Salen-derived catalysts containing secondary basic groups in the addition of diethylzinc to aldehydes

Article abstract of DOI:10.1021/ol016535u

matrix presented A set of modular bifunctional salen catalysts which contain Lewis acid and Lewis base activating groups is described. These groups can be altered independently to control nucleophilic and electrophilic activation of the reacting substrates. These salen-derived catalysts show enhanced reactivity in the addition of diethylzinc to aldehydes with respect to most other salen, amino alcohol, and diamine derived catalysts and reactivity comparable to that of Ti complexes of bis-sulfonamides and diols.

Full text of DOI:10.1021/ol016535u

ORGANIC
LETTERS
2001
Vol. 3, No. 19
3053-3056
Salen-Derived Catalysts Containing
Secondary Basic Groups in the Addition
of Diethylzinc to Aldehydes
Erin F. DiMauro and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
marisa@sas.upenn.edu
Received August 3, 2001
ABSTRACT
A set of modular bifunctional salen catalysts which contain Lewis acid and Lewis base activating groups is described. These groups can be
altered independently to control nucleophilic and electrophilic activation of the reacting substrates. These salen-derived catalysts show enhanced
reactivity in the addition of diethylzinc to aldehydes with respect to most other salen, amino alcohol, and diamine derived catalysts and
reactivity comparable to that of Ti complexes of bis-sulfonamides and diols.
The use of bifunctional ligand systems in catalysis is an
attractive method of emulating the reactivity of natural
enzymes.1 Over the past decade, catalysts containing chiral
ligands with two or more reactive sites have proven suc-
cessful in the asymmetric construction of C-C bonds.2 In
particular, complexes containing both a Lewis acid center
and a Lewis basic moiety have recently emerged as powerful
catalysts.3
electrophile of a given reaction and with the optimal spacing
and orientation between groups. The structurally well-defined
and rigid salen architecture was chosen as a starting point,
leading to general structure 1 (Figure 1). In a prior report,
The purpose of this work is to construct scaffolds in which
these elements can be independently manipulated. In par-
ticular, new compounds can be envisioned with functional
groups specifically tailored to activate the nucleophile and
(1) (a) Murthy, N. N.; Mahroof-Tahir, M.; Karlin, K. D. J. Am. Chem.
Soc. 1993, 115, 10404-10405. (b) Pessiki, P. J.; Dismukes, G. C. J. Am.
Chem. Soc. 1994, 116, 898-903. (c) Gobel, M. W. Angew. Chem., Int. Ed.
1994, 33, 1141-1143. (d) Young, M. J.; Chin, J. J. Am. Chem. Soc. 1995,
117, 10577-10578. (e) Kodera, M.; Shimakoshi, H.; Kano, K. Chem.
Commun. 1996, 1737-1738.
(2) For reviews, see: (a) Sawamura, M.; Ito, Y. Chem. ReV. 1992, 92,
857-871. (b) Steinhagen, H.; Helmchen, G. Angew. Chem., Int. Ed. Engl.
1996, 35, 2339-2342. (c) van den Beuken, E. K.; Ferringa, B. L.
Tetrahedron 1998, 54, 12985-13011. (d) Rowlands, G. J. Tetrahedron
2001, 57, 1865-1882.
Figure 1.
the utility of the Lewis acid/Bronsted base BINOL-salen 2
in asymmetric Michael reactions has been outlined.4 In this
Letter, the potential of compounds such as 1 to act as
bifunctional Lewis acid/Lewis base catalysts is examined.5
10.1021/ol016535u CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/18/2001

To probe the bifunctional activity of these ligands, the
addition of Et2Zn to benzaldehyde was selected for initial
study. When a â-aminoalkoxy zinc catalyst such as 3 is
employed, this reaction proceeds by dual activation of the
aldehyde electrophile and diethylzinc nucleophile (Figure
2).3b,c,6 In applying framework 1 to this reaction, an apical
catalyze the addition of Et2Zn to aldehydes with excellent
enantioselectivity, these catalysts are generally less reactive
than the titanium-based systems.6 Herein we report the
discovery of a new class of catalysts that demonstrate
excellent reactivity and good enantioselectivity in the absence
of Ti(OiPr)4.
