Hydrazones as Singular Reagents in Asymmetric Organocatalysis

MINIREVIEW Hydrazones as singular reagents in asymmetric organocatalysis María de Gracia Retamosa,[b],‡ Esteban Matador,[a],‡ David Monge,*[a] José M. Lassaletta*[b] and Rosario Fernández*[a] [a] Title(s), Initial(s), Surname(s) of Author(s) including Corresponding Author(s) Department Institution Address 1 E-mail: [b] Title(s), Initial(s), Surname(s) of Author(s) Department Institution Address 2 Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate)) It will come later MINIREVIEW Abstract: This Minireview summarizes strategies and developments regarding the use of hydrazones as reagents in asymmetric organocatalysis, their distinct roles in nucleophileelectrophile reactions, cycloadditions and cyclizations. The key structural elements governing the reactivity of these reagents in a preferred pathway will be discussed, as well as their different interactions with organocatalysts, leading to diverse activation modes. Along these studies, the synthetic equivalence of N- monoalkyl-, N,N-dialkyl- and N-acyl hydrazones with several synthons is also highlighted. Emphasis is also put on the mechanistic studies performed to understand the observed reactivities. Finally, the functional group transformations performed from the available products has also been analysed, highlighting the synthetic value of these methodologies, which served to access numerous families of valuable multifunctional compounds and nitrogen-containing heterocycles. 1. Introduction Hydrazones have emerged in recent years as a versatile family of reagents with multiple applications in organic synthesis.[1] They are usually stable compounds, readily accessible from the condensation between hydrazines or hydrazides and carbonyl compounds, among other methods. Their core skeleton (N-N=C) provides these nitrogen reagents with multiple reactivity patterns (Figure 1), depending on the substitution pattern (R1-R3), the nature of the reaction partners (nucleophiles, electrophiles and others), the mode of activation by different catalysts and the reaction conditions. Consequently, several types of hydrazones have been investigated in C-N and C-C bond forming processes. N-Monosubstituted hydrazones (type A), and eventually N- sulfonyl hydrazones (type C, X = S) have been employed as N- centered nucleophiles. Moreover, pioneering work by Baldwin and co-workers showed that metallated aldehyde N- monosubstituted hydrazones might disclose an ambident nucleophilic reactivity (N vs C-selectivity) which was strongly influenced by the substitution patterns (R1, R2).[2] A proper design of bulky hydrazones (type A, R2 = tBu or Tr) as anionic aza-enolate precursors enhanced the C-selectivity that, together with subsequent release of the masked carbonyl group allowed their use as acyl anion equivalents. N,N-Dialkylhydrazones (type B) are characterized by an ambiphilic behavior at the azomethine carbon, expressed in reactions with nucleophiles (imine-like reactivity) and electrophiles (aza-enamine reactivity).[1] These reactions afford hydrazone or hydrazine adducts which are valuable precursors for the synthesis of multifunctional compounds and nitrogen-containing heterocycles. Additionally, the utility of N-acyl hydrazones (type C, X = C) as stable imine surrogates has been widely demonstrated.[3] Figure 1. Hydrazones as ambiphilic reagents in asymmetric organocatalysis. During years, the role of hydrazones in asymmetric synthesis had been associated with the efficiency of (S)-1-amino-2- methoxymethylpyrrolidine (SAMP) and related proline-derived auxiliaries.[4] Nowadays, though, hydrazones are emerging as versatile entities in the field of asymmetric catalysis, able to play different roles depending on the scenario. On the one hand, chiral N-ligands based on N,N-dialkylhydrazones have met an increasing number of useful applications[5] but, on the other hand, the use of this type of hydrazones as reagents in catalytic, enantioselective procedures has been hampered by the high affinity or sensitivity of these nitrogen-containing reagents towards most Lewis acids, that often led to undesired side reactions (decomposition, dimerization, or catalyst deactivation).