Formamidine Ureas as Tunable Electrophiles

Article abstract of DOI:10.1002/chem.200305388

Formamidine urea compounds exchange imine fragments with primary nitrogen nucleophiles, allowing the preparation of a variety of derivatives from a single precursor. The reactivities of these species are governed primarily by the electron-donating power o

Full text of DOI:10.1002/chem.200305388

FULL PAPER
Formamidine Ureas as Tunable Electrophiles
David D. DÌaz and M. G. Finn*[a]
Abstract: Formamidine urea compounds exchange imine fragments with primary
nitrogen nucleophiles, allowing the preparation of a variety of derivatives from a
single precursor. The reactivities of these species are governed primarily by the
electron-donating power of the substituents and are tunable over a range of >103
in first-order rates of hydrolysis.
Keywords: electrophiles
amidines ¥ hydrolysis ¥ synthesis
design ¥ ureas
¥
form-
Introduction
Formamidines are of interest in synthetic chemistry[1] and
have been used extensively as pesticides (e.g., amitraz,
chlordimeform, formetanate)[2] and as pharmacological
agents.[3] The reported biochemical targets of formamidines
include adrenergic, histamine, and neurochemical re-
c,3a,3b,4]
ceptors,[2a
monoamine oxidase,[2e,5] and prostaglandin
E2 synthesis.[6] Their use as ligands in transition-metal com-
plexes has also been noted.[7] Recently, well-defined poly-
meric structures containing large numbers of amidine
groups were reported.[8] The uses of formamidines in organic
synthesis have been quite diversified, including such roles as
auxiliaries in asymmetric synthesis,[9] protecting groups for
primary amines,[10] electrophiles,[11] and linkers in solid-phase
synthesis.[12] General routes to formamidines and related
compounds are dominated by condensation (amine+form-
amide)[13] and exchange (amine+formamidine acetals)[10,14]
processes.
We recently reported an efficient preparation of form-
amidine ureas 1 from isonitriles and ureas in the presence
of acid chlorides (Scheme 1).[15] The previously known meth-
ods of formamidine synthesis had not been applied to, or
were ineffective in, the incorporation of the urea moiety,
which may be expected to enhance the biological activity of
such structures. Here we describe a facile exchange reaction[16]
Scheme 1.
with nucleophilic amines, which provides access to formami-
dine ureas of wide scope at the formamidine position.
Results and Discussion
Formamidines are electrophilic at the central carbon atom,
and we anticipated that the carbamoyl substituent would
perhaps enhance this reactivity relative to simple alkyl- or
arylformamidine structures. We observed that the freebase
form of formamidine ureas 1 undergo clean exchange with
primary nitrogen nucleophiles at room temperature
(Scheme 2). The reaction presumably proceeds through a
[a] Dr. D. D. DÌaz, Prof. M. G. Finn
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute, 10550 N. Torrey Pines Rd.
La Jolla, CA 92037 (USA)
Fax : (+1)858-784-8850
E-mail: mgfinn@scripps.edu
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author. Representative
1H NMR and 13C NMR spectra for the compounds described in the
Experimental Section and full details of kinetics measurements.
Scheme 2.
303
Chem. Eur. J. 2004, 10, 303 309
DOI: 10.1002/chem.200305388
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

FULL PAPER
tetrahedral intermediate,[11,17]
which ejects amine in prefer-
ence to urea (Scheme 2), estab-
lishing an equilibrium between
formamidine urea species. Sim-
ilar substitution reactions have
been described with diaryl-
and N-acylformamidines,[18] but
these are less efficient than the
process described here. The
formamidine urea is therefore
analogous in its electrophilicity
to formamidine acetals,[10,14]
shown at the bottom of
Scheme 2. Since we have been
unable to capture formamidine
acetals with substituted ureas,
the methodology of Schemes 1
and 2 represents the best way
so far developed to prepare
structurally diverse formami-
dine urea compounds.
Table 1. Nucleophilic substitution of 2 under standard conditions.
RÀNH2
Product
Yield [%][a]
67
RÀNH2
Product
Yield [%][a]
83
3
21
4
5
69
73
22
23
81
78
6 (X=H)
7 (X=Me)
8 (X=OMe)
9 (X=NMe2)
32 49
61
24
66
25 (X=H)
26 (X=Me)
10
66
67
11 (X=Br)
12 (X=Cl)
13
62
68
27
28
62
66
Among the formamidine
ureas reported earlier,[15] 1,3-
dimethyl-1-tert-butyliminometh-
ylurea hydrochloride (2, see
scheme in Table 1) emerged as
the most effective starting ma-
terial for the exchange process.
This compound can be conven-
iently obtained from tert-butyl-
isocyanide on a 40 g scale, and
the bulky nature of the tert-
butyl group makes its substitu-
tion irreversible. Table 1 sum-
marizes a set of exchange reac-
tions between 2 and a variety
of aromatic and aliphatic pri-
mary amines, hydroxylamines,
hydrazines, and hydrazides.
Triethylamine was employed to
neutralize the starting hydro-
chloride salt, and the use of
1.5 equivalents of nucleophile
gave slightly better yields than
1.0 equivalent.
14
65
29
15
16
63MeNHNH
79
30
31
48
53
2
17
18
74
77
32
33
59
34
19
20
80
76
34
51[b]
MeOÀNH2
[a] Yields of analytically pure compounds after chromatography. [b] Obtained under more dilute conditions
(0.01m in 2), after 20 h at reflux.
For a series of anilines (giving 6 9), yields were low due
to poor nucleophilicity, increasing slightly with increasing
electron-donating power of the para-substituent; 4-nitroani-
line was entirely unreactive. The process allows the intro-
duction of amines bearing other reactive functionalities
(compounds 10 15), chiral groups (compounds 16, 17), and
a solid support (from aminomethylpolystyrene, not shown).
While the crude reaction mixtures with hydrazines and hy-
drazides giving 30 33 appeared to be quite clean, these com-
pounds were difficult to elute from silica gel and so suffered
some losses in yield upon purification. Reactions with
RONH2 and RNHNH2 nucleophiles were generally effec-
tive, even when incorporating sterically hindered compo-
nents (22, 24, 31). When solubility was poor, as with the N-
acetylphenylalanine hydrazide which gave 34, reaction in re-
fluxing CH2Cl2 was required, often at higher dilution, to
obtain acceptable yields. Most of the reactions shown bene-
fit in terms of speed and yield from reaction at elevated
temperatures, but were performed at room temperature for
convenience.
