Convergent synthesis of piperidines by the union of conjugated alkynes with lmines: A unique regioselective bond construction for heterocycle synthesis

Article abstract of DOI:10.1021/ol902169k

A two-step process Is described for the union of aromatic imines, conjugated alkynes, and aldehydes that results In a stereoselective synthesis of highly substituted piperidines. This synthetic process has been made possible by defining a unique reglosele

Full text of DOI:10.1021/ol902169k

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4982-4985
Convergent Synthesis of Piperidines by
the Union of Conjugated Alkynes with
Imines: A Unique Regioselective Bond
Construction for Heterocycle Synthesis
Ming Z. Chen and Glenn C. Micalizio*
Department of Chemistry, The Scripps Research Institute, Scripps Florida,
Jupiter, Florida 33458
micalizio@scripps.edu
Received September 18, 2009
ABSTRACT
A two-step process is described for the union of aromatic imines, conjugated alkynes, and aldehydes that results in a stereoselective synthesis
of highly substituted piperidines. This synthetic process has been made possible by defining a unique regioselective functionalization of
conjugated alkynes that establishes a suitably functionalized substrate for subsequent heterocycle-forming cationic annulation. Given the
flexibility of the coupling process, heterocycles can be accessed through a process that establishes up to four stereogenic centers and four
fused rings.
Substituted piperidines are structural motifs found in a variety
of natural products and small molecules of biomedical
relevance.1 Despite the significant advances made that define
chemical methods suitable for the construction of this
heterocyclic core, the stereocontrolled preparation of highly
substituted piperidines remains a challenge in chemical
synthesis.2 Of the many methods available, cationic annu-
lation of suitably functionalized amines with aldehydes (via
Pictet-Spengler or aza-Prins cyclization) has long been
recognized as a useful pathway to a subset of functionalized
piperidines.3,4 Aside from problems associated with the
control of these cationic annulation reactions, preparation
of complex unsaturated amine substrates suitable for these
heterocycle-forming processes can be cumbersome. Here, we
describe a bimolecular bond construction for the selective
union of conjugated alkynes with imines as a means to
establish appropriate functionality for subsequent stereose-
lective cationic annulation. Specifically, the process described
(3) (a) Bohlmann, F.; Winterfeldt, E.; Overwien, H.; Pagel, H. Chem.
Ber. 1962, 95, 944–948. (b) Grob, C. A.; Wohl, R. A. HelV. Chem. Acta
1966, 49, 2175–2189. (c) Cope, A. C.; Burrows, W. D. J. Org. Chem. 1966,
(1) (a) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679–
3681. (b) Ka¨llstro¨m, S.; Leino, R. Bioorg. Med. Chem. 2008, 16, 601–635.
(2) For recent reviews, see: (a) Escolano, C.; Amat, M.; Bosch, J.
Chem.sEur. J. 2006, 12, 8198–8207. (b) Cossy, J. Chem. Rec. 2005, 5,
70–80. (c) Buffat, M. G. P. Tetrahedron 2004, 60, 1701–1729. (d)
Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron
2003, 59, 2953–2989.
29, 3099–3103.
(4) For recent reviews of cationic annulation reactions in heterocycle
synthesis, see: (a) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41,
4367–4416. (b) Blumenkopf, T. A.; Overman, L. E. Chem. ReV. 1986, 86,
857–873. (c) Overman, L. E. Aldrichim. Acta 1995, 28, 107–120. (d) Royer,
J.; Bonin, M.; Micouin, L. Chem. ReV. 2004, 104, 2311–2352. (e) Cox,
E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797–1842
.
10.1021/ol902169k CCC: $40.75
Published on Web 10/09/2009
 2009 American Chemical Society

