A systematic study on the use of different organocatalytic activation modes for asymmetric conjugated addition reactions of isoindolinones

Article abstract of DOI:10.1016/j.tet.2016.12.036

In this article we describe a series of new asymmetric Michael reactions of carboxylate-3-substituted isoindolinones used as nucleophiles in the synthesis of valuable chiral tetrasubstituted derivatives. It has been shown that the reactivity and enantiose

Full text of DOI:10.1016/j.tet.2016.12.036

Accepted Manuscript
A systematic study on the use of different organocatalytic activation modes for
asymmetric conjugated addition reactions of isoindolinones
Francesco Scorzelli, Antonia Di Mola, Francesco De Piano, Consiglia Tedesco, Laura
Palombi, Rosanna Filosa, Mario Waser, Antonio Massa
PII:
S0040-4020(16)31322-9
10.1016/j.tet.2016.12.036
TET 28328
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 August 2016
Revised Date: 5 December 2016
Accepted Date: 16 December 2016
Please cite this article as: Scorzelli F, Di Mola A, De Piano F, Tedesco C, Palombi L, Filosa R, Waser
M, Massa A, A systematic study on the use of different organocatalytic activation modes for asymmetric
conjugated addition reactions of isoindolinones, Tetrahedron (2017), doi: 10.1016/j.tet.2016.12.036.
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A systematic study on the use of different
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organocatalytic activation modes for asymmetric
conjugated addition reactions of isoindolinones.
Francesco Scorzelli, Antonia Di Mola, Francesco De Piano, Consiglia Tedesco, Laura Palombi, Rosanna Filosa,
Mario Waser and Antonio Massa*
Dipartimento di Chimica e Biologia, Università di Salerno, Via Giovanni Paolo II, 132, 84084-Fisciano, SA, Italy.
E-mail: amassa@unisa.it; Fax: +39-089-969603; Tel: +39-089-969565
O
O
O
O
R'
OH
O
X
N
X
Ar
X
R''
N R
N
R
R''
Cat.:
prolinol-TMS ether
Cat.:
EtO2C
up to 96% ee
EtOOC
up to 91% ee
cinchona based PTC or
hydrogen donors
Ar
COOEt
R'
X=H, Br, EtO, NO2
R=H, Alkyl, Bn, Ph
R'=Me, Ar
O
R''=H, Ar

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A systematic study on the use of different organocatalytic activation modes for
asymmetric conjugated addition reactions of isoindolinones.
Francesco Scorzelli,a Antonia Di Mola,b Francesco De Piano,a Consiglia Tedesco,a Laura Palombi,a Rosanna Filosa,c
Mario Waserd and Antonio Massaa,*
aDipartimento di Chimica e Biologia, Università di Salerno, Via Giovanni Paolo II, 132, 84084-Fisciano, SA, Italy.
E-mail: amassa@unisa.it; Fax: +39-089-969603; Tel: +39-089-969565
bDipartimento di Farmacia, Università di Salerno, Via Giovanni Paolo II, 132, 84084-Fisciano, SA, Italy.
c Dipartimento di Medicina Sperimentale, Università di Napoli, Napoli, Italy
d Institute of Organic Chemistry, Johannes Kepler University Linz, Altenbergerstr. 69, 4040 Linz, Austria
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In this article we describe a series of new asymmetric Michael reactions of carboxylate-3-
substituted isoindolinones used as nucleophiles in the synthesis of valuable chiral
tetrasubstituted derivatives. It has been shown that the reactivity and enantioselectivity
strongly depend on the substitution pattern of the isoindolinone, requiring either cinchona-
alkaloid based phase transfer catalysts or chiral hydrogen donors. Moreover, prolinol-TMS
ether-based secondary amine catalysts permitted the development of Michael/cyclization
tandem reaction with cynnamaldehyde for the synthesis of aza-polycyclic derivatives.
Available online
Keywords:
Keyword_1 Nitrogen heterocycles.
Keyword_2 Tetrasubstituted stereocenters
Keyword_3 Chiral phase transfer catalysis
Keyword_4 Bifunctional organocatalysis
Keyword_5 Iminium ion catalysis
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
derivatives which could be employed for the synthesis of
bioactive compounds.
In recent years chiral 3,3-disubstituted isoindolinones have
become increasingly attractive because of the wide range of
different biological activities that are associated with this
structural motif.1 For example, a series of compounds like 1, a
potential drug for the treatment of cardiac arrhythmias,1a or
the derivative 2, useful for the treatment of atherosclerosis1b
and the urea-containing isoindolinone 3, a blood pressure
regulator1c (Figure 1) have been the subject of extensive
investigations. However, the isolation of enantioenriched
examples of these targets has so far largely been achieved via
chromatographic separation of the racemates using chiral
stationary phases1a,b or by the use of chiral auxiliaries.1c Until
recently only a few catalytic asymmetric methodologies have
been developed to access 3,3-disubstituted isoindolinones
using either chiral metal complexes2 or chiral phosphoric
acids3. This is in contrast with the larger number of
asymmetric methodologies that are available for the synthesis
of chiral 3-substituted isoindolinones.4 This prompted us to
develop a more general route towards 3,3-disubstituted
isoindolinones via asymmetric catalysis mediated by chiral
small molecules (organocatalysis) oriented towards
Our attention focused on compounds of general structure 45
(Figure 1) that are surprisingly unprecedented as intermediates
in asymmetric reactions. As recently reported for analogous
isobenzofuranones,6 these compounds, activated by an ester
group, can be successfully employed as nucleophiles in a
number of asymmetric transformations. In addition, the
presence of a further nucleophilic moiety, i.e. the free NH
group of 4 when R=H, can be particularly useful for the
synthesis of aza-polycyclic compounds 5. This is of particular
interest as asymmetric methodologies for the synthesis of
targets 5 are rare.7
We initially focused on asymmetric Michael reactions
utilizing methyl vinyl ketone and thus obtained products that
serve as valuable intermediates for further transformations.
Initial results were encouraging with high yields (95%) and
moderate to good enantioselectivities (up to 76% ee) obtained
in the presence of chiral ammonium salts under phase transfer
conditions although neutral bifunctional organocatalysts were
less effective.8 However, only a very limited number of
isoindolinones (three in total) and catalysts were tested
leaving substantial room for further improvement.

2
Tetrahedron
Considering the novel nature of using nucleophilic
esterification and radical bromination and then into the target
ACCEPTED MANUSCRIPT
isoindolinones in asymmetric catalysis, we felt it would be
particularly useful to expand the scope of this work by
focusing on, i) a wider screening of chiral ammonium salts
and organocatalysts and ii) a detailed analysis of the substrate
scope by changing both the nucleophilic part and the Michael
acceptor. Alongside focusing on the use of compounds 4 in
asymmetric C-C bond forming reactions, we also addressed
the synthesis of new isoindolinones 4 with different
substituents on both the lactam and the aromatic ring by
introducing either new synthetic strategies or by modifying
and optimizing known routes to these compounds.
isoindolinones upon reaction with different amines.
Br
CO2Et
CO2Et
Br
CO2H
CO2H
CO2H
CO2H
a
b
6b
48% (conv 50%)
7b
90%
6a
c
O
Br
CO2Et
CO2Et
Br
d
N-R
CO2Et
Br
4i-l
8b
F
O
O
83%
65-94%
N
R
N
Ph
OR'
CO2Et
Scheme 1. Synthetic pathway to 5-bromoisoindolinones 4i-4l: a) KBrO3,
H2SO4, 90 °C, 2 h; b) H2SO4, EtOH reflux, 24 h; c) NBS, AIBN, CCl4, 85 °C,
NHtBu
F
2
O
1
20 h; d) RNH2, CH3CN
.
inhibition of MTP
and Apo B secretion1b
drug for the treatment of cardiac arrhythmias1a
O2N
CO2H
CO2H
H2N
CO2H
CO2H
CO2H
a
b
CO2H
O
6c
88%
6d
78%
6a
X
N
R
c, d
f, g, h
4
EWG
HO
CO2H
CO2H
Nucleophilic
isoindolinones
O
O
O2N
6e
N-Ph
O
45%
NH
F
CO2Et
O
N
NHMe
4n
e, f
N
MeO
HN
72%
3
EWG
renin inhibitor1c
EtO
CO2Et
CO2Et
5 pyrrolizidine scaffold
70%
g, h
Figure 1. Examples of pharmacologically active 3,3-disubstituted
isoindolinone derivatives and pyrrolozidines and the general
structure of nucleophilic isoindolinones 4 used in this study.
O
EtO
N-R
CO2Et
4m
65%
2. Results and discussion
Scheme 2. Synthetic pathways to 5-ethoxy and 5-nitroisoindolinones 4n and
4m: a) HNO3, H2SO4, 0 °C, 2 h; b) H2, Pd/C 5%, MeOH; c) NaNO2, H2SO4,
0 °C, 2 h; d) H2SO4, H2O, reflux; e) K2CO3, CH3CH2I, DMF, 48 h; f) H2SO4,
2.1 Synthesis of nucleophilic isoindolinones 4.
EtOH reflux, 24 h; g) NBS, AIBN, CCl4, 85 °C, 20 h; h) RNH2, CH3CN
.
