Aza-heterocyclic frameworks through intramolecular π-system trapping of spiro-N-acyliminiums generated from isoindolinone

Article abstract of DOI:10.1039/d0nj04052e

Spiro-acetoxylactams as key substrates were obtained straightforwardly by the tandem regioselective reduction/O-acylation of spiro-isoindolinone-imides. The latter were produced in large scale in three steps from homophthalic acid. These imides were useful to provide in one step isoindolinones bearing hydroxymethyl-amide functions, tethered at quaternary carbon centre with promising biological issues. Submitted to Br?nsted (TFA neat) and Lewis acid (trimethylsilyltrifluoro-methanesulfonic (TMSOTf) 10 mol%), the spiro-acetoxylactams undergo π-cyclization of spiro-N-acyliminiums to provide diastereoselectively with π-aromatic original pyrrolopyrido- and pyrroloazepino-isoindoles fused or not to aromatic systems. With π-olefins, pyrrolopyridines and pyrrolo-azepines fused to isoindoline or containing amino-acids were isolated. A reaction mechanism producing all these systems is also discussed.

Full text of DOI:10.1039/d0nj04052e

View Article Online
View Journal
NJC
New Journal of Chemistry
Accepted Manuscript
A journal for new directions in chemistry
This article can be cited before page numbers have been issued, to do this please use: S. Chortani, M.
Othman, A. M. Lawson, A. Romdhane, H. Ben Jannet, M. Knorr, L. Brieger, C. Strohman and A. Daïch, New
J. Chem., 2020, DOI: 10.1039/D0NJ04052E.
Volume 42
This is an Accepted Manuscript, which has been through the
Number
6
21 March 2018
Pages 3963-4776
Royal Society of Chemistry peer review process and has been
accepted for publication.
NJC
New Journal of Chemistry
rsc.li/njc
A journal for new directions in chemistry
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 1144-2546
PAPER
Chechia Hu, Tzu-Jen Lin et al.
Yellowish and blue luminescent graphene oxide quantum dots
prepared via a microwave-assisted hydrothermal route using
H2O2 and KMnO4 as oxidizing agents
rsc.li/njc

Please do not adjust margins
Page 1 of 11
New Journal of Chemistry
1
2
3
4
View Article Online
DOI: 10.1039/D0NJ04052E
NJC
5
6
7
8
9
ARTICLE
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Aza-heterocyclic frameworks through intramolecular -system
trapping of spiro-N-acyliminiums generated from isoindolinone
Sarra Chortani,a,b Mohamed Othman,*a Ata Martin Lawson,a Anis Romdhane,b Hichem Ben Jannet,b
Received 00th January 20xx,
Accepted 00th January 20xx
Michael Knorr,c Lukas Brieger,d Carsten Strohmann,d and Adam Daïch*a,†
DOI: 10.1039/x0xx00000x
Spiro-acetoxylactams as key substrates were obtained straightforwardly by the tandem regioselective reduction/O-acylation
of spiro-isoindolinone-imides. The latter were produced in large scale in three steps from homophthalic acid. These imides
were useful to provide in one step isoindolinones bearing hydroxymethyl-amide functions, tethered at quaternary carbon
centre with promising biological issues. Submitted to Brönsted (TFA neat) and Lewis acid (trimethylsilyltrifluoro-
methanesulfonic (TMSOTf) 10 mol%), the spiro-acetoxylactams undergo -cyclization of spiro-N-acyliminiums to provide
diastereoselectively with -aromatic original pyrrolopyrido- and pyrroloazepino-isoindoles fused or not to aromatic systems.
With -olefins, pyrrolopyridines and pyrrolo-azepines fused to isoindoline or containing amino-acids were isolated. A
reaction mechanism producing all these systems is also discussed.
www.rsc.org/
growing interest in these spiro-oxindole systems has been
Introduction
undeniably well justified, spiro-[isoindoline-1,3′-pyrrolidin]-3-
one derivatives bearing spiro-isoindolone ring as
regioisomers, remain less common or even rare.
a
N-Heterocyclic systems are of great importance since they
constitute a high rich molecules source for applications in
numerous sectors of chemical sciences with agricultural,
pharmaceutical and cosmetics uses and so one. Aza-spiro-
compounds1 and especially spiro-[oxindole-3,3’-pyrrolidine]
derivatives belonging to the same affiliation have received great
attention since several decades. Both natural and synthetic
products are concerned because they are well known for their
broad range of biological activities.2 They show for example a
high potential as inhibitors of p53-MDM2 protein-protein
interactions that are pivotal for modulating the tumor
suppressing ability of p53-proteins.3 However, despite the
a.S. Chortani, Dr. M. Othman, Dr. A. M. Lawson, Prof. A. Daïch†
Normandie Univ., UNILEHAVRE, FR 3038 CNRS, URCOM, 76600 Le Havre, France. EA
3221, INC3M CNRS-FR 3038, UFR ST, BP: 1123, 25 rue Philipe Lebon, F-76063 Le Havre
Cedex, France
E-mail: mohamed.othman@univ-lehavre.fr ; E-mail: adam.daich@univ-lehavre.fr ;
ORCID Adam Daïch: orcid.org/0000-0002-6942-0519
https://urcom.niv-lehavre.fr/spip.php?article102
b S. Chortani, Dr. A. Romdhane, Prof. H. Ben Jannet,
Laboratory of Heterocyclic Chemistry, LR11ES39, Faculty of Science of Monastir,
University of Monastir, Avenue of Environment, 5019 Monastir, Tunisia
c
Prof. M. Knorr
Institut UTINAM‒UMR CNRS 6213, Université Bourgogne Franche-Comté, 16
Route de Gray, 25030 Besançon, France
https://www.utinam.cnrs.fr/
d L. Brieger, Prof. C. Strohmann
Anorganische Chemie, Technische Universität Dortmund, Otto-Hahn-Strasse 6,
44227 Dortmund, Germany
http://www.ccb.tu-dortmund.de/fb03/de/Forschung/AC/index.html
Electronic supplementary information (ESI) available. For ESI and crystallographic
data in CIF for CCDC 1848784 and 2022086 (two compounds) or another electronic
format see DOI: 10.1039/x0xx00000x
Scheme 1 Biological active known spiro-[isoindoline-1,3′-pyrrolidin]-3-one derivatives
I-III, precedent reports (i and ii) and the present study (iii).
† Corresponding author
This journal is © The Royal Society of Chemistry 20xx
New J. Chem., 2020, 00, 1-11 | 1
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 2 of 11
ARTICLE
Journal Name
1
2
3
4
5
In this line, the few examples reported so far exhibit and (+/-)-
interesting pharmacological activities as shown in Scheme 1. systems.
Compounds of type bearing a spiro-[isoindoline-1,3
5
(Scheme 1) as new families of aza-hetercyclic
View Article Online
DOI: 10.1039/D0NJ04052E
I
′-
pyrrolidin]-3-one subunit as well as their sulfone analogues II
were first patented to treat diabetes mellitus and associated
conditions.4 It was furthermore demonstrated that they possess
aldose reductase inhibitor (ARI) and antihyperglycemic
properties.5 Other related spiro-derivatives containing oxindole
instead of a pyrrolidinone moiety were also patented in 2019
for their use for the treatment of cancer or diseases of the
immune system.6 From our part, we have broadened very
recently the scope of application of this type of compounds. In
a recent study, a wide screening has revealed that among
twenty heterocycles tested, compound III acts as a very potent
human farnesyltransferase (FTase) inhibitor and constitutes
thus in the same time a new leading drug within this new family
of FTase inhibitors.7
6
7
8
9
Results and discussion
Synthesis & characterisation of spiro-isoindolinone-imides (+/-)-1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The required spiro-isoindolinone-imides of type
synthesized following a simple, fast and general protocol
already reported by us.7,9 From a wide range of commercially
1 were first
available primary amines or synthetically accessible
-bromo-
acetamides 6 14
,
the targeted compounds (+/-)- were obtained
1
straightforwardly starting from homophthalic acid (HPA). The
spiro-cyclization was accomplished by using the well-known 4-
step sequence (outlined in Scheme 2). This sequence includes:
i) esterification of diacid HPA under reflux in presence of
gaseous HCl, ii) radical bromination of the obtained diester (e.g.,
NBS, AIBNcat, CCl4 at reflux), followed by iii) condensation with
excess of primary amine R1-NH2, and finally iv) addition of
Most of the hitherto described approaches providing these
types of imide containing spiro-compounds rely on only two
major efficient strategies. To this quite limited arsenal, one may
add the marginal domino addition/spiro-cyclization starting on
isoindolin-1-one containing activated methylene group at its C3-
position.4 Concretely, while recent metal-catalyzed cascade
cyclizations providing these systems in only one operation
raised as the direct and efficient protocol,8 it remains,
nevertheless, limited by numerous practical aspects.
Concerning the second approach developed by us,7,9 and
inspired partially from another,10,11 consists of two cascade
sequences starting from readily available homophthalic acid
brominated acetamides
6 in the presence of K2CO3 as a base.
The spiranic compounds (+/-)-1a-k were thus obtained in yields
ranging from 43 up to 95% yield (for the last step), after
recrystallization from anhydrous ethanol (Table 1).
(
HPA) (Scheme 2).11 This method, providing the requisite spiro-
imides (+/-)- pivotal for this study, remains modular, economic
1
and can be realized in large scale.
Scheme 2 General scheme leading to the key spiranic compounds (+/-)-1a-k.
Our group is strongly implicated in the chemistry of N-
acyliminium salts exploring the C–C bond12 and C–heteroatom13
bond forming reactions for the elaboration of complex
molecules with promising pharmaceutical activities. With this
expertise in mind, allied to our specific interest in spiro-
cyclization, we have reported previously the preparation of
Table 1 Spiranic compounds (+/-)-1a-k obtained according to the general sequence
in Scheme 2.a,b
diverse spiro-isoindoles (+/-)-
latter were generated from imides (+/-)-
2
via N-acyliminium species. These
, associated with
1
through ruthenium-catalysed ring closing metathesis of spiro-
diolefins and the corresponding en-yne via the intermediacy of
(i
, Scheme 1).9a Following this protocol, we also reported a
Entry
1
R1
Bn
R2
Product
1a
Yield (%)c
709a
66
60
77
IV
series of 3-spiro-indolizines containing an isoindole ring of type
(+/-)- through intramolecular arylation of spiro-N-acyliminium
species ii, Scheme 1). These such synthetized compounds
Bn
Allyl
Bn
Bn
Bn
Bn
Bn
Bn
2
3
4
5
p-MeOBn
Furan-2-ylmethyl
Thien-2-ylmethyl
p-MeOPh
Allyl
1b
1c
1d
1e
1f
1g
1h
1i
1j
3
V
(
have been evaluated in vitro for their inhibitory activity on
human FTase and numerous of them showed excellent
inhibitory activity with IC50 on human FTase in the low
nanomolar range, as exemplified by product III which has an IC50
of 1.9 nM (Scheme 1).
43
6
957
857
75
7
8
Propargyl
Phenethyl
Based on these synthetic and biological considerations, we
have envisioned in the present project to explore synthetic
9
3,4-DiMeOPhenethyl Bn
76
86
91
10
11
Thien-2-ylethyl
Homoallyl
Allyl
Bn
opportunities based on this strategy to use spiro-imides (+/-)-
for the generation of reactive N-acyliminium salts . The latter
are able to involve via strategy iii chemoselective -cationic
1
1k
V
a All reactions were performed at reflux. b Reactions were performed on 2 mmol scale of

