Multidimensional Screening and Methodology Development for Condensations Involving Complex 1,2-Diketones

Abstract

Multidimensional reaction screening employing complex 1,2-cycloheptanediones is described. The studies have enabled the discovery of regioselective, Lewis acid-mediated condensations with substituted ureas and a diastereoselective hydrogenation process which proceeds via an interesting allylpalladium hydride isomerization.

Multidimensional reaction screening^1,2 is an efficient high-throughput approach for the discovery of new synthetic methodologies and complex chemotypes.^3,4 Previous reaction screening efforts utilizing bicyclo [3.2.1]octanoids led to the discovery of a retro-Diekmann-type fragmentation which afforded highly functionalized cycloheptenones.⁴ We were interested in using the cycloheptenone scaffolds as substrates for additional reaction discovery projects focused on condensations. Condensations of 1,2-dicarbonyls allow facile access to heterocyclic and hetero-polycyclic compounds generating chemotypes with even greater complexity. In the current study, we evaluated a wide range of condensation partners^5-14 with complex 1,2- cycloheptanediones. Herein, we report our initial screening results and subsequent development of regioselective condensations to afford novel heterocyclic frameworks.

As shown in Scheme 1, the synthesis of the target screening scaffolds originated from [5+2] cycloaddition of quinone monoketal 1 and β-trans-methylstyrene to afford bicyclo[3.2.1]octanoid 2. Retro-Dieckmann-type ring-opening of 2 afforded the corresponding cycloheptenones 3.^4,15 Subsequent acid-mediated O-demethylation of α-methoxyenone 4 afforded 1,2-diketone 5. Interestingly, O-demethylation of secondary amide 6 afforded α-hydroxyketone 7.

Scheme 1.

Scaffold synthesis and preliminary results.

Preliminary efforts to probe the reactivity of scaffolds 5 and 7 were carried out using known imidazole-forming conditions. While reaction with scaffold 5 afforded the desired imidazole 8, reaction with scaffold 7 unexpectedly afforded oxazoline 9 with high diastereoselectivity(Scheme 1). The major diastereomer of oxazoline 9 was confirmed by X-ray crystallographic analysis.^16,17

Having established preliminary reactivity, we carried out a comprehensive multidimensional reaction screen utilizing scaffolds 5 and 7b (Figure 1). For this screen, 18 condensation partners were selected using both ethanol and acetonitrile as solvents (80 °C, 24 h) in the presence of either pyridinium p-toluenesulfonate (PPTS), diisopropylethylamine (DIEA), or without additive.

Figure 1.

Multidimensional screening parameters.

Each reaction was performed using 3 μmol of substrate (approx. 1 mg scale) with 1.0 equiv of both reaction partner and additive (total reaction volume of 60 μL, 0.05 M). Reaction partners that were used as hydrochlo-ride salts required use of 2.0 equiv of base. Each reaction was prepared in 1 mL oven-dried glass vials with minimal exposure to air from corresponding reagent stock solutions prepared in both EtOH and CH₃CN. The reactions were capped with silicon rubber septa and placed in a heated reaction block (80 °C) fastened to an orbital shaker and agitated for 24 hours. The reactions were diluted to 1 mL and analyzed using UPLC/MS/ELSD.¹⁸ Reactions affording >20 % conversion to a major product were subsequently scaled up and reaction products were isolated for characterization.

As anticipated, 1,2-diketone scaffold 5 underwent a number of reactions to afford new products (Figure 2). Condensation with 1,2-phenylenediamine and (1S,2S)-(+)-diaminocyclohexane afforded pyrazines 10 and 11, respectively.⁶ Reactions with 2-aminothiophenol⁷ and 6-amino-m-cresol⁸ also resulted in the formation of adducts, but as complex mixtures that were unstable to isolation. Reaction with S-methylsemicarbazide hydroiodide under acid conditions resulted in the formation of triazines 12a and 12b (2:1 mixture of regioisomers).⁹ Although the two regioisomers were isolated, the structures could not be assigned based on standard NMR analysis. Condensation with 2-aminobenzaldehyde gave rise to a mixture of four quinoline products (13a-d). Interestingly, these quinoline products were obtained under acidic conditions which is in contrast to typical Friedländer condensation conditions (KOH, EtOH, reflux).¹⁰ Additionally, acid-catalyzed condensations using urea,¹¹ guanidine hydro-chloride,¹² and benzamidine hydrochloride¹³ afforded the cycloheptadiene products 14, 15, and 16a, respectively. In the case of the reaction with urea, alkenyl imidazolone 16a readily oxidized to the corresponding cycloheptatriene 16b upon exposure to ambient atmosphere.

Figure 2.

Representative Condensation products.

Although screening with the α-hydroxyketone 7b substrate indicated successful conversion to new products, we found that these products were generally unstable to purification. This suggests that while initial imine formation was taking place, subsequent cyclizations were not occurring due to unexpected stability of the N-acylhemiaminal. However, we did observe reaction of 7b with isocyanates¹⁴ (DIEA, CH CN, 80 °C, 24 h) to afford the unusual alkenyl oxazolidinones 17 and 18 (Figure 2). Surprisingly, 17 and 18 were remarkably stable under both acidic and basic conditions.

We next selected the condensation of 1,2-diketone 5 with S-methylsemicarbazide hydroiodide for initial follow-up with the goal of developing a regioselective condensation. Although there are numerous reports of reactions with 1,2-dicarbonyls, there are a limited number of studies that address the issue of regioselectivity when non-symmetric substrates were utilized.¹⁹ In general, regioselectivity is a direct result of inherent reactivity of the carbonyls.^19c,e Despite modest advancements, obtaining regioselectivity with scaffolds of greater complexity remains a significant challenge. Accordingly, we conducted a series of triazene-forming reactions utilizing various catalysts and conditions (Table 1).

Table 1.

Optimization of triazine regioselectivity

entry	Solvent	temp/time	catalysta	additive	12a:12b	% convb
1	EtOH	rt, 4h	-	-	2 : 1	100
2	THF/H2O (9:1)	rt, 4h	-	-	1 : 1	100
3	THF/H2O (9:1)	rt, 2h	Sc(OTf)3	-	1 : 2	100
4	TFE	rt, 2h	-	-	6 : 1	79
5	TFE	rt, 2h	Sc(OTf)3	-	5 : 1	51
6	TFE	rt, 2h	Sc(OTf)3	4 Å MS	1 : 3	30
7	TFE	0 °C, 16h	Sc(OTf)3	4 Å MS	1 : 14	68
8	TFE	0 °C, 16h	La(OTf)3	4 Å MS	1 : 10	85
9	TFE	0 °C, 16h	Zn(OTf)2	4 Å MS	1 : 1	50
10	CH3CN	0 °C, 16h	Sc(OTf)3	4 Å MS	1 : 17	57
11	CH3CN	0 °C, 16h	Sc(OTf)3	4 Å MS	1 : 24c	70

^aLewis Acid (1 equiv).

^bCalculated from UPLC/ELS percent conversions.

^cSemicarbazide (2 equiv).

Generally, it was observed that replacement of EtOH with 2,2,2-trifluoroethanol (TFE) or CH₃CN enhanced the regioselectivity 3-fold. Conversely, use of THF:H₂O (9:1) resulted in a reduction of regioselectivity (Table 1, entry 2). These results suggest that the presence of a nucleophilic solvent such as EtOH or H₂O leads to the formation of a derived hemiketal or hydrate, respectively, with the slightly more electrophilic ketone thus decreasing regioselectivity. Unexpectedly, addition of Sc(OTf)₃ resulted in an inversion of regioselectivity (Table 1, entry 3). While the addition of 4 Å MS resulted in a slight enhancement of inversion, additional enhancement was achieved by conducting the reaction at 0 °C for 16 h and by using extensively dried S-methylsemicarbazide hydroiodide (Table 1, entry 7). The conversion was ultimately improved by using two equivalents of S-methylsemicarbazide (Table 1, entry 11). To the best our knowledge, this study represents the first use of a Lewis acid to invert the regioselectivity of a 1,2-dicarbonyl condensation.

Although two regioisomers were isolated, we were unable to assign the structures of 12a and 12b using standard NMR analysis due to the overlapping of several key proton resonances. Attempts to grow suitable crystals for X-ray analysis were also unsuccessful. We therefore sought to synthesize an alternative substrate with fewer more defined proton resonances. Previous work had demonstrated that bicyclo[3.2.1]octanoid 2 undergoes a retro-Dieckmann-type ring opening with pyrrolidine in the presence of TBD.⁴ Unfortunately, this methodology was limited in scope of the secondary amine reagent. Thus, a revised route to the cycloheptenone scaffold was developed that would allow for greater variability of the tertiary amide. We found that performing the fragmentation reaction with water in the presence of DBU afforded the corresponding carboxylic acid 19 as a viable functional handle (Scheme 2). HATU coupling with dimethylamine afforded the desired cycloheptenone 20 in 65 % yield over two steps. Subsequent O-demethylation, followed by condensation with S-methylsemicarbazide, afforded triazines 22a and 22b.

Scheme 2.

Synthesis of alternative triazines.

With triazines 22a and 22b in hand, we were able to determine their regiochemistries using ¹⁵N-HMBC NMR analysis²⁰ (Scheme 2).¹⁷ Based on these experiments, we postulated that the inherently more reactive ketone is beta to the phenyl group (C-1) and that the Lewis acid may preferentially activate the ketone beta to the amide group (C-2).

To further understand the mechanism leading to regioselectivity we turned our attention to condensations with urea, which was also identified in the initial screen. Our first objective, however, was to control the oxidative process occurring during the course of the reaction. It was found that degassing the reaction with argon significantly prevented the oxidative process (Table 2, entry 2) while purging the reaction with O₂ increased the degree of oxidation (Table 2, entry 3). With a viable method for controlling oxidation, the next step was to attempt the condensation with the non-symmetrical N-ethylurea. As anticipated, condensation with 1,2-diketone 5 gave rise to a mixture of regioisomers 23a and 23b (Scheme 3). Regiochemical assignments were confirmed by 1D NOE analysis.¹⁷ As the unsubstituted urea nitrogen is expected to be more reactive, we anticipated that the initial condensation may occur with the slightly more electrophilic C-1 ketone as observed for condensation with S-methylsemicarbazide (cf. Scheme 2).