Our initial efforts were directed towards the synthesis of a
series of isoindolinones
4
with
a
focus on the
Interestingly the lactamization of the diethyl α-
bromohomophthalates required careful fine-tuning
functionalization of the aryl moiety. Reported strategies
describe the synthesis of isoindolinones 4 through two routes:
1) reaction of 3-unsubstituted isoindolinones with CO2 under
strongly basic conditions9 or 2) displacement/lactamization of
diethyl α-bromohomophthalate with primary amines.5
However, only a few derivatives have been reported so far
with no examples bearing substituents on the aryl ring. Thus,
we considered the latter approach, focusing on the elaboration
of the homophthalic acid 6a that was successfully used for the
synthesis of diversely substituted isoindolinones 4 according
to Schemes 1 and 2. Bromination10a utilising KBrO3 or
nitration10b of 6a led to intermediates that were smoothly
transformed into the substituted α-bromohomophthalates 8 by
8
depending on the nature of the amine (the details are
summarized in Table 1). Unsurprisingly, aniline was less
reactive than the other amines and higher temperature was
required (Entries 8, 12, 14). The reaction of 4k with BnNH2
was also problematic at room temperature because of the
formation of undesired byproducts. Gratifyingly the reaction
proceeded smoothly via lowering the temperature to 0 °C
(Entry 11). In contrast, the more activated p-NO2 derivative
4n gave satisfactory yield from reaction with aniline (Entry
14), while other amines led to decomposition products.

3
solvent and K CO as base at -40 °C (Table 2, entry 4)
ACCEPTED MANUSCRIPT
2
3
Table 1. Synthesis of nuclophilic isoindolinones 4.
where other solvents and bases were less effective. The other
catalysts that were tested highlighted the importance of
maintaining a free -OH group at the C-9 position of the
catalyst, since O-allyl derivative (11b, see Table 2, entry 2)
showed less satisfying catalytic activity (low yield and low
selectivity).
O
X
R-NH2
X
CO2Et
CO2Et
N-R
CO2Et
CH3CN
Br
4a-n
8a-d
At this point, we reasoned that it would be useful to further
undertake a systematic investigation regarding the structural
key-features of the catalysts, testing all the cinchona
diastereomers bearing different substituents on the ammonium
portion (Figure 2, Table 2). The anthracenyl quininium salt
11c showed comparable results with respect to the analogue
11a (entry 5), while other diastereomeric catalysts 12a, 12b
and 12c that gave to the opposite product enantiomer led to a
slightly lower selectivity (entries 3, 6 and 7). It should be
noted that it is a common phenomenon where the use of
pseudoenantiomeric cinchona alkaloid derivatives does not
always give identical selectivities for both enantiomers,13a and
thus it came as no surprise that similar challenges were
Entry
15
2
X
R
4
T (°C)
t (h) Yielda %
H
H
H
H
H
H
H
H
Br
Br
Br
Br
EtO
NO2
Bn
n-Bu
n-hexyl
Me
4a
4b
4c
4d
4e
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
70
R.T.
R.T.
0
70
R.T.
70
5
4
6
18
5
24
24
96
24
8
24
72
93
97
76
85
83
65
90
57
66
80
94
75
89
90
65
72
3
411
55
6
propargyl
3,5-(CF3)2-C6H3CH2 4f
4-EtOC6H4CH2
7
8
9
10
11
12
13
14
4g
4h
4i
4j
4k
4l
Ph
n-Bu
n-hexyl
Bn
Ph
n-Bu
Ph
observed in this study. The derivative 11d with
a
4m
4n
benzotriazole group installed on the cinchonidinium salt was
comparable to 11a (entry 8), while also in this case, its
diastereomeric counterpart 12d gave slightly lower
enantioselectivity and reactivity (entries 9 and 10). Other
catalysts with hindered aromatic groups on the ammonium
side14 (11e-11j and 12e, entries 11-16), were less effective
than 11a and 11d. Only 12e with a 3-Ph-C6H4 substituent
reversed the trend, giving higher ee than 11e (entries 11 and
12). The presence of an additional -OH group on quinoline
ring in 11j, despite the possibility of hydrogen bond
network,15 gave disappointing results (entry 17). Other
catalysts like Maruoka’s axially chiral binaphthyl-based
ammonioum salts,16 bifunctional urea-cinchona ammonium
salts (Dixon's catalyst),17 cinchona derived sulfonamides18 or
dimers19 or salts derived from trans-cyclohexyl diamine
recently described by our group20 proved to be less effective
and no further structural changes thereafter were investigated
(these data can be found in Table S1 in the on line supporting
information). Despite the moderate enantio-enrichment, the
absolute configuration (AC) of (-)-10a was determined to be S
by Vibrational Circular Dichroism (VCD).21
aIsolated yields
The synthesis of free NH-isoindolinone was particularly
challenging. The previously reported11 method based on the
use of Pd/C and cyclohexadiene or hydrogen for the reduction
of azide 9a (X=H), was found to be not applicable to 9b
(X=Br) where de-halogenation was the mainly observed
(Scheme 3).
O
X
CO2Et
CO2Et
X
CO2Et
CO2Et
X
a
b
N-H
CO2Et
N3
9a-b
Br
8a-b
X= H, Br
4o: X= H, yield= 71%
X= Br, dehalogenation
c
O
X
N-H
CO2Et
4o-p
X= H, yield= 70%
X= Br, yield= 55%
X-
R
R
X-
H
N
OH
Scheme 3. Synthetic pathway to free NH isoindolinones. a) NaN3, CH3CN,
24 h; d) 1,4-cyclohexadiene, Pd/C 10%, EtOH, 2 h, 70 °C; c) P(Me)3,
THF/H2O (4/1), dry THF.
Ar
N
OR'
Ar
N
N
Other reducing agents like CeCl312a or NaBH412b were also not
effective. To our delight the Staudinger methodology12c
allowed us to overcome this obstacle and led to the target
compounds in reasonable yields when P(Me)3 was used under
nitrogen in THF/H2O mixture (PPh3 gave low yields and more
complex mixtures that were difficult to purify).
12a: R=H, Ar=Ph, X- = Cl-
11a: R=H, R' = H, Ar = 9-anthracenyl, X- = Cl-
11b: R=H, R' = allyl, Ar = 9-anthracenyl, X- = Br-
11c: R=OMe, R' = H, Ar = 9-anthracenyl, X- = Cl
11d: R=H, R' = H, Ar = 1-benzotriazole, X- = Cl-
11e: R=H, R' = H, Ar = 3-Ph-C6H4-, X- = Br-
11f: R=H, R' = H, Ar = phenyl, X- = Br-
11g: R=H, Ar = 3,5-diMe-phenyl, X- = Br-
11h R=H, Ar = 3,5-ditBu-phenyl, X- = Br-
11i: R=H, Ar = b-Np, X- = Br-
12b: R=H, Ar = 9-anthracenyl, X- = Cl-
- 12c: R=OMe, Ar = 9-anthracenyl, X- = Cl-
12d: R=H, R' = H, Ar = 1-benzotriazole, X- = Cl-
12e: R=OMe, Ar = 3-Ph-C6H4-, X- = Br-
2.2 Chiral phase transfer catalysts.
11j: R=OH, R' = H, Ar = phenyl, X- = Br-
Our preliminary screening performed on 4a8 showed that
cinchonidinium salt 11a (Figure 2) with an anthracenyl group
on the ammonium side gave the highest selectivity, leading to
74% ee in the Michael reaction of 4a with methyl vinyl
ketone (compound 10, Table 2, entries 1-4). The optimal
reaction conditions were identified as using of DCM as
Figure 2. Some of the chiral phase transfer catalysts used. The
structures and the results obtained with other catalysts are reported in
the online supporting information.

4
Tetrahedron
ACCEPTED MANUSCRIPT
Table 2. Asymmetric Michael reaction of N-benzyl isoindolinone
With data so far collected in hand, we investigated the effects
4a with methyl vinyl ketone under phase transfer conditions
of structural modifications on the isoindolinone scaffold at
ester and lactam group and on the phenyl ring on the outcome
of this reaction in the presence of the best performing
catalysts. Interestingly, all these efforts soon revealed a rather
complex picture that justified the previous exhaustive catalyst
screening and analysis of conditions. Modifications of the
ester position showed that hindered substituents like a t-butyl
group in 4ac give less satisfactory results in terms of yield and
enantioselectivity compared to methyl and ethyl groups
(Table 3, entries 1-3).8 When we investigated the effect of
different substituents on the lactam moiety, like H, substituted
benzyl, alkyl and phenyl groups, we observed a very
interesting phenomenon. It turned out that for isoindolinone
4b, bearing a n-butyl substituent on the nitrogen, catalyst 11d
gave better results than 11a which allowed us to obtain 10b
with a good enantioselectivity of 81% ee at -40 °C in very
high yield (entries 4-6). Notably, with some of the other
isoindolinones, catalyst 11d gave less satisfactory results than
11a illustrating again the need for a comparative screening of
different ammonium salts for different substrates. Good levels
of enantioselectivity were reached with the isoindolinones 4c
and 4e, bearing propargyl and n-hexyl substituents (78% and
84% ee respectively, entries 7 and 9), while decreasing the
size of the substituent group in 4d had a detrimental effect on
the observed selectivity (entry 8). Other isoindolinones with
O
O
O
PTC (10 mol%),
K2CO3
+
NBn
NBn
DCM, conditions
EtOOC
10a
COOEt
4a
O
Entry
PTC
T (°C) t (h) Yield (%)a ee (%)b
(10 mol %)
11a
11b
12a
11a
12c
18
28
38
48
5
6
7
8
9
10
11
12
13
14
15
16
17
r.t.
r.t.
r.t.
