Preparation and Regioselective Ring Opening Reactions of Fused Bicyclic N-Aryl Aziridines

Abstract

Presented herein is a systematic evaluation of ring opening reactions of bicyclic N-aryl aziridines. This class of compounds has not seen extensive study in the context of ring opening reactions making the site of reaction difficult to predict, potentially limiting their use as intermediates in the synthesis of nitrogen-containing molecules. Our recent successful ring opening strategy in the synthesis of hunterine A prompted us to systematically evaluate this transformation using related aziridines. Our findings show that ring opening reactions of bicyclic N-aryl aziridines occur with exquisite regioselectivity under a variety of conditions.

Graphical Abstract

INTRODUCTION

Aziridines are three-membered heterocycles that frequently serve as key intermediates in synthetic organic chemistry.¹ The strained nature of aziridines enables myriad ring opening reactions that make them useful building blocks for the preparation of nitrogen-containing molecules.² As such, central to their synthetic utility is the ability to control or predict the site at which these ring opening reactions occur. While the regioselectivities of these transformations vary according to the structure of the aziridine and reaction conditions, these systems have been well-studied and general trends have been established for the well-studied class of “standard” aziridines, defined herein as aziridines in which the nitrogen substituent is not connected to either of the aziridine carbon atoms.^2b,3

In contrast, ring opening reactions of “fused bicyclic” aziridines, those in which the nitrogen substituent is connected to one of the aziridine carbon atoms, have been the subject of fewer studies⁴ and general reactivity trends have not been elucidated nor systematically evaluated. Therefore, the reaction site can be considerably more challenging to predict. Scheme 1 highlights select examples that showcase the disparate nature of fused bicyclic aziridine ring opening regioselectivity.

Scheme 1. Fused bicyclic aziridine ring openings.

In our recent synthesis of hunterine A (9), a late-stage, regioselective ring opening of N-aryl aziridine 7 was crucial for the installation of the necessary hydroxymethyl moiety found in the natural product (Scheme 2).⁵ We reasoned that the steric bias of the neighboring quaternary center would significantly influence the regiochemical outcome of the reaction. However, since few bicyclic N-aryl aziridines have been reported and studied in the context of ring opening^6,7 this strategy carried some degree of risk. We were gratified to observe that ring opening yielded the desired product 8 that could be deacetylated to give the natural product (9). In a related eight-membered system, Chattopadhyay and coworkers observed a similar outcome when treating 10 with AcOH in H₂O.⁸ The additional neighboring substitution may also play a role in the regiochemical outcome of this transformation.

Scheme 2. Ring opening of fused bicyclic N-aryl aziridines.

The success of our synthetic strategy coupled with a paucity of studies concerned with bicyclic N-aryl aziridine ring opening prompted us to further investigate the reactivity of these systems. Based on the results in Scheme 2, it appeared that achieving exclusive regioselectivity was possible and that through a more systematic evaluation of related compounds we might be able to elucidate general trends in reactivity, as have been established for “standard” aziridines. To do so, we aimed to synthesize a series of simplified bicyclic N-aryl aziridines (12, Scheme 3) that would allow for modulation of the ring size and that would not be affected by the same steric influence and conformational restrictions of 7. Additionally, the variety of outcomes observed in the ring openings of other bicyclic aziridines shown in Scheme 1 suggested that the site of reaction could vary according to reaction conditions and size of the fused ring.

Scheme 3. Proposed simplified bicyclic N-aryl aziridine for systematic study of ring opening.

RESULTS AND DISCUSSION

Preparation of the simplified bicyclic N-aryl aziridines proved to be more challenging than initially envisioned. We attempted to employ an azide/alkene intramolecular dipolar cycloaddition and triazoline photolysis to synthesize these aziridines. However, our initial attempts to execute this set of transformations were met with failure (Scheme 4). In our hands, azide 13 was slow to undergo dipolar cycloaddition, and the cycloadduct appeared to decompose, as evidenced by observation of quinoline 15 as one of the major products by crude ¹H NMR, along with a small amount of what we tentatively assigned as putative aziridine 16. Unfortunately, attempts to purify the mixture and verify the formation of this aziridine only led to further decomposition. Azide 17 was even slower to react and the putative cycloadduct was not stable to any attempted forms of purification. We hypothesized that incorporating substituents at the benzylic position (19) would accelerate the rate of intramolecular cycloaddition⁹ as well as prevent any potentially deleterious reactions resulting from elimination/oxidation at the benzylic position and provide a more robust route to the desired compounds. We expected that the benzylic substituents would have little steric influence on the aziridine opening due to their distal location relative to the possible sites of reaction. This strategy ultimately proved successful.

Scheme 4. Initial attempts to synthesize simplified bicyclic N-aryl aziridines.

Malonate 20 was alkylated in a divergent manner to access the products containing pendant olefins with different methylene spacer lengths (Scheme 5). Treatment of 20 with K₂CO₃ and allyl bromide in acetone afforded 21 in 95% yield. Alternatively, treatment with NaH and 4-iodo-1-butene in DMF afforded 22 in 77% yield. With both intermediates of different tether lengths in hand, identical synthetic sequences could be performed to arrive at the desired aziridines. Treatment of the alkylated compounds with DIBAL–H, followed by protection of the diol as the acetonide, and finally a lithiation/borylation sequence gave aryl BPin compounds 25 and 26 in respective 53% and 38% yields over three steps. While attempts to perform Chan-Evans-Lam couplings or Buchwald-Hartwig aminations from the aryl BPin or bromide compounds were unsuccessful, installation of the necessary nitrogen atom was accomplished through a protocol developed by Morken and coworkers.¹⁰ The aryl BPin compounds were treated with a mixture of MeONH₂ and n-BuLi at cryogenic temperature, followed by heating to 60 °C, allowing for isolation of the anilines 27 and 28 in 88% and 76% yields. Conversion of the anilines to the corresponding aryl azides was accomplished with t-BuONO and TMSN₃.¹¹ It should be noted attempts to directly convert the aryl bromides or BPin compounds to the corresponding azides (29, 30) was also unsuccessful. Allowing azide 29 to stand in benzene at ambient temperature for twelve hours led to formation of triazoline 31 in 61% yield over two steps. Formation of 32 required heating to 50 °C for 4 days. Both compounds were crystalline solids, the structures of which could be unambiguously determined by X-ray crystallography (CCDC 2441000 and 2441002). Overall, these results highlight the improved stability and reaction rates imparted by benzylic substitution. Finally, irradiation of each compound with long-wave UV light (centered at 330 nm)¹² gave the desired aziridines 33 and 34.

Scheme 5. Successful synthesis of bicyclic N-aryl aziridines.

While this strategy was not directly amenable to the synthesis of the analogous aziridine fused to a five-membered ring (n = 0), we attempted to synthesize a structurally similar compound (Scheme 6). Beginning with methyl ester 35, a known sequence delivered bromide 36. Following a similar borylation, amination protocol delivered aniline 37. At this stage, azidation under previously employed conditions presumably formed 38 in situ that then rapidly underwent cycloaddition and subsequently extruded nitrogen to give an inseparable mixture of imine 39 and putative aziridine 40 in a 4:1 ratio. There appeared to be no way to prevent spontaneous loss of nitrogen, nor was there any form of chromatography that could separate these two compounds and leave the very sensitive 40 intact. Triazolines fused to five-membered rings have been isolated, but we were unable to find examples where the nitrogen substituent was an aromatic ring, suggesting that these compounds may suffer from unique instability issues. Overall, this indicated that the cycloaddition method is not generally suited for the synthesis of bicyclic N-aryl aziridines where the aziridine is fused to a five-membered ring. Unfortunately, this meant that we were unable to evaluate ring openings using this type of substrate and continued forward using the six- and seven-membered substrates 33 and 34.

Scheme 6. Failed synthesis of five-membered ring fused substrate.

Our investigation of the aziridine ring opening reactions began with the seven-membered aziridine 34 that was most similar to our previous synthetic intermediate 7. Gratifyingly, ring-opening with acetic acid proceeded smoothly to deliver 41 in 74% yield (Scheme 7, A). It is noteworthy that the reaction did not proceed at ambient temperature and required heating to 60 °C for conversion to the ring-opened product. We were unable to detect the formation of any other products or constitutional isomers resulting from the alternative ring opening reaction.

Scheme 7. A) Ring opening of bicyclic N-aryl aziridines B) Failed ring opening reactions without aziridine activation.

Because our previous report had also used acetic acid and led to the same outcome, the subsequent ring openings were performed using reactants other than oxygen-based nucleophiles and conditions that did not involve protic acids. Dauban and Dodd reported ring opening of 1 at the more substituted aziridine carbon (shown in Scheme 1) using TMSN₃ and catalytic TBAF.^4a When treating 34 with the same reagents at 60 °C, we again observed exclusive ring opening at the least-substituted position, forming 42 in 81% yield, the structure of which was unambiguously determined by X-ray crystallography (CCDC 2440998). As a final test, we opted to perform a ring opening analogous to that reported by Hayashi in which treatment of the non-activated bicyclic aziridine 3 (shown in Scheme 1) with BnBr resulted in ring opening at the more substituted position.^4b Treatment of 34 with BnBr in MeCN at 60 °C did allow for ring opening to occur, although with partial removal of the acetonide protecting group. Thus, a two-step procedure of ring opening and reprotection was employed. This enabled clean isolation of 43 in 65% yield with no indication of products resulting from alternative ring opening reactions. The results of these experiments led us to hypothesize that the regioselectivity of these transformations is influenced primarily by the nature of the aziridine.

With these results in hand, we turned our attention to evaluating the same ring opening reactions using six-membered substrate 33 and were surprised to observe the same exclusively regioselective outcomes (Scheme 7, A). Opening with acetic acid proceeded in a similar 62% yield to give 44. Although we could not detect any of the other constitutional isomer, we did detect a small amount of an apparent ring opening/dimerization product. The reaction with TMSN₃ afforded 45 in 72% yield, and opening with BnBr followed by reprotection gave 46 in 57% yield. The transformations involving TMSN₃ and AcOH proceeded at milder temperatures than in the seven-membered case. We assumed that this reflected increased strain in the azabicyclo[4.1.0]heptane motif of 33 relative to the azabicyclo[5.1.0]octane motif found in 34, discussed later in Figure 1. In all cases, no constitutional isomers resulting from the alternative ring opening were observed.

Figure 1.

Conformational analysis of aziridines, identification of relationship between lone pair conjugation and N1–C1 bond length and potential similarities to aziridine activation. Comparison of alkoxysulfonylaziridines and fused bicyclic aziridines. Thermal ellipsoids are shown at 50% probability.