-bromoacetamides 6. c Isolated yields.
spiro-cyclization in to more complex structures of type (+/-)-
4
2 | New J. Chem., 2020, 00, 1-11
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 11
New Journal of Chemistry
Please do not adjust margins
Journal Name
All these heterocycles have been identified by exploiting their
1H and 13C NMR spectra including the DEPT routine. The 1H NMR of two diastereoisomers) and (+/-)-9a-kD(OmI:i1x0t.u10re39a/Dls0oNJo0f40t5w2oE
spectra reveal a doublet of doublet with a constant 2J coupling diastereoisomers) were then purified by flash chromatography
of 19 Hz corresponding to the diastereotopic methylene on silica gel column. The two purified regioisomers were
protons (CH2) of the succinimide ring. The 13C NMR spectra of isolated in high yields ranging from 73% up to 99% in two steps,
1a-k show the presence of three quaternary carbon atoms calculated from imides (+/-)-1a-k as starting materials.
ARTICLE
The resulting crude spiro-acetoxylactams (+/-)-8Vaie-wkAr(tmicleixOtnulirnee
1
2
3
4
5
6
7
8
(C=O) of the succinimide and isoindolone rings at
≈ 174 ppm and ≈ 168 ppm, respectively, followed by the diastereoisomers. The diastereoisomeric ratios (dr) highlighted
resonances due to the 'spiranic carbon' occurring at ≈ 68–70 in Table 2 were often determined on the basis of the integration
 ≈ 172 ppm, Unfortunately, it was difficult to separate the mixture of the two
9