Table 2.

Oxidation during urea condensation.^a

Entry	atm	16a : 16b
1	air	1 : 1
2	argon	32 : 1
3	oxygen	1 : 3

^aCalculated from UPLC/ELS percent conversions.

Scheme 3.

Condensation with ethylurea.

We next conducted a Lewis acid screen to determine if regiochemical control would be possible with substituted ureas. Generally, substituted ureas were found to be substantially less reactive than S-methylsemicarbazide which required alternative conditions to obtain regioselectivity. As indicated in Table 3, all Lewis acids investigated resulted in the inversion of regioselectivity with Zn(OTf)₂ being the most effective catalyst. Thus, the incorporation of a Lewis acid in place of a Brønsted acid ultimately rendered the C-2 ketone to be more reactive similar to the regioselective synthesis of triazines 12 and 22.

Table 3.

Lewis acid screening results.^a

entry	catalyst	23a : 23b
1	CSAb	2 : 1
2	Sc(OTf)3	1 : 2
3	Yb(OTf)3	1 : 2
4	Y(OTf)3	1 : 2
5	La(OTf)3	1 : 2
6	Mg(OTf)2	1 : 4
7	Fe(OTf)2	1 : 4
8	Mn(OTf)2	1 : 8
9	Zn(OTf)2	1 : 9

^aCalculated from UPLC/ELS percent conversions.

^bCSA (1 equiv).

To gain insight into the role of the Lewis acid, mechanistic studies were initiated utilizing ¹H and ¹³C NMR analyses of substrate 5 in the presence of Zn(OTf)₂ (Figure 4 and 5). We observed a downfield shift of all the 1,2-cycloheptanedione ring protons except the α-phenyl methine proton (D) which shifted slightly upfield (Figure 4). The addition of Zn(OTf)₂ did not significantly alter coupling constants indicating that the 1,2-cycloheptanedione ring conformation was not significantly altered. ¹³C NMR spectra revealed selective broadening of the two ketone resonances at 196 ppm and 197 ppm. Given that Zn(II) is diamagnetic, we did not anticipate the observed resonance broadening. We propose that Fe(II), a common impurity (1-20 ppm) in Zn(OTf)₂, is likely responsible for the resonance broadening suggesting that Fe(II) or Zn(II) may chelate the 1,2-diketone and not the more Lewis basic amide functionality. Since Fe(OTf)₂ also induces significant inversion of regioselectivity, it is expected that these Lewis acids share a common metal coordination site.

Figure 4.

¹H NMR evidence for mechanism (in CD₃CN).

Figure 5.

¹³C NMR evidence for chelation (in CD₃CN).

Based primarily on the ¹H and ¹³C NMR studies, we propose a mechanism for the regioselective condensation (Figure 6). Using conformational analysis followed by energy minization,²¹ we determined that, in the absence of Zn(OTf)₂, the oxygen lone pair on the amide carbonyl is positioned in close proximity to the α-phenyl methine altering its electronic environment. We believe that chelation of Zn(OTf)₂ to the 1,2-diketone lowers the LUMO for both carbonyls triggering rotation of the amide carbonyl forming a stabilizing n-π* interaction with the C-1 ketone. The C-2 ketone is unable to undergo a similar n-π* interaction due to significant steric clash upon further rotation of the amide. It is also notable that replacement of the pyrrolidine with N-methylcyclohexylamine resulted in complete loss of regioselectivity likely due to greater steric interactions inhibiting amide rotation.

Figure 6.

Proposed stereoelectronic effects leading to condensation regioselectivity.²¹

We next probed additional substituted ureas (Table 4). It was found that the Zn(OTf)₂-mediated reaction maintained reasonable regioselectivity over a wide range of functionality. However, a slight reduction in selectivity was observed with increasing steric bulk of the ureas substitution (Table 4, entries 1-4). Additionally, we observed that greater electron deficiency was accompanied with a slight decrease in yield (Table 4, entries 8-10). In the case of N-acetylurea, no reaction was observed. Condensations with 1,3-disubstituted ureas, such as 1-methyl-3-phenylurea and 1-ethyl-3-phenylurea, indicated that the phenyl substituted nitrogen is more nucleophilic (Table 4, entries 12 and 13). Reactions with a Brønsted acid catalyst (CSA) were also carried out in select cases. While both allylurea and p-chlorophenylurea resulted in similar regioselectivity as ethylurea, 1-ethyl,3-phenylurea gave similar results as the Zn(OTf)_2- mediated reaction. The Zn(OTf)₂-mediated regioselective condensation was also applied to a substituted thiourea with good results. However, in this instance a stoichiometric amount of Zn(OTf)₂ was required to achieve comparable regioselectivity (Table 4, entry 14).

Table 4.

Scope of urea condensation regioselectivity.

entry	urea	X	R1	R2	Yielda,b	rr	product
1		O	H	ethyl	92 % (99 %)b	77:23 (47:53)b	23a/23b
2		O	H	methyl	99 %	66:34	24a/24b
3		O	H	isopropyl	99 %	71:29	25a/25b
4		O	H	tert-butyl	88 %	65:35	26a/26b
5		O	H	allyl	98 % (96 %)b	82:18 (46:54)b	27a/27b
6		O	Et	propargyl	91 %	81:19	28a/28b
7		O	H	benzyl	98 %	82:18	29a/29b
8		O	H	phenyl	99 %	77:23	30a/30b
9		O	H	4-chlorophenyl	85 % (96 %)b	85:15 (46:54)b	31a/31b
10		O	H	4-bromophenyl	80 %	76:24	32a/32b
11		O	Et	ethyl	93 %	-	33
12		O	Ph	methyl	98 %	76:24	34a/34b
13		O	Ph	ethyl	99 % (99 %)b	78:22 (64:36)b	35a/35b
14		S	H	ethyl	99 %	80:20c	36a/36b

^aCombined isolated yield using Zn(OTf)₂ (0.2 equiv) with 4 Å MS.

^bCombined isolated yield using CSA (1.0 equiv).

^cRequired Zn(OTf)₂ (1.0 equiv) with 4 Å MS.

Due to the oxidative instability of the alkenyl imidazolones, we sought to determine the oxidation/reduction potential of these interesting ring systems with the intent of increasing stability. We first carried out oxidation of alkenyl imidazolone 23a using DDQ (1.2 equiv) which afforded the desired cycloheptatriene 37 along with the pseudo-aromatic cycloheptimidazolone (2-hydroxy-1,3-diazaazulene)²² 38 (Scheme 4). Acylation of the urea prevented over oxidation and afforded exclusively cycloheptatriene 39 in moderate yield over two steps.

Scheme 4.

Further transformations of cycloheptadiene 23a

Diastereoselective hydrogenation of alkenyl imidazolone 23a with 10 % Pd/C (H-Cube, 50 bar, 50 °C) afforded cycloheptene 40 as a single diastereomer (Scheme 5). The stereochemical assignment was confirmed by 1D NOE analysis.¹⁷ Diastereoselectivity is likely achieved through steric interaction imparted by the pseudo-axial methyl effectively blocking the re-face (Scheme 5). Unfortunately, reduction of the styrenyl olefin did not result in an appreciable decrease in oxidative decomposition.

Scheme 5.

Diastereoselective reduction of alkenyl imidazolone 23a.²¹

Interestingly, N-acylation of cycloheptene 40 resulted in only a slight increase in stability which suggests that the electronics of the imidazolone ring plays a significant role in oxidative decomposition. It should be noted that imidazolone rings with greater electron density, such as disubstituted urea condensates 33-35, underwent decomposition more readily. Initial attempts to fully reduce alkenyl imidazolone 23a with 10 % Pd/C using extremely harsh conditions (H-Cube, 90 bar, 80 °C) still afforded cycloheptene 40 as the major product as well as some reduction of the phenyl ring. However, full reduction of 23a was achieved with Raney Ni (H-Cube, 90 bar, 80 °C) to afford imidazolidinone 41 as a 1:1 mixture of diastereomers (Scheme 6). Hydrogenation of the imidazolone olefin effectively eliminated the occurrence of oxidative decomposition.

Scheme 6.

Hydrogenations of alkenyl imidazolone 23a.

Unfortunately, hydrogenation with Raney Ni using harsh H-Cube conditions was highly variable due to variability in catalyst cartridge batches. As a result, an alternative more reliable approach for reducing the imidazolone olefin was required. Remarkably, it was discovered that full reduction of the acetylated alkenyl imidazolone 42 with 10 % Pd/C under considerably milder conditions (H-Cube, 30 bar, 90 °C) afforded imidazolidinone 43 as a single diastereomer (Scheme 6). We also observed full reduction of the acetylated alkenyl imidazolone 44 to afford imidazolidinone 45 as a single diastereomer albeit requiring slightly harsher conditions.

As previously described, we propose that the styrenyl olefin undergoes diastereoselective hydrogenation first via the well established Horiuti-Polanyi half-hydrogenation mechanism²³ affording the allylpalladiumhydride intermediate 46 (Figure 7). Subsequent isomerization occurs with retention of stereo-chemistry to afford intermediate 47 which may in part be favored due to stabilization by coordination of the amide acetyl oxygen.²⁴ Subsequent reductive elimination of palladium provides the net 1,4-addition product 48 as a single diastereomer. We were also able to isolate intermediate 48 under milder conditions (H-Cube, 10 bar, 40 °C). Stereochemical assignments for 48 were confirmed by 1D NOE analysis.¹⁷ Diastereoselective hydrogenation of the resulting enamine affords the fully reduced product 43. Diastereoselectivity of the final reduction is due to blocking of the re-face by the flanking phenyl and N-acylurea. Further evidence for the allylpalladium hydride isomerization mechanism was provided by a failed attempt to reduce the acetylated imidazolone 49 (H-Cube, 10 bar 40 °C) (Scheme 7).

