Selective N-debenzylation of benzylamino derivatives of 1,6-anhydro-β-D-hexopyranoses

Article abstract of DOI:10.1021/ol005746g

(matrix presented) When the series of 2-, 3-, and 4-(benzylamino)-2-, 3-, and 4-deoxy derivatives of 1,6-anhydro-β-D-hexopyranoses in the D-gluco, D-lyxo, and D-arabino configurations were reacted with diisopropyl azodicarboxylate, N-benzyl groups were selectively cleaved in the presence of O-benzyl groups. The yields ranged from 51 to 97percent. The debenzylation of some aliphatic benzylamines is also discussed.

Full text of DOI:10.1021/ol005746g

ORGANIC
LETTERS
2000
Vol. 2, No. 12
1681-1683
Selective N-Debenzylation of
Benzylamino Derivatives of
1,6-Anhydro-â-D-hexopyranoses
Jiri Kroutil,* Tomas Trnka, and Miloslav Cerny
Department of Organic Chemistry, Charles UniVersity, AlbertoV 6,
128 43 Prague 2, Czech Republic
kroutil@natur.cuni.cz.
Received March 2, 2000
ABSTRACT
When the series of 2-, 3-, and 4-(benzylamino)-2-, 3-, and 4-deoxy derivatives of 1,6-anhydro-â-D-hexopyranoses in the D-gluco, D-lyxo, and
D-arabino configurations were reacted with diisopropyl azodicarboxylate, N-benzyl groups were selectively cleaved in the presence of O-benzyl
groups. The yields ranged from 51 to 97%. The debenzylation of some aliphatic benzylamines is also discussed.
The benzyl group is frequently used as a protecting group
for amino, hydroxyl and thiol groups,1 especially in carbo-
hydrate chemistry. Its high chemical stability toward many
reagents used for modifying sugar skeletons along with the
existence of relatively easy methods for its introduction and
mild conditions for its deprotection are the main reasons for
its dominance over other protecting groups. However, in
many cases it is very difficult to selectively remove one
benzyl group in the presence of others.2 One possible solution
to this problem is hydrogenation under various conditions,
as the reactivity order of N-benzyl and O-benzyl groups
toward hydrogenation is dependent upon pH and solvent.
Often though, this selectivity is too low to obtain reasonable
reaction yields. The development of new methods for
selective debenzylation is, therefore, still a challenge.
In this letter, we present a procedure for the N-debenzyl-
ation of various secondary benzylamines derived from the
1,6-anhydro-â-D-hexopyranose skeleton (Figure 1) by reac-
tion with diisopropyl azodicarboxylate (DIAD).
† e-mail: trnka@natur.cuni.cz.
Figure 1. The benzylamino derivatives of 1,6-anhydro-â-D-
hexopyranoses used for the reaction with diisopropyl azodicar-
boxylate (Bn ) benzyl and Ts ) p-toluenesulfonyl).
‡ e-mail: mila@natur.cuni.cz.
(1) (a) Kocienski, P. J. Protecting Groups; Thieme: Stuttgart, 1994. (b)
Greene, T. W.; Nuts, P. G. M. ProtectiVe Groups in Organic Synthesis,
3rd ed.; J. Wiley: New York, 1999. (c) McCloskey, C. M. AdV. Carbohydr.
Chem. Biochem. 1957, 12, 137.
(2) (a) Reetz, M. T. Chem. ReV. 1999, 99, 1121. (b) Hartung, W. H.;
Simonoff, R. Org. React. 1953, 7, 263. (c) House, H. O.; Wickham, P. P.;
Mu¨ller, H. C. J. Am. Chem. Soc. 1962, 84, 3139.
Esters of azodicarboxylic acid are known to be dealkyl-
ating agents for amines. The reaction of an amine with dialkyl
azodicarboxylates is complex and the actual product depends
10.1021/ol005746g CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/16/2000

