The prins cascade cyclization reaction for the synthesis of angularly-fused tetrahydropyran and piperidine derivatives

Article abstract of DOI:10.1002/ejoc.201201387

2-Arylethylbut-3-en-1-ol is found to undergo smooth Prins cascade reactions with various aldehydes in the presence of Sc(OTf)₃ (10 mol-%) and a stoichiometric amount of TsOH to afford the corresponding trans-fused hexahydro-1H-benzo[f]isochrome

Full text of DOI:10.1002/ejoc.201201387

FULL PAPER
DOI: 10.1002/ejoc.201201387
The Prins Cascade Cyclization Reaction for the Synthesis of Angularly-Fused
Tetrahydropyran and Piperidine Derivatives
B. V. Subba Reddy,*[a] Harish Kumar,[a] Prashant Borkar,[a] J. S. Yadav,[a] and B. Sridhar[b]
Keywords: Synthetic methods / Domino reactions / Heterocycles / Cyclization / Cooperative effects / Aldehydes
2-Arylethylbut-3-en-1-ol is found to undergo smooth Prins
cascade reactions with various aldehydes in the presence of
Sc(OTf)3 (10 mol-%) and a stoichiometric amount of TsOH to
afford the corresponding trans-fused hexahydro-1H-benzo-
[f]isochromenes in good yields with excellent selectivity.
Likewise, N-tosyl-2-phenethylbut-3-en-1-amine gives trans-
fused octahydrobenzo[f]isoquinoline derivatives under sim-
ilar conditions. This is the first example of the synthesis of
hexahydro-1H-benzo[f]isochromene and octahydrobenzo-
[f]isoquinoline from 2-arylethylbut-3-en-1-ol and N-tosyl-2-
phenethylbut-3-en-1-amine, respectively.
ever, the scope of these tandem processes has not been ex-
plored to construct benzo[f]isochromene and benzo[f]iso-
quinoline scaffolds from easily accessible 2-arylethylbut-3-
en-1-ol and N-tosyl-2-phenethylbut-3-en-1-amine, respec-
tively. Such skeletons are found in aromatized salvinorin A
and dopamine congeners (Figure 1).[9]
Introduction
The Prins cyclization reaction is a powerful synthetic
route for the stereoselective construction of tetrahydro-
pyran (THP) rings that are a core structural unit of many
natural products.[1,2] It has been successfully applied to the
total synthesis of THP-containing polyether antibiotics and
other complex natural products.[3] In particular, the intra-
molecular Prins-cyclization reaction is very useful to con-
struct bicyclic compounds such as bicyclo[3.3.1]nonane,[4a]
azaspiro[4,4]nonane,[4b] and bicyclo[3,2,1]octane.[4c] In-
spired by an intramolecular Prins reaction with tethered nu-
cleophiles[5–7] we have successfully demonstrated the stereo-
selective synthesis of heterobicycles and tricycles.[8] How-
Results and Discussion
In continuation of our research on Prins-type cyclization
reactions and its application to the total synthesis of natural
products,[10] we herein report a new strategy for the stereo-
selective synthesis of hexahydro-1H-benzo[f]isochromene
and octahydrobenzo[f]isoquinoline derivatives by means of
Prins cascade cyclization reactions by using a combination
of Sc(OTf)3 (10 mol-%) and a stoichiometric amount of
TsOH (Scheme 1).
Figure 1. Biologically active benzo[f]isochromene and benzo[f]iso-
quinoline derivatives.
Scheme 1. A tandem process for the hexahydro-1H-benzo[f]iso-
chromene and octahydrobenzo-[f]isoquinoline motifs.
[a] Natural Product Chemistry,
We first attempted the cyclization of 2-phenylethylbut-3-
en-1-ol with 2-nitrobenzaldehyde by using various acid cat-
alysts. To optimize the reaction conditions, several acid cat-
alysts were screened and the results are presented in Table 1.
Of the various catalysts, InCl3 (20 mol-%) at 25 °C gave the
desired product only in 25% yield (Table 1, Entry a)
whereas no cyclization was observed with molecular iodine
Uppal Road, Tarnaka, 500007 Hyderabad, India
Fax: +91-40-27160512
E-mail: basireddy@iict.res.in
Homepage: www.iictindia.org
[b] Laboratory of X-ray, Crystallography, Indian Institute of
Chemical Technology,
Uppal Road, Tarnaka, Hyderabad, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201387.
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1993

B. V. Subba Reddy, H. Kumar, P. Borkar, J. S. Yadav, B. Sridhar
FULL PAPER
(20 mol-%; Table 1, Entry b). By using Sc(OTf)3 (10 mol-%)
the desired product was obtained only in 30% yield after a
long reaction time (Table 1, Entry c). A stoichiometric
amount of TsOH gave the required product in 55% yield.