As the first step toward development of this class of
catalysts, the nature of the tether for the Lewis base was
examined. The tether must be short and/or rigid enough to
prevent internal complexation to the metal. A number of
different tethers satisfy this criteria, leading to a variety of
useful bifunctional salens, two of which are shown below
(Figure 3).
Figure 2.
coordination site on the salen metal center could act as a
Lewis acid site to activate the aldehyde7 while the tethered
base could independently activate the Et2Zn nucleophile (4,
Figure 2).8
In the search for highly reactive Lewis acid catalysts for
this reaction, titanium complexes of chiral diols and bis-
(sulfonamide) ligands have proven the most successful to
date.9 One drawback of these systems is the requirement for
a stoichiometric amount of Ti(OiPr)4. Although various chiral
ligands (amino alcohols, diols, etc.) have been reported to
Figure 3.
The ease of preparation of the salen backbone lends itself
to the rapid modular construction of a number of bifunctional
ligands in which both the tether and diamine linker can be
varied. Achiral and racemic compounds of type 1 have
formerly been used as binucleating agents in the preparation
of bimetallic complexes10 and as ditopic ligands for salt
extraction.11 Salens 7, 8,12 and 9 can be synthesized in three
simple steps from phenol 10 (Scheme 1). The syntheses of
5 and 6 are somewhat longer, but similarly straightforward.13
(3) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551-5553. (b) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J.
Am. Chem. Soc. 1986, 108, 6071-6072. (c) Noyori, R.; Kitamura, M.
Angew. Chem., Int. Ed. Engl. 1991, 30, 49-69. (d) Kitajima, H.; Ito, K.;
Aoki, Y.; Katsuki, T. Bull. Chem. Soc. Jpn. 1997, 70, 207-217. (e) Ooi,
T.; Kondo, Y.; Maruoka, K. Angew. Chem., Int. Ed. Engl. 1997, 36, 1183-
1184. (f) Sibi, M. P.; Cook, G. R.; Liu, P. Tetrahedron Lett. 1999, 40,
2477-2480. (g) Puigjaner, C.; Vidal-Ferran, A.; Moyano, A.; Pericas, M.
A.; Riera, A. J. Org. Chem. 1999, 64, 7902-7911. (h) Takamura, M.;
Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Chem. Pharm. Bull.
2000, 48, 1586-1592. (i) Hamashima, Y.; Sawada, D.; Nogami, H.; Kanai,
M.; Shibasaki, M. Tetrahedron, 2001, 57, 805-814. (j) Gamble, M. P.;
Smith, A. R. C.; Wills, M. J. Org. Chem. 1998, 63, 6068-6071.
(4) DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2001, 3, 1641-1644.
(5) A few examples of chiral salens with secondary functional groups
have been reported. Phosphines: (a) Quirmbach, M.; Kless, A.; Holz, J.;
Tararov, B.; Bo¨rner, A. Tetrahedron: Asymmetry 1999, 10, 1803-1811.
(b) Kless, A.; Kadyrov, R.; Bo¨rner, A.; Holz, J.; Kagan, H. B Tetrahedron
Lett. 1995, 36, 4601-4602. Phenol ethers: (c) Keller, F.; Rippert, A. J.
HelV. Chim. Acta 1999, 82, 125-137.
Scheme 1a
(6) For a recent review, see: (a) Pu, L.; Yu, H. Chem. ReV. 2001, 101,
757-824. (b) Soai, K.; Shibata, T. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
pp 911-922.
a (a) SnCl4, CH2O, nBu3N. (b) CH2O, morpholine, HOAc. (c)
diamine, EtOH.
(7) For previous applications of salen ligands as catalysts in the Et2Zn
addition to aldehydes, see ref 5c and the following: Cozzi, P. G.; Papa,
A.; Umani-Ronchi, A. Tetrahedron Lett. 1996, 37, 4613-4616.
(8) Bifunctional catalysts have been proposed in the Et2Zn additions with
binaphthyl-3, 3′-dicarboxamides. See ref 3d.