on the type of amine used. Aliphatic primary amines give
debenzylated amines 4, 6, 8, 10, 12, 14, and 16. No other
products were formed. The results are summarized in Table
1.
3,4,5
amides
while aromatic amines (e.g., aniline5,6 or tolui-
dine7) lead to a triazane adduct, I (Figure 2), or form ring
substitution products (e.g., 2,5-dimethylaniline3).
Table 1. Reactants, Products and Reaction Conditions for the
Reaction of Benzylamines with Diisopropyl Azodicarboxylate
no. reactant product method11 temp °C
time
yielda%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1
2
A
B
B
b
reflux
55
reflux
55
reflux
50
reflux
50
50
reflux
50
55
rt
rt
rt
55
50
rt
reflux
reflux
2 h
48 h
2 h
64 h
2 h
48 h
10.5 h
64 h
64 h
12 h
64 h
4 d
2 d
7 d
14 d
-
7 d
-
-
-
81
85
84
60
75
67
58
51
59
60
62
97
89
55
52d
e
Figure 2. Proposed structures (I and II) for the reaction product
of an amine with dialkyl azodicarboxylates.
3
5
4
6
A
B
A
B
B
A
B
Bc
A
A
A
B
B
A
B
B
Secondary amines form either an amide (e.g., piperidine
7
9
8
and dimethylamine8) or adducts with triazane structure I,9,10
10
4
or the structure II (Figure 2). These adducts produce
11
13
15
17
12
14
16
18
aldehydes and dealkylated primary amines upon acidic
hydrolysis.4,5
Tertiary amines react with dialkyl azodicarboxylates to
form adducts of structure II,8 which are hydrolyzed by dilute
hydrochloric acid to give dealkylated secondary amines. The
yields range from good to high (73-91%). Thus, the
dealkylation of tertiary amines with dialkyl azodicarboxylates
is a feasible synthetic procedure, whereas no successful
utilization of this method for secondary amines has previ-
ously been reported.
19
21
20
-
62
e
e
22
-
f
a Isolated yields. b The reaction was conducted in a pyridine-water (50:
1) mixture. c Reaction mixture was chromatographed on silica gel (toluene-
acetone 2:1 mixture) in order to separate DIHD. d In addition 12% of the
reactant was isolated by chromatography on silica gel (toluene-acetone
When 1,6-anhydro-4-O-benzyl-2-(benzylamino)-2-deoxy-
â-D-glucopyranose 1 was reacted with DIAD in toluene, the
debenzylated amine 2, benzaldehyde, and diisopropyl hydra-
zinodicarboxylate (DIHD) were formed. 11 GC-MS analysis
of the reaction mixture showed that benzaldehyde and DIHD
were formed in approximately equal amounts. After hy-
drolysis of DIHD, 2-amino-1,6-anhydro-4-O-benzyl-2-deoxy-
â-D-glucopyranose 2 was isolated in 81% yield. Similarly
other N-benzylamino derivatives 3, 5, 7, 9, 11, 13, and 15
were treated with DIAD to obtain the corresponding N-
e
2:1 mixture). Decomposition of benzylamine. f Starting material was
recovered. All prepared compounds were characterized.
The rate of reaction with DIAD was affected by the choice
of solvent and temperature. The presence of HCl in the
reaction mixture (reported as a necessary component12) is
not critical for successful debenzylation. However, in the
case of compound 1, HCl greatly accelerates the reaction
(compare entries 2 and 4 in Table 1).
We did not prove the presence of adducts I or II in the
reaction mixture by either NMR (1H and 13C) or by the IR
spectral characteristics listed in refs 8-10. The attempts to
isolate these adducts by varying the reaction conditions failed.
Nevertheless, there is indirect evidence that the reaction
involves attack at the nitrogen atom of the benzylamino
group: The reaction proceeds slowly with benzylamines 5,
7, and 9 where steric interactions between the 1,6-anhydro
bridge and the C-3 benzylamino group are likely to diminish
the accessibility of the nitrogen atom toward attack by DIAD.
When aliphatic benzylamines 17, 19, 21, and 22 (Figure
3) were treated with DIAD, the results were much less
satisfactory and the course of the reaction often depended
upon the solvent and the structure of the benzylamine.
Generally the reaction was quite slow in toluene at room
temperature, whereas heating in a mixture of pyridine and
(3) Diels, O. Liebigs Ann. Chem. 1922, 429, 1.
(4) Diels, O.; Paquin, M. Chem. Ber. 1913, 46, 2000.
(5) Diels, O.; Fritzsche, P. Chem. Ber. 1911, 44, 3018.
(6) Cooper, K. E.; Ingold, E. H. J. Chem. Soc. 1926, 1894.
(7) Misra, G. S.; Srivastava, S. B. J. Ind. Chem. Soc. 1960, 37, 177.
(8) (a) Makriyannis, A. Ph.D. Dissertation, University of Kansas, 1967.
(b) Smissman, E. E.; Makriyannis, A. J. Org. Chem. 1973, 38, 1652.
(9) Kenner, G. W.; Stedman, R. J. J. Chem. Soc. 1952, 2089.
(10) (a) Egger, N.; Hoesch, L.; Dreiding, A. S. HelV. Chim. Acta 1983,
66, 1416. (b) Linke, K. H.; Go¨hausen, H. J. Chem. Ber. 1971, 104, 301.
(11) Typical experimental procedure for N-debenzylation with DIAD:
Method A (in toluene). To a solution of benzylamine 1 (1 mmol, 340 mg)
in toluene (5 mL) was added DIAD (220 µL, 1.1 equiv), and the mixture
was stirred at the given temperature until TLC showed no starting material.
The mixture was concentrated in vacuo, and the resulting oil was treated
with 5% NaOH in water-ethanol (in order to hydrolyze the DIHD) for
several days at room temperature. After evaporation of ethanol and dilution
with an equal volume of water, the debenzylated amine 2 was extracted
with dichloromethane (repeatedly) and crystallized from a mixture of
ethanol-ether-light petroleum ether. Method B (in pyridine-concentrated
HCl mixture). A solution of benzylamine 1 (1 mmol, 340 mg), concentrated
HCl (ca. 35%, 0.1 mL), and DIAD (220 µL, 1.1 equiv) in pyridine (5 mL)
was heated to the given temperature until benzylamine disappeared. After
evaporation of the solvent, the reaction mixture was treated following the
same procedure as in method A.
(12) Kroutil, J.; Trnka, T.; Budesinsky, M.; Cerny M. Collect. Czech.
Chem. Commun. 1998, 63, 813.
1682
Org. Lett., Vol. 2, No. 12, 2000