[6] Alternatively, the milder nature of the interactions involved in organocatalytic activation[7] have recently been shown to be particularly appropriated for the characteristics of hydrazones. Engagement of the appropriate hydrazone type, interacting through basic sites (amine and imine like nitrogens), H-bond donor (NH in N-monosubstituted hydrazones) or H-bond acceptor (X=O, in N-acyl hydrazones) functionalities with different organocatalysts has emerged as a promissing strategy for the development of new reactivity patterns. In this Minireview, we aim to outline the currently available methodologies that use hydrazones as key reagents in asymmetric organocatalysis. The structural elements which modulate the different reactivities, the plausible activation modes, as well as the mechanistic aspects that explain the observed reactivities and stereoselectivities will be discussed, aiming to offer a timely and clear overview of this growing topic and its key concepts. 2. Hydrazones as nucleophiles From a structural viewpoint, hydrazones can be considered as 2-azaenamines and, consequently, behave as ambident nucleophiles that react with electrophiles either at the amine sp3 nitrogen or at the azomethine carbon by virtue of the n→π conjugation (Scheme 1). In general, the nitrogen atom is the most nucleophilic center and monosubstituted hydrazones (R3 = H) usually yield products E after reaction with electrophilic R1 N N R3 R2 R1 N N HX O R2 A B C Nu H-bond donor H-bond acceptor easy synthesis, stable reagents multiple reactivity patterns versatile tranformations recognition by organocatalysts R1 N N HR2 EE Nu E +++ −− H-bond donor H-bond acceptor H-bond acceptor [a] Dr. D. Monge, E. Matador, Dr. R. Fernández Departamento de Química Orgánica, Universidad de Sevilla and Centro de Innovación Avanzada (ORFEO-CINQA) C/ Prof. García González, 1, 41012 Sevilla, Spain E-mail: [email protected], [email protected] [b] Dr. M. G. Retamosa, Dr. J. M. Lassaletta Instituto de Investigaciones Químicas (CSIC-US) and Centro de Innovación en Química Avanzada (ORFEO-CINQA) Avda. Américo Vespucio, 49, 41092 Sevilla, Spain E-mail: [email protected]. [‡] These authors contributed equally to this work. MINIREVIEW species E+. However, hydrazonium species D formed from N,N- dialkylhydrazones (R2, R3 ≠ H) cannot evolve in the same way and, eventually, the irreversible C-attack can proceed to afford products F via diazenium intermediates. In the particular case of formaldehyde N,N-dialkylhydrazones (FDAHs; R1 = H, R2, R3 ≠ H), the minimum steric hindrance around the azomethine carbon dramatically enhances the nucleophilic reactivity at this center and allows formation of products F through an essentially irreversible C–C bond forming process. Scheme 1. Nucleophilic reactivity profile of hydrazones. Maji and Mayr have recently reported on the C-nucleophilicity quantification of representative FDAHs, 1a (N = 6.98) and 1b (N = 7.94). As expected, these values are lower than those of common enamines and comparable to those of enamides (Figure 2).[8] The nucleophilicity can be modulated by tuning the structure of the dialkylamino fragment, being the pyrrolidine ring more effective than N,N-dimethylamino group in the n→π conjugation and, therefore, 1-methyleneaminopyrrolidine 1b has been one of the most used FDAHs. Figure 2. Comparison of nucleophilicity parameters N of the N,N-FDAH 1a,b with those of enamines and enamides. The marked aza-enamine character of FDAHs and their equivalences with formyl and cyanide anions have been exploited for the functionalization of a wide palette of electrophiles. Moreover, 1-methyleneamino-2-(1- methoxymethyl) pyrrolidine and related proline-derived formaldehyde hydrazones have been used as chiral analogues of 1b for the synthesis of enantiomerically enriched formylated and/or cyanated derivatives.[9] David Monge received his PhD in 2007 at University of Sevilla under the supervision of Prof. Rosario Fernández and José M. Lassaletta. After he worked as postdoctoral researcher at CSIC (Sevilla) for BayerCropScience GmBH (2007-2008) and he joined the group of Prof. Karl Anker Jørgensen at Center for Catalysis at the University of Aarhus (Denmark, 2009-2010). In 2011 he returned to University of Sevilla, where he was a postdoctoral “Juan de la cierva” fellow and was promoted to Associate researcher in 2015. His current research interests include green chemistry and asymmetric metal catalysis and organocatalysis, with emphasis on hydrazones as reagents or ligands. Esteban Matador received his B. S. degree from University of Sevilla in 2014. A year later, he finished his M.S. and he is now pursuing his Ph.D. degree in R. Fernández and J. M. Lassaletta group at the same University. His research interest focuses on the use of hydrazones as reagents or ligands in asymmetric catalysis. Mª de Gracia Retamosa received her PhD in 2008 at University of Alicante under the guidance of Prof. Carmen Nájera and José Miguel Sansano. After she did several postdoctoral stages [Prof. Michael Greaney at University of Edimburgh (2009), Prof. Jesús M. Sanz at University Miguel Hernández (Elche, 2009-2011) and Prof. Fernando P. Cossío at the University