Figure 7.

Proposed mechanism for diastereoselective hydrogenation.

Scheme 7.

Reduction/isomerization of an N-acetylimidazolone.

We were also able to isolate enamine 48 upon treatment of 49 with acetic acid (Scheme 7). The selectivity of the acid-mediated isomerization suggests that the observed syn-diastereomer is thermodynamically favored. Accordingly, computational studies²¹ for imidazolone 49 and both the syn- and anti-diastereomers from isomerization were performed. As indicated in Figure 8, the ground-state energy of the syn-diastereomer 48 is 1 Kcal lower in energy than the parent imidazolone 49 and 4.8 Kcal lower in energy than the anti-diastereomer 50. These results confirm that the syn-diastereomer 48 is thermodynamically favored.

Figure 8.

Ground-state energetics of imidazolone isomerizations.²¹

Interesting, similar calculations performed on imidazolone 40, which lacks the N-acetyl, revealed isomerization to either the syn- or anti-diastereomer is not favored with ground-states energies of +5.6 Kcal and +8.4 Kcal, respectively (Figure 8). These findings, in part, help explain the results obtained for the Raney Ni hydrogenation in which diastereoselective reduction of imidazolone 40 was not observed. Without isomerization to afford bulky functionality flanking the olefin, hydrogenation occurs equally from both the si- and re-face.

In summary, multidimensional screening of condensations reactions enabled the discovery of regioselective Lewis acid-mediated condensations with a densely functionalized 1,2-diketone scaffold. We determined that regioselective condensations may be conducted using Lewis acid chelation with the 1,2-diketone leading to a proposed n-π* interaction with a pendant amide carbon-yl. This unique approach to achieving regioselectivity apparently relies on a presence of the proximal amide which may form a stabilizing n-π* interaction with the nearest neighboring carbonyl.. Regioselective condensations with substituted ureas led to the ultimate discovery of a novel diastereoselective hydrogenation which proceeds via an interesting allylpalladium hydride isomerization. Taken together, these discoveries provide a regioselective and diastereoselective route to a number of densely functionalized cycloheptane urea scaffolds. Application of the methodology developed to chemical library synthesis is currently underway and will be reported in due course.

General Information

¹H NMR spectra were recorded at 400 MHz at ambient temperature unless otherwise stated. ¹³C NMR spectra were recorded at 100.0 MHz at ambient temperature unless otherwise stated. Chemical shifts are reported in parts per million relative to CDCl₃ (¹H, δ 7.27; ¹³C, δ 77.0) and CD₃OD (¹H, δ 3.31; ¹³C, δ 49.0). Data for ¹H NMR are reported as follows: chemical shift, integration, multiplicity (ovrlp = overlapping, s = singlet, d = doublet, t = triplet, q = quartet, qt = quintuplet, m = multiplet) and coupling constants are reported as values in hertz. Infrared spectra were recorded on a Nicolet Nexus 670 FT-IR spectrophotometer. High-resolution mass spectra were obtained in the Boston University Chemical Instrumentation Center using a Waters Q-TOF mass spectrometer. Analytical LC was performed on a Waters Acquity UPLC with PDA, ELS and SQ detectors. An Acquity UPLC BEH 2.1 × 50 mm 1.7 μM C18 column was used for analytical LC. Analytical thin-layer chromatography was performed using 0.25 mm silica gel 60-F plates. Otherwise, flash chromatography was performed using 200-400 mesh silica gel. Yields refer to chromatographically and spectroscopically pure materials, unless otherwise stated. Acetonitrile, THF, and CH₂Cl₂ were purified by passing through two packed columns of neutral alumina. All reactions were carried out in oven-dried glassware under an argon atmosphere unless otherwise noted. Chemical names were generated using MDL AutoNom 2000. The Arthur™ Suite Reaction Planner was used for experimental procedure planning.

General procedure for the synthesis of diketone 5, diketone 21, and α–hydroxyketone 7a/b

To a 20 mL vial was added cycloheptenone 4 (170 mg, 0.52 mmol) followed by DMSO (10 mL). Once fully dissolved, 1.2 M HCl (10 mL) was added. The reaction was heated to 100 °C and stirred for 4 h. The reaction was cooled, diluted with water (25 mL) and partitioned into CH₂Cl₂ (20 mL × 3). The organic layer was washed with brine (25 mL), dried over sodium sulfate, filtered, and evaporated in vacuo and the crude material purified by flash chromatography (SiO₂, 9:1 CH₂Cl₂:EtOAc) to afford 5 (76 %, 124 mg, 0.40 mmol).

Diketone 5

¹H NMR (400 MHz, CD₃CN) δ 0.73 (d, J = 7.0 Hz, 3 H), 1.79 - 1.87 (m, 2 H), 1.88 - 1.94 (m, 2 H), 2.40 - 2.49 (m, 1 H), 2.55 (dd, J = 13.3, 1.6 Hz, 1 H), 2.88 (dd, J = 16.0, 7.0 Hz, 1 H), 3.00 - 3.07 (m, 1 H), 3.11 (dd, J = 16.0, 2.0 Hz, 1 H), 3.29 (d, J = 13.3, 12.0 Hz, 1 H), 3.32 - 3.38 (m, 2 H), 3.43 - 3.51 (m, 2 H), 3.54 - 3.62 (m, 1 H), 7.22 - 7.28 (m, 3 H), 7.32 - 7.38 (m, 2 H).

¹³C NMR (100 MHz, CD₃CN) δ 19.9, 25.4, 27.2, 44.4, 45.1, 47.0, 48.3, 48.9, 48.9, 50.6, 128.0, 128.4, 130.2, 147.5, 172.4, 195.6, 197.0.

IR (thin film) νmax 2973, 1710, 1701, 1653, 1635, 1616, 1559, 1465, 1457, 703 cm⁻¹.

HRMS calculated for C₁₉H₂₄NO₃: 314.1756, found: 314.1751 (M+H).

α–Hydroxyketone 7a. (99 %, 38 mg, 0.11 mmol)

¹H NMR (400 MHz, CDCl₃) δ 0.91 (d, J = 7.0 Hz, 3 H), 2.08 - 2.17 (m, 1 H), 2.20 (d, J = 13.6 Hz, 1 H), 2.33 (d, J = 18.2 Hz, 1 H), 2.39 (t, J = 11.7 Hz, 1 H), 2.51 (dd, J = 13.6, 8.7 Hz, 1 H), 2.75 (dd, J = 18.2, 11.7 Hz, 1 H), 2.89 (d, J = 8.7 Hz, 1 H), 4.15 (d, J = 14.7 Hz, 1 H), 4.72 (d, J = 14.7 Hz, 1 H), 4.88 (s, 1 H), 6.88 (d, J = 7.8 Hz, 2 H), 7.17 - 7.22 (m, 1 H), 7.22 - 7.29 (m, 3 H), 7.32 (t, J = 7.2 Hz, 2 H), 7.36 - 7.40 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃) δ 19.7, 39.0, 42.0, 43.7, 44.6, 47.0, 47.6, 89.1, 126.6, 126.8, 128.0, 128.5, 128.9, 129.8, 136.4, 144.2, 173.5, 205.9.

IR (thin film) νmax 3415, 2935, 1690, 1454, 1401, 1380, 1348, 1138, 1117, 702 cm⁻¹.

HRMS calculated for C₂₂H₂₄NO₃: 350.1756, found: 350.1764 (M+H).

α–Hydroxyketone 7b. (97 %, 37 mg, 0.098 mmol)

¹H NMR (400 MHz, CDCl₃) δ 0.90 (d, J = 7.0 Hz, 3 H), 2.08 - 2.16 (m, 1 H), 2.18 (d, J = 13.7 Hz, 1 H), 2.33 (dd, J = 18.2, 2.0 Hz, 1 H), 2.37 (td, J = 12.0, 2.0 Hz, 1 H), 2.49 (dd, J = 13.7, 8.6 Hz, 1 H), 2.74 (dd, J = 18.2, 12.0 Hz, 1 H), 2.87 (dd, J = 8.6, 2.0 Hz, 1 H), 3.77 (s, 3 H), 4.06 (d, J = 14.7 Hz, 1 H), 4.70 (d, J = 14.7 Hz, 1 H), 4.90 (s, 1 H), 6.83 (d, J = 8.8 Hz, 2 H), 6.89 (d, J = 7.0 Hz, 2 H), 7.15 - 7.21 (m, 1 H), 7.22 - 7.28 (m, 2 H), 7.30 (d, J = 8.8 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃) δ 19.7, 39.0, 41.2, 43.6, 44.4, 46.9, 47.6, 55.2, 89.1, 113.6, 126.6, 126.8, 128.8, 128.5, 131.2, 144.2, 159.2, 173.4, 206.1.

IR (thin film) νmax 3425, 2935, 1690, 1513, 1247, 1177, 1138, 1112, 1032, 703, 668 cm⁻¹.

HRMS calculated for C₂₃H₂₆NO₄: 380.1862, found: 380.1867 (M+H).

Diketone 21. (73 %, 60 mg, 0.21 mmol)

¹H NMR (400 MHz, CD₃CN) δ 0.71 (d, J = 6.6 Hz, 3 H), 2.41 - 2.50 (m, 1 H), 2.55 (dd, J = 13.3, 1.6 Hz, 1 H), 2.83 (dd, J = 16.0, 7.4 Hz, 1 H), 2.89 (s, 3 H), 2.95 - 3.02 (m, 1 H), 3.09 (s, 3 H), 3.10 (dd, J = 16.0, 2.0 Hz, 1 H), 3.29 (dd, J = 13.3, 12.0 Hz, 1 H), 3.67 - 3.75 (m, 1 H), 7.21 - 7.29 (m, 3 H), 7.32 - 7.38 (m, 2 H).

