Silver-catalyzed cycloisomerization of 1,n-allenynamides

Article abstract of DOI:10.1021/ol201041h

A variety of allenynamides can undergo cycloisomerization reactions in the presence of silver triflate thus leading to the formation of N-containing heterocycles incorporating cross-conjugated trienes. Access to new dienic 4-piperidinone and azepane motifs was achieved. An extension to one-pot tandem sequences involving silver-catalyzed cycloisomerization/Diels-Alder reaction was also examined.

Full text of DOI:10.1021/ol201041h

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2952–2955
Silver-Catalyzed Cycloisomerization of
1,n-Allenynamides
Pierre Garcia,† Youssef Harrak,† Lisa Diab,† Pierre Cordier,† Cyril Ollivier,†
Vincent Gandon,‡ Max Malacria,*,† Louis Fensterbank,*,† and Corinne Aubert*,†
ꢀ
ꢀ
UPMC Univ Paris 06, Sorbonne Universites, Institut Parisien de Chimie Moleculaire
(UMR CNRS 7201),4 place Jussieu, C. 229, 75005 Paris, France, and Univ Paris-Sud,
UMR CNRS 8182, 91405 Orsay, France
max.malacria@upmc.fr; louis.fensterbank@upmc.fr; corinne.aubert@upmc.fr
Received April 20, 2011
ABSTRACT
A variety of allenynamides can undergo cycloisomerization reactions in the presence of silver triflate thus leading to the formation of N-containing
heterocycles incorporating cross-conjugated trienes. Access to new dienic 4-piperidinone and azepane motifs was achieved. An extension to one-
pot tandem sequences involving silver-catalyzed cycloisomerization/DielsꢀAlder reaction was also examined.
Over the past decade, remarkable advances have been
made in the field of ynamide chemistry. Numerous studies
have illustrated the versatility of such a function in a range
of reactions1 featuring radical cascades, cycloadditions,
ring closure metathesis, intramolecular carbopalladations,
and cycloisomerization2 transformations providing a di-
verse array of novel N-heterocyclic core structures for the
synthesis of potential pharmacophores. For instance, in
2004, we showed that the PtCl2-catalyzed ene-ynamide
cycloisomerization can lead to original aza-1,3-dienes or
aza-bicyclo compounds.2a
In this context, we decided to study the behavior of
allenynamides in the presence of π-acid transition metals
(MT) suchascopper(II), silver(I), platinum(II), and gold(I)
salts. Considering that under π-acid catalysis allenynes
react usually through initial triple bond activation,3 we
anticipated that the inherent polarization of the ynamide
triple bond should allow a strong electrophilic activation
by coordination of the metal and then trigger a nucleo-
philic attack from the allenic part to generate unusual
reactive unsaturated piperidine allylic cation intermediates
of type A (Scheme 1). The latter should evolve differently
† UPMC Univ Paris 06.
‡ Univ Paris-Sud.
(1) (a) For recent reviews on ynamide chemistry, see: (a) DeKorver,
K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Shi, Z.; Zhang, Y.; Hsung, R. P.
Chem. Rev. 2010, 110, 5064. (b) Evano, G.; Coste, A.; Jouvin, K. Angew.
Chem., Int. Ed. 2010, 49, 2840.
(3) For a detailed review on transition-metal-catalyzed cycloisome-
rization of allenynes involving alkyne or allene activation, see: Aubert,
C.; Fensterbank, L.; Garcia, P.; Malacria, M.; Simonneau, A. Chem.
Rev. 2011, 111, 1954. For selected works of our group, see: (a) Cadran,
(2) (a) Marion, F.; Coulomb, J.; Courillon, C.; Fensterbank, L.;
Malacria, M. Org. Lett. 2004, 6, 1509. (b) Marion, F.; Coulomb, J.;
Servais, A.; Courillon, C.; Fensterbank, L.; Malacria, M. Tetrahedron
2006, 62, 3856. (c) Zhang, Y.; Hsung, R. P.; Zhang, X.; Huang, J.; Slater,
B. W.; Davis, A. Org. Lett. 2005, 7, 1047. (d) Buzas, A.; Gagosz, F. Org.
Lett. 2006, 8, 515. (e) Poloukhtine, A.; Popik, V. V. J. Am. Chem. Soc.
