Allenyl sulfones and allenyl sulfides in the synthesis of 3-pyrrolines. A novel nucleophilic [3 + 2] cycloaddition on allenyl sulfones giving rearranged cycloadducts

Article abstract of DOI:10.1021/ol902097d

Efficient methodologies for the synthesis of regloisomeric 3-pyrrolines by reaction of electron-deficient imines and sulfur-containing allenyl derivatives are presented. Lithiated thioallenes give 2-aryl-3-phenylsulfonyl-3-pyrrolines, whereas allenyl sulf

Full text of DOI:10.1021/ol902097d

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4778-4781
Allenyl Sulfones and Allenyl Sulfides in
the Synthesis of 3-Pyrrolines. A Novel
Nucleophilic [3 + 2] Cycloaddition on
Allenyl Sulfones Giving Rearranged
Cycloadducts|
Elena Moreno-Clavijo,† Ana T. Carmona,† Hans-Ulrich Reissig,‡
Antonio J. Moreno-Vargas,† Eleuterio Alvarez,§ and Inmaculada Robina*,†
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidad de SeVilla,
Prof. Garc´ıa Gonza´lez, 1, E-41012 SeVille, Spain, Freie UniVersita¨t Berlin, Institut fu¨r
Chemie und Biochemie, Takustr. 3, D-14195 Berlin, Germany, and Instituto de
InVestigaciones Qu´ımicas, CSIC-USE, Americo Vespucio 49, SeVille, Spain
robina@us.es
Received June 30, 2009
ABSTRACT
Efficient methodologies for the synthesis of regioisomeric 3-pyrrolines by reaction of electron-deficient imines and sulfur-containing allenyl
derivatives are presented. Lithiated thioallenes give 2-aryl-3-phenylsulfonyl-3-pyrrolines, whereas allenyl sulfones furnish the isomeric 2-aryl-
4-phenylsulfonyl-3-pyrrolines through migration of the sulfonyl group that catalyzes the nucleophilic [3 + 2] cycloaddition.
Nitrogen-containing heterocyclic systems have attracted
widespread attention in organic and medicinal chemistry.1
Many procedures for the construction of azacycles have been
developed.2 Allenes are useful building blocks in organic
synthesis as a result of their unique reactivity that is governed
by the type of substituents. Electron-donating groups activate
C-3 for reactions with nucleophiles and C-2 for reactions
with electrophiles. Allenes have also been involved in the
synthesis of azacycles.3 The smooth synthesis of 3-pyrroline
derivatives by 1,2-addition of R-lithiated alkoxyallenes to
imines and subsequent cyclization has been reported.4
Thioallenes as another type of electron-rich allene have been
less studied.5 Electron-withdrawing substituted allenes, such
as unsaturated systems, allow reaction at C-2 with nucleo-
philes by conjugate addition, and the resulting C-1 carbanion
| Dedicated to Prof. P. Vogel on the occasion of his 65th birthday.
† Universidad de Sevilla.
(3) Recent reviews: (a) Zimmer, R.; Reissig, H.-U. Modern Allene
Chemistry; Krause, N., Hasmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004;
Chapter 8, p 425. (b) Brasholz, M.; Reissig, H.-U.; Zimmer, R. Acc. Chem.
Res. 2009, 42, 45.
‡ Freie Universitaet Berlin.
§ Instituto de Investigaciones Qu´ımicas.
(1) Michael, J. P. In The Alkaloids; Cordell, G. A., Ed; Academic Press,
San Diego, CA, 2001; Vol. 55.
(4) (a) Okala Amombo, M. O.; Hausherr, A.; Reissig, H.-U. Synlett 1999,
1871. (b) Flo¨gel, O.; Reissig, H.-U. Synlett 2004, 895.
(2) (a) Le Marquand, P.; Tam, W. Angew. Chem., Int. Ed. 2008, 47,
2926. (b) Fisera, L. Top. Heterocycl. Chem. 2007, 287. (c) Wolfe, J. P.
Synlett 2008, 2913. (d) Ma, S. Pure Appl. Chem. 2008, 80, 695.
(5) (a) Kim, J. T.; Kel’in, A. V.; Gevorgyan, V. Angew. Chem., Int. Ed.
2003, 42, 98. (b) Winter, R. F. Eur. J. Inorg. Chem. 1999, 2121.
10.1021/ol902097d CCC: $40.75
Published on Web 10/02/2009
 2009 American Chemical Society

