Mild and efficient removal of hydroxyethyl unit from 2-hydroxyethyl ether derivatives leading to alcohols

Article abstract of DOI:10.1021/ol051135i

(Chemical Equation Presented) CAN is a good reagent for the transformation of 2-hydroxyethyl ether units to alcohols. Significantly, many functional groups can tolerate the reaction conditions, although they do not survive under many previously reported removal conditions. The reaction mechanism is clarified.

Full text of DOI:10.1021/ol051135i

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3303-3306
Mild and Efficient Removal of
Hydroxyethyl Unit from 2-Hydroxyethyl
Ether Derivatives Leading to Alcohols
Hiromichi Fujioka,* Yusuke Ohba, Hideki Hirose, Kenichi Murai, and
Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6, Yamada-oka,
Suita, Osaka, 565-0871, Japan
fujioka@phs.osaka-u.ac.jp; kita@phs.osaka-u.ac.jp
Received May 16, 2005
ABSTRACT
CAN is a good reagent for the transformation of 2-hydroxyethyl ether units to alcohols. Significantly, many functional groups can tolerate the
reaction conditions, although they do not survive under many previously reported removal conditions. The reaction mechanism is clarified.
The transformation of 2-hydroxyethyl ether units to alcohols
is very important, especially for asymmetric synthesis with
C2-symmetric chiral acetals from chiral 2,3-butanediol or
chiral hydrobenzoin, because such units are formed by the
cleavage of the C-O bond of the dioxolane rings in the
nucleophilic substitution reactions. The usual method for the
removal of 2-hydroxyethyl ether units from 2,3-butanediol
involves a multistep sequence, i.e., oxidation of a secondary
alcohol and then Birch reduction1 or Baeyer-Villiger reac-
tion followed by methanolysis.2 On the other hand, for the
2-hydroxyethyl ether units derived from chiral hydrobenzoin,
(1) oxidation of the secondary alcohol followed by reductive
elimination3 or (2) Birch reduction or hydrogenolysis are
usually used.4 However, such reactions are not applicable
to compounds having labile functions such as carbonyl,
halogen, and olefin groups. Recently, asymmetric synthesis
using a chiral hydrobenzoin has increased rapidly because
of the ready availability of optically pure hydrobenzoin via
the Sharpless asymmetric dihydroxylation of trans-stilbene.5
We now present a very mild, efficient, and highly general
one-pot removal method for 2-hydroxyethyl ether units to
give alcohols (Scheme 1).
Scheme 1. Transformation of 2-Hydroxyethyl Ethers to
Alcohols
Quite recently, we wanted to obtain an alcohol 2 from 1
by removal of the 2-hydroxy-1,2-diphenylethylene unit. We
succeeded in effecting this transformation with cerium
ammonium nitrate (CAN), the desired alcohol 2 being
obtained in good yield (Table 1, entry 1).6 On the other hand,
the usual way to remove the 2-hydroxy-1,2-diphenylethyl
unit, i.e., the Birch reduction or hydrogenolysis, led to poor
results, giving a complex mixture due to the presence of the
iodide and lactone moieties (entries 2, 3). Other reaction
conditions, i.e., phenyliodine diacetate (PIDA)-I2,7 Pb-
(1) Bartlett, P. A.; Johnson, W. S.; Elliott, J. D. J. Am. Chem. Soc. 1983,
105, 2088.
(2) McNamara, J. M.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 7371.
(3) Alexakis, A.; Trevitt, G. P.; Bernardinelli, J. Am. Chem. Soc. 2001,
123, 4358.
(4) Fujioka, H.; Kitagawa, H.; Nagatomi, Y.; Kita, Y. J. Org. Chem.
1996, 61, 7309.
(5) Wang, Z.-M.; Sharpless, K. B. J. Org. Chem. 1994, 59, 8302.
(6) Fujioka, H.; Ohba, Y.; Hirose, H.; Murai, K.; Kita, Y. Angew. Chem.,
Int. Ed. 2005, 44, 734.
10.1021/ol051135i CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/24/2005

