Catalytic Pictet-Spengler reactions using Yb(OTf)3

Article abstract of DOI:10.1016/j.bmc.2005.05.018

The catalytic Pictet-Spengler reactions proceeded in high yields with high regioselectivity in the presence of a catalytic amount of Yb(OTf)₃ and a dehydrating agent at room temperature. High regioselectivities were obtained in these reactions,

Full text of DOI:10.1016/j.bmc.2005.05.018

Bioorganic & Medicinal Chemistry 13 (2005) 5154–5158
Catalytic Pictet–Spengler reactions using Yb(OTf)3
*
ꢀ
Kei Manabe, Daisuke Nobutou and Shu Kobayashi
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 25 April 2005; revised 9 May 2005; accepted 9 May 2005
Available online 21 June 2005
Abstract—The catalytic Pictet–Spengler reactions proceeded in high yields with high regioselectivity in the presence of a catalytic
amount of Yb(OTf)3 and a dehydrating agent at room temperature. High regioselectivities were obtained in these reactions, and
it is suggested that the reactions proceeded under kinetic control.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
examined to activate the phenolic moiety of m-tyramine.
It was revealed that an aqueous 1 M NaOH solution (50
mol%) accelerated the reaction in MeOH at room tem-
perature for 24 h to afford the desired product in 39%
yield (1/2 = 3/97, not shown in the table). However,
the yield was not further improved even after examina-
tion of several reaction conditions. Moreover, metal ace-
tates such as NaOAc, Ni(OAc)2, and Zn(OAc)2 were not
effective. Then, several Lewis acids and Brønsted acids
were tested as catalysts. It was found that, among them,
several water-compatible Lewis acids gave promising re-
sults (entries 2–11).8 In particular, Yb(OTf)3 was found
to be the most effective catalyst (entry 11).9 On the other
hand, Brønsted acids such as trifluoromethanesulfonic
acid, acetic acid, and trifluoroacetic acid were not effec-
tive (entries 12–14).
Pictet–Spengler reaction has been known for almost 100
years.1 However, it is still a powerful methodology to
synthesize 1,2,3,4-tetrahydroisoquinoline or b-carboline
derivatives effectively.2 A lot of natural and unnatural
biologically important alkaloids have been synthesized
utilizing this reaction as one of key steps;3 however,
there is certainly room for improvement of the reaction.
For instance, Pictet–Spengler reaction requires heating
and large excess amounts of strong Brønsted acids for
unreactive substrates to obtain satisfactory levels of con-
versions,4 while reactive ones do not necessarily need
harsh reaction conditions.5 In addition, it has not been
fully investigated with respect to what kinds of activa-
tors in small amounts are the most effective to catalyze
Pictet–Spengler reaction even for reactive substrates.6
Furthermore, there have been very few reports on cata-
lysts which could control regioselectivity or enantio-
selectivity of the Pictet–Spengler reaction.5,7 Based on
this background, we have screened several catalyst sys-
tems for Pictet–Spengler reaction, and now report that
Yb(OTf)3 gives promising results.
An imine intermediate and water formed at the initial
stage of this reaction, and we thought that this water
might disturb a further reaction. Thus, we then added
various dehydrating agents to improve the yield further.
As shown in Table 2, we tested three kinds of molecular
sieves and Drierite, and in all cases these dehydrating
agents increased both yields and regioselectivities
(entries 1–5). On the other hand, the desired reactions
proceeded only sluggishly without Yb(OTf)3 even if
MS 3A was added (entries 6 and 7). Finally, the amount
of Yb(OTf)3 could be reduced to 1 mol% combined with
MS 3A (entry 8).
2. Results and discussion
We chose benzaldehyde and reactive m-tyramine as
model substrates,5a,b and searched for activators in this
reaction (Table 1). First, several basic conditions were
Under optimized conditions, substrate scope of the cat-
alytic Pictet–Spengler reaction was examined (Table 3).
A substituted aromatic aldehyde gave the desired prod-
uct in high yield with excellent regioselectivity (entry 1).
The reactions proceeded in good yields with high
Keywords: Catalytic reaction; Lewis acid; Pictet–Spengler reaction;
Ytterbium triflate.
