# Formation of 3-Alkynylidenephthalides by Gold(I)-Catalyzed Alkynylative Cyclization of o-Alkynylbenzoic Acids under Visible Light Irradiation

María Ballarín-Marión, Jorge C Herrera-Luna, Vincent Corcé, Héloïse Dossmann, Cyril Ollivier, Virginie Mouriès-Mansuy, Louis Fensterbank

<figure><img src="image_1.png" /></figure>

## ► To cite this version:

María Ballarín-Marión, Jorge C Herrera-Luna, Vincent Corcé, Héloïse Dossmann, Cyril Ollivier, et al. Formation of 3-Alkynylidenephthalides by Gold(I)-Catalyzed Alkynylative Cyclization of o-Alkynylbenzoic Acids under Visible Light Irradiation. Journal of Organic Chemistry, 2024, 89 (22), pp.16242-16248. 10.1021/acs.joc.4c01876. hal-05355647

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# Formation of 3-Alkynylidenephthalides by Gold(I)-Catalyzed Alkynylative Cyclization of o-Alkynylbenzoic Acids under Visible Light Irradiation

María Ballarín-Marión,<fnref n="1" /> Jorge C. Herrera-Luna,<fnref n="1" /> Vincent Corcé,<fnref n="1" /> Héloïse Dossmann,<fnref n="1" /> Cyril Ollivier*,<fnref n="1" /> Virginie Mouriès-Mansuy*,<fnref n="1" /> Louis Fensterbank*<fnref n="1" />,<fnref n="2" />

<figure><img src="image_3.png" /></figure>

**ABSTRACT:** Herein, we report a Csp<fnref n="2" />-Csp cross-coupling process involving the merger of gold catalysis and visible light photocatalysis leading to the alkynylative cyclization of o-alkynyl benzoic acids. The corresponding and previously undescribed alkynylidenephthalide products were obtained as mixtures of E:Z isomers. The key C-C bond formation is based on the photoactivation of the oxidative addition of an alkynyliodide to a vinylgold(I) intermediate resulting from an initial 5-exo-dig cyclization pathway, as supported by mechanistic studies including DFT calculations.

## INTRODUCTION

Over the past two decades, homogeneous gold catalysis has been extensively used to efficiently promote a variety of synthetically valuable processes.<fnref n="1" /> In particular, gold(I) complexes are the most effective catalysts for the electrophilic activation of unsaturated derivatives like alkynes.<fnref n="2" /> In general, the gold catalyst acts as a soft π-Lewis acid, activating the triple bond for inter- or intramolecular nucleophilic addition. The organogold(I) intermediate formed typically undergoes protodemetallation leading to the corresponding hydrofunctionalized product.³,⁴ Thus, a broad number of transformations involving carbon, nitrogen, oxygen or other nucleophiles have been reported.

In the quest for step economy and access to molecular complexity, *in situ* post-functionalization of the organogold intermediate is desirable, for instance *via* cross coupling reactions.⁵ This implies an oxidative addition on Au(I) which is difficult to establish, due to the high redox potential of the Au(III)/Au(I) cycle couple (E = 1.41V),⁶ and the need to set a stabilizing environment for an Au(III) intermediate. An initial but not fully satisfactory solution has consisted in using an exogenous oxidant to facilitate the

Au(I)/Au(III) transition.³,⁷ In a context of enhanced sustainability, the Bourissou, Russell, and Patil groups⁸ showed that the use of hemi-labile ligands on Au(I) can efficiently promote the oxidative addition step. For their part, Glorius and Toste proposed a redox neutral approach by merging Au(I) catalysis with visible-light photoredox catalysis in a dual catalytic process.⁹ In this process, the protodemetallation step can be redirected in favor of an arylation step involving aryl radicals generated by photoredox catalysis. Our group exploited this methodology by using o-alkynyl phenols as nucleophiles and aryldiazonium salts as radical precursors to obtain arylated benzofurans upon household light bulb irradiation.¹⁰ However, this approach is limited to easily reduced radical precursors. For this reason, we introduced in 2019 a novel approach to Csp₂-Csp bond formation based on an oxidative addition to a photosensitized organogold(I) intermediate.¹¹ This process enabled the direct synthesis of alkynylated benzofurans using o-alkynyl phenols as nucleophiles and alkynyl iodides as cross-coupling partners.¹² More recently, this energy transfer-based approach was extended to the synthesis of 2,3-disubstituted indoles from o-alkynyl anilines. Remarkably, the reaction proceeded in the absence of a

