Synthesis of cyanoformamides from primary amines and carbon dioxide under mild conditions. Synthesis of ceratinamine

Article abstract of DOI:10.1039/b912043b

Treatment of primary amines with tetramethylphenylguanidine (PhTMG) and a cyanophosphonate at -10 °C under an atmosphere of carbon dioxide provides cyanoformamides in very high to excellent yields. The reaction proceeds efficiently within a short time. By

Full text of DOI:10.1039/b912043b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of cyanoformamides from primary amines and carbon dioxide under
mild conditions. Synthesis of ceratinamine†
Eduardo Garc´ıa-Egido, Jairo Paz, Beatriz Iglesias and Luis Mun˜oz*
Received 19th June 2009, Accepted 30th June 2009
First published as an Advance Article on the web 23rd July 2009
DOI: 10.1039/b912043b
Treatment of primary amines with tetramethylphenylguanidine (PhTMG) and a cyanophosphonate at
-10 ◦C under an atmosphere of carbon dioxide provides cyanoformamides in very high to excellent
yields. The reaction proceeds efficiently within a short time. By-products were not detected in most runs
and epimerization was not found when optically pure a-aminoesters were used as substrates. As an
example, the reaction was applied to the synthesis of the marine natural product ceratinamine.
from tetracyanoethylene oxide and butylsulfide)8 (Scheme 1)
Introduction
or triphosgene followed by treatment with the cyanide ion.5b
Cyanoformamides, also called carbamoyl cyanides, are not very
Other methods use more sophisticated reagents like 4-chloro-
5H-1,2,3-dithiazol-5-one (4),7 isonitroso Meldrum’s acid (5)9 or
common compounds either in organic synthesis or in natural
products chemistry. In fact, the first natural product with this
its tosyl derivative 5-[(tosyloxy)imino]-2,2-dimethyl-1,3-dioxane-
4,6-dione (6) (Scheme 1).10 The use of this type of compounds
is not always desirable, not only because of their toxicity and
complexity, but also because of the high reactivity of the system.
Cyanoformamides can be potentially useful intermediates in
organic synthesis and, as a result, new and simple methods for
their preparation are necessary.
functionality in its structure, ceratinamine (1) (Fig. 1), was isolated
in 1996 by Fusetani and co-workers from the marine sponge
Pseudoceratina purpurea1 and was synthesized later by Ganem and
Schoenfeld.2 Ceratinamine is cytotoxic and has potent antifouling
activity. A related compound, 7-hydroxyceratinamine (2) (Fig. 1),
was isolated three years later from the marine sponge Aplysinella
sp. by Schmitz.3 Although N,N-dimethylcyanoformamide was
isolated from several vegetables and fruits—such as tomatoes,
oranges and apples—as a degradation metabolite of a pesticide,4
other natural products with the cyanoformamide functionality
have not been isolated to date.
Scheme 1
In this paper we describe the preparation of carbamoyl cyanides
under very mild conditions through the low temperature reaction
of primary amines and carbon dioxide at atmospheric pressure
with a cyanophosphonate. This methodology has been applied
to the synthesis of the natural product ceratinamine. A similar
method has previously been devised for the preparation of
carbamoyl azides from primary amines11 and 2-oxazolidinones
from 1,2-amino alcohols.12
Fig. 1
In spite of their potential use in the synthesis of complex
molecules, there are only a few reports in the literature that describe
the use of cyanoformamides for this purpose. Two outstanding
examples are the synthesis of complex lactams by intramolec-
ular cyanoamidation of unsaturated cyanoformamides5 and the
preparation of tetrazoles by reaction of cyanoformamides and
aluminium azide.6 Cyanoformamides have also been proposed as
intermediates in the synthesis of symmetrical N,N¢-dialkylureas.7
Only a few methods have been described in the literature
to prepare cyanoformamides from amines. The most simple
approaches make use of reagents like carbonyl cyanide 3 (prepared
Results and discussion
The methodology described here relies on the formation of a
stabilized carbamate anion by treatment of an amine with carbon
dioxide in the presence of a pentasubstituted guanidine. Reaction
of this carbamate anion with either diethylcyanophosphonate
(DEPC) or diphenylcyanophosphonate (DPPC) cleanly gave the
cyanoformamide (Scheme 2). The reaction conditions (temper-
ature and solvent) previously optimized for the synthesis of
Departamento de Qu´ımica Orga´nica, Facultade de Qu´ımica, Universidade
de Vigo, 36310 Vigo, Spain. E-mail: lmunoz@uvigo.es
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra. See DOI: 10.1039/b912043b
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explain some of the problems described in the isolation of
ceratinamine (1) and related compounds. As this is a rapid reaction
that gives excellent yields it is not necessary to add an excess of
nucleophile (i.e., cyanide) to the reaction medium, a situation in
contrast to that for azides.
Although most of the experiments described here were carried
out using PhTMG as the base, the yields of cyanoformamides
did not seem to be as base-dependent as the yields of carbamoyl
azides. For example, significant differences were not found when
DBU was used instead of PhTMG.
Scheme 2
Another subtle difference between the two reactions concerns
the by-products found in some experiments. The preparation of
carbamoyl azides mainly yields symmetrical ureas as by-products.
Surprisingly, ureas have not been detected in the preparation of
cyanoformamides. In fact, only parabanic acid derivatives have
been isolated from the reaction media, and even then only in very
small amounts and in cases where the amine function is bound
to a methylene group (7a, entry 2; 7i, entry 10; Table 1). These
compounds were identified by the absence of a signal for the
carbamoyl azides were successfully applied to the preparation of
cyanoformamides.11
The results of the reaction for several amines under different
conditions are shown in Table 1. The yields are generally excellent
and in all cases the data refer to isolated and purified products.
By-products were not detected in most runs and, in cases where
such compounds were detected, they were present at levels less
than 5–10%.
1
amide proton in the H NMR spectrum together with the shift
The spectroscopic characterization of carbamoyl cyanides 8 can
be easily performed. These compounds have a weak IR band at
2230–2240 cm-1 and this is typical of the cyano group. The 13C
NMR spectra show signals for the carbonyl and the nitrile carbons
in the region 142–143 ppm and at 111 ppm, respectively. These
two chemical shifts are upfield compared to the expected values
for both types of carbon when considered alone. This suggests a
strong interaction between these two carbon atoms.
of the carbonyl carbons to 152–156 ppm. The structures were also
confirmed by mass spectrometry.
Parabanic acid derivatives 11 have been known in the literature
for a long time.13 These compounds were obtained by reaction of
an isocyanate with cyanide followed by hydrolysis, as shown in
Scheme 3. A possible mechanism has been proposed.14
Although the methods for the preparation of carbamoyl azides11
and cyanoformamides are almost identical in a formal sense, the
outcomes of the reactions are dissimilar in several respects. Firstly,
the reaction to form cyanoformamides proceeds quite rapidly and
is normally complete within 1 hour. Indeed, we have observed that
the yields can decrease markedly if the reaction time is extended
unnecessarily. This means that longer reaction times lead to the
formation of by-products by decomposition of the carbamoyl
cyanides in the reaction medium. This type of behaviour could
Scheme 3
We have proposed isocyanates as possible intermediates in this
kind of reaction and we therefore carried out several experiments
to degrade cyanoformamides 8 in the presence of different bases. It
was found that 5-imino-2,4-imidazolidinediones 10 were formed
cleanly in variable yields depending on the base. For example,
triethylamine promotes a slow reaction with the recovery of
starting material but DBU leads to a more rapid reaction that goes
to completion (see Experimental). This result is fully consistent
with previous literature reports.9
In addition to the parabanic acid derivative 11a, a phospho-
rylated by-product 12a was isolated from benzylamine (7a) when
diphenylcyanophosphonate was used as the electrophile (entry 2,
Table 1). The reaction of L-tryptophan methyl ester (7p) (entry
19, Table 1) gave a similar result with DPPC, thus allowing the
isolation of the phosphorylated compound 12p together with a
small amount of the bis-cyanoformamide 13 (Fig. 2).
