A mild and selective method for N-Boc deprotection

Article abstract of DOI:10.1016/S0040-4039(01)02225-0

A new mild method to remove N-tert-butyloxycarbonyl groups using TBAF in refluxing THF is reported. In all cases, the corresponding N-free products are obtained in good yields. The reactions are selective for acid- and base-sensitive groups, such as tert-butyl and alkyl esters, aldehydes.

Full text of DOI:10.1016/S0040-4039(01)02225-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 589–591
A mild and selective method for N-Boc deprotection
Sylvain Routier,* Laurence Sauge´, Nathalie Ayerbe, Ge´rard Coudert and Jean-Yves Me´rour
Institut de Chimie Organique et Analytique, associe´ au CNRS, Universite´ d’Orle´ans, BP 6759, 45067 Orle´ans Cedex 2, France
Received 6 November 2001; revised 21 November 2001; accepted 22 November 2001
Abstract—A new mild method to remove N-tert-butyloxycarbonyl groups using TBAF in refluxing THF is reported. In all cases,
the corresponding N-free products are obtained in good yields. The reactions are selective for acid- and base-sensitive groups, such
as tert-butyl and alkyl esters, aldehydes. © 2002 Elsevier Science Ltd. All rights reserved.
Acid labile N-Boc methodologies are widely used in
organic synthesis to prepare various functionalized hete-
rocycles as well as natural or non-natural amino acid
derivatives to build scaffold or bioactive products.1
Cleavage of the tert-butyloxycarbonyl protective group
involves formic acid, trifluoroacetic acid, bromhydric
acid or Lewis acids.2 Isobutene, generated in these acidic
conditions, was reported to give some electrophilic
additions; in this case, the use of scavengers was recom-
mended. In addition, several organic functions are
incompatible with these methods. For N-Boc aromatic
hererocycles, basic conditions (NaOMe and NH3) were
used2 whereas formation of an alkoxide anion was
reported to induce in specific cases the intramolecular
cleavage of the carbamic moiety.3 Recently, selective
deprotection of tert-butyl ester was reported using a
CeCl3·7H2O–NaI system4 or SiO2 in refluxing toluene.5
In contrast, N-Boc amino acid derivatives were selec-
The deprotection reactions7 were performed on different
N-Boc derivatives using a 1 M Bu4NF solution in THF.
The results are shown in Table 1. The free base com-
pounds were obtained in high yields. The reaction was
first optimized with the N-Boc-indole 1 (entry 1). No
reaction was observed using Bu4NF hydrate, Bu4NF on
silica gel and KF as reagents. Only partial cleavage was
observed with 10 equiv. of Bu4NF at room teperature for
8 days. At reflux, 2 equiv. of Bu4NF afforded indole 1a
in 1 day in 81% yield. Reaction time was also modulated
using 5 or 10 equiv. of fluorinated salt to afford 1a in
91 and 93% yield, respectively, with complete disappear-
ance of the starting material 1 and reaction time was
reduced from 8 to 3 h.8 THF as solvent gave better results
than DMF.
Most assays described in Table 1 were carried out using
5 equiv. of Bu4NF in a reaction time limited to 8 h.
Reactions performed with N-Boc-carbazole 2 (entry 2)
and N-Boc-aniline 3 (entry 3) gave a quantitative cleav-
age of the Boc group. Interestingly, the N-Boc-indoline
4 (entry 4) affords only the starting material. In the same
manner, N-Boc-N-methylaniline 5 does not react under
these conditions. Acid sensitive groups like tert-butyl
esters (entries 6 and 7), aldehyde (entry 8), and basic
sensitive groups, like aromatic ester (entry 9), were not
affected. All compounds 6a–9a were isolated in good
yields. Complete reaction was obtained with compound
6 using 10 equiv. of reagent. The reaction time was also
reduced as described for indole 1.
6
tively removed by HNO3 in the presence of tert-butyl
esters. Bu4NF has been used for the removal of some
benzenesulphonyl groups7 but never for the cleavage of
acidic sensitive groups. In this regard, using this reagent,
we have developed a new mild method to remove N-Boc
protective groups in the presence of several sensitive
organic functions (Scheme 1).
The maleimide moiety is also compatible with this
reaction. Compounds 10 and 10a were used to perform
mono- or di-deprotection (Scheme 2).
Scheme 1. General scheme for Bu4NF cleavage of N-Boc
protective groups.
With 5 equiv. of TBAF, the reaction using 10 was
almost complete (5% recovery of 10) and compounds
* Corresponding author. Tel.: (33) 2 38 49 48 53; fax: (33) 2 38 41 72
81; e-mail: sylvain.routier@univ-orleans.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02225-0

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S. Routier et al. / Tetrahedron Letters 43 (2002) 589–591
Table 1. Cleavage of N-Boc protected compounds with Bu4NF

