Alkynyl Halo-Aza-Prins Annulative Couplings

This article is a comprehensive report describing our studies in the field of aza-alkynyl Prins chemistry, comparing and contrasting the different reaction partners and reactivities observed during method development. The synthetic strategies combine an alkynyl aza-Prins coupling with an annulation, enabling the preparation of different nitrogen-containing heterocycles. Different iminium ions are explored as viable electrophiles for an alkynyl Prins cyclization, terminated by capture with a halogen nucleophile to form a vinyl halide. The synthetic utility of this functional handle is exploited through a number of Suzuki cross-couplings, allowing for the preparation of a modest library of compounds. In most cases, the Prins couplings are highly selective for the vinyl halides with E geometry, resulting from anti-addition across the alkyne.


■ INTRODUCTION
The alkynyl aza-Prins cyclization allows for the rapid generation of molecular complexity from simple starting materials. 1A wide range of methods have been developed to promote the efficient Prins reaction of alkynes with different reaction partners.Alkyl amines (Scheme 1A), 2 alpha-cyanoamines, 3 hemiaminals (Scheme 1B), 4−10 and sulfonamides (Scheme 1C). 17−22 have all been employed as iminium ion precursors.
The Overman group has spearheaded research in the field of the alkynyl aza-Prins cyclization of secondary or tertiary alkylamines. 2,3These reactions are often difficult due to the basic nature of the electron-rich nitrogen center, which explains the harsh conditions needed for cyclization.Scheme 1A shows an example of these reactions with a secondary benzylamine 1 in the presence of camphorsulfonic acid (CSA) or tosylic acid (TsOH), and an excess of sodium iodide (NaI), to afford adducts like 3 via iminium 2. 2 A number of reports have also described cyclizations of alkynes and N-acyliminium ion electrophiles.These often start with hemiaminals like 4, which can be dehydrated to form the electrophilic N-acyliminium intermediate 5.The subsequent alkynyl Prins cyclization then gives products like 6 in the presence of a halide nucleophile, 4−7 or 7 upon hydrolysis 8−10 (Scheme 1B).
N-Sulfonyl iminium ions are the last class of electrophiles that have been employed in alkynyl aza-Prins chemistry.In these cyclizations, sulfonamide reactants are leveraged for the preparation of functionalized pyrazoles, 11 indoles, 12 indolines, 13 and piperidines. 14,15Recently, a report by Hou et al. shows the use of bromotrimethylsilane (TMSBr) to promote the reaction of a sulfonamide 8 and a carbonyl coupling partner 9 to make tosyl-piperidines like 11 via N-tosyl iminium intermediate 10 (Scheme 1C).
In this paper, we provide a comprehensive report of our work in the field of alkynyl aza-Prins cyclization. 16These studies were informed by our previous work on reaction cascades initiated by analogous alkynyl oxa-Prins cyclizations. 17,18Specifically, we have developed the first aza-Prins coupling of primary amines with benzaldehyde derivatives for the synthesis of functionalized quinazolinones, via an Nacyliminium intermediate.We also showcase conditions for the alkynyl aza-Prins cyclization of a phthalimide-derived Nacyliminium electrophile, allowing for the synthesis of functionalized isoindolones.Finally, we explore the coupling of aliphatic aldehydes with sulfonamides to generate N-tosyl iminiums capable of undergoing an alkynyl aza-Prins cyclization, resulting in the preparation of tosyl-piperidines.Through comparison of these different cases, we offer insights related to reactivity and conditions optimal for achieving the three types of cyclizations.
Regarding the specifics of the proposed mechanism for these cyclizations, the body of previous work on oxa-and aza-alkynyl Prins cyclizations offers plenty of data, but no consensus, on whether the reaction proceeds through a discrete vinyl cation intermediate (a stepwise process), or involves simultaneous cyclization and halide capture (a concerted process).In alkynyl alternative, gives 16a in 81% yield (entry 4).Cyclizations using other halide sources (Et 4 NBr, LiCl, and LiF) are less efficient, with low yields and complex mixtures observed.Overall, iodide sources give the best results, and we settled on NaI as the halide source for the rest of the study.Fifteen equivalents of AcOH give optimal yields of the vinyl halide product 16a and minimize the formation of undesired vinyl acetate 16b, which becomes more favored at higher acetic acid concentrations.When the amount of acetic acid is reduced, reactions become sluggish and take over 24 h to go to completion.
