Synthetic route to rare isoindolones derivatives

Article abstract of DOI:10.1002/ejoc.201403649

The isoindolone scaffold is present in many biologically active compounds. Here, we have developed a shorter and more efficient synthesis of tetrahydropyrido[2,1-a]isoindolone. The key step of this approach is a cyclization to form the γ-lactam ring under

Full text of DOI:10.1002/ejoc.201403649

FULL PAPER
DOI: 10.1002/ejoc.201403649
Synthetic Route to Rare Isoindolones Derivatives
Killian Oukoloff,[a] Frédéric Buron,[b] Sylvain Routier,[b] Ludovic Jean,*[a] and
Pierre-Yves Renard*[a]
Keywords: Synthetic methods / C–C coupling / Cyclization / Metalation / Nitrogen heterocycles / Tin
The isoindolone scaffold is present in many biologically
active compounds. Here, we have developed a shorter and
more efficient synthesis of tetrahydropyrido[2,1-a]isoindol-
one. The key step of this approach is a cyclization to form
namely hexahydroazepino[2,1-a]isoindolone and hexahydro-
azocino[2,1-a]isoindolone, have been prepared in only three
steps in 39, 25, and 19% overall yields, respectively. This
novel strategy offers a shorter alternative to existing pro-
the γ-lactam ring under Shibasaki’s conditions. Thus, tetra- cedures.
hydropyrido[2,1-a]isoindolone and superior analogues,
Introduction
Some of the natural alkaloids isolated from Berberis, for
example Lennoxamine and Magallanesine, contain the iso-
indolone skeleton. This scaffold is widely present in biolo-
gically active compounds, including non-nucleoside HIV-1
reverse transcriptase inhibitors,[1] inhibitors of tubulin poly-
merization,[2] kinases inhibitors,[3] antiobesity agents,[4]
TNF-α inhibitors,[5] and urotensin-II receptor antagonists
(Figure 1).[6] The pharmaceutical importance of these com-
pounds has led medicinal chemists to develop many syn-
thetic approaches to prepare these heterocycles.[7]
In 2012, Valmerins were developed as serine and threon-
ine kinase inhibitors, especially for cyclin-dependent protein
kinases and glycogen synthase kinase 3, which are validated
targets for therapies such as leukemia, solid tumors, and
Alzheimer’s disease (Figure 2). The biological activity of
Valmerins has been evaluated both in vitro and in vivo, and
Routier et al. proved the drugability of these Valmerins
through their efficacy on tumor growth inhibition in mice
xenogreph models.[8]
Figure 1. Examples of natural and biologically active compounds
containing the isoindolone ring.
Although the attractiveness of Valmerins is established,
the first described synthetic access to these tetrahydropyr-
ido[2,1-a]isoindolone scaffolds in seven steps limits the up-
scaling and modulation of the tricyclic scaffold. The princi-
pal synthetic approach used to access to tetrahydropyr-
ido[2,1-a]isoindolones is based on the generation of an N-
Figure 2. Structures of tetrahydropyrido[2,1-a]isoindolone 1a and
Valmerins derivatives 2.
[a] Normandie Univ, COBRA, UMR 6014 & FR 3038; UNIV
Rouen; INSA Rouen; CNRS, IRCOF,
acyliminium ion in situ, followed by addition of the appro-
priate nucleophilic reagents.[9] Moreover access to the hexa-
hydro azepino and azocino[2,1-a]isoindolones scaffolds is
rarely described.[7a,10] To circumvent these limitations, we
revisited the existing synthetic access to this scaffold, and
set up a novel alternative strategy. The main advantages of
the new approach include a reduced number of steps and
1 Rue Tesnières, 76821 Mont-Saint-Aignan Cedex, France
E-mail: ludovic.jean@univ-rouen.fr
pierre-yves.renard@univ-rouen.fr
http://ircof.crihan.fr/
[b] Institut de Chimie Organique et Analytique, Université
d’Orléans, UMR CNRS 7311,
rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403649.
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Eur. J. Org. Chem. 2015, 2450–2456

Synthetic Route to Rare Isoindolones Derivatives
increased global yields, and the route provides flexibility for desired vinyl trifluoromethanesulfonate 6a in 58% yield. To
medicinal chemists in terms of chemical access and substi- achieve Csp2–Csp2 bond formation, a range of conditions for
tution patterns.
the intramolecular coupling reaction were tested (Table 1).
We thus propose in this paper to follow an original retro-
synthetic pathway (Scheme 1) that offers, as a key step, an
intramolecular Csp2–Csp2 bond formation from imide 4a. In
this strategy, the acylated enamine intermediate 3a results
from the coupling reaction between a vinyl triflate and an
aryl bromide or from the condensation of the aryl anion,
generated in situ, on the imide. Precursor 4a is prepared
from carboxylic acid 5 and commercially available lactams.
Scheme 1. Retrosynthetic pathway used to access tetrahydropyr-
ido[2,1-a]isoindolone 1a.