of the Basque Country and Donostia International Physics Center (2012-2016)]. Recently, she has joined R. Fernández and J. M. Lassaletta group as postdoctoral researcher [CSIC (Sevilla)]. Her current resarch interests include asymmetric metal and organocatalysis and synthesis of compound with pharmacological interest. Rosario Fernández studied chemistry at the University of Sevilla and received both her BS degree (1980) and her PhD degree (1985) under the supervision of Prof. Antonio Gómez Sánchez. She was a NATO postdoctoral fellow at the University of Paris- Sud (Orsay, France) in the laboratory of Prof. Serge David from 1986 to 1987. In 1987 she returned to the University of Sevilla, where she was promoted to Associate Professor. In 2008 she became a Full Prof. at the same University. Her current research interests include asymmetric synthesis and enantioselective catalysis, in both aspects, asymmetric metal catalysis and organocatalysis. E E N E NN R1H R2 R3NN R1H R2 R3NN R1H R3-H+ R3 = H -H+ E NN R1H E R2 R2, R3 = Alk NN H R1 R2 R3 E NN R1 R2 R3 R2 E O H R1 = H DE F R1 = H E H H N N H H N N N 6.98 7.84 ∼10 N O ∼6.25 HN Ph Me O HH 1a 1b MINIREVIEW José María Lassaletta received his PhD in 1990 from the University of Seville. After a postdoctoral stage in the ‘Instituto de la Grasa y sus Derivados’ (CSIC, Seville) he joined the group of Professor Richard R. Schmidt (U. Konstanz, Germany). In 1995 he moved to the Instituto de Investigaciones Químicas (CSIC, Seville), where he was promoted to Tenured Scientist in 1996, Research Scientist in 2005 and Research Professor in 2009. He is currently interested in the development of synthetic methodologies, cross-coupling and C–H activation strategies, and ligand design with emphasis on hydrazones and N-heterocyclic carbenes, and asymmetric organocatalysis. 2.1. Addition of aldehyde N,N-dialkylhydrazones to imines The first example using FDAHs in asymmetric organocatalysis was reported by Dixon in 2005.[10] 1-Methyleneaminopirrolidine 1b readily added to N-Boc aryl imines 2 in the presence of binaphtol-type catalysts, of which Ph2-BIMBOL (S)-II was found to be the most efficient one (Scheme 2). Application of this system afforded the corresponding α-aminohydrazones (R)-3 in fair to good yields and moderate enantioselectivities. These adducts could be directly transformed into Strecker–type products, such as (R)-4, by oxidative cleavage (N-oxidation/ aza-Cope elimination) of the hydrazone moiety using magnesium monoperoxy phthalate (MMPP) as the oxidant.[11] Later, Rueping and co-workers reported improved catalytic efficiency of BINOL-derived chiral phosphoric acid (R)-III in the same reaction.[12] The results achieved by using these catalytic systems indicate a direct correlation between acidity and catalytic activity,[13] while other factors like the establishment of additional H-bond cooperative networks, steric hindrance around reaction site or π–π stacking interactions might have an essential impact in the selectivity. Scheme 2. First organocatalysts employed in reaction of 1- methyleneaminopyrrolidine 1b with N-Boc protected imines 2. In 2008, Maruoka and co-workers went a step further to achieve reactivity with arylaldehyde N,N-dialkylhydrazones. Thus, the catalytic efficiency of axially chiral dicarboxylic acids IV overcame that of by BIMBOL II or phosphoric acid catalyst III and, using a lower catalyst loading of only 5 mol%, hydrazones 5 could also be used as acyl anion equivalents to afford αaminohydrazones (R)-6 in moderate to good yields and high enantioselectivities (Scheme 3).[14] The versatility of the hydrazone functionality was demonstrated with the synthesis of α-aminoketone (R)-7 by ozonolysis. This activation strategy was successfully extended to vinylogous imino aza-enamine reactions (addition at C3-position) between α,β-unsaturated aldehyde hydrazones 8 and N-benzoyl protected imines 9.[15] The synthetic potential of the 1,2-addition products (S)-10 was highlighted by their direct transformation into alkenyl amines, exemplified by (S)-11. To the best of our knowledge, axially chiral dicarboxylic acids IV represent the only catalysts able to facilitate nucleophilic asymmetric additions of N,N- dialkylhydrazones of aldehydes different from formaldehyde. OH Ph Ph OH OH OH Ph Ph Ar O O Ar P O OH Ar = 9-phenanthryl H H N N+ NBoc N H N N Boc R R Catalyst Conditions 1b 2 N H Boc N MMPP R = H (R)-4 73%, 52% ee C N R OH OH R pKa BINOLs BIMBOLs Phosphoric acids Increasing catalytic activity (S)-II (20 mol%) CDCl3, rt (R)-3 44-87%, 17-75% ee (R)-III (10 mol%) CHCl3, 0 °C (S)-3 48-82%, 74-91% ee (S)-II (pKa ⎡ 3-3.5) (pKa ⎡ 9-10) (S)-I(R)-III * MINIREVIEW Scheme 3. Asymmetric dicarboxylic acid-catalysed additions of formaldehyde, aryl- and alkenylaldehyde hydrazones to imines. 