Facile three-component coupling procedure for the synthesis of substituted tetrahydroisoindole-1,3-diones from α,β-unsaturated aldehydes

Article abstract of DOI:10.1021/ol0101436

(equation presented) A new one-pot procedure for the efficient synthesis of a small library of amino-functionalized tetrahydroisoindole-1,3-dione derivatives was developed. This three-component coupling reaction comprises subsequent condensation and Diels-Alder reactions of ubiquitous available starting materials (α,β-unsaturated aldehydes, amide, and maleimide). The synthesized compounds share a substituted tetrahydroisoindole motif in an endo fashion.

Full text of DOI:10.1021/ol0101436

ORGANIC
LETTERS
2001
Vol. 3, No. 18
2895-2898
Facile Three-Component Coupling
Procedure for the Synthesis of
Substituted
Tetrahydroisoindole-1,3-diones from
r,â-Unsaturated Aldehydes
Axel Jacobi von Wangelin, Helfried Neumann, Dirk Go1rdes,
Anke Spannenberg, and Matthias Beller*
Institut fu¨r Organische Katalyseforschung an der UniVersita¨t Rostock e.V.,
Buchbinderstr. 5-6, 18055 Rostock, Germany
matthias.beller@ifok.uni-rostock.de
Received June 26, 2001
ABSTRACT
A new one-pot procedure for the efficient synthesis of a small library of amino-functionalized tetrahydroisoindole-1,3-dione derivatives was
developed. This three-component coupling reaction comprises subsequent condensation and Diels−Alder reactions of ubiquitous available
starting materials (r,â-unsaturated aldehydes, amide, and maleimide). The synthesized compounds share a substituted tetrahydroisoindole
motif in an endo fashion.
In recent years, research in academia and industry has
increasingly emphasized the search for atom-efficient trans-
formations of easily available starting materials into complex
organic molecules.1 In this respect, reactions that provide
maximum diversity, that is, reactions with high exploratory
power, are especially desirable. Here, expeditious multicom-
ponent reactions (MCR)2 as well as domino reaction
sequences offer significant advantages over stepwise proce-
dures.3 The Diels-Alder reaction provides one of the most
powerful tools for the synthesis of complex organic mol-
ecules by virtue of its versatility and stereocontrol and
therefore typifies a favorable transformation in efficient
reaction sequences. Consistently, several reported MCRs
feature Diels-Alder chemistry with substituted diene build-
ing blocks.4
Recently, we reported a new one-pot protocol for the facile
synthesis of diversely substituted amino-functionalized cy-
clohexene derivatives.5 The developed three-step domino
reaction sequence involves the in situ preparation of a
1-acylamino-1,3-butadiene species (I) as the key intermedi-
ate, which several groups have proven a versatile diene
building block for mechanistic investigations and natural
product syntheses.6 Access to I was accomplished upon
(1) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259. (c) Trost, B. M. In Transition Metals
for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim,
1998; p 1.
(2) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (b)
Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6,
3321.
(3) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115. (b) Tietze, L. F.; Modi,
A. Med. Res. ReV. 2000, 20, 304. (c) Tietze, L. F.; Haunert, F. In Stimulating
Concepts In Chemistry; Shibasaki, M., Stoddart, J. F., Vo¨gtle, F., Eds.;
Wiley-VCH: Weinheim, 2000; p 39.
(4) (a) Posner, G. H. Chem. ReV. 1986, 86, 831. (b) Winkler, J. D. Chem.
ReV. 1996, 96, 167.
(5) Neumann, H.; Jacobi von Wangelin, A.; Go¨rdes, D.; Spannenberg,
A.; Beller, M. J. Am. Chem. Soc. 2001 in press.
10.1021/ol0101436 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/15/2001