<footnote n="1">¹Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, 4 place Jussieu, 75005 Paris, France</footnote>

<footnote n="2">²Collège de France, Chaire Activations en Chimie Moléculaire, 11 place Marcelin Berthelot, 75005 Paris, France</footnote>
photocatalyst, thanks to the static quenching of emissive potassium sulfonamide aggregates formed in situ by the vinylgold(I) intermediate.¹³

Phthalides are characterized by a bicyclic nucleus derived from the fusion of a γ-lactone with a benzene ring. Intramolecular cyclization of o-alkynylbenzoic acids can afford both phthalide and isocoumarin derivatives via respectively 5-exo and 6-endo cyclization modes.¹⁴ As both of these skeletons represent an important class of naturally occurring lactones with a wide range of biological activities, their selective synthesis has received considerable attention. Baldwin's rules predict that both 5-exo-dig and 6-endo-dig cyclizations are favorable, making selective synthesis difficult in practice.¹⁵ The cycloisomerization of o-alkynylbenzoic acids to form 3-alkylidenephthalides has been widely investigated using various catalysts, such as Pd(II),¹⁶ CuCl₂,¹⁷ AuCl,¹⁸ and Rh(I).¹⁹ Depending on the nature of the catalyst and the substituents on the o-alkynylbenzoic acid, either 3-alkylidenephthalides or isocoumarins are favored. To the best of our knowledge, the synthesis of 3-alkynylidenephthalides has not yet been reported and herein, we describe a gold(I)-catalyzed alkynylative cyclization of o-alkynylbenzoic acids that leads to these intriguing derivatives.

**Optimisation studies.** We first focused on the reaction of **1a** with an alkynyliodide partner in the presence of a base. Initial experiments with 5 mol% of [Au-CF₃] ([PF₃Ph)₃PAuCl]) and 1 mol% [Ru(bpy)₃](PF₆)₂ afforded a 35% isolated yield of the cross coupling product derived from a 5-exo cyclization pathway, alkynylated 3-ylidenephthalide **3aa**, as a mixture of E:Z isomers, together with a small amount of the 6-endo cyclization product (**3aa-6-endo**) (Table 1, entry 1), accompanied by the undesired iodophthalide **4a** (44% isolated yield). The structure of **4a** was confirmed by comparison with previously described iodophthalides.²⁰ The structure of **3aa** was safely confirmed by independently synthesizing the *E* and the 6-endo isomers by a selective method (see SI for the selective synthesis of **3aa-6-endo** and **E-3aa**). Crystals of **3aa**

were also grown from a CH₂Cl₂ solution and allowed an X-ray diffraction (XRD) analysis. Increasing the gold(I) catalyst loading to 10 mol% gave a higher **3aa** yield of 51% (entry 2). In this case, the formation of **4a** was notably reduced to 21%. Then, reducing the reaction time to 4 hours afforded **3aa** in a slightly higher yield (58%, entry 3). Dilution to 0.05 M also improved the yield to 67% (entry 4). Other photocatalysts such as [Ir(dFCF₃ppy)₂(dtbbpy)](PF₆) and 4CzIPN proved to be competent (respectively 63 and 64%, entries 5,6). Also, using PPh₃AuCl as catalyst instead of [Au-CF₃] gave **3aa** in a lower 60% yield (entry 7). Finally, the reaction was conducted using different inorganic bases, such as K₃PO₄, K₂CO₃ and Na₂CO₃ which all afforded **3aa** in lower yields, presumably due to a lesser solubility (See SI, Table S1). Some control tests were performed to get an insight into the mechanism of the reaction. Interestingly, the reaction without photocatalyst yielded **3aa** in 58%, as estimated by NMR (49% isolated yield) (entry 8). This result indicates that the presence of a photocatalyst was not indispensable, but it slightly improves the reaction yield. Finally, reaction without base, light or gold catalyst resulted in very low yields, or even in no product at all (entries 9-11). In the last case, **4a** was obtained in 52% yield, suggesting that this byproduct originates from another pathway than the reductive elimination from a Au(III) intermediate.²¹ Moreover, the reaction without [Au-CF₃], photocatalyst and light provided **4a** in 48% (entry 12), while **3aa** was not detected.

