Stereoselective 1,3-Insertions of Rhodium(II) Azavinyl Carbenes

NIH Public Access Author Manuscript J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. NIH-PA Author Manuscript Published in final edited form as: J Am Chem Soc. 2014 January 8; 136(1): 195–202. doi:10.1021/ja408185c. Stereoselective 1,3-Insertions of Rhodium(II) Azavinyl Carbenes Stepan Chuprakov, Brady T. Worrell, Nicklas Selander, Rakesh K. Sit, and Valery V. Fokin* Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA Abstract NIH-PA Author Manuscript Rhodium(II) azavinyl carbenes, conveniently generated from 1-sulfonyl-1,2,3-triazoles, undergo a facile, mild and convergent formal 1,3-insertion into N–H and O–H bonds of primary and secondary amides, various alcohols, and carboxylic acids to afford a wide range of vicinally bisfunctionalized Z-olefins with perfect regio- and stereoselectively. Utilizing the distinctive functionality installed through these reactions, a number of subsequent rearrangements and cyclizations expand the repertoire of valuable organic building blocks constructed by reactions of transition metal carbene complexes, including α-allenyl ketones and amino-substituted heterocycles. INTRODUCTION Transition metal-catalyzed reactions of diazo compounds are powerful methods for the formation of carbon-carbon and carbon-heteroatom bonds via additions and insertions of highly reactive metal-carbene intermediates.1 Thus, rhodium(II) and copper(I) carbenes derived from α-diazocarbonyl compounds readily undergo 1,1-insertion into N–H2 and O– H3 bonds to afford easy access to α-amino or α-oxy derivatives of ketones and esters (eq 1). NIH-PA Author Manuscript Certain electron-deficient 1,2,3-triazoles have recently emerged as convenient progenitors of diazo species.4 Generally stable, crystalline compounds, they are easily prepared under mild copper(I)-catalyzed conditions from the corresponding sulfonyl azides and terminal alkynes (eq 2).5 1-Sulfonyltriazoles 1 exist in equilibrium with their diazoimine tautomers 1’,6 which can be efficiently intercepted by transition metal catalysts to give rise to highly reactive rhodium(II) azavinyl carbenes 2 (eq 3). Although these intermediates share many features with the well-known donor-acceptor carbenes obtained from diazo carbonyl compounds (eq 1),7 the aforementioned equilibrium and the presence of the aldimine group significantly alter their reactivity. The ring-chain tautomerism, which normally favors the ring structure 1, slowly feeds the diazo imine species in the reaction, thus obviating controlled addition requirements and simplifying experimental setup. The pendant imine group allows finetuning of steric and electronic properties of carbene 2.8 Its reactivity can be further Corresponding Author. [email protected]. ASSOCIATED CONTENT Supporting Information. Full experimental procedures, characterization data, NMR spectra, and crystallographic data. This material is available free of charge via the Internet at http://pubs.acs.org The authors declare no competing financial interest. Chuprakov et al. Page 2 NIH-PA Author Manuscript exploited, for example in subsequent cyclizations, expanding the repertoire of molecular architectures available from diazo compounds. Recent additions to the rapidly growing list of applications of 1-sulfonyl-1,2,3-triazoles under Rh(II) catalysis include transannulations and cyclopropanations,9 C–H insertion,10 ketone formation with water and O–H insertions/ rearrangements,11 ring expansions,8,12 rearrangement reactions,12a and arylation with boronic acids.13 Given the efficiency of both the Cu(I)-catalyzed formation of triazole 15 and its subsequent Rh(II)-catalyzed denitrogenative reactions,8–13 this sequence of simple transformations can be viewed as a two-step regio- and stereoselective bis-functionalization of the acetylenic backbone. (1) NIH-PA Author Manuscript (2) (3) NIH-PA Author Manuscript (4) We have recently reported a highly efficient insertion of Rh(II) azavinyl carbenes 2 into the C–H bonds of unactivated alkanes (eq 3).10a This 1,1-insertion likely proceeds via a direct hydride abstraction involving a three-membered transition state.10b In contrast, due to the polarized nature of N–H and O–H bonds, we expected that they would react with azavinyl carbene 2 through a different insertion pathway.1 For example, it has previously been proposed that insertion of rhodium carbenes derived from diazo ketones or esters into O–H