Table 1 Yields of cyanoformamides from various amines
Phosphorus
reagent
Entry
Amine (7)
8 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
benzylamine (a)
DEPC
DPPC
DPPC
DEPC
DEPC
DEPC
DEPC
DPPC
DPPC
DPPC
DEPC
DPPC
DEPC
DEPC
DEPC
DEPC
DPPC
DEPC
DPPC
DEPC
DPPC
99
91
78
96
99
98
99
85
78
70
89
79
95
87
96
82
82
85
81
96
82
benzylamine (a)
4-methoxybenzylamine (b)
(R)-a-methylbenzylamine (c)
2-(1-cyclohexenyl)ethylamine (d)
cyclohexylamine (e)
homoveratrylamine (f)
2-amino-3-methylbutane (g)
2-methoxyethylamine (h)
glycine methyl ester (i)
(R)-phenylglycine ethyl ester (j)
L-Ala-OMe (k)
L-Phe-OMe (l)
L-Val-OMe (m)
D-Val-OMe (n)
Racemization was not detected when a-amino esters were used
as substrates. The optical purity for valine derivatives was assessed
by GC on a chiral support after derivatization of the carbamoyl
cyanide as a urea with dimethylamine (>99.5%). In addition,
evidence for the presence of diastereomers was not found by NMR
for the cyanoformamide prepared from L-isoleucine.
L-Glu(OMe)-OMe (o)
L-Glu(OMe)-OMe (o)
L-Trp-OMe (p)
L-Trp-OMe (p)
L-Ile-OMe (q)
L-Asp(OMe)-OMe (r)
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chlorotrimethylsilane), whereas typical deprotection conditions,
such as TFA in dichloromethane, produced a small amount of
decomposition by-products.
The synthesis of ceratinamine (1) was carried out as shown
in Scheme 5. Tyramine (16) was brominated in high yield and
the amino group was protected in the standard way as the BOC
derivative. Phenol 18 was alkylated with 1,3-dibromopropane in
basic acetone, and the second amine functionality was introduced
in the classical two-step procedure: substitution of bromide with
azide followed by reduction. Although some problems were
encountered in this reduction, it was efficiently carried out
through the reaction with triphenylphosphine and subsequent
hydrolysis of the iminophosphorane with water. Cyanoformamide
22 was formed in good yield under the conditions described
here. Finally, deprotection under mild acidic conditions produced
ceratinamine (1) in excellent yield. The spectra of the synthetic
ceratinamine are identical to those of a natural sample. The
overall yield of ceratinamine obtained using our synthetic route
was 64% from tyramine (70% from dibromotyramine), which is
slightly higher than the previously reported synthesis (52% from
dibromotyramine).2
Fig. 2
In contrast to the situation in the reaction medium, evidence for
instability of the carbamoyl cyanides was not found on handling
these compounds in the laboratory. Indeed, these compounds
could be purified by flash chromatography without substantial
decomposition, whereas storage at -18 ◦C for several months did
not have a significant effect on the purity of the compounds.
Attempts to prepare the corresponding cyanoformamides from
aliphatic secondary amines produced a totally different outcome,
which was similar to what happened in the case of carbamoyl
azides.11 Application of the optimized reaction conditions to
dibutylamine produced the mixed anhydride (Fig. 3) in good
yield (84%) as the only product after long reaction times (17 h).
An extremely low yield of cyanoformamide (9%) could only be
obtained after an extended reaction period (60 h). Similar results
were found on applying the same procedure to other secondary
amines.
In summary, we have developed a convenient synthetic strategy
for the preparation, under very mild conditions, of cyanofor-
mamides from primary amines and carbon dioxide. The practical
applicability of this methodology has been demonstrated by
the efficient synthesis of ceratinamine, a natural product with
biological activity.
Experimental
General methods
Dry acetonitrile was distilled from calcium hydride under an argon
atmosphere. All the reagents were obtained from commercial sup-
pliers and used as received unless otherwise indicated. Thin layer
chromatography (TLC) was performed using plates coated with
Kieselgel 60 F254, and column chromatography was performed
using Kieselgel 60 according to the method of Still et al.15 NMR
spectra were recorded on 400 MHz Bruker Instruments spectrome-
ters. 1H and 13C NMR spectra were recorded in deuterated solvents
Fig. 3
In order to assess the viability of the method with more
complex molecules, we decided to carry out the synthesis of
ceratinamine (1). The main problem in this synthesis is the selective
introduction of the cyanoformamide functionality on one of the
amino groups. This requires the use of a protective group on
the second amino function, which can be deprotected without
affecting the carbamoyl cyanide moiety. The tert-butoxycarbonyl
(BOC) group was assessed as shown in Scheme 4. Monoprotected
octyl-1,8-diamine was transformed into the corresponding car-
bamoyl cyanide 14 in good yield. The BOC deprotection step was
efficiently achieved under very mild acidic conditions (phenol,
(mostly CDCl3) and were referred to the solvent residual peak. 31
P
NMR spectra were externally referred to an 85% H3PO4 solution.
J values are given in Hz.
General procedure for the synthesis of cyanoformamides
A
solution of the amine and tetramethylphenylguanidine
(PhTMG) (115 mol%; 215 mol% for hydrochlorides) in anhydrous
acetonitrile (0.05 M) was chilled in a salt/ice bath and then
dry CO2 (g) was slowly bubbled through until saturation was
achieved. DEPC (110 mol%) was added and CO2 bubbling was
continued for 10 min. The mixture was stirred for 1 hour at
0
◦C under a CO2 atmosphere. The mixture was poured onto
EtOAc (150 mL) and the solution washed with water (3¥) and 5%
HCl (3¥). The organic layer was dried over Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by
flash chromatography.
Benzylcarbamoyl cyanide (8a). Following the general pro-
Scheme 4
cedure and starting from benzylamine (0.214 g, 2.0 mmol),
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Scheme 5
purification by flash chromatography (hexane/EtOAc 9:1 to 7:1)
gave 8a as a white crystalline solid (0.318 g, 99%). Rf 0.50
(hexane/EtOAc 1:1); mp 68.2–69.2 ◦C; nmax(KBr)/cm-1 3277br,
2240w, 1621br, 1554, 1452 and 695; dH (400 MHz; CDCl3; Me4Si)
(two rotamers, ratio 9:1) 4.52 (1.8 H, d, J 5.9), 4.69 (0.2 H, d, J
5.9), 6.48 (1 H, br s) and 7.29–7.42 (5 H, m); dC (100 MHz; CDCl3;
Me4Si) (major rotamer) 44.4, 111.4, 128.0, 128.4, 129.0, 135.1 and
143.1; m/z (EI) 160 (M+, 100%), 133 (12), 104 (18), 91 (33), 79
(15); HRMS (EI) 160.0629 (M+. C9H8N2O requires 160.0637).
When the reaction was carried out starting from the amine
(1.099 g, 10.26 mmol) and DPPC (3.191 g, 12.31 mmol, 120 mol%),
purification yielded the expected cyanoformamide 8a (1.488 g,
91%), a white solid identified as 12a (0.010 g, 0.3%) and a
colourless oil identified as 11a (0.140 g, 4.6%).
111.3, 114.1, 127.2, 129.3, 143.0 and 159.2; HRMS (ESI) 213.0642
([M + Na]+. C10H10N2NaO2 requires 213.0634).
(R)-(1-Phenylethyl)carbamoyl cyanide (8c). Following the gen-
eral procedure and starting from amine 7c (1 g, 8.25 mmol) and
DEPC (1.37 mL, 8.25 mmol, 100 mol%), purification by flash
chromatography (silica gel, hexane/EtOAc 8:1) gave compound
8c as a colourless oil that solidified on standing (1.380 g, 96%).
