Different reactivity of hydroxylamine with carbamoyl azides and carbamoyl cyanides: Synthesis of hydroxyureas and carbamoyl amidoximes

Article abstract of DOI:10.1021/jo1014855

The carbamoylating agents carbamoyl azides and carbamoyl cyanides (aka cyanoformamides) react with hydroxylamine in different ways, leading in the first case to N-hydroxyureas and, in the case of carbamoyl cyanides, to carbamoyl amidoxime derivatives. The

Full text of DOI:10.1021/jo1014855

pubs.acs.org/joc
Different Reactivity of Hydroxylamine with Carbamoyl
Azides and Carbamoyl Cyanides: Synthesis of Hydroxyureas and
Carbamoyl Amidoximes
ꢀ
Jairo Paz, Carlos Perez-Balado, Beatriz Iglesias, and Luis Munoz*
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ꢀ
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Departamento de Quımica Organica, Facultade de Quımica, Universidade de Vigo,
Campus Universitario, 36310 Vigo, Spain
lmunoz@uvigo.es
Received July 28, 2010
The carbamoylating agents carbamoyl azides and carbamoyl cyanides (aka cyanoformamides) react
with hydroxylamine in different ways, leading in the first case to N-hydroxyureas and, in the case of
carbamoyl cyanides, to carbamoyl amidoxime derivatives. The synthetic procedure developed for the
latter type of compound, which represents an interesting precursor for heterocyclic structures,
allowed the highly efficient preparation of a wide selection of examples. The Z configuration of the
double bond in the amidoxime moiety was proposed on the basis of comparison between experi-
mental and calculated 13C and 15N NMR chemical shift values for the isopropyl and benzyl
derivatives.
Introduction
by hydroxyamination of the carbamoyl chloride or the
isocyanate with hydroxylamine in a basic medium.1b,4 The
intermediate isocyanate can also be prepared by a Curtius
rearrangement from an acyl azide.5 Alternatively, hydroxyami-
nation can also be achieved by using benzyloxyamine to yield
the corresponding N-benzyloxyurea, which can be subsequently
reduced.1b,6 On the other hand, reaction of an amine with
4-nitrophenyl chloroformate and then with hydroxylamine also
gives an N-hydroxyurea, albeit in a low yield of 30% for both
reaction steps.7 More straightforward procedures, which give
good results in specific cases, are based on the reaction of an
amine with phenyl N-hydroxycarbamates,8 N-benzyloxycar-
bamates9 (in the latter case followed by reduction), or tert-butyl
N-mesitylenesulfonoxycarbamate, followed by acid hydrolysis.10
N-Alkyl-N0-hydroxyureas are interesting organic com-
pounds with relevant biological activity. The hydroxyurea
functional group is capable of interacting with a variety of
proteins by making use of its metal-chelating and redox prop-
erties.1 The simple N-hydroxyurea is currently in use for the
treatment of a variety of cancers and sickle cell disease.2 The
mechanism of action of this compound, although not fully
understood, is believed to be based on the release of nitric
oxide.3
N-Hydroxyureas have been traditionally prepared from
amines by acylation with phosgene or triphosgene, followed
(1) (a) Makarov, A. A.; Yakovlev, G. I.; Mitkevich, V. A.; Higgin, J. J.;
Raines, R. T. Biochem. Biophys. Res. Commun. 2004, 319, 152–156.
(b) Uesato, S.; Hashimoto, Y.; Nishino, M.; Nagaoka, Y.; Kuwajima, H.
Chem. Pharm. Bull. 2002, 50, 1280–1282.
(5) Greco, M. N.; Hageman, W. E.; Powell, E. T.; Tighe, J. J.; Persico,
F. J. J. Med. Chem. 1992, 35, 3180–3183.
(2) (a) Paz-Ares, L.; Donehower, R. C.; Chabner, B. A. Hydroxyurea. In
Cancer Chemotherapy and Biotherapy Principles and Practice; Chabner,
B. A., Longo, D. L., Eds.; Lippincott, Williams and Wilkins: Philadelphia,
2005; pp 229-236. (b) Halsey, C.; Roberts, I. A. Br. J. Haematol. 2003, 120,
177–186.
(6) Ichimori, K.; Stuehr, D. J.; Atkinson, R. N.; King, S. B. J. Med. Chem.
1999, 42, 1842–1848.
(7) Smith, H. K.; Beckett, R. P.; Clements, J. M.; Doel, S.; East, S. P.;
Launchbury, S. B.; Pratt, L. M.; Spavold, Z. M.; Thomas, W.; Todd, R. S.;
Whittaker, M. Bioorg. Med. Chem. Lett. 2002, 12, 3595–3599.
(8) Campestre, C.; Tortorella, P.; Agamennone, M.; Preziuso, S.; Biasone,
A.; Nuti, E.; Rossello, A.; Gallina, C. Eur. J. Med. Chem. 2008, 43, 1008–1014.
(9) Parrish, D. A.; Zou, Z.; Allen, C. L.; Day, C. S.; King, S. B. Tetra-
hedron Lett. 2005, 46, 8841–8843.
(3) King, S. B. Curr. Med. Chem. 2003, 10, 437–452.
(4) Jain, R.; Sundram, A.; Lopez, S.; Neckermann, G.; Wu, C.; Hackbarth,
C.; Chen, D.; Wang, W.; Ryder, N. S.; Weidmann, B.; Patel, D.; Trias, J.; White,
R.; Yuan, Z. Bioorg. Med. Chem. Lett. 2003, 13, 4223–4228.
DOI: 10.1021/jo1014855
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Published on Web 11/04/2010
J. Org. Chem. 2010, 75, 8039–8047 8039
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Paz et al.
JOCArticle
Direct displacement of a benzotriazole group by hydroxyl-
amine has also produced N-hydroxyureas, although the isolated
yields range from extremely low to only moderate.11 Carbonyl-
diimidazole and carbonylditriazole have also been used for
the transient preparation of hydroxy- or alkoxyureas,12 and
15N-labeled hydroxyurea has been prepared in a one-pot pro-
cedure in 74% yield from trimethylsilyl isocyanate.13 Most of
these methods suffer from significant drawbacks, especially
when applied to sensitive substrates. Yields are often poor to
moderate, and this makes the procedure of little synthetic utility.
