Tetramethylnorbornadiene, a versatile alkene for cyclopentenone synthesis through intermolecular Pauson-Khand reactions

Article abstract of DOI:10.1021/ol301545e

1,2,3,4-Tetramethyl-bicyclo[2.2.1]hepta-2,5-diene (TMNBD, for tetramethylnorbornadiene) has been prepared and used successfully as an acetylene equivalent in the synthesis of substituted cyclopentenones. TMNBD is easily accessible on a multigram scale and displays excellent reactivity toward the intermolecular Pauson-Khand reaction. Conjugate additions on the resulting tricyclic compounds proceed with exquisite diastereoselectivity. The retro-Diels-Alder reaction of these TMNBD derivatives occurs under much smoother conditions than those required for its norbornadiene homologues.

Full text of DOI:10.1021/ol301545e

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3534–3537
Tetramethylnorbornadiene, a Versatile
Alkene for Cyclopentenone Synthesis
through Intermolecular PausonꢀKhand
Reactions
ꢀ
Marc Reves, Agustı Lledo, Yining Ji, Emma Blasi, Antoni Riera,* and
Xavier Verdaguer*
ꢀ
´
´
Unitat de Recerca en Sıntesi Asimetrica (URSA-PCB) Institute for Research in
Biomedicine (IRB) and Departament de Quımica Organica, Universitat de Barcelona,
ꢁ
´
ꢁ
c/Baldiri Reixac, 10, E-08028 Barcelona, Spain
antoni.riera@irbbarcelona.org; xavier.verdaguer@irbbarcelona.org
Received June 5, 2012
ABSTRACT
1,2,3,4-Tetramethyl-bicyclo[2.2.1]hepta-2,5-diene (TMNBD, for tetramethylnorbornadiene) has been prepared and used successfully as an
acetylene equivalent in the synthesis of substituted cyclopentenones. TMNBD is easily accessible on a multigram scale and displays excellent
reactivity toward the intermolecular PausonꢀKhand reaction. Conjugate additions on the resulting tricyclic compounds proceed with exquisite
diastereoselectivity. The retro-DielsꢀAlder reaction of these TMNBD derivatives occurs under much smoother conditions than those required for
its norbornadiene homologues.
Metal-mediated reactions play an important role in our
continuing efforts toward new ways of constructing com-
plex molecules. For the synthesis of five-membered rings,
there is no match for the PausonꢀKhand reaction (PKr) in
terms of potential flexibility and atom economy.1 This
reaction, discovered in 1971 by Pauson and Khand,2 is a
transition-metal-mediated reaction with three compo-
nents, an alkyne, an alkene, and carbon monoxide, which
leads to variety of synthetically useful cyclopentenones.
A versatile application of norbornadiene Pausonꢀ
Khand adducts is the conjugate addition/retro-Dielsꢀ
Alder sequence (Scheme 1).
the cyclopentenone. After the corresponding retro-Dielsꢀ
Alder (rDA) reaction, these products lead to cyclopente-
none rings with different substituents and a defined stereo-
chemistry.3
Such retro-DielsꢀAlder reactions have found wide ap-
plication in synthesis.4 They can be performed under flash
vacuum pyrolysis at high temperatures (500ꢀ600 °C) pro-
vided that the substrates are simple and robust enough.5
Alternative protocols at lower temperatures require the
ꢀ
(3) (a) Verdaguer, X.; Vazquez, J.; Fuster, G.; Bernardes-Genisson,
V.; Greene, A. E.; Moyano, A.; Pericas, M. A.; Riera, A. J. Org. Chem.
ꢀ
ꢁ
1998, 63, 7037–7052. (b) Bernardes, V.; Kann, N.; Riera, A.; Moyano,
The steric hindrance imposed by the norbornene ring
enforces a diastereoselective addition from the exo face of
ꢁ
A.; Pericas, M. A.; Greene, A. E. J. Org. Chem. 1995, 60, 6670–6671.
