Tuning the reactivity of Au-complexes in an Au(i)/chiral Bronsted acid cooperative catalytic system: An approach to optically active fused 1,2-dihydroisoquinolines

Article abstract of DOI:10.1039/c2cc17450b

An enantioselective cooperative catalysis protocol, utilizing achiral Au(i) complexes and chiral Bronsted acids, has been developed for the synthesis of optically pure fused 1,2-dihydroisoquinolines starting from 2-alkynylbenzaldehydes and 2-aminobenzamides. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc17450b

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COMMUNICATION
Tuning the reactivity of Au-complexes in an Au(I)/chiral Brønsted acid
cooperative catalytic system: an approach to optically active fused
1,2-dihydroisoquinolinesw
Nitin T. Patil,* Anil Kumar Mutyala, Ashok Konala and Ramesh Babu Tella
Received 29th November 2011, Accepted 27th January 2012
DOI: 10.1039/c2cc17450b
An enantioselective cooperative catalysis protocol, utilizing achiral
Au(I) complexes and chiral Brønsted acids, has been developed
for the synthesis of optically pure fused 1,2-dihydroisoquinolines
starting from 2-alkynylbenzaldehydes and 2-aminobenzamides.
no convergent enantioselective methods leading to the formation
of optically active 1,2-dihydroisoquinolines have been disclosed
in the literature so far.7 Given the importance of these fused
isoquinoline derivatives and their potential biological properties,
the development of new methodologies for their preparation in
an enantioselective manner is of great importance for organic
and medicinal chemists.
The enantioselective cooperative/relay catalysis combining
metal catalysis and organocatalysis has emerged as a promising
strategy in organic synthesis.1 The concept is extremely
challenging because practically it is difficult to discover the
right choice of chiral metal catalyst and/or organocatalyst
combination. Unlike biological processes in which Nature
takes advantage of enzyme architecture to facilitate a reaction
cascade, it is difficult to conduct such reactions in a flask
because of the compatibility issues with the starting materials,
intermediates and other catalysts present from the onset of the
reaction. Often tuning of reactivity of either of the catalysts is
necessary in order to make the catalytic system compatible. In
particular, a cooperative process wherein soft transition metal
ions are employed to activate alkyne functionality2 would be
considered a difficult task. While in the literature some reports
describe this chemistry,3 there exist only few examples of an
enantioselective process that utilizes achiral Au catalysts and
chiral Brønsted acids as catalysts.4
Table 1 Feasibility and optimization studiesa
Entry Au
HA (4) Solvent
Yieldb (%) erc
1
2
3
4
5
6
7
8
AuCl
Ph3PAuCl
Ph3PAuOTf
4a
4a
4a
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
90
41
82
49
46
72
63
61
05d
92
83
82
91
92
50 : 50
61 : 39
69 : 31
74 : 26
59 : 41
89 : 11
84 : 16
85 : 15
89 : 11
92 : 08
39 : 61e
69 : 31
56 : 44
98 : 02f,g
96 : 04f
82 : 18f
90 : 10f
92 : 08f
Ph3PAuSbF6 4a
Ph3PAuBF4
Ph3PAuMe
5a–AuMe
4a
4a
4a
4a
4b
4c
4d
4e
4f
4c
4c
4c
4c
4c
5b–AuMe
9
Ph3PAuMe
Ph3PAuMe
Ph3PAuMe
Ph3PAuMe
Ph3PAuMe
Ph3PAuMe
Ph3PAuMe
Ph3PAuMe
Ph3PAuMe
Ph3PAuMe
Fused 1,2-dihydroisoquinolines are of broad interest due to their
vast abundance in natural products5 and pharmaceutically impor-
tant compounds.6 Noteworthily, to the best of our knowledge,
10
11
12
13
14
15
16
17
18
CH3CN 74
THF 57
Toluene 65
CHCl3 92
a
Reaction conditions: 0.24 mmol 1a, 0.24 mmol 2a, 5 mol% 4,
5 mol% Au catalysts, 50 mg MS 4 A, solvent (2 mL), 0 1C, 24 h then
rt, 24 h. Isolated yields. From HPLC analysis using an OD-H
b
c
d
column. Recovery of corresponding aminal (91 : 09 er) in 85% yield.
e
f
g
Opposite enantiomer was obtained. 2 mol% PPh3AuMe. ꢀ5 1C,
32 h then rt, 24 h.
