Oxidative addition of secondary C-X bonds to palladium(0): A beneficial anomeric acceleration

Article abstract of DOI:10.1021/om200221r

The oxidative addition of secondary electrophiles to Pd(0) is significantly accelerated by anomeric effects. In contrast to cyclohexyl bromide, acetobromo-α-d-glucose undergoes invertive oxidative addition to tris(triethylphosphine)palladium(0) to generate a stable, isolable organometallic complex, Pd(PEt₃)₂(Br)(AcO-β-glucose), which has been fully characterized but is prone to β-acetoxy elimination.

Full text of DOI:10.1021/om200221r

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Oxidative Addition of Secondary CÀX Bonds to Palladium(0):
A Beneficial Anomeric Acceleration
Colleen Munro-Leighton,† Laura L. Adduci,† Jennifer J. Becker,*,‡ and Michel R. Gagnꢀe*,†
†Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, United States
‡U.S. Army Research Office, P.O. Box 12211, Research Triangle Park, North Carolina 27709, United States
S Supporting Information
b
ABSTRACT: The oxidative addition of secondary electrophiles to
Pd(0) is significantly accelerated by anomeric effects. In contrast to
cyclohexyl bromide, acetobromo-R-D-glucose undergoes invertive
oxidative addition to tris(triethylphosphine)palladium(0) to generate
a stable, isolable organometallic complex, Pd(PEt3)2(Br)(AcO-β-
glucose), which has been fully characterized but is prone to β-acetoxy elimination.
Scheme 2
he SN2-like oxidative addition of secondary alkyl halides is
T
kinetically difficult1 and continues to hold back the universal
adoption of Pd-based methods for secondary CÀC, CÀN, and
CÀO bond-forming catalysis.2 While developments in the cross-
coupling of primary alkyl electrophiles using Pd catalysts have
progressed smoothly,3 secondary electrophiles have thus far
required methodologies wherein the catalyst readily adopts
radical mechanisms for oxidative addition.4,5 A noteworthy
recent addition is a (Xantphos)Pd catalyst for the cross-coupling
of 2°-benzyl bromide (with inversion) with aryl and vinyl
Grignard reagents.6 An additional well-recognized problem with
alkyl halide electrophiles is the facility with which intermediate
organometallic complexes undergo β-hydride elimination reactions.
Several elegant solutions based on di- and triamine ligands (Ni)3,7 or
carefully tuned phosphines (Pd, primary alkyl-X)3 and broad bite
angle diphosphines (Pd, secondary alkyl-Br)6 have inhibited this
tendency and significantly improved the viability of such methods.
Lemieux reported more than 50 years ago that the glycosyl
bromide class of secondary electrophiles was remarkable in that
they could, with BrÀ catalysis, react with nucleophiles as weak as
secondary alcohols (Scheme 1).8 The outcome of these studies
was the development of methods for the synthesis of complex R-
disaccharides, which rely on a low but steady state concentration
of a reactive (lacking anomeric stabilization) β-bromo glycoside.
was supported by results from Scott, who showed that Pd(PPh3)4
(1À5 mol %, 50 °C) catalyzes the conversion of benzyl-protected
C1-mesylates into oxyglycals via a process proposed to require
CÀO oxidative addition and β-hydride elimination (Scheme 2).9
The goal of nucleophilic CÀX activation was attractive in the
context of a broader research theme targeting the conversion of
polysaccharides into value-added chemical feedstocks. Since the
leaving group in the CÀO oxidative addition of a polysaccharide
would necessarily be oxygen-based, the focus was on nonradical
methods of activating glycosyl electrophiles.10,11
As expected, no reaction occurred between Pd(PEt3)3 (1)12 and
secondary electrophiles such as cyclohexyl bromide (Scheme 3a).
In contrast, 31P NMR spectroscopy showed that, over 8 h,
acetobromo-R-D-glucose (2) reacted at room temperature with 1
to give a single isomer of Pd(PEt3)2(Br)(AcO-β-glu) (3), the
product of invertive bromide displacement (Scheme 3b).13 Pur-
ification of the reaction mixture by column chromatography
allowed for isolation of 3, although decomposition on the column
limited the isolated yield (34%).14
Scheme 1
Isolated 3 has been characterized by 1H, 31P, and 13C NMR
spectroscopy, and all data are consistent with formation of a
single “β-glucosyl” isomer. The 1H NMR spectrum is highlighted
by seven resonances in the pyranose region (3À6 ppm), includ-
ing a signal at 4.19 ppm corresponding to C1H with 3JPÀH = 3
and 14 Hz; the diastereotopic nature of the phosphorus nuclei
Since anomeric effects play such a dramatic role in the invertive
substitution chemistry of glycosyl halides, we questioned whether
such effects could be harnessed to kinetically facilitate an SN2-like
oxidative addition of Pd(0). The feasibility of this transformation
Received: March 11, 2011
Published: April 19, 2011
r
2011 American Chemical Society
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initiated mechanistic studies. Suggestive of a pre-equilibrium
PEt3-dissociation pathway were experiments showing that added
phosphine, but not added bromide, significantly inhibited the β-
elimination. After 14 days at room temperature, 40% conversion
of 3 to 4 was observed; 5 equiv of PEt3 and 5 equiv of BrÀ led to
1À5% and 35% conversion, respectively. Noting that the stere-
ochemistry of the sugar prevents the complex from adopting the
conformation necessary for synperiplanar elimination of OAc
(but not hydride) and that the PdÀC1ÀC2ÀOAc dihedral angle
