Studies on DMDO-mediated benzylidene acetal oxidation

Article abstract of DOI:10.1016/j.tetlet.2008.08.062

We have shown that dimethyldioxirane (DMDO) can be used to effect an oxidative partial deprotection of benzylidene acetals derived from both 1,2- and 1,3-diols to afford hydroxy benzoate products. A wide range of functional groups are tolerated, and good to excellent yields are usually observed. The reactions are easy to perform and produce little waste other than acetone.

Full text of DOI:10.1016/j.tetlet.2008.08.062

Tetrahedron Letters 49 (2008) 6390–6392
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Tetrahedron Letters
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Studies on DMDO-mediated benzylidene acetal oxidation
David K. Mycock a, Alexandra E. Sherlock a, Paul A. Glossop b, Christopher J. Hayes a,
*
a School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
b Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We have shown that dimethyldioxirane (DMDO) can be used to effect an oxidative partial deprotection of
benzylidene acetals derived from both 1,2- and 1,3-diols to afford hydroxy benzoate products. A wide
range of functional groups are tolerated, and good to excellent yields are usually observed. The reactions
are easy to perform and produce little waste other than acetone.
Received 24 July 2008
Revised 14 August 2008
Accepted 19 August 2008
Available online 23 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Benzylidene acetals are often used to protect 1,2- and 1,3-diols
during organic synthesis,1 and various reductive2–5 and oxi-
dative6–14 methods have been examined with different levels of
success for their complete or partial deprotection. For example,
during our recent total synthesis of (+)-lactacystin,15 we needed
to perform a selective partial deprotection of the benzylidene ace-
tal 1a in order to access the primary alcohol 2a (Scheme 1). Unfor-
tunately, none of the available methods were particularly well
suited to our needs as they either introduced unwanted function-
ality (i.e., alkyl bromides when NBS6 is used) or had issues with
regiocontrol (i.e., production of primary benzoates in the case of
bipyridinium chlorochromate/m-CPBA12b). Fortunately, we were
able to show that the benzylidene acetal 1a could be oxidised with
DMDO16 to give the partially deprotected secondary benzoate ester
2a as the major new product. In this Letter, we report our recent
findings on the scope, limitations and mechanistic insight of this
oxidative deprotection method.
dilute solution (ꢀ0.1 M) in acetone according to the literature
procedure,18 and its concentration was determined via iodometric
titration immediately prior to use.
We first chose to examine the oxidation of 1,3-dioxolanes 1b–j
derived from 1,2-diols (Table 1). Thus, 1 equiv of DMDO (0.1 M in
acetone) was added to each acetal, and the resulting solution
was stirred at 0–4 °C for 20 h. Removal of the volatiles in vacuo
then gave the crude product from which the ratio of secondary
2b–j to primary 3b–j benzoate esters was determined by 1H
NMR. The materials were then purified by column chromatography
and the isolated yields were recorded.
We were pleased to see that excellent conversion was observed
in all cases, and good to excellent yields of the ester products were
obtained. It can be seen from the results in Table 1 that regiocon-
trol in this reaction is a subtle balance of both steric and electronic
factors. For example, acetals 1b, 1c and 1d give the secondary ben-
zoates 2b, 2c and 2d as the major regioisomers, whilst the 4,4-
dimethyl-1,3-dioxolane 1e gave the primary benzoate 3e as the
major product. It appears that in simple mono-substituted acetals
(i.e., 1b–d) there is a preference for the formation of the more hin-
dered secondary benzoate ester, but when the steric demand
becomes too great, as in the case of product 2e, then there is a
reversal of selectivity to give the least hindered benzoate 3e. Elec-
tronic effects were then probed by using acetals 1f–j in the oxida-
tion, and in all cases the primary benzoate esters 3f–j were the
major products (Table 1).
The nature of the aromatic group present in the acetal was also
examined and we were pleased to see that both electron-donating
(para-methoxy in 1g) and electron-withdrawing (para-nitro in 1h)
substituents were well tolerated without adversely affecting either
yield or regiochemical distribution.
Based upon these results, we postulate that the mechanism of
the reaction involves initial CH-oxidation19 of the benzylidene
acetal methine to afford the corresponding hemiorthoacetal 4
(Scheme 2). This intermediate then collapses to give 5 and/or 6
as transient intermediates, with the relative proportion of each
Our first task was to prepare a range of benzylidene acetals
from 1,2- and 1,3-diols and this was readily achieved using well-
known methods.17 Examples were chosen to explore the chemo-
selectivity and functional group tolerance, as well as the influence
of both steric and electronic factors on the regiochemical outcome
of the reaction (Table 1). DMDO was prepared and used as a
OH
OH
OH
DMDO (3 equiv.)
