Palladium-mediated [2+1] cycloaddition of norbornene derivatives with ynamides

Article abstract of DOI:10.1002/adsc.201200903

An efficient palladium-catalyzed [2+1] cycloaddition between ynamides and norbornenes or norbornadienes is reported. Both phosphapalladacycles and palladium/secondary phosphine oxide catalytic systems were found to be competent for the transformation allowing the preparation of aminomethylenecyclopropanes. The reaction showed general applicability to various functionalized bicyclo[2.2.1]hept-2-enes and ynamides. A chiral phosphapalladacycle was tested to carry out this transformation in an enantioselective fashion.

Full text of DOI:10.1002/adsc.201200903

COMMUNICATIONS
DOI: 10.1002/adsc.201200903
Palladium-Mediated [2+1]Cycloaddition of Norbornene
Derivatives with Ynamides
Hervꢀ Clavier,a,* Aymeric Lepronier,a Nathalie Bengobesse-Mintsa,a
David Gatineau,a Hꢀlꢁne Pellissier,a Laurent Giordano,a Alphonse Tenaglia,a
and Gꢀrard Buonoa,*
a
Centrale Marseille, Aix-Marseille Universitꢀ, CNRS, iSm2 UMR 7313, 13397,
E-mail: herve.clavier@univ-amu.fr or gerard.buono@univ-amu.fr
Received: October 9, 2012; Published online: February 1, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200903.
Abstract: An efficient palladium-catalyzed [2+
1]cycloaddition between ynamides and norbornenes
or norbornadienes is reported. Both phosphapalla-
dacycles and palladium/secondary phosphine oxide
catalytic systems were found to be competent for
the transformation allowing the preparation of ami-
nomethylenecyclopropanes. The reaction showed
general applicability to various functionalized
bicycloACHTUNGTRENNUNG[2.2.1]hept-2-enes and ynamides. A chiral
phosphapalladacycle was tested to carry out this
transformation in an enantioselective fashion.
Scheme 1. Main strategies for the preparation of aminome-
thylenecyclopropanes.
Keywords: cycloaddition; cyclopropanes; norbor-
nenes; palladium; phosphorus; ynamides
clopropane A using a palladium-mediated [2+1]cy-
cloaddition between an activated alkene and an yn-
Methylenecyclopropanes (MCPs) are a unique class
of carbocyclic compounds with a strained three-mem-
amide partner.[9]
ACHTUNGTRENNUNG
As a part of our research program dedicated to the
bered ring and an exo methylene moiety.[1] In addition transition metal-promoted formations of carbocy-
to being versatile synthons for a myriad of organic cles,[10] it was discovered that catalyst 2a promoted
transformations,[2] they are found in natural prod- the hydroalkynation of alkyl- and aryl-substituted al-
ucts.[3] They have also been incorporated in biological- kynes to norbornadienes 1 to afford coupling products
ly active substances such as nucleosides analogues 3 (Scheme 2).[11] On the other hand, with the same re-
that are established as powerful antiviral agents actants, the catalytic behaviour of palladium(II) com-
against a broad range of viruses.[4] In these drugs, the plexes prepared from secondary phosphine oxides
aminomethylenecyclopropane moiety A seems to play (SPO)[12] was found to be different since MCP deriva-
a crucial role. To date only few methods allow the tives 4 were achieved.[13] These results prompted us to
preparation of such a pattern.[5] As depicted in evaluate both palladium-based catalytic systems for
Scheme 1, the synthesis of aminomethylenecyclopro- the preparation of aminomethylenecyclopropane A.
panes has been achieved from the cyclopropanecar-
We started examining the benchmark substrates
baldehydes by aminal formation and subsequent rear- norbornadiene (nbd) 1a and ynesulfonamide 5a and
rangement into A by heating.[6] For the synthesis of found that the formation of aminomethylenecyclopro-
nucleoside analogues, Somekawa and Zemlicka inde- pane 6a could be achieved by using both catalytic sys-
pendently reported the use of 1-bromo-1-(bromome- tems (Table 1). Nonetheless, the combination of
thyl)cyclopropane for an N-alkylation, followed by an PdACTHNUTRGENUN(G OAc)2 (5 mol%) with SPOs was found to be less
in situ b-elimination.[7,8] Herein, we report an alterna- efficient and exclusively limited to the use of
tive approach for the synthesis of aminomethylenecy- PhCyP(O)H as SPO (entries 4–6). The screening of
Adv. Synth. Catal. 2013, 355, 403 – 408
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
403

Hervꢀ Clavier et al.
