Capture-ROMP-release: Application to the synthesis of amines and alkyl hydrazines

Article abstract of DOI:10.1016/S0040-4039(03)01806-9

Application of a capture-ROMP-release strategy for the chromatography-free purification of Mitsunobu reaction products is described. Norbornenyl-tagged reagents are utilized for standard solution phase Mitsunobu chemistry. Post-reaction phase-switching is accomplished via in situ ring-opening metathesis polymerization (ROMP) followed by precipitation of the polymer with methanol. Release of the product from the polymer affords amines and alkyl hydrazine derivatives with good yields and purities.

Full text of DOI:10.1016/S0040-4039(03)01806-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7187–7190
Capture-ROMP-release: application to the synthesis of amines
ꢀ
and alkyl hydrazines
a
a
b, ,†
a,
Shubhasish Mukherjee, Kevin W. C. Poon, Daniel L. Flynn * and Paul R. Hanson *
a
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582, USA
b
Neogenesis Pharmaceuticals, Inc., 840 Memorial Drive, Cambridge, MA 02139, USA
Received 8 March 2003; revised 16 July 2003; accepted 24 July 2003
Abstract—Application of a capture-ROMP-release strategy for the chromatography-free purification of Mitsunobu reaction
products is described. Norbornenyl-tagged reagents are utilized for standard solution phase Mitsunobu chemistry. Post-reaction
phase-switching is accomplished via in situ ring-opening metathesis polymerization (ROMP) followed by precipitation of the
polymer with methanol. Release of the product from the polymer affords amines and alkyl hydrazine derivatives with good yields
and purities.
©
2003 Elsevier Ltd. All rights reserved.
8
,11
The search for efficient technologies for the preparation
of large chemical libraries is currently an active area o1f
investigation in the area of combinatorial chemistry.
Strategies that integrate synthesis with purification have
ogy.
The salient features involve the use of
monomeric, norbornenyl-tagged
organic-soluble,
reagents that enjoy all the features of solution phase
reactions (facile reaction kinetics, ease of monitoring),
and the added advantage of solid phase resins (filter-
ability). In this strategy, the tags can be utilized in an
initial capturing event (Mitsunobu reaction), followed
by post-reaction in situ ROM polymerization resulting
in high-load polymers that can be filtered from the
reaction and isolated as free-flowing powders. Subse-
quent treatment with an appropriate reagent releases
the captured species as a new chemical entity. This
strategy allows phase switching to be utilized for purifi-
cation purposes. Norbornenyl- and oxanorbornenyl-
tagged reaction monomers are the reagents of choice
due to their robust performance in ROM polymeriza-
tion procedures, as well as their ease of preparation.
2
been particularly successful. Various methodologies
have been explored to facilitate impurity removal3/
product purification, including solid polymer supports
4
5
6
and reagents; scavenging resins; chemical tags; and
organic soluble supports, reagents and scavenging
agents.
7
–10
In the area of chemical tagging, in situ
polymerization via ring-opening metathesis polymeriza-
tion (ROMP) is emerging as an attractive technol-
In the area of impurity elimination, the Mitsunobu
12
reaction has previously been the target of several
groups. A variety of methods have been developed to
facilitate the separation of the Mitsunobu by-products
6
d,13
Scheme 1. Reagents and conditions: (a) i. ROH (4), PPh3,
DIAD, CH Cl , reflux; ii. 1 mol% 2, CH Cl , reflux; iii.
(Ph PO and DEADH ) from the desired product.
3 2
2
2
2
2
EtOCHꢀCH ; iv. MeOH then filter; (b) NH NH , THF,
We have recently reported the use of a capture-ROMP-
release strategy for chromatography-free purification of
2
2
2
reflux.
14
Mitsunobu reactions. This approach incorporates an
inexpensive and readily obtainable N-hydroxysuccin-
imide derivative as a norbornenyl-tagged acid in the
Mitsunobu reaction. The method was inspired by the
previous work of Barrett and co-workers who have
taken a novel approach to the removal of Mitsunobu
ꢀ
Supplementary data associated with this article can be found at
doi:10.1016/S0040-4039(03)01806-9
*
Corresponding
authors.
E-mail:
dflynn@deciphera.com;
phanson@ku.edu
Present address: Deciphera Pharmaceuticals, Inc.
†
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01806-9