O
OBz
OH
OH
O
O
O
N
H
N
H
2a
N
H
3a
acetone, 0 oC
OBz
O
Ph
1a
trace
90%
Scheme 1. Previous DMDO oxidation of a benzylidene acetal.
* Corresponding author. Tel.: +44 0115 951 3045; fax: +44 0115 951 3564.
E-mail address: chris.hayes@nottingham.ac.uk (C. J. Hayes).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.062

D. K. Mycock et al. / Tetrahedron Letters 49 (2008) 6390–6392
6391
Table 1
O
O
DMDO-mediated oxidation of 1,3-dioxolanesa
H
OH
Yieldb
(%)
Ar
O
R
Ar
O
R
Entry Acetal
(cis:trans)
Products
(ratio 2:3)
O
O
4
n = 0,1
n
1
O
BzO
R = electron donating
R = electron withdrawing
HO
O
1
2
76
OH
3b
OBz
2b
Ph
1b
H
O
H
O
(89 : 11)
(1 : 1)
O
O
n
Ar
Ar
O
O
n
O
O
BzO
HO
HO
6
R
R
5
OH
3c
85
OBz
2c
Ph
H transfer
H transfer
O
1c
(90 : 10)
O
R
(2 : 1)
HO
O
Ar
Ar
O
OH
Ph
Ph
Ph
OBz
2d
BzO
O
O
R
OH
n
n
3
4
5
83
81
84
Ph
Primary benzoate 3
2
Secondary benzoate
1d
3d
(1 : 1)
(71 : 29)
Scheme 2. Proposed mechanism for DMDO acetal oxidation.
O
O
Ph
BzO
HO
HO
alkoxide 5 is more stable than the secondary alkoxide 6, hence
the secondary benzoate 2 is favoured over the primary benzoate
3. Conversely, if R is electron-deficient (i.e., R = CH2Cl, CH2O), the
secondary alkoxide 6 is favoured over the primary alkoxide 5 and
the primary benzoate 3 is the major product. The only exception
to this trend is example 1e, where steric hindrance dominates over
the electronic effect.
An alternative mechanism involving SN2 substitution of an
intermediate oxocarbenium ion20 was discounted by performing
the DMDO oxidation on the (R)-enantiomer of 1f, which was pre-
pared from the commercially available diol (R)-8 (Scheme 3). Thus,
(R)-1f gave the expected secondary alcohol product 3f upon expo-
sure to DMDO. The stereochemistry at the secondary hydroxyl cen-
tre was determined to be (R) (>95% ee) by chiral HPLC of its
dibenzoate derivative 9. An authentic sample of (R)-9 was prepared
from (R)-8 in good yield, and a racemic standard was prepared
from our previous racemic sample of 3f.
OH
OBz
2e
3e
(20 : 80)
1e
BzO
Cl
Cl
Cl
O
Cl
O
OH
3f
O
OBz
2f
Ph
1f
(1 : 1)
(7 : 93)
Cl
O
pMBzO
HO
pMBzO
Cl
2g
OH
6
92
3g
1g
MeO
(7 : 93)
(1 : 1)
Cl
These results clearly support the mechanism presented in
Scheme 2 as the reaction proceeds with >95% retention of
stereochemistry at the secondary hydroxyl stereocentre. If the
O
O
pNBzO
Cl
HO
pNBzO
Cl
OH
7
8
9
74
79
73
3h
2h
1h
O2N
(8 : 92)
OH2
(1 : 1)
Cl
Cl
O
Cl
O
O
OH
(S)-3f
BzO
OAc
OAc
OAc
O
HO
Ph
O
SN2
Ph
O
OH
OBz
7f
Ph
inversion not observed
2i
3i
1i
(7 : 93)
(1 : 1)
O
Cl
O
Scheme 2
84%
BzO
O
O
HO
O
O
O
OH
(R)-3f
Ph
O
HO
3j
O
Ph
BzO
X
Ph
2j
1j
(R)-1f, X = H
retention observed
DMDO
4f
, X = OH
Cl
BzCl, pyridine
DCM, 68%
Cl
Cl
(1 : 1)
(7 : 93)
O
Cl
O
a
BzCl, pyridine
HO
Cl
Conditions: DMDO (0.1 M, 1 equiv), acetone, 0 °C.
Combined isolated yield.
O
b
OH
(R)-8
Ph
O
DCM, 93%
(R)-9
Ph
being determined by the stability of the alkoxide leaving group. In
the case of R being electron-donating (i.e., R = alkyl), the primary
Scheme 3.

