A ruthenium-catalyzed, atom-economical synthesis of nitrogen heterocycles

Article abstract of DOI:10.1021/ja807696e

The Ruthenium catalyzed, atom-economical domino redox isomerization/cyclization of tethered aminopropargyl alcohols is reported. This process displays a broad scope and functional group tolerance. Furthermore, it presents a novel retrosynthetic disconnect

Full text of DOI:10.1021/ja807696e

Published on Web 11/12/2008
A Ruthenium-Catalyzed, Atom-Economical Synthesis of Nitrogen
Heterocycles
Barry M. Trost,* Nuno Maulide, and Robert C. Livingston
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received September 29, 2008; E-mail: bmtrost@stanford.edu
Scheme 1. Proposal for a Domino Redox Isomerization/Cyclization
Reaction of Tethered Propargyl Alcohols
Nitrogen-containing heterocycles are ubiquitous subunits of a
variety of biologically active substances.1 Although this has spurred
the development of a considerable body of synthetic methods aimed
at their efficient preparation,2 there is a continuous need for new
processes which can produce functionalized azacyclic substructures
while maximizing atom economy.
Our laboratory has recently been interested in harnessing the
potential of alkynes as vehicles for bond-forming reactions.3
Although the chemistry of the venerable carbonyl group offers
multiple possibilities for the elaboration of complexity and the
forging of new carbon-carbon and carbon-heteroatom bonds, we
believe that the triple bond, with its robustness and inertness toward
many of the typical conditions used to manipulate carbonyl
functionality, presents itself as a very appealing alternative. The
design of mild and chemoselective methods for the activation of
alkynes constitutes an exciting field at the forefront of developments
in contemporary organometallic chemistry.4
One such method, termed the ruthenium-catalyzed redox isomer-
ization,5 implicitly renders a propargyl alcohol as a suitable synthon
for an enal/enone, greatly reducing the number of operational
manipulations of such sensitive intermediates. We hypothesized that
the ability to juxtapose an appropriately substituted nitrogenated
tether with a propargyl alcohol appendage could allow the direct
synthesis of nitrogen heterocycles by a reaction cascade composed
of redox isomerization and intramolecular cyclization, as shown
in Scheme 1.
Table 1. Redox Isomerisation of Tethered (Tosylamino)propargyl
Alcohols
Thus, following complexation of the active catalyst derived from
1 to the triple bond and activation of the alcohol substituent, a [1,2]-
hydrogen shift should provide the vinylmetal species 2.5 From this
intermediate, the desired azacyclic products 3 could be formed either
through protonolysis of 2 and Michael addition (the latter of which
may be assisted by the Ru complex) or through nitrogen coordina-
tion to Ru and reductive elimination.
Key advantages of such a strategy, apart from the inherent atom
economy of the whole process, lie in minimizing the manipulations
of sensitive, R,ꢀ-unsaturated carbonyl functionality as well as
providing ripe opportunity to take advantage of the unique reactivity
of terminal alkynes in the preparation of substrates. For instance
(eq 1), double deprotonation of the known ω-alkynyltosylamine
46 followed by quenching the dianion with acetaldehyde cleanly
provides the aminoalcohol substrate 5b in high yield, with no need
for functional group manipulations.
entry
n
R
yielda
1
2
3
4
1
1
1
1
2
2
2
2
H (6a)
Me (6b)
75%
79%
92%
77%
77%
72%
68%
80%
-(CH2)2Ph (6c)
-(CH2)4CO2Et (6d)
H (6e)
5b
6b
7b
8b
Me (6f)
-(CH2)2Ph (6g)
-CH2OBn (6h)
a All yields are for pure, isolated products. b Performed with 10 mol
% CSA (see Scheme 1).
directly provided pyrrolidine 6a in 75% yield from a simple acyclic
precursor. The ability to successfully isolate aldehyde 6a bears
testament to the mildness of this catalytic system.
We then examined the scope of this transformation. It can be
seen in Table 1 (entries 1-4) that a variety of differently substituted
pyrrolidines are readily accessible from simple propargyl alcohols
through this methodology. Importantly, all reactions proceed to
completion within short reaction times (60 min), regardless of
whether the carbonyl entity generated is an aldehyde or a ketone.7
Extension to the homologous piperidines was then sought. In
the event, a slight modification of the reaction conditions proved
necessary (Scheme 2). As shown, increasing the amount of acid
cocatalyst (CSA) was crucial to obtain full conversion of substrate
Gratifyingly, this plan proved immediately successful. In one of
our first attempts (Table 1, entry 1), reacting the tosylaminoalcohol
5a with catalytic amounts of the ruthenium complex 1, in the
presence of indium triflate and camphorsulphonic acid (CSA),
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16502 J. AM. CHEM. SOC. 2008, 130, 16502–16503
10.1021/ja807696e CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Study on the Formation of Piperidine 4e
piperidinone derivatives are very useful building blocks for drug
discovery,14 and the ability to obtain cyclized products with different
levels of protection of the carbonyl group is bound to be an asset
in multistep synthetic planning.
In summary, we have developed a new atom-economical,15
domino synthesis of nitrogen heterocycles. It was shown that both
sulfonamides and carbamates are compatible with the overall
process and participate in the domino reaction to form heterocycles
