Catalytic asymmetric mannich reaction of glycine derivatives with N-tosylimines using copper(I)/TF-biphamphos complex

Article abstract of DOI:10.1002/adsc.201000252

The direct asymmetric Mannich reaction of glycine Schiff bases with N-tosylimines has been developed with the tetrakis(acetonitrile)copper(I) tetrafluoroborate [Cu(CH₃CN)₄BF₄]/TF-Bipham- Phos complex. This catalytic system performs well over a broad range of substrates, furnishing anti-adducts of various α,β-diamino acid esters in good yields with up to 94:6 diastereoselectivity and 97% enantioselectivity.

Full text of DOI:10.1002/adsc.201000252

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DOI: 10.1002/adsc.201000252
Catalytic Asymmetric Mannich Reaction of Glycine Derivatives
with N-Tosylimines using Copper(I)/TF-BiphamPhos Complex
Gang Liang,a,b Min-Chao Tong,a,b Haiyan Tao,a and Chun-Jiang Wanga,*
a
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, Peopleꢀs Republic of China
Fax : (+86)-27-6875-4067; e-mail: cjwang@whu.edu.cn
G. Liang, M.-C. Tong made equal contributions to this work.
b
Received: April 1, 2010; Revised: July 1, 2010; Published online: August 16, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000252.
Abstract: The direct asymmetric Mannich reaction
of glycine Schiff bases with N-tosylimines has been
developed with the tetrakis(acetonitrile)copper(I)
proach to this reaction. Recently, Kobayashi and co-
workers reported a chrial guanidine-catalyzed direct
Mannich reaction of fluorenone imines with good dia-
stereoselectivity and enantioslectivity.[12,13] In spite of
these important contributions, the direct catalytic
asymmetric Mannich-type reaction of glycine-derived
Schiff bases with various imines is still challenging
and the development of new and efficient catalytic
systems showing high reactivity and enantio-/diaste-
reoselectivity is still in high demand. Recently, we re-
ported that a series of Cu(I) and Ag(I)/TF-Bipham-
Phos complexes[14] showed excellent results in the cat-
alytic asymmetric 1,3-dipolar cycloaddition of various
azomethine ylides with electron-deficient alkenes
(Figure 1). Extending the application of the easily
available chiral ligands TF-BiphamPhos (one or two
steps from TF-BIPHAM)[14a] in asymmetric catalysis,
tetrafluoroborate
[CuACHTUGNTERNNU(G CH3CN)4BF4]/TF-Bipham-
Phos complex. This catalytic system performs well
over a broad range of substrates, furnishing anti-ad-
ducts of various a,b-diamino acid esters in good
yields with up to 94:6 diastereoselectivity and 97%
enantioselectivity.
Keywords: asymmetric catalysis; diastereoselectiv-
ity; enantioselectivity; glycine Schiff bases; Man-
nich reaction; N-tosylimines
Chiral a,b-diamino acids are key structural compo- herein we report a direct catalytic Mannich-type reac-
nents in many biologically active compounds and as tion of glycine-derived Schiff base and various imines
well as important building blocks in organic synthe- catalyzed by Cu(I)/(S)-TF-Biphamphos with excellent
sis.[1] The direct catalytic asymmetric Mannich-type yields, good diastereoselectivity (up to 96:4) and ex-
reaction of glycine-derived Schiff bases[2] with various cellent enantioselectivity (up to 97% ee).
imines has become one of the most powerful and effi-
cient methods for the construction of these com- tion of glycine-derived Schiff base 2 and N-tosylimine
pounds.[3,4] Since the pioneering work of Jørgensen 3a with 10 mol% Cu
(CH3CN)4BF4/(S)-TF-Bipham-
Our initial investigation began with the model reac-
AHCTUNGTRENNUNG
and co-workers employing Cu(I)/phosphine-oxazoline phos complex in the presence of Et3N, and the repre-
complexes,[5] much attention has been paid to devel- sentative results are summarized in Table 1. To our
oping diastereo-/enantioselective catalytic protocols delight, the reaction was finished smoothly at room
for this reaction over the last few years. Some chiral
metal complex-catalyzed direct asymmetric Mannich
reactions of glycine-derived Schiff bases have been re-
ported by Hou using Cu(I)/ferrocene-based phospha-
nyloxazoline,[6] Carretero using Cu(I)/Fe-sulphos[7]
and Feng using Cu(II)/N,N’-dioxide complexes[8] with
excellent performances, respectively.[9] Maruoka and
Shibasakiꢀs seminal work showed that N-spiro C2-
symmetrical quaternary ammonium salts[10] and tar-
trate-derived diammonium salts (TaDiASs) as chiral
phase-transfer catalyst[11] also provide a possible ap- Figure 1. Structures of TF-BiphamPhos ligands (1a–1e).
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Gang Liang et al.
