IBX-mediated α-hydroxylation of α-alkynyl carbonyl systems. A convenient method for the synthesis of tertiary alcohols

Article abstract of DOI:10.1021/jo051898j

IBX (o-iodoxybenzoic acid) is an excellent reagent for the α-hydroxylation of α-alkynyl carbonyl compounds without giving dehydrogenation products. The convenient procedure proves to be useful for the construction of a variety of tertiary alcohols (55-91%

Full text of DOI:10.1021/jo051898j

SCHEME 1. IBX-Induced r-Hydroxylation of
Carbonyl Compounds
IBX-Mediated r-Hydroxylation of r-Alkynyl
Carbonyl Systems. A Convenient Method
for the Synthesis of Tertiary Alcohols
Stefan F. Kirsch*
Department Chemie, Technische Universita¨t Mu¨nchen,
Lichtenbergstr. 4, D-85747 Garching, Germany
stefan.kirsch@ch.tum.de
Received September 9, 2005
as a nucleophile.6-9 To date, there has been no report of
R-hydroxylation of carbonyl compounds through IBX-
mediated oxygen transfer. Such transformations have
been traditionally accomplished by the reaction of eno-
lates and silyl enol ethers with oxygen electrophiles,10
although its synthetic utility is somewhat depreciated by
a lack of general routes to generate tertiary alcohols.11,12
We disclose herein an efficient approach to R-substituted
R-hydroxy R-alkynyl carbonyl compounds by an oxidation
in the R-position of R-alkynyl carbonyl compounds and
2-alkynyl alcohols mediated by IBX.
Nicolaou and co-workers developed an excellent method
for the dehydrogenation of aldehydes and ketones that
provides R,â-unsaturated carbonyl compounds using IBX
at elevated temperatures (1 f 3, Scheme 1).5 Preliminary
work has shown that reaction of 2-phenylcyclohexanone
(-R1R2- ) -(CH2)2-, R3 ) Ph) with 1.5 equiv of IBX in
DMSO at 40 °C produced a mixture of 2-hydroxy-2-
phenylcyclohexanone (31%), 6-phenylcyclohex-2-enone
(33%), and traces of 2-phenylcyclohex-2-enone after 24
h. This result indicates that a tertiary alcohol is formed
in the presence of stoichiometric amounts of IBX with
the dehydrogenation between R2 and R3 (with R3 ) Ph)
being almost suppressed. Unfortunately, the 2-position
and the 6-position of 2-phenylcyclohexanone were simul-
taneously oxidized by IBX without favoring the 2-posi-
tion. Encouraged by this result, it was planned to find
suitable substrates 1 for the selective R-hydroxylation of
carbonyl compounds via IBX-mediated oxygen transfer
under formation of tertiary alcohol 2 (Scheme 1).
IBX (o-iodoxybenzoic acid) is an excellent reagent for the
R-hydroxylation of R-alkynyl carbonyl compounds without
giving dehydrogenation products. The convenient procedure
proves to be useful for the construction of a variety of tertiary
alcohols (55-91%) under mildly acidic conditions.
The synthetic use of o-iodoxybenzoic acid (IBX)1 as an
oxidizing agent was initially demonstrated by Frigerio
and Santagostino in 1994 for the oxidation of alcohols to
carbonyl compounds.2 Since then, the synthetic value of
IBX has been extended to a variety of other useful
oxidative transformations.3-5 Recently, some interesting
conversions have been described which proceed probably
via intramolecular delivery of oxygen and expulsion of
iodosobenzoic acid (IBA) using the oxide ligand of IBX
In an attempt to obtain selectivity for tertiary alcohol
2, we explored substrates, which contain sterically less
(1) For the synthesis of IBX, see: (a) Hartmann, C.; Meyer, V. Chem.
Ber. 1893, 26, 1727-1732. (b) Frigerio, M.; Santagostino, M.; Sputore,
S. J. Org. Chem. 1999, 64, 4537-4538.
(6) Besides the more likely SET-based mechanism, an ionic mech-
anism was discussed for the IBX-mediated dehydrogenation of carbonyl
compounds: ref 5b.
(7) The reaction of p-cresol with IBX gave 4-methyl-1,2-bisphenol:
ref 5b.
(8) The benzylic oxidation using IBX can be explained via intramo-
lecular oxygen transfer: ref 5b.
(9) (a) Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.; Pettus,
T. R. R. Org. Lett. 2002, 4, 285-288. (b) Shibuya, M.; Ito, S.; Takahashi,
M.; Iwabuchi, Y. Org. Lett. 2004, 6, 4303-4306.
