Formal [3+2]-cycloaddition-based approach using ethoxymethylene malonate derivatives: Novel and expedient access to functionalized N -acyliminium precursors

Article abstract of DOI:10.1055/s-0030-1258530

Combination of a base, ethoxymethylene malonates, and α- bromoacetamides was used to reach structurally diverse α-alkoxy γ- lactams via a direct aza-MIRC sequence in excellent yields. Subsequent acidic treatment allowed the formed pyrrolo [2,1-a]isoquinoline alkaloid core to be isolated in high yield.

Full text of DOI:10.1055/s-0030-1258530

LETTER
2197
Formal [3+2]-Cycloaddition-Based Approach Using Ethoxymethylene
Malonate Derivatives: Novel and Expedient Access to Functionalized
N-Acyliminium Precursors
A
ccess to
F
unctionaliz
o
ed
N
-Acylim
u
inium Precu
s
rsors sa Saber,a Sébastien Comesse,*a Vincent Dalla,*a Adam Daïch,*a Morgane Sanselme,b Pierre Netchitaïloa
a
Fax +33(02)32744391; E-mail: sebastien.comesse@univ-lehavre.fr; E-mail: vincent.dalla@univ-lehavre.fr; E-mail:
adam.daich@univ-lehavre.fr
UPRES-EA 3233, IRCOF, Université de Rouen, 1 Rue Tesnière, 76821 Mont-Saint-Aignan Cedex, France
b
Received 30 May 2010
these approaches, the 1,2-dipolar potential of DEEM has
also been exploited for the efficient preparation of highly
functionalized 3-arylidene-(or alkenylidene)tetrahydro-
furans of type 7 using a three-component reaction involv-
ing a palladium-mediated cyclization (Scheme 2, eq. 1).10
In this context, we wish to present herein a new aspect of
the latter reactivity mode that expands the scope of the
commercially available ethoxymethylene derivatives 1
and provides an expedient and innovative entry into a
novel variety of a-alkoxy-g-lactam scaffolds 9 as remark-
able N-acyliminium precursors (Scheme 2, eq. 2).11
Abstract: Combination of a base, ethoxymethylene malonates, and
a-bromoacetamides was used to reach structurally diverse a-
alkoxy-g-lactams via a direct aza-MIRC sequence in excellent
yields. Subsequent acidic treatment allowed the formed pyrrolo
[2,1-a]isoquinoline alkaloid core to be isolated in high yield.
Key words: [3+2] annulation, aza-heterocycle, tandem reaction,
a-alkoxy-g-lactams, N-acyliminium, a-amidoalkylation
Commercially available diethyl ethoxymethylene mal-
onate (DEEM), ethyl ethoxymethylene cyanoacetate, and
ethoxymethylene malononitrile (1) are powerful tools for
the synthesis of cyclic and heterocyclic frameworks.1 The
presence of two electron-withdrawing groups (EWG)
within these structures makes them versatile useful build-
ing blocks in organic synthesis. Importantly, their reactiv-
ity can be classified according to three main modes as: (1)
biselectrophiles (Scheme 1, paths A–C), (2) dienophiles/
dipolarophiles (Scheme 1, paths D and E) and (3) 1,2-di-
poles (Scheme 2, equation 1). The seminal developments
of dialkyl alkoxymethylene malonates and their deriva-
tives have mainly focused on reactions with primary
anilines to typically provide enamines 2 through substitu-
tion of the alkoxy group (Scheme 1, path A). Under ther-
mal conditions, the aza-Michael addition is commonly
followed by a cyclization step onto one of the ester func-
tions (EWG) to furnish the corresponding 4-quinolones 3
(path B).2 Many variants of such tandem aza-Michael ad-
dition–intramolecular acylation using various 1,3-bisnu-
cleophiles are known. In these cases, both cyclic and
acyclic amidine and aminal-type reactants forming pyrim-
idin-4-ones 4 as typified in path C,3 ureas,4 and their sul-
fonyl analogues H2N(SO2)NHR5 were investigated.