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Table 1. Screening studies of the asymmetric Mannich-type
reaction of glycine Schiff base 2 with N-tosylimine 3a using
TF-BiphamPhos 1.[a]
reaction time (Table 1, entry 6). Glycine tert-butyl
ester benzophenone Schiff base 2b could also be em-
ployed in this transformation producing the corre-
sponding adduct with similar diastereoselectivity
albeit lower enantioselectivity compared with glycine
methyl ester benzophenone Schiff base 2a (Table 1,
entries 1 vs. 7).
Having established (S)-TF-BiphamPhos 1a as the
optimal ligand, we then investigated the effects of
metal precursor, solvent, base, and temperature to
further optimize the reaction condition. The results
are summarized in Table 2. Except for the low activity
of CuACTHNUTRGNE(UNG OTf)2/1a (Table 2, entry 5), Cu(I) and Ag(I)
salts combined with chiral ligand 1a showed similar
reactivities and enantioselectivities for this transfor-
Table 2. Optimization of the asymmetric Mannich-type reac-
tion of glycine Schiff base 2 with N-tosylimine 3a.[a]
[a]
All of the reactions were carried out with 0.10 mmol of 2
and 0.15 mmol of 3a in 2 mL of DCM at room tempera-
ture. CuBF4 =Cu
ACHTNUGRTEN(NNUG CH3CN)4BF4. The Cu/L/base ratio was
1:1.1:1.5.
Isolated yield.
Determined by HPLC analysis.
[b]
[c]
[d]
The absolute configuration of the major anti-adducts was
determined as (2R,3R) by comparing the optical rotation
and HPLC retention time with the corresponding data in
the literature.
temperature in DCM with (S)-TF-Biphamphos 1a in
6 h, and the desired adduct formed in 95% yield with
good anti-selectivity (85:15) and enantioselectivity
(88% ee) (Table 1, entry 1). The reaction rate was re-
duced remarkably without Et3N as the extra base. We
then conducted the reaction using other (S)-TF-Bi-
phamPhos ligands (1b–1e). When the phenyl group
on the phosphorus atom of ligand 1a was replaced by
a xylyl group (1b) or 3,5-bis(trifluoromethyl)phenyl
group (1c), the corresponding enantioselectivity of
the Mannich adduct dropped from 88% to 74% and
54%, respectively, along with decreased diastereose-
lectivity (Table 1, entries 1–3). Ligand 1d containing
the bulky cyclohexyl group on the phosphorus atom,
which exhibited excellent results for asymmetric 1,3-
dipolar cycloadditions of azomethine ylides with vinyl
phenyl sulfone,[14c] showed lower diastereoselectivity
(65:35) and 72% ee (Table 1, entry 4). Ligand 1e,
bearing two bromines at the 3,3’-position of the TF-
BIPHAM backbone, afforded almost the same enan-
tioselectivity as the simplest ligand 1a but with a
slightly lower diastereoselectivity (Table 1, entry 5),
although excellent reactivity and substrate scope have
been achieved with the sterically hindered chiral
ligand 1e for asymmetric 1,3-dipolar cycloadditions of
azomethine ylides with various conjugated carbonyl
dipolarophiles.[14a,b] The catalyst loading was also suc-
cessfully reduced to 3 mol%, and a comparable result
(78:22 dr, 83% ee) was still achieved with an extended
[a]
The reactions were carried out with 0.10 mmol of 2 and
0.15 mmol of 3a in 2 mL of solvent. CuClO4 =Cu-
A
ACHTNUGTRNEN(NUG CH3CN)4BF4, DBU=1,8-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
methylaminopyridine.
Isolated yield.
Determined by HPLC analysis.
The absolute configuration of the major anti-product 4a
was determined as (2R,3R) by comparing its optical rota-
tion and the HPLC retention time with the data in the
literature.
[b]
[c]
[d]
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Catalytic Asymmetric Mannich Reaction of Glycine Derivatives with N-Tosylimines
mation, however, a slightly higher diastereoselectivity lent diastereo-/enantioselectivity (Table 3, entries 1–
was observed with Cu(I) precursors (Table 2, en- 7). The substitution pattern of the phenyl ring in 3
tries 1–4, 6 and 7). A preliminary screening of solvent has a significant effect on the transformation: an
effects showed that DCM was the best solvent of ortho-substituent group has a negative effect on the
choice, other solvents such as CH3CN, toluene, ether diastereoselectivity and enantioselectivity, which were
and THF gave lower diastereo- and enantioselectivi- probably caused by the unfavorable steric congestion
ties (Table 2, entries 4, 8–11). Among the examined (Table 2, entries 8 and 9). Noticeably, heteroaromatic
bases, DABCO gave the best results in terms of the tosylimines 3k and 3l were also viable substrates as
yield and stereoselectivity (Table 2, entry 17). Reduc- was the 2-naphthylaldehyde-derived tosylimine 3j, af-
ing the temperature to À308C in DCM led to full fording the corresponding product with 95% ee
conversion with 94:6 diastereoselectivity and 97% ee (Table 3, entries 10–12). Aliphatic tosylimine 3m and
for the major anti-diastereomer within 24 h (Table 2, 3n derived from branched cyclohexanecarboxalde-
entry 18). Thus, the optimized reaction conditions hyde and 2-methylpropionaldehyde also worked well
were established as 10 mol% of Cu
TF-Biphamphos 1a and 15 mol% DABCO at À308C sponding products with 92% ee (Table 3, entries 13
in DCM. and 14). However, for aliphatic tosylimine 3o derived
ACHTNUGTRNEN(NUG CH3CN)4BF4/(S)- in this catalytic system and gave rise to the corre-
The generality and limitations of this direct Man- from linear butyraldehyde, only moderate enantiose-
nich reaction were investigated under the optimized lectivity was achieved although the diastereoselectiv-
reaction conditions, and the results are summarized in ity still remained at the same good level (Table 3,
Table 3. Aryl tosylimines with either an electron-with- entry 15). The relative configurations of the major
drawing or electron-donating substituent on the aro- Mannich adducts 4a–o were assigned by comparison
1
matic ring gave anti-selective Mannich adducts as the of the H NMR of the major products with the known
major products in 70–92% yields with good to excel- compounds.[5,6] The absolute configuration of com-
pound 4a was determined to be (2R,3R) by compari-
son of its optical rotation and the corresponding
Table 3. Asymmetric Mannich-type reaction of glycine
HPLC retention time with the data in literature re-
Schiff base 2 with various N-tosylimines 3 catalyzed by
ports,[6,8] and those of other adducts were tentatively
proposed on the basis of these results.
