An efficient route to 1-aminoisoquinolines via AgOTf-catalyzed reaction of 2-alkynylbenzaldoxime with amine

Article abstract of DOI:10.1039/c1ob05582h

2-Alkynylbenzaldoxime reacts with amine catalyzed by silver triflate under mild conditions, leading to 1-aminoisoquinolines in good yield. This reaction proceeds efficiently with good functional group tolerance. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05582h

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An efficient route to 1-aminoisoquinolines via AgOTf-catalyzed reaction of
2-alkynylbenzaldoxime with amine†
Danqing Zheng,a Zhiyuan Chen,a Jianping Liu*b and Jie Wu*a,c
Received 12th April 2011, Accepted 12th May 2011
DOI: 10.1039/c1ob05582h
Table 1 Initial studies for AgOTf-catalyzed reaction of 2-
alkynylbenzaldoxime 1a with cyclohexylamine 2a
2-Alkynylbenzaldoxime reacts with amine catalyzed by
silver triflate under mild conditions, leading to 1-
aminoisoquinolines in good yield. This reaction proceeds
efficiently with good functional group tolerance.
It is well recognized that N-heterocycles hold an important
and special place among pharmaceuticals and natural products.
Thus, significant efforts continue to be given to the method-
ologies development for the generation of nitrogen-containing
heterocycles.1 In the last few decades, intense attention has been
paid continuously to isoquinoline derivatives due to their immense
biological importance in many nature products and small molecule
chemotherapeutics.2 1-Aminoisoquinoline is an important class of
compounds among the family of isoquinolines, which shows re-
markable biological activities. For example, 1-aminoisoquinoline
derivatives have been reported as selective inhibitors of mu-
tant protein kinase and anti-tumor reagents.3 Additionally, due
to their structural versatility, 1-aminoisoquinolines have been
demonstrated as valuable intermediates in organic synthesis, which
could be easily converted into functionalized isoquinolines. The
methods for the preparation of 1-aminoisoquinolines include
substitutional reaction of 1-haloisoquinolines by amines4 and
transition metal-catalyzed coupling reactions of amines with 1-
haloisoquinolines.5 However, these approaches usually suffered
from harsh conditions, high temperature, strong base, or expen-
sive metal catalysts. Moreover, a drawback associated with the
methods is that a toxic compound such as POCl3 has to be
utilized for 1-haloisoquinolines formation.6 Recently Londregan
and co-workers described the reaction of pyridine-N-oxide with
amine promoted by a phosphonium salt for the synthesis of
2-aminopyridines.7 During our efforts for natural product-like
compounds construction, we and others found that isoquinoline-
N-oxide could be easily formed from 2-alkynylbenzaldoxime in the
presence of electrophiles or suitable metal salts.8,9 Inspired by these
Entry
Base
PyBroP (equiv)
Solvent
Yield (%)a
1
2
3
4
5
6
7
8
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
Et3N
1.2
0
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
THF
1,4-dioxane
CH2Cl2
Toluene
MeCN
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
20
NR
77
64
80
57
56
58
70
69
29
27
20
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
9
10
11
12
13
nBu3N
DBU
pyridine
NaOAc
a Isolated yield based on 2-alkynylbenzaldoxime 1a.
results, we conceived that 1-aminoisoquinoline scaffold could be
generated via a reaction of 2-alkynylbenzaldoxime with amine in
the presence of a metal catalyst and a suitable phosphonium salt.
To demonstrate the feasibility of this projected route, we started
to explore the possibility of this transformation.
Our studies commenced with the reaction of 2-
alkynylbenzaldoxime 1a with cyclohexylamine 2a (Table 1).
