Thiophenol-mediated improvement of the Pictet-Spengler cyclization of N-tosyl-β-phenethylamines with aldehydes

Article abstract of DOI:10.1016/j.tetlet.2006.08.097

The Lewis acid-catalyzed Pictet-Spengler condensation of N-tosyl-β-phenethylamines with aldehydes is improved by the addition of thiophenol, furnishing better yields of 1-substituted tetrahydroisoquinolines at a given time.

Full text of DOI:10.1016/j.tetlet.2006.08.097

Tetrahedron Letters 47 (2006) 7545–7549
Thiophenol-mediated improvement of the
Pictet–Spengler cyclization of N-tosyl-b-phenethylamines
with aldehydes
Claudio C. Silveira,a,* Adriano S. Vieiraa and Teodoro S. Kaufmanb,*
aDepartamento de Quı´mica, Universidade Federal de Santa Maria, 97105.900, Santa Maria, RS, Brazil
bInstituto de Quı´mica Orga´nica de Sı´ntesis (CONICET-UNR), Suipacha 531, (S2002LRK) Rosario, Argentina
Received 15 August 2006; revised 22 August 2006; accepted 23 August 2006
Abstract—The Lewis acid-catalyzed Pictet–Spengler condensation of N-tosyl-b-phenethylamines with aldehydes is improved by the
addition of thiophenol, furnishing better yields of 1-substituted tetrahydroisoquinolines at a given time.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The Pictet–Spengler condensation of b-arylethylamines
with aldehydes and ketones as carbonyl components is
now established as one of the most powerful methods
toward the synthesis of 1,2,3,4-tetrahydroisoquinolines
(THIQ) and 1,2,3,4-tetrahydro-b-carbolines (THBC);1
other nitrogen heterocycles have also been prepared
employing this strategy.2 One of the useful variations
of the Pictet–Spengler reaction entails the use of electron
withdrawing groups, such as acyl or sulfonyl moieties,
bound to the starting b-arylethylamine. This allows the
convenient preparation of certain otherwise inaccessible
heterocycles, including optically active compounds.3
Masked carbonyls, among them acetals, enol ethers, as
well as a-halo-a-phenylthio-, a-halo-a-phenylseleno-
and similar derivatives have also been employed as
equivalents of the carbonyl component.4 It is notewor-
thy that Comins and Badawi reported that an enolether,
being more reactive than the corresponding aldehyde,
underwent a Pictet–Spengler reaction under conditions
where the aldehyde itself failed to react.5a
recently disclosed that the electrophilic cyclization of
an aldehyde onto an aromatic ring in a morphine inter-
mediate could be successfully effected in the presence of
ethyleneglycol, which actively participated in the reac-
tion mechanism, seeming to be essential to accelerate
the reaction and improve the yields. In addition, during
the synthesis of an analog of the stephaoxocane alka-
loids eletefine and stephaoxocanidine, we observed that
the addition of ethanol was key to the success of the
Jackson-type cyclization of an N-tosylaminoaldehyde
into a 1,2-dihydroisoquinoline derivative, the aldehyde
itself being completely unreactive in the absence of the
alcohol.5d Finally, Ito and Tanaka reported that
condensation of N-tosyl-3,4-dimethoxyphenethylamine
with 4-bromobenzaldehyde and piperonal required pro-
longed reflux conditions in chloroform and toluene,
respectively.6 In connection with our ongoing research
on the synthesis of tetrahydroisoquinolines employing
organochalcogen derivatives, we have recently reported
the Pictet–Spengler reaction of N-sulfonyl-b-arylethyl-
amines with thioorthoesters as carbonyl components,7
and were further interested in studying the Pictet–Spen-
gler condensation of these sulfonamides with the chem-
ically related phenylthioacetals.
