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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 Downloaded from http://pubs.acs.org on November 28, 2016

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ACS Catalysis

Gold-catalyzed access to 1H-isochromenes: reaction development and mechanistic insight Eder Tomás-Mendivil,a Clément F. Heinrich,a Jean-Claude Ortuno,b Jérôme Starck,b* Véronique Micheleta* a

PSL Research University, Chimie ParisTech-CNRS, 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 Croissy-Seine, France

ABSTRACT 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 of 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 goldvinyl 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 AuC bond of gold-vinyl complex proceeds through a protodemetallation 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.

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Keywords: gold, domino process, cyclization, Hanztsch ester, 1H-isochromene. 1. INTRODUCTION 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 C-C 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.1-3 In this sense, following our program dedicated to gold4 and silver5 catalysis, our group recently described an efficient approach for the synthesis of functionalized 1Hisochromenes via a gold-catalyzed domino cyclization/reduction process (Scheme 1).6 R'

[AuCl2(Pic)] (1-5 mol%) R'

HEH (1.2 equiv.) R

O

R toluene, rt, 1-5 h

R = EWG, EDG R' = Alk, Ar

O

18 examples yields up to 96%

Scheme 1. Synthesis of functionalized 1H-isochromenes via a gold-catalyzed domino cyclization/reduction process. The 1H-isochromene 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 metal-catalyzed cyclization of ortho-carbonylalkynylaryls in the presence of selected nucleophiles (Scheme 2).9-11 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


2

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R'

H R' [M]

O E

O

R Nu

R [M]

[M]

A

R'

R' H

O D

O

R Nu

R

B

[M]

NuH

R' O C

R

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 ortho-alkynylaryl- 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 π-activation of alkyne A by coordination of the transition-metal to the triple bond (B) and subsequent 6-endo-dig 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 metal-alkenyl 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: (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 5-exodig attack on the alkyne (Scheme 3).12 Now, the domino process has been reversed to a nucleophilic addition/cyclization transformation. (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 C-C 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. p-NO2) increase the electrophilicity of the carbon atom directly attached to the carbonylaryl core, enhancing 5-exo 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. (ii) [Msoft] C

C O

R

Base NuH

(i)

Nu

R'

R' = EWG, EDG (iii) [Mhard] (ii)

R' O

O

+

Nu

R Nu

R

E

F

6-endo-dig

5-exo-dig

Scheme 3. Regioselectivity: 5-exo-dig vs 6-endo-dig. 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 gold-catalyzed cyclization of ortho-alkynylbenzaldehydes in the presence of selected nucleophiles like Hantzsch ester and methanol. Such studies allowed us to isolate the first gold-alkenyl stable complex of general structure D (Scheme 2) involved in the reaction mechanism. 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 ESI-MS 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 orthoalkynylbenzoates.17 On the other hand, taking into account that a respectable number of gold-alkenyl 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 gold-alkenyl intermediate, they found, among others, that the speed of the proton transfer depends on the π-accepting/donating ability of the substituents on the alkenyl group. Such ability conditions the strength of the Au-C bond and therefore the activation energy barrier. Thus, π-accepting groups attract density from the metal strengthening the metal-carbon bond


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and making them stable; i. e. they can be isolated. In contrast, π-donating groups weaken AuC bond and the protodeauration step takes place quickly. 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 gold-alkenyl complex G (Figure 1; L = PPh3, R = nBu),18a was perfectly stable and isolable by silica-gel 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 π-accepting/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: Me

L

PPh3

O

Au

Au

R

R

Ph

O

O

Cl Au Cl Ph

O

OGlyc C

O

G NMR

L = PPh3 ; R = nBu X-ray

Yu et al. (2015)

Yu et al. (2011)

Me NMR, EXAFS and ESI-MS

L = PMe3 ; R = Me DFT Hashmi, Yates, Ariafard et al. (2015)

Nguyen et al. (2012) This work: chelate effect [AuIII]

L

N [Au]

O R Nu D

O 1

Figure 1. Previously detected gold-benzopyrilium species (C), related stable gold-alkenyl 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 gold-alkenyl specie by chelate effect (Figure 1).21 Substrate 1 was prepared by a Sonogashira cross-coupling reaction between readily available 2-ethynylbenzaldehyde and 2bromopyridine (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 1H-isochromene 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. N

[AuCl2(Pic)] (5 mol%) HEH (1.2 equiv.)

N

toluene, rt, 24 h

O

(eq. 1)

2 traces Cl

O 1

KAuCl4H2O (1 equiv.) HEH (1 equiv.) toluene, rt, 5 min (eq. 2)

Cl Au

N

O

3

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. nBu

nBu

[AuCl2(Pic)] (5 mol%) O O 4

HEH (1.2 equiv.) MeOH, rt, 24 h 55%

OMe 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 means of 1H 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 DMSO-d6 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 Au-promoted activation of the triple bond and subsequent nucleophilic attack of the solvent are reversible. In order to drive the equilibrium towards gold-alkenyl 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 1) KAuCl4H2O (1 equiv.) MeOH, rt, 2 h O 1

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2) NaBF4 (10 equiv.) 90%

Cl Au

N

O OMe 6

Scheme 6. Synthesis of chelate gold-alkenyl complex 6.