Similar sequences using also 1,2-bisnucleophiles such as
hydrazines6 and hydroxylamines7 have also been devel-
oped. Alternatively, ethoxymethylene derivatives can be
employed as dienophiles in Diels–Alder reactions leading
to bicyclo- or oxabicyclohexenes 5 (path D)8, while 1,3-
dipolar cycloadditions with oximes allow an efficient ac-
cess to bicyclic systems 6 (path E).9 Complementary to
This work complements a related [3+2] annulation of al-
lylsilanes and chlorosulfonyl isocyanate recently devel-
oped by Woerpel and co-workers.12
X
O
EWG
EWG'
R1
R1
CO2Et
path C
EWG
N
path D
EWG'
OR
N
5 X = CH2, O
4
EWG, EWG' = CO2Me,
CO2Et, CN
OR
path E
R = OMe, OEt
1
EWG
EWG'
path B
path A
CO2Et
CO2Et
R1
N
O
R2
OEt
N
H
CO2Et
n
O
2
6
EWG = CO2Et
R1 = Ar
N
H
n = 1, 2
3
Scheme 1 Use of ethoxymethylene derivatives 1 in the synthesis of
the corresponding enaminones 2 and various heterocyclic compounds
3–6
Over the last decade, we have investigated several aspects
in the chemistry of N-acyliminium ions, including the
main heterocyclization process, the catalytic intermolecu-
lar and intramolecular a-amidoalkylations as well as the
preparation of potential drug candidates.13
Another ongoing program in our group focuses on the de-
velopment of new tandem and domino processes for the
synthesis of heterocyclic systems containing one or more
nitrogen atom(s).14 In this paper, we describe our prelimi-
nary findings in a merging of both aspects for an unprec-
SYNLETT 2010, No. 14, pp 2197–2201
x
x
.x
x
.2
0
1
0
Advanced online publication: 27.07.2010
DOI: 10.1055/s-0030-1258530; Art ID: G16710ST
© Georg Thieme Verlag Stuttgart · New York

2198
M. Saber et al.
LETTER
Table 1 Conditions for the Synthesis of a-Alkoxy-g-lactams 9a–i
R3
R3
EWG
this
EWG
EWG'
CO2Et
EWG'
OR
work
CO2Et
OEt
EWG
Br
ref.10
Br
O
NHR1
EWG'
OR2
OR
N
R1
9
EWG
EWG'
OR2
O
NaH, THF
1
+
O
7
O
O
N
8
NH
R1
R1
( )-9
(equation 1)
(equation 2)
8a–d
1a–d
Scheme 2 1,2-Dipolar properties of ethoxymethylene derivatives 1
Entry Amide 8
Michael
g-Lactam
Yield drf
(%)c
in the synthesis of heterocyclic compounds
(R1)a
acceptor 1 (R2) product 9b
edented and expedient approach to N-acyliminium ion
precursors and their use in the straightforward synthesis of
tricyclic core of the bioactive alkaloid crispine A. Our
strategy builds on our previously developed formal [3+2]
cycloaddition using benzylidene malonates and a-
bromoacetamides of type 8.14b In the present work, the
Michael acceptor components have been switched to
alkoxymethylene malonate derivatives 1 without alter-
ation of the aza-MIRC reactivity, providing us with an ef-
ficient and expedient access to substituted g-lactams 9.
