On the Synthesis of
[1,3]Azaphospholo[4,5-f]quino(xa)lines and
2,3-Dihydro-[1,3]azaphospholo[4,5-f]quino(xa)line
1-oxides

Mohamed Ali Dridi, Mohamed Hasyeoui, Frédéric Lassagne, William Erb, Charline Piroud, Thomas Robert, Stéphane Bach, Ali Samarat, Soufiane Touil, Florence Mongin

► To cite this version:

Mohamed Ali Dridi, Mohamed Hasyeoui, Frédéric Lassagne, William Erb, Charline Piroud, et al. On the Synthesis of [1,3]Azaphospholo[4,5-f]quino(xa)lines and 2,3-Dihydro-[1,3]azaphospholo[4,5-f]quino(xa)line 1-oxides. European Journal of Organic Chemistry, 2025, pp.e202500080. 10.1002/ejoc.202500080. hal-04975365

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# On the Synthesis of [1,3]Azaphospholo[4,5-f]quino(xa)lines and 2,3-Dihydro-[1,3]azaphospholo[4,5-f]quino(xa)line 1-oxides

Mohamed Ali Dridi,[a, b] Mohamed Hasyeoui,[a, b] Frédéric Lassagne,[a] William Erb,[a] Charline Piroud,[c, d] Thomas Robert,[c, d] Stéphane Bach,[c, d] Ali Samarat,[b] Soufiane Touil,[*][b] and Florence Mongin*[a]

Despite their potential in areas such as medicinal chemistry and organic materials, scaffolds in which quinoline and quinoxaline are fused to phosphacycles such as 1,3-oxaphosphole, 1,3-azaphosphole, *P*-arylated and *P*-alkoxylated 2,3-dihydro-1,3-azaphosphole *P*-oxides have, to our knowledge, never been reported. In this study we have developed a synthetic approach to [1,3]azaphospholo[4,5-f]quinolines and -quinoxalines from quinolin-6-amine and quinoxalin-6-amine. These were converted to 5-phosphanylquino(xa)lin-6-amines by regioselective iodination in position 5, cross-coupling with diethyl phosphite

and reduction. Formation of the azaphosphole ring was then achieved by reaction with *N*,*N*-dimethylformamide dimethyl acetal. Attempts at C–H arylation in position 2 did not lead to the desired derivatives but rather to 1-arylated 2,3-dihydro-[1,3]azaphospholo[4,5-f]quino(xa)line 1-oxides. Access to 1-alkoxylated 2,3-dihydro-[1,3]azaphospholo[4,5-f]quinoline 1-oxides was also developed using as key steps cross-coupling with ethyl phosphinate formed *in situ* and the subsequent Kabachnik-Fields reaction. The resulting tricyclic compounds were finally tested against a panel of disease-related protein kinases.

## Introduction

Organophosphorus compounds continue to attract considerable interest from researchers because of their wide range of applications, particularly in the fields of medicine, chemistry and materials science.[1] As Todd stated in 1981 with 'Where there's life, there's phosphorus',[2] it is widely recognised that phosphorus molecules play a crucial role in biological proc-

esses. This is why compounds containing the element phosphorus have long been used as agrochemicals or as active pharmaceutical ingredients in drugs for various targets.[3] One example is the zoledronic diphosphonic acid (Figure 1, compound A), developed for the treatment of bone diseases.[4] As well as conferring biological activity, the introduction of phosphorus into organic compounds enables the design of novel molecular materials with exceptional optoelectronic properties,[5] as well as the development of ligands for the extraction of heavy metals[6] or for use in transition metal-catalysed cross-coupling reactions[7] and asymmetric synthesis.[8]

Among the most interesting organophosphorus compounds, phosphorus heterocycles, which combine the benefits of the phosphorus atom and heterocyclic scaffolds, play a crucial role in biological processes.[9] As a result, the pharmaceutical industry has long been interested in developing drugs containing *P*-heterocycles, such as the oxazaphosphorine ifosfamide, used as an alkylating agent in the treatment of various cancers[3,10] (Figure 1, compound B). It is also interesting to note that aromatic phosphorus compounds such as 1,3-benzoxaphosphole,[11] 1,3-benzothiaphosphole[12] and 1,3-benzazaphosphole[11c,13] can provide valuable electronic and

<figure><img src="image_3.png" /><figcaption>**Figure 1.** Structures of zoledronic acid (A), (S)-ifosfamide (B), 1,3-benzoxa-, 1,3-benzothia- and 1,3-benzazaphospholes (C), and a chiral (S)-ligand efficiently used in atroposelective Suzuki-Miyaura cross-coupling reactions (D).</figcaption></figure>

