A. Ilangovan and R. G. Kumar
the reagents required for the preparation of carbamate de-
rivatives or Dde protecting group. This study establishes
BECV as a versatile amine protecting group that makes use
of component materials that are readily available, selectively
protect and deprotect under mild conditions and is stable
under delicate functional group transformations of varied
applications in organic synthesis. In view of these advantag-
es the BECV group could be used as an amine protecting
group in line with the well established Dde, Fmoc, Cbz, and
Boc protecting groups. Further studies, especially on the ap-
plication of BECV group to peptide synthesis in solid-phase
organic synthesis are currently in progress in our research
group.
Scheme 3. Orthogonal stability of BECV group.
In order to check the stability of BECV group towards
basic and acidic conditions,[5] compounds 19b–21b were
treated with 10% TFA in CH2Cl2, 10% aq. HCl and 20%
piperazine in DMF separately at room temperature. All
compounds displayed excellent acid/base stability for more
than 24 h. In addition as discussed above, the BECV was
also stable towards bases such as NaH, KOH, K2CO3, NEt3.
This implies that the NH-BECV group is adaptable to reac-
tion conditions involving both strong acids as well as base.
After deprotection we were able to isolate mono-BECV
(E) as well as di-BECV (F) protected ethylenediamine
(Scheme 4), in addition to free aniline (G). Based on this we
propose the following mechanism (Scheme 4) for deprotec-
tion reaction. We have also observed that, when mono-
BECV protected ethylenediamine (E) was left at room tem-
perature for longer time, it was converted into di-BECV
protected ethylenediamine (F) and free ethylenediamine
(B).
Experimental Section
General procedure for the protection of amine with BECV group: To a
solution of aniline or amine (1 equiv) in ethanol (5% w/v) diethyl ethoxy-
methylenemalonate (1 equiv) was added and stirred at room temperature
(~288C). After the reaction had been completed, ethanol was evaporated
from the reaction mixture under reduced pressure to obtain the corre-
sponding BECV protected aniline or amine in 77–99% yield.
General procedure for the deprotection of BECV group using ethylene-
diamine: To a solution of BECV protected aniline or amine (1 equiv) in
ethanol (5ꢁ w/v), ethylenediamine (4 equiv) was added and stirred at
room temperature. After the completion of reaction, water was added,
extracted with ethyl acetate (3ꢁ(5ꢁ w/v)). The combined organic layer
was dried (Na2SO4), evaporated under reduced pressure and passed
through a short column (silica gel, hexane/EtOAc) to obtain the corre-
sponding aniline or amine in 75–99% yield.
2-[(4-Hydroxyphenylamino)methylene]malonic acid diethyl ester (10a):
To
a solution of 4-aminophenol (10, 0.500 g, 4.5 mmol) in ethanol
(2.5 mL), diethyl ethoxymethylenemalonate (925 mL, 4.5 mmol) was
added and stirred at room temperature for 15 min. The ethanol in reac-
tion mixture was evaporated under reduced pressure. The title compound
was obtained as a white solid (1.26 g, 99%). M.p. 1298C; 1H NMR
(400 MHz, [D6]DMSO): d = 1.22–1.28 (m, 6H), 4.09–4.22 (m, 4H), 6.80
(d, J=8.8 Hz, 2H), 7.18 (d, J=8.8 Hz, 2H), 8.30 (d, J=14.0 Hz, 1H),
9.47 (s, 1H), 10.70 ppm (d, J=14.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d = 14.2, 14.3, 60.3, 60.3, 91.7, 116.5, 119.0, 131.9, 153.0, 154.4,
166.6, 169.0 ppm; IR (KBr): n˜ = 710, 767, 803, 834, 869, 1010, 1031,
1092, 1218, 1354, 1379, 1415, 1463, 1517, 1591, 1622, 1657, 2520, 2619,
2744, 2876, 2933, 2982, 3036, 3200 cmꢀ1
; LCMS (TOF): calcd for
C14H17NO5: 279.29; found: 280.2 [M+H]; elemental analysis calcd (%)
for C14H17NO5: C 60.21, H 6.14, N 5.02; found: C 60.45, H 5.98, N 5.12.
Scheme 4. Mechanism for deprotection.
2-[(4-Allyloxyphenylamino)methylene]malonic acid diethyl ester (10b):
A mixture of 10a (0.500 g, 1.7 mmol), KOH (0.150 g, 2.6 mmol) in ace-
tone (5 mL) was stirred at room temperature for 30 min. Allyl bromide
(232 mL, 2.6 mmol) was added and stirred at room temperature for 3 h.
Water (10 mL) was added and extracted with ethyl acetate (3ꢁ10 mL).
The combined organic layer was washed with water (5 mL), dried
(Na2SO4) and evaporated under reduced pressure. Title compound was
obtained a white solid (0.48 g, 85%) after passing the crude product
through column chromatography (silica gel, hexane/EtOAc 8:2). M.p.
Conclusion
In summary, we have developed a simple method for the se-
lective protection of amino group as NH-BECV and depro-
tection of the BECV group, at room temperature, on vari-
ous substrates such as anilines, aliphatic amines and amino
acids. This method is useful for selective functional group
transformations of the OH, NH2, SH and COOH groups in
the presence of the NH2 group. The BECV protecting group
is stable towards both strong acids as well as strong bases
except primary amine. The reagents DEMM and ethylenedi-
amine, used for protection and deprotection, respectively,
are readily available at much cheaper price compared with
1
488C; H NMR (400 MHz, CDCl3): d = 1.28–1.37 (m, 6H), 4.19–4.31 (m,
4H), 4.52 (t, J=4.8 Hz, 2H), 5.27 (d, J=10.4 Hz, 1H), 5.39 (d, J=
17.2 Hz, 1H), 5.97–6.07 (m,1H), 6.90 (d, J=8.8 Hz, 2H), 7.05 (d, J=
8.8 Hz, 2H), 8.41 (d, J=14.0 Hz, 1H), 10.96 ppm (d, J=14.0 Hz, 1H);
13C NMR (100 MHz, CDCl3): d = 14.2, 14.3, 59.8, 60.1, 92.4, 115.7, 117.7,
118.6, 132.7, 132.8, 152.4, 156.0, 165.7, 169.0 ppm; IR (KBr): n˜ = 516,
555, 758, 792, 945, 991, 1026, 1091, 1175, 1229, 1309, 1386, 1414, 1442,
1473, 1514, 1607, 1680, 2904, 2981, 3252 cmꢀ1; elemental analysis calcd
(%) for C17H21NO5: C 63.94, H 6.63, N 4.39; found: C 63.82, H 6.55, N
4.41.
2942
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 2938 – 2943