Large-Scale Synthesis of Symmetric Tetramine Ligands by Using a Modular Double Reductive Amination Approach

Article abstract of DOI:10.1002/ejoc.201700772

Tetramine ligands play an important role in a broad range of transition metal catalyzed transformations. We here present a flexible and modular approach to this class of ligands using a double reductive amination strategy. Thus, the target molecules were prepared in a highly efficient manner in only three steps, from commercially available starting materials. Excellent overall yields, of up to 96 % were reached. Notably, chiral C ₂-symmetric ligands are available using this procedure. All reactions are easily scalable and the tetramine ligands were obtained in excellent purity, while only a single chromatographic purification is required at the end of the three step sequence.

Full text of DOI:10.1002/ejoc.201700772

A Journal of
Accepted Article
Title: Large Scale Synthesis of Symmetric Tetramine Ligands Using a
Modular Double Reductive Amination Approach
Authors: Maik Tretbar and Christian B. W. Stark
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700772
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700772
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201700772
SHORT COMMUNICATION
Large Scale Synthesis of Symmetric Tetramine Ligands Using a
Modular Double Reductive Amination Approach
Maik Tretbar,[a,b] and Christian B. W. Stark*[a,b]
Abstract: Tetramine ligands play an important role in a broad range
of transition metal catalyzed transformations. We here present a
flexible and modular approach to this class of ligands using a double
reductive amination strategy. Thus, the target molecules were
prepared in a highly efficient manner in only three steps, from
commercially available starting materials. Excellent overall yields, of
oxidations[8,9] with hydrogen peroxide as terminal oxidant have
been reported. [7] The details, however, on how to control iron’s
delicate redox chemistry through tailor-made ligands appear far
from being understood. A straight-forward and flexible synthesis
of stabilizing ligands is a key to the success of this objective.
The most relevant sites of ligand modification are summarized in
Figure 1 (right). These include variations at the backbone
(marked in red in Figure 1), in the middle wing (R’, coloured in
blue in Figure 1), and at the periphery close to the aromatic
nitrogen donors (R’’, marked in green in Figure 1).
2
up to 96 % were reached. Notably, chiral C -symmetric ligands are
available using this procedure. All reactions are easily scalable and
the tetramine ligands were obtained in excellent purity, while only a
single chromatographic purification is required at the end of the three
step sequence.
Figure 1. Toftlund’s “BPMEN”-ligand L1 and potential sites of modification.
Introduction
Transition metal catalysis is a key enabling technology of
modern organic synthesis. The vast majority of these processes
use specifically designed ligands to control reactivity and
selectivity of the catalytically active metal center.[1,2] Factors to
influence these two central elements of catalysis include a.)
steric shielding, b.) modulation of electronic properties, and c.)
fixation of geometry (e. g. bite-angle and configuration) around
the metal center. The optimization of all these parameters
usually requires evaluation of a large number and broad
spectrum of ligands. In order to keep this process as effective as
possible a flexible and efficient ligand synthesis is desirable.[2]
Over the past years, ligand stabilized iron oxidation catalysis has
attracted significant and steadily increasing attention.[3] Based
on mechanistic considerations and a structural analysis of non-
heme iron proteins, a number of artificial ligand systems for
biomimetic oxidation catalysis have been developed, many of
[10]
As part of our ongoing interest in oxidation catalysis
and
[11]
related synthetic applications,
scalable and modular approach to tetramine ligands.
