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Synthesis 2009(6): 869-887  
DOI: 10.1055/s-0028-1087980
REVIEW
© Georg Thieme Verlag Stuttgart ˙ New York

Stereoselective Transformations of meso Bicyclic Hydrazines: Versatile Access to Functionalized Aminocyclopentanes

Chloée Bournaud, Florence Chung, Alejandro Pérez Luna, Morgane Pasco, Gauthier Errasti, Thomas Lecourt, Laurent Micouin*
Laboratoire de Chimie Thérapeutique, UMR 8638 associée au CNRS et à l"Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques 4, av de l’Observatoire, 75270 Paris cedex 06, France
Fax: +33(1)43291403; e-Mail: laurent.micouin@parisdescartes.fr;

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Publication History

Received 22 December 2008
Publication Date:
02 March 2009 (online)

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Biographical Sketches

Chloée Bournaud was born in 1978 in Saint-Denis (France). She studied at the Ecole Nationale Supérieure de Chimie de Clermont-Ferrand, where she received her engineer diploma in 2002. In 2006, she obtained her PhD under the supervision of Dr. Laurent Micouin (UMR 8638, Paris Descartes University). Then she obtained a postdoctoral position in the research group of Professor A. Alexakis at the University of Geneva (Switzerland). Since October 2008, she has been carrying out postdoctoral research in the laboratory of Professor J.-C. Fiaud under the guidance of Professor G. Vo-Thanh (UMR 8182, Paris Sud University). Her research studies focus on the field of asymmetric synthesis of nitrogen compounds and the development of new chiral catalysts and their application in synthesis.
Florence Chung was born in 1980 in Paris (France). She completed her master’s degree in chemistry in 2004 at the University Paris Descartes. In 2007, she obtained her PhD under the guidance of Dr. Laurent­ Micouin (UMR 8638, Paris Descartes University) on the fragment-based synthesis of tRNA ligands. She obtained a master diploma in management of technology and innovation in 2008 and started management activities. Currently, she is consultant for SMEs to help them finance their R&D activities.
Alejandro Perez Luna was born in London in 1977. He studied at the Ecole Nationale Supérieure de Chimie de Paris, where he obtained an engineer diploma in 2000. He obtained his PhD in the laboratory of Professor Henri-Philippe Husson (Paris Descartes University) under the guidance of Dr. Laurent Micouin in 2003. After a postdoctoral stay at the University of Geneva (Switzerland) as a Lavoisier Fellow in Professor Ernst Peter Kündig’s group, he got a permanent position in CNRS in 2004 and returned to Paris (Université Pierre et Marie Curie, Paris VI) as Chargé de Recherche in Professor Fabrice Chemla’s group. His scientific interests include the fields of metal-mediated synthesis, organozinc chemistry and asymmetric synthesis.
Morgane Pasco was born in Paris (France) in 1984. She studied at the Ecole Nationale Supérieure de Chimie de Paris (ENSCP ParisTech) where she obtained a master’s degree in 2007. She is currently in the second year of her PhD studies and is working on the functionalization of aminocyclopentanes in the field of fragment-based approach under the direction of Dr. Laurent Micouin (Paris Descartes University).
Gauthier Errasti was born in Soissons (France) in 1981. He studied at the Ecole Supérieure de Physique et de Chimie Industrielles de la ville de Paris (ESPCI ParisTech), where he obtained an engineer diploma in 2006. Since October 2006, he has been working on his PhD on the synthesis of asymmetric cyclohexyl amines by desymmetrization under the direction of Dr. Laurent Micouin (Paris Descartes University).
Thomas Lecourt was born in Vitry sur Seine in the south of Paris (France) in 1975. He studied at the Faculté des Sciences Pharmaceutiques et Biologiques (Paris Descartes University) in Paris, where he obtained a diploma in Pharmacy in 2004. He obtained his PhD under the guidance of Professor Pierre Sinaÿ at the Ecole Normale Supérieure in Paris in 2003. After a postdoctoral stay in Bristol (United Kingdom), under the supervision of Professor Varinder K. Aggarwal, he returned to Paris as a Maître de Conférences in the laboratory of Doctor Laurent Micouin (UMR 8638 CNRS - Paris Descartes University) in 2005. His scientific interests include the development of selective transformations on saccharide scaffolds, carbenoids and organoaluminum chemistry, and the design of bioactive compounds.
Laurent Micouin was born in Clermont Ferrand (France) in 1968. He studied at the Ecole Nationale Supérieure de Chimie de Paris, where he obtained an engineer diploma in 1990. He obtained his PhD in the laboratory of Professor Henri-Philippe Husson (Paris Descartes University) under the guidance of Professor J.-C. Quirion in 1995. After a postdoctoral stay in Marburg (Germany) as a Humboldt Fellow under the direction of Professor Paul Knochel, he got a permanent position in CNRS in 1996 and turned back to Paris (UMR 8638, Paris Descartes University) as Chargé de Recherche, and, since October 2005, Directeur de Recherche. His scientific interests include the development of new methods in the field of asymmetric synthesis of nitrogen compounds, organoaluminum chemistry, and the development of new tools in the field of fragment-based approaches for the discovery of bioactive compounds.

Abstract

Bicyclic hydrazines, prepared by cycloaddition of cyclopentadiene and diazo compounds, have great synthetic potential. Numerous asymmetric transformations of these building blocks have been developed, involving the electrophilicity of their strained double bond, ring-opening reactions or skeletal rearrangements. All these transformations are fully diastereoselective, and, in some cases­, enantioselective, enabling the preparation of a wide range of useful synthetic intermediates from a single precursor in a few synthetic steps.

1 Introduction

2 Preparation and Conformational Properties of Bicyclic
Hydrazines

3 Synthetic Transformations without Ring Fragmentation

3.1 Hydroboration

3.2 Hydroformylation and Halocarbomethoxylation

3.3 Dihydroxylation and Aminohydroxylation

3.4 Hydroarylation

3.5 Sequential Arylation-Alkynylation

3.6 Arylative Cyclization

3.7 Cyclopropanation

3.8 Pauson-Khand Reaction

3.9 Cycloaddition Reactions

4 Synthetic Transformations with Ring Fragmentation

4.1 Palladium-Catalyzed Ring-Opening Reactions

4.2 Copper-Catalyzed Ring-Opening Reactions

4.3 Rhodium-Catalyzed Ring-Opening Reactions

4.4 Ruthenium-Catalyzed Ring-Opening-Metathesis Reactions and Oxidative Cleavage

5 Rearrangements

5.1 Rearrangements Involving Allylic Cations

5.2 Rearrangements Involving Aziridiniums

6 Synthetic Applications

7 Conclusion

Key words

asymmetric synthesis - bicyclic hydrazines - ring-opening­ reactions - amines - asymmetric catalysis

