Gold-Catalyzed Access to 1H-Isochromenes: Reaction Development and Mechanistic Insight

Article abstract of DOI:10.1021/acscatal.6b02636

The gold-catalyzed domino cyclization/nucleophilic reaction of ortho-carbonylalkynylaryls has been studied. Thus, 2-(pyridin-2-ylethynyl)benzaldehyde has been chosen to isolate key intermediates that may take part in the reaction mechanism. Employing Hantzsch ester (HEH) as nucleophile, it has been impossible to isolate the corresponding gold-alkenyl specie; however, when methanol was used as solvent (and nucleophile), the expected chelate gold-vinyl complex was isolated and unambiguously characterized by X-ray analysis. When HEH is present in the alcoholic reaction mixture, isotopic studies show that the cleavage of the Au-C bond of gold-vinyl complex proceeds through a protodemetalation pathway, rather than a plausible metal-hydride reductive elimination mechanism. Finally, with the aim of broadening the scope of the cyclization/reduction reaction previously reported, we present that the catalytic system is robust and applicable for a diverse family of challenging substrates presenting ester, aldehyde, ether, alkene, and alkyne functionalities.

Full text of DOI:10.1021/acscatal.6b02636

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Article
Gold-catalyzed access to 1H-isochromenes:
reaction development and mechanistic insight
Eder Tomás-Mendivil, Clément F. Heinrich, Jean-Claude Ortuno, Jérôme Starck, and Veronique Michelet
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02636 • Publication Date (Web): 28 Nov 2016
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Gold-catalyzed access to 1H-isochromenes:
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reaction development and mechanistic insight
Eder TomásꢀMendivil,a Clément F. Heinrich,a JeanꢀClaude Ortuno,b Jérôme Starck,b* Véronique
Micheleta*
a PSL Research University, Chimie ParisTechꢀCNRS, Institut de Recherche de Chimie Paris,
11 rue P. et M. Curie, 75005 Paris, France
b Institut de Recherches Servier, 125 Chemin de Ronde, 78290 CroissyꢀSeine, France
ABSTRACT
The goldꢀcatalyzed domino cyclization/nucleophilic reaction of orthoꢀcarbonylalkynylaryls
has been studied. Thus, 2ꢀ(pyridinꢀ2ꢀylethynyl)benzaldehyde has been chosen to isolate key
intermediates that may take part of the reaction mechanism. Employing Hantzsch ester
(HEH) as nucleophile it has been impossible to isolate the corresponding goldꢀalkenyl specie,
however when methanol was used as solvent (and nucleophile) the expected chelate goldꢀ
vinyl complex was isolated and unambiguously characterized by XꢀRay analysis. When HEH
is present in the alcoholic reaction mixture, isotopic studies show that the cleavage of the Auꢀ
C bond of goldꢀvinyl complex proceeds through a protodemetallation pathway, rather than a
plausible metalꢀhydride reductive elimination mechanism. Finally, with the aim of
broadening the scope of the cyclization/reduction reaction previously reported, we present
that the catalytic system is robust and applicable for a diverse family of challenging
substrates presenting ester, aldehyde, ether, alkene and alkyne functionalities.
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Keywords: gold, domino process, cyclization, Hanztsch ester, 1Hꢀisochromene.
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1. INTRODUCTION
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Homogeneous gold catalysis has become an essential tool in modern organic synthesis due to
its versatility on the construction of elaborate molecules hardly achievable employing
standard methods.1 The chemistry behind this noble metal relies on its ability to activate CꢀC
unsaturated bonds towards nucleophilic addition.1,2 Such a simple concept has been tirelessly
studied during the last 20 years, leading to a variety of multicomponent or cascade synthetic
strategies.1ꢀ3 In this sense, following our program dedicated to gold4 and silver5 catalysis, our
group recently described an efficient approach for the synthesis of functionalized 1Hꢀ
isochromenes via a goldꢀcatalyzed domino cyclization/reduction process (Scheme 1).6
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R'
[AuCl2(Pic)] (1ꢀ5 mol%)
HEH (1.2 equiv.)