(9) (a) Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1991, 30,
1321-1323. (b) Seebach, D.; Beck, A. K.; Schmidt, B.; Wang, Y. M.
Tetrahedron 1994, 50, 4363-4384. (c) Takahashi, H.; Kawakita, T.;
Yoshioka, M.; Kobayashi, S.; Ohno, M. Tetrahedron Lett. 1998, 30, 7095-
7098. (d) Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi,
S. Tetrahedron 1992, 48, 5691-5700. (e) Pritchett, S.; Woodmansee, D.
H.; Gantzel, P.; Walsh, P. J. J. Am. Chem. Soc. 1998, 120, 6423-6424. (f)
Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 40,
92-138.
The zinc complexes of ligands 5-914 (eq 1) were
examined as catalysts for the addition of Et2Zn to benz-
aldehyde (Table 1, eq 2). A comparison of the reactivity of
(10) (a) Liable-Sands, L. M.; Incarvito, C.; Rheingold, A. L.; Qin, C. J.;
Gavrilova, A. L.; Bosnich, B. Inorg. Chem. 2001, 40, 2147-2155. (b)
Adams, H.; Fenton, D. E.; Haque, S. R.; Heath, S. L.; Ohba, M. J. Chem.
Soc., Dalton Trans. 2000, 1849-1856. (c) De Angelis, S.; Solari, E.; Gallo,
E.; Floriani; C.; Chiesi-Villa, A.; Rizzoli, C. Inorg. Chem. 1996, 35, 5995-
6003. (d) Karunakaran, S.; Kandaswamy, M. J. Chem. Soc., Dalton Trans.
1995, 1851-1855.
3054
Org. Lett., Vol. 3, No. 19, 2001

Table 1. Addition of Diethylzinc to Benzaldehyde Using
Bifinctional Catalysts (eqs 1 and 2)
Table 2. Addition of Diethylzinc to Benzaldehyde (eq 2)
Using the Zinc Metal Complexes from Salensa
entry
ligand
M
t (h)
convn (%)a,b
ee (%)a,c
e
pKa
entry ligand T (°C) t (h) convn (%)b,c ee (%)c,d HA+
1
2
3
4
5
6
7
8
9
5
6
7
8
9
8
8
8
8
Zn
Zn
Zn
Zn
Zn
Ni
Cu
Mg
18
4
2
2
2
2
2
2
2
81 (3)
95 (1)
84
100
95
99 (2)
100
99
28 (S)
2 (R)
23 (S)
54 (S)
19 (S)
32 (R)
10 (S)
3 (S)
1
2
15
8
-30
-30
-30
-30
-50
rt
6
12
6
90
98
72
99
97
95
76 (S)
80 (S)
77 (S)
51 (S)
78 (S)
18 (R)
18 (R)
57 (S)
21 (S)
82 (S)
73 (S)
48 (S)
52 (S)
9
6
3
8
6
4
5
6
7
8
9
10
11
12
13
16
16
17
17
18
19
20
20
21
21
6
20
3
6
6
6
30
6
6
6
5
5
-3
-3
d
Ti(OPr)2
100
55 (S)
-30
-30
-30
-30
-30
rt
8 (3)
2 (15)
3 (7)
85
33
NA
NA
9
a Determined by chiral GC (CyclodexB column). b Values in parentheses
refer to the amount of benzyl alcohol byproduct. c Absolute configuration
assigned by comparison to the literature. d Reaction not homogeneous.
9
9
9
90 (5)
5 (11)
-30
the different zinc complexes (entries 1-5) revealed that
salens containing amine Lewis bases (7, 8, and 9) were much
more efficient catalysts than the salens containing ethereal
Lewis bases (5 and 6). This result is consistent with the
supposition that superior activation of the nucleophilic Et2Zn
would be achieved with a more Lewis basic group.
Since the zinc complex of the trans-cyclohexanediamine-
derived salen 8 displayed the best reactivity and selectivity
(entry 4), complexes of 8 were investigated further. While
the Ni,15 Cu, Mg, and Ti(OiPr)2 complexes16 with 8 were
also effective catalysts (entries 6-9), no increase in enantio-
selectivity was observed.
