HETEROCYCLES

Paper | Regular issue | Vol. 92, No. 12, 2016, pp. 2166-2200
Received, 1st September, 2016, Accepted, 21st October, 2016, Published online, 10th November, 2016.

■ Strategic and Tactical Approaches to the Synthesis of 5,6-Dihydro-[1,2,4]oxadiazines

Johan J. N. Veerman,* Yorik B. Bruseker, Bart C. J. van Esseveldt, Rebecca Glen, Bryce A. Harrison, Erik H. Heijne, Andrew J. McRiner, Tommi M. Meulemans, Peter van Rijnsbergen, Wim Zonneveld, Matthew G. Bursavich,* and Duane A. Burnett

Department of Chemistry, Mercachem B.V., Kerkenbos, 1013, Nijmegen 6546BB, Netherlands

Abstract

Three methods were developed for the synthesis of substituted 5,6-dihydro-4H-[1,2,4]oxadiazines. The desired oxadiazine rings were synthesised via reductive amination, addition to an iminium ion intermediate and by condensation of a diamine with an imidate. For all methods the scope with respect to the substituents that could be introduced was explored. It was found that the imidate condensation route was the most versatile and the products could be isolated in yields up to 91%. This route is also suitable for the introduction of chirality on the C5 and C6 position of the oxadiazine rings.

introduction
Small heterocycles are important structures in pharmaceuticals and other bioactive compounds, as they provide a central scaffold around which substituents can be placed in a well-defined manner to probe the biological activity.1 Therefore, the development of efficient and general methodology to access these heterocyclic scaffolds is an important endeavour.2 As part of a medicinal chemistry program, the synthesis of 3,5-biaryl substituted 5,6-dihydro-4H-[1,2,4]oxadiazines was of interest. This heterocyclic scaffold has an already established pharmaceutical relevance and is for example present in a non-ATP-competitive MK2 inhibitor (1, Figure 1) to treat inflammatory diseases such as arthritis.3 In addition, it has been used as a central scaffold in a lead compound for the treatment of Alzheimer’s disease (2)4 and in BRX-235 (Iroxanadine, 3), a drug which acts as a potent cardioprotective agent.5

A survey of the literature reveals a few early examples on the synthesis of 5,6-dihydro-4H-[1,2,4]oxadiazines.6 However, to the best of our knowledge, the first report in this field was contributed by Rajagopalan and Talaty.7 They developed a two-step procedure in which an 1-aroylaziridine oxime undergoes ring-opening by hydrochloric acid, followed by a cyclization of the intermediate chloride under alkaline conditions. This strategy proved to be a useful synthetic method and was further elaborated by other groups.8, 9 A modification of this approach was reported by Cho et al. who used the Lewis acid scandium(III) triflate in combination with chlorotrimethylsilane to promote ring opening and cyclization of aziridin-1-yl oximes to 5,6-dihydro-4H-[1,2,4]oxadiazines.10 Tabei and co-workers reported the synthesis of a mixture of geometrical isomers of 3-aryl-5-ethoxycarbonylmethylene-5,6-dihydro-4H-[1,2,4]oxadiazine derivatives via reaction of benzamide oximes with bromoacetoacetyl bromides.11 Other approaches involve the reaction of aliphatic nitro compounds and acetyl chloride with β-diketones leading to tri-substituted [1,2,4]oxadiazine derivatives12 and the condensation of benzamidoximes with glyoxal to furnish 3-aryl-trans-5,6-dihydroxy-5,6-dihydro-4H-[1,2,4]oxadiazines.13 More recent examples for the synthesis of the oxadiazine scaffold include ring expansion of fluorooxazolines with hydroxylamine hydrochloride,14 and cyclo-condensation reaction of mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates with hydroxylamine.15
For our purposes we needed an approach where the substituent on the 5 position could be selectively introduced and easily modified. Based on a retrosynthetic analysis, three routes to the target oxadiazines were devised (Scheme 1).

The first route comprises a novel intramolecular reductive amination. The second route features a nucleophilic addition onto an in situ generated iminium ion. Additions to (N-acyl)iminium ions are well precedented in literature,16 but there are no known examples on an oxadiazine system. The third route is based on the condensation of an appropriate diamine onto an imidate building block. There are a few examples known for this type of cyclisation in literature, but only for simple diamines.17 As we envisioned these methods to be suitable for the introduction of a variety of R groups as well as the synthesis of chiral derivatives, the scope of these approaches was explored.

RESULTS AND DISCUSSION
First, the reductive amination approach was investigated (Table 1). Hydroxybenzimidamide 4 was alkylated with bromoacetophenone using sodium hydride in DMF to generate intermediate 5a. Analysis of the reaction mixture by LCMS showed full consumption of 4 and formation of two products with correct mass. Analysis of the crude product by 1H NMR showed this to be a mixture of 5a and the corresponding cyclic aminal 5’a in a 9:1 ratio. Attempts to isolate the intermediates by column chromatography were problematic, as the compounds co-eluted. Furthermore, only a low yield (25%) of the mixture 5a/5a’ was recovered after column chromatography, indicating the product to be instable on silica. Therefore, the crude mixture of the alkylation reaction was used in the subsequent reduction step and the yield was determined over the two steps.

The reduction of crude 5a/5’a using NaBH4 in MeOH failed and only starting material was observed (Table 1, entry 1). The reduction using NaBH(OAc)3 in acetic acid/methanol also failed with mainly decomposition observed (entry 2). Treatment with NaBH(OAc)3 in DCE with TFA as additive showed traces of product formation, but the reaction did not go to completion. Additionally, reduction of the ketone of 5a to the corresponding alcohol was observed by LCMS (entry 3). As the cyclisation to the imine/aminal intermediate appeared to be the problem and to prevent reduction of ketone 5a, the mixture of 5a/5’a was first heated in MeOH/AcOH to induce cyclisation. After heating at 60 °C for 1 hour, full conversion into a mixture of the corresponding imine/methoxyaminal was observed by LCMS. Addition of NaBH3CN to the mixture afforded the product 6a in 35% yield over the two steps (entry 4). Substitution of NaBH3CN for NaBH(OAc)3 or NaBH4 under the same conditions gave lower yields. Despite the low yield, all the intermediate formed in the alkylation was converted into the product according to LCMS analysis, so the alkylation reaction was investigated in more detail. In order to assess the alkylation, the crude product from the alkylation reaction was converted into 6a using conditions B and the overall yield over two steps was determined. A first test with K2CO3 in methanol failed with the formation of many undesired products as observed by LCMS (entry 5). The alkylation with Cs2CO3 in DMF proceeded somewhat better, although elevated temperature was needed and 6a was isolated in low yield (entry 6). The use of K2CO3 in acetone afforded 6a in a similar yield of 16% (entry 7). Finally, polystyrene supported 2-tert-butylimino-2-diethylimino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (PS-BEMP) was used as the base (entry 8). A fast and fairly clean reaction was observed by LCMS at room temperature and the intermediate mixture 5a/5’a was conveniently isolated after filtration of the base and concentration. Upon reductive amination 6a was isolated in a reasonable 57% yield over the two steps. The conditions in entry 8 were used in the subsequent reactions to determine the scope of this procedure. The 4-methoxyphenyl derivative 6b was synthesised in 40% yield (entry 9), but introduction of an electron withdrawing 4-chlorophenyl group to obtain 6c failed completely (entry 10), which was caused by a failed alkylation reaction as the intermediates 5c/5’c were not be observed by LCMS. Introduction of a methyl (entry 11), cyclohexyl (entry 12) or tBu (entry 13) group afforded the products 6d, 6e and 6f in 12%, 51% and 43% yields, respectively. Finally, introduction of an ester (entry 14) or a 4-pyridyl group (entry 15) was attempted, but the products could not be isolated. In the ester case some alkylation was observed, but the reduction failed. In the pyridine case, the alkylation did not work and the intermediates 5h/5’h were not observed. Although this route gave access to a number of oxadiazine derivatives, the yields were not very high. Moreover, both the alkylation and reductive amination conditions seem to be substrate specific, hampering easy analogue generation. The low yield in the alkylation might be due to a proton transfer of the halo ketone to deprotonated 4, resulting in a poor alkylation/side product formation. This would match the trend observed in the examples above, as the more easily enolisable halo ketones give lower yields or no reaction at all.
To check this hypothesis, an alternative route was devised, where an allyl group was introduced as a masked ketone (Table 2). First, hydroxybenzimidamide 4 was alkylated with 3-bromo-2-methylpropene allyl bromide to afford alkene 8d in 81% yield. In this case, NaH/DMF afforded the product in higher

yield than PS-BEMP in acetonitrile. Next, the double bond was converted into the ketone using OsO4/NaIO4.18 Clean conversion was observed by LCMS and the crude product (100% yield) was used directly in the reductive amination to provide 6d in 57% yield over two steps (entry 1). This approach indeed confirmed that the problem is the alkylation step and not the reduction, as the initial procedure afforded the product in only 12% yield. In order to synthesize derivatives, 4 was alkylated with 2,3-dibromoprop-1-ene affording building block 7 in 75% yield. The introduction of a phenyl group was effected by a Suzuki reaction to afford 8a in an acceptable 72% yield. The double bond was oxidised to afford the intermediate mixture 5a/5a’ (see Table 1) in quantitative yield. Subsequent purification by column chromatography again led to partial decomposition resulting in an isolated yield of only 30%. As expected, direct reduction of the crude intermediate afforded 6a in 80% yield (entry 2). Although this route is one step longer, it does give access to additional targets as a plethora of R groups can be introduced by palladium catalysis. To explore the scope, a few simple phenyl derivatives with electron donating and withdrawing groups were synthesized. The substituent at the 4-position of the phenyl ring did not have much influence on the Suzuki reaction as the introduction of a 4-methoxy-, 4-methyl-, 4-chloro- and 4-fluorophenyl proceeded in similar yields of 60–63% (entries 3–6, products 8b, 8i, 8c and 8j, respectively). For the 4-chloro derivative 8c, however, the Suzuki reaction was run at 70 °C using 1.1 equivalent of boronic acid to prevent the formation of oligomers (entry 5). Gratifyingly, the subsequent oxidations/reductive aminations proceeded in 59–71% yields, now allowing access to electron poor aromatic substituents as well. The introduction of a 3-methoxy- and 3-chlorophenyl afforded alkenes 8k (entry 7) and 8l (entry 8) in 62% and 55% yield, respectively. Subsequent oxidation/reduction afforded the corresponding oxadiazines 6k and 6l in 75% and 66% yield, respectively. Next, the introduction of heteroaryls was tested. Introduction of a 3-benzofuran gave the precursor 8m in 66% yield (entry 9). The subsequent ketone formation gave clean conversion, but in the reductive amination several small unidentified impurities formed, resulting in only 38% isolated yield of 6m. A 2-(N-methyl)indole was introduced in almost quantitative yield (entry 10). While the conversion into the ketone proceeded smoothly, the reductive amination failed to deliver the product. Several unidentified products formed and after tedious purification, some over-reduced 6n (reduction of the indole to the indolinyl) was isolated in 12% yield.19 Finally, introduction of a pyridine was attempted and the Suzuki reaction afforded 8o in 62% yield (entry 11). The oxidative cleavage to the ketone went slowly and took 16 hours to reach completion. The subsequent reductive amination afforded product 6o in only 22% yield. The synthesis of the corresponding 4-pyridyl derivative was also attempted, but failed as the synthesis of the intermediate alkene by either Suzuki or Stille reaction did not work. This strategy provides an improvement over the initial alkylation/reductive amination procedure, but still takes four steps and therefore a shorter approach was investigated: the direct introduction of nucleophiles on the 5-position by nucleophilic attack on an iminium ion intermediate (Table 3).

In order to test Route 2, compound 4 was O-alkylated with bromoacetaldehyde diethyl acetal to afford compound 9. Next, prolonged stirring with sulfuric acid in ethanol gave the cyclic ethoxy aminal 10 in 69% yield after column chromatography. The coupling of 10 with furan as the nucleophile in formic acid afforded the product 6p in 92% yield (Table 3, entry 1). In order to shorten the route, intermediate 9 was heated for 15 minutes in formic acid to generate the intermediate iminium ion 11 in situ. The mixture was cooled to room temperature and furan was added as the nucleophile again. Gratifyingly, product 6p was isolated in similar yield of 88% (entry 2). Next, a set of (hetero)aromatic nucleophiles was added to screen the scope of this reaction starting from 9. As expected, both indole (entry 3) and N-methyl-indole (entry 4) could be coupled in good yields at room temperature to afford products 6q and 6r. Additionally, indazole also reacted at room temperature to afford the product 6s in 87% yield (entry 5). The addition of benzofuran (entry 6) required heating to afford the product 6t in 53% yield. Benzo[b]thiophene (entry 7) was added in good yield as well resulting in the formation of 2-isomer 6u in 69% yield. Formation of some additional regioisomers was also observed by LCMS, but these could not be isolated in pure form. The coupling of benzo[d][1,3]dioxole afforded the product 6v in 74% yield as a single 5-isomer (entry 8). As expected, anisole also reacted, leading to the formation of the 2- and 4-methoxy regioisomeric products 6w and 6b in a 1:3.3 ratio in 87% overall yield (entry 9). The limit of this addition was reached using toluene as the nucleophile (entry 10). A trace of product 6i was observed in the reaction mixture by LCMS, but over time side product formation was observed. As expected, the reaction with the more electron poor chlorobenzene to obtain 6l failed completely (entry 11). Next, the addition of some non-aromatic nucleophiles was tested starting from 10 using BF3·OEt2 as the Lewis acid in dichloromethane, conditions commonly used in the coupling of nucleophiles with N-acyliminium ions.20 Introduction of an allyl unit was effected in 64% yield to afford product 6x (entry 12). Although there is an electron withdrawing hydroxylimine group attached to the intermediate iminium ion, the reaction was quite slow and needed 20 hours to reach completion. A reaction with the silyl enol ether of acetophenone was initially tested with BF3·OEt2 as the Lewis acid. A rapid reaction was observed, but the initial product reacted with the excess nucleophile resulting in the formation of oligomers. When Sc(OTf)3 was used as the Lewis acid, the ketone 6y could be isolated in 33% yield.