Some of the reagents are toxic and hazardous, and in addition,
intermediates such as carbamoyl chlorides and isocyanates are
rather unstable toward nucleophilic attack.
Carbamoyl azides are reported to be good carbamoylating
agents toward nitrogen nucheophiles.14 Similarly, amines
have been shown to react with carbamoyl cyanides (aka
cyanoformamides) in dichloromethane at room tempera-
ture, producing the corresponding ureas in high yields15
and suggesting that carbamoyl cyanides are also good car-
bamoylating agents.
Recently, we described the preparation of carbamoyl
azides and carbamoyl cyanides through the low temperature
reaction of primary amines and carbon dioxide, in acetoni-
trile, with tetramethylphenylguanidine as a base and either
diphenylphosphoryl azide16 or a cyanophosphonate17 as the
electrophile. When the reactivity of both types of compounds
was tested toward nitrogen nucleophiles such as amines and
hydrazines, we found that carbamoyl azides were excellent
carbamoylating agents but carbamoyl cyanides gave a mix-
ture of compounds in addition to the expected urea.18
Hydroxylamine provided the most extreme case, producing
none of the corresponding urea when reacted with carba-
moyl cyanides.19
In this paper we describe a comparative study on the
reaction of hydroxylamine with carbamoyl azides and car-
bamoyl cyanides. Thus, we report a new and convenient
high-yielding method for the preparation of N-hydroxyureas
by hydroxyamination of carbamoyl azides. On the other
hand, we show that the reaction of hydroxylamine with
carbamoyl cyanides leads to carbamoyl amidoximes as single
products in high yields and short reaction times. Carbamoyl
amidoximes are interesting precursors for the synthesis of
heterocyclic structures.20 However, these compounds have
received limited attention, and there are hardly any published
methods concerning their preparation. These compounds have
only been prepared by the reaction of N(S)-substituted mono-
thiooxamides with hydroxylamine in refluxing pyridine21 or by
aminolysis of nitroisoxazolone in acetonitrile at 50 °C.22
Results and Discussion
The methodology described here is based on the efficient
reaction between carbamoyl azides and nitrogen nucleo-
philes, specifically amines, which displace the azide group
to yield the target ureas.14 However, the extension of this
methodology to the preparation of N-hydroxyureas from
carbamoyl azides and hydroxylamine has proven to be
somewhat challenging, with experimental drawbacks and
limitations identified in our initial attempts to develop a
synthetic methodology. In an attempt to overcome these
limitations, we directed our efforts at the fine-tuning and
optimization of all the experimental details, a process that led
to the development of several synthetic procedures that allow
the transformation of different types of carbamoyl azides
into the corresponding N-hydroxyureas.
SCHEME 1
The reaction was initially performed by adding a solution
of the carbamoyl azide 1a in dichloromethane to a mixture of
hydroxylamine hydrochloride and triethylamine in metha-
nol, with a workup procedure that included a washing step
with 10% aqueous HCl (Scheme 1). This approach led to the
isolation of the hydroxyurea 2a in very good yield. This
method was successfully applied to the synthesis of several
N-hydroxyureas (Table 1, entries 1-10, procedure A).
Although the expected products were isolated in very good
yields (84-95%), an unidentified byproduct was also de-
tected in all experiments. Furthermore, extraction from the
aqueous phase of some of the compounds proved to be
particularly difficult due to the small size of some molecules
(e.g., allylamine or isopropylamine derivatives 2d and 2f) or
to the presence of polar groups (e.g., glutamic acid or
homoveratrylamine derivatives 2g and 2i).
(10) Krause, J. G.; Leskiw, B. D.; Emery, M. L.; McGahan, M. E.;
McCourt, M. P.; Priefer, R. Tetrahedron Lett. 2010, 51, 3568–3570.
ꢁ ꢀ
(11) (a) Opacic, N.; Zorc, B.; Cetina, M.; Mrvos-Sermek, D.; Raic-Malic,
S.; Mintas, M. J. Peptide Res. 2005, 66, 85–93. (b) Opacic, N.; Barbaric, M.;
ꢁ
ꢀ
ꢀ
ꢁ ꢀ
ꢀ
ꢀ
Zorc, B.; Cetina, M.; Nagl, A.; Frkovic, D.; Kralj, M.; Pavelic, K.; Balzarini,
J.; Andrei, G.; Snoeck, R.; De Clercq, E.; Raic-Malic, S.; Mintas, M. J. Med.
ꢀ
ꢀ
ꢀ
In order to devise a more efficient method for the prepara-
tion of N-hydroxyureas, we decided to change the experimen-
tal conditions. The use of potassium carbonate in acetonitrile
led to a cleaner process and the reaction of carbamoyl azide 1a
gave the expected hydroxyurea 2a, albeit in low yield (30%),
together with a new product identified as the N-carbamoyloxy-
urea 3 (61%) (Figure 1). This compound seems to arise
from the reaction between the hydroxyurea 2a and the starting
azide 1a, a hypothesis corroborated by the results shown in
Scheme 2.
Chem. 2005, 48, 475–482.
(12) Kurz, T.; Geffken, D.; Widyan, K. Tetrahedron 2004, 60, 2409–2416.
(13) Yasaki, G.; Xu, Y.; King, S. B. Synth. Commun. 2000, 30, 2041–2047.
(14) Lieber, E.; Minnis, R. L., Jr.; Rao, C. N. R. Chem. Rev. 1965, 65,
377–384.
(15) Chang, Y.-G.; Lee, H.-S.; Kim, K. Tetrahedron Lett. 2001, 42, 8197–
8200.
ꢀ ꢀ ~
´
a-Egido, E.; Fernandez-Suarez, M.; Munoz, L. J. Org. Chem.
(16) Garcı
2008, 73, 2909–2911.
(17) Garcıa-Egido, E.; Paz, J.; Iglesias, B.; Munoz, L. Org. Biomol. Chem.
~
´
2009, 7, 3991–3999.
(18) Unpublished results.