defines a two-step, three-component coupling reaction be-
tween conjugated alkynes, imines, and aldehydes for the
stereoselective synthesis of piperidines containing up to four
stereogenic centers and four fused rings.
From the outset, we sought a bimolecular alkyne-imine
coupling that would enable the synthesis of allylic amines
well suited for cationic annulation (1 f 2, and 2 + 3 f 4;
Figure 1). With this goal in mind, we were aware of the
functionalization of an internal alkyne and overrides the
influence of simple nonbonded steric interactions.6 The
knowledge gleaned from this study served as a guiding
principle for the design of the first step of the heterocycle
synthesis described here. While targeting a bond construction
that, as in our previous studies, would require stoichiometric
quantities of Ti(O-i-Pr)4, the potential of such a process in
complex heterocycle synthesis and the inability to generate
the desired substitution in 2 with available catalytic methods
drove our investigation of this chemistry.
As illustrated in Figure 2, alkoxide-directed C-C bond
formation provides an exceptionally powerful means to
Figure 1. Regioselective union of conjugated alkynes with imines
for heterocycle synthesis.
numerous methods available for metal-catalyzed reductive
coupling of conjugated alkynes with carbonyl electrophiles.
Unfortunately, the selectivity of these coupling reactions is
uniformly dictated by the presence of π-conjugation and
delivers an isomeric product to that required for the
heterocycle synthesis of interest here (2 vs 5; Figure 1).5
Recently, we have defined a Ti-mediated alkyne-imine
coupling reaction for the synthesis of allylic amines and
γ-lactams where a tethered alkoxide directs regioselective
Figure 2. Alkoxide-directed union of conjugated alkynes with
imines.
deliver the unique regioisomer required here, where C-C
bond formation occurs R-to the conjugated π-system, in
opposition to that expected from the electronic effects that
dictate the regiochemical course of related reductive coupling
reactions.5 The selective production of 6-12 highlights the
effectiveness of this reductive cross-coupling reaction with
a variety of aromatic and heteroaromatic conjugated alkynes.
While demonstrating the compatibility of the coupling
reaction with electron rich aromatics, aromatic halides,
thiophenes, furans, pyrroles, and indoles, these reactions
provided single regioisomers of coupled products in 52-66%
yield.
(5) (a) Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221–
4223. (b) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003, 42,
1364–1367. (c) Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem.
Soc. 2004, 126, 3698–3699. (d) Miller, K. M.; Luanphaisarnnont, T.;
Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 4130–4131. (e)
Miller, K. M.; Jamison, T. F. Org. Lett. 2005, 7, 3077–3080. (f) Kong,
J.-R.; Cho, C.-W.; Krische, M. J. J. Am. Chem. Soc. 2005, 125, 11269–
11276. (g) Sa-ei, K.; Montgomery, J. Org. Lett. 2006, 8, 4441–4443. (h)
Komanduri, V.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 16448–16449.
(i) Cho, C.-W.; Krische, M. J. Org. Lett. 2006, 8, 3873–3876. (j) Ngai,
M.-Y.; Barchuk, A.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 280–
281. (k) Cho, C.-W.; Skucas, E.; Krische, M. J. Organometallics 2007, 26,
3860–3867. (l) Hong, Y.-T.; Cho, C.-W.; Skucas, E.; Krische, M. J. Org.
Lett. 2007, 9, 3745–3748. (m) Patman, R. L.; Chaulagain, M. R.; Williams,
V. M.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2066–206. For coupling
reactions of isolated alkynes with activated imines: (n) Skucas, E.; Kong,
J. R.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 7242–7243. (o) Barchuk,
A.; Ngai, M.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 8432–8433. (p)
Ngai, M.; Barchuk, A.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 12644–
12645.
The successful formation of 13-16 demonstrates that this
metal-mediated coupling process is equally effective with
enyne-containing substrates. Here, high regioselectivity is
possible in a chemoselective coupling process, where no
(6) McLaughlin, M.; Takahashi, M.; Micalizio, G. C. Angew. Chem.,
Int. Ed. 2007, 46, 3912–3914.
Org. Lett., Vol. 11, No. 21, 2009
4983

evidence was found for the functionalization of the conju-
gated alkene of the starting enyne.
With a site-selective convergent coupling reaction in hand,
we shifted our attention to exploring the unique reactivity
of the allylic amine products derived from this coupling
process. As anticipated on the basis of well-precedented
Pictet-Spengler chemistry,4e cationic annulation of substrates
containing conjugated aromatics defines a concise pathway
to polysubstituted fused bicyclic heterocycles (Figure 3).
Figure 4. Cationic annulation via aza-Prins-initiated cyclization.
reaction is complex. For example, cyclization of an enyne
bearing a (Z)-disubstituted alkene leads to the generation of
a bicyclic product 22 with good levels of stereoselection (dr
) 12:1), while cyclization of a related isomeric enyne
proceeds with very low levels of stereoselection (i.e., 23 is
derived from the (E)-disubstituted alkene and is produced
as a 1.6:1 mixture of stereoisomers). This observed lack of
stereospecificity is consistent with stepwise cyclization
terminated by diastereoselective addition to an intermediate
allylic carbocation.9
Figure 3. Cationic annylation via Pictet-Spengler-like cyclization.
In an effort to enhance diastereoselection, we examined
the cyclization of enynes where the alkene was constrained
in a five-membered ring. Perhaps due to the expected
preference for formation of a cis-fused saturated aza-indane
over the trans-fused isomer, all cationic annulation reac-
tions with this subset of enynes proceeded with very high
levels of diastereoselection (24-26; dr g 20:1 in all cases).
As observed previously in the annulation reaction of
substrates containing conjugated aromatics, in these more
complex cyclization reactions, stereoselection was observed
for the formation of the central piperidine bearing 2,6-trans-
substitution (i.e., 25 and 26).
While the generation of 17 and 18 (via acid-promoted
addition to 1,3,5-trioxane in EtOH or CH3CN) demonstrates
the basic reactivity profile of interest with electron-rich and
heteroaromatic systems, the formation of 19-21 highlights
that good levels of stereocontrol are possible in convergent
annulation with aldehydes. In all cases, high selectivity for
the formation of the 2,6-trans-disubstituted piperidines was
observed (dr g 20:1).
Moving on, cationic annulation of the 1,3-diene-containing
allylic amines (derived from reductive cross-coupling of enynes
with aromatic imines) provides a unique opportunity for the
rapid generation of complex heterocycles. Here, cationic an-
nulation terminated by C-O bond formation defines a concise
pathway to bi-, tri-, and tetracyclic piperidines with typically
very high levels of stereoselection (Figure 4).7,8
This regioselective reductive cross-coupling reaction between
enynes and aromatic imines can be rendered asymmetric. As
depicted in Figure 5, use of a phenylglycine-modified aromatic
Our preliminary investigation of this reaction pathway
indicated that the stereochemical course of the annulation
(9) Resubjecting each diastereomer of 23 to the reaction conditions did
not lead to any observable interconversion. As such, the mixture of products
obtained in this annulation reaction is deemed likely to result from a stepwise
process entailing formation of a secondary allylic cation followed by C-O
bond formation, not stereospecific cationic cyclization followed by acid-
promoted isomerization of the product.
(10) The relative stereochemistry of products 29 and 31 was assigned
in analogy to previously described alkoxide-directed reductive cross-coupling
reactions of chiral imine 28 (see ref 6 and literature cited therein). For the
initial report that describes use of a phenylglycine-based imine in diaste-
reoselective reductive coupling of aromatic imines with terminal alkynes,
see: Fukuhara, K.; Okamoto, S.; Sato, F. Org. Lett. 2003, 5, 2145–2148.
(7) For examples of annulation reactions between iminium ions and 1,3-
dienes, see: (a) Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107,
1768–1769. (b) Grieco, P. A.; Kaufman, M. D. J. Org. Chem. 1999, 64,
6041–6048. (c) Liu, J.; Sung, R. P.; Peters, S. D. Org. Lett. 2004, 6, 3989–
3992.
(8) For an interesting example of a tandem aza-Prins reaction followed
by intramolecular C-O bond formation in the context of total synthesis,
see: Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008,
130, 16864–16866.
4984
Org. Lett., Vol. 11, No. 21, 2009