MeO2C
CO2Me
O
OMe
1d
8a (All)
1a (Me)
93
91
–
–
N
9a
MeO2C
CO2Me
OMe
2d
8b (Propar) 1a (Me)
O
N
In this sense, a first set of reactions was settled starting
from either dimethyl methoxymethylene malonate
(DMMM) or DEEM of type 1 and a-bromoacetamides
8a–d using NaH as base in THF at room temperature. We
were delighted to observe that side products potentially
arising from ethoxide displacement were never observed,
with only the expected a-alkoxy-g-lactams 9a–d being
obtained in high yields ranging from 88% up to 95%
(Table 1, entries 1–4).15 Switching the Michael acceptor
structure from malonates to cyanoacetates did not alter the
efficacy of the tandem process and the desired ethoxy lac-
tams 9e–h were also isolated in good yields and excellent
diastereoselectivities along (entries 5–8). The syn rela-
tionship between the ethoxy group and the nitrile function
in these adducts was confirmed by a single X-ray analysis
performed onto adduct 9h (Figure 1)16 and stands in
agreement with our previous work in this area.14b Unfor-
tunately, the above conditions were shown to be less effi-
cient in the case of ethoxymethylene malononitrile (1d),
and under these conditions, the aminal 9i was isolated in
an unsatisfying 48% yield (entry 9) probably due to com-
petitive polymerization of the starting material 1d. After
further screening of the reaction conditions (base, sol-
vent), K2CO3 in refluxing acetonitrile (entry 10) appeared
to be the best combination to provide the expected system
9i in a very good yield of 89% after purification.17
9b
EtO2C
CO2Et
OEt
O
3d
4d
5d
8a (All)
8c (Bn)
8a (All)
1b (Et)
1b (Et)
1c (Et)
95
88
95
–
N
9c
EtO2C
CO2Et
OEt
–
O
N
Ph
9d
EtO2C
CN
O
OEt
N
>95:5
9e
EtO2C
CN
6d
8b (Propar) 1c (Et)
90
89
>95:5
>95:5
O
OEt
N
Having established the capacity of ethoxymethylene mal-
onate derivatives 1, with a-bromoacetamides 8 and a base,
to provide an unusual aza-MIRC cascade process in form-
ing substituted a-alkoxy-g-lactams as remarkable N-
acyliminium precursors, we next sought to outline the
utility of this approach in polyazaheterocyclic synthesis.
9f
EtO2C
N
CN
7d
8c (Bn)
1c (Et)
O
OEt
In fact, heterocyclic systems bearing azabicyc-
lo[4.3.0]nonane skeleton are of great biological impor-
tance since they are found in a wide range of bioactive
natural products and therefore, the formation of this
framework has been, and continues to be, of interest.
Ph
9g
Synlett 2010, No. 14, 2197–2201 © Thieme Stuttgart · New York

LETTER
Access to Functionalized N-Acyliminium Precursors
2199
Table 1 Conditions for the Synthesis of a-Alkoxy-g-lactams 9a–i
(continued)
EWG
Br
EWG'
OR2
EWG
EWG'
OR2
NaH, THF
+
O
O
N
NH
R1
R1
( )-9
8a–d
1a–d
Entry Amide 8
Michael
g-Lactam
Yield drf
(%)c
(R1)a
acceptor 1 (R2) product 9b
EtO2C
CN
8d 8d (DMPE) 1c (Et)
90
>95:5
O
OEt
N
Figure 1 Stick model plot of hydroxy lactam 9h; for clarity, hydro-
gen atoms are omitted
2
Ph(OMe)2
CN
9h
NC
N
of an intramolecular a-amidoalkylation reaction subse-
quent to the N,O-acetal formation. Our tandem aza-MIRC
strategy using commercially available DEEM (1b) was
successfully applied to the known N-(3,4-dimethoxy-
phenethyl)-a-bromoacetamide 8e providing the a-alkoxy-
g-lactam 9j in an excellent yield of 96% (Scheme 3).
9d
48
89
–
–
8c (Bn)
1d (Et)
O
OEt
Ph
10e
9i
a For abbreviations used for alkyl and arylalkyl groups, see (a) All:
allyl, (b) Propar: propargyl, (c) Bn: benzyl, and (d) DMPE:
3,4-dimethoxyphenylethyl.
With a quaternary center equipped with two electron-
withdrawing groups resident to the N,O-acetalic carbon,
this novel substrate class a priori 9j seems sterically and
electronically unsuitable for N-acyliminium ion chemis-
try. Therefore, the reactivity of the representative com-
pound 9j for the intramolecular a-amidoalkylation
reaction was originally believed to be challenging, and
prompted us to first use a large excess of trifluoroacetic
acid as N-acyliminium promoter. N,O-Acetal 9j was in-
deed subjected to 7 equivalents of TFA in refluxing ace-
tonitrile overnight, and we were delighted to isolate the
targeted tricyclic system 10 via the probable intermediacy
of the cationic species I in a good yield of 87%
(Scheme 3). The reaction was further optimized by grad-
ually reducing the charge of Brønsted acid (TFA) which
fell down to 3 equivalents20 without loss of the efficacy.