¹³C NMR (100 MHz, CD₃CN) δ 19.7, 36.2, 39.4, 44.5, 45.1, 46.1, 48.2, 50.5, 128.0, 128.4, 130.1, 147.4, 174.1, 195.8, 197.0.

IR (thin film) νmax 2960, 1709, 1684, 1653, 1635, 1617, 1559, 1506, 1457, 1419, 704 cm⁻¹.

HRMS calculated for C₁₇H₂₁NO₃Na: 310.1419, found: 310.1407 (M+Na).

General procedure for the synthesis of imidazole 8 and oxazoline 9a-b

To an oven-dried vial was added diketone 5 (40 mg, 0.13 mmol) and ammonium acetate (40 mg, 0.52 mmol) followed by anhydrous ethanol (1 mL) and benzaldehyde (15 μL, 0.14 mmol). The reaction vial was sealed with a Teflon-lined cap and heated to 80 °C for 3 h with continuous stirring. The reaction was cooled, concentrated in vacuo and purified by flash chromatography (SiO₂, gradient 30:1 CH₂Cl₂:MeOH to 10:1 CH₂Cl₂:MeOH) to afford 8 (36 %, 18 mg, 0.046 mmol).

Imidazole 8

¹H NMR (400 MHz, CD₃OD) δ 1.12 (d, J = 7.0 Hz, 3 H), 1.73 - 1.82 (m, 4 H), 2.40 (t, J = 6.8 Hz, 1 H), 2.76 (d, J = 14.5 Hz, 1 H), 2.88 - 2.98 (m, 1 H), 2.98 – 3.07 (ovrlp m, 1 H), 3.02 – 3.10 (ovrlp m, 1 H), 3.05 – 3.12 (ovrlp m, 1 H), 3.13 – 3.20 (ovrlp m, 1 H), 3.13 – 3.23 (ovrlp m, 1 H), 3.17 – 3.25 (ovrlp m, 1 H), 3.25 – 3.32 (m, 1 H), 3.32 – 3.40 (m, 1 H), 7.15 - 7.22 (m, 1 H), 7.22 - 7.31 (m, 4 H), 7.35 - 7.42 (m, 1 H), 7.42 - 7.49 (m, 2 H), 7.84 (d, J = 8.2 Hz, 2 H).

¹³C NMR (100 MHz, CD₃OD) δ 14.7, 24.0, 25.0, 26.9, 29.3, 41.4, 43.2, 47.1, 47.2, 126.3, 127.6, 129.2, 129.5, 129.9, 130.1, 130.2, 132.0, 133.2, 144.9, 147.0, 175.2.

IR (thin film) νmax 3057, 2971, 2877, 1635, 1493, 1437, 1380, 1265, 773, 734, 702 cm⁻¹.

HRMS calculated for C₂₆H₃₀N₃O: 400.2389, found: 400.2389 (M+H).

Oxazoline 9a. Purified by flash chromatography (SiO₂, 6:3:1 petroleum ether:CH₂Cl₂:EtOAc) (72 %, 26 mg, 0.058 mmol)

¹H NMR (400 MHz, CDCl₃) δ 0.88 (d, J = 6.6 Hz, 3 H), 2.09 - 2.16 (ddq, J = 10.9, 6.6, 1.8 Hz, 1 H), 2.21 (d, J = 12.9 Hz, 1 H), 2.40 (ddd, J = 12.9, 10.9, 2.3 Hz, 1 H), 2.67 (dd, J = 19.0, 2.3 Hz, 1 H), 2.69 (dd, J = 12.9, 8.6 Hz, 1 H), 2.80 (ddd, J = 19.0, 12.9, 3.1 Hz, 1 H), 2.82 (dd, J = 8.6, 1.8 Hz, 1 H), 4.40 (d, J = 14.9 Hz, 1 H), 4.60 (d, J = 14.9 Hz, 1 H), 6.82 (d, J = 3.1 Hz, 1 H), 6.92 (d, J = 7.4 Hz, 2 H), 7.14 - 7.22 (m, 1 H), 7.23 - 7.29 (m, 3 H), 7.34 - 7.40 (m, 7 H), 7.49 (d, J = 7.0 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃) δ 20.6, 37.4, 39.5, 43.2, 44.2, 44.4, 47.7, 103.1, 105.5, 126.1, 126.7, 126.8, 127.9, 128.5, 128.6, 128.8, 128.9, 129.0, 136.9, 138.4, 144.7, 170.9, 173.1.

IR (thin film) νmax 3030, 2965, 2936, 1698, 1494, 1454, 1395, 1153, 1044, 1017, 736, 699, 668 cm⁻¹.

HRMS calculated for C₂₉H₂₉N₂O₂: 437.2229, found: 437.2236 (M+H).

Oxazoline 9b. Purified by flash chromatography (SiO₂, 6:3:1 petroleum ether:CH₂Cl₂:EtOAc) (61 %, 22 mg, 0.048 mmol)

¹H NMR (400 MHz, CDCl₃) δ 0.86 (d, J = 6.6 Hz, 3 H), 2.06 - 2.15 (ddq, J = 10.9, 6.6, 1.8 Hz, 1 H), 2.18 (d, J = 12.5 Hz, 1 H), 2.35 (ddd, J = 12.5, 10.9, 2.3 Hz, 1 H), 2.64 (dd, J = 19.0, 2.3 Hz, 1 H), 2.66 (dd, J = 12.5, 8.1 Hz, 1 H), 2.78 (ddd, J = 19.0, 12.5, 3.3 Hz, 1 H), 2.79 (dd, J = 8.1, 1.8 Hz, 1 H), 3.79 (s, 3 H), 4.27 (d, J = 14.8 Hz, 1 H), 4.61 (d, J = 14.8 Hz, 1 H), 6.82 - 6.93 (m, 5 H), 7.13 - 7.21 (m, 1 H), 7.22 - 7.28 (m, 2 H), 7.34 - 7.44 (m, 7 H).

¹³C NMR (100 MHz, CDCl₃) δ 20.5, 37.4, 39.5, 42.6, 44.1, 44.4, 47.7, 55.3, 103.1, 105.5, 113.8, 126.1, 126.6, 126.7, 128.6, 128.7, 128.9, 129.1, 130.5, 138.4, 144.8, 159.2, 171.1, 173.0.

IR (thin film) νmax 3029, 2936, 2836, 1696, 1513, 1395, 1278, 1248, 1178, 1036, 736, 699 cm⁻¹.

HRMS calculated for C₃₀H₃₁N₂O₃: 467.2335, found: 467.2323 (M+H).

General procedure for the synthesis of Triazine 12a/b and 22a/b

To an oven-dried vial was added diketone 5 (40 mg, 0.13 mmol) followed by anhydrous EtOH (1 mL). Next, S-methylsemicarbazide hydroiodide (91 mg, 0.39 mmol) was added and the reaction was stirred for 6 h at rt. The reaction was concentrated in vacuo and purified by flash chromatography (SiO₂, gradient 9:1 CH₂Cl₂:EtOAc to 3:1 CH₂Cl₂:EtOAc) to afford 12a (38 %, 19 mg, 0.050 mmol) and 12b (19 %, 9 mg, 0.025 mmol).

Triazine 12a. R_f=0.55 (CH₂Cl₂:MeOH, 20:1)

¹H NMR (400 MHz, CDCl₃) δ 0.69 (d, J = 7.0 Hz, 3 H), 1.72 - 1.83 (m, 2 H), 1.85 - 1.94 (m, 2 H), 2.11 - 2.25 (m, 1 H), 2.58 (s, 3 H), 3.08 (dd, J = 15.2, 7.8 Hz, 1 H), 3.18 - 3.27 (m, 3 H), 3.28 - 3.44 (m, 6 H), 7.10 - 7.18 (m, 3 H), 7.21 - 7.28 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃) δ 13.9, 18.7, 24.3, 26.3, 37.5, 41.0, 43.5, 44.1, 45.0, 45.6, 47.0, 126.4, 128.7, 145.9, 156.6, 160.6, 170.2, 170.6.

IR (thin film) νmax 2953, 2927, 2873, 1628, 1445, 1376, 1343, 1265, 1165, 734, 702 cm⁻¹.

HRMS calculated for C₂₁H₂₇N₄OS: 383.1906, found: 383.1893 (M+H).

Triazine 12b. R_f=0.33 (CH₂Cl₂:MeOH, 20:1)

¹H NMR (400 MHz, CDCl₃) δ 0.74 (d, J = 6.6 Hz, 3 H), 1.76 - 1.89 (m, 2 H), 1.91 - 2.02 (m, 2 H), 2.23 (m, 1 H), 2.60 (s, 3 H), 3.07 (dd, J = 14.1, 2.0 Hz, 1 H), 3.19 - 3.29 (m, 2 H), 3.33 (m, 2 H), 3.40 (dd, J = 14.9, 2.7 Hz, 1 H), 3.45 - 3.52 (m, 2 H), 3.53 - 3.62 (m, 2 H), 7.15 - 7.23 (m, 3 H), 7.27 - 7.33 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃) δ 13.8, 19.4, 24.3, 26.3, 35.2, 44.0, 44.2, 44.4, 44.5, 45.5, 46.9, 126.5, 128.7, 145.8, 155.2, 161.4, 170.4, 171.3.

IR (thin film) νmax 2972, 2873, 1630, 1443, 1376, 1295, 1262, 734, 702 cm⁻¹.

HRMS calculated for C₂₁H₂₇N₄OS: 383.1906, found: 383.1915 (M+H).

Triazine 22a. (30 %, 14 mg, 0.039 mmol), R_f=0.52 (CH₂Cl₂:MeOH, 20:1)

¹H NMR (400 MHz, CDCl₃) δ 0.68 (d, J = 6.9 Hz, 3 H), 2.14 - 2.24 (m, 1 H), 2.57 (s, 3 H), 2.79 (s, 3 H), 3.01 (s, 3 H), 3.06 (dd, J = 15.0, 7.6 Hz, 1 H), 3.20 (dd, J = 15.0, 2.8 Hz, 1 H), 3.26 - 3.33 (m, 2 H), 3.33 - 3.39 (m, 1 H), 3.39 - 3.43 (m, 1 H), 7.10 - 7.17 (m, 3 H), 7.21 - 7.26 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃)δ 13.9, 18.4, 35.7, 37.3, 37.9, 40.7, 41.3, 43.6, 45.1, 126.5, 128.7, 145.7, 156.5, 160.5, 170.7, 171.9.