R'
R
R
O
O
toluene, rt, 1ꢀ5 h
R = EWG, EDG
R' = Alk, Ar
18 examples
yields up to 96%
Scheme 1. Synthesis of functionalized 1Hꢀisochromenes via a goldꢀcatalyzed domino
cyclization/reduction process.
The 1Hꢀisochromene skeleton is found in a wide range of natural products and
pharmaceuticals, being in many cases part of the core of the biological active molecule.7
Therefore, it is not surprising that the design of efficient synthetic strategies to build up such
structures has always been of high interest for organic chemists.8 In our early approach we
followed one of the most studied pathways that implies the transition metalꢀcatalyzed
cyclization of orthoꢀcarbonylalkynylaryls in the presence of selected nucleophiles (Scheme
2).9ꢀ11 However, while most of contributions in this field include C, N and O nucleophiles,9,10
ours employs a hydride transfer from Hantzsch ester (HEH).6,11
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R'
H
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R'
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[M]
O
O
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R Nu
R
A
E
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[M]
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[M]
R'
R'
H
O
Nu
O
R
D
B
R
[M]
NuH
R'
O
R
C
Scheme 2. Proposed cyclization/nucleophilic addition mechanism.
The most important intents to unravel the way the reaction takes place have come from the
hands of the groups of Belmont9i and Abbiati.9l,9r Both authors employed alcohols (especially
methanol) as nucleophiles and orthoꢀalkynylarylꢀ and heteroarylaldehydes as substrates.
They agreed that the regioselectivity of the cycloisomerization step in this transformation is
the most intriguing issue to rationalize and varies mainly depending on the basicity of the
medium. Thus, as shown in Scheme 2, it is generally accepted that in the absence of a base
the reaction goes via πꢀactivation of alkyne A by coordination of the transitionꢀmetal to the
triple bond (B) and subsequent 6ꢀendoꢀdig attack of the carbonyl moiety leading to
isobenzopyrylium intermediate C. This specie, proposed as key intermediate in 2004 by
Yamamoto et al.,9d is highly reactive towards nucleophilic addition to form metalꢀalkenyl
intermediate D. Final protodemetallation step regenerates the catalytic active specie and
liberates product E.
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However, as stated before the regioselectivity of the process is highly dependent on the
medium; the different factors responsible for the mechanism and outcome of the reaction
being:
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(i) Basicity: the base promotes deprotonation of the nucleophile (e. g. methanol)
enhancing the attack on the aldehyde to form an hemiacetal anion that facilitates the 5ꢀexoꢀ
dig attack on the alkyne (Scheme 3).12 Now, the domino process has been reversed to a
nucleophilic addition/cyclization transformation.
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(ii) Nature of the metal: a given transition metal in high oxidation state (hard nature,
oxophilic) tends to activate the carbonyl moiety rather than that in lower oxidation state (soft
nature, carbophilic) which will coordinate to the CꢀC triple bond (Scheme 3).9d,13
(iii) Substituents (R and R’): the electronic effect of both groups conditions the
electrophilicity of each carbon atom in the alkyne (Scheme 3). For instance, the presence of
electron withdrawing groups in R’ (e. g. pꢀNO2) increase the electrophilicity of the carbon
atom directly attached to the carbonylaryl core, enhancing 5ꢀexo attack.6
With this in mind, regardless of the regioselectivity, the domino process may take place
and be understood as
a
consecutive nucleophilic addition/cyclization or
cyclization/nucleophilic addition process.
[M
]
(ii)
soft
R'
R'
= EWG, EDG
C
O
R'
(iii)
C
O
+
O
[Mhard
(ii)
]
Nu
R
R Nu
R
Base
NuH
Nu
F
E
(i)
6-endo-dig
5-exo-dig
Scheme 3. Regioselectivity: 5ꢀexoꢀdig vs 6ꢀendoꢀdig.
The elucidation of a reaction mechanism and identification of the key intermediates in a
catalytic process is of high interest not only to understand how the transformation works,14
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but also to modify in a rational manner the activity of the catalysts. In this sense, herein we
would like to present our last mechanistic studies related to the goldꢀcatalyzed cyclization of
orthoꢀalkynylbenzaldehydes in the presence of selected nucleophiles like Hantzsch ester and
methanol. Such studies allowed us to isolate the first goldꢀalkenyl stable complex of general
structure D (Scheme 2) involved in the reaction mechanism.