(19) In contrast, there is one literature report that shows that aromatic
hydroxylamines react with acetyl cyanide by displacing the cyano group:
Lobo, A. M.; Marques, M. M.; Prabhakar, S.; Rzepa, H. S. J. Org. Chem.
1987, 52, 2925–2927.
(20) (a) Yarovenko, V. N.; Kosarev, S. A.; Zavarzin, I. V.; Krayushkin,
M. M. Russ. Chem. Bull. Int. Ed. 2002, 51, 1504–1509. (b) Yarovenko, V. N.;
Kosarev, S. A.; Zavarzin, I. V.; Krayushkin, M. M. Russ. Chem. Bull. Int. Ed.
2002, 51, 1857–1861.
(21) Yarovenko, V. N.; Kosarev, S. A.; Zavarzin, I. V.; Krayushkin,
M. M. Russ. Chem. Bull. 1998, 47, 1947–1951.
(22) (a) Nishiwaki, N.; Okajima, Y.; Tamura, M.; Asaka, N.; Hori, K.;
Tohda, Y.; Ariga, M. Heterocycles 2003, 60, 303–308. (b) Tamura, M.; Ise,
Y.; Okajima, Y.; Nishiwaki, N; Ariga, M. Synthesis 2006, 20, 3453–3461.
8040 J. Org. Chem. Vol. 75, No. 23, 2010

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TABLE 1. Synthesis of N-Hydroxyureas from Carbamoyl Azides
aCarbamoyloxyurea 6 was isolated in 18% yield. bCarbamoyloxyurea 9 was isolated in 13% yield.
The formation of the N-carbamoyloxyurea side product ap-
pears to be a consequence of a lack of hydroxylamine in the
reaction medium. As a result, a new procedure (procedure B) was
devised that involved the portionwise addition of the base to the
mixture of azide 1a and NH2OH HCl in CH3CN, which led to
3
isolation of urea 2a in 92% yield (Table 1, entry 1, procedure B).23
This procedure was applied to the synthesis of N-hydroxy-
ureas 2b and 2h, but inconsistent results were obtained
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SCHEME 2
(Table 1, entries 2 and 8, procedure B). Compound 2b was
isolated in 84% yield along with a small amount (13%) of the
N-carbamoyloxyurea 6 (Figure 2). The L-valine methyl ester
derivative 2h could only be isolated in a low yield (41%),
accompanied by the carbamoyloxyurea derivative 7 (32% yield)
(Figure 2), when the reaction was carried out on a 1.45 mmol
scale. However, a larger scale experiment (3.10 mmol) led to the
isolation of the N-carbamoyl-N-hydroxyurea 8 in 78% yield
(Figure 2). The formation of this type of byproduct was not
observed in subsequent procedures of synthesis of N-hydroxyureas.
Carbamoyl azides derived from R-aminoesters have been
efficiently transformed into the corresponding N-hydroxyureas,
with isolated yields in the range of 91-99% and reaction times
between 1 and 3 h (Table 1, entries 1, 7, 8, 11 and 14-20,
procedure D). However, under these reaction conditions the
carbamoyl azide derived from (R)-R-methylbenzylamine, the
precursor of 2b, proved to be fairly unreactive and gave only low
conversion rates after 3 h, with most of the starting azide (66%)
recovered (Table 1, entry 2, procedure D). Longer reaction times
did not seem to improve the results for this particular azide.
Regardless of the experimental procedure followed in the
synthesis of the N-hydroxyureas derived from R-amino-
esters, these compounds should not be kept in the basic
reaction medium for prolonged periods due to the possibility
of intramolecular reaction between the hydroxylamino and
ester groups. In fact, in some of the experiments aimed at the
synthesis of N-hydroxyurea 2a, traces of the N-hydroxyhy-
dantoin byproduct 10a were detected (Figure 3).
FIGURE 1
FIGURE 3
This type of cyclized product is not unprecedented and has
been previously observed in the synthesis of N-hydroxyureas
derived from aminoesters in which the ester group is located
at a distance of four bonds from the hydroxylated nitrogen.26
This situation was further corroborated by our own results,
which showed that the reaction of N-hydroxyurea 2a with
K2CO3 in CH3CN yields the corresponding hydantoin 10a
quantitatively after 10 h.
Strict control of the reaction time must be maintained
during the synthesis of N-hydroxyureas from aminoester-
derived carbamoyl azides in order to avoid the formation of
these unwanted side products.
In order to study this process and to investigate the general
tendency of the R-aminoesters derived N-hydroxyureas to pro-
duce N-hydroxyhydantoins in basic media, we reacted several
N-hydroxyureas with K2CO3 (200 mol %) and Cs2CO3 (100
and 200 mol %) in CH3CN. The results are shown in Table 2.
The use of potassium carbonate as the base led to the slow
evolution of N-hydroxyureas derived from L-Phe-OMe,
L-Ala-OMe, and L-Glu-OMe into the corresponding N-hydroxy-
hydantoins. These processes required long reaction times
(8-12 h) to achieve high conversion rates (Table 2, entries 2,
FIGURE 2
In order to minimize the generation of side products that
could arise from the reaction between the N-hydroxyurea and
the carbamoyl azide, the addition procedure was modified
again in an effort to guarantee an excess of free hydroxylamine
throughout the whole process by allowing the reaction of the
base with hydroxylamine hydrochloride before the addition of
the substrate.24 The results of the reaction for several carba-
moyl azides derived from different amines are shown in Table 1
(entries 2-4, 7 and 10-14, procedure C). N-Hydroxyureas
were prepared in good yields, although the carbamoyloxyurea
derivatives were isolated in several cases (entries 2 and 4). The
formation of these byproducts cannot be completely ruled out for
the remaining examples, even though they were not detected.
An alternative experimental procedure was finally devel-
oped in an attempt to improve the solubility of the hydro-
xylamine hydrochloride in the reaction medium, and this
involved reducing the particle size by grinding.25 The results
for several carbamoyl azides are shown in Table 1 (entries
1-2, 7-8, 11 and 14-20, procedure D).
(23) Procedure B: see Experimental Section.
(24) Procedure C: see Experimental Section.
(25) Procedure D: see Experimental Section.
