Unexpected reversible nitrogen atom transfer in the synthesis of polysubstituted imides and 7-aza-hexahydroindolones via enaminonitrile γ-lactams

Article abstract of DOI:10.1016/j.tetlet.2009.01.072

An effective route to novel polysubstituted imides is described, which involves the reaction of enaminonitrile γ-lactams derived from N-alkylated α-bromoacetamides and malononitrile with acryloyl chloride derivatives. This preceded via a sequence 1,4-addi

Full text of DOI:10.1016/j.tetlet.2009.01.072

Tetrahedron Letters 50 (2009) 1459–1462
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unexpected reversible nitrogen atom transfer in the synthesis of
polysubstituted imides and 7-aza-hexahydroindolones
via enaminonitrile
c-lactams
b
c
a,
*
Nabila Oukli a,b, Sébastien Comesse a, , Nafa Chafi , Hassan Oulyadi , Adam Daïch
*
a URCOM, EA 3221, INC3M, FR-CNRS 3038, UFR des Sciences & Techniques de l’Université du Havre, BP: 540, 25 rue Philippe Lebon, F-76058 Le Havre Cedex, France
b LCOPM, Département de Chimie, Faculté des Sciences de l’Université de Djillali Liabès, B.P: 89, Sidi Bel-Abbés, Algeria
c IRCOF-UMR 6014 CNRS, INC3M, FR-CNRS 3038, Place Emile Blondel, Université de Rouen, F-76131 Mt-St-Aignan Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An effective route to novel polysubstituted imides is described, which involves the reaction of enamino-
Received 27 October 2008
Revised 5 January 2009
Accepted 13 January 2009
Available online 19 January 2009
nitrile
c
-lactams derived from N-alkylated
a
-bromoacetamides and malononitrile with acryloyl chloride
-lactam
derivatives. This preceded via a sequence 1,4-addition-intramolecular peptidic coupling and a
c
hydrolysis in a one ‘pot-procedure’. These imides were regioselectively reduced into corresponding N-
acyliminium precursors, which subsequently submitted to an intramolecular aza-cyclization in acidic
medium to provide novel 7-hexahydro-aza-indoles.
Keywords:
7-Aza-indoles
Ó 2009 Elsevier Ltd. All rights reserved.
7-Hexahydro-aza-indoles
Enaminonitrile
c
-Lactams
d-Lactams
Tandem process
N-Acyliminiums species
Alkaloids
1. Introduction
3 addressed to the treatment of respiratory infections.6 Another
aspect of this azacyclic system was demonstrated also by its pres-
7-Aza-indole derivatives, which could be considered as bioisos-
teres of indoles, occupy a central position in modern heterocyclic
chemistry due to their physicochemical and therapeutic proper-
ties. They are yet to be discovered intensively in nature,1 but they
constitute important subunits of numerous inorganic polynuclear
materials and interesting class of pharmaceuticals and investiga-
tional drugs.2,3 In this context, these derivatives have been
reported to possess a range of biological activities and have the
potential to act as kinase inhibitors, cannabinoid CB-1 modulators,
cardio-vascular components, antitumor agents, and agonists or
antagonists of other various pathologies.3
ence as remarkable scaffold in alkaloids neoxaline (4a) and oxaline
(4b), which were found to inhibit cell proliferation and arrest the
cell cycle during M phase in Jurkat cells.7 Furthermore, it is also
present in the antidepressant hexahydropyridoindoles of type 5,8
in synthetic hexahydropyrroloquinolines 6 which curiously have
not shown any biological activity,9 and finally in the structurally
complex perophoramidine alkaloid (7) which induces apoptosis
via Poly(ADP-ribose) polymerase-1 (PARP-1) cleavage—a signal of
irreparable DNA damage.10
2. Results and discussion
Although the importance of aromatic 7-aza-indoles has been
widely demonstrated, the subgroup of 7-hexahydro-aza-indoles
on the other hand has scarcely been explored. For example, the
latter skeleton is incorporated in the defensive secretion of milli-
pede Rhinocricus padbergi product 1,4 in components of type 2,5
and as a pharmacophore group in the antibacterial moxifloxacin
Only two structures bearing the above prototype 7-hexahydro-
aza-indole nucleus are known in the literature (Schemes 1 and 2).