With these optimized conditions, a few experiments exploring the scope were performed (Scheme 3).As seen in the optimization Table 1, the reaction of benzaldehyde 13a and amine 15a results in the formation of aza-Prins adduct 16a in 81% yield.A 3-chlorobenzaldehyde produces 16c in good yield.As expected, a comparison of the results for 16d and 16e shows that better results are obtained with sodium iodide, relative to sodium bromide.Not surprisingly, a drop in yield is observed in the formation of 16f, in which the carbamate is deactivated by the methoxy substituent.The enyne 15a employed for the synthesis of 16a−f has a 4.6:1 E/Z isomer ratio, and both isomers engage in the Prins cyclizations.The E/Z ratios of 16a-f range from 3.1:1 to 7.5:1, depending upon the degree of isomerization during the cyclization, and whether the isomers can be separated during purification.The pyrrolidine adduct 16g is produced in only 13% yield.The arenyne reactant 15c engages to afford a modest yield of 16h.The corresponding azepine adduct 16i is not observed at all, amid a complex mixture of undesired products.
The proposed mechanism for this reaction is shown in Scheme 4. Condensation of amine 15 and aldehyde in 13 generates imine I.The imine then adds to the carbamate group, releasing methanol and forming N-acyliminium II. 20,21lectrophile II then undergoes alkynyl Prins cyclization to form the final quinazolinone product 16.

The Journal of Organic Chemistry
Continuing to explore primary enyne amine coupling partners, the isopropyl aldehyde reactant delivers ammonium salt 16j using the optimized conditions in 92% crude yield (eq 1), although the product is unstable and decomposes upon isolation.
Aza-Prins Cyclization of Phthalimide Derivatives.The first study of alkynyl aza-Prins reactions conducted in our lab involved phthalimide-derived alkynes 17. 16 As shown in Scheme 5, halotrimethylsilane reagents work well for arenyne-derived substrates 17a−l.Adducts 18, 19, and 20, containing vinyl chloride, bromide, and iodide moieties, respectively, can all be synthesized in good yield.Six-and seven-membered rings form smoothly, while five-membered rings do not.Alkyne 19l, with a methyl substituent at the carbon next to the nitrogen, cyclizes to afford 19l with moderate diastereoselectivity (6:1 dr).The E isomer is formed exclusively in cyclizations that form six-membered rings unless the system is unusually hindered or electron-releasing (19e and 19i).Seven-membered rings are obtained as E/Z mixtures.Both steric and electronic factors seem to influence the selectivity.
Alongside this cyclization study of arenyne-linked phthalimide derivatives 17a−l, we evaluated enyne-linked reactants 17m−q.In contrast to the arenynes, Bi(III) halide salts are optimal promoters for the enyne cyclizations. 22Yields are higher for di-and trisubstituted alkenes, compared to the terminal enyne 19o (Scheme 6).The Journal of Organic Chemistry Finally, we tested cyclization onto the N-acyliminium ion intermediate generated from succinimide-derived reactant 17r.Scheme 7 shows that the developed conditions delivered 19r in good yield.
Alkynyl Aza-Prins Annulation with Sulfonamides.In order to develop methods complementary to our previous work on alkynyl oxa-Prins cyclizations, 17 we chose to target Nsulfonyl iminium electrophiles as intermediates in the intramolecular alkynyl aza-Prins reaction.Table 2 summarizes some of our efforts for optimizing the aza-Prins cyclization.
