Radical deoxygenation of hydroxyl groups via phosphites

Article abstract of DOI:10.1021/ja0462777

A highly efficient, two-step sequence method for the deoxygenation of hydroxyl groups has been developed. The method involves the preparation of the 2-(2-iodophenyl)ethyl methyl phosphite derivative of an alcohol using methyl dichlorophosphite and 2-(2-iodophenyl)ethanol. Treatment of the phosphite intermediate with (n-Bu)₃SnH/AIBN in refluxing benzene cleanly produces the deoxygenation product of the original alcohol. Copyright

Full text of DOI:10.1021/ja0462777

Published on Web 09/25/2004
Radical Deoxygenation of Hydroxyl Groups via Phosphites
Liming Zhang† and Masato Koreeda*,†,¶
Departments of Chemistry and Medicinal Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
Received June 23, 2004; E-mail: Koreeda@umich.edu
Scheme 1. Fragmentation of Phosphoranyl Radicals
Deoxygenation of alcohol hydroxyl groups continues to play an
indispensable role in the synthesis of organic compounds,1 par-
ticularly complex natural products containing multifunctional
groups. Among plenteous methods at our disposal for effecting such
transformations, the radical reaction of a large array of O-
thiocarbonyl derivatives, the Barton-McCombie reaction,2 is
possibly the most versatile and widely employed by practicing
synthetic chemists, owing to its phenomenal functional group
tolerance. The method has been exceptionally effectual for the
deoxygenation of secondary alcohols, whereas its application to
the deoxygenation of primary3,4 and tertiary alcohols5 has met with
mixed results. In addition, the formation of side products often has
been recognized. Therefore, the development of an alternate method
for the deoxygenation of alcohols that obviates these drawbacks
would be highly desirable.
Scheme 2. Phosphorus-Mediated Deoxygenation Pathway
Phosphoranyl radicals, X4P•, are most commonly generated by
radical addition to trivalent phosphorus molecules and have
appreciable lifetimes.6 Depending upon the nature of the ligands
on phosphorus, these phosphoranyl radicals can adopt either trigonal
bipyramidal or quasi-tetrahedral structures with the single electron
confined to a P-X antibonding orbital or delocalized to π-acceptor
ligands.6 Phosphoranyl radicals of type R′3P‚-XR may undergo
either R-scission with the cleavage of a P-R′ bond or â-scission
with the cleavage of the X-R bond (Scheme 1). While R-scissions
correspond to overall homolytic substitutions at the phosphorus,7
â-scissions result in the oxidation of phosphorus(III) to phosphorus-
(V) and, importantly, the deoxygenation of R-OH when X ) O.8
In the following, we describe an efficient method for the radical-
based deoxygenation of an alcohol group by the use of its phosphite
derivative.
Scheme 3. Radical Deoxygenation through a Phosphite
Intermediate and Competition between the Two â-Scission
Processesa
We envisaged that the deoxygenation of alcohols could be
achieved by a two-step sequence (Scheme 2); alcohol 2 is first
converted into its trivalent phosphorus derivative 3, and then the
aryl radical generated under standard radical conditions could
intramolecularly attack the phosphorus atom to form the phospho-
ranyl radical 4. It was expected that the presence of a benzene ligand
would impede the R-sission pathway.9 Consequently, the fragmen-
tation of radical 4 by the â-scission would likely be favored,
producing the radical (R•) which should lead to the reduction
product R-H upon hydrogen abstraction.
Our initial attempt emplyoing the [2-(2′-iodophenyl)phenyl]-
phenylphosphinite derivative of an alcohol resulted in the formation
of a complex mixture.10 However, the use of a phosphite derivative
3 [R′ ) OMe; X ) O; n ) 2] resulted in clean formation of the
reduction product, 7,6 thus overall constituting highly efficient
deoxygenation of alcohols 2.
The preparation of the phosphite derivative was readily achieved
by successive treatments of an alcohol with CH3OPCl2 and 2-(2′-
iodophenyl)ethyl alcohol11 (see 8 f 9, Scheme 3). Upon subjection
of phosphite 9 to standard radical conditions [(n-Bu)3SnH (1.4 mol
a Reagents and conditions: (i) Cl2POCH3 (2.5 mol equiv)/(i-Pr)2NEt (7.5
mol equiv)/THF, -78 °C; 2-(2′-iodophenyl)ethanol (3.5 mol equiv), -78
°C to room temperature. (ii) (n-Bu)3SnH (1.4 mol equiv), AIBN (cat)/
benzene, reflux, 2 h.
equiv), AIBN (cat), benzene, reflux, 2 h], phosphite 9 was all
consumed, and the corresponding deoxygenation product 13 and
phosphonate 11 were isolated each in 62% yield. In addition,
phosphonate 14 was also obtained in 29% yield. The formation of
13 (as well as 11) and phosphonate 14 is the result of the â-scissions