2
24
2
90
95
89
97
91
45
93
97
95
90
92
97
94
96
94
95
93
56
11
-55c
74
-40
-40
-40
-40
-40
-20
-40
-20
-20
-40
-20
-20
-20
-40
24
24
24
24
24
8
40
24
24
24
24
24
24
48
70
12b
12c
11d
12d
12d
11e
12e
11f
11g
11h
11i
-59 c
-65 c
72
-64 c
-54 c
48
-64 c
66
57
50
48
15
11j
substituted
benzylamines
gave
slightly
lower
enantioselectivity than 4a, an effect that was more
pronounced with the electron-donating ethoxy substituent
(entries 10-11 vs entry 1). Good yields and enantioselectivities
were also obtained with the isoindolinone 4h bearing a phenyl
group on the lactam ring (entry 12).
aIsolated yield. bDetermined by HPLC using a chiral stationary phase. cThe
opposite enantiomer was obtained, as given by HPLC analysis.
Table 3. Different isoindolinones in phase transfer catalyzed
asymmetric Michael reactions
O
O
O
R''
R''
PTC (10 mol%),
K2CO3
+
NR'
NR'
DCM, -40 °C
ROOC
10
COOR
4
O
Entry
4
R
R'
R''
PTC
(10 mol %)
11a
T (°C)
t (h)
10
Yield (%)a
ee (%)b
18
28
38
4
5
6
7
8
9
10
4a
4ab
4ac
4b
4b
4b
4c
4d
4e
4f
Et
Me
t-Bu
Et
Et
Et
Et
Et
Et
Et
Bn
Bn
Bn
n-Bu
n-Bu
n-Bu
n-hexyl
Me
H
H
H
H
H
H
H
H
H
H
-40
-40
-40
-20
-40
-40
-20
-20
-40
-40
24
24
48
18
40
48
24
24
50
5
10a
10ab
10ac
10b
10b
10b
10c
10d
10e
10f
97
98
60
95
96
93
92
96
95
90
74
70
45
76
71
81
84
60
78
70
11a
11a
11a
11a
11d
11d
11a
11a
CH2CCH
3,5-(CF3)2-
C6H3CH2
4-EtOC6H4CH2
Ph
11a
11
12
13
14
15
16
17
18
19
4g
4h
4i
4j
4k
4l
4m
4o
4o
Et
Et
Et
Et
Et
Et
Et
Et
Et
H
H
11a
11d
11d
11a
11a
11a
11d
11a
11d
-40
-40
-40
-40
-40
-40
-40
-40
-40
17
20
6
10
18
6
15
8
3
10g
10h
10i
10j
10k
10l
10m
10n
10n
98
97
92
95
97
88
88
97
98
67
74
91
90
79
72
55
20
50
n-Bu
n-hexyl
Bn
Ph
n-Bu
Br
Br
Br
Br
EtO
H
H
H
H
aIsolated yield. bDetermined by HPLC using a chiral stationary phase

5
Then, the effect of substituents on the aromatic ring of the
isoindolinones was investigated using catalysts 11a and 11d
(entries 13-19, Table 3 reports the best result for each
nucleophile). The presence of bromine in 4i and 4j was
beneficial in comparison to the parent unsubstituted
isoindolinone giving high ees of 91% and 90% (Entries 13
and 14). On the other hand nucleophiles 4k and 4l bearing a
benzyl or a phenyl N-substituent performed less selectively
(Entries 15 and 16). In addition, the isoindolinone 4m with a
strong electron-donating group gave only moderate
enantioselectivity (Entry 17), while 4n with a nitro group was
not reactive at all. A significantly lower enantioselectivity was
observed reacting the NH-free isoindolinone 4o, even if the
catalyst 11d led to significantly higher ee in comparison with
11a (entries 18 and 19).
chalcone (Table 5). Under these new conditions, both
ACCEPTED MANUSCRIPT
quinine and bifunctional epi-quinine 14 were less effective
than chiral phase transfer catalysts for reactions of methyl
vinyl ketone (compare entries 1-3 of Table 5 with data of
Table 2). In sharp contrast, when using chalcone as an
acceptor (entry 5, Table 5) we observed an appreciable
increase of the enantiomeric excess by using catalyst 14 (73%
ee), with good yield and very good diastereoselectivity
(compare also with entry 3 of Table 3 and Table 4). In
contrast, quinine itself was less efficient as a catalyst for this
reaction (entry 4 of Table 5). Interestingly, this outcome is
somewhat comparable with a recently described diastereo-
and enantioselective aldol initiated cascade reaction of free
NH isoindolinones 4o with 2-cyano benzaldehydes.23 We
were then able to improve the selectivity further in the
presence of 20 mol% of squaramide derivative 15, which gave
the product 13a in 80% ee and 96/4 dr (entry 7).
After variation of the isoindolinone nucleophiles, other enone
and enal-based Michael acceptors were tested. We focused on
chalcone and cinnamaldehyde to study the diastereoselectivity
of the reaction and the possibility of the formation of tricylic
derivatives.
Surprisingly, the N-substituted isoindolinones 4a and 4b did
not react with chalcone possibly due to the increased steric
hindrance at the nucleophilic carbon (Table 4, entries 1 and
2). On the other hand, 4o reacted smoothly with chalcone
giving the acyclic derivative 13 in high yield, high
diastereoselectivity but with no enantioselectivity (entry 3).
Surprisingly, this issue could not be resolved by testing
alternative catalysts and conditions and it has to be admitted
that a rational for this striking difference is still missing.
Other
bifunctional
organocatalysts
as
well
as
pseudoenantiomeric cinchona alkaloid derivatives were also
tested but gave lower selectivities than 15, while DCM proved
to be the most effective solvent (see Table S2 of the
supporting information for these additional data). Under the
conditions of entry 7, other chalcones were tested next. A
higher reactivity was observed with 4-nitro-chalcone, leading
to the final product 13b in high yields in shorter reaction
times, with high diastereoselectivity (>99/1) and good
enantioselectivity (entries 8 and 9). Good results were also
obtained with 4-chloro-, 2-chloro- and 4-methoxy-chalcones
(entries 10-13) and with the introduction of the new Br-
substituted nucleophile 4p (entry 14). Only in the presence of
a CF3–aryl substituent a lower enantioselectivity was obtained
(entry 15).
Table 4. Michael reaction of the chalcone under asymmetric phase-
transfer catalysis.
O
O
O
11a (10 mol%),
K2CO3
R
N
+
R
N
Ph
Ph
DCM, -40 °C,
24 h
MeO
EtOOC
13
Ph
N
H
MeO
COOEt
N
Ph
4
NH
S
O
NH
OH
N
N
F3C
CF3
quinine
Entry
4
R
Yield 13
d.r.b
ee (%)
14
(%)a
O
N
MeO
1
2
3
4a
4b
4o
Bn
n-Bu
H
--
--
--
O
N
H
--
HN
96
95/5
2
N
aIsolated yield. bDetermined by HPLC on chiral column.
F3C
CF3
15
2.3 Bifunctional tertiary amine-based organocatalysts.
Figure 3. Some of the bifunctional organocatalysts used in this study.
The limitations observed when using chalcones under chiral
phase-transfer conditions in the presence of the free NH
isoindolinone 4o (Table 4) prompted us to continue our
investigations by focusing on chiral tertiary amine-based
organocatalytic systems instead. Starting from the results
described in Table 4, we focused on the bifunctional
organocatalysts derived from cinchona alkaloids and trans-
cyclohexane diamine, which are widely used in asymmetric
conjugated additions22 (Figure 3).
Finally, by slow evaporation of a chloroform/hexane solution
of rac-13c we were able to obtain diffraction quality single
crystals (Figure 4) which allowed us to determine the relative
configuration being (RR-SS)24 and the other derivatives were
assigned by analogy (unfortunately enantioenriched products
could not be crystallized in satisfying quality).
These catalysts were first tested for comparison in the
reactions of 4a and 4o with both methyl vinyl ketone and

6
Tetrahedron
ACCEPTED MANUSCRIPT
Table 5. Michael reactions of chalcones in the presence of
bifunctional organocatalysts
O
O
O
X
X
cat
N
R
+
R
N
R'
R''
DCM, r.t.
