Molecular sieves 4A work to mediate the catalytic metal enolization of nucleophile precursors: application to catalyzed enantioselective Michael addition reactions

Article abstract of DOI:10.1016/j.tetlet.2008.05.156

Molecular sieves 4A (MS4A) work effectively as base leading to catalytic generation of nickel(II) enolate or nitronate nucleophiles through deprotonation of the α-hydrogen atom of nucleophile precursors on treatment with a catalytic amount of chiral nickel(II) ions. The resulting reactive intermediates can be successfully trapped with α,β-unsaturated carbonyl electrophiles to produce the corresponding Michael adducts in good yields with high enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2008.05.156

Tetrahedron Letters 49 (2008) 5220–5223
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Molecular sieves 4A work to mediate the catalytic metal enolization
of nucleophile precursors: application to catalyzed enantioselective
Michael addition reactions
b
a
Masayuki Hasegawa b, , Fumiyasu Ono , Shuji Kanemasa
*
a Institute for Materials Chemistry and Engineering, 6-1 Kasugakoen, Kasuga 816-8580, Japan
b Department of Molecular and Material Sciences, Graduate School of Engineering Sciences, Kyushu University, 6-1 Kasugakoen, Kasuga 816-8580, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Molecular sieves 4A (MS4A) work effectively as base leading to catalytic generation of nickel(II) enolate
Received 14 April 2008
Revised 26 May 2008
Accepted 28 May 2008
Available online 14 June 2008
or nitronate nucleophiles through deprotonation of the
treatment with a catalytic amount of chiral nickel(II) ions. The resulting reactive intermediates can be
successfully trapped with ,b-unsaturated carbonyl electrophiles to produce the corresponding Michael
adducts in good yields with high enantioselectivities.
a-hydrogen atom of nucleophile precursors on
a
Ó 2008 Published by Elsevier Ltd.
We have recently developed two catalytic activation methods of
nucleophile precursors, such as cyclic 1,3-dicarbonyl compounds,
malononitriles, and nitromethane: (1) the double catalytic activa-
tion method using both catalytic amounts of chiral cationic nicke-
l(II) and amine catalysts1 and (2) the catalysis with chiral nickel(II)
acetate tetrahydrate in alcohol media.2 These methods have been
successfully applied to the enantioselective Michael addition reac-
Me
+
N
MeNO2
N
1
a
2a
O
Me
N
N
R,R-DBFOX/Ph
CH2NO2
O
tions with
a
,b-unsaturated carbonyl acceptors. We believe that
Ph
O
3a
these processes involve the reversible generation of metal enolates
and related reactive species.
N
O
Ni
H
Additive Time/h Yield/% %ee
X2Ln
However, nitromethane (1) was rather difficult to be activated
through either of these methods due to its low enolization ability.3
Thus, the reactions of 1 with 1-crotonoyl-3,5-dimethylpyrazole
(2a) at room temperature in the presence of a catalytic amount
(10 mol %) of the chiral catalyst A derived from R,R-DBFOX/Ph
ligand and nickel(II) acetate tetrahydrate in THF (1/THF = 1:1 v/v),
either with or without 2,2,6,6-tetramethylpiperidine (TMP), pro-
duced the Michael adduct 3a only in 15% and 42% yields after 24
and 72 h, respectively (Scheme 1). However, we have found during
our preliminary works that the same reaction was highly acceler-
ated in the presence of MS4A (500 mg/mmol of 2a), and the excel-
lent enantioselectivity of 98% ee was observed.
In the present Letter, we will report a new catalytic activation
method of nitromethane as nucleophile precursor with the com-
bined use of a Lewis acid and MS4A in alcohol media. The resulting
reactive intermediate can be successfully employed in the enantio-
selective nitromethane Michael addition reactions.
