Mol Divers DOI 10.1007/s11030-014-9530-x

FULL-LENGTH PAPER

Synthesis of triazolo-fused benzoxazepines and benzoxazepinones via Passerini reactions followed by 1,3-dipolar cycloadditions Fabio De Moliner · Martina Bigatti · Chiara De Rosa · Luca Banfi · Renata Riva · Andrea Basso

Received: 14 April 2014 / Accepted: 9 May 2014 © Springer International Publishing Switzerland 2014

Abstract Azidobenzaldehydes can be used in Passerini three-component condensations to synthesize small collections of triazolo-fused heterocycles in an efficient and combinatorial fashion upon post-condensation azide–alkyne cycloadditions. Triazolo-fused benzoxazepinones were obtained in moderate to good overall yields with a concise two-step protocol. Triazolo-fused benzoxazepines were instead prepared by means of a longer, yet straightforward route comprising a Passerini reaction, hydrolysis of the ester moiety, O-alkylation with propargylic bromides, and 1,3dipolar cycloaddition. Keywords Benzoxazepines · Benzoxazepinones · Azidoaldehydes · Multicomponent reactions · MCRs · Passerini reaction · Dipolar cycloaddition · Microwaves

Introduction Azidoaldehydes have emerged over the last 10 years as useful building blocks in multicomponent reactions (MCRs). In this respect, the azido group has been proved ideal for postcondensation transformations taking place after the multicomponent step, and involving additional functional groups Electronic supplementary material The online version of this article (doi:10.1007/s11030-014-9530-x) contains supplementary material, which is available to authorized users. F. De Moliner · M. Bigatti · C. De Rosa · L. Banfi · R. Riva · A. Basso (B) Department of Chemistry and Industrial Chemistry, University of Genova, Via Dodecaneso 31, 16146 Genoa, Italy e-mail: [email protected]; [email protected] Present Address: C. De Rosa Aptuit Srl, Via Fleming 4, 37135 Verona, Italy

installed in the starting components and/or formed during the MCR itself [1,2]. Such an approach is a powerful tool for the rapid generation of complexity and diversity in a combinatorial fashion [3], since it allows the production of several different scaffolds with a single synthetic methodology, thus meeting the requirements of diversity-oriented synthesis [4]. Indeed, the azide moiety is rather unreactive in the mild conditions usually employed to perform most MCRs, but it can give [3+2] cycloadditions with triple bonds upon simple heating [5,6], and it is easily engaged in Staudinger aza-Wittig reactions onto carbonyl groups after the addition of a phosphine [7,8]. Our group has been active in this field by investigating the application of unusual α-azidoaldehydes in Passerini reactions [9,10], which led to the development of straightforward two-step routes for the preparation of 5carboxamide-oxazolines [11] and triazolo-fused dihydrooxazinones [12]. However, the elusive and labile nature of these chemical species represent a limitation to their use, as it makes isolation, storage, and handling difficult. Their in situ generation from the corresponding alcohols [13] or acetals [14] is, therefore, required. 2-Azidobenzaldehydes are a much more popular class of azidoaldehydes that do not suffer from the aforementioned drawbacks. Thanks to their full stability and ready accessibility from commercially available starting materials [15–18], they have in fact been widely utilized not only in the well-known Ugi [19] and Passerini [9] reactions followed by Staudinger aza-Wittig cyclizations to obtain a plethora of heterocyclic nuclei such as benzoxazines [20], dihydroquinazolines [21,22], dihydrobenzodiazepines [23], and indoloquinazolines [24], but also in less common Van Leusen imidazole syntheses [25] and Streckertype processes [26]1 coupled with Huisgen intramolecular cycloadditions [27,28]. In this context, it is quite surprising to 1

For an overview on Strecker and Strecker-type processes, see: [26].

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Scheme 1 Two-step synthesis of benzoxazepinones 4. Reagents and conditions (i) DCM, rt; (ii) PhMe, reflux; (iii) DMF, 150 ◦ C (MW, 150 W). Sets of the starting materials are shown in the bottom part

notice that no reports describing a Passerini reaction involving aromatic azidoaldehydes and propynoic acids combined with a subsequent 1,3-dipolar cycloaddition are available in the literature to date.

Results and discussion Prompted by our previous experience with this chemistry, we decided to undertake studies to evaluate the feasibility of a synthetic protocol based on such sequence (Scheme 1), that would provide a fast and expeditious entry into a family of unusual and intriguing triazolo-fused benzoxazepinones. Initially, the multicomponent step was conducted by dissolving an azidobenzaldehyde 1, an isocyanide 2 and a propynoic acid 3 in dichloromethane and stirring the resulting mixture overnight at room temperature, according to a standard procedure to perform the Passerini reaction [10]. Although the P-3CC is well known for its robustness and wide scope, we were aware of some issues that could arise from the presence of a triple bond in one of the building blocks. In particular, the acetylene moiety is prone to undergo an addition to isocyanides to give zwitterionic species, which can in turn evolve into numerous different adducts upon interaction with the additional components such as dipolarophiles, although this phenomenon is typically favored by elevated temperatures [29]. Consequently, we were pleased to observe that the condensation proceeded smoothly affording compounds 4 in moderate to good isolated yields ranging from 33 to 83 % after column chromatography, without formation of significant amounts of side products. This finding is in accordance with the previous reports by us [12] and by others [30,31] dealing with the use of acetylenic acids in the Passerini reac-

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tion. Overall, three aldehydes, four isocyanides, and four acids were employed, with propynoic acid 3a turning out to perform poorly (entry 2, Table 1), and sometimes even failing to give any major product (entry 9, Table 1), most likely because of its tendency to decompose [12]. On the other hand, the remaining reactants were all able to provide satisfactory outcomes, notwithstanding slow reaction rates and in some cases difficulty to drive the P-3CC to completion. The acyclic precursors were subsequently submitted to the 1,3-dipolar cycloaddition step, which according to our experience, was likely to be triggered by thermal conditions alone, without the need for any catalyst or additive. Nevertheless, the reaction was found to be rather slow unless when carried out at high temperatures. Microwave heating of a DMF solution of 4 at 150 ◦ C (method A) proved capable to afford the desired product 5, but the strategy lacked general applicability, since title compounds were sometimes not detected at all, whereas in most other cases it was not possible to isolate them in pure form. In fact, this methodology was in most instances plagued by the formation of many by-products, which either had to be removed by means of non trivial purification methods or resulted virtually impossible to separate from 5. On the basis of our studies [12] on the cyclization of Passerini products via azide–alkyne reactions, we thus tried to run the post-condensation elaboration in refluxing toluene by applying conventional heating in an oil bath (method B). Gratifyingly, the transformation was observed to take place in a generally cleaner way with broader scope, although complete conversion was achieved only after several days, probably due to deactivation of the triple bond by the nearby electronwithdrawing ester group [32]. Further optimization efforts varying solvent and conditions resulted in no improvements, being the use of chloroform [33] and the combination of

