Bi(OTf)3-Catalysed Access to 2,3-Substituted Isoindolinones and Tricyclic N,O-Acetals by Trapping of Bis-N-Acyliminium Species in a Tandem Process

Article abstract of DOI:10.1002/ejoc.201600530

New 1,3-bis-N-acyliminium species generated easily with nontoxic Bi(OTf)₃catalyst at very low loadings (2 mol-%) were trapped inter- and intramolecularly with various poly-nucleophiles. This mild, efficient, practical and general tandem approach provides an array of substituted isoindolinones and cyclic N,O-acetals.

Full text of DOI:10.1002/ejoc.201600530

DOI: 10.1002/ejoc.201600530
Full Paper
Tandem C- and O-Amidoalkylation
Bi(OTf) -Catalysed Access to 2,3-Substituted Isoindolinones and
3
Tricyclic N,O-Acetals by Trapping of Bis-N-Acyliminium Species
in a Tandem Process
Ahmed Aliyenne,[ Frédéric Pin, Vijaykumar D. Nimbarte, Ata Martin Lawson,
a,b]
[a]
[a]
[a]
[a]
[c]
[d]
[d]
Sébastien Comesse, Morgane Sanselme, Vincent Tognetti,* Laurent Joubert, and
[
a]
Adam Daïch*
Abstract: New 1,3-bis-N-acyliminium species generated easily cleophiles. This mild, efficient, practical and general tandem ap-
with nontoxic Bi(OTf) catalyst at very low loadings (2 mol-%) proach provides an array of substituted isoindolinones and cy-
3
were trapped inter- and intramolecularly with various poly-nu- clic N,O-acetals.
Introduction
rigidified piperazines as solubilizing or hydrophobic groups in
[
6a]
medicinal chemistry
as well as epidiselenodiketo-piperazi-
The coupling of N-acyliminium species, generally formed in situ
by acidic treatment of an amide or lactam bearing a leaving
group at the α-position, constitutes one of the more powerful
C–C bond forming reactions used widely in contemporaneous
synthetic organic chemistry.[1] The high reactivity of these cati-
ons due to the presence of a carbonyl function on the nitrogen
atom, gives unlimited possibilities to these species and enables
rapid access to a wide range of natural and unnatural polycyclic
[6b,6c]
nes.
The latter group belongs to the class of natural prod-
ucts referred to as epidithiodiketopiperazines (ETPs); the ETPs
command a good deal of importance for their redox properties.
The 1,5-bis-electrophiles in the imidazolidinone and benzimid-
azolidinone areas for their part, were embarked in the first syn-
thesis of cyclophanes via corresponding dithiacyclophanes (Fig-
[7]
ure 1). The importance of these findings undoubtedly in-
creases the attractiveness of this chemistry, especially when the
target molecules have notable biological activities and their
production may or may not be accompanied with environmen-
tally weak effects.
[
2]
systems including alkaloids. Although C–C bond forming
methods have been extensively investigated, approaches to the
formation of C–heteroatom bonds remain scarce. Yet C–hetero-
atom bond formation constitutes a novel and powerful strategy
by which to access new complex compounds containing cyclic
mixed N,O-, N,N-, N,S-, and N,Se-acetals, as we have recently
[
3]
noted. Interestingly, the application of these cations as 1,3-
bis-electrophile units has been reported in only two reaction
series with external carbon and oxygen nucleophiles (Figure 1)
[
4]
leading to piperidines, 2-oxo-N-arylpyrrolidine-1-carboxam-
[
5]
ides and 1,3-diaryl ureas, respectively. In addition, exploration
of bis-N-acyliminium species such as the 1,4-bis-electrophiles in
the piperazine series, have allowed quick and easy access to
[
a] Normandie Univ., UNIHAVRE, CNRS, URCOM,
6600 Le Havre, France
7
E-mail: adam.daich@univ-lehavre.fr
https://urcom.univ-lehavre.fr/spip.php?article102
b] Ecole Normale Supérieure de Nouakchott, Département des Sciences
Exactes,
[
Figure 1. Precursors of bis-N-acyliminium species. Spheres represent the in-
tended electrophilic centers.
B.P. 990, Ksar Nouakchott, Mauritania
[
[
c] Normandy Univ., UNIROUEN, COBRA, UPRES-EA
7
6000 Rouen, France
d] Normandy Univ., UNIROUEN, CNRS, COBRA,
6000 Rouen, France
Results and Discussion
7
E-mail: vincent.tognetti@univ-rouen.fr
http://www.lab-cobra.fr/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600530.
Our group has been interested for decades in the development
of tandem processes combining heterocyclisation and intramo-
lecular π-amidoalkylations starting from N-aryl-(or heteroaryl-
Eur. J. Org. Chem. 2016, 3592–3602
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)
oxy-(thio- or seleno-)methyl amidals under Brönsted acid con- quent reactions. Lactam 8A was obtained easily from its parent
[
9]
ditions using, in particular, neat TFA in precise ratios relative to α-hydroxy lactam 1a, by reaction with acetic anhydride [i.e.,
the reactant.
From these results, we became intrigued by the behaviour, isolated yield]. As shown in Scheme 2, the reaction of 8A (as
in acidic media, of these hydroxy lactams in the selenium series. an N-acyliminium precursor) with allyltrimethylsilane 9a
[
8]
Ac O (2 equiv.), DCM, DMAP , NEt (2 equiv.), r.t, 12 h; 92 %
2 cat 3
[
11]
Indeed, treatment of N-acyliminium precursors 1a and 1b in (1.2 equiv.) as a model nucleophile in the presence of Bi(OTf)
neat TFA at room temperature provides exclusively 2a and 2b, (1 mol-% in 0.5 MeCN, r.t) according to our earlier report
respectively, in high yields (91 %; Scheme 1) as the π-cyclisa- dealing with inter- and intramolecular amidoalkyation reactions
3
M
tion[ and the tandem selenocyclisation/isomerisation/π-cycli- for related substrates,
9]
[11a]
provided a mixture of 4 separable
[
10]
sation products.
products. To our satisfaction, this product mixture included
allyl-N-homoallyl bis-adduct 10a (Scheme 2, Table 1, Entry 1).
The use of 2.4 equiv. of 9a did not change the reaction profile.
Interestingly, these results demonstrate, in addition to the bis-
electrophile character of substrate 8A, the amphoteric character
of selenium as both a nucleophile and electrophile which relies
on the fact that the bond dissociation energy of C–O (257 kcal/
mol) is much stronger to that of the C–Se linkage (139 kcal/
[
18]
mol). To avoid generation of organoselenium by-products 3-
phenylselenyl-2-(phenylselenyl-methyl)-isoindolin-1-one (11),
allylphenylselane (12), and 1,2-diphenyldiselane (13), we next
checked the tandem process using other new electrophilic bis-
N,O-acetals in the isoindolin-1-one series such as 8B–D (Sup-
porting Information). From these results (Table 1), it became
apparent that the best formulation involves the use of bis-acet-
ate 8D with 2 mol-% Bi(OTf) in acetonitrile (87 %, Table 1, Entry
3
7
). On the other hand, 1 equiv. of AlCl is needed for the pro-
3
duction of compound 10a, albeit in only 56 % yield (Table 1,
Entry 9) whereas the same reaction using substrate 8C failed
under all conditions regardless of catalyst.
Scheme 1. Cyclisation of N-phenylselenylmethyl amidals 1a,b in acidic media
and bioactive cyclic N,O-acetals 4–7.
Additionally, our research has focused on the formation-
cleavage of ether oxide linkages such as in cyclic N-acyl-substi-
tuted N,O-acetals using eco-friendly approaches involving
[
11]
[
Bi(OTf)3] or domino reactions; these may or may not be as-
[
12]
sociated with DFT calculation.
In this general context we
herein report the results of our investigations into the design
of new 1,3-bis-N-acyliminium precursors (Figure 1) in the isoin-
dolone series and their use in tandem processes to produce a
small library of functionalized isoindolones and fused substi-
tuted bicyclic lactams with high synthetic and biological poten-
[
13]
tial. Mechanistic aspects of these reactions are also discussed
on the basis of experimental and theoretical considerations. In-
deed, due to their stability with a range of bases, weaker acids
Scheme 2. Screening of the α-amidoalkylation reaction conditions.
Having demonstrated both the effectiveness of the tandem
and redox conditions, these types of cyclic N-acyl-substituted process and the ability of Bi(OTf) at very low loadings (2 mol-
3
N,O-acetals are commonly used as precursors of N-acyliminium %) to promote the bis-α-amidoalkylation reaction via formal
[
14]
cations, protecting groups for their parent lactams and chiral 1,3-bis-cation formation independent of ancillary bis-N-acyl-
platforms for the asymmetric synthesis of substituted piperidine iminium precursors 8A, 8B and 8D as synthetic equivalent sub-
[
13]
[15]
systems. In addition, prominent natural product 4 and un- strates, we envisioned extending this tandem reaction to other
[
16]
natural agents 5–7 (Scheme 1) represent excellent examples
of these types of systems that display important biological ac- employing reaction conditions similar to those in Table 1, Entry
tivities.
7, reaction of substrate 8D with 2.2 equiv. of trimethylsilyl azide
For our study, α-acetoxy lactam 8A was preferred, for kinetic (9b) provided expected diazide product 10b in an excellent
simple carba- and aza-mono-nucleophiles (Scheme 3). Thus, by
[
17]
reasons,
as one of the primary starting materials for subse- 98 % yield after only 30 min. In addition, silyl enol ethers such
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Table 1. Screenings of catalyst, bis-electrophile (Bis-E) and the reaction conditions in the α-amidoalkylation.
Entry
Bis-E
Conditions
Reagent 9a
10a
11
12
13
Yield [%]
Other [%]
1
2
3
4
5
6
7
8
9
8A
8A
8B
8C
8D
8D
8D
8D
8D
Bi(OTf)
Bi(OTf)
Bi(OTf)
Bi(OTf)
Bi(OTf)
Bi(OTf)
3
3
3
3
3
3
, 1 mol-%, 30 min
, 1 mol-%, 45 min
, 1 mol-%, 12 h
, 1 mol-%, 12 h
, 1 mol-%, 12 h
, 1 mol-%, 12 h
1.2 equiv.