N
H
O
none
72
24
24
42
15
quant
>99
83
98
TMPb
MS4Ac
Ph
A: X = OAc, Ln = nH2O
B: X = ClO4, Ln = 3H2O
C: X = BF4, Ln = nH2O
aA (10 mol%), additive, 1/THF = 1:1
v/v, rt. b10 mol%. c500 mg/mmol.
Scheme 1. MS4A mediated rate acceleration of nitromethane Michael addition
reactions catalyzed with nickel(II) acetate complex A.
When the reaction of 1 with 2a was carried out in t-butyl alco-
hol (1/t-BuOH = 1:1 v/v) at room temperature in the presence of a
catalytic amount (10 mol %) of the chiral catalyst A derived from
R,R-DBFOX/Ph ligand and nickel(II) acetate tetrahydrate, this reac-
tion was complete in 24 h to give the Michael adduct 3a in 95%
yield with the enantioselectivity of 98% ee (Scheme 2, entry 1),
but a little more rate enhancement was needed. Although a cata-
lytic amount of TMP (10 mol %) was added to the above reaction,
no significant rate enhancement was observed (entry 2). The pres-
ence of acetic acid lowered the reactivity, and trifluoroacetic acid
as stronger acid inhibited the reaction (entries 4 and 5). This
* Corresponding author.
E-mail address: kn-hase@mm.kyushu-u.ac.jp (M. Hasegawa).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.05.156

M. Hasegawa et al. / Tetrahedron Letters 49 (2008) 5220–5223
5221
to react with a mixture of 1 and 2a in Eq. 2. MS4A was treated with
1 for 3 h and MS4A was filtered off, and the filtrate was allowed to
react with a mixture of B and 2a in Eq. 3. It was found that the
effective catalytic activation was observed only when MS4A was
treated with a mixture of nitromethane (1) and the catalyst B
(Eq. 1). Other two procedures (Eqs. 2 and 3) were totally ineffec-
tive. This indicates that nucleophile precursor 1 was activated with
MS4A only in the presence of catalyst B. MS4A may have worked to
increase the concentration of a reactive intermediate, probably the
corresponding nickel(II) enolate.7 This will be disscussed later.
The experimental procedure including the removal of MS4A
through filtration after the catalytic preactivation of nucleophile
precursors, followed by treatment with acceptor 2a, resulted in
even faster reaction. Thus, the Michael addition reaction of 1 with
2a, catalyzed by the cationic nickel(II) complex C, was complete in
30 min at room temperature, but the enantioselectivity observed
in this reaction was unfortunately lower (70% ee, Scheme 4) than
the reaction catalyzed by the nickel(II) acetate complex A (>99%
ee, Scheme 2).8 Other metal complex catalysts derived from nick-
el(II) bromide and chloride showed high catalytic activity and sat-
isfactory selectivity. However, cobalt(II) chloride complex showed
a rather low reactivity.
a
R
R
N
1
+
N
N
N
CH2NO2
O
2a-e
O
3a-e
Entry
R
Additive
mol% Time/h
3
Yield/% %ee
95 98
1
2
3
4
5
6
7
8
9
Me
–
–
10
24
22
24
48
3
24
12
72
72
2
a
quant >99
TMP
46
>99
CH3COOH 40
CF3COOH 50
-
-
quant >99
MS4A
MS5A
MS4A
MS4A
MS4A
b
b
b
b
b
b
66
77
71
25
90
96
>99
96
98
98
Ph
b
c
d
e
i
t
-Pr
-Bu
10
EtOOC MS4A
aA (10 mol%), additive, 1/ -BuOH = 1:1 v/v, rt. b500 mg/mmol.
t
Scheme 2. MS4A mediated nitromethane Michael addition reactions catalyzed
with the chiral nickel(II) acetate complex A.
By the way, how quickly does the preactivation including cata-
lytic generation of the reactive intermediate take place by the aid
of MS4A? In order to answer this question, we performed the reac-
tion monitoring experiments under various preactivation times as
described below in Scheme 5.