The exchange process gave the best results in chlorinated
solvents, with the order of effectiveness being CH2Cl2,
1,2-dichloroethane, CHCl3, CCl4 @THF, CH3CN@toluene,
benzene, Et2O@pyridine>1,4-dioxane>DMSO, DMF@
acetone, MeOH. No byproducts or other impurities were
observed in any solvent. Use of the secondary amine mor-
304
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Chem. Eur. J. 2004, 10, 303 309

Formamidine Ureas
303 309
pholine instead of primary
amines gave a mixture of as yet
uncharacterized
compounds,
and secondary amines did not
appear to catalyze the substitu-
tion of primary amines.
The biological activity of for-
mamidine ureas and their deriv-
atives is likely to be limited by
their rates of hydrolysis.[19] In
our initial report, we described
the relatively rapid hydrolysis
of the parent compounds to
urea and amine.[15] This process
is presumed to begin with nu-
cleophilic attack of water or hy-
droxide on the formamidine
carbon to give a hemiorthoa-
mide intermediate, and can be
promoted by either acid or
Figure 1. Left: UV-visible spectrum of compound 6 in 0.1m phosphate buffer, pH 7.0; arrow indicates increas-
ing time. Right: first-order kinetics plots for the hydrolysis of compounds 6 9 in 0.1m phosphate buffer,
pH 7.0, monitored every 10 min over 15 h at 23Æ18C. Rate constants are in units of minÀ1
.
base. Both type of mechanisms have been implicated in the
hydrolysis of formamidines and N-acylformamidines, with a
direct relationship between the electron-withdrawing power
of substituents and the hydrolysis rate observed.[17,18] With a
variety of formamidine ureas in hand, we examined the
rates of hydrolysis as a function of the electron-donating
ability of the formamidine substituent and, therefore, the
electrophilicity of the formamidine carbon.
Hydrolysis of formamidine ureas was accompanied by a
loss in intensity of the main absorbance band at approxi-
mately 280 nm (Figure 1); this made for the convenient
monitoring of aqueous hydrolytic stability as a function of
pH. Figure 1 shows first-order kinetics plots for the disap-
pearance of aniline-substituted compounds 6 9 at pH 7.0.
Stability was found to be enhanced by electron-donating
para-substituents in the order: NMe2 @OMe>MeꢀH. The
dimethylamino compound 9 was far more stable at neutral
pH than would be expected on the basis of Hammett type
considerations, showing a reduction in hydrolysis rate of at
least two orders of magnitude relative to the methoxy deriv-
ative 8.
Kinetic analyses of formamidine urea hydrolysis were sim-
ilarly performed for 11 additional compounds spanning a
range of stabilities. Figure 2 shows these results in the form
of a plot of half-life in three different buffers, calculated
from the experimentally determined first-order rate con-
stants, for those compounds for which appreciable hydrolysis
was observed within 16 h at room temperature. The rates of
hydrolysis were neither dependent on the nature of the
buffer nor its concentration. Not shown are data for the
other compounds 22, 27, 30, 32, and 34, which were ob-
served to be highly resistant to hydrolysis. The hydrolysis
rate constants for these compounds are therefore estimated
to be less than 1î10À4 minÀ1 (half-life >116 h). Full details
Figure 2. Left: Chart showing half-lives calculated from first-order kinetics plots of hydrolysis of formamidine ureas in 0.1m acetate buffer (pH 5.0), 0.1m
phosphate buffer (pH 7.0), and 0.1m bicarbonate buffer (pH 9.0), each at 23Æ18C. Omitted are bars corresponding to the >116 h half-lives of 22, 27, 30,
32, and 34. Right: Summary of the range of half-lives toward hydrolysis in aqueous solution versus the nature of the terminal formamidine substituent in
derivatives of 1,3-dimethylurea.
305
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M. G. Finn and D. D. DÌaz
FULL PAPER
are given in the Supporting Information. The stable com-
pounds comprise adducts of an oxime (22), hydrazine (30),
and three hydrazides (27, 32, 34). Their resistance to hydrol-
ysis is presumably due to the stabilization provided to the
formamidine carbon atom by the electron-donating ability
of the highly nucleophilic nitrogen centers of each of these
substituents. Note especially that oxime adduct stability is
substantially diminished with aromatic conjugation (18).
Thus, the reactivities of formamidine ureas can be tuned
over a wide range with changes in the formamidine substitu-
ent, as summarized by the scheme on the right-hand side of
Figure 2.
With the exception of propargylamine derivative 13, hy-
drolysis was observed to occur slowest at pH 9. Both acid-
and base-mediated mechanisms may be operative,[17,20] but
these data suggest that acidic catalysis may be more
common for formamidine ureas. Indeed, amidines and N-
acylamidines have been shown to be fairly strong hydrogen-
bond acceptors.[21] Furthermore, the Br˘nsted basicities of
N,N-dimethylformamidines R1N=CHÀNMe2 in ethanol are
only approximately five orders of magnitude less than the
corresponding primary amines R1NH2.[22] Formamidine
ureas are likely to be somewhat less basic than this, but still
basic enough to respond to mild acid catalysis. Hydrazide
adduct 33, bearing an ortho-phenolic group, was as stable as
the other hydrazide compounds examined (no decomposi-
tion observed for 12 h at pH 5 and 7, although a full kinetic
analysis was not performed), indicating that its phenolic hy-
droxyl group does not participate intramolecularly in form-
amidine hydrolysis.
Experimental Section
General: 1H and 13C NMR spectra were recorded on Bruker DRX-500,
AMX-400, or Varian Mercury 200 spectrometers in CDCl3 or CD3OD as
solvent. Mass spectra were taken using a HP 1100 LC/MS spectrometer
(model G1946A) with mobile phase composed of 90:10 CH3OH:H2O
containing 0.1% CF3CO2H. Elemental analyses were performed by Mid-
west MicroLab. Melting points were measured in a Thomas Hoover ca-
pillary melting point apparatus and are uncorrected. Infrared spectra
were recorded on a MIDAC EM200 instrument with horizontal attenuat-
ed total reflectance accessory from Pike Instruments. UV-visible meas-
urements were performed on a HP 845x UV-visible spectrophotometer
in the 190 1100 nm range, in quartz cells with 1 cm path length. Optical
¾
rotations were determined for solutions in chloroform on an Autopol III
polarimeter (Rudolph Research). Column chromatography was per-
formed on EM Science silica gel, 40 63micron mesh. TLC analysis was
facilitated by the use of the following stains in addition to UV light with
fluorescent-indicating plates: phosphomolybdic acid, vanillin/EtOH, anis-
aldehyde/EtOH, or KMnO4/H2O. Purification of some compounds was
performed by preparative TLC on UNIPLATETM 20î20 cm plates
(2000 microns, silica gel GF) plates. CH2Cl2 was dried by passage through
activated alumina columns;[24] dry Et3N and other solvents used in this
work were purchased from Aldrich. Reactions requiring anhydrous con-
ditions were performed under nitrogen. Buffer (0.1m) and amine solu-
tions were prepared immediately before use.
