Indole Resin: A Versatile New Support for the Solid-Phase Synthesis of Organic Molecules

Full text of DOI:10.1021/jo9806052

5
300
J . Org. Chem. 1998, 63, 5300-5301
In d ole Resin : A Ver sa tile New Su p p or t for
th e Solid -P h a se Syn th esis of Or ga n ic
Molecu les
2a from the coupling of a carboxylic acid to the resin-bound
amine 1a (cap ) H) was reported to be difficult due to the
steric interference of the flanking methoxy groups on the
linker.3 The synthesis of sulfonamides from 1a was not
successful.4 The synthesis of ureas from 1a or 1b has not
been reported.
As part of our high-speed chemistry efforts, we were
interested in developing a general solid-phase method for
the preparation of nitrogenous products bearing no evidence
of attachment to a solid support.8 Herein, we report our
initial results using the indole-terminated resin 5. This
resin is prepared in a facile three-step sequence and can be
used to synthesize a wide range of secondary amides,
sulfonamides, and ureas in high yield and under mild
conditions.
,4
Kimberly G. Estep,* Christopher E. Neipp,
Linda M. Stephens Stramiello, Mavis D. Adam,
Martin P. Allen, Shaughnessy Robinson, and
Eric J . Roskamp
Pfizer Central Research, Eastern Point Road,
Groton, Connecticut 06340
Received April 3, 1998
Combinatorial solid-phase chemistry is gaining momen-
tum throughout the pharmaceutical industry as a powerful
tool for preparing libraries of druglike organic molecules.
The synthesis and general use of the indole resin 5 is
described in Scheme 1. Indole-3-carboxaldehyde 3 was
alkylated with ethyl bromoacetate in DMF at 80 °C, and
after saponification with KOH in methanol (88% overall
yield), the acid 4 was coupled to aminomethylated polysty-
1
Recent advances have been reviewed.2 In general terms,
solid-phase chemistry can be broken down into three com-
ponents: (1) the solid support, often a polystyrene resin; (2)
the product molecule; and (3) the chemical tether (linker),
which connects the two.
9
rene using N,N-diisopropylcarbodiimide (DIC), 1-hydroxy-
i
benzotriazole (HOBt), and Pr2EtN in DMF/CH2Cl2 (10% v/v)
As the repertoire of solid-phase reactions expands to
include the synthesis of more diverse targets, there is an
increasing need for robust linkers that not only are cleaved
in high yield under mild conditions but that also afford
products bearing no extraneous functionality associated with
resin attachment. One recent class of such “clean-break”
linkers are those that are used to connect a nitrogen-
containing product to a solid support via an N-(alkoxybenzyl)
to afford indole resin 5. The incorporation of 4 to the solid
support was monitored using single-bead FT-IR (CdO
-
1
absorption at 1665 cm ) and was judged complete based
on a negative Kaiser test.10 The elaboration of resin 5 into
products 7-32 proceeded with the reductive amination of
the carboxaldehyde of 5 using a primary amine and (CH3)4-
NBH(OAc)3 in dichloroethane (16 h) followed by treatment
with NaBH3CN in MeOH (6 h).11 The resulting resin-bound
secondary amines 6 were then treated with a variety of
substitutent (1a ,3 1b, and 1c ). Acid-mediated cleavage
,4
5,6
5,6
“nitrogen-capping groups” under standard conditions for
solid-phase synthesis. For example, treatment of 6 with
carboxylic acids (4 equiv) in the presence of bromotrispyr-
rolidinophosphonium hexafluorophosphate (PyBroP, 4 equiv)
i
and Pr2NEt (8 equiv) in dichloromethane afforded resin-
1
2
bound amides 7-19, treatment of 6 with a sulfonyl chloride
i
(
5 equiv), Pr2NEt (5 equiv), and DMAP (0.3 equiv) in 10%
DMF/dichloroethane afforded sulfonamides 20-25, treat-
ment of 6 with an isocyanate (5 equiv) in dichloromethane
afforded ureas 26-28, and treatment of 6 with a chlorofor-
i
mate (4 equiv), Pr2NEt (8 equiv), and DMAP (0.3 equiv) in
dichloromethane afforded carbamates 29 and 30. Products
of these electron-rich tethers affords secondary amides
(
2a ),3 ureas (2b), or sulfonamides (2c) in which the resin
-5
5
5,6
were cleaved from the solid support using 50% TFA/CH -
2
1
3
attachment is replaced by a single proton. This method is
conceptually very attractive, since it capitalizes on the vast
diversity and availability of primary amines, carboxylic
acids, sulfonyl chlorides, and isocyanates, and the products
bear no evidence of resin attachment. In practice, however,
these linkers appear to have significant limitations. We
encountered difficulty reliably synthesizing the 4-formyl-3,5-
Cl , typically using a 4 h exposure.
