A simple synthetic protocol for the protection of amides, lactams, ureas, and carbamates

Article abstract of DOI:10.1016/S0040-4039(02)01964-0

A new procedure for protecting the amide, lactam, urea, and carbamate NH group with a triphenylmethyl (Tr) group is described. The utility of this method is illustrated with molecules that contain other functional groups. A mild deprotection using trifluoroacetic acid makes this a useful method for attaching amide groups on resin for combinatorial synthesis.

Full text of DOI:10.1016/S0040-4039(02)01964-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8063–8066
A simple synthetic protocol for the protection of amides,
lactams, ureas, and carbamates
Dandu R. Reddy, Mohamed A. Iqbal,* Robert L. Hudkins, Patricia A. Messina-McLaughlin and
John P. Mallamo
Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA
Received 16 August 2002; revised 9 September 2002; accepted 11 September 2002
Abstract—A new procedure for protecting the amide, lactam, urea, and carbamate NH group with a triphenylmethyl (Tr) group
is described. The utility of this method is illustrated with molecules that contain other functional groups. A mild deprotection
using trifluoroacetic acid makes this a useful method for attaching amide groups on resin for combinatorial synthesis. © 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
methyl-protecting group5 and further found this
approach to be a versatile for protection of amides and
lactams, ureas and carbamates. The triphenylmethyl
(Tr) substituted indenocarbazole 4 was isolated in
excellent yield (72%) by reacting indenocarbazole 3,
triphenylmethanol and p-toluenesulfonic acid (p-TsOH)
in refluxing toluene (Scheme 1).6 During the course of
our investigation, a similar amide protection scheme
was published using an amide, 4,4%-dimethoxybenzhy-
drol in acetic acid, acetic anhydride, and a catalytic
amount of sulfuric acid7.
The indolocarbozoles, K252a 1 and Staurosporine 2,
exhibit a wide range of biological activities.1 In continu-
ation of our exploration of these ring systems, we
prepared 32 and sought a method of protection of the
lactam nitrogen where by routine substitution reactions
could be carried out on the indole nitrogen, for exam-
ple. Ultimately, the identification of a suitable protect-
ing group could be applied to both solution- and
solid-phase combinatorial methods.
There are relatively few methods available for the pro-
tection of an amide group.3,4 After examination of a
number of approaches we found that 3 could be readily
protected at the lactam nitrogen using a triphenyl-
Keywords: novel procedure; protecting group; amides; lactam; ureas;
carbamates.
* Corresponding author. E-mail: miqbal@cephalon.com
Scheme 1. Reagents and conditions: (a) triphenylmethanol,
p-TsOH, benzene, reflux; (b) TFA, CH2Cl2, water, rt.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01964-0

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2. General procedure
water, brine, dried and evaporated. The reaction
product was purified on a silica gel column using
hexane and ethyl acetate (varying proportions based on
the product) as eluent.
A solution of amide (0.864 mmol), triphenylmethanol
(0.576 mmol, 0.67 equiv.) and p-TsOH (0.288 mmol) in
benzene (15 mL) was refluxed using Dean–Stark
apparatus under argon. Completion of the reaction was
monitored by analytical TLC. The solution was cooled
to room temperature, quenched with 2% aqueous
sodium bicarbonate solution, and extracted with ethyl
acetate (3×5 mL). The organic layer was washed with
3. Results and discussion
This synthetic strategy was subsequently extended to
other organic molecules such as amides, lactams, ureas,
Table 1.