As mentioned in our previous reports,8 silver triflate was
demonstrated as the best metal catalyst for isoquinoline-N-oxide
formation via 6-endo-cyclization of 2-alkynylbenzaldoxime.9
Thus, the reaction was catalyzed by 10 mol% of silver triflate
in the presence of PyBroP (bromotrispyrrolidinophosphonium
hexafluorophosphate, 1.2 equiv) and iPr2NEt (3.0 equiv) in
dichloroethane. To our delight, the reaction proceeded to afford
the desired product 3aa in 20% yield (Table 1, entry 1). No
reaction took replace in a blank experiment without the addition
of PyBroP (Table 1, entry 2). This result highlights an important
role of PyBroP for final outcome. With this promising lead in
hand we next sought to improve the efficiency of the reaction.
The yield was increased to 77% when 2.0 equiv of PyBroP was
employed in the reaction (Table 1, entry 3). Further screens of
aDepartment of Chemistry, Fudan University, 220 Handan Road, Shanghai,
200433, China. E-mail: jie_wu@fudan.edu.cn; Fax: +86 21 6564 1740;
Tel: +86 21 6510 2412
bEENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200031,
China
cState Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Shanghai, 200032, China
† Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, 1H and 13C NMR spectra of compounds
3. See DOI: 10.1039/c1ob05582h
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Table 2 Silver triflate-catalyzed reaction of 2-alkynylbenzaldoxime 1 with
amine 2
investigated (Table 2, entries 15–28). All reactions worked well
to produce the expected 1-aminoisoquinolines in good yields. As
we can see, the groups attached on the triple bond did not affect
the final outcome. Moreover, substitutions including electron-
withdrawing groups and electron-donating groups on the aromatic
ring of 2-alkynylbenzaldoximes were well tolerated. For example,
reaction of 2-(2-cyclopropylethynyl)-4,5-dimethoxybenzaldehyde
oxime 1o with cyclohexylamine 2a gave rise to the desired 1-
aminoisoquinoline 3pa in 83% yield (Table 2, entry 28).
Entry R1, R2
R3, R4
Yield (%)a
For the possible mechanism, according to Londregan’ report7
and our recent result,8 we reasoned that isoquinoline-N-oxide A
would be formed first via AgOTf-catalyzed 6-endo-cyclization of 2-
alkynylbenzaldoxime 1, which subsequently acted as a nucleophile
to replace the bromide of PyBroP to afford intermediate B
(Scheme 1). Then amine would be involved in the reaction.
After intermolecular nucleophilic addition and deprotonation,
the desired 1-aminoisoquinoline 3 would be generated with the
release of 1-(dipyrrolidin-1-ylphosphoryl)pyrrolidine D. Actually,
without the addition of silver catalyst, no formation of the desired
product was observed for the reaction of 2-alkynylbenzaldoxime
1 with amine in the presence of PyBroP. Good conversion and
yield were obtained when isoquinoline-N-oxide A was treated
with PyBroP and amine, which provided a strong support for
the proposed mechanism.
1
2
3
4
5
6
7
8
H, cyclopropyl (1a)
Cyclohexyl, H (2a)
n-Bu, H (2b)
80 (3aa)
70 (3ab)
66 (3ac)
63 (3ad)
81 (3ae)
76 (3af)
66 (3ag)
77 (3ah)
63 (3ai)
54 (3aj)
40 (3ak)
H, cyclopropyl (1a)
H, cyclopropyl (1a)
H, cyclopropyl (1a)
H, cyclopropyl (1a)
H, cyclopropyl (1a)
H, cyclopropyl (1a)
H, cyclopropyl (1a)
H, cyclopropyl (1a)
H, cyclopropyl (1a)
H, cyclopropyl (1a)
H, cyclopropyl (1a)
H, cyclopropyl (1a)
H, cyclopropyl (1a)
H, C6H5 (1b)
t-Bu, H (2c)
Bn, H (2d)
-(CH2)5- (2e)
n-Pr, n-Pr (2f)
C6H5, H (2g)