2007, 129, 12062. (f) Buzas, A.; Istrate, F.; Gagosz, F. Tetrahedron 2009,
65, 1889. (g) Hashmi, A. S.; Salathie, R.; Frey, W. Synlett 2007, 11, 1763.
(h) Istrate, F. M.; Buzas, A. K.; Jurberg, I. D.; Odabachian, Y.; Gagosz,
F. Org. Lett. 2008, 10, 925. (i) Lin, G.-Y.; Li, C.-W.; Hung, S.-H.; Liu,
R.-S. Org. Lett. 2008, 10, 5059. (j) Hashmi, A. S.; Rudolph, M.; Bats, J.;
Frey, W.; Rominger, F.; Oeser, T. Chem.;Eur. J. 2008, 14, 6672. (k)
Yao, P.-Y.; Zhang, Y.; Hsung, R.; Zhao, K. Org. Lett. 2008, 10, 4275. (l)
Dooleweerdt, K.; Ruhland, T.; Skrydstrup, T. Org. Lett. 2009, 11, 221.
(m) Couty, S.; Meyer, C.; Cossy, J. Angew. Chem., Int. Ed. 2006, 45,
6726. (n) Couty, S.; Meyer, C.; Cossy, J. Tetrahedron 2009, 65, 1809.
ꢀ
N.; Cariou, K.; Herve, G.; Aubert, C.; Fensterbank, L.; Malacria, M.;
Marco-Contelles, J. J. Am. Chem. Soc. 2004, 126, 3408. (b) Zriba, R.;
Gandon, V.; Aubert, C.; Fensterbank, L.; Malacria, M. Chem.;Eur. J.
2008, 14, 1482.
(4) For selected recent works on thermal [2 þ 2] intramolecular
isomerization of allenynes, see: (a) Cao, H.; Van Ornum, S. G.;
Deschamps, J.; Flippen-Anderson, J.; Laib, F.; Cook, J. M. J. Am.
Chem. Soc. 2005, 127, 933. (b) Brummond, K. M.; Chen, D. Org. Lett.
2005, 7, 3473. (c) Mukai, C.; Hara, Y.; Miyashita, Y.; Inagaki, F. J. Org.
Chem. 2007, 72, 4454. (d) Jiang, X.; Ma, S. Tetrahedron 2007, 63, 7589.
(e) Ohno, H.; Mizutani, T.; Kadoh, Y.; Aso, A.; Miyamura, K.; Fujii,
N.; Tanaka, T. J. Org. Chem. 2007, 72, 4378. (f) Buisine, O.; Gandon, V.;
Fensterbank, L.; Aubert, C.; Malacria, M. Synlett 2008, 751. (g) Alcaide,
B.; Almendros, P.; Aragoncillo, C. Chem. Soc. Rev. 2010, 39, 783.
r
10.1021/ol201041h
Published on Web 05/02/2011
2011 American Chemical Society

for the cycloisomerization6 of 1a. Total conversion was
achieved with AgOTf after 24 h in dichloromethane at
25°C and furnished2ain61% isolated yield (Table 1, entry
6). Increasing the reaction temperature significantly re-
duced the reaction time but without improving the yield.
Interestingly, the reaction can proceed with cheaper salts
like Cu(OTf)2, albeit in lower yield.
Scheme 1. Hypothesis on Reactivity of Allenynamides towards
π-Acid Transition Metals (MT)
Table 2. Influence of the Ynamide Substitution
according to the substitution pattern of both ynamide and
allene partners.
