An amine sulfonamide organocatalyst for promoting direct, highly enantioselective α-aminoxylation reactions of aldehydes and ketones

Article abstract of DOI:10.1016/j.tetlet.2004.08.029

A novel, pyrrolidine sulfonamide-based organocatalyst has been developed and used to catalyze direct, efficient and α-aminoxylation reactions of aldehydes and ketones with excellent regio- and enantioselectivities. Unlike l-proline, the new catalyst exhib

Full text of DOI:10.1016/j.tetlet.2004.08.029

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7235–7238
An amine sulfonamide organocatalyst for promoting direct, highly
enantioselective a-aminoxylation reactions of aldehydes and ketones
a,
Wei Wang, Jian Wang, Hao Li and Lixin Liao
a
a
b
*
a
Department of Chemistry, University of New Mexico, Albuquerque, NM 87131-0001, USA
Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, South Beijing road 40-1, Urumqi 830011, China
b
Received 20 July 2004; accepted 5 August 2004
Available online 21 August 2004
Abstract—A novel, pyrrolidine sulfonamide-based organocatalyst has been developed and used to catalyze direct, efficient
a-aminoxylation reactions of aldehydes and ketones with excellent regio- and enantioselectivities. Unlike L-proline, the new catalyst
exhibits high activity and enantioselectivity when used in a variety of organic solvents.
Ó 2004 Elsevier Ltd. All rights reserved.
The development of efficient, stereoselective catalytic
reactions, which can be used to construct optically active
a-hydroxy carbonyl compounds, has continued to at-
tract considerable synthetic interest. A number of dia-
stereoselective and enantioselective methods for the
synthesis of these substances have been reported. Most
employ indirect approaches, requiring preformation of
enolates and enolate equivalents from the corresponding
we have recently initiated an investigation aimed at
designing novel small organic catalysts capable of pro-
moting highly stereoselective organic reactions on a
1
5–17
number of structurally diverse organic substrates.
In this communication, we report the results of a study,
which has led to the development of a novel (S)-pyrrol-
idine sulfonamide based organocatalyst for direct a-
aminoxylation reactions of aldehydes and ketones with
high regio- and enantioselectivities (>97% ee) in good
yields.
1
ketones and aldehydes. From the viewpoint of econ-
omy, direct a-aminoxylation reactions of aldehydes
and ketones are more attractive. Recently, an elegant
enantioselective a-oxidation reaction of tin enolates with
nitrosobenzene has been developed by Yamomoto and
The carboxylic acid proton in proline plays a critical role
in enhancing the reactivity and stereoselectivity of pro-
2
4,18
his co-workers. Based on the observations, MacMillan,
line based catalyst.
known to be ineffective in catalyzing reactions (Fig.
In contrast, L-prolinamide is
Zhong, Cordova, and Hayashi, independently uncov-
ered direct, nitrosobenzene based, proline-catalyzed
enantioselective a-aminoxylation reactions of aldehydes
1
8
1). The acidity of NH protons in L-prolinamide is
much less than that of a carboxyl group in proline
and, as a result, the significant difference in catalytic
activity between these two substances is likely due to
their different acidity. We hypothesized that increasing
the acidity of the NH amide protons would lead to a
significant enhancement in the catalytic activity of L-prol-
3
,4
and ketones.
Inspired by the pioneering work of List, Barbas, III and
5
Learner, proline has received considerable attention in
recent years as the foundation of small organic mole-
6
cule-based organocatalysts for asymmetric synthesis.
inamide. It is known that the pK of trifluoromethane-
a
Surprisingly, however, relatively few efficient organocat-
alysts other than chiral amino acids have been probed
for use in asymmetric organic transformations including
sulfonamide in wateris 6.3, which is compa ra ble to that
3
,4,6–14
a-aminoxylations.
As a result of this deficiency,
O
O
O
S
CF3
OH
NH
2
NH
N
H
N
H
O
N
H
Keywords: Asymmetric catalysis; Aldehydes; Ketones; a-Aminoxyl-
ation; Pyrrolidine sulfonamide.
I
proline
L-prolinamide
*
Corresponding author. Tel.: +1 505 277 0756; fax: +1 505 277
609; e-mail: wwang@unm.edu
2
Figure 1. A pyrrolidine sulfonamide-based organocatalyst I.
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.029