via exo- and endo-type cyclizations. Given the inherent availability
of propargyl alcohols through classical alkynylation chemistry, this
catalytic domino reaction remarkably disconnects the R-position
of a substituted nitrogen heterocycle to a triple bond (of a propargyl
alcohol) in a retrosynthetic manner, further increasing the arsenal
of possible chemical approaches to the synthesis of alkaloids.
Further investigations on this process are underway and will be
reported in due course.
Table 2. Comparative Redox Isomerization of Differently
Substituted Aminopropargyl Alcohols
entry
R
R′
PG
yielda
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health (NIH-13598) for their generous
support of our programs. N.M. is grateful to the Fundac¸a˜o para a
Cieˆncia e Tecnologia (FCT) for the awarding of a Postdoctoral
fellowship. We thank Johnson Matthey for a generous gift of
ruthenium complexes.
1
2
3
4
5
Me
Me
Me
Me
H
H
H
H
H
Ph
Ts (6e)
79%
92%
85%
77%
75%b
SO2Ph (6i)
o-Ns (6j)
Boc (6k)
Boc (6l)
a All yields are for pure, isolated products. b Isolated as a 3:1 mixture
of diastereomers.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Scheme 3. Access to 4-Piperidinones
References
(1) See, for example: The Alkaloids: Chemistry and Biology; Cordell, G. A.,
Ed.; Academic Press: San Diego, CA, 2000; Vol. 54. and others in this
series.
(2) For recent reviews, see: (a) Lawrence, A. K.; Gademann, K. Synthesis 2008,
331–351. (b) Lopez, M. D.; Cobo, J.; Nogueras, M. Curr. Org. Chem. 2008,
12, 718–750. (c) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139–165.
(3) (a) Trost, B. M.; Weiss, A. H. Angew. Chem., Int. Ed. 2007, 46, 7664–
7666, and references therein. (b) Trost, B. M.; Ball, Z. T.; Laemmerhold,
K. M. J. Am. Chem. Soc. 2005, 127, 10028–10038.
(4) (a) Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH:
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to the piperidine product.8 Interestingly, we observed a direct
proportionality effect between the amount of acid employed and
the ratio of cyclic/acyclic product, an observation which is
counterintuitive as one would have predicted that such a cyclization
might be favored by increasingly basic, rather than acidic conditions
(Scheme 2).9,10
The functional group tolerance of this reaction is high. In
particular, aromatic rings (Table 1, entries 3 and 7), esters (entry
4), and ethers (entry 8) all can be present without interfering with
the catalytic system.
Furthermore, other widely employed nitrogen-protecting moieties
also function as competent nucleophiles, as shown in Table 2 (PG
) Boc, benzenesulfonyl, and nosyl). It is interesting to note that
changing the nitrogen substituent on a similar substrate (entries
1-4) appears to have only a slight influence on the efficiency of
the reaction.11 This is an important observation, given the notable
ease of unraveling of the Boc or nosyl moieties.12
Finally, we found that shifting the position of the propargyl
alcohol through the carbon backbone of the substrates results in
interesting variations on this theme. For instance (Scheme 3), if
the internal propargyl alcohol 8a is employed as a substrate, a
simple one-pot, two-stage operation (addition of methanolic potas-
sium carbonate to the mixture) furnishes the tetrahydropiperidone
9a in good yield. In complementary fashion, if the cyclization step
is carried out under acidic conditions,13 the analogous N-Boc
piperidinone ketal 9b can be obtained in 65% overall yield. Such
(5) (a) Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 1995, 117, 9586–
9587. (b) Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 2008, 130,
11970–11978.
(6) See the Supporting Information.
(7) The catalytic loadings could also be lowered even further (to 1 mol% of
1), though this resulted in an increase of the reaction time with little variation
of yield. For instance, Table 1, entry 1: 1 mol % 1, 1 mol % In(OTf)3, 3
mol % CSA results in 4 h reaction, 69% yield.
(8) For recent reviews on the synthesis of piperidines, see: (a) Laschat, S.;
Dickner, T. Synthesis 2000, 1781–1813. (b) Weintraub, P. M.; Sabol, J. S.;
Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 2953–2989. (c) Buffat,
M. G. P. Tetrahedron 2004, 60, 1701–1729.
(9) Control experiments reveal that the conversion of acyclic 6e′ to cyclized
6e appears to require the presence of both the ruthenium catalyst and the
acid additive.
(10) Unsurprisingly, when substrates possessing a longer tether are used azepine
formation does not spontaneously take place under these conditions and
only the acyclic, R,ꢀ-unsaturated aldehyde is obtained.
(11) For examples of ruthenium-promoted synthesis of nitrogen heterocycles
through C-N bond formation, see: (a) Naota, T.; Murahashi, S. Synlett
1991, 693–694. (b) Trost, B. M.; Pinkerton, A. B.; Kremzow, D. J. Am.
Chem. Soc. 2000, 122, 12007–12008. (c) Li, G.-Y.; Chen, J.; Yu, W.-Y.;
Hong, W.; Che, C.-M. Org. Lett. 2003, 5, 2153–2156. (d) Deng, Q.-H.;
Xu, H.-W.; Yuen, A. W.-H.; Xu, Z.-J.; Che, C.-M. Org. Lett. 2008, 10,
1529–1532.
(12) (a) Kocienski, P. J. Protecting Groups; Georg Thieme: New York, 1994.
(b) Greene, T. W.; Wuts, P. G. M. Protecting Groups in Organic Chemistry;
Wiley: New York, 1991.
(13) Abrunhosa-Thomas, I.; Roy, O.; Barra, M.; Besset, T.; Chalard, P.; Troin,
Y. Synlett 2007, 1613–1615.
(14) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679–3681.
(15) Trost, B. M. Science 1991, 254, 1471–1477.
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