Stereocontrolled synthesis of bicyclic ureas and sulfamides via Pd-catalyzed alkene carboamination reactions

Abstract

The synthesis of bicyclic ureas and sulfamides via palladium-catalyzed alkene carboamination reactions between aryl/alkenyl halides/triflates and alkenes bearing pendant cyclic sulfamides and ureas is described. The substrates for these reactions are generated in 3–5 steps from commercially available materials, and products are obtained in good yield with up to >20:1 diastereoselectivity. The stereochemical outcome of the sulfamide alkene addition is consistent with a mechanism involving anti-aminopalladation of the alkene, whereas the stereochemical outcome of the urea alkene addition is consistent with a syn-aminopalladation mechanism.

Graphical Abstract

1. Introduction

A number of interesting biologically active natural products feature substituted polycyclic nitrogen heterocycle motifs.¹ These include tricyclic guanidines such as the batzelladine² and merobatzelladine alkaloids (e.g., merobatzelladine B)³ (Figure 1) and the tetraponerine T1–T8 alkaloids.⁴ In many instances these families of natural products contain members with differing relative stereochemistry. For example, merobatzelladine B possesses a cis-relationship between the C^4a hydrogen atom and the C³ alkyl chain,³ whereas batzelladine K displays a trans- relationship between these groups.^2c Similarly, the odd numbered tetraponerines (T–1, 3, 5, and 7) exhibit cis stereochemistry between the C^4a and C³ groups, whereas the even numbered members of the family have trans C^4a/C³ stereochemistry.

Fig 1.

Polycyclic alkaloid natural products

Many routes for the synthesis of polycyclic guanidines, including the batzelladines and merobatzelladines, involve construction of a bicyclic urea, which is then further elaborated to the guanidine.⁵ Moreover, a 2-(alkylamino)pyrrolidine derivative, that in principle could be accessed via reduction of a bicyclic urea or sulfamide, was a key intermediate in a prior synthesis of the tetraponerines.⁶ In addition to serving as useful synthetic intermediates, substituted cyclic ureas and sulfamides act as peptidomimetics⁷ that display a wide spectrum of biological activity, such as antivirals⁸, HIV protease inhibitors⁹, and hydroxysteroid dehydrogenase inhibitors¹⁰. As such, there has been considerable interest in the development of methods for the stereocontrolled synthesis of these structures.¹¹

We have previously reported a new approach to the construction of cyclic ureas and sulfamides via Pd-catalyzed alkene carboamination reactions¹² between aryl/alkenyl halide/triflate electrophiles and alkenes bearing pendant ureas¹³ or sulfamides (Scheme 1, eq 1).¹⁴ These transformations proceed in generally good yields with high diastereoselectivities, as illustrated by the Pd-catalyzed carboamination of urea 1 to afford bicyclic urea 2 in 91% yield with >20:1 dr; this reaction was a key step in the asymmetric synthesis of (–)-merobatzelladine B (Scheme 1, eq 2).¹⁵ We have also described asymmetric desymmetrization reactions of ureas derived from cis–2,5-diallylpyrrolidine that afford products with high levels of enantioselectivity; this latter method was applied to the synthesis of an epimer of batzelladine K (Scheme 1, eq 3).¹⁶

Scheme 1.

Synthesis of cyclic ureas and sulfamides via Pd- catalyzed alkene carboamination reactions

Although these transformations have demonstrated utility, as illustrated through the syntheses shown in Scheme 1, the scope of this approach to the construction of bicyclic ureas remains largely unexplored.¹⁵ For example, no cases of formation of bicyclo [4.4.0] ring systems have previously been described. Moreover, the synthesis of 9-epi-batzelladine K also illustrates a significant limitation of this method. We would have preferred to make the naturally occurring isomer of batzelladine K, but we have consistently observed complete substrate control in these reactions; in all cases the products contain a cis-relationship between the C³ alkyl group and the C^4a hydrogen atom. These transformations do not provide access to the diastereomeric product with a trans relationship between the C³ alkyl/ C^4a hydrogen substituents, which would be needed to access batzelladine K rather than its epimer.

In this article we describe our studies on expanding the scope of our previously reported strategy for the synthesis of bicyclic ureas via Pd-catalyzed alkene carboamination reactions.¹⁵ This includes studies on the reactivity of a variety of aryl and alkenyl halide coupling partners, as well as preparation of both bicyclo[4.3.0] and bicyclo[4.4.0] ring systems. We also describe a method for the construction of bicyclic sulfamides analogous to 2,¹⁷ along with the corresponding bicyclo[4.4.0] congeners, but that possess the opposite stereochemical relationship between the C³ alkyl group and the C^4a H atom as compared to the ureas. Finally, we illustrate the conversion of these bicyclic products to 2-(alkylamino)pyrrolidine derivatives.

2. Results and discussion.

2.1. Synthesis of bicyclic ureas via Pd-catalyzed alkene carboamination reactions

During the course of model studies directed towards the synthesis of (–)-merobatzelladine B, we briefly examined Pd- catalyzed coupling reactions between 3a and either p- tolylbromide or E-1-decenylbromide.¹⁵ As shown in Table 1, entries 1–2, these transformations afforded desired products 4a and 4b in good yield with high diastereoselectivity. In order to examine the scope of Pd-catalyzed coupling reactions of ureas derived from cyclic amines, we treated 3a-b with a range of different aryl halide electrophiles. Transformations of substrates bearing electron-donating groups proceeded in high yield (entries 3–4 and 7), although lower yields were obtained with electron- poor and/or ortho-substituted aryl bromides (entries 5–6). To further illustrate the scope of this transformation, substrate 3b bearing a methyl group at the internal alkene carbon was coupled with 4-bromobiphenyl to afford 4g in excellent yield and dr, although a higher reaction temperature (125 °C) was required (entry 7). In contrast, substrates bearing 1,2-disubstituted alkenes were unreactive. We also carried out the coupling of p- methoxybenzyl protected substrate 3c with Z-1-bromobutene, which we used as a model system in our studies leading up to the synthesis of merobatzelladine B.¹⁵ As shown in eq 4, this transformation provided the desired product 4i in 67% yield with >20:1 dr. The coupling of PMP-protected substrate 3a with Z-1- bromobutene led to a similar outcome, affording 4h in 58% yield with >20:1 dr.

Table 1.

Pd-Catalyzed carboamination reactions of 2-allylpyrrolidinyl ureas^a

entry	urea	R	product	yieldb (%)	drc
1	3a	p-MeC6H4	4a	70	14:1
2	3a	E-1-decenyl	4b	77	18:1
3	3a	p-PhC6H4	4c	87	16:1
4	3a		4d	86	10:1
5	3a	o-F3CC6H4	4e	68	10:1
6	3a	p-O2NC6H4	4f	46	>20:1
7	3b	p-PhC6H4	4g	97	15:1d

^aConditions: 1.0 equiv 3a or 3b, 2 equiv NaO^tBu, 2 mol% Pd₂(dba)_3, 8 mol% PCy₃•HBF₄, 2 equiv, ArBr, toluene (0.2 M), 110 °C, 4–16 h.

^bIsolated yields (average of two or more experiments).

^cDiastereomeric ratio of the pure isolated product. Diastereomeric ratios of isolated materials were identical to those of crude products.

^dThe reaction was conducted in xylenes solvent (0.2 M) at 125 °C.

In order to further explore the scope of the urea carboamination reactions we prepared 2-allylpiperidinyl urea 5 and coupled it with Z-1-bromobutene using our standard reaction conditions. This transformation provided the desired product 6a in 69% yield, and 8:1 dr (eq 5), although the use of 5 equiv of both the alkenyl bromide and the base, plus a slightly higher catalyst loading, was necessary to obtain satisfactory results. However, we were surprised to find these standard reaction conditions were not effective for the coupling of PMP-protected substrate 5 with aryl bromides.

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Consequently, we examined the use of other bases and ligands for coupling reactions of 5 with aryl bromides, and after some optimization we found that use of Cs₂CO₃ as base, Pd(OAc)₂ as the palladium source, and Dpe-Phos as the ligand provided the desired products in moderate yield (Table 2).¹⁸ The stereochemical outcome of these reactions was analogous to that for transformations of pyrrolidinyl ureas 3a-c. However, chemical yields were generally lower than those obtained in reactions of 3a-c due to incomplete consumption of starting material. The origin of this difference in reactivity is not clear, but could conceivably be due to differences in the conformational flexibility of 5-membered vs. 6-membered rings. In both systems, there is likely a ground state energy preference for pseudoaxial orientation of the allyl group to minimize allylic strain interactions with the urea moiety,¹⁹ which would position the alkene fairly distant from the metal center in the key palladium amido intermediate that undergoes syn-aminopalladation (Scheme 2). However, due to the greater conformational flexibility of 5-membered rings, the presumably reactive conformation in which the allyl group is pseudoequatorial may be more energetically accessible, leading to faster reaction rates relative to the rate of catalyst deactivation.

Table 2.

Pd-Catalyzed carboamination reactions of 2-allylpiperidinyl ureas^a

entry	R	product	yieldb (%)	drc
1	p-MeOC6H4	6b	35	15:1
2	m-F3CC6H4	6c	47	15:1
3	p-PhC(O)C6H4	6d	59	10:1

^aConditions: 1.0 equiv substrate, 2 equiv Cs₂CO₃, 4 mol% Pd(OAc)_2, 6 mol% Dpe-Phos 2 equiv, RBr, toluene (0.2 M), 110 °C, 4–16 h.

^bIsolated yields (average of two or more experiments).

^cDiastereomeric ratio of the pure isolated product. Diastereomeric ratios of isolated materials were identical to those of crude products.

Scheme 2.

Catalytic cycle – syn-aminopalladation

2.2. Mechanism and stereochemistry

Our prior studies on urea carboamination reactions suggest the transformations described above likely proceed through the mechanism illustrated in Scheme 2.¹² The reactions are initiated by oxidative addition of the aryl/alkenyl halide to Pd(0) to afford intermediate 7, which reacts with the urea substrate 3 or 5 and base to afford amido complex 8. The Pd-amido complex undergoes syn-aminopalladation to provide 9,²⁰ which undergoes C–C bond-forming reductive elimination to afford the bicyclic urea product 4 or 6. The observed cis-relationship between the angular hydrogen atom and the arylmethyl group in the products derives from aminopalladation via a boat-like transition state during the syn-aminopalladation of 8 to 9.¹⁵

While this method is useful for the stereocontrolled construction of bicyclic ureas, the stereoselectivity is substrate controlled. The conversion of 3 or 5 to bicyclic ureas with a cis- relationship between the angular C^4a hydrogen atom and the C³ arylmethyl group proceeds with generally high levels of stereocontrol, but the syn-aminopalladation mechanism allows for the selective formation of only the cis stereoisomer; diastereomeric molecules bearing a trans-relationship between the C^4a angular hydrogen atom and the C³ arylmethyl group are not accessible through this manifold.

Although the syn-aminopalladation mechanism illustrated in Scheme 2 provides selective access to only the cis stereoisomer, we reasoned that it may be possible to access the trans stereoisomer by inducing the transformations to proceed via an alternative mechanistic pathway. As shown in Scheme 3, we hypothesized that if the transformations could be made to proceed via anti-aminopalladation of the alkene (following oxidative addition and alkene coordination to Pd), the anti- aminopalladation of Pd-alkene complex 11 would likely proceed via a chair-like transition state to afford 12. Reductive elimination from 12 would then provide bicyclic urea product 13, which contains a trans-relationship between the C^4a hydrogen atom and C³ arylmethyl group. In addition, although most of our previously reported Pd-catalyzed alkene carboamination reactions proceed via syn-aminopalladation,¹² we have observed that urea and sulfamide substrates can be induced to undergo carboamination via anti-aminopalladation under appropriate conditions. Specifically, factors that facilitate the formation of cationic intermediate palladium complexes (such as use of aryl triflates in place of aryl bromides, use of relatively polar solvents, etc.) promote the anti-addition pathway.¹⁴ For example, treatment of urea 14 with an aryl bromide in toluene afforded syn-addition product 15 in 91 % yield and 7:1 dr using a Pd/Dpe-Phos catalyst. In contrast, the Pd/RuPhos catalyzed coupling of 14 with phenyl triflate in benzotrifluoride solvent afforded anti- addition product 16 in 80% yield and 10:1 dr (Scheme 4).¹⁴

Scheme 3.

Catalytic cycle – anti-aminopalladation

Scheme 4.

Syn- vs. anti-addition

To test this hypothesis, we examined the coupling of p- nitrophenyl protected urea 17 with phenyl triflate using the conditions optimized for anti-aminopalladation. As shown in eq 6, this transformation did lead to a change in product stereochemistry, as 18 was produced as the major stereoisomer. However, the diastereoselectivity of this transformation was low (2:1 dr), and no increase in selectivity was observed despite numerous changes to the reaction conditions, catalyst/ligand system, and protecting group.

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2.3. Synthesis of bicyclic sulfamides via Pd-catalyzed alkene carboamination reactions

We postulated that two factors might be the cause of the modest diastereoselectivity observed for the coupling of 17 with phenyl triflate: (1) the rates of syn- and anti-aminopalladation may be comparable; and/or (2) the transition states/intermediates leading to the two possible stereoisomers may be close in energy. Both of these factors can be heavily influenced by the structural and electronic features of the substrate. Many reports have illustrated that slight changes to substrate structure can dramatically influence the mechanism of aminopalladation reactions and in turn, the ratio of products resulting from syn– or anti-addition.^14,21 We reasoned that employing a less nucleophilic substrate, such as a sulfamide, might favor anti-aminopalladation by decreasing the likelihood that the substrate would form the Pd–N bond required to undergo syn-migratory insertion.²⁰ We also thought that changing the geometry of the substrate from the trigonal planar carbonyl group to the tetrahedral sulfonyl group may influence the stereodetermining transition states/intermediates leading to the two possible stereoisomers, and consequently the selectivity of the desired transformation could potentially be improved. Additionally, in prior studies on Pd-catalyzed asymmetric desymmetrization reactions of ureas derived from 2,5-diallylpyrrolidine, we observed that the nature of the protecting group on the cyclizing nitrogen atom had a significant influence on diastereoselectivity,¹⁶ and we reasonedthis might also be the case for sulfamide substrates.

In order to test this hypothesis, 2-allylpyrrolidinyl sulfamide substrates 19a-c were synthesized and coupled with phenyl triflate using conditions we have previously shown to facilitate anti-aminopalladation pathways (Table 3).¹⁴ We were gratified to discover that substrate 19a, which contains an N-PMP group, did react with significantly higher diastereoselectivity (6:1 dr) than urea 17.²² In contrast, N-alkyl protecting groups provided the desired products 20b-c in comparable yield, but with lower (3:1) dr. Thus, the N–PMP group was selected for subsequent studies.

Table 3.

Influence of protecting group on diastereoselectivity^a

entry	sulfamide	product	yieldb (%)	drc
1	19a	20a	80d	6:1
2	19b	20b	86	3:1
3	19c	20c	82	3:1

^aConditions: 1.0 equiv substrate, 2 equiv LiO^tBu, 4 mol% Pd(OAc)_2, 10 mol% C-Phos 2 equiv Ph–OTf, PhCF₃ (0.2 M), 100 °C, 16 h.

