Three-component one-pot synthesis of functionalised (Z)-4-benzylidene (and alkenylidene) pyrrolidines

Article abstract of DOI:10.1016/S0040-4039(02)02383-3

A three-component synthesis of stereodefined 4-benzylidene-(or alkenylidene)-pyrrolidines from simple, readily available starting materials is described. This one-pot process is initiated by a conjugate addition of a propargylamine to a gem-diactivated olefin subsequently followed by a carbopalladation involving an aryl halide (or vinyl triflate).

Full text of DOI:10.1016/S0040-4039(02)02383-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9311–9314
Three-component one-pot synthesis of functionalised
(
Z)-4-benzylidene (and alkenylidene) pyrrolidines
St e´ phane Azoulay, Nuno Monteiro and Genevi e` ve Balme*
Laboratoire de Chimie Organique 1, CNRS UMR 5622, Universit e´ Claude Bernard-Lyon I, CPE. 43, Bd du 11 Novembre 1918,
9622 Villeurbanne, France
6
Received 16 September 2002; revised 18 October 2002; accepted 21 October 2002
Abstract—A three-component synthesis of stereodefined 4-benzylidene-(or alkenylidene)-pyrrolidines from simple, readily avail-
able starting materials is described. This one-pot process is initiated by a conjugate addition of a propargylamine to a
gem-diactivated olefin subsequently followed by a carbopalladation involving an aryl halide (or vinyl triflate). © 2002 Elsevier
Science Ltd. All rights reserved.
In recent years, an intense interest in the development
of new multicomponent reactions has arisen due to
their ability to generate molecular complexity and
ogy. These compounds are indeed of special interest
due to the large number of biologically active com-
pounds containing this moiety.
3
(1)
diversity in a minimum number of steps. These reac-
tions are therefore ideally suited for generating libraries
of small molecules and particularly druglike hetero-
(2)
1
cyclic compounds. As part of our research program
directed at developing transition metal-mediated multi-
component processes, we recently reported a three-com-
Preliminary assays to gauge the possibility of adapting
the process to the use of propargylamines as conjugate
donors were conducted with the commercially available
N-methylpropargylamine (1a). When 1a was reacted
with equimolar amounts of dimethyl benzylidene mal-
onate (2a) and iodobenzene (3a) under conditions simi-
lar to those previously applied to propargyl alcohols
(1.1 equiv. n-BuLi, 5 mol% PdCl (PPh ) , THF–
ponent
synthesis
of
highly
substituted
3
-(4)-benzylidenetetrahydrofurans using equimolar
quantities of readily available propargyl alcohols, aryl
halides (and vinyl triflates), and gem-diactivated olefins
(
Eq. (1)). The methodology was based on a cascade
2
conjugate addition–carbopalladation sequence. Adjust-
ment of the reaction conditions was made so as to
avoid any recovery of excess reagents and, most impor-
tantly, to inhibit the competitive formation of 3-(4)-
methylene tetrahydrofurans as side products (Eq. (2)).
We now report the results of our recent efforts devoted
to the synthesis of pyrrolidines based on this methodol-
2
3 2
DMSO, rt, 3 h), the expected pyrrolidine 4a was indeed
obtained after aqueous workup and silica gel chro-
matography, albeit in a disappointing 27% isolated
yield. Substantial amounts of the reactants were found
at the end of the reaction (GC analysis), a problem that
could not be solved by means of longer reaction times.
In prospect of possible combinatorial applications, the
ideal situation would be to avoid tedious and time-con-
suming purifications. Propargylamines may be easily
removed by aqueous washes, and conjugate acceptors
Keywords: multicomponent reactions; palladium catalysis; carbocycli-
sation; pyrrolidines.
4
*
Corresponding author. Tel.: +(0)4-72-43-14-16; fax: +(0)4-72-43-12-
4; e-mail: balme@univ-lyon1.fr
by scavenging techniques. However, removal of aryl
1
halides and vinyl triflates clearly relies on chromato-
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02383-3