A mixture of chiral and cationic complex catalyst B and nitro-
methane (1) in t-butyl alcohol (1/t-butyl alcohol = 1:1 v/v) was
allowed to interact with MS4A at room temperature for a fixed
indicates that the reversible process for catalytic generation of
basic intermediate may be involved in the reaction, and the react-
ing species reversibly generated is quenched through protonation
with acidic additives. To our delight, the reaction was finished in
a short time of 3 h in the presence of MS4A to give a quantitative
yield of 3a with an absolute enantioselectivity (entry 5), while
MS5A was less effective (entry 6).4,5 The catalytic reactions of 1
with a variety of Michael acceptors 2b–e under the catalysis of A
were also efficiently mediated by MS4A (entries 7–10).
One possibility for the highly enhanced rate acceleration
observed in the above reactions would be based upon the effective
catalytic generation of intermediary nickel(II) enolate in high con-
centration by the aid of MS4A. If this is the case, the cationic nick-
el(II) catalyst B should be the catalyst of choice since B is a stronger
Lewis acid than nickel(II) acetate complex A.6 Actually, adduct 3a
was produced quantitatively in 4 h at room temperature under
the catalysis of the DBFOX/Ph complex B derived from nickel(II)
perchlorate hexahydrate in the reaction of 1 with 2a in t-butyl
alcohol in the presence of MS4A (Eq. 1 of Scheme 3).
In order to confirm the role of MS4A in the catalytic activation
of nitromethane (1), we examined three experimental procedures
shown in Scheme 3. A mixture of catalyst B and MS4A was treated
with or without 1 for 3 h, MS4A was filtered off, and then the fil-
trate was allowed to react with 2a for 30 min in Eq. 1 or allowed
a
3a
Time/h
1
+ 2a
Metal salt
Yield/%
%ee
Ni(OAc)2•4H2O
Ni(BF4)2•6H2Ob
NiBr2
3
0.5
3
4
4
quant
quant
quant
quant
28
>99
70
94
93
89
NiCl2
CoCl2
aDBFOX/Ph + metal salt (10 mol% each), MS4A (500 mg/mmol),
1/
-BuOH = 1:1 v/v, rt. bMS4A was filtered off after stirring for 3 h,
then the filtrate was used in the reaction.
t
Scheme 4. Use of a variety of metal salts.
a, b
Catalyst: B (10 mol%), MS4A (500 mg/mmol).
N
N
MeNO2 (1)
b
N
N
MS4A
1
2a
eq 1
B
3a
CH2NO2
O
O
2a
3a
3 h in THF/
t
-BuOH
30 min
4 h
37% (80% ee)
quant
aB (10 mol% each), MS4A (500 mg/mmol), 1/
t-BuOH = 1:1
3 h in MeNO2/t-BuOH
v/v, rt, x h.
bMS4A was filtered off, and then the filtrate was treated with
b
MS4A
1
2a
eq 2
eq 3
B
1
No reaction
No reaction
2a at room temperature for 0.5 h.
3 h in THF/
t
-BuOH
30 min
Activation (x h)
Yield/%
% ee
b
B
MS4A
2a
5 min
0.5
1
2
3
52
80
98
97
quant
18
86
74
79
79
76
71
3 h in THF/
t
-BuOH
30 min
bMS4A was filtered off, and the filtrate was used for the following
procedure.
26
Scheme 3. Experimental procedures for the catalytic activation of nitromethane
with B by the aid of MS4A.
Scheme 5. How quick is the Ni(II) nitronate generation?

5222
M. Hasegawa et al. / Tetrahedron Letters 49 (2008) 5220–5223
and 6. The authors believe that the nickel(II) enolate D of nitro-
1, rt, 10 min
C
DBFOX/Ph + Ni(BF4)2•6H2O
Chiral Ni(II) catalyst
methane has been catalytically generated as reactive nucleophiles
in the presence of a catalytic amount of nickel(II) ion catalyst and
MS4A.
in t-BuOH
DBFOX/Ph•NiBF4
Mz = 603.1
1)
2)
MS4A is added.