[a]D +112.13 (c 0.92 in CHCl3); nmax(NaCl)/cm-1 3286, 3059,
25
3039, 2982, 2935, 2877, 2801, 2236, 1678 and 1539; dH (400 MHz;
CDCl3; Me4Si) (two rotamers 0.95:0.05) 1.53 (2.85 H, d, J 7.0),
1.61 (0.15 H, d, J 6.8), 5.08 (1 H, p, J 4 ¥ 7.0), 7.28–7.45 (5 H,
m) and 7.86 (1 H, br d, J 7.4); dC (100 MHz; CDCl3; Me4Si)
(major rotamer) 21.0, 50.5, 111.3, 126.0, 127.9, 128.7, 140.4 and
142.4; HRMS (ESI) 197.0681 ([M + Na]+. C10H10N2NaO requires
197.0685).
Diphenyl
benzyl(cyanocarbonyl)phosphoramidate
(12a).
n
max(NaCl)/cm-1 3066, 2233, 1695 and 1591; dH (400 MHz;
(2-Cyclohexenylethyl)carbamoyl cyanide (8d). Following the
general procedure and starting from 2-(1-cyclohexenyl)ethylamine
(0.250 g, 2.0 mmol), purification by flash chromatography (hex-
ane/EtOAc 19:1 to 9:1) gave the product 8d as a white crystalline
solid (0.352 g, 99%). Rf 0.645 (hexane/EtOAc 4:1); mp 48.5–
49.0 ◦C; nmax(KBr)/cm-1 3278br, 2932br, 2238w, 1668br and
1559br; dH (400 MHz; CDCl3; Me4Si) (two rotamers 92:8) 1.53–
1.67 (4 H, m), 1.91 (2 H, d, J 1.5), 2.02 (2 H, dd, J 2.2 and 1.3),
2.19 (2 H, t, J 6.7), 3.42 (1.8 H, q, J 6.2), 3.55 (0.08 H, q, J 6.2),
5.51 (1 H, br d, J 1.1), 6.47 (0.08 H, br s) and 6.52 (0.92 H, br s);
dC (100 MHz; CDCl3; Me4Si) (major rotamer) 22.1, 22.6, 25.1,
27.7, 36.7, 38.2, 111.6, 124.8, 126.1, 133.2 and 143.0; m/z (EI) 178
(M+, 6%), 108 (100), 95 (59), 93 (45), 79 (46), 69 (49); HRMS (EI)
178.1108 (M+. C10H14N2O requires 178.1106).
CDCl3; Me4Si) d 4.98 (2 H, d, J 11.5) and 7.04–7.46 (15 H, m);
dC (100 MHz; CDCl3; Me4Si) 49.5, 110.1, 119.9 (d, J 4.8), 126.1,
128.2, 128.4, 128.6, 129.9, 134.7, 144.9 and 149.2 (d, J 7.3); dP
(160 MHz; CDCl3) -10.82; HRMS (ESI) 393.1002 ([M + H]+.
C21H18N2O4P requires 393.0999).
1,3-Dibenzylimidazolidine-2,4,5-trione
(11a). nmax(NaCl)/
cm-1 3032 and 1726; dH (400 MHz; CDCl3; Me4Si) 4.76 (2 H, s)
and 7.16–7.50 (5 H, m); dC (100 MHz; CDCl3; Me4Si) 42.9, 128.6,
128.9 (2C), 134.3, 153.3 and 156.3; HRMS (ESI) 295.1083 ([M +
H]+. C17H15N2O3 requires 295.1077).
(4-Methoxybenzyl)carbamoyl cyanide (8b). Following the gen-
eral procedure and starting from 4-methoxybenzylamine (1 g,
7.29 mmol) and DPPC (1.890 g, 7.29 mmol, 100 mol%), purifi-
cation by flash chromatography (silica gel, hexane/EtOAc 10:1
to 5:1) yielded 8b as a colourless oil that solidified on standing
(1.080 g, 78%). nmax(NaCl)/cm-1 3293, 3056, 3007, 2941, 2839,
2235, 1686, 1612 and 1515; dH (400 MHz; CDCl3; Me4Si) (two
rotamers 0.95:0.05) 3.82 (3 H, s), 4.40 (1.9 H, d, J 5.7), 4.58 (0.1
H, d, J 6.1), 6.91 (2 H, d, J 8.5), 7.23 (2 H, d, J 8.4) and 7.71 (1
H, br s); dC (100 MHz; CDCl3; Me4Si) (major rotamer) 43.6, 55.1,
Cyclohexylcarbamoyl cyanide (8e). Following the general pro-
cedure and starting from cyclohexylamine (0.198 g, 2.0 mmol),
purification by flash chromatography (hexane/EtOAc 19:1 to 9:1)
gave the product 8e as a white solid (0.295 g, 98%). Rf 0.50
(hexane/EtOAc 9:1); mp 80.2–81.1 ◦C; nmax(KBr)/cm-1 3275br,
2935br, 2854, 2240w, 1663br and 1559; dH (400 MHz; CDCl3;
Me4Si) (two rotamers) 1.15–1.44 (5 H, m), 1.56–1.82 (3 H, m), 1.95
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(2 H, m), 3.79–3.88 (1 H, m) and 6.16 (1 H, br s); dC (100 MHz;
CDCl3; Me4Si) (major rotamer) 24.4, 25.0, 32.0, 50.0, 111.7 and
142.3; m/z (EI) 152 (M+, 0.02%), 109 (92), 96 (11), 82 (100), 67
(47); HRMS (EI) 152.0944 (M+. C8H12N2O requires 152.0950).
CDCl3; Me4Si) 39.5, 53.0, 152.2, 155.6 and 166.2; HRMS (ESI)
259.0571 ([M + H]+. C9H11N2O7 requires 259.0561).
(R)-Ethyl 2-(cyanocarbonylamino)-2-phenylacetate (8j). Fol-
lowing the general procedure and starting from amine 7j (2.090 g,
11.66 mmol) and DEPC (1.93 mL, 11.66 mmol, 100 mol%),
purification by flash chromatography (silica gel, hexane/EtOAc
15:1 to 12:1) gave compound 8j as a colourless oil that solidified
(3,4-Dimethoxyphenethyl)carbamoyl cyanide (8f). Following
the general procedure and starting from homoveratrylamine
(0.362 g, 2.0 mmol), purification by flash chromatography
(hexane/EtOAc 9:1 to 3:1) gave the product 8f as a white
solid (0.464 g, 99%). Rf 0.50 (hexane/EtOAc 1:1); mp 89.2–
90.0 ◦C; nmax(KBr)/cm-1 3286br, 2229w, 1701, 1515 and 1265;
dH (400 MHz; CDCl3; Me4Si) (two rotamers 19:1) 2.83 (2 H, t, J
6.9), 3.61 (0.95 H, q, J 6.8), 3.76 (0.05 H, q, J 6.8), 3.88 (3 H, s),
3.89 (3 H, s), 6.17 (1 H, br s), 6.69 (1 H, d, J 1.9), 6.73 (1 H, dd,
J 8.1 and 1.9) and 6.85 (1 H, d, J 8.2); dC (100 MHz; CDCl3;
Me4Si) (major rotamer) 34.1, 41.5, 55.7, 55.8, 111.4, 111.5, 111.7,
120.6, 129.8, 143.2, 147.7 and 148.9; m/z (EI) 234 (M+, 17%), 207
(11), 164 (11), 151 (100); HRMS (EI) 234.1002 (M+. C12H14N2O3
requires 234.1004).
