Synthesis of tetrahydroisoquinolines and isochromans via Pictet-Spengler reactions catalyzed by Br?nsted acid-surfactant-combined catalyst in aqueous media

Article abstract of DOI:10.1016/j.tet.2007.02.123

Perfluorooctanesulfonic acid (PFOSA), Br?nsted acid-surfactant-combined catalyst, efficiently catalyzes the Pictet-Spengler reactions of β-arylethyl carbamate derivatives with aldehydes in water. The present reaction is accelerated by the addition of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). PFOSA in HFIP-water (10 v/v %) is also successfully applied to the oxa-Pictet-Spengler reactions of β-arylethyl alcohol compounds.

Full text of DOI:10.1016/j.tet.2007.02.123

Tetrahedron 63 (2007) 4039–4047
Synthesis of tetrahydroisoquinolines and isochromans via
Pictet–Spengler reactions catalyzed by Brønsted acid–
surfactant-combined catalyst in aqueous media
*
Akio Saito, Masaki Takayama, Aru Yamazaki, Junko Numaguchi and Yuji Hanzawa
*
Laboratory of Organic Reaction Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen,
Machida, Tokyo 194-8543, Japan
Received 30 January 2007; revised 26 February 2007; accepted 28 February 2007
Available online 2 March 2007
Abstract—Perfluorooctanesulfonic acid (PFOSA), Brønsted acid–surfactant-combined catalyst, efficiently catalyzes the Pictet–Spengler
reactions of b-arylethyl carbamate derivatives with aldehydes in water. The present reaction is accelerated by the addition of 1,1,1,3,3,3-hexa-
fluoro-2-propanol (HFIP). PFOSA in HFIP–water (10 v/v %) is also successfully applied to the oxa-Pictet–Spengler reactions of b-arylethyl
alcohol compounds.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Oxa-Pictet–Spengler reaction is a variation of the Pictet–
Spengler reaction, and thus isochroman compounds can be
obtained from b-arylethyl alcohol derivatives with alde-
hydes (Scheme 2).9,10 Although some catalytic reactions
have been developed,11 to our knowledge, these examples
have been limited to the reaction in nonaqueous media.12
The Pictet–Spengler reaction was reported for the first time in
1911,1 and the reaction became a powerful methodology for
preparing tetrahydroisoquinoline and indole molecules.2,3
The Pictet–Spengler reaction takes part in the cyclization
of imines or iminium ions formed by dehydration reaction
of b-arylethyl amine derivatives with aldehydes (Scheme 1).
In organic solvent, the catalytic reactions of tryptamine and
m-tyramine have been achieved by the use of Brønsted
acid,4 Lewis acid,5 or organocatalyst,6 while less reactive
b-phenethylamine derivative requires a large excess of the
strong Brønsted acid. Recently, it has been reported that a
zeolite-type adsorbent, which can be recycled, efficiently
catalyzed the Pictet–Spengler reactions of less reactive b-
phenethylamine derivative in ethanol.7 Although the reac-
tions in water or aqueous media have been known, they
require large excess of strong Brønsted acid and/or have
the limitation in reactants.8
RCHO
O
OH
O
R
R
Scheme 2.
Recently, a variety of organic reactions in water or aqueous
media have been studied from the viewpoint of green chem-
istry, and have been received attention in the light of unique
physical and chemical properties of water.13 In the commonly
reported aqueous reactions, Brønsted acid–surfactant-
combined catalyst (BASC) has been known to play an impor-
tant role not only for the activation of the substrate butalsofor
the solubilization of organic substrates by the formation of
colloidal dispersions. In addition, it is noteworthy that
BASC works well for dehydration reactions such as the
esterification and etherification in water as well as three-
component Mannich reactions and aza Diels–Alder reactions
including dehydrative formation of imine derivatives.14,15,16
The efficiency of BASC for dehydration reactions in water
encouraged us to examine the Pictet–Spengler reactions in
water, and we reported in a communication that perfluoro-
octanesulfonic acid (PFOSA) as BASC efficiently catalyzes
the Pictet–Spengler reactions of b-arylethyl carbamate
RCHO
N
HN
N
R'
R'
R'
R
R
Scheme 1.
Keywords: Surfactant; Brønsted acid; Pictet–Spengler reaction; Isoquino-
line; Isochroman.
* Corresponding authors. Tel./fax: +81 (0)42 721 1569; e-mail addresses:
akio-sai@ac.shoyaku.ac.jp; hanzaway@ac.shoyaku.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.123

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A. Saito et al. / Tetrahedron 63 (2007) 4039–4047
derivatives with aldehydes in water.17 Interestingly, these re-
actions in water were found to be accelerated by the addition
of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). Further study
using various substrates revealed the efficiency of PFOSA–
HFIP system for the oxa-Pictet–Spengler reaction of b-aryl-
ethyl alcohols in water. In this paper, we describe the mild
and facile Pictet–Spengler reaction and its oxygen version.
investigated the additive effect of alcohol (3 equiv to sub-
strate) in the reaction of 1 with n-heptanal (1.2 equiv) in
the presence of PFOSA (20 mol %) at room temperature
for 4 h (Fig. 1). Compared with hydrocarbon alcohols, the
fluorinated alcohol, in particular, 1,1,1,3,3,3-hexafluoro-2-
propanol (HFIP) exerted a marked effect on the formation
of 2a. Thus, in the presence of HFIP, 1 was consumed at
room temperature within 4 h to give 2a in 99% yield, in
which the concentration of HFIP in water corresponds to
11.5 v/v % (entry 10, Table 1). HFIP showed its efficiency
for the use of DBSA as well (entry 14), while the reaction
with fluorinated alkanesulfonic acids such as PFBSA and
TfOH were slightly accelerated (entries 11 and 12). The
sole use of HFIP did not yield 2a in the absence of catalyst
(entry 14). These results indicate that hydrophobicities of
2. Results and discussion
2.1. Pictet–Spengler reaction in water
At the outset, we focused our initial efforts on the screening
of Brønsted acid catalysts for the Pictet–Spengler reaction of
carbamate 1 with n-heptanal in water at room temperature
(Table 1). Carbamate 1 was expected to form a reactive
N-acyl iminium intermediate,18,19 while the use of 1 equiv
hydrochloric or sulfuric acid ended with the recovery of 1
(entries 1 and 2).20 Although Brønsted acids such as trifluoro-
acetic acid (TFA), p-toluenesulfonic acid (TsOH), and tri-
fluoromethanesulfonic acid (TfOH) have been reported to
be good catalysts for the Pictet–Spengler reactions in organic
solvents,19,21 they were ineffective catalysts in water (entries
3–5). On the other hand, the use of n-dodecylbenzenesulfonic
acid (DBSA), which is known as BASC,14 or a combination
of Brønsted acid and sodium dodecyl sulfate (SDS)15 slightly
increased the yield of 2a (entries 6 and 7). Notably, perfluoro-
alkanesulfonic acids such as perfluorobutanesulfonic acid
(PFBSA, entry 8) and PFOSA22,23 accelerated the reactions
of 1, and 20 mol % PFOSA brought about 2a in 90% yield
at room temperature for 18 h (entry 9).24
100
90
80
70
60
50
40
30
20
10
0
99
67
42
38
25
5
13
Figure 1. Additive effect of alcohol (3 equiv to 1) in the PFOSA
(20 mol %)-catalyzed reaction of 1 with n-heptanal (1.2 equiv) at rt for
4 h in water (1 mL). (Yield of 2a was determined by 1H NMR. TFE:
2,2,2-trifluoroethanol; HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol.)
