Applications of multicomponent reactions for the synthesis of diverse heterocyclic scaffolds

Article abstract of DOI:10.1021/ol7018357

A four-component coupling process involving sequential reactions of aldehydes, primary amines, acid chlorides, and nucleophiles has been developed to prepare multifunctional substrates that may be employed in subsequent ring-forming reactions to generate

Full text of DOI:10.1021/ol7018357

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4223-4226
Applications of Multicomponent
Reactions for the Synthesis of Diverse
Heterocyclic Scaffolds
James D. Sunderhaus, Chris Dockendorff, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin Texas 78712
sfmartin@mail.utexas.edu
Received July 31, 2007
ABSTRACT
A four-component coupling process involving sequential reactions of aldehydes, primary amines, acid chlorides, and nucleophiles has been
developed to prepare multifunctional substrates that may be employed in subsequent ring-forming reactions to generate a diverse array of
functionalized heterocyclic scaffolds. This new approach to diversity-oriented synthesis was then applied to the first total synthesis of the
isopavine alkaloid (±)-roelactamine.
Diversity-oriented synthesis (DOS) continues to be an area
of importance at the interface of the fields of organic
synthesis and chemical biology.1 At the heart of DOS are
the synthetic methods needed for the efficient generation of
collections of functionally and stereochemically diverse small
molecules, especially those possessing skeletons found in
natural products or drug-like molecules.2 Perhaps the most
promising and powerful method for generating these col-
lections of molecules is by sequencing multicomponent
reactions (MCRs) with subsequent transformations that
further increase molecular complexity and diversity.3 Ideally,
the MCRs that are implemented should be versatile so that
any combination of functional groups can be incorporated
into the reaction products. This capability will enable
maximal use of ring-forming processes and refunctionaliza-
tions that comprise the synthome, which is the set of all
reactions available to the chemist for the synthesis of small
molecules, to transform these key intermediates into target
structures.
The venerable isocyanide-based Ugi four-component reac-
tion (4CR)4 has been widely utilized for the rapid assembly
of functionalized intermediates that may be readily trans-
formed by Diels-Alder reactions,5 Heck cyclizations,6 ring-
closing metathesis (RCM),7 dipolar cycloadditions,8 nucleo-
(4) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (b)
Zhu, J. Eur. J. Org. Chem. 2003, 1133.
(5) (a) Paulvannan, K. Tetrahedron Lett. 1999, 40, 1851. (b) Wright, D.
L.; Robotham, C. V.; Aboud, K. Tetrahedron Lett. 2002, 43, 943. (c) Lee,
D.; Sello, J. K.; Schrieber, S. L. Org. Lett. 2000, 2, 709. (d) Sello, J. K.;
Andreana, P. R.; Lee, P. R.; Schreiber, S. L. Org. Lett. 2003, 5, 4125.
(6) (a) Gracias, V.; Moore, J. D.; Djuric, S. W. Tetrahedron Lett. 2004,
45, 417. (b) Xiang, Z.; Luo, T.; Lu, K.; Cui, J.; Shi, X.; Fathi, R.; Chen, J.;
Yang, Z. Org. Lett. 2004, 6, 3155.
(7) (a) Beck, B.; Larbig, G.; Mejat, B.; Magnin-Lachaux, M.; Picard,
A.; Herdtweck, E.; Do¨mling, A. Org. Lett. 2003, 5, 1047. (b) Hebach, C.;
Kazmaier, U. Chem. Commun. 2003, 596. (c) Banfi, L.; Basso, A.; Guanti,
G.; Riva, R. Tetrahedron Lett. 2003, 44, 7655. (d) Piscopio, A. D.; Miller,
J. F.; Koch, K. Tetrahedron 1999, 55, 8189. (e) Krelaus, R.; Westermann,
B. Tetrahedron Lett. 2004, 45, 5987. (f) Anthoine-Dietrich, S.; Banfi, L.;
Basso, A.; Damonte, G.; Guanti, G.; Riva, R. Org. Biomol. Chem. 2005, 3,
97. (g) Kazmaier, U.; Hebach, C.; Watzke, A.; Maier, S.; Mues, H.; Huch,
V. Org. Biomol. Chem. 2005, 3, 136.
(1) (a) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43,
46. (b) Spring, D. R. Org. Biomol. Chem. 2003, 1, 3867. (c) Strausberg, R.
L.; Schreiber, S. L. Science 2003, 300, 294.
(2) For routes to privileged structures, see: Horton, D. A.; Bourne, G.
T.; Smythe, M. L. Chem. ReV. 2003, 103, 893.
(3) Marcaccini, S.; Torroba, T. Multicomponent Reactions; Zhu, J.,
Bienayme, H., Eds.; Wiley-VCH: Wienheim, 2005; pp 33. (b) Do¨mling,
A. Chem. ReV. 2006, 106, 17.
10.1021/ol7018357 CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/21/2007

