Unusual reactivity of bicyclo[2.2.1]heptene derivatives during the ozonolysis

Article abstract of DOI:10.1016/j.tet.2007.06.084

This paper describes mechanistic studies on the ozonolysis of bicyclo[2.2.1]heptene derivatives 6 and 7 obtained from (R)-(+)-pulegone through the cyclopentadiene 5 and its Diels-Alder reaction with maleic anhydride. The ozonolysis of the tricyclic diol 7

Full text of DOI:10.1016/j.tet.2007.06.084

Tetrahedron 63 (2007) 9100–9105
Unusual reactivity of bicyclo[2.2.1]heptene derivatives during
the ozonolysis
a
Isabelle Kondolff, Marie Feuerstein, Celine Reynaud, Michel Giorgi,
a
a
b
ꢀ
Henri Doucetc, and Maurice Santelli
a,
*
*
aLaboratoire de Syntheꢁse Organique, UMR 6180 CNRS, France
b
´
Spectropo^le, Faculte des Sciences de St-Jerome, Aix-Marseille Universite, Avenue Escadrille Normandie-Niemen,
´ ^
´
13397 Marseille Cedex 20, France
Institut Sciences Chimique de Rennes, ‘Catalyse et Organometalliques’,
c
´
Universite de Rennes, Campus de Beaulieu, 35042 Rennes, France
´
Received 21 November 2006; revised 22 June 2007; accepted 26 June 2007
Available online 4 July 2007
Abstract—This paper describes mechanistic studies on the ozonolysis of bicyclo[2.2.1]heptene derivatives 6 and 7 obtained from (R)-(+)-
pulegone through the cyclopentadiene 5 and its Diels–Alder reaction with maleic anhydride. The ozonolysis of the tricyclic diol 7 led to
the ketone 8 with the same skeleton while the anhydride 6 gave rise to the epoxide 10 and the bis-lactone 11. The structure of 8, 10 and
11 are confirmed by X-ray analysis. These unexpected results are discussed in terms of a p complex between ozone and the double bond.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
to pulegone 3 gave the dienic alcohol 4, which was cyclised
into cyclopentadiene 5 using a palladium-catalysed reac-
tion.4 A stereoselective Diels–Alder addition with maleic
anhydride5 followed by LiAlH4 reduction led to a very inter-
esting compound 7, quite similar to 1, and able to give an op-
tically active tetrapodal ligand if the conversion in the tetraol
by ozonolysis is a success. To our great surprise, the action of
ozone6 on 7 followed by a reductive treatment in the same
flask with NaBH4, afforded a ketone 8 (Scheme 2) which ap-
peared as hemiketal instead of the expected tetraol.7 In order
to confirm the structure of 8, the ditosylate 9 was prepared by
a classical tosylation reaction in 24% overall yield from 7
(9.5% overall yield from (R)-(+)-pulegone). Its crystals
were suitable for X-ray analysis (Fig. 1). Interestingly, we
noted that the a-hydrogen atom to the ketone is in endo
position (S-configuration).
In the course of the synthesis of a new ligand, Tedicyp, use-
ful for the palladium-catalysed reactions,1 we had previously
reported the easy conversion of norbornene derivative 1 into
an acetonide of cis,cis,cis-tetrakis(hydroxymethyl)cyclo-
pentane 2 by ozonolysis followed by a reductive treatment
in the same flask with NaBH4 (Scheme 1).2
1. O3 / CH2Cl2
HO
O
O
HO
2. NaBH4 / EtOH
O
O
2, 83%
1
Ph2P
Ph2P
PPh2
PPh2
Tedicyp
The presence of two polar hydroxymethyl groups near the
double bond could induce this abnormal ozonolysis. In order
to verify this, we examined the reactivity towards ozonolysis
of the olefin 6. With this substrate, a very slow reaction
occurred (reaction time 6 h) giving rise to a mixture of the
epoxide 10 together with the bis-lactone-alcohol 11.
Gratifying, the epoxide 10 appears as the result of an exo at-
tack of ozone (Scheme 3). The structures of 10 and 11 were
confirmed by X-ray analysis (Figs. 2 and 3).
Scheme 1.