**Mechanistic studies.** The vinylgold(I) complex **5** was synthesized as a unique *E* isomer by reacting an equimolar amount of benzoic acid **1a** and [Au-CF₃] catalyst in the presence of 2.5 equivalents of Cs₂CO₃ (Scheme 1a). Crystals of **5** were grown from a Et₂O solution and allowed an XRD analysis. It exhibits a broad absorption band tailing over 400 nm with a maximum at 353 nm. This allowed us to study the reaction between **5** and alkyne **2a** at 0.1 M in CD₃CN under blue LED irradiation (Scheme 1b).

<table><caption>Table 1 - Optimization of the reaction conditions.</caption><thead><tr><th>Entry</th><th>Catalyst (mmol%)</th><th>Time (h)</th><th>Concentration (M)</th><th>Photocatalyst</th><th>Base</th><th>3aa (E:Z:6-endo)</th><th>4a (E:Z)</th></tr></thead><tbody><tr><td>1</td><td>[Au-CF<sub>3</sub>] (5)</td><td>16</td><td>0.067</td><td>[Ru(bpy)<sub>3</sub>](PF<sub>6</sub>)<sub>2</sub></td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>35 (43:47:10)</td><td>44 (45:55)</td></tr><tr><td>2</td><td>[Au-CF<sub>3</sub>] (10)</td><td>16</td><td>0.067</td><td>[Ru(bpy)<sub>3</sub>](PF<sub>6</sub>)<sub>2</sub></td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>51 (52:42:6)</td><td>21 (30:70)</td></tr><tr><td>3</td><td>[Au-CF<sub>3</sub>] (10)</td><td>4</td><td>0.067</td><td>[Ru(bpy)<sub>3</sub>](PF<sub>6</sub>)<sub>2</sub></td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>58 (62:26:12)</td><td>16 (65:35)</td></tr><tr><td>4</td><td>[Au-CF<sub>3</sub>] (10)</td><td>4</td><td>0.05</td><td>[Ru(bpy)<sub>3</sub>](PF<sub>6</sub>)<sub>2</sub></td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>67<sup>a</sup> (51:34:15)</td><td>17 (57:43)</td></tr><tr><td>5</td><td>[Au-CF<sub>3</sub>] (10)</td><td>4</td><td>0.05</td><td>Ir[dF(CF<sub>3</sub>)ppy]<sub>2</sub>(dtbbpy)PF<sub>6</sub></td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>63 (49:45:6)</td><td>10 (45:55)</td></tr><tr><td>6</td><td>[Au-CF<sub>3</sub>] (10)</td><td>4</td><td>0.05</td><td>4CzIPN</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>64 (59:35:6)</td><td>10 (48:52)</td></tr><tr><td>7</td><td>PPh<sub>3</sub>AuCl (10)</td><td>4</td><td>0.05</td><td>[Ru(bpy)<sub>3</sub>](PF<sub>6</sub>)<sub>2</sub></td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>60 (47:47:6)</td><td>31 (27:73)</td></tr><tr><td>8</td><td>[Au-CF<sub>3</sub>] (10)</td><td>4</td><td>0.05</td><td>-</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>49<sup>a</sup> (63:29:8)</td><td>12 (76:24)</td></tr><tr><td>9</td><td>[Au-CF<sub>3</sub>] (10)</td><td>4</td><td>0.05</td><td>[Ru(bpy)<sub>3</sub>](PF<sub>6</sub>)<sub>2</sub></td><td>-</td><td>n.d.</td><td>n.d.</td></tr><tr><td>10<sup>b</sup></td><td>[Au-CF<sub>3</sub>] (10)</td><td>4</td><td>0.05</td><td>[Ru(bpy)<sub>3</sub>](PF<sub>6</sub>)<sub>2</sub></td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>10 (66:0:34)</td><td>40 (100:0)</td></tr></tbody></table>
11 - 4 0.05

12<sup>b</sup> - 4 0.05

Reaction conditions: **1a** (0.3 mmol), **2a** (0.33 mmol), base (0.3 mmol), gold catalyst (5-10 mol%), photocatalyst (1 mol%) in 6 mL of degassed acetonitrile at room temperature for 4-16 hours under blue LEDs irradiation. Isolated yields. E:Z:6-endo ratios determined by ¹H NMR. <sup>a</sup>NMR yield of entry 4: 68%; entry 8: 58% (using 1,3,5-trimethoxybenzene as internal standard). <sup>b</sup> No light. n.d.: not detected