Although the oxadiazines can be N-alkylated, the iminium ion reaction sequence was also tested for the synthesis of N-substituted derivatives (Scheme 2). This way, the position of the N-alkyl group is unambiguous and it allows for the introduction of R groups that might be difficult to install afterwards. Starting from intermediates 12a and 12b, the iminium ion precursors 13a and 13b were synthesized. The subsequent introduction of a furan group did not proceed at room temperature as before with the unsubstituted derivative 9, but required additional heating. The methyl derivative 14a was isolated in 58% yield after heating for 4 hours at 70 °C. The phenyl derivative required heating overnight to provide product 14b in 68% yield. Although giving access to a variety of 5-substituted oxadiazine targets, this approach is limited to the use of electron rich nucleophiles and also does not give access to optically pure derivatives. Therefore, the synthesis of a chiral diamine 16 was started to test the construction of oxadiazines by condensation with an imidate (Scheme 3).

The commercially available N-Boc-phenylglycinol 15 was converted into the diamine 16 in 3 steps. Next, the diamine was stirred at room temperature overnight with ethyl benzimidate hydrochloride 19a leading to intermediate 17a. Upon heating to 100 °C for 2 hours, intramolecular attack of the nitrogen onto the imidate, followed by elimination of ammonia led to clean conversion into S-6a and the product was isolated in 84% yield. The free amine must be used in the reaction, attempts to perform the cyclisation reaction with the initially isolated dihydrochloride salt of 16 failed as the intermediate did not form. Starting the reaction at 100 °C directly also afforded the product, but in lower yield. At higher temperature the amine of the intermediate can react with a second equivalent of the imidate leading to side product formation. Gratifyingly, chiral HPLC analysis showed no racemization had taken place in the synthesis of S-6a. Considering the number of (optically pure) amino alcohols/amino acids available, this route gives access to an array of (optically pure) oxadiazines. As expected, variation on the 3 position could easily be effected by changing the starting imidate. The methyl derivative S-18b already cyclised by stirring at room temperature overnight in 82% yield. Both the cyclohexyl (S-18c) and 2-pyridyl (S-18d) derivatives required some additional heating to give the products in 91% and 85% yield, respectively.
Encouraged by these results, the scope with respect to the diamines that can be used in the cyclization was explored using ethyl benzimidate hydrochloride 19a as the imidate (Table 4). The unsubstituted oxadiazine derivative 21a was obtained in 63% yield (entry 1). Either a 4-, 5-, or 6-methyl group was installed on the oxadiazine starting from the appropriate diamine to afford 21b (entry 2, 74%), 6d (entry 3, 77%) and 21d (entry 4, 57% yield), respectively. The somewhat lower yield for 21d was the result of double addition of the diamine to the imidate, caused by the increased nucleophilicity of the N-methylated amine. A [5-6] cis (21e, 53%, entry 5), or trans (21f, 71%, entry 6) annulated cyclohexyl ring was installed on the oxadiazine in reasonable yields. A smaller [5-6] cis annulated cyclopentyl ring (21g, entry 7) could be introduced in 78% yield as well. As expected, the cyclization to the corresponding trans annulated derivative 21h was more difficult (entry 8), but the product could be isolated in 25% yield after heating for 48 hours. Introduction of a [4-5] annulated ring was also possible in high yield starting from the prolinol derived diamine 20i to afford 21i in 80% yield (entry 9). Finally, introduction of a quaternary center was probed. The 5,5-dimethyl substituted oxadiazine 21j was synthesized in 83% yield starting from amine 20j (entry 10). Starting from diamine 20k, the spiro-fused oxadiazine 21k was synthesized in 87% yield (entry 11). Based on these results, the synthesis of a large number of substituted oxadiazines can conveniently be accomplished starting from easily accessible diamines.
In summary, three approaches for the synthesis of substituted 5,6-dihydro-4H-[1,2,4]oxadiazines were investigated. The first approach via alkylation with a haloketone, followed by reductive amination, gave moderate to low yields. Additionally, the procedure was found to have a limited scope. These problems could partly be alleviated by a multi-step approach involving alkylation with 2,3-dibromoprop-1-ene, followed by introduction of R groups via a Suzuki reaction, oxidative cleavage of the double bond and reductive ring closure. The direct introduction of substituents at the 5-position by addition to an iminium ion provided new analogues in one synthetic step; however, the scope was limited to electron rich nucleophiles. The condensation of a diamine with an imidate was found to be the most versatile route. This route allowed for variation of substituents at the 3, 4, 5 and 6 position of the oxadiazine in good yields. Furthermore, depending on the diamine used, optically pure oxadiazines could be prepared.

EXPERIMENTAL
General Experimental Methods. All solvents and reagents were used as purchased from commercial suppliers without further purification. Starting materials which were not commercially available were synthesized by previously reported methods. Flash column chromatography was performed using prepacked silica gel (20−40 mesh) columns. Analytical thin-layer chromatography was performed on Merck 60 F254 glass plates. Visualization was accomplished with UV light, iodine, anisaldehyde or potassium permanganate, followed by heating. Melting points were measured on a calibrated standard melting point apparatus and are uncorrected. 1H NMR spectra were recorded in CDCl3 or DMSO-d6 on a 300 or 400 MHz Bruker spectrometer and are reported in ppm using TMS (0.00 ppm) as an internal standard. Proton-decoupled 13C NMR spectra were recorded on a 101 MHz Bruker spectrometer and are reported in ppm using the internal solvent residual signal as an internal standard. Optical rotations were measured in MeOH on a polarimeter with a 100 mm cell (c given in g/100 mL) operating at λ= 589 nm, corresponding to the sodium D line, at the indicated temperatures. Basic preparative HPLC was performed on a Reveleris Prep system: Detection: UV (220/254 nm), Column: XSelectTM CSH C18, 145x25 mm, particle size 10 μm, Flow: 40 mL/min, Eluent A: 10 mM ammonium bicarbonate in water pH = 9.0); Eluent B: 99% acetonitrile + 1% 10 mM ammonium bicarbonate in water; 5% B to 100% B gradient. Acidic preparative HPLC was performed on a Reveleris Prep system: Detection: ELSD, UV 220 nm/254 nm), Column: Phenomenex Luna C18, 150x25 mm, particle size 10 μm, Flow: 40 mL/min, Eluent A: 0.1% (v/v) Formic acid in water, Eluent B: 0.1% (v/v) Formic acid in acetonitrile, 5% B to 100% B gradient. The product containing fractions were lyophilized to obtain the products.