[a] M. A. Dridi, Dr. M. Hasyeoui, F. Lassagne, Dr. W. Erb, Prof. F. Mongin
Univ Rennes, CNRS,
ISCR (Institut des Sciences Chimiques de Rennes) – UMR 6226
F-35000 Rennes (France)
E-mail: florence.mongin@univ-rennes.fr

[b] M. A. Dridi, Dr. M. Hasyeoui, Prof. A. Samarat, Prof. S. Touil
University of Carthage, Faculty of Sciences of Bizerte
LR18ES11, Laboratory of Hetero-Organic Compounds and Nanostructured
Materials
Zarzouna, 7021 Bizerte (Tunisia)
E-mail: soufiane.touil@fsb.rnu.tn

[c] C. Piroud, T. Robert, Dr. S. Bach
Sorbonne Université, CNRS, UMR8227,
Integrative Biology of Marine Models Laboratory (LBI2 M)
Station Biologique de Roscoff
F-29680 Roscoff (France)

[d] C. Piroud, T. Robert, Dr. S. Bach
Sorbonne Université, CNRS, FR2424, Plateforme de criblage KISSf
(Kinase Inhibitor Specialized Screening facility)
Station Biologique de Roscoff
F-29680 Roscoff (France)

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Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202500080

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© 2025 The Author(s). European Journal of Organic Chemistry published by
Wiley-VCH GmbH. This is an open access article under the terms of the
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photophysical properties to materials containing them (Figure 1, C). In addition, 2,3-dihydro derivatives of these heteroaromatic compounds, featuring a chiral tertiary phosphine, have proved to be efficient ligands in asymmetric metal-catalysed reactions (Figure 1, D).[14]

In the framework of a project dedicated to the synthesis of oxazolo[5,4-f]quinoxaline analogues, we focused on the synthesis of structures A-C in which a pyridine or pyrazine ring is fused to a 1,3-benzoxa- or 1,3-benzazaphosphole, as well as on that of the related phosphine oxides D and E (Figure 2). Indeed, despite their potential interest in fields such as medicinal chemistry and organic materials, such compounds have, to our knowledge, never been prepared.

We report here on our efforts to synthesise these original polycyclic molecules.

## Proposed synthesis strategy

We have recently reported the regioselective iodination of quinoxalin-6-amine[15] and quinolin-6-amine[16] at position 5. We have rationalised these results using the amplitudes of the highest occupied molecular orbital (HOMO) coefficients and the distribution of charges on the C atoms of our substrates, both obtained using the HuLiS calculator.[17] As shown in Figure 3, quinolin-6-ol also appears to have HOMO coefficients and charges on C atoms in favour of regioselective reactions in position 5 with electrophiles.

We therefore planned to use these three substrates to access all the tricyclic structures A-E as follows. After iodination at C5, a cross-coupling reaction would introduce a phosphoryl group that could be converted to a primary phosphine if

<figure><img src="image_7.png" /><figcaption>**Figure 2.** [1,3]Oxaphospholo[4,5-f]quinoline (A), [1,3]azaphospholo[4,5-f]quinolines (B), [1,3]azaphospholo[4,5-f]quinoxalines (C), 2,3-dihydro-[1,3]azaphospholo[4,5-f]quinoline 1-oxides (D) and 2,3-dihydro-[1,3]azaphospholo[4,5-f]quinoxaline 1-oxides (E) targeted in the present study.</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>**Figure 3.** HOMO coefficients and charges on the C atoms of quinoxalin-6-amine (left), quinolin-6-amine (middle) and quinolin-6-ol (right).</figcaption></figure>

required. Finally, the phosphacycle could be constructed by reacting the hydroxy- or aminoquino(xa)line containing an appropriate phosphoryl group with a suitable electrophile (Figure 4).

## Attempted synthesis of [1,3]oxaphospholo[4,5-f]quinoline (A)

To prepare the required 5-iodoquinolin-6-ol (1), we first reproduced a protocol described by Greaney and co-workers who used $KI_3$ to iodinate the sodium salt of quinolin-6-ol.[18] However, in our hands, the expected iodinated product 1 was only isolated in a moderate 25% yield (Scheme 1, top). This led us to attempt the use of $I_2$ (2.5 equiv) in the presence of $NaHCO_3$ in a 4:1 dioxane-water mixture. Although this protocol is suitable for iodinating quinoxalin-6-amine at C5,[15] it only afforded 1 in 34% yield (Scheme 1, middle). We finally replaced $I_2$ with 4-(dimethylamino)-N-iodopyridinium iodide (1.1 equiv), a new green reagent recently proposed for aromatic regioselective iodination,[19] this allowed us to isolate 1 in 39% yield (Scheme 1, bottom). Taken together, these results suggest that the iodination of quinoxalin-6-ol is less straightforward than that of amines.