25
on standing (2.411 g, 89%). [a]D -37.60 (c 3.34 in CHCl3);
n
max(NaCl)/cm-1 3302, 3061, 3035, 2986, 2941, 2239, 1740, 1696
and 1528; dH (400 MHz; CDCl3; Me4Si) (two rotamers 0.97:0.03)
1.21 (3 H, t, J 2 ¥ 7.1), 4.19 (1 H, dq, J 10.8, 3 ¥ 7.1), 4.28 (1 H,
dq, J 11.1, 3 ¥ 7.3), 5.56 (0.03 H, d, J 8.6), 5.60 (0.97 H, d, J 7.4),
7.51–7.20 (5 H, m), 7.73 (0.03 H, br d, J 7.8) and 8.30 (0.97 H, br d,
J 7.0); dC (100 MHz; CDCl3; Me4Si) (major rotamer) 13.7, 56.9,
62.8, 111.0, 127.1, 129.0, 134.3, 142.3 and 169.3; HRMS (ESI)
233.0924 ([M + H]+. C12H13N2O3 requires 233.0921).
(S)-Methyl 2-(cyanocarbonylamino)propanoate (8k). Follow-
ing the general procedure and starting from amine 7k (1.369 g,
13.28 mmol) and DPPC (3.442 g, 13.28 mmol, 100 mol%),
purification by flash chromatography (silica gel, hexane/EtOAc
(3-Methylbutan-2-yl)carbamoyl cyanide (8g). Following the
general procedure and starting from amine 7g (1.5 g, 17.21 mmol)
and DPPC (4.461 g, 17.21 mmol, 100 mol%), purification by flash
chromatography (silica gel, hexane/EtOAc 12:1) gave compound
8g as a colourless oil that solidified on standing (2.049 g, 85%).
25
6:1 to 4:1) gave compound 8k as a white solid (1.639 g, 79%). [a]D
+32.15 (c 1.32 in CHCl3); nmax(NaCl)/cm-1 3310, 3059, 3002, 2958,
2852, 2238, 1747, 1701 and 1540; dH (400 MHz; CDCl3; Me4Si)
(two rotamers 0.93:0.07) 1.49 (2.79 H, d, J 7.1), 1.72 (0.21 H, d, J
7.4), 3.78 (0.21 H, s), 3.81 (2.79 H, s), 4.61 (0.93 H, p, J 4 ¥ 7.2),
4.91 (0.07 H, q, J 3 ¥ 7.4), 6.74 (0.07 H, br s) and 7.24 (0.93 H,
br s); dC (100 MHz; CDCl3; Me4Si) (major rotamer) 17.8, 49.1,
53.2, 111.1, 142.4 and 171.6; HRMS (ESI) 179.0430 ([M + Na]+.
C6H8N2NaO3 requires 179.0427).
n
max(NaCl)/cm-1 3281, 3060, 2970, 2880, 2236, 1678 and 1543; dH
(400 MHz; CDCl3; Me4Si) (two rotamers 0.89:0.11) 0.82–0.99 (6
H, m), 1.14 (2.67 H, d, J 6.8), 1.25 (0.33 H, d, J 6.6), 1.75 (1 H,
m), 3.74 (0.11 H, m), 3.88 (0.89 H, m), 6.48 (0.11 H, br s) and
6.87 (0.89 H, br s); dC (100 MHz; CDCl3; Me4Si) (major rotamer)
16.8, 18.2 (2C), 32.5, 52.1, 111.7 and 142.7; HRMS (ESI) 141.1025
([M + H]+. C7H13N2O requires 141.1022).
(S)-Methyl 2-(cyanocarbonylamino)-3-phenylpropanoate (8l).
Following the general procedure and starting from amine 7l
(1.299 g, 7.25 mmol) and DEPC (1.20 mL, 7.25 mmol, 100 mol%),
purification by flash chromatography (silica gel, hexane/EtOAc
(2-Methoxyethyl)carbamoyl cyanide (8h). Following the gen-
eral procedure and starting from amine 7h (0.786 g, 10.46 mmol)
and DPPC (2.711 g, 10.46 mmol, 100 mol%), purification by
flash chromatography (silica gel, hexane/EtOAc 6:1 to 4:1) gave
compound 8h as a yellowish oil (1.049 g, 78%). nmax(NaCl)/cm-1
3282, 3061, 2991, 2938, 2896, 2833, 2236, 1694 and 1544; dH
(400 MHz; CDCl3; Me4Si) (two rotamers 0.92:0.08) 3.38 (3 H, s),
3.73–3.44 (4 H, m), 6.68 (0.08 H, br s) and 7.04 (0.92 H, br s); dC
(100 MHz; CDCl3; Me4Si) (major rotamer) 39.8, 58.5, 69.5, 111.4
and 143.3; HRMS (ESI) 129.0660 ([M + H]+. C5H9N2O2 requires
129.0658).
25
6:1 to 4:1) gave compound 8l as a white solid (1.6 g, 95%). [a]D
+120.34 (c 0.9 in CHCl3); nmax(NaCl)/cm-1 3298, 3032, 2955, 2854,
2237, 1744, 1695 and 1536; dH (400 MHz; CDCl3; Me4Si) (two
rotamers 0.96:0.04) 3.13 (1 H, dd, J 14.1 and 5.7), 3.19 (1 H, dd,
J 14.1 and 5.7), 3.79 (3 H, s), 4.75 (0.04 H, m), 4.88 (0.96 H, dt, J
7.8, 2 ¥ 5.7), 6.51 (0.04 H, br s), 6.95 (0.96 H, br s), 7.03–7.12 (2 H,
m) and 7.21–7.38 (3 H, m); dC (100 MHz; CDCl3; Me4Si) (major
rotamer) 37.2, 53.0, 54.0, 111.0, 127.7, 128.9, 129.1, 134.3, 142.4
and 170.1; HRMS (ESI) 255.0737 ([M + Na]+. C12H12N2NaO3
requires 255.0740).
Methyl 2-(cyanocarbonylamino)acetate (8i). Following the
general procedure and starting from amine 7i (0.350 g, 3.93 mmol)
and DPPC (1.019 g, 3.93 mmol, 100 mol%), purification by
flash chromatography (silica gel, hexane/EtOAc 4:1 to 3:1) gave
compound 8i as a yellowish oil (0.389 g, 70%) together with a
small amount of a white solid identified as 11i (0.046 g, 9%).
(S)-Methyl 2-(cyanocarbonylamino)-3-methylbutanoate [L-
valine methyl ester carbamoyl cyanide] (8m). Following the
general procedure and starting from L-valine methyl ester
hydrochloride (0.168 g, 1.0 mmol), purification by flash
chromatography (hexane/EtOAc 19:1 to 9:1) gave the product 8m
as a volatile colourless oil (0.159 g, 87%). Rf 0.25 (hexane/EtOAc
n
max(NaCl)/cm-1 3303, 3062, 3006, 2961, 2854, 2240, 1747, 1693
and 1544; dH (400 MHz; CDCl3; Me4Si) (two rotamers 0.97:0.03)
3.75 (3 H, s), 4.08 (1.94 H, d, J 5.6), 4.21 (0.06 H, d, J 6.4) and
7.86 (1 H, br s); dC (100 MHz; CDCl3; Me4Si) (major rotamer)
41.3, 52.8, 111.0, 143.4 and 168.5; HRMS (ESI) 143.0450 ([M +
H]+. C5H7N2O3 requires 143.0451).
