Chiral phase-transfer-catalyzed intramolecular aza-michael reactions for the asymmetric synthesis of isoindolinones

Article abstract of DOI:10.1002/ejoc.201403573

Asymmetric intramolecular aza-Michael reactions catalyzed by cinchoninium phase-transfer organocatalysts are used for the synthesis of optically active isoindolinones. Selected oligomeric cinchoninium salts are efficient and selective catalysts for the in

Full text of DOI:10.1002/ejoc.201403573

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FULL PAPER
DOI: 10.1002/ejoc.201403573
Chiral Phase-Transfer-Catalyzed Intramolecular aza-Michael Reactions for the
Asymmetric Synthesis of Isoindolinones
Stéphane Lebrun,[a,b] Romain Sallio,[a,b] Mélanie Dubois,[a,b]
Francine Agbossou-Niedercorn,[a,c,d] Eric Deniau,*[a,b] and Christophe Michon*[a,c,d]
Keywords: Organocatalysis / Asymmetric catalysis / Phase-transfer catalysis / Aza-Michael additions / Nitrogen
heterocycles
Asymmetric intramolecular aza-Michael reactions catalyzed
by cinchoninium phase-transfer organocatalysts are used for
the synthesis of optically active isoindolinones. Selected
oligomeric cinchoninium salts are efficient and selective cat-
alysts for the intramolecular addition of alkenylated benz-
amide substrates. The resulting compounds are useful inter-
mediates for the synthesis and development of benzodiazep-
ine-receptor agonists.
ists have a variety of synthetic strategies at their disposal
for the racemic synthesis of 3-(N,N-disubstituted)acet-
amido-isoindolinones, mainly based upon metal-catalyzed
tandem reactions.[6]
Introduction
Over the past decade, the isoindolinone ring system has
emerged as a valuable pharmacophore owing to the physio-
logical and chemotherapeutic properties of many of its de-
rivatives.[1] In particular, enantiopure compounds bearing a
polysubstituted acetamido group at C-3 (Figure 1) have
been extensively studied and play an important role as key
targets for the pharmaceutical industry. Highly function-
alized models, such as JM-1232 (1)[1,2] and DN-2327 (pazin-
aclone, 2)[2,3] have been reported as benzodiazepine-recep-
tor agonists for the treatment of anxiety. Isoindolinone 3,
bearing an acetylguanidine group, has been studied as an
NHE1 inhibitor,[4] whereas N-(3-amino-2-hydroxypropyl)-
substituted alkanamides such as 4 have been reported as
inhibitors of the β-secretase enzyme for the treatment of
Alzheimer’s disease.[5] From these studies, the importance
of the absolute configuration of the stereocenter to the
pharmacological activity emerged clearly.[2c] Consequently,
the development of short, versatile and efficient procedures
for the stereocontrolled preparation of these highly func-
tionalized 3-substituted isoindolinones constitutes an area
of current interest, and alternative methods are currently
the object of intensive synthetic endeavour. Organic chem-
Figure 1. Examples of pharmacologically active chiral 3-(N,N-di-
substituted)acetamido-isoidolinones.
[a] Université Lille Nord de France,
As most isoindolinones have been synthesized directly
from ortho-halogenated benzamides through fast palla-
dium-catalyzed tandem Heck and aza-Michael reac-
tions,[6a–6j] the stereoselectivity of the synthetic pathway is
hard to control, and the isolation of key reaction intermedi-
ates is rather difficult.[6h,6i]
The asymmetric synthesis of isoindolinones has involved
two strategies. First, the use of a chiral auxiliary is very
helpful for various chemical reactions. The diastereoselec-
tive nucleophilic additions[7] or hydride reductions[8] of N-
acyliminium species could be achieved. These chiral bicyclic
59000 Lille, France
[b] Université Lille 1, UCCS-CCM-CASECO UMR 8181 CNRS,
Bât. C3(2), 59655 Villeneuve d’Ascq Cedex, France
E-mail: eric.deniau@univ-lille1.fr
http://cmf.univ-lille1.fr/fiche_deniau.html
[c] CNRS, UCCS UMR 8181,
59655 Villeneuve d’Ascq, France
[d] ENSCL, UCCS-CCM-CASECO, Bât C7, CS 90108,
59652 Villeneuve d’Ascq, France
E-mail: christophe.michon@ensc-lille.fr
http://uccs.univ-lille1.fr/index.php/annuaire/
15-fiches-personnels/221-michon-christophe
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403573.
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E. Deniau, C. Michon et al.
FULL PAPER
lactams can also be accessed by α-amino alkylation reac- date. The first involves a catalytic asymmetric reduction of
tions involving a 3-metallated isoindolinone and various a 3-alkoxycarbonylmethylene isoindolinone followed by a
electrophiles.[9] An alternative synthetic approach is based two-step ester–amide interconversion sequence.[17a] The sec-
upon the lactam ring construction with the concomitant ond example has enabled the asymmetric synthesis of iso-
creation of a stereogenic centre at the C-3 position. This indolones from arylhydroxamates and weak alkyl-donor
has been achieved by a two-component reaction involving or -acceptor diazo derivatives under mild conditions with a
an ortho-lithiated dialkylbenzamide with chiral hydraz- catalyst based on a rhodium(III) center coordinated by a
ones[10] or by a diastereoselective imine addition–cyclization chiral cyclopentadienyl ligand.[17b] The third example used
sequence.[11,12] Enantioenriched isoindolinones have also an asymmetric copper(I)-catalyzed alkynylation/lactamiz-
been synthesized by Diels–Alder reactions,[13] Heck reac- ation cascade for the synthesis of diversely substituted iso-
tions[14] and radical-induced cyclizations.[15] An elegant indolinones.[17c] Following our separate but ongoing inter-
method has also been based on an anionic cyclization and a ests in the synthesis of isoindolinones[7d,8c,8g,12] and aza-
rearomatization of α-aminocarbanionic species, which were Michael reactions,[18] we have envisaged a new reaction
prepared by the use of N-benzylbenzamide derivatives and pathway that could afford isoindolinones from asymmetric
a chiral base.[16]
intramolecular aza-Michael reactions of benzamides by the
The asymmetric synthesis of isoindolinones has also construction of the lactam ring system and the concomitant
been achieved through a second strategy, which implied the control of the stereogenic centre at C-3. The stereoselecti-
control of the stereogenic centre at the α position to the vity of the intramolecular aza-Michael reaction could be
lactam nitrogen atom by a chiral catalyst. To the best of controlled by the catalyst chirality. The aza-Michael reac-
our knowledge, only three examples have been reported to tion of activated alkenes with amines has been applied
Scheme 1. Synthesis of substrates.