Additives able to modify in situ the reactivity of the car-
bonyl component have shown to have a profound influ-
ence on the yield of different cyclizations involving
aldehydes. MacLean and Cundasawmy5b effected a Bob-
bitt-type cyclization in an aqueous-ethanolic medium
and the group of Ogasawara and co-workers5c more
As expected, we observed that the Pictet–Spengler con-
densation of N-sulfonyl-3,4-dimethoxyphenethylamine
with the phenylthioacetal of benzaldehyde went to
completion much faster than with the corresponding
aldehyde (Scheme 1). Since the synthesis of phenylthio-
acetals involves the reaction of thiophenol with alde-
hydes under Lewis acid catalysis,8 we supposed that
*
Corresponding authors. Tel./fax: +54 341 4370477 (T.S.K.); e-mail
addresses: silveira@quimica.ufsm.br; kaufman@iquios.gov.ar
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.097

7546
C. C. Silveira et al. / Tetrahedron Letters 47 (2006) 7545–7549
BF3.Et2O (1.5 equiv.), PhCHO (2 equiv.), CH2Cl2, 25ºC, 17 h
(73%)
MeO
MeO
MeO
N
N
H
Ts
MeO
Ts
BF3.Et2O (1.5 equiv.), PhCH(SPh)2 (2 equiv.), CH2Cl2, 25ºC, 17 h
(94%)
Scheme 1.
the overall transformation could be conveniently carried
out as a one pot process. Herein, we report the results of
our study of the effects of thiophenol (1) on the Pictet–
Spengler condensation of N-sulfonyl-b-phenethylamines
with aldehydes.
Four differently substituted N-tosyl-b-phenethylamines
(2) and a series of 17 carbonyl compounds were
employed (Table 1), including 14 mono-, di-, and tri-
substituted benzaldehydes, isobutyraldehyde, and cyclo-
hexane carboxaldehyde as non-aromatic aldehydes, and
Table 1. Effect of the addition of thiophenol (1) on the Pictet–Spengler synthesis of 1-substituted N-tosyl-1,2,3,4-tetrahydroisoquinolines (3)9,10
R1 R1
R-CHO (4), conditions
R2
R2
N
N
SH
R3
H
Ts
R3
Ts
R
3
1
2
Entry no. R1
R2
R3
R (aldehyde)
Solvent
CH2Cl2
ClCH2CH2Cl 80
ClCH2CH2Cl 40
CH2Cl2
CH2Cl2
ClCH2CH2Cl 50
ClCH2CH2Cl 40
Temp (ꢁC) Time (h) PhSH
Yield with
Yield without
(equiv) additive (%) additive (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe OMe C6H5
25
17
3
24
8
6
6
8
5
5
8
24
72
3
16
6
3
8
22
28
32
1.5
5
6
12
48
48
48
24
3
0.1
0.4
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0a
0.4
1.0b
1.0c
1.0d
94
96
42
91
86
87
85
75
84
81
73
66
49
42
91
85
82
71
85
81
88
85
83
86
0
73
49
15
19
58
63
57
31
68
63
48
47
31
21
13
48
43
38
24
60
53
57
48
41
0
OMe OMe 2-NO2–C6H4
OMe OMe 2-Me–C6H4
OMe OMe 2-Cl–C6H4
OMe OMe 2-Br–C6H4
OMe OMe 2-OMe–C6H4
OMe OMe 4-NO2–C6H4
OMe OMe 4-Me–C6H4
OMe OMe 4-Cl–C6H4
OMe OMe 4-Br–C6H4
OMe OMe 4-OMe–C6H4
25
25
CH2Cl2
CH2Cl2
CH2Cl2
25
25
25
ClCH2CH2Cl 50
OMe OMe 3-OMe–4-OH–C6H3 ClCH2CH2Cl 50
OMe OMe 3,5-(OMe)2–C6H3
OMe OMe 2,4,6-(OMe)3–C6H2
OMe OMe 2-CF3–C6H4
OMe OMe i-C3H7
Me
Me
Me
Me
ClCH2CH2Cl 50
ClCH2CH2Cl 80
CH2Cl2
CH2Cl2
25
25
H
H
H
H
i-C3H7
ClCH2CH2Cl 70
ClCH2CH2Cl 80
ClCH2CH2Cl 80
ClCH2CH2Cl 80
ClCH2CH2Cl 25
ClCH2CH2Cl 40
ClCH2CH2Cl 50
ClCH2CH2Cl 60
ClCH2CH2Cl 80
ClCH2CH2Cl 80
ClCH2CH2Cl 80
ClCH2CH2Cl 50
ClCH2CH2Cl 80
ClCH2CH2Cl 50
4-MeO–C6H4
4-NO2–C6H4
2-Cl–C6H4
OMe OMe c-C6H11
OMe OMe
OMe OMe
OMe OMe
H
H
H
H
H
H
H
H
H
H
H
4-MeO–C6H4
4-NO2–C6H4
2-Br–C6H4
i-C3H7
H
H
i-C3H7
0
0
49
48
32
0
0
47
45
47
OMe OMe Pinacolone
OMe OMe 4-OMe–C6H4
OMe OMe 4-OMe–C6H4
OMe OMe 4-OMe–C6H4
24
a ZnBr2 (2.0 equiv) was employed.