To introduce the phosphoryl group by cross-coupling, we relied on the copper-catalysed formation of phosphonates from aryl halides and dialkyl phosphites, a ligand-free reaction developed by Han and co-workers.[20] To this end, 1 was treated with diethyl phosphite and $Cs_2CO_3$ (2 equiv each) in the presence of Cul (10 mol%). After 12 h reaction in toluene at reflux, the phosphonate 2 was isolated in 41% yield (Scheme 2, left). Competitive formation of quinolin-6-ol (loss of the phosphoryl group) and diethyl 6-quinolyl phosphate (O-functionalisation of quinolin-6-ol), compounds identified by

<figure><img src="image_9.png" /><figcaption>**Figure 4.** Proposed synthesis strategy to access A-E from commercially available substrates.</figcaption></figure>

<figure><img src="image_10.png" /><figcaption>**Scheme 1.** The three protocols tested to iodinate quinolin-6-ol at its 5 position.</figcaption></figure>
<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /><figcaption>**Scheme 2.** Synthesis of 3 from 5-iodoquinolin-6-ol (1).</figcaption></figure>

NMR and HMRS, was noted, explaining both the moderate yield recorded and the tedious purification of 2.

In order to progress towards [1,3]oxaphospholo[4,5-f]quinoline (A), we needed to reduce 2 to the corresponding primary phosphine 3. While the reaction using (Me₂HSi)₂O (8 equiv) and Ti(OiPr)₄ (1 equiv) in toluene at reflux[21] for 5 h only led to degradation products,[22] 3 was obtained in 57% yield using LiAlH₄ in tetrahydrofuran (THF) at room temperature (rt)[23] (Scheme 2, right).

Access to unsubstituted [1,3]oxaphospholo[4,5-f]quinoline (A) represents a major challenge. Indeed, to our knowledge, compounds containing the 1,3-benzoxaphosphole unit have only been obtained substituted at C2.[24] Nevertheless, inspired by the synthesis of 1,3-benzazaphospholes,[25] we treated 3 with N,N-dimethylformamide (DMF) dimethyl acetal (1 equiv) in DMF at rt for 2 h or at 50 °C for 1 h. However, probably due to the instability of the primary phosphine 3 in these conditions, only a complex mixture was obtained.[26] In addition to quinolin-6-ol, we spotted a new phosphorus-containing compound in this mixture; however, its low stability hampered any purification attempt.

### Synthesis of [1,3]azaphospholo[4,5-f]quinolines (B)

These disappointing results prompted us to abandon our first objective and turn to the synthesis of original [1,3]azaphospholo[4,5-f]quinolines (B). To access the unsubstituted tricyclic heterocycle B1, 5-iodoquinolin-6-amine[16] was initially converted to phosphonate 4. While the conditions used to prepare 2 only gave the expected product in 27% yield, carrying out the reaction at a milder temperature of 80 °C for 72 h pleasingly provided 4 in a much better 91% yield (Scheme 3, left).

The reduction of 4 to the corresponding primary phosphine 5 was here successfully achieved using (Me₂HSi)₂O (8 equiv) and Ti(OiPr)₄ (1 equiv) in refluxing toluene for 5 h[21] (82%; Scheme 3, right). However, attempts to reach full conversion by extending

the reaction times led to the formation of quinolin-6-amine (loss of PH₂).[27]

To access B1, we first heated a solution of 5 in DMF dimethyl acetal at 80 °C for 6 h. However, under these conditions, we not only obtained the expected tricyclic compound (isolated in 63% yield) but also its N-methylated derivative B2 (37% yield; Scheme 4, top). Indeed, as well as being a formylation reagent, the electrophile released by heating DMF dimethyl acetal is also known to perform the methylation of NH-containing heterocycles.[28] It was pleasing to note that employing only one equivalent of acetal in DMF at 50 °C resulted in the quantitative formation of B1 after just 1 h (Scheme 4, bottom).

