Control of product distribution in the domino metathesis reactions of N-alkynyl 2-azabicyclo[2.2.1]hept-5-en-3-ones. A convenient synthesis of functionalized γ-lactams and indolizidinones

Article abstract of DOI:10.1016/j.tetlet.2003.10.197

In this report we describe the domino metathesis of N-alkynyl-2-aza-3-oxo- [2.2.1]hept-5-enes. The distribution of products of the domino processes of ROM-CM or ROM-RCM-CM depends on the starting material and on the catalyst used. A sequence of metathesis events has been proposed to account for these results. The procedure can be of use for the synthesis of lactams and indolizidinones.

Full text of DOI:10.1016/j.tetlet.2003.10.197

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 565–567
Control of product distribution in the domino metathesis reactions
of N-alkynyl 2-azabicyclo[2.2.1]hept-5-en-3-ones. A convenient
synthesis of functionalized c-lactams and indolizidinones
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Odon Arjona, Aurelio G. Csaky, Vanessa Leon, Rocıo Medel and Joaquın Plumet
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Departamento de Quımica Organica, Facultad de Quımica, Universidad Complutense, E-28040 Madrid, Spain
Received 30 September 2003; revised 21 October 2003; accepted 30 October 2003
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Dedicated to Profs. Manuel Lora-Tamayo and Antonio Gonzalez Gonzalez. In Memoriam
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Abstract—In this report we describe the domino metathesis of N-alkynyl-2-aza-3-oxo-[2.2.1]hept-5-enes. The distribution of
products of the domino processes of ROM–CM or ROM–RCM–CM depends on the starting material and on the catalyst used.
A sequence of metathesis events has been proposed to account for these results. The procedure can be of use for the synthesis
of lactams and indolizidinones.
Ó 2003 Elsevier Ltd. All rights reserved.
The sequential transformation of the alkenes obtained in
O
O
K2CO3, KOH, TEBA
(CH2)nX
5, R=H, n=1, X=Br
6, R=Me, n=1, X=Br
7, R=H, n=3, X=Cl
metathesis reactions1 (domino process) constitutes an
attractive application of this synthetic method, in par-
ticular in the case of bicyclic and other strained sys-
tems.2 In the case of [2.2.1]bicyclic alkenes, the ring
opening metathesis (ROM)–cross metathesis (CM) and
ROM–CM–ring closing metathesis (RCM) sequences
have been considered for norbornene,3 7-oxanorborn-
ene,4 and 2-azanorbornene5 derivatives (Fig. 1).
N
()n
NH
R
C C
4
R
1, R=H, n=1 (85%)
2, R=Me, n=1 (92%)
3, R=H, n=3 (75%)
Scheme 1.
Despite the synthetic potential of these processes, to the
best of our knowledge the domino metathesis in N-
alkynyl bicyclic compounds has not yet been consid-
ered.6 In this way, the metathetical reactions of
compounds 1–3 (Scheme 1) with ethylene using catalysts
A and B (Fig. 2)7 have been studied and constitute the
objective of the present report.
Compounds 1–3 were prepared by the reaction of lac-
tam 4 with the appropriate halide8;9 (Scheme 1).
X
X
R
R
R
Y
Y
CM
X
The reactions of compounds 1–3 with ethylene (1 atm) in
the presence of the ruthenium catalysts A or B afforded
()n
()n
ROM
ROM-CM
R
Y
X
()n
()n
PCy3
Y
Ar
N
N Ar
RCM
Cl
Cl
H
Ru
PCy3
Cl
Cl
ROM-RCM-CM
H
Ph
Ru
PCy3
Ph
Figure 1.
A
Ar = 2,4,6-trimethylphenyl
Keywords: Metathesis; Azabicyclic; Lactams; Indolizidinones.
* Corresponding authors. Tel./fax: +34-913944193; e-mail: plumety@
quim.ucm.es
B
Figure 2.
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.197