we herein describe a simple,
[12]
Results and Discussion
With the aim to develop a modular synthesis of tetradentate
nitrogen donor ligands,[ we first investigated a set of different
tactics for their assembly. Scheme 1 summarizes different
approaches in a simplified retrosynthetic analysis. Both N-
alkylations and reductive aminations (as well as combinations
12]
which are designed as methane monoxygenase (MMO)
mimetics.[
4-9]
Structurally, most of these ligands, feature a
tetramine system with two terminal pyridines connected to a
central diamine unit via a C -bridge (Figure 1). A prototypical
2
example is Toftlund’s so-called BPMEN ligand (L1 in Figure 1;
BPMEN = N,N’-dimethyl-N,N’-bispyridine-2-ylmethyl-ethane-1,2-
diamine). [4]
Many impressive applications of such ligand stabilized iron
oxidations e. g. in olefin epoxidations[3,6] and biomimetic C-H-
[
[
a]
b]
Dr. M. Tretbar, Prof. Dr. C. B. W. Stark
Fachbereich Chemie, Institut für Organische Chemie
Universität Hamburg
Martin-Luther-King-Platz 6, 20146 Hamburg (Germany)
E-mail: stark@chemie.uni-hamburg.de
https://www.chemie.uni-hamburg.de/oc/stark/
Initial experiments for this investigation were carried out at:
Fakultät für Chemie und Mineralogie, Institut für Organische
Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig
(Germany).
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Retrosynthetic considerations for the modular assembly of
tetramine ligands.
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European Journal of Organic Chemistry
10.1002/ejoc.201700772
SHORT COMMUNICATION
thereof) were selected as the most promising tools for the
envisaged C-N-bond formations.
In most instances good to excellent yields of crystalline materials
(1a-11a) with an average yield of 82% were obtained (Table 1,
entries 1-11). Results were found to be fairly independent of the
backbone substitution and whether a pyridine aldehyde or
ketone (Table 1, entries 7, 8 and 11, 12) was used as the
Strategies were evaluated for their efficiency and flexibility to
access compounds of the general structure shown in Figure 1
and Scheme 1. After some experimentation we found a double
reductive amination route to be most effective (Scheme 1). Thus, substrate. Notably, E-selectivity was high, even when a diaryl
a central diamine was first reductively coupled with a 2-carbonyl
pyridine (Table 1). The required backbone diamines were either
ketone was used for condensation (cf. for instance Table 1,
entry 8). Imine configuration was unambiguously determined
both by X-ray crystallography (where appropriate) as well as by
1H-NMR spectroscopic investigations (see Figure 2 and the SI
purchased from commercial suppliers or in the case of rac-trans-
13]
1
,2-diaminocyclo-pentane,[
rac-trans-1,2-diamino-1,2-diphen-
yl-ethane[ and rac-trans-9,10-dihydro-9,10-ethano-anthracene-
14]
N
for details). Due to a vicinal n  * interaction the imine proton
1
1,12-diamine[15] synthesized according to literature procedures.
In order to obtain high yields and a high purity of tetramines 1b-
2b it was found to be most efficient to isolate the intermediary
resonances of E-isomers show a clear downfield shift as
compared to the Z-configured products. We were thus able to
determine the configuration of all diimines synthesized except
for diimine 12a which proved not to be isolable (see the
supporting information for details). In this case the crude
material was directly used for the next step.
1
diimines 1a-12a prior to reduction (Table 1). Best results were
Table 1. Yields for diimine formation and their subsequent reduction.
Figure 2. Representative X-ray structure of an E,E-diimine (9a) and chemical
1
shift trends in H-NMR analyses of E- versus Z-imines.
Entry
Diamine
n, R
Pyridine
R’, R’’
Yield
Diimine
Yield
Tetramine
1
2
3
4
5
0, H
H, H
H, H
H, H
1a (98%)
2a (86%)
3a (62%)
4a (43%)
5a (94%)
1b (99%)
2b (99%)
3b (99%)
4b (84%)
5b (98%)
0, -CH
0, -CH
0, -CH
0,
2
2
2
2 2
CH CH -
(CH
(CH
2
)
2
CH
CH
2
2
-
-
Subsequent reduction of diimines 1a-12a (Table 1) with sodium
borohydride in methanol proceeded smoothly and resulted in the
formation of analytically pure products 1b-12b in excellent yields.