Results and Discussion
The first synthetic route we explored was the Pd-medi-
ated cross-coupling reaction between an aromatic bromide
and a vinylic derivative formed from the enolate form of 4a
(triflate or analogue). The formation of 4a (Scheme 2) was
Scheme 2. Synthetic route using an intramolecular coupling reac-
tion.
First, we followed the method described by Le et al.,
achieved by treatment of commercially available 2-bromo- namely a palladium-catalyzed intramolecular coupling re-
3-nitrobenzoic acid (5) with thionyl chloride to give the cor- action between aryl and vinyl halides mediated by in-
responding acyl chloride quantitatively, which was immedi- dium.[11] Under these conditions with a catalytic amount of
ately added to a solution of deprotonated (n-butyllithium, Pd/C or Pd(PPh3)4 and one equivalent of 100 mesh indium,
–78 °C) δ-valerolactam. Such a procedure afforded the de- only starting material or degradation products were ob-
sired imide 4a in 78% yield. Triflation of 4a was achieved tained (Table 1, entry 1). By using only palladium(II) cata-
by using LiHMDS as a base at low temperature and lyst under basic conditions [10 mol-% PdCl2(dppf) with
quenching the oxanion with phenyltriflimide to furnish the K3PO4; dppf = 1,1Ј-bis(diphenylphosphino)ferrocene] un-
Table 1. Conditions used for intramolecular cyclization of 6a.
Entry Conditions
Catalyst system
Yield [%][a]
Solvent
T
t
[°C]
[h]
[b]
1
2
3
4
5
6
7
8
9
10
Pd/C or Pd(PPh3)4 (0.025 equiv.), In (1.0 equiv.), LiCl (1.5 equiv.)
PdCl2(dppf)·CH2Cl2 (0.1 equiv.), K3PO4 (2.0 equiv.)
Pd(OAc)2 (0.1 equiv.), dppp (0.2 equiv.), K3PO4 (2.0 equiv.)
PdCl2 (0.1 equiv.), Davephos (0.2 equiv.), K3PO4 (2.0 equiv.)
PdCl2(dppf)·CH2Cl2 (0.1 equiv.), K3PO4 (2.0 equiv.)
Pd(PPh3)4 (0.1 equiv.), K3PO4 (2.0 equiv.)
Cu powder (10.0 equiv.), Pd2(dba)3 (0.1 equiv.)
Cu powder (10.0 equiv.), PdCl2(dppf)·CH2Cl2 (0.1 equiv.)
Cu powder (10.0 equiv.)
DMF
100
120
120 (300 W)
120
3
2
2
18
16
16
2
2
2
3
–
1,4-dioxane/water (9:1)
1,4-dioxane/water (9:1)
1,4-dioxane/water (9:1)
THF
THF
DMSO
30
[b]
–
–
[c]
reflux
reflux
80
50
50
22
[b]
–
31
[b]
DMSO
DMSO
–
24
40
1. PdCl2(PPh3)2 (0.05 equiv.), PPh3 (0.1 equiv.), B2Pin2 (1.5 equiv.), K2CO3 (2.0 equiv.) 1,4-dioxane
r.t.
2. Pd(OAc)2 (0.1 equiv.), PPh3 (0.2 equiv.), K3PO4 (2.0 equiv.)
Pd(PPh3)4 (0.2 equiv.), LiCl (20.0 equiv.), Me3SnSnMe3 (1.2 equiv.)
water
1,4-dioxane
100
120
1.5
16
11
54
[a] Isolated yield. [b] Degradation. [c] Inseparable mixture of product and starting material.
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der microwave activation, the desired coupling product 7a was observed (e.g., nucleophilic addition of nBuLi on imide
was afforded in 30% isolated yield (entry 2). Other Pd function). At lower temperature, cyclization occurred in
sources (either as Pd0 or PdII) were tested unsuccessfully 34% yield (entry 2). In addition to this method, Moreau et
(entries 3, 4, and 6). Replacement of the 1,4-dioxanne/water al. reported the synthesis of Nuevamine by using tBuLi in-
mixture as solvent by tetrahydrofuran (THF) gave similar stead of nBuLi.[17] Unfortunately, compound 8a was ob-
results (entry 5 vs. 2).
tained in only 15% yield (entry 3) under these conditions.
The disappointing yields prompted us to explore other The use of an excess of tBuLi led only to complete degrada-
conditions. Banwell et al. described the intermolecular for- tion (entry 4).
mation of C–C bonds between aryl halides and vinyl halides
Table 2. Conditions for intramolecular cyclization of 4a.
Entry Conditions
Yield [%][a]
by using an excess of copper(0) and a catalytic amount of
palladium source [e.g., Pd(PPh3)4, PdCl2(dppf) or
Pd2dba3].[12] In our case, these conditions led to the desired
product 7a in only 31% yield (entry 7) with a Pd0 source,
and none with a palladium(II) catalyst (entry 8). It should
be noted that 7a was obtained in similar yield (entry 9)
without the palladium catalyst.