The cross-coupling product **3aa** was obtained in 66% yield as a 1:1 E:Z ratio (¹H NMR yield) after 1.5 h in the presence of the photocatalyst, instead of 38% without. After 3 h, comparable yields of **3aa** (66-72%) with or without photocatalyst were obtained. Note also that the formation of iodophthalide **4a** was not observed in these reactions. Here, the presence of the ruthenium-based photocatalyst would accelerate a reaction that is already working under direct irradiation.

**Scheme 1 - a) Synthesis of the vinylgold complex 5. b) Monitoring of the cross-coupling reaction between the vinylgold 5 and the alkyne 2a. ORTEP representation of 5. Thermal ellipsoids are shown with 30% probability. Atom labelling: carbon = white, oxygen = red, fluorine = green, phosphorus = orange and gold = yellow. CCDC: 2328330.**

<figure><img src="image_4.png" /><figcaption>b) Monitoring of cross-coupling reaction</figcaption></figure>

<figure><img src="image_5.png" /></figure>

<table><thead><tr><th>Entry</th><th>Time (h)</th><th>Photocatalyst</th><th>3aa (E:Z)</th><th>4a (E:Z)</th></tr></thead><tbody><tr><td>1</td><td>1.5</td><td rowspan="2">None</td><td>38 (49:51)</td><td>n.d.</td></tr><tr><td>2</td><td>3</td><td>72 (51:49)</td><td>n.d.</td></tr><tr><td>3</td><td>1.5</td><td rowspan="2">[Ru[bpy]<sub>3</sub>](PF<sub>6</sub>)<sub>2</sub><br>(1 mol%)</td><td>66 (45:55)</td><td>n.d.</td></tr><tr><td>4</td><td>3</td><td>66 (45:55)</td><td>n.d.</td></tr></tbody></table>

Furthermore, as vinylgold **5** is formed as E-isomer, the E-Z isomerization would occur after the formation of the **E-3aa** product. To validate this hypothesis, we carried out some photoisomerization reactions (Table 2). Direct irradiation of **E-3aa** gave rise to a E:Z mixture of isomers in a 45:55 ratio after 24h. The addition of 1 mol% of [Ru(bpy)<sub>3</sub>](PF<sub>6</sub>)<sub>2</sub> accelerated this photoisomerization,<sup>22</sup> reaching the same E:Z ratio of 47:53 in only 1.5 h.

<figure><img src="image_6.png" /><figcaption>**Table 2 - Photoisomerization reactions.**</figcaption></figure>

[Ru(bpy)<sub>3</sub>](PF<sub>6</sub>)<sub>2</sub> Cs<sub>2</sub>CO<sub>3</sub> Traces 52 (50:50)

- Cs<sub>2</sub>CO<sub>3</sub> n.d. 48 (100:0)

<table><thead><tr><th>Entry</th><th>Photocatalyst (1mol%)</th><th>E:Z (1.5h)</th><th>E:Z (24h)</th></tr></thead><tbody><tr><td>1</td><td>[Ru(bpy)<sub>3</sub>](PF<sub>6</sub>)<sub>2</sub></td><td>47:53</td><td>47:53</td></tr><tr><td>2</td><td>None</td><td>75:25</td><td>45:55</td></tr></tbody></table>

Starting E:Z ratio of 100:0.

To assess the potential formation of a cesium aggregate in the reaction medium, as was the case in our previous studies with potassium N-tosylamides,<sup>13</sup> we recorded the absorption spectrum of the benzoate cesium salt (1a-Cs). We did not observe a change of the absorption pattern as a function of concentration, revealing that an aggregate formation does not seem to take place in the reaction conditions (See SI Fig. S4).

