Synthesis of Functionalized 1H-Isochromene Derivatives via a Au-Catalyzed Domino Cycloisomerization/Reduction Approach

Article abstract of DOI:10.1021/acs.orglett.5b03146

A Au-catalyzed versatile and efficient access to 1H-isochromenes is reported. The efficiency of the [AuCl₂(Pic)] complex (1-5 mol %) was demonstrated and allowed a domino cycloisomerization/reduction reaction process starting from a wide range of functionalized ortho-alkynylbenzaldehydes and one example of ortho-alkynylpyridinylaldehyde. The smooth reaction conditions were amenable to aryl- and alkyl-substituted alkynyl derivatives, as well as functionalized halogen and ether moieties, leading to a chemo- and regioselective 6-endo-cyclization with good to excellent yields.

Full text of DOI:10.1021/acs.orglett.5b03146

Letter
pubs.acs.org/OrgLett
Synthesis of Functionalized 1H‑Isochromene Derivatives via a Au-
Catalyzed Domino Cycloisomerization/Reduction Approach
Eder Tomas-Mendivil,† Jerome Starck,‡ Jean-Claude Ortuno,*,‡ and Veronique Michelet*,†
́
́
̂
́
†Chimie ParisTech, PSL Research University, CNRS, Institut de Recherche de Chimie Paris (IRCP), F-75005 Paris, France
‡Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy-Seine, France
S
* Supporting Information
ABSTRACT: A Au-catalyzed versatile and efficient access to 1H-isochromenes is reported. The efficiency of the [AuCl2(Pic)]
complex (1−5 mol %) was demonstrated and allowed a domino cycloisomerization/reduction reaction process starting from a
wide range of functionalized ortho-alkynylbenzaldehydes and one example of ortho-alkynylpyridinylaldehyde. The smooth
reaction conditions were amenable to aryl- and alkyl-substituted alkynyl derivatives, as well as functionalized halogen and ether
moieties, leading to a chemo- and regioselective 6-endo-cyclization with good to excellent yields.
unctionalized 1H-isochromene frameworks are found in a
Bu group) in the presence of copper and silver complexes.8 An
Fvariety of natural products, bioactive molecules, and alternative strategy for the synthesis of isochromene involves the
pharmaceuticals.1 They have important biological effects
use of functionalized benzylic alcohols, but it suffers from
including antitumor properties,2 and their efficient and versatile
regiocontrol as well as a longer synthetic pathway for the
preparation of starting alcohols (Scheme 1, eq 2).3 Considering
our previous reports on gold-catalyzed cyclization of alcohols and
carboxylic acids9 and our interest in diversity-oriented synthesis
(DOS),10 we anticipated that readily available ortho-alkynylaryl
aldehyde derivatives may be suitable substrates for such a domino
cycloisomerization/reduction reaction process. We wish, there-
fore, to report therein our preliminary results on the general,
efficient, and unprecedented synthesis of original and function-
alized 1H-isochromenes starting from ortho-alkynylaryl-
aldehydes (Scheme 1, eq 3).
synthesis has been a great source of inspiration to chemists.3
Among various methods to prepare the isochromene skeleton,
one particularly straightforward and atom economical process
has been the use of transition-metal-catalyzed cyclization of
ortho-alkynylarylaldehydes or ortho-alkynylbenzylalcohols.4−7
Inspired by the seminal work of Asao, Yamamoto and co-
workers on gold-catalyzed formal [4 + 2] benzannulation of
ortho-alkynylbenzaldehydes,5 further contributions implied
domino processes in the presence of C, O, or N nucleophiles.6,7
(Scheme 1, eq 1). The implication of hydride as an external
nucleophile has been only studied very recently and, to the best
of our knowledge, has been limited to ketones as a carbonyl
moiety and mostly aryl-substituted alkynes (2 examples with n-
At the outset of our studies, the readily prepared ortho-n-
butylacetylenyl benzaldehyde 1a was selected as a model
substrate in order to optimize the catalytic system and a
Hantzsch ester11 (HEH) was chosen as the hydride source
(Table 1). Considering the supremacy of π-gold complexes as
intermediates,12 we first tested the cationic commercially
available [Au(NTf2)(PPh3)] complex as the catalytic source of
electrophilic activation. Pleasingly, the 6-endo cyclization mode
smoothly operated as well as the in situ reduction in the presence
of 5 mol % of gold and 1.2 equiv of HEH at rt, leading to the
desired 1H-isochromene 2a in 86% isolated yield (Table 1, entry
1).13 Further optimization showed that the catalyst loading could
be diminished for such a domino process (Table 1, entries 2−3).
