Selective synthesis of carbamate protected polyamines using alkyl phenyl carbonates

Article abstract of DOI:10.1055/s-2002-34859

Utilising alkyl phenyl carbonates, an economical, practical and versatile method for selective Boc, Cbz and Alloc protection of polyamines has been developed. This method allows Boc, Cbz and Alloc protection of primary amines in the presence of secondary amines by reaction of the polyamines with the alkyl phenyl carbonates. Also, this method allows mono carbamate protection of simple symmetrical aliphatic α,ω-alkanediamines in high yields with respect to the diamine. Finally, the method allows selective carbamate protection of a primary amine located on a primary carbon in the presence of a primary amine located on a secondary or a tertiary carbon in excellent yields.

Full text of DOI:10.1055/s-2002-34859

PAPER
2195
Selective Synthesis of Carbamate Protected Polyamines Using Alkyl Phenyl
Carbonates
Selective Synthesis of
i
C
arba
m
c
ate Protec
t
h
edPolyamin
a
es
U
singA
e
lkyl Phenyl
l
C
arbonates Pittelkow, Rasmus Lewinsky, Jørn Bolstad Christensen*
Chemical Laboratory II, The H. C. Ørsted Institute, University of Copenhagen, Universitetsparken 5, 2100 Denmark
Fax +45(353)20212 ; E-mail: jbc@kiku.dk
Received 27 May 2002; revised 12 July 2002
Abstract: Utilising alkyl phenyl carbonates, an economical, practi-
O
O
cal and versatile method for selective Boc, Cbz and Alloc protection
of polyamines has been developed. This method allows Boc, Cbz
and Alloc protection of primary amines in the presence of second-
ary amines by reaction of the polyamines with the alkyl phenyl car-
bonates. Also, this method allows mono carbamate protection of
simple symmetrical aliphatic , -alkanediamines in high yields
with respect to the diamine. Finally, the method allows selective
carbamate protection of a primary amine located on a primary car-
bon in the presence of a primary amine located on a secondary or a
tertiary carbon in excellent yields.
O
O
O
O
1
2
O
O
O
3
Key words: protecting groups, amines, regioselectivity, chemose-
Figure 1
lectivity, carbonates
tert-Butyl phenyl carbonate (1) is commercially available.
Benzyl phenyl carbonate (2) and allyl phenyl carbonate
(3) were prepared by a slight modification of the pub-
lished method for benzyl phenyl carbonate by reaction be-
tween phenyl chloroformate and the respective alcohol
(benzyl alcohol and allyl alcohol) in the presence of pyri-
dine. The three carbonates are stable, easy handled and
can be stored refrigerated without noticeable decomposi-
Aliphatic polyamines are a class of compounds with a va-
riety of interesting functions. These range from being part
of toxins in spiders and wasps, through neurotransmission
in humans and fruit-ripening in plants, to ligands in inor-
ganic chemistry.1–4 Also, they have proved useful as link-
ers and building blocks in supramolecular architectures.5
A problem often encountered in the synthesis, or in the tion (a problem often encountered with the alkyl chloro-
synthetic use of polyamines, is selective protection of the formates).24
amino groups. This synthetic challenge has been dealt
Recently, a selective method for Boc and Cbz protection
with in a number of ways6 and elegant multi-step synthet-
of primary amino groups in polyamines based on O-alkyl
ic procedures have been developed to strategically incor-
O -(N-succinimidyl) carbonates was published.25 Howev-
porate protection groups in polyamines.7,8
er the selectivity of the method relies on performing the
Alkyl phenyl carbonates have only found limited use as reactions at –40 °C. Furthermore, selectivity for reaction
acylating agents in formation of carbamates in spite of the on primary amino groups over secondary amino groups
number of reports in the literature.9–18 The kinetics of the has been shown with the commercially available reagent,
reaction between alkyl aryl carbonates and primary and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile
secondary amines have been investigated previously, and (BOC-ON), also at low temperatures.26
it has clearly been shown that secondary amines react
The two natural polyamines spermidine (4) and spermine
(5), and the two symmetrical triamines diethylenetriamine
much slower than primary amines.19,20
This result inspired the work presented herein, where a se- (6) and dipropylenetriamine (7) were chosen as the
lective method for carbamate protection of polyamines polyamines for this study, all containing both primary and
using alkyl phenyl carbonates is developed.
secondary amino moieties. We found the reaction be-
tween the polyamines and the alkyl phenyl carbonates af-
forded chemoselective carbamate protection of the
primary amino groups in high yields (Scheme 1).
The alkyl phenyl carbonates investigated in this study
were tert-butyl phenyl carbonate (1),21 benzyl phenyl car-
bonate (2)22 and allyl phenyl carbonate (3)23 introducing
the Boc (tert-butoxycarbonyl), Cbz (benzyloxycarbonyl) Performing the reactions at room temperature in CH2Cl2
and Alloc (allyloxycarbonyl) protecting groups, respec- (or in DMF) using 1.1 equivalent alkyl phenyl carbonate
tively (Figure 1).
per primary amino group gave the chemoselective car-
bamate protected polyamines after aqueous workup. The
prepared compounds and the obtained yields are present-
ed in Table 1 (protected amines 15–26).
Synthesis 2002, No. 15, Print: 29 10 2002.
Art Id.1437-210X,E;2002,0,15,2195,2202,ftx,en;T06202SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2196
M. Pittelkow et al.
PAPER
O
yields with respect to the benzyl chloroformate, but it suf-
fers from difficulties in controlling the pH in the reaction
mixture. Dibenzyl carbonate has also been used for this
purpose,30 but like the Boc protection with di-tert-butyl
dicarbonate this requires a large excess of the diamine.