2. Results and discussion
In order to prepare a new chiral tetrapodal phosphine ligand,
we considered its preparation from (R)-(+)-pulegone. The
known stereoselective addition of allyl Grignard reagent3
Keywords: Ozonolysis; Bicyclo[2.2.1]heptene; Pulegone; Dicyclopenta-
diene; Tetraol.
* Corresponding authors. Fax: +33 4 91289112; e-mail addresses: henri.
doucet@univ-rennes1.fr; m.santelli@univ-cezanne.fr
The mechanism of ozonolysis reaction9 has been thoroughly
studied, and the Criegee mechanism with the formation
of the 1,2,3-trioxolane (primary ozonide)10,11 has been
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.084

I. Kondolff et al. / Tetrahedron 63 (2007) 9100–9105
9101
Pd(OAc)2
- dppe
OH
O
O
MgCl
Et2O
O3
O
O
CH2Cl2
/ MeOH
CF3CO2H
- AcOH
O
H
O
H
O
O
(–60 °C)
5 (65%)
3
4 (91%)
10 (20%)
6
O
H
O
H
O
+
O
O
OH
O
O
O
O
H
O
O
11 (30%)
O
O
O
6 (86%)
Scheme 3.
O
O3
/ CH2Cl2
LiAlH4
THF
the course of the ozonolysis reaction or during the purifica-
tion steps.23 According to Bailey, the formation of an ep-
oxide (with retaining the stereochemistry of the olefin)17a
results from an addition of ozone to the double bond giving
rise to the open p complex24 a precursor of the epoxide d via
intermediates b or c with release of oxygen (Scheme 4).25
According to this process, an alkyl or hydrogen migration
can lead to the formation of carbonyl compound e. Such
compound has been observed by Schank in the course of
the ozonolysis of 9,90-bifluoronylidene (Scheme 5).26
HO
HO
HO
HO
H
(–60 °C)
H
7 (78%)
8
OH
O
TsCl
H
O
TsO
TsO
H
HO
H
H
9 (24% overall yield)
The most recent calculations on the mechanisms of ozonoly-
sis of propene revealed that the partial ozonolysis mecha-
nism as the source of epoxide and singlet molecular
oxygen can be a favoured channel. In the transition state
of this process, ozone attacks the terminal alkenic carbon
Scheme 2.
C24
C25
C26
C3
C23
C20
C21
C4
C7
C22
C16
C5
C28
O7
C29
C2
O6
C19
C18
C17
C6
C27
C1
C17
O4
C33
C32
C12
C13
S2
C8
O3
S1
C11
C4
O5
C5
C10
O1
O18
C1
O2
C11
C3
C9
C12
C6
C14
O21
C10
C2
C13
C15
C15
C7
Figure 1. ORTEP drawing of 9.8
C9
C14
O19
accepted.12 However, as Murray has underlined ‘it is diffi-
cult to come to any definite conclusions regarding a complete
mechanism of ozonolysis other than that it is more compli-
cated than originally thought’.13–15 It is well known that
the ozone can react with hindered olefins to give an epox-
ide16–19 with release of singlet molecular oxygen.20 But, to
the best of our knowledge, no ketones with the same skeleton
than the reacting alkenes were the primary products of the
ozonolysis.21,22 Some ketones have been obtained but these
compounds resulted from the rearrangement of epoxides in
C8
O20
C16
Figure 2. ORTEP drawing for 10. Non-hydrogen atoms are drawn with 25%
probability thermal ellipsoids, while the hydrogen atoms are portrayed with
an artificial small radius.

9102
I. Kondolff et al. / Tetrahedron 63 (2007) 9100–9105
O3
O
+
C12
MeOH
- CH2Cl2
0° C
C17
O
C11
O22
C13
7.5:1 (no overall yield given)
C5
O23
O18
C4
Scheme 5.
C1
C7
C6
C3
O3
C10
C15
CH2Cl2
O
+
70% yield
O
C2
C8
O21
CH3CO3H
O19
C9
C14
O20
C16
O
70:30 (88% yield)
Figure 3. ORTEP drawing for 11. Non-hydrogen atoms are drawn with 25%
probability thermal ellipsoids, while the hydrogen atoms are portrayed with
an artificial small radius.
