Pd(0)/Cu(I)-Mediated Direct Arylation of 2 '-Deoxyadenosines: Mechanistic Role of Cu(I) and Reactivity Comparisons with Related Purine Nucleosides

Thomas E. Storr; Christoph G. Baumann; Robert J. Thatcher; Sara De Ornellas; Adrian C. Whitwood; Ian J. S. Fairlamb

doi:10.1021/jo9012282

Pd(0)/Cu(I)-Mediated Direct Arylation of 2 '-Deoxyadenosines: Mechanistic Role of Cu(I) and Reactivity Comparisons with Related Purine Nucleosides

Thomas E. Storr, Christoph G. Baumann, Robert J. Thatcher, Sara De Ornellas, Adrian C. Whitwood, Ian J. S. Fairlamb

Research output: Contribution to journal › Article › peer-review

Abstract

Pd/Cu-mediated direct arylation of 2'-deoxyadenosine with various aryl iodides provides 8-arylated 2'-deoxyadenosine derivatives in good yields, Following significant reaction optimization, it has been determined that a substoichiometric quantity of piperidine (secondary amine) in combination with cesium carbonate is necessary for effective direct arylation. The general synthetic protocol allows lower temperature direct arylations, which minimizes deglycosylation. The origin of the piperidine effect primarily derives from the in situ generation of Pd(OAc)(2)[(CH2)(5)NH](2). Various copper(l) salts have been evaluated; only CUI provides good yields of the 8-arylated-2'-deoxyadenosines. Copper(l) appears to have a high binding affinity for 2'-deoxyadenosine, which explains the mandatory requirement for stoichiometric an S 0 this key component. The conditions are compared with more general direct arylation protocols, e.g., catalytic Pd, ligand, acid additives, which do not employ copper(l), In each case, no delectable arylation of 2'-deoxyadenosine was noted. The conformational preferences of the 8-aryl-2'-deoxyadenosine products have been determined by detailed spectroscopic (NMR) and single crystal X-ray diffraction studies. Almost exclusively, the preferred solution-state conformation was determined to be syn-C2'-endo (ca. 80%). The presence of a 2-pyridyl group at the 8-position further biases the solution-state equilibrium toward this conformer (ca. 88%), due to an additional H-bond between H1' and the pyridyl nitrogen atom. The Pd/Cu catalyst system has been found to be unique for adenosine type substrates, the reactivity of which has been placed into context with the reported direct arylations of related 1H-imidazoles. The reactivity of other purine nucleosides has been assessed, which has revealed that both 2'-deoxyguanosine and guanosine are incompatible with the Pd/Cu-direct arylation conditions. Both substrates appear to hinder catalysis, akin to the established inhibitory effects in Suzuki cross-couplings with arylboronic acids.

Original language	English
Pages (from-to)	5810-5821
Number of pages	12
Journal	Journal of Organic Chemistry
Volume	74
Issue number	16
DOIs	https://doi.org/10.1021/jo9012282
Publication status	Published - 21 Aug 2009

Keywords

CATALYZED DIRECT ARYLATION
CROSS-COUPLING REACTIONS
C-H ARYLATION
PROTON-ABSTRACTION MECHANISM
DIRECT C-2 ARYLATION
NUCLEOBASE-INCLUDING BACKBONE
PHENOL CARCINOGEN EXPOSURE
INTRAMOLECULAR ARYLATION
FLUORESCENT NUCLEOSIDE
MAGNETIC-RESONANCE

