Silver-catalyzed domino hydroarylation/cycloisomerization reactions of ortho-alkynylbenzaldehydes: An entry to functionalized isochromene derivatives

Article abstract of DOI:10.1021/ol5021256

A Ag-catalyzed versatile and efficient access to 1H,1-arylisochromenes is reported. Starting from ortho-alkynylbenzaldehydes bearing various substitution patterns on the benzaldehyde and alkynyl units, the use of silver triflate (10 mol %) allowed a domino hydroarylation/cycloisomerization reaction process, leading to aryl-functionalized 1H-isochromene (>10 compounds, 80-98% yields). Notably, the reaction conditions were also compatible with benzaldehydes bearing an aliphatic-substituted alkynyl moiety with modest to good yields (34-88%, 10 compounds).

Full text of DOI:10.1021/ol5021256

Letter
pubs.acs.org/OrgLett
Silver-Catalyzed Domino Hydroarylation/Cycloisomerization
Reactions of ortho-Alkynylbenzaldehydes: An Entry to
Functionalized Isochromene Derivatives
Gaelle Mariaule,†,‡ Gregory Newsome,§ Patrick Y. Toullec,§ Philippe Belmont,*,†,‡
̈
and Veronique Michelet*,§
́
†Institut Curie, UMR CNRS 176, 26 rue d’Ulm, 75005 Paris, France
‡Universite
́ ́
Paris Descartes, Faculte de Pharmacie de Paris, UMR CNRS 8638, 4 avenue de l’Observatoire, 75006 Paris, France
§PSL Research University, Chimie ParisTech-CNRS, Institut de Recherche de Chimie Paris, 11 rue P. et M. Curie, 75005 Paris,
France
S
* Supporting Information
ABSTRACT: A Ag-catalyzed versatile and efficient access to 1H,1-arylisochromenes is reported. Starting from ortho-
alkynylbenzaldehydes bearing various substitution patterns on the benzaldehyde and alkynyl units, the use of silver triflate (10
mol %) allowed a domino hydroarylation/cycloisomerization reaction process, leading to aryl-functionalized 1H-isochromene
(>10 compounds, 80−98% yields). Notably, the reaction conditions were also compatible with benzaldehydes bearing an
aliphatic-substituted alkynyl moiety with modest to good yields (34−88%, 10 compounds).
Scheme 1. [M]-Catalyzed Domino Processes
etal-catalyzed cycloisomerization reactions have become
Min recent years an efficient and useful tool for access to
highly functionalized carbo- and heterocycles.1 Among them,
the cyclization processes implying an alkynyl partner and thus
π-metal-complexes as intermediates have been thoroughly
studied and have allowed the discovery of novel skeleton
rearrangements and new reactions. The privileged reactivity of
various polyunsaturated partners such as 1,n-enyne,2 allenyne3
or carbonyl-yne4 derivatives has opened the way to original
scaffolds under racemic or enantioselective conditions. The
complexity of the resulting polycyclic structures has been
heightened by the intervention of other nucleophiles (oxygen,
carbon, nitrogen nucleophiles), favoring domino processes. As
part of our ongoing programs toward cycloisomerization
processes implying carbophilic π-activation in the presence of
gold,5,6 platinum,7 or silver8 catalysts, we became interested in
the carbonyl-yne cycloisomerization reactions in the presence
of an external nucleophile, which is of particular interest since it
allows the direct access to oxygen-containing heterocycles of
high biological value.9 We8 and others contributed in some key
developments for the domino cyclofunctionalization in the
presence of terminal alkynes,10 phosphites,11 nitrogen,12
activated methylenes,13 allyl trialkylsilanes,4a,g and hydride14
as nucleophiles, or oxygen-containing15 nucleophiles, the latter
being the most successful ones (Scheme 1, eq 1).16 The
implication of aromatics and heteroaromatics as external
nucleophiles has been scarcely studied and to the best of our
knowledge limited to indole as a nucleophile in the presence of
silver and palladium complexes.17 Considering our previous
report on domino hydroarylation/cycloisomerization reactions
of enynes18 (Scheme 1, eq 2), we anticipated that carbonyl-yne
derivatives may be suitable substrates for such processes. We
wish therefore to report our preliminary results on the domino
functionalization of ortho-alkynylbenzaldehydes in the presence
of electron-rich aromatic rings, leading to original 1H-
isochromenes (Scheme 1, eq 3).19
Received: July 19, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
First, the readily available ortho-phenylacetylenyl benzalde-
hyde 1a was chosen as a model substrate, trimethoxybenzene
2a was the external nucleophile, and silver salts were the
catalytic source of electrophilic activation. Various silver salts
had already given rise selectively to 5-exo-dig or 6-endo-dig
cyclization modes in the presence of alcohols.8 It is noteworthy
that Beeler, Porco and co-workers had tested the reactivity of
trimethoxybenzene in the presence of various transition metal
complexes including a silver catalyst without success.13 The use
of 5 mol % AgOTf in dichloromethane at rt led to 100%
conversion but a 16% isolated yield of the adduct 3a resulting
from a hydroarylation/6-endo-dig cyclization process (entry 1,
Table 1). The use of other silver salts (AgSbF6, AgPF6, Table 1,
confirmed by X-ray spectroscopy analysis of a bromo analogue
(Figure 1 and Supporting Information).