Scheme 6.
O
CO2H
OH
atom followed by a dissociation of the O–O bond to form
molecular oxygen and propenyl oxyl diradical, which col-
lapses into methyloxirane.27
O
O
O(–)
(+)O
O(–)
+
O
(+)
O
b
As noted by Hochstetler, in the course of the epoxide forma-
tion from a highly substituted olefin, the attack of ozone oc-
curred from the apparent more hindered face of the olefins
and led to the isomer of the epoxide coming from the peracid
reaction (Scheme 6).28
O
O2
+
OH
Scheme 7.
In the course of the ozonolysis of the 1-(ortho-carboxy-
phenyl)-1-phenylethene, Bailey has obtained 35% of phtha-
lide resulting from a cyclisation of the corresponding
intermediate b (Scheme 7).17b
unified mechanism explains the formation of 8 and 10
from the same intermediate f.
Applied to the case of the ozonolysis of 6 or 7, we can con-
sider that ozone attacks the exo face of the double bond29 on
the less substituted side to give the corresponding intermedi-
ate b. Then, after release of molecular oxygen, a zwitterionic
intermediate f is obtained. With the anhydride 6, f quickly
collapses into epoxide 10, while for the diol 7, a more polar
environment makes a 1,2-migration of the endo hydrogen
atom easier, which gave the ketone 8 (Scheme 8). This
Further works are running to explain the formation of poly-
oxygenated compound 11.
3. Conclusion
We have observed that the double bond of norbornene deriv-
atives presents a very particular reactivity towards ozone.
O
(–)O
O(+)
(+)O
(–)O
O
(–)O
O(+)
+
O
a
O
O(–)
O
O
O
O(+)
C
(–)O
O
(+)
(–)O
C
(+)
O O
C
O
+ O
O
O
O
c
C
e
ozonation
products
molozonide
b
(sing.)
+
O O
C
C
d
Scheme 4.

I. Kondolff et al. / Tetrahedron 63 (2007) 9100–9105
9103
4. Experimental section
O
O
H
O(–)
(+)O
O(–)
O
(+)
4.1. General
R
R
1O2
R
R
H
b
6 or 7
TLC was performed on silica gel 60 F254. Flash chro-
matography was performed on silica gel (230–400 mesh)
obtained from Macherey–Nagel and Co. CH2Cl2 was
distilled before use from calcium hydride and THF was dis-
tilled from sodium-benzophenone. 1H and 13C NMR spectra
were recorded in CDCl3 solutions at 300, and 75 MHz, re-
spectively. Chemical shifts are reported in parts per million
relative to CDCl3 (signals for residual CHCl3 in the CDCl3:
O
O
O(–)
O
H
(+)
R
O
10
R
H
f
O(–)
O
1
7.24 for H NMR and 77.16 (central) for 13C NMR). Car-
(+)
H
HO
HO
bon–proton couplings were determined by DEPT sequence
experiments.
HO
HO
H
H
H
8
Scheme 8.
4.1.1. (3R)-3,7,7,8-Tetramethylbicyclo[4.3.0]nona-1(6),8-
diene (5). In a Schlenk tube under argon atmosphere, palla-
dium acetate (0.5 g, 2.2 mmol, 2.5%) and 1,2-bis(diphenyl-
phosphino)ethane (0.87 g, 2.2 mmol, 2.5%) were added
to degassed CH2Cl2 (10 mL). After 10 min of stirring,
CH2Cl2 was removed under vacuum. With a syringe, acetic
acid (100 mL), 4 (17.3 g, 89 mmol) and trifluoroacetic acid
(0.6 mL) were added and the reaction was then refluxed for
20 h. The reaction mixture was poured into water and the
aqueous phase was extracted several times with diethyl
ether. The combined organic layers were washed with satu-
rated sodium hydrogenocarbonate, dried (MgSO4) and
evaporated in vacuo to give an oil, which is distilled
(53 ꢀC/0.2 Torr) to give 5 (10.2 g, 65%).4
Although numerous 1,3-dipolar additions to norbornene de-
rivatives have been described,30 it seems that the primary in-
teraction of the ozone with the double bond did not follow
a 1,3-dipolar addition but more likely an electrophilic addi-
tion with the formation of a p complex in the early stage of
the reaction.