On the basis of the reactivity of the zinc complex of 8,
several further derivatives, 15-21, were examined to directly
probe the role of the Lewis base component (Table 2). An
even more active catalyst was observed with the slightly more
basic piperidyl salen 15,12 resulting in 90% conversion after
6 h at -30 °C (entry 1). Under the same conditions, the
a Reactions performed in PhCH3 using 10 mol % of ligand and 2.1 equiv
of Et2Zn. b Determined by chiral GC (CyclodexB column). c Values in
parentheses refer to the amount of benzyl alcohol byproduct. d Absolute
configuration assigned by comparison to the literature. e Estimated from
the pKa(H2O) values of N-methylmorpholine, N-methylpiperidine, benzyl-
amine, methylamine, pyridine (Jencks, W. P.; Regenstein, J. Ionization
Constants of Acids and Bases. In Handbook of Biochemistry and Molecular
Biology, 3rd Ed.; CRC Press: Cleveland, 1975; Vol. 1), and dimethyl ether
(Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry 3rd Ed.; Harper & Row: New York, 1987).
slightly less basic morpholine analogue 8 (entry 3) provided
lower conversion (72%). However, after 12 h at -30 °C with
the morpholine catalyst (entry 2), good conversion (98%)
and enantioselectivity (80% ee) were observed. Surprisingly,
the less basic pyridyl derivative 1617 provided the most
reactive catalyst (entries 4 and 5). With the methyl ether
derivative 17, a much less reactive catalyst was formed which
caused only 8% conversion after 6 h at -30 °C (entry 7).15
Indeed, significant conversion was only observed at higher
temperatures (i.e., rt, entry 6).
A similar loss in reactivity was observed with salens
lacking secondary Lewis bases. For example, the catalyst
derived from tert-butyl salen 18 provided only 2% conversion
after 6 h at -30 °C (entry 8) along with significant amounts
of the reduced byproduct benzyl alcohol (15%). Indeed, the
catalyst derived from 18 requires 18 h at room temperature
to achieve high conversion (90%).18 To rule out any steric
effect from the larger tert-butyl groups in 18, an isosteric
analogue (19) of 8 and 15 was synthesized. With the catalyst
(11) (a) Tasker, P. A.; White, D. J. Eur. Pat. WO0058225, 2000. (b)
Miller, H. A.; Laing, N.; Parsons, S.; Parkin, A.; Tasker, P. A.; White, D.
J. J. Chem. Soc., Dalton Trans. 2000, 3773-3782. (c) White, D. J.; Laing,
N.; Miller, H. A.; Parsons, S.; Coles, S.; Tasker, P. A. Chem. Commun.
1999, 2077-2078.
(12) Ligands 8 and 15 have previously been synthesized in racemic
form: see ref 11.
(13) See Supporting Information.
(14) Zinc complexes were prepared in situ by stirring the ligand with an
equivalent amount of Et2Zn for 1 h at room temperature prior to the addition
of substrates.
(15) A reversal in facial selectivity was observed for this catalyst, which
may indicate a different binding mode of the lignad or substrates for this
case or an alternate mechanism.
(16) Ni and Cu complexes of 8 were prepared from the corresponding
metal acetates (see Supporting Information) while the Mg and Ti(OiPr)2
complexes were generated in situ by treatment of 8 with 1 equiv of MgBu2
or Ti(OiPr)4 for 1 h.
(17) For a previous synthesis of ligand 16, see: Lam, F.; Xi Xu, J.; Shing
Chan, K. J. Org. Chem. 1996, 61, 8414-8418.
Org. Lett., Vol. 3, No. 19, 2001
3055

derived from 19 (entry 9), again almost no conversion (3%)
was observed after 6 h at -30 °C. Catalysts derived from
salens 20 and 21, containing R-branched amines, were less
reactive (entries 10-13).
From these results, it appears that a good Lewis base is
necessary to achieve a more active catalyst. Furthermore,
the thermodynamic and kinetic basicity of this Lewis base
can be correlated to catalyst reactivity. Figure 4 illustrates a
consistent with this observation is illustrated in Figure 2.
