Keteniminium ion-initiated cascade cationic polycyclization

Article abstract of DOI:10.1021/ja504818p

A novel and efficient keteniminium-initiated cationic polycyclization is reported. This reaction, which only requires triflic acid or bistriflimide as promoters, affords a straightforward entry to polycyclic nitrogen heterocycles possessing up to three co

Full text of DOI:10.1021/ja504818p

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Communication
Keteniminium Ion-Initiated Cascade Cationic Polycyclization
Cédric Theunissen, Benoit Metayer, Nicolas Henry, Guillaume Compain, Jerome
Marrot, Agnès Martin-Mingot, Sébastien Thibaudeau, and Gwilherm Evano
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 16 Jun 2014
Downloaded from http://pubs.acs.org on June 30, 2014
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Keteniminium Ion-Initiated Cascade Cationic Polycyclization
Cédric Theunissen,a Benoît Métayer,b Nicolas Henry,a Guillaume Compain,b Jérome Marrot,c Agnès
Martin-Mingot,b Sébastien Thibaudeaub,* and Gwilherm Evanoa,*
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a Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Université Libre de Bruxelles, Avenue
F. D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium.
b Superacid group in "Organic Synthesis" team, Université de Poitiers, CNRS UMR 7285 IC2MP, Bât. B28, 4 rue Michel
Brunet, TSA 51106, 86073 Poitiers Cedex 09, France.
c Institut Lavoisier de Versailles, UMR CNRS 8180, Université de Versailles Saint-Quentin en Yvelines, 45, avenue des
Etats-Unis, 78035 Versailles Cedex, France.
Supporting Information Placeholder
towards the use of other acids, used in excess, as promoters to
avoid the use of HF: results of these studies are shown in Figure
1. While no reaction was observed with mild acids such as acetic
acid or trifluoroethanol, the use of stronger acids such as sulfuric
or hydrochloric acids did not allow for a clean reaction due to
competitive hydrolysis or hydrochlorination7b yielding to 3a or
4aCl, respectively, and to extensive degradation. A clean and fast
reaction was observed when switching to triflic acid, which
smoothly promoted the polycyclization. The best conditions were
found to rely on an excess of this reagent in order to avoid the
competitive formation of the hardly separable amide 3a which
was still formed when using 0.1 to 5 equivalents of TfOH. We
envisioned that the formal hydrolysis of the ynamide, which most
certainly results of trapping of the intermediate keteniminium ion
ABSTRACT: A novel and efficient keteniminium-initiated
cationic polycyclization is reported. This reaction, which only
requires triflic acid or bistriflimide as promoters, affords a
straightforward entry to polycyclic nitrogen heterocycles pos-
sessing up to three contiguous stereocenters and seven fused
cycles. These complex, polycyclic molecules can be obtained in a
single operation from readily available ynamides which were
shown to be remarkable building blocks for multiple, consecutive
cationic transformations.
The development of efficient and straightforward methods for
the synthesis of complex, polycyclic molecular scaffolds in a
single operation is fueled by the strong and growing demand for
such processes in most areas of chemical synthesis. In this con-
text, cationic polycyclization reactions, mostly inspired by the
biosynthesis of natural products such as steroids and alkaloids,1
have emerged as valuable tools for the generation of diverse
polycyclic skeletons with unmatched efficiency. Among the cati-
onic intermediates involved in such reactions, carbocations2 and
iminium ions3 are the most frequently encountered, the cyclization
of polyprenoids and sequences involving multiple Mannich reac-
tions being iconic processes for the construction of polycyclic
structures from remarkably simple starting materials.4 Surprising-
ly, and to the best of our knowledge, keteniminium ions have
never been used in polycyclization reactions despite the possibil-
ity to use these highly reactive intermediates as strong electro-
philic anchors for multiple consecutive cationic transformations,
which might provide a straightforward access to complex hetero-
cycles.5-7 Herein, we disclose an unprecedented keteniminium
ion-initiated cascade polycyclization based on a Brønsted acid-
mediated reaction from suitably functionalized ynamides yielding
to polycyclic nitrogen heterocycles.8
by the triflate counterion followed by hydrolysis of the intermedi-
7i,14
ate unstable N,O-ketene acetal 4aOTf
,
could be avoided by
using a weakly nucleophilic counterion such as bistriflimidate that
should enable a polycyclization under catalytic conditions.15 To
our delight, the use of 20 mol% of bistriflimide indeed promoted a
clean polycyclization yielding to 2a in 90% yield, provided that
the reaction was performed at room temperature for 20h. As an
important note, π-acid metal catalysts including gold and copper
complexes were found to be totally inefficient to promote the
reaction and mostly gave hydrolysis or extensive decomposition,
therefore demonstrating the superiority of Brønsted acid promot-
ers for this polycyclization.
