Syn-selective asymmetric mannich reaction of sulfonyl imines with iminoesters catalyzed by the N,N,N-tridentate bis(imidazolidine)pyridine (PyBidine)-Cu(OTf)2 complex

Article abstract of DOI:10.1002/chem.201201537

Chiral ligand: The [PyBidine-Cu(OTf)₂] (Tf= trifluoromethanesulfonate) complex catalyzed the asymmetric Mannich reaction of sulfonyl imines and iminoesters to give the products in a high syn-selective manner. For both 4-toluene (Ts)- and 4-nitrophenylsulfonyl (Ns)-imines, the syn-adducts were obtained in up to 99 % ee (see scheme). Copyright

Full text of DOI:10.1002/chem.201201537

COMMUNICATION
DOI: 10.1002/chem.201201537
syn-Selective Asymmetric Mannich Reaction of Sulfonyl Imines with
Iminoesters Catalyzed by the N,N,N-Tridentate Bis(imidazolidine)pyridine
(PyBidine)–CuACHTNUGRTENUNG(OTf)2 Complex
Takayoshi Arai,* Asami Mishiro, Eri Matsumura, Atsuko Awata, and Mayu Shirasugi[a]
The significant role of chiral amines and amino acids in
living systems has stimulated research and development on
the catalytic asymmetric synthesis of these molecules in
their natural and/or unnatural forms. In particular, a wide
range of optically active a,b-diamino acids have been found
to be key structural components in bioactive compounds
and have become valuable synthetic intermediates.[1] For ex-
ample, a library of bicyclic diketopirazines was designed and
synthesized as peptide b-turn mimics.[2] The importance of
structurally and biologically fascinating a,b-diamino acids
has prompted the development of new general and efficient
procedures for the asymmetric synthesis of these simple, yet
polyfunctional molecules.
Of the various approaches for accessing a,b-diamino
acids, the Mannich reaction of glycine-derived Schiff bases
with imines is the most general and straightforward method,
and studies in the last decade have been focused on the de-
velopment of the catalytic asymmetric Mannich reaction.[3]
In 2003, Jørgensen succeeded in the first syn-selective Man-
nich reaction by using CuI/phosphine-oxazoline.[4a] With this
as a turning report, chiral-metal catalysts were developed
for both the direct asymmetric syn-selective Mannich reac-
tion[4] and the anti-selective version.[5] Arrayꢀs and co-work-
ers,[4b,5a] and Hou and co-workers[6] reported fascinating ex-
amples of diastereo-switchable enantioselective Mannich re-
actions. These metal-catalyzed Mannich reactions were ach-
ieved by using chiral bidentate ligands. As an alternative
method to these metal-catalyzed reactions, groups of Mar-
uoka,[7a] Shibasaki,[7b,c] Kobayashi,[7d] and Barbas III[7e] have
reported the syn-stereoselective organocatalytic asymmetric
reaction. Although these pioneering works are outstanding
contributions to the asymmetric Mannich reaction, success-
ful metal-catalyzed syn-selective reactions of glycine-derived
Schiff bases with various imines have been limited,[4] and
the development of additional synthetically useful catalytic
systems having broad generality is still in high demand.[8–14]
Herein, we report a new syn-selective asymmetric Mannich
reaction by using a N,N,N-tridentate Cu catalyst.
We have succeeded in the development of new chiral
N,N,N-tridentate imidazoline or imidazolidine-containing li-
gands for metal-catalyzed asymmetric reactions. For exam-
ple, the N-tethered bis(imidazoline) ligand, abbreviated as
Nb-imidazoline (L1), was found to be an efficient ligand for
Cu-catalyzed asymmetric benzoylation of meso-diols.[15] For
the chiral N,N,N-tridentate imidazoline ligand, Beller and
co-workers reported the excellent bis(imidazoline)pyridine
ligand (PyBim, L2) for the catalytic asymmetric epoxidation
of alkenes.[16,17] Recently, we extended the imidazoline motif
to imidazolidine in the design of a new chiral ligand and suc-
ceeded in the development of the bis(imidazolidine)pyridine
ligand (PyBidine, L3).[18] The chiral N,N,N-tridentate ligand
would strongly coordinate to a metal cation to create a well-
defined reaction sphere, which contributes to simplifying the
reaction pathway by reducing the number of possible transi-
tion states, giving the product with high stereoselectivity.
The [L3–CuACTHNUGRTENUNG(OTf)2] (Tf=trifluoromethanesulfonate) com-
plex was found to be an excellent catalyst for the [3+2] cy-
cloaddition of iminoesters and nitroalkenes to give the opti-
cally active pyrrolidine compounds in a highly endo-selec-
tive manner.[18] This success stimulated us to apply the PyBi-
dine–metal complex for other reactions using iminoesters.
