Dual secondary amine/N-heterocyclic carbene catalysis in the asymmetric Michael/cross-benzoin cascade reaction of β-oxo sulfones with enals

Article abstract of DOI:10.1002/ejoc.201100690

Polyfuncionalized cyclopentanones with three contiguous stereogenic centers were formed in good to excellent yields and stereoselectivities by utilizing a secondary amine/N-heterocyclic carbene catalytic system in the reaction of β-oxo sulfones with unsaturated aldehydes. In addition, the influence of the catalysts on the diastereoselectivity of the final product was studied by ¹H NMR spectroscopy. The combination secondary amine/N-heterocyclic carbene turned out to be a good dual catalytic system for the reaction of β-oxo sulfones with enals leading to polyfunctionalized cyclopentanones in good to excellent yields and stereoselectivities. Further improvement of the enantiomeric excess is possible by crystallization. Direct observations by NMR spectroscopy revealed that the carbene catalyst alone is triggering the diastereoselectivity.

Full text of DOI:10.1002/ejoc.201100690

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100690
Dual Secondary Amine/N-Heterocyclic Carbene Catalysis in the Asymmetric
Michael/Cross-Benzoin Cascade Reaction of β-Oxo Sulfones with Enals
Dieter Enders,*[a] André Grossmann,[a] He Huang,[a] and Gerhard Raabe[a]
Dedicated to Professor Dieter Hoppe on the occasion of his 70th birthday
Keywords: Domino reactions / Umpolung / Michael addition / Organocatalysis / Carbenes
Polyfuncionalized cyclopentanones with three contiguous
stereogenic centers were formed in good to excellent yields
and stereoselectivities by utilizing a secondary amine/N-het- product was studied by H NMR spectroscopy.
sulfones with unsaturated aldehydes. In addition, the influ-
ence of the catalysts on the diastereoselectivity of the final
1
erocyclic carbene catalytic system in the reaction of β-oxo
hydes using a secondary amine/NHC dual catalytic system
Introduction
has recently been published,[7a] we started our investigations
In the past two decades the field of N-heterocyclic carb-
by applying the reaction conditions reported. The reaction
of crotonaldehyde (1a) with (phenylsulfonyl)acetone (2a)
proceeded well with the aminocatalyst 4a and the NHC pre-
enes (NHC)[1] developed rapidly to become inter alia a
powerful tool in organocatalysis.[2] Recently, cascade reac-
tions[3] received growing attention from the scientific com-
cursor 5 resulting in high yields and enantioselectivities but
munity since they lower the cost and reduce the time needed
modest diastereoselectivities of the cascade product
for the synthesis of complex molecules.[4] The interlinking
(Table 1, Entry 1). Only two of four possible diastereomers
of these two important areas of organic chemistry provides
a fast access to densely functionalized compounds difficult
to prepare by other methods. Although a large number of
known transformations already exists by employing the um-
were observed in a ratio of approximately 2:1. Unfortu-
nately, the purification of product 3a and separation from
the excess of ketone 2a was impossible by column
chromatography, because both compounds have similar Rf
values on silica gel, and therefore the reaction conditions
were re-optimized. First other catalytic systems 4b/5 and 4c/
5 were tested but were inferior in selectivity and reactivity
(Table 1, Entries 2 and 3). After several tests using 4a/5 at
polung concept using NHC catalysis, publications dealing
with the application of NHCs in domino reactions[5,7] are
still limited. Since domino reactions solely catalyzed by an
NHC appeared challenging, recent publications indicated
that cooperative[6] and dual catalysis[7] could be promising
low temperature in combination with higher base loadings,
we achieved good conditions leading to the cascade product
alternatives.
in virtually quantitative yield, high ee and moderate dr,
while the starting materials were applied in nearly equi-
molar amounts (Table 1, Entry 4).
Results and Discussion
We were intrigued by the possibilities of utilizing dual
catalytic systems and hence envisioned that β-oxo sulfones
A, which are known substrates[8,9] for the organocatalytic
Michael addition, might undergo a Michael/cross-benz-
oin[10] cascade reaction with enals B to form, via the
Michael adducts C, polyfunctionalized cyclopentanones D
bearing three contiguous stereogenic centers (Scheme 1).
Since the reaction of β-oxo carbonyl compounds with alde-
Scheme 1. Retrosynthetic analysis.
[a] Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany
Fax: +49-241-809-2127
Subsequently, we focused on the scope of the reaction.
First the variation of the Michael acceptor was studied
(Table 2; 3a–c). The long-chain leaf aldehyde (1b) and cinn-
E-mail: enders@rwth-aachen.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100690.
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Eur. J. Org. Chem. 2011, 4298–4301