Stirred for 5 min at rt.
When nickel(II) acetate is used as catalyst in the reaction with
nucleophile precursors, acetic acid is formed together with the
nickel(II) enolates. Since acetic acid is a rather weak acid, the
resulting nickel(II) enolates can survive in alcohol media not to
cause serious deactivation of the enolate by protonation (Eq. 1 of
Fig. 1). On the other hand, when catalyzed with cationic nickel(II)
ions MX (X = ClO4 or BF4) instead, the highly strong acid HX is
formed as a result of the reversible metal enolization, and the
resulting protonic acid works to protonate the nickel(II) enolates.
Neverthless, cationic nickel(II) catalysts B and C showed higher
catalytic activity than nickel(II) acetate A in the presence of MS4A.
This indicates that MS4A has worked as effective proton scaven-
ger.8 Thus, MS4A(Na) underwent ion exchange reaction with the
strong acid HX (X = ClO4 or BF4) produced in the catalytic enoliza-
tion reaction so that a mixture of the protonated Molecular
sieves MS4A(H) and neutral sodium salt NaX could be produced.9
This ion exchange reaction10 should be more favored in alcohol
media.
Chiral Ni(II) nitronate
O
D
3) MS4A is filtered off.
N
O
Ni•DBFOX/Ph
Mz = 576.0
Scheme 6. Ion spray TOF mass spectral analysis of the preactivation process.
period of time (Âh as preactivation time), and then the MS4A used
was removed off through filtration. The filtrate was then allowed
to react with the acceptor molecule 2a at room temperature for
30 min. After the usual workup including chromatographic purifi-
cation, the yield and enantioselectivity of adduct 3a were recorded.
This procedure was repeated for several preactivation times, and
the results obtained are summarized in Scheme 5.
After 5 min of preactivation time, adduct 3a was produced in
52% yield, and 80% after 30 min of preactivation. The yield of
adduct 3a became quantitative after 1 h, indicating that MS4A
could act as a strong mediator under the catalysis of cationic
nickel(II) catalyst B. In addition, the preactivation of nitromethane
(1) needed only a short period of time. However, when the preac-
tivation of 1 was performed at room temperature for a time longer
than 1 day, the catalytic activation almost disappeared. This means
that the reacting intermediate catalytically generated is rather
unstable under the reaction conditions. The intermediate under-
goes partial decomposition to reduce the concentration of nickel(II)
enolate as reactive transient species.
The reactive intermediate catalytically generated by the aid of
MS4A was characterized as the nickel(II) nitronate of nitromethane
(1) on the basis of ion spray TOF masspectral analysis (Scheme 6).
When an alcohol solution of 1:1 catalytic mixture of DBFOX/Ph chi-
ral ligand and nickel(II) fluoroborate hexahydrate was treated with
an excess amount of 1 at room temperature in 10 min, an ion peak
corresponding to the chiral complex C only appeared at m/z =
603.1, but no ion peak being observed for the nickel(II) nitronate
of 1. However, a new ion peak appeared at m/z = 576.0, assignable
as the chiral nickel(II) nitronate D, immediately after MS4A was
added to the above solution; this ion peak finally grew up as the
far major peak after 1 h at room temperature. It is now clear that
MS4A is essential for the catalytic generation of nickel(II) nitronate
intermediate D, and that the concentration of D becomes maxi-
mized in the reaction mixture.
In conclusion, we have succeeded to find an effective synthetic
method for the catalytic generation of metal enolates or related
reactive intermediates from nucleophile precursors by the aid of
a mixture of Lewis acid catalyst and MS4A in alcohol media. Use
of strong Lewis acid catalyst is more favored for the generation
of catalytic species in high concentration. This catalytic method
should be widely applied to a variety of synthetic reactions.
