Enantioenriched isoindolinones from chiral phase-transfer-catalyzed intramolecular aza-michael reactions

Article abstract of DOI:10.1055/s-0033-1339487

Optically active isoindolinones are synthesized by asymmetric intramolecular aza-Michael reactions using cinchoninium phase-transfer organocatalysts. The resulting compounds are useful intermediates for the synthesis and development of benzodiazepine-rece

Full text of DOI:10.1055/s-0033-1339487

LETTER
▌1785
letter
Enantioenriched Isoindolinones from Chiral Phase-Transfer-Catalyzed Intra-
molecular Aza-Michael Reactions
Isoindolinones from Organocatalyzed Aza-Michael Reactions
Romain Sallio,a,b Stéphane Lebrun,a,b Nadège Schifano-Faux,a,c Jean-François Goossens,a,c Francine Agbossou-
Niedercorn,a,d,e Eric Deniau,*a,b Christophe Michon*a,d,e
a
Université Lille Nord de France, 59000 Lille, France
b
Université Lille 1, Laboratoire de Chimie Organique Physique, EA CMF 4478, Bâtiment C3(2), 59655 Villeneuve d’Ascq Cedex, France
Fax +33(3)20436585; E-mail: Eric.Deniau@univ-lille1.fr
c
UDSL, EA 4481, 59000 Lille, France
d
CNRS, UCCS UMR 8181, 59655 Villeneuve d’Ascq, France
e
ENSCL, CCM-CCCF, Bât C7, CS 90108, 59652, Villeneuve d’Ascq, France
E-mail: Christophe.Michon@ensc-lille.fr
Received: 22.05.2013; Accepted after revision: 01.07.2013
tion of these highly functionalized 3-substituted isoindoli-
Abstract: Optically active isoindolinones are synthesized by asym-
nones constitutes an area of current interest, and
metric intramolecular aza-Michael reactions using cinchoninium
alternative methods are currently the object of intense
phase-transfer organocatalysts. The resulting compounds are useful
synthetic endeavor. Organic chemists have at their dispos-
al a variety of synthetic strategies for the racemic synthe-
sis of 3-(N,N-disubstituted)acetamido isoindolinones
mainly based upon metal-catalyzed tandem reactions.4 To
the best of our knowledge, in these bicyclic lactams, con-
trol of the stereogenic center α to the nitrogen has only
been achieved through catalytic asymmetric reduction of
a 3-alkoxycarbonylmethylene isoindolinone followed by
a two-step ester–amide interconversion sequence.5 The
aza-Michael reaction involving the reaction of activated
alkenes and amines was mainly applied in organic synthe-
sis through the use of various metal or organic catalysts;6
phase-transfer catalysis has been less studied for aza-
Michael reactions.7,8 Herein, we wish to disclose an alter-
native, efficient and new synthetic route to enantioen-
riched 3-(N,N-disubstituted)acetamido isoindolinones.
intermediates for the synthesis and development of benzodiazepine-
receptor agonists.
Key words: organocatalysis, phase-transfer catalysis, aza-Michael,
heterocycles, isoindolinone
2,3-Dihydro-1H-isoindol-1-ones (isoindolinones), also
called phthalimidines, represent a class of bicyclic lac-
tams that have attracted much attention from the scientific
community due to the broad scope of their biological ac-
tivities.1
O
O
N
N
N
O
O
N
Considering that most isoindolinones have been synthe-
sized directly from ortho-halogenated benzamides
through fast palladium-catalyzed tandem Heck and aza-
Michael reactions,4a–j we concluded that the stereoselec-
tivity of such a synthetic pathway would be difficult to
control and the isolation of key reaction intermediates
would be challenging.4h,i Hence, we envisioned a retro-
synthetic strategy depicted in Scheme 1. Isoindolinones 3
may be available from an asymmetric intramolecular aza-
Michael reaction of benzamides 4 by the construction of
the lactam ring system and the concomitant control of the
stereogenic center at C3. The stereoselectivity of the intra-
molecular aza-Michael reaction should be controlled by
the catalyst chirality.
Me
N
N
N
Cl
O
O
JM-1232 (1)
DN-2327 (2)
Figure 1 Examples of synthetic pharmacalogically active chiral 3-
(N,N-disubstituted)acetamido isoidolinones
In particular, enantiopure compounds bearing a polysub-
stituted acetamido group at C-3 (Figure 1) have been ex-
tensively studied and play an important role as key targets
for the pharmaceutical industry. Indeed, highly function-
alized models, such as JM-1232 (1)2 and DN-2327 (pazi-
naclone, 2)3 have been reported as benzodiazepine-
receptor agonists for the treatment of anxiety. From these
studies, the importance of the absolute configuration of
the stereocenter on the pharmacological activity became
clear.2c Consequently, the development of short, versatile
and efficient procedures for the stereocontrolled prepara-
The required benzamides 4 should be easily obtained from
the corresponding unsaturated benzoic acids 5 by cou-
pling with an array of secondary amines. The acid 5
should, in turn, be readily prepared through a two-step se-
quence involving a cross-coupling Heck type reaction be-
tween 2-bromoester 7 and acrylamides 8 followed by
deprotection of the tert-butyl esters 6. The new synthetic
route required the preliminary elaboration of the unsatu-
SYNLETT 2013, 24, 1785–1790
Advanced online publication: 01.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339487; Art ID: ST-2013-B0477-L
© Georg Thieme Verlag Stuttgart · New York

