Expedient synthesis of secondary amines bound to indole resin and cleavage of resin-bound urea, amide and sulfonamide under mild conditions

Article abstract of DOI:10.1016/S0040-4039(03)01456-4

Highly efficient, new protocols for the attachment of primary amines to indole aldehyde resin using Ti(OⁱPr)₄-NaBH₄ and CH(OMe)₃-NaBH₃CN-HOAc are reported. Mild cleavage conditions for the release of urea, amide and sulfonamide products from the solid support using 1% trifluoroacetic acid (TFA) are developed.

Full text of DOI:10.1016/S0040-4039(03)01456-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6099–6102
Expedient synthesis of secondary amines bound to indole resin
and cleavage of resin-bound urea, amide and sulfonamide under
mild conditions
Sukanta Bhattacharyya,* Owen W. Gooding and Jeff Labadie
Argonaut Technologies, 1101 Chess Drive, Foster City, CA 94404, USA
Received 16 May 2003; revised 10 June 2003; accepted 10 June 2003
Abstract—Highly efficient, new protocols for the attachment of primary amines to indole aldehyde resin using Ti(OiPr)4–NaBH4
and CH(OMe)3–NaBH3CN–HOAc are reported. Mild cleavage conditions for the release of urea, amide and sulfonamide
products from the solid support using 1% trifluoroacetic acid (TFA) are developed.
© 2003 Elsevier Ltd. All rights reserved.
The electron-rich alkoxybenzaldehyde resins1 are valu-
able linkers for the attachment of various primary
amines by reductive amination reactions. Reaction of
the resin-bound secondary amine intermediates with a
variety of electrophiles allows solid-phase synthesis of
amides, sulfonamides and ureas. The products are
released from the solid support by acid-mediated cleav-
age of the N-alkoxybenzyl bond and do not carry any
evidence of resin attachment. The synthesis offers easy
introduction of two diversity points in succession.
Accordingly, the conception is highly attractive in light
of nitrogen-based library generation as a wide range of
primary amines, acid chlorides, acid anhydrides, car-
boxylic acids, sulfonyl chlorides and isocyanates are
commercially available. However, the utility2 of alkoxy-
benzaldehyde linkers has significant limitations as both
the nature of the primary amine and the electrophile
influence the reaction efficiency. Moreover, strong
acidic conditions (>90% TFA) required for cleavage of
the products from the solid support often compromise
product purity due to potential leaching from the resin
upon exposure to TFA.
resin 1 was sluggish that required the sequential use of
tetramethylammonium triacetoxyborohydride in
dichloroethane for 16 h followed by sodium cyanoboro-
hydride in methanol for 6 h. The resin-bound products
were typically released from the solid support with a
50% solution of TFA in dichloromethane.
In the context of our efforts on functionalized resin
development, we sought to enhance the efficacy of the
indole resin 1 by developing new, expedient protocols
for the attachment of primary amines and milder cleav-
age conditions for release of the products from the solid
support. In connection with our ongoing investigations
on reductive amination reactions, we have earlier
reported a versatile, mild method for the reductive
amination of carbonyl compounds using titanium iso-
propoxide and sodium borohydride.4 In an effort to
expand the utility of this reagent combination in solid-
phase organic synthesis, we report here its novel appli-
cation in the reductive amination of the resin 1, leading
to a highly efficient, expedient protocol for the attach-
ment of various primary amines. Alternatively, we
developed another expedient method for attaching pri-
mary amines to the indole resin 1 using sodium
To address these shortcomings, Estep et al. has recently
described3 an indole aldehyde resin 1 and demonstrated
its broad application in the syntheses of amides, sulfon-
amides, ureas, guanidines and carbamates. Nonetheless,
the reported procedure for reductive amination of the
Keywords: indole aldehyde resin; primary amines; reductive amina-
tion.
* Corresponding author. Tel.: +650-655-4229; fax: +650-655-4329;
e-mail: sbhattacharyya@argotech.com
cyanoborohydride
and
trimethyl
orthoformate
(TMOF).5 In both of the cases, the reactions were rapid
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01456-4

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S. Bhattacharyya et al. / Tetrahedron Letters 44 (2003) 6099–6102
Table 1. Synthesis of urea, amide and sulfonamide from indole aldehyde resin