(26) Defoin, A.; Brouillard-Poichet, A.; Streith, J. Helv. Chim. Acta 1992,
75, 109–123.
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TABLE 2. Intramolecular Reaction in Basic Conditions of R-Aminoester-Derived N-Hydroxyureas
3, and 4). Compounds 10a and 10s were obtained in high
yields (98% and 91%, respectively; Table 2, entries 2 and 3),
whereas the yield for the glutamic acid derivative was much
lower (39%; Table 2, entry 4) and the presence of a new
byproduct was detected. The formation of this compound
can be attributed to a second cyclization process between the
heterocyclic NH group and the remaining methyl ester group
of hydantoin 10g, a process that leads to the pyroglutamic
acid derivative 11 (Scheme 3).
In turn, carbamoyl cyanides were also reacted with hydro-
xylamine, directly applying the methodology thus far devel-
oped. Reaction of carbamoyl cyanide 12a with a mixture of
hydroxylamine hydrochloride and Et3N in MeOH/CH2Cl2
led to isolation of the carbamoyl amidoxime 13a, resulting
from addition of hydroxylamine to the nitrile group, as the
only product. This compound was obtained in high yield
within a short reaction time (<5 min) (Scheme 4).
SCHEME 4
SCHEME 3
An optimized procedure for the preparation of carbamoyl
amidoximes that avoids the use of an aqueous workup was
therefore developed. The use of an excess of KOH or tBuOK
as a base, in MeOH, gave the results shown in Table 3. The
yields are excellent in all cases and they refer to isolated and
purified products.
All of these reactions were complete in approximately 10 min and
gave the corresponding carbamoyl amidoxime as the only product.
Our results show that, under these reaction conditions,
carbamoyl cyanides behave as activated nitriles and hydro-
xylamine selectively reacts with the cyanide group.
On the other hand, all of the experiments carried out with
cesium carbonate led to the expected N-hydroxyhydantoins in
high yields and short reaction times (Table 2, entries 2-8). The
time factor could be the reason for the high yield obtained in this
case of the L-Glu-OMe derivative 10g (96%; Table 2, entry 4).
Our results show that the standard carbamoyl azides react
more slowly than the ones derived from R-aminoesters. The
higher reactivity of the latter compounds is a clear advantage in
the synthesis of the corresponding N-hydroxyureas that mini-
mizes the possible formation of N-hydroxyhydantoin byprod-
uct. Steric reasons do not seem to account for this difference in
reactivity between the two groups of carbamoyl azides because
the least hindered structures are also the least reactive ones.
The experimental procedure developed for the synthesis of
carbamoyl amidoximes was also applied to several carba-
moyl azides in order to compare the reactivity of azides and
cyanides under the reaction conditions employed. In this
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TABLE 3. Synthesis of Carbamoyl Amidoximes from Cyanoforma-
mides
structure of unknown molecules.29 As a result, we decided to
apply this methodology to our molecules.
The conformational space of the carbamoyl amidoxime
group was explored in order to find all possible minima. First
of all, Z and E isomers around the CdN bond were built, and
the following bonds were subsequently considered for rota-
tion (180°): N3-O4, C1-C2, and N6-C1 (see Figure 4 for
numbering scheme).
FIGURE 4. Conformational minima of the amidoxime moiety.
The amide bond N6-C1 was found to be much more
stable in the trans conformation, as the cis alternative has
to be nonplanar to accommodate all atoms. The s-cis and
s-trans conformations for the C1-C2 bond and the two
planar dispositions for the N3-O4 bond were considered,
yielding a total of 4 starting conformations for each config-
uration of the double bond. When all of the starting con-
formations had been minimized, only two conformers for
each configuration of the double bond were found (Figure 4).
In general, the calculations show that the Z conformers are
more stable than the E ones. In all cases, Z1 is the most stable
conformation and is at least 4 kcal/mol lower in energy than
the next minimum.
Compounds 13j and 13d, with isopropyl and benzyl side
chains, respectively, were fully modeled in order to calculate
their NMR chemical shifts. Rotation around the Csp3-N6
bond in each compound yielded 3 and 2 minima, respec-
tively, for each amidoxime moiety conformer. The 12 struc-
tures of compound 13j and the 8 structures of 13d were
minimized in DMSO (PCM model) with three different basis
sets: 6-31G(d), 6-311þG(d,p), and 6-311þG(2d,p). All of the
minimized structures, together with their energies, are in-
cluded in the Supporting Information section.
Isotropic shieldings were calculated for each minimized
structure in DMSO at the same level of theory as the mini-
mization. 15N and 13C NMR chemical shifts were calculated
according to the linear regression formulas proposed by
Franca et al.30 and van Eikema Hommes et al.,31 respec-
tively. Both authors propose two equations, one for isotropic
shieldings calculated with the 6-31G(d) basis set and the
other for isotropic shieldings calculated at a higher level of
theory [6-311þG(d,p) for 13C and 6-311þG(2d,p) for 15N].
The chemical shifts for the amidoxime moiety conformers
are presented in Table 4. Each value was obtained by
averaging the individual chemical shifts from all side chain
conformers according to their respective free energies by
means of a Boltzmann distribution. Two sets of calculated
chemical shifts are presented for each compound: one with
all the chemical shifts calculated with the smallest basis set
(level A) and the other with the 13C NMR chemical shifts
calculated with the 6-311þG(d,p) basis set (level B) and the
15N NMR chemical shifts calculated with the 6-311þG(2d,p)
context, azides proved to be less reactive than cyanides, and
after 2 h, the starting carbamoyl azide was recovered to-
gether with the expected N-hydroxyurea and the product
from the addition of hydroxylamine to the carbonyl group
through the hydroxyl oxygen atom (Scheme 5).
Computational Study
The configuration of the amidoxime moiety could not be
established from routine experimental data. However, com-
parison between calculated and experimental NMR chemical
shifts has been used in structural analysis to propose the
conformation,27 stereochemical features,28 and even the whole
(27) (a) Forsyth, D. A.; Sebag, A. B. J. Am. Chem. Soc. 1997, 119, 9483–
9494. (b) Stahl, M.; Schopfer, U. J. Chem. Soc., Perkin Trans. 2 1997, 905–908.
