[4 + 2] Cycloadditions of N-alkenyl iminium ions: Structurally complex heterocycles from a three-component Diels-Alder reaction sequence

Article abstract of DOI:10.1021/ja8028153

N-Alkenyl iminium ions serve as conduits to three-component [4 + 2] cycloaddition reactions accessing structurally and stereochemically diverse piperidine derivatives. These cationic 2-azadienes participate in endo- or exo-selective [4 + 2] cycloadditions with electron-rich and neutral alkene dienophiles to generate a tetrahydropyridinium ion as the initial cycloadduct. In situ nucleophilic addition to the cycloaddition-derived iminium ion completes the three-component coupling sequence and affords a versatile synthesis of structurally complex piperidines. Copyright

Full text of DOI:10.1021/ja8028153

Published on Web 06/25/2008
[4 + 2] Cycloadditions of N-Alkenyl Iminium Ions: Structurally Complex
Heterocycles from a Three-Component Diels-Alder Reaction Sequence
Nihar Sarkar, Abhisek Banerjee, and Scott G. Nelson*
UniVersity of Pittsburgh Center for Chemical Methodologies and Library DeVelopment, Department of Chemistry,
UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received May 2, 2008; E-mail: sgnelson@pitt.edu
Nitrogen-containing heterocycles are ubiquitous substructures in a
myriad of biologically active natural products and small-molecule
pharmaceuticals.1 Accordingly, a wide range of target-directed and
diversity-oriented synthesis activities are devoted to heterocycle
synthesis. As a strategy for expanding existing hetero-Diels-Alder-
based approaches to heterocycle synthesis, we were attracted to cationic
2-azadienes 1 as conduits to three-component [4 + 2] cycloaddition
reactions accessing structurally and stereochemically diverse piperidine
derivatives (Figure 1).2 The putative N-alkenyl iminium ion-alkene
[4 + 2] cycloadditions would generate tetrahydropyridinium ion
cycloadducts 2, allowing further functionalization through nucleophilic
addition to the transposed iminium ion 2. Herein, we describe N-alkenyl
iminium ions 1 as enabling tools for three-component [4 + 2]
cycloaddition-iminium ion addition reactions that afford an efficient
and versatile synthesis of highly substituted piperidines.
Preliminary assessment of the N-alkoxymethyl enamines as par-
ticipants in the multicomponent Diels-Alder reaction sequence utilized
3a as the diene precursor (eq 2). Allyltrimethylsilane (5) was selected
as a representative electron-rich dienophile offering the ancillary
advantage that excess reagent would directly alkylate the tetrahydro-
pyridinium ion cycloadduct. Accordingly, adding enamine 4a to a
mixture of allyltrimethylsilane (3 equiv) and TiCl4 (1 equiv, CH2Cl2,
-78 °C) delivered the C1-alkylated piperidine 6 (89%). Cycloaddition
proved to be highly endo-selective with incomplete facial selectivity
during nucleophilic addition to the iminium ion cycloadduct 7
providing 6 as a 2:1 mixture of C1 epimers.11
Despite the prominence of 2-azadienes in the Diels-Alder lexicon,3,4
reaction designs offering in situ functionalization of incipient cycload-
ducts as a conduit to expanded functionality or structural diversity are
relatively rare.5 This analysis inspired our interest in developing a
general method for accessing cationic 2-azadienes under conditions
conducive to realizing the putative intermolecular cycloaddition-iminium
ion functionaliztion reaction sequence (Figure 1). Literature precedent
Rapid cycloaddition with electron-rich olefins is a defining feature
of the N-alkenyl iminium ion dienes. For example, reacting 3a with
TiCl4, without allyl silane present, affects [4 + 2] cycloaddition with
un-ionized enamine 3a to generate iminium ion 8 (eq 3); quenching
cycloadduct 8 with allyl silane 5 promotes C1 allylation in addition to
ionization/allylation of the pendant N,O-acetal to afford the tetrasub-
stituted piperidine 9 as a 4:1 mixture of C1 epimers (85%).12
Alternatively, hydride-mediated reduction of 8 generated the 3,4,5-
trisubstituted piperidine 10 as a single endo-diastereomer. Consistent
with the preceding allyl silane cycloadducts, the enamine cycloadditions
were highly endo-selective.13,14 The four newly formed C-C σ-bonds
in 9 exemplify the opportunities afforded by this reaction sequence
for expanding structural diversity available from the traditional
Diels-Alder manifold.