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2. RESULTS AND DISCUSSION
At the beginning of our studies, we wondered if it would be possible to isolate any of the
intermediates described in the proposed and most plausible mechanism (i.e. domino
cyclization/nucleophilic addition; Scheme 2). It is generally accepted that benzopyrylium
specie C is highly reactive and challenging to isolate.15 In this sense, Nguyen et al. detected
for the first time such specie employing NMR, EXAFS and ESIꢀMS techniques by mixing
equimolar amounts of AuCl3 and the corresponding alkynylketone in acetonitrile (Figure 1,
C).16 Interestingly, the major compound was not the expected monomer but dimer never
proposed before. Years later, Yu and coworkers observed by means of NMR an analogous
unstable gold intermediate C during the glycosylation reaction with glycosyl orthoꢀ
alkynylbenzoates.17
On the other hand, taking into account that a respectable number of goldꢀalkenyl
complexes are known,17,18 we thought that the isolation of intermediate D could be
achievable. In this sense, Hashmi, Yates, Ariafard and coworkers recently reported “a
theoretical study on the protodeauration step in gold(I)ꢀcatalyzed organic reactions”.19
Although protodeauration step is usually fast in transformations that involve the formation of
a goldꢀalkenyl intermediate, they found, among others, that the speed of the proton transfer
depends on the πꢀaccepting/donating ability of the substituents on the alkenyl group. Such
ability conditions the strength of the AuꢀC bond and therefore the activation energy barrier.
Thus, πꢀaccepting groups attract density from the metal strengthening the metalꢀcarbon bond
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and making them stable; i. e. they can be isolated. In contrast, πꢀdonating groups weaken Auꢀ
C bond and the protodeauration step takes place quickly.
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In order to predict the stability of intermediate D and therefore the feasibility of its
isolation, it is noteworthy that Yu et al. found that structurally related goldꢀalkenyl complex
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n
G (Figure 1; L = PPh3, R = Bu),18a was perfectly stable and isolable by silicaꢀgel column
chromatography. The same group also showed more recently further reactivity of complex G
with gold, leading to diauration reaction.20 Indeed, such specie was unable to behave as an
active catalyst and it is the decomposition product of glycosyl derivative C in Figure 1.17 On
the other hand, theoretical studies showed that the activation energy (ꢁG≠) of the
protodeauration reaction of compound G (Figure 1; L = PMe3, R = Me) is 7.2 kcal/mol,
which stays in the group of the most unstable complexes present in the work.19 To the best of
our knowledge, no experimental or theoretical data has been reported for species like D, but
considering the πꢀaccepting/donating ability of the substituents in D (donating; methylene) vs
G (accepting; carbonyl), we conclude that D should be less stable than G.
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Previous works:
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Me
L
PPh3
Au
Au
O
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R
R
Ph
O
O
Cl Au
Cl
Ph
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O
OGlyc
NMR
C
G
O
L = PPh3 ; R = nBu X-ray
Yu et al. (2011)
Me
Yu et al. (2015)
NMR, EXAFS
and ESI-MS
L = PMe3 ; R = Me DFT
Hashmi, Yates, Ariafard
Nguyen et al. (2012)
et al. (2015)
This work: chelate effect
[AuIII]
L
N
[Au]
O
R Nu
D
O
1
Figure 1. Previously detected goldꢀbenzopyrilium species (C), related stable goldꢀalkenyl
compounds (G) and our proposal for the present work: isolation of key intermediate D.