COMMUNICATIONS
Figure 1. Ball-and-stick representation of by-product 7a
(most of the hydrogens have been omitted for clarity).
1
while it was detected as traces by H NMR from the
crude reaction mixture using catalysts 2a and 2b (en-
tries 1–3). The structure of compound 7a was unam-
biguously determined by X-ray analysis (Figure 1). Its
formation results from the valence isomerization
process[13a,14] of 6a, which seems to be favoured by
electron-rich phosphapalladacycle 2c triggering the
splitting of the distal bond of the MCP subunit. Reac-
tion time investigations showed that, at 258C, 24 h
were required for consumption of ynamide 5a; the
mass balance accounting for degradation (entries 11
and 12). However, a slight thermal activation to 40
and 608C led to a considerable decrease in reaction
time (entries 13 and 14).
Scheme 2. Palladium-mediated hydroalkynation versus [2+
1]cycloaddition of norbornenes with alkynes.
Table 1. Palladium-catalyzed [2+1]cycloaddition of norbor-
nadiene 1a with ynamide 5a: effect of reaction parameters.[a]
Having established the optimal reaction conditions,
we further investigated the reaction scope with
a range of bicycloACTHNUTRGNEUNG[2.2.1]hepta-2,5-diene derivatives
(Table 2). 7-Oxygen substituted norbornadienes were
tolerated but led to moderate yields or longer reac-
tion times (entries 2 and 3) compared to electron-rich
substituted equivalents (entries 4 and 5). Other bicy-
clic substrates were converted in the corresponding
tricyclo[3.2.1.02,4]oct-6-enes 6, except for 1,4-dihydro-
1,4-epoxynaphthalene 1i which gave rise to a complex
mixture (entry 9). Despite extended heating at 608C,
[2+1]cycloaddition on the less reactive 1,4-dihydro-
1,4-ethanonaphthalene 1j failed (entry 10).[15] In all
the cases studied, reaction occurred on the less hin-
dered double bond.
In the light of these results, we decided to examine
the scope of the cycloaddition further by testing
bicycloACTHNUTRGENUG[N 2.2.1]hept-2-ene derivatives 8 (Table 3). Al-
though the reactivity was found to be lower, we were
pleased to isolate the cycloadduct 9a arising from the
reaction of norbornene 8a in a moderate yield (65%,
entry 1). The treatment of substrates 8b and 8c with
ynamide 5a and phosphapalladacycle 2a afforded the
expected cycloadducts but with a low diastereoselec-
tivity (entries 2 and 3). Whereas the diaza compound
[a]
Reaction conditions: ynamide 5a (0.5 mmol), nbd 1a
(1 mmol), 2a (2.5–5 mol% [Pd]), DCE (3 mL, 0.17M),
258C.
[b]
18% of product 7a were also isolated.
several phosphapalladacycles 2 demonstrated that the 8f was well tolerated (entry 6), the reaction of maleic
use of 2c as catalyst proceeded with the formation of anhydride derivative 8d and substituted oxanorbor-
by-product 7a in 18% yield in addition to 48% of 6a, nene 8g required heating to 608C to provide the cor-
404
asc.wiley-vch.de
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 403 – 408

Palladium-Mediated [2+1]Cycloaddition of Norbornene Derivatives with Ynamides
Table 2.
