CfYVcrYY0M

co2h

OMe 105

OMe R1 106

C02Me

EDC, NMP

OMe 105

^.R2 1. lithium p-methoxyacetanllide THF, DM F then R3X

^.R2 1. lithium p-methoxyacetanllide THF, DM F then R3X

r2"ir

Scheme 15.33. Ellman's 1,4-benzodiazepine-2,5-dione synthesis.

Polymer-supported amines have also been used for reductive aminations with aldehydes. There are several examples where Rink amide resin has been reduc-tively alkylated [59b, 62b, 75a]. Katritzky et al. formed a variety of imines (both electron-rich and -poor aromatic aldehydes) with TMOF and reduced them with LiBH4 [75a]. Rivero and coworkers also used a two-step reductive amination procedure to prepare a library of 500 macrocycles (Scheme 15.34) [62b]. Benzyloxy-

NHMtt

1. R1CHO, TMOF

Mtt = 4-methyltrityl

1. R1CHO, TMOF

Mtt = 4-methyltrityl

1. Fmoc-NHCHR2C02H, DIC N^R1 2. Piperidine, DMF

1. Fmoc-NHCHR2C02H, DIC N^R1 2. Piperidine, DMF

R3 R4

NHMtt

R3 O

Scheme 15.34. Macrocycle synthesis incorporating reductive amination as a diversity element.

Tab. 15.1. Recent libraries using reductive amination (since January 2000).

Library

Reactants"

Reducing agent

Methodb

Reference

Secondary amides

Aniline/aldehydes

NaBH4

B

74e

Macrolides

Aldehyde/primary amines

NaBH3CN

B

58b

Secondary amines/aldehydes

Tertiary amines

Hydroxylamine/aldehydes

BAP

B

67

Tetrahydro-

Aldehydes/amino alcohol

NaBH(OAc)3

A

78f

quinoxalines

Peptide aldehydes

Aldehydes/primary amines

NaBH(OAc)3

A

83

Macrocycles

Primary amine/aldehydes

NaBH(OAc)3

B

62b, 85

3,4-Dihydro-1,4-

Anilines/ketones

NaBH3CN

A

84

benzothiazines

(intramolecular)

Quinoxalinones

Aldehydes/amino acid

NaBH(OAc)3

A

86

Pyrrolidines

Primary amine/aldehydes

NaBH3CN

A

87

2-Carboxyindoles

5-Aminoindole/aldehydes

NaBH3CN

A

88

b-Ketoamides/

Aldehydes/primary amines

LiBH4

B

75b

imidazoles

Amines/amides

Aldehydes/primary amines

BAP

B

72c

Tricyclics

Primary amine/

NaBH(OAc)3

A

89

cinnamaldehydes

Piperidines

Aldehydes/primary amines

BAP

B

72b

Tertiary

Hydroxylamine/aldehydes

NaBH(OAc)3

A

90

methylamines

Phenolic amino

Primary amines/aldehydes

NaBH(OAc)3

B

91

acids

Neoglycopeptides

Amino acids/b-glycoside

NaBH3CN

A

92

aldehydes

Lysine/glutamic

Amino acids/aldehydes

NaBH(OAc)3

B

93

acid derivatives a First entry is resin-bound component.

b A, one-step procedure, in situ imine formation/reduction; B, two-step procedure, imine formation then reduction.

acid derivatives a First entry is resin-bound component.

b A, one-step procedure, in situ imine formation/reduction; B, two-step procedure, imine formation then reduction.

aniline and p-benzyloxybenzylamine (BOBA) resins have also been reductively alkylated with aldehydes and NaBH4 using two-step procedures [74c,e].

15.2.12.5 Recent Examples of Reductive Amination on Resin

There is a large number of libraries that have incorporated a reductive amination step. This fact highlights the power and reliability of reductive amination for library synthesis. Recently, a number of libraries have been prepared using reductive amination chemistry. These library syntheses are listed in Table 15.1.