Figure 1. Influence of the acid promoter for the polycycliza-
tion
Based on our interest in the chemistry of ynamides,9,10 which
are now readily available through an array of efficient reactions,11
we recently investigated their reactivity under fluorinating super-
acidic conditions.7g While most ynamides studied were found to
be smoothly transformed to the corresponding fluorinated en-
amides in pure fluorhydric acid upon generation of highly reactive
N-acyl-keteniminium ions followed by nucleophilic addition of
the fluoride ion, we were surprised to note a completely different
reaction outcome starting from ynamide 1a. Indeed, after reaction
in HF, 1a gave tetracyclic compound 2a12 as a single diastereoi-
somer and in 79% yield (Figure 1).13 To explore the possibility to
generalize this process, we focused our efforts in the first instance
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With a set of conditions for the polycyclization based on the
use of excess triflic acid (Conditions A) or catalytic bistriflimide
(Conditions B), we next evaluated the generality of our procedure
in a series of cascade bicyclizations. To this end, a set of N-
benzyl-ynamides 1a-m possessing representative substitution
patterns, readily prepared using our previously reported proce-
dure,11d were submitted to the cationic polycyclization (Figure 2).
The cyclization proceeded smoothly in most cases and with full
diastereoselectivity (exclusive formation of the cis isomers) under
both stoichiometric and catalytic conditions, the former being
more efficient in the most challenging cases (2b,d,e,j and l). A
variety of tolyl groups on the starting ynamide were found to be
suitable for the polycyclization, including deactivated ones (1d,e)
which however required the use of triflic acid. The nature of the
aromatic ring on the benzyl moiety in 1, which must act as the
terminal nucleophile in the polycyclization, had a stronger impact
on the reaction. Indeed, the desired polysubstituted indenotetrahy-
droisoquinolines 2 could be readily obtained starting from simple
N-benzyl-ynamides (2a-e, 2j-m) and in the case of electron-
donating group suitably placed in the meta position to direct the
terminal cyclization (2f,h). Moving this electron-donating substit-
uent to the para position (2g,i) resulted in a more substrate-
dependent cyclization which was found to still be operative with a
methyl substituent (2g) but inefficient with a more donating
methoxy group (2i). Other electron-withdrawing groups on the
starting ynamide were equally well tolerated, including a carba-
mate (2j) and an easily deprotected nosyl group (2k), the cycliza-
tion being however a bit more sluggish and less efficient with the
former. Finally, we briefly evaluated the possibility of diastere-
oselective polycyclizations yielding to enantiopure nitrogen poly-
cyclic compounds by reacting 4-phenyl-oxazolidinone- and α-
methylbenzylamine- derived ynamides 1l and 1m. Although
moderate levels of diastereoselectivity were observed with these
substrates (69:31 to 86:14), these chiral ynamides were however
readily transformed to the corresponding enantiopure highly
substituted tetra- and penta- cyclic products 2l12 and 2m16 which
could therefore be obtained in a single operation from readily
available starting materials.
Importantly, the cyclization is not limited to the small scale
(ca 100 mg) used for the scope and limitation studies described
above as it could be conveniently performed on a 1.3 gram scale
from 1a in 90% yield using catalytic amounts of bistriflimide as
the promoter.