1 Introduction

The original publication in 1928 by Diels and Alder of the now-classical Diels-Alder reaction [¹] is a well-known landmark for organic chemists and has probably outshined the report, published three years earlier, by Diels, Blom and Koll of a similar reaction between cyclopentadiene and azodicarbonyl derivatives. [²] This highly favored reaction can deliver, within a few hours, multigram quantities of cycloadducts 1, generally isolated in a quantitative manner by a simple precipitation from cyclohexane as stable solids (Figure  [¹] ). Besides its historical importance, this textbook experiment enables straightforward access to pyridazine heterocyclic systems with the simultaneous formation of two carbon-nitrogen bonds from cyclopentadiene with perfect atom-economy. Surprisingly, most of the synthetic applications of this remarkable reaction have been restricted for a long time to the preparation of cyclic diazenes from cycloadducts 1, and subsequent diradical generation by nitrogen extrusion. [³] Although this approach proved to be very efficient for the preparation of complex carbo-polycyclic skeletons [4] and is still actively used for mechanistic investigations on diradical species, [5] the two carbon-nitrogen bonds are lost during this process. However, cycloadducts 1 can be expected to have a much broader synthetic potential:

(1) the strained double bond of this diaza analogue of norbornene should be very reactive towards electrophiles;

(2) ring fragmentations, via nitrogen-nitrogen bond reduction, carbon-carbon oxidative cleavage or ring-opening metathesis or allylic carbon-nitrogen cleavage are also expected to be thermodynamically favored; and

(3) skeletal rearrangements involving carbocationic intermediates, typically observed in the norbornene series, could also be observed with these cycloadducts.

Figure 1 General reactivity pattern of meso bicyclic hydrazines

The combination of all these transformations should provide a useful synthetic arsenal for a large-scale elaboration of various functionalized amino-, diamino- or hydrazinocyclopentanes, potentially valuable scaffolds for target- or diversity-oriented synthesis of biologically active compounds. [6] The control of the diastereoselectivity of these various transformations, known to be generally hampered by the conformational flexibility of monocyclic or acyclic cyclopentane precursors, should be favored on rigid bicyclic adducts. [7] Last but not least, the meso symmetry of these compounds enables the development of stoichiometric or catalytic desymmetrization reactions, with potential access to enantioenriched material. [8]

The aim of this review is to summarize all the stereoselective transformations performed on meso bicyclic hydrazines, most of them being reported in the last decade, and to highlight the great synthetic potential of these widely available versatile building blocks.

2 Preparation and Conformational Properties of Bicyclic Hydrazines

Cycloadducts 1 are commonly obtained within a few hours in nearby quantitative yield from cyclopentadiene and acyldiazenes (Table  [¹] ). [9] Solvent or protective groups have little influence on the course of the reaction, which can be routinely performed on a 20 to 30 gram scale from commercially available dialkylazodicarboxylates. In limited cases, contamination of commercial diazenes by trace hydrogen chloride, resulting from their preparation by oxidation of the corresponding hydrazines with hypochlorite solution, can inhibit the cycloaddition and accelerate the gaseous decomposition of the dienophile. [¹0]

Table 1 Preparation of meso Bicyclic Hydrazines 1

R Reaction conditions Compd Yield (%) Ref.
Me Et2O, 5 ˚C 1a 100 [¹¹]
Et Et2O, 36 ˚C 1b  95 [¹²]
i-Pr CH2Cl2, r.t. 1c  81 [¹³]
t-Bu C6H6, r.t. 1d  91 [¹4]
Bn Et2O, 10 ˚C 1e 100 [¹5]
(CH2)2Ts 20 ˚C 1f >90 [¹6]
CH2CCl3 CCl4 1g  90 [¹7]

Acyldiazenes that are not commercially available or that are unstable can be generated by the in situ oxidation of the corresponding hydrazines. [¹8] This procedure is generally used for the preparation of polycyclic hydrazines such as 2, [¹9] 3, [²0] 4 [²¹] or cycloadducts from dialkoyldiazenes [²²] or alkoxyphosphinyldiazenes (Figure  [²] ). [²³]

Figure 2 Examples of meso polycyclic hydrazines

Cycloaddition with cyclic diazenes can lead to endo, exo or ‘planar’ isomers. Compounds 2 are preferentially obtained as endo isomers, as demonstrated by X-ray crystallographic studies, the two lone pairs of the pyramidal nitrogens being pseudo equatorial. [²4] These isomers are configurationally stable, but it has been demonstrated that compound endo-2b can isomerize to exo-2b using photochemical activation in the presence of triethylamine. [²5] Similarly, reduction of the double bond of compounds 2 leads to saturated exo isomers. The nitrogen atoms of cycloadducts 4 are planar. The conformational behavior of simple cycloadducts 1 is more complex. In addition to the possible conformational equilibrium through nitrogen inversion, they can exist as two symmetrical (S1, S2) and one dissymmetrical (DS) rotamers (Figure  [³] ).

Figure 3 Rotameric forms of bicyclic hydrazines

This dynamic behavior has been investigated by NMR and UV spectroscopic studies. Compound 1a gives a well-defined symmetrical ¹H NMR spectrum at 30 ˚C, but three different methyl signals of unequal intensities are observed at -58 ˚C, as a result of hindered rotation around the N-COOR bond at this temperature, and planar nitrogen atoms. [²6] This behavior is increasingly pronounced with the size of the R group, leading to non-equivalent ¹³C NMR signals for the two ethylenic carbons of compounds 1b-e at 20 ˚C as a result of interaction with non-equivalent inverting nitrogen lone pairs, and hindered carbamate rotations. [²7 ] This conformational equilibrium has several consequences: NMR studies of bicyclic hydrazines will always deliver spectra with very broad signals and require high-temperature experiments for correct structural assignments. Furthermore, the existence at ambient or lower temperature of several slowly equilibrating conformers with different symmetries can strongly complicate mechanistic interpretations of desymmetrization reactions of these ‘meso’ compounds. Finally, the pyramidal character of nitrogens ensures that the endo-face of these bicycles is permanently shielded by one carbamate group, preventing any addition from this face. As a result, it can be expected that all the intermolecular reactions of the double bond should be extremely exo diastereoselective.

3 Synthetic Transformations without Ring Fragmentation

The obvious structural analogy of compounds 1 with norbornene has been exploited to investigate the numerous asymmetric transformations described on this simple non-functional strained alkene. Diastereoselective or enantio­selective transformations have been envisaged.

3.1 Hydroboration

The hydroboration of compound 1a was first described by Allred et al. [²8] This reaction has proved to be exclusively exo-selective, leading to alcohol 5a, with the concomitant formation of fragmentation compounds 6a and 7a (Scheme  [¹] ). The formation of these by-products has been investigated, and can be explained by the β-anti elimination of the transient borane (leading to 6a) and subsequent hydroboration of the fragmentation product (leading to 7a after oxidative workup). This fragmentation is triggered by nucleophilic attack onto the borane, and is particularly important when generating the borane in situ from borohydrides. [²9 ] It can be circumvented by using diborane solutions, and performing the oxidation at 0 ˚C, with a premixed aqueous solution of sodium hydroxide and hydrogen peroxide. Under these conditions, compound 5a can be obtained in 85% yield from 1a on a 50 gram scale. [³0]

Scheme 1 Reagents and conditions: (a) (i) BH3, THF, 0 ˚C; (ii) H2O2, HO-.