1
2
3
4
nBuLi (1.1 equiv.), THF, –78 °C, 3 h
nBuLi (1.1 equiv.), THF, –100 °C, 3 h
tBuLi (2.2 equiv.), THF –78 °C then r.t., 16 h
tBuLi (4.0 equiv.), THF, –78 °C then r.t., 16 h
20
34
15
[b]
–
[a] Isolated yield. [b] Degradation.
We then envisioned an intramolecular palladium-cata-
lyzed Suzuki–Miyaura coupling reaction. The borylation of
vinyl triflate 6a in situ followed by C–C cross-coupling reac-
tion of the vinyl borane with the aryl bromide gave the
desired product 7a in 40% yield (entry 10).[13] Encouraged
by this increase in yield, we evaluated the tin-mediated
Stille–Kelly reaction. This has been performed by using
hexamethylditin in the presence of a catalytic amount of
Pd(PPh3)4 to give 7a in 54% yield (entry 11).[14]
Based on these results, we evaluated a milder strategy
with which to form the aryl anion. Shibasaki et al. reported
cyclization by using a stannyl aryl anion generated on aryl
halide from Me3SiSnBu3 and fluoride or chloride ion
(Scheme 4).[18]
With the acylenamine in hand, the final step was
achieved by simultaneous Pd0 catalyzed hydrogenation of
alkene and nitro functions in quantitative yield. To summa-
rize, the tetrahydropyrido[2,1-a]isoindolone 1a has been
synthesized in four steps with an overall yield of 24% (in-
stead of seven steps, 28% overall yield).
By following the same synthetic scheme, the hexa-
hydroazepino[2,1-a]isoindolone 1b was obtained in 12%
overall yield. Notably, Stille–Kelly coupling gave 7b in only
33% yield because of steric hindrance. Nevertheless, to our
knowledge, this synthetic route is the first approach that
allows the preparation of hexahydroazepino[2,1-a]isoind-
olones such as 1b in only four steps.
To increase the cyclization yield further, we used a
second strategy involving C–C bond formation by nucleo-
phile addition of in situ generated aryl anion on the imide.
Thus, we investigated the intramolecular reaction involving
lithiated anions on imide 4a. First, the formation of the
corresponding organolithium intermediate via a metal-
halogen exchange was examined (Scheme 3).
Scheme 4. Cyclization by using Shibasaki’s conditions.
Several solvents, temperature, and halogen source were
assayed to optimize this two-step cascade. First, by using
fluoride sources [e.g., cesium fluoride and tetrabutylammo-
nium fluoride (TBAF)] to generate the tributyltin anion
(Table 3, entries 1–3), the desired cyclized compound 8a
was obtained in moderate yield (up to 42%). The use of a
chloride source allowed 8a to be accessed with better yields.
Whereas the use of either tetraethylammonium chloride
(Et4NCl) or cesium fluoride in N,N-dimethylformamide
(DMF) gave similar results (entry 4 vs. entry 1), benzyl tri-
ethyl ammonium chloride (Et3BnNCl) in DMF appeared
to be the best system, and yields under these conditions
increased to 51% (entry 5).
Table 3. Conditions for intramolecular cyclization of 4a.
Entry Conditions[a]
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
CsF (2 equiv.), DMF, 0 °C then room temp., 16 h
CsF (2 equiv.), DMF, 0 °C then 60 °C, 16 h
TBAF (2 equiv.), THF, 0 °C, 2 h
42
17
20
39
51
30
17
13
51
20[c]
Et4N+Cl– (2 equiv.), DMF, 0 °C then room temp., 16 h
Et3BnN+Cl– (2 equiv.), DMF, 0 °C then 60 °C, 16 h
Et3BnN+Cl– (2 equiv.), THF, 0 °C then reflux, 24 h
Et3BnN+Cl– (2.0 equiv.), DMA, 0 °C then 60 °C, 0.5 h
MgOTf2 (2.0 equiv.), DMF, 0 °C then 60 °C, 16 h
LiOTf (2.0 equiv.), DMF, 0 °C then 60 °C, 1 h
LiOTf (3.0 equiv.), DMF, 0 °C then 60 °C, 16 h
Scheme 3. Cyclization by using Parham’s conditions.
Wolf et al. previously used Parham’s conditions to induce
such intramolecular cyclizations of N-acyl-2-bromobenz-
amides.[15] By using nBuLi at low temperature for 2 h
(Table 2, entry 1),[16] the desired product 8a was formed in
[a] Carried out with 2.0 equiv. Me3SiSnBu3. [b] Isolated yield.
20% yield, but concomitant formation of many byproducts [c] Carried out with 3.0 equiv. Me3SiSnBu3.
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Synthetic Route to Rare Isoindolones Derivatives
Finally, Lewis acids were tested in place of halide ions.