We next envisioned the replacement of the arene by a suitably
functionalized alkene as the terminal nucleophile in the polycy-
clization, which could provide a remarkably straightforward entry
to tricyclic indenotetrahydropyridines 6, compounds that are at the
core structure of complex alkaloids such as haouamine A 7.17
Ynamides 5a,b, bearing a substituent on the internal carbon of the
alkene in order to stabilize the carbocation that would be formed
at this position during the second cyclization, were therefore
subjected to the acid-mediated cascade cationic cyclization (Fig-
ure 3). To our delight, the cyclization, which was definitely more
audacious in the allyl series than in the benzyl one, provided the
desired tricyclic nitrogen heterocycles 6 in moderate to good
yields. In both cases, mixtures of polycycles 6a,b and 6a’,b’ were
obtained, the former being formed predominantly. For the sake of
curiosity, the reaction of unsubstituted N-allyl-ynamide 5c was
also evaluated and was found, as expected, to be reluctant to
undergo the cyclization, therefore demonstrating the requirement
for the substitution of the alkene for the cyclization to occur.
Figure 2. Scope of the polycyclization of N-benzyl-ynamides
Figure 3. Polycyclization of N-allyl-ynamides
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Encouraged by the successful acid-mediated bicyclization of
2bD₃, indicating that a shift of deuterium had occurred during the
polycyclization. An intramolecular competition experiment was
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ynamides and in an effort to bring this reaction one step further,
we then tested the possibility of increasing the level of structural
complexity of the formed nitrogen polycycles by introducing an
additional substituent on the polycyclic core. Ynamide 8 was
therefore treated with either excess triflic acid at 0 °C for 5
minutes or catalytic bistriflimide at rt for 20h and was found to be
smoothly transformed to the corresponding polycycle 912 in excel-
lent yields (Scheme 1). Importantly, complete diastereoselectivity
was observed in both cases, the polycyclization therefore estab-
lishing three contiguous stereocenters in a single step.
finally performed by studying the cyclization of ynamide 1aCD₃
,
which possesses both methyl and deuterated methyl groups. A
mixture of deuterated polycycles 2aCD₃ (deuterated at C12)
and 2aD₃’
Scheme 3. Deuteration studies
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Scheme 1. Double diastereoselective polycyclization
All these results set the stage to the more challenging case of a
double cationic cascade cyclization. We indeed finally evaluated
the possibility of performing a double cyclization from bis-
ynamides 10 and 12, which could hopefully provide a remarkably
straightforward access to heptacyclic nitrogen heterocycles from
structurally simple “flat” starting materials (Scheme 2). To our
delight, the polycyclization was found to be quite robust since,
upon treatment of substrates 10 and 12 with triflic acid, the corre-
sponding polycyclized targets 11/11’ and 13/13’ were found to be
readily formed within 5 minutes at 0 °C and could be isolated in
74% yield in both cases. For this double polycyclization, the use
of bistriflimide was found to be less efficient and caused exten-
sive degradation of the starting bis-ynamides.
(deuterated at C6a and C7) were formed in a 77:23 ratio, showing
that the hydrogen was preferentially transferred over the deuteri-
um and also suggesting a kinetic isotopic effect for the shift of
hydrogen.
Based on these experiments, and notably on the position of
the deuterium atoms in 2aD₄ and 2bD₃, the mechanism shown in
Scheme 4 can be proposed to rationalize our cationic polycycliza-
tion. The reaction would be initiated by protonation of the elec-
tron-rich alkyne of the starting ynamide I yielding a highly reac-
tive N-tosyl- or N-acyl- keteniminium ion II. A [1,5]-sigmatropic
hydrogen shift would then occur, generating conjugated iminium
III (in resonance with the bis-allylic carbocationic form IV). The
first cycle would then be formed by a 4π conrotatory electrocy-
clization yielding to V (in the manner of the Nazarov reaction),
which is in accordance with the observed stereochemical outcome
of the double diastereoselective polycyclization in which three
stereocenters are formed (Scheme 1).19 A second cyclization
Scheme 2. Double polycyclization from bis-ynamides
between this intermediate benzylic carbocation
V and the
Having demonstrated the efficiency of our new cationic poly-
cyclization, we next focused our efforts on gaining more insights
into the mechanism of this reaction. To this aim, a series of exper-
iments shown in Scheme 3 were performed starting from deuter-
ated ynamides and acids. Upon treatment of 1a with a large ex-
cess of deuterated triflic acid TfOD, the resulting polycycle 2aD₄
was shown to only partially incorporate a deuterium atom at the
benzylic ring junction (C11b) in addition to the expected full deu-
teration of the electron-rich trisubstituted aromatic ring, a reaction
that was also shown to occur after the polycyclization as demon-
strated with the conversion of 2a to 2aD₃ under the standard reac-
tion conditions. The use of one equivalent of deuterated bistriflim-
ide Tf2ND18 for the polycyclization of 1a resulted in no deuter-
ation of the polycyclic product, demonstrating a strong kinetic
isotopic effect for the initial protonation of the ynamide.
arene/alkene subunit would finally account for the formation of
polycycle VI as well as its cis ring junction. Importantly, two key
parameters can account for the success of this transformation.