While these transformations are not an exhaustive evaluation of all ring opening conditions reported for aziridines, they are representative of diverse conditions in which different sites of reaction have been observed. In a mechanistic sense, each transformation likely proceeds in a similar manner via initial activation (protonation, silylation, alkylation) of the aziridine nitrogen, followed by nucleophilic attack. Therefore, as a final test we thought it pertinent to evaluate whether this type of activation was necessary for the ring opening to proceed. Du Bois¹³ as well as Dauban and Dodd^4a have reported that bicyclic aziridines derived from sulfamates can undergo ring-opening reactions in the absence of strong activation; 1 will undergo ring opening in the presence of methanol, amines, and in the presence of NaN₃ in DMF with an exclusive preference for opening at the more substituted position (2 and 47, Scheme 6, B). Treatment of 33 and 34 with MeOH resulted in no reaction even at elevated temperature. Likewise, both aziridines failed to react in the presence of NaOMe or the more Lewis acidic LiOMe in refluxing MeOH. Furthermore, there were no signs of ring opening in the presence of NaN₃ (Scheme 7, B). Thus, stronger activation of these aziridines appears to be necessary for ring opening to occur.

Having evaluated ring opening reactions of the N-aryl bicyclic aziridines, we considered the possibility of performing similar reactions using the triazoline precursors, as such transformations have been documented.¹⁴ Treating triazoline 32 with acetic acid at ambient temperature resulted in ring opening to give the same acetylated product 41 in 31% NMR yield (Scheme 8). This was accompanied by formation of the imine product 48, a frequently encountered decomposition product of this type of triazoline.^12c,15 A similar outcome was observed when treating 32 with TMSN₃ and TBAF at 60 °C with azide 42 being observed in 56% NMR yield, accompanied by 27% of the imine. Treatment with benzyl bromide resulted only in non-specific decomposition.

Scheme 8. Ring opening reactions of triazolines and formation of imine/enamine byproducts.

*NMR yields recorded with respect to a 2,4,6-trimethoxybenzene internal standard

As in the case of the opening of aziridines, the six-membered substrates reacted at lower temperatures. Treatment of 31 with acetic acid resulted in formation of 44 in 30% yield by NMR. This was accompanied by formation of a putative imine/enamine product (49), assigned by analogy to the seven-membered product. Unlike the seven-membered analog, this product proved to be highly unstable and recalcitrant to purification. We were able to obtain high-resolution mass spectrometry data that suggested the molecule had a formula consistent with this imine/enamine. Ring opening with TMSN₃ performed similarly to give 45 in 75% NMR yield, and treatment with BnBr again resulted only in a complex profile. Additionally, both triazolines failed to react in the presence of methanole, NaOMe or LiOMe at elevated temperature, or NaN₃. Taken together, these results indicate that triazolines behave similarly to the anaologous N-aryl aziridines with respect to the regioselectivity of ring opening but are more prone to decomposition in these transformations.

Since the origin of regioselectivity for the ring opening of bicyclic aziridines is substrate dependent (as seen in Scheme 1), we sought to better understand the exclusive regioselectivities observed through analysis of the crystal structures of 33 and 34 (Figure 1, CCDC 2441001 and 2440999). Of course, the solid state aziridine structures may not reflect the solution phase conformations of these molecules, and activation of the aziridine under the reaction conditions likely distorts both ground state structures. Unfortunately, it was not possible to obtain a crystal structure of a protonated or otherwise activated aziridine intermediate. However, analysis of these ground state structures still provides valuable information that may help understand the reactivity of these systems, discussed below. It should be noted that both aziridines crystallized with two molecules in the asymmetric unit, thus bond lengths and torsion angles are shown as averages and the uncertainties shown in parentheses have been propagated.

In the seven-membered substrate 34, the molecule is oriented such that the aziridine lone pair is nearly perfectly aligned with the aromatic π-system, made clear by the nearly identical torsion angles (Figure 1, top left). In contrast, 33 adopts a conformation in which the aziridine lone pair does not overlap as effectively with the aromatic π-system and results in a considerable difference in the same torsion angles (Figure 1, top right). When comparing the relevant bond lengths of the seven-membered and six-membered substrates, it appears that this loss of conjugation does not significantly affect the length of the N1–C2 bond (1.476(2) for 34 and 1.476(4) for 33), while the N1–C1 bond length increases with loss of conjugation (1.474(2) for 34 and 1.485(4) for 33). This difference may be due to improved orbital overlap between the aromatic π-system and the N1–C1 σ* orbital in this conformation of 33, supported by the G–F–N1–C1 torsion angle being nearly 90°. Experimentally these differences in conjugation are supported by the observation that reactions of the seven-membered aziridine require elevated temperatures relative to the six-membered aziridine. These differences in ground state structure do not on their own explain why both aziridines undergo ring opening at the same position (C1) but instead call attention to the correlation between loss of lone pair conjugation and N1–C1 bond elongation.

Du Bois and coworkers have suggested that the regioselectivity in ring openings of fused bicyclic alkoxysulfonylaziridines may be explained by consideration of torsional strain. Attack of 50 by azide leads selectively 51, the same selectivity seen in conversion of 1 to 2 (Figure 1, middle left). Comparison of the crystal structures of 50 and 51 shows that attack at C2 leads to little conformational change. Thus, the authors speculate that attack at C1 is disfavored due to the significant torsional strain that would be imparted in that transition state. By comparison, analysis of 34 and 42 reveals that a significant conformational change occurs between aziridine and azide-opened product (Figure 1, middle right). Thus, the same arguments cannot be easily made to explain the regioselectivity of the fused bicyclic N-aryl aziridines.

While we do not wish to speculate too heavily, the observed correlation between loss of conjugation and bond elongation as well as drastic conformational change between aziridine starting material and ring opened product have led us to suggest the following. Each ring opening likely proceeds through activation (protonation, silylation, alkylation) to form an aziridinium where lone pair conjugation would be disrupted (Figure 1, 52). In turn, this could engender a conformational change that would cause N1–C1 bond elongation in an analogous fashion to that observed when comparing the ground state structures 34 and 33. The greater reactivity of 33 could be due to a predisposed elongation in the ground state. Ring opening then would occur preferentially at the site of the longer, weaker bond. Although not perfectly analogous, bond elongation due to stabilization of cationic species by hyper-conjugation has been observed.¹⁶

Overall, our observations are in line with general regioselectivity trends for the ring opening of “standard” unactivated aziridines.^3a,b Given this parallel, we conducted a further investigation by examining the effect of additional aziridine substitution as we thought this would provide a more holistic picture of the reactivity of these compounds. To this end, aniline 28 was subjected to olefin metathesis with either styrene or 2-methyl-2-butene to install additional olefinic substitution (Scheme 9). These compounds were then converted to the corresponding azides and heated effect cycloaddition. Notably, the both azides failed to undergo cycloaddition at 50 °C as had previously been observed. Instead, cycloaddition only occurred near 90 °C, and this temperature proved to be sufficient to cause loss of nitrogen. Luckily, the aziridines could be cleanly isolated from these reactions, albeit in slightly lower yield than in cases without terminal substitution.

Scheme 9. Synthesis of aziridines with additional substitution and their ring opening with acetic acid.

Treatment of aziridine 53 with acetic acid at elevated temperature resulted in attack at C1 with presumed Walden inversion and no formation of alternative ring opening products or other diastereomers. The strong electronic activation at C1 is likely responsible for the regioselectivity. Treatment of aziridine 54 with acetic acid at elevated temperature led to formation of the electronically favored C1 opened product, although with apparent transfer of the acetyl group, to give 56. This is the only case in which acetyl transfer was observed (see Supporting Information for discussion). These regioselectivities observed are consistent with those in ring openings of analogous “standard” unactivated aziridines,^3a,b suggesting that N-aryl aziridines can generally be expected to react in the same manner as “standard” unactivated aziridines that have similar substitution patterns.

CONCLUSION

In conclusion, we have disclosed a synthetic route for the preparation of fused bicyclic N-aryl aziridines and have performed a systematic evaluation of the ring opening reactions of these molecules with a variety of heteroatom nucleophiles, inspired by our recent total synthesis efforts. Notably, each ring opening proceeds with exclusive regioselectivity. Mechanistically, the reactions are believed to proceed via initial activation of the aziridine followed by nucleophilic attack. Additionally, we found that the triazoline precursors to these aziridines were also competent substrates for ring opening reactions, albeit with concomitant formation of imine/enamine byproducts. Through X-ray crystallographic analysis of the aziridines, we were able to glean information about aziridine lone pair conjugation and its correlation with N–C bond lengths that may contribute to the exclusive regioselectivities observed. We further probed the effects of additional substitution and have found that these fused bicyclic N-aryl aziridines react in similar manner to “standard” unactivated aziridines. We hope these insights will help inform future studies involving fused bicyclic N-aryl aziridines as well as those concerned with elucidating the origins of aziridine ring opening regioselectivity.

EXPERIMENTAL SECTION

General Information.

Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon.¹⁸ Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, p-anisaldehyde, or KMnO4 staining. Silicycle SiliaFlash^® P60 Academic Silica gel (particle size 40–63 μm) was used for flash chromatography. ¹H NMR spectra were recorded on Varian Inova 500 MHz and Bruker 400 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm) or C₆D₅H (δ 7.16 ppm). ¹³C NMR spectra were recorded on a Varian Inova 500 MHz spectrometer (125 MHz) and Bruker 400 MHz spectrometers (100 MHz) and are reported relative to CDCl₃ (δ 77.16 ppm) or C₆D₆ (δ 128.06) . Data for ¹H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d = broad doublet. Data for ¹³C NMR are reported in terms of chemical shifts (δ ppm). Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm⁻¹) with respect to a blank measurement. High resolution mass spectra (HRMS) were obtained from an Agilent 6230 Series TOF with an Agilent Jet Stream ion source in electrospray ionization (ESI+) mode. Reagents were purchased from commercial sources and used as received unless otherwise stated.

Safety.

Azides and triazolines are reactive, potentially explosive and toxic molecules. Although these compounds displayed relative thermal stability and no incidents occurred during the preparation of any compounds described herein, they should be handled with care. Additionally, TMSN₃ can rapidly hydrolyze in the presence of water to hydrazoic acid (HN₃) which is volatile, toxic, and explosive.

Dimethyl 2-(2-bromophenyl)malonate (20):

Prepared according to a modified procedure from Cai and coworkers.¹⁹ To a flame-dried flask with stir bar was added methyl 2-(2-bromophenyl)acetate (35) (prepared according to Coe and coworkers²⁰) (9.76 g, 40.3 mmol, 1.0 equiv). Dimethyl carbonate (129 mL) was added and the solution was cooled to 0 °C. NaH (60% wt, 5.11 g, 121 mmol, 3.0 equiv) was added portionwise. The cooling bath was removed, and the mixture was heated to 50 °C for 14 hours. After cooling to ambient temperature, water (500 mL) was added, the layers were separated, the aqueous layer was extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude reside was purified by flash column chromatography (30% EtOAc in hexanes) to give malonate 20 as a white solid (9.17 g, 75% yield). Characterization data were in accord with those reported in the literature;²¹ a ¹H NMR spectrum is provided for reference.

