A phosphine-catalyzed [3 + 2] annulation reaction of modified allylic compounds and N-tosylimines

Article abstract of DOI:10.1021/ol801661y

(Chemical Equation Presented) A phosphine-catalyzed annulation of modified allylic ylides with various aromatic imines to form 3-pyrrolines was developed. The presence of a substituent in the allylic compound is crucial for this reaction. Without the substituent, (E)-dienylimines will be produced via the dimerization of the allylic compounds.

Full text of DOI:10.1021/ol801661y

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4481-4484
A Phosphine-Catalyzed [3 + 2]
Annulation Reaction of Modified Allylic
Compounds and N-Tosylimines
Suqing Zheng and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai, 200032, China
xylu@mail.sioc.ac.cn
Received July 23, 2008
ABSTRACT
A phosphine-catalyzed annulation of modified allylic ylides with various aromatic imines to form 3-pyrrolines was developed. The presence
of a substituent in the allylic compound is crucial for this reaction. Without the substituent, (E)-dienylimines will be produced via the dimerization
of the allylic compounds.
Reports of phosphines as nucleophilic catalysts in the reaction
of alkynoates or allenoates have grown significantly.1,2
Recently, we developed phosphine-catalyzed [3 + 2] and
[3 + 6] annulation reactions of carbon-phosphorus ylides
with electron-deficient olefins.3
In these reactions, simple allylic compounds, which can
be easily obtained by one-step transformation from the
product of the Morita-Baylis-Hillman reaction, were used
as the three-carbon unit instead of the alkynoates or alle-
noates. Compared with alkynoates or allenoates, the allylic
compounds have some special reactivities, which stimulated
us to explore the new reaction with other kinds of electro-
philes.
(1) For reviews on phosphine-catalyzed reactions, see: (a) Methot, J. L.;
Roush, W. R. AdV. Synth. Catal. 2004, 346, 1035. (b) Lu, X.; Zhang, C.;
Xu, Z. Acc. Chem. Res. 2001, 34, 535
.
3-Pyrrolines are a class of compounds, generally used as
intermediates for the synthesis of five-membered nitrogen-
containing heterocyclic natural products and pharmaceutical
compounds.4 Among the numerous known methodologies,
the [3 + 2] cycloaddition provides the most versatile method
for the formation of pyrrolines.5 Recently, there are many
reports related to the phosphine-catalyzed [3 + 2] annulation
reaction of 2,3-butadienoates or 2-butynoates with N-
tosylimines to form pyrrolines (Scheme 1).2,6 Herein, we
wish to report the reaction of allylic compounds with
N-tosylimines under the catalysis of a tertiary phosphine.
(2) Recent reports on phosphine-catalyzed reactions, see: (a) Wurz, R. P.;
Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234. (b) Wilson, J. E.; Fu, G. C.
Angew. Chem., Int. Ed. 2006, 45, 1426. (c) Virieux, D.; Guillouzic, A.-F.;
Cristau, H.-J. Tetrahedron 2006, 62, 3710. (d) Jean, L.; Marinetti, A.
Tetrahedron Lett. 2006, 47, 2141. (e) Nair, V.; Biju, A. T.; Mohanan, K.;
Suresh, E. Org. Lett. 2006, 8, 2213. (f) Lu, X.; Lu, Z.; Zhang, X.
Tetrahedron 2006, 62, 457. (g) Scherer, A.; Gladysz, J. A. Tetrahedron
Lett. 2006, 47, 6335. (h) Mercier, E.; Fonovic, B.; Henry, C. E.; Kwon, O.;
Dudding, T. Tetrahedron Lett. 2007, 48, 3617. (i) Castellano, S.; Fiji,
H. D. G.; Kinderman, S. S.; Watanabe, M.; de Leon, P.; Tamanoi, F.; Kwon,
O. J. Am. Chem. Soc. 2007, 129, 5843. (j) Wallace, D. J.; Sidda, R. L.;
Reamer, R. A. J. Org. Chem. 2007, 72, 1051. (k) Henry, C. E.; Kwon, O.
Org. Lett. 2007, 9, 3069. (l) Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc.
2007, 129, 10988. (m) Tran, Y. S.; Kwon, O. J. Am. Chem. Soc. 2007,
129, 12632. (n) Sriramurthy, V.; Barcan, G. A.; Kwon, O. J. Am. Chem.
Soc. 2007, 129, 12928. (o) Creech, G. S.; Kwon, O. Org. Lett. 2008, 10,
429. (p) Fang, Y.-Q.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 5660.
(3) (a) Du, Y.; Lu, X.; Zhang, C. Angew. Chem., Int. Ed. 2003, 42,
1035. (b) Du, Y.; Feng, J.; Lu, X. Org. Lett. 2005, 7, 1987. (c) Feng, J.;
Lu, X.; Kong, A.; Han, X. Tetrahedron 2007, 63, 6035.
(4) (a) Green, M. P.; Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002,
43, 6609. (b) Huwe, C. M.; Blechert, S. Tetrahedron Lett. 1995, 36, 1621.
(c) Burley, I.; Hewson, A. T. Tetrahedron Lett. 1994, 35, 7099.
10.1021/ol801661y CCC: $40.75
Published on Web 09/11/2008
2008 American Chemical Society

