On the hydroxylation of bicyclo[2.1.0]pentane using dioxiranes

Article abstract of DOI:10.1016/S0040-4039(01)01434-4

The oxidation of bicyclo[2.1.0]pentane by isolated dimethyldioxirane and by the more powerful methyl(trifluoromethyl)dioxirane, affords selectively, the corresponding endo-2 alcohol along with the 2,3-diol in high yield, and no rearrangement products; this suggests that a concerted O-insertion mechanism should be preferred over radical pathways.

Full text of DOI:10.1016/S0040-4039(01)01434-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7087–7090
On the hydroxylation of bicyclo[2.1.0]pentane using dioxiranes
Ruggero Curci,* Lucia D’Accolti and Caterina Fusco
Centro C.N.R. ‘M.I.S.O.’, Department of Chemistry, University of Bari, v. Amendola 173, I-70126 Bari, Italy
Received 21 May 2001; revised 27 July 2001; accepted 3 August 2001
Abstract—The oxidation of bicyclo[2.1.0]pentane by isolated dimethyldioxirane and by the more powerful methyl(tri-
fluoromethyl)dioxirane, affords selectively, the corresponding endo-2 alcohol along with the 2,3-diol in high yield, and no
rearrangement products; this suggests that a concerted O-insertion mechanism should be preferred over radical pathways. © 2001
Elsevier Science Ltd. All rights reserved.
1
7a
Dioxiranes, especially the isolated dimethyldioxirane
(
(
(2) has been employed as a calibrated free-radical
2
DMD) (1a) and methyl(trifluoromethyl)dioxirane
‘clock’ in order to determine the rate of oxygen
rebound (kOH) by measuring the ratio of the unrear-
ranged alcohol insertion product 3 to the amount of
rearranged cyclopent-3-enol resulting from capture of a
hydroxyl radical by a cyclopent-3-enyl radical. Ortiz de
Montellano and Stearns examined the P-450 hydroxyla-
tion of 2 and established a 7:1 ratio of unrearranged to
3
TFD) (1b) in the isolated form, are nowadays well
established as useful oxidants for a variety of oxyfunc-
tionalizations of organic substrates. The efficient oxy-
functionalization of unactivated alkane CꢀH bonds of
alkanes under extremely mild conditions undoubtedly
3
b
ranks as a landmark in dioxirane chemistry. It has
been noted that the selective hydroxylation of alkanes
by cytochrome P-450 enzymes and by dioxiranes
present several features in common; in both cases, the
mechanism does not seem to involve free-radicals (i.e.
radicals freely diffusing through the solution). With
this in mind, we have now applied both dioxiranes 1a
and 1b to the oxidation of bicyclo[2.1.0]pentane (BCP)
7a
rearranged (U/R) alcohols, indicating a rate for oxy-
4
10
−1 −1
gen rebound of kOH=1.7×10
M
s
based on the
known rate for the ring opening of the bicy-
7b,c
clo[2.1.0]pent-2-yl radical.
5
Representative results of the dioxirane hydroxylation of
BCP (2) are collected in Table 1.
(
2).
O
O
CH3
R
C
OH
OH
no rearrangement
products detected
+
(1)
(
1a: R = CH3;
OH
1
b: R = CF )
3
0
- 20 °C
2
3
4
For the dioxiranes, an alternative to the established
oxenoid’ O-insertion into alkane CꢀH bonds consists
in an initial H-abstraction to give a radical pair
Dimethyldioxirane (1a) (ca. 0.1 M in acetone) and
methyl(trifluoromethyl)dioxirane (1b) [0.5–0.8 M in
1,1,1-trifluoropropanone (TFP)] solutions were pre-
‘
’
1
2
’
6
2,3
ꢀ
ꢀR HO-CR R -O ꢀꢀ; this would be followed by fast
pared as already reported in detail. The substrate 2
in-cage collapse to products, similar to the ‘oxygen
rebound’ envisaged for the iron-containing cytochrome
was synthesized and purified by a given literature pro-
8
cedure; to this, dioxirane 1a or 1b was added in
4
,5
P-450 enzymes. For the latter, bicyclo[2.1.0]pentane
acetone or TFP solution, respectively. The reactions
were carried out under the conditions given in Eq. (1)
and Table 1 on a 5–20 mL scale, and monitored by GC
and GC–MS. It should be noted that dioxirane oxida-
tions of probe 2 were run under pseudo-first order
conditions using a large excess of substrate over dioxi-
rane in order to minimize secondary reactions and over
oxidation.
Keywords: dioxiranes; bicyclo[2.1.0]pentane; free-radical ‘clock’;
insertions; oxenoids; radicals.
*
Corresponding author. Fax: +39-080-5442924; e-mail: csmirc17@
area.ba.cnr.it
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01434-4

