Organocatalytic enantioselective (3+2) cycloaddition using stable azomethine ylides

Article abstract of DOI:10.1039/c1cc15671c

We have developed a highly efficient procedure for carrying out the catalytic enantioselective (3+2) cycloaddition between enals and stable azomethine ylides such as isoquinolinium and phthalizinium methylides. Under the optimized reaction conditions highly substituted chiral pyrroloisoquinolines and pyrrolophthalazines have been obtained in high yields and excellent diastereo- and enantioselectivities.

Full text of DOI:10.1039/c1cc15671c

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COMMUNICATION
Organocatalytic enantioselective (3+2) cycloaddition using stable
azomethine ylideswz
´
´
Naiara Fernandez, Luisa Carrillo,* Jose L. Vicario,* Dolores Badıa and Efraim Reyes
Received 13th September 2011, Accepted 4th October 2011
DOI: 10.1039/c1cc15671c
We have developed a highly efficient procedure for carrying out
the catalytic enantioselective (3+2) cycloaddition between enals and
stable azomethine ylides such as isoquinolinium and phthalizinium
methylides. Under the optimized reaction conditions highly
substituted chiral pyrroloisoquinolines and pyrrolophthalazines
have been obtained in high yields and excellent diastereo- and
enantioselectivities.
in other examples which proceed in a non-enantioselective
fashion is well documented.4 It should also be pointed out that
many examples of compounds of this type have been prepared
and isolated and are known to be stable reagents that can be
handled without special precautions.
With these precedents in mind, we decided to survey the use
of isoquinolinium and phthalizinium methylides in the organo-
catalytic enantioselective (3+2) cycloaddition reaction with
a,b-unsaturated aldehydes using a chiral secondary amine as
catalyst (Fig. 1). This reaction was initially developed for the
first time in our laboratories using a-iminomalonates as
azomethine ylide precursors and relies on the ability of the
secondary amine catalyst to activate the dipolarophile by
reversible iminium ion formation.5 The use of this particular
class of stable azomethine ylides proposed herein would
open a direct and highly modular way for the stereoselective
preparation of pyrroloisoquinolines and pyrrolophthalazines
which is a structure present in several useful compounds with
applications as therapeuticals or in materials chemistry.6
We started using the reaction between isoquinolinium-
2-dicyanomethylide7 and crotonaldehyde, as a representative
model system in which we could optimize the different experi-
mental parameters (Table 1). We initially tested the conditions
The (3+2) cycloaddition reaction between alkenes and azomethine
ylides is one of the most powerful and direct methodologies for
the preparation of polysubstituted pyrrolidines,1 which is a
structural architecture present in many natural products. In
particular, the catalytic enantioselective version of this trans-
formation shows up as a highly attractive approach for building
up this heterocyclic moiety in a stereocontrolled way.2 In this
context, several metal-based catalytic systems have been developed
which allow carrying out this reaction with excellent levels of
stereocontrol. In addition to this approach, the advent of
organocatalysis has also contributed to the field with some
examples which show the excellent performance exhibited by
small organic molecules to promote this transformation by
activating the dipole or the dipolarophile by means of
H-bonding interactions or by iminium ion formation.3
However, despite all these efforts, all the methodologies
reported up to date have focused on the use of a-imino esters
as azomethine ylide precursors,2,3 being these usually unstable
species generated in situ in the reaction medium by means of a
deprotonation/metallation sequence in the metal-catalyzed
reactions or, alternatively, by a prototropy process in the
related organocatalytic versions. Surprisingly, the use of iminium
methylide reagents as 1,3-dipoles in catalytic enantioselective
(3+2) cycloadditions still remains elusive in the chemical
literature even though their ability to participate as 1,3-dipoles
Department of Organic Chemistry II, UPV/EHU. P.O. Box 644,
48080 Bilbao, Spain. E-mail: marisa.carrillo@ehu.es,
joseluis.vicario@ehu.es; Fax: +34 94 601 2748;
Tel: +34 94 601 5454
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
13C-NMR spectra and chiral HPLC traces. Crystal data file for com-
pound 4d is also provided. CCDC 844312. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c1cc15671c
Fig. 1 The different approaches reported for catalytic enantioselective
(3+2) cycloadditions through in situ formation of azomethine ylide
and the use of stable isoquinolinium/phthalizinium methylides studied
herein.
1
procedures, characterisation of all new compounds, copies of H and
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12313–12315 12313