As the formation of 2-substituted 1,3-benzazaphospholes from 2-phosphinoaniline has already been reported, we also attempted the reaction of 5 with ethyl acetimidate hydrochloride (MeC(=NH)OEt·HCl; 1:1 equiv) in methanol at reflux for 12 h.[29] Although the formation of the expected derivative B (R=Me; R'=H) was observed, it proved impossible to isolate the pure product. We also attempted to react 5 with triphosgene (1 equiv) in CH₂Cl₂ containing Et₃N (1 equiv)[30] for 12 h at 50 °C, but observed no reaction.

We also evaluated the possibility to carry out a reaction between 5 and acyl chlorides. However, we soon discovered that the primary phosphine was not compatible with the conditions required for the formation of the phosphacycle B. Indeed, when 5 was treated with 3-methoxybenzoyl chloride (1 equiv) in the presence of K₂CO₃ (2 equiv) in MeCN at reflux,[25] we only observed the formation of N-(3-methoxybenzoyl)quinolin-6-amine and quinolin-6-amine. Switching 3-methoxybenzoyl chloride to nicotinoyl chloride allowed the target 2-substituted phosphacycle B (R=3-pyridyl; R'=H) to be formed. However, it was not possible to get a pure product due to the competitive formation of N-(nicotinoyl)quinolin-6-amine and N-(nicotinoyl)-5-phosphanyl-quinolin-6-amine.

Finally, reacting 5 with nicotinimidoyl chloride hydrochloride (1 equiv) in acetone containing Et₃N (1 equiv)[31] at rt (up to 24 h) only led to degradation products. The reduced nucleophilicity of the phosphino group, which is likely influenced by the presence of the π-deficient azine ring, could explain why these reactions did not meet success.

<figure><img src="image_13.png" /><figcaption>**Scheme 3.** Synthesis of 5 from 5-iodoquinolin-6-amine.</figcaption></figure>

<figure><img src="image_14.png" /><figcaption>**Scheme 4.** Conversion of 5 to the tricyclic compounds B1 and B2.</figcaption></figure>
<figure><img src="image_15.png" /></figure>

Synthesis of [1,3]azaphospholo[4,5-f]quinoxalines (C)

To synthesise the tricyclic heterocycles C, we first considered 5-iodoquinoxalin-6-amine[15] as starting material. As before, it was converted to the phosphonate 6, which was then reduced to the primary phosphine 7 (Scheme 5, top). As with 5, compound 7 was converted to either [1,3]azaphospholo[4,5-f]quinoxaline (C1; 95% yield) or its N-methylated derivative C2 (35% yield), depending on the reaction conditions (Scheme 5, bottom).

Inspired by a study reported in 2024,[32] we performed an NMR spectroscopic study of compound 7 in two different solvents, CDCl₃ and (CD₃)₂SO. The ¹H NMR spectra showed a significant change in chemical shift for the NH₂ group (4.60 ppm and 6.16 ppm, respectively) that could be due to stronger NH···O=S hydrogen bond in the latter solvent (no change for the PH₂ group). In addition, a difference was also observed in ³¹P NMR (with chemical shifts of −173 ppm and −167 ppm, respectively), suggesting different conformations in solution with ratios varying according to the nature of the solvent. A similar solvent dependence was observed for 3 in ³¹P NMR (chemical shifts of −174 ppm and −167 ppm, respectively).

To access derivatives C with an R group at C8, we then identified 3-chloro-5-iodoquinoxalin-6-amine[33] as a perfect starting material (Scheme 6). It was involved in a copper-catalysed cross-coupling reaction with diethyl phosphite to afford phosphonate 8, in turn reduced to the expected primary

phosphine 9. It should be mentioned that the chloro group was well tolerated in these two steps, but behaved as a leaving group in the subsequent conversion of 9 to 8-chloro-3-methyl[1,3]azaphospholo[4,5-f]quinoxaline (C3) using DMF dimethyl acetal as solvent. Indeed, in addition to the expected product (29% yield), the formation of the dimethylamino derivative C3' was also recorded (6% yield). To avoid this competitive substitution, the reaction was then carried out using only one equivalent of DMF dimethyl acetal in DMF at rt, affording 8-chloro[1,3]azaphospholo[4,5-f]quinoxaline (C4) in a better 52% yield.

[1,3]Azaphospholo[4,5-f]quinoxalines (C) are heterocycles closely related to oxazolo[4,5-f]quinoxalines, a family of compounds endowed with biological activities. We were therefore keen to evaluate the replacement of oxazole by [1,3]azaphosphole in the potent oxazolo[4,5-f]quinoxaline inhibitors of glycogen synthase kinase 3 (GSK-3) CD-07 and MH124[16] (Figure 5).