7
188
S. Mukherjee et al. / Tetrahedron Letters 44 (2003) 7187–7190
by-products with the development of an impurity anni-
Table 1. Capture-ROMP-release to amines
1
5
8,16
hilation reagent and ROMPgel technology
utilizing
the Grubbs benzylidene catalyst [(PCy ) (Cl) Ruꢀ
3
2
2
1
7
CHPh, 1]. In continuation of our interest in this area,
we now describe the capture ROMP-release strategy for
the synthesis of alkyl amines and hydrazine deriva-
1
8
tives.
Amines and hydrazine derivatives have a wide variety
of biological activities besides their obvious applica-
tions in organic synthesis. The method we employ
utilizes a post-capture polymerization event that effec-
tively removes Mitsunobu by-products without the use
of chromatography. For the synthesis of amines we
have performed Mitsunobu reaction between exo-7-
oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide (3) and a
1
9
variety of alcohols 4a–e (Scheme 1). These intermedi-
ates were phase-switched by subjecting the crude reac-
tion mixture to ROMP conditions using 0.5–1.0 mol%
2
0,21
of (ImesH )(PCy )-(Cl) RuꢀCHPh (2)
catalyst at 0.2
2
3
2
M concentration. Once the monomer was consumed in
the reaction (as monitored by GC and TLC), the
reaction mixture was quenched with excess ethyl vinyl
ether to generate a differentially soluble polymer that is
soluble in organic solvents such as THF, CH Cl ,
2
2
CHCl and insoluble in MeOH. The differential solubil-
3
ity behavior of the polymer was exploited by precipitat-
ing it from methanol. Excess Mitsunobu reagents and
by-products were next removed by filtration and wash-
ing the polymer 2–3 times with methanol to yield 5 as
a free-flowing powder in good to excellent yields (Table
Scheme 2. Reagents and conditions: (a) i. ROH, PPh , DIAD,
3
CH Cl , reflux; ii. 1 mol% 2, CH Cl , reflux; iii. EtOCHꢀCH ;
2
2
2
2
2
1).
iv. MeOH then filter; (b) NH NH , THF, reflux.
2
2
A second phase switching operation was carried out to
release the corresponding amine 6 from the alkylsucci-
nate functionalized polymer 5 using hydrazine. Biphasic
extraction (Et O/H O) of the reaction mixture resulted
Table 2. Capture-ROMP-release to alkylhydrazines
2
2
in the removal of spent polymer and excess hydrazine
yielding the desired amines in good purity (Table 1).
Mosher ester analysis was used to determine the ee of
amine 6c and was found to be 92% ee. No traces of
1
Ph PO or DIADH were observed by GC or H NMR
3
2
1
analysis. No polymeric residue was observed by H
NMR of the crude, isolated amines. In addition, an
ICP-MS measurement following the protocol reported
by Georg and co-workers was used to determine the
ruthenium level that was found to be 0.043 mg per 5 mg
of sample. This level is well below the acceptable ranges
that have been reported for ruthenium removal in
22
2
2
2
2,23
RCM processes.
Similarly, the synthesis of hydrazine derivatives can be
achieved using a variety of alcohols 8a–b and 4c–e as
outlined in Scheme 2. Thus, alcohols 8a–b and 4c–e
were captured on exo-N-benzyloxycarbonylamino-
oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide (7) via
the Mitsunobu reaction (Scheme 2). After completion
of the reaction, the reaction mixture was evaporated to
dryness. Following a similar ROMP protocol as
described above, a differentially soluble polymer was
obtained. The reaction mixture was poured into
methanol to precipitate the polymer 9a–e in moderate
to good yields (Table 2). The hydrazine derivatives were
cleaved from the polymer by refluxing 9 in THF in the
presence of anhydrous hydrazine for 5 h. Finally, the
polymeric by-product was removed by biphasic extrac-
tion (Et O/H O) to afford hydrazine derivatives 10a–e
in good yields and purities (Table 2). Again, Mosher
ester analysis was used to establish the stereochemical
integrity of hydrazine derivative 10c which was found
to be 96% ee.
2
2

S. Mukherjee et al. / Tetrahedron Letters 44 (2003) 7187–7190
7189
It is important to note that the conditions of the ROM
polymerization event ultimately affect the properties of
the resulting polymers. The concentration of the reac-
tion mixture during the ROM polymerization was criti-
cal, with concentration between 0.1–0.2 M being
sufficient. If the reaction mixture was too concentrated,
gel formation was observed in some cases, and traces of
Mitsunobu by-product were observed in the final prod-
ucts, presumably due to inclusion during the polymer-
ization process. Also, the length of the polymer plays
an important role. Generally, we found that a better
yield of polymer was obtained when using 0.5 mol% of
catalyst (Gaussian distribution of ꢀ200-mers) when
compared to 1.0–3.0 mol% (Gaussian distribution of
Macpherson, Director of the Plasma Analytical Labo-
ratory at the University of Kansas, for carrying out the
ICP-MS measurement.
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