2
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Intramolecular aza-Michael Reactions
widely in organic synthesis.[19–21] On the one hand, chiral tion conditions, Maruoka catalyst (S)-28 afforded 27a in
auxiliaries or substrates have been used for diastereo- or high yield with 20%ee (Table 1, Entry 2). The use of cin-
enantiocontrolled aza-Michael reactions. On the other choninium salt 30a as a catalyst led to similar results
hand, various organic or metal catalysts could be applied (Table 1, Entry 5), whereas poor asymmetric induction was
for asymmetric aza-Michael reactions.[19–21] Whereas achieved by the use of cinchonidinium salt 29a, Corey cata-
Brønsted acids or bases and primary or secondary amines lyst 29b or quinidinium salt 31 (Table 1, Entries 3, 4 and 6).
have been widely used as chiral organocatalysts,[19,20] phase- The use of cinchoninium salt 30a in combination with other
transfer catalysis has been less studied for asymmetric aza- bases (Table 1, Entries 7–9; DBU = 1,8-diazabicyclo[5.4.0]-
Michael reactions.[22,23] Following our preliminary com- undec-7-ene) or solvents (Table 1, Entries 10 and 11) did
munication,[23m] we wish to disclose herein a full and under- not improve the ee initially obtained (Table 1, Entry 5). To
standable study on an alternative, efficient and new syn- check if bromide was the best counteranion for 30a, iodide
thetic route for enantioenriched 3-(N,N-disubstituted)acet- and tetrafluoroborate anions were tried by in situ ion ex-
amido-isoindolinones.
change, but no ee improvement arose from these attempts
(Table 1, Entries 13 and 14). In addition, cinchoninium salt
30b bearing a chloride anion was unselective (Table 1, Entry
12). Finally, the use of catalyst 30a at 0 °C also resulted in
a complete loss of the enantiomeric excess of 27a (Table 1,
Results and Discussion
To perform the foreseen asymmetric intramolecular aza- Entry 15).
Michael reaction, alkenylated benzamide substrates were
designed and synthesized. Depending on the reagent sub-
Table 1. First catalytic attempts.
stituents, different synthetic pathways had to be applied. A
first synthetic route involved the preliminary elaboration of
the unsaturated tert-butyl benzoic acid esters 15a–15h
through a palladium-catalyzed Heck cross-coupling reac-
tion between aryl bromide 5 and various acrylamides 8–14
(Scheme 1). The removal of the tert-butyl protecting group
was then achieved by treatment with trifluoroacetic acid to
furnish the benzoic acids 16a–16h, which could be directly
used for the next step without any purification. The cou-
pling of these highly conjugated carboxylic acids with sev-
eral primary amines finally delivered the required parent
amides 17a–17l in good yields.
Reagents 20a and 20b were synthesized through Heck
cross-coupling reactions between aldehydes 6–7 and acryl-
amide 8 to avoid side reactions. The subsequent hydrolysis
of 18a and 18b led to carboxylic acids 19a and 19b, which
were directly coupled with aniline to afford the desired
amides 20a and 20b. However, although acid 22 could be
readily prepared from reagent 5 and ester 21, its direct cou-
pling with aniline led to the corresponding cyclized product
24a. Hence, benzamide derivatives 23a–23c had to be pre-
pared by an alternative synthetic pathway from N-phenyl-
benzamide (25, Scheme 1). First, an ortho-lithiation step
followed by a trapping with tert-butyldimethylsilyl chloride
(TBDMSCl) led to the intermediate 2-(tert-butyldimethyl-
silyl)-N-phenylbenzamide (26). Second, a catalytic amide-
directed palladadesilylation–alkenylation offered the de-
Entry Catalyst Base
Solvent T [°C] Yield [%][a] ee [%][b]
1
2
3
–
28
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
DBU
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
20
0
74
77
73
70
75
75
19
78
80
76
73
75
78
72
75
0
20
3
29a
29b
30a
31
30a
30a
30a
30a
30a
30b
30a
30a
30a
20
20
20
20
20
20
20
20
20
20
20
20
0
4
8
5[c]
6
21
13
–
6
4
7
3
0
7
8
9
10
11
12
13[d]
14[e]
15
KOH 50% toluene
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
THF
CH2Cl2
toluene
toluene
toluene
toluene
18
21
0
[a] Isolated yield. [b] Measured by HPLC. [c] No reaction after 6 h.
[d] With 10 mol-% NaI. [e] With 10 mol-% NaBF4.
We next screened various mono- and polynuclear or-
sired benzamides 23a–23c in good yields under mild condi- ganocatalysts based on a cinchonine core for the aza-
tions.[24]
Michael reaction of benzamide 17a (Table 2, Scheme 2).
The asymmetric intramolecular aza-Michael reaction of The substitution effect of the benzyl fragment was the first
substrate 17a was first studied as a model to screen various modification of cinchoninium catalyst 30a studied. Whereas
privileged phase-transfer catalysts and optimize the reac- an ortho-fluoro substituent led to a loss of asymmetric in-
tion conditions (Table 1 and Scheme 2). As some aza- duction (Table 2, Entries 1 and 2), a para-tert-butyl frag-
Michael reactions have been achieved without the use of ment had no effect on the selectivity of the reaction
any catalyst or additional reagent,[18,19f,25] we first per- (Table 2, Entry 3). The change from a benzyl to an an-
formed control experiments. The reaction of reagent 17a thracenyl group resulted in the complete loss of enantio-
solely in the presence of a base such as Cs2CO3 in toluene selection (Table 2, Entry 4). Disappointing results were also
led to product 27a (Table 1, Entry 1). Under the same reac- obtained for the functionalization of the alcohol fragment
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Scheme 2. Organocatalysts used in this study.
of cinchoninium 30a. Whereas an allyl function did not of 17a. We were glad to obtain isoindolinone 27a in 95%
change the course of the reaction provided Cs2CO3 was conversion (78% isolated yield) and 76%ee (Table 2, En-
used a base (Table 2, Entries 6–7), a methyl substituent led try 19).
to the complete loss of the asymmetric induction (Table 2,
Catalyst 37a was optimized for the aza-Michael reaction
Entry 5). To improve the ability of the alcohol fragment to of benzamide 17a by trying some scaffold modifications as
form hydrogen bonds with the substrate, carbamate and well as different reaction conditions (Table 3, Scheme 2).
