A first case of asymmetric catalysis induced by metal-free bisoxazolines

Article abstract of DOI:10.1002/ejoc.200800179

Metal-free bisoxazolines catalyze the Diels-Alder reaction of N-substituted maleimides with anthrone derivatives leading to products in excellent yields and enantioselectivities up to 70%. A mechanism relying on Bronsted-base catalysis is assumed to be involved with formation of an ion pair between the protonated catalyst and the anthrone enolate, which acts as a diene. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800179

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800179
A First Case of Asymmetric Catalysis Induced by Metal-Free Bisoxazolines
Deniz Akalay,[a] Gerd Dürner,[a] and Michael W. Göbel*[a]
Keywords: Asymmetric catalysis / Bisoxazolines / Cycloaddition / Enantioselectivity / Organocatalysis
Metal-free bisoxazolines catalyze the Diels–Alder reaction of
N-substituted maleimides with anthrone derivatives leading
to products in excellent yields and enantioselectivities up to
70%. A mechanism relying on Brønsted-base catalysis is as-
sumed to be involved with formation of an ion pair between
the protonated catalyst and the anthrone enolate, which acts
as a diene.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
of metal ions ranging from alkali- to transition metals may
then be used to prepare catalytically active chiral com-
plexes. However, to the best of our knowledge, no case of
asymmetric catalysis has been described with bisoxazoline
ligands acting entirely without coordinated metal-ions.[7]
In spite of the low basicity of bisoxazolines – when com-
pared to bisamidine 1 – the obvious structural analogy of
both classes encouraged us to try and catalyze the cycload-
dition of anthrones to maleimides with bisoxazolines 8a–8d
(Scheme 2).
Introduction
Bisamidine 1, a new type of chiral base that we have
introduced recently, adopts the form of a conjugated en-
amine-imine tautomer after protonation, resulting in an al-
most planar structure.[1] Compound 1 thus can play a two-
fold role in organocatalytic transformations, as a Brønsted-
base or, after protonation, as a mild metal-free electrophile
(Scheme 1). Base-induced stereoselective transformations
mediated by 1 are currently under investigation. The cyclo-
additions of anthrone 2a and N-alkyl- or N-arylmaleimides
3 are well known examples for base-catalyzed Diels–Alder
reactions and have been studied extensively.[2] Chiral bases
such as cinchona alkaloids 5,[3] pyrrolidines 6,[4] and cyclic
guanidine 7[5] have been shown to promote these reactions
to give products 4 with moderate to excellent enantio-
selectivities. Bisamidine 1, due to its high basicity, is a good
catalyst in terms of reaction rates. However, we still have to
optimize stereoselectivities.
Scheme 1. Protonation states of chiral bisamidine 1.[1]
Since their introduction in 1991, C2-symmetrical bisoxa-
zolines 8 have become one of the most important ligand
systems for stereoselective transformations.[6] Starting from
amino acids, a large number of compounds with various
spacers and side chains can be easily generated. All kinds
Scheme 2. Base-catalyzed Diels–Alder reaction of anthrone 2a and
N-phenylmaleimide 3a.
[a] Institute of Organic Chemistry and Chemical Biology, Johann
Wolfgang Goethe University of Frankfurt,
Results and Discussion
Max-von-Laue-Str. 7, 60438 Frankfurt am Main, Germany
Fax: +49-69-798-29464
Initial experiments started with the Diels–Alder reaction
of anthrone 2a and N-phenylmaleimide 3a in CH2Cl2 cata-
lyzed by the bisoxazolines 8a–8d. Due to the low Brønsted-
E-mail: M.Goebel@chemie.uni-frankfurt.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 2365–2368
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2365

D. Akalay, G. Dürner, M. W. Göbel
SHORT COMMUNICATION
basicity of the bisoxazolines, high catalyst loadings of Table 2. Scope of the bisoxazoline-catalyzed Diels–Alder reaction.