Interestingly, the combination of Sc(OTf)3 (10 mol-%) and
a stoichiometric amount of TsOH gave the product in 86%
yield in a short reaction time (Table 1, Entry e). Under opti-
mized conditions, the reaction requires Sc(OTf)3 (10 mol-
%) and TsOH (1.0 equiv.) in dichloromethane at room tem-
perature. The high reactivity of the above reagent system
may be attributed to synergistic/cooperative effects between
the Lewis acid i.e. Sc(OTf)3 and the Brønsted acid i.e.
TsOH.[11] Therefore, a tandem process requires both
Brønsted acid and Lewis acid to furnish good results. Un-
der the above conditions, desired product 3a was obtained
in 86% yield with high trans-stereoselectivity (dia-
stereomeric ratio: 90:10; Table 2, Entry a). The trans/cis ra-
Figure 2. Characteristic coupling constants and chemical structure
of 3b.
1
tio was determined from the H NMR spectroscopic data
of the crude product. The two diastereomers were insepa-
rable by silica gel column chromatography.
Table 1. Screening of various acid catalysts for the Prins cyclization
reaction of 2-phenylethylbut-3-en-1-ol with 2-nitrobenzaldehyde.[a]
Figure 3. ORTEP diagram of 3b.
Other aromatic aldehydes such as 4-chloro- and 4-iso-
propylbenzaldehydes are also found to be effective in pro-
viding the desired products in good yields (Table 2, En-
tries c and d). Next, we extended this cascade process to
other aryl-tethered homoallylic alcohols i.e. 2-(4-methoxy-
phenethyl)but-3-en-1-ol (1, R = OMe). Interestingly, vari-
ous aromatic aldehydes like 4-fluorobenzaldehyde, 4-meth-
ylbenzaldehyde and 1-naphthaldehyde underwent smooth
cyclization reactions with 4-methoxyphenyl-tethered homo-
allyl alcohol to furnish the corresponding trans-fused hexa-
hydro-1H-benzo[f]isochromenes in good yields (Table 2,
Entries e, f and h). The present method works not only with
aromatic aldehydes but also with aliphatic aldehydes such
as cyclohexanecarboxaldehyde to afford the alkyl-substi-
tuted hexahydro-1H-benzo[f]isochromene (Table 2, En-
try g). In all cases, the reaction afforded trans-fused prod-
ucts with good to excellent diastereoselectivity. The forma-
tion of the minor cis-fused product might occur through
trapping of the secondary carbenium ion from the same
face as the dihydrostyryl substituent. Unlike electron-rich
[a] The reaction was performed on a 0.5 mmol scale. [b] Isolated
yield. [c] Trans/cis ratio was determined from the 1H NMR spectro-
scopic data of the crude product.
Under optimized conditions, thiophene-2-carbaldehyde aryl-tethered homoallylic substrates, the electron-deficient
also participated well in a tandem process to afford pre- homoallylic alcohols are not so effective for this cyclization.
dominantly trans-fused product 3b in 85% yield (trans/cis For example, treatment of 2-[4-(trifluoromethyl)phenethyl]-
ratio = 90:10; Table 2, Entry b). The structure and stereo- but-3-en-1-ol with benzaldehyde gave the desired product in
chemistry of 3b were established by means of double quan- very low yield (Ͻ 10%) under similar conditions. Unlike
tum filtered correlation spectroscopy (DQFCOSY). Proton the reported method, no dihydropyran was formed under
2-H shows a large coupling of 11.3 Hz with 1-H indicating our reaction conditions.[3j]
an axial orientation of 2-H. Proton 4a-H shows a large cou-
Inspired by the results obtained with aryl-tethered homo-
pling (J = 10.5 Hz) with 10b-H that also shows a large cou- allylic alcohol, we extended our efforts to examine this tan-
pling with one of the 1-H protons indicating that 4a-H and dem process with phenyl-tethered homoallyl N-tosylamide.
10b-H are in axial orientations. Thus, the fusion of two Accordingly, N-tosyl-2-phenethylbut-3-en-1-amine (4) was
rings is trans as shown in Figure 2. Furthermore, the struc- treated with isobutyraldehyde in the presence of Sc(OTf)3
ture of 3b was confirmed by X-ray crystallography (Fig- (10 mol-%) and a stoichiometric amount of TsOH in 1,2-
ure 3).[12]
dichloroethane (DCE). No reaction was observed at room
1994
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Eur. J. Org. Chem. 2013, 1993–1999

Synthesis of Angularly-Fused Tetrahydropyran and Piperidine Derivatives
Table 2. Synthesis of hexahydro-1H-benzo[f]isochromene derivatives through Prins cascade cyclization reactions.[a]
[a] The reactions were performed on a 0.5 mmol scale. [b] All the products were characterized by 1H and 13C NMR spectroscopy, IR and
1
mass spectroscopy. [c] Yield refers to pure products after column chromatography. [d] Diastereomeric ratio was determined from the H
NMR spectra of the crude product.
temperature, however, by increasing the reaction tempera- a large coupling of 10 Hz with 1-H indicating an axial ori-
ture to 80 °C, corresponding product isopropyl-substituted entation of 2-H. Also 4a-H shows a large coupling (J =
octahydrobenzo[f]isoquinoline 5a was obtained in 78% 11 Hz) with 10b-H that further shows a large coupling with
yield with exclusive trans-selectivity (Scheme 2, Table 3, En- one of the 1-H protons indicating that 4a-H and 10b-H are
try a).
in an axial position. Thus, the fusion of two rings is trans
as shown in Figure 4.