7236
W. Wang et al. / Tetrahedron Letters 45 (2004) 7235–7238
1
9
of acetic acid (pKa of 4.76). However, in DMSO,
trifluoromethanesulfonamide has an even greater acidity
(
Table 2. Catalyst I catalyzed direct a-aminoxylation reactions of
different ketones
1
9
pK of 9.7) than that of acetic acid (pK 12.3). With
a a
O
O
O
N
these observations in mind, we envisioned that incorpo-
ration of trifluoromethanesulfonamide moiety into a
pyrrolidine system would create a new class of amine–
sulfonamide bifunctional organocatalysts that could
function in the same way as proline in catalyzing organic
reactions.
catalyst I (20% mol)
ONHPh
+
Ph
R1
R2
RT, DMSO
R1
R2
1a-d
2
3a-d
a
b
Entry
Product
% Yield
% ee
O
The first generation catalyst in this family, I (Fig. 1) con-
tains a primary trifluoromethanesulfonamide group
linked to a chiral pyrrolidine backbone. The pyrrolidine
sulfonamide I is readily prepared from (S)-2-amino-1-N-
Cbz-pyrrolidine by using a known reaction sequence
1
84
>99
>99
1a
O
O
8
6
2
0
2
3
(
see Supplementary data). Preliminary studies showed
1b
that I effectively catalyzed nitrosobenzene induced
a-aminoxylation reactions of aldehydes and ketones
with comparable and, in some cases, even greater activ-
ity and efficiency than does proline.
O
1c
94
98
O
O
O
In an exploratory study, the reaction of cyclohexanone
1
of catalyst I at room temperature was carried out in dif-
ferent solvents. The results revealed that I exhibited a
high catalytic efficiency in its promotion of high yielding
a with nitrosobenzene 2 in the presence of 20mol%
4
71
97
1d
ee Determined by chiral HPLC analysis (Chiralpak AD or AS-H).
6
2–85%, a-aminoxylation reactions, that proceeded with
a
Isolated yields.
excellent enantioselectivities (>99% ee) and high regio-
selectivities (Table 1). Independent of the solvent used,
the reactions were completed in 20min and they
afforded O-addition product 3a exclusively. In contrast,
solvents had a significant effect on proline-catalyzed
a-aminoxylation reaction yields and enantioselectivi-
b
fourcyclic and acyclic ketones p ro moted by 20mol%
I
are given in Table 2. These processes took place
smoothly to give O-addition products exclusively in
good yields and with high enantioselectivities. As with
cyclohexanone, cyclic ketones 1b,c, and acyclic ketone
3
a,b,d
ties.
Based on this exploratory study, DMSO was
selected as a solvent forthe studies desc ri bed below.
1
d gave adducts 3b–d in high yields (86%, 94% and
To demonstrate the generality of direct a-aminoxyla-
tions catalyzed by I, reactions of a variety of ketone sub-
strates with nitrosobenzene in DMSO at room
temperature were explored. The results of reactions of
71%, respectively) with excellent enantioselectivities
(>99%, 98% and 97%, respectively). The effect of cata-
lyst loading on reaction efficiency was also studied using
1a and 2 as an example. Remarkably, a catalyst loading
as low as 1.0mol% still led to significantly fast reaction
2
1
without any loss of enantioselectivity (>99% ee).
Table 1. Effect of solvents on the asymmetric a-aminoxylation
reactions
a
a-Aminoxylation reactions of nitrosobenzene with alde-
hydes, catalyzed by I, were probed next. Under the same
reaction conditions described above, efficient reaction
occurred within 0.5h following slow addition of nitroso-
benzene (Table 3). Owing to theirinstability, the alde-
hyde O-addition products were reduced by NaBH4
in situ to produce the more stable 2-aminoxy alcohols
O
O
O
N
catalyst I (20% mol)
ONHPh
+
Ph
RT, 20 min, solvent
1a
2
3a
b
c
Entry
Solvent
DMSO
% Yield
% ee
3
b
3
e–i prior to purification and characterization. Again,
1
2
3
4
5
6
84
85
62
77
66
76
>99
>99
>99
>99
>99
>99
reactions resulted in efficient (66–81%), highly regio- and
enantioselective (>99% ee) formation of O-addition
products (Table 3).
CHCl
DMF
THF
3
3
CH CN
EtOAc
A similar tar nsition-state model
II to that used to
rationalize proline-catalyzed a-aminoxylation reactions
of ketones and aldehydes can be used to explain the
regio- and stereochemical courses of the processes cata-
a
Reaction conditions: A solution of 2 (2equiv) in DMSO was added
by a syringe pump over 10min to a solution of 1a (1equiv) and I
(0.2equiv) in DMSO and the reaction was continued for an addi-
3
b–d
lyzed by I (Fig. 2).
In this model, the enamine
tional 10min (see Supplementary data).
Isolated yields.
Enantiomeric excess (ee) determined by chiral HPLC analysis
b
c
formed by reaction of (S)-pyrrolidine sulfonamide I with
the enolizable ketone oraldehyde is attacked by nit ro -
sobenzene from the less hindered Si face through a chair
(Chiralpak AD).

