2-Alkenoyl pyridine N-oxides, highly efficient dienophiles for the enantioselective Cu(II)-bis(oxazoline) catalyzed diels - Alder reaction

Article abstract of DOI:10.1021/ol0705752

2-Alkenoyl pyridine N-oxides are introduced as a new kind of efficient dienophiles for the Cu(II)-bis(oxazoline) (BOX) catalyzed enantioselective Diels-Alder reaction affording higher reactivity and enantioselectivity (ee's up to 96%) than the correspondi

Full text of DOI:10.1021/ol0705752

ORGANIC
LETTERS
2007
Vol. 9, No. 10
1983-1986
2-Alkenoyl Pyridine N-Oxides, Highly
Efficient Dienophiles for the
Enantioselective Cu(II)
−Bis(oxazoline)
Catalyzed Diels
−
Alder Reaction†
Santiago Barroso, Gonzalo Blay, and Jose´ R. Pedro*
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica, UniVersitat de Vale`ncia,
C/Dr. Moliner 50, E-46100 Burjassot, Vale`ncia, Spain
jose.r.pedro@uV.es
Received March 8, 2007
ABSTRACT
2-Alkenoyl pyridine N-oxides are introduced as a new kind of efficient dienophiles for the Cu(II)−bis(oxazoline) (BOX) catalyzed enantioselective
Diels−Alder reaction affording higher reactivity and enantioselectivity (ee’s up to 96%) than the corresponding nonoxidized 2-alkenoyl pyridines.
The Diels-Alder (DA) reaction is one of the most powerful
organic transformations, and it constitutes a versatile method
for the synthesis of many building blocks for the total
synthesis of bioactive natural products.1 The opportunity to
generate up to four stereogenic centers in a stereocontrolled
way has stimulated great interest in the development of
enantioselective procedures for this transformation. Remark-
able progress toward this goal has been achieved through
the use of both chiral auxiliaries2 and chiral catalysts.3
Although some examples of organocatalytic reactions have
appeared recently in the literature,4 enantioselective DA
reaction is most often effected by chiral Lewis acid catalysis.
However, although a relatively large number of Lewis acid
catalysts based on aluminum, boron, magnesium, and transi-
tion metals have been used for this purpose,3 the overall
substrate scope of the reaction remains limited. Earlier studies
with monodentate dienophiles have focused mainly on the
reaction of unsaturated aldehydes,3 especially with an R-sub-
stituent, and in less extension on the reaction of alkylacry-
lates5 and quinones.6 Furthermore, a number of effective
bidentate dienophiles have been reported. Thus, 3-alkenoyl-
1,3-oxazolidin-2-ones have proven to be very efficient
substrates with a large number of metal-based catalysts and
have become the standard test for new catalyst development.3
Examples of less studied chelating dienophiles include
N-hydroxyacrylamides,7 R′-hydroxyenones,8 unsaturated
R-ketoesters,9 2-alkylidene-1,3-dicarbonyl compounds,10 or
(4) (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 2458-2460. (b) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V.
H. Nature 2003, 424, 146. (c) Wilson, R. M.; Jen, W. S.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2005, 127, 11616-11617. (d) Kim, K. H.; Lee,
K. S.; Lee, D.-W.; Ko, D.-H.; Ha, D.-C. Tetrahedron Lett. 2005, 46, 5991-
5994. (e) Lemay, M.; Ogilvie, W. W. Org. Lett. 2005, 7, 4141-4144. (f)
Sakakura, A.; Suzuki, K.; Nakano, K.; Ishihara, K. Org. Lett. 2006, 8, 2229-
2232.
(5) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002, 124,
9992-9993.
(6) (a) Jarvo, E. R. B.; Lawrence, M.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2005, 44, 6043-6046. (b) Breuning, M.; Corey, E. J. Org. Lett.
2001, 3, 1559-1562.
† Dedicated to Prof. Ramo´n Mestres on the occasion of his retirement.