R
Ph
O
O
H2N
NH2
N
n
H
m
R = tert-butyl,
benzyl or allyl
4 m = 2, n = 3
6 m = 1, n = 1
7 m = 2, n = 2
A general method to selectively introduce the Alloc pro-
tection group once on , -diamines has not, to the best of
our knowledge, been developed. The preparation of some
of the compounds has been reported previously, though
generally in low yields.31–34
O
O
H
R
O
N
R
N
N
O
m
H
H
n
15-23
We found that reacting the , -diamines 8–12 with one
equivalent of alkyl phenyl carbonate (Scheme 2) in etha-
nol at room temperature (with the tert-butyl phenyl car-
bonate reflux was necessary) afforded the mono
carbamate protected diamine in good to high yields (pro-
tected amines 27–41 in the Table).
O
R
Ph
H
N
O
O
NH2
H2N
N
H
R = tert-butyl,
benzyl or allyl
5
O
H
H
O
R
N
N
O
O
N
N
R
R
Ph
O
H
H
O
O
O
R
H2N
NH2
n
H2N
N
O
n
H
24-26
R = tert-butyl,
benzyl or allyl
8 n = 2
9 n = 3
10 n = 4
11 n = 5
12 n = 6
Scheme 1
27- 41
The three different protection groups introduced on the
primary amino groups are orthogonal, which means that
they can respectively be removed, under different condi-
tions,6 and this strategy therefore opens synthetic path-
ways, for manipulation of the secondary amino groups
present in the polyamines. In general the Boc protection
group can be removed under acidic conditions, the Cbz
protection group can be removed by catalytic hydrogena-
tion and the Alloc protection group can be removed by
treatment with Pd. Both Adamczyk25 and Phanstiel26 have
used this strategy in their synthetic work. Other orthogo-
nal protection groups for amines and general conditions
for their removal has been described elsewhere, and an ex-
cellent selection is available.6
Scheme 2
Small amounts of bis alkyloxycarbonyl , -alkanedi-
amines and unreacted , -alkanediamine are easily re-
moved during the aqueous workup. As evident from the
results, selectivity for mono protection decreases with the
length of the alkane chain, and when sufficiently long (5
methylene groups) there was no longer selectivity for
mono protection (yields were approximately 50%).
Scaling up this process showed to be amenable as the
mono protection of 1,2-ethanediamine was carried out on
a large scale (0.33 mol).
The selectivity in the introduction of the three protection
groups was further tested by reaction with unsymmetrical
aliphatic diamines. Selectivity towards reaction with pri-
mary amines located on a primary carbon in the presence
of a primary amine located on either a secondary or a ter-
tiary carbon was studied by reaction of the alkyl phenyl
carbonates with the two diamines, 2-methyl-1,2-pro-
panediamine (13) and 1,2-propanediamine (14)
(Scheme 3). Both of these diamines were successfully
mono carbamate protected on the primary amino groups
located on the primary carbon atom in high yields with the
three carbonates (protected amines 42–47 in the Table 1).
This remarkable selectivity has only been reported on few
occasions previously, also using mixed carbonates.25,35
Much to our surprise these highly selective reactions pre-
ceded best when two equivalents of alkyl phenyl carbon-
ate were used.
The usefulness of mono carbamate protected , -al-
kanediamines is evident from many applications in syn-
thetic procedures7 and by the numerous ways they have
been prepared.6
The most common direct method (one pot) for the prepa-
ration of the mono Boc protected , -diamines has been
developed by Krapcho and co-workers where di-tert-bu-
tyl dicarbonate is reacted with an excess (6–7 equiv) of the
, -alkanediamine.27,28 This method gives high yields
with respect to the di-tert-butyl dicarbonate, but low
yields with respect to the , -diamine. Moreover the pro-
cedure requires slow addition of the di-tert-butyl dicar-
bonate at 0 °C which, in our experience, can cause
problems with respect to crystallisation of the di-tert-bu-
tyl dicarbonate during the addition period.
The mono Cbz carbamate protected , -alkanediamines
have been prepared by slow addition of benzyl chlorofor-
mate to an excess of the , -diamines in a buffered solu-
tion by Denny and co-workers.29 This method gives good
In summary, this paper describes a highly selective, ver-
satile and practical method for carbamate protection of
Synthesis 2002, No. 15, 2195–2202 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Selective Synthesis of Carbamate Protected Polyamines Using Alkyl Phenyl Carbonates
2197
aliphatic polyamines using alkyl phenyl carbonates as the
acylating agent.
Unless otherwise stated, all starting materials were obtained from
commercial suppliers and used as received. Solvents were HPLC
1
grade and were used as received. H NMR and 13C NMR spectra
were recorded on a 300 MHz NMR (Varian) apparatus (300 MHz
1
for H NMR and 75 MHz for 13C NMR) or on a 400 MHz NMR
1
(Bruker) apparatus (400 MHz for H NMR and 100 MHz for 13C
NMR). Proton chemical shifts are reported in ppm downfield from
tetramethylsilane (TMS) and carbon chemical shifts in ppm down-
field of TMS using the resonance of the deuterated solvent as inter-
nal standard. Mps were measured on a Büchi B-140 apparatus and
are uncorrected. Elemental analysis was performed by Mrs Karin
Linthoe. Fast-atom bombardment (FAB) mass spectra were record-
ed on a Jeol JMS-HX 110A Tandem Mass Spectrometer in the pos-
itive ion mode using m-nitrobenzylalcohol (m-NBA) as the matrix.