General procedure for formamidine urea substitution: Et3N (2.6 mmol,
1.1 equiv) was added to a solution of 1,3-dimethyl-1-tert-butyliminometh-
ylurea hydrochloride (2) (2.4 mmol, 1.0 equiv) in dry CH2Cl2 (25 mL) at
room temperature under a nitrogen atmosphere. The reaction mixture
was stirred for 5 min, and then the nucleophilic amine (3.6 mmol,
1.5 equiv) was added. In cases in which the nucleophile was used as its
hydrochloride salt (18, 20, 21, 22, 23), an additional equivalent of triethyl-
amine was used. The reaction mixture was stirred at room temperature
for 12 h, diluted with CH2Cl2, washed with brine, dried (MgSO4), filtered,
concentrated, and purified by column chromatography to yield the form-
amidine urea derivative. The hygroscopic products were dried under
vacuum and stored under nitrogen. Note that in many cases, the reactions
may be heated to obtain equal or slightly better yields than those report-
ed above with shorter reaction time. Note that aniline derivatives 6 9 are
somewhat unstable in the solid state at room temperature, but are stable
in CH2Cl2 or methanol solution for extended periods. The remaining for-
mamidine ureas are more stable in the solid state, but should be stored
under nitrogen in a refrigerator for extended periods.
The reaction of 2 with a thiol nucleophile resulted not in
exchange at the formamidine position, but rather attack at
the urea carbonyl to give thiolcarbamate 35,[23] and presuma-
bly N-tert-butyl-N’-methylformamidine, which would be ex-
pected to hydrolyze upon workup [Eq. (1)]. Thiolcarba-
mates are not available by direct substitution of ureas with
thiols, so the observed reaction is of some theoretical and
practical interest and is under current investigation.
General procedure for measurement of hydrolysis kinetics: Stock solu-
tions of each compound of interest were prepared in 3mL MeOH imme-
diately before use. The stock solution was then diluted into the indicated
buffer (minimum dilution was 1:100) to a concentration giving an absorb-
ance value at lmax of 1.1Æ0.1. The reaction mixture was immediately
transferred to a quartz cuvette, sealed, and monitoring at lmax was com-
menced, with spectra acquired every 10 minutes for 16 h. Each sample
was then checked daily until the absorbance value varied by less than Æ
0.005 for two successive days, at which point the sample was judged to
have been fully hydrolyzed. These data were used to construct plots of
ln(% formamidine urea remaining) versus time, which were linear over a
substantial portion of the reaction. The slopes of these lines are the ob-
served first-order rate constants for hydrolysis. See Supporting Informa-
tion for details.
In summary, we have described a general exchange reac-
tion between formamidine ureas and nitrogen nucleophiles,
allowing the synthesis of compounds bearing a wide variety
of substituents from a single isonitrile precursor (which is
used to gain entry to the formamidine urea skeleton). Form-
amidine ureas, being related to biologically active form-
amidines and bearing multiple sites for potential hydrogen-
bonding interactions, are of interest for the design of novel
pharmacophores. We have also shown that the electrophilic
reactivity of formamidine ureas can be tuned over a wide
range, which may make them useful as covalent or reversi-
ble inhibitors of certain classes of enzymes.
Compound characterization
General: Examination of spectroscopic data for the described compounds
revealed the following characteristic resonances. H NMR: d=ca. 2.9 and
3.4 (s, 3H, urea NHMe), ca. 9.0 ppm (brs, 1H, CÀH of formamidine
group); 13C NMR: d=ca. 157(C=O), ca. 149 (C=N), ca. 30 and 26 ppm,
(urea NHMe). IR: n˜ =ca. 3300 (NÀH stretching vibration), ca. 1550 (NÀH
bending vibration), 1650 1750 cmÀ1 (C=O).
1
1,3-Dimethyl-1-tert-butyliminomethyl)urea (2): Compound 2 has been
previously reported as the hydrochloride salt.[15] The freebase form exhib-
its the following characteristics. Gummy syrup (hygroscopic); 1H NMR
(CDCl3): d=1.27 (s, 9H), 2.94 (s, 3H), 3.23 (s, 3H), 7.71 (s, 1H),
9.77 ppm (brs, 1H); 13C NMR (CDCl3): d=26.6, 30.7, 33.9, 54.9, 148.3,
157.2 ppm; IR (thin film): n˜ =3350, 2964, 1669, 1554, 1323, 1222, 1077,
306
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Chem. Eur. J. 2004, 10, 303 309

Formamidine Ureas
303 309
1001 cmÀ1; MS: m/z (%): 194 (2) [M+Na]+, 173(10) [ M+2]+, 172 (100)
[M+1]+, 157 (55); elemental analysis calcd (%) for C8H17N3O¥0.5H2O: C
53.31, H 10.07, N 23.31; found: C 53.49, H 9.95, N 23.44.
C7H14N6O¥1/3H2O: C 41.17, H 7.24, N 41.15; found: C 41.12, H 6.97, N
39.98.
1,3-Dimethyl-1-(3-bromopropyl)iminomethylurea (11): This compound
was prepared from 2 and 3-bromopropylamine hydrobromide. Colorless
1,3-Dimethyl-1-(2-furylmethyl)iminomethylurea (3): This compound was
1
1
prepared from 2 and furfurylamine. Colorless oil (hygroscopic); H NMR
oil (hygroscopic); H NMR (CDCl3): d=2.14 2.23(m, 2H), 2.90 (s, 3H),
(CDCl3): d=2.89 (s, 3H), 3.20 (s, 3H), 4.51 (s, 2H), 6.21 (s, 1H), 6.34 (s,
1H), 7.92 (s, 1H), 9.06 ppm (brs, 1H); 13C NMR (CDCl3): d=27.6, 30.8,
51.7, 107.2, 110.7, 142.4, 151.6, 153.3, 156.2 ppm; IR (thin film): n˜ =3341,
2951, 1679, 1534, 1309, 1076, 991 cmÀ1; MS: m/z (%): 197 (10) [M+2]+,
196 (100) [M+1]+ ; elemental analysis calcd (%) for C9H13N3O2: C 55.37,
H 6.71, N 21.52; found: C 49.08, H 6.75, N 21.22.
