Chiral Copper Complexes of Phosphino Sulfenyl Ferrocenes as Efficient Catalysts for Enantioselective Formal Aza Diels-Alder Reactions of N-Sulfonyl Imines

Article abstract of DOI:10.1021/ja038494y

In the presence of a catalytic amount of silver perchlorate, copper(I) bromide complexes of planar chiral 1-phosphino-2-sulfenylferrocenes behave as very efficient chiral Lewis acids catalysts in the formal Aza Diels-Alder reaction of N-arylsulfonyl aldim

Full text of DOI:10.1021/ja038494y

Published on Web 12/20/2003
Chiral Copper Complexes of Phosphino Sulfenyl Ferrocenes as Efficient
Catalysts for Enantioselective Formal Aza Diels-Alder Reactions of
N-Sulfonyl Imines
Olga Garc´ıa Manchen˜o, 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
Received September 12, 2003; E-mail: juancarlos.carretero@uam.es
Scheme 1. Copper-Catalyzed Reaction of Danishefsky’s Diene
with N-Sulfonyl Imine 3a in the Presence of Ligand (R)-1a
Six-membered nitrogen heterocycles are key units in medicinal
chemistry and very interesting intermediates in organic synthesis.1
The catalytic enantioselective Aza Diels-Alder reaction (ADAR)
of electron-rich dienes with aldimines is conceptually an extremely
powerful strategy for the construction of this type of structures with
high enantiopurity.2 However, to the best of our knowledge, only
three catalyst systems have been described to date for this
asymmetric process:3 the zirconium-binaphthol complexes devel-
oped by Kobayashi et al.,4 the silver catalysts of phosphine peptide
Schiff bases reported by Snapper and Hoveyda,5 and the copper
complexes of BINAP and phosphino-oxazolines described by
Jørgensen et al.6 Despite the fact that N-sulfonyl imines are very
appealing heterodienophiles because of their low LUMO energy
and the expected high crystallinity of their adducts,7 the use of such
imino dienophiles in catalytic asymmetric ADAR has been es-
sentially restricted to the bidentate and highly reactive N-tosyl imine
of ethyl glyoxylate.6
Scheme 2. Preparation of Chiral Cu(I) Complexes of Ligands
(R)-1
As part of an ongoing program showing the wide potential in
enantioselective catalysis of the readily available planar chiral
phosphino sulfenyl ferrocenes 1,8 we describe herein that the
copper(I) complexes of these ligands act as highly efficient chiral
Lewis acids in enantioselective formal ADAR of N-sulfonyl
aldimines with the Danishefsky’s diene (2a) and derivatives.
We selected as model reaction the ADAR of diene 2a with the
N-tosylimine of benzaldehyde (3a), process for which the highest
reported enantioselectivity was a moderate 48% ee.6b As the first
experiment, we performed this reaction in the presence of 10 mol
% of the enantiopure ligand (R)-1a8 and Cu(MeCN)4ClO4 in CH2Cl2
at room temperature. Complete evolution was observed after 5 h,
affording mainly the acyclic Mannich-type addition product2 4a
rather than the expected Diels-Alder adduct. Nevertheless, the
formal Diels-Alder product, the dihydropyridone 5a, was readily
obtained upon addition of TFA to the reaction mixture (83% yield,
74% ee). As shown in Scheme 1, similar results were achieved
using other copper(I) salts such as Cu(MeCN)4PF6 (72% yield, 77%
ee) and CuOTf (80% yield, 76% ee). The absolute R configuration
of 5a was unambiguously established by X-ray analysis.9
To prove the P,S-bidentate character of ligands 1 in this Cu-
catalyzed reaction, we turned our attention toward the isolation of
their Cu(I) complexes. Simple combination of equimolar amounts
of ligands 18 and CuX (X ) Cl, Br) in THF/MeOH afforded in
nearly quantitative yields the air-stable Cu(I) dimeric complexes 6
and 7 as single epimers at sulfur. The tetrahedral P,S,X,X-
coordination at copper and the absolute R configuration at sulfur
were unambiguously established by X-ray analysis of 6a9 (Scheme
2).
a CuX (X ) Cl, Br), THF/MeOH, rt, 10 min.
Table 1. Optimization of the Cu(I) Catalyst
entry
Cu complex
time (h)
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6
20
20
20
20
3
79
70
58
60
66
96
89
90
80
71
71
55
57
80
7a
7f
2
80
1
93(97)c
a Isolated yield after column chromatography. b Determined by HPLC
(Chiralpak AD column). c T ) -20 °C (1 h, 87% yield).
