PAPER
Selective N-Debenzylation of Benzylamines by Diisopropyl Azodicarboxylate
448
Reaction of Benzylamines 3, 7, and 11 with DIAD
O
O
O
To a solution of benzylamine 3 (102 mg, 0.3 mmol), 7 (177 mg, 1
mmol) or 11 (181 mg, 1.2 mmol) in THF (1 mL), DIAD was added
(67 mL, 0.34 mmol, 223 mL, 1.13 mmol, or 268 mL, 1.36 mmol, re-
spectively). Reaction mixtures were kept at r.t. until the yellow col-
or of DIAD disappeared. After 14 d, the mixtures were evaporated
and analyzed by the techniques mentioned above in the text. For
NMR measurement, the same mixture of benzylamine 3 with DIAD
was prepared using deuterated THF.
O
NHTs
O
O
NHTs
R
BnO
BnO
R
R
NHTs
OBn
18 R = NHBn
19 R = NH3 Cl
20 R = NHBn
21 R = NH3 Cl
22 R = NHBn
23 R = NH3 Cl
+
-
+
-
+
O
O
O
O
N3
N3
BnO
Debenzylation of Trans-(2-benzyl amino)cyclohexanol (16)
Racemic trans-(2-benzyl amino)cyclohexanol (16) (205 mg, 1
mmol), DIAD (217 mL, 1.1 mmol), and THF (2 mL) were mixed
and stirred at r.t. until the starting benzylamine disappeared (15 d).
To the solution, 5% aq HCl (2 mL) was added and the mixture was
stirred at r.t. for 7 d. After hydrolysis of the imine, the mixture was
evaporated under reduced pressure and the residue was triturated by
CHCl3 (3 mL) yielding solid trans-2-aminocyclohexanol hydro-
chloride (17) (129 mg, 85%). Its identity was confirmed by compar-
ison with an authentic specimen on the basis of NMR spectra.
R
OBn
R
24 R = NHBn
26 R = NHBn
27 R = NH3 Cl
+
-
+
-
25 R = NH3 Cl
Figure 3 Tosylamino and azido derivatives of 1,6-anhydro-b-D-
glucopyranose used for N-debenzylation with DIAD and the corre-
sponding products.
Table 3 Reaction Details for N-Debenzylation of Benzylamines 18,
20, 22, 24, and 26
Debenzylation of Benzylamine 18
1,6-Anhydro-4-O-benzyl-3-(benzylamino)-2,3-dideoxy-2-(tosy-
lamino)-b-D-glucopyranose (18)7 (83 mg, 0.167 mmol) was dis-
solved in THF (1 mL) and DIAD (38 mL, 0.183 mmol) was added.
The solution was heated under reflux for 19 h. TLC revealed the
presence of imine (Rf ca. 0.5) and DIHD (Rf ca. 0.6) which were vi-
sualized as colored spots by anisaldehyde detection reagent (grey
and yellow color, respectively). To the solution, THF (2 mL) and
5% aq HCl (0.5 mL) were added and the mixture was refluxed for 4
d. During this time, imine had gradually disappeared and amine hy-
drochloride 19 was formed. The mixture was evaporated under re-
duced pressure and the residue was partitioned between CHCl3 (30
mL) and 5% aq HCl (3 × 30 mL). The combined aqueous layers
were evaporated in vacuo yielding a white powder. Its crystalliza-
tion (EtOH–Et2O) afforded pure 3-amino-1,6-anhydro-4-O-benzyl-
Reactant
Product
Reaction in Acidic hy- Yield (%)
THF
drolysis
Time
Time
18
20
22
24
26
19
21
23
25
27
19 h
10 h
27 h
10 h
21 h
4 d
2 d
3 da
6 h
2 d
93
85
83
72
91
2,3-dideoxy-2-(tosylamino)-b-D-glucopyranose
hydrochloride
a Hydrolysis performed at r.t.
(19). Yield: 69 mg (93%); mp 163–166 °C (dec.); [a]D = –89 (c 0.11
in H2O).