Of the various possible countersubstrates for the iminoesters
in the [PyBidine–CuACTHNUTRGNE(UNG OTf)2]-catalyzed reaction, the Mannich
reaction with sulfonyl imines was of interest due to the syn-
thetic importance of a,b-diamino acids.
This study began with the exploration of the appropriate
catalyst for the Mannich reaction of iminoester 1a and tosyl-
imine 2a as the model substrates (Table 1). Referring to
Fengꢁs and co-workers report,[5b] Cu
ACTHNUTRGNE(UNG OAc)2 for the three
types of chiral tridentate ligands (L1–L3) was examined
first. Although the catalytic activities of the [L1~L3–Cu-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
tivity, and both diastereomers recorded moderate enantio-
meric excess (ee, Table 1, entry 3). More Lewis acidic [L3–
CuACTHUNTRGENNG(U OTf)2] drastically improved the ee of both isomers to
[a] Prof. T. Arai, A. Mishiro, E. Matsumura, A. Awata, M. Shirasugi
Department of Chemistry, Graduate School of Science
Chiba University
give the products with 93% ee (syn) and 95% ee (anti;
Table 1, entry 6). Interestingly, the isolated chemical yields
were improved by reducing the catalyst amount to 5 mol%
(Table 1, entry 7). This is due to the prevention of substrate
decomposition caused by the small amount of catalyst by re-
Inage, Chiba 263-8522 (Japan)
Fax : (+81)43-290-2889
E-mail: tarai@faculty.chiba-u.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201537.
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Table 1. Screening of the chiral tridentate-amine ligand–metal catalyst
for the Mannich reaction of 1a and 2a.
98% ee (Table 2, entry 4). Although the reaction proceeded
without a base, the conversion resulted in low yield (Table 2,
entry 5). Finally, the use of iPr2NEt as the basic additive
gave the product in 99% ee for both diastereoisomers. The
inorganic base of K2CO3 was also efficient, whereas Cs2CO3
reduced the ee of the products (Table 2, entries 7 and 8).
Under the optimized conditions for entry 6 (Table 2), the
generality of the [L3–CuACTHNUTRGNE(UGN OTf)2]-catalyzed asymmetric Man-
nich reaction of iminoesters and tosylimines was examined,
and the results are shown in Table 3. Both electron-deficient
Entry
Ligand
Metal salt
t [h]
Yield [%]
(syn/anti)
ee [%]
ACHTUNGTRENUN(NG syn/anti)
U
Table 3. Mannich reaction of iminoesters and tosylimines catalyzed by
[L3–CuACHTUNGTRNEUNG
(OTf)2].[a]
[a]
[a]
[a]
1
2
3
4
5
L1
L2
L3
L1
L2
L3
L3
L3
L3
L3
L3
L3
Cu
Cu
Cu
Cu
Cu
Cu
Cu
N
34
20
39
20
20
21
21
18
18
20
21
21
32 (69:31)
24 (72:28)
41 (83:17)
21 (56:44)
15 (69:31)
42 (74:26)
85 (74:26)
51 (81:19)
31 (74:26)
34 (75:25)
21 (75:25)
42 (83:17)
3:17
5:18
34:43
20:65
40:64
93:95
93:95
59:68
86:82
46:13
R1
R2
t [h]
Yield [%]
(syn/anti)
ee [%]
ACHTUNGTRENNUNG(syn/anti)
6
Entry
7[b]
8[b]
9[b]
10[b]
11[b]
12[b]
U
[d]
1
2
3
4
Me
Me
Me
Me
Ph
21
23
22
23
77 (90:10)
74 (93:7)
81 (95:5)
85 (85:15)
99:99
99:61
97:97
98:89
Cu
ACHTUGNRTEN(NUGN ClO4)2
[d]
[d]
4-BrC6H4
4-NO2C6H4
4-MeOC6H4
Ni(ClO4)2
AHCTUNGTRENNUNG
Co
Zn
rac/rac
3:3
A
N
[a] Monohydrate. [b] L3 (5.5 mol%) and metal salt (5 mol%) were used.
[c] (CuOTf)2·C6H6 was used. [d] Hexahydrate.
5
6
7
8
9
Me
Me
Me
Me
Me
Et
4-MeC6H4
3-NO2C6H4
2-BrC6H4
3,4-(OCH2O)-C6H3
2-thienyl
22
22
24
22
27
35
69 (89:11)
96 (96:4)
85 (40:60)
78 (91:9)
91 (90:10)
81 (90:10)
98:94
99:95
97:97
98:86
99:65
99:98
ducing the acidity of the reaction media. Of the several cat-
ionic salts of first-row transition metals that were examined
10
Ph
(Table 1, entries 7–12), the selection of CuACTHNURTGNENG(U OTf)2 was critical
to provide the products in high yield with excellent ee
(Table 1, entry 7).