Since an addition of alcohol to aqueous surfactant has been
known to show changes in properties of surfactant,25 we
Table 1. Screening of Brønsted acid catalysts for the Pictet–Spengler reaction in watera
MeO
MeO
MeO
n-C6H13CHO
(1.2 equiv)
catalyst, additive
H2O
+
HN
N
MeO
CO2Me
CO2Me
n-C6H13
1
2a
Entry
Catalystb (mol %)
Additiveb (equiv)
Temperature (ꢀC)
Time (h)
Yield of 2ac (%)
Yield of 1c (%)
1
2
3
4
5
6
7
8
HCl (100)
H2SO4 (100)
TFA (20)
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
60
18
18
18
18
18
18
18
18
18
4
4
4
4
4
4
1.5
24
24
—
—
—
2
4
11
27
61
90 (84)
99 (97)
80
21
—
99 (95)
14
99 (96)
99 (97)
99 (99)
99
99
99
97
92
89
69
36
—
—
18
75
99
—
85
—
—
—
—
—
—
—
TsOH (20)
TfOH (20)
TfOH (20)
DBSA (20)
PFBSA (20)
PFOSA (20)
PFOSA (20)
PFBSA (20)
TfOH (20)
—
DBSA (20)
DBSA (20)
PFOSA (20)
PFOSA (10)
PFOSA (5)
SDS (0.2)
—
—
9
—
10
11
12
13
14
15
16d
17
18
HFIP (3)
HFIP (3)
HFIP (3)
HFIP (3)
HFIP (3)
i-PrOH (3)
HFIP (3)
HFIP (3)
HFIP (3)
a
Reaction concentration: 1/water¼0.42 mmol/1 mL.
Equivalent to 1.
b
c
d
Yield was determined by 1H NMR with toluene as an internal standard, and yield in parentheses was isolated yield.
Neat condition.

A. Saito et al. / Tetrahedron 63 (2007) 4039–4047
4041
catalysts are important for the reaction in HFIP–water. On
the other hand, the addition of i-PrOH was inferior to that
of HFIP even in the reaction with hydrocarbon surfactant
(entry 14 vs 15).26 Although it is considered that the additive
effect of HFIP takes part in the enhancement of acidity of
catalyst, there are no marked differences in pH for each cat-
alyst (PFOSA, DBSA, or TfOH) solution in HFIP–water.27
Table 2. Regardless of hydrophobicities of aldehydes,
many aldehydes successfully reacted with carbamate 1 by
PFOSA in water or in HFIP–water, and the corresponding
cyclized products were obtained in high yields in most cases.
The use of t-BuCHO or ketone compounds (acetone or ace-
tophenone), however, gave no cyclized product along with
recovery of 1. In both reactions in water and in HFIP–water,
water-soluble aldehydes (R¼Et, H, i-Pr) showed inferior re-
activities to that of water-insoluble aldehydes (R¼n-hexyl,
n-dodecyl, c-hexyl). A similar observation has been reported
in the DBSA-catalyzed esterification of carboxylic acids
with alcohols in water.14b It has been suggested that hydro-
phobic substrates readily assemble together with DBSA
through hydrophobic interactions to form emulsion droplets
and the hydrophobicity of substrates as well as DBSA facil-
itates the dehydration in water.14b In the present reaction,
hydrophobic substrates and PFOSA in the absence of HFIP
would be considered to form an analogous hydrophobic
area enough to exclude water molecules. Although the role
of HFIP is unclear,28,29 the hydrophobic fluorinated alcohol
might have a beneficial effect for the aggregation of sub-
strates and PFOSA in water.
It should be mentioned that HFIP–water concentration pro-
file in Figure 2 leads to 10–20 v/v % as the optimum concen-
tration for PFOSA-catalyzed reaction of 1 with n-heptanal.
Although the reaction of 1 with 3 equiv HFIP under the
neat condition (entry 16, Table 1) was faster than that in wa-
ter, the yield of 2a at the endpoint was unchanged. Thus, it is
obvious that HFIP is an useful adjunct to PFOSA during the
formation of 2a in water. The use of less amount of PFOSA
(5 or 10 mol %) as a catalyst in HFIP–H2O required a
prolonged reaction time and higher temperature to afford
product 2a in excellent yield (entries 17 and 18, Table 1).
The present catalytic Pictet–Spengler reaction of carbamate
1 in water was applied to various aldehydes as shown in
We next examined the effect of substituent on the aromatic
ring (Table 3). When m-tyramine derivative 3 was used,
the reactions with both n-heptanal and benzaldehyde pro-
ceeded smoothly, and the corresponding para-cyclized prod-
ucts 4a and 4e were obtained as a major isomer, respectively
(entries 3 and 4). Likewise, 3-MeO substituted derivative 5
afforded good results (entries 5 and 6). On the other hand,
carbamate 7, which has no activating substituent, did not
bring about the cyclization reaction (entries 7 and 8).
100
90
81 81
80
70
60
50
40
30
20
10
0
80
76
71
59
54
35
2.2. Oxa-Pictet–Spengler reaction in water
0
5
10 15 20 25 30 35 40 45 50 55
HFIP-water (V/V%)
The established efficiency of the PFOSA in HFIP–water for
the catalytic Pictet–Spengler reaction of b-arylethyl carba-
mate derivatives encouraged us to examine the oxa-Pictet–
Spengler reaction of b-arylethyl alcohol 9 (Scheme 3). In
the reported oxa-Pictet–Spengler reactions in organic
Figure 2. HFIP–water concentration profile for the PFOSA (20 mol %)-
catalyzed reaction of 1 with n-heptanal (1.2 equiv) in solvent (1 mL) at rt
for 1.5 h. (Yield of 2a was determined by 1H NMR.)
Table 2. Catalytic Pictet–Spengler reactions of 1 with various aldehydes
MeO
MeO
PFOSA (20 mol%)
RCHO
+
HN
N
HFIP-H2O or H2O
MeO
MeO
CO2Me
CO2Me
1
R
2
Aldehyde (equiv)
Reaction in HFIP–watera
Reaction in waterb
Time (h)
Temperature (ꢀC)
Time (h)
2 (%)c
Temperature (ꢀC)
2 (%)c
n-C6H13CHO (1.2)
n-C11H23CHO (1.2)
EtCHO (1.2)
37% Formaline (1.2)
PhCHO (1.2)
c-C6H11CHO (1.8)
i-PrCHO (1.8)
t-BuCHO (2.5)
rt
rt
rt
rt
90
90
90
90
4
4
10
8
19
4
20
18
2a (97)
2b (90)
2c (95)
2d (86)
2e (94)
2f (99)
2g (96)
2h (—)f
rt
18
18
5
2
18
2a (84)
2b (92)
2c (99)d
2d (93)
2e (81)e
60
60
60
90
a
Reaction concentration: 1/HFIP/water¼0.42 mmol/130 mL/1 mL.