3.29 (s, 3H), 3.51 3.58 (m, 2H), 3.81 3.89 (m, 2H), 8.48 (s, 1H),
9.35 ppm (brs, 1H); 13C NMR (CDCl3): d=27.6, 30.4, 31.8, 32.7, 60.1,
152.9, 156.9 ppm; IR (thin film): n˜ =3327, 2941, 1686, 1527, 1308, 1075,
997 cmÀ1; MS: m/z (%): 238 (100) [M+2]+, 237 (10) [M+1]+, 236 (94)
[M]+ ; elemental analysis calcd (%) for C7H14BrN3O¥1.5H2O: C 31.95, H
6.51, Br 30.37, N 15.97; found: C 31.86, H 6.43, Br 29.99, N 16.14.
1,3-Dimethyl-1-(C-benzo[1,3]dioxol-5-yl-methyl)iminomethylurea
(4):
1,3-Dimethyl-1-(3-chloropropyl)iminomethylurea (12): This compound
was prepared from 2 and 3-chloropropylamine hydrochloride. Colorless
oil (hygroscopic); H NMR (CDCl3): d=2.05 2.19 (m, 2H), 2.90 (s, 3H),
3.31 (s, 3H), 3.52 3.59 (m, 2H), 3.65 3.70 (m, 2H), 8.51 (s, 1H),
9.23ppm (brs, 1H); 13C NMR (CDCl3): d=27.3, 30.5, 34.1, 43.0, 53.2,
152.9, 156.9 ppm; IR (thin film): n˜ =3349, 2951, 1668, 1539, 1310, 1069,
980 cmÀ1; MS: m/z (%): 193(11) [ M+2]+, 192 (100) [M+1]+ ; elemental
analysis calcd (%) for C7H14ClN3O: C 43.87, H 7.36, Cl 18.50, N 21.92;
found: C 43.54, H 7.56, Cl 18.17, N 21.90.
This compound was prepared from 2 and piperonylamine. Light yellow
oil (hygroscopic); 1H NMR (CDCl3): d=2.92 (s, 3H), 3.31 (s, 3H), 4.52
(s, 2H), 6.18 (s, 2H), 6.72 6.76 (m, 3H), 7.93 (s, 1H), 9.27 ppm (brs,
1H); 13C NMR (CDCl3): d=26.9, 32.7, 60.1, 101.3, 108.6, 120.7, 134.1,
146.9, 148.1, 148.4, 156.9 ppm; IR (thin film): n˜ =3340, 2946, 1671, 1534,
1309, 1249, 1072, 935 cmÀ1; MS: m/z (%): 272 (9) [M+Na]+, 251 (15)
1
[M+2]+, 250 (100) [M+1]+
; elemental analysis calcd (%) for
C12H15N3O3: C 57.82, H 6.07, N 16,86; found: C 57.44, H 6.08, N 17.26.
1,3-Dimethyl-1-benzyliminomethylurea (5): This compound was prepared
from
1,3-Dimethyl-1-(prop-2-ynyl)iminomethylurea (13): This compound was
prepared from 2 and propargylamine. Colorless oil (hygroscopic); 1H
NMR (CDCl3): d=2.51 (s, 1H), 2.95 (s, 3H), 3.27 (s, 3H), 4.28 (s, 2H),
8.09 (s, 1H), 9.02 ppm (brs, 1H); 13C NMR (CDCl3): d=27.1, 62.9, 75.0,
79.9, 148.9, 156.8 ppm; IR (thin film): n˜ =3354, 2952, 1661, 1536,
1306 cmÀ1; MS: m/z (%): 238 (97) [M+Na]+, 217 (11) [M+2]+, 216 (100)
[M+1]+ ; elemental analysis calcd (%) for C9H17N3O3: C 50.22, H 7.96, N
19.52; found: C 49.93, H 7.51, N 19.23.
2
and benzylamine. Gummy syrup (hygroscopic); 1H NMR
(CDCl3): d=2.93 (s, 3H), 3.27 (s, 3H), 4.62 (s, 2H), 7.33 7.40 (m, 2H),
7.40 7.42 (m, 3H), 8.54 (s, 1H), 9.37 (brs, 1H); 13C NMR (CDCl3): d=
32.7, 59.3, 127.0, 128.5, 140.3, 156.9, 163.1; IR (thin film): n˜ =3340, 2939,
1671, 1554, 1317, 1084 cmÀ1; MS: m/z (%): 228 (6) [M+Na]+, 207 (7)
[M+2]+, 206 (100) [M+1]+, 149 (38); elemental analysis calcd (%) for
C11H15N3O¥2H2O: C 54.76, H 7.94, N 17.42; found: C 55.03, H 7.66, N
17.67.
1,3-Dimethyl-1-allyliminomethylurea (14): This compound was prepared
from 2 and allylamine. Colorless oil (hygroscopic); 1H NMR (CDCl3):
d=2.91 (s, 3H), 3.27 (s, 3H), 4.03 (d, J=17.0 Hz, 2H), 5.12 5.14 (m,
2H), 5.84 6.18 (m, 1H), 8.53ppm (s, 1H); 13C NMR (CDCl3): d=27.0,
32.8, 58.8, 115.7, 134.8, 148.7, 156.9 ppm; IR (thin film): n˜ =3342, 2964,
1656, 1552, 1073, 796 cmÀ1; MS: m/z (%): 157 (9) [M+2]+, 156 (100)
[M+1]+ ; elemental analysis calcd (%) for C7H13N3O: C 54.17, H 8.44, N
27.08; found: C 54.17, H 8.43, N 27.01.
1,3-Dimethyl-1-phenyliminomethylurea (6): This compound was prepared
from 2 and aniline. Colorless oil (hygroscopic): 1H NMR (CDCl3): d=
3.02 (s, 3H), 3.37 (s, 3H), 7.08 (d, J=7.7 Hz, 2H), 7.22 7.24 (m, 1H),
7.39 7.42 (m, 2H), 8.06 (brs, 1H); 13C NMR (CDCl3): d=27.3, 30.8,
121.5, 125.2, 129.7, 149.5, 151.5, 156.4 ppm; IR (thin film): n˜ =3353, 2947,
1658, 1534, 1308, 1087, 1011 cmÀ1; MS: m/z (%): 214[M+Na]+ (17),
193[M+2]+ (15), 192 [M+1]+ (100); HRMS calcd for C10H14N3O:
192.1137; found: 192.1139.