[2+1]Cycloaddition with a variety of norbornadiene
Table 3. ACTHNGUTERNN[UG 2+1]Cycloaddition with a variety of norbornene
derivatives and ynamide 5a.[a]
derivatives 8 and ynamide 5a.[a]
[a]
Reaction conditions: ynamide 5a (0.5 mmol), norbornene
8 (0.6 mmol), 2a (2.5 mol%), DCE (3 mL, 0.17M), 408C.
Reaction carried out at 608C.
[b]
compound 10e, isolated in good yield, was used to
confirm the aminomethylenecyclopropane structure
by single crystal X-ray determination (Figure 2).
When the reaction was performed with the vinylogous
indole-containing ynamide 5h, the anticipated product
was obtained, but as an inseparable mixture with an
unidentified compound. Carrying out the reaction
[a]
Reaction conditions: ynamide 5a (0.5 mmol), nbd
1 (1 mmol), 2a (2.5 mol%), DCE (3 mL, 0.17M), 408C.
Reaction carried out at 608C.
[b]
responding products in low to moderate yields (en-
tries 4 and 7). Under the same reaction conditions the
electron-poor tetracyano compound 8e was found to
be inert (entry 5).
We then examined the transformation scope with
respect to the ynamide partner (Table 4). In addition
to the N-substituted phenylynamide 5a, the alkyl ana-
logues 5b and 5c gave rise to the corresponding ad-
ducts with moderate yields (entries 1 and 2). On the
other hand, allyl counterpart 5d led to the formation
of a complex mixture (entry 3). While ynesulfon-
ACHTUNGTRENNUNGamides were found to be relatively good partners for
the [2+1]cycloaddition (entries 4 and 5), an ynecar-
bamate, such as 5g, gave the corresponding cycload-
Figure 2. Ball-and-stick representation of the cycloadduct
duct with a moderate yield (entry 6). The para-nosyl 10e (hydrogen atoms have been omitted for clarity).
Adv. Synth. Catal. 2013, 355, 403 – 408
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
405

Hervꢀ Clavier et al.
COMMUNICATIONS
Table 4. ACHTUNGTRENNUNG
[2+1]Cycloaddition with a variety of ynamides 5.[a]
Scheme 3. Asymmetric [2+1]cycloaddition using an optical-
ly active phosphapalladacycle.
(Scheme 3). Whereas the reaction proceeded smooth-
ly at room temperature, giving 80% yield after 4 h,
the chiral induction observed was modest but promis-
ing for further development considering that no opti-
mization of catalyst design has been done.
In modern organic chemistry, there is always the
need for new, efficient, and selective methodologies
for the synthesis of complex molecules. Herein, we
have reported a new palladium-catalyzed intermolec-
ular [2+1]cycloaddition of bicycloACTHNUTRGNEUNG[2.2.1]hept-2-ene
derivatives with ynamides giving rise to aminomethy-
lenecyclopropane A. We have shown that either phos-
phapalladacycles or the PdACHTNUGTRENUNG(OAc)2/PhCyP(O)H com-
bination are able to promote this transformation. Op-
timal catalytic conditions and key parameters have
been identified. Thus, excellent yields have been
reached, of up to 88%, for variously substituted yn-
AHCTUNGTREGaNNUN mides and norbornenes. Preliminary results to per-
form this transformation in an enantioselective fash-
ion are encouraging and further developments are un-
derway in our laboratory as also is the study of mech-
anistic considerations.
[a]
Reaction conditions: ynamide 5 (0.5 mmol), norborna-
diene 1 (1 mmol), 2a (2.5 mol%), DCE (3 mL, 0.17M),
408C. Ns =4-nitrobenzenesulfonyl.
[b]
Reaction performed with 5 mol% of Pd
[PhCyP(O)H]2 instead of 2a.
ACHTUNGERTN(NUNG OAc)2/
ACHTUNGTRENNUNG
Experimental Section
with the PdACHTUNGTRENNUNG(OAc)2/PhCyP(O)H system turned out to
be cleaner since only 10h was isolated in the satisfac-
tory yield of 77% (entry 7).