Luminescence quenching experiments were undertaken. First, the impact of vinylgold(I) **5** on the steady-state luminescence of the excited state of [Ru(bpy)<sub>3</sub>](PF<sub>6</sub>)<sub>2</sub> ([Ru(bpy)<sub>3</sub>]<sup>2+</sup>) was investigated. Some decrease in the emission could be observed upon gradual addition of **5**, presumably corresponding to a bimolecular quenching. Similar observation was made with 4CzIPN suggesting that **5** acts as a quencher of the excited state of both photocatalysts (See SI Fig. S7-S10). A decrease in the [Ru(bpy)<sub>3</sub>](PF<sub>6</sub>)<sub>2</sub> luminescence was also observed when increasing the concentration of **E-3aa**, indicating that the latter acts as a quencher for [Ru(bpy)<sub>3</sub>]<sup>2+</sup> (See SI Fig. S11-S14). Time-dependent density-functional theory (TD-DFT) calculations were performed to support these observations. The calculated T<sub>1</sub> state for **5*** (E<sub>T</sub> = 52.0 kcal/mol) lied sufficiently close to [Ru(bpy)<sub>3</sub>]<sup>2+</sup> (E<sub>T</sub> = 48.6 kcal/mol) (See SI Fig S16) and lower than 4CzIPN* (E<sub>T</sub> = 59.7 kcal/mol)<sup>23</sup> to guarantee the possibility of EnT. In contrast and based on the calculated E<sub>T</sub> of 39.9 kcal/mol for **E-3aa***, an easier EnT between [Ru(bpy)<sub>3</sub>]<sup>2+</sup> and **E-3aa** could be at play (Fig. S16). The calculations also evidenced that the E-Z isomerization in the triplet state proceeds via a low transition state (5.5 kcal/mol above **E-3aa** (T<sub>1</sub>), (See SI Fig. S17). Additionally, light on/off experiments were undertaken, showing no product formation in the dark phase, which discarded the possibility of a radical chain pathway (See SI Fig. S18).

Taking into account the luminescence studies, control experiments, TD-DFT calculations and previous reports,<sup>12</sup> we propose the mechanism illustrated in Scheme 2. The catalytic cycle would begin with the formation of the E-vinylgold(I) **5** intermediate through the reaction of the benzoate salt formed *in situ* with the gold catalyst. Vinyl-gold(I) **5** could then reach its triplet state **5*** through two potential pathways. First **5** could be directly photoexcited through the absorption of blue light (S<sub>0</sub>-S<sub>1</sub> absorption followed by intersystem crossing (ISC) to the T<sub>1</sub> state, pathway A). Of note, the absorption spectrum of **5** showed a clear bathochromic shift compared to the previously studied vinylgold complexes based on a benzofuran or an indole scaffold (See SI Fig S3).<sup>12,13</sup> Second, the excited photocatalyst ([Ru(bpy)<sub>3</sub>]<sup>2+</sup> or 4CzIPN*) would induce an energy transfer process to vinylgold(I) **5**, as demonstrated by
luminescence quenching studies (Pathway B). This pre-
sumably minor pathway could rationalize the slight in-
crease of yield in the presence of [Ru(bpy)₃]²⁺ or 4CzIPN.
Then, as in our previous reports,¹²,¹³ the triplet state of 5
would undergo oxidative addition to the alkynyl iodide.
Finally, reductive elimination liberates the alkynylated

phthalide **E-3aa** and completes the catalytic cycle. As ex-
plained above, **E-3aa** phthalide is partially photoisomer-
ized to its **Z-3aa** isomer. A similar pathway would also
proceed from an initial **6-endo** cyclization, although this
product is the minor regioisomer, with the final **E:Z:6-endo**
products ratio being 51:34:15.

<figure><img src="image_7.png" /><figcaption>**Table 3 - Scope of o-alkynylbenzoic acids and alkynes.**</figcaption></figure>
<figure><img src="image_8.png" /></figure>

1
1 equiv

2
1.1 equiv

3xx (E:Z:6-endo)