1786
R. Sallio et al.
LETTER
O
directly to the corresponding cyclized products 3 when
acrylamide fragments were replaced by conjugated esters.
O
O
R3
OH
O
N
H
N
R3
The asymmetric intramolecular aza-Michael reactions of
substrates 4a–d was studied by screening various phase-
transfer catalysts (Scheme 3) and reaction conditions (Ta-
ble 1). Because some aza-Michael reactions have been
shown to proceed without the use of any catalyst or addi-
tional reagent,6e,9 we first performed a number of control
experiments. Conducting the reaction with reagent 4a led
to product 3a by using a base such as Cs2CO3, in toluene
(entry 1). Using the same reaction conditions, Maruoka
catalyst (S)-11 and cinchoninium salt 13a were shown to
afford 3a in high conversions with 20 and 21% enantio-
meric excess (ee), respectively (entries 2 and 5), whereas
poor asymmetric induction was achieved by the use of
cinchonidinium salt 12a or 12b (entries 3 and 4). The use
of cinchoninium salt 13a in combination with other bases
(entries 6–8) or solvents (entries 9 and 10) did not im-
prove the initially obtained ee value (entry 5). The bro-
mide couteranion of 13a was shown to be preferred to the
chloride of 13b (entries 5 and 11); other anions like iodide
and tetrafluoroborate were tried by ion exchange in situ
but no improvement in the ee value arose from these at-
tempts (entries 12 and 13). Finally, the use of catalyst 13a
at 0 °C resulted in complete loss of enantiomeric excess in
the product 3a (entry 14).
R1
R1
R1
N
N
R2
R2
N
R2
3a–d
4a–d
5a–c
O
O
O
O
R1
Ot-Bu
Ot-Bu
R1
N
R2
+
Br
O
N
6a–c
7
8a–c
R2
O
Scheme 1 Retrosynthetic analysis of chiral 3-substituted isoindoli-
nones
rated tert-butyl benzoic acid esters 6a–c, which were
readily prepared through a palladium-catalyzed Heck
cross-coupling between aryl bromide 7 and various acryl-
amides 8a–c (Scheme 2).
Removal of the tert-butyl protecting group was then
achieved by treatment with trifluoroacetic acid to furnish
benzoic acids 5a–c, which were then engaged in the next
step without further purification. Coupling of these highly
conjugated carboxylic acids with aniline 9 and 2-amino-
pyridine 10 finally delivered the required parent amides
4a–d. It was worth noting that this coupling reaction led
The effect of substitution of the benzyl fragment of cin-
choninium 13a on the reaction was then studied. Whereas
an ortho-fluoro substituent led to loss of asymmetric in-
duction (entry 15), a para-positioned tert-butyl fragment
O
Y
N
O
2
( )n
Ot-Bu
8a–c, Et3N
O
Ot-Bu
Y
Pd(OAc)2 (5 mol%)
dppf (10 mol%)
DMSO, Δ, 12 h
Br
N
O
( )n
6a 72%
6b 81%
6c 69%
7
O
O
XNH2 9-10
X
N
DCC, DMAP
TFA
N
H
OH
O
CH2Cl2
r.t., 12 h
CH2Cl2
r.t., 3 h
Y
Y
N
( )n
( )n
O
5a–c
4a–d
O
O
O
X
Ph
Ph
N
H
N
H
N
H
O
O
O
N
N
N
O
O
O
4a X = Ph, n = 0,
Y = CH2, 67%
4d X = Ph, n = 1,
Y = C(OC2H4O),70%
4c X = Ph, n = 1,
Y = O, 65%
4b X = 2-pyridyl, n = 0,
Y = CH2, 73%
Scheme 2 Synthesis of 3-substituted isoindolinone precursors
Synlett 2013, 24, 1785–1790
© Georg Thieme Verlag Stuttgart · New York

