A one-pot, three-component approach to functionalised tetrahydroisoquinolines using domino Heck-aza-Michael reactions

Article abstract of DOI:10.1002/ejoc.201001621

A one-pot, three-component method incorporating a domino Heck-aza-Michael reaction has been developed for the rapid synthesis of functionalised tetrahydroisoquinolines. Following the in situ generation of an acrylamide, a domino process involving intermol

Full text of DOI:10.1002/ejoc.201001621

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001621
A One-Pot, Three-Component Approach to Functionalised
Tetrahydroisoquinolines Using Domino Heck–aza-Michael Reactions
Daniel L. Priebbenow,[a] Frederick M. Pfeffer,*[a] and Scott G. Stewart*[b]
Keywords: Tetrahydroisoquinoline / Multicomponent reactions / Domino reactions / Heck reaction / Aza-Michael
addition / Palladium
A one-pot, three-component method incorporating a domino
Heck–aza-Michael reaction has been developed for the rapid
synthesis of functionalised tetrahydroisoquinolines. Follow-
ing the in situ generation of an acrylamide, a domino process
involving intermolecular Heck reaction and subsequent
intramolecular aza-Michael addition affords tetrahydroiso-
quinolines bearing C1-acetamide functionality.
Attempted domino Heck–aza-Michael processes, where the
alkene employed has been generated in situ, have not been
successful.[1a]
Introduction
In recent years, palladium-catalysed domino Heck–aza-
Michael reactions have been developed for the synthesis of
a range of functionalised N-heterocycles including benzo-
fused sultams,[1] tetrahydro-β-carbolines,[2] tetrahydroiso-
quinolines,[2b,3] isoindolines[2b] and isoindolinones.[4] These
N-heterocyclic scaffolds have been prepared by treating aryl
halides with relatively cheap palladium catalysts and are
somewhat limited to the range of commercially available ac-
rylate-based starting materials. The ideal domino Heck–
aza-Michael process would allow for the use of function-
alised electron-deficient terminal alkenes. As such, the
scope of these reactions could be dramatically improved if,
in one pot, the alkene could be readily generated and then
undergo the domino Heck–aza-Michael reaction.
The tetrahydroisoquinoline scaffold is central to a
number of naturally occurring alkaloids, some of which ex-
hibit interesting biological activity as antitumor and anti-
biotic agents.[5] The C1-acetamide tetrahydroisoquinoline
core (Figure 1) has also been employed in medicinal chem-
istry studies,[6] for example compound 1, which was devel-
oped as a ligand for the melanocortin subtype-4 receptor.[7]
Further examples include those generated as reversible in-
hibitors of cysteine proteases,[8] as well as bradykinin 1 an-
tagonists for treating pain and inflammation (compound 2,
Figure 1).[9]
One-pot, multicomponent processes, like domino reac-
tions, are an efficient means of completing multiple syn-
thetic steps without the need for purification of intermedi-
ates. Three-component domino Heck–aza-Michael reac-
tions to date have involved variations in the domino precur-
sor, that is, the first step of the multicomponent reaction
was the preparation of the aryl halide.[1,3] However, the elec-
tron-deficient terminal alkenes employed for these three-
component domino reactions have been limited to commer-
cially available ester, carboxylic acid and ketone derivatives.
Figure 1. C1-amide substituted tetrahydroisoquinoline medical
chemistry agents.
A range of synthetic strategies have been reported to
access C1-substituted tetrahydroisoquinoline scaffolds.[3,10]
Our group has recently discovered a palladium-catalysed
domino Heck–aza-Michael reaction for the synthesis
[a] School of Life and Environmental Sciences, Deakin University
Geelong 3217, Victoria, Australia
Fax: +61-3-5227 1040
E-mail: fred.pfeffer@deakin.edu.au
[b] School of Biomedical, Biomolecular and Chemical Sciences,
University of Western Australia,
of
a series of C1-substituted tetrahydroisoquinolines
(Scheme 1).[2b] The domino Heck–aza-Michael process re-
quires a catalytic system that facilitates fast Heck reaction
between the domino precursor and an electron-deficient ter-
minal alkene. Following this process aza-Michael cycli-
sation takes place to form the new N-heteroycle (Scheme 1).
Crawley 6009, Western Australia, Australia
Fax: +61-8-6488 1005
E-mail: sgs@cyllene.uwa.edu.au
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001621.
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Functionalised Tetrahydroisoquinolines
Scheme 1. Domino Heck–aza-Michael reaction to access C1-substituted tetrahydroisoquinolines.