^bIsolated yields (average of two or more experiments).

^cDiastereomeric ratio of the pure isolated product. Diastereomeric ratios of isolated materials were identical to those of crude products.

^dNMR yield with phenanthrene as an internal standard.

During the course of these studies, we observed inconsistent results for the coupling of 19a with phenyl triflate, including highly variable yields and impurity profiles. It was noted that using anhydrous LiO^tBu directly from the glove box led to significant amounts of side products resulting from Heck arylation and/or oxidative amination of the alkene, whereas using LiO^tBu stored on the bench under nitrogen led to an improved reaction profile. We reasoned that the difference in reactivity may be due to the bench-stored sample picking up small amounts of water from the air, which would generate lithium hydroxide and tert-butanol. After some experimentation, we found that changing the solvent from benzotrifluoride to tert-butanol led to significantly improved and reproducible yields, and greatly diminished the formation of side products resulting from Heck arylation or oxidative amination of the alkene.²³ Under these conditions, LiO^tBu obtained directly from the glovebox and LiO^tBu stored on the bench gave comparable results.

With suitable reaction conditions in hand, we proceeded to explore the scope of the bicyclic sulfamide-forming reactions. As shown in Table 4, the transformations of 19a are effective with both aryl and alkenyl triflate electrophiles, and provide products 20a and 20d-i in moderate to good yield with diastereoselectivities in the range of 5–10:1 dr. Yields and diastereoselectivities were comparable with both electron-rich and electron-poor aryl triflates. However, reactions of alkenyl triflates proceeded in slightly lower yield (entries 6–7). Reactions of substrate 19d, which contains an allyl group at C5, proceeded with slightly higher diastereoselectivities than were observed with 19a (entries 8–9). Use of short reaction times (2 h) with substrate 19d was necessary in order to avoid undesired isomerization of the product’s allyl group to an internal alkene.

Table 4.

Pd-Catalyzed carboamination reactions of 2-allylpyrrolidinyl sulfamides^a

entry	sulfamide	R	product	yieldb (%)	drc
1	19a	Ph	20a	89	7:1
2	19a	p-tBuC6H4	20d	78	6:1
3	19a	p-MeOC6R4	20e	70	7:1
4	19a	p-PhC(O)C6H4	20f	61d	8:1 (5:1)
5	19a	o-MeC6H4	20g	87	5:1
6	19a	1-cyclohexenyl	20h	63d	6:1
7	19a	E-1-decenyl	20i	45d	10:1f,g
8	19d	Ph	20j	65e	20:1 (12:1)
9	19d	p-MeOC6H4	20k	63e	>20:l (13:1)
10	19b	Z-1-bromobutene	201	30h	5:1

^aConditions: 1.0 equiv substrate, 2 equiv LiO^tBu, 4 mol% Pd(OAc)_2, 10 mol% C-Phos 2 equiv, R–OTf, ^tBuOH (0.2 M), 82 °C, 16 h.

^bIsolated yields (average of two or more experiments).

^cDiastereomeric ratio of the pure isolated product. Diastereomeric ratios of isolated materials were identical to those of crude products unless otherwise noted in parentheses.

^dThe reaction was conducted with 3.0 equiv of LiO^tBu and 3.0 equiv R-OTf.

^eThe reaction time was 2 h.

^f1-Decenyl triflate was employed as 5:1 mixture of E:Z isomers.

^gThe dr was determined following hydrogenation of 20j. The crude dr of 20j could not be determined directly due to the presence of E/Z alkene stereoisomers. However, we estimate the crude dr to be ca. 5–10:1.

^hThe reaction was conducted in PhCF₃ as solvent using NaO^tBu as the base, with 2.0 equiv added LiOTf, and a reaction temperature of 100 °C.

The coupling of 19b with the alkenyl bromide Z-1-bromobutene (entry 10) was achieved in modest yield and 5:1 diastereoselectivity when 2 equiv of LiOTf was added to the reaction mixture, with slightly modified conditions (PhCF₃ as solvent and NaO^tBu as base).²⁴

The relatively high diastereoselectivities observed (5–13:1) are both interesting and surprising, as other related alkene carboamination reactions that proceed via anti-aminopalladation typically provide low (ca 1–3:1) diastereoselectivity unless there is a substituent at the allylic position of the alkene.²⁴ The relatively high selectivity observed in reactions of 19a-d may be due to either thermodynamic or kinetic control. As shown in Scheme 5, the aminopalladation step in the catalytic cycle is likely reversible, especially since the cyclizing nitrogen atom is relatively electron-poor.²⁵ The reductive elimination step is most likely not reversible, and there appear to be significant unfavorable 1,3-diaxial interactions present in intermediates 21b and 22b where the alkene or arylmethyl group is positioned in a pseudoaxial position that are not present in intermediates 21a and 22a.²⁶ So, if the rates of reductive elimination from 22a or 22b are comparable, the relative equilibrium populations of 22a or 22b would dictate the outcome. Alternatively, the activation energy for reductive elimination from 22b may be higher than that for reductive elimination from 22a if strain in the transitionstate for reductive elimination from 22 is significant.

Scheme 5.

Control of stereoselectivity

We subsequently elected to explore the reactivity of 2- allylpiperidine-derived sulfamides for the synthesis of bicyclo[4.4.0] heterocyclic ring systems (Table 5). In contrast to the reactions of urea derivatives, in which the pyrrolidinyl and piperidinyl derived substrates had considerably different reactivity, and required different reaction conditions, our standard parameters were effective with both pyrrolidinyl (19a-d) and piperidinyl sulfamides (23). The coupling of 23 with a range of different aryl and alkenyl triflates provided products in comparable yields, but slightly lower diastereoselectivities, than were observed in reactions of 19a. The origin of the lower diastereoselectivities is not clear, but the differences are also relatively small (5–10:1 vs. 3–6:1). A range of electronic properties of the aryl triflate were tolerated, and the transformation was also effective with the heteroaryl bromide 2- bromothiophene and the alkenyl bromide Z-1-bromobutene when 2 equiv of LiOTf was added to the reaction mixture (eq 7–8). These latter two substrates are noteworthy, as the butenyl group and the 2-thiophenyl group²⁷ could conceivably be reduced to the alkyl side chain present in batzelladine K and the tetraponerine alkaloids.

Table 5.

Pd-Catalyzed carboamination reactions of 2-allylpiperidinyl sulfamides^a

entry	R	product	yieldb (%)	drc
1	Ph	24a	80	5:1
2	1-cyclohexenyl	24b	85	5:1
3	p-tBuC6H4	24c	71	4:1
4	o-MeC6H4	24d	83	4:1
5		24e	87	5:1
6	p-MeOC6H4	24f	76	3:1

^aConditions: 1.0 equiv substrate, 2 equiv LiO^tBu, 4 mol% Pd(OAc)_2, 10 mol% C-Phos 2 equiv, R–OTf, ^tBuOH (0.2 M), 82 °C, 16 h.

^bIsolated yields (average of two or more experiments).

^cDiastereomeric ratio of the pure

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2.4. Elaboration of products

To further demonstrate the potential synthetic utility of the transformations described above, we elected to examine deprotection of products 24a and 4i (Scheme 6). After some experimentation, we found that treatment of 24a with concentrated HBr led to cleavage of the SO₂ group, with concomitant demethylation of the p-methoxyphenyl group. Oxidation of the resulting product, in a one-pot process, with ceric ammonium nitrate then removed the nascent p- hydroxyphenyl group to provide diamine 25 in 75% yield (eq 9). The PMB protecting group was cleaved from 4i by hydrogenation, with concomitant reduction of the alkene, to afford 26 in 92% yield (eq 10). The urea carbonyl was removed to provide diamine 26 in 57% yield through reduction with LiAlH₄ and subsequent treatment with hydroxylamine (eq 11).

Scheme 6.

Elaboration of products

3. Conclusion

In conclusion, Pd-catalyzed alkene carboamination reactions between ureas or sulfamides derived from 2-allylpyrrolidine or 2- allylpiperidine are coupled with a range of aryl or alkenyl halides or triflates to afford bicyclic ureas or sulfamides. As shown in Scheme 7, the coupling of sulfamides with aryl/alkenyl triflates affords bicyclic products with trans relative stereochemistry between the C³ arylmethyl group and the angular C^4a hydrogen atom in good yield with moderate, but synthetically useful, levels of diastereoselectivity. In contrast, the reactions of analogous urea derivatives with aryl/alkenyl bromides affords bicyclic products with cis relative stereochemistry, in moderate to good yield, and with good diastereoselectivity. The change in the stereochemical outcome of these transformations is due to a change in reaction mechanism. Circumstances (conditions, substrate structure) that lead to a syn-aminopalladation pathway provide the cis-disubstituted products, whereas reactions that proceed via anti-aminopalladation afford the trans-disubstituted products.

Scheme 7.

Summary

4. Experimental section

4.1. General

All reactions were carried out under nitrogen atmosphere in flame- or oven-dried glassware. All reagents were obtained from commercial sources and were used as obtained unless otherwise noted. Bis-(dibenzylidineacetone) dipalladium(0), palladium (II) acetate, tricyclohexylphosphonium tetrafluoroborate, CPhos, and Dpe-phos were purchased from Strem Chemical Co. and used without further purification. Dichloromethane, toluene, and tetrahydrofuran were purified using a GlassContour solvent purification system. N-Boc-2-allylpyrrolidine,²⁸ N-Boc-2-(2– methallyl)pyrrolidine,²⁹ N-Boc-2-allylpiperidine,²⁸ E-1- bromodecene,³⁰ Z-1-bromobut-1-ene,³¹ 19d,¹⁶ the oxooxazolidin sulfonamides used to prepare 19a-c,^14a and 1-decenyl triflate,^14a were synthesized according to published procedures. Aryl triflates were either purchased from commercial sources, or prepared according to the procedure of Frantz et. al.32 Benzotrifluoride was purified by distillation from P₂O₅, and xylenes were purified by distillation from CaH₂ prior to use. Structural and stereochemical assignments were based on 2–D COSY and NOESY experiments. Ratios of diastereomers were determined by ¹H NMR analysis. Yields refer to isolated yields of compounds estimated to be ≥95% pure as determined by ¹H NMR analysis unless otherwise noted. The yields reported in the experimental section describe the result of a single experiment, whereas yields reported in Tables 1–2, and 4–5 are averages of two or more experiments. Thus, the yields reported in the experimental section may differ from those shown in Tables 1–2 and 4–5.

4.2. Preparation of starting materials

4.2.1. General procedure 1:synthesis of urea substrates

A clean, flame-dried round bottom flask equipped with a stir bar was cooled under a stream of nitrogen and charged with N- Boc-2-allylpyrrolidine,²⁸ N-Boc-2-(2–methallyl)pyrrolidine,²⁹ or N-Boc-2-allylpiperidine²⁸ (1.0 equiv) and dichloromethane (0.2 M). The resulting solution was cooled to 0 °C and trifluoroacetic acid (10.0 equiv) was added. The reaction mixture was stirred until judged as complete by thin layer chromatography (c.a. 4 hours), then diluted with water and quenched with ammonium hydroxide until pH reached 12. The organic layer was reserved, and the aqueous layer extracted with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude intermediate was then carried on to the next step without any additional purification.

The crude intermediate was re-dissolved in dichloromethane (0.2M) and charged to a new clean, dry round bottom flask with a stir bar. The appropriately substituted isocyanate (1.2 equiv) was added slowly, and the resulting reaction stirred at 20 °C until judged as complete by TLC (ca. 4–14 hours). After concentration in vacuo, the resulting residue was purified via flash column chromatography on silica gel (20–40% ethyl acetate/hexanes gradient).

4.2.1.1. (±)-2-Allyl-N-(4- methoxyphenyl)pyrrolidine-1-carboxamide 3a

The title compound was prepared from N-Boc-2- allylpyrrolidine (1.3 g, 6.1 mmol) following General Procedure 1. This procedure afforded 997 mg (81% yield) of the title compound as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.29 (d, J = 9.5 Hz, 2 H), 6.83 (d, J = 9.0 Hz, 2 H), 6.07 (s, 1 H), 5.82 (ddt, J = 17.0, 10.0, 7.5 Hz, 1 H), 5.13–5.07 (m, 2 H), 4.07–4.04 (m, 1 H), 3.78 (s, 3 H), 3.45–3.42 (m, 2 H), 2.60–2.55 (m, 1 H), 2.22–2.16 (m, 1 H), 2.04–1.93 (m, 3 H), 1.83–1.79 (m, 1 H); ¹³C NMR (125 MHz, CDCl₃) δ 155.6, 154.3, 135.2, 132.2, 121.7, 117.4, 114.1, 57.2, 55.5, 46.3, 38.7, 29.5, 23.8; IR (film) 3306, 1639 cm⁻¹. HRMS (ESI⁺ TOF) m/z [M + H]⁺: C₁₅H₂₀N₂O₂ 261.1598; found 261.1599.

4.2.1.2. (±)-N-(4-Methoxyphenyl)-2-(2- methylallyl)pyrrolidine-1-carboxamide 3b

The title compound was prepared from N-Boc-2-(2– methallyl)pyrrolidine (663 mg, 2.9 mmol) following General Procedure 1. This procedure afforded 186 mg (23% yield) of the title compound as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.31–7.27 (m, 2 H), 6.84–6.83 (m, 2 H), 6.11 (s, 1 H), 5.63–5.60 (m, 1 H), 5.46–5.44 (m, 1 H), 4.03–4.01 (m, 1 H), 3.78 (s, 3 H), 3.47–3.44 (m, 2 H), 2.55 (dd, J = 4.1, 13.6 Hz, 1 H), 2.23–2.03 (m, 1 H), 2.01–1.94 (m, 3 H), 1.79–1.67 (m, 1 H), 1.82 (s, 3 H); ¹³C NMR (126 MHz, CDCl₃) δ 155.5, 154.4, 132.3, 126.6, 121.8, 121.7, 114.0, 57.6, 55.5, 46.3, 31.6, 29.9, 23.8, 13.1; IR (film) 2966.8, 1638.0, 1638.0, 1510.1 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₁₆H₂₂N₂O₂ 275.1754; found 275.1760.