We began our investigations with the 1,6-allenynamide
1a containing a silylated ynamide (R1 = TMS) and a
trisubstituted allene (R2 = H, R3 = R4 = Me). Control
experiments confirmed that no reaction occurred under
metal-freeconditions.4 Indeed, thermolysisof1afor24h at
reflux in toluene resulted in a quantitative recovery of the
starting material. Based on previous studies showing that
allenynes can be cycloisomerized in the presence of plati-
num and gold salts,3 we first selected PtCl2 as well as AuCl
as catalysts which rapidly proved to be inefficient (Table 1,
Table 1. Screening of Metal Salt Catalysts
temp
time
(h)
conv
(%)
yield
(%)
entry
catalyst
(°C)
1
2
3
4
5
6
7
8
9
PtCl2
AuCl
reflux
reflux
reflux
reflux
reflux
25
48
24
24
24
6
0
0
0
0
AuClPPh3
AuClPPh3/AgSbF6
AgSbF6
80
40
32
52
61
60
52
49
75
100
100
100
100
100
AgOTf
24
8
AgOTf
reflux
25
With these optimized reaction conditions in hand, we
then examined the substrate scope by looking first at the
influence of the substitution at the ynamide terminus.
Unsubstituted and methyl-substituted ynamides 1b and
1c both gave a complex mixture of products (Table 2).
While TMS compound 1arequired a long reaction time (24
h, see Table 1), an acceleration of the cycloisomerization
process was evident when starting from allenynamide 1d
bearing a phenyl group. Indeed, within 2 h, a complete
conversion toward the corresponding Z-Alder-ene pro-
duct 2d was observed. The introduction of a para-methoxy
substituent to the aryl group (PMP) slightly improved the
yield for a similar reaction time. Interestingly, performing
the reaction with the ester-substituted substrate 1f led to
Cu(OTf)2
Cu(OTf)2
2
reflux
0.33
entries 1ꢀ2). Conversely, the choice of the phosphine-
coordinated gold complex, AuClPPh3, in the presence or
not of AgSbF6 allowed access to the Alder-ene type
cycloadduct 2a showing a cross-conjugated triene moiety
as a single diastereomer but in moderate yield and with
incomplete conversion after 24 h under reflux in dichlor-
omethane (Table 1, entries 3ꢀ4). The uncommon tetrahy-
dromethylene vinylpyridine structure and the Z-config-
uration of the exocyclic double bond were both confirmed
by X-ray analysis.5 Yet, among the π-acid transition
metalstested, silversaltswerefoundtobe the mostefficient
(6) (a) Silver in Organic Chemistry; Harmata, M., Eds.; John Wiley &
Sons Inc.: 2010. For a recent review on silver-catalyzed cycloisomerization
reactions, see: Belmont, P.; Parker, E. Eur. J. Org. Chem. 2009, 6075.
(5) Crystallographic data deposited with the Cambridge Crystallo-
graphic Data Centre, Cambridge, UK (Reference CCDC 794305).
Org. Lett., Vol. 13, No. 11, 2011
2953

the formation of the unexpected bicyclic lactone 3f in an
excellent yield after 2 h. The same feature was observed
with propargylic alcohol moieties. The corresponding
2,3,5,7-tetrahydro-1H-pyrano[4,3-b]pyridine type com-
pounds resulting from a tandem cycloisomerization and
subsequent hydroxycyclization starting from 1g and 1h
were isolated in moderate to good yields although a
prolonged reaction time was required. Noteworthy, ter-
tiary alcohol 1i cyclized to 3i accompanied with 4 resulting
from a dehydrative cation-ene cyclization of 1i.
furnished the expected Alder-ene type compound 2a. By
contrast, a simple methyl substitution at the internal
position generated the isomeric cross-conjugated triene
6k8 exhibiting an exocyclic 1,2-diene moiety potentially
amenable to DielsꢀAlder reactions as shown later. Sub-
stitution at both extremities provided contrasted results.
Indeed, permethylated allene 1l subjected to the same
reaction conditions gave a 5.3:1 mixture of isomeric
trienes 2l and 6l in favor of the Alder-ene type product.