In order to progress towards [1,3]azaphospholo[4,5-f]quinoxalines bearing a suitable substituent at their position 8, C4 was treated with thiomorpholine (1.2 equiv) in the presence of iPr₂NEt (1 equiv) in DMSO at 80 °C for 18 h. However, while we were mainly expecting the substitution product C5, this was only obtained in an estimated 15% yield in a mixture containing several unidentified degradation products. In contrast, when the substitution reactions were carried out from phosphonate 8 using both thiomorpholine and the less nucleophilic thiazolidine, the expected 3-substituted derivatives 10 and 10' were isolated in yields of 69% and 42% respectively (Scheme 7, top). It should be noted that 10 was also prepared by a cross-coupling reaction between 5-iodo-3-(N-thiomorpholino)quinoxalin-6-amine[16] and diethyl phosphite (78% yield after a short optimisation; Scheme 7, bottom).

The reduction of 10 to the primary phosphine 11 was first attempted using (Me₂HSi)₂O (8 equiv) and Ti(OiPr)₄ (1 equiv) in toluene at reflux for 6 h.[21] However, slow conversion resulted in the formation of only 44% of the desired product. Interestingly, a slightly better yield (56%) was obtained using an excess of LiAlH₄ as reducing agent in THF at 10 °C for 20 min[23] (Scheme 8, top). However, employing an excess of iBu₂AlH (5 equiv at rt for 2 h and a further 5 equiv at 40 °C for 2 h)[34] did not lead to phosphonate reduction. The 8-substituted [1,3]azaphospholo[4,5-f]quinoxaline C5 was finally obtained in 30% yield under the same predefined conditions (Scheme 8, bottom).

<figure><img src="image_16.png" /><figcaption>Scheme 5. Synthesis of C1 and C2 from 5-iodoquinoxalin-6-amine.</figcaption></figure>

<figure><img src="image_17.png" /><figcaption>Scheme 6. Synthesis of C3 and C4 from 3-chloro-5-iodoquinoxalin-6-amine.</figcaption></figure>

<figure><img src="image_18.png" /><figcaption>**Figure 5.** Structures and kinase affinity against the two isoforms of GSK-3 of CD-07 and MH-124 (left) and planned phosphorus-containing analogues (right).</figcaption></figure>
<figure><img src="image_19.png" /></figure>

<figure><img src="image_20.png" /><figcaption>Scheme 7. Synthesis of the 3-substituted phosphonates 10 and 10'.</figcaption></figure>

<figure><img src="image_21.png" /><figcaption>Scheme 8. Synthesis of the 8-substituted [1,3]azaphospholo[4,5-f]quinoxaline C5.</figcaption></figure>

Despite the failure faced when **5** was treated with different electrophiles to obtain 2-substituted [1,3]azaphospholo[4,5-f]quinolines, we also studied the reactivity of the primary phosphines derived from quinoxalin-6-amine. Firstly, our efforts to react **7** with nicotinimidoyl chloride hydrochloride (1 equiv) in the presence of Et₃N (1 equiv),[31] whether in refluxing THF or in acetone at rt (6 to 24 h), only led to decomposition products.

The behaviour of such phosphines towards aldehydes was then studied. To this end, compound **9** was engaged in reactions with 3-pyridinecarboxaldehyde and phthalaldehyde (1 equiv) in the presence of 4-toluenesulfonic acid (15 mol%) in refluxing toluene.[35] However, these conditions allowing cyclocondensation in the case of 2-phosphhylanilines proved unsuitable here. Indeed, complex mixtures still containing the aldehyde were observed after 4 to 12 h of reaction. Furthermore, when compound **11** was treated in similar conditions with 3-pyridinecarboxaldehyde (1 equiv), only phosphine degradation was noticed (aldehyde recovered) after 12 h in toluene at reflux. These results could be attributed to a lower reactivity of the amine and phosphine functions of 5-phosphanylquinoxalin-6-amine (due to the presence of the diazine ring) when compared with 2-phosphhylanilines.