4.2.1.3. (±)-2-Allyl-N-(4- methoxybenzyl)pyrrolidine-1-carboxamide 3c

The title compound was prepared from 4-methoxybenzyl isocyanate (1.8 mL, 12.6 mmol) and N-Boc-2-allylpyrrolidine (1.77 g, 8.4 mmol) via General Procedure 1. This procedure afforded 862 mg (37%) of the title compound as a pale yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.25 (d, J = 8.0 Hz, 2 H), 6.90 (d, J = 8.5 Hz, 2 H), 5.78 (dddd, J = 6.6, 7.8, 10.2, 16.9 Hz, 1 H), 5.10–5.00 (m, 2 H), 4.43–4.30 (m, 3 H), 3.97 (m, 1 H), 3.80 (s, 3 H), 3.34–3.23 (m, 2 H), 2.54–2.49 (m, 1 H), 2.18–2.08 (m, 1 H), 72.02–1.82 (m, 3 H), 1.78–1.73 (m, 1 H); ¹³C NMR (175 MHz, CDCl₃) δ 158.8, 156.6, 135.3, 131.9, 129.1, 117.1, 113.9, 56.8, 55.3, 46.0, 44.1, 38.8, 29.4, 23.6; IR (film) 3324, 1626 cm^–1. HRMS (ESI⁺ TOF) m/z [M + H]⁺: calcd for C₁₆H₂₂N₂O₂ 275.1754; found 275.1747

4.2.1.4. (±)-2-Allyl-N-(4-methoxyphenyl)piperidine- 1-carboxamide 5

The title compound was prepared from N-Boc-2- allylpiperidine (762 mg, 3.4 mmol) following General Procedure 1. This resulted in 355 mg (38% yield) of the title compound as a pale yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.23–7.17 (m, 2 H), 6.85–6.75 (m, 2 H), 6.32 (s, 1 H), 5.79 (ddt, J = 7.2, 10.1, 17.2 Hz, 1 H), 5.18–5.02 (m, 2 H), 4.29–4.21 (m, 1 H), 3.91 (dt, J = 3.1, 13.4 Hz, 1 H), 3.76 (s, 3 H), 2.93 (td, J = 2.8, 13.1 Hz, 1 H), 2.52–2.47 (m, 1 H), 2.32–2.27 (m, 1 H), 1.71–1.52 (m, 5 H), 1.54–1.40 (m, 1 H); ¹³C NMR (126 MHz, CDCl₃) δ 155.6, 135.4, 132.6, 122.2, 122.1, 117.3, 114.0, 55.5, 51.1, 39.3, 34.3, 27.9, 25.5, 18.8; IR (film) 2934.8, 1628.9, 1509.5, 1416.8 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₁₆H₂₂N₂O₂ 275.1761; found 275.1761.

4.2.1.5. (±)-2-Allyl-N-(4-nitrophenyl)pyrrolidine- 1-carboxamide 17

The title compound was prepared from N-Boc-2- allylpyrrolidine (887 mg, 4.2 mmol) following General Procedure 1. The chromatographed product material was diluted with dichloromethane (35 mL) and washed with 1M HCl (2 × 15 mL) to remove any remaining 4-nitroanniline. This procedure afforded 290 mg (25%) of the title compound as a yellow solid: mp = 104–106 °C. ¹H NMR (700 MHz, CDCl₃) δ 8.15 (d, J = 9.1 Hz, 2 H), 7.58 (d, J = 9.1 Hz, 2 H), 6.64 (s, 1 H), 5.84–5.78 (m, 1 H), 5.17–5.09 (m, 2 H), 4.09 (s, br, 1 H), 3.53–3.46 (m, 2 H), 2.56 (dt, J = 5.3, 12.4 Hz, 1 H), 2.25–2.18 (m, 1 H), 2.09–2.02 (m, 1 H), 2.04–1.94 (m, 2 H), 1.86–1.82 (m, 1 H); ¹³C NMR (175 MHz, CDCl₃) δ 152.7, 145.4, 142.3, 134.7, 125.1, 118.0, 117.9, 57.5, 46.5, 38.5, 29.6, 23.7; IR (film) 3314, 1652, 1501, 1329 cm^–1. HRMS (ESI⁺ TOF) m/z [M + H]⁺: calcd for C₁₄H₁₇N₃O₃ 276.1343; found 276.1344.

4.2.2. General procedure 2: synthesis of sulfamide substrates

A clean, flame-dried round bottom flask equipped with a stir bar was cooled under a stream of nitrogen and charged with N- Boc-2-allylpyrrolidine or N-Boc-2-allylpiperidine²⁸ (1.0 equiv), dichloromethane (0.2 M), and trifluoroacetic acid (1.0 M). The reaction mixture was stirred until judged as complete by thin layer chromatography (c.a. 4 hours), then diluted with water and quenched with ammonium hydroxide until pH reached 12. The organic layer was reserved, and the aqueous layer extracted with dichloromethane. Organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting crude intermediates were then carried on to the next step without any additional purification.

A separate clean, flame-dried round bottom flask was cooled under a stream of nitrogen, and charged with the appropriate N- protected-2-oxo-oxazolidanone-3-sulfonamide^14a (1.2 equiv), 4- dimethylaminopyridine (0.2 equiv), and a stir bar, and then was evacuated and backfilled with nitrogen. Acetonitrile (0.12 M based on added amine) was added, followed by triethylamine (3.0 equiv), and then the reaction vessel was heated in an oil bath to 75 °C. After one hour at 75 °C, the crude 2-allylpyrrolidine or 2-allylpiperidine from above was added, and the reaction mixture stirred at 75 °C overnight (approximately 16 hours). The mixture was cooled to 20 °C, solvent was removed in vacuo, and the residue was partitioned between dichloromethane and 3M hydrochloric acid (aq). The organic layer was reserved, and the aqueous layer extracted with dichloromethane. Organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo, and the resulting residue purified via flash column chromatography on silica gel (20–40% ethyl acetate/hexanes gradient).

4.2.2.1. (±)-2-Allyl-N-(4- methoxyphenyl)pyrrolidine-1-sulfonamide 19a

The title compound was prepared from N-Boc-2- allylpyrrolidine (1.06 g, 5.0 mmol) following General Procedure 2. This procedure afforded 808 mg (68%) of the title compound as a pale yellow oil. ¹H NMR (700 MHz, CDCl₃) δ 7.18 (d, J =9.1 Hz, 2 H), 6.85 (d, J = 9.1 Hz, 2 H), 6.30 (s, br, 1 H), 5.70–5.61 (m, 1 H), 5.05–4.99 (m, 2 H), 3.79 (s, 3 H), 3.79–3.77 (m, 1 H), 3.36–3.27 (m, 2 H), 2.46–2.41 (m, 1 H), 2.12 (dt, J = 13.9, 8.5 Hz, 1 H), 1.86–1.73 (m, 3 H), 1.70–1.66 (m, 1 H); ¹³C NMR(175 MHz, CDCl₃) δ 157.2, 134.5, 130.1, 123.7, 117.5, 114.4, 60.3, 55.5, 49.1, 39.9, 30.1, 24.2; IR (film) 3267, 1327, 1245, 1146 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₁₄H₂₀N₂O₃S 297.1267; found 297.1274.

4.2.2.2. (±)-2-Allyl-N-benzylpyrrolidine-1- sulfonamide 19b

The title compound was prepared from N-benzyl-2- oxooxazolidine-3-sulfonamide (2.1 g, 8.3 mmol) and N-Boc-2- allylpyrrolidine (2.1 g, 10.0 mmol) in two steps following General Procedure 2. This procedure afforded 1.22 g (52%) of the title compound as a pale-yellow solid: mp = 38–41 °C. ¹H NMR (700 MHz, CDCl₃) δ 7.30–7.20 (m, 5 H), 5.72–5.64 (m, 1 H), 5.03–4.96 (m, 2 H), 4.68 (s, br, 1 H), 4.15 (s, 2 H), 3.76 (ddt, J = 3.9, 7.8, 9.0 Hz, 1 H), 3.31–3.24 (m, 1 H), 3.16 (ddd, J = 4.9, 6.6, 9.5 Hz, 1 H), 2.46 (dddt, J = 1.4, 4.0, 6.8, 13.7 Hz, 1 H), 2.18–2.10 (m, 1 H), 1.84–1.69 (m, 3 H), 1.68–1.61 (m, 1 H); ¹³C NMR (175 MHz, CDCl₃) δ 137.0, 134.6, 128.7, 127.9, 127.9, 117.5, 59.6, 49.0, 47.4, 40.1, 30.3, 24.3; IR (film) 3282, 1312, 1143 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₁₄H₂₀N₂O₂S 281.1318; found 281.1325.

4.2.2.3. (±)-2-Allyl-N-(4- methoxybenzyl)pyrrolidine-1-sulfonamide 19c

The title compound was prepared from N-(4-methoxybenzyl)- 2-oxooxazolidine-3-sulfonamide (2.4 g, 8.3 mmol) and N-Boc-2- allylpyrrolidine (2.1 g, 10.0 mmol) following General Procedure 2. This procedure afforded 1.10 g (43%) of the title compound as a yellow solid: mp = 39–42 °C. ¹H NMR (700 MHz, CDCl₃) δ 7.25 (d, J = 9.1 Hz, 2 H), 6.88 (d, J = 8.4 Hz, 2 H), 5.77 (ddt, J = 7.1, 10.2, 17.2 Hz, 1 H), 5.12–5.04 (m, 2 H), 4.16 (s, 2 H), 3.88–3.79 (m, 1 H), 3.80 (s, 3 H), 3.37 (dt, J = 7.3, 9.9, Hz, 1 H), 3.25 (ddd, J = 5.1, 6.7, 9.7 Hz, 1 H), 2.56–2.53 (m, 1 H), 2.27–2.19 (m, 1 H), 1.95–1.79 (m, 3 H), 1.75–1.69 (m, 1 H); ¹³C NMR (175 MHz, CDCl₃) δ 159.3, 134.7, 129.3, 129.0, 117.5, 114.1, 59.6, 55.3, 49.1, 47.0, 40.1, 30.3, 24.3; IR (film) 3289, 1302, 1247, 1144 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₁₅H₂₂N₂O₃S 311.1424; Found 311.1416.

4.2.2.4. (±)-(2S*,5R*)-2,5-Diallyl-N-(4- methoxyphenyl)pyrrolidine-1-sulfonamide 19d

The title compound was prepared from N-(4-methoxyphenyl)- 2-oxooxazolidine-3-sulfonamide (1.6 g, 5.9 mmol) and (±)- (E,2R*,5S*)-tert-butyl 2-allyl-5-[3– (trimethylsilyl)allyl]pyrrolidine-1-carboxylate (2.3 g, 7.1 mmol) following General Procedure 2. This procedure afforded 1.46 g (73%) of the title compound as an off-white solid: mp = 57–60 °C. ¹H NMR (700 MHz, CDCl₃) δ 7.19 (d, J = 8.4 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 5.75–5.67 (m, 2 H), 5.07–5.02 (m, 4 H), 3.79 (s, 3 H), 3.79–3.74 (m, 2 H), 2.50 (dt, J = 5.5, 12.0 Hz, 2 H), 2.16 (dt, J = 8.3, 14.8 Hz, 2 H), 1.77–1.71 (m, 2 H), 1.68–1.62 (m, 2 H); ¹³C NMR (175 MHz, CDCl₃) δ 157.2, 134.6, 130.0, 123.7, 117.5, 114.4, 61.6, 55.4, 40.4, 29.0; IR (film) 3268, 1508, 1247, 1151 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₁₇H₂₄N₂O₃S, 337.1580; found 337.1580.

4.2.2.5. (±)-2-Allyl-N-(4-methoxyphenyl)piperidine- 1-sulfonamide 23

The title compound was prepared from N-Boc-2- allylpiperidine (2.0 g, 8.9 mmol) following General Procedure 2. This afforded 1.25 g (45% yield) of the title compound as a yellow oil. ¹H NMR (700 MHz, CDCl₃) δ 7.12–7.07 (m, 2 H), 6.86–6.81 (m, 2 H), 6.15 (s, 1 H), 5.72–5.64 (m, 1 H), 5.06–4.99 (m, 2 H), 3.98–3.92 (m, 1 H), 3.78 (s, 3 H), 3.59 (dd, J = 4.5, 14.0 Hz, 1 H), 2.97 (td, J = 2.8, 13.3 Hz, 1 H), 2.41–2.30 (m, 2 H), 1.59–1.49 (m, 2 H), 1.50–1.37 (m, 2 H), 1.33–1.22 (m, 2 H); ¹³C NMR (176 MHz, CDCl₃) δ 157.1, 135.0, 130.1, 123.3, 117.3, 114.4, 55.5, 53.5, 41.4, 34.1, 26.7, 24.9, 18.0; IR (film) 3271.5, 1509.0, 1246.2, 1142.1 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₁₅H₂₂N₂O₃S 311.1424; found 311.1422.

4.3. Preparation of products

4.3.1. General procedure 3: Synthesis of bicyclic pyrrolidinyl ureas

A clean, flame-dried Schlenk tube equipped with a stir bar was cooled under a stream of nitrogen and charged with the urea substrate, Pd₂(dba)₃, tricyclohexylphosphonium tetrafluoroborate, sodium tert-butoxide, and aryl or alkenyl bromide. The tube was purged with nitrogen and 2.5 mL toluene per 1 mmol substrate was added via syringe. The reaction mixture was heated to 110 °C with stirring until judged complete as determined by TLC analysis. Subsequently, the crude reaction mixture was diluted with ethyl acetate (2 mL) and quenched with saturated aqueous ammonium chloride (3 mL). The organic layer was separated, and the aqueous layer extracted with ethyl acetate (2 mL x 2). The collected organic layers were then dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo and purified by flash chromatography on silica gel using 20–60% ethyl acetate/hexanes as the eluent unless otherwise noted.

4.3.1.1. (±)-(3R*,4aR*)-2-(4-Methoxyphenyl)-3-(4- methylbenzyl)hexahydropyrrolo[1,2-c] pyrimidin- 1(2H)-one 4a

A flame-dried Schlenk tube was cooled under a stream of N₂ and charged with Pd₂(dba)₃ (6.4 mg, 0.007 mmol), PCy₃•HBF₄ (10.3 mg, 0.028 mmol) and NaO^tBu (50 mg, 0.52 mmol). The flask was purged with N₂, then a solution of 3a (83 mg, 0.35 mmol) in toluene (3.5 mL) was added via syringe and the resulting mixture was stirred at rt for 5 min. 4-Bromotoluene (89 mL, 0.52 mmol) was added and the flask was heated to 110 °C and stirred overnight (ca. 14 h). The mixture was cooled to room temperature and saturated aqueous NH₄Cl (3 mL) and ethyl acetate (3 mL) were added. The organic layer was filtered through a plug of silica gel and the silica gel was washed with ethyl acetate (10 mL). The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Analysis of the crude material by ¹H NMR revealed the product had been formed as a 14:1 mixture of diastereomers. The crude material was purified by flash chromatography on silica gel to afford 78 mg (70%) of the title compound as a pale yellow oil with 14:1 dr. Data are for the major isomer. ¹H NMR (500 MHz, CDCl₃) δ7.19 (d, J = 9.0 Hz, 2 H), 7.06 (d, J = 8.0 Hz, 2 H), 6.92–6.90 (m, 4 H), 3.96 (dt, J = 4.5, 11.5 Hz, 1 H), 3.82 (s, 3 H), 3.82–3.76 (m, 1 H), 3.60 (dt, J = 7.5, 11.5 Hz, 1 H), 3.55–3.51 (m, 1 H), 3.02 (dd, J = 3.8, 13.8 Hz, 1 H), 2.64 (dd, J = 11.0, 13.5 Hz, 1 H), 2.30 (s, 3 H), 2.13 (dt, J = 5.5, 12.0 Hz, 1 H), 2.05–1.95 (m, 2 H), 1.88–1.82 (m, 1 H), 1.54 (dt, J = 2.5, 12.5 Hz, 1 H) 1.50–1.44 (m, 1 H); ¹³C NMR (125 MHz, CDCl₃) δ 157.5, 154.4, 135.9, 135.5, 134.8, 130.1, 129.2, 128.8, 114.2, 60.4, 55.4, 52.5, 46.1, 38.1, 33.8, 29.5, 23.4, 20.9; IR (film) 1640 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₆N₂O₂, 351.2071; found 351.2071

