New access to trisubstitutea 3-pyrrolines under phosphine catalysis

Article abstract of DOI:10.1021/ol901758k

Conjugated dienes, properly activated by electron-withdrawing groups on both ends, are shown to be suitable substrates for phosphinepromoted organocatalytic processes. Their reactions with imines, under phosphine catalysis, afford a new and efficient synthetic approach to functionalized 3-pyrrolines.

Full text of DOI:10.1021/ol901758k

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4406-4409
New Access to Trisubstituted
3-Pyrrolines under Phosphine Catalysis
Marie Schuler, Deepti Duvvuru, Pascal Retailleau, Jean-Franc¸ois Betzer, and
Angela Marinetti*
Institut de Chimie des Substances Naturelles, CNRS, UPR 2301.
1, aV. de la Terrasse - 91198 Gif-sur-YVette Cedex
angela.marinetti@icsn.cnrs-gif.fr
Received July 30, 2009
ABSTRACT
Conjugated dienes, properly activated by electron-withdrawing groups on both ends, are shown to be suitable substrates for phosphine-
promoted organocatalytic processes. Their reactions with imines, under phosphine catalysis, afford a new and efficient synthetic approach to
functionalized 3-pyrrolines.
Nucleophilic phosphines are known to be useful mild
catalysts for the conversion of imines into nitrogen hetero-
cycles via [3 + 2]1 and [4 + 2]2 cyclization reactions, in
which either electron-poor allenes or alkynes behave as the
three- or four-carbon synthons.3 The synthetic potential of
these reactions has been largely demonstrated by the
preparation of biologically relevant natural products4 as well
as by using them to access a range of pyrrolidines and
piperidines for pharmaceutical applications.5 In this context,
with the aim of extending the scope of phosphine organo-
catalysis, we disclose here a new approach to 2,3,5-
trisubstituted 3-pyrrolines, based on the use of conjugated
dienes as the three carbon units in annulation reactions on
activated imines. This new method complements the previous
ones, as far as it allows access to a different range of
3-pyrrolines from easily available new substrates.
(1) (a) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461–3464. (b) Xu,
Z.; Lu, X. J. Org. Chem. 1998, 63, 5031–5041. (c) Xu, Z.; Lu, X.
Tetrahedron Lett. 1999, 40, 549–552. (d) Zhao, G.-L.; Shi, M. J. Org. Chem.
2005, 70, 9975–9984. (e) Zhu, X.-F.; Henry, C. E.; Kwon, O. Tetrahedron
2005, 61, 6276–6282. (f) Tang, X.; Zhang, B.; He, Z.; Gao, R.; He, Z.
AdV. Synth. Catal. 2007, 349, 2007–2017. (g) Meng, L.-G.; Cai, P.; Guo,
Q.; Xue, S. J. Org. Chem. 2008, 73, 8491–8496. (h) Zhang, B.; He, Z.;
Xu, S.; Wu, G.; He, Z. Tetrahedron 2008, 64, 9471–9479. (i) Jean, L.;
Marinetti, A. Tetrahedron Lett. 2006, 47, 2141–2145. (j) Fleury-Bre´geot,
N.; Jean, L.; Retailleau, P.; Marinetti, A. Tetrahedron 2007, 63, 11920–
11927. (k) Scherer, A.; Gladysz, J. A. Tetrahedron Lett. 2006, 47, 6335–
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5661. (m) Pinto, N.; Fleury-Bre´geot, N.; Marinetti, A. Eur. J. Org. Chem.
2009, 146–151.
Our strategy of using conjugated dienes as starting
materials has been developed, based on the well-known
activation of bis(enones) by phosphorus nucleophiles leading
to the so-called intramolecular Rauhut-Currier reactions,6
(4) Tran, Y. S.; Kwon, O. Org. Lett. 2005, 7, 4289–4291.
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F.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 5843–5845. (d) Watanabe, M.;
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4716–4717. (b) Zhao, G.-L.; Shi, M. Org. Biomol. Chem. 2005, 3, 3686–
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8710. (e) Aroyan, C. E.; Dermenci, A.; Miller, S. J. Tetrahedron 2009, 65,
4069–4084.
(3) Nitrogen heterocycles are also available by combining imines with
enones, acrolein, or allylic carbonates, under phosphine catalysis: (a) Shi,
M.; Xu, Y.-M. Eur. J. Org. Chem. 2002, 696–701. (b) Meng, X.; Huang,
Y.; Chen, R. Chem. Eur. J. 2008, 14, 6852–6856. (c) Ma, G.-N.; Wang,
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10.1021/ol901758k CCC: $40.75
Published on Web 09/02/2009
 2009 American Chemical Society

