# Improving the Photochemical Skeletal Enlargement of Pyridines to 1,2-Diazepines with Isocyanates

Clément Ghiazza, Aurélie Damond, Jérôme Marrot, Xavier Moreau

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Clément Ghiazza, Aurélie Damond, Jérôme Marrot, Xavier Moreau. Improving the Photochemical Skeletal Enlargement of Pyridines to 1,2-Diazepines with Isocyanates. Advanced Synthesis and Catalysis, 2024, 10.1002/adsc.202401201. hal-04831578

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# Improving the Photochemical Skeletal Enlargement of Pyridines to 1,2-Diazepines with Isocyanates

Clément Ghiazza,ª,*, Aurélie Damond,ª Jérôme Marrot,ª and Xavier Moreauª

ª Université Paris-Saclay, UVSQ, CNRS, UMR 8180 Institut Lavoisier de Versailles, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France
E-mail: clement.ghiazza@uvsq.fr

Manuscript received: September 24, 2024; Revised manuscript received: October 29, 2024;
Version of record online: ■■, ■■

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Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202401201

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© 2024 The Author(s). Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

**Abstract:** In this work, we extend the one-pot protocol to synthesize 1,2-diazepines from commercially available and cheap starting materials. Capitalizing on isocyanate derivatives as activating agents, the photochemical skeletal enlargement occurs, while preserving key functional groups embedded in more than 30 substrates. We also demonstrated that isocyanates can be generated in situ exploiting the wealth of methods starting from bench stable resources. Compare to previous strategies, the use of these precursors prevents the presence of deleterious HCl traces in the system, thus enabling the synthesis of 1,2-diazepines in high yields over up to 5 sequential steps.

**Keywords:** 1,2-Diazepine; Isocyanate; Skeletal enlargement; Pyridine; Heterocycles

## Introduction

The quest for molecular complexity and non-traditional disconnections is a constant effort in organic synthesis and medical chemistry.[1-3] In fact, many venerable textbooks relate the direct correlation between the increasing complexity of a drug candidate and its chances of success in clinical trials. Among the scrutinized parameters, three-dimensional heterocyclic substrates with a reduced aromatic character are often considered essential to improve the host-guest selectivity with a targeted receptor due to a well-suited shape complementarity.[4-7] Naturally, saturation reactions, especially at advanced stages of the synthesis, have aroused considerable attention.[8] In contrast, a recent emerging approach is the dearomative enlargement of flat and aromatic rings (Scheme 1, A).[9-11] If the ring size remained unchanged during traditional saturations, the substrate undergoes a ring expansion in this case; thus, also contributing to the modulation of the physico-chemical properties. This strategy has already been applied for the ring expansion of 5-membered heterocycles;[12-14] and more recently, for the synthesis

<figure><img src="image_5.png" /><figcaption>**Scheme 1.** Context of the study. MSH: O-(mesitylsulfonyl)hydroxylamine.</figcaption></figure>

<figure><img src="image_6.png" /></figure>
of the scarcely represented 7-membered rings from pyridine and benzene derivatives via the insertion of C, [15–18] N[19–22] or O atoms.[23,24]

Since the pioneering work of Streith, Snieckus and Sasaki, the photochemical 1,2-diazepine rearrangement remained underexplored due to synthetic limitations.[25–28] However, our group recently reported a user-friendly strategy enabling the one-pot synthesis of these 7-membered heterocycles (Scheme 1, B).[20] We demonstrated that several activating agents were amenable to trigger the reaction, including sulfonyl chlorides, benzoyl chlorides or alkyl chloroformates. Overall, even though the scope encompassed many electronically and sterically different pyridines, the yields were average. A reason to explain this synthetic restriction can be due to the presence of water in the system. In fact, MSH (O-(mesitylsulfonyl)hydroxylamine) was isolated as an hydrate, usually around 30% w/w, to prevent its spontaneous decomposition. Hence, chlorinated activating groups are also known to be relatively unstable and release HCl upon hydrolysis. In fact, we also showed that TMSCl (trimethylsilyl chloride) with residual amounts of water could trigger the ring contraction of 1,2-diazepines into pyrazoles via a ring-opening of the 7-membered ring. The yields were quite modest and competitive decomposition was often observed due to the presence of sensitive sites on the presumed intermediate. The same year, a similar report by Houk and Zheng confirmed these considerations, and even flow chemistry was not able to improve the efficiency of the ring contraction.[21]

In this regard, it seems important to develop an alternative strategy relying on HCl-free precursors. Therefore, we turned our attention to isocyanate derivatives as these species are commercially available; or generated in situ from diverse abundant resources (Scheme 1, C). We anticipate that this novel strategy could give rise to yet unprecedented molecules, with improved robustness, and in high yields by preventing their decomposition.

## Results and Discussion

A first attempt was performed using 1-aminopyridinium iodide and a slight excess of commercially available phenyl isocyanate with triethylamine as base under UV light irradiation (Scheme 2, A). Gratifyingly, the corresponding 1,2-diazepine derivative 2 was isolated in 88% yield. The obtained substance turned out to be stable and can be stored for weeks on the bench under normal atmosphere without displaying any noticeable alteration. Moreover, treatment of the crude 1,2-diazepine with TMSCl did not lead to the pyrazole analogue, thus proving the resistance of 2 under acidic conditions. This observed robustness clearly outperforms the durability of 1-benzoylated

<figure><img src="image_7.png" /><figcaption>**Scheme 2.** Preliminary results. Isolated yields of pure products are reported. Yields in parentheses were determined by ¹H qNMR spectroscopy with mesitylene as internal standard. A) Screening of activators. B) Formation of the pyrazolo[1,5-a]pyridine core via S-atom deletion. C) Optimization: **1** (0.10 mmol, 1.0 equiv.), base (0.20 mmol, 2.0 equiv.), PhNCO (0.15 mmol, 1.5 equiv.), solvent (0.5 mL).</figcaption></figure>

1,2-diazepines.[20] In contrast, the isothiocyanate analogue did not lead to any trace of the desired product **3** under similar conditions. Analysis of the crude mixture revealed the presence of pyridine as the major product resulting from a deleterious N – N cleavage of the transient pyridinium ylide.[29] As anticipated, the dimethylcarbamic chloride was also suitable as activating group, although with a moderate yield of 55% for compound **4**. As for isothiocyanates, the carbamothioic chloride did not furnish the corresponding 1,2-diazepine **5**.

We assume that the inefficiency of the rearrangement of pyridinium ylides obtained with isothiocyanates is the delocalization of the negative charge on the sulfur atom which triggers unproductive side-events. Hence, the ylide **6** was prepared and mixed with ethylbromoacetate in CHCl₃ at 65°C for 2 hours (Scheme 2, B). The crude mixture was followed by TLC and revealed a clean spot-to-spot conversion. Based on the literature, we envisaged an equilibrium between **6** and **7**, followed by a S<sub>N</sub>2 displacement of the bromide to yield the salt **8**. Further reacting this intermediate with an excess of potassium carbonate at room temperature for one night allowed us to isolate

<figure><img src="image_8.png" /></figure>
and fully characterize the heteroaromatic compound **12** comprising a pyrazolo[1,5-*a*]pyridine core in 36%. To explain the formation of the latter, the group of Kakehi suggested a mechanistic proposal in 1987 with analogous structures.[30] In their scenario, a base induced cyclization takes place resulting in the formation of **9**. A second deprotonation promotes the ring contraction (**10**) and the subsequent sulfur atom extrusion from the scaffold resulting in the formation of **11**. Finally, an aerobic oxidation restores the overall aromaticity and the bicyclic substrate. This mechanistic evidence seems to indicate a certain delocalization of the negative charge on the sulfur atom, which has been shown to be detrimental for the diazepine rearrangement.[27]

With this knowledge in hands, we wanted to take advantage of the improved resistance of **2** to evaluate other sets of conditions (Scheme 2, C). First, representative solvents were interrogated with triethylamine as base and revealed that, beyond CH₂Cl₂, THF was also suitable to prepare **2** in 84% yield. Surprisingly, both CH₃CN and DMSO seemed to foster side-reactions which resulted in low yields. Then, we turned our attention to the exploration of other bases for this rearrangement. Interestingly, even in the absence of base, the desired product was detected in 13%. In the event of an undesired N – N bond cleavage resulting from a triplet excited state, pyridine can be produced in the mixture. Noteworthy, although the conversion is low (24% yield), it is fully compatible with the other components. Finally, inorganic bases also gave good results up to 87% yield with K₃PO₄.

The diazepine rearrangement was also conducted on gram-scale and delivered 1.2 g of **2** (95% yield), thus showcasing the scalability of our photochemical method (Scheme 3). This operationally simple protocol was then extended to other isocyanates in order to evaluate the functional group compatibility. First of all, 1-naphtyl isocyanate was amenable and successfully afforded **13**, although with a modest yield. More interestingly, aryl halides in both *ortho* or *para* positions proved to be suitable and gave the corresponding 1,2-diazepines in 60% to quantitative yield (**14** to **16**). Moreover, we could achieve the synthesis of the desired products bearing strongly electronically depleted aromatic system in good to quantitative yields (**17** to **20**). Unfortunately, nitro substituents were not amenable, probably due to their incompatible behavior under UV light irradiation. Electron donating groups such as methoxy gave interesting outcomes depending on their position on the ring. *Meta*-substituted phenyl isocyanates posed no difficulties and provided **22** in quantitative yield. However, installed in the para-position, a methoxy group turned out to be incompatible since only traces of the desired diazepine **23** were found in the crude mixture. Nonetheless, we could clearly identify the transient ylide **23Y** as the major product which gave suitable crystals for X-ray

<figure><img src="image_9.png" /><figcaption>**Scheme 3.** Scope and limitations. Isolated yields of pure products are reported. General conditions: **1** (0.20 mmol, 1.0 equiv.), NEt₃ (0.40 mmol, 2.0 equiv.), isocyanate derivative (0.30 mmol, 1.5 equiv.), CH₂Cl₂ (1 mL). a) **1** (6.0 mmol, 1.0 equiv.), NEt₃ (12.0 mmol, 2.0 equiv.), phenyl isocyanate (9.0 mmol, 1.5 equiv.), CH₂Cl₂ (20 mL); 3 days. b) **1** (0.25 mmol, 2.5 equiv.), NEt₃ (0.50 mmol, 5.0 equiv.), m-phenylene diisocyanate (0.10 mmol, 1.0 equiv.), CH₂Cl₂ (1 mL). c) Yield determined by ¹H qNMR spectroscopy with mesitylene as internal standard.</figcaption></figure>

diffraction. Interestingly, two diazepines rearrangements can take place on the same molecule as seen in compound **24**. Beyond aryl isocyanates, primary and secondary alkyl derivatives boded well under our developed conditions and gave the desired 7-membered analogues in 35% to quantitative yields (**25** to **29**). It should be noted that a competitive substitution of the chlorine atom occurs in compound **28**, thus lowering the isolated yield. In addition, despite many attempts, compound **29** could not be isolated with common techniques. In fact, we observed an irreversible grafting of the trimethoxysilyl moiety on the stationary phase (silica gel and alumina) during its purification.

<figure><img src="image_10.png" /></figure>
Taking advantage of our previously reported one-pot protocol, we endeavored the exploration of the scope and limitations with diversely substituted pyridines (Scheme 4, **A**). Naked pyridine was first engaged as a reference under this sequential procedure and the desired diazepine **2** was isolated in 70% yield. Pyridines decorated with both alkyl and aryl substituents in *ortho*, *meta* or *para* were well tolerated and gave yields ranging from 62% to quantitative for all the substrates (30 to 33, 35, 38 and 39). However, a

pyridine bearing an amide moiety in *para* position only gave low amount of the corresponding 1,2-diazepine (34). Interestingly, when 3-bromopyridine is engaged under these conditions, 2 regioisomers (36a and 36b) were successfully separated in a 58:42 ratio. This result is consistent with previously established activating agents which preferentially gave the 4-substituted 1,2-diazepine due to steric effects.[20] We also tested the resistance of a TMS-protected primary alcohol under these conditions. We were glad to collect the desired product **37** with a free hydroxyl group in 62% yield resulting from the cleavage of the protecting group on silica gel. In contrast, the same pyridine was converted to its 1,2-diazepine analogue with ethyl chloroformate as activating group. As expected, the protecting group does not survive, thus permitting competitive reactions on the nucleophilic alcohol group (see details in SI, compound 50).

The efficiency of this transformation contrasts with the overall yields obtained when chloroformate derivatives are employed as activating groups. This trend is even more exacerbated when bisacodyl was subjected to the same conditions, delivering the corresponding drug analogue **39** in quantitative yield after an effortless purification.

Even though many isocyanates are commercially available, they remain quite expensive in comparison with known precursors. In addition, these compounds are subject to hydrolysis when stored without thorough precautions. While this does not release HCl, it does decrease the amount of reactant in solution. In this regard, we wondered whether we could prepare isocyanates in situ and perform all these steps in the same reactor. In this context, we first took advantage of the well-established Curtius rearrangement, namely the thermal rearrangement of acyl azides to isocyanates starting from **40** (Scheme 4, B).[31] We were delighted to isolate the corresponding 1,2-diazepine in 61% yield overall. Isocyanates can also be prepared from bench stable, cheap and available anilines when reacted with phosgene surrogates. Subjecting 4-iodoaniline under basic conditions with triphosgene allowed us to generate the corresponding isocyanate en route for the synthesis of **42** in a satisfactory yield of 31%.

As this transformation exceeded our expectations, we envisaged to engage directly carboxylic acids in a telescoped procedure to generate isocyanates. We could anticipate several pitfalls: 1) the compatibility with the azidation agent and all the reactants must be controlled, 2) the direct addition of the carboxylic acid on the isocyanate must be prevented, and 3) the resulting acyl azide must be fully converted to the isocyanate congener to avoid the direct acylation of the 1-aminopyridinium salt **1**. Pivalic acid **43** was selected to probe the reactivity of tertiary isocyanates under our conditions. Hence, refluxing the latter with DPPA (Diphenylphosphoryl azid) and triethylamine in 1,4-

<figure><img src="image_11.png" /><figcaption>**Scheme 4.** Extending the scope of the skeletal enlargement of pyridines. Isolated yields of pure products are reported. General conditions: pyridine (0.10 mmol, 1.0 equiv.), MSH·xH₂O (1.4 equiv.), 4 Å MS (30–40 mg), CH₂Cl₂ (0.5 mL) *then* PhNCO (0.2 mmol, 2.0 equiv.), NEt₃ (0.30 mmol, 3.0 equiv.). a) From TMS-protected starting material. b) Path I: **40** (0.18 mmol, 1.5 equiv.), 1,4-dioxane (1 mL) *then* **1** (0.12 mmol, 1.0 equiv.), NEt₃ (0.24 mmol, 2.0 equiv.). c) Path II: **41** (0.4 mmol, 2.0 equiv.), triphosgene (0.1 mmol, 0.5 equiv.), NEt₃ (1.20 mmol, 6.0 equiv.), CH₂Cl₂ (1 mL) *then* **1** (0.2 mmol, 1.0 equiv.). d) Path III: **43** or **45** (0.30 mmol, 1.5 equiv.), DPPA (0.30 mmol, 1.5 equiv.), NEt₃ (0.80 mmol, 4.0 equiv.), 1,4-dioxane (1 mL) *then* **1** (0.2 mmol, 1.0 equiv.).</figcaption></figure>

<figure><img src="image_12.png" /></figure>
dioxane, followed by its reaction in the presence of 1 under UV light irradiation permitted the synthesis of 44 in 85% yield.[32] This sequence is not only restricted to aliphatic carboxylic acid and was also amenable for thiophene derivatives as illustrated in 46, although prepared in lower yield.

Finally, we also demonstrated that both pyridines and carboxylic acids could be directly engaged as starting material (Scheme 4, C). In 2 separated vials, we could prepare the transient reactive partners in situ and mix them under UV light irradiation. Thus, we could perform the 5 steps (azidation – Curtius rearrangement – amination – ylide formation – 1,2-diazepine rearrangement) in a single sequence to generate the complex 1,2-diazepine analogues, including 49 in 65% yield.

## Conclusion

In conclusion, we herein report an improved protocol to prepare 7-membered 1,2-diazepines in a single-flask operation from abundant resources. Commercially available or in situ generated isocyanate derivatives enabled the facile formation of bench stable 1,2-diazepine analogues in high yields compared to previously established protocols. We noted a wide functional group tolerance encompassing many interesting handles for further transformations. In addition, the scope virtually encompasses any aniline or carboxylic acid available to construct complex architectures.