[a] Tosylimines (1.5 equiv) were used. [b] Diastereomeric ratio after a
single recrystallization from MeOH. [c] ee after a single recrystallization
from MeOH. n.d.=not determined.
Encouraged by the superior results by using the [PyBi-
dine–Cu
G
and -enriched aromatic tosylimines with substituents at the
3- and/or 4-positions were successfully converted to the
products in a highly syn-selective manner, and the ee of the
major syn-adducts showed excellent ee ranging from 97 to
99% ee. The tosylimine derived from 2-bromobenzaldehyde
reduced the syn/anti selectivity to 40:60, although both dia-
stereoisomers still had high ee (Table 2, entry 7). The tosyl-
imine with a thiophene ring was also transformed without
difficulty to give the syn-product with 99% ee (Table 2,
entry 9). Unfortunately, from the aliphatic imines and/or ala-
nine-derived Schiff bases as the reaction substrates, the
Mannich adducts was obtained in trace.
mized for this particular [L3–CuAHCNUTGTRENNUNG
(Table 2). The reaction can be carried out in CH2Cl2, tol-
uene, and THF at a similar level of asymmetric induction. In
THF, the reaction proceeded smoothly at 08C by adding
1.5 equivalents of 2a to give the product in 88% yield with
86:14 syn/anti-selectivity. The syn-adduct was formed in
Table 2. Optimization of the [L3–Cu
of 1a and 2a.
ACHTUNGRTEN(NUNG OTf)2]-catalyzed Mannich reaction
From the Mannich adduct, the N-tosyl functionality can
be deprotected conventionally by treatment with Mg/
MeOH[19] or phenol in HBr/HOAc solution at reflux by ad-
dition of H2O.[20] However, for the application of the catalyt-
ic asymmetric Mannich reaction to the synthesis of complex
molecules, the N-nosyl (Ns) protecting group is more readily
removed by using thiols under mild conditions.[21,22] Thus,
the [L3–CuACTHNUGRTENUNG(OTf)2]-catalyzed Mannich reaction of iminoest-
ers with nosylimines was also examined, and the results are
shown in Table 4.
Entry
Solvent
Addi-
tive[a]
T
[8C]
Yield [%]
(syn/anti)
ee [%]
(syn/anti)
N
1[b]
2[b]
3[b]
4[c]
5[c]
6[c]
7[c]
8[c]
CH2Cl2
toluene
THF
THF
THF
THF
THF
THF
Et3N
Et3N
Et3N
Et3N
–
iPr2NEt
K2CO3
Cs2CO3
RT
RT
RT
0
0
0
85 (74:26)
81 (83:17)
76 (78:22)
88 (86:14)
29 (87:13)
77 (90:10)
65 (92:8)
93:95
89:97
97:93
98:96
90:96
99:99
99:95
45:14
0
0
Although the [L3–(CuOTf)2] catalyst could not promote
the reaction by using 2-Ns-imine (Table 4, entry 2), 4-Ns-
imines were successfully converted to the desired products
74 (71:29)
[a] Additive (0.1 equiv) was used. [b] 2a (1.1 equiv) was used. [c] 2a
(1.5 equiv) was used.
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Selective Asymmetric Mannich Reaction of Sulfonyl Imines
Table 4. Mannich reaction of iminoesters and nosylimines catalyzed by
COMMUNICATION
[L3–CuACHTUNGTRENNUNG
(OTf)2].[a]
Entry
R1
R2
t [h]
Yield [%]
(syn/anti)
ee [%]
ACHTUNGTRENUN(NG syn/anti)
U
1[b]
2[c]
3[b]
Me
Me
Me
Ph
Ph
4-ClC6H4
36
24
23
90 (92:8)
trace
72 (93:7)
99:99
–/–
95:80
A
(>99:n.d.)[e]
ACHTUNGTRENNUNG
4[b]
5[b]
Me
Me
4-NO2C6H4
4-MeC6H4
23
35
88 (92:8)
43 (76:24)
99:90
78:94
A
ACHTUNGTRENNUNG
6[b]
7[b]
8[b]
Me
Me
Et
3-NO2C6H4
3,4-(OCH2O)-C6H3
Ph
19
35
35
88 (93:7)
68 (93:7)
90 (92:8)
Scheme 2. Plausible mechanism of the Mannich reaction.
93:91
99:82
[a] Nosylimines (1.5 equiv) were used. [b] 4-Ns-imines were used. [c] 2-
Ns-imines were used at RT. [d] Diastereomeric ratio after a single recrys-
with imines. In addition, because L1 and L2 did not function
as efficient catalysts for the Mannich reaction, the NH func-
tionality in the PyBidine (L3) must play a significant role
for activating the substrates in this catalytic scenario. This
discovery will be helpful for the design and application of
the PyBidine–metal complex to further asymmetric catalysis.
