A branched domino reaction: Asymmetric organocatalytic two-component four-step synthesis of polyfunctionalized cyclohexene derivatives

Article abstract of DOI:10.1002/anie.201209581

Take two: By employing two equivalents of an aldehyde in an asymmetric organocatalytic domino reaction, the nucleophilic enamine intermediate is also converted into the corresponding iminium species through oxidation with o-iodoxybenzoic acid. Thus, polyfunctionalized cyclohexene derivatives are formed from two simple starting materials in good yields and stereoselectivities (see scheme; Bn=benzyl, EWG=electron-withdrawing group). Copyright

Full text of DOI:10.1002/anie.201209581

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Chemie
DOI: 10.1002/anie.201209581
Asymmetric Synthesis
A Branched Domino Reaction: Asymmetric Organocatalytic Two-
Component Four-Step Synthesis of Polyfunctionalized Cyclohexene
Derivatives**
Xiaofei Zeng, Qijian Ni, Gerhard Raabe, and Dieter Enders*
Traditionally, domino reactions are defined as processes of
two or more bond-forming reactions, in which the subsequent
transformation takes place at the functionalities obtained in
the former transformation under identical reaction condi-
tions.[1,2] In linear domino reactions, the progress of the
former step will always affect that of the next steps (Fig-
ure 1a). Among the domino/cascade reactions, organocata-
“oxidative enamine catalysis”, o-iodoxybenzoic acid (IBX)
and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) were
used as the oxidants for converting the enamines to iminium
ions in the presence of the amine catalyst, which facilitated
the further nucleophilic addition to afford the b-functional-
ized products. Shortly after, Rueping and co-workers[9]
reported an enantioselective oxidative domino reaction, in
which an allylic alcohol was oxidized in situ to an aldehyde by
MnO2, followed by the tandem cyclopropanation and 1,4-
addition reactions with high yields and enantioselectivities.
Very recently, Jang and co-workers presented a combination
of a copper complex and a chiral amine for the transformation
of allylic alcohols to enantiomerically enriched b-functional-
ized aldehydes. In this sequence, the allylic alcohols were
oxidized to aldehydes followed by the formation of iminium
intermediates.[10] We wondered whether both the enamine
and iminium salt intermediates derived from the aldehyde
and catalyst could be simultaneously applied in the same
cascade reaction, which means that two parallel reactions
starting from the aldehyde occur at the same time during the
transformation process (Scheme 1).
Figure 1. General sequences of linear and branched domino reactions.
lytic enantioselective reactions[3] have been developed at
a remarkable pace after the revitalization of the field of
organocatalysis.[4,5] However, we planned to develop another
kind of domino reaction, which we call a “branched domino
reaction” (Figure 1b). In this domino sequence, the starting
material can be used in two parallel reactions at the same time
under identical conditions to generate two intermediates,
which will then act as reactants in the next reaction step to
form the desired product. In this version, the progress of the
first step will have no effect on the second step, and higher
overall yields could be achieved. This will enable the efficient
synthesis of complex molecules from a few simple starting
materials in an ecologically and economically manner.
Scheme 1. The generation of both a Michael donor and Michael
acceptor from the same aldehyde.
Herein we report the use of an aldehyde as both
nucleophile and electrophile in such a branched domino
reaction for the formation of six-membered-ring derivatives
through oxidative enamine catalysis (Scheme 2).
In 2011, Wang and co-workers[6] and Hayashi et al.[7]
independently reported the diphenylprolinol trimethylsilyl
ether (I)[8] catalyzed enantioselective b-functionalization of
aldehydes through oxidation of enamines, formed from the
amine catalyst and aldehydes, to iminium ions. In this
First, we needed to figure out whether the enamine
generated from aldehyde and amine catalyst could act as
nucleophile in the presence of an oxidant such as IBX. We
carried out the reaction of dihydrocinnamaldehyde (2a;
1.2 equiv) and nitrostyrene (1a; 1.0 equiv) in the presence
of (R)-I (10 mol%) and IBX (1.0 equiv). To our delight, the
nucleophilic addition product could be obtained in good
yield,[8b,11] indicating that the Michael addition is possible in
the presence of IBX. Based on contributions from our
group[12] and others[13–15] regarding organocatalyzed enantio-
selective three-component domino reactions leading to
polysubstituted cyclohexene derivatives, we continued our
study with the reaction of nitrostyrene (1a) and dihydrocin-
namaldehyde (2a) in the presence of catalyst (R)-I and
oxidant for the formation of the cyclohexenyl ring system
(Scheme 2). In this study, 3.0 equivalents of dihydrocinna-
[*] Dr. X. Zeng, M. Sc. Q. Ni, Prof. Dr. G. Raabe, Prof. Dr. D. Enders
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: enders@rwth-aachen.de
Homepage: http://www.oc.rwth-aachen
[**] We thank the BASF SE and the former Degussa AG for the donation
of chemicals. Dr. X. Zeng thanks the Alexander von Humboldt
Foundation for a postdoctoral fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209581.
