Combining α-amidoalkylation reactions of N-acyliminium ions with ring-closing metathesis: Access to versatile novel isoindolones spirocyclic compounds

Article abstract of DOI:10.1016/j.tetlet.2013.07.077

A novel approach to diversely spirocyclic isoindoles has been developed by using N-acyliminium/ring-closing metathesis strategy. Spirocyclization precursors, diolefinic, and enyne spiro-fused-isoindole derivatives have been obtained by a regioselective reduction of the spiro-imide compounds, followed by the allylation of the N-acyliminium intermediates (generated from the acetoxylactam compounds). Ruthenium catalyzed ring-closing metathesis of the above unsaturated derivatives provided novel spiroisoindoles.

Full text of DOI:10.1016/j.tetlet.2013.07.077

Tetrahedron Letters 54 (2013) 5227–5231
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Combining
a-amidoalkylation reactions of N-acyliminium ions
with ring-closing metathesis: access to versatile novel isoindolones
spirocyclic compounds
⇑
Anthony Pesquet, Mohamed Othman
a URCOM, EA 3221, INC3M, FR-CNRS 3038, Université du Havre, BP: 540, 25 rue Philippe Lebon, F-76058 Le Havre Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 April 2013
Revised 9 July 2013
Accepted 12 July 2013
Available online 20 July 2013
A novel approach to diversely spirocyclic isoindoles has been developed by using N-acyliminium/ring-
closing metathesis strategy. Spirocyclization precursors, diolefinic, and enyne spiro-fused-isoindole
derivatives have been obtained by a regioselective reduction of the spiro-imide compounds, followed
by the allylation of the N-acyliminium intermediates (generated from the acetoxylactam compounds).
Ruthenium catalyzed ring-closing metathesis of the above unsaturated derivatives provided novel
spiroisoindoles.
Keywords:
Metathesis
Ó 2013 Elsevier Ltd. All rights reserved.
Spiroisoindoles
N-Acyliminium ion
Tandem reaction
Alkaloids
Isoindolinone and C3 isoindolinone-derived heterocycles1 are
prevalent structural motifs in numerous synthetic and natural
products, which exhibit important biological activities. Many of
them have been prepared and examined as antihypertensive,2 anti-
psychotic,3 antiinflammatory,4 anesthetic,5 antiulcer,6 and vasodi-
latory7 agents. Antiviral,8 antileukemic,9 and aldose reductase
inhibitory10 properties have also been observed in this class of
structures.
On the other hand, indoles and oxindoles derivatized at C3 as
spirocarbocycles, spirolactones, and spiroheterocycles are elegant
targets in organic synthesis because of their significant biological
activities.11 For example, rhynchophylline (4),12 a natural alkaloid
isolated from the traditional Chinese medicinal herb Uncaria
rhynchophylla, has been identified as a neuroprotective and anti-
cancer agent. The spiroimides (5), another example of the spiroox-
indole derivatives, are unnatural spirooxindole compounds, being
well known as aldose reductase inhibitors, antihyperglycemic
agents,13 and also efficient for the treatment of allergic inflamma-
tory diseases.14 Finally, petropodine (6) and its stereoisomers, an-
other alkaloids from the spirooxindole family, are produced by
Uncaria tomentosa, and have been shown to modulate the function
of muscarin serotonin receptors (Fig. 1).15
interest in the development of synthetic methodologies toward
original aza-heterocyclic systems embodying the 3-isoindolinone
moiety with promising pharmaceutical properties,16 we describe
herein the synthesis of novel spiro-fused-isoindole products of
types II and III (Fig. 2). For this purpose a combination of N-acyli-
minium ion chemistry17 and ring-closing metathesis reactions
(RMC) is explored.18–20
Our retrosynthetic analysis of spiroisoindolinones II and III is
shown in Scheme 1. These compounds could be assembled from
the 3-allylic spirosuccinimide
A via ring-closing metathesis
(RCM) protocol. Access to A would then be achieved by a selective
O
O
O
Cl
O
O
N
NH
N
N
N
O
N
O
O
O
Aldose reductase inhibitor: 2 Lennoxamin: 3
Zoplicone (anxiolytic): 1
O
O
O
O
N
N
D
E
R
N
O
D
E
Inspired by the interesting biological activities of the spiro-
oxindole alkaloids, and in connection with our current research
H
O
A
H
O
H
O
B
A
H
O
B
O
N
R
O
O
HO
N
R
N
H
H
Rhynchophylline: 4
Petropodine: 6
Spiroimide: 5
⇑
Corresponding author.