General Procedure for the Palladium-Mediated
[2+1]Cycloaddition
Due to the E/Z geometry of the carbon-carbon
double bond in the methylenecyclopropane moiety,
A Schlenk flask, under nitrogen, was charged with Herr-
mann–Beller catalyst (11.2 mg, 0.0125 mmol, 0.05 equiv. in
[2+1]cycloadducts showed a peculiar chirality called Pd.), and DCE (1 mL). Successively, were added norborna-
diene derivative (1 mmol, 2 equiv.) or norbornene derivative
(0.6 mmol, 1.2 equiv.), ynamide (0.5 mmol) and DCE
(1 mL). The resulting mixture was stirred at the stipulated
temperature for the indicated time. Volatiles were removed
and the crude mixture was purified by column chromatogra-
phy on silica gel using a Combiflash Companion [4 g SiO2
45 mm; PE/AcOEt 95:5 (5 min) gradient].
The Supporting Information contains the experimental
details, product characterization and NMR spectra. The CIF
files of carbocycles 7a and 10e have also been deposited as
geometrical enantiomorphic isomerism (cis-trans
enantiomerism or Z-E enantiomerism).[16,17] We had
previously demonstrated that the asymmetric [2+
1]cycloaddition between alkyne and norbornene
could be achieved using chiral secondary phosphine
oxides as enantioselectivity inductors with enantio-
meric excesses of up to 95% ee.[18] Since the synthesis
of enantiopure phosphapalladacycle 11 has been re-
cently reported,[19] we decided to test this catalyst in
an asymmetric [2+1]cycloaddition with ynamide 5a CCDC 870844 and CCDC 870845. These data can be ob-
406
asc.wiley-vch.de
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 403 – 408

Palladium-Mediated [2+1]Cycloaddition of Norbornene Derivatives with Ynamides
tained free of charge from The Cambridge Crystallographic
[7] a) C. Cheng, T. Shimo, K. Somekawa, M. Kawaminami,
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Tetrahedron Lett. 1997, 38, 9005–9008; b) C. Cheng, T.
Shimo, K. Somekawa, M. Baba, Tetrahedron 1998, 54,
2031–2040; c) Y.-L. Qiu, M. B. Ksebati, R. G. Ptak,
B. Y. Fan, J. M. Breitenbach, J.-S. Lin, Y.-C. Cheng,
E. R. Kern, J. C. Drach, J. Zemlicka, J. Med. Chem.
1998, 41, 10–23; d) Y.-L. Qiu, J. Zemlicka, Synthesis
1998, 1447–1452.
Acknowledgements
We thank the CNRS and the ANR (program BLAN07-
1 190839) for funding and the Ministꢀre de l’enseignement
supꢁrieur et de la recherche (A.L. and D.G. Ph.D. grants).
We are grateful to Christophe Chendo and Dr. Valꢁrie Mon-
nier for mass spectrometry analyses and Dr. Michel Giorgi
for X-ray determination (Spectropole, Fꢁdꢁration des Scien-
ces Chimiques de Marseille). We also thank Dr. Nicolas Van-
thuyne for chiral HPLC separation.
[8] M. Limbach, A. Lygin, M. Es-Sayed, A. de Meijere,
Eur. J. Org. Chem. 2009, 1357–1364.
[9] For comprehensive reviews, see: a) G. Evano, A. Coste,
K. Jouvin, Angew. Chem. 2010, 122, 2902–2921; Angew.
Chem. Int. Ed. 2010, 49, 2840–2859; b) K. A. DeKorver,
H. Li, A. G. Lohse, R. Hayashi, Z. Lu, Y. Zhang, R. P.
Hsung, Chem. Rev. 2010, 110, 5064–5106.
[10] a) H. Clavier, K. Le Jeune, I. De Riggi, A. Tenaglia, G.
Buono, Org. Lett. 2011, 13, 308–311; b) T. Achard, A.
Lepronier, Y. Gimbert, H. Clavier, L. Giordano, A. Te-
naglia, G. Buono, Angew. Chem. 2011, 123, 3614–3618;
Angew. Chem. Int. Ed. 2011, 50, 3552–3556; c) A. Tena-
glia, S. Marc, L. Giordano, I. De Riggi, Angew. Chem.
