Modular, automated synthesis of spirocyclic tetrahydronaphthyridines from primary alkylamines

ABSTRACT Spirocyclic tetrahydronaphthyridines (THNs) are valuable scaffolds for drug discovery campaigns, but access to this 3D chemical space is hampered by a lack of modular and scalable

synthetic methods. We hereby report an automated, continuous flow synthesis of α-alkylated and spirocyclic 1,2,3,4-tetrahydro-1,8-naphthyridines (“1,8-THNs”), in addition to their

regioisomeric 1,6-THN analogues, from abundant primary amine feedstocks. An annulative disconnection approach based on photoredox-catalysed hydroaminoalkylation (HAA) of halogenated

vinylpyridines is sequenced in combination with intramolecular SNAr _N_-arylation. To access the remaining 1,7- and 1,5-THN isomers, a photoredox-catalysed HAA step is telescoped with a

palladium-catalysed C–N bond formation. Altogether, this provides a highly modular access to four isomeric THN cores from a common set of unprotected primary amine starting materials, using

the same bond disconnections. The simplifying power of the methodology is illustrated by a concise synthesis of the spirocyclic THN core of Pfizer’s MC4R antagonist PF-07258669. SIMILAR

CONTENT BEING VIEWED BY OTHERS DIRECT ACCESS TO SPIROCYCLES BY PD/WINGPHOS-CATALYZED ENANTIOSELECTIVE CYCLOADDITION OF 1,3-ENYNES Article Open access 27 September 2021 ACCESSING LADDER-SHAPE

AZETIDINE-FUSED INDOLINE PENTACYCLES THROUGH INTERMOLECULAR REGIODIVERGENT AZA-PATERNÒ–BÜCHI REACTIONS Article Open access 16 February 2024 MODULAR ACCESS TO CHIRAL BRIDGED

PIPERIDINE-Γ-BUTYROLACTONES VIA CATALYTIC ASYMMETRIC ALLYLATION/_AZA_-PRINS CYCLIZATION/LACTONIZATION SEQUENCES Article Open access 02 January 2024 INTRODUCTION Bicyclic compounds featuring

saturated _N_-heterocycles fused to (hetero)aromatic units are highly prized in medicinal chemistry1,2,3,4, offering a combination of polar functionality, high Fsp3-content, and rigidly

disposed groups on the aromatic core that can engage in key interactions with a protein target (e.g., H-bonds)5,6. Tetrahydronaphthyridines (THNs) are semi-saturated bicycles that ring-fuse

a piperidine with a pyridine—these in turn being the two most popular _N_-heterocycles deployed in small-molecule pharmaceuticals7,8. Positioning of the two THN nitrogen atoms generates

eight different structural isomers: four of which (1A–D) can be considered as CH → N bioisosteres of tetrahydroquinolines (THQs), and the remaining four (structures 2) as CH → N bioisosteres

of tetrahydroisoquinolines (THIQs) (Fig. 1a). The substitution of CH units for N atoms in (hetero)aromatic systems can impart orders of magnitude improvements in key physicochemical (e.g.,

solubility) and pharmacological parameters9, and synthetic strategies that could provide facile access to any THN isomer (e.g., 1A–D) would be highly enabling. Without a trivial naming

convention for THNs, we shall hereafter refer to structures 1 as “THNs” and their isomeric counterparts 2 as “THINs”10,11,12,13,14,15,16, by analogy to THQs and THIQs. Amongst other

applications17,18, THNs have found use as guanidine mimetics of the arginine binding motif in RGD-binding integrin inhibitors (e.g., 3)19,20. Scaffold morphing of quinolines to THNs can also

be an effective tactic to improve aqueous solubility, as exemplified during the development of the FGFR4 selective inhibitor Roblitinib (FGF401) 4 (Fig. 1b)21. Spirocyclisation of fused,

semi-saturated _N_-heterocycles is also emerging as a powerful design strategy for medicinal chemistry. When compared to their flat, all-aromatic counterparts, partial saturation and

installation of a spirocycle simultaneously increases Fsp3, reduces structural flexibility, and introduces alternative exit vectors for access to novel 3D chemical space22. In favourable

cases, this can lead to greatly enhanced potency, selectivity, solubility, and metabolic stability23,24. For instance, Pfizer have exploited a spirocyclic THN as the core of their MC4R

antagonist PF-07258669 5, which is currently in phase I clinical trials for the treatment of appetite loss (Fig. 1c)25. The spirocycle in 5 was rationally designed to enforce a

