Recent Advances on Asymmetric Nitroso Aldol Reaction


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Recent Advances on Asymmetric Nitroso Aldol Reaction
Pedro Merino,*a Tomás Tejero,a Ignacio Delsoa,b and Rosa Matutec
a Laboratorio de Síntesis Asimétrica. Departamento de Síntesis y Estructura de Biomoléculas. Instituto de Síntesis Química y Catálisis Homogénea (ISQCH). Universidad de Zaragoza. CSIC. Campus San Francisco. 50009 Zaragoza, Aragón, Spain. b Servicio de Resonancia Magnética Nuclear. CEQMA. Universidad de Zaragoza. CSIC. Campus San Francisco. 50009 Zaragoza, Aragón, Spain. c Departamento de Ingeniería Química y Tecnologías del Medio Ambiente. Escuela Universitaria de Ingeniería Industrial. Edificio Torres Quevedo. Campus Actur. 50014 Zaragoza, Aragón, Spain; Phone: +34 876 553783. E-mail: [email protected]
Graphical Abstract
Biographical Sketch Abstract The reaction of aromatic nitroso derivatives with enolizable carbonyl compounds (nitroso aldol reaction) to give either α-hydroxyamino or α-aminoxycarbonyls is an important synthetic method. This review illustrates the recent advances in rendering the process regio- and enantioselective as well as catalytic. By employing metal and organic catalysts one can generate a range of α-amino (α-oxyamination) and α-hydroxy (αaminoxylation) carbonyl derivatives with total regioselectivity and high levels of enantiomeric excess.

1. Introduction The introduction of amino and oxygen functionalities in an organic molecule is among the most important tools employed in synthetic chemistry, particularly if it is achieved in an enantioselective way. Chiral molecules bearing amino and/or hydroxy groups are ubiquitous in natural products and therapeutic drugs; also, they are of a great utility as synthetic intermediates. Of particular interest are those derivatives in which the heteroatom is in proximity to other reactive functional group, like a carbonyl, that allow for further chemical elaboration. In this context, organic nitroso compounds 1 are valuable intermediates because of the particular reactivity of the nitroso group1,2 that allow multiple reactivity as N- and O-electrophiles in amination and hydroxylation reactions, respectively (nitroso aldol)3 as well as enophiles in cycloaddition reactions (Scheme 1).4 Both the nitroso ene5-7 and nitroso Diels-Alder8-11 reactions have been studied widely.
Scheme 1. Main reactivity of nitroso compounds
The main problem of the nitroso aldol reaction is the regioselectivity. If the addition takes place on the nitrogen atom of the nitroso group, α-amino carbonyls 2 are obtained, through an α-oxyamination process. On the other hand, when the addition take place on the oxygen atom of the nitroso group, α-hydroxy carbonyls 3 are obtained through a typical α-aminoxylation reaction. In some instances, the term “nitroso aldol reaction” only refers to the α-oxyamination process by analogy between N=O and C=O funtionalities whereas the term “α-aminoxylation” is preferred for the O-selective

reactions. Since both processes correspond to the reaction between a carbonyl group and a nitroso compound we will consider both of them in this revision. In general, the regioselectivity of the reaction can be controlled by the action (or absence) of a Lewis acid. Whereas the reaction proceeds through N-addition with in situ generated or preformed enolates (usually, lithium, tin or silicon),12 O-addition is observed if the reaction is catalyzed by a Lewis acid (Scheme 2).13 In addition to trimethylsilyl triflate, various metal ions including copper, cobalt, iron, silver, gold and hafnium promote an O-selective nitroso aldol reaction.14 It has been suggested15 that in the Lewis acid promoted reaction, the aminooxy compounds could come from a nitroso dimer generated in situ in the presence of the Lewis acid. Simple enolates would give rise to hydroxyamino compounds through the nitroso monomer.
Scheme 2. Regioselective nitroso aldol reactions In the last years, remarkable advances have been made in the use of nitroso compounds for preparing α-amino and α-hydroxy carbonyl compounds in an enantioselective way through asymmetric α-aminoxylation16 and α-oxyamination17 reactions, respectively. Some aspects of nitroso aldol reaction have been included as a part of more general reviews,1,3,4 including those dedicated to the highly reactive nitrosocarbonyl compounds.18 This review aims to provide coverage -from the last 15 years- of recent advances in nitroso aldol reactions mainly considering both metal-catalyzed and organocatalyzed processes. In addition to nitroso aldol reactions with aldehydes and ketones, we review reactions of related enamines with nitroso compounds. The review has been categorized by the type of catalysis. For the sake of clarity, differences in regioselectivity have been discussed when necessary for each particular case.
2. Metal-Catalyzed Reactions