J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 3 NIH-PA Author Manuscript bonds may proceed via the formation of an ylide intermediate, followed by intra- or intermolecular proton abstraction, resulting in the overall 1,1-insertion (eq 1). As evidenced by previous work, products derived from azavinyl carbenes 2 are often isolated in the stable enamide tautomeric form, as opposed to the sulfonyl imine derivative.11–13 We envisioned that the related insertion of carbene 2 into O–H and N–H bonds could operate via two distinct mechanistic pathways (eq 4): i. a direct 1,1-insertion followed by tautomerization, which could lead to an isomeric mixture of enamide products (path a); or ii. The formation of an ylide intermediate 3, followed by a stereospecific proton transfer (via a presumed hydrogen bond-stabilized five-membered transition state) that could result in the synselective formation of enamide products (path b, eq 4). Herein, we report a modular and mild formal 1,3-insertion reaction of rhodium(II) azavinyl carbenes with various N–H and O–H-containing reactants yielding highly functionalized enamide products as single geometrical isomers. We propose that this insertion reaction operates through the ylidemediated mechanism (path b, eq 4), consistent with the high Z-selectivity observed in this process. RESULTS AND DISCUSSION NIH-PA Author Manuscript N–H insertions with primary amides The distinct reactivity of rhodium(II) azavinyl carbenes 2 towards N–H bonds was first observed when 1-mesyl triazole 1a was allowed to react with 2 equivalents of methyl carbamate 4a in the presence of 1 mol% Rh(II) octanoate dimer at 65°C (Table 1, entry 1). Direct α-amination (1,1-insertion), similar to that previously reported for diazoesters reacting with carbamates,2 was not observed in the N–H insertion with azavinyl carbenes 2. Instead, diamine 5a was rapidly formed in high yield as a single regio- and stereoisomer. The identity of this product was established by single crystal X-ray analysis, confirming the Z-geometry of the double bond (Figure 1).14 NIH-PA Author Manuscript Optimization of the reaction conditions revealed that the amount of carbamate 4a could be reduced to only 1.1 equiv (Table 1, entry 2) and the use of different organic solvents (toluene or 1,2-DCE) was not beneficial (Table 1, entries 3–4). Additionally, it was observed that rhodium(II) acetate gave comparable results to the more soluble rhodium(II) octanoate catalyst (Table 1, entry 5), however, the latter proved to be a superior catalyst when used in a larger scale reactions (Table 1, entries 6–7). With optimized conditions in hand (Table 1, entry 7), we examined the scope of this N–H insertion reaction.15 Variously substituted 1-sulfonyl-1,2,3-triazoles 1 reacted smoothly with an array of primary amides 4 leading to the substituted Z-enamides 5 with complete stereoselectivity (Table 2). Varying the electronic or steric nature of the sulfonyl group at N-1 of triazole 1 did not greatly affect the efficiency of this reaction. Accordingly, aliphatic and aromatic sulfonyl groups as well as sulfamoyl derivatives were tolerated in this reaction, giving excellent yields of products 5a–d (84%–95%, Table 2). As Table 2 illustrates, a number of carbamates were effective in the formal 1,3-insertion with triazole 1, including halosubstituted and bulky t-butyl variants of 4, which gave superb J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 4 NIH-PA Author Manuscript yields of the corresponding products 5e and 5f, respectively (96% and 93%). Additionally, alkyl, alkenyl and aryl amides 4 readily afforded the desired products 5g–5i in good yields, while a number of functional groups were tolerated in this reaction (e.g. nitrile and nitro groups). The efficiency of this transformation was not significantly affected by the nature of the C-4 aryl group in triazole 1. Thus, the substrates with electron-rich, electron-deficient or heterocyclic groups gave comparable yields of the corresponding diamine products (5j–m, Table 2). Moreover, sulfonamides were also found to undergo facile N–H insertion to afford the expected 1,2-bissulfonamide products 5n–5r in good yields. Remarkably, the structurally complex Celecoxib analog was shown to furnish the desired N–H insertion product 5p in excellent yield (91%), despite bearing a pendent basic nitrogen atom. NIH-PA Author Manuscript The lack of information on these diamine products in the literature16 prompted