566
O. Arjona et al. / Tetrahedron Letters 45 (2004) 565–567
O
N
RCM
O
12a
O
N
()n
catalyst B
ROM-CM
N
()n
alkyne - alkene
CM
R
R
1-3
O
N
()n
Scheme 2.
R
Table 1. Metathesis reactions of compounds 1–3 with ethylenea
9b, R = Me, n = 1
9c, R = H, n = 3
Product distributionb
No
1–3
Catalyst t (h)
8
9
10
11
12
Scheme 4.
1
2
3
4
5
6
1
2
3
1
2
3
A
A
A
B
B
B
15
15
15
5
––
25
50
––
––
––
25
15
30
––
80
98
60
20
17
––
––
––
––
––
––
––
15
––
––
––
––
98
––
––
The overall comparison of these results deserves some
comments (Scheme 5). In the case of alkyne–alkene
cross metathesis with catalyst A, the reaction starts at
the triple bond.10 Formation of the metallacyclobutene
on the triple bond11 competes with formation of the
related metallacyclobutane on the endocyclic double
bond. In the case of compound 1, coordination of the
catalyst with the carbonyl group may favor metalla-
cyclobutene formation (intermediate Ia, path a).1a
However, in the case of compound 2 steric effects due to
the presence of the terminal CH3 group may counter-
balance coordinative effects, thus giving rise to a ran-
dom distribution of reaction products. Finally, in the
case of compound 3 (path b) the distance between the
triple bond and the carbonyl group hinders the opera-
tion of stabilizing interactions by chelation on the lateral
chain, and therefore, the initial formation of the
metallacyclobutane (intermediate IIc) predominates
over metallacyclobutene formation (intermediate Ic).
5
5
a Sealed tube, 1 atm ethylene, CH2Cl2, reflux, 10% catalyst.
b Isolated yield.
compounds 8–12 in variable amounts depending on the
structure of the starting materials and the reaction
conditions (Scheme 2, Table 1).
From these results we deduced that, when using catalyst
A in the case of compounds 1 and 3, which only differ in
the length of the lateral alkyne chain, two single but
different metathetical processes are dominant (Scheme
3): (i) in the case of 1, the intermolecular alkyne–alkene
metathesis (compound 10a, entry 1) is the dominant
metathetical event, and (ii) in the case of 3, the ROM–
CM (compound 8c, entry 3) is the predominant path.
Under similar reaction conditions compound 2, which
differs from 1 in the nature of the R substituent of the
alkyne moiety, a mixture of the different reaction
products was obtained (entry 2).
It should be pointed out that the new functionalization
present in 10a and 8c opens the possibility for meta-
On the other hand, by using B as the catalyst (Scheme
4), compound 1 afforded the domino ROM–CM–RCM
product 12a in high yield (entry 4), whereas 3 gave rise
to product 9c (entry 6), which is the result of the
simultaneous ROM–CM of the alkene moiety together
with the CM of the alkyne. Under these reaction con-
ditions compound 2 behaved similarly to 3, giving rise to
9b (entry 5) as the major reaction product.
O
O
catalyst A
alkyne-alkene
CM
catalyst A
ROM-CM
N
()n
N
O
N
()3
1, n = 1
3, n = 3
10a
Scheme 3.
8c
Scheme 5.

