Paracyclophanes in action: Asymmetric catalytic dialkylzinc addition to imines using [2.2]paracyclophane-based N,O-ligands as catalysts

Article abstract of DOI:10.1002/ijch.201100078

The asymmetric addition of dibutylzinc to imines is achieved by employing [2.2]paracyclophane-based ketimine ligands with good to excellent enantioselectivities. A comparison to other organozinc reagent is made. Copyright

Full text of DOI:10.1002/ijch.201100078

Full Paper
DOI: 10.1002/ijch.201100078
Paracyclophanes in Action: Asymmetric Catalytic
Dialkylzinc Addition to Imines Using [2.2]Paracyclophane-
based N,O-Ligands as Catalysts
Stefan Dahmen*[a] and Stefan Brꢀse*[b]
Abstract: The asymmetric addition of dibutylzinc to imines
is achieved by employing [2.2]paracyclophane-based keti-
mine ligands with good to excellent enantioselectivities. A
comparison to other organozinc reagent is made.
Keywords: amines · cyclophanes · zinc
thylzinc.[2d,4] Examples for the use of also commercially
available dibutylzinc, however, are very rare.[2c,7] This is
even more astonishing since the products, e.g., chiral
phenyl pentylamine derivatives,[8,9] cannot easily been
made by any other asymmetric catalytic method.
We have concentrated our efforts on the dibutylzinc
addition using a class of [2.2]paracyclophane-based keti-
mine ligands 1 and 2 (Figure 1), which have already been
successfully applied in related processes.[5a,b] These li-
gands, first reported by the Rozenberg group,[6] are readi-
ly available as both enantiomers in few steps. The catalyt-
ic reaction employing a-amido sulfones 3 as masked
imine precursors[11] belongs to the latter class of solely
zinc-mediated processes. We here report the first in-depth
investigation on the asymmetric catalytic addition of
butyl groups to imines.
The addition of dibutylzinc to a-amido sulfone 3a pro-
ceeds via a two-step process (Table 1). Deprotonation of
the sulfone by one equivalent of dibutylzinc generates the
formyl imine 4a in situ via elimination of the sulfinate. In
a second step, the addition of another equivalent of zinc
reagent takes place. In contrast to, for example, tert-butyl
carbamate protected imines, which can be isolated and
are employed in a variety of catalytic processes, formyl
imines tend to be easily hydrolyzed to the corresponding
Chiral amines represent one of the most actively investi-
gated classes of compounds due to their importance as
building blocks for biologically active compounds. Hence,
the catalytic asymmetric preparation of amines by addi-
tion of organometallic reagents to C=N bonds is a field of
considerable importance to homogeneous catalysis.[1]
While there have been numerous efforts to control the
stereoselectivity of this reaction either by chiral auxiliar-
ies[1a,b] or (stoichiometric) chiral ligands,[1d] the catalytic
asymmetric addition of simple alkylmetals has only been
achieved quite recently. In this context, the enantioselec-
tive addition of alkylzinc reagents to imines has attracted
considerable interest in the last years. Two concepts can
be distinguished: the addition of zinc reagents catalyzed
by a transition metal complex other than zinc,[2–4] and the
in situ formation of active catalyst based on the zinc com-
plex of (usually) an N,O-ligand.[5]
Most of the studies reported so far are on the catalytic
ethylation of imines using diethylzinc as readily available,
reactive, and selective zinc reagent. Some studies have
also given examples of, or been entirely focused on, dime-
[a] S. Dahmen
BASF SE, ED/DN - H201
67056 Ludwigshafen (Germany)
phone:+49 (0)621 6097720
fax:+49 (0)621 606697720
e-mail: Stefan.dahmen@basf.com
[b] S. Brꢀse
Institute of Organic Chemistry, Karlsruhe Institute of Technolo-
gy
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
phone:+49 (0)721 608-4 2902
fax:+49 (0)721 608-4 8581
e-mail: braese@kit.edu
Figure 1. Ketimine ligands.
Isr. J. Chem. 2012, 52, 139 – 142
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Table 1. Optimization of reaction conditions (selected examples).[a]
S. Dahmen and S. Brꢀse
Entry
Catalyst
(mol%)
Conditions
conv.[b]
(%)
ee[c] (%)
1
2
3
4
5
6
7
8
9
(Rp,S)-2 (2)
(Rp,S)-2 (2)
(Rp,S)-2 (2)
(Sp,S)-2 (2)
(Sp,S)-1 (2)
(Rp,S)-1 (2)
(Rp,S)-1 (0.5)
(Rp,S)-1 (1)
(Rp,S)-1 (5)
(Rp,S)-2 (5)
RT, 16 h, heptane
>99
98
85
95
94
99
88
95
>99
>99
83 (R)
84 (R)
84 (R)
50 (S)
68 (S)
88 (R)
66 (R)
75 (R)
88 (R)
90 (R)
108C, 16 h, heptane
À208C, 16 h, heptane/toluene
108C, 16 h, heptane
108C, 16 h, heptane
108C, 16 h, heptane
108C, 16 h, heptane
108C, 16 h, heptane
108C, 16 h, heptane
108C, 16 h, heptane
10
[a] Substrate 3a (0.25 mmol), ligand, dibutylzinc (0.75 mmol). [b] Determined by GC and RP-HPLC. [c] Determined with chiral stationary
phase HPLC (Chiralcel OD).
aldehydes. However, when formed in situ, they are excel-
lent substrates for the catalytic addition of zinc reagents.
First results using our reference catalyst (Rp,S)-2 indi-
cated that a reaction temperature of 108C was optimal
using a highly unpolar reaction medium such as heptane
(entry 2). In fact, the reactions were run solely in the 1
molar dibutylzinc in heptane stock solution without
adding more solvent. Previous studies had also shown
that related addition processes can also be optimized for
a different temperature window when more polar sol-
vents such as toluene were used (entry 3).[5b] In this case
the results in heptane were identical to the experiments
in a heptane/toluene mixture at lower temperature. We
therefore carried out a ligand screening with the experi-
mentally simpler heptane protocol which, by comparison,
also resulted in better reproducibility (deviation in repeti-
tive runs <1% ee).
Ligand (Rp,S)-1 gave slightly better results for the sub-
strate 3a than (Rp,S)-2 when employed on a 2 mol%
level (entry 8 vs. 2). When we optimized the ligand load-
ing however, we obtained product 5a in 90% ee with
5 mol% of (Rp,S)-2 (entry 10) and in 88% ee with
5 mol% of (Rp,S)-1 (entry 9). It must also be mentioned
that the enantioselectivity of the process is highly depen-
dent on the quality of the employed dibutylzinc. Com-
mercially available dibutylzinc solutions of optically iden-
tical quality can result in differences in enantioselectivity
of more than 20% ee. This is probably due to residual
zinc salts in the solution, which can dramatically enhance
undirected background reactions. In a previous work on
the arylation of aldehydes, we have been able to counter-
act the effect of zinc salts by additives such as polyethy-
lene glycol ethers (Di-MPEG)[12] or, in other cases, meth-
ane sulfonamide. However in the case of imine substrates,
we have so far not been able to observe positive effects
of additives on enantioselectivity.
Given the small difference in enantioselectivity for the
ligands (Rp,S)-2 and (Rp,S)-1, we chose to employ both li-
gands in a broader substrate screening (Table 2). In
nearly all cases, excellent enantioselectivity could be ach-
ieved. All substituted phenyl substrates gave enantiose-
lectivities of 90% ee or higher. Only the 1-naphthyl imine
derivative (entries 11, 12) gave rise to somewhat lower
enantioselectivity (68% ee). As expected however, nei-
ther of the two ligands gave the best ee for each substrate.
Interestingly, ligand (Rp,S)-2 seems to be superior for 4-
substituted substrates (entries 2, 6, 10), while (Rp,S)-1
consistently gave better results for 3-substituted imine
precursors (entries 3 and 7). This was both true for elec-
tron-rich as well as electron-poor substrates. Clearly, the
steric demand of substituent plays a more important role
than its electronic properties, a fact often observed in di-
ethylzinc addition reactions to aldehydes.
When compared to the results of the diethylzinc addi-
tion reactions,[5a] the catalysts showed somewhat lower se-
lectivity. They have to be applied on a 5 mol% scale to
achieve satisfactory enantioselectivity, while in the former
case 2 mol% sufficed for most substrates. We attribute
this behavior to a combination of the slightly lower reac-
tivity and higher steric demand of the dibutylzinc reagent.
Representative reaction conditions for the synthesis of
5a: Ligand (Rp,S)-1 (5.4 mg, 5 mol%) and the imine sub-
strate 3a (69 mg, 0.25 mmol) were weighted into a 10 mL
crimp vial and a magnetic stir bar was added. The vial
140
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Isr. J. Chem. 2012, 52, 139 – 142