At this point and with the goal of trapping intermediate D, two solutions arise to
overcome such an issue: modify the ligand (L) or the alkenyl substituents. Taking into
account that in our catalytic system (Scheme 1) the precatalyst is a square planar gold(III)
complex, we anticipated that the introduction of a pyridine moiety in R’ could stabilize the
proposed goldꢀalkenyl specie by chelate effect (Figure 1).21 Substrate 1 was prepared by a
Sonogashira crossꢀcoupling reaction between readily available 2ꢀethynylbenzaldehyde and 2ꢀ
bromopyridine (see SI for further details). Under previously optimized catalytic conditions,6
employing 5 mol% [AuCl2(Pic)],22 1.2 equivalents of HEH, in toluene, at room temperature
for 24 h, only traces of 1Hꢀisochromene 2 were formed (Scheme 4, Eq. 1). This behavior
could be explained as a plausible poisoning of the metal and it was indeed an excellent
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opportunity to isolate the proposed intermediate. When equimolar amounts of substrate 1,
HEH and KAuCl4·H2O were mixed in order to generate complex 3 (Scheme 4, Eq. 2),
decomposition of the gold(III) salt was observed by deposition of elemental gold (golden
mirror). Aldehyde 1 remained unchanged and the HEH was oxidized forming the
corresponding pyridine. Control experiments showed that HEH is able to reduce [AuCl2(Pic)]
complex in toluene as immediate formation of gold mirror is observed. A plausible
mechanism would proceed through the reduction of Au(III) to Au(I) and disproportionation
of the last to form Au(0) and Au(III).23 Indeed, in our previous study6 we observed that
deposition of gold(0) took place when the catalytic reaction was about to be completed,
meaning that the active gold species remain in solution until no more substrate is present.
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N
[AuCl2(Pic)] (5 mol%)
HEH (1.2 equiv.)
O
toluene, rt, 24 h
(eq. 1)
N
2
traces
Cl
O
Cl Au
N
KAuCl4—H2O (1 equiv.)
HEH (1 equiv.)
1
O
toluene, rt, 5 min
3
(eq. 2)
Instead, Gold
mirror formed
Scheme 4. Cyclization/reduction essays of 1 in the presence of HEH.
As stated before, the groups of Belmont and Abbiati employed methanol as nucleophile for
their mechanistic studies. Both agreed that gold complexes are not very reactive unless a base
is added in the reaction medium.9i,l,r However, in our previous study,6 we observed that the
described catalytic system employing a Au(III) complex without any base was active also in
methanol although a significant decrease of the kinetics was observed (1 h in toluene vs 24 h
in methanol for full conversion) suggesting that the solvent may be playing a role as
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nucleophile too. Indeed, as shown in Scheme 5, once the reaction was finished isochromene
derivative 5 in which a molecule of methanol was incorporated was isolated in moderate 55%
yield. Such a notorious decrease in the reaction rate may be caused by the presence of more
stable intermediates generated in the medium. In the absence of HEH in the medium, the
reaction gave the same result and product 5 was obtained in 59% yield. It’s noteworthy that
we also conducted the control experiment without substrate 4 i.e. by mixing gold catalyst,
Hantzsch ester in MeOH, and reduction of Au(III) to Au(I) and Au(0) was partially observed.
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nBu
nBu
[AuCl2(Pic)] (5 mol%)
O
O
HEH (1.2 equiv.)
MeOH, rt, 24 h
OMe
4
55%
5
Scheme 5. Domino cyclization/methanol addition reaction.
To demonstrate such hypothesis we mixed equimolar amounts of KAuCl4·H2O and 1 in
methanol at room temperature and an orange precipitate was formed after 5 minutes (Scheme
6, step 1). The suspension was stirred for 2 h and the crude reaction mixture was analyzed by
1
means of H NMR spectroscopy. In CDCl3 a mixture of free aldehyde 1 and characteristic
signals for gold complex 6 were observed in 1 : 2 (1 : 6) ratio, while in DMSOꢀd6 only
substrate 1 was found. This means that complex 6 in the presence of DMSO, HCl and KCl,
decomposes leading to the formation of [AuCl3(DMSO)] and back to 1. Thus, we assume that
in methanol the Auꢀpromoted activation of the triple bond and subsequent nucleophilic attack
of the solvent are reversible. In order to drive the equilibrium towards goldꢀalkenyl specie 6,
excess of NaBF4 was added. After evaporation and cleaning with dichloromethane, complex
6 was isolated in high yield (90%) (Scheme 6, step 2).
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Cl
N
4
5
1) KAuCl4—H2O (1 equiv.)