1,3-Dimethyl-1-(2-morpholin-4-yl-ethyl)iminomethylurea (15):This com-
pound was prepared from 2 and 4-(2-aminoethyl)morpholine. Colorless
1,3-Dimethyl-1-p-tolyliminomethylurea (7): This compound was prepared
1
from
2
and p-toluidine. Light yellow oil (hygroscopic); 1H NMR
oil (hygroscopic); H NMR (CDCl3): d=2.12 2.61 (m, 4H), 2.94 (s, 3H),
(CDCl3): d=2.40 (s, 3H), 2.99 (s, 3H), 3.55 (s, 3H), 6.97 (d, J=6.6 Hz,
2H), 7.19 (d, J=7.3Hz, 2H), 8.04 ppm (s, 1H); 13C NMR (CDCl3): d=
21.2, 27.2, 30.8, 121.2, 130.2, 134.8, 148.7, 151.2, 157.4 ppm; IR (thin film):
n˜ =3357, 2959, 1655, 1526, 1300, 1078, 1007 cmÀ1; MS: m/z (%): 228 (3)
3.08 (s, 3H), 3.18 (s, 3H), 3.28 3.54 (m, 2H), 3.55 3.79 (m, 4H), 8.54 (s,
1H), 9.28 ppm (brs, 1H); 13C NMR (CDCl3): d=26.7, 30.6, 53.6, 54.0,
60.1, 66.9, 152.5, 156.9 ppm; IR (thin film): n˜ =3357, 2950, 1675, 1583,
1321, 1111, 983 cmÀ1; MS: m/z (%): 251 (7) [M+Na]+, 230 (13) [M+2]+,
[M+Na]+, 207 (15) [M+2]+, 206 (100) [M+1]+
;
HRMS calcd for
229 (100) [M+1]+
; elemental analysis calcd (%) for C10H20N4O2
C11H16N3O: 206.1293; found: 206.1295.
¥1.5H2O: C 47.04, H 9.08, N 21.94; found: C 47.04, H 8.88, N 22.14.
1,3-Dimethyl-1-(4-methoxyphenyl)iminomethylurea (8). This compound
was prepared from 2 and p-anisidine. Light yellow oil (hygroscopic); 1H
NMR (CDCl3): d=2.93 (s, 3H), 3.31 (s, 3H), 3.83 (s, 3H), 6.90 (d, J=
9.0 Hz, 2H), 6.99 (d, J=10.0 Hz, 2H), 8.50 (s, 1H), 9.06 ppm (brs, 1H);
13C NMR (CDCl3): d=27.0, 32.7, 55.9, 142.7, 150.7, 154.6, 156.6ppm; IR
(thin film): n˜ =3349, 2930, 1675, 1518, 1296, 1223, 1074 cmÀ1; MS: m/z
(%): 223(13) [ M+2]+, 222 (100) [M+1]+ ; HRMS calcd for C11H16N3O2:
222.1243; found: 222.1240.
1,3-Dimethyl-1-[(S)-a-cyclohexylethyl)iminomethylurea (16): This com-
pound was prepared from 2 and (S)-(+)-1-cyclohexylethylamine. Color-
less oil (hygroscopic); [a]2D3 =+71.1 (c=2.5 in CHCl3); 1H NMR
(CDCl3): d=0.94 1.02 (m, 2H), 1.19 (d, J=6.6 Hz, 3H), 1.29 1.32 (m,
3H), 1.73 1.83 (m, 5H), 2.91 2.93 (m, 1H), 2.94 (s, 3H), 2.96 (s, 3H),
7.68 (s, 1H), 9.65 ppm (brs, 1H); 13C NMR (CDCl3): d=20.8, 26.5, 26.6,
26.8, 29.5, 30.1, 44.4, 67.2, 150.1, 157.1 ppm; IR (thin film): n˜ =3357,
2919, 2855, 1660, 1539, 1447, 1326, 1077, 996 cmÀ1; MS: m/z (%): 248 (10)
[M+Na]+, 227 (14) [M+2]+, 226 (100) [M+1]+ ; elemental analysis calcd
(%) for C12H23N3O ¥1/3H2O: C 62.30, H 10.31, N 18.16; found: C 62.67,
H 10.33, N 18.40.
1,3-Dimethyl-1-(4-dimethylaminophenyl)iminomethylurea (9): This com-
pound was prepared from
2 and N,N-dimethyl-p-phenylenediamine.
Black gummy syrup (hygroscopic); 1H NMR (CDCl3): d=2.89 (s, 3H),
2.96 (s, 6H), 3.25 (s, 3H), 6.90 (d, J=7.7 Hz, 2H), 7.03(d, J=7.6 Hz,
2H), 8.55 (s, 1H), 9.23ppm (brs, 1H); 13C NMR (CDCl3): d=27.2, 32.7,
41.4, 113.9, 117.0, 145.2, 147.9, 148.9, 156.7 ppm; IR (thin film): n˜ =3333,
2922, 1650, 1513, 1300, 1083, 813 cmÀ1; MS: m/z (%): 236 (16) [M+2]+,
1,3-Dimethyl-1-[(R)-a-phenethyl)iminomethylurea (17): This compound
was prepared from 2 and (R)-a-methylbenzylamine. Colorless oil (hygro-
scopic); [a]2D3 =À49.7 (c=1.5 in CHCl3); 1H NMR (CDCl3): d=1.61 (d,
J=7.0 Hz, 3H), 2.92 (s, 3H), 3.21 (s, 3H), 4.40 4.44 (m, 1H), 7.21 7.23
(m, 5H), 7.84 (s, 1H), 9.42 ppm (brs, 1H); 13C NMR (CDCl3): d=27.1,
30.0, 65.8, 126.5, 127.1, 128.9, 145.8, 151.6, 157.0 ppm; IR (thin film): n˜ =
3340, 2974, 1654, 1534, 1441, 1316, 1071 cmÀ1; MS: m/z (%): 242 (9)
[M+Na]+, 221 (13) [M+2]+, 220 (100) [M+1]+, 130 (69); elemental anal-
ysis calcd (%) for C12H17N3O¥1/8H2O: C 65.06, H 7.85, N 18.97; found: C
65.03, H 8.11, N 18.64.
235 (100) [M+1]+
; HRMS calcd for C12H19N4O: 235.1559; found:
235.1552.