A general asymmetric O-selective nitroso aldol reaction was developed using tin enolates derived from ketones and nitrobenzene. Optimization studies led to the identification of catalysts that produce excellent regio- and enantioselectivities for a range of alkyl and aryl-substituted tin enolates. The catalysts consisted of BINAP-silver complexes formed by combining (R)-BINAP and (R)-TolBINAP with silver salts such as AgOTf and AgClO4 (Table 1).19 The reaction was independent of any variation in cyclic tin enolate, although tributyl tin enolates had slightly increased N-selectivity. Taking into account that N-selective nitroso aldol reactions occur in the absence of catalyst, a competitive experiment between tributyl and trimethyl tin enolates demonstrated that the higher reactivity of tributyltin enolates resulted in more significant uncatalyzed process.
Table 1 O‐Nitroso Aldol Reaction of Tin Enolatesa

enolate

R

cataly yield

stb

(%)

Bu

A

95

Bu

B

92

Bu

C

93

Me

B

95

Me

C

94

Me

B

78

Bu

A

97

Bu

C

97

Bu

B

96

Me

C

97

Me

B

94

Bu

C

90

6:7
>99:1 >99:1 >99:1 >99:1 >99:1 >99:1 85:15 83:17 >99:1 >99:1
>99:1 66:34

ee% of 6
95 91 92 97 94 96 91 95 95 88
87 85

Me

B

92

>99:1

90

Me

C

96

>99:1

85

Me

B

93

>99:1

92

Bu

C

90

91:9

85

OSnR3

Me

B

95

92:8

82

Me

B

92

81:19

94

a Reactions were conducted with 1.0 equiv of nitrosobenzene and 1.0 equiv of tin enolate. b Catalyst A: (R)‐ BINAP∙AgClO4. Catalyst B: (R)‐TolBINAP∙AgOTf. Catalyst C: (R)‐TolBINAP∙AgClO4.
The reaction was extended, with excellent results, to less toxic disilanyl enol ethers 8 by using silver tetrafluoroborate as silver source and 3,3'-diphenyl (S)-binol-derived phosphite 9 as a ligand (Scheme 3).20 The reaction required an excess of cesium fluoride to proceed.
Scheme 3
α-Aminooxy ketones were prepared with enantioselectivities of up to 99% from alkenyl trichloroacetates 10 by using t-Bu-QuinoxP* 11 in complex with AgOAc as the chiral catalyst and dibutyl(methoxy)-λ3-stannane as the achiral cocatalyst (Table 2).21 The reaction, which is not completely O-selective, seems to proceed through a tin enolate formed in situ which adds enantioselectively to nitrosobenzene in the presence of the chiral catalyst. The driving force of the catalytic cycle originates from the rapid methanolysis of an intermediate tin amide.

Table 2 O‐Nitroso Aldol Reaction of alkenyl trichloroacetatesa

enolate

n = 1 n = 2 n = 3
R = H R = Me

yield (%)
81 65 72
92 24

6:7

ee% of 6

76:24

97

89:11

99

68:32

96

>99:1

99

82:18

95

90

96:4

97

68

91:9

97

71

97:3

97

R = Ph

8

51:49

92

R = Et

21

<1:99

3

a Reactions were conducted with 1.0 equiv of nitrosobenzene and 2.0 equiv of alkenyl trichloroacetate.

The first example of Cu-catalyzed O-nitroso aldol reaction has been reported by Yamamoto and co-workers.22 The methodology was applied to β-keto(thio)esters 12 and highly enantioenriched α-aminooxy-β-ketoesters 15 were prepared (Scheme 4). The nitroso derivative was generated in situ from the commercially available N-Boc hydroxylamine 13 and manganese(IV) as an oxidant. The reaction was conducted in the presence of copper(II) triflate and bisoxazoline (R,R)–PhBox 14 as ligand. The slow addition of N–Boc–hydroxylamine was crucial to avoid condensation between the in situ formed nitrosocarbonyl species and excess 13. The reaction showed a high preference for O-selectivity and only traces of N-nitroso carbonyl aldol were detected.

OO

R1

X

R2 12

O
tBuO NHOH 13
Cu(OTf)2 (10 mol%) MnO2 (5 equiv)
CH2Cl2, rt, 24 h

O

O

NN

Ph

14

Ph

(12 mol%)

OO

R1

X

R2 O

NHBoc

15

OO

R

S

O

NHBoc

R = iPr
R = cyclohexyl
R = PhCH2 R = Ph
R = 4-MeOC6H5 R = 4-BrC6H5 R = PhCH=CH2

(73%, 99% ee) (74%, 99% ee) (83%, 98% ee) (68%, 99% ee) (52%, 99% ee) (60%, 98% ee) (77%, 98% ee)