E-mail address: mohamed.othman@univ-lehavre.fr (M. Othman).
Figure 1. Representative isoindole and spirooxindole alkaloids.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.077

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A. Pesquet, M. Othman / Tetrahedron Letters 54 (2013) 5227–5231
O
R
N
E
O
O
O
O
O
H
N
H
N
E
D
E
D
3
N
N
N
N
O
R1
R1
R1
HO
R1
A
B
N
B
A
B
N
O
A
N
R
O
O
O
O
O
2
OH
5
N
R2
N
N
R2
N
R2
1 R2
O
R
O
(I) ( )3-Spiroisoindole-
( )3-Spiroisoindole- (III)
(II)
3-Spiroindolizine oxindole
( )-11a-d (B: Min)
( )-10a-d
( )-10a-d
( )-11a-d (A: Maj)
Figure 2.
Scheme 3. Concept of the regioselective reduction of imide ( )-10a–d into
hydroxy-lactams ( )-11a–d.
O
N
O
O
R2
N
R2
N
Table 2
Optimization of the a-amidoalkylation reaction of acetoxylactam ( )-12c
RMC
O
O
O
N
N
R1
N R1
N
R1
Ph
Ph
Ph
N
N
N
II
Nu (2 equiv)
OAc
acid
A
O
B
O
N-acyliminium ions
C
O
M
R2
R
and/or
N
HN
CO2H
solvent, t,
N
O
OAc
rt
1) [H]
2) L A
17c
14c
( )
Sn(Bu)
( )
O
O
12c
( )
O
N
,
(Nu-1)
3 (Nu-2)
Si(Me)3
R2
N
Nu
=
CO2Et
R1
III
O
Entry
Acid (equiv)
Nu
Solvent
Product
Yield (%)
O
R1
N
N
1
2
3
4
5
6
7
8
TFA (excess)
BF3ÁEt2O (2)
TiCl4
Nu-1
—
—
—
—
—
NRa
NRb,c
NRb,c
NRb,c
NRb
43
Nu-1
Nu-1
Nu-1
Nu-1
Nu-1
Nu-1
Nu-1
Nu-2
Nu-2
Nu-2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
C
D
O
O
Bi(OTf)3 (0.1)
TIPSOTf (0.1)
TIPSOTf (0.1)
TMSOTf (0.1)
TMSOTf (0.1)
TIPSOTf (1)
TMSOTf (1)
TMSOTf (0.5)
Scheme 1. Retrosynthetic analysis of the target of types II and III.
—
( )-17c
—
( )-17c
( )-14c
( )-14c
( )-14c
NRb
37d
54
H
O
O
N
R2
R2
N
N
CO2Et
R1
CO2Et
R1
9
10
11
O
74
i
33e
R1
N
N
a
b
c
9a-d
( )
Hydroxylactam ( )-11c was partially recovered.
Starting material ( )-12c was partially recovered.
Similar results were obtained when CH2Cl2 was replaced by CH3CN.
5% of ( )-14c was observed in the reaction mixture.
O
7a-c O
O
( )10a-d
ii
R2
O
d
e
O
O
R2
Br
R2
N
H
N
N
N
N
Besides ( )-14c, derivative ( )-17c and the recovered staring material ( )-12c
8a-c
were obtained in 12% and 28% yields respectively.
