Direct asymmetric Michael addition of cyclic N-sulfonylimines to α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/chem.201002592

As traditional electrophiles, imines have been extensively applied in Mannich-type reactions for the synthesis of amine compounds. On the other hand, owing to the electronwithdrawing character of the imine functionality, the α-protons of imines also show some acidity; thus, imines tend to act as nucleophiles for α-functionalization reactions, although stoichiometric amounts of strong base are usually required. It is expected that the acidity of the a-protons of imines would be greatly increased in compounds that have highly electron-withdrawing substituents on the nitrogen atom; therefore, the direct-type reactions of imines might be realized under mild catalytic conditions. Indeed, in 2008, Kobayashi and co-workers proved this synthetic possibility in the direct Mannich reaction of the N-tosylimine of acetophenone with an activated imine by the catalysis of simple Net₃ ; unfortunately, its applicability is limited due to tautomerization and elimination of the functional groups in the products.As a consequence, the structurally more stable tautomers of imines, enecarbamates and enamides, are generally selected and utilized as the nucleophiles, and have been well explored by Kobayashi and other groups over the past few years, through the catalysis of either metal-based or organic molecules

Full text of DOI:10.1002/chem.201002592

DOI: 10.1002/chem.201002592
Direct Asymmetric Michael Addition of Cyclic N-Sulfonylimines to
a,b-Unsaturated Aldehydes
Xiao-Feng Xiong,[a] Hang Zhang,[a] Jing Peng,[a] and Ying-Chun Chen*[a, b]
As traditional electrophiles, imines have been extensively
applied in Mannich-type reactions for the synthesis of amine
compounds.[1] On the other hand, owing to the electron-
withdrawing character of the imine functionality, the a-pro-
tons of imines also show some acidity; thus, imines tend to
act as nucleophiles for a-functionalization reactions, al-
though stoichiometric amounts of strong base are usually re-
quired.[2] It is expected that the acidity of the a-protons of
imines would be greatly increased in compounds that have
highly electron-withdrawing substituents on the nitrogen
atom; therefore, the direct-type reactions of imines might be
realized under mild catalytic conditions. Indeed, in 2008,
Kobayashi and co-workers proved this synthetic possibility
in the direct Mannich reaction of the N-tosylimine of aceto-
phenone with an activated imine by the catalysis of simple
NEt3; unfortunately, its applicability is limited due to tauto-
merization and elimination of the functional groups in the
products.[3] As a consequence, the structurally more stable
tautomers of imines, enecarbamates and enamides, are gen-
erally selected and utilized as the nucleophiles, and have
been well explored by Kobayashi and other groups over the
past few years, through the catalysis of either metal-based[4]
or organic molecules.[5]
imines as direct nucleophiles in asymmetric synthesis, such
as the first Michael addition to a,b-unsaturated aldehydes,
might be realized by iminium catalysis with chiral secondary
amines 1,[7] as outlined in Scheme 1.
Scheme 1. Reversal of the reactivity of cyclic N-sulfonylimines: direct Mi-
chael addition to a,b-unsaturated aldehydes; TMS=trimethylsilyl, TES=
triethylsilyl, Bn=benzyl.
The study began with the reaction of cyclic N-sulfonyl-
AHCTUNGTREGiNNNU mine 2a with crotonaldehyde 3a by using the catalysis of
a,a-diphenylprolinol O-TMS ether 1a (10 mol%) and 4-ni-
trobenzoic acid (PNBA, 10 mol%) in THF at room temper-
ature. Fortunately, the desired Michael addition proceeded
smoothly, and adduct 4a was isolated in high yield with
moderate diastereoselectivity and a good ee value (Table 1,
entry 1). Solvent screenings showed that inferior results
were obtained in CH3CN and DMF (Table 1, entries 2 and
3), and that almost no reaction occurred in toluene or
CH2Cl2 (Table 1, entries 4 and 5). Acid additives were inves-
tigated next. Lower stereoselectivity was observed if o-fluo-
robenzoic acid (OFBA) was applied (Table 1, entry 6); for-
tunately, the enantioselectivity was greatly improved in the
presence of benzoic acid (BA, Table 1, entry 7). However,
slightly inferior stereocontrol was observed if AcOH was
used (Table 1, entry 8).
Subsequently, additional secondary amine catalysts were
tested. Better results could not be obtained by utilizing the
catalysis of the more bulky 1b and c[8] (Table 1, entries 9
and 10), and free a,a-diphenylprolinol 1d and the MacMil-
lan catalyst 1e afforded no conversion (Table 1, entries 11
and 12). Gratifyingly, the Michael addition still completed at
08C within 24 h and excellent enantioselectivity and a good
d.r. were delivered (Table 1, entry 13), even at a higher con-
centration (Table 1, entry 14). Finally, we found that the dia-
stereomeric mixture 4a could be efficiently transformed into
Cyclic N-sulfonylimines, which can be easily prepared
from the abundant, commercially available industrial mate-
rial saccharin, have long been employed in organic synthesis
as electrophiles.[6] They are more stable than the acyclic N-
sulfonylimines and are not likely to tautomerize to their cor-
responding enamides. Moreover, the a-protons are expected
to have lower pKa values owing to the strong electron-with-
drawing effect of the N-sulfonyl group. As a result, we envi-
sioned that the application of saccharin-derived cyclic
[a] X.-F. Xiong, H. Zhang, J. Peng, Prof. Dr. Y.-C. Chen
Key laboratory of Drug-Targeting and
Drug Delivery System of the Education Ministry
Department of Medicinal Chemistry
West China School of Pharmacy
Sichuan University, Chengdu, 610041 (P.R.China)
Fax : (+86)2885502609
E-mail: ycchenhuaxi@yahoo.com.cn
[b] Prof. Dr. Y.-C. Chen
State Key Laboratory of Biotherapy
West China Hospital, Sichuan University
Chengdu, 610041 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002592.
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Chem. Eur. J. 2011, 17, 2358 – 2360