Cl Au
N
MeOH, rt, 2 h
6
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9
2) NaBF4 (10 equiv.)
90%
O
O
OMe
1
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6
Scheme 6. Synthesis of chelate goldꢀalkenyl complex 6.
Au(III)ꢀalkenyl complex 6 is stable towards air and moisture and its molecular structure was
unambiguously determined by means of singleꢀcrystal Xꢀray diffraction analysis (Figure 2).
As expected, the geometry around the metallic center is square planar, with angles around the
metal between 81.51(14)ꢀ96.39(11)°. The Au(1)ꢀC(7) bond distance is 2.041(4) Å, being in
the range of the previously reported goldꢀalkenyl complexes (alkenylꢀAu compounds around
2.04 Å while carbeneꢀAu complexes around 1.95 Å).18h,24 The observed Au(1)ꢀN(1) distance
(2.032(3) Å) fits well with those described in the literature for Au(III) complexes containing
Nꢀcoordinated pyridine moieties.25 Such observations, together with the high planarity within
the whole molecule (N(1)ꢀC(5)ꢀC(6)ꢀC(7) dihedral angle = 0.72º and N atom showing sp2
hybridization), the short C(6)ꢀC(7) distance (1.347(5) Å), and long bond lengths of C(5)ꢀC(6)
and C(7)ꢀC(8) (1.456(5) and 1.464(5) Å, respectively), suggest that the alkenyl C(7) atom
stays negatively charged, discarding its possible carbenic nature. It is also worth to note that
the Au(1)ꢀC(6) distance is too long (2.805(3) Å) to consider both bound.
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Figure 2. ORTEPꢀtype view of the structure of the Au(III)ꢀalkenyl complex 6 showing the
crystallographic labeling scheme. Thermal ellipsoids are drawn at 50% probability level.
Selected bond distances (Å) and angles (deg): Au(1)−C(7) = 2.041(4); Au(1)−Cl(1) =
2.3645(10); Au(1)−Cl(2) = 2.2647(11); Au(1)−N(1) = 2.032(3); C(5)−C(6) = 1.456(5);
C(6)−C(7) = 1.347(5); C(7)−C(8) = 1.464(5); C(6)−O(1) = 1.365(4); C(10)−O(1) = 1.431(4);
C(10)−O(2) = 1.399(4); C(5)−N(1) = 1.352(5); C(7)−Au(1)−Cl(1) = 174.52(10);
N(1)−Au(1)−Cl(2) = 172.81(9); C(7)−Au(1)−N(1) = 81.51(14); C(7)−Au(1)−Cl(2) =
96.39(11); Cl(1)−Au(1)−Cl(2) = 88.69(4); N(1)−Au(1)−Cl(1) = 93.20(10); C(5)−C(6)−C(7)
=
120.4(3);
N(1)−C(5)−C(6)
=
112.6(3);
O(1)−C(10)−O(2)
=
110.3(3);
N(1)−C(5)−C(6)−C(7) = 0.72.
