Catalytic enantioselective 1,3-dipolar cycloaddition of azomethine ylides with vinyl sulfones

Article abstract of DOI:10.1021/ol060314c

A general protocol for the enantioselective catalytic 1,3-dipolar cycloaddition of azomethine ylides with aryl vinyl sulfones is described. Nearly complete exo selectivity and enantioselectivities up to 85% ee are attained with Cu(CH₃CN)_4<

Full text of DOI:10.1021/ol060314c

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1795-1798
Catalytic Enantioselective 1,3-Dipolar
Cycloaddition of Azomethine Ylides with
Vinyl Sulfones
Toma´s Llamas, Ramo´n Go´mez Arraya´s, and Juan C. Carretero*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias,
UniVersidad Auto´noma de Madrid, Cantoblanco 28049 Madrid, Spain
juancarlos.carretero@uam.es
Received February 6, 2006
ABSTRACT
A general protocol for the enantioselective catalytic 1,3-dipolar cycloaddition of azomethine ylides with aryl vinyl sulfones is described. Nearly
complete exo selectivity and enantioselectivities up to 85% ee are attained with Cu(CH3CN)4ClO4/Taniaphos as the catalyst system. The resulting
enantioenriched 3-sulfonyl cycloadducts are versatile intermediates in the synthesis of 2,5-disubstituted pyrrolidines.
The 1,3-dipolar cycloaddition of azomethine ylides with
alkenes is an extremely powerful and convergent strategy
for the stereoselective synthesis of substituted pyrrolidines,
a structural motif found in many alkaloids as well as an
important building blocks for natural product synthesis.1
Toward the goal of developing enantioselective variants of
this reaction with maximum chemical efficiency, the metal-
assisted catalytic asymmetric cycloaddition of azomethine
ylides with electron-deficient alkenes is receiving increasing
attention.2 Since the first protocol reported by Jørgensen et
al. in 2002,3 some efficient enantioselective procedures have
been described with Zn(II),3 Ag(I),4 Cu(I),5 and Cu(II)6
complexes of a variety of chiral N,N-, P,P- P,N-, and P,S-
bidentate ligands as catalysts. Despite the high levels of
asymmetric induction achieved, a drawback of these proce-
dures is that they have been generally applied to a narrow
range of activated alkenes, typically commercially available
conjugated carbonyl dipolarophiles such as acrylates, male-
ates, fumarates, and maleimides.
In this context, it is surprising that the catalytic enantio-
selective 1,3-dipolar cycloaddition of vinyl sulfones has been
scarcely studied, especially considering the high electron-
deficient character of the CdC bond of R,â-unsaturated
sulfones,7 their high regiocontrol shown in this reaction,7a,8
and the great chemical versatility of the sulfonyl group.7c,9
To the best of our knowledge, the reaction of phenyl vinyl
(4) (a) Zeng, W.; Zhou, Y.-G. Org. Lett. 2005, 7, 5055. (b) Stohler, R.;
Wahl, F.; Pfaltz, A. Synthesis 2005, 1431. (c) Kno¨pfel, T. F.; Aschwanden,
P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Chem., Int. Ed.
2004, 43, 5971. (d) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc.
2003, 125, 10174. (e) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem.
Soc. 2002, 124, 13400.
(1) For reviews on pyrrolidine synthesis and related alkaloids, see: (a)
Michael, J. P. Nat. Prod. Rep. 2004, 21, 625. (b) Cheng, Y.; Huang, Z.-T.;
Wang, M.-X. Curr. Org. Chem. 2004, 8, 325. (c) Michael, J. P. Alkaloids
2001, 55, 91. For applications of pyrrolidine derivatives as organocatalysts,
see: (d) Notz. W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37,
580.
(2) For a review, see: Na´jera, C.; Sansano, J. M. Angew. Chem., Int.
Ed. 2005, 44, 6272.
(3) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2002, 41, 4236.
(5) (a) Cabrera, S.; Go´mez Arraya´s, R.; Carretero, J. C. J. Am. Chem.
Soc. 2005, 127, 16394. (b) Gao, W.; Zhang, X.; Raghunath, M. Org. Lett.
2005, 7, 4241.
(6) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.; Minakata, S.;
Komatsu, M. Org. Lett. 2003, 5, 5043.