4.3.1.2. (±)-(E,3R*,4aR*)-2-(4-Methoxyphenyl)-3- (undec-2-en-1-yl)hexahydropyrrolo[1,2-c] pyrimidin-1(2H)-one 4b

The title compound was prepared in a manner analogous to 4a except using Pd₂(dba)₃ (6.4 mg, 0.007 mmol), PCy₃•HBF₄ (10.3 mg, 0.028 mmol) and NaO^tBu (67 mg, 0.70 mmol), a solution of 3a (83 mg, 0.35 mmol) in toluene (3.5 mL), and a solution of (E)-1-bromodec-1-ene (153 mg, 0.70 mmol) in toluene (1 mL). Analysis of the crude material by ¹H NMR revealed the product had been formed as a 18:1 mixture of diastereomers. The crude material was purified by flash chromatography on silica gel to afford 98 mg (77%) of the title compound as a pale yellow oil with 18:1 dr. Data are for the major isomer. ¹H NMR (500 MHz, CDCl₃) δ 7.13 (d, J = 9.0 Hz, 2 H), 6.86 (d, J = 9.0 Hz, 2 H), 5.42 (dt, J = 7.5, 15.5 Hz, 1 H), 5.16 (dt, J = 7.0, 15.0 Hz, 1 H), 3.79 (s, 3 H), 3.76–3.73 (m, 1 H), 3.68–3.62 (m, 1 H), 3.58 (dt, J = 7.5, 11.5 Hz, 1 H), 3.50–3.46 (m, 1 H), 2.39 (dt, J = 5.0, 13.5 Hz, 1 H), 2.24 (ddt, J = 1.5, 2.0, 13.0 Hz, 1 H), 2.20–2.11 (m, 2 H), 2.00–1.91 (m, 3 H), 1.85–1.78 (m, 1 H), 1.62 (dt, J = 5.0, 12.3 Hz, 1 H), 1.49 (ddt, J = 7.5, 10.0, 12.0 Hz, 1 H), 1.30–1.23 (m, 12 H), 0.87 (t, J = 7.0 Hz, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 157.5, 154.4, 135.7, 134.2, 129.3, 125.4, 114.1, 58.7, 55.4, 52.5, 46.0, 35.9, 33.9, 32.5, 31.8, 30.3, 29.4, 29.2, 29.1, 23.4, 22.6, 14.1 (one carbon signal is absent due to incidental equivalence); IR (film) 1640 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₅H₃₈N₂O₂ 399.3006; found 399.3009

4.3.1.3. (±)-(3R*,4aR*)-3-[(1,1’-biphenyl)-4- ylmethyl] −2-(4-methoxyphenyl)hexahydropyrrolo [1,2-c] pyrimidin-1(2H)-one 4c

The title compound was prepared from substrate 3a (53 mg, 0.20 mmol), 4-bromobiphenyl (95 mg, 0.41 mmol), NaO^tBu (40 mg, 0.42 mmol), Pd₂(dba)₃ (3.4 mg, 0.007 mmol), and PCy₃•HBF₄ (6.8 mg, 0.018 mmol) according to General Procedure 3. This procedure afforded 64 mg (77%) of the title compound as a brown foamy solid. The compound was obtained as a 16:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.55 (d, J = 7.6 Hz, 2 H), 7.48 (d, J = 7.8 Hz, 2 H), 7.42 (t, J = 7.6 Hz, 2 H), 7.33 (t, J = 7.4 Hz, 1 H), 7.23 (d, J = 13.3 Hz, 2 H), 7.09 (d, J = 7.8 Hz, 2 H), 6.91 (d, J = 8.6 Hz, 2 H), 4.09–4.00 (m, 1 H), 3.81 (s, 3 H), 3.80–3.76 (m, 1H) 3.65–3.59 (m, 1 H), 3.59–3.49 (m, 1 H), 3.10 (dd, J = 4.2, 13.6 Hz, 1 H), 2.74 (dd, J = 11.0, 13.6 Hz, 1 H), 2.17–1.84 (m, 4 H), 1.63–1.45 (m, 2 H); ¹³C NMR (176 MHz, CDCl₃) δ 157.7, 154.5, 140.7, 139.4, 137.1, 135.6, 129.4, 129.2, 128.8, 127.3, 127.0, 114.2, 60.5, 55.4, 52.7, 46.2, 38.4, 33.9, 29.8, 23.5 (one carbon signal is absent due to incidental equivalence); IR (film) 2931.6, 2228.0, 1627.9, 1447.5 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₇H₂₈N₂O₂ 413.2224; found 413.2220.

4.3.1.4. (±)-(3R*,4aR*)-3-(Benzo[d] [1,3] dioxol-5- ylmethyl)-2-(4-methoxyphenyl) hexahydropyrrolo[1,2-c]pyrimidin-1(2H)-one 4d

The title compound was prepared from substrate 3a (41 mg, 0.16 mmol), 1-bromo-3,4-methylenedioxybenzene (48 μL, 0.40 mmol), NaO^tBu (40 mg, 0.42 mmol), Pd₂(dba)₃ (3.6 mg, 0.008 mmol), and PCy₃•HBF₄ (6.7 mg, 0.018 mmol) according to General Procedure 3. This procedure afforded 48 mg (79%) of the title compound as a pale brown foam. The compound was obtained as a 10:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (500 MHz, CDCl₃) δ 7.20–7.14 (m, 2 H), 6.93–6.86 (m, 2 H), 6.69 (d, J = 8.3 Hz, 1 H), 6.48 (dt, J = 2.0, 4.0 Hz, 2 H), 5.90 (s, 2 H), 3.97–3.89 (m, 1 H), 3.81 (s, 3 H), 3.79–3.71 (m, 1 H), 3.65–3.48 (m, 2 H), 2.96 (dd, J = 4.2, 13.7 Hz, 1 H), 2.59 (dd, J = 11.1, 13.7 Hz, 1 H), 2.20–1.75 (m, 4 H), 1.61–1.42 (m, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 158.0, 154.8, 148.1, 146.5, 135.9, 132.1, 129.6, 122.4, 114.6, 109.6, 108.7, 101.3, 60.9, 55.8, 53.0, 46.6, 38.8, 34.3, 30.0, 23.9; IR (film) 2936.5, 1626.3, 1445.6, 1240.4 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₄N₂O₄ 381.1809; found 381.1805.

4.3.1.5. (±)-(3R*,4aR*)-2-(4-Methoxyphenyl)-3-[2- (trifluoromethyl)benzyl] hexahydropyrrolo[1,2-c] pyrimidin-1(2H)-one 4e

The title compound was prepared from substrate 3a (41 mg, 0.16 mmol), 2-bromobenzotrifluoride (55 μL, 0.40 mmol), NaO^tBu (41 mg, 0.42 mmol), Pd₂(dba)₃ (3.4 mg, 0.007 mmol), and PCy₃•HBF₄ (5.6 mg, 0.015 mmol) according to General Procedure 3. This procedure afforded 49 mg (78%) of the title compound as a brown foam. The compound was obtained as a >20:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.56 (d, J = 8.0 Hz, 1 H), 7.42–7.38 (m, 1 H), 7.28–7.21 (m, 1 H), 7.15–7.05 (m, 3 H), 6.85 (d, J = 8.3 Hz, 2 H), 4.15 (dd, J = 5.4, 10.6 Hz, 1 H), 3.82–3.78 (m, 1 H), 3.78 (s, 3 H), 3.62–3.51 (m, 2 H), 3.18–3.12 (m, 1 H), 3.04–2.96 (m, 1 H), 2.17–1.82 (m, 4 H), 1.62–1.57 (m, 1 H), 1.50–1.43 (m, 1 H); ¹³C NMR (176 MHz, CDCl₃) δ 157.7 154.3, 136.6, 135.2, 131.7, 130.5, 129.2, 129.1 (q, J = 220 Hz), 126.6, 126.3, 114.5, 60.0, 55.3, 52.5, 46.1, 35.2, 33.8, 30.2, 23.4 (one carbon signal is absent due to incidental equivalence); ¹⁹F NMR (377 MHz, CDCl₃) d –58.8; IR (film) 2934.5, 1628.7, 1510.6, 1450.1, 1342.7 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₃F₃N₂O₂ 405.1784; Found 405.1781.

4.3.1.6. (±)-(3R*,4aR*)-2-(4-Methoxyphenyl)-3-(4- nitrobenzyl)hexahydropyrrolo[1,2-c] pyrimidin- 1(2H)-one 4f

The title compound was prepared from substrate 3a (40 mg, 0.15 mmol), 1-bromo-4-nitrobenzene (83 mg, 0.41 mmol), NaO^tBu (40 mg, 0.42 mmol), Pd₂(dba)₃ (3.6 mg, 0.008 mmol), and PCy₃•HBF₄ (5.6 mg, 0.015 mmol) according to General Procedure 3. This procedure afforded 23 mg (39%) of the title compound as a sticky brown solid. The compound was obtained as a >20:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (500 MHz, CDCl₃) δ 8.12 (d, J = 8.1 Hz, 2 H), 7.29–7.16 (m, 4 H), 6.91–6.89 (m, 2 H), 4.10–4.07 (m, 1 H), 3.82 (s, 3 H), 3.81–3.75 (m, 1 H), 3.65–3.49 (m, 2 H), 3.17 (dd, J = 4.5, 13.6 Hz, 1 H), 2.85 (dd, J = 10.5, 13.7 Hz, 1 H), 2.18–2.15 (m, 1 H), 2.06–1.94 (m, 2 H), 1.93–1.83 (m, 1 H), 1.67–1.64 (m, 1 H), 1.51–1.44 (m, 1 H); ¹³C NMR (126 MHz, CDCl₃) δ 157.9, 154.2 146.8, 145.7, 130.1 129.8, 129.1, 123.8, 114.3, 60.0, 55.5, 52.6, 46.2, 38.9, 33.9, 30.1, 23.4; IR (film) 2931.3, 1604.9, 1509.5, 1446.0 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₃N₃O₄ 382.1761; found 382.1758.

4.3.1.7. (±)-(3R*,4aR*)-3-[(1,1’-Biphenyl)-4- ylmethyl] −2-(4-methoxyphenyl)-3- methylhexahydropyrrolo[1,2-c] pyrimidin-1(2H)-one 4g

The title compound was prepared from substrate 3b (42 mg, 0.15 mmol), 4-bromobiphenyl (89 mg, 0.38 mmol), NaO^tBu (38 mg, 0.40 mmol), Pd₂(dba)₃ (3.1 mg, 0.006 mmol), and PCy₃•HBF₄ (5.6 mg, 0.015 mmol) according to General Procedure 3. This procedure afforded 64 mg (97%) of the title compound as a brown solid, mp 73–74 °C. The compound was obtained as a >20:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (500 MHz, CDCl₃) δ 7.54 (d, J = 7.7 Hz, 2 H), 7.48–7.42 (m, 2 H), 7.41–7.37 (m, 2 H), 7.31–7.27 (m, 1 H), 7.20–7.11 (m, 4 H), 6.88 (d, J = 8.3 Hz, 2 H), 3.95–3.91 (m, 1 H), 3.79 (s, 3 H), 3.64–3.58 (m, 1 H), 3.51 (t, J = 10.2 Hz, 1 H), 3.17 (d, J = 13.3 Hz, 1 H), 3.00 (d, J = 13.3 Hz, 1 H), 2.20–2.00 (m, 2 H), 1.99–1.97 (m, 1 H), 1.92–1.81 (m, 1 H), 1.50–1.43 (m, 1 H), 1.41–1.34 (m, 1 H), 1.00 (s, 3 H); ¹³C NMR (126 MHz, CDCl₃) δ 158.5, 155.3, 140.6, 139.5, 136.4, 132.2, 131.0, 128.8, 127.3, 126.93, 126.88, 114.0, 59.3, 55.4, 52.6, 46.3, 43.8, 37.9, 34.0, 27.7, 23.2; IR (film) 2930.4, 1603.5, 1509.9, 1435.6 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₈H₃₀N₂O₂ 427.2380; found 427.2376.

4.3.1.8. (±)-(Z,3R*,4aR*)-2-(4-methoxybenzyl)-3- (pent-2-en-1-yl)hexahydropyrrolo[1,2-c] pyrimidin- 1(2H)-one 4h

The title compound was prepared from substrate 3a (274 mg, 1.0 mmol) and (Z)-1-bromobutene (2.0 mL, 4.0 mmol, 2.0 M solution in toluene), NaO^tBu (384 mg, 4.0 mmol), Pd₂(dba)₃ (18.3 mg, 0.02 mmol), and PCy₃•HBF₄ (29.5 mg, 0.08 mmol) according to a modification of General Procedure 3. This procedure afforded 219 mg (67%) of the title compound as a brown oil. The compound was obtained as a >20:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.21 (d, J = 8.4 Hz, 2 H), 6.83 (d, J = 8.4 Hz, 2 H), 5.50–5.44 (m, 1 H), 5.23 – 5.17 (m, 1 H), 5.13 (d, J = 15.1 Hz, 1 H), 4.03 (d, J = 15.1 Hz, 1 H), 3.79 (s, 3 H), 3.60 (dt, J = 10.5, 6.0 Hz, 1 H), 3.58–3.54 (m, 1 H), 3.49 (dt, J = 9.1, 1.8 Hz, 1 H), 3.25–3.21 (m, 1 H), 2.38 (dd, J = 13.5, 6.7 Hz, 1 H), 2.19 (dt, J = 14.4, 9.4 Hz, 1 H), 2.09–1.94 (m, 5 H), 1.80 (ttd, J = 12.5, 9.6, 6.6 Hz, 1 H), 1.43 (qd, J = 11.9, 7.1 Hz, 1 H), 1.25 (td, J = 12.3, 5.0 Hz, 1 H), 0.95 (t, J = 7.5 Hz, 3 H); ¹³C NMR (175 MHz, CDCl₃) δ 158.6, 155.0, 134.5, 131.3, 129.1, 124.5, 113.8, 55.2, 53.4, 52.6, 47.9, 46.1, 33.9, 30.6, 30.1, 23.5, 20.8, 14.2; IR (film) 1626 cm^–1. (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₀H₂₈N₂O₂ 329.2224; found 329.2221.