LETTER
Isoindolinones from Organocatalyzed Aza-Michael Reactions
1787
12a X = Br, Ar = Ph
12b X = Cl, Ar = 9-anthracenyl
Br–
Q =
OH
H
N
N
X–
N
Ar
H
F
OH
OR
N
F
F
Q
Ar
Q
N
X–
14a Ar = o-C6H4
14b Ar = m-C6H4
14c Ar = p-C6H4
H
N
Ar
13a X = Br, Ar = Ph, R = H
13b X = Cl, Ar = Ph, R = H
Br–
N
13c X = Cl, Ar = o-FC6H4, R = H
13d X = Br, Ar = p-(t-Bu)C6H4, R = H
13e X = Cl, Ar = 9-anthracenyl, R = H
13f X = I, Ar = Ph, R = Me
Q
F
F
15
13g X = Br, Ar = Ph, R = allyl
(S)-11
Q
Q
F
Scheme 3 Phase-transfer catalysts applied to the intramolecular aza-Michael reactions of reagents 4a–d
had no effect on the selectivity of the reaction (entry 16). (entry 22). Encouraged by this result, we prepared trimer-
The change from a benzyl to an anthracenyl group result- ic cinchoninium catalyst 15 and allowed it to react with
ed in complete loss of enantioselection (entry 17). Disap- 4a. We were glad to obtain isoindolinone 3a in 95% con-
pointing results were also obtained from the version (78% isolated yield) and 76% ee (entry 24).
functionalization of the alcohol fragment from cinchonin- Whereas the use of K2CO3 did not allow any reaction (en-
ium 13a (entries 18–20). Whereas an allyl function did not try 25), changing the temperature (entry 26) or solvent
change the course of the reaction, provided Cs2CO3 was (entry 27) led to a decrease of 3a enantioselectivity using
used as a base, a methyl substituent led to complete loss catalyst 15. Reagent 4b, bearing a 2-pyridyl substituent,
of asymmetric induction. Because we were unable to im- led to product 3b in 72% yield but no enantioselectivity
prove catalyst 13a by scaffold modification, we decided was observed (entry 28). Asymmetric aza-Michael reac-
to investigate oligomeric cinchoninium salts7b,10 based on tions of benzamide substrates 4c–d worked well using cat-
13a. Whereas, dimeric catalysts 14a and 14c afforded 3a alyst 15, although enantioselectivities of 3c–d were lower,
in lower ee than 13a (entries 5, 21 and 23), meta-substitut- with ee values around 60% (entries 29 and 30).
ed cinchoninium salt 14b led to product 3a in a 45% ee
Table 1 Phase-Transfer-Catalyzed Intramolecular Aza-Michael Reaction of 4a–da
O
O
X
4a X = Ph, n = 0, Y = CH2
4b X = 2-pyridyl, n = 0, Y = CH2
4c X = Ph, n = 1, Y = O
catalyst (10 mol%)
N
H
N
X
3a–d
base,
solvent,
conditions
4d X = Ph, n = 1, Y = C(OC2H4O)
Y
N
Y
N
( )n
O
( )n
O
Entry
Reagent
Catalyst
Base (1.3 equiv)
Solvent
Temp (°C)
Yield (%)b
ee (%)c
1
2
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
none
(S)-11
12a
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
r.t.
0
74
77
73
70
75
19
78
80
76
73
0
20
3
3
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
4
12b
13a
8
5d
6
21
–
13a
7
13a
DBU
6
8e
9
13a
KOH 50% aq.
Cs2CO3
Cs2CO3
4
13a
7
10
13a
CH2Cl2
3
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1785–1790