(28) (a) Barone, G.; Duca, D.; Silvestre, A.; Gomez-Paloma, L.; Riccio, R.;
Bifulco, G. Chem.;Eur. J. 2002, 14, 3240–3245. (b) Bifulco, G.; Gomez-Paloma,
L.; Riccio, R. Tetrahedron Lett. 2003, 44, 7137–7141. (c) Fattorusso, C.;
Stendardo, E.; Appendino, G.; Fattorusso, E.; Luciano, P.; Romano, A.;
Taglialatela-Scafati, O. Org. Lett. 2007, 9, 2377–2380.
(29) Rychnovsky, S. D. Org. Lett. 2006, 8, 2895–2898.
(30) Franca, C. A.; Pis Diez, R.; Jubert, A. H. J. Mol. Struct. 2008, 856, 1–8.
(31) van Eikema Hommes, N. J. R.; Clark, T. J. Mol. Model. 2005, 11,
175–185.
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SCHEME 5
TABLE 4. 13C and 15N NMR Chemical Shift Values for the Amidoxime
Moiety Conformers
sion of NH2OH HCl (600 mol %) in MeOH (1 mL) and the
3
reaction temperature was maintained with a room temperature
water bath. The mixture was diluted with CH2Cl2 (10 mL) and
stirred for 5-10 min. The carbamoyl azide (100 mol %) was
added and the resulting mixture was stirred during the time
indicated for each case. The reaction mixture was cooled to 0 °C
with a H2O/ice bath and 10% aqueous HCl saturated with NaCl
(10 mL) was added. The two phases were separated and the
aqueous solution was extracted with AcOEt (6-8ꢀ). The
combined organic layers were dried over Na2SO4 and filtered
and the solvents removed under reduced pressure. The crude
product was purified by flash chromatography on silica gel to
give the corresponding N-hydroxyurea. Procedure B (K2CO3):
C1
C2
N3
N5
N6
R2
R = iPr
A
Z1
Z2
E1
E2
157.6 145.4 -96.3 -312.5 -256.6 0.99975
159.3 149.8 -73.1 -315.0 -245.9 0.99907
156.4 149.3 -88.2 -317.9 -238.0 0.99883
160.5 145.5 -36.5 -325.1 -242.9 0.98768
156.4 144.4 -98.6 -318.1 -254.5 0.99974
158.1 149.9 -82.6 -318.8 -242.8 0.99925
154.8 148.2 -91.5 -320.9 -234.8 0.99794
158.9 145.1 -45.7 -327.3 -240.3 0.99049
B/C Z1
Z2
E1
E2
Expt 159.8 145.9 -91.7 -320.2 -258.6
R = Bn
A
Z1
Z2
E1
E2
158.8 145.3 -95.7 -312.2 -266.2 0.99968
160.1 149.8 -72.0 -314.9 -253.8 0.99878
157.5 149.0 -87.5 -317.4 -248.4 0.99827
161.1 145.3 -35.3 -325.2 -251.2 0.98755
157.1 144.2 -97.8 -317.8 -264.7 0.99950
158.9 149.7 -80.8 -318.9 -252.7 0.99872
155.1 147.9 -90.7 -320.7 -244.7 0.99706
159.4 144.0 -35.6 -329.1 -248.9 0.98620
A mixture of the carbamoyl azide (100 mol %), NH2OH HCl
3
(400 mol %) and K2CO3 (200 mol %) in CH3CN was stirred for
1 h. K2CO3 (100 mol %) was added and stirring was continued
for 1 h. A further portion of K2CO3 (100 mol %) was added and
the mixture was stirred until complete disappearance of the
carbamoyl azide (TLC). The mixture was filtered, concentrated
and purified by flash chromatography on silica gel to give the
corresponding N-hydroxyurea. Procedure C (K2CO3): A mix-
B/C Z1
Z2
E1
E2
Expt 160.9 145.8 -90.6 -320.0 -274.0
ture of NH2OH HCl (400 mol %) and K2CO3 (300 mol %) in
basis set (level C). Experimental chemical shifts in DMSO for
each compound are included for comparison.
3
CH3CN was stirred for 30-40 min. The carbamoyl azide (100
mol %) was added and the resulting mixture was stirred for 1 h.
After the addition of a further portion of K2CO3 (100 mol %)
the mixture was stirred until complete disappearance of the
carbamoyl azide (TLC). The mixture was filtered and concen-
trated and the residue was purified by flash chromatography
on silica gel to give the corresponding N-hydroxyurea. Proce-
Although all calculated chemical shifts agree rather
well with the experimental values, only the square of the
Pearson’s correlation coefficient of the Z1 conformer is
higher than 0.999 for both compounds in the two sets of
calculations. Conformation Z2 also shows good correlation
coefficients, but for all sets of data they are smaller than the
Z1 coefficients.
The agreement between calculated and experimental
NMR chemical shifts together with the relative energy values
calculated for all conformations suggest a Z configuration for
the amidoxime CdN double bond. These results are also
consistent with Z1 being the most favored conformation in
solution.
dure D (K2CO3): A suspension of finely ground NH2OH HCl
3
(600 mol %) in CH3CN was stirred for 5-10 min. After this
time, K2CO3 (300 mol %) was added over 5-10 min, followed
by the carbamoyl azide (100 mol %) and a further portion of
K2CO3 (400 mol %). The mixture was stirred for 1 h and a final
portion of K2CO3 (100 mol %) was added. The mixture was
stirred for the indicated time, diluted with CH2Cl2, filtered, and
concentrated and the residue was purified by flash chromatog-
raphy on silica gel to give the corresponding N-hydroxyurea.
(S)-Methyl 2-(3-Hydroxyureido)-3-phenylpropanoate (2a).
