Multicomponent assembly and diversification of novel heterocyclic scaffolds derived from 2-arylpiperidines

Article abstract of DOI:10.1021/ol201010s

A collection of structurally diverse, polyheterocyclic scaffolds comprising a 2-arylpiperidine subunit were synthesized using a Mannich-type multicomponent assembly process, followed by appropriately sequenced ring-forming reactions. An improved procedure

Full text of DOI:10.1021/ol201010s

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3102–3105
Multicomponent Assembly and
Diversification of Novel Heterocyclic
Scaffolds Derived from 2-Arylpiperidines
Simon Hardy and Stephen F. Martin*
Department of Chemistry and Biochemistry, The Texas Institute for Drug and
Diagnostic Development, The University of Texas at Austin, Austin, Texas 78712,
United States
sfmartin@mail.utexas.edu
Received April 15, 2011
ABSTRACT
A collection of structurally diverse, polyheterocyclic scaffolds comprising a 2-arylpiperidine subunit were synthesized using a Mannich-type
multicomponent assembly process, followed by appropriately sequenced ring-forming reactions. An improved procedure for removal of N-4-
pentenoyl groups was developed; one-pot sequences for tandem urea/thiourea formation and cyclization and tandem enolate arylation/alkylation
were discovered. A novel entry to bridged tetrahydroquinoline scaffolds exploiting A1,3 strain was also invented. Derivatization of several
scaffolds was achieved by cross-coupling and N-functionalization.
The continuing demand for small molecules with useful
therapeutic properties has necessitated more expedient
access to screening libraries containing diverse heterocyclic
scaffolds.1 The identification of so-called privileged sub-
structures, chemotypes that interact with multiple biologi-
cal targets, and their inclusion in chemical libraries has
proven effective toward discovering small molecule probes
to study a broad range of known and emerging biological
targets.2 In order to prepare such compounds, there is a
continuing need for developing new approaches that en-
able the rapid generation of functionalized heterocycles
that may be easily elaborated and derivatized.
diversity-oriented synthesis (DOS).3 This strategy involves
the construction of molecular frameworks followed by
parallel, complexity-generating, ring-forming reactions.
We have developed a novel and useful variant of this
strategy that features a Mannich-type multicomponent
assembly process (MCAP) to generate intermediates that
may be quickly elaborated by ring-forming reactions that
are preprogrammed by the functionality present in the
inputs in the MCAP.4,5 Ideally, one would be able to access
different, functionalized scaffolds having privileged struc-
tures from a single intermediate that is generated by the
(3) (a) Comer, E.; Rohan, E.; Deng, L.; Porco, J. A., Jr. Org. Lett.
2007, 9, 2123–2126. (b) Nielsen, T. E.; Schreiber, S. L. Angew. Chem.,
Int. Ed. 2008, 47, 48–56. (c) Sunderhaus, J. D.; Martin, S. F. Chem.;
Eur. J. 2009, 15, 1300–1308.
One successful approach toward this end is the build/
couple/pair approach that was pioneered in the context of
(1) (a) Lipinski, C. A.; Lombard, F.; Dominy, B. W.; Feeney, P. J.
Adv. Drug Delivery Rev. 1997, 23, 3–25. (b) Ghose, A. K.; Viswanadhan,
V. N.; Wendoloski, J. J. J. Comb. Chem. 1999, 1, 55–68. (c) Lovering, F.;
Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752–6756.
(2) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893–930. (b) Che, Y.; Brooks, B. R.; Marshall, G. R. J. Comput.-
Aided Mol. Des. 2006, 20, 109–130. (c) Welsch, M. E.; Snyder, S. A.;
Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347–361.
(4) For the original application of this approach, see: Martin, S. F.;
Benage, B.; Geraci, L. S.; Hunter, J. E.; Mortimore, M. P. J. Am. Chem.
Soc. 1991, 113, 6161–6171.
(5) (a) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Org. Lett.
2007, 9, 4223–4226. (b) Sunderhaus, J. D.; Dockendorff, C.; Martin,
S. F. Tetrahedron 2009, 65, 6454–6469. (c) Donald, J. R.; Martin, S. F.
Org. Lett. 2011, 13, 852–855. (d) Sahn, J. J.; Su, J. Y.; Martin, S. F. Org.
