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Regiodivergent palladium-catalyzed alkene difunctionalization reactions between diethyl malonate and 1,5-dienes bearing a triflate group at C2 are described. Use of tris(2,4-di

This article describes continued studies on Pd-catalyzed alkene diamination reactions between N-allylguanidines or ureas and O-benzoylhydroxylamine derivatives, which serve as N-centered electrophiles. The transformations generate cyclic guanidines and ureas bearing dialkylaminomethyl groups in moderate to good yield. We describe new mechanistic experiments that have led to a revised mechanistic hypothesis that involves a key oxidative addition of the electrophile to a PdII complex, followed by reductive elimination from PdIV to form the alkyl carbon-nitrogen bond. In addition, we demonstrate that acac, not phosphine, serves as a key ligand for palladium. Moreover, simple acac derivatives bearing substituted aryl groups outperform acac in the catalytic reactions, and phosphines inhibit catalysis in many cases. These discoveries have led to a significant expansion in the scope of this chemistry, which now allows for the coupling of a variety of cyclic amines, acyclic secondary amines, and primary amines. In addition, we also demonstrate that these new conditions allow for the use of amide nucleophiles, in addition to guanidines and ureas.

This article describes continued studies on Pd-catalyzed alkene diamination reactions between N-allylguanidines or ureas and O-benzoylhydroxylamine derivatives, which serve as N-centered electrophiles. The transformations generate cyclic guanidines and ureas bearing dialkylaminomethyl groups in moderate to good yield. We describe new mechanistic experiments that have led to a revised mechanistic hypothesis that involves a key oxidative addition of the electrophile to a Pd(II) complex, followed by reductive elimination from Pd(IV) to form the alkyl carbon-nitrogen bond. In addition, we demonstrate that acac, not a phosphine, serves as a key ligand for palladium. Moreover, simple acac derivatives bearing substituted aryl groups outperform acac in the catalytic reactions, and phosphines inhibit catalysis in many cases. These discoveries have led to a significant expansion in the scope of this chemistry, which now allows for the coupling of a variety of cyclic amines, acyclic secondary amines, and primary amines. In addition, we also demonstrate these new conditions allow for the use of amide nucleophiles, in addition to guanidines and ureas.

Palladium-catalyzed alkene difunctionalization reactions between alkenes bearing tethered aryl or alkenyl triflates and enolate nucleophiles are described. The transformations form two C–C bonds, a ring, and up to two stereocenters, while producing substituted cyclopentane derivatives that contain appended carbonyl functionality. Products are formed with up to >20:1 diastereoselectivity, and formation of sterically congested bonds between quaternary carbon atoms is feasible.

The Pd-catalyzed coupling of malonate nucleophiles with alkenes bearing tethered aryl or alkenyl triflates is described. These alkene difunctionalization reactions afford malonate-substituted cyclopentanes that contain fused aryl or cycloalkenyl rings. The transformations generate a five-membered ring, two C-C bonds, and provide products bearing up to three stereocenters with good chemical yield and generally high diastereoselectivity.

Over the past few years our group has described a new type of alkene difunctionalization reaction in which aryl or alkenyl triflates bearing tethered alkenes are coupled with various nucleophiles to afford carbocyclic products. The products are formed in moderate to good chemical yield, with generally high levels of stereoselectivity. Our progress to date in this area, which includes reactions of amine, alcohol, enolate, and indole nucleophiles, is described in this review.

The synthesis of cyclic and bicyclic ureas via a ruthenium-catalyzed cross-metathesis / aza-Michael reaction strategy between protected alkenyl ureas and Michael acceptors is described. The substrates for these reactions are generated in 1–3 steps from commercially available materials, and products are formed in moderate yield with up to >20:1 diastereoselectivity.

