Isolation of Ugi four-component condensation primary adducts: A straightforward route to isocoumarins

Article abstract of DOI:10.1021/ol9028622

(Chemical Equation Presented) Ugi four-component condensation (Ugi-4CC) between 2-formylbenzoic acid, phenacylamine dimethyl acetal, and isocyanides afforded 1H-isochromen-1-ones (isocoumarins). These products, where structure corresponds to the tautomeric enediamine form of the Ugi-4CC primary adducts, were stable enough to allow their isolation and characterization. Stable isocoumarins were also obtained by employing anilines as the amino component In the Ugi four-component condensation.

Full text of DOI:10.1021/ol9028622

ORGANIC
LETTERS
2010
Vol. 12, No. 4
788-791
Isolation of Ugi Four-Component
Condensation Primary Adducts: A
Straightforward Route to Isocoumarins
Cristina Faggi,† Mar´ıa Garc´ıa-Valverde,‡ Stefano Marcaccini,*,§ and
Gloria Menchi§
CRIST, UniVersita` di Firenze, Italy, Departamento de Qu´ımica, UniVersidad de
Burgos, Spain, and Dipartimento di Chimica Organica, UniVersita` di Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
stefano.marcaccini@unifi.it
Received December 11, 2009
ABSTRACT
Ugi four-component condensation (Ugi-4CC) between 2-formylbenzoic acid, phenacylamine dimethyl acetal, and isocyanides afforded 1H-
isochromen-1-ones (isocoumarins). These products, where structure corresponds to the tautomeric enediamine form of the Ugi-4CC primary
adducts, were stable enough to allow their isolation and characterization. Stable isocoumarins were also obtained by employing anilines as
the amino component in the Ugi four-component condensation.
In the well-known Ugi four-component condensation (Ugi-
4CC), amines 1, carbonyl compounds 2, carboxylic acids 3,
Scheme 1. Ugi Four-Component Condensation
and isocyanides 4 react to afford R-acylamino amides 5
(Scheme 1).1,2
According to the commonly accepted mechanism proposed
by Ugi,3 the amine, the carbonyl compound, and the acid
† CRIST.
‡ Universidad de Burgos.
§ Universita` di Firenze.
(1) Reviews: (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168–3210. (b) Ugi, I. Pure Appl. Chem. 2001, 73, 187–191. (c) Do¨mling,
A. Curr. Opin. Chem. Biol. 2002, 6, 306–313. (d) Ugi, I.; Werner, B.;
Do¨mling, A. Molecules 2003, 8, 53–66. (e) Zhu, J. Eur. J. Org. Chem.
2003, 1133–1144. (f) Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt, P.
Chem.sEur. J. 2000, 6, 3321–3329. (g) Do¨mling, A. Chem. ReV. 2006,
are in equilibrium with the iminium carboxylate 6 in the
reaction medium. The R-addition of the iminium carboxylate
onto the carbenoid carbon of the isocyanide leads to the
formation of the primary four-component adduct 7, which
undergoes an intramolecular acylation known as Mumm
rearrangement to give the stable Ugi adduct 5 (Scheme 2).
Other reaction mechanisms have been proposed to account
for the stereochemical features of the Ugi-4CC.4 However,
106, 17–89
.
(2) The term Ugi four-component condensation usually refers to the
reaction between amines, carbonyl compounds, carboxylic acids, and
isocyanides. Really, there are many kinds of Ugi reactions since large
variations of the nature of the components are possible. See for example
refs 1a,g and Marcaccini, S.; Torroba, T. Nature Protocols 2007, 2, 632–
639
.
(3) Ugi, I. Angew. Chem., Int. Ed. 1962, 1, 8–21.
10.1021/ol9028622  2010 American Chemical Society
Published on Web 01/27/2010