Specific examples include a diketopiperizine library effort at Affymax that relies on reductive amination for a key diversity step (Scheme 15.35) [65a, 82]. Groth and Meldal reported a combinatorial approach to N-terminal peptide aldehydes and di-ketopiperazines using reductive amination [83]. They found that NaBH(OAc)3 in dimethyl sulfoxide (DMSO)/CH2Cl2/AcOH (50:50:1) was optimal after an exten-

R1 R1 F

NaBH3CN DIC, CH2CI2

113 114

115 116

Scheme 15.35. Affymax's solid-phase approach to diketopiperazines.

sive study of conditions, thus emphasizing the importance of varying reaction conditions for successful reductive aminations. Barany and coworkers prepared a set of 3,4-dihydro-1,4-benzothiazines using a one-pot alkylation-intramolecular reductive amination to prepare the thiazine core [84]. A group at Abbott has prepared an antibiotic screening library of 70,000 macrolides [58b]. The synthesis involved three reductive amination steps (aldehydes with a primary amine and two secondary amines) to introduce diversity and began with a preconstructed macrolide core.

15.2.13

Azide Reductions

15.2.13.1 General Considerations

Reductions of aromatic azides provide anilines that are handles for diversification and may be incorporated into benzo-fused heterocycles. Tin (SnCl2), phosphine, or sulfur reagents are commonly used to carry out this transformation. Under some tin reduction conditions, side-reactions, such as azide displacement or N-acetyla-tion, can be problematic. In these cases, phosphine- or sulfur-mediated azide reductions can be used as replacements.

15.2.13.2 Azide Reductions in Glycopeptide Preparations

Solid-phase azide reductions are heavily used in glycopeptide preparations. The azide is frequently used as a point of attachment for the peptide, but may also be a handle for diversification. The most commonly used reductants are sulfur based, such as DTTor 1,3-propanedithiol, although phosphines have been used in several examples.

Peters et al. [94] in an early example, and later Rademann and Schmidt [95], obtained N-acetates from azide reductions using thioacetic acid and pyridine in solidphase glycopeptide preparations. Danishefsky and coworkers used both thiophenol and 1,3-propanedithiol with Hiinigs base in THF to effect azide reduction in solid-supported trisaccharide- and disaccharide-containing glycopeptides, thus avoiding N-acetate formation [96]. Glycopeptides have also been prepared on solid support via azide reduction using DTT and 1,8-diazabicyclo[5.4.0]undecene-7 (DBU) in

DMF [97]. A modified Staudinger reaction has been applied to the preparation of amides using a solid-supported glycoazide in a one-pot procedure (Scheme 15.36) [98].

ACA0c5^^N3 HOBt,PBu3 ~

117 118

Scheme 15.36. Modified Staudinger reaction for the preparation of glycopeptides.

15.2.13.3 Small Molecule Libraries Incorporating Azide Reduction

A variety of small molecule libraries has been synthesized that incorporate azide reductions using primarily SnCl2 and triarylphosphines. Ellman's group has prepared several small molecule arrays by generating diversity at the amine prepared by a tin-mediated azide reduction (Scheme 15.37) [16, 99]. Kim and coworkers have also prepared a group of oligoureas using a tin-mediated azide reduction [100].

R1 N3

H 0H R2

3. TFA, CH2CI2

Scheme 15.37. Examples ofsmall-molecule synthesis using azide reductions.

Another example from Chiron is the preparation of a small group of 1,4-benzo-diazepine-2,5-diones by a PBu3-mediated azide reduction [101]. Reaction of the resulting aniline with a pendant ester formed the diazepine heterocycle. Trifluoro-acetic acid cleavage provided 21 benzodiazepines in good yields (Scheme 15.38). Kahne and coworkers also used aqueous PMe3 to reduce azides on a TentaGel-supported carbohydrate [102].