These products, as the bioactive 1 and 2a,b, were reported by the
tandem aldol type reaction/isomerization of substrate 8 under
heating4a and the cyclo condensation of the dinitrile-ketones or
corresponding nitrile-acid-ketones 9 under acidic conditions at
low temperatures (Scheme 2).5 In our group, we are interested in
the development of simple tandem approaches toward aza-hetero-
cyclic systems with promising pharmaceutical activities starting
* Corresponding authors. Tel.: +33 02 32 74 44 03; fax: +33 02 32 74 43 91 (A.D).
E-mail addresses: sebastien.comesse@univ-lehavre.fr (S. Comesse), adam.
daich@univ-lehavre.fr, adam.daich@wanadoo.fr (A. Daïch).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.072

1460
N. Oukli et al. / Tetrahedron Letters 50 (2009) 1459–1462
H
N
Br
R2
R2
CN
NH2
O
CN
NaH, THF, r.t.
NC
OR1
N
H
O
O
N
N
H
O
N
R1
NH
R1
( )−11
H
F
OMe
N
MeO
O
( )−12
1: Defensive secretion
N
HN
Ar
R3
O
aza-annulation
Not observed
CH2Cl2, r.t.
path B
N
path A
O
Lg
14
O
N
N
H
O
O
R3
O
N
H
R3
R2
Lg
HN
4a: R1=H, Neoxaline
4b:
NC
CN
R2
CO2H
2a: Ar=Ph
NH2
Cl
2b:
Ar=3,4-diMeOPh
3: Moxifloxacin
O
R1=Me, Oxaline
OMe
OEt
O
O
N
N
R1
N
O
R8
R2
R7
Cl
R1
N
N
( )−10
( )−13
R4
X
Scheme 3. Synthesis of polysubstituted imides ( )-13 via pathway B.
N
R6
N
R9
X
N
N
Cl
N
N
Br
R3
R5
H
Table 1
Synthesis of polysubstituted imides ( )-13 via pathway B
7:
6: X=O or H,H
Perophoramidine
5:
X=O or H,H
Entry
R1
R2
R3
Product 12
Yield (%)
Product 13
Yield (%)
Scheme 1. Representative natural and unnatural polyhydro-7-aza-indoles.
1
2
3
4
PhCH2
Ph(CH2)2
PhCH2
PhCH2
H
H
Me
H
H
H
H
Me
12a
12b
12c
—
96a
96
94
—
13a
13b
13c
13d
60 (—)
69 (—)
56 (80)b
45 (00)b
Ar
R3
CN
R2
O
O
O
a
The reaction was conducted with 1 equiv of
a-bromoacetamide 11 and
O
N
H
O
N
H
N
O
N
H
2.5 equiv of malononitrile in the presence of 2.5 equiv of NaH in THF at rt.
N
R1
O
N
b
Diastereomer excess determined by 1H NMR analyses.
1
( )−2a,b
10
( )−
Ref.4a
Ref.5
Ar
R2
Br
substrates of type ( )-12. For example, 2-amino-3-cyano-N-eth-
oxycarbonyl-4,5-dihydropyrroles (in which the C@O function is
attached to the nitrogen atom of the pyrrolidine nuclei) with ben-
zoyl chloride,17a ethoxalyl chloride,17b and acetylenic esters18 gave
the corresponding N-acylated and azepines products, respectively.
In the latter case, the azepine system resulting from the ring
expansion was accompanied, in certain cases, with the N-alkena-
tion product. In addition, the aza-annulation with acrylate deriva-
O
Ewg
N
H
O
N
H
Ewg
NH
O
8
O
R1
( )−9:
Ewg=CN, CO2H
( )−11
Scheme 2. Retrosynthetic schemes leading to known 7-aza-indoles 1 and 2a,b and
our targets 10.
tives of an enaminonitrile containing a
yet been described.
c-lactam skeleton has not
from versatile reagents as N-alkyl-
purpose, we have recently explored their synthetic potential in
tandem sequences to accede high functionalized -lactams and
symmetrical and unsymmetrical bis-spiro-imides by reaction with
activated olefins12 and malonate derivatives,13 respectively.