urea quaternary ammonium catalysts 32a–32b were investi- Several trimeric catalysts were prepared by using cinchon-
gated.[26] Although the use of carbamate 32a slightly im- idine, quinidine and reduced cinchonine. However, al-
proved the ee, catalyst 32b was not selective (Table 2, En- though all attempts afforded 27a in good yields, lower ee
tries 8–9). As catalyst 30a could not be improved by any values were obtained, and salt 37a remained the catalyst of
scaffold modification, we decided to investigate oligomeric choice (Table 3, Entries 1–5). Regarding the reaction condi-
cinchoninium salts based on 30a.[22b,27] Dimeric catalysts tions, we noticed the use of other bases did not improve the
33a–33c, built on a benzene core, were first investigated. reaction outcome. K2CO3 did not allow any reaction, and
Whereas salts 33a and 33c afforded 27a in lower ee than aqueous KOH led to lower ee values (Table 3, Entries 6 and
salt 30a (Table 2, Entries 1, 10 and 12), meta-substituted 7). Moreover, the use of an additional amount of Triton X
cinchoninium salt 33b led to the product 27a in 45%ee surfactant resulted in a complete loss of enantioselectivity
(Table 2, Entry 11). The use of dimeric catalysts 34a, 34b (Table 3, Entry 8). Different solvents led to a decrease of
and 35 based on naphthyl and anthracenyl cores resulted 27a enantioselectivity (Table 3, Entries 9 and 10). The use
in lower enantioselectivities (Table 2, Entries 13–15), and a of catalyst 37a at 0 or 50 °C did not significantly change
dimeric catalyst based on a biphenyl core afforded product the yield or ee (Table 3, Entries 1, 11 and 12).
27a in 41%ee (Table 2, Entries 16–18). Encouraged by the
The organocatalyzed aza-Michael reaction of benzamide
result obtained with dimeric catalyst 33b, we prepared tri- 17a was completed in 5 h with a half-life of ca. 3 h, and the
meric cinchoninium catalyst 37a and used it in the reaction enantioselectivity was stable during the reaction (see Sup-
4
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Intramolecular aza-Michael Reactions
Table 2. Screening of various catalysts for the phase-transfer-cata- porting Information, Table S1 and Figure S1). Once sub-
lyzed intramolecular aza-Michael reaction of benzamide 17a.
strate 17a had fully reacted, the yield and enantioselectivity
were stable with time. Hence, according to these data, any
retro-aza-Michael reaction was unlikely.[18a,28] Finally, the
plot of ln(nreagent 17a) versus time gave a curve that could
not be fitted with a first-order kinetic law by the linear
least-squares technique (Figure S2).
High yields of 27a (82 to 100%) were obtained indepen-
dently of the reaction scale (0.08 to 0.31 mmol) and the
Entry
Catalyst
Yield [%][a]
ee [%][b]
catalyst loading (Table 3, Entry 14; Table S2). To achieve
the best enantioselectivity, a 20 mol-% catalyst loading was
required (Table 3, Entry 14). The addition of more catalyst
resulted in no further improvement, and a decreased load-
ing of 37a to 5 or 1 mol-% led to lower ee (Table 3, En-
tries 13 and 15; Table S2 and Figure S3).
1[c]
2[c,d]
3[e]
4
30a
30c
30d
30e
30f
30g
30g
32a
32b
33a
33b
33c
34a
34b
35
75
74
77
73
80
74
71
78
82
79
75
71
82
78
70
75
76
100
78
21
0
20
0
0
21
6
5
6
7[c,f]
8
To explore the substrate scope of this phase-transfer-cat-
alyzed intramolecular aza-Michael reaction, various benz-
amides were reacted in the presence of catalyst 37a under
selected reaction conditions (Table 4). On the whole, the re-
actions proceeded smoothly to afford the products in good
yields without any substituent effects. A reaction time of at
least 12 h was needed to allow all substrates to react. Re-
garding the variation in enantioselectivity, several trends
could be observed. First, although a 20 mol-% catalyst
loading led to the highest ee for products 27a–27c, 27e–27g,
27j and 27m (Table 4, Entries 1–6, 9–14, 18–19 and 23–24),
better results were obtained with a 10 mol-% catalyst load-
ing for products 27d, 27h, 27k and 27n (Table 4, Entries 7–
8, 15–16, 20–21 and 25–26). Considering the R2 substituent,
benzamide substrates 17b and 17c with cyclic amines re-
acted well, although the ees of 27b and 27c (68 and 72%)
were lower than the ee of 27a (Table 4, Entries 3–6). With
the exception of reagent 17g, substituted with bulky iso-
propyl groups (Table 4, Entries 13–14), the use of noncyclic
amines as the R2 substituent afforded products 27d–27f
with ees equivalent to or higher than the ee of 27a (Table 4,
Entries 7–12). When R2 was an O-alkyl group, the resulting
isoindolinones 24a–c could be isolated in good yields, but
poor enantiomeric excesses were obtained (Scheme 3,
Table S3). According to our data, any retro-aza-Michael re-
action was again unlikely.[18a,28]
23
5
9
10
11
12
13
14
15
16
17
18
19
17
45
12
32
32
10
6
41
6
76
36a
36b
36c
37a
[a] Isolated yield. [b] Measured by HPLC. [c] Same result with tolu-
ene/CHCl3 (7:3). [d] Same result with 50% aq. KOH as base. [e]
Same result with 30 mol-% of catalyst. [f] 50% aq. KOH.
Table 3. Optimization of catalyst 37a.
Entry Catalyst Base
[mol-%] (1.3 equiv.)
Solvent
Time Yield
[h]
ee
[%][a]
[%][b]
1
2
3
4
5
6
37a (10) Cs2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
CH2Cl2
toluene
toluene
toluene
toluene
toluene
24
24
24
24
24
24
24
24
24
24
24
24
5
78
79
83
77
78
0
73
65
75
73
79
76
85
82
80
76
10
29
32
35
–
30
0
5
37b (10) Cs2CO3
37c (10) Cs2CO3
37d (10) Cs2CO3
37e (10) Cs2CO3
37a (10) K2CO3
37a (10) KOH[c]
37a (10) KOH[c]
37a (10) Cs2CO3
37a (10) Cs2CO3
37a (10) Cs2CO3
37a (10) Cs2CO3
7
8[d]
9
10
11[e]
12[f]
13
14[g]
15
2
74
76
71
86
87
Scheme 3.
37a (5)
Cs2CO3
37a (20) Cs2CO3
37a (30) Cs2CO3
5
5
Regarding the substituent R1, the reactivity of reagents
17g–17k proved that the nature of R1 was critical to reach
a good enantioselectivity (Table 4, Entries 13–21). A phenyl
substituent was preferred to 2-naphthyl, benzyl, 2-pyridyl
or alkyl substituents. Finally, whereas the reactivity of sub-
[a] Isolated yield, 0.08 mmol reaction scale. [b] Measured by HPLC.