By switching the internal group from methyl to phenyl,
triene 2m was formed in equal amounts along with the
tricyclic pyridindene derivative 7 arising from a tandem
Alder-ene type cycloisomerization/FriedelꢀCrafts process.9
1,3-Disubstitution at both internal and terminal posi-
tions provided exclusively compounds of type 6 whatever
the nature of R3 substituents (R3 = Me orR3 = Ph). TheZ,
Z-configuration of 6n has been established by NOE experi-
ments. When R3 = Ph, both silylated and desilylated10
adducts were formed in a 3.3:1 ratio.11 Interestingly, shorter
reaction times from 10 min to 3 h were observed with all
substrates including a methyl at the internal position.
Table 3. Influence of the Allene Substitution
Scheme 2. Propargyl Acetate Rearrangement/Cycloisomeriza-
tion Sequence
Based on our experience on platinum and gold chem-
istry, one of the most attractive applications would be to
combine, in a one-pot procedure, a silver-catalyzed pro-
pargyl acetate rearrangement to allenylester12 with the
cycloisomerization process. Gratifyingly, treatment of 1p
with 10 mol % of AgOTf in toluene at reflux during 5 h
yielded the corresponding dienic 4-piperidinone system 6p
in 51% yield (Scheme 2).
The next parameter we investigated was the substitu-
tion of the allene function. Both the nature and the
position of substituents proved to influence the cycloi-
somerization process. Thus, the unsubstituted TMS-
allenynamide 1j did not afford any cycloadduct. Instead,
a slow and incomplete conversion to the corresponding
acyclic acetamide 5 took place in dichloromethane at rt
overnight (Table 3, entry 1).7 As seen before, the presence
of a gem-dimethyl group at the external allene carbon
(8) The structure and the Z-configuration of the exocyclic double
bond were both confirmed by X-ray analysis (Reference CCDC 794304).
ꢁ
(9) Lemiere, G.; Gandon, V.; Agenet, N.; Goddard, J.-P.; de Kozak,
A.; Aubert, C.; Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed.
2006, 45, 7596.
(10) Desilylation of the N-tosyl enamide motif presumably proceeds
through a silver triflate activation of the double bond followed by a TMS
cleavage of the intermediate B (Scheme 4).
(11) The Z,Z configuration of 6o has been assigned by analogy with 6n.
(12) For Ag-catalyzed [3,3] rearrangement of propargyl esters, see:
(a) Saucy, G.; Marbet, R.; Lindlar, H.; Isler, O. Helv. Chim. Acta 1959,
42, 1945. (b) Schlossarczyk, H.; Sieber, W.; Hesse, M.; Hansen, H.-J.;
Schmid, H. Helv. Chim. Acta 1973, 56, 875. (c) Oelberg, D. G.; Schiavelli,
M. D. J. Org. Chem. 1977, 42, 1804. (d) Zhao, J.; Hughes, C. O.; Toste,
F. D. J. Am. Chem. Soc. 2006, 128, 7436. (e) Cookson, R. C.; Cramp,
M. C.; Parsons, P. J. Chem. Commun. 1980, 197. (f) Bowden, B.;
Cookson, R. C.; Davis, H. A. J. Chem. Soc., Perkin Trans. 1 1973,
2634. (g) Sromek, A. W.; Kel’in, A. V.; Gevorgyan, V. Angew. Chem.,
Int. Ed. 2004, 43, 2280.
(7) Due to the presence of water, formation of acetamide 5 from
ynamide 1j might take place first by TMS cleavage followed by the
hydrolysis of the terminal ynamide. (a) For deprotection of trimethylsi-
lyl acetylenes catalyzed by silver triflate, see: Orsini, A.; Viterisi, A.;
Bodlenner, A.; Weibel, J.-M.; Pale, P. Tetrahedron Lett. 2005, 46, 2259.
(b) For hydrolysis of ynamide, see: Zhang, X.; Li, H.; You, L.; Tang, Y.;
Hsung, R. Adv. Synth. Catal. 2006, 348, 2437.