Scheme 3
Table 1 Selective Protection of Polyamines with Alkyl Phenyl Carbonates
Amine
Protected Aminea
Yieldb (%)
15 PG = Boc
16 PG = Cbz
17 PG = Alloc
61
72
52
6
7
18 PG = Boc
19 PG = Cbz
20 PG = Alloc
73
77
73
21 PG = Boc
22 PG = Cbz
23 PG = Alloc
78
71
89
4
24 PG = Boc
25 PG = Cbz
26 PG = Alloc
86
67
98
5
27 PG = Boc
28 PG = Cbz
29 PG = Alloc
65
64
67
8
30 PG = Boc
31 PG = Cbz
32 PG = Alloc
68
72
86
9
33 PG = Boc
34 PG = Cbz
35 PG = Alloc
63
63
77
10
11
12
13
36 PG = Boc
37 PG = Cbz
38 PG = Alloc
50
56
51
39 PG = Boc
40 PG = Cbz
41 PG = Alloc
49
48
46
42 PG = Boc
43 PG = Cbz
44 PG = Alloc
91
97
96
45 PG = Boc
46 PG = Cbz
47 PG = Alloc
70
69
75
14
a PG = Protection Group: Boc = Me3COCO, Cbz = PhCH2OCO, Alloc = CH2CHCH2OCO.
b Yields are based on the polyamine.
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M. Pittelkow et al.
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HRMS were recorded on a Micromass Q-TOF apparatus using elec-
trospray ionisation (ESI) technique.
13C NMR (CDCl3): = 40.3, 48.4, 66.4, 127.8, 128.0, 128.2, 136.3,
156.5.
MS (FAB): m/z = 372.1 (MH+).
Benzyl Phenyl Carbonate (2)
16·HCl
To a mixture of benzyl alcohol (108.0 g, 1.0 mol), pyridine (100
mL) and CH2Cl2 (175 mL) in a 500 mL 3-necked flask equipped
with a condenser, mechanical stirring and an addition funnel was
added phenyl chloroformate (156.0 g, 1.0 mol) over a period of 1 h.
The reaction mixture was stirred for an additional 3 h, and H2O (250
mL) was added. The ether phase was washed with aq H2SO4 (2 M;
White crystals; mp 202–204 °C.
1H NMR (DMSO-d6): = 3.00 (t, 4 H, J = 6 Hz), 3.36 (q, 4 H, J =
6 Hz), 5.04 (s, 4 H), 7.28–7.36 (m, 10 H), 7.53 (t, 2 H, J = 6 Hz),
9.25 (br s, 2 H).
13C NMR (DMSO-d6): = 36.9, 46.5, 65.6, 127.8, 127.9, 128.4,
2
250 mL), dried (Na2SO4), filtered and concentrated in vacuo.
136.9, 156.2.
The crude product was distilled in vacuum to give 2.
Anal. Calcd for C20H26N3O4Cl: C, 58.89; H, 6.42; N, 10.30; Cl,
8.69. Found: C, 58.99; H, 6.24; N, 10.29; Cl, 8.56.
Yield: 180.2 g (79%); colourless oil; bp 146–150 °C/0.2 mmHg
(127–131 °C/0.1 mmHg).
1H NMR (CDCl3): = 5.37 (s, 2 H), 7.18–7.48 (m, 10 H).
[2-(2-Allyloxycarbonylaminoethylamino)ethyl]carbamic Acid
Allyl Ester (17)
Synthesised according to the general procedure from diethylenetri-
amine using CH2Cl2 as the solvent.
Allyl Phenyl Carbonate (3)
Preparation by the procedure described for benzyl phenyl carbon-
ate.
Yield: 7.0 g (52%); white solid; mp 55–57 °C.
Yield 159.5 g (90 %); colourless oil; bp 75–78 °C/0.2 mmHg.
1H NMR (CDCl3): = 4.8 (d, 2 H, J = 5.7 Hz), 5.31–5.48 (m, 2 H),
5.94–6.10 (m, 1 H), 7.22–7.46 (m, 5 H).
1H NMR (CDCl3): =1.32 (br s, 1 H), 2.64 (t, 4 H, J = 6 Hz), 3.17
(q, 4 H, J = 6 Hz), 4.45 (d, 4 H, J = 5 Hz), 5.10–5.23 (m, 4 H), 5.61
(br s, 2 H), 5.72–5.89 (m, 2 H).
13C NMR (CDCl3): = 40.3, 48.3, 65.1, 117.2, 132.7, 156.3.
MS (FAB): m/z = 272 (MH+).
Carbamate Protection of Polyamines with Alkyl Phenyl Car-
bonates; General Procedure
To a solution of the polyamine (0.05 mol) in DMF (50 mL) or
CH2Cl2 (100 mL) was added the appropriate alkyl phenyl carbonate
(1.1 equiv per primary amino group). The reaction mixture was
stirred overnight at r.t. and poured into a phosphate buffer (2 L;
0.025 M K2HPO4 and 0.025 M NaH2PO4). The pH was adjusted to
3 with aq H2SO4 (2 M), and the mixture was extracted with CH2Cl2
(2 250 mL). The aq phase was made strongly alkaline with aq
NaOH (9 M), and extracted with CH2Cl2 (3 250 mL). The organic
phase was dried (Na2SO4), filtered and concentrated in vacuo. The
residual solvents were removed by drying the protected amines at
0.1 mmHg at 40 °C.
Anal. Calcd for C12H21N3O4: C, 53.12; H, 7.80; N, 15.49. Found: C,
52.96; H, 8.00; N, 15.50.
[3-(3-tert-Butoxycarbonylaminopropylamino)propyl]carbamic
Acid tert-Butyl Ester (18)
This compound was synthesised according to the general procedure
from dipropylenetriamine using DMF as the solvent.
Yield: 12.1 g (73%); white solid; mp 67–69 °C.
1H NMR (CDCl3): = 1.43 (s, 18 H), 1.63 (quint, 4 H), 2.64 (t, 4 H,
J = 6 Hz), 3.19 (q, 4 H), 5.20 (br s, 2 H).