Table 2 Rhodium-Catalyzed Asymmetric Hydroboration

Entry Compd Solvent Liganda Yield (%) ee (%) Configb
 1 1e toluene (S,S)-BDPP 40 66 (1S)
 2 1e THF (S,S)-BDPP 47 64 (1S)
 3 1e Et2O (S,S)-BDPP 56 60 (1S)
 4 1e DME (S,S)-BDPP 90 84 (1S)
 5 1e CH2Cl2 (S,S)-BDPP  3 ndc ndc
 6 1e DME (R)-BINAP 20  0 (1S)
 7 1e DME (R)-QUINAP 11 24 (1S)
 8 1e DME (S,S)-DIOP 46 44 (1R)
 9 1e DME L1 30  4 (1R)
10 1e DME L2 13  0 ndc
11 1e DME L3 20  2 (1S)
12 1e DME L4  5  6 (1S)
13 1e DME L5 36  6 (1R)
14 1e DME L6 <5 ndc ndc
15 1b DME (S,S)-BDPP 49 83 ndc
16 1c DME (S,S)-BDPP 50 80 ndc
17 1d DME (S,S)-BDPP 58 80 ndc
18 2b DME (S,S)-BDPP 78 60 ndc
a BDPP = 2,4-bis(diphenylphosphino)pentane; BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; QUINAP = 1-(2-diphenyl­phosphino-1-naphthyl)isoquinoline; DIOP = 4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane.
b (1S) means (1S,4R,5R).
c Absolute configuration not determined.

The structural analogy of adducts 1 with norbornene has led to the development of enantioselective versions of this reaction. The metal-catalyzed hydroboration with dialkoxyboranes [³¹] has been selected for this purpose among various desymmetrization strategies reported on norbornene. [³²] Under the best conditions (Table  [²] , entry 4), the alcohols could be obtained with ee up to 84% and 90% yield. [³³] It is interesting to note that the stereochemical outcome of the reaction was the same as previously reported for the hydroboration of norbornene with this ligand. Similarly, the use of (S,S)-4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane [(S,S)-DIOP] led to the alcohol of opposite configuration, as already observed for norbornene. [³¹c] This reaction can be conducted on a scale of 5 to 10 grams. Dimethoxyethane proved to be the solvent of choice (entries 1-5), and the enantioselectivity was not affected by the nature of the carbamate moiety (entries 15-17) whereas compound 2b was hydroborated with lower enantioselectivity. Although several hydroboration reactions have been reported in dimethoxyethane at -78 ˚C, it is conducted preferentially at -50 ˚C in order to avoid the freezing of dimethoxyethane (mp -58 ˚C). Only a few ligands were evaluated in this reaction (entries 6-14), 2,4-bis(diphenylphosphino)pentane (BDPP) seems to be the most appropriate among several P,P, [³²o] [³4] P,N [³5] or monodentate ligands. [³6] Other boranes can be used for this transformation, such as pinacolborane, but catecholborane seems to be the optimal reagent with these substrates. [³7]

The nature of the rhodium source has some influence on the reaction course (Table  [³] ). Interestingly, the formation of compound 5e was observed in the absence of ligand, accompanied by the fully hydrogenated substrate 8e (entry 5). The lower selectivity obtained with [Rh(µCl)nbd]2 (entry 3) could thus be related to an incomplete formation of the chiral catalytic species under the reaction conditions. A lower metal loading also led to a decrease of conversion and enantioselectivity (entry 2). The use of cationic rhodium precatalyst only affected the hydroboration reaction slightly (entry 4).

Table 3 Asymmetric Hydroboration: Precatalyst Influence

Entry Precatalyst, amount (mol%) Product Yield (%)a ee (%)b
1 [Rh(µCl)cod]2 (1) 5e 90 84
2 [Rh(µCl)cod]2 (0.5) 5e 48 58
3 [Rh(µCl)nbd]2 (1) 5e 78 64
4 [Rh(cod)]BF4 (1) 5e 88 76
5c [Rh(µCl)cod]2 (1) 5e8e 14
35 		-
-
a Isolated yield. b (1S,4R,5R) is the major enantiomer.
c No ligand.

Although iridium-catalyzed hydroboration of endocyclic alkenes is known to be sluggish, [³8] as bicyclic hydrazines are extremely reactive substrates towards electrophilic transformations, hydroboration with iridium catalysts was investigated. The use of electron-rich diphosphines such as Josiphos, [³9] P,N ligands, [40] monodentate phosphoramidites or phosphites [4¹] enabled the reaction to proceed smoothly in tetrahydrofuran (Scheme  [²] ).

Scheme 2 Iridium-catalyzed asymmetric hydroboration: selected ligands­

Interestingly, a complete reversal of the enantioselectivity was noticed when switching from rhodium to iridium, with the same ligands. [³9] This phenomenon was attributed to a mechanistic divergence in which a metal-hydride insertion is involved with rhodium, whereas a boryl migration is believed to occur with iridium. Although this reversal of enantioselectivity proved to be systematic with these meso substrates, it should be noted that the exact mechanism of metal-catalyzed hydroboration has been discussed for decades and seems to be highly dependent on substrate, metal and borane sources. [4²]

3.2 Hydroformylation and Halocarbomethoxyl­ation

The asymmetric hydroformylation of norbornene has been reported by several groups, using platinum or rhodium precatalysts and various diphosphine ligands. [4³] Enantiomeric excesses were generally moderate, until a recent report from an Angem process team describing this reaction with the combination of Rh(CO)2(acac) and TangPhos affording 92% ee and 100% conversion starting from 753 grams of norbornene. [4³e]

The corresponding reaction on bicyclic hydrazines is less documented. One example of racemic hydroformylation of compound 2b has been described, [44] and two reports on asymmetric hydroformylation have been disclosed (Table  [4] ). [4³e] [45]

Table 4 Rhodium-Catalyzed Asymmetric Hydroformylation

Entry Substrate Rh Ligand PH2/CO (bar) Temp (˚C) Yield (%)a ee (%)b
 1c 1d Rh(CO)2(acac) L12  35 60 ndd 56
 2c 1d Rh(CO)2(acac) L10  35 60 ndd 19
 3c 1d Rh(CO)2(acac) L9  35 60 ndd  8
 4c 1e Rh(CO)2(acac) L12  35 60 ndd 60
 5c 1e Rh(CO)2(acac) L10  35 60 ndd 44
 6c 1e Rh(CO)2(acac) L19  35 60 ndd  3
 7 1e Rh(CO)2(acac) L11  40 80 84 45
 8 1e Rh(CO)2(acac) L11  20 45 85 53
 9 1e [Rh(cod)Cl]2 L11  20 45 18 50
10 1e RhHCO(PPh3)3 L11  20 45 88 53
11 1e Rh(CO)2(acac) L11  20 20 80 59
12 2a Rh(CO)2(acac) L11  45 80 84 52
13 4 Rh(CO)2(acac) L11 100 -4 21 77
a Isolated yield of alcohol 10. b Determined by chiral HPLC of 10.
c Conversion and ee determined for the aldehyde 9.
d 100% conversion.