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S. Azoulay et al. / Tetrahedron Letters 43 (2002) 9311–9314
graphic purifications. It was thus decided to revisit the
parameters of the reaction so as to bring it to comple-
tion or at least limit the amount of unreacted iodoben-
zene. The most significant results of this study are
summarised in Table 1.
amines were essentially unreactive. All benzylidene and
alkylidene malonates tested gave satisfactory results
except for p-nitrophenyl derivative 2e which led to
inseparable mixtures of pyrrolidines 4 and 5 (Table 2,
entries 5 and 8). It is worth noting that the reaction
opens access to potentially interesting nicotine deriva-
tives (Table 2, entry 2). The reactivity of olefins bearing
activating groups other than esters was also investi-
gated. Inclusion of a sulfonyl or nitro moiety in these
reactants was of particular interest as it was anticipated
from previous work that the resulting cyclised products
Gratifyingly, we found that substitution of n-BuLi for
NaH had a dramatic effect on the kinetics of the
reaction. Within the same period of time as previously
allotted (3 h), only small amounts of iodobenzene
remained unreacted and the yield of 4a was raised to
7
61% (Table 1, entry 2). As expected, the use of excesses
could be functionalised further by allylic substitution.
of both the propargylamine and the conjugate acceptor
had also a beneficial effect on the yield of 4a (up to
Disappointingly, as exemplified by the reaction of ethyl
2-phenylsulfonyl cinnamate (2g) (Table 2, entry 7),
poor results were obtained with vinyl sulfones. On the
other hand, nitroolefins, e.g. 1-nitrocyclohexene and
b-methyl-b-nitrostyrene, gave complex mixtures of
uncharacterised products. We also attempted to react
commercially available ethyl 2-cyanocinnamate and
benzylidene malononitrile, but these starting materials
furnished preferably the two-component cycloaddition
products 5.
8
5%), with the aryl iodide being entirely consumed
(
Table 1, entries 4, 5). However, with large excesses of
these reagents (>1.1 equiv.), we began to observe the
formation of significant amounts of the unwanted 4-
5
methylene pyrrolidine analogue 5a which unfortu-
nately exhibited a similar polarity to that of 4a. As
regards the ease of purification, best results were thus
obtained using only a slight excess (1.1 equiv.) of these
reactants. Under these conditions, 4a could be obtained
in satisfactory purity by simple aqueous workup and
filtration of the crude product through a short pad of
silica gel. Alternatively, conventional chromatography
afforded analytically pure 4a in 65% yield (Table 1,
entry 4).
In another experiment we succeeded in assembling five
reactants by using 1,4-diodobenzene (3f) as a biscou-
pling species. Thus, reaction of 3f with two equivalents
of the sodium salt of 1a and two equivalents of 2a
yielded the symmetrical product 6 resulting from two
conjugate addition–carbopalladation processes. Four
CꢀC and two CꢀN bonds were created in a single
operation. Compound 6 was isolated in 54% yield as a
The new reaction conditions were then applied to a
series of propargylamines, aryl halides (or vinyl trifl-
ates), and gem-diactivated olefins in order to probe the
scope and limitations of the three-component reaction
8
single diastereomer, presumably the meso form, as
depicted in Eq. (3).
(3)
6
(
Table 2). The reaction showed promising structural
In conclusion, we have shown that a series of hitherto
unknown 4-benzylidene (and alkenylidene) pyrrolidines
can be assembled from readily available, when not
commercially disposable, starting materials. The one-
flexibility with respect to each component. N-alkyl
propargylamines 1a,b participated in the reaction
whereas N-tosyl, N-Boc, and N-benzyl protected
Table 1. Reaction of N-methylpropargylamine (1a) with dimethyl benzylidene malonate (2a) and phenyl iodide (3a) to yield
4a
Entry
Ratio 1a:2a:3a
1:1:1
Base
Solvent
Time (h)
Yield (%)a
27b
1
2
n-BuLi
NaH
THF–DMSO
3
3
(
3–2)
THF–DMSO
3–2)
1:1:1
61b
(
3
1:1:1
NaH
THF
4
35b,c
4
1.1:1.1:1
NaH
THF–DMSO
3
65
(
3–2)
THF–DMSO
3–2)
5
1.5:1.5:1
NaH
2.5
85c
(
a
Isolated yields calculated with respect to the quantities of iodobenzene introduced in the reaction.
Reaction was not complete.
Small amounts (ca. 5–10%) of the corresponding 4-methylene pyrrolidine 5 were isolated as side product.
b
c

S. Azoulay et al. / Tetrahedron Letters 43 (2002) 9311–9314
9313
a
Table 2. Three-component synthesis of 4-benzylidene (and alkenylidene) pyrrolidines

