Molecular Diversity (2005) 9: 291–293

DOI: 10.1007/s11030-005-4386-8

c Springer 2005

Short communication

Rapid deprotection of N-Boc amines by TFA combined with freebase generation

using basic ion-exchange resins

Natarajan Srinivasan, Alexander Yurek-George & A. Ganesan∗

School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom
(∗ Author for correspondence, E-mail: ganesan@soton.ac.uk, Tel: +44(0)2380 593897, Fax: +44(0)2380 596805)

Received 30 July 2004; Accepted 21 October 2004

Key words: Boc amines, deprotection, microwave, ion-exchange resins, polymer-supported scavengers

Summary
The deprotection of N -Boc amines was rapidly accomplished using 5 equivalents of TFA in methylene chloride in a focused
microwave instrument with irradiation at 60 ◦ C for 30 min. The freebase amines are then obtained by scavenging the crude
reaction mixture with the basic Amberlyst A-21 ion-exchange resin. This procedure is suitable for the parallel deprotection of
N -Boc amines.

Abbreviations: Boc, t-butyloxycarbonyl; TFA, trifluoroacetic acid

Recently, we prepared some tryptophan amides by coupling
N -Boc tryptophan with an amine followed by acidic depro-
tection of the N -Boc group. Although the deprotection ap-
peared clean by TLC, the product yields after aqueous extrac-
tion were poor. We then tried avoiding an aqueous workup by
using Bergbreiter and Romo’s protocol [1] with Amberlyst
A-15 sulfonic acid ion-exchange resin. While this method
has worked well with other deprotections in our experience,
the results were still unsatisfactory in the case of the trypto-
phan amides. These difficulties have prompted us to develop
new conditions for the rapid deprotection of N -Boc amines
by TFA, coupled with purification of the product without
aqeuous workup, by scavenging the TFA by the weakly basic
Amberlyst A-21 resin (Scheme 1).
Scheme 1.
In the literature, Boc deprotection conditions [2] using
500 mol% of dry HCl in ethanol were reported by Rapoport.
We were interested in substituting the acid and solvent with
TFA in dry CH2 Cl2 . This avoids the need for reagent prepara-
tion beforehand, while methylene chloride as solvent is com-
patible with a broader range of organic substrates. We then
carried out a series of N -Boc amine deprotections varying
the number of equivalents of TFA, temperature, and time us-
ing the Personal Chemistry SmithSynthesizerTM focused mi-
crowave instrument [3]. Previously, [4] microwave-assisted
N -Boc deprotection has been reported by Siro et al. with a
large excess of silica gel in a domestic oven, but extensive
washing was needed for product isolation.
Our model studies established that the deprotections us-
ing 500 mol% TFA under microwave irradiation at 60 ◦ C was
complete in 30 min. The microwave heating does not appear
to be essential in this procedure: similar yields and conver-
sions were obtained with conventional heating at 80 ◦ C (oil
bath temperature) for 40 min. We have observed a similar
phenomenon when comparing conventional and microwave
heating for some other reactions: the former has given similar
results when longer reaction times and higher oil bath tem-
peratures are used. Both of these measures help compensate
for the very rapid heating achieved by the microwave instru-
ment, and imply that at least in these particular reactions a
special ‘microwave effect’ was not involved.
As mentioned in the beginning of the article, reaction