_cis_-relationship between the N–H bond and the adjacent N(sp2) lone pair, which is the optimal geometry for target binding but opposite to the (_trans_) conformer favoured in solution for

the non-constrained analogue. Despite the many opportunities for structural and physicochemical tuning that THNs can offer, their widespread adoption in early-stage drug discovery has likely

been hampered by their poor commercial availability, and the scarcity of THN synthesis approaches that are readily amenable to library generation. Other than the semi-hydrogenation of

naphthyridines26,27,28, which can present regio- and chemoselectivity challenges, several routes to THNs have been devised based on the annulation of 2-aminopyridines. These processes tend

to be relatively labour-intensive29,30, and whilst catalytic annulations do exist31,32, their functional group tolerance is low. Inverse electron demand, intramolecular, hetero-Diels-Alder

reactions of tethered imidazolyl33 or alkynyl34,35,36 triazines sequenced with N2 extrusion are also on record for THN synthesis, but the substrate syntheses require multiple steps.

Moreover, none of the above approaches are amenable to _spirocyclic_ THN synthesis. Another distinct strategy is to form THNs via the _N_-arylative cyclisation of γ-pyridyl amines, either by

intramolecular Pd-catalysed C–N coupling25,37,38, SNAr reactions37,38,39, or Chichibabin reactions40,41. γ-Pyridyl amines 6 can themselves be constructed via Sonogashira-hydrogenation

sequences25,41, _B_-alkyl Suzuki-Miyaura coupling40, or the SN2 ring-opening of cyclic sulfamidates 9 with _ortho_-lithiated halopyridines39 (Fig. 2a). Whilst these approaches can enable

access to spirocyclic THNs, the chemistry is not well suited to library synthesis, given the meagre commercial availability of α-(di)substituted propargylic amines (7), allylic amines (8),

or γ-hydroxy amines as starting materials. Yu and co-workers have developed a Pd-catalysed γ-C(sp3)–H arylation of primary alkylamines that can access γ-pyridyl amines, and applied this to a

single example of THN synthesis, but the amines amenable to this procedure are largely unfunctionalized and have limited commercial availability42. Recently, visible-light

photoredox-catalysed approaches have been reported by ourselves and Gaunt et al., respectively, for the modular synthesis of γ-aryl primary amines by the C–C bond-forming coupling of readily

available primary alkylamines 1037 or ketone-derived imines 1138 with styrenes. Between these two disclosures, four examples of spirocyclic 1,2,3,4-tetrahydro-1,8-naphthyridine synthesis

were showcased, proceeding via the SNAr cyclisation of (isolated) γ-pyridyl amines from the photoredox step. In this work, we show that photoredox-catalysed hydroaminoalkylation43,44,45

(HAA) of halogenated vinyl pyridines, followed by intramolecular _N_-arylation via SNAr, can be sequenced in continuous flow46,47,48,49,50,51,52,53,54,55,56 to enable an automated synthesis

of α-alkylated and spirocyclic 1,2,3,4-tetrahydro-1,8-naphthyridines (“1,8-THNs”) 13, in addition to their regioisomeric 1,6-THN analogues 14 (Fig. 2b). To access the corresponding 1,7- and

1,5-THN isomers—15 and 16, respectively—a photoredox-catalysed HAA step can be telescoped with a palladium-catalysed C–N bond formation. Altogether, this provides a highly modular approach

to four THN isomers 13–16 from a common set of unprotected primary amine starting materials 10, using the same bond disconnections. RESULTS AND DISCUSSION REACTION OPTIMISATION

Photoredox-catalysed hydroaminoalkylation (HAA) of 2-fluoro-3-vinylpyridine 17 with cyclohexylamine 10A gives γ-pyridyl amine 18A in 97% yield, and subjection of this purified material to

DIPEA (1.5 equiv) in DMF at 120 °C for 20 h delivers the corresponding THN 13A in 92% yield via intramolecular SNAr cyclisation37. In order to sequence these reactions together in continuous

flow, we transferred the chemistry to a Vapourtec R-series flow system equipped with a Uniqsis PhotoSyn LED photoreactor (420 nm LEDs, ~260 W radiant output power, 5-ml reactor coil) and a

high-temperature tube reactor (up to 250 °C). As per the batch procedure, the photoredox-catalysed HAA was initially carried out with 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile

(3DPA2FBN) as the photocatalyst, and tetrabutylammonium azide (Bu4N+N3–) as the hydrogen atom transfer (HAT) catalyst57,58. However, we found that Bu4N+N3– could be replaced with cheaper and

far less hygroscopic sodium azide (NaN3), which is soluble in DMF at 0.06 M. For the SNAr step, a temperature of 180 °C with _t_R = 20 min proved sufficient for complete conversion (see

Supplementary Table 1). By running both steps in sequence in continuous flow, an overall yield of 98% of spirocyclic THN 13A could be obtained from 2-fluoro-3-vinylpyridine 17 and

cyclohexylamine 10A as feedstocks (in a 1:1 ratio). This corresponds to a productivity of 2.20 mmol h–1 (445 mg h–1). AUTOMATED CONTINUOUS FLOW SYNTHESIS OF THNS FROM PRIMARY ALKYLAMINES

With an optimised continuous flow protocol in hand, we next sought to execute an automated library synthesis of ‘lead-like’5,59 THN products 13, using an autosampler to sequentially load

different amine substrates into the Vapourtec flow system. The same autosampler also serves as a fraction collector, into which the steady-state solutions of each product 13 are dispensed

(Fig. 3a and see Supplementary Data 1 for NMR spectra of all compounds). Each run using 1.50 mmol of the vinylpyridine substrate takes ~90 min, which corresponds to 16 compounds in a 24 h

period, or 40 compounds total over 60 h if all rack positions are utilised. Cyclic primary amines 10A–D of varying ring sizes were well tolerated, and amine 10E bearing benzylic C–H bonds

also participated smoothly. Various functionalities including free hydroxyl groups (13F, O), ethers (13G, K), thioethers (13H), carbamates (13I, J, P), and imidazoles (13Q) proved compatible

with the process. For amines bearing electronegative atoms attached to the β- or γ-carbon (10G–K, O, P), a slightly elevated temperature of 200 °C proved necessary in most cases to drive

the SNAr step to completion within the 20 min residence time. Strained four-membered ring substrates 3-amino-_N_-Boc-azetidine 10J and 3-aminooxetane 10K proved especially challenging for

the photoredox step, on account of their α-C–H bonds being strengthened by ring strain and inductive effects57; amine 10J for example gave only 49% yield of 13J, along with 46% of unreacted

10J. By increasing the stoichiometry of amines 10J and 10K to 3 equivalents, however, the valuable spirocyclic THNs 13J and 13K could be obtained in 80% and 61% yields, respectively.

Non-spirocyclic THNs are also readily accessible via this methodology; isopropylamine 10L was used, for example, to generate α,α-dimethyl-substituted THN 13L in 75% yield. For

α-monoalkylated amines (10M–Q), it proved necessary to use 3.0 equivalents of the amine substrate, to mitigate against the formation of undesired dialkylated products during the photoredox

α-C–H alkylation step37. As ethylamine 10M is a gas at ambient pressure, it was dispensed as a 2.0 M solution in THF, affording the simple α-methylated THN 13M in 36% yield. Ethanolamine 10O

and _N_-Boc ethylenediamine 10P also proved to be effective substrates, generating α-hydroxymethyl- and α-aminomethyl-substituted THNs 13O and 13P, respectively. We next sought to extend

our automated synthesis protocol to the formation of isomeric 1,2,3,4-tetrahydro-1,6-naphthyridines (“1,6-THNs”) 14, using 4-chloro-3-vinylpyridine 18 as a radical acceptor (Fig. 3b). Whilst

the chlorinated compound 18 is far easier to access than its 4-fluoropyridine-derived60 counterpart, the decreased SNAr reactivity of the C–Cl bond necessitated that the temperature of the

flow SNAr step be raised still further to 220 °C. Under these conditions, a small library of spirocyclic 1,6-THNs 14A–E could be prepared in 46–64% yield. GRAM-SCALE REACTION AND RESOLUTION

OF THN ENANTIOMERS To demonstrate the scalability of our THN synthesis in flow, we executed the reaction of 4-aminopiperidine substrate 10I on gram scale on a 5-ml reactor coil, delivering