IR (thin film) νmax 2928, 1634, 1493, 1376, 1341, 1261, 1132, 734, 703 cm⁻¹.

HRMS calculated for C₁₉H₂₅N₄OS: 357.1749, found: 357.1757 (M+H).

Triazine 22b. (19 %, 9 mg, 0.025 mmol), R_f=0.29 (CH₂Cl₂:MeOH, 20:1)

¹H NMR (400 MHz, CDCl₃) δ 0.67 (d, J = 6.9 Hz, 3 H), 2.16 - 2.25 (m, 1 H), 2.54 (s, 3 H), 2.77 (s, 3 H), 3.02 (dd, J = 14.2, 2.0 Hz, 1 H), 3.07 (s, 3 H), 3.22 (dd, J = 14.2, 11.0 Hz, 1 H), 3.36 - 3.44 (m, 3 H), 3.44 - 3.50 (m, 1 H), 7.09 - 7.18 (m, 3 H), 7.21 - 7.27 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃ ) δ 13.8, 19.0, 35.7, 37.9, 41.8, 44.1, 44.6, 126.6, 128.7, 145.6, 155.1, 161.6, 171.4, 172.2.

IR (thin film) νmax 2929, 1635, 1517, 1492, 1375, 1296, 1261, 1155, 1133, 729, 702 cm⁻¹.

HRMS calculated for C₁₉H₂₅N₄OS: 357.1749, found: 357.1745 (M+H).

Cycloheptenone 19

To a vial was added bicyclo[3.2.1]octanoid 2 (40 mg, 0.16 mmol) followed by CH₃CN (1 mL) and H₂O (100 μL). Next, DBU (24 μL, 0.16 mmol) was added and the reaction was stirred at rt for 4 h. The reaction was diluted with H₂O (1 mL), rendered acidic (approx. pH 3) with the addition of 1 N HCl, and extracted with CH₂Cl₂ (10 mL ×3). The organic layer was washed with brine (25 mL), dried over sodium sulfate, filtered, and evaporated in vacuo. The crude material was purified by flash chromatography (SiO₂, 20:1 CH₂Cl₂:MeOH) to afford 19 (98 %, 43 mg, 0.16 mmol). R_f=0.30 (CH₂Cl₂:MeOH, 20:1).

¹H NMR (400 MHz, CDCl₃) δ 0.87 (d, J = 6.3 Hz, 3 H), 2.53 - 2.60 (m, 2 H), 2.80 (d, J = 17.4 Hz, 1 H), 3.05 (dd, J = 17.4, 11.9 Hz, 1 H), 3.71 (s, 3 H), 3.95 (t, J = 5.2 Hz, 1 H), 5.97 (d, J = 6.1 Hz, 1 H), 7.15 - 7.20 (m, 2 H), 7.20 - 7.26 (m, 1 H), 7.27 - 7.34 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃) δ 15.4, 41.4, 44.2, 45.8, 48.3, 55.5, 106.1, 127.0, 127.7, 128.8, 143.5, 153.1, 178.0, 197.0.

IR (thin film) νmax 3063, 2964, 2933, 1734, 1684, 1653, 1456, 1203, 1175, 1145, 735, 703 cm⁻¹.

HRMS calculated for C₁₆H₁₉O₄: 275.1283, found: 275.1291 (M+H).

Cycloheptenone 20

To a vial was added cycloheptenone 19 (40 mg, 0.15 mmol) followed by CH₂Cl₂ (1 mL). Next was added 2.0 M N,N-dimethylamine in THF (0.38 mL, 0.75 mmol), DIEA (31 μL, 0.18 mmol), and HATU (63 mg, 0.17 mmol). The reaction was stirred at rt for 6 h. The reaction was evaporated in vacuo and resulting residue purified by flash chromatography (SiO₂, 20:1CH₂Cl₂:MeOH) to afford 20 (66 %, 30 mg, 0.10 mmol).

¹H NMR (400 MHz, CD₃OD) δ 0.76 (d, J = 6.6 Hz, 3 H), 2.21 - 2.34 (m, 1 H), 2.53 (dd, J = 12.2, 9.2 Hz, 1 H), 2.59 (d, J = 17.6 Hz, 1 H), 2.98 (s, 3 H), 3.21 (s, 3 H), 3.42 (dd, J = 17.6, 12.2 Hz, 1 H), 3.66 (s, 3 H), 4.39 (t, J = 5.5 Hz, 1 H), 6.24 (d, J = 5.5 Hz, 1 H), 7.19 - 7.27 (m, 3 H), 7.29 - 7.35 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃) δ 15.4, 36.2, 37.4, 40.5, 40.8, 46.0, 48.0, 55.5, 109.4, 126.9, 127.6, 128.8, 144.1, 152.5, 171.4, 197.3.

IR (thin film) νmax 2962, 2932, 1683, 1646, 1495, 1456, 1399, 1209, 1142, 731, 703 cm⁻¹.

HRMS calculated for C₁₈H₂₃NO₃Na: 324.1576, found: 324.1594 (M+Na).

Imidazolones 16a and 16b

To a vial was added diketone 5 (40 mg, 0.13 mmol), urea (10 mg, 0.17 mmol), and CSA (30 mg, 0.13 mmol) followed by absolute ethanol (1 mL). The reaction mixture was heated to 80 °C, and stirred for 20 h. The reaction was concentrated in vacuo and purified by flash chromatography (SiO₂, 1:1, CH₂Cl₂:acetone) to afford diene 16a (48 %, 21 mg, 0.062 mmol) and triene 16b (32 %, 14 mg, 0.042 mmol).

Imidazolone 16a. R_f=0.1 (CH₂Cl₂:acetone, 1:1)

¹H NMR (400 MHz, CD₃OD) δ 1.16 (d, J = 7.0 Hz, 3 H), 1.78 - 1.90 (m, 4 H), 2.62 (dd, J = 17.5, 2.4 Hz, 1 H), 2.97 (dd, J = 12.7, 2.4 Hz, 1 H), 3.09 (dd, J = 17.5, 12.7 Hz, 1 H), 3.15 - 3.25 (m, 2 H), 3.33 - 3.48 (m, 3 H), 6.31 (s, 1 H), 7.23 (t, J = 7.4 Hz, 1 H), 7.32 (t, J = 7.6 Hz, 2 H), 7.43 (d, J = 7.4 Hz, 2 H).

¹³C NMR (100 MHz, CD₃OD) δ 12.8, 24.4, 25.2, 26.9, 40.3, 41.3, 47.2, 47.9, 115.0, 118.5, 121.1, 126.5, 128.3, 129.7, 143.8, 145.0, 155.8, 175.2.

IR (thin film) νmax 2971, 2874, 1700, 1684, 1653, 1635, 1437, 1373, 1040, 734, 698 cm⁻¹.

HRMS calculated for C₂₀H₂₄N₃O₂: 338.1869, found: 338.1870 (M+H).

Imidazolone 16b. R_f=0.15 (CH₂Cl₂:acetone, 1:1)

¹H NMR (400 MHz, CD₃OD) δ 1.06 (d, J = 7.4 Hz, 3 H), 1.65 - 1.95 (m, 4 H), 3.17 - 3.26 (m, 1 H), 3.37 - 3.48 (m, 3 H), 4.02 (q, J = 7.4 Hz, 1 H), 6.61 (s, 1 H), 6.65 (s, 1 H), 7.25 - 7.32 (m, 1 H), 7.32 - 7.39 (m, 2 H), 7.54 (d, J = 7.8 Hz, 2 H).

¹³C NMR (100 MHz, CD₃OD) δ 14.2, 24.7, 27.1, 39.4, 47.2, 51.3, 114.3, 118.0, 122.1, 126.3, 126.9, 128.3, 128.9, 129.7, 136.6, 143.5, 155.9, 172.7.

IR (thin film) νmax 2970, 1699, 1684, 1653, 1576, 1559, 1436, 1419, 723, 697 cm⁻¹.

HRMS calculated for C₂₀H₂₂N₃O₂: 336.1712, found: 366.1706 (M+H).

General procedure for the synthesis of alkenyl imidazolone 23-35 and alkenyl imidazolthione 36

To a oven-dried vial was added activated 4 Å molecular sieves (approx. 25 mg), diketone 5 (40 mg, 0.13 mmol), N-ethylurea (12 mg, 0.14 mmol), and Zn(OTf)₂ (10 mg, 0.026 mmol) followed by anhydrous CH₃CN (1 mL). The reaction mixture was then degassed by bubbling argon through the solution for 15 min. Finally, the vial was sealed with a Teflon-lined cap, heated to 100 °C, and stirred for 5 h. The reaction was cooled and filtered through Celite to remove the sieves. The resulting filtrate was concentrated in vacuo and purified by flash chromatography (SiO₂, gradient 50:1 CH₂Cl₂:MeOH to 20:1 CH₂Cl₂:MeOH) to afford 23a (71 %, 33 mg, 0.090 mmol) and 23b (21 %, 10 mg, 0.027 mmol).

N-Ethylimidazolone 23a. R_f=0.20 (CH₂Cl₂:MeOH, 20:1)

¹H NMR (400 MHz, CD₃OD) δ 1.17 (d, J = 7.2 Hz, 3 H), 1.20 (t, J = 7.0 Hz, 3 H), 1.80 - 1.90 (m, 4 H), 2.64 (dd, J = 17.9, 3.5 Hz, 1 H), 2.99 (dd, J = 12.9, 3.5 Hz, 1 H), 3.12 (dd, J = 17.9, 12.9 Hz, 1 H), 3.18 - 3.25 (m, 2 H), 3.34 - 3.49 (m, 3 H), 3.71 - 3.84 (m, 2 H), 6.36 (s, 1 H), 7.26 (t, J = 7.3 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 2 H), 7.46 (d, J = 8.0 Hz, 2 H).

