Synthesis of TRIP and analysis of phosphate salt impurities

Article abstract of DOI:10.1055/s-0030-1258505

The chiral phosphoric acid TRIP, a useful Brnsted acid catalyst, easily becomes contaminated with metal impurities in the form of phosphate salts during synthesis. This significantly reduces the content of free acid in the product which can hamper the cat

Full text of DOI:10.1055/s-0030-1258505

LETTER
2189
Synthesis of TRIP and Analysis of Phosphate Salt Impurities
S
M
ynthesis of TRIP artin Klussmann,* Lars Ratjen, Sebastian Hoffmann, Vijay Wakchaure, Richard Goddard, Benjamin List*
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Fax +49(208)3062999; E-mail: klusi@mpi-muelheim.mpg.de; E-mail: list@mpi-muelheim.mpg.de
Received 21 May 2010
In the aforementioned reactions, asymmetry was intro-
duced by the conjugate base of TRIP 2. The chiral phos-
phate can also effect stereoselectivity if employed in the
Abstract: The chiral phosphoric acid TRIP, a useful Brønsted acid
catalyst, easily becomes contaminated with metal impurities in the
form of phosphate salts during synthesis. This significantly reduces
the content of free acid in the product which can hamper the catalyt-
9
form of salts in reactions with cationic intermediates, a
ic activity. Methods to easily judge whether TRIP contains mainly strategy also termed asymmetric counteranion directed
1
10
the free acid or phosphate salts are presented, using H NMR spec- catalysis (ACDC). The TRIP anion has proven to induce
troscopy or a simple pH test. An improved synthetic protocol for
TRIP was established that reliably produces the free acid.
high levels of stereoselectivity in combination with organ-
ic counterions, for example, in the transfer hydrogenation
and epoxidation of a,b-unsatured aldehydes
10,11
Key words: asymmetric catalysis, phosphates, imine hydrogena-
and ke-
tion, Brønsted acids, organocatalysis
12
tones, respectively. The use of the TRIP anion in other-
wise achiral transition-metal complexes1 enabled
3
asymmetric gold-catalyzed allene cyclizations and pal-
14
In recent years, relatively strong chiral Brønsted acids
ladium-catalyzed allylic alkylations with high levels of
have emerged as powerful catalysts for many asymmetric stereoselectivity. Furthermore, TRIP was also the catalyst
1
transformations. Particularly effective are phosphoric ac- of choice in combinations of Brønsted acid and transition-
ids 1 with an axially chiral binaphthyl backbone bearing metal catalysis.15
sterically demanding substituents in the 3-positions, first
Interestingly, alkali or alkaline earth salts of chiral phos-
introduced as catalysts by Akiyama and Terada2
phates 1 can also be efficient catalysts.16 Feng and co-
(
Figure 1). Among the many differently substituted bi-
workers reported the use of sodium salts of 1 in an
enantioselective Strecker reaction1 and Ishihara and co-
workers reported the use of alkali or alkaline earth salts
naphthyl-phosphoric acids, 3,3¢-bis(2,4,6-triisopropyl-
phenyl)-1,1¢-binaphthyl-2,2¢-diyl hydrogenphosphate (2,
abbreviated TRIP), emerged as a particularly powerful
6b
1
6a
for an enantioselective cyanosilylation of ketones and a
Mannich reaction.1 In all these cases, the chiral induc-
tion was dependent on the metal counterion and the mode
of preparation of the salts.
3
one in terms of activity and stereoselectivity.
6c
i-Pr
i-Pr
R
Lately, Ishihara pointed out the possible salt formation
and contamination of BINOL-derived phosphoric acids 1
during purification on silica gel and warned that such im-
purities might have a substantial influence on the cata-
i-Pr
O
O
O
O
O
O
P
P
OH
OH
i-Pr
16c
lyst’s performance. Other groups working with chiral
R
Brønsted acids had observed similar phenomena. Ding
and coworkers found that washing the catalyst with HCl
improved the activity, obviously by regenerating some
i-Pr
TRIP (2)
1
i-Pr
1
7
free acid from its salt. Rueping and coworkers discussed
the possibility that a calcium salt of the chiral phosphate
was the actual catalyst.18 Here we present findings from
our own laboratory regarding this matter and an improved
synthetic protocol for TRIP.
Figure 1 Chiral binaphthyl phosphoric acids: general structure 1
and TRIP 2
TRIP was first introduced for the asymmetric transfer hy-
drogenation of imines. Other notable applications in
4
The synthesis of TRIP followed established synthetic
procedures2 and the compound has become commer-
cially available in the meantime. However, during our ini-
tial studies we sometimes noticed small differences
between batches of TRIP synthesized in our laboratories.
These seemed to relate to a partial salt formation of TRIP.
In order to establish a reliable synthetic method for TRIP
and other chiral phosophoric acids and to provide a uni-
form quality of the compound for research, we investigat-
ed this situation in detail.
which TRIP turned out to be the best asymmetric Brøn-
,19
sted acid catalyst include the reductive amination of a-
5
branched aldehydes, an aldol conjugate reduction–reduc-
6
tive amination cascade, Friedel–Crafts and Pictet–
7
8
Spengler reactions and cycloadditions.
SYNLETT 2010, No. 14, pp 2189–2192
x
x
.x
x
.2
0
1
0
Advanced online publication: 16.07.2010
DOI: 10.1055/s-0030-1258505; Art ID: G13510ST
Georg Thieme Verlag Stuttgart · New York
©