Mol Divers Table 1 Scope of the two step synthesis of benzoxazepinones 4

Entry

Aldehyde

Isocyanide

Acid

Final product

Yield of 4 (%)

Method

Yield of 5 (%)

1

1a

2b

3b

5a

59

A

21

2

1a

2b

3a

5b

17

B

14

3

1a

2b

3b

5c

70

B

78

4

1a

2d

3c

5d

57

A

68

5

1b

2a

3d

5e

63

A

30

6

1b

2c

3c

5f

38

B

85

7

1b

2d

3b

5g

77

B

59

8

1b

2d

3c

5h

53

B

36

9

1c

2a

3a

5i

/

A /B

/

10

1c

2c

3d

5j

82

B

53

toluene with microwave irradiation incapable to give better results. Despite the limited reactivity of 4, a small collection of nine unprecedented triazolo-fused benzoxazepinones (Table 1) was prepared thereof, and the alternative use of the two methodologies allowed for the attainment of a good level of diversity with minimal operational effort. It is worth noting that, even though somehow hampered by the difficulties in the second step, the sequence represents a straightforward preparation of uncommon molecules with potential biological significance [34,35]. As a matter of fact, while regioisomeric species bearing a carbonyl in the three positions have been assembled in the past from propargyl azidobenzoates [36,37], the synthesis of benzoxazepin2-ones fused with a triazole ring is to the best of our knowledge unprecedented. Prompted by the wide potential of this approach, we then moved to explore possible modifications of the methodology, that could enable access to additional appealing heterocyclic scaffolds and overcome the drawback posed by the deactivating effect of the ester moiety in 4. In this respect, the use of a carboxylic input having a methylene unit between the triple bond and the carbonyl functionality in the P-3CC seemed ideal. Mindful of the ability of nitriles to act as dipolarophiles in intramolecular [3+2] cycloadditions with azides [38], we postulated that the use of cyanoacetic acid 6 to get α-acyloxyamide 7 would pave the way to the generation of tetrazole-containing chemotype 8 (Scheme 2). Disappointingly, after a Passerini condensation with 1a and 2b, which rendered 7 in a 49 % isolated yield, the subsequent cyclization step turned out to be unfeasible even upon prolonged heating in the neat state [39].

In the light of this failure, an alternative library implying the replacement of the acid component with a propargyl alcohol was designed (Scheme 3). The novel strategy could afford triazolo-fused benzoxazepines 11, which are almost unprecedented in the literature [40], and could avoid the formation of the troublesome ester bond impairing the reactivity of the alkyne (and presumably decreasing resistance of the final compounds to in vivo hydrolysis). Unfortunately, alkylative Passerini [41] reaction between 2-azido benzaldehydes, isocyanides, and propargyl alcohols proved to be unrealizable, and an alternative strategy was investigated. A viable option to accomplish this goal was found to be the design of a pathway encompassing a truncated Passerini reaction [42] followed by O-alkylation with propargyl bromides for initial diversity generation prior to the final azide–alkyne cycloaddition-based cyclization step. Preliminary attempts to react 2-azidobenzaldehydes and isocyanides in the presence of either trifluoroacetic acid [43] or boric acid [44] turned out to give rather sluggish outcomes, and a Passerini reaction involving acetic acid as the carboxylic partner was identified as a straightforward route (Scheme 4) thanks to the very facile deacetylation [45]. As both hydrolysis and O-alkylation require basic conditions to take place, a convenient approach performing the two transformations in onepot was envisioned upon simultaneous treatment of 12 with bromides 13, which can be effortlessly prepared from the corresponding alcohols via the mesylates [46], and a 30 % sodium hydroxide solution under phase-transfer conditions. Gratifyingly, compounds 10 could be assembled by means of the above-mentioned pathway, and no concomitant N-

Scheme 2 Attempted synthesis of benzoxazocinone 8. Reagents and conditions (i) DCM; rt; (ii) heating

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Scheme 3 Postulated alkylative Passerini-based approach toward 13

Scheme 4 Passerini reaction-hydrolysis-O-alkylation sequence toward benzoxazepines 11. Reagents and conditions (i) DCM, rt; (ii) NaOH 30 %, Bu4 NBr 0.1 eq, DCM, rt; (iii) PhMe, 100 ◦ C, MW, 150 W). Sets of the starting materials are shown in the bottom part

Table 2 Scope of the Passerini reaction-hydrolysis-Oalkylation sequence toward benzoxazepines 11

a

Partial spontaneous cyclization to 10 took place

Entry

Aldehyde

Isocyanide

Bromide

Final product

Yield of 10 (%)

Yield of 11 (%)

1 2 3 4 5 6 7 8 9 10

1a 1a 1a 1a 1a 1a 1a 1b 1b 1b

2a 2b 2b 2b 2b 2e 2f 2a 2a 2a

13a 13a 13b 13c 13d 13d 13a 13a 13b 13c

11a 11b 11c 11d 11e 11f 11g 11h 11i 11j

/a /a /a 86 59 36 /a /a 81 Quantitative

62 58 65 99 79 92 74 68 97 77

alkylation of the amidic nitrogen ever occurred, in accordance with literature precedents [47,48]. The P-3CR between 2-azidobenzaldehydes, isocyanides, and acetic acid was, therefore, run under the usual mild conditions in DCM, and crude material 12 was submitted to the one-pot hydrolysis/alkylation process without further purification, generally providing a very satisfactory outcome. With compounds 10 in hand, we were delighted to observe that the planned 1,3-dipolar cycloaddition between the azido group and the triple bond often displayed a marked tendency to happen spontaneously. When purified 10 were left standing at room temperature, their partial conversion into 11 was in fact often observed, particularly in the case of products possessing a terminal alkyne. Pleased by this finding, we then

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started to investigate an efficient strategy to pursue the formation of 11, which was quite easily achieved by means of microwave irradiation of a toluene solution of 10. The optimized methodology was thus exploited to generate a small collection of ten benzoxazepines 11 (Table 2) in typically very good overall yields. Overall, two 2-azidobenzaldehydes 1, four isocyanides 2 ,and four propargyl bromides 13 made up the diversity-generating pool. Noteworthy, we recently reported [49] that 2-azidobenzylalcohols can be used instead of aldehydes 1: in situ oxidation with diacetoxyiodobenzene and TEMPO followed by the addition of the isocyanide afforded the acetylated Passerini adducts 12, exploiting convenient liberation of acetic acid from the oxidizing agent [50].