¹H NMR: (600 MHz, CDCl₃) δ 7.60 (dd, J = 8.0, 1.3 Hz, 1H), 7.48 (dd, J = 7.8, 1.7 Hz, 1H), 7.34 (td, J = 7.6, 1.3 Hz, 1H), 7.20 (ddd, J = 8.0, 7.4, 1.2 Hz, 1H), 5.28 (s, 1H), 3.79 (s, 6H)

Dimethyl 2-allyl-2-(2-bromophenyl)malonate (21):

Malonate 20 (3.85 g, 13.4 mmol, 1.0 equiv) was charged to round bottom flask equipped with a magnetic stir bar. Acetone (45 mL, 0.3 M) was added followed by K₂CO₃ (7.42 g, 53.7 mmol, 4 equiv) and allyl bromide (4.87 g, 3.48 mL, 40.2 mmol, 3 equiv). A reflux condenser was added to the flask and the system was flushed with nitrogen before refluxing for 14 hours. After this time, the mixture was cooled to ambient temperature. Water (200 mL) was added and the mixture was extracted with Et₂O (3×100 mL). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to give a colorless oil (4.39 g, 95% yield) that was sufficiently pure for use without further purification.

¹H NMR: (400 MHz, CDCl₃) δ 7.58 (dd, J = 7.8, 1.4 Hz, 1H), 7.29 (ddd, J = 8.0, 7.2, 1.4 Hz, 1H), 7.21 – 7.10 (m, 2H), 5.77 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H), 5.02 (ddt, J = 17.1, 2.0, 1.4 Hz, 1H), 4.93 (ddt, J = 10.1, 2.1, 1.1 Hz, 1H), 3.79 (s, 6H), 3.23 (dt, J = 7.2, 1.3 Hz, 2H).

¹³C{¹H} NMR: (100 MHz, CDCl₃) δ 170.3, 137.2, 134.8, 133.6, 130.1, 129.1, 127.4, 123.9, 118.5, 64.9, 53.2, 38.9.

IR: (neat film, NaCl) 2950, 1746, 1470, 1432, 1256, 1212, 1136, 1026, 918, 744 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₁₄H₁₅BrO₄Na [M+Na]⁺: 349.0046 found 349.0044

Dimethyl 2-(2-bromophenyl)-2-(but-3-en-1-yl)malonate (22):

To a flame-dried flask with stir bar was added a mineral oil dispersion of NaH (60 wt%, 1.92g, 47.91 mmol, 1.5 equiv). The flask was purged and backfilled three times and cooled to 0 °C. DMF was added to the flask (15 mL), followed by malonate 20 (9.17 g, 31.94 mmol, 1.0 equiv) as a solution in DMF (15 mL) and stirred for 10 minutes at 0 °C then 20 minutes at ambient temperature. 4-iodo-1-butene²² (11.63 g, 63.9 mmol, 2.0 equiv) was added as a solution in DMF (15 mL) to the reaction mixture. The flask was heated in a heating block at 70 °C for 15 h. After this time, the reaction mixture was cooled to ambient temperature. Water (250 mL) was added and the mixture was extracted with EtOAc (3×75 mL). The combined organic layers were washed with 10% aq. LiCl (100 mL), brine (100 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude oil was purified by flash column chromatography (20 → 30% Et₂O in hexanes) to give compound 22 as a colorless oil (8.35 g, 77% yield).

¹H NMR: (500 MHz, CDCl₃) δ 7.59 (dd, J = 7.9, 1.5 Hz, 1H), 7.32 – 7.28 (m, 1H), 7.19 – 7.14 (m, 2H), 5.78 (ddt, J = 16.8, 10.1, 6.5 Hz, 1H), 4.99 (dd, J = 17.1, 1.7 Hz, 1H), 4.93 (dd, J = 10.2, 1.6 Hz, 1H), 3.79 (s, 6H), 2.58 – 2.53 (m, 2H), 1.99 – 1.90 (m, 2H)

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ 170.6, 137.9, 137.2, 134.8, 130.1, 129.1, 127.5, 124.0, 115.0, 64.5, 53.2, 33.6, 29.9

IR: (neat film, NaCl) 2950, 1738, 1432, 1256, 1205, 1022, 912, 748, 674 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C15H17BrO4Na [M+Na]⁺: 363.0205 found 363.0209

2-(2-(5-Allyl-2,2-dimethyl-1,3-dioxan-5-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25):

To a flame-dried flask equipped with stir bar was added compound 21 (4.20 g, 12.8 mmol, 1.0 equiv). The flask was purged and backfilled with nitrogen three times. CH₂Cl₂ (32 mL) was added and the stirred solution was cooled to −78 °C. DIBAL–H (neat, 16.0 mL, 89.6 mmol, 7 equiv) was added dropwise and the solution was allowed to warm to ambient temperature over the course of three hours and stirred for an additional twelve hours at the same temperature. After this time, the solution was cooled to 0 °C. EtOAc (10 mL) was added carefully. Then Et₂O (250 mL) was added followed by aqueous Rochelle’s salt solution (250 mL) and stirred vigorously until two relatively clear layers formed. The layers were separated and the aqueous layer was extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to give a colorless oil (2.40 g) that was used without further purification.

The crude oil (2.40 g) was added to a flame-dried flask with stir bar. CH₂Cl₂ (44 mL) was added followed by 2,2,-dimethoxypropane (6.5 mL, 53.1 mmol, 6 equiv), and the resulting solution was cooled to 0 °C. Pyridinium p-toluenesulfonate (0.222 g, 0.885 mmol, 10 mol %) was added. The reaction was warmed to ambient temperature and stirred for two hours, after which time TLC indicated consumption of the diol. The solution was cooled to 0 °C and satd. Aq. NaHCO3 (50 mL) was added. The layers were separated, and the aqueous layer was extracted with CH₂Cl₂ (3×20 mL). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to give a colorless oil (2.2 g).

The crude oil (2.2 g) was azeotroped with benzene then dried under high vacuum for >2 hours. After this time an oven-dried stir bar is added followed by THF (44 mL) and the solution was cooled to −78 °C. n-BuLi (2.5 M in hexanes, 5.32 mL, 13.3 mmol, 1.5 equiv) was added dropwise at −78 °C and stirred for one hour. Isopropylpinacolylborate (3.25 mL, 15.93 mmol, 1.8 equiv) was added dropwise at −78 °C. The solution was then warmed to 0 °C and stirred for two hours. The reaction was quenched with water 50 mL. The layers were separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0 → 30% Et₂O in hexanes) to afford compound 25 as a colorless oil (1.592 g, 53% yield over 3 steps).

¹H NMR: (400 MHz, CDCl₃) δ 7.63 (dd, J = 7.4, 1.7 Hz, 1H), 7.35 (td, J = 7.5, 1.6 Hz, 1H), 7.25 – 7.18 (m, 2H), 5.39 (ddt, J = 17.4, 10.1, 7.3 Hz, 1H), 5.02 (ddt, J = 17.0, 2.4, 1.3 Hz, 1H), 4.92 (ddd, J = 10.1, 2.3, 1.1 Hz, 1H), 4.15 (s, 4H), 2.84 (dt, J = 7.4, 1.2 Hz, 2H), 1.48 (s, 3H), 1.38 (overlapping singlets, 15H).

¹³C{¹H} NMR: (100 MHz, CDCl₃) δ 146.6, 135.6, 134.4, 129.9, 126.7, 125.8, 117.7, 98.0, 84.2, 67.6, 41.2, 39.3, 26.3, 24.9, 21.7 One aromatic signal is not observed due to boron quadrupolar relaxation.

¹¹B NMR: (128 MHz, CDCl₃) δ 32.5. Externally referenced to BF₃•OEt₂ (δ 0.0)

IR: (neat film, NaCl) 3070, 2980, 2938, 2870, 1488, 1436, 1372, 1340, 1304, 1200, 1144, 1090, 916, 860, 838, 760, 748, 670 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₂₁H₃₂BO₄ [M+H]⁺: 359.2388 found 359.2390

2-(2-(5-(But-3-en-1-yl)-2,2-dimethyl-1,3-dioxan-5-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (26):

To a flame-dried flask equipped with stir bar was added compound 22 (4.78 g, 14.00 mmol, 1.0 equiv). The flask was purged and backfilled with nitrogen three times. CH₂Cl₂ (46 mL) was added and the stirred solution was cooled to −78 °C. DIBAL–H (neat, 17.47 mL, 98.0 mmol, 7 equiv) was added dropwise and the solution was allowed to warm to ambient temperature over the course of 3 hours, and stirred for an additional 12 hours at this temperature. After this time, the solution was cooled to 0 °C. EtOAc (10 mL) was added carefully. Then Et₂O (250 mL) was added followed by aqueous Rochelle’s salt solution (250 mL) and stirred vigorously until two relatively clear layers formed. The layers were separated and the aqueous layer was extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄ and concentrated under reduced pressure to give a crude oil (2.8 g) that was used without further purification.

The crude oil (2.8 g) was added to a flame dried flask with stir bar. CH₂Cl₂ (43 mL) was added followed by 2,2,-dimethoxypropane (6.32 mL, 51.6 mmol, 6 equiv), and the resulting solution was cooled to 0 °C. Pyridinium p-toluenesulfonate (0.216 g, 0.859 mmol, 10 mol %) was added. The reaction was warmed to ambient temperature and stirred for 2 hours, after which time TLC indicated consumption of the diol. The solution was cooled to 0 °C and satd. aq. NaHCO₃ (50 mL) was added. The layers were separated, and the aqueous layer was extracted with CH₂Cl₂ (3×20 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄ and concentrated under reduced pressure to give a colorless oil (2.3 g).

The crude oil (2.3 g) was azeotroped with benzene then dried under high vacuum for >2 hours. After this time an oven-dried stir bar is added followed by THF (35 mL) and the solution was cooled to −78 °C. n-BuLi (2.5 M in hexanes, 4.25 mL, 10.6 mmol, 1.5 equiv) was added dropwise at −78 °C and stirred for 1 hour. Isopropylpinacolylborate (2.60 mL, 12.74 mmol, 1.8 equiv) was added dropwise at −78 °C. The solution was then warmed to 0 °C and stirred for 2 hours. The reaction was quenched with water (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0 → 30% Et₂O in hexanes) to afford compound 26 as a colorless oil (1.975 g, 38% yield over 3 steps).

¹H NMR: (400 MHz, CDCl₃) δ 7.60 (dd, J = 7.4, 1.6 Hz, 1H), 7.36 (ddd, J = 8.0, 7.1, 1.6 Hz, 1H), 7.30 (dd, J = 8.0, 1.3 Hz, 1H), 7.22 (td, J = 7.3, 1.3 Hz, 1H), 5.73 (ddt, J = 16.8, 10.2, 6.5 Hz, 1H), 4.92 (dq, J = 17.1, 1.7 Hz, 1H), 4.86 (ddt, J = 10.2, 2.2, 1.2 Hz, 1H), 4.21 (d, J = 11.6 Hz, 2H), 4.12 (d, J = 11.6 Hz, 2H), 2.13 – 2.04 (m, 2H), 1.70 (dddd, J = 9.1, 6.4, 3.9, 1.4 Hz, 2H), 1.47 (s, 3H), 1.39 – 1.35 (overlapping singlets, 15H)

¹³C{¹H} NMR: (100 MHz, CDCl₃) δ 146.7, 139.0, 135.4, 129.8, 127.0, 125.7, 114.3, 98.1, 84.2, 68.2, 41.7, 34.3, 28.3, 25.6, 25.0, 22.4. One aromatic signal is not observed due to boron quadrupolar relaxation.