A) With [Ru(bpy)₃](PF₆)₂

B) With 4CzIPn

Scope of benzoic acids

<figure><img src="image_9.png" /></figure>

**3aa<sup>a,b,c</sup>**
A) 67% (51:34:15)
B) 64% (59:35:6)

<figure><img src="image_10.png" /></figure>

**3ba**
A) 61% (49:48:3)
B) 65% (59:37:4)

<figure><img src="image_11.png" /></figure>

**3ca**
A) 48% (39:26:35)
B) 55% (49:19:32)

<figure><img src="image_12.png" /></figure>

**3da**
A) 63% (50:46:4)
B) 68% (64:31:5)

<figure><img src="image_13.png" /></figure>

**3ea**
A) 54% (50:44:5)
B) 56% (53:43:4)

<figure><img src="image_14.png" /></figure>

**3fa**
A) 54% (76:24:0)
B) 57% (80:20:0)

Scope of alkynes

<figure><img src="image_15.png" /></figure>

**3ab**
A) 60% (46:48:6)
B) 69% (60:36:4)

<figure><img src="image_16.png" /></figure>

**3ac**
A) 54% (48:45:7)
B) 58% (54:34:12)

<figure><img src="image_17.png" /></figure>

**3ad<sup>c</sup>**
A) 58% (53:42:5)
B) 49% (47:50:3)

<figure><img src="image_18.png" /></figure>

**3ae**
A) 74% (51:43:6)
B) 59% (51:42:7)

<figure><img src="image_19.png" /></figure>

**3af**
A) 68%<sup>b</sup> (83:11:6)
B) 71% (68:23:9)

<figure><img src="image_20.png" /></figure>

**3ag**
A) 54% (48:45:7)
B) 53% (55:34:11)

<figure><img src="image_21.png" /></figure>

**3ah**
A) 40%<sup>b</sup> (57:0:43)
B) 68%<sup>b</sup> (75:25:0)

<figure><img src="image_22.png" /></figure>

**3ai**
A) 20%<sup>b</sup>
B) 24%<sup>b</sup>

<figure><img src="image_23.png" /></figure>

**3aj<sup>c</sup>**
A) 20%<sup>b</sup> (43:45:12)
B) 15%<sup>b</sup> (55:39:6)

<figure><img src="image_24.png" /></figure>

**3ak**
A) 49% (56:41:3)
B) 82% (52:43:5)

Isolated yields of 3xx as mixture of isomers (in parentheses the ratio of E:Z:6-endo in the crude product). a 1 mmol scale: 55% (51:40:9) (using [Ru(bpy)₃](PF₆)₂). b E-isomer as only isolable product. c XRD structures were obtained (see SI).

**Scope of the reaction.** Having established optimal reaction conditions, we explored the scope of the reaction. Even though the reaction from **1a** with [Ru(bpy)₃]²⁺ afforded a better yield of **3aa** compared to 4CzIPN (67% vs 64%, Table 1), we decided to explore the use of this organic photocatalyst with various substrates, obtaining the desired products generally in slightly higher yields compared to [Ru(bpy)₃]²⁺ (Table 3). The impact of the nature and position of the substituents on the aryl moiety of the o-alkynylbenzoic acid was studied and found to be crucial to the efficiency of the process. The presence of a methyl substituent in para or meta position resulted in significantly higher yields than in the ortho position. This is probably due to the increased steric hindrance in the ortho position, making the cyclization reaction more difficult to achieve. In addition, electron-withdrawing groups, such as fluorine or chlorine substituents, led to slightly lower yields. The effect of the substituent on the aryl moiety of the alkynyl iodide was also studied. The presence of electron donating methyl and methoxy groups led to good yields (**3ab** to **3ae**, from 58% to 74%) as well as the presence of electron

withdrawing groups (chlorine and trifluoromethyl substituents): from 54% to 68% (**3af-3ag**). The cyano-derivative **3ah** was obtained in moderate yield with [Ru(bpy)₃]²⁺ (40%) but in higher yield with 4CzIPN (68%). Substitution of the aryl moiety by an alkyl or a vinyl group adversely affected the reaction (24% of **3ai** and 20% of **3aj**). The presence of heteroaromatic rings such as the 2-pyridinyl ring resulted in the desired phthalide **3ak** in up to 82% yield with 4CzIPN. In all examples, between 10 and 20% of the corresponding iodo derivative was also formed. Finally, a 1 mmol reaction of **1a** under standard conditions with [Ru(bpy)₃]²⁺ as photocatalyst afforded **3aa** in 55% isolated yield (E:Z:6-endo, 51:40:9).