[c] KOH 50% in water. [d] With 5 mol-% of Triton X. [e] Reaction
at 50 °C. [f] Reaction at 0 °C. [g] Same results on 0.25 and
0.31 mmol reaction scales.
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Table 4. Scope of amide substrates 17a–17l, 20a and 20b.
[a] Isolated yield, 0.08 mmol reaction scale. [b] Measured by HPLC. [c] Same results on 0.25 and 0.31 mmol reaction scales.
strates 20a and 20b proved that the enantioselectivity was Table 4, Entries 7–8 and 22). Finally, the enantiopurity of
much less dependent on the nature of substituents R3 and products such as 27a, 27e, 27f, 27m and 27n could not be
R4 (products 27m and 27n; Table 4, Entries 23–26), the re- improved by recrystallization. Moreover, in attempts to de-
actions of reagents 17d and 17l confirmed that tertiary fine the absolute stereochemistry of the synthesized isoin-
amides were the best substituents on the Michael acceptor dolinones by X-ray structure determination, we failed to
to reach a high enantioselection (products 27d and 27l; obtain any single crystals of the reported compounds.
6
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Intramolecular aza-Michael Reactions
76%ee). The ee was measured by HPLC with an AD CSP at 25 °C
with (70:30) n-hexane/EtOH (0.5 mL/min), λ = 275 nm, tR(minor)
= 32.9 min and tR(major) = 36.7 min.
Conclusions
We have developed a new synthetic route to optically
active isoindolinones, which are useful intermediates for the
synthesis and development of benzodiazepine-receptor ago-
nists. To access such isoindolinones, asymmetric intra-
3-(2-Morpholin-4-yl-2-oxoethyl)-2-phenyl-2,3-dihydroisoindol-1-one
(27b): Yield 80% (21 mg), m.p. 155–156 °C. Rf (100% EtOAc) 0.58.
IR: ν = 2940, 2853, 1693, 1635, 1597, 1498, 1394, 1373, 1234, 1114,
˜
molecular aza-Michael reactions are a valuable synthetic 1029, 970, 862, 756, 692 cm–1. 1H NMR (300 MHz, CDCl3): δ =
2.43 (dd, J = 17.0, 9.8 Hz, 1 H, CH2CO), 2.90 (dd, J = 17.0, 3.7 Hz,
1 H, CH2CO), 3.14–3.28 (m, 2 H, CH2), 3.42–3.58 (m, 2 H, CH2),
3.67–3.74 (m, 4 H, 2ϫCH2), 5.90 (dd, J = 9.8, 3.7 Hz, 1 H, CH),
7.24–7.31 (m, 1 H, Harom), 7.40–7.67 (m, 7 H, Harom) 7.93 (d, J =
7.2 Hz, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 36.4,
42.1, 45.8, 57.7, 66.3, 66.7, 123.2 (2 ϫ CH), 123.3, 124.1, 125.6,
128.8, 129.3 (2ϫCH), 131.7, 132.4, 136.6, 145.1, 166.9, 168.4 ppm.
route, provided selected oligomeric cinchoninium salts are
used as phase-transfer catalysts. However, specific substitu-
tion patterns on the amide nitrogen atom and to a lesser
extent on the Michael acceptor were necessary to reach
high enantioselectivities. Further developments related to
this project will be reported in the future.
C
20H20N2O3 (336.39): calcd. C 71.41, H 5.99, N 8.33; found C
71.49, H 6.10, N 8.09. [α]2D0 = +76 (c = 0.88, CHCl3, for 61%ee).
The ee was measured by HPLC with an AD CSP at 25 °C with
(60:40) n-hexane/EtOH (1 mL/min), λ = 203 nm, tR(minor) =
22.4 min and tR(major) = 39.4 min.
Experimental Section
General Remarks: Melting points were determined with a Reichert-
Thermopan apparatus. NMR spectra were recorded with a Bruker
AV 300 spectrometer and referenced against internal tetramethylsil-
ane. Coupling constants (J) are given in Hz and rounded to the
nearest 0.1 Hz. IR absorption spectra were recorded with a Perkin–
Elmer 881 spectrometer. HPLC analyses were performed with a
Hitachi-VWR LaChromElite L-2000 instrument. Elemental analy-
ses were obtained with a Carlo–Erba CHNS-11110 analyzer. Flash
chromatography was performed with Sorbent Technologies 32–
63 μm 60 Å silica gel. Reactions were monitored by thin layer
chromatography with Sorbent Technologies 0.20 mm silica gel 60 Å
plates. Dry glassware was obtained by oven-drying and assembly
under inert gas. Dry nitrogen was used as the inert atmosphere.
The glassware was equipped with rubber septa, and reagent trans-
fers were performed by syringe techniques. Tetrahydrofuran (THF)
was distilled from sodium benzophenone ketyl before use. Meth-
anol, ethanol and 2-propanol were distilled from magnesium turn-
ings, CH2Cl2 was dried with CaH2, and toluene was dried with
sodium. See Supporting Information for other details.
3-{2-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-2-oxoethyl}-2-phenyl-2,3-di-
hydroisoindol-1-one (27c): Yield 75% (23 mg), m.p. 137–138 °C. Rf
(100% EtOAc) 0.60. IR: ν = 2968, 2920, 1689, 1633, 1597, 1498,
˜
1
1456, 1384, 1220, 1145, 1105, 1035, 945, 759, 698 cm–1. H NMR
(300 MHz, CDCl3): δ = 2.45 (dd, J = 16.0, 9.5 Hz, 1 H, CH2CO),
2.92 (dd, J = 16.0, 3.4 Hz, 1 H, CH2CO), 3.21–3.36 (m, 2 H, CH2),
3.65–3.84 (m, 4 H, 2 ϫ CH2), 3.91–4.02 (m, 6 H, OCH2CH2O,
CH2), 5.90 (dd, J = 9.5, 3.4 Hz, 1 H, NCH), 7.22–7.27 (m, 2 H,
Harom), 7.42–7.64 (m, 6 H, Harom), 7.92–7.96 (m, 1 H, Harom) ppm.
13C NMR (75 MHz, CDCl3): δ = 34.8, 35.4, 36.4, 40.0, 43.5, 57.8,
64.5 (2ϫCH2), 106.6, 123.1 (2ϫCH), 123.3, 124.1, 125.5, 128.7,
129.3 (2 ϫ CH), 131.7, 132.4, 136.7, 145.3, 166.9, 167.9 ppm.
C
23H24N2O4 (392.45): calcd. C 70.39, H 6.16, N 7.14; found C
70.30, H 6.03, N 7.29. [α]2D0 = +55 (c = 0.12, CHCl3, for 61%ee).
The ee was measured by HPLC with an AD CSP at 25 °C with
(60:40) n-hexane/EtOH (1 mL/min), λ = 203 nm, tR(minor) =
22.4 min and tR(major) = 29.4 min.