Reaction concentration: 1/water¼0.42 mmol/1 mL.
Isolated yield.
Aldehyde: 2.5 equiv.
PFOSA: 1.2 equiv.
Recovery of 1: 99%.
b
c
d
e
f

4042
A. Saito et al. / Tetrahedron 63 (2007) 4039–4047
Table 3. Catalytic Pictet–Spengler reactions of various carbamatesa
Entry
Carbamate
Aldehyde
Condition
Temperature (ꢀC)
Product
Yield (%)b
Time (h)
MeO
MeO
MeO
MeO
1
2
n-C6H13CHO
PhCHO
rt
90
4
19
2a: R¼n-C6H13
2e: R¼Ph
97
94
N
HN
CO2Me
CO2Me
2
1
R
HO
HO
3
4
n-C6H13CHO
PhCHO
rt
90
4
18
4a: R¼n-C6H13
4e: R¼Ph
90 (7.6:1)c
84 (16:1)c
N
HN
CO2Me
CO2Me
4
3
R
MeO
MeO
5
6
n-C6H13CHO
PhCHO
rt
90
10
5
6a: R¼n-C6H13
6e: R¼Ph
95 (14:1)c
99 (16:1)c
N
HN
CO2Me
CO2Me
6
5
R
d
7
8
n-C6H13CHO
PhCHO
90
90
20
15
8a: R¼n-C6H13
8e: R¼Ph
—
—
N
HN
d
CO2Me
CO2Me
7
8
R
a
All Reactions of carbamates (0.42 mmol) with aldehyde (1.2 equiv) were carried out in the presence of PFOSA (20 mol %) in HFIP–water (130 mL/1 mL).
Isolated yield.
Regioisomer ratio (para/ortho cyclized product).
Recovery of 7: 98%.
b
c
d
n-C6H13CHO
40
35
30
25
20
15
10
5
MeO
MeO
MeO
MeO
catalyst
OH
O
34
HFIP-H2O
n-C6H13
9
10a
26
Scheme 3.
solvent, Brønsted acid such as TsOH in the presence of de-
hydrating reagent (Na2SO4 and molecular sieves) has been
known to be an efficient catalyst.11a,b TsOH of 10 mol %,
however, turns out to be inefficient for the reaction of alcohol
9 with n-heptanal (1.2 equiv) in HFIP–water (10 v/v %) at
room temperature (Fig. 3). On the other hand, PFOSA ex-
erted a remarkable effect in the reaction of 9, and the product
10a was obtained in 34% yield at room temperature for 2 h
along with recovery of 9 in 58% (Fig. 3). It also turns out
that HFIP–water concentration profile in Figure 4 showed
10 v/v % as the optimum concentration for PFOSA-
catalyzed reaction of 9 with n-heptanal.
9
2
0
0
10
20
30
40
50
HFIP-water (V/V%)
Figure 4. HFIP–water concentration profile for the PFOSA (10 mol %)-
catalyzed reaction of 9 with n-heptanal (1.2 equiv) in solvent (1 mL) at rt
for 2 h. (Yield of 10a was determined by 1H NMR.)
(10 v/v %) was examined (Tables 4 and 5). By use of
10 mol % PFOSA, the reaction of alcohol 9 with n-heptanal
completed at room temperature for 48 h giving rise to 10a
in 93% yield (entry 1, Table 4). PFOSA (10–20 mol %) in
HFIP–water could be applied to oxa-Pictet–Spengler reac-
tions of 9 with other aldehydes and the desirable products
were obtained in good yields (entries 2–7). As in the reactions
of carbamates (vide ante), water-soluble aldehydes (R¼Et,
H, i-Pr) showed the poor reactivity to that of water-insoluble
aldehydes (R¼n-hexyl, n-dodecyl, c-hexyl). As shown in
Table 5, 3-MeO substituted derivative 11 reacted smoothly
with both n-heptanal and benzaldehyde to give the corre-
sponding para-cyclized products 12a and 12e in high yields
as a single isomer, respectively (entries 1 and 2). Phenethyl
alcohol 13, however, afforded no cyclized products (entries
3 and 4).
Under the optimized conditions, scope of the PFOSA-
catalyzed oxa-Pictet–Spengler reactions in HFIP–water
40
35
34
30
25
25
20
15
16
10
5
12
2
0
2.3. Pictet–Spengler reaction versus intermolecular
Friedel–Crafts reaction
Figure 3. Catalysts (10 mol % to 9) for the reaction of 9 with n-heptanal
(1.2 equiv) at rt for 2 h in HFIP–water (10 v/v %, 1 mL). (Yield of 10a
was determined by 1H NMR.)
In the mechanistic points, the formation of tetrahydro-
isoquinoline or isochroman compounds under the present

A. Saito et al. / Tetrahedron 63 (2007) 4039–4047
4043
Table 4. Catalytic oxa-Pictet–Spengler reactions of 9 with various alde-
H
N
MeO
MeO
hydesa
n-C6H13CHO
(1.2 equiv)
Ph
CO2Me
+
+
MeO
MeO
MeO
PFOSA (10 mol%)
7
15
RCHO
+
OH
O
HFIP-H2O (10 V/V%)
MeO
Ph
R
PFOSA
9
10
MeO
MeO
MeO
MeO
(20 mol%)
or
OH
N
HFIP-H2O
90 °C, 40 h
Entry Aldehyde (equiv)
Temperature (ꢀC) Time (h) 10 (%)b
CO2Me
17 n-C6H13
(not formed)
16 n-C6H13
(not formed)
1
2
n-C6H13CHO (1.2)
n-C11H23CHO (1.8) rt
EtCHO (1.8) rt
37% Formaline (3.6) 60
PhCHO (2.4)
c-C6H11CHO (4.8)
i-PrCHO (4.8)
rt
48
48
96
72
18
4
10a (93)
10b (91)
10c (87)
10d (86)
10e (95)
10f (84)
10g (60)
3
4c
5
Scheme 5.
90
90
90
6c
7c
3. Conclusion
24
a
b
c
For the purpose of the catalytic Pictet–Spengler reactions of
b-arylethyl carbamate derivatives in water, PFOSA was
found to be efficient. It was also found that the addition of
HFIP towater significantly accelerates the catalytic reactions
with various aldehydes. PFOSA in 10 v/v % HFIP–water
systems was applied to the oxa-Pictet–Spengler reactions
of b-arylethyl alcohol compounds with various aldehydes.
We believe that the present method could be contributed to
the syntheses of tetrahydroisoquinoline and isochroman
compounds from the standpoint of the reduction of organic
solvent.
Reaction concentration: 1/HFIP–water¼0.42 mmol/1 mL.
Isolated yield.