**Post-functionalization.** Phthalides serve as valuable scaffolds for the elaboration of natural products and other molecules of interest. Werz *et al.* reported the reduction of the commercially available phthalide with LiAlH₄ into the corresponding diol.²⁴ Here, reaction of **3aa** and **3fa** with 1 equivalent of LiAlH₄ resulted in the formation of the benzo[c]oxepin-5(1H)-one **6a** and **6b** in 58% and 72% yield respectively (Scheme 3a). Crystals of **6a** were grown from
a CH₂Cl₂ solution and an XRD analysis confirmed the struc-
ture. In 1996, Sano et al. reported the synthesis of this type
of 7-membered ring heterocycle via the formation of an
allenyl ketone intermediate.²⁵ In our case, the reaction
involves the reduction of the lactone moiety, leading to the
formation of the aryl allenyl ketone (Int-A). Inspired by the
work of Sano, we propose that this allenyl ketone under-
goes nucleophilic attack by the alcohol moiety, leading to
the formation of Int-B. Subsequent reorganization and
trapping of a proton affords the final product. Recently,
Commeiras et al. reported the synthesis of isoindolin-1-
one derivatives through the reaction of 3-benzylidene-
phthalide and n-butylamine under ultrasonic irradiation.²⁶
Inspired by this work, we attempted the reaction of 3aa
with 2 equivalents of n-butylamine under thermal condi-
tions (Scheme 3b). In our case, we observed the introduc-
tion of two butylamine groups. First, nucleophilic attack of
the amine on the carbonyl group results in the opening of
the lactone ring. A second n-butylamine molecule would
then attack the triple bond, leading to the formation of the
(but-2-enoyl)benzamide derivative (7a) as final product in
60% yield. NOESY NMR analysis determined that the major
isomer is the Z isomer in a Z:E ratio of 93:7.

<figure><img src="image_25.png" /><figcaption>Scheme 3 - Post-functionalization of the 3-alkynylydene phthalide. ORTEP representation of 6a. Thermal ellipsoids are shown with 30% probability. Atom labelling: carbon = white, oxygen = red, and fluorine = green. CCDC: 2333055.</figcaption></figure>

In conclusion, we have developed the first approach to the
synthesis of various 3-alkynylidenephthalides by gold(I)-
catalyzed alkynylative cyclization of o-alkynylbenzoic acids
under blue LED irradiation. These phthalides are obtained
in moderate to good yields as E:Z mixtures, often accom-
panied by minor amounts of iodo derivatives 4 and of the
corresponding 6-endo isocoumarin. Based on lumines-
cence and DFT studies, a mechanistic manifold has been
proposed featuring a direct irradiation pathway and a
minor photocatalyzed pathway, the key step consisting of
the interaction of a photoexcited vinyl gold(I) intermediate

with an alkynyliodide partner. Post-functionalization of the
resulting phthalides enabled us to synthetize two ben-
zo[c]oxepin-5(1H)-ones via a new ring enlargement reac-
tion and a (but-2-enoyl)benzamide derivative through the
reaction of 3aa with n-butylamine.

ASSOCIATED CONTENT

Data Availability Statement

The data underlying this study are available in the published
article and its Supporting Information.

**Supporting Information**

Experimental details and analytical data, NMR spectra, X-Ray
crystal structure determination. The Supporting Information is
available free of charge on the ACS Publications website.

Accession Codes

CCDC 2328326 (E-3aa), 2328327 (Z-3aa), 2328328 (E-3ad), 2328329 (E-3aj), 2328330 (5) and 2333055 (6a) contains 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

AUTHOR INFORMATION

Corresponding Author

* Cyril Ollivier – Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, IPCM, 75005 Paris, France, email : [cv-riil.ollivier@sorbonne-universite.fr](mailto:cv-riil.ollivier@sorbonne-universite.fr)

*Virginie Mouriès-Mansuy – Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, IPCM,75005 Paris, France, email : [virginie.mansuy@sorbonne-universite.fr](mailto:virginie.mansuy@sorbonne-universite.fr)

*Louis Fensterbank – Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, IPCM, 75005 Paris, France
Collège de France, Chaire Activations en Chimie Moléculaire,
Paris, France, email : [louis.fensterbank@sorbonne-universite.fr](mailto:louis.fensterbank@sorbonne-universite.fr)

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENT

The authors thank Sorbonne Université, CNRS, IUF and Collège
de France for financial support as well as ANR-20-CE07-0038
LuxOr for providing a PhD grant to M.B.M and Generalitat Va-
lenciana for providing a postdoc grant (CIAPOS/2022/174) to
J.C.H.L. They are also grateful to Mr. Jérémy Forte and Geoffrey
Gontard for the XRD analyses, as well as to Blaise Dumas,
Thomas Le Saux and Ludovic Jullien (ENS) for photophysical
measurments.

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