can interact with various electrophiles.6 Allenyl esters 1 have
been widely used as three-carbon zwitterions in nucleophile-
catalyzed [3 + 2] cycloadditions with electron-deficient
imines 2 as dipolarophiles, providing 3-alkoxycarbonyl
3-pyrrolines 3 (Scheme 1).7 Phosphines have mainly been
together with γ-adduct 9 (77% combined yield) (Scheme 3).
Subsequent 5-endo cyclization of 8 under AgNO3/K2CO3 or
Scheme 3
Scheme 1
used as catalyst in these reactions, pioneered by Lu and co-
workers8 and also developed by many other groups.9
Unsaturated sulfones are versatile reagents. They easily
give stabilized R-anions able to react with several electro-
philes.10 A sulfone substituent also activates an adjacent
π-system toward several cycloaddition reactions, making
unsaturated sulfones to act as excellent dienophiles in
Diels-Alder11 and [2 + 2]12 cycloadditions. Reactions of
allenyl sulfones with diazomethane13 and with N-phenylni-
trones14 and anionic [3 + 2] cycloaddition with electron-
deficient alkenes15 have also been described.
Despite the fact that the chemistry of allenyl sulfones has
been widely studied16 and that there is a similarity between
conjugate additions and cycloadditions of allenyl sulfones
and those of allenyl esters, as far as we are aware, anionic
[3 + 2] cycloadditions of allenyl sulfones with electron-
deficient imines have not been reported.
Here we report the synthesis of 3-pyrrolines of type 5
bearing a phenylsulfonyl moiety at C-3, which are analogues
of alkoxycarbonyl pyrrolines 3, by reaction of electron-
deficient imines 2 with allenyl thioethers in a three-step
procedure involving final oxidation. We also present for the
first time the reaction of electron-deficient imines 2 and
allenyl sulfones 6 that furnishes, in a promoted single step,
regioisomeric 3-pyrrolines of type 7 (Scheme 2).
AuCl catalysis afforded the corresponding 3-phenylthio-3-
pyrroline 10, which by oxidation with MMPP was converted
into sulfone 5a. When the transformation was carried out in
a single step by reaction of 2a with 612,19 in the presence of
a nucleophilic mediator, regioisomeric 2-aryl-4-(phenylsul-
fonyl)-1-tosyl-3-pyrroline 7a was obtained.
In our studies, we first screened conditions for the
nucleophilic cycloaddition of 2a and 6 in the presence of
different nucleophilic mediators (NaNO2, NaSO2Ph, PR3),
solvents, temperatures, and order of addition of components.
All of the reactions were carried out at room temperature
with 25% promoter. Lower temperatures and a smaller
amount of promoter slowed the reaction and gave inferior
yields. In these cases, compounds of type 11 were detected
by NMR (5% conversion). NaNO2 or NaSO2Ph proved to
be the best promoters giving similar yields, although reac-
tions are slightly quicker with the latter. Because of the
ambident character of this anion, we chose NaNO2 for solvent
screening conditions and mechanistic studies.20 Anhydrous
solvents gave poorer yields than those having traces of water
(entries 4 and 5). Mixtures of THF and EtOH speeded
reactions and increased the yields (entries 1 and 2 and 4 and
6). The order of addition of components is crucial for the
Scheme 2
(11) Hayakaw, K.; Nishiyama, H.; Kanematsu, K. J. Org. Chem. 1985,
50, 512.
(12) Padwa, A.; Lipka, H.; Watterson, S. H.; Murphree, S. S. J. Org.
Chem. 2003, 68, 6238.
Reaction of 417 (generated in situ from 1-phenyl thioprop-
1-yne)18 with tosyl imine 2a gave the desired R-adduct 8
(13) Padwa, A.; Filipkowski, M. A.; Kline, D. N.; Murphree, S. S.;
Yeske, P. E. J. Org. Chem. 1993, 58, 2061.
(14) Padwa, A.; Kline, D. N.; Norman, B. H. J. Org. Chem. 1989, 54,
810.
(6) Ma, S. Chem. ReV. 2005, 105, 2829.
(7) (a) Zhao, G.-L.; Shi, M. J. Org. Chem. 2005, 70, 9975. (b) Zhu, X.;
Henry, C. E.; Kwon, O. Tetrahedron 2005, 61, 6276. (c) Fang, Y.-Q.;
Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 5660. (e) Ma, S. Aldrichimica
Acta 2007, 40, 91.
(15) Padwa, A.; Yeske, P. E. J. Org. Chem. 1991, 56, 6386.
(16) (a) Back, T. G. Tetrahedron 2001, 57, 5263. (b) Ma, S.; Li, L.;
Wei, Q.; Xie, H.; Wang, G.; Shi, Z.; Zhang, J. Pure Appl. Chem. 2000, 72,
1739. (c) Padwa, A.; Ni, Z.; Watterson, S. H. Pure Appl. Chem. 1996, 68,
831.
(8) Xu, Z.; Lu, X. J. Org. Chem. 1998, 63, 5031.
(9) (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (b)
Methot, J. L.; Roush, W. R. AdVn. Synth. Catal. 2004, 346, 1035.
(10) Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon Press:
Oxford, U.K., 1993.
(17) Bridges, A. J.; Thomas, R. D. J. Chem. Soc., Chem. Commun. 1984,
694.
(18) Pourcelot, G.; Cadiot, P. Bull. Soc. Chim. Fr. 1966, 9, 3016.
(19) Ma, S.; Ren, H.; Wei, Q. J. Am. Chem. Soc. 2003, 125, 4817
.
Org. Lett., Vol. 11, No. 21, 2009
4779

