Synthesis of 2-(Isoquinolin-1-yl)prop-2-en-1-ones via Silver(I)-Catalyzed One-Pot Tandem Reaction of ortho-Alkynylbenzaldoximes with Propargylic Alcohols

Article abstract of DOI:10.1021/acs.orglett.9b02952

The silver(I)-catalyzed reaction of ortho-alkynylbenzaldoximes with propargylic alcohols represents a new strategy for the divergent one-pot synthesis of 2-(isoquinolin-1-yl) prop-2-en-1-ones via tandem 6-endo-cyclization, 1,3-dipolar cycloaddition, and intramolecular dehydrative opening of the 2,3-dihydroisoxazole ring. This synthetic protocol tolerates a wide variety of ortho-alkynylbenzaldoximes and propargylic alcohols and affords the corresponding products in excellent yields.

Full text of DOI:10.1021/acs.orglett.9b02952

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 2‑(Isoquinolin-1-yl)prop-2-en-1-ones via Silver(I)-
Catalyzed One-Pot Tandem Reaction of ortho-
Alkynylbenzaldoximes with Propargylic Alcohols
Ali Nikbakht,† Saeed Balalaie,*,†,‡ and Bernhard Breit*,§
†Peptide Chemistry Research Center, K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran
‡Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
§Institut fu
̈
r Organische Chemie, Albert-Ludwigs-Universitat Freiburg, Albertstrasse 21, 79104 Freiburg im Breisgau, Germany
̈
S
* Supporting Information
ABSTRACT: The silver(I)-catalyzed reaction of ortho-alkynylbenzaldoximes with propargylic alcohols represents a new
strategy for the divergent one-pot synthesis of 2-(isoquinolin-1-yl) prop-2-en-1-ones via tandem 6-endo-cyclization, 1,3-dipolar
cycloaddition, and intramolecular dehydrative opening of the 2,3-dihydroisoxazole ring. This synthetic protocol tolerates a wide
variety of ortho-alkynylbenzaldoximes and propargylic alcohols and affords the corresponding products in excellent yields.
π-Acidic metal catalyzed reactions have revolutionized the art
and science of organic synthesis due to their ability to elaborate
and extend carbon frameworks via a series of C−C and C−
heteroatom bonds formations. These reactions have the
potential to provide reactive intermediates compatible with a
broad range of functionalities in a highly efficient and facile
manner under mild reaction conditions.1 Such intermediates
can be harnessed as valuable synthetic building blocks for
further transformations through tandem reactions.2 They can
be applied in intermolecular or intramolecular cascade
reactions to generate complex molecular frameworks from
simple starting materials in a single step. In particular,
functionalized alkynes can be employed for generation of
active species through π-acidic metal catalyzed activation of the
alkyne moieties.3 Among them, ortho-alkynylbenzaldoximes are
excellent candidates due to their potential to form reactive
isoquinoline-N-oxide intermediates in the presence of Lewis
acid catalysts4 or electrophiles5 that can subsequently undergo
a number of reactions.
In this regard, intense interest has been directed toward the
reactions of ortho-alkynylbenzaldoximes with many different
types of unsaturated compounds with excellent reactivity in
various 1,3-dipolar cycloaddition reactions.6 These types of
reactions lead to the formation of complex small molecules via
novel skeletal rearrangement reactions.7 The nature of these
intramolecular skeletal rearrangement reactions and the
possible reaction products depend on the nature of the
unsaturated compounds involved. For example, the reaction of
ortho-alkynylbenzaldoximes (I) with carbodiimides (II) in the
presence of catalytic amounts of silver triflate affords the
corresponding 1-(isoquinolin-1-yl)ureas (III) through tandem
6-endo-cyclization, 1,3-dipolar cycloaddition, and intramolecu-
lar rearrangement.8 Employing arynes in the silver(I)-catalyzed
tandem reaction of ortho-alkynylbenzaldoximes gives rise to the
corresponding 2-oxa-6-azabicyclo[3.2.2]nona-6,8-dienes (V).9
This reaction proceeds via tandem 6-endo-cyclization, 1,3-
dipolar cycloaddition, and radical intramolecular rearrange-
ment. Through a similar mechanism, silver(I)-catalyzed
reactions of ortho-alkynylbenzaldoximes with alkylidenecyclo-
propanes10 (VI) and 1-((cyclopropylidenemethyl)-2-alkynyl)-
arenes11 (VIII) furnish the corresponding derivatives of benzo-
7-azabicyclo[4.2.2]dec-7-en-4-one (VII) and 1-((1,3-dihydro-
isobenzofuran-1-yl)methyl)isoquinoline (IX), respectively
(Scheme 1).