The conditions that were developed for primary amines (see Table 1) do not promote cyclization of the corresponding sulfonamides 21a (entry 1).Using CSA in water, in the presence of a halide ion 2c leads to decomposition upon heating to 100 °C and no reaction at lower temperatures.Catalytic FeCl 3 in the presence of TMSCl 14b gives the halo-aza-Prins product in low yields.
As we were working on developing conditions for these cyclizations, Hou and co-workers reported using TMSBr in benzene to promote a similar aza-Prins reaction. 15Application of this TMSBr protocol delivers 59% of aza-Prins product 23a.Switching solvents to toluene and keeping the reaction at −20 °C leads to an improved yield of 23a (75%; Scheme 8).
Using these optimized conditions, the scope of the alkynyl Prins annulation was explored (Scheme 8).Isobutyraldehyde  outperforms all other aldehydes examined, giving access to Prins adducts 23a−c,f−i.Both enynes and arenynes perform with comparable efficiency under these conditions.Using enyne 21a with a 4.1:1 E/Z isomer ratio results in the formation of tosyl-piperidine 23a in a 4:1 E/Z mixture, suggesting that alkene isomerization during annulation is minimal.The reaction of an enyne with a shorter tether is problematic, giving low yields of tosyl pyrrolidine 23c and complex mixtures.It is not possible to prepare the azepine Prins adduct 23d under these conditions�only a complex mixture is observed.An alpha-methyl substituent slows reaction rates dramatically and, after heating to 40 °C for 3 days, only 28% of 23g was obtained as a 7:1 mixture of diastereomers.Notably, the stereochemical relationship of the methyl and isopropyl substituents was assigned as anti by NOESY (see Supporting Information). 23This outcome was quite surprising because a wealth of literature reports document the formation of oxa-Prins cyclization products with syn disposition of substituents. 18,24Aldehydes with a tethered arene nucleophile react to afford products 23i−k, and we note that reactions need to be kept colder for better yields.Adducts 23j and 23k afford E/Z mixtures, whereas 23i is isolated as a single E isomer, albeit in lower yield.
To rule out thermodynamic equilibration as the origin of the E/Z mixtures, the major isomer (E olefin) of 23k was isolated by column chromatography and resubjected to the reaction conditions.After 16 h, no change was observed by 1 H NMR, indicating that the alkynyl aza-Prins reaction is irreversible and therefore kinetically controlled.
Cross-Coupling of Aza-Prins Coupling Products.Prins adducts 23 can be further functionalized via Suzuki crosscouplings to give access to more diverse libraries of compounds (Scheme 9).After screening a few different sets of conditions, we found that SPhos, in combination with palladium acetate, potassium carbonate, and the corresponding aryl boronic acid, can afford products 24 after heating to 110 °C.Electron-neutral, rich, and deficient aryl boronic acids work well under these Suzuki conditions to afford products 24a−c from arenyne-derived Prins adduct 23f.Enyne-derived Prins adducts 23b and 23a also react cleanly to afford Suzuki products 24d−g and 24h,i, respectively.
The E geometry was retained in most cases, except cases with electron-deficient boronic acids (24g and 24h).Crosscouplings of ethyl boronic acid, as well as pyridine and pyrimidine boronic acids, did not afford the corresponding cross-coupled products.

■ SUMMARY
The three variants of the alkynyl aza-Prins reaction have been developed as versatile methods for the synthesis of Nheterocycles containing a vinyl halide functional handle.We describe the construction of three different heterocyclic systems: quinazolinones from coupling primary amines (with pendent alkyne) with o-formyl carbamates, isoindolones from hemiaminals derived from phthalimide, and N-tosyl-piperidines from coupling of sulfonamides and aliphatic aldehydes.All cyclizations produced adducts with a vinyl halide functional handle, and we show that these can participate in Suzuki crosscoupling reactions.