3.1. X-ray crystallography
CCDC-623382 (for 9), CCDC-644677 (for 10) and CCDC-
647538 (for 11), contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html
[or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax (internat.):
+44 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk]. A
summary of the crystal data, data collection, and refinements
are given in Table 1.
4.1.2. (1R,5R,8S,9S,13R)-1,5,14,14-Tetramethyl-11-oxa-
tetracyclo[6.5.1.03,8.09,13]tetradec-2-en-10,12-dione (6).
To a solution of the diene 5 (19 g, 0.11 mol) in toluene
(300 mL) was added maleic anhydride (13.19 g, 0.13 mol).
The stirred solution was refluxed for 2 h. After concentration
under reduced pressure, the crude product (25.91 g, 86%)
was used in the following step.4
Table 1. Crystal data and structure refinement for 9, 10, and 11
9
10
11
Formula
Mw
C31H40O7S2
588.78
C17H22O4
290.35
C17H22O6
322.35
Crystal colour
Crystal size/mm3
Crystal system
Space group
colourless
0.6ꢁ0.4ꢁ0.3
Monoclinic
P21/c
17.2494(6)
11.4532(4)
15.7494(3)
104.994(2)
3005.5(2)
4
colourless
0.4ꢁ0.2ꢁ0.05
Orthorhombic
P212121
6.7184(1)
13.0938(3)
17.0682(5)
colourless
0.4ꢁ0.2ꢁ0.2
Orthorhombic
P212121
10.0718(2)
10.8913(2)
14.2773(4)
˚
a/A
˚
b/A
˚
c/A
b/ꢀ
˚
V/A
3
1501.48(6)
4
1.284
0.9
2107
1566.15(6)
4
1.367
1.03
1655
Z
Dc/g cmꢂ3
1.299
2.23
5747
m(Mo Ka)/cmꢂ1
No. of unique data
No. parameters refined
No. refl. in refinement
R
359
190
213
(5740; F2>4sF2: 5323)
0.0832 [F2>4sF2]
0.1782a
(2107; F2>4sF2: 1734)
0.0644 [F2>4sF2]
0.1678 [F2>4sF2]b
1.219
(1655; F2>4sF2: 1655)
0.057 [F2>4sF2]
0.1642 [F2>4sF2]c
1.068
wR
Goodness of fit
˚
Residual Fourier/eA
1.175
ꢂ0.583; 0.886
ꢂ3
ꢂ0.337; 0.541
ꢂ0.388; 0.23
a
w ¼ 1=½s2ðF20Þ þ 8:0959Pꢃ where P ¼ ðF02 þ 2F2cÞ=3:
2
b
c
w ¼ 1=½s2ðF02Þ þ ð0:0738PÞ þ 0:266Pꢃ where P ¼ ðF02 þ 2F2cÞ=3:
2
w ¼ 1=½s2ðF02Þð0:1165PÞ þ 0:5311Pꢃ where P ¼ ðF02 þ 2F2cÞ=3:

9104
I. Kondolff et al. / Tetrahedron 63 (2007) 9100–9105
4.1.3. (D)-(1R,5R,8S,9S,10R)-1,5,11,11-Tetramethyl-
9,10-di(hydroxymethyl)tricyclo[6.2.1.03,8]undec-2-ene
(7). To a stirred solution of LiAlH4 (10 g, 3 equiv,
263 mmol)) in anhydrous THF (200 mL) at 0 ꢀC under argon
was added the anhydride 6 (24 g, 87 mmol) in anhydrous
THF (300 mL). The stirred reaction mixture was heated at
60 ꢀC for 2 h. The suspension was cooled and slowly added
to ice saturated with aqueous ammonium chloride and the
aqueous phase was extracted with diethyl ether. The com-
bined organic layers were washed with brine, dried
(MgSO4) and evaporated in vacuo to give an oil, which is
purified by flash chromatography on silica gel (CH2Cl2/
AcOEt (50:50)) to give diol 7 (17.9 g, 68 mmol, 78% for
the two steps). White crystals, mp 92 ꢀC, [a]D20 57.8 (c 1.0,
4.1.5. (1R,2S,4R,6S,9S,10S,14R)-1,6,15,15-Tetramethyl-
3,12-dioxapentacyclo[7.5.1.02,4.04,9.010,14]tetradecan-
11,13-dione (10) and (1S,2S,4S,5S,6R,9R,10R,11S)-10,11-
dicarboxy-2,4-dihydroxy-3-oxa-1,6,12,12-tetramethyl-
tricyclo[7.2.1.04,9]dodecan-5-ol dilactone (11). Ozone in
oxygen was bubbled through a stirred solution of 6 (800 mg,
2.92 mmol) in CH2Cl2 (130 mL) and methanol (70 mL) at
ꢂ60 ꢀC until a blue colour appeared (w6 h). The mixture
was flushed with argon and dimethylsulfide (5 mL) is added.