CuBF4/1a.[a]
Based on the relative and absolute configuration of
4a and previous studies,[15] the high anti-selectivity ob-
served in the CuACTHNUTRGNEUNG(CH3CN)4BF4/(S)-TF-BiphamPhos
(1a) catalyzed asymmetric Mannich reaction of gly-
cine Schiff bases with N-tosylimines can be rational-
ized by the proposed tetracoordinated complex[15]
shown in Figure 2. The in situ-formed azomethine
ylide is coordinated to the metallic center and orient-
ed in such a transition state because of the steric re-
pulsion between the phenyl group in the ylide and the
phenyl ring on the phosphorus atom of the chiral
ligand, and the highly steric congestion imposed by
the latter effectively blocks N-tosylimine (3a) from
approaching from the back side of the azomethine
[a]
The reaction were carried out with 0.1 mmol of 2 and
0.15 mmol of 3 in 2 mL CH2Cl2.
Isolated yield.
[b]
[c]
[d]
Determined by chiral HPLC analysis.
The absolute configurations of the major anti-adducts
were determined as (2R,3S) by comparing the HPLC re-
tention time with HPLC data in the literatures.
The reaction was run at 08C for 12 h.
Figure 2. Proposed transition state leading to the anti-
adduct.
[e]
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Gang Liang et al.
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ylide and forms the anti-product (2R,3R)-4a through
the a front side attack, which is compatible with the
experimental results. The stereoselectivity of the pro-
posed transition state could be enhanced through the
possible coordination of the lone pair of electrons of
the nitrogen atom in imine (3a) with the Cu(I) center.
We cannot rule out the possible hydrogen bond inter-
action[15b,c] between the sulfonamide group of the N-
tosylimine and the NH2 group of the chiral (S)-TF-Bi-
phamPhos ligand (1a), which also facilitates stabiliza-
tion of the proposed transition state. Nevertheless, the
real catalytic mechanism still needs further investiga-
tion.
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tosylimines. The efficient CuACHTUNGRTNE(UNG CH3CN)4BF4/TF-Bi-
phamPhos catalytic system exhibited excellent perfor-
mance, affording anti-adducts of various a,b-diamino
acid esters in good yields with up to 94:6 diastereose-
lectivity and 97% enantioselectivity. Further investi-
gations of the mechanism and applications of TF-Bi-
phamPhos in asymmetric catalysis are ongoing in our
laboratory and will be reported in due course.
Experimental Section
General Procedure
Under argon atmosphere the solution of ligand (S)-TF-Bi-
phamPhos 1a(7.1 mg, 0.011 mmol) and CuACTHNUGTRNEUNG(CH3CN)4BF4
(3.1 mg, 0.01 mmol) was stirred at room temperature for
about 1 h. After it had been cooled to the indicated temper-
ature, the glycine Schiff base 2 (25.3 mg, 0.10 mmol) was
added then followed by DABCO (0.0133 mmol) and tosyli-
mine (0.15 mmol). Once the starting material had been con-
sumed (monitored by TLC), the mixture was concentrated
to dryness and purified directly by column chromatography
(ethyl acetate/petroleum ether=1:5) to give the correspond-
ing adducts, which was then directly analyzed by chiral
HPLC to determine the anti/syn ratio and enantiomeric
excess.
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Acknowledgements
[9] A Ni(II)/glycine derivative complex was also reported
for the Mannich reaction with a-amido sulfones, see: J.
Wang, T. Shi, G. H. Deng, H. L. Jiang, H. Liu, J. Org.
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This work was supported by the National Natural Science
Foundation of China (20702039, 20972117), SRFD
(20090141110042), and the Fundamental Research Funds for
the Central Universities.
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