2
190
M. Klussmann et al.
LETTER
1
Initially, we had noticed differences in the H NMR spec-
tra of TRIP synthesized in our laboratories. Although each
NMR spectrum was satisfying in itself as were the results
1
from mass spectroscopy, the H NMR spectra were not al-
ways identical. We found two types of batches, A and B,
that were best distinguishable by the pattern of the isopro-
pyl CH signals (Figure 2).
Figure 3 Testing the different batches of TRIP with pH paper. Left:
type B, right: type A.
Table 1 Trace Element Analysis by ICP-OESa
Batch Na
K
Mg
3590 7482 <5
20 83 20
Ca
Al
Si
560 15
725
Fe Pd Zn
A
6151 29
16 13
7
5
1
Figure 2 Excerpt of the H NMR spectra of two different batches of
B
9
<5 <5
TRIP in DMSO-d , type A and B
6
a
Values in ppm.
TRIP of batch A showed two signals of four and two pro-
tons while batch B showed three separate signals of two
protons each for the six isopropyl CH groups. DMSO-d6
was the most suitable solvent to see this difference, but
other solvents could be used as well (see Supporting In-
from silicon, again supporting that it is the free acid
Table 1).
(
Most likely, not all of these metal impurities were present
as TRIP salts. Especially Si probably occurred in some
formation). This finding prompted us to investigate the form of silica, leftover from chromatographic purifica-
reason behind these differences, although in asymmetric tion. Nevertheless, if one assumes the other metals to be
reactions, the two kinds of TRIP seemed to behave simi- present exclusively as salts with one to three TRIP anions
larly.
depending on the oxidation state of the metal, an estimat-
ed amount of 81% of type A TRIP would be present in the
form of a salt. For type B, one arrives at only around 1%
of salt. These values are an estimation of the maximum
amount of salt only, but they support the assumption that
type A is mainly a salt with some free acid present while
type B is the desired free acid 2.
The addition of small amounts of water or different sol-
vents did not change the spectra of either type of TRIP, so
such impurities could be ruled out as the reason for the dif-
ference. However, we found that addition of acid or base
had a significant effect. Adding either ammonia or pyri-
dine to TRIP of type B shifted the peaks in the NMR to
look like type A. Adding HCl to TRIP of type A resulted The question arose as to whether the unintended use of
1
in a H NMR of type B. Adding acid to type B or base to salt-containing TRIP in catalytic reactions had influenced
type A did not induce a shift in the signals. Clearly, type the reaction outcome. We compared the performance of
both types of TRIP as catalysts in an asymmetric transfer
hydrogenation (Table 2).4a
B is the free acid while type A is at least partially a phos-
phate salt.
A quick test with pH paper supported this assumption, as
a solution of type B TRIP in methanol gave a pH of ca. 1–
Table 2 Asymmetric Transfer Hydrogenation of Imines
EtO2C
CO2Et
1.4 equiv)
catalyst 2, 35 °C
2
, while type A TRIP was only mildly acidic with a pH of
PMP
PMP
around 5 (Figure 3).
N
HN
(
N
H
The nature of the base added in the above NMR experi-
ments had no further effect on the signals of TRIP. As no
organic impurity could be detected in the NMR spectra of
type A batches, we presumed them to be inorganic salts. Entry
TRIP (mol%) Solvent
Time (h) Conv. (%) ee (%)
A trace element analysis by ICP-OES revealed various al-
kali and alkaline earth metals to be present as major impu-
rity but also several other metals. Most notably, silicon
was found, a likely impurity from silica gel chromatogra-
phy. Type B revealed only traces of metal impurities apart
1
A (1.0)
A (1.0)
B (1.0)
toluene
toluene
toluene
2.5
24
3
31
>95
96
88
88
88
2
3
Synlett 2010, No. 14, 2189–2192 © Thieme Stuttgart · New York