General procedure A for the synthesis of 5-substituted 3-phenyl-5,6-dihydro-4H[1,2,4]oxadiazines via alkylation and reductive amination. To a solution of N'-hydroxybenzimidamide 4 (250 mg, 1.84 mmol) in MeCN (4 mL), PS-BEMP (2.2 mmol/g, 1.2 equiv, 1 g) was added. After stirring for 15 min at rt, the bromo- or chloroketone (1.5 equiv.) in MeCN (2 mL) was added and the mixture was stirred for 2 h. The solids were removed by filtration and the filtrate was concentrated to afford the crude alkylated intermediate. This was dissolved in a mixture of MeOH (9 mL) and acetic acid (3 mL), heated to 60 °C for 1 h, sodium cyanoborohydride (127 mg, 2.02 mmol, 1.1 equiv.) was added and the mixture was stirred at 60 °C for an additional 3 h. The mixture was poured into an aqueous 1M NaOH solution (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried using Na2SO4 and concentrated to afford the crude product, that was further purified as described.
3,5-Diphenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6a). General procedure A was followed, using 2-bromo-1-phenylethan-1-one. Purification by silica flash column chromatography (30% EtOAc in n-heptane) afforded compound 6a (254 mg, 57% yield) as a crystalline solid; mp 110 – 111 °C; 1H NMR (400 MHz, CDCl3) δ 7.72 – 7.67 (m, 2H), 7.49 – 7.34 (m, 8H), 5.05 (s, 1H), 4.76 – 4.69 (m, 1H), 4.33 – 4.23 (m, 1H), 3.76 (dd, J = 11.1, 7.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 152.9, 138.8, 130.5, 129.2, 128.9, 128.8, 127,0, 126.0, 77.5, 69.8, 54.4; HRMS (ESI-TOF) m/z Calcd for C15H15N2O 239.1184 [M + H]+; Found 239.1190; Chiral HPLC: tR: 8.58 and 13.24 min, 1:1 mixture (column: Chiralpak AD-H, 250 x 4.6 mm, 5 μm, eluent: 20% EtOH in heptane, flow: 1 mL/min, temp: 25 °C); IR (νmax, cm-1): 3289, 1599; Anal. Calcd for C15H14N2O: C, 75.61; H, 5.92; N, 11.76%. Found: C, 75.78; H, 6.13; N, 12.01%.
5-(4-Methoxyphenyl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6b). General procedure A was followed using 2-bromo-1-(4-methoxyphenyl)ethan-1-one. Purification by silica flash column chromatography (35% EtOAc in n-heptane) followed basic preparative HPLC afforded compound 6b (200 mg, 40% yield) as an amorphous solid; 1H NMR (400 MHz, CDCl3) δ 7.71 – 7.64 (m, 2H), 7.48 – 7.37 (m, 3H), 7.32 – 7.26 (m, 2H), 6.96 – 6.89 (m, 2H), 5.02 (s, 1H), 4.70 – 4.61 (m, 1H), 4.29 – 4.19 (m, 1H), 3.81 (s, 3H), 3.70 (dd, J = 11.0, 7.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 160.0, 152.9, 132.9, 130.8, 130.4, 128.8, 128.2, 126.0, 114.6, 69.9, 55.5, 53.8; HRMS (ESI-TOF) m/z Calcd for C16H17N2O2 269.1287 [M + H]+; Found 269.1290; IR (νmax, cm-1): 3318, 1604; Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44%. Found: C, 71.67; H, 6.26; N, 10.56%.
5-Methyl-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6d). General procedure A was followed using 1-chloropropan-2-one. Purification by silica flash column chromatography (30% EtOAc in n-heptane) followed by basic preparative HPLC afforded compound 6d (41 mg, 12% yield) as an amorphous solid; 1H NMR (400 MHz, CDCl3) δ 7.69 – 7.56 (m, 2H), 7.51 – 7.34 (m, 3H), 4.60 (s, 1H), 4.19 – 4.06 (m, 1H), 3.85 – 3.65 (m, 1H), 3.50 (dd, J = 10.8, 7.1 Hz, 1H), 1.27 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 152.5, 133.2 , 130.3, 128.8, 126.0, 69.4, 45.8, 18.6; HRMS (ESI-TOF) m/z Calcd for C10H13N2O 177.1028 [M + H]+; Found 177.1030; IR (νmax, cm-1): 3232, 1603; Anal. Calcd for C10H12N2O: C, 68.16; H, 6.86; N, 15.90%. Found: C, 67.87; H, 7.26; N, 16.11%.
5-Cyclohexyl-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6e). General procedure A was followed using 2-bromo-1-cyclohexylethan-1-one. Purification by trituration from EtOAc afforded compound 6e (233 mg, 51% yield) as a crystalline solid; mp 165 – 166 °C; 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.60 (m, 2H), 7.46 – 7.36 (m, 3H), 4.73 (s, 1H), 4.07 (dd, J = 11.0, 3.4 Hz, 1H), 3.81 (dd, J = 11.0, 6.0 Hz, 1H), 3.38 – 3.30 (m, 1H), 1.91 (d, J = 12.2 Hz, 1H), 1.86 – 1.76 (m, 3H), 1.76 – 1.67 (m, 1H), 1.57 – 1.48 (m, 1H), 1.35 – 1.16 (m, 3H), 1.16 – 1.01 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 152.8, 133.3, 130.2, 128.7, 126.0, 66.0, 55.0, 40.6, 29.1, 28.9, 26.4, 26.0; HRMS (ESI-TOF) m/z Calcd for C15H21N2O 245.1654 [M + H]+; Found 245.1654; IR (νmax, cm-1): 3360, 1606; Anal. Calcd for C15H20N2O: C, 73.74; H, 8.25; N, 11.47%. Found: C, 73.70; H, 8.41; N, 11.09%.
5-(tert-Butyl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6f). General procedure A was followed using 1-bromo-3,3-dimethylbutan-2-one. Purification by silica flash column chromatography (35% EtOAc in n-heptane) followed by basic preparative HPLC afforded compound 6f (178 mg, 43% yield) as an amorphous solid; 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.56 (m, 2H), 7.51 – 7.34 (m, 3H), 4.74 (s, 1H), 4.17 – 4.03 (m, 1H), 3.83 (dd, J = 11.2, 6.6 Hz, 1H), 3.41 – 3.23 (m, 1H), 1.03 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 153.4, 133.3, 130.3, 128.8, 126.0, 64.9, 58.6, 33.6, 26.0; HRMS (ESI-TOF) m/z Calcd for C13H19N2O 219.1498 [M + H]+; Found 219.1497; IR (νmax, cm-1): 3204, 1606; Anal. Calcd for C13H18N2O: C, 71.53; H, 8.31; N, 12.83%. Found: C, 71.21; H, 8.65; N, 12.78%.
N'-((2-Bromoallyl)oxy)benzimidamide (7). To a solution of N'-hydroxybenzimidamide 4 (2.28 g, 16.8 mmol) in dry DMF (15 mL) under nitrogen atmosphere at 0 °C, was added sodium hydride (60% dispersion in mineral oil, 738 mg, 18.4 mmol). The resulting suspension was stirred at rt for 20 min, 2,3-dibromoprop-1-ene (3.69 g, 18.4 mmol) was added and the mixture was stirred at rt for 20 h. The reaction mixture was poured into water and was extracted with EtOAc twice. The combined organic layers were washed with brine, dried using Na2SO4, concentrated and the crude product was purified by silica flash column chromatography (10% to 60% EtOAc in n-heptane) to afford compound 7 (3.2 g, 75% yield) as an oil; 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.57 (m, 2H), 7.45 – 7.33 (m, 3H), 5.97 – 5.91 (m, 1H), 5.66 – 5.60 (m, 1H), 4.89 (s, 2H), 4.72 – 4.65 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 152.8, 132.2, 130.1, 129.7, 128.6, 126.0, 117.6, 77.0; HRMS (ESI-TOF) m/z Calcd for C10H12BrN2O 255.0133 [M + H]+; Found 255.0130.
N'-((2-Methylallyl)oxy)benzimidamide (8d). To a solution of N'-hydroxybenzimidamide 4 (500 mg, 3.67 mmol) in dry DMF (15 mL) under nitrogen atmosphere, sodium hydride (60% dispersion in mineral oil, 154 mg, 3.86 mmol) was added in portions and the resulting suspension was stirred at rt for 30 min. Then, a solution of 3-bromo-2-methylpropene (992 mg, 7.34 mmol) in dry DMF (5 mL) was added and the resulting mixture was stirred at rt for 1 h. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with water, brine, dried using Na2SO4, concentrated and purified by silica flash column chromatography (20% EtOAc in n-heptane) to afford compound 8d (579 mg, 81% yield) as an oil; 1H NMR (400 MHz, CDCl3) δ 7.71 – 7.55 (m, 2H), 7.45 – 7.30 (m, 3H), 5.09 – 4.96 (m, 1H), 5.00 – 4.89 (m, 1H), 4.83 (s, 2H), 4.54 (s, 2H), 1.89 – 1.73 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 152.0, 142.6, 132.7, 130.0, 128.7, 126.0, 112.2, 19.9; HRMS (ESI-TOF) m/z Calcd for C11H15N2O 191.1184 [M + H]+; Found 191.1180.
General procedure B for the synthesis of N'-((2-substituted allyl)oxy)benzimidamides via Suzuki cross-coupling. Through a 0.2 M solution of 7, Na2CO3 (3 equiv.) and the appropriate boronic acid (2.2 equiv.) in DME/water (2:1, v/v), nitrogen was bubbled for 10 min. Then, 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.05 equiv.) was added and the mixture was heated at the indicated temperature for the indicated time. The reaction was cooled to rt, partitioned between water and EtOAc, the organic layer was separated, dried using Na2SO4 and concentrated to afford the crude product that was purified as indicated.
N'-((2-Phenylallyl)oxy)benzimidamide (8a). General procedure B was followed starting from 7 (250 mg, 0.98 mmol) using phenylboronic acid and stirring at 80 °C for 30 min. Purification by silica flash column chromatography (5% to 35% EtOAc in n-heptane) afforded compound 8a (180 mg, 72% yield) as an oil; 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, J = 7.5, 1.7 Hz, 2H), 7.51 (d, J = 7.3 Hz, 2H), 7.43 – 7.19 (m, 6H), 5.57 (s, 1H), 5.41 (s, 1H), 5.01 (s, 2H), 4.74 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 152.4, 144.3, 139.0, 132.6, 130.0, 128.7, 128.4, 127.8, 126.2, 126.0, 114.9, 75.6; HRMS (ESI-TOF) m/z Calcd for C16H17N2O 253.1341 [M + H]+; Found 253.1341.
N'-((2-(4-Methoxyphenyl)allyl)oxy)benzimidamide (8b). General procedure B was followed starting from 7 (250 mg, 0.98 mmol) using 4-methoxyphenylboronic acid and stirring at 80 °C for 30 min. Purification by basic preparative HPLC afforded compound 8b (169 mg, 61% yield) as an oil; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.44 – 7.33 (m, 3H), 6.88 (d, J = 8.5 Hz, 2H), 5.50 (s, 1H), 5.32 (s, 1H), 4.99 (s, 2H), 4.76 (s, 2H), 3.81 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 159.3, 152.2, 143.4, 132.5, 131.4, 129.9, 128.6, 127.3, 125.9, 113.7, 113.2, 75.7, 55.3; HRMS (ESI-TOF) m/z Calcd for C17H19N2O2 283.1457 [M + H]+; Found 283.1446.
N'-((2-(4-Chlorophenyl)allyl)oxy)benzimidamide (8c). General procedure B was followed starting from 7 (209 mg, 0.82 mmol) using 1.1 equiv. of 4-chlorophenylboronic acid and stirring at 70 °C for 30 min. Purification by silica flash column chromatography (5% to 30% EtOAc in n-heptane) afforded compound 8c (148 mg, 63% yield) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.7 Hz, 2H), 7.49 – 7.34 (m, 5H), 7.31 (d, J = 8.2 Hz, 2H), 5.56 (s, 1H), 5.43 (s, 1H), 4.98 (s, 2H), 4.74 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 152.4, 143.3, 137.4, 133.6, 132.5, 130.1, 128.8, 128.6, 127.6, 126.1, 115.6, 75.5; HRMS (ESI-TOF) m/z Calcd for C16H16ClN2O 287.0958 [M + H]+; Found 287.0951.
N'-((2-(4-Methylphenyl)allyl)oxy)benzimidamide (8i). General procedure B was followed starting from 7 (150 mg, 0.59 mmol) using 4-methylphenylboronic acid and stirring at 80 °C for 1 h. Purification by basic preparative HPLC afforded compound 8i (94 mg, 60% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, J = 7.7, 1.8 Hz, 2H), 7.48 – 7.31 (m, 5H), 7.14 (d, J = 8.0 Hz, 2H), 5.54 (s, 1H), 5.36 (s, 1H), 4.99 (s, 2H), 2.34 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 152.3, 144.0, 137. 6, 136.0, 132.6, 130.0, 129.1, 128.7, 126.1, 126.0, 114.0, 75.6, 21.2; HRMS (ESI-TOF) m/z Calcd for C17H19N2O 267.1497 [M + H]+; Found 267.1500.
N'-((2-(4-Fluorophenyl)allyl)oxy)benzimidamide (8j). General procedure B was followed starting from 7 (150 mg, 0.59 mmol) using 4-fluorophenylboronic acid and stirring at 80 °C for 1 h. Purification by basic preparative HPLC afforded compound 8j (97 mg, 61% yield) as an oil; 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 7.7, 1.7 Hz, 2H), 7.53 – 7.44 (m, 2H), 7.43 – 7.31 (m, 3H), 7.06 – 6.97 (m, 2H), 5.50 (s, 1H), 5.38 (s, 1H), 4.75 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 162.5 (d, J = 246.6 Hz), 152.4, 143.4, 135.0 (d, J = 3.2 Hz), 132.5, 130.1, 128.7, 127.9 (d, J = 8.0 Hz), 126.0, 115.3 (d, J = 21.3 Hz), 114.9, 75.6; HRMS (ESI-TOF) m/z Calcd for C16H16FN2O 271.1247 [M + H]+; Found 271.1245.