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Conclusions In summary, we have herein demonstrated that employment of 2-azidobenzaldehydes in MCR-based pathways involving a Passerini reaction for initial diversity generation coupled with Huisgen [3+2] azide–alkyne cycloaddition allows for the rapid construction of the otherwise challenging triazolofused benzoxazepinones and benzoxazepines scaffolds 5 and 11. Wide scope, versatility, and operative simplicity represent the key features of this approach comprising efficient, high-yielding, and atom-economic chemical transformations requiring easily accessible starting materials, no controlled operational conditions and simple purifications of the final products. We believe that such strategies will make possible the easy preparation of large diverse libraries of the title compounds in a combinatorial format.

Experimental section General experimental methods NMR spectra were recorded on a Varian Mercury-300 instrument at 300 MHz (1 H) and 75 MHz (13 C) and the chemical shifts (δ) are expressed in parts per million relative to tetramethylsylane (TMS) as internal standard (0.00 ppm) (the following abbreviations have been employed: s: singlet, d: doublet, t: triplet, sext: sextuplet, dd: double doublet, dt: double triplet, ddd: double double doublet, m: multiplet, and br: broad) . Coupling constants are reported in Hertz. NMR acquisitions were performed at 295 K and CDCl3 was used as a solvent. HR-MS were acquired on a Waters Micro Mass LCT, employing an ESI+ ionization method and TOF as analyzer. Microwave-assisted reactions were performed with CEM Discover. Reactions were monitored by TLC. TLC analyses were carried out on silica gel plates (thickness = 0.25 mm), viewed at UV (λ = 254 nm) and developed with Hanessian stain (dipping into a solution of (NH4 )4 MoO4 · 4H2 O (21 g) and Ce(SO4 )2 · 4H2 O (1 g) in H2 SO4 (31 mL) and H2 O (469 mL) and warming). Column chromatography was performed with the “flash” methodology using 220–400 mesh silica. Solvents employed as eluents and for all other routinary operations, as well as anhydrous solvents and all reagents used were purchased from commercial suppliers and employed without any further purification. Azidobenzaldehydes 1 were prepared according to Ref. [15]. Propargyl bromides 13 were prepared according to Ref. [46]. General procedure for the preparation of Passerini adducts 4 2-Azidobenzaldehyde 1 (1 mmol), isocyanide 2 (1.5 mmol) and carboxylic acid 3 (1 mmol) were dissolved in dry DCM

(4 mL) in a 10-mL round-bottomed flask and stirred at room temperature for 5 days. Volatiles were then removed under reduced pressure, and the crude product was purified by means of flash chromatography to afford Passerini adduct 4. 1-(2-Azidophenyl)-2-(cyclohexylamino)-2-oxoethyl 3-(trimethylsilyl)propiolate (4a) White foam (235 mg, 59 % yield) upon flash chromatography (silica gel, PE/Et2 O 7:3). R f = 0.28 (silica gel, PE/Et2 O 7:3). 1 H NMR (300 MHz, CDCl3 ) δ = 7.47 (d, J = 8.1 Hz, 1H), 7.40 (t, J = 7.0 Hz, 1H), 7.27 (d, J = 1.3 Hz, 1H), 7.17 (t, J = 8.3 Hz, 1H), 6.27 (s, 1H), 6.08 (d, J = 8.0 Hz, 1H), 3.70–3.79 (m, 1H), 1.02–2.00 (m, 10H), 0.25 (s, 9H). 13 C NMR (75 MHz, CDCl3 ) δ = 166.2, 151.5, 138.4, 130.7, 129.8, 126.3, 125.4, 118.6, 96.7, 93.8, 72.1, 48.6, 33.0, 25.6, 24.8, 0.7. HR-MS found: [M+H]+ 399.1862; C20 H27 N4 O3 Si requires 399.1853. 1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl propiolate (4b) Yellow wax (51 mg, 17 % yield) upon flash chromatography (silica gel, PE/EtOAc 8:2). R f = 0.31 (silica gel, PE/EtOAc 8:2). 1 H NMR (300 MHz, CDCl3 )δ= 7.36–7.50 (m, 2H), 7.13–7.23 (m, 2H), 6.21 (s, 1H), 6.01 (s, 1H), 3.00 (s, 1H), 1.36 (s, 9H). 13 C NMR (75 MHz, CDCl3 ) δ = 166.0, 151.2, 138.4, 130.8, 129.7, 126.3, 125.5, 118.7, 76.7, 74.2, 72.5, 52.1, 28.9. HR-MS found: [M+H]+ 301.1305; C15 H17 N4 O3 requires 301.1301. 1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl 3-(trimethylsilyl)propiolate (4c) Yellow wax (261 mg, 70 % yield) upon flash chromatography (silica gel, PE/EtOAc 9:1). R f = 0.27 (silica gel, PE/EtOAc 9:1). 1 H NMR (300MHz, CDCl3 ) δ = 7.46–7.51 (m, 2H), 7.36–7.44 (m, 2H), 6.20 (s, 1H), 6.01 (s, 1H), 1.37 (s, 9H), 0.25 (s, 9H). 13 C NMR(75MHz, CDCl3 ) δ = 166.2, 151.4, 138.2, 130.5, 129.6, 126.4, 125.3, 118.5, 96.5, 93.8, 77.3, 72.0, 51.9, 28.7, −0.8. HR-MS found: [M+H]+ 373.1690; C18 H25 N4 O3 Si requires 373.1697. 1-(2-Azidophenyl)-2-(4-(benzyloxy)phenylamino)-2-oxoethyl hex-2-ynoate (4d) Orange wax (267 mg, 57 % yield) upon flash chromatography (silica gel, PE/EtOAc 8:2). R f = 0.40 (silica gel, PE/EtOAc 8:2). 1 H NMR (300 MHz, CDCl3 ) δ = 7.84–7.88 (m, 1H), 6.91–7.46 (m, 13H), 6.42 (s, 1H), 5.04 (s, 2H), 2.35 (t, J = 8.1 Hz, 2H), 1.59–1.65 (m, 2H), 1.03 (t, J = 8.1 Hz, 3H). 13 C NMR (75 MHz, CDCl3 ) δ = 165.1, 156.0, 152.1, 138.2, 137.0, 130.7, 130.4, 129.8, 128.7, 128.1, 127.6, 126.0, 125.5, 121.9, 118.5, 115.5, 92.3, 72.6, 72.0, 70.4, 21.1, 20.9, 13.7. HR-MS found: [M+H]+ 469.1868; C27 H25 N4 O4 requires 469.1877. 1-(2-Azido-5-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl 3-phenylpropiolate (4e) Light yellow foam (275 mg, 63 % yield) upon flash chromatography (silica gel, CH2 Cl2 /PE 7 : 3 + 3 %Et2 O). R f = 0.38 (silica gel, CH2 Cl2 /PE