further investigation of their reactivity. In the course of our studies, we noted that these compounds were extremely configurationally stable: no isomerization of the double bond was noted even under forcing conditions. Furthermore, the configuration of the double bond remained intact even upon liberation of one of the amino groups: the Bocgroup in diamine 5f could be efficiently removed using standard deprotection treatment with TFA (eq 5). The deprotected amine could be isolated as a single isomer in excellent yield as the trifluoroacetate salt 6, which could further undergo hydrogenation, yielding the saturated diamine salt 7 in similarly good yield (eq 5). (5) (6) NIH-PA Author Manuscript In addition, we found that the catalytic hydrogenation of the enamide products 5 could be coupled with N–H insertion in an efficient and operationally simple one-pot procedure to deliver the saturated diamine 8 in excellent yield (eq 6). This sequential procedure constitutes a simple route to vicinal diamines, which are valuable organic building blocks and common structural motifs found in many biologically active natural products, pharmaceuticals, and chiral ligands.17 N–H insertions with secondary amides Having identified an efficient route to diamine products 5 from primary amides 4 and triazoles 1, we were naturally interested in exploring the reactivity of azavinyl carbenes with secondary amides. When compared to the unsubstituted congeners, secondary amides are J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 5 NIH-PA Author Manuscript more challenging substrates for N–H insertion reactions due to only one active N–H bond and the increased steric demands. In the conventional carbene reactions using diazocarbonyl compounds, the low activity of secondary amides or carbamates is usually circumvented by the use of a large excess of amide, slow addition of the diazo compound or, most commonly, by taking advantage of facile intramolecular insertion into a proximal N–H bond.1 Given the intrinsically low concentration of the active diazoimine form of triazole 1, in effect mimicking high dilution and large excess techniques used for traditional diazocarbonyl compounds, we envisioned that a practical rhodium(II)-catalyzed intermolecular 1,3insertion between a secondary N–H bond and triazole 1 could be achievable. NIH-PA Author Manuscript To test this possibility, we subjected triazole 1a to reaction with oxazolidinone 9a in the presence of rhodium(II) octanoate 13a in CHCl3 at 100°C. To our surprise, along with 53% of the expected diamine 10a, ketone derivative 11a was formed in significant quantities (25%, Table 3). We propose that the formation of ketone 11a arises from an initial O–H insertion of azavinyl carbene into the hydroxy-tautomer of 9a, followed by rearrangement of the putative intermediate 12 (Table 3). Similarly, reaction of tosyl-substituted triazole 1b with oxazolidinone 9a under identical reaction conditions (1 mol% of Rh(II) octanoate) provided nearly a 1:1 mixture of the corresponding N–H and O–H insertion products in moderate overall yield (Table 3). The observed mixture of products (10 and 11) likely originates from the amide/imidic acid tautomerization equilibrium of substrate 9a and subsequent competing formation of O- or Nylides by the addition of Rh(II) azavinyl carbenes 2. Therefore, the outcome of the 1,3insertion reaction is expected to be determined primarily by the substrate, namely the energy barrier of the aforementioned tautomerization. It has previously been shown that the electronic character of the carboxylate ligands on the rhodium complex can greatly bias the reactivity of the Rh-carbene, which often allows for high levels of chemoselectivity (e.g. O– H versus C–H).18 Taking into account the implicit difference in electronics of the tautomeric forms of 9a, we hypothesized that the use of electronically different ligands on rhodium could improve the selectivity of this reaction. NIH-PA Author Manuscript To this end, we screened a panel of catalysts 13a–13h (Figure 2) in conjunction with both triazoles 1a and 1b to ascertain the parameters affecting product distribution (Table 3). When phenylacetic acid-derived catalysts Rh2(TPA)4 13c19 and Rh2(PCC)4 13d20 (Figure 2) were employed with 1-mesyl triazole 1a, higher selectivity towards N–H insertion product 10a was noted (73% and 79% respectively, Table 3), while formation of ketone 11a was suppressed (13% and 7% respectively, Table 