Unexpected anionically driven ring opening of a norbornene system

Article abstract of DOI:10.1016/S0040-4039(02)01019-5

A norbornene moiety fused to a π-deficient heterocyclic system (quinoxaline) was found to undergo ring opening in a basic medium, possibly through a mechanism of retroaldol type.

Full text of DOI:10.1016/S0040-4039(02)01019-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5311–5313
Unexpected anionically driven ring opening of a norbornene
system
Carmen Lo´pez, Olga Caaman˜o, Antonio R. Hergueta, Marcos D. Garc´ıa and Franco Ferna´ndez*
Departamento de Qu´ımica Orga´nica, Facultade de Farmacia, Universidade de Santiago de Compostela,
E-15782 Santiago de Compostela, Spain
Received 28 May 2002; accepted 29 May 2002
Abstract—A norbornene moiety fused to a p-deficient heterocyclic system (quinoxaline) was found to undergo ring opening in a
basic medium, possibly through a mechanism of retroaldol type. © 2002 Elsevier Science Ltd. All rights reserved.
In the course of research on the synthesis of fused-hete-
rocycle analogues of the anti-HIV agent abacavir we
found we needed to prepare diacid 1, to achieve which
we considered oxidative cleavage of 2a or 3a.1 In what
appears to be the only published paper reporting syn-
thesis of compound 2a2 it was stated that both 2a and
2b fail to give the corresponding diketones 3 when
subjected to the conditions of Swern’s reaction, which
instead afford 63–75% yields of alcohols 4 as the only
products. Since we found that 2a is also unstable,
undergoing spontaneous alteration at room tempera-
ture, and since we planned to use it on more than one
occasion in exploring its oxidative cleavage under
diverse conditions, we decided to prepare a stable
derivative that could be converted to 2a immediately
before use. Accordingly, we synthesized dibenzoate 5,3
starting from the commercially available mixture of
racemic endo and exo norbornenyl acetates 6 (Scheme
1).
the mildest conditions compatible with effective sapon-
ification of the benzoate groups (0.9 M KOH in
MeOH/H2O, rt, 12 h) it afforded a crude product that
upon flash chromatography on silica gel gave a 66%
yield of a dark green solid. This product proved to
undergo alteration when left standing in solution, but
1
immediately after purification afforded IR, MS and H
and 13C NMR data compatible with its being the
enediol 12.4 This identification was confirmed by single-
crystal X-ray crystallography of the stable diacetylated
derivative 13 (Fig. 1),5 which was obtained by acetyla-
tion of 12 with Ac2O/pyridine.
Scheme 2 shows a plausible explanation of the forma-
tion of 12. Under the basic working conditions, the diol
2a formed from 5 will be in equilibrium with its
monoalkoxide, which because of the stress in the
bridged ring system must be highly susceptible to ring
opening. The resulting carbanion 14 will be stabilized
by its charge being formally located on the carbon a to
position 3 of the p-deficient quinoxaline system, and
following protonation of this carbon the resulting a-
hydroxyaldehyde 15 will be susceptible to base-cata-
lyzed isomerization to the a-hydroxyketone 17 via the
enediol 16 (a well-known reaction in sugar chemistry).
Because of the likelihood of rearrangements of Wag-
ner–Meerwein type due to its norbornene moiety, acid
hydrolysis of 5 was not attempted. Initial attempts at its
saponification to 2a gave only intractable mixtures or
unaltered starting material. However, when subjected to
OH
CO2H
R
R
N
N
OH
OH
N
R
R
N
N
O
O
R
R
N
N
N
CO2H
3a R,R = (CH=CH)2
3b R = H
4a R,R = (CH=CH)2
4b R = H
1
2a R,R = (CH=CH)2
2b R = H
Keywords: quinoxaline-fused norbornene; ring opening; anionic intermediates; basic medium.
* Corresponding author. Tel.: +34 981 563 100; fax: +34 981 594 912; e-mail: qofranco@usc.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01019-5

