3792
J . Org. Chem. 1999, 64, 3792-3793
Tr iisop r op ylsilyloxyca r bon yl (“Tsoc”): A New
P r otectin g Gr ou p for 1° a n d 2° Am in es
Bruce H. Lipshutz,* Patrick Papa, and J ohn M. Keith
Department of Chemistry, University of California,
Santa Barbara, California 93106
F igu r e 1.
Ta ble 1. Tsoc P r otection /Dep r otection of Am in es
Received February 16, 1999
The plethora of protecting groups for basic nitrogen which
can be found in the literature attest to the importance of
this aspect of amine chemistry.1 While interesting and clever
new choices continue to appear on a quite frequent basis,2
the field is nonetheless essentially dominated by use of the
Boc,3 Cbz,4 and Fmoc5 moieties, presumably owing to their
proven service. Unlike protecting group chemistry of alco-
hols, which is heavily weighted toward silicon, relatively few
amine derivatives are available which take advantage of a
chemospecific fluoride-mediated unmasking. The hydrolytic
lability of silylated amines (e.g., sta-base)6 has encouraged
use of heartier carbamate (e.g., Teoc; C(O)OCH2CH2SiMe3)7
and sulfonamide (e.g., SES; SO2CH2CH2TMS)8 residues.
However, these are rather expensive and require steps for
precursor preparation. Moreover, while deprotection of Teoc
is oftentimes effected by mild fluoride ion, a SES derivative
requires CsF in refluxing CH3CN. Noticeably absent from
this repertoire is the direct preparation9 of a stable protect-
ing group analogous to Boc, Cbz, and Fmoc (i.e., a carbam-
ate) which contains a readily available trisubstituted silicon
atom attached directly to oxygen (Figure 1). In this report
we describe the triisopropylsilyloxycarbonyl moiety (i.e., the
Tsoc group) as a novel, easily formed, and isolable carbamate
protecting group for primary and secondary amines.
P r otection . N-Tsoc derivatives are easily fashioned by
initially treating the amine dissolved in DMF or CH2Cl2
containing Et3N (1-3 equiv) at -78 °C with dry CO2 gas or
with crushed dry ice. After ca. 30-60 min, the mixture con-
taining the carbamic acid salt 1 is treated with TIPS-OTf
(1 equiv).10 Warming to room temperature followed by a
standard aqueous extractive workup and chromatography
on SiO2 affords the protected material (Scheme 1).
Several illustrative examples can be found in Table 1.
Yields tend to be good in most cases. Notably, hydroxyl group
protection is not necessary (entries 2, 8, and 9). While less
basic anilines lead to the anticipated carbamates, anilines
which are further deactivated by attachment of an electron-
withdrawing group (entry 7) did not go to completion. Other
silyl carbamates, such as that formed using t-BuPh2SiCl (to
give 2, Scheme 2), can also be isolated, an alternative should
a
b
Using carbon dioxide gas. Isolated, chromatographically
purified materials. c Using dry ice. GC yield using decane as an
internal standard.
d
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis;
Wiley: New York, 1991; 2nd ed. Kocienski, P. J . Protecting Groups; Thieme:
Stuttgart, 1994.
Sch em e 1
(2) For recent representative reports, see: Sinha, S.; Ilankumaran, P.;
Chandrasekaran, S. Tetrahedron Lett. 1999, 40, 771; Fukase, Y.; Fukase,
K.; Kusumoto, S. ibid. 1999, 40, 1169.
(3) Tarbell, D. S.; Yamamoto, Y.; Pope, B. M. Proc. Natl. Acad. Sci. U.S.A.
1972, 69, 730.
(4) Bergmann, M.; Zervas, L. Ber. 1932, 65, 1192.
(5) Carpino, L. A.; Han, G. Y. J . Org. Chem. 1972, 37, 3404.
(6) Magnus, P.; Djuric, S.; Venit, J . Tetrahedron Lett. 1981, 22, 1787.
(7) Carpino, L. A.; Tsau, J . H.; Ringsdorf, H.; Fell, E.; Hettrich, G. J .
Chem. Soc., Chem. Commun. 1978, 358.
(8) Weinreb, S. M.; Demko, D. M.; Lessen, T. A.; Demers, J . P. Tetra-
hedron Lett 1986, 27, 2099. Weinreb, S. M.; Chase, C. E.; Wipf, P.; Venka-
traman, S. Org. Synth. 1997, 75, 161.
(9) The corresponding TBS analogues have been made from N-Boc
derivatives using TBS-OTf; cf. Sakaitani, M.; Ohfune, Y. J . Am. Chem. Soc.
1990, 112, 1150; J . Org. Chem. 1990, 55, 870.
(10) Knausz, D.; Meszticzky, A.; Szakacs, L.; Csakvari, B. J . Organomet.
Chem. 1983, 256, 11. Inesi, A.; Mucciante, V.; Rossi, L. J . Org. Chem. 1998,
63, 1337. See also: Cragg, R. H.; Lappert, M. F. J . Chem. Soc. A 1966, 82.
Yoder, C. H.; Komoriya, A.; Kochanowski, J . E.; Suydam, F. H. J . Am. Chem.
Soc. 1971, 93, 6515.
a more hearty derivative bearing a UV tag be desireable.
Moreover, success using this silylating agent implies that
less reactive, and less expensive, chlorides may be employed.
Amino acid esters were given special attention, in par-
ticular concerning the issues of racemization and compat-
ibility with the Boc, Cbz, and Fmoc groups. Both L-Phe-OMe
and L-Leu-OMe were readily converted to their N-Tsoc
10.1021/jo990272o CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/12/1999