After stirring at room temperature overnight, the crude mix-
ture was washed with water, dried and evaporated in vacuo to
give an oil, which is purified by flash-chromatography on sil-
ica gel eluting with petroleum ether/diethyl ether 3:2 to give
white crystals of 10 (170 mg, 0.58 mmol, 20% from 6) and
white crystals of 11 (284 mg, 0.88 mmol, 30% from 6).
Compound 10: mp 125 ꢀC, [a]D24 ꢂ16 (c 1.7, CH2Cl2); 1H
(CDCl3, 300 MHz) d 3.14 (2H, d, J¼4.2 Hz), 3.10 (1H, s),
2.24–2.16 (1H, m), 1.95 (1H, td, J¼13.4, 4.9 Hz), 1.87–
1.55 (3H, m), 1.34 (6H, s), 1.06 (3H, d, J¼5.85 Hz), 1.01
(1H, s), 0.94 (1H, br d, J¼4.7 Hz), 0.74 (3H, s); the 13C
NMR spectra revealed a conformationally mobile system
at room temperature: (CDCl3, 75 MHz) d 173.4 (s), 171.3
(s), 60.0 (s), 59.4 (d), 58.0 (s), 57.2 (d), 57.1 (s), 54.3 (d),
54.0 (d), 53.7 (d), 52.2 (s), 52.1 (s), 49.9 (s), 49.8 (s), 34.5
(t), 31.6 (t), 30.1 (d), 29.1 (t), 27.1 (d), 26.1 (t), 25.1 (t),
22.0 (q), 21.75 (q), 20.5 (q), 20.4 (q), 20.0 (t), 18.0 (q),
11.7 (q), 11.6 (q). Anal. Calcd for C17H22O4: C, 70.32; H,
7.64. Found: C, 70.43; H, 7.72.
1
CH2Cl2). H NMR (CDCl3, 300 MHz) d 5.10 (1H, br s),
4.6 (2H, br s), 3.76 (1H, dd, J¼10.8, 3.2 Hz), 3.61 (1H,
dd, J¼11.2, 2.8 Hz), 3.39 (2H, td, J¼11.2, 2.5 Hz), 2.40
(1H, ddd, J¼11.6, 8.6, 3.3 Hz), 2.26 (2H, br dd, J¼11.5,
2.2 Hz), 1.76–1.15 (6H, m), 0.92 (3H, s), 0.84 (3H, d,
J¼6.4 Hz), 0.65 (3H, s), 0.58 (3H, s); 13C NMR (CDCl3,
75 MHz) d 145.1 (s), 128.7 (d), 62.7 (t), 61.9 (t), 60.8
(s), 56.0 (s), 55.3 (s), 52.9 (d), 50.5 (d), 37.8 (t), 33.9 (t),
30.2 (d), 24.8 (t), 22.4 (q), 17.5 (q), 17.1 (q), 14.1 (q).
Anal. Calcd for C17H28O2: C, 77.22; H, 10.67. Found: C,
77.17; H, 10.81.
4.1.4. (1R,3R,5R,8S,9S,10R)-1,5,11,11-Tetramethyl-9,10-
di(tosyloxymethyl)tricyclo[6.2.1.03,8]undecan-2-one (9).