amines containing a CHCHN moiety has been reported.13
This mechanism proceeds via an enamine intermediate and
requires 2 equiv of dialkyl azodicarboxylate. However, since
all of the studied benzylamines except methyl N-benzyl-
glycinate 19 contain a CHCHN moiety, this mechanism could
only account for the differences between 19 and the other
aliphatic amines. Therefore, the reason that the 1,6-anhydro-
â-D-hexopyranoses are N-debenzylated cleanly by DIAD
while the aliphatic benzylamines are not is probably due to
the considerably limited steric flexibility of the sugar skeleton
rather than to the existence of a competing mechanism.
The described procedure for N-debenzylation tolerates the
presence of other types of benzyl groups (O-benzyl) as well
as other functional groups in the molecule (free hydroxyl
and O-tosyl group). Toluene is the recommended reaction
solvent because it gave satisfactory yields of debenzylation
for most of the investigated benzylamino derivatives.
Figure 3. Aliphatic benzylamines used for the reaction with
diisopropyl azodicarboxylate (Bn ) benzyl).
concentrated HCl led to either complete decomposition or
recovery of the starting benzylamine. While simple (N-
benzylamino)ethanol 22 did not react with DIAD at all,
racemic trans-2-(benzyl amino)cyclohexanol 17 gave the
corresponding amine in 52% yield in toluene, but was totally
decomposed in the pyridine-concentrated HCl mixture.
Similar results were obtained for N-benzyl-2,2-dimethoxy-
ethylamine 21 which has an acetal moiety and should mimic
the 1,6-anhydro-â-D-hexopyranose derivative 1.
Acknowledgment. This work was supported by Ministry
of Education of Czech Republic (grant no. VS 96 140).
Kindful assistance of Ms. Pamela Blevins (The University
of Kansas Libraries) in obtaining Makriyannis’s Dissertation
is also acknowledged.
The difference in reactivity toward DIAD between the
sugar derivatives and the aliphatic benzylamines is perplex-
ing. One alternate mechanism for the dealkylation of tertiary
OL005746G
(13) Colonna, M.; Marchetti, L. Gazz. Chim. Ital. 1969, 99, 14.
Org. Lett., Vol. 2, No. 12, 2000
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