ꢁ
(c) Verdaguer, X.; Moyano, A.; Pericas, M. A.; Riera, A.; Bernardes, V.;
Greene, A. E.; Alvarez-Larena, A.; Piniella, J. F. J. Am. Chem. Soc.
1994, 116, 2153. (d) Bernardes, V.; Verdaguer, X.; Kardos, N.; Riera, A.;
Moyano, A.; Pericas, M. A.; Greene, A. E. Tetrahedron Lett. 1994, 35,
575.
(4) Klunder, A. J. H.; Zhu, J.; Zwanenburg, B. Chem. Rev. 1999, 99,
1163–1190.
(5) (a) Ripoll, J. L.; Rouessac, A.; Rouessac, F. Tetrahedron 1978, 34,
19–40. (b) Stork, G.; Nelson, G. L.; Rouessac, F.; Gringore, O. J. Am.
Chem. Soc. 1971, 93, 3091–3092.
(1) (a) Lee, H.-W.; Kwong, F.-Y. Eur. J. Org. Chem. 2010, 789–811.
(b) Gibson, S. E.; Mainolfi, N. Angew. Chem., Int. Ed. 2005, 44, 3022–
3037. (c) Blanco-Urgoiti, J.; Anorbe, L.; Perez-Serrano, L.; Dominguez,
G.; Perez-Castells, J. Chem. Soc. Rev. 2004, 33, 32–42. (d) Gibson, S. E.;
Stevenazzi, A. Angew. Chem., Int. Ed. 2003, 42, 1800–1810.
(2) (a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.;
Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977–981. (b) Khand,
I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. J. Chem. Soc. D: Chem.
Commun. 1971, 36a–36a.
ꢁ
(6) Grieco, P. A.; Abood, N. J. Org. Chem. 1989, 54, 6008–6010.
r
10.1021/ol301545e
Published on Web 06/26/2012
2012 American Chemical Society

exo-tricyclo[5.2.1.02,6]tricyclodeca-4,8-dien-3-one scaffold.
Considering the success achieved with pentamethyltricyclo-
decenones, we sought to synthesize unknown tetramethyl-
norbornadiene10 1 (TMNBD) and to study the effect of
introducing four methyl groups in the norbornadiene ring
instead. We developed a scalable synthesis of TMNBD,
studied its behavior toward catalytic PKr’s, and assessed
the reactivity of the corresponding PK adducts toward
conjugate addition and rDA reactions.
Scheme 1. PKrꢀConjugate AdditionꢀrDA Sequence
Scheme 3. Preparation of TMNBD
presence of a Lewis6 or Bronsted7 acid and a diene scave-
e
nger. Under such conditions, however, the [4 þ 2] cyclor-
eversion of functionalized precursors suffers from accom-
panying side reactions (eliminations, isomerizations, etc.)
which have hindered the use of this approach at late stages
of elaborated syntheses. In the context of the synthesis of
(þ)-prostaglandin A2, Grieco and Abood reported that
cycloreversion could be accelerated by employing the
corresponding pentamethyltricyclodecenones. These are
derived in turn from the DielsꢀAlder adduct of penta-
methylcyclopentadiene and benzoquinone (Scheme 2).8
Other substituted cyclopentadienes have also been em-
ployedastheleaving group withlittlerelevance insynthetic
terms.9
We envisaged a DielsꢀAlder reaction between 1,2,3,4-
tetramethylcyclopentadiene and a synthetic acetylene
equivalent for the preparation of TMNBD. After much
experimentation with a variety of standard dienophiles we
were able to isolate the desired diene by reductive desulfo-
nylation from adduct 3, albeit in a disappointingly low
yield (Scheme 3). We then turned our attention to 1,2-
dichloroalkane precursors which are reported to undergo
reductive elimination in the presence of alkaline metals.11
Thus, 4 was accessed in good yield by a DielsꢀAlder
reaction between trans-dichloroethylene and 1,2,3,4-tetra-
methylcyclopentadiene in a pressure vessel. We were unable
to obtain any diene when 4 was exposed to magnesium. In
contrast, reaction with lithium provided TMNBD in good
yields on a multigram scale after purification by distillation.
