Concise synthesis of tricyclic isoindolinones via one-pot cascade multicomponent sequences

Article abstract of DOI:10.1021/ol9003965

A series of enantiopure tricyclic isoindolinones has been successfully synthesized through a one-pot selective cascade process from furan derivatives. The synthesis is straightforward and gave good overall yields taking into account the concomitant format

Full text of DOI:10.1021/ol9003965

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1817-1820
Concise Synthesis of Tricyclic
Isoindolinones via One-Pot Cascade
Multicomponent Sequences
Raouf Medimagh,† Sylvain Marque,*,† Damien Prim,*,† Je´roˆme Marrot,† and
Saber Chatti‡
Institut LaVoisier de Versailles (ILV) UMR CNRS 8180, UniVersite´ de
Versailles-Saint-Quentin-en-YVelines, 45 AVenue des Etats-Unis,
78 035 Versailles, Cedex, France, and Laboratoire de Chimie Verte, Institut National
de Recherche et d’Analyse Physico-chimique (INRAP), Poˆle Technologique de Sidi
Thabet, 2020 Sidi Thabet, Tunisia
prim@chimie.uVsq.fr; sylVain.marque@chimie.uVsq.fr
Received February 25, 2009
ABSTRACT
A series of enantiopure tricyclic isoindolinones has been successfully synthesized through a one-pot selective cascade process from furan
derivatives. The synthesis is straightforward and gave good overall yields taking into account the concomitant formation of five C-C, C-O,
and C-N bonds. The strategy was extended to the preparation of a thiazolidine analogue.
Rapid synthesis of complex molecules in a single operation
without isolation of intermediates is one of the current
concerns of the scientific community1 that drives increasing
efforts. Recently, cascade multicomponent reactions (CMCR)
have emerged as powerful and bond-forming efficient tools
that allow the preparation of polycyclic targets by connecting
several components in a one-pot sequential and efficient
manner.2 Due to their high versatility,3 small heterocycles
were particularly attractive in CMCR. In this context, we
became interested in the preparation of potentially biological
active enantiopure tricyclic lactam-isoindolinone deriva-
tives4 (Scheme 1). Traditionally, the synthesis of such targets
(X ) O), recently rationalized by Allin et al.,5 was realized
using 2-formylbenzoic acid and amino alcohols through the
formation of bonds (d) and (e). We anticipated that the
carboxylic group, essential to the formation of the lactam
† Universite´ de Versailles-Saint-Quentin-en-Yvelines.
‡ Institut National de Recherche et d’Analyse Physico-chimique (INRAP).
(1) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115. (b) Enders, D.; Grondal,
C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (c) Chapman,
C. J.; Frost, C. Synthesis 2007, 1.
(2) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (b)
Tietze, L. F.; Evers, T. H.; To¨pken, E. Angew. Chem., Int. Ed. 2001, 40,
903. (c) Do¨mling, A. Chem. ReV. 2006, 106, 17. (d) Bienayme´, H.; Hulme,
C.; Oddon, G.; Schmitt, P. Chem.sEur. J. 2000, 6, 3321.
(4) For selected examples, see: (a) Comins, D. L.; Schilling, S.; Zhang,
Y. Org. Lett. 2005, 7, 95. (b) Allin, S. M.; Northfield, C. J.; Page, M. I.;
Slawin, A. M. Z. Tetrahedron Lett. 1998, 39, 4905. (c) Chen, M.-D.; He,
M.-Z.; Zhou, X.; Huang, L.-Q.; Ruan, Y.-P.; Huang, P.-Q. Tetrahedron
2005, 61, 1335.
(3) (a) Constantino, L.; Barlocco, D. Curr. Med. Chem. 2006, 13, 65.
(b) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893. (c) Isambert, N.; Lavilla, R. Chem.sEur. J. 2008, 14, 8444.
(5) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M. Z.
Tetrahedron Lett. 1997, 38, 3627.
10.1021/ol9003965 CCC: $40.75
Published on Web 03/25/2009
2009 American Chemical Society