Scheme 1
.
[3 + 2] Reaction of Methyl 2,3-Butadienoate with
N-Tosylimines
Table 1. Effect of Phosphine Catalysts on the Formation of 3aa
from 1a and 2aa
entry
catalyst (10 mol %)
1a/2a
yieldb (%)
1
2
3
4c
5
6
PPh3
PPh3
PPh3
PPh3
PBu3
PPh2Et
2:1
2:1.5
1:1
2:1.5
2:1.5
2:1.5
73
86
62
78
-
80
d
To initiate our study, compound 1a and imine 2a were
stirred in toluene at room temperature under 10 mol % of
PPh3 as the catalyst. Unfortunately, we did not obtain the
product pyrroline as expected from the reaction of allenoate
and N-tosylimine, but only (E)-dienylimine 3aa was obtained
in 62% yield (Scheme 2). The structure of compound 3aa
a Reaction conditions: Under Ar, a mixture of 1a, 2a, and catalyst in
toluene was stirred at room temperature for 2 days. b Isolated yields. c 20
mol % of PPh3 was used. d Complicated products.
Table 2. Synthesis of 3 from 1a and N-Tosyliminesa
Scheme 2
was confirmed by X-ray crystallography of the analogous
compound 3ad substituted with a p-bromophenyl group.7
Varying the ratio of 1a/2a could not change the product
to pyrroline. When the ratio of 1a/2a was 2:1.5, the yield
could be improved to 86% (Table 1, entry 2). Changing PPh3
to the more nucleophilic phosphine PPh2Et, the reaction also
proceeded smoothly, but no product was obtained when the
strong nucleophilic phosphine PBu3 was used. The reaction
proceeded smoothly in many solvents except polar solvents
such as acetonitrile or DMF. Toluene was the best solvent.
The reaction could occur with various substituted N-
tosylimines, and electron-donating group substituted N-
tosylimines led to better yields (Table 2, entries 1 and 6).
In this reaction, highly substituted (E)-dienylimines could
be obtained in one step. These compounds are useful in
hetero-Diels-Alder reactions8 and can be used as intermedi-
ates for the synthesis of γ-amino acids.9 The synthetic utility
of this reaction can be further demonstrated by the Al2O3-
a Reaction conditions: Under Ar, a mixture of 1a (0.20 mmol), 2 (0.15
mmol), and PPh3 (0.02 mmol) in toluene was stirred at room temperature
for 2 days. b Isolated yields.
mediated hydrolysis of the imino group to ketone 5ad
(Scheme 3).
Scheme 3
(5) (a) Padwa, A. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 4, p 1069. (b) Wade,
P. A. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: New York, 1991; Vol. 4, p 1111. (c) Confalone, P. N.; Huie,
E. M. Org. React. 1988, 36, 1. (d) Pearson, W. H. In Studies in Natural
Products Chemistry; Rahman, A. U., Ed.; Elsevier: Amsterdam, 1988; Vol.
1, p 323. (e) Batia, B. A.; B, N.; Portnoy, M. Heterocycles 2006, 67, 511.
(f) Young, I. S.; Williams, J. L.; Kerr, M. A. Org. Lett. 2005, 7, 953.
(6) (a) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (b) Xu, Z.; Lu,
X. J. Org. Chem. 1998, 63, 5031. (c) Zhu, X. F.; Henry, C. E.; Kown, O.
Tetrahedron 2005, 61, 6276.
A possible mechanism for this unexpected phosphine-
catalyzed reaction is proposed (Scheme 4). The phosphine
reacted with modified allylic compound 1a to form the
phosphonium salt A. The in situ generated tert-butoxide
anion deprotonated this salt to afford ylide B which was
added to another molecule of 1a to produce C. C was
deprotonated by the in situ generated tert-butoxide again to
give ylide D. The ylide D was added to the imine 2 to
produce E. After hydrogen transfer, E was changed to F
(7) CIF files are included in the Supporting Information.
(8) (a) Hetero Diels-Alder Methodology in Organic Synthesis; Boger,
D. L., Weinreb, S. M., Eds.; Academic Press: San Diego, 1987. (b) Boger,
D. L.; Corbett, W. L.; Wiggins, J. M. J. Org. Chem. 1990, 55, 2999. (c)
Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A. M. J. Am. Chem.
Soc. 1991, 113, 1713.
(9) (a) Juaristi, E. EnantioselectiVe Synthesis of ꢀ-Amino Acids; Wiley-
VCH: New York, 1997. (b) Gellman, S. H. Acc. Chem. Res. 1998, 31, 17.
4482
Org. Lett., Vol. 10, No. 20, 2008