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7 : 3 + 3 %Et2 O). 1 H NMR (300 MHz, CDCl3 ) δ =7.59– 7.66 (m, 2H), 7.35–7.49 (m, 4H), 7.52 (d, J = 2.2 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 6.29 (s, 1H), 6.18 (d, J = 8.3 Hz, 1H), 3.82–3.90 (m, 1H), 1.13–2.02 (m, 10H). 13 CNMR (75 MHz, CDCl3 ) δ = 165.7, 152.1, 137.9, 133.3, 131.3, 130.8, 130.6, 129.7, 128.9, 128.1, 119.8, 119.2, 88.9, 79.9, 71.5, 48.7, 33.1, 25.5, 24.9. HR-MS found: [M+H]+ 437.1389; C23 H22 ClN4 O3 requires 437.1381.

7.2 Hz, 3H). 13 C NMR (75 MHz, CDCl3 ) δ = 169.5, 167.7, 152.3, 136.9, 133.5, 133.3, 132.7, 131.2, 128.8, 127.1, 126.6, 119.3, 88.6, 80.0, 72.9, 61.9, 41.5, 18.1, 14.2. HR-MS found: [M + H]+ 421.1513; C22 H21 N4 O5 requires 421.1513.

1-(2-Azido-5-chlorophenyl)-2-(2-ethoxy- 2-oxoethylamino)2-oxoethyl hex-2-ynoate (4f) Yellow wax (155 mg, 38 % yield) upon flash chromatography (silica gel, PE/EtOAc 85:15). R f = 0.38 (silica gel, PE/EtOAc 85:15). 1 H NMR (300 MHz, CDCl3 ) δ = 7.49 (d, J = 2.2 Hz, 1H), 7.35– 7.41 (m, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.88 (m, 1H), 6.33 (s, 1H), 4.11 (m, 4H), 2.36 (t, J = 8.1 Hz, 2H), 1.64 (m, 2H), 1.29 (t, J = 7.6 Hz, 3H), 1.03 (t, J = 8.1 Hz, 3H). 13 C NMR (75 MHz, CDCl ) δ = 169.3, 166.9, 151.8, 3 136.9, 130.7, 130.6, 129.3, 127.6, 119.6, 92.6, 72.4, 70.8, 61.9, 41.5, 21.0, 20.9, 14.2, 13.6. HR-MS found: [M+H]+ 407.1132; C18 H20 ClN4 O5 requires 407.1123.

Passerini adduct 4 was dissolved in dry DMF (3 mL) in a 8-mL MW vial and the solution was heated at 150 ◦ C by means of microwave irradiation (P = 200 W). Reaction mixture was then diluted with water (10 mL) and extracted with Et2 O (3 × 10 mL). The organic layer was dried over Na2 SO4 , filtered and concentrated under reduced pressure. Crude product was purified by means of flash chromatography to afford triazolobenzoxazepinone 5.

1-(2-Azido-5-chlorophenyl)-2-(4-(benzyloxy)phenylamino) -2-oxoethyl3-(trimethylsilyl)propiolate (4g) Yellow oil (411 mg, 77 % yield) upon flash chromatography (silica gel, PE/EtOAc 85:15). R f = 0.27 (silica gel, PE/EtOAc 85:15). 1 H NMR (300 MHz, CDCl ) δ = 7.87 (s, 1H), 7.50(d, 3 J = 2.1 Hz, 1H), 7.28–7.42 (m, 8H), 7.15–7.06 (m, 1H), 6.87–6.96 (m, 2H), 6.36 (s, 1H), 5.04 (s, 2H), 0.28 (s, 9H). 13 C NMR (75 MHz, CDCl ) δ = 164.3, 156.1, 151.2, 3 136.9, 136.8, 130.7, 129.6, 128.7, 128.1, 127.6, 122.0, 119.7, 115.6, 115.4, 97.7, 93.4, 71.5. 70.4, −0.8. HR-MS found: [M+H]+ 533.1401; C27 H26 ClN4 O4 Si requires 533.1413. 1-(2-Azido-5-chlorophenyl)-2-(4-(benzyloxy)phenylamino)2-oxoethyl hex-2-ynoate (4h) Yellow wax (267 mg, 53 % yield) upon flash chromatography (silica gel, PE/EtOAc 8:2). R f = 0.22 (silica gel, PE/EtOAc 85:15). 1 H NMR (300 MHz, CDCl3 ) δ = 7.97 (br, s, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.25–7.46 (m, 8H), 7.22 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 7.7 Hz, 2H), 6.35 (s, 1H), 5.03 (s, 2H), 2.36 (t, J = 8.0 Hz, 2H), 1.65 (m, 2H), 1.03 (t, J = 8.0 Hz, 3H). 13 C NMR (75 MHz, CDCl ) δ = 164.5, 156.1, 151.9, 3 136.9, 136.8, 130.6, 129.5, 128.7, 128.1, 127.6, 121.9, 119.7, 115.1, 92.9, 72.4, 71.3, 70.3, 21.0, 20.9, 13.7. HR-MS found: [M+H]+ 503.1480; C27 H24 ClN4 O4 requires 503.1487. 1-(2-Azido-3-methylphenyl)-2-(2-ethoxy-2-oxoethylamino)2-oxoethyl 3-phenylpropiolate (4j) Yellow oil (345 mg, 82 % yield) upon flash chromatography (silica gel, PE/EtOAc 7:3). R f = 0.58 (silica gel, PE/EtOAc 7:3). 1 H NMR (300 MHz, CDCl3 ) δ = 7.16–7.63 (m, 8H), 6.91 (br, s, 1H), 6.60 (s, 1H), 4.00–4.27 (m, 4H), 2.47 (s, 3H), 1.29 (t, J =