The scope of the aza-Prins cascade reaction was studied
with N-tosyl-2-phenethylbut-3-en-1-amine (4) and various
aldehydes and the results are summarized in Table 3. Simi-
larly, n-octanal reacted well to afford corresponding prod-
uct 5e under identical reaction conditions (Table 3, En-
try e). Aromatic aldehydes such as 4-methyl-, 4-bromo- and
4-nitro-benzaldehydes also reacted smoothly with 4 afford-
ing aryl-substituted trans-fused octahydrobenzo[f]isoquin-
Scheme 2. Synthesis of octahydrobenzo[f]isoquinoline by aza-Prins
cascade cyclization reaction.
The structure and stereochemistry of 5a was charac- olines in good yields (Table 3, Entries b, c and d). In most
terized by using DQFCOSY techniques. Proton 2-H shows cases, aromatic aldehydes gave products in higher yields
Eur. J. Org. Chem. 2013, 1993–1999
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1995

B. V. Subba Reddy, H. Kumar, P. Borkar, J. S. Yadav, B. Sridhar
FULL PAPER
Table 3. Synthesis of octahydrobenzo[f]isoquinolines derivatives by
aza-Prins cascade cyclization reaction.[a]
Figure 4. Characteristic coupling constants and chemical structure
of 5a.
Scheme 3. Deprotection of 5a.
Although various acids were studied for this conversion
(Table 1), the combination of Sc(OTf)3 (10 mol-%) and a
stoichiometric amount of TsOH was found to give the best
results in both Prins and aza-Prins cascade reactions. Next,
we examined the effect of various solvents such as dichloro-
methane, DCE and toluene. Dichloromethane appeared to
give the best results for the Prins cyclization reaction, and
DCE was found to give high conversions in the aza-Prins
cyclization reaction. This method is simple and convenient
and provides the desired products in good yields with good
to excellent stereoselectivity.
A plausible mechanism for a tandem Prins process is pro-
posed in Scheme 4. The reaction was assumed to proceed
through the formation of an oxocarbenium ion generated
in situ from the hemi-acetal that is in turn formed by the
reaction of a homoallylic alcohol with an aldehyde under
acidic conditions. This is followed by attack of the olefin
generating a carbocation that is simultaneously trapped by
a tethered aryl nucleophile to give the desired hexahydro-
1H-benzo[f]isochromene. In this reaction, the Brønsted acid
activates the aldehyde to generate the hemi-acetal from the
aldehyde and a homoallylic alcohol whereas the Lewis acid
[a] The reactions were performed on a 0.5 mmol scale. [b] All the
products were characterized by 1H and 13C NMR spectroscopy, IR
and mass spectroscopy. [c] Yield refers to pure products after col-
umn chromatography.
than aliphatic counterparts. In the case of the aza-Prins cy-
clization reaction, a tethered aryl nucleophile attacks the
six-membered cyclic carbocation selectively from the equa-
torial side resulting in the exclusive formation of the trans-
isomer.
Next, we attempted the deprotection of the N-tosyl
group of 5a by using lithium naphthalide at –40 °C to gen-
erate free amine 6 to be evaluated as a dopamine congener
(Scheme 3).
Scheme 4. A plausible reaction pathway for a tandem Prins reac-
tion.
1996
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Eur. J. Org. Chem. 2013, 1993–1999

Synthesis of Angularly-Fused Tetrahydropyran and Piperidine Derivatives
3017, 2921, 2853, 1609, 1577, 1525, 1456, 1346, 1305, 1142, 1071,
facilitates the olefin cyclization as well as a Friedel–Crafts
reaction. Therefore, both the Brønsted acid and Lewis acid
are essential to facilitate the reaction.
767, 741, 705, 567 cm–1. HRMS (APCI): calcd. for C19H19NO3
[M]+ 310.14377; found 310.14394.