Procedure A: Following the general procedure, the carbamoyl
azide 1a (160 mg, 0.64 mmol, 100 mol %) was treated with
Conclusions
In summary, we have shown that carbamoyl azides and
carbamoyl cyanides react with hydroxylamine in different
ways leading, in the first case, to the expected N-hydroxy-
ureas. Several experimental procedures were developed for
the efficient preparation of different types of ureas. In the case
of carbamoyl cyanides, the reaction with hydroxylamine leads
to the carbamoyl amidoxime derivatives. The synthetic proce-
dure developed for this last type of compound allowed the
highly efficient preparation of a range of examples. The Z
configuration of the amidoxime moiety double bond, which
could not be established from routine experimental data, was
proposed on the basis of comparison between experimental
and calculated 13C and 15N NMR chemical shift values for the
isopropyl and benzyl derivatives.
NH2OH HCl (269 mg, 3.87 mmol, 600 mol %) and Et3N
3
(0.80 mL, 5.76 mmol,900 mol %) inMeOH/CH2Cl2 (1:10, 11 mL)
for 8 min to afford, after flash chromatography (silica gel,
AcOEt/hexane 1:1 f 2:1), the title compound 2a (145 mg,
95% yield) as a colorless solid. Procedure B: Following the
general procedure, the carbamoyl azide 1a (600 mg, 2.42 mmol,
100 mol %), NH2OH HCl (673 mg, 9.68 mmol, 400 mol %)
3
and K2CO3 (1.34 g, 9.68 mmol, 400 mol %) in CH3CN
(150 mL) afforded, after flash chromatography (silica gel,
AcOEt/hexane 1:2 f 1:1), the N-hydroxyurea 2a (529 mg, 92%
yield) as a colorless solid. Procedure D: Following the general
procedure, the carbamoyl azide 1a (400 mg, 1.61 mmol, 100 mol %)
was treated with NH2OH HCl (672 mg, 9.67 mmol, 600 mol %)
3
and K2CO3 (1.50 g, 10.82 mmol, 700 mol %) in CH3CN (50 mL)
for 2 h to afford, after flash chromatography (silica gel, AcOEt/
hexane 1:1), the N-hydroxyurea 2a (348 mg, 91% yield) as a
Experimental Section
1
colorless solid. H NMR (400 MHz, CDCl3): δ 8.33 (br s, 1H),
General Procedures for the Synthesis of N-Hydroxyureas.
Procedure A (Et3N): Et3N (900 mol %) was added to a suspen-
7.59 (br s, 1H), 7.3-7.0 (m, 5H), 6.49 (d, J = 8.2 Hz, 1H), 4.72
(q, J = 3 ꢀ 6.6 Hz, 1H), 3.65 (s, 3H), 3.11 (dd, J = 13.4, 5.1 Hz,
J. Org. Chem. Vol. 75, No. 23, 2010 8045

Paz et al.
JOCArticle
1H), 3.07 (dd, J = 13.2, 6.2 Hz, 1H) ppm. 13C NMR (100 MHz,
CDCl3): δ 172.5, 161.3, 135.7, 129.1, 128.4, 126.9, 53.5, 52.3,
37.9 ppm. FT-IR (NaCl): ν 3305, 3066, 3030, 2951, 1723 (CdO
was treated with Cs2CO3 (194 mg, 0.60 mmol, 100 mol %) in
CH3CN (10 mL) for 2 h to afford, after flash chromatography
(silica gel, MeOH/CH2Cl2 1:8 f 1:1), the title compound 10a
ester), 1659 (CdO urea), 1542 cm-1. [R]D þ24° (c 4.10,
(120 mg, 97% yield) as a colorless solid. H NMR (400 MHz,
23
1
CHCl3). MS (ESIþ): m/z (%) 261 ([M þ Na]þ, 100), 258 (13),
239 ([M þ H]þ, 13). HRMS (ESIþ) calcd for C11H14N2NaO4
261.0846; found 261.0846.
CD3OD): δ 7.3-7.2 (m, 5H), 4.32 (dd, J = 6.0, 4.6 Hz, 1H), 3.13
(dd, J = 14.1, 4.5 Hz, 1H), 3.01 (dd, J = 14.1, 6.0 Hz, 1H) ppm.
1H NMR (400 MHz, DMSO-d6): δ 10.74 (br s, 0.58H), 8.15 (br s,
1H), 7.3-7.1 (m, 5H), 4.32 (m, 1H), 2.98 (dd, J = 14.1, 4.8 Hz,
1H), 2.91 (dd, J = 14.1, 5.7 Hz, 1H) ppm. 13C NMR (100 MHz,
CD3OD): δ 170.9, 157.0, 136.3, 130.8, 129.5, 128.1, 57.2, 37.8
ppm. 13C NMR (100 MHz, DMSO-d6): δ 168.5, 154.7, 135.5,
129.7, 128.2, 126.7, 54.8, 36.3 ppm. FT-IR: ν 3265, 3033, 2929,
2806, 1761 (CdO), 1707 (CdO), 1495 cm-1. [R]25D -106° (c 2.10,
MeOH). MS(ESIþ):m/z(%) 229([Mþ Na]þ, 81), 207 ([M þ H]þ,
100). HRMS (ESIþ) calcd for C10H11N2O3 207.0764; found
207.0757.
1-(2-Cyclohexenylethyl)-3-hydroxyurea (2c). Procedure A: Fol-
lowing the general procedure, the carbamoyl azide 1c (170 mg, 0.88
mmol, 100 mol %) was treated with NH2OH HCl (365 mg,
5.25 mmol, 600 mol %) and Et3N (1.11 mL, 7.92 mmol,
900 mol %) in MeOH/CH2Cl2 (1:10, 11 mL) for 1 h to afford,
after flash chromatography (silica gel, AcOEt/hexane
1:1fAcOEt), the title compound 2c (148 mg, 91% yield) as a
colorless solid. Procedure C: Following the general procedure,
the carbamoyl azide 1c (200 mg, 1.03 mmol, 100 mol %),
3
General Procedure for the Synthesis of Carbamoyl Amidox-
imes. KOH or tBuOK (200 mol %) was added to a solution of
NH2OH HCl (250 mol %) in MeOH and the mixture was
stirred for 5-10 min. The carbamoyl cyanide was added and
the final mixture was stirred for 10 min. The mixture was filtered
and the solvents removed under reduced pressure. The crude
product was purified by flash chromatography on silica gel to
give the corresponding amidoxime.