In case of the Cbz protected amines 16 and 19, the corresponding
hydrochlorides were found to insoluble in H2O, and could be
formed simply by addition of aq HCl (2 M) to the crude amines. The
hydrochlorides thus obtained were crystallised from EtOH to give
the analytically pure salts 16 HCl and 19 HCl.
13C NMR (CDCl3): = 28.3, 29.7, 38.9, 47.3, 156.0.
MS (FAB): m/z = 332.1 (MH+).
[3-(3-Benzyloxycarbonylaminopropylamino)propyl]carbamic
Acid Benzyl Ester (19)
Synthesised according to the general procedure from dipropylene-
triamine using CH2Cl2 as the solvent.
In case of the natural polyamines 4 and 5 the reactions were carried
out on a 5–10 mmol scale.
Yield: 17.0 g (77%); white waxy solid; mp 56–58 °C.
[2-(2-tert-Butoxycarbonylaminoethylamino)ethyl]carbamic
Acid tert-Butyl Ester (15)
This was synthesised according to the general procedure from dieth-
ylenetriamine using DMF as the solvent [and a catalytic amount of
Et3N (5 mL)].
1H NMR (CDCl3): = 1.22 (br s, 1 H), 1.63 (t, 4 H, J = 6 Hz), 2.62
(t, 4 H, J = 6 Hz), 3.18–3.25 (m, 4 H), 5.05 (s, 4 H) 5.53 (br s, 2 H),
7.30 (s, 10 H).
13C NMR (CDCl3): = 29.3, 39.1, 47.0, 66.1, 127.6, 127.9, 128.1,
136.5, 156.3.
Yield: 9.3 g (61%); white solid; mp 73–75 °C.
1H NMR (CDCl3): = 1.36 (s, 18 H), 1.86 (br s, 1 H), 2.64 (t, 2 H,
J = 6 Hz), 3.13 (q, 2 H, J = 6 Hz), 5.12 (br s, 2 H).
13C NMR (CDCl3): = 28.2, 40.1, 48.6, 78.9, 156.0.
MS (FAB): m/z = 400.2 (MH+).
19 HCl
White crystals; mp 208–210 °C.
MS (FAB): m/z = 304.2 (MH+).
1H NMR (DMSO-d6): = 1.68–1.79 (m, 4 H), 2.84 (t, 4 H, J = 7
Hz), 3.08 (q, 4 H, J = 6 Hz), 5.01 (s, 4 H), 7.35 (m, 10 H), 8.96 (br
s, 2 H).
13C NMR (DMSO-d6): = 26.2, 37.6, 44.6, 65.4, 127.8, 127.9,
128.2, 128.4, 137.2, 156.3.
[2-(2-Benzyloxycarbonylaminoethylamino)ethyl]carbamic
Acid Benzyl Ester (16)
Synthesised according to the general procedure from diethylenetri-
amine using CH2Cl2 as the solvent.
Yield: 13.5 g (72%); white solid; mp 73–75 °C.
1H NMR (CDCl3): = 1.25 (br s, 1 H), 2.73 (s, 4 H), 3.25 (s, 4 H),
5.08 (s, 4 H), 5.19 (br s, 2 H), 7.33 (s, 10 H).
Anal. Calcd for C22H30N3ClO4: C, 60.61; H, 6.94; N, 9.63; Cl, 8.13.
Found: C, 60.71; H, 6.91; N, 9.46; Cl, 8.00.
Synthesis 2002, No. 15, 2195–2202 ISSN 0039-7881 © Thieme Stuttgart · New York

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Selective Synthesis of Carbamate Protected Polyamines Using Alkyl Phenyl Carbonates
2199
[3-(3-Allyloxycarbonylaminopropylamino)propyl]carbamic
Acid Allyl Ester (20)
13C NMR (CDCl3): = 27.8, 28.6, 29.8, 39.1, 47.4, 49.6, 79.1,
156.3.
Synthesised according to the general procedure from dipropylene-
triamine using CH2Cl2 as the solvent.
MS (FAB): m/z = 403.4 (MH+).
Yield: 11.0 g (73%); white solid; mp 52–54 °C.
N1,N8-Bis(benzyloxycarbonyl)spermine (25)
This compound was synthesised according to the general procedure
from spermine (1.64 g, 8.12 mmol) using CH2Cl2 as the solvent.
1H NMR (CDCl3): = 1.24 (br s, 1 H), 1.60 (quint, 4 H), 2.59 (t, 4
H, J = 7 Hz), 3.20 (q, 4 H, J = 6 Hz), 4.49 (d, 4 H, J = 5 Hz), 5.08–
5.23 (m, 4 H), 5.60 (br s, 2 H), 5.73–5.89 (m, 2 H).
Yield: 2.57 g (67 %); white solid; mp 72–75 °C.
13C NMR (CDCl3): = 29.3, 39.1, 47.1, 65.0, 117.1, 132.8, 156.1.
MS (FAB): m/z = 300.2 (MH+).
1H NMR (CDCl3): = 1.21 (br s, 2 H), 1.49 (m, 4 H), 1.64 (quint, 4
H, J = 6.4 Hz), 2.58 (m, 4 H), 2.65 (t, 4 H, J = 6.4 Hz), 3.27 (q, 4 H,
J = 5.5 Hz), 5.09 (s, 4 H), 5.68 (br s, 2 H), 7.30–7.38 (m, 10 H).
13C NMR (CDCl3): = 27.9, 29.6, 40.2, 48.0, 49.8, 66.6, 128.1,
128.6, 136.9, 156.6.
Anal. Calcd for C14H25N3O4: C, 56.17; H, 8.42; N, 14.04. Found: C,
56.16; H, 8.24; N, 14.06.
N1,N8-Bis(tert-butoxycarbonyl)spermidine (21)
MS (FAB): m/z = 471.4 (MH+).