N'-((2-(3-Methoxyphenyl)allyl)oxy)benzimidamide (8k). General procedure B was followed starting from 7 (150 mg, 0.59 mmol) using 3-methoxyphenylboronic acid and stirring at 80 °C for 1 h. Purification by basic preparative HPLC afforded compound 8k (103 mg, 62% yield) as an oil; 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.44 (m, 2H), 7.33 – 7.22 (m, 3H), 7.16 (t, J = 8.0 Hz, 1H), 7.05 – 6.99 (m, 1H), 6.99 – 6.94 (m, 1H), 6.74 (dd, 1H), 5.47 (s, 1H), 5.32 (d, J = 1.2 Hz, 1H), 4.90 (s, 2H), 4.68 (s, 2H), 3.69 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 159.6, 152.3, 144.2, 140.5, 132.5, 129.9, 129.3, 128.6, 126.0, 118.7, 115.1, 113.2, 112.0, 75.5, 55.3; HRMS (ESI-TOF) m/z Calcd for C17H19N2O2 283.1447 [M + H]+; Found 283.1450.
N'-((2-(3-Chlorophenyl)allyl)oxy)benzimidamide (8l). General procedure B was followed starting from 7 (150 mg, 0.59 mmol) using 1.1 equiv. of 3-chlorophenylboronic acid and stirring at 70 °C for 1 h. Purification by basic preparative HPLC afforded compound 8l (93 mg, 55% yield) as an oil; 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.55 (m, 3H), 7.51 (s, 1H), 7.45 – 7.32 (m, 6H), 7.29 – 7.21 (m, 4H), 5.57 (s, 1H), 5.45 (d, 2H), 4.97 (s, 3H), 4.75 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 152.4, 143.4, 140.9, 134.4, 132.5, 130.1, 129.7, 128.7, 127.8, 126.5, 126.1, 124.5, 116.2, 75.4; HRMS (ESI-TOF) m/z Calcd for C16H16ClN2O 287.0951 [M + H]+; Found 287.0950.
N'-((2-(Benzofuran-3-yl)allyl)oxy)benzimidamide (8m). General procedure B was followed starting from 7 (250 mg, 0.98 mmol) using benzofuran-3-boronic acid and stirring at 80 °C for 2 h. Purification by silica flash column chromatography (20% EtOAc in n-heptane) afforded compound 8m (270 mg, 66% yield) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.86 – 7.80 (m, 2H), 7.63 – 7.59 (m, 2H), 7.49 (dd, J = 7.1, 1.8 Hz, 1H), 7.41 – 7.33 (m, 3H), 7.33 – 7.25 (m, 2H), 5.79 (s, 1H), 5.56 – 5.51 (m, 1H), 4.95 (s, 2H), 4.81 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 155.6, 152.3, 142. 9, 136.4, 132.5, 130.1, 128.7, 126.2, 126.0, 124.5, 123.1, 121.2, 119.6, 115.1, 111.7, 76.5; HRMS (ESI-TOF) m/z Calcd for C18H17N2O2 293.1290 [M + H]+; Found 293.1289.
N'-((2-(1-Methyl-1H-indol-2-yl)allyl)oxy)benzimidamide (8n). General procedure B was followed starting from 7 (250 mg, 0.98 mmol) using 1-methyl-2-indoleboronic acid pinacol ester and stirring at 80 °C for 90 min. Purification by silica flash column chromatography (20% EtOAc in n-heptane) afforded compound 8n (296 mg, 97% yield) as an oil; 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.53 (m, 3H), 7.45 – 7.33 (m, 3H), 7.34 – 7.28 (m, 1H), 7.27 – 7.18 (m, 1H), 7.14 – 7.07 (m, 1H), 6.55 (s, 1H), 5.70 (d, J = 1.3 Hz, 1H), 5.38 (s, 1H), 4.94 (s, 2H), 4.74 (s, 2H), 3.77 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 152.5, 139.1, 138.5, 137.5, 132.6, 130.1, 128.7, 126.0, 121.9, 120.7, 119.8, 117.9, 109.6, 101.4, 76.2, 31.3; HRMS (ESI-TOF) m/z Calcd for C19H20N3O 306.1606 [M + H]+; Found 306.1611.
N'-((2-(Pyridin-3-yl)allyl)oxy)benzimidamide (8o). General procedure B was followed starting from 7 (200 mg, 0.78 mmol) using pyridine-3-boronic acid and stirring at 80 °C for 3 h. Purification by silica flash column chromatography (45% EtOAc in n-heptane) afforded compound 8o (126 mg, 62% yield) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.52 (d, J = 3.9 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.60 (dd, J = 7.6, 1.5 Hz, 2H), 7.47 – 7.33 (m, 3H), 7.31 – 7.22 (m, 1H), 5.62 (s, 1H), 5.51 (s, 1H), 5.00 (s, 2H), 4.77 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 148.9, 141.9, 133.6, 132.5, 130.1, 128.7, 126.1, 116.8, 75.3; HRMS (ESI-TOF) m/z Calcd for C15H16N3O 254.1293 [M + H]+; Found 254.1290.
General procedure C for the synthesis of 5-substituted 3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazines via oxidative cleavage and reductive amination. To a 0.15 M solution of the appropriate N'-allyloxy-benzimidamide in THF/water (3:1, v/v), osmium tetroxide (4 wt% in water, 0.05 equiv.) and sodium periodate (3.5 equiv.) were added. The mixture was stirred at rt for 1 h (unless indicated otherwise), diluted with water and extracted with DCM twice. The combined organic layers were washed with brine, dried using Na2SO4 and concentrated to afford the crude intermediate. A 0.15 M solution of crude intermediate in MeOH/acetic acid (3:1, v/v) was heated to 60 °C for 1 h and sodium cyanoborohydride (1.1 equiv.) was added. The mixture was stirred at 60 °C for 3 h, poured into a 1M sodium hydroxide solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried using Na2SO4 and concentrated to afford the crude product which was purified as described.
3,5-Diphenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6a). General procedure C was followed using N'-((2-phenylallyl)oxy)benzimidamide 8a (150 mg, 0.55 mmol). Purification by silica flash column chromatography (30% EtOAc in n-heptane) afforded compound 6a (104 mg, 80% yield) as a solid.
5-(4-Chlorophenyl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6b). General procedure C was followed using N'-((2-(4-methoxyphenyl)allyl)oxy)benzimidamide 8b (137 mg, 0.49 mmol). Purification by silica flash column chromatography (35% EtOAc in n-heptane) afforded compound 6b (77 mg, 59% yield) as a solid.
5-(4-Chlorophenyl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6c). General procedure C was followed using N'-((2-(4-chlorophenyl)allyl)oxy)benzimidamide 8c (117 mg, 0.41 mmol). The oxidative cleavage was stirred for 2 h. Purification by silica flash column chromatography (30% EtOAc in n-heptane) afforded compound 6c (75 mg, 66% yield) as a solid; 1H NMR (400 MHz, CDCl3) δ 7.74 – 7.61 (m, 2H), 7.50 – 7.35 (m, 5H), 7.35 – 7.28 (m, 2H), 5.07 (s, 1H), 4.82 – 4.61 (m, 2H), 4.30 – 4.17 (m, 1H), 3.77 (dd, J = 11.1, 6.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 152.9, 137.9, 134.3, 132.6, 130.5, 129.2, 128.8, 128.3, 126.0, 69.4, 53.5; HRMS (ESI-TOF) m/z Calcd for C15H14ClN2O 273.0793 [M + H]+; Found 273.0795; IR (νmax, cm-1): 3297, 1601; Anal. Calcd for C15H13ClN2O: C, 66.06; H, 4.80; N, 10.27%. Found: C, 65.73; H, 4.51; N, 10.24%.
5-Methyl-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6d). General procedure C was followed using N'-((2-methylallyl)oxy)benzimidamide 8d (575 mg, 3.0 mmol). Purification by silica flash column chromatography (35% EtOAc in n-heptane) afforded compound 6d (311 mg, 57% yield) as a solid.
5-(4-Methylphenyl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6i). General procedure C was followed using N'-((2-(4-methylphenyl)allyl)oxy)benzimidamide 8i (71 mg, 0.27 mmol). Purification by silica flash column chromatography (0% to 60% EtOAc in n-heptane) followed by lyophilization afforded compound 6i (46 mg, 68% yield) as an amorphous solid; 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.65 (m, 2H), 7.48 – 7.36 (m, 3H), 7.24 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 5.08 (s, 1H), 4.69 – 4.62 (m, 1H), 4.22 (dd, J = 11.0, 4.0 Hz, 1H), 3.69 (dd, J = 11.0, 7.5 Hz, 1H), 2.36 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 152.9, 138.6, 135.8, 132.9, 130.4, 129.8, 128.8, 126.9, 126.0, 69.8, 54.0, 21.2; HRMS (ESI-TOF) m/z Calcd for C16H17N2O 253.1341 [M + H]+; Found 253.1337; IR (νmax, cm-1): 3332, 1606.
5-(4-Fluorophenyl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6j). General procedure C was followed using N'-((2-(4-fluorophenyl)allyl)oxy)benzimidamide 8j (85 mg, 0.31 mmol). Purification by silica flash column chromatography (0% to 60% EtOAc in n-heptane) followed by lyophilization afforded compound 6j (57 mg, 71% yield) as an amorphous solid; 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.60 (m, 2H), 7.48 – 7.35 (m, 3H), 7.35 – 7.28 (m, 2H), 7.12 – 7.02 (m, 2H), 5.29 (s, 1H), 4.72 – 4.61 (m, 1H), 4.15 (dd, J = 11.1, 3.8 Hz, 1H), 3.70 (dd, J = 11.1, 6.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 162.8 (d, J = 247.2 Hz), 152.9, 135.1 (d, J = 3.1 Hz), 132.7, 130.4, 128.8, 128.6 (d, J = 8.2 Hz), 126.0, 116.0 (d, J = 21.7 Hz), 69.5, 53.5; HRMS (ESI-TOF) m/z Calcd for C15H14FN2O 257.1090 [M + H]+; Found 257.1088; IR (νmax, cm-1): 3344, 1602; Anal. Calcd for C15H13FN2O: C, 70.30; H, 5.11; N, 10.93%. Found: C, 70.06; H, 5.03; N, 10.90%.
5-(3-Methoxyphenyl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6k). General procedure C was followed using N'-((2-(3-methoxyphenyl)allyl)oxy)benzimidamide 8k (83 mg, 0.29 mmol). Purification by silica flash column chromatography (0% to 60% EtOAc in n-heptane) followed by lyophilization afforded compound 6k (59 mg, 75% yield) as an amorphous solid; 1H NMR (400 MHz, CDCl3) δ 7.77 – 7.61 (m, 2H), 7.52 – 7.36 (m, 3H), 7.37 – 7.28 (m, 1H), 6.95 (d, J = 7.7 Hz, 1H), 6.92 – 6.85 (m, 2H), 5.10 (s, 1H), 4.73 – 4.60 (m, 1H), 4.25 (dd, J = 11.0, 4.0 Hz, 1H), 3.81 (s, 3H), 3.74 (dd, J = 11.0, 7.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 160.3, 152.8, 140.5, 132.9, 130.4, 130.3, 128.8, 126.0, 119.1, 113.8, 112.8, 69.7, 55.4, 54.2; HRMS (ESI-TOF) m/z Calcd for C16H17N2O2 269.1290 [M + H]+; Found 269.1288.
5-(3-Chlorophenyl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6l). General procedure C was followed using N'-((2-(3-chlorophenyl)allyl)oxy)benzimidamide 8l (83 mg, 0.29 mmol). Purification by silica flash column chromatography (0% to 60% EtOAc in n-heptane) followed by lyophilization afforded compound 6l (52 mg, 66% yield) as an amorphous solid; 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.59 (m, 2H), 7.48 – 7.36 (m, 3H), 7.35 – 7.29 (m, 3H), 7.25 – 7.19 (m, 1H), 5.33 (s, 1H), 4.70 – 4.61 (m, 1H), 4.14 (dd, J = 11.1, 3.8 Hz, 1H), 3.73 (dd, J = 11.1, 6.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 152.9, 141.5, 135.0, 132.6, 130.5, 130.4, 128.8, 128.7, 127.1, 126.0, 125.1, 69.3, 53.7; HRMS (ESI-TOF) m/z Calcd for C15H14ClN2O 273.0795 [M + H]+; Found 273.0791.
5-(Benzofuran-3-yl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6m). General procedure C was followed using N'-((2-(benzofuran-3-yl)allyl)oxy)benzimidamide (8m) (190 mg, 0.65 mmol). Purification by silica flash column chromatography (30% EtOAc in n-heptane) afforded compound 6m (67 mg, 38% yield) as an oil; 1H NMR (400 MHz, CDCl3) δ 7.63 – 7.54 (m, 4H), 7.49 (d, J = 8.3 Hz, 1H), 7.44 – 7.37 (m, 1H), 7.36 – 7.28 (m, 3H), 7.26 – 7.20 (m, 1H), 5.44 (s, 1H), 4.95 – 4.86 (m, 1H), 4.19 (dd, J = 11.1, 4.0 Hz, 1H), 3.98 (dd, J = 11.1, 6.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 155.8, 152.9, 142.8, 132.6, 130.4, 128.7, 126.0, 125.6, 125.0, 123.1, 119.9, 119.0, 112.0, 67.5, 46.6; HRMS (ESI-TOF) m/z Calcd for C17H15N2O2 279.1134 [M + H]+; Found 279.1132.