1788
R. Sallio et al.
LETTER
Table 1 Phase-Transfer-Catalyzed Intramolecular Aza-Michael Reaction of 4a–da (continued)
O
O
X
4a X = Ph, n = 0, Y = CH2
4b X = 2-pyridyl, n = 0, Y = CH2
4c X = Ph, n = 1, Y = O
catalyst (10 mol%)
N
H
N
X
3a–d
base,
solvent,
conditions
4d X = Ph, n = 1, Y = C(OC2H4O)
Y
N
Y
N
( )n
O
( )n
O
Entry
Reagent
Catalyst
Base (1.3 equiv)
Solvent
Temp (°C)
Yield (%)b
ee (%)c
11
12e
13f
14
15g,h
16
17
18
19
20g
21
22
23
24
25
26
27
28
29
30
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
13b
13a
13a
13a
13c
13d
13e
13f
13g
13g
14a
14b
14c
15
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOH 50% aq.
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
toluene
toluene
toluene
r.t.
r.t.
r.t.
0
75
78
72
75
74
77
73
80
74
71
79
75
71
78
0
0
18
21
0
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
–5
r.t.
r.t.
r.t.
r.t.
0
20
0
0
21
6
17
45
12
76
–
15
15
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
69
73
72
80
75
45
2
15
15
0
15
59
61
15
a Reaction time: 24 h.
b Isolated yield after purification by flash chromatography.
c Measured by HPLC (Daicel Chiralpak AD CSP; hexane–i-PrOH, 7:3; 20 °C; 0.5 mL/min; 275 nm).
d No reaction after 6 h.
e With 10 mol% NaI.
f With 10 mol% NaBF4.
g The same result was obtained by using toluene–CHCl3 (7:3).
h The same result was obtained by using KOH (50% aq) as base.
In summary, we have developed a new synthetic route to
optically active isoindolinones, which are useful interme-
diates for the synthesis and development of benzodiaze-
pine-receptor agonists.11 To access such isoindolinones,
asymmetric intramolecular aza-Michael reactions proved
to be a valuable synthetic route provided selected oligo-
meric cinchoninium salts were used as phase-transfer cat-
alysts. Further results and improvements related to this
project will be reported in due course.
Acknowledgment
The French ‘Ministère de la Recherche et des Nouvelles Technolo-
gies’ is gratefully acknowledged for a PhD fellowship (R.S.). Dr. F.
Agbossou-Niedercorn and Dr. C. Michon thank the French National
Research Agency for grant project ANR-09-BLAN-0032-02. Sup-
port from CNRS and Université Lille 1 is warmly acknowledged.
Funding from the Région Nord-Pas de Calais with ‘Projet Prim:
Etat-Région’ (mainly for SFC and elemental analysis equipment)
and with ‘Fonds Européen de Développement Régional (FEDER)’
are also greatly appreciated. Ms C. Delabre (UCCS) is thanked for
HPLC and GC-MS analyses. Ms M. Dubois (CMF) is thanked for
Synlett 2013, 24, 1785–1790
© Georg Thieme Verlag Stuttgart · New York

