Chiral zwitterions from vicinal diamines: Effective and recoverable asymmetric enamine catalysts

Article abstract of DOI:10.1055/s-0030-1259512

A series of chiral zwitterionic vicinal diamines were designed and synthesized. The zwitterionic catalysts demonstrated good reactivity and enantioselectivity in asymmetric enamine-based transformations and could be readily recycled and reused for four ti

Full text of DOI:10.1055/s-0030-1259512

CLUSTER
495
Chiral Zwitterions from Vicinal Diamines: Effective and Recoverable
Asymmetric Enamine Catalysts
Recoverable
A
sym
u
metric Enam
p
ine Catalyst
u
s
Qiao, Long Zhang, Sanzhong Luo,* Jin-Pei Cheng
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. of China
Fax +86(10)62554446; E-mail: luosz@iccas.ac.cn
Received 28 October 2010
ty.5 The zwitterionic-type product could be easily purified
via a simply filtration–wash procedure and no chromatog-
raphy was needed in this process. Unlike the chiral
amine–Brønsted acid conjugates which are often syrup-
type materials, the chiral zwittertions are obtained as
white powders and can be conveniently handled.6 In addi-
tion, the zwitterions are barely soluble in less polar sol-
vent such as diethyl ether, ethyl acetate, and THF but well
soluble in high polar solvent such as DMF, DMSO, par-
ticularly the environmentally benign PEG and ionic liq-
uids, a beneficial property for biphasic catalysis.
Abstract: A series of chiral zwitterionic vicinal diamines were de-
signed and synthesized. The zwitterionic catalysts demonstrated
good reactivity and enantioselectivity in asymmetric enamine-
based transformations and could be readily recycled and reused for
four times.
Key words: chiral zwitterion, organocatalysts, enamine, catalyst
immobilization
The use of chiral amine–Brønsted acid conjugates has
been proved to be a powerful strategy for both enamine-
and iminium-based catalysis as evidenced by the preva-
lence of chiral pyrrolidine diamines in asymmetric orga-
nocatalysis.1 Recently, chiral primary amine–Brønsted
acid conjugates, particularly those from vicinal diamines,
have also been found to be viable bifunctional amino cat-
alysts for a range of transformations.2 In the typical chiral
diamine–acid conjugate systems, it has been known that
the acids not only facilitate the aminocatalytic cycle, but
also play essential role in stereocontrol with the protonat-
ed amino group normally serving as the critical H-bond
interacting moiety (Scheme 1).1d Therefore, the judicious
selections of acid, chiral amine, and their combinations
become very crucial for effective catalysis. Though en-
dowed with combinatorial flexibility, the bi-/multicompo-
nent catalytic systems pose considerable challenges for
mechanism studies and also lack of convenience for syn-
thetic manipulations. As a continuation to our effort in this
area,2,3 we herein present an alternative zwitterion strate-
gy for the amine–acid catalysis. In this strategy, the amine
and acid moieties are covalently connected and the result-
ing zwitterion would function similarly like its acid–base
ion-pair counterpart as a H-bonding donor. Our studies in-
dicate that such chiral zwitterions are indeed viable amino
catalyst with additional advantages such as readily recy-
clability and reusability due to their zwitterionic nature.
chiral amine-acid binary catalysts
N
N
⋅TfOH
NH2
N
⋅TfOH
H
this work: chiral zwitterions
covalent
connections
+H
amine
amine
X–
HX
O
O
O
zwitterion
S
acid base salt
R
+
N
R1
1,3-propanesultone
+
e.g.
N
H
–O3S
N
H
R2
N
H
H
X–
Scheme 1 Catalyst design strategy
The asymmetric direct Michael addition between isobu-
tyraldehyde and b-nitrostyrene was selected as a bench-
mark for testing our zwitterions.7 As shown in Table 1,
only trace product could be obtained with pyrrolidine-
amide catalyst 3a (Scheme 2, Table 1, entry 1). However,
when using secondary-secondary diamine zwitterions 3b
as the catalyst, the Michael product could be formed with
36% yield and 54% ee in 48 hours (Table 1, entry 2). To
our delight, significant improvements on both stereoselec-
tivity and yield were observed when using secondary-
tertiary diamine zwitterions as the catalyst (Table 1, en-
tries 3–5). The best results (24 h, 80% yield, 78% ee) were
achieved with catalyst 3e which bears an isopentyl group
(Table 1, entry 5). Compared with the common ion-pair
catalyst 4 (Table 1, entry 6), the zwitterions catalyst 3e
demonstrated a slightly higher activity while maintained
The zwitterion organocatalysts could be synthesized fol-
lowing a simple two-step procedure.4 First, the ring-open-
ing reaction of 1,3-propanesultone or 2-sulfobenzoic
anhydride and secondary amines gave the N-protected
zwitterion products which were then subject to deprotec-
tion with Pd/C to afford the final product with high puri-
SYNLETT 2011, No. 4, pp 0495–0498
x
x.
x
x.