Table 1 Screening for the best reaction conditions
overall efficiency of the reactions in terms of yield, endo selectivity
and/or enantioselectivity is considered as a whole.
We continued our work with the identification of the best
solvent for the reaction (entries 7–13). As it can be seen in the
table, in general ethereal solvents were found to be the most
efficient ones in terms of enantioselectivities (entries 4, 7 and 8),
still observing that THF was the most appropriate one in terms of
both chemical efficiency and stereoselectivity (entry 4). In general,
the reaction proceeded with significantly lower enantioselectivity
with the other solvents employed (entries 9–13). We also evaluated
the temperature of the reaction observing that, working at 4 1C
furnished cycloadduct 4a with lower yield and similar diastereo-
and enantioselectivity (entry 14) for a longer reaction time (4 days)
and that carrying out the reaction at even lower temperature
(entry 15) resulted in an improvement of the endo-selectivity,
although the yield resulted significantly affected. After all these
experiments, it was concluded that the best conditions for the
reaction were those depicted in entry 4 of Table 1.
Yielda
T/1C (%)
eec
Entry Catalyst Additive Solvent
endo/exob (%)
1
2
3
4
5
6
7
8
3a
3a
3b
3c
3d
3e
3c
3c
3c
3c
3c
3c
3c
3c
3c
—
—
H2Od
—
THF
THF
r.t. 52
r.t. 38
r.t. 83
r.t. 87
r.t. 32
r.t. 33
r.t. 64
47 : 53
45 : 55
80 : 20
88 : 12
71 : 28
82
83
20
88
46
PhCO2H THF
We also decided to evaluate the possible occurrence of an
uncatalyzed background reaction as the origin of the loss of
stereoselectivity. Interestingly, when 1a and 2a were stirred in
THF for 4 days in the absence of any catalyst (entry 16),
cycloadduct 4a was formed in 40% yield as a single exo diaster-
eoisomer. Moreover, we also observed that TFA was also able to
accelerate the reaction, leading to the formation of 4a in higher
yield after 2 days, although as a mixture of diastereoisomers
(entry 17). These two experiments indicate the tendency of the
system to undergo reaction without any catalyst which can explain
the low stereoselectivities obtained in cases in which the yield was
rather high and also points towards an active role of the 3c/TFA
catalytic system to participate in the acceleration of the reaction
which provides cycloadduct 4a in good yields for a much shorter
reaction time and in high endo-selectivity and enantioselectivity.
Once the best protocol for the reaction had been found, we
proceeded next to evaluate the scope of the reaction with
regard to the use of other a,b-unsaturated aldehydes and to
the performance of phthalizinium dicyanomethylide11 1b as
1,3-dipole in this transformation. As it can be seen in Table 2,
the reaction proceeded in a satisfactory way in most of the
cases studied, furnishing cycloadducts 4a–f in moderate to
good yields, high endo-selectivity and enantioselectivities in the
range of 85 Z 99% ee.12 The reaction tolerates well the use of
different b-alkyl substituted a,b-unsaturated aldehydes, although
both the yield and the diastereoselectivity of the process became
importantly affected as the size of the chain increased (entries 1–3).
In contrast, b-aryl substituted enals reacted efficiently regard-
less of the electronic nature of the aromatic ring (entries 4–6).
It should be noted that, when phthalizinium dicyanomethylide
1b was employed using 2a as dipolarophile, cycloadduct 4g
was isolated with good yield but as a 3 : 2 mixture of diastereo-
isomers (entry 7). Nevertheless, the major endo isomer was
isolated as a highly enantioenriched material. This led us to
survey modified conditions in order to improve this result and,
after several attempts, it was found that the reaction proceeded
in a very efficient manner by changing to toluene as solvent
(entry 8). These conditions were further extended to other a,b-
unsaturated aldehydes 2b–f with the same general behavior as
that observed for 1a but obtaining, in general, a better perfor-
mance with regard to enantioselection (entries 9–13).
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
—
THF
THF
THF
Et2O
>95 : o5 44
67 : 33
83 : 17
77 : 23
88
74
68
1,4-Dioxane r.t. 66
9
Toluene
CHCl3
CH3CN
DMF
EtOH
THF
THF
THF
THF
r.t. 36
r.t. 50
r.t. 31
r.t. 40
r.t. 80
10
11
12
13
14
15
16
17
>95 : o5 38
77 : 33
83 : 17
99 : 1
82 : 18
94 : 6
16
8
46
87
88
4
57
ꢀ30 53
r.t. 40
r.t. 70
o5 : >95 —
TFA
33 : 67
—
a
Yield of major diastereoisomer after flash column chromatography
b
purification. Determined by 1H-NMR analysis of crude reaction
c
mixture. ee of pure endo diastereoisomer determined by HPLC
d
(see ESIz). 4.0 equiv. of water were used as additive.
previously used in our initial report which comprised the use
of 3a as catalyst in the presence of 4 equiv. of water as an
additive in THF at r.t. (entry 1)5 but in this case the reaction
proceeded with moderate yield, furnishing an almost 1 : 1
mixture of endo/exo diastereoisomers with the endo isomer being
formed in 82% ee.8 The reaction in the absence of water
performed similarly in terms of stereocontrol but with a poorer
chemical yield (entry 2). We next switched to the use of derivative
3b (entry 3), which was employed together with a Brønsted
acid co-catalyst.9 In this case, a cleaner reaction occurred but
the enantioselectivity of the major endo cycloadduct resulted
affected. We next evaluated the performance of catalyst 3c in
the presence of TFA as co-catalyst (entry 4), a combination that
had proven its efficiency in the (3+2) cycloaddition between
nitrones and enals,10 observing that this system performed very
well with respect to the endo-selectivity control and furnished
cycloadduct 4a in good yield and a promising 88% ee. It should be
stressed that, under these conditions, a remarkably fast reaction
occurred, observing that all the starting material had been con-
sumed after 30 min, in deep contrast with the other experiments
involving proline-based catalysts 3a and 3b for which typically
3–4 days were required to bring the reaction to completion. Other
related imidazolidinone catalysts were also tested (entries 5 and 6)
but without observing any significant improvement when the
c
12314 Chem. Commun., 2011, 47, 12313–12315
This journal is The Royal Society of Chemistry 2011