PFOSA: 20 mol %.
condition would be possible to proceed through the inter-
molecular Friedel–Crafts type reaction of aryl core of
substrate with aldehyde (path b, Scheme 4) prior to the gen-
eration of N-acyl iminium or oxonium ion intermediate A as
we expected (path a). To gain a better understanding, we
attempted the reaction of 3,4-dimethoxybenzene 15 with
n-heptanal (Scheme 5). Under similar condition to 2a (entry
6, Table 1), the presumed product 16 was not obtained even
at 90 ꢀC for 40 h. The three-component coupling reaction of
15, n-heptanal, and carbamate 7 did not afford the product 17
either, but recovered compound 15 (Scheme 5). By taking
into consideration of N-acyl iminium ion-activated Pictet–
Spengler or Mannich reaction18 and oxa-Pictet–Spengler re-
action9, we believe that the present process involves N-acyl
iminium or oxonium intermediate A as shown in Scheme 4.
4. Experimental
4.1. General
Carbamates 1, 3, 5, and 7 were prepared by the reported pro-
cedure in literatures.30 Substrates 9, 11, and 13 are commer-
cially available. Column chromatography was performed on
silica gel (63–200 mm mesh, spherical, neutral). 1H and 13
C
NMR spectra were measured at 300.4 and 75.5 MHz in
CDCl3, respectively, and the chemical shifts aregivenin parts
per million using CHCl3 (7.26 ppm) in CDCl3 for 1H NMR
and CDCl3 (77.0 ppm) for 13C NMR as an internal standard.
From NMR spectra of tetraisoquinoline compounds 2, 4, and
6, each ca. 1:1 rotamer mixture was observed. Mass spectra
and HRMS were recorded by FAB method.
MeO
MeO
MeO
MeO
RCHO, PFOSA
XH
X
HFIP-H2O
X = NCO2Et, O
R
1 or 9
2 or 10
a
b
MeO
MeO
MeO
XH
OH
4.2. Screening of Brønsted acid catalyst for
Pictet–Spengler reaction in water
or
X
MeO
R
A
B
R
To a mixture of carbamate 1 (0.42 mmol) and Brønsted
acid (0.084 or 0.42 mmol) in water (1.0 mL) was added
Scheme 4.
Table 5. Catalytic oxa-Pictet–Spengler reactions of some carbamatesa
Entry
Carbamate
Aldehyde (equiv)
Temperature (ꢀC)
Time (h)
Product
Yieldb (%)
MeO
MeO
1
2
CH3(CH2)5CHO (1.2)
PhCHO (2.4)
rt
90
48
18
12a: R¼CH3(CH2)5
93
86
O
OH
12e: R¼Ph
11
R
c
3
4
CH3(CH2)5CHO (1.2)
PhCHO (2.4)
90
90
20
15
14a: R¼CH3(CH2)5
14e: R¼Ph
—
O
c
—
OH
13
R
a
All Reactions of carbamates (0.42 mmol) with aldehyde (1.2 equiv) were carried out in the presence of PFOSA (10 mol %) in HFIP–water (10 v/v %, 1 mL).
Isolated yield.
Phenethyl alcohol 13 was recovered.
b
c

4044
A. Saito et al. / Tetrahedron 63 (2007) 4039–4047
n-heptanal (0.50 mmol). After being stirred at ambient tem-
perature for 18 h, the reaction mixture was quenched with
saturated aq NaHCO3 and brine, and extracted with ether.
The organic layer was dried over MgSO4, and the filtrate
was concentrated to dryness to give a crude mixture. The ra-
tio of 2a/1 and the yield of 2a were determined by 1H NMR
using toluene (50 mL, 0.47 mmol) as an internal standard.
13C NMR (75 MHz, CDCl3) d: 10.8, 27.7, 28.0, 29.4, 29.6,
37.3, 37.9, 52.4, 55.6, 55.8, 55.9, 109.8, 110.1, 111.3, 111.4,
125.6, 125.9, 129.6, 129.9, 147.2, 147.5, 156.3. FAB-LM
m/z: 280 (M+H). FAB-HM Calcd for C15H21NO4:
280.1579. Found: 280.1579. Anal. Calcd for C15H21NO4:
C, 64.59; H, 7.57; N, 4.87. Found: C, 64.50; H, 7.58; N, 5.01.
4.3.4. N-(Methoxycarbonyl)-6,7-dimethyloxy-1,2,3,4-
tetrahydroisoquinoline (2d). The H NMR spectra of 2d
1
4.3. General procedure for PFOSA-catalyzed
Pictet–Spengler reactions in HFIP–water
were identical to that reported in the literature.31
To a mixture of carbamate 1, 3, 5, or 7 (0.42 mmol), perfluoro-
octanesulfonic acid (PFOSA, 0.084 mmol), and hexafluoro-
isopropanol (HFIP, 1.3 mmol) in water (1.0 mL) was added
aldehyde (0.50–1.0 mmol). After being stirred until the con-
sumption of starting carbamate by TLC analysis, the reac-
tion mixture was quenched with saturated aq NaHCO3 and
brine, and extracted with ether. The organic layer was dried
over MgSO4, and the filtrate was concentrated to dryness to
give a crude mixture. Purification by silica gel column chro-
matography (hexane/AcOEt¼6:1) gave a pure product 2, 4,
or 6.
4.3.5. N-(Methoxycarbonyl)-6,7-dimethyloxy-1-phenyl-
1,2,3,4-tetrahydroisoquinoline (2e). The 1H NMR spectra
of 2e were identical to that reported in the literature.19
4.3.6. N-(Methoxycarbonyl)-1-cyclohexyl-6,7-dimethyl-
oxy-1,2,3,4-tetrahydroisoquinoline (2f). Pale yellow oil.
IR (neat) n cmꢁ1: 1697, 1255. 1H NMR (300 MHz, CDCl3)
d: 0.92–1.25 (5H, m), 1.49–1.81 (6H, m), 2.69–2.90 (2H,
m), 3.39–3.54 (1H, m), 3.67 (3H, s), 3.74–3.85 (0.5H, m),
3.81 (6H, s), 3.98–4.12 (0.5H, m), 4.61 (0.5H, d,
J¼8.4 Hz), 4.76 (0.5H, d, J¼8.6 Hz), 6.54 (0.5H, br s),
6.66 (1.5H, br s). 13C NMR (75 MHz, CDCl3) d: 26.1,
26.2, 26.3, 27.0, 27.3, 29.7, 29.8, 30.6, 30.7, 39.0, 39.6,
52.3, 52.4, 55.7, 55.9, 56.0, 59.0, 59.7, 111.2, 111.4, 111.5,
111.6, 126.1, 126.4, 128.4, 128.9, 146.4, 146.5, 147.6,
147.7, 156.4, 156.7. FAB-LM m/z: 334 (M+H). FAB-HM
Calcd for C19H28NO4: 334.2018. Found: 334.2019.
4.3.1. N-(Methoxycarbonyl)-6,7-dimethyloxy-1-hexyl-
1,2,3,4-tetrahydroisoquinoline (2a). Colorless crystals.
