Protection of the carbonyl group as 1,2,4-trioxane and its regeneration under basic conditions

Article abstract of DOI:10.1021/ol052378d

(Chemical Equation Presented) An experimental protocol demonstrating the protection of the carbonyl group as 1,2,4-trioxane, the stability of the protecting group under a variety of reaction conditions, and the regeneration of the carbonyl group with Triton B in THF at room temperature is presented. The method provides a useful alternative for the protection of carbonyl compounds having acid-sensitive moieties.

Full text of DOI:10.1021/ol052378d

ORGANIC
LETTERS
2005
Vol. 7, No. 25
5673-5676
Protection of the Carbonyl Group as
1,2,4-Trioxane and Its Regeneration
under Basic Conditions1
Chandan Singh* and Heetika Malik
DiVision of Medicinal and Process Chemistry, Central Drug Research Institute,
Lucknow 226001, India
chandancdri@yahoo.com
Received October 2, 2005
ABSTRACT
An experimental protocol demonstrating the protection of the carbonyl group as 1,2,4-trioxane, the stability of the protecting group under a
variety of reaction conditions, and the regeneration of the carbonyl group with Triton B in THF at room temperature is presented. The method
provides a useful alternative for the protection of carbonyl compounds having acid-sensitive moieties.
The selective protection of the carbonyl group as O,O-acetals/
ketals and its subsequent regeneration is an important
transformation in synthetic organic chemistry. The depro-
tection is often achieved by aqueous acid hydrolysis, but in
recent years several mild reagents/conditions have been
reported to accomplish this reaction. These include CeCl3‚
7H2O,2 FeCl3,3 CAN,4 Bi (NO3)3‚5H2O,5 Ce(OTf)3,6 Bi-
(OTf)3,7 SmCl3/TMSCl,8 I2,9 and F-10 for specially designed
silylated ketals. However, considering the importance of this
transformation in multistep organic synthesis, new protecting
groups removable under complimentary conditions are still
needed. As part of our endeavor to develop structurally
simple synthetic substitutes for antimalarial drug artemisi-
nin,11 we have earlier reported a photooxygenation route for
the synthesis of 1,2,4-trioxanes. Preparation of â-hydroxy-
hydroperoxides by photooxygenation of suitably substituted
(7) Carrigan, M. D.; Sarapa, D.; Smith, R. C.; Wieland, L. C.; Mohan,
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Chem. 2004, 69, 8932.
(10) Lipshutz, B. H.; Mollard, P.; Lindsley, C.; Chang, V. Tetrahedron
Lett. 1997, 38, 1873.
(11) For reviews on artemisinin and its analogues, see: (a) Klayman,
D. L. Science 1985, 228, 1049. (b) Luo, X. D.; Shen, C. C. Med. Res. ReV.
1987, 7, 29. (c) Zaman, S. S.; Sharma, R. P. Heterocycles 1991, 32, 1593.
(d) Zhou, W S.; Xu, X. X. Acc. Chem. Res. 1994, 27, 211. (e) Cumming,
J. N.; Ploypradith, P.; Posner, G. H. AdV. Pharmacol. 1997, 37, 2253. (f)
Bhattacharya, A. K.; Sharma, R. P. Heterocycles 1999, 51, 1681. (g)
Borstnik, K.; Paik, I.; Shapiro, T. A.; Posner, G. H. Int. J. Parasitol. 2002,
32, 1661. (h) Ploypradith, P., Acta Trop. 2004, 89, 329. (i) O’Neill, P. M.;
Posner, G. H. J. Med. Chem. 2004, 47, 2945.
(1) CDRI communication number 6797.
(2) Marcantoni, E.; Nobili, F.; Bartoli, G.; Bosco, M.; Sambri, L. J. Org.
Chem. 1997, 62, 4183.
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Org. Chem. 1997, 62, 6684.
(4) (a) Marko, I. E.; Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-M.;
Quesnel, Y.; Vanherck, J.-C. Angew. Chem., Int. Ed. 1999, 38, 3207. (b)
Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-M.; Quesnel, Y.; Marko, I. E.
Tetrahedron Lett. 1999, 40, 1799. (c) Ates, A.; Gautier, A.; Leroy, B.;
Plancher, J.-M.; Quesnel, Y.; Vanherck, J.-C.; Marko, I. E. Tetrahedron
2003, 59, 8989.
(5) Eash, K. J.; Pulia, M. S.; Wieland, L. C.; Mohan, R. S. J. Org. Chem.
2000, 65, 8399.
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Sindona, G.; Bartoli, G. J. Org. Chem. 2002, 67, 9093.
10.1021/ol052378d CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/11/2005