(7) (a) Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon Press:
Oxford, UK, 1993. (b) Tanaka, K.; Kaji, A. In The Chemistry of Sulphones
and Sulphoxides; Patai, S., Rappoport, Z., Stirling, C., Eds.; Wiley: New
York, 1988; Chapter 15, p 759. (c) Fuchs, P. L.; Braish, T. F. Chem. ReV.
1986, 86, 903.
10.1021/ol060314c CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/30/2006

sulfone with (()-alanine methyl ester 2-naphthaldehyde
Schiff base in the presence of stoichiometric amounts of
AgOTf and a chiral P,P-ligand, reported by Grigg et al.,10
constitutes the only scattered example on the participation
of a vinyl sulfone in chiral Lewis acid-promoted 1,3-dipolar
cycloadditon of azomethine ylides, the pyrrolidine cycload-
duct being obtained in 70% ee.
Table 1. CuI- and AgI-Catalyzed Enantioselective
Cycloaddition of Phenyl Vinyl Sulfone with
N-Benzylideneglycine Methyl Ester
We describe herein a systematic study on metal-catalyzed
asymmetric 1,3-dipolar cycloaddition of vinyl sulfones with
azomethine ylides, reaching ee values up to 85% ee in the
presence of the catalyst system Cu(I)-Taniaphos.
entrya
ligand (L*)
(R)-Binap
yieldb (%)
ee (%)c
1
2
3
4
5
6
7e
8
63
21
29
71
19
2
65
83
71
79
69
77
62
78
87
-26 (-13)d
-19
-42
Taking into account our recent results in enantioselective
Cu(I)-catalyzed 1,3-dipolar cycloadditions,5a we chose as the
model reaction the cycloaddition of N-benzylideneglycine
methyl ester (1a) with phenyl vinyl sulfone (2a) in the
presence of catalytic amounts of Cu(CH3CN)4ClO4 (10 mol
%), a chiral ligand (10 mol %), and Et3N11 as base (18 mol
%). Interestingly, most of the ligands used led to complete
conversion within 6-24 h in toluene12 at 0 °C, providing
with complete regioselectivity and very high exo-selectivity13
the cycloadduct 3a. The enantioselectivity exerted by a
representative set of chiral ligands is shown in Table 1.
Low to moderate enantiocontrol was attained from well-
established commercially available P,P-ligands, such as
Binap, Chiraphos, Norphos, and Phanephos (19-42% ee;
entries 1-4), while very low reactivity and enantioselectivity
were observed in the case of N,N-bisoxazoline (BOX) ligands
(entries 5 and 6). On the other hand, the monodentate
phosphoramidite described by Feringa et al.14 provided 3a
almost in racemic form (entry 7).
(S,S)-Chiraphos
(S,S)-Norphos
(S)-Phanephos
(R,R)-Bn-BOX
(R,R)-PyBOX
phosphoramidite
Fesulphos 1
Fesulphos 2
Fesulphos 3
Josiphos
-37
5
9
3
51 (62)d
59 (51)d
53 (52)d
-4
9
10
11
12
13
14
15
Mandyphos
Walphos 1
Walphos 2
16
58 (-6)d
62 (-40)d
83 (63)d
Taniaphos
a Reaction conditions: 1a (1.0 equiv), 2a (1.0 equiv), Cu(CH3CN)4ClO4
or AgOAc (10 mol %), L* (10 mol %), Et3N (18 mol %), toluene, 0 °C,
6-24 h. b Isolated yield after chromatographic purification. c Determined
by HPLC (Chiralpak AS). d In parentheses ee in the presence of AgOAc
(10 mol %) instead of Cu(CH3CN)4ClO4. e Reaction performed in CH2Cl2
at room temperature.
In contrast, the ferrocene P,S-ligands developed by our
group (Fesulphos ligands)15 provided moderate enantiose-
lectities, within the range 50-60% ee (entries 8-10).
Speculating that chiral 1,2-disubstituted ferrocene structures
could be appropriate ligands for this reaction, we finally
surveyed several commercially available P,N- and P,P-
(8) For examples on the participation of vinyl sulfones in 1,3-dipolar
cycloaddition with azomethine ylides, see: (a) Wittland, C.; Risch, N. J.