when the enone functions are tethered by either two or three
atoms chains. The postulated mechanism of these reactions
is depicted in Scheme 1 (left). We reasoned that if the two
Scheme 2
.
Attempted Reactions of Conjugated Dienes with
Imines in the Presence of PMePh2
Scheme 1. Intramolecular Rauhut-Currier Reaction (Left) and
the Suggested Variant Involving Trapping of I by Imines
(Right)
a Syn:anti ratio ) 90:10. b Syn:anti ratio ) 85:15.11
tively. Pyrrolines 4b and 5a were produced as mixtures of
two isomers in about 9:1 ratios, tentatively assigned as the
2,5-syn and anti diastereomers. The syn isomer is the major
product.11 When starting from the unsymmetric substrate 2a,
the cyclization might occur, in principle, on each one of the
electron-poor C-C double bonds. The reaction proceeded,
actually, with high regioselectivity, leading to pyrroline 5a.
The inertness of the diester toward the above cyclization
reactions is in line with the known reluctance of bisenoates
to undergo intramolecular Rauhut-Currier type cycliza-
tions.6b-d The behavior of the mixed enone-enoate substrate
2a is however rather surprising. Indeed, the isolated product
5a results from the initial addition of the phosphorus
nucleophile to the enoate double bond (R2 ) OMe, step a
in Scheme 1), while the enone function serves as the Michael
acceptor in the subsequent ring-closing step c. This contrasts
with literature data showing that intramolecular Rauhut-
Currier reactions on enone-enoates take place with the
opposite regiochemistry: enones being the more electrophilic
of the two Michael acceptors of the bifunctional substrates,
they preferentially undergo the initial addition of the
phosphorus nucleophile.6b-d,12 The observed, unusual cy-
clization manifold leading to 5a might be determined by
either electronic effects and orbitals distribution on the diene
or the relative reaction rates of the two possible phosphine-
diene adducts with the imine in step b.
electron-poor olefinic functions of the substrates were directly
connected, as in conjugated dienes (n ) 0 in Scheme 1), the
Rauhut-Currier type reactions would be disfavored due to
the short distance between the carbanionic center of I and
the potential olefinic acceptor. In this case, it should be
possible to trap the zwitterionic intermediate I with electro-
philic substrates, such as activated imines (step b in Scheme
1, right). This would create a three atom spacer between the
negatively charged atom (the nitrogen center in II) and the
enone function, thus enabling an intramolecular nucleophilic
addition to take place (step c), following a classical
Rauhut-Currier type process. Pyrrolines IV are expected
to be quickly accessed in this way, from a reaction sequence
which formally combines intramolecular Rauhut-Currier and
aza-Morita-Baylis-Hillman7 type reactions.
It must be pointed out here that cyclizations in Scheme 1
seem to be uniquely susceptible to phosphine catalysis since
they did not proceed in the presence of nitrogen Lewis bases
such as DABCO, DMAP, or Et3N.
After optimization of the reaction conditions,13 the method
appeared to be applicable to a wide range of substrates and
notably to dienic enone-esters with various R1 substituents. The
6-oxo-dienoates 2b-2o were conveniently accessed as E/Z
mixtures from the commercially available (E)-4-oxobut-2-enoic
acid ethyl ester, via Wittig-type reactions (Scheme 3).
To test the feasibility of the catalytic manifold above, we
examined the reactions between N-tosylbenzaldimine 3a and
both symmetrical and unsymmetrical dienic substrates, i.e., the
diester 1a,8 the diketone 1b,9 and the enone-ester 2a10 in the
presence of MePPh2 as the Lewis base catalyst (Scheme 2).
Their reactions with N-tosylbenzaldimine have been per-
formed with either PBu3 or PMePh2, at 50 and 120 °C,
respectively. Neither PPh3 nor PCy3 were efficient catalysts for
Dimethyl trans-trans muconate 1a failed to react with
the imine, while the anticipated cyclization products 4b and
5a were obtained from 1,4-dibenzoyl-1,3-butadiene 1b and
the 6-oxo-6-phenylhexadienoic acid methyl ester 2a, respec-
(8) Boisvert, L.; Beaumier, F.; Spino, C. Org. Lett. 2007, 9, 5361–5363.
(9) Perlmutter, H. D.; Trattner, R. B. J. Org. Chem. 1978, 43, 2056–
2057.
(7) (a) Perlmutter, P.; Teo, C. C. Tetrahedron Lett. 1984, 25, 5951–
5952. (b) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem. 2007, 2905–2916. (c)
Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 4614–
4628.
(10) Allen, J. V.; Bergeron, S.; Griffiths, M. J.; Mukherjee, S.; Roberts,
S. M.; Williamson, N. M.; Wu, L. E. J. Chem. Soc., Perkin Trans. 1 1998,
3171–3179.
Org. Lett., Vol. 11, No. 19, 2009
4407