2.4 equiv.
1.2 equiv.
1.2 equiv.
1.2 equiv.
2.4 equiv.
1.2 equiv.
1.2 equiv.
1.2 equiv.
19
28
44
–
51
76
87
45
56
9
8
–
–
–
–
–
–
–
18
24
–
–
–
–
–
–
–
6
4
–
–
–
–
–
–
–
52
64
–
–
[a]
44
8C (20 %)
[b]
0
–
51
76
87
45
56
8D (27 %)
8D (15 %)
–
8D (35 %)
–
Bi(OTf)
3
, 2 mol-%, 30 min
AlCl
AlCl
3
, 10 mol-%, 12 h
, 100 mol-%, 1 h
3
[
a] 20 % of reactant 8C resulting from the hydrolysis and MeO and/or AcO groups exchange via the N-acyliminium intermediate was recovered. [b] No reaction
occurred.
as 9c–e also proved themselves competent nucleophiles when
From these results (Scheme 3), it seems that the order of
presented with bis-N-acyliminium precursor 8D affording, after increasing heterocyclic reactivity (indazole → benzo[b]-
30 min, coupled products 10c–e in yields ranging from 68– furan → benzo[b]thiophene) is perfectly transposable to the
92 % after silica gel column chromatography. The impact of the amidoalkylation results. Herein, the yields for these transforma-
heterocyclic nucleus nucleophilicity on the α-amidoalkylation tions are much lower than those obtained with silanes 9a,b and
process was then measured by considering separately three silyl enol ether 9c–e derivatives which act as mono-nucleo-
types of simple heterocycles 9f–h using our standard reaction philes under the conditions employed. This observation can be
protocol starting from diacetate reactant 8D. After 1 h of reac- qualitatively rationalized on the basis of the nucleophilicity of
tion with 9f, α-hydroxy lactam bearing benzo[b]furane nucleus the corresponding reactive atoms in the isolated reactants in
[
19]
9
f as the sole reaction product, was isolated in 48 % yield. The terms of the constant sign domains of the first state-specific
OH group results from hydrolysis of the acetoxy group during grand canonical dual descriptor (which extends frontier molec-
[
20]
work-up. By using benzo[b]-thiophene (9g), which is more re- ular orbital theory). We found (see Figures S1–S2 in Support-
active than benzo[b]furane (9f), the double amidoalkylation re- ing Information) that this value is –0.0029 atomic units (a.u.) for
action provided 10g in 65 % after purification. Finally, with in- the C atom in 9a, but is more than three times lower in abso-
α
dazole (9h) as nucleophile, the reaction was never complete lute value for the nucleophilic N atom in indazole 9h
even if the reaction was heated at 60 °C for 30 min; the reaction (–0.0009 a.u.).
failed when other Lewis acids were used. In this case, isolated
Encouraged by the viability of the aforementioned double
product 10h (36 %) results from mono-N-amidoalkylation and α-amidoalkylation examples with mono-nucleophiles, we then
was accompanied by 15 % of unreacted starting diacetate 8D. chose to study the reactivity of aryl systems able to have two
Additional heating for longer times, diminished the reaction nucleophilic sites located at the 1- and 3-positions. The latter
yield and/or led to decomposition of the reaction mixture.
might allow, via the tandem process, the construction of nitro-
Scheme 3. Double α-amidoalkylation of bis-electrophile precursor 8D with mono-nucleophiles under the catalytic influence of Bi(OTf)
3
.
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5
6
gen heterocycles containing N-acyl-substituted N,O-acetals with of C –O bond cleavage and can be broken down into two
diverse functionalities. Along these lines of thought, we investi- elementary steps: first, lengthening of this bond (via TS2, af-
gated the scope and limitations of our Bi(OTf) -catalysed reac- fording C4), is followed by migration of the OAc moiety
3
tion protocol using diacetate 8D as the bis-N-acyliminium pre- (through TS3) so that an intramolecular hydrogen bond is
2
6
cursor and various phenols 14a–j bearing different electron- formed (in C5) between O and the proton on O . A subsequent
withdrawing (EWG) and electron-donating (EDG) substituents proton transfer occurs with a small barrier in terms of ΔE but
as bis-heteronucleophiles; the results of these efforts are sum- spontaneous from a ΔG° point of view to form intermediate C6;
marized in Scheme 4.
Various 4bH-benzo[5,6][1,3]oxazino[2,3-a]isoindol-12(10H)-
ones (15a–j) could thus be conveniently prepared (24–68 %
yield of isolated compounds) in a one-pot procedure. This proc-
ess proceeds through a newly tandem process based on the
heterocyclisation reaction using the nucleophilicity of the oxy-
gen atom and subsequent π-cyclisation onto the N-acyliminium
cation; the order of these events is advisable to define. With
phenol 14a as a model bis-heteronucleophile, the tandem proc-
ess led to the isolation of cyclic N,O-acetal 15a in 68 % yield;
its structure was confirmed by X-ray analysis after crystallization
(
see the ORTEP drawing in Scheme 4).
Preliminary DFT calculations were then performed to eluci-
date the mechanism of this reaction, as pictured in Figure 2
and Figure 3. Starting from complex C1, formed by the stacked
phenol (as model substrate) and 8D in interaction with two
AlCl molecules (stemming from the dissociation of Al Cl , cho-
3
2
6
sen here as Lewis basis for computational reasons), nucleophilic
3
1
attack of the C atom by carbon C (through transition state
Figure 2. First part of the potential energy surface (standard Gibbs energy, in
kcal/mol) for the formation of compound 15a on the basis of DFT calculations
at the ωB97X-D/6-31++G(d,p) IEFPCM level of theory. Color code for atoms:
H in white, C in grey, N in blue, O in red, Al in pink, Cl in green.
3
4
TS1) leads to the rupture of the C –O bond, giving intermedi-
ate C2. Intermediate C2 then evolves to C3 after AcOAlCl3–
elimination. The second stage of the transformation consists
Scheme 4. Intramolecular double α-amidoalkylation of new bis-electrophile 8D under the catalytic influence of Bi(OTf)
3
with bis-heteronucleophiles.
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this species then undergoes AcOHAlCl3 elimination to afford drawing of this product (Scheme 4 and the footnote) also indi-
2
5
C7. Finally, nucleophilic addition of O to C in a heterocyclisa- cates the presence of a hydrogen bond between the CO and
tion process using O2 as an internal nucleophile affords OH functions on the benzene ring. This fact, allied with the
(
through TS5) the expected six-membered ring, and finally, cy- electron-donating character of the carbonyl function, likely ex-
clised product 15a. The formation of the latter is only slightly plains abortion of the intramolecular oxo-amidoalkylation reac-
exothermic, suggesting that the conversion of reactants might tion necessary for completion of the tandem process leading
be not complete. The three main activation barriers for this ultimately to cyclic N,O-acetals in both cases. Finally, with fused
complex mechanism are associated with: i) the first nucleophilic phenols, the use of sesamol furnished expected cyclic product
attack leading to the C–C bond formation (21.3 kcal/mol, rate- 15i in 56 % yield whereas the use of ꢀ-naphthol provided ex-
5
6
determining step), ii) the C –O bond rupture (8.7 kcal/mol), pected product 15j in (45 %), its regioisomer 16j (22 %) and
and iii) the final cyclisation (5.7 kcal/mol). These facts are con- bis-addition adduct 17j (15 %) as a single atropisomer (as se-
sistent with formation, by amidoalkylation, of the C–O bond cured by X-ray analysis) after purification and recrystallization
which is reversible in acid media; this is not the case however, (Scheme 4). Interestingly, similar studies using phenols or ꢀ-
for the C–C bond (see the Supporting Information for computa- naphthols and N-benzoyl-indolinols under Lewis acid α-amido-
tional details).
alkylation conditions provide the C–C coupled products as a
pair of atropisomers accompanied, in certain cases, with N,O-
acetal 2-arylindoline products.
[
24]
As an illustration of the potential utility of this tandem proc-
ess, resulting allyl-N-homoallyl derivative 10a and diazide 10b
were then submitted to ring closure metathesis (RCM) and click
reactions (Scheme 5), respectively, using standard conditions.
nd
Thus, reaction of Grubbs 2 generation catalyst (5 mol-%) with
[
25]
1
0a in CH Cl at room temperature
for 24 h provided the
2
2
cyclic adduct 7,8,9,11a-tetrahydro-5H-azepino[2,1-a]isoindol-5-
one (19) in quantitative yield; no traces of 18 were observed.
In contrast to our case, the use of CH Cl has been reported to
2
2
be problematic with Grubbs catalysts containing N-(pent-4-
[
26a]
enyl)-3-(hex-1-enyl)isoindolin-2-one
vinylisoindolin-2-one components.
or N-(pent-4-enyl)-3-
In these cases Ti(OiPr)4/
[
26b]
toluene was used to generate 19 instead of 18 even though
the relative energies of these species based on B3LYP/6-311G(d)
[
26b]
calculations favour the generation of 18.
Figure 3. 2nd part of the potential energy surface (standard Gibbs energy, in
kcal/mol) for the formation of 15a on the basis of DFT calculations at the
ωB97X-D/6-31++G(d,p) IEFPCM level of theory. Color code for atoms is same
as in Figure 2.
All characteristic data of cyclised compound 15a are identi-
cal to those published recently by Roy and co-workers during
their application of a bimetallic Ir–Sn catalyst for tandem reac-
tion sequence of heterocyclisation/isomerisation/π-cyclisation
[
21]
using 3-hydroxy-N-phenyoxymethylisoindolin-1-one.
This se-
[
3]
quence was initially proposed by us in reports dealing with
[
8–10,22]
[10,23]
and selenium[10]-containing N-acyl-
sulfur,
oxygen
iminum precursors. o-Substituted phenols with Bn, OH and Br
also undergo the desired chemistry to render cyclic N,O-acetals
1
5b–d in moderate to low yields of 43 %, 45 % and 27 %, re-
spectively. Interestingly the p-bromophenol resulted in the for-
mation of expected cyclic N,O-acetal 15e with 65 % yield. A
second family of o-carbonylphenols evaluated here underscores
the impact of o-phenol α-position activation, particularly on the
production of cyclisation products. In fact, reaction of salicylal-
Scheme 5. Bis-nucleophile adducts 10a and 10b as applied in RCM and click
chemistry reactions.