Firstly, the use of a strong acid promoter such as TfOH or Tf2NH
is essential to avoid trapping the intermediate keteniminium ion
by the conjugated base, i.e. the weakly nucleophilic anions TfO-
or Tf2N-. Secondly, the nature and the high reactivity of this key
N-acyl-keteniminium ion intermediate is also crucial since switch-
ing to a less reactive N,N-dialkyl-keteniminium ion,20 which can
be generated from the corresponding amide under Ghosez’s con-
ditions,21 was shown to be detrimental and no cyclization oc-
curred in this case.
Scheme 4. Proposed mechanism for the cationic polycycliza-
tion
To gain insights on the activation of the benzylic C-H bond in
the starting ynamide, the cyclization of 1bCD₃ was performed and,
if the reaction was found to be less efficient compared to the one
involving the non-deuterated analogue, complete deuteration at
C6a and C7 was observed in the resulting polycyclized product
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In conclusion, we have developed a novel and highly efficient
keteniminium-initiated cationic polycyclization. This reaction,
which just requires an acid as the promoter, affords a straightfor-
ward entry to polycyclic nitrogen heterocycles possessing up to
three contiguous stereocenters and seven fused cycles that can be
obtained in a single operation from readily available ynamides.
The broad availability of the starting ynamides implies that an
extensive range of substituents can be selectively incorporated on
the polycyclic products. In addition to its use in heterocyclic
chemistry, medicinal chemistry and natural product synthesis, for
which we envision great acceptance, this new and simple polycy-
clization extends the chemistry of ynamides which were shown to
be excellent building blocks for multiple, consecutive cationic
transformations.
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Eds.; Wiley: New York, 1976, pp. 421-532. (b) Madelaine, C.; Valerio,
V.; Maulide, N. Chem. Asian J. 2011, 6, 2224.
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Catal. 2011, 353, 263. (b) Gati, W.; Rammah, M. M.; Rammah, M. B.;
Couty, F.; Evano, G. J. Am. Chem. Soc. 2012, 134, 9078. (c) Laouiti, A.;
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NMR spectra for all new compounds and cif files. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
* gevano@ulb.ac.be, sebastien.thibaudeau@univ-poitiers.fr.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The authors thank the Université Libre de Bruxelles, the Universi-
té de Poitiers, the CNRS, and the ANR (project VINFLUSUP
ANR-11-JS07-003-01) for financial support. C.T., B.M. and G.C.
respectively acknowledge the Fonds pour la formation à la Re-
cherche dans l’Industrie et dans l’Agriculture (F.R.I.A.), the ANR
and the Région Poitou-Charentes for graduate fellowships. The
authors also thank Prof. Michel Luhmer (ULB) and the reviewers
for their insightful suggestions.
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Chem. Soc. 1966, 88, 3861. (b) Johnson, W. S.; Semmelhack, M. F.;
Sultanbawa, M. U. S.; Dolak, L. A. J. Am. Chem. Soc. 1968, 90, 2994. (c)
van Tamelen, E. E. Acc. Chem. Res. 1968, 1, 111. (d) van Tamelen, E. E.;
McCormick, J. P. J. Am. Chem. Soc. 1969, 91, 1847. (e) Goldsmith, D. J.;
Phillips, C. F. J. Am. Chem. Soc. 1969, 91, 5862. (f) Bender, J. A.; Arif,
A. M.; West, F. G. J. Am. Chem. Soc. 1999, 121, 7443. (g) Ishihara, K.;
Nakamura, S.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 4906. For
selected recent examples, see: (h) Sakakura, A.; Ukai A.; Ishihara, K.
Nature 2007, 445, 900. (i) Zhao, Y.-J.; Chng, S.-S.; Loh, T.-P. J. Am.