No further purification was required (Table 1, see supporting
information for details). Thus, the tetramine core structures were
prepared in high efficiency without the necessity of any
chromatographic purification step. It is worth noting that the
reverse approach of using a reductive amination of central 1,2-
dicarbonyls (either dialdehydes or oxalic acid derivatives) with 2-
aminomethyl pyridines was ineffective (Scheme 1, 1 step of
Route B).
Interestingly, sodium borohydride reduction of prochiral diimines
7a and 8a (Table 1, entries 7 and 8) proceeded not only in high
yields but also with excellent diastereoselectivities (Scheme 2).
)
2 2
H, CH
H, H
3
3
dihydro-ethano-
anthracenediamine
6
0, dihydro-ethano-
anthracenediamine
H, CH
6a (92%)
6b (99%)
7a (25%)[a]
7
8
9
0, H
0, H
0, Ph
1, H
CH
3
, H
7b (99%)
8b (94%)
9b (97%)
10b (96%)
Ph, H
H, H
H, H
8a (80%)
9a (87%)
10a
16
st
10
11
12
(
100%)[b]
2
In both cases the (racemic) C -symmetric isomer was isolated
1, H
1, H
CH
3
, H
11a
11b (89%)
99%)[b]
as the only detectable isomer in 99 and 94 % yield, respectively.
Control experiments revealed that the stereoselectivity was low
and irreproducible when the reductive amination was carried out
without isolation of crystalline E,E-diimine intermediates (7a and
(
Ph, H
12a (--)[c]
12b (67%)[d]
Reagents and conditions: i) MeOH, HCOOH (catal.) then recrystallization; ii)
NaBH in MeOH. [a] Isolation of diimine by freeze drying. [b] This diimine did
8a). The overall diastereoselectivity for the diimine reductions is
4
most likely a result of the second reduction event occurring as
an intramolecular process (Scheme 2). This reaction is believed
to proceed via a seven membered transition state with the boron
hydride still attached to the initially reduced imine nitrogen. In
fact, the basic nitrogen of its neighboring pyridine is also likely to
coordinate to the Lewis-acidic boron center and thus result in an
even more highly ordered [5.3.0]-bicyclic transition state with a
more highly reactive borate reducing agent (Scheme 2). The R’
substituent of the reduced imine system is assumed to adopt a
pseudo-equatorial position. Likewise, the pyridine substituent of
the prochiral imine would be positioned in a pseudo-equatorial
orientation of the seven-membered ring of the [5.3.0]-bicycle,
leading to an intramolecular hydride attack to the second imine
not crystallize; for details see the supporting information. [c] Diimine was not
isolated but reduced in situ. [d] Isolated yield over two steps.
achieved when the crystalline E,E-diimines (1a-12a) were
precipitated from cold methanol (see the SI for details). It is
worth of note that precipitation of E,E-diimines already occurred
during the course of the reaction. Consequently, the reaction
equilibrium shifted favorably leading to improved isolated yields.
In addition, in situ precipitation presumably prohibited products
from undergoing subsequent reactions. Both these aspects are
a clear advantage of route A over route B (Scheme 1). The
outcome for diimine preparations according to route A are
summarized in Table 1.[16]
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European Journal of Organic Chemistry
10.1002/ejoc.201700772
SHORT COMMUNICATION
with formation of the 1,6-syn product. This model, schematically
depicted in Scheme 2, gives a conceivable explanation for the
high d,l-selectivity (rather than formation of the meso-isomer or
mixtures thereof) obtained in the reduction of prochiral diimines
(
7a and 8a). In addition to spectroscopic means the
stereochemical outcome of these reactions was unambiguously
confirmed through X-ray analyses of different derivatives (vide
infra). Notably, for diimine substrates (11a and 12a) with an
Scheme 4. Unwanted aminal formation during attempted reductive amination
of diamine 3b.
3 2
extended backbone (connecting C - instead of C -chain) the
same selectivity was observed although in this case an eight-
membered or [6.3.0]-bicyclic transition state has to be passed
through leading to ligands with meso-geometry (not shown in
Scheme 2).
