Applications of the Ugi reaction with ketones

Article abstract of DOI:10.1016/j.tetlet.2008.05.073

A convenient synthesis of highly functionalized, α,α-disubstituted amino acid amide derivatives has been accomplished by using cyclic and acyclic ketones as the carbonyl inputs in the Ugi multicomponent reaction. An application of this extension of the Ugi reaction to the synthesis of α,α-divinyl amino acids that may be cyclized via ring-closing metathesis to provide highly substituted pyrrolidines is described.

Full text of DOI:10.1016/j.tetlet.2008.05.073

Tetrahedron Letters 49 (2008) 4501–4504
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Tetrahedron Letters
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Applications of the Ugi reaction with ketones
*
Suvi T. M. Simila, Stephen F. Martin
Department of Chemistry and Biochemistry, The University of Texas, Austin, TX 78712, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthesis of highly functionalized, a,a-disubstituted amino acid amide derivatives has been
accomplished by using cyclic and acyclic ketones as the carbonyl inputs in the Ugi multicomponent reac-
Received 29 April 2008
Revised 8 May 2008
Accepted 12 May 2008
Available online 20 May 2008
tion. An application of this extension of the Ugi reaction to the synthesis of -divinyl amino acids that
a,a
may be cyclized via ring-closing metathesis to provide highly substituted pyrrolidines is described.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Ugi reaction
Multicomponent reaction
Ring-closing metathesis
The design and development of convergent strategies to synthe-
size diverse arrays of drug-like compounds for biological screening
is an important objective in contemporary chemical biology and
medicinal chemistry. In this context, the use of multicomponent
reactions (MCRs),1 followed by post-condensation modifications
via various ring-forming reactions, has proven to be a powerful
tool as such processes can rapidly lead to the generation of libraries
of functionalized compounds with diverse heterocyclic scaffolds.
Indeed, our group has long had an interest in discovering new
MCRs as well as expanding the scope of existing ones to rapidly ac-
cess both alkaloid and drug-like motifs.2,3
O
R1 NH2
R4
R5 NC
+
+
CO2H +
R2
R3
1
2
3
4
O
R1
N
R4
CONHR5
R2
R3
5
The Ugi reaction is arguably one of the most important MCRs,
and it is widely used in the pharmaceutical industry for preparing
collections of compounds.4 This powerful reaction involves a
one-pot condensation of an amine 1, a carbonyl compound 2, a car-
boxylic acid 3, and an isocyanide 4 to provide a substituted pep-
tide-like product 5 (Scheme 1). Although the Ugi MCR has proven
to be quite versatile, there are some limitations that become appar-
ent upon examination of the literature. For example, the reaction is
widely applicable to a variety of readily available amines, carbox-
ylic acids, and aldehydes, but commercial access to isocyanides is
more restricted than for the other three components. Moreover,
it is often desirable to convert the initially formed amide into carb-
oxyl derivatives and other functional groups. The latter issue has
been nicely addressed by the invention of a number of so-called
convertible isocyanides that can be elaborated after the condensa-
tion into various functional groups.5 Aldehydes are widely used as
components, but there are relatively few examples of the use of
ketones as inputs. For example, Ugi reactions with simple ketones
Scheme 1.
O
n( )
CO2H
t
-Bu NC
+
+
+
NH2
6
7
8
9
O
O
n( )
n( )
N
N
CONHt-Bu
CONH
t
-Bu
10
11
n = 1,2
Scheme 2.
such as acetone, cyclopentanone, and cyclohexanone are known to
* Corresponding author. Tel.: +1 512 471 3915; fax: +1 512 471 4180.