As a second application, di-1,2,3-triazole compound 20 was
dehyde provided expected cyclic system 15f (24 %) accompa- isolated in 76 % yield after the reaction of diazide 10b with
nied by separable hydroxyl lactam 16f (38 %), and the reaction phenylacetylene (2.2 equiv.) in the presence of Hünig's base
of 2-hydroxyacetophenone led exclusively to non-cyclised (3 equiv.) and catalytic CuI (20 mol-%) in tBuOH/H O (1:1) for
2
[
27]
hydroxy lactam product 16h (31 %). However, the use of acti- 48 h at room temperature and subsequent purification. Inter-
vated p-methoxy-salicylaldehyde resulted in isolation of cyclic estingly, beyond the numerous applications of triazole com-
compound 16g (42 %) as the sole reaction product. The struc- pounds, aryl systems containing the di-1,2,3-triazole have been
ture of 16h was also confirmed by X-ray analysis. The ORTEP found to display important antimicrobial activities associated
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with modulated hemolytic activities; this modulation appears to 0.2 mmol) in CH
Cl
(10 mL) at 10–15 °C with stirring.[11a] The mix-
2
2
ture was stirred at room temperature overnight and quenched by
be dependent upon the precise position of each 1,2,3-triazole
moiety.
[
28]
addition of a saturated aqueous solution of NaHCO . The aqueous
3
layer was extracted with CH Cl (20 mL), and organic layers were
2
2
combined, dried with MgSO , and evaporated under reduced pres-
4
sure. The acetate derivative, namely 3-oxo-2-[(phenylsel-
enyl)methyl]isoindolin-1-yl acetate (8A), was then obtained after
purification of the residue by chromatography on a silica gel col-
umn. After recrystallization from a mixture of dry diethyl ether and
dry hexane the pure title product 8A as a yellow solid was isolated
in 92 % yield (662.9 mg), m.p. 138–141 °C (decomposition). IR (KBr):
Conclusions
In conclusion, we have developed a mild, efficient, practical and
general Bi(OTf) -catalysed double inter- and intramolecular am-
3
idoalkylation for the synthesis of an array of 2,3-substituted
isoindolinones and tricyclic N-acyl-substituted N,O-acetals. The
–
1 1
ν˜ = 1683, 1648 cm . H NMR (CDCl , 200 MHz): δ = 2.03 (s, 3 H),
3
nontoxic Bi(OTf) catalyst is used in low loadings (2 mol-%) and
3
4
7
1
8
.63 (d, J = 12.5 Hz, 1 H), 5.49 (d, J = 12.5 Hz, 1 H), 7.07 (s, 1 H),
.18–7.25 (m, 3 H), 7.43–7.58 (m, 5 H), 7.31 (dd, J = 7.2 and 2.3 Hz,
the new bis-N-acyliminium species generated during reaction
can be trapped, particularly in an intramolecular manner, in tan-
dem/domino processes using the combination of π-cationic cy-
13
H) ppm. C NMR (50 MHz, CDCl ): δ = 21.05 (CH ), 30.08 (CH ),
3
3
2
0.76 (CH), 123.86 (CH), 124.41 (CH), 128.14 (CH), 128.62 (C), 129.40
clisation and hetero-α-amido-alkylation with the oxygen atom (2CH), 130.53 (CH), 131.41 (C), 132.95 (CH), 134.35 (CH), 134.45 (CH),
serving as an internal nucleophile. The power of this approach, 140.94 (C), 166.82 (CO), 170.95 (CO) ppm. C17 Se (360.27):
calcd. C 56.68, H 4.20, N 3.89; found C 56.56, H 4.09, N 3.79.
H15NO
3
supported by preliminary DFT calculations, was ultimately illus-
trated by two reaction examples providing fused polyhydro-
pyrrolo[1,2-a]azepinone and isoindolinone-containing triazole
2
-(Methoxymethyl)-3-oxoisoindolin-1-yl Acetate (8B): This prod-
uct 8B, obtained from known 3-hydroxy-2-(methoxymethyl)isoindo-
[
29]
heterocycles with promising applications in chemical synthesis. lin-1-one, by using same procedure as for the preparation of 8A,
was isolated as a white solid in 85 % yield and used in the next step
without further purifications and manipulations, m.p. 114–116 °C
1
Experimental Section
(decomposition). H NMR (CDCl
(
3
, 200 MHz): δ = 2.14 (s, 3 H), 3.33
s, 3 H), 4.84 (d, J = 10.9 Hz, 1 H), 5.10 (d, J = 10.9 Hz, 1 H), 7.13 (s,
General: Unless otherwise noted, reactions were carried out under
an argon atmosphere, in flame dried, single-neck, round-bottomed
flasks fitted with a rubber septum, with magnetic stirring. Air- or
water-sensitive liquids and solutions were transferred via syringe.
Thin layer chromatography (TLC) was performed using silica gel
analytical plates (F254) of 0.25 mm thickness. The detection on TLC
plates was performed by UV light at 254 or 365 nm or using a
1
H), 7.51–7.66 (m, 3 H), 7.86 (d, J = 6.3 Hz, 1 H) ppm.
3-Methoxy-2-(methoxymethyl)isoindolin-1-one (8C): This prod-
uct 8C, was synthesized by employing the reported procedure,[
which based on N-acyliminium chemistry starting from 3-hydroxy-
2-(methoxymethyl)-isoindolin-1-one
methyl)isoindolin-1-one.
30]
[
29]
or 3-hydroxy-2-(hydroxy-
[
31]
After 15 h of the reaction at room tem-
permanganate or p-anisaldehyde revelator followed by heating us- perature this product was isolated as a white solid in 80–86 % yield
ing a heat gun. Purification of reaction products was generally done
by flash chromatography with silica gel 60 Å, 220–440 mesh, or by
using interchim puriflash 430. All commercially available starting
materials and catalysts have been used without further purification.
and used in the next without further manipulations, m.p. 122–
125 °C (decomposition). H NMR (CDCl
3.39 (s, 3 H), 4.76 (d, J = 12.0 Hz, 1 H), 5.17 (d, J = 12.0 Hz, 1 H),
6.07 (s, 1 H), 7.28–7.66 (m, 3 H), 7.89 (d, J = 6.0 Hz, 1 H) ppm.
): δ = 49.93 (CH ), 56.58 (CH ), 60.85 (CH ),
2
1
, 200 MHz): δ = 2.99 (s, 3 H),
3
1
3
C
Dichloromethane, acetonitrile were purified by distillation under ar- NMR (50 MHz, CDCl
3
3
3
gon from CaH immediately prior to use. Proton nuclear magnetic 85.49 (CH), 123.80 (CH), 124.08 (CH), 130.11 (CH), 132.19 (C), 132.76
2
1
resonance spectra ( H NMR) and carbon nuclear magnetic reso-
(CH), 140.87 (C), 168.30 (CO) ppm.
13
nance spectra ( C NMR) were recorded with a 300 Ultra Shield
instrument Bruker 300 (300 MHz/75 MHz) or Bruker AC200
(1-Acetoxy-3-oxoisoindolin-2-yl)methyl Acetate (8D): This reac-
tant was obtained in two steps via 1-hydroxy-3-oxoisoindolin-2-yl-
methyl acetate. Thus to solution of known N-(acetoxy-
(20 g, 91.24 mmol) in a mixture of dichloro-
(200 MHz/50 MHz) NMR spectrometer. Recorded shifts for protons
a
are reported in parts per million (δ scale) downfield from tetrameth-
ylsilane and are referenced to residual protium in the NMR solvents
[32]
methyl)phthalimide
methane/methanol in, 1:1 ratio 400 mL was added sodium borohy-
dride (5.2 g, 136.86 mmol) in one portion at –30 °C. The reaction
mixture was stirred for two hours and the resulting solution was
poured to a saturated solution of NaHCO3 and extracted with
CH Cl . The organic phases were combined, dried with magnesium
(
CHCl : δ = 7.26; [D ]DMSO: δ = 2.50 ppm). Chemical shifts for car-
3 6
bon resonances are reported in parts per million (δ scale) downfield
from tetramethylsilane and are referenced to the carbon resonances
of the solvent (CDCl : δ = 77.0; [D ]DMSO: δ = 39.5 ppm). Data are
3
6
2
2
represented as follows: chemical shift, integration, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, dq = doublet of quar-
tets, dd = doublet of doublets, m = multiplet), and coupling con-
stant (J, Hz). The infrared (IR) absorption spectra were record using
a Frontier FT-IR instrument (Perkin–Elmer) and are reported in wave-
sulfate and evaporated to give the α-hydroxy lactam, (1-hydroxy-3-
oxoisoindolin-2-yl)methyl acetate, as a white solid in 93 % yield,
m.p. 135–137 °C. IR (neat): ν˜ = 3325, 3090, 2991, 2946, 1726, 1694,
1
617, 1469, 1443, 1413, 1365, 1321, 1302, 1241, 1204, 1179, 1105,
–1
1
049, 1011, 939, 891, 856, 837, 801, 787, 744, 712, 687, 712, 697 cm .
–1
numbers (cm ). High resolution mass spectra (HRMS) were per-
formed with a 6530 Q-TOF Agilent system mass spectrometer (ESI).
Melting points were taken on a SMP10 capillary apparatus (Stuart)
and are uncorrected.