This compound was synthesised according to the general procedure
from spermidine (1.08 g, 7.40 mmol) using DMF as the solvent.
N1,N8-Bis(allyloxycarbonyl)spermine (26)
This compound was synthesised according to the general procedure
from spermine (1.64 g, 8.12 mmol) using CH2Cl2 as the solvent.
Yield: 2.00 g (78%); white solid; mp 70–72 °C.
1H NMR (CDCl3): = 1.20–1.30 (br s, 1 H), 1.42 (s, 18 H), 1.52 (m,
4 H), 1.63 (quint, 2 H, J = 7.0 Hz), 2.59 (t, 2 H, J = 6.4 Hz), 2.65 (t,
2 H, J = 6.4 Hz), 3.11 (q, 2 H, J = 5.9 Hz), 3.19 (q, 2 H, J = 6.4 Hz),
4.82 (br s, 1 H), 5.20 (br s, 1 H).
13C NMR (CDCl3): = 26.9, 27.7, 28.4, 29.5, 38.9, 40.3, 47.4, 49.2,
79.0, 156.0, 156.2.
Yield: 2.93 g (98 %); white solid; mp 39–41 °C.
1H NMR (CDCl3): = 1.47 (quint, 4 H, J = 3.3 Hz), 1.53 (br s, 2 H),
1.61 (quint, 4 H, J = 6.6 Hz), 2.55 (t, 4 H, J = 5.9 Hz), 2.63 (t, 4 H,
J = 6.6 Hz), 3.21 (d, 4 H, J = 4.4 Hz), 4.49 (d, 4 H, J = 5.1 Hz), 5.13
(dd, 2 H, J = 1.1, 10.3 Hz), 5.23 (dd, 2 H, J = 1.1, 17.2 Hz), 5.72 (br
s, 2 H), 5.86 (m, 2 H, J = 5.9 Hz).
13C NMR (CDCl3): = 27.6, 29.4, 39.8, 47.7, 49.5, 65.1, 117.2,
133.0, 156.2.
MS (FAB): m/z = 346.3 (MH+).
N1,N8-Bis(benzyloxycarbonyl)spermidine (22)6
This compound was synthesised according to the general procedure
from spermidine (1.12 g, 7.72 mmol) using DMF as the solvent.
MS (FAB): m/z = 371.3 (MH+).
HRMS (ESI): m/z calcd for C18H35N4O4 (MH+): 371.2658; found:
Yield: 2.27 g (71%); white solid; mp 78–80 °C.
371.2630.
1H NMR (CDCl3): = 1.48–1.60 (m, 5 H), 1.65 (m, 2 H), 2.59 (t, 2
H, J = 6.4 Hz), 2.62 (t, 2 H, J = 6.4 Hz ), 3.18 (q, 2 H, J = 6.4 Hz),
3.26 (q, 2 H, J = 6.4 Hz), 5.09 (s, 4 H), 5.20 (br s, 1 H), 5.52 (br s,
1 H), 7.25–7.45 (m, 10 H).
13C NMR (CDCl3): = 27.1, 27.8, 29.6, 39.7, 41.0, 47.5, 49.3, 66.7,
128.2, 128.6, 129.6, 136.7, 136.8, 156.7.
Mono Carbamate Protection of Aliphatic Diamines; General
Procedure
Alkyl phenyl carbonate (5.0 mmol) (in the cases of the unsymmet-
rical diamines 10 mmol of alkyl phenyl carbonate was used) was
added to a stirring solution of diamine (5.0 mmol) in absolute EtOH
(20 mL). The reaction mixture was stirred over night at r.t. (reflux
in the case of tert-butyl phenyl carbonate) followed by removal of
the volatiles in vacuo. H2O (25 mL) was added and the pH adjusted
to 3 by addition of aq HCl (2 M) followed by extraction with CH2Cl2
(2 50 mL). The aq phase was then made strongly alkaline by ad-
dition of aq NaOH (2 M) and extracted with CH2Cl2 (3 80 mL).
The organic phase was dried (Na2SO4), filtered and concentrated in
vacuo to afford the desired products.
MS (FAB): m/z = 414.3 (MH+).
N1,N8-Bis(allyloxycarbonyl)spermidine (23)
Synthesised according to the general procedure from spermidine
(1.16 g, 7.97 mmol) using CH2Cl2 as the solvent.
Yield: 2.23 g (89%); white solid; mp 41–43 °C.
1H NMR (CDCl3): = 1.00–1.20 (br s, 1 H), 1.53 (m, 4 H), 1.66
(quint, 2 H, J = 6.6 Hz), 2.60 (t, 2 H, J = 6.6 Hz), 2.68 (t, 2 H, J =
6.2 Hz), 3.18 (q, 2 H, J = 6.2 Hz), 3.27 (q, 2 H, J = 6.2 Hz), 4.54 (d,
4 H, J = 5.5 Hz), 5.19 (dd, 2 H, J = 1.5, 10.3 Hz), 5.29 (dd, 2 H, J =
1.5, 17.2 Hz), 5.57 (br s, 2 H), 5.91 (m, 2 H).
(2-Aminoethyl)carbamic Acid tert-Butyl Ester (27)
From 1,2-ethanediamine (33.3 mmol).
Yield: 3.44 g (65%); colourless oil.
13C NMR (CDCl3): = 27.2, 27.7, 29.4, 39.8, 40.8, 47.7, 49.2, 65.3,
117.4, 133.0, 156.2.
MS (FAB): m/z = 314.3 (MH+).