1,3-Dimethyl-1-(3-azidopropyl)iminomethylurea (10): This compound
was prepared from 2 and 3-azidopropylamine; note: this amine was used
as a 0.62m solution in toluene. Colorless oil (hygroscopic); 1H NMR
(CDCl3): d=1.89 1.94 (m, 2H), 3.23 (s, 3H), 3.43 (t, J=6.6 Hz, 2H), 3.49
(t, J=6.6 Hz, 2H), 7.82 (s, 1H), 9.21 ppm (brs, 1H); 13C NMR (CDCl3):
d=26.9, 30.9, 33.9, 152.7, 156.9 ppm; IR (thin film): n˜ =3344, 2944, 2101,
1662, 1534, 1312, 997 cmÀ1; MS: m/z (%): 221 (22) [M+Na]+, 200 (10)
1,3-Dimethyl-1-phenoxyiminomethylurea (18): This compound was pre-
pared from 2 and O-phenylhydroxylamine hydrochloride. White solid
(hygroscopic); m.p. 96 978C; 1H NMR (CD3OD): d=2.89 (s, 3H), 3.30
(s, 3H), 6.99 7.02 (m, 1H), 7.16 (d, J=8.0 Hz, 2H), 7.32 7.35 (m, 2H),
[M+2]+, 199 (100) [M+1]+
;
elemental analysis calcd (%) for
307
Chem. Eur. J. 2004, 10, 303 309
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

M. G. Finn and D. D. DÌaz
FULL PAPER
9.02 ppm (s, 1H); 13C NMR (CD3OD): d=26.7, 29.5, 113.7, 121.4, 129.2,
148.8, 156.6, 160.3ppm; IR (thin film): n˜ =3335, 3061, 2949, 1670, 1545,
1476, 1223, 933 cmÀ1; MS: m/z (%): 230 (100) [M+Na]+, 209 (5) [M+2]+,
208 (39) [M+1]+ elemental analysis calcd (%) for C10H13N3O2: C 57.96,
H 6.32, N 20.28; found: C 57.56, H 6.09, N 19.95.
8.1 Hz, 2H), 8.96 ppm (s, 1H); 13C NMR (CD3OD): d=19.1, 26.5, 30.0,
126.2, 127.9, 163.8, 131.9, 141.3, 145.4, 155.4 ppm; IR (thin film): n˜ =3103,
2777, 2656, 1703, 1572, 1296, 1043 cmÀ1; MS: m/z (%): 271 (28) [M+Na]+
,
249 (37) [M+1]+, 192 (100); elemental analysis calcd (%) for
C12H16N4O2¥0.5H2O: C 54.12, H 6.81, N 18.02; found: C 54.23, H 7.19, N
17.76.
1,3-Dimethyl-1-(tetrahydro-2H-pyran-2-yloxy)iminomethylurea (19): This
compound was prepared from 2 and O-(tetrahydro-2H-pyran-2-yl)hy-
droxylamine. Colorless oil (hygroscopic); 1H NMR (CDCl3): d=1.65
1.77 (m, 4H), 1.85 1.90 (m, 2H), 2.95 (s, 3H), 3.22 (s, 3H), 3.66 3.69 (m,
1H), 3.96 4.00 (m, 1H), 5.20 (s, 1H), 6.65 (brs, 1H), 8.45 ppm (s, 1H);
13C NMR (CDCl3): d=19.9, 25.6, 27.8, 29.2, 32.4, 62.8, 100.7, 148.8,
1,3-Dimethyl-1-(octanoyl)hydrazonomethyl)iminomethylurea (27): This
compound was prepared from 2 and octanoic hydrazide. White solid (hy-
groscopic); m.p. 124 1258C; 1H NMR (CD3OD): d=0.98 (t, J=6.6 Hz,
3H), 1.39 1.42 (m, 8H), 1.68 1.75 (m, 2H), 2.28 (t, J=7.4 Hz, 3H), 2.88
(s, 3H), 3.26 (s, 3H), 8.75 ppm (s, 1H); 13C NMR (CD3OD): d=13.4,
22.7, 26.0, 26.6, 29.1, 29.2, 29.3, 31.9, 34.5, 145.5, 157.1, 170.9 ppm; IR
(thin film): n˜ =3247, 2929, 1658, 1531, 1300 cmÀ1; MS: m/z (%): 279 (100)
[M+Na]+, 258 (4) [M+2]+, 257 (31) [M+1]+ ; elemental analysis calcd
(%) for C12H24N4O2: C 56.52, H 9.40, N 21.46; found: C 56.22, H 9.40, N
21.46.
155.9 ppm; IR (thin film): n˜ =3356, 2949, 1666, 1537, 1348, 1018 cmÀ1
;
;
MS: m/z (%): 238 (97) [M+Na]+, 217 (11) [M+2]+, 216 (100)[M+1]+
elemental analysis calcd (%) for C9H17N3O3: C 50.22, H 7.96, N 19.52;
found: C 49.93, H 7.51, N 19.23.
1,3-Dimethyl-1-methoxyiminomethylurea (20): This compound was pre-
pared from 2 and methoxylamine hydrochloride. White solid (hygroscop-
ic); m.p. 107 1088C; 1H NMR (CD3OD): d=2.85 (s, 3H), 3.15 (s, 3H),
3.79 (s, 3H), 7.25 (brs, 1H), 8.63 ppm (s, 1H); 13C NMR (CD3OD): d=
26.6, 29.5, 61.01, 146.01, 156.9 ppm; IR (thin film): n˜ =3339, 2949, 1642,
1529, 1348, 1058 cmÀ1; MS: m/z (%): 168 (5) [M+Na]+, 147 (6) [M+2]+,
146 (96) [M+1]+, 105 (38), 60 (100); elemental analysis calcd (%) for
C5H11N3O2: C 41.37, H 7.64, N 28.95; found: C 41.64, H 7.76, N 28.59.
Ethyl ester of N’-(1,3-dimethylureidomethylene)hydrazinecarboxylic acid
(28): This compound was prepared from 2 and ethyl carbazate. White
solid (hygroscopic); m.p. 72 738C; 1H NMR (CD3OD): d=1.39 (t, J=
7.4 Hz, 3H), 2.89 (s, 3H), 3.28 (s, 3H), 3.28 3.38 (m, 2H), 7.42 (brs, 1H),
8.75 ppm (s, 1H); 13C NMR (CD3OD): d=13.4, 26.6, 29.2, 46.9, 145.5,
157.0, 170.9 ppm; IR (thin film): n˜ =3307, 2928, 2859, 1653, 1536, 1299,
1077 cmÀ1; MS: m/z (%): 225 (39) [M+Na]+, 204 (8) [M+2]+, 203
(100)[M+1]+ ; elemental analysis calcd (%) for C7H14N4O3: C 41.58, H
6.98, N 27.71; found: C 55.89, H 7.32, N 27.56.
