A polymer-bound 1,3-diketone: A highly efficient scavenger for hydrazines, and primary amines

Article abstract of DOI:10.1055/s-2003-39295

A 1,3-diketone resin was developed as the basis for a selective scavenger for hydrazines. In addition, it can be employed for the selective removal of primary amines in the presence of secondary amines which is of fundamental importance in the purification of reductive alkylations. The resin's specificity is based on the sequestration of the hydrazine via their polymer-attached pyrazoles and of the primary amines via their enamines.

Full text of DOI:10.1055/s-2003-39295

LETTER
983
A Polymer-Bound 1,3-Diketone: A Highly Efficient Scavenger for Hydrazines,
and Primary Amines
A
Polymer-bound
w
1,3-Diketone e Schön,*b Josef Messinger,b Nuria Merayo,a Grzegorz Juszkiewicz,b Andreas Kirschning*a
a
Institut für Organische Chemie der Universität Hannover, Schneiderberg 1b, 30167 Hannover, Germany
Fax +49(511)7623011; E-mail: andreas.kirschning@oci.uni-hannover.de
b
Solvay Pharmaceuticals GmbH, Hans-Böckler-Allee 20, 30173 Hannover, Germany
Fax +49(511)8572195; E-mail: uwe.schoen@solvay.com
Received 11 April 2003
nium species9 are typical immobilized functionalities in
use.
Abstract: A 1,3-diketone resin was developed as the basis for a se-
lective scavenger for hydrazines. In addition, it can be employed for
the selective removal of primary amines in the presence of second-
ary amines which is of fundamental importance in the purification
of reductive alkylations. The resin’s specificity is based on the se-
questration of the hydrazine via their polymer-attached pyrazoles
and of the primary amines via their enamines.
In this report, we describe a new 1,3-diketone resin 3 with
remarkable scavenging properties towards hydrazines and
amines.
Diketone 3 previously served as an intermediate en route
to functionalized polymer 4, which is an amidating agent
for primary and secondary amines.10 It was prepared on
large scale from the Merrifield resin 5 by simple one-pot
oxidation followed by reductive coupling with 2,4-penta-
dione 6 (Scheme 1).11 1,3-Diketone resin 3 can be stored
at 4 °C for months without degradation or loss of activi-
ty.12
Key words: amines, combinatorial chemistry, hydrazines, polymer
supported reagent, scavenger resin
Functionalized polymers have become an universal syn-
thetic tool in organic synthesis,1 because this hybrid solid/
solution phase technique allows simple purification and
the possibility to use reagents in excess to drive reactions
in solution to completion. The opportunity to employ this
technique in conjunction with continuous flow processes
is particularly appealing as this application would create
an ideal almost workup-free technique for automated so-
lution phase synthesis.2,3
O
O
O
O
, TMSCl
NaI, CH2Cl2
X
6
5 X= CH2Cl
1 X= CHO
3
DMSO, NaHCO3
Besides polymer-bound reagents and catalysts resins with
scavenging properties play a major role among function-
alized polymers.4 On the other hand, amines and related
hydrazines as well as hydroxyl amines are some of the
most important classes of compounds that are employed
in industrial high throughput syntheses towards com-
pound libraries with pharmaceutical potential. As these
compounds are often employed in excess, various scav-
enging resins for the removal of these molecules are al-
ready in use. As far as amines are concerned, aldehyde 1,5
b-ketoester 2,6 isatoic anhydride,7 isocyanate8 and diazo-
Scheme 1
Initially, we studied the scavenging property of resin 3 to-
wards alkylated as well as mono- and bisacylated hydra-
zines and compared the results with those obtained for
resin 1 (Figure 1). The reaction times are given after
which the hydrazines were fully removed from solution
(threefold excess of resins 1 and 3, r.t., if not otherwise
noted CH2Cl2; detection by TLC or GC). After filtration
HN
NH2
O
O
N
N
O
O
H
O
O
4
1
2
3
Figure 1
Synlett 2003, No. 7, Print: 02 06 2003.