LETTER
Isoindolinones from Organocatalyzed Aza-Michael Reactions
1789
technical assistance and Dr. A. Couture for helpful comments. Dr.
C. Michon dedicates this work to Prof. J. Lacour (University of
Geneva).
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http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1785–1790

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R. Sallio et al.
LETTER
M. B. Synlett 2009, 653. (k) Ku, J.-M.; Jeong, B. S.; Jew, S.
S.; Park, H. G. J. Org. Chem. 2007, 72, 8115. (l) Li, M.;
Zhou, P.; Roth, H. F. Synthesis 2007, 55.
MHz, CDCl3): δ = 168.1 (CO), 166.9 (CO), 145.3 (C), 136.7
(C), 132.3 (CH), 131.7 (C), 129.1 (2 × CH), 128.7 (CH),
125.5 (CH), 124.1 (CH), 123.3 (2 × CH), 123.2 (CH), 57.8
(CH), 46.6 (CH2), 45.8 (CH2), 38.5 (CH2), 25.9 (CH2), 24.3
(CH2). Anal. Calcd for C20H20N2O2: C, 74.98; H, 6.29; N,
8.74. Found: C, 75.20; H, 6.41; N, 8.64.
Compound 4a: Obtained from 6a (2 mmol). Yield: 429 mg
(67%); mp 194 °C; Rf = 0.62 (EtOAc). IR: 2970, 1672, 1647,
1585, 1442, 1327, 754, 690 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 1.78–1.94 (m, 4 H, 2 × CH2), 3.36–3.42 (m, 4
H, 2 × NCH2), 6.53 (d, J = 15.6 Hz, 1 H, =CH), 7.11 (t, J =
7.4 Hz, 1 H, Ar-H), 7.28–7.43 (m, 5 H, Ar-H), 7.53 (d,
J = 6.9 Hz, 1 H, Ar-H), 7.65–7.71 (m, 2 H, Ar-H), 7.76 (d,
J = 15.6 Hz, 1 H, CH=), 8.67 (br s, 1 H, NH). 13C NMR (75
MHz, CDCl3): δ = 167.6 (CO), 164.4 (CO), 138.8 (CH),
138.3 (C), 137.1 (C), 133.2 (C), 129.9 (CH), 129.0 (2 × CH),
128.0 (CH), 124.5 (CH), 122.1 (2 × CH), 120.1 (CH), 46.6
(CH2), 46.0 (CH2), 26.0 (CH2), 24.1 (CH2). Anal. Calcd for
C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C, 75.05; H,
6.20; N, 8.83.
(11) General Procedure: Benzamide 4a (0.078 mmol), base (1.3
equiv) and catalyst (10 mol%) were stirred for 20 h at r.t. in
toluene (1 mL). The resulting reaction was monitored by
TLC until completion. The crude product was purified by
flash chromatography on silica gel (EtOAc–hexane, 40:60)
to afford, after evaporation of solvents, product 3a as a white
solid. The enantiomeric excess of 3a was determined by
HPLC analysis (Daicel Chiralpak AD CSP; hexane–EtOH
(7:3); 20 °C; 0.5 mL/min; 275 nm).
Compound 3a: Mp 185 °C; Rf = 0.40 (EtOAc–hexane,
40:60); [α]D20 +76 (c 0.43, CHCl3, for 76% ee). IR: 1689,
1627, 1446, 1388, 1149, 758, 698 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 1.74–1.83 (m, 4 H, 2 × CH2), 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, 1 H, Ar-H), 7.42–7.63 (m, 4 H, Ar-H), 7.63–7.68 (m,
3 H, Ar-H), 7.92 (d, J = 7.1 Hz, 1 H, Ar-H). 13C NMR (75
Synlett 2013, 24, 1785–1790
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