Scheme 2. Proposed three-component domino Heck–aza-Michael reaction to access tetrahydroisoquinolines.
Using this method tetrahydroisoquinolines 4–8 were formed served when the reaction was repeated by using only acryl-
by reaction of 2-bromophenethylamine (3) with commercial oyl chloride; attempts to also generate the tetrahydroiso-
acrylates using either the Pd(OAc)2/PPh3 or the Pd(OAc)2/ quinolines in a multicomponent manner where all reagents
DavePhos in K2CO3 and toluene catalytic system.
were present from the outset, also failed.) Following this
This methodology allowed for the incorporation of vari- initial success, a range of amines, varying in nucleophilic
ous functionalities at R including ester, nitrile and ketone; character were subsequently used in this one-pot process.
however, neither the reaction with acrylic acid nor acryl- The amines, including alkyl primary amines (Table 1, En-
amide was amenable (most likely due to deprotonation un- tries 1–7), arylamines (Table 1, Entries 8–10), acyclic sec-
der the reaction conditions). As the generation of tetra- ondary amines (Table 1, Entries 11), cyclic secondary
hydroisoquinolines bearing C1-acetamide functionality was amines (Table 1, Entries 12–13), and amino acids (Table 1,
desirable, a modification of the original domino process was entries 14–16), were tested to explore the scope of this reac-
sought. To this end, a three-component domino Heck–aza- tion sequence.
Michael process that would provide rapid and efficient ac-
The first attempt with tryptamine only resulted in trace
cess to C1-functionalised tetrahydroisoquinolines was de- amounts of the desired tetrahydroisoquinoline. This lack of
vised (Scheme 2). Nucleophilic addition of primary or sec- reactivity appeared to be due to the insolubility of either
ondary amines 12 to acryloyl chloride (11), prior to the the initial amine or corresponding acrylamide in toluene.
aforementioned domino reaction would afford a vast array To overcome this, a few drops of DMF were added to the
of acrylamides. If acrylamide formation occurred under the reaction mixture following addition of the amine nucleo-
same mildly basic conditions required for both the Heck phile. This approach quickly proved successful with the
and aza-Michael steps in this domino process, a sequential second attempt using tryptamine to afford tetrahydroiso-
one-pot three-component acylation and domino Heck–aza- quinoline 14 in 92% yield (Entry 2, Table 1). During the
Michael reaction for the synthesis of tetrahydroisoquinol- synthesis of a series of C1-acetamide substituted tetra-
ines was plausible.
hydroisoquinolines, a number of other amines also required
Herein we report the first three-component domino the addition of DMF to improve solubility.
Heck–aza-Michael reaction, for the synthesis of function-
The one-pot, three-component domino Heck–aza-
alised tetrahydroisoquinolines, where in one pot, the elec- Michael process proved to be quite general, with high yields
tron-deficient alkene is generated, then subsequently un- (up to 97%) of the C1-acetamide tetrahydroisoquinolines
dergoes domino Heck–aza-Michael reaction.
observed when alkylamines, arylamines, secondary amines
and amino acids were used. Several of the tetrahydroiso-
quinolines accessed by using this methodology (14, 26, 27)
resemble a number of the aforementioned medicinal chem-
Results and Discussion
To investigate this one-pot process, benzylamine was ini- istry agents (Figure 1). The only limiting factor in this pro-
tially chosen as the amine nucleophile. This first reaction cess appeared to be solubility of the amine and correspond-
involved the addition of acryloyl chloride (11) to a solution ing acrylamide.
of benzylamine, and potassium carbonate in toluene. After
For the domino process employing 2-nitrobenzylamine
stirring at room temperature for 1 h, Pd(OAc)2, PPh3 and hydrochloride (Table 1, Entry 7), the in situ deprotection of
the 2-bromophenethylsulfonamide substrate 3 were added the 2-nitrobenzyl group occurred to afford tetrahydroiso-
sequentially and the resultant mixture heated to 120 °C for quinoline 19. The 2-nitrobenzyl group is readily cleaved un-
16 h. To our delight, a simple workup followed by flash der photolytic conditions in polar solvents (254–365 nm),[11]
chromatography afforded the desired N-benzylacet- As this reaction was carried out in toluene in a dark fume-
amidotetrahydroisoquinoline 13 in excellent yield (97%). hood, deprotection of the 2-nitrobenzyl group under our
(As expected, no domino product or Heck adduct was ob- reaction conditions was unexpected. However, the basic
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. L. Priebbenow, F. M. Pfeffer, S. G. Stewart
Table 1. (Continued).
SHORT COMMUNICATION
Table 1. Formation of functionalised tetrahydroisoquinolines by
using a three-component domino Heck–aza-Michael reaction.