OO

R

O

O

NHBoc

R = iPr R = cyclohexyl R = PhCH2 R = Et

(82%, 96% ee) (86%, 97% ee) (86%, 96% ee) (91%, 97% ee)

OO

OO

S O
NHBoc
(78%, 93% ee)

S O
NHBoc
(90%, 99% ee)

Scheme 4
The reaction has also been carried out by generating the nitroso derivative under aerobic oxidation conditions from the corresponding N-(benzyloxycarbonyl) hydroxylamine 17. The procedure involved mixing of all reagents at room temperature and illustrated a fully catalytic process in both oxidation and enolization processes.23 A combination of copper(I) chloride and copper(II) acetate was used as Lewis acid; chirality was induced by using ligand 14 (Scheme 5). Notably, when copper(II) acetate was replaced by copper(II) triflate and no chiral ligand was added the reaction was N-selective providing, obviously, racemic substrates.24 The choice of the ester was crucial for achieving good values of enantioselectivity, the more sterically demanding groups (e.g. tert-butyl and 2,6-xylyl) giving rise to the best values.

Scheme 5 A model of addition has been suggested based on the experimental observations (Figure 1). Read de Alaniz and co-workers proposed23 the approach of the nitrosocarbonyl to the catalyst-coordinated β-ketoester by the same face in which the counterion occupies an axial position, thus preventing both coordination of the nitroso species to the Lewis acid and unfavourable steric interactions between the protecting group of the nitroso species and the complex. In agreement with this proposal is the observation that bulkier protecting groups, such as Boc, provided better enantioselectivities.22
Figure 1. Model of addition for Cu-catalyzed nitroso aldol reaction (X = counterion)
Application of the methodology illustrated in Scheme 4 allowed preparation of substituted α-aminooxyphosphonates 20 of synthetic utility when β-ketophosphonates 19 were employed as starting materials. An example is illustrated in Scheme 6 showing the possibility of obtaining α-hydroxyphosphonates 21, α,β-dihydroxyphosphonates 22 and β-amino-α-hydroxyphosphonates 23.25 The reaction proceeded in very good yields and enantioselectivities with both acyclic and cyclic substrates at the ketone moiety. On

the other hand, compounds bearing an ester (Scheme 6, R = OMe) or thioester (Scheme 5, R = SPh) in place of the ketone group gave no reaction.
Scheme 6
The vinylogous nitroso Mukaiyama aldol reaction has been reported by using silyl enolates derived from α,β-unsaturated esters as starting materials and acetic acid or HF·Py as promoters.26 Nitrosobenzene was added in an excess thus promoting the N-O cleavage of the in situ generated γ-aminoxy species. Under such conditions racemic γhydroxy α,β-unsaturated esters were obtained. When the reaction was conducted with silyl enolate 24 derived from (-)-carvone, enantiomerically pure (+)-5α-hydroxycarvone 25 was obtained (Scheme 7).
Scheme 7
The first example of a catalytic enantioselective N-nitroso aldol reaction was reported using BINAP-silver complexes27 which were developed based on previously reported asymmetric catalysts that promote O-selective reactions.19 In particular, for the reaction between tin enolates and nitrosobenzene, whereas AgOTf, AgOAc and AgOCOCF3derived 1:1 complexes with (R)-BINAP were shown to be efficient catalysts in Oselective nitroso aldol reactions (see above), the reaction catalyzed by the 2:1 complex

26, generated from 0.4 equiv of (R)-BINAP for AgOTf, resulted completely N-selective affording high enantioselectivites (Table 3).
Table 3 N‐Nitroso Aldol Reaction of Tin Enolatesa

enolate

R
n = 1 n = 2 n = 3

yield (%)
90 95 96

6:7
3:97 4:96 <1:99

94

<1:99

ee% of 7 86 >99 97
77

97

<1:99

98

a Reactions were conducted with 1.0 equiv of nitrosobenzene and 1.0 equiv of tin enolate.
Alkenyl trichloroacetates have been reported to undergo N-nitroso aldol reactions with nitrosobenzene using dibutyltin dimethoxide as a catalyst, which is regenerated by methanol.28 However, no chiral version of the reaction has been developed. On the other hand, the same group reported the catalytic enantioselective N-nitroso aldol reaction of γ,δ-unsaturated δ-lactones 27 using a chiral tin bromide ethoxide as a catalyst generated in situ from the corresponding tin dibromide 29.29 Notably, the reaction took place smoothly providing high enantioselectivities with nitrosoarenes 28 bearing a bulky substituent at ortho-position; on the contrary, with nitrosobenzene (28, R = H) both yield and enantioselectvity were low (Table 4). In general, no traces of the O-adduct were detected. With β,γ-unsaturated γ-lactones lower chemical yields and enantioselectivities were obtained.

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Recent Advances on Asymmetric Nitroso Aldol Reaction