9
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S. Azoulay et al. / Tetrahedron Letters 43 (2002) 9311–9314
pot three-component reaction described herein comple-
ments our previous results obtained with propargyl
alcohols. It operates most efficiently with N-alkyl-
propargylamines, the alkyl group thereby introducing
an additional element of diversity.
in hexanes, approx. 50 mL, 0.1 mmol) was added dropwise
to a well stirred suspension of PdCl (PPh ) (35 mg, 0.05
2
3 2
mmol) in DMSO (2 mL) under a nitrogen atmosphere
until a dark red homogeneous solution was obtained. In a
separate flask, N-methylpropargylamine (76 mg, 1.1
mmol) was added dropwise to a suspension of NaH (60%
in mineral oil, 44 mg, 1.1 mmol) in THF (3 mL) under a
nitrogen atmosphere. The solution was stirred at rt for 10
min and then successively treated with dimethyl benzyli-
dene malonate (220 mg, 1.1 mmol), iodobenzene (204 mg,
1.0 mmol), and the freshly prepared palladium complex
solution. The reaction mixture was stirred at rt for 3 h and
References
1
. For reviews, see: Bienaym e´ , H.; Hulme, C.; Oddon, G.;
Schmitt, P. Chem. Eur. J. 2000, 6, 3321–3329; D o¨ mling,
A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210;
Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 366–
after usual workup with aqueous NaHCO solution and
3
3
74; Dax, S. L.; McNally, J. J.; Youngman, M. A. Curr.
dichloromethane, the combined organic layers were dried
over Na SO and concentrated in vacuo. The residue was
subjected to column chromatography (silica gel; ethyl ace-
Med. Chem. 1999, 6, 255–270; Armstrong, R. W.; Combs,
A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc.
Chem. Res. 1996, 29, 123–131.
. (a) Bottex, M.; Cavicchioli, M.; Hartmann, B.; Monteiro,
N.; Balme, G. J. Org. Chem. 2001, 66, 175–179; (b)
Gar c¸ on, S.; Cavicchioli, M.; Vassiliou, S.; Hartmann, B.;
Monteiro, N.; Balme, G. J. Org. Chem. 2001, 66, 4069–
2
4
tate/petroleum ether) to afford pyrrolidine 4a (237 mg,
1
2
3
65%) as a solid. Mp 138–139°C. H NMR (CDCl
, 300
3
MHz) l 7.45–7.25 (m, 10H), 6.75 (s, 1H), 4.46 (s, 1H), 4.26
(dd, J=13.7 and 1.7 Hz, 1H), 3.81 (s, 3H), 3.38 (dd,
13
J=13.7 and 1.7 Hz, 1H), 3.21 (s, 3H), 2.27 (s, 3H).
NMR (CDCl , 75 MHz) l 169.6, 169.1, 137.5, 137.1,
136.5, 128.7, 128.4, 128.1, 128.0, 126.9, 76.4, 75.1, 70.8,
59.8, 53.0, 52.2, 40.5. Anal. calcd for C22 ; C, 72.31;
C
4
073.
3
. (a) O’Hagan, D. Nat. Prod. Rev. 2000, 17, 435–446 and
previous annual reports; (b) Massiot, G.; Delaude, C. In
The Alkaloids; Brossi, A., Ed.; Academic Press: New
York, 1986; p. 27; (c) Numuta, A.; Ibuka, T. In The
Alkaloids; Brossi, A., Ed.; Academic Press: New York,
H
23NO
4
H, 6.34; N, 3.84. Found C, 72.16; H, 6.38; N, 3.84%.
7. (a) Clique, B.; Vassiliou, S.; Monteiro, N.; Balme, G. Eur.
J. Org. Chem. 2002, 1493–1499; (b) Woods, M.; Monteiro,
1
987; p. 31.
N.; Balme, G. Eur. J. Org. Chem. 2000, 1711–1718.
1
4
. (a) Eames, J.; Watkinson, M. Eur. J. Org. Chem. 2001,
8. Selected data for compound 6: H NMR (CDCl
3
, 300
1
213–1224; (b) Thompson, L. A. Curr. Opin. Chem. Biol.
MHz) l 7.45 (d, J=6.6 Hz, 4H), 7.40–7.25 (m, 10H), 6.76
(s, 2H), 4.48 (s, 2H), 4.30 (d, J=13.9 Hz, 2H), 3.83 (s,
6H), 3.41 (d, J=13.9 Hz, 2H), 3.23 (s, 6H), 2.29 (s, 6H).
2
000, 324–337; (c) Hodges, J. C. Synlett 2000, 152–158.
5
. Clique, B.; Monteiro, N.; Balme, G. Tetrahedron Lett.
13
1
999, 40, 1301–1304.
C NMR (CDCl
, 75 MHz) l 169.8, 169.4, 137.8, 137.1,
3
6
. Representative procedure for the three-component reac-
tion. Synthesis of dimethyl 4-benzylidene-1-methyl-2-
phenyl-pyrrolidine-3,3-dicarboxylate (4a). n-BuLi (2.0 M
136.3, 129.0, 128.8, 128.4, 126.9, 75.5, 71.2, 60.2, 53.4,
+
52.5, 40.9. HRMS: calcd for C38
found 653.2861.
H N O (MH ) 653.2863;
40 2 8