The Pd-catalyzed coupling of N-allylguanidines or N-allylureas with O-benzoylhydroxylamine derivatives affords cyclic guanidines or cyclic ureas bearing dialkylaminomethyl groups. The desired products are obtained in good yield, and substrates bearing substituents at the allylic position are transformed with moderate diastereoselectivity. The mechanism of these reactions appears to involve anti-aminopalladation of the alkene, followed by a rare sp(3)C–sp(3)N bond-forming reductive elimination from an alkylpalladium complex that contains β-hydrogen atoms.

The asymmetric synthesis of six-membered cyclic sulfamides via palladium-catalyzed alkene carboamination reactions of N-homo­allylsulfamides with aryl halides is described. High levels of enantio­selectivity were obtained with a catalyst composed of Pd2dba3 and (S)-Siphos-PE.

An introductory general chemistry laboratory course was developed to provide an authentic research experience in environmental chemistry. First- and second-year students learned general chemistry concepts and laboratory skills in the context of snow chemistry while participating in the course-based undergraduate research experience. Students were guided through all steps of the research process, including research question development, data collection and processing, interpretation of results in the context of scientific literature, and both written and oral presentations. A key component of the course was an individual laboratory experiment in which snow samples from the Arctic were analyzed for pH and ion content. Assessment of the course via pre- and postcourse surveys indicated that students, the majority of whom were women, experienced greater gains in confidence of research skills and general attitudes toward chemistry as compared to the traditional general chemistry laboratory course. This course r...

Intermolecular alkene difunctionalization reactions between terminal alkenes bearing a pendant aryl or alkenyl triflate electrophile and exogenous alcohol or phenol nucleophiles are described. These transformations afford substituted indanyl or alkylidenecyclopentyl ethers in high yield with excellent diastereoselectivity. The transformations proceed through intermolecular capture of an intermediate [Pd(II)-alkene]+[OTf]− complex by the alcohol or phenol nucleophile.

The synthesis of substituted γ- and δ-lactams via palladium-catalyzed alkene carboamination reactions between aryl halides and alkenes bearing pendant amides is described. The substrates for these reactions are generated in 1–3 steps from commercially available materials, and products are obtained in good yield with up to >20:1 diastereoselectivity. The stereochemical outcome of the alkene addition is consistent with a mechanism involving anti-aminopalladation of the alkene.

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.

The Pd-catalyzed alkene carboheteroarylation of aryl and alkenyl triflate electrophiles bearing pendant alkenes with heteroaromatic nucleophiles affords substituted carbocycles with 3-indolyl or 3-pyrrolyl groups. The products are obtained in moderate to good yields, and the use of alkenyl triflate substrates produces products with high diastereoselectivities. The transformation is believed to proceed via a Friedel-Crafts-like reaction between the heteroaromatic nucleophile and an intermediate electrophilic palladium complex.

A new type of Pd-catalyzed alkene carboamination reaction that provides direct access to enantioenriched 2-aminoindanes from 2-allylphenyltriflate derivatives and aliphatic amines is described. A catalyst generated in situ from Pd(OAc)2 and (S)-tert-ButylPHOX provides the functionalized carbocycles in good yield with up to >99:1 er. The transformations occur via a key anti-aminopalladation that involves intermolecular attack of an amine nucleophile on an arylpalladium alkene complex.

Modified reaction conditions that facilitate Pd-catalyzed alkene carboamination reactions of electron-deficient nitrogen nucleophiles are reported. Pent-4-enylamine derivatives bearing N-tosyl or N-trifluoroacetyl groups are coupled with aryl triflates to afford substituted pyrrolidines in good yield. These reactions proceed via a mechanism involving anti-aminopalladation of the alkene, which differs from previously reported analogous reactions of N-aryl and N-boc pentenylamines. The application of these conditions to a formal synthesis of (±)-aphanorphine is also described.

This review summarizes recent developments in palladium-catalyzed alkene carboalkoxylation and carboamination reactions. New synthetic methods that have been reported in the past four years are described, along with mechanistic issues and the influence of mechanism on product stereochemistry. The applications of these transformations to the synthesis of natural products and other biologically relevant compounds are also discussed.