Scale Up
tert-Butyl phenyl carbonate (20.0 g, 0.33 mol) was added to a stir-
ring solution of 1,2-ethanediamine (64.62 g, 0.33 mol) in absolute
EtOH (200 mL). The reaction mixture was refluxed overnight
(keeping the temperature of the oil bath at a maximum of 80 °C) fol-
lowed by removal of the volatiles in vacuo. H2O (300 mL) was add-
ed and the pH adjusted to 3 by addition of aq HCl (2 M) followed
by extraction with CH2Cl2 (4 500 mL). The aq phase was then
made strongly alkaline by addition of aq NaOH (2 M) and extracted
with CH2Cl2 (5 500 mL). The organic phase was dried (Na2SO4),
filtered and concentrated in vacuo to afford 27.
Anal. Calcd for C14H25N3O4: C, 57.49; H, 8.67; N, 13.41. Found: C,
57.29; H, 8.67; N, 13.33.
N1,N8-Bis(tert-butoxycarbonyl)spermine (24)
Synthesised according to the general procedure from spermine
(1.06 g, 5.25 mmol) using DMF as the solvent.
Yield: 1.89 g (86 %); white solid.
1H NMR (CDCl3): = 1.40 (s, 18 H), 1.52 (m, 4 H), 1.63 (quint, 4
H, J = 6.6 Hz), 1.93 (br s, 2 H), 2.59 (m, 4 H), 2.65 (t, 4 H, J = 6.6
Hz), 3.17 (q, 4 H, J = 5.8 Hz), 5.19 (br s, 2 H).
Yield: 34.6 g (65%); colourless oil.
1H NMR (CDCl3): = 1.43 [br s, 11 H, (CH3)3 and NH2], 2.78 (t, 2
H, J = 5.9 Hz), 3.15 (q, 2 H, J = 5.9 Hz), 4.96 (br s, 1 H, NHCO).
Synthesis 2002, No. 15, 2195–2202 ISSN 0039-7881 © Thieme Stuttgart · New York

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M. Pittelkow et al.
PAPER
13C NMR (CDCl3): = 28.3, 41.5, 42.6, 79.2, 156.1.
(4-Aminobutyl)carbamic Acid Benzyl Ester (34)
From 1,4-butanediamine (5 mmol).
MS (FAB): m/z = 161.1 (MH+).
Yield: 0.70 g (63%); colourless oil.
(2-Aminoethyl)carbamic Acid Benzyl Ester (28)
From 1,2-ethanediamine (5 mmol).
1H NMR (CDCl3): = 1.42–1.58 (m, 6 H), 2.67–2.75 (m, 2 H),
3.15–3.25 (m, 2 H), 5.03 (br s, 1 H), 5.09 (s, 2 H), 7.29–7.39 (m, 5
H).
Yield: 0.62 g (64%); colourless oil.
1H NMR (CDCl3): = 1.38 (br s, 2 H), 2.76–2.85 (m, 2 H), 3.19–
3.36 (m, 2 H), 5.10 (s, 2 H), 5.24 (br s, 1 H), 7.31–7.37 (m, 5 H).
13C NMR (CDCl3): = 27.3, 30.6, 40.8, 41.6, 66.5, 127.9, 128.0,
128.4, 136.5, 156.3.
13C NMR (CDCl3): = 41.5, 43.6, 66.5, 127.9, 128.0, 128.4, 136.4,
156.5.
MS (FAB): m/z = 223.0 (MH+).
(4-Aminobutyl)carbamic Acid Allyl Ester (35)
From 1,4-butanediamine (5 mmol).
MS (FAB): m/z = 195.1 (MH+).
(2-Aminoethyl)carbamic Acid Allyl Ester (29)
Yield: 0.66 g (77%); colourless oil.
From 1,2-ethanediamine (5 mmol).
1H NMR (CDCl3): = 1.46–1.55 (m, 4 H), 2.00 (br s, 2 H), 2.68–
2.74 (m, 2 H), 3.13–3.20 (m, 2 H), 4.53 (d, 2 H, J = 4.4 Hz), 5.14
(br s, 1 H), 5.15–5.31 (m, 2 H), 5.82–5.96 (m, 1 H).
13C NMR (CDCl3): = 27.2, 30.2, 40.7, 41.4, 65.2, 117.3, 132.9,
156.1.
Yield: 0.48 g (67%); colourless oil.
1H NMR (CDCl3): = 2.04 (br s, 2 H), 2.81 (t, 2 H, J = 5.8 Hz), 3.22
(m, 2 H), 4.53 (d, 2 H, J = 5.5 Hz), 5.15–5.31 (m, 2 H), 5.45 (br s,
1 H), 5.82–5.97 (m, 1 H).
13C NMR (CDCl3): = 41.4, 43.2, 65.3, 117.4, 132.8, 156.4.
MS (FAB): m/z = 173.0 (MH+).
MS (FAB): m/z = 145.0 (MH+).
Anal. Calcd for C14H25N3O4: C, 55.79; H, 9.36; N, 16.27. Found: C,
55.70; H, 9.57; N, 16.58.
(3-Aminopropyl)carbamic Acid tert-Butyl Ester (30)
From 1,3-propanediamine (13.5 mmol).
(5-Aminopentyl)carbamic Acid tert-Butyl Ester (36)
From 1,5-pentanediamine (5 mmol).
Yield: 1.61 g (68%); colourless oil.
Yield: 0.52 g (50%); colourless oil.
1H NMR (CDCl3): = 1.40 (s, 9 H), 1.55–1.65 (m, 2 H), 2.26 (br s,
2 H), 2.74 (t, 2 H, J = 6.4 Hz), 3.13–3.20 (m, 2 H), 5.08 (br s, 1 H).
13C NMR (CDCl3): = 28.2, 32.7, 38.1, 39.2, 78.8, 156.0.
MS (FAB): m/z = 175.1 (MH+).