(1) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650-1667.
(2) (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988,
110, 1238-1256. (b) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem.
Soc. 1984, 106, 4261-4263. (c) Oppolzer, W.; Chapuis, C.; Bernardinelli,
G. HelV. Chim. Acta 1984, 67, 1397-1401.
(3) (a) Evans, D. A.; Johnson, J. S. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
1999; Vol. 3. (b) Cycloaddition Reactions in Organic Synthesis; Kobayashi,
S., Jørgensen, K. A., Eds.; Wiley-VCH: New York, 2002. (c) Lewis Acids
in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH: New York. 2000;
Vols. 1 and 2.
10.1021/ol0705752 CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/21/2007

acrylimides.11 The development of new templates which
ensure a proper coordination of the substrate to the catalyst
and allow an effective chirality transfer to the product
constitutes an important goal.
2-Alkenoyl pyridines are bidentate substrates which can
chelate to a metal center by virtue of the pyridine and
carbonyl group lone electron pairs. Engberts et al. have
reported DA reaction between aza-chalcones and cyclopenta-
diene in aqueous media (Scheme 1). The reaction is catalyzed
dienophiles such as 3-alkenoyl-1,3-oxazolidin-2-ones fail to
react. Finally, Reetz et al. have described copper-phthalo-
cyanine conjugates of serum albumins as catalysts for this
DA reaction, obtaining enantioselectivities up to 98% work-
ing at a 20 µmol scale which decrease upon increasing the
scale of the reaction.18 It should be noted that in the two
last examples chirality is transferred from a bioorganic
macromolecule, i.e., DNA or a protein, and not from the
ligand which is directly linked to the metal ion. Despite these
precedents, the substrate scope for the enantioselective DA
reaction with 2-alkenoyl pyridines is very limited, cyclo-
pentadiene being the only diene that has been studied so far.
Therefore, the development of an efficient and highly
enantioselective catalytic system for the DA reaction with
2-alkenoyl pyridines as dienophiles which relies on easily
available catalysts and on general applicability to a large
number of dienes is still under investigation.
Scheme 1. Diels-Alder Reaction of Azachalcone and
Cyclopentadiene
Because metal complexes with bis(oxazoline) ligands
(BOX)19 have found successful application in a large number
of enantioselective reactions with bidentate substrates, we
decided to use this kind of ligand in our research. However,
when we carried out the reaction between benzylidene-2-
acetylpyridine (1) and cyclopentadiene (2) using the com-
mercially available BOX ligand 6 in the presence of either
Cu(II) or Zn(II) triflates, we obtained the expected product
3 but with low diastereo- and enantioselectivity (Table 1,
by Lewis acid12 and also by micelles.13 Schreiner et al. have
reported catalysis by neutral hydrogen bond donors for this
reaction in either organic solvents or water.14 The enantio-
selective version of this reaction was first reported by
Engberts using Cu2+-amino acid complexes obtaining
moderate ee’s up to 74%.15 Jitsukawa et al. described the
use of functionalized bis(oxazoline) complexes as catalysts,
although these authors reported the reaction between ben-
zylidine-2-acetylpyridine (1) and cyclohexadiene as the only
example of reaction with their system.16 Recently, Roelfes
and Feringa have described DNA-based catalysis for this
reaction using copper(II) complexes of heteroaromatic
ligands in the presence of salmon testes or calf tymus DNA.17
ee’s up to 99% are obtained, although conversions are
sometimes low depending on the aromatic substituent of the
substrate. Results also depend on the heteroaromatic ligand
coordinated to the metal. Remarkably, other bidentate
Table 1. Results of the Diels-Alder Reaction of 1 and 4a
with Cyclopentadiene (2) According to Schemes 1 and 2a
temp time
ee endo ee exo
entry dienophile L
M
(°C) (h) endo/exob (%)b
(%)b
1
2
3
4
5
6
7
1
1
6
6
6
6
6
7
7
Zn
Cu
Zn
Cu
Cu -40
Cu
Cu -40
0
0
0
0
22
22
2.5
81.5:18.5
86:14
96:4
23
19
91
96
95
-96c
-92c
41
11
35
81
76
-94c
-90c
4a
4a
4a
4a
4a
0.3 97.5:2.5
3
1
3
98.5:1.5
96.5:3.5
92.5:7.5
0
a
All experiments were carried out under nitrogen, dienophile (0.25
mmol), M(OTf)2 (0.025 mmol), (S,S)-L (0.025 mmol), 2 (1.8 mmol), and
CH2Cl2 (1.5 mL); full conversion in all cases (TLC). b Determined by HPLC
using a chiralpack AD-H column. The opposite enantiomers to those of
entries 3-5 were obtained.