1
H NMR (CDCl , 300 MHz): δ = 2.07 (s, 3 H), 2.17 (s, 3 H), 5.48 (d,
3
J = 10.9 Hz, 1 H), 5.69 (d, J = 10.9 Hz, 2 H), 7.12 (s, 1 H), 7.57–7.63
13
(m, 3 H), 7.86 (d, J = 7.2 Hz, 1 H) ppm. C NMR (75 MHz, CDCl3):
δ = 20.81 (CH ), 20.99 (CH ), 64.15 (CH ), 80.71 (CH), 124.18 (CH),
3
3
2
3
-Oxo-2-[(phenylselenyl)methyl]isoindolin-1-yl Acetate (8A): 124.43 (CH), 130.52 (CH), 130.96 (C), 133.43 (CH), 141.30 (C), 167.78
Acetic anhydride (0.38 mL, 4 mmol) was added dropwise to a solu-
(CO), 170.73 (CO), 170.73 (CO) ppm. Without further purification, to
a stirring solution of the precedent α-hydroxy lactam (18 g,
[
9]
tion of 3-hydroxy-2-[(phenylselenyl)methyl]isoindolin-1-one (21,
38 mg, 2 mmol), NEt3 (0.56 mL, 4 mmol), and DMAP (24.4 mg,
6
81.37 mmol) in 300 mL of dry CH Cl2 was added triethylamine
2
Eur. J. Org. Chem. 2016, 3592–3602
www.eurjoc.org
3597
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
8
9.51 mmol, 12.49 mL, acetic anhydride 9.2 mL, 97.64 mmol and a colorless oil in 87 % yield. IR (neat): ν˜ = 3081, 2979, 2923, 1677,
–
1 1
catalytic amount of DMAP. The reaction mixture was stirred at room
temperature for one hour. After evaporation to dryness, the crude
1468, 1409, 993, 914, 733, 697 cm . H NMR (CDCl , 300 MHz): δ =
3
2.35–2.50 (m, 2 H), 2.61–2.70 (m, 1 H), 2.75–2.82 (m, 1 H), 3.17–3.26
mixture was diluted with water, extracted three times with CH Cl2 (m, 1 H), 4.09–4.18 (m, 1 H), 4.54–4.67 (m, 1 H), 4.98–5.13 (m, 4 H),
2
and then concentrated under reduced pressure to give α-acetoxy
5.31–5.47 (m, 1 H), 4.76–5.91 (m, 1 H), 7.42–7.55 (m, 3 H), 7.83 (d,
lactam 8D which was recrystallized from cyclohexane/CH Cl2 to
J = 8.0 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl ): δ = 32.76 (CH ),
2
3
2
give a pure white product in 95 % yield, m.p. 125–127 °C. IR (neat):
32.28 (CH ), 39.29 (CH ), 58.63 (CH), 117.15 (CH ), 119.32 (CH),
2 2 2
ν˜ = 3019, 2975, 2940, 1736, 1725, 1617, 1468, 1445, 1407, 1364, 122.30 (CH), 123.55 (CH), 128.17 (CH), 131.25 (CH), 132.50 (C), 135.07
+
1
6
8
4
342, 1234, 1207, 1193, 1174, 1157, 1020, 949, 925, 889, 846, 730, (CH), 144.69 (C), 168.52 (CO) ppm. ESI-HRMS, C H NO: [M + H] :
15 17
–1
1
+
98 cm . H NMR (CDCl , 300 MHz): δ = 2.07 (s, 3 H), 4.33 (d, J = calculated 228.1388, found 228.1388; [M + Na] : calculated
.7 Hz, 1 H), 5.48 (s, 2 H), 5.99 (d, J = 8.6 Hz, 1 H), 7.53 (dq, J = 8.1, 250.1207, found 250.1218; [2M + Na] : calculated 477.2517, found
3
+
Hz, 1 H), 7.64 (d, J = 3.9 Hz, 2 H), 7.77 (d, J = 7.5 Hz, 1 H) ppm.
C NMR (75 MHz, CDCl ): δ = 20.90 (CH ), 63.49 (CH ), 81.23 (CH),
477.2519.
1
3
3
3
2
3
-Azido-2-(azidomethyl)isoindolin-1-one (10b): This product was
1
23.77 (CH), 123.85 (CH), 130.02 (CH), 130.28 (C), 130.30 (CH), 140.79
prepared according to the general procedure and obtained as a
colorless oil in 98 % yield. IR (neat): ν˜ = 3051, 2946, 2092, 1710,
1616, 1468, 1399, 1360, 1312, 1296, 1202, 1153, 1092, 1010, 955,
(
C), 167.90 (CO) ppm.
General Procedure of the Treatment in Acid Media of 3-Oxo-2-
(phenylselenyl)methyl]isoindolin-1-yl Acetate (8A): To a stirred
solution of 3-oxo-2-[(phenylselenyl) methyl]isoindolin-1-yl acetate (d, J = 12.7 Hz, 1 H), 5.37 (d, J = 12.7 Hz, 1 H), 5.69 (s, 1 H), 7.68 (tt,
J = 7.4, 14.6 Hz, 3 H),7.92 (d, J = 7.5 Hz, 1 H) ppm. 13C NMR (75 MHz,
8A, 1 equiv.) and allyltrimethylsilane (9a, 1.2–2.4 equiv.) in 10 mL
–
1 1
[
876, 952, 742, 703, 677 cm . H NMR (CDCl , 300 MHz): δ = 4.76
3
(
of dry CH CN was added in one portion of bismuth(III) trifluoro- CDCl ): δ = 55.79 (CH ), 72.98 (CH), 123.60 (CH), 124.61 (CH), 130.54
3
3
2
methane-sulfonate [Bi(OTf) , 0.01 equiv.]. When the reaction was
over (monitored by TLC using CH Cl as eluent), a saturated aque-
(C), 130.79 (CH), 130.64 (CH), 140.14 (C), 167.44 (CO) ppm. ESI-HRMS,
3
+
2
2
C H N O: [M + Na] : calculated 252.0609, found 252.0608.
9 7 7
ous solution of NaHCO3 was added. The aqueous layer was then
extracted twice with CH Cl (2 × 10 mL), and the organic layers
3
-(3,3-Dimethyl-2-oxobutyl)-2-(4,4-dimethyl-3-oxopentyl)iso-
2
2
indolin-1-one (10c): This product was prepared according to the
general procedure and obtained as a white solid in 92 % yield; m.p.
were combined, dried with MgSO , and the solvents evaporated.
4
The resulting crude reaction mixture was separated by chromatog-
raphy on a silica gel column to provide expected product 10a (19–
7
1
1–73 °C. IR (neat): ν˜ = 2956, 2929, 2906, 2873, 1700, 1692, 1677,
–1 1
467, 1412, 1366, 1089, 1079, 995, 980, 748, 720, 691 cm . H NMR
2
8 % yield) and by-products 11 (8–9 % yield), 12 (18–24 % yield)
and 13 (4–6 % yield).
-(Phenylselenyl)-2-[(phenylselenyl)methyl]isoindolin-1-one
11): This by-product obtained during the reaction of bis-cation
precursor 8A with allyltrimethylsilane (9a) under the catalytic influ-
ence of Bi(OTf) was isolated as a yellow solid in 8–9 % yield, m.p.
(300 MHz, CDCl ): δ = 1.04 (s, 3 H), 1.09 (s, 3 H), 2.67 (dd, J = 18.1,
3
7
1
7
.9 Hz, 1 H), 2.84 (dd, J = 12.9, 6.4 Hz, 2 H), 3.12 (dd, J = 18.1, 4.4 Hz,
3
(
H), 3.28 (dt, J = 14.1, 6.9 Hz, 1 H), 3.97–4.08 (m, 1 H), 5.00 (dd, J =
.5, 4.6 Hz, 1 H), 7.26 (t, J = 6.2 Hz, 1 H), 7.31–7.45 (m, 1 H),7.71 (d,
13
J = 7.2 Hz, 1 H) ppm. C NMR (75 MHz, CDCl ): δ = 26.19 (CH ),
26.26 (CH ), 35.07 (CH ), 35.61 (CH ), 40.07 (CH ), 44.14 (C), 44.33
3
3
3
3 2 2 2
–
1 1
1
(
49–152 °C (decomposition). IR (KBr): ν˜ = 1685, 1658 cm . H NMR
(C), 55.71 (CH), 122.64 (CH), 123.32 (CH), 128.21 (CH), 131.56 (CH),
CDCl , 200 MHz): δ = 4.90 (d, J = 12.0 Hz, 1 H), 5.74 (d, J = 12.0 Hz,
3
131.74 (C), 145.96 (C), 168.26 (CO), 213.41 (CO), 214.29 (CO) ppm.
ESI-HRMS, C21H29NO : [M + H] : calculated 344.2225, found
344.2226; [M + Na] : calculated 366.2044, found 366.2041; [2M +
Na] : calculated 709.4191, found 709.4186.
1
H), 6.07 (s, 1 H), 7.00–7.14 (m, 4 H), 7.16–7.30 (m, 6 H), 7.44–7.57
+
3
(
(
m, 4 H) ppm. 13C NMR (50 MHz, CDCl ): δ = 60.37 (CH ), 93.25
+
3
2
CH), 123.50 (CH), 124.15 (CH), 124.29 (CH), 128.01 (CH), 128.58 (CH),
+
1
1
28.59 (CH), 128.97 (CH), 129.24 (CH), 129.38 (CH), 129.46 (CH),
30.75 (C), 131.69 (C), 132.17 (C), 134.04 (2CH), 136.59 (2CH), 143.86
3
-(2-Oxocyclopentyl)-2-[(2-oxocyclopentyl)methyl]isoindolin-1-
one (10d): This product was prepared according to the general
procedure and obtained as a white solid in 68 % yield, m.p. 147–
(
C), 166.42 (CO) ppm. C H NOSe (457.29): calcd. C 55.16, H 3.75,
21 17 2
N 3.06; found C 55.09, H 3.68, N 3.01.