2011, 123, 9228–9231; Angew. Chem. Int. Ed. 2011, 50,
9062–9065; d) H. Clavier, L. Giordano, A. Tenaglia,
Angew. Chem. 2012, 124, 8776–8779; Angew. Chem.
Int. Ed. 2012, 51, 8648–8651.
[11] a) A. Tenaglia, L. Giordano, G. Buono, Org. Lett. 2006,
8, 4315–4318; see also: b) A. Tenaglia, K. Le Jeune, L.
Giordano, G. Buono, Org. Lett. 2011, 13, 636–639.
[12] For reviews on secondary phosphine oxides, see: a) L.
Ackermann, Synthesis 2006, 1557–1571; b) L. Acker-
mann, R. Born, J. H. Spatz, A. Althammer, C. J.
Gschrei, Pure Appl. Chem. 2006, 78, 209–214; c) L. Ac-
kermann, Synlett 2007, 507–526; d) L. Ackermann, in:
Phosphorus Ligands in Asymmetric Catalysis, Vol. 2,
(Ed.: A. Bçrner), Wiley-VCH, Weinheim, 2008,
pp 831–847; e) T. M. Shaikh, C.-M. Weng, F.-E. Hong,
Coord. Chem. Rev. 2012, 256, 771–803.
References
[1] For reviews on the synthesis of MCPs, see: a) A.
Brandi, A. Goti, Chem. Rev. 1998, 98, 589–635; b) G.
Audran, H. Pellissier, Adv. Synth. Catal. 2010, 352,
575–608.
[2] For reviews on synthetic applications of MPCs, see:
a) A. Brandi, S. Cicchi, M. Cordero, A. Goti, Chem.
Rev. 2003, 103, 1213–1269; b) M. Rubin, M. Rubina, V.
Gevorgyan, Chem. Rev. 2007, 107, 3117–3179; c) H.
Pellissier, Tetrahedron 2010, 66, 8341–8375; d) A.
Ahmad, I. Marek, Chem. Eur. J. 2010, 16, 9712–9721;
for recent selected examples, see: e) F. Lꢃpez, A. Del-
gado, J. R. Rodrꢄguez, L. Castedo, J. L. MascareÇas, J.
Am. Chem. Soc. 2004, 126, 10262–10263; f) M. Gulꢄas,
Juan Durꢅn, F. Lꢃpez, L. Castedo, J. L. MascareÇas, J.
Am. Chem. Soc. 2007, 129, 11026–11027; g) J. Terao, M.
Tomita, S. P. Singh, N. Kambe, Angew. Chem. 2010,
122, 148–151; Angew. Chem. Int. Ed. 2010, 49, 144–147;
h) S. Saito, K. Maeda, R. Yamasaki, T. Kitamura, M.
Nakagawa, K. Kato, I. Azumaya, H. Masu, Angew.
Chem. 2010, 122, 1874–1877; Angew. Chem. Int. Ed.
2010, 49, 1830–1833; i) T. Inami, T. Kurahashi, S. Mat-
subara, Chem. Commun. 2011, 47, 9711–9713; j) A. P.
Evans, P. A. Inglesby, J. Am. Chem. Soc. 2012, 134,
3635–3638.
[3] Selected examples: a) J. R. Evans, E. J. Napier, R. A.
Fletton, J. Antibiot. 1978, 31, 952–958; b) T. Nemoto,
M. Ojika, Y. Sakagami, Tetrahedron Lett. 1997, 38,
5667–5670; c) T. Nemoto, G. Yoshino, M. Ojika, Y. Sa-
kagami, Tetrahedron 1997, 53, 16699–16710.
[4] a) J. Zemlicka, in: Recent Advances in Nucleosides:
Chemistry and Chemotherapy, (Ed.: C. K. Chu), Elsevi-
er Science, Amsterdam, 2002, pp 327–357; b) J. Zem-
licka, in: Advances in Antiviral Drug Design, (Ed.: E.
