First intermolecular Pauson-Khand reaction of 7-azanorbornenes. Control of the regioselectivity by the effect of the substituents attached to the olefinic partner

Article abstract of DOI:10.1016/S0040-4039(01)00393-8

High regioselectivity in the intermolecular Pauson-Khand reaction of 7-azanorborn-5-enes has been found by using 5-bromo-2-endo-tosyl derivatives as the olefinic partner.

Full text of DOI:10.1016/S0040-4039(01)00393-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3085–3087
First intermolecular Pauson–Khand reaction of 7-azanorbornenes.
Control of the regioselectivity by the effect of the substituents
attached to the olefinic partner
Od o´ n Arjona,* Aurelio G. Cs a´ k y¨ , Roc ´ı o Medel and Joaqu ´ı n Plumet*
Departamento de Qu ´ı mica Org a´ nica I, Facultad de Qu ´ı mica, Universidad Complutense, 28040 Madrid, Spain
Received 21 February 2001; accepted 7 March 2001
Abstract—High regioselectivity in the intermolecular Pauson–Khand reaction of 7-azanorborn-5-enes has been found by using
5-bromo-2-endo-tosyl derivatives as the olefinic partner. © 2001 Elsevier Science Ltd. All rights reserved.
Among the different types of cycloannulation reactions
for the assembly of cyclopentenones, the Pauson–
respect to the alkene moiety. In these cases, two
regioisomeric cyclopentenones can be expected from the
intermolecular Pauson–Khand reaction. Control of the
regioselectivity is crucial in the development of synthet-
ically useful intermolecular reactions of this type.
Khand reaction,
a formal [2+2+1] cycloaddition
between an alkyne, an alkene and CO promoted by
Co (CO) , has progressively become one of the most
2
8
1
versatile approaches. In this context, the Pauson–
Khand reaction of bicylic alkenes has deserved special
consideration, as the stereochemical information con-
tained in the bicycles is conserved throughout the pro-
cess, allowing for the synthesis of annulated
cyclopentenones with total control of the relative stereo-
chemistry of the chains attached at positions C-4 and
3
–5
Studies carried out on bicyclo[2.2.1]heptenes,
bicy-
5
6,7
clo[3.2.0]heptenes, 8-oxabicyclo[3.2.1]octenes, 7-oxa-
8
9
bicyclo[2.2.1]heptenes, bicyclo[3.3.0]octenes and 2,3-
diaza bicyclo[2.2.1]heptenes have shown that the regio-
chemical outcome of the reaction is substrate-
dependent, and mainly stems from steric interactions
between the alkene and the alkyne–Co (CO) moiety at
4
2
C-5. However, regiochemical issues arise when the
2
6
starting bicycles are not symmetrically substituted with
two different levels: (i) the coordination step; (ii) the
Scheme 1. Reagents and conditions: (i) HCꢀC-SO Tol; (ii) NaBH , MeOH, 0°C, 15 min; (iii) PhSeBr, CHCl , rt, 6 h; (iv)
2
4
3
H O /NaOH, THF, 0°C–rt, 18 h.
2
2
*
0
Corresponding author.
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00393-8