Scheme 2
Table 1. Attempts for Removal of 2-Hydroxy-1,2-
diphenylethyl Unit of 1
The reactions of the 2-hydroxy-1,2-diphenylethyl ether
derivatives 3a-c of 3-phenylpropanol 4 were first examined.
The reaction of the hydroxy compound 3a proceeded
smoothly to give the alcohol 4 in quantitative yield; on the
other hand, the addition of 4-amino-(2,2,5,5-tetramethylpi-
peridine-N-oxide) (TEMPO), a radical scavenger, or O-
protected compounds (Me-ether 3b and acetate 3c) did not
afford the alcohol 4 at all, and the starting materials were
recovered (Scheme 2).
The reaction worked well for various 2-hydroxyethyl ether
compounds of 3-phenylpropanol 4 (Table 2); thus, the
2-hydroxy-1,2-diphenylethyl group 3a (entry 1), 2-hydroxy-
2- or 1-phenylethyl groups 3d or 3e (entries 2, 3), and
2-hydroxy-2,3-dimethyl group 3f (entry 4) all gave the
alcohol 4 in good yields. It is noteworthy that 2-hydroxy-
2-methyl compound 3g and 2-hydroxy-monomethylated
mixture (1-Me and 2-Me (3g) mixture) 3h still gave 4 in
good yields, although excess CAN and longer reaction times
entry
conditions
yield
80%
decomp
decomp
decomp
ndg
1
2
3
4
5
6
7
CAN/CH3CN-H2O
Birch reductiona
hydrogenationb
c
PIDA, I2
d
Pb(OAc)4
a
RuCl3, NaIO4
DDQf
decomp
nr
a Ca (10 equiv), EtOH (10 equiv)/liquid NH3, Et2O. b Pd(OH)2 (0.1
equiv)/EtOH, H2 (1 atm). c Phenyl iodine diacetate (PIDA) (2.5 equiv), I2
(1 equiv). d Pb(OAc)4 (1.2 equiv), pH 7 buffer (0.1 M)/MeOH-CH2Cl2 )
1/2. e RuCl3‚3H2O (2.2 mol %), NaIO4 (20 equiv)/CH3Cn-CCl4 ) 1/1.
f DDQ (2 equiv), CH2Cl2-H2O ) 18/1. g Major product was the compound
reduced to iodines.
(OAc)4,8 and RuCl3-NaIO4,9 usually used for the removal
of the 2-hydroxyethyl unit from the N-2-hydroxyethyl-N-
alkylamine, also gave poor results (entries 4-6). It is
noteworthy that DDQ,10 which is interchangeable with CAN
in many cases, did not work at all in this case (entry 7, Table
1). Although the CAN method has previously been applied
to the compounds derived from 1,2-di-(4-methoxyphenyl)-
1,2-diol,11 it appears that the authors went to the trouble of
preparing a rather special diol, 1,2-di-(4-methoxyphenyl)-
1,2-diol, for deprotection by CAN because the deprotection
of 4-methoxyphenylmethyl ethers by CAN is widely recog-
nized.12,13 On the other hand, no report for the deprotection
of the compounds derived from hydrobenzoin or other diols
by CAN has appeared, to the best of our knowledge.
Furthermore, the reaction mechanism for the deprotection
of the compounds derived from 1,2-di-(4-methoxyphenyl)-
1,2-diol was also not discussed. Therefore, we studied this
reaction and its mechanism in detail.
Table 2. Reactions of Various 2-Hydroxytheyl Ethers of
3-Phenylpropanol 4 with CAN (2.0 equiv) in CH3CN-H2O
(1/1) at Room Temperature.
(7) Boto, A.; Hernandes, R.; Montoya, A.; Suarez, E. Tetrahedron Lett.
2004, 45, 1559.
(8) Chakraborty, T. K.; Reddy, G. V. J. Org. Chem. 1992, 57, 5462.
(9) Ranganathan, D.; Saini, S. J. Am. Chem. Soc. 1991, 113, 1042.
(10) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
(11) (a) Andrus, M. B.; Meredith, E. L.; Hicken, E. J.; Simmons, B. L.;
Glancey, R. R.; Ma, W. J. Org. Chem. 2003, 68, 8162. (b) Andrus, M. B.;
Meredith, E. L.; Simmons, B. L.; Soma Sekhar, B. B. V.; Hicken, E. J.
Org. Lett. 2002, 4, 3549. (c) Andrus, M. B.; Mendenhall, K. G.; Meredith,
E. L.; Soma Sekhar, B. B. V. Tetrahedron Lett. 2002, 43, 1789. (d)
Andrus, M. B.; Meredith, E. L.; Soma Sekhar, B. B. V. Org. Lett. 2001, 3,
259.
(12) Andrus et al. developed a new asymmetric aldol reaction first using
the chiral diol, (S,S)-hydrobenzoin, as a chiral auxiliary and then hydro-
genation for its removal (Andrus, M. B.; Soma, B. B. V.; Meredith, E. L.;
Dalley, N. K. Org. Lett. 2000, 2, 3035). However, the method was not
applied to compounds having functional groups labile under hydrogeno-
lysis conditions (ref 11c). For the total synthesis of (+)-geldanamycins,
they used 1,2-di-(4-methoxyphenyl)-1,2-diol as the chiral diol (refs
11a,b,d).
a Reaction was carried out using 4.0 equiv of CAN. b Reaction was
carried out using 6.0 equiv of CAN. c Reaction was carried out using 6.0
equiv of CAN at 60 °C.
(13) Green, T. W.; Wuts, P. G. ProtectiVe Groups in Organic Synthesis,
3rd ed.; John Wiley and Sons: New York, 1999.
3304
Org. Lett., Vol. 7, No. 15, 2005