1
Mp 56–57 ꢀC. IR (KBr) n cmꢁ1: 1658, 1259. H NMR
(300 MHz, CDCl3) d: 0.72–0.89 (3H, m), 1.01–1.48 (8H,
m), 1.53–1.79 (2H, m), 2.55 (1H, dt, J¼15.9, 3.5 Hz),
2.69–2.90 (1H, m), 3.04–3.29 (1H, m), 3.64 (3H, s), 3.76
(3H, s), 3.78 (3H, s), 3.88–4.02 (0.5H, m), 4.09–4.22 (0.5H,
m), 4.90 (0.5H, dd, J¼9.2, 4.1 Hz), 5.02 (0.5H, dd, J¼8.1,
5.0 Hz), 6.44–6.53 (2H, m). 13C NMR (75 MHz, CDCl3) d:
14.0, 22.6, 26.2, 26.2, 28.0, 29.1, 29.2, 31.7, 36.7, 36.8, 37.2,
37.9, 52.5, 54.3, 54.5, 55.8, 56.0, 109.8, 110.1, 111.4, 111.5,
125.6, 125.9, 129.9, 130.3, 147.3, 147.6, 156.2. FAB-LM m/
z: 336 (M+H). FAB-HM Calcd for C19H30NO4: 336.2179.
Found: 336.2175. Anal. Calcd for C19H29NO4: C, 67.74; H,
8.76; N, 4.09. Found: C, 68.03; H, 8.71; N, 4.18.
4.3.7. N-(Methoxycarbonyl)-1-isopropyl-6,7-dimethyl-
oxy-1,2,3,4-tetrahydroisoquinoline (2g). Colorless crys-
1
tals. IR (neat) n cmꢁ1: 1698, 1254. H NMR (300 MHz,
CDCl3) d: 0.92–1.02 (6H, m), 1.92–2.19 (1H, m), 2.68–
2.97 (2H, m), 3.30–3.54 (1H, m), 3.71 (3H, s), 3.74–3.92
(0.5H, m), 3.85 (6H, s), 4.06–4.17 (0.5H, m), 4.64 (0.5H,
d, J¼8.3 Hz), 4.78 (0.5H, d, J¼8.5 Hz), 6.56–6.68 (2H,
m). 13C NMR (75 MHz, CDCl3) d: 19.6, 19.7, 20.2, 20.3,
27.2, 27.4, 33.8, 33.9, 39.0, 39.6, 52.3, 52.5, 55.8, 55.9,
60.2, 60.3, 111.1, 111.2, 111.4, 111.5, 126.2, 126.4, 128.6,
129.1, 146.6, 146.7, 147.6, 147.7, 156.4, 156.7. FAB-LM
m/z: 294 (M+H). FAB-HM Calcd for C16H23NO4:
293.1627. Found: 293.1627.
4.3.2. N-(Methoxycarbonyl)-6,7-dimethyloxy-1-undecyl-
1,2,3,4-tetrahydroisoquinoline (2b). Colorless crystals.
1
Mp 41–42 ꢀC. IR (KBr) n cmꢁ1: 1701, 1257. H NMR
(300 MHz, CDCl3) d: 0.86 (3H, t, J¼6.9 Hz), 1.16–1.52
(18H, m), 1.59–1.84 (2H, m), 2.60 (1H, dt, J¼15.9,
3.5 Hz), 2.74–2.86 (1H, m), 3.10–3.32 (1H, m), 3.70 (3H,
s), 3.82 (3H, s), 3.83 (3H, s), 3.91–4.08 (0.5H, m), 4.14–
4.30 (0.5H, m), 4.91–5.02 (0.5H, m), 5.02–5.14 (0.5H, m),
6.49–6.60 (2H, m). 13C NMR (75 MHz, CDCl3) d: 14.0,
22.6, 26.2, 27.7, 28.0, 29.2, 29.4, 29.5, 29.6, 31.8, 36.6, 36.8,
37.2, 37.9, 52.4, 54.3, 54.4, 55.8, 55.9, 109.8, 110.1, 111.3,
111.5, 125.6, 125.9, 129.8, 130.2, 147.3, 147.6. FAB-LM
m/z: 406 (M+H). FAB-HM Calcd for C24H40NO4:
406.2949. Found: 406.2958. Anal. Calcd for C24H39NO4:
C, 71.07; H, 9.69; N, 3.45. Found: C, 71.47; H, 9.44; N, 3.24.
4.3.8. N-(Methoxycarbonyl)-1-hexyl-6-hydroxy-1,2,3,4-
tetrahydroisoquinoline (4a). Colorless oil. IR (neat) n
1
cmꢁ1: 3329, 1672, 1232. H NMR (300 MHz, CDCl3) d:
0.78–0.98 (3H, m), 1.15–1.48 (8H, m), 1.58–1.89 (2H, m),
2.58–2.74 (1H, m), 2.75–2.92 (1H, m), 3.18–3.39 (1H, m),
3.74 (3H, s), 3.88–3.99 (0.5H, m), 4.07–4.17 (0.5H, m),
4.97 (0.5H, dd, J¼9.2, 4.9 Hz), 5.07 (0.5H, dd, J¼8.1,
5.7 Hz), 6.60 (1H, s), 6.67 (0.5H, d, J¼8.4 Hz), 6.70 (0.5H,
d, J¼8.1 Hz), 6.89 (0.5H, d, J¼8.1 Hz), 6.91 (0.5H, d,
J¼8.4 Hz). 13C NMR (75 MHz, CDCl3) d: 14.1, 22.6, 26.2,
28.2, 28.6, 29.0, 29.2, 31.8, 36.9, 37.1, 37.6, 38.1, 52.8,
54.6, 54.8, 113.6, 115.0, 115.2, 128.0, 128.2, 129.5, 129.7,
135.0, 135.2, 154.7, 156.6, 156.7. FAB-LM m/z: 292
(M+H). FAB-HM Calcd for C17H26NO3: 292.1913. Found:
292.1896. Anal. Calcd for C17H25NO3: C, 70.07; H, 8.65;
N, 4.81. Found; C, 70.19; H, 8.56; N, 4.63.
4.3.3. N-(Methoxycarbonyl)-6,7-dimethyloxy-1-ethyl-
1,2,3,4-tetrahydroisoquinoline (2c). Colorless crystals.
1
Mp 71–72 ꢀC. IR (KBr) n cmꢁ1: 1697, 1263. H NMR
(300 MHz, CDCl3) d: 0.94 (3H, t, J¼6.7 Hz), 1.69–1.82
(2H, m), 2.60 (1H, dt, J¼15.9, 3.7 Hz), 2.73–2.92 (1H, m),
3.08–3.31 (1H, m), 3.69 (3H, s), 3.81 (3H, s), 3.82 (3H, s),
3.90–4.07 (0.5H, m), 4.13–4.28 (0.5H, m), 4.88 (0.5H,
t, J¼6.8 Hz), 5.00 (0.5H, t, J¼6.8 Hz), 6.56 (2H, br s).
4.3.8.1. N-(Methoxycarbonyl)-1-hexyl-8-hydroxy-
1,2,3,4-tetrahydroisoquinoline (o-4a). Colorless crystals.