(2S*,4aR*,10bS*)-2-(Thiophen-2-yl)-2,4,4a,5,6,10b-hexahydro-
1H-benzo[f]isochromene (3b): (Table 2, Entry b). Yield 85 % as a
white solid, m.p. 140–142 °C. 1H NMR (300 MHz, CDCl3): δ =
7.37–7.30 (m, 3 H), 7.18–7.10 (m, 4 H), 4.53 (dd, J = 11.3, 2.2 Hz,
1 H), 4.14 (dd, J = 3.7, 10.5 Hz, 1 H), 3.45 (dd, J = 10.5, 11.3 Hz,
1 H), 2.97–2.86 (m, 2 H), 2.73–2.66 (m, 1 H), 2.56–2.50 (m, 1 H),
1.88–1.69 (m, 2 H), 1.61–1.38 (m, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 141.4, 138.6, 136.5, 133.1, 129.2, 128.5, 127.4, 126.2,
125.8, 124.5, 79.7, 73.5, 41.6, 38.6, 38.3, 28.8, 24.6 ppm. IR (neat):
The cyclization reaction could also proceed through a
3,3-sigmatropic rearrangement as proposed by Overmann
et al., but the product is as same as the Prins cyclization
reaction.[13]
Conclusions
In summary, we have demonstrated a new Prins cascade
reaction process for the stereoselective synthesis of a wide
range of trans-fused hexahydro-1H-benzo[f]isochromene
and octahydrobenzo[f]isoquinoline derivatives in good
yields with high selectivity. This cascade process provides
easy access to angularly-fused oxa- and aza-tricycles in a
single-step process. Thus, newly prepared octahydrobenzo-
[f]isoquinoline derivatives can be evaluated as dopamine
congeners.
ν
= 2921, 2851, 1484, 1453, 1358, 1255, 1089, 1039, 763, 738,
˜
max
701, 546 cm–1. HRMS (APCI): calcd. for C17H18OS [M]+
270.10729; found 270.10750.
(2S*,4aR*,10bS*)-2-(4-Chlorophenyl)-2,4,4a,5,6,10b-hexahydro-
1H-benzo[f]isochromene (3c): (Table 2, Entry c). Yield 80 % as a
1
semi solid. H NMR (300 MHz, CDCl3): δ = 7.30–7.28 (m, 2 H),
7.20–7.10 (m, 4 H), 7.12–7.06 (m, 1 H), 7.08–6.90 (m, 1 H), 4.83
(dd, J = 11.3, 1.5 Hz, 1 H), 4.13 (dd, J = 11.3, 3.7 Hz, 1 H), 3.48
(dd, J = 11.3, 10.5 Hz, 1 H), 2.96–2.88 (m, 2 H), 2.74–2.69 (m, 1
H), 1.84–1.70 (m, 4 H), 1.51–1.37 (m, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 145.9, 138.3, 136.4, 129.1, 126.4, 126.1,
125.7, 124.5, 123.5, 76.0, 41.4, 38.4, 38.1, 28.7, 24.4 ppm. IR (neat):
Experimental Section
ν
max = 2923, 2853, 1490, 1455, 1364, 1273, 1218, 1089, 1037, 1014,
˜
General: Dichloromethane was dried according to a standard lit-
erature procedure. The reactions were performed in oven-dried two-
necked round-bottomed flasks under an argon atmosphere. Glass
syringes were used to transfer solvent. Products were purified by
column chromatography on silica gel of 60–120 or 100–200 mesh.
Thin-layer chromatography plates were visualized by using ultravi-
olet light and/or exposure to iodine vapours and/or exposure to
methanolic acidic solution of p-anisaldehyde followed by heating
(Ͻ1 min) on a hot plate (–250 °C). Organic solutions were concen-
trated on a rotary evaporator at 35–40 °C. IR spectra were recorded
on FTIR spectrometer. 1H and 13C NMR spectra were recorded in
CDCl3 with a 300, 400, 500 or 600 MHz NMR spectrometers with
TMS as an internal standard. Mass spectra were recorded with a
mass spectrometer by using the electrospray ionization (ESI) or
atmospheric pressure chemical ionization (APCI) techniques.
825, 768, 740, 562 cm–1. HRMS (APCI): calcd. for C19H19ClO
[M]+ 298.11189; found 298.11197.
(2S*,4aR*,10bS*)-2-(4-Isopropylphenyl)-2,4,4a,5,6,10b-hexahydro-
1H-benzo[f]isochromene (3d): (Table 2, Entry d). Yield 82% as a
pale yellow liquid. H NMR (300 MHz, CDCl3): δ = 7.34 (d, J =
7.9 Hz, 2 H), 7.24–7.19 (m, 2 H), 7.17–7.09 (m, 4 H), 4.52 (d, J =
10.8 Hz, 1 H), 4.13 (dd, J = 10.8, 3.9 Hz, 1 H), 3.44 (t, J = 10.8 Hz,
1 H), 3.00–2.83 (m, 2 H), 2.72–2.67 (m, 1 H), 2.59 (m, 1 H), 1.95–
1.72 (m, 3 H), 1.65 (q, J = 11.8 Hz, 1 H), 1.49–1.41 (m, 1 H), 1.24
(d, J = 6.9 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 140.2,
138.9, 136.6, 129.1, 128.7, 126.5, 126.4, 126.2, 126.1, 126.0, 125.8,
124.6, 80.5, 73.6, 41.8, 38.7, 38.0, 33.9, 31.5, 30.2, 28.9, 24.1 ppm.