S. Bhattacharyya et al. / Tetrahedron Letters 44 (2003) 6099–6102
6101
1% (v/v) TFA in dichloromethane (DCM) at ambient
temperature.12 These conditions are much milder than
the cleavage protocols reported in the literature. The
results for a set of primary amine, acid chloride, sulfo-
nyl chloride and isocyanate are summarized in Table 1.
In all cases, the crude products were analyzed by HPLC
and had 95–100% purity. The products were character-
with complete conversion in 6 h. We have found that
the product amides, sulfonamides and ureas can be
cleaved from the solid support under very mild reaction
conditions by using as low as 1% TFA in
dichloromethane at room temperature. The synthesis is
outlined in Scheme 1.
1
ized by their H NMR spectra13 and comparison with
The scope of the resin-bound secondary amine synthe-
sis was assessed on a set of primary amines using both
of the reductive amination methods. With Ti(OiPr)4–
NaBH4, a mixture of the indole resin 1,6 the primary
amine and Ti(OiPr)4 in anhydrous THF was stirred at
ambient temperature for 4 h to allow the formation of
the intermediate titanium(IV) complex 2.4 The complete
consumption of the aldehyde group in the resin 1 was
indicated by a qualitative 2,4-dinitrophenylhydrazine
(DNP) test of the beads. Absolute ethanol was then
added followed by NaBH4, and the resulting mixture
stirred for a further period of 2 h at room temperature.7
The resin-bound secondary amines were isolated by
filtration followed by washing with THF, MeOH and
DCM. The reactions were performed under standard
anhydrous conditions and we have not encountered any
problem with precipitated titanium oxides as reported
earlier.8
those reported in the literature.3 The isolated yields
were excellent, based on the initial loading of the indole
resin 1 (0.93 mmol/g). Unlike the reported protocols for
cleavage using strong acidic conditions, the present
method offers clean release of the products without any
contamination from leaching of the resin.
In summary, we have reported new, expedient methods
for the attachment of primary amines to indole-alde-
hyde resin 1 using Ti(OiPr)4–NaBH4 and CH(OMe)3–
NaBH3CN–HOAc. We have demonstrated that the
product amide, sulfonamide and urea can be released
from the solid support under very mild conditions using
1% TFA in dichloromethane. In view of the facile,
high-yielding conversions, the protocols described
herein should find wide application in nitrogen-based
library synthesis.
References
1. (a) Swayze, E. E. Tetrahedron Lett. 1997, 38, 8465; (b)
Ngu, M.; Patel, D. V. Tetrahedron Lett. 1997, 38, 973; (c)
Fivush, A. M.; Willson, T. M. Tetrahedron Lett. 1997, 38,
7151; (d) Sarantakis, D.; Bicksler, J. J. Tetrahedron Lett.
1997, 38, 7325; (e) Bilodeau, M. T.; Cunningham, A. M.
J. Org. Chem. 1998, 63, 2800; (f) Harikrishanan, L. S.;
Hollis Showalter, H. D. Synlett 2000, 1339; (g) Makino,
S.; Nakanishi, E.; Tsuji, T. J. Comb. Chem. 2003, 5, 73.
2. Boojamra, C. G.; Burow, K. M.; Thomson, L. A.; Ell-
man, J. J. Org. Chem. 1997, 62, 1240.
With TMOF–NaBH3CN, a mixture of the resin 1,
TMOF, and the primary amine in THF was stirred at
room temperature for 4 h. NaBH3CN and a catalytic
amount of acetic acid were then added and the resulting
mixture was further stirred for 2 h.9 The resulting
polymer-bound secondary amines obtained from both
of the methods were found to be compatible to a
variety of reaction conditions leading to the synthesis of
resin-bound amides,10 sulfonamides10 and ureas.11
Cleavage of the products from the support were
effected under very mild conditions by using as low as
3. Estep, K. G.; Neipp, C. E.; Stramiello, L. M. S.; Adam,
M. D.; Allen, M. P.; Robinson, S.; Roskamp, E. J. J.
Org. Chem. 1998, 63, 5300.
4. For examples, see: (a) Bhattacharyya, S. Tetrahedron
Lett. 1994, 35, 2401; (b) Bhattacharyya, S. J. Org. Chem.
1995, 60, 4928; (c) Bhattacharyya, S.; Chatterjee, A.;
Williamson, J. S. Synlett 1995, 1079; (d) Neidigh, K. A.;
Avery, M. A.; Williamson, J. S.; Bhattacharyya, S. J.
Chem. Soc., Perkin Trans. 1 1998, 2527; (e) Bhat-
tacharyya, S.; Neidigh, K. A.; Avery, M. A.; Williamson,
J. S. Synlett 1999, 1781.
5. (a) Szardenings, A. K.; Burkoth, T. S.; Look, G. C.;
Campbell, D. A. J. Org. Chem. 1996, 61, 6720; (b)
Matthews, J.; Rivero, R. A. J. Org. Chem. 1997, 62, 6090.
6. Indole-aldehyde resin, PS-Indole-CHO was obtained
from Argonaut Technologies.
7. Ti(OiPr)4–NaBH4 method: A mixture containing the resin
(0.5 g, 0.46 mmol) in THF (4 ml), Ti(OiPr)4 (1.0 mmol)
and the primary amine (1.0 mmol) was agitated at rt for
4 h. Then, a solution of NaBH4 (2 ml, ca. 0.75 M) in
absolute EtOH was added and the resulting mixture
stirred for a further period of 2 h. The supernatant liquid
was drained off and the resin washed with THF (8
mL×2), MeOH (8 mL×3) and DCM (8 mL×2).
Scheme 1. Reagents and conditions: (a) i. RNH2, Ti(OiPr)4,
THF, rt, 4 h, ii. abs. EtOH, rt, 2 h. (b) i. RNH2, TMOF,
THF, rt, 4 h, ii. HOAc, NaBH3CN, rt, 2 h. (c) R1COCl, NEt3
or R1SO2Cl, NEt3 or R1NCO, DCM, rt, 14 h. (d) 1% v/v
TFA (4 equiv.), DCM, rt, 4 h.