1,3-Dimethyl-1-allyloxyiminomethylurea (21): This compound was pre-
pared from 2 and O-allylhydroxylamine hydrochloride. White solid (hy-
groscopic); m.p. 98 998C; 1H NMR (CD3OD): d=2.85 (s, 3H), 3.15 (s,
3H), 4.48 (d, J=5.9 Hz, 2H), 5.24 (d, J=10.6 Hz, 1H), 5.34 (d, J=
18.7 Hz, 1H), 6.01 6.09 (m, 1H), 8.66 ppm (s, 1H); 13C NMR (CD3OD):
d=26.6, 29.5, 74.7, 116.6, 134.8, 146.2, 156.9 ppm; IR (thin film): n˜ =
3344, 2922, 1647, 1538, 1345, 1047, 938 cmÀ1; MS: m/z (%): 194 (13)
[M+Na]+, 173(10) [ M+2]+, 172 (100) [M+1]+ ; elemental analysis calcd
(%) for C7H13N3O2: C 49.11, H 7.65, N 24.54; found: C 49.46, H 7.29, N
24.09.
1,3-Dimethyl-1-[(5-dimethylamino-1-naphthylsulfonyl)hydrazono]imino-
methylurea (29): This compound was prepared from 2 and dansylhydra-
zine. Yellow solid (hygroscopic); m.p. 167 1688C; 1H NMR (CD3OD):
d=2.76 (s, 3H), 2.95 (s, 6H), 2.97 (s, 3H), 7.34 (d, J =7.7 Hz, 1H), 7.62-
7.68 (m, 2H), 8.30 (d, J=13.9 Hz, 1H), 8.50 (s, 1H), 8.53 (d, J=8.8 Hz,
1H), 8.65 ppm (d, J=8.8 Hz, 1H); 13C NMR (CD3OD): d=26.4, 29.1,
44.8, 115.4, 120.0, 123.3, 128.0, 130.1, 130.5, 130.6, 134.7, 148.0, 152.1,
155.5, 156.8 ppm; IR (thin film): n˜ =3403, 3118, 2945, 1658, 1537, 1465,
1320, 1143 cmÀ1; MS: m/z (%): 386 (38) [M+Na]+, 365 (24) [M+2]+, 3 64
(100) [M+1]+ ; elemental analysis calcd (%) for C16H21N5O3S: C 52.88, H
5.82, N 19.27; S, 8.82; found: C 52.75, H 6.13, N 18.91; S, 8.56.
1,3-Dimethyl-1-tert-butoxyiminomethylurea (22): This compound was
prepared from 2 and O-(tert-butyl)hydroxylamine hydrochloride. White
solid (hygroscopic); m.p. 70 718C; 1H NMR (CD3OD): d=1.32 (s, 9H),
2.86 (s, 3H), 3.18 (s, 3H), 8.55 ppm (s, 1H); 13C NMR (CD3OD): d=
25.2, 25.4, 28.3, 76.3, 143.3, 155.5 ppm; IR (thin film): n˜ =3469, 3195,
3026, 1722, 1602 cmÀ1; MS: m/z (%): 210 (5) [M+Na]+, 189 (9) [M+2]+,
188 (100) [M+1]+ ; elemental analysis calcd (%) for C7H11N3O: C 54.89,
H 7.24, N 27.43; found: C 54.57, H 7.25, N 27.80.
1,3-Dimethyl-1-(methylhydrazono)iminomethylurea (30): This compound
was prepared from 2 and methylhydrazine. Gummy syrup (hygroscopic);
1H NMR (CD3OD): d=2.90 (s, 3H), 3.09 (s, 3H), 3.16 (s, 3H), 6.13 (brs,
1H), 8.67 ppm (s, 1H); 13C NMR (CD3OD): d=26.3, 31.9, 42.4, 145.6,
161.5 ppm; IR (thin film): n˜ =3357, 2979, 1627, 1571, 1413, 1297,
1039 cmÀ1; MS: m/z (%): 167 (10) [M+Na]+, 146 (8) [M+2]+, 145 (100)
[M+1]+ ; elemental analysis calcd (%) for C5H12N4O: C 41.65, H 8.39, N
38.86; found: C 41.78, H 8.79, N 38.99.
1,3-Dimethyl-1-benzyloxyiminomethylurea (23): This compound was pre-
pared from 2 and O-benzylhydroxylamine. White solid (hygroscopic);
m.p. 84 858C; 1H NMR (CD3OD): d=2.84 (s, 3H), 3.13 (s, 3H), 5.01 (s,
2H), 7.35 7.43 (m, 5H), 8.67 ppm (s, 1H); 13C NMR (CD3OD): d=26.6,
29.6, 75.9, 127.7, 128.3, 128.4, 138.3, 146.5, 156.8 ppm; IR (thin film): n˜ =
3370, 2931, 1652, 1527, 1350, 1036 cmÀ1; MS: m/z (%): 244 (35) [M+Na]+
, 223(12) [ M+2]+, 222 (100) [M+1]+ ; elemental analysis calcd (%) for
C11H15N3O2: C 59.71, H 6.83, N 18.99; found: C 59.62, H 6.64, N 18.64.
1,3-Dimethyl-1-[(2,4,6-trichlorophenyl)hydrazono]iminomethylurea (31):
This compound was prepared from 2 and 2,4,6-trichlorophenylhydrazine.
Beige solid (hygroscopic); m.p. 141 1428C; 1H NMR (CD3OD): d=2.88
(s, 3H), 3.21 (s, 3H), 7.45 (s, 2H), 8.67 ppm (s, 1H); 13C NMR (CD3OD):
d=26.4, 29.9, 126.9, 127.0, 128.7, 128.8, 140.2, 145.0, 157.2 ppm; IR (thin
film): n˜ =3331, 3230, 2940, 1677, 1561, 1441, 1352, 1268, 1074 cmÀ1; MS:
m/z (%): 331 (18) [M+Na]+, 310 (88) [M+2]+, 309 (100) [M+1]+, 261
(50); elemental analysis calcd (%) for C10H11Cl3N4O: C 38.80, H 3.58; Cl,
34.36, N 18.10; found: C 38.62, H 3.55; Cl, 33.98, N 18.53.
1,3-Dimethyl-1-trityloxyiminomethylurea (24): This compound was pre-
pared from 2 and O-tritylhydroxylamine. White solid (hygroscopic); m.p.
100 1018C; 1H NMR (CD3OD): d=2.75 (s, 3H), 2.96 (s, 3H), 7.30 7.43
(m, 15H), 8.66 ppm (s, 1H); 13C NMR (CD3OD): d=26.4, 30.3, 90.7,
127.4, 129.3, 144.8, 146.3, 156.8 ppm; IR (thin film): n˜ =3351, 3061, 2948,
1669, 1537, 1283, 977 cmÀ1; MS: m/z (%): 396 (100) [M+Na]+, 375 (3)
[M+2]+, 374 (54) [M+1]+ ; elemental analysis calcd (%) for C23H23N3O2:
C 73.97, H 6.21, N 11.25; found: C 74.07, H 6.23, N 11.30.
