Chiral dihydrobenzo[1,4]oxazines as catalysts for the asymmetric transfer-hydrogenation of α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tet.2011.10.051

A new class of organocatalysts based on the structure of 2,3-dihydrobenzo[1,4]oxazine was prepared and applied in the enantioselective transfer-hydrogenation of α,β-unsaturated aldehydes with Hantzsch ester as hydride donor. These catalysts proved to be particularly effective for the conjugate reduction of β,β-diaryl-substituted acrylaldehydes leading to saturated aldehydes bearing a stereogenic center with two different aryl groups with enantioselectivities of up to 91% ee.

Full text of DOI:10.1016/j.tet.2011.10.051

Tetrahedron 67 (2011) 10287e10290
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Tetrahedron
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Chiral dihydrobenzo[1,4]oxazines as catalysts for the asymmetric transfer-
hydrogenation of
a
,b
-unsaturated aldehydes
*
Christian Ebner, Andreas Pfaltz
Department of Chemistry, University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 August 2011
Received in revised form 10 October 2011
Accepted 12 October 2011
Available online 20 October 2011
A new class of organocatalysts based on the structure of 2,3-dihydrobenzo[1,4]oxazine was prepared and
applied in the enantioselective transfer-hydrogenation of
a,b-unsaturated aldehydes with Hantzsch ester
as hydride donor. These catalysts proved to be particularly effective for the conjugate reduction of
b,b-
diaryl-substituted acrylaldehydes leading to saturated aldehydes bearing a stereogenic center with two
different aryl groups with enantioselectivities of up to 91% ee.
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to Professor Gilbert Stork on the
occasion of his 90th birthday
Keywords:
Asymmetric catalysis
Organocatalysis
Hantzsch ester
Acrylaldehydes
Transfer-hydrogenation
1. Introduction
spectrometric screening of organocatalysts4 we had become in-
terested in chiral 2,3-dihydrobenzo[1,4]oxazines 2. Based on the
Organocatalyzed asymmetric transfer-hydrogenation has
emerged as a mild and very selective method for the conjugate
generally accepted mechanism2 of asymmetric transfer-hydroge-
nation we thought that compounds of this type could be a useful
extension to the known catalysts for this reaction (Scheme 1).
reduction of a,b
-unsaturated aldehydes or ketones.1 The catalyst,
typically a chiral pyrrolidine or imidazolidinone derivative with
a stereogenic center next to the N atom, activates the aldehyde by
forming an iminium ion, while the substituent at the stereogenic
center shields one of the enantiotopic faces of the substrate. With
dihydropyridines such as Hantzsch esters as the hydrogen source
the method mimics enzymatic reductions with NADH or FADH2 as
cofactors.2 Its scope is often complementary to that of analogous
metal-catalyzed transformations. Especially for the conjugate re-
duction of a,b-unsaturated aldehydes this methodology has proved
to be of great value since metal-catalyzed reductions often lead to
the corresponding alcohols rather than to the saturated aldehydes.3
To date only a limited number of catalysts have been applied in
this reaction, namely MacMillan’s imidazolidinones,1b,c,e,h proline
derivatives,1f,g and a catalyst system introduced by List and co-
workers1d based on amino acid esters in combination with chiral
phosphoric acids. In connection with our work on mass
Scheme 1. Mode of stereoinduction.
* Corresponding author. Tel.: þ41 61 2671108; fax: þ41 61 2671103; e-mail ad-
dress: andreas.pfaltz@unibas.ch (A. Pfaltz).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.051

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C. Ebner, A. Pfaltz / Tetrahedron 67 (2011) 10287e10290
Table 1
Catalyst screening
The iminium intermediate can adopt a cis or a trans confor-
mation and discrimination between these two isomers by the
catalyst is crucial for achieving high enantioselectivity, because in
the (E)- and (Z)-isomer the opposite faces of the
shielded. Assuming a planar conformation of the unsaturated imi-
nium -system the (E) isomer should be strongly favored due to the
p-system are
p
steric repulsion between the olefinic H atom and the benzene ring.
Thus the reaction is expected to proceed via the (E) isomer and
hydride attack from the less hindered side, making benzoxazines of
this type attractive catalyst candidates.
Entry
Catalyst
t [h]
0.25
0.75
0.5
4
Conv.a [%]
eeb [%] (config.)
1
2
3
4
5
2a
2b
10a
10b
10b
>99
>99
>99
<10
<10
61 (R)
40 (R)
59 (R)
26 (R)
25 (R)
2. Results and discussion
24
Synthesis of different dihydrobenzooxazines
2 and dihy-
dronaphthooxazines 10 was achieved starting from commercially
available amino alcohols 5 (Scheme 2).5 These were N-Boc pro-
tected and converted to the cyclic sulfamidates 7a,b. Subsequent
reaction with 2-bromophenol followed by acidic N-Boc depro-
tection yielded the benzoxazine precursors 8a,b, which were then
cyclized to the desired organocatalysts 2a,b by BuchwaldeHartwig
amination.6 Naphthyl derivatives 10a,b were obtained by nucleo-
philic cleavage of sulfamidates 7a,b with 2-bromonaphthalen-2-ol
and subsequent palladium-catalyzed ring closure (for details, see
Supplementary data).
