Two efficient N-acylation methods mediated by solid-supported reagents for weakly nucleophilic heterocyclic amines

Article abstract of DOI:10.1055/s-1999-2987

Two efficient acylation methods utilizing solid-supported reagents have been developed for weakly nucleophilic heterocyclic amines. The novel approaches by chemoselective purification and polymeric-supported reagents facilitate library synthesis of divers

Full text of DOI:10.1055/s-1999-2987

LETTER
1957
Two Efficient N-Acylation Methods Mediated by Solid-Supported Reagents
for Weakly Nucleophilic Heterocyclic Amines
Kyungjin Kim,* Kang Le
Roche Research Center, Hoffmann-La Roche, Inc., Nutley, NJ 07110-1199, USA
Fax +1-973-235-6084; E-mail: kyungjin.kim@roche.com
Received 6 August 1999
reagents2 followed by chemoselective purification to re-
Abstract: Two efficient acylation methods utilizing solid-support-
move the trace starting material. The second is the devel-
ed reagents have been developed for weakly nucleophilic heterocy-
opment of an acylation method using a commercially
clic amines. The novel approaches by chemoselective purification
available polymer-supported BEMP.3 These two conve-
and polymeric-supported reagents facilitate library synthesis of di-
verse heterocyclic amides that are found in several pharmaco- nient procedures reported herein facilitate preparation of
phores.
diverse heterocyclic amides from the corresponding
amines possessing only moderate reactivity.
Keywords: acylation, amide, chemoselective purification, combi-
natorial chemistry, solid-supported reagents
Several polymeric acyl-transfer resins were examined for
their ability to acylate commercially available 2-aminopy-
ridine 1 and 2-aminothiazole 2 analogues. The polymeric
active ester of 4-hydroxy-3-nitrobenzophenone 3 proved
to be most efficient (Scheme 1).4 While the acylation of
simple amines with these resins is usually finished within
1 h at room temperature, slightly modified acylation con-
ditions for amines 1 and 2 were required. A mixture of the
amine (1.0 equiv) and resins (2.0 equiv) in a THF solution
required heating to 60 °C overnight to yield the corre-
sponding acylated-products 4 and 5. However, a trace
amount of starting material was monitored by TLC de-
spite numerous conditions applied to drive the compound
to complete acylation by the variation of reaction time,
temperature, and equivalents of resins.5 At this point, sol-
id-supported reagents encompassing both organic poly-
mers and inorganic solid materials were examined to
purify the reaction mixture. Our approach to the chemose-
lective separation is based on the different basicity be-
tween amines and amides. Several ion exchange resins,
acidic polymer resins, and short pads of inorganic solids
were investigated. Amberlite IRA-120 resin proved to be
a most effective scavenging resin to remove the starting
amines (Chemoselective Purification). This scavenging
method was easily applied as a parallel or high-throughput
format to purify the acylation mixture. The purification
procedures are as follows. After heating overnight, the
acylation reaction mixture was treated with an excess
amount of Amberlite IRA-120 resin and shaken for 0.5 h
to provide acyl-adducts 4 and 5 in high purities (>84%).6
Table 1 displayed some amide products prepared by the
combination of chemoselective purification and polymer-
ic-supported reagents.
The N-acylation reaction is a useful tool for lead optimi-
zation and lead generation. While numerous acylation
conditions have been developed, the introduction of acyl-
functionality to several heterocyclic amines has been
problematic due to their moderate reactivity. Such reac-
tions usually require harsh reaction conditions and subse-
quent laborious separation steps of unreactive starting
material amines.1 This difficulty has hindered combinato-
rial chemistry methods to provide diverse heterocyclic
amides. In the present paper, we describe two efficient
methods utilizing solid-supported reagents to acylate
weakly nucleophilic heterocyclic amines that are com-
monly found in diverse pharmacophores. The first method
is a modified acylation approach of polymeric acylating
Interestingly, the acylated adducts 5 of 2-aminothiazole
analogues 2 were purified in overall moderate yield (43-
94%); however, in the case of the acylation of 2-aminopy-
ridine analogue 1, only trace amounts of amide product 4
were isolated (10-20%) under the described scavenging
conditions. We assumed that Amberlite IR-120 resin is
acidic enough to scavenge both amine 1 and amide 4. For
Scheme 1
Synlett 1999, No. 12, 1957–1959 ISSN 0936-5214 © Thieme Stuttgart · New York