25 mol-% were required to obtain satisfactory yields. The
highest asymmetric induction was observed with the steri-
cally most demanding compound 8d (Table 1, entry 4). The
(S,S)-configuration could be assigned to the major product
enantiomer 4a by comparison of the optical rotation with
literature data.[8] We tested bisoxazoline 8d in different sol-
vents and found the best results in CH2Cl2. In acetonitrile,
Entry[a] 2 [R1, R2] R3
Product Yield ee [%][c]
the cycloaddition yielded entirely racemic material (see Sup-
porting Information). Upon variation of the reaction tem-
perature between –25 and 50 °C, nearly constant enantio-
selectivities were observed. The best value of 47% ee was
found at 23 °C (catalyst 8d, CH2Cl2; for details see Support-
ing Information).
[%][b]
1
2
2a [H, H] Ph (3a)
2b [H, Cl] 3a
4a
4b
4c
4d
4e
4f
85
68
99
92
99
94
99
87
94
76
67
76
47
39
43
41
40
70
40
53
67
42
41
46
3
4
5
2a
2a
2a
iPr (3b)
tBu (3c)
Cy (3d)
6
2c [Cl, H] 3d
7
8
9
10
11
12
2a
2a
2c
2a
2a
2a
Bn (3e)
CHPh2 (3f)
3f
3-F-(C6H4)- (3g)
4-Br-(C6H4)- (3h)
4-MeO-(C6H4)- (3i)
4g
4h
4i
Table 1. Comparison of bisoxazolines as catalysts for the cycload-
dition leading to 4a.
Entry[a]
Catalyst
Yield [%][b]
ee [%][c]
4j
4k
4l
1
2
3
4
ent-8a
8b
60
71
73
85
–3[d]
22
7
8c
[a] All reactions were carried out using maleimide 3 (0.1 mmol),
anthrone 2 (1.1 equiv.) and 8d (0.25 equiv.) in 1 mL of absol.
CH2Cl2 at room temperature for 24 h. [b] Isolated yield after col-
umn chromatography. [c] Enantiomeric excess was determined by
HPLC using Chiralpak IA column.
8d
47
[a] All reactions were carried out using maleimide 3a (0.1 mmol),
anthrone 2a (1.1 equiv.) and catalyst (0.25 equiv.) in 1 mL of absol.
CH2Cl2 at room temperature for 24 h. [b] Isolated yield after col-
umn chromatography. [c] Enantiomeric excess was determined by
HPLC using Chiralpak IA column. [d] A negative ee stands for an
excess of ent-4a.
intermediate in the bisoxazoline-catalyzed reactions. In the
neutral state, bisoxazolines favour the flexible non-conju-
gated form characterized by four hydrogen-bond acceptor
sites. Enol 2d may bind weakly to the catalyst as shown
in Scheme 3 (left). While this orientation might explain the
transfer of chirality, many others also exist. Sampling over
all binding modes can hardly explain selectivities up to 70%
ee.
Using the optimized conditions, we explored the scope
of the bisoxazoline-catalyzed Diels–Alder reaction of vari-
ous N-substituted maleimides and different anthrone deriv-
atives. Dienes 2b and 2c were prepared by regioselective re-
ductions of 1,8-dichloroanthraquinone.[9] Maleimides 3 are
either accessible by Mitsunobu reaction[10] or by addition
of the corresponding amine to maleic anhydride followed
by an intramolecular ring closure.[11] Both electron-donat-
ing and electron-withdrawing substituents were tolerated in
R3 and furnished the products in good to excellent yields
and moderate enantioselectivities. Consistent with a Diels–
Alder reaction of normal electron demand, the use of the
electron-poor anthrone 2b dropped the yield (Table 2, entry
2). A dramatic increase in enantioselectivity was observed
with diene 2c. The presence of the 1,8-chloro substituents
next to the carbonyl function, raised the ee value from 40
to 70% (entries 5 and 6). The combination of 2c and dien-
ophile 3f, which yielded the highest selectivity in the reac-
tion with unsubstituted anthrone 2a (entry 8) failed to im-
prove further the level of asymmetric induction (entry 9).