10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

ppm. These values are comparable to those reported in the values of the angular protons (CH-OAc), which exhibit chemical
literature for related compounds.7,9
shifts in the range of  ≈ 5.92-6.16 ppm.
Reduction and acylation of (+/-)-1 affording (+/-)-8 and (+/-)-9.
Discussion of the parameters directing the imide reduction
diastereoselectivity.
Spiranic compounds 1a-k were then subjected to a in situ
reduction reaction, followed by an acetylation of the spiro- It is worth mentioning that in the light of these results from
hydroxy-lactams intermediates 11a-k (Scheme 3). The latter reduction of a wide range of spiranic products (+/-)-1a-k
compounds can be isolated and characterized before their (Scheme 3; Table 2), an important effect can be advanced.
further use if necessary. In a next step, the resulting spiro-
acetoxylactams 8,9(a-k) (purified by silica gel flash
Table 2 Diastereoisomeric ratios of spiro-acetoxylactams 8a-k and 8a-k generated
chromatography) were subsequently used as N-acyliminium ion
precursors. The choice of acetoxylactams to the detriment of
according to Scheme 3.a
V
corresponding hydroxylactams was made for two practical
reasons: i) the NMR spectrum of the latter are generally more
complex due to CH(OH) couplings observed in almost all cases
(J ≈ 8-12 Hz) and therefore those of acetoxylactams CH(OAc) are
simpler to interpret, in particular when many regio- and
stereoisomers exist in the reaction media, and ii) it is well
demonstrated that acetoxylactams are more reactive than the
corresponding hydroxylactams towards various nucleophiles
under acidic environment.15
dr Ratio dr Ratio dr Ratio Yield
8:9
8A:8B 9A:9B (%)b
Prodts R1
R2
The reduction of spiranic compounds (+/-)-1a-k was
experimentally achieved by using an protocol developed by
Martin et al.16 and our group,7,9,15 using a large excess of NaBH4
(4 equivalents) in the presence of an anhydrous mixture
EtOH/THF (1:1) at 0 °C for 1 to 3 hours. After the completion of
the reaction (monitored by TLC), the mixture was hydrolysed
classically in aqueous hydrochloric acid and the crude spiro-
hydroxylactams intermediates were acetylated (e.g., Ac2O,
Et3N, DMAPcat) in CH2Cl2 at rt for 1 h (Scheme 3).
8a/9a Bn
8b/9b p-MeOBn
8c/9c Furan-2-ylmethyl Bn 100:0
8d/9d Thien-2-ylmethyl Bn 100:0
8e/9e p-MeOPh
8f/9f Allyl
8g/9g Propargyl
8h/9h Phenethyl
8i/9i 3,4-MeOPhenEt Bn 70:30
8j/9j Thien-2-ylethyl
8k/9k Homoallyl
Bn 100:0
Allyl 100:0
82:18
78:22
60:40
67:33
100:0
80:20
80:20
77:23
72:28
72:28
76:24
-
-
-
-
91
939a
87
63
90
957
817
91
93
86
Bn 50:50
Bn 95:05
Bn 50:50
Bn 50:50
50:50
-
c
50:50
50:50
57:43
70:30
50:50
Allyl 57:43
Bn 75:25
75
a dr Ratios extracted from of the integration’s values of the angular protons (CH-OAc). b
c
Yields from purified reaction mixture. The 9A:9B dr ratio is difficult to calculate
considering the 8:9 dr ratio of 95:05.
Apart from the trajectory of Bürghi-Dunitz (angle of 107 °)12
taken by the hydride anion that is generally mentioned during
the imide reduction and which is commonly well accepted to
explain the good level of diastereoselectivity observed, a
second phenomenon is induced by the nature of substituent R1.
Furthermore, a third factor, which has never been mentioned
before so far, can be advanced. It seems to be related to the
occurrence of a plausible - stacking between the olefinic C=C
bond of the R1 residue and C=O of the imide, making the
carbonyl adjacent to the spiranic carbon more reactive.17 In
Scheme 3 Chemoselective and regioselective reduction/acylation reactions of spiro-
succinimides (±)-1a-k.
This journal is © The Royal Society of Chemistry 20xx
New J. Chem., 2020, 00, 1-11 | 3
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 4 of 11
ARTICLE
Journal Name
1
2
3
4
5
6
7
8
fact, with spiro-imides (+/-)-1a-d and (+/-)-1f, in which a single improved 98% yield. Again, the product was obtainVeiedwaAsrtiaclesiOnnglilnee
methylene group CH2 is present as spacer between the nitrogen diastereoisomer.
DOI: 10.1039/D0NJ04052E
atom of the isoidolinone ring, on one hand, and the
-aromatic system, on the other hand, the regioselectivity of
the reduction reaction is total (entries 1-4 of Table 2). In these
cases, the dr ratio between compounds and is 100:0 (except
-olefin or

8
9
for product (+/-)-1f which have a dr value of 95:05 practically
assailable to 100:0). In addition, the 8A:8B dr ratio in these
cases is in favour of the regioisomer (+/-)-8A. In other cases, the
dr ratios are lower or even non-existent. In fact, they range from
the best case of 70:30 (case of 1i) down to the complete
absence of the selectivity 50:50 (case of imides (+/-)-1e, (+/-)-1g
and (+/-)-1h).
The total lack of selectivity in the case of (+/-)-1g is probably due to
the presence of a propargylic C≡C triple bond as p-rich system. The
linearity of the latter due to the hybridization of its carbons keeps it
away and by consequent render them unfavourable for the plausible
− interaction. As for spiro-imide (+/-)-1e, there is no spacing
between the aromatic ring and nitrogen atom of the isoindolinone
moiety, making a stacking interaction for steric reasons extremely
marginal and non-existent. The same outcome may be mentioned for
derivatives (+/-)-1h-k. In the letter case, the presence of two
methylene groups (CH2)2 (in R1 group) places the  aromatic system
away from the imide carbonyl function. Ultimately, these arguments
match perfectly with our experimental findings and constitute thus a
coherent set corroborating our hypothesis.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Reactivity studies of 8 under Brönsted and Lewis acids.
To finalize this study, the
chosen as electrophilic substrate to investigate the possibility to
induce an intramolecular -amidoalkylation reaction. As
-spiro-acetoxylactam (+/-)-8a was
Scheme 4 Acid-promoted intramolecular −amidoalkylation of N-acyliminium species
(+/-)-V into the targeted possible aza-heterocyclic systems 4, 5 or 10.

outlined in Scheme 4, N-acyliminium ion precursor (+/-)-8a (n =
1) can allow reasonably the annellation of a 6-membred ring
exploiting the nucleophilicity of the R1 group (strategy iii) to
provide finally pentacyclic system (+/-)-5a. Otherwise,
formation of 5-membred ring (+/-)-10a exploiting the
nucleophilicity of the R2 group is conceivable in competitive
manner (strategy ii), as outlined in Scheme 1. With this
perspective in mind, and beyond the interest of this substrate
tethering two nucleophilic centres, our choice of acid promoter
concerns the use of Brönsted acid (TFA) and Lewis acid,
trimethylsilyltrifluoromethanesulfonic acid (TMSOTf). We and
other resesearch group have demonstrated that These these
acids are appropriate for the convenient generation of even
very sensitive cationic species.7,9,24
At the outset, we carried out the reaction of (+/-)-8a in neat
TFA as catalyst and solvent at room temperature for 24 hours.
In this case we isolated, after recrystallization from anhydrous
ethanol, the expected polycyclic nitrogen product (+/-)-5a in
72% yield as a single diastereoisomer. After other exploratory
attempts with different Brönsted or Lewis acids, one of the best
experimental conditions found (and not very restrictive) to
accomplish this transformation appears to be the use of
TMSOTf as Lewis acid. Under these conditions, only 10 mol% in
CH3CN were sufficient to provide at room temperature after 24
hours the expected cyclic product (+/-)-5a in a significantly
As for spiro-acetoxylactam (+/-)-8aA in pure form, the mixture
of diasteroisomers (+/-)-8a(A,B) can also be converted to the
cyclized product (+/-)-5a as a single diastereoisomer. These
results suggest that the stereochemical outcome during the
cyclization process is controlled at the spiro-N-acyliminium
cations (+/-)- level, and independently of the relative
-
V
stereochemistry of spiro-acetoxylactam precursors. The use of
small amounts of this acid (e.g., 5 mol%) leads to a partial
transformation of the spiro-acetoxylactam (+/-)-8, giving rise to
formation of an inseparable mixture in a 1/1 ratio of the
pentacyclic product (+/-)-5a and the spiro-hydroxylactam (+/-)-
11a. The latter, which is a hydrolysis product of spiro-
acetoxylactam (+/-)-8a
diastereoisomers (+/-)-11aA and (+/-)-11aB
Having demonstrated the powerfulness of the
,
exists as
a
mixture of two
.