2.2. Conjugate addition of formaldehyde N,N-dialkyl hydrazones to enoates Our research group considered hydrogen-bonding organocatalysts as an alternative to Brønsted acid catalysts for developing reactions involving formaldehyde N,N- dialkylhydrazones and enoate surrogates.[16] It was found that the 1,4-addition of 1-methyleneaminopyrrolidine 1b to β,γunsaturated α-ketoesters 12 was strongly accelerated by catalytic amounts of multiple H-bond donors such as thioureas. Thiourea V [ArF = 3,5-(CF3)2C6H3] derived from (1S,2R)- aminoindan-2-ol allowed the preparation of adducts (R)-13 in good yields and moderate to good enantioselectivities (Scheme 4).[17] The versatility of these masked 1,4-dicarbonyl compounds was illustrated by their transformation into α-keto γ-cyano esters (R)-14 promoted by MMPP and the synthesis of succinate derivate (R)-15 following an ozonolysis/oxidative decarboxylation sequence. The presence of the hydroxyl group in the aminoindanol scaffold proved to be essential for both reactivity and selectivity, supporting a bifunctional mode of action by the catalyst V. Accordingly, the acidic hydrogen atoms of the thiourea would activate the substrate while the approach of the hydrazone to the ester might be driven by an OH–N hydrogen bond, resulting in the addition of the azomethine carbon to the Re face of the C=C bond. Scheme 4. Enantioselective addition of 1-methyleneaminopyrrolidine 1b to β,γ-unsaturated α-ketoesters 12 and proposed stereochemical model. 2.3. Addition of formaldehyde N-tert-butylhydrazone to carbonyl compounds The asymmetric 1,2-addition of acyl anion equivalents to carbonyl compounds is a powerful synthetic tool that provides direct access to densely functionalized carbinols.[18] As discussed above, the marked aza-enamine character of 1- methyleneaminopyrrolidine 1b had been exploited in enantioselective organocatalytic additions to imines[10,12,14,15] and Michael acceptors.[17] This approach, however, failed to afford high enantioselectivities in 1,2-addition to carbonyl compounds. We envisaged that replacement of the pyrrolidino group of 1b by a N-tert-butylamino group in 16 should still favor reactivity at the azomethine carbon for steric reasons, while providing additional interaction opportunities with bifunctional organocatalysts (Figure 3). (S)-10 39-87%, 63-93% ee MS (4Å), CH2Cl2 −35 °C H R1 N NNBoc NH N N R22 R1 (R)-3 or 6 35-89%, 84-96% ee MS (4Å), CHCl3 −30 °C (R)-IVa (5 mol%) R1 O + N N R1NH N NR1 NBz + 9 8 (R)-IVb (10 mol%) N H Boc O Ph R1 = Ph, R2 = H i) O3, CH2Cl2, −78 °C (R)-7 84%, 95% ee N H CN Bz (S)-11 96%, 91% ee MMPP R2 R2 R2 Boc Bz ii) Me2S 1b: R1 = H 5: R1 = Ar CN Ar COOH COOH Ar (R)-IVa: Ar = 4-tBu-2,6-Me2C6H2 (R)-IVb: Ar = 4-Ad-2,6-Me2C6H2 R O O OEt 60-82%, 58-80% ee CH2Cl2, −45/−60 °C R O O OEt N N (R)-13 N H N H S ArF OH V (10 mol%) + 1b 12 (R)-15 56% (3 steps), 80% ee R O O OEt N O O OMe MeO MMPP i) O3, MeOH, −78 °C ii) H2O2-HCOOH iii) SOCl2, MeOH (R)-14 H H N N C N H O 74-88%, 78-80% ee O O R N H N H S O CF3 CF3 N N H OEt H Re-face attack MINIREVIEW Figure 3. Dual activation strategy with formaldehyde N-tert-butyl hydrazone 16. D-H: H-bond donor, A: H-bond acceptor. This strategy was successfully applied to perform highly enantioselective additions (formally hetero-carbonyl-ene reactions) to α-keto esters, that reached very high enantioselectivities by using BINAM-derived bis-ureas VI (Scheme 5).[19] Scheme 5. Enantioselective addition of formaldehyde tert-butylhydrazone 16 to α-ketoesters 17 and further derivatizations. The key racemization–free diazene to aldehyde transformation (18→19), which serves to demonstrate the synthetic equivalence of 16 with the formyl anion, could be efficiently performed via 'one pot' tautomerization/hydrolysis promoted by HCl in a byphasic H2O/Et2O medium. Aldehydes 19 showed a limited stability and did not resist chromatographic purification, but the crude products could be reduced with Bu4NBH4 to afford diols 20 or used in Wittig reactions to yield enones 21 or unsaturated esters 22 and lactones 23 in good overall yields and without racemization. Unexpectedly, bis-urea catalysts (R)-VI showed a better catalytic activity than the bis-thiourea analogs (R)-VII, and both types of catalysts afforded opposite major enantiomers, suggesting that different activation modes operate in each case. Considering the higher H-bond acceptor capability of the urea carbonyl group, a key interaction with the NH group of 16 was considered. Accordingly, 1H-NMR spectra recorded for 16 in the presence of increasing amounts of (R)-VI showed a progressive upfield shift of the azomethine protons, as