Lett. 2011, 13, 2590–2593.
r
10.1021/ol201010s
Published on Web 05/20/2011
2011 American Chemical Society

multicomponent assembly process. We now report the
successful realization of this goal and its application to the
diversity-oriented synthesis of compounds having the fused
aryl piperidine substructures 1 and 2 in which the secondary
amino group serves as a handle for further skeletal diversi-
fication (Figure 1). Significantly, the 2-arylpiperidine sub-
unit is present in NK1 receptor antagonists such as 3,6 and
the cis-fused octahydropyrrolo[3,2-c]pyridine core in 2 is
found in CCR 5 antagonists as exemplified by 4.7
Scheme 1. Multicomponent Assembly of Amines 13 and 14
The versatility of the aldehyde 9 as a precursor of other
heterocyclic systems was then explored. For example,
condensation of 9 with N,O-bis(trimethylsilyl)sarcosine
(15) in toluene at room temperature, followed by thermo-
lysis of the putative intermediate oxazolidinone at 135 °C
in a sealed tube, afforded 17 in 62% yield (Scheme 2).9,10
The yield of the corresponding reaction of 9 with sarcosine
(16) togive17waslower-yielding, withβ-eliminationof the
amide moiety from the starting aldehyde 9 being a major
side reaction. Reaction of 17 with iodine in a mixture
of THF and aqueous HCl gave the desired secondary
amine 18. Optimal selectivity for cleavage of the amide
17 required a higher concentration of HCl than was used
for hydrolysis of amide 11. The amine 18 thus obtained is a
versatile substrate for the generation of libraries based on
N-functionalizations such as sulfonylation to furnish 19.
Figure 1. MCAP-derived 2-arylpiperidines 1 and 2 and related
bioactive compounds 3 and 4.
On the basis of previous work, we envisioned that
dipolar cycloadditions of unsaturated aldehydes would
lead to suitable precursors of 1 and 2.5 We had also found
that acid chlorides are the preferred electrophilic activators
of imines toward addition reactions with π-nucleophiles in
Mannich-type, multicomponent assembly processes. Be-
cause most tertiary amide derivatives of 1 and 2 would be
difficult to hydrolyze to give the secondary amines 1 and 2,
it was necessary to identify a tertiary amide moiety that
could be easily removed. It had been shown that N-4-
pentenamides can be cleaved under mild conditions,8 so we
queried whether the amides 9 and 10 would serve as viable
intermediates for preparing 1 and 2. Accordingly, con-
densation of bromobenzaldehydes 5 and 6 with allylamine
gave intermediate imines that were allowed to react in situ
with 4-pentenoyl chloride (7) and vinyl ether 8 in the
presence of catalytic amounts of TMSOTf to furnish 9
and 10 in very good overall yields (Scheme 1). Heating 9
and 10 with N-methylhydroxylamine and intramolecular
dipolar cycloaddition of the intermediate nitrones gave the
isoxazolidines 11 and 12 as single diastereomers. The
relative configuration of 11 was confirmed by X-ray
crystallography. Treatment of 11 and 12 with iodine in a
mixture of THF and aqueous HCl led to facile removal of
the N-4-pentenoyl group and formation of 13 and 14,
respectively. The presence of HCl in this modified protocol
for removing N-4-pentenoyl groups was essential to mini-
mize side reactions involving iodohydrin formation that
ensued when water alone was used as a cosolvent.
Scheme 2. Access to Pyrrolidine-Fused Scaffolds by an Azo-
methine Ylide Cycloaddition
We then explored several tactics for two-dimensional
diversification of these scaffolds using the (4-bromop-
henyl)piperidines 12 and 14. For example, Suzukiꢀ
Miyaura coupling of 14 was readily effected on treatment
with various arylboronic acids using Pd(PPh3)4 as the
catalyst to give biphenyls as illustrated by the preparation
of 20 (Scheme 3).11 The secondary amine moiety in 20 is
amenable to a variety of N-functionalization processes as
exemplified by reductive alkylation of 20 to give amine 21.
(6) Xiao, D.; Palani, A.; Wang, C.; Tsui, H.-C.; Shih, N.-Y.; Reichard,
G. A. European Patent EP 1,747,221, April 6, 2005.
(7) Shah, S. K.; Chen, N.; Guthikonda, R. N.; Mills, S. G.; Malkowitz,
L.; Springer, M. S.; Gould, S. L.; DeMartino, J. A.; Carella, A.; Carver, G.;
Holmes, K.; Schleif, W. A.; Danzeisen, R.; Hazuda, D.; Kessler, J.;
Lineberger, J.; Miller, M.; Emini, E. A.; MacCoss, M. Bioorg. Med. Chem.
Lett. 2005, 15, 977–982.
(9) Marx, M. A.; Grillot, A.-L.; Louer, C. T.; Beaver, K. A.; Bartlett,
P. A. J. Am. Chem. Soc. 1997, 119, 6153–6167.
(10) Grigg, R.; Idle, J.; McMeekin, P.; Vipond, D. J. Chem. Soc.,
Chem. Commun. 1987, 49–51.
(8) Madsen, R.; Roberts, C.; Fraser-Reid, B. J. Org. Chem. 1995, 60,
7920–7926.
(11) Hadjuk, P. J.; Bures, M.; Praestgaard, J.; Fesik, S. W. J. Med.