sequential condensations of two R-CH2-containing aldehydes
with an amide according to Scheme 1.
Scheme 2. 1-Acylamino-2-cyclohexene Synthesis via a
Condensation-Cycloaddition Domino Reaction Sequence
Starting from R,â-Unsaturated Aldehydes
Scheme 1. Condensation Sequences toward Substituted
1-Acylamino Butadiene Building Blocks Starting from Simple
Aldehydes (top, I) or R,â-Unsaturated Aldehydes (bottom, II)7
perform the desired reaction sequence in a stepwise manner.
However, isolation of 1-acylamino-1,3-butadienes proved
quite troublesome, and as a result of the presence of several
equilibrating species, yields are generally poor. Fortunately,
in situ trapping of the intermediate amidodienes with
maleimide selectively gave the corresponding 1-acylamino-
2-cyclohexene Diels-Alder adducts in good yields (Scheme
2, Table 1).
Ubiquitous available amides, such as acetamide (R1 ) Me)
and benzamide (R1 ) Ph), cleanly reacted with crotonalde-
hyde to give the desired bicyclic systems in 85% and 91%
yield, respectively. Other commercially available R,â-
unsaturated aldehydes afforded the corresponding 3a,4,7,-
7a-tetrahydroisoindole-1,3-dione systems in somewhat lower
yields (56-82%). In general, the product yields decrease as
the substituents become bulkier. Both acetamide and benz-
amide exhibited equivalent reactivities with similar yields,
with conversions being best accomplished after 24 h at 120
°C. A notable aspect that adds to the facile practicality of
the reaction is the workup procedure. Isolation and purifica-
tion of the acetamide- and benzamide-bearing compounds
was achieved by removal of the solvent and subsequent
washing with ethyl acetate and ethanol, respectively.
Spectroscopic characterization of the Diels-Alder adducts
Owing to the incorporation of two identical aldehyde
molecules, substitution of the diene backbone in I is limited
to the 2 and 4 positions only. Obviously, the use of R,â-
unsaturated aldehydes, which might constitute an intermedi-
ate in the formation of I, would afford 1-acylamino-1,3-
butadiene building blocks with four potential substitution
centers along the 1,3-butadiene backbone (II) and hence
significantly increase the substrate diversity.
Here, we report the first multicomponent coupling reaction
of R,â-unsaturated aldehydes with various amides (via type
II dienes) and a dienophile, providing a series of 1-acyl-
amino-2-cyclohexene derivatives. We focused on the syn-
thesis of 4-N-acylamino-3a,4,7,7a-tetrahydroisoindole-1,3-
dione derivatives8 by employing maleimide as a truly
powerful dienophile. Initial attempts were undertaken to
1
was achieved by H and 13C NMR and MS. The latter
exhibited the parent ions and the expected fragmentation
patterns involving cleavage of the amide moiety. Two-
1
1
dimensional H-1H and H-13C NMR experiments unam-
biguously established the stereochemical structure of the
synthesized products. As with our recently reported multi-
component coupling involving simple aldehydes,5 all Diels-
Alder adducts were found to adopt an endo configuration.
In no case were hetero Diels-Alder adducts observed.
Regarding the stereochemistry of the amide moiety and
of the methyl substituents in 4a,b and 5a,b, analyses of the
1H-1H coupling constants revealed the exclusive formation
of the all-syn products. This results in bowl-shaped cyclo-
hexenes with all substituents on one side of the ring (syn).
Equivalent structures have been crystallographically con-
firmed.9 Subjection of N,N-dimethyl urea as amide equivalent
to the described one-pot reaction conditions afforded the
(6) Syntheses involving 1-acylamino-1,3-butadienes: (a) Oppolzer, W.;
Fro¨stl, W. HelV. Chim. Acta 1975, 58, 587. (b) Oppolzer, W.; Fro¨stl, W.
HelV. Chim. Acta 1975, 58, 590. (c) Oppolzer, W.; Fro¨stl, W.; Weber, H.
P. HelV. Chim. Acta 1975, 58, 593. (d) Oppolzer, W.; Flaskamp, E. HelV.
Chim. Acta 1977, 60, 204. (e) Overman, L. E.; Clizbe, L. A. J. Am. Chem.
Soc. 1976, 98, 2352, 8295. (f) Overman, L. E.; Taylor, G. F.; Jessup, P. J.
Tetrahedron Lett. 1976, 36, 3089. (g) Overman, L. E.; Jessup, P. J.
Tetrahedron Lett. 1977, 18, 1253. (h) Overman, L. E.; Taylor, G. F.; Petty,
C. B.; Jessup, P. J. J. Org. Chem. 1978, 43, 2164. (i) Overman, L. E.;
Lesuisse, D.; Hashimoto, M. J. Am. Chem. Soc. 1983, 105, 5373. (j) Martin,
S. F.; Li, W. J. Org. Chem. 1991, 56, 642. (k) Alonso, D. A.; Alonso, E.;
Najera, C.; Yus, M. Synlett 1997, 491. Antibody-catalyzed reactions: (l)
Yli-Kauhaluoma, J. T.; Ashley, J. A.; Lo, C.-H.; Tucker, L.; Wolfe, M.
M.; Janda, K. D. J. Am. Chem. Soc. 1995, 117, 7041.
(7) A complete reaction scheme would also involve several other
equilibrating species, such as imines, aminals, and 1,3-bis(acylamino)-but-
1-ene derivatives, as well as σ and π bond rotamers. See ref 5.
(8) A solid-phase approach toward hydroxy-substituted tetrahydroisoin-
dole-1,3-diones involving silyldienol ether substrates has recently been
reported: Smith, E. M. Tetrahedron Lett. 1999, 40, 3285.
2896
Org. Lett., Vol. 3, No. 18, 2001