Art Id.1437-2096,E;2003,0,07,0983,0986,ftx,en;G02103ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

984
U. Schön et al.
LETTER
1
and concentration we also recorded H NMR spectra to immobilized as pyrazoles and not as imines (lane 3)
further verify the results. As expected, at least one nucleo- (Figure 3).
philic NH2-group is required for efficiently conducting
the scavenging process. Bisacylated hydrazides do not re-
act under the conditions. In most cases, scavenging resin
3 was superior to aldehyde 1 as the process proceeded
Recently, Bradley and co-workers introduced b-ketoester
2, which shows high selectivity for primary amines over
secondary amines.6 In comparison to 1,3-diketone resin 3,
polymer 2 behaves differently in the scavenging of hydra-
zines. Addition of alkyl-substituted hydrazines to the b-
keto group initiates a cyclization and finally release of
more rapidly and often less material (2 equiv instead of
2.7 equiv) was needed. We also found that hydrazine can
be removed under identical conditions (Figure 2).13
pyrazolone 10 into solution (Scheme 3). Hydrazine reacts
At this point it became necessary to collect structural data in a similar manner to yield 5-methyl-2,4-dihydropyrazol-
on the nature of the scavenged species. Either one equiv- 3-one (10, R = H). In contrast, monoacylated hydrazines
alent of hydrazine reacts with diketone resin 3 to yield im- are removed from solution by functionalized resin 2 be-
mobilized pyrazoles or two molecules of hydrazine react cause the second nitrogen lacks nucleophilicity for cleav-
with each of the two keto groups in resin 3 to furnish two ing the ester bond. In both cases, the crude products were
polymer-bound imine moieties. Consequently, we treated almost pure, which is a clear indication that the first step,
phenylhydrazine with 1,3-diketone 7 and found that, as the attachment to the keto group proceeds fast while the
expected, only pyrazole 8 was isolated while formation of second release step is much slower. Although this trans-
adduct 9 could not be detected (Scheme 2).
formation clearly shows that b-ketoester 2 is not broadly
suited for the scavenging of hydrazines, it needs to be
pointed out that it may deliberately be utilized for the
preparation of these heterocycles in a catch and release
mode.17
O
O
Ph
Ph
Ph
N
N
N
N
Ph
7
Ph
NH2
not
R
N
R
NH2
N
N
H
CH2Cl2
N
O
O
H
Ph
Ph
8 (61%)
O
O
CH2Cl2
9
10
2
Scheme 2
R= H
2 h, r.t., 21%
6 h, r.t., 46%
19 h, r.t., 50%
The FT-ATR-infrared spectrum of pyrazole 8 was com-
pared with the spectra of those products which resulted
from the scavenging of phenylhydrazine and aniline, re-
spectively with resin 3. By comparison of the spectra (lane
1 and 2), we obtained strong evidence that hydrazines are
R= –(CH2)2–CN 2 h, r.t., 23%
22 h, r.t., 56%
R= Ph
1 h, r.t., 3%
22 h, r.t., 40%
Scheme 3
O
O
O
H
H
O
O
N
N
O
NH2
NH2
N
NH2
O
N
H
O
N
H
O
O
H
1: 48h
3: 4h
1: 72h
3: 3h
1: n. r.
3: n. r.
1: 72h
3: 8h
NO2
H
N
H
N
NH2
N
N
H
NH2
NH
NH2
NH2
2*HCl
O2N
1: 3h
3: 2h
1: 96h
3: 96h
1: 2hb
3: 23hb
1: 4h
3: 1.5h
S
N
NH
NH2
H2N NH2
1: 23h
3: 23h
1: 48h
3: 2h
Figure 2 Hydrazines and acylhydrazines used in scavenging experiments.14,15
a) 1 (2.7 equiv), CH2Cl2, r.t. or 3 (2 equiv), CH2Cl2, r.t.; b) due to lack of solubility the scavenging process was conducted in 1,4-dioxane.