While all variants of the alkynyl aza-Prins annulation generate piperidine ring systems smoothly, the success of five-and seven-membered ring formation varies widely.Low yields are consistently observed in the formation of pyrrolidine derivatives 16g (Scheme 3), 18k (Scheme 5), and 23c (Scheme 8).For the longer tether, while no cyclization is observed at all in two cases (16i; Scheme 3 and 23d; Scheme 8), the target azepine is formed in very good yield with the phthalimide-derived N-acyliminium electrophile (18j−20j, Scheme 5).While yields are unaffected by tether length, the E/Z selectivity in these cyclizations is significantly diminished, presumably because the typically favorable anti-addition pathway is compromised by the geometry of the larger ring.Notably, the corresponding cyclizations in the alkynyl oxa-Prins series are reasonably efficient: both the five-and sevenmembered ring targets are formed in good yields.17a A number of different combinations of promoter/halide sources have proved effective for carrying out alkynyl halo-aza-Prins cyclizations.For primary amine annulations, sodium halides combined with acetic acid are optimal, whereas the dehydrative cyclizations of phthalimide-derived hemiaminals are accomplished using either halotrimethylsilanes (TMSX) or bismuth trihalide reagents (BiX 3 ).TMSX performs better for arenyne hemiaminals, while BiX 3 salts work better for enyne hemiaminals.For annulations of sulfonamide reactants, TMSX is best.The combination of protic acid (TfOH or Tf 2 NH) and tetrabutylammonium salts, which are the conditions of choice in our alkynyl halo-oxa-Prins cyclizations, 17 do not give good results in the halo-aza-Prins context.Regarding halide ion Scheme 9. Suzuki Arylation of the Vinyl Halide The Journal of Organic Chemistry addition, iodide works best for the carbamate-derived iminium (Scheme 3), whereas chlorine, bromide, and iodide all perform well in the phthalimide-derived version of the reaction.Iodide was not tested in the sulfonamide annulations.In alkynyl oxa-Prins chemistry, 17 bromide and iodide are both competent, whereas chloride is not as efficient.
The E isomer dominates in every aza-Prins cyclization scenario we examined, consistent with previous reports on alkynyl Prins cyclizations.24a, 25 In the o-formyl carbamate annulations (Scheme 3), E/Z selectivity is moderate, whereas many of the cyclizations of phthalimide-derived iminium ions (Scheme 5) and sulfonyl iminium ions (Scheme 8) generate E isomer only (Scheme 5).This E isomer could result from either a concerted reaction pathway (anti-addition across the alkyne) or a stepwise one involving a vinyl cation intermediate.It was determined by experiment that the alkynyl halo-Prins cyclization is not reversible, meaning that E/Z mixtures are generated through a kinetic process.Therefore, a vinyl cation intermediate is implicated in cyclizations where the Z isomer is observed.

■ CONCLUSIONS
These findings contribute to the expanding toolkit of synthetic chemists and hold significant promise for the synthesis of diverse nitrogen-containing compounds with potential applications in medicinal chemistry and drug discovery.
■ EXPERIMENTAL SECTION General Remarks.All reactions were carried out under an argon atmosphere in flame-dried glassware with magnetic stirring.Syringe needles used to dispense solvent were not flame-dried.Reagents were used as obtained from commercial suppliers without further purification.Tetrahydrofuran (THF), diethyl ether (Et 2 O), methylene chloride (DCM), 1,2-dichloroethane (DCE), and toluene (PhMe) were purchased from Fisher and dispensed using the Glass Contour solvent purification system.1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) was purchased from Oakwood Chemicals and used without further drying (bottle stored in a desiccator after opening).Celite 545 was purchased from EMD. ACS-grade hexanes, toluene, ethyl acetate, and DCM were used for column chromatography.Thin-layer chromatography (TLC) was performed on precoated silica gel 60 F254 glasssupported plates from EMD, and visualization was performed with a UV lamp followed by staining with p-anisaldehyde solution followed by heating.Column chromatography was carried out on EM Science silica gel (60 Å pore size, 230−400 mesh).Preparatory TLC (prep-TLC) was carried out using Analtech Uniplate F254 Prep-20 × 20 cm TLC plates.Deuterated chloroform was purchased from Cambridge Isotope Laboratories.For reactions that required heating, an oil bath was employed.