EtOOC
R''
COOEt
R'
10 or 13
4
O
Entrya
1
2
3
4
5
6
7
8d
9d
10
11
12
13
14
15
Cat. (mol %)
Quinine (10)
14 (10)
14 (10)
Quinine (10)
14 (10)
15 (10)
15 (20)
15 (10)
15 (5)
15 (20)
15 (10)
15 (10)
15 (20)
14 (10)
15 (20)
R
X
R'
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R''
H
H
t (d)
5
5
5
5
5
5
5
2
6
2
5
4
7
2
3
Yield (%)b
10a: 60
10a: 65
10o: 90
13a: 94
13a: 75
13a: 51
13a: 72
13b: 92
13b: 91
13c: 96
13c: 85
13d: 93
13e: 86
13f: 95
13g: 91
d.r.c
--
--
--
ee (%)c
48
45
13
50
73
77
80
81
80
83
77
75
70
70
52
4a: Bn
4a: Bn
4o: H
4o: H
4o: H
4o: H
4o: H
4o: H
4o: H
4o: H
4o: H
4o: H
4o: H
4p: H
4o: H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
H
H
Ph
Ph
Ph
Ph
93:7
91:9
93/7
96/4
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
93/7
96/4
4-NO2C6H4
4-NO2C6H4
4-ClC6H4
4-ClC6H4
2-ClC6H4
4-MeOC6H4
Ph
2-CF3C6H4
Ph
aReaction performed at [4] = 25 mM
bIsolated yield.
cDetermined by HPLC using a chiral stationary phase.
dReaction performed at [4] = 10 mM.
In comparison H-donor catalyst 15 gave a higher dr with
moderate enantioselectivity, but the low reactivity was
not promising enough for further optimization (entry 4).
Table 6. Michael reactions of cinnamaldehyde.
O
O
O
X
X
O
Catalyst
NH
Ph
+
NH
CO2Et
MeOH/DCM,
conditions
Ph
EtO2C
4o: X=H,
4p: X=Br
O
O
OH
Ph
OH
Ph
N
N
X
N
X
H
+
OTMS
Figure 4. X-ray molecular structure of rac-13c. Thermal
17
EtO2C
major
ellipsoids are drawn at 50% probability level.24
EtO2C
minor
Ph
Ph
16a: X=H,
16b: X=Br,
Entry
4
Cat.
T (°C) t (h) 16: Yield d.r.b
ee (%)b
2.4 Asymmetric synthesis of aza-tricyclic derivatives via
organocatalytic cascade/hemi-aminalization reaction.
(%)a
1
4o
4o
4o
4o
4o
4p
11a/K2CO3
11a/K2CO3
11d/K2CO3
15
r.t.
-40
-40
r.t.
4
16a: 85 55/45
16a: 91 66/34
16a: 95 60/40
16a: 90 80/20
16a: 85 53/47
16b: 85 60/40
10/25
20/40
12/15
60/20
87/96
61/30
The reaction of 4o with cinnamaldehyde in the presence
of catalysts 11a or 11d led to the tricyclic derivative 16a
in high yield (Table 6, entries 1-3). Even if we obtained
only two diastereomers, rather low dr and ee were
observed confirming the already previously reported
challenges of controlling this acceptor under chiral phase
transfer conditions.
2
18
24
96
18
18
3
4
526
17
-15
-15
6
17
aIsolated yield. bDetermined by HPLC on chiral column.

7
and 11a (10 mol%) in CH2Cl2 (1.5 mL). The reaction was
Nevertheless, this type of aza-tricyclic compounds, the
benzopyrrolizidinones, are known for their biological
ACCEPTED MANUSCRIPT
monitored by TLC until the disappearance of 4. Then, the mixture
was purified directly by flash chromatography affording 10 in the
range of 60-97% yields.
activity7
and
consequently
new
asymmetric
methodologies were investigated. We then focused on the
covalent activation of the electrophile via iminium ion
catalysis, using proline based organocatalysts.25 To our
delight, an impressive increase of the enantioselectivity
was observed using the TMS-ether of diphenylprolinol 17
giving the product with up to 96% ee and in good yield
(entry 5).26 Several substituted cinnamaldehydes were
reacted with similar efficiency,26 while the introduction
of the new Br-substituted nucleophile 4p gave an
unexpected lower ee (entry 6). The relative and absolute
configuration of the tricyclic derivatives was addressed
by X-ray analysis and by mechanistic investigations as
disclosed previously.25b,26
Adducts 10a, 10ab, 10ac, 10b, 10o have been already described in
ref. 8, 16a in ref. 26.
10c.
Ethyl
-2-hexyl-3-oxo-1-(3-oxobutyl)isoindoline-1-
carboxylate. Purification by chromatography (hexane/ethyl acetate
20:
7/3) gave a pale oil. Yield: 92%. [α]D -7.2 (c = 0.6, CHCl3). IR
1
(KBr) ν: 2960, 2932, 1750, 1700, 1206, 1187, 734 cm-1. H-NMR
(CDCl3, 300 MHz) δ: 7.85 (d, 1H, J= 7.2 Hz), 7.57-7.48 (m, 2H),
7.41 (d, 1H, J= 7.2 Hz), 4.22-4.04 (m, 2H), 3.49-3.27 (m, 2H), 2.82
(ddd, 1H, J3= 5.4 Hz, J2= 10.8 Hz, J1= 15.0 Hz), 2.51 (ddd, 1H, J3=
4.5 Hz, J2= 10.5 Hz, J1= 15.0 Hz), 2.01 (ddd, 1H, J3= 4.5 Hz, J2=
10.8 Hz, J1= 15.0 Hz), 1.75 (ddd, 2H, J3= 5.4 Hz, J2= 10.5 Hz, J1=
15.0 Hz), 1.57 (ddd, 1H, J3= 6.0 Hz, J2= 12.3 Hz, J1= 15.0 Hz),
1.38-1.25 (m, 6H), 1.17 (t, 3H, J= 7.2 Hz), 0.89 (t, 3H, J= 6.3 Hz).
13C-NMR (CDCl3, 75 MHz) δ: 206.9, 170.6, 169.4, 143.1, 132.4,
132.3, 129.5, 124.0, 121.9, 71.6, 62.5, 42.0, 36.7, 31.7, 30.6, 28.5,
27.3, 26.2, 22.8, 14.2, 14.1. MS (ESI): m/z = 360 (M+ H)+. Anal.
calcd for: C21H29NO4: C, 70.17; H, 8.13; N, 3.90. Found: C, 70.45;
H, 8.38; N, 3.66. Chiral HPLC: OD-H column, hexane/iPrOH (9:1),
flow: 0.6 ml/min, t: 13.3 min (minor) and 14.6 min (major); ee 84%.
3. Conclusions
We have demonstrated that 3-carboxylate substituted
isoindolinones 4 are effective nucleophiles in asymmetric
Michael reactions to access valuable chiral derivatives
containing
a
tetra-substituted carbon stereocenter.
A
10d.
Ethyl
2-methyl-3-oxo-1-(3-oxobutyl)isoindoline-1-
comparative study of different catalytic systems and
conditions was necessary to establish structure-activity
relationships and for the development of efficient asymmetric
versions of the reaction. Good results in terms of yield and
enantioselectivity (up to 91% ee), were obtained in the
reaction of N-substituted isoindolinones with methyl vinyl
ketone in the presence of chiral ammonium salts, while the
free-NH-containing 4o performed more sluggishly. On the
other hand, 4o was better suited for reactions with chalcones
in the presence of bifunctional amine-H-bonding donor
containing organocatalysts and in reactions with
cinnamaldehyde in the presence of diphenylprolinol
trimethylsilyl (TMS) ether. In this latter case, valuable
tricyclic pyrrolo-isoindolinones were obtained via a cascade
Michael/hemi-aminalization reaction, in good yields and with
enantioselectivities up to 96% ee. Notably, these studies
showed that seemingly small changes in the substrate
structure may require a totally different catalytic activation
mode to obtain the target product with high levels of
stereoselectivity. These strict requirements may be useful in
future studies about new applications in other asymmetric
reactions and in the synthesis of bioactive compounds.
carboxylate. Purification by chromatography (hexane/ethyl acetate
7/3) gave a yellow oil. Yield: 93%. [α]D20: - 8.7 (c = +0.5, CHCl3). IR
1
(KBr) ν: 2962, 2931, 1748, 1702, 1205, 1186, 731 cm-1. H-NMR
(CDCl3, 250 MHz) δ: 7.84 (d, 1H, J= 7.2 Hz), 7.53-7.51 (m, 3H),
4.25-4.04 (m, 2H), 3.02 (s, 3H), 2.78 (ddd, 1H, J3= 5.5 Hz, J2= 10.0
Hz, J1= 15.0 Hz), 2.50 (ddd, 1H, J3= 5.5 Hz, J2=10.0 Hz, J1=15.0
Hz), 1.92-1.89 (m, 4H), 1.70 (ddd, 1H, J3= 5.5 Hz, J2=10.0 Hz,
J1=15.0 Hz), 1.20 (t, 3H, J= 7.2 Hz). 13C-NMR (CDCl3,75 MHz) δ:
206.4, 169.7, 168.5, 142.4, 131.9, 131.8, 129.3, 123.6, 121.9, 70.7,
62.2, 42.7, 36.1, 29.9, 25.9, 13.9. MS (ESI): m/z = 290 (M + H)+.
Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84. Found: C,
66.52; H, 6.51; N, 4.67. Chiral HPLC: IA-3 column, hexane/iPrOH
(8:2), flow: 0.8 ml/min, t: 13.3 min (major) and 15.5. min (minor);
ee 60%.
10e. Ethyl 3-oxo-1-(3-oxobutyl)-2-(prop-2-ynyl)isoindoline-1-
carboxylate. Purification by chromatography (hexane/ethyl acetate
7/3) gave a yellow oil. Yield: 92%. [α]D20: - 4.6 (c= 1, CHCl3). IR
1
(KBr) ν: 3448, 3274,1732,1696, 1636, 1386, 1248 cm-1. H-NMR
(CDCl3, 250 MHz) δ: 7.86 (d, 1H, J= 7.0 Hz), 7.58-7.48 (m, 3H),
4.74 (dd, 1H, J2= 2.5 Hz, J1= 18.0 Hz ), 4.23-4.03 (m, 3H), 2.85
(ddd, 1H, J3= 5.3 Hz, J2= 11.0 Hz, J1= 15.0 Hz), 2.68 (ddd, 1H, J3=
4.5 Hz, J2= 11.0 Hz, J1= 15.0 Hz), 2.32 (ddd, 1H, J3= 4.5 Hz, J2=
11.0 Hz, J1= 15.0 Hz), 2.17 (t, 1H, J= 2.5 Hz), 1.92 (s, 3H), 1.73
(ddd, 1H, J3= 5.3 Hz, J2=11.0 Hz, J1= 15.0Hz), 1.21 (t, 3H, J= 7.1
Hz). 13C-NMR (CDCl3, 75 MHz) δ: 207, 169.9, 168.3, 142.9, 132.8,
131.3, 129.7, 124.3, 122.3, 78.4, 71.9, 71.5, 62.7, 37.1, 30.2, 30.1,
27.1, 14.2. MS (ESI): m/z = 314 (M + H)+. Anal. Calcd for
C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: 69.19; H, 5.98; N,
4.57. Chiral HPLC: IA-3 column, hexane/iPrOH (8:2), flow:
0.6ml/min, t: 16.5 min (major) and 20.7 min (minor); ee 78%.
4. Acknowledgement
This work was supported by MUIR and University of Salerno.
We are grateful to Dr. Christopher C. Stimson for
proofreading and correcting the final version of this
manuscript.
10f.
Ethyl
2-(3,5-bis(trifluoromethyl)benzyl)-3-oxo-1-(3-
Purification by
oxobutyl)isoindoline-1-carboxylate.
chromatography (hexane/ethyl acetate 8/2) gave a white solid (52
mg). Yield: 81%. Mp. 94-95 °C (ethyl acetate/hexane). [α]D20: -16.7
(c = 0.5, CHCl3). IR (KBr) ν: 2988, 2926, 1735, 1714, 1699, 1278,
1180, 1121 cm-1. 1H-NMR (CDCl3, 250 MHz) δ: 7.93-7.77 (m, 3H),
7.61 (s, 1H), 7.60-7.52 (m, 2H), 7.45 (dd, 1H, J2= 4.0 Hz, J1= 6.5
Hz), 4.91 (d, 1H, J= 15.6 Hz), 4.65 (d, 1H, J= 15.8Hz), 3.99-3.91
(m, 2H), 2.80-2.77 (m, 1H), 2.46-2.38 (m, 1H), 1.75 (s, 3H), 1.61
(dd, 2H, J2= 7.0 Hz, J1= 12.0 Hz), 1.04 (t, 3H, J= 7.1 Hz). 13C-NMR
(CDCl3, 150 MHz) δ: 205.9, 169.7, 168.8, 143.1, 139.9, 132.8, 131.8
5. Experimental
For detailed experimental information, spectra and chromatograms
of all the new compounds and procedures and for the preparation of
3-Carboethoxy-isoindolinones 4 see supporting information.
Procedure for enantioselective Michael reaction with methyl
vinyl ketone. The Michael acceptor (1.5 eq) was added at -40 °C to
a stirred solution of 4 (0.1 mmol, 1 eq.), K2CO3 (0.1 mmol, 1 eq.)

8
Tetrahedron
(q, JC-F = 33.0 Hz), 131.0, 129.2, 128.6, 124.3, 123.6 (q, JC-F
=
m/z = 439 (M+ H)+. Anal. calcd for: C21H28BrNO4: C, 57.54; H,
ACCEPTED MANUSCRIPT
264.0 Hz), 122.2, 122.1, 71.7, 62.7, 44.4, 36.3, 29.8, 26.5, 13.9. MS
(ESI): m/z= 402 (M + H)+. Anal. Calcd for C24H21F6NO4: C, 57.49;
H, 4.22; N, 2.79. Found: C, 57.55; H, 4.37; N, 2.91. Chiral HPLC:
OD-H column, hexane/iPrOH (9:1), flow: 0.6 ml/min, t: 13.1 min
(major) and 15.4 min (minor); ee 70%.
6.64; N, 3.20. Found: C, 57.35; H, 6.41; N, 3.46. Chiral HPLC: OD-
column, hexane/ iPrOH (9:1), flow: 0.6 ml/min, t: 13.8 min
H
(minor) and 15.4 min (major); ee 91%.
10k. Ethyl 2-benzyl-5-bromo-3-oxo-1-(3-oxobutyl)isoindoline-1-
carboxylate. Purification by chromatography (hexane/ethyl acetate
8/2) gave a waxy solid. Yield: 97%. [α]D20: + 22.6 (c = 0.5, CHCl3).
10g. Ethyl 2-(4-ethoxybenzyl)-3-oxo-1-(3-oxobutyl)isoindoline-1-
carboxylate. Purification by chromatography (hexane/ethyl acetate
7/3) gave a slightly yellow waxy solid. Yield: 97%. [α]D20: -5.5 (c =
0.22, CHCl3). IR (KBr) ν: 2984, 1725, 1691, 1397, 1384, 1244 cm-1.
1H-NMR (CDCl3, 300 MHz) δ: 7.89 (dd, 1H, J2= 2.7 Hz, J1= 6.6
Hz), 7.54-7.50 (m, 2H), 7.38 (d, 3H, J= 8.4 Hz), 6.79 (d, 2H, J= 8.7
Hz), 5.02 (d, 1H, J= 15.3 Hz), 4.26 (d, 1H, J= 15.3 Hz), 4.00-3.93
(m, 4H), 2.70 (ddd, 1H, J3= 5.5 Hz, J2= 9.7 Hz, J1= 15.2 Hz), 2.39
(ddd, 1H, J3= 4.7 Hz, J2= 9.7 Hz, J1= 15.3 Hz), 1.64 (s, 3H), 1.51-
1.45 (m, 2H), 1.37 (t, 3H, J= 6.9 Hz), 1.09 (t, 3H, J= 7.2 Hz). 13C-
NMR (CDCl3, 75 MHz) δ: 206.7, 170.0, 169.1, 158.3, 143.7, 132.2,
131.7, 130.4, 129.2, 123.9, 121.5, 114.3, 71.6, 63.3, 62.2, 44.2, 36.0,
29.5, 26.3, 14.7, 13.7. MS (ESI): m/z = 410 (M + H)+. Anal. Calcd
for C24H27NO5: C, 70.40; H, 6.65; N, 3.42. Found: C, 70.30; H, 6.57;
N, 3.22. Chiral HPLC: OD-H column, hexane/iPrOH (9:1), flow: 0.6
ml/min, t: 36.1 min (major) and 42.7 min (minor); ee 67%.
IR (KBr) ν: 2958, 2925, 1733, 1699, 1238 cm-1. H-NMR (CDCl3,
1
300 MHz) δ: 8.03 (d, 1H, J= 1.5 Hz), 7.61 (s, 1H), 7.66 (d, 1H, J2=
1.8 Hz, J1= 8.1 Hz), 7.27 (d, 2H, J= 8.1 Hz), 7.28- 7.21 (m, 4H),
5.07 (d, 1H, J= 15.0 Hz), 4.34 (d, 1H, J= 15.0 Hz), 4.01-3.95 (m,
2H), 2.66 (ddd, 1H, J3= 5.1 Hz, J2= 10.2 Hz, J1= 15.6 Hz), 2.38 (ddd,
1H, J3= 5.4 Hz, J2= 10.8 Hz, J1= 15.7 Hz), 1.64 (s, 3H), 1.47-1.41
(m, 2H), 1.09 (t, 3H, J= 6.9 Hz). 13C-NMR (CDCl3, 75 MHz) δ:
206.2, 169.3, 167.6, 141.6, 136.9, 135.2, 133.6, 129.1, 127.7, 127.2,
123.5, 123.2, 71.6, 62.4, 44.9, 35.9, 29.4, 26.1, 13.7. MS (ESI): m/z
= 443 (M + H)+. Anal. Calcd for C22H22BrNO4: C, 59.47; H, 4.99;
N, 3.15. Found: C, 59.71; H, 5.11; N, 2.99. Chiral HPLC: OD-H
column, hexane/iPrOH (9:1), flow: 0.8 ml/min, t: 17.7 min (major)
and 21.5 min.(minor); ee 79%.