1
1
7
49 °C. IR (neat): ν = 3021, 2948, 2873, 1728, 1684, 1611, 1466, 1454,
409, 1302, 1268, 1209, 1191, 1157, 1125, 1094, 998, 923, 830, 782,
29, 697, 683 cm . H NMR (300 MHz, CDCl ): δ = 1.25–2.75 (m, 14
˜
Allyl Phenyl Sulfide (12): Product 12, which has identical physico-
chemical characteristics to those reported in the literature, was ob-
tained in 18–24 % yield.[
–1
1
3
33]
H), 2.79–2.86 (dd, 1 H), 4.07–4.15 (dd, 1 H), 5.18 (s, 1 H), 7.38–7.59
(m, 3 H), 7.83 (d, J = 7.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 36.07 (CH ), 37.24 (CH ), 41.88 (CH ), 56.43 (CH), 123.00 (CH),
1
,2-Diphenyldiselane (13): Product 13, commercially available, has
identical physicochemical characteristics to those reported in the
2
2
2
literature and was obtained in 4–6 % yield.[
34]
123.48 (CH), 128.13 (CH), 128.18 (CH), 128.38 (CH), 128.66 (CH),
General Procedure for the α-Amidoalkylation: To a solution of 128.83 (CH), 131.74 (CH),131.83 (C), 133.39 (CH), 133.76 (CH), 136.48
α-acetoxy lactam 8D (100 mg, 0.38 mmol) in dry acetonitrile (3 mL)
were added 0.91 mmol of allyltrimethylsilane and 2 mol-%,
(C), 136.51 (C), 145.97 (C), 168.65 (CO), 197.41 (CO), 198.42
+
(CO) ppm. ESI-HRMS, C19
H21NO
: [M + Na] : calculated 334.1418,
3
(
0.0076 mmol, 4.98 mg) of Bi(OTf) . The reaction mixture was stirred found 334.1423.
3
at room temperature (monitored by TLC at regular interval). The
reaction was quenched with a saturated aqueous solution of NaH-
3
-(2-Oxo-2-phenylethyl)-2-(3-oxo-3-phenylpropyl)isoindolin-1-
one (10e): This product was prepared according to the general
procedure and obtained as a white solid in 76 % yield; m.p. 128–
130 °C. IR (neat): ν = 3052, 2948, 2873, 1728, 1684, 1611, 1409, 1302,
CO . The aqueous layer was than extracted with CH Cl (2 × 15 mL)
3
2
2
and the combined organic layers were dried with MgSO . After re-
4
˜
moval of solvent under reduced pressure, the resulting crude was
purified by flash chromatography on silica gel to provide expected
bis-adducts 10a–h and cyclized products 15a–j and 16j. See Sup-
porting Information for spectral characteristics of these compounds.
–1 1
1157, 923, 729, 697 cm . H NMR (300 MHz, CDCl ): δ = 3.24–3.33
3
(m, 1 H), 3.37–3.57 (m, 2 H), 3.68–3.82 (m, 2 H), 4.27–4.36 (m, 1 H),
5.36–5.40 (m, 1 H), 7.44–7.64 (m, 9 H), 7.84–7.87 (m, 1 H), 7.85–8.00
13
(m, 4 H) ppm. C NMR (75 MHz, CDCl ): δ = 36.07 (CH ), 37.24
3 2
3
-Allyl-2-(but-3-en-1-yl)isoindolin-1-one (10a): This product was
(CH ), 41.88 (CH ), 56.43 (CH), 123.00 (CH), 123.48 (CH), 128.13 (CH),
2 2
prepared according to the general procedure and obtained as a
128.18 (CH), 128.38 (CH), 128.66 (CH), 128.83 (CH), 131.74
3598 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2016, 3592–3602
www.eurjoc.org

Full Paper
(
CH),131.83 (C), 133.39 (CH), 133.76 (CH), 136.48 (C), 136.51 (C),
7.91 (d, J = 7.0 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl ): δ = 39.28
3
1
45.97 (C), 168.65 (CO), 197.41 (CO), 198.42 (CO) ppm. ESI-HRMS, (CH ), 82.12 (CH), 117.92 (CH), 118.77 (C), 122.56 (CH), 123.79 (CH),
2
+
C H NO : [M + H] : calculated 384.1599, found 384.1606; [M +
123.88 (CH), 127.33 (CH), 128.33 (CH), 130.49 (CH), 132.29 (CH),
132.51 (C), 140.57 (C), 152.45 (C), 166.70 (CO) ppm. ESI-HRMS,
25
21
3
+
+
Na] : calculated 406.1418, found 406.1425; [2M + Na] : calculated
89.2939, found 789.2955.
+
7
C H NO : [M + Na] : calculated 260.0686, found 260.0693.
15
11
2
2
-(Benzofuran-3-ylmethyl)-3-hydroxyisoindolin-1-one (10f): Di-
6-Benzyl-4bH-benzo[5,6][1,3]oxazino[2,3-a]isoindol-12(10H)-
one (15b): Diacetate 8D (100 mg, 0.38 mmol), o-benzylphenol (14b,
acetate 8D (100 mg, 0.38 mmol), benzo[b]furan (9f, 1.1 equiv.,
0
.418 mmol) and 2 mol-% of Bi(OTf) were reacted according to the 1.1 equiv., 0.418 mmol) and 2 mol-% of Bi(OTf) were reacted ac-
3
3
general procedure to provide 10f as a white solid in 48 % yield;
cording to the general procedure to give 15b as a white solid in
m.p. 171–173 °C. IR (neat): ν˜ = 3079, 3051, 2920, 1682, 1468, 1460, 43 % yield; m.p. 109–111 °C. IR (neat): ν˜ = 3027, 2916, 2853, 1710,
–
1 1
1
(
425, 1399, 1361, 1044, 905, 759, 727, 707, 661 cm
.
H NMR
1692, 1462, 1429, 1355, 1298, 1193, 1141, 1074, 1022, 994, 818, 782,
–
1 1
300 MHz, CDCl ): δ = 4.12 (d, J = 7.1 Hz, 1 H), 4.46 (d, J = 15.7 Hz,
745, 729, 697 cm . H NMR (300 MHz, CDCl ): δ = 4.03 (q, J =
3
3
1
H), 4.81 (d, J = 15.7 Hz, 1 H), 5.84 (d, J = 6.6 Hz, 1 H), 6.66 (s, 1
15.0 Hz, 2 H), 4.60 (d, J = 16.9 Hz, 1 H), 5.19 (d, J = 16.9 Hz, 1 H),
5.82 (s, 1 H), 6.97–7.06 (m, 1 H), 7.11 (d, J = 7.3 Hz, 2 H), 7.17–7.42
(m, 5 H), 7.57–7.63 (m, 3 H), 7.92 (d, 1 H) ppm. C NMR (75 MHz,
H), 7.17–7.27 (m, 2 H), 7.40 (d, J = 7.9 Hz, 1 H), 7.46–7.51 (m, 2 H),
1
3
13
7
.56–7.63 (m, 2 H), 7.69 (d, J = 7.5 Hz, 1 H) ppm. C NMR (75 MHz,
CDCl ): δ = 36.04 (CH ), 81.62 (CH), 105.24 (CH), 111.26 (CH), 120.99
CDCl ): δ = 35.95 (CH ), 39.52 (CH ), 82.21 (CH), 118.85 (C), 122.29
3
2
3
2
2
(CH), 122.87 (CH), 123.45 (CH), 123.59 (CH), 124.31 (CH), 128.08 (C),
(CH), 123.78 (CH), 123.82 (CH), 125.50 (CH), 126.03 (CH), 128.35 (CH),
1
29.84 (CH), 130.96 (C), 132.63 (CH), 143.96 (C), 152.78 (C), 154.99 128.90 (CH), 129.22 (CH), 130.45 (CH), 130.53 (C), 132.22 (CH), 132.68
+
(C), 169.40 (CO) ppm. ESI-HRMS, C H NO : [M + H] : calculated
(C), 140.64 (C), 150.44 (C), 166.70 (CO) ppm. ESI-HRMS, C H NO :
22 17 2
1
7
+
13
3
+
+
2
3
80.0973, found 280.0974; [M + Na] : calculated 302.0792, found [M + H] : calculated 328.1337, found 328.1335; [M + Na] : calculated
+
+
02.0809; [2M + Na] : calculated 581.1687, found 581.1698.
350.1156, found 350.1157; [2M + Na] : calculated 677.2415, found
77.2411.
6
3
-(Benzo[b]thiophen-3-yl)-2-(benzo[b]thiophen-3-ylmethyl)-
isoindol-in-1-one (10g): Diacetate 8D (100 mg, 0.38 mmol),
benzo[b]thiophene (9g, 1.1 equiv., 0.418 mmol) and 2 mol-% of
6-Hydroxy-4bH-benzo[5,6][1,3]oxazino[2,3-a]isoindol-12(10H)-
one (15c): Diacetate 8D (100 mg, 0.38 mmol), cathecol (14c,
Bi(OTf) were reacted according to the general procedure to give 1.1 equiv., 0.418 mmol) and 2 mol-% of Bi(OTf) were reacted ac-
3
3
1
0g as a white solid in 65 % yield; m.p. 208–210 °C. IR (neat): ν˜ =
cording to the general procedure to give 15c as a brown solid in
3
1
074, 2987, 1682, 1613, 1467, 1425, 1398, 1359, 1278, 1199, 1142, 45 % yield; m.p. 225–227 °C. IR (neat): ν˜ = 3234, 3063, 2920, 1688,
–
1
1
–
1
081, 1045, 1019, 977, 906, 840, 760, 735, 707, 660 cm . H NMR
1615, 1597, 1478, 1435, 1351, 1185, 1030, 985, 814, 729, 681 cm .