4.3.1.9. (±)-(Z,3R*,4aR*)-2-(4-methoxyphenyl)-3- (pent-2-en-1-yl)hexahydropyrrolo[1,2-c] pyrimidin- 1(2H)-one 4i

The title compound was prepared from substrate 3a (52 mg, 0.2 mmol) and (Z)-1-bromobutene (200 μL, 0.4 mmol, 2.0 M solution in toluene), NaO^tBu (38 mg, 0.40 mmol), Pd₂(dba)₃ (3.7 mg, 0.004 mmol), and PCy₃•HBF₄ (6.0 mg, 0.016 mmol) according to General Procedure 3. This procedure afforded 36 mg (58%) of the title compound as a brown oil. The compound was obtained as a >20:1 mixture of diastereomers as judged by¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.14 (d, J = 8.4 Hz, 2 H), 6.87 (d, J = 9.1 Hz, 2 H), 5.47–5.40 (m, 1 H), 5.14–5.10 (m, 1 H), 3.80 (s, 3 H), 3.80–3.74 (m, 1 H), 3.69–3.61 (m, 1 H), 3.58 (td, J = 10.6, 7.4 Hz, 1 H), 3.50 (ddd, J = 10.9, 8.8, 2.0 Hz, 1 H), 2.36–2.30 (m, 1 H), 2.30–2.26 (m, 1 H), 2.19 (ddd, J = 13.3, 3.5,1.4 Hz, 1 H), 2.16–2.10 (m, 1 H), 2.01–1.92 (m, 3 H), 1.87–1.77 (m, 1 H), 1.64 (td, J = 12.3, 5.2 Hz, 1 H), 1.51 (tdd, J = 12.1, 10.0, 7.1 Hz, 1 H), 0.90 (t, J = 7.5 Hz, 3 H); ¹³C NMR (175 MHz, CDCl₃) δ 157.5, 154.4, 135.7, 134.5, 129.2, 124.2, 114.1, 58.7, 55.4, 52.6, 46.0, 33.9, 30.5, 30.4, 23.4, 20.7, 14.0; IR (film) 1638 cm^–1. (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₁₉H₂₆N₂O₂ 315.2067; found 315.2070.

4.3.1.10. (±)-(Z,3R*,4aR*)-2-(4-methoxyphenyl)-3- (pent-2-en-1-yl)octahydro-1H-pyrido[1,2-c] pyrimidin-1-one 6a

The title compound was prepared from substrate 5 (55 mg, 0.2 mmol) and (Z)-1-bromobutene (500 μL, 1.0 mmol, 2.0 M solution in toluene), NaO^tBu (96 mg, 1.0 mmol), Pd₂(dba)₃ (5.5 mg, 0.006 mmol), and PCy₃•HBF₄ (9.0 mg, 0.024 mmol) according to a modification of General Procedure 3. This procedure afforded 45 mg (69%) of the title compound as a brown oil. The compound was obtained as an 8:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.14 (d, J = 9.1 Hz, 2 H), 6.86 (d, J = 8.4 Hz, 2 H), 5.47–5.41 (m, 1 H), 5.17–5.14 (m, 1 H), 4.58 (d, J = 13.3 Hz, 1 H), 3.79 (s, 3 H), 3.59–3.55 (m, 1 H), 3.30 (dddd, J = 13.7, 11.0, 6.1, 3.6 Hz, 1 H), 2.57 (td, J = 12.7, 2.9 Hz, 1 H), 2.42–2.39 (m, 1 H), 2.27 (dt, J = 14.2, 9.4 Hz, 1 H), 2.04–1.93 (m, 3 H), 1.84 (d, J = 12.6 Hz, 1 H), 1.74–1.68 (m, 2 H), 1.50–1.35 (m, 2 H), 1.31–1.24 (m, 2 H), 0.93 (t, J = 7.7 Hz, 3 H); ¹³C NMR (175 MHz, CDCl₃) δ 157.6, 155.0, 136.4, 134.5, 129.0, 124.1, 114.0, 57.1, 55.4, 50.8, 43.5, 33.6, 32.8, 30.9, 25.3, 24.0, 20.8, 14.1; IR (film) 1637 cm^–1. (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₀H₂₈N₂O₂ 329.2224; found 329.2228.

4.3.2. General procedure 4: synthesis of bicyclic piperidinyl ureas

A clean, flame-dried Schlenk tube equipped with a stir bar was cooled under a stream of nitrogen and charged with the urea substrate, Pd(OAc)₂, Dpe-Phos, Cs₂CO₃, and aryl bromide. The tube was purged with nitrogen and 2.5 mL toluene per 1 mmol substrate was added via syringe. The reaction mixture was heated to 110 °C with stirring until judged complete as determined by TLC analysis. Subsequently, the crude reaction mixture was diluted with ethyl acetate and quenched with saturated aqueous ammonium chloride. The organic layer was separated, and the aqueous layer extracted with ethyl acetate. The collected organic layers were then dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo and purified by flash chromatography on silica gel using 20–60% ethyl acetate/hexanes as the eluent unless otherwise noted.

4.3.2.1. (±)-(3R*,4aR*)-3-(4-Methoxybenzyl)-2-(4- methoxyphenyl)octahydro-1H-pyrido[1,2-c] pyrimidin-1-one 6b

The title compound was prepared from substrate 5 (45 mg, 0.16 mmol), 4-bromoanisole (50 μl, 0.40 mmol), Cs₂CO₃ (126 mg, 0.39 mmol), Pd(OAc)₂ (1.7 mg, 0.008 mmol), and Dpe-Phos (7.5 mg, 0.014 mmol) according to General Procedure 4. This procedure afforded 23 mg (37%) of the title compound as a light brown oil. The compound was obtained as a >20:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (500 MHz, CDCl₃) δ 7.15 (d, J = 8.7 Hz, 2 H), 6.97 (d, J = 8.5 Hz, 2 H), 6.92–6.84 (m, 2 H), 6.80 (d, J = 8.4 Hz, 2 H), 4.66–4.57 (m, 1 H), 3.80 (s, 3 H), 3.80–3.77 (m, 1H), 3.77 (s, 3 H), 3.43–3.34 (m, 1 H), 3.08–2.99 (m, 1 H), 2.68–2.56 (m, 2 H), 1.90–1.82 (m, 3 H), 1.73–1.69 (m, 2 H), 1.52–1.35 (m, 2 H), 1.25–1.16 (m, 1 H); ¹³C NMR (126 MHz, CDCl₃) δ 158.2, 157.6, 154.9, 136.5, 130.1, 130.0, 129.0, 114.1, 114.0, 59.0, 55.4, 55.2, 50.7, 43.5, 38.4, 33.6, 32.1, 25.4, 24.0; IR (film) 1635.6, 1510.9, 1457.2, 1245.7 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₃H₂₈N₂O₃ 381.2173; found 381.2170.

4.3.2.2. (±)-(3R*,4aR*)-2-(4-Methoxyphenyl)-3-[3- (trifluoromethyl)benzyl] octahydro-1H-pyrido[1,2- c] pyrimidin-1-one 6c

The title compound was prepared from substrate 5 (48 mg, 0.17 mmol), 3-bromobenzotrifluoride (60 μl, 0.40 mmol), Cs₂CO₃ (117 mg, 0.36 mmol), Pd(OAc)₂ (1.4 mg, 0.006 mmol), and Dpe-Phos (5.8 mg, 0.011 mmol) according to General Procedure 4. This procedure afforded 36 mg (56%) of the title compound as a viscous brown oil. The compound was obtained as a >20:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.49–7.47 (m, 1 H), 7.40–7.38 (m, 1 H), 7.29–7.22 (m, 2 H), 7.18–7.10 (m, 2 H), 6.95–6.84 (m, 2 H), 4.63 (dd, J = 1.9, 13.2 Hz, 1 H), 3.87 (dd, J = 3.3, 7.2 Hz, 1 H), 3.81 (s, 3 H), 3.42–3.40 (m, 1 H), 3.16 (dd, J = 4.8, 13.6 Hz, 1 H), 2.81–2.76 (m, 1 H), 2.64–2.61 (m, 1 H), 1.98–1.81 (m, 3 H), 1.77–1.69 (m, 2 H), 1.49–1.45 (m, 2 H), 1.32–1.22 (m, 1 H); ¹³C NMR (176 MHz, CDCl₃) δ 157.8, 154.7, 139.0, 136.2, 132.5, 130.8 (q, 234 Hz), 129.1, 129.0, 125.5, 124.8, 123.5, 114.2, 58.6, 55.4, 50.7, 43.5, 39.2, 33.6, 32.4, 25.3, 24.0; ¹⁹F NMR (377 MHz, CDCl₃) d −62.6; IR (film) 1635.7, 1511.3, 1444.6, 1331.5, 1233.5 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₅H₂₅C₃N₂O₃ 419.1941; found 419.1938.

4.3.2.3. (±)-(3R*,4aR*)-3-(4-Benzoylbenzyl)-2-(4- methoxyphenyl)octahydro-1H-pyrido[1,2-c] pyrimidin-1-one 6d

The title compound was prepared from substrate 5 (42 mg, 0.15 mmol), 4-bromobenzophenone (103.1 mg, 0.39 mmol), Cs₂CO₃ (122 mg, 0.37 mmol), Pd(OAc)₂ (1.4 mg, 0.006 mmol), and Dpe-Phos (6.6 mg, 0.012 mmol) according to General Procedure 4. This procedure afforded 43 mg (54%) of the title compound as a viscous yellow oil. The compound was obtained as a >20:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (500 MHz, CDCl₃) δ 7.75 (d, J = 7.7 Hz, 2 H), 7.72–7.65 (m, 2 H), 7.57 (t, J = 7.4 Hz, 1 H), 7.48–7.39 (m, 2 H), 7.22–7.08 (m, 4 H), 6.93–6.83 (m, 2 H), 4.67–4.56 (m, 1 H), 3.91–3.83 (m, 1 H), 3.79 (s, 3 H), 3.42–3.39 (m, 1 H), 3.16 (dd, J = 4.7, 13.6 Hz, 1 H), 2.79 (dd, J = 10.3, 13.4 Hz, 1 H), 2.65–2.59 (m, 1 H), 1.93–1.81 (m, 3 H), 1.74–1.68 (m, 2 H), 1.52–1.37 (m, 2 H), 1.29–1.21 (m, 1 H); ¹³C NMR (126 MHz, CDCl₃) δ 196.2, 157.7, 154.8, 143.0, 137.5, 136.3, 135.9, 132.4, 130.5, 129.9, 129.0, 128.9, 128.3, 114.2, 58.7, 55.4, 50.8, 43.5, 39.5, 33.6, 32.4, 25.3, 24.0; IR (film) 1633.8, 1603.6, 1510.0, 1443.5, 1276.0 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₉H₃₀N₂O₃ 455.2329; found 455.2324.

4.3.3. General procedure 5: synthesis of bicyclic ureas and sulfamides from aryl triflates (for reactions carried out in benzotrifluoride)

A test tube was charged with Pd(OAc)₂ (0.04 equiv), a phosphine ligand (0.1 equiv), and LiOtBu (2.0 equiv). The test tube was purged with N₂ then the appropriate aryl triflate (2.0 equiv) was added, followed by the appropriate substrate (1.0 equiv) in benzotrifluoride (0.2 M). The tube was heated to 100 °C and stirred overnight or until the starting material was completely consumed as judged by ¹H NMR analysis. The mixture was cooled to room temperature and saturated aqueous NH₄Cl (5 mL/mmol substrate) and dichloromethane (5 mL/mmol substrate) were added. The layers were separated and the organic layer was concentrated in vacuo. The crude material was purified by flash chromatography on silica gel.

4.3.3.1. (±)-(3S*,4aR*)-3-Benzyl-2-(4- nitrophenyl)hexahydropyrrolo[1,2-c] pyrimidin- 1(2H)-one 18

General procedure 5 was employed for the coupling of 7 (55 mg, 0.2 mmol) and phenyl triflate (65 μL, 0.4 mmol), using a catalyst composed of Pd(OAc)₂ (1.8 mg, 0.008 mmol), and RuPhos (9.3 mg, 0.02 mmol). This procedure afforded 66 mg (94%) of the title compound as a yellow solid and as a 2:1 mixture of diastereomers as determined by ¹H NMR analysis: mp = 51–55 °C. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 8.26 (d, J = 9.1 Hz, 2 H), 7.56 (d, J = 8.4 Hz, 2 H), 7.29–7.23 (m, 3 H), 7.04 (d, J = 7.0 Hz, 2 H), 4.14 (tt, J = 3.9, 10.6 Hz, 1 H), 3.58–3.47 (m, 3 H), 2.85 (dd, J = 3.8, 13.5 Hz, 1 H), 2.32 (dd, J = 10.1, 13.4 Hz, 1 H), 2.26–1.46 (m, 6 H); ¹³C NMR (175 MHz, CDCl₃) δ 153.5, 147.5, 145.2, 137.0, 129.0, 128.7, 128.6, 126.7, 124.0, 58.2, 54.7, 46.0, 41.6, 35.0, 33.5, 23.0; IR (film) 1639, 1515, 1339 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₀H₂₁N₃O₃ 352.1656; found 352.1656.

4.3.3.2. (±)-(3S*,4aR*)-3-Benzyl-2-(4- methoxyphenyl)hexahydro-2H-pyrrolo[1,2- b] [1,2,6] thiadiazine-1,1-dioxide 20a

General procedure 5 was employed for the coupling of 19a (59 mg, 0.2 mmol) and phenyl triflate (65 μL, 0.4 mmol), using a catalyst composed of Pd(OAc)₂ (1.8 mg, 0.008 mmol), and CPhos (8.7 mg, 0.02 mmol). This procedure provided an 80% NMR yield (using phenanthrene as an internal standard) of the title compound that was a 6:1 mixture of diastereomers as determined by ¹H NMR analysis. Data for this compound are provided below in entry 4.3.4.1.

4.3.3.3. (±)-(3S*,4aR*)-2,3-Dibenzylhexahydro-2H- pyrrolo[1,2-b] [1,2,6] thiadiazine-1,1-dioxide 20b

General procedure 5 was employed for the coupling of 19b (56 mg, 0.2 mmol) and phenyl triflate (65 μL, 0.4 mmol), using a catalyst composed of Pd(OAc)₂ (1.8 mg, 0.008 mmol), and CPhos (8.7 mg, 0.02 mmol). This procedure afforded 61 mg (86%) of the title compound as a white solid and as a 3:1 mixture of diastereomers as determined by ¹H NMR analysis: mp = 113– 116 °C. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.42 (d, J = 7.0 Hz, 2 H), 7.34–7.18 (m, 6 H), 7.07 (d, J = 7.0 Hz, 2 H), 4.59 (d, J = 16.2 Hz, 1 H), 4.15 (d, J = 16.1 Hz, 1 H), 4.15–4.09 (m, 1 H), 3.50–3.46 (m, 1 H), 3.26–3.21 (m, 2 H), 2.92 (dd, J = 4.6, 13.4 Hz, 1 H), 2.54 (dd, J = 10.5, 13.4 Hz, 1 H), 2.07–2.01 (m, 1 H), 1.98–1.90 (m, 1 H), 1.83–1.75 (m, 1 H), 1.71–1.49 (m, 3 H); ¹³C NMR (175 MHz, CDCl₃) δ 138.5, 137.4, 129.2, 128.5, 128.4, 127.7, 127.2, 126.7, 61.6, 60.8, 49.6, 45.8, 40.6, 31.6, 30.7, 21.1; IR (film) 1333, 1155 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₀H₂₄N₂O₂S 357.1631; found 357.1632.