LETTER
Synthesis of TRIP
2191
Both the partial salt and the free acid of TRIP catalyzed of HCl and a base will give the free acid and the salt, re-
the reaction to give the chiral amine with the same enanti- spectively, which can now be used as references. These
omeric excess of 88% (Table 2, entries 1–3). But the free tests can be performed directly in the NMR tube as well.
acid was significantly more active: within 3 hours, essen-
In summary, we have been able to show that the chiral
tially full conversion was reached (Table 2, entry 3) while
phosphoric acid TRIP easily becomes contaminated with
with using the partial salt A, only 31% conversion was
metal impurities during the synthesis, leading to a product
containing phosphate salts. This significantly reduces the
content of free acid in the product which can appreciably
reached within the same time and it took 24 hours for full
conversion (Table 2, entries 1 and 2).
The main source of the metal impurities found in TRIP A hamper the catalytic activity. We found methods to easily
could not unambigously be determined. We presume that judge the quality of TRIP with respect to the salt content,
1
either chromatographic purification on silica gel or the using H NMR spectroscopy or simply pH paper. An im-
various metal-containing reagents during the synthesis are proved synthetic protocol for TRIP was established that
responsible. Nevertheless, we developed an improved reliably produces the free acid.
synthetic method for TRIP that would reliably yield the
free acid (Scheme 1, also see the Supporting Information).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
i-Pr
MgBr
i)
4
Acknowledgment
Br
i-Pr
i-Pr
Generous support by the Max-Planck-Society, the Deutsche For-
schungsgemeinschaft (Priority Program 1179 Organocatalysis),
and the Fonds der Chemischen Industrie is gratefully acknowled-
ged.
Ni(PPh3)2Cl2 (10 mol%)
Et2O, 6 h, reflux
OMe
OMe
ii) BBr3, CH2Cl2,
24 h, r.t.
45% (2 steps)
Br
3
References and Notes
i-Pr
i-Pr
(1) (a) Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) Terada,
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i-Pr
OH
OH
i-Pr
POCl3, pyridine,
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(
2) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
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1
2
H2O, 3 h, reflux,
CH2Cl2–HCl
9
(3) Adair, G.; Mukherjee, S.; List, B. Aldrichimica Acta 2008,
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41, 31.
i-Pr
5
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Scheme 1
(
2
Starting from compound 3, the triisopropylphenyl groups
were introduced by a nickel-catalyzed Kumada coupling
with preformed Grignard reagent 4. Deprotection of the
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3
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4
5% yield over two steps. Introduction of the phosphoric
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acid group was achieved by reaction with phosphoryl
chloride followed by hydrolysis, giving 2 in nearly quan-
titative yield. Key to receiving the free acid in pure form
was a thorough washing of TRIP with hydrochloric acid
after the final step. The product received in this way could
easily be crystallized from acetonitrile in contrast to
batches containing a mixed salt. Thus, we could obtain
single crystals suitable for X-ray crystallography (see the
(
8) (a) Akiyama, T.; Tamura, Y.; Itoh, J.; Morita, H.; Fuchibe,
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(
(
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2
0
Supporting Information).
(
13) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science
2
007, 317, 496.
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strong organic Brønsted acids, too. A quick analysis with
pH paper will give a first estimate whether the product is
mainly the desired acid or has transformed into a salt. A
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NMR: treating a sample of the Brønsted acid with excess
(
(
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M. Klussmann et al.
LETTER
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(
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2
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(
Synlett 2010, No. 14, 2189–2192 © Thieme Stuttgart · New York