-cationic
cyclization approach using both TFA solvent free (Method I) or
TMSOTf 10 mol% in dry CH3CN (Method II) at room temperature
via the spiro-N-acyliminium cation (+/-)-
the extension of this reaction to spiro-N-acyliminiums species
bearing -rich systems (Scheme 4). At this stage, and in order to
carry out a comparative work, the starting substrates (+/-)-
8(A,B) were separated into two categories those bearing aryl-
nucleophilic and those bearing olefin- -nucleophilic fragments.
Both spiro-N-acyliminium precursors were also systematically
involved in the -amidoalkylation reaction according to
V, we then envisioned


-


4 | New J. Chem., 2020, 00, 1-11
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 11
New Journal of Chemistry
Please do not adjust margins
Journal Name
ARTICLE
1
2
3
4
5
6
7
8
9
Method I and Method II. The results obtained with the first aryl-
-nucleophiles category are summarized in Table 3.
The findings of these investigations (Table 3) deserve some
View Article Online

comments. So, in the case of substrate (+/D-O)-I8: 1e0(.A10,3B9)/fDo0rNwJ0h4i0c5h2nE
= 0, no cyclization occurred. The spiro-hydroxylactam (+/-)-11e
resulting from deprotection of spiro-acetoxylactam (+/-)-8e was
Table 3 6- and 7-Membered rings obtained by application of Method I and Method
II in acidic environment to -spiro-acetoxy-lactams (+/-)-8a-e and (+/-)-8h-j
recovered as a sole distereoisomer A. Weighing the sensitivity