Our objective herein was to construct the 7-hexahydro-aza-in-
a
-bromoacetamides.11 For this
In this context, the
was used as the model system for our study. So, under a variety of
reaction conditions used, 1 equiv of -lactam ( )-12a and 1.5 equiv
c-lactam ( )-12a and acryloyl chloride (14a)
c
c
of 14a in CH2Cl2 at room temperature seems to be the best combi-
nation under which the main product obtained after the aqueous
classical work-up of the reaction was identified as the imide ( )-
13a in 60% yield (Scheme 3, path B). Interestingly, the use of other
acrylate such as methyl- or ethyl acrylate also delivers the unex-
pected product ( )-13a but in small quantities, and it is very diffi-
cult to isolate from the crude mixture. In all cases, no traces of 7-
hexahydro-aza-indole product ( )-10a (Scheme 3, path A) were
detected in the reaction mixture.
dole products ( )-10 or equivalents starting from N-alkyl-
moacetamides of type ( )-11. For this purpose, the use of
enaminonitrile -lactams ( )-12, obtained from ( )-11, with ,b-
a-bro-
c
a
unsaturated carbonyl derivatives 14 (Michael acceptors) in associ-
ation with N-acyliminium chemistry in an efficient and concise
manner could be a valuable strategy to provide these targets
(Schemes 2 and 3).
At the outset, we investigated reactions of N-alkyl-
a
-bromoac-
As shown in Scheme 4, the suggested reaction mechanism illus-
trates a cascade process, by way of a tandem ring closure/ring
opening of the d-lactam skeleton. This produces unexpected nitro-
gen atom transfer from the enamine function of the enaminonitrile
etamides ( )-11 with malononitrile.14 After large screening, we
found that treatment of ( )-11a (R1@Bn, R2@H) and malononitrile
in THF in the presence of NaH as a base leads to the formation of
enaminonitrile
c
-lactam ( )-12a in an excellent 96% yield (Scheme
c-lactam ( )-12a into the amide function of the imide derivative
3, Table 1, entry 1). With other substituents, the reaction under the
above conditions seems to be general, and the reaction products
( )-12b,c were obtained in excellent yields of 96% and 94%, respec-
tively (Table 1, entries 2 and 3). Besides, it is well established now
that enamines15 or N-alkylenamines stabilized through conjuga-
tion with electron-withdrawing group16 undergo aza-annulation
with acrylate derivatives to provide a convergent route for the con-
struction of d-lactams. However, only few papers have been pub-
lished on the chemistry of heterocyclic enaminonitriles related to
( )-13a. In fact, the formed N-acyliminium intermediate A was
obtained from substrate ( )-12a and acryloyl chloride (14a) via
an initial 1,4-addition followed by a spontaneous imine/acid chlo-
ride peptidic coupling. This cation A, stabilized through the conju-
gation with nitrogen lone pair of the c-lactam nucleus, provided
after aqueous hydrolysis the amide-imide product ( )-13a. Inter-
estingly, in our quest for trapping intermolecularly the cation A,
the addition of a hydride reagent such as NaBH4, ethyldiisopropyl-
amine, or a nucleophile such as allyltrimethylsilane19 before the

N. Oukli et al. / Tetrahedron Letters 50 (2009) 1459–1462
1461
R3
O
O
R3
R2
NC
CN
NC
R2
R2
R2
CN
NaBH4
EtOH, 0 ºC
NH2
NH2
O
O
Cl
14a,b
O
O
O
OH
O
O
NH2
..
N
R1
N
R1
N
N
R1
N
O
17a-c
R1 ( )−
H
( )−13a-c
, Cl
N
A
Me
12a-c
( )−
H
H
H
HCl, H2O
EtOH
H2O
O
H
BF3.Et2O
Product
R2
16c
( )−
H
CH2Cl2, r.t.