decrease of characteristic signal of the furylimine species.
1
Careful observation of H NMR spectra of crude material
Scheme 1
.
Access to Tricyclic Isoindolinones from
5-Amino-2-furaldehydes
clearly indicated the disappearance of the starting furan
protons as well as those of furylimine and the presence of
cycloadduct characteristic signals. This seminal result paved
the way to selective sequential cascades involving the early
and in situ formation of an amino furylimine species, which
then may undergo Diels-Alder cycloaddition with diethyl
maleate. Gratifyingly, optimization of the reaction condi-
tions,7,8 reactant ratios, as well as media concentration
allowed the determination of the optimal 1/amino alcohol
2/dienophile 3 ratio as 1:1:2. Under Dean-Stark conditions
in refluxing toluene (Scheme 2), the target molecules were
obtained in high conversion and yield.
moiety, could be installed at the aromatic ring through a
Diels-Alder reaction involving furan derivatives as the
diene- and carboxylic ester-substituted activated dienophiles.
This strategy would provide an expedient and straightforward
access to tricyclic isoindolinones starting from easily avail-
able activated furaldehydes. We have contributed to this area
by addressing the reactivity of activated 5-amino-2-furalde-
hydes6 in one-pot, two-step sequences.7 The latter afforded
polysubstituted aromatics or oxabicyclic structures by in situ
trapping of versatile aminofuraldehydes intermediates. An
intriguing question was whether we would be able to
selectively create five concomitant bonds (a)-(e) to succes-
sively form the aromatic ring, the imine-oxazolidine moiety,
and the isoindolinone heterocycle by ring-closing lactam-
ization (Scheme 1). An additional and critical point was the
diastereoselective formation of the oxazolidine ring step
under rather hard Diels-Alder conditions and in the presence
of electrophiles such as carbethoxy groups.
Scheme 2. One-Pot Access to Tricyclic Isoindolinone 4a
Based on previous studies devoted to Diels-Alder reac-
tions,7,8 we have been exploring the possibility of achieving
the one-pot three component four-steps preparation of
enantiopure tricyclic isoindolinones.
The selective access to tricyclic lactams 4a deserves some
comments (Scheme 3). Condensation of an R-amino alcohol
with an aldehyde is known to give a mixture of the expected
hydroxy imine such as I and the corresponding ring-closed
Initial Diels-Alder reactions involving 5-amino-2-fural-
dehydes with 3 equiv of diethyl maleate were unsuccessful.8
In fact, an increase of the reactivity of the diene was required
to allow [4 + 2] cycloadditions using diethyl maleate as the
dienophile. In this context, cycloadducts could be recently
obtained using 5-amino-2-furanmethanols, arising from the
reduction of the parent carboxaldehyde moiety, as the diene.
Moreover, previous comparisons between furaldehyde de-
rivatives and their corresponding hydrazones as potential
dienes pointed to the enhanced reactivity of the latter.9 Based
on these findings, we anticipated that the early formation of
a furylimine would allow a further cycloaddition to take
place. Indeed, the reaction of 5-amino-2-furaldehyde 1a with
diethyl maleate in the presence of phenylglycinol was
Scheme 3. Evolution of Possible Intermediates
1
monitored by H NMR and evidenced the formation of a
transient furylimine species at an early stage of the process.
Interestingly, we were able to observe the progressive
(6) (a) Prim, D.; Kirsch, G. Tetrahedron 1999, 55, 6511. (b) Prim, D.;
Kirsch, G.; Nicoud, J. F. Synlett 1998, 383. (c) Migianu, E.; Prim, D.; Kirsch,
G. Synlett 2000, 459.
(7) Medimagh, R.; Marque, S.; Prim, D.; Chatti, S.; Zarrouk, H. J. Org.
Chem. 2008, 73, 2191.
(8) Medimagh, R.; Marque, S.; Prim, D.; Chatti, S. Heterocycles 2009,
78, 679
.
(9) Potts, K. T.; Walsh, E. B. J. Org. Chem. 1988, 53, 1199.
1818
Org. Lett., Vol. 11, No. 8, 2009

Table 1. Tricyclic Isoindolinones from Various Amino Alcohols
b
compd
NR1R2
yield (%)a
amino alcohol
[R]D (deg)
4a
4b
4c
4d
4e
4f
R1, R2 ) morpholinyl
R1, R2 ) morpholinyl
R1, R2 ) morpholinyl
R1, R2 ) morpholinyl
R1 ) Me, R2 ) 4-anisidinyl
R1 ) Me, R2 ) allyl
40
65
35
45
34
33
35
(R)-phenylglycinol
(S)-phenylalaninol
(S)-alaninol
-98
-12
-5
+16
+93
-169
(-)-norephedrine
(S)-phenylglycinol
(S)-phenylalaninol
2-amino-2-methylpropanol
4g
R1, R2 ) morpholinyl
a Isolated yields. b Calculated in CH2Cl2, see the experimental procedures for concentration details.
oxazolidine II.10 Monitoring the reaction by 1H NMR clearly
evidenced that the hydroxy imine species I was the early
and predominant intermediate produced (singlet 7.9 ppm)
in full agreement with literature data.11 The transient hydroxy
imine I underwent cycloaddition leading to the intermediate
III, which may equilibrate with IV.
The one-pot sequence was then extended to several amino
alcohols in combination with variously substituted 5-amino-
2-furaldehydes (cyclic, aromatic, and allylic amino subtitu-
ents), affording 4b-g in fair to good yields ranging from
33 to 65% yields in four steps (Table 1).
In the last step, ring closure with concomitant loss of
1
ethanol cleanly produced the target lactam 4a. H NMR
spectra of the crude did not reveal the presence of side
products. Although both intermediates III and IV existed in
solution, lactamization process most likely occurred from
oxazolidine IV, according to literature data.5
1
Careful examination of H NMR spectra of the crude
material confirmed the presence of only one of the possible
diastereomers. As observed in the case of oxazolidines arising
from aromatic aldehydes bearing electron-withdrawing
groups,5,12 the selective cyclization process from III is
assumed to afford the more favored trans isomer IV.
Relative configuration of C18-C15 has been determined
both by single-crystal X-ray analysis13 and by NOE experi-
ments (Figure 1). The absolute configuration was assigned
on the basis of the fixed stereocenter of the starting amino
alcohol.
Figure 1. ORTEP X-ray plot and NOE for 4a.
For all these cases, only one diastereomer was selectively
obtained during the oxazolidine ring construction, even under
rather harsh reaction conditions.
Interestingly, the use of amino alcohol bearing an ad-
ditional chiral center such as norephedrine affected neither
the isolated yield nor the selective chirality transfert process
(10) Allin, S. M.; Hodkinson, C. C.; Taj, N. Synlett 1996, 781.
(11) Scialdone, M. A.; Meyers, A. I. Terahedron Lett. 1994, 35, 7533.
(12) Agami, C.; Rizk, T. Tetrahedron 1985, 41, 537
Org. Lett., Vol. 11, No. 8, 2009
.
1819