Asymmetric Michael/Cross-Benzoin Cascade Reaction
Table 1. Optimization of the reaction conditions.[a]
tive 3k contained a second isomer in a 3:1 and 4:1 ratio,
respectively. In all these cases the polyfuncionalized cyclo-
pentanones were formed in good yields and excellent
enantioselectivities.[11] It is worthwhile to point out that
these compounds are all crystalline solids. To our delight,
they form conglomerates as shown in the case of 3d. After
a single crystallization step only one pure enantiomer of
this compound was isolated with 99% ee. Furthermore, as
was demonstrated with 3d, this reaction could be performed
on a gram scale with a comparable yield and stereoselecti-
vity. As a further extension of the protocol α-substituted α-
(phenylsulfonyl) ketones 2l–n were used. As expected, the
additional α-substituent decreased the reaction rate and the
yield. Attempts to prolong the reaction time to 3 d still pro-
vided only modest yields. The cyclic ketones 2l,m performed
better than the acyclic one (2n). By comparison, cyclo-
pentanone substrate 2l resulted in a higher product yield
but much lower enantio- and diastereoselectivity than the
cyclohexanone substrate 2m.
Entry
Catalysts
Yield of 3 [%][b]
dr[c]
ee [%][d]
Table 2. Substrate scope of the asymmetric Michael/benzoin dom-
ino reaction.[a]
1
2
4a/5
4b/5
4c/5
4a/5
85
8
78
99
63:37
57:43
69:31
66:34
88
55
67
86
3
4[e]
[a] Reactions (Entries 1–3) were performed by using 1 equiv. of cro-
tonaldehyde (1a) (0.76 mmol scale), 2 equiv. of β-oxo sulfone 2a,
20 mol-% of 4, 10 mol-% of 5, 10 mol-% of NaOAc in CHCl3
(0.25 m) at room temperature; all reagents were added sequentially.
[b] Sum of the yields of isolated 3a and epi-3a. [c] Diastereomeric
ratio of 3a and epi-3a determined by 1H NMR spectroscopy of the
crude reaction mixture. [d] Determined by HPLC analysis on a
chiral stationary phase; major diastereomer. [e] This reaction was
performed by using 1.2 equiv. of crotonaldehyde (1a) (0.76 mmol
scale), 1.0 equiv. of β-oxo sulfone 2a and 20 mol-% of 4 in CHCl3
(0.25 m) at room temperature; after 24 h, 10 mol-% of 5 and
30 mol-% of KOAc were added.
3
R1
R2
R3 Yield [%][b] dr[c] ee [%][d]
a
b
Me
nPr
Ph
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
99
67
33
72 (44)
70
85
80
81
68
74
66:34
58:42
99:1
99:1
99:1
99:1
74:26
99:1
99:1
99:1
79:21
67:33
99:1
n.d.
86
96
94
92 (99)
90
91
83
83
97
93
c
amic aldehyde (1c) showed lower reactivity towards the nu-
cleophile 2a than the crotonaldehyde (1a), although the re-
action proceeded with higher enantioselectivity. Prolonging
the reaction time had no effect on the yield in these cases.
Therefore, the higher level of asymmetric induction may be
explained with the increased steric demand, while the lim-
ited conversions are possibly caused by the deprotection of
the amine catalyst leading to the less effective catalyst 4b
(Table 1, Entry 2), this being in line with what was reported
by Jørgensen et al.[9a] The ratio of the two observed dia-
stereomers was modest for 3a and 3b. Fortunately, they can
d[e]
e
Ph
4-BrC6H4
4-PhC6H4
3-O2NC6H4
f
g
h
Me 3-MeOC6H4
Me
Me
i
j
3,4-F2C6H3
2-naphthyl
k
Me 2-benzofuryl
96
53
90
41
l[f]
m[f]
n[f]
Me
Me
Me
–C3H6–
–C4H8–
Me
20
91
n.d.
Me
Ͻ 5[g]
[a] All reactions were performed by using 1.2 equiv. of crotonalde-
be separated by column chromatography to yield the pure hyde (1a) (0.76 mmol scale), 1.0 equiv. of β-oxo sulfone 2a and
20 mol-% of 4 in CHCl3 (0.25 m) at room temperature; after 24 h,
diastereomers. Furthermore, cinnamaldehyde provided only
a single diastereomer of the product, possibly indicating a
strong electronic or stereoelectronic influence on the dia-
10 mol-% of 5 and 30 mol-% of KOAc were added. [b] Sum of the
yields of isolated 3 and epi-3. [c] Diastereomeric ratio of 3 and
1
epi-3 determined by H NMR spectroscopy of the crude reaction
stereoselectivity here. With this observation in hand, we
predicted that the change of the nucleophile to (phenylsulf-
onyl)acetophenones 2d–i and other β-oxo sulfones bearing
naphthyl or benzofuranyl groups 2j–k would react in a
highly diastereselective manner. As anticipated, in most
mixture. [d] Determined by HPLC analysis on a chiral stationary
phase; major diastereomer; values in parentheses indicate yield and
ee after crystallization. [e] This reaction was performed on a
7.6 mmol scale. [f] The reaction time of the Michael addition step
1
was prolonged to 3 d. [g] Estimated by H NMR spectroscopy.
1
cases only one diastereomer could be observed in the H
The absolute configuration of the cyclopentanone prod-
NMR spectra of the crude reaction mixture. Only the prod- uct 3d was determined by X-ray crystal structure analysis
uct 3g bearing a nitro group and the benzofuranyl deriva- (Figure 1). The structure matched well with the NOE con-
Eur. J. Org. Chem. 2011, 4298–4301
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. Enders, A. Grossmann, H. Huang, G. Raabe
SHORT COMMUNICATION
tacts for 3g measured by NMR spectroscopy. Interestingly, with one Michael adduct epimer along with a rapid epi-
this structure indicated a different configuration in the α- merization of the less reactive one. In summary, the dia-
position to the carbonyl group than the one determined by stereomeric ratio of the final product was unaffected by the
Rovis et al.[7a] for substrates bearing a carbonyl group in- amine catalyst and is completely determined by the NHC
stead of the sulfonyl group. Additionally, NOE contacts of catalyst.
the products 3a and 3n[12] were measured, because no exam-
ples with aromatic moieties (R2) were published. Both com-
pounds have the (R) configuration here, which is consistent
with the result reported in the literature.[7a]
1
Figure 2. Direct observation of the reaction progress for 3d by H
NMR spectroscopy; for details see Supporting Information; all
curves are polynomial plots of the data points.
Figure 1. ORTEP plot of 3d determined by X-ray analysis[13] and
NOE measurements of 3a and 3g.
This interesting result led to further investigations in or-
der to gain a deeper insight into the influences of the NHC
and TMS-protected diphenylprolinol catalysts on the dia-
stereoselectivity. Therefore, a kinetic study was undertaken
Figure 3. Development of the diastereomeric ratio of the cross-
benzoin reaction precursor of 3d; for details see Supporting Infor-
mation; the curve is the polynomial plot of the data points.
in which the reaction progress for 3d was observed directly
by 1H NMR spectroscopy (Figure 2). In contrast to an
analysis by GC, this method makes it possible to determine
the dr of the Michael addition product (referred to as C in
Scheme 1) and the cross-benzoin product[14] directly in the
Conclusions
reaction vessel (Figure 3). At the beginning of the Michael
addition a moderate diastereomeric excess (de) of 60% was
measured for the product of this first step. As the reaction
progressed, this value dropped continuously. This decrease
became even faster after the addition of the carbene precur-
sor and the base. Virtually no diastereomeric excess was left
after approximately 4 h, while the carbene catalyst con-
verted only 50% of the Michael addition product. The reac-
tion without the addition of the carbene precursor followed
the same route. Thus, we assume that this epimerization is
due to a deprotonation and re-protonation in the α-position
to the ketone and the phenylsulfonyl group under basic con-
ditions. This analysis was also performed with compound
3a and resulted in a similar curve progression for the de
of the Michael adduct.[13] It is worth mentioning that the
diastereomeric ratio of 3a during its formation remained
nearly constant and is therefore independent of the de of
the cross-benzoin reaction precursor. An explanation may
We developed an organocatalytic cascade reaction be-
tween β-oxo sulfones and enals by utilizing a dual second-
ary amine/N-heterocyclic carbene catalytic system. The po-
lyfuncionalized cyclopentanones bearing a synthetically
useful β-(phenylsulfonyl) group, an α-hydroxy function and
three contiguous stereocenters are formed mostly in good
yields, modest to excellent diastereoselectivities and very
good enantiomeric excesses. Further improvement of the ee
value can be achieved by re-crystallization. Kinetic studies
revealed that the carbene catalyst solely controls the ob-
served diastereoselectivity.
Experimental Section
General Procedure for the Synthesis of Polysubstituted Cyclopenta-
nones: A solution of β-oxo sulfone 2 (1 equiv.) and the aldehyde 1
(1.2 equiv.) in CHCl3 (0.25 m) was cooled to –35 °C and then
be that in a dynamic kinetic process the NHC reacts faster charged with the catalyst 4a (20 mol-%). After the mixture had
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Eur. J. Org. Chem. 2011, 4298–4301