To provide further evidence for this model, the reaction in
eq 2 was examined for a nonlinear effect using the Zn
complex derived from 8. A linear correlation was found
between the product enantiomeric excess and the enantio-
meric excess of 8, consistent with monomeric catalyst model
4.20
To demonstrate that the catalyst system developed can
accept different substrates, a number of other aldehydes were
examined in the Et2Zn addition with 8 (eq 3, Table 3).
Table 3. Addition of Diethylzinc to Aldehydes (eq 3) Using
8Zna
entry
R
t (h)
convn (%)b
ee (%)b
1
2
3
4
5
6
Ph
12
36
10
36
24
36
98
97
92
99
78
84
80
89
83
69
75
91
p-MeO-C6H4
p-Cl-C6H4
o-Me-C6H4
cHx
(CH3CH2)2CH
a Reactions performed in PhCH3 using 10 mol % of ligand and 2.1 equiv
of Et2Zn. b Determined by chiral GC (CyclodexB column).
Figure 4. Conversion vs pKa of the conjugate acid of the Lewis
base in bifunctional salens for the reaction in eq 2 (6 h, -30 °C).
Similar levels of conversion and enantiomeric excess were
obtained for aromatic aldehydes as well as aliphatic alde-
hydes.
A set of modular bifunctional salen catalysts has been
described which contain Lewis acid and Lewis base activat-
ing groups. These groups can be altered independently to
control nucleophilic and electrophilic activation of the
reacting substrates. All of the salen ligands described are
easily prepared crystalline solids that are stable to air and
moisture. The morpholinyl, piperidyl, and pyridyl salen
derived catalysts show enhanced reactivity with respect to
most other salen, amino alcohol, and diamine derived
catalysts21 and reactivity comparable to that of Ti complexes
of bis-sulfonamides and diols.9 This promising class of
ligands is currently being examined in related reactions.
plot of the pKa values of the conjugate acids of the Lewis
base components for the salens described in Table 2 against
conversion. For the derivatives in which the base is attached
by a methylene group to the salen ring system, a similar
steric environment is expected in the vicinity of the sp3 base.
As such, the observed linear correlation between the con-
jugate acid pKa values and reactivity of 15, 8, and 17 most
likely reflects a difference in reactivity due to the inherent
basicity (thermodynamic). On the other hand, the departure
from this trend with pyridyl derivative 16 indicates that the
less hindered pyridine with softer Lewis base character
possesses superior kinetic basicity in this catalyst structure.
Departure from the trend is also observed with R-branched
amine derivatives 20 and 21, indicating decreased kinetic
basicity as a result of steric hindrance.
Acknowledgment. Financial support was provided by the
National Institutes of Health (GM59945), Merck Research
Laboratories, and DuPont. We thank Prof. Patrick Walsh for
helpful discussions and the use of GC instrumentation.
The above data support a direct role for the Lewis base in
the course of the reaction. In addition, the enantiomeric
excess of the reaction in eq 2 with the Zn complex from 8
did not vary significantly as a function of conversion,19
indicating that the composition of the catalytic species does
not change over the course of the reaction. One model (4)
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL016535U
(18) Cozzi et al. (ref 7) have reported that 18 provides up to 70% ee in
the addition of Et2Zn to PhCHO using a different set of conditions. To
obtain good yields, reaction temperatures of 0 °C or room temperature were
required.
(20) In reactions performed using the same conditions, the following
selectivities were observed for PhCHO at 97% conversion: 100% ee 8,
76% ee product; 50% ee 8, 37% ee product.
(19) Using 10 mol % of catalyst at -35 °C over 15 h, the following
data were collected: 9% conversion, 83% ee; 47% conversion, 85% ee;
81% conversion; 86% ee; 94% conversion, 87% ee.
(21) In a direct comparison (2 mol %, 0 °C), the Zn complex of 8 was
found to be at least 3-fold more reactive than the DAIB (see ref 3b-c, 6)
or MIB (Nugent, W. Chem. Commun. 1999, 1369-1370) zinc complexes.
3056
Org. Lett., Vol. 3, No. 19, 2001