success of the reaction (best results obtained under conditions
C) (Table 1).
Scheme 4
Table 1. Screening of Reaction Conditions with NaNO2
reaction
time (h) (%) 7a
yield
addition order of
reactantsa
entry
solvent
THF dry
THF/EtOH 2:1
THF/EtOH 2:1
THF dry
1
2
3
4
5
6
20
3.5
10
45
40
8
25
43
38
38
50
60
A
A
B
C
C
C
intermediate 13, which after 5-endo-trig cyclization21 followed
by ꢀ-heteroatom elimination gave 3-pyrroline 7a, since the
sulfinate anion is both a good leaving group and a good
nucleophile. As the reaction takes place with several promoters,
we needed to invoke the formation of benzenesulfinate anion
as initiator (see Scheme 5). The ORTEP drawing of compound
7a is shown in Figure 1.
THF
THF/EtOH 2:1
a A: Solvent added to a mixture of promoter (NaNO2) and reactants
(molar ratio 2a:6 ) 1.2:1). B: Solvent added to a mixture of promoter and
reactants (molar ratio 2a:6 ) 1:3). C: Excess of 6 (2a:6 ) 1:1.5-2.5) slowly
added over a suspension of the promoter and imine in solvent.
Compounds 5a and 7a were fully characterized by their
spectroscopic data. The major difference was found for the
vinyl protons (6.9 ppm, m, for 5a and 6.5 ppm, m, for 7a)
and for the corresponding carbons (136.9 ppm for 5a and
139.3 ppm for 7a) of the pyrroline framework. The structure
of 7a was unambiguosly confirmed by X-ray crystallography
(Figure 1). Although under the reaction conditions 7a was
Scheme 5
Figure 1. ORTEP drawing of compound 7a.
Plausible mechanisms for its generation in anhydrous
solvent (pathway A) and in the presence of EtOH as
cosolvent (pathway B) are indicated in Scheme 5. Thus,
nucleophilic addition of the promoter to 6 gave intermediate
15, which may subsequently react with 6, resulting in a
complex mixture, or cyclize to a five-membered ring, which
after ꢀ-elimination released the benzenesulfinate anion (A).
In the presence of EtOH, intermediate 15 may be protonated
to give 16, which upon addition of the ethoxide anion
released benzenesulfinate anion (B). These pathways might
obtained as a racemate, each enantiomer separates into its
own enantiomeric crystal by crystallization preferential, and
one of them was selected from the crystals. The X-ray
analysis indicated the 1,3-relationship between the phenyl
and the phenylsulfonyl moieties.
A plausible mechanism for this nucleophile-catalyzed single-
step preparation of 7a is depicted in Scheme 4. To account for
the high regioselectivity of the formation of 7a, we required
the participation of intermediate 12 in the process, which might
be obtained by conjugate addition to 6 of the in situ generated
benzenesulfinate anion. Nucleophilic addition of 12 to 2a gave
(20) See Supporting Information for more details.
(21) For other exceptions of the Baldwin rules, see: Amjad, M.; Knight,
D. W. Tetrahedron Lett. 2006, 47, 2825.
4780
Org. Lett., Vol. 11, No. 21, 2009