Figure 1. [4 + 2]Cycloadditions of N-alkenyl iminium ion dienes.
implicated N-alkoxymethyl enamines (e.g., 3) as convenient precursors
to the desired N-alkenyl iminium ion dienes via Lewis acid mediated
N,O-acetal ionization (eq 1).4d,f,6 In the absence of a well-established
method for preparing these N-alkoxymethyl enamines,7 we selected
metal-catalyzed isomerization of allylic amine derivatives as a
convenient route to the requisite diene precursors.8 Indeed, the easily
obtained allylic sulfonamides 4a,b participated in highly E-selective
olefin isomerization using either Ir(I)- or Ru(II)-based catalysts to afford
the putative diene precursors 3a,b in high yield.9,10
The N-alkenyl iminium ions express sufficient reactivity to engage
electronically unactivated olefins as dienophiles in [4 + 2] cycload-
ditions. Activating 3a with TiCl4 (1 equiv) in the presence of
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10.1021/ja8028153 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
Scheme 2
cyclohexene and quenching the intervening cycloadduct 11 with
allyltrimethylsilane or ketene acetal 12 delivered the perhydroiso-
quinoline derivatives 13 (59%) and 14 (57%), respectively, as single
diastereomers (Scheme 1). These cycloadditions are highly exo-
selective, suggesting that minimized nonbonded interactions are the
determining factor in transition state organization. Ensuing nucleophilic
addition to the cycloaddition-derived iminium ion 11 proceeds from
the convex face of the cis-fused octahydroisoquinoline ring system to
deliver 13 (or 14) with the fully stereocontrolled construction of three
new C-C σ-bonds. Norbornene participates in similarly selective
cycloadditions with trimethylsilylcyanide or enol silane functionaliza-
tion of the intervening cycloadduct 15, affording cycloadducts 16 and
17, respectively. Cyclooctene also reacts as the dienophile with 3a to
afford the [6.4.0] bicyclic heterocycle 18 (67%), wherein amine-
mediated deprotonation was used as an altenative method for deriva-
tizing the intervening iminium ion.
The utility of indole in the cycloaddition-alkylation sequence is
illustrative of how similar reaction components can be alternated as
dienophiles or nucleophiles to access dramatically different architectural
types. N-Methyl indole functions as an effective nucleophile toward
cycloadduct 11 to afford the perhydroisoquinoline 19 (53%) (Scheme
2). However, N-methyl indole is too Lewis basic to be compatible
with the preceding Lewis acid mediated cycloaddition. N-Tosyl indole
(20) possesses the correct electronics to participate in efficient [4 +
2] cycloaddition with 3a but lacks sufficient nucleophilicity to add to
the intervening cycloadduct 21. As a result, ensuing iminium ion
functionalization could be achieved independent of the preceding
cycloaddition event; in this case, amine-mediated deprotonation of 21
delivered the tricyclic indole 22 in 77% yield.
Acknowledgment. Support from the National Institutes of Health
(R01 GM63151 and P50 GM067082 supporting the UPCMLD) and
the Merck Research Laboratories is gratefully acknowledged.
Supporting Information Available: Experimental procedures and
1H and 13C spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) For selected reviews, see: (a) Sondhi, S. M.; Singhal, N.; Johar, M.; Reddy,
B. S.; Lown, J. W. Curr. Med. Chem. 2002, 9, 1045. (b) Newton, R. F.
PharmaChem 2003, 2, 44. (c) Whitehouse, M. W. Curr. Med. Chem. 2005,
12, 2931.