1,3-Dimethyl-1-[(furan-2-carbonyl)hydrazono]iminomethylurea (32): This
compound was prepared from 2 and 2-furoic acid hydrazide. White solid
(hygroscopic); m.p. 138 1398C; 1H NMR (CD3OD): d=2.90 (s, 3H), 3.31
(s, 3H), 6.69 (brs, 1H), 7.28 (brs, 1H), 7.78 (brs, 1H), 8.98 ppm (brs,
1H); 13C NMR (CD3OD): d=26.6, 29.3, 112.0, 115.0, 145.6, 146.8, 147.0,
156.1, 157.0 ppm; IR (thin film): n˜ =3374, 2968, 2605, 2493, 1620, 1539,
1302, 1177, 1029 cmÀ1; MS: m/z (%): 247 (100) [M+Na]+, 225 (10)
[M+1]+ ; elemental analysis calcd (%) for C9H12N4O3: C 48.21, H 5.39, N
24.99; found: C 48.63, H 5.72, N 24.59.
1,3-Dimethyl-1-(benzoyl-hydrazonomethyl)iminomethylurea (25): This
compound was prepared from 2 and benzhydrazide. White solid (hygro-
scopic); m.p. 155 1568C; 1H NMR (CD3OD): d=2.91 (s, 3H), 3.33 (s,
3H), 7.55 7.58 (m, 2H), 7.62 7.65 (m, 1H), 7.92 7.94 (m, 2H), 8.98 ppm
(s, 1H); 13C NMR (CD3OD): d=26.6, 29.4, 127.5, 128.7, 131.9, 133.5,
146.8, 157.0, 165.5 ppm; IR (thin film): n˜ =3343, 2973, 1657, 1621, 1529,
1296 cmÀ1; MS: m/z (%): 257 (100) [M+Na]+, 236 (5) [M+2]+, 235 (40)
[M+1]+ ; elemental analysis calcd (%) for C11H14N4O2¥0.5H2O: C 54.31,
H 6.22, N 23.03; found: C 54.75, H 6.31, N 22.82.
1,3-Dimethyl-1-[2-hydroxybenzoyl)-hydrazono]iminomethylurea
(33):
This compound was prepared from 2 and salicylhydrazide. Beige solid
(hygroscopic); m.p. 184 1858C; 1H NMR (CD3OD): d=2.90 (s, 3H), 3.33
(s, 3H), 6.99 7.01 (m, 2H), 7.47 (m, 1H), 7.88 (d, J=7.7 Hz, 1H),
8.98 ppm (s, 1H); 13C NMR (CD3OD): d=26.6, 29.3, 115.2, 117.5, 119.3,
127.8, 133.9, 147.0, 157.0, 160.0, 166.0 ppm; IR (thin film): n˜ =3315, 3231,
3053, 2921, 1650, 1589, 1521, 1296, 1215 cmÀ1; MS: m/z (%): 273(89)
[M+Na]+, 251 (13) [M+1]+, 65 (100); elemental analysis calcd (%) for
1,3-Dimethyl-1-(4-methylbenzoyl-hydrazonomethyl)iminomethylurea
(26): This compound was prepared from 2 and p-toluic hydrazide. White
solid (hygroscopic); m.p. 142 1438C; 1H NMR (CD3OD): d=2.48 (s,
3H), 2.90 (s, 3H), 3.33 (s, 3H), 7.38 (d, J=8.5 Hz, 2H), 7.83(d, J=
308
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 303 309

Formamidine Ureas
303 309
C11H14N4O3¥0.5H2O: C 49.25, H 6.01, N 20.88; found: C 49.69, H 5.98, N
20.53.
e) L. G. Costa, D. S. Wu, G. Olibet, S. D. Murphy, Neurotoxicol. Ter-
atol. 1989, 11, 405 411.
[5] S. A. Aziz, C. O. Knowles, Nature 1973, 242, 417 418.
[6] G. K. Yim, M. P. Holsapple, W. R. Pfister, R. M. Hollingsworth, Life
Sci. 1978, 23, 2509 2515.
[7] a) D. I. Arnold, F. A. Cotton, J. H. Matonic, C. A. Murillo, Polyhe-
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Chem. 1997, 134, 376 381.
[8] F. Bˆhme, C. Kunert, H. Komber, D. Voigt, P. Friedel, M. Khodja,
H. Wilde, Macromolecules 2002, 35, 4233 4237, and references
therein.
[9] a) A. I. Meyers, R. Hutchings, Heterocycles 1996, 42, 475 478;
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[10] S. Vincent, S. Mons, L. Lebeau, C. Mioskowski, Tetrahedron Lett.
1997, 38, 7527 7530.
N-{(1S)-1-benzyl-2-{(2E)-2-
{{methyl[(methylamino)carbonyl]amino}methyllene}hydrazine}-2-oxoe-
thyl}acetamide (34): This compound was prepared from the freebase
form of 2 and acetyl-l-phenylalanine hydrazine. It was purified by prepa-
rative reversed-phase HPLC using a Polaris C18 A5m column, eluting
with a 0 100% gradient of CH3CN in water. White solid; m.p. 109
1108C; [a]2D3 =+28.3( c=0.12 in H2O); H NMR (D2O): d=1.94 (s, 3H),
1
2.74 (s, 3H), 3.03 (dd, J=7.4, 2.7 Hz, 2H), 3.08 (s, 3H), 4.43 (t, J=
8.1 Hz, 1H), 7.22?7.33 (m, 5H), 8.33 ppm (s, 1H); 13C NMR (D2O): d=
21.9, 27.1, 29.8, 37.7, 54.8, 127.6, 129.1, 129.6, 136.5, 148.9, 157.8, 168.9,
174.3ppm; IR (thin film): n˜ =3276, 3067, 1666, 1630, 1525, 1296 cmÀ1
MS: m/z (%): 342 (34) [M+Na]+, 321 (18) [M+2]+, 320 (100) [M+1]+
HRMS calcd for C15H22N5O3Na: 342.1537; found: 342.1544.
;
;
[11] S. J. Benkovic, T. H. Barrows, P. R. Farina, J. Am. Chem. Soc. 1973,
95, 8414 8420.
[12] P. S. Furth, M. S. Reitman, A. F. Cook, Tetrahedron Lett. 1997, 38,
5403 5406, and references therein.
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We thank The Skaggs Institute for Chemical Biology for support of this
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Received: July 25, 2003[F5838]
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