E-mail address: sfmartin@mail.utexas.edu (S. F. Martin).
proceed in high yields in one-pot reactions.6 N-Methyl and
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.073

4502
S. T. M. Simila, S. F. Martin / Tetrahedron Letters 49 (2008) 4501–4504
N-benzyl piperidones have also been employed as ketone compo-
nents to give good yields of products,7 and a library of spiro keto
piperazines has been synthesized utilizing N-alkyl and N-aryl pi-
peridones as the ketone components in an Ugi MCR.8 However,
use of acyclic dialkyl and diaryl ketones typically requires prefor-
mation of the imine intermediate in a separate step, and the yields
of the Ugi adducts tend to be modest.9
During the course of recent efforts to develop facile approaches
to alkaloid natural products and other nitrogen heterocycles, we
were attracted to the possibility of employing an Ugi MCR followed
by a ring-closing metathesis reaction (RCM).10 In particular, we
envisioned that an Ugi MCR using an unsaturated amine 6, a func-
tional equivalent of divinyl ketone 7, which is known to be unsta-
ble,11 crotonic acid (8) and an isocyanide like 9 would lead to an
adduct 10 that might be cyclized via an asymmetric ring-closing
metathesis (ARCM)12 to generate highly substituted pyrrolidine
and piperidine derivatives 11 in enantiomerically pure form
(Scheme 2). This plan presented a unique opportunity to explore
the scope of the Ugi MCR reaction with ketones and to probe the
feasibility of cyclizing tetraene substrates containing prochiral
vinyl groups in a ARCM. Although tandem Ugi/RCM processes to
access bicyclic lactams (6- and 7-membered rings),13 9-membered
NH2
O
PhMe, Dean-Stark
120 °C, 20 h;
R
MeO
O
+
N
then 8, 9/ MeOH
25 °C, 5 d
R
R
R
t
-BuHNOC
OMe
12: R = NMe2
13: R = SPh
14
15: R = NMe2 (0%)
16: R = SPh (30%)
1)
mCPBA, CH2Cl2
MeO
O
19 or 20
−78 °C, 1 h
X
N
Ti(i
PrO)4
2)
p-xylene, pyridine
CH2Cl2
140 °C, 300W
t-BuHNOC
93%
17
O
MeO
N
t
-BuHNOC
18
N
N
P(Cy)3
Mes
Mes
Cl
Cl
Ru
Ru
Cl
Ph
Cl
Ph
P(Cy)3
P(Cy)3
19
20
Scheme 3.
O
SPh
TiCl4, Et3N, CH2Cl2
NH2
+
N
O
SP
then 8, 9, MeOH
25 °C, 3 d
PhS
SPh
21
CONH
t-Bu
13
22
35%
1)
mCPBA, CH2Cl2
–78 → –20 °C, 1 h
N
O
2) p-xylene, pyridine
CONHt-Bu
140 °C, 300W
68%
23
20, CH2Cl2, rt
N
95%
CONHt-Bu
O
24
Scheme 4.

S. T. M. Simila, S. F. Martin / Tetrahedron Letters 49 (2008) 4501–4504
4503
lactams,14 and macrocyclic peptides15 are known, the preparation
of compounds related to 11 via Ugi/ARCM is not.16 Herein, we wish
to report some of our findings on the use of ketones in Ugi MCRs
Compound 16 was readily transformed into the divinyl sub-
strate 17 in excellent overall yield by S-oxidation with mCPBA to
give an intermediate bis-sulfoxide that underwent facile elimina-
tion upon thermolysis. Although this elimination could be effected
under conventional reflux conditions (18 h), it was considerably
more facile in a microwave reactor (4 h). Unfortunately, in a series
of exploratory experiments, we were unable to induce the RCM of
17 to give 18 using either Grubbs 1st or 2nd generation catalysts
19 and 20, respectively; only unreacted starting material was
recovered. Reasoning that the amide carbonyl oxygen atom of
compound 17 might form an unreactive 6-membered chelated
structure with the metal carbene on one of the vinyl groups,20 Ti(i-
PrO)4 was added as a co-catalyst. However, this tactic was unavail-
ing, and 17 was again recovered.
and on the synthesis of
as substrates for RCM.
a,a-divinyl peptidic compounds that serve
Our initial focus was upon acyclic ketones that could be easily
refunctionalized via elimination reactions to provide the requisite
a,a-divinyl amino acid derivatives. We quickly discovered, how-
ever, that acyclic ketones, such as 1217 and 1318 did not provide
any of the desired Ugi products in one-pot reaction with the ben-
zylamine 14 and the acid and isocyanide components 8 and 9,
respectively (Scheme 3). However, after some experimentation,
we found that preforming the imine derived from 13 and 14 via Le-
wis acid catalysis (TiCl4)19 or azeotropic distillation followed by the
addition of acid 8 and isocyanide 9 provided the adduct 16 in 30%
yield. Because all attempts to preform the imine from 12 and 14
were unsuccessful, none of the Ugi adduct 15 could be prepared.
In order to obviate formation of unreactive chelates involving
amides, a related sequence of reactions was conducted in which
allylamine (21) was condensed with 13 in the presence of TiCl4
R1
O
O
N
R3
R3 CO2H
+
R1
25
NH2
NC
+
+
R2
R2
R2
R2
CONH
t-Bu
26
27
28
29
Amines
Ketones
Acids
O
O
CO2H
NH2
27a
CO2H
N
PhS
N
N
H
Me
25a
25b
25c
Ac
27b
26a
26b
NH2
NH2
NH2
O
O
O
26c
S
26d
O
MeO
O
TBSO
OTBS
26e
O
25d
OMe
O
N
O
MeO
O
N
N
CONHt-Bu
CONHt-Bu
CONHt-Bu
HN
AcN
MeN
MeN
29c (71%)
29a (99%)
29b (71%)
MeO
O
N
SPh
O
N
O
N
CONHt-Bu
CONHt-Bu
CONHt-Bu
HN
TBSO
TBSO
29f (62%)
S
O
29d (99%)
29e (64%)
Scheme 5.

4504
S. T. M. Simila, S. F. Martin / Tetrahedron Letters 49 (2008) 4501–4504
and Et3N, and the resultant imine was allowed to react with the
carboxylic acid 8 and the isocyanide 9 to provide the allylic amine
22 in 35% yield (Scheme 4). Selective S-oxidation of the two sulfide
moieties as before and subsequent thermolysis gave 23 in 65%
yield. Gratifyingly, the RCM of 23 with Grubbs 2nd generation cat-
alyst 20 (5 mol %) provided the highly substituted pyrrolidine 24 in
95% yield. A number of diverse and novel compounds related to 24
may be accessed by varying the acid and the isocyanide com-
pounds in the Ugi reaction.
References and notes
1. (a) Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH:
Weinheim, 2005; (b) Zhu, J. Eur. J. Org. Chem. 2003, 1133–1144; (c) Dömling,
A. Chem. Rev. 2006, 106, 17–89.
2. (a) Martin, S. F.; Benage, B.; Geraci, L. S.; Hunter, J. E.; Mortimore, M. J. Am.
Chem. Soc. 1991, 113, 6161–6171; (b) Martin, S. F.; Clark, C. C.; Corbett, J. W. J.
Org. Chem. 1995, 60, 3236–3242; (c) Ito, M.; Clark, C. C.; Mortimore, M.; Goh, J.
B.; Martin, S. F. J. Am. Chem. Soc. 2001, 123, 8003–8010.
3. Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Org. Lett. 2007, 9, 4223–4226
and references cited therein.
4. Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
5. For convertible isocyanides, see: (a) Keating, T. A.; Armstrong, R. W. J. Am.
Chem. Soc. 1995, 117, 7842–7843; (b) Keating, T. A.; Armstrong, R. W. J. Am.
Chem. Soc. 1996, 118, 2574–2583; (c) Lindhorst, T.; Bock, H.; Ugi, I. Tetrahedron
1999, 55, 7411–7420; (d) Linderman, R. J.; Binet, S.; Petrich, S. R. J. Org. Chem.
1999, 64, 336–337; (e) Rikimaru, K.; Yanagisawa, A.; Kan, T.; Fukuyama, T.
Synlett 2004, 1, 41–44; (f) Pirrung, M. C.; Ghorai, S. J. Am. Chem. Soc. 2006, 128,
11772–11773; (g) Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett. 2007, 9,
3631–3634; (h) Tanaka, Y.; Hasui, T.; Suginome, M. Org. Lett. 2007, 9, 4407–
4410.
6. For selected examples, see: (a) Mironov, M. A.; Tokareva, M. I.; Ivantsova, M. N.;
Mokrushin, V. S. Russ. J. Org. Chem. 2004, 40, 847–853; (b) Kalinski, C.;
Umkehrer, M.; Gonnard, S.; Jäger, N.; Ross, G.; Hiller, W. Tetrahedron Lett. 2006,
47, 2041–2044.
7. (a) Beck, B.; Hess, S.; Dömling, A. Bioorg. Med. Chem. Lett. 2000, 10, 1701–1705;
(b) Dömling, A.; Achatz, S.; Beck, B. Bioorg. Med. Chem. Lett. 2007, 17, 5483–
5486.
During the course of these studies, we discovered that a number
of functionalized ketones containing heteroatoms could be em-
ployed that might serve as useful inputs in Ugi MCRs to give
adducts in high yields according to the process generally depicted
in Scheme 5. For example, the heterocyclic ketones 1-methyl-
4-piperidone (26a), 1-acetyl-4-piperidone (26b), tetrahydro-4H-
pyran-2-one (26c), and tetrahydro-4H-thiopyran-2-one (26d) were
each found to participate in Ugi MCRs that proceeded readily in
one-pot operations without preforming the ketimine.21 Although
the Ugi MCR involving 26a has been recently reported to be effi-
cient,8 the only example of which we are aware of the use of 26d
is in a solid-phase Ugi process that was low yielding.22 To our
knowledge, there are no reports in the literature of employing
26b and 26c in Ugi MCRs; however, 26c and 26d have been used
in some specialized isocyanide-based MCRs.23,24 Protected dihy-
droxyacetone derivatives such as 26e have not been used in Ugi
MCRs. The amino inputs employed in these exploratory investiga-
tions were tryptamine (25a), benzylamine (25b), 4-methoxy-
benzylamine (25c), and aminoacetaldehyde dimethyl acetal
(25d), whereas the carboxylic acid components were crotonic acid
(27a) and b-phenylthiopropionic acid (27b). Because of its com-
mercial availability, tert-butylisocyanide (28) was chosen as the
universal isocyanide component. The utility of the method is
exemplified by the preparation of the highly functionalized
adducts 29a–f.
8. Habashita, H.; Kokubo, M.; Hamano, S.; Hamanaka, N.; Toda, M.; Shibayama, S.;
Tada, H.; Sagawa, K.; Fukushima, D.; Maeda, K.; Mitsuya, H. J. Med. Chem. 2006,
49, 4140–4152.
9. (a) Yamada, T.; Yanagi, T.; Omote, Y.; Miyazawa, T.; Kuwata, S.; Sugiura, M.;
Matsumoto, K. J. Chem. Soc., Chem. Commun. 1990, 1640–1641; (b) Costa, S. P.
G.; Maia, H. L. S.; Pereira-Lima, S. M. M. A. Org. Biomol. Chem. 2003, 1, 1475–
1479; (c) Pinto, F. C. S. C.; Pereira-Lima, S. M. M. A.; Ventura, C.; Albuquerque,
L.; Concalves-Maia, R.; Maia, H. L. S. Tetrahedron 2006, 62, 8184–8198.
10. For a review of applications of RCM to the preparation of heterocycles, see:
Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–2238. and references cited
therein.
