Asymmetric michael addition of N-Boc-protected oxindoles to nitroalkenes catalyzed by a chiral secondary amine

Article abstract of DOI:10.1002/chem.201200079

New mission for prolinol ethers: A secondary-amine-catalyzed Michael addition of N-Boc-protected oxindoles to nitroalkenes through a Bronsted base activation mode has been developed, furnishing the products in excellent yields (88-98%), diastereoselectivi

Full text of DOI:10.1002/chem.201200079

DOI: 10.1002/chem.201200079
Asymmetric Michael Addition of
ACHTUNGTNERNNUNG -Boc-Protected Oxindoles to
ACHTUNGTRENNUNG
Chuan Wang, Xuena Yang, and Dieter Enders*[a]
Over the last decade, chiral secondary amines have
turned out to be very powerful catalysts for the efficient and
highly stereoselective functionalizations of various carbonyl
compounds through covalent activation modes such as imi-
nium ion, enamine, and singly occupied molecular orbital
(SOMO) activation.[1–4] Despite remarkable progress in this
field, the substrate scope of these reactions is restricted to
aldehydes and ketones thus limiting the applications of
chiral secondary amines in catalysis. Although pyrrolidine is
a common base used in organic synthesis, surprisingly, only
very few efforts have been made to investigate its use as
a chiral Brønsted base catalyst, whereas cinchona alkaloids
and guanidines have attracted significant attention.[5] Fur-
thermore, to the best of our knowledge, most of the devel-
oped reactions using secondary amines as H-acceptors em-
ployed chiral diaryl prolinols as bifunctional catalysts afford-
ing the products mostly in moderately good enantioselectivi-
ties.[6] We became interested in the possibility of developing
highly diastereo- and enantioselective Michael additions
using chiral secondary amines as Brønsted base catalysts.
The oxindole core exists as a characteristic structural fea-
ture in a large number of naturally occurring and synthetic
alkaloids exhibiting various biological and pharmacological
activities; of which, the most notable are its anti-tumor
properties.[7] Therefore, many methods have been developed
to approach 3,3-disubstituted oxindoles in a highly enantio-
selective manner.[8] Michael additions of oxindoles to nitroo-
lefins are of particular interest as the Michael adducts can
be readily converted to alkaloids or their derivatives.[9,10] Al-
though several reports about Michael additions of N-pro-
tected oxindoles to nitroalkenes have been described, the
catalysts used are either derived from expensive chiral pre-
cursors or synthesized through a long and challenging syn-
thetic route.[9a–f] In this context we wish to report a Michael
addition of oxindoles to nitroolefins catalyzed by a chiral
pyrrolidine, which can be simply synthesized from the cheap
amino acid proline (Scheme 1).
Scheme 1. Asymmetric Michael addition of 1a to nitrostyrene 2a em-
ploying pyrrolidine-type catalysts.
In the first instance we performed the reaction between
the N-Boc-protected oxindole 1a and nitrostyrene 2a at
room temperature in chloroform under the catalysis of (S)-
diphenyl prolinol TMS-ether 4. The reaction was complete
within 2 h and gave the Michael adduct in a high yield
(98%) and diastereomeric ratio (d.r.=91:9), albeit with very
low enantiomeric excess (ee) (3% ee; Table 1, entry 1). Low-
ering the reaction temperature to À358C led to an increase
of the enantiomeric excess (27% ee), whereas the yield
(98%) remained high (Table 1, entry 2). Then, several enan-
tiopure secondary amines 5–8 were tested for this reaction.
In the cases of (R)-2-methoxymethylpyrrolidine (5) and the
diamine 6 the reactions proceeded in good to high yields
(72–96%) and with excellent diastereoselectivities (d.r.=
97:3–99:1), however, no improved enantioselectivities (À6
to 12% ee) were obtained (Table 1, entries 3 and 4). When
(S)-diphenyl prolinol 7 was used as catalyst, an inverse and
higher enantioselectivity (À40% ee) was achieved but the
catalytic activity diminished dramatically (Table 1, entry 5).