.
of the acetate function to the hydrolysis reaction in acid
medium, the latter treated according to Methods I and II as
described above, remained entirely unchanged and did not
undergo any further transformation.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With the furan substrate (+/-)-8c(A,B), the cyclization was
only observed using Method II where the acid is present in a
catalytic amounts diluted in the solvent (TMSOTf 10 mol%). The
starting material (+/-)-8c was highly sensitive vis-a-vis different
pure acids as reported in related works19 involving N-
acyliminiums ions. Nevertheless, the expected cyclized product
(+/-)-5c was isolated with an appreciable yield of 62%.
Elsewhere, Method II clearly appears to be more advantageous
than Method I in terms of yields since the difference can range
from 5% up to 26% in the best case except in the case of the
furan derivative (+/-)-8c for which only Method II is
appropriate. No deviations concerning the size of the 6- or 7-
membered ring formed during the reaction process were
observed. A competing formation of a 5-membred ring systems
never occurred, independently of the series of substrates
Method Ia Method IIb Structure of the
Yieldc
I/II (%)
Prodt(s)
dr Ratio
dr Ratio
obtained product
72/98d
X-Ray
5aA
100:0
100:0
70:30
70:30
5b(A,B)
5cA
62/88
-e/62
Inseparable Inseparable
employed (n = 0, 1, 2). It seems that -cationic cyclizations in all
cases follows the ring closure Baldwin’s rules20 since exclusively
the 6-endo-tet or 7-endo-tet ring closure occurred in both cases
(n = 1, 2).
Degradation 100:0
Another aspect of the reaction should be emphasized. As
shown in Table 3, the stereochemical outcome at the C-angular
position during the -cyclization of the reactants (+/-)-8a-f,h-j is
similar to that reported in the literature for related structures
from succinimide and phthalimide series.12,13 Interestingly, one
exception is observed for the reactants (+/-)-8b,i bearing one or
two methoxy groups on the their aromatic ring. In these cases,
the reaction seems to proceed via the -aromatic attack on the
opposite side to the bulky isoindolinone moiety. This leads to
diastereospecific formation of the pentacyclic racemic products
5aA, 5cA, 5dA, 5hA and 5jA, whose molecular structures were
secured by X-ray crystallographic analysis (Figure 1).21
5dA
100:0
100:0
100:0
70/84
99/99
72/77
11e(A,B) 100:0
5hA
100:0
80:20
100:0
63:37
73/92
X-Ray
(Maj)
5i(A,B)
5jA
Separable Separable
100:0
100:0
72/90
a
b
c
Method I: TFA excess, r.t, 24 h. Method II: 10 mol% of TMSOTf, CH3CN, r.t, 24 h.
Isolated yields or yields from 1H NMR spectra in the case of mixture. With 5 mol% of
TMSOTf, inseparable mixture of pentacycle (+/-)-5aA/hydroxyl lactam (+/-)-11a(A,B) in
1/1 ratio was obtained. e Only the decomposition of the substrates was observed.
d
Scheme 5 Proposed transition state of the −amidoalkylation through stable N-acyliminium
species (+/-)-8(a,B).
This journal is © The Royal Society of Chemistry 20xx
New J. Chem., 2020, 00, 1-11 | 5
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 6 of 11
ARTICLE
Journal Name
1
2
3
4
5
group with those of R1 one, R2 was fixed by a benzyl group because
no 5-endo-tet reaction was observed in ourDpOreI:c1e0d.1e0n3t9w/Do0rNkJw04it0h52E-
aromatic and heteroaromatic systems.
View Article Online
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Fig. 1 Molecular structure of the isomer (+/-)-5aA.21
For the cyclization of reactants 8b and 8i, the formation of two
diastereoisomers (+/-)-5b(A,B) and (+/-)-5i(A,B) is in average in 2/1
up to 4/1 ratio, depending on the methodology of the -cationic
cyclization used with the same stereochemical outcome for the
major isomer A. The latter findings clearly demonstrate the impact
of the electron-donating MeO group on the aryl ring of the N-
substituted moiety on the spiro-cyclization process. This inductive
+M effect stabilizes probably two types of approaches of the -rich
system/N-acyliminium cation, leading to the formation of two
transition states. Ultimately, the relative configuration of the newly
formed stereogenic centre at the angular carbon (C19) was confirmed
to be R as determined by X-Ray analysis of a single-crystal of product
(+/-)-5iA as major isomer (Figure 2).22
Scheme 6 Acid-promoted −amidoalkylation of N-acyliminium species (+/-)-V using
propargyl, allyl or homoallyl -system as internal nucleophile.
In the case of reactant (+/-)-8g (n = 1) bearing a propargyl
substituent as R1, the linear geometry of the triple bond
combined with its relative distance from the cationic centre
confers to this group an unfavourable orientation with respect
to the electrophilic spiro-N-acyliminium ion (+/-)-V. Therefore,
the targeted cyclic ketone (+/-)-4g could not be obtained even
after varying the reaction temperature. Instead, we recovered
the spiro-hydroxylactam (+/-)-11g(A,B), generated by the
deprotection of the starting spiro-acetoxylactam (+/-)-8g during
the work-up.
Faced with this failure, we then focused on the allyl series. For
the spiro-acetoxylactam (+/-)-8f(A,B) with n = 1 we observed
different important findings, depending on the nature of the
acid, its quantity and the solvent, slightly different from the
conditions of Methods I and II. The results are presented in
Table 4.
Table 4 Screnning of the acid-promoted cyclization of spiro-acetoxylactam (+/-)-8f
beyond Methods I and II
.
Entry Acid
Quantity Solvent Isolated product Yield (%)b
a
1
2
3
4
5
6
7
8
TFA
Excess
-
(+/-)-11f
(+/-)-11f
55
83
37
73
43
50
40
74
Fig. 2 Molecular structure of (+/-)-5iA as major isomer.22
Et2O.BF3 200 mol% -a
TMSOTf 10 mol% CH3CN (+/-)-12f
TMSOTf 10 mol% CH2Cl2 (+/-)-11f
TIPSOTf
TIPSOTf
TMSOTf 100 mol% CH3CN (+/-)-12f
TMSOTf 100 mol% CH2Cl2 (+/-)-4f
Having demonstrated that aromatic and heteroaromatic systems
(Table 3) are able to trap a spiro-N-acyliminium species generated in
acid medium according to the above discussed Methods I and II to
promote a -cationic spiro-cyclization, we sought to extend this
protocol on cationic species bearing propargyl,23 allyl24 and
homoallyl25 -rich functionalities as potential internal nucleophile
(Scheme 6). In order to avoid any nucleophilic competition of the R2
10 mol% CH3CN (+/-)-12f
10 mol% CH2Cl2 (+/-)-11f
a Reactions were performed solvent free. b Isolated yields.
6 | New J. Chem., 2020, 00, 1-11
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 11
New Journal of Chemistry
Please do not adjust margins
Journal Name
During our experimentation, we noticed that reaction of
ARTICLE
1
2
3
4
5
6
7
8
View Article Online
DOI: 10.1039/D0NJ04052E
spiro-acetoxylactam (+/-)-8f with TFA (Method I) (Table 4, entry
1) or 2 equivalents of neat Et2O.BF3 (Table 4, entry 2) failed to
provide the cyclized product (+/-)-4f. Instead, the spiro-
hydroxylactam (+/-)-11f, a congener of spiro-acetoxylactam (+/-
)-8f, was obtained in 55% and 83%, respectively. To our surprise,
the same reaction using a catalytic amount of TMSOTf (10
mol%), either in dry CH3CN (Table 4, entry 3) or dry CH2Cl2 (Table
4, entry 4), did not favoured the cyclization process but rather
lead to the heterocyclic amino-acid (+/-)-12f (37%) or spiro-
hydroxylactam (+/-)-11f (73%) shown in Scheme 6, respectively.
After numerous attempts, it appeared that the use of an
equimolar amount of TMSOTf in anhydrous CH2Cl2 at room
temperature for 24 hours leads to the expected cyclic product
(+/-)-4f with an isolated yield of 74% (Table 4, entry 8).
However, performing the same reaction in CH3CN (Table 4,
entry 7), produced the heterocyclic amino-acid (+/-)-12f in 40%
yield. This result is similar to that observed during the treatment
of the same spiro-acetoxylactam (+/-)-8f with only 10 mol% of
TMSOTf in dry CH3CN leading to (+/-)-12f in 37-43% yields.9a
Worth mentioning is also the observation that the use of 10
mol% of TIPSOTf instead of TMSOTf either in anhydrous CH3CN
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(Table 4, entry 5) or CH2Cl2 (Table 4, entry 6) under same Scheme 7 Proposed mechanism leading to aza-heterocyclic systems (+/-)-4f,k and
conditions also did not allow to furnish the expected product
(+/-)-4f. We observed, instead, the formation of (+/-)-12f (43%)
by using CH3CN and (+/-)-11f (50%) by using CH2Cl2.
The optimized reaction conditions determined for (+/-)-4f
(Table 4, entry 8) were next applied to the synthesis of (+/-)-4k
starting from spiro-acetoxylactam (+/-)-8k in homoallylic series
(Table 5). Thus, during the reaction of (+/-)-8k under those
heterocyclic amino-acids in pyrrolopyridine and pyrroloazepine series (+/-)-12f,k.
Based on these results, we propose a plausible mechanism for
the acid-mediated -cationic cyclization of spiro-acetoxylactam

(+/-)-
(+/-)-
8
V
implying the generation of spiro-N-acyliminium species
as key intermediate (Scheme 7).
Spiro-N-acyliminium species (+/-)-
V,
formed in situ,
undergoes an intramolecular -cyclization to furnish the
conditions, which are apparently favourable for the -cationic