10l. Ethyl 5-bromo-3-oxo-1-(3-oxobutyl)-2-phenylisoindoline-1-
carboxylate. Purification by chromatography (hexane/ethyl acetate
7/3) gave a pale oil. Yield: 88%. [α]D20: +17.8 (c = 0.4 CHCl3). IR
(KBr) ν: 2969, 2927, 1742, 1714, 1360, 1240 cm-1. 1H-NMR (CDCl3,
250 MHz) δ: 8.10 (d, 1H, J= 1.5 Hz), 7.74 (dd, 1H, J2= 1.75 Hz, J1=
8 Hz), 7.43-7.29 (m, 6H), 4.26-4.05 (m, 2H), 2.87 (ddd, 1H, J3= 4.7
Hz, J2= 10.7 Hz, J1= 13.7 Hz), 2.49 (ddd, 1H, J3= 5.1 Hz, J2= 11.0
Hz, J1= 15.7 Hz), 2.08 (ddd, 1H, J3= 4.7 Hz, J2= 10.7 Hz, J1= 13.7
Hz), 1.90 (s, 3H), 1.74 (ddd, 1H, J3= 5.1 Hz, J2= 11.0 Hz, J1= 15.7
Hz), 1.14 (t, 3H, J= 7.1 Hz). 13C-NMR (CDCl3, 62.5 MHz) δ: 206.4,
170.1, 167.1, 141.8, 136.1, 135.8, 134.0, 129.6, 128.0, 127.2, 125,
124.1, 123.3, 72.5, 63.0, 36.6, 30.2, 25.6, 14.1. MS (ESI): m/z = 431
(M+ H) +. Anal. calcd for:C21H20BrNO4: C, 58.62; H, 4.68; N, 3.26.
Found: C, 58.35; H, 4.28; N, 3.66. Chiral HPLC: OD-H column ,
hexane/iPrOH (9:1), flow: 0.8 ml/min, t: 18.2 min (major) and 22.6
min. (minor); ee 72%.
10h.
Ethyl
3-oxo-1-(3-oxobutyl)-2-phenylisoindoline-1-
carboxylate. Purification by chromatography (hexane/ethyl acetate
8/2) gave a yellow waxy solid. Yield: 80%. [α]D20: +6.4 (c = 0.3,
CHCl3). IR (KBr) ν: 2961, 2922, 1730, 1702, 1384, 1351 cm-1. H-
1
NMR (CDCl3, 250 MHz) δ: 7.97 (d, 1H, J= 6.8 Hz ), 7.59-7.56 (m,
2H), 7.45-7.29 (m, 4H), 7.60-7.52 (m, 2H), 7.25 (s, 1H), 4.19-4.11
(m, 2H), 2.91 (ddd, 1H, J3= 4.7 Hz, J2= 11.0 Hz, J1= 15.3 Hz), 2.49
(ddd, 1H, J3= 4.9 Hz, J2= 10.7 Hz, J1= 15.2 Hz), 2.05 (ddd, 1H, J3=
5.0 Hz, J2= 10.7 Hz, J1= 15.1 Hz), 1.86 (s, 3H), 1.78-1.72 (m, 2H),
1.12 (t, 3H, J= 6.4 Hz). 13C-NMR (CDCl3, 75 MHz) δ: 206.6, 170.5,
168.8, 143.1, 136.1, 133.2, 131.8, 126.8, 125.1, 121.9, 72.5, 63.0,
43.1, 36.7, 30.3, 26.3, 14.2. MS (ESI): m/z = 352 (M + H)+. Anal.
Calcd for C21H21NO4: C, 71.78; H, 6.02; N, 3.99. Found: C, 71.58;
H, 6.22; N, 4.08. Chiral HPLC: IA-3 column, hexane/ iPrOH (8:2),
flow: 0.8 ml/min, t: 18.8 min (major) and 26.9 min (minor); ee 74%.
10m. Ethyl 2-butyl-5-ethoxy-3-oxo-1-(3-oxobutyl)isoindoline-1-
carboxylate . Purification by chromatography (hexane/ethyl acetate
8/2) gave a yellow waxy solid. Yield: 88%. [α]D20: -8.9 (c= 0.6,
10i. Ethyl 5-bromo-2-butyl-3-oxo-1-(3-oxobutyl)isoindoline-1-
carboxylate. Purification by chromatography (hexane/ethyl acetate
1
7/3) gave
a
white solid. Yield: 92%. Mp. 44-45°C (ethyl
CHCl3). IR (KBr) ν: 2958, 2927, 1742, 1696, 1258, 1237 cm-1. H-
acetate/hexane). [α]D20: -31.4 (c= 0.4, CHCl3). IR (KBr) ν: 2965,
2933, 1741, 1701, 1240 cm-1. 1H-NMR (CDCl3, 250 MHz) δ: 7.96
(d, 1H, J= 1.7 Hz), 7.65 (dd, 1H, J2= 1.8 Hz, J1= 8.1 Hz), 7.28 (d,
1H, J= 8.0 Hz), 4.20-4.05 (m, 2H), 2.85-2.72 (m, 2H), 2.52 (ddd, 1H,
J3= 4.5 Hz, J2= 10.6 Hz, J1= 15.3 Hz), 2.46 (ddd, 1H, J3= 4.5 Hz, J2=
10.5 Hz, J1= 15.3 Hz), 1.98 (s, 3H), 1.95-1.92 (m, 2H), 1.30 (q, 4H,
J= 7.4 Hz), 1.17 (t, 3H, J= 7.2 Hz), 0.94 (t, 3H, J= 7.1 Hz). 13C-
NMR (CDCl3, 75 MHz) δ: 206.1, 169.6, 167.6, 141.4, 135.3, 134.9,
127.1, 123.4, 123.3, 71.1, 62.9, 42.0, 36.3, 29.9, 29.6, 25.5, 20.5,
13.8, 13.4. MS (ESI): m/z= 411 (M + H)+. Anal. Calcd for
C19H24BrNO4: C, 55.62; H, 5.90; N, 3.41. Found: C, 55.46; H, 6.10;
N, 3.22. Chiral HPLC: IA-3 column, hexane/iPrOH (7:3), flow: 0.6
ml/min, t: 10.8 min (major) and 19.5 min (minor); ee 91%.
NMR (CDCl3, 250 MHz) δ: 7.28 (s, 2H), 7.06 (dd, 1H, J2= 2.4 Hz,
J1= 8.4 Hz), 4.18-4.04 (m, 4H), 3.45-3.28 (m, 2H), 2.78 (ddd, 1H,
J3= 5.5 Hz, J2= 10.8 Hz, J1= 15.0 Hz), 2.46 (ddd, 1H, J3= 4.7 Hz, J2=
9.2 Hz, J1= 15.1 Hz), 2.05-1.93 (m+ s, 4H), 1.80-1.70 (m, 4H), 1.45-
1.36 (m, 4H), 1.16 (t, 3H, J= 7.1 Hz), 0.93 (t, 3H, J= 7.2 Hz). 13C-
NMR (CDCl3, 75 MHz) δ: 206.8, 170.5, 169.1, 160.1, 134.7, 133.5,
122.6, 120.5, 107, 70.9, 63.9, 62.1, 41.6, 36.4, 30.3, 30.0, 25.9, 20.5,
14.6, 13.8, 13.7. MS (ESI): m/z = 376 (M + H)+. Anal. Calcd for
C17H23NO4: C, 66.86; H, 7.59; N,4.59. Found: C, 66.76; H, 7.34; N,
4.71. Chiral HPLC: IE-3 column , hexane/iPrOH (8:2), flow: 0.6
ml/min, t: 40.6 min (major) and 51.5 min.(minor); ee 55%.
Procedure for asymmetric organocatalytic Michael reaction of
chalcones.
A solution of isoindolinone 4o or 4p (0.048mmol) in DCM (2 mL),
chalcone (1.5 equiv.) and squaramide epiquinine 15 (20 mol%) was
stirred at room temperature for the required time. The solvent was
evaporated and the diastereoisomeric ratio (dr) was determined by
1H-NMR of crude product. Purification of the crude mixture by
flash chromatography (hexane/ethyl acetate 1:1) afforded the
required compounds.
10j. Ethyl 5-bromo-2-hexyl-3-oxo-1-(3-oxobutyl)isoindoline-1-
carboxylate. Purification by chromatography (hexane/ethyl acetate
7/3) gave a waxy solid. Yield: 95%. [α]D20 : -18.8 (c = 0.83, CHCl3).