Although the hydroformylation reaction always delivers the exo compounds 9 in a fully diastereoselective manner, these aldehydes are sensitive and easily epimerize or lead to fragmentation of the bicycle. [44] It is therefore more convenient to analyze this transformation after in situ reduction to the corresponding alcohols 10. The combination of Rh(CO)2(acac) and diphosphines L9-L11 enables the hydroformylation to proceed with excellent conversion and ee up to 60% with bicycles 1d,e (Table  [4] ). The best results seem to be obtained at relatively low pressure and temperature for these substrates, but still need to be improved. More rigid substrates such as 4 are hydroformylated with higher enantioselectivity, but the general poor solubility of these planar compounds will probably complicate further optimization.

One example of halocarbomethoxylation of bicyclic hydrazines has been reported, with the concomitant formation of the meso diester 11 (Scheme  [³] ). [46]

Scheme 3

3.3 Dihydroxylation and Aminohydroxylation

As for norbornene, the excellent reactivity of the double bond of bicyclic hydrazines enables a smooth dihydroxylation using a small amount of osmium tetroxide catalyst (Scheme  [4] ). [47] This exclusively exo dihydroxylation can be conducted on a large scale (>10 grams), delivering excellent precursors for the preparation of hydroxylated diaminocyclopentanes (see above).

Scheme 4 Reagents and conditions: (a) OsO4 (cat.), NMO (1.2 equiv), acetone-H2O (2:1); (b) OsO4 (cat.), Et3NO, t-BuOH, H2O, Py.

The Sharpless asymmetric aminohydroxylation reaction, scarcely reported for the desymmetrization of Z alkenes, [48] has been investigated on compound 1e (Table  [5] ). [49]

Table 5 Asymmetric Aminohydroxylation of 1e

Entry RNH2 Solvent Time Yield (%)a ee (%)b
 1 TsNH2 MeCN-H2O (1:1)  5 d 48  0
 2 MsNH2 MeCN-H2O (1:1) 24 h 78 16
 3 BocNH2 n-PrOH-H2O (1:1) 24 h 56  3
 4 BnCO2NH2 n-PrOH-H2O (1:1) 24 h - ndc
 5 TsNH2 n-PrOH-H2O (1:1)  4 d 75  5
 6 TsNH2 t-BuOH-H2O (1:1)  5 d 46  0
 7 TsNH2 MeCN-H2O (2:1)  5 d 71  0
 8 MsNH2 n-PrOH-H2O (1:1)  9 d 30 19
 9 MsNH2 THF-H2O (1:1) 24 h 72  4
10d MsNH2 MeCN-H2O (1:1) 24 h 68 12
11e MsNH2 MeCN-H2O (1:1) 24 h 73  8
12f MsNH2 MeCN-H2O (1:1) 24 h 62  6
13g MsNH2 MeCN-H2O (1:1) 24 h 53  0
14h MsNH2 MeCN-H2O (1:1) 48 h 67 24
a Isolated yield. b Determined by chiral HPLC.
c Not determined.
d With (DHQD)2AQN.
e With (DHQD)2PYR.
f With (DHQD)MEQ.
g With (DHQD)(4-chlorobenzoate).
h A 2.5 ratio of ligand to osmium was used.

Aminoalcohols 15 were obtained in 30-78% yield as single diastereomers, but with very low ee. This poor selectivity can be tentatively explained by the relative steric hindrance of the substrate, which barely fits into the binding pocket of the chiral catalyst. This phenomenon is corroborated by the unusually low turnover frequency of the catalytic cycle.

3.4 Hydroarylation

Norbornene is a substrate of choice for the study of metal-catalyzed reductive arylation since its metallo-arylation delivers a reactive species devoid of any hydride for the classical evolution to a Heck-type product by a β-hydride syn-elimination. Bicyclic hydrazines behave similarly, provided that the transient organometallic species is stable enough to undergo a second intra- or intermolecular reaction faster than a β-fragmentation of the strained carbon-nitrogen bond (Scheme  [5] ).

Scheme 5

The palladium-catalyzed hydroarylation of hydrazine 1b has been reported. It delivers the hydroarylated hydrazine 16 with 17 as a side product (Table  [6] ). [50] The arylation occurs exclusively in an exo manner. The proposed structure of 17 seems to be incorrect and it is probably the fragmentation product of general structure 18 (Table  [7] ), as proposed by the same authors in a subsequent patent. [5¹] The fragmentation is more pronounced with electron-deficient aromatic systems (Table  [6] , entries 2 and 4).

Table 6 Palladium-Catalyzed Hydroarylation of 1b

Entry RX Product Yield (%)a
1 PhI 16a18a 77
 5
2

16b18b 52
21
3

16c
18c 		77
 6
4

16d
18d 		46
26
5

16e
18e 		86
 2
a Isolated yield.
Table 7 Palladium-Catalyzed Hydroarylation of Polycyclic Hydrazines

Entry Compd Ar Product Yield (%)a
1 2b Ph 19a20a 18 46
2 4 Ph 21a22a  3 67
3 2b

19b20b  5 63
4 4

21b22b  4 64
5 2b

19c20c  7 63
6 4

21c22c  6 69
a Isolated yield.

A similar transformation has been reported on polycyclic hydrazines 2b and 4 (Table  [7] ).

In this case, the fragmentation products 20 and 22 are the major products of the reaction, especially if a fluoride source is added to the reaction mixture. [5¹] This preferential pathway has been explained by an acid-catalyzed fragmentation triggered by a nucleophilic attack of the fluoride onto the organopalladium intermediate. Structural assignment of fragmentation product 20a was secured by X-ray crystal structure analysis.

An important improvement of this method was described to occur when switching from palladium to rhodium. Dia­stereoselective and enantioselective hydroarylation of 1d was reported with several heterocycles using rhodium hydroxide as precatalyst and Josiphos as chiral ligand (Table  [8] ). [5²]

The mechanism of this remarkable transformation has been investigated in detail (Scheme  [6] ), using deuteration studies.

Scheme 6 The chemodivergent pathway of a rhodium-catalyzed hydroarylation reaction

The formation of the hydroarylated compound under non-reducing conditions can be explained by a stereoselective carborhodation, leading to intermediate A. With heterocycles having an activated ortho hydrogen, the rhodium center undergoes an oxidative addition, leading to intermediate B. Reductive elimination followed by proto-demetalation with boronic acid delivers the hydroarylated species. This pathway is favored over the fragmentation process if the oxidative addition is faster than the fragmentation, explaining why only ‘activated’ heterocycles are efficient in this transformation. It is interesting to note that the first steps of this pathway are very similar to the first steps of the palladium-based Catellani reaction using norbornene as a catalyst. [5³]

Table 8 Rhodium-Catalyzed Asymmetric Hydroarylation of 1d

Entry Ar Product Yield (%) ee (%)
1

23a 89 62
2

23b 66 99
3

23c 47 98
4

23d 39 83

3.5 Sequential Arylation-Alkynylation

The relative stability of the organopalladium intermediate of the arylation reaction enables a tandem coupling process with alkynes (Table  [9] ). This diastereoselective sequential­ functionalization opens the way to polysubstituted diaminocyclopentanes. [50]

Table 9 Palladium-Catalyzed Tandem Arylation-Alkynylation of 1b

Entry RX Product Yield (%)
1 PhI 24a 52
2 PhCH=CH2Br 24b 18
3 BnCl 24c 12

3.6 Arylative Cyclization

A variation of the tandem coupling process has been proposed using hydroxyrhodium species as a catalyst and bifunctional organoboron reagents (Scheme  [7] ). [54] The use of t-Bu-amphos, an electron-rich, sterically bulky ligand, is essential for preventing the proto-deborylation of the organorhodium intermediate in water before the conjugate addition step. This reaction enables the creation of three asymmetric centers in only one step, in a fully diastereoselective manner.