NOED (400 MHz, CD₃OD) irrad. δ 6.36 (beta-phenyl, CH) 9 % enhancement at 3.77 (alpha-urea, CH₂).

¹³C NMR (100 MHz, CD₃OD) δ 12.5, 15.2, 24.6, 25.1, 26.9, 35.9, 40.5, 41.0, 47.2, 47.9, 113.3, 118.4, 121.0, 126.7, 128.4, 129.8, 144.3, 145.5, 154.5, 175.0.

IR (thin film) νmax 3164, 2973, 2873, 1700, 1697, 1684, 1653, 1635, 1617, 1437, 759, 733, 699 cm⁻¹.

HRMS calculated for C₂₂H₂₈N₃O₂: 366.2182, found: 366.2189 (M+H).

N-Ethylimidazolone 23b. R_f=0.29 (CH₂Cl₂:MeOH, 20:1)

¹H NMR (400 MHz, CD₂Cl₂:CD₃OD, 1:5.2) δ 1.17 (d, J = 7.0 Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.80 - 1.92 (m, 4 H), 2.69 (dd, J = 17.5, 3.2 Hz, 1 H), 2.97 (dd, J = 12.7, 3.2 Hz, 1 H), 3.12 (dd, J = 17.5, 12.7 Hz, 1 H), 3.17 - 3.26 (m, 2 H), 3.36 - 3.51 (m, 3 H), 3.61 - 3.83 (m, 2 H), 6.31 (s, 1 H), 7.24 (t, J = 7.43 Hz, 1 H), 7.33 (t, J = 7.24 Hz, 2 H), 7.43 (d, J = 8.02 Hz, 2 H).

NOED (400 MHz, CD₃OD) irrad. δ 2.69 (beta-amide, CH₂) 6 % enhancement at 3.72 (alpha-urea, CH₂).

¹³C NMR (100 MHz, CD₂Cl₂:CD₃OD, 1:5.2) δ 12.7, 15.1, 23.7, 24.9, 26.7, 36.5, 39.8, 41.2, 46.9, 47.7, 114.7, 117.2, 121.1, 126.2, 128.0, 129.4, 143.3, 144.6, 154.0, 174.7.

IR (thin film) νmax 2973, 2874, 1700, 1696, 1684, 1653, 1635, 1617, 1437, 1374, 765, 732, 698 cm⁻¹.

HRMS calculated for C₂₂H₂₈N₃O₂: 366.2182, found: 366.2189 (M+H).

N-tert-Butylimidazolone 26a

26a: (57 %, 29 mg, 0.074 mmol), R_f=0.15 (CH₂Cl₂:MeOH, 20:1).26b: (31 %, 16 mg, 0.040 mmol), R_f=0.26 (CH₂Cl₂:MeOH, 20:1).

¹H NMR (400 MHz, CD₂Cl₂:CD₃OD, 1:9.4) δ 1.20 (d, J = 7.0 Hz, 3 H), 1.67 (s, 9 H), 1.76 - 1.89 (m, 4 H), 2.59 (dd, J = 18.1, 4.0 Hz, 1 H), 2.92 (dd, J = 13.1, 4.0 Hz, 1 H), 3.10 (dd, J = 18.1, 13.1 Hz, 1 H), 3.13 - 3.20 (m, 2 H), 3.33 - 3.48 (m, 3 H), 6.70 (s, 1 H), 7.21 - 7.30 (m, 1 H), 7.32 - 7.42 (m, 4 H).

¹³C NMR (100 MHz, CD₂Cl₂:CD₃OD, 1:9.4) δ 11.9, 24.6, 25.0, 26.7, 31.4, 40.0, 40.6, 47.0, 47.7, 58.1, 117.3, 119.3, 122.0, 126.5, 128.0, 129.6, 142.5, 144.9, 154.8, 174.5.

IR (thin film) νmax 2970, 1675, 1635, 1591, 1430, 1128, 1032, 766, 698 cm⁻¹.

HRMS calculated for C₂₄H₃₂N₃O₂: 394.2495, found: 394.2505 (M+H).

N-Propargylimidazolone 28a

28a: (74 %, 36 mg, 0.096 mmol), R_f=0.17 (CH₂Cl₂:MeOH, 20:1).28b: (17 %, 8 mg, 0.022 mmol), R_f=0.22 (CH₂Cl₂:MeOH, 20:1).

¹H NMR (400 MHz, CD₃OD) δ 1.17 (d, J = 7.0 Hz, 3 H), 1.78 - 1.96 (m, 16 H), 2.63 (dd, J = 18.1, 3.0 Hz, 4 H), 2.70 (t, J = 2.5 Hz, 4 H), 2.98 (dd, J = 12.9, 3.0 Hz, 4 H), 3.12 (dd, J = 18.1, 12.9 Hz, 4 H), 3.18 - 3.28 (m, 8 H), 3.38 - 3.50 (m, 3 H), 4.45 (dd, J = 18.4, 2.5 Hz, 1 H), 4.61 (dd, J = 18.4, 2.5 Hz, 1 H), 6.53 (s, 1 H), 7.27 (t, J = 7.3 Hz, 1 H), 7.36 (t, J = 7.8 Hz, 2 H), 7.47 (d, J = 7.4 Hz, 2 H)

¹³C NMR (100 MHz, CD₃OD) δ 12.6, 24.4, 25.0, 26.8, 30.4, 40.2, 40.8, 47.1, 47.8, 73.5, 79.2, 113.4, 118.4, 121.1, 126.6, 128.3, 129.6, 143.9, 145.2, 154.0, 174.8.

IR (thin film) νmax 2971, 2874, 1685, 1635, 1593, 1431, 1387, 734, 700, 633 cm⁻¹.

HRMS calculated for C₂₃H₂₆N₃O₂: 376.2025, found: 376.2018 (M+H).

N-Phenylimidazolone 28a

28a: (76 %, 41 mg, 0.099 mmol), R_f=0.17 (CH₂Cl₂:MeOH, 20:1).28b: (23 %, 12 mg, 0.030 mmol), R_f=0.24 (CH₂Cl₂:MeOH, 20:1).

¹H NMR (400 MHz, CD₂Cl₂:CD₃OD, 1:6.8) δ 1.23 (d, J = 7.03 Hz, 3 H), 1.75 - 1.94 (m, 4 H), 2.71 (dd, J = 18.4, 3.1 Hz, 1 H), 3.00 (dd, J = 12.9, 3.1 Hz, 1 H), 3.19 - 3.24 (m, 2 H), 3.21 (ovrlp dd, J = 18.4, 12.9 Hz, 1 H), 3.36 - 3.50 (m, 3 H), 5.98 (s, 1 H), 7.14 - 7.22 (m, 1 H), 7.23 - 7.27 (m, 4 H), 7.31 (d, J = 7.42 Hz, 2 H), 7.38 - 7.43 (m, 1 H), 7.47 - 7.52 (m, 2 H).

¹³C NMR (100 MHz, CD₂Cl₂:CD₃OD, 1:6.8) δ 12.7, 24.4, 25.0, 26.8, 40.1, 40.8, 47.0, 47.8, 113.9, 119.4, 121.2, 126.3, 128.1, 129.2, 129.3, 129.4, 130.3, 135.3, 143.7, 144.7, 154.2, 174.7.

IR (thin film) νmax 2972, 2875, 1700, 1696, 1684, 1635, 1595, 1499, 1437, 1379, 757, 732, 700, 668 cm⁻¹.

HRMS calculated for C₂₆H₂₈N₃O₂: 414.2182, found: 414.2183 (M+H).

N-Phenyl, N’-ethylimidazolone 35a

35a: (77 %, 44 mg, 0.10 mmol), R_f=0.36 (CH₂Cl₂:MeOH, 20:1).35b: (22 %, 13 mg, 0.029 mmol), R_f=0.29 (CH₂Cl₂:MeOH, 20:1).

¹H NMR (400 MHz, CD₃OD) δ 1.22 (d, J = 7.0 Hz, 3 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.75 - 1.90 (m, 4 H), 2.36 (d, J = 15.2 Hz, 1 H), 2.91 - 3.07 (m, 2 H), 3.16 - 3.28 (m, 2 H), 3.32 - 3.44 (m, 3 H), 3.83 - 3.95 (m, 2 H), 6.48 (s, 1 H), 7.23 - 7.32 (m, 1 H), 7.34 - 7.41 (m, 4 H), 7.47 (d, J = 7.4 Hz, 1 H), 7.49 - 7.58 (m, 4 H).

NOED (400 MHz, CD₃OD) irrad. δ 6.48 (beta-phenyl, CH) 9 % enhancement at 3.90 (alpha-urea, CH₂).

¹³C NMR (100 MHz, CD₃OD)δ 12.6, 15.2, 25.1, 26.9, 36.6, 40.4, 41.1, 47.1, 47.8, 112.8, 118.4, 122.0, 126.8, 128.6, 129.2, 129.8, 129.8, 130.6, 135.7, 144.1, 146.7, 153.4, 174.9.

IR (thin film) νmax 2972, 2873, 1695, 1636, 1419, 1387, 764, 721, 696 cm⁻¹.

HRMS calculated for C₂₈H₃₁N₃O₂: 442.2495, found: 442.2494 (M+H).

N-Ethylimidazolthione 36a

36a: (79 %, 39 mg, 0.10 mmol), R_f=0.31 (CH₂Cl₂:MeOH, 20:1).36b: (20 %, 10 mg, 0.026 mmol), R_f=0.40 (CH₂Cl₂:MeOH, 20:1).