1H NMR (CDCl3): = 1.36–1.43 (s, 9 H), 1.44–1.53 (m, 6 H), 2.70
(t, 2 H, J = 6.2 Hz), 3.00–3.11 (m, 2 H), 3.74 (br s, 2 H), 4.80 (br s,
1 H).
13C NMR (CDCl3): = 23.8, 28.3, 29.6, 31.7, 40.3, 41.1, 78.8,
155.9.
(3-Aminopropyl)carbamic Acid Benzyl Ester (31)
From 1,3-propanediamine (5 mmol).
MS (FAB): m/z = 203.0 (MH+).
Yield: 0.75 g (72%); colourless oil.
(5-Aminopentyl)carbamic Acid Benzyl Ester (37)
From 1,5-pentanediamine (5 mmol).
1H NMR (CDCl3): = 1.52 (br s, 2 H), 1.62 (quint, 2 H, J = 6.4 Hz),
2.75 (t, 2 H, J = 6.4 Hz), 3.27 (q, 2 H), 5.09 (s, 2 H), 5.33 (br s, 1
H), 7.30–7.36 (m, 5 H).
13C NMR (CDCl3): = 32.9, 39.1, 39.6, 66.5, 127.8, 127.9, 128.3,
136.6, 156.4.
Yield: 0.66 g (56%); colourless oil.
1H NMR (CDCl3): = 1.27–1.37 (m, 2 H), 1.38–1.52 (m, 4 H), 1.80
(br s, 2 H), 2.66 (t, 2 H, J = 6.4 Hz), 3.11–3.20 (m, 2 H), 5.06 (s, 2
H), 7.30–7.35 (m, 5 H).
13C NMR (CDCl3): = 23.8, 29.6, 32.8, 40.7, 41.6, 66.3, 127.8,
127.8, 128.3, 136.5, 156.3.
MS (FAB): m/z = 209.1 (MH+).
(3-Aminopropyl)carbamic Acid Allyl Ester (32)
From 1,3-propanediamine (5 mmol).
MS (FAB): m/z = 237.1 (MH+).
Yield: 0.68 g (86%); colourless oil.
(5-Aminopentyl)carbamic Acid Allyl Ester (38)3
From 1,5-pentanediamine (5 mmol).
1H NMR (CDCl3): = 1.62 (quint, 2 H, J = 6.4 Hz), 1.91 (br s, 2 H),
2.76 (t, 2 H, J = 6.4 Hz), 3.25 (q, 2 H), 4.52 (d, 2 H, J = 4.69 Hz),
5.14–5.30 (m, 2 H), 5.48 (br s, 1 H), 5.81–5.97 (m, 1 H).
13C NMR (CDCl3): = 32.5, 38.8, 39.4, 65.2, 117.3, 132.9, 156.3.
MS (FAB): m/z = 159.0 (MH+).
Yield: 0.47 g (51%); colourless oil.
1H NMR (CDCl3): = 1.31–1.41 (m, 2 H), 1.44–1.55 (m, 4 H), 2.71
(t, 2 H, J = 5.3 Hz), 2.99 (br s, 2 H), 3.13 (q, 2 H), 4.53 (d, 2 H, J =
5.3 Hz), 4.99 (br s, 1 H), 5.15–5.32 (m, 2 H), 5.82–5.97 (m, 1 H).
13C NMR (CDCl3): = 23.8, 29.6, 32.1, 40.7, 41.4, 65.3, 117.4,
132.9, 156.2.
Anal. Calcd for C14H25N3O4: C, 53.15; H, 8.92; N, 17.71. Found: C,
53.37; H, 9.08; N, 18.01.
MS (FAB): m/z = 187.1 (MH+).
(4-Aminobutyl)carbamic Acid tert-Butyl Ester (33)
From 1,4-butanediamine (5 mmol).
(6-Aminohexyl)carbamic Acid tert-Butyl Ester (39)
From 1,6-hexanediamine (15.5 mmol).
Yield: 0.59 g (63%); colourless oil.
1H NMR (CDCl3): = 1.37 (s, 9 H), 1.41–1.46 (m, 4 H), 1.90 (br s,
2 H), 2.63–2.68 (m, 2 H), 3.01–3,10 (m, 2 H), 4.85 (br s, 1 H).
13C NMR (CDCl3): = 27.2, 28.2, 30.3, 40.2, 41.4, 78.8, 155.8.
Yield: 1.63 g (49%); colourless oil.
1H NMR (CDCl3): = 1.26–1.32 (m, 4 H), 1.37–1.44 (m, 13 H),
2.14 (br s, 2 H), 2.65 (t, 2 H, J = 7.0 Hz), 3.05 (q, 2 H), 4.66 (br s, 1
H).
MS (FAB): m/z = 189.0 (MH+).
Synthesis 2002, No. 15, 2195–2202 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Selective Synthesis of Carbamate Protected Polyamines Using Alkyl Phenyl Carbonates
2201
13C NMR (CDCl3): = 26.3, 26.4, 28.2, 29.8, 33.0, 40.3, 41.7, 78.8,
155.8.
MS (FAB): m/z = 217.1 (MH+).
1H NMR (CDCl3): = 1.10 (d, 3 H, J = 6.0 Hz), 1.42 (s, 9 H), 2.77
(br s, 2 H), 2.88–2.97 (m, 1 H), 3.03–3.10 (m, 1 H), 3.11–3.22 (m,
1 H), 5.17 (br s, 1 H).
13C NMR (CDCl3): = 21.2, 28.2, 47.2, 47.7, 79.1, 156.2.
(6-Aminohexyl)carbamic Acid Benzyl Ester (40)
From 1,6-hexanediamine (5 mmol).
MS (FAB): m/z = 175.0 (MH+).
Yield: 0.60 g (48%); colourless oil.
(2-Aminopropyl)carbamic Acid Benzyl Ester (46)
From 1,2-propanediamine (5 mmol).