Whereas magnesium triflate in DMF gave poor yields of
cyclized product (13%, entry 8), and cooper triflate [Cu-
(OTf)2] proved unsuccessful (result not shown), surpris-
ingly, the use of two equivalents of LiOTf in DMF at 60 °C
furnished 8a in a satisfactory 51% yield (entry 9). The use
of an excess or a stoichiometric amount of reagent did not
improve the reactivity (entry 10).
Experimental Section
General: Column chromatography purifications were performed on
silica gel (40–63 μm) from Macherey–Nagel. Thin-layer chromatog-
raphy (TLC) was carried out on Merck DC Kieselgel 60 F-254
aluminum sheets. Compounds were visualized by either illumina-
tion with a short-wavelength UV lamp (λ = 254 nm) or by staining
with a 3.5% (w/v) phosphomolybdic acid solution in absolute eth-
anol. Anhydrous solvents were purchased from Sigma–Aldrich or
dried by following standard procedures (CH2Cl2: distillation over
P2O5, THF: distillation over Na/benzophenone).
To achieve the sequence, a one-pot, three-step procedure
was used: (1) elimination of the tertiary alcohol upon treat-
ment with TsOH followed by (2) reduction of the resulting
Microanalyses were carried out with a Carlo–Erba 1106. H, 13C,
1
alkene concomitantly with (3) reduction of the nitro group and 19F NMR spectra were recorded with a Bruker DPX 300 spec-
trometer (Bruker, Wissembourg, France). Chemical shifts are ex-
pressed in parts per million (ppm) from CDCl3 (δH = 7.26 ppm, δC
= 77.16 ppm), [D6]DMSO (δH = 2.50 ppm, δC = 39.52 ppm), or
CD3OD (δH = 3.31 ppm, δC = 49.00 ppm). J values are expressed
in Hz. Mass spectra were obtained with a Finnigan LCQ Advan-
tage MAX (ion trap) apparatus equipped with an electrospray
source or with a Shimadu GC–MS-GP 2010 apparatus by using
direct injection and isobutane chemical ionization. Melting points
were measured with a Stuart SMP30 melting-point apparatus.
to give 1a in quantitative yield. By using this alternative
route, 1a was obtained in a global yield of 39% in three
steps. Having the optimized conditions for cyclization in
hand, this strategy was then applied to superior analogues,
which gave improved yields compared with those obtained
through the aforementioned Stille–Kelly strategy. Thus, the
hexahydroazepino[2,1-a]isoindolone 1b and the hexahydro-
azocino[2,1-a]isoindolone 1c were prepared in three steps in
an overall yield of 25 and 19%, respectively (Scheme 5).
Imide Synthesis. General Procedure A: To a solution of thionyl
chloride (32.0 equiv.) was added 2-bromo-3-nitrobenzoic acid
(1.0 equiv.), and the resultant mixture was stirred and heated at
80 °C for 3 h. After cooling to room temperature, the reaction mix-
ture was concentrated. To a solution of lactam (1.1 equiv.) in an-
hydrous THF (0.1 mol/L), n-butyllithium (2.5 m in hexane,
1.05 equiv.) was added at –78 °C. The mixture was stirred for 0.5 h
at –78 °C and a solution of acyl chloride dissolved in anhydrous
THF (1.3 mol/L) was slowly added. The mixture was stirred at
–78 °C for 2.5 h then the reaction was quenched with aq. satd.
NH4Cl. The aqueous layer was extracted with EtOAc and the com-
bined organic layer was washed successively with water and brine,
dried with MgSO4, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel.
Vinyl Triflate Synthesis. General Procedure B: To a solution of
hexamethyldisilazane (1.2 equiv.) in anhydrous THF (1.4 mol/L) at
0 °C was added n-butyllithium (2.5 m in hexane, 1.2 equiv.), and the
resultant mixture was stirred for 0.5 h. After cooling at –78 °C, a
solution of imide (1.0 equiv.) contained in anhydrous THF
(0.4 mol/L) was added slowly and the resultant mixture was stirred
for 0.5 h. N-Phenyltrifluoromethanesulfonimide (1.2 equiv.) con-
tained in anhydrous THF (1.1 mol/L) was added and the mixture
was stirred at –40 °C for 3 h. The reaction was quenched with aq.
satd. NH4Cl and the aqueous layer was extracted with EtOAc. The
combined organic layer was washed successively with water and
brine, dried with MgSO4, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel.
Scheme 5. Second route to isoindolones 1a–c.
Conclusions
In this study, we have developed a shorter synthetic route
to isoindolone derivatives fused to six-, seven-, and eight-
membered rings. This optimization led us to develop two
methods to create such complex tricyclic derivatives in only
three steps. The tetrahydropyrido[2,1-a]isoindolone 1a was
obtained in three steps with an overall yield of 39% (vs.