N,N-Dibenzyl-2-(3-oxo-2-phenyl-2,3-dihydro-1H-isoindol-1-yl)acet-
amide (27d): Yield 71 % (25 mg), m.p. 189–190 °C. Rf (100 %
General Procedure for the Intramolecular aza-Michael Reaction.
Preparation of Isoindolinones 27a–27n: A mixture of benzamide
17a–17l, 20a or 20b (0.08 mmol), base (1.3 equiv.) and catalyst
(10 mol-%) was stirred for 6 to 24 h (Table 2) in toluene (2 mL) at
room temperature. The resulting reaction mixture was monitored
by TLC until complete. The crude product was purified by flash
chromatography (silica gel, eluted with EtOAc and petroleum ether
mixtures) to afford products 27a–27n after evaporation of the sol-
vents under vacuum. The enantiomeric excesses of 27a–27n were
determined by HPLC with Daicel ChiralpakTM AD and IA chiral
stationary phases (CSPs).
EtOAc) 0.88. IR: ν = 2965, 2920, 1673, 1546, 1491, 1388, 1251,
˜
1
1142, 1056, 763, 602 cm–1. H NMR (300 MHz, CDCl3): δ = 2.43
(dd, J = 16.2, 9.6 Hz, 1 H, CH2CO), 2.97 (dd, J = 16.2, 4.3 Hz, 1
H, CH2CO), 4.12 (d, J = 17.2 Hz, 1 H, NCH2Ph), 4.12 (d, J =
17.2 Hz, 1 H, NCH2Ph), 4.47 (d, J = 14.7 Hz, 1 H, NCH2Ph), 4.66
(d, J = 14.7 Hz, 1 H, NCH2Ph), 5.90 (dd, J = 9.6, 4.3 Hz, 1 H,
NCH), 6.80–6.83 (m, 2 H, Harom), 7.11–7.66 (m, 16 H, Harom), 7.85
(d, J = 6.9 Hz, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ
= 35.9, 47.5, 48.8, 56.8, 122.1 (2ϫCH), 122.3, 123.1, 124.5, 125.1
(2 ϫ CH), 126.6, 126.7, 127.4 (2 ϫ CH), 127.7 (4 ϫ CH), 128.3
(2ϫCH), 130.8 (2ϫCH), 131.2, 134.4, 135.6, 135.7, 144.1, 165.8,
169.3 ppm. C30H26N2O2 (446.55): calcd. C 80.69, H 5.87, N 6.27;
found C 80.53, H 6.01, N 6.09. [α]2D0 = +85 (c = 0.32, CHCl3, for
74%ee). The ee was measured by HPLC with an IA CSP at 25 °C
with (40:60) n-hexane/CH2Cl2 (0.5 mL/min), λ = 272 nm, tR(minor)
= 16.5 min and tR(major) = 27.7 min.
3-(2-Oxo-2-pyrrolidin-1-ylethyl)-2-phenyl-2,3-dihydroisoindol-1-one
(27a): Yield 80% (21 mg), m.p. 185–186 °C. Rf (100% EtOAc) 0.29.
IR: ν = 2958, 2860, 1689, 1627, 1446, 1388, 1149, 758, 698 cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 1.74–1.83 (m, 4 H, 2ϫCH2),
2.40 (dd, J = 15.6, 8.8 Hz, 1 H, CH2CO), 2.85 (dd, J = 15.6, 4.3 Hz,
1 H, CH2CO), 3.07–3.19 (m, 2 H, NCH2), 3.34–3.55 (m, 2 H,
NCH2), 5.88 (dd, J = 8.8, 4.3 Hz, 1 H, NCH), 7.23 (t, J = 7.3 Hz, N,N-Dicyclohexyl-2-(3-oxo-2-phenyl-2,3-dihydro-1H-isoindol-1-yl)-
1 H, Harom), 7.42–7.63 (m, 4 H, Harom) 7.63–7.68 (m, 3 H, Harom), acetamide (27e): Yield 75% (26 mg), m.p. 174–175 °C. Rf (100%
7.92 (d, J = 7.1 Hz, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3):
δ = 24.0, 25.7, 38.3, 45.5, 46.6, 58.0, 123.2, 123.3 (2ϫCH), 124.1,
125.5, 128.7, 129.1 (2 ϫ CH), 131.7, 132.3, 136.7, 145.3, 166.9,
168.1 ppm. C20H20N2O2 (320.39): calcd. C 74.98, H 6.29, N 8.74;
found C 75.20, H 6.41, N 8.64. [α]2D0 = +76 (c = 0.43, CHCl3, for
EtOAc) 0.88. IR: ν = 2931, 2854, 1618, 1597, 1496, 1442, 1392,
˜
1
1315, 1213, 997, 894, 746, 692 cm–1. H NMR (300 MHz, CDCl3):
δ = 0.75–1.92 (m, 20 H, 10 CH2), 2.33 (dd, J = 15.6, 9.6 Hz, 1 H,
CH2CO), 2.48–2.75 (m, 1 H, NCH), 2.91 (dd, J = 15.6, 3.4 Hz, 1
H, CH2CO), 3.09–3.21 (m, 1 H, NCH), 5.94 (dd, J = 9.6, 3.4 Hz,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O43573
/KAP1
Date: 05-02-15 12:06:16
Pages: 11
E. Deniau, C. Michon et al.
FULL PAPER
1 H, NCH), 7.13–7.20 (m, 1 H, Harom), 7.36–7.66 (m, 5 H, Harom), 3-(2-Oxo-2-pyrrolidin-1-ylethyl)-2-pyridin-2-yl-2,3-dihydroisoindol-
7.71 (d, J = 7.6 Hz, 2 H, Harom), 7.93 (d, J = 7.3 Hz, 1 H, Harom 1-one (27i): Yield 72% (18 mg), m.p. 89–90 °C. Rf (100% EtOAc)
ppm. 13C NMR (75 MHz, CDCl3): δ = 25.0 (2 ϫ CH2), 25.4 0.20. IR: ν = 3325, 2929, 2850, 1703, 1625, 1583, 1571, 1469, 1435,
)
˜
(2ϫCH2), 26.6, 29.7, 30.1 (2ϫCH2), 30.4 (2ϫCH2), 31.0, 46.2
1369, 1301, 1244, 1143, 1089, 893, 779, 651 cm–1 1H NMR
.