It is worth noting the importance of the lithium source on
the reaction outcome. When lithium with a high sodium
content was used (0.5%), an important increase in reactiv-
ity was observed, reaching total conversion after 24 h.
The use of the same source of lithium for extended reac-
tion times led only to decomposition of the desired olefin.
The stereospecific nature of such eliminations also deserves
a comment; early attempts to prepare 1 from cis-dichloro
a
Scheme 2. Grieco’s Strategy towards PGA2
a The retro-DielsꢀAlder reaction was facilitated by the methyl
groups.
We report here on the implementation of this strategy
into our PKr-based approach to substituted cyclopente-
nones. This route offers several advantages: a more favorable
step count, the versatility of the PKr assembly toward the
alkyne counterpart, and the stereodirecting ability of the
(7) Demuynck, A. L. W.; Levecque, P.; Kidane, A.; Gammon, D. W.;
Sickle, E.; Jacobs, P. A.; De Vos, D. E.; Sels, B. F. Adv. Synth. Catal.
2010, 352, 3419–3430.
(8) Grieco, P. A.; Abood, N. J. Chem. Soc., Chem. Commun. 1990,
410–412.
(10) IUPAC nomenclature: 1,2,3,4-tetramethyl-bicyclo[2.2.1]hepta-
2,5-diene.
(9) (a) Kotha, S.; Banerjee, S.; Patil, M. P.; Sunoj, R. B. Org. Biomol.
Chem. 2006, 4, 1854–1856. (b) Magnus, P.; Cairns, P. M.; Moursounidis,
J. J. Am. Chem. Soc. 1987, 109, 2469–2471.
(11) (a) Shahlai, K.; Hart, H. J. Am. Chem. Soc. 1990, 112, 3687–
3688. (b) Brown, A. C.; Carpino, L. A. J. Org. Chem. 1985, 50, 1749–
1750.
Org. Lett., Vol. 14, No. 13, 2012
3535

derivative 6 (derived from the DielsꢀAlder adduct of vinyl
carbonate) only met with failure.
reactions. Upon treatment with catalytic amounts of
tetra(n-butyl)ammonium trihydrate, the R-silylketones
smoothly reacted to provide substrates 9aꢀc in excellent
yields (Scheme 4).
Once we secured a reliable preparative synthesis of
TMNBD, we started studying the behavior of this strained
olefin toward catalytic PKr’s with different acetylenes,
using Co2(CO)8 as a catalyst (Table 1). Reaction occurs
exclusively at the less substituted and therefore less hin-
dered double bond. The corresponding exo fused adducts
were obtained in good yields. The reaction proceeds with
remarkable diastereoselectivity since we were unable to
isolate any of the endo isomers. The reaction conditions
employed here would typically deliver an 85:15 diastereo-
meric ratio using norbornadiene instead.12
Table 2. Conjugate Additions
Table 1. Catalytic PKr’s with TMNBD
conditions
yield
86%
prod.
R1
R2
i-Pr
1
2
3
4
5
6
i-PrMgCl (1.2 equiv),
CuI (0.1 equiv, Et2O
PhMgCl (2 equiv),
CuI (0.1 equiv), Et2O
PMPMgCl (2 equiv),
CuI (0.1 equiv), Et2O
BuLi (2 equiv),
8a
TMS
50%
50%
60%
32%
78%
8b
8c
8d
8e
8f
TMS
TMS
TMS
n-Bu
H
Ph
PMP
n-Bu
Me
R
yield
product
CuCN (1equiv), Et2O
MeLi (2 equiv),
1
2
3
4
TMS
Ph
89%
85%
85%
79%
7a
7b
7c
7d
CuI (1 equiv), Et2O
CH2CHMgBr (1.5
equiv), CuI (0.1
n-Bu
vinyl
CH2OTBDPS
equiv), THF
7
TBAF 3H2O (0.1
99%
8ga
H
CH2NO2
3
We then subjected trimethylsilylacetylene and n-butyl
equiv), CH3NO2
adducts (7a and 7c) to conjugate addition with a set of
different organolithium and Grignard reagents in combi-
nation with copper(I) salts, in either catalytic or stoichio-
metric amounts. Under these conditions the reaction
yielded compounds 8aꢀ8f with complete diastereoselec-
tivity. A 2D-NOESY experiment of derivative 8a con-
firmed that the nucleophile attacked from the less
hindered exo face of the cyclopentenone ring, with the
TMS group adopting a trans arrangement with respect to
the R2 group. The R-silyl enone 7a proved to be an
excellent Michael acceptor in accordance with previous
findings,13 and the corresponding R-silylketones were ob-
tained in moderate to good yields (Table 2, entries 1ꢀ4). In
contrast, the n-butyl derivative 7c displayed more sluggish
reactivity and lower yields were obtained due to the fact
that total conversion was not reached (table 2, entry 5).