In terms of mechanism, the product 4 may either result
from a concerted cycloaddition or a stepwise process via
Michael adduct 9 followed by an aldol addition. Michael
Figure 1. Structures of enol 2d, enolate 2e, and of Michael adducts
9 and 10.
In contrast, the bisoxazolines seem to adopt a planar
adducts of type 10 were shown previously to be secondary conjugated form in the monoprotonated state exhibiting
products resulting from a retro aldol reaction of 4 (Figure 1). two hydrogen-bond donor and two acceptor sites: upon ad-
They are formed preferentially in protic solvents and were dition of one equivalent of trifluoroacetic acid to com-
not observed in our study. According to Koerner and Rick- pound 8d, a strong absorption band around 280 nm occurs
born, all evidence points towards a Diels–Alder mechanism (see Supporting Information) demonstrating the enamine-
with enolate 2e acting as a diene.[2a,2b] Stereochemical argu- imine conjugation, which has been observed previously in
ments strengthen the view that enol 2d is not the relevant bisoxazoline–metal complexes[12] and structurally related
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Eur. J. Org. Chem. 2008, 2365–2368

Asymmetric Catalysis Induced by Metal-Free Bisoxazolines
of intermediate A (Scheme 4) in the reaction mixture thus
must be very low, consistent with long reaction times and
the need for rather large amounts of catalyst.
Conclusions
In summary, we have developed the first asymmetric ca-
talysis by a bisoxazoline in the absence of any metal ions.
With bulky groups in the catalyst and proper substituents in
the substrates, good enantioselectivities and excellent yields
could be achieved. Since reaction rates correlate with the
Brønsted basicity of the catalysts, future experiments will
include stronger bases like bisamidines, which will allow a
reduction in the amount of catalyst.
Scheme 3. Some coordination modes of enol 2d and neutral bisoxa-
zolines.
semicorrins.[13] Photoelectron spectra of neutral bisoxa-
zolines also indicate the presence of conjugated tautomers
in the gas phase.[14] This parallels the behaviour of monoca-
tionic bisamidine 1 as shown in Scheme 1. The enamine-
imine tautomers of protonated catalysts would be excellent
hosts to accommodate the oxyanion of enolate 2e in a con-
tact ion pair stabilized by two hydrogen bonds. The close
proximity of the chiral centers to the diene in such com-
plexes could well explain the observed stereoselectivity.
When enamine-imine conjugation is prevented by alkyl
groups as in bisoxazoline 8c, the catalyst function is severely
impaired (Table 1, entry 3). These data suggest the mecha-
nism depicted in Scheme 4. Acting as a Brønsted base, the
bisoxazoline deprotonates the anthrone in the first step. The
resulting contact ion pair A then allows the transfer of chi-
rality from the catalyst to the product in the subsequent
Diels–Alder reaction. The anion of product 4, a much
stronger base compared to the enolate of anthrone 2, depro-
tonates 8d·H+ upon dissociation of complex B thus closing
the catalytic cycle. Polar solvents such as acetonitrile are
expected to separate ion pair A thereby destroying the
stereoselectivity of the process (see Supporting Infor-
mation). UV/Vis spectrometry permits to quantify the ex-
tent of deprotonation of anthrone 2a. In CH2Cl2, strong
Brønsted bases such as DBU induce an intense orange
color by complete conversion of 2a into its enolate 2e (see
Supporting Information). Triethylamine as a weaker base
gives visible color effects only at concentrations above
0.1 , sufficient to induce complete Diels–Alder reactions
of 2a with maleimides within 15 min.[2a] No color develop-
ment at all is observed with bisoxazolines. Concentrations
Experimental Section
General: NMR: Bruker DPX 250 (1H: 250 MHz; 13C: 63 MHz) or
Bruker AM 300 (1H: 300 MHz; 13C: 75 MHz; 19F: 282 MHz).