1 H NMR spectra were recorded at room temperature on a 400 MHz Bruker AVANCE spectrometer or a 500 MHz Bruker AVANCE spectrometer.Chemical shifts are given in parts per million (ppm) referenced to solvent residual proton resonance (δ = 7.26 for CHCl 3 ).NMR data are reported as chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dq = doublet of quartets, and br = broad), coupling constants (J) given in Hz, and integration.In those cases where two stereoisomers are present, and the ratio is greater than 3:1, only chemical shifts from the major stereoisomer are listed.For these cases, a characteristic peak from both major and minor stereoisomers is given, with proton integrations, from which the ratio of stereoisomers can be extrapolated.
24a,25 13 C NMR spectra were recorded at room temperature unless otherwise stated on a 125 or 101 MHz Bruker AVANCE spectrometer with proton decoupling.Chemical shifts are given in parts per million (ppm) from referenced to solvent carbon resonance (δ = 77.0 for CHCl 3 ).In cases where two stereoisomers are present in greater than a 2:1 ratio, only chemical shifts from the major stereoisomer are listed.For these cases, a characteristic peak from both major and minor stereoisomers is given, with proton integrations, from which the ratio of stereoisomers can be extrapolated.In cases where two stereoisomers are present in less than a 2:1 ratio, all peaks are listed.For spectra where the solvent residue is present, yields were obtained after placing the sample under vacuum and bringing it to a constant weight.High-resolution mass spectra (HRMS) were measured at the University of Rochester Mass Spectrometry Resource Lab.Measurements were performed using a Thermo QExactive Plus hybrid quadrupole-Orbitrap mass spectrometer, and the scans were performed using the Orbitrap.X-ray crystallography data were collected by Dr. William W. Brennessel at the X-ray Crystallographic Facility of the University of Rochester, Rochester, NY 14627 (USA).The instrumentation used was a Rigaku XtaLab Synergy-S Dualflex diffractometer with a HyPix-6000HE HPC area detector at 100 K.
General Procedures.The benzaldehydes 13 were prepared from the corresponding 2-aminophenyl benzoic acids: (1) reduction of the corresponding carboxylic acid to the benzyl alcohol was done with conditions from Zhao et al., 26 (2) aniline protection to carbamate was done using conditions from Mei et al., 27 and (3) reoxidation of the benzyl alcohol was done with conditions from Chong et al. 28 Amines 15 were synthesized using the procedures below: Mitsunobu with phthalimide and 4-pentyn-1-ol: 29 To a flask purged with argon and equipped with a stir bar, 4pentyn-1-ol (1.0 g, 1 equiv), phthalimide (1.3 equiv), PPh 3 (1.3 equiv), and dry THF (125 mL) were added.The flask was brought to 0 °C, and DIAD (1.3 equiv) was added dropwise.The reaction mixture was let to be stirred for 3.5 h at room temperature until completion and monitored by TLC (usually using 20% EtOAc/ hexanes as the eluent).The reaction mixture was diluted with water (125 mL) and extracted with hexanes (3 × 125 mL).The combined organic was washed with brine (125 mL) and concentrated via rotary evaporation.The crude was purified by column chromatography, eluting with 0−20% EtOAc/hexanes.Product spectra match literature precedent.
The alkynyl phthalimide above was cross-coupled to the desired vinyl group using a Sonogashira cross-coupling. 17,18Then, deprotection was performed using previously reported conditions 28 to afford the amines 15, which required no further purification.

Table 2 .
Optimization of Alkynyl Aza-Prins Reaction with Sulfonamides Benzyl-protecting group used instead of tosyl.c 10.0 equiv of NaI used as halide source.d 1.0 equiv of TMSCl used as halide source.e Complex mixture of products observed.
a 4.0 equiv of TBAI used as halide source.b a Reaction done at 0 °C.b Reaction heated to 40 °C for 3 days.c Reaction done at −40 °C.