b EtSH (1.0 equiv) was used in place of PhSH.
c tBuSH (1.0 equiv) was used in place of PhSH.
d MeOH (1.0 equiv) was used in place of PhSH.

C. C. Silveira et al. / Tetrahedron Letters 47 (2006) 7545–7549
7547
pinacolone as a test ketone. Among the substituted
BF3.Et2O
-Et2O,
-HF
Route b
O
benzaldehydes, it was observed that the reaction showed
an improvement of the product yields in the presence of
thiophenol as additive. Generally, this trend was more
evident when the starting aldehydes carried an ortho
substituent than when the related para-substituted
derivatives were employed (entries 2–6 vs 7–11).
N
N
N
-BF3
8
Ts
R'
H
Ts
B
S
R
R
R
Ar
F
F
F2B O
F-
2
10
11
H
BF3.Et2O,
Route a
SPh
N
SPh
Ts
+
-PhS-
R
8
+PhS-
SPh
SPh
An analogous behavior was observed when other N-tos-
yl-b-phenethylamines were employed. Noteworthy, the
addition of thiophenol showed a marked increase in
the cyclization leading to the trifluoromethyl derivative
of entry 15, while the more activated aldehydes gave
comparatively lower conversions (entries 12–14).
10
R'
HS
7
6
R'
9
1
BF3.Et2O,
CH2Cl2
CHO
Yields were also influenced by the degree of activation
of the aromatic moiety. When iso-butyraldehyde was
employed, in the presence of thiophenol the activated
3,4-dimethoxy derivative provided good yields of the
expected product after 3 h at room temperature (entry
16). Similar results were obtained with the less active
3-methyl derivative, after 8 h at 70 ꢁC (entry 17); how-
ever, the less reactive N-sulfonyl-b-phenethylamine gave
no product in refluxing 1,2-dichloroethane, even after
48 h, under either BF3ÆEt2O or ZnBr2 Lewis acid promo-
tion (entries 25 and 26). A similar trend was observed
when 4-nitro- and 4-methoxy-benzaldehyde were used
as carbonyl components.
R'
BF3.Et2O
4
HO
N
N+
N
Ts
Ts
Ts
R
R
R
5
6
3
R'
R'
R'
Scheme 2. The proposed mechanism for the improvement of the
Pictet–Spengler cyclization reaction mediated by thiophenol.
source of key intermediate 8 en route toward 6, through
an acid-catalyzed transacetalization.13 The nitrogen of
sulfonamide 2 is non-nucleophilic and, therefore, it
seems unlikely that this itself is the species attacking 8.
However, upon coordination with the Lewis acid it
may undergo a loss of a proton, becoming more reactive
(10 or 11).14 This species would then attack 8, with a
loss of the Lewis acid, furnishing 7. The release of 1 dur-
ing the next stage could explain the improved yields ob-
served even when sub-stoichiometric amounts of
thiophenol were employed.