OAc
R1
OH
R1
iii
Ph
O
O
O
O
( ) 12a-d
11a-d
( )
N
Ph
O
Ph
OAc
N
N
Scheme 2. Reaction conditions: (i) K2CO3, bromoacetamide 8, CH3CN, reflux, 12 h,
53–83%; (ii) NaBH4, EtOH, 0 °C (1.5–3 h); (iii) Ac2O, Et3N, 4-DMAP, CH2Cl2, rt, 3 h,
73–93%.
TMSOTf
12c
N
N
N
AcO
15c
( )
O 13c
O
O
( )
Table 1
Ph
Ph
Results of the two-step (reduction and acetylation) synthesis of the acetoxylactams
N
N
( )-12a–d
O
O
OAc
OAc
Entry
R1
R2
Product
Yielda (%)
drb
HN
CO2H
N
1
2
3
4
PMB
Bn
Allyl
Propargyl
Allyl
Propargyl
Bn
( )-12a
( )-12b
( )-12c
( )-12d
93
73
93
91
82:18
70:30
78:22
80:20
17c
( )
16c
( )
O
Bn
Scheme 4. Plausible mechanism for the formation of ( )-17c.
a
Isolated yields.
Determined by 1H NMR (200 MHz) integration of the hydrogen attached to the
b
step and in satisfactory yields. This straightforward approach is a
real improvement of the existing methods for the synthesis of spi-
roisoindoles bearing an imide function.
a-nitrogen carbon on the crude reaction mixture.
22
The next step was the synthesis of the required a-acetoxy- lac-
reduction of the spirosuccinimide C, followed by the allylation of
the N-acyliminium intermediate B. The latter spirocycle C is readily
accessible in a tandem process from the well-known phthalimidine
D.
As a starting point of our study, the requisite spirosuccinimides
( )-10 were synthesized according to the procedure shown in
Scheme 2.21 Treatment of phthalimidines 7 with K2CO3 to effect
enolate formation followed by reaction with various N-substituted
tams ( )-12. Regioselective reduction of imides ( )-10a–d was per-
formed with a large excess of NaBH4 in dry ethanol at 0 °C under
carefully controlled conditions23 for 1.5–3 h and afforded
a-
hydroxylactams ( )-11a–d as diastereoisomeric mixtures, which
were used in the next step without further purification. After acyl-
ation of the hydroxylactams ( )-11a–d with acetic anhydride, the
desired N-acyliminium ion precursors ( )-12a–d were isolated in
very good yields (73–93%) and in good levels of diastereoselection
after the two stages (Table 1).
a-bromoacetamides of type 8 furnishes spiroimides ( )-10 in one

A. Pesquet, M. Othman / Tetrahedron Letters 54 (2013) 5227–5231
5229
Table 3
even after a prolonged reaction time (entries 1–3). Similarly, a cat-
alytic amount (10 mol %) of Lewis acids such as Bi(OTf)3,26 TIP-
SOTf,17h and TMSOTf,27 which are traditionally recognized as
Yields and diastereomeric ratios for compounds ( )-14a–d
Entry
Substrate
Product
Yielda (%)
drb
highly efficient for this kind of a-amidoalkylation reactions, failed
O
to catalyze this allylation when the reaction was performed in CH2-
Cl2 (Table 2, entries 4, 5, and 7). In contrast, the analogous reac-
tions in CH3CN resulted in the formation of compound ( )-17c
(Table 2, entries 6 and 8).
The reaction mechanism for this cascade sequence is proposed
along Scheme 4. The reaction is initiated by the generation of N-
acyliminium ion 13c. Indeed of the intermolecular allylation of
N
1
( )-11a
76
100:0
N
O
( )14a
OMe
O
N
13c, intramolecular a-amidoalkylation reaction takes place to form
spiroindolizidine ( )-16c. The formed tetracyclic intermediate ( )-
16c is not stable and opens to form the ultimate derivative ( )-17c,
probably because of the high ring strain involved within the forma-
tion of the six-membered ring within the spiro-fused-isoindole
product ( )-17c. Further studies exploring and exploiting this dif-
ference of reactivity are ongoing and will be reported in a forth-
coming full letter.