IR (KBr) ν: 2975, 2935, 1740, 1702, 1242 cm-1. 1H-NMR (CDCl3, 75
MHz) δ: 7.98 (d, 1H, J= 1.5Hz), 7.67 (dd, 1H, J2= 1.5 Hz, J1= 8.1
Hz), 7.30 (d, 1H, J= 8.1 Hz), 4.21-4.08 (m, 2H), 3.43-3.32 (m, 2H),
2.79 (ddd, 1H, J3= 5.4 Hz, J2= 10.5 Hz, J1= 15.0 Hz), 2.51 (ddd, 1H,
J3= 5.4 Hz, J2= 10.5 Hz, J1= 15.0 Hz), 2.04-1.92 (m, 4H), 1.81-1.70
(m, 1H), 1.63-1.52 (m, 1H), 1.42-1.26 (m, 5H), 1.19 (t, 3H, J= 6.9
Hz), 0.90 (t, 3H, J= 6.6 Hz).13C-NMR (CDCl3, 75 MHz) δ: 206.5,
170.0, 167.8, 141.8, 135.2, 134.4, 127.2, 123.8, 123.6, 71.4, 62.7,
42.2, 36.6, 31.6, 30.2, 28.4, 27.2, 26.1, 22.7, 14.2, 14.0. MS (ESI):
13a. Ethyl 3-oxo-1-(3-oxo-1,3-diphenylpropyl)isoindoline-1-
carboxylate. Yield: 72 %, waxy solid; d.r. 96/4, [α]D20: + 49.5 (c=
0.44, CHCl3). IR (KBr) ν: 3441, 3431, 1726, 1690, 1241 cm-1.1H-
NMR (CDCl3, 300 MHz) δ: 7.95 (d, J= 7.4 Hz, 2H, Ar) 7.93 (d, J=

9
7.7 Hz, 1H, Ar), 7.56-7.53 (m, 3H, Ar) 7.44-7.35 (m, 3H, Ar) 7.10
(d, J = 7.3 Hz, 2H, Ar), 6.99 (d, 3H, J= 6.7 Hz, Ar), 4.56 (dd, 1H,
J2= 4.2 Hz, J1= 9.9 Hz), 4.23 (q, 2H, J =7.2 Hz), 3.93 (dd, J2= 9.9
Hz, J1 = 17.0 Hz, 1H), 3.36 (dd, 1H, J2= 3.9 Hz, J1= 17.0 Hz), 1.10
(t, J =7.2 Hz, 3H). 13C-NMR (CDCl3, 62.5 MHz) δ: 196.8, 170.9,
170.2, 143.9, 136.6, 136.5, 133.1, 131.8, 131.3, 128.9, 128.4, 128.3,
128.1, 127.6, 127.0, 124.1, 123.3, 71.5, 62.6, 47.2, 40.0, 13.8. MS
(ESI): m/z = 414 (M + H)+. Anal. calcd for C26H23NO4: C, 75.53; H,
5.61; N, 3.39. Found: C, 75.40; H, 5.75; N, 3.25. Chiral HPLC: IA-3
column, hexane/iPrOH (8:2), flow: 0.6 ml/min, t: 17.38 min (minor),
20.92 min (major); ee 80%.
124.1, 123.7, 122.8, 113.3, 85.4, 71.9, 63.7, 62.9, 55.1, 46.8, 40.4,
ACCEPTED MANUSCRIPT
29.9, 14.2. MS (ESI): m/z = 444 (M + H)+. Anal. calcd for
C27H25NO5: C, 73.12; H, 5.68; N, 3.16. Found: C, 73.32; H, 5.55; N,
3.19. Chiral HPLC: IA-3 column, hexane/iPrOH (9:1), flow: 0.7
ml/min, t: 45.21 min (minor) and 55.32 min (major); ee 70%.
13f.
Ethyl
5-bromo-3-oxo-1-(3-oxo-1,3-diphenylpropyl)
isoindoline-1-carboxylate. Yield: 95%, white solid; mp. 208-209 °C
(ethyl acetate/hexane); d.r. 93/7; [α]D20: +14.8 (c = 1, CHCl3). IR
(KBr) ν: 3202, 1742, 1704, 1680, 1235, 1219 cm-1. 1H-NMR
(CDCl3, 300 MHz) δ: 7.93 (dt, 3H, J2= 6.0 Hz, J1= 10.0 Hz), 7.70-
7.55 (m, 3H), 7.45 (t, 2H, J= 6.0 Hz), 7.11-7.04 (m, 5H), 4.53 (dd, 1
H, J2= 6.0 Hz, J1= 9.0 Hz), 4.31-4.21 (m, 2H), 3.88 (dd, 1H, J2= 6.0
Hz, J1= 15.0 Hz), 3.33 (dd, 1H, J2= 6.0 Hz, J1= 15.0 Hz), 1.27 (t, 3H,
J = 9.0 Hz). 13C-NMR (CDCl3, 150 MHz) δ: 198.2, 171.2, 170.7,
144.1, 138.0, 136.9, 136.3, 134.7, 130.3, 130.1, 129.6, 129.4, 128.9,
128.1, 127.3, 124.7, 72.8, 64.3, 48.5, 41.5, 31.1, 15.4. MS (ESI): m/z
= 493 (M+ H)+. Anal. calcd for:C26H22BrNO4: C, 63.42; H, 4.50; N,
2.84. Found: C, 63.25; H, 4.28; N, 2.59. Chiral HPLC: IA-3 column,
hexane/iPrOH (8:2), flow: 0.6 ml/min, t: 19.5 min (minor) and 26.8
min (major); ee 70%.
13b.
Ethyl
1-(1-(4-nitrophenyl)-3-oxo-3-phenylpropyl)-3-
oxoisoindoline-1-carboxylate. Yield: 92%, waxy solid; d.r. >99:1,
[α]D20: + 61.8 (c = 0.17, CHCl3). IR (KBr) ν: 3443, 3436, 1596, 1390
cm-1. 1H-NMR (CDCl3, 300 MHz) δ: 9.20 (br s, 1H), 8.02 (d, J= 6.0
Hz, 2H), 7.86 (t, J= 8.1 Hz, 3H), 7.69-7.58 (m, 3H), 7.46-7.38 (m,
3H), 7.34 (d, 2H, J = 8.1 Hz), 4.77 (dd, J2= 2.7 Hz, J1=10.7 Hz, 1H),
4.34-4.19 (m, 3H), 3.41 (dd, J2= 2.4 Hz, J1= 10.7 Hz, 1H), 1.31 (t, J=
6.5 Hz, 3H). 13C-NMR (75 MHz, CDCl3) δ: 196.46, 172.0, 169.9,
147.0, 144.7, 143.8, 136.3, 133.9, 132.8, 131.2, 130.1, 129.8, 128.9,
128.4, 123.9, 123.1, 71.8, 63.4, 46.9, 40.1, 14.3. MS (ESI): m/z =
459 (M + H)+. Anal. calcd for C26H22N2O4 : C, 68.11; H, 4.84; N,
6.11. Found: C, 68.30; H, 4.62; N, 6.25. Chiral HPLC: IC column,
hexane/iPrOH (8:2), flow: 0.6 ml/min, t: 37.9 (major) min and 48.5
min (minor); ee 81%.
13g.
Ethyl
1-(3-(2-(trifluoromethyl)phenyl)-3-oxo-1-
phenylpropyl)-3-oxoisoindoline-1-carboxylate. Yield: 91% , waxy
solid; d.r. 96/4 ; [α]D20: +38.6 (c = 1, CHCl3). IR (KBr) ν: 3441,
3419, 1649, 1610, 1420, 1389 cm-1. 1H -NMR (CDCl3, 300 MHz) δ:
8.72 (br s, 1H), 8.21 (d, J= 6.5 Hz, 2H), 7.83-7.78 (m, 2H), 7.59-7.52
(m, 3H), 7.39-7.31 (m, 1H), 7.14 (d, J= 6.5 Hz, 2H), 7.04-6.94 (m,
3H), 4.59 (dd, J2= 3.8 Hz, J1= 10.0 Hz, 1H), 4.32-4.21 (m, 2H), 4.10
(dd, J2= 10.0 Hz, J1= 16.0 Hz, 1H), 3.41 (dd, J2= 3.8 Hz, J1=16.0
Hz, 1H), 1.27 (t, J= 7.1 Hz, 3H). 13C-NMR (CDCl3, 150 MHz) δ:
195.8, 171.4, 170.4, 144.0, 137.1, 136.5, 132.0, 131.5, 131.4, 129.7,
129.3, 129.1, 129.0, 128.9, 127.8, 127.4, 125.0, 124.1, 123.7 (q, JC-F
= 270.0 Hz),123.5, 71.7, 62.8, 47.2, 40.4, 14.0. MS (ESI): m/z = 482
(M+ H)+. Anal. calcd for C27H22F3N2O4: C, 67.35; H, 4.61; N, 2.91.
Found: C, 67.61; H, 4.81; N, 2.68. Chiral HPLC: AD column,
hexane/iPrOH (9:1), flow: 0.6 ml/min, t: 28.52 min (minor) and
34.22 min (major); ee 52%.
13c.
Ethyl
1-(1-(4-chlorophenyl)-3-oxo-3-phenylpropyl)-3-
oxoisoindoline-1-carboxylate. Yield: 96%, waxy solid; d.r. >99:1,
[α]D20: +6.3 (c = 1, CHCl3). IR (KBr) ν: 3441, 3433, 1644, 1637,
1
1389, 1364 cm-1. H -NMR (CDCl3, 300 MHz) δ: 8.59 (br s, 1H),
7.98 (t, J= 7.1 Hz, 2H), 7.80 (d, J= 7.7 Hz, 1H), 7.62-7.54 (m, 3H),
7.47-7.37 (m, 3H), 7.07 (d, J= 8.5 Hz, 2H), 6.96 (d, J= 8.8 Hz, 2H),
4.60 (dd, J2= 3.9 Hz, J1= 10 Hz, 1H), 4.32-4.21 (m, 2H), 4.04 (dd,
J2=10 Hz, J1=17.2 Hz, 1H), 3.33 (dd, J2= 3.9 Hz, J1= 17.2 Hz, 1H),
1.29 (t, J= 7.1 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) δ: 196.9,
171.7, 170.4, 144.1, 136.6, 135.4, 133.6, 133.1, 132.4, 131.4, 130.5,
129.4, 128.8, 128.5, 128.1, 124.0, 123.8, 71.9, 63.0, 46.7, 40.2, 14.2.