5-(Pyridin-3-yl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6o). General procedure C was followed using N'-((2-(pyridin-3-yl)allyl)oxy)benzimidamide (8o) (310 mg, 1.22 mmol). The oxidative cleavage was stirred for 16 h. Purification by silica flash column chromatography (5% MeOH in DCM) afforded compound 6o (66 mg, 22% yield) as an off white solid; 1H NMR (400 MHz, CDCl3) δ 8.53 – 8.42 (m, 2H), 7.68 – 7.58 (m, 3H), 7.47 – 7.39 (m, 1H), 7.39 – 7.31 (m, 2H), 7.27 (dd, J = 7.9, 4.8 Hz, 1H), 5.96 (d, J = 2.2 Hz, 1H), 4.74 – 4.62 (m, 1H), 4.08 (dd, J = 11.1, 3.7 Hz, 1H), 3.78 (dd, J = 11.1, 5.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 153.2, 149.6, 148.3, 135.7, 134.7, 132.5, 130.5, 128.7, 126.0, 123.9, 68.8, 51.8; HRMS (ESI-TOF) m/z Calcd for C14H14N3O 240.1137 [M + H]+; Found 240.1138.
General procedure D for the alkylation of (N-substituted) N'-hydroxybenzimidamides. To a solution of the appropriate N'-hydroxybenzimidamide and 1-bromo-2,2-diethoxyethane (1.1 equiv.) in DMSO was added KOH (1.2 equiv.) and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with water, extracted with EtOAc, the combined organic extracts were washed twice with 0.1 M aqueous sodium hydroxide solution and once with brine. The organic layer was dried over Na2SO4, concentrated and the crude product was purified by silica flash column chromatography using the indicated gradient.
N'-(2,2-Diethoxyethoxy)benzimidamide (9). General procedure D was followed using N'-hydroxybenzimidamide 4 (10.0 g, 73.7 mmol) in 100 mL of DMSO. Purification by silica flash column chromatography (15% to 30% EtOAc in n-heptane) afforded compound 9 (14.3 g, 77% yield) as an oil; 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.57 (m, 2H), 7.47 – 7.33 (m, 3H), 4.86 (t, J = 5.3 Hz, 3H), 4.11 (d, J = 5.4 Hz, 2H), 3.76 (dq, J = 9.5, 7.1 Hz, 2H), 3.61 (dq, J = 9.4, 7.0 Hz, 2H), 1.24 (t, J = 7.1 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 152.5, 132.6, 130.1, 128.7, 126.0, 100.5, 73.6, 62.6, 15.5; HRMS (ESI-TOF) m/z Calcd for C13H20N2O3Na 275.1372 [M + Na]+; Found 275.1374.
5-Ethoxy-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (10). To a solution of N'-(2,2-diethoxyethoxy)benzimidamide 9 (5.0 g, 19.8 mmol) in EtOH (200 mL), H2SO4 (1.94 g, 19.8 mmol) in water (10 mL) was added and the mixture was stirred at 65 °C for 1 week. The reaction mixture was quenched using solid sodium bicarbonate. When gas evolution had ceased, the reaction mixture was concentrated to approximately 50 mL volume and partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc twice. The combined organic layes were washed with water, brine, dried over Na2SO4, concentrated and the crude product was purified by column chromatography (45% to 65% EtOAc in n-heptane) to afford compound 10 (2.8 g, 69% yield) as a solid; mp 112 – 113 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 5.0 Hz, 1H), 7.71 – 7.59 (m, 2H), 7.51 – 7.37 (m, 3H), 4.86 – 4.78 (m, 1H), 4.07 – 3.98 (m, 1H), 3.76 – 3.64 (m, 1H), 3.54 – 3.38 (m, 2H), 1.15 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 151.2, 132.5, 129.9, 128.3, 125.9, 77.2, 65.9, 61.2, 15.1; HRMS (ESI-TOF) m/z Calcd for C11H15N2O2 207.1134 [M + H]+; Found 207.1139.
N'-(2,2-Diethoxyethoxy)-N-methylbenzimidamide (13a). General procedure D was followed using N'-hydroxy-N-methylbenzimidamide 12a (488 mg, 3.25 mmol) in 5 mL of DMSO. Purification by silica flash column chromatography (0% to 30% EtOAc in n-heptane) afforded compound 13a (444 mg, 51% yield) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.61 – 7.30 (m, 5H), 5.47 – 5.12 (m, 1H), 4.06 (d, J = 5.4 Hz, 2H), 3.75 (dq, J = 9.4, 7.1 Hz, 2H), 3.60 (dq, J = 9.5, 7.1 Hz, 2H), 2.71 (d, J = 5.3 Hz, 3H), 1.24 (t, J = 7.1 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 157.6, 131.2, 129.7, 128.8, 128.6, 100.5, 73.3, 62.6, 30.8, 15.6; HRMS (ESI-TOF) m/z Calcd for C14H22N2NaO3 289.1528 [M + Na]+; Found 289.1529.
N'-(2,2-Diethoxyethoxy)-N-phenylbenzimidamide (13b). General procedure D was followed using N'-hydroxy-N-phenylbenzimidamide 12b (577 mg, 2.72 mmol) in 5 mL of DMSO. Purification by silica flash column chromatography (8% to 30% EtOAc in n-heptane) afforded compound 13b (392 mg, 44% yield) as an oil; 1H NMR (400 MHz, CDCl3) δ 7.46 – 7.39 (m, 2H), 7.39 – 7.21 (m, 4H), 7.14 – 7.04 (m, 2H), 6.95 – 6.87 (m, 1H), 6.68 – 6.60 (m, 2H), 4.89 (t, J = 5.4 Hz, 1H), 4.17 (d, J = 5.4 Hz, 2H), 3.83 – 3.71 (m, 2H), 3.68 – 3.56 (m, 2H), 1.25 (t, J = 7.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 152.0, 139.9, 131.2, 129.8, 128.9, 128.6, 128.5, 122.8, 121.4, 100.4, 73.7, 62.7, 15.6; HRMS (ESI-TOF) m/z Calcd for C19H24N2NaO3 351.1684 [M + Na]+; Found 351.1705.
General procedure E for the synthesis of 5-substituted 3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazines via iminium ion additions. A 0.25 M solution of N'-(2,2-diethoxyethoxy)benzimidamide (9) in formic acid was heated to 100 °C for 15 min and then cooled to rt. Next, 5 equivalents of nucleophile were added and the mixture was stirred at the indicated temperature for the indicated time. The mixture was concentrated, co-evaporated with DCM twice and the product was purified as indicated.
5-(Furan-2-yl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6p). General procedure E was followed starting from 9 (1.14 g, 4.52 mmol) using furan as the nucleophile and stirring at rt for 20 h. Purification by silica flash column chromatography (20% to 40% EtOAc in n-heptane) afforded compound 6p (0.91 g, 88% yield) as a solid; mp 115 – 116 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.76 – 7.59 (m, 4H), 7.49 – 7.36 (m, 3H), 6.44 (dd, J = 3.2, 1.8 Hz, 1H), 6.40 – 6.32 (m, 1H), 4.77 (q, J = 3.7 Hz, 1H), 4.01 (dd, J = 11.0, 4.1 Hz, 1H), 3.91 (dd, J = 11.0, 3.5 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 153.6, 151.8, 142.3, 132.7, 129.8, 128.2, 126.0, 110.5, 106.9, 65.8, 47.2; HRMS (ESI-TOF) m/z Calcd for C13H13N2O2 229.0977 [M + H]+; Found 229.0985; IR (νmax, cm-1): 3377, 1605; Anal. Calcd for C13H12N2O2: C, 68.21; H, 5.10; N, 12.07%. Found: C, 67.97; H, 4.82; N, 11.88%. Compound 6p was also synthesised from 10 by stirring with furan for 20 h at rt in 92% yield.
5-(1H-Indol-3-yl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6q). General procedure E was followed starting from 9 (106 mg, 0.42 mmol) using indole as the nucleophile (2 equiv. added directly, an additional 2 equiv. after 30 min, followed by an additional 1 equiv. after 1 h) and stirring at rt for 20 h. Purification by silica flash column chromatography (15% to 50% EtOAc in n-heptane) followed by basic preparative HPLC afforded compound 6q (82 mg, 70% yield) as an amorphous solid; 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.76 – 7.67 (m, 2H), 7.62 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.48 – 7.32 (m, 5H), 7.14 – 7.05 (m, 1H), 7.04 – 6.95 (m, 1H), 5.02 – 4.93 (m, 1H), 4.11 (dd, J = 10.8, 4.0 Hz, 1H), 3.85 (dd, J = 10.8, 6.6 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 152.4, 136.5, 133.1, 129.6, 128.2, 126.1, 125.5, 123.6, 121.2, 118.8, 118.7, 113.4, 111.7, 68.1, 47.0; HRMS (ESI-TOF) m/z Calcd for C17H16N3O 278.1293 [M + H]+; Found 278.1294; IR (νmax, cm-1): 3310, 1607; Anal. Calcd for C17H15N3O: C, 73.63; H, 5.45; N, 15.15%. Found: C, 73.36; H, 5.44; N, 15.14%.
5-(1-Methyl-1H-indol-3-yl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6r). General procedure E was followed starting from 9 (109 mg, 0.43 mmol) using 1-methylindole as the nucleophile (3 equiv. added directly, an additional 2 equiv. after 1 h) and stirring at rt for 20 h. Purification by acidic preparative HPLC afforded compound 6r (108 mg, 86% yield) as a yellow amorphous solid; 1H NMR (400 MHz, DMSO-d6) δ 7.76 – 7.68 (m, 2H), 7.68 – 7.61 (m, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.49 – 7.37 (m, 4H), 7.35 (s, 1H), 7.21 – 7.12 (m, 1H), 7.08 – 7.00 (m, 1H), 5.01 – 4.93 (m, 1H), 4.09 (dd, J = 10.8, 3.9 Hz, 1H), 3.85 (dd, J = 10.8, 6.2 Hz, 1H), 3.77 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 152.3, 136.8, 133.1, 129.7, 128.2, 127.8, 126.1, 125.9, 121.3, 119.0, 118.8, 112.8, 109.9, 68.1, 46.7, 32.4; HRMS (ESI-TOF) m/z Calcd for C18H18N3O 292.1449 [M + H]+; Found 292.1448; IR (νmax, cm-1): 3180, 1606; Anal. Calcd for C18H17N3O: C, 74.20; H, 5.88; N, 14.42%. Found: C, 73.84; H, 6.10; N, 14.61%.
5-(1H-Indazol-3-yl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6s). General procedure E was followed starting from 9 (110 mg, 0.44 mmol) using indazole as the nucleophile and stirring at rt for 84 h. Purification by silica flash column chromatography (20% to 50% EtOAc in n-heptane) afforded compound 6s (106 mg, 87% yield) as a solid; mp 172 – 174 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 4.7 Hz, 1H), 8.15 (d, J = 0.9 Hz, 1H), 7.83 – 7.69 (m, 3H), 7.63 (dd, J = 8.6, 0.8 Hz, 1H), 7.54 – 7.42 (m, 3H), 7.40 – 7.32 (m, 1H), 7.20 – 7.11 (m, 1H), 6.43 – 6.35 (m, 1H), 4.24 (dd, J = 11.7, 2.7 Hz, 1H), 4.03 (dd, J = 11.7, 3.1 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 152.7, 138.5, 133.4, 131.9, 130.3, 128.5, 126.2, 126.0, 124.4, 120.9, 120.8, 110.8, 66.5, 65.0; HRMS (ESI-TOF) m/z Calcd for C16H15N4O 279.1246 [M + H]+; Found 279.1248; IR (νmax, cm-1): 3191, 1611; Anal. Calcd for C16H14N4O: C, 69.05; H, 5.07; N, 20.13%. Found: C, 68.88; H, 4.86; N, 20.07%.
5-(Benzofuran-2-yl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6t). General procedure E was followed starting from 9 (111 mg, 0.44 mmol) using benzofuran as the nucleophile and stirring at 100 °C for 2.5 h. Purification by SCX chromatography, basic preparative HPLC, followed by acidic preparative HPLC afforded compound 6t (65 mg, 53% yield) as an amorphous solid; 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 4.2 Hz, 1H), 7.76 – 7.66 (m, 2H), 7.66 – 7.59 (m, 1H), 7.59 – 7.53 (m, 1H), 7.52 – 7.40 (m, 3H), 7.33 – 7.19 (m, 2H), 6.87 – 6.81 (m, 1H), 4.96 (q, J = 3.5 Hz, 1H), 4.22 (dd, J = 11.1, 3.4 Hz, 1H), 3.98 (dd, J = 11.1, 3.4 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 156.8, 154.2, 151.8, 132.7, 129.9, 128.3, 128.0, 126.0, 124.1, 122.9, 121.0, 111.1, 103.9, 65.3, 47.6; HRMS (ESI-TOF) m/z Calcd for C17H15N2O2 279.1133 [M + H]+; Found 279.1130; IR (νmax, cm-1): 3323, 1603; Anal. Calcd for C17H14N2O2: C, 73.37; H, 5.07; N, 10.07%. Found: C, 72.82; H, 4.90; N,9.97 %.
5-(Benzo[b]thiophen-2-yl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6u). General procedure E was followed starting from 9 (0.51 g, 2.0 mmol) using benzo[b]thiophene as the nucleophile and stirring at 100 °C for 4 h. Purification by silica flash column chromatography (25% acetone in n-heptane) afforded a mixture of isomers. Further purification by silica flash column chromatography (18% to 40% EtOAc in n-heptane) afforded 6u (408 mg, 69%) as a solid; mp 87 – 89 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.06 – 8.01 (m, 1H), 8.01 – 7.95 (m, 1H), 7.78 (d, J = 3.4 Hz, 1H), 7.77 – 7.70 (m, 2H), 7.66 – 7.61 (m, 1H), 7.51 – 7.37 (m, 5H), 5.19 (q, J = 3.7 Hz, 1H), 4.08 (dd, J = 11.0, 3.6 Hz, 1H), 3.96 (dd, J = 11.0, 4.6 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 152.3, 140.2, 136.9, 135.5, 132.9, 129.8, 128.3, 126.1, 124.6, 124.5, 124.3, 123.1, 121.9, 66.9, 48.2, HRMS (ESI-TOF) m/z Calcd for C17H15N2OS 295.0905 [M + H]+; Found 295.0906; IR (νmax, cm-1): 3310, 1605; Anal. Calcd for C17H14N2OS: C, 69.36; H, 4.79; N, 9.52%. Found: C, 69.22; H, 4.53; N, 9.22%.