2
0
1
1
Advanced online publication: 27.01.2011
DOI: 10.1055/s-0030-1259512; Art ID: Y11810ST
© Georg Thieme Verlag Stuttgart · New York

496
Y. Qiao et al.
CLUSTER
R
R
+
HN
R
+
–
a)
b)
–
SO3
HN
SO3
N
H
N
N
N
H
Cbz
Cbz
2
3
1
O
+
+
HN
+
N
–
–
SO3
N
SO3
N
H
H2
–O3S
N
N
H2
H
H
3c
3b
3a
O
H
+
HN
–
+
HN
+N
SO3
–O
S
–
SO3
N
N
H
N
H
H
O
4
3d
3e
Scheme 2 Reagents and conditions: a) R = H: for 3a, 2-sulfobenzoic anhydride, toluene, r.t.; for 3b, 1,3-propanesultone, toluene, r.t.;
R = alkyl group: 1,3-propanesultone, toluene, reflux; b) Pd/C, H2, MeOH–H2O (1:1).
the same enantioselectivity, thus verifying the viability of very well when using isobutyraldehyde as a donor produc-
the zwitterions catalytic strategy. Furthermore, the chiral ing the desired Michael products in high yields and good
zwitterionic catalyst could be easily recycled and reused. enantioselectivities. Both electron-rich and electron-
After each run, catalyst 3e could be recycled by precipita- deficient nitrostyrenes could be employed in this reaction.
tion with diethyl ether. The recycled catalyst was directly Cyclohexanecarboxaldehyde could also be used as the
used in the next run upon removing the residue organic Michael donor, and the Michael adduct was obtained in
solvent. It is found that the zwitterions could be reused at 90% yield with 44% ee.
least four times while maintaining high enantioselectivity
with slightly decreased activity (Table 1, entries 7–9).
O
O
Ar
R1
3e (20 mol%), r.t.
NO2
Ar
Encouraged by these results, we next examined the scope
of the reaction with a series of a,a-disubstituted aldehyde
donors and nitroolefins using catalyst 3e. The results were
summarized in Scheme 3. As shown, the reaction worked
+
H
H
NO2
[BMIM]BF4, 200 µL
R1
R2
R2
Ph
NO2
Cl
Table 1 Catalyst Screening and Recyclinga
O
O
O
O
O
Ph
catalyst (20 mol%)
[BMIM]BF4, r.t.
NO2
Ph
NO2
NO2
+
NO2
H
H
NO2
H
H
H
20 h, 93% yield, 78% ee 30 h, 91% yield, 74% ee 36 h, 90% yield, 77% ee
OMe
Entry
Catalystb
Time (h)
48
Yield (%)
trace
36
ee (%)c
–
1
3a
3b
3c
3d
3e
4
2
48
54
O
O
O
NO2
3
48
99
73
H
NO2
NO2
H
H
4
48
98
74
36 h, 91% yield, 75% ee 72 h, 80% yield, 74% ee 36 h, 90% yield, 46% ee
5
24
80
78
Scheme 3 Substrate scope of direct Michael reactions catalyzed by
chiral zwitterions
6
24
63
78
7d
8e
9f
3e
3e
3e
30
96
79
To further demonstrate the potentials of our catalysts, the
direct aldol reaction was also tested (Scheme 4). Under
the catalysis of zwitterions 3e, the aldol product could be
obtained in excellent yield and high ee when using isobu-
tyraldehyde as the donor. However, the reactions of
ketone donors demonstrated only moderate enantioselec-
tivities and diastereoselectivities, results that can be as-
cribed to the insufficient acidity of the zwitterionic
moiety.8
36
81
79
48
88
76
a Reactions conditions: aldehyde (1 mmol), nitrostyrene (0.25 mmol),
[BMIM]BF4 (200L).
b Catalyst structures are shown in Figure 1.
c Determined by HPLC analysis.
d The second reuse of the catalyst.
e The third reuse of the catalyst.
f The fourth reuse of the catalyst.