W. Wang et al. / Tetrahedron Letters 45 (2004) 7235–7238
7237
References and notes
Table 3. Catalyst I catalyzed direct a-aminoxylation of different
aldehydes
1
. Reviews of hydroxylation: (a) Davis, F. A.; Chen, B. C. In
Houben Weyl: Methods of Organic Chemistry; Helmchen,
G., Hoffman, R. W., Mulzer, J., Schaumann, E., Eds.;
Georg Thieme: Stuttgart, 1995; Vol. E 21, p 4497; (b)
Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919–
934.
O
OH
O
N
1
) catalyst I (20% mol)
ONHPh
H
+
Ph
2
) NaBH4
R1
1
R1
3e-i
e-i
2
2
3
. (a) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc.
2003, 125, 6038–6039; (b) Momiyama, N.; Yamamoto, H.
J. Am. Chem. Soc. 2004, 126, 5360–5361.
. Aldehydes as substrates: (a) Brown, F. J.; Brochu, M. P.;
Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003,
a
b
Entry
R
1
% Yield
% ee
1
2
3
4
5
i-Pr, 1e
CH , 1f
81
66
73
74
79
>99
>99
>99
>99
>99
3
n-Pr, 1g
n-Bu, 1h
1
2
25, 10808–10809; (b) Zhong, G. Angew. Chem., Int. Ed.
003, 42, 4247–4250; Ketones as substrates: (c) Bøgevig,
2
PhCH , 1i
A.; Sunden, H.; C o´ rdova, A. Angew. Chem., Int. Ed. 2004,
3, 1109–1112; (d) Hayashi, Y.; Yamaguchi, J.; Sumiya,
a
Isolated yields.
ee Determined by chiral HPLC analysis (Chiralpak AD or AS-H).
4
b
T.; Shoji, M. Angew. Chem., Int. Ed. 2004, 43, 1112–1115.
. During the manuscript preparation, Yamamoto and co-
workers reported a pyrrolidine tetrazole catalyzed the
reaction: Momiyama, N.; Torii, H.; Saito, S.; Yamamoto,
H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5374–5378.
4
O
N
5. List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem.
Soc. 2000, 122, 2395–2396.
Ph N
R1
H
S
N
O
CF3
O
6
. For a review of proline-catalyzed asymmetric transforma-
tions, see: List, B. Tetrahedron 2002, 58, 5573–5590.
. Fora re view of amino acids and peptides as catalysts, see:
Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481–
II
R
2
7
Figure 2. Proposed transition-state model for a-aminoxylation
reactions.
2
. For a review on amine-catalyzed reactions, see: France, S.;
495.
8
Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev. 2003,
1
03, 2985–3012.
9
. For a general review on organocatalysis, see: Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726–3748,
and references cited therein.
transition state to afford the O-addition product enan-
tioselectively. The CF SO -group may also play a role
in controlling the stereochemistry of the process by
offering further interference for attack at the Re face.
A detailed study probing this proposal is under current
investigation.
3
2
1
1
0. Fora er view on Shi ketone-based epoxidation catalyst,
see: Frohn, M.; Shi, Y. Synthesis 2000, 1979–2000, and
reference cited therein.
1. Forexamples using MacMillan catalyst, see: (a) Ah re ndt,
K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243–4244; (b) Jen, W. S.; Wiener, J. J. M.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874–
In conclusion, a novel pyrrolidine sulfonamide catalyst
I, which promotes direct, highly efficient a-aminoxyl-
ation reactions of aldehydes and ketones with nitroso-
benzene, has been developed. This catalyst displays
excellent levels of enantioselectivity for re actions of ke-
tones (>97% ee) and aldehydes (>99% ee). Furthermore,
it also exhibits high catalytic activities and enantioselec-
tivities when used in a wide variety of organic solvents.
Further efforts to evaluate the scope of the a-aminoxyl-
ation reactions described above and to explore other or-
ganic transformations using new types of catalysts are
9
875; (c) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2001, 123, 4370–4371; (d) Austin, J. F.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 1172–
1
173; (e) Northrup, A. B.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2002, 124, 2458–2459; (f) Paras, N.
A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
7
894–7895; (g) Brown, S. P.; Goodwin, N. C.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2003, 125, 1192–1193; (h)
Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2004, 126, 4108–4109.
1
7
underway.
12. For results from Jørgenson and his group, see: (a)
Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org.
Chem. 2002, 67, 8331–8338; (b) Halland, N.; Aburel, P. S.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 661–
Acknowledgements
6
65; (c) Bernardi, L.; Gothelf, A. S.; Hazell, R. G.;
This research was supported by start-up funds from the
Department of Chemistry, University of New Mexico.
We thank Professor Patrick S. Mariano for making crit-
ical editorial comments about the manuscript.
Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583–2591; (d)
Melchiorre, P.; Jørgensen, K. A. J. Org. Chem. 2003, 68,
4
151–4157; (e) Juhl, K.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2003, 42, 1498–1501; (f) Halland, N.; Hansen, T.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 4955–
4
3. Forexamples using Jacobsen thiou er a catalyst, see: (a)
957.
1
Supplementary data
Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
4
102–4103; (b) Wenzel, A. G.; Jacobsen, E. N. J. Am.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2004.08.029.
Chem. Soc. 2002, 124, 12964–12965; (c) Vachal, P.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012–
10013.