4.3.3.4. (±)-(3S*,4aR*)-3-Benzyl-2-(4- methoxybenzyl)hexahydro-2H-pyrrolo[1,2- b] [1,2,6] thiadiazine-1,1-dioxide 20c

General procedure 5 was employed for the coupling of 19c (62 mg, 0.2 mmol) and phenyl triflate (65 μL, 0.4 mmol), using a catalyst composed of Pd(OAc)₂ (1.8 mg, 0.008 mmol), and CPhos (8.7 mg, 0.02 mmol). This procedure afforded 63 mg (82%) of the title compound as a red-brown oil and as a 3:1 mixture of diastereomers as determined by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.32 (d, J = 8.4 Hz, 2 H), 7.26–7.15 (m, 3 H), 7.08 (d, J = 7.0 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 4.51 (d, J = 15.9 Hz, 1 H), 4.08 (d, J = 16.1 Hz, 1 H), 4.11–4.03 (m, 1 H), 3.80 (s, 3 H), 3.48–3.42 (m, 1 H), 3.27–3.21 (m, 2 H), 2.92 (dd, J = 13.3, 4.9 Hz, 1 H), 2.55 (dd, J = 13.4, 10.3 Hz, 1 H), 2.06–1.98 (m, 1 H), 1.96–1.85 (m, 1 H), 1.82–1.76 (m, 1 H), 1.70–1.46 (m, 3 H); ¹³C NMR (175 MHz, CDCl₃) δ 158.8, 137.5, 130.4, 129.1, 129.1, 128.5, 126.6, 113.7, 61.3, 60.7, 55.2, 49.3, 45.9, 40.7, 31.6, 30.9, 21.3; IR (film) 1332, 1245, 1155 cm^–1. MS (ESI) 387.1725 (387.1737 calcd for C₂₁H N+26 2O₃S, M + H).

4.3.4. General procedure 6: synthesis of bicyclic sufamides (for reactions carried out in tert- butanol)

A test tube was charged with Pd(OAc)₂ (0.04 equiv), a phosphine ligand (0.1 equiv), and LiOtBu (2.0–3.0 equiv). The test tube was purged with N₂ then the appropriate aryl or alkenyl triflate (2.0–3.0 equiv) was added, followed by the appropriate substrate (1.0 equiv) in tert-butanol (0.1 M). The tube was heated to 82 °C and stirred overnight or until the starting material was completely consumed as judged by ¹H NMR analysis. The mixture was cooled to room temperature and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel.

4.3.4.1. (±)-(3S*,4aR*)-3-Benzyl-2-(4- methoxyphenyl)hexahydro-2H-pyrrolo[1,2- b] [1,2,6] thiadiazine-1,1-dioxide 20a

General procedure 6 was employed for the coupling of 19a (59 mg, 0.2 mmol) and phenyl triflate (65 μL, 0.4 mmol), using a catalyst composed of Pd(OAc)₂ (1.8 mg, 0.008 mmol), and CPhos (8.7 mg, 0.02 mmol). This procedure afforded 67 mg (90%) of the title compound as a white solid and as a 7:1 mixture of diastereomers as determined by ¹H NMR analysis: mp = 45– 48 °C. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.39 (d, J = 8.4 Hz, 2 H), 7.29–7.20 (m, 3 H), 7.06 (d, J = 7.7 Hz, 2 H), 6.91 (d, J = 9.1 Hz, 2 H), 4.26–4.19 (m, 1 H), 3.80 (s, 3 H), 3.53 (td, J = 5.7, 9.5 Hz, 1 H), 3.38 (td, J = 5.8, 9.5 Hz, 1 H), 2.81 (dd, J = 4.4, 13.6 Hz, 1 H), 2.21–2.08 (m, 2 H), 2.07–1.91 (m, 3 H), 1.68–1.53 (m, 3 H); ¹³C NMR (175 MHz, CDCl₃) δ 159.4, 137.4, 130.9, 130.4, 129.1, 128.6, 126.6, 114.3, 61.8, 60.2, 55.4, 46.5, 40.4, 32.6, 31.3, 21.3; IR (film) 1506, 1337, 1248, 1158 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₀H₂₄N₂O₃S 373.1580; found 373.1589.

4.3.4.2. (±)-(3S*,4aR*)-3-[4-(tert-Butyl)benzyl] −2- (4-methoxyphenyl)hexahydro-2H-pyrrolo[1,2-b] [1,2,6] thiadiazine-1,1-dioxide 20d

General procedure 6 was employed for the coupling of 19a (59 mg, 0.2 mmol) and 4-(tert-butyl)phenyl triflate (113 mg, 0.4 mmol), using a catalyst composed of Pd(OAc)₂ (1.8 mg, 0.008 mmol), and CPhos (8.7 mg, 0.02 mmol). This procedure afforded 62 mg (72%) of the title compound as a white solid and as a 7:1 mixture of diastereomers as determined by ¹H NMR analysis: mp = 61–63 °C. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.39 (d, J = 9.1 Hz, 2 H), 7.27 (d, J = 7.7 Hz, 2 H), 6.98 (d, J = 8.4 Hz, 2 H), 6.90 (d, J = 9.1 Hz, 2 H), 4.25–4.19 (m, 1 H), 3.81 (s, 3 H), 3.80–3.76 (m, 1 H), 3.54–3.49 (m, 1 H), 3.41–3.34 (m, 1 H), 2.77 (dd, J = 4.3, 13.7 Hz, 1 H), 2.14–2.09 (m, 2 H), 2.07–1.87 (m, 2 H), 1.70–1.52 (m, 3 H), 1.29 (s, 9 H); ¹³C NMR (175 MHz, CDCl₃) δ 159.4, 149.5, 134.2, 130.9, 130.4, 128.7, 125.4, 114.3, 61.8, 60.2, 55.4, 46.5, 39.9, 37.4, 34.4, 32.6, 31.3, 21.3; IR (film) 1506, 1338, 1247, 1158 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₄H₃₂N₂O₃S 429.2215; found 429.2215.

4.3.4.3. (±)-(3S*,4aR*)-3-(4-Methoxybenzyl)-2-(4- methoxyphenyl)hexahydro-2H-pyrrolo[1,2-b] [1,2,6] thiadiazine-1,1-dioxide 20e

General procedure 6 was employed for the coupling of 19a (59 mg, 0.2 mmol) and 4-methoxyphenyl triflate (72 μL, 0.4 mmol), using a catalyst composed of Pd(OAc)₂ (1.8 mg, 0.008 mmol), and CPhos (8.7 mg, 0.02 mmol). This procedure afforded 52 mg (65%) of the title compound as a white solid and as a 7:1 mixture of diastereomers as determined by ¹H NMR analysis: mp = 48–51 °C. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.38 (d, J = 8.4 Hz, 2 H), 6.97 (d, J = 8.4 Hz, 2 H), 6.91 (d, J = 9.1 Hz, 2 H), 6.80 (d, J = 8.4 Hz, 2 H), 4.20–4.14 (m, 1 H), 3.85 (s, 3 H), 3.80 (s, 3 H), 3.80–3.73 (m, 1 H), 3.56–3.46 (m, 1 H), 3.37 (td, J = 5.7, 9.4 Hz, 1 H), 2.74 (dd, J = 4.4, 13.7 Hz, 1 H), 2.15–2.08 (m, 2 H), 2.04–1.91 (m, 2 H), 1.64–1.50 (m, 3 H); ¹³C NMR (175 MHz, CDCl₃) δ 159.4, 158.3, 130.9, 130.4, 130.0, 129.3, 114.3, 113.9, 61.9, 60.3, 55.4, 55.2, 46.5, 39.5, 32.5, 31.3, 21.3; IR (film) 1507, 1338, 1247, 1158 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₆N₂O₄S 403.1686; found 403.1679.

4.3.4.4. (±)-(3S*,4aR*)-{4-{[2-(4-Methoxyphenyl)- 1,1-dioxidohexahydro-2H-pyrrolo[1,2-b] [1,2,6] thiadiazin-3-yl] methyl}phenyl}(phenyl)methanone 20f

General procedure 6 was employed for the coupling of 19a (59 mg, 0.2 mmol) and 4-benzoylphenyl triflate (132 mg, 0.4 mmol), using a catalyst composed of Pd(OAc)₂ (1.8 mg, 0.008 mmol), and CPhos (8.7 mg, 0.02 mmol). The diastereoselectivity of the reaction was judged to be 5:1 dr as determined by ¹H NMR analysis prior to flash chromatography. This procedure afforded 62 mg (65%) of the title compound as a white solid and as a 8:1 mixture of diastereomers as determined by ¹H NMR analysis: mp = 58–61 °C. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.78 (d, J = 7.7 Hz, 2 H), 7.72 (d, J = 8.4 Hz, 2 H), 7.59 (t, J = 7.5 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 2 H), 7.38 (d, J = 8.8 Hz, 2 H), 7.18 (d, J = 7.9 Hz, 2 H), 6.91 (d, J = 8.7 Hz, 2 H), 4.33–4.28 (m, 1 H), 3.79 (s, 3 H), 3.79–3.77 (m, 1 H), 3.54 (td, J = 5.7, 9.4 Hz, 1 H), 3.39 (td, J = 5.8, 9.3 Hz, 1 H), 2.87 (dd, J = 4.8, 13.7 Hz, 1 H), 2.33 (dd, J = 9.8, 13.7 Hz, 1 H), 2.19–2.12 (m, 1 H), 2.01–1.95 (m, 2 H), 1.68–1.62 (m, 3 H); ¹³C NMR (175 MHz, CDCl₃) δ 196.2, 159.5, 142.4, 137.5, 136.1, 132.5, 130.9, 130.4, 130.2, 130.0, 129.0, 128.3, 114.4, 61.5, 60.1, 55.4, 46.5, 40.4, 32.9, 31.4, 21.3; IR (film) 1654, 1605, 1506, 1339, 1278, 1249, 1157 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₇H₂₈N₂O₄S 477.1843; found 477.1847.

4.3.4.5. (±)-(3S*,4aR*)-2-(4-Methoxyphenyl)-3-(2- methylbenzyl)hexahydro-2H-pyrrolo[1,2-b] [1,2,6] thiadiazine-1,1-dioxide 20g

General procedure 6 was employed for the coupling of 19a (59 mg, 0.2 mmol) and 2-tolyl triflate (96 mg, 0.4 mmol), using a catalyst composed of Pd(OAc)₂ (1.8 mg, 0.008 mmol), and CPhos (8.7 mg, 0.02 mmol). This procedure afforded 65 mg (84%) of the title compound as a white solid and as a 5:1 mixture of diastereomers as determined by ¹H NMR analysis: mp = 39– 43 °C. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.41 (d, J = 9.1 Hz, 2 H), 7.12–7.10 (m, 3 H), 7.05–7.02 (m, 1 H), 6.91 (d, J = 9.1 Hz, 2 H), 4.24–4.17 (m, 1 H), 3.82 (s, 3 H), 3.81–3.74 (m, 1 H), 3.55 (td, J = 5.7, 9.4 Hz, 1 H), 3.43–3.36 (m, 1 H), 2.75 (dd, J = 4.4, 13.8 Hz, 1 H), 2.22 (dd, J = 10.5, 13.8 Hz, 1 H), 2.18 (s, 3 H), 2.13 (ddt, J = 6.5, 9.6, 12.6 Hz, 1 H), 2.09–1.95 (m, 2 H), 1.67–1.60 (m, 3 H); ¹³C NMR (175 MHz, CDCl₃) δ 159.4, 136.3, 135.5, 130.9, 130.5, 130.4, 130.1, 126.8, 125.9, 114.3, 60.4, 60.2, 55.4, 46.5, 37.9, 32.7, 31.3, 21.3, 19.6; IR (film) 1506, 1338, 1248, 1157 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₆N₂O₃S 387.1737; found 387.1745.

4.3.4.6. (±)-(3S*,4aR*)-3-(Cyclohex-1-en-1- ylmethyl)-2-(4-methoxyphenyl)hexahydro-2H- pyrrolo[1,2-b] [1,2,6] thiadiazine-1,1-dioxide 20h

General procedure 6 was employed for the coupling of 19a (59 mg, 0.2 mmol) and 1-cyclohexenyl triflate (63 μL, 0.6 mmol), using a catalyst composed of Pd(OAc)₂ (1.8 mg, 0.008 mmol), and CPhos (8.7 mg, 0.02 mmol). This procedure afforded 55 mg (73%) of the title compound as a pale yellow oil and as a 6:1 mixture of diastereomers as determined by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.32 (d, J = 8.4 Hz, 2 H), 6.87 (d, J = 9.1 Hz, 2 H), 5.33 (s, 1 H), 4.13–4.07 (m, 1 H), 3.87–3.82 (m, 1 H), 3.79 (s, 3 H), 3.51 (td, J = 5.6, 9.4 Hz, 1 H), 3.36 (td, J = 5.8, 9.4 Hz, 1 H), 2.20 (ddt, J = 6.5, 9.7, 12.7 Hz, 1 H), 2.08–1.42 (m, 15 H); ¹³C NMR (175 MHz, CDCl₃) δ 159.2, 133.1, 131.0, 130.4, 124.9, 114.0, 60.4, 58.5, 55.4, 46.4, 42.8, 33.0, 31.4, 28.2, 25.2, 22.8, 22.2, 21.3; IR (film) 1506, 1337, 1248, 1156 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₀H₂₈N₂O₃S, 377.1893; found 377.1903.

4.3.5. (±)-(E,3S*,4aR*)-2-(4-Methoxyphenyl)-3- (undec-2-en-1-yl)-hexahydro-2H-pyrrolo[1,2-b] [1,2,6] thiadiazine-1,1-dioxide 20i

General procedure 6 was employed for the coupling of 19a (15 mg, 0.05 mmol) and 1-decenyl triflate (29 μL, 0.15 mmol, 5:1 mixture of E/Z isomers), using a catalyst composed of Pd(OAc)₂ (0.45 mg, 0.002 mmol), and CPhos (2.2 mg, 0.005 mmol). The crude diastereoselectivity of the reaction could not be precisely determined directly due to the formation of a complex mixture of diastereomers and E/Z isomers. However, the crude diastereoselectivity was estimated to be between 5:1 and 10:1 dr as determined by ¹H NMR analysis prior to flash chromatography. Following flash chromatography, this procedure afforded 10 mg (46%) of the title compound as a pale yellow oil and as a 10:1 mixture of diastereomers as determined by ¹H NMR analysis following hydrogenation of the olefin (see below for details). Data are for the major isomer. ¹H NMR (500 MHz, CDCl₃) δ 7.34 (d, J = 9.0 Hz, 2 H), 6.88 (d, J = 9.1 Hz, 2 H), 5.46–5.41 (m, 1 H), 5.26–5.20 (m, 1 H), 4.01–3.90 (m, 2 H), 3.80 (s, 3 H), 3.52 (td, J = 6.0, 9.4 Hz, 1 H), 3.40 (td, J = 5.8, 9.4 Hz, 1 H), 2.20 (ddt, J = 6.7, 9.8, 12.8 Hz, 1 H), 2.10–1.91 (m, 3 H), 1.88–1.78 (m, 3 H), 1.73–1.54 (m, 2 H), 1.33–1.26 (m, 13 H), 0.88 (t, J = 7.0 Hz, 3 H); ¹³C NMR (175 MHz, CDCl₃) δ 159.3,

133.3, 130.9, 130.2, 123.8, 114.2, 60.4, 60.0, 55.4, 46.6, 32.8, 31.9, 31.5, 31.4, 29.7, 29.4, 29.4, 29.3, 27.4, 22.7, 21.4, 14.1; IR (film) 2922, 1507, 1349, 1248, 1161 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₄H₃₈N₂O₃S 435.2676; found 435.2678.

4.3.5.1. (±)-(3S*,4aR*)-2-(4-Methoxyphenyl)-3- undecylhexahydro-2H-pyrrolo[1,2-b] [1,2,6] thiadiazine-1,1-dioxide (reduction of 20i).