(2) (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35,
8019-8022. (b) De Munari, S.; Frigerio, M.; Santagostino, M. J. Org.
Chem. 1996, 61, 9272-9279. For recent examples, see: (c) More, J.
D.; Finney, N. S. Org. Lett. 2002, 4, 3001-3003. (d) Thottumkara, A.
P.; Bowsher, M. S.; Vinod, T. K. Org. Lett. 2005, 7, 2933-2936.
(3) For reviews, see: (a) Wirth, T. Angew. Chem., Int. Ed. 2001, 40,
2812-2814. (b) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102,
2523-2584. (c) Kumar, I. Synlett 2005, 1488-1489. (d) Wirth, T.
Angew. Chem., Int. Ed. 2005, 44, 3656-3665.
(4) (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem.,
Int. Ed. 2000, 39, 625-628. (b) Nicolaou, K. C.; Zhong, Y.-L.; Baran,
P. S. Angew. Chem., Int. Ed. 2000, 39, 2525-2529. (c) Nicolaou, K. C.;
Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2001, 123, 3183-3185.
(d) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem.
Soc. 2004, 126, 5192-5201. (e) Schulze, A.; Giannis, A. Adv. Synth.
Catal. 2004, 346, 252-256.
(5) (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc.
2000, 122, 7596-7597. (b) Nicolaou, K. C.; Montagnon, T.; Baran, P.
S.; Zhong, Y.-L. J. Am. Chem. Soc. 2002, 124, 2245-2258. (c) Nicolaou,
K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int. Ed. 2002, 41,
993-996. (d) Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison,
S. T. Angew. Chem., Int. Ed. 2002, 41, 996-1000.
(10) (a) Jones, A. B. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 7, pp 151-
191. (b) Davis, F. A.; Chen, B.-C. In Methods of Organic Chemistry
(Houben-Weyl), 4th ed.; Helmchen, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Eds.; Thieme: New York, 1995; Vol. E21b, pp 4497-
4518. (c) Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E. Org. React.
2003, 62, 1-356.
(11) For selected examples for the synthesis of tertiary alcohols via
R-hydroxylation of carbonyl compounds, see: (a) Davis, F. A.; Weismill-
er, M. C. J. Org. Chem. 1990, 55, 3715-3717. (b) Shea, K. J.; Sakata,
S. T. Tetrahedron Lett. 1992, 33, 4261-4264.
(12) Christoffers, J.; Baro, A.; Werner, T. Adv. Synth. Catal. 2004,
346, 143-151.
10.1021/jo051898j CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/03/2005
10210
J. Org. Chem. 2005, 70, 10210-10212

TABLE 1. IBX-Mediated Formation of 2 from 1 and 4a
a Conditions: (a) Method A: 0.64 mmol 1, 1.5 equiv IBX, 23 °C, [substrate] ) 0.5 M, DMSO; (b) Method B: 0.42 mmol 4, 3.0 equiv
IBX, 23 °C, [substrate] ) 0.5 M, DMSO. b All compounds 4 are trans isomers. c Isolated yield of 2 after column chromatography. Average
of two experiments. d TBS ) tert-butyldimethylsilyl. e THP ) 2-tetrahydropyranyl. f TMS ) trimethylsilyl. g Bn ) benzyl. h Diastereomeric
ratio of 2h determined by 1H NMR of crude mixture. i Yield of the shown diastereoisomer 2h after column chromatography (d.r. > 95:5).
j The relative configuration of 2h was determined by NOESY experiments.
demanding alkyne substituents for R3 (R3 ) CtCR).
Thus, we examined initially the hydroxylation of 2-(2-
phenylethynyl)cyclohexanone (1a) to tertiary alcohol 2b
using 1.5 equiv of IBX in DMSO. Indeed, IBX was
effective, giving alcohol 2b in 84% yield after 20 h at room
temperature (Table 1, entry 2). To our delight, the
formation of R,â-unsaturated carbonyl compounds through
dehydrogenation was not observed under these condi-
tions.13 As summarized in Table 1, the conversion of
various ketones 1 to the corresponding tertiary alcohols
2 can be accomplished in good yields under notably
practical conditions: 1.5 equiv of IBX, DMSO (0.5 M),
23 °C, reaction times 12-20 h (method A) (entries 2-5).