4:1); [a]D +45.19 (c 1.41 in CHCl3); nmax(neat)/cm-1 3309br,
25
2970, 2238w, 1748br, 1701br, 1540br and 1217; dH (400 MHz;
CDCl3; Me4Si) (two rotamers, ratio 96:4) 0.87 and 0.97 (5.96 H,
d, J 6.9), 1.01 (0.12 H, d, J 7.3), 2.25 (1 H, m), 3.80 (2.88 H, s),
3.82 (0.12 H, s), 4.41 (0.04 H, dd, J 8.9 and 4.7), 4.60 (0.96 H, dd,
J 8.8 and 4.7) and 7.47 (1 H, br d, J 7.4); dC (100 MHz; CDCl3;
Me4Si) (major rotamer) 17.5, 18.8, 31.3, 52.9, 58.0, 111.2, 143.0
and 170.8; m/z (EI) 234 (M+), 142 (25%), 125 (100), 115 (11),
Dimethyl 2,2¢-(2,4,5-trioxoimidazolidine-1,3-diyl)diacetate (11i).
n
max(NaCl)/cm-1 3556, 3001, 2960, 2856 and 1748; dH (400 MHz;
CDCl3; Me4Si) 3.76 (3 H, s) and 4.40 (2 H, s); dC (100 MHz;
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110 (46), 72 (10); HRMS (EI) 184.0856 (M+. C8H12N2O3 requires
184.0848).
145.1 and 171.5; dC (100 MHz; DMSO-d6; Me4Si) 25.5, 52.3,
52.6, 110.7, 111.8, 116.0, 119.7, 120.2, 124.4, 125.7, 126.1, 130.9,
134.3, 140.7, 142.9 and 169.7; HRMS (ESI) 325.0928 ([M + H]+.
C16H13N4O4 requires 325.0931).
(R)-Methyl 2-(cyanocarbonylamino)-3-methylbutanoate [D-
valine methyl ester carbamoyl cyanide] (8n). Following the
general procedure and starting from D-valine methyl ester
hydrochloride (0.168 g, 1.0 mmol), purification by flash
chromatography (hexane/EtOAc 19:1 to 9:1) gave the product 8n
as a volatile colourless oil (0.175 g, 96%). Rf 0.25 (hex/EtOAc
(S)-Methyl 2-[cyanocarbonyl(diphenoxyphosphoryl)amino]-3-
(1H-indol-3-yl)propanoate (12p).
n
max(NaCl)/cm-1 3412, 3062,
2952, 2235, 1748, 1695 and 1591; dH (400 MHz; CDCl3; Me4Si)
3.51 (1 H, dd, J 15.2 and 10.4), 3.55 (3 H, s), 3.71 (1 H, dd, J
15.3 and 5.6), 5.39 (1 H, m), 6.66–6.85 (2 H, m), 6.97 (1 H, s),
7.05–7.37 (11 H, m), 7.60 (1 H, d, J 7.2) and 8.00 (1 H, br s); dC
(100 MHz; CDCl3; Me4Si) 24.7, 52.7, 60.5, 109.9, 110.0, 111.2,
118.7, 119.8, 120.0 (d, J 4.6), 120.2 (d, J 4.7), 122.2, 123.5, 126.0,
126.2, 126.9, 129.7, 129.8, 136.3, 144.4, 149.4 (d, J 8), 149.6 (d, J
7.7) and 168.4 (d, J 3.3); dP (160 MHz; CDCl3) -11.34; HRMS
(ESI) 504.1308 ([M + H]+. C26H23N3O6P requires 504.1319).
23
4:1). [a]D -43.63 (c 1.71 in CHCl3). Spectroscopic data are
identical to those of its enantiomer (8m).
(S)-Dimethyl 2-(cyanocarbonylamino)pentanedioate [L-glutamic
acid dimethyl ester carbamoyl cyanide] (8o). Following the
general procedure and starting from L-glutamic acid dimethyl
ester hydrochloride (0.212 g, 1.0 mmol), purification by flash
chromatography (hexane/EtOAc 9:1) gave the product 8o as a
24
yellowish oil (0.172 g, 82%). Rf 0.50 (hexane/EtOAc 1:1); [a]D
(2S,3S)-Methyl 2-(cyanocarbonylamino)-3-methylpentanoate
[L-isoleucine methyl ester carbamoyl cyanide] (8q). Following
the general procedure and starting from L-isoleucine methyl
ester hydrochloride (0.182 g, 1.0 mmol), purification by flash
chromatography (hexane/EtOAc 9:1 to 4:1) gave the product 8q
as a volatile yellowish oil (0.191 g, 96%). Rf 0.45 (hexane/EtOAc
+21.40 (c 1.05 in CHCl3); nmax(neat)/cm-1 3299br, 2958, 2238w,
1742br, 1700br, 1540br, 1440 and 1218br; dH (400 MHz; CDCl3;
Me4Si) 2.04–2.15 (1 H, m), 2.25 (1 H, m), 2.37–2.47 (2 H, m), 3.70
(3 H, s), 3.79 (3 H, s), 4.64 (1 H, m, J 5.2) and 7.83 (1 H, br s);
dC (100 MHz; CDCl3; Me4Si) 26.4, 29.7, 52.1, 52.5, 53.3, 111.1,
143.0, 170.3 and 173.2; m/z (EI) 228 (M+), 169 (59%), 142 (41),
137 (100), 110 (28), 109 (89), 82 (47); HRMS (EI) 228.0755 (M+.
C9H12N2O5 requires 228.0746).
4:1); [a]D +51.72 (c 2.01 in CHCl3); nmax(neat)/cm-1 3309br,
23
2968, 2237w, 1746br, 1700br, 1539br and 1216br; dH (400 MHz;
CDCl3; Me4Si) (two rotamers, ratio 96:4) 0.93–0.96 (6 H, m), 1.24
(1 H, m), 1.45 (1 H, m), 1.97 (1 H, m), 3.83 (2.88 H, s), 3.83 (0.12
H, s), 4.48 (1 H, dd, J 10.1 and 4.7), 4.64 (0.96 H, dd, J 8.5 and
4.6), 6.83 (0.04 H, br s) and 7.22 (0.96 H, br s); dC (100 MHz;
CDCl3; Me4Si) (major rotamer) 11.5, 15.4, 25.1, 38.0, 52.8, 57.3,
111.2, 142.7 and 170.6; m/z (EI) 198 (M+, 3%), 142 (83), 139
(100), 115 (58), 110 (83), 83 (13), 69 (90); HRMS (EI) 198.1001
(M+. C9H14N2O3 requires 198.1004).
(S)-Methyl 2-(cyanocarbonylamino)-3-(1H-indol-3-yl)propano-
ate [L-tryptophan methyl ester carbamoyl cyanide] (8p). Follow-
ing the general procedure and starting from L-tryptophan methyl
ester hydrochloride (0.255 g, 1.0 mmol), purification by flash
chromatography (hexane/EtOAc 4:1) gave the product 8p as a
yellowish solid (0.232 g, 85%). Rf 0.20 (hexane/EtOAc 2:1); mp
110.7–111.7 ◦C; [a]D +82.08 (c 2.10 in CHCl3); nmax(neat)/cm-1
27
3462, 3326br, 2237w, 1731br, 1679br, 1526br, 1370, 1253 and 744;
dH (400 MHz; CDCl3; Me4Si) 3.24–3.34 (2 H, m), 3.67 (3 H, s),
4.85 (1 H, dt, J 7.8 and 5.3), 6.90 (1 H, d, J 2.2), 6.99 (1 H, br d,
J 7.1), 7.03–7.20 (2 H, m), 7.29 (1 H, d, J 8.0), 7.43 (1 H, d, J 7.8)
and 8.10 (1 H, br s); dC (100 MHz; CDCl3; Me4Si) 27.1, 53.0, 53.8,
108.6, 111.1, 111.5, 118.2, 120.1, 122.6, 123.0, 127.2, 136.1, 142.6
and 170.4; m/z (EI) 271 (M+, 6%), 244 (10), 130 (100); HRMS
(EI) 271.0964 (M+. C14H13N3O3 requires 271.0957).