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General procedure for the preparation of triazolobenzoxazepinones 5 according to method A: use of microwave irradiation

General procedure for the preparation of triazolobenzoxazepinones 5 according to method B: Use of conventional heating Passerini adduct 4 was dissolved in dry toluene (5 mL) in a 10-mL round-bottomed flask and the solution was refluxed under nitrogen for 2 days. The solvent was then removed under reduced pressure, and the crude product was purified by means of flash chromatography to afford triazolobenzoxazepinone 5. N-cyclohexyl-4-oxo-3-(trimethylsilyl)-4, 6-dihydrobenzo [e] [1,2,3]triazolo[5,1-c][1,4]oxazepine-6 carboxamide (5a) Prepared according to method A. Light brown oil (49 mg, 21 % yield) upon flash chromatography (silica gel, PE/EtOAc 6:4). R f = 0.47 (silica gel, PE/EtOAc 6:4). 1 H NMR (300 MHz, CDCl ) δ = 8.04(d, J = 7.8 Hz, 3 1H), 7.67 (dt, J = 7.7, 2.0 Hz, 1H), 7.46–7.58 (m, 2H), 6.78–6.86 (m, 1H), 5.60 (s, 1H), 3.96–4.03 (m, 1H), 1.13– 2.18 (m, 10H), 0.46 (s, 9H). 13 C NMR (75 MHz, CDCl3 ) δ = 163.6, 157.9, 155.3, 136.5, 133.8, 131.7, 130.1, 127.8, 127.1, 123.6, 75.3, 49.2, 33.4, 33.0, 25.5, 25.0, 1.3. HRMS found: [M + H]+ 399.1843; C20 H27 N4 O3 Si requires 399.1853. N-tert-butyl-4-oxo-4,6-dihydrobenzo[e][1, 2, 3]triazolo[5, 1 -c][1,4]oxazepine-6-carboxamide (5b) Prepared according to method B. White foam (18 mg, 14 % yield) upon flash chromatography (silica gel, PE/EtOAc 7:3). R f = 0.20 (silica gel, PE/EtOAc 7:3).1 H NMR (300 MHz, CDCl3 ) δ = 8.46 (s, 1H), 8.08 (d, J = 7.4 Hz, 1H), 7.70 (dt, J = 9.0, 2.1 Hz, 1H), 7.51–7.64 (m, 2H), 6.70 (br, s, 1H), 5.56 (s, 1H), 1.49 (s, 9H).13 C NMR (75 MHz, CDCl3 ) δ = 163.4, 156.6, 140.5, 136.4, 131.9, 130.4, 129.5, 128.5, 127.1,

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123.4, 77.4, 75.5, 52.8, 28.9. HR-MS found: [M + H]+ 301.1295; C15 H17 N4 O3 requires 301.1301. N-tert-butyl-4 -oxo-3- (trimethylsilyl)-4, 6-dihydrobenzo [e] [1,2,3]triazolo[5,1-c][1,4]oxazepine-6-carboxamide (5c) Prepared according to method B. White foam (203 mg, 78 % yield) upon flash chromatography (silica gel, PE/EtOAc 8:2). R f = 0.20 (silica gel, PE/EtOAc 8:2). 1 H NMR (300 MHz, CDCl3 ) δ = 8.08 (d, J = 7.4 Hz, 1H), 7.66 (dt, J = 9.0, 2.2 Hz, 1H), 7.47–7.59 (m, 2H), 6.74 (br, s, 1H), 5.51 (s, 1H), 1.50 (br, s, 9H), 0.46 (s, 9H). 13 C NMR(75MHz, CDCl3 ) δ = 163.7, 157.9, 155.3, 136.5, 133.9, 131.7, 130.0, 127.8, 127.4, 123.6, 77.5, 75.4, 53.7, 28.9, −1.4. HR-MS found: [M + H]+ 373.1694; C18 H25 N4 O3 Si requires 373.1697. N-(4-(benzyloxy)phenyl)-4-oxo-3-propyl-4,6-dihydrobenzo [e][1,2,3]triazolo[5,1-c][1,4]oxazepine-6-carboxamide (5d) Prepared according to method A. Yellow oil (182 mg, 68 % yield) upon flash chromatography (silica gel, PE/EtOAc 6:4). R f = 0.54 (silica gel, PE/EtOAc 6:4). 1 H NMR (300 MHz, CDCl ) δ = 8.62 (br, s, 1H), 8.05 3 (d, J = 7.4Hz, 1H), 7.31–7.71 (m, 11H), 7.02 (d, J = 8.6 Hz, 1H), 5.81 (s, 1H), 5.10 (s, 2H), 3.02 (t, J = 8.1 Hz, 2H), 1.77–1.96 (m, 2H), 1.05 (t, J = 8.1Hz, 3H). 13 C NMR (75 MHz, CDCl ) δ = 162.3, 157.1, 156.7, 3 156.1, 137.2, 137.0, 136.8, 133.4, 131.8, 130.5, 129.6, 128.8, 128.3, 127.7, 126.8, 124.9, 123.5, 115.6, 75.4, 70.5, 22.5, 14.1. HR-MS found: [M+H]+ 469.1864; C27 H25 N4 O4 requires 469.1877. 8-Chloro-N-cyclohexyl-4-oxo-3-phenyl-4,6-dihydrobenzo[e] triazolo[5,1-c][1,4]oxazepine-6-carboxamide (5e) Prepared according to method A. Yellow wax (83 mg, 30 % yield) upon flash chromatography (silica gel, CH2 Cl2 /PE8:2 + 2 %Et2 O). R f = 0.24 (silica gel, CH2 Cl2 /PE8:2+2 %Et2 O). 1 H NMR (300 MHz, CDCl ) δ =7.95–8.04 (m, 4H), 7.66 3 (dd, J = 7.4, 2.1 Hz, 1H), 7.46–7.53 (m, 3H), 6.80 (br, s, 1H), 5.73 (s, 1H), 4.00 (br, s, 1H), 1.18–2.09 (m, 10H). 13 C NMR (75 MHz, CDCl3 ) δ = 162.8, 157.2, 152.8, 136.4, 134.8, 130.3, 129.0, 128.9, 128.3, 124.9, 124.0, 74.5, 49.3, 33.0, 25.5, 25.1. HR-MS found: [M + H]+ 437.1374; C23 H22 ClN4 O3 requires 437.1381. Ethyl 2-(8-chloro-4-oxo-3-propyl-4,6-dihydrobenzo[e][1,2, 3]triazolo[5,1-c][1,4]oxazepine-6-carboxamido)acetate (5f) Prepared according to method B. Brown oil (132 mg, 85 % yield) upon flash chromatography (silica gel, CH2 Cl2 /PE9 : 1 + 5 %Et2 O). R f = 0.18 (silica gel, CH2 Cl2 /PE9 : 1 + 5 %Et2 O). 1 H NMR(300 MHz, CDCl3 )δ = 7.93–7.97 (m, 1H), 7.74 (br, s, 1H), 7.60–7.65 (m, 2H), 5.80 (s, 1H), 4.12–4.33 (m, 4H), 2.95 (t, J = 8.3 Hz, 2H), 1.72–1.91 (m, 2H), 1.32 (t, J = 7.3 Hz, 3H), 1.01 (t, J = 7.9 Hz, 3H). 13 C NMR (75 MHz, CDCl3 ) δ = 169.0,