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8. Khan, N. M.; Arumugam, V.; Balasubramanium, S. Tet-
temperature. The supernatant liquid is drained off and
the resin washed with DMF, MeOH and DCM.
rahedron Lett. 1996, 37, 4819.
9. TMOF–NaBH3CN method: A mixture of PS-Indole-
CHO resin (0.5 g, 0.46 mmol), THF (2 mL), TMOF (2
mL) and the primary amine (1.0 mmol) was agitated at
ambient temperature for 4 h. Then, a solution of
NaBH3CN (1.0 mL, 1 M) in THF and acetic acid (0.1
mL) were added. The resulting mixture was stirred for 2
h. The supernatant liquid was drained off and the resin
washed with THF (8 mL×2), MeOH (8 mL×3) and DCM
(8 mL×2).
12. The resin-bound product was suspended in 1% (v/v) TFA
(3 mL, ca. 4 mol equiv.) and the mixture agitated at
ambient temperature for 4 h. The color of the resin
became deep purple. The supernatant liquid was collected
and the resin was washed with DCM (2×2 mL). The
combined solution was concentrated to afford pure prod-
ucts in excellent yields. All products were characterized
1
by H NMR spectral analysis.
1
13. Representative H NMR spectra of the products derived
from 2-phenethylamine: Amide (entry 9): l (CDCl3, 300
MHz): 2.02 (s, 3H), 2.84 (t, 2H, J=6 Hz), 3.58 (q, 2H,
J=6 Hz), 5.77 (br s, 1H), 7.18–7.4 (m, 5H). Sulfonamide
(entry 3): l (CDCl3, 300 MHz): 1.4 (s, 9H), 2.8 (t, 2H,
J=6.5 Hz), 3.18–3.32 (m, 2H), 4.42 (br s, 1H), 7.04–7.12
(m, 2H), 7.2–7.38 (m, 3H), 7.5 (d, 2H, J=8 Hz), 7.7 (d,
2H, J=8 Hz). Urea (entry 4): l (CDCl3, 300 MHz): 2.8
(t, 2H, J=7 Hz), 3.4 (t, 2H, J=7 Hz), 4.26 (s, 2H),
7.06–7.4 (m, 10H).
10. To a suspension of the resin-bound secondary amine (0.1
g) in DCM (2 mL) and triethylamine (1 mL) was added
an acid chloride/sulfonyl chloride (0.5 mmol). The result-
ing mixture was agitated overnight at ambient tempera-
ture. The supernatant liquid is drained off and the resin
washed with DMF, MeOH and DCM.
11. To a suspension of the resin-bound secondary amine (0.1
g) in DCM (2 mL) was added an isocyanate (0.5 mmol).
The resulting mixture was agitated overnight at ambient