5-(Benzo[d][1,3]dioxol-5-yl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6v). General procedure E was followed starting from 9 (110 mg, 0.44 mmol) using 1,3-benzodioxole as the nucleophile and stirring at 100 °C for 4.5 h. Purification by silica flash column chromatography (40% to 65% EtOAc in n-heptane) afforded compound 6v (91 mg, 74% yield) as a solid; mp 155.5 – 156.5 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.75 – 7.66 (m, 2H), 7.62 (d, J = 2.9 Hz, 1H), 7.50 – 7.38 (m, 3H), 6.97 – 6.88 (m, 2H), 6.85 (dd, J = 8.1, 1.5 Hz, 1H), 6.00 (s, 2H), 4.63 (q, J = 3.6 Hz, 1H), 3.95 (dd, J = 10.9, 3.6 Hz, 1H), 3.70 (dd, J = 10.9, 5.0 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 152.3, 147.3, 146.5, 134.9, 132.9, 129.8, 128.3, 126.0, 120.0, 108.1, 107.2, 100.9, 68.9, 52.1; HRMS (ESI-TOF) m/z Calcd for C16H15N2O3 283.1082 [M + H]+; Found 283.1088; IR (νmax, cm-1): 3320, 1604; Anal. Calcd for C16H14N2O3: C, 68.07; H, 5.00; N, 9.92%. Found: C, 67.67; H, 4.67; N, 9.79%.
5-(2-Methoxyphenyl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6w) and 5-(4-methoxyphenyl)-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6b). General procedure E was followed starting from 9 (110 mg, 0.44 mmol) using anisole as the nucleophile and stirring at 100 °C for 2.5 h. Purification by silica flash column chromatography (20% to 40% EtOAc in n-heptane) and lyophilization afforded compound 6w (23 mg, 20% yield) as an amorphous yellow solid and compound 6b (79 mg, 67% yield) as an amorphous pink solid; 6w: 1H NMR (400 MHz, DMSO-d6) δ 7.77 – 7.67 (m, 2H), 7.53 (d, J = 3.9 Hz, 1H), 7.50 – 7.39 (m, 3H), 7.33 – 7.25 (m, 1H), 7.22 (dd, J = 7.5, 1.6 Hz, 1H), 7.04 (dd, J = 8.2, 0.8 Hz, 1H), 7.01 – 6.92 (m, 1H), 4.97 (q, J = 3.6 Hz, 1H), 3.92 (dd, J = 10.8, 3.5 Hz, 1H), 3.84 (s, 3H), 3.78 (dd, J = 10.8, 3.6 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 155.9, 152.5, 133.0, 129.8, 128.6, 128.4, 128.3, 127.3, 125.9, 120.2, 110.7, 67.0, 55.5, 47.2; HRMS (ESI-TOF) m/z Calcd for C16H17N2O2 269.1290 [M + H]+; Found 269.1287; IR (νmax, cm-1): 3382, 1603; Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44%. Found: C, 71.51; H, 5.97; N, 9.99%.
5-Allyl-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6x). To a solution of 10 (250 mg, 1.21 mmol) in DCM (5 mL) at 0 °C under nitrogen atmosphere allyltrimethylsilane (693 mg, 6.06 mmol) and BF3·OEt2 (860 mg, 6.06 mmol) were added. The mixture was allowed to come to rt and stirred for 20 h. It was poured out onto sat. aq. sodium bicarbonate, the layers were separated, the organic layer was dried using Na2SO4, concentrated and purified by silica flash column chromatography (0% to 50% EtOAc in n-heptane) to afford compound 6x (156 mg, 64% yield) as an oil that solidified upon standing; 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.55 (m, 2H), 7.47 – 7.31 (m, 3H), 5.91 – 5.73 (m, 1H), 5.25 – 5.21 (m, 1H), 5.21 – 5.17 (m, 1H), 4.92 (s, 1H), 4.18 – 4.02 (m, 1H), 3.73 – 3.54 (m, 2H), 2.50 – 2.36 (m, 1H), 2.33 – 2.17 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 152.5, 133.0, 133.0, 130.2, 128.7, 125.9, 119.3, 67.6, 48.8, 37.5; HRMS (ESI-TOF) m/z Calcd for C12H15N2O 203.1184 [M + H]+; Found 203.1182; IR (νmax, cm-1): 3323, 1607; Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98; N, 13.85%. Found: C, 71.09; H, 7.20; N, 13.65%.
1-Phenyl-2-(3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazin-5-yl)ethan-1-one (6y). 1-Phenyl-1-trimethyl- siloxyethylene (242 mg, 1.26 mmol) was slowly added to a suspension of 10 (200 mg, 0.97 mmol) and scandium trifluoromethanesulfonate (48 mg, 0.10 mmol) in DCM (5 mL) at 0 °C under an argon atmosphere. The mixture was allowed to come to rt and stirred for 24 h. Additional 1-phenyl-1-trimethylsiloxyethylene (242 mg, 1.26 mmol) was added and stirring was continued for 24 h. The mixture was concentrated under reduced pressure and the residue was purified by silica flash chromatography (10% to 60% EtOAc in n-heptane) to afford compound 6y (90 mg, 33% yield) as a gum; 1H NMR (400 MHz, CDCl3) δ 8.05 – 7.93 (m, 2H), 7.66 – 7.56 (m, 3H), 7.55 – 7.45 (m, 2H), 7.45 – 7.33 (m, 3H), 5.65 (s, 1H), 4.38 – 4.22 (m, 1H), 4.12 – 3.97 (m, 2H), 3.57 (dd, J = 18.0, 9.8 Hz, 1H), 3.28 (dd, J = 18.0, 3.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 198.9, 153.1, 136.5, 133.9, 132.7, 130.4, 128.9, 128.8, 128.2, 126.0, 67.3, 46.4, 43.0; HRMS (ESI-TOF) m/z Calcd for C17H17N2O2 281.1290 [M + H]+; Found 281.1293; IR (νmax, cm-1): 3207, 1684, 1608; Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.76; N, 9.99%. Found: C, 73.08; H, 5.75; N, 10.02%.
5-(Furan-2-yl)-4-methyl-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (14a). General procedure E was followed starting from 13a (198 mg, 0.74 mmol) using furan as the nucleophile and stirring at 70 °C for 4 h. Purification by silica flash column chromatography (0% to 50% EtOAc in n-heptane), followed by basic preparative HPLC afforded compound 14a (105 mg, 58% yield) as an amorphous solid; 1H NMR (400 MHz, DMSO-d6) δ 7.69 (dd, J = 1.8, 0.9 Hz, 1H), 7.55 – 7.34 (m, 5H), 6.53 – 6.43 (m, 2H), 4.71 (t, J = 3.9 Hz, 1H), 4.15 (dd, J = 11.3, 4.2 Hz, 1H), 4.03 (dd, J = 11.3, 3.7 Hz, 1H), 2.63 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 156.1, 151.6, 142.8, 132.5, 129.4, 128.6, 128.4, 110.6, 107.9, 66.4, 54.3, 37.8, HRMS (ESI-TOF) m/z Calcd for C14H15N2O2 243.1133 [M + H]+; Found 243.1139; IR (νmax, cm-1): 1591; Anal. Calcd for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56%. Found: C, 69.04; H, 5.73; N, 11.69%.
5-(Furan-2-yl)-3,4-diphenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (14b). General procedure E was followed starting from 13b (171 mg, 0.52 mmol) using furan as the nucleophile and stirring at 70 °C for 20 h. Purification by silica flash column chromatography (0% to 50% EtOAc in n-heptane), followed by basic preparative HPLC afforded compound 14b (108 mg, 68% yield) as an amorphous solid; 1H NMR (400 MHz, DMSO-d6) δ 7.69 (dd, J = 1.8, 0.9 Hz, 1H), 7.55 – 7.34 (m, 5H), 6.53 – 6.43 (m, 2H), 4.71 (t, J = 3.9 Hz, 1H), 4.15 (dd, J = 11.3, 4.2 Hz, 1H), 4.03 (dd, J = 11.3, 3.7 Hz, 1H), 2.63 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 151.9, 151.0, 144.9, 142.7, 133.5, 129.0, 128.2, 128.1, 125.1, 125.0, 110.7, 107.7, 66.3, 55.4; HRMS (ESI-TOF) m/z Calcd for C19H17N2O2 305.1290 [M + H]+; Found 305.1286; IR (νmax, cm-1): 1588; Anal. Calcd for C19H16N2O2: C, 74.98; H, 5.30; N, 9.20%. Found: C, 74.80; H, 5.27; N, 9.17%.
(S)-2-(Aminooxy)-1-phenylethan-1-amine (16). At 0 °C, diisopropyl azodicarboxylate (1.79 g, 8.85 mmol, 1.72 mL) was added to a solution of tert-butyl (S)-(2-hydroxy-1-phenylethyl)carbamate 15 (2.00 g, 8.43 mmol), N-hydroxyphthalimide (1.44 g, 8.85 mmol) and triphenylphosphine (2.32 g, 8.85 mmol) in THF (50 mL). The mixture was stirred at rt for 1 h, concentrated and the residue was purified by silica flash chromatography (5% to 25% EtOAc in n-heptane) to obtain a solid. Further purification by silica flash chromatography (0% to 2% MeOH in DCM) afforded tert-butyl (S)-(2-((1,3-dioxoisoindolin-2-yl)oxy)-1-phenylethyl)carbamate (3.01 g, 93%) as a solid; 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.77 (m, 2H), 7.77 – 7.70 (m, 2H), 7.42 – 7.36 (m, 2H), 7.34 – 7.27 (m, 2H), 7.25 – 7.16 (m, 1H), 5.92 (s, 1H), 5.04 (s, 1H), 4.60 – 4.41 (m, 2H), 1.44 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 163.5, 155.6, 138.6, 134.7, 128.8, 128.7, 127.7, 126.6, 123.7, 80.4, 80.0, 28.5. Hydrazine monohydrate (0.433 g, 8.66 mmol, 0.422 mL) was added to a suspension of tert-butyl (S)-(2-((1,3-dioxoisoindolin-2-yl)oxy)-1-phenylethyl)carbamate (3.01 g, 7.87 mmol) in EtOH (25 mL) and the mixture was stirred at rt for 15 min. The solids were filtered off, the filtrate was concentrated and the residue was purified by silica flash column chromatography (1% to 6% MeOH in DCM) to obtain the crude product. Further purification by silica flash column chromatography (20% to 100% EtOAc in n-heptane) afforded tert-butyl (S)-(2-(aminooxy)-1-phenylethyl)carbamate (1.60 g, 80%) as a solid; 1H NMR (400 MHz, DMSO-d6) as a mixture of rotamers δ 7.42 – 7.26 (m, 5H), 7.26 – 7.18 (m, 1H), 6.04 (s, 2H), 4.89 – 4.75 (m, 0.9H), 4.75 – 4.59 (m, 0.1H), 3.63 (dd, J = 10.6, 8.3 Hz, 1H), 3.55 (dd, J = 10.7, 5.5 Hz, 1H), 1.47 – 1.13 (m, 9H); 13C NMR (101 MHz, DMSO-d6) δ 155.2, 141.3, 128.1, 126.8, 126.8, 77.8, 52.8, 28.2; HRMS (ESI-TOF) m/z Calcd for C13H21N2O3 253.1552 [M + H]+; Found 253.1569. Saturated hydrochloric acid in EtOAc (10 mL) was added to a solution of tert-butyl (S)-(2-(aminooxy)-1-phenylethyl)carbamate (1.55 g, 6.14 mmol) in EtOAc (10 mL). The mixture was stirred at rt for 1 h and concentrated. The residue was dissolved in MeOH (20 mL), K2CO3 (2.0 g, 18.4 mmol) was added and the mixture was stirred at rt for 1 h. The solids were filtered off, the filtrate was concentrated and purified by silica flash column chromatography (10% (7M NH3 in MeOH) in DCM) to afford compound 16 (764 mg, 82%) as an oil; 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.32 (m, 4H), 7.29 – 7.25 (m, 1H), 4.29 (dd, J = 8.7, 4.0 Hz, 1H), 3.79 (dd, J = 10.3, 4.0 Hz, 1H), 3.67 (dd, J = 10.3, 8.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 142.6, 128.6, 127.5, 126.9, 81.9, 54.5; HRMS (ESI-TOF) m/z Calcd for C8H13N2O 153.1028 [M + H]+; Found 153.1038.
General procedure F for the synthesis of substituted 5,6-dihydro-4H-[1,2,4]oxadiazines via condensation of a diamine with an imidate. A 0.25 M solution of a diamine and an imidate (1 equiv.) was stirred in acetic acid at rt for 16 h, followed by heating to 100 °C for the indicated time. The mixture was concentrated, dissolved in DCM, washed with sat. NaHCO3, dried using Na2SO4, concentrated and the crude product was purified as described. When the diamine was a HCl salt, the free base was first prepared by stirring the compound in MeOH with K2CO3 (3 equiv.) for 30 min, followed by filtration and concentration of the filtrate, assuming quantitative yield.
(S)-3,5-Diphenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (S-6a). General procedure F was followed using (S)-2-(aminooxy)-1-phenylethan-1-amine 16 (93 mg, 0.61 mmol) and ethyl benzimidate hydrochloride and stirring at 100 °C for 2 h. Purification by silica flash column chromatography (50% EtOAc in n-heptane) afforded compound S-6a (123 mg, 84% yield) as a crystalline solid; mp 129 – 131 °C; [α]D23.5 = 109.3 (c 1, MeOH); Chiral HPLC: tR: 13.31 min, 100% (column: Chiralpak AD-H, 250 x 4.6 mm, 5 µm, eluent: 20% EtOH in heptane, flow: 1 mL/min, temp: 25 °C).
(S)-3-Methyl-5-phenyl-5,6-dihydro-4H[1,2,4]oxadiazine (S-18b). General procedure F was followed using (S)-2-(aminooxy)-1-phenylethan-1-amine 16 (161 mg, 1.06 mmol) and ethyl acetimidate hydrochloride, additional heating was not required. Purification by silica flash column chromatography (1% to 6% MeOH in DCM) afforded compound S-18b (152 mg, 82% yield) as a solid; mp 154 – 155.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.25 (m, 5H), 4.89 (s, 1H), 4.62 – 4.46 (m, 1H), 4.20 – 3.99 (m, 1H), 3.60 (dd, J = 11.1, 7.2 Hz, 1H), 1.95 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 151.3, 139.0, 129.0, 128.6, 126.8, 69.5, 54.2, 18.4; HRMS (ESI-TOF) m/z Calcd for C10H13N2O 177.1028 [M + H]+; Found 177.1024; IR (νmax, cm-1): 3198, 1615; Anal. Calcd for C10H12N2O: C, 70.28; H, 5.48; N, 17.56%. Found: C, 70.58; H, 5.45; N, 18.03%; [α]D24 60.0 (c 1.1, MeOH).