expected from a higher electron density at the azomethine carbon. As observed also in 1H-NMR experiments, a second urea moiety activates the keto ester by means of an H–bond network with participation of one of the acidic ortho CH bonds of the (CF3)2C6H3 groups. All the collected experimental evidences, as well as the observed absolute configuration, are consistent with the mechanism and stereochemical model shown in Scheme 6. As envisaged in the original design (Figure 3), bis-urea VI behaves as a bifunctional catalysts, performing a dual activation of both reactants. In the ternary complex formed, the relatively bulky aromatic group of the substrate avoids the more hindered inner region of the catalyst, thus facilitating the attack of the activated (H–bonded) hydrazone reagent from the Re face. Scheme 6. Proposed mechanism and stereochemical model. Aiming to expand the scope of this dual activation strategy, we reported later on the enantioselective reactions of FTBH (16) with isatins 24[20] and α-keto phosphonates 25,[21] leading to highly functionalized diazenes 26 and 27 in good yields and NNH HH Y O RNN DD HH H A 16 Steric protection prevents N-attack H-donor Interactions with catalyst R O O OEt 67-99%, 72-99% ee (R)-18 + 16 17: R = Ar, HetAr R HO N N tBu CO2Et Toluene −15 to −45 °C H N O H NArF N H O N H ArF H N S H NArF N H S N H ArF CF3 CF3 ArF = (R)-VI (R)-VII (R)-19 R HO O CO2Et (R)-VI (2-10 mol%) HCl (aq)/ Et2O H O NNH tBu H H R HO CH2OH CO2Et Bu4NBH4 CH2Cl2 (R)-20, 50-85% Ph HO CO2Et O Me (R)-21, 67% Ph HO CO2Et O OMe (R)-22, 63% Ph O CO2Et O (R)-23, 28% X O PPh3 − + X = Me X = OMe + − N H O N H CF3 F3CH N O H N CF3 CF3 OEt H N O H N F3C CF3 H N N N O N CF3 F3C H O O H H Ternary complex R OEt H N O H N F3C CF3 H N N N O N CF3 F3C H O O H H Zwitterionic Intermediate R RCO2Et O NNH HH RCO2Et HO NN tBu 17 16 (R)-18 + - (R)-VI MINIREVIEW enantioselectivities (Scheme 7). Subsequent high-yielding and racemization-free transformations provide direct access to relevant azoxy compounds 28 and 29, enones 30 bearing an oxindole scaffold, and N-PMP protected phosphaisoserines 31. Remarkably, most of these transformations can be performed in a 'one pot' fashion without isolation of diazene or aldehyde intermediates. Scheme 7. Enantioselective addition of FTBH 16 to isatins 24 and acyl phosphonates 25. 2.4. Conjugate addition of N-monoalkylhydrazones to nitroalkenes Preliminary investigations had shown that simple formaldehyde N,N-dialkylhydrazones 1a,b readily add to nitroalkenes, spontaneously or promoted by thiourea catalysts,[22] but the enantioselective organocatalytic version could not be successfully developed for these reagents. Previously, aldehyde N-substituted hydrazones were reported to react with nitroalkenes to afford pyrazoles through a formal 1,3- cycloaddition/oxidation sequence under basic, acid or thermal conditions.[23] In these reactions, the regioselectivity is assumed to be controlled by the first nucleophilic attack (C vs N) driven by hydrazone structure or reaction conditions via hydrazoniumnitronate intermediates I-1 or I-2 (Scheme 8, left). Interestingly, FTBH (16) allowed C-selective conjugate addition to nitroalkenes 32 under mild conditions. This unprecedented diaza-ene reaction could be catalyzed by (R)-BINAM-derived bis-thiourea (R)-VII to afford the corresponding diazenes (R)-33 in good yields and moderate enantioselectivities.[24] These products were transformed into β-nitro-nitriles (S)-35 employing a two-step alkylation/oxidative cleavage protocol from the tautomeric hydrazones (R)-34. Scheme 8. Enantioselective reactions of N-monoalkylhydrazones with nitroalkenes. On the other hand, Jørgensen and co-workers described a new reaction pathway exerted by ketone-derived N- methylhydrazones 36 (Scheme 7, right). Asymmetric H-bonding activation of nitro-olefins by Jacobsen-type thiourea VIII R O 90-99%, 94-99% ee (R)-27 25 R HO N N tBu PO3Me2 Toluene, −78 °C R HO CHO PO3Me2 (R)-VI (10 mol%) PO3Me2 MMPP MeOH HCl (aq)/Et2O R HO N N tBu PO3Me2 (R)-29 60-95%, 84-98% ee N O Bn RO O Me (R)-30 65-70%, 96% ee R HO NHPMP PO3Me2 (R)-31 40-55%, 90-97% ee 16 H O NNH tBu H H O N O O Bn NN tBu N O HO Bn NN tBu N O HO Bn 24 (R)-26 (R)-28 MMPP MeOH Toluene, −78 °C (R)-VI (7-10 mol%) i) RX, CH3CN, Cs2CO3 ii) HCl (aq)/Et2O iii) Me O PPh3 O PMPNH2 NaCNBH3 'one-pot' − + − X XX N R1 NH R3 N R1 N R3 R4 N O O H I-2 R4NO2 NN R1 R3 R4 1,3,5-Trisubstituted pyrazoles R4 N R1 N R3 N O O NN R1 R3 R4 I-1 1,3,4-Trisubstituted pyrazoles H (R)-VII (15 mol%) Cy/Toluene 0 °C R3NO2 N N tBu 60-96%, 26-68% ee R2 R2 = H VIII (5 mol%) HN N Me R4 NO2 R1 R2 Toluene −30 °C 55-93%, 80-99% ee 7:1->20:1 dr NN H O S N H tBu CF3 CF3 Ph VIII (R)-33 37 R3NO2 N HN Me Ph HN (S)-35 NH 38 16: R1, R2 = H, R3 = tBu 36: R1 = Ar, Alk, R2 = Alk, R3 = Me R3NO2 N NH tBu TFA CH2Cl2, 0 °C (R)-34 O F3C Cl Cbz 83-94%, 56-62% ee 32 + + ++ +− − − − MINIREVIEW facilitated the formal 1,3-dipolar cycloaddition with hydrazones 36, acting as N-nucleophiles in the first bond formation.