Figure 1. X-ray structure of 3-(4-bromophenyl)-1-(2,4,6-trimethoxy-
phenyl)-1H-isochromene 3h.
a
Table 1. Optimization of Reaction Conditions
The scope of the reaction was then studied, and for this
purpose, various ortho-alkynyl benzaldehydes (Scheme 2) were
Scheme 2. Structures of Substrates 1b−s
b
entry
[M]
solvent
time (h)
yield (conv) %
1
AgOTf
AgPF6
AgSbF6
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
/
DCM
DCM
DCM
DCE
DCE
DMF
DMF
DMF
DMF
DMF
DMF
DMF
8
16
14
14
32
14
32
52
71
81
91
0
2
3
4
5
6
7
8
9
8
8
6.5
6.5
21
40
28
19
3
c
c
synthesized according to a classical Sonogashira cross-coupling
starting from the corresponding ortho-bromo benzaldehydes
4−7.20 We selected not only known derivatives such as 1a−1c,
1e, 1h−1n, and 1p but also novel fluoro-functionalized
compounds (1d, 1f, 1g, 1r, 1s), amino- 1o, or trimethoxy
substituted 1q, their preparations being performed overall in
excellent yields.20
d
de
,
de f
, ,
10
11
12
ef
,
3−24
3−8
efg
, ,
h
/
0
a
For all entries, unless noted differently, 5 mol % [AgOTf], 2a (3
b
equiv), room temperature, solvent (0.25 M). Isolated yields or
conversion by H NMR are indicated. 6 equiv of 2a. [M] (10 mol
%). DMF (0.5 M). Reaction performed at 80 °C. Reaction
performed with HOTf (10 mol %). Along with unidentified products.
The optimized hydroarylation/cyclization conditions (Table
1, entry 10) were screened for a large array of ortho-alkynyl
benzaldehydes, with trimethoxybenzene (2a) as the nucleophile
(Scheme 3). The influence of the substitution on the aromatic
ring of the alkynyl moieties was first investigated (3b−i). The
yields were all excellent (80−98%), regardless of the
substitution pattern on the phenyl ring. Indeed, all the para-
substituted derivatives (methyl 3b 83%, fluoro 3d 85%,
trifluoromethyl 3e 98%, bromo 3h 81%, trimethoxy 3i 80%,
nitro 3j 93%) were obtained efficiently without influencing the
nature of the substitutive electron-withdrawing or -donating
groups. Comparison of ortho-substituted derivatives (fluoro 3f
88%, trifluoromethyl 3g 81%) with the para-substituted
derivatives (fluoro 3d 85%, trifluoromethyl 3e 98%) showed
that there was no influence by the fluoro group, a slight
decrease of the yield being observed in the case of the more
hindered trifluoromethyl group (98% to 81%). The main
difference was in the reaction time being much longer for the
ortho derivatives (7.5 h for 3f and 30 h for 3g) compared to the
para ones (2 h). Meta-substituted derivatives (methoxy 3c,
86%; trimethoxy 3i, 80%) were also easily obtained. Following
these excellent results, we decided to investigate the challenging
hydroarylation/cyclization process on nude (R2 = H), TMS-
substituted and alkyl-substituted ortho-alkynyl benzaldehydes. It
is noteworthy that alkyl-substituted-alkynyl substrates have
been much less studied than their aromatic counterparts mostly
due to sluggish reactions. Interestingly, starting either from
c
d
1
e
f
g
h
entries 2, 3), did not bring any improvement, and solvent
switching to DCE allowed isolating 3a in 32% yield along with
undesired compounds (Table 1, entry 4). Increasing the
amount of 2a (6 equiv) was detrimental (14% yield, Table 1,
entry 5). A significant improvement was observed when DMF
was used as the reaction solvent (32%, Table 1, entry 6), and
the yield increased up to 52% when the amount of 2a was
doubled (6 equiv, entry 7).
The main drawback was the reaction time (40 h); therefore,
we successively increased the AgOTf amount (Table 1, entry
8), concentrated the reaction medium (Table 1, entry 9), and
performed the reaction at 80 °C (Table 1, entry 10), and this
resulted in access to arylisochromenes 3a in an excellent 91%
yield in only 3 h. Control experiments achieved in the absence
of catalysts (entry 11) or in the presence of HOTf (entry 12)
showed clearly the crucial role of silver in the catalysis, putting
aside the impact of Brønsted acid traces. The reactivity of
diverse metallic salts such as Cu-, Au-, Pd-, or Pt-based catalysts
was studied showing either no conversion or lower isolated
yields.