3). Next, performance of Rh(II) carboxylate complexes containing amino acid derived ligands 13e–13h (Figure 2) was tested. Rh2(S-NTTL)4 catalyst 13h21 in combination with 1-mesyl triazole 1a was found to afford N–H insertion product 10a in excellent yield and virtually as the exclusive product of the reaction (>95:5 selectivity). Structurally related catalyst 13g was only slightly less efficient in the reaction with 1-mesyl triazole 1a, while the electronically similar achiral Rh2(PTCC)4 complex 13e22 gave low selectivity and only moderate yields of the insertion products (Table 3). The regioselectivity of the insertion reaction with 1-tosyl triazole 1b was found less responsive to the nature of the Rh(II) J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 6 catalyst. The most effective catalyst Rh2(PCC)4 13d, only afforded moderate selectivity towards N–H insertion (~6:1), but gave a good overall yield (Table 3). NIH-PA Author Manuscript The scope of the N–H insertion reaction with secondary amides under these optimized conditions was examined next. As expected (vide supra), the selectivity and efficiency of the reaction were highly dependent on the nature of the amide partner (Table 4). Thus, reaction of 1-mesyl triazole 1a with N-methyl benzamide in the presence of Rh2(S-NTTL)4 produced intractable mixtures of products at elevated temperatures (75 °C). However, we found that this substrate reacted at room temperature, and after prolonged reaction times (36 hours) afforded a good yield of the corresponding N–H insertion product 10c (Table 4). This product was subjected to single crystal X-ray analysis, confirming the predicted Z-geometry of the double bond (Figure 3).23 NIH-PA Author Manuscript Interestingly, competing formation of the O–H insertion product was never observed with a thiolactone-containing acetamide substrate regardless of the catalyst used (10d, 10f–g, Table 4). N-Sulfamoyl triazoles 1,9n however, required higher temperatures (100°C) and the more stable Rh2(PCC)4 catalyst 13d to assure a high yield of the 1,3-insertion with this amide substrate (10f–g), while N-mesyl triazole 1a reacted smoothly in the presence of Rh(II) octanoate dimer providing enamide product 10d in good yield (Table 4). Likewise, it was found that bis-N-Boc hydrazine and 4-phenylurazol reacted with different triazoles 1 regioselectively in the presence of Rh2(Oct)4 giving exclusively the N–H insertion products 10h–10j (77%–89%, Table 4). Overall, the electronic character of the C-4 substituent of 1-mesyl triazole 1a had little to no effect on the reactivity or selectivity in the reaction with oxazolidinone (cf. 10a and 10e, Table 4). NIH-PA Author Manuscript Another factor contributing to the selectivity of the 1,3-insertion reaction with secondary amides is the relative steric hindrance of the -OH and -NH groups. Thus, the 5-phenylsubstituted analog of oxazolidinone 9a smoothly underwent exclusive O–H insertion/ rearrangement with 1-mesyl triazole 1a in the presence of catalyst 13a, giving ketone 11c in 75% yield (Table 5). The insertion reaction of 4-(p-methoxyphenyl)-substituted triazole with the same amide was similarly selective, furnishing the corresponding rearranged product 11d in good isolated yield. Naturally, the O–H insertion discrimination observed in these cases, as opposed to the ambiguous selectivity of the parent carbamate 9a (Table 3), can be attributed to the increased steric congestion of the N–H bond in the amide tautomer. Similar reactivity was noted with N-phenylacetamide; although the corresponding product 11e was obtained in poor yield (37% due to instability on silica gel, Table 5), steric arguments can likely be used to explain the observed exclusive formation of the O–H insertion product, particularly when compared to the insertion reaction with isomeric Nmethyl benzamide (10b, Table 3). Likewise, when oxindole, the cyclic analog of Nphenylacetamide, was employed, selective O–H insertion/rearrangement products 11f–11h were formed in high yields (72%–93%). Similarly, reactions of 1-mesyl- and 1-tosyl triazoles 1 with 4-phenyl-pyridazinone afforded analogous aminated heterocyclic products 11i–11k in excellent yields (80%–97%). In the latter cases, formation of a stable J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 7 heteroaromatic system could be an additional factor contributing to a higher population of the hydroxy-tautomer, giving rise to the observed selectivity noted