Scheme 3. Reaction Mechanism of 3a
Table 3. Reactions of Various 2-Hydroxyethyl Ethers (5)
were necessary (entries 5, 6), while the reaction of the
unsubstituted 2-hydroxyethyl compound 3i did not proceed
(entry 7).
The results in Scheme 2 and Table 2 suggested the reaction
mechanism shown in Scheme 3. The reaction is rationalized
using the 2-hydroxy-1,2-diphenyethyl ether 3a. We contend
that the following sequence is in operation: The first step
involves formation of the O-Ce(IV) bond to give i. Radical
cleavage of the C-C bond then occurs to give the radical
intermediate ii. Single-electron transfer then proceeds to
give the cationic species iii. Finally, nucleophilic addition
of water occurs to give hemiacetal iv, which breaks down
to give the alcohol 4 and benzaldehyde.14,15 This mechanistic
proposal involving radical cleavage was confirmed from the
fact that the reaction of 3a did not proceed at all in the
presence of the radical scavenger, TEMPO, as already
described.
a Performed with 4.0 equiv of CAN.
Table 3 shows the results of various substrates 5. Many
functional groups such as esters 5a,b (entries 1, 2), olefins
5c,d (entries 3, 4), Me-ether 5e (entry 5), Bn-ether 5f (entry
6), acetate 5g (entry 7), tosylate 5h (entry 8), and iodine 5i
(entry 9) tolerated these reaction conditions, whereas p-
methoxybenzyl (PMB)-ether 5j gave the diol 6h. These facts
show that the reaction here is very mild and has a wide
generality.
In conclusion, we proved that CAN deprotects a variety
of ethers derived from various diols, including hydrobenzoin.
We have also clarified its reaction mechanism. The reaction
is very mild and efficient, and many functional groups are
tolerant of the reaction. Therefore, this study adds a new
aspect to synthetic organic chemistry and is potentially
The significant advantages of our method were also
clarified by the successful reactions of compounds 716 and
10a,b6 (Scheme 4), which contain functional groups such
as bromine, olefin, and acetal units in 7 and iodine, acetal,
and nitrile units in 10a,b. A domino three-step sequence was
also shown to be viable for converting 7 into the ene bromo
lactol 8, which exists as a 2:1 mixture of hemiacetals.17 Its
structure was determined by its conversion to lactone 9.
Compounds 10a,b also gave the acetals 11a,b in a single
operation. These would allow for new chiral synthones
because they have many functional groups for further
transformation.
Scheme 4. Domino-Type Reactions
(14) For oxidative cleavage of 1,2-glycols by CAN for reference, see:
Trahanovsky, W. S.; Gilmore, J. R.; Heaton, P. C. J. Org. Chem. 1973, 38,
760.
(15) Formation of benzaldehyde in the reaction mixtures from 3a,d,e
1
was determined by H NMR.
(16) Fujioka, H.; Kotoku, N.; Sawama, Y.; Nagatomi, Y.; Kita, Y.
Tetrahedron Lett. 2002, 43, 4825.
(17) For deprotection of acetals by CAN, see: (a) Ates, A.; Gautier, A.;
Leroy, B.; Plancher, J.-M.; Quesnel, Y.; Vanherck, J.-C.; Marko´, I. E.
Tetrahedron 2003, 59, 8989. (b) Marko´, I. E.; Ates, A.; Gautier, A.; Leroy,
B.; Plancher, J.-M.; Quesnel, Y.; Vanherck, J.-C. Angew. Chem., Int. Ed.
1999, 38, 3207. For hydrolysis of acetal units in compounds 7 and 10,
the reactions were carried out at 60 °C and excess amounts of CAN were
used.
Org. Lett., Vol. 7, No. 15, 2005
3305

important in asymmetric synthesis involving C2-symmetric
diols as described in the introduction of this Letter.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Science and Culture, Japan.
OL051135I
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Org. Lett., Vol. 7, No. 15, 2005