1
(300 MHz, [D ]DMSO, 344 K): δ = 4.29 (d, J = 15.3 Hz, 1 H), 5.28 (d,
H NMR (300 MHz, CDCl ): δ = 4.59 (d, J = 17.0 Hz, 1 H), 5.23 (d, J =
6
3
J = 15.2 Hz, 1 H), 5.96 (s, 1 H), 6.90–7.41 (m, 7 H), 7.53 (dt, J = 14.9,
17.0 Hz, 1 H), 5.57 (s, 1 H), 6.04 (s, 1 H), 6.78 (d, J = 7.5 Hz, 1 H),
6.88–7.00 (m, 2 H), 7.62–7.80 (m, 2 H), 7.79 (d, J = 7.1 Hz, 1 H), 7.93
(d, J = 7.1 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl ): δ = 39.08 (CH ),
1
3
7
.3 Hz, 2 H), 7.93 (dd, J = 12.3, 7.3 Hz, 2 H) ppm. C NMR (75 MHz,
[
D ]DMSO): δ = 37.54 (CH ), 59.88 (CH), 121.10 (CH), 121.68 (CH),
6
2
3
2
1
1
22.85 (CH), 123.22 (CH), 123.29 (CH), 124.23 (CH), 124.45 (CH),
82.74 (CH), 113.88 (CH), 118.17 (CH), 119.31 (C), 122.86 (CH), 123.77
(CH), 124.05 (CH), 130.78 (CH), 132.34 (CH), 132.52 (C), 139.78 (C),
26.05 (CH), 128.71 (CH), 131.40 (C), 132.26 (CH), 137.51 (C), 139.74
+
(C), 140.63 (C), 167.18 (CO) ppm. ESI-HRMS, C H NOS : [M + H] : 140.00 (C), 145.18 (C), 166.58 (CO) ppm. ESI-HRMS, C H NO : [M
2
5
17
2
15 11
+
3
+
+
calculated 412.0829, found 412.0832; [M + Na] : calculated + H] : calculated 254.0816, found 254.0818; [M + Na] : calculated
+
+
4
8
34.0648, found 434.0648; [2M + Na] : calculated 845.1399, found 276.0635, found 276.0634; [2M + Na] : calculated 529.1373, found
45.1407.
529.1381.
2
-[(1H-Indazol-1-yl)methyl]-3-hydroxyisoindolin-1-one (10h):
6-Bromo-4bH-benzo[5,6][1,3]oxazino[2,3-a]isoindol-12(10H)-
Diacetate derivative 8D (100 mg, 0.38 mmol), indazole (9 h, one (15d): Diacetate 8D (100 mg, 0.38 mmol), o-bromophenol
1
.1 equiv., 0.418 mmol) and 2 mol-% of Bi(OTf) were reacted ac- (14d, 1.1 equiv., 0.418 mmol) and 2 mol-% of Bi(OTf) were reacted
3
3
cording to the general procedure at 60 °C to give 10h in 36 % yield;
according to the general procedure to give 15d as a white solid in
m.p. 157–159 °C. IR (neat): ν˜ = 3682, 3313, 1690, 1466, 1419, 1294, 27 % yield; m.p. 165–167 °C. IR (neat): ν˜ = 3083, 2956, 2916, 1728,
–
1 1
1
(
044, 1014, 764, 747, 685 cm . H NMR (300 MHz, CDCl ): δ = 5.43 1575, 1462, 1454, 1421, 1349, 1232, 1199, 1137, 1004, 911, 816, 741,
3
–
1 1
d, J = 7.4 Hz, 1 H), 5.93 (d, J = 7.6 Hz, 1 H), 5.98 (d, J = 14.6 Hz, 1
691 cm . H NMR (300 MHz, CDCl ): δ = 4.61 (d, J = 17 Hz, 1 H),
3
H), 6.30 (d, J = 14.6 Hz, 1 H), 7.19 (t, J = 7.5 Hz, 1 H), 7.43–7.53 (m,
5.19 (d, J = 16.9 Hz, 1 H),5.82 (s, 1 H), 6.97–7.06 (m, 1 H), 7.11 (d,
2
4
H), 7.56–7.60 (m, 2 H), 7.71 (d, J = 8.1 Hz, 4 H), 7.81 (d, J = 7.4 Hz, J = 7.3 Hz, 2 H), 7.17–7.42 (m, 5 H), 7.57–7.63 (m, 3 H), 7.92 (d, 1
1
3
13
H), 7.90 (d, J = 8.5 Hz, 1 H) 7.99 (s, 1 H) ppm. C NMR (75 MHz,
H) ppm. C NMR (75 MHz, CDCl ): δ = 35.25 (CH ), 82.63 (CH),
3 2
CDCl ): δ = 51.51 (CH ), 80.63 (CH), 110.19 (CH), 120.95 (CH), 121.67
112.01 (C), 120.55 (C), 123.23 (CH), 123.93 (CH), 124.13 (CH), 126.43
3
2
(
1
CH), 123.65 (CH), 123.85 (CH), 124.16 (C), 127.55 (CH), 129.91 (CH), (CH), 130.71 (CH), 132.08 (CH), 132.35 (C), 132.55 (CH), 140.15 (C),
+
30.71 (C), 132.93 (CH), 134.57 (CH), 139.42 (C), 143.69 (C), 167.14 149.20 (C), 166.64 (CO) ppm. ESI-HRMS, C H BrNO : [M + H] : cal-
15 10 2
+
(CO) ppm. ESI-HRMS, C H N O : [M + Na] : calculated 302.0904,
culated 315.9972, found 315.9954.
1
6 13 3 2
found 302.0908.
8
-Bromo-4bH-benzo[5,6][1,3]oxazino[2,3-a]isoindol-12(10H)-
4
bH-Benzo[5,6][1,3]oxazino[2,3-a]isoindol-12(10H)-one (15a):
one (15e): Diacetate 8D (100 mg, 0.38 mmol), p-bromophenol (14e,
Diacetate derivative 8D (100 mg, 0.38 mmol), phenol (14a,
1.1 equiv., 0.418 mmol) and 2 mol-% of Bi(OTf) were reacted ac-
3
1
.1 equiv., 0.418 mmol) and 2 mol-% of Bi(OTf) were reacted ac- cording to the general procedure to give 15e as a white solid in
3
[
21]
cording to the general procedure to give 15a as a white solid in
65 % yield; m.p. 167–169 °C (White semisolid); IR (neat): ν˜ = 3039,
6
2
7
1
2
8 % yield; m.p. 124–126 °C (120–122 °C);[21] IR (neat): ν˜ = 3058, 2921, 1726, 1616, 1579, 1482, 1426, 1409, 1340, 1273, 1217, 1143,
–
1
916, 2863, 1710, 1583, 1486, 1421, 1355, 1286, 1145, 1014, 812,
1117, 1083, 1009, 989, 958, 905, 881, 808, 767, 730, 689, 679 cm .
–1
1
1
57, 770, 735 cm . H NMR (300 MHz, CDCl ): δ = 4.61 (d, J =
H NMR (300 MHz, CDCl ): δ = 4.53 (d, J = 17.1 Hz, 1 H), 5.16 (d, J =
3
3
6.9 Hz, 1 H), 5.21 (d, J = 12.4 Hz, 1 H), 5.99 (s, 1 H), 7.01–7.10 (m,
H), 7.21–7.27 (m, 2 H), 7.61–7.68 (m, 2 H), 7.79 (d, J = 7.3 Hz, 1 H),
17.1 Hz, 1 H),5.94 (s, 1 H), 6.88 (d, J = 9.0 Hz, 1 H), 7.29 (d, J = 5.2 Hz,
2 H), 7.62 (tt, J = 17.8, 8.8 Hz, 2 H), 7.75 (d, J = 7.2 Hz, 1 H), 7.88 (d,
Eur. J. Org. Chem. 2016, 3592–3602
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Full Paper
J = 7.2 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl ): δ = 38.87 (CH ),
1207, 1056, 1022, 967, 782, 747, 691 cm–1. 1H NMR (300 MHz,
3
2
8
2.13 (CH), 114.70 (C), 119.65 (CH), 120.77 (C), 123.81 (CH), 123.94
CDCl ): δ = 2.66 (s, 3 H), 4.24 (d, J = 8 Hz, 1 H), 4.64 (d, J = 14.8 Hz,
3
(CH), 129.92 (CH), 130.62 (CH), 131.31 (CH), 132.27 (C), 132.41 (CH), 1 H), 4.82 (d, J = 14.8 Hz, 1 H), 5.85 (d, J = 7.7 Hz, 1 H), 6.91 (t, J =
1
5
40.20 (C), 151.54 (C), 166.50 (CO) ppm. C H BrNO (314.99): C 7.7 Hz, 1 H), 7.43–7.60 (m, 3 H), 7.64 (d, J = 7.3 Hz, 1 H), 7.73 (t, J =
1
5
10
2
6.99, H 3.19, N 4.43; found C 56.78, H 3.11, N 4.35.
9.0 Hz, 2 H), 13.03 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl ): δ = 26.76
3
(
1
CH ), 37.04 (CH ), 81.49 (CH), 119.37 (CH), 119.56 (C), 123.35 (CH),
26.00 (CH), 129.71 (CH), 130.57 (CH), 130.71 (CH), 131.65 (C), 132.19
3 2
1
2-Oxo-10,12-dihydro-4bH-benzo[5,6][1,3]oxazino[2,3-a]iso-
indole-6-carbaldehyde (15f): Diacetate 8D (100 mg, 0.38 mmol),
-hydroxybenzaldehyde (14f, 1.1 equiv., 0.418 mmol) and 2 mol-%
of Bi(OTf) were reacted according to the general procedure to give
(
(
CH), 138.28 (CH), 143.42 (C), 160.20 (C), 167.29 (CO) 205.08
2
+
CO) ppm. ESI-HRMS, C H NO : [M + Na] : calculated 320.0898,
17
15
+
4
3
found 320.0897; [2M + Na] : calculated 617.1899, found 617.1887.
15f as a white solid in 24 % yield (in addition to this cyclized com-
pound, 16f was also isolated); m.p. 192–194 °C. IR (neat): ν = 3051,
5aH-[1,3]Dioxolo[4′′,5′′:4′,5′]benzo[1′,2′:5,6][1,3]oxazino[2,3-a]-
isoindol-10(12H)-one (15i): Diacetate 8D (100 mg, 0.38 mmol),
˜
2
1
1
7
956, 2920, 2845, 1708, 1678, 1591, 1468, 1421, 1238, 1197, 1135,
–1 1
010, 739, 689 cm . H NMR (300 MHz, CDCl ): δ = 4.65 (d, J =
sesamol (14i, 1.1 equiv., 0.418 mmol) and 2 mol-% of Bi(OTf) were
3
3
7.0 Hz, 1 H), 5.28 (d, J = 17.0 Hz, 1 H),6.13 (s, 1 H), 7.16 (t, J =
.6 Hz, 1 H), 7.47 (d, J = 7.5 Hz, 1 H), 7.66 (t, J = 7.3 Hz, 1 H), 7.73
reacted according to the general procedure to give 15i as a brown
solid in 56 % yield; m.p. 161–163 °C. IR (neat): ν˜ = 3055, 2992, 2916,
1710, 1635, 1621, 1504, 1478, 1431, 1351, 1242, 1143, 1032, 935,
(
t, J = 7.3 Hz, 1 H), 7.77–7.86 (m, 2 H), 7.94 (d, J = 7.2 Hz, 1 H) ppm.