allylic alcohols and their acid-catalyzed condensation with
aldehydes/ketones are the key steps of this method.12,13 In
fact, both of these steps can be accomplished in a single pot
to furnish 1,2,4-trioxanes in good yields at 0 °C to room
temperature (Scheme 1). The reaction of â-hydroxyhydro-
alcohol 2b in 34% yield. Similar results were observed when
trioxane 1b was treated with n-butylamine or diisopropy-
lamine in HMPA. A major solvent effect was observed in
the reaction of 1a with NaOMe. Whereas the reaction was
complete in HMPA within 15 min, it took more than 8 h in
methanol. After experimenting with several bases and
solvents, Triton B in THF was found to be the most efficient
system for the regeneration of the ketones. Thus the reaction
of trioxane 1b with Triton B in THF at room temperature
was complete within 1 h and furnished 2-adamantanone in
84% yield (Scheme 3).15
Scheme 1
Scheme 3
peroxides with unhindered ketones is fast and gives the
corresponding trioxanes in good yields; the reaction with
hindered ketones, e.g., comphor, is extremely slow and yields
are poor.14
The method is safe and has been used in our laboratory
for the preparation of a large number of â-hydroxyhydrop-
eroxides and 1,2,4-trioxanes on a multigram scale. Several
trioxanes prepared by this method have shown promising
antimalarial activity against multi-drug-resistant malaria in
a mice model.14 We have further explored the application
of this methodology in chemistry and present herein an
experimental protocol demonstrating the protection of the
carbonyl group as 1,2,4-trioxane, the stability of the protect-
ing group under the conditions of a variety of organic
reactions, and the regeneration of the carbonyl group under
basic conditions at ambient temperature.
A unique feature of these trioxanes is the presence of a
1-substituted vinyl group at C-6 of the trioxane, which
together with a peroxy group makes 6-H quite acidic; it
appears at around δ 5.2 ppm in the 1H NMR spectra of these
trioxanes and at δ 5.0 ppm for the corresponding 1,3-
dioxolanes. Similarly, in 13C NMR spectra C-6 of these
trioxanes and the corresponding 1,3-dioxolanes appears at
∼δ 80.5 and 76.9 ppm, respectively. In fact, during the
course of this work it was observed that these trioxanes
undergo a very facile cleavage under mild basic conditions
to regenerate the carbonyl compounds and R,â-unsaturated
keto alcohols (Scheme 2).
From these preliminary experiments it was clear that
ketones could be protected as 1,2,4-trioxanes using easily
accessible â-hydroxyhydroperoxides and again regenerated
under basic conditions at ambient temperature. Having
achieved this we examined the stability of 1,2,4-trioxane
moiety under conditions of a variety of reactions, an essential
requirement of a good protecting group. Toward this end
we studied the chemistry of the carbonyl group of trioxanes
4a and 4b, easily accessible16 by monoprotection of 1,4-
cyclohexanedione with â-hydroxyhydroperoxides 3a,b
(Scheme 4).
Scheme 4
Scheme 2
Trioxanes 4a and 4b on Reformatsky reaction with Zn/
BrCH2CO2Et in benzene furnished the â-hydroxyesters 5a
(13) For alternative methods for the preparation of 1,2,4-trioxanes see:
(a) O’Neill, P. M.; Mukhtar, A.; Ward, S. A.; Bickley, J. F.; Davies, J.;
Bachi, M. D.; Stocks, P. A. Org. Lett. 2004, 6, 3035. (b) O’Neill, P. M.;
Pugh, M.; Davies, J.; Ward, S. A.; Park, B. K. Tetrahedron Lett. 2001, 42,
4569. (c) Bloodworth, A. J.; Johnson, K. A. Tetrahedron Lett. 1994, 35,
8057. (d) Bloodworth, A. J.; Shah, A. J. Chem. Soc., Chem. Commun. 1991,
947. (e) Posner, G. H.; Oh, C. H.; Milhous, W. K. Tetrahedron Lett. 1991,
32, 4235. (f) Bunnelle, W. H.; Isbell, T. A.; Barnes, C. L.; Qualls, S. J.
Am. Chem. Soc. 1991, 113, 8168. (g) Avery, M. A.; Jennings-White, C.;
Chong, W. K. M. J. Org. Chem. 1989, 54, 1792. (h) Kepler, J. A.; Philip,
A.; Lee, Y. W.; Morey, M. C.; Caroll, F. I. J. Med. Chem. 1988, 31, 713.
(i) Jefford, C. W.; Jaggi, D.; Boukouvalas, J.; Kohmoto, S. J. Am. Chem.
Soc. 1983, 105, 6498.
Thus the reaction of trioxane 1a with NaHCO3 in hex-
amethylphosphoramide (HMPA) at room temperature for 8
h furnished 2-adamantanone in 62% yield along with keto
alcohol 2a in 38% yield. Similar reaction of trioxane 1b with
NaHCO3 furnished 2-adamantanone in 66% yield and keto-
(12) Singh, C. Tetrahedron Lett. 1990, 31, 6901. (b) Singh, C.: Gupta,
N.; Puri, S. K. Tetrahedron Lett. 2005, 46, 205.
5674
Org. Lett., Vol. 7, No. 25, 2005