3
086
O. Arjona et al. / Tetrahedron Letters 42 (2001) 3085–3087
insertion step. On the other hand, the regiochemistry of
intramolecular Pauson–Khand reactions can also be
modified by complexation effects. Thus, the attachment
of heteroatoms in the alkene moiety, in particular sul-
selenyl group originated decomposition of the starting
materials.
Careful reaction conditions must be chosen in handling
compounds 2–4 in order to avoid the retro-Diels–Alder
reaction. The N-methylmorpholine N-oxide promoted
Pauson–Khand reaction of 7-azanorbornadienes 2a,b
with complex 5 was carried out at rt under two differ-
10
fur, has proven to be of great use. No such effect has
been observed in the intermolecular version with
4
–8
bicyclic alkenes. However, heteroatoms (halogen and
OR) directly bonded to the alkene carbons have been
shown to control the regioselectivity of cyclopentenone
formation in a concomitant cycloaddition–reduction
ent conditions: (A) in CH Cl2 solution; and (B) in
2
CH Cl solution in the presence of 4 A molecular sieves
,
2
2
8
,11
sequence.
and using a reaction vessel which had been previously
washed with NaOH and dried. However, retrocycload-
dition to the starting pyrroles 1a,b was the only reac-
tion observed.
7
-Azabicyclo[2.2.1]heptenes, which are easily prepared
from the cycloaddition of pyrroles with electron-
deficient alkynes, have been widely used as starting
materials for the preparation of bioactive molecules.
1
2
13
On the other hand, when the 7-azanorbon-5-ene 3a,
with the tosyl group in endo position, was made to react
with 5 under the aforementioned experimental condi-
tions (Scheme 2), a mixture of the regioisomeric
Taking into account the synthetic potential of these
bicycles together with the above given considerations,
we have chosen these substrates in order to explore the
regioselectivity of their intermolecular Pauson–Khand
reaction, in what constitutes, as far as we know, the
first report of this process on 7-azanorbornene
derivatives.
1
4,15
cyclopentenones 6 and 7 was isolated.
The forma-
tion of the diastereomeric endo cyclopentenones was
not observed.
The results are given in Table 1. Better yields were
observed following reaction conditions B, although the
regiochemistry was low in both cases (entries 1 and 2).
On the other hand, treatment of the 5-bromoderivative
Cycloaddition of pyrroles 1 with p-(tolyl)ethynylsulfone
12
(
Scheme 1) afforded the 7-azanorbornadienes 2a,b.
Selective reduction of the double bond conjugated with
the sulfone moiety gave the 7-azanorborn-5-enes 3a and
4
a with complex 5 under reaction conditions A took
3b as a 75:25 mixture, which was separated by chro-
place in a completely regioselective fashion (entry 3),
whereas under reaction conditions B a drop in regio-
selectivity was observed, although the yield was better
(entry 4). Insertion of the cobalt moiety away from the
halogen was preferred, giving rise to the formation of 6
as a major product. It is also worth mentioning that,
under reaction conditions B, partial reduction of 4a to
3a was noticed (15% 3a).
matography. On the other hand, regioselective bro-
mophenylselenation of 2a followed by reduction of the
conjugated double bond and oxidative elimination of
the phenylselenyl group allowed for the synthesis of the
bromoderivatives 4a and 4b as a 25:75 mixture (70%
yield), which was separated by chromatography.
Attempted bromophenylselenation of compounds 3a or
3b followed by oxidative elimination of the phenyl-
Scheme 2. Reagents and conditions: Conditions A: CH Cl , NMO; Conditions B: CH Cl , 4 A molecular sieves, NaOH, NMO.
,
2
2
2
2