1
3
–1 1
C NMR (75 MHz, CDCl ): δ = 38.96 (CH ), 82.32 (CH), 119.75 (C), 840, 778, 737, 691 cm . H NMR (300 MHz, CDCl ): δ = 4.85 (d, J =
3
2
3
1
(
1
22.30 (CH), 123.91 (CH), 124.12 (CH), 125.15 (C), 127.41 (CH), 130.90 9.9 Hz, 1 H), 5.74 (s, 1 H), 5.80 (s, 1 H), 5.86 (s, 1 H), 6.0 (d, J = 9.9 Hz,
CH), 132.19 (C), 132.64 (CH), 133.47 (CH), 139.95 (C), 154.86 (C), 1 H), 6.34 (s, 1 H), 6.91 (s, 1 H), 6.91 (t, J = 7.4 Hz, 1 H), 6.91 (t, J =
66.54 (CO), 188.57 (CHO) ppm. ESI-HRMS, C H NO : [M + H] : 7.4 Hz, 1 H), 6.91 (d, J = 7.6 Hz, 1 H), 6.91 (d, J = 7.5 Hz, 1 H) ppm.
+
1
6
11
3
+
13
calculated 266.0816, found 266.1725; [M + Na] : calculated
88.0635, found 288.0634.
C NMR (75 MHz, CDCl ): δ = 56.83 (CH ), 69.56 (CH), 99.80 (CH),
3 2
2
101.34 (CH ), 104.93 (CH), 113.09 (CH), 123.24 (CH), 124.76 (CH),
2
1
28.97 (CH), 131.35 (C), 132.95 (CH), 142.89 (C), 145.29 (C), 147.66
2
-Hydroxy-3-[(1-hydroxy-3-oxoisoindolin-2-yl)methyl]benzalde-
+
(C), 169.40 (CO) ppm. ESI-HRMS, C H NO : [M + Na] : calculated
16 11 4
+
hyde (16f): Diacetate 8D (100 mg, 0.38 mmol), 2-hydroxybenzalde-
hyde (14f, 1.1 equiv., 0.418 mmol) and 2 mol-% of Bi(OTf)3 were
reacted according to the general procedure to give 16f as a white
3
5
04.0585, found 304.0584; [2M + Na] : calculated 585.1273, found
85.1283.
solid in 38 % yield (in addition to this compound, 15f was also 7aH-Naphtho[1′,2′:5,6][1,3]oxazino[2,3-a]isoindol-12(14H)-one
isolated); m.p. 174–176 °C. IR (neat): ν = 3329, 2916, 2849, 1694,
(15j): Diacetate derivative 8D (100 mg, 0.38 mmol), 2-naphthol (14j,
˜
1
6
651, 1617, 1468, 1411, 1280, 1207, 1052, 1016, 939, 788, 743,
1.1 equiv., 0.418 mmol) and 2 mol-% of Bi(OTf) were reacted ac-
3
–1 1
95 cm . H NMR (300 MHz, CDCl ): δ = 2.74 (d, J = 11.8 Hz, 1 cording to the general procedure to give 15j as a white solid in
3
H)4.41 (d, J = 14.8 Hz, 1 H), 4.97 (d, J = 14.8 Hz, 1 H),5.66 (d, J = 45 % yield (in addition to this compound, two products 16j and
1
1.4 Hz, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 7.53–7.60 (m, 5 H), 7.80 (d,
17j were isolated); m.p. 208–210 °C. IR (neat): ν˜ = 3063, 2928, 2857,
1
3
J = 7.3 Hz, 1 H), 9.88 (s, 1 H), 11.00 (s, 1 H) ppm. C NMR (75 MHz,
CDCl ): δ = 42.04 (CH ), 81.22 (CH), 118.16 (CH), 120.45 (C), 123.43 683 cm . H NMR (300 MHz, CDCl ): δ = 4.92 (d, J = 16.9 Hz, 1 H),
1728, 1617, 1597, 1516, 1466, 1423, 1201, 1131, 998, 804, 739, 709,
–
1 1
3
2
3
(CH), 123.62 (CH), 128.78 (C), 130.19 (CH), 131.33 (C), 132.60 (CH),
5.53 (d, J = 16.9 Hz, 1 H), 6.08 (s, 1 H), 7.19 (d, J = 8.9 Hz, 1 H), 7.47
1
33.71 (CH), 137.49 (CH), 143.51 (C), 161.14 (C), 167.08 (CO), 196.47
(t, J = 7.4 Hz, 1 H), 7.55–7.90 (m, 7 H), 7.95 (d, J = 7.3 Hz, 1 H) ppm.
+
13
(CHO) ppm. ESI-HRMS, C H NO : [M + Na] : calculated 306.0741,
C NMR (75 MHz, CDCl ): δ = 37.74 (CH ), 81.95 (CH), 110.90 (C),
1
6
13
4
3
2
found 306.0739.
118.76 (CH), 121.34 (CH), 123.84 (CH), 123.96 (CH), 124.59 (CH),
27.29 (CH), 128.70 (CH), 129.08 (CH), 129.61 (C), 130.55 (CH), 130.92
C), 132.34 (CH), 132.63 (C), 140.48 (C), 150.03 (C), 166.65 (CO) ppm.
1
(
8
-Methoxy-12-oxo-10,12-dihydro-4bH-benzo[5,6][1,3]ox-
azino[2,3-a]isoindole-6-carbaldehyde (15g): Diacetate derivative
D (100 mg, 0.38 mmol), 2-hydroxy-5-methoxybenzaldehyde (14g,
.1 equiv., 0.418 mmol) and 2 mol-% of Bi(OTf) were reacted ac-
+
ESI-HRMS, C19H13NO : [M + H] : calculated 288.1024, found
2
8
1
+
288.1033; [M + Na] : calculated 310.0843, found 310.0839.
3
cording to the general procedure to provide cyclized product 15g
as a white solid in 42 % yield; m.p. 214–216 °C. IR (neat): ν˜ = 3048,
8H-Naphtho[1′,2′:5,6][1,3]oxazino[4,3-a]isoindol-10(14bH)-one
(16j): Diacetate 8D (100 mg, 0.38 mmol), 2-naphthol (14j, 1.1 equiv.,
2
1
919, 2853, 1718, 1692, 1677, 1597, 1467, 1416, 1320, 1286, 1202,
0.418 mmol) and 2 mol-% of Bi(OTf) were reacted according to the
3
–
1 1
144, 1051, 1019, 1010, 983, 855, 822, 735, 689 cm
.
H NMR
general procedure to give 16j as a white solid in 22 % yield (in
addition to this product, 15j and 17j were also isolated); m.p. 172–
(
300 MHz, CDCl ): δ = 3.85 (s, 3 H),4.62 (d, J = 17.1 Hz, 1 H), 5.25 (d,
3
J = 17.1 Hz, 1 H),6.08 (s, 1 H), 7.03 (d, J = 1.9 Hz, 1 H), 7.30 (d, J =
.2 Hz, 1 H), 7.66 (t, J = 7.3 Hz, 1 H), 7.72 (t, J = 7.3 Hz, 1 H), 7.80
174 °C. IR (neat): ν = 3055, 3015, 2936, 1698, 1621, 1599, 1510, 1468,
˜
2
1385, 1365, 1345, 1282, 1218, 1197, 1149, 1062, 996, 967, 814, 741,
1
3
–1 1
(d, J = 7.4 Hz, 1 H), 7.94 (d, J = 7.2 Hz, 1 H) ppm. C NMR (75 MHz,
703, 681 cm . H NMR (300 MHz, CDCl ): δ = 4.91 (d, J = 9.6 Hz, 1
3
CDCl ): δ = 39.16 (CH ), 55.89 (CH ), 82.41 (CH), 109.73 (CH), 120.49 H), 6.22 (d, J = 9.6 Hz, 1 H), 6.71 (s, 1 H), 7.10 (d, J = 8.9 Hz, 1 H),
3
2
3
(
1
CH), 121.24 (C), 123.88 (CH), 124.08 (CH), 125.43 (C), 130.85 (CH),
7.41–7.57 (m, 3 H), 7.63–7.77 (m, 2 H), 7.86 (d, J = 8.1 Hz, 1 H), 7.90–
32.25 (C), 132.60 (CH), 140.03 (C), 154.53 (C), 166.50 (CO), 188.31 7.98 (m, 2 H), 8.38 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR (75 MHz,
+
(CHO) ppm. ESI-HRMS, C H NO : [M + H] : calculated 296.0922,
CDCl ): δ = 56.36 (CH), 70.81 (CH ), 114.27 (C), 119.48 (CH), 123.12
3 2
17
+
13
4
found 296.0919; [M + Na] : calculated 318.0741, found 318.074; [2M (CH), 124.37 (CH), 124.52 (CH), 124.65 (CH), 126.60 (CH), 128.99 (CH),
+
+
Na] : calculated 613.1585, found 613.1577.
129.11 (CH), 129.17 (CH), 130.26 (C), 131.47 (C), 131.84 (C), 132.99
(
[
3
5
CH), 145.07 (C), 153.00 (C), 171.26 (CO) ppm. ESI-HRMS, C H NO :
19 13 2
2
-(3-Acetyl-2-hydroxybenzyl)-3-hydroxyisoindolin-1-one (16h):
+
+
M + H] : calculated 288.1024, found 288.102; [M + Na] : calculated
Diacetate derivative 8D (100 mg, 0.38 mmol), 2-hydroxyacetophe-
none (14h, 1.1 equiv., 0.418 mmol) and 2 mol-% of Bi(OTf) were
reacted according to the general procedure to give 16 h as a white
+
10.0843, found 310.0837; [2M + Na] : calculated 597.1789, found
97.1784.