workup [5] is often the bottleneck in organic synthesis. We
devised a rapid and quantitative procedure for liberating the
freebase amine without aqueous workup. The crude reaction
mixture is diluted, and stirred with an excess of the weakly
basic Amberlyst A-21 ion-exchange resin (1000 mol%) for
30 min. Simple filtration and concentration then yield the
freebase amine in high purity.
Table 1 indicates a series of N -Boc amines that were
successfully deprotected by our protocol. While 2–3 equiv-
alents of TFA were sufficient in some cases, others required
up to 5 equivalents. The standard experimental given below
292
Table 1. Microwave-assisted N -Boc deprotection with TFA
a Isolated yields, %. Compound purity was assessed by LC-MS and NMR.
employs 5 equivalents of TFA in CH2 Cl2 as solvent for
deprotections on 100 mg scale. We have performed deprotec-
tions on 1 g scale, in which case switching to the less volatile
1,2-dichloroethane as solvent is advisable to avoid pressure
buildup in the sealed tube. Entries 6, 10, and 12 indicate the
potential for selective N -Boc deprotection in the presence
of O-tert-butyl esters and O-TBDMS silyl ethers. Although
some competing deprotection of the O-tert-butyl ester takes
place, our purification method affords only the desired prod-
uct as any free acid remains bound to the basic resin.
Overall, N -Boc deprotection by TFA in the microwave
followed by TFA scavenging with the ion-exchange resin
is highly efficient and readily adapted to parallel synthesis.
The speed of the process compares favorably with typical [6]
N -Boc deprotections. For example, the Bergbreiter-Romo
method with Amberlyst A-15 resin usually takes 4–12 h, and
increases to 29 h for entry 7 and 4 days for entry 9.
In conclusion, the present TFA protocol for N -Boc de-
protection is rapid and amenable to parallel synthesis. While
the microwave-assisted deprotection was somewhat faster,
conventional heating was found to accomplish similar con-
versions. Equally important as the deprotection conditions, a
simple and inexpensive high-throughput method for product
purification based on TFA scavenging by an ion-exchange
resin was developed.
Experimental section
General methods
Dichloromethane was freshly distilled from CaH2 . TFA was
distilled and stored over CaCl2 . Commercial Amberlyst A-21
resin (Fluka, 4.8meq/gm) was purified by washing with
methanol (25 mL to 25 g resin), stirring for 5 min, and filtra-
tion. This treatment was repeated twice with dry THF (20 mL)
and CH2 Cl2 (20 mL). The resulting resin was further dried
under high vacuum for 5 h to give a free-flowing solid that
was stored in an amber colored bottle.
The N -Boc amine in entry 2 is commerically available,
while that in entry 10 was prepared by TBDMS silylation [7]
of the free alcohol. All other N -Boc amines were prepared
by standard methods [8]. Except for the bis-N -Boc derivative
of 1,5-diaminonaphthalene in entry 8, all N -Boc amines and
their deprotection products in Table 1 are known compounds.
General procedure for microwave-assisted N -Boc
deprotection
To a solution of the N -Boc protected amine (100 mg, 1
equiv) in CH2 Cl2 (2 mL) in a sealed microwave vial under
Ar atmosphere was added TFA (5.0 equiv). This was heated
in a Personal Chemistry SmithSynthesizerTM focused mi-
crowave instrument at 60 ◦ C with stirring for 30 min. The
reaction mixture was diluted with CH2 Cl2 (2 mL), treated