Interestingly, the use of the less expensive dichloro(2-pyridine-
Scheme 1. [M]-Catalyzed Access to 1H-Isochromenes
Received: October 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03146
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b
c
entry
cat. [M] (mol %)
solvent
time (h) conv (yield %)
1
[Au(NTf2)(PPh3)] (5)
[Au(NTf2)(PPh3)] (5)
[Au(NTf2)(PPh3)] (1)
[AuCl2(Pic)] (5)
[AuCl2(Pic)] (1)
AuCl3 (1)
toluene
CH3CN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
THF
16
16
3
>99 (86)
2
90
3
>99
4
1
>99
5
1
>99 (86)
Figure 1. Structures of substrates 1b−t.
6
1
93
0
7
Au2O3 (0.5)
1
derivatives (Supporting Information (SI)).17 Considering the
importance of organofluorine compounds in various areas
including pharmaceuticals, agrochemicals, and materials,18 we
selected 1b−d as potential key building blocks for the
development of potential drug candidates. An aldehyde bearing
an electron-donating group such as 1e was also prepared.
Regarding the substitution on the alkynyl moiety, several other
groups other than n-butyl have been targeted such as silyl (1f),
hindered alkyl and cycloalkyl (1h, 1l) groups as well as
functionalized alkyl (1i−j), benzyl (1k), and cycloalkenyl (1m)
groups. Aryl-substituted alkynes bearing either electron-donating
or -withdrawing groups (1p−r) and a naphthyl-functionalized
aldehyde 1s were also prepared from 1g. A pyridinyl derivative 1t
was also prepared starting from 5-bromo-2-chloropyridine-4-
carbaldehyde.
8
AgSbF6 (1)
24
8
33
0
9
Ag2O (0.5)
10
11
12
13
14
Ag2CO3 (0.5)
8
0
PdCl2 (1)
1
0
PtCl2 (1)
1
41
0
Cu(OAc)2·H2O (1)
−
[AuCl2(Pic)] (1)
[AuCl2(Pic)] (1)
[AuCl2(Pic)] (1)
[AuCl2(Pic)] (1)
([AuCl2(Pic)] (1)
1
24
24
2
0
d
e
15
>99
16
17
18
19
>99
>99
>99
>99
1
CH3CN
1
MeOH
24
a
b
Conditions: aldehyde 1a and 1.2 equiv of HEH. Determined by 1H
c
d
e
NMR. Isolated yields. Reaction without HEH. Decomposition of
1a.
We first investigated the influence of the substitution on the
alkyl-substituted alkynes under the optimized conditions
(Scheme 2). The yields were good for fluoro-substituted
carboxylato)gold [AuCl2(Pic)]14 complex led to excellent results
(Table 1, entries 4−5) in 1 h of reaction time. Other sources of
8
gold(III) catalyst such as AuCl3 or Au2O3 gave a lower or no
Scheme 2. Domino Cyclization/Reduction of Alkyl-
Substituted Alkynes
conversion (Table 1, entries 6−7). Notably, no 5-exo-dig
cyclization was observed whereas this mode of cyclization was
found to be highly competitive in the presence of gold trichloride
in the case of ortho-alkynylarylketones.8a The observed total
regioselectivity in favor of the 6-endo adduct was in full
agreement with recent findings on an α-substituent effect for
gold-catalyzed cycloisomerization reactions of ortho-alkynyl-
benzylcarbamates.15
Various other salts, such as silver salts, known to be efficient for
domino acetalization/cycloisomerization reactions of aldehydes
in either a 5-exo or 6-endo process,7a,h,i were tested without
success (Table 1, entries 8−10). The use of Pd, Pt, or Cu
electrophilic catalysts were engaged in the same domino process
(Table 1, entries 11−13) and led to low or no conversion.