Au(III)-alkenyl complex 6 is stable towards air and moisture and its molecular structure was unambiguously determined by means of single-crystal X-ray 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 gold-alkenyl complexes (alkenyl-Au compounds around 2.04 Å while carbene-Au 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 N-coordinated 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. ORTEP-type 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 quantitative formation of protonated 1H-isochromene 7 and oxidation of HEH to the corresponding pyridine, observed by 1H 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 specie (O=PPh3) was observed by

31

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 goldhydride 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. N

1) KAuCl4H2O (1 equiv.) MeOH, rt, 5 min 2) HEH (1 equiv.), 1 h

Cl

EtO2C

(1)

Cl

OMe

1 (A) 2)

+

O

3) PPh3 (1 equiv.) 30 min

O

HN + AuCl(PPh3) + KCl

N H

82% isolated yield

8HCl

7HCl

H N

CO2Et

1) EtO2C

CO2Et H H

Cl

Cl Cl Au

Cl Au

N

3) PPh3

H N

Cl Au

fast 7HCl + 8HCl + K(AuCl2)

O

O

O

OMe

C

(2) O 1 (A)

1H-NMR

OMe

6 (D)

N

N

9 Cl

Cl 1) KAuCl4H2O (1 equiv.) CD3OD, rt, 5 min 2) HEH (1 equiv.), 1 h 78 %

H

D

DN

O OCD3 7-3dDCl

DN EtO2C

+

O OCD3

1 : 2.3

7-4dDCl

+ Cl

CO2Et N D 8DCl

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 1H-isochromenes via a gold-catalyzed 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, silyl-protected derivative 12 and benzyl adduct 11c, via classical Sonogashira cross-couplings (Scheme 8, Eq. 1) and silylation of alcohol 11b. An


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ester-functionalized alkyne 13 was synthesized according to a multi-step 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.

Br (1)

O

R1

+

OH

TBSCl, Imidazole DCM, 0 °C, 3 h

= H, 84% 11b

R2

= TBS, 73% 12

11c 75%

nBu

Ph O

O

O 1. K2CO3, MeOH 2. HOC3H6OH, PTSA 3. n-BuLi, ClCO2Me 4. HCl 90% overall yield

O

R2

R1

14

OBn

O

11a 86%

Br

11a-f

OR2

O

(2)

O

PhMe : i-Pr2NH (3 : 1) 50 °C, 16 h

10

Br

R1

[PdCl2(PPh3)2] (2.5 mol %) CuI (1.5 mol%)

R1 = SiMe3 11d

11e 73%

11f 28%

R1 = CO2Me 13

+ O

nBu

[PdCl2(PPh3)2] (2.5 mol %) CuI (1.5 mol%) nBu

O

PhMe : i-Pr2NH (3 : 1) 50 °C, 16 h, 96% nBu

15

[PdCl2(PPh3)2] (2.5 mol %) CuI (1.5 mol%) 10, PhMe : i-Pr2NH (3 : 1) 50 °C, 16 h, 54% (3)

O

O

17

O 16

CuCl2 (20 mol %) pyridine, Na2CO3 O2 (1 atm), PhMe 75 °C, 2 h, 96%

O O 18

Scheme 8. Synthesis of functionalized ortho-alkynylbenzaldehydes. 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 bis-aldehyde 17 in 54% yield starting from the known alkyne 16 via a Pdcatalyzed cross-coupling reaction employing substrate 10 as arylbromide. Taking advantage of the Glaser-Hay Cu-catalyzed 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). 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 ortho-alkynyl benzaldehydes (Table 1). The presence of a protic function such as an alcohol was non-compatible with the reaction conditions: despite a full conversion of starting material 11a (room temperature and 0°C), the desired 1H-isochromene 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 TBS- and benzyl-protected 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 electron-withdrawing 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 ortho-alkynyl aldehydes.


15

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R'

R

Entry

O

Page 16 of 39

[AuCl2(Pic)] (5 mol %) HEH (1.2 equiv)

R'

toluene, rt, 30 min - 2 h

Substrate

O

R

Yielda

Product OH

1

11a

19a

0%

2

12

19b

86%

3

11c

19c

95%

4

13

19d

55%

5

11e

19e

97%

6

11f

19f

56%b

7

15

19g

92%

8

17

19h

25%

9c

18

19i

69%

a

O

isolated yield. b + 34% of starting alkynyl-aldehyde 11f. [Au(NTf2)(PPh3)] (5% mol) was used at 90 °C.

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 by-products 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


16

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ACS Catalysis

occurred in the presence of cationic [Au(NTf2)(PPh3)] catalyst at 90 °C and allowed the formation of bis-isochromene 19i in 69% yield (Table 1, entry 9).