N
CN
R3
O
NC
N
H
Ph
R2
H
O
H
NH2
H
R2
CN
CN
N
N
H
O
O
O
EtO
N
Aza-Cyclization
- H
Ph
O
O
R1
N
R1
16a-c
( )−
( )−13a-d
( )−15a
N
N
O
O
H N
2..
H
H
R1
Scheme 4. Mechanistic pathways leading to substituted imides ( )-13a–d.
Ba-c
( )−
Scheme 5. Scheme leading to 7-hexahydro-aza-indole derivatives ( )-16a–c via
aza-cyclization and NOE effect on the product ( )-16c.
hydrolysis step failed. In all these cases, only the unexpected imide
( )-13a was isolated. In this line when the reaction was quenched
with ethanol a
a-ethoxy-bis-lactam ( )-15a was, in our satisfac-
tion, isolated and fully characterized.20 The latter, under the acidic
(HCl/H2O) hydrolysis, led to the formation of the amide-imide
identical to product ( )-13a outlined above via the intermediacy
of the cation A in near quantitative yield. Again, the ring opening
proceeded in regioselective manner, which indicated that the cat-
ion A is privileged in the six membered ring to the detriment of the
possible five membered one.
Table 2
Synthesis of 7-hexahydro-aza-indole derivatives ( )-16a–c via aza-cyclization of N-
acyliminium cationsa
Entry
R1 group
R2 group
Product
Yieldb (%)
dr (%)
1
2
3
PhCH2
Ph(CH2)2
PhCH2
H
H
Me
16a
16b
16c
60
98
98
>95
>95
>95
a
The reaction was conducted with 2 equiv of BF3ÁEt2O in CH2Cl2 at rt for 24 h.
Isolated yield (in 2 steps) after flash chromatography.
Intrigued positively by the originality of this new tandem
sequence, we next examined its utility to synthesize a range of
substitutedimides ( )-13 by introducingdifferentpoints of diversity
with R1, R2, and R3 groups. In this sense, twoadditionalN-substituted
b
According to the previous reports, in which it was shown that
Lewis acid (BF3.Et2O)22 and Brönsted acid (HCO2H, AcOH, TFA,
a-bromoacetamides ( )-11b,c were allowed to react with enone
and PTSA)23 are good catalysts for intramolecular aza-amido-alkyl-
substrates 14a,b using optimized conditions, and the results are
summarized in Table 1. We have shown as expected that the steric
hindrance of the N-substituted a-bromoacetamide (12c) or the en-
ation, treatment of
a
-hydroxyl lactam ( )-17a with BF3ÁEt2O in
CH2Cl2 at room temperature for 24 h afforded product ( )-16a in
60% yield after flash chromatography calculated in two steps.24
This product, isolated as a single diastereomer, resulted from an
intramolecular cyclization of the N-acyliminium intermediate
( )-Ba with a nitrogen atom as nucleophile. Having successfully
established the appropriate conditions for C-N bond formation to
access original systems such as 7-hexahydro-aza-indoles, intramo-
one (14b) plays a pivotal role in the reaction yields (entries 3 and
4), which were of 56 and 45% yields instead of 60 and 69% in the case
of entries 1 and 2 (Table 1). Moreover, by the use of crotonyl chloride
(14b) with ( )-12a, the compound ( )-13d (entry 4) was obtained as
a mixture of two diastereomers in roughly equal amount (1H NMR).