Adduct 7e resulting from protodesilylation of 7a also
proved to be a good substrate. Additionally, we prepared
the nitro derivative 8g by fluoride catalyzed conjugate
addition of nitromethane, which occurs with simultaneous
R-silyl cleavage (Table 2, entry 7).
a Product from conjugate addition and concomitant silyl cleavage.
Scheme 4. Fluoride Catalyzed Removal of the TMS Group
With a variety of tricyclodecenones in hand, the stage
was set for the key retro-cycloaddition reaction. We initi-
ally compared the relative reactivity of adduct 9b, contain-
ing the tetramethylnorbornene manifold, with that of the
corresponding norbornene analog when subjected to rDA
reaction(Table3, entries1 and2). The adductderived from
norbornadiene (10), in the presence of methyl aluminum
dichloride andmaleicanhydride, requireda temperatureof
50 °C for the reaction to take place. In contrast, substrate
9b reacted smoothly at only 0 °C when subjected to the
same reagent combination and reaction was complete
within a much shorter time. Thus, we managed to lower
by some 50 °C the reaction temperature by the addition of
For compounds 8aꢀc removal of the rather labile TMS
group was carried out prior to any attempt to perform rDA
ꢀ
ꢀ
(12) Cabot, R.; Lledo, A.; Reves, M.; Riera, A.; Verdaguer, X.
Organometallics 2007, 26, 1134–1142.
ꢀ
ꢀ
(13) (a) Vazquez-Romero, A.; Rodrıguez, J.; Lledo, A.; Verdaguer,
´
X.; Riera, A. Org. Lett. 2008, 10, 4509–4512. (b) Iqbal, M.; Duffy, P.;
ꢀ
Evans, P.; Cloughley, G.; Allan, B.; Lledo, A.; Verdaguer, X.; Riera, A.
Org. Biomol. Chem. 2008, 6, 4649–4661. (c) Iqbal, M.; Li, Y.; Evans, P.
Tetrahedron 2004, 60, 2531–2538.
3536
Org. Lett., Vol. 14, No. 13, 2012

four methyl groups to the extruding cyclopentadiene frag-
ment. These results are in good agreement with the ones
obtained by Grieco using pentamethyl endo-fused ciclode-
cenones.8 This chemistry was extended to the different
conjugate addition products synthesized, and we obtained
good yields of the desired cyclopentenones for most sub-
strates. Only compound 8e with a higher substitution
pattern gave a less satisfactory result (Table 3).
Table 4. Enantioselective PausonꢀKhand Reactions
Thermogravimetric analysis of compounds 9a and 10
gives us qualitative insight into the activation temperatures
for the purely thermal process. Compound 10 (a liquid at
rt) displays an endothermic process with an onset at 245 °C
accompanied by a reduction in mass. This is ascribed to the
retro-DielsꢀAlder decomposition into volatile fragments
(cyclopentadiene, 11a). For solid compound 9a a first
endotherm without reduction is observed at 77 °C which
corresponds to the compound’s melting point, and a
second heat absorption with concomitant mass reduction
indicating the rDA process is observed at 199 °C. The
roughly 50 °C difference observed between the two reac-
tion endotherms nicely matches the trend observed for the
Lewis acid mediated reaction.
complex
R
yield
ee
prod.