with these substrates. NIH-PA Author Manuscript With the ketone-containing compounds 11i and 11k in hand, we were intrigued by the possibility of an intramolecular dehydrative condensation that would lead to unique fused heterocycles. To this end, 11i and 11k were submitted to acidic conditions (H2SO4/AcOH, 3:2) at elevated temperature. The desulfonylated hitherto unknown pyridazoimidazoles 14a and 14b were formed in excellent yields (86% and 80% respectively, eq 7). (7) NIH-PA Author Manuscript O–H insertions with carboxylic acids We recognized that the insertion of azavinyl carbenes into O–H bonds of carboxylic acids could yield intermediates akin to 12 (Table 5); a subsequent rearrangement would furnish synthetically appealing N-acyl α-amino ketones. To explore this transformation, we subjected 1-tosyl-1,2,3-triazole 1b to the reaction with a slight excess of benzoic acid in the presence of 1 mol% of rhodium(II) octanoate dimer 13a in CHCl3 at 75°C. To our delight, 2-acyloxy-enamine 16a was rapidly formed as a sole, isolable product in 91% yield (Table 6). Surprisingly, the anticipated spontaneous rearrangement of product 16a into the N-acyl α-amino ketone did not occur; further heating or treatment with base, acid or various amine catalysts only yielded decomposition products. Similar results were obtained employing a number of different carboxylic acids 15 (Table 6). Thus, pivalic acid, N-Boc-protected proline and 2-furoic acid were effective in the O–H insertion with 1-mesyl triazole 1a, giving excellent yields of the 2-acyloxy-enamine products 16c–e, respectively (75%–94%, Table 6). NIH-PA Author Manuscript Next, it was found that the use of less bulky or non-aromatic carboxylic acids 15 under identical reaction conditions led to a direct formation of the N-acyl α-amino ketones 17 (Table 7). Presumably, the easily accessible primary alkyl-, alkenyl-, or alkynyl-substituted carbonyl group in the initial O–H insertion product 16 could rapidly be attacked by the nitrogen atom of enamide to furnish the rearranged products 17a–d in good yields (63%– 76%, Table 7). O–H insertions with alcohols As a logical expansion of our study, we sought to explore simple alcohols as reactive substrates in 1,3-insertion reactions of rhodium(II) azavinyl carbenes.24 First, 1-tosyl triazole 1b was tested in the reaction with ethanol in the presence of rhodium(II) octanoate dimer catalyst. While the expected alkoxy enamine was smoothly formed in high yield as judged by crude NMR, isolation by silica gel chromatography was problematic due to J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 8 NIH-PA Author Manuscript instability of the product. We hypothesized that the use of bulkier alcohol reactants could give more stable and isolable O–H insertion products. Indeed, treatment of triazole 1b with isopropyl alcohol afforded the desired alkoxy enamine 19a in good isolated yield (78%, Table 8). Use of isopropyl alcohol was equally effective with 1-mesyl triazole 1a to afford product 19b (69%, Table 8). Further exploration in regards to the scope of effective alcohol components 18 revealed that several secondary and tertiary alcohols were successful in this O–H insertion reaction, efficiently producing the corresponding alkoxy enamine products 19c–f in good yields (69%–83%, Table 8). This O–H insertion was also efficient with triphenyl silanol as a reactant, giving rise to various silyl enol ethers in good yields (Table 7). This silanol substrate was found to be effective with multiple triazoles 1 possessing various aryl groups at the C-4 position (19j–l), as well as with different aryl sulfonyl groups at N-1 (19g–i). Of note, silyl enol ethers 19 generated by this 1,3-insertion reaction were formed as a single geometrical isomer and are formal descendants of alpha-amino ketones. These valuable electronically rich olefinic building blocks are not accessible by direct deprotonation-silylation of the corresponding ketone products due to the presence of the pendant amide moiety.25 NIH-PA Author Manuscript Interestingly, when propargyl alcohol and triazole 1a were allowed to react under standard 1,3-insertion conditions (vide supra), the usual O–H insertion product was not observed. Instead, the expected product 21 underwent smooth Saucy-Marbet type [3,3]-sigmatropic rearrangement to afford the α-allenyl ketone 22a in high isolated yield (83%, Table 9).26 Naturally, we were interested in studying the scope of this novel