The aliphatic aldehydes tested exhibited the same kind
of yield improvement upon addition of thiophenol
(entries 16, 17, and 21). However, not unexpectedly,
the transformation did not take place with pinacolone
as the carbonyl component even in the presence of the
thiol (entry 27). This can be ascribed to the sterically
hindered nature of this ketone and to the lower reactiv-
ity of its carbonyl group. The use of other promoters
was also explored. However, ethyl mercaptan, tert-butyl
mercaptan, and methanol were not capable of producing
the reaction rate enhancement seen with thiophenol
(entries 28–30).
In light of the proposed mechanism, the different results
observed when 1, MeOH and aliphatic mercaptans were
used could be ascribed to the improved ability of thio-
phenol to produce intermediate 6. Perhaps this is due
to an easier formation of 712 (relative to production of
5 in its absence) or to the better charge stabilization
The mechanism of the Pictet–Spengler condensation for
the synthesis of THBC differs from that proposed
for the production of THIQ.11 In the latter case, it is
assumed (Scheme 2, route a) that upon initial reaction
of b-arylethylamine 2 with the carbonyl component 4
under Lewis acid catalysis, a hemiaminal type interme-
diate (5) is formed;1f next, this is converted into an imin-
ium ion (6), which performs the aromatic substitution
leading to the ring closed heterocycle (3). Formation
of this iminium species is the key to the cyclization.
The results of Table 1 suggest that addition of thiophe-
nol (1) to the reaction medium may favor the formation
of cyclized products (route b) perhaps by a three-com-
ponent condensation leading to Mannich-derived N,S-
acetal intermediate 7.12 Alternatively, generation of 7
could take place after attack of sulfonamide 2 to the sul-
fur-stabilized cation 8, formed by the addition of 1 to
aldehyde 4 under Lewis acid promotion (route b). How-
ever, we cannot rule out the reversible addition of thio-
phenol to intermediate 8, as a possible side reaction that
may lead to thioacetal 9, which in turn could act as a
`
capability of the phenylthio moiety (8), vis-a-vis its
alkylthio congeners, during ion pairing with intermedi-
ate 6. We have found an analogous behavior among
thioorthoesters7 and the group of Hevesi also noted a
similar but less evident trend, while studying methyl
and phenyl selenoorthoesters.15
In conclusion, we have demonstrated that the addition
of PhSH improves the formation of tetrahydroisoquino-
line products in the Pictet–Spengler cyclocondensation
of N-sulfonyl-b-phenethylamines with aldehydes.
Among the benzaldehyde derivatives, the degree of
improvement is greater when the aldehyde carries an
ortho substituent than when the substituent is located
in the para position. This simple modification allows a
convenient, more expeditious synthesis of 1-substituted
tetrahydroisoquinolines.

7548
C. C. Silveira et al. / Tetrahedron Letters 47 (2006) 7545–7549
added dichloromethane solutions of BF3ÆEt2O (1.5 equiv)
Acknowledgments
and PhSH (0.1–2 equiv). The reaction was left to proceed
under the conditions (time and temperature) shown in
Table 1. Then, the reaction was quenched with brine
(5 mL) and the products were extracted with EtOAc
(4 · 20 mL); the combined extracts were washed once with
brine (5 mL), dried (Na2SO4), concentrated under reduced
pressure, and the residue was submitted to column
chromatography.
The authors acknowledge the financial support provided
´
by CAPES, MCT/CNPq and Fundacion Antorchas.
T.S.K. also thanks CONICET and ANPCyT (Project
06-12532).