Scheme 1
CPC Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500 607, India. E-mail: nitin@iict.res.in;
Fax: +91-40-27193382
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc17450b
c
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A central theme of the research in our laboratory is the
development of p-acid catalyzed reactions8 and merging p-acid
catalysis with organocatalysis9 for the synthesis of nitrogen
containing heterocycles. Recently, we reported an AuCl-catalyzed
coupling–cyclization strategy for the synthesis of isoquinoline-
fused polycyclic compounds employing 2-alkynylbenzaldehydes
and various aromatic amines bearing tethered nucleophiles.8b
On the basis of the proposed rudimentary mechanism, we
postulated that the reaction can be made enantioselective
under a cooperative catalysis utilizing achiral Au(I) complexes
and chiral Brønsted acids10 to give optically active hetero-
cycles as outlined in Scheme 1. A major concern is that the
Au(I)X salts would racemize the relatively labile optically pure
aminals, generated in situ by the enantioselective condensation
of 1 with 2, leading to the racemic products 3. The challenge,
therefore, was to search for a suitable achiral gold(I) catalyst
which should only catalyze hydroamination and should not
take part in the condensation process. We surmised that this
crucial tuning of Lewis acidity of gold(I) complexes can be
achieved by varying the counter-ion.11
in DCE at 0 1C, 24 h then at rt for 24 h (entry 1). The desired
product 3a was obtained in 90% yield; however, the er was
found to be 50 : 50. The use of 5 mol% Ph3PAuCl and
5 mol% of 4a afforded 3a in 41% yield and 61 : 39 er (entry 2).
Under the similar reaction conditions, various cationic Au
complexes such as Ph3PAuOTf (entry 3), Ph3PAuSbF6 (entry 4)
and Ph3PAuBF4 (entry 5) were examined. None of the above
reactions showed higher enantioselectivity of the product,
but validated our proposal that the tuning of counter-ion
might have a significant role in obtaining the product with
higher enantioselectivity. Consequently, the enantioselective
condensation/hydroamination cascade was attempted using
Ph3PAuMe and 4a. Gratifyingly, the reaction gave the product
3a in 72% yield in 89 : 11 enantiomeric ratio (entry 6). In
order to know the effect of the phosphine ligand, the Au
complexes 5a and 5b were synthesized and tested for their
reactivities (entries 7 and 8). In both the cases, the reaction was
found to be very sluggish indicating that the sterically bulky
phosphine ligands hamper the rate of hydroamination reaction.
Next, our studies were aimed at the screening of chiral
phosphoric acid catalysts 4 bearing various type of substituents
at the 3,30-position on the binaphthyl backbone. As shown in
entries 9–13, all of the chiral catalysts 4 exhibited excellent
performance in terms of yields (except entry 9); however,
enantioselectivities were found to be strongly dependent on
the C-3 substituents. Out of the chiral phosphoric acids
examined, the catalyst 4c was proved to be the best, giving
To test this newly proposed idea of cooperative catalysis, we
began by choosing readily available 2-phenylalkynylbenzaldehyde
(1a) and 2-amino-5-bromobenzamide (2a)12 as the coupling
partners using a catalyst combination of Au(I) salts and chiral
phosphoric acids. The results of this study are summarized in
Table 1. At the outset, the proposed enantioselective reaction
was performed using 1a, 2a, 5 mol% AuCl and 5 mol% of 4a