Scheme 7

3.7 Cyclopropanation

The use of conjugated bifunctional vinylboron reagents instead of aromatic analogues is an extension of the preceding reaction. In this case, the initial carborhodation is followed by a rare 1,6-conjugate addition, leading to the formation of a cyclopropyl ring (Scheme  [8] ). The exclusive formation of a Z-olefin is the result of the proto­demetalation of an oxo-π-allyl rhodium intermediate complex. [55]

Scheme 8

A ruthenium-catalyzed cyclopropanation of hydrazine 1b was reported (Scheme  [9] ). Interestingly, this reaction does not seem to involve a ruthenium vinylcarbenoid species (which could have favored ring-opening-metathesis side reactions), but proceeds instead via a ruthenocyclopentene, followed by two intramolecular carboxylate transfers. [56]

Scheme 9

In contrast, a metal vinylidene complex was evoked as a key intermediate in the alkylidenecyclopropanation of hydrazine­ 1e catalyzed by platinum(II)-coordinated phosphinous­ acid (Scheme  [¹0] ). [57] The classical cyclopropanation of bicyclic hydrazines with diazomethane was also reported. [58]

Scheme 10

3.8 Pauson-Khand Reaction

The diastereoselective reaction of hydrazine 1b with cobaltcarbonyl acetylene complexes was first reported by Pauson and Khand. [59] The challenging enantioselective version of this intermolecular reaction has been evaluated on the same substrate with various chiral N-oxides as additives. [60] The modest levels of enantioselectivity parallel the results obtained with norbornene (Scheme  [¹¹] ).

Scheme 11

3.9 Cycloaddition Reactions

Several [2+2], [6¹] [3+2] [¹³] [6²] or [4+2] [6³] cycloaddition reactions have been reported on bicyclic hydrazines (Figure  [4] ). All occurred diastereoselectively, generally with excellent chemical yields.

Figure 4 Selected examples of cycloadducts from bicyclic hydra­zines

4 Synthetic Transformations with Ring Fragmentation

Although sometimes circumvented, the β-fragmentation of metalated bicyclic hydrazines can be a favorable process, delivering functionalized hydrazinocyclopentenes of great synthetic value. Several methods have been designed in order to render this pathway synthetically useful.

4.1 Palladium-Catalyzed Ring-Opening Reactions

As already mentioned in reductive arylation studies (see section 3.4), the β-fragmentation of the transient organopalladium intermediate can be the main pathway following the carbopalladation step. This reactivity was first exploited in allylation reactions.

The palladium(II)-catalyzed allylation of bicyclic hydrazines was reported to deliver 1,2 disubstituted cyclopentenes in a diastereoselective manner (Table  [¹0] ). Allyltributyltin is the reagent of choice in this transformation, whereas the use of allyltrimethylsilane leads to lower yields. This reaction is catalyzed by Lewis acids, and takes place faster when conducted in ionic liquids. [64] Similar reactivity was reported with phenyltributyltin as a nucleophile. [65]

Table 10 Palladium-Catalyzed Allylation-Fragmentation of Hydrazines­

Entry Compd Solvent Time (h) Product Yield (%)
1 1b toluene  5 37 95
2 1b [bmim]PF6  1 37 90
3 2a toluene 36 38 20
4 2a [bmim]PF6  8 38 89
5 2b [bmim]PF6  8 39 95
6 2c [bmim]PF6  8 40 88
7 2d [bmim]PF6 10 41 85
8 2e [bmim]PF6 10 42 95
9 2f [bmim]PF6 10 43 78

A similar stereoselective ring opening was reported to take place with aryl- or alkenylboronic acids (Table  [¹¹] ). [66] This palladium-catalyzed fragmentation is assisted by iodine, which proved to be superior than scandium triflate in this case. A large variety of racemic trans vicinal disubstituted hydrazinocyclopentenes have been prepared according to this procedure.

Table 11 Palladium-Catalyzed Arylative Fragmentation of Hydrazines

Entry Compd R² Time (h) Product Yield (%)
 1 1b Ph 24 18a 93
 2 1b

36 44 79
 3 1b

36 45 72
 4 1b

36 46 53
 5 1c Ph 24 47 63
 6 1c

36 48 73
 7 1c

36 49 77
 8 1d

36 50 37
 9 2b Ph 24 20a 35
10 2b

36 51 61
11 2c

36 52 60
12 2c Ph 24 53 52
13 2e Ph 24 54 56
14 2f Ph 24 55 40
15 2b

36 56 84
16 2c

36 57 89
17 2f

36 58 64
18 2e

36 59 33

Another development of this palladium(II)-catalyzed transformation was reported to use organoindiums as nucleophiles. The use of these preformed organometallic species enables the stereoselective introduction not only of an allyl function, but also of benzyl groups (Table  [¹²] ). [67]

Table 12 Palladium-Catalyzed Fragmentation with Organoindium Nucleophiles

Entry Compd R²Br Product Yield (%)
 1 1b allylBr 37 95
 2 1c allylBr 60 86
 3 1d allylBr 61 88
 4 1e allylBr 62 80
 5 1b BnBr 63 89
 6 1c BnBr 64 80
 7 1d BnBr 65 75
 8 1e BnBr 66 72
 9 1b 4-O2NC6H4CH2Br 67 43
10 1c 4-O2NC6H4CH2Br 68 35

All of the previous fragmentation reactions occur following a palladium(II) carbometalation step. A different fragmentation pathway, based on a palladium(0)-palladium(II) catalytic cycle, has been proposed. Although palladium-catalyzed allylic substitutions of allylic amines are quite uncommon, [68] the oxidative insertion of a palladium(0) species into the carbon-nitrogen bond of bicyclic hydrazines could be favored by strain release. Several ‘soft’ nucleophiles can indeed react with bicyclic hydrazines in the presence of palladium(0) precatalysts, leading to various 1,4-cis-hydrazinocyclopentenes in a diastereoselective manner (Table  [¹³] ). [69]

Table 13 Palladium-Catalyzed Allylic Substitution of Hydrazines

Entry NuH Product Yield (%)
1a PhOH 69 83
2a 3-BrC6H4OH 70 83
3b phthalimide 71 84
4 CH3NO2 72 75
5c CH2(CO2Et)2 73 76
6c CH2(CO2 t-Bu)2 74 75
a Addition of a small amount of NaH (5 mol%) was necessary to generate the reactive Pd(0) species.
b Performed with Pd2(dba)3 under reflux.
c NaH (1 equiv) of was used.

As the oxidative insertion is assumed to be the stereodetermining step of this process, several chiral ligands were investigated in order to control the enantioselectivity of this fragmentation. The best results were obtained with phenyloxazoline (PHOX) ligands, leading to the 1,4-cis-hydrazinocyclopentenes with enantioselectivities of up to 58% ee (Table  [¹4] ). Although this result is still to be improved, enantioenriched products (90% ee) were obtained after a single recrystallization. The regio-, diastereo- and enantioselectivities of this transformation have been assessed by X-ray crystallography.