cyclization of the allylic series, we observed curiously an
instantaneous degradation of the starting material (Table 5,
Entry 4). The use of CH2Cl2 instead of CH3CN under the same
conditions (Table 5, entry 5) did not change the course of the
reaction. However, the same reaction carried out under milder
conditions of Method II (10 mol% TMSOTf) yielded the hitherto
unknown amino acid (+/-)-12k with a very good yield of 86%
(Table 5, entry 3). Nevertheless, the use of an excess of TFA
cationic tricyclic species (+/-)-VI, which in turn is trapped by
acetate group present in the media,9a to deliver finally the
sensitive intermediates (+/-)-VII (n = 1) and (+/-)-VIII (n = 2).
Then, lactam hydrolysis of the latter occurs to provide finally the
two amino-acids, pyrrolopyridine (+/-)-12f and pyrrolo-azepine
(+/-)-12k. In a very competitive manner, these acetate-bearing
compounds 12 can then evolve to product (+/-)-4f (n = 1) by
trans-elimination of one molecule of AcOH or to the tricyclic
alcohol (+/-)-4k (n = 2) via acetate hydrolysis. The latter can also
be obtained directly from the carbocation (+/-)-VI (n = 2) by
water attack and subsequent deprotonation.
(Method I) led, after recrystallization from anhydrous ethanol,
in contrast to the allylic series, to the interesting cyclized alcohol
(+/-)-4k as the sole reaction product with a fair yield of 65%
(Table 5, entry 6).
The different reactivity pattern of the two cyclic carbocationic
sites at the 6- or 7-membered rings is probably not due to
differences in energetic stability between the two species but
rather to a congestion problem of the first compared to the
Table 5 Screnning of acid-promoted cyclization of spiro-acetoxylactam (+/-)-8k
beyond Methods I and II
.
Entry Acid
Quantity Solvent Isolated product Yield (%)b second. In fact, a 6-membered ring scaffold represents a system
b
b
Et2O.BF3 400 mol% -a
TMSOTf 10 mol% CH3CN (+/-)-12k
TMSOTf 10 mol% CH2Cl2 (+/-)-11k
TMSOTf 100 mol% CH3CN
TMSOTf 100 mol% CH2Cl2
TFA
-
-
that virtually compensates eclipses and angle deformations by
adopting less-strained conformations thus favouring an
elimination reaction.
1
2
3
4
5
6
86
86
b
b
-
-
-
b
b
-
Conclusions
a
Excess
-
(+/-)-4k
65
In summary, spiro-isoindolinone containing imides (+/-)-1a–k
were obtained in a three-step sequence according to our
published approach.7
a
b
Reactions were performed solvent free. Degradation of the starting material.
c Isolated yields.
This journal is © The Royal Society of Chemistry 20xx
New J. Chem., 2020, 00, 1-11 | 7
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 8 of 11
ARTICLE
Journal Name
1
2
3
4
5
6
7
8
9
a UV-lamp at 254 nm and 365 nm. Column chromatoVgireawpAhrtiieclse Ownelirnee
DOI: 10.1039/D0NJ04052E
performed with a CombiFlash Rf Companion (Teledyne-Isco System)
These imides, which could be obtained in large scale, undergo
sodium borohydride reduction followed by O-acylation in a
tandem process or not to give spiro-acetoxylactams (+/-)-8a
–k
using RediSep packed columns. IR spectra were recorded on a Varian
640-IR FT-IR Spectrometer. Elemental analyses (C, H, N) of new
compounds were determined on a Thermo Electron apparatus by
‘Pôle Chimie Moléculaire-Welience’, Faculté de Sciences Mirande,
Université de Bourgogne, Dijon, France. LC-MS was accomplished
using an HPLC combined with a Surveyor MSQ (Thermo Electron)
equipped with APCI source.
along with their regioisomers (+/-)-9a . Both isomers could be
–k
isolated in a regioselective and diasteroselective manner in
good to excellent yields.
The spiro-acetoxylactams (+/-)-8a–k obtained as sole
products or after chromatographic separation from the mixture
were submitted to Brönsted (TFA solvent free) and Lewis acid
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(TMSOTf 10 mol% in acetonitrile). These reactions undergo
cationic cyclization through spiro-N-acyliminiums intermediates
(+/-)- to provide diastereoselectively original pyrrolopyrido-
isoindoles (+/-)-5a and pyrroloazepino-isoindoles (+/-)-5h–j
-
General procedure for the preparation of spiro-succinimides (±)-1a-
k.
V
–
e
To a solution of N-alkylated isoindolin-1-one 77,9 (0.01 mol) in 100 mL
of anhydrous CH3CN were added potassium carbonate (0.015 mol,
2.07 g) and bromoacetamide 6 (0.015 mol) under dry argon
atmosphere. The mixture was then refluxed for 24 h. The solution
was cooled at room temperature and filtered through a plug of celite.
After removal of solvent under reduced pressure, the crude was
analysed by 1H NMR spectroscopy then purified by flash
chromatography on silica gel column using a mixture of cyclohexane
and AcOEt as eluent.
fused or not to arene and heteroarene systems. The structure
of the latter was confirmed by X-Ray analysis. Interestingly, with
reactants bearing
-olefin, polyhydro-pyrrolopyridines and
pyrroloazepines fused to isoindoline (+/-)-4f,k or containing
interesting amino-acids (+/-)-12f,k were isolated as pioneered
by us in precedent work.9a Depending on the employed acid and
reaction conditions, we were finally able to control totally the
course of the reaction to deliver exclusively the desired
compound.
Worth noting is the finding that conducting -cyclization using
General Procedure for the Preparation of Spiro-hydroxylactams (±)-
11(A,B).
To a solution of spiro-succinimide (±)-1 (2.5 mmol) in a mixture of
TMSOTf in 10 mol% is in almost all cases are superior compared
to neat TFA. The stereochemical outcome of the intramolecular
amidoalkylation seems to proceed via a single transition state
as reported for related structures by us and others. There is, THF/EtOH (1:1) was added sodium borohydride (10 mmol, 4 equiv.)
however, an exception when the arene tethered at the nitrogen
atom of the isoindolinone ring bears one or two methoxy
group(s). A more detailed rationalization of the findings
presented here deserve to be further elaborated by future
investigations including DFT computing.
Ultimately, the reaction mechanisms producing all these
systems including the regioselective spiro-imides reduction and
-amidoalkylation of the intermediate cationic species are also
at 0°C then the mixture was left under stirring at room temperature
for 4 h. The reaction mixture was then cooled to 0 °C and quenched
by addition of 1 mL of water then acidified to pH 3 by 2M HCl
solution. The mixture was extracted twice by 30 mL of
dichloromethane and the organic layer was dried over MgSO4 then
evaporated to dryness. The oily residue was purified by flash
chromatography on
a silica gel column using a mixture of