O. Arjona et al. / Tetrahedron Letters 45 (2004) 565–567
567
€
of Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012,
should also be considered.
thesis-Diels–Alder reaction sequences that have been
proved to be an interesting and economical bond
forming method.12
ꢀ €
2. For some recent reviews, see: (a) Arjona, O.; Csaky, A. G.;
Plumet, J. Eur. J. Org. Chem. 2003, 611; (b) Arjona, O.;
ꢀ €
Csaky, A. G.; Plumet, J. Synthesis 2000, 857; (c) Blechert,
S. Pure Appl. Chem. 1999, 71, 1393.
On the other hand, the use of the more active13 catalyst
B allowed a convenient synthesis of the functionalized
indolizidinone14 12a from compound 1 (Table 1, entry
4). The previously observed formation of 10a as the
major product using A as catalyst (Table 1, entry 1)
appears to indicate that 10a is the most important
intermediate for the formation of 12a: after formation of
10a, ROM followed by RCM affords 12a (Scheme 5).
3. See, for instance: (a) Katayama, H.; Nayao, M.; Ozawa,
F. Organometallics 2003, 22, 586; (b) Mayo, P.; Tam, W.
Tetrahedron 2002, 58, 9513; (c) Katayama, H.; Urushima,
H.; Nishioka, T.; Wada, C.; Nayao, M.; Ozawa, T. Angew.
Chem., Int. Ed. 2000, 39, 4513; (d) Karlou-Eyrisch, K.;
Muller, B. K. M.; Herzig, C.; Nuyken, O. J. Organomet.
Chem. 2000, 606, 3; (e) Cuny, G. D.; Cao, J. R.; Sidhu, A.;
Hauske, J. R. Tetrahedron 1999, 55, 8169; (f) Stragies, R.;
Blechert, S. Synlett 1998, 169; (g) Snaper, M. L.; Tallarico,
J. A.; Randall, M. L. J. Am. Chem. Soc. 1997, 119, 1478;
(h) Schneider, M. F.; Blechert, S. Angew. Chem., Int. Ed.
1996, 35, 411.
Again making use of catalyst B, when a methyl group
was attached to the alkyne moiety (compound 2) or
when a three-carbon methylene chain separated the two
reactive centers (compound 3), pyrrolidinones15 9b,c
were the most important products (Table 1, entries 5
and 6). Steric (compound 2) and entropic (compound 3)
factors appear to be the origin of the failure of the CM
or RCM reaction to give 12b and 12c, respectively. It
should be pointed out that, according to our previous
comments, compounds 9b,c should be formed in these
cases from IIb,c via ROM–CM (Scheme 5, path b) fol-
lowed by alkyne–alkene CM.
ꢀ €
4. (a) Arjona, O.; Csaky, A. G.; Mula, B.; Murcia, C.;
Plumet, J. J. Organomet. Chem. 2001, 627, 105; (b)
ꢀ €
Arjona, O.; Csaky, A. G.; Murcia, C.; Plumet, J. Tetra-
ꢀ €
hedron Lett. 2000, 41, 9777; (c) Arjona, O.; Csaky, A. G.;
Murcia, C.; Plumet, J. J. Org. Chem. 1999, 64, 9739; (d)
Scheneider, M. F.; Lucas, H.; Velder, J.; Blechert, S.
Angew. Chem., Int. Ed. 1997, 36, 257.
5. (a) Dunne, A. M.; Mix, S.; Blechert, S. Tetrahedron Lett.
2003, 44, 2733; (b) Ishikura, M.; Saijo, M.; Hino, A.
Heterocycles 2003, 59, 573; (c) Ishikura, M.; Saijo, M.;
Hino, A. Heterocycles 2002, 57, 241; (d) Arjona, O.;
With respect to quinolizidines 11, these compounds were
formed in very poor yields in all the cases considered.
The well known kinetic preference for the formation of
five membered ring systems14 should be overcome by the
higher steric effects associated with the Ô1,1-disubstitutedÕ
double bond of the dienic system. Only in the case of 11b,
with the same degree of substitution in both double
bonds, is this kinetic preference partially manifested.16
ꢀ €
Csaky, A. G.; Medel, R.; Plumet, J. J. Org. Chem. 2002,
67, 1380; (e) Huwe, C. M.; Velder, J.; Blechert, S. Angew.
Chem., Int. Ed. 1996, 35, 2376.
6. For an isolated case in the 7-oxanorbornene series, see
Ref. 4b. A description of the process can be found in
Ref. 2a, p 619.
7. For the synthesis and uses of the most common catalysts
for the metathesis reactions, see Ref. 2a and: Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
8. For a review on the chemistry of substituted 2-azabicy-
clo[2.2.1]hept-5-enes, see: Brandt, P.; Andersson, P. G.
Synthesis 2000, 1092.
9. Compound (+)-4 is commercially available in optically
pure form. All compounds described herein were synthe-
sized using (+)-4 as starting material.
10. See Ref. 2c, p 1395. For some recent reviews on alkyne–
alkene metathesis reactions, see Ref. 1a and: Bentz, D.;
Laschat, S. Synthesis 2003, 1766.
In summary, in this report the domino metathesis
reactions of N-alkynyl-2-aza-3-oxo-[2.2.1]hept-5-enes
are described. In order to account for the observed
distribution of products, a sequence of metathesis events
has been proposed. The synthetic utility of the process
was also emphasized.
11. We recognise implicitly the ChauvinÕs well known mech-
anism for metathesis reactions: Herisson, J. L.; Chauvin,
Y. Macromol. Chem. 1971, 141, 161, For a full discussion
see Ref. 1d, p 3018 and references cited therein.
12. See, for instance: Banti, D.; North, M. Tetrahedron Lett.
2002, 43, 1561, See also Ref. 11.
Acknowledgements
ꢀ
Ministerio de Ciencia y Tecnologıa (Project No.
BQU2000-0653) is gratefully thanked for financial sup-
port. One of the authors (V.L.) thanks Ministerio de
ꢀ
Ciencia y Tecnologıa for a postdoctoral grant.
13. Catalyst B has proven of superior activity than A in CM
processes. See Ref. 1a.
14. For a general review on the synthesis of nitrogen
containing compounds by RCM, including the indoliz-
idine ring system, see: Phillips, A. J.; Abell, A. D.
Aldrichim. Acta 1999, 32, 75. For more recent references
on the synthesis of the indolizidine ring system by RCM,
see for instance: (a) Zaminer, J.; Stapper, C.; Blechert, S.
Tetrahedron Lett. 2002, 43, 6739; (b) Groaning, M. D.;
Meyers, A. I. Chem. Comm. 2000, 1027; (c) Voigtmann,
U.; Blechert, S. Synthesis 2000, 893.
15. See, for instance: (a) Ref. 1d, p 3033; (b) Wallace, D. J.
Tetrahedron Lett. 2003, 44, 2145, and references cited
therein.
16. All new compounds showed spectroscopic and analytical
data consistent with the assigned structures.
References and Notes
1. The alkene metathesis reaction is one of the most valuable
synthetic tools in organic chemistry today and an impres-
sive amount of literature has been devoted to this topic.
From 2003 the following general reviews should be
considered: (a) Connon, S. J.; Blechert, S. Angew. Chem.,
Int. Ed. 2003, 42, 1900; (b) Grubbs, R. H.; Trnka, T. M.;
Sanford, M. S. Fundam. Mol. Catal. 2003, 3, 187; (c)
Soderberg, B. C. G. Coord. Chem. Rev. 2003, 241, 147; (d)
In a general context, the seminal comprehensive review