(2) Kobayashi, S., Jorgensen, K. A., Eds. Cycloaddition Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, Germany, 2002.
(3) For reviews, see: (a) Povarov, L. S. Russ. Chem. ReV. 1967, 36, 656. (b)
Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1969, 8, 602. (c) Giordano,
C.; Ribaldone, G.; Borosotti, G. Synthesis 1971, 92. (d) Boger, D. L.
Tetrahedron 1983, 39, 2869. (e) Weinreb, S. M.; Scola, P. M. Chem. ReV.
1989, 89, 1525. (f) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P.
Tetrahedron 2002, 58, 379.
(4) For selected relevant examples, see: (a) Bradsher, C. K.; Solomons, T. W. G.
J. Am. Chem. Soc. 1958, 80, 933. (b) Trifonov, L. S.; Orahovats, A. S.
Heterocycles 1984, 22, 355. (c) Shono, T.; Matsumara, Y.; Uchida, K.;
Kobayashi, H. J. Org. Chem. 1985, 50, 3243. (d) Cheng, Y.; Ho, E.;
Mariano, P. S.; Ammon, H. L. J. Org. Chem. 1985, 50, 5678. (e) Jnoff, E.;
Ghosez, L. J. Am. Chem. Soc. 1999, 121, 2617. (f) Suga, S.; Nagaki, A.;
Tsutsui, Y.; Yoshida, J. Org. Lett. 2003, 5, 945. (g) Akiyama, T.; Morita,
H.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128, 13070.
(5) For spectacular examples of cascade reactions involving N-protonated
2-azadienes, see: (a) Heathcock, C. H. Angew. Chem., Int. Ed. Engl. 1992,
31, 665. (b) Heathcock, C. H. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 14323.
(6) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff,
C. A. Chem. ReV. 2004, 104, 1431.
(7) For an alternate route to related enamides, see: Coleman, R. S.; Liu, P.-H.
Org. Lett. 2004, 6, 577.
(8) Zacuto, M. J.; Xu, F. J. Org. Chem. 2007, 72, 6298.
(9) (a) Nelson, S. G.; Bungard, C. J.; Wang, K. J. Am. Chem. Soc. 2003, 125,
13000. (b) Nelson, S. G.; Wang, K. J. Am. Chem. Soc. 2006, 128, 4232.
(10) (a) Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew. Chem.,
Int. Ed. 2002, 41, 4732. (b) Alcaide, B.; Almendros, P.; Alonso, J. M.;
Luna, A. Synthesis 2005, 668.
(11) For the allylation of related tetrahydropyridinium ions, see: Okitsu, O.;
Suzuki, R.; Kobayashi, S. J. Org. Chem. 2001, 66, 809.
(12) The structures of compounds 9, 10, 13, and 19 were confirmed by X-ray
diffraction analysis.
(13) “Endo” describes the orientation of the dienophile’s electron-donating
substituent relative to the diene.
(14) While the factors responsible for the observed endo-diastereoselection have
not been definitively elucidated, attractive electrostatic interactions between
diene and dienophile provide one possible explanation: Garcia, J. I.;
Mayoral, J. A.; Salvatella, L. Eur. J. Org. Chem. 2004, 85.
The C1-substituted N-alkoxymethyl enamine 3b provides access to
azadienes possessing substitution at both terminal carbons (eq 4). Lewis
acid mediated ionization of racemic 3b generates the anticipated
mixture of (Z,E)- and (E,E)-dienes 23 and 24, respectively. In situ
cycloaddition of the more reactive (Z,E)-diene 23 affords the tetra-
substituted piperidine 25 with high endo-selectivity (44%).
N-Alkenyl iminium ions enable multicomponent cycloaddition-
iminium ion functionalization reactions, affording efficient access to
structurally diverse and stereochemically rich piperidine derivatives.
These attributes are expected to render this methodology generally
useful in both target-directed and diversity-oriented synthesis activities.
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