Anal. Calcd for C20H25ClN2O5S (440.94): C, 54.48; H, 5.71; N,
6.35; Cl, 8.04 . Found: C, 54.68; H, 5.85; N, 6.32; Cl, 8.44.
Melting points were determined on a Botius melting point micro-
apparatus and are uncorrected. The optical rotations were measured
on an Autopol III (Rudolph Research, Flanders, NJ) polarimeter at
23 °C. The 1H and 13C NMR spectra were measured on a Varian IN-
OVA-400 (1H at 400 MHz and 13C at 100 MHz) instrument in
C4D8O (referenced to TMS) or in CD3SOCD3 at 25 °C. The 1H-1H-
Debenzylation of Benzylamine 20
1,6-Anhydro-4-O-benzyl-2-(benzylamino)-2,3-dideoxy-3-(tosy-
lamino)-b-D-glucopyranose (20)7 (60 mg, 0.121 mmol) was dis-
solved in THF (1 mL) and DIAD (28 mL, 0.135 mmol) was added.
The solution was heated under reflux for 10 h. Reaction was moni-
tored by TLC and stopped after consumption of benzylamine 20. To
the mixture, THF (5 mL) and 5% aq HCl (5 mL) were added and the
mixture was refluxed for 2 d. During this time, imine had gradually
disappeared and amine hydrochloride 21 was formed. The mixture
was worked up as described above for the preparation of amine 19
and afforded 2-amino-1,6-anhydro-4-O-benzyl-2,3-dideoxy-3-(to-
sylamino)-b-D-glucopyranose hydrochloride (21). Yield: 45 mg
(85%); mp 169–173 °C (dec.); [a]D = –10 (c 0.15, H2O).
1
COSY and NOESY and H-13C-HMQC techniques were used for
the structural assignments. The IR spectra were recorded on a Per-
kin-Elmer 490 spectrometer in CHCl3 solutions at 23 °C. GC–MS
analyses were carried out on a Hewlet-Packard HP 6890 gas chro-
matograph equipped with a HP5MS column (30 m long, inner diam-
eter 250 mm, thickness of stationary phase 0.25 mm) and with
Hewlett Packard HP 5973 mass selective detector (with EI ioniza-
tion, 70 eV). MS–ESI spectra were recorded on a Bruker ESQUIRE
3000 instrument with the samples dissolved in MeOH. TLC was
carried out on DC Alufolien with Kiesegel F254. TLC plates were
developed with hexane–EtOAc (3:2) solvent system and visualized
by UV detection at 254 nm or by an anisaldehyde detection reagent
(composition: anisaldehyde: 10 mL, HOAc: 4 mL, concd H2SO4:
12.5 mL, EtOH: 340 mL). THF was distilled from LiAlH4 prior use.
DIAD (95% purity), 2-benzylamino ethanol and dibenzylamine
were purchased from Sigma-Aldrich company. All reactions were
carried under an Ar atmosphere. NMR spectral parameters are sum-
marized in Tables 4 (1H) and 5 (13 C).
Anal. Calcd for C20H25ClN2O5S (440.94): C, 54.48; H, 5.71; N,
6.35. Found: C, 54.55; H, 5.72; N, 6.42.
Debenzylation of Benzylamine 22
1,6-Anhydro-2-O-benzyl-4-(benzylamino)-3,4-dideoxy-3-(tosy-
lamino)-b-D-glucopyranose (22)7 (121 mg, 0.245 mmol) was dis-
solved in THF (3 mL) and DIAD (56 mL, 0.27 mmol) was added.
The solution was heated under reflux for 27 h. Reaction was moni-
tored by TLC and stopped after consumption of benzylamine 22.
During this time, imine and DIHD were formed in the reaction mix-
ture. To the mixture, 5% aq HCl (1 mL) was added and the mixture
was stirred for 3 d at r.t. During this time, imine had gradually dis-
Synthesis 2004, No. 3, 446–450 © Thieme Stuttgart · New York