### Synthesis of 2,3-dihydro-[1,3]azaphospholo[4,5-f]quinoline 1-oxides (D) and 2,3-dihydro-[1,3]azaphospholo[4,5-f]quinoxaline 1-oxides (E)

To pursue our efforts to develop phosphorus analogues of CD-07 and MH-124, we next explored a pathway using C-H arylation to introduce a pyridine ring at C2 of [1,3]azaphospholo[4,5-f]quinoxaline (C1). This represents a major challenge as such reaction, to our knowledge, has never been reported. Nevertheless, inspired by the work of Bellina, Rossi and co-workers who carried out such a reaction on benzimidazole,[36] we treated C1 with 3-iodopyridine (2 equiv), Pd(OAc)₂ (5 mol%) and Cul (2 equiv) in DMF at 140 °C. However, after 16 h of reaction, the expected 2-substituted derivative was not identified and we only managed to isolate 1-(3-pyridyl)-2,3-dihydro-[1,3]azaphospholo[4,5-f]quinoxaline 1-oxide (E1; 16% yield). Under similar reaction conditions, the quinoline analogue D1 was also formed from B1 but could not be isolated (Scheme 9).

When B2 and C2 were engaged in similar reaction conditions, only traces of the related products D2 and E2 were formed while degradation was mainly observed. However, it is interesting to note that, in the case of N-substituted 1,3-benzazaphospholes, P-arylation has been optimised by Heinicke and co-workers in 2015.[37] Consequently, provided that D1 and E1 would behave as potent kinase inhibitors, it would be interesting to apply their optimised conditions (catalytic PdCl₂, 2 equiv CsOAc, DMF, 125 °C, overnight) to prepare the methylated analogues D2 and E2.

To reach additional D-type structures (R ≠ H), we investigated the synthesis of quinoline- and quinoxaline-5-phosphinates 12 and 13 from the corresponding iodides (Scheme 10, top and middle). Indeed, numerous palladium-catalysed cross-coupling reactions in the presence of tertiary amines have been reported from simple aryl iodides and alkyl phosphinates.[38] In the early 2000s, Montchamp and co-workers developed stable equivalents of H₃PO₂ such as anilinium hypophosphite (PhNH₃·OP(O)H₂),[39] their facile conversion to alkyl phosphinates using tetraalkyl orthosilicates,[39] as well as one-pot protocols combining this conversion with a palladium-catalysed P-arylation.[40] Curious as to whether these conditions could work in our case, we reacted 5-iodo-3-(N-thiomorpholino)quinoxalin-6-amine with PhNH₃·OP(O)H₂, Si(OEt)₄ and 1,4-diazabicyclo[2.2.2]octane (DABCO) (3 equiv each) in the presence of Pd(OAc)₂ and Ph₂P(CH₂)₃PPh₂ (2 mol% each) in toluene

<figure><img src="image_22.png" /><figcaption>Scheme 9. Formation of 1-(3-pyridyl)-2,3-dihydro-[1,3]azaphospholo[4,5-f]quinoline 1-oxide (D1) and 1-(3-pyridyl)-2,3-dihydro-[1,3]azaphospholo[4,5-f]quinoxaline 1-oxide (E1) from B1 and C1, respectively.</figcaption></figure>
<figure><img src="image_23.png" /></figure>

<figure><img src="image_24.png" /><figcaption>**Scheme 10.** Synthesis of the phosphinates 12 and 13 and Kabachnik-Fields reactions from 13 giving D3 and D4.</figcaption></figure>

at reflux for 12 h. While **12** was isolated in a low 12% yield (Scheme 10, top), no clear improvement was observed using an aminoalkoxysilane to facilitate the work-up and isolation of the product[40b] (15% yield). We repeated the reaction from 5-iodoquinolin-6-amine in MeCN and were able to isolate the expected product **13** in 23% yield (Scheme 10, middle). In both cases, the low yield was explained by the recovery of both the starting material and its deiodinated derivative.

Finally, Kabachnik-Fields reactions from **13**, using 4-(trifluoromethyl)benzaldehyde and pyridine-3-carboxaldehyde (1 equiv) in the presence of InCl₃ (10 mol%) in THF at reflux,[41] led to the 2-arylated 1-ethoxy-2,3-dihydro-[1,3]azaphospholo[4,5-f]quinoline 1-oxides **D3** and **D4** successfully (44% and 78% yields respectively; Scheme 10, bottom). Only decomposition products were obtained when similar reaction conditions were applied to aminophosphonate **12** using 4-(trifluoromethyl)benzaldehyde while starting material was recovered at rt. As mentioned previously, this probably results from the lower nucleophilicity of the amine due to the presence of the diazine ring.