A flask equipped with a stirbar was charged with 20i (10 mg, 0.023 mmol) and methanol (2 mL). Pd/C (10 mg) was added to the solution and the flask was capped with a rubber septum. The flask was briefly flushed with hydrogen and then a hydrogen- filled balloon attached to a needle (via an adaptor) was connected to the flask through the septum. The mixture was stirred at rt until the starting material had been consumed as judged by ESI⁺ MS analysis (ca. 1 hr). The crude product was then filtered through a plug of celite to remove the Pd/C and washed with methanol (5 mL). The crude material was concentrated in vacuo and required no further purification. This procedure afforded 9 mg (90%) of the title compound as a clear colorless oil and as a 10:1 mixture of diastereomers as determined by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.32 (d, J = 8.4 Hz, 2 H), 6.87 (d, J = 9.1 Hz, 2 H), 4.00–3.94 (m, 1 H), 3.88–3.78 (m, 1 H), 3.80 (s, 3 H), 3.50 (td, J = 9.4, 5.6 Hz, 1 H), 3.35 (td, J = 9.4, 5.9 Hz, 1 H), 2.21 (ddt, J = 6.3, 9.6, 12.5 Hz, 1 H), 2.07–1.92 (m, 2 H), 1.81 (dt, J = 3.2, 13.9, Hz, 1 H), 1.73–1.57 (m, 2 H), 1.35–1.04 (m, 20 H), 0.88 (t, J = 7.2 Hz, 3 H); ¹³C NMR (175 MHz, CDCl₃) δ 159.2, 131.0, 130.4, 114.1, 60.7, 60.4, 55.4, 46.4, 33.4, 33.1, 31.9, 31.5, 29.6, 29.6, 29.4, 29.4, 29.3, 29.3, 25.4, 22.7, 21.2, 14.1; IR (film) 1507, 1345, 1248, 1161 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₄H₄₀N₂O₃S 437.2832; found 437.2836.

4.3.5.2. (±)-(3S*,4aR*,7S*)-7-Allyl-3-benzyl-2-(4- methoxyphenyl)hexahydro-2H-pyrrolo[1,2-b] [1,2,6] thiadiazine-1,1-dioxide 20j

General procedure 6 was employed for the coupling of 19d (67 mg, 0.2 mmol) and phenyl triflate (65 μL, 0.4 mmol), using a catalyst composed of Pd(OAc)₂ (1.8 mg, 0.008 mmol), and CPhos (8.7 mg, 0.02 mmol). The diastereoselectivity of the reaction was judged to be 12:1 dr as determined by ¹H NMR analysis prior to flash chromatography. This procedure afforded 51 mg (62%) of the title compound as a pale yellow oil and as a 20:1 mixture of diastereomers as determined by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.40 (d, J = 8.4 Hz, 2 H), 7.26–7.19 (m, 3 H), 7.09 (d, J = 7.0 Hz, 2 H), 6.88 (d, J = 9.1 Hz, 2 H), 5.78 (ddt, J = 7.1, 11.2, 15.8 Hz, 1 H), 5.10–5.04 (m, 2 H), 4.41 (tdd, J = 2.6, 5.3, 9.9 Hz, 1 H), 3.82 (s, 3 H), 3.77–3.72 (m, 1 H), 3.44 (tdd, J = 3.0, 5.0, 11.3 Hz, 1 H), 2.82 (dd, J = 5.3, 13.8 Hz, 1 H), 2.64–2.58 (m, 1 H), 2.37 (dt, J = 7.8, 14.0 Hz, 1 H), 2.11 (dd, J = 10.0, 13.8 Hz, 1 H), 2.01–1.94 (m, 1 H), 1.90 (ddt, J = 8.9, 10.2, 13.0 Hz, 1 H), 1.78–1.68 (m, 2 H), 1.68–1.53 (m, 2 H); ¹³C NMR (175 MHz, CDCl₃) δ 159.4, 137.3, 134.4, 131.4, 130.5, 129.1, 128.5, 126.7, 117.7, 114.0, 62.8, 61.7, 57.8, 55.4, 40.0, 39.8, 32.9, 30.5, 26.8; IR (film) 1506, 1344, 1249, 1155 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₃H₂₈N₂O₃S 413.1893; found 413.1895.

4.3.5.3. (±)-(3S*,4aR*,7S*)-7-Allyl-3-(4- methoxybenzyl)-2-(4-methoxyphenyl)hexahydro-2H- pyrrolo[1,2-b] [1,2,6] thiadiazine-1,1-dioxide 20k

General procedure 6 was employed for the coupling of 19d (67 mg, 0.2 mmol) and 4-methoxyphenyl triflate (72 μL, 0.4 mmol), using a catalyst composed of Pd(OAc)₂ (1.8 mg, 0.008 mmol), and CPhos (8.7 mg, 0.02 mmol). The diastereoselectivity of the reaction was judged to be 13:1 dr as determined by ¹H NMR analysis prior to flash chromatography. This procedure afforded 57 mg (64%) of the title compound as a white solid and as a >20:1 mixture of diastereomers as determined by ¹H NMR analysis: mp = 44–46 °C. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.39 (d, J = 8.6 Hz, 2 H), 7.00 (d, J = 8.6 Hz, 2 H), 6.88 (d, J = 9.1 Hz, 2 H), 6.81 (d, J = 8.4 Hz, 2 H), 5.82–7.73 (m, 1 H), 5.10–5.04 (m, 2 H), 4.39–4.35 (m, 1 H), 3.82 (s, 3 H), 3.78 (s, 3 H), 3.77–3.72 (m, 1 H), 3.46–3.39 (m, 1 H), 2.76 (dd, J = 5.3, 13.9 Hz, 1 H), 2.61 (dd, J = 6.0, 14.4 Hz, 1 H), 2.37 (dt, J = 7.9, 15.0 Hz, 1 H), 2.04 (dd, J = 10.0, 13.9 Hz, 1 H), 2.01–1.88 (m, 2 H), 1.78–1.68 (m, 2 H), 1.62–1.53 (m, 2 H); ¹³C NMR (175 MHz, CDCl₃) δ 159.5, 158.4, 134.4, 131.5, 130.6, 130.0, 129.3, 117.7, 114.0, 113.9, 62.9, 61.9, 57.9, 55.4, 55.2, 39.8, 39.1, 32.9, 30.5, 26.8; IR (film) 1507, 1345, 1247, 1156 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₄H₃₀N₂O₄S 443.1999; found 443.1993.

4.3.5.4. (±)-(Z,3S*,4aR*)-2-Benzyl-3-(pent-2-en-1- yl)hexahydro-2H-pyrrolo[1,2-b] [1,2,6] thiadiazine- 1,1-dioxide 20l

A modified version of General Procedure 6 was employed for the coupling of 19b (56 mg, 0.2 mmol) and (Z)-1-bromobutene (400 μL, 0.8 mmol, 2.0 M solution in PhCF₃), using NaOtBu (96 mg, 1.0 mmol), LiOTf (156 mg, 1.0 mmol), and a catalyst composed of Pd(OAc)₂ (1.8 mg, 0.008 mmol), and CPhos (8.7 mg, 0.02 mmol). The reaction was heated to 100 °C and stirred overnight or until the starting material was completely consumed as judged by ¹H NMR analysis. The mixture was cooled to room temperature and saturated aqueous NH₄Cl (5 mL/mmol substrate) and dichloromethane (5 mL/mmol substrate) were added. The layers were separated and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel. This procedure afforded 20 mg (30%) of the title compound as a pale yellow brown oil and as a 5:1 mixture of diastereomers as determined by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.44–7.29 (m, 4 H), 7.24 (t, J = 7.4 Hz, 1 H), 5.41–5.37 (m, 1 H), 5.19–5.13 (m, 1 H), 4.50 (d, J = 16.2 Hz, 1 H), 4.11 (d, J = 16.2 Hz, 1 H), 3.90–3.85 (m, 1 H), 3.47 (td, J = 5.4, 9.0 Hz, 1 H), 3.40–3.31 (m, 1 H), 3.24 (td, J = 6.1, 9.3 Hz, 1 H), 2.25–2.08 (m, 3 H), 1.95–1.80 (m, 5 H), 1.59–1.45 (m, 2 H), 0.88 (t, J = 7.7 Hz, 3 H); ¹³C NMR (175MHz, CDCl₃) δ 138.7, 134.7, 128.4, 127.6, 127.1, 123.9, 60.9, 60.6, 49.2, 45.9, 31.7, 31.6, 31.3, 21.0, 20.7, 13.9; IR (film) 1334, 1156 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₁₈H₂₆N₂O₂S 335.1788; found 335.1793.

4.3.5.5. (±)-(3S*,4aR*)-3-Benzyl-2-(4- methoxyphenyl)octahydropyrido[1,2- b] [1,2,6] thiadiazine-1,1-dioxide 24a

General procedure 6 was employed for the coupling of 23 (62 mg, 0.2 mmol) and phenyl triflate (65 μL, 0.4 mmol), using a catalyst composed of Pd(OAc)₂ (1.8 mg, 0.008 mmol), and CPhos (8.7 mg, 0.02 mmol). This procedure afforded 65 mg (84%) of the title compound as a white solid and as a 5:1 mixture of diastereomers as determined by ¹H NMR analysis: mp = 46– 49 °C. Data are for the major isomer. ¹H NMR (500 MHz, CDCl₃) δ 7.41 (d, J = 8.5 Hz, 2 H), 7.28–7.20 (m, 3 H), 7.07 (d, J = 7.5 Hz, 2 H), 6.91 (d, J = 9.0 Hz, 2 H), 4.41–4.37 (m, 1 H), 3.82 (s, 3 H), 3.59–3.43 (m, 2 H), 2.97–2.88 (m, 1 H), 2.79 (dd, J = 4.8, 13.6 Hz, 1 H), 2.13 (dd, J = 10.1, 13.7 Hz, 1 H), 1.89–1.65 (m, 4 H), 1.58–1.36 (m, 4 H); ¹³C NMR (175 MHz, CDCl₃) δ 159.4, 137.2, 131.2, 130.0, 129.1, 128.5, 126.7, 114.2, 60.4, 57.1, 55.4, 44.3, 40.3, 32.1, 31.9, 24.9, 21.9; IR (film) 1507, 1338, 1250, 1156 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₆N₂O₃S 387.1737; found 387.1737.

4.3.5.6. (±)-(3S*,4aR*)-3-(Cyclohex-1-en-1- ylmethyl)-2-(4-methoxyphenyl)octahydropyrido[1,2- b] [1,2,6] thiadiazine 1,1-dioxide 24b

The title compound was prepared from substrate 23 (62 mg, 0.20 mmol), cyclohex-1-en-1-yl trifluoromethanesulfonate (70 μl, 0.40 mmol), LiO^tBu (35 mg, 0.44 mmol), Pd(OAc)₂ (2.4 mg, 0.011 mmol), and CPhos (11.9 mg, 0.027 mmol) according to General Procedure 6. This procedure afforded 60 mg (77%) of the title compound as a sticky off-white foam. The compound was obtained as a 2:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (500 MHz, CDCl₃) δ 7.36 (d, J = 8.3 Hz, 2 H), 6.86 (d, J = 8.4 Hz, 2 H), 5.32 (s, 1 H), 4.29–4.21 (m, 1 H), 3.79 (s, 3 H), 3.62–3.46 (m, 2 H), 2.91–2.85 (m, 1 H), 2.32–2.28 (m, 1 H), 2.20–2.16 (m, 1 H), 2.00–1.45 (m, 16 H); ¹³C NMR (176 MHz, CDCl₃) δ 159.3, 132.9, 131.2, 130.0, 124.7, 114.0, 57.3, 57.1, 55.4, 44.4, 42.5, 32.9, 32.1, 28.3, 25.2, 25.0, 22.8, 22.3, 21.6; IR (film) 1505.6, 1441.8, 1337.8, 1246.8 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₁H₃₀N₂O₃S 391.2050; found 391.2049.

4.3.5.7. (±)-(3S*,4aR*)-3-[4-(tert-Butyl)benzyl] −2- (4-methoxyphenyl)octahydropyrido[1,2-b] [1,2,6] thiadiazine 1,1-dioxide 24c

The title compound was prepared from substrate 23 (65 mg, 0.21 mmol), 4-(tert-butyl)phenyl trifluoromethanesulfonate (112 μl, 0.40 mmol), LiO^tBu (40 mg, 0.50 mmol), Pd(OAc)₂ (1.8 mg, 0.008 mmol), and CPhos (7.4 mg, 0.017 mmol) according to General Procedure 6. This procedure afforded 80 mg (86%) of the title compound as a sticky light brown foam. The compound was obtained as a 4:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.41 (d, J = 8.4 Hz, 2 H), 7.31–7.26 (m, 2 H), 6.99 (d, J = 8.0 Hz, 2 H), 6.90 (d, J = 9.0 Hz, 2 H), 4.44–4.32 (m, 1 H), 3.81 (s, 3 H), 3.58–3.50 (m, 1 H), 3.48–3.44 (m, 1 H), 2.93–2.89 (m, 1 H), 2.75 (dd, J = 4.7, 13.7 Hz, 1 H), 2.08 (dd, J = 10.2, 13.7 Hz, 1 H), 1.84–1.64 (m, 6 H), 1.51–1.40 (m, 2 H), 1.29 (s, 9 H); ¹³C NMR (176 MHz, CDCl₃) δ 159.4, 149.5, 134.0, 131.2, 129.1, 128.7, 125.4, 114.3, 66.2, 60.5, 57.1, 55.4, 44.3, 39.8, 34.4, 32.2, 31.9, 31.4, 25.0, 21.9 (one carbon signal is absent due to incidental equivalence); IR (film) 1507.6, 1336.4, 1247.1, 1157.0 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ Calculated for C₂₅H₃₄N₂O₃S 443.2363; found 443.2364.

4.3.5.8. (±)-(3S*,4aR*)-2-(4-Methoxyphenyl)-3-(2- methylbenzyl)octahydropyrido[1,2-b] [1,2,6] thiadiazine 1,1-dioxide 24d

The title compound was prepared from substrate 23 (57 mg, 0.18 mml), 2-tolyl trifluoromethanesulfonate (96 μl, 0.40 mmol), LiO^tBu (30 mg, 0.37 mmol), Pd(OAc)₂ (2.3 mg, 0.010 mmol), and CPhos (7.7 mg, 0.018 mmol) according to General Procedure 6. This procedure afforded 49 mg (67%) of the title compound as a sticky off-white foam. The compound was obtained as a 4:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.41 (d, J = 8.2 Hz, 2 H), 7.14–7.06 (m, 4 H), 6.95–6.87 (m, 2 H), 4.41–4.36 (m, 1 H), 3.79 (s, 3 H), 3.59–3.47 (m, 2 H), 2.97–2.92 (m, 1 H), 2.72 (dd, J = 4.9, 14.0 Hz, 1 H), 2.19–2.16 (m, 1 H), 2.16 (s, 3 H), 1.90 (dt, J = 12.1, 14.4 Hz, 1H), 1.73–1.64 (m, 5 H), 1.55–1.38 (m, 2 H); ¹³C NMR (176 MHz, CDCl₃) δ 159.5, 136.3, 135.4, 131.1, 130.5, 130.0, 128.6, 126.8, 126.0, 114.4, 59.1, 57.0, 55.4, 44.2, 37.6, 32.3, 31.8, 25.0, 21.8, 19.5; IR (film) 1606.1, 1506.1, 1463.5, 1338.8 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₈N₂O₃S 401.1893; found 401.1891.