We have since
2
discovered that 2-5% TFA/CH Cl (4 h) is sufficient for most
2
2
products.
Using the above synthetic route, we have prepared the
examples listed in Table 1. In all instances, the crude
products were obtained with a high degree of purity as
7
dimethoxyphenol used to prepare resin-bound amines 1a
(8) During the preparation of this paper, the synthesis of N-substituted
3
,4
(
cap ) H). Cleavage of the products from resins 1a , 1b,5
amides using the Rink linker were reported: Garigipati, R. S. Tetrahedron
Lett. 1997, 38, 6807-6810. Brown, E. G.; Nuss, J . M. Tetrahedron Lett.
5
,6
and 1c often requires g90% TFA. The synthesis of amides
1
997, 38, 8457-8460.
(
9) Aminomethyl polystyrene resin (1% cross-linked, 200-400 mesh) with
(
1) (a) Dolle, R. E. Mol. Diversity 1997, 2, 223-236. (b) Gordon, E. M.;
a loading of 0.70-0.75 mequiv/g was purchased from Bachem and used
without further treatment.
Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144-154. (c) Patel, D.
V.; Gordon, E. M. Drug Discovery Today 1996, 1, 134-144.
(10) Kaiser, E.; Colescott, R. L.; Bossinger, C. D.; Cook, P. I. Anal.
Biochem. 1970, 34, 595-598.
(11) The use of sequential hydride reagents represents the standard
reductive amination conditions used by our laboratory. These conditions
(2) (a) Hermkens, P. H. H.; Ottenheijm, H. C. J .; Rees, D. C. Tetrahedron
1
997, 53, 5643-5678. (b) Balkenhohl, F.; von dem Bussche-H u¨ nnefeld, C.;
Lansky, A.; Zechel, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288-2337.
c) Fr u¨ chtel, J . S.; J ung, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 17-42.
3) Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J . J . Org.
Chem. 1997, 62, 1240-1256.
4) Holmes, C. P.; Marquess, D. New Linkers for Generating Substituted
(
are based on our observation that (CH
ficient for complete reduction, while NaBH
in unsatisfactory yield.
3
)
4
NBH(OAc)
3
alone is often insuf-
(
3
CN can afford impure products
(
(12) Other acid coupling conditions: carboxylic acid (4 equiv), HOBt (8
i
Amides and Ureas from Solid Supports. Presented at the 213th National
Meeting of the American Chemical Society, San Francisco, CA; American
Chemical Society: Washington, DC, 1997; ORGN 383.
2
equiv), DIC (8 equiv), and Pr NEt (4 equiv) in 10% DMF/dichloroethane;
carboxylic acid (4 equiv), phenyl dichlorophosphate (4 equiv), and triethy-
lamine (8 equiv) in THF; carboxylic acid (5 equiv), TFFH (5 equiv), and
i
(5) Swayze, E. E. Tetrahedron Lett. 1997, 38, 8465-8468.
(6) Ngu, M.; Patel, D. V. Tetrahedron Lett. 1997, 38, 973-976.
(7) Landi, J r., J . J .; Ramig, K. Synth. Commun. 1991, 21, 167-171.
Pr
2
NEt (5 equiv) in DMF.
(13) The cleavage of 7 in 50% TFA/CH
complete in 30 min, as determined by HPLC analysis.
2
2
Cl at room temperature was
S0022-3263(98)00605-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/11/1998

Communications
J . Org. Chem., Vol. 63, No. 16, 1998 5301
Sch em e 1
Sch em e 2
them through a short plug of silica gel. The final yields for
amide, sulfonamide, and urea products were >85%, and
often >90% overall, as determined from the loading of the
indole aldehyde 5.14 Primary amines with R-branching
reacted satisfactorily (12), as did the aniline examples (16,
1
7, 25, and 28). The reaction of resin-bound amines with
chloroformates was less successful, as our standard condi-
tions afforded products in need of chromatography and in
modest yield (29 and 30). The guanidine 31 was obtained
in 96% yield by treating 6 with N,N′-bis-BOC-thiourea and
DIC.15 It is noteworthy that aniline 32 was released from
the resin in excellent yield despite the absence of an
activating R2 capping group, while the analogous treatment
of resin-bound benzylamine 6 (R ) 4-OMePhCH2) with up
to 95% TFA afforded none of the uncapped product 33.
