Efficient Horner-Wadsworth-Emmons intramolecular cyclisation of a N-substituted phthalimide promoted by KF-Alumina: a general tool for the synthesis of functionalised isoindolinones

Article abstract of DOI:10.1016/j.tetlet.2009.04.029

An intramolecular Horner-Wadsworth-Emmons reaction promoted by KF-Alumina involving a N-substituted phthalimide, cleanly and efficiently furnishes an interesting α,β-unsaturated tricyclic enone which may undergo selective alkylations at the α′-position.

Full text of DOI:10.1016/j.tetlet.2009.04.029

Tetrahedron Letters 50 (2009) 3050–3053
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Tetrahedron Letters
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Efficient Horner–Wadsworth–Emmons intramolecular cyclisation
of a N-substituted phthalimide promoted by KF-Alumina: a general tool
for the synthesis of functionalised isoindolinones
Vittorio Pace a, Fernando Martínez a, Clara I. Nova b, María Fernández a,
José Vicente Sinisterra a,b, Andrés R. Alcántara a,b,
*
a Department of Organic and Pharmaceutical Chemistry, Pharmacy Faculty, Complutense University, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain
b Industrial Biotransformations Service (SBI), Scientific Park of Madrid (PTM), C/Santiago Grisolia 2, 28760 Tres Cantos, Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
An intramolecular Horner–Wadsworth–Emmons reaction promoted by KF-Alumina involving a N-substi-
Received 27 February 2009
Revised 31 March 2009
Accepted 3 April 2009
Available online 14 April 2009
tuted phthalimide, cleanly and efficiently furnishes an interesting a,b-unsaturated tricyclic enone which
may undergo selective alkylations at the a0-position.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Horner–Wadsworth–Emmons reaction
Isoindolinones
Cyclisation
Heterogeneous catalysis
Enones
Isoindolinones constitute the core of several natural com-
pounds, such as magallanesine1 (Fig. 1), an isoindolobenzazocine
isolated from the South-American plant Berberis darwinii, a penta-
cyclic nucleus with a characteristic benzazocine ring system in
which the nitrogen is present as a vinylogous imide, and could
be formally derived by the intramolecular cyclisation of an appro-
priate phthalimide derivative. Moreover, the interest towards iso-
All the methodologies above reported involve the employment
of some reagents, such as organometallic compounds, which
should be avoided in order to promote an eco-friendlier process,
according to modern synthetic chemistry principles; thus, we con-
sidered that a Wittig-type process could be more appropriate for
preparing such structures.
In fact, the Wittig reaction of compounds different from alde-
hydes and ketones has been extensively studied;12 more con-
cretely, Wittig reaction of imides is applicable to intramolecular
processes and has been employed in the preparation of a wide
range of heterocyclic systems.13 An useful alternative to classical
Wittig reaction is represented by the Horner–Wadsworth–Em-
mons reaction (HWE),14 in which the nucleophilic ylid is obtained
from a b-ketophosphonate. However, to the best of our knowledge,
only a few examples have applied this attractive methodology to
imide chemistry, generally reporting low reaction yields.15 On
the contrary, related carbonyl compounds such as lactones, may
indolinones from a medicinal chemistry perspective is prompted
2a
because of their presence in 5-HT1A
,
5-HT2,2a,b or D2 antago-
nists,2a,b as well as in antileukemic drugs.2c
Considerable efforts have been directed towards the synthesis
of isoindolinones (phthalimidines). They have been prepared via
Grignard3 or lithiation4 procedures, as well as by Diels–Alder cyc-
loadditions,2c,5 rearrangement6 and photochemical reactions.7 The
reduction of N-substituted phthalimides8 and the condensation of
phthalaldehyde9 also afford isoindolinones. In addition, different
palladium-catalysed syntheses of isoindolinones have been re-
ported,10 while, on the other hand, isoindolin-1-ones have also
been prepared via electrophilic cyclisation of o-(1-alkynyl)benz-
amides,3 or by the addition of in situ generated organoalanes to
acyliminium ions.11
O
O
OMe
N
O
OMe
O
* Corresponding author. Tel.: +34 91 3941820; fax: +34 91 3941822.
E-mail address: andresr@farm.ucm.es (A.R. Alcántara).
Figure 1. Magallanesine.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.029