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10.1021/jo9012282

http://pubs.acs.org/doi/abs/10.1021/jo9012282

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@article{f9f94ce1cb58471198ed35e2a77b2e06,

title = "Pd(0)/Cu(I)-Mediated Direct Arylation of 2 '-Deoxyadenosines: Mechanistic Role of Cu(I) and Reactivity Comparisons with Related Purine Nucleosides",

abstract = "Pd/Cu-mediated direct arylation of 2'-deoxyadenosine with various aryl iodides provides 8-arylated 2'-deoxyadenosine derivatives in good yields, Following significant reaction optimization, it has been determined that a substoichiometric quantity of piperidine (secondary amine) in combination with cesium carbonate is necessary for effective direct arylation. The general synthetic protocol allows lower temperature direct arylations, which minimizes deglycosylation. The origin of the piperidine effect primarily derives from the in situ generation of Pd(OAc)(2)[(CH2)(5)NH](2). Various copper(l) salts have been evaluated; only CUI provides good yields of the 8-arylated-2'-deoxyadenosines. Copper(l) appears to have a high binding affinity for 2'-deoxyadenosine, which explains the mandatory requirement for stoichiometric an S 0 this key component. The conditions are compared with more general direct arylation protocols, e.g., catalytic Pd, ligand, acid additives, which do not employ copper(l), In each case, no delectable arylation of 2'-deoxyadenosine was noted. The conformational preferences of the 8-aryl-2'-deoxyadenosine products have been determined by detailed spectroscopic (NMR) and single crystal X-ray diffraction studies. Almost exclusively, the preferred solution-state conformation was determined to be syn-C2'-endo (ca. 80%). The presence of a 2-pyridyl group at the 8-position further biases the solution-state equilibrium toward this conformer (ca. 88%), due to an additional H-bond between H1' and the pyridyl nitrogen atom. The Pd/Cu catalyst system has been found to be unique for adenosine type substrates, the reactivity of which has been placed into context with the reported direct arylations of related 1H-imidazoles. The reactivity of other purine nucleosides has been assessed, which has revealed that both 2'-deoxyguanosine and guanosine are incompatible with the Pd/Cu-direct arylation conditions. Both substrates appear to hinder catalysis, akin to the established inhibitory effects in Suzuki cross-couplings with arylboronic acids.",

keywords = "CATALYZED DIRECT ARYLATION, CROSS-COUPLING REACTIONS, C-H ARYLATION, PROTON-ABSTRACTION MECHANISM, DIRECT C-2 ARYLATION, NUCLEOBASE-INCLUDING BACKBONE, PHENOL CARCINOGEN EXPOSURE, INTRAMOLECULAR ARYLATION, FLUORESCENT NUCLEOSIDE, MAGNETIC-RESONANCE",

author = "Storr, {Thomas E.} and Baumann, {Christoph G.} and Thatcher, {Robert J.} and {De Ornellas}, Sara and Whitwood, {Adrian C.} and Fairlamb, {Ian J. S.}",

year = "2009",

month = aug,

day = "21",

doi = "10.1021/jo9012282",

language = "English",

volume = "74",

pages = "5810--5821",

journal = "Journal of Organic Chemistry",

issn = "0022-3263",

publisher = "American Chemical Society",

number = "16",

}

TY - JOUR

T1 - Pd(0)/Cu(I)-Mediated Direct Arylation of 2 '-Deoxyadenosines

T2 - Mechanistic Role of Cu(I) and Reactivity Comparisons with Related Purine Nucleosides

AU - Storr, Thomas E.

AU - Baumann, Christoph G.

AU - Thatcher, Robert J.

AU - De Ornellas, Sara

AU - Whitwood, Adrian C.

AU - Fairlamb, Ian J. S.