(7) (a) Corminboeuf, O.; Renaud, P. Org. Lett. 2002, 4, 1731-1733.
(b) Corminboeuf, O.; Renaud, P. Org. Lett. 2002, 4, 1735-1738.
(8) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M.; Gonza´lez, A.; Arceo, E. J.
Am. Chem. Soc. 2003, 125, 13942-13493.
c
(9) Zhou, J.; Tang, Y. Org. Biomol. Chem. 2004, 2, 429-433.
(10) Yamauchi, M.; Aoki, T.; Li, M.-Z.; Honda, Y. Tetrahedron:
Asymmetry 2001, 12, 3113-3118.
entries 1 and 2). Very recently, Jørgensen et al.20 have
described that N-oxypyridin-2-carbaldehydes are better sub-
strates than the corresponding pyridin-2-carbaldehydes in the
Cu(II)-BOX catalyzed Mukaiyama reaction with silylketene
acetals. In this communication, we describe for the first time
the use of 2-alkenoyl pyridine N-oxides as dienophiles for
the enantioselective DA reaction catalyzed by Cu(II)-BOX
(11) Sibi, M. P.; Ma, Z.; Itoh, K.; Prabagaran, N.; Jasperse, C. P. Org.
Lett. 2005, 7, 2349-2352.
(12) Otto, S.; Bertoncin, F.; Engberts, J. B. F. N. J. Am. Chem. Soc.
1996, 118, 7702-7707.
(13) (a) Otto, S.; Engberts, J. B. F. N.; Kwak, J. C. T. J. Am. Chem.
Soc. 1998, 120, 9517-9525. (b) Rispens, T.; Engberts, J. B. F. N. Org.
Lett. 2001, 3, 941-943. (c) Rispens, T.; Engberts, J. B. F. N. J. Org. Chem.
2002, 67, 7369-7377.
(14) Wittkopp, A.; Schreiner, P. R. Chem.-Eur. J. 2003, 9, 407-414.
(15) (a) Otto, S.; Engberts, J. B. F. N. J. Am. Chem. Soc. 1998, 120,
4238-4239. (b) Otto, S.; Engberts, J. B. F. N. J. Am. Chem. Soc. 1999,
121, 6798-6806.
(16) Matsumoto, K.; Jitsukawa, K.; Masuda, H. Tetrahedron Lett. 2005,
46, 5687-5690.
(17) (a) Roelfes, G.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44,
3230-3232. (b) Roelfes, G.; Boersma, A. J.; Feringa, B. L. Chem. Commun.
2006, 635-637.
(18) Reetz, M. T.; Jiao, N. Angew. Chem., Int. Ed. 2006, 45, 2416-
2419.
(19) For a review on BOX-catalyzed reactions, see: Desimoni, G.; Faita,
G.; Jørgensen, K. A. Chem. ReV. 2006, 106, 3561-3651.
(20) (a) Landa, A.; Minnkila¨, A.; Blay, G.; Jørgensen, K. A. Chem.-
Eur. J. 2006, 12, 3472-3483. (b) Landa, A.; Richter, B.; Johansen, R. L.;
Minkkila¨, A.; Jørgensen, K. A. J. Org. Chem. 2007, 72, 240-245.