Chem. 2000, 43, 3443–3447.
Org. Lett., Vol. 13, No. 12, 2011
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Pd(OAc)2/BINAP, and Cs2CO3 was stirred at room tem-
perature; once urea formation was complete, the mixture
was simply heated to provide 29 via a palladium-catalyzed
intramolecular N-arylation (Scheme 5).15 It is important to
ensure complete formation of the intermediate urea 28
before heating; mixtures of cyclized and uncyclized ureas
are otherwise obtained. The dihydroquinazolin-2-one sub-
structure present in 29 is found in Naþ/Ca2þ exchange
inhibitors and antipsychotic agents.16,17 In a related trans-
formation, the amine 13 was subjected to a novel one-pot
sequence of thiourea formation and palladium-catalyzed
cyclization to give the 2-imino-1,3-benzothiazinane 31 via
the intermediate thiourea 30.18 It is necessary to use Pd[(t-
Bu3P)]2 in order to obtain good yields in this latter process.
Scheme 3. Biaryl Synthesis via Suzuki Coupling
Although the secondary amine 14 can be used as a
starting material in carbonꢀcarbon bond-forming cross-
couplings, it was necessary to employ the corresponding
amide 12 in order to engage the aryl bromide moiety in
carbonꢀheteroatom bond-forming reactions. For exam-
ple, the amide 12 underwent Ullmann-type coupling with
imidazole in the presence of CuBr and the β-ketoester
ligand 22to afford the N-arylimidazole23(Scheme 4).12 N-
Arylimidazoles are structures of biological interest and are
found in several compounds with anticonvulsant activity.13
The analogous BuchwaldꢀHartwig coupling of 12 with
piperidine using Pd(OAc)2 and the phosphine ligand 24
provided the N-arylpiperidine 25.14 Subsequent removal of
the pentenamide group from 25 delivered the amine 26.
That 26 is a useful substrate for diversification by N-
functionalization is illustrated by formation of the urea
27 on treatment of 26 with ethyl isocyanate.
Scheme 5. Synthesis of the Dihydroquinazolin-2-one 29 and
2-Imino-1,3-benzothiazinane 31
Scheme 4. Cross-Coupling of 12 with Nitrogen Nucleophiles
and N-Refunctionalization
It occurred to us that we might also form carbonꢀ
carbon bonds to form new rings via enolate arylations.
In this context, we discovered that reaction of 32, which
was obtainedby N-acylation ofamine 13withphenylacetyl
chloride, with excess LDA in the presence of DMPU
effected the desired cyclization, presumably via a benzyne
intermediate (Scheme 6).19 In situ methylation of the
intermediate enolate 33 resulting from this process pro-
ceeded from the sterically more accessible face to give 34
with >95:5 dr (LCꢀMS).20,21 Although quenching 33
with 3,5-di-tert-butyl-4-hydroxytoluene (BHT) occurred
with high diastereoselectivity, the resulting lactam 35 un-
derwent facile epimerization to give mixtures (ca. 2:1) of
diastereomers. Thebiological relevanceofcompoundssuch
as 34 arises from the observation that 4,4-disubstituted
(15) Ferraccioli, R.; Carenzi, D. Synthesis 2003, 1383–1386.
(16) Hasegawa, H.; Muraoka, M.; Ohmori, M.; Matsui, K.; Kojima,
A. Bioorg. Med. Chem. 2005, 13, 3721–3735.
In addition to the obvious possibilities for generating
libraries from the parent scaffolds 11, 12, and 17 and their
derived amines, we were intrigued by the opportunity
of using these cycloadducts as precursors of more com-
plex heterocycles. For example, a one-pot sequence was
developed in which a mixture of 13, phenyl isocyanate,
(17) Orjales, A.; Mosquera, R.; Toledo, A.; Pumar, C.; Labeaga, L.;
ꢀ
Innerarity, A. Eur. J. Med. Chem. 2002, 37, 721–730.
(18) For a related reaction, see: Orain, D.; Blumstein, A.-C.; Tasdelen,
E.; Haessig, S. Synlett 2008, 2433–2436.
(19) For examples of base-mediated enolate arylations via benzynes,
see: (a) Kessar, S. V.; Singh, P.; Chawla, R.; Kumar, P. J. Chem. Soc.,
Chem. Commun. 1981, 1074–1075. (b) Flann, C. J.; Overman, L. E.;
Sarkar, A. K. Tetrahedron Lett. 1991, 32, 6993–6996.
(12) Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863–3867.