From a mechanistic point of view, it is important to highlight, that the observed reversibility,
together with the stability of complex 6, in a protic and polar solvent like methanol suggests
that in the mechanism shown in Scheme 2 every step between A and D is fast or low energy
demanding and therefore reversible and the protodemetallation step is the rate limiting one
and irreversible. This fact is only true in case the nucleophile (MeOH) could also play the
role of a good leaving group,9a,9k but not in the case of the formal hydride incorporated from
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the HEH. Such hypothesis prompted us to test whether we could “trap” isobenzopyrylium
intermediate C in the presence of the Hantzsch ester (the hydride would not be a good
leaving group) and isolate intermediate D (Nu = H). Thus, the addition of one equivalent of
HEH to the equimolar mixture of aldehyde 1 and KAuCl4 in methanol led to the selective and
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quantitative formation of protonated 1Hꢀisochromene 7 and oxidation of HEH to the
1
corresponding pyridine, observed by H NMR analysis (Scheme 7, Eq. 1). The addition of
one equivalent of PPh3 confirmed the presence of Au(I) species in solution evidenced by
precipitation of a white solid and identified as [AuCl(PPh3)] (82% isolated yield).26 We
discarded that triphenylphosphine could act as reducing agent of Au(III) as no oxidized
31
specie (O=PPh3) was observed by P NMR analysis of the crude mixture.23 These findings
suggest that, although species A and D are in equilibrium through isobenzopyrylium
intermediate C under these reaction conditions, the HEH reacts significantly faster with gold
complex 6 (D) than with C, or that the presence of C in the reaction medium is insignificant,
giving as a result the selective reduction of Au(III) to Au(I). If this is the case, a key goldꢀ
hydride intermediate, figured as 9, may be generated and its subsequent reductive elimination
would lead to the products. We assume that no protodeauration of 6 (D) and later reduction of
ꢀ
AuCl4 takes place considering its high stability in methanol (note that it was synthetized and
isolated in this solvent). When the same process was conducted in CD3OD (Scheme 7, Eq. 2),
we observed the formation of 7-4d and 7-3d in a 2.3 : 1 ratio, which goes in favor with a
protodemetallation step, the formation of 7 being explained by the use of one equivalent of
hydrated gold complex. We also performed control experiments in the case of substrate 1.
Without Hantzsch ester, in CD3OD, the reaction of 1 with 1 equivalent of gold led to a
mixture of 1 and 6-3d (1 : 5.6 ratio) with no trace of 7-4d. This experiment tends to prove that
the protodemetallation step occurs on intermediate 9 and not intermediate 6. When Hantzsch
ester was preliminary stirred in CD3OD for H/D exchange, the domino process led to a higher
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D/H incorporation ratio (6.7 : 1), which confirms that the NH function of Hantzsch ester
partially participate in the protodemetallation step.
7
8
9
N
1) KAuCl4—H2O (1 equiv.)
MeOH, rt, 5 min
2) HEH (1 equiv.), 1 h
Cl
HN
EtO2C
CO2Et
+ AuCl(PPh3) + KCl
(1)
+
O
10
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N
H
3) PPh3 (1 equiv.)
30 min
O
82%
isolated yield
Cl
OMe
—HCl
1 (A)
8
—HCl
7
H
N
2)
1)
EtO2C
CO2Et
H
H
3) PPh3
Cl
H
Cl
Cl Au
Cl Au
N
Cl Au
N
N
fast
7
—HCl + 8—HCl + K(AuCl2)
O
O
O
1HꢀNMR
OMe
OMe
C
6 (D)
9
Cl
Cl
N
D
DN
H
DN
1) KAuCl4—H2O (1 equiv.)
CD3OD, rt, 5 min
EtO2C
Cl
CO2Et
(2)
+
+
O
O
N
D
O
2) HEH (1 equiv.), 1 h
78 %
OCD3
7-4d—DCl
OCD3
1 : 2.3
8—DCl
1
(
A)
7-3d—DCl
Scheme 7. Reactivity studies on the cyclization/nucleophilic addition of 1 in the presence of
gold and HEH in MeOH and CD3OD.
Our other idea when we addressed the issue of studying the way the synthesis of
functionalized 1Hꢀisochromenes via a goldꢀcatalyzed domino cyclization/reduction process
worked (Scheme 1), included the broadening of the scope of the methodology and the
demonstration of the utility of the catalytic approach. With this aims in mind we synthesized
a family of new substrates, focusing on those that could be challenging or that could give us
some information about the reactivity (Scheme 8). We first envisaged evaluating the
influence of protic alcohols and usual protective groups such as silyl or benzyl ethers. We
therefore prepared alcohol 11a, silylꢀprotected derivative 12 and benzyl adduct 11c, via
classical Sonogashira crossꢀcouplings (Scheme 8, Eq. 1) and silylation of alcohol 11b. An
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esterꢀfunctionalized alkyne 13 was synthesized according to a multiꢀstep high yielding
sequence. Our diversity oriented synthesis interest also prompted us to prepare conjugated
alkenyl enyne 11e and diynes 11f and 15 (Scheme 8, Eq. 2) in respectively 73%, 28% and
96% yields.