28% in seven steps as described by Routier et al.).[8] In con-
trast to the other reported strategies, this synthesis allowed
easy access to superior analogues; thus, the hexahydroazep-
Cyclization by Stille–Kelly Coupling. General Procedure C: To a
solution of vinyl triflate (1.0 equiv.) in anhydrous and degassed di-
oxane (0.12 mol/L) in a sealed tube, was added LiCl (2.0 equiv.),
hexamethylditin (1.2 equiv.), and Pd(PPh3)4 (0.2 equiv.). The result-
ant mixture was stirred and heated to reflux for 16 h, then the reac-
tion was quenched with a satd. aq. solution of potassium fluoride.
The aqueous layer was extracted with Et2O and the combined or-
ganic layer was washed successively with water and brine, dried
ino[2,1-a]isoindolone 1b and the hexahydroazocino[2,1-a]- with MgSO4, and concentrated under reduced pressure. The resi-
due was purified by flash chromatography on silica gel.
isoindolone 1c were prepared in 25 and 19% overall yields,
respectively. This work will be fully applied to medicinal
chemistry programs and to the design of kinases inhibitors
and in the preparation of novel Valmerins generations.
Reduction. General Procedure D: To solution of enamide
a
(1 equiv.) in degassed methanol (0.1 mol/L) was added Pd/C
(0.1 equiv., 10 wt.-% loading) and the mixture was stirred under
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L. Jean, P.-Y. Renard et al.
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hydrogen for 2 h. The mixture was filtered through a pad of Celite
and the filtrate was concentrated under reduced pressure.
2 H), 1.92–1.84 (m, 2 H) ppm. 13C NMR (75 MHz, [D6]DMSO,
55 °C): δ = 165.1, 150.6, 139.0, 138.0, 131.1, 129.6, 125.9, 118.0 (q,
J = 319 Hz), 110.1, 110.0, 46.3, 21.8, 21.4 ppm. 19F NMR
(282 MHz, [D6]DMSO, 55 °C): δ = –73.20 ppm. MS (CI): m/z =
460, 458, 230, 228. C13H10BrF3N2O6S (459.19): calcd. C 34.00, H
2.20, N 6.10, S 6.98; found C 34.02, H 2.22, N 5.98, S 7.05.
Cyclization by Stannyl Anion. General Procedure E: To a solution
of imide (1.0 equiv.) in anhydrous DMF (0.16 mol/L) was added
benzyltriethylammonium chloride (2.0 equiv.) and the solution was
cooled to 0 °C. The solution was vigorously stirred, tributyl(tri-
methylsilyl)stannane was slowly added, then the mixture was
heated at 70 °C for 16 h. After cooling to room temperature, the
reaction was quenched with a satd. aq. solution of potassium fluor-
ide. The aqueous layer was extracted with EtOAc and the combined
organic layer was washed successively with water then brine, dried
with MgSO4, and concentrated under reduced pressure. The resi-
due was purified by flash chromatography on silica gel.
1-(2-Bromo-3-nitrobenzoyl)-4,5,6,7-tetrahydro-1H-azepin-2-yl Tri-
fluoromethanesulfonate (6b): General procedure B was followed by
using imide 4b (300 mg). Purification by flash chromatography (cy-
clohexane/EtOAc, 7:3 v/v) gave 6b (208 mg, 50%) as a brown oil.
1H NMR (300 MHz, [D6]DMSO): δ = 7.95 (dd, J = 7.8, 1.8 Hz, 1
H), 7.63 (t, J = 7.8 Hz, 1 H), 7.57 (dd, J = 7.7, 1.8 Hz, 1 H), 5.84
(s, 1 H), 4.05 (s, 2 H), 2.70 (s, 2 H), 1.74 (s, 4 H) ppm. 13C NMR
(75 MHz, [D6]DMSO, 328 K): δ = 176.2, 167.3, 150.0, 143.3, 129.4,
129.3, 128.8, 124.0, 120.0 (q, J = 275 Hz), 108.7, 42.7, 27.5, 22.9,
Elimination and Reduction. General Procedure F: To a solution of
cyclized compound (1 equiv.), in anhydrous and degassed CH2Cl2
(0.2 mol/L) was added p-toluenesulfonic acid (0.1 equiv.) and Pd/C
(0.1 equiv., 10 wt.-%) and the mixture was stirred under hydrogen
(1 atm) overnight. The mixture was degassed, filtered through Ce-
lite, and the filtrate was washed with a satd. aq. solution of
22.8 ppm. 19F NMR (282 MHz, [D6]DMSO, 328 K):
δ =
–77.56 ppm. MS (CI): m/z = 474, 472, 326, 324, 230, 228, 184, 182.
C14H13F3N2O6S (394.32): calcd. C 35.53, H 2.56, N 5.92, S 6.78;
found C 35.74, H 2.99, N 5.58, S 6.31.