Scheme 4
.
Proposed Mechanism for the Formation of 3
Table 3. Effect of Phosphine Catalysts on the Formation of
Pyrroline 4bea
entry
catalyst (10 mol %)
temperature (°C)
yieldb (%)
1
PPh3
rt
-
2
3
PPh3
PPh3
PPh3
PPh3
PEtPh2
PEtPh2
PEt2Ph
PEt2Ph
PBu3
80
110
110
110
rt
rt
rt
rt
rt
12
72
85
73
26
47
24
40
42
4c
5d
6
7e
8
9e
10e
a Reaction conditions: Under Ar, a mixture of 1b (76 mg, 0.24 mmol),
2e (51 mg, 0.2 mmol), and catalyst in toluene (1 mL) was stirred at the
temperature indicated. b Isolated yields. c 2 mL of toluene was used. d 1b
(37 mg, 0.12 mmol) in toluene (0.5 mL) was added over 12 h with a syringe
pump to a mixture of PPh3 and 2e (26 mg, 0.1 mmol) in toluene (0.5 mL)
at 110 °C. The mixture was stirred further for 1 h. e 20 mol % of catalyst
was used.
which afforded intermediate G by elimination of PPh3.
Finally, 3 was formed by isomerization.
On the basis of the above mechanism, it was suggested
that the reason why the reaction could not produce 3-pyr-
rolines might be due to the high reactivity of 1a to add to
another molecule of 1a to obtain the dimerized intermediate
C. It occurred to us that it is possible to facilitate the
formation of 3-pyrrolines if the steric bulkiness of 1 is
increased. To test the feasibility of this idea, 1b (1.2 equiv),
the phenyl-substituted analogue of 1a, was used to react with
imine 2e (1 equiv) in refluxing toluene using PPh3 (10 mol
%) as the catalyst. Fortunately, product 4be was isolated in
85% yield as a single isomer (Table 3, entry 4).
Table 4. Synthesis of 3-Pyrrolines from Various Iminesa
Many phosphines (Table 3) could catalyze this reaction,
among which PPh3 gave the best result. Solvents also were
tested, and toluene still was the best solvent. The reaction
was found to be general and to occur with different
substituted N-tosylimines, providing the 2,5-disubstituted
3-pyrrolines in moderate to excellent yields (Table 4).
Chloro- and bromo-substituted aryl N-tosylimines can afford
nearly quantitative yields (Table 4, entries 3 and 4). N-
Tosylimines with electron-donating aryl substituents gave
lower yields (Table 4, entries 1 and 6).
a Reaction conditions: Under Ar, a mixture of 1b (0.24 mmol), 2 (0.2
mmol), and PPh3 (0.02 mmol) in toluene (2 mL) was stirred at 110 °C.
b Isolated yields. c 4 mL of toluene was used.
To investigate the scope of this reaction, a variety of
modified allylic tert-butyl carbonates were used to react with
N-tosylimine 2e (Table 5). For various aryl-substituted allylic
tert-butyl carbonates, reactions could provide moderate yields
(Table 5, entries 1-4), while alkyl-substituted allylic tert-
butyl carbonates gave relatively poor results (Table 5, entries
5 and 6). The reaction of tert-butyl ester could also proceed
very well (Table 5, entry 7). The cis-stereochemistry of these
products was confirmed by X-ray crystallography of the
analogous compound 4bc substituted with a p-chlorophenyl
group.7 Thus, this novel reaction potentially provides a new
approach to the preparation of multifunctionalized 3-pyrro-
lines.
A plausible mechanism for this phosphine-catalyzed [3 +
2] annulation reaction of the substituted allylic compounds
with N-tosylimines is proposed (Scheme 5). The reaction
might be initiated by the formation of the phosphoniun salt
A via the addition of PPh3to 1b. A was deprotonated by the
in situ generated tert-butoxide anion affording ylide B.
Subsequent nucleophilic addition of the ylide B to the
electron-deficient imine 2e yielded the intertmediate H.
Intramolecular annulation of the imine to the olefinic double
bond occurred with the elimination of PPh3 to yield the
product 4be and completed the catalytic cycle.
Org. Lett., Vol. 10, No. 20, 2008
4483