164.7, 156.9, 156.0, 135.9, 134.9, 131.7, 128.2, 127.9, 124.6, 124.3, 74.5, 61.9, 41.2, 27.5, 22.1, 14.1, 13.8. HR-MS found: [M + H]+ 407.1124; C18 H20 ClN4 O5 requires 407.1123. N-(4-(benzyloxy)phenyl)-8-chloro-4-oxo-3 - (trimethylsilyl)4,6-dihydrobenzo[e][1,2,3]triazolo[5,1-][1,4]oxazepine-6carboxamide (5g) Prepared according to method B. Dark yellow wax (242 mg, 59 % yield) upon flash chromatography (silica gel, CH2 Cl2 /PE6:4 + 5 %Et2 O). R f = 0.30 (silica gel, CH2 Cl2 /PE6:4 + 5 %Et2 O). 1 H NMR (300 MHz, CDCl3 ) δ = 8.53 (br, s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.34–7.69 (m, 10H), 7.03 (d, J = 8.6 Hz, 1H), 5.75 (s, 1H), 5.12 (s, 2H), 0.46 (s, 9H). 13 C NMR (75 MHz, CDCl3 ) δ = 161.5, 157.0, 156.6, 155.8, 136.6, 136.0, 134.7, 133.2, 131.8, 129.2, 128.6, 128.1, 128.0, 127.5, 124.8, 122.2, 115.4, 70.3, −1.7. HR-MS found: [M+H]+ 533.1403; C27 H26 ClN4 O4 Si requires 533.1413. N-(4-(benzyloxy)phenyl)-8-chloro-4-oxo-3-propyl-4,6-dihydrobenzo[e][1,2,3]triazolo[5,1-c][1,4]oxazepine-6-carboxamide (5h) Prepared according to method B. Dark yellow wax (96 mg, 36 % yield) upon flash chromatography (silica gel, CH2 Cl2 /PE7:3 + 3 %Et2 O). R f = 0.53 (silica gel, CH2 Cl2 /PE7:3 + 3 %Et2 O). 1 H NMR (300 MHz, CDCl3 ) δ = 8.56 (br, s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.26– 7.66 (m, 10H), 7.02 (dd, J = 8.5, 1.6 Hz, 1H), 5.77 (s, 1H), 5.09 (s, 2H), 3.00 (t, J = 7.8 Hz, 2H), 1.85 (m, 2H), 1.05 (t, J = 7.8 Hz, 3H). 13 C NMR (75MHz, CDCl3 ) δ = 161.7, 156.8, 156.7, 156.3, 136.5, 135.8, 134.8, 131.6, 129.0, 128.4, 127.9, 127.8, 127.3, 124.3, 124.2, 122.1, 115.2, 74.3, 70.0, 27.4, 22.0, 13.8. HR-MS found: [M + H]+ 503.1499; C27 H24 ClN4 O4 requires 503.1487. Ethyl 2-(10-methyl-4-oxo-3-phenyl-4,6-dihydrobenzo[e][1, 2,3]triazolo[5,1-c][1,4]oxazepine-6-carboxamido)acetate (5j) Prepared according to method B. Dark yellow wax (183 mg, 53 % yield) upon flash chromatography (silica gel, CH2 Cl2 /PE9:1 + 7 %Et2 O). R f = 0.49 (silica gel, CH2 Cl2 /PE 9:1 + 7 %Et2 O). 1 H NMR (300 MHz, CDCl3 ) δ = 7.96–8.02 (m, 2H), 7.72–7.80 (br, m, 1H), 7.38–7.54 (m, 6H), 5.78 (s, 1H), 4.11–4.28 (m, 4H), 2.55 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H). 13 C NMR (75 MHz, CDCl3 ) δ = 169.2, 165.3, 158.1, 149.8, 134.6, 134.4, 134.3, 129.9, 129.7, 129.5, 128.5, 128.4, 128.3, 125.2, 124.9, 75.8, 61.7, 41.0, 19.8, 14.1. HR-MS found: [M + H]+ 421.1510; C22 H21 N4 O5 requires 421.1513. General procedure for the preparation of triazolobenzoxazepines 11 2-Azidobenzaldehyde 1 (1 mmol), isocyanide 2 (1 mmol), and acetic acid (57 μL, 1 mmol) were dissolved in dry DCM (4 mL) in a 50-mL round-bottomed flask and stirred at room