Interestingly, with 2 equivalents of TFA only the corre-
sponding a-hydroxylactam, not presented in Scheme 3,
b For EWG and EWG¢ groups see directly the structure in column 4.
c Isolated yields.
d Conditions: NaH, THF, 0 °C, 3 h.
e Alternative method: K2CO3, MeCN, reflux, 2 h.
f Determined by 1H NMR on the crude mixture.
The alkaloid (+)-crispine A (11), isolated in 2002 by Zhao
and co-workers from Carduus crispus,18 exhibits impor-
tant activity against notably some human cancer lines, and
constitutes a prototypical example of such interesting
azabicyclo[4.3.0]nonanes. Therefore, methods enabling a
simple access to its tricyclic core and analogous thereof
continue to be stimulating and to date, some racemic and
enantioselective syntheses have been published.19 In order
to highlight the interest of our novel N,O-acetal system as
N-acyliminium ion precursors, we turned our attention to
the two-steps synthesis of this tricyclic skeleton by means
Br
EtO2C
N
CO2Et
OEt
EtO2C
CO2Et
i
O
+
O
96%
NH
OEt
OMe
1b
ii
87%
OMe
OMe
OMe
8e
9j
CO2Et
CO2Et
O
EtO2C
CO2Et
N
π-cyclization
OMe
OMe
I
O
N
N
OMe
OMe
OMe
OMe
(+)-crispine A (11)
( )-10
Scheme 3 Reagents and conditions: (i) NaH, THF, 0 °C, 3 h; (ii) TFA, MeCN, reflux, overnight.
Synlett 2010, No. 14, 2197–2201 © Thieme Stuttgart · New York

2200
M. Saber et al.
LETTER
(13) For representative and recent papers on heterocyclization,
see: (a) Pesquet, A.; Daïch, A.; Decroix, B.; Van Hijfte, L.
Org. Biomol. Chem. 2005, 3, 3937. (b) Hamid, A.; Oulyadi,
H.; Daïch, A. Tetrahedron 2006, 62, 6398. (c) Oukli, N.;
Comesse, S.; Chafi, N.; Oulyadi, H.; Daïch, A. Tetrahedron
Lett. 2009, 50, 1459. For catalytic a-amidoalkylation
process, see: (d) Ben Othman, R.; Bousquet, T.; Othman,
M.; Dalla, V. Org. Lett. 2005, 7, 3535. (e)Pin, F.; Comesse,
S.; Garrigues, B.; Marchalín, Š.; Daïch, A. J. Org. Chem.
2007, 72, 1181. (f) Ben Othman, R.; Affani, R.; Tranchant,
M. J.; Antoniotti, S.; Duñach, E.; Dalla, V. Angew. Chem.
Int. Ed. 2010, 49, 776.
was isolated after the reaction workup in nearly quantita-
tive yield.
In conclusion, we have investigated a new field in the
chemistry of alkoxymethylene derivatives by showcasing
their ability to provide an alternative access to novel and
densely functionalized a-alkoxy-g-lactams. This was op-
erated through a formal [3+2] cycloaddition with diverse-
ly functionalized a-bromoacetamides. These species
bearing two electron-withdrawing groups were isolated in
both high yields and diastereoselectivities. The value of
these new N-acyliminium ion precursors was demonstrat-
ed with the synthesis of the azatriheterocyclic scaffold of
crispine A with an overall yield of 83% in two steps start-
ing from commercially available DEEM. Finally, we are
currently exploring the scope of this tandem process for
the access to more challenging N,O-acetals. The investi-
gation of both intramolecular and intermolecular catalytic
a-amidoalkylations of this novel N,O-acetals class is also
under way in our group and the results will be published
in due time.
(14) (a) Allous, I.; Comesse, S.; Daïch, A. Lett. Org. Chem. 2008,
3, 73. (b) Comesse, S.; Sanselme, M.; Daïch, A. J. Org.
Chem. 2008, 73, 5566. (c) Pin, F.; Comesse, S.; Sanselme,
M.; Daïch, A. J. Org. Chem. 2008, 73, 1975.
(15) Typical Procedure for the Preparation of 9a–j
The required alkoxymethylene derivative 1a–d (1.0 mmol)
and N-alkyl-a-bromoacetamide (8a–e, 1.1 mmol) were
dissolved in freshly distilled THF (10 mL) at 0 °C. NaH (48
mg, 60% suspension in mineral oil, 1.2 mmol) was then
added in small portions, and the mixture was stirred for 3 h.