5312
C. Lo´pez et al. / Tetrahedron Letters 43 (2002) 5311–5313
There have been several reports of rearrangements of
Wagner–Meerwein type and ring-opening reactions
involving cationic intermediates which are undergone
by systems with a bicyclo[2.2.1]heptene moiety fused to
a benzene ring,6 or to an heteroaromatic ring,7 but as
far as we know this is the first example of a base-pro-
moted ring opening involving a carbanion intermediate.
We are currently exploring the scope and utility of this
novel type of reaction.
O
R
OBz
RO
OR'
OR'
AcO
a)
d)
OBz
10 (R = H2)
11 (R = O)
6
7 (R = Ac; R' = H)
8 (R = Ac; R' = Bz)
9 (R = H; R' = Bz)
b)
e)
c)
OR
OR
N
OBz
N
N
g)
f)
N
OBz
Acknowledgements
5
12 (R = H)
13 (R = Ac)
h)
The authors thank the Xunta de Galicia for financial
support under project PGIDT01PXI20302PR.
Scheme 1. Reagents and conditions: (a) OsO4/NMNO/
Me2CO–H2O, 40°C, 18 h; (b) BzCl/Py, rt, 24 h; (c) K2CO3/
MeOH, rt, 30 min; (d) CrO3·Py/DCM, rt,
6 h; (e)
SeO2/xylene; 140°C; 24 h; (f) o-(C6H4)(NH2)2/ZnCl2/THF,
66°C, 18 h; (g) 0.9 M KOH/MeOH–H2O, rt, 12 h; (h)
Ac2O/Py, rt; 14 h.
References
1. For syntheses of the corresponding benzo-fused analogues,
see: (a) Ferna´ndez, F.; Garc´ıa-Mera, X.; Morales, M.;
Rodr´ıguez-Borges, J. E. Synthesis 2001, 239–242; (b) Fer-
na´ndez, F.; Garc´ıa-Mera, X.; Morales, M.; Rodr´ıguez-
Borges, J. E.; De Clercq, E. Synthesis 2002, 1084–1090.
2. Kobayashi, T.; Kobayashi, S. Molecules 2000, 5, 1062–
1067.
3. (exo,exo)-1,2,3,4-Tetrahydro-1,4-methanophenazine-2,3-diyl
dibenzoate (5): mp 194–195°C. 1H NMR (300 MHz,
CDCl3) l=2.44 (1H, d, J=10.3, 11-Hsyn), 2.96 (1H, d,
J=10.3, 11-Hanti), 3.87 (2H, s, 1-H+4-H), 5.48 (2H, s,
2-H+3-H), 7.28 (4H, t, J=7.7, 2×[3,5-H2]benzoyl), 7.50 (2H,
t, J=7.3, 2×[4-H]benzoyl), 7.73 (2H, dd, J=6.2,3.4, 7-H+8-
H), 7.90 (4H, d, J=8.0, 2×[2,6-H2]benzoyl), 8.06 (2H, dd,
J=6.2,3.4, 6-H+9-H). 13C NMR (75 MHz, CDCl3) l=
42.02 (CH2, C11), 50.14 (CH, C1+C4), 73.31 (CH, C2+
C3), 128.67 (CH, [C3+C5]benzoyl), 129.62 (CH, C7+C8),
129.77 (C, [C1]benzoyl), 129.89 (CH, C6+C9), 130.08 (CH,
[C2+C6]benzoyl), 133.59 (CH, [C4]benzoyl), 142.37 (C, C5a+
C9a), 159.87 (C, C4a+C10a), 165.56 (C, CO). IR (KBr)
1731, 1716, 1276, 1120, 971, 760, 708 cm−1. EIMS (70 eV),
m/z (%), 437 (14, M+1), 436 (47, M+); 331 (16, M−
C6H5CO); 209 (11), 181 (8), 169 (11), 105 (100, C6H5CO+),
77 (24, C6H5+).
Figure 1. ORTEP plot of the molecular structure of 13 in the
solid state.
Finally, isomerization of 17 to the enediol 12 will be
favored by the exocyclic CꢀC bond of the latter being
conjugated with the aromatic quinoxaline system.
4. 1-(2,3-Dihydro-1H-cyclopenta[b]quinoxalin-1-ylidene)-1,2-
1
ethanediol (12): H NMR (300 MHz, CDCl3) l=2.77–2.81
O
OH
N
N
OH
OH
N
N
N
N
OH
O
HO
H2O
2a
14
OH
OH
O
H2O
O
OH
HO
OH
N
N
N
N
N
HO
HO
12
N
16
17
15
Scheme 2. Suggested mechanism for the formation of 12 from 2a.

C. Lo´pez et al. / Tetrahedron Letters 43 (2002) 5311–5313
5313
(2H, m, 2%-H2), 3.02–3.06 (2H, m, 3%-H2), 3.59 (1H, ws,
D2O exch., 2-OH), 4.34 (2H, s, 2-H2), 7.04 (1H, d, J=7.9,
tary publication No. CCDC 185239. Copies of the data
can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge, CB2 1EZ, UK.
Hquinoxaline), 7.19 (1H, t, J=7.6, Hquinoxaline), 7.32 (1H, t,
6. (a) Dastan, A.; Demir, U.; Balci, M. J. Org. Chem. 2000,
6534–6538; (b) Adam, W.; Carballeira, N.; Scheutzow, D.;
Peters, K.; Peters, E. M.; Von Schnering, H. G. Chem.
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G. J. Am. Chem. Soc. 1976, 98, 6304–6308.
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Trans. 1 2000, 2731–2739; (b) Kobayashi, T.; Miki, K.;
Nikaeen, B.; Baba, H. Tetrahedron 1999, 55, 13179–13192;
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J=7.6, Hquinoxaline), 7.56 (1H, d, J=7.9, Hquinoxaline), 10.32
(1H, ws, D2O exch., 1-OH). 13C NMR (75 MHz, CDCl3)
l=22.71 (CH2, C2%), 30.17 (CH2, C3%), 65.72 (CH2, C2),
105.94 (C), 115.78 (CH), 124.67 (CH), 128.64 (CH), 129.27
(C), 129.64 (CH), 136.49 (C), 143.28 (C), 171.09 (C),
194.61 (C). IR (KBr) 3434, 3418, 1644, 1610, 1580, 1558,
1232, 1068, 901, 770, 600 cm−1. EIMS (70 eV), m/z 228
(32, M+), 197 (71, M−CH2OH), 170 (41, M−C2H2O2), 169
(61, M−COCH2OH), 168 (26, M−OCHCH2OH), 58 (100,
C2H2O2+).
5. Crystallographic data for 13 have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-