MS (ESI): m/z = 448 (M + H)+. Anal. calcd for C26H22ClN2O4: C,
69.72; H, 4.95; N, 3.13. Found: C, 69.51; H, 4.74; N, 3.27. Chiral
HPLC: IA-3 column, hexane/iPrOH (8:2), flow: 0.6 ml/min, t: 19.41
min (minor) and 23.76 min (major); ee 83%.
Procedure for organocatalytic enantioselective cascade
Michael/cyclization reaction.26
To
a
solution of (S)-(–)-α,α-Diphenyl-2-pyrrolidinemethanol
trimethylsilyl ether 17 (15 mol %, 0.015 mmol) and benzoic acid (15
mol %, 0.015 mmol) in MeOH (0.40 mL) was added
cinnamaldehyde (1.5 equiv, 0.15 mmol). After the resulting mixture
was stirred at room temperature for 15 min, a previously prepared
solution of the isoindolinone 4p (0.10 mmol) in MeOH (0.6 mL)
and DCM (0.05 mL) was added dropwise at -15 °C, and the reaction
mixture was stirred for the required time. The solvent was then
13d.
Ethyl
1-(1-(2-chlorophenyl)-3-oxo-3-phenylpropyl)-3-
oxoisoindoline-1-carboxylate. Yield: 93%, waxy solid; d.r. >99:1,
[α]D20: + 5.4 (c = 0.21,CHCl3). IR (KBr) ν: 3433, 3431, 1725, 1690,
1242 cm-1. 1H -NMR (CDCl3, 400 MHz) δ: 8.43 (br s, 1H), 7.99 (d,
J= 8.1 Hz, 2H), 7.93 (d, J= 7.8 Hz, 1H), 7.59-7.32 (m, 7H), 7.08 (d,
J= 7.9 Hz, 1H), 6.97 (t, J= 7.5 Hz, 1H), 6.89 (t, J= 7.8 Hz, 1H), 5.38
(dd, J2= 4.5 Hz, J1= 10.0 Hz, 1H), 4.31-4.18 (m, 2H), 3.95 (dd, J2=
10 Hz, J1= 16.0 Hz, 1H), 3.43 (dd, J2= 4.5 Hz, J1= 16.0 Hz, 1H),
1.28 (t, J= 7.1 Hz, 3H).13C -NMR (CDCl3, 100 MHz) δ: 196.9,
171.9, 170.4, 143.6, 136.6, 135.6, 135.0, 133.5, 132.0, 131.2, 129.6,
129.4, 128.8, 128.5, 127.9, 126.8, 124.6, 123.2, 72.0, 63.1, 41.6,
41.4, 14.2. MS (ESI): m/z = 448 (M + H)+. Anal. calcd for
C26H22ClN2O4: C, 69.72; H,4.95; N, 3.13. Found: C, 69.41; H, 4.65;
N, 3.43. Chiral HPLC: IA-3 column, hexane/iPrOH (8:2), flow: 0.6
ml/min, t: 15.7 min (minor) and 21.83 min (major); ee 75%.
1
evaporated and the diastereomeric ratio (dr) was determined by H-
NMR of the crude product. The crude mixture was purified by flash
chromatography (Hexane/Ethyl acetate 1/1) to afford the pure adduct
as a mixture of diastereoisomers.
16b. Ethyl 7-bromo-2,3,5,9b-tetrahydro-3-hydroxy-5-oxo-1-
phenyl-1H-pyrrolo[2,1-a] isoindole carboxylate. Yield: 97%,
waxy solid; d.r = 40/60; IR (KBr) ν: 2958, 2927, 1739,1717, 1703,
1092, 1070 cm-1. 1H-NMR (CDCl3, 300 MHz) δ: 7.97 (d, 1H, J= 6.0
Hz, minor diast), 7.71-7.66 (m, 2H), 7.42-7.39 (m, 4H), 7.30-7.19
(m, 5H), 7.11-7.05 (m, 4H), 6.80 (dd, 2H, J2= 3.0 Hz, J1= 9.0 Hz),
6.11 (dd, 1H, J2= 6.0 Hz, J1= 12.0 Hz), 5.81 (dd, 1H, J2= 3.0 Hz, J1=
6.1 Hz, minor diast.), 4.36-4.22 (m, 3H), 4.02 (dd, 1H, J2= 6.0 Hz,
J1= 12.0 Hz, minor diast.), 3.90 (ddd, 1H, J3= 6.0 Hz, J2= 12.0 Hz,
J1= 16.0 Hz, minor diast.), 3.12 (ddd, 1H, J3= 6.0 Hz, J2=12.0 Hz,
J1= 16.0 Hz minor diast), 2.89 (m, 1H), 2.70 (m, 1H),1.34 (t, 3H, J1=
6.0 Hz), 0.93 (t, 3H, J= 6.0 Hz, minor diast). 13C-NMR (CDCl3, 150
MHz) δ: 172.8, 170.6, 169.9, 169.6, 143.5, 142.2, 139.4, 136.9,
136.5, 135.8, 135.7, 134.9, 130.2, 130.1, 130.0, 129.8, 129.5, 129.4,
129.1, 128.9, 128.6, 128.4, 127.4, 125.3, 124.8, 81.0, 80.7, 64.5,
64.0, 56.1, 51.4, 46.0, 44.6, 15.5, 14.8. MS (ESI): m/z = 416.2 (M+
13e. Ethyl 1-(1-(4-methoxyphenyl)-3-oxo-3-phenylpropyl)-3-
oxoisoindoline-1-carboxylate. Yield: 86%, waxy solid; d.r. >99:1,
[α]D20: + 43.1 (c= +0.4, CHCl3). IR (KBr) ν: 3433, 3419, 1649, 1389,
1365 cm-1. H -NMR (300 MHz, CDCl3) δ: 8.16 (brs, 1H), 7.97 (d,
1
J= 9.0 Hz, 2H), 7.79 (d, J= 9.0 Hz, 1H), 7.60-7.42 (m, 3H), 7.27-
7.39 (m, 3H), 7.02 (d, J= 6.0 Hz, 2H), 6.53 (d, J= 9.0 Hz, 2H), 4.51
(dd, J2= 3.1 Hz, J1= 9.3 Hz, 1H), 4.29-4.20 (m, 2H), 3.94 (dd, J2=
9.9 Hz, J1= 16.5 Hz, 1H), 3.77 (s, 3H, minor diast), 3.58 (s, 3H), 3.31
(dd, J2= 3.1 Hz, J1= 16.8 Hz, 1H), 1.28 (t, 3H, J= 7.1 Hz). 13C-NMR
(CDCl3, 75 MHz) δ: 197.3, 171.9, 170.6, 158.6, 144.3, 136.8, 133.5,
133.3, 132.1, 131.5, 130.7, 130.1, 129.2, 128.8, 128.6, 128.4, 124.3,

10
Tetrahedron
H) +. Anal. calcd for: C20H18BrNO4: C, 57.71; H, 4.36; N, 3.36.
8) Scorzelli, F.; Di Mola, A.; Palombi, L.; Massa, A. Molecules
ACCEPTED MANUSCRIPT
Found: C, 57.55; H, 3.48; N, 3.26. Chiral HPLC: IA-3 column,
hexane-ethanol (8:2), flow: 0.6 ml/min, minor diastereomer: 23.5
min and 25.2 min. Major diastereomer: 35.1 min and 57.7 min; ee
minor 30%; ee major 61%.
2015, 20, 8484.
9) Couture, A.; Deniau, E.; Ionescu, D.; Grandclaudon, P.
Tetrahedron Lett. 1998, 39, 2319.
10) a) Deliömeroğlu, M.K.; Özcan, S.; Balcia M. ARKIVOC 2010,
140. b) Billamboz, M.; Fabrice, B.; Barreca, M. L.; De Luca, L.;
Mouscadet, J. F.; Calmels, C.; Andreola, M-L.; Witvrouw, M.;
Christ, F.; Debyser, Z.; Cotelle, P. J. Med. Chem. 2008, 51, 7717.
11) Conn, E. L.; Hepworth, D.; Qi, Y.; Rocke, B. N.; Ruggeri, R. B.;
Zhang Y. PCT WO 2011/ 145022 A1.
6.Notes and references
1) a) Bjoere, A.; Bostroem, J.; Davidsson, O.; Emtenaes, H.; Gran,
H.; Iliefski, T.; Kajanus, J.; Olsson, R.; Sandberg, L.; Strandlund, G.
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Shirakawa, S.; Maruoka, K. Angew. Chem. Int. Ed. 2013, 52, 4312.
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