[25] Subsequent cyclization afforded 4-nitropirazolidines 37, in which oxidative formation of pyrazoles would be blocked due to the presence of a quaternary stereogenic center (R1 and R2 ≠ H). These products 37, obtained in good to excellent yields with high to excellent stereocontrol (enantio- and diastereoselectivity), were also used as precursors of 1,2,3-triamines, exemplified by the synthesis of 38. 2.5. Conjugate addition of N-monosubstituted hydrazones to α,β-unsaturated ketones/aldehydes The aza-Michael reaction[26] involving hydrazones as N-centered nucleophiles had been scarcely investigated. In 2007, Jørgensen and co-workers reported on the first enantioselective organocatalytic 1,4-addition of aryl-substituted N-methyl hydrazones 39 to cyclic enones 40. The expected adducts 41 were isolated with moderate enantioselectivities using cinchona alkaloid IX as the catalyst (Scheme 9).[27] Scheme 9. Enantioselective addition of N-methy hydrazones 39 to cyclic enones 40. As observed in other related thia-Michael additions,[28] the hydroxyl group in IX was found to be essential to induce enantioselectivity. The interaction between the catalyst and hydrazone was observed by 1H-NMR in some cases and, accordingly, the postulated working model includes an H-bond between the hydroxyl group and the enone carbonyl, accounting for its activation, while the quinuclidine moiety drives the approach of the hydrazone through a second (NH–N) H-bond interaction. A minimum steric repulsion between the aromatic ring in the catalyst and the enone led to a preferred orientation, in agreement with the observed (S) absolute configuration. The use of aminocatalysis[29] as an obvious strategy for the activation of α,β-unsaturated carbonyl compounds in this context remained elusive until 2012, when Vicario's group described the first example of an aza-Michael reaction involving an N-tosyl hydrazone under iminium activation.[30] The choice of pyruvaldehyde 2-tosyl hydrazone 42 as a bifunctional reagent bearing a strategically installed formyl group was essential for completing a cyclization process, thereby avoiding reversibility issues frequently observed in aza-Michael reactions. Thus, diarylprolinol (S)-Xa in the presence of benzoic acid as cocatalyst promotes the reaction of 42 with alkyl- and arylsubstituted enals 43 to afford 2,3-dihydropyridazines (R)-44 in good yields and with excellent stereocontrol (Scheme 10). The overall process might be described as a three-step aza- Michael/aldol reaction/dehydration cascade through iminium/enamine catalysis. Scheme 10. Enantioselective aza-Michael/aldol condensation cascade between pyruvaldehyde N-tosyl hydrazone 42 and cyclic enones 43. In 2012, the same group introduced a new push-pull monosubstituted hydrazone design to switch from N- to C- selectivity for an acylation strategy of α,β-unsaturated aldehydes[31] (Figure 4). Figure 4. Push-pull monosubstituted hydrazone design for nucleophilic acylation strategies. The optimized hydrazone structure incorporated an electrondonating group (EDG) at nitrogen, typically p-methoxyphenyl (X = OMe) and an electron–withdrawing group (EWG) as the azometine carbon substituent (α-anion stabilizing), hence resulting in an increased reactivity of the azomethine carbon. Under iminium catalysis provided by the silylprolinol ether (R)- Xb, the projected 1,4-additon of hydrazones 45 to α,βunsaturated aldehydes 43 afforded diazenes 46 as a mixture of diasteroisomers (Scheme 11). These highly functionalized O n O N Me N X Y R R 40 39 + IX (20 mol%) N MeO HO N H toluene, rt 75-99%, 31-77% ee (S)-41 H NNH Me X Y N Et OAr H O N Me N H Ar Si-face attack n Me N HN Ts H O O R + 43: R = Alkyl, Aryl 42 (S)-Xa (20 mol%) N HOTMS ArF ArF NN Ts CHOMe R 49-91%, 85-97% ee PhCO2H toluene, rt (R)-44 NNH HEWG X NN EWG X H EDG − + MINIREVIEW adducts showed high tendency to decompose and, therefore, subsequent tranformations were required. Treatment of 46 with HCl in a biphasic Et2O/H2O medium gave cyclic 1,4- dihydropyridazine derivative (S)-47. Moreover, aldehyde oxidation in 46 employing Pinnick conditions afforded the corresponding γ-hydrazonocarboxylic acids (S)-48 in excellent yields and high enantioselectivities. To complete the indirect βglyoxylation of enals from hydrazones 45, representative γhydrazonocarboxylic acids (S)-48 were transformed into diesters (S)-49 by a three-step reaction sequence including oxidation of the azomethine carbon, esterification and hydrolytic cleavage, without erosion of enantiomeric purity. Scheme 11. Enantioselective reactions of push-pull hydrazones 45 with α,βunsaturated aldehydes 43 and subsequent derivatizations. The above-mentioned combination of push-pull hydrazone and iminium activation was also exploited by Rueping and coworkers to perform the reaction between trifluoromethylated N- arylhydrazones 50 and various aliphatic, aromatic and heteroaromatic α,β-unsaturated aldehydes 43 for the synthesis of 1,4-dihydropyridazines (S)-51 (Scheme 12).