NaHCO3. The organic layer was dried with MgSO4 and concen- 10-Nitro-3,4-dihydropyrido[2,1-a]isoindol-6(2H)-one (7a): General
trated under reduced pressure without further purification.
procedure C was followed by using vinyl triflate 6a (100 mg). Purifi-
cation by flash chromatography (cyclohexane/EtOAc, 4:1 v/v) gave
7a (27 mg, 54%) as a pale-yellow solid; m.p. 79–80 °C. 1H NMR
(300 MHz, CD3OD): δ = 8.21 (dd, J = 8.1, 1.0 Hz, 1 H), 8.08 (dd,
J = 7.6, 1.0 Hz, 1 H), 7.70 (t, J = 7.6 Hz, 1 H), 6.67 (t, J = 4.8 Hz,
1 H), 3.88–3.84 (m, 1 H), 2.54 (dd, J = 11.0, 6.1 Hz, 1 H), 2.05–
1.97 (m, 1 H) ppm. 13C NMR (75 MHz, CD3OD): δ = 164.8, 145.4,
133.7, 132.2, 130.8, 129.1, 128.8, 127.6, 118.5, 40.0, 24.3, 21.6 ppm.
MS (CI): m/z = 230.
1-(2-Bromo-3-nitrobenzoyl)piperidin-2-one (4a): General procedure
A was followed by using 2-bromo-3-nitrobenzoic acid (5; 2.15 g)
and 2-piperidone (0.89 g). Purification by flash chromatography
(cyclohexane/EtOAc, 7:3 v/v) gave 4a (2.09 g, 78%) as a pale-yellow
solid; m.p. 103–104 °C. 1H NMR (300 MHz, CDCl3): δ = 7.77 (dd,
J = 8.0, 1.7 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 1 H), 7.39 (dd, J = 7.8,
1.7 Hz, 1 H), 3.93 (t, J = 6.5 Hz, 2 H), 2.54 (t, J = 6.5 Hz, 2 H),
2.00–1.88 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.3,
169.0, 150.1, 143.7, 130.3, 128.5, 125.1, 110.0, 44.9, 34.1, 22.3,
10-Nitro-7,8,9,10-tetrahydro-5H-azepino[2,1-a]isoindol-5-one (7b):
20.5 ppm. MS (CI): m/z = 327, 329. C12H11BrN2O4 (327.13): calcd. General procedure C was followed by using vinyl triflate 6b
C 44.06, H 3.39, N 8.56; found C 43.99, H 3.43, N 8.48.
(148 mg). Purification by flash chromatography (cyclohexane/
EtOAc, 4:1 v/v) gave 7b (25 mg, 33%) as a pale-yellow solid; m.p.
97–98 °C. 1H NMR (300 MHz, CDCl3): δ = 8.07 (dd, J = 7.8,
1.0 Hz, 1 H), 7.91 (dd, J = 8.0, 1.0 Hz, 1 H), 7.55 (t, J = 7.8 Hz, 1
H), 6.35 (t, J = 6.1 Hz, 1 H), 4.05–4.02 (m, 2 H), 2.58 (dd, J =
12.0, 6.0 Hz, 2 H), 1.99–1.92 (m, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 165.1, 144.5, 134.5, 132.2, 128.8, 127.8, 127.6, 127.3,
117.9, 42.6, 26.9, 26.6, 26.4 ppm. MS (ESI+): m/z = 245 [M +
H]+. C13H12N2O3 (244.25): calcd. C 63.93, H 4.95, N 11.47; found
C 63.72, H 5.12, N 11.03.
1-(2-Bromo-3-nitrobenzoyl)azepan-2-one (4b): General procedure A
was followed by using 2-bromo-3-nitrobenzoic acid (5; 800 mg) and
caprolactam (377 mg). Purification by flash chromatography (cy-
clohexane/EtOAc, 7:3 v/v) gave 4b (769 mg, 75%) as a pale-yellow
solid; m.p. 145–146 °C. 1H NMR (300 MHz, CDCl3): δ = 7.78 (dd,
J = 8.0, 1.6 Hz, 1 H), 7.49 (t, J = 8.0 Hz, 1 H), 7.34 (dd, J = 7.7,
1.6 Hz, 1 H), 4.11–4.08 (m, 2 H), 2.71–2.67 (m, 2 H), 1.85–1.84 (m,
6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 176.5, 168.2, 150.1,
144.0, 129.8, 128.4, 124.9, 110.0, 43.8, 39.0, 29.4, 28.3, 23.7 ppm.
C13H14N2O4 (262.26): calcd. C 45.77, H 3.84, N 8.21; found C 10-Amino-1,2,3,4-tetrahydropyrido[2,1-a]isoindol-6(10bH)-one (1a):
45.58, H 3.96, N 7.86.
General procedure D was followed by using 7a (103 mg) to give 1a
(90 mg, 99%). NMR spectra are in accordance with those reported
previously.[8]
1-(2-Bromo-3-nitrobenzoyl)azocan-2-one (4c): General procedure A
was followed by using 2-bromo-3-nitrobenzoic acid (5; 2 g) and 1-
aza-2-cyclooctanone (1.1 g). Purification by flash chromatography
(cyclohexane/EtOAc, 7:3 v/v) gave 4c (1.78 g, 66%) as a pale-yellow
10-Amino-7,8,9,10,11,11a-hexahydro-5H-azepino[2,1-a]isoindol-5-
one (1b): General procedure D was followed by using 7b (25 mg)
solid; m.p. 108–109 °C. 1H NMR (300 MHz, CDCl3): δ = 7.77 (dd, to give 1b (22 mg, 99%) as a pale-yellow solid; m.p. 163–164 °C.
