Development of the Pictet-Spengler reaction catalyzed by AuCl 3/AgOTf

Article abstract of DOI:10.1021/jo0524775

Mild and efficient AuCl₃/AgOTf-catalyzed Pictet-Spengler reactions were developed to afford in good yields a variety of tetrahydroisoquinoline and tetrahydro-β-carboline ring systems, which constitute important motifs in biologically active nat

Full text of DOI:10.1021/jo0524775

TABLE 1. Optimization Studies for the Pictet-Spengler Reaction
Development of the Pictet-Spengler Reaction
of 1aa
Catalyzed by AuCl3/AgOTf
So Won Youn
Department of Chemistry, Pukyong National UniVersity,
Busan 608-737, Korea
entry
catalyst
PdCl2
additive
yield (%)b
1
2
3
4
5
6
7
8
-
-
20
<10
trace
20
40
30
20
AgOTf
-
AgOTf
-
AgOTf
AgOTfc
AgSbF6
AgBF4
AgClO4
Ag(O2CCF3)
AgOTf
-
sowony@pknu.ac.kr
AuCl
ReceiVed December 1, 2005
AuCl3
9
-
10
11
12
13
14
15
16
17
18
-
20
AuBr3
Sc(OTf)3
AlCl3
20
20
15
15
trace
<5
<20
-
-
CeCl3‚7H2O
AgOTf
-
AgOTf
ZnCl2
a All reactions were carried out with catalyst (10 mol %) and additive
(20 mol %) in ClCH2CH2Cl (0.02 M) at 60 °C for 24 h, unless otherwise
noted. b Determined by 1H NMR using trichloroethylene as an internal
standard. c Using 30 mol % of AgOTf.
Mild and efficient AuCl3/AgOTf-catalyzed Pictet-Spengler
reactions were developed to afford in good yields a variety
of tetrahydroisoquinoline and tetrahydro-â-carboline ring
systems, which constitute important motifs in biologically
active natural and synthetic organic compounds.
Spengler reaction. Herein we report the efficient Pictet-Spengler
reaction catalyzed by AuCl3/AgOTf.
The Pictet-Spengler reaction1 has been shown to be useful
and important for the synthesis of tetrahydroisoquinoline and
tetrahydro-â-carboline ring systems, which are present in
numerous natural and synthetic organic compounds possessing
various biological activities.2 Strong Brønsted acids3 are most
commonly employed to promote the Pictet-Spengler reaction,
involving the cyclization of an electron-rich aromatic ring onto
an imine. The few recent examples of Lewis acid catalyzed
Pictet-Spengler reaction involved highly reactive species such
as nitrone,4 or ionic liquid and microwave irradiation to enhance
the reactivity.3c,5 Recently, gold6 has been shown to catalyze a
variety of C-C bond-forming reactions. In the quest to develop
a mild and practical protocol, we envisioned the potential
application of such a catalytic system for the desired Pictet-
At the outset of the studies, a broad spectrum of potential
metal salts and complexes were tested in the cyclization of 1a,
and the effects of silver salt additives were determined (Table
1; for complete data, see Supporting Information). With the
exception of AuCl3, Sc(OTf)3, AlCl3, and CeCl3‚7H2O, most
of the metal complexes examined did not show the ability to
produce the desired product 2a. Analysis of the crude reaction
1
mixture by H NMR showed that nearly all of the complexes
tested induced some degree of imine hydrolysis. In an attempt
to increase the electrophilicity at the metal centers by giving
the weakly coordinating counterions, reactions were run in the
presence of silver salt additives. As a general trend, it was found
that the conversion of 1a increased upon the addition of silver
salt; however, the amount of imine hydrolysis also increased.
Among them AgOTf showed outstanding effects, and a control
experiment has shown that AgOTf itself is not responsible for
the catalytic activation (see Supporting Information).
We were delighted to identify an exciting lead, which
unambiguously stood out in the array of experiments. The
combination of AuCl3 and AgOTf was optimal in this reaction
system to produce 2a in 40% yield (Table 1, entry 6). Decreasing
the amount of catalyst and reaction temperature caused lower
yields. To boost the reactivity, TMSCl4,5 was added to the
reaction mixture; however, the addition of TMSCl (0.1 equiv)
had only a marginal effect.
(1) For reviews, see: (a) Whaley, W. M.; Govindachari, T. R. In Organic
Reactions; Adams, R., Ed.; Wiley: New York, 1951; Vol. 6, p 151. (b)
Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797-1842.
(2) (a) Brown, R. T. In Indoles; Saxton, J. E., Ed.; Wiley-Interscience:
New York, 1983; Part 4. (b) Bentley, K. W. Nat. Prod. Rep. 2004, 21,
395-424 and references therein.
(3) (a) Dunetz, J. R.; Ciccolini, R. P.; Fro¨ling, M.; Paap, S. M.; Allen,
A. J.; Holmes, A. B.; Tester J. W.; Danheiser, R. L. Chem. Commun. 2005,
4465-4467. (b) Nakamura, S.; Tanaka, M.; Taniguchi, T.; Uchiyama, M.;
Ohwada, T. Org. Lett. 2003, 5, 2087-2090. (c) Kuo, F.-M.; Tseng, M.-C.;
Yen, Y.-H.; Chu, Y.-H. Tetrahedron 2004, 60, 12075-12084. (d) Seayad,
J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086-1087.
(4) Tsuji, R.; Yamanaka, M.; Nishida A.; Nakagawa, M. Chem. Lett.
2002, 428-429 and references therein.
Product 2a could be obtained in the presence of 10 mol %
AuCl3 and 20 mol % AgOTf at 80 °C in 34% isolated yield,
whereas no desired products were produced with the substrates
derived from benzaldehyde (1b) and p-nitrobenzaldehyde (1c),
even with the addition of stoichiometric amount of TMSCl along
(5) Srinivasan N.; Ganesan, A. Chem. Commun. 2003, 916-917.
(6) (a) Hashmi, A. S. K. Gold Bull. 2003, 36, 3-9. (b) Hashmi, A. S.
K. Gold Bull. 2004, 37, 51-65. (c) Shi, Z.; He, C. J. Am. Chem. Soc. 2004,
126, 13596-13597. (d) Luo, Y.; Li, C.-J. Chem. Commun. 2004, 1930-
1931 and references therein.
10.1021/jo0524775 CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/17/2006
J. Org. Chem. 2006, 71, 2521-2523
2521