1
2
3
4
12b
12d
12e
12f
Ph
94%
80%
95%
77%
99%
94%
94%
98%
(ꢀ)-7b
(ꢀ)-7d
(ꢀ)-7e
(ꢀ)-7f
CH2OTBDPS
CH2NHBoc
4-F-Ph
asymmetric PKr’s, for which we rely on an extended
inventory of purpose-designed chiral ligands.14 Cobalt
complexes 12b and 12dꢀf featuring our N-phosphino-
tert-butylsulfinamide chiral ligand14d were subjected to
reaction with excess TMNBD to provide the corre-
sponding PausonꢀKhand adducts in excellent yields
and enantioselectivities (Table 4).
In conclusion, we have developed a reliable and versatile
sequence toward substituted cyclopentenones using an
optimized retro-DielsꢀAlderreaction asthe keystep. With
easy access to multigram quantities of diene 1, a myriad of
PKr-conjugate addition combinations can be envisaged
providing an equally vast number of cyclopentenone pre-
cursors. TMNBD derivatives display exquisite reactivity
in the rDA reactions which anticipate the success of this
strategy with more functionalized substrates. With homo-
chiral PausonꢀKhand precursors at hand, this technology
can eventually be applied to efficient and modular synth-
eses of biologically relevant products, such as prostaglan-
dins and analogues.
Table 3. Retro-DielsꢀAlder Reactions of Tricyclic Decenones
s. m.
R1
R2
Ph
X
temp, time
yield
prod.
1
2
3
4
5
10
9a
9b
9c
8e
H
H
50 °C, 1.5 h
0 °C, 0.5 h
0 °C, 0.5 h
0 °C, 0.5 h
0 °C, 0.5 h
73%
76%
71%
70%
47%
11a
11a
11b
11c
11d
H
Ph
Me
Me
Me
Me
H
PMP
i-Pr
Me
H
n-Bu
Acknowledgment. We thank MICINN (CTQ2011-
23620, predoctoral fellowships to M.R. and Y.J., “Juan
de la Cierva” fellowship to A.L.) and Generalitat de
Catalunya (2009SGR 00901) for financial support. A.L.
thanks EU for a Marie Curie Career Integration Grant
(CIG).
Finally, we addressed the preparation of TMNBD
PausonꢀKhand adducts in enantiopure form to further
enhance the synthetic potential of this technology.
Our research group has a long-standing experience in
ꢀ
(14) (a) Reves, M.; Riera, A.; Verdaguer, X. Eur. J. Inorg. Chem. 2009,
Supporting Information Available. Experimental pro-
cedures, spectral and analytical data for all new com-
pounds. Thermogravimetric analysis of 9a and 10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
4446–4453. (b) Ferrer, C.; Riera, A.; Verdaguer, X. Organometallics 2009,
28, 4571–4576. (c) Reves, M.; Achard, T.; Sola, J.; Riera, A.; Verdaguer, X.
J. Org. Chem. 2008, 73, 7080–7087. (d) Sola, J.; Reves, M.; Riera, A.;
Verdaguer, X. Angew. Chem., Int. Ed. 2007, 46, 5020–5023. (e) Verdaguer,
ꢁ
ꢀ
ꢀ
ꢁ
X.; Lledo, A.; Lopez-Mosquera, C.; Maestro, M. A.; Pericas, M. A.; Riera,
ꢁ
A. J. Org. Chem. 2004, 69, 8053–8061. (f) Verdaguer, X.; Pericas, M. A.;
Riera, A.; Maestro, M. A.; Mahia, J. Organometallics 2003, 22, 1868–1877.
(g) Verdaguer, X.; Moyano, A.; Pericas, M. A.; Riera, A.; Maestro, M. A.;
ꢁ
Mahia, J. J. Am. Chem. Soc. 2000, 122, 10242–10243.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3537