Palladium-catalyzed carboamination reactions of N-allylguanidines bearing cleavable N-cyano or N-arylsulfonyl protecting groups are described. The reactions afford cyclic guanidine products in good yield, and transformations of substrates bearing internal alkenes proceed with high diastereoselectivity. Deuterium labeling studies indicate these transformations proceed via anti-aminopalladation pathways.

Heating, ventilation, and air conditioning (HVAC) systems in commercial buildings can provide ancillary services (AS) to the power grid, but by providing AS their energy consumption may increase. This inefficiency is evaluated using round-trip efficiency (RTE), which is defined as the ratio between the decrease and the increase in the HVAC system's energy consumption compared to the baseline consumption as a result of providing AS. This paper evaluates the RTE of a 30,000 m2 commercial building providing AS. We propose two methods to estimate the HVAC system's settling time after an AS event based on temperature and the air flow measurements from the building. Experimental data gathered over a 4-month period are used to calculate the RTE for AS signals of various waveforms, magnitudes, durations, and polarities. The results indicate that the settling time estimation algorithm based on the air flow measurements obtains more accurate results compared to the temperature-based algorithm. Further, we study the impact of the AS signal shape parameters on the RTE and discuss the practical implications of our findings.

Amino-substituted alkylidenecyclopentanes were synthesized through a stereoselective intermolecular Pd-catalyzed alkene carboamination reaction between alkenyl triflates bearing a pendant alkene and exogenous amine nucleophiles. The reactions are effective with a range of different substrate combinations, and proceed with generally high diastereoselectivity. Use of (S)-tBuPhox as the ligand in reactions of achiral substrates provides enantioenriched products with up to 98.5:1.5 e.r.

Intramolecular Pd-catalyzed alkene carboamination reactions of substituted 2-allyl-N-(2-bromobenzyl)anilines are described. The substrates for these reactions are generated in two steps from readily available 2-allylanilines and 2-bromobenzaldehyde derivatives. The transformations afford substituted tetrahydroindoloisoquinolines, an uncommon class of fused bicyclic heterocycles, in good yield. The mechanism of these transformations is described, and a model that accounts for the observed product stereochemistry is proposed.

A catalyst composed of Pd2(dba)3 and (S)-Siphos-PE provides excellent results in Pd-catalyzed alkene carboamination reactions between aniline derivatives bearing pendant alkenes and aryl or alkenyl halides. These transformations generate tetrahydroquinolines and tetrahydroquinoxalines that contain quaternary carbon stereocenters with high levels of asymmetric induction. In addition this catalyst also effects the asymmetric synthesis of tetrahydroisoquinolines via related transformations of 2-allylbenzylamines. In contrast to most other approaches to the asymmetric synthesis of these compounds, which frequently involve functional group interconversion or a single C–C or C–N bond-forming event, the carboamination reactions generate both a C–N bond, a C–C bond, and a stereocenter.

The Pd-catalyzed coupling of γ-hydroxyalkenes with aryl bromides affords enantiomerically enriched 2-(arylmethyl)tetrahydrofuran derivatives in good yield and up to 96:4 e.r. This transformation was achieved through the development of a new TADDOL/2-arylcyclohexanol-derived chiral phosphite ligand. The transformations are effective with an array of different aryl bromides, and can be used for the preparation of products bearing quaternary stereocenters.

Treatment of N-(arylmethyl)-N-aryl glycine methyl ester derivatives with Bu2BOTf and iPr2NEt effects an aza-[1,2]-Wittig rearrangement that provides N-aryl phenylalanine methyl esters in good yields. Analogous substrates bearing N-carbonyl groups are converted to 1,4,2-oxazaborole derivatives under similar conditions.

A new approach to the synthesis of substituted 5-membered cyclic guanidines is described. Palladium-catalyzed alkene carboamination reactions between acyclic N-allyl guanidines and aryl or alkenyl halides provide these products in good yield. This method allows access to a number of different cyclic guanidine derivatives in only two steps from readily available allylic amines.