*
Corresponding author. Tel: +81 3 5841 4790; fax: +81 3 5684 0634;
e-mail: skobayas@mol.f.u-tokyo.ac.jp
0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.05.018

K. Manabe et al. / Bioorg. Med. Chem. 13 (2005) 5154–5158
5155
Table 1. Effect of metal catalysts
Entry
Catalyst
Yield (%)a
1/2
9/91
1
2
None
22
22
40
39
24
20
19
17
21
33
59
25
15
34
Zn(OTf)2
ln(OTf)3
Bi(OTf)3
Sm(OTf)3
Eu(OTf)3
Tb(OTf)3
Dy(OTf)3
Er(OTf)3
Lu(OTf)3
Yb(OTf)3
CF3SO3H
AcOH
16/84
11/89
9/91
3
4
5
15/85
12/88
12/88
13/87
14/86
11/89
15/85
10/90
13/87
12/88
6
7
8
9
10
11
12
13
14
CF3COOH
a Combined NMR yield of 1 and 2.
Table 2. Effect of dehydrating agents
Entry
x
Time (h)
Dehydrating agent
Yield (%)a
1/2
1
10
10
10
10
10
—
10
1
24
24
24
24
24
8
None
53
94
90
94
97
22
82
92
11/89
3/97
4/96
2/98
8/92
7/93
3/97
5/95
2b
3b
4b
5
MS 3A
MS 4A
MS 5A
Drierite
MS 3A
MS 3A
MS 3A
6b,c
7b
8b
8
24
a Combined NMR yield of 1 and 2.
b Molecular sieves of powder form were used.
c Without Yb(OTf)3.
Table 3. Substrate scope of the catalytic Pictet–Spengler reactions
Entry
R
Yield (%)a
1/2
1
2
3
4
4-t-BuC6H4
2-Pyridyl
i-Bu
98
60
1/99
7/93
10/90
—
55
Complex mixture
PhCH@CH (trans)
a Combined NMR yield of 1 and 2.
regioselectivity when heteroaromatic and aliphatic alde-
hydes were used (entries 2 and 3). However, an a,b-un-
saturated aldehyde caused severe side reactions, and the
desired product could not be obtained when trans-cinna-
maldehyde was used (entry 4). When less reactive
b-phenethylamine derivatives than m-tyramine (e.g,

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K. Manabe et al. / Bioorg. Med. Chem. 13 (2005) 5154–5158
Table 4. Kinetic versus thermodynamic control
Entry
Time (h)
Yield (%)a
1/12
1
0.5
8
7
82
90
94
6
2 alone
3/97
3/97
2
3
16
4
5b
24
24
3/97
2 alone
a Combined NMR yield of 1 and 2.
b At 0 °C.
3-methoxy-b-phenethylamine, 3,5-dimethoxy-b-phen-
ethylamine, and 4-hydroxy-b-phenethylamine) were
tried, the reactions stopped at the formation of imine
intermediates, and no cyclized products were obtained.
In entries 1–3, regioisomers were formed, and we next
tried to confirm whether the regioselectivity of the reac-
tion was controlled kinetically or thermodynamically.
Thus, we checked the regioisomer ratio during the reac-
tion course (Table 4). As a result, the ratio hardly chan-
ged within 24 h, and the product 2 cyclized at the para
position to the phenolic hydroxyl group was always ob-
tained as a major isomer. In addition, the cyclized prod-
uct 2 was also produced as a predominant isomer when
the reaction temperature was decreased from 25 to 0 °C
(entry 5). These results suggest that the regioisomer ratio
was determined kinetically rather than thermodynami-
cally. When the ortho cyclized product 1 corresponding
to entry 1 in Table 3 was exposed to the same reaction
conditions as those in Table 3, the same ortho cyclized
product 1 was recovered and no para cyclized product
was observed (Eq. 1). This result also suggests that the
regioselectivity of the reaction was determined under ki-
netic control.
aldehydes were condensed. These results suggest that
regioselectivity of the Pictet–Spengler reaction was
determined by kinetic, rather than thermodynamic con-
trol. Further investigations to develop catalytic enantio-
selective Pictet–Spengler reactions are now in progress.