3
solid in 31 % yield, M.p. 104–106 °C. IR (neat): ν˜ = 3281, 3055, 3011, 3-(2-Hydroxynaphthalen-1-yl)-2-[(2-hydroxynaphthalen-1-
2
960, 2924, 1672, 1635, 1617, 1470, 1435, 1365, 1300, 1274, 1246, yl)methyl]isoindolin-1-one (17j): Diacetate 8D (100 mg,
Eur. J. Org. Chem. 2016, 3592–3602
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
0
.38 mmol), 2-naphthol (14j, 1.1 equiv., 0.418 mmol) and 2 mol-% CCDC 1060286 (for 15a), 1060287 (for 16h), and 1060288 (for 17j)
of Bi(OTf) were reacted according to the general procedure to give
contain the supplementary crystallographic data for this paper.
3
17j as a white solid in 15 % yield (in addition to this products,
These data can be obtained free of charge from The Cambridge
compounds 15j and 16j were also isolated); m.p. 260–265 °C (de- Crystallographic Data Centre.
composition). IR (neat): ν˜ = 3547, 3500–2300 (large), 3059, 2845,
–
1 1
1
651, 1631, 1415, 1234, 1211, 1167, 1009, 810, 741, 707 cm . H
Acknowledgments
NMR (300 MHz, DMSO): δ = 4.44 (d, J = 14.4 Hz, 1 H), 5.29 (d, J =
1
1
4.4 Hz, 1 H), 6.20 (s, 1 H), 6.97–7.31 (m, 8 H), 7.46 (dt, J = 7.3,
8.2 Hz, 2 H), 7.64–7.82 (m, 5 H), 7.90 (d, J = 7.2 Hz, 1 H), 9.41 (s, 1
The authors thank the Campus France and the Service of Coop-
eration and Cultural Action (SCAC) of the French Embassy in
Mauritania for Postdoc fellowship attributed to A. A. and for
financial support of this research program. L. J. and V. T. ac-
knowledge the Centre National de la Recherche Scientifique
13
H), 9.88 (s, 1 H) ppm. C NMR (75 MHz, [D ]DMSO): δ = 34.39 (CH ),
6
2
5
(
1
6.12 (CH), 111.12 (C), 112.82 (C), 118.00 (CH), 118.13 (CH), 120.67
CH), 122.09 (CH), 122.18 (CH), 122.53 (CH), 123.11 (CH), 126.29 (CH),
27.86 (C), 128.04 (CH), 128.26 (CH), 128.37 (C), 128.74 (CH), 129.26
(
1
CH), 130.11 (CH),131.37 (C), 131.95 (CH), 132.39 (C), 130.09 (C), (CNRS) and the Labex SynOrg for funding. The CRIAAN com-
46.57 (C), 154.31 (C), 155.26 (C), 167.81 (CO) ppm. ESI-HRMS, puter center at Normandie Univ. is thanked for support.
+
C H NO : [M + H] : calculated 432.1599, found 432.1591; [M +
2
9
21
3
+
Na] : calculated 454.1418, found 454.1414.
Keywords: Homogeneous catalysis · Domino reactions ·
7
,8,9,11a-Tetrahydro-5H-azepino[2,1-a]isoindol-5-one (19): To a Bismuth · Carbocations · Nitrogen heterocycles · Oxygen
solution of 10a (100 mg, 0.44 mmol) in CH Cl (84 mL) at room
2
2
nd
heterocycles
temperature under argon was added Grubbs 2 generation cata-
lyst (18.67 mg, 0.022 mmol). The mixture was stirred for 24 h and
then filtered through Celite. The organic layer was then washed
[
1] a) H. Hiemstra, W. N. Speckamp, Additions to N-Acyliminium Ions, in: Com-
prehensive Organic Synthesis (Eds.: B. M. Trost, I. Flemming), Pergamon
Press: Oxford, UK, 1991, vol. 2, chapter 4.5, p. 1047–1082; b) H. DeKon-
ing, W. N. Speckamp, Methods in Organic Chemistry in Stereoselective Syn-
thesis (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann), Thi-
eme, Stuttgart, Germany, 1996, vol. E21/3, p. 1952–2010; c) R. A. Pilli, D.
Russowsky, Trends Org. Chem. 1997, 6, 101–123; d) W. N. Speckamp, M. J.
Moolenaar, Tetrahedron 2000, 56, 3817–3856; e) B. E. Maryanoff, H. C.
Zhang, J. H. Cohen, I. J. Turchi, C. A. Maryanoff, Chem. Rev. 2004, 104,
with water, brine, dried with MgSO and the solvents evaporated.
4
The solvent was removed, and the residue was purified by column
chromatography EtOAc/cyclohexane (1:9) to provide product 19 as
a brown oil in quantitative yield. This product, isolated earlier as a
colorless oil, was reported inconveniently to be product 18 in refer-
ence 9a; the structure was subsequently corrected to be 19 by same
authors in ref.[
9b] [26]
.
IR (neat): ν˜ = 3023, 2928, 2892, 2865, 1670,
1
7
2
1
1
2
613, 1468, 1415, 1296, 1284, 1201, 1147, 1098, 1018, 937, 800, 757,
07 cm . H NMR (300 MHz, CDCl ): δ = 2.06 (t, J = 13 Hz, 1 H),
.27–2.38 (m, 2 H), 2.70 (dd, J = 7.8, 15.8, Hz, 1 H), 3.14 (t, J =
0.9 Hz, 1 H), 4.23 (ddd, J = 5.9, 13.5 Hz, 1 H), 4.40 (d, J = 11.2 Hz,
H), 5.78–5.90 (m 1 H), 5.94–6.05 (m 1 H), 7.34 (dd, J = 7.5, 15.2 Hz,
H), 7.44 (t, J = 7.3 Hz, 1 H), 7.74 (d, J = 7.4 Hz, 1 H) ppm. 13C NMR
1
2
431–1628 and references cited therein. f) A. Yazici, S. G. Pyne, Synthesis
009, 339–368; g) A. Yazici, S. G. Pyne, Synthesis 2009, 513–541.
–1 1
3
[
2] a) H. Hiemstra, W. N. Speckamp, N-Acyliminium Ions as Intermediates in
Alkaloid Synthesis, in: The Alkaloids (Ed.: A. Bossi), Academic Press, New
York, 1988, vol. 32, chapter 4, p. 271–339; b) C. M. Marson, ARKIVOC
2001, 1, 1–16.
[
3] A. Daïch, A. Ghinet, B. Rigo, Addition to N-Acyliminium Ions of Heteroat-
oms such as Oxygen, Nitrogen, Sulfur, and Selenium as Internal Nucleo-
philes, in: Comprehensive Organic Synthesis, 2 edition (Eds.: G. A. Molan-
(
(
75 MHz, CDCl ): δ = 27.79 (CH ), 34.76 (CH ), 41.31 (CH ), 60.25
3 2 2 2
CH), 121.84 (CH), 123.53 (CH), 128.20 (CH), 128.33 (CH), 131.37 (CH),
32.08 (C), 132.70 (C), 145.25 (C), 167.56 (CO) ppm. ESI-HRMS,
nd
1
der, P. Knochel), Oxford, UK, Elsevier, 2014, vol. 2, chapter 2.21, p. 682–
+
C13H13NO: [M + H] : calculated 200.1075, found 200.1072; [M +
7
42.
4] T. Shono, Y. Matsumura, K. Uchida, H. Kobayashi, J. Org. Chem. 1985, 50,
243–3245.
+
+
Na] : calculated 222.0894, found 222.0889; [2M + Na] : calculated
21.1891, found 421.1889.
[
4
3
[
[
5] Y. Wei, H. Ding, S. Lin, F. Liang, Org. Lett. 2011, 13, 1674–1677.
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3
1
-(4-Phenyl-1H-1,2,3-triazol-1-yl)-2-[(4-phenyl-1H-1,2,3-triazol-
-yl)methyl]isoindolin-1-one (20): To a solution of diazide 10b
(
(
0.502 mmol) was added phenylacetylene (2.2 equiv.), copper iodide
0.1 mmol) and DIPEA (3 equiv.) in THF. After the reaction was
stirred for 48 h, the reaction mixture was concentrated under re-
duced pressure and the obtained residue subjected to column chro-
matographic purification using a mixture of CH Cl /EtOAc (7:3) as
[
[
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3
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eluent. Expected product 20 was isolated as a white viscous semi-
solid in 76 % yield. IR (neat): ν˜ = 3119, 2915, 2920, 2853, 1716, 1613,
[
2
1
6
482, 1466, 1440, 1371, 1232, 1212, 1125, 1074, 1042, 836, 759,
89 cm . H NMR ([D ]DMSO, 300 MHz): δ = 5.97 (d, J = 14.6 Hz, 1
[
–1 1
6
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H), 5.28 (d, J = 17.0 Hz, 1 H),6.13 (s, 1 H), 7.16 (t, J = 7.6 Hz, 1 H),
6
1
.24 (d, J = 14.6 Hz, 1 H), 7.32 (dd, J = 12.2, 7.2 Hz, 6 H), 7.54 (d, J =
0.6 Hz, 2 H), 7.76 (t, J = 20.9 Hz, 6 H), 7.99 (d, J = 5.5 Hz, 1 H), 8.35
[
1
3
(s, 1 H), 8.50 (s, 1 H) ppm. C NMR (75 MHz, [D ]DMSO): δ = 53.95
6
(CH ), 71.87 (CH), 120.09 (CH), 121.18 (CH), 123.90 (CH), 123.94 (CH),
2
[
1
1
25.22 (CH), 125.26 (CH), 127.86 (CH), 128.04 (CH), 128.67 (CH),
29.62 (C), 129.99 (C), 130.23 (C), 130.82 (CH), 134.01 (CH), 140.75
(C), 146.53 (C), 147.27 (C), 166.92 (CO) ppm. ESI-HRMS, C H N O:
25 19 7
+
+
[
4
M + H] : calculated 434.1729, found 434.1752; [M + Na] : calculated
56.1548, found 456.157.
Eur. J. Org. Chem. 2016, 3592–3602
www.eurjoc.org
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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[
[
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Received: April 28, 2016
Published Online: June 24, 2016
Eur. J. Org. Chem. 2016, 3592–3602
www.eurjoc.org
3602
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim