Rapid microwave-assisted deprotection of N-Cbz and N-Bn derivatives

Article abstract of DOI:10.1016/S0040-4039(01)00969-8

Catalytic-transfer hydrogenation in iso-propanol under microwave irradiation has been performed to rapidly deprotect N-Cbz and N-Bn derivatives. The method is particularly suitable for the synthesis of short peptides and can also be carried out on supported molecules. The rapid cleavage of chiral molecules derived from (S)-1-phenylethylamine can be very useful for asymmetric synthesis of nitrogen containing compounds.

Full text of DOI:10.1016/S0040-4039(01)00969-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5191–5194
Rapid microwave-assisted deprotection of N-Cbz and N-Bn
derivatives
Maria Caterina Daga,a Maurizio Taddeia,* and Greta Varchib
aDipartimento di Chimica, Universita` degli Studi di Sassari, Via Vienna 2, 07100 Sassari, Italy
bDipartimento di Chimica Organica ‘A. Mangini’ Universita` di Bologna, Via Risorgimento 4 40136 Bologna, Italy
Received 23 May 2001; revised 4 June 2001; accepted 6 June 2001
Abstract—Catalytic-transfer hydrogenation in iso-propanol under microwave irradiation has been performed to rapidly deprotect
N-Cbz and N-Bn derivatives. The method is particularly suitable for the synthesis of short peptides and can also be carried out
on supported molecules. The rapid cleavage of chiral molecules derived from (S)-1-phenylethylamine can be very useful for
asymmetric synthesis of nitrogen containing compounds. © 2001 Elsevier Science Ltd. All rights reserved.
The benzyl carbamate (Cbz) and the benzyl (Bn) pro-
tective groups are very popular for amines.1 This suc-
cess depends on the easy and selective procedures for
removal, based on catalytic hydrogenation, catalytic-
transfer hydrogenation and other reducing reactions.2
Although catalytic-transfer hydrogenation is a more
efficient deprotection procedure than catalytic hydro-
genation, it has not been largely used as it must be
carried out in high boiling solvents for relatively long
times with potential damage of particularly sensitive
organic compounds.2,3
Dipeptide 1 was employed to find the best reaction
conditions. This product could be deprotected using
Pd/C and HCOONH4 in boiling toluene for 5 h, or
with cyclohexene in boiling MeOH for 12 h. In both
cases the desired product was always obtained together
with 20–40% of diketopiperazine 3 (Scheme 1).5
On this reaction, different kinds of catalysts, hydrogen
donors, solvents and microwave conditions were tested
to find the best results. The reactions were carried out
in an unmodified domestic microwave oven following
the so called MORE (microwave organic reaction
enhancement) techniques.4 The reactions were carried
out in an Erlenmeyer flask covered with a filter funnel
to prevent spillage during the experiments. Moreover, a
beaker with water was placed in the oven together with
the reaction flask to modulate the microwave energy
input into the hydrogenation mixture.
Following
a recent report on the influence of
microwave on the catalytic hydrogenation of double
bonds,4 we found that amino groups, protected as Cbz
or Bn, can be deprotected in few minutes by
microwave-assisted-transfer hydrogenation with Pd/C
in i-PrOH as the solvent and HCOONH4 as the hydro-
gen donor.
Ph
O
Ph
H
N
H
N
O
a
O
H
N
Ph
CbzHN
OMe
H2N
OMe
OH
O
O
N
H
OH
O
1
OH
2
3
Scheme 1. (a) Pd/C (10%), HCOONH4, toluene, reflux for 5 h or Pd/C (10%), cyclohexene MeOH 1/1, reflux for 12 h.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00969-8

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M. C. Daga et al. / Tetrahedron Letters 42 (2001) 5191–5194
Pd/C and HCOONH4 were the best choice whereas
i-PrOH resulted in the better compromise between a
safe and a high yielding solvent. In fact, when ethylene
glycol was used (bp 198°C)4 and the flask was exposed
to microwaves for 2 min, the solvent did not reach the
boiling point and the deprotection of 1 was complete
according to TLC analysis. Unfortunately the yield of
isolated 2 was not very high (60–65%) as the separation
of the NH2-free dipeptide from the polar ethylene gly-
col was difficult. On the other hand, when i-PrOH was
used (bp 82°C), complete deprotection occurred
together with boiling of the solvent. To reduce the risk
of the presence of solvent vapors inside the oven we
operated as follows: the product was dissolved6 with
Table 1. Deprotection of different N-Cbz and N-Bn derivatives
Substrate
n. of cycles
yield of the
free amine (%) a
Substrate
Ph
n. of cycles
yield of the
free amine (%) a
Cbz
N
O
5
93
H
N
3
95b
Ph
N
O
CbzHN
OMe
10
1
O
OH
H
O
N
NHPr
8
CbzHN
H2N
3
5
93b
90b
COOMe
18
N
O
O
11
4
Cbz
Cbz
8
N
O
95
MeO-PEG
N
90b
COOMe
NHCbz
N
12
Cbz
5
O
8
95
90
NHCbz
O
3
95c
MeO
13
6
OH
HO
90b
OEt
4
4
3
CbzHN
OH
HO
7
O
N
14
H2N
CbzHN
Ph
4
4
OH
OH
OEt
OEt
FmocHN
FmocHN
(d)
Ph
17
Ph
O
95
O
8
O
NBz2
O
NH2
H
N
19 70e
OCH2Ph
15
OCH2Ph
(d)
5
90b
NHBz
95
OEt
NHTs
CbzHN
9
O
16
a) Yields determined on the product, recovered after filtration and evaporation of the solvent, that resulted pure at 1H NMR analysis (300
MHz). b) The absence of racemisation was controlled as described in ref. 8. c) Yields related to the corresponding hydrochloride. d)
These products were deprotected using a microwave organic synthesis apparatus (Synthewave 402, Prolabo) doing a single cycle of 20
min with 30 W of power (75°C). e) Yields of product isolated by column chromatography.

M. C. Daga et al. / Tetrahedron Letters 42 (2001) 5191–5194
5193
CN
NH2
CN
a
Ph
NH
Ph
NH
O
20
21
22a
80 : 20
22b
CN
COOH
b, c
Ph
NH
NH2
23
22a
Scheme 2. (a) NaCN, AcOH, MeOH, rt, 24 h; (b) MeOH, dry HCl, 2 h, followed by LiOH, MeOH, H2O, 16 h; (c) HCOONH4,
Pd/C, i-PrOH, MW (600 W), eight cycles of 1 min of irradiation and 1 min of rest.
i-PrOH in the flask and HCOONH4 (4 equiv.) and
Pd/C 10% (5% in weight respect to the substrate)
added. The flask was irradiated for 1 min at 600 W and
the deprotection monitored by TLC. If starting mate-
rial was present, additional cycles of 1 min at 600 W
followed by at least 1 min of rest were applied until no
trace of the starting material was present at TLC
analysis. In the case of compound 1, deprotection was
complete after three cycles. Compound 2 was isolated
in high yield (95%) after filtration of the catalyst and
evaporation of the solvent. No trace of diketopiper-
azine 3 was observed at the TLC analysis.
Finally, the procedure was successfully applied to the
cleavage of the benzyl group in a chiral compound
obtained by reaction of (S)-1-phenethylamine (20).
For example, Strecker reaction11 of 20 with butanal
(21) gave compound 22 in 75% yield as a mixture of
diastereoisomers (80:20) that can be simply separated
by column chromatography. The major isomer,
(1S,2S)-2-(1-phenylethylamino)butyronitrile (22a) was
transformed12 into enantiomerically pure (
L)-norvaline
23 in 75% yield.13 (Scheme 2)
In conclusion, a mild, simple and short method for
deprotection of nitrogen using microwave irradiation in
solution has been developed and its potential has been
demonstrated. The application of this methodology to
more complex syntheses on polymeric support is cur-
rently under investigation in our laboratory.
To explore the scope of the microwave acceleration, the
hydrogenolysis of different substrates was investigated.
The results shown in Table 1 demonstrate that the
procedure can be successfully applied to different kinds
of substrates. Compounds 4–11 afforded the depro-
tected amine always in yield higher than 90%. In the
presence of allylic groups (11) hydrogenolysis of the
Cbz occurred together with hydrogenation of the dou-
ble bond. In the presence of N-Fmoc groups (as in the
case of doubly protected lysine 8) we observed that,
after four cycles (1 min irradiation and 1 min of rest),
Cbz was completely removed and Fmoc was not depro-
tected. Nevertheless when N-FmocProOMe was sub-
mitted to ten cycles of irradiation and rest we observed
10% of deprotection.7 The microwave-assisted depro-
tection was also fully compatible with enantiomerically
pure amino acids and peptides as no racemization was
observed in amines derived from compounds 1, 4, 5, 7,
9 and 11.8 Finally, deprotection can be successfully
carried out also on substrates supported on MeO-PEG
(MW 5000) 12 and even on a Wang-type resin 13. In
this last case, after eight cycles we did not observe
cleavage from the resin.9
Acknowledgements
This work was supported by grants from the University
of Sassari (Fondi ex-60%).
References
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2. Green, T. W.; Wuts, P. G. M. Protective Groups in
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The ammonium formate catalytic-transfer hydrogena-
tion accelerated by microwaves can be also applied to
the deprotection of benzyl amines. The procedure was
particularly useful for compound 1410 that gave a polar
polyhydroxy pyrrolidine in 5 min (three cycles) after the
simple work-up. This procedure was also compatible
with tosyl and even with benzyl esters as demonstrated
by selective deprotection of compound 15.
6. Insoluble products can be solubilized in i-PrOH irradiat-
ing with microwaves the flask (600 W for 1 min) before
adding HCOONH4 and the catalyst.
.

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M. C. Daga et al. / Tetrahedron Letters 42 (2001) 5191–5194
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1H NMR (300 MHz).
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Stout, D. M.; Black, L. A.; Matier, W. L. J. Org.
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K. J. Org. Chem. 1991, 56, 1274.
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type resin. See: Anwer, M. K.; Spatola, A. F. Tetra-
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