It has been reported by Zhou and coworkers that the reduction of a primary azide with SnCl2 and thiophenol provided significant amounts of an azide displacement product (resulting from attack by thiophenol) [103]. To circumvent this

vN3 1. PBu3, toluene

124 125

Scheme 15.38. Synthesis of 1,4-benzodiazepine-2,5-diones using an azide reduction.

problem, aqueous PPh3 provided the amine in good yield without any azide displacement and allowed the synthesis of an array of hydroxybisamides. Nicolaou et al. also used an aqueous PPh3-mediated azide reduction methodology to provide an amine for diversification in the preparation of a library of 50 sarcodictyins [104].

15.2.13.4 Recent Examples of Azide Reduction on Resin

A variety of recent libraries has incorporated azide reductions in their synthetic approach and are summarized in Table 15.2. For example, a library of phenolic steroids has been prepared by Poirier and coworkers using both tin- and phosphine-mediated azide reductions on various solid supports [105]. The phosphine reduction was employed when an o-nitrobenzyl ether linkage was used to avoid reduction of the nitro group on the linker [105b]. A library of substituted oxazoles has been prepared via derivatization of an amine generated from an azide reduction with DTT and Hiinigs base (Scheme 15.39) [106]. A small library of 1,3-oxazolidines has been prepared using a tin-mediated azide reduction on solid support [107]. An azide on solid support has also been reduced with TMSI. This acidic protocol was used to avoid base-induced formation of a lactam side-product when using DTT/ DBU [108].

A library of 1300 disaccharides has been prepared on solid phase via azide reduction with aqueous PMe3 followed by amine derivatization with isocyanates and

Tab. 15.2. Recent libraries utilizing azide reduction (since January 1999).

Library

Reducing agent

Reference

Glycopeptides

PhSH or 1,3-propanedithiol, DIEA

96b

DTT, DBU

97b

PBu3

98

DTT, DBU or TMSI

108

Hydroxybisamides

Aqueous PPh3

103

Estradiols

Aqueous PPh3

105a

SnCl2, PhSH, TEA or aqueous PPh3

105b

Oxazoles

DTT, DIEA

106

1,3-Oxazolidines

SnCl2, PhSH, TEA

107

Disaccharides

Aqueous PMe3

109

1,3-Bis(acylamino)-2-butanones

SnCl2, PhSH, TEA

78e

Phenylglycinnamides

Aqueous PMe3

110

N3 XR3

126 127

Scheme 15.39. Synthesis of oxazoles incorporating an azide reduction.

acids (Scheme 15.40) [109]. An array of 18 1,3-bis-(acylamino)-2-butanones has been prepared in which diversity was generated at an amine prepared by a SnCl2 azide reduction [78e]. Notably, a dimethyl ketal survived the conditions of this tinmediated reduction. A library of phenylglycinnamides has been prepared by generating a galactosylamine by means of an azide reduction with 1,3-propanedithiol [110]. The galactosylamine was used in a series of Ugi reactions and cleaved from the resin to generate eight different phenylglycinnamides.

CW w

RlĀ°NS^SPh pcONH^LsPh b 1. PMe3, H2Q, THF-EtOH _ AcO o~J

Scheme 15.40. Disaccharide derivatization at an amine generated by an azide reduction.

15.2.14

Nitro Group Reductions

15.2.14.1 General Considerations

The reduction of aromatic nitro groups to anilines is an often-used transformation in combinatorial chemistry. The aromatic nitro group serves two important functions: it facilitates SNAr reactions and provides an amine for further manipulation following reduction. A frequent use of the resulting aniline in library synthesis has been in the preparation of various benzo-fused heterocyclic compounds (Scheme 15.41) [111].

There are a variety of protocols that have been developed for the reduction of nitro groups, and each offers different advantages and disadvantages. Some experimentation may be required to find suitable conditions for the system under study since the most frequently used reducing reagent (SnCl2), while quite reliable, does not always provide consistent results [112].

15.2.14.2 Tin-mediated Nitro Reductions

The reduction of aromatic nitro groups is often carried out using a tin reagent (usually an aqueous solution of SnCl2 in DMF) [113, 114]. Acidic conditions typi-

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