¹¹B NMR: (128 MHz, CDCl₃) δ 32.9. Externally referenced to BF3•OEt₂ (δ 0.0)

IR: (neat film, NaCl) 3066, 2978, 2936, 2862, 1436, 1372, 1340,

1302, 1258, 1144, 1090, 1050, 858, 838, 752, 670 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₂₂H₃₄BO₄ [M+H]⁺: 373.2545 found 373.2542

2-(5-Allyl-2,2-dimethyl-1,3-dioxan-5-yl)aniline (27):

To a flame dried flask with stir bar was added a THF solution of MeONH₂ (1.6 M, 12.9 mL, 20.65 mmol, 4.6 equiv) followed by an addition 60 mL of THF. The solution was cooled to −78 °C and stirred for 10 minutes. n-BuLi (2.5 M, 8.3 mL, 20.65 mmol, 4.6 equiv) was added dropwise. The resulting solution was stirred at −78 °C for 30 minutes. BPin 25 (1.592 g, 4.44 mmol, 1.0 equiv) was added dropwise as a solution in THF (10 mL). The resulting solution was stirred 5 minutes at −78 °C, then the cooling bath was removed and the solution was allowed to warm to ambient temperature (~30 mins). After warming to ambient temperature, the reaction mixture was heated to 60 °C for an additional 15 hours. After this time, the reaction was cooled to 0 °C and quenched by the addition of water (150 mL). EtOAc (50 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (30 → 50% Et₂O in hexanes) to afford aniline 27 as a pale yellow oil (972 mg, 88% yield).

¹H NMR: (500 MHz, CDCl₃) δ 7.10 – 7.01 (m, 2H), 6.75 – 6.70 (m, 1H), 6.67 (dd, J = 7.8, 1.4 Hz, 1H), 5.64 (ddt, J = 17.1, 10.1, 6.9 Hz, 1H), 5.15 (dd, J = 17.0, 1.8 Hz, 1H), 5.08 – 5.01 (m, 1H), 4.41 (s, 2H), 4.08 (d, J = 11.9 Hz, 2H), 3.87 (d, J = 11.9 Hz, 2H), 2.86 (dt, J = 7.0, 1.4 Hz, 2H), 1.48 (s, 3H), 1.44 (s, 3H)

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ 145.9, 134.2, 128.3, 127.8, 125.5, 118.1, 118.1, 118.1, 99.5, 66.3, 42.3, 39.1, 25.0, 23.2.

IR: (neat film, NaCl) 3460, 3362, 2988, 2876, 1640, 1498, 1450, 1372, 1258, 1226, 1200, 1162, 1088, 920, 834, 746 cm⁻¹.

HRMS: (ESI⁺) m/z calc’d for C15H21NO2 [M+H]⁺: 248.1645 found 248.1647

2-(5-(But-3-en-1-yl)-2,2-dimethyl-1,3-dioxan-5-yl)aniline (28):

To a flame dried flask with stir bar was added a THF solution of MeONH₂ (1.8 M, 8.85 mL, 15.93 mmol, 3.0 equiv) followed by an additional 48 mL of THF. The solution was cooled to −78 °C and stirred for 10 minutes. n-BuLi (2.5 M, 6.37 mL, 15.93 mmol, 3.0 equiv) was added dropwise. The resulting solution was stirred at −78 °C for 30 minutes. BPin 26 (1.975 g, 5.31 mmol, 1.0 equiv) was added dropwise as a solution in THF (14 mL). The resulting solution was stirred 5 minutes at −78 °C, then the cooling bath was removed, and the solution was allowed to warm to ambient temperature (~30 mins). After warming to ambient temperature, the reaction mixture was heated to 60 °C for an additional 15 hours. After this time, the reaction was cooled to 0 °C and quenched by the addition of water (150 mL). Ethyl acetate (50 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (30 → 50% Et₂O in hexanes) to afford aniline 28 as a colorless oil (1.049 g, 76% yield).

¹H NMR: (500 MHz, CDCl₃) δ 7.09 – 7.00 (m, 2H), 6.77 – 6.70 (m, 1H), 6.66 (dd, J = 7.9, 1.4 Hz, 1H), 5.83 (ddt, J = 16.7, 10.1, 6.4 Hz, 1H), 5.01 (dt, J = 17.1, 1.8 Hz, 1H), 4.95 (dd, J = 10.2, 1.8 Hz, 1H), 4.33 (br s, 2H), 4.13 (d, J = 11.8 Hz, 2H), 3.90 (d, J = 11.9 Hz, 2H), 2.16 – 2.09 (m, 2H), 1.94 – 1.86 (m, 2H), 1.49 (s, 3H), 1.43 (s, 3H)

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ 146.0, 138.7, 128.3, 127.8, 125.3, 118.3, 118.2, 114.6, 99.3, 66.9, 42.4, 33.6, 28.4, 24.9, 23.2.

IR: (neat film, NaCl) 1456, 3366, 3076, 2990, 2940, 2876, 1640, 1500, 1450, 1374, 1258, 1226, 1200, 1166, 1090, 912, 834, 750 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C16H24NO2 [M+H]⁺: 262.1802 found 262.1803

2’,2’-Dimethyl-3a,4-dihydro-3H-spiro[[1,2,3]triazolo[1,5-a]quinoline-5,5’-[1,3]dioxane] (31):

To a flame-dried test tube with stir bar was added aniline 27 (100 mg, 0.40 mmol, 1.0 equiv). The vessel was evacuated and backfilled with nitrogen three times. Acetonitrile (2.0 mL) was added and the solution was cooled to 0 °C. Tert-butyl nitrite (167 mg, 0.192 mL, 1.6 mmol, 4.0 equiv) was added and the solution was stirred for five minutes. Then TMSN₃ (140 mg, 0.16 mL, 1.2 mmol, 3.0 equiv) was added dropwise. After fifteen minutes bubbling ceased, and TLC analysis indicated complete consumption of the aniline. The reaction was warmed to ambient temperature, concentrated under reduced pressure and purified by flash column chromatography (1 → 5 → 10% Et₂O in hexanes) to give azide 29 as a colorless oil (100 mg, 91% yield). Note: Azide 29 rapidly undergoes intramolecular cycloaddition (half life ~3 h in solution). Concentration of the crude reaction mixture should be performed with bath temperatures ≤ 25 °C, and flash column purification should be performed with haste. As such, it was not possible to obtain sufficiently pure samples of azide 29 without contamination of triazoline 31, therefore, characterization data are only reported for the triazoline product 31 following cycloaddition.

To the obtained azide 29 (100 mg, 0.365 mmol, 1.0 equiv) in a 20 mL vial was added benzene (5 mL). The vial was flushed with nitrogen and the solution was allowed to stir at ambient temperature for 12 hours, protected from light. After this time, the reaction mixture was concentrated under reduced pressure. Hexanes (5 mL) were added causing precipitation of a white solid. The mixture was concentrated under reduced pressure, hexanes (5 mL) were again added, the mixture was filtered, and triazoline 31 was collected as a white crystalline solid (67 mg, 61% yield over 2 steps, 67% yield from azide 29). This triazoline proved more sensitive than the seven-membered analog. Therefore, it was not stored for periods >1 week and was protected from light, as prolonged exposure to light (>24 hours at ambient temperature) resulted in discoloration of the solid. Crystals for X-ray analysis were grown by layer diffusion of heptane into a solution of 31 dissolved in minimal Et₂O at −20 °C (protected from light).

¹H NMR: (400 MHz, C₆D₆) δ 7.90 (dd, J = 8.1, 1.3 Hz, 1H), 7.20 (dd, J = 7.9, 1.4 Hz, 1H), 7.08 (ddd, J = 8.1, 7.3, 1.4 Hz, 1H), 6.87 (ddd, J = 7.9, 7.3, 1.3 Hz, 1H), 4.01 (d, J = 11.6 Hz, 1H), 3.84 (dd, J = 16.6, 11.3 Hz, 1H), 3.68 (dd, J = 12.0, 1.6 Hz, 1H), 3.60 (dd, J = 16.7, 7.1 Hz, 1H), 3.37 (dd, J = 12.0, 2.2 Hz, 1H), 3.07 – 2.94 (m, 2H), 2.22 – 2.13 (m, 1H), 1.42 (s, 3H), 1.34 (s, 3H), 0.70 – 0.58 (m, 1H).

¹³C{¹H} NMR: (100 MHz, C₆D₆) δ 138.8, 127.0, 125.2, 122.9, 119.1, 98.3, 72.4, 69.6, 67.2, 46.8, 36.5, 32.3, 28.0, 19.9. One aromatic signal is obscured by C₆D₆.

IR: (neat film, NaCl) 3040, 2990, 2942, 2874, 1604, 1484, 1454, 1372, 1258, 1200, 1158, 1092, 1010, 906, 830, 756 cm⁻¹.

HRMS: (ESI⁺) m/z calc’d for C₁₅H₁₉NO₂ [M–N₂]⁺: 246.1489 found 246.1483.

MP: 92 °C (dec.).

5-(2-Azidophenyl)-5-(but-3-en-1-yl)-2,2-dimethyl-1,3-dioxane (30):

To a flame dried flask with stir bar was added aniline 28 (0.999 g, 3.82 mmol, 1.0 equiv). The flask was evacuated and backfilled with nitrogen three times. Acetonitrile (19 mL) was added and the solution was cooled to 0 °C. Tert-butyl nitrite (1.82 mL, 15.28 mmol, 4.0 equiv) was added and the resulting solution was stirred for 5 minutes. Then TMSN₃ (1.51 mL, 11.46 mmol, 3.0 equiv) was added dropwise. The solution was maintained at 0 °C for 10 minutes then warmed to ambient temperature. After maintaining at ambient temperature for an additional 15 minutes, TLC analysis indicated complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (0 → 20% Et₂O in hexanes) to afford azide 30 as a colorless oil (0.921 g, 84% yield).

¹H NMR: (400 MHz, C₆D₆) δ 7.27 – 7.21 (m, 1H), 6.89 – 6.83 (m, 2H), 6.71 – 6.67 (m, 1H), 5.66 (ddt, J = 16.8, 10.2, 6.5 Hz, 1H), 4.94 – 4.84 (m, 2H), 4.21 – 4.16 (m, 2H), 3.96 (d, J = 11.8 Hz, 2H), 2.14 – 2.07 (m, 2H), 1.68 – 1.53 (m, 2H), 1.42 (s, 3H), 1.30 (s, 3H).

¹³C{¹H} NMR: (100 MHz, C₆D₆) δ 139.0, 138.2, 133.3, 130.3, 128.2, 124.8, 119.6, 114.5, 98.2, 67.2, 41.2, 32.1, 28.8, 24.3, 23.9.

IR: (neat film, NaCl) 3080, 2990, 2938, 2870, 2126, 1484, 1444, 1370, 1288, 1258, 1200, 1092, 910, 844, 834, 750 cm⁻¹.

HRMS: (ESI⁺) m/z calc’d for C₁₆H₂₂N₃O₂ [M+H]⁺: 288.1707 found 288.1710.