with Amberlyst A-21 resin (10 equiv) for 30 min, filtered,
and washed (CH2 Cl2 , 4 mL or 1:1 CH2 Cl2 /MeOH for more
polar compounds). The combined filtrates were evaporated
to provide the product freebase amine.
Deprotections on a 1 g scale were carried out with the
compound dissolved in 5 mL of 1,2-dichloroethane. For de-
protections without the microwave instrument, the reaction
vessel was conventionally heated at 80 ◦ C (oil bath tempera-
ture) for 40 min.
1,5-[N ,N  -(tert-Butyloxycarbonyl)amino]-
diaminonaphthalene
Brown solid, mp 204 ◦ C; IR 3271, 1712, 1687 cm−1 ; 1 H
NMR (400 MHz, DMSO-d6 ) δ 9.18 (s, 2H), 7.84 (d,
2H, J = 8.5 Hz,), 7.54 (d, 2H, J = 7.5 Hz), 7.45 (t,
2H, J = 8.0 Hz), 1.49 (s, 18H); 13 C NMR (100 MHz,
DMSO-d6 ) δ 154.5(C), 134.6(C), 129.3(C), 125.6(CH),
121.9(CH), 120.2(C), 79.3(CH), 28.6(CH3 ); MS (ES) 381.2
(M + Na).
Acknowledgment
We thank the Combinatorial Centre of Excellence for
funding.
References
1. Liu, S.-Y., Zhao, C., Bergbreiter, D.E. and Romo, D., Simultaneous
deprotection and purification of BOC-amines based on ionic resin cap-
ture, J. Org. Chem., 63 (1998) 3471–3473.
2. Gibson, F.S., Bergmeier, S.C. and Rapoport, H., Selective removal of
an N-Boc protecting group in the presence of a tert-butyl ester and
other acid-sensitive groups, J. Org. Chem., 59 (1994) 3216–3218.
3. For recent reviews of microwave-assisted organic reactions, see: (a)
Lidstrom, P., Tierney, J., Wathey, B. and Westman, J., Microwave as-
sisted organic synthesis – a review, Tetrahedron, 57 (2001) 9225–
9283. (b) Nuchter, M., Ondruschka, B., Bonrath, W. and Gum, A.,
Microwave assisted synthesis – a critical technology overview, Green
293
Chemistry, 6 (2004) 128–141. (c) Xu, Y. and Guo, Q.X., Syntheses of
heterocyclic compounds under microwave irradiation, Heterocycles,
63 (2004) 903–974.
4. Siro, J.G., Martı́n, J., Garcı́a-Navio, J.L., Remuiňan, M.J. and Vaquero,
J.J., Easy microwave assisted deprotection of N-Boc derivatives, Syn-
lett (1998) 147–148.
5. For a review, see: Tzschucke, C.C., Markert, C., Bannwarth, W., Roller,
S., Hebel, A. and Haag, R., Modern separation techniques for the
efficient workup in organic synthesis, Angew. Chem. Int. Ed. 41 (2002)
3964–4000.
6. For example: (a) Greene, T.W. and Wuts, P.G.M., Protecting Groups
in Organic Synthesis, Wiley, New York, 1999; 3rd ed., pp. 518–525.
(b) Stahl, G.L., Walter, R. and Smith, C.W., General procedure for the
synthesis of mono-N-acylated 1,6-diaminohexanes, J. Org. Chem., 43
(1978) 2285–2286. (c) Boeckman, R.K., Jr. and Potenza, J.C., Cate-
chol boron halides – mild and selective reagents for cleavage of com-
mon protecting groups, Tetrahedron Lett., 26 (1985) 1411–1414. (d)
Houghten, R.A., Beckman, A. and Ostresh, J.M., Use of 10-percent
sulfuric acid/dioxane for removal of N-α-tertiary-butyloxycarbonyl
group during solid-phase peptide-synthesis, Int. J. Peptide Prot. Res.,
27 (1986) 653–658. (e) Sakaitane, M. and Ohfune, Y., Syntheses and
reactions of silyl carbamates. 1. Chemoselective transformation of
amino protecting groups via tert-butyldimethylsilyl carbamates, J. Org.
Chem., 55 (1990) 870–876. (f) Nudelman, A., Bechor, Y., Falb, E.,
Fischer, B., Wexler, B.A. and Nudelman, A., Acetyl chloride-methanol
as a convenient reagent for: a) quantitative formation of amine hy-
drochlorides b) carboxylate ester formation c) mild removal of N-t-Boc-
protective group, Synth. Commun., 28 (1998) 471–474. (g) Kotsuki,
H., Ohishi, T., Araki, T. and Arimura, K., A facile new method for
selective deprotection of N-(tert-butoxycarbonyl)-protected carbox-
amides with Yb(OTf)3 supported on silica gel, Tetrahedron Lett., 39
(1998) 4869–4870. (h) Bose, D.S. and Lakshminarayana, V., Lewis
acid-mediated selective removal of N-tert-butoxycarbonyl protective
group (t-Boc), Synthesis, (1999) 66–68. (i) Strazzolini, P., Melloni,
T. and Giumanini, A.G., Selective nitrolytic deprotection of N-Boc-
amines and N-Boc-amino acids derivatives, Tetrahedron, 57 (2001)
9033–9043. (j) Routier, S., Saugé, L., Ayerbe, N., Coudert, G. and
Mérour, J.-Y., A mild and selective method for N-Boc deprotection,
Tetrahedron Lett., 43 (2002) 589–591. (k) Bose, D.S., Kumar, K.K.
and Reddy, A.V.N., A new protocol for selective deprotection of N-tert-
butoxycarbonyl protective group (t-boc) with Sn(OTf)2 , Synth. Com-
mun., 33 (2003) 445–450.
7. Smith, P.M. and Thomas, E.J., Approaches to a synthesis of galbonolide
B, J. Chem. Soc., Perkin Trans., 1 (1998) 3541–3556.
8. Ponnusamy, E., Fotadar, U., Spisni, A. and Fiat, D., A novel method for
the rapid, nonaqueous tert-butoxycarbonylation of some O-17-labeled
amino-acids and O-17-NMR parameters of the products, Synthesis
(1986) 48–49.