(2ϫCH), 58.0, 122.9 (2ϫCH), 123.2, 124.0, 125.3, 128.6, 129.2 (300 MHz, CDCl3): δ = 1.80–1.87 (m, 4 H, 2ϫCH2), 2.35 (dd, J
(2ϫCH), 131.7, 132.3, 136.9, 148.7, 167.1, 168.9 ppm. C28H34N2O2 = 15.4, 9.6 Hz, 1 H, CH2CO), 3.12–3.30 (m, 2 H, NCH2), 3.48 (dd,
(430.59): calcd. C 78.10, H 7.96, N 6.51; found C 78.29, H 7.88, N
J = 15.4, 3.3 Hz, 1 H, CH2CO), 3.53–3.59 (m, 2 H, NCH2), 6.17
(dd, J = 9.6, 3.3 Hz, 1 H, NCH), 7.05–7.09 (m, 1 H, Harom), 7.50
6.68. [α]2D0 = +83 (c = 0.80, CHCl3, for 86%ee). The ee was mea-
sured by HPLC with an AD CSP at 25 °C with (70:30) n-hexane/ (t, J = 7.4 Hz, 1 H, Harom), 7.57 (td, J = 7.6, 1.2 Hz, 1 H, Harom),
EtOH (0.5 mL/min), λ = 202 nm, tR(minor) = 11.9 min and
tR(major) = 13.1 min.
7.72–7.81 (m, 2 H, Harom) 7.92 (d, J = 7.4 Hz, 1 H, Harom), 8.42–
8.45 (m, 1 H, Harom), 8.57–8.61 (m, 1 H, Harom) ppm. 13C NMR
(75 MHz, CDCl3): δ = 24.4, 26.0, 39.1, 45.8, 46.6, 57.1, 115.6,
119.4, 124.0, 124.1, 128.4, 131.6, 132.8, 137.8, 146.2, 147.8, 151.1,
167.8, 168.7 ppm. C19H19N3O2 (321.38): calcd. C 71.01, H 5.96, N
13.08; found C 71.13, H 6.14, N 12.98. The ee was measured by
HPLC with an AD CSP at 25 °C with (70:30) n-hexane/EtOH
(1 mL/min), λ = 203 nm, tR(minor) = 30.9 min and tR(major) =
37.1 min.
N,N-Diisopropyl-2-(3-oxo-2-phenyl-2,3-dihydro-1H-isoindol-1-yl)-
acetamide (27f): Yield 77% (21 mg), m.p. 110–111 °C. Rf (100%
EtOAc) 0.85. IR: ν = 3444, 2970, 1685, 1625, 1494, 1379, 1325,
˜
1220, 1149, 1132, 1043, 759, 692 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 1.00 (d, J = 5.0 Hz, 3 H, CH3), 1.03 (d, J = 5.0 Hz, 3
H, CH3), 1.40 (d, J = 6.7 Hz, 3 H, CH3), 1.47 (d, J = 6.7 Hz, 3 H,
CH3), 2.35 (dd, J = 15.7, 9.5 Hz, 1 H, CH2CO), 2.91 (dd, J = 15.7,
3.6 Hz, 1 H, CH2CO), 3.57–3.73 (m, 2 H, 2 CH), 5.93 (dd, J = 9.5,
3.6 Hz, 1 H, NCH), 7.18–7.25 (m, 1 H, Harom), 7.39–7.70 (m, 7 H,
Harom) 7.93 (d, J = 7.7 Hz, 1 H, Harom) ppm. 13C NMR (75 MHz,
CDCl3): δ = 20.6, 20.7, 20.9, 20.95, 46.0, 47.7, 49.8, 58.0, 123.2
(2ϫCH), 123.3, 124.0, 125.4, 128.5, 129.2 (2ϫCH), 132.2, 136.8,
145.6, 149.4, 168.5, 171.4 ppm. C22H26N2O2 (350.46): calcd. C
75.40, H 7.48, N 7.99; found C 75.28, H 7.36, N 8.21. [α]2D0 = +92
(c = 0.12, CHCl3, for 81%ee). The ee was measured by HPLC with
an AD CSP at 25 °C with (70:30) n-hexane/EtOH (0.5 mL/min), λ
= 203 nm, tR(minor) = 12.5 min and tR(major) = 15.9 min.
3-Cyclohexyl-3(2-oxo-2-pyrrolidin-1-ylethyl)-2-phenyl-2,3-dihydro-
isoindol-1-one (27j): Yield 80% (21 mg), m.p. 55–56 °C. Rf (100%
EtOAc) 0.50. IR: ν = 2930, 2854, 16490, 1589, 1562, 1438, 1361,
˜
1
1256, 891, 761, 680 cm–1. H NMR (300 MHz, CDCl3): δ = 1.21–
1.47 (m, 4 H, 2ϫCH2), 1.68–1.95 (m, 9 H, 5ϫCH2), 2.05–2.13 (m,
1 H, CH2), 2.37 (dd, J = 15.3, 9.5 Hz, 1 H, CH2CO), 3.07 (dd, J
= 15.3, 4.2 Hz, 1 H, CH2CO), 3.09–3.18 (m, 1 H, NCH2), 3.27–
3.36 (m, 1 H, NCH2), 3.55–3.62 (m, 2 H, NCH2), 3.74–3.86 (m, 1
H, NCH), 5.22 (dd, J = 9.5–4.2 Hz, 1 H, NCH), 7.42–7.48 (m, 3
H, Harom), 7.76–7.84 (m, 1 H, Harom) ppm. 13C NMR (75 MHz,
CDCl3): δ = 24.4, 25.5, 26.0, 26.1, 26.2, 30.8, 31.2, 39.8, 45.9, 46.8,
53.9, 57.1, 122.7, 123.3, 128.2, 131.3, 132.5, 146.1, 168.2, 168.3
ppm. C20H26N2O2 (326.44): calcd. C 73.59, H 8.03, N 8.58; found
C 73.48, H 7.95, N 8.69. [α]2D0 = +44 (c = 0.50, CHCl3, for 49%ee).
The ee was measured by HPLC with an IA CSP at 25 °C with
(90:10) n-hexane/iPrOH (0.5 mL/min), λ = 202 nm, tR(minor) =
32.4 min and tR(major) = 37.0 min.