2’,2’-Dimethyl-3,3a,4,5-tetrahydrospiro[benzo[f][1,2,3]triazolo[1,5-a]azepine-6,5’-[1,3]dioxane] (32):

Azide 30 (0.920 g, 3.20 mmol, 1.0 equiv) was charged to a flask followed by benzene (64 mL). The flask was flushed with nitrogen then heated to 50 °C in a heating block for 96 h under a nitrogen atmosphere. After this time, an NMR aliquot indicated complete consumption of the starting azide. The solution was cooled to ambient temperature and concentrated under reduced pressure. 50 mL of hexanes were added to the flask, causing precipitation of a white solid. This mixture was again concentrated under reduced pressure. Hexanes (50 mL) were again added, and the mixture was filtered. The solid residue was washed with hexanes (10 mL) and dried under vacuum to give triazoline 32 as a white crystalline solid (0.454 g, 49% yield). 32 is stable at ambient temperature for several months without showing signs of decomposition, however, as a precaution it was protected from light during prolonged storage. Crystals suitable for X-ray analysis were grown by layer diffusion of pentane into a solution of 32 in minimal CH₂Cl₂.

¹H NMR: (400 MHz, C₆D₆) δ 7.61 (dt, J = 7.9, 1.0 Hz, 1H), 7.03 – 6.97 (m, 1H), 6.95 – 6.92 (m, 2H), 4.35 (dd, J = 12.1, 2.7 Hz, 1H), 4.21 (d, J = 11.1 Hz, 1H), 4.15 (dd, J = 16.6, 11.0 Hz, 1H), 3.65 – 3.54 (m, 2H), 3.31 (dd, J = 16.6, 13.3 Hz, 1H), 2.59 – 2.44 (m, 2H), 1.66 – 1.53 (m, 1H), 1.46 (s, 3H), 1.39 (ddt, J = 14.3, 4.4, 3.2 Hz, 1H), 1.23 (s, 3H), 0.95 (td, J = 13.7, 3.2 Hz, 1H).

¹³C{¹H} NMR: (101 MHz, C₆D₆) δ 144.4, 134.9, 128.0, 126.3, 125.7, 122.5, 98.2, 74.3, 68.7, 63.7, 59.0, 39.7, 29.13, 29.11, 27.8, 20.3.

IR: (neat film, NaCl) 2990, 2940, 2858, 1508, 1486, 1450, 1386, 1370, 1202, 1170, 1094, 1058, 978, 832, 756, 684, 676, 648 cm⁻¹.

HRMS: (ESI⁺) m/z calc’d for C₁₆H₂₂N₃O₂ [M+H]⁺: 288.1707 found 288.1715.

MP: 127 °C (dec.)

2’,2’-Dimethyl-1a,2-dihydro-1H-spiro[azirino[1,2-a]quinoline-3,5’-[1,3]dioxane] (33):

Triazoline 31 (62 mg, 0.2268 mmol) was charged to a flask with stir bar and 4.5 mL of benzene were added. Argon gas was bubbled through the solution for 5 minutes with stirring to remove oxygen then sealed. The flask was placed in a Lutzchem photobox equipped with Hitachi F8T5-BLB UVA lamps centered at 350 nm and irradiated for 4 hours. After this time the solution was concentrated under reduced pressure. The crude aziridine was purified by flash column chromatography (10 → 50% EtOAc in hexanes) to afford aziridine 33 as a crystalline solid (50 mg, 90% yield). Crystals suitable for X-ray diffraction were grown by adding dissolving 33 in minimal Et₂O and carefully layering with pentane.

¹H NMR: (400 MHz, C₆D₆) δ 7.28 (ddd, J = 7.7, 2.5, 1.4 Hz, 2H), 7.08 (ddd, J = 7.9, 7.3, 1.5 Hz, 1H), 6.89 (td, J = 7.5, 1.3 Hz, 1H), 4.20 (d, J = 11.5 Hz, 1H), 4.01 (dd, J = 11.7, 1.9 Hz, 1H), 3.78 (dd, J = 11.8, 1.2 Hz, 1H), 3.38 (dd, J = 11.5, 1.8 Hz, 1H), 2.67 (dd, J = 13.4, 7.2 Hz, 1H), 2.35 (dddd, J = 8.2, 7.2, 4.7, 3.5 Hz, 1H), 2.18 (dd, J = 4.7, 1.2 Hz, 1H), 1.48 (s, 3H), 1.38 (s, 3H), 1.20 (dd, J = 3.5, 1.2 Hz, 1H), 0.60 (ddd, J = 13.4, 8.3, 1.2 Hz, 1H).

¹³C{¹H} NMR: (100 MHz, C₆D₆) δ 150.0, 132.5, 128.6, 125.2, 124.3, 122.5, 98.3, 67.5, 67.2, 42.1, 36.0, 30.2, 29.7, 26.2, 21.8.

IR: (neat film, NaCl) 2990, 2862, 1484, 1450, 1370, 1312, 1196, 1088, 984, 834, 750 cm⁻¹.

HRMS: (ESI⁺) m/z calc’d for C₁₅H₂₀NO₂ [M+H]⁺: 246.1489 found 246.1487.

MP: 86–90 °C

2’,2’-Dimethyl-1,1a,2,3-tetrahydrospiro[azirino[1,2-a]benzo[f]azepine-4,5’-[1,3]dioxane] (34):

Triazoline 32 (0.365 g, 1.27 mmol) was charged to a flask with stir bar and 25 mL of benzene were added. Argon gas was bubbled through the solution for 5 minutes with stirring to remove oxygen and sealed. The flask was placed in a Lutzchem photobox equipped with Hitachi F8T5-BLB UVA lamps centered at 350 nm and irradiated for 8 hours. After this time the solution was concentrated under reduced pressure. The crude aziridine was purified by flash column chromatography (10 → 50% EtOAc in hexanes) to afford aziridine 34 as a crystalline solid (0.260 g, 79% yield). Crystals suitable for X-ray diffraction were grown by adding one drop of EtOAc to 3 mg of aziridine 34, heating the sealed vial to 80 °C, and allowing the solution to slowly cool to ambient temperature.

¹H NMR: (400 MHz, C₆D₆) δ 7.11 – 7.00 (m, 2H), 6.92 – 6.87 (m, 1H), 6.86 (dd, J = 7.8, 1.4 Hz, 1H), 4.64 (dd, J = 11.7, 1.9 Hz, 1H), 4.46 – 4.38 (m, 1H), 4.15 (d, J = 11.3 Hz, 1H), 3.70 (d, J = 1.9 Hz, 1H), 2.22 (ddd, J = 14.4, 13.1, 5.4 Hz, 1H), 2.13 (d, J = 4.7 Hz, 1H), 1.98 (dtd, J = 11.1, 4.3, 2.8 Hz, 1H), 1.66 (ddt, J = 14.3, 5.1, 2.3 Hz, 1H), 1.51 (s, 3H), 1.38 (d, J = 3.5 Hz, 1H), 1.30 (s, 3H), 1.15 – 1.03 (m, 1H), 0.72 (dddd, J = 14.3, 13.1, 11.4, 5.5 Hz, 1H).

¹³C{¹H} NMR: (100 MHz, C₆D₆) δ 151.5, 130.1, 126.7, 122.7, 122.2, 98.1, 69.9, 67.7, 39.4, 38.3, 35.4, 28.8, 26.7, 25.8, 22.5. One carbon signal is obscured by C₆D₆.

IR: (neat film, NaCl) 3054, 2986, 2924, 2860, 1482, 1446, 1370, 1312, 1260, 1196, 1166, 1090, 838, 762, 748 cm⁻¹.

HRMS: (ESI⁺) m/z calc’d for C₁₆H₂₂NO₂ [M+H]⁺: 260.1645 found 260.1651.

MP: 96–99 °C

2-(2-methylbut-3-en-2-yl)aniline (37):

Note: The preparation of 36 en route to 37 has been previously reported and is included for clarity. Each step in the sequence proceeded cleanly such that only one final purification was necessary.

To a round bottom flask was added hexamethyldisilazane (3.52 g, 21.8 mmol, 2.5 equiv) and THF (27 mL). The solution was cooled to 0 °C and n-BuLi (2.13 M in hexanes, 10.2 mL, 21.8 mmol, 2.5 equiv) was added dropwise. The solution was stirred for 1.5 hours. Methyl ester 35 (2.00 g, 8.73 mmol, 1 equiv) was added as a solution in THF (18 mL) and stirred at ambient temperature for 2 hours. Then MeI (3.10 g, 21.8 mmol, 2.5 equiv) was added and the mixture was stirred for 15 hours. Water (100 mL) was added and the mixture was stirred for 1 hour. The layers were separated and the organic layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, and concentrated to give methyl 2-(2-bromophenyl)-2-methylpropanoate²³ as a light orange solid (2.02 g, 90% yield) that was used without further purification.

To a round bottom flask was added lithium aluminum hydride (328 mg, 8.65 mmol, 1.1 equiv) and flask was cooled to −20 °C. Et₂O (45 mL) was added. Crude methyl 2-(2-bromophenyl)-2-methylpropanoate (2.02 g, 7.86 mmol, 1 equiv) was added as a solution in Et₂O (10 mL). The solution was maintained at −20 °C for 30 minutes before being warmed to ambient temperature and stirred for an additional 6 hours. The reaction was then cooled to 0 °C and cautiously quenched with 3N HCl (9 mL). The mixture was poured into water (50 mL), the layers separated, and the aqueous layer was extracted with Et₂O (3×20 mL). The combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, and concentrated to give 2-(2-bromophenyl)-2-methylpropan-1-ol²³ as a colorless oil (1.73 g, 96% yield) that was used without further purification.

To round bottom flask was added 2-(2-bromophenyl)-2-methylpropan-1-ol (1.73 g, 7.55 mmol, 1 equiv) as a solution in CH₂Cl₂ (38 mL). The solution was cooled to 0 °C and pyridinium chlorochromate (3.26 g, 15.1 mmol, 2 equiv) was added. The solution was warmed to ambient temperature and stirred for an additional 5 hours after which time TLC indicated complete consumption of the alcohol. Celite (40 g) was added to the reaction and the heterogeneous mixture was concentrated under reduced pressure. The resulting solid was added to the top of a short pad of silica gel and eluted with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to give 2-(2-bromophenyl)-2-methylpropanal²⁴ as a colorless oil (1.48 g, 87% yield) that was used without further purification.

To a round bottom flask was added methyl triphenylphosphonium bromide (4.66 g, 13.0 mmol, 2 equiv) and THF (10 mL). The solution was cooled to 0 °C, then n-BuLi (2.13 M in hexanes, 6.1 mL, 13.0 mmol) was added dropwise and the solution became clear and deep orange. 2-(2-bromophenyl)-2-methylpropanal (1.48 g, 6.52 mmol, 1 equiv) was added dropwise as a solution in THF (11 mL). The resulting mixture was warmed to ambient temperature and stirred for 12 hours. The reaction was quenched by the addition of water (5 mL). The mixture was concentrated under reduced pressure, then water (50 mL) was added and the mixture was extracted with hexanes (4×10 mL). Celite (20 g) was added, and the combined organic layers were concentrated under reduced pressure. The solid suspension was added to the top of a short pad of silica and eluted with hexanes (100 mL). The filtrate was concentrated to give 1-bromo-2-(2-methylbut-3-en-2-yl)benzene (36)²⁵ as a colorless oil (955 mg, 65% yield) that was used without further purification.