explain the generation of the benzenesulfinate anion, the
acceleration of the reaction when using EtOH as cosolvent,
and the slower reactions and lower yields obtained in
anhydrous solvents that may lead to allene polymerization.
To verify the feasibility of these assumptions, an experiment
with the allenyl sulfone 6 and NaNO2 as promoter was
performed (Scheme 6). The resulting benzenesulfinate anion
Table 2. Scope for Nucleophilic Cycloaddition of Imines 2 and
6 in THF/EtOH (2:1)
Scheme 6
entry
Ar
P
reaction time (h) 7a-e yield(%)
1
2
3
4
Ph
Ph
Ts
SES
8
15
15
8
7
15
60
64
66
70
39
38
p-MeO-Ph Ts
p-Cl-Ph
p-O2N-Ph
p-O2N-Ph
Ts
Ts
Ts
5
6a
a THF was used as solvent.
from addition of EtOH (see Supporting Information). The
use of THF alone does not increase the yield of the
corresponding pyrroline 7e (entry 6).
generated through pathway A or B reacted with 6 to provide
12, which generated known compound 20.22 Reaction of 20
with 2a in the presence of K2CO3 afforded pyrroline 7a. A
similar behavior of allenyl sulfones triggered by Ph3P
generating benzenesulfinate anion was reported.23 Another
possibility that might be considered is the reaction of
intermediate 15 with imine (pathway C) giving 17, which
may cycle to 18. This specie could release the benzenesulfi-
nate anion to furnish compound 19, which could be detected
in the ESI-MS spectra of the crude product but could not be
isolated.
The moderate yields obtained (best yield 60%) are not
surprising considering the complexity of the overall path-
ways. The precursors can give undesired reactions, the imine
being hydrolyzed to the corresponding aldehyde and the
allenyl sulfone undergoing oligomerization. Additionally, part
of the allenyl sulfone is consumed furnishing 20. In fact this
compound was detected in all of the reactions as side product.
To establish the scope of the reaction, a small library of
aryl imines (see Supporting Information) were made to react
with 6 under the optimized conditions. The reaction was
found to occur with different substituted N-tosylimines and
with N-(trimethylsilyl)ethanesulfonyl (SES) imine 2b (Table
2). Reaction with the p-chlorophenyl imine 2d delivered the
best result. For the p-nitrophenyl derivative 7e (entry 5)
medium to poor yield was obtained. The higher reactivity
of imine 2e implies the formation of a byproduct coming
In summary, we have developed two procedures for the
regiodivergent synthesis of isomeric 2-aryl-3-pyrrolines from
allenes and electron-deficient imines. The three-step sequence
employing a lithiated thioallene establishes a route to 2-aryl-
3-phenylsulfonyl-3-pyrrolines. The one-pot procedure from
allenyl sulfones implies migration of the sulfonyl group,
which catalyzes an anionic [3 + 2] cyclization-elimination
reaction. This represents a new, efficient, atom-economic,
and mild route to synthesize 2-aryl-4-phenylsulfonyl-3-
pyrrolines.
This behavior is different from that reported for alkoxy-
carbonyl-substituted allenes. Allenyl sulfones give sulfonyl
rearranged 3-pyrrolines as a result of the ability of the
benzenesulfinate anion to act as nucleophile as well as a
leaving group. Efforts are underway to extend the scope of
the reaction including chiral reactants.
Acknowledgment. We thank MEC Spain (CTQ2007-
61254/BQU, CTQ2008-01565/BQU), FPU fellowship for
E.M-C., Junta de Andaluc´ıa (FQM-345) and Dr. M. Angulo
for NMR discussions (CITIUS, Univ. of Seville).
Supporting Information Available: Detailed experimen-
tal procedures, characterization data and spectra for all
compounds. X-ray crystallographic data for 7a and 7c in CIF
format. This material is available free of charge via the
Internet at http://pubs.acs.org.
(22) Padwa, A.; Kline, D. N.; Norman, B. H. Tetrahedron Lett. 1988,
29, 265, and references therein.
(23) Lu, C.; Lu, X. Tetrahedron 2004, 60, 6575.
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