1
IR (KBr) n cmꢁ1: 3324, 1670, 1126. H NMR (300 MHz,

A. Saito et al. / Tetrahedron 63 (2007) 4039–4047
4045
CDCl3) d: 0.78–0.97 (3H, m), 1.15–1.52 (8H, m), 1.53–1.72
(1H, m), 1.81–2.01 (1H, m), 2.74 (1H, ddd, J¼16.4, 4.2,
3.4 Hz), 2.79–3.03 (1H, m), 3.21–3.45 (1H, m), 3.73 (1.5H,
s), 3.76 (1.5H, s), 3.94–4.06 (0.5H, m), 4.15–4.27 (0.5H,
m), 5.30 (0.5H, dd, J¼10.3, 3.4 Hz), 5.46 (0.5H, dd,
J¼10.1, 3.8 Hz), 5.89 (1H, br s), 6.62 (1H, d, J¼7.5 Hz),
6.64 (0.5H, br s), 6.67 (1H, d, J¼7.5 Hz), 6.98 (0.5H, t,
J¼7.5 Hz), 7.00 (0.5H, t, J¼7.5 Hz). 13C NMR (75 MHz,
CDCl3) d: 14.1, 22.7, 26.2, 26.3, 27.9, 28.2, 29.0, 29.2,
31.8, 31.9, 33.5, 33.6, 36.9, 37.6, 50.5, 50.6, 52.6, 52.8,
112.8, 113.1, 120.4, 121.1, 125.6, 125.8, 126.9, 127.0,
134.9, 135.6, 151.9, 152.6, 156.7, 156.8. FAB-LM m/z: 292
(M+H). FAB-HM Calcd for C17H26NO3: 292.1913. Found:
292.1908.
(3H, m), 1.21–1.49 (8H, m), 1.53–1.96 (2H, m), 2.69
(0.4H, dd, J¼4.5, 3.0 Hz), 2.74 (0.6H, dd, J¼4.5, 3.1 Hz),
2.82–3.02 (1H, m), 3.19–3.41 (1H, m), 3.71 (3H, s), 3.81
(1.2H, s), 3.84 (1.8H, s), 3.98 (0.4H, ddd, J¼13.4, 5.9,
3.1 Hz), 4.21 (0.6H, ddd, J¼13.2, 6.3, 3.0 Hz), 5.26 (0.6H,
dd, J¼10.2, 3.3 Hz), 5.41 (0.4H, dd, J¼9.9, 3.7 Hz), 6.66–
6.75 (2H, m), 7.11 (0.4H, t, J¼7.8 Hz), 7.13 (0.6H, d,
J¼7.8 Hz). 13C NMR (75 MHz, CDCl3) d: 14.1, 22.7,
26.1, 26.2, 27.8, 28.2, 28.9, 29.1, 31.8, 33.5, 33.6, 36.6,
37.4, 50.2, 50.3, 52.4, 52.5, 55.2, 107.7, 107.9, 120.9,
121.3, 126.9, 127.0, 127.2, 127.5, 134.9, 135.1, 155.5,
155.8, 156.3, 156.4. FAB-LM m/z: 306 (M+H). FAB-HM
Calcd for C18H28NO3: 306.2069. Found: 306.2066.
4.3.11. N-(Methoxycarbonyl)-1-phenyl-6-methoxy-1,2,-
3,4-tetrahydroisoquinoline (6e). Colorless crystals. Mp
83–84 ꢀC. IR (KBr) n cmꢁ1: 1697, 1230. 1H NMR
(300 MHz, CDCl3) d: 2.66 (1H, dt, J¼16.1, 3.8 Hz), 2.81–
3.01 (1H, m), 3.09–3.24 (1H, m), 3.70 (3H, s), 3.74 (3H, s),
3.82–4.19 (1H, m), 6.21 (0.5H, br s), 6.33 (0.5H, br s), 6.66
(1H, s), 6.68 (1H, d, J¼8.2 Hz), 6.90 (1H, d, J¼8.2 Hz),
7.05–7.28 (5H, m). 13C NMR (75 MHz, CDCl3) d: 28.7,
38.0, 52.7, 55.3, 57.3, 112.5, 113.4, 127.3, 127.5, 128.2,
129.5, 136.3, 142.8, 156.0, 158.4. FAB-LM m/z: 298
(M+H). FAB-HM Calcd for C18H20NO3: 298.1491. Found:
298.1467. Anal. Calcd for C18H20NO3: C, 72.71; H, 6.44;
N, 4.71. Found: C, 72.77; H, 6.51; N, 4.61.
4.3.9. N-(Methoxycarbonyl)-1-phenyl-6-hydroxy-1,2,3,4-
tetrahydroisoquinoline (4e). Colorless oil. IR (neat) n
1
cmꢁ1: 3318, 1672, 1232. H NMR (300 MHz, CDCl3) d:
2.65 (1H, dt, J¼16.2, 3.9 Hz), 2.81–2.96 (1H, m), 3.16–
3.32 (1H, m), 3.80 (3H, s), 3.88–4.15 (1H, m), 6.17–6.43
(1H, m), 6.64–6.76 (2H, m), 6.87 (1H, d, J¼9.0 Hz), 7.11–
7.31 (5H, m). 13C NMR (75 MHz, CDCl3) d: 28.4, 38.1,
53.0, 57.4, 113.8, 115.1, 126.8, 127.4, 128.2, 129.5, 136.2,
142.5, 155.1, 156.4. FAB-LM m/z: 284 (M+H). FAB-HM
Calcd for C17H18NO3: 284.1286. Found: 280.1275.
4.3.9.1. N-(Methoxycarbonyl)-1-phenyl-8-hydroxy-
1,2,3,4-tetrahydroisoquinoline (o-4e). Colorless crystals.
1
Mp 205–206 ꢀC. IR (neat) n cmꢁ1: 3334, 1660, 1247. H
4.3.11.1. N-(Methoxycarbonyl)-1-phenyl-8-methoxy-
1,2,3,4-tetrahydroisoquinoline (o-6e). Pale yellow oil. IR
(neat) n cmꢁ1: 1697, 1230. 1H NMR (300 MHz, CDCl3) d:
2.67–2.80 (1H, m), 2.88–3.07 (1H, m), 3.09–3.29 (1H, m),
3.67 (1.5H, s), 3.68 (1.5H, s), 3.75 (1.5H, s), 3.81 (1.5H, s),
3.82–3.95 (0.5H, m), 3.94–4.10 (0.5H, m), 6.52 (0.5H, s),
6.68 (0.5H, s), 6.74 (1H, d, J¼7.2 Hz), 6.81 (1H, t,
J¼7.2 Hz), 7.12 (1H, d, J¼7.2 Hz), 7.16–7.32 (5H, m). 13C
NMR (75 MHz, CDCl3) d: 27.8, 28.1, 37.7, 37.9, 52.8,
53.0, 55.4, 108.1, 120.8, 121.2, 126.9, 127.4, 127.7, 127.8,
128.0, 128.2, 136.1, 136.5, 141.9, 142.1, 156.0, 156.3. FAB-
LM m/z: 298 (M+H). FAB-HM Calcd for C18H20NO3:
298.1491. Found: 298.1485.
NMR (300 MHz, CDCl3) d: 2.71 (0.5H, dd, J¼4.0,
3.6 Hz), 2.76 (0.5H, dd, J¼3.8, 3.6 Hz), 2.87–3.07 (1H, m),
3.08–3.24 (1H, m), 3.74 (1.5H, s), 3.80 (1.5H, s), 3.86–4.13
(1H, m), 5.34 (0.5H, br s), 5.91 (0.5H, br s), 6.50 (0.5H, br s),
6.67 (1H, d, J¼7.8 Hz), 6.72 (0.5H, br s), 6.76 (0.5H, d,
J¼7.8 Hz), 6.80 (0.5H, d, J¼7.8 Hz), 7.12 (1H, t, J¼
7.8 Hz), 7.16–7.33 (5H, m). 13C NMR (75 MHz, CDCl3)
d: 27.8, 28.2, 37.5, 37.8, 52.9, 53.2, 113.2, 113.5, 120.8,
121.3, 122.7, 127.5, 127.7, 128.0, 128.3, 136.2, 136.8,
141.1, 152.3, 152.8, 155.8, 156.4. FAB-LM m/z: 284
(M+H). FAB-HM Calcd for C17H18NO3: 284.1286. Found:
284.1287.