Asymmetric Michael/Cross-Benzoin Cascade Reaction
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KOAc (30 mol-%) were consecutively added in one portion. While
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reached room temperature. The crude product was directly purified
by column chromatography to afford 3 as a colourless solid.
Supporting Information (see footnote on the first page of this arti-
cle): Complete experimental details and spectroscopic data for all
new compounds.
Acknowledgments
This work was supported by the Fonds der Chemischen Industrie
and the Deutsche Forschungsgemeinschaft (SeleCa – international
research training group).
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[11] Compounds 3g and 3h showed low solubility in most organic
solvents. Therefore, it was difficult to obtain reproducable ee
values by HPLC analysis. The values in Table 2 are the lowests
that were measured. Since these two compounds also form con-
glomerates, we assume that the variation in the ee values is due
to partial crystallisation on the HPLC column. The average of
the measured values for 3g was 92 %.
[12] For the NOE measurements of 3n, see Supporting Information.
[13] CCDC-819238 contains the supplementary crystallographic-
data for the compound 3d reported in this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[14] For the corresponding diagrams of 3a, see Supporting Infor-
mation.
Received: May 17, 2011
Published Online: June 15, 2011
Minor changes have been made since publication in Early View.
Eur. J. Org. Chem. 2011, 4298–4301
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