When the reaction was carried out starting from L-tryptophan
methyl ester hydrochloride (0.410 g, 1.88 mmol) and DPPC
(0.487 g, 1.88 mmol, 100 mol%), purification by flash chromatog-
raphy gave, in addition to the cyanoformamide 8p (0.415 g, 81%),
a white solid identified as 13 (0.011 g, 2%) and a colourless oil
identified as 12p (0.024 g, 3%).
(S)-Dimethyl 2-(cyanocarbonylamino)succinate (8r). Follow-
ing the general procedure and starting from amine 7r (1.101 g,
6.83 mmol), PhTMG (1.371 g, 7.17 mmol, 105 mol%), DPPC
(1.770 g, 6.83 mmol, 100 mol%) and CO2 in CH3CN (15 mL),
purification by flash chromatography (silica gel, hexane/EtOAc
6:1→4:1) gave compound 8r as a colourless oil (1.192 g, 82%).
[a]D25 +56.99 (c 2.94 in CHCl3); nmax(NaCl)/cm-1 3308, 3042, 2958,
2854, 2240, 1743, 1699 and 1534; dH (400 MHz; CDCl3; Me4Si)
(two rotamers, ratio 0.98:0.02) 2.81 (1 H, dd, J 17.6 and 4.28), 2.94
(1 H, dd, J 17.6 and 4.9), 3.57 (3 H, s), 3.66 (3 H, s), 4.76 (1 H, dt,
J 8.8 and 2 ¥ 4.5), 7.45 (0.02 H, br d, J 10.0), 8.22 (0.98 H, br d,
J 8.0); dC (100 MHz; CDCl3; Me4Si) (major rotamer) 34.8, 48.7,
51.9, 52.9, 110.8, 142.8, 169.0 and 170.5; HRMS (ESI) 215.0672
([M + H]+. C8H11N2O5 requires 215.0662).
(S)-Methyl 3-[1-(cyanocarbonyl)-1H-indol-3-yl]-2-(cyanocar-
bonylamino)propanoate (13).
Treatment of carbamoyl cyanides with bases. Method 1 DBU
(0.18 mL, 1.21 mmol, 100 mol%) was added to a solution of
carbamoyl cyanide 8c (0.21 g, 1.21 mmol) in CH3CN (7 mL). The
resulting mixture was stirred for 16 h, after which time the solvent
was removed under reduced pressure. Purification of the residue by
flash chromatography (hexane/EtOAc 10:1 to 2:1) yielded 10c as a
colourless oil (0.16 g, 81%), together with a white solid identified as
1,3-bis[(R)-1-phenylethyl]urea (0.02 g, 15%). 5-Imino-1,3-bis[(R)-
1-phenylethyl]imidazolidine-2,4-dione (10c). dH (400 MHz; CDCl3;
Me4Si) 1.89 (3 H, d, J 7.4), 1.94 (3 H, d, J 7.3), 5.42 (1 H, q, J 3 ¥
7.4), 5.61 (1 H, q, J 3 ¥ 7.3), 7.29–7.42 (6 H, m), 7.45–7.57 (4 H, m)
and 8.92 (1 H, br s); dC (100 MHz; CDCl3; Me4Si) 17.0, 17.2, 51.2,
n
max(NaCl)/cm-1 3303, 3110, 3032,
2955, 2853, 2236, 1745, 1698, 1606 and 1537; dH (400 MHz;
acetone-d6; Me4Si) 3.36 (1 H, dd, J 15.1 and 8.3), 3.48 (1 H, dd, J
15.0 and 5.3), 3.74 (3 H, s), 4.99 (1 H, td, J 2 ¥ 8.3, 5.2), 7.41–7.55
(2 H, m), 7.74 (1 H, m), 7.86 (1 H, s), 8.24 (1 H, m) and 9.33 (1
H, br d, J 8.0); dH (400 MHz; DMSO-d6; Me4Si) 3.15 (1 H, dd, J
14.9 and 9.2), 3.28 (1 H, dd, J 15.0 and 5.2), 3.66 (3 H, s), 4.77 (1
H, ddd, J 9.0, 7.5 and 5.2), 7.37–7.51 (2 H, m), 7.68 (1 H, br d,
J 6.8), 7.77 (1 H, s), 8.15 (1 H, br d, J 7.7) and 10.51 (1 H, br d,
J 7.4); dC (100 MHz; acetone-d6; Me4Si) 28.1, 54.1, 54.4, 112.3,
113.4, 118.3, 121.6, 122.8, 126.1, 127.9, 128.2, 133.3, 136.9, 142.6,
3996 | Org. Biomol. Chem., 2009, 7, 3991–3999
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51.3, 127.2, 127.3, 127.8, 128.0, 128.4, 128.5, 139.1, 139.4, 152.0,
153.7 and 155.6; HRMS (ESI) 322.1543 ([M + H]+. C19H20N3O2
requires 322.1550). 1,3-Bis[(R)-1-phenylethyl]urea.16 dH (400 MHz;
CDCl3; Me4Si) 1.39 (6 H, d, J 6.8), 4.60 (2 H, br s), 4.76 (2 H, m),
7.10–7.16 (4 H, m) and 7.19–7.30 (6 H, m); dC (100 MHz; CDCl3;
Me4Si) 23.4, 50.2, 125.7, 127.1, 128.6, 144.0 and 156.7.
8-(Cyanocarbonylamino)octan-1-amine hydrochloride (15).
Compound 14 (0.060 g, 0.2 mmol) was dissolved in 5 mL of a
CH2Cl2 solution that was 1 M TMSCl/3 M phenol (obtained by
mixing 5 mL of a 4 M solution of TMSCl in CH2Cl2 with 15 mL
of a 4 M solution of phenol in CH2Cl2). The mixture was stirred
for 20 min at room temperature under an argon atmosphere.
The solvent was removed under reduced pressure and phenol
was removed by distillation in a Kugelrohr oven under high
vac◦uum (1–2 mm Hg), with the temperature maintained below
70 C. The residue was triturated and washed several times with
ether, yielding 15 as a white crystalline solid (0.043 g, 90%).
dH (400 MHz; MeOH-d4; Me4Si) 1.37 (8 H, m), 1.55 (2 H, m),
1.65 (2 H, m), 2.92 (2 H, t, J 7.6) and 3.25 (2 H, t, J 7.0); dC
(100 MHz; MeOH-d4; Me4Si) 27.4, 27.8, 28.6, 29.7, 30.1, 31.1,
40.8, 41.0, 113.1 and 145.1; HRFABMS (positive, mNBA matrix)
m/z 198.1600 ([M + H]+. C10H20N3O requires 198.1606).
Treatment of carbamoyl cyanides with bases. Method 2 Tri-
ethylamine (0.19 mL, 1.36 mmol, 400 mol%) was added to a
solution of carbamoyl cyanide 8c (0.06 g, 0.34 mmol) in CH2Cl2
(8 mL). The resulting mixture was stirred for 14 h, after which time
the solvent was removed under reduced pressure. Purification of
the residue by flash chromatography (hexane/EtOAc 10:1) yielded
10c (0.04 g, 71%), together with unreacted carbamoyl cyanide
(0.01 g, 20%).
tert-Butyl 8-aminooctylcarbamate. BOC2O (2.18 g, 2.3 mL,
10.00 mmol, 100 mol%) and Et3N (4.18 mL, 30.00 mmol,
300 mol%) were added to a solution of octane-1,8-diamine (2.00 g,
13.89 mmol) in THF/H2O 4:1 (50 mL). The resulting mixture was
stirred at room temperature for 23 h. THF was removed under
reduced pressure, 2 M K2CO3 (15 mL) was added and the mixture
was extracted several times with EtOAc. The organic phase
was dried over Na2SO4, filtered and concentrated under reduced
pressure. Purification by flash chromatography (hexane/EtOAc
1:1) gave tert-butyl 8-aminooctylcarbamate as a yellowish oil
(0.435 g, 30%). nmax(KBr)/cm-1 3361br, 2971, 2927br, 2853, 1684br,
1521, 1365, 1249 and 1174br; dH (400 MHz; CDCl3; Me4Si) 1.27
(9 H, s), 1.41 (12 H, br s), 2.65 (2 H, t, J 7.0), 3.06 (2 H, t, J 6.2)
and 4.61 (1 H, s); dC (100 MHz; CDCl3; Me4Si) 26.6, 26.7, 28.4,
29.2, 29.3, 30.1, 33.6, 40.5, 42.2, 78.9 and 155.9; m/z (EI) 244 (M+,
28%), 187 (51), 171 (100), 159 (44), 143 (45), 114 (36), 100 (38), 86
(56); HRMS (EI) 244.2149 (M+. C13H28N2O2 requires 244.2151).