The reaction was carefully quenched by addition of a sat. aq
NH4Cl solution (10 mL). The aqueous layer was extracted
with EtOAc (3 × 10 mL), the organic layers were combined,
dried over MgSO4, and evaporated. The residue was then
chromatographed on silica gel and provided the desired
a-alkoxy-g-lactams 9a–j.
Acknowledgment
We are grateful to the University of Le Havre for the aid ‘ATER po-
sition’, attributed to M.S. and to our colleague M.-J. Tranchant for
technical assistance.
Physical Data for 9j
This product was isolated as colorless oil; yield 96%
(EtOAc–cyclohexane, 30:70). IR (KBr): 3419, 1965 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.15 (t, J = 7.0 Hz, 3 H),
1.22–1.23 (m, 6 H), 2.61 (d, J = 17.7 Hz, 1 H), 2.82 (m, 2 H),
3.19–3.29 (m, 1 H), 3.42 (d, J = 17.7 Hz, 1 H), 3.64 (q,
J = 7.0 Hz, 2 H), 3.75–3.81 (m, 1 H), 3.84 (s, 3 H), 3.86 (s,
3 H), 4.10–4.32 (m, 4 H), 5.42 (s, 1 H), 6.73–6.81 (m, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): d = 14.1, 14.2, 15.5, 33.8,
36.5, 42.8, 56.0, 56.1, 59.9, 62.4, 62.5, 67.3, 91.7, 111.5,
112.2, 120.7, 131.5, 147.9, 149.2, 166.7, 169.3, 171.4 ppm.
(16) Full crystallographic data have been deposited at the
Cambridge Crystallographic Data Centre; CCDC reference
number 777319 for product 9h. Copies of the data can be
obtained free of charge at the following address:
References and Notes
(1) For a review concerning the use of alkoxymethylene-
malonates in organic synthesis, see: Milata, V. Aldrichimica
Acta 2001, 34, 20; and the references cited therein.
(2) For a recent example in the synthesis of bioactive
compounds, see: Hua, B.; Bernotas, R.; Unwalla, R.; Collini,
M.; Quinet, E.; Feingold, I.; Goos-Nilsson, A.;
Wilhelmsson, A.; Nambi, P.; Evans, M.; Wrobel, J. Bioorg.
Med. Chem. Lett. 2010, 20, 689.
(3) Moffett, R. B. J. Heterocycl. Chem. 1980, 17, 341.
(4) Gómez, C.; Manzano, T.; Navarro, P. Heterocycles 1980,
14, 769.
(5) Tamura, Y.; Miki, Y.; Sumida, Y.; Ikeda, M. J. Chem. Soc.,
Perkin Trans. 1 1973, 2580.
http://www.ccdc.cam.ac.uk.
(17) Optimized Procedure for the Preparation of Compounds
9a–i
Starting from ethoxymethylene malononitrile (1d, 270 mg,
2.2 mmol) and N-alkyl-a-bromoacetamide (8c, 1 mmol)
were dissolved in freshly distilled MeCN (10 mL). K2CO3
(166 mg, 1.2 mmol) was then added, and the mixture was
stirred for 2 h under reflux. The reaction was filtered through
a small pad of Celite 545 using CH2Cl2, and the organic layer
was evaporated. The residue was then purified by chroma-
tography on silica gel column and provided the desired a-
alkoxy-g-lactam.
(6) Desimoni, G.; Righetti, P. P.; Selva, E.; Tacconi, G.; Riganti,
V.; Specchiarello, M. Tetrahedron 1977, 33, 2829.
(7) Whitehead, C. W. J. Am. Chem. Soc. 1952, 74, 4267.
(8) Katagiri, N.; Watanabe, N.; Kaneko, C. Chem. Pharm. Bull.
1990, 38, 69.
(9) Ali, S. A.; Wazeer, M. I. M. J. Chem. Soc., Perkin Trans. 2
1990, 1035.
(10) (a) Ferrié, L.; Bouyssi, D.; Balme, G. Org. Lett. 2005, 7,
3143. (b) Garçon, S.; Vassiliou, S.; Cavicchioli, M.;
Hartmann, B.; Monteiro, N.; Balme, G. J. Org. Chem. 2001,
66, 4069.