11. Laronze, J.-Y.; Sapi, J.; Levy, J. Synthesis 1988, 619–621.
12. For reviews on enantioselective olefin metathesis, see: (a) Hoveyda, A. H. In
Grubbs, R. H., Ed.; Handbook of Metathesis; Wiley-VCH: Weinheim, Germany,
2003; Vol. 2, Chapter 2.3; (b) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2003, 42, 4592–4633; (c) Hoveyda, A. H.; Schrock, R. R. Chem. Eur. J. 2001, 7,
945–950.
13. Krelaus, P.; Westermann, B. Tetrahedron Lett. 2004, 45, 5987–5990.
14. Banfi, L.; Basso, A.; Guanti, G.; Riva, R. Tetrahedron Lett. 2003, 44, 7655–7658.
15. Hebach, C.; Kazmaier, U. Chem. Commun. 2003, 596–597.
16. For a related example of a van Leusen MCR/RCM sequence, see: Gracias, V.;
Gasiecki, A. F.; Djuric, S. W. Org. Lett. 2005, 7, 3183–3186.
17. Blicke, F.; McCarty, F. J. Org. Chem. 1959, 24, 1376–1379.
18. Angiolini, L.; Carlini, C.; Tramontini, M.; Ghedini, N. Polymer 1989, 30, 564–
569.
19. Moss, N.; Gauthier, J.; Ferland, J.-M. Synlett 1994, 142–144.
20. (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446–452; (b)
Arisawa, M.; Nishida, A.; Nakagawa, M. J. Organomet. Chem. 2006, 691,
5109–5121; (c) Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119,
9130–9136; See also: (d) Ghosh, A. K.; Cappiello, J.; Shin, D. Tetrahedron Lett.
1998, 39, 4651–4654; (e) Yang, Q.; Xiao, W.-J.; Yu, Z. Org. Lett. 2005, 7, 871–
874.
In summary, we have found that a variety of ketones participate
in either stepwise or one-pot Ugi MCRs to give good to excellent
yields of adducts having a number of different functional groups
that can be utilized in various post-condensation reactions. In
one novel application of this strategy, we developed a route to
highly substituted pyrrolidines via an Ugi reaction followed by a
cyclization via RCM. The applications of these and related pro-
cesses to the syntheses of biologically active natural and unnatural
products are the subject of current investigations, the results of
which will be reported in due course.
Acknowledgments
21. General procedure for preparing 29a–f: The isocyanide 28 (1.1 mmol) was added
to a solution of amines 25a–e (1.1 mmol), ketones 26a–d (1 mmol), acids
27a,b (1.1 mmol) in MeOH (1 mL) at room temperature, and the solution was
stirred for 18 h. The solvent was removed under reduced pressure, and the
residue was dissolved in EtOAc (20 mL). The organic solution was washed with
satd aq NaHCO3 (2 Â 20 mL) and brine (20 mL) and dried (Na2SO4), and the
solvent was removed under reduced pressure. The crude product was purified
either via flash column chromatography on silica gel (eluting with 1–2% MeOH
in CH2Cl2) or by crystallization from EtOH.
We are grateful to the National Institutes of Health (GM25439
and GM31077), the Robert A. Welch Foundation, Pfizer, Inc., Merck
Research Laboratories, Hoffmann-La Roche, and Boehringer-Ingel-
heim for their generous support. We also thank Dr. Richard Peder-
son (Materia, Inc.) for catalyst support.
22. Szardenings, A. K.; Burkoth, T. S.; Lu, H. H.; Tien, D. W.; Campbell, D. A.
Tetrahedron 1997, 53, 6537–6593.
Supplementary data
23. Bossio, R.; Marcaccini, R.; Pepino, R. Liebigs Ann. Chem. 1993, 11, 1229–
1231.
24. Marcaccini, S.; Pepino, R.; Polo, C.; Pozo, M. C. Synthesis 2001, 1, 85–88.
Supplementary data (spectral and characterization data for
all new compounds) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.073.