Table 1. Generation of Functionalized Ketones from 1,2,4-Trioxanes
Org. Lett., Vol. 7, No. 25, 2005
5675

and 5b in 83% and 88% yields, respectively, as mixtures of
diastereomers that were separated by column chromatogra-
phy. â-Hydroxyester 5a on reduction with LiAlH4 in dry
diethyl ether at 0 °C furnished the diol 6a in 72% yield.
Trioxane 4a on reaction with triethylphonacetate/NaH and
triethylphosphon-2-propionate/NaH in dimethoxyethane fur-
nished the Wittig products 7a and 8a in 93% and 83% yields,
respectively. Trioxane 4b under similar reaction conditions
furnished 7b and 8b in 93% and 84% yields, respectively.
These products were isolated as inseparable mixtures of
geometrical isomers. Trioxane 4a reacted smoothly with
NaBH4 in methanol to furnish the corresponding hydroxy
derivative 9a in 96% yield as inseparable mixture of
diastereomers, which on reaction with succinic anhydride/
Et3N in CH2Cl2 furnished the corresponding hemisuccinate
10a in 91% yield; 10a on treatment with CH2N2 in ether
furnished the corresponding methyl ester 11a. Reductive
amination of trioxane 4a with 4-methoxyaniline and 2-ami-
nobiphenyl in the presence of NaBH(OAc)3 in CH2Cl2
furnished the amino-functionalized trioxanes 12a and 13a
in 61% and 91% yields, respectively, as mixtures of
diastereomers. Trioxane moiety was also found stable under
the condition of Grignard reaction, though the yields of the
products were modest. Thus trioxane 4a reacted with
MeMgBr and PhMgBr at 0 °C to furnish hydroxy derivatives
14a and 15a in 54% and 57% yields, respectively (Figure
1). Both of these products were mixtures of diastereomers
that were separated by chromatography on silica gel. These
experiments demonstrate that a variety of reactions of the
carbonyl group can be accomplished without affecting the
trioxane moiety.17 Finally, several of these functionalized
trioxanes were reacted with Triton B in THF at ambient
temperature to give the corresponding 4-functionalized
cyclohexanones in more than 80% yield (Table 1).
Figure 1. Derivatives of trioxanes 4a and 4b.
droxycyclohexanone (entry 9). However, the deprotection
in this case could be achieved by heating with n-BuNH2 in
THF (entry 10).
In conclusion, we have demonstrated that ketones can be
protected as 1,2,4-trioxanes using easily accessible â-hy-
droxyhydroperoxides, that the trioxane moiety survives under
conditions of a variety of organic reactions, and that the keto
group can be regenerated in high yield under basic conditions
at ambient temperature. Historically a ketal group has been
commonly used for the protection of the carbonyl group.
The trioxane as protective group is very similar to the ketal
group as far its formation is concerned and can serve as a
useful alternative protecting group for carbonyl compounds
as it can be removed under mild basic conditions.18,19
The functional groups such as â-hydroxyesters (entry 4)
and R,â-unsaturated esters (entries 6 and 7) and amines
(entries 11 and 12) were found stable under these conditions.
The succinoyl group was hydrolyzed to furnish the 4-hy-
Acknowledgment. H.M. is grateful to the Council of
Scientific and Industrial Research (CSIR), New Delhi for
the award of a Senior Research Fellowship.
(14) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem.
Lett. 1992, 2, 497. (b) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg.
Med. Chem. Lett. 1995, 5, 1913. (c) Singh, C.; Gupta, N.; Puri, S. K. Bioorg.
Med. Chem. 2004, 12, 5553. (d) Singh, C.; Kanchan, R.; Srivastava, D.;
Puri, S. K. Bioorg. Med. Chem. Lett. 2005, in press.
(15) Typical Procedure for Regeneration of Ketones with Triton
B/THF. To a solution of the trioxane 1b (0.10 g, 0.28 mmol) in THF (3
mL) was added Triton B (40% in methanol, 0.1 mL), and the mixture was
stirred at room temperature for 1 h. Solvent was evaporated under vacuum,
and the crude product was purified by column chromatography over silica
gel using AcOEt/hexane (0.2:10) as eluant to furnish 2-adamantanone (0.036
g, 84% yield).
Supporting Information Available: Experimental details
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL052378D
(16) Singh, C.; Malik, H.; Puri, S. K. Bioorg. Med. Chem. 2004, 12,
1177.
(17) Some of these functionalized trioxanes have shown a high order of
antimalarial activity: (a) Singh, C.; Malik, H.; Puri, S. K. Bioorg. Med.
Chem. Lett. 2004, 14, 459. (b) Singh, C.; Malik, H.; Puri, S. K. Bioorg.
Med. Chem. Lett. 2005, 15, 4484
(18) Recently trioxepanes have been used as a redox cleavable carbonyl
protecting group: Ahmeed, A.; Dussault, P. H. Org. Lett. 2004, 6, 3609.
(19) During the course of our work on antimalarial 1,2,4-trioxanes, we
have prepared a large number of â-hydroxyhydroperoxides and 1,2,4-
trioxanes on a multigram scale. In our hands these compounds have behaved
well, but the usual precautions for handling of peroxides are recommended.
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