Scheme 5
Table 5. Synthesis of 3-Pyrrolines 4 from Different Allylic
Compoundsa
a Reaction conditions: Under Ar, a mixture of 1 (0.24 mmol), 2e (0.2
mmol), and PPh3 (0.02 mmol) in toluene (2 mL) was stirred at 110 °C.
b Isolated yields. c 1f (85 mg, 0.24 mmol) in toluene (1 mL) was added
over 12 h with a syringe pump to a mixture of PPh3 and 2e (52 mg, 0.2
mmol) in toluene (1 mL) at 110 °C. The mixture was stirred further for
1 h.
substituent. The appealing features of this process involve
the availability of the starting materials, the simple manipula-
tion, and the high stereoselectivity of the reaction.
In conclusion, a novel phosphine-catalyzed reaction of
modified allylic tert-butyl carbonates with N-tosylimines has
been developed. The presence of substituents in allylic tert-
butyl carbonates is crucial for this reaction. For allylic tert-
butyl carbonates with substituents, a phosphine-catalyzed [3
+ 2] annulation of modified allylic tert-butyl carbonates with
N-tosylimines occurred to give 3-ethoxycarbonyl-2,5-cis-
disubstituted-3-pyrrolines in moderate to good yields with
high stereoselectivity. Highly substituted dienylimines 3 were
obtained from allylic tert-butyl carbonates without any
Acknowledgment. We thank the National Natural Science
Foundation of China (20572121) and Chinese Academy of
Sciences for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL801661Y
4484
Org. Lett., Vol. 10, No. 20, 2008