1
IR (neat): ν
= 2956, 2924, 2863, 1490, 1457, 1363, 1093, 963,
˜
max
828, 768, 739, 574 cm–1. HRMS (APCI): calcd. for C22H26O [M]+
306.19782; found 306.19567.
Typical Procedure for Prins Cascade Cyclization Reaction: To a
stirred solution of 2-arylethylbut-3-en-1-ol (1; 0.5 mmol) and alde-
hyde (0.6 mmol) in dry dichloromethane (5 mL) was added Sc-
(OTf)3 (10 mol-%) and TsOH (0.5 mmol, 1 equiv.). The resulting
mixture was stirred at room temperature under an nitrogen atmo-
sphere for the specified time (Table 2). After completion of the re-
action as indicated by TLC, the mixture was quenched with satu-
rated NaHCO3 solution (1.0 mL) and extracted with dichlorometh-
ane (2ϫ 5 mL). The organic layers were combined, washed with
brine (3ϫ 5 mL), dried with anhydrous Na2SO4, and concentrated
in vacuo. The resulting crude product was purified by silica gel
column chromatography (100–200 mesh) with ethyl acetate/hexane
as eluent to afford the pure product.
(2S*,4aR*,10bS*)-2-(4-Fluorophenyl)-9-methoxy-2,4,4a,5,6,10b-
hexahydro-1H-benzo[f]isochromene (3e): (Table 2, Entry e). Yield
88% as a yellow liquid. 1H NMR (300 MHz, CDCl3): δ = 7.39 (dd,
J = 8.3, 3.0 Hz, 1 H), 7.07–7.02 (m, 3 H), 6.79–6.69 (m, 2 H), 4.52
(dd, J = 11.3, 2.2 Hz, 1 H), 4.15 (dd, J = 11.3, 3.7 Hz, 1 H), 3.75
(s, 3 H), 3.43 (dd, J = 11.3, 10.5 Hz, 1 H), 2.89–2.83 (m, 1 H), 2.67
(td, J = 11.3, 3.0 Hz, 1 H), 2.51–2.45 (m, 1 H), 1.83–1.39 (m, 5
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.6, 157.9, 139.8,
138.7, 130.0, 128.6, 127.8, 127.7, 115.4, 115.1, 111.7, 110.2, 79.8,
73.5, 65.3, 41.9, 38.7, 29.7, 28.0, 24.8 ppm. IR (neat): ν
= 2956,
˜
max
2924, 2863, 1490, 1457, 1363, 1093, 963, 828, 768, 739, 574 cm–1.
HRMS (APCI): calcd. for C20H21FO2 [M]+ 312.15201; found
312.15047.
(2S*,4aR*,10bS*)-2-(2-Nitrophenyl)-2,4,4a,5,6,10b-hexahydro-
1H-benzo[f]isochromene (3a): (Table 2, Entry a). Yield 86 % as a
brown solid, m.p. 110–114 °C. 1H NMR (300 MHz, CDCl3): δ =
7.93 (d, J = 9.0 Hz, 1 H), 7.84 (d, J = 7.5 Hz, 1 H), 7.64 (t, J =
(2S*,4aR*,10bS*)-9-Methoxy-2-p-tolyl-2,4,4a,5,6,10b-hexahydro-
1H-benzo[f]isochromene (3f): (Table 2, Entry f) Yield 78% as a yel-
1
low liquid. H NMR (300 MHz, CDCl3): δ = 7.30 (d, J = 7.5 Hz,
6.8 Hz, 1 H), 7.46–7.40 (m, 1 H), 7.21–7.10 (m, 4 H), 5.15–5.12 (m, 2 H), 7.16 (d, J = 7.5 Hz, 2 H), 7.01 (d, J = 7.5 Hz, 1 H), 6.73–
1 H), 4.15 (dd, J = 11.3, 3.7 Hz, 1 H), 3.47 (t, J = 11.3 Hz, 1 H),
6.69 (m, 2 H), 4.50 (dd, J = 11.3, 2.6 Hz, 1 H), 4.14 (dd, J = 11.3,
3.7 Hz, 1 H), 3.74 (s, 3 H), 3.45 (dd, J = 11.3, 10.5 Hz, 1 H), 2.89–
2.98–2.91 (m, 1 H), 2.88–2.77 (m, 2 H), 1.86–1.69 (m, 2 H), 1.61–
1.37 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 147.6, 138.4, 2.83 (m, 1 H), 2.65 (td, J = 11.3, 3.0 Hz, 1 H), 2.48 (dt, J = 6.0,
138.1, 136.3, 133.4, 129.0, 128.2, 128.0, 126.1, 125.7, 125.5, 124.1,
75.7, 73.4, 41.4, 38.7, 37.6, 28.7, 24.4 ppm. IR (neat): ν = 3064,
3.0 Hz, 1 H), 2.35 (s, 3 H), 1.83–1.56 (m, 4 H), 1.49–1.39 (m, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 139.9, 139.6, 137.2,
˜
max
Eur. J. Org. Chem. 2013, 1993–1999
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1997

B. V. Subba Reddy, H. Kumar, P. Borkar, J. S. Yadav, B. Sridhar
FULL PAPER
129.8, 129.0, 128.4, 125.9, 111.8, 109.9, 80.3, 73.4, 55.2, 41.9, 38.6,
H), 2.32 (s, 3 H), 2.26 (s, 3 H), 1.75–1.48 (m, 5 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 143.0, 136.7, 136.6, 135.6, 129.8, 129.5,
129.1, 126.8, 126.6, 126.1, 125.8, 25.7, 55.5, 47.4, 38.0, 36.6, 31.9,
38.1, 27.9, 24.7, 21.1 ppm. IR (neat): νmax = 2922, 2852, 1609, 1577,
˜
1498, 1460, 1280, 1248, 1223, 1157, 1146, 1094, 1073, 1039, 815,
712, 561 cm–1. HRMS (APCI): calcd. for C21H24O2 [M]+
308.17708; found 308.17709.