PY - 2009/8/21

Y1 - 2009/8/21

N2 - Pd/Cu-mediated direct arylation of 2'-deoxyadenosine with various aryl iodides provides 8-arylated 2'-deoxyadenosine derivatives in good yields, Following significant reaction optimization, it has been determined that a substoichiometric quantity of piperidine (secondary amine) in combination with cesium carbonate is necessary for effective direct arylation. The general synthetic protocol allows lower temperature direct arylations, which minimizes deglycosylation. The origin of the piperidine effect primarily derives from the in situ generation of Pd(OAc)(2)[(CH2)(5)NH](2). Various copper(l) salts have been evaluated; only CUI provides good yields of the 8-arylated-2'-deoxyadenosines. Copper(l) appears to have a high binding affinity for 2'-deoxyadenosine, which explains the mandatory requirement for stoichiometric an S 0 this key component. The conditions are compared with more general direct arylation protocols, e.g., catalytic Pd, ligand, acid additives, which do not employ copper(l), In each case, no delectable arylation of 2'-deoxyadenosine was noted. The conformational preferences of the 8-aryl-2'-deoxyadenosine products have been determined by detailed spectroscopic (NMR) and single crystal X-ray diffraction studies. Almost exclusively, the preferred solution-state conformation was determined to be syn-C2'-endo (ca. 80%). The presence of a 2-pyridyl group at the 8-position further biases the solution-state equilibrium toward this conformer (ca. 88%), due to an additional H-bond between H1' and the pyridyl nitrogen atom. The Pd/Cu catalyst system has been found to be unique for adenosine type substrates, the reactivity of which has been placed into context with the reported direct arylations of related 1H-imidazoles. The reactivity of other purine nucleosides has been assessed, which has revealed that both 2'-deoxyguanosine and guanosine are incompatible with the Pd/Cu-direct arylation conditions. Both substrates appear to hinder catalysis, akin to the established inhibitory effects in Suzuki cross-couplings with arylboronic acids.

AB - Pd/Cu-mediated direct arylation of 2'-deoxyadenosine with various aryl iodides provides 8-arylated 2'-deoxyadenosine derivatives in good yields, Following significant reaction optimization, it has been determined that a substoichiometric quantity of piperidine (secondary amine) in combination with cesium carbonate is necessary for effective direct arylation. The general synthetic protocol allows lower temperature direct arylations, which minimizes deglycosylation. The origin of the piperidine effect primarily derives from the in situ generation of Pd(OAc)(2)[(CH2)(5)NH](2). Various copper(l) salts have been evaluated; only CUI provides good yields of the 8-arylated-2'-deoxyadenosines. Copper(l) appears to have a high binding affinity for 2'-deoxyadenosine, which explains the mandatory requirement for stoichiometric an S 0 this key component. The conditions are compared with more general direct arylation protocols, e.g., catalytic Pd, ligand, acid additives, which do not employ copper(l), In each case, no delectable arylation of 2'-deoxyadenosine was noted. The conformational preferences of the 8-aryl-2'-deoxyadenosine products have been determined by detailed spectroscopic (NMR) and single crystal X-ray diffraction studies. Almost exclusively, the preferred solution-state conformation was determined to be syn-C2'-endo (ca. 80%). The presence of a 2-pyridyl group at the 8-position further biases the solution-state equilibrium toward this conformer (ca. 88%), due to an additional H-bond between H1' and the pyridyl nitrogen atom. The Pd/Cu catalyst system has been found to be unique for adenosine type substrates, the reactivity of which has been placed into context with the reported direct arylations of related 1H-imidazoles. The reactivity of other purine nucleosides has been assessed, which has revealed that both 2'-deoxyguanosine and guanosine are incompatible with the Pd/Cu-direct arylation conditions. Both substrates appear to hinder catalysis, akin to the established inhibitory effects in Suzuki cross-couplings with arylboronic acids.

KW - CATALYZED DIRECT ARYLATION

KW - CROSS-COUPLING REACTIONS

KW - C-H ARYLATION

KW - PROTON-ABSTRACTION MECHANISM

KW - DIRECT C-2 ARYLATION

KW - NUCLEOBASE-INCLUDING BACKBONE

KW - PHENOL CARCINOGEN EXPOSURE

KW - INTRAMOLECULAR ARYLATION

KW - FLUORESCENT NUCLEOSIDE

KW - MAGNETIC-RESONANCE

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U2 - 10.1021/jo9012282

DO - 10.1021/jo9012282

M3 - Article

C2 - 19630437

SN - 0022-3263

VL - 74

SP - 5810

EP - 5821

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

IS - 16

ER -

Pd(0)/Cu(I)-Mediated Direct Arylation of 2 '-Deoxyadenosines: Mechanistic Role of Cu(I) and Reactivity Comparisons with Related Purine Nucleosides

Abstract

Keywords

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