To a round bottom flask was added 1-bromo-2-(2-methylbut-3-en-2-yl)benzene (955 mg, 4.24 mmol, 1 equiv) and THF (21 mL) and the solution was cooled to −78 °C. n-BuLi (2.5 M in hexanes, 6.36 mmol, 1.5 equiv) was added dropwise, and the mixture was stirred for 1 hour. i-PrOBPin (1.56 mL, 7.64 mmol, 1.8 mmol) was added neat dropwise to the solution and stirred for 1 hour. The solution was then warmed to ambient temperature and quenched by the addition of water. The layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, and concentrated under reduced pressure to give 4,4,5,5-tetramethyl-2-(2-(2-methylbut-3-en-2-yl)phenyl)-1,3,2-dioxaborolane as a colorless oil that was used without further purification.

To a round bottom flask was added MeONH₂ (2.66 M in THF, 6.38 mL, 17.0 mmol, 4 equiv) was added followed by an additional 53 mL of THF and the solution was cooled to −78 °C. n-BuLi (2.5 M in hexanes, 6.8 mL, 17.0 mmol, 4 equiv) was added dropwise and the solution was stirred for 30 minutes. The previously obtained aryl Bpin (assumed quantitative yield) was added as a solution in THF (10 mL). The solution was warmed to ambient temperature then heated to 60 °C for 14 hours. Water (100 ml) was added followed by 3N HCl (8 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column (0 → 5% Et₂O in hexanes) to give the title compound as a light yellow oil (393 mg, 57% yield over 2 steps) with a small amount of residual Et₂O.

¹H NMR: (400 MHz, CDCl₃) δ 7.29 – 7.22 (m, 1H), 7.07 (ddd, J = 7.8, 7.2, 1.5 Hz, 1H), 6.81 – 6.72 (m, 1H), 6.62 (dd, J = 7.8, 1.4 Hz, 1H), 6.06 (dd, J = 17.7, 10.6 Hz, 1H), 5.24 – 5.12 (m, 2H), 3.95 (br s, 2H), 1.46 (s, 6H).

¹³C{¹H} NMR: (100 MHz, CDCl₃) δ 147.7, 145.3, 131.0, 127.6, 126.6, 118.5, 117.4, 112.2, 40.9, 26.7.

IR: (neat film, NaCl) 3446, 3370, 3080, 2968, 2876, 1620, 1494, 1446, 1410, 1378, 1298, 1262, 1010, 916, 748 cm⁻¹.

HRMS: (ESI⁺) m/z calc’d for C₁₁H₁₆N [M+H]⁺: 162.1277, found 162.1270.

(2’,2’-Dimethyl-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,5’-[1,3]dioxan]-2-yl)methyl acetate (41):

To a 1 Dr vial with stir bar was added aziridine 34 (20 mg, 0.077 mmol, 1.0 equiv). Benzene (0.77 mL) was added followed by AcOH (22 μL, 0.385 mmol, 5.0 equiv). The vial was flushed with argon, sealed, and heated to 60 °C for 24 hours. After this time the vial was cooled to ambient temperature and 60 μL of Et₃N were added. The mixture was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (20 → 60 % Et₂O in hexanes) to give acetyl compound 35 as a white amorphous solid (18.2 mg, 74% yield). Synthesis of 35 beginning with triazoline 32 was performed in an analogous fashion at ambient temperature instead of 60 °C. Flash column chromatography afforded imine 42 in sufficient purity for structural assignment.

¹H NMR: (400 MHz, C₆D₆) δ 7.12 (dd, J = 7.8, 1.6 Hz, 1H), 6.97 (td, J = 7.5, 1.6 Hz, 1H), 6.89 (td, J = 7.5, 1.4 Hz, 1H), 6.54 (dd, J = 7.7, 1.4 Hz, 1H), 4.44 (dd, J = 11.7, 2.2 Hz, 1H), 4.23 (d, J = 11.3 Hz, 1H), 4.03 (d, J = 11.6 Hz, 1H), 3.96 – 3.84 (m, 2H), 3.66 (dd, J = 11.2, 9.0 Hz, 1H), 3.49 (s, 1H), 2.78 (dddd, J = 10.3, 9.1, 3.7, 2.8 Hz, 1H), 2.24 (ddd, J = 15.1, 7.0, 3.3 Hz, 1H), 1.62 (m, 4H), 1.49 (s, 3H), 1.47 – 1.33 (m, 2H), 1.31 (s, 3H)

¹³C{¹H} NMR: (100 MHz, C₆D₆) δ 169.9, 148.4, 134.8, 127.5, 127.2, 122.5, 122.4, 98.1, 68.2, 67.5, 65.1, 57.0, 39.8, 29.8, 27.7, 26.9, 21.4, 20.3

IR: (neat film, NaCl) 3356, 2990, 2940, 2868, 1744, 1602, 1474, 1370, 1234, 1200, 1088, 1044, 972, 932, 836, 756 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₁₈H₂₅NO₄ [M+H]⁺:320.1856 found 320.1858

See SI for 2D NMR data

Characterization data for (48):

¹H NMR: (400 MHz, C₆D₆) δ 7.28 (ddd, J = 7.4, 1.5, 0.8 Hz, 1H), 7.14 (m, 2H), 6.97 (ddd, J = 8.1, 7.1, 1.5 Hz, 1H), 3.96 – 3.87 (m, 2H), 3.82 – 3.74 (m, 2H), 2.07 (t, J = 7.1 Hz, 2H), 1.91 (s, 3H), 1.75 (dd, J = 7.6, 6.7 Hz, 2H), 1.43 (s, 3H), 1.20 (s, 3H).

¹³C{¹H} NMR: (100 MHz, C₆D₆) δ 174.1, 150.3, 132.3, 126.5, 125.7, 124.7, 98.1, 68.2, 39.1, 38.6, 31.2, 27.2, 26.3, 21.7

IR: (neat film, NaCl) 2990, 2940, 2862, 1644, 1478, 1454, 1372, 1256, 1198, 1090, 1032, 838, 752, 745 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₁₆H₂₂NO₂ [M+H]⁺: 260.1645 found 260.1640

2-(Azidomethyl)-2’,2’-dimethyl-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,5’-[1,3]dioxane] (42):

To a flame-dried 1 Dr vial with stir bar was added aziridine 34 (20 mg, 0.077 mmol, 1.0 equiv). The vial was purged and backfilled with nitrogen three times. THF (0.77 mL) was added, followed by TMSN₃ (20.3 μL, 0.154 mmol, 2.0 equiv) then TBAF (1.0 M in THF, 15 μL, 0.015 mmol, 20 mol %). The vial was then sealed and heated to 60 °C for 18 hours. After this time, the reaction mixture was passed through a plug of silica gel, eluting with EtOAc (2 mL). The filtrate was concentrated under reduced pressure. The crude reside was purified by flash column chromatography (10 → 30% Et₂O in hexanes) to give the title compound as a colorless solid (18.9 mg, 81% yield). Crystals suitable for X-ray analysis were grown by dissolving 42 in minimal hot Et₂O, followed by addition of hexanes, and allowing to stand at −20 °C. Synthesis of 42 beginning with triazoline 32 was performed in an analogous fashion.

¹H NMR: (400 MHz, CDCl₃) δ 7.15 (dd, J = 7.8, 1.5 Hz, 1H), 7.10 (td, J = 7.5, 1.5 Hz, 1H), 6.97 (td, J = 7.6, 1.4 Hz, 1H), 6.81 (dd, J = 7.7, 1.4 Hz, 1H), 4.43 (dd, J = 11.8, 2.3 Hz, 1H), 4.32 (d, J = 11.4 Hz, 1H), 4.00 (d, J = 11.7 Hz, 1H), 3.95 (dd, J = 11.5, 2.3 Hz, 1H), 3.70 (s, 1H), 3.48 (dd, J = 12.2, 3.7 Hz, 1H), 3.26 (dd, J = 12.2, 10.1 Hz, 1H), 2.97 (tt, J = 9.7, 3.6 Hz, 1H), 2.30 (ddd, J = 13.9, 6.1, 3.5 Hz, 1H), 1.86 – 1.67 (m, 2H), 1.60 (ddd, J = 14.9, 10.7, 4.1 Hz, 1H), 1.46 (s, 3H), 1.42 (s, 3H)

¹³C{¹H} NMR: (100 MHz, CDCl₃) δ 147.6, 134.2, 127.7, 126.6, 122.8, 122.4, 98.2, 67.9, 64.9, 56.8, 56.2, 39.5, 29.4, 28.7, 26.9, 21.1

IR: (neat film, NaCl) 3338, 2992, 2936, 2868, 2100, 1602, 1472, 1454, 1372, 1258, 1200, 1084, 836, 756, 682 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₁₆H₂₃N₄O₂ [M+H]⁺: 303.1816

found 303.1815

MP: 93–96 °C

See SI for 2D NMR data

1-Benzyl-2-(bromomethyl)-2’,2’-dimethyl-1,2,3,4-tetrahydrospiro[benzo[b]azepine-5,5’-[1,3]dioxane] (43):

To a flame-dried 1 Dr vial with stir bar was added aziridine 34 (20 mg, 0.077 mmol, 1.0 equiv). The vial was evacuated and backfilled with nitrogen three times. Acetonitrile (0.26 mL) was added followed by BnBr (15.8 mg, 11 μL, 0.093 mmol, 1.2 equiv). The vial was sealed and heated to 60 °C for 18 h. After this time, the reaction mixture was concentrated under reduced pressure. Dry CH₂Cl₂ (0.25 mL) was added to the crude reaction mixture followed by 2,2-dimethoxypropane (48 mg, 56 μL, 6 equiv) and PPTS (1.9 mg, 0.0077 mmol, 10 mol%). The reaction mixture was stirred under a nitrogen atmosphere for six hours, then satd. aq. NaHCO₃ (1 mL) was added. The layers were separated, and the aqueous layer was extracted with CH₂Cl₂ (3×1 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0 → 20% Et₂O in hexanes) to give the title compound as a white foam (21.6 mg, 65% yield).

¹H NMR: (400 MHz, C₆D₆) δ 7.24 (dt, J = 8.7, 2.1 Hz, 3H), 7.14 – 7.00 (m, 4H), 6.99 – 6.94 (m, 1H), 6.91 (dd, J = 7.9, 1.4 Hz, 1H), 4.49 (d, J = 11.4 Hz, 1H), 4.20 (d, J = 11.3 Hz, 1H), 4.12 – 4.01 (m, 3H), 3.57 (dd, J = 11.4, 1.8 Hz, 1H), 3.29 (dq, J = 8.1, 5.3 Hz, 1H), 3.12 (dd, J = 10.1, 5.5 Hz, 1H), 2.63 (dd, J = 10.1, 8.4 Hz, 1H), 1.94 – 1.75 (m, 2H), 1.45 (s, 3H), 1.34 (m, 4H), 1.23 – 1.11 (m, 1H)

¹³C{¹H} NMR: (100 MHz, C₆D₆) δ 147.2, 138.8, 137.6, 129.7, 128.8, 127.7, 127.5, 127.4, 123.8, 123.3, 98.0, 69.1, 66.0, 57.9, 57.8, 40.2, 32.4, 27.7, 26.6, 25.6, 22.7

IR: (neat film, NaCl) 2990, 2936, 2860, 1594, 1492, 1452, 1370, 1254, 1198, 1092, 930, 834, 754, 700 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₂₃H₂₉BrNO₂ [M+H]⁺: 430.1376 found 430.1372

See SI for 2D NMR data

(2’,2’-Dimethyl-2,3-dihydro-1H-spiro[quinoline-4,5’-[1,3]dioxan]-2-yl)methyl acetate (44):

To a 1 Dr vial with stir bar was added aziridine 33 (13 mg, 0.053 mmol, 1.0 equiv) followed by benzene (0.53 mL) and acetic acid (17.5 mg, 16.7 μL, 0.292 mmol, 5.5 equiv). The vial was flushed with nitrogen and stirred at ambient temperature for 48 hours. Et₃N (40 μL) was added and the mixture was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0 → 30% Et₂O in hexanes) to give acetate the title compound as an amorphous solid (10 mg, 62% yield). Synthesis of 44 from 31 was performed in an analogous fashion at 0 °C.