In contrary, the use of acryloyl chloride (14a) with ( )-12c led to the
formation of polysubstituted imide ( )-13c with good diastereo-
meric excess (80%) determined by 1H NMR analyses of the crude
reaction mixture (entry 3). In the second part of this work, we
decided to investigate the reactivity of the imides of type ( )-13 par-
ticularly by examining their behavior by using N-acyliminim chem-
istry. These are of interest since the transformation could target the
racemates 7-hexahydro-aza-indole products ( )-16 as a reducing
homologue of compounds 10 that are difficult to be obtained from
intermediates A (Schemes 2 and 4).
lecular
a-aza-amidoalkylation was performed with two other a-
hydroxy lactam precursors ( )-17b,c bearing the same nucleophile
as above but different R1 and R2 groups. The results obtained are
summarized in Table 2. From the table, it is clear that the a-hydro-
xy lactams ( )-17b,c were cyclized to the novel 7-hexahydro-aza-
indoles ( )-16b,c in essentially quantitative yields also in two steps
(entries 2 and 3 in Table 2) and a very high degree of diastereose-
lectivity (dr >95%). The latter fact coupled with a prediction in this
kind of cyclization reaction made on the basis of model studies
(Scheme 5) advanced notably for the major part by the Speckamp’s
group25 and others22,26 led to the proposed angular carbon stereo-
chemistry in components ( )-16a–c. In fact, the relative stereo-
chemicals relationship was established using selective NOE
difference measurements on a Bruker AVIII-600 MHz NMR spec-
troscopy instrument. For instance, for a bis-lactam product ( )-
16c (Scheme 5), a strong NOE effect was observed confirming the
So, the polysubstituted amide-imides ( )-13a–c were then sub-
mitted to the reduction reaction, for the isolation of the correspond-
ing
a-hydroxy lactams ( )-17a–c as N-acyl-iminium cation
precursors (Scheme 5). According to our reports in this field,21 the
reduction of imides ( )-13a–c was carried out with a slight excess
of NaBH4 (1.5 equiv) in dry ethanol at 0 °C to provide the expected
a-hydroxy lactams ( )-17a–c easily in near quantitative yields.
According to the 1H NMR analysis of the crude product, a pair of dia-
stereomers appeared to have been formed in non equivalent ratios.
Furthermore, as we did not succeed in separating the couple of dia-
stereomers, the mixture being purified by flash chromatography
(SiO2, AcOEt/cyclohexane) was used in the next step without any
other purification. This was, of course, of no consequence since the
stereogenic center at C5-position of products ( )-17a–c was to be
destroyed at a later stage in the aza-cyclization reaction.
cis-orientation of the Me group and the angular proton H7a
.
3. Conclusion
In this study, enaminonitrile
in excellent yields by a simple and known reaction of N-alkylated
-bromoacetamides ( )-11 and malononitrile. Their reaction with
activated enone derivatives 14 afforded a set of polysubstituted
c-lactams ( )-12 were synthesized
a

1462
N. Oukli et al. / Tetrahedron Letters 50 (2009) 1459–1462
Relat. Elem. 2007, 182, 121–132; (b) El-Emary, T. I.; Khodairy, A. Phosphorus,
Sulfur Silicon Relat. Elem. 2006, 181, 1073–1085; (c) Swelam, S. A.; Fawzy, N. M.
Egypt J. Chem. 2004, 47, 565–577; (d) Resnyanska, E. V.; Tverdokhlebov, A. V.;
Tolmachev, A. A.; Volovenko, Y. M.; Shokol, T. V. Heterocycles 2004, 63, 797–
807; (e) El-Gaby, M. S. A.; Gaber, A. M.; Atalla, A. A.; Al-Wahab, K. A. A. Farmaco
2002, 57, 613–618; (f) Dave, C. G.; Parikh, V. A. Synth. Commun. 2001, 31, 1301–
1306; (g) Abbady, M. A.; Abdel-Hafez, S. H. Phosphorus, Sulfur Silicon Relat. Elem.
2000, 160, 121–140; (h) Schaefer, H.; Gewald, K. Monatsh. Chem. 1989, 120,
315–322.
imides ( )-13, which involved an original tandem ring closure/ring
opening of a d-lactam nucleus in acceptable yields. As the desirable
7-hexahydro-aza-indole ( )-10 was not isolated directly due its
fast hydrolysis during the work up, its formation, however, was
proved by isolating an ethoxy equivalent ( )-15a when the reac-
tion was quenched with ethanol. The latter after acidic hydrolysis
led to polysubstituted imides ( )-13 as above.