Synlett 2003, No. 7, 983–986 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
A Polymer-Bound 1,3-Diketone
985
Figure 3 IR spectra of the scavenging reaction in solution and with resin 3.16
In the next phase of the project we investigated the scav-
enging property of diketone resin 3 towards primary and
secondary amines. The selective removal of primary
amines in the presence of secondary amines is a crucial
NH2
N
H
>>
task in high throughput synthesis as reductive alkylations
12
13
NH2
play a key role in the design of compound libraries.6 Thus,
in a competition experiment we treated a 1:1 mixture of
benzylamine 12 and dibenzylamine 13 with resin 3 (2
equiv). After 4 hours (CH2Cl2, r.t.) the primary amine 12
was completely scavenged while the secondary amine 13
could be reisolated in 95% yield (and 81% yield after 48
>>
NH2
N
H
h). Likewise, when the reaction was repeated in methanol,
typically employed in reductive aminations, 91% of the
secondary amine was present after 26h.
14
15
NH2
In a related set of experiments, we studied the properties
of resin 3 towards a mixture of aniline 15 and phenylhy-
drazine 14. These were mixed as a 1:1 ratio (each 1 equiv)
in dichloromethane and treated with the 1,3-diketone resin
3 (4 equiv). After 30 minutes, phenyl hydrazine 14 was
completely removed from solution while aniline 15 could
be reisolated in 64% yield (Figure 4). Complete purifica-
tion of such a mixture could be achieved within 2 hours by
reducing the amount of scavenger resin 3 to 2 equivalents.
When we switched to more reactive amines than pheny-
lamine, resin 3 still showed a pronounced selectivity for
>
NH2
N
H
14
12
Figure 4 Relative scavenging properties of resin 3 in competition
experiments with amines and hydrazines.
Acknowledgment
phenyl-hydrazine 14. Thus, a 1:1 mixture of benzylamine We are indebted to the Fonds der Chemischen Industrie for finan-
cial support.
12 and phenyl-hydrazine 14 in dichloromethane was treat-
ed with the diketone resin 3 (2 equiv) for 4 hours. After
this time, no phenyl hydrazine could be detected while
50% of benzylamine was still present in the residue.
References
(1) (a) Kirschning, A.; Monenschein, H.; Wittenberg, R. Angew.
In conclusion, it has been shown that the 1,3-diketone res-
Chem. Int. Ed. 2001, 40, 650. (b) Ley, S. V.; Baxendale, I.
in 3 can be used as a scavenging reagent for hydrazines.
In addition, it selectively removes primary amines in the
presence of secondary amines and is able to distinguish
between hydrazines and amines.
R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.; Longbottom,
D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J.
Chem. Soc., Perkin Trans. 1 2000, 3815. (c) Drewry, D. H.;
Coe, D. M.; Poon, S. Med. Res. Rev. 1999, 19, 97.
Synlett 2003, No. 7, 983–986 ISSN 1234-567-89 © Thieme Stuttgart · New York

986
U. Schön et al.
LETTER
during 6 h via a syringe pump. The mixture was gently
stirred overnight at r.t. and then treated with water (50 mL).
After 10 min the resin was filtered and successively washed
with methanol, water, methanol, acetone, dichloromethane,
methanol, and dried in high vacuum.
It has to be pointed out that after thorough optimization we
had to notice the need for excessive washing of the resin
before use, because it tends to bind impurities including
iodine. Resin 3 can be stored at 4 °C and stays active for
months. The commercial Merrifield resin 5 as well as 1,3-
diketone resin 3 were analyzed by combustion analysis.
Found for 5: C 77.63, H 6.37, Cl 15.69 (equals about 4.42
mmol/g loading); found for 3: C 79.55, H 7.17, Cl 0.47
(equals about 3.37 mmol/g loading).
(2) Reviews: (a) Fletcher, P. D. I.; Haswell, S. J.; Pombo-Villar,
E.; Warrington, B. H.; Watts, P.; Wong, S. Y. F.; Zhang, X.
Tetrahedron 2002, 58, 4735. (b) DeWitt, S. H. Curr. Opin.
Chem. Biol. 1999, 3, 350.
(3) Kirschning, A.; Altwicker, C.; Dräger, G.; Harders, J.;
Hoffmann, N.; Hoffmann, U.; Schönfeld, H.; Solodenko,
W.; Kunz, U. Angew. Chem. Int. Ed. 2001, 40, 3995.
(4) (a) Flynn, D. L.; Devraj, R. V.; Parlow, J. J. In Solid Phase
Organic Synthesis; Burgess, K., Ed.; Wiley: New York,
2000, 149–194. (b) Parlow, J. J.; Devraj, R. V.; South, M. S.