¹H NMR (400 MHz, CD₂Cl₂:CD₃OD, 1:4.1) δ 1.16 (d, J = 7.0 Hz, 3 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.86 (m, 4 H), 2.74 (dd, J = 17.9, 3.4 Hz, 1 H), 2.97 (dd, J = 13.1, 3.4 Hz, 1 H), 3.19 (ovrlp dd, J = 17.9, 13.1 Hz, 1 H), 3.19 - 3.27 (m, 2 H), 3.34 - 3.49 (m, 3 H), 4.08 - 4.29 (m, 2 H), 6.40 (s, 1 H), 7.27 - 7.33 (m, 1 H), 7.38 (t, J = 7.6 Hz, 2 H), 7.46 (d, J = 7.4 Hz, 2 H).

¹³C NMR (100 MHz, CD₂Cl₂:CD₃OD, 1:4.1) δ 11.9, 13.4, 22.9, 23.9, 25.7, 38.7, 39.3, 45.9, 46.7, 111.9, 123.4, 125.5, 125.6, 127.5, 128.5, 142.7, 146.0, 158.7, 173.2.

IR (thin film) νmax 3174, 3055, 2971, 2933, 2873, 1636, 1608, 1476, 1448, 1414, 1378, 1276, 1210, 1137, 758, 733, 698 cm⁻¹.

HRMS calculated for C₂₂H₂₈N₃OS: 382.1953, found: 382.1947 (M+H).

General procedure for the synthesis of cycloheptatriene 37, 38, and 39

To a oven-dried vial was added N-ethylimidazolone 20a (40 mg, 0.13 mmol) followed by anhydrous CH₂Cl₂ (1 mL). Next DDQ (36 mg, 0.16 mmol) was added and the reaction was stirred at rt for 2 h. The reaction was diluted with CH₂Cl₂ (10 mL) and washed with sat. NaHCO₃ (10 mL × 2) and brine (10 mL). The organic portion was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO₂, gradient 50:1 CH₂Cl₂:MeOH to 20:1 CH₂Cl₂:MeOH) to afford 37 (71 %, 33 mg, 0.090 mmol) and 38 (21 %, 10 mg, 0.027 mmol).

Cycloheptatriene 37

¹H NMR (400 MHz, CD₂Cl₂:CD₃OD, 1:6) δ 1.04 (d, J = 7.2 Hz, 3 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.61 - 1.94 (m, 4 H), 3.15 - 3.24 (m, 1 H), 3.33 - 3.47 (m, 3 H), 3.73 - 3.95 (m, 2 H), 3.99 - 4.09 (m, 1 H), 6.64 (s, 1 H), 6.65 (s, 1 H), 7.26 - 7.33 (m, 1 H), 7.34 - 7.40 (m, 2 H), 7.56 (d, J = 7.8 Hz, 2 H).

¹³C NMR (100 MHz, CD₂Cl₂:CD₃OD, 1:6) δ 12.7, 13.7, 24.0, 25.8, 35.4, 38.0, 45.9, 49.5, 111.7, 116.5, 120.1, 125.0, 127.1, 127.3, 127.6, 128.3, 135.2, 142.2, 153.0, 171.1

IR (thin film) νmax 3172, 2974, 2874, 1700, 1596, 1443, 1405, 1378, 750, 732, 698 cm⁻¹.

HRMS calculated for C₂₂H₂₆N₃O: 364.2025, found: 364.2024 (M+H).

Cycloheptimidazolone 38

¹H NMR (400 MHz, CD₃OD) δ 1.28 (t, J = 7.2 Hz, 3 H), 1.96 - 2.08 (m, 4 H), 2.24 (s, 3 H), 3.15 - 3.24 (m, 1 H), 3.32 - 3.41 (m, 1 H), 3.56 - 3.66 (m, 1 H), 3.66 - 3.74 (m, 1 H), 4.10 (q, J = 7.2 Hz, 2 H), 7.40 (d, J = 7.4 Hz, 2 H), 7.47 - 7.52 (m, 1 H), 7.52 - 7.59 (m, 2 H), 7.64 (s, 1 H), 7.86 (s, 1 H).

¹³C NMR (100 MHz, CD₃OD) δ 13.8, 23.8, 25.3, 26.9, 37.1, 47.0, 49.7, 120.5, 125.8, 129.1, 129.6, 130.1, 139.1, 145.2, 146.5, 151.4, 155.0, 163.7, 167.2, 170.4.

IR (thin film) νmax 2958, 2924, 2852, 1701, 1635, 1616, 1653, 1447, 1418, 1078, 731, 703 cm⁻¹.

HRMS calculated for C₂₂H₃₄N₃O₂: 362.1869, found: 362.1873 (M+H).

Cycloheptatriene 39. (50 %, 22 mg, 0.055 mmol)

¹H NMR (400 MHz, CD₃OD) δ 1.00 (d, J = 7.0 Hz, 3 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.80 - 1.98 (m, 4 H), 2.68 (s, 3 H), 3.37 - 3.57 (m, 3 H), 3.57 - 3.67 (m, 1 H), 3.77 - 3.98 (m, 2 H), 4.03 - 4.10 (m, 1 H), 6.65 (s, 1 H), 7.30 - 7.36 (m, 1 H), 7.36 - 7.41 (m, 3 H), 7.68 (d, J = 7.0 Hz, 2 H).

¹³C NMR (100 MHz, CD₃OD) δ 13.1, 14.2, 25.3, 26.0, 27.2, 37.1, 39.4, 47.3, 51.3, 111.6, 120.0, 120.5, 127.4, 128.2, 128.7, 129.2, 129.6, 143.2, 152.4, 172.1, 173.8.

IR (thin film) νmax 2973, 2875, 1724, 1621, 1603, 1409, 1372, 1358, 1317, 1276, 749, 731, 700 cm⁻¹.

HRMS calculated for C₂₄H₂₈N₃O₃: 406.2131, found: 406.2128 (M+H).

Cycloheptene 40

Imidazolone 23a (40 mg, 0.11 mmol) was dissolved in MeOH (10 mL) and flowed (0.5 mL/min) through a 10 % Pd/C cartridge at 50 bar and 50 °C using the H-Cube. The collected reaction mixture was concentrated in vacuo and the resulting residue was purified by flash chromatography (SiO₂, gradient 50:1 CH₂Cl₂:MeOH to 20:1 CH₂Cl₂:MeOH) to afford 40 (99 %, 40 mg, 0.11 mmol).

¹H NMR (400 MHz, CD₃OD) δ 0.93 (d, J = 7.0 Hz, 3 H), 1.15 (t, J = 7.2 Hz, 3 H), 1.81 - 1.93 (m, 2 H), 1.96 - 2.07 (m, 2 H), 2.11 - 2.21 (m, 1 H), 2.40 (dd, J = 16.4, 3.5 Hz, 1 H), 2.62 (dd, J = 15.0, 2.1 Hz, 1 H), 2.93 - 3.05 (m, 1 H), 3.06 - 3.25 (m, 3 H), 3.32 - 3.37 (m, 1 H), 3.45 (dt, J = 11.8, 7.2 Hz, 1 H), 3.55 (dt, J = 10.2, 7.0 Hz, 1 H), 3.62 - 3.70 (m, 2 H), 3.76 (dt, J = 10.4, 6.5 Hz, 1 H), 7.18 - 7.28 (m, 1 H), 7.32 - 7.36 (m, 4 H).

NOED (400 MHz, CD₃OD) irrad. δ 0.93 (CH₃) 3 % enhancement at 3.00 (β-NH, CH), 4 % at 3.14 (β-NEt, CH).

¹³C NMR (100 MHz, CD₃OD) δ 6.6, 15.4, 23.7, 25.1, 25.2, 27.1, 36.2, 42.2, 47.2, 48.0, 48.7, 50.0, 117.3, 118.9, 127.7, 128.4, 129.6, 147.0, 154.4, 175.0.

IR (thin film) νmax 3049, 2973, 1699, 1684, 1653, 1635, 1457, 1437, 1419, 736, 701 cm⁻¹.

HRMS calculated for C₂₂H₃₀N₃O₂: 368.2338, found: 368.2346 (M+H).

Imidazolidinone 41

Imidazolone 23a (40 mg, 0.11 mmol) was dissolved in MeOH (10 mL) and flowed (0.5 mL/min) through a Raney Ni cartridge at 90 bar and 80 °C using the H-Cube hydrogenator. The collected reaction mixture was concentrated invacuo and the resulting residue was purified by preparative HPLC to afford 41a (50 %, 20 mg, 0.054 mmol) and 41b (49 %, 20 mg, 0.054 mmol).

Imidazolidinone 41a

¹H NMR (400 MHz, CD₃OD) δ 0.76 (d, J = 6.6 Hz, 3 H), 0.96 (t, J = 7.2 Hz, 3 H), 1.78 (dd, J = 16.0, 4.3 Hz, 1 H), 1.86 (dq, J = 7.0, 6.5 Hz, 2 H), 1.95 - 2.05 (m, 3 H), 2.07 - 2.17 (m, 2 H), 2.38 (ddd, J = 15.8, 11.3, 1.8 Hz, 1 H), 2.76 (dq, J = 14.0, 7.0 Hz, 1 H), 3.06 (dd, J = 11.1, 3.3 Hz, 1 H), 3.12 (dd, J = 10.2, 2.7 Hz, 1 H), 3.25 - 3.35 (m, 1 H), 3.35 - 3.46 (m, 2 H), 3.55 (dt, J = 10.2, 6.8 Hz, 1 H), 3.68 (dt, J = 10.2, 6.6 Hz, 1 H), 4.12 (ddd, J = 10.9, 3.9, 2.3 Hz, 1 H), 4.20 (ddd, J = 10.9, 4.7, 1.6 Hz, 1 H), 7.16 - 7.22 (m, 3 H), 7.26 - 7.32 (m, 2 H).

¹³C NMR (100 MHz, CD₃OD) δ 7.6, 12.6, 25.2, 27.2, 27.2, 28.3, 36.5, 39.8, 43.6, 45.0, 47.2, 48.0, 53.0, 58.1, 127.3, 129.1, 129.3, 147.2, 163.9, 176.1.