4. Experimental
4.1. General
Infrared (IR) spectra were recorded on a JASCO FT/IR-
610 spectrometer. Nuclear magnetic resonance (NMR)
spectra were recorded on a JEOL JNM-LA300 or
JNM-LA400 spectrometer in CD3OD or DMSO-d6.
The peaks derived from the deuterated solvents were
used as internal standards for 1H NMR (d: 3.30 for
CD3OD and d: 2.49 for DMSO-d6) and 13C NMR (d:
49.0 for CD3OD and d: 39.5 for DMSO-d6). Mass spec-
tra were measured with a Bruker BIO TOF-II spectrom-
eter. Preparative thin-layer chromatography (TLC) was
carried out using Wakogel B-5F. All other reagents were
purified based on standard procedures unless otherwise
noted. Starting materials are commercially available or
were synthesized by the reported procedure.11
4.2. A typical experimental procedure for Pictet–Spengler
reaction (Table 2, entry 2)
ð1Þ
To a two-necked 10-mL flask, Yb(OTf)3 (12.4 mg, 0.02
mmol) was added under an atmosphere of argon, and
dried in vacuo at 200 °C for 2 h. After cooling the flask
at room temperature, well-dried molecular sieves 3A
(40.0 mg) was added under an atmosphere of argon.
Then, 0.5 mL of dry CH2C12, benzaldehyde (21.2 mg,
0.20 mmol), and m-tyramine (27.4 mg, 0.20 mmol) were
added successively, and the reaction mixture was stirred
at 25 °C. After 24 h, the reaction was quenched with an
aqueous saturated sodium bicarbonate solution (3 mL),
and organic compounds were extracted with ethyl
acetate. The organic layer was dried over anhydrous
sodium sulfate, and evaporated. To the crude reaction
mixture, an appropriate amount of trimethylsilylpro-
panesulfonic acid sodium salt (10–20 mg) was added
under an atmosphere of argon as an internal standard
for the analysis of crude 1H NMR spectra in DMSO-d6.
3. Conclusion
We investigated effective catalyst systems for Pictet–
Spengler reaction where benzaldehyde and m-tyramine
were used as model substrates. After screening of vari-
ous activators, Yb(OTf)3 was found to be the most effec-
tive catalyst. With the help of some dehydrating
agents,10 both yield and regioselectivity were improved,
and catalytic Pictet–Spengler reaction proceeded
smoothly under mild reaction conditions in high yield
with high regioselectivity. In addition, it was demon-
strated that cyclization reactions occurred at the para
position to the phenolic hydroxyl group preferentially
to the ortho position when m-tyramine and various

K. Manabe et al. / Bioorg. Med. Chem. 13 (2005) 5154–5158
5157
4.3. A typical experimental procedure for the synthesis of
1-phenyl-1,2,3,4-tetrahydroisoquinoline derivatives12
155.47, 144.48, 137.49, 129.57, 128.99, 128.64, 127.98,
124.11, 120.96, 113.27, 56.03, 38.23, 29.21; IR (KBr,
cmꢀ1) 3417, 3287, 3032, 2925, 2856, 2635, 2379, 2328,
1729. HRMS calcd for C19H15NOÅH+ (M+H+)
226.1232. Found 226.1221.
To a one-necked 10-mL flask equipped with a reflux
condenser, m-tyramine (52.3 mg, 0.38 mmol), benzalde-
hyde (53.8 mg, 0.51 mmol), and pyridine (1.0 mL) were
added successively. The reaction mixture was stirred and
refluxed for 2 h. After cooling the flask at room temper-
ature, a 10% aqueous sodium hydroxide solution was
added to basify the media, and the aqueous layer was
washed with Et2O. To the aqueous layer, 10% aqueous
HCl was added to acidify the media and then, a 28%
aqueous ammonia solution was added to basify the
media again. The organic compounds were extracted
with dichloromethane. The organic layer was dried over
anhydrous sodium sulfate, and evaporated. Pyridine (1.0
mL) was added to the crude reaction mixture, and the
solution was stirred at room temperature. Then, trifluo-
roacetic anhydride (0.5 mL, 9.0 equiv.) was added
slowly, and the reaction mixture was stirred overnight.