Chem. Soc. 2007, 129, 492. (j) Snyder, S. A.; Treitler, D. S.; Brucks, A. P.
J. Am. Chem. Soc. 2010, 132, 14303. (k) Pronin, S. V.; Shenvi, R. A. Nat.
Chem. 2012, 4, 915. (l) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2012,
134, 11992. (m) Moore, J. T.; Soldi, C.; Fettinger, J. C.; Shaw, J. T. Chem.
Sci. 2013, 4, 292. (n) Wolstenhulme, J. R.; Rosenqvist, J.; Lozano, O.;
(10) For reviews, see: (a) Evano, G.; Coste, A.; Jouvin, K. Angew.
Chem. Int. Ed. 2010, 49, 2840. (b) DeKorver, K. A.; Li, H.; Lohse, A. G.;
Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064.
(c) Evano, G.; Jouvin, K.; Coste, A. Synthesis 2013, 45, 17. (d) Wang, X.-
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N.; Yeom, H.-S.; Fang, L.-C.; He, S.; Ma, Z.-X.; Kedrowski, B. L.; Hsung
R. P. Acc. Chem. Res. 2014, 47, 560.
(15) (a) Matthieu, B.; Ghosez, L. Tetrahedron 2002, 58, 8219. (b) An-
toniotti, S.; Dalla, V.; Duñach, E. Angew. Chem. Int. Ed. 2010, 49, 7860.
(16) The relative configurations of 2m and 2m’ were established on the
basis of NOE experiments. See Supporting Information for details.
(17) Garrido, L.; Zubía, E.; Ortega, M. J.; Salva, J. J. Org. Chem. 2003,
68, 293.
(18) Prepared immediately before use by sublimation from LiNTf2 in
D2SO4 according to: DesMarteau, D. D.; Lu, C. J. Fluorine Chem. 2007,
128, 1326.
(19) The C6a/C7 relative configuration in 9 (Scheme 1) would result
from the 4π conrotatory electrocyclization of intermediate IV in which the
stereochemistry of the two alkenes would be as depicted in Scheme 4, ie
with R5 and N- substituents directed outwards to favor conformation
required for the electrocyclization. As in the Nazarov reaction, E-Z isom-
erization would occur before the cyclization which would then become
stereoselective.
(20) The reaction of N-benzyl-N-methyl-2-(o-tolyl)acetamide with tri-
flic anhydride and collidine in dichloromethane – standard conditions for
the generation of keteniminium triflates from tertiary amides –21 did not
provide a trace of the corresponding cyclized product.
1
2
3
4
5
6
7
8
(11) For general methods for the synthesis of ynamides, see: (a) Dunetz,
J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011. (b) Zhang, Y.; Hsung, R.
P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6, 1151.
(c) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833. (d)
Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew. Chem. Int. Ed.
2009, 48, 4381. (e) Jouvin, K.; Couty, F.; Evano, G. Org. Lett. 2010, 12,
3272. (f) Jia, W.; Jiao, N. Org. Lett. 2010, 12, 2000. (g) Sueda, T.; Oshi-
ma, A.; Teno, N. Org. Lett. 2011, 13, 3996. (h) Jouvin, K.; Heimburger,
J.; Evano, G. Chem. Sci. 2012, 3, 756. (i) Souto, J. A.; Becker, P.; Iglesias,
A.; Muñiz, K. J. Am. Chem. Soc. 2012, 134, 15505.
(12) Structures and configurations of 2a, 2l and 9 were established by
X-ray analysis: see Supporting Information for details.
(13) For a previously reported multi-step synthesis of indenotetrahy-
droisoquinolines, see: Hagishita, S.; Shiro, M.; Kuriyama K. J. Chem.
Soc., Perkin Trans. 1 1984, 1655.
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(14) The formation of an intermediate N,O-ketene acetal B related to
4aOTf could be evidenced by NMR upon reacting ynamide A with triflic
acid in CD2Cl2 at -20 °C. See Supporting Information for details.
(21) Schmidt, C.; Sahraoui-Taleb, S.; Differding, E.; Dehasse-De Lom-
baert, C. G.; Ghosez, L. Tetrahedron Lett. 1984, 25, 5043.
TOC graphic.
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