The use of silver salts led selectively to the heterocycle
resulting from a 6-endo-dig cyclization. This was unambiguously
B
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Organic Letters
Letter
Scheme 3. Hydroarylation/Cyclization of Alkynylaldehydes
with Trimethoxybenzene
Scheme 4. Hydroarylation/Cyclization of Alkynylaldehydes
with Aryl Nucleophiles
method to substrate 1r having an alkyl substitution on the
alkynyl moiety (Scheme 4). Moreover, the introduction of
dimethylaniline 9 was also possible, whereas a different
reactivity had been observed by Beeler and Porco’s group
under stoichiometric silver conditions.13 The corresponding
functionalized aniline 15 was isolated in a nonoptimized 50%
yield, the conversion being 71%.19,4h,i Gratifyingly, the reaction
conditions were compatible with N-Me indole 10, as a
nucleophile, yielding isochromene 16 in 83% yield, providing
the fact that only 1 equiv of the nucleophile was used to avoid
side-product formation. The reactions of 3-methylbenzofuran
and 3-methylbenzo[b]thiophene with 1a afforded only traces of
the corresponding arylated derivatives.
Mechanistically, we anticipated that, after π-activation of the
alkyne and domino hydroarylation/cyclization step, the source
of proton involved in the protodemetalation step would come
from the acidic C−H bond of the nucleophile. Thus, we
18b
performed the reaction using deuterated compound 2a-d3
and obtained derivative 3a-d3 with 84% deuteration at the vinyl
position (Scheme 5), the slight erosion originating from traces
of water in the reaction mixture.
ortho-alkynyl benzaldehydes bearing a terminal alkyne (1k) or
from a TMS-protected one (1l), formation of the unsubstituted
isochromene 3k in a moderate 45% yield resulted. It is
noteworthy that the reaction required smoother conditions
than in the case of aryl-substituted substrates and was
performed at rt to diminish the formation of byproducts.
Pleasingly, we could also isolate isochromenes substituted by a
n-propyl (3m, 34%) or a tert-butyl group (3n, 65%). The N-
methylbenzyl group (1o) was unreactive, even upon extended
heating (up to 48 h), most probably due to a silver
complexation by the aliphatic nitrogen.8c Remarkly, the
reaction of ortho-alkynyl benzaldehyde 1p bearing methox-
ymethyl (MOM) groups on the alkynyl moiety led to
isochromene 3p in high yield. Finally, the influence of the
substitution of the benzaldehyde ring was investigated. The
presence of electron-donating groups (such as in 1q) had a
detrimental effect, as the desired adduct was isolated in 33%
yield. Remarkably, the reaction conditions were compatible
with fluoro- and trifluoro-substituted benzaldehydes, as
functionalized isochromenes 3r−3s were obtained in 88% yield.
The scope of the Ag-catalyzed hydroarylation/cycloisomeri-
zation domino reaction was also studied in the presence of
other carbon nucleophiles (Scheme 4). The use of dimethox-
ybenzene 8 as a nucleophile yielded isochromenes 13 and 14 in
acceptable yields (58% and 47% respectively). The reactions
were performed at lower temperature to avoid the formation of
byproducts (50 °C, 15−17 h), and we were able to apply our
Scheme 5. Labeling Study - Protodemetallation Step
Of note is the compatibility of the reaction conditions with a
bromide group (3h). Moreover, we were able to perform a Pd-
catalyzed Hartwig−Buchwald reaction21 on 3h (Scheme 6)
attesting to the robustness of the isochromenes (100 °C, 16 h).
In conclusion, we have developed an unprecedented silver-
catalyzed hydroarylation/cycloisomerization domino reaction
on ortho-alkynyl benzaldehydes, leading to functionalized
Scheme 6. Hartwig−Buchwald Reaction
C
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
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, J.-P. J. Am.
■
S
̂
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Experimental details and crystallographic data. This material is
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AUTHOR INFORMATION
Corresponding Authors
■
(7) (a) Ye, L.; Chen, Q.; Zhang, J.; Michelet, V. J. Org. Chem. 2009,
*E-mail: philippe.belmont@parisdescartes.fr.
74, 9550. (b) Toullec, P. Y.; Chao, C.-M.; Chen, Q.; Gladiali, S.;
̂
Genet, J.-P.; Michelet, V. Adv. Synth. Catal. 2008, 350, 2401.
*E-mail: veronique.michelet@chimie-paristech.fr.
(c) Pradal, A.; Gladiali, S.; Michelet, V.; Toullec, P. Y. Chem.Eur.
Notes
J. 2014, 20, 7128.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the CNRS, ATIP CNRS-INCa,
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