(11) For authoritative reviews in this field, see: (a) Maryanoff,
B. E.; Zhang, H. C.; Cohen, J. H.; Turchi, I. J.; Maryanoff,
C. A. Chem. Rev. 2004, 104, 1431. (b) Speckamp, W. N.;
Moolenaar, M. J. Tetrahedron 2000, 56, 3817.
(12) Leonard, N. M.; Woerpel, K. A. J. Org. Chem. 2009, 74,
6915; and references cited therein.
Physical Data for Compound 9i
This product was isolated as colorless oil; yield 89%
(EtOAc–cyclohexane, 20:80). IR (KBr): 2982, 2257, 1723
cm–1. 1H NMR (300 MHz, CDCl3): d = 1.14 (t, J = 6.9 Hz,
3 H), 3.02 (d, J = 16.8 Hz, 1 H), 3.17 (d, J = 16.8 Hz, 1 H),
3.49 (dq, J = 15.2, 7.0 Hz, 1 H), 3.74 (dq, J = 15.2, 7.0 Hz, 1
H), 3.94 (d, J = 14.9 Hz, 1 H), 4.82 (s, 1 H), 4.94 (d, J = 14.9
Hz, 1 H), 7.12–7.15 (m, 2 H), 7.21–7.29 (m, 3 H) ppm.
13C NMR (75 MHz, CDCl3): d = 14.8, 35.0, 38.7, 44.8, 67.8,
90.4, 111.7, 113.4, 128.2, 128.6, 129.2, 134.0, 167.0 ppm.
(18) Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002,
58, 6795.
Synlett 2010, No. 14, 2197–2201 © Thieme Stuttgart · New York

LETTER
Access to Functionalized N-Acyliminium Precursors
2201
(19) For recent examples, see: (a) Chiou, W.-H.; Lin, G.-H.;
Hsu, C.-C.; Chaterpaul, S. J.; Ojima, I. Org. Lett. 2009, 11,
2659. (b) Evanno, L.; Ormala, J.; Pihko, P. M. Chem. Eur. J.
2009, 15, 12963. (c) Coldham, I.; Jana, S.; Watson, L.;
Martin, N. G. Org. Biomol. Chem. 2009, 7, 1674; and the
references cited therein.
(20) Synthesis of Diethyl 8,9-Dimethoxy-3-oxo-2,3,5,6-
tetrahydropyrrolo[2,1-a]isoquinoline-1,1 (10bH)-
dicarboxylate (10)
combined, dried over MgSO4, and evaporated. The residue
was purified by chromatography on silica gel column to
provide 10.
Physical Data for Compound 10
This product was isolated as colorless crystals; mp 157–
159 °C (recrystallized from Et2O); yield 87% (EtOAc–
cyclohexane, 30:70). IR (KBr): 1728, 1691 cm–1. 1H NMR
(300 MHz, CDCl3): d = 0.84 (t, J = 7.0 Hz, 3 H), 1.36 (t,
J = 7.0 Hz, 3 H), 2.60 (d, J = 16.4 Hz, 1 H), 2.79–3.03 (m, 3
H), 3.05 (d, J = 16.4 Hz, 1 H), 3.62–3.84 (m, 2 H), 3.84 (s, 6
H), 4.29–4.50 (m, 3 H), 5.54 (s, 1 H), 6.57 (s, 1 H), 7.30 (s,
1 H) ppm. 13C NMR (75 MHz, CDCl3): d = 13.7, 14.3, 28.6,
37.8, 40.1, 60.9, 62.0, 26.6, 110.8, 110.5, 123.6, 127.9,
147.7, 148.4, 168.9, 169.8, 170.7 ppm.
TFA (0.23 mL, 3 mmol) was added dropwise at r.t. to a
solution of a-alkoxy-g-lactam 9j (438 mg, 1 mmol) in
freshly distilled MeCN (10 mL). The mixture was refluxing
overnight, cooled to 0 °C and then carefully hydrolyzed with
a sat. solution of NaHCO3 (10 mL). The aqueous layer was
extracted with EtOAc (3 × 10 mL), the organic layers were
Synlett 2010, No. 14, 2197–2201 © Thieme Stuttgart · New York