While the compounds listed in Table 1 were prepared
using the indole linker coupled to an aminomethyl polysty-
rene support, our preliminary results indicate that the indole
linker may be used with acid-labile resins (e.g., Wang, Rink,
or Rink AM) without affecting the purity or yields of the
amide products. A mechanism for product release is pro-
posed in Scheme 2 using resin-bound amide 34 as the
exemplar. In the case of aminomethyl polystyrene (X ) NH),
cleavage occurs at bond b via protonation of the amide and
elimination of the product 35 from the electron-rich indole
core. Although the use of Wang or Rink resin introduces
an alternative site of acid lability (bond a), treatment of these
resins with TFA in dichloromethane (5% for Rink, 50% for
Wang) again induced cleavage exclusively at bond b, afford-
ing 35 in high yield with no evidence of indole-containing
byproducts. The lack of indole impurities in the crude
product 35 indicates that scission at bond a does not occur
after 35 is eliminated. The high yields listed in Table 1
suggest that the resin-bound cation 36 does not react with
those solution-phase products after they are released. No
cation scavengers were used.
Ta ble 1. Syn th esis of P r od u cts R1NHR2 Usin g In d ole
Resin 5
no.
R1
R2
yielda
7
8
9
3,4-di-OMe-Ph(CH2)2
2-Cl-PhCH2
3-pyridinylmethyl
2-thienylmethyl
2-pyrrolidinone-1-(CH2)3
PhCH2C(CH3)H
1-adamantylmethyl
CH3O(CH2)3
4-OMe-PhCH2
3,5-di-Me-4-OTBS-Ph
3,5-di-Me-4-OTBS-Ph
PhCH2
PhCH2
Et
Et2N(CH2)3
PhCH2
PhCH2
PhCH2
3,5-di-Me-4-OTBS-Ph
PhCH2
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH2NHFmoc
COCH2NHFmoc
COC6H13
COC6H13
COC3H7
SO2-p-tolyl
SO2-p-tolyl
SO2Ph-4-OMe
SO2Ph-2,5-di-OMe
SO2-p-tolyl
SO2-p-tolyl
CONHC3H7
CONHPh
CONH-o-tolyl
CO2Ph
CO2C3H7
CdNH(NH2)
H
H
>99
>99
97
100
89
83
95
97
>99
>99
95
89
91
99
93
96
96
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
99
>99
88
86
>99
59
In summary, we have found the indole resin 5 to be an
ideal support for preparing libraries of amides, ureas,
sulfonamides, guanidines, carbamates, and aniline-contain-
ing products. We are currently exploring the performance
of 5 with a wider range of chemistries. These results will
be reported in due course.
PhCH2
3,5-di-Me-4-OTBS-Ph
PhCH2
PhCH2
80
96
4-OMe-PhCH2
3,5-di-Me-4-OTBS-Ph
4-OMe-PhCH2
Su p p or tin g In for m a tion Ava ila ble: Experimental details
and NMR spectral data for compounds 7-32 (39 pages).
>99
0
a
J O9806052
Isolated yields based on the loading of 5. All compounds were
base-line pure by proton NMR.
(
14) The loading of 5 was determined using a “cleave and weigh”
1
assessed by H NMR. When impurities were present, they
procedure: 5 was reductively aminated with p-methoxybenzylamine, acy-
lated with acetic anhydride, and cleaved with 50% TFA/dichloromethane
and the resulting acetamide quantified. The loading of 5 was calculated to
reflect the amount of acetamide obtained and was typically between 0.5
and 0.7 mequiv/g.
were minor and could be attributed to residual coupling
reagents (HOBt, Et3N-HCl) or unidentified aliphatic ma-
terials presumed to leach from the resin upon exposure to
TFA. These contaminated products were purified by passing
(15) Robinson, S.; Roskamp, E. J . Tetrahedron 1997, 53, 6697-6705.