cascade, involving formation of the previously unknown and apparently highly reactive electron-rich propargyloxy enamides 21 en route to versatile and valuable allenyl-containing building blocks.27 NIH-PA Author Manuscript It was found that a series of variously substituted propargyl alcohols 20 underwent this O–H insertion/rearrangement cascade smoothly to afford the corresponding allene products 22b– h in good yields (72%–87%, Table 9). Increasing the steric bulk at the propargyl position of alcohol 20 did not affect the efficiency of this reaction (22c–d, Table 9). Moreover, internal alkynes bearing either 1-aryl or 1-halo substituents furnished the corresponding tetrasubstituted allenes in good yields (22e–g, Table 9). The use of a racemic mono-methyl propargyl alcohol 14 afforded allene 22h in high yield, albeit with moderate diastereoselectivity (dr 73:27). The structures of products 22 were evident from NMR data, however, additional confirmation was obtained through single crystal X-ray analysis of αallenyl ketone 22e (Figure 4).28 CONCLUSIONS A new family of highly efficient O–H and N–H insertion reactions of rhodium(II) azavinyl carbenes reported here exploits the distinct reactivity of these reactive intermediates directly generated from 1-sulfonyl-1,2,3-triazoles. As opposed to 1,1-insertions typically observed with conventional donoracceptor carbenes derived from diazo carbonyl precursors, these reactions proceed via an unusual formal 1,3-insertion pathway, stereoselectively yielding densely functionalized Z-enamide products. The regioselectivity of the 1,3-insertion (N–H J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 9 NIH-PA Author Manuscript vs. O–H) was often determined by the nature of the substrate; however, it could also be controlled by the catalyst in a number of cases. The Z-enamide products undergo further transformations to furnish valuable heterocyclic products and building blocks amenable for further derivatization. These novel and highly modular methods for regio-, chemo- and stereoselective bis-amination and oxyamination of the acetylenic triple bond via C–N and C–O bond-forming reactions underscore the versatility of acetylenes and should find applications in the synthesis of complex molecular architectures. EXPERIMENTAL Typical Preparative Procedure NIH-PA Author Manuscript To a 2–5 mL microwave vial 1-mesyl-4-phenyl-1,2,3-triazole 1a (0.223 g, 1.0 mmol) and methyl carbamate 4a (0.083g, 1.1 mmol) were added, followed by 7.8 mg (0.01 mmol) of rhodium(II) octanoate dimer 13a. The vial was sealed with a Teflon microwave cap, and dry CHCl3 (4.0 mL) was added to the reaction mixture. The vial was stirred at 75 °C in an oil bath for 30 min or until the reaction was complete by TLC and LC-MS analysis. Column chromatography on silica gel, using ethyl acetate-hexane mixture (2:1) as eluent, was directly performed on the reaction mixture to afford 0.257g (0.95 mmol, 95% yield) of (Z)methyl (2-(methylsulfonamido)-1-phenylvinyl)carbamate 5a as colorless crystalline solid. 5a: 1H NMR (500 MHz, CDCl3): δ = 7.53 (d, J = 10.0 Hz, 1H), 7.39–7.33 (m, 4H), 7.32– 7.28 (m, 1H), 6.40 (bs, 1H), 6.10 (s, 1H), 3.80 (s, 3H), 3.10 (s, 3H) ppm; 13C NMR (126 MHz, DMSO-d6): δ = 154.8, 137.1, 128.3, 126.6, 124.2, 119.4, 117.2, 51.7, 41.1 ppm; LRMS (ESI): m/z 293.2 [M + Na]+. Supplementary Material Refer to Web version on PubMed Central for supplementary material. Acknowledgments This work was supported by the National Institute of General Medical Sciences, National Institutes of Health (GM-087620) and National Science Foundation (CHE-0848982 and CHE-1302043). N.S. acknowledges a postdoctoral fellowship from the Swedish Research Council (VR). We also thank Dr. Arnold L. Rheingold and Dr. Curtis E. Moore for X-ray analyses. NIH-PA Author Manuscript REFERENCES 1. Doyle, MP.; McKervey, MA.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds. Wiley; New York: 1998. 2. For rhodium(II)-catalyzed intermolecular N–H insertions, see: Paulissen R, Hayez E, Hubert AJ, Teyssie P. Tetrahedron Lett. 1974:607. Osipov SN, Sewald N, Kolomiets AF, Fokin AV, Burger K. Tetrahedron Lett. 1996; 37:615. Bagley MC, Buck RT, Hind SL, Moody CJ, Slawin AMZ. Synlett. 1996:825. For copper(I)-catalyzed intermolecular N–H insertions, see: Yates P. J. Am. Chem. Soc. 1952; 74:5376. Lee EC, Fu GC. J. Am. Chem. Soc. 2007; 129:12066. [PubMed: 17877350] 3. 