The reaction outcomes suggested that allyltrimethylsilane was
not sufficiently reactive to undergo reaction with the N-acylimini-
um ion 13c. Consequently, we turned our attention to replacing the
trimethylsilyl group (Si(Me)3) with a more reactive functionality
such as (Sn(Bu)3).
To our delight, treatment of ( )-12c with (Nu-2) in the presence
of 1 equiv of TIPSOTf at rt in CH3CN for 6 h resulted in the forma-
tion of the desired adduct ( )-14c as a single diastereoisomer in
54% yield. Besides ( )-14c, derivative ( )-17c and the recovered
starting material ( )-12c were obtained in 5% and 14% yields
respectively (Table 2, entry 9). The chemical yield of ( )-14c was
improved significantly by using 1 equiv of TMSOTf in CH3CN for
4 h, and ( )-14c was obtained in 74% yield (Table 2, entry 10). A
dramatic decrease in the yield (33%) of ( )-14c was observed when
the amount of TMSOTf was reduced from 1 equiv to 50 mol % (Ta-
ble 2, entry 11). Similar conditions (1 equiv of TMSOTf, CH3CN at rt
for 4 h) appeared successful for the other N-acyliminium precur-
sors ( )-12a,b,d to provide the other expected RCM precursors
( )-14a,b,d in high yields and with excellent diastereoselectivity
as shown in Table 3.
2
( )-11b
97
100:0
N
O
14b
( )
O
O
N
3
4
( )-11c
74
72
100:0
75:25
N
O
( ) 14c
N
( )-11d
N
14d
O ( )
a
Isolated yields.
Determined by 1H NMR (200 MHz) integration of the hydrogen attached to the
-nitrogen carbon on the crude reaction mixture.
b
a
Nu (AllylSn(Bu)3)
O
O
LA
N
N
R1
O
O
R1
AcO
N
O
N
O
N
R2
N
R1
R2
R2
Possible
transition state
( ) 14a-d (Maj)
( ) 12a-d
Because of
a-hydroxy-lactams ( )-11a–d and corresponding
a-acetoxy-lactams ( )-12a–d were used in
a-amidoalkylation
Scheme 5. Plausible mechanism for the formation of ( )-14a–d.
reaction via the racemate acyliminium species, no attempts were
dedicated to the isolation of ( )-11a–d and ( )-12a–d, respectively.
Elsewhere, all attempts to isolate allyl compounds ( )-14a–d, as of
the acidic stable products, in crystalline form for the X-ray struc-
ture determinations were aborted.
However, the formation of exclusive isomers ( )-14a–c or both
isomers ( )-14d can be explained by the p-allyl attack of the cation
It is noteworthy that our recently reported one-pot reduction–
acetylation protocol could be used as a shortened procedure.24
However, on a large scale of 2 g of 10a, the yield dropped down
(78% instead of 93%), and so the two-step procedure was preferred.
Importantly, in all cases, the reaction seems to be highly regiose-
lective because during the reduction process (NaBH4 or LiEt3BH)
only regioisomers ( )-11a–d were obtained.
intermediate being formed in acidic media. Presumably the nucle-
ophile approaches the iminium intermediate from the least hin-
dered side, which is opposite to the bulky NR1 group. This fact is
probably at the origin of the high diastereoselectivity we observed
(see Scheme 5). After successful formation of a range of RCM pre-
cursors, the ring-closing metathesis reaction of diene ( )-14a and
enyne ( )-14b was first investigated.