## Activity as Protein Kinase Inhibitors

As the compounds obtained so far unfortunately do not contain both an aromatic ring at C2 and an aliphatic amine at C8, as initially expected (Figure 5), we finally planned to prepare three CD-07/MH-124 analogues that meet this criterion, although not containing a phosphacycle. Therefore, we reacted 8-chloro-2-(3-pyridyl)oxazolo[5,4-f]quinoxaline[16] with HP(O)(OEt)₂ and HP-(O)(OiPr)₂ (2.4 equiv) as reported previously[42] [5 mol% of Pd(OAc)₂, 10 mol% of 1,1'-bis(diphenylphosphino)ferrocene (dppf), 2.4 equiv of Et₃N, toluene, reflux, 2 h] and isolated the phosphonates F1 and F2 in good yields. In addition, F1 was dealkylated in mild conditions, as described previously,[43]

affording the corresponding phosphonic acid F3 in good yield (Scheme 11).

The compounds synthesized within this study were finally evaluated[44] against a panel of disease-related protein kinases: cyclin-dependent kinase 9 (CDK9/Cyclin T), proto-oncogene kinases PIM1 and PIM2, dual specificity tyrosine phosphorylation regulated kinase 1 A (DYRK1 A), Cdc2-like kinase 1 (CLK1), glycogen-synthase kinase-3 (GSK-3 isoforms α/β), mitotic kinase Haspin and vascular endothelial growth factor receptor 2 tyrosine-protein kinase VEGFR2 (Table 1).

Compared with MH-124, the introduction of a phosphorous atom led to a loss of affinity towards the kinases GSK-3 for most of our compounds. Compound F1 appeared to be the most promising, with good solubility and an affinity for GSK-3α similar to that of 8-unsubstituted 2-(3-pyridyl)oxazolo[5,4-f]quinoxaline.[16] For future work, it would be interesting to prepare analogues of D4 substituted at C8 by a cyclic aliphatic amine.

## Conclusions

In this study, our aim was to develop syntheses of quinoline and quinoxaline derivatives fused with phosphacycles. Although certain objectives could not be achieved, either due to stability issues or reduced reactivity of the primary phosphino and amino functions in the presence of the fused azine or diazine, it proved possible to construct [1,3]azaphospholo[4,5-f]quinolines and -quinoxalines, as well as 2,3-dihydro-[1,3]azaphospholo[4,5-f]quinoline 1-oxides and -quinoxaline 1-oxides.

The success we met during our four-step synthesis of [1,3]azaphospholo[4,5-f]quinolines and -quinoxalines is mainly due to the relatively good stability of our intermediate primary phosphines.[45] Horký, Pietschnig and co-workers demonstrated in 2023 a key role of singlet oxygen in the aerobic oxidation of primary phosphines, as well as the presence of singlet oxygen quenchers as a way to increase their air stability.[46] Phenols and, above all, anilines are known singlet oxygen quenchers,[47] and the presence of these functions in compounds 3, 5, 7 and 9 could inhibit their oxidation. In contrast, the presence of a sulfur-containing substituent (N-thiomorpholino) could reduce the stability of the phosphines, as previously observed.[46]

While the compounds obtained so far have not met our expectations in terms of bioactivity, this work has provided a

<figure><img src="image_25.png" /><figcaption>**Scheme 11.** Synthesis of F1 and F2 from 8-chloro-2-(3-pyridyl)oxazolo[5,4-f]quinoxaline and dealkylation of F1 to give F3.</figcaption></figure>
<table><caption>**Table 1.** Inhibitory activities (in black) of synthesized compounds against a panel of cancer-related protein kinases. The table displays the percentages of remaining kinase activity, detected after treatment with 10 µM (or 1 µM) of the tested compounds. Results are expressed in % of maximal activity, i.e. measured in the absence of inhibitor but with an equivalent dose of DMSO (solvent of the tested compounds). ATP concentration used in the kinase assays was 10 µM. Kinases are from human origin except when it is specified (Rn: *Rattus norvegicus*; Mm: *Mus musculus*).</caption><thead><tr><th>Kinase/Cpd</th><th>MH-124</th><th>B1</th><th>D1</th><th>D3</th></tr></thead><tbody><tr><td>CDK9/Cyclin T</td><td>20 (58)</td><td>73 (98)</td><td>[a] ([a])</td><td>94 (96)</td></tr><tr><td>PIM1</td><td>23 (71)</td><td>30 (60)</td><td>97 ([a])</td><td>94 (88)</td></tr><tr><td>PIM2</td><td>-</td><td>-</td><td>75 (96)</td><td>-</td></tr><tr><td>DYRK1A<sup>[b]</sup></td><td>2 (15)</td><td>48 ([a])</td><td>97 (73)</td><td>[a] ([a])</td></tr><tr><td>CLK1<sup>[c]</sup></td><td>-</td><td>78 ([a])</td><td>91 (96)</td><td>[a] ([a])</td></tr><tr><td>GSK-3α</td><td>3 (6)</td><td>73 (81)</td><td>[a] (89)</td><td>88 (85)</td></tr><tr><td>GSK-3β</td><td>7 (10)</td><td>90 (87)</td><td>[a] ([a])</td><td>88 (92)</td></tr><tr><td>Haspin</td><td>7 (27)</td><td>32 (84)</td><td>[a] ([a])</td><td>96 ([a])</td></tr><tr><td>VEGFR2</td><td>25 (84)</td><td>42 (78)</td><td>-</td><td>80 (86)</td></tr><tr><th>Kinase/Cpd</th><th>D4</th><th>E1</th><th>F1</th><th>F3</th></tr><tr><td>CDK9/Cyclin T</td><td>[a] (96)</td><td>[a] ([a])</td><td>99 ([a])</td><td>97 ([a])</td></tr><tr><td>PIM1</td><td>77 (78)</td><td>84 ([a])</td><td>63 (81)</td><td>85 (74)</td></tr><tr><td>PIM2</td><td>-</td><td>69 (68)</td><td>-</td><td>-</td></tr><tr><td>DYRK1A<sup>[b]</sup></td><td>[a] ([a])</td><td>78 (75)</td><td>32 (83)</td><td>59 (69)</td></tr><tr><td>CLK1</td><td>[a,c] ([a,c])</td><td>99<sup>[c]</sup> ([a,c])</td><td>65 ([a])</td><td>86 ([a])</td></tr><tr><td>GSK-3α</td><td>77 (74)</td><td>97 (99)</td><td>45 (93)</td><td>85 (96)</td></tr><tr><td>GSK-3β</td><td>78 (89)</td><td>[a] ([a])</td><td>56 (83)</td><td>[a] ([a])</td></tr><tr><td>Haspin</td><td>81 (84)</td><td>[a] ([a])</td><td>82 (81)</td><td>85 (84)</td></tr><tr><td>VEGFR2</td><td>67 (85)</td><td>-</td><td>89 ([a])</td><td>78 (77)</td></tr></tbody></table>

[a] ≥ 100. [b] RnDYRK1A. [c] MmCLK1.

better understanding of the reactivity of azinic and diazinic primary aminophosphines and could therefore open up new prospects in the field of phosphorus-based bioactive molecules or organic materials.

## Acknowledgements

F. L., W. E. and F. M. thank the "Comité d'Ille et Vilaine 35" de la Ligue Contre le Cancer, the Université de Rennes and the Centre National de la Recherche Scientifique for supporting this research. A. S. and S. T. gratefully acknowledges the Tunisian Ministry of Higher Education and Scientific Research for the financial support (grants for M. H. and M. A. D.). C. P., T. R. and S. B. thank the Cancéropôle Grand Ouest ("Marine molecules, metabolism and cancer" network), IBiSA (French Infrastructures en sciences du vivant : biologie, santé et agronomie) and Biogenouest (Western France life science and environment core facility network supported by the Conseil Régional de Bretagne) for supporting the KISSf screening facility (FR2424, CNRS and Sorbonne Université).

## Conflict of Interests

The authors declare no conflict of interest.

## Data Availability Statement

The data that support the findings of this study will be available from the corresponding author upon reasonable request.

Keywords: 1,3-azaphosphole · quinoline · quinoxaline · primary phosphine · kinase inhibitor

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Manuscript received: January 21, 2025

Revised manuscript received: February 18, 2025

Accepted manuscript online: February 18, 2025

Version of record online: ■■, ■■
RESEARCH ARTICLE

<figure><img src="image_27.png" /></figure>

Syntheses of quinoline and quinoxaline derivatives fused with phosphazycles were developed from commer-

cially available quinolin-6-amine and quinoxalin-6-amine.

M. A. Dridi, Dr. M. Hasyeoui, F. Lassagne, Dr. W. Erb, C. Piroud, T. Robert, Dr. S. Bach, Prof. A. Samarat, Prof. S. Touil*, Prof. F. Mongin*

1-9

**On the Synthesis of**
[1,3]Azaphospholo[4,5-f]quino(xa)lines and 2,3-Dihydro-[1,3]azaphospholo[4,5-f]quino(xa)line 1-oxides

<figure><img src="image_28.png" /></figure>