(S)-3-Cyclohexyl-5-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (S-18c). General procedure F was followed using (S)-2-(aminooxy)-1-phenylethan-1-amine 16 (177 mg, 1.16 mmol) and ethyl cyclohexanecarbimidate hydrochloride and stirring at 100 °C for 30 min. Purification by silica flash column chromatography (10% to 60% EtOAc in n-heptane) afforded compound S-18c (258 mg, 91% yield) as a solid; mp 105 – 106 °C; 1H NMR (400 MHz, CDCl3) δ 7.46 – 7.33 (m, 3H), 7.33 – 7.29 (m, 2H), 4.64 – 4.54 (m, 1H), 4.51 (s, 1H), 4.28 – 4.04 (m, 1H), 3.60 (dd, J = 11.1, 7.5 Hz, 1H), 2.23 (tt, J = 11.9, 3.4 Hz, 1H), 2.06 – 1.93 (m, 2H), 1.93 – 1.79 (m, 2H), 1.78 – 1.69 (m, 1H), 1.54 – 1.14 (m, 5H); 13C NMR (101 MHz, CDCl3) δ 158.0, 139.3, 129.1, 128.5, 126.8, 69.9, 54.2, 42.0, 31.0, 30.8, 26.22, 26.18, 26.0; HRMS (ESI-TOF) m/z Calcd for C15H21N2O 245.1654 [M + H]+; Found 245.1657; IR (νmax, cm-1): 3229, 1609; Anal. Calcd for C15H20N2O: C, 73.74; H, 8.25; N, 11.47%. Found: C, 73.50; H, 8.47; N, 11.54%; [α]D24 47.6 (c 1, MeOH).
(S)-5-Phenyl-3-(pyridin-2-yl)-5,6-dihydro-4H-[1,2,4]oxadiazine (S-18d). General procedure F was followed using (S)-2-(aminooxy)-1-phenylethan-1-amine 16 (161 mg, 1.06 mmol) and methyl picolinimidate and stirring at 100 °C for 2 h. Purification by silica flash column chromatography (10% to 60% EtOAc in n-heptane) afforded compound S-18d (215 mg, 85% yield) as a solid; mp 105 – 106.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 4.7 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.75 (td, J = 7.8, 1.7 Hz, 1H), 7.47 – 7.28 (m, 6H), 6.94 (s, 1H), 4.84 – 4.66 (m, 1H), 4.40 – 4.24 (m, 1H), 3.74 (dd, J = 10.9, 7.0 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 150.2, 148.7, 148.2, 139.0, 136.9, 129.1, 128.5, 126.9, 124.9, 120.3, 70.2, 53.6; HRMS (ESI-TOF) m/z Calcd for C14H14N3O 240.1137 [M + H]+; Found 240.1138; IR (νmax, cm-1): 3398, 1618; Anal. Calcd for C14H13N3O: C, 70.28; H, 5.48; N, 17.56%. Found: C, 70.58; H, 5.45; N, 17.83%; [α]D24 145.5 (c 1.1, MeOH).
2-(Aminooxy)propan-1-amine dihydrochloride (20b). tert-Butyl (2-(aminooxy)propyl)carbamate21 (500 mg, 2.63 mmol) was added to a 4 M solution of HCl in EtOAc (10 mL) and stirred for 1 h at rt. Evaporation of the reaction mixture afforded compound 20b (420 mg, 98%) as a solid; mp 194 – 195 °C (decomp.); 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 3H), 8.37 (s, 3H), 4.62 – 4.44 (m, 1H), 3.07 (m, 2H), 1.33 (d, J = 6.3 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 77.21, 41.23, 16.45; HRMS (ESI-TOF) m/z Calcd for C3H11N2O 91.0864 [M + H]+; Found 91.0871.
(1R,2S)-2-(Aminooxy)cyclohexan-1-amine (20e). To a solution of tert-butyl ((1R,2R)-2-hydroxycyclohexylcarbamate (1.0 g, 4.64 mmol) and N-hydroxyphthalimide (909 mg, 5.57 mmol) in dry THF (70 mL) was added triphenylphosphine (1.83 g, 6.96 mmol) and diisopropyl azodicarboxylate (1.35 mL, 6.96 mmol) and the mixture was stirred at rt for 3 h. The mixture was diluted with water (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica flash column chromatography (40% EtOAc in n-heptane) to afford tert-butyl ((1R,2S)-2-((1,3-dioxoisoindolin-2-yl)oxy)cyclohexyl)carbamate (1.18 g, 71%) as a solid; 1H NMR (400 MHz, CDCl3) δ 7.88 – 7.84 (m, 2H), 7.80 – 7.75 (m, 2H), 5.85 (br d, J = 7.0 Hz, 1H), 4.36 (s, 1H), 3.69 (br s, 1H), 2.27 – 2.23 (m, 1H), 1.97 – 1.69 (m, 4H), 1.60 – 1.35 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 164.2, 155.7, 134.7, 129.0, 123.7, 87.2, 79.2, 51.7, 29.4, 28.5, 27.6, 24.4, 19.6. To a solution of tert-butyl ((1R,2S)-2-((1,3-dioxoisoindolin-2-yl)oxy)cyclohexyl)carbamate (450 mg, 1.25 mmol) in DCM (40 mL) was added TFA (20 mL) and the mixture was stirred at rt for 3 h. The reaction mixture was concentrated and the residue was coevaporated with toluene (3 × 25 mL), DCM (25 mL) and Et2O (25 mL) to give an off-white foam as residue. This was dissolved in EtOH (35 mL), hydrazine monohydrate (0.47 mL, 9.6 mmol) was added and the mixture was stirred at rt for 16 h. The solids were filtered off, the filtrate was concentrated on silica and purified by silica flash column chromatography (10% (7M NH3 in MeOH) in DCM) to afford 20e (116 mg, 65%) as an oil; 1H NMR (400 MHz, CDCl3) δ 3.70 (dt, J = 6.9, 3.2 Hz, 1H), 3.23 (m, 1H), 1.92 – 1.86 (m, 1H), 1.72 – 1.44 (m, 5H), 1.38 – 1.31 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 82.2, 50.5, 29.8, 26.5, 22.2, 21.6; HRMS (ESI-TOF) m/z Calcd for C6H15N2O 131.1184 [M + H]+; Found 131.1195.
(1R,2R)-2-(Aminooxy)cyclohexan-1-amine (20f). To a solution of tert-butyl ((1R,2S)-2-hydroxycyclohexylcarbamate (0.5 g, 2.32 mmol) and N-hydroxyphthalimide (568 mg, 3.48 mmol) in dry THF (40 mL) was added triphenylphosphine (914 mg, 3.48 mmol) and diisopropyl azodicarboxylate (0.67 mL, 3.48 mmol) and the mixture was stirred at rt for 72 h. The mixture was diluted with water (70 mL) and extracted with DCM (3 × 70 mL). The combined organic layers were washed with brine (70 mL), dried over Na2SO4, concentrated and purified by silica flash column chromatography (45% EtOAc in n-heptane) to afford tert-butyl ((1R,2R)-2-((1,3-dioxoisoindolin-2-yl)oxy)cyclohexyl)carbamate (563 mg, 67%) as a solid; 1H NMR (400 MHz, CDCl3) δ 7.86 – 7.82 (m, 2H), 7.78 – 7.74 (m, 2H), 5.61 (br s, 1H), 3.98 – 3.91 (m, 1H), 3.64 – 3.57 (m, 1H), 2.41 (br d, J = 10.5 Hz, 1H), 2.19 – 2.15 (m, 1H), 1.83 – 1.60 (m, 3H), 1.44 (s, 9H), 1.40 – 1.18 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 164.3, 155.9, 134.7, 128.9, 123.7, 88.7, 79.3, 53.2, 31.8, 30.5, 28.6, 23.9, 23.7. To a solution of tert-butyl ((1R,2R)-2-((1,3-dioxoisoindolin-2-yl)oxy)cyclohexyl)carbamate (540 mg, 1.49 mmol) in DCM (40 mL) was added TFA (20 mL) and the mixture was stirred at rt for 1 h. The reaction mixture was concentrated and the residue was coevaporated with toluene (3 × 25 mL), DCM (25 mL) and Et2O (25 mL) to give an off-white foam as residue. This was dissolved in EtOH (35 mL), hydrazine monohydrate (0.6 mL, 12.3 mmol) was added and the mixture was stirred at rt for 16 h. The solids were filtered off, the filtrate was concentrated on silica and purified by silica flash column chromatography (10% (7M NH3 in MeOH) in DCM) to afford 20f (115 mg, 55%) as an oil; 1H NMR (400 MHz, CDCl3) δ 3.15 (ddd, J = 10.2, 9.3, 4.2 Hz, 1H), 2.62 (ddd, J = 10.8, 9.3, 4.4 Hz, 1H), 2.20 – 2.17 (m, 1H), 1.89 – 1.84 (m, 1H), 1.76 – 1.73 (m, 1H), 1.67 – 1.63 (m, 1H), 1.27 – 1.11 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 89.0, 53.7, 34.3, 29.6, 24.8, 24.5; HRMS (ESI-TOF) m/z Calcd for C6H15N2O 131.1184 [M + H]+; Found 131.1196.
1-(Aminooxy)-2-methylpropan-2-amine dihydrochloride (20j). Under an argon atmosphere, potassium bis(trimethylsilyl)amide (1 M in THF, 29.8 mL, 29.8 mmol) was added to a solution of acetone oxime (2.18 g, 29.8 mmol) in dry DMF (100 mL). A solution of 4,4-dimethyl-2-(trifluoromethyl)-4,5-dihydrooxazole22 (3.33 g, 19.9 mmol) in dry DMF (25 mL) was added and the mixture was heated at 80 °C for 2 h. The mixture was quenched with saturated aqeuous NH4Cl and extracted with EtOAc twice. The combined organic layers were washed with water, brine, dried over Na2SO4, concentrated and the residue was purified by silica flash column chromatography (5% to 25% EtOAc in n-heptane) to afford 2,2,2-trifluoro-N-(2-methyl-1-((propan-2-ylideneamino)oxy)propan-2-yl)acetamide (3.45 g, 68%) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 3.93 (s, 2H), 1.89 (s, 3H), 1.88 (s, 3H), 1.43 (s, 6H). A solution of 2,2,2-trifluoro-N-(2-methyl-1-((propan-2-ylideneamino)oxy)propan-2-yl)acetamide (3.45 g, 13.5 mmol) and sodium hydroxide (2.5 g, 42 mmol) in MeOH (75 mL) and water (75 mL) was heated at 55 °C for 16 h in a closed flask. The mixture was extracted with DCM (4 × 75 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford propan-2-one O-(2-amino-2-methylpropyl) oxime (1.95 g, 95%) as an oil; 1H NMR (400 MHz, CDCl3) δ 3.82 (s, 2H), 1.89 (s, 3H), 1.88 (s, 3H), 1.13 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 154.7, 83.4, 53.6, 50.9, 50.4, 27.5, 22.0, 15.7. A solution of propan-2-one O-(2-amino-2-methylpropyl) oxime (1.95 g, 12.8 mmol) in 2 M aqueous HCl (100 mL) was heated at 90 °C for 16 h. The mixture was concentrated under reduced pressure and triturated from EtOH (30 mL) to afford 20j (1.30 g, 57%) as a solid; 1H NMR (400 MHz, DMSO-d6) δ 11.28 (bs, 3H), 7.91 (bs, 3H), 4.08 (s, 2H), 1.31 (s, 6H), spectral data identical to literature.23
1-((Aminooxy)methyl)cyclopentan-1-amine (20k). To a solution of (1-aminocyclopentyl)methanol (1.60 g, 13.9 mmol) and N,N-diisopropylethylamine (3.59 g, 27.8 mmol) in DCM (75 mL) at 0 °C, trifluoroacetic anhydride (3.79 g, 18.06 mmol) was slowly added and the resulting mixture was stirred at rt for 90 min. Saturated aqueous NaHCO3 was added, the layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and the residue was purified by silica flash column chromatography (10% to 50% EtOAc in n-heptane) to obtain 2,2,2-trifluoro-N-(1-(hydroxymethyl)cyclopentyl)acetamide (2.68 g, 91% yield) as a solid; 1H NMR (400 MHz, CDCl3) δ 6.42 (s, 1H), 3.71 (s, 2H), 2.49 (s, 1H), 2.00 – 1.75 (m, 6H), 1.75 – 1.61 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 157.3 (q, J = 36 Hz), 115.9 (q, J = 288 Hz), 67.0, 66.7, 34.9, 24.3. At 0 °C, diisopropyl azodicarboxylate (2.69 g, 13.3 mmol) was added to a solution of 2,2,2-trifluoro-N-(1-(hydroxymethyl)cyclopentyl)acetamide (2.68 g, 12.7 mmol) and triphenylphosphine (3.50 g, 13.3 mmol) in DCM (100 mL). The mixture was stirred at rt for 30 min, concentrated, pentane (100 mL) was added and the mixture was stirred vigorously for 1 h. The solids were filtered off, washed with pentane and concentrated to afford 2-(trifluoromethyl)-3-oxa-1-azaspiro[4.4]non-1-ene as a yellow oil, which was used crude in the next step. Under an argon atmosphere potassium bis(trimethylsilyl)amide (1 M in THF, 18.1 mL, 18.1 mmol) was added to a solution of acetone oxime (1.32 g, 18.1 mmol) in dry DMF (40 mL). A solution of 2-(trifluoromethyl)-3-oxa-1-azaspiro[4.4]non-1-ene from the previous step in dry DMF (20 mL) was added and the mixture was heated at 80 °C for 2 h. The mixture was quenched with saturated aqeuous NH4Cl and extracted with EtOAc. The combined organic layer was washed with water, brine, dried over Na2SO4, concentrated and the residue was purified by silica flash column chromatography (5% to 25% EtOAc in n-heptane) to afford 2,2,2-trifluoro-N-(1-(((propan-2-ylideneamino)oxy)methyl)cyclopentyl)acetamide (2.83 g, 71% over 2 steps) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 3.98 (s, 2H), 2.19 – 2.07 (m, 2H), 1.99 – 1.89 (m, 2H), 1.88 (s, 3H), 1.87 (s, 3H), 1.80 – 1.68 (m, 2H), 1.67 – 1.54 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 156.40, 156.1 (q, J = 36 Hz), 116.0 (q, J = 289 Hz), 75.9, 66.1, 33.3, 25.0, 21.7, 15.6; HRMS (ESI-TOF) m/z Calcd for C11H17F3N2O2Na 289.1140 [M + Na]+; Found 289.1144. A solution of 2,2,2-trifluoro-N-(1-(((propan-2-ylideneamino)oxy)methyl)cyclopentyl)acetamide (2.23 g, 8.38 mmol) and sodium hydroxide (1.68 g, 41.9 mmol) in MeOH (75 mL) and water (75 mL) was heated at 55 °C for 16 h in a closed flask. The mixture was extracted with DCM (4 × 75 mL), the combined organic layers were dried over Na2SO4 and concentrated to afford propan-2-one O-((1-aminocyclopentyl)methyl) oxime (1.42 g, 99%) as an oil; 1H NMR (400 MHz, CDCl3) δ 3.92 (s, 2H), 1.88 (s, 3H), 1.87 (s, 3H), 1.84 – 1.73 (m, 2H), 1.73 – 1.57 (m, 4H), 1.49 – 1.38 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 154.6, 81.7, 61.5, 38.0, 24.5, 21.8, 15.6; HRMS (ESI-TOF) m/z Calcd for C9H19N2O 171.1497 [M + H]+; Found 171.1492. A solution of propan-2-one O-((1-aminocyclopentyl)methyl) oxime (1.22 g, 7.15 mmol) in 2 M aqueous hydrochloric acid (100 mL) was heated at 90 °C for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by silica flash chromatography (5% to 10% (7M NH3 in MeOH) in DCM) to afford 20k (724 mg, 79%) as an oil; 1H NMR (400 MHz, CDCl3) δ 3.58 (s, 2H), 1.88 – 1.69 (m, 2H), 1.69 – 1.51 (m, 4H), 1.51 – 1.34 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 84.9, 61.4, 38.3, 24.5; HRMS (ESI-TOF) m/z Calcd for C6H15N2O 131.1184 [M + H]+; Found 131.1188.