10
model reaction 2 + 3a in the presence of 10 mol % of AgClO4
as halogen scavenger (Table 1). Under these silver-assisted condi-
tions for in situ generation of the presumed active cationic Cu
catalyst, the complex 6a furnished the ADAR product in similar
yield (79%), but with somewhat higher enantioselectivity (80% ee,
entry 1) compared with the results obtained in the absence of a
silver salt (Scheme 1, 74-77% ee). As expected, the reaction proved
With this set of copper complexes in hand, possessing varied
electronic and steric environments around the phosphorus atom,
we studied their efficiency as chiral catalysts (5.1 mol %) for the
9
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10.1021/ja038494y CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
of the N-sulfonyl dihydropyridones 5.12 Finally, from a practical
point of view, it is important to note that products 5 are quite stable
and easy-to-handle crystalline solids, giving rise to enantiopure
samples (>99.5% ee) upon a single recrystallization.13
In summary, novel copper(I) Lewis acid catalysts, relying on
planar chiral 1-phophino-2-sulfenylferrocenes, show excellent activ-
ity, enantioselectivity, and structural scope in asymmetric ADAR
between N-sulfonylaldimines and Danishefsky’s type dienes. The
mechanistic origin of the high enantiocontrol and the extension of
this study to other heterodienophiles and dienes are under current
investigation.
Acknowledgment. Support has been provided by MCYT
(BQU2000-0226). O.G.M. gratefully acknowledges a M.E.C.
Predoctoral Fellowship. R.G.A. thanks the MCYT for a “Contrato
Ramo´n y Cajal”.
Supporting Information Available: Experimental procedures and
characterization data of new compounds, copies of NMR spectra, and
X-ray crystallography data of (+)-5a and (+)-6a (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
Table 2. Scope of the ADAR Catalyzed by Complex 7f
1
2
3
ent
R
R
R
prod yield(%)a
ee(%)b
1
2
3
4
5
6
7
8
9
H
Ph
p-Tol
p-Tol
p-Tol
p-Tol
5a
5b
5c
5d
5e
5f
90
82
78
76
39
85
66
65c
64
57
61
78
56
58
58
93(97)c
93
H
H
H
H
H
H
H
o-Tol
(p-F)C6H4
(p-OMe)C6H4
(p-NMe2)C6H4 p-Tol
2-Naph
PhCHdCH
n-Pr
88(93)c
91
93
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
86(93)c
83(96)c
73c(82)d
87(92)e
88c
5g
5h
5i
Me Ph
10 Me PhCHdCH
5j
11
12
13
14
15
H
H
H
H
H
Ph
(p-OMe)C6H4 5k
(p-OMe)C6H4 5m
(p-OMe)C6H4 5n
(p-OMe)C6H4 5o
94
(p-F)C6H4
2-Naph
PhCHdCH
Ph
90
82
76
(p-NO2)C6H4
5p
90
References
a Isolated yield. b Determined by HPLC. Absolute configuration assigned
by analogy with that of 5a.9 c T ) -20 °C. d T ) -78 °C. e T ) 0 °C.
(1) For reviews: (a) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine: Structure,
Preparation and Synthetic Applications of Piperidine and its DeriVatiVes;
Elsevier: Amsterdam, 1991. (b) Bailey, P. D.; Millwood, P. A.; Smith,
P. D. Chem. Commun. 1998, 633. (c) O’Hagan, D. Nat. Prod. Rep. 2000,
17, 435. (d) Michael, J. P. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: San Diego, 2001; Vol. 55. For the potential of enantiopure
dihydropyridones in alkaloid synthesis, see: (e) Comins, D. L.; Huang,
S.; McArdle, C. L.; Ingalls, C. L. Org. Lett. 2001, 3, 469.
(2) For a review on catalytic enantioselective additions to imines, see:
Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
to be deeply influenced by the substitution at phosphorus. Com-
plexes 6b-e afforded the dihydropyridone 5a in lower yields and
enantioselectivities (entries 2-5) than the model complex 6a. On
the contrary, the bulky R-naphthylphosphino derivative 6f proved
to be more reactive than 6a (3 h instead of 6 h), affording 5a in
excellent yield (96%, entry 6) with the same enantioselectivity (80%
ee).
Interestingly, the dimeric (bromo)Cu complexes 7 showed a
remarkable higher reactivity (entries 7 and 8). To our delight,
complex 7f, having the highly sterically demanding R-naph-
thylphosphine moiety, exhibited excellent values of reactivity,
chemical yield (87-90%) and asymmetric induction (93% ee at
room temperature and 97% ee at -20 °C, entry 8).
(3) This transformation was first achieved by Yamamoto using a stoichiometric
amount of a chiral boron complex: Hattori, K.; Yamamoto, H. J. Org.
Chem. 1992, 57, 3264.
(4) (a) Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem., Int. Ed.
1998, 37, 979. (b) Kobayashi, S.; Kusakabe, K.-i.; Komiyama, S.; Ishitani,
H. J. Org. Chem. 1999, 64, 4220. (c) Kobayashi, S.; Kusakabe, K.-i.;
Ishitani, H. Org. Lett. 2000, 2, 1225.