4.3.5.9. (±)-(3S*,4aR*)-3-(Benzo[d] [1,3] dioxol-5- ylmethyl)-2-(4-methoxyphenyl)octahydropyrido[1,2- b] [1,2,6] thiadiazine 1,1-dioxide 24e

The title compound was prepared from substrate 23 (64 mg, 0.21 mmol), benzo[d][1,3]dioxol-5-yl trifluoromethanesulfonate (100 μl, 0.40 mmol), LiO^tBu (35 mg, 0.44 mmol), Pd(OAc)₂ (2.2 mg, 0.010 mmol), and CPhos (10.0 mg, 0.023 mmol) according to General Procedure 6. This procedure afforded 70 mg (79%) of the title compound as a sticky white foam. The compound was obtained as a 5:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (500 MHz, CDCl₃) δ 7.47–7.34 (m, 2 H), 6.97–6.86 (m, 2 H), 6.71–6.66 (m, 1 H), 6.55 (s, 1 H), 6.53–6.47 (m, 1 H), 5.91 (s, 2 H), 4.31–4.28 (m, 1 H), 3.80 (s, 3 H), 3.52–3.48 (m, 2 H), 2.97–2.91 (m, 1 H), 2.69–2.66 (m, 1 H), 2.04 (dd, J = 10.1, 13.7 Hz, 1 H), 1.84–1.65 (m, 5 H), 1.54–1.40 (m, 3 H); ¹³C NMR (126 MHz, CDCl₃) δ 159.4, 147.7, 146.3, 131.1, 130.0, 128.5, 122.1, 114.4, 109.3, 108.3, 101.0, 60.5, 57.0, 55.4, 44.3, 40.0, 32.1, 31.8, 24.8, 21.8; IR (film) 1504.4, 1442.5, 1337.0, 1246.3 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₆N₂O₅S 431.1635; found 431.1634.

4.3.5.10. (±)-(3S*,4aR*)-3-(4-Methoxybenzyl)-2-(4- methoxyphenyl)octahydropyrido[1,2-b] [1,2,6] thiadiazine 1,1-dioxide 24f

The title compound was prepared from substrate 23 (63 mg, 0.20 mmol), 4-methoxyphenyl trifluoromethanesulfonate (72 μl, 0.40 mmol), LiO^tBu (30 mg, 0.37 mmol), Pd(OAc)₂ (1.3 mg, 0.006 mmol), and CPhos (10.1 mg, 0.023 mmol) according to General Procedure 6. This procedure afforded 58 mg (72%) of the title compound as a sticky off-white foam. The compound was obtained as a 4:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.40 (d, J = 8.4 Hz, 2 H), 7.00–6.93 (m, 2 H), 6.93–6.86 (m, 2 H), 6.86–6.75 (m, 2 H), 4.38–4.30 (m, 1 H), 3.80 (s, 3 H), 3.76 (s, 3 H), 3.56–3.50 (m, 1 H), 3.49–3.42 (m, 1 H), 2.92–2.88 (m, 1 H), 2.71 (dd, J = 4.8, 13.8 Hz, 1 H), 2.10–2.03 (m, 1 H), 1.86–1.72 (m, 3 H), 1.72–1.64 (m 2 H), 1.56–1.39 (m, 3 H); ¹³C NMR (176 MHz, CDCl₃) δ 159.4, 158.3, 131.2, 130.5, 130.0, 129.1, 114.3, 113.9, 60.5, 57.1, 55.4, 55.2, 44.3, 39.4, 32.2, 31.9, 25.0, 22.0; IR (film) 1506.8, 1442.4, 1338.2, 1338.2 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₈N₂O₄S 417.1837; found 417.1843.

4.3.5.11. (±)-(3R*,4aR*)-2-(4-Methoxyphenyl)-3- (thiophen-2-ylmethyl)octahydropyrido[1,2b] [1,2,6] thiadiazine 1,1-dioxide 24g

A modified version of General Procedure 6 was employed for the coupling of substrate 23 (62 mg, 0.20 mmol) and 2- bromothiophene (40 μl, 0.41 mmol), using LiO^tBu (30 mg, 0.37 mmol), lithium trifluoromethanesulfonate (64 mg, 0.41 mmol), and a catalyst composed of Pd(OAc)₂ (2.3 mg, 0.010 mmol), and CPhos (8.4 mg, 0.019 mmol). The reaction was heated to 100 °C and stirred overnight or until the starting material was completely consumed as judged by ¹H NMR analysis. The mixture was cooled to room temperature and saturated aqueous NH₄Cl (5 mL/mmol substrate) and dichloromethane (5 mL/mmol substrate) were added. The layers were separated and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel. This procedure afforded 58 mg (74%) of the title compound as a sticky light brown foam. The compound was obtained as a 6:1 mixture of diastereomers as judged by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.40 (d, J = 8.5 Hz, 2 H), 7.19–7.13 (m, 1 H), 6.92–6.88 (m, 3 H), 6.76–6.73 (m, 1 H), 4.45–4.33 (m, 1 H), 3.80 (s, 3 H), 3.56–3.46 (m, 2 H), 3.01–2.89 (m, 2 H), 2.45 (dd, J = 9.5, 14.9 Hz, 1 H), 1.74–1.64 (m, 8 H); ¹³C NMR (176 MHz, CDCl₃) δ 159.5, 139.1, 131.1, 127.0, 126.9, 126.1, 124.3, 114.3, 60.4, 56.8, 55.4, 44.2, 34.3, 32.0, 31.7, 24.9, 21.6; IR (film) 1505.5, 1441.0, 1338.2, 1248.7 cm⁻¹. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₁₉H₂₄N₂O₃S₂ 393.1301; found 393.1302.

4.3.5.12. (±)-(Z,3S*,4aR*)-2-(4-Methoxyphenyl)-3- (pent-2-en-1-yl)octahydropyrido[1,2-b] [1,2,6] thiadiazine-1,1-dioxide 24h

A modified version of General Procedure 6 was employed for the coupling of 23 (62 mg, 0.2 mmol) and (Z)-1-bromobutene (400 μL, 0.8 mmol, 2.0 M solution in PhCF₃), using NaOtBu (96 mg, 1.0 mmol), LiOTf (156 mg, 1.0 mmol) and a catalyst composed of Pd(OAc)₂ (1.8 mg, 0.008 mmol), and CPhos (8.7 mg, 0.02 mmol). The reaction was heated to 100 °C and stirred overnight or until the starting material was completely consumed as judged by ¹H NMR analysis. The mixture was cooled to room temperature and saturated aqueous NH₄Cl (5 mL/mmol substrate) and dichloromethane (5 mL/mmol substrate) were added. The layers were separated and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel. This procedure afforded 60 mg (82%) of the title compound as a pale yellow oil and as a 5:1 mixture of diastereomers as determined by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (700 MHz, CDCl₃) δ 7.38 (d, J = 8.4 Hz, 2 H), 6.88 (d, J = 9.1 Hz, 2 H), 5.51–5.40 (m, 1 H), 5.25–5.19 (m, 1 H), 4.13–4.06 (m, 1 H), 3.80 (s, 3 H), 3.67–3.62 (m, 1 H), 3.49 (ddd, J = 3.7, 6.6, 10.8 Hz, 1 H), 2.99 (ddd, J = 3.5, 8.4, 11.7 Hz, 1 H), 2.04 (dt,J = 6.0, 13.8 Hz, 1 H), 1.92–1.66 (m, 8 H), 1.62–1.45 (m, 3 H), 0.88 (t, J = 7.5 Hz, 3 H); ¹³C NMR (175 MHz, CDCl₃) δ 159.3,134.7, 131.1, 130.0, 123.5, 114.2, 59.5, 56.7, 55.4, 44.1, 32.1, 31.7, 31.4, 24.9, 21.5, 20.7, 13.9; IR (film) 1506, 1339, 1248, 1159 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₁₉H₂₈N₂O₃S 365.1893; found365.1905.

4.3.6. Elaboration of products

4.3.6.1. (±)-(S*,R*)-1-Phenyl-3-(pyrrolidin-2- yl)propan-2-amine 25

The title compound was prepared via the following two-step one-pot procedure. The first step was carried out according to the published work by Snyder and Heckert.³³ A flask equipped with a stirbar and reflux condenser was charged with 24a (66 mg, 0.18 mmol). Hydrobromic acid (48%, 4 mL) was slowly added to the flask and the reaction was heated to 120 ^OC and stirred until the starting material had been completely consumed (ca. 2 h) as judged by MS ESI+ analysis (297.1 m/z, M + H⁺). The mixture was cooled to rt, CH₃CN (2 mL) was added, followed by a solution of ceric ammonium nitrate (494 mg, 0.9 mmol) in H₂O (2 mL) and then stirred overnight (ca. 8 hr) at rt. Dichloromethane (8 mL) was added to the solution, the mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was carefully basified with NH₄OH to pH > 12 and extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were washed with Na₂SO₃ (1 × 10 mL) and brine (1 × 10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This procedure afforded 27 mg (75%) of the title compound as a yellow brown oil and as a 7:1 mixture of diastereomers as determined by ¹H NMR analysis. Data are for the major isomer. ¹H NMR (500 MHz, CDCl₃) δ 7.30 (t, J = 8.0 Hz, 2 H), 7.22 (t, J = 8.0 Hz, 1 H), 7.17 (d, J = 7.5 Hz, 2 H), 3.37–3.33 (m, 1 H), 3.15–3.12 (m, 1 H), 3.06–2.97 (m, 2 H), 2.86 (s, br, 3 H), 2.79 (dd, J = 4.9, 13.3 Hz, 1 H), 2.54 (dd, J = 8.2, 13.3 Hz, 1 H), 2.02–1.97 (m, 1 H), 1.83–1.77 (m, 2 H), 1.70–1.66 (m, 1 H), 1.48–1.43 (m, 1 H), 1.37–1.32 (m, 1 H); ¹³C NMR (175 MHz, CDCl₃) δ 138.7, 129.3, 128.5, 126.4, 58.5, 52.4, 45.8, 45.7, 41.7, 32.1, 24.6; IR (film) 3360, 2929 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₁₃H₂₀N₂ 205.1699; found 205.1700.

4.3.6.2. (±)-(3R,4aR)-3- Pentylhexahydropyrrolo[1,2-c] pyrimidin-1(2H)-one 26

A flame-dried flask was cooled under vacuum and charged with 10% Pd/C (120 mg). The flask was capped with a rubber septum, evacuated and backfilled with nitrogen. A solution of 4f (66 mg, 0.2 mmol) in methanol (8 mL) was added to the flask via a syringe, followed by acetic acid (0.2 mL). The flask was briefly flushed with hydrogen and then a hydrogen-filled balloon attached to a needle (via an adaptor) was connected to the flask through the septum. The mixture was placed in an oil bath at 50 °C and the reaction was stirred overnight (ca. 16 h). The crude material was then filtered through a plug of celite to remove the Pd/C and washed with methanol (5 mL). The crude material was concentrated in vacuo and purified by flash chromatography on silica gel to afford 38.5 mg (92%) of the title compound as a pale yellow solid: mp = 63–66 °C. ¹H NMR (700 MHz, CDCl₃) δ 4.79 (s, br, 1 H), 3.54–3.44 (m, 3 H), 3.39–3.32 (m, 1 H), 2.15–2.08 (m, 1 H), 1.97–1.92 (m, 2 H), 1.80–1.74 (m, 2 H), 1.54–1.25 (m, 9 H), 0.88 (t, J = 7.0 Hz, 3 H); ¹³C NMR (175 MHz, CDCl₃) δ 155.3, 52.3, 50.0, 45.3, 36.8, 33.6, 32.2, 31.6, 25.7, 23.0, 22.6, 14.0; IR (film) 3214, 1650 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₁₂H₂₂N₂O 211.1805; found 211.1812.

4.3.6.3. (±)-(Z,R,R)-N-(4-Methoxybenzyl)-1- (pyrrolidin-2-yl)hept-4-en-2-amine 27

This compound was prepared via a modification of a published procedure by Trost.³⁴ A flame-dried flask was cooled under vacuum and charged with LAH (190 mg, 5.0 mmol). A reflux condenser was attached to the flask and the apparatus was evacuated and backfilled with nitrogen. Diethyl ether (4 mL) was added, followed by a solution of 4i (66 mg, 0.2 mmol) in diethyl ether (4 mL). The flask was placed in an oil bath and allowed to reflux overnight (ca. 16 h). The reaction flask was allowed to cool to rt and then the mixture was diluted with ether (10 mL). The reaction flask was placed in an ice bath and quenched slowly with water (2 mL). 1M NaOH (2 mL) was added, followed by more water (2 mL) and the biphasic mixture was stirred vigorously for 15 min. The mixture was decanted, dried with Na₂SO₄, and concentrated in vacuo. The crude product appeared to by clean by ¹H NMR and taken unto the next step without further purification. A round bottom flask, equipped with a stirbar was charged with the crude product and aqueous 0.01% HCl (10 mL). H₂NOH•HCl (69 mg, 1.0 mmol) was added and the reaction mixture was heated to 60 °C in an oil bath and stirred until the starting material had been consumed as judged by ESI⁺ MS analysis (ca. 60 min). The reaction was cooled to rt and aqueous 1M HCl (20 mL) was added. The solution was then washed with CHCl₃ (2 × 20 mL) and then the aqueous layer was carefully basified with Na₂CO₃ and extracted with CHCl₃ (3 × 20 mL). The combined organic layers were dried with Na₂SO₄ and concentrated in vacuo to afford 35 mg (57%) of the title compound as a pale yellow oil. ¹H NMR (700 MHz, CDCl₃) δ 7.22 (d, J = 8.2 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 5.52–5.46 (m, 1 H), 5.33–5.30 (m, 1 H), 3.79 (s, 3 H), 3.75 (d, J = 12.8 Hz, 1 H), 3.69 (d, J = 12.8 Hz, 1 H), 3.17 (s, br, 1 H), 2.97–2.94 (m, 1 H), 2.85–2.80 (m, 1 H), 2.75–2.71 (m, 1 H), 2.28 (dt, J = 6.7, 13.9 Hz, 1 H), 2.22 (dt, J = 6.7, 14.1 Hz, 1 H), 2.1–2.06 (m, 2 H), 1.85 (td, J = 7.3, 12.6 Hz, 1 H), 1.73–1.66 (m, 2 H), 1.63–1.51 (m, 2 H), 1.25 (m, 1 H), 0.95 (t, J = 7.6 Hz, 3 H); ¹³C NMR (175 MHz, CDCl₃) δ 158.6, 134.3, 129.3, 125.2, 113.8, 56.3, 55.3, 54.9, 50.5, 46.2, 39.8, 31.9, 31.8, 25.1, 20.8, 14.3 (one carbon signal is absent due to incidental equivalence); IR (film) 3002, 1611, 1511, 1246 cm^–1. HRMS (ESI⁺ TOF) m/z: [M + H]⁺ calcd for C₁₉H₃₀N₂O 303.2431; found 303.2427.