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[PubMed: 23477345] Schultz EE, Sarpong R. J. Am. Chem. Soc. 2013; 135:4696. [PubMed: 23477843] Parr BT, Green SA, Davies HML. J. Am. Chem. Soc. 2013; 135:4716. [PubMed: 23477809] Spangler JE, Davies HML. J. Am. Chem. Soc. 2013; 135:6802. [PubMed: 23607705] Alford JS, Spangler JE, Davies HML. J. Am. Chem. Soc. 2013; 135:11712. [PubMed: 23915171] For cyclopropanations, see: Chuprakov S, Kwok SW, Zhang L, Lercher L, Fokin VV. J. Am. Chem. Soc. 2010; 131:18034. [PubMed: 19928917] Grimster N, Zhang L, Fokin VV. J. Am. Chem. Soc. 2010; 132:2510. [PubMed: 20131915] Alford JS, Davies HML. Org. Lett. 2012; 14:6020. [PubMed: 23153274] Culhane JC, Fokin VV. Org. Lett. 2011; 13:4578. [PubMed: 21812453] 10. Chuprakov S, Malik JA, Zibinsky M, Fokin VV. J. Am. Chem. Soc. 2011; 133:10352. [PubMed: 21619004] For a discussion of mechanism, see: Doyle MP. Hegedus LS. Catalytic Carbene Complexes in Organic Synthesis: Diazodecomposition – Insertion and Ylide Chemistry. Comprehensive Organometallic Chemistry II. 1995; Vol. 12(Chapter 5.2)New YorkPergamon Press 11. (a) Miura T, Biyajima T, Fujii T, Murakami M. J. Am. Chem. Soc. 2012; 134:194. [PubMed: 22129424] (b) Miura T, Tanaka T, Biyajima T, Yada A, Murakami M. Angew. Chem. Int. Ed. 2013; 52:3883. 12. (a) Selander N, Worrell BT, Fokin VV. Angew. Chem. Int. Ed. 2012; 51:13054.(b) Miura T, Funakoshi Y, Morimoto M, Biyajima T, Murakami M. J. Am. Chem. Soc. 2012; 134:17440. [PubMed: 23043352] 13. Selander N, Worrell BT, Chuprakov S, Velaparthi S, Fokin VV. J. Am. Chem. Soc. 2012; 134:14670. [PubMed: 22913576] 14. The structure has been deposited with the Cambridge Crystallographic Data Centre (CCDC 934421). See SI for details. 15. Simple and weakly basic amines (such as aniline) have been studied as substrates in this reaction, however, in all cases failed to afford the desired N-H insertion products. 16. No reports of vicinal diamine compounds akin to products 5 or 10 could be found using Scifinder Scholar. 17. For recent review, see: Jong SD, Nosal DG, Wardrop DJ. Tetrahedron. 2012; 68:4067. [PubMed: 22888177] 18. (a) Padwa A, Austin DJ, Hornbuckle SF, Semones MA. J. Am. Chem. Soc. 1992; 114:1874.(b) Padwa A, Austin DJ, Price AT, Semones MA, Doyle MP, Protopopova MN, Winchester WR, Tran A. J. Am. Chem. Soc. 1993; 115:8669. 19. (a) Hashimoto S, Watanabe N, Ikegami S. Tetrahedron Lett. 1992; 33:2709.(b) Hashimoto S, Watanabe N, Sato M, Ikegami S. Tetrahedron Lett. 1993; 34:5109. J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 11 NIH-PA Author Manuscript 20. The previously unreported catalyst, 1-phenylcyclohexane carboxylate (PCC) rhodium(II) dimer was prepared in a similar manner to ref. 18a. See SI for experimental details. 21. Müller P, Allenbach Y, Robert E. Tetrahedron: Asymmetry. 2003; 14:779. 22. The previously unreported catalyst, 1-phthalamidocyclohexane carboxylate (PTCC) rhodium(II) dimer was prepared in a similar manner to ref. 18b. See SI for experimental details. 23. The structure has been deposited with the Cambridge Crystallographic Data Centre (CCDC 934423). See SI for details. 24. A singular example of an O–H insertion with tert-butanol under rhodium(II)-catalysis was recently shown to give the synselective 1,3-insertion product in a moderate yield. See ref. 11. 25. Aggarwal VK, Sheldon CG, Macdonald GJ, Martin WP. J. Am. Chem. Soc. 2002; 124:10300. [PubMed: 12197731] 26. While this manuscript was in preparation, a singular example of this transformation was reported, however, the product was not isolated (NMR yield reported). See ref. 11b. 27. Norbert, K.; Hashmi, ASK. Modern Allene Chemistry. New York: Wiley; 2004. 28. The structure has been deposited with the Cambridge Crystallographic Data Centre (CCDC 934422). See SI for details. NIH-PA Author Manuscript NIH-PA Author Manuscript J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 12 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 1. Crystal structure of enamide product 5a. J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 13 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 2. Rhodium(II) carboxylates catalysts employed in this study. NIH-PA Author Manuscript J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 14 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 3. Crystal structure of secondary diamine 10c. J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 15 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 4. Crystal structure of α-allenyl ketone 22e. NIH-PA Author Manuscript