4.3.10. N-(Methoxycarbonyl)-1-hexyl-6-methoxy-1,2,3,4-
tetrahydroisoquinoline (6a). Colorless oil. IR (neat) n
4.4. General procedure for PFOSA-catalyzed
oxa-Pictet–Spengler reactions in HFIP–water
1
cmꢁ1: 1701, 1230. H NMR (300 MHz, CDCl3) d: 0.73–
0.88 (3H, m), 1.11–1.42 (8H, m), 1.49–1.78 (2H, m), 2.63
(1H, dt, J¼16.3, 4.0 Hz), 2.72–2.96 (1H, m), 3.08–3.34
(1H, m), 3.65 (3H, s), 3.70 (3H, s), 3.81–3.94 (0.5H, m),
4.14–4.19 (0.5H, m), 4.92 (0.5H, dd, J¼8.9, 4.4 Hz), 5.03
(0.5H, dd, J¼7.9, 5.5 Hz), 6.56 (1H, s), 6.66 (0.5H, d,
J¼8.4 Hz), 6.67 (0.5H, d, J¼8.4 Hz), 6.92 (0.5H, d,
J¼8.4 Hz), 6.95 (0.5H, d, J¼8.4 Hz). 13C NMR (75 MHz,
CDCl3) d: 14.1, 22.6, 26.0, 26.3, 28.5, 28.8, 29.1, 29.2,
31.8, 37.0, 37.1, 37.4, 38.1, 52.5, 54.3, 54.5, 55.2, 112.1,
112.4, 113.4, 127.9, 128.2, 130.3, 130.5, 135.1, 135.3, 156.3,
158.0. FAB-LM m/z: 306 (M+H). FAB-HM Calcd for
C18H28NO3: 306.2069. Found: 306.2070. Anal. Calcd for
C18H27NO3: C, 70.79; H, 8.91; N, 4.59. Found: C, 70.85;
H, 8.97; N, 4.44.
To a mixture of carbamate 9, 11, or 13 (0.42 mmol) and per-
fluorooctanesulfonic acid (PFOSA, 0.042 or 0.084 mmol) in
HFIP–water (10 v/v %, 1.0 mL) was added aldehyde (0.50–
2.0 mmol). After being stirred until the consumption of start-
ing carbamate by TLC analysis, the reaction mixture was
quenched with saturated aq NaHCO3 and brine, and extracted
with ether. The organic layer was dried over MgSO4, and the
filtrate was concentrated to dryness to give a crude mixture.
Purification by silica gel column chromatography (hexane/
AcOEt¼10:1) gave a pure product 10 or 12.
4.4.1. 6,7-Dimethoxy-1-hexyl-3,4-dihydro-1H-isochromene
1
(10a). Colorless oil. IR (neat) n cmꢁ1: 1514, 1107. H NMR
(300 MHz, CDCl3) d: 0.86 (3H, t, J¼6.8 Hz), 1.20–1.52 (8H,
m), 1.70–1.89 (2H, m), 2.57 (1H, dt, J¼16.0, 3.6 Hz), 2.82–
2.92 (1H, m), 3.67–3.75 (1H, m), 3.83 (6H, s), 4.05–4.12 (1H,
m), 4.65 (1H, dd, J¼7.8, 2.7 Hz), 6.53 (1H, s), 6.56 (1H, s).
13C NMR (75 MHz, CDCl3) d: 13.9, 22.5, 25.1, 28.6, 29.3,
4.3.10.1. N-(Methoxycarbonyl)-1-hexyl-8-methoxy-
1,2,3,4-tetrahydroisoquinoline (o-6a). IR (neat) n cmꢁ1
:
1701, 1261. 1H NMR (300 MHz, CDCl3) d: 0.87–0.93

4046
A. Saito et al. / Tetrahedron 63 (2007) 4039–4047
31.7, 36.0, 55.7, 55.9, 63.0, 75.4, 107.9, 111.4, 125.9, 130.4,
147.3. FAB-LM m/z: 279 (M+H). FAB-HM Calcd for
C17H27O3: 279.1961. Found: 279.1953.
4.4.7. 6,7-Dimethoxy-1-isopropyl-3,4-dihydro-1H-iso-
chromene (10g). Colorless crystals. Mp 48–50 ꢀC. IR
(KBr) n cmꢁ1: 1512, 1103. 1H NMR (300 MHz, CDCl3) d:
0.71 (3H, d, J¼6.8 Hz), 1.15 (3H, d, J¼6.8 Hz), 2.19 (1H,
qqd, J¼6.8, 6.8, 2.7 Hz), 2.47 (1H, d, J¼15.9 Hz), 2.89–
2.99 (1H, m), 3.65 (1H, ddd, J¼11.3, 11.3, 3.0 Hz), 3.84
(3H, s), 3.85 (3H, s), 4.16 (1H, ddd, J¼11.3, 5.5, 1.7 Hz),
4.59 (1H, d, J¼2.7 Hz), 6.56 (1H, s), 6.58 (1H, s). 13C
NMR (75 MHz, CDCl3) d: 15.0, 19.8, 29.0, 33.4, 55.8,
56.0, 64.2, 79.9, 107.8, 111.4, 127.1, 129.8, 147.3, 147.5.
FAB-LM m/z: 237 (M+H). FAB-HM Calcd for C14H21O3:
237.1491. Found: 237.1483.
4.4.2. 6,7-Dimethoxy-1-undecyl-3,4-dihydro-1H-isochro-
mene (10b). Colorless crystals. Mp 41–43 ꢀC. IR (KBr) n
1
cmꢁ1: 1522, 1111. H NMR (300 MHz, CDCl3) d: 0.80
(3H, t, J¼6.7 Hz), 1.18–1.46 (18H, m), 1.62–1.79 (2H, m),
2.53 (1H, dt, J¼15.9, 3.6 Hz), 2.78–2.88 (1H, m), 3.67–
3.71 (1H, m), 3.78 (3H, s), 3.78 (3H, s), 4.01–4.07 (1H, m),
4.6 (1H, dd, J¼8.0, 2.8 Hz), 6.48 (1H, s), 6.52 (1H, s). 13C
NMR (75 MHz, CDCl3) d: 14.1, 22.7, 25.3, 28.7, 29.4, 29.8,
29.9, 31.9, 36.1, 55.9, 56.0, 63.2, 75.6, 108.0, 111.5, 126.0,
130.5, 147.4. FAB-LM m/z: 349 (M+H). FAB-HM Calcd
for C22H37O3: 349.2742. Found: 349.2755. Anal. Calcd for
C22H36O3: C, 75.82; H, 10.41. Found: C, 75.52; H, 10.11.