2,6-Dibromotyramine hydrobromide [4-(2-aminoethyl)-2,6-
dibromophenol hydrobromide] (17). A solution of KBr (15 g)
and bromine (3 mL) in water (50 mL) was added dropwise to
a solution of tyramine hydrochloride (1.740 g, 10 mmol) in a
mixture of ethanol/water 1:1 (10 mL) until a permanent yellow
colour appeared. Water (20 mL) was added and the precipitate
was filtered off and washed with saturated aqueous sodium
bisulfite and water (3¥). Compound 17 was obtained as a white
crystalline solid (3.317 g, 91%). nmax(KBr)/cm-1 3310, 3205,
3137, 2987, 2915, 1473, 1145 and 868; dH (400 MHz; MeOH-d4;
Me4Si) 2.86 (2 H, t, J 7.6), 3.14 (2 H, t, J 7.6) and 7.44 (2
H, s); dC (100 MHz; MeOH-d4; Me4Si) 32.9, 41.8, 112.6, 132.0,
133.8 and 151.6; m/z (EI) 293/295/297 (M+, 45%/100%/49%),
268/266/264 (48/99/52), 185/187 (29/27), 155/157 (21/22), 105
(23), 80/82 (77/76); HRMS (EI) 294.9035 (M+. C8H9NO79Br81Br
requires 294.9030).
4-(2-tert-Butoxycarbonylaminoethyl)-2,6-dibromophenol [tert-
butyl 3,5-dibromo-4-hydroxyphenethylcarbamate] (18). BOC2O
(1.310 g, 1.38 mL, 6.00 mmol) and triethylamine (1.214 g, 1.67 mL,
12.00 mmol) were added to a stirred solution of 17 (1.128 g,
3.00 mmol) in THF/H2O 1:1 (12 mL). The resulting mixture was
stirred at room temperature for 14 h. THF was removed under
reduced pressure and the residue was dissolved in EtOAc (100 mL).
The solution was washed with 5% HCl (3¥). The organic phase
was dried over Na2SO4, filtered and concentrated under reduced
pressure. The crude product was purified by flash chromatography
(hexane/EtOAc 9:1 to 3:1). Compound 18 was obtained as a
white crystalline solid (1.174 g, 99%). Rf 0.40 (hexane/EtOAc
4:1); mp 108.6–111.6 ◦C; nmax(KBr)/cm-1 3362, 1681, 1533, 1475,
1365, 1273, 1252, 1163 and 738; dH (400 MHz; CDCl3; Me4Si)
2.68 (2 H, t, J 6.6), 3.28 (2 H, q, J 6.6), 4.56 (1 H, br s), 5.92
(1 H, s) and 7.25 (2 H, s); dC (100 MHz; CDCl3; Me4Si) 28.5,
34.7, 41.6, 79.5, 109.8, 132.2, 133.6, 148.0 and 155.8; m/z (EI)
393/395/397 (M+), 337/339/341 (31%/61%/30%), 276/278/280
(51/100/50), 263/265/267 (13/25/13); HRMS (EI) 394.9711
(M+. C13H17NO379Br81Br requires 394.9555).
tert-Butyl 8-(cyanocarbonylamino)octylcarbamate (14). A so-
lution of tert-butyl 8-aminooctylcarbamate (0.271 g, 1.11 mmol) in
dry acetonitrile (5 mL) was added to a flask containing PhTMG
(0.244 g, 1.28 mmol). Acetonitrile (10 mL) was added and the
resulting solution was cooled with a salt/ice bath under an inert
atmosphere. CO2 (g) was bubbled through the solution for 10 min
and DEPC (0.199 g, 0.185 mL, 1.22 mmol) was added dropwise.
CO2 (g) was bubbled through for a further 5 min and the solution
was stirred under a CO2 (g) atmosphere for 1 h, allowing the
reaction to reach room temperature. The mixture was dissolved in
EtOAc (100 mL) and the organic phase was washed with water
(3¥) and 5% HCl (3¥). The organic layer was dried over Na2SO4,
filtered and concentrated under reduced pressure. Purification by
flash chromatography (hexane/EtOAc 9:1 to 4:1) gave14 as a white
crystalline solid (0.287 g, 90%). Rf 0.5 (hexane/EtOAc 2:1); mp
54.6–55.1 ◦C; nmax(KBr)/cm-1 3267br, 3278, 2933, 2859, 2234w,
1685br, 1526br, 1253 and 1171; dH (400 MHz; CDCl3; Me4Si) (two
rotamers 92:8) 1.32 (9 H, s), 1.45 (8 H, br s), 1.51–1.61 (4 H, m),
3.11 (2 H, q, J 6.3), 3.35 (1.84 H, q, J 6.7), 3.49 (0.16 H, q, J
6.9), 4.13 (0.16 H, s), 4.54 (0.84 H, s), 6.20 (0.16 H, s) and 6.61
(0.84 H, s); dC (100 MHz; CDCl3; Me4Si) (major rotamer) 26.5,
28.5, 28.8, 29.0, 30.0, 40.4, 40.5, 43.3, 79.2, 111.7, 142.3 and 156.2;
m/z (EI) 297 (M+, 0.2%), 211 (41), 197 (87), 171 (100), 169 (54),
154 (49), 86 (41), 74 (32), 69 (44); HRMS (EI) 297.2060 (M+.
C15H27N3O3 requires 297.2052).
tert-Butyl 3,5-dibromo-4-(3-bromopropoxy)phenethylcarbamate
(19). Compound 18 (0.500 g, 1.27 mmol) and K2CO3
(0.876 g, 6.35 mmol, 500 mol%) were added to a solution of
1,3-dibromopropane (2.56 g, 1.3 mL, 12.7 mmol, 1000 mol%)
in dry acetone (10 mL). The resulting mixture was stirred at room
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temperature under an argon atmosphere for 15 h. The solvents
were removed under reduced pressure and the residue was dis-
solved in EtOAc (100 mL)and washed with water (3¥). The organic
layer was dried over Na2SO4, filtered and evaporated. Purification
of the crude product by chromatography (hexane/EtOAc 9:1 to
7:1) yielded 19 as a white crystalline solid (0.648 g, 99%). Rf 0.50
(hexane/EtOAc 4:1); mp 72.6–73.6 ◦C; nmax(KBr)/cm-1 3365br,
1684, 1528, 1456, 1364, 1277, 1250 and 1162br; dH (400 MHz;
CDCl3; Me4Si) 1.44 and 1.45 (9 H total, two s), 2.41 (2 H, q, J 5.9),
2.72 (2 H, t, J 6.7), 3.33 (2 H, q, J 6.5), 3.73 (2 H, td, J 6.6 and 1.0),
4.12 (2 H, t, J 5.7), 4.57 (1 H, br s) and 7.34 (2 H, s); dC (100 MHz;
CDCl3; Me4Si) 28.3 (q), 29.9 (t), 33.3 (t), 34.9 (t), 41.3 (t), 70.6
(t), 79.3 (s), 118.0 (s), 132.9 (d), 137.9 (s), 151.2 (s), 155.7 (s); m/z
(EI) 513/515/517/519 (M+, 1%/3%/3%/1%), 457/459/501/503
(33/100/98/33), 396/398/400/402 (28/83/81/27), 276/278/280
(26/51/25), 263/265/267 (29/55/28); HRMS (EI) 514.9133 (M+.