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Table 1: The effects of different oxidants and solvents on the domino
reaction.[a]
Entry
Oxidant
Solvent
Yield [%][b]
d.r.[c]
ee [%][d]
>99
1
2
3
4
5
6
7
8
IBX
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
toluene
benzene
EtOAc
THF
55
>20:1
m-CPBA
tBuOOH
H2O2
DDQ
MnO2
PCC
IBX
IBX
IBX
IBX
n.r.[e]
n.r.[e]
n.r.[e]
n.r.[e]
12
Scheme 2. Amine-catalyzed cascade reactions for the enantioselective
synthesis of cyclohexene derivatives.
n.d.[f]
n.d.[f]
n.r.[e]
55
56
60
38
maldehyde were used to facilitate the further oxidative
enamine catalysis. Interestingly, the cyclohexene derivative
was detected by NMR spectroscopy and LC-MS of the crude
after completion of the reaction, and further purification by
column chromatography afforded compound 3a in moderate
yields. Some other chiral and achiral amines were also tested
in this reaction. Pyrrolidine (II) could promote the reaction
and gave the desired cascade product in 35% yield, and the
use of the enantiomeric catalyst (S)-I resulted in the
enantiomer of 3a. However, almost no reaction occurred
when (S)-proline was used. Thus, the catalysts (R)-I and (S)-I
were found to be the best (Scheme 3).
12:1
8:1
10:1
3:1
2:1
3:1
>99
99
99
91
93
–
9
10
11
12
13
IBX
IBX
45
21
n-hexane
[a] Reactions were carried out with 1 (0.2 mmol), 2 (0.6 mmol), oxidant
(0.3 mmol), and catalyst (R)-I (0.01 mmol) in different solvents (0.1m)
at RT. [b] Yield of isolated 3a. [c] Determined by H NMR spectroscopy
and HPLC analysis (on a chiral stationary phase) of the crude product.
[d] Determined by HPLC analysis on a chiral stationary phase. [e] n.r.: no
reaction. [f] n.d.: not determined.
1
IBX with 5 mol% of catalyst (R)-I or (S)-I in 0.1m CHCl3 at
room temperature.
Under the optimized reaction conditions, we next tested
the utility of this approach for the branched domino reaction
through oxidative enamine/iminium catalysis with a range of
nitroalkenes (Table 2). All reactions proceeded well and
provided the desired products in moderate to good yields,
with virtually complete enantioselectivities and good to
excellent diastereoselectivities. The diastereomeric ratio of
the products was affected by the positions and electronic
properties of the substitutents on the aromatic ring of the
nitroolefins. For those with electron-donating groups (para,
meta, or ortho; Table 2, entries 2–5), lower diastereomeric
ratios were obtained. On the other hand, higher ratios could
be achieved when the nitroolefins with electron-withdrawing
groups were used. However, the yields and enantioselectiv-
ities of this reaction were not sensitive to the electronic
properties, and excellent ee values were obtained for all cases.
The use of a nitroolefin derived from a heteroaromatic
aldehyde (Table 2, entry 11) also provided the cyclized
product with similar yield and selectivity. Furthermore,
when the dihydrocinnamaldehyde was changed to (E)-5-
phenylpent-4-enal (2b), the corresponding cyclohexenyl
product 3l was also formed with excellent stereoselectivity
(Scheme 4). As expected, the enantiomer of catalyst I
promoted the oxidative enamine/iminium catalysis as well
and led to the corresponding enantiomers with virtually the
same results.
Scheme 3. Investigation of different amine catalysts.
Next, we focused on the improvement of the diastereo-
selectivity and yield of this reaction (Table 1). We first
evaluated the effect of different oxidants during the enam-
ine/iminium catalysis cascade process. Reagents such as m-
chloroperbenzoic acid (m-CPBA), tBuOOH, H2O2, DDQ
and PCC were not effective at all for this reaction (Table 1,
entries 2–5 and 7) and MnO2 only gave a low yield (Table 1,
entry 6), while IBX was proven to be the best oxidant. Further
investigations showed that 1.5 equivalents of IBX led to the
best result (see the Supporting Information). Then the solvent
effect of this reaction was studied. The cascade reaction
proceeded smoothly in all solvents listed in Table 1 and the
desired product could be obtained with moderate to good
yield as well as good enantioselectivity except in n-hexane
(Table 1, entry 13). This may be a result of the poor solubility,
however, the diastereoselectivity was sensitive to the solvents.
Of those tested, CHCl3 was found to give the highest
diastereoselectivity. Further optimization of the catalytic
loading and reaction concentration showed that the best
result could be achieved in the presence of 1.5 equivalents of
The two-component cascade reaction was also carried out
on a gram scale. 20 mmol of 1a were reacted with 3.0 equiv-
alents of 2a in the presence of 5 mol% of (R)-I and
1.5 equivalents of IBX in CHCl3, and the desired product
was obtained in 67% yield and with excellent diastereo- and
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Table 2: Reaction of nitroalkenes with dihydrocinnamaldehyde.[a]
Entry
1
R
Cat.
