Gold catalysis: The benefits of N and N,O ligands

Article abstract of DOI:10.1002/anie.200460232

The golden key: The use of N and N,O ligands for gold(III) complexes leads to stable catalysts that facilitate an efficient synthesis of tetrahydroisoquinolines with substitution patterns difficult to access by classic methods (see picture). (Chemical equ

Full text of DOI:10.1002/anie.200460232

Angewandte
Chemie
Homogeneous Catalysis
Gold Catalysis: The Benefits of N and N,O
Ligands**
A. Stephen K. Hashmi,* Jan P. Weyrauch,
Matthias Rudolph, and Elzen Kurpejovic´
Dedicated to Professor Johann Mulzer
on the occasion of his 60th birthday
The catalysis of organic reactions by gold compounds has
[
1,2]
been recently shown to be a powerful tool in synthesis.
When gold(i) compounds are used as precatalysts, ligands
Figure 1. Reaction of 1 with AuCl . Reaction conditions: CD CN, 108C,
3
3
a) 3.3 mol% AuCl ; b) 5.0 mol% AuCl .
3
3
[
3–8]
[9]
such as phosphanes
gold(iii) precatalysts are mainly simple halides; other
or phosphites can be applied. The
[
2]
[
10]
examples include one thioether-containing,
one phos-
[
9]
[11]
phite-containing, and organogold(iii) compounds.
[
12]
For the gold-catalyzed phenol synthesis, AuCl usually
3
delivers good results with simple substrates, but with more
complicated ones a significant loss of activity is observed. At
lower temperature, kinetic studies with our most simple test-
substrate 1 (see Scheme 1) showed that the problem with
Scheme 1. Conversion of the test-substrate 1 with AuCl as the precata-
3
lyst; Ts=tosyl (reaction conditions see Figure 1).
regard to the loss of activity occurs even with as much as
5
mol% of catalyst (Figure 1). With small amounts of catalyst,
the conversion remains incomplete.
We have now tested several gold(i) and gold(iii) complexes
with different ligands as catalysts for this reaction. Gold(i)
complexes showed low selectivity and led to several side
products. Satisfactory results in terms of activity, long-term
stability and product-selectivity were obtained only with
gold(iii) complexes with pyridine derivatives, some of which
contained chelating oxygen functionalities. The most inter-
esting complexes were precatalysts 3–6. The complexes did
not suffer deactivation, as shown in Figure 2 for 3—the
activity even holds in a second catalytic run. Unlike with
Figure 2. Reaction of 1 with the precatalyst 3. Reaction conditions:
CD CN, 458C, 5 mol% 3. After 25 h the same amount of 1 was added.
3
[
13]
observed for 3–6, clearly proving that here the complexes are
precatalysts. This is also the reason for the higher activity in
the second run, since the catalytically active species is already
present and does not have to be formed in a slow reaction.
With as little as 0.07 mol% of 3 a complete conversion
could be achieved; this corresponds to 1180 instead of the
usual 20–50 turnovers. The complexes 4–6 are also highly
stable catalysts; a comparison of their activity is depicted in
Figure 3: the acceptor-substituted pyridine carboxylate 5 is
the most reactive one, followed by the unsubstituted 4 and the
donor-substituted 6. Nevertheless, the initial activity of 3, 4,
AuCl , a mechanistically interesting induction period was
3
[
*] Prof. Dr. A. S. K. Hashmi, Dipl.-Chem. J. P. Weyrauch,
Dipl.-Chem. M. Rudolph, Dipl.-Chem. E. Kurpejovic´
Institut für Organische Chemie
Universität Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
Fax: (+49)711-685-4321
E-mail: hashmi@hashmi.de
and 6 is lower than that of AuCl . In part, this problem can be
solved by switching to dichloromethane/acetonitrile mixtures
or even pure dichloromethane (as shown for 3 in Figure 4). In
[
**] This work was supported by the Fonds der Chemischen Industrie,
J.P.W. is grateful for a Doktoranden-Stipendium. A number of gold
complexes were generously provided by Johnson Matthey.
3
Angew. Chem. Int. Ed. 2004, 43, 6545 –6547
DOI: 10.1002/anie.200460232
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6545