Ozone in oxygen was bubbled through a stirred solution of
7 (6 g, 22.7 mmol) in CH2Cl2 (200 mL) containing 2 drops
of an ethanolic solution of ‘Sudan III’(Eastman Kodak)
(ozonizable red dye as internal standard)31 at ꢂ60 ꢀC until
the red colour disappeared. The mixture was flushed with ar-
gon and cooled to ꢂ80 ꢀC. A suspension of NaBH4 (2.5 g,
3 equiv, 68.1 mmol) in EtOH was slowly added. After stir-
ring at room temperature overnight, the crude mixture was
filtered on CeliteÒ. To a stirred solution of tosyl chloride
(18 g, 4 equiv, 95 mmol) in anhydrous pyridine (200 mL)
cooled to ꢂ20 ꢀC was added crude 8. After 5 h stirring at
0 ꢀC, the solution was poured onto crushed ice and
CH2Cl2 (200 mL) was added, the mixture was stirred and
layers were separated. The aqueous phase was extracted
with CH2Cl2 and the combined organic phases were washed
with 1 N HCl, water, brine and then dried over MgSO4. After
filtration and concentration in vacuo, the colourless residue
was purified by flash-chromatography on silica gel eluting
with petroleum ether/diethyl ether 3:1 to give white crystals
of 9 (3.2 g, 5.4 mmol, 24% from 7), mp 117 ꢀC, [a]D26 7.8
1
Compound 11: mp 220 ꢀC, [a]D24 ꢂ19 (c 2.2, CH2Cl2); H
NMR (CDCl3, 300 MHz) d 5.58 (1H, s), 3.81 (1H, s), 3.05
(2H, m), 2.05–1.75 (4H, m), 1.70–1.51 (2H, m), 1.24 (3H,
s), 1.11 (3H, s), 1.05 (3H, d J¼6.8 Hz), 0.88 (3H, s); 13C
NMR (CDCl3, 75 MHz) d 173.7 (s), 172.6 (s), 109.9 (s),
105.8 (d), 73.4 (d), 56.0 (s), 54.8 (s), 52.7 (d), 50.4 (d),
43.8 (s), 35.6 (d), 25.4 (t), 24.6 (t), 21.8 (q), 21.2 (q), 17.8
(q), 15.3 (q). Anal. Calcd for C17H22O6: C, 63.34; H, 6.88.
Found: C, 63.40; H, 6.92.
Acknowledgements
I.K. and M.F. are grateful to the MEN for a grant and C.R.
thanks the Institut de Recherche Servier (Suresnes, Fr
92150). The CNRS and the Ministeꢁre de la Recherche are
thanked for their financial support.
1
References and notes
(c 1.0, CH2Cl2). H NMR (CDCl3, 300 MHz) d 7.79 (2H,
d, J¼8.1 Hz), 7.72 (2H, d, J¼8.1 Hz), 7.36 (2H, d,
J¼8.1 Hz), 7.32 (2H, d, J¼8.1 Hz), 4.26–4.09 (2H, m),
3.95–3.88 (1H, m), 3.80–3.73 (1H, m), 2.44 (6H, s), 2.21
(1H, m), 2.0–1.41 (9H, m), 1.23 (3H, s), 0.80 (3H, s), 0.76
(3H, s), 0.72 (3H, s); the 13C NMR spectra revealed a confor-
mationally mobile system at room temperature: (CDCl3,
75 MHz) d 219.2 (s), 218.0 (s), 145.3 (s), 145.2 (s), 132.8
(s), 132.7 (s), 132.4 (s), 132.3 (s), 130.2 (d) (2C), 130.0 (d)
(2C), 128.3 (d), 128.26 (d), 128.2 (d), 128.1 (d), 68.2 (t),
68.0 (t), 67.1 (t), 61.8 (s), 61.7 (s), 51.0 (s), 50.7 (s), 48.1
(s), 47.8 (s), 45.3 (d), 42.5 (d), 41.1 (d), 31.6 (t), 28.4 (t),
26.2 (t), 21.8 (q) (2C), 19.1 (q), 18.2 (q), 17.3 (q), 17.25
(q), 8.8 (q), 8.7 (q). Anal. Calcd for C31H40O7S2: C, 63.24;
H, 6.85. Found: C, 63.18; H, 6.98.
1. Doucet, H.; Santelli, M. Synlett 2006, 2001–2015.
ꢁ
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˚
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