[32] The strong inductive effect of the CF3 group combined with the effect of acetic acid as an additive promoted a rapid formation of γhydrazonoaldehydes I-2 (acid–catalyzed diazene-to-hydrazone isomerization from I-1). Intramolecular hemiaminal formation and dehydration assisted by TFA led to the desired trifluorometylated heterocycles (S)-51 in good yields and high enantioselectivities. Scheme 12. Enantioselective cascade reactions of push-pull hydrazone 50 with α,β-unsaturated aldehydes 43. Recently, Ye and co-workers re-investigated the reaction of N- monosubstituted hydrazones with enones.[33] Preliminary results employing aryl-substituted N-methyl hydrazones 39 and 2- cyclohexenone in the presence of several amines as catalysts confirmed the aza-Michael reaction as the initial step in this process, in concordance with the previous results by Jørgensen.[27] However, prolonged reaction times and acid additives favored the formation of carba-Michael adducts which, upon subsequent intramolecular cyclization, lead to hemiaminaltype products 54 (Scheme 13). The reaction of N- monosubstituted hydrazones 52 (R2 = Alkyl and Aryl) and different enones 53 (cyclic and acyclics) catalyzed by primarysecondary diamine XI in the presence of variable ammounts of o-fluorobenzoic acid afforded enantioenriched bicyclic products 54 or 1,4-dihydropyridazines (R)-55 depending on the substitution patterns in both substrates. Scheme 13. Enantioselective reactions of N-monosubstituted hydrazones 52 with α,β-unsaturated ketones 53 and subsequent cyclizations. Ar = 3,5-(CF3)C6H3 (R)-Xb (10 mol%) N HOTBS Ar Ar 24-89% 60:40-95:5 dr toluene, rt R1O2C R2 N NPMP O NaClO2, KH2PO4 2-methyl-2-butene t-BuOH/H2O, 4 °C 70-98%, 74-99% ee R1O2C R2 N CO2H HN PMP NPMP NEtO2C nBu i) PIFA, MeCN/H2O, 0 °C ii) K2CO3, EtOH, 0 °C iii) HClcc, CHCl3, 4 °C EtO2C O CO2Et R2 O R2 + 43 45 O EtO2C NNH HR1O2C PMP Et2O/H2O HCl 6M 46 (S)-48 (S)-47 70%, 92% ee R1 = Et (S)-49 70-81%, 92-99% ee − O R + 43 50 I-2 (S)-51 H NNH Ar F3C N N F3C R Ar i) (S)-Xb (10 mol%) AcOH CH2Cl2, 0 °C ii) TFA (40 mol%) 59-82%, 76-99% ee NH N CF3 R Ar I-1 O NH N CF3 R Ar O + N NR1 R3 R2 R4 (R)-55 N NR2 R1 OH or (1S,5S)-54 H NtBu NH2 (S)-XI (10 mol%) R4 O R3 + 53 52 H NNH R2 R1o-F-PhCO2H (40-160 mol%) CPME, rt 69-98% 90-96% ee R1 = Aryl, COX R2 = Alkyl, Ar 55-99% 85-95% ee R4 ON R3 R2 N R1 H Aza-Michael Addition Carba-Michael Addition time R4 O R3 NNH R2 R1 H+ MINIREVIEW Scheme 28. Enantioselective synthesis of 2-pyrazolines (S)-88 by 6π electrocyclizations of α,β-unsaturated hydrazones (E)-87. Based on the reactions between trifluoromethylated N- arylhydrazones 50 and α,β-unsaturated aldehydes 43 (previously developed under aminocatalytic activation, section 2.5), Rueping and co-workers, performed a related phosphoric acid catalyzed strategy for the synthesis of 3-trifluoromethyl-1,4- dihydropyridazines (S)-51 (Scheme 29).[52] For this system, a plausible mechanism based on NMR spectroscopy and ESI-MS measurements was proposed. First, a condensation between the N-arylhydrazone and the α,β-unsaturated aldehyde provides the chiral ion pair I-1, from which a 6π disrotatory electrocyclization results in the formation of a second intermediate I-2. The catalytic cycle is completed with a proton abstraction by the phosphate anion to release the heterocycle (S)-51, along with the phosphoric acid XVId. Scheme 29. Enantioselective synthesis of 1,4-dihydropyridazines (S)-51 by 6π electrocyclizations involving trifluoromethylated N-aryl hydrazones 50 and enals. 4.3. Fischer Indolization of cyclohexanone hydrazones The Fischer indolization of phenylhydrazones, first reported over 125 years ago, is probably the most widely used procedure for the construction of indoles.[53] The development of the first catalytic enantioselective version of this reaction was a difficult task, due to the inherent poisoning of Brønsted acid catalysts by the ammonia formed during reaction, among other reasons. Remarkably, in 2011 List and co-workers identified a cation exchange resin for the efficient removal of ammonia from the reaction media, thereby increasing the turnover of phosphoric acid catalyst. Thus, the combination of a chiral (R)-SPINOL phosphoric acid (R)-XXII with Amberlite® CG50 resin was used to achieve highly enantioselective indolizations from 4- substituted cyclohexanone derived N-aryl N-benzyl hydrazones 89, leading to 3-substituted tetrahydrocarbazoles (S)-90 in moderate to good yields (Scheme 30).