1984
Org. Lett., Vol. 9, No. 10, 2007

complexes, affording better results than the corresponding
2-alkenoyl pyridines.
Table 2. Results of the Diels-Alder Reaction between
2-Alkenoyl Pyridine N-Oxides 4a-d and Different Dienes
Catalyzed by Cu(II)-6a
2-Alkenoyl pyridine N-oxides 4a-d were prepared by
aldol reaction from 2-acetylpyridine N-oxide and aldehydes.
When we subjected compound 4a to the DA reaction with
cyclopentadiene (2) in conditions identical to those for the
corresponding aza-chalcone 1, we found the reaction pro-
ceeding much faster and with higher diastereo- and enantio-
selectivity (Scheme 2). The major diastereomer product was
Scheme 2. Diels-Alder Reaction between Alkenoyl Pyridine
N-Oxides and Cyclopentadiene
a
b
Reaction conditions as in Table 1, entry 4, unless noted otherwise.
Isolated product after column chromatography. c Determined by HPLC using
chiral stationary phase columns. d ee for the major isomer.e Endo/exo ratio.
f
Reaction carried out with 1a (0.7 mmol), 6 (0.007 mmol), and Cu(OTf)2
(0.007 mmol). 1,4-10/1,3-10 ratio.
g
determined to be endo-5a by NOE experiments and by its
conversion into the known compound endo-3 (see Scheme
3 below). Copper(II) triflate gave slightly better results than
Scheme 3
complex gave rise to a slight decrease in both diastereo- and
enantioselectivity.
zinc(II) triflate (Table 1, entries 3 and 4), affording product
5a with a 97.5:2.5 endo/exo ratio and 96% ee for the major
endo diastereomer.
A preliminary study of the substrate scope of the reaction
has been carried out using the Cu(II)-6 complex as catalyst
at 0 °C. The R group on the dienophile was amenable to
variation. Substrates 4b and 4c bearing an aromatic ring were
rapidly converted to the corresponding DA products with
high yield, diastereo-, and enantioselectivity, regardless of
the nature of the substituent on the phenyl ring (Table 2,
entries 1-4). The dienophile also tolerates an alkyl group
Both the Cu(II)-6 and Zn(II)-6 complexes yielded the
same major enantiomer for endo-5a. Lowering the temper-
ature to -40 °C did not change the result significantly. When
tert-butyl bis(oxazoline) 7 was used instead of ligand 6, the
reaction also took place with high diastereo- and enantiomeric
excess (entry 6), but the reaction yielded the opposite
enantiomers as is the case with other reactions catalyzed by
6 or 7.21 Lowering the temperature with the Cu(II)-7
(21) (a) Evans, D. A.; Johnson, J. S. J. Am. Chem. Soc. 1998, 120, 4895-
4896. (b) Johansen, M.; Jørgensen, K. A. J. Org. Chem. 1995, 60, 5757-
5762.
Org. Lett., Vol. 9, No. 10, 2007
1985

attached to the double bond (entry 5). Thus, the reaction with
the tert-butyl-substituted 4d afforded the major endo-adduct
in 93% ee together with the exo-adduct in 70% ee, in a short
reaction time. Experiments also showed that the amount of
catalyst can be reduced to as low as 1 mol % and the reaction
scaled up at least three times without a noticeable effect on
the yield and stereoselectivity (Table 2, entry 2).
endo-adduct obtained by reaction of compound 1 with
cyclopentadiene (2), therefore confirming the structural
assignment for the major diastereomer obtained from the
reaction with 4a in Scheme 2. Furthermore, a comparison
of the retention times in HPLC shows that compound endo-3
obtained according to Scheme 3 is the enantiomer of the
product obtained by Engberts from 1 and 2 upon catalysis
with Cu(II)-N-methyl-L-tyrosine.15b On the other hand, the
characteristic chemistry of pyridine N-oxides can be used to
perform transformations on the heterocyclic ring. As an
example, we have carried out the regioselective cyanation
of endo-5a by a modified Reissert-Henze reaction23 to give
endo-13 in 83% yield (Scheme 3).