The reaction was stopped with 1 N aqueous HCl,
and the organic compounds were extracted with ethyl
acetate. The organic layer was washed with 1 N aqueous
HCl, saturated aqueous sodium bicarbonate, and brine
successively, dried over anhydrous sodium sulfate, and
evaporated. Purification by silica gel chromatography
gave the desired N-protected cyclized products (6-OH
adduct: 45.7 mg, 37%, 8-OH adduct: 11.8 mg, 10%).
To each protected isomer in methanol, an aqueous
sodium hydroxide solution (10 equiv.) was added, and
the reaction mixture was stirred overnight. The depro-
tection reactions proceeded quantitatively, and were
stropped with 1 N aqueous HCl. A saturated aqueous
sodium bicarbonate solution was then added to basify
the media again. After extraction with ethyl acetate, fol-
lowed by drying and concentration, the desired 1,2,3,4-
tetrahydroisoquinoline derivatives were obtained in
pure forms.
4.6. l-(4-tert-Butyl-phenyl)-6-hydroxy-l,2,3,4-
tetrahydroisoquinoline
1H NMR (DMSO-d6) d: 9.09 (br s, 1H), 7.29 (d, 2H,
J = 8.2Hz), 7.13 (d, 2H, J = 8.2Hz), 6.48 (s, 1H), 6.43–
6.36 (m, 2H), 4.82 (s, 1H), 3.04–2.97 (m, 1H), 2.88–
2.74 (m, 2H), 2.65–2.55 (m, 1H), 1.25 (s, 9H); 13C
NMR (DMSO-d6) d: 155.13, 148.95, 142.72, 136.36,
129.36, 128.56, 128.42, 124.64, 114.71, 112.88, 60.32,
41.55, 34.14, 31.21, 29.47; IR (KBr, cmꢀ1) 3429, 3276,
2964, 2875, 2801, 2667, 2600. HRMS calcd for
C19H23NOÅH+ (M+H+) 282.1858. Found 282.1849.
4.7. l-(4-tert-Butyl-phenyl)-8-hydroxy-l,2,3,4-
tetrahydroisoquinoline
1H NMR (DMSO-d6) d: 9.04 (br s, 1H), 7.27–7.17 (m,
2H), 7.01–6.89 (m, 3H,), 6.59 (d, 1H, J = 7.4 Hz), 6.53
(d, 1H, J = 7.4 Hz), 5.04 (s, 1H), 2.82–2.52 (m, 4H),
1.24 (s, 9H); 13C NMR(DMSO-d6) d: 153.81, 148.13,
141.84, 136.91, 127.81, 126.68, 124.58, 124.20, 119.50,
111.81, 53.70, 38.67, 37.21, 34.06, 31.23, 28.66; IR
(KBr, cmꢀ1) 3395, 3284, 3028, 2957, 2873, 2719, 2622.
HRMS calcd for C19H23NOÅH+ (M+H+) 282.1858.
Found 282.1854.
4.8. l-iso-Butyl-6-hydroxy-l,2,3,4-tetrahydroisoquinoline
1H NMR (CD3OD) d: 6.92 (d, 1H, J = 8.4 Hz), 6.58 (dd,
1H, J = 8.4, 2.3 Hz), 6.49 (d, 1H, J = 2.3 Hz), 3.97–3.83
(m, 1H), 3.21–3.08 (m, 1H), 2.93–2.63 (m, 3H), 1.92–
1.77 (m, 1H), 1.67–1.55 (m, 2H), 1.00 (d, 3H, J = 6.4
Hz), 0.97 (d, 3H, J = 6.9 Hz); 13C NMR (CD3OD) d:
184.52, 164.82, 159.27, 156.25, 144.03, 142.48, 82.09,
75.05, 69.39, 58.10, 53.63, 52.34, 49.76; IR (KBr,
cmꢀ1) 3379, 3308, 2958, 2679, 2603, 2377. HRMS calcd
for C13H19NOÅH+ (M+H+) 206.1545. Found 206.1543.