Aware that Lewis acid catalyzed reaction of propargylic
alcohols with a broad spectrum of nucleophiles and electro-
philes has been extensively employed in the synthesis of
various classes of heterocyclic compounds in recent years,12 we
have envisioned that propargylic alcohols may be suitable
reaction partners in the reaction with ortho-alkynyl-
benzaldoximes. Herein, we wish to report a silver(I)-catalyzed
one-pot tandem reaction of ortho-alkynylbenzaldoximes with
propargylic alcohols for the step-economic synthesis of
corresponding 2-(isoquinolin-1-yl)prop-2-en-1-ones via a
reaction cascade involving 6-endo-cyclization, [3 + 2] cyclo-
Received: August 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02952
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Tandem Reactions of ortho-Alkynylbenzaldoximes with Different Types of Unsaturated Compounds with Excellent
Reactivity in Various 1,3-Dipolar Cycloaddition Reactions
addition, and intramolecular dehydrative opening of the 2,3-
dihydroisoxazole ring.
Initially, for testing our hypothesis, the reaction of 1a with
2a was carried out in the presence of a catalytic amount of
AgOTf (10 mol %) in DMF at 110 °C. Product 3a was
obtained as the sole product in 91% isolated yield and
exclusive regioselectivity (Table 1, entry 1). By using AgNO3
With the optimized reaction conditions in hand (10 mmol %
AgOTf in DMF at 110 °C), we then explored the substrate
scope of this tandem reaction using various ortho-alkynylben-
zaldoximes and propargylic alcohols. The results are
summarized in Scheme 2. The reaction showed high generality
and functional group tolerance and afforded a variety of 2-
(isoquinolin-1-yl)prop-2-en-1-ones in excellent yields. As
illustrated in Scheme 2, a wide range of symmetrical
propargylic alcohols with either an electron-poor or electron-
rich aryl substituent lead to the desired product in good to
high yields. Furthermore, propargylic alcohols derived from
cyclic ketones behaved well (3d, 3l, 3m, 3r, 3s, 3x, 3y). It is
notable that propargylic alcohols having an alkyl group in the
R3 position instead of a phenyl group were well tolerated and
provided the tandem products in good to high yields (3h, 3n,
3t, 3z), However, unsubstituted propargylic alcohols at the
terminal position and the α position of the alcohol or
propargylic alcohols having two alkyl groups at the α position
of the alcohol did not lead to the desired product. Both
aromatic and aliphatic groups at the alkynyl part of ortho-
alkynylbenzaldoximes are tolerated under the reaction
conditions. On the other hand electron-withdrawing groups
(Cl and NO2) and electron-donating group (OMe) on the
ortho-alkynylbenzaldoximes behaved well in this catalytic
system.
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
AgOTf
AgNO3
AgBF4
(Ph3P)AuCl
Bi(OTf)3
InCl3
In(OTf)3
Sc(OTf)3
ZnCl2
solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
110
110
110
110
110
110
110
110
110
110
110
110
100
120
91
22
49
NR
NR
52
40
15
19
85
38
22
71
90
c
c
9
DMF
Using unsymmetrical-substituted propargylic alcohol led to
the expected products in high yield (3za, 3zb) albeit as a
mixture of diastereomers.