¹H NMR: (400 MHz, C₆D₆) δ 7.20 (dd, J = 7.8, 1.5 Hz, 1H), 6.97 (ddd, J = 8.1, 7.2, 1.4 Hz, 1H), 6.75 – 6.66 (m, 1H), 6.26 (dd, J = 8.0, 1.3 Hz, 1H), 4.19 (d, J = 11.5 Hz, 1H), 3.99 (dd, J = 11.0, 3.6 Hz, 1H), 3.82 (dd, J = 11.9, 1.7 Hz, 1H), 3.77 (s, 1H), 3.68 (dd, J = 11.0, 7.4 Hz, 1H), 3.60 (dd, J = 11.9, 2.2 Hz, 1H), 3.34 (dd, J = 11.5, 2.2 Hz, 1H), 3.20 – 3.09 (m, 1H), 2.51 (dd, J = 13.2, 2.6 Hz, 1H), 1.64 (s, 3H), 1.49 (s, 3H), 1.38 (s, 3H), 1.22 (ddd, J = 13.4, 11.9, 1.7 Hz, 1H)

¹³C{¹H} NMR: (101 MHz, C₆D₆) δ 170.0, 145.5, 127.9, 127.3, 122.7, 118.1, 115.4, 98.2, 70.2, 68.9, 68.1, 47.2, 35.7, 32.2, 28.3, 20.3, 19.9

IR: (neat film, NaCl) 3364, 2990, 2944, 2862, 1738, 1606, 1496, 1370, 1228, 10990, 1036, 828, 752 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₁₇H₂₄NO₄ [M+H]⁺: 306.1700 found 306.1698

See SI for 2D NMR data

2-(Azidomethyl)-2’,2’-dimethyl-2,3-dihydro-1H-spiro[quinoline-4,5’-[1,3]dioxane] (45):

To a flame-dried 1 Dr vial with stir bar was added aziridine 33 (20 mg, 0.082 mmol, 1.0 equiv). The vial was purged and backfilled with nitrogen three times. THF (0.82 mL) was added, followed by TMSN₃ (18.8 mg, 21.4 μL, 0.163 mmol, 2.0 equiv) then TBAF (1.0 M in THF, 16.3 μL, 0.0163 mmol, 20 mol %). The vial was then sealed and stirred at ambient temperature for 18 hours. After this time, the reaction mixture was passed through a plug of silica gel, eluting with EtOAc (2 mL). The filtrate was concentrated under reduced pressure. The crude reside was purified by flash column chromatography (10 → 30% Et₂O in hexanes) to give azide 39 as a colorless solid (17.0 mg, 72% yield). Synthesis of 45 from triazoline 31 was performed in an analogous fashion.

¹H NMR: (400 MHz, C₆D₆) δ 7.13 (dd, J = 7.8, 1.5 Hz, 1H), 6.96 (ddd, J = 8.1, 7.2, 1.5 Hz, 1H), 6.70 (td, J = 7.5, 1.3 Hz, 1H), 6.22 (dd, J = 8.0, 1.3 Hz, 1H), 4.18 (d, J = 11.6 Hz, 1H), 3.78 (dd, J = 11.9, 1.7 Hz, 1H), 3.68 (s, 1H), 3.50 (dd, J = 11.9, 2.3 Hz, 1H), 3.29 (dd, J = 11.5, 2.3 Hz, 1H), 2.92 – 2.81 (m, 1H), 2.60 (dd, J = 11.8, 3.8 Hz, 1H), 2.52 (dd, J = 11.8, 8.7 Hz, 1H), 2.40 (dt, J = 13.2, 2.4 Hz, 1H), 1.50 (s, 3H), 1.36 (s, 3H), 1.04 (ddd, J = 13.4, 11.6, 1.7 Hz, 1H).

¹³C{¹H} NMR: (100 MHz, C₆D₆) δ 145.4, 128.0, 127.1, 122.6, 118.2, 115.6, 98.1, 70.2, 68.9, 56.5, 47.3, 35.8, 33.1, 28.7, 19.5

IR: (neat film, NaCl) 3664, 2990, 2940, 2870, 2104, 1606, 1490, 1448, 1268, 1194, 1090, 1032, 930, 830, 750 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₁₅H₂₁N₄O₂ [M+H]⁺: 289.1659 found 289.1655

See SI for 2D NMR data

1-Benzyl-2-(bromomethyl)-2’,2’-dimethyl-2,3-dihydro-1H-spiro[quinoline-4,5’-[1,3]dioxane] (46):

To a flame-dried 1 Dr vial with stir bar was added aziridine 33 (20 mg, 0.082 mmol, 1.0 equiv). The vial was evacuated and backfilled with nitrogen three times. Acetonitrile (0.3 mL) was added followed by BnBr (16.7 mg, 11.6 μL, 0.098 mmol, 1.2 equiv). The vial was sealed and heated to 60 °C for 18 h. After this time, the reaction mixture was concentrated under reduced pressure. Dry CH₂Cl₂ (0.3 mL) was added to the crude reaction mixture followed by 2,2-dimethoxypropane (51 mg, 60 μL, 6 equiv) and PPTS (2.0 mg, 0.0082 mmol, 10 mol%). The reaction mixture was stirred under a nitrogen atmosphere for six hours, then satd. aq. NaHCO₃ (1 mL) was added. The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3×1 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0 → 30% Et₂O in hexanes) to give the title compound as an orange oil (19.2 mg, 57% yield). Note: the product is somewhat unstable and degrades over the course of several weeks.

¹H NMR: (400 MHz, C₆D₆) δ 7.35 (dd, J = 7.7, 1.7 Hz, 1H), 7.13 – 7.06 (m, 2H), 7.06 – 7.00 (m, 3H), 6.96 (ddd, J = 8.5, 7.3, 1.6 Hz, 1H), 6.73 (td, J = 7.5, 1.2 Hz, 1H), 6.57 (dd, J = 8.3, 1.2 Hz, 1H), 4.23 – 4.11 (m, 2H), 3.96 (d, J = 16.9 Hz, 1H), 3.80 (d, J = 11.6 Hz, 1H), 3.66 (dd, J = 11.6, 1.8 Hz, 1H), 3.51 (dd, J = 11.6, 1.8 Hz, 1H), 3.25 (dddd, J = 9.5, 7.9, 4.9, 3.1 Hz, 1H), 3.07 (dd, J = 10.5, 3.1 Hz, 1H), 2.97 (dd, J = 10.5, 7.5 Hz, 1H), 2.48 (dd, J = 13.7, 5.0 Hz, 1H), 1.85 (dd, J = 13.7, 9.4 Hz, 1H), 1.47 (s, 3H), 1.41 (s, 3H)

¹³C{¹H} NMR: (100 MHz, C₆D₆) δ 146.3, 139.2, 128.8, 128.4, 127.3, 127.1, 126.5, 126.2, 118.4, 114.7, 98.4, 68.8, 68.7, 55.5, 54.8, 36.2, 34.9, 34.4, 26.6, 21.6

IR: (neat film, NaCl) 2986, 2940, 2866, 1492, 1450, 1370, 1224, 1196, 1090, 830, 754, 742, 730 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₂₂H₂₇BrNO₂ [M+H]⁺: 416.1220 found 416.1217

See SI for 2D NMR data

2’,2’-dimethyl-1-phenyl-1,1a,2,3-tetrahydrospiro[azirino[1,2-a]benzo[f]azepine-4,5’-[1,3]dioxane] (53):

To a 25 mL Schlenk tube was added styrene (279 mg, 2.68 mmol, 7 equiv) followed by aniline 28 (100 mg, 0.38 mmol, 1 equiv) as a solution in CH₂Cl₂ (3.8 mL). Grubbs catalyst 1^st generation [CAS: 172222–30-9] (9.5 mg, 0.012 mmol, 3 mol%) was added and the mixture was sparged with argon for 3 minutes then connected to a nitrogen line and heated to 40 °C for 10 hours. The reaction was concentrated and purified by silica gel flash column (0 → 20% EtOAc in hexanes) to give the intermediate (E)-2-(2,2-dimethyl-5-(4-phenylbut-3-en-1-yl)-1,3-dioxan-5-yl)aniline (57) as an off-white foam (53 mg, 41% yield).

¹H NMR: (500 MHz, CDCl₃) δ 7.35 – 7.27 (m, 4H), 7.21 (td, J = 6.8, 1.6 Hz, 1H), 7.11 – 7.05 (m, 2H), 6.77 (td, J = 8.2, 1.3 Hz, 1H), 6.69 (dd, J = 7.8, 1.4 Hz, 1H), 6.36 (d, J = 15.7 Hz, 1H), 6.21 (dt, J = 15.8, 6.6 Hz, 1H), 4.31 (s, 2H), 4.17 (d, J = 11.8 Hz, 2H), 3.96 (d, J = 11.8 Hz, 2H), 2.26 – 2.18 (m, 2H), 2.10 – 2.02 (m, 2H), 1.51 (s, 3H), 1.46 (s, 3H).

¹³C{¹H} NMR: (125 MHz, CDCl₃) δ 146.0, 137.8, 130.5, 130.0, 128.6, 128.3, 127.8, 127.0, 126.0, 125.3, 118.5, 118.2, 99.3, 67.0, 45.0, 42.4, 33.9, 27.8, 25.0, 23.0.

IR: (neat film, NaCl) 3460, 3362, 3244, 3024, 2990, 2938, 2876, 1622, 1496, 1448, 1374, 1308, 1258, 1224, 1198, 1160, 1092, 1066, 1032, 966, 910, 834, 746, 694 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₂₂H₂₈NO₂ [M+H]⁺: 338.2115, found 338.2116.

To a flame dried test tube was added the obtained aniline (53 mg, 0.16 mmol, 1 equiv) followed by MeCN (0.8 mL) and the solution was cooled to 0 °C. t-BuONO (65 mg, 0.63 mmol, 4 equiv) was added and the solution was stirred for 5 minutes, then TMSN₃ (54 mg, 0.47 mmol, 3 equiv) was added dropwise and the solution was stirred for 30 minutes at 0 °C. The reaction was then warmed to ambient temperature and concentrated under reduced pressure. The crude residue was passed through a plug of silica eluting with Et₂O and concentrated. The resulting azide was dissolved in toluene (2.0 mL) and heated to 90 °C. After 48 hours, the reaction was concentrated under reduced pressure and the crude residue was purified by silica gel flash column (0 → 10% Et₂O in hexanes) to give the title compound as a white foam (18.5 mg, 34% yield over 2 steps).