(see 4d). It is worth noting that increase of substitution at
the amino alcohol, when using 2-amino-2-methylpropanol,
only poorly affected conversion and yields, 4g being obtained
in 35% yield.
Table 2. Solvent-Free Obtention of 4a
conditions
We next examined the use of amino thiol instead of amino
alcohol, in order to prepare the corresponding thiazolidine
5 (Scheme 4). Attempts to use aminoethanethiol hydrochlo-
solvent
toluene
solvent free
time (h)
T (°C)
yield (%) (four steps)
96
24
Dean-Stark
115
40
41
three-component cascade process. This unprecedented selec-
tive sequence involved the formation of a transient imine
followed by Diels-Alder cycloaddition, oxazolidine ring
closure, and lactamization reactions. The formation of five
concomitant C-C, C-O, and C-N bonds, under appealing
solvent-free conditions, fulfills not only current organic
chemistry concerns but also green chemistry principles. In
addition, this methodology could be extended to the forma-
tion of thiazolidine analogues by using amino thiols instead
of amino alcohols.
Scheme 4. Synthesis of Tricyclic Thiazolidine 5
Acknowledgment. We are very grateful to the Universite´
de Versailles-Saint-Quentin-en-Yvelines for material support
and to CNRS for financial support, especially for a grant
(R.M.) and ANR program (ANR-07-CP2D-14-01).
ride without neutralization failed. In fact, neutralization of
the latter prior to the reaction sequence was not required,
and the presence of an additional base in the media such as
K2CO3 (1 equiv) was successful, allowing a selective
preparation of 5 in 58% yield.
Among the classic tools to measure the reaction efficiency,
alternative ones, such as “greenness”,14 have begun to
emerge. In this context, solvent-free reactions that induce
benefits such as cost savings, decreased energy consumption,
and reduced reaction times become an appealing alternative
to enhance this factor.15 With this in mind, we decided to
test the feasibility of our sequence under solvent-free
conditions. Reacting the components in aforementioned
proportions in a sealed tube at 115 °C afforded the desired
product 4a in 24 h in 41% yield (Table 2). It is worthy to
note that reaction time could be significantly reduced without
loss of yield or stereoselectivity.
Supporting Information Available: Experimental pro-
cedure and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL9003965
(13) Crystal data: C23H24N2O5, Mw ) 408.44, orthorhombic, space group
P212121; dimensions: a ) 8.7153(7) Å, b ) 9.8625(9) Å, c ) 24.055(2) Å,
V ) 2067.7(3) Å3; Z ) 4; µ ) 1.312 mm-1; 36210 reflections measured at
100 K; independent reflections: 3404 [2497 Fo > 4σ (Fo)]; data were
collected up to a 2θmax value of 60.10° (99.2% coverage). Number of
variables: 297; R1 ) 0.0399, wR2 ) 0.1060, S ) 1.072; highest residual
electron density 0.214 e Å-3 (all data R1 ) 0.0702, wR2 ) 0.1295). CCDC
717782.
(14) Walsh, P. J.; Li, H.; Anaya de Parrodi, C. Chem. ReV. 2007, 107,
2503.
In summary, we succeeded in the efficient preparation of
enantiopure tricyclic isoindolinones via a novel one-pot,
(15) (a) Cave, G. W. V.; Raston, C. L.; Scott, J. L. Chem. Commun.
2001, 2159. (b) Tanaka, K.; Toda, F. Chem. ReV. 2000, 100, 1025.
1820
Org. Lett., Vol. 11, No. 8, 2009