[a] A few drops of DMF were added to aid in amine solubility. [b]
In situ deprotection of the 2-nitrobenzyl group occurred during
reaction, and the product isolated was the tetrahydroisoquinoline
acetamide in 32% yield. [c] When chiral amino acids were subject
to this domino process (Entries 14–15, Table 1) the resultant tetra-
hydroisoquinoline was isolated as a mixture of diastereomers in a
ratio of 1:1.
conditions and high temperatures employed in this reaction
sequence proved sufficient to cleave the 2-nitrobenzyl
group.
Multicomponent reactions using a chiral amino acid pre-
cursor (Table 1, Entries 14, 15) were carried out to identify
whether a stereoselective variant of this one-pot process was
achievable. The introduction of a stereogenic centre at the
C1-position of the newly formed tetrahydroisoquinoline
was monitored by NMR spectroscopy. Unfortunately, in
these particular cases where a chiral amino acid was used,
the products were determined to be present as a 1:1 mixture
of diastereomers, inseparable by standard column
chromatography. As such, the presence of a stereocentre in
the acrylamide R moiety had no significant induction ef-
fects on the stereochemistry at the C1-position of the tetra-
hydroisoquinoline heterocycle formed during the domino
process.
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Eur. J. Org. Chem. 2011, 1632–1635

Functionalised Tetrahydroisoquinolines
Hsiung, J. T. Mullaney, T. P. O’Brian, P. L. Ornstein, R. R.
Rothhaar, J. M. Zgombick, K. Briner, Bioorg. Med. Chem.
Lett. 2005, 15, 4459.
Conclusions
A domino Heck–aza-Michael process has been devel-
oped where in one pot, the electron-deficient alkene gener-
ated by reaction between acryloyl chloride and an amine,
undergoes domino Heck–aza-Michael reaction to afford a
series of C1-acetamide tetrahydroisoquinolines. This is the
first example of a domino Heck–aza-Michael reaction that
allows the electron-deficient terminal alkene to be readily
varied in a one-pot process. This multicomponent domino
reaction proved to be quite general, by using a range of
primary and secondary amines to afford functionalised
tetrahydroisoquinolines, in moderate to excellent yields (28–
97%). This one-pot process, when employed in a medicinal
chemistry setting would facilitate the rapid generation of
compound libraries.
[7]
a) Q. Shi, P. L. Ornstein, K. Briner, T. I. Richardson, M. B.
Arnold, R. T. Backer, J. L. Buckmaster, E. J. Canada, C. W.
Doecke, L. W. Hertel, N. Honigschmidt, H. M. Hsiung, S. Hu-
sain, S. L. Kuklish, M. J. Martinelli, J. T. Mullaney, T. P.
O’Brien, M. R. Reinhard, R. Rothhaar, J. Shah, Z. P. Wu, C. Y.
Xie, J. M. Zgombick, M. J. Fisher, Bioorg. Med. Chem. Lett.
2006, 16, 2341; b) J. Bullington, A. Metzger (Palatin Technol-
ogies Inc.), Amine Substituted Piperidine Melanocortin Recep-
tor-Specific Compounds, WO 2010/065799, 2010.
[8]
[9]
G. A. Dossetter, N. M. Heron (Astrazeneca AB), 1,2-Cyclohex-
ane Dicarboxamides as Cathepsin Inhibitors, WO 2009/001128,
2008.
a) G. Beke, É. Bozó, G. Czíra, J. Éles, S. Farkas, K. Hornok, É.
Schmidt, É. Szentirmay, I. Vágó, M. Vastag (Richter Gedeon
Vegyészeti Gyár RT), New Phenanthradine Derivatives as
Bradykinin Antagonists, WO 2007/072092, 2007; b) S. Ob-
erbörsch, M. Reich, B. Sundermann, W. Englberger, S. Hees,
R. Jostock, S. Schunck, E. Bijsterveld, F. Theil (Grünenthal
GmbH), Substituted Sulfonamide Derivatives, WO 2009/
115257, 2009; c) J. Huszar, Z. Timar, K. K. Szalai, G. Keseru,
F. Fulop, B. Penke, Eur. J. Med. Chem. 2008, 43, 1552.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed description of all experimental procedures and ana-
lytical data for all compounds.
[1] a) A. Rolfe, K. Young, P. R. Hanson, Eur. J. Org. Chem. 2008,
5254; b) A. Rolfe, K. Young, K. Volp, F. Schoenen, B. Neuen-
swander, G. H. Lushington, P. R. Hanson, J. Comb. Chem.