6392
D. K. Mycock et al. / Tetrahedron Letters 49 (2008) 6390–6392
Table 2
In conclusion, we have shown that DMDO can be used to effect
DMDO-mediated oxidation of 1,3-dioxanesa
an oxidative partial deprotection of benzylidene acetals derived
from both 1,2- and 1,3-diols.21 A wide range of functional groups
are tolerated, and good to excellent yields are usually observed.
The reactions are easy to perform and produce little waste other
than acetone, and as a consequence this method could find use
in a number of synthetic applications.
Entry
Acetal
Products
Yieldb
(%)
(ratio 2:3)
OH
OH
OH
OBz
OH
OH
O
O
1
90
O
O
N
H
2a
N
H
O
N
H
1a
OBz
O
Ph
Ph
Acknowledgements
3a
(100 : 0)
We thank Matthew D. Selby (Pfizer) for his interest in this work,
and the EPSRC (DTA studentship to DM) and Pfizer for providing
financial support.
OBz
OH
O
O
N
H
2k
N
H
2
3
52
60
OH
OBz
O
O
N
H
1k
References and notes
3k
O
1. Kocienski, P. J. Protecting Groups; Thieme: Stuttgart, New York, 1994; pp 96–
102.
2. (a) Eliel, E. L.; Badding, V. G.; Rerick, M. N. J. Am. Chem. Soc. 1962, 84, 2371; (b)
Eliel, E. L.; Pilato, L. A.; Badding, V. G. J. Am. Chem. Soc. 1962, 84, 2377.
3. Adam, G.; Seebach, D. Synthesis 1988, 373.
(100 : 0)
O
HO
OBz
OBz OH
3l
4. Johnsson, R.; Olsson, D.; Ellervik, U. J. Org. Chem. 2008, 73, 5226 and references
cited therein.
2l
Ph
5. Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983, 1593.
6. (a) Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1035; (b) Hanessian, S.;
Plessas, N. R. J. Org. Chem. 1969, 34, 1045; (c) Hanessian, S.; Plessas, N. R. J. Org.
Chem. 1969, 34, 1053; (d) Hullar, T. L.; Siskin, S. B. J. Org. Chem. 1970, 35, 225;
(e) Binkley, R. W.; Goewey, G. S.; Johnston, J. C. J. Org. Chem. 1984, 49, 992.
7. (a) Deslongchamps, P.; Moreau, C.; Frehel, D.; Chenevert, R. Can. J. Chem. 1975,
53, 1204; (b) Deslongchamps, P.; Moreau, C. Can. J. Chem. 1971, 49, 2465 and
references cited therein.
1l
(20 : 80)
NHCbz
NHCBz
4
5
74
70
O
O
O
BzO
BzO
OH
8. Hosokawa, T.; Imada, Y.; Murahashi, S. I. J. Chem. Soc., Chem. Commun. 1983,
1245.
2m
OAc
1m
Ph
9. Sueda, T.; Fukuda, S.; Ochiai, M. Org. Lett. 2001, 3, 2387.
10. Huang, N. J.; Xu, L. H. Synth. Commun. 1990, 20, 1563.
11. Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O. Synlett 1999, 777.
12. (a) Chidambaram, N.; Bhat, S.; Chandrasekaran, S. J. Org. Chem. 1992, 57, 5013;
(b) Luzzio, F. A.; Bobb, R. A. Tetrahedron Lett. 1997, 38, 1733.
13. Adinolfi, M.; Barone, G.; Guariniello, L.; Iadonisi, A. Tetrahedron Lett. 1999, 40,
8439.
14. (a) Chen, Y. S.; Wang, P. G. Tetrahedron Lett. 2001, 42, 4955; (b) Karimi, B.;
Rajabi, J. Synthesis 2003, 2373.
15. (a) Hayes, C. J.; Sherlock, A. E.; Green, M. P.; Wilson, C.; Blake, A. J.; Selby, M. D.;
Prodger, J. C. J. Org. Chem. 2008, 73, 2041; (b) Hayes, C. J.; Sherlock, A. E.; Selby,
M. D. Org. Biomol. Chem. 2006, 4, 193.
16. For related acetal oxidations with DMDO see: (a) Akbalina, Z. F.;
Abushakhmina, G. M.; Kabal’nova, N. N.; Zlotskii, S. S.; Shereshovets, V. V.
Russ. J. Gen. Chem. 2002, 72, 1406; (b) Akbalina, Z. F.; Zlotskii, S. S.; Kabal’nova,
N. N.; Grigor’ev, I. A.; Kotlyar, S. A.; Shereshovets, V. V. Russ. J. Appl. Chem. 2002,
75, 1120.