7
088
R. Curci et al. / Tetrahedron Letters 42 (2001) 7087–7090
a
Table 1. Hydroxylation of bicyclo[2.1.0]pentane (2) by dimethyldioxirane (1a) and methyl(trifluoromethyl)dioxirane (1b)
Entry
Dioxirane (M)
BCP (2) (M)
Temp. (°C)
Reaction time (min)
Conversion (%)b
(% Yield of products)c
Alcohol (3)
Diol (4)
1
2
3
4
5
6
7
8
9
(1a) 0.018
(1a) 0.018
(1a) 0.002
(1a) 0.002
(1a) 0.024
(1a) 0.002
(1a) 0.002
(1b) 0.002
(1b) 0.001
0.181
0.181
0.181
0.181
0.028
0.028
0.033
0.209
0.002
20
20
20
20
20
20
20
0
60
150
15
27
150
120
90
5
30
40
75
60
82
70
25
35
95
35
89
70
11
30
–
–
–
–
–
21
8
\99
\99
\99
\99
\99
79
d
0
92
a
All reactions were run in stoppered flasks under an air blanket (unless noted otherwise), using as solvent the ketone parent of the dioxirane, i.e.
acetone for dioxirane 1a and 1,1,1-trifluoropropanone for dioxirane 1b. Residual dioxirane was determined either by iodometry and/or by a
reported GC method (Ref. 3b).
b
c
Substrate conversion is referred to a stoichiometric amount of dioxirane (limiting reagent) consumed; it was determined by GC [VOCOL, 60
m×0.53 mm ID, 3.0 mm film thickness; 40°C (20 min), 40–220°C (6°C/min); t : 4.3 min] by using n-dodecane external standard and A112
R
(1,2,2-trichloro-1,2,2-trifluoroethane) as internal standard.
Yields are based on the amount of substrate converted and were determined by GC at the conditions in footnote b (t : 11.60 and 14.65 min,
R
for 3 and 4, respectively) using n-dodecane as external standard; products were identified by GS–MS [Hewlett–Packard mod. 5970 (EI 70 eV),
and mod. 5890 GC (SPB-1, 30 m×0.25 mm ID, 0.25 mm film thickness)].
Reaction run using solutions purged with pure, oxygen-free nitrogen gas.
d
From runs performed under the conditions given in
entry 5, the product was isolated in mixture with unre-
acted BCP and gave MS and a H NMR spectra in
ously the exact stereochemistry of the vic-diol formed.
1
Ensuing hydroxylation of BCP to the endo-C-2 alcohol
3 and formation of the C-2,C-3 diol 4 is remarkable. In
fact, the dioxirane oxidation of sec-alcohol functionali-
ties to carbonyls is normally 50–100 times faster than
good agreement with those reported for the unrear-
7a
ranged endo-C-2 alcohol 3. Since the reactions were
run on relatively small scale using excess substrate, the
amount of the C-2,C-3 diol 4 formed (entries 1, 2, 8 and
1
f
hydroxylation of ‘unactivated’ alkane CꢀH bonds. In
contrast, overoxidation of alcohol 3 to the correspond-
ing carbonyl is precluded in the case at hand, most
likely because of unfavorable angle strain in the bicyclic
C-2 ketone.
9) was not sufficient to permit isolation; however, this
compound was characterized by GC–MS. In fact, its
+
’
mass spectrum exhibits an intense M peak at m/z 100
+
+
(
(
22%), and HRMS (CI mode) [M+H] at 101.0603
9
calcd: 101.0603). This is at variance with the parent
alcohol 3, which presents a prominent [M−H] peak at
m/z 83 (53%) rather than a M peak (m/z 84, 6%). The
above MS fragmentation pattern of 4 is characteristic
of cyclic vic-diols, presenting inter alia the base peak at
+
More remarkable is the lack of rearrangement products
derived from radical pathways. Indeed, the main oxida-
tion product expected from the ultra-fast ring opening
of cyclopent-3-enyl radicals is the rearranged cyclopen-
+
’
12a
+
tenol 5a; possible products from further oxidation of
12b 12c
m/z 41 [C H ] (100%) and relevant peaks at m/z 82
3
5
+
+
5a include epoxyalcohols 6a and 7a, ketone 8, and
12d
[
[
M−H O] (54%) and 72 [M−C H ] (44%), m/z 57
2 2 4
+ +
in turn from this epoxyketone 9.
M−C H O] (32%), and m/z 70 [M−CH O] (70%).
2
3
2
RO
RO
O
RO
O
O
O
O
5a,b
6a,b
a: R = H; b: R = Ac
7a,b
8
9
The latter is typical of strained-ring trans-1,2-diols such
as trans-cyclobutane-1,2-diol, being markedly less
abundant for the corresponding cis-cyclobutane-1,2-
Authentic1 samples of these compounds were
2b–d
obtained;
then, acetates 5b–7b were readily pre-
pared upon reaction of the appropriate alcohol with
1
0
diol. Thus, the trans configuration is more likely for
diol 4. The prevalent anti stereoselectivity observed in
the bis hydroxylation of BCP might be rationalized in
terms of dipole orientation of the incoming dioxirane
with respect to the initially introduced OH moiety, so
that O-insertion into the adjacent CꢀH from the oppo-
Ac O and pyridine. The latter reference compounds
2
were also made available because of the artifactual
13
claim that the dioxirane oxidation of alkanes might
lead to acetate products by an out-of cage radical-chain
13b
sequence. In this respect, it is quite telling that none
of the putative products above could be detected by GC
and GC–MS analyses of the reaction mixtures. Control
experiments showed that compounds 5–9 are ade-
11
site face becomes favored by electrostatic interactions.
Work is in progress in order to establish unambigu-

R. Curci et al. / Tetrahedron Letters 42 (2001) 7087–7090
7089
quately stable to the reaction conditions to permit
detection; we could determine a minimum GC detection
limit of less than 0.2% for authentic admixtures of 5–9.
Therefore, the ratio of U/R products presented by the
dioxirane oxidation of BCP exceeds 500:1. On this
ground, given the precise horology available for the
(National Project: ‘Activation of Peroxide Species in
Innovative Selective Oxidation Processes’) is gratefully
acknowledged. Thanks are due to Dr. R. Mello (Uni-
versity of Valencia, Spain) for performing the HRMS
analyses.
ring opening of the bicyclo[2.1.0]pent-2-yl radical (k =
r
9
−1
7c
2×10 s at 25°C), one can estimate that, if a radical
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Acknowledgements
Partial support of this work by the Ministry of Univer-
sity, Scientific and Technological Research of Italy

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