TFA¼trifluoro acetic acid.
a
Determined by GC analysis of the reaction mixture.
Determined by GC analysis (Chiraldex G-TA).
b
ester (entry 8). The results show that dihydrobenzoxazine de-
rivatives are very reactive catalysts. However, the enantioselectiv-
ities in the reduction of substrate 1a are lower than those reported
for the best catalysts.
Table 2
Optimization studies
Entry
Solvent
T [ꢀC]
t [h]
0.25
0.25
0.25
0.50
1.25
15
3
1
R
Conv.a [%]
eeb [%] (config.)
1
2
3
4
5
6
7
8
CHCl3
CH2Cl2
Toluene
Et2O
Dioxane
CHCl3
CHCl3
CHCl3
25
25
25
25
25
ꢁ25
ꢁ50
25
Et
Et
Et
Et
Et
Et
Et
t-Bu
>99
>99
>99
>99
>99
>99
>99
>99
61 (R)
57 (R)
56 (R)
69 (R)
63 (R)
66 (R)
67 (R)
59 (R)
Scheme 2. Catalyst syntheses. Conditions: I: Boc2O, NEt3, THF, rt, 1.5 h; II: (1) SOCl2,
imidazole, NEt3, DCM, 0 ꢀC/rt, 18 h; (2) NaIO4, RuO2$H2O, H2O/EtOAc, 0 ꢀC, 1 h; III: (1)
2-bromophenol, NaH, DMF, RT, 18 h; (2) concd H2SO4, dioxane/H2O, 1 h; IV: (1) 1-
bromonaphthalen-2-ol, NaH, DMF, rt, 18 h; (2) concd H2SO4, dioxane/H2O, 1 h; V:
Pd(OAc)2, Xantphos, t-BuONa, toluene, 100 ꢀC, 18 h.
TFA¼trifluoroacetic acid.
a
Determined by GC analysis of the reaction mixture.
Determined by GC analysis (Chiraldex G-TA).
b
We also examined a-substituted acrylaldehydes 12 as substrates.
For initial experiments
b
-methyl cinnamaldehyde ((E)-1a) was
However, catalysts 2a,b and 10a,b proved to be unreactive and no
reduction product was detected even after 18 h (Scheme 3). These
results were consistent with ESI-MS studies, which we carried out to
evaluate the tendency of the catalysts to form an iminium in-
termediate with the substrate. As expected, the sterically de-
manding tert-butyl-substituted catalysts 2b and 10b did not form
iminium salts. With the more reactive benzyl-substituted catalysts
signals of iminium salts were detected but the intensity was very
low. Interestingly, the dihydronaphthoxazine derivative 10a showed
the strongest iminium signal in the MS, although the signal ratio of
the iminium salt to the free catalyst was still very low (1:24) com-
pared to the ratios measured for the more reactive substrate 1a.7
chosen as model substrate. When catalyst 2a was applied at room
temperature we were pleased to find full conversion to the desired
product 11a already after 15 min (Table 1, entry 1). Furthermore we
found an ee of 61% in favor of the (R)-enantiomer. Catalyst
screening showed that benzyl-substituted derivatives induced
higher enantioselectivities than the tert-butyl analogues. Catalyst
10b showed only low activity resulting in less than 10% conversion
even after 24 h (entry 5).
Next, different reaction conditions were evaluated (Table 2). The
nature of the solvent had only a small influence on the enantiose-
lectivity (entries 1e5). The best result was obtained in Et2O yielding
11a with full conversion after 30 min and 69% ee. However, when
the reaction in Et2O was carried out at lower temperature, it did not
reach completion anymore. The reaction in CHCl3 was faster and
could be carried out at low temperature. We found that the ee in-
creased with decreasing temperature but it did not exceed 67% ee
(entry 7). The steric demand of the Hantzsch ester had essentially
no effect on the ee as shown in the reaction with the di-tert-butyl
Scheme 3. Attempted transfer-hydrogenation of
fluoroacetic acid).
a-methyl cinnamaldehyde (TFA¼tri-

C. Ebner, A. Pfaltz / Tetrahedron 67 (2011) 10287e10290
10289
Table 3
Optimization studies
b
-Methyl cyclohexanone (14) proved to be unreactive as well.
When we applied the same conditions as reported in literature for
a different catalyst system,1e no conversion was observed (Scheme
4). As expected, no iminium signals could be detected by ESI-MS in
this case.