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11
12
13
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R1
[PdCl2(PPh3)2] (2.5 mol %)
Br
CuI (1.5 mol%)
R1
(1)
+
O
O
PhMe : iꢀPr2NH (3 : 1)
50 °C, 16 h
10
11a-f
OH
OR2
OBn
O
O
O
R2 = H, 84% 11b
R2 = TBS, 73% 12
TBSCl, Imidazole
DCM, 0 °C, 3 h
11c
75%
11a
86%
nBu
R1
Ph
O
O
O
1. K2CO3, MeOH
R1 = SiMe3 11d
R1 = CO2Me 13
11e
73%
11f
28%
2. HOC3H6OH, PTSA
3. nꢀBuLi, ClCO2Me
4. HCl
90% overall yield
nBu
[PdCl2(PPh3)2] (2.5 mol %)
CuI (1.5 mol%)
Br
+
O
(2)
nBu
O
PhMe : iꢀPr2NH (3 : 1)
Br
50 °C, 16 h, 96%
14
15
nBu
[PdCl2(PPh3)2] (2.5 mol %)
CuI (1.5 mol%)
O
O
10, PhMe : iꢀPr2NH (3 : 1)
50 °C, 16 h, 54%
17
(3)
O
16
CuCl2 (20 mol %)
pyridine, Na2CO3
O
O
O2 (1 atm), PhMe
75 °C, 2 h, 96%
18
Scheme 8. Synthesis of functionalized orthoꢀalkynylbenzaldehydes.
We finally wished to challenge the compatibility of the catalytic process with another
aldehydic functionality and the potential polycyclization/reduction process. We therefore
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prepared the bisꢀaldehyde 17 in 54% yield starting from the known alkyne 16 via a Pdꢀ
catalyzed crossꢀcoupling reaction employing substrate 10 as arylbromide. Taking advantage
of the GlaserꢀHay Cuꢀcatalyzed homodimerization reaction developed under oxidative
conditions,27 we efficiently got access to diyne 18 in the presence of copper dichloride,
pyridine, sodium carbonate under 1 atm of dioxygen (Scheme 8, Eq. 3).
10
11
12
13
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The previously optimized cyclization/reduction conditions employing 5 mol% of
commercially available [AuCl2(pic)] and 1.2 equivalents of Hantzsch ester in toluene at room
temperature, were then screened on the prepared orthoꢀalkynyl benzaldehydes (Table 1).
The presence of a protic function such as an alcohol was nonꢀcompatible with the reaction
conditions: despite a full conversion of starting material 11a (room temperature and 0°C), the
desired 1Hꢀisochromene 19a was not detected (Table 1, entry 1). This may be due to
competitive cyclization the alcohol moiety as described by the group of Abbiati,9r but no
cleanly identified product could be isolated. The case of protected ethers was much more
rewarding: both TBSꢀ and benzylꢀprotected ethers 12 and 11c participated in the domino
process and cleanly gave the corresponding derivatives 19b and 19c in good to excellent
yields (Table 1, entries 2 and 3). Pleasingly the presence of an electronꢀwithdrawing group
such as an ester, directly linked to the alkyne led to the adduct 19d in moderate 55% yield
(Table 1, entry 4). Conjugated styryl group was also amenable during the domino process as
the desired diene 19e was isolated in an excellent 97% yield (Table 1, entry 5). The reactivity
of diyne 11f was much lower and increasing the temperature led to degradation of starting
material. The enyne 19f was thus obtained at room temperature in fair 56% yield and 34% of
starting material 11f was recovered (Table 1, entry 6).
Table 1. Cyclization/reduction of functionalized orthoꢀalkynyl aldehydes.
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R'
[AuCl2(Pic)] (5 mol %)
HEH (1.2 equiv)
R'
4
5
6
7
8
9
O
O
toluene, rt, 30 min ꢀ 2 h
R
R
Entry
1
Substrate
Product
Yielda
OH
0%
11a
12
19a
19b
O
10
11
12
13
14
15
16
17
18
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2
3
86%
95%
11c
13
19c
19d
4
5
6
7
55%
97%
56%b
92%
11e
11f
15
19e
19f
19g
8
25%
17
18
19h
19i
9c
69%
a
b
c
isolated yield.