1H NMR (CDCl3): = 1.28–1.35 (m, 4 H), 1.38–1.51 (m, 4 H), 1.67
(br s, 2 H), 2.66 (t, 2 H, J = 6.4 Hz), 3.17 (q, 2 H), 4.95 (br s, 1 H),
5.07 (s, 2 H), 7.31–7.37 (m, 5 H).
13C NMR (CDCl3): = 26.3, 26.4, 29.8, 33.3, 40.8, 41.8, 66.4,
127.9, 127.9, 128.3, 136.5, 156.2.
Yield: 0.72 g (69%); colourless oil.
1H NMR (CDCl3): = 1.05 (d, 3 H, J = 6.4 Hz), 1.69 (br s, 2 H),
2.87–3.04 (m, 2 H), 3.14–3.24 (m, 1 H), 5.08 (s, 2 H), 5.50 (br s, 1
H), 7.28–7.37 (m, 5 H).
MS (FAB): m/z = 251.0.
13C NMR (CDCl3): = 21.1, 46.6, 48.5, 66.4, 127.8, 127.9, 128.3,
136.4, 156.5.
MS (FAB): m/z = 209.0 (MH+).
(6-Aminohexyl)carbamic Acid Allyl Ester (41)2
From 1,6-hexanediamine (5 mmol).
Yield: 0.46 g (46%); colourless oil.
(2-Aminopropyl)carbamic Acid Allyl Ester (47)
From 1,2-propanediamine (5 mmol).
1H NMR (CDCl3): = 1.32–1.38 (m, 4 H), 1.46–1.56 (m, 4 H),
2.73–2.81 (m, 2 H), 3.17 (q, 2 H), 3.59 (br s, 2 H), 4.55 (d, 2 H, J =
5.3 Hz), 4.85 (br s, 1 H), 5.18–5.33 (m, 2 H), 5.85–5.98 (m, 1 H).
13C NMR (CDCl3): = 26.2, 26.2, 29.7, 31.8, 40.7, 41.3, 65.3,
117.4, 132.9, 156.2.
Yield: 0.59 g (75%); colourless oil.
1H NMR (CDCl3): = 1.08 (d, 3 H, J = 5.9 Hz), 2.92–3.24 (m, 5 H,
CH, CH2 and NH2), 4.53 (d, 2 H, J = 5.3 Hz), 5.71 (br s, 1 H), 5.81–
5.96 (m, 1 H).
MS (FAB): m/z = 201.0.
13C NMR (CDCl3): = 20.4, 46.7, 47.9, 65.4, 117.4, 132.8, 156.5.
MS (FAB): m/z = 159.0 (MH+).
(2-Amino-2-methylpropylcarbamic Acid tert-Butyl Ester (42)
Anal. Calcd for C14H25N3O4: C, 53.15; H, 8.92; N, 17.71. Found: C,
53.35; H, 8.98; N, 17.51.
From 2-methyl-1,2-propanediamine (17.2 mmol).
Yield: 2.97 g (91%); colourless oil.
1H NMR (CDCl3): = 1.09 (s, 6 H), 1.43 (s, 9 H), 1.48 (br s, 2 H),
3.00 (d, 2 H, J = 6.4 Hz), 4.97 (br s, 1 H).
Acknowledgements
13C NMR (CDCl3): = 28.0, 28.3, 50.3, 52.0, 79.0, 156.3.
We thank Trine Christensen for valuable technical assistance.
MS (FAB): m/z = 189.1 (MH+).
References
(2-Amino-2-methylpropyl)carbamic Acid Benzyl Ester (43)
From 2-methyl-1,2-propanediamine (5 mmol).
(1) Geneste, H.; Hesse, M. Chem. Unserer Zeit 1998, 32, 206.
(2) Cohen, S. S. Nature (London) 1978, 274, 209.
(3) Cohen, S. S. Introduction to the Polyamines; Prentice-Hall:
Englewood Cliffs, 1971.
(4) Cohen, S. S. A Guide to the Polyamines; Oxford University
Press: New York, 1998.
Yield: 1.08 g (97%); colourless oil.
1H NMR (CDCl3): = 1.10 (s, 6 H), 1.97 (br s, 2 H), 3.08 (d, 2 H,
J = 6.4 Hz), 5.10 (s, 2 H), 5.42 (t, 1 H, J = 6.4 Hz), 7.33–7.37 (m,
5 H).
13C NMR (CDCl3): = 27.8, 50.3, 52.1, 66.6, 127.9, 127.9, 128.3,
136,4, 156.8.
(5) de Brabander-van den Berg, E. M. M.; Meijer, E. W. Angew.
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MS (FAB): m/z = 223.1 (MH+).
(2-Amino-2-methylpropyl)carbamic Acid Allyl Ester (44)
From 2-methyl-1,2-propanediamine (5 mmol).
Yield: 0.83 g (96%); colourless oil.
1H NMR (CDCl3): = 1.08 (s, 6 H), 1.56 (br s, 2 H), 3.04 (d, 2 H,
J = 6.4 Hz), 4.6 (d, 2 H), 5.15–5.32 (m, 2 H), 5.33 (br s, 1 H), 5.83–
5.97 (m, 1 H).
13C NMR (CDCl3): = 28.0, 50.0, 52.3, 65.4, 117.4, 132.8, 156.7.
MS (FAB): m/z = 173.0 (MH+).
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Anal. Calcd for C14H25N3O4: C, 55.79; H, 9.36; N, 16.27. Found: C,
55.57; H, 9.23; N, 16.43.
(2-Aminopropyl)carbamic Acid tert-Butyl Ester (45)5
From 1,2-propanediamine (18.8 mmol).
Yield: 2.30 g (70%); colourless oil.
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PAPER
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Synthesis 2002, No. 15, 2195–2202 ISSN 0039-7881 © Thieme Stuttgart · New York