Control experiments in the absence of catalyst or HEH (Table 1,
entries 14−15) gave no conversion and decomposition of the
starting material (conversion >99%) respectively, showing
clearly the crucial role of gold and a hydride source.16 Other
solvents such as CH2Cl2, THF, CH3CN, and MeOH were
compatible with the reaction conditions despite a slower kinetic
in the case of methanol (entries 16−19). Using the optimized
system consisting of 1 mol % of [AuCl2(Pic)] and 1.2 equiv of
HEH at rt in toluene, the aldehyde scope of the reaction was
explored.
arylaldehydes (2b−d) (∼80%). A slight decrease of the isolated
yield was observed in the case of an electron-donating substituted
aldehyde such as 1,3-benzo dioxolane derivative 2e. The mild
reaction conditions were compatible with hindered tert-butyl,
cyclopropanyl, or benzyl groups (2h, 2l, and 2k, 87%, 72%, and
82% yields respectively) and functionalized alkyl groups such as
chloropropanyl and methoxymethyl moieties (2i−j). The
presence of an alkenyl group (such as in 1m) had a detrimental
As stated before, the commercially availability and functional
diversity of ortho-bromo-arylaldehydes is much higher than those
for the corresponding benzylic alcohols. For this purpose, various
ortho-alkynyl arylaldehydes (Figure 1) were synthesized
according to a classical Sonogashira cross-coupling starting
from the corresponding commercially available ortho-bromo
B
DOI: 10.1021/acs.orglett.5b03146
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
effect, presumably because of the possible reactivity of the
resulting conjugated diene 2m.19 The only limitation was found
in the reactivity of TMS-functionalized and nonsubstituted
alkynyl aldehyde 1f and 1g: no conversion was observed for 1f20a
whereas full conversion was detected for 1g with no trace of the
desired adduct. The reaction led to a complex mixture of
nonidentified derivatives.20b Finally, the domino process was
successfully conducted on a gram scale in the case of aldehyde 1a,
and the resulting 1H-isochromene 2a was isolated in 96% yield.
Following these valuable results, we decided to investigate the
domino process on aryl-substituted alkynes, where we
anticipated a trickier endo/exo process due to electronic effects
(Scheme 3).4,12 The reactivity of 1n was studied and required 5
Figure 2. ORTEP-type view of the structure of 2p.
chemistry. Further studies will focus on applications for
heterocyclic carbonyl-yne derivatives23 and postfunctionalization
of the valuable functionalized 1H-isochromenes.
ASSOCIATED CONTENT
* Supporting Information
■
Scheme 3. Domino Cyclization/Reduction of Aryl-
Substituted Alkynes and Heterocyclic Aldehyde
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03146.
Experimental procedures and characterization data of new
products (PDF)
X-ray diffraction data for 2p (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jean-claude.ortuno@fr.netgrs.com.
*E-mail: veronique.michelet@chimie-paristech.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Minister
Recherche and the Centre National de la Recherche Scientifique
(CNRS). E.T.-M. is grateful to the Institut de Recherches Servier
for a grant. The authors thank L.-M. Chamoreau (UMR 8232,
■
̀
e de l’Education et de la
mol % catalysts for full and clean conversion of starting material.
Similarly to Crabtree’s report in the presence of an Ir catalyst for
a benzyl alcohol analogue of 1n, the cyclization occurred
exclusively according to a 6-endo process.21 Pleasingly, the
cyclization/reduction reactions of other substituted patterns on
the phenyl ring also allowed the exclusive formation of 6-endo
1H-isochromene derivatives (2o, 2q−s, Scheme 3, eq 1) in good
to excellent yields (60−89%).
́
Institut Parisien de Chimie Moleculaire) for X-ray structure
analysis. Johnson Matthey Inc. is acknowledged for generous
loans of HAuCl4, PdCl2, and PtCl2.
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DOI: 10.1021/acs.orglett.5b03146
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