OAc
O
OH
Ph
1n
2n
OTBS
OTBS
O
O
6
93
BzO
OH
Ph
2o
1o
a
Conditions: DMDO (0.1 M, 1 equiv), acetone, 0 °C.
Combined isolated yield.
17. Brasili, L.; Sorbi, C.; Franchini, S.; Manicardi, M.; Angeli, P.; Marucci, G.;
Leonardi, A.; Poggesi, E. J. Med. Chem. 2003, 46, 1504.
b
18. (a) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847; (b) Adam, W.;
Curci, R.; Edwards, J. O. Acc. Chem. Res. 1989, 22, 205 and references cited
therein.
19. (a) Murray, R. W.; Jeyaraman, R.; Mohan, L. J. Am. Chem. Soc. 1986, 108, 2470;
(b) Curci, R.; Daccolti, L.; Fiorentino, M.; Fusco, C.; Adam, W.; Gonzaleznunez,
M. E.; Mello, R. Tetrahedron Lett. 1992, 33, 4225.
20. This mechanism is invoked for the NBS-mediated cleavage of benzylidene
acetals (see Ref. 6).
oxocarbenium ion 7f was involved in producing 3f, we would
expect to see either inversion of stereochemistry resulting from
SN2 attack of water (Scheme 3), or loss of stereochemistry via an
equivalent SN1 pathway (not shown).
21. Typical procedure: Benzylidene acetal 1c (82.4 mg, 0.40 mmol) was treated
with a solution of DMDO (4 mL of a 0.10 M solution in acetone, 1 equiv) and
the mixture was stirred at 0 °C for 20 h. The solution was allowed to reach
room temperature and was then concentrated in vacuo. The crude material
was purified by column chromatography using petroleum ether 40–60 and
EtOAc (3:1) to give benzoates 2c and 3c as a 90:10 mixture (75 mg, 85%). (Data
In addition to the oxidation of 1,3-dioxolanes, we also per-
formed a series of experiments using 1,3-dioxanes as substrates
(Table 2). As observed previously in the dioxolane series, oxidation
of the alkyl-substituted acetals 1a and 1k afforded the secondary
benzoates 2a and 2k as the major products. Both examples also
show that the oxidation can be performed in the presence of
hydroxyls, electron-deficient alkenes and amide NH groups. Acetal
1l gave a reversal of regioselection and afforded the primary ben-
zoate 3l as the major product. This is a similar behaviour to that
seen with 1e (Table 1) in the dioxolane series, and its formation
can be rationalised in a similar way (i.e., the tertiary ester 2l is ste-
rically hindered). The acetals 1m–o demonstrate good functional
group compatibility with the oxidation conditions, with acetate
1n, OTBS 1o and NHCBz 1m groups being well tolerated.
for 2c): m
max/cmÀ1 (CHCl3) 2972, 1710, 1279, 911; dH (400 MHz; CDCl3) 8.10–
8.07 (2H, m, ArH), 7.61–7.57 (1H, m, ArH), 7.49–7.45 (2H, m, ArH), 4.96 (1H, dd,
J 7.9 and 2.5, CHOBz), 3.98 (1H, dd, J 12.2 and 2.5, HOCHH), 3.78 (1H, dd, J 12.2
and 8.8, HOCHH), 1.05 (9H, s, C(CH3)3); dC (100 MHz; CDCl3) 167.5 (C), 133.1
(CH), 130.2 (C), 129.7 (CH), 128.5 (CH), 83.6 (CH), 62.9 (CH2), 34.0 (C) 26.3
(CH3); m/z (ESI+) (M+Na, C13H18NaO3 requires 245.1148. Found 245.1143).
(Data for 3c): m
max/cmÀ1 (CHCl3) 3012, 2965, 1718, 1276, 909; dH (270 MHz;
CDCl3) 8.09–8.03 (2H, m, ArH), 7.60–7.55 (1H, m, ArH), 7.50–7.45 (2H, m, ArH),
4.55 (1H, dd, J 11.3 and 2.4, CHHOBz), 4.25 (1H, dd, J 11.3 and 8.6, CHHOBz),
3.66 (1H, dd, J 8.9 and 2.4, HOCH), 1.03 (9H, s, C(CH3)3); dC (100 MHz; CDCl3)
167.0 (C), 133.2 (CH), 130.0 (C), 129.7 (CH), 128.5 (CH), 77.5 (CH), 67.1 (CH2),
34.1 (C) 25.9 (CH3); m/z (ESI+) (M+Na, C13H18NaO3 requires 245.1148. Found
245.1142).