4.4. l-Phenyl-6-hydroxy-l,2,3,4-tetrahydroisoquinoline
1H NMR (DMSO-d6) d: 9.14 (br s, 1H), 7.31–7.16 (m,
5H), 6.52–6.46 (m, 1H), 6.45–6.36 (m, 2H), 4.86 (s,
1H), 3.08–2.96 (m, 1H), 2.90–2.72 (m, 2H), 2.67–2.53
(m, 1H); 1H NMR (CD3OD): d: 7.35–7.16 (m, 5H),
6.56 (d, 1H, J = 2.1 Hz), 6.48 (d, 1H, J = 8.6 Hz), 6.46
(dd, 1H, J = 2.1, 8.6 Hz), 4.98 (s, 1H), 3.21–3.11 (m,
1H), 3.02–2.89 (m, 2H), 2.83–2.69 (m, 1H); 13C NMR
(CD3OD) d: 156.94, 145.51, 137.47, 130.21, 130.21,
129.74, 129.45, 128.52, 115.80, 114.42, 62.42, 29.98; IR
(KBr, cmꢀ1) 3438, 3281, 3034, 2955, 2932, 2790, 2656,
2551. HRMS calcd for C15H15NOÅH+ (M+H+)
226.1232. Found 226.1239.
4.9. 1-iso-Butyl-8-hydroxy-1,2,3,4-tetrahydroisoquinoline
1H NMR (CD3OD) d: 6.93 (dd, 1H, J = 7.7, 8.0 Hz),
6.57 (d, 1H, J = 7.7 Hz), 6.56 (d, 1H, J = 8.0 Hz),
4.30–4.22 (m, 1H), 3.23–3.12 (m, 1H), 3.00–2.80 (m,
2H), 2.76–2.64 (m, 1H), 1.91–1.80 (m, 1H), 1.69–1.58
(m, 2H), 1.04 (d, 3H, J = 6.9 Hz), 0.96 (d, 3H, J = 6.9
Hz); 13C NMR (CD3OD) d: 150.00, 136.25, 127.78,
127.13, 1201.04, 113.30, 49.91, 42.73, 38.33, 29.26,
25.93, 24.56, 21.40; IR (KBr, cmꢀ1) 3410, 3041, 2959,
2864, 2722, 2378, 2338, 1729, 1681. HRMS calcd for
C13H19NOÅH+ (M+H+) 206.1545. Found 206.1543.
4.5. l-Phenyl-8-hydroxy-l,2,3,4-tetrahydroisoquinoline
1H NMR (DMSO-d6) d: 9.06 (br s, 1H), 7.34–7.02 (m,
5H), 6.99 (dd, 1H, J = 7.8 Hz), 6.61 (d, 1H, J = 7.8
Hz), 6.55 (d, 1H, J = 7.8 Hz), 5.10 (s, 1H), 2.87–2.52
(m, 4H); 1H NMR (CD3OD) d: 7.32–7.15 (m, 3H),
7.10 (d, 2H, J = 7.8 Hz), 7.04 (dd, 1H, J = 7.8 Hz),
6.70 (d, 1H, J = 7.8 Hz), 6.55 (d, 1H, J = 7.8 Hz), 5.31
(s, 1H), 3.01–2.71 (m, 4H); 13C NMR (CD3OD) d:
4.10. 1-(2-Pyridyl)-6-hydroxy-1,2,3,4-
tetrahydroisoquinoline
1H NMR (CD3OD) d: 8.56–8.44 (m, 1H), 7.82–7.68 (m,
1H), 7.37–7.27 (m, 1H), 7.26–7.19 (m, 1H), 6.60 (d, 1H,
J = 2.4 Hz), 6.55 (d, 1H, J = 8.6 Hz), 6.50 (d, 1H,

5158
K. Manabe et al. / Bioorg. Med. Chem. 13 (2005) 5154–5158
Synthesis; Pergamon Press: Oxford; Vol. 6, chapter 4.2; (b)
Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev 2004,
104, 3341.
J = 2.4, 8.6 Hz), 5.10 (s, 1H), 3.20–3.07 (m, 1H), 3.03–
2.71 (m, 3H); 13C NMR (CD3OD) d: 164.13, 157.27,
149.96, 138.54, 137.67, 129.84, 128.10, 125.01, 124.03,
116.24, 114.60, 62.95, 42.10, 30.00; IR (KBr, cmꢀ1
)
3. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797.
4. (a) Whaley, W. M.; Govindachari, T. R. Org. React. 1951,
6, 151; for superacids approach, see: (b) Yokoyama, A.;
Ohwada, T.; Shudo, K. J. Org. Chem. 1999, 64, 611.
5. (a) Kametani, T.; Fukumoto, K.; Agui, H.; Yagi, H.;
Kigasawa, K.; Sugahara, H.; Hiiragi, M.; Hayasaka, T.;
Ishimaru, H. J. Chem. Soc. (C) 1968, 112; (b) Kametani,
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A. J. Org. Chem. 1981, 46, 4931.
3267, 3052, 3014, 2925, 2817, 2706, 2603, 1882, 1681.
HRMS calcd for C14H14N2OÅH+ (M+H+) 227.1184.
Found 227.1195.
4.11. 1-(2-Pyridyl)-8-hydroxy-1,2,3,4-
tetrahydroisoquinoline
1H NMR (CD3OD) d: 8.59–8.54 (m, 1H), 7.71–7.65 (m,
1H), 7.30–7.24 (m, 1H), 7.07 (dd, 1H, J = 7.9, 7.9 Hz),
6.96 (d, 1H, J = 7.9 Hz), 6.71 (d, 1H, J = 7.9 Hz), 6.59
(d, 1H, J = 7.9 Hz), 5.30 (s, 1H), 3.02–2.70 (m, 4H);
13C NMR (CD3OD) d: 163.67, 155.86, 149.77, 137.99,
137.94, 128.97, 124.17, 123.49, 123.04, 121.20, 113.31,
57.54, 39.10, 29.54; IR (KBr, cmꢀ1) 3409, 3276, 3056,
2925, 2855, 2374, 1679. HRMS calcd for C14H14N2OÅH+
(M+H+) 227.1184. Found 227.1171.
6. For Lewis acid catalysis, see: Srinivasan, N.; Ganesan, A.
Chem. Commun. 2003, 916.
7. (a) Yamada, H.; Kawate, T.; Matsumizu, M.; Nishida, A.;
Yamaguchi, K.; Nakagawa, M. J. Org. Chem. 1998, 63,
6348; (b) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc.
2004, 126, 10558; for diastereoselective approaches using
chiral auxiliaries, see: (c) Waldmann, H.; Schmidt, G.;
Henke, H.; Burkard, M. Angew. Chem. Int. Ed. Engl.
1995, 34, 2402; (d) Gremmen, C.; Wanner, M. J.;
Koomen, G.-J. Tetrahedron Lett. 2001, 42, 8885.
8. Kobayashi, S.; Nagayama, S.; Busujima, T. J. Am. Chem.
Soc. 1998, 120, 8287.
9. (a) Kobayashi, S. Synlett 1994, 689; (b) Kobayashi, S.;
Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. Rev.
2002, 102, 2227, we also tested a wide variety of Lewis
acids in a THF/water mixed solvent, but all attempts
resulted in low yields.
10. (a) For the same catalyst system, see: Kobayashi, S.;
Hachiya, I. J. Org. Chem. 1994, 59, 3590; for the Yb(OTf)3
and TMSC1 system, see: (b) Tsuji, R.; Nakagawa, M.;
Nishida, A. Tetrahedron: Asymmetry 2003, 14, 177; (c)
Tsuji, R.; Yamanaka, M.; Nishida, A.; Nakagawa, M.
Chem. Lett. 2002, 428.
Acknowledgments
This work was partially supported by ERATO, Japan
Science and Technology Corporation (JST), and a
Grant-in-Aid for Scientific Research from Japan Society
of the Promotion of Science (JSPS).
References and notes
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12. Kametani, T.; Kigasawa, K.; Hiiragi, M.; Ishimaru, H.
J. Chem. Soc. (C) 1971, 2632.
2. (a) For recent reviews, see: Bringmann, G.; Ewers, C. L. J.;
Walter, R. In Trost, B. M., Ed.; Comprehensive Organic