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K. Kim, K. Le
LETTER
(i) 1a (1.0 eq), polymeric BEMP (1.5 eq), phenylacetyl chloride
(2.0 eq), THF, rt, O/N; (ii) polymeric trisamine (3.76 mmol/g, 5 eq),
rt, O/N
Scheme 2
Encouraged by this result, we investigated further acyla-
tions of several weakly nucleophilic heterocyclic amines
which usually require harsh reaction conditions and labo-
rious work-up steps. The reactions were carried out as a
high-throughput format to provide the corresponding
acyl-adducts in moderate yields and high purities.8 The
structures of amines and acyl chlorides are displayed in
Table 2.
In conclusion, two efficient and convenient acylation
methods utilizing solid-supported reagents were devel-
oped for weakly nucleophilic heterocyclic amines. Cur-
rently, further acylations of diverse heterocyclic amines
that failed to provide the corresponding acylated adducts
in solution phase are in progress as a high-throughput for-
mat for new lead generation.
Acknowledgement
The authors thank Dr. Robert, Jr. Goodnow for suggestions on the
manuscript.
References and Notes
(1) Green, T.W.; Wuts, P.G.M. Protective groups in organic
synthesis; Wiley Interscience: John Wiley, 1991, 349-357 and
references therein.
(2) (a) Carpino, L.A.; Cohen, B.J.; Lin, Y.Z.; Stephens, Jr. K.E.;
Triolo, S.A. J. Org. Chem. 1990, 55, 251-259. (b) Cohen, B.J.;
Karoly-Hafeli, H.; Patchornik, A. J. Org. Chem. 1984, 49,
922-924. (c) Pop, I.E.; Deprez, B.P.; Tartar, A.L. J. Org.
Chem. 1997, 62, 2594-2603. (d) Reichwein, J.F.; Liskamp,
M.J. Tetrahedron Lett. 1998, 39, 1243-1246.
(3) (a) Schwesinger, R. Chimia 1985, 39, 269-272. (b) Xu, W.;
Mohan, R.; Morrissey, M.M. Bioorg. Med. Chem. Lett. 1998,
8, 1089-1092: polymer-bound BEMP is available from Fluka
Chemical Corp.
this reason, a different pathway was explored to acylate 2-
aminopyridine 1 and consequently an efficient polymeric
base induced acylation efficiently using polymer-support-
ed BEMP (2-tert-butylimino-2-diethylamino-1,3-dimeth-
yl-perhydro-1,3,2-diazaphosphorine) which is frequently
used in diverse alkylation reactions as a base.3 To test the
polymeric base, the mixture of 2-amino-5-chloropyridine
1a, phenylacetyl chloride, and polymer-bound BEMP in
THF solution was agitated overnight at room temperature
and then subsequently treated with polymer-bound
trisamine7 to remove excessive acyl chloride. Remark-
ably, the acylation outlined in Scheme 2 proceeded
smoothly to afford the corresponding acyl-adduct 6 in
85% yield and 97% purity.
(4) Polymeric 4-hydroxy-3-nitrobenzophenone 3 was prepared
according to reference 2(b).
(5) Base induced acylation was also investigated including a
strong base such as potassium tert-butoxide.
(6) The purity was determined by a C18 reverse phase HPLC
column, WR-C18 3u 120A (30 x 3.2 mm) of ES Industries in
10-90% CH3CN/H2O containing 0.02 TFA and monitored at
215 nm using a UV detector and by SEDEX 55 Evaporative
Light Scattering Detector (ELSD). The purity scores reported
herein are based on ELSD.
(7) Booth, R.J.; Hodges, J.C. J. Am. Chem. Soc. 1997, 119, 4882:
polymer-bound trisamine is available from Argonaut
Technologies (San Carlos, CA).
Synlett 1999, No. 12, 1957–1959 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Two Efficient N-Acylation Methods Mediated by Solid-Supported Reagents
1959
(8) FlexChemTM reaction block (48 well) of Robbins Scientific
Corp. was used for acylations and typical experimental
procedures are as follows: The mixture of amine (0.2 mmol),
acyl chloride (0.4 mmol), and polymer-bound BEMP (0.3
mmol) in 2 ml THF solution was slowly agitated at room
temperature. After overnight reaction, polymeric trisamine
(3.76 mmol/g, 1.0 mmol) was dispensed by ArgoScoopTM, a
pre-calibrated scoop from Argonaut Technologies, to remove
excessive acyl chloride and then the mixture was shaken for 5
h and filtered to a 48 well plate to provide amides,
respectively. If necessary, the filtrate was passed through a
silica gel pad packed in a 48-well block of FlexChemTM to
provide highly pure amide products.
Article Identifier:
1437-2096,E;1999,0,12,1957,1959,ftx,en;S05699ST.pdf
Synlett 1999, No. 12, 1957–1959 ISSN 0936-5214 © Thieme Stuttgart · New York