When using formaldehyde in the presence of an excess of
sodium cyanoborohydride and catalytic amounts of formic acid
aminal formation was reversible and gradually lead to the
formation of the desired N,N’-dimethylated ligands (Scheme 5).
This process was significantly slower for substrates 10b, 11b,
and 12b with an extended backbone but eventually these
hexahydropyrimidines 15 were also fully converted to the final
ligands (Scheme 5). Complete conversion required stirring for at
least 12 hours at room temperature in these cases (see the SI
for details).
Scheme 2. Diastereoselective reduction of prochiral E,E-diimes.
Next, the methylation of the central secondary diamines was
investigated. We first tested methyl iodide as alkylating reagent.
A representative experiment is depicted in Scheme 3. Careful
control of reaction conditions allowed to isolate 45% of the
desired ligand (L11) together with significant amounts of the
mono-methylated product 11d. It is probably not too surprising
that competing N-quaternisations (not shown in Scheme 3) or
some mono-methylation could not effectively be suppressed,
resulting in diminished yields of the desired ligand.
Scheme 5. Reductive amination of 1,2- and 1,3-diamines via intermediary
cyclic aminals.
Formation of the aminal intermediate was also confirmed
through isolation of intermediary aminals (cf. Scheme 4) and
also served to establish the relative stereochemistry using X-ray
analysis. An example is provided with the ortep-plot of
hexahydropyrimidine 15 represented in Figure 3.
Figure 3. X-ray structure and relative stereochemistry of the
hexahydropyrimidine side product 15 derived from 12b (n = 1, R = H, R’ = Ph,
R’’ = H).
Scheme 3. Exemplary alkylation of tetramine 11b using methyl iodide.
In order to avoid exhaustive or peripheral methylation we
screened reductive amination conditions in parallel to the
alkylation procedures. These reactions were found to proceed
fairly sluggishly and products isolated after short reaction times
or when using sodium borohydride (Scheme 4) were saturated
cyclic aminals (imidazolidines 14 and hexahydropyrimidines 15,
respectively) rather than the desired reduction products. A
selected example yielding aminal 13 in high yield is shown in
Scheme 4.
Under optimized conditions using formaldehyde and an excess
of sodium cyanoborohydride in the presence of catalytic
amounts of formic acid all starting material (1b-12b) with a
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European Journal of Organic Chemistry
10.1002/ejoc.201700772
SHORT COMMUNICATION
central secondary diamine were smoothly converted to the
desired ligands L1-L12 (Scheme 6). Thus, all target compounds
were easily produced in gram quantities.
Keywords: ligand synthesis • amines • tetramines • reductive
amination • catalysis
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Conclusions
1
In summary, we have developed a straightforward and highly
efficient modular approach for the synthesis of tetramine ligands
using a double reductive amination sequence. Thus, a central
diamine containing two terminal primary amino groups was
condensed with two equivalents of a 2-carbonyl substituted
pyridine derivative to yield a crystalline diimine intermediate.
Precipitation of this intermediate was crucial in order to obtain
high yields for the subsequent borohydride reduction. In the
case of prochiral diimines a high diastereoselectivity in favor for
[
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1
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European Journal of Organic Chemistry
10.1002/ejoc.201700772
SHORT COMMUNICATION
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SHORT COMMUNICATION
Tetramine Ligands
Maik Tretbar, Christian B. W. Stark*
Page No. – Page No.
Large Scale Synthesis of Symmetric
Tetramine Ligands Using a Modular
Double Reductive Amination
Approach
We here present a flexible and modular approach to tetramine ligands using a
double reductive amination strategy. Thus, target molecules were prepared in a
highly efficient manner and in only three steps. Excellent yields, of up to 96 % over
three steps were obtained. Prochiral substrates yield the chiral C
isomer selectively. All reactions are easily scalable and only a single
chromatographic purification is required at the end of the three step sequence.
2 S
- or C -symmetric
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