J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 16 Table 1 NIH-PA Author Manuscript N–H Insertion with Primary Amides: Optimization of the Reaction Conditionsa entry catalyst 4a, equiv solvent yield, %b 1 Rh2(Oct)4 2 CHCl3 90 2 Rh2(Oct)4 1.1 CHCl3 95 3 Rh2(Oct)4 1.1 1,2-DCE 79 4 Rh2(Oct)4 1.1 PhMe 0 5 Rh2(OAc)4 1.1 CHCl3 95 6 Rh2(OAc)4 1.1 CHCl3 89c 7 Rh2(Oct)4 1.1 CHCl3 95c a NIH-PA Author Manuscript Conditions: triazole 1a (0.20 mmol), methyl carbamate 4a and Rh2L4 (1.0 mol%) in 1 mL of dry CHCl3 at 65°C for 30 min in a microwave reactor. b NMR yield. c Isolated yield (1.0 mmol scale). NIH-PA Author Manuscript J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 17 Table 2 NIH-PA Author Manuscript Substrate Scope for the Rh(II)-Catalyzed N–H Insertion of Primary Amidesa,b NIH-PA Author Manuscript a Conditions: 1-sulfonyl-1,2,3-triazole 1 (1.0 mmol), amide 4 (1.1 mmol) and Rh2(Oct)4 (0.01 mmol), 3 mL of dry CHCl3, 75°C, 1–3 h. b Isolated yields. c 100°C. NIH-PA Author Manuscript J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Table 3 J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. R= Ms 1a Ts 1b %b of Chuprakov et al. Effect of Rh(II) Catalyst (13a–h) on Regioselectivity of the Insertion with 2-oxazolidonea Rh(II) carboxylate catalysts (Figure 2) 13a 13b 13c 13d 13e 13f 13g 13h 10a 53c 42 73 79 48 - 83 95 11a 25c 25 13 7 24 - 8 <5 10b 30 42 40 77 45 58 60 - 11b 29 40 13 13 40 23 30 - a Conditions: triazole 1a–b (0.20 mmol), 9a (0.22 mmol) and Rh2L4 (0.002 mmol) in 1 mL of dry CHCl3 at 100°C for 1 h. b NMR yields. c Isolated yield (1.0 mmol scale). Page 18 Chuprakov et al. Page 19 Table 4 NIH-PA Author Manuscript Substrate Scope for the Rh(II)-Catalyzed N–H Insertion of Secondary Amidesa,b NIH-PA Author Manuscript NIH-PA Author Manuscript a General conditions: triazole 1 (1.0 mmol), 9 (1.1 mmol) and Rh2L4 (0.005–0.010 mmol) in 4 mL of dry CHCl3 at 75°C; A: Rh2(S-NTTL)4 (13h) 0.5 mol%; B: Rh2(PCC)4 (13d) 1 mol%; C: Rh2(Oct)4 (13a) 1 mol%. b Isolated yield. J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. c Page 20 rt, 36 h. d 120 °C, 5 h. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 21 Table 5 NIH-PA Author Manuscript Substrate Scope for the Rh(II)-Catalyzed O–H Insertion of Secondary Amidesa,b NIH-PA Author Manuscript NIH-PA Author Manuscript a General conditions: triazole 1 (1.0 mmol), 9 (1.1 mmol) and Rh2L4 (0.005–0.010 mmol) in 4 mL of dry CHCl3 at 75°C; A: Rh2(S-NTTL)4 (13h) 0.5 mol%; B: Rh2(PCC)4 (13d) 1 mol%; C: Rh2(Oct)4 (13a) 1 mol%. b Isolated yield. J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. c Page 22 rt, 36 h. d rt, 5 h. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 23 Table 6 NIH-PA Author Manuscript Rh2(Oct)4-Catalyzed O–H Insertion with Carboxylic Acidsa,b NIH-PA Author Manuscript a General reaction conditions: triazole 1 (1.0 mmol), acid 15 (1.1 mmol) and Rh2(Oct)4 (0.01 mmol), 3 mL of dry CHCl3 at 75°C for 30 min. b Isolated yields are shown. NIH-PA Author Manuscript J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 24 Table 7 NIH-PA Author Manuscript Rh(II)-Catalyzed O–H Insertion/ Rearrangement Cascade with Carboxylic Acidsa,b NIH-PA Author Manuscript a General reaction conditions: triazole 1 (1.0 mmol), acid 15 (1.1 mmol) and Rh2(Oct)4 (0.01 mmol), dry CHCl3 (3 mL), 75°C for 30 min. b Isolated yields. NIH-PA Author Manuscript J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 25 Table 8 NIH-PA Author Manuscript Substrate Scope for the Rh(II)-Catalyzed O–H Insertion with Alcohols and Triphenylsilanola,b NIH-PA Author Manuscript NIH-PA Author Manuscript a General reaction conditions: triazole 1 (1.0 mmol), alcohol 18 (1.1 mmol) and Rh2(Oct)4 (0.01 mmol), 3 mL of dry CHCl3 at 75°C for 1–5 h. b Isolated yields are shown. J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. c Page 26 Catalyst 13b was used instead of Rh2(Oct)4. d 10 mmol scale. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript J Am Chem Soc. Author manuscript; available in PMC 2015 January 08. Chuprakov et al. Page 27 Table 9 NIH-PA Author Manuscript O–H Insertion/[3,3]-Sigmatropic Rearrangement Cascade with Propargyl Alcoholsa,b NIH-PA Author Manuscript NIH-PA Author Manuscript a General reaction conditions: triazole 1 (1.0 mmol), propargyl alcohol 20 (1.1 mmol), Rh(II) carboxylate (0.01 mmol), dry CHCl3 (3 mL), 75°C for 0.5–3 h. (A) Rh2(Oct)4, (B) Rh2(Piv)4, (C) Rh2(PCC)4. b Isolated yields. J Am Chem Soc. Author manuscript; available in PMC 2015 January 08.