1.85 g of spirocyclic THN 13I in 87% yield (equating to a productivity of 600 mg h–1) (Fig. 4a). Whilst these reactions inevitably produce racemic materials, resolution of the THNs via

chiral preparative HPLC provides convenient access to both enantiomers, as exemplified for THN 13N on a 520 mg scale (Fig. 4b and see Supplementary Figs. 4–8 for HLPC traces). ACCESS TO THN

DERIVATIVES WITH FUNCTIONAL HANDLES ON THE PYRIDINE RING Another important objective was to demonstrate further elaboration of the THN products on the pyridine ring. One strategy, which is

especially useful for C(6) functionalisation, is to carry out electrophilic halogenation or catalytic C–H borylation61 reactions (i.e., 19–21) (Fig. 5a). In order to access THNs 23 and 25

halogenated _ortho_ or _para_ to the pyridine nitrogen, we utilised vinyl pyridines 22 and 24, respectively, with the necessary chloro handles preinstalled. Using this strategy, the

C(7)-chloro THN 23 was isolated in 68% yield, and the C(5)-chloro THN 25 in 31% yield (Fig. 5b). The latter isomer was anticipated to be the most challenging, requiring the amine nucleophile

to distinguish between a _para_-chloro and an _ortho_-fluoro site of attack during the SNAr step39. Taken together, these strategies enable vector growth from any ring position on the fused

pyridine moiety of 1,8-THNs, which is likely to be of significant value for fragment-based drug discovery1,2,3,4. STEPWISE SYNTHESIS OF OTHER THN ISOMERS Varying the position of the

pyridine nitrogen atom in these spirocyclic THN scaffolds is another highly desirable objective from a medicinal chemistry standpoint9. Having already demonstrated an automated flow

synthesis of 1,8- and 1,6-THNs 13 and 14 from primary alkylamine feedstocks, we were motivated to develop a practical catalytic solution to access 1,7- and 1,5-THN isomers, based on the same

photoredox-catalysed HAA disconnection approach. With intramolecular _N_-arylation via SNAr no longer being feasible, we instead opted to carry out this key step using palladium catalysis.

Following a flow photoredox HAA of amine 10I with 3-chloro-4-vinylpyridine 26, γ-pyridyl amine 27 was isolated in 25% yield. The low yield in this case was traced to extensive polymerisation

side reactions, for which vinylpyridine 26 seems to be particularly prone. Subsequent cyclisation via a Buchwald-Hartwig C–N coupling then gave 1,7-THN 28 in 79% yield (Fig. 6a). An

analogous sequence using 3-chloro-2-vinylpyridine 29 gave 1,5-THN in an overall 47% yield over the two steps (Fig. 6b). APPLICATION TO THE SYNTHESIS OF PFIZER’S MC4R ANTAGONIST PF-07258669 5

Finally, we sought to apply our methodology to a concise synthesis of the spirocyclic THN core (35) of Pfizer’s MC4R antagonist PF-07258669 5, which was previously synthesised in 15 total

steps (11 steps LLS) (Fig. 7a)25. In our case, starting from commercially available 3-amino _N_-Boc pyrrolidine 32, a photocatalytic HAA reaction with vinylpyridine 33 in continuous flow

gave γ-pyridyl amine 34 (427 mg) in 79% yield. Attempted thermal SNAr cyclisation of 34 at 220 °C in a high-temperature tubular reactor (_t_R = 20 min) gave only 22% yield of THN 35,

indicating that the methyl substituent α- to the pyridine nitrogen deactivates this pathway. Fortunately, an intramolecular, palladium-catalysed Buchwald-Hartwig _N_-arylation process (as

used in the Pfizer route) proved more efficacious, delivering the spirocyclic THN core 35 in 84% yield (Fig. 7b). Taking into account a 3-step synthesis of vinyl pyridine 33, the longest

linear sequence is five steps. The industrial route, whilst 11 steps in the longest linear sequence, is enantioselective, compared to a racemic synthesis in our case. Nevertheless, this

illustrates how dramatically the synthesis of complex spirocyclic amines can be streamlined when using a photoredox annulation strategy from unprotected amines57. CONCLUSION In summary, we

have developed an automated, continuous flow synthesis of α-alkylated and spirocyclic 1,2,3,4-tetrahydro-1,8-naphthyridines (“1,8-THNs”), in addition to their regioisomeric 1,6-THN

analogues, from abundant primary amine feedstocks. An annulative disconnection approach based on photoredox-catalysed hydroaminoalkylation (HAA) of halogenated vinylpyridines is sequenced in

combination with intramolecular SNAr _N_-arylation. To access the remaining 1,7- and 1,5-THN isomers, a photoredox-catalysed HAA step is telescoped with a palladium-catalysed C–N bond

formation. Altogether, this provides a highly modular access to four isomeric THN cores from a common set of unprotected primary amine starting materials, using the same bond disconnections.