4-iPrC6H4, H (2h)
4-ClC6H4, H (2i)
4-NCC6H4, H (2j)
4-NO2C6H4, H (2k)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
4-EtO2CC6H4, H (2l) 62 (3al)
C6H5, Me (2m)
58 (3am)
50 (3an)
55 (3ba)
52 (3ca)
60 (3da)
60 (3ea)
61 (3fa)
54 (3ga)
68 (3ha)
63 (3ia)
62 (3ja)
84 (3ka)
71 (3la)
80 (3ma)
76 (3na)
83 (3oa)
H, 2-pyridinyl (2n)
Cyclohexyl, H (2a)
Cyclohexyl, H (2a)
Cyclohexyl, H (2a)
Cyclohexyl, H (2a)
Cyclohexyl, H (2a)
Cyclohexyl, H (2a)
Cyclohexyl, H (2a)
Cyclohexyl, H (2a)
Cyclohexyl, H (2a)
Cyclohexyl, H (2a)
Cyclohexyl, H (2a)
Cyclohexyl, H (2a)
Cyclohexyl, H (2a)
H, 4-MeC6H4 (1c)
H, 4-ClC6H4 (1d)
H, n-Bu (1e)
4-F, n-Bu (1f)
4-F, 4-MeC6H4 (1g)
4-OMe, C6H5 (1h)
5-F, C6H5 (1i)
5-F, 4-MeC6H4 (1j)
5-F, cyclopropyl (1k)
5-Cl, C6H5 (1l)
5-Cl, cyclopropyl (1m)
5-Me, C6H5 (1n)
4,5-(OMe)2, cyclopropyl (1o) Cyclohexyl, H (2a)
a Isolated yield based on 2-alkynylbenzaldoxime 1.
solvents indicated that the reaction worked the most efficiently
in 1,4-dioxane to furnish the desired 1-aminoisoquinoline 3aa in
80% yield (Table 1, entries 4–8). Additionally, survey of bases
revealed that iPr2NEt was the best choice (Table 1, entries 9–13).
The reactivity was diminished when the amount of base was
reduced (data not shown in Table 1).
Scheme 1 Possible mechanism for silver triflate-catalyzed reaction of
2-alkynylbenzaldoxime 1 with amine 2.
In conclusion, we have developed a novel and efficient approach
to functionalized 1-aminoisoquinolines via silver triflate-catalyzed
reaction of 2-alkynylbenzaldoxime with amine. The presence of
PyBroP is essential for the successful transformation. The good
functional groups tolerance at different positions of the substrates
is demonstrated. The library of 1-aminoisoquinolines is under
construction currently, due to the easy availability of starting
materials and the efficiency of this method. The subsequent
biological screens of these 1-aminoisoquinoline library members
will be evaluated, and these results will be reported in due course.
Having demonstrated the viability of this AgOTf-cayalyzed
strategy we next investigated the scope of the transformation.
To assess the impact of the structural and functional motifs
on the reaction we tested a range of 2-alkynylbenzaldoxime 1
with amine 2 (Table 2). All the reactions were completed in
15 h. For the reaction of 2-(2-cyclopropylethynyl)benzaldehyde
oxime 1a, a variety of amines were examined (Table 2, entries
1–14). Not only aliphatic amines but also anilines were all good
partners in the reactions. Additionally, different functional groups
including chloro, cyano, nitro, and ester groups attached on
the aromatic ring of anilines were all tolerated. Moreover, it
was noticeable that reactions of 2-alkynylbenzaldoxime 1a with
secondary amines proceeded smoothly as well to afford the
corresponding products. For instance, 2-alkynylbenzaldoxime 1a
reacted with piperidine 2e, leading to 1-aminoisoquinoline 3ae
in 81% yield (Table 2, entry 5). A similar outcome was observed
when diisopropylamine 2f was utilized in the reaction (Table 2,
entry 6). In extending this useful transformation, reactions of
various 2-alkynylbenzaldoximes with cyclohexylamine 2a were
Acknowledgements
Financial support from the National Natural Science Foundation
of China (21032007) is gratefully acknowledged.
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Org. Biomol. Chem., 2011, 9, 4763–4765 | 4765
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