Table 2 Substrate scope for the enantioselective synthesis of fused 1,2-dihydroisoquinolines 3a,b
Entry
1
2
3
Yield (%)
er
1
2
3
4
5
6
7
8
1a R1, R2 = H, R3 = Ph
1a
1a
1a
1a
1a
2b R4, R5, R6, R7 = H
3bc
3c
82
76
59
64
71
65
36
74
86
89
93
84
93
95
86
91
81
91
78
91
92
84
90
84
94 : 06
90 : 10
81 : 19
97 : 03
95 : 05
93 : 07
81 : 19
90 : 10
99 : 01
99 : 01
98 : 02
97 : 03
99 : 01
97 : 03
93 : 07
97 : 03
90 : 10
98 : 02
94 : 06
95 : 05
98 : 02
94 : 06
97 : 03
98 : 02
2c R4 = F, R5, R6, R7 = H
2d R4 = Cl, R5, R6, R7 = H
3dd
3ed
3fd
3gd
3hd,e
3i
2e R4, R5, R7 =H, R6 = Cl
2f R4, R6, R7 = H, R5 = OMe
2g R5, R6, R7 = H, R4 = Me
1a
1b R1 = H, R2 = Me, R3 = Ph
2h R4, R6 = H, R5 = Cl, R7 = Me
2b
2b
2a
2a
2b
2b
2a
2b
2a
2f
2c
2b
2b
2a
2b
2a
2a
9
1c R1 = F, R2 = H, R3 = Ph
1c
3j
3k
3l
3m
3n
3o
3p
3q
3r
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1d R1, R2 = H, R3 = p-tolyl
1d
1e R1 = F, R2 = H, R3 = p-tolyl
1e
1f R1, R2 = H, R3 = p-tbut-phenyl
1f
1f
1f
3s
3t
1g R1, R2 = H, R3 = m-OMe–Ph
1h R1, R2 = H, R3 = 3,5-di-methylphenyl
1h
3u
3v
3w
3x
3yc
1i R1, R2 = H, R3 = 1-cyclohexenyl
1i
1j R1, R2 = H, R3 = cyclohexyl
a
Reaction conditions: 0.24 mmol 1, 0.24 mmol 2, 5 mol% 4c, 2 mol% Ph3PAuMe, 50 mg MS 4 A, DCE (2 mL), ꢀ5 1C, 32 h, then rt 24 h.
b
c
d
e
Isolated yields. ꢀ5 1C, 32 h then rt 48 h. 5 mol% 4c, 5 mol% Ph3PAuMe, ꢀ5 1C, 32 h then rt 48 h. Corresponding aminal obtained in 52%
yield with 84 : 16 er.
c
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3a in 92% yield and 92 : 08 er (entry 10). Interestingly, lowering
the catalyst loading of PPh3AuMe resulted in a slight increase
in enantiomeric ratio, 98 : 02 (entry 14). As can be judged
from entries 15–18, solvents such as CH3CN, THF, toluene
and CHCl3 are not superior.
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Next, the reaction of 2-alkynylbenzaldehydes 1 with various
2-aminobenzamides 2 was examined under the optimized
conditions (Table 1, entry 14) and the representative results
are summarized in Table 2. The reaction proved to be general,
since 2-aminobenzamides, bearing substituents at various
positions in the aromatic ring, reacted effectively with various
2-alkynylbenzaldehydes to afford the target products in
moderate to good overall yields (59–95%) and excellent
enantioselectivities (81 : 19–99 : 01 er). However, in the case
of 3h the reaction was found to be sluggish. In some of the
cases the amount of Au catalysts used had to be re-optimized,
in order to avoid unreacted aminals in the crude reaction mixtures
or to increase the formation of 3d, 3e, 3f, 3g and 3h. It is worth
noting that the halo substituent on the 2-aminobenzamides had
no significant influence on the reactivity. The halo-substituted
fused isoquinolines can serve as versatile synthons13 enabling
introduction of various functional groups. Importantly, the
reaction conditions are so mild that no significant dehydro-
genation took place even after stirring for a long time and the
final products 3a–y were obtained in high enantiomeric ratios.13
In summary, we developed an enantioselective cooperative
catalytic protocol in which tuning the reactivity of the Au(I)
center is a crucial factor for obtaining the product with high ee’s.
NTP and AKM/AK thanks DST and CSIR for financial
assistance.
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13 See ESIw for mechanistic studies, diversification of products and
related information.
c
3096 Chem. Commun., 2012, 48, 3094–3096
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