Table 14 Palladium-Catalyzed Asymmetric Allylic Substitutions

Entry Compd NuH Product Yield (%)a ee (%)b
1 1e PhOH 69 82 50
2c 1e PhOH 69 80 58
3 1c PhOH 75 88 40
4 1d PhOH 76 75 36
5 2b PhOH - <5 nd
6 1e 3-BrC6H4OH 70 72 50
7 1e phthalimide 71 84 30
8 1e CH3NO2 72 70 44
9 1e CH2(CO2Et)2 73 82 45
10 1e CH2(CO2 t-Bu)2 74 71 49
a Isolated yield.
b Determined by chiral HPLC.
c Performed in toluene.

4.2 Copper-Catalyzed Ring-Opening Reactions

Copper is generally considered to be an excellent catalyst for allylic substitutions involving ‘hard’ nucleophiles such as alkylzinc or alkylaluminum reagents. [70] The combination of copper salts and phosphoramidite ligand L15 has been reported to catalyze the nucleophilic fragmentation of bicyclic hydrazines. 1,2-trans-Hydrazinocyclopentenes were obtained with enantioselectivities up to 86% and excellent conversions (Table  [¹5] ). [7¹]

Table 15 Copper/Phosphoramidite-Catalyzed Asymmetric Ring-Opening Reaction

Entry Compd R²M Product Conv (%) ee (%)a
 1 2b Et2Zn 75  38  3
 2 4 Et2Zn 75  22  8
 3 4 Bu2Zn 76  34 18
 4 2b Et3Al 75 >98 66 (+)
 5 2b Me3Al 77 >98 80 (+)
 6 4 Et3Al 75  94 78 (+)
 7 4 Me3Al 78 >98 86 (+)
 8b 4 Me3Al 78 >98 64 (-)
 9 4 (Pr)3Al 79 >98 54 (+)
10 4 (i-Bu)3Al 80s  95 14 (-)
a Determined by chiral HPLC. b With L16 as a preligand.

The dramatic reactivity differences observed when changing dialkylzinc for trialkylaluminum nucleophiles (entries 2 and 6) and the unusual reversal of enantioselectivity obtained with L16 (entries 7 and 8) was later explained by the reaction of the phosphoramidite with trialkylaluminum, generating in situ a dialkyl phosphoramine which proved to be the real ligand in this asymmetric transformation (Scheme  [¹²] ). [7²]

Scheme 12

This mechanistic investigation enabled the preparation of a new class of ligands (dialkyl or diarylphosphoramines, the ‘simplephos’ family) [7³ ] which proved very efficient for this copper-catalyzed transformation (Table  [¹6] ).

Table 16 Copper/Simplephos-Catalyzed Asymmetric Ring-Opening Reaction

Entry Compd L R²M Yield (%) ee (%)a
 1 4 L17 Me3Al 94 79 (-)
 2 2b L17 Me3Al 86 67 (-)
 3 2b L18 Me3Al 74 72 (+)
 4 2b L19 Me3Al 92 46 (-)
 5 2b L20 Me3Al 85 85 (+)
 6 4 L17 Et3Al  6 55
 7 2b L17 Et3Al 56 48
 8 2b L21 Me3Al 78 90 (-)
 9 2b L22 Me3Al 81 94 (-)
10 2b L23 Me3Al 85 88 (-)
11 4 L21 Me3Al 90 89 (-)
12 4 L22 Me3Al 85 86 (-)
13 4 L23 Me3Al 12 78 (-)
a Determined by chiral HPLC.

4.3 Rhodium-Catalyzed Ring-Opening Reactions

Although palladium catalyzes the arylative fragmentation of bicyclic hydrazines with arylboronic acids, this transformation leads to racemic trans-1,2-hydrazino cyclopentenes. The use of rhodium as catalyst has, in contrast, been reported to enable an enantioselective arylative ring opening (Table  [¹7] ). Thus, enantioselectivities up to 89% were obtained for this transformation using [Rh(C2H4)Cl]2 and TolBINAP as a ligand. [74]

Table 17 Rhodium-Catalyzed Asymmetric Arylative Fragmentation of Hydrazines with L24

Entry Ar Time (h) Conv (%) Yield (%) ee (%)a
1 Ph 12 >98 nd 52
2 4-IC6H4 18 >98 62 54
3 4-MeOC6H4 18  90 65 52
4 2-MeOC6H4 48  40 35  0
5 3-MeOC6H4 18 >98 90  0
6 3-FC6H4 18 >98 88 70
7 4-MeC6H4 18 >98 90 46
8 3-NCC6H4 18 >98 65 12
9 3-O2NC6H4 48  95 20 89
a Determined by chiral HPLC.

A major improvement of this reaction was described recently, using t-Bu-Josiphos ligand and [Rh(cod)OH]2 as precatalyst (Table  [¹8] ). The presence of water is important for minimizing the competitive pathway leading to the hydroarylated bicyclic hydrazine (see section 3.4). Under these conditions, the 1,2-hydrazinocyclopentenes can be obtained in excellent enantioselectivities. [5²]

Table 18 Rhodium-Catalyzed Asymmetric Arylative Fragmentation of Hydrazines with Josiphos Ligand

Entry Ar Yield (%) ee (%)
 1 2-FC6H4 53  99
 2 2-MeC6H4 99  97
 3 2-Me-4-MeOC6H3 55  99
 4 2-MeOC6H4 75  99
 5 5-Cl-2-MeOC6H3 96    99
 6 4-F-2-MeOC6H3 54 >99
 7 2-(1-methoxyquinolyl) 91  96
 8 naphthyl 68  99
 9 4-F3CC6H4 49  84
10 4-MeO2CC6H4 58  86
11 Ph 85  68
12 3-MeO-4-MeOC6H3 80  50

Not only aromatic boronic acids, but also alkynylboronic esters can serve as nucleophiles in this transformation, leading to interesting alkynyl cyclopentenic hydrazines with enantiomeric excess values up to 66% (Table  [¹9] ). [75]

Table 19 Rhodium-Catalyzed Asymmetric Alkynylative Fragmentation of Hydrazines

Entry Compd R² Conv (%) Yield (%) ee (%)
1 1e n-Bu 66 43 60
2a 1e n-C6H13 25 nd 38
3 1e Ph 85 67 66
4 1d Ph 83 48 52
5a 1d PhCºC 25 nd 33
6 1e t-Bu 43 36 54
7a 1e TMS 38 18 58
a Performed with TolBINAP L24.