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temperature for 3 days. Propargylbromide 13 (1.2 mmol), tetrabutylammonium bromide (32.2 mg, 0.1 mmol), and 3.6 mL of a 30 % w/v NaOH solution in H2 O (5.0 mmol) were then added, and the reaction was stirred at room temperature overnight. Upon completion, the reaction was worked up in DCM and H2 O. The organic layer was washed with brine and concentrated under reduced pressure, and the crude product was purified by means of flash chromatography to afford αalkoxyamide 10. Compound 10 was dissolved in dry toluene (3 mL) in a 8-mL MW vial and the solution was heated at 100 ◦ C by means of microwave irradiation (P = 200 W). The solvent was then removed under reduced pressure, and the crude product was purified by means of flash chromatography to afford triazolobenzoxazepine 11. N-cyclohexyl-4,6-dihydrobenzo[e][1,2,3]triazolo[5,1-c] [1, 4]oxazepine-6-carboxamide (11a) Dark yellow wax (194 mg, 62 % yield) upon flash chromatography (silica gel, PE/EtOAc 7:3). R f = 0.11 (silica gel, PE/EtOAc 3:2). 1 H NMR (300 MHz, CDCl ) δ=7.93 (d, J = 7.8 Hz, 1H), 3 7.81 (s, 1H), 7.48–7.66 (m, 3H), 6.61 (br, d, J = 8.1 Hz, 1H), 4.96 (s, 1H), 4.87 (d, J = 13.2 Hz, 1H), 4.66 (d, J = 13.2 Hz, 1H), 3.71–3.84 (m, 1H), 1.06–1.90 (m, 10H). 13 C NMR (75 MHz, CDCl ) δ = 167.0, 136.1, 133.0, 132.5, 3 130.8, 130.5, 129.6, 128.1, 122.9, 76.9, 57.1, 48.0, 33.0, 32.8, 25.3, 24.8, 24.7. HR-MS found: [M+H]+ 313.1671; C17 H21 N4 O2 requires 313.1665.

N-tert-butyl-3-phenyl-4,6-dihydrobenzo[e][1,2,3]triazolo[5, 1-c][1,4]oxazepine-6-carboxamide (11d) White foam (310 mg, 99 % yield) upon flash chromatography (silica gel, PE/EtOAc 3:2). R f = 0.29 (silica gel, PE/EtOAc 3:2). 1 H NMR (300 MHz, CDCl ) δ = 7.97–8.00 (m, 1H), 3 7.79–7.83 (m, 2H), 7.42–7.69 (m, 6H), 6.51 (s, 1H), 5.05 (s, 1H), 4.90 (d, J = 13.5 Hz, 1H), 4.85 (d, J = 13.5 Hz, 1H), 1.24 (s, 9H). 13 C NMR (75 MHz, CDCl3 ) δ = 167.6, 136.0, 131.3, 130.9, 130.0, 129.7, 129.1, 128.8, 128.2, 127.4, 123.1, 78.1, 57.5, 51.3, 28.5. HR-MS found: [M+H]+ 363.1826; C21 H23 N4 O2 requires 363.1822. N-tert-butyl-3-(3-methoxyphenyl)-4,6-dihydrobenzo[e][1, 2, 3]triazolo[5,1-c][1,4]oxazepine-6-carboxamide (11e) White foam (183 mg, 79 % yield) upon flash chromatography (silica gel, PE/EtOAc 3:2). R f = 0.29 (silica gel, PE/EtOAc 3:2). 1 H NMR (300 MHz, CDCl3 ) δ = 7.97 (d, J = 8.4 Hz, 1H), 7.32–7.68 (m, 6H), 6.99 (ddd, J = 8.4, 2.7, 0.9 Hz, 1H), 6.52 (s, 1H), 5.04 (s, 1H), 4.90 (d, J = 13.5 Hz, 1H), 4.84 (d, J = 13.5 Hz, 1H), 3.90 (s, 3H), 1.24 (s, 9H). 13 C NMR (75, MHz, CDCl ) δ = 167.5, 160.1, 144.8, 3 136.0, 131.3, 129.2, 128.2, 131.3, 130.9, 130.1, 129.7, 123.0, 119.5, 114.4, 112.9, 77.0, 57.5, 55.4, 51.3, 28.4. HR-MS found: [M+H]+ 393.1925; C22 H25 N4 O3 requires 393.1927.

N-tert-butyl-4,6-dihydrobenzo[e][1,2,3]triazolo[5,1-c][1,4] oxazepine-6-carboxamide (11b) Brown wax (166 mg, 58 % yield) upon flash chromatography (silica gel, PE/EtOAc 7:3). R f = 0.15 (silica gel, PE/EtOAc 3:2). 1 H NMR (300 MHz, CDCl3 ) δ = 7.93 (d, J = 8.1 Hz, 1H), 7.81 (s, 1H), 7.50–7.67 (m, 3H), 6.49 (br, s, 1H), 4.93 (s, 1H), 4.81 (d, J = 13.5 Hz, 1H), 4.71 (d, J = 13.5 Hz, 1H), 1.31 (s, 9H). 13 C NMR (75 MHz, CDCl3 ) δ = 167.3, 136.0, 133.1, 132.4, 130.9, 130.8, 129.6, 128.3, 123.0, 77.6, 57.1, 51.3, 28.5. HR-MS found: [M+H]+ 287.1511; C15 H19 N4 O2 requires 287.1509.

N-(2,2-dimethoxyethyl)-3-(3-methoxyphenyl)-4,6-dihydrobenzo[e][1,2,3]triazolo[5,1-c][1,4]oxazepine-6-carboxamide (11f) Yellow oil (141 mg, 92 % yield) upon flash chromatography (silica gel, PE/EtOAc 7:3). R f = 0.33 (silica gel, PE/EtOAc 7:3). 1 H NMR (300 MHz, CDCl3 ) δ = 7.99 (d, J = 8.4 Hz, 1H), 7.31–7.69 (m, 6H), 6.97–7.01 (m, 1H), 6.92 (br, t, J = 5.7 Hz, 1H), 5.11 (s, 1H), 4.99 (d, J = 13.5 Hz, 1H), 4.78 (d, J = 13.5 Hz, 1H), 4.31 (t, J = 5.1 Hz, 1H), 3.90 (s, 3H), 3.30–3.53 (m, 2H), 3.37 (s, 3H), 3.31 (s, 3H). 13 C NMR (75 MHz, CDCl3 ) δ = 168.5, 160.1, 145.1, 136.3, 131.3, 129.3, 127.7, 131.0, 130.5, 130.1, 129.7, 123.0, 119.7, 114.5, 112.9, 102.3, 57.7, 55.4, 54.4, 54.3, 40.7. HR-MS found: [M+H]+ 425.1828; C22 H25 N4 O5 requires 425.1826.