[54] Ar1N H NAr2Chlorobenzene 30 °C N N Ar2 Ar1 R O O R P O OH (S)-XVIc (10 mol%) (S)-88 85-99%, 76-96% ee (E)-s-trans-87 Ar1 N N Ar2 H O H N N Ar2 Ar1 H H P O O OOP OH O OO (Z)-s-cis-I-1 P O OO * * * 6π electrocyclization I-2 (S)-XVIc: R = 9-anthracenyl + + − − H NNH Ar CF3 + N N F3C Ar (S)-51 64-87%, 69-98% ee O OPOH O R R (R)-XVId: R = 9-phenanthryl 50 toluene, rt PO O O ∗∗ O N N F3C R1 Ar I-1 PO O O ∗∗ O N N F3C R1 Ar I-2 H R1 6π disrotatory electrocyclization (R)-XVId (8 mol%) O R1 43 P OH O OO * −++ − MINIREVIEW Scheme 30. First highly enantioselective Fischer Indolization catalysed by SPINOL-phosphate acid (R)-XXII. In agreement with the accepted mechanism for Fischer indolization, the catalyst (R)-XXII is thought to facilitate a hydrazone-enehydrazine tautomerization (I-1 to I-2, first step, Scheme 31). In this last intermediate I-2, different H-bond networks might be drawn. It´s proposed that one of the possible diastereomeric ion pairs undergoes the irreversible [3,3]- sigmatropic rearrangement faster (I-2 to I-3), accounting for the observed asymmetric induction via a DKR process.[55] The intermediate I-3 is a highly unstable double imine in which the aromaticity is immediately restored through a series of proton shifts and a C-N bond formation, yielding the product (S)-90, along with the ammonium salt of the catalyst. Finally, the active catalyst is regenerated by cation exchange by the resin. Scheme 31. Proposed mechanism for the asymmetric phosphoric acid catalysed Fischer indolization of N-aryl N-benzyl hydrazones 89. Summary and Outlook Hydrazones are ubiquitous reagents in organic synthesis that, according to the examples shown along this review, seem to be particularly well suited for organocatalytic activations which, in general, work under mild reaction conditions. Several welldesigned types of hydrazones have been developed to discover new reaction profiles which include nucleophilic formylation/acylation or cyanation strategies, cascade reactions where hydrazones sequentially act as nucleophile and electrophile or cycloaddition/cyclization processes to access valuable multifunctional compounds and nitrogen-containing heterocycles thereof. In this Minireview article, successful examples employing hydrazone reagents in combination with diverse organocatalysts (H-bonding-, Brønsted acid-, secondary/primary amine-, NHC-catalysts, and others) have been summarized. Plausible interactions between reagents and (often multifunctional) organocatalysts, sometimes supported by experimental evidences, have been used to propose activation modes, mechanisms and stereochemical models constructed to explain the outcome of the analysed reactions. It can be anticipated that these discoveries will inspire the development of new organocatalysts and activation strategies resulting in new applications of hydrazone-based reagents showing their true potential in asymmetric synthesis. Acknowledgements Authors acknowledge Ministerio de Economía y Competitividad of Spain (CTQ2013-48164-C2-1-P, CTQ201348164-C2-2-P, and predoctoral fellowship to E. M.), European FEDER funds, Junta de Andalucía (Grant 2012/FQM 1078, and a postdoctoral fellowship to M. G. R.) and Universidad de Sevilla (postdoctoral contract to D. M.). Keywords: Hydrazones • Asymmetric organocatalysis • H- bonding • Brønsted acid • Formylation/acylation • N-containing heterocycles [1] R. Lazny, A. 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Das, C. M. R. Volla, I. Atodiresei, W. Bettray, M. Rueping, Angew. Chem. Int. Ed. 2013, 52, 8008-8011. [53] B. Robinson, Chem. Rev. 1963, 63,373-401. [54] S. Müller, M. J. Webber, B. List, J. Am Chem. Soc. 2011, 133, 18534- 18537. [55] H. Pellissier, Adv. Synth. Catal. 2011, 353, 659-676. MINIREVIEW MINIREVIEW This Minireview summarizes strategies and developments regarding the use of N-monoalkyl-, N,N-dialkyl- and N-acyl hydrazones as reagents in asymmetric organocatalysis. The key structural elements governing their reactivities, and their diverse activation modes with organocatalysts will be discussed. Finally, versatile tranformations to access numerous multifunctional compounds and nitrogen-containing heterocycles are shown. María de Gracia Retamosa, Esteban Matador, David Monge,* José M. Lassaletta* and Rosario Fernández* Page No. – Page No. Hydrazones as singular reagents in asymmetric organocatalysis