References and notes
1. (a) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394–13395; (b) Itoh, K.;
Oderaotoshi, Y.; Kanemasa, S. Tetrahedron: Asymmetry 2003, 14, 635–639; (c)
Itoh, K.; Kanemasa, S. Tetrahedron Lett. 2003, 44, 1799–1802; (d) Kanemasa, S.;
Itoh, K. Eur. J. Org. Chem. 2004, 4741–4753; (e) Itoh, K.; Hasegawa, M.; Tanaka,
J.; Kanemasa, S. Org. Lett. 2005, 7, 979–981.
2. Ono, F.; Hasegawa, M.; Tanaka, J.; Kanemasa, S. Tetrahedron Lett., 2008, 49,
accepted for publication.
3. pKa Values measured in DMSO of the following nucleophile precursors:
dimedone: 11.16 (a) Arnett, E. M.; Harrelson, J. A., Jr. J. Am. Chem. Soc. 1987, 109,
809–812; malononitrile: 11.1 and nitromethane: 17.2 (b) Matthews, W. S.;
Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.; Cornforth, F. J.; Drucker, G. E.;
Margolin, Z.; McCallum, R. J.; McCollum, G. J.; Vanier, N. R. J. Am. Chem. Soc.
1975, 97, 7006–7014.
4. MS3A was similarly effective as well.
5. Commercially available MS4A powder was used without further preactivation
procedure in the present reactions.
6. A strong Lewis acid catalyst should be kinetically favored for the catalytic
generation of metal enolates as the forward transformation, but the ready
proton quenching with the resulting strong acid is even more favored
thermodynamically. If MS4A works as effective proton scavenger, the
combined use of a strong Lewis acid and MS4A should result in the effective
generation of metal enolates in high concentration.
Thus, MS4A effectively worked as base to induce the catalytic
process as described in the experiments shown in Schemes 3, 5,
Metal acetate catalyzed enolization
O
Me
MS4A(Na)
M
O
Q
OM
Q
O
H
+
AcOH
(eq 1)
Y
Q = N or C
Y = R or O
MS 4A mediated catalytic enolization
MX
OM
Q
MS4A(Na)
O
Q
+
HX
MS4A(H) + NaX (eq 2)
H
Y
Figure 1. Nickel(II) enolates as reacting intermediates catalytically generated.

M. Hasegawa et al. / Tetrahedron Letters 49 (2008) 5220–5223
5223
7. For the generation and reactions of nickel(II) enolate, see: (a) Campora, J.;
Maya, C. M.; Palma, P.; Carmona, E.; Gutierrez-Puebla, E.; Ruiz, C. J. Am. Chem.
Soc. 2003, 125, 1482–1483; (b) Mahandru, G. M.; Skauge, A. R.; Chowdhury, S.
K.; Amarasinghe, K. K. D.; Heeg, M. J.; Montgomery, J. J. Am. Chem. Soc. 2003,
125, 13481–13485.
Sletzinger, M. Tetrahedron Lett. 1975, 16, 3979–3982; (b) Terada, M. Synth. Org.
Chem. Jpn. 2007, 65, 748–759.
9. It has remained unclear so far that the combined use of a strong Lewis acid
catalyst and MS4A led to a low enantioselectivity in the Michael addition
reactions.
8. Previous reports presenting the reaction examples in which MS4A worked as
effective base in synthetic organic reactions: (a) Weinstock, L. M.; Karady, S.;
Roberts, F. E.; Hoinowski, A. M.; Brenner, G. S.; Lee, T. B. K.; Lumma, W. C.;
10. Ion exchange of MS4A is well known in water: (a) Sherman, J. D. Appl. Sci. 1984,
80, 583–623; (b) Townsend, R. P.; Harjula, R. Mol. Sieves 2002, 3, 1–42.