C16H22NO379Br281Br requires 514.9129).
The resulting mixture was diluted with more acetonitrile (10 mL)
and was cooled with a salt/ice bath under an inert atmosphere.
CO2 was slowly bubbled through the mixture for 10 min. DEPC
(0.058 g, 0.054 mL, 0.36 mmol) was added dropwise and the stream
of CO2 was maintained for a further 5 min. The reaction was stirred
and the temperature was allowed to rise to room temperature over
1.5 h. The mixture was dissolved in EtOAc (100 mL) and was
washed with water (3¥) and 5% HCl (2¥). The organic phase
was dried over Na2SO4, filtered and concentrated under reduced
pressure. Purification by flash chromatography (hexane/EtOAc
9:1 to 3:1) gave 22 as a white crystalline solid (0.125 g, 87%).
Rf 0.25 (hexane/EtOAc 3:1); mp 107.7–108.7 ◦C; nmax(KBr)/cm-1
3359br, 3223, 3056, 2237w, 1666br, 1534br, 1471, 1456, 1368, 1269,
1256 and 1168br; dH (400 MHz; CDCl3; Me4Si) 1.45 (9 H, s), 2.13
(2 H, q, J 5.4), 2.75 (2 H, t, J 6.9), 3.34 (2 H, q, J 6.6), 3.72 (2
H, q, J 6.0), 4.13 (2 H, t, J 5.4), 4.57 (1 H, br s), 7.07 (1 H, br s)
and 7.37 (2 H, s); dC (100 MHz; CDCl3; Me4Si) (major rotamer)
28.3, 28.4, 35.0, 38.7, 41.4, 71.5, 79.6, 111.7, 117.9, 133.0, 138.4,
143.2, 150.8 and 155.8; m/z (FAB+) 504/506/508 ([M + H]+,
15%/33%/16%); HRFABMS (positive, mNBA matrix) 506.0120
([M + H]+. C18H24N3O479Br81Br requires 506.0113).
tert-Butyl 4-(3-azidopropoxy)-3,5-dibromophenethylcarbamate
(20). A 0.5 M solution of NaN3 in DMSO (1.06 mL, 35 mg,
0.53 mmol) was added to 19 (0.250 g, 0.49 mmol). The mixture
was stirred at room temperature under an argon atmosphere for
23 h. Water (10 mL) was added and the mixture was extracted
with ether (3¥). The organic layer was washed with water (2¥)
and brine (1¥). The organic phase was dried over MgSO4, filtered
and concentrated under reduced pressure, yielding 20 as a white
crystalline solid (0.224 g, 98%). Rf 0.50 (hexane/EtOAc 4:1);
mp 64.3–65.5 ◦C; nmax(KBr)/cm-1 3346br, 2093br, 1674, 1539,
1288 and 1253; dH (400 MHz; CDCl3; Me4Si) 1.45 (9 H, s),
2.11 (2 H, q, J 6.3), 2.72 (2 H, t, J 6.9), 3.33 (2 H, q, J
6.7), 3.67 (2 H, t, J 6.7), 4.08 (2 H, t, J 5.8), 4.55 (1 H,
br s) and 7.35 (2 H, s); dC (100 MHz; CDCl3; Me4Si) (major
rotamer) 28.1, 29.7, 35.1, 41.4, 48.2, 69.9, 79.5, 118.1, 132.9,
137.9, 151.4 and 155.7; m/z (EI) 476/478/480 (M+, 2%/4%/2%),
420/422/424 (51/100/50), 359/361/363 (21/40/20), 313/315
(14/15), 276/278/280 (27/52/25), 263/265/267 (33/63/30),
240/242 (15/13); HRMS (EI) 476.0048 (M+. C16H22N4O379Br2
requires 476.0059).
Ceratinamine hydrochloride (1). Compound 22 (0.060 g,
12 mmol) was added to a CH2Cl2 solution (2.5 mL) that was
1M in TMSCl and 3M in phenol. The mixture was stirred at
room temperature under an inert atmosphere for 20 min. The
solvent was removed under reduced pressure and the phenol was
distilled off in a Kugelrohr oven under high vacuum (1–2 mm
Hg), with the temperature maintained below 70 ◦C. The solid
residue was triturated and washed several times with ether to give
1 as a white crystalline solid (0.047 g, 90%). Mp 188.1 ◦C (dec.);
n
max(KBr)/cm-1 3277, 3044, 2941, 2240w, 1668, 1457 and 1259;
dH (400 MHz; MeOH-d4; Me4Si) 2.10 (2 H, q, J 6.6), 2.93 (2 H,
t, J 7.6), 3.17 (2 H, t, J 7.2), 3.57 (2 H, t, J 7.1), 4.04 (2 H, t,
J 5.9) and 7.56 (2 H, s); dH (400 MHz; DMSO-d6; Me4Si) 2.00
(2 H, q, J 6.5), 2.84 (2 H, t, J 7.2), 3.07 (2 H, t, J 7.2), 3.42 (2
H, q, J 6.6), 3.96 (2 H, t, J 6.0), 7.60 (2 H, s), 7.91 (3 H, br s)
and 9.97 (1 H, br s); dC (100 MHz; MeOH-d4; Me4Si) 30.1, 33.2,
38.4, 41.5, 71.7, 113.1, 119.5, 134.5, 137.3, 142.3 and 153.6; dC
(100 MHz; DMSO-d6; Me4Si) 28.5, 31.3, 38.8, 39.2, 70.5, 112.3,
117.4, 133.1, 136.9, 142.9 and 151.0; m/z (FAB+) 404/406/408
([M + H]+, 6%/12%/6%); HRFABMS (positive, mNBA matrix)
405.9590 (M+. C13H16N3O279Br81Br requires 405.9589).
tert-Butyl 4-(3-aminopropoxy)-3,5-dibromophenethylcarbamate
(21). A mixture of 20 (0.200 g, 0.42 mmol) and Ph3P (0.100 g,
0.42 mmol) was stirred in dry THF (2 mL) at room temperature
under an argon atmosphere for 3.5 h. Water (0.011 g, 0.63 mmol,
150 mol%) was added and the mixture was stirred for a further
19 h. The mixture was concentrated to dryness and the residue
was dissolved in 5% citric acid (30 mL). The resulting white
mixture was washed with hexane/EtOAc 1:1 (3¥). The aqueous
phase was basified to pH > 12 with 2 M NaOH and extracted
with CH2Cl2 (4¥). The organic phase was dried over MgSO4,
filtered and concentrated under reduced pressure to give 21 as
a yellowish viscous oil (0.165 g, 86%), which was used without
further purification. dH (400 MHz; CDCl3; Me4Si) 1.45 (9 H, s),
1.99 (2 H, q, J 6.3), 2.72 (2 H, t, J 6.8), 3.02 (2 H, q, J 6.6), 3.33
(2 H, t, J 6.6), 4.07 (2 H, t, J 6.0), 4.57 (1 H, br s) and 7.34 (2
H, s); dC (100 MHz; CDCl3; Me4Si) (major rotamer) 28.2, 33.6,
34.8, 39.1, 41.4, 71.1, 79.2, 118.0, 132.8, 137.7, 151.5 and 155.7.
Acknowledgements
Financial support (projects PGIDT99-PXI30105A and
BQU200202807) from the Xunta de Galicia and Ministerio
de Educacio´n y Ciencia is gratefully acknowledged. E.G.-E.
acknowledges the Xunta de Galicia for a fellowship.
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3998 | Org. Biomol. Chem., 2009, 7, 3991–3999
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The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 3991–3999 | 3999
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