of the PO-R (route a) and the RO-CH3 groups (route b),
respectively. In view of the synthetic potential of the reaction to
¶ Department of Chemistry.
† Department of Medicinal Chemistry.
9
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J. AM. CHEM. SOC. 2004, 126, 13190-13191
10.1021/ja0462777 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Preparation of Phosphites 15 and Radial Deoxygenation
of Alcohols 2
group seems to indicate that the intermediate phosphoranyl radical
adopts most likely not a trigonal bipyramidal structure, but other
structures such as a quasi-tetrahedral ligand π-electronic structure
where the single electron is delocalized throughout the benzene
ring.6,7 If a trigonal bipyramidal radical structure were close to that
of the transition state for the â-scission, one would expect bulky
groups to be preferentially attached to the resulting phosphonate
product instead of being involved in the fragmentation pathway,
as observed by Barton8a in the preparation of highly hindered
phosphates from phosphites. Regardless of the transition-state
structure in the system examined here, there seems to be site
selectivity for â-scission involving the bulkier or more substituted
carbon center occupying that site.
In summary, we have developed a highly versatile method for
the deoxygenation of alcohols. This two-step sequence is highly
efficient, particularly for the deoxygenation of relatively hindered
alcohols, including tertiary alcohols. The purification of the
deoxygenation product is readily achieved, as the phosphonate
byproducts are considerably more polar.
Supporting Information Available: Spectral data and experimental
procedures. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
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1975, 1574-15. For reviews, see: (b) Hatwig, W. Tetrahedron 1983,
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Chemistry; Cambridge University Press: Cambridge, UK, 1993. (e)
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a,b See conditions i and ii, respectively, in Scheme 3. c Yield of isolated,
chromatographically pure products. d The ratio of the products from the
PO-R bond scission and the scission of PO-CH3 bonds. Estimated by
integrations of the corresponding peaks in the 1H and 31P NMR spectra of
the crude reaction mixture. e Yield estimated by GC-MS using n-decane
as an internal standard. f 17â-Methyl product.
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A. Synthesis 1981, 743-745. (b) Kirwan, J. N.; Roberts, B. P.; Willis, C.
R. Tetrahedron Lett. 1990, 31, 5093-5096.
(4) For other thiocarbonyl variations, see: (a) Barton, D. H. R.; Jang, D. O.;
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effect the deoxygenation of alcohols, the scope of this newly
uncovered reaction was next explored.
As summarized in Table 1, phosphites 15 were accessed under
basic conditions in good to excellent yield from the corresponding
alcohols 2, including highly congested alcohols. Radical reduction
of all phosphites 15 was equally efficient. The phosphite of a highly
congested, neopentyl-type primary alcohol (entry 1) provided the
corresponding deoxygenated product in 81% yield, together with
a small amount of the phosphonate product 16 from the PO-CH3
(7) Walton, J. C. Acc. Chem. Res. 1998, 31, 99-107.
1
cleavage, as estimated from the H and 31P NMR spectra of the
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crude product. In the reduction of the phosphite derivatives of
relatively hindered secondary alcohols (entries 2-5), the undesired
â-scission involving the PO-CH3 bond seems to become less
prominent. This marked relative acceleration of the PO-R bond
cleavage of the phosphites of these hindered alcohols is likely due
to the steric compression effect surrounding the hydroxyl groups
of these alcohols. This preference for the cleavage of the PO-R
over the PO-CH3 bonds is even more pronounced in the case of
tertiary alcohol derivatives (entries 6 and 7), and virtually no product
resulting from the PO-CH3 cleavage, i.e., 16, was detected.
Significantly, unlike xanthate derivatives of tertiary alcohol,5 these
phospites of tertiary alcohols are thermally stable, even in refluxing
benzene.
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(10) Zhang, L.; Koreeda, M. Unpublished results.
(11) Prepared by the reduction of commercially available 2-iodophenylacetic
acid by the method of Larock: Pletnev, A. A.; Larock, R. C. J. Org.
Chem. 2002, 67, 9428-9438.
The diminished contribution of the fragmentation of the PO-
CH3 bond with increasing steric hindrance surrounding the hydroxyl
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