NH2OH HCl (286 mg, 4.12 mmol, 400 mol %) and K2CO3
3
(569 mg, 4.12 mmol, 400 mol %) in CH3CN (80 mL) afforded,
after flash chromatography (silica gel, AcOEt/hexane
1:2f1:1), the title compound 2c (160 mg, 84% yield) as a
colorless solid. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, J =
1.0 Hz, 1H), 8.22 (br s, 1H), 6.50 (t, J = 2 ꢀ 5.8 Hz, 1H), 5.38
(m, 1H), 3.11 (m, 2H), 2.04 (t, J = 2 ꢀ 7.1 Hz, 2H), 2.0-1.8 (m,
3
1
4H), 1.6-1.4 (m, 4H) ppm. H NMR (400 MHz, CD3OD): δ
(R,Z)-2-Amino-2-(hydroxyimino)-N-(1-phenylethyl)acetamide
(13b). Reaction with KOH: Following the general procedure, the
reaction of NH2OH HCl (249 mg, 3.59 mmol, 250mol %), KOH
8.17 (br s, 0.09 H), 6.62 (m, 0.59 H), 5.48 (m, 1H), 3.27 (m, 2H),
2.15 (t, J = 2 ꢀ 7.0 Hz, 2H), 2.0-1.9 (m, 4H), 1.64 (m, 2H), 1.57
(m, 2H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 161.3, 135.1,
121.6, 38.1, 37.2, 27.7, 24.6, 22.4, 21.9 ppm. 13C NMR (100 MHz,
CD3OD): δ 164.3, 136.1, 124.1, 39.2, 38.7, 29.0, 26.2, 24.0, 23.5
ppm. FT-IR: ν 3420, 3316, 3225, 2914, 2884, 2843, 1635 (CdO),
1551 cm-1. MS (EIþ): m/z (%) 184 ([M]þ, 3), 168 (15), 151 (12),
122 (13), 108 (89), 95 (36), 93 (71), 91 (28), 79 (100), 77 (45).
HRMS (EIþ) calcd for C9H16N2O2 184.1212; found 184.1213.
(2S,9R)-Methyl 2-Benzyl-4,7-dioxo-9-phenyl-5-oxa-3,6,8-triaza-
decan-1-oate (4). K2CO3 (79 mg, 0.57 mmol, 100 mol %) was
added to a solution of the N-hydroxyurea 2b (102 mg, 0.57 mmol,
100 mol %) and the carbamoyl azide 1a (141 mg, 0.57 mmol,
100 mol %) in CH3CN(10mL) andthemixturewasstirredfor3h.
The mixture was adsorbed onto silica gel and purified by flash
chromatography (silica gel, AcOEt/hexane 1:2 f 1:1.5) to afford
3
(162 mg, 2.88 mmol, 200 mol %) and carbamoyl cyanide 12b
(250 mg, 1.44 mmol, 100 mol %) in MeOH (10 mL) afforded,
after flash chromatography (silica gel, AcOEt/hexane 1:4 f 1:2),
the title compound 13b (295 mg, 99% yield) as a colorless oil.
Reaction with tBuOK: Following the general procedure, the
reaction of NH2OH HCl (249 mg, 3.59 mmol, 250 mol %),
3
tBuOK (323 mg, 2.88 mmol, 200 mol %) and carbamoyl cyanide
12b (250 mg, 1.44 mmol, 100 mol %) in MeOH (10 mL) afforded,
after flash chromatography (silica gel, AcOEt/hexane 1:4 f 1:2),
the title compound 13b (296 mg, 99% yield) as a colorless oil. 1H
NMR (400 MHz, CDCl3): δ 8.73 (br s, 1H), 7.4-7.1 (m, 6H), 5.29
(br s, 2H), 5.12 (p, J = 4 ꢀ 7.0 Hz, 1H), 1.44 (d, J = 6.9 Hz, 3H)
ppm. 1H NMR (600 MHz, DMSO-d6): δ9.84(s, 1H), 8.10 (d, J =
8.4 Hz, 1H), 7.4-7.3 (m, 4H), 7.22 (m, 1H), 5.64 (br s, 2H), 5.00
(p, J = 4 ꢀ 7.2 Hz, 1H), 1.43 (d, J = 7.0 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3): δ 159.4, 146.4, 142.2, 128.5, 127.4, 126.0,
48.9, 21.5 ppm. 13C NMR (100 MHz, DMSO-d6): δ 160.1, 145.9,
144.2, 128.2, 126.7, 126.0, 48.1, 21.8 ppm. FT-IR (NaCl): ν 3480,
3348, 3065, 3032, 2979, 2931, 2874, 1646 (CdO amide þ CdN
oxime), 1532, 1450 cm-1. [R]24D -1° (c 2.38, CHCl3). MS (ESIþ):
m/z (%) 230 ([M þ Na]þ, 25), 208 ([M þ H]þ, 100). HRMS
(ESIþ) calcd for C10H14N3O2 208.1080; found 208.1082.
1
the title compound 4 (205 mg, 94% yield) as a colorless oil. H
NMR (400 MHz, CDCl3): δ 8.45 (br s, 1H), 7.4-7.2 (m, 8H),
7.2-7.0 (m, 2H), 6.70 (d, J = 8.2 Hz, 1H), 6.28 (d, J = 7.9 Hz,
1H), 4.97 (p, J = 4 ꢀ 7.0 Hz, 1H), 4.58 (td, J = 2 ꢀ 7.4, 5.7 Hz,
1H), 3.66 (s, 3H), 3.13 (dd, J = 13.9, 5.6 Hz, 1H), 3.04 (dd, J =
13.9, 7.1 Hz, 1H), 1.43 (d, J = 7.0 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3): δ 171.4, 158.2, 155.0, 142.9, 135.4, 129.0,
128.4, 128.3, 127.0 (2 ꢀ), 125.8, 55.3, 52.3, 49.3, 37.4, 21.9 ppm.
FT-IR (NaCl): ν 3306, 3086, 3062, 3030, 2977, 2953, 2872, 1740
(CdO), 1681 (CdO), 1604, 1539, 1496 cm-1. [R]27D þ15° (c 5.80,
CHCl3). MS (ESIþ): m/z (%) 408 ([M þ Na]þ, 37), 386 ([M þ H]þ,
100). HRMS (ESIþ) calcd for C20H24N3O5 386.1710; found
386.1700.