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W. Wang et al. / Tetrahedron Letters 45 (2004) 7235–7238
1
4. ForOtherexamples, see: (a) Huang, Y.; Unni, A. K.;
Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146; (b)
Evans, C. A.; Miller, S. J. J. Am. Chem. Soc. 2003, 125,
18. Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F. J. Am.
Chem. Soc. 2001, 123, 5260–5261.
19. (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463; (b)
Bordwell, F. G.; Branca, J. C.; Hughes, D. L.; Olmstead,
W. N. J. Org. Chem. 1980, 41, 3305–3313; (c) Bordwell, F.
G.; Algrim, D. J. Org. Chem. 1976, 41, 2507–2508.
20. Recently we have developed a more efficient 3-step
synthesis of the catalyst from commercially available N-
Cbz-L-prolinamide instead of 6-step from N-Cbz-L-Pro-
line reported in the patent: Burch, R. M.; Patch, R. J.;
Shearer, B. G.; Perumattam, J. J.; Natalie, K. J., Jr. WO
Patent 9203415, 1992.
12394–12395; (c) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.;
Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am.
Chem. Soc. 2003, 125, 5262–5263; (d) Torii, H.; Nakadai,
M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem.,
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1
1
1
5. We recently reported a L-prolinamide catalyzed a-selen-
enylation of aldehydes: Wang, W.; Wang, J.; Li, H. Org.
Lett. 2004, 6, 2817–2820.
6. This catalyst can catalyze the Mannich-type reactions:
Wang, W.; Wang, J.; Li, H. Tetrahedron Lett., accepted
forpublication. doi:10.1016/j.tetlet.2004.08.032.
21. 20mol% I: 15min, 84% yield, >99% ee; 10mol% I: 30min,
80% yield, >99% ee; 5mol% I: 50min, 72% yield, >99% ee;
2mol% I: 2.5h, 70% yield, >99% ee; 1mol% I: 6.5h, 64%
yield, >99% ee.
7. We have found this catalyst can efficiently facilitate the
asymmetric Aldol and Michael addition reactions.