(13) Ohmori, J.; Sakamoto, S.; Kubota, H.; Shimizu-Sasamata, M.;
Okada, M.; Kawasaki, S.; Hidaka, K.; Togami, J.; Furuya, T.; Murase,
K. J. Med. Chem. 1994, 37, 467–475.
(20) For another example of a tandem enolate arylation/alkylation
process, see: Goehring, R. R.; Sachdeva, Y. P.; Pisipati, J. S.; Sleevi,
M. C.; Wolfe, J. F. J. Am. Chem. Soc. 1985, 107, 435–443.
(21) The structure of 34 was established by X-ray crystallographic
analysis of its quaternary methiodide salt.
(14) Zim, D.; Buchwald, S. L. Org. Lett. 2003, 5, 2413–2415.
3104
Org. Lett., Vol. 13, No. 12, 2011

Scheme 6. Dihydroisoquinolin-3-one Synthesis by a Diastereo-
selective Tandem Enolate Arylation/Alkylation
Scheme 7. Synthesis and Diversification of Amino Alcohol 38
Exploiting A1,3 Strain of N-Acyl-2-arylpiperidines
dihydroisoquinolin-3-ones have vasorelaxant properties,22
and several 4-aryltetrahydroisoquinolines exhibit central
nervous system activity.23 Reductive cleavage of the
isoxazolidine NꢀO bond of 34 with nickel boride provided
the amino alcohol 36, which is primed for further diversi-
fication by a variety of N-functionalizations.
followed by dipolar cycloadditions to generate diverse
collections of 2-arylpiperidines. New aspects of the process
include use of the 4-pentenoyl group as an activating
electrophile in the MCAP and as an amine-protecting
group that is easily removed using iodine in the presence
of aqueous acid. This new tactic for deprotecting N-4-
pentenoyl groups will render it more attractive for
future applications. The versatility of the initially formed
cycloadducts as precursors of diverse heterocyclic
cores that are suitably functionalized for further transfor-
mations was established. Indeed, the methods developed
for tandem urea or thiourea formation and cyclization as
well as enolate arylation and alkylation will be broadly
applicable in DOS. The novel entry to bridged tetrahy-
droquinoline scaffolds exploiting A1,3 strain is also
expected to be generally useful. The application of these
techniques to the synthesis of pilot-scale compound
libraries is ongoing, and further results will be reported
in due course.
Several strategies for further transforming amino alco-
hols derived from isoxazolidines may be illustrated begin-
ning with the cycloadduct 37, which was prepared as
previously described.5 Although reductive cleavage of the
NꢀO bond in 37 with nickel boride was accompanied with
extensive dehalogenation, use of zinc in aqueous HCl at
0 °C gave 38 in 83% yield (Scheme 7).24 N-Acylation of 38
proceeded with concomitant O-acylation; however, the
simple expedient of protecting the primary hydroxyl group
in 38 in situ as a TMS ether enabled highly efficient amide
formation as exemplified by a one-pot synthesis of 39.
The cis relationship between the methylamino group
and the 2-bromphenyl substituent in 38 can be exploited by
an intramolecular BuchwaldꢀHartwig coupling, which
was achieved by heating 38 in the presence of Pd(OAc)2/
BINAP and Cs2CO3, to give the bridged tetrahydroquino-
line 40 (Scheme 7). The preferred axial orientation of the
aryl group in 38 that is enforcedby A1,3 strain involving the
N-acetyl group presumably facilitates cyclization.25 The
conformationally constrained bicyclic tetrahydroquino-
line framework in 40 is a promising scaffold for DOS as
exemplified by using the primary alcohol in 40 as a
functional handle in a Mitsunobu reaction to give the
succinimide 41.
Acknowledgment. We thank the National Institutes of
Health (GM 86192) and the Robert A. Welch Foundation
(F-0652) for their generous support of this work. We also
thank Dr. Vincent Lynch (University of Texas at Austin)
for performing X-ray crystallography.
Supporting Information Available. Experimental pro-
1
cedures, spectral data and copies of H NMR and 13C
NMR spectra for all new compounds and 15, and CIF
files for 11 and the methiodide salt of 34. This material is
available free of charge via the Internet at http://pubs.acs.
org.
In summary, we have significantly expanded the scope
of our Mannich-type, multicomponent assembly process
(22) Lin, C. H.; Lin, M. S.; Lin, Y. H.; Chen, I. M.; Lin, P. R.; Cheng,
C-.Y.; Tsai, M. C. Pharmacology 2003, 67, 202–210.
(23) Garris, P. A.; Ben-Jonathon, N. Brain Res. 1991, 556, 123–129.
(24) Stephens, B. E.; Liu, F. J. Org. Chem. 2009, 74, 254–263.
(25) (a) Johnson, F. Chem. Rev. 1968, 68, 375–413. For recent,
related applications, see: (b) Coombs, T. C.; Lushington, G. H.;
Douglas, J.; Aube, J. Angew. Chem., Int. Ed. 2011, 50, 2734–2737.
(c) Reference 5d.
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