¹H NMR: (500 MHz, C₆D₆) δ 7.25 – 7.21 (m, 2H), 7.18 (t, J = 7.6 Hz, 2H), 7.14 – 7.08 (m, 2H), 7.01 (td, J = 7.5, 1.3 Hz, 1H), 6.94 – 6.85 (m, 2H), 4.63 (dd, J = 11.7, 1.8 Hz, 1H), 4.49 (d, J = 11.7 Hz, 1H), 4.16 (d, J = 11.3 Hz, 1H), 3.70 (dd, J = 11.4, 1.7 Hz, 1H), 2.76 (d, J = 2.8 Hz, 1H), 2.18 (td, J = 13.7, 5.3 Hz, 1H), 2.12 (dt, J = 11.3, 2.8 Hz, 1H), 1.79 – 1.71 (m, 1H), 1.52 (s, 3H), 1.34 (s, 3H), 1.11 (ddd, J = 14.6, 5.4, 1.9 Hz, 1H), 0.98 (tdd, J = 13.6, 11.3, 5.5 Hz, 1H).

¹³C{¹H} NMR: (100 MHz, C₆D₆) δ 150.4, 139.4, 129.4, 128.3, 127.1, 126.6, 126.2, 122.4, 122.2, 97.8, 69.4, 67.5, 52.2, 46.5, 39.0, 28.6, 26.0, 25.1, 22.4..

IR: (neat film, NaCl) 2990, 2938, 2866, 1598, 1484, 1446, 1372, 1312, 1260, 1200, 1164, 1090, 938, 842, 832, 752, 700 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₂₂H₂₆NO₂ [M+H]⁺: 336.1958, found 336.1960.

1,1,2’,2’-tetramethyl-1,1a,2,3-tetrahydrospiro[azirino[1,2-a]benzo[f]azepine-4,5’-[1,3]dioxane] (54):

To a 25 mL Schlenk tube was added aniline 28 (50 mg, 0.19 mmol, 1 equiv) followed by 2-methyl-2-butene (1.15 mL) and CH₂Cl₂ (0.8 mL). Hoveyda-Grubbs Catalyst 2^nd generation [CAS: 301224–40-8] (8.4 mg, 0.013 mmol, 7 mol %) was added and the reaction was sparged with argon for 3 minutes. The flask was connected to a nitrogen line and heated to 40 °C for 6 hours. The mixture was then concentrated and purified by silica gel flash column (0 → 20% Et₂O in hexanes) to give 2-(2,2-dimethyl-5-(4-methylpent-3-en-1-yl)-1,3-dioxan-5-yl)aniline (58) as a yellow oil (55mg, 95% yield).

¹H NMR: (400 MHz, CDCl₃) δ 7.09 – 7.00 (m, 2H), 6.74 (td, J = 7.5, 1.4 Hz, 1H), 6.68 (dd, J = 8.2, 1.4 Hz, 1H), 5.10 (ddt, J = 7.0, 5.5, 1.4 Hz, 1H), 4.51 (s, 2H), 4.13 (d, J = 11.8 Hz, 2H), 3.87 (d, J = 11.9 Hz, 2H), 2.05 – 1.94 (m, 2H), 1.81 (dd, J = 10.5, 6.4 Hz, 2H), 1.66 (s, 3H), 1.51 (s, 3H), 1.47 (s, 3H), 1.41 (s, 3H).

¹³C{¹H} NMR: (100 MHz, CDCl₃) δ 145.7, 131.9, 128.5, 127.7, 125.7, 124.3, 118.5, 118.3, 99.4, 67.1, 42.6, 35.0, 25.8, 24.6, 23.6, 22.8, 17.8.

IR: (neat film, NaCl) 3458, 3366, 3242, 2988, 2932, 2874, 1628, 1498, 1448, 1374, 1258, 1226, 1198, 1158, 1092, 834, 750 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₁₈H₂₈NO₂ [M+H]⁺: 290.2115, found 290.2113.

To a flame dried test tube with stir bar was added the previously obtained aniline (55 mg, 0.19 mmol, 1 equiv) and MeCN (1.0 mL) and the solution was cooled to 0 °C. t-BuONO (78.4 mg, 0.76 mmol, 4 equiv) was added slowly and stirred for 5 minutes then TMSN₃ (66 mg, 0.57 mmol, 3 equiv) was added dropwise. The resulting solution was stirred at 0 °C for 30 minutes then warmed to ambient temperature and concentrated under reduced pressure. The crude residue was passed through a short pad of silica gel eluting with 5% Et₂O in hexanes and concentrated again. The obtained azide was then dissolved in toluene (2.5 mL) and heated to 90 °C for 48 hours. After this time the reaction was concentrated and the residue was purified by preparative TLC (30% Et₂O/3% Et₃N in hexanes) to give the title compound as a yellow oil (11 mg, 20% yield over 2 steps)

¹H NMR: (400 MHz, C₆D₆) δ 7.12 – 7.01 (m, 2H), 6.93 – 6.84 (m, 1H), 6.63 (dd, J = 8.4, 1.4 Hz, 1H), 4.72 (dd, J = 11.7, 2.2 Hz, 1H), 4.27 (d, J = 11.6 Hz, 1H), 4.18 (d, J = 11.1 Hz, 1H), 3.74 (dd, J = 11.2, 2.1 Hz, 1H), 2.42 (ddd, J = 14.3, 13.1, 5.5 Hz, 1H), 1.97 (dd, J = 11.9, 2.6 Hz, 1H), 1.53 (d, J = 0.7 Hz, 3H), 1.48 (ddt, J = 14.2, 5.5, 2.3 Hz, 1H), 1.31 – 1.25 (m, 4H), 1.15 (s, 3H), 0.94 (dddd, J = 14.2, 13.1, 11.8, 5.6 Hz, 1H), 0.82 (s, 3H).

¹³C{¹H} NMR: (100 MHz, C₆D₆) δ 147.8, 130.4, 128.6, 127.9, 127.4, 127.3, 123.1, 121.3, 98.1, 70.4, 67.8, 46.9, 43.8, 39.4, 29.0, 27.7, 26.5, 22.4, 21.8, 15.7.

IR: (neat film, NaCl) 2990, 2924, 2864, 1482, 1454, 1374, 1264, 1198, 1160, 1090, 1032, 934, 840, 754, 684 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₁₈H₂₆NO₂ [M+H]⁺: 288.1958, found 288.1961.

Acetate (55):

To a 1 Dr vial was added aziridine 53 (15 mg, 0.045 mmol, 1 equiv) followed by benzene (0.45 mL) and AcOH (21 μL, 0.37 mmol, 8.3 equiv). The vial was flushed with nitrogen, then sealed and heated to 80 °C for 36 hours. The reaction vessel was cooled to ambient temperature then Et₃N (51 μL) was added and the mixture was concentrated under reduced pressure. The crude residue was purified by silica gel flash column (0 → 20% Et₂O in hexanes) to give the title compound as a white foam (15 mg, 84% yield, single diastereomer).

¹H NMR: (400 MHz, C₆D₆) δ 7.21 (dd, J = 7.9, 1.7 Hz, 2H), 7.16 – 7.15 (m, 1H), 7.14 – 7.03 (m, 4H), 6.90 – 6.80 (m, 2H), 6.22 – 6.13 (m, 1H), 5.87 (d, J = 7.6 Hz, 1H), 4.47 (dd, J = 11.7, 2.1 Hz, 1H), 4.23 (d, J = 11.3 Hz, 1H), 4.06 (d, J = 11.6 Hz, 1H), 3.88 (dd, J = 11.4, 2.1 Hz, 1H), 3.33 (s, 1H), 3.13 (ddd, J = 9.6, 7.6, 3.1 Hz, 1H), 2.41 (ddd, J = 14.0, 6.1, 3.4 Hz, 1H), 2.05 – 1.84 (m, 2H), 1.56 (s, 3H), 1.49 (s, 4H), 1.30 (s, 3H).

¹³C{¹H} NMR: (100 MHz, C₆D₆) δ 169.4, 148.3, 138.2, 134.7, 128.8, 128.8, 128.2, 127.5, 127.2, 122.5, 122.4, 98.1, 77.8, 68.3, 65.2, 61.4, 39.8, 30.1, 27.1, 26.8, 21.5, 20.5.

IR: (neat film, NaCl) 3348, 2990, 2940, 2862, 1742, 1472, 1370, 1232, 1202, 1168, 1090, 1028, 972, 836, 758, 702 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₂₄H₃₀NO₄ [M+H]⁺: 396.2169, found 396.2171.

Acetate (56):

To a 1 Dr vial was added aziridine 54 (10 mg, 0.035 mmol, 1 equiv) followed by benzene (0.35 mL) and AcOH 11 μL, 0.19 mmol, 5.5 equiv). The vial was flushed with nitrogen, then sealed and heated to 60 °C for 36 hours. The reaction vessel was cooled to ambient temperature then Et3N (40 μL) was added and the mixture was concentrated under reduced pressure. The crude residue was purified by silica gel flash column (40 → 80% EtOAc in hexanes) to give the title compound as an amorphous solid (7.2 mg, 67% yield).

¹H NMR: (400 MHz, CDCl₃) δ 7.71 (dd, J = 7.9, 1.5 Hz, 1H), 7.39 (td, J = 7.6, 1.7 Hz, 1H), 7.32 (td, J = 7.4, 1.5 Hz, 1H), 7.28 (d, J = 1.7 Hz, 1H), 4.52 (dd, J = 12.3, 4.7 Hz, 1H), 4.33 (d, J = 11.6 Hz, 1H), 3.81 – 3.64 (m, 3H), 3.06 (s, 1H), 1.95 (ddd, J = 14.8, 6.5, 1.9 Hz, 1H), 1.86 (s, 4H), 1.70 – 1.56 (m, 1H), 1.46 (s, 3H), 1.42 (s, 3H), 1.31 (s, 3H), 1.28 – 1.22 (m, 1H), 0.98 (s, 3H).

¹³C{¹H} NMR: (100 MHz, CDCl3) δ 174.1, 138.9, 138.6, 131.9, 129.4, 128.9, 128.0, 98.3, 74.9, 69.9, 68.7, 63.6, 40.5, 30.3, 25.0, 24.2, 23.6, 23.5.

IR: (neat film, NaCl) 3442, 2988, 2874, 1632, 1492, 1382, 1372, 1332, 1198, 1164, 1094, 1038 cm⁻¹

HRMS: (ESI⁺) m/z calc’d for C₂₀H₃₀NO₄ [M+H]⁺: 348.2169, found 348.2162.

Supplementary Material

The Supporting Information is available free of charge on the ACS Publications website.

Supporting Information: ¹H, ¹³C NMR, and IR spectra of all new compounds; 2D NMR data for structural assignments of ring opened products (PDF)

CCDC Accession Codes 2440998-2441002

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.