Entry
Catalyst
Solvent
T [ꢀC]
t [min]
Conv.a [%]
eeb [%] (config.)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
CHCl3
Et2O
25
25
25
ꢁ20
ꢁ40
25
15
30
60
45
210
60
>99
>99
>99
>99
50
75
40
<10
76 (þ)
63 (þ)
72 (þ)
78 (þ)
n.d.
79 (þ)
73 (þ)
n.d.
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
2a
Scheme 4. Attempted transfer-hydrogenation of
chloroacetic acid, p-TsOH¼p-toluenesulfonic acid).
b-methyl cyclohexanone (TCA¼tri-
2b
10a
10b
25
25
120
300
As these catalysts showed no activity in the reduction of enones or
-substituted acrylaldehydes but were able to reduce -di-
substituted acrylaldehydes with high activity, we focused our at-
tention on -diaryl-acrylaldehydes. The resulting saturated
aldehydes with a diaryl-substituted stereogenic center in the
TFA¼trifluoroacetic acid; n.d. denotes ‘not determined’.
a
Determined by GC analysis of the reaction mixture.
a
b
b
Determined by HPLC analysis (Daicel Chiracel AD-H) of the corresponding al-
cohol after reduction with NaBH4.
b,b
four catalysts tested, benzoxazines 2a and 2b gave better results in
terms of reactivity than naphthoxazines 10a and 10b. Dihy-
drobenzoxazine 2a emerged as the catalyst of choice for this re-
action, as it was the only catalyst that gave full conversion, although
the tert-butyl derivative 2b induced slightly higher enantiose-
lectivity (entry 6).
Having found the optimal reaction conditions (Table 3, entry 4)
we examined the substrate scope (Table 4). Catalyst 2a showed
high activity and enantioselectivities between 78% and 91% ee for
b
position are of interest as potential precursors for the synthesis of
bioactive natural products or drugs such as tolteridine,8 mim-
osifoliol9 or arpromidine.10 Only very few examples of enantiose-
lective conjugate reductions of 1-acceptor-substituted 2,2-
diarylalkenes can be found in literature.10,11 However, no such re-
actions of b,b-diaryl-acrylaldehydes have been reported yet.
Synthesis of the required substrates was accomplished follow-
ing known literature procedures.12 Starting from commercially
available ethyl 3-phenylpropiolate (16a), ethyl acrylates (E)-18
were obtained by copper-catalyzed conjugate addition of the cor-
responding arylboronic acids 17 with perfect E/Z selectivity. Re-
duction to the allylic alcohols (E)-19 with NaBH4 and subsequent
oxidation with MnO2 afforded the desired acrylaldehydes (E)-1
(Scheme 5). In a similar fashion substrate (Z)-1e was obtained from
3-(4-fluorophenyl)-propiolate (16c), which was prepared by a li-
gand-free copper(I)-catalyzed Sonogashira-type coupling13 of (4-
fluorophenyl)boronic acid with ethyl propiolate (16b) (for de-
tailed synthetic procedures and scope, see Supplementary data).
a range of
b,b-diaryl-acrylaldehydes with different steric and
Table 4
Scope of the reactiona
Scheme 5. Substrate synthesis. Conditions: I: Cu(I)OAc, MeOH, rt, 18 h; II: NaBH4,
ZnCl2, NEt3, THF, reflux, 3 h; III: MnO2, CHCl3, rt, 2 d; IV: 4-FeC6H4eB(OH)2, CuI, Ag2O,
Cs2CO3, DCE, 80 ꢀC, 36 h; V: PheB(OH)2, Cu(I)OAc, MeOH, rt, 18 h.
Initial experiments with these substrates gave very promising re-
sults. Subsequent optimization studies were carried out using
substrate (E)-1b (Table 3). In the reaction with catalyst 2a CHCl3
proved to be the best solvent yielding the corresponding saturated
aldehyde in 76% ee with full conversion after 15 min (entry 1). As
observed before in the reduction of 2-methylcinnamaldehyde (1a)
the reaction times were remarkably short, allowing us to lower the
reaction temperature to ꢁ20 ꢀC. Under these conditions conversion
was still complete within 1 h while the ee increased to 78% (entry
4). When the temperature was further decreased to ꢁ50 ꢀC the
reaction did not go to completion anymore (entry 5). Among the
TFA¼trifluoroacetic acid; n.d. denotes ‘not determined’.
a
Screening reactions were carried out on a 0.1 mmol scale. Conversion de-
termined by GC analysis of the reaction mixture, ee determined by HPLC analysis of
the corresponding alcohol on a chiral stationary phase after reduction with NaBH4.
When given, the absolute configuration was determined by comparison of the sign
of optical rotation of the saturated aldehyde with literature data.14
b
When the reaction was carried out on a 10-fold scale (1 mmol), 81% yield (89%
conv.) and 82% ee (S) were obtained.