Scheme 2. Mechanism of Ugi-4CC
Figure 2
ellipsoids.
. ORTEP drawing of 13a with 30% probability thermal
in all of the mechanisms the final step consists of the Mumm
rearrangement of the primary R-adduct.
Although an impressive number of Ugi-4CCs have been
performed, mainly because of the widespread application of
combinatorial techniques,5 to the best of our knowledge, only
the successful isolation of the primary adducts 8 and 9 has
been reported as unpublished results,6 half a century after
the discovery of this fundamental reaction (Figure 1).
confirmed by X-ray diffraction analysis (Figure 2). Upon
treatment of a THF solution of 13a with a trace of acid, a
rapid and quantitative isomerization to the “normal” Ugi-
4CC adduct 14a, namely, N-cyclohexyl-2-(2,2-dimethoxy-
2-phenyl)ethyl-1,3-dihydro-1-oxoisoindol-3-carboxamide, took
place. Prolonged exposure of 13a to higher concentrations
of hydrochloric acid afforded quantitatively the deprotected
Ugi-4CC adduct 15a. The same product 15a was also
obtained in the same conditions by employing 14a as the
starting material. Analogously, we obtained compounds 13b,
14d, and 15b by employing tert-butyl isocyanide (12b) in
the place of cyclohexyl isocyanide (12a) (Scheme 3).
Figure 1. Previously isolated Ugi-4CC primary adducts.
In the course of our studies on isocyanide-based multi-
component reactions,7 we attempted to perform an Ugi-4CC
between 2-formylbenzoic acid (10), phenacylamine dimethyl
acetal (11), and cyclohexyl isocyanide (12a) in methanol.8,9
After 18 h stirring at rt a yellow solid 13a, mp 148.5-150
°C, was isolated by filtration. The analytical and spectral
data of 13a confirmed that this product was the Ugi primary
R-adduct in the tautomeric enediamine form, namely, 3-(N-
cyclohexyl)amino-4-[N-(2,2-dimethoxy-2-phenyl)ethyl]amino-
1H-isochromen-1-one. The assigned structure 13a was further
Scheme 3
.
Formation of the Ugi-4CC Primary Adducts 13 and
Their Transformations
(4) Banfi, L.; Basso, A.; Guanti, G.; Riva, R. In Multicomponent
Reactions; Zhu, J., Bienayme´, H., Eds.;Wiley-VCH: Weinheim, 2005; pp
1-32.
(5) Hulme, C. In Multicomponent Reactions; Zhu, J., Bienayme´, H., Eds.;
Wiley-VCH: Weinheim, 2005; pp 311-341.
(6) Gokel, G., Lu¨dke, G., Ugi, I. In Isocyanide Chemistry; Ugi, I., Ed.;
Academic Press: New York, 1971; pp 158-159.
(7) (a) Marcaccini, S.; Torroba, T. In Multicomponent Reactions; Zhu,
J., Bienayme´, H., Eds.; Wiley-VCH: Weinheim, 2005; pp 33-75. (b)
Carrillo, R. M.; Neo, A. G.; Lo´pez-Garc´ıa, L.; Marcaccini, S.; Marcos, C. F.
Green Chem. 2006, 8, 787–789. (c) Neo, A. G.; Carrillo, R. M.; Barriga,
S.; Moma´n, E.; Marcaccini, S.; Marcos, C. F. Synlett 2007, 327–329. (d)
Garc´ıa-Valverde, M.; Macho, S.; Marcaccini, S.; Rodr´ıguez, T.; Rojo, J.;
Torroba, T. Synlett 2007, 33–36. (e) Marcos, C. F.; Marcaccini, S.; Menchi,
G.; Pepino, R.; Torroba, T. Tetrahedron Lett. 2008, 49, 149–152. (f) Corres,
N.; Delgado, J. J.; Garc´ıa-Valverde, M.; Marcaccini, S.; Rodr´ıguez, T.; Rojo,
J.; Torroba, T. Tetrahedron 2008, 64, 2225–2232. (g) Faggi, C.; Neo, A. G.;
Marcaccini, S.; Menchi, G.; Revuelta, J. Tetrahedron Lett. 2008, 49, 2099–
2102. (h) San˜udo, M.; Garc´ıa-Valverde, M.; Marcaccini, S.; Delgado, J. J.;
Rojo, J.; Torroba, T. J. Org. Chem. 2009, 74, 2189–2192.
The successful isolation of the Ugi primary adducts 13
can surely be ascribed to the rigid nature and to the aromatic
character of the isochromenone ring.
Org. Lett., Vol. 12, No. 4, 2010
789