In most of the isolated products the syn:anti ratio is higher
than 9:1, and it increases to >99:1 for pyrroline 5g as well
as for the alkyl-substituted ketones of entries 12 and 13. The
syn:anti ratios of 5 are irrespective of the E/Z isomer ratios
of the starting dienes.
Scheme 3. Synthesis of the 6-Oxo-dienoates 2b-o
The syn stereochemistry has been assigned to the major
isomers of 5, based on X-ray diffraction studies on a representa-
tive compound, 5g (entry 6). Crystals of 5g have been obtained
from a dichloromethane solution by slow addition of pentane.
The ORTEP drawing is shown in Figure 1.14
these cyclizations. Depending on the substrate, yields and
diastereomeric ratios may vary slightly, as a function of the
phosphorus catalyst and the reaction temperature. For each
substrate, the optimized conditions and results are reported in
Table 1.
Table 1. Synthesis of Pyrrolines 5b-o from Various
6-Oxodienoatesa
Figure 1. ORTEP view of pyrroline 5g showing the relative syn
arrangement of the ring substituents. Displacement ellipsoids are
at the 30% level.
Finally, to further establish the scope of this new cycliza-
tion reaction, a variety of N-Ts imines have been prepared
and reacted then with the 6-oxo-hexadienoates 2b (R1 ) Ph)
and 2m (R1 ) t-Bu). Representative results are given in Table
2, showing that the reaction may tolerate electron-rich and
electron-poor aryl substituents on the imine carbon.
Most notably, not only aryl-substituted but also a repre-
sentative alkyl-substituted imine 3h could be reacted with
dienoates 2b,m to afford the corresponding 2-alkyl-substi-
tuted pyrrolines 6h and 7h in good yields.
As a general trend, the t-Bu substituted 6-oxo-dienoate
2m (entries 8-13) gives very clean reactions, almost total
diastereoselectivity and higher yields than the benzoyl-
substituted diene 2b (entries 1-7).
(11) The molecular structure and the syn stereochemistry of the major
product have been established by X-ray diffraction studies (see Figure 1).
The minor isomer has not been unambiguously characterized; nevertheless,
selected NMR signals have been assigned by COSY experiments. Assign-
ments support the 3-pyrroline structure. For compound 5a′ (minor product),
a Reactions performed at a 0.3 mmol scale, with a 1:1 diene:imine ratio,
under Ar in toluene (1 mL) for 18 h. b Reaction temperature: 120 °C.
c Reaction temperature: 50 °C. d In the crude reaction mixture.
2
3
NMR data are the following: δ 3.32 (dd, JHH ) 18.3 Hz, JHH ) 9.3 Hz,
1H, CH2CO), 4.54 (dd, 2JHH ) 18.3 Hz, 3JHH ) 3.9 Hz, 1H, CH2CO), 5.39
3
4
3
3
(m, 1H, JHH ) 9.3 Hz, JHH ) 5.7 Hz, JHH ) 3.9 Hz, JHH ) 1.8 Hz,
NCHCH2), 5.85 (dd, 4JHH ) 5.7 Hz, 4JHH ) 1.5 Hz, 1H, CHPh) ppm. The
corresponding NMR data for the major product 5a are the following: δ
As shown in Table 1, these reactions delivered the
expected pyrrolines in moderate to good yields, starting from
aryl ketones with both electron-donating and -withdrawing
substituents (entries 1-9), as well as from naphthyl (entry
10) and thienyl ketones (entry 11). Alkyl ketones may also
be suitable substrates, and especially high yields were
obtained from dienone 2m which displays a t-Bu substituted
carbonyl function (entry 12). Decreasing yields are given
by dienones with secondary and primary alkyl groups (entries
13 and 14).
3.36 (dd, 2JHH ) 17.7 Hz, 3JHH ) 10.6 Hz, 1H, CH2CO), 4.04 (dd, 2JHH
)
)
3
3
3
17.7 Hz, JHH ) 3.8 Hz, 1H, CH2CO), 5.10 (ddt, JHH ) 10.6 Hz, JHH
3.8 Hz, 3JHH ) 4JHH ) 1.9 Hz, 1H, NCHCH2), 5.58 (t, 4JHH ) 1.9 Hz, 1H,
CHPh) ppm.
(12) Brown, P. M.; Ka¨ppel, N.; Murphy, P. J.; Coles, S. J.; Hursthouse,
M. B. Tetrahedron 2007, 63, 1100–1106.
(13) For full details on solvents and catalyst screenings, see Supporting
Information.
(14) Crystallographic data for this compound have been deposited at
the CCDC, Cambridge, UK, with the deposit number 741184.
(15) Guan, X.-Y.; Shi, M. J. Org. Chem. 2009, 74, 1977–1981.
4408
Org. Lett., Vol. 11, No. 19, 2009