In the case of (S)-diarylprolinol TMS-ether 8 the product
[a] Dr. C. Wang, Dipl.-Chem. X. Yang, Prof. Dr. D. Enders
Institute of Organic Chemistry
RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
Fax : ( +49)241-809-2127
E-mail: enders@rwth-aachen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200079.
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Chem. Eur. J. 2012, 18, 4832 – 4835

COMMUNICATION
Table 1. Optimization of the reaction conditions for the Michael addition.[a]
amine group plays a crucial role in the activation of
the substrate (Table 1, entry 15). Furthermore, we
screened various diaryl and dialkyl prolinol ethers
12–17 for this reaction. The catalyst 12 with
a larger aryl ring was found to improve the enantio-
selectivity (À63% ee) to some degree (Table 1,
entry 16). Surprisingly, when the less sterically de-
manding (R)-2-methoxymethylpyrrolidine 13 was
employed as catalyst, the product was furnished in
Entry
Cat.
T
[8C]
t
Solvent
Yield
[%][b]
d.r.[c]
ee[c]
[h]
1
2
3
4
5
6
7
8
4
4
5
6
7
8
4
4
4
4
4
4
RT
2
CHCl3
CHCl3
98
98
96
72
46
21
98
82
<5
65
74
78
97
98
<5
96
98
98
98
96
94
98
91:9
97:3
99:1
3
À35
À35
À35
À35
À35
À60
À60
À60
À60
À60
À60
À60
À60
À60
À60
À60
À60
À60
À60
À60
À60
16
16
16
16
16
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
27
À6
12
À40
À6
52
CHCl3/CH2Cl2 =4:1
CHCl3/CH2Cl2 =4:1
CHCl3/CH2Cl2 =4:1
CHCl3/CH2Cl2 =4:1
CHCl3/CH2Cl2 =4:1
EtOAc
MeOH
ether
THF
toluene
CHCl3/CH2Cl2 =4:1
CHCl3/CH2Cl2 =4:1
CHCl3/CH2Cl2 =4:1
CHCl3/CH2Cl2 =4:1
CHCl3/CH2Cl2 =4:1
CHCl3/CH2Cl2 =4:1
CHCl3/CH2Cl2 =4:1
CHCl3/CH2Cl2 =4:1
CHCl3/CH2Cl2 =4:1
CHCl3/CH2Cl2 =4:1
97:3
87:13
33:46
98:2
95:5
18
a
better enantioselectivity (70% ee; Table 1,
9
n.d.[d]
51:49
66:34
65:35
>99:1
93:7
n.d.[d]
8
entry 17). Encouraged by this result we carried out
this reaction with several other dialkyl prolinol
ethers 14–16 (Table 1, entries 18–20) and the best
result with respect to both yield (98%) and stereo-
selectivities (d.r.>99:1, 83% ee) was obtained
when (S)-didodecyl prolinol TMS-ether 15 was uti-
lized as the catalyst (Table 1, entry 19). Moreover,
(S)-dibenzyl TMS-prolinol ether 17 was tested for
this reaction providing no improved result (Table 1,
entry 21). Finally, we lowered the catalyst loading
of 15 to 10 mol% and the reaction was complete
within 24 h affording the product in excellent yield
(98%), diastereoselectivity (d.r.>99:1), and high
enantioselectivity (83% ee; Table 1, entry 22).
10
11
12
13
14
15
16
17
18
19
20
21
22[e]
19
19
51
32
9
10
11
12
13
14
15
16
17
15
51:49
>99:1
99:1
>99:1
>99:1
95:5
2
À63
70
77
83
29
26
>99:1
>99:1
83
[a] The reactions were performed on a 0.25 mmol scale of N-Boc-protected oxindole
1a using nitrostyrene 2a (1.2 equiv) and catalyst (20 mol%) in solvent (5.0 mL).
[b] Yields of isolated product. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] Not determined. [e] Carried out with 10 mol% catalyst.
After optimizing the reaction conditions we start-
ed to evaluate the substrate scope of this reaction
was obtained in a low yield (21%) and with inverse stereo-
selectivities (d.r.=33:46, À6% ee), indicating that the fea-
ture of the aromatic ring of the catalyst showed influence on
both its catalytic activity and selectivity (Table 1, entry 6).