D. R. Reddy et al. / Tetrahedron Letters 43 (2002) 8063–8066
8065
Table 1. (Continued)
a
1-Methyl-2-pyrrolidinone was used as co-solvent.
b Toluene was used as the solvent.
c Mixture of benzene and toluene was used as solvent.
d Excess of starting material was used.
e 1.9 equiv. of starting material was used.
f 3 equiv. of starting material was used.
g 1.4 equiv. of triphenylmethanol and 1 equiv. of indenocarbazole 3 was used.
h Unless otherwise indicated benzene was used as solvent.
i Reported yields are based on triphenylmethanol.
carbamate, and the results are shown in Table 1.8 This
procedure is compatible with the presence of functional
groups such as olefin, nitro, chloro, and ester. Also, the
presence of electron withdrawing or donating groups
on aromatic benzamide derivatives did not affect the
yields as illustrated by entries 11 and 12. A lower yield
was observed in the case of triphenylmethyl pyrithyl-
dione (entry 15). It is noted that the five- and four-
membered ring lactams (entries 17 and 18) are unstable
the lower observed yields. In these two instances, there
was no improvement in yield even after the addition of
excess starting materials. Additionally, a selective pro-
tection of primary amide in the presence of a hindered
carbamate can be achieved by this method (entries 19
and 20).
This communication describes a simple procedure for
the regiospecific protection of an amide nitrogen. In
general, a triphenylmethyl protected product was
during these reaction conditions and may account for

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D. R. Reddy et al. / Tetrahedron Letters 43 (2002) 8063–8066
deprotected using TFA to liberate the expected product
in excellent yield.9 Nonetheless, deprotection of 4 with
TFA gave 3 and 4a (40–50%). Use of several cationic
scavengers such as anisole, thioanisole, dimethylsulfide,
phenol, thiophenol, ethanedithiol, benzylmercaptan, tri-
ethylsilane, tributylphosphine, and water has been
reported.10 None of these scavengers in different combi-
nations and proportions decrease the formation of 4a.
However, the protection of 3 with 4,4%-dimethoxybenz-
hydrol furnished the expected product, which upon
deprotection with 5% TFA returned 3 and small
amount (<3%) of the corresponding byproduct.6
2. Hudkins, R. L; Knight, E., Jr. US Pat. 5,705,511, 1998.
3. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis; Wiley-Interscience: New York, 1990;
pp. 349–359.
4. (a) Schneider, C. H.; Eberle, A. N. Peptides 1992, 285–
287; (b) Sieber, P.; Riniker, B. Tetrahedron Lett. 1991, 32,
739–742.
5. (a) He, M.; Buisine, E.; Tartar, A.; Sergherert, C. Bioorg.
Med. Chem. Lett. 1994, 4, 2845–2850; (b) Dutta, A. K.;
Xu, C.; Reith, M. E. A. J. Med. Chem. 1996, 39, 749–756;
(c) A mixture of indenocarbazole 3, triphenylmethyl chlo-
ride and 4-dimethylaminopyridine in neat pyridine was
heated to 100–120°C for 48 h; (d) The acid-catalyzed
protocol for ether bond formation using an alcohol,
triphenylmethanol, and p-TsOH was applied to the inde-
nocarbazole 3.
Acknowledgements
6. (a) Triphenylmethyl indenocarbazole 4 was characterized
by 1H and 13C NMR, IR, mass spectroscopic methods
and elemental analysis; (b) Deprotection of triphenyl-
methyl indenocarbazole 4 with trifluoroacetic acid (with
or without cationic scavengers) resulted in the isolation of
indenocarbazole 3 and one other side-product, 4a.
7. Henneuse, C.; Boxus, T.; Tesolin, L.; Pantano, G.;
Marchand-Brynaert, J. Synthesis 1996, 495–501.
8. All new compounds were fully characterized by HPLC,
NMR, and mass spectroscopic methods.
9. The triphenylmethyl group was deprotected from Z-
Gln(Tr)-OMe using 90% TFA in dichloromethane and
water to isolate Z-Gln-OMe in 84% yield (entry 19).
10. (a) Albericio, F.; Kneib-Cordonier, N.; Biancalana, S.;
Gera, L.; Masada, R. I.; Hudson, D.; Barany, G. J. Org.
Chem. 1990, 55, 3730–3743; (b) Beck-Sickinger, A. G.;
Schnorrenberg, G.; Metzger, J.; Jung, G. Int. J. Peptide
Protein Res. 1991, 38, 25–31.
We thank Drs. Chung Ho Park and Neil Johnson for
helpful discussions and for providing compound 3. We
also thank Dr. Jeffry Vaught for his continuing support
and Drs. James C. Kauer, Edward R. Bacon, and
Jasbir Singh for their critical review of this manuscript.
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