The polysubstituted imide systems containing a primary amide
function obtained ( )-13 with this protocol were then used as valu-
able templates to provide original and novel 7-hexahydro-aza-in-
doles in two steps. For this purpose, their regioselective
reduction with sodium borohydride afforded a mixture of two dia-
stereomers of hydroxy lactams ( )-17, inseparable, in nearly quan-
titative yields. From these observations, the latter were then
treated (without their total characterization) in acidic medium
(BF3ÁEt2O) and provided the expected 7-hexahydro-aza-indoles
( )-16 containing substituents via stable N-acyliminium species
with a very high degree of diastereoselectivity (dr >95%).
15. (a) Ref.14f and references cited therein.; Enaminonitriles are important building
blocks for the construction of a variety of fused aza-heterocyclic systems. For
this end, see also: (b) Taylor, E. C.; McKillop, A. In Advanced Organic Chemistry;
Taylor, E. C., Ed.; Interscience: New York, 1970; Vol. 7, (c) Paulvannan, K.; Stille,
J. R. J. Org. Chem. 1992, 57, 5319–5328.
16. For representative examples in this area, see: (a) Paulvannan, K.; Stille, J. R. J.
Org. Chem. 1994, 59, 1613–1620; (b) Barta, N. S.; Brode, A.; Stille, J. R. J. Am.
Chem. Soc. 1994, 116, 6201–6206; (c) Agami, C.; Hamon, L.; Kadouri-Puchot, C.;
Le Guen, V. J. Org. Chem. 1996, 61, 5736–5742; (d) Agami, C.; Dechoux, L.;
Hebbe, S. Tetrahedron Lett. 2002, 43, 2521–2523.
17. (a) Sonoda, M.; Kuriyama, N.; Tomioka, Y.; Yamazaki, M. Chem. Pharm. Bull.
1982, 30, 2357–2363; (b) Sonoda, M.; Kuriyama, N.; Tomioka, Y.; Yamazaki, M.
Chem. Pharm. Bull. 1986, 34, 886–892.
18. Matsunaga, H.; Sonoda, M.; Tomioka, Y.; Yamazaki, M. Chem. Pharm. Bull. 1984,
32, 2596–2601.
Finally, we anticipated that the transformations developed in
this project, particularly in the access to 7-hexahydro-aza-indoles
containing substituents, would find further applications in synthe-
sis of aromatic 7-aza-indoles with promising biological properties.
Work toward these systems is currently in progress, and the results
will be reported in due course.
19. For trapping of N-acyliminium species with allyltrimethyl-silane, see for
example: Pin, F.; Comesse, S.; Garrigues, B.; Marchalin, S.; Daïch, A. J. Org. Chem.
2007, 72, 1181–1191. and references cited therein.
20. Typical Procedure for the synthesis of polysubstituted imides ( )-13: Acryloyl
chloride (14a, 500
ll, 6,0 mmol) was added at 0 °C to a solution of ( )-12a–c
(4.0 mmol) in CH2Cl2 (40 mL). After 12 h at rt, the reaction mixture was cooled
to 0 °C and quenched carefully by addition of an aqueous saturated solution of
NaHCO3 (50 mL). The aqueous layer was extracted with CH2Cl2 (3 Â 30 mL),
and the organic layers were combined, dried over MgSO4, and evaporated. The
residue was then purified by chromatography on silica gel to furnish 13a–c
(AcOEt/cyclohexane). In the case of 15a, ethanol was added in place of the
aqueous saturated solution of NaHCO3. Selected data for ( )-1-benzyl-7a-ethoxy-
2,6-dioxooctahydro-1H-pyrrolo[2,3-b]pyridine-3a-carbonitrile (15a): An analytical
sample was obtained by recrystallization from dry ethanol. This product was
isolated as a white solid: mp = 163–165 °C; Yield = 65% (AcOEt/cyclohexane,
Acknowledgments
The authors are grateful to the Algerian and French Governments for
the Graduate Fellowship (2006–2008) attributed to one of us, N. Oukli.