De Clercq), Elsevier, Amsterdam, 2007, pp 113–167.
[5] For relatively unconventional examples, see: a) J.
Montgomery, G. M. Wieber, L. S. Hegedus, J. Am.
Chem. Soc. 1990, 112, 6255–6263; b) A. T. McNichols,
P. J. Stang, D. M. Addington, Tetrahedron Lett. 1994,
35, 437–440; c) V. Nair, A. T. Biju, S. C. Mathew, Syn-
thesis 2007, 697–704.
[13] a) J. Bigeault, L. Giordano, G. Buono, Angew. Chem.
2005, 117, 4831–4835; Angew. Chem. Int. Ed. 2005, 44,
4753–4757; b) J. Bigeault, L. Giordano, I. De Riggi, Y.
Gimbert, G. Buono, Org. Lett. 2007, 9, 3567–3570; c) J.
Bigeault, I. De Riggi, Y. Gimbert, L. Giordano, G.
Buono, Synlett 2008, 1071–1075.
[14] The tricyclo[3.2.1.02,4]oct-6-ene structure is known to
rearrange into tetracyclo[3.3.0.02,8.04,6]octane following
either a photoinduced process, see: a) H. Prinzbach, W.
Eberbach, G. von Veh, Angew. Chem. 1965, 77, 454–
455; Angew. Chem. Int. Ed. Engl. 1965, 4, 436–437;
a thermal activation, see: b) D. Aue, H. M. J. Meshish-
nek, J. Am. Chem. Soc. 1977, 99, 223–231; c) J. Krebs,
D. Guggisberg, U. Stꢆmpfli, M. Neuenschwander, Helv.
Chim. Acta 1986, 69, 835–848; or a rhodium-promoted
pathway, see: d) H. C. Volger, H. Hogeveen, M. M. P.
Gaasbeek, J. Am. Chem. Soc. 1969, 91, 218–219; e) D.
Kaufmann, H.-H. Fick, O. Schallner, W. Spielmann, L.-
M. Meyer, P. Gçlitz, A. De Meijere, Chem. Ber. 1983,
116, 587–609.
[15] a) P. R. Khoury, J. D. Goddard, W. Tam, Tetrahedron
2004, 60, 8103–8112; b) M. Balci, M. Gꢇney, A. Dastan,
A. Azizoglu, J. Org. Chem. 2007, 72, 4756–4762.
[6] A. G. Cook, S. B. Herscher, D. J. Schultz, J. A. Burke, J.
[16] a) E. L. Eliel, S. H. Wilen, L. N. Mander, in: Stereo-
Org. Chem. 1970, 35, 1550–1554.
chemistry of Organic Compounds, Wiley, New York,
Adv. Synth. Catal. 2013, 355, 403 – 408
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
407

Hervꢀ Clavier et al.
COMMUNICATIONS
1994, pp 1137–1138; b) R. E. Lyle, G. G. Lyle, J. Org.
Chem. 1957, 22, 856; c) R. E. Lyle, G. G. Lyle, J. Org.
Chem. 1959, 24, 1679–1684; d) G. G. Lyle, E. T. Pelosi,
J. Am. Chem. Soc. 1966, 88, 5976–5979.
Bogdan, C. Roussel, I. Grosu, Chirality 2011, 23, 167–
171.
[18] D. Gatineau, D. Moraleda, J.-V. Naubron, T. Bꢇrgi, L.
Giordano, G. Buono, Tetrahedron: Asymmetry 2009,
20, 1912–1917.
[19] D. Gatineau, L. Giordano, G. Buono, J. Am. Chem.
Soc. 2011, 133, 10728–10731.
[17] For recent examples, see: a) S. Chandrasekhar, S. K.
Gorla, Tetrahedron: Asymmetry 2006, 17, 92–98; b) C.
Cismas, N. Vanthuyne, H. Rispaud; R. A. Varga, E.
408
asc.wiley-vch.de
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 403 – 408