O. Arjona et al. / Tetrahedron Letters 42 (2001) 3085–3087
3087
Table 1. Reaction of 7-azanorbornenes 3 and 4 with the
Co (CO) –alkyne complex 5
977–981. For selected recent reviews see: (a) Schore, N.
E. In Comprehensive Organometallic Chemistry II; Hege-
dus, L. S., Ed.; Elsevier: Oxford, UK, 1995; Vol. 12 pp.
2
6
No. Reaction conditionsa 3, 4
Product ratiob (% yield)c
703–739; (b) Geis, O.; Schmalz, H.-G. Angew. Chem., Int.
Ed. 1998, 37, 911–914; (c) Chung, Y. K. Coord. Chem.
Rev. 1999, 188, 297–341.
. See: Balsells, J.; V a´ zquez, J.; Moyano, A.; Peric a` s, M. A.;
Riera, A. J. Org. Chem. 2000, 65, 7291–7302 and refer-
ences cited therein.
1
2
3
4
5
A
B
A
B
B
3a
3a
4a
4a
3b
6:7=65:35 (45)
6:7=50:50 (85)
6:7=100:0 (60)
6:7=80:20 (80)
8:9=70:30 (10)
2
1
0:11=70:30 (10)
3. (a) Mac Werter, S. E.; Sampath, V.; Olmstead, M. M.;
Schore, N. E. J. Org. Chem. 1988, 53, 203–205; (b)
Schore, N. E.; Nadji, S. D. J. Am. Chem. Soc. 1990, 112,
6
7
A
B
4b
4b
8:9=100:0 (50)
8:9=70:30 (40)
10:11=70:30 (5)
4
41–442.
4. Derdau, V.; Laschat, S.; Jones, P. G. Eur. J. Org. Chem.
000, 681–689.
a
b
c
Conditions A: CH Cl , NMO. Conditions B: CH Cl , 4 A
,
molecu-
2
2
2
2
2
lar sieves, NaOH, NMO.
1
5. Kowalczyk, B. A.; Smith, T. C.; Dauben, W. G. J. Org.
Determined by integration of the H NMR spectra (CDCl , 300
3
MHz) of the crude reaction products.
Isolated combined yields after chromatography.
Chem. 1998, 63, 1379–1389.
6. de Meijere, A.; Wessjohann, L. Synlett 1990, 20–32.
7. (a) La Belle, B. E.; Knudsen, M. J.; Olmstead, M. M.;
Hope, H.; Yanuck, M. D.; Schore, N. E. J. Org. Chem.
When the 7-azanorbon-5-ene 3b, with the tosyl group in
exo position, was made to react with complex 5, the
corresponding cyclopentenones 8 and 9 were obtained
in low yield, together with a 1:1 mixture of their endo
1985, 50, 5215–5222; (b) Price, M. E.; Schore, N. E. J.
Org. Chem. 1989, 54, 5662–5667; (c) Price, M. E.; Schore,
N. E. Tetrahedron Lett. 1989, 30, 5865–5868.
1
5,16
8. Arjona, O.; Cs a´ k y¨ , A. G.; Murcia, M. C.; Plumet, J. J.
Org. Chem. 1999, 64, 7338–7341.
. Monta n˜ a, A.-M.; Moyano, A.; Peric a` s, M. A.; Serratosa,
diastereomers 10 and 11 (entry 5).
However, when
the bromoderivative 4b was used as the starting mater-
ial, the diastereo- and regioselective formation of 8 was
observed by using reaction conditions A (entry 6).
When reaction conditions B were used instead, drop in
regioselectivity, reduction of 4b to 3b (10% 3b) and
formation of the corresponding diastereomeric endo
cyclopentenones were noticed (entry 7).
9
F. Tetrahedron 1985, 41, 5995–6003.
1
1
1
0. Adrio, J.; Carretero, J. C. J. Am. Chem. Soc. 1999, 121,
411–7412.
7
1. Kerr, W. J.; McLaughlin, M.; Pauson, P. L.; Robertson,
S. M. Chem. Comm. 1999, 2171–2172
2. (a) Altenbach, H. J.; Bleck, B.; Marco, J. A.; Vogel, E.
Angew. Chem., Int. Ed. 1982, 21, 778; (b) Altenbach, H.
J.; Constant, D.; Martin, H. D.; Mayer, B.; M u¨ ller, M.;
Vogel, E. Chem. Ber. 1991, 124, 791–801; (c) Chen, Z.;
Trudell, M. L. Chem. Rev. 1996, 96, 1179–1193.
3. (a) Leung-Toung, R.; Liu, Y.; Muchowski, J. M.; Wu, Y.
L. J. Org. Chem. 1998, 63, 3235–3250; (b) Giblin, G.;
Jones, C. D.; Simpkins, N. S. J. Chem. Soc., Perkin
Trans. 1 1998, 3689–3697.
In summary, the diastereo- and regioselective inter-
molecular Pauson–Khand reaction of 7-azanorborn-5-
enes has been described for the first time. The presence
of bromine in the 5-position was required to ensure
complete regioselectivity, and a tosyl substituent in
1
2-endo position was needed in order to avoid the forma-
tion of endo cyclopentenones. These findings may be
extended to the control of the Pauson–Khand reaction
in other bicyclic systems.
1
1
4. All compounds described herein are racemic mixtures.
Satisfactory analyses were found for all of them.
5. The structural assignment of compounds 6, 8, 10 and 7,
1
9
, 11 was carried out on the basis of their H NMR
Acknowledgements
(
CDCl , 300 MHz) spectra. Thus, a chemical shift differ-
3
ence of 0.7–1.2 ppm was observed between the H-2 and
H-6 signals of compounds 6, 8, 10, while this value was
of 0–0.6 ppm for compounds 7, 9, 11. Similar differences
had been previously observed in the Pauson–Khand
adducts of 2-substituted 7-oxanorbornenes and phenyl-
acetylene. See Ref. 8.
Ministerio de Ciencia y Tecnolog ´ı a (Project BQU2000-
0
653) is gratefully thanked for finantial support. One of
us (R.M.) thanks Ministerio de Educaci o´ n y Cultura
(
Spain) for a predoctoral grant.
1
6. Coupling of H-2 and H-6 of the endo adducts 10 and 11
1
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