Communications
The major benefit in preparative terms of using these
precatalysts in this reaction is that they enable the preparation
of benzoannelated heterocycles with a phenolic hydroxy
group in a position which is difficult to achieve by employing
[
12d]
classic synthetic methodology.
The most significant targets
are antitumor antibiotics from the tetrahydroisoquinoline
[
15]
family,
which—with this substitution pattern—are not
readily accessible by the Pictet–Spengler or related reac-
[
16]
tions. As reported previously, with 5 mol% or less AuCl no
3
[
12a]
complete conversion could be achieved,
quantitative conversion of 7a at room temperature
Scheme 2). And even the Z-protected substrate 7b (Z =
CO CH Ph) gave a clean reaction with 6. With cationic
but 6 gave a
(
2
2
gold(i) complexes we could not achieve the product selectivity
reported here.
Figure 3. Comparison of the activities of 4–6 (with test-substrate 1).
Reaction conditions: room temperature, 5 mol% of catalyst, MeCN.
Scheme 2. Conversion of the substrates 7a and 7b with the
precatalyst 6.
In conclusion, the development of the gold(iii) precata-
lysts 3–6 represents a first step in catalyst-tuning by ligand
design, a major focus of research for most other transition
metals. These results provide good evidence for the establish-
ment of significantly more effective gold catalysts.
Figure 4. Activity of 3 in the conversion of 1 in different solvents. Reac-
tion conditions: room temperature, 5 mol% 3, a) CH Cl /
2
2
MeCN=80:20; b) CH Cl /MeCN=100:0; c) CH Cl /MeCN=90:10.
2
2
2
2
spite of the slower conversion, these complexes are superior Experimental Section
to other transition-metal complexes known to catalyze this
Complex 7a (300 mg, 861 mmol) and complex 6 (15.7 mg, 38.7 mmol;
4.5 mol%) in CH Cl (1.50 mL) were stirred at room temperature for
[
12c,14]
reaction (Figure 5).
2
2
4
h. The solvent was removed in vacuo, and column chromatography
yielded 8a (284 mg; 95%) .
a: M.p. 166–1678C. R (petroleum ether/dichloromethane/ethyl
8
f
acetate, 10:3:1) = 0.10; IR (neat): n˜ = 3514, 1587, 1530, 1467, 1346,
1
6
311, 1260, 1235, 1216, 1161, 992, 958, 873, 854, 805, 763, 737, 691, 619,
À1
1
00, 580 cm ; H NMR (CDCl , 250 MHz): d = 2.20 (s, 3H), 2.88 (t,
3
J = 5.9 Hz, 2H), 3.43 (t, J = 5.9 Hz, 2H), 4.31 (s, 2H), 4.82 (s, 1H), 6.60
(
8
d, J = 7.7 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 8.04 (d, J = 9.0 Hz, 2H),
1
3
.36 ppm (d, J = 9.0 Hz, 2H); C NMR (CDCl , 126 MHz): d = 15.57
3
(q), 28.93 (t), 43.82 (t), 43.85 (t), 118.63 (s), 120.12 (s), 121.06 (d),
1
24.74 (d, 2C), 129.12 (d, 2C), 129.29 (d), 132.53 (s), 143.38 (s), 150.51
+
(s), 150.53 ppm (s); MS (70 eV): m/z (%): 348 (31)[M ], 161 (100),
1
34 (41), 91 (10). C, H, N analysis calcd (%) for C H N O S (348.38):
1
6
16
2
5
C 55.16, H 4.63, N 8.04; found: C 55.16, H 4.66, N 8.07.
Received: April 6, 2004
Keywords: alkynes · gold · heterocycles · homogeneous
.
catalysis · N,O ligands
Figure 5. Comparison of the activity of 3 with the activities of different
transition-metal catalysts (product 2). Reaction conditions: 5 mol%
catalyst, AuCl : 108C, MeCN; 3: 458C, MeCN; PdCl : 458C, MeCN;
3
2
[
{IrCl(cod)} ]: 458C, MeCN; [Ru (CO) ]: 458C, benzene; PtCl : 458C,
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3
12
2
MeCN; [{RhCl(cod)} ]: 458C, MeCN.
2
6
546
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www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 6545 –6547

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