Catalytic asymmetric desymmetrization reactions are powerful and efficient tools for the synthesis of chiral molecules.[i] These transformations convert simple achiral substrates into complex enantioenriched products through the differentiation of two enantiotopic groups, and can generate complex structures bearing multiple stereocenters in a highly controlled fashion. As such, the development of asymmetric desymmetrization reactions that allow for the construction of important structural motifs is of considerable utility. Tricyclic guanidines are an interesting class of compounds that could potentially be accessed via catalytic asymmetric desymmetrization reactions (Figure 1). These scaffolds are displayed in a wide variety of biologically active natural products,[ii] including the batzelladine alkaloids[iii] (e.g. batzelladine K, 1),[iiic] the merobatzelladine alkaloids (e.g., merobatzelladine B, 2),[iv] and the crambescidin alkaloids[v] (e.g., crambescidin 359, 3).[vb] Many synthetic routes to these compounds involve the generation of a fused-bicyclic urea or guanidine derivative (e.g., 4), which is then transformed to the tricyclic guanidine in subsequent steps.[vi,vii,viii] As such, development of a concise asymmetric synthesis of 4 could provide access to a broad array of interesting alkaloids. Figure 1 Bioactive guanidine alkaloids prepared from bicyclic urea precursors We recently reported an asymmetric synthesis of the tricyclic guanidine natural product (+)-merobatzelladine B (2), which featured a new strategy for the construction of bicyclic ureas and polycyclic guanidines via Pd-catalyzed carboamination reactions of enantiomerically enriched 2-allylpyrrolidine-1-carboxamide derivatives 5 (Scheme 1).[viii] These reactions provided bicyclic urea products 6 in good yield with excellent diastereoselectivity, but control of absolute stereochemistry required the chiral-auxiliary mediated introduction of the C2 stereocenter during the fairly lengthy asymmetric synthesis of 5 (7–9 steps).[ix] Scheme 1 Synthesis of bicyclic ureas via Pd-catalyzed asymmetric desymmetrization A potentially more attractive route to enantiomerically enriched bicyclic ureas and related bi- and tricyclic guanidines would involve the asymmetric Pd-catalyzed desymmetrization of meso-2,5-diallylpyrrolidnyl urea 7. This approach would allow for facile introduction of different R1-substituents, and the alkene present in product 8 provides a convenient handle for further elaboration to tricyclic guanidine products or more highly substituted urea derivatives. In addition, the meso substrate 7 can be prepared in only four steps. Our preliminary studies in this area are described in this communication. These transformations represent the first examples of asymmetric desymmetrizations of bis-alkene substrates in intermolecular Pd-catalyzed alkene carboamination reactions, and also the first examples of six-membered ring formation in an asymmetric Pd-catalyzed alkene carboamination.[x,xi,xii] In initial experiments we elected to employ a catalyst composed of Pd2(dba)3/(S)-Siphos-PE[xiii] for desymmetrization reactions of 7, as we previously illustrated this complex provides good results in related asymmetric carboamination reactions of simple N-allyl urea derivatives.[xiv,xv] We decided to first optimize the structure of the urea N-aryl group, as prior studies in our lab suggested this group may have a significant influence on the level of asymmetric induction.[xiv] Thus, we explored the coupling of Z-1-bromobutene[xvi] with ureas 7 bearing different N-aryl substituents. As shown in Table 1, the use of electron-poor p-cyanophenyl or p-nitrophenyl N-aryl groups resulted in the formation of products 8 with the highest levels of both diastereoselectivity and enantioselectivity. However, these electron-poor substrates were transformed in modest chemical yield due to competing cleavage of the urea moiety (entries 5–6). Use of the electron-rich p-methoxyphenyl group led to improved yields but with lower levels of stereocontrol. After some exploration we found that a substrate bearing a p-chlorophenyl group was transformed to the desired product with both good chemical yield and stereoselectivity (entry 3).