10
11
12
13
14
AgOTf
AgOTf
AgOTf
AgOTf
DMSO
1,4-Dioxane
Toluene
DMF
1
All compounds were characterized by IR, H NMR, 13C
NMR, and HRMS spectral analysis. Furthermore, the
molecular structures of the products were confirmed by the
single crystal X-ray diffraction analysis of compounds 3l and
3m (Figure 1).
AgOTf
DMF
a
Reaction conditions (unless otherwise specified): 1a (0.2 mmol), 2a
(0.2 mmol), catalyst (10 mol %), solvent (1 mL), temp °C, 12 h.
b
c
Isolated yields. No reaction observed.
A plausible mechanism is proposed in Scheme 3. In the first
step, through silver(I)-catalyzed 6-endo cyclization of ortho-
alkynylbenzaldoximes8,91, isoquinoline-N-oxides A are formed.
They undergo a facile 1,3-dipolar cycloaddition reaction with
propargylic alcohols 2 leading to cycloadduct intermediates B.
Finally, a ring-opening/dehydration sequence render the
desired 2-(Isoquinolin-1-yl) prop-2-en-1-ones 3. To gain
more insight into the reaction mechanism, the intermediate
A was prepared independently and was subsequently reacted
with propargylic alcohol 2a under catalyst-free conditions.
However, no 1,3-diploar cycloaddition proceeded, which
suggests that silver triflate also catalyzes the 1,3-dipolar
cycloaddition step.
or AgBF4 as the catalyst, the reaction yield decreased
dramatically to 22% and 49%, respectively (Table 1, entries
2−3). When (Ph3P)AuCl or Bi(OTf)3 were employed, no
reaction was observed (Table 1, entries 4−5), whereas InCl3,
In(OTf)3, Sc(OTf)3, and ZnCl2 gave 52%, 40%, 15%, and 19%
yields, respectively (Table 1, entries 6−9). There was no
reaction in the absence of the catalyst. The screening of various
solvents revealed that the reaction proceeds efficiently in DMF.
Moreover, the effect of the temperature was also investigated.
By lowering the temperature from 110 to 100 °C, the yield was
decreased to 71% (Table 1, entry 13). When the reaction
temperature was increased from 110 to 120 °C, no
improvement in yield was observed (Table 1, entry 14).
In conclusion, we have established a facile route to prepare
2-(isoquinolin-1-yl) prop-2-en-1-ones through a silver(I)-
B
DOI: 10.1021/acs.orglett.9b02952
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrates Scope for the Silver(I)-Catalyzed One-Pot Tandem Reaction of ortho-Alkynylbenzaldoximes with
Propargylic Alcohols
Scheme 3. Proposed Mechanism for the Silver(I)-Catalyzed
One-Pot Tandem Reaction of ortho-Alkynylbenzaldoximes
with Propargylic Alcohols
Figure 1. ORTEP view of compounds 3l and 3m.
catalyzed one-pot tandem reaction of ortho-alkynyl-
benzaldoximes with propargylic alcohols. The reaction features
a broad substrate scope and good functional group tolerance,
C
DOI: 10.1021/acs.orglett.9b02952
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02952.
Experimental procedures and characterizations (PDF)
Accession Codes
CCDC 1899726 and 1899744 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: balalaie@kntu.ac.ir.
*E-mail: bernhard.breit@chemie.uni-freiburg.de.
ORCID
Saeed Balalaie: 0000-0002-5764-0442
Bernhard Breit: 0000-0002-2514-3898
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for a fellowship from the Alexander von
Humboldt Foundation for the Research Group Linkage
Programme financial support. We thank Dr. Daniel Kratzert
for X-ray crystal structure analysis (Institut fu
̈
r anorganische
̈
Chemie, Albert-Ludwigs-Universitat Freiburg).
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DOI: 10.1021/acs.orglett.9b02952
Org. Lett. XXXX, XXX, XXX−XXX