Table 2 Scope of the reaction
Entry
Ylide
Aldehyde
R
Prod.
Solvent
Yielda (%)
endo/exob
eec (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
2a
2b
2c
2d
2e
2f
2a
2a
2b
2c
2d
2e
2f
Me
nPr
4a
4b
4c
4d
4e
4f
4g
4g
4h
4i
THF
THF
THF
THF
THF
THF
THF
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
87
51
45
70
63
73
98
91
72
64
61
63
60
88 : 12
65 : 35
63 : 37
>95 : o5
>95 : o5
>95 : o5
63 : 44
86 : 14
83 : 17
77 : 23
91 : 9
88
84
84
94
88
84
>99
>99
>99
95
nC8H17
Ph
p-(MeO)C6H4
p-(NO2)C6H4
Me
Me
nPr
9
10
11
12
13
nC8H17
Ph
4j
4k
4l
97
90
99
p-(MeO)C6H4
p-(NO2)C6H4
71 : 29
80 : 20
a
b
Yield of pure endo diastereoisomer after flash column chromatography purification. Determined by 1H-NMR analysis of crude reaction
c
mixture. ee of pure endo diastereoisomer determined by HPLC (see ESIz).
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this point, we could also grow crystals for compound 4d suitable
for X-ray analysis. This also allowed us to unambiguously
establish the absolute configuration of all compounds 4a–l.
In conclusion we have demonstrated that isoquinolinium
and phthalizinium methylides can be used as efficient azomethine
ylides which participate in (3+2) cycloaddition reaction in
the presence of chiral imidazolidinone 3a as catalyst leading to
the formation of pyrroloisoquinoline and pyrrolophthalazine
cycloadducts in good yields and high diastereo- and enantio-
selectivities under the optimized reaction conditions.
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determination of this minor product.
The authors thank the Spanish MICINN (CTQ2008-00136/
BQU), EJ/GV (Grupos IT328-10) and UPV/EHU (fellowships
to N.F. and E.R.) for financial support.
Notes and references
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12313–12315 12315