Since IBX is known to oxidize alcohols, it was also
possible to obtain the tertiary alcohols 2 starting from
2-alkynyl alcohols 4 in the presence of 3.0 equiv of IBX
(method B) (entries 1, 6-12),14 a modification that is
particularly advantageous with 2-alkynylcycloalkanones
that undergo a facile isomerization to the conjugated
allenones. In the case of trans-2-alkynylcyclopentanol 4a,
for example, clean oxidation to the corresponding five-
membered ketone 1 is sometimes difficult,15 but treat-
ment with 3.0 equiv of IBX led to the formation of
2-hydroxycyclopentanone 2a in moderate yield (entry 1).
With these methods in hand, 2-hydroxy carbonyl com-
pounds 2 were formed in good yields with R being aryl
and heteroaryl substituents (entries 1-3, 6, 7, 10, 11).
Moreover, substrates with alkyl substituents at the
alkyne terminus were effectively converted into the
tertiary alcohols (entries 4, 5, and 9). The reaction of
substrate 4d (R ) TMS) with 3.0 equiv of IBX also took
place in high yield (entry 8). Although not extensively
examined at this point, functional groups such as ether
(entry 10), silyl ether (entry 4), and acetal (entries 5 and
9) are well tolerated. Substrates containing a six-
membered ring system gave the tertiary alcohols 2 as
oxidation products in excellent regioselectivity, as did
substrates containing a simple acyclic skeleton (entries
11 and 12). The oxidation of benzyl ether 4f proceeded
in moderate diastereoselectivity (dr ) 74:26) with the
hydroxy group favoring a position trans to the benzyloxy
group (entry 10).
Several additional observations merit note. This method
is limited to the conversion of ketones 1 and secondary
alcohols 4; aldehydes and primary alcohols were not
(13) Other hypervalent iodine compounds were not used in such
R-hydroxylations.
(14) Ketone 1 was detected as the intermediary occurring species
in the transformation 4 f 2 by capillary gas chromatography and by
thin-layer chromatography.
(15) (a) Carlson, R. G.; Cox, W. W. J. Org. Chem. 1977, 42, 2382-
2386. (b) Murray, T. F.; Samsel, E. G.; Varma, V.; Norton, J. R. J.
Am. Chem. Soc. 1981, 103, 7520-7528.
J. Org. Chem, Vol. 70, No. 24, 2005 10211

2-Hydroxy-2-(2-phenylethynyl)cyclohexanone (2b). Gen-
eral Procedure for the IBX-Mediated r-Hydroxylation of
r-Alkynyl Carbonyl Compounds 1 (Method A). IBX (0.48
mmol, 134 mg) was added to a solution of ketone 1a (82 mg,
0.64 mmol) in DMSO (1.3 mL), and the reaction vial was sealed,
protected from light, and stirred at room temperature. After 3
h, additional IBX (0.48 mmol, 134 mg) was added. The reaction
mixture was then stirred at room temperature for 17 h (until
TLC analysis indicated complete consumption of starting mate-
rial) and diluted with CH2Cl2 (10 mL), and stirring was
continued for 30 min to precipitate the insoluble byproduct,
which was removed by filtration. The precipitate was washed
with CH2Cl2 (2 × 5 mL), and the combined filtrate was
subsequently diluted with aqueous saturated NaHCO3 (20 mL).
The phases were separated, and the aqueous phase was ex-
tracted with CH2Cl2 (2 × 5 mL). The combined organic phases
were washed with water (30 mL) and brine (30 mL), dried (Na2-
SO4), and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica (10% Et2O/pentane)
to afford 2b as a pale yellow oil (115 mg, 0.54 mmol, 84%).
General Procedure for the IBX-Mediated R-Hydroxyla-
tion Starting from 2-Alkynyl Alcohols 4 (Method B). IBX
(0.42 mmol, 118 mg) was added to a solution of alcohol 4b (84
mg, 0.42 mmol) in DMSO (0.9 mL), and the reaction vial was
sealed, protected from light, and stirred at room temperature.
After 4 h, additional IBX (0.84 mmol, 235 mg) was added. The
reaction mixture was then stirred at room temperature for 11 h
(until TLC analysis indicated complete consumption of starting
material) and diluted with CH2Cl2 (10 mL), and stirring was
continued for 30 min to precipitate the insoluble byproduct,
which was removed by filtration. The precipitate was washed
with CH2Cl2 (2 × 5 mL), and the combined filtrate was
subsequently diluted with aqueous saturated NaHCO3 (20 mL).