IR (thin film) νmax 2971, 2928, 2874, 1700, 1684, 1676, 1653, 1635, 1617, 1457, 1437, 1379, 1276, 731, 703 cm⁻¹.

HRMS calculated for C₂₂H₃₂N₃O₂: 370.2495, found: 370.2500 (M+H).

Imidazolidinone 41b

¹H NMR (400 MHz, CD₃OD) δ 0.73 (d, J = 7.0 Hz, 3 H), 1.06 (t, J = 7.2 Hz, 3 H), 1.81 (dd, J = 14.8, 3.9 Hz, 1 H), 1.84 - 1.90 (m, 2 H), 1.94 - 2.08 (m, 4 H), 2.11 - 2.26 (m, 2 H), 2.95 (dd, J = 10.2, 3.1 Hz, 1 H), 2.99 - 3.09 (m, 2 H), 3.26 - 3.34 (m, 1 H), 3.37 - 3.46 (m, 2 H), 3.53 (dt, J = 10.2, 7.0 Hz, 1 H), 3.72 (dt, J = 10.5, 6.6 Hz, 1 H), 3.95 (ddd, J = 11.3, 9.8, 3.91 Hz, 1 H), 4.02 (ddd, J = 11.3, 9.8, 4.3 Hz, 1 H), 7.15 - 7.25 (m, 3 H), 7.27 - 7.35 (m, 2 H).

NOED (400 MHz, CD₃OD) irrad. δ 3.95 (α-NH, CH) 4 % enhancement at 2.95 (α-amide, CH), and 1 % at 1.81 (β-amide, CH₂); irrad. δ 4.02 (α-NEt, CH) 6 % enhancement at 3.01 (α-phenyl, CH), 2 % at 1.06 (CH₃).

¹³C NMR (100 MHz, CD₃OD) δ 8.0, 13.2, 25.1, 27.2, 28.2, 28.8, 36.2, 40.1, 47.2, 47.6, 47.9, 48.0, 55.2, 59.9, 127.2, 128.9, 129.3, 147.6, 162.9, 175.6.

IR (thin film) νmax 2971, 2873, 1689, 1631, 1436, 1375, 1272, 732, 702 cm⁻¹.

HRMS calculated for C₂₂H₃₂N₃O₂: 370.2495, found: 370.2494 (M+H).

Imidazolidinone 43

Imidazolone 42 (40 mg, 0.098 mmol) was dissolved in EtOAc (10 mL) and flowed (0.5 mL/min) through a 10 % Pd/C cartridge at 30 bar and 90 °C using the H-Cube. The collected reaction mixture was concentrated in vacuo and the resulting residue was purified by flash chromatography (SiO₂, gradient 50:1 CH₂Cl₂:MeOH to 20:1 CH₂Cl₂:MeOH) to afford 43 (99 %, 40 mg, 0.098 mmol).

R_f=0.39 (CH₂Cl₂:MeOH, 20:1)

¹H NMR (400 MHz, CD₃OD) δ 0.74 (d, J = 6.8 Hz, 3 H), 1.10 (t, J = 7.2 Hz, 3 H), 1.79 - 1.92 (m, 2 H), 1.93 - 2.06 (m, 4 H), 2.12 - 2.25 (m, 3 H), 2.45 (s, 3 H), 3.00 - 3.12 (m, 2 H), 3.22 (dq, J = 14.5, 7.5 Hz, 1 H), 3.28 - 3.35 (m, 1 H), 3.40 - 3.57 (m, 3 H), 3.78 (dt, J = 10.2, 6.4 Hz, 1 H), 4.03 (td, J = 9.9, 6.3 Hz, 1 H), 4.42 - 4.54 (m, 1 H), 7.13 - 7.26 (m, 3 H), 7.27 - 7.35 (m, 2 H).

NOED (400 MHz, CD₃OD) irrad. δ 4.03 (α-NEt, CH) 3 % enhancement at 3.01 (α-phenyl/α-amide, CH), 5 % at 4.48 (α-NAc, CH); irrad. δ 4.48 (α-NAc, CH) 6 % enhancement at 3.01 (α-amide/α-phenyl, CH), 5 % at 4.03 (α-NEt, CH).

¹³C NMR (100 MHz, CD₃OD) δ 8.0, 12.6, 24.2, 25.1, 25.4, 27.2, 28.3, 36.8, 39.7, 46.0, 47.2, 47.9, 56.0, 57.4, 127.3, 128.9, 129.3, 147.6, 155.8, 172.2, 175.2.

IR (thin film) νmax 2972, 2875, 1726, 1679, 1634, 1426, 1377, 1351, 1270, 726, 703, 617 cm⁻¹.

HRMS calculated for C₂₄H₃₄N₃O₃: 412.2600, found: 412.2582 (M+H).

Imidazolidinone 45

Imidazolone 44 (40 mg, 0.098 mmol) was dissolved in EtOAc (10 mL) and flowed (0.5 mL/min) through a 10 % Pd/C cartridge at 50 bar and 50 °C using the H-Cube. The collected reaction mixture was concentrated in vacuo and the resulting residue was purified by flash chromatography (SiO₂, gradient 50:1 CH₂Cl₂:MeOH to 20:1 CH₂Cl₂:MeOH) to afford 45 (99%, 40 mg, 0.098 mmol).

R_f=0.41 (CH₂Cl₂:MeOH, 20:1)

¹H NMR (400 MHz, CD₃OD) δ 0.66 (d, J = 6.8 Hz, 3 H), 1.14 (t, J = 7.1 Hz, 3 H), 1.79 - 1.92 (m, 3 H), 1.95 - 2.09 (m, 3 H), 2.16 - 2.31 (m, 3 H), 2.43 (s, 3 H), 2.94 (dd, J = 9.3, 2.0 Hz, 1 H), 3.15 (dd, J = 11.1, 3.7 Hz, 1 H), 3.21 (dq, J = 14.5, 7.0 Hz, 1 H), 3.34 (s, 1 H), 3.41 - 3.62 (m, 3 H), 3.73 (dt, J = 10.2, 6.5 Hz, 1 H), 4.01 (ddd, J = 11.6, 8.80, 6.0 Hz, 1 H), 4.45 - 4.56 (m, 1 H), 7.13 - 7.20 (m, 3 H), 7.23 - 7.31 (m, 2 H).

NOED (400 MHz, CD₃OD) irrad. δ 4.01 (α-NEt, CH) 2 % enhancement at 1.14 (NEt, CH₃), 3 % at 2.22 (CH), 3 % at 2.94 (α-amide, CH), 5 % at 4.51 (α-NAc, CH); irrad. δ 4.51 (α-NAc, CH) 7 % enhancement at 3.15 (α-phenyl, CH), 5 % at 4.01 (α-NEt, CH).

¹³C NMR (100 MHz, CD₃OD) δ 8.3, 12.6, 24.2, 25.2, 25.4, 27.2, 27.7, 36.8, 39.9, 45.2, 47.3, 48.0, 49.9, 55.6, 58.2, 127.2, 128.7, 129.2, 146.5, 155.9, 172.0, 175.5.

IR (thin film) νmax 2971, 2874, 1727, 1678, 1634, 1426, 1377, 1352, 1323, 1270, 733, 715, 701, 615 cm⁻¹.

HRMS calculated for C₂₄H₃₄N₃O₃: 412.2600, found: 412.2582 (M+H).

Cycloheptene 48

Imidazolone 42 (30 mg, 0.074 mmol) was dissolved in EtOAc (7.5 mL) and flowed (0.5 mL/min) through a 10 % Pd/C cartridge at 10 bar and 40 °C using the H-Cube. The collected reaction mixture was concentrated in vacuo and the resulting residue was purified by flash chromatography (SiO₂, gradient 50:1 CH₂Cl₂:MeOH to 20:1 CH₂Cl₂:MeOH) to afford 48 (79 %, 24 mg, 0.058 mmol).

¹H NMR (500 MHz, CD OD, 45 °C) δ 0.86 (d, J = 6.8 Hz, 3 H), 1.20 (t, J = 7.2 Hz, 3 H), 1.72 - 1.80 (m, 1 H), 1.81 - 1.93 (m, 2 H), 1.95 - 2.04 (m, 2 H), 2.06 - 2.11 (m, 1 H), 2.14 (d, J = 13.4 Hz, 1 H), 2.49 (s, 3 H), 3.27 - 3.31 (m, 1 H), 3.33 - 3.37 (m, 1 H), 3.41 - 3.47 (m, 1 H), 3.47 - 3.54 (m, 1 H), 3.54 - 3.61 (m, 1 H), 3.61 - 3.69 (m, 1 H), 3.75 - 3.84 (m, 1 H), 3.95 (d, J = 5.1 Hz, 1 H), 4.97 (d, J = 11.2 Hz, 1 H), 5.10 (d, J = 5.6 Hz, 1 H), 7.21 - 7.25 (m, 1 H), 7.32 - 7.41 (m, 4 H).

NOED (400 MHz, CD₃OD) irrad. δ 3.95 (α-phenyl, CH) 8 % enhancement at 3.35 (α-amide, CH), 6 % at 4.97 (α-NAc, CH); irrad. δ 4.97 (α-NAc, CH) 7 % enhancement at 3.35 (α-amide, CH), 7 % at 3.95 (α-phenyl).

¹³C NMR (125 MHz, CD₃OD, 45 °C) δ 8.7, 12.0, 24.3, 25.0, 26.1, 27.1, 36.2, 39.9, 47.1, 47.8, 50.6, 57.5, 98.8, 127.6, 128.7, 129.6, 138.7, 145.9, 154.6, 171.7, 174.4.

IR (thin film) νmax 2971, 2932, 2875, 1740, 1734, 1695, 1684, 1635, 1419, 1374, 1232, 703, 626, 603 cm⁻¹.

HRMS calculated for C₂₄H₃₂N₃O₃: 410.2444, found: 410.2438 (M+H).