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C. Ebner, A. Pfaltz / Tetrahedron 67 (2011) 10287e10290
electronic properties. Both electron-donating (substrate 1d) and
electron-withdrawing (1e and 1f) aryl groups were tolerated. With
the more sterically demanding substrates 1c and 1g incomplete
conversions were observed, while the enantioselectivities were still
at 82% and 87% ee, respectively. The phenanthrene derivative 1h
proved to be unreactive. Apparently, the phenanthrenyl group in-
duced too much steric hindrance, so only traces of product were
formed.
For comparison we also tested MacMillan’s (S)-2-(tert-butyl)-3-
methylimidazolidin-4-one under the conditions reported for the
hydrogenation of substrate (E)-1a.1c The conversion of substrate
(E)-1e after 2 h was only 26%. After 18 h the conversion reached 65%
but did not further increase from there on. The hydrogenation
product 11e was formed in 62% ee.
The absolute configuration of the major enantiomers produced
in these reactions is in agreement with the model of stereo-
induction shown in Scheme 1. Sterically controlled Re-facial hy-
dride transfer to the (E)-iminium salt derived from (E)-1c, for
example, should lead to (S)-11c and indeed, this was the major
enantiomer found. Experiments with the cis/trans isomers (Z)-1e
and (E)-1e showed that the sense of chiral induction depends on
the configuration of the C]C bond. Reduction of (E)-1e resulted in
(S)-11e with 91% ee while (Z)-1e gave the opposite enantiomer (R)-
11e with 80% ee.
0.12 mmol,1.20 equiv) and catalyst 2a (4.50 mg, 0.02 mmol, 20 mol
%) in CHCl3 (0.5 ml, 0.2 M) was added TFA (0.456 mg, 4 mol, 4 mol
m
%) at ꢁ20 ꢀC. The conversion was followed by GC analysis of an
aliquot of the reaction mixture and full conversion was achieved
after 2 h. After removal of the solvent under reduced pressure the
residue was purified by column chromatography (SiO2, 2ꢂ20 cm,
pent/Et2O¼5:1) and the desired compound was obtained as a col-
orless oil (19.2 mg, 84%). The analytical data matched the literature
values.14 Rf (SiO2, pent/Et2O) 0.21; GC (Macherey-Nagel Optima 5
PhMeSi, 100 ꢀC, 2 min, 10 K/min, 270 ꢀC, 10 min): 14.2 min (11e),
15.3 min ((E)-1e); MS (EI, 70 eV): m/z (%)¼228 (61), 210 (30), 186
(24), 185 (100), 183 (59), 170 (15), 165 (67), 121 (139), 105 (28), 104
(10), 103 (14), 101 (10), 91 (10), 77 (17), 75 (10), 63 (12), 51 (25), 50
(11). The ee was determined by HPLC analysis of the corresponding
alcohol. For this purpose the aldehyde 11c was dissolved in MeOH
(1 ml) and the solution was cooled to 0 ꢀC. Then NaBH4 (15.9 mg,
0.421 mmol, 5.00 equiv) was added and the mixture was stirred for
1 h before it was quenched with satd NH4Cl-solution. After ex-
traction with EtOAc and drying over MgSO4, the solvent was re-
moved under reduced pressure. HPLC analysis (Daicel Chiracel OD-
H, hept/i-PrOH¼95:5, 0.5 ml/min, 40 ꢀC, tR¼32.7 min (R), 37.2 min
(S)) indicated 91% ee in favor of the (S)-enantiomer.
Acknowledgements
In this respect, the stereochemical course differs from that re-
ported for the reduction of the
b
-methyl-substituted acrylaldehyde
-alkyl derivatives.1 For
b-alkyl-substituted sub-
Financial support by the Swiss National Science Foundation is
gratefully acknowledged.
1a and related
b
strates a stereoconvergent pathway was observed, which leads to
the same product enantiomer starting either from the (E)- or the
(Z)-isomer. This stereoconvergence has been rationalized by rapid
cis/trans isomerization via a dienamine intermediate under the
reaction conditions. Obviously, such an isomerization reaction is
Supplementary data
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2011.10.051.
not possible for b,b-diaryl-substituted acrylaldehydes and therefore
(E)- and (Z)-isomers are converted to opposite enantiomers.
According to the model for the enantioselective step shown in
Scheme 1, it is the interaction of the catalyst with the less
substituted a-C atom rather than the prochiral b
-CAr1Ar2 unit that
References and notes
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To a solution of (E)-3-(4-fluorophenyl)-3-phenyl-acrylaldehyde
((E)-1e, 22.6 mg, 0.1 mmol,1.00 equiv), Hantzsch ester (4a, 30.2 mg,