Synlett 2011, No. 4, 495–498 © Thieme Stuttgart · New York

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Recoverable Asymmetric Enamine Catalysts
497
O
O
OH
R2
O
R1
R3
R3
3e (20 mol%)
+
H
R1
R2
O
[BMIM]BF4 (200 µL), r.t.
NO2
NO2
O
OH
O
OH
OH
H
NO2
NO2
NO2
12 h, 98% yield, 88% ee
24 h, 76% yield, 53% ee
36 h, 91% yield,
anti/syn = 67:33, 66% ee (anti)
Scheme 4 Aldol reaction catalyzed by zwitterion 3e
+
–
+
–
SO3
SO3
N
NH
Cbz
N
H
H
a)
b)
N
N
Cbz
NH2
H
H
7
6
5
O
O
OH
O
7 (20 mol%)
H
PEG-200 (200 µL)
H2O (40 µL) r.t.
+
R
R
O
OH
O
OH
O
OH
NO2
CN
Ph
14 h, 98% yield,
anti/syn = 19:1, 98% ee (anti)
60 h, 99% yield,
anti/syn = 7:1, 95% ee (anti)
80 h, 75% yield,
anti/syn = 8:1, 94% ee (anti)
O
OH
O
OH Br
O
OH Cl
80 h, 67% yield,
anti/syn = 6:1, 94% ee (anti)
60 h, 88% yield,
anti/syn = 15:1, 97% ee (anti)
60 h,88% yield,
anti/syn = 14:1, 97% ee (anti)
Scheme 5 Synthesis of zwitterion 7 and its catalytic application. Reagents and conditions: a) 1,3-propanesultone, toluene, reflux; b) Pd/C,
H2, MeOH–H2O (1:1).
We further expanded the utility of this zwitterions strategy enamine-based transformations such as Michael and aldol
to the chiral primary amine catalyst. Primary-tertiary di- reactions and can be utilized as a novel and practical alter-
amine zwitterions 7 was synthesized following a similar native to the typical chiral amine–brønsted acid conjugate
route. The obtained zwitterionic catalyst 7 was then tested catalysts. Further applications of the catalysts to other
in the direct aldol reaction (Scheme 5). To our delight, the types of reactions are currently under way in our laborato-
reactions between cyclohexanone and aryl aldehydes ry.
worked very well with up to 98% yield, 98% ee and 19:1
dr. These results are comparable to that obtained with
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
chiral amine–Brønsted acid conjugate catalysts.8b In addi-
tion, the zwitterions catalyst 7 can also be recycled and re-
used with similar activity and stereoselectivity.
Acknowledgment
In conclusion, we have developed a new and facile ap-
proach for the synthesis of chiral zwitterionic ammonium
sulfonates catalysts. These bifunctional zwitterionic cata-
The project was supported by the Natural Science Foundation
(NSFC 20632060 and 20702052), MOST (2009ZX09501-018) and
lysts demonstrate good activity and enantioselectivity in CAS.
Synlett 2011, No. 4, 495–498 © Thieme Stuttgart · New York

498
Y. Qiao et al.
CLUSTER
1042 cm–1. HRMS: m/z calcd for C15H30N2O3S [M + H]+:
319.2050; found: 319.2049. [a]D20 +33.8 (c 0.5, MeOH).
Compound 3d: 1H NMR (300 MHz, D2O): d = 3.80–3.82
(m, 1 H), 3.37–3.42 (t, J = 7.2 Hz, 2 H), 2.92–2.97 (m, 3 H),
2.71–2.78 (m, 4 H), 2.37 (s, 2 H), 2.04–2.25 (m, 3 H), 1.95–
1.97 (m, 2 H), 1.76–1.82 (m, 1 H), 0.95 (s, 9 H). 13C NMR
(D2O, 75 MHz): d = 66.7, 58.1, 57.0, 54.7, 49.0, 45.1, 32.1,
28.0, 27.8, 22.8, 21.4. IR (neat): 3446, 2953, 2867, 2828,
1644, 1481, 1464, 1394, 1361, 1186, 1042 cm–1. HRMS:
m/z calcd for C13H28N2O3S [M + H]+: 293.1893; found:
293.1891. [a]D20 +16.8 (c 0.5, MeOH).
References and Notes
(1) (a) Berkessel, A.; Groger, H. Asymmetric Organocatalysis;
Wiley-VCH: Weinheim, 2005. (b) Dalko, P. I.
Enantioselective Organocatalysis; Wiley-VCH: Weinheim,
2007. (c) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed.