Prakt. Chem. 2000, 342, 311. (b) Laduron, F.; Viehe, H. G. Tetrahedron
Lett. 2002, 58, 3543. (c) Clark, R. B.; Pearson, W. H. Org. Lett. 1999, 1,
349. (d) Plancquaert, M.-A.; Redon, M.; Janousek, Z.; Viehe, H. G.
Tetrahedron 1996, 52, 4383.
(9) For a review on desulfonylation/functionalization strategies, see:
Na´jera, C.; Yus, M. Tetrahedron 1999, 55, 10547.
(10) Grigg, R. Tetrahedron: Asymmetry 1995, 6, 2475.
(11) Other bases such as DPA, DBU, and K2CO3 provided similar or
somewhat lower enantioselectivity in the model reaction.
(12) The CuI-Taniaphos catalyzed reaction of 1a with 2a was studied in
five different solvents (toluene, THF, CH2Cl2, Et2O, and DMF). Toluene
and THF provided the best enantioselectivities (83% ee in both cases),
whereas CH2Cl2 led to the lowest asymmetric induction (62% ee).
(13) In all cases only the exo adduct 3a was detected in the 1H NMR
spectra of the crude reaction mixture. This stereochemical result sharply
contrasts with the supposedly endo-selectivity described in the previous
example of silver-azomethine ylide cycloaddition of phenyl vinyl sulfone
(see ref 10).
(14) For a review, see: Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
(15) (a) Garc´ıa Manchen˜o, O.; Priego, J.; Cabrera, S.; Go´mez Arraya´s,
R.; Llamas, T.; Carretero, J. C. J. Org. Chem. 2003, 68, 3679. For recent
applications of Fesulphos in asymmetric catalysis, see: (b) Cabrera, S.;
Go´mez Arraya´s, R.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc. 2005,
127, 17938. (c) Garc´ıa Manchen˜o, O.; Go´mez Arraya´s, R.; Carretero, J. C.
Organometallics 2005, 24, 557. (d) Cabrera, S.; Go´mez Arraya´s, R.;
Carretero, J. C. Angew. Chem., Int. Ed. 2004, 43, 3944. (e) Garc´ıa
Manchen˜o, O.; Go´mez Arraya´s, R.; Carretero, J. C. J. Am. Chem. Soc. 2004,
126, 456. See also ref 5a.
ferrocene ligands (entries 11-15). Gratifyingly, we found
an excellent reactivity and a significant enhancement of the
enantioselectivity in the presence of Taniaphos16 (entry 15),
which provided 3a in 87% yield and 83% ee.17 Recrystal-
lization of this sample (CH2Cl2-hexane, -20 °C) afforded
3a in enantiomerically pure form. Interestingly, a reduction
of the catalyst loading from 10 to 5 mol % did not affect
(16) Ireland, T.; Grossheimann, G.; Wieser-Jeunesse, C.; Knochel, P.
Angew. Chem. Int. Ed. 1999, 38, 3212.
1796
Org. Lett., Vol. 8, No. 9, 2006

Table 2. Cu(I)-Taniaphos-Catalyzed Reaction of Azomethine
Precursor 1a with Aryl Vinyl Sulfones 2a-d
entrya
sulfone
time (h)
product
yield (%)b
ee (%)c
1
2
3
4
5
2a
2b
2c
2d
2e
4
24
3
3
24
3a
3b
3c
3d
3e
87
71
87
72
nr
83
75d
83
50
nr
Figure 1. Crystal structure of 3a.
a Reaction conditions: 1a (1.0 equiv), 2 (1.0 equiv), Cu(CH3CN)4ClO4
(10 mol %), Taniaphos (10 mol %), Et3N (18 mol %), toluene, 0 °C. b In
pure product after silica gel chromatography. c Determined by HPLC
(Chiralpak AS). d Determined by HPLC from its N-methyl derivative (see
the Supporting Information for details).
the enantioselectivity of the reaction between 1a and 2a (83%
ee in both cases), although a slight decrease of the reactivity
(24 h instead of 6 h at 0 °C) was observed.18 The relative
and absolute (2R,3S,5R) configuration of 3a was unequivo-
cally established by X-ray diffraction analysis (Figure 1).