The phases were separated, and the aqueous phase was ex-
tracted with CH2Cl2 (2 × 5 mL). The combined organic phases
were washed with water (30 mL) and brine (30 mL), dried (Na2-
SO4), and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica (10% EtOAc/pentane)
to afford 2b as a pale yellow oil (72 mg, 0.34 mmol, 80%): Rf
0.39 (20% EtOAc/pentane); 1H NMR (500 MHz, CDCl3) δ 1.69
(dt, J ) 13.6, 3.9 Hz, 1 H), 1.76 (dt, J ) 3.5, 13.1 Hz, 1 H), 1.91-
1.93 (m, 1 H), 2.12 (tt, J ) 13.6, 3.6 Hz, 1 H), 2.11-2.20 (m, 1
H), 2.57-2.61 (m, 2 H), 3.04 (dt, J ) 6.2, 13.7 Hz, 1 H), 4.32 (s,
1 H), 7.33-7.38 (m, 3 H), 7.46 (dd, J ) 7.3, 1.4 Hz, 2 H); 13C
NMR (90.6 MHz, CDCl3) δ 22.9, 27.7, 37.3, 42.5, 74.1, 87.5, 87.8,
122.0, 128.3, 128.8, 131.8, 207.5; LRMS (EI) 214 (80) [M+], 185
(62), 157 (58), 129 (100); HRMS 214.0993 [214.0994 calcd for
transformed at room temperature or at elevated temper-
atures. It was not necessary to take special precautions
to exclude air and moisture from the reaction mixture.
To ensure reproducible yields, it was advantageous to add
IBX in two portions to the reaction mixture.16 A concen-
tration of 0.5 M in the substrate was ideal to achieve good
conversion in the oxidation of both the ketones 1 and the
alcohols 4. A too high concentration of IBX in DMSO
(>2.0 M) led to solubility problems, while concentrations
<0.2 M resulted in significantly lower yields due to
competitive reduction of IBX by DMSO.5b During the
reaction course, a white precipitate was formed which
was mainly composed of IBA.5b The alkynyl moiety
appears to be essential for the rapid and clean oxygen
transfer from IBX at room temperature.17 Performing the
hydroxylation at 60 °C gave a significant amount of
unidentified decomposition products with the tertiary
alcohol 2 remaining the main product.18 Reaction of
carbonyl compounds containing alkyl substituents at C2
rather than alkynyl did not take place in the presence of
IBX at room temperature. At elevated temperatures,
these substrates (e.g., 2-methylcyclohexanone) did not
provide the corresponding tertiary alcohols, forming
instead product mixtures which mainly contained dehy-
drogenation products.19
In conclusion, a new method for the selective R-hy-
droxylation of R-alkynyl carbonyl compounds was devel-
oped. The IBX-mediated reaction can be conducted under
convenient conditions to provide tertiary alcohols. As
enolate formation by reaction with bases is not required,
this mildly acidic method is a practical alternative to
previously reported R-hydroxylation procedures.10c Fur-
ther studies, including detailed investigations into mech-
anism and applications in total synthesis, are currently
underway.
Experimental Section
General Experimental Details. Alkynyl alcohols 4 were
prepared according to published procedures by alkynylation of
oxiranes [LiCtCR (1 equiv), BF3‚OEt2 (1 equiv), -78 °C, THF].20
All R-alkynyl carbonyl compounds 1 were synthesized by the
oxidation of the corresponding alkynyl alcohols 4 with PCC.21
DMSO contained less than 0.005% of water. IBX was prepared
according to a procedure developed by Santagostino and co-
workers.1b
C
14H14O2 (M+)].
Acknowledgment. This project was supported by
the “Bundesministerium fu¨r Bildung und Forschung”
and the “Fonds der Chemischen Industrie”. S.F.K.
thanks Professor T. Bach and Prof. L. E. Overman for
persistent encouragement.
(16) Adding IBX at once to the reaction mixture gave varying yields
for the conversion 1a f 2b (51-88%).
(17) The origin of this effect remains unclear.
(18) A facile dehydration of the tertiary alcohols 2 giving R,â-
unsaturated carbonyl compounds 3 was not observed under these
conditions.
(19) Tertiary alcohols were not detected as intermediary species in
the IBX-mediated dehydrogenation of carbonyl compounds.
(20) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391-394.
(21) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16, 2647-
2650.
Supporting Information Available: Product character-
ization data and copies of 1H and 13C NMR spectra for tertiary
alcohols 2a-j. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO051898J
10212 J. Org. Chem., Vol. 70, No. 24, 2005