28.7, 26.2, 21.5, 20.9 ppm. IR (neat): νmax = 2920, 2851, 1449, 1335,
˜
1219, 1159, 1092, 919, 772, 670, 556 cm–1. HRMS (APCI): calcd.
for C27H37NO2S [M + H]+ 440.26178; found 440.26117.
(2S*,4aR*,10bS*)-2-Cyclohexyl-9-methoxy-2,4,4a,5,6,10b-hexa-
hydro-1H-benzo[f]isochromene (3g): (Table 2, Entry g). Yield 75%
as a semi solid. 1H NMR (300 MHz, CDCl3): δ = 7.01 (d, J =
(2S*,4aR*,10bS*)-2-(4-Bromophenyl)-3-tosyl-1,2,3,4,4a,5,6,10b-
octahydrobenzo[f]isoquinoline (5c): (Table 3, Entry c). Yield 88% as
1
8.3 Hz, 1 H), 6.80–6.68 (m, 3 H), 5.03–4.9 (m, 1 H), 4.20 (dd, J = a white solid, m.p. 144–146 °C. H NMR (300 MHz, CDCl3): δ =
11.3, 3.7 Hz, 1 H), 3.79 (s, 3 H), 3.22 (dd, J = 11.3, 10.5 Hz, 1 H),
2.85–2.80 (m, 1 H), 2.48–2.39 (m, 1 H), 2.32–2.24 (m, 1 H), 2.07–
2.0 (m, 1 H), 1.92 (d, J = 12.0 Hz, 1 H), 1.78–1.54 (m, 6 H), 1.48–
7.72 (d, J = 7.9 Hz, 2 H), 7.45 (d, J = 7.9 Hz, 2 H), 7.29 (d, J =
7.9 Hz, 2 H), 7.24 (d, J = 6.9 Hz, 1 H), 7.18 (d, J = 6.9 Hz, 1 H),
7.02–7.15 (m, 3 H), 5.45 (d, J = 3.9 Hz, 1 H), 3.94 (dd, J = 13.9,
1.25 (m, 8 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 140.6, 129.8, 3.9 Hz, 1 H), 2.90–2.75 (m, 4 H), 2.39 (s, 3 H), 1.78–1.52 (m, 4 H),
128.7, 111.0, 110.6, 82.4, 73.2, 55.3, 43.2, 41.6, 39.1, 29.6, 29.1,
28.9, 27.9, 26.6, 26.2, 24.8, 14.1 ppm. IR (neat): νmax = 2924, 2853,
1.42–1.30 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.3,
138.2, 137.9, 136.7, 131.9, 129.8, 129.3, 128.5, 126.8, 126.2, 125.9,
˜
1610, 1498, 1451, 1279, 1246, 1145, 1100, 772 cm–1. HRMS 124.6, 55.3, 47.5, 37.9, 36.5, 31.8, 28.6, 26.1, 21.5 ppm. IR (neat):
(APCI): calcd. for C20H28O2 [M + H]+ 301.21514; found
301.21621.
ν
= 2922, 2854, 1596, 1488, 1452, 1335, 1159, 1092, 1010, 943,
˜
max
919, 812, 741, 674, 544 cm– 1. HRMS (APCI): calcd. for
C26H26BrNO2S [M + H]+ 496.09404; found 496.09743.