In conclusion, the syn-selective Mannich reaction of sulfo-
nylimines and glycine-derived Schiff bases was achieved by
tallization from AcOEt. [e] ee after
AcOEt. n.d.=not determined.
a single recrystallization from
with high syn-selectivity and excellent ee. The result with 2-
Ns-imine might suggest an obstructive coordination of the 2-
NO2 group onto the Cu centers, which disturbs the reaction
progress.
using [PyBidine–CuACHTNUGTRNEUNG(OTf)2]. The unique advantage of the
With the highly enantiomeric-enriched products obtained
from 4-nosylimines in hand, the deprotection of the 4-nosyl
functionality was examined, as shown in Scheme 1.
PyBidine has been realized in the Mannich reaction, in addi-
tion to the [3+2] cycloaddition reaction.[18] The detailed re-
alization of the PyBidine ligand function for the asymmetric
induction and its application to further asymmetric reactions
are in progress.
Experimental Section
General procedure of the syn-selective asymmetric Mannich reaction:
PyBidine (L3) (0.011 mmol) and CuACHTNUTRGNENG(U OTf)2 (0.010 mmol) were added to a
Scheme 1. Simple preparation of the a,b-diamino acid methyl ester.
two-necked round-bottomed flask containing a stir bar under Ar. Di-
chloromethane (1.00 mL) was added to the flask and the mixture was
stirred for 2 h. After removal of the solvent under reduced pressure,
THF (1.00 mL) was added as a reaction solvent. To the resulting solution,
iminoester (0.20 mmol) and iPr2NEt (0.02 mmol) were added at RT, then
imine (0.30 mmol) was added at 08C. After being stirred for the time in-
dicated in Table 3 or 4, the solution was removed under reduced pres-
sure. The diastereomeric ratio was determined by 1H NMR spectroscopy
of the crude mixture. The resulting crude mixture was purified by silica-
gel column chromatography to give the product. The ee of the products
were determined by chiral stationary phase HPLC by using Daicel Chir-
alcel OD-H and OJ-H and Chiralpak AD-H and AS-H columns.
Starting from a product with 99% ee, the deprotection of
the 4-nosyl functionality was achieved by treatment with
odorless dodecanethiol at room temperature, after hydroly-
sis of the imine portion. The a,b-diamino acid methyl ester
was easily obtained, still retaining high syn-diastereoselectiv-
ity and ee.
The outcome of the [L3–CuACTHNUTRGNE(UNG OTf)2]-catalyzed Mannich re-
action can be explained by the mechanism depicted in
Scheme 2.
From the glycine-derived Schiff base, a Cu enolate is first
formed by the assistance of an amine base. The Cu enolate
then reacts with the sulfonyl imine, which reduces the steric
repulsion between the benzophenone imine and R1SO2 sub-
stituent to give the product in a syn-stereoselective manner.
In this model, the mode of enantioface selection on the imi-
noester is the same as the previously reported [3+2] cyclo-
addition reaction.[18] This is the first important demonstra-
tion of a N,N,N-tridentate imidazolidine ligand in the metal-
catalyzed Mannich reaction of glycine-derived Schiff bases
Acknowledgements
This work was supported by a Grant-in Aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science and Technology
(Japan), and The Naito Foundation Natural Science Scholarship.
Keywords: asymmetric
synthesis
·
chirality
·
enantioselectivity · Mannich reaction · synthetic methods
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T. Arai et al.
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Received: May 3, 2012
Published online: && &&, 0000
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www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!

Selective Asymmetric Mannich Reaction of Sulfonyl Imines
COMMUNICATION
Asymmetric Synthesis
T. Arai,* A. Mishiro, E. Matsumura,
A. Awata, M. Shirasugi . . . . . &&&& — &&&&
syn-Selective Asymmetric Mannich
Reaction of Sulfonyl Imines with
Iminoesters Catalyzed by the N,N,N-
Tridentate Bis(imidazolidine)pyridine
Chiral ligand: The [PyBidine–Cu-
(OTf)2] (Tf=trifluoromethanesulfo-
nate) complex catalyzed the asymmet-
ric Mannich reaction of sulfonyl imines
and iminoesters to give the products in
a high syn-selective manner. For both
G
4-toluene- (Ts)- and 4-nitrophenylsul-
fonyl (Ns)-imines, the syn-adducts
were obtained in up to 99% ee (see
scheme).
(PyBidine)–CuACHTNUGRTENUNG(OTf)2 Complex
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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ÞÞ
These are not the final page numbers!