NaHCO3 to yield the biscarbamate 3a in excellent yield
(Scheme 2).
example, Bbc-protected aniline 3a could be deblocked in
84% yield with 1.1 equiv of 1, in 45 min. However, other
substrates 3b-i required 2 equiv of 1 for faster deprotection.
The utility of resin-bound tetrathiomolybdate for depro-
tecting Poc group under ultrasonic conditions has already
been reported.1 Accordingly, when 3g was ultrasonicated
(ultrasonic cleaning bath, 40 kHz, CH3OH, 28 °C, 1 h) with
2 equiv of resin-bound tetrathiomolybdate (tetrathiomolyb-
date bound to Amberlite IRA-400 anion-exchange resin) the
Bbc group was deblocked, yielding the corresponding amine
4 in 92% yield (Scheme 4).
Scheme 2. Preparation of the Biscarbamate of Aniline 3a
Using 2
The Bbc-protected aniline 3a on treatment with 2 equiv
of tetrathiomolybdate 1 (CH3CN, rt, 30 min) afforded aniline
in 95% yield (Scheme 3).
Scheme 4. Deblocking of Bbc Group with Resin-Bound
Tetrathiomolybdate
Scheme 3. Deblocking of Bbc-Protected Aniline 3a with 1
These experiments were extended to a few other amines,
which when treated with 2 (CH2Cl2, NaHCO3, 0 °C to rt, 3
h) afforded the Bbc-protected derivatives 3a-i in very good
yields (Table 1). Secondary amino groups of piperidine and
N-methylaniline reacted with 2 under the same conditions
to give the corresponding carbamates in yields comparable
to those of the primary amines studied (entries e and f). Even
the relatively hindered amino groups of phenylglycine methyl
ester and methyl 2-amino-2-methylpropanoate yielded the
corresponding biscarbamates in 87% and 79% yield, respec-
tively (3h and 3i).
The biscarbamates 3a-i were then treated with tetrathio-
molybdate 1 (2 equiv, 28 °C, 30 min, CH3CN), and all of
them underwent deprotection to the corresponding amines
in excellent yields (Table 1). In all cases, the deprotection
could be effected in less than 30 min. This is a definite
advantage over the deprotection of Poc-protected amines,
which require ultrasonic conditions.1
It is evident from the above results that the compound 2
could be used as a new reagent for protecting amines by
converting them to the biscarbamates. Therefore, it was
decided to extend the study to amino acids and use the Bbc-
protected amino acids in peptide synthesis. Toward this goal,
BbcCl was added to a precooled solution of phenylalanine
(1.1 equiv) in NaOH-NaHCO3 buffer (28 °C, 4 h) to get
Bbc-Phe-OH (5g) in 88% yield (Scheme 5). Compound 5g
Scheme 5. Preparation of Bbc-Phe-OH from Phenylalanine
and BbcCl (2)
extracted from the reaction mixture, after acidification, was
pure (from TLC) and did not require any further purification.
However, a crystalline sample could be obtained by recrys-
tallization from a ethyl acetate-hexane mixture.
All the biscarbamates studied were crystalline solids,
except 3e. Figure 1 shows the single-crystal X-ray structure
of compound 3h.
A few other amino acids were treated with BbcCl (2) under
the above reaction conditions to get the corresponding Bbc-
protected amino acids in excellent yields (Table 2). In all
cases, the products obtained, 5a-h, were very pure, as
observed from NMR, and did not require any further
purification.8
To use the Bbc group as a new protecting group for amines
in peptide synthesis, it is necessary to establish the orthogo-
nality of this group with the existing protective groups. We
(7) Crystal structure data for 3h: C24H24N2O8, M ) 468.45, tetragonal,
space group P41212, a ) 9.0402(2) Å, c ) 29.7809(10) Å, V ) 2433.85-
(11) Å3, Z ) 4, T ) 298 K, R ) 0.0608, Rw ) 0.1285.
Figure 1. ORTEP diagram for 3h.7
(8) All the compounds (5a-h, except 5e and 5f) were crystalline and
could easily be purified by recrystallizing from hot ethyl acetate. Compounds
5e and 5f were crystallized from ethyl acetate-hexane mixture over a long
period of time.
It was also observed that not all of the biscarbamates
studied required 2 equiv of 1 for complete deprotection. For
4948
Org. Lett., Vol. 7, No. 22, 2005