The simplifying power of the methodology is illustrated by a concise synthesis of the spirocyclic THN core (35) of Pfizer’s MC4R antagonist PF-07258669 (5). METHODS A general procedure for

the flow chemistry protocol described in Fig. 3 can be found in Supplementary Methods (pages S4–5), plus photographs and schematics of the setup in Supplementary Figs. 1–3. Representative

procedure for the automated continuous flow synthesis of 1,2,3,4-tetrahydro-1,8-naphthyridine (13a): following the General Procedure (pages S4–5), 5 ml of reagent feed A

[2-fluoro-3-vinylpyridine 17 (185 mg, 1.50 mmol, 1.0 equiv) and 3DPA2FBN (9.6 mg, 15.0 μmol, 1 mol%) in anhydrous DMF], 5 ml of reagent feed B [cyclohexylamine 10A (149 mg, 1.50 mmol, 1.0

equiv) and NaN3 (19.5 mg, 300 μmol, 20 mol%) in anhydrous DMF], and 10 ml of reagent feed C [DIPEA (291 mg, 2.25 mmol, 1.5 equiv) in anhydrous DMF] were reacted in flow, setting the

high-temperature tube reactor to 180 °C. The steady-state mixture (10 ml) was collected and concentrated in vacuo on an Asynt spiral evaporator. Purification via automated flash column

chromatography on SiO2 gel (12 g) in 40–60 °C petroleum ether (5 CV) then 100:0 → 0:100 40–60 °C petroleum ether–EtOAc (over 20 CV) then EtOAc (5 CV) gave 13A as a colourless, crystalline

solid (149 mg, 98%, productivity = 2.20 mmol h–1). DATA AVAILABILITY Detailed experimental procedures and characterisation of compounds can be found in Supplementary Methods in the 

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Scholar  Download references ACKNOWLEDGEMENTS This work was supported by the Engineering and Physical Sciences Research Council (EP/X026566/1). A.J.C. thanks the Royal Society for a

University Research Fellowship (UF150533), the University of Bath for a Global Doctoral Scholarship (Q.C.) and both AstraZeneca and UCB for generous financial support. The authors gratefully

acknowledge the technical staff within Chemistry at the University of Bath for technical support and assistance in this work, including the Material and Chemical Characterisation Facility

(MC²) (https://doi.org/10.15125/mx6j-3r54). We also acknowledge Dr Michelle Garnsey at Pfizer for helpful discussions. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Chemistry,

University of Bath, Claverton Down, Bath, BA2 7AY, UK Qiao Cao, Joshua D. Tibbetts & Alexander J. Cresswell * Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge, CB4 0WG, UK

Gail L. Wrigley * UCB, 216 Bath Road, Slough, SL1 3WE, UK Adam P. Smalley Authors * Qiao Cao View author publications You can also search for this author inPubMed Google Scholar * Joshua D.

Tibbetts View author publications You can also search for this author inPubMed Google Scholar * Gail L. Wrigley View author publications You can also search for this author inPubMed Google

Scholar * Adam P. Smalley View author publications You can also search for this author inPubMed Google Scholar * Alexander J. Cresswell View author publications You can also search for this

author inPubMed Google Scholar CONTRIBUTIONS A.J.C. designed and supervised the project, with additional input and supervisory support provided by G.L.W. and A.P.S. Q.C. planned and carried

out all of the experimental work, with the exception of the syntheses of compounds 29 and 30, which were prepared by J.D.T. A.J.C. wrote the manuscript with assistance from the other

co-authors. CORRESPONDING AUTHOR Correspondence to Alexander J. Cresswell. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. PEER REVIEW PEER REVIEW

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CITE THIS ARTICLE Cao, Q., Tibbetts, J.D., Wrigley, G.L. _et al._ Modular, automated synthesis of spirocyclic tetrahydronaphthyridines from primary alkylamines. _Commun Chem_ 6, 215 (2023).

https://doi.org/10.1038/s42004-023-01012-2 Download citation * Received: 13 July 2023 * Accepted: 22 September 2023 * Published: 04 October 2023 * DOI:

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