3. CONCLUSION We

have

therefore

cyclization/nucleophilic

extended addition

the of

methodology

of

the

gold-catalyzed

ortho-carbonylalkynylaryls,

by

domino

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 2-(pyridin-2-ylethynyl)benzaldehyde gave rise to the corresponding gold-alkenyl species, whose structure was confirmed by X-Ray analysis. Isotopic studies showed that the cleavage of the Au-C bond of gold-vinyl complex proceeds through a protodemetallation pathway, rather than a plausible metal-hydride 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 ester-, aldehyde-, ether-, alkene- and alkyne-functionalized and allowed an atom-economical and easy access to various 1H-isochromene derivatives. Further studies will focus on practical and industrial applications of the valuable functionalized 1Hisochromenes. EXPERIMENTAL SECTION General procedure for the gold-catalyzed synthesis of 1H-isochromenes To a stirred solution of alkynyl-aldehyde (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 0.5-2 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. 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 X-ray 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: [email protected] and Dr. V. Michelet: [email protected]. Notes The authors declare no competing financial interest

REFERENCES


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4808-4813. (b) Huang, L.; Rominger, F.; Rudolph, M.; Hashmi, A. S. K. Chem. Commun. 2016, 52, 6435-6438. 22. For the first use of complex [AuCl2(Pic)] in catalysis, see: Hashmi, A. S. K.; Weyrauch, J. P.; Rudolph, M.; Kurpejović, E. Angew. Chem. Int. Ed. 2004, 43, 6545-6547. 23. For studies addressing the selective reduction of gold(III) species employing phosphines as reducing agent leading to gold(I) and phosphine oxides, see: (a) Chao, C.-M.; Genin, E.; Toullec, P. Y.; Genêt, J.-P.; Michelet, V. J. Organomet. Chem. 2009, 694, 538545. (b) Hahn, C.; Cruz, L.; Villalobos, A.; Garza, L.; Adeosuna, S. Dalton Trans. 2014, 43, 16300-16309 and references cited therein. While nitrogen ligands show a strong affinity to gold(III) (see: (c) Cinellu, M. A.; Minghetti, G.; Cocco, F.; Stoccoro, S.; Zucca, A.; Manassero, M.; Arca, M. Dalton Trans. 2006, 5703-5716), the weak coordination of gold(I) to nitrogen might even support the disproportionation of the gold(I) species as gold(III) will be stabilized (see: (d) Khin, C.; Hashmi, A. S. K.; Rominger, F. Eur. J. Inorg. Chem. 2010, 1063-1069.). 24. (a) Wang, Y.; Muratore, M. E.; Echavarren, A. M. Chem. Eur. J. 2015, 21, 7332-7339. (b) dos Santos Comprido, L. N.; Klein, J. E. M. N.; Knizia, G.; Kästner, J.; Hashmi, A. S. K. Angew. Chem. Int. Ed. 2015, 54, 10336-10340. (c) dos Santos Comprido, L. N.; Klein, J. E. M. N.; Knizia, G.; Kästner, J.; Hashmi, A. S. K. Chem. Eur. J. 2016, 22, 2892-2895. 25. Tomás-Mendivil, E.; Toullec, P. Y.; Borge, J.; Conejero, S.; Michelet, V.; Cadierno, V.

ACS Catal. 2013, 3, 3086-3098 and references cited therein and references cited therein. 26. Leyva, A.; Zhang, X.; Corma, A. Chem. Commun. 2009, 4947-5044. 27. (a) Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422-424. (b) Hay, A. S. J. Org. Chem. 1962, 27, 3320-3321. (c) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int.


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Ed. 2000, 39, 2632-2657. (d) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833-835.


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ACS Catalysis

FOR TABLE OF CONTENTS USE ONLY

Gold-catalyzed access to 1H-isochromenes: reaction development and mechanistic insight Eder Tomás-Mendivil, Clément F. Heinrich, Jean-Claude Ortuno, Jérôme Starck,* and Véronique Michelet*


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Figure 1 133x137mm (300 x 300 DPI)


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Figure 2 100x83mm (96 x 96 DPI)


ACS Catalysis

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Scheme 1 129x38mm (300 x 300 DPI)


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Scheme 2 121x114mm (300 x 300 DPI)


ACS Catalysis

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Scheme 3 144x47mm (300 x 300 DPI)


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Scheme 4 135x84mm (300 x 300 DPI)


ACS Catalysis

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Scheme 5 118x32mm (300 x 300 DPI)


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Scheme 6 131x44mm (300 x 300 DPI)


ACS Catalysis

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Scheme 7 248x146mm (300 x 300 DPI)


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Scheme 8 138x202mm (300 x 300 DPI)


ACS Catalysis

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Table 1 223x178mm (300 x 300 DPI)


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Graphical abstract 157x108mm (300 x 300 DPI)


Isochromenes - ACS Publications - American Chemical Society

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