To improve the enantioselectivity we conducted the reaction
at À608C in a mixture of chloroform/dichloromethane (4:1),
which gave the product after 24 h in higher stereoselectivi-
ties (d.r.=98:2, 52% ee) without decrease of the yield
(98%; Table 1, entry 7). Next, a brief solvent screening was
undertaken at À608C by using (S)-diphenyl prolinol TMS-
ether 4 as catalyst. Unfortunately, no improved enantiose-
lectivity was acquired. In the case of ethyl acetate as solvent
the product was obtained in a high yield (82%) and diaste-
reoselectivity (d.r.=95:5), whereas the reaction in methanol
was nearly shut down (Table 1, entries 8 and 9). In the other
solvents both the diastereomeric ratios and enantiomeric ex-
cesses decreased to a low level (d.r.=66:34–51:49, 8–
19% ee; Table 1, entries 10–12).
Subsequently, we investigated how the substituents on the
catalyst influence the outcome of this reaction. At first we
varied the protective group of the alcohol moiety of the cat-
alyst. In the case of the catalyst 9 bearing a less bulky me-
thoxy group, an almost identical result was obtained (97%,
d.r.>99:1, 51% ee) in comparison to its TMS analogue
(Table 1, entry 13). Employing the more sterically demand-
ing (S)-diphenyl prolinol TBDPS-ether 10 as catalyst result-
ed in a drop of both diastereo- and enantioselectivity (d.r.=
93:7, 32% ee; Table 1, entry 14). In the next instance the re-
action was carried out under the catalysis of benzyl-protect-
ed (S)-diphenyl prolinol TMS-ether 11. In this case only
traces of product were formed indicating that the secondary
by varying the structure of both N-Boc-protected oxindoles
1 and nitroolefins 2. Generally, all the reactions were com-
pleted within 24 h at À608C under the catalysis of TMS-di-
dodecyl prolinol ether 15 affording the products consistently
in high to excellent yields (88–98%) and excellent diastereo-
selectivities (d.r. 98:2–>99:1; Table 2). In the case of 3-ary-
loxindoles, the substituents at the C5 position of the indole
ring appeared to influence the level of stereoselectivities.
When the oxindole 1a,b were used as precursors, the prod-
ucts 3a–c were obtained with good enantioselectivities (82–
84% ee), whereas in the case of 5-methoxy-3-phenyl oxin-
dole 1c, the reaction afforded the product 3d with virtually
complete asymmetric induction (>99% ee). When 3-benzyl
oxindoles 1d–h were reacted as nucleophiles with various
aromatic and heteroaromatic nitroalkenes 2a–d, the reac-
tions proceeded well and provided the products 3e–l in ex-
cellent diastereo- and enantioselectivities (d.r.=98:2–>
99:1, 91–97% ee). Moreover, 3-methyl oxindole 1i was also
found to be an active precursor for the Michael addition to
nitrostyrene 2a furnishing the product 3m in a high yield
(88%), excellent diastereomeric ratio (d.r.>99:1) and good
enantiomeric excess (83% ee). A limitation of this reaction
was observed in the case of aliphatic nitroolefin 2e, which
did not react with the oxindole 1d even at room tempera-
ture.
The relative and absolute configuration of 3e and 3m was
assigned to be S for the quaternary center and R for the ter-
tiary center by comparing their NMR spectra and optical ro-
tations with the corresponding analyses reported in the liter-
ature.[13] The configuration of the other products was de-
duced assuming a uniform reaction pathway.
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4833

D. Enders et al.
Table 2. Yields and stereoselectivities of the Michael addition of N-Boc
oxindoles 1 to nitroalkenes 2.[a]
chain of the catalyst so that the nitroalkene approaches the
oxindole favorably from its Si face.