Considering that AgOAc has been the most used precata-
lyst in enantioselective 1,3-dipolar cycloadditions of azo-
methine ylides, we briefly studied the silver-mediated
reaction between 1a and 2a using AgOAc instead of Cu-
(CH3CN)4ClO4. Except for the case of Fesulphos 1 (Table
1, entry 8, value in parentheses), all tested ligands induced
lower asymmetric induction than that of the copper-catalyzed
process. It is worth noting that in the Ag-promoted reaction
Taniaphos proved also to be the best ligand.
2e,20 which led to the recovery of the starting material
unaltered. Disappointingly, in comparison with 2a, none of
the new vinyl sulfones 2b-e produced an enhancement of
the enantioselectivity. As the best result, the thiophenyl vinyl
sulfone 2b provided the same asymmetric induction (83%
ee), while the potentially coordinating 2-pyridyl derivative
2d21 gave the lowest enantiocontrol (50% ee).
Having found the Cu(I)-Taniaphos combination as the
optimal catalytic system, we studied the effect of the
substitution at the aryl vinyl sulfone. In this regard substrates
2b-d,19 of varied electronic properties at the aryl moiety,
were surveyed in the Cu(I)-Taniaphos-catalyzed reaction of
1a (Table 2).
Similarly to the model substrate 2a, vinyl sulfones 2b-d
led to a single diasteromer exo-3, whose configuration was
assigned by chemical analogy with 3a and the similarity of
their 1H NMR data. Pyrrolidines 3 were isolated in all cases
with good yields (71-87%), except for the case of the
electronically richer o-(N,N-dimethylamino)phenyl sulfone
Next, to establish the scope of this 1,3-dipolar cycload-
dition with regard to the dipole component, a variety of
substituted azomethine ylide precursors were studied with
use of 5 mol % of Cu(I)-Taniaphos. The results are collected
in Table 3.
The cycloaddition is widely general regardless of the
substitution at the aromatic ring of the aryl imine. Both
electronically rich and electronically poor arenes, as well as
substitution at para, meta, and ortho position, are well
tolerated (entries 1-7). The reaction was highly exo-
stereoselective for all these 1,3-dipoles, providing in good
yields (71-92%) a single pyrrolidine (4-10) with enantio-
selectivities depending on the particular aryl group. Para-
and meta-substituted aromatic rings led to enantioselectivities
very similar to that of the model reaction (82-85% ee),
whereas the reaction with bulkier imines, such as the
2-naphthyl imine 1g (entry 6) and the o-tolyl imine 1h (entry
7), was significantly less enantioselective (65% and 41% ee,
respectively). Aliphatic imines (entry 8) and the R-substituted
1,3-dipole precursor 1j (entry 9) were also suitable substrates,
the latter giving rise to the pyrrolidine 12 with a stereogenic
quaternary center at C-5 (80% ee). However, in this case
the chemical yield was much lower, likely due to the
(17) Typical experimental procedure: A mixture of Taniaphos (6.9 mg,
0.01 mmol) and Cu(CH3CN)4ClO4 (3.2 mg, 0.01 mmol) in toluene (1 mL)
was stirred at room temperature for 30 min. Then, a solution of 1a (35.6
mg, 0.20 mmol) in toluene (0.5 mL) and Et3N (5 µL, 0.036 mmol) were
added. The mixture was cooled to 0 °C, treated with a solution of 2a (33.6
mg, 0.20 mmol) in toluene (0.5 mL), and stirred at 0 °C for 24 h. The
reaction mixture was filtered through Celite and concentrated. The residue
was purified by flash chromatography (hexanes-EtOAc 3:1) to afford 3a
as a white solid; yield 60 mg (87%).
(18) By contrast, an unpractical very slow reaction was observed by
decreasing the catalyst loading to 2 mol %.
(19) Sulfones 2b-d were readily available by reaction of the corre-
sponding aryl disulfide with vinylmagnesium bromide and subsequent
oxidation of the resulting thioether to sulfone with Na2W7O4‚2H2O/H2O2.
The preparation of 2e required the condensation of methyl o-(N,N-
dimethylamino)phenyl sulfone with formaldehyde as the key step. See the
Supporting Information for details.
