani, M.;
Gastaldi, S. S.; Bertrand, M. P. Tetrahedron 2010, 66, 413–445 and
references cited therein. (b) Pastor, I. M.; Yus, M. Curr. Org. Chem. 2007,
11, 925–957.
(37) Yadav, J. S.; Padmavani, B.; Reddy, B. V. S.; Venugopal, Ch.;
Rao, A. B. Synlett 2007, 13, 2045–2048.
(38) (a) Greeves, N.; Aspinall, H. C.; Bissett, J. S.; Levin, D.
Tetrahedron Lett. 2002, 43, 319–321. (b) Greeves, N.; Aspinall, H. C.;
Bissett, J. S.; Levin, D. Tetrahedron Lett. 2002, 43, 323–325.
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