N,N-Diisopropyl-2-(2-naphthalen-2-yl-3-oxo-2,3-dihydro-1H-iso-
indol-1-yl)acetamide (27g): Yield 78% (25 mg), m.p. 173–174 °C. Rf
(100% EtOAc) 0.84. IR: ν = 2925, 1695, 1627, 1448, 1402, 1377,
˜
1348, 1328, 1207, 1132, 1043, 796, 773, 759, 696 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 1.12–1.46 (m, 12 H, 4ϫCH3), 2.38–2.72
(m, 2 H, CH2), 3.24–3.76 (m, 2 H, 2ϫCH), 5.72–5.97 (m, 1 H,
NCH), 7.47–8.01 (m, 11 H, Harom) ppm. 13C NMR (75 MHz,
CDCl3): δ = 20.5, 20.6, 21.0 (2ϫCH3), 38.3, 45.9, 48.2, 61.6, 123.3,
123.7, 124.2, 125.4, 125.8, 126.3, 126.7, 128.5, 128.6, 129.1, 131.6,
132.1, 146.7, 168.0 (2ϫCO) ppm. C26H28N2O2 (400.52): calcd. C
77.97, H 7.05, N 6.99; found C 78.16, H 7.12, N 6.83. [α]2D0 = +27
(c = 0.20, CHCl3, for 21%ee). The ee was measured by HPLC with
an AD CSP at 25 °C with (70:30) n-hexane/EtOH (0.5 mL/min), λ
= 220 nm, tR(major) = 18.7 min and tR(minor) = 28.1 min.
3-(2-Oxo-2-pyrrolidin-1-ylethyl)-2-pentyl-2,3-dihydroisoindol-1-one
(27k): Yield 72% (18 mg), m.p. 62–63 °C. Rf (100% EtOAc) 0.43.
IR: ν = 2954, 2872, 1683, 1635, 1627, 1446, 1415, 1371, 1255, 1093,
˜
754, 696 cm–1 1H NMR (300 MHz, CDCl3): δ = 0.88 (t, J =
.
7.0 Hz, 3 H, CH3), 1.26–1.38 (m, 4 H, 2ϫCH2), 1.52–1.73 (m, 2
H, CH2), 1.80–1.96 (m, 4 H, 2ϫCH2), 2.42 (dd, J = 15.5, 8.0 Hz,
1 H, CH2CO), 2.84 (dd, J = 15.7, 5.5 Hz, 1 H, CH2CO), 3.08–3.17
(m, 1 H, CH2), 3.19–3.25 (m, 1 H, CH2), 3.29–3.26 (m, 1 H, CH2),
3.57 (t, J = 7.0 Hz, 2 H, NCH2), 3.94–4.01 (m, 1 H, CH2), 5.20
(dd, J = 8.0, 5.5 Hz, 1 H, NCH), 7.41–7.53 (m, 3 H, Harom), 7.80–
7.85 (m, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9,
22.4, 24.4, 26.0, 28.0, 29.1, 38.4, 40.2, 46.0, 46.8, 56.3, 122.8, 123.5,
128.3, 131.1, 132.2, 145.8, 168.1, 168.2 ppm. C19H26N2O2 (314.43):
calcd. C 72.58, H 8.33, N 8.91; found C 72.67, H 8.10, N 9.01. The
ee was measured by HPLC with an IB CSP at 25 °C with (95:05)
n-hexane/EtOH (0.5 mL/min), λ = 201 nm, tR(minor) = 40.4 min
and tR(major) = 42.5 min.
2-(4-Methoxybenzyl)-3-(2-oxo-2-pyrrolidin-1-ylethyl)-2,3-(dihydro-
1H-isoindol-1-yl)acetamide (27h): Yield 77 % (22 mg), m.p. 130–
131 °C. R (100% EtOAc) 0.37. IR: ν = 2954, 1685, 1627, 1610,
˜
f
1508, 1446, 1396, 1298, 1240, 1174, 1029, 804, 754, 690 cm–1. H
1
NMR (300 MHz, CDCl3): δ = 1.65–1.74 (m, 4 H, 2ϫCH2), 2.37
(dd, J = 16.0, 6.5 Hz, 1 H, CH2CO), 2.56 (dd, J = 16.0, 6.5 Hz, 1
H, CH2CO), 2.76–2.85 (m, 1 H, NCH2), 2.95–3.06 (m, 1 H,
NCH2), 3.36–3.40 (m, 2 H, NCH2), 3.68 (s, 3 H, OCH3), 4.57 (d,
J = 15.1 Hz, 1 H, CH2Ph), 4.75 (d, J = 15.1 Hz, 1 H, CH2Ph), 5.10
(t, J = 6.5 Hz, 1 H, NCH), 6.73 (d, J = 8.6 Hz, 2 H, Harom), 7.16 N-Benzyl-2-(3-oxo-2-phenyl-2,3-dihydro-1H-isoindol-1-yl)acetamide
(d, J = 8.6 Hz, 2 H, Harom), 7.34–7.45 (m, 3 H, Harom), 7.81 (m, 1 (27l): Yield 66% (19 mg), m.p. 75–76 °C. Rf (100% EtOAc) 0.75.
H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.2, 25.8, 38.9,
44.2, 45.8, 46.4, 55.3, 57.0, 113.9 (2 ϫ CH), 122.7, 123.7, 128.3,
129.2 (2ϫCH), 130.0, 131.6, 131.8, 145.9, 158.9, 167.8, 168.5 ppm.
C22H24N2O3 (364.44): calcd. C 72.50, H 6.64, N 7.69; found C
72.59, H 6.75, N 7.33. [α]2D0 = +48 (c = 0.16, CHCl3, for 22%ee).
The ee was measured by HPLC with an AD CSP at 25 °C with
IR: ν = 2950, 2840, 1690, 1625, 1442, 1389, 1130, 776, 698 cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 2.18 (dd, J = 14.8, 9.0 Hz, 1 H,
CH2CO), 2.89 (dd, J = 14.8, 4.3 Hz, 1 H, CH2CO), 4.30 (dd, J =
14.6, 5.5 Hz, 1 H, NCH2Ph), 4.46 (dd, J = 14.6, 5.5 Hz, 1 H,
NCH2Ph), 5.71 (dd, J = 9.0, 4.3 Hz, 1 H, NCH), 5.89 (br s, 1 H,
NH), 7.18–7.57 (m, 13 H, Harom), 7.81–7.85 (m, 1 H, Harom) ppm.
(70:30) n-hexane/EtOH (0.5 mL/min), λ = 203 nm, tR(major) = 13C NMR (75 MHz, CDCl3): δ = 40.0, 43.8, 57.8, 123.0, 123.5 (2
27.3 min and tR(minor) = 32.5 min. CH), 124.1, 125.8, 127.7, 128.0 (2ϫCH), 128.7 (2ϫCH), 128.8,
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43573
/KAP1
Date: 05-02-15 12:06:16
Pages: 11
Intramolecular aza-Michael Reactions
niau, P. Grandclaudon, C. Hoarau, J. Org. Chem. 1998, 63,
129.3 (2ϫCH), 131.7, 132.3, 136.5, 137.7, 144.5, 166.9, 169.0 ppm.
C23H20N2O2 (356.42): calcd. C 77.51, H 5.66, N 7.86; found C
77.40, H 5.80, N 7.76. [α]2D0 = +44 (c = 1.21, CHCl3, for 49%ee).
