Convenient protection of amines as carbamates using polymer-bound HOBT as catalyst

Article abstract of DOI:10.1039/a802020e

A method for the facile protection of primary and secondary amines as carbamate (Cbz, Fmoc and t-Boc) derivatives using polymer bound 1-hydroxybenzotriazole (HOBT) is reported.

Full text of DOI:10.1039/a802020e

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Convenient protection of amines as carbamates using polymer-bound
HOBT as catalyst
Kleanthis G. Dendrinos and Aristotle G. Kalivretenos*
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County,
Baltimore, MD 21250, USA
A method for the facile protection of primary and second-
ary amines as carbamate (Cbz, Fmoc and t-Boc) derivatives
using polymer bound 1-hydroxybenzotriazole (HOBT) is
reported.
Although yields of some reactions were near quantitative,
others gave lower yields of product. In these cases, if the reac-
tion of the amine were incomplete, then the carbamate product
should be contaminated with the amine. In reactions involving
volatile amines, any unreacted amine is potentially removed
during the concentration step. In contrast, the presence of
much higher boiling amines (e.g. 1,5-diaminopentane, 3-amino-
propan-1-ol, valine) should be observed in the filtrate if
unreacted. In the cases studied, unreacted amine was not
observed in the concentrated filtrate. A possible explanation for
this is the inefficient removal of the amine or carbamate
product from the immobilized reagent during filtration and
subsequent washing. The fact that we can reactivate the poly-
mer and reproduce the reaction with no loss of polymer activ-
ity, or unexpected products, suggests there is no formation of
resin bound carbamates.
A variety of primary and secondary amines were chosen,
including those with other reactive functional groups (e.g.
3-aminopropan-1-ol, 6-aminohexanoic acid, valine). In all
cases, reactions were selective for the amino group. Utilizing the
general reaction protocol, Fmoc and Cbz derivatives were
obtained in fair to excellent yields, although the yields were
poor to fair for the t-Boc derivatives. This may be due to steric
hindrance at the polymer active site from the tert-butyl group
in either the polymer activation step with Boc2O (resulting in
inefficient polymer loading), or during the coupling step. Steric
arguments may also be invoked to explain the rather poor yield
of the Fmoc derivative of diisopropylamine (35%, Table 1). The
only aromatic amine used in this study was p-phenetidine,
which provided a fair yield of the Cbz derivative (65%), but a
rather poor yield of the Fmoc derivative (30%). Based on the
rather low product recovery, other aromatic amines were not
studied.
The widespread use of combinatorial libraries in the search
for biologically active lead compounds has led to recent
advances in the use of solid-phase organic synthesis tech-
niques.1 As a result, more recently, a variety of organic
reactions have been successfully carried out in the solid
phase.2 Our current research is directed at the development of
polymer bound reagents for amino group modification, includ-
ing the use of polymer-bound 1-hydroxybenzotriazole (P-
HOBT). P-HOBT was originally developed as a highly reactive
N-acylating agent for the formation of peptide bonds,3 and has
recently been used for the synthesis of simple amides.4 Other
successful polymer-bound acylating agents include N-hydroxy-
succinimide,5 carbodiimide6 and triphenylphosphine.7 We have
utilized P-HOBT for the synthesis of medium-ring lactams
from linear precursors,8 and the preparation of N-hydroxy-
succinimide (NHS) esters.9 Moreover, we have shown P-HOBT
to be recyclable and stable for extended periods under ambient
conditions.9 Herein, we report the convenient protection of
primary and secondary amines as fluorenylmethoxycarbonyl
(Fmoc), benzyloxycarbonyl (Cbz) and tert-butoxycarbonyl
(t-Boc) carbamates utilizing P-HOBT.
P-HOBT was prepared from Bio-Rad SM-2 dried macro-
porous beads (polystyrene–divinylbenzene copolymer resin,
100–200 mesh, MW cutoff 2000) according to the method of
Fridkin and Patchornik.3 The activity of P-HOBT was deter-
mined to be 0.25 mmol gϪ1 based on the synthesis of
N-isopropylacetamide.9 For the protection reaction, P-HOBT
was suspended in CH2Cl2 and reacted with Boc2O, or with
Fmoc-Cl or Cbz-Cl in the presence of pyridine (1.5 equiv.
based on P-HOBT used) to yield the immobilized carbonates
(Scheme 1). The resulting polymer was collected by filtration
and re-suspended in CH2Cl2 (or 3:1 DMF–H2O, depending on
amine solubility). The amine, as limiting reagent, was added
and the suspension was rocked for 3–20 hours. The suspension
was subsequently filtered, and the filtrate concentrated under
reduced pressure to yield the carbamate product, which was
analyzed to be pure by TLC and/or 1H NMR.
Of note, several reactions were carried out utilizing water as a
co-solvent due to amine solubility. The water did not appear to
affect reactivity or recovery of products. This suggests the reac-
tion may be optimized to the convenient protection of water
soluble amines (e.g. amino acids) with a suitable choice of
aqueous buffer or aqueous buffer/organic solvent systems. We
are currently studying this possibility.
In summary, a new method has been developed for the facile
protection of amino groups as carbamate moieties utilizing
Boc2O,
O
or CbzCl (pyridine),
or FmocCl (pyridine)
NOH
N
OR
NO
N
CH2Cl2, rt
N
N
P-HOBT
R′ NH
R′′
O
+
RO
N
R′′
P-HOBT
CH2Cl2, rt
R′
Scheme 1 General method for carbamate protection of amines
J. Chem. Soc., Perkin Trans. 1, 1998
1463