2009, 11, 732.
[10] a) E. D. Cox, J. M. Cook, Chem. Rev. 1995, 95, 1797; b) M.
Chrzanowska, M. D. Rozwadowska, Chem. Rev. 2004, 104,
3341; c) S. W. Youn, Org. Prep. Proced. Int. 2006, 38, 505; d)
A. B. J. Bracca, T. S. Kaufman, Tetrahedron 2004, 60, 10575; e)
W. J. Huang, O. V. Singh, C. H. Chen, S. S. Lee, Helv. Chim.
Acta 2004, 87, 167; f) W. M. Whaley, T. R. Govindachari, Org.
React. 1951, 6, 151; g) A. S. Capilla, M. Romero, M. D. Pujol,
D. H. Caignard, P. Renard, Tetrahedron 2001, 57, 8297; h) D. S.
Kashdan, J. A. Schwartz, H. Rapoport, J. Org. Chem. 1982, 47,
2638; i) M. Nicoletti, D. O’Hagan, A. M. Z. Slawin, J. Chem.
Soc. Perkin Trans. 1 2002, 116; j) J. Selvakumar, A. Makri-
yannis, C. R. Ramanathan, Org. Biomol. Chem. 2010, 8, 4056;
k) D. Enders, J. X. Liebich, G. Raabe, Chem. Eur. J. 2010, 16,
9763; l) M. Amat, V. Elias, N. Llor, F. Subrizi, E. Molins, J.
Bosch, Eur. J. Org. Chem. 2010, 4017; m) I. Schuster, L. Lazar,
F. Fulop, Synth. Commun. 2010, 40, 2488; n) L. F. Tietze, Y. F.
Zhou, E. Topken, Eur. J. Org. Chem. 2000, 2247; o) L. F.
Tietze, N. Rackelmann, I. Muller, Chem. Eur. J. 2004, 10, 2722;
p) I. Bonnaventure, A. B. Charette, Tetrahedron 2009, 65, 4968.
[11] a) W. Wu, B. P. Stupi, V. A. Litosh, D. Mansouri, D. Farley, S.
Morris, S. Metzker, M. L. Metzker, Nucleic Acids Res. 2007,
35, 6339; b) B. B. Snider, M. V. Busuyek, Tetrahedron 2001, 57,
3301; c) P. C. Huang, G. J. Hsu, B. R. Zhuang, K. Sung, Amino
Acids 2008, 34, 449.
[2] a) D. L. Priebbenow, L. C. Henderson, F. M. Pfeffer, S. G. Ste-
wart, J. Org. Chem. 2010, 75, 1787; b) D. L. Priebbenow, S. G.
Stewart, F. M. Pfeffer, Org. Biomol. Chem. 2011, 9, 1508.
[3] R. Ferraccioli, D. Carenzi, M. Catellani, Tetrahedron Lett.
2004, 45, 6903.
[4] M. Wahab Khan, A. F. G. Masud Reza, Tetrahedron 2005, 61,
11204.
[5] a) K. W. Bentley, Nat. Prod. Rep. 2006, 23, 444; b) J. A. Bjork-
lund, T. Frenzel, M. Rueffer, M. Kobayashi, U. Mocek, C. Fox,
J. M. Beale, S. Groger, M. H. Zenk, H. G. Floss, J. Am. Chem.
Soc. 1995, 117, 1533; c) J. D. Scott, R. M. Williams, Chem. Rev.
2002, 102, 1669; d) Y. Y. Chen, F. R. Chang, Y. C. Wu, J. Nat.
Prod. 1996, 59, 904; e) A. Moreau, A. Couture, E. Deniau, P.
Grandclaudon, S. Lebrun, Tetrahedron 2004, 60, 6169; f) V. G.
Kartsev, Med. Chem. Res. 2004, 13, 325; g) K. Takahashi, F.
Tomita, J. Antibiot. 1983, 36, 468; h) F. Tomita, K. Takahashi,
K. Shimizu, J. Antibiot. 1983, 36, 463.
[6] a) M. J. Fisher, R. T. Backer, I. Collado, O. de Frutos, S. Hu-
sain, H. M. Hsiung, S. L. Kuklish, A. I. Mateo, J. T. Mullaney,
P. L. Ornstein, C. G. Paredes, T. P. O’Brian, T. I. Richardson,
J. Shah, J. M. Zgombick, K. Briner, Bioorg. Med. Chem. Lett.
2005, 15, 4973; b) M. J. Fisher, R. T. Backer, S. Husain, H. M.
Received: December 2, 2010
Published Online: February 8, 2011
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