philic aromatic substitution,9 and other reactions to generate
a number of heterocyclic structures. Post-condensation
reactions used in conjunction with the van Leusen10 and
Petasis11 3-component reactions have also been exploited to
fabricate novel molecules for biological screening.12
Some years ago we discovered a multicomponent reaction
that featured vinylogous Mannich reactions of electron-rich
dienes with N-acyl iminium ions generated in situ by
N-acylation of imines to give adducts that were readily
transformed into complex indole alkaloids.13 In the context
of DOS, we envisioned that a related four-component process
involving the combination of an amine 1, an aldehyde 2,
and an acylating agent 3 might generate a reactive N-acyl
iminium ion that could be subsequently trapped with a
nucleophile 4 to give a highly functionalized amide 5
(Scheme 1).14 In a variant of this protocol, the nucleophile
for effecting the enantioselective addition of many types of
nucleophiles to CdN double bonds,16 there is an opportunity
to prepare amides of general type 5 in enantiomerically pure
form.
To establish the underlying feasibility of this approach to
DOS, we initiated exploratory studies, some representative
examples of which are summarized herein. In these experi-
ments, we focused on combining unsaturated amines, aryl
aldehydes, simple acid chlorides, and allylic and π-nucleo-
philes to prepare adducts that could be further transformed
by cyclizations involving RCM, Dieckmann and Heck
reactions, and Diels-Alder and dipolar cycloadditions. For
example, methyl 2-formylbenzoate (7) was condensed with
either allyl or propargyl amine to give intermediate imines
that were treated sequentially with acetyl chloride and
allylzinc bromide to furnish adducts 8 and 9, each in a one
pot operation (Scheme 2). In a slight modification of this
Scheme 1. Sequential MCR/Cyclization Strategy for DOS
Scheme 2. Sequential MCR/RCM/Dieckmann Cyclization and
MCR/RCM/CM/Dieckmann Cyclization
could be added to an intermediate imine, and the amine thus
formed could be N-acylated to furnish 5.15 This experimental
flexibility together with the ready availability of numerous
reactants 1-4 allows for the incorporation of high levels of
functional and structural diversity in the products 5, so that
a number of different subsequent cyclizations might be
performed to generate an array of heterocyclic scaffolds in
only a few steps from commercially available starting
materials. Furthermore, because there are numerous methods
procedure, we discovered that 9 could be isolated in 76%
yield if the crude intermediate imine was isolated prior to
acylation and allylation. Compound 8 was then converted
into the benzazepine 12 via a RCM using Grubbs catalyst
10 followed by a Dieckmann cyclization. In a related process,
9 was transformed via an enyne RCM/CM cascade that was
catalyzed by the Hoveyda-Grubbs catalyst (11)17 and in
which styrene served as a fifth component to give an
intermediate that was cyclized by a Dieckmann condensation
to give 13. These two examples illustrate how simply
changing one of the inputs for the 4CR allows for differential
processing of the initial adduct into targets of varying
complexity. Importantly, the keto amide and alkene groups
in 12 and 13 serve as potential initiation sites for further
diversification.
(8) (a) Akritopoulou-Zanze, I.; Gracias, V.; Moore, J. D.; Djuric, S. W.
Tetrahedron Lett. 2004, 45, 3421. (b) Akritopoulou-Zanze, I.; Gracias, V.;
Djuric, S. W. Tetrahedron Lett. 2004, 45, 8439.
(9) (a) Tempest, P.; Ma, V.; Kelly, M. G.; Jones, W.; Hulme, C.
Tetrahedron Lett. 2001, 42, 4963. (b) Cristau, P.; Vors, J.-P.; Zhu, J. Org.
Lett. 2001, 3, 4079. (c) Cristau, P.; Vors, J.-P.; Zhu, J. Tetrahedron 2003,
59, 7859.
(10) (a) Gracias, V.; Gasiecki, A. F.; Djuric, S. W. Tetrahedron Lett.
2005, 46, 9049. (b) Gracias, V.; Darczak, D.; Gasiecki, A. F.; Djuric, S.
W. Tetrahedron Lett. 2005, 46, 9053.
(11) Kumagai, N.; Muncipinto, G.; Schreiber, S. L. Angew. Chem., Int.
Ed. 2006, 45, 3635.
(12) For a recent example of a related application involving functional
group pairing, see: Comer, E.; Rohan, E.; Deng, L.; Porco, J. A., Jr. Org.
Lett. 2007, 9, 2123.
(13) For some examples, see: (a) Martin, S. F.; Benage, B.; Geraci, L.
S.; Hunter, J. E.; Mortimore, M. J. Am. Chem. Soc. 1991, 113, 6161. (b)
Martin, S. F.; Clark, C. C.; Corbett, J. W. J. Org. Chem. 1995, 60, 3236.
(c) Ito, M.; Clark, C. C.; Mortimore, M.; Goh, J. B.; Martin, S. F. J. Am.
Chem. Soc. 2001, 123, 8003.
(14) For a review of additions to N-acyl iminium ions, see: Speckamp,
W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817. For more recent
examples see: (a) Fischer, C.; Carriera, E. M. Org. Lett. 2004, 6, 1497. (b)
Black, D. A.; Arndtsen, B. A. J. Org. Chem. 2005, 70, 5133. (c) Wei, C.;
Li, C.-J. Lett. Org. Chem. 2005, 2, 410. (d) Black, D. A.; Arndtsen, B. A.
Tetrahedron 2005, 61, 11317. (e) Black, D. A.; Arndtsen, B. A. Org. Lett.
2006, 8, 1991. (f) Zhang, L.; Malinakova, H. C. J. Org. Chem. 2007, 72,
1484.
The nature of the aldehyde component may also be altered
to access other cyclization manifolds and different hetero-
cyclic systems. For example, use of 2-bromobenzaldehyde
(14) in the 4CR generates substrates amenable to Heck
cyclizations (Scheme 3). To this end, the tertiary amide 15
(16) For a review of enantioselective additions to CdN bonds, see:
Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541.
(17) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
(15) For a related 4CR, see: Yin, Y.; Zhao, G.; Li, G.-L. Tetrahedron
2005, 61, 12042.
4224
Org. Lett., Vol. 9, No. 21, 2007