References and notes
10. Spectral data for selected compounds: 6,7-Dimethoxy-2-
(toluene-4-sulfonyl)-1-p-tolyl-1,2,3,4-tetrahydroisoquino-
line. Mp: 121–122 ꢁC; IR (KBr, cmÀ1): 2934, 2835, 1611,
1. (a) Whaley, W. M.; Govindachari, T. R. The Pictet–
Spengler Synthesis of Tetrahydroisoquinolines and
Related Compounds. In Organic Reactions; Adams, R.,
Ed.; John Wiley and Sons: New York, USA, 1951; Vol. 6,
p 151; (b) Kametani, T. In The Total Synthesis of Natural
Products; ApSimon, J., Ed.; Wiley: New York, USA,
1977; Vol. 3, pp 1–272; (c) Kutney, J. P. In The Total
Synthesis of Natural Products; ApSimon, J., Ed.; Wiley:
New York, USA, 1977; Vol. 3, pp 273–288; (d) Jones, G.
In Comprehensive Heterocyclic Chemistry; Katritzky, A.
R., Rees, C. W., Eds.; Pergamon: Oxford, UK, 1984; Vol.
2, pp 438–440; (e) Cox, E. D.; Cook, J. M. Chem. Rev.
1995, 95, 1797; (f) Kaufman, T. S. Synthesis of Optically-
Active Isoquinoline and Indole Alkaloids Employing the
Pictet–Spengler Condensation with Removable Chiral
Auxiliaries Bound to Nitrogen. In New Methods for the
Asymmetric Synthesis of Nitrogen Heterocycles; Vicario, J.
L., Ed.; Research SignPost: Trivandrum, 2005; pp 99–147,
Chapter 4.
1
1519, 1464, 1337, 1247, 1159, 1018, 857, 731, and 658; H
NMR (200 MHz, CDCl3, d): 2.30 (s, 3H), 2.32 (s, 3H),
2.41–2.73 (m, 2H), 3.14–3.29 (m, 1H), 3.74 (s, 3H), 3.75–
3.80 (m, 1H), 3.81 (s, 3H), 6.12 (s, 1H), 6.43 (s, 2H), 7.06–
7.11 (m, 6H), and 7.56 (d, J = 8.2 Hz, 2H); 13C NMR
(50 MHz, CDCl3, d): 20.89, 21.25, 26.02, 38.50, 55.72,
55.82, 58.50, 110.74, 111.17, 125.86 (2C), 126.93 (2C),
128.61 (2C), 128.76 (2C), 129.11 (2C), 137.22, 137.94,
138.50, 142.74, 147.75, and 148.07; EI-MS [m/z (%)]: 437
(M+, 11), 346 (51), 281 (98), 280 (100), 266 (32), 191 (34),
165 (29), 91 (71), and 65 (23). Elemental analysis: Found C,
68.99; H, 6.25; N, 3.28; C25H27NO4S requires C, 68.62; H,
6.22; N, 3.20. 6,7-Dimethoxy-1-(2-methoxyphenyl)-2-(tolu-
ene-4-sulfonyl)-1,2,3,4-tetrahydroisoquinoline. Mp: 95.1–
96.2 ꢁC; IR (KBr, cmÀ1): 2935, 2835, 1598, 1517, 1462,
1330, 1228, 1159, 1031, 975, and 657; 1H NMR (200 MHz,
CDCl3, d): 2.34 (s, 3H), 2.55–2.65 (m, 1H), 2.74–2.91 (m,
1H), 3.34–3.49 (m, 1H), 3.68 (s, 3H), 3.70 (s, 3H), 3.71–3.81
(m, 1H), 3.83 (s, 3H), 6.41 (s, 1H), 6.48 (s, 2H), 6.76–6.83
(m, 3H), 7.10 (d, J = 8.2 Hz, 2H), 7.17–7.26 (m, 1H), and
7.53 (d, J = 8.2 Hz, 2H); 13C NMR (50 MHz, CDCl3, d):
21.25, 26.81, 39.41, 53.41, 54.90, 55.70 (2C), 110.25, 110.57,
110.95, 119.75, 126.02, 126.92 (2C), 127.35, 128.85 (2C),
129.47, 129.91, 130.47, 138.10, 142.34, 147.43, 147.84, and
156.95; EI-MS [m/z (%)]: 453 (M+, 10), 346 (37), 298 (100),
282 (73), 268 (41), 191 (36), 165 (52), 91 (94), and 65 (26).