cyclohexane and AcOEt as eluent.
discussed.
General procedure for the synthesis of α-acetoxylactams (±)-8(A,B).
To a solution of spiro-hydroxylactam (±)-11 (A,A’) (mixture of two
diastereoisomers, 0.7 mmol) in 10 mL of CH2Cl2 were added acetic
anhydride (1.5 eq.), triethylamine (1.5 eq.) and dimethylamino-
pyridine (DMAP, 0.1 eq.) then the reaction mixture was stirred at
room temperature for 1 hour. The reaction mixture was then washed
with a saturated aqueous solution of NaHCO3 (10 mL) and extracted
twice with dichloromethane. The organic layer was dried over MgSO4
and evaporated under reduced pressure to give an oil residue which
was purified by flash column chromatography on silica gel column
using cyclohexane-ethyl acetate to afford α-acetoxylactams (±)-
8(A,B).
Experimental Section
General remarks.
The main text of the article should appear here with headings as
appropriate. Starting materials are commercially available and were
used without further purification (suppliers: Carlo Erba Reagents
S.A.S., Thermo Fisher Scientific Inc., and Sigma-Aldrich Co.). Melting
points were measured on a MPA 100 OptiMelt® apparatus and are
uncorrected. Nuclear magnetic resonance (NMR) spectra were
1
acquired at 300 MHz for H NMR and at 75 MHz for 13C NMR on a
Bruker Advance III 300 MHz spectrometer with tetramethylsilane
(TMS) as internal standard, at room temperature (rt). Chemical shifts
(δ) are expressed in ppm relative to TMS. Splitting patterns are
designed: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; m,
multiplet; sym m, symmetric multiplet; br s, broaden singlet; br t,
broaden triplet. Coupling constants (J) are reported in Hertz (Hz).
Thin layer chromatographies (TLC) were realized on Macherey Nagel
silica gel plates with fluorescent indicator and were visualized under
General procedure for -cationic cyclization of α-acetoxylactams
(±)-8(A,B)
To a solution of α-acetoxylactam (±)-8(A,B) (pure form or mixture of
two diastereoisomers 0.7 mmol) in 2 mL of acetonitrile was added 10
mol% of TMSOTf then the reaction mixture was stirred at room
temperature for 2 h. The reaction mixture was neutralized with a
8 | New J. Chem., 2020, 00, 1-11
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 11
New Journal of Chemistry
Please do not adjust margins
Journal Name
ARTICLE
1
2
3
4
5
6
7
8
9
4
5
J. E. Wroel and N. J. Lawrenceville, American Home Products
saturated aqueous solution of NaHCO3 (10 mL) and extracted twice
with dichloromethane (20 mL). The organic layer was dried over
MgSO4 and evaporated in vacuo to give a white product which was
purified by flash column chromatography on silica gel column to give
compounds (±)-5(A,B) or (±)-11e(A,B).
View Article Online
Corp.US 4900739, 1990.
J. Wrobel, A. Dietrich, S. A. Woolson, DJ.OMI: 1il0le.1n0,39M/D.0MNJc0C4a0le52bE,
M. C. Harrison, T. C. Hohman, J. Sredy and D. Sullivan, J. Med.
Chem., 1992, 35, 4613–4627.
J. Zhu, J. Cai, G. Li, Z. You, Y. Wu, R. Han, Yo. Ge, L. Wang and
J. Wang, Sichuan Kelun Botai Bio-pharmaceutical Co., Ltd.;
CN109928979, 2019.
A. Pesquet, H. Marzag, M. Knorr, C. Strohmann, A. M. Lawson,
A. Ghinet, J. Dubois, F. Amaury, A. Daïch and M. Othman, Org.
Biomol. Chem., 2019, 17, 2798–2808 and the references cited
therein.
For a recent review on spiro-cyclization of maleimides by
transition-metal-catalyzed C-H activation, see: R. Manoharan
6
7
Conflicts of interest
There are no conflicts to declare.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
9
Crystallographic data
and M. Jeganmohan, Asian J. Org. Chem., 2019
https://doi.org/10.1002/ajoc.201900054
, 8,
Full crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre (CCDC n° 1848784 for
(+/-)-5aA and 2022086 for (+/-)-5iA). Copies of the data can be
obtained free of charge at http://www.ccdc.com
Crystal data for product (+/-)-5aA: C25H20N2O2 (M = 380.43
g/mol), monoclinic space group P21/c, a = 10.115(6), b =
22.716(8), c=8.414(6)Å, V = 1887.6(19) Å3, Z = 4, Dc = 1.339
g/cm3, μ = 0.086 mm-1, h/k/lmax = 12/27/9, Nref = 3296, R1 =
0.0506[I > 2σ(I)] and wR2 = 0.1352, Npar = 343, S = 1.031 for all
38636 reflections, Data completeness = 0.999, CCDC reference
number 1848784.
Crystal data for product (+/-)-5iA: C28H26N2O4 (M = 454.11
g/mol), monoclinic space group P21/c, a = 8.4505(17), b =
19.920(4), c = 13.650(3) Å, V = 1281.8(3) Å3, Z = 4, Dc = 1.317
g/cm3, μ = 0.089 mm-1, h/k/lmax = 10/25/17, Nref = 5004, R1 =
0.0466 [I > 2σ(I)] and wR2 = 0.1241, Npar = 309, S = 1.067 for all
20461 reflections. Data completeness = 0.935, CCDC reference
number 2022086.
(a) A. Pesquet and M. Othman, Tetrahedron Lett., 2013, 54,
5227–5231; (b) I. Allous, S. Comesse and A. Daïch, Lett. Org.
Chem., 2008, 5, 73–78.
10 (a) I. Allous, S. Comesse, D. Berkeš, A. Alkyat and A. Daïch,
Tetrahedron Lett., 2009, 50, 4411–4415; (b) I. Allous, S.
Comesse, M. Sanselme and A. Daïch, Eur. J. Org. Chem., 2011
5303–5310.
,
11 F. Scorzelli, A. Di Mola, F. De Piano, C. Tedesco, L. Palombi, R.
Filosa, M. Waser and A. Massa, Tetrahedron, 2017, 73, 819–
828 and the references cited therein.
12 For reviews on N-acyliminiums chemistry, see: (a) W. N.
Speckamp and M. J. Moolenaar, Tetrahedron, 2000, 56, 3817–
3856; (b) B. E. Maryanoff, H. C. Zhang, J. H. Cohen, I. J. Turchi
and C. A. Maryanoff, Chem. Rev., 2004, 104, 1431–1628; (c) A.
Yazici and S. G. Pyne, Synthesis, 2009, 339–368; (d) Yazici and
S. G. Pyne, Synthesis, 2009, 513–541 ; (e) P. Wu and T. E.
Nielsen, Chem. Rev., 2017, 117, 7811−7856.
13 For heterocyclization reactions using N-acyliminiums species,
see: A. Daïch, A. Ghinet and B. Rigo, in Comprehensive Organic
Synthesis, 2nd edition; G. A. Molander and P. Knochel, Eds.;
Elsevier, Oxford, 2014, Vol. 2, Chap. 2.21, pp. 682–742.
14 S. Cesa, V. Mucciante and L. Rossi. Tetrahedron, 1999, 55,
193–200.
15 (a) F. Pin, S. Comesse, B. Garrigues, Š. Marchalín and A. Daïch,
J. Org. Chem., 2007, 72, 1181–1191 and the references cited
therein; (b) M. Berthet, A. Beauseigneur, C. Moine, C. Taillier,
M. Othman and V. Dalla, Chem. Eur. J., 2018, 24, 1278–1282
and the references cited therein.
Acknowledgements
The authors thank warmly Campus France for supporting this
research project by giving facilities to one of us, SC. The authors
also gratefully acknowledge the ‘Institut Normand de Chimie
Moléculaire, Médicinale et Macromoléculaire, INC3M FR-CNRS
3038’, the ‘Normand Network’, the URCOM laboratory and the
University of Le Havre Normandy of ‘Normandie-Université’ for