S. Routier et al. / Tetrahedron Letters 43 (2002) 589–591
591
After hydrolysis, tert-butanol, CO2 and HF are effec-
tively produced. Another possibility was b-elimination12
(b), which gives the amide, isobutene, CO2 and HF
under the acidic cleavage conditions. In both cases, HF
was neutralised by the released amide.
At first sight, mechamism (a) seems more appropriate
to explain the inertness of tert-butyl ester derivatives.
Scheme 2. Reaction performed with a bis-N-Boc indolic com-
pound containing a maleimide group.
Several N-Boc protected aromatic compounds are eas-
ily deprotected by Bu4NF. This method is compatible
with several acidic and basic sensitive groups, like
esters, aldehydes or maleimides. Selective deprotection
could be achieved with substrates containing both aro-
matic and aliphatic N-Boc groups. Studies are in pro-
gress to trap the intermediates with electrophiles and to
provide more insight into this reaction.
10a and 10b were isolated in 82 and 10% yield, respec-
tively. When increasing the quantity of Bu4NF (10
equiv.), compound 10 was converted to 10a and 10b in
22 and 74% yield, respectively. A further reaction could
be performed with the isolated compound 10a to afford
10b in 94% yield. All reactions were performed in 8 h.
Silyl derivatives are often utilized to protect hydroxy
groups or free indolic nitrogen atoms. A common mode
of deprotection consists of the use of a fluorinated
References
1. Jarowinski, K.; Kocienski, P. J. Chem. Soc., Perkin
Trans. 1 2001, 2109–2135.
2. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley & Sons: New
York, 1999; pp. 518–525 and 617–618.
agent. For 2-OTBDMS-N-Boc-aniline,
a selective
deprotection of oxygen atoms was realized using 1.1
equiv. of reagent at room temperature. The 2 hydroxy-
N-Boc aniline was obtained in 91% yield.
3. Buon, C.; Chacun-Lefe`vre, L.; Rabot, R.; Bouyssou, P.;
Coudert, G. Tetrahedron 2000, 56, 605–614.
4. Marcantoni, E.; Massaccesi, M.; Torregiani, E.; Bartoli,
G.; Bosco, M.; Sambri, L. J Org. Chem. 2001, 66, 4430–
4432.
5. Jackson, R. W. Tetrahedron Lett. 2001, 42, 5163–5165.
6. Strazzolini, P.; Melloni, T.; Giumanini, A. G. Tetra-
hedron 2001, 57, 9033–9043.
7. Yasuhara, A.; Sakamoto, T. Tetrahedron Lett. 1998, 39,
595–596.
8. Standard procedure: N-Boc-indole 1 (200 mg, 0.92 mmol)
was dissolved under argon in 6 mL of dry THF. A 1 M
solution of Bu4NF (4.6 mL, 4.6 mmol) in THF was then
added and the reaction mixture was refluxed for 8 h.
After cooling to room temperature, water (20 mL) was
added. After extraction with AcOEt (2×20 mL), the
organic layers were washed with brine (10 mL), dried
with Na2SO4, filtered and the solvent was removed under
reduced pressure. The crude product was purified by flash
chromatography (petroleum ether/AcOEt 98/2) to afford
indole 1a (98 mg, 91%).
In the case of aminoalkyl compounds, deprotection was
not so easy; 10 equiv. of reagent were needed to afford
the free amine 11a in only 54% yield with recovery of
the starting material 11 (44% yield). Selectivity between
indole and amino alkyl deprotection was studied using
compound 12 which bears both aliphatic and indolic
N-Boc protection. Only the indolic deprotection was
observed in all cases. 5 equiv. of reagent afforded only
12% of mono indolic deprotected product 12a whereas
10 equiv. of reagent afforded 67% of 12a. This reaction
was achieved in 8 h with 15 equiv. of TBAF. Com-
pound 12a was directly extracted and could be used
without further purification.
Several proposals could explain the mechanism of this
reaction (Scheme 3). First, fluorine may be assimilated
as a nucleophile9,10 (a) which directly added to the
carbonyl group. The aminated residue could be consid-
ered as a leaving group and Boc-F was produced.11
9. Soon, H. W.; Parker, M. H.; Ploypradith, P.; Northrop,
J.; Posner, G. H. Tetrahedron Lett. 1998, 39, 1533–1536.
10. Moughamir, K.; Atmani, A.; Mestdagh, H.; Rolando, C.;
Francesch, C. Tetrahedron Lett. 1998, 39, 7305–7306.
11. Dang, V. A.; Olofson, R. A. J. Org. Chem. 1990, 55,
1851–1854.
12. Coutant, C.; Jacquinet, J.-C. J. Chem. Soc., Perkin Trans.
1 1995, 1573–1581.
Scheme 3. Postulated mechanism.