Elemental analysis: Found C, 66.48; H, 6.13; N, 3.27;
C25H27NO5S requires C, 66.20; H, 6.00; N, 3.09. 6,7-
Dimethoxy-2-(toluene-4-sulfonyl)-1-(2-trifluoromethyl-phen-
yl)-1,2,3,4-tetrahydroisoquinoline. Mp: 106.2–107.0 ꢁC;
IR (KBr, cmÀ1): 2935, 2854, 1612, 1517, 1454, 1348,
1247, 1161, 1037, 916, 817, 715, and 657; 1H NMR
(200 MHz, CDCl3, d): 2.34 (s, 3H), 2.64–2.70 (m, 2H),
3.43–3.61 (m, 2H), 3.66 (s, 3H), 3.79 (s, 3H), 6.35 (s, 1H),
6.44 (s, 2H), 7.13 (d, J = 8.2 Hz, 2H), 7.17–7.37 (m, 3H),
7.56 (d, J = 8.2 Hz, 2H), and 7.69–7.74 (m, 1H); 13C NMR
(50 MHz, CDCl3, d): 21.26, 26.78, 40.71, 54.84, 55.66,
55.73, 110.66, 111.08, 125.91, 126.36, 126.70, 127.32 (2C),
127.51, 128.13, 128.77, 129.13 (2C), 131.03, 131.64, 136.68,
141.22, 142.97, 147.80, and 148.10; EI-MS [m/z (%)]: 491
(M+, 2), 346 (30), 335 (57), 266 (43), 191 (23), 176 (17), 165
(36), 91 (100), 65 (32), and 44 (63). Elemental analysis:
Found C, 60.97; H, 4.95; N, 2.73; C25H24F3NO4S requires
C, 61.09; H, 4.92; N, 2.85. 6,7-Dimethoxy-2-(toluene-4-
sulfonyl)-1-(2-bromophenyl)-1,2,3,4-tetra-hydroisoquino-
line. Mp: 59.2–60.3 ꢁC; IR (KBr, cmÀ1): 2951, 2934, 2834,
1611, 1516, 1464, 1348, 1250, 1162, 1025, 915, 815, 710, and
´
´
2. Beke, G.; Szabo, L. F.; Podanyi, B. J. Nat. Prod. 2002, 65,
649.
3. Larghi, E. L. L.; Amongero, M.; Bracca, A. B. J.;
Kaufman, T. S. Arkivoc 2005, xii, 98.
4. (a) Jackes, B.; Deeks, R. H. L.; Shah, P. K. J. J. Chem.
Soc. (D) 1969, 1283; (b) Singh, K.; Deb, P. K. Tetra-
hedron Lett. 2000, 41, 4977; (c) Bringmann, G.; Ewers, C.
L. J.; Walter, R. Use of Carbonyl Derivatives for Hetero-
cyclic Synthesis. In Comprehensive Organic Synthesis;
Winterfeldt, E., Ed.; Pergamon Press: Oxford, UK, 1991;
Vol. 6, pp 736–740; (d) Leonard, M. S.; Hauze, D. B.;
Carroll, P. J.; Joullie, M. M. Tetrahedron 2003, 59, 6933;
´
(e) Gonzalez, J. F.; de la Cuesta, E.; Avendano, C.
˜
Tetrahedron Lett. 2003, 44, 4395; (f) Kang, I.-J.; Wang,
H.-M.; Su, C.-H.; Chen, L. C. Heterocycles 2002, 57, 1; (g)
Kohno, H.; Yamada, K. Heterocycles 1999, 51, 103; (h)
Lee, S. S.; Kim, S. H.; Yoon, H. S.; Lee, C.-H. Bull.