The diolefinic spirosuccinimide ( )-14a was subjected to first
generation Grubbs’ catalyst G1 (3 mol %, CH2Cl2 at reflux for 8 h),
resulting in the formation of the six-membred ring indolizidine
product ( )-18a in 74% yield after silica gel column chromatogra-
phy. Similarly, the same reaction conditions when applied to enyne
( )-14b afforded spiroindolizidine ( )-18b in 85% yield. Similarly
( )-14c gave ( )-18c in low yield of 34% along with starting mate-
rial ( )-14c in 40% yield. Similar results were obtained when CH2-
Cl2 was replaced by C2H4Cl2 (30%) or toluene (28%). For successful
total closure of compound ( )-14c, the second generation Grubbs’
catalyst G2 (2 Â 5 mol %) was required, giving the seven-mem-
The regiospecificity of the reduction can be explained based on
the concept pioneered by Speckamp’s group in this area.25 In fact,
as a result of the Bürghi–Dunitz (107°) angle there are two possible
trajectories for the hydride to approach the carbonyl function of
the spiro-imide ( )-10a–d. In this context, the reduction of the car-
bonyl at position 2 is favored leading to ( )-11a–d as major regioi-
somers (see Scheme 3).
Afterward, the intermolecular allylation reaction was investi-
gated. For this purpose, a model reaction between acetoxylactam
( )-12c and allyltrimethylsilane (Nu-1) (or allyltributylstanate
(Nu-2)) was examined under a wide range of conditions. The ob-
tained results are summarized in Table 2.
A careful screening of acids revealed that conventional Brønsted
or Lewis acids did not promote any transformation, irrespective of
the solvent and the amount of acid, and the starting material ( )-
12c or its parent hydroxylactam ( )-11c was partially recovered

5230
A. Pesquet, M. Othman / Tetrahedron Letters 54 (2013) 5227–5231
Table 4
References and notes
Optimal RCM conditions for the synthesis of spirocycles ( )-18a–da
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R2
N
O
O
O
R2
N
N
Path
1
N
ii
G2
i
N
N
R1
R1
Path
2
G1
O
O
O
( )18c,d
( )18a,b
( )
14a-d
O
N
O
N
PCy3
Ru
PCy3
Cl
Cl
N
N
O
Ph
O
GrubbsI = G1
( )
18b 85%
( ) 18a
74%
OMe
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N
N
Mes
Cl
Mes
Ph
N
N
O
O
Ru
PCy3
Cl
N
N
O
Grubbs II = G2
O
( ) 18c
_
64%
( )18d
a
Reaction conditions: (i) G1, 3 mol %, CH2Cl2, reflux, 8 h, ( )-18a, 74%, ( )-18b,
85%. (ii) G2, (2 Â 5 mol %), toluene, reflux, 24 h, ( )-18c, 64%.
bered ring product ( )-18c in 64% yield. Treatment of enyne ( )-
14d with first or second generation Grubbs’ catalysts did not pro-
vide the desired spirocycle ( )-18d even under harsher reaction
conditions. Even if the reasons of the cyclization reaction were
not yet defined exactly, we speculate nevertheless that the lack
of reactivity of substrate ( )-14d is due to the ring strain inherent
to the spirocyclic product and probably to the perpendicular posi-
tioning of the alkene function toward the alkyne one and vice versa
(Table 4).
To the best of our knowledge, this represents the first report of
the synthesis of 3-spiroisoindole derivatives from the readily avail-
able phthalimidines 7.
15. Kang, T. H.; Matsumoto, K.; Murakami, Y.; Takayama, H.; Kitajima, M.; Aimi, N.;
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In this Letter, we successfully introduced a new and expedient
synthetic entry to spiroisoindolones ( )-18, which have till date
not been described. A central step in this synthesis is the ring-clos-
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Acknowledgement
The authors are grateful to Pr. Adam Daïch (URCOM) for many
fruitful discussions throughout the course of this work.
Supplementary data
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in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
07.077.

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