Furthermore, the X-ray analysis of 13a showed that the
alkoxy groups had no stabilizing effects such as strong
hydrogen bonds. Thus, the sole effect of the alkoxy groups
seemed to result in a reduced strength of the nitrogen basicity
due to the inductive effect of the oxygen atoms. Keeping in
mind that the Ugi-4CC between 2-acylbenzoic acids, iso-
cyanides, and strongly basic amines afforded the secondary
adducts,8c,d we reasoned that the use of a scarcely basic
amine might result in the stabilization of the primary
R-adduct. To verify this hypothesis, we reacted 2-formyl-
benzoic acid (10), isocyanides 12, and anilines 16. As
expected we were able to isolate the Ugi-4CC primary
adducts 17 in satisfactory yields (Table 1).
at room temperatures showed a fair stability. The tendency
of compounds 17 to rearrange to the Ugi secondary adducts
18 was accelerated at higher temperatures. In the presence
of traces of acid the rearrangement took place almost
instantaneously as demonstrated by the quick disappearance
of the yellow color (Scheme 4).
Scheme 4
.
Acid-Induced Rearrangement of Isocoumarins 17 to
Isoindolinones 18
Table 1. Formation of 3-(N-Substituted)amino-4-arylamino-1H-
isochromen-1-ones 17
This behavior was taken into account when preparing the
deuterochloroform solutions for recording the NMR spectra.
Since hydrogen chloride is known to be a common con-
taminant of chloroform, commercial deuterochloroform was
stirred with potassium carbonate in D2O and dried prior to
use.
Naturally occurring and synthetic products containing the
isocoumarin ring display a wide variety of interesting
biological activities such as protease inhibitory,10 antiviral,11
anti histamine release,12 cytotoxic,13 phytotoxic,14 antifungal,
antibacterial, antialgal,15 anticoagulant,16 and antitumor17
properties.
entry
R
isocyanide
Ar
C6H5
4-FC6H5
3-ClC6H5
4-ClC6H5
4-FC6H5
amine product yield (%)
1
2
3
4
5
6
c-C6H11
c-C6H11
c-C6H11
c-C6H11
4-CH3C6H4
c-C6H11
12a
12a
12a
12a
12c
12a
16a
16b
16c
16d
16b
17a
17b
17c
17d
17e
17f
57
58
62
68
64
82
4-CH3C6H4 16e
Although a large number of isocoumarins are known,18
those bearing amino groups in the heterocyclic portion of
the ring are rare, and to the best of our knowledge, only a
few synthetic routes have been reported.19,20
Interestingly, 3-amino-4-arylamino-1H-isochromen-1-ones
were recently prepared by Opatz and Ferenc via a Strecker
It must be emphasized that careful control of the reaction
conditions was crucial to ensure both good yields and facile
workup of compounds 17. In fact, compounds 17 are stable
in the solid state, whereas in solution they show a tendency
to rearrange to the secondary Ugi products. Thus, if too high
temperatures and/or prolonged reaction periods were em-
ployed, mixtures of 17 and secondary adducts were always
found. If reaction conditions were too mild, the reactions
afforded mixtures of 17 and the Schiff’s base arising from
the reaction between 10 and 16. After some experimentation
we were able to optimize the reaction conditions to ensure
satisfactory yields of pure products by means of an experi-
mentally simple general method.
(10) (a) Heynekamp, J. J.; Hunsaker, L. A.; Vander Jagt, T. A.; Royer,
R. E.; Deck, L. M.; Vander Jagt, D. L. Bioorg. Med. Chem. 2008, 16, 5284–
5294. (b) Waters, S. P.; Fennie, M. W.; Kozlowski, M. C. Org. Lett. 2006,
8, 3243–3246. (c) Bihlel, F.; Que´le´ver, G.; Lelouard, H.; Petit, A.; Alve`s
da Costa, C.; Pourquie´, O.; Checler, F.; Thellend, A.; Pierre, P.; Kraus,