Paracyclophanes in Action: Asymmetric Catalytic Dialkylzinc Addition to Imines Using [2.2]Paracyclophane-based N,O-Ligands
Table 2. Substrate scope[a]
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Entry
Imine 3, R=
Catalyst
Yield[b] (%)
ee[c] (%)
1
2
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4
5
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8
4-MeO-C6H4
4-MeO-C6H4
3-Cl-C6H4
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(Rp,S)-2
(Rp,S)-1
(Rp,S)-2
(Rp,S)-1
(Rp,S)-2
(Rp,S)-1
(Rp,S)-2
81
85
91
89
85
80
85
87
81
85
94
92
92
94
97
92
88
91
97
93
84
90
68
68
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9
10
11
12
1-naphtyl
[a] Substrate (0.25 mmol), ligand (5 mol%), dibutylzinc
(0.75 mmol), 16 h. Optimal reaction temperatures: 208C (entries 1,
2), 108C (entries 11, 12), 08C (entries 3–10). [b] Isolated yield. [c]
Determined by HPLC with chiral stationary phase (Chiralcel OD).
Absolute configuration established as (R) via Cbz-protected 1-
phenyl pentylamine derived from 5a by comparison with literature
values.[10]
was closed and flushed with argon for several minutes.
Subsequently, the vial was placed into a magnetically
stirred reaction block and cooled to 108C. Dibutylzinc
(0.75 mL, 1.0 molar solution in heptane, Fluka or Al-
drich) was added and the heterogeneous mixture was
stirred for 16 h. Aqueous workup and chromatography on
silica afforded the desired product 5a in 95% yield and
88% ee (Chiralcel OD, 1.0 mLminÀ1. heptane/2-propanol
90/10).
In conclusion, we have reported the first study dedicat-
ed to the asymmetric catalytic addition of dibutylzinc to
imine substrates giving rise to 1-aryl pentylamine deriva-
tives in high yield and good to excellent enantioselectivi-
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Acknowledgments
T. Dahmen is acknowledged for experimental support
and M. Ridder for carefully reading the manuscript. S.B.
thanks the Deutsche Forschungsgemeinschaft (DFG) for
support through project B2 of SFB/TRR 88 (“Koopera-
tive Effekte in homo- und heterometallischen Komplex-
en”).
Isr. J. Chem. 2012, 52, 139 – 142
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S. Dahmen and S. Brꢀse
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Received: July 26, 2011
Accepted: October 11, 2011
Published online: January 19, 2012
142
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