3-Phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (21a). General procedure F was followed using 2-(aminooxy)ethan-1-amine dihydrochloride 20a24 (194 mg, 1.30 mmol) and ethyl benzimidate hydrochloride and stirring at 100 °C for 3 h. Purification by silica flash column chromatography (15% to 60% EtOAc in n-heptane) afforded compound 21a (132 mg, 63% yield) as a solid; mp 130 – 132 °C; 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.54 (m, 2H), 7.47 – 7.33 (m, 3H), 4.80 (s, 1H), 4.07 – 3.98 (m, 2H), 3.60 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 130.3, 128.7, 126.0, 63.1, 40.9; HRMS (ESI-TOF) m/z Calcd for C9H10N2O 163.0872 [M + H]+; Found 163.0871; IR (νmax, cm-1): 3299, 1599; Anal. Calcd for C9H10N2O: C, 66.65; H, 6.21; N, 17.27%. Found: C, 66.46; H, 6.41; N, 17.50%.
6-Methyl-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (21b). General procedure F was followed using 2-(aminooxy)propan-1-amine dihydrochloride 20b (200 mg, 1.22 mmol) and ethyl benzimidate hydrochloride and stirring at 100 °C for 3 h. Purification by silica flash column chromatography (15% to 60% EtOAc in n-heptane) afforded compound 21b (161 mg, 74% yield) as a solid; mp 133 – 133.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.55 (m, 2H), 7.46 – 7.33 (m, 3H), 4.79 (s, 1H), 3.90 – 3.76 (m, 1H), 3.54 – 3.45 (m, 1H), 3.31 – 3.15 (m, 1H), 1.34 (d, J = 6.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 152.2, 133.1, 130.2, 128.7, 126.0, 67.8, 46.7, 17.6; HRMS (ESI-TOF) m/z Calcd for C10H13N2O 177.1028 [M + H]+; Found 177.1024; IR (νmax, cm-1): 3341, 1604; Anal. Calcd for C10H12N2O: C, 68.16; H, 6.86; N, 15.90%. Found: C, 67.79; H, 7.32; N, 16.24%.
5-Methyl-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (6d). General procedure F was followed using 1-(aminooxy)propan-2-amine dihydrochloride 20c23 (176 mg, 1.07 mmol) and ethyl benzimidate hydrochloride and stirring at 100 °C for 3 h. Purification by silica flash column chromatography (15% to 60% EtOAc in n-heptane gradient) afforded compound 6d (145 mg, 77% yield) as a solid.
4-Methyl-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (21d). A modified general procedure F was followed using 2-(aminooxy)-N-methylethan-1-amine dihydrochloride 20d17b (200 mg, 1.23 mmol) and ethyl benzimidate hydrochloride and stirring at 100 °C for 4 h. The methanol solution of the free base was not concentrated, but used as such for the formation of the intermediate as the diamine was volatile. Upon complete formation of the intermediate (rt, 16 h), the mixture was concentrated and the cyclisation was performed in AcOH as usual. Purification by silica flash chromatography (20% to 100% EtOAc in n-heptane) afforded compound 21d (123 mg, 57%) as an oil; 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.34 (m, 5H), 4.18 – 4.07 (m, 2H), 3.49 – 3.40 (m, 2H), 2.75 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 157.4, 132.6, 129.6, 128.8, 128.4, 63.8, 48.37, 39.7; HRMS (ESI-TOF) m/z Calcd for C10H13N2O 177.1028 [M + H]+; Found 177.1030; IR (νmax, cm-1): 1590; Anal. Calcd for C10H12N2O: C, 68.16; H, 6.86; N, 15.90%. Found: C, 67.31; H, 7.08; N, 15.71%.
(4aR,8aS)-3-Phenyl-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,2,4]oxadiazine (21e). General procedure F was followed using (1R,2S)-2-(aminooxy)cyclohexan-1-amine 20e (100 mg, 0.77 mmol) and ethyl benzimidate hydrochloride and stirring at 100 °C for 3 h. Purification by silica flash column chromatography (50% EtOAc in n-heptane) afforded compound 21e (88 mg, 53% yield) as a solid; mp >190 °C (decomp.); 1H NMR (400 MHz, DMSO-d6) δ 7.63 – 7.60 (m, 2H), 7.44 – 7.37 (m, 3H), 7.18 (d, J = 4.1 Hz, 1H) 3.71 (q, J = 3.5 Hz, 1H), 3.44 – 3.39 (m, 1H), 1.90 – 1.83 (m, 1H), 1.70 – 1.53 (m, 4H), 1.50 – 1.23 (m, 3H); 13C NMR (101 MHz, DMSO-d6) δ 150.3, 133.1, 129.4, 128.2, 125.7, 69.8, 48.5, 29.7, 27.9, 22.5, 20.4; HRMS (ESI-TOF) m/z Calcd for C13H17N2O 217.1341 [M + H]+; Found 217.1342; IR (νmax, cm-1): 3324, 1604; Anal. Calcd for C13H16N2O: C, 72.19; H, 7.46; N, 12.95%. Found: C, 72.34; H, 7.85; N, 12.87%; [α]D23 = -46.7 (c = 1, MeOH).
(4aR,8aR)-3-Phenyl-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,2,4]oxadiazine (21f). General procedure F was followed using (1R,2S)-2-(aminooxy)cyclohexan-1-amine 20f (100 mg, 0.77 mmol) and ethyl benzimidate hydrochloride and stirring at 100 °C for 3 h. Purification by silica flash column chromatography (50% EtOAc in n-heptane) afforded compound 21f (118 mg, 71% yield) as a solid; mp 141 – 142 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.64 – 7.62 (m, 2H), 7.44 – 7.37 (m, 3H), 6.97 (s, 1H), 3.12 (ddd, J = 11.4, 7.8, 4.0 Hz, 1H), 3.02 – 2.96 (m, 1H), 2.02 – 1.91 (m, 2H), 1.77 (m, 1H), 1.67 (d, J = 12.2 Hz, 1H), 1.43 – 1.15 (m, 4H); 13C NMR (101 MHz, DMSO-d6) δ 151.3, 133.2, 129.5, 128.1, 125.9, 76.2, 53.5, 29.7, 28.3, 24.1, 23.3; HRMS (ESI-TOF) m/z Calcd for C13H17N2O 217.1341 [M + H]+; Found 217.1341; IR (νmax, cm-1): 3334, 1600; Anal. Calcd for C13H16N2O: C, 72.19; H, 7.46; N, 12.95%. Found: C, 72.45; H, 7.38; N, 12.81%; [α]D23.5 = -78.5 (c = 1, MeOH).
(4aS,7aR)-3-Phenyl-4,4a,5,6,7,7a-hexahydrocyclopenta[e][1,2,4]oxadiazine (21g). General procedure F was followed using (1S,2R)-2-(aminooxy)cyclopentan-1-amine 20g25 (184 mg, 1.54 mmol) and ethyl benzimidate hydrochloride and stirring at 100 °C for 2 h. Purification by silica flash column chromatography (5% to 60% EtOAc in n-heptane) afforded compound 21g (243 mg, 78% yield) as a solid; mp 195 – 195.5 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.70 – 7.60 (m, 2H), 7.49 – 7.31 (m, 4H), 3.72 – 3.61 (m, 1H), 3.61 – 3.55 (m, 1H), 2.06 – 1.90 (m, 2H), 1.79 – 1.63 (m, 2H), 1.61 – 1.39 (m, 2H); 13C NMR (101 MHz, DMSO-d6) δ 152.3, 132.9, 129.6, 128.2, 125.7, 72.7, 53.9, 31.8, 28.8, 20.1; HRMS (ESI-TOF) m/z Calcd for C12H15N2O 203.1184 [M + H]+; Found 203.1180; IR (νmax, cm-1): 3311, 1602; Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98; N, 13.85%. Found: C, 70.81; H, 7.44; N, 13.99%; [α]D24 102.2 (c 1.01, MeOH).
(4aS,7aS)-3-Phenyl-4,4a,5,6,7,7a-hexahydrocyclopenta[e][1,2,4]oxadiazine (21h). General procedure F was followed using (1S,2S)-2-(aminooxy)cyclopentan-1-amine dihydrochloride 20h25 (280 mg, 1.48 mmol) and ethyl benzimidate hydrochloride and stirring at 100 °C for 48 h. Purification by silica flash column chromatography (10% to 50% EtOAc in n-heptane) afforded compound 21h (75 mg, 25% yield) as a solid; mp 140 – 141 °C; 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.63 (m, 2H), 7.46 – 7.34 (m, 3H), 4.91 (s, 1H), 3.67 (dt, J = 11.2, 7.5 Hz, 1H), 3.30 – 3.13 (m, 1H), 2.22 – 2.04 (m, 2H), 2.02 – 1.82 (m, 2H), 1.78 – 1.62 (m, 1H), 1.53 – 1.40 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 151.6, 133.2, 130.2, 128.7, 126.3, 80.3, 54.1, 26.6, 25.3, 18.1; HRMS (ESI-TOF) m/z Calcd for C12H15N2O 203.1184 [M + H]+; Found 203.1190; IR (νmax, cm-1): 3179, 1595; Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98; N, 13.85%. Found: C, 71.14; H, 7.44; N, 14.08%; [α]D23 -109.0 (c 0.77, MeOH).
(S)-4-Phenyl-6,7,8,8a-tetrahydro-1H-pyrrolo[1,2-d][1,2,4]oxadiazine (21i). General procedure F was followed using (S)-O-(pyrrolidin-2-ylmethyl)hydroxylamine 20i23 (322 mg, 2.58 mmol) and ethyl benzimidate hydrochloride and stirring at 100 °C for 16 h. Purification by silica flash column chromatography (5% to 70% EtOAc in n-heptane) afforded compound 21i (419 mg, 80% yield) as a solid; mp 138.5 – 140 °C; 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.47 (m, 2H), 7.47 – 7.33 (m, 3H), 4.43 (dd, J = 10.4, 3.9 Hz, 1H), 3.74 – 3.58 (m, 1H), 3.58 – 3.47 (m, 1H), 3.18 (dd, J = 10.4, 9.2 Hz, 1H), 3.10 – 2.93 (m, 1H), 2.31 – 2.10 (m, 1H), 1.89 – 1.69 (m, 2H), 1.69 – 1.55 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 155.7, 133.8, 129.6, 128.5, 128.3, 68.6, 54.2, 51.3, 28.5, 22.9; HRMS (ESI-TOF) m/z Calcd for C12H15N2O 203.1184 [M + H]+; Found 203.1179; IR (νmax, cm-1): 1538; Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98; N, 13.85%. Found: C, 71.29; H, 7.06; N, 13.65%. [α]D23 32.2 (c 0.99, MeOH).
5,5-Dimethyl-3-phenyl-5,6-dihydro-4H-[1,2,4]oxadiazine (21j). A modified general procedure F was followed using 1-(aminooxy)-2-methylpropan-2-amine dihydrochloride 20j (250 mg, 1.41 mmol) and ethyl benzimidate hydrochloride and stirring at 100 °C for 24 h. The methanol solution of the free base was not concentrated, but used as such for the formation of the intermediate as the diamine was volatile. Upon complete formation of the intermediate (rt, 16 h), the mixture was concentrated and the cyclisation was performed in AcOH as usual. Purification by silica flash column chromatography (5% to 60% EtOAc in n-heptane) afforded compound 21j (223 mg, 83%) as a solid; mp 139 – 140 °C; 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.58 (m, 2H), 7.47 – 7.35 (m, 3H), 4.54 (s, 1H), 3.68 (s, 2H), 1.32 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 152.0, 133.2, 130.2, 128.6, 126.0, 73.6, 49.4, 26.4; HRMS (ESI-TOF) m/z Calcd for C11H15N2O 191.1184 [M + H]+; Found 191.1179; IR (νmax, cm-1): 3255, 1595; Anal. Calcd for C11H14N2O: C, 69.45; H, 7.42; N, 14.73%. Found: C, 69.68; H, 7.37; N, 14.57%.
7-Phenyl-9-oxa-6,8-diazaspiro[4.5]dec-7-ene (21k). General procedure F was followed using 1-((aminooxy)methyl)cyclopentan-1-amine 20k (162 mg, 1.22 mmol) and ethyl benzimidate hydrochloride and stirring at 100 °C for 5 h. Purification by silica flash column chromatography (5% to 50% EtOAc in n-heptane) afforded compound 21k (229 mg, 87% yield) as a solid; mp 113 – 113.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.55 (m, 2H), 7.48 – 7.32 (m, 3H), 4.70 (s, 1H), 3.75 (s, 2H), 1.97 – 1.77 (m, 4H), 1.77 – 1.59 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 152.1, 130.2, 128.7, 126.1, 71.7, 60.2, 37.9, 23.9; HRMS (ESI-TOF) m/z Calcd for C13H17N2O 217.1341 [M + H]+; Found 217.1339; IR (νmax, cm-1): 3232, 1601; Anal. Calcd for C13H16N2O: C, 72.19; H, 7.46; N, 12.95%. Found: C, 72.50; H, 7.73; N, 13.21%

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