J.-L. Bioorg. Med. Chem. 2003, 11, 3141–3152. (d) Kerrigan, J. E.;
Oleksyszyn, J.; Cam, C.-M.; Selzler, J.; Powers, J. C. J. Med. Chem. 1995,
38, 544–552.
(11) Waters, S. P.; Kozlowski, M. C. Tetrahedron Lett. 2001, 42, 3567–
3570.
(12) Qadeer, G.; Rama, N. H.; Shah, S. J. H. ArkiVoc 2007, 14, 12–19.
(13) (a) Devienne, K. F.; Raddi, M. S. G.; Varanda, E. A. Z. Naturforsch.
2002, 57c, 85–88. (b) Whyte, A. C.; Gloer, J. B.; Scott, J. A.; Malloch, D.
J. Nat. Prod. 1996, 59, 765–769.
With regard to the stability of compounds 17 in solution,
it must be underlined that their solutions in neutral solvents
(8) The use of 2-formylbenzoic acids and 2-acylbenzoic acids in
isocyanide-based multicomponent reactions is well-known. Passerini reac-
tions: (a) Passerini, M.; Ragni, G. Gazz. Chim. Ital. 1931, 61, 964–969. (b)
Falck, J. R.; Manna, S. Tetrahedron Lett. 1981, 22, 619–620. Ugi reactions:
(c) Hanusch-Kompa, C.; Ugi, I. Tetrahedron Lett. 1998, 39, 2725–2728.
(d) Zhang, J.; Jacobson, A.; Rusche, J. R.; Herlihy, W. J. Org. Chem. 1999,
64, 1074–1076. (e) Marcaccini, S.; Pepino, R.; Polo, C.; Pozo, M. C.
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Meindl, K.; Schulz, T.; Stalke, D.; Beifuss, U. Synthesis 2008, 3649–3656.
(9) Some authors regard this kind of reactions as Ugi-3C-4CR or Ugi-
3CR: Ramo´n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602–1634.
According to the definition given by Ugi himself ( Ugi, I.; Do¨mling, A.;
Ho¨rl, W. EndeaVour, New Series 1994, 18, 115-122), “The reagents may
be different individual molecules or they may be different functional groups
of the same reagent”, this reaction must be regarded as a true Ugi four-
component condensation.
(14) (a) Tabacchi, R. Pure Appl. Chem. 1994, 66, 2299–2302. (b) Okuno,
T.; Oikawa, S.; Goto, T.; Sawai, K.; Shirahama, H.; Matsumoto, T. Agric.
Biol. Chem. 1986, 50, 997–1001.
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2547–2553.
(17) Can˜edo, L. M.; Ferna´ndez Puentes, J. L.; Baz, J. P.; Acebal, C.; de
la Calle, F.; Gra´valos, D. G.; de Quesada, T. G. J. Antibiot. 1997, 50, 175–
176.
(18) Reviews: (a) Barry, R. D. Chem. ReV. 1964, 64, 229–260. (b)
Napolitano, E. Org. Prep. Proced. Int. 1997, 29, 631–664.
(19) Wells, J. N.; Wheeler, W. J.; Davisson, L. M. J. Org. Chem. 1971,
36, 1503–1506
(20) Boyd, G. V.; Monteil, R. L. J. Chem. Soc., Perkin Trans. 1 1978,
1338–1350
.
.
790
Org. Lett., Vol. 12, No. 4, 2010

reaction between 2-formylbenzoic acid, anilines, and potas-
sium cyanide in the presence of acetic acid.21 In a successive
paper the same authors described the facile rearrangement
of these products to dihydroisoindolinones.22 The method
of Opatz and Ferenc and the present one are closely related,
both being based on multicomponent reactions. However, it
must be underlined that our method allows the introduction
of another diversity point in the isocoumarin ring.
In conclusion, we have described a procedure that con-
sistently allows the isolation of the usually elusive Ugi-4CC
primary adducts. Furthermore, the synthetic route described
in this Letter allows a facile access to the isocoumarin ring.
Supporting Information Available: Detailed experimen-
tal procedures and spectral data for all new compounds and
X-ray analysis of the isocoumarin 13a, including CIF file.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Opatz, T.; Ferenc, D. Eur. J. Org. Chem. 2005, 817–821.
(22) Opatz, T.; Ferenc, D. Eur. J. Org. Chem. 2006, 121–126.
OL9028622
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