2004, 43, 5138. (d) Saito, S.; Yamamoto, H. Acc. Chem.
Res. 2004, 37, 570. (e) Notz, W.; Tanaka, F.; Barbas, C. F.
III. Acc. Chem. Res. 2004, 37, 580. (f)Mukherjee, S.; Yang,
J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
(2) For recent examples, see: (a) Luo, S. Z.; Xu, H.; Li, J.;
Zhang, L.; Cheng, J.-P. J. Am. Chem. Soc. 2007, 129, 3074.
(b) Chen, W.; Du, W.; Duan, Y.-Z.; Wu, Y.; Yang, S.-Y.;
Chen, Y.-C. Angew. Chem. Int. Ed. 2007, 46, 7667.
(c) Kano, T.; Tanaka, Y.; Osawa, K.; Yurino, T.; Maruoka,
K. J. Chem. Commun. 2009, 1956. (d) Yang, Y.-Q.; Chen,
X.-K.; Xiao, H.; Liu, W.; Zhao, G. Chem. Commun. 2010,
46, 4130. (e) Liu, C.; Lu, Y. Org. Lett. 2010, 12, 2278.
(f) Luo, S. Z.; Qiao, Y. P.; Zhang, L.; Li, J.; Li, X.; Cheng,
J.-P. J. Org. Chem. 2009, 74, 9521. (g) Li, J.; Fu, N. K.; Li,
X.; Luo, S. Z.; Cheng, J.-P. J. Org. Chem. 2010, 75, 4501.
(h) Hu, S. S.; Li, J.; Xiang, J.; Pan, J.; Luo, S. Z.; Cheng,
J.-P. J. Am. Chem. Soc. 2010, 132, 7216. (i) Luo, S. Z.;
Zhou, P.; Li, J.; Cheng, J.-P. Chem. Eur. J. 2010, 16, 4457.
(j) For a review, see: Xu, L.-W.; Luo, J.; Lu, Y. Chem.
Commun. 2009, 1807.
Compound 3e: 1H NMR (300 MHz, D2O): d = 3.84 (s, 1 H),
3.33–3.38 (t, J = 6.6 Hz, 2 H), 2.66–3.03 (m, 7 H), 1.96–2.26
(m, 5 H), 1.71–1.77 (m, 1 H), 1.57–1.61 (m, 1 H), 1.40–1.42
(m, 1 H), 0.92–0.94 (d, J = 6 Hz, 6 H). 13C NMR (75 MHz,
D2O): d = 57.5, 54.7, 51.6, 51.4, 48.7, 45.2, 33.8, 28.2, 26.0,
23.0, 22.0, 21.9, 20.8. IR (neat): 3460, 2957, 2871, 1651,
1467, 1384, 1368, 1196, 1042 cm–1. HRMS: m/z calcd for
C13H28N2O3S [M + H]+: 293.1893; found: 293.1882.
[a]D20 +12.2 (c 0.5, MeOH).
Compound 7: 1H NMR (300 MHz, D2O): d = 3.09–3.14 (m,
1 H), 2.94–3.03 (br s, 2 H), 2.51–2.79 (m, 4 H), 2.16–2.20
(d, J = 11.4 Hz, 1 H), 1.80–2.00 (m, 5 H), 1.57–1.63 (m, 1
H), 1.33–1.44 (m, 6 H), 0.92–0.96 (q, J = 3.6, 6.3 Hz,). 13
C
NMR (75 MHz, D2O): d = 62.7, 50.9, 48.8, 48.2, 47.8, 36.9,
30.2, 25.9, 24.6, 23.8, 23.2, 23.0, 22.3, 21.8. IR (neat): 3483,
3447, 2951, 2867, 1637, 1468, 1383, 1367, 1207, 1183, 1043
cm–1. HRMS: m/z calcd for C14H30N2NaO3S [M + Na]+:
329.1869; found: 329.1868. [a]D20 +59.4 (c 0.5, MeOH).
(6) Upon long-term storage (>3 months), the solid becomes
syrup due to the absorption of moisture. This syrup can be
restored to solid power after dried under vaccum.
(3) For a review, see: Luo, S. Z.; Zhang, L.; Cheng, J.-P. Chem.
Asian J. 2009, 4, 1184.
(4) Zhang, L.; Luo, S. Z.; Mi, X. L.; Liu, S.; Qiao, Y. P.; Xu, H.;
Cheng, J.-P. Org. Biomol. Chem. 2008, 6, 567.