## Experimental Section

### General Procedure A, from 1-aminopyridinium Iodide

To an oven-dried 8 mL screw-caped tube under normal atmosphere are added 1-aminopyridinium iodide 1 (44.4 mg, 0.20 mmol, 1.0 equiv.), CH₂Cl₂ (1 mL), the isocyanate derivative (0.30 mmol, 1.5 equiv.) and NEt₃ (56 µL, 0.40 mmol, 2.0 equiv.). The mixture is stirred and irradiated in a well-ventilated photochemical reactor at 365 nm for 16 h. The crude mixture is concentrated under reduced pressure and purified by column chromatography on silica gel (cyclohexane/EtOAc, visualization method UV) to afford the desired products. Note: Apart from a few exceptions, all the synthesized 1,2-diazepines are yellow and easy to detect visually.

### General Procedure B, from Pyridines

To an oven-dried 8 mL screw-caped tube under normal atmosphere are added MSH (the mass depends on the %water, 0.14 mmol, 1.4 equiv.), pyridine derivative (0.1 mmol, 1 equiv.), oven-dried 4 Å molecular sieves (30–40 mg) and anhydrous CH₂Cl₂ (0.5 mL). The mixture is stirred for 1 h in a preheated oil bath at 40 °C. The reaction is then allowed to cool down to 25 °C and the isocyanate derivative (0.20 mmol, 2 equiv.) and NEt₃ (42 µL, 0.3 mmol, 3 equiv.) are added. The mixture is

stirred and irradiated in a well-ventilated photochemical reactor at 365 nm for 16 h. The crude mixture is filtered on a short plug of celite (2–3 cm in a glass pipette), concentrated under reduced pressure and purified by column chromatography (or home-made preparative TLC) on silica gel (cyclohexane/EtOAc, visualization method UV) to afford the desired products. Note: Apart from a few exceptions, all the synthesized 1,2-diazepines are yellow and easy to detect visually.

## General Procedure C, from Pyridines and Carboxylic Acids

### Solution A

To an oven-dried 8 mL screw-caped tube under normal atmosphere are added MSH (the mass depends on the %water, 0.14 mmol, 1.4 equiv.), pyridine derivative (0.1 mmol, 1.0 equiv.), oven-dried 4 Å molecular sieves (30–40 mg) and anhydrous CH₂Cl₂ (0.5 mL). The mixture is stirred for 1 h in a preheated oil bath at 40 °C. The reaction is then allowed to cool down to 25 °C.

### Solution B

To an oven-dried 25 mL round bottom flask under normal atmosphere are added carboxylic acid (0.15 mmol, 1.5 equiv.), DPPA (41 mg, 0.15 mmol, 1.5 equiv.) and anhydrous 1,4-dioxane (0.5 mL). Then, NEt₃ (56 µL, 0.4 mmol, 4.0 equiv.) is slowly added. The mixture is stirred at reflux for 2 h in a preheated oil bath at 120 °C. The reaction is then allowed to cool down to 25 °C is transferred to solution A. The combined mixture is stirred and irradiated in a well-ventilated photochemical reactor at 365 nm for 16 h. The crude mixture is concentrated under reduced pressure and purified by column chromatography on silica gel (cyclohexane/EtOAc, visualization method UV) to afford the desired products.

CCDC-2384883 and CCDC-2384884 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.

## Acknowledgements

Financial support for this work was provided by the Centre National de la Recherche Scientifique (CNRS), Université de Versailles-St-Quentin-en-Yvelines (UVSQ), Université Paris Saclay (UPSaclay). This work was also supported by ANR PIA funding: ANR-20-IDEE-0002 and as part of France 2030 program ANR-11-IDEX-0003, awarded by the Graduate School Chemistry of the Université Paris-Saclay. Flavien Bourdreux is acknowledged for his support with NMR spectroscopy. We specially thank Dr M. Barday for insightful discussions.
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Improving the Photochemical Skeletal Enlargement of
Pyridines to 1,2-Diazepines with Isocyanates

*Adv. Synth. Catal. **2024**, *366*, 1–7

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

C. Ghiazza*, A. Damond, J. Marrot, X. Moreau

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