General Procedure for the Synthesis of N-Hydroxyhydantoins.
K2CO3 or Cs2CO3 (100-200 mol %) was added to a solution
of the N-hydroxyurea in CH3CN and the mixture was stirred
for the indicated time. The reaction mixture was diluted with
MeOH (5 mL), adsorbed onto silica gel and purified by flash
chromatography on silica gel to give the corresponding N-
hydroxyhydantoin.
(S)-5-Benzyl-3-hydroxyimidazolidine-2,4-dione (10a). Reaction
with K2CO3: Following the general procedure, the N-hydroxy-
urea 2a (100 mg, 0.42 mmol, 100 mol %) was treated with K2CO3
(116 mg, 0.84 mmol, 200 mol %) in CH3CN (10 mL) for 10 h to
afford, after flash chromatography (silica gel, MeOH/CH2Cl2
1:10 f 1:1), the title compound 10a (85 mg, 98% yield) as a
colorless solid. Reaction with Cs2CO3: Following the general
procedure, the N-hydroxyurea 2a (142 mg, 0.60 mmol, 100 mol %)
Procedure for the Synthesis of Carbamoyl Amidoximes Applied
to Carbamoyl Azide 1a. (S)-Methyl 2-(3-Hydroxyureido)-3-phe-
nylpropanoate (2a) and (S)-Methyl 2-(Aminooxycarbonylamino)-
3-phenylpropanoate (14). Reaction with KOH: Following the
general procedure, the reaction of carbamoyl azide 1a (190 mg,
0.77 mmol, 100 mol %), NH2OH HCl (266 mg, 3.83 mmol,
3
500 mol %) and KOH (184 mg, 3.28 mmol, 429 mol %) in MeOH
(10 mL) for 2 h afforded, after flash chromatography (silica gel,
AcOEt/hexane 1:2 f 2:1), the N-hydroxyurea 2a (99 mg, 54%
yield) as a colorless solid and compound 14 (46 mg, 25% yield) as
a colorless oil. A proportion of the carbamoyl azide 1a was
recovered (38 mg, 19%). Reaction with tBuOK: Following the
general procedure, the reaction of carbamoyl azide 1a (200 mg,
0.81 mmol, 100 mol %), NH2OH HCl (140 mg, 2.01 mmol, 250
3
mol %) and tBuOK (182 mg, 1.62 mmol, 200 mol %) in MeOH
(10 mL) for 5 h afforded, after flash chromatography (silica gel,
AcOEt/hexane 1:2f2:1), the N-hydroxyurea 2a (99 mg, 52%
yield) as a colorless solid and compound 14 (52 mg, 27% yield) as
a colorless oil. A proportion of the carbamoyl azide 1a was
8046 J. Org. Chem. Vol. 75, No. 23, 2010

Paz et al.
JOCArticle
recovered(37mg, 18%). (S)-Methyl2-(aminooxycarbonylamino)-
3-phenylpropanoate (14). 1H NMR (400 MHz, CDCl3): δ
7.3-7.2 (m, 3H), 7.2-7.18 (m, 2H), 6.12 (d, J = 7.3 Hz, 0.90H),
5.46 (br s, 2H), 4.65 (dt, J = 8.3, 2 ꢀ 5.9 Hz, 1H), 3.72 (s, 3H), 3.15
(dd, J = 13.9, 5.6 Hz, 1H), 3.08 (dd, J = 13.9, 6.4 Hz, 1H) ppm. 1H
NMR (400 MHz, DMSO-d6): δ 7.78 (d, J = 8.2 Hz, 1H), 7.3-7.2
(m, 5H), 6.83 (br s, 2H), 4.31 (ddd, J = 9.7, 8.2, 5.0 Hz, 1H), 3.63
(s, 3H), 3.07 (dd, J = 13.8, 5.0 Hz, 1H), 2.93 (dd, J = 13.7, 9.7 Hz,
1H) ppm. 13C NMR (100 MHz, CDCl3): δ 171.6, 157.2, 135.5,
129.1, 128.6, 127.2, 54.9, 52.4, 38.0 ppm. 13C NMR (100 MHz,
DMSO-d6): δ 172.1, 157.7, 137.2, 129.0, 128.3, 126.5, 55.3, 52.0,
36.4 ppm. MS (ESIþ): m/z (%) 180 (100), 181 (16), 195 (9), 235
(26), 279 (10), 297 (6).
Computational Methods. All calculations were performed using
the hybrid Becke three-parameter Lee-Yang-Parr DFT B3LYP
functional,32 the reliability of which in calculations on ground state
geometries has been widely assessed.33 Geometries were fully opti-
mized with the following three basis sets: 6-31G(d), 6-311þG(d,p)
and 6-311þG(2d,p). The absence of imaginary frequencies in the
vibrational analysis verified that all structures corresponded to true
energy minima. Solvent effects in DMSO were studied in terms of
SCFR formalism by employing the PCM solvation model.34 NMR
shieldings were calculated for each optimized geometry at the same
level of theory at which the structure was optimized. All the
calculations were computed by using the Gaussian 09 program.35
13C and 15N chemical shifts were calculated using the linear regres-
sion equations of Franca30 and van Eikema Hommes,31 respectively.
Two chemical shift values at two different levels of theory were
obtained for each nucleus. Comparison of calculated and experi-
mental values was performed by computing the square of the
Pearson correlation coefficient (R2).
Acknowledgment. Financial support from the Xunta de
ꢀ
Galicia and Ministerio de Educacion y Ciencia is gratefully
acknowledged.
Supporting Information Available: Experimental proce-
dures and characterization data for those compounds not
1
included in the Experimental Section and copies of H NMR,
13C NMR, and HMBC-NH spectra, calculation details, ener-
gies, calculated NMR isotropic shieldings and chemical shifts,
Cartesian coordinates and structure plots for conformers of
compounds 13j and 13d. This material is available free of charge
via the Internet at http://pubs.acs.org.
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Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.;
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Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.;
Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.;
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