The ee was measured by HPLC with an AD CSP at 25 °C with
(70:30) n-hexane/EtOH (0.5 mL/min), λ = 202 nm, tR(major) =
30.2 min and tR(minor) = 61.7 min.
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D. J. Wustrow, K. T. Zoski, S. Z. Whetzel, A. E. Corbin, T. A.
Pugsley, T. G. Heffner, L. D. Wise, Bioorg. Med. Chem. Lett.
1998, 8, 1499; f) A. Couture, E. Deniau, P. Grandclaudon, C.
Hoarau, Tetrahedron 2000, 56, 1491; g) C. Riedinger, J. A. En-
dicott, S. J. Kemp, L. A. Smyth, A. Watson, E. Valeur, B. T.
Golding, R. J. Griffin, I. R. Hardcastle, M. E. Noble, J. M.
McDonnel, J. Am. Chem. Soc. 2008, 130, 16038.
6-Benzyloxy-3-(2-oxo-2-pyrrolidin-1-ylethyl)-2-phenyl-2,3-dihydro-
isoindol-1-one (27m): Yield 72 % (24 mg), m.p. 156–157 °C. Rf
[2]
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(100% EtOAc) 0.58. IR: ν = 2956, 2865, 1687, 1621, 1445, 1389,
˜
1
1141, 771, 695 cm–1. H NMR (300 MHz, CDCl3): δ = 1.74–1.85
(m, 4 H, 2ϫCH2), 2.34 (dd, J = 15.6, 8.9 Hz, 1 H, CH2CO), 2.83
(dd, J = 15.6, 4.3 Hz, 1 H, CH2CO), 3.09–3.12 (m, 2 H, NCH2),
3.35–3.52 (m, 2 H, NCH2), 5.15 (s, 2 H, OCH2Ph), 5.79 (dd, J =
8.9, 4.3 Hz, 1 H, NCH), 7.18–7.25 (m, 2 H, Harom), 7.32–7.46 (m,
8 H, Harom), 7.54 (d, J = 8.4 Hz, 1 H, Harom), 7.64–7.69 (m, 2 H,
Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.3, 25.9, 38.7,
45.8, 46.6, 57.5, 70.4, 107.7, 121.3, 123.3 (2ϫCH), 124.4, 125.5,
127.6 (2 ϫ CH), 128.1, 128.7 (2 ϫ CH), 129.1 (2 ϫ CH), 133.1,
136.4, 136.8, 137.9, 159.6, 166.8, 168.2 ppm. C27H26N2O3 (426.51):
calcd. C 76.03, H 6.14, N 6.57; found C 76.21, H 6.36, N 6.11.
[α]2D0 = +51 (c = 0.65, CHCl3, for 66%ee). The ee was measured by
HPLC with an AD CSP at 25 °C with (70:30) n-hexane/EtOH
(0.5 mL/min), λ = 213 nm, tR(major) = 61.5 min and tR(minor) =
70.9 min.
[5]
[6]
6-Benzyloxy-5-methoxy-3-(2-oxo-2-pyrrolidin-1-ylethyl)-2-phenyl-
2,3-dihydroisoindol-1-one (27n): Yield 80% (29 mg), m.p. 207–
208 °C. R (100% EtOAc) 0.40. IR: ν = 2899, 1691, 1627, 1496,
˜
f
1448, 1379, 1307, 1271, 1128, 981, 866, 773, 700 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 1.75–1.84 (m, 4 H, 2ϫCH2), 2.33 (dd, J
= 15.6, 8.9 Hz, 1 H, CH2CO), 2.86 (dd, J = 15.6, 4.3 Hz, 1 H,
CH2CO), 3.08–3.12 (m, 2 H, NCH2), 3.37–3.50 (m, 2 H, NCH2),
3.94 (s, 3 H, OCH3), 5.22 (s, 2 H, OCH2Ph), 5.74 (dd, J = 8.9,
4.3 Hz, 1 H, NCH), 7.14–7.48 (m, 10 H, Harom), 7.61–7.64 (m, 2
H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.3, 25.9, 38.9,
45.8, 46.7, 56.4, 57.3, 71.0, 105.9, 107.5, 123.0 (2ϫCH), 123.9,
125.1, 127.4 (2ϫCH), 128.1, 128.6 (2ϫCH), 129.1 (2ϫCH),
20
136.5, 137.1, 139.6, 149.3, 153.8, 167.0, 168.4 ppm. [α] = +63 (c
D
= 0.70, CHCl3, for 86%ee). The ee was measured by HPLC with
an AD CSP at 25 °C with (70:30) n-hexane/EtOH (0.1 mL/min), λ
= 205 nm, tR(minor) = 347.0 min and tR(major) = 365.0 min.
Acknowledgments
The French Ministère de la Recherche et des Nouvelles Technol-
ogies is gratefully acknowledged for a PhD fellowship (R. S.). Sup-
port from the Centre National de la Recherche Scientifique
(CNRS) and Université de Lille is warmly acknowledged. F. A.-N.
and C. M. thank the French National Research Agency (ANR)
for grant project ANR-09-BLAN-0032-02. Funding from Région
Nord-Pas de Calais within “Projet Prim: Etat-Région” and “Fonds
Européen de Développement Régional (FEDER)” are also greatly
appreciated. Mr Vincent Rysak and Mr. William Van Den Berghe
are thanked for their help with the experiments. Dr. Nadège Schi-
fano-Faux and Prof. Jean-Francois Goossens (UDSL, EA 4481)
are thanked for their help with some HPLC analyses. Ms Céline
Delabre (UCCS) is thanked for GC–MS analyses.
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www.eurjoc.org
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/KAP1
Date: 05-02-15 12:06:16
Pages: 11
E. Deniau, C. Michon et al.
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Received: December 4, 2014
Published Online: ᭿
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43573
/KAP1
Date: 05-02-15 12:06:16
Pages: 11
Intramolecular aza-Michael Reactions
Organocatalysis
S. Lebrun, R. Sallio, M. Dubois,
F. Agbossou-Niedercorn, E. Deniau,*
C. Michon* ..................................... 1–11
Chiral Phase-Transfer-Catalyzed Intramo-
lecular aza-Michael Reactions for the
Asymmetric Synthesis of Isoindolinones
Asymmetric intramolecular aza-Michael
reactions with cinchoninium phase-transfer
organocatalysts are used for the synthesis
of optically active isoindolinones. The re-
sulting compounds are useful intermediates
for the synthesis and development of
benzodiazepine-receptor agonists.
Keywords: Organocatalysis / Asymmetric
catalysis / Phase-transfer catalysis / Aza-
Michael additions / Nitrogen
heterocycles
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11