imine (28) leads to moderate stereoselection in the formation
of the functionalized allylic amines 29 (dr ) 85:15) and 31 (dr
) 75:25).10
presence of substituted piperidines in natural products and
small molecules of biomedical relevance, we anticipate that
this two-step, three-component coupling process will be of
great utility in chemical synthesis. The ease of use, low cost,
and unique reactivity profile of Ti(O-i-Pr)4 combine to define
a powerful system of increasing utility in defining unique
and highly regioselective bond constructions in organic
chemistry.11,12
Acknowledgment. We gratefully acknowledge financial
support of this work by the American Cancer Society
(RSG-06-117-01), Boehringer Ingelheim, Eli Lilly & Co.,
and the National Institutes of Health-NIGMS (GM80266
and GM80266-04S1).
Supporting Information Available: Experimental pro-
cedures and tabulated spectroscopic data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 5. Preliminary studies in asymmetric synthesis.
OL902169K
(11) It is instructive to compare the cost associated with running
reductive cross-coupling chemistry based on stoichiometric Ti(O-i-Pr)4 with
reported processes that employ substoichiometric quantities of Ni, Rh, Ir,
and Ru catalysts. For a hypothetical reductive cross-coupling reaction run
on a 1 mol scale, the following costs are associated with the purchase of
required metal (in each case the typical mol % reported for each system
has been used for the calculation): 1 mol of Ti(O-i-Pr)4 ) $18; 10 mol %
Ni(COD)2 ) $591; 5 mol % [Rh(COD)2]OTf ) $4391; 5 mol %
[Ir(COD)2]BARF ) $6465; 5 mol % Ru(O2CCF3)2(CO)(PPh3)2 ) $11,612
(costs calculated for purchase from Strem 2008 catalogue). While typically
2 equivalents of Grignard reagent are employed in the reduction of the
Ti(IV) alkoxide (additional $184), the cost of required ligands associated
with the other systems is not factored into the costs listed above. Finally,
the analysis presented above is based on published procedures that report
catalyst loadings between 5 and 10 mol %, with associated turnover numbers
between 5 and 20.
In conclusion, we have described a two-step three-
component coupling process for the synthesis of stereode-
fined and highly substituted piperidines. Site-selective union
of readily available conjugated alkynes with aromatic imines
provides a means of accessing allylic amine products not
readily available with other reductive cross-coupling methods
(where C-C bond formation occurs R- to the conjugated
π-system). As a result of the unique selectivity of this alkyne-
imine cross-coupling reaction, subsequent cationic annulation
with carbonyl electrophiles defines a powerful pathway to
highly substituted piperidines. The complex annulation
processes discovered are typically highly selective, generating
up to four stereogenic centers (dr is typically g20:1) and
four fused rings. Due to the rapid access to structural
complexity afforded by this chemical process and ubiquitous
(12) While the removal of toxic metal impurities in reaction products
is a problem that surfaces in many applications of metal-catalyzed reactions
in pharmaceutical process chemistry (i.e., Pd-, Ni-, or Ru-), the byproducts
of this Ti(O-i-Pr)4-mediated coupling reaction include i-PrOH, Mg salts,
simple hydrocarbons, and TiO2sa nontoxic species encountered daily in
toothpaste, sunscreen, and paint.
Org. Lett., Vol. 11, No. 21, 2009
4985