Yield [%][b]
d.r.[c]
ee [%][d]
Scheme 5. The gram-scale reaction.
(R)-I
(S)-I
(R)-I
(S)-I
(R)-I
(S)-I
(R)-I
(S)-I
(R)-I
(S)-I
(R)-I
(S)-I
(R)-I
(S)-I
(R)-I
(S)-I
(R)-I
(S)-I
(R)-I
(S)-I
(R)-I
(S)-I
3a, 58
ent-3a,60
3b, 58
ent-3b, 55
3c, 51
ent-3c, 54
3d, 48
ent-3d, 45
3e, 45
ent-3e, 49
3 f, 59
ent-3 f, 55
3g, 48
ent-3g, 50
3h, 60
ent-3h, 58
3i, 62
ent-3i, 65
3j, 45
ent-3j, 49
3k, 48
ent-3k, 51
>20:1
>20:1
12:1
10:1
10:1
9:1
9:1
8:1
>20:1
>20:1
>20:1
>20:1
10:1
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
99
Ph
2
3-MeOC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
3,4-OCH2OC6H3
1-naphthyl
4-FC6H4
3
4
5
6
7
9:1
>20:1
>20:1
14:1
8
4-ClC6H4
9
2-ClC6H4
13:1
98
>20:1
>20:1
>20:1
>20:1
>99
>99
95
10
11
4-NO2C6H4
1-Boc-indolyl[e]
>99
[a] Reactions were carried out with 1 (0.5 mmol), 2a (1.5 mmol), oxidant
(0.75 mmol), and catalyst (R)-I or (S)-I (0.025 mmol) in CHCl3 (0.1m) at
room temperature. [b] Yield of the isolated products 3. [c,d] See Table 1.
[e] Boc=tert-butoxycarbonyl
Scheme 6. The substrate scope of the reaction of aldehyde 2 with 2-(2-
oxoindolin-3-ylidene)acetate derivatives 4 to form the spiro com-
pounds 5.
Scheme 4. The reaction of nitrostyrene with (E)-5-phenylpent-4-enal.
enamine IV is oxidized to the corresponding iminium ion VI,
which reacts as a Michael acceptor with V to form inter-
mediate VII through aldol condensation. Finally, hydrolysis
leads to cyclohexene product 3 and release of the catalyst
(Scheme 7).
enantioselectivity. Thus, this reaction might be suitable for
scale up and large-scale chemical production (Scheme 5).
Next, we investigated the reactions of aldehyde 2a with 2-
(2-oxoindolin-3-ylidene)acetate derivatives 4a–h instead of
nitroolefins to afford oxindole-derived spirocyclic compounds
5 (Scheme 6). All substrates 4 reacted well with 2a under the
same conditions to give the corresponding spiro products 5a–
h in good yields and with excellent diastereo- and enantio-
selectivities. All products listed were fully characterized, and
the absolute configuration of compound 5b was confirmed by
X-ray crystallography (see the Supporting Information).[13b,16]
Our results, together with the proposed mechanisms by
Wang[6] and co-workers and Hayashi[7] et al. suggest that
aldehyde 1 first reacts with amine catalyst I to form an
enamine intermediate IV, which performs a Michael addition
with nitroalkene 2, leading to adduct V. Simultaneously,
In conclusion, we have developed a two-component four-
step branched domino reaction of polyfunctionalized cyclo-
hexene derivatives through an asymmetric organocatalytic
cascade of a Michael addition with parallel oxidation,
a second Michael addition and a final aldol condensation, in
which both the enamine nucleophile and the iminium
electrophile are derived from the same aldehyde. The desired
products could be obtained in moderate to good yields, with
good to excellent diastereoselectivities and excellent enan-
tioselectivities. Especially for spirocyclic products, excellent
results were observed, and the parallel oxidation step did not
have an negative effect on the cascade. The novel branched
domino reaction reported here makes use of mild reaction
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Scheme 7. Proposed catalytic cycle of the branched domino reaction
through oxidative enamine catalysis.
conditions and only two cheap starting materials, and will thus
be useful in pharmaceutical research and diversity-oriented
synthesis.
Experimental Section
General procedure: IBX (210 mg, 0.75 mmol, 1.5 equiv) was added to
a solution of nitroalkene (0.5 mmol, 1.0 equiv) and catalyst (R)-I or
(S)-I (8.2 mg, 0.025 mmol, 5 mol%) in CHCl3 (5.0 mL), and the
resulting mixture was stirred at room temperature for 2 min followed
by addition of the aldehyde (1.5 mmol, 3.0 equiv). The reaction was
stirred for another 2–3 d until conversion of the nitroolefin was
complete (monitored by thin-layer chromatography). The reaction
mixture was directly purified by flash column chromatography (SiO2,
diethyl ether/pentane 1:4–1:1) to afford the desired product as
a colorless solid.
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Received: November 29, 2012
Published online: January 25, 2013
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Keywords: asymmetric synthesis · cyclohexene derivatives ·
domino reactions · organocatalysis · oxidative enamine catalysis
.
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