In summary, we have presented here a new type of
dienophile for the Cu(II)-BOX catalyzed enantioselective
Diels-Alder reaction. 2-Alkenoyl pyridine N-oxides not only
showed increased reactivity but also had higher levels
of enantioselectivity than the corresponding nonoxidized
2-alkenoyl pyridines. Unlike other related catalytic systems,
high conversions and ee’s are obtained regardless of the
nature of the substituent on the double bond of the dienophile,
allowing either aryl or alkyl groups. The high efficiency of
the reaction is also maintained with dienes other than
cyclopentadiene. We have shown that the DA adducts can
be deoxygenated to the corresponding pyridine adducts
without loss of optical purity, but it could also be possible
to take advantage of the characteristic pyridine N-oxide
chemistry to carry out transformations on the heteroaromatic
ring which could be otherwise difficult to perform. Research
on this regard as well as on expanding the scope of the DA
reaction with these substrates is under development.
Dienes other than cyclopentadiene were also studied using
compound 4a as the dienophile.22 As expected, the less
reactive cyclohexadiene required longer reaction time,
although the reaction was complete in 30 h affording the
corresponding adduct 8 with fair diastereoselectivity and high
enantioselectivity for the endo-adduct (Table 2, entry 6). It
should be mentioned that the nonoxidized benzylidene-2-
acetylpyridine (1) does not react with cyclohexadiene in the
presence of the Cu(II)-6 complex even at room tempera-
ture.16 2,3-Dimethyl butadiene also required 21 h of reaction
to afford the expected product 9 with excellent yield and
enantioselectivity (Table 2, entry 7). Of major significance
were the results with more problematic dienes. With isoprene,
the DA reaction gave a 96:4 mixture of two regioisomeric
products 10 having the methyl and carbonylpyridyl groups
in 1,4- and 1,3-relative positions on the cyclohexene ring,
respectively. The major 1,4-regioisomer was obtained in 92%
ee (Table 2, entry 8). Similar levels of selectivity were
obtained with other difficult dienes such as piperylene (entry
9) and 1-phenylbutadiene (entry 10). In these cases, the
reaction yielded primarily the corresponding endo-adducts
having a cis disposition between the carbonylpyridyl group
and the substituent (methyl or phenyl) proceeding from the
diene. No regioisomeric products were observed in the
reaction mixtures. In both cases, the major diastereomers
endo-11 and endo-12 were obtained in 94% ee.
Acknowledgment. Financial support from the Ministerio
de Educacio´n y Ciencia (CTQ 2006-14199), Generalitat
Valenciana (GV 05/10), and the Universitat de Vale`ncia
(UV-AE-20060244) is acknowledged. S.B. thanks the U.V.
for a pre-doctoral grant (V Segles program).
An important aspect related with the chemistry reported
here is that the optically active pyridine N-oxide adducts can
be deoxygenated to the corresponding pyridine adducts by
treatment with In/NH4Cl without noticeable loss of enan-
tiomeric purity. Thus, a 91% enantiomerically pure endo-
5a (Table 1, entry 3) was converted into compound endo-3,
having identical optical purity, with 75% yield (Scheme 3).
Compound endo-3 obtained in this way showed spectral
features identical to those described by Engberts12 for the
Supporting Information Available: General experimen-
1
tal procedures, characterization data, and H NMR and 13C
NMR spectra for compounds 4a-d and for the major Diels-
Alder products 3, 5, and 8-13. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0705752
(22) No DA reaction took place between the poorly reactive diene furan
and compound 4a. Instead, a sluggish Michael addition of furan to enone
4a was observed at room temperature.
(23) Fife, K. F. J. Org. Chem. 1983, 48, 1375-1377.
1986
Org. Lett., Vol. 9, No. 10, 2007