FTIR: Perkin–Elmer 1600 Series. Elemental analysis: Heraeus
CHN Rapid. Melting points (uncorrected): Kofler hot-plate micro-
scope. Optical rotation: Perkin–Elmer polarimeter 241. UV spectra:
Varian Cary 1E spectrophotometer.
Typical Procedure for Bisoxazoline-Catalyzed Diels–Alder Reactions
of Anthrone Derivatives 2 with N-Substituted Maleimides 3: N-phen-
ylmaleimide 3a (17.4 mg, 0.1 mmol), anthrone 2a (21.4 mg,
0.11 mmol) and bisoxazoline 8d (6.7 mg, 0.025 mmol) were dis-
solved in 1 mL of absol. CH2Cl2 and stirred for 24 h at room tem-
perature. The reaction mixture was purified by flash column
chromatography (n-hexane/EtOAc, 4:1) to afford 4a as a colorless
crystalline solid.
4a: Yield 31.1 mg, 85%; m.p. 199–201 °C (lit. 208–209 °C).[4a]
[α]2D0 = +24.6 (c = 1.15, CHCl3). 1H NMR (250 MHz, CDCl3): δ =
3.28 (d, J = 8.5 Hz, 1 H, CH-COH), 3.49 (dd, J1 = 3.6, J2 = 8.6 Hz,
1 H, CH-CH-CH), 4.54 (s, 1 H, OH), 4.84 (d, J = 3.5 Hz, 1 H,
CH-CH-CH-COH), 6.45–6.52 (m, 2 H, aryl-H), 7.20–7.36 (m, 8 H,
aryl-H), 7.40–7.43 (m, 1 H, aryl-H), 7.55–7.58 (m, 1 H, aryl-H),
7.72–7.75 (m, 1 H, aryl-H) ppm. 13C NMR (63 MHz, CDCl3): δ =
44.79, 47.66, 50.78, 77.30, 120.88, 121.09, 123.76, 124.69, 126.26,
126.84, 126.92, 127.24, 127.35, 128.97, 129.11, 130.86, 136.62,
138.83, 140.92, 142.26, 175.59, 177.11 ppm. IR (KBr): ν = 3416
˜
(m), 3070 (w), 2961 (w), 1773 (w), 1699 (s), 1596 (w), 1494 (m),
1458 (m), 1381 (s), 1296 (w), 1266 (w), 1245 (w), 1175 (s), 1136 (w),
1073 (w), 1056 (w), 1028 (w), 990 (w), 962 (w), 946 (w), 922 (w),
846 (w), 786 (w), 770 (s), 756 (m), 724 (w), 690 (w) cm–1.
C24H17NO3 (367.40): calcd. C 78.46, H 4.66, N 3.81; found C
78.40, H 4.73, N 3.61. HPLC conditions: CHIRALPAK IA col-
umn (250ϫ4.6 mm), n-hexane/propan-2-ol/CH2Cl2 (64:19:17),
flow-rate 0.7 mLmin–1, tmajor = 10.5 min, tminor = 12.0 min, 47%
ee.
The racemic compound was prepared with triethylamine (10 µL)
instead of bisoxazoline. After 30 min the crude product was also
purified by flash column chromatography.
Supporting Information (see also the footnote on the first page of
this article): Characterisation data for Diels–Alder adducts 4; re-
sults for optimal reaction conditions. UV spectra of 2a and 8d and
copies of chromatograms obtained with chiral columns.
Scheme 4. Proposed catalytic cycle.
Eur. J. Org. Chem. 2008, 2365–2368
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2367

D. Akalay, G. Dürner, M. W. Göbel
SHORT COMMUNICATION
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Acknowledgments
Financial support provided by the Deutsche Forschungsgemein-
schaft (DFG) (Priority Program “Organocatalysis” SPP1179) and
by the FAZIT-Stiftung is gratefully acknowledged. We would like
to thank Mr. Sebastian Popp, Mr. Claas Hoffend, and Mrs.
Felicitas von Rekowski for great help in the laboratory.
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Received: February 14, 2008
Published Online: April 9, 2008
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Eur. J. Org. Chem. 2008, 2365–2368