(5) Spectral Data for Catalyst 3a
1H NMR (300 MHz, D2O): d = 7.93–7.95 (m, 1 H), 7.63–
7.66 (m, 2 H), 7.48–7.51 (m, 1 H), 3.78–3.91 (m, 2 H), 3.65–
3.70 (m, 1 H), 3.33–3.48 (m, 2 H), 2.04–2.23 (m, 3 H), 1.82–
1.89 (m, 1 H). 13C NMR (75 MHz, D2O): d = 172.5, 139.5,
133.1, 131.6, 127.8, 127.2, 60.6, 45.4, 39.8, 26.8, 22.6. IR
(neat): 3403, 3077, 2977, 2886, 1637, 1595, 1566, 1531,
1431, 1316, 1234, 1170, 1143, 1085, 1018, 833, 767, 731
cm–1. HRMS: m/z calcd for C12H16N2O4S [M + H]+:
285.0904; found: 285.0902. [a]D20 +32.2 (c 0.5, MeOH).
Compound 3b: 1H NMR (300 MHz, D2O): d = 3.72 (br s, 1
H), 3.33 (br s, 2 H), 2.82–2.97 (br, 6 H), 2.22 (s, 1 H), 1.97–
2.06 (m, 4 H), 1.73 (s, 1 H). 13C NMR (75 MHz, D2O): d =
59.0, 49.3, 48.8, 47.1, 45.5, 28.1, 23.6, 23.1. IR (neat): 3422,
2964, 2866, 1644, 1461, 1419, 1186, 1042 cm–1. HRMS:
m/z calcd for C8H18N2O3S [M + H]+: 223.1111; found:
223.1109. [a]D20 +32.2 (c 0.5, MeOH).
(7) (a) Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F.
III. Org. Lett. 2004, 6, 2527. (b) Wang, W.; Wang, J.; Li, H.
Angew. Chem Int Ed. 2005, 44, 1369. (c) Mase, N.;
Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas,
C. F. III. J. Am. Chem. Soc. 2006, 128, 4966. (d) Lalonde,
M. P.; Chen, Y. G.; Jacobsen, E. N. Angew. Chem. Int. Ed.
2006, 45, 6366. (e) Sato, A.; Yoshida, M.; Hara, S. Chem.
Commun. 2008, 46, 6242. (f) Zhang, X.-J.; Liu, S.-P.; Li,
X.-M.; Yan, M.; Chan Albert, S. C. Chem. Commun. 2009,
7, 833. (g) Yoshida, M.; Sato, A.; Hara, S. Org. Biomol.
Chem. 2010, 8, 3031. (h) Xiao, J.; Xu, F.-X.; Lu, Y.-P.; Loh,
T.-P. Org. Lett. 2010, 12, 1220. (i) Chen, J.-R.; Cao, Y.-J.;
Zou, Y.-Q.; Tan, F.; Fu, L.; Zhu, X.-Y.; Xiao, W.-J. Org.
Biomol. Chem. 2010, 8, 1275. (j) He, T. X.; Gu, Q.; Wu,
X.-Y. Tetrahedron 2010, 66, 3195. (k) Bai, J.-F.;Xu, X.-Y.;
Huang, Q.-C.; Peng, L.; Wang, L.-X. Tetrahedron Lett.
2010, 51, 2803.
Compound 3c: 1H NMR (300 MHz, D2O): d = 3.80–3.84 (t,
J = 6.6 Hz, 1 H), 3.37–3.41 (br, 2 H), 2.91–2.96 (br, 3 H),
2.62–2.75 (m, 4 H), 2.35 (br s, 2 H), 2.02–2.23 (m, 4 H), 1.94
(br s, 2 H), 1.75 (br, 7 H), 1.53 (br s, 1 H), 1.26–1.28 (br, 4
H), 0.91–0.94 (br, 2 H). 13C NMR (75 MHz, D2O): d = 60.9,
57.9, 55.7, 52.5, 48.9, 45.2, 35.3, 31.6, 28.0, 26.6, 25.9, 25.8,
22.9, 21.3. IR (neat): 3444, 2923, 2850, 1644, 1453, 1203,
(8) (a) Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002,
58, 8167. (b) Luo, S. Z.; Li, J.; Zhang, L.; Xu, H.; Cheng,
J.-P. Chem. Eur. J. 2008, 14, 1273. (c) Luo, S. Z.; Li, J.; Xu,
H.; Zhang, L.; Cheng, J.-P. Org. Lett. 2007, 9, 3675.
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