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Table 1 Carbamates obtained via P-HOBT
Carbamate products (% yield)
mmol, 0.88 equiv. of NH2 groups based on activated polymer).
The suspension was rocked at 25 ЊC for 5 h. The polymer was
then filtered and washed with CH2Cl2 (4 × 5 ml). The filtrate
and washings were combined and concentrated to yield 0.015 g
(68%) of N,NЈ-bis(benzyloxycarbonyl)-1,5-diaminopentane.
1H NMR (300 MHz, CDCl3, TMS internal reference) 1.35
(m, 2H, Cbz-NHCH2CH2CH2CH2CH2NH-Cbz), 1.50 (m,
4H, Cbz-NHCH2CH2CH2CH2CH2NH-Cbz), 3.17 (m, 4H,
Cbz-NHCH2CH2CH2CH2CH2NH-Cbz), 4.80 (br s, 2H, 2 NH),
5.08 (s, 4H, 2 ArCH2O), 7.34 (br s, 10H, ArH) (FAB LRMS
Calcd. for C21H27N2O4 [M ϩ 1]ϩ 371; Found: [M ϩ 1]ϩ 371).
All other carbamate products were formed in an analogous
fashion to N,NЈ-bis-Cbz-1,5-diaminopentane. All carbamate
products provided satisfactory 1H NMR and MS analysis.
Amine Used
N-Cbz
N-Fmoc
N-t-Boc
isopropylamine
piperidine
n-hexylamine
-valine benzyl ester
1,5-diaminopentanea
6-aminohexanoic acidb
3-aminopropan-1-ol
-valineb
p-phenetidine
benzylamine
pyrrolidine
diisopropylamine
60
84
86
74
68
61
78
85
79
82
67
99
92
43
30
99
88
35
35
43
21
60
65
a bis-carbamate derivative, b DMF–H2O (3:1) used as solvent in place
of CH2Cl2.
Acknowledgements
The authors thank the University of Maryland, Baltimore
County for financial support.
polymer bound HOBT. The major advantages of this method
include the ability to prepare protected amines in pure form
with no work-up, and the potential for automation. As a result,
this methodology is not only amenable to combinatorial chem-
istry, but will also be useful for the protection of amino moieties
in complex, biologically active compounds, including the use of
aqueous reaction conditions for water soluble amines.
References
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Experimental section
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General
All carbamate forming reactions utilizing P-HOBT were
carried out in 8 ml Extract-CleanTM solid phase extraction
tubes (from Alltech Associates, Inc.), equipped with a dispos-
able inlet cap and a one-way stopcock on the outlet. Reactions
were mixed by gentle rocking and filtration was carried out
using a 12-port solid phase extraction manifold connected to a
water aspirator. All yields reported are isolated yields of
products obtained directly by concentration of the filtrate
from the P-HOBT mediated carbamate forming reaction, with
purity based on thin-layer chromatography (TLC) and NMR
spectroscopy. Mass spectra were obtained by the Mass
Spectrometry Laboratory at the University of Maryland,
College Park, Maryland.
N,NЈ-Bis(benzyloxycarbonyl)-1,5-diaminopentane
Benzyl chloroformate (0.060 g, 0.050 ml, 0.35 mmol, 2.6 equiv.)
was added to a suspension of P-HOBT (0.135 mmol, 0.541 g,
0.25 mmol gϪ1, 1.0 equiv.) in 5 ml of CH2Cl2, followed by the
addition of pyridine (0.039 g, 0.040 ml, 0.49 mmol, 3.6 equiv.).
The suspension was rocked at 25 ЊC for 1 h. At this time, the
polymer was filtered, washed with CH2Cl2 (3 × 5 ml), DMF
(3 × 5 ml), CH2Cl2 (3 × 5 ml) and dry Et2O (3 × 5 ml). The
dried polymer was suspended in CH2Cl2 (5 ml) followed by
the addition of 1,5-diaminopentane (0.0061 g, 0.0070 ml, 0.060
Paper 8/02020E
Received 12th March 1998
Accepted 12th March 1998
1464
J. Chem. Soc., Perkin Trans. 1, 1998