Table 1. Acetamide (R1 ) Me) and Benzamide (R1 ) Ph)
Table 2. N,N-Dimethyl Urea Functionalized
Tetrahydroisoindole-1,3-dione Derivativesa
Functionalized Tetrahydroisoindole-1,3-dione Derivativesa
a Conditions: 10 mmol amide, 5 mmol aldehyde, 10 mmol maleimide,
5 mmol Ac2O, 1 mol % p-TSA, 10 mL of NMP; 100 °C, 24 h. b Isolated,
nonoptimized yields.
3a,4,7,7a-tetrahydroisoindole-1,3-dione (1d) was obtained in
79% yield (Scheme 3). The X-ray crystal structure analysis
Scheme 3. Benzenesulfonamide Functionalized
Tetrahydroisoindole-1,3-dione Derivativea
a Conditions: 10 mmol amide, 5 mmol aldehyde, 10 mmol maleimide,
5 mmol Ac2O, 1 mol % p-TSA, 10 mL of NMP; 120 °C, 24 h. b Isolated,
nonoptimized yields.
a Conditions: 10 mmol amide, 5 mmol aldehyde, 10 mmol
maleimide, 5 mmol Ac2O, 1 mol % p-TSA, 10 mL of NMP; 120
°C, 48 h. b Isolated, nonoptimized yields.
corresponding N-4-ureyl-3a,4,7,7a-tetrahydroisoindole-1,3-
dione derivatives. Yields are slightly lower compared to
acetamide, mostly as a result of elimination of urea from
the target molecule.10 Again, all Diels-Alder adducts contain
an endo bicyclic system with all substituents on one side of
the cyclohexene ring (syn).
Sulfonamides are another family of amide equivalents this
one-pot protocol has been successfully applied to. When
employing crotonaldehyde, N-4-benzenesulfonylamino-
of 1d11 confirmed the proposed endo configuration of the
bicyclic system with syn-substitution on the cyclohexene ring.
(11) X-ray data of 1d were collected on a STOE-IPDS diffractometer
using graphite monochromated Mo KR radiation. The structure was solved
by direct methods (SHELXS-86, Sheldrick, G. M. Acta Crystallogr. A 1990,
46, 467.) and refined by full matrix least-squares techniques against F2
(SHELXL-93, Sheldrick, G. M., University of Go¨ttingen, Germany, 1993.).
XP (Siemens Analytical X-ray Instruments, Inc.) was used for structure
representations. Crystal data for 1d: crystal dimensions 0.5 × 0.5 × 0.4,
colorless prisms, space group P21/n, monoclinic, a ) 10.707(2), b )
6.907(1), c ) 19.518(4) Å, â ) 98.39(3)°, V ) 1428.0(4) Å3, Z ) 4, Fcalcd
) 1.425 g cm-1, 4084 reflections measured, 2161 were independent of
symmetry, and 1762 were observed (I > 2σ(I)), R1 ) 0.040, wR2 (all data)
) 0.111, 211 parameters
(9) Spannenberg, A.; Neumann, H.; Jacobi von Wangelin, A.; Go¨rdes,
D.; Beller, M. Unpublished results.
(10) Traces of elimination product (dihydroisoindole-1,3-dione) were
detected.
Org. Lett., Vol. 3, No. 18, 2001
2897

pot procedure to give N-4-acylamino-3a,4,7,7a-tetra-
hydroisoindole-1,3-diones.
The described methodology constitutes the most simple
and direct high-yield approach to this class of compounds
and, to the best of our knowledge, is the first example of a
multicomponent coupling of R,â-unsaturated aldehydes,
amides, and olefins.
Dienophiles other than maleimide, such as maleic anhy-
dride, acrylonitrile, and dialkyl acetylenedicarboxylates, give
somewhat lower yields in Diels-Alder adducts, and these
results will soon be communicated.
Acknowledgment. The authors gratefully acknowledge
generous financial support from Degussa AG, the state
Mecklenburg-Western Pomerania, and the Bundesministe-
rium fu¨r Bildung und Forschung (BMBF).
Figure 1. Crystal structure of 1d (ellipsoids at the 30% level).
Supporting Information Available: Crystal data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The molecular structure is depicted in Figure 1. Bond
distances and angles are in the expected ranges.
In conclusion, we have shown that R,â-unsaturated alde-
hydes, various amides, and maleimide readily react in a one-
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Org. Lett., Vol. 3, No. 18, 2001