N-tert-butyl-3-propyl-4,6-dihydrobenzo[e][1,2,3]triazolo[5, 1-c][1,4]oxazepine-6-carboxamide (11c) Yellow wax (214 mg, 65 % yield) upon flash chromatography (silica gel, PE/EtOAc 3:2). R f = 0.27 (silica gel, PE/EtOAc 3:2). 1 H NMR (300 MHz, CDCl ) δ = 7.91 (d, J = 7.5 Hz, 3 1H), 7.47–7.61 (m, 3H), 6.50 (s, 1H), 4.89 (s, 1H), 4.74 (d, J = 13.5 Hz, 1H), 4.61 (d, J = 13.5 Hz, 1H), 2.67– 2.84 (m, 2H), 1.79 (sext, J = 7.5, Hz 2H), 1.32 (s, 9H), 1.01 (t, J = 7.5 Hz, 3H). 13 C NMR (75 MHz, CDCl3 ) δ = 167.5, 145.4, 136.4, 129.5, 128.2, 130.7, 130.6, 129.3, 122.8, 77.3, 56.6, 51.2, 28.5, 26.9, 23.1, 13.9. HR-MS found: [M + H]+ 329.1971; C18 H25 N4 O2 requires 329.1978.

N-butyl-4,6-dihydrobenzo[e][1,2,3]triazolo[5,1-c][1,4]oxazepine-6-carboxamide (11g) Dark yellow oil (212 mg, 74 % yield) upon flash chromatography (silica gel, PE/EtOAc 7:3). R f = 0.07 (silica gel, PE/EtOAc 3:2). 1 H NMR (300 MHz, CDCl3 ) δ = 7.95 (dd, J = 8.1, 1.2 Hz, 1H), 7.81 (s, 1H), 7.63 (dt, J = 7.5, 1.8 Hz, 1H), 7.48–7.57 (m, 2H), 6.77 (br, s, 1H), 4.98 (s, 1H), 4.90 (d, J = 13.5, 1H), 4.65 (d, J = 13.5, 1H), 3.20–3.39 (m, 2H), 1.24–1.54 (m, 4H), 0.94 (t, J = 7.2 Hz, 3H). 13 C NMR (75 MHz, CDCl3 ) δ = 168.0, 136.2, 133.0, 132.5, 130.8, 130.2, 129.6, 128.1, 123.0, 76.9, 57.3, 39.0, 31.5, 20.1, 13.7. HR-MS found: [M + H]+ 287.1516; C15 H19 N4 O2 requires 287.1509.

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8-chloro-N-cyclohexyl-4,6-dihydrobenzo[e] [1, 2, 3] triazolo [1,4]oxazepine-6-carboxamide (11h) White foam (236 mg, 68 % yield) upon flash chromatography (silica gel, PE/EtOAc 3:7 → 1:6). R f = 0.08 (silica gel, PE/EtOAc 3:2). 1 H NMR (300 MHz, CDCl ) δ = 7.90 (d, J = 8.4 Hz, 1H), 3 7.81 (s, 1H), 7.60 (dd, J = 8.4, 2.4 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 6.55 (br, d, J = 8.1 Hz, 1H), 4.91 (s, 1H), 4.91 (d, J = 13.8 Hz, 1H), 4.70 (d, J = 13.8 Hz, 1H), 3.71–3.84 (m, 1H), 1.05–1.92 (m, 10H). 13 C NMR (75 MHz, CDCl3 ) δ = 166.4, 135.4, 134.7, 132.9, 132.6, 131.0, 130.5, 129.8, 124.3, 57.5, 48.1, 33.1, 32.9, 25.4, 24.8, 24.7. HR-MS found: [M+H]+ 347.1278; C17 H20 ClN4 O2 requires 347.1276.

8-chloro-N-cyclohexyl-3-propyl-4,6-dihydrobenzo[e][1,2,3] triazolo[5,1-c][1,4]oxazepine-6-carboxamide (11i) White foam (305 mg, 97 % yield) upon flash chromatography (silica gel, PE/EtOAc 3:2). R f = 0.22 (silica gel, PE/EtOAc 3:2). 1 H NMR (300 MHz, CDCl3 ) δ = 7.86 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 8.4, 2.1 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 6.57 (d, J = 8.1 hz, 1H), 4.90 (s, 1H), 4.82 (d, J = 13.5 Hz, 1H), 4.59 (d, J = 13.5 Hz, 1H), 3.73– 3.85 (m, 1H), 2.66–2.82 (m, 2H), 1.06–1.94 (m, 12 H), 1.00 (t, J = 7.2 Hz, 13H). 13 C NMR (75 MHz, CDCl3 ) δ = 166.5, 145.7, 135.1, 135.0, 130.8, 130.2, 129.7, 129.4, 124.1, 76.4, 57.1, 48.2, 33.1, 32.8, 26.8, 25.4, 24.8, 24.7, 23.0, 13.8. HR-MS found: [M + H]+ 389.1758; C20 H26 ClN4 O2 requires 389.1745.

8-chloro-N-cyclohexyl-3-phenyl-4,6-dihydrobenzo[e][1,2,3] triazolo[5,1-c][1,4]oxazepine-6-carboxamide (11j) Yellow oil (326 mg, 77 % yield) upon flash chromatography (silica gel, PE/EtOAc 3:2). R f = 0.36 (silica gel, PE/EtOAc 3:2). 1 H NMR (300 MHz, CDCl3 ) δ = 7.94 (d, J = 8.7 hz, 1H), 7.75–7.78 (m, 2H), 7.62 (dd, J = 8.7, 2.4 Hz, 1H), 7.42–7.56 (m, 4H), 6.57 (br, d, J = 8.1 Hz, 1H), 5.00 (s, 1H) 5.00 (d, J = 13.5 Hz, 1H), 4.82 (d, J = 13.5Hz, 1H), 3.70–3.83 (m, 1H), 0.99–1.92 (m, 10H). 13 C NMR (75 MHz, CDCl ) δ = 166.5, 145.4, 135.5, 3 134.8, 131.0, 130.7, 129.8, 129.7, 129.1, 129.0, 128.9, 127.5, 124.3, 58.0, 48.3, 33.1, 32.8, 25.4, 24.8, 24.7. HR-MS found: [M + H]+ 423.1596; C23 H24 ClN4 O2 requires 423.1589.

Supporting information Copies of 1 H NMR and 13 C NMR spectra for compounds 5 and 11. Acknowledgments “Synthetic Methodologies for Generation of Biologically Relevant Molecular Diversity”, University of Genova for financial support.

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