J = 8.0, 1.6 Hz, 1 H), 7.47 (t, J = 8.0 Hz, 1 H), 7.33 (dd, J = 7.7,
1H NMR (300 MHz, CDCl3): δ = 7.29–7.22 (m, 2 H), 6.79 (dd, J
= 7.0, 1.7 Hz, 1 H), 4.53 (dd, J = 6.3, 4.5 Hz, 1 H), 4.00 (ddd, J =
1.6 Hz, 1 H), 4.11–4.08 (m, H), 2.71–2.67 (m, H), 1.85–1.84 (m, 4
H), 1.62 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 177.3, 14.0, 7.8, 3.3 Hz, 1 H), 3.71 (s, 2 H), 3.36 (ddd, J = 14.0, 8.5,
168.6, 150.2, 144.1, 129.5, 128.4, 124.8, 110.4, 43.5, 36.1, 29.3, 29.1,
2.7 Hz, 1 H), 2.38–2.28 (m, 1 H), 2.00–1.92 (m, 1 H), 1.85–1.66 (m,
26.1, 24.1 ppm. C14H15BrN2O4 (355.19): calcd. C 47.34, H 4.26, N 4 H), 1.54–1.43 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
7.89; found C 47.26, H 4.30, N 7.72.
169.1, 141.0, 133.8, 130.2, 129.3, 118.2, 113.5, 60.0, 43.6, 31.0, 29.6,
26.6, 25.7 ppm. MS (ESI+): m/z = 217 [M + H]+. C13H16N2O
(216.28): calcd. C 72.19, H 7.46, N 12.95; found C 71.91, H 7.37,
N 12.91.
1-(2-Bromo-3-nitrobenzoyl)-1,4,5,6-tetrahydropyridin-2-yl Trifluoro-
methanesulfonate (6a): General procedure B was followed by using
imide 4a (543 mg). Purification by flash chromatography (cyclohex-
ane/EtOAc, 7:3) gave 6a (442 mg, 58%) as a pale-yellow solid; m.p.
10b-Hydroxy-10-nitro-1,2,3,4-tetrahydropyrido[2,1-a]isoindol-
6(10bH)-one (8a): General procedure E was followed by using imide
4a (50 mg). Purification by flash chromatography (petroleum ether/
1
95–96 °C. H NMR (300 MHz, [D6]DMSO, 55 °C): δ = 8.09 (dd,
J = 7.9, 1.6 Hz, 1 H), 7.76 (t, J = 7.9 Hz, 1 H), 7.68 (dd, J = 7.7,
1.7 Hz, 1 H), 5.70 (t, J = 3.9 Hz, 1 H), 3.59 (s, 2 H), 2.38–2.32 (m, EtOAc, 7:3 v/v) gave 8a (19 mg, 51%) as a pale-yellow solid; m.p.
2454
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 2450–2456

Synthetic Route to Rare Isoindolones Derivatives
159–160 °C. 1H NMR (300 MHz, CDCl3): δ = 8.32 (dd, J = 8.2, (ANR) (project MultiClick, grant number ANR-12-BS07-0008-01)
1.0 Hz, 1 H), 8.19 (dd, J = 7.5, 1.0 Hz, 1 H), 7.71 (dd, J = 8.2,
for financial support. This work was partially supported by INSA
7.5 Hz, 1 H), 4.37–4.31 (m, 1 H), 4.06 (s, 1 H), 3.26 (td, J = 13.1, Rouen, Rouen University, Centre National de la Recherche Sci-
3.4 Hz, 1 H), 2.71 (dt, J = 5.3, 2.4 Hz, 1 H), 2.22–2.08 (m, 1 H),
1.86–1.81 (m, 2 H), 1.42 (ddd, J = 13.5, 8.5, 3.9 Hz, 2 H) ppm. 13
entifique (CNRS) and Region Haute-Normandie (CRUNCh net-
work). The authors are also grateful to P. Martel (University of
C
NMR (75 MHz, CDCl3): δ = 162.2, 143.9, 141.7, 135.0, 131.0, Rouen) for low-resolution mass analyses, A. Marcual and M. Hu-
130.1, 127.7, 87.5, 37.1, 34.7, 24.9, 19.3 ppm. MS (ESI+): m/z =
249 [M + H]+. C12H12N2O4 (248.24): calcd. C 58.06, H 4.87, N
11.29; found C 58.18, H 4.97, N 11.26.
bert-Roux (CNRS) for high-resolution mass analyses, and E. Petit
(INSA de Rouen) for elemental analyses.