Curr. Opin. Chem. Biol. 1999, 3, 320. (c) Flynn, D. L.;
Devraj, R. V.; Naing, N.; Parlow, J. J. Med. Chem. Res.
1998, 8, 219.
(5) (a) Kaldor, S. W.; Siegel, M. G.; Fritz, J. E.; Dressman, B.
A.; Hahn, P. J. Tetrahedron Lett. 1996, 37, 7193.
(b) Creswell, M. W.; Bolton, G. L.; Hodges, J. C.; Meppen,
M. Tetrahedron 1998, 54, 3983.
(6) (a) Yu, Z.; Alesso, S.; Pears, D.; Worthington, P. A.; Luke,
R. W. A.; Bradley, M. Tetrahedron Lett. 2000, 41, 8963.
(b) Yu, Z.; Alesso, S.; Pears, D.; Worthington, P. A.; Luke,
R. W. A.; Bradley, M. J. Chem. Soc., Perkin Trans. 1 2001,
1947.
(7) Coppola, G. M. Tetrahedron Lett. 1998, 39, 8233.
(8) Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997, 119,
4882.
(9) Dahmen, S.; Bräse, S. Angew. Chem. Int. Ed. 2000, 39, 3681.
(10) Dräger, G.; Solodenko, W.; Messinger, J.; Schön, U.;
Kirschning, A. Tetrahedron Lett. 2002, 43, 1401.
(11) Sakai, T.; Miyata, K.; Tsuboi, S.; Utaka, M. Bull. Chem. Soc.
Jpn. 1989, 62, 4072.
(12) Preparation of 2,4-pentandione resin 3: To a suspension of
Merrifield polymer (2.5 g, 4.3 mmol chloride/g, 2% DVB,
200–400 mesh) in dry DMSO (25 mL) was added sodium
bicarbonate (9.24 g, 110 mmol) and gentle stirring was
continued at 155 °C under nitrogen for 20 h. Ice-cold water
was added, the resin was filtered and successively washed
with water, methanol, dichloromethane, methanol, and dried
in high vacuum at 30 °C over P2O5.
(13) In addition, resin 3 is also able to scavenge hydroxylamine
such as the HCl salt of benzylhydroxylamine, which was
removed in CH2Cl2 at room temperature within eight hours.
(14) Typical scavenger procedure with 1: To a solution of
ethylcarbazate (16 mg, 0.165 mmol) in dichloromethane
(1 mL) was added benzaldehyde resin 1 (150 mg, 3.0 mmol
aldehyde/g) and stirred at r.t. until all hydrazine has reacted.
The procedure was monitored with TLC or GC. After 72 h
the suspension was filtered, the resin was washed with
dichloromethane (3 × 2 mL), and the combined filtrates were
evaporated in high vacuum. No residue remained in the
flask.
Typical scavenger procedure with 3: To a solution of
ethylcarbazate (17 mg, 0.165 mmol) in dichloromethane
(1 mL) was added 2,4-pentandione resin 3 (100 mg, 3.3
mmol diketone/g) and stirred at r.t. until all hydrazine has
reacted. The procedure was monitored with TLC or GC.
After 3 h the suspension was filtered, the resin was washed
with dichloromethane (3 × 2 mL), and the combined filtrates
were evaporated under high vacuum. No residue was found
in the flask.
(15) Commonly, hydrazines were completely scavenged within
the given time. Occasionally, we observed a residue after
filtration and evaporation of the solvent which originated
from resin impurities.
(16) Texier-Boullet, F.; Klein, B.; Hamelin, J. Synthesis 1986,
409.
The dried resin (ca. 2.2 g) was suspended in dry
dichloromethane (30 mL) and sodium iodide (8.24 g, 55
mmol) was added. Gentle stirring was continued under
nitrogen and trimethylchlorosilane (6.98 mL, 55 mmol) and
acetylacetone (1.65 mL, 16 mmol) were added separately
(17) Kirschning, A.; Monenschein, H.; Wittenberg, R. Chem.–
Eur. J. 2000, 6, 4445.
Synlett 2003, No. 7, 983–986 ISSN 1234-567-89 © Thieme Stuttgart · New York