[xvii] Table 1 N-Aryl group effects.[a] As shown in Table 2, the asymmetric desymmetrization reactions of 7c are effective with a number of different alkenyl and aryl bromide electrophiles. The main side products generated in these reactions were cis-2,5-diallylpyrrolidine (resulting from competing urea cleavage) and an unsaturated bicyclic urea that is generated by competing β-hydride elimination of an intermediate alkylpalladium complex.[xviii] In the reaction of 7c with E-1-bromohexene a regioisomeric side product bearing a 2-hex-1-enyl group was also generated.[xix] Table 2 Reaction Scope.[a] The best enantioselectivities were obtained when either alkenyl bromides, electron-rich aryl bromides, or electron-neutral aryl bromides were employed as substrates. Diastereoselectivities were generally higher with the alkenyl electrophiles than with aryl electrophiles. Use of sterically hindered aryl bromides (entries 14–15) or electron-poor aryl bromides (entries 9, 11, and 13) led to lower diastereo- and enantioselectivities. Selectivities improved when NaOMe was used in place of NaOtBu in reactions of electron-poor aryl bromides (entries 10 and 12), although yields decreased in these cases. To further demonstrate the utility of the asymmetric desymmetrization reactions, we examined the deprotection of 8c and the conversion of 8c to tricyclic guanidine derivatives. As shown in equation 1, cleavage of the N-p-chlorophenyl group can be accomplished via Pd-catalyzed N-arylation with acetamide[xx, xxi] followed by oxidation of the resulting N-aryl amide with ceric ammonium nitrate. This sequence afforded 9 in 65% yield over two steps. (1) The conversion of 8c to tricyclic guanidine 12 was carried out as shown in Scheme 2. Treatment of 8c with POCl3 followed by NH3 provided bicyclic guanidine 10 in 78% yield. Wacker oxidation of 10 afforded hemiaminal 11, which was then transformed to tricyclic product 12 in 70% yield with 5:1 dr via reductive amination with NaBH3CN.[xxii] Overall, the synthesis of 12, which is structurally related to the batzelladine and merobatzelladine alkaloids, was accomplished in 5 steps and 41% yield from meso-2,5-diallylpyrrolidinyl urea 7c. In addition, this is the first example of a Wacker oxidation/ring-closure sequence to generate a tricyclic guanidine.[xxiii,xxiv] Scheme 2 Conversion of 8c to a tricyclic guanidine derivative Finally, 8c was converted to tricyclic guanidine 16, which is an unnatural stereoisomer of batzelladine k,[xxv,xxvi] as shown in Scheme 3. To avoid problems with base-mediated epimerization of the C4 stereocenter, the Pd-catalyzed N-arylation with acetamide was carried out prior to Wacker oxidation of the alkene. This two-step sequence provided 13 in 65% yield. Reduction of the alkene followed by CAN deprotection generated urea 14, which was converted to guanidine aminal 15 by O-methylation and treatment with ammonia.[xxvii] The reduction of 15 proceeded with modest diastereoselectivity (3:1 dr), but upon purification 9-epi-batzelladine k was isolated as a single stereoisomer in 48% yield over three steps from 14. Scheme 3 Conversion of 8c to 9-epi-batzelladine K. In conclusion we have developed a concise route to enantiomerically enriched bicyclic ureas via Pd-catalyzed desymmetrizing carboamination reactions of meso-diallylpyrroldinyl ureas. These transformations effect formation of both a C–N and a C–C bond, and provide products bearing three stereocenters with good levels of diasteroselectivity and enantioselectivity. These reactions illustrate the potential utility of asymmetric Pd-catalyzed alkene carboamination for desymmetrization processes and provide synthetically valuable products in a straightforward manner. Further exploration of enantioselective Pd-catalyzed alkene difunctionalization reactions are currently underway.