(5) Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2003, 125, 4018.
(6) (a) Yao, S.; Johannsen, M.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 1998, 37, 3121. (b) Yao, S.; Saaby, S.; Hazell, R. G.; Jørgensen,
K. A. Chem. Eur. J. 2000, 6, 2435.
Next, with optimized catalyst 7f in hand, a variety of other
N-sulfonyl imines were prepared and tested under our standard
reaction conditions. Table 2 delineates the wide scope of this
catalytic ADAR. A survey of representative imino dienophiles
revealed a high degree of stereochemical fidelity with a number of
electronically varied aromatic imines (entries 1-6, 86-93% ee at
room temperature; 93-97% ee at -20 °C). The high reactivity and
enantioselectivity displayed by the tosyl imine of cinnamaldehyde
(83% ee, entry 7) are noteworthy. Lowering the reaction temperature
to -20 °C enhanced the enantioselectivity to 96% ee, the reaction
being complete within 1 h (82% yield). As far as we know, this is
the first example of a catalytic enantioselective ADAR of R,â-
unsaturated imino dienophiles.11 This procedure was also success-
fully applied to the highly reactive aldimines of enolizable aliphatic
aldehydes, a kind of heterodienophiles scarcely studied in enantio-
selective ADAR.4c Thus, the tosylimine of butyraldehyde (3h)
reacted with Danishefsky’s diene in 30 min at -20 °C, in the
presence of the catalyst system 7f/AgClO4, to provide the dihy-
dropyridone 5h in 73% ee (entry 8). The aliphatic tosylimine 3h is
so reactive that the reaction can be carried out even at -78 °C,
raising the enantioselectivity to 82% ee
(7) For recent examples on sulfonyl imino dienophiles in ADAR, see for
instance: (a) Bauer, T.; Szyman´ski, S.; Jez´ewski, A.; Gluzin´ski, P.;
Jurczak, J. Tetrahedron: Asymmetry 1997, 8, 2619. (b) Morgan, P. E.;
McCague, R.; Whiting, A. J. Chem. Soc., Perkin Trans. 1 2000, 515.
(8) Manchen˜o, O. G.; Priego, J.; Cabrera, S.; Arraya´s, R. G.; Llamas, T.;
Carretero, J. C. J. Org. Chem. 2003, 68, 3679.
(9) See Supporting Information for detailed X-ray data.
(10) This formal ADAR also takes place using the catalytic pair ligand 1 +
AgClO4, instead of the halo copper complexes 6 - 7 + AgClO4. However,
this Ag-catalyzed process is slower and less enantioselective than the Cu-
mediated reaction. For instance, in the presence of 10 mol % of AgClO4
and 10.2 mol % of ligand (R)-1a or (R)-1f the model reaction 2a + 3a
requires 24 h for completion (CH2Cl2, rt), giving rise to the dihydropyridine
5a in 55% ee from (R)-1a and 73% ee from (R)-1f (67-68% chemical
yield).
(11) For recent examples of R,â-unsaturated imino dienophiles in ADAR,
see: (a) Loncaric, C.; Manabe, K.; Kobayashi, S. AdV. Synth. Catal. 2003,
345, 475. (b) Loncaric, C.; Manabe, K.; Kobayashi, S. Chem. Commun.
2003, 574.
(12) For instance, the tosylamides 5a and 5g, having an aryl and an alkenyl
group at C-2 respectively, afforded the chiral 4-oxopiperidines 8a and 8g
in satisfactory yields (58-64%, unoptimized) upon treatment with Zn/
AcOH at room temperature.
For the deprotection of sulfonamides, see: (a) Greene, T. W.; Wuts, P.
G. M. ProtectiVe Groups in Organic Synthesis, 3rd ed; John Wiley &
Sons: New York, 1999; p 603-615. For the selective deprotection of
p-nitrophenyl sulfonamides, see: (b) Fukuyama, T.; Jow, C.-K.; Cheung,
M. Tetrahedron Lett. 1995, 36, 6373.
Interestingly, the presence of an additional substituent at the diene
(diene 2b, entries 9 and 10) or a change in the nature of the
arylsulfonyl group of the heterodienophile (entries 11-15) provided
similar results in terms of both chemical yield and enantioselectivity.
The first issue is important for the synthesis of more substituted
dihydropyridones (compounds 5i and 5j), whereas the second aspect
offers varied possibilities for the deprotection of the amino group
(13) For instance, from samples of dihydropyridones 5a and 5h of 92 and 78%
ee, respectively,
a single recrystallization from n-hexanes-CH2Cl2
provided enantiomerically pure compounds (>99.5% ee, 60-70% yield).
JA038494Y
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