4.4.8. 1-Hexyl-6-methoxy-3,4-dihydro-1H-isochromene
(12a). Colorless oil. IR (neat) n cmꢁ1: 1502, 1105. 1H
NMR (300 MHz, CDCl3) d: 0.80 (3H, t, J¼6.7 Hz), 1.18–
1.46 (8H, m), 1.62–1.89 (2H, m), 2.59 (1H, dt, J¼16.2,
3.6 Hz), 2.87 (1H, dd, J¼9.4, 5.9 Hz), 3.63–3.68 (1H, m),
3.71 (3H, s), 4.01–4.08 (1H, m), 4.62 (1H, dd, J¼8.1,
2.7 Hz), 6.56 (1H, d, J¼2.7 Hz), 6.67 (1H, dd, J¼8.5,
2.7 Hz), 6.92 (1H, d, J¼8.5 Hz). 13C NMR (75 MHz,
CDCl3) d: 14.1, 22.7, 25.2, 29.4, 29.5, 31.9, 36.1, 55.2,
63.1, 75.7, 112.4, 113.3, 125.9, 130.9, 135.2, 157.7. FAB-
LM m/z: 249 (M+H). FAB-HM Calcd for C16H25O2:
249.1855. Found: 249.1867.
4.4.3. 6,7-Dimethoxy-1-ethyl-3,4-dihydro-1H-isochro-
mene (10c). Colorless oil. IR (neat) n cmꢁ1: 1512, 1138.
1H NMR (300 MHz, CDCl3) d: 0.98 (3H, t, J¼7.3 Hz),
1.70–1.85 (1H, m), 1.88–2.01 (1H, m), 2.59 (1H, dt,
J¼15.9, 3.6 Hz), 2.85–2.95 (1H, m), 3.70–3.78 (1H, m),
3.84 (3H, s), 3.85 (3H, s), 4.08–4.15 (1H, m), 4.58–4.65
(1H, m), 6.55 (1H, s), 6.59 (1H, s). 13C NMR (75 MHz,
CDCl3) d: 9.50, 28.7, 28.8, 55.8, 56.0, 63.2, 107.9, 111.5,
126.2, 130.1, 147.4. FAB-LM m/z: 232.2 (M+H). FAB-
HM Calcd for C13H19O3: 223.1334. Found: 223.1335.
4.4.9. 6-Methoxy-1-phenyl-3,4-dihydro-1H-isochromene
(12e). The H NMR spectra of 12e were identical to that
1
4.4.4. 6,7-Dimethoxy-3,4-dihydro-1H-isochromene (10d).
Colorless crystals. Mp 60–62 ꢀC. IR (KBr) n cmꢁ1: 1516,
1095. 1H NMR (300 MHz, CDCl3) d: 2.70 (2H, t, J¼
5.7 Hz), 3.76 (3H, s), 3.78 (3H, s), 3.88 (2H, t, J¼5.7 Hz),
4.63 (2H, s), 6.40 (1H, s), 6.54 (1H, s). 13C NMR
(75 MHz, CDCl3) d: 27.8, 55.9, 65.4, 67.7, 107.3, 111.7,
125.0, 126.7, 147.5, 147.7. FAB-LM m/z: 195 (M+H).
FAB-HM Calcd for C11H15O3: 195.1021. Found: 195.1011.
Anal. Calcd for C11H14O3: C, 68.02; H, 7.27. Found; C,
68.00; H, 7.36.
reported in the literature.32
Acknowledgements
This work was supported by Grant-in-Aid for Young Scien-
tists (B), MEXT Japan (No. 17790021). A generous dona-
tion of HFIP by Central Glass Co., Ltd is gratefully
acknowledged.
References and notes
4.4.5. 6,7-Dimethoxy-1-phenyl-3,4-dihydro-1H-isochro-
mene (10e). Colorless crystals. Mp 73–75 ꢀC. IR (KBr) n
1
cmꢁ1: 1514, 1090. H NMR (300 MHz, CDCl3) d: 2.74
1. Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030.
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Wiley-Interscience: New York, NY, 1983; Part 4 (The
Monoterpenoid Indole Alkaloids); (b) Bentley, K. W. Nat.
Prod. Rep. 2004, 21, 395 and references therein.
(1H, dt, J¼16, 4.0 Hz), 2.99–3.09 (1H, m), 3.65 (3H, s),
3.85–3.93 (4H, m), 4.14 (1H, dt, J¼11.3, 5.2 Hz), 5.68
(1H, s), 6.24 (1H, s), 6.66 (1H, s), 7.28–7.38 (5H, m). 13C
NMR (75 MHz, CDCl3) d: 28.3, 55.9, 63.5, 79.1, 109.8,
111.2, 126.1, 128.1, 128.9, 128.9, 142.2, 147.3, 147.9.
FAB-LM m/z: 271 (M+H). FAB-HM Calcd for C17H19O3:
271.1334. Found: 271.1319. Anal. Calcd for C17H18O3: C,
75.53; H, 6.71. Found: C, 75.21; H, 6.77.
4. Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128,
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K.; Huebner, H.; Metz, H.; Schroeder, H. D.; Zeile, K. Justus
Liebigs Ann. Chem. 1965, 684, 159; (c) Kawai, M.; Deng, Y.;
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4.4.6. 1-Cyclohexyl-6,7-dimethoxy-3,4-dihydro-1H-iso-
chromene (10f). Colorless crystals. Mp 79–81 ꢀC. IR
(KBr) n cmꢁ1: 1517, 1107. 1H NMR (300 MHz, CDCl3) d:
1.03–1.84 (11H, m), 2.47 (1H, d, J¼15.8 Hz), 2.86–2.97
(1H, m), 3.65 (1H, ddd, J¼11.1, 11.1, 3.0 Hz), 3.85 (3H,
s), 3.85 (3H, s), 4.14 (1H, ddd, J¼11.1, 5.8, 1.9 Hz), 4.56
(1H, s), 6.57 (1H, s), 6.58 (1H, s). 13C NMR (75 MHz,
CDCl3) d: 25.6, 26.5, 26.5, 27.0, 29.0, 30.3, 43.8, 55.8,
56.1, 64.1, 79.8, 108.0, 111.4, 127.2, 129.3, 147.3, 147.3.
FAB-LM m/z: 276 (M). FAB-HM Calcd for C17H25O3:
277.1804. Found: 277.1831. Anal. Calcd for C17H24O3: C,
73.88; H, 8.75. Found: C, 73.54; H, 8.60.

A. Saito et al. / Tetrahedron 63 (2007) 4039–4047
4047
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27. We have carried out the pH determination of catalyst (80 mmol)
solutions in HFIP (130 mL)–water (1 mL) by pH meter.
PFOSA: 1.15. DBSA: 1.21. TfOH: 1.15.
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water, it has been reported that hydrochloride salt of 3,4-di-
methoxyphenethylamine (1) gave no cyclized product. In our
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