COMMUNICATION
Table 1. Screening studies of the asymmetric reaction of cyclic N-
sulfonyl
imine 2a and crotonaldehyde 3a.[a]
Table 2. Substrate scope and limitations.[a]
ACHTUNGTRENNUNG
Entry
2
R
R1
R2
t [h][b] Yield [%][c] ee [%][d]
1
2
2a
2b
2c
2d
2e Cl
2 f
2a
2a
2a
2d
2d
2d
2d
2d
2d
H
H
H
H
nPr Me
20
20
8
24
36
24
30
36
36
5a, 73
5b, 73
5c, 68
5d, 67
5e, 66
5 f, 63
5g, 70
5h, 68
5i, 65
5j, 55
5k, 55
5l, 51
5m, 48
5n, 50
5o, 60
97
96
65
75
93
96
96
99
97
89
90
90
93
89
90
Bn
Ph
H
Me
Me
Me
3[e]
4
5[f]
6
7
8
9
10
11
12
13
14
15
nPr Me
Entry
1
Acid
Solvent
Yield [%][b]
d.r.[c]
ee [%][d]
tBu nPr Me
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1a
1a
1a
PNBA
PNBA
PNBA
PNBA
PNBA
OFBA
BA
AcOH
BA
BA
BA
TFA
BA
BA
BA
THF
90
85
87
–
3.9:1
3.6:1
3.8:1
–
80
71
77
–
H
H
H
H
H
H
H
H
H
nPr Et
nPr nPr
nPr nBu
MeCN
DMF
toluene
CH2Cl2
THF
THF
THF
THF
THF
THF
THF
THF
THF
H
H
H
H
H
H
PhS
Ph
m-ClC6H4
p-MeC6H4
2-furyl
ACHTUNGTRENNUNG
–
–
–
90
88
86
90
85
–
2.6:1
4.0:1
3.2:1
3.0:1
5.1:1
–
75
92
87
92
85
–
18
28
18
24
2-thienyl
10[e]
11
12
13[f]
14[f,g]
15[f,g]
[a] Unless otherwise stated, the reactions were performed with
2
(0.1 mmol), 3 (0.15 mmol), 1a (10 mol%), and benzoic acid (10 mol%)
in THF (0. 6 mL) at 08C. Then a tandem process was conducted to give
tricyclic compounds 5. [b] For the first Michael addition step. [c] Isolated
yield of 5 after the three steps. [d] Based on chiral HPLC analysis. [e] At
À408C. [f] At À208C, 1b (10 mol%) as the catalyst.
–
–
–
90
90
73[h]
5.9:1
5.7:1
–
96
97
97[h]
THF
[a] Unless otherwise stated, the reactions were performed with 2a
(0.1 mmol), 3a (0.15 mmol), 1 (10 mol%), and acid (10 mol%) in solvent
(1.0 mL) in less than 24 h. [b] Isolated yield of diastereomeric 4a. [c] By
1H NMR analysis. [d] Based on chiral HPLC analysis after derivation
(major isomer), see the Supporting Information. [e] For 40 h. [f] At 08C.
[g] In solvent (0.6 mL). [h] Data refers to tricyclic product 5a.
enals containing a b-branched alkyl group. Finally, some
enals with b-aryl or -heteroaryl substituents were studied in
the reaction with simple methyl imine 2d, and high enantio-
selectivity was generally achieved (Table 2, entries 11–15).
We conducted some further intriguing syntheses with the
multifunctional Michael adducts 4. Although the attempted
intramolecular cross-coupling reaction between imine and
aldehyde groups failed under nBu3SnH/azobisisobutyroni-
trile-mediated radical conditions,[10] it was found that the
imine group can be chemoselectively reduced to afford dia-
stereomeric mixture 6, after a domino cyclization, which was
smoothly dehydroxylated to give enantiopure piperidine de-
rivative 7a (Scheme 2). Following this strategy, we utilized
simple acrolein to prepare chiral product 7b, which has no
substitution at the 4-position of the piperidine ring, although
the enantioselectivity was moderate. In addition, we applied
Yoon’s Ru-based photoredox catalytic method to Wittig-re-
action derivative 8 that was formed from adduct 4b.[11] The
imine group still seems to be more electrophilic and reac-
tive, and complicated piperidine derivative 9 (its absolute
structure has been unambiguously determined by X-ray
crystallographic analysis)[12] and its diastereomer 9’ were
generated,[13] which were converted to a single product 10
after simple dehydration.
a single tetrahydropyridine 5a by a tandem 1,8-diazabicyclo-
ACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU)-catalyzed tautomerization/hemia-
minal formation/dehydroxylation process without affecting
the high enantiopurity (Table 1, entry 15).
With the optimal reaction conditions in hand, we then ex-
amined the scope and limitations of the new organocatalytic
asymmetric transformations. In general, the direct Michael
addition of cyclic N-sulfonylimines 2 to a,b-unsaturated al-
dehydes 3 was conducted at 08C in THF by the catalysis of
1a and benzoic acid. Then, the tandem sequence was per-
formed to deliver tricyclic materials 5, which are more easily
analyzed. The results are summarized in Table 2. Initially,
some cyclic imines 2 were tested in the reaction with croto-
naldehyde 3a. Excellent enantioselectivity was obtained for
imine 2b, containing an a-benzyl group (Table 2, entry 2).
a-Phenyl-substituted imine 2c exhibited high reactivity,
even at À408C, but only a moderate ee could be obtained
(Table 2, entry 3). Modest enantioselectivity was also at-
tained for methyl imine 2d (Table 2, entry 4). The substitu-
tion effect on the aryl ring of cyclic imines was explored,
and good results were achieved for 2e and f (Table 2, en-
tries 5 and 6).[9] Subsequently, an array of a,b-unsaturated
aldehydes were investigated. Outstanding ee values were ob-
tained for other linear alkyl-substituted enals (Table 2, en-
tries 7–9), as well as for a functionalized substrate (Table 2,
entry 10). Unfortunately, poor reactivity was observed for
In conclusion, we have demonstrated that the electrophil-
ic reactivity of the traditional cyclic N-sulfonylimines can be
reversed, as exemplified in the first direct asymmetric Mi-
chael addition reaction of these compounds to a,b-unsatu-
rated aldehydes, by employing the iminium catalysis of a
chiral secondary amine. The subsequent base-mediated
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www.chemeurj.org
2359

Y.-C. Chen et al.
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azobisisobutyronitrile, DIPEA=N,N-diisopropylethylamine, bpy=2,2’-bi-
pyridine.
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imine group tautomerization/hemiaminal formation/dehy-
droxylation process efficiently delivered tricyclic piperidine
derivatives in moderate to excellent enantioselectivity (up
to 99% ee). We believe that these cyclic N-sulfonylimines
could be applied in more direct asymmetric reactions with
other electrophiles under mild conditions, and useful nitro-
gen-containing chiral products with molecular diversity
would be accessible. The results of our investigations to that
end will be reported in due course.
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11, 2848–2851.
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ref. [6c] did not react.
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Acknowledgements
[12] CCDC-799810 (9) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
We are grateful for the financial support from the NSFC (20772084 and
21021001), the PCSIRTC (IRT0846), and the National Basic Research
Program of China (973 Program; 2010CB833300).
[13] For a plausible reaction mechanism, see the Supporting Informa-
tion.
Keywords: aldehydes · aminocatalysis · Michael addition ·
piperidines · sulfonylimines
Received: September 8, 2010
Published online: January 17, 2011
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Chem. Eur. J. 2011, 17, 2358 – 2360