(20) For the use of o-(N,N-dimethylamino)phenyl vinyl sulfones in the
Heck reaction, see: (a) Mauleo´n, P.; Nu´n˜ez, A. A.; Alonso, I.; Carretero,
J. C. Chem. Eur. J. 2003, 9, 1511. (b) Mauleo´n, P.; Alonso, I.; Carretero,
J. C. Angew. Chem., Int. Ed. 2001, 40, 1291.
(21) For the use of 2-pyridyl sulfones in transition metal-catalyzed
processes, see: (a) Mauleo´n, P.; Carretero, J. C. Chem. Commun. 2005,
4961. (b) Mauleo´n P.; Carretero, J. C. Org. Lett. 2004, 6, 3195. (c) Llamas,
T.; Go´mez Arraya´s, R. AdV. Synth. Catal. 2004, 346, 1651.
Org. Lett., Vol. 8, No. 9, 2006
1797

Scheme 1. Desulfonylation Reactions on the Cycloadduct 3a
Table 3. Cu(I)-Taniaphos-Catalyzed Reaction of a Variety of
Azomethine Precursors with Phenyl Vinyl Sulfone
entrya
1
R1
R2 product yield (%)b ee (%)c
pure cis-1,5-disubstituted pyrrolidine 14 was isolated in 61%
yield.22 It must be noted that in the sequence 1,3-dipolar
cycloaddition + desulfonylation the phenyl vinyl sulfone acts
as a synthetic equivalent of ethylene, a type of unactivated
olefin unsuitable for the reaction with azomethine ylides.
In conclusion, a general protocol for the catalytic enan-
tioselective 1,3-dipolar cycloaddition of vinyl sulfones with
azomethine ylides has been developed. The CuI-Taniaphos
catalyst system (5-10 mol %) showed the best performance,
providing 3-sulfonyl pyrrolidines with very high exo selec-
tivity and enantioselectivities in the range 41-85% ee.
Transformation of the reaction products into enantiopure 2,5-
disubstituted pyrrolidines highlighted their synthetic potential.
Mechanistic studies, as well as the extension to other types
of 1,3-dipoles are under current investigation.
1
2
3
4
5
6
7
8
9
1b p-F(C6H4)
1c p-OMe(C6H4)
1d m-F(C6H4)
1e m-OMe(C6H4)
1f m-Tol
1g 2-Naph
1h o-Tol
1i Cy
H
H
H
H
H
H
H
H
Me
4
5
6
7
8
9
10
11
12
91
71
83
71
74
71
92
50
38e
82
84
85d
85
79d
65
41
69
80
1j Ph
a Reaction conditions: 1 (1.0 equiv), 2 (1.0 equiv), Cu(CH3CN)4ClO4
(5 mol %), Taniaphos (5 mol %), Et3N (18 mol %), toluene, 0 °C, 24 h.b In
pure product after silica gel chromatography. c Determined by HPLC
(Chiralpak AD). d Determined by HPLC from its N-methyl derivative (see
the Supporting Information). e The other isomer was isolated in 4% yield.
sensitivity of the process to steric effects at the azomethine
component.
Acknowledgment. This work was supported by the
Spanish Ministerio de Educacio´n y Ciencia (MEC, project
BQU2003-0508) and Consejer´ıa de Educacio´n de la CAM
(MAT/0016/2004). T.L. thanks the CAM for a Predoctoral
Fellowship. R.G.A. thanks the MEC for a Ramo´n y Cajal
Contract. Solvias AG is also gratefully acknowledged for a
generous gift of Taniaphos and other ferrocene chiral ligands.
Finally, to illustrate some synthetic possibilities of the
enantioenriched 3-sulfonylated pyrrolidine products, we
explored some desulfonylation reactions (Scheme 1).9 After
N-methylation of a recrystallyzed sample of 3a (ee >99%)
with MeI (NaH, DMF, rt) to give 13 (92% yield) and further
reductive desulfonylation with Na(Hg), the enantiomerically
(22) The acyclic γ,δ-unsaturated R-aminoester 15 was also isolated as a
byproduct with a 29% yield in the desulfonylation step, as a result of a
Julia-like reaction involving the cleavage of the C-N bond. For related
Julia-like reactions, see: Iradier, F.; Go´mez Arraya´s, R.; Carretero, J. C.
Org. Lett. 2001, 3, 2957 and references therein.
Supporting Information Available: Full experimental
details, copies of 1H NMR and 13C NMR of all new
compounds, and X-ray crystallography data for (-)-exo-3a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL060314C
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Org. Lett., Vol. 8, No. 9, 2006