V. Pace et al. / Tetrahedron Letters 50 (2009) 3050–3053
3051
undergo intramolecular HWE type-condensation, thus providing
an useful synthetic route to analogous five-membered ring
structures.16
lowed us to report high chemoselective procedures in N-allylation
of anilines.21 So we checked the viability of the reaction on the b-
ketophosphonate by using KF-Alumina.22 This catalyst had been al-
ready employed in such HWE chemistry by different authors,23
although they described the limitation of its use in classical reac-
tions involving aldehydes and ketones.
In this Letter we wish to report a convenient procedure, based
on a HWE intramolecular cyclisation of a b-ketophosphonate 1,
prepared from N-substituted phthalimides, for the construction
of the heterofused isoindolinone 2, namely 2H-pyrrolo[2,1-a]isoin-
dole-2,5(3H)-dione. As can be seen in Scheme 1, mechanism reac-
tion involves the nucleophilic intramolecular addition of carbanion
1a generated from the phosphonate 1 to the phthalimide carbonyl,
followed by spontaneous elimination of phosphate from the
As detailed in Table 1, the best result, 93% of cyclisation prod-
uct, was obtained under KF-Alumina catalysis at 60 °C in only
1 h. It seemed that solvent effect was not dramatic, since at the
same temperature acetonitrile and DMF gave comparable results
(entries 1 and 3). Remarkably, by increasing temperature the
amount of cyclisation product decreased: this can be explained
by the fact that, since reaction is an equilibrium, temperature could
shift it towards the open form (entries 1 and 2). Interestingly, the
milder basic nature of KF-Celite (entry 4) did not allow to achieve
the cyclisation, and furthermore the use of unsupported KF (entry
5) was also ineffective. Ordinary bases used in organic synthesis
(tBuOK, NaOMe or NaH) were also effective to promote this trans-
formation in analogous reaction times (entries 6–8) with slightly
lower yields. Furthermore, the synthetic utility of the supported
catalyst is readily demonstrable.22,24 All reactions can be carried
out cleanly, rapidly and in high yield under mild conditions,
whereas attempts to carry out the same reactions with unsup-
ported catalyst frequently either fail or result in the formation of
mixture of products. This not only becomes environmentally be-
nign but also offers economically favourable situation as compared
to cumbersome and cost-effective separation of the products in
corresponding homogeneous procedures.
The simplicity of our reaction conditions led to higher yield of
adduct 2 compared to before-mentioned methodologies based on
a classical Wittig reaction.17b,c More concretely, we have maxi-
mised the yield and minimised the reaction time: Bestmann, re-
ported only a 56% of isolated yield of 2 after 12 h.17c These
results are in excellent agreement with the general higher reactiv-
ity of ylids derived from phosphonates towards those obtained
from phosphoranes.25 Furthermore, work-up of HWE reactions is
easier compared to that of their Wittig counterparts, as phospho-
nate esters are soluble in water and elimination of the supported
KF is performed simply by filtering the reaction mixture in vacuo.
Of particular synthetic value is the generation of the enolate of
oxaphosphetane 1c and formation of the highly stable
rated cyclic ketone 2.
a,b-unsatu-
Previously, compound 2 has been prepared by flash vacuum
pyrolysis (FVP) of stabilized phosphorous ylides under drastic reac-
tion conditions: in particular, performing the cyclisation at 750 °C
(as described by Aitken,17a) represents a major drawback, because
of the severe complexity of reaching those extreme conditions in
normal laboratories. Alternatively, Caballero et al. obtained this tri-
cyclic system as an undesired product of the Wittig reaction be-
tween
a
phosphorane
and
N-phenylsulfonylindole-3-
carbaldehyde.17b Finally, Bestmann and co-workers noticed the
formation of pyrroloisoindolediones as the consequence of the
intramolecular cyclisation promoted by heating of an appropriate
phosphoranylideneketenimine.17c
The effective precursor of b-ketophosphonate 118 is 3-phthalim-
ido-1-iodopropan-2-one 4, easily obtained in quantitative yield by
an interesting new route consisting in ring opening of 2,3-epox-
ypropylphthalimide 3 with concentrated HCl, subsequent oxida-
tion of the resulting chlorohydrine using the Jones reagent and,
finally, a Finkelstein process to afford the desired a-iodoketone 4,
which underwent a subsequent Arbuzov reaction19 to yield phos-
phonate 1, as depicted in Scheme 2. It is worth noting that carrying
out the Arbuzov reaction on a-iodoketone 4 without solvent under
reflux allows eliminating any Perkow side reaction, which usually
is obtained along with the desired nucleophilic displacement,20 so
that, under these reaction conditions, we obtained b-ketophospho-
nate 1 exclusively.
We examined the possibility to promote the cyclisation of the
b-ketophosphonate under basic conditions, as depicted in Scheme
1. Table 1 shows the experimental results obtained using different
bases. The first choice was supported KF, which had previously al-
the cyclic
a,b-unsaturated enone so formed, which may be alkyl-
ated selectively at the a0-position of the ketone as described by
O
EtO
OEt
P
OEt
OEt
O
O
O
O
O
P
O
O
P
OEt
O
OEt
base
N
N
N
O
O
O
1
1a
1b
O
EtO
O
P
OEt
O
-PO(OEt)2OH
O
N
N
O
O
1c
2
Scheme 1. HWE intramolecular cyclisation mechanism.