2954
Org. Lett., Vol. 13, No. 11, 2011

An extension of the cycloisomerization process to the
formation of seven-membered rings was also envisaged.
Homologation of the carbon chain of 1k to 1q provided
azepane 9, showing a desilylated cross-conjugated triene,
in 58% yield when the reaction was carried out in toluene
at reflux (3 h) (Scheme 3).13
Scheme 4. Proposed Reaction Mechanism
Scheme 3. Application to Azepane Core Synthesis
The formation of the three classes of compounds, type 2,
3 and 6, can be rationalized mechanistically by first
assuming a preliminary activation of the triple bond by
the silver cation which promotes a 6-exo-dig cyclization.
The transient intermediate can evolve along two different
pathways depending on the stability of the allylic carboca-
tion. Starting from terminal gem-disubstitued allenes, path
I appears to be favored. In this case, when the ynamide is
substituted by a nucleophilic alcohol or ester group, the
cationic species A1 can be trapped intramolecularly to
give the corresponding bicyclic compound 3 after proto-
demetalation;14 otherwise a simple elimination/protode-
metalation sequence can occur and furnish compound
(Z)-2. Due to the steric hindrance between R1 and R3/
R4, the enamine double bond undergoes silver-catalyzed
isomerization which justifies its Z configuration.15 When
the allene is substituted at the internal position, path II
involving the formation of intermediate A2 and subse-
quent elimination/protodemetalation/isomerization oper-
ates preferentially to provide compound 6 (Scheme 4).
Finally, we tested the reactivity of trienes of type 6 and 9
toward dienophiles in a one-pot cycloisomerization/
DielsꢀAlder sequence. To our delight, reaction of alleny-
namide 1k in the presence of N-phenyl maleimide and
10 mol % silver triflate furnished tricycle 10 as the result of
the expected tandem process. When performing the reac-
tion in toluene at reflux rather than in CH2Cl2 at rt,
homologous substrate 1q followed the same trends and
reacted with an appreciable 43% yield to form endo-desily-
lated 7,6,5-annulated heterocyclic system 11 (Scheme 5).
Scheme 5. Tandem Cycloisomerization/DielsꢀAlder Reactions
In summary, we have shown that cycloisomerization of
allenynamides can take place in the presence of silver
triflate. This efficient catalytic process provides the forma-
tion of novel isomeric tetrahydro pyridine-based trienes,
4-piperidinone, and also azepane motifs in good to excel-
lent yields depending upon the substitution pattern of the
allene moiety and the length of the sidechain. Remarkably,
formation of trienes in the presence of N-phenyl maleimide
produces polycyclic ring systems via a cycloisomerization/
DielsꢀAlder sequence. There is no doubt that such a
method will be particularly appealing in the context of
the total synthesis of alkaloids. Efforts along these lines are
underway in our laboratory.
(13) Only 6% of cycloadduct were isolated when the reaction was
performed at rt in CH2Cl2.
(14) It is noteworthy that formation of pyridindene derivative 7
follows the same pathway through an intramolecular FriedelꢀCrafts
reaction.
Acknowledgment. We thank UPMC, CNRS, IUF
(M.M., L.F.), and Agence Nationale de la Recherche
(Grant No. ANR-06-BLAN-03-02, “ALLENES”).
(15) For Z/E isomerization of double bond promoted by silver
triflate, see: (a) Goossen, L. J.; Ohlmann, D. M.; Dierker, M. Green
Chem. 2010, 12, 197. (b) Zificsak, C. A.; Mulder, J. A.; Rameshkumar,
C.; Wei, L.-L.; Hsung, R. P. Tetrahedron 2001, 57, 7575. (c) Himbert, G.
In Methoden Der Organischen Chemie (Houben-Weyl); Kropf, H.,
Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart, 1993; p 3267.
(d) Ficini, J. Tetrahedron 1976, 32, 448.
Supporting Information Available. Experimental pro-
cedures, characterization data, X-ray data, and NMR
spectra of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 11, 2011
2955