Korean Chem. Soc. 2003, 24, 1041; (i) Kubo, A.; Saito, N.;
Kawakami, N.; Matsuyama, Y.; Miwa, T. Synthesis 1987,
824; (j) Cheung, G. K.; Earle, M. J.; Fairhurst, R. A.;
Heaney, H.; Shihaibar, K. F.; Eyley, S. C.; Ince, F. Synlett
1991, 721; (k) Kohno, H.; Sekine, Y. Heterocycles 1996,
42, 141; (l) Silveira, C. C.; Bernardi, C. R.; Braga, A. L.;
Kaufman, T. S. Tetrahedron Lett. 1999, 40, 4969; (m)
Silveira, C. C.; Bernardi, C. R.; Braga, A. L.; Kaufman, T.
S. Tetrahedron Lett. 2001, 42, 8947.
5. (a) Comins, D. L.; Badawi, M. M. Tetrahedron Lett. 1991,
32, 2995; (b) MacLean, D. B.; Cundasawmy, N. E. Can. J.
Chem. 1972, 50, 3028; (c) Nagata, H.; Miyazawa, N.;
Ogasawara, K. Chem. Commun. 2001, 1094; (d) Bianchi,
D. A.; Cipulli, M. A.; Kaufman, T. S. Eur. J. Org. Chem.
2003, 4731.
6. Ito, K.; Tanaka, H. Chem. Pharm. Bull. 1977, 25, 1732.
7. Silveira, C. C.; Bernardi, C. R.; Braga, A. L.; Kaufman, T.
S. Tetrahedron Lett. 2003, 44, 6137.
1
657; H NMR (200 MHz, CDCl3, d): 2.35 (s, 3H), 2.76 (t,
J = 6.0 Hz, 2H), 3.44–3.65 (m, 2H), 3.70 (s, 3H), 3.80 (s,
3H), 6.38 (s, 1H), 6.48 (s, 1H), 6.51 (s, 1H), 7.02–7.10 (m,
3H), 7.14 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 1H), and
7.68 (d, J = 8.4 Hz, 2H); 13C NMR (50 MHz, CDCl3, d):
21.35, 27.26, 41.00, 55.75 (2C), 58.18, 110.10, 111.05,
123.72, 125.47, 126.81, 127.35, 127.47 (2C), 128.77, 129.14
(2C), 130.50, 133.15, 136.36, 142.30, 143.00, 147.84,
and 148.10; EI-MS [m/z (%)]: 501 (M+, 4), 346 (80), 266
(93), 191 (39), 176 (29), 165 (75), 91 (100), and 65 (33).
8. Bailey, P. D. J. Chem. Res. 1987, 202.
9. Typical procedure: To a solution of b-phenethylamine
(20–30 mg) in CH2Cl2 or ClCH2CH2Cl (1 mL) cooled to
À20 ꢁC under an argon atmosphere were successively

C. C. Silveira et al. / Tetrahedron Letters 47 (2006) 7545–7549
7549
Elemental analysis: Found C, 57.53; H, 4.72; N, 3.09;
C24H24BrNO4S requires C, 57.37; H, 4.81; N, 2.79.
11. Fujita, E.; Nagao, Y.; Kaneko, K. Chem. Pharm. Bull.
1978, 26, 3743.
13. Thioacetals have been employed for the synthesis of
tetrahydroisoquinoline derivatives, via thionium ions, see:
Padwa, A.; Waterson, A. G. J. Org. Chem. 2000, 65,
235.
12. (a) Beifuss, U.; Ledderhose, S.; Ondrus, V. Arkivoc 2005,
v, 147; (b) Koepler, O.; Laschat, S.; Baro, A.; Fischer, P.;
Miehlich, B.; Hotfilder, M.; le Viseur, C. Eur. J. Org.
Chem. 2004, 3611.
14. Chandrasekhar, S.; Karri, P. Tetrahedron Lett. 2006, 47,
2249.
15. Hevesi, L.; Nsunda, K. M. Tetrahedron Lett. 1985, 26,
6513.