(2S*,4aR*,10bS*)-9-Methoxy-2-(naphthalen-1-yl)-2,4,4a,5,6,10b-
hexahydro-1H-benzo[f]isochromene (3h): (Table 2, Entry h). Yield
(2S*,4aR*,10bS*)-2-(4-Nitrophenyl)-3-tosyl-1,2,3,4,4a,5,6,10b-
octahydrobenzo[f]isoquinoline (5d): (Table 3, Entry d). Yield 80% as
1
76% as a white liquid. H NMR (300 MHz, CDCl3): δ = 8.18 (d,
J = 8.3 Hz, 1 H), 7.68 (d, J = 6.7 Hz, 1 H), 7.56–7.42 (m, 4 H), a brown solid, m.p. 140–142 °C. 1H NMR (300 MHz, CDCl3): δ =
7.05 (d, J = 9.0 Hz, 1 H), 6.73–6.70 (m, 3 H), 5.27 (dd, J = 11.3
and 2.2 Hz, 1 H), 4.26 (dd, J = 11.3, 3.7 Hz, 1 H), 3.70 (s, 3 H),
8.13 (d, J = 9.0 Hz, 2 H), 7.69–7.62 (m, 3 H), 7.54 (d, J = 8.3 Hz,
2 H), 7.20–7.18 (m, 3 H), 7.15–6.96 (m, 2 H), 5.50 (d, J = 4.5 Hz,
3.61 (dd, J = 11.3, 10.5 Hz, 1 H), 2.95–2.78 (m, 2 H), 2.73–2.67 1 H), 3.95 (dd, J = 12.8, 4.5 Hz, 1 H), 2.91–2.86 (m, 1 H), 2.83–
(m, 1 H), 1.85 (m, 3 H), 1.56–1.42 (m, 2 H) ppm. 13C NMR 2.79 (m, 1 H), 2.75–2.68 (m, 2 H), 2.34 (s, 3 H), 2.25 (t, J = 11.3 Hz,
(75 MHz, CDCl3): δ = 157.4, 133.4, 130.0, 129.5, 128.4, 128.1, 1 H), 1.69–1.57 (m, 1 H), 1.56–1.36 (m, 3 H) ppm. 13C NMR
127.6, 125.5, 125.1, 125.0, 123.0, 122.9, 111.4, 109.7, 76.1, 73.4,
(75 MHz, CDCl3): δ = 146.9, 137.3, 136.7, 136.2, 130.0, 129.7,
54.8, 41.7, 38.4, 36.7, 27.5, 24.4 ppm. IR (neat): νmax = 2923, 2853,
129.3, 127.7, 127.1, 126.8, 126, 125.9, 125.8, 124.6, 55.7, 47.8, 37.9,
˜
1610, 1498, 1460, 1245, 1222, 1141, 773 cm–1. HRMS (APCI):
calcd. for C24H24O2 [M]+ 344.17708; found 344.17700.
36.7, 32.2, 28.6, 26.2, 21.6 ppm. IR (neat): νmax = 2924, 2851, 1599,
˜
1519, 1492, 1452, 1344, 1219, 1159, 1092, 920, 855, 712, 671,
550 cm–1. HRMS (APCI): calcd. for C26H26N2O4S [M + H]+
496.16874; found 463.16874.
Typical Procedure for Aza-Prins Cascade Cyclization Reaction: To
a stirred solution of 4-methyl-N-(6-arylhex-3-enyl)benzenesulfon-
amide (4; 0.5 mmol) and aldehyde (0.6 mmol) in dry DCE (5 mL)
was added Sc(OTf)3 (10 mol-%) and TsOH (0.5 mmol). The re-
sulting mixture 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
(2ϫ 5 mL). The organic phases were combined, washed with brine
(3ϫ 2 mL), dried with anhydrous Na2SO4 and concentrated in
vacuo. The resulting crude product was purified by silica gel col-
umn chromatography (60–120 mesh) with ethyl acetate/hexane as
eluent to afford the pure product.
(2R*,4aR*,10bS*)-2-Heptyl-3-tosyl-1,2,3,4,4a,5,6,10b-octahydro-
benzo[f]isoquinoline (5e): (Table 3, Entry e). Yield 78% as a pale
yellow liquid. 1H NMR (300 MHz, CDCl3): δ = 7.70 (d, J = 7.5 Hz,
2 H), 7.20 (d, J = 8.3 Hz, 2 H), 7.13–7.04 (m, 4 H), 4.27–4.20 (m,
1 H), 3.80 (dd, J = 14.3, 3.7 Hz, 1 H), 2.90–2.79 (m, 3 H), 2.66–
2.56 (m, 1 H), 2.38 (s, 3 H), 2.30–2.23 (m, 1 H), 1.81–1.72 (m, 1 H),
1.68–1.49 (m, 3 H), 1.46–1.21 (m, 13 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 142.9, 138.5, 136.7, 129.7, 129.1, 126.9, 126.1, 125.8,
124.7, 53.7, 46.4, 38.2, 36.2, 32.1, 31.9, 30.3, 29.4, 29.2, 28.8, 26.7,
26.5, 22.7, 21.5 ppm. IR (neat): ν
= 2953, 2856, 1490, 1456,
˜
max
1334, 1157, 1091, 1024, 987, 920, 814, 740, 667, 595, 551 cm–1
.
HRMS (APCI): calcd. for C27H37NO2S [M + H]+ 440.26178; found
440.26117.