Furthermore, we have also investigated the application of
the pyrrolidine catalyst 15 in other Michael additions. Two
examples were shown in Scheme 2. In the case of N-phenyl
3
R1
R2
R3
Yield d.r.[c]
[%][b]
ee
[%][c]
a
b
c
d
e
e[d]
f
g
h
i
j
k
l
m
n
CH3
CH3
H
Ph
Ph
Ph
Ph
2-furyl
Ph
p-CH3C6H4 97
Ph
Ph
p-FC6H4
p-CH3C6H4 92
2-furyl
Ph
98
98
96
>99:1
83
84
82
>99
97
97
97
91
94
92
92
92
91
83
–
98:2
>99:1
>99:1
>99:1
>99:1
>98:2[e]
>98:2[e]
98:2
98:2
99:1
99:1
99:1
OCH3 Ph
H
H
H
H
H
H
H
H
H
H
H
Bn
Bn
Bn
Bn
98
98
91
Bn
95
98
98
98
97
88
0
m-FC6H4CH2
Scheme 2. Michael additions catalyzed by didodecyl prolinol TMS-ether
15.
p-MeOC6H4CH2 Ph
p-CH3C6H4CH2 Ph
piperonylmethyl Ph
Me
Bn
Ph
nPr
>99:1
–
maleimide 18 as the Michael acceptor and the oxindole 1h
as the nucleophile, the reaction proceeded well at À608C af-
fording the product 19 in an excellent yield (98%), diaste-
reomeric ratio (d.r.> 99:1) and high enantioselectivity
(89% ee). Additionally, the Michael addition involving pyra-
zinone 20 and nitrostyrene 2a could also be efficiently cata-
lyzed by the didodecyl prolinol TMS-ether 15 giving the
adduct 21 in a high yield (86%) and moderate enantioselec-
tivity (50% ee).
In summary, we have developed a secondary amine-cata-
lyzed asymmetric Michael addition of N-Boc-protected ox-
indoles to nitroolefins. This process was efficiently promoted
by didodecyl prolinol TMS-ether through a Brønsted base
activation mode furnishing the products in excellent yields
(88–98%), diastereoselectivities (d.r.=98:2–>99:1), and
with high to excellent enantioselectivities (82–>99% ee).
Remarkably, this catalyst was found to be active in other
Michael additions, which will be reported in due course. Fur-
thermore, applications of the Brønsted base activation mode
of secondary amines with other nucleophile and electrophile
combinations are also ongoing in our laboratories.
[a] The reactions were performed on a 0.25 mmol scale of N-Boc-protect-
ed oxindoles 1 using nitroalkenes 2 (1.2 equiv) and catalyst 15 (10 mol%)
in a mixture of chloroform/dichloromethane (4:1; 5.0 mL). [b] Yields of
isolated product. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] Carried out on a 1 mmol scale. [e] d.r. of isolated product de-
1
termined by using H NMR spectroscopy.
A proposed transition state of this reaction is illustrated
in Figure 1, in which the pyrrolidine catalyst activates both
the oxindole in its enol form and the nitro group of the Mi-
chael acceptor through hydrogen bonds. The Re face of the
prochiral Ca of the oxindole is shielded by the bulky side
Experimental Section
General procedure for the Michael addition of N-Boc oxindoles to nitro-
olefins: Nitroolefins 2 (0.30 mmol) were added to a solution of 3-substi-
tuted N-Boc oxindoles 1 (0.25 mmol) and didodecyl prolinol TMS-ether
15 (10 mol%) in a mixture of chloroform/dichloromethane (4:1; 5 mL) at
À60C8. After stirring for 24 h the solvent was removed in vacuum and
the residue was purified by flash column chromatography on silica gel
Figure 1. Proposed favored transition state of the Michael addition of N-
Boc-protected oxindoles 1 to nitroalkenes 2.
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Asymmetric Michael Addition
COMMUNICATION
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Acknowledgements
We thank the former Degussa AG and the BASF SE for the donation of
chemicals.
Keywords: asymmetric synthesis · Brønsted bases · Michael
addition · organocatalysis · oxindoles
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[13] For a detailed information about the determination of the configura-
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Received: January 9, 2012
Published online: March 20, 2012
Chem. Eur. J. 2012, 18, 4832 – 4835
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4835