Scheme 3. Sequential MCR/RCM/Heck Reaction
Scheme 5. Sequential MCR/Heck Cyclization
was synthesized and subjected to a two step sequence of
cyclizations involving first a RCM and then a Heck reaction
to give 16.
In a similar sequence of reactions, the protected indole-
carboxaldehyde 17 was converted into 18 that was then
elaborated into the bridged bicyclic tetracycle 19 by sequen-
tial RCM and Heck reactions (Scheme 4). Both 16 and 19
might be condensed with selected amines to generate 1,3-
dipoles that would react with proximal double or triple bonds
via [3+2] dipolar cycloadditions to generate diverse hetero-
cyclic scaffolds. To investigate the feasibility of this strategy
for DOS, the bromoaldehyde 14 was first treated with bis-
(trimethylsilyl)allylamine in the presence of catalytic amounts
of TMSOTf, whereupon acetyl chloride and the enol ether
23 were added to deliver the adduct 24 in 78% yield (Scheme
6). When 24 was condensed with sarcosine in refluxing
Scheme 4. Sequential MCR/RCM/Heck Cyclization
Scheme 6. Sequential MCR/[3+2] Dipolar Cycloaddition
possess functionality that might be exploited for additional
diversification.
Having explored nucleophiles that enabled RCM as one
of the possible cyclization manifolds, we turned our attention
to other nucleophiles such as ketene acetals and enol ethers
that would permit us to develop other cyclizations to create
heterocyclic products. After some experimentation, we
discovered that multicomponent reactions using these nu-
cleophiles proceeded more efficiently when the imines were
generated from the reactions of aldehydes with bis(tri-
methylsilyl)alkylamines in the presence of catalytic amounts
in TMSOTf.18 This tactic for imine formation is a nice
complement to the more common reaction of an amine with
an aldehyde.
Accordingly, treatment of the indolic aldehyde 17 with
commercially available bis(trimethylsilyl)allylamine in the
presence of 10 mol % TMSOTf smoothly provided an
intermediate imine that was treated in situ with acetyl
chloride and the silyl ketene acetal 20 to furnish the amide
21 in 72% yield (Scheme 4). When the bromoindole 21 was
heated in a microwave oven in the presence of 10%
Pd(OAc)2, 20% PPh3, and Et3N, a Heck cyclization occurred
giving 22a in 85% yield and its isomer 22b (12% yield).
The ester and olefin functions would then serve as points
for subsequent elaborations.
toluene, the intermediate azomethine ylide readily underwent
a [3+2] cycloaddition to give 25. Similarly, the reaction of
24 with N-methylhydroxylamine under the same conditions
generated a nitrone that underwent facile [3+2] cycloaddition
to provide 26.19 Both 25 and 26 are nicely functionalized
for a number of further transfomations.
The intramolecular Diels-Alder reaction is another pow-
erful reaction for the synthesis of complex molecules, so we
selected inputs that would enable such transformations on
the intermediate MCR adducts. For example, we discovered
that when pentadienyl trimethylsilane 29 and acryloyl
chloride were added to the imine generated in situ from the
reaction of 3,4-dimethoxybenzaldehyde (27) with bis(tri-
methylsilyl)allylamine in the presence of 10 mol %
TMSOTf, the resulting product underwent spontaneous
The use of silyl enol ethers as inputs in the 4CR generates
aldehydes that can potentially be used in a variety of
subsequent transformations. For example, such aldehydes
(19) The stereochemistry of 25 was established by correlating its NMR
spectra with those of the corresponding aryl iodide, which was prepared
similarly and the structure of which was established by X-ray analysis of
its hydrochloride salt. The structure of 26 was also verified by X-ray analysis
of its hydrochloride salt.
(18) Morimoto, T.; Sekiya, M. Chem. Lett. 1985, 1371.
Org. Lett., Vol. 9, No. 21, 2007
4225