(2S*,4aR*,10bS*)-2-Isopropyl-3-tosyl-1,2,3,4,4a,5,6,10b-octa-
hydrobenzo[f]isoquinoline (5a): (Table 3, Entry a). Yield 78% as a
1
pale yellow liquid. H NMR (300 MHz, CDCl3): δ = 7.71 (d, J =
Procedure for Synthesis of Free Amine 6 from 5a (N-Tosyl Deprotec-
tion): To a stirred solution of (2S*,4aR*,10bR*)-2-isopropyl-3-to-
syl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]isoquinoline (5a;
0.1 mmol) in anhydrous THF (2 mL) was added a Li-naphthalide
7.9 Hz, 2 H), 7.21 (d, J = 7.9 Hz, 2 H), 7.15–7.08 (m, 3 H), 7.05–
7.03 (m, 1 H), 3.86 (dd, J = 13.9, 3.9 Hz, 1 H), 3.80 (dd, J = 9.9,
4.9 Hz, 1 H), 2.57–2.53 (m, 1 H), 2.42 (d, J = 13.9 Hz, 1 H), 2.37
(s, 3 H), 2.15–2.09 (m, 1 H), 1.74–1.55 (m, 3 H), 1.40–1.32 (m, 1 H), solution (prepared by using 4 equiv. lithium and 8 equiv. naphthal-
1.01 (dd, J = 9.9, 6.9 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 142.8, 138.9, 138.5, 136.7, 129.7, 129.1, 126.8, 126.0, 125.7, 124.6,
60.1, 46.9, 37.5, 36.3, 29.5, 28.7, 26.7, 26.3, 21.5, 20.4, 20.1 ppm.
ene in 2 mL THF) at –40 °C dropwise. The reaction mixture was
stirred at the same temperature for 20 to 30 min and then quenched
with saturated NH4Cl solution (0.5 mL), diluted with water (2 mL)
and extracted with ethyl acetate (2ϫ 2 mL). The organic phases
IR (neat): ν
= 2963, 2922, 2871, 1598, 1452, 1335, 1156, 1091,
˜
max
1053, 1019, 971, 814, 764, 668, 594, 550 cm–1. HRMS (APCI): were combined, washed with brine (2ϫ 1 mL), dried with anhy-
calcd. for C23H29NO2S [M]+ 383.19135; found 383.19180.
drous Na2SO4 and concentrated in vacuo. The resulting crude
product was purified by silica gel column chromatography (60–
120 mesh) with methanol/chloroform as eluent to afford pure prod-
uct 6.
(2S*,4aR*,10bS*)-2-p-Tolyl-3-tosyl-1,2,3,4,4a,5,6,10b-octahydro-
benzo[f]isoquinoline (5b): (Table 3, Entry b). Yield 75% as a semi
1
solid. H NMR (300 MHz, CDCl3): δ = 7.69 (d, J = 8.1 Hz, 2 H),
7.23 (m, 6 H), 7.12–7.02 (m, 4 H), 6.99–6.98 (m, 1 H), 5.40 (d, J (2S*,4aR*,10bS*)-2-Isopropyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-
1
= 3.5 Hz, 1 H), 3.88 (dd, J = 13.7, 3.5 Hz, 1 H), 2.91–2.16 (m, 4
isoquinoline (6): (Scheme 3). Yield 82% as a semi solid. H NMR
1998
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1993–1999

Synthesis of Angularly-Fused Tetrahydropyran and Piperidine Derivatives
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3.35 (m, 1 H), 3.33–3.22 (m, 1 H), 2.96–2.69 (m, 2 H), 2.66–2.49
(m, 2 H), 2.22–1.75 (m, 5 H), 1.49–1.37 (m, 1 H), 1.20 (d, J =
5.8 Hz, 3 H), 1.03 (d, J = 5.8 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 136.7, 136.3, 129.3, 126.5, 126.0, 124.6, 59.6, 44.6,
Choi, M. H. Chang, Org. Lett. 2002, 4, 2025–2028; b) Z.-H.
Chen, Y.-Q. Tu, S.-Y. Zhang, F.-M. Zhang, Org. Lett. 2011, 13,
724–727; c) B. V. S. Reddy, G. Narasimhulu, Y. V. Reddy, P. P.
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36.1, 35.2, 28.6, 28.5, 26.5, 25.5, 20.4, 19.6 ppm. IR (neat): ν
=
˜
max
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3417, 2925, 2851, 1587, 1454, 1380, 1218, 771, 743 cm–1. MS (ESI):
m/z = 230 [M + H]+. HRMS (ESI): calcd. for C16H23N [M + H]+
230.1903; found 230.1908.
Supporting Information (see footnote on the first page of this arti-
1
cle): Preparation of starting materials, copies of H and 13C NMR
spectra of products, copies of 1H and 13C NMR spectra of starting
materials.
Acknowledgments
H. K. and P. B. thank the Council of Scientific and Industrial Re-
search (CSIR), New Delhi for the award of a fellowship.
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[12] CCDC-887311 contains supplementary crystallographic data
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Received: October 18, 2012
Published Online: February 11, 2013
Eur. J. Org. Chem. 2013, 1993–1999
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1999