+ 34% of starting alkynylꢀaldehyde 11f.
[Au(NTf2)(PPh3)] (5% mol) was used at 90 °C.
The diyne 15 reacted very nicely and smoothly, allowing access to functionalized
isochromene 19g in 92% yield, which demonstrated the compatibility of the domino process
with alkyne (Table 1, entry 7). Regarding the presence and reactivity of other aldehydic
functionality, the cyclization/reduction of 17 gave a low 25% yield of aldehyde 19h and no
other byꢀproducts were isolated (Table 1, entry 8). Finally, whereas no reaction was observed
under classical conditions for diyne 18, we were pleased to find that two domino processes
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occurred in the presence of cationic [Au(NTf2)(PPh3)] catalyst at 90 °C and allowed the
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formation of bisꢀisochromene 19i in 69% yield (Table 1, entry 9).
7
8
9
3. CONCLUSION
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We have therefore extended the methodology of the goldꢀcatalyzed domino
cyclization/nucleophilic addition of orthoꢀcarbonylalkynylaryls, by studying the
cyclization/reduction process. We have shed some light on parts of the mechanism by
designing and preparing a chelating substrate, which allowed the isolation of a Au(III)ꢀvinyl
complex. Whereas the use of the Hantzsch ester (HEH) as nucleophile was unsuccessful,
employing MeOH with 2ꢀ(pyridinꢀ2ꢀylethynyl)benzaldehyde gave rise to the corresponding
goldꢀalkenyl species, whose structure was confirmed by XꢀRay analysis. Isotopic studies
showed that the cleavage of the AuꢀC bond of goldꢀvinyl complex proceeds through a
protodemetallation pathway, rather than a plausible metalꢀhydride reductive elimination
mechanism. We have also broadened the scope of the cyclization/reduction reaction by
preparing functionalized and challenging substrates. We showed that the catalytic system was
amenable for esterꢀ, aldehydeꢀ, etherꢀ, alkeneꢀ and alkyneꢀfunctionalized and allowed an
atomꢀeconomical and easy access to various 1Hꢀisochromene derivatives. Further studies will
focus on practical and industrial applications of the valuable functionalized 1
isochromenes.
Hꢀ
EXPERIMENTAL SECTION
General procedure for the gold-catalyzed synthesis of 1H-isochromenes To a stirred
solution of alkynylꢀaldehyde (1 equiv.) in dry toluene was added [AuCl2(pic)] (5 mol%) and
Hantzsch ester (HEH, 1.2 equiv.). The solution was stirred until the starting material was
consumed, shown by TLC (usually 0.5ꢀ2 hours). The resulting mixture was concentrated
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under vacuum and directly purified by silica gel chromatography (PE/Et2O 100/0 to 90/10)
affording the title compound. Experimental details are provided in the Supporting
Information.
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SUPPORTING INFORMATION
Experimental procedures, Analytical data, and NMR spectra for all new compounds are
reported (PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
ACKNOWLEDGMENTS
This work was supported by the Ministère de l’Education et de la Recherche and the Centre
National de la Recherche Scientifique (CNRS), Dr. E.T.ꢀM. and Dr. C.F.H. are grateful to
Institut de Recherches Servier for a grant. The authors thank Dr. L.ꢀM. Chamoreau (UMR
8232, Institut Parisien de Chimie Moléculaire) for Xꢀray structure analysis and Dr. A. Carrër
for the graphical abstract design. Johnson Matthey Inc. is acknowledged for generous loans
of HAuCl4 and PdCl2.
AUTHOR INFORMATION
Corresponding Authors
Dr. J. Starck: jerome.starck@servier.com and
Dr. V. Michelet: veronique.michelet@chimieꢀparistech.fr.
Notes
The authors declare no competing financial interest
REFERENCES
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Gold-catalyzed access to 1H-isochromenes: reaction development and mechanistic
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Eder TomásꢀMendivil, Clément F. Heinrich, JeanꢀClaude Ortuno, Jérôme Starck,* and
Véronique Michelet*
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Figure 1
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Figure 2
100x83mm (96 x 96 DPI)
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