Scheme 7. Tandem MCR/Diels-Alder and Dipolar
Scheme 8. First Synthesis of (()-Roelactamine (36)
Cycloadditions
sequentially with the benzyl Grignard reagent 33 and then
the acid chloride 34 to provide 35 (Scheme 8). When 35
was treated with concentrated HCl/MeOH (2:1), it underwent
facile double cyclization to give (()-roelactamine (36), an
alkaloid that was isolated in 1992 from Roemeria refracta
DC.23
[4+2] cyclization to give 30 in 78% yield (Scheme 7).20 The
stereochemistry of 30 was established by hydride reduction
to the corresponding amine and X-ray analysis of its
methiodide salt. In a related cascade reaction, condensation
of 2-azidobenzaldehyde (28) with propargyl amine furnished
an imine that was treated with acetyl chloride and the ketene
acetal 20 to furnish the triazole 31 via a [3+2] dipolar cyclo-
addition.
The preceding examples nicely highlight how adducts
obtained from multicomponent reactions involving amines,
aldehydes, acylating agents, and organometallic reagents can
be rapidly transformed by cascade reactions to generate
polycyclic heterocycles that are endowed with useful func-
tionality for further manipulation and diversification. The
versatility of this strategy for DOS may be further exempli-
fied by its application to natural product synthesis. In
particular, we envisioned that such a four-component reaction
might be exploited to assemble compounds such as 35, which
might serve as precursors of the doubly benzanulated
azabicyclo[3.2.2]nonane core structures found in the iso-
pavine family of alkaloids.21,22 Gratifyingly, we discovered
that the condensation of piperonal (32) with methylamine
provided an imine in situ that was allowed to react
In summary, we have developed a novel approach for DOS
that may be applied to the facile synthesis of a broad range
of functionalized heterocycles. The key element of the
strategy is a one pot process incorporating four components
to assemble highly functionalized templates that may be
transformed via various cyclization manifolds into a diverse
collection of functionalized heterocyclic scaffolds containing
several new rings. The flexibility associated with each of
the inputs of the MCR allows for the incorporation of a broad
range of functional groups and substituents that serve as
initiation points for further diversification. The utility of this
strategy for DOS was further exemplified by its application
to the first synthesis of the isopavine alkaloid (()-roelac-
tamine (36). Applications of this methodology to the
synthesis of novel libraries of heterocycles may be easily
envisioned.
Acknowledgment. We thank the National Institutes of
Health (GM 25439), Pfizer, Inc., Merck Research Labora-
tories, and the Robert A. Welch Foundation for their generous
support of this research and Dr. Vincent Lynch (University
of Texas at Austin) for performing X-ray crystallography.
(20) For a related reaction, see: Yamaguchi, R.; Hamasaki, T.; Sasaki,
T.; Ohta, T.; Utimoto, K.; Kozima, S.; Takaya, H. J. Org. Chem. 1993, 58,
1136.
(21) Go¨zler, B.; Lantz, M. S.; Shamma, M. J. J. Nat. Prod. 1983, 46,
293.
Supporting Information Available: Representative ex-
perimental procedures for conducting multicomponent reac-
1
tions and copies of H and 13C NMR spectra for all new
(22) For selected syntheses, see: (a) Gozler, B. The Alkaloids; Brossi,
A, Ed.; Academic Press: New York, 1987; Vol. 31, pp 343. (b) Gottlieb,
L.; Meyers, A. I. J. Org. Chem. 1990, 55, 5659. (c) Carrillo, L.; Bad´ıa, D.;
Dom´ınguez, E.; Vicario, J. L.; Tellitu, I. J. Org. Chem. 1997, 62, 6716. (d)
Shinohara, T.; Takeda, A.; Toda, J.; Sano, T. Heterocycles 1998, 48, 981.
(e) Dragoli, D. R.; Burdett, M. T.; Ellman, J. A. J. Am. Chem. Soc. 2001,
123, 10127. (f) Tambar, U. K.; Enber, D. C.; Stoltz, B. M. J. Am. Chem.
Soc. 2006, 128, 11752.
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL7018357
(23) Go¨zler, B.; O¨ nu¨r, M. A.; Bilir, S.; Hesse, M. HelV. Chem. Acta.
1992, 75, 260.
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