The silver-catalyzed hydroamination of tosyl-protected N-allylguanidines is described. These reactions provide substituted cyclic guanidines in high yields. The reactions are amenable to the construction of quaternary stereocenters as well as both monocyclic and bicyclic guanidine products.

A new Pd-catalyzed alkene carboalkoxylation strategy for the preparation of 2,3-dihydrobenzofurans is described. This method effects the coupling of readily available 2-allylphenol derivatives with aryl triflates to generate a wide range of functionalized 2,3-dihydrobenzofurans in good yields and diastereoselectivities (up to >20:1). Use of newly developed reaction conditions that promote anti-heteropalladation of the alkene is essential in order to generate products in high yield.

The synthesis of cyclic sulfamides by enantioselective Pd-catalyzed alkene carboamination reactions between N-allylsulfamides and aryl or alkenyl bromides is described. High levels of asymmetric induction (up to 95:5 e.r.) are achieved using a catalyst composed of [Pd2 (dba)3 ] and (S)-Siphos-PE. Deuterium-labelling studies indicate the reactions proceed through syn-aminopalladation of the alkene and suggest that the control of syn- versus anti-aminopalladation pathways is important for asymmetric induction.

The silver-catalyzed hydroamination of tosyl-protected N-allylguanidines is described. These reactions provide substituted cyclic guanidines in high yields. The reactions are amenable to the construction of quaternary stereocenters as well as both monocyclic and bicyclic guanidine products.

The synthesis of cyclic sulfamides by enantioselective Pd-catalyzed alkene carboamination reactions between N-allylsulfamides and aryl or alkenyl bromides is described. High levels of asymmetric induction (up to 95:5 e.r.) are achieved using a catalyst composed of [Pd2 (dba)3 ] and (S)-Siphos-PE. Deuterium-labelling studies indicate the reactions proceed through syn-aminopalladation of the alkene and suggest that the control of syn- versus anti-aminopalladation pathways is important for asymmetric induction.

A new class of alkene carboamination reaction is developed which gives access to the title compound via a key anti-aminopalladation step.

The Pd-catalyzed coupling of γ-hydroxyalkenes with aryl bromides affords enantiomerically enriched 2-(arylmethyl)tetrahydrofuran derivatives in good yield and up to 96:4 e.r. This transformation was achieved through the development of a new TADDOL/2-arylcyclohexanol-derived chiral phosphite ligand. The transformations are effective with an array of different aryl bromides, and can be used for the preparation of products bearing quaternary stereocenters.

A new aza-[1,2]-Wittig rearrangement of N-aryl-N-benzyl glycine methyl esters involving a rare benzyl group migration is developed.

A new gold(I)-catalyzed multicomponent synthesis of β-alkoxy ketones from aldehydes, alcohols, and alkynes is described. This atom economical synthesis was achieved through the use of the gold complex (SPhos)AuNTf2 as a catalyst, and allows for the preparation of a diverse array of β-alkoxy ketone products. Mechanistic studies illustrate that these reactions proceed via gold(I)-catalyzed hydrolysis of the alkyne to an aryl ketone, which then undergoes an aldol reaction with an oxocarbenium ion generated in situ from the aldehyde and alcohol components.

Positive water effect: A catalyst composed of [Pd(2)(dba)(3)] (dba=dibenzylideneacetone) and (S)-Siphos-PE is effective for the enantioselective coupling of N-allyl ureas with aryl bromides to afford 4-substituted imidazolidin-2-ones. Added water leads to significantly improved enantioselectivities with electron-poor aryl halide substrates. It is suggested that the C-C bond-forming reductive elimination is the enantiodetermining step in these reactions.

The synthesis of tropane derivatives via intramolecular Pd-catalyzed alkene difunctionalization reactions is described. Enantiopure N-aryl-γ-aminoalkenes bearing an aryl or alkenyl halide adjacent to the amino group were converted to benzo- or cycloalkenyl-fused tropane products in good yield and with no loss of enantiopurity.