The high affinity of rhodium for carbon monoxide and its reactivity with boronic acids has been exploited to increase the chemical diversity generated by the fragmentation of bicyclic hydrazines. When conducted under an atmosphere of carbon monoxide, a formal allylic substitution with acyl anion nucleophiles can be obtained, leading to cyclopentenic 1,2-hydrazino ketones in a diastereoselective manner and excellent chemical yields (Table  [²0] ). An enantioselective version of this remarkable transformation is to be developed. [76]

Table 20 Rhodium-Catalyzed Carbonylative Arylation of Hydrazines

Entry R Product Yield (%)
 1 Ph 81 94
 2 4-MeOC6H4 82 96
 3 3-MeOC6H4 83 84
 4 2-Me-4-MeOC6H3 84 91
 5 2-MeC6H4 85 84
 6 3-MeC6H4 86 94
 7 4-MeC6H4 87 91
 8 2-naphthyl 88 88
 9 3-TMSC6H4 89 83
10 3-CH2=CHC6H4 90 83
11 4-ClC6H4 91 83
12 4-FC6H4 92 77
13 4-F3CC6H4 93 57
14 4-AcC6H4 94 38
15 3-thienyl 95 39
16 (E)-styryl 96 63

4.4 Ruthenium-Catalyzed Ring-Opening-Meta­thesis Reactions and Oxidative Cleavage

By analogy with norbornene, the ring-opening metathesis of bicyclic hydrazines has been investigated. As expected, oligomerization of 1b is promoted by Grubbs’ catalyst whereas cross-metathesis product 97/98 is obtained as a Z/E mixture in the presence of a terminal aromatic alkene. [77]

Scheme 13

Several catalysts have been described for the asymmetric ring opening of bicyclic hydrazines (Table  [²¹] ). Catalyst 99 delivers only the E isomer with enantiomeric excess values ranging from 68% to 92%; the enantioselectivity of this transformation varies with the steric requirements of the terminal alkene partner. [78] In contrast, catalysts 100 and 101 led to an olefinic mixture, in 68% ee for the major E isomer. [79]

Table 21 Asymmetric Ring Opening of Bicyclic Hydrazines

Entry Compd R² Catalyst* Yield (%) (E/Z) ee (%) E (Z)
1 1b Ph 99 65 (100:0) 92
2 1b n-Hex 99 55 (100:0) 68
3 1b c-Hex 99 53 (100:0) 87
4 2b Ph 100 99 (1.2:1) 68 (15)
5 2b Ph 101 nd (1.2:1) 68 (10)

The ruthenium tetroxide mediated oxidative cleavage of compound 102 can deliver cyclic hydrazoacetic ester 103 in an efficient manner (Scheme  [¹4] ). [80]

Scheme 14  Reagents and conditions: (a) RuO2, NaIO4, EtOAc; (b) CH2N2, MeOH, 89% overall yield.

5 Rearrangements

Ring fragmentations accompanied by skeletal rearrangements have been frequently described on norbornene and related strained bicycles. [8¹] A similar behavior has been reported with bicyclic hydrazines.

5.1 Rearrangements Involving Allylic Cations

The thermal and/or catalyzed fragmentation of bicyclic hydrazines has been intensively investigated. [8²] A [3,3]-sigmatropic rearrangement has been proposed to explain the stereoselective formation of compound 104 from the corresponding bicyclic hydrazine (Scheme  [¹5] ). The corresponding hydrazines 1 do not rearrange under similar thermal conditions. This transformation is also dramatically accelerated by acids. [8²d] The preference for a concerted pathway instead of a two-step process has been assessed by kinetic studies. [8²a]

Scheme 15 Reagents and conditions: (a) thermal activation (100 ˚C) or acidic activation.

On the other hand, the diastereoselective formation of compound 106 has been reported to involve a cationic intermediate (Scheme  [¹6] ). The formation of the [5.5]bicyclic heterocycle 107 has been ruled out by analysis of spectral data. [8³]

Scheme 16 Reagents and conditions: (a) CF3COOH, CCl4, r.t., quant.

The acid-catalyzed rearrangement of hydrazines 1d,e has been reported. The diastereoselective formation of [5.6]bicycles 108 and 109 was first described under various acidic conditions. [69] These structures have recently been reassigned by X-ray crystallography to be the [5.5]bicyclic systems 110 and 111 (Table  [²²] ). [84] This correct structural assignment rules out a concerted [3,3]-sigmatropic pathway for this transformation which can be conducted on a large scale (10 grams) using sulfuric acid in trifluoroethanol (entry 5). The use of copper as catalyst enables very fast and efficient access to these bicycles (entries 6 and 7).

Table 22 Acid-Catalyzed Rearrangement of Hydrazines 1d,e

Entry Compd Acid (equiv) Time Yield (%)
1 1e SnCl4 (0.5) 2 h 73
2 1e Zn(OTf)2 (1.0) 24 h 82
3 1e BF3˙OEt2 (1.0)  1 h 43
4 1e CF3COOH  1 h 55
5 1e H2SO4 18 min 90
6 1e (CuOTf)2PhH (0.1)  5 min 98
7 1d (CuOTf)2PhH (0.1)  5 min 99

This rearrangement can be coupled with a functionalization of the final hydrazine by N-arylation in a sequential manner, using the same copper source (Table  [²³] ). [84] The overall transformation is highly efficient.

Table 23 Sequential Ring-Opening and N-Arylation of Hydrazines 1d,e

Entry Compd Ar Yield (%)
1 1d Ph 81
2 1e Ph 48
3 1d 4-O2NC6H4 72
4 1d 4-ClC6H4 66
5 1d 4-(TsNMe)C6H4 74
6 1d 4-MeO2CC6H4 72
7 1d 3-F3CC6H4 62
8 1d 3-MeOC6H4 66
9 1d 3-thienyl 62

5.2 Rearrangements Involving Aziridiniums

As for norbornene, electrophilic additions onto bicyclic hydrazines can trigger interesting skeletal rearrangements. The transient secondary cation can indeed be stabilized by one nitrogen, leading to an aziridinium which can be attacked in a regioselective manner, affording the expected 1,2-adduct or a rearranged hydrazine (Scheme  [¹7] ).

Scheme 17

This interesting rearrangement occurs under halogenation conditions (Table  [²4] ). [85]

Table 24 Halogenation of Bicyclic Hydrazines

Entry Compd X2 Product Yield (%)
1 1b Br2 114 57
2 4 Br2 115 84
3 1a Cl2 116 nd

A similar transformation has been described from the epoxide 117. [86] A reactive aziridinium intermediate can indeed be generated from this compound under various acidic conditions, and trapped regioselectively by several nucleophiles, leading to polyfunctional bicycles (Table  [²5] ) in a diastereoselective manner.

Table 25 Acid-Assisted Nucleophilic Opening of Epoxide 117

Entry Reaction conditions Nu Product Yield (%)
1 HBr, MeOH Br 118 49
2 H2SO4, CF3CH2OH OH 119 45
3 H2SO4, MeOH OMe 120 50
4 Et2AlCl, CH2Cl2 Cl 121 68
5a C5H11C≡CAlMe2, CH2Cl2 C5H11C≡C 122 59
6a PhC≡CAlMe2, CH2Cl2 PhC≡C 123 63
7a Cl(CH2)3C≡CAlMe2, CH2Cl2 Cl(CH2)3C≡C 124 63
a Prepared according to a literature method. [87]

6 Synthetic Applications

Despite a plethora of reactivity studies and stereoselective transformations of bicyclic hydrazines, only a limited number of synthetic applications of these methods have been reported. Most of them have focused on obtaining polysubstituted cyclopentane-1,3-diamines.

Compound 129 was obtained from diol 14 in enantiomerically pure form during a general study toward the preparation of cyclic diaminopolyols. [47b] The meso 1,3-diamine 127 was obtained by hydrogenolysis of the corresponding diazo 126, itself prepared in three steps from 14. The final compound was obtained by enzymatic desymmetrization of compound 128, followed by acetylation (Scheme  [¹8] ).