3052
V. Pace et al. / Tetrahedron Letters 50 (2009) 3050–3053
OEt
O
O
O
O
O
O
P
O
OEt
a, b, c
d
I
N
N
N
O
O
O
3
4
1
Scheme 2. Preparation of b-ketophosphonate 1. Reagents and conditions: (a) CHCl3, HCl 37%, 0 °C, 30 min, quant.; (b) CrO3, acetone 0 °C, 30 min, quant.; (c) NaI, acetone, rt,
2 h, quant.; and (d) PO(Et)3, neat, reflux 4 h, 91%.
Table 1
In conclusion, we have described the first use of KF-Alumina as
an effective base to promote HWE intramolecular reaction on a
Cyclisation of b-ketophosphonate promoted by different bases via Scheme 1
Entry
Cyclisation producta (%)
Conditions
phthalimide, obtaining selectively an isoindolinone, which repre-
sents a starting structure for further modifications at a0-position
1
2
3
4
5
6
7
8
93
70
88
—
KF-Alumina (1.0 equiv), MeCN, 60 °C, 1 h
KF-Alumina (1.0 equiv), MeCN, 82 °C, 1 h
KF-Alumina (1.0 equiv), DMF, 60 °C, 1 h
KF-Celite (1.0 equiv), MeCN, 60 °C, 12 h
KF (1.0 equiv), MeCN, 60 °C, 12 h
of the cyclic
a,b-unsaturated ketone, by choosing appropriately
the electrophile agent.
—
Acknowledgements
86
78
81
tBuOK (1.0 equiv), MeCN, 60 °C, 1 h
NaH (1.0 equiv), DMF, 0 °C to rt, 1.5 h
NaOMe (1.0 equiv), THF, rt, 2 h
This work was partly supported by a Research Project of the
CAM (Comunidad Autónoma de Madrid, QO-UCM, ref. S-0505/
PPQ/0344). One of the authors (V. Pace) thanks the MEC (Spanish
Ministry of Education and Science) for a Ph.D. grant (MEC FPU
AP2005-5112).
a
Isolated yield.
O
O
1. LDA, THF, -78 ºC
N
N
Supplementary data
R'
2. RX (1.2 eq), -78ºC to rt
3 h, 72-90%
R
O
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.04.029.
5a-e, R' = H
6, R' = Me
2
R = Me, Et, Bn, allyl, 2-chloroallyl
X = I, Br
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