(58.1° in the crystal structure of 3) was unsuitable for anti-
periplanar elimination, we considered two possible elimination
transition states: one in which the pyranosyl ring has undergone
complete ring inversion to orient all substituents axially
(including the monophosphine ÀPd(PEt3)(I) unit), and one
in which the ring has partially inverted to adopt a boat structure
(Scheme 4). To distinguish between these two possibilities, a
derivative of 5 was synthesized in which full ring inversion was
inhibited by tethering of the C4 and C6 positions with a
benzylidene group (Pd(PEt3)2(I)(3-AcO-4,6-benzylidene glu-
copyranose) (7)). The failure of this modification to reduce the
rate of elimination (50% of 7 had undergone elimination after
1.5 days at 40 °C vs 2 days for 5) indicated that a mechanism
requiring full ring inversion was not necessary and thus suggested
the likelihood of the pathway involving a boat transition state
(Scheme 4).
Figure 1. ORTEP of Pd(PEt3)2(Br)(AcO-β-glu) (3) (50% probability; H
atoms and one molecule of the asymmetric unit omitted for clarity). Selected
average bond lengths (Å) and angles (deg): PdÀC1, 2.051; PdÀBr, 2.537;
C1ÀPdÀBr, 175.80; P1ÀPdÀP2, 173.08; H1ÀC1ÀPdÀP1, 163.19;
H1ÀC1ÀPdÀP2, 13.22.
was also evident in the 31P NMR spectrum (AB quartet, 2JPP
=
404 Hz).15 The formation of the β-anomer was additionally
implied by the vicinal H1ÀH2 coupling constant (3JH ÀH
=
1
2
11 Hz), suggestive of a diaxial arrangement.16 Single crystals of 3
were grown by slow evaporation of a hexanes solution, and X-ray
diffraction confirmed the β-stereoisomer assignment and
showed the pyranosyl moiety to adopt a chair conformation
(Figure 1). To our knowledge, this represents the first reported
crystal structure of a palladium pyranosyl complex and only the
second C1-organometallic complex10 of a fully oxygenated sugar.
Scheme 4
Scheme 3
To examine how the stereochemistry of the C2 substituent
affected the stability of the C1-organopalladium species, we
carried out a reaction of R-D-mannopyranosyl bromide tetra-
benzoate with 1. In contrast to the case for the glucose-based
electrophile, this reaction immediately yielded tri-O-benzoylglu-
cal and Pd(PEt3)2(Br)(OBz) (Scheme 5, confirmed by 1H NMR
spectroscopy).
Under the same conditions that produced 3, Pd(PEt3)3 reacts
even more quickly (2 h) with acetoiodo-R-D-glucose to give
Pd(PEt3)2(I)(AcO-β-glu) (5). Glycosyl chloride analogues were
unreactive, establishing the reactivity trend Cl , Br < I.1,17
Reaction rates were also sensitive to ligand basicity, with less
electron-rich metal centers being slower to react. For example,
the modestly less basic18 Pd(PMePh2)3 required 3 days to react
with acetobromo-R-D-glucose (cf. 8 h for Pd(PEt3)3), affording
Pd(PMePh2)2(Br)(AcO-β-glu) (6).
Scheme 5
In contrast to the reactivity observed by Scott, wherein C1-
organometallic complexes generated from oxidative addition of
Pd(PPh3)4 and glucosyl mesylate rapidly eliminate β-hydride,9
benzene solutions of 3 slowly react via a β-acetoxy elimination
process to give tri-O-acetylglucal (4) and trans-Pd(PEt3)2(Br)-
(OAc) (Scheme 3). In light of this diverging behavior, we
Finally, the sensitivity of the reaction to variation in the phos-
phine ligand was investigated. For example, commercially available
bis(tricyclohexylphosphine)palladium(0) (PCy3 cone angle 170°
vs 132° for PEt3) reacts with 2 to directly produce 4 and trans-
Pd(PCy3)2(Br)(OAc) (8) within 5 min at room temperature
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: mgagne@unc.edu (M.R.G.).
’ ACKNOWLEDGMENT
Support from the U.S. Department of Energy (FG02-
05ER15630), the U.S. Army Research Office, the National Research
Council (fellowship to C.M.-L.), and the UNC Institute for the
Environment/Progress Energy Foundation (fellowship to L.L.A.) is
gratefully acknowledged.
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Figure 2. ORTEP of trans-Pd(PCy3)2(Br)(OAc) (8) (50% probability;
H atoms and one component of the disordered OAc ligand omitted for
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Scheme 6
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’ ASSOCIATED CONTENT
S
Supporting Information. Text, figures, and tables giv-
b
ing characterization data and experimental details and
CIF files giving X-ray crystallographic data for 3 and 8.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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À
(13) Mn(CO)5 has been reported to also cleanly invert glycosyl
bromides to the β-organometallic product: DeShong, P.; Slough, G. A.;
Elango, V.; Trainor, G. L. J. Am. Chem. Soc. 1985, 107, 7788–7790.
(14) The source of the comparative stability of 2 versus the Scott
putative intermediate is not known. Possible candidates include the
effect of phosphine, temperature, or the protecting group (Bn vs Ac).
(15) Hoffman, R. A.; Forsen, S.; Gestblom, B. NMR Basic Princ.
Progr. 1971; 71.
(16) Lambert, J. B.; Shurvell, H. F.; Lightner, D. A.; Cooks, R. G.
Organic Structural Spectroscopy; Simon & Schuster: Upper Saddle River,
NJ, 1998.
(17) Oxidative addition of a CÀO bond proved unsuccessful, as 1
and glucopyranose pentabenzoate do not react.
(18) Tolman, C. A. Chem. Rev. 1977, 77, 313–348.
(19) Even in the presence of excess PCy3, direct conversion of 2 to 4
is observed upon treatment with Pd(PCy3)2.
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