their financial support and technical help and facilities.
16 S. F. Martin, H. J. Chen, A. K. Courtney, Y. Liao, M. Pätzel, M.
N. Ramser and A. S. Wagman, Tetrahedron, 1996, 52, 7251–
7264.
17 For an example of rare carbonyl- electron interactions, see:
J. E. Gautrot, P. Hodge, D. Cupertino and M. Helliwell, New J.
Chem., 2006, 30, 1801–1807 and the references cited therein.
18 (a) M. Saber, S. Comesse, V. Dalla, A. Daïch, M. Sanselme and
P. Netchitaïlo, Synlett, 2010, 2197–2201; (b) J.-F. Fleury, P.
Netchitaïlo and A. Daïch, Synlett, 2011, 1821–1826; (c) G.-M.
Dumitriu, E. Bîcu, U. Eryuruk, D. Belei, B. Rigo, A. Daïch and A.
Ghinet, Synlett, 2016, 27, 934–940; (d) A. Hamid, A. Souizi, A.
M. Lawson, M. Othman, A. Ghinet, B. Rigo and A. Daïch, Arab.
J. Chem., 2019, 12, 680–693.
Notes and references
1
For recent review on spiro-isoindole compounds, see: (a) P.-
W. Xu, J.-S. Yu, C. Chen, Z.-Y. Cao, F. Zhou and J. Zhou, ACS
Catal., 2019, 9, 1820−1882; (b) J. Bariwal, L. G. Voskressensky
and E. V. Van der Eycken, Chem. Soc. Rev., 2018, 47, 3831–
3848; (c) Z.-Y. Cao, F. Zhou and J. Zhou, Acc. Chem. Res., 2018
51, 1443−1454.
19 For pertinent examples of -amidoalkylation reaction in furan
,
series, see: (a) A. E. Metz, K. Ramalingam and M. C. Kozlowski,
Tetrahedron Lett., 2015, 56, 5180–5184; (b) M. D. Rose, M. P.
2
3
For recent review, see: S. S. Panda, R. A. Jones, P. Bachawala
and P. P. Mohapatra, Mini Rev. Med. Chem., 2017, 17, 1515–
1536.
For recent review related to inhibitors of p53–MDM2
interactions, see: (a) A. K. Gupta, M. Bharadwaj, A. Kumar and
Cassidy, P. Rashatasakhon and A. Padwa, J. Org. Chem., 2007
,
72, 538–549; (c) S. P. Tanis, M. V. Deaton, L. A. Dixon, M. C.
McMills, J. W. Raggon and M. A. Collins, J. Org. Chem., 1998
63, 6914–6928.
,
20 (a) J. E. Baldwin, J. Chem. Soc. Chem. Commun., 1976, 734–
736; (b) I. V. Alabugin, K. Gilmore and M. Manoharan, J. Am.
Chem. Soc., 2011, 133, 12608–12623.
R. Mehrotra, Top. Curr. Chem., (Z
)
2017
,
375.
https://doi.org/10.1007/s41061-016-0089-0; (b) C. Sheng, G.
Dong, Z. Miao, W. Zhang and W. Wang, Chem. Soc. Rev., 2015
44, 8238–8259.
,
This journal is © The Royal Society of Chemistry 20xx
New J. Chem., 2020, 00, 1-11 | 9
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 10 of 11
ARTICLE
Journal Name
1
2
3
4
5
6
7
8
9
21 Crystal structure determination of 5aA was accomplished on
each was assigned a fixed isotropic displacemeVnietwpAartricalme Oentliener
a Bruker D8 Venture four-circle diffractometer by Bruker AXS
based on a riding model.
DOI: 10.1039/D0NJ04052E
GmbH using a PHOTON II CPAD detector. X-ray radiation (Mo- 23 For representative examples of propargyl group as internal
Kα, k = 0.71073 Å) was generated by microfocus sources IµS
Mo by Incoatec GmbH with HELIOS mirror optics and a single-
hole collimator by Bruker AXS GmbH. For the data collection,
the programs APEX 3 Suite (v,2018.7-2) with the integrated
nucleophile, see: (a) M. Das and A. K. Saikia, J. Org. Chem.,
2018, 83, 6178−6185; (b) H. E. Schoemaker, T. Boer-Terpstra,
J. Dijkink and W. N. Speckamp, Tetrahedron, 1980, 36,
143−148.
programs SAINT (integration) and SADABS (absorption 24 For representative examples of allyl group as internal
correction) by Bruker AXS GmbH were used. Using Olex226 the
nucleophile, see: (a) K. Indukuri, R. Unnava, M. J. Deka and A.
K. Saikia, J. Org. Chem., 2013, 78, 10629−10641; (b) A. K.
Saikia, K. Indukuri and J. Das, Org. Biomol. Chem., 2014, 12,
7026−7035.
SHELXT27
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
structures were solved with the
structure solution
program using intrinsic phasing and refined with SHELXL
against F2 with the full-matrix least squares method. The non-
hydrogen atoms were refined anisotropically. All hydrogen 25 For an example of homoallyl group as internal nucleophile,
atoms were placed in geometrically calculated positions and
each was assigned a fixed isotropic displacement parameter
based on a riding model
see: D. F. Taber, R. S. Hoerrner and M. D. Hagen, J. Org. Chem.,
1991, 56, 1287–1289.
26 O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard and
22 Crystal structure determination of 5iA was accomplished on a
Bruker APEX II CCD diffractometer equipped with a CCD area
detector. Suitable crystals of 5iA were covered with an inert
H. Puschmann, OLEX2: A complete structure solution,
refinement and analysis program, J. Appl. Crystallogr., 2009
42, 339–341.
,
oil perfluoro-polyalkylether) and used for X-ray crystal 27 (a) L. Palatinus and G. Chapuis, J. Appl. Crystallogr., 2007, 40,
structure determination. Graphite monochromated Mo-Kα
radiation (k = 0.71073 Å) was used. The crystal structure was
solved with intrinsic phasing SHELXT27 and refined against F2
with the full-matrix least-squares method (SHELXL ver.
2018/3).28 The processing and finalization of the crystal
786–790; (b) G. M. Sheldrick, Acta Crystallogr., 2015, A71, 3–
8; (c) M. C. Burla, R. Caliandro, M. Camalli, B. Carrozzini, G. L.
Cascarano, C. Giacovazzo, M. Mallamo, A. Mazzone, G.
Polidori and R. Spagna, J. Appl. Crystallogr., 2012, 45, 357–
361; (d) G. M. Sheldrick, Acta Crystallogr., 2015, C71, 3–8.
structure data was done with the program Olex2.26 The non- 28 (a) S. Parsons, H. D. Flack and T. Wagner, Acta Crystallogr.,
hydrogen atoms were refined anisotropically. All hydrogen
atoms were placed in geometrically calculated positions and
2013, B69, 249–259; (b) R. W. Hooft, L. H. Straver and A. L.
Spek, J. Appl. Crystallogr., 2008, 41, 96–103.
10 | New J. Chem., 2020, 00, 1-11
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 11 of 11
New Journal of Chemistry
Please do not adjust margins
Journal Name
ARTICLE
1
2
3
4
5
6
7
8
View Article Online
DOI: 10.1039/D0NJ04052E
Aza-heterocyclic frameworks through intramolecular -system trapping of spiro-N-
acyliminiums generated from isoindolinone
Sarra Chortani,a,b Mohamed Othman,*a Ata Martin Lawson,a Anis Romdhane,b Hichem Ben Jannet,b Michael Knorr,c Lukas
Brieger,d Carsten Strohmann,d and Adam Daïch*a,†
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Sentence (maximum 20 words)
Spiro-acetoxylactams, obtained easily by the tandem carbonyl reduction/O-acylation, were submitted to
acids giving through -cationic cyclization aza-heterocyclic systems including amino-acids.
This journal is © The Royal Society of Chemistry 20xx
Org. Biomol. Chem., 2018, 00, 1-11 | 11
Please do not adjust margins