20:80); IR (KBr)
m 3417, 3192, 2098, 2939, 2241, 1722, 1690, 1492,
1448 cmÀ1 1H NMR (300 MHz, CDCl3): d 8.33 (s, 1H), 7.27 (s, 5H), 4.62 (d,
;
References and notes
J = 15.5 Hz, 1H), 4.31 (d, J = 15.5 Hz, 1H), 3.42–3.55 (m, 2H), 3.19 (d,
J = 17.0 Hz, 1H), 2.66 (td, J = 18.0 and 5.0 Hz, 1H), 2.64 (d, J = 17.0 Hz, 1H),
2.40 (dt, J = 18.0 and 3.8 Hz, 1H), 2.19 (dt, J = 13.5 and 3.8 Hz, 1H), 1.96 (td,
J = 13.5 and 4.4 Hz, 1H), 1.10 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
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28.0, 14.8. Anal. Calcd for C17H19N3O3: C, 65.16; H, 6.11; N, 13.41. Found: C,
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1
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24. Typical procedure for the aza-cyclization reaction of hydroxy lactams ( )-17.
BF3ÁOEt2 (500
ll, 3.6 mmol) was added at rt to a solution of hydroxyl lactams
( )-17a–c (1,8 mmol) in CH2Cl2 (20 mL). After 12 h of the reaction, the
mixture was cooled to 0 °C and quenched carefully by addition of an aqueous
saturated solution of NaHCO3 (30 mL). The aqueous layer was extracted with
CH2Cl2 (3 Â 20 mL), and the organic layers were combined, dried over MgSO4,
and evaporated. The residue was further purified by chromatography on silica
gel column by using a mixture of AcOEt/cyclohexane as eluent. Selected data
for ( )-2,6-Dioxo-1-phenethyloctahydro-1H-pyrrolo[2,3-b]pyridine-3a-carbonitrile
(16b): This product was isolated as
Yield = 98% (AcOEt/cyclohexane, 20:80); IR (KBr)
1684 cmÀ1 1H NMR (300 MHz, CDCl3): d 7.90 (br s, 1H), 7.27–7.15 (m, 5H),
a
white solid: mp = 197–199 °C;
m
3346, 2930, 2240,
;
4.77 (d, J = 3.6 Hz, 1H), 3.74 (dt, J = 14.1 and 7.1 Hz, 1H), 3.32 (dt, J = 14.1 and
7.1 Hz, 1H), 2.91–2.78 (m, 2H), 2.86 (d, J = 16.9 Hz, 1H), 2.55 (d, J = 16.9 Hz,
1H), 2.48 (ddd, J = 18.0, 10.9 and 5.3 Hz, 1H), 2.29 (dt, J = 18.0 and 4.8 Hz, 1H),
2.05 (dt, J = 14.1 and 5.3 Hz, 1H), 1.97 (ddd, J = 15.0, 10.9 and 4.8 Hz, 1H); 13C
NMR (75 MHz, CDCl3): d 170.8, 168.0, 138.0, 129.0, 128.7, 127.2, 119.5, 70.3,
41.3, 40.7, 33.6, 33.1, 28.2, 27.8. Anal. Calcd for C16H17N3O2: C, 67.83; H, 6.05;
N, 14.83. Found: C, 67.67; H, 5.89; N, 14.69.
12. Comesse, S.; Sanselme, M.; Daïch, A. J. Org. Chem. 2008, 73, 5566–5569. and
references cited therein.
13. Allous, I.; Comesse, S.; Daïch, A. Lett. Org. Chem. 2008, 5, 73–78. and references
cited therein.
14. For representative examples of this process using different conditions, see: (a)
El-Osaily, Y. A.; Sarhan, A. A. O.; El-Dean, A. M. Kamal. Phosphorus, Sulfur Silicon
25. (a) Veenstra, S. J.; Speckamp, W. N. J. Am. Chem. Soc. 1981, 103, 4645–4646; (b)
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26. Gramain, J. C.; Remuson, R. Tetrahedron Lett. 1985, 26, 4083–4086.