TABLE 3. Acyl-Pictet-Spengler Reactions Catalyzed by
SCHEME 1. Pictet-Spengler Reactions Catalyzed by
AuCl3/AgOTf
AuCl3/AgOTa
TABLE 2. Optimization for the Acyl-Pictet-Spengler Reaction of
1a Using AuCl3/AgOTfa
a All reactions were carried out with AuCl3 (1 mol %), AgOTf (2 mol
%), AcCl (1 equiv), and 2,6-lutidine (1 equiv) in CH3CN (0.02 M) at room
temperature for 12 h, unless otherwise noted. b Isolated yields. c Performed
without 2,6-lutidine.
yield (%)b
entry
acylating agent
solvent
2a
6a
62
1
2
3
4
5
6
7
8
AcCl
Ac2O
ClCO2Et
AcCl
AcCl
AcCl
AcCl
AcCl
AcCl
AcCl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
toluene
CH3CN
1,4-dioxane
THF
CH2Cl2
THF/CH2Cl2 (1:4)
CH3CN
trace
14
27
methodology has been reported to promote the Pictet-Spengler
reaction.3a,8b-c
45
40c
50
20
With the preliminary results of the Pictet-Spengler reaction
in the presence of AuCl3/AgOTf, we set out to explore the scope
of acyl-Pictet-Spengler reactions. Compound 1a underwent
cyclization in the presence of acetyl chloride and AuCl3/AgOTf
in 1,2-dichloroethane at room temperature to provide 6a in 62%
yield (Table 2, entry 1). On the other hand, acetic anhydride
and ethyl chloroformate were less effective (Table 2, entries 2
and 3). Interestingly, it was also found that any base such as
NEt3, pyridine, 2,6-lutidine, etc. afforded only trace amount of
desired product 6a along with decomposition. Various solvents
were examined, and CH3CN appeared preferable. Gratifyingly,
the reaction also provided an excellent yield even when the
amount of AuCl3/AgOTf was reduced to 1 mol % (Table 2,
entry 10).
We proceeded to examine the substrate scope of AuCl3/
AgOTf-catalyzed acyl-Pictet-Spengler reactions. In some pre-
vious reports, only special imines, such as an aliphatic imine8c
and N-protected tryptamine derivative,3a were successful.
Waldmann8b reported that several days are required for aromatic
imines and the reaction did not proceed with R,â-unsaturated
imine. In contrast, in our reaction system various imines obtained
by condensation of 3,4-dimethoxyphenethylamine or tryptamine
with aldehydes were used without further purification, and yields
were equally good with both electron-deficient and electron-
16
74
19
71
11
43
20
60
9
8
50
10d
<10
87(81)
a All reactions were carried out with AuCl3 (10 mol %), AgOTf (20
mol %), and acylating agent (1 equiv) in solvent (0.02 M) at room
temperature for 24 h, unless otherwise noted. b Yields were determined by
1H NMR using trichloroethylene as an internal standard; isolated yield is
given in parentheses. c R ) CO2Et. d Performed with 1 mol % AuCl3 and
2 mol % AgOTf.
with complete hydrolysis (Scheme 1). The similar reactions of
3a and 3c gave the corresponding â-carbolines, 5, which
precursor (4a) is known to be very unstable,7 and 4c, respec-
tively, whereas once again 3b showed very low reactivity to
give only a trace amount of 4b (Scheme 1).
These results led us to explore more reactive variants of the
Pictet-Spengler reaction. The challenge of the Pictet-Spengler
reaction appears to be associated with the low reactivity of the
imine substrate. Therefore, strong Brønsted acid,3 highly reactive
substrates,4 high reaction temperature, or microwave irradiation3c,5
have been employed to promote the reaction. Meanwhile, a
general strategy to enhance the reactivity of imine involves
generation of the corresponding N-acyliminium ions8a due to
the electron-withdrawing effect of the N-acyl group, and this
(8) (a) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. ReV. 2004, 104, 1431-1628. (b) Schmidt, G.;
Waldmann, H.; Henke H.; Burkard, M. Chem. Eur. J. 1996, 2, 1566-1571.
(c) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558-
10559 and references therein.
(7) Tietze, L. F.; Zhou, Y.; To¨pken, E. Eur. J. Org. Chem. 2000, 2247-
2252.
2522 J. Org. Chem., Vol. 71, No. 6, 2006

evaporated, and the residue was purified by column chromatography
on silica gel (EtOAc/n-hexanes ) 1:1 to EtOAc only) to give the
corresponding product (2a, 4c, 5).
rich aromatic imines as well as aliphatic imines (Table 3).
Heteroaromatic imines (Table 3, entries 5, 6, 13, and 14), R,â-
unsaturated imines (Table 3, entries 7 and 15), and free (NH)
indole-derived imines (Table 3, entries 9-16) were all successful
in this reaction. It should be noted that a base such as 2,6-lutidine
was required for optimal conversion in most cases, except for
1a, 1h, and 3a.
In summary, we have developed the Pictet-Spengler reaction
catalyzed by AuCl3/AgOTf. To enhance the reactivity of imine,
an acylating agent was involved. It is likely that this reaction
proceeds an electrophilic pathway involving imine activation
by coordinating gold(III) complex. The process is mild and
efficient and can be used to synthesize a variety of tetrahy-
droisoquinoline and tetrahydro-â-carboline derivatives that
constitute important motifs in biologically active natural and
synthetic organic compounds.
General Procedure for Acyl-Pictet-Spengler Reactions Using
AuCl3/AgOTf. A mixture of 1 mol % AuCl3 and 2 mol % AgOTf
in CH3CN was stirred vigorously for 1 h. To a resulting solution
was added the imine substrate (1a-h or 3a-h) dissolved in CH3-
CN (0.02 M), AcCl (1 equiv), and 2,6-lutidine (if required, 1 equiv)
successively at room temperature. After 12 h, the solvent was
evaporated, and the residue was purified by column chromatography
on silica gel (EtOAc/n-hexanes ) 3:1 to EtOAc only) to give the
corresponding product (6a-h or 7a-h).
Acknowledgment. This work was supported by the Korea
Research Foundation Grant (KRF-2004-003-C00118). The
author thanks Pukyong National University for generous
financial support.
Experimental Section
Supporting Information Available: Full experimental details,
complete data for the systematic screening, and spectral charac-
terization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
General Procedure for Pictet-Spengler Reactions Using
AuCl3/AgOTf. A mixture of 10 mol % AuCl3 and 20 mol % AgOTf
in ClCH2CH2Cl was stirred vigorously for 1 h. To the resulting
solution was added the imine substrate (1a-c or 3a-c) dissolved
in ClCH2CH2Cl (0.02 M). After 24 h at 80 °C, the solvent was
JO0524775
J. Org. Chem, Vol. 71, No. 6, 2006 2523