Scheme 18  Reagents and conditions: (a) Me2C(OMe)2, CH2Cl2, camphorsulfonic acid (cat.), r.t., 12 h, 95%; (b) 2 N KOH, 2-PrOH, reflux, 2 h, then HCl, CuCl2 (3 equiv), then NH3 (aq), 85%; (c) H2, Pt, AcOH, r.t., 12 h, then HCl (aq), 83%; (d) BnCOCl, NaHCO3, t-BuOH-H2O (1:1), 75-85%; (e) penicillin amidase, 0.2 M phosphate buffer (pH 7.6), 91% ee; then Ac2O, pyridine, DMAP, 82%.

The reduction of hydrazines has been investigated (Table  [²6] ). Among various reduction conditions, the use of sodium in ammonia proved to be a general way to obtain various cyclopentanediamides. [47a] Interestingly, the epoxide was not affected during the reduction (entry 2).

Table 26 Reductive Opening of Bicyclic Hydrazines by Sodium/Ammonia

Entry Compd X Y Product Yield (%)
1 130 H H 134 100
2 131 -O-
 135  48
3 132 OH OH 136  59
4 133 OH H 137  65

The use of benzylcarbamate as protective group enables the one-pot reductive cleavage and protecting group removal of the hydrazines (Table  [²7] ). This protocol is generally very efficient, and delivers the corresponding diamine as its bis-acetate salt. The use of platinum(IV) oxide instead of platinum black enables a reproducible reduction on a large amount of material (10 gram scale).

Table 27 Hydrogenolysis of Hydrazines

Entry Compd X Y Z Product Yield (%)a
1 5e OH H H 140 99
2 119 OH H OH 141 96
3 120 OMe H OH 142 95
4 13e OH OH H 143 99
5 138 OH NHMs H 144 99
6 139 OH NHBoc H 145 95
a Isolated yield of the bis-acetate salt.

A similar reduction has been used to obtain meso diami­nodicarboxylic acids of potential biological activity (Scheme  [¹9] ). [80]

Scheme 19  Reagents and conditions: (a) 6 M HCl, AcOH, 100 ˚C, 98%; (b) PtO2, H2, 2 M HCl, 99%.

The reactivity of rearranged hydrazine 111 was exploited for the synthesis of several mannosidase inhibitors (Scheme  [²0] ). [88] All the polar groups were successively introduced in a fully stereoselective manner, leading to aminocyclopentitols in a few steps. Both final compounds are low micromolar inhibitors of jack bean α-mannosidase.

Scheme 20 Reagents and conditions: (a) SeO2, KH2PO4, diglyme, 170 ˚C, 69%; (b) KH, MeI, THF, 75%; (c) OsO4, NMO, THF-H2O, 99%; (d) Li, NH3, -33 ˚C, 50%; (e) LiOH, THF-H2O, 99%.

The chemical diversity offered by the reactivity of bicyclic hydrazines has been exploited in a fragment-based strategy for the design of active compounds. Small libraries generated from bicyclic hydrazines using some of the above-mentioned transformations have been prepared and used in such an approach for the preparation of tRNA ligands such as 152 [89] and enzyme bisubstrate inhibitors such as 153 (Figure [5] ). [90]

Figure 5 Selected examples of ligands or inhibitors prepared from bicyclic hydrazines

7 Conclusion

The reactivity of bicyclic hydrazines, first described in the late 1920s, has been investigated in depth, mainly in the last decade. Numerous synthetic transformations of these easily available building blocks have been disclosed, all of them delivering diastereomerically pure compounds using simple experimental conditions. In some, albeit still limited, cases, not only diastereoselective, but also enantioselective transformations have been set up, affording synthetically useful derivatives in a few steps. The functional and stereochemical diversity generated from these hydrazines will undoubtedly be improved upon and used in the future for the elaboration of more complex structures.

35

The low reactivity and selectivity observed with the QUINAP ligand could arise from the lower stability of the catalytic species generated from neutral rhodium precatalyst (Prof. J. M. Brown, personal communication to L.M.). Cationic rhodium sources have not been evaluated with this ligand in this study.

36

Pérez Luna, A.; unpublished results.

49

Bournaud, C.; unpublished results.

35

The low reactivity and selectivity observed with the QUINAP ligand could arise from the lower stability of the catalytic species generated from neutral rhodium precatalyst (Prof. J. M. Brown, personal communication to L.M.). Cationic rhodium sources have not been evaluated with this ligand in this study.

36

Pérez Luna, A.; unpublished results.

49

Bournaud, C.; unpublished results.

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Figure 1 General reactivity pattern of meso bicyclic hydrazines

Figure 2 Examples of meso polycyclic hydrazines

Figure 3 Rotameric forms of bicyclic hydrazines

Scheme 1 Reagents and conditions: (a) (i) BH3, THF, 0 ˚C; (ii) H2O2, HO-.

Scheme 2 Iridium-catalyzed asymmetric hydroboration: selected ligands­

Scheme 3

Scheme 4 Reagents and conditions: (a) OsO4 (cat.), NMO (1.2 equiv), acetone-H2O (2:1); (b) OsO4 (cat.), Et3NO, t-BuOH, H2O, Py.

Scheme 5

Scheme 6 The chemodivergent pathway of a rhodium-catalyzed hydroarylation reaction

Scheme 7

Scheme 8

Scheme 9

Scheme 10

Scheme 11

Figure 4 Selected examples of cycloadducts from bicyclic hydra­zines

Scheme 12

Scheme 13

Scheme 14  Reagents and conditions: (a) RuO2, NaIO4, EtOAc; (b) CH2N2, MeOH, 89% overall yield.

Scheme 15 Reagents and conditions: (a) thermal activation (100 ˚C) or acidic activation.

Scheme 16 Reagents and conditions: (a) CF3COOH, CCl4, r.t., quant.

Scheme 17

Scheme 18  Reagents and conditions: (a) Me2C(OMe)2, CH2Cl2, camphorsulfonic acid (cat.), r.t., 12 h, 95%; (b) 2 N KOH, 2-PrOH, reflux, 2 h, then HCl, CuCl2 (3 equiv), then NH3 (aq), 85%; (c) H2, Pt, AcOH, r.t., 12 h, then HCl (aq), 83%; (d) BnCOCl, NaHCO3, t-BuOH-H2O (1:1), 75-85%; (e) penicillin amidase, 0.2 M phosphate buffer (pH 7.6), 91% ee; then Ac2O, pyridine, DMAP, 82%.

Scheme 19  Reagents and conditions: (a) 6 M HCl, AcOH, 100 ˚C, 98%; (b) PtO2, H2, 2 M HCl, 99%.

Scheme 20 Reagents and conditions: (a) SeO2, KH2PO4, diglyme, 170 ˚C, 69%; (b) KH, MeI, THF, 75%; (c) OsO4, NMO, THF-H2O, 99%; (d) Li, NH3, -33 ˚C, 50%; (e) LiOH, THF-H2O, 99%.

Figure 5 Selected examples of ligands or inhibitors prepared from bicyclic hydrazines