11a-Hydroxy-1-nitro-7,8,9,10,11,11a-hexahydro-5H-azepino[2,1-a]-
isoindol-5-one (8b): General procedure E was followed by using
imide 4b (500 mg). Purification by flash chromatography (petro-
leum ether/EtOAc, 7:3 v/v) gave 8b (175 mg, 45%) as a pale-yellow
solid; m.p. 127–128 °C. 1H NMR (300 MHz, CDCl3): δ = 8.31 (dd,
J = 8.2, 1.0 Hz, 1 H), 8.13 (dd, J = 7.4, 1.0 Hz, 1 H), 7.70 (t, J =
9.0 Hz, 1 H), 4.41 (s, 1 H), 4.11–4.03 (m, 1 H), 3.35 (ddd, J = 14.3,
10.3, 3.9 Hz, 1 H), 2.65 (dd, J = 15.2, 7.8 Hz, 1 H), 2.25 (ddd, J =
15.2, 10.5, 1.3 Hz, 1 H), 1.88–1.76 (m, 3 H), 1.71–1.66 (m, 1 H),
1.56–1.48 (m, 1 H), 0.90–0.78 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 164.5, 144.0, 141.3, 135.3, 131.0, 129.4, 128.2, 91.6,
39.6, 38.7, 29.5, 26.3, 22.8 ppm. MS (ESI–): m/z = 261 [M – H]–.
HRMS (ESI–): m/z calcd. for C13H14N2O4 261.0881; found
261.0878.
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12a-Hydroxy-1-nitro-8,9,10,11,12,12a-hexahydroazocino[2,1-a]iso-
indol-5(7H)-one (8c): General procedure E was followed by using
imide 4c (500 mg). Purification by flash chromatography (petro-
leum ether/EtOAc, 7:3 v/v) gave 8c (170 mg, 44%) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ = 8.27 (dd, J = 8.2, 1.0 Hz, 1 H),
8.16 (dd, J = 7.4, 1.0 Hz, 1 H), 7.71 (t, J = 12.0 Hz, 1 H), 4.27 (s,
1 H), 4.01 (dt, J = 14.8, 4.9 Hz, 1 H), 3.42 (ddd, J = 14.8, 10.9,
4.0 Hz, 1 H), 2.48–2.41 (m, 1 H), 2.19–2.12 (m, 1 H), 1.73–1.61 (m,
2 H), 1.56–1.45 (m, 2 H), 1.25–1.14 (m, 2 H), 0.96–0.81 (m, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.8, 144.3, 140.3,
135.5, 131.1, 129.6, 128.0, 91.1, 39.1, 31.8, 26.4, 25.8, 23.7,
22.3 ppm. HRMS (ESI–): m/z calcd. for C14H16N2O4 275.1037;
found 275.1032.
[5]
[6]
[7]
[8]
10-Amino-1,2,3,4-tetrahydropyrido[2,1-a]isoindol-6(10bH)-one (1a):
General procedure F was followed by using 8a (30 mg) to give 1a
(24 mg, 99 %). NMR spectra are in accordance with those de-
scribed previously.[8]
[9]
10-Amino-7,8,9,10,11,11a-hexahydro-5H-azepino[2,1-a]isoindol-5-
one (1b): General procedure F was followed by using 8b (100 mg) to
give 1b (62 mg; 75%). NMR spectra are in accordance with those
reported above.
1-Amino-8,9,10,11,12,12a-hexahydroazocino[2,1-a]isoindol-5(7H)-
one (1c): General procedure F was followed by using 8c (170 mg)
to give 1c (92 mg, 65%) as a pale-yellow solid; m.p. 172–173 °C.
1H NMR (300 MHz, CDCl3): δ = 7.31–7.22 (m, 2 H), 6.79 (dd, J
= 7.3, 1.3 Hz, 1 H), 4.50 (t, J = 4.2 Hz, 1 H), 4.19 (dt, J = 14.2,
5.4 Hz, 1 H), 3.72 (s, 2 H), 3.16 (ddd, J = 14.2, 9.8, 4.0 Hz, 1 H),
2.31–2.26 (m, 1 H), 2.19–2.13 (m, 2 H), 1.76–1.50 (m, 2 H), 1.45–
1.32 (m, 3 H), 1.17–1.13 (m, 1 H), 0.92–0.85 (m, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 169.0, 141.2, 134.3, 129.3, 129.2,
118.3, 113.8, 60.5, 42.1, 27.3, 27.1, 25.6, 24.0, 22.1 ppm. HRMS
(ESI+): m/z calcd. for C14H18N2O [M + H]+ 231.1492; found
231.1492.
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Acknowledgments
[15]
Labex SynOrg (ANR-11-LABX-0029) is acknowledged for a PhD
Fellowship to K. O. and the Agence Nationale de la Recherche
Eur. J. Org. Chem. 2015, 2450–2456
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FULL PAPER
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Received: December 18, 2014
Published Online: February 23, 2015
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Eur. J. Org. Chem. 2015, 2450–2456