dienes 2 as substrates gives access to a new range of 2,3,5-
trisubstituted 3-pyrrolines. The known approaches, which
make use of 3-substituted allenoates or butynoates,1c-f,h,5c,15
alkynyl ketones,1g enones3a or allylic compounds,3d and aryl
imines as reactants, have been applied so far to the synthesis
of 2-aryl-substituted pyrrolines, with either simple alkyls
(Me, Et, Pr, n-Bu, t-Bu, n-Pent, n-Hex, c-C5H9CH2) or aryl
groups in the 5 position. As shown in Tables 1 and 2 above,
the new method opens the way to both 2-alkyl- and 2-aryl-
substituted pyrrolines with carbonylmethyl functions on the
C-5 carbon.
Table 2. Variations of the Imine Partnersa
diene
imine R3
p-ClC6H4
p-NO2C6H4 3c
p-CF3C6H4 3d 6d PBu3
p-MeOC6H4 3e
1-naphthyl 3f
2-thienyl
prod.
cat.
yield (%)
dr
b
In conclusion, we have developed a simple, general, and
practical method for the synthesis of new 2,3,5-trisubstituted
3-pyrrolines from easily available dienic derivatives, under
phosphine catalysis. Future studies will focus on the devel-
opment of related organocatalytic transformations of dienic
substrates, as well as on synthetic applications of the
functionalized pyrroline scaffolds above.
1
2
3
4
5
6
7
8
9
2b
2b
2b
2b
2b
2b
2b
3b 6b PMePh2
64
38
42
24
46
67
68
71
85
71
88
70
69
85:15
90:10
90:10
85:15
>95:5
85:15
>99:1
>99:1
>99:1
>95:5
>95:5
>99:1
>99:1
6c
PMe2Phc
c
6e
6f
PMe2Phc
c
PBu3
b
3g 6g PMePh2
3h 6h PBu3
c
i-Pr
b
b
b
b
b
b
2m p-ClC6H4
2m p-CF3C6H4 3d 7d PMePh2
3b 7b PMePh2
Acknowledgment. Authors warmly thank the Agence
Nationale de la Recherche (ANR) for financial support to
M.S. and the COST PhoSciNet Action for supporting
research topics on phosphine organocatalysis.
10 2m p-MeOC6H4 3e
11 2m 1-naphthyl 3f
7e
7f
PMePh2
PMePh2
12 2m 2-thienyl
3g 7g PMePh2
13 2m i-Pr
3h 7h PMePh2
a Reactions performed at a 0.3 mmol scale, with a 1:1 diene:imine ratio,
under Ar in toluene (1 mL) for 18 h. b Reaction temperature: 120 °C.
c Reaction temperature: 50 °C.
Supporting Information Available: General experimental
procedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The above results show that, compared to other phosphine-
based organocatalytic methods, the use of the conjugated
OL901758K
Org. Lett., Vol. 11, No. 19, 2009
4409