1-acylsemicarbazides by ring opening of iminodiaziridines with carboxylic acids: Novel, expeditious access to the azapeptide motif

Article abstract of DOI:10.1055/s-0030-1257868

Carboxylic acids react rapidly and quantitatively with iminodiaziridines to afford 1,2,4-trisubstituted 1-acylsemicarbazides in a multistep sequence. In this way, a carboxy group is readily converted into an azapeptide motif. Broad signals in high-field H and C NMR spectra recorded for the products are indicative of dynamic processes. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1257868

3358
PAPER
1-Acylsemicarbazides by Ring Opening of Iminodiaziridines with Carboxylic
Acids: Novel, Expeditious Access to the Azapeptide Motif
N
ovel Access toth
e
e
A
zapepti
l
de Mot
m
if ut Quast,*1 Edeltraud Schmitt, Karl-Heinz Ross
Institut für Organische Chemie der Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
Fax +49(541)8141935; E-mail: hquast@uni-osnabrueck.de
Received 11 March 2010
Dedicated to Professor Manfred Schulz on the occasion of his 80th birthday
In the course of our initial studies on iminodiaziridines 3,6
Abstract: Carboxylic acids react rapidly and quantitatively with
iminodiaziridines to afford 1,2,4-trisubstituted 1-acylsemicarba-
zides in a multistep sequence. In this way, a carboxy group is readily
we found that, surprisingly, they could not be titrated with
0.1 M perchloric acid in acetic acid,8 even though their
structure would suggest that they are sufficiently basic.
1
converted into an azapeptide motif. Broad signals in high-field H
and 13C NMR spectra recorded for the products are indicative of dy- This result was explained in terms of formation from 3 of
namic processes.
non-basic compounds, namely, 1-acylsemicarbazides 5,
by reaction with acetic acid (Scheme 1). We have now
taken up these early observations and report here on the
synthesis of 1-acylsemicarbazides 5 from iminodiaziri-
dines 3.
Key words: azapeptides, heterocycles, hydrolysis, ring-opening,
semicarbazides
Iminoaziridines 2 transform carboxylic acids 1 into a-acyl-
amino amides 4 in a very rapid and efficient sequence
(Scheme 1)2 that is driven by stepwise relief of strain and
resembles click reactions.3 Therefore, 2 represents a use-
ful source for the peptide motif in 4. However, in most
cases, this transformation is more conveniently carried out
with the help of the Ugi reaction.4 Being aza-analogues of
2, iminodiaziridines 3 may be expected to produce the
azapeptide motif in 1-acylsemicarbazides 5 in a similar
sequence; however, this is not paralleled by a Ugi four-
component condensation. Since azapeptides constitute an
important class of peptidomimetics,5 we were intrigued by
the prospect of opening a novel route to these compounds
by means of 3.
The parent iminodiaziridine and monoalkyliminodiaziri-
dines are elusive intermediates that are generated by base-
induced 1,3-elimination from N-chloroguanidines or N-
hydroxyguanidine O-sulfonic acids and are immediately
hydrolyzed to semicarbazides under the reaction condi-
tions.9 To probe the sensitivity to water of the starting tri-
alkyl-substituted iminodiaziridines 3, we briefly studied
the hydrolysis of 3a and 3b (Scheme 2).
The 1H NMR spectra of solutions of 3a in dioxane–water
(20:1) – a mixture that allowed us to conveniently monitor
the hydrolysis by using 1H NMR spectroscopy – remained
unchanged at room temperature for one to two days. Heat-
ing at reflux temperature for approximately two hours re-
sulted in complete hydrolysis of 3a to afford
semicarbazide 6a, which was isolated in 69–77% yield as
colorless, low-melting crystals.10 Addition of small
amounts of hydrochloric acid (0.01 equiv) accelerated the
hydrolysis of 3a as expected, whereas, in the presence of
KOH (0.01 equiv), 80% of 3a survived for two hours in a
boiling solution.
O
N
R
OH
R
N
+
X
N
H
O
N
X
O
1
2, X = CH
3, X = N
4, X = CH
5, X = N
When heating of the dioxane–water solution at reflux was
continued for two to three days, di(tert-butyl)urea (10)
was isolated (78% yield) along with a solution of di(tert-
butyl)hydrazine (9a). Oxidation of the latter by stirring
under air gave a solution of the azo compound 1111 in 60–
70% yield (based on 3a), as determined by UV/Vis and 1H
NMR spectroscopic analysis. The urea 10 arises from iso-
cyanate 8, whose appearance as intermediate was corrob-
orated by the observation of a weak/medium isocyanate
band in the IR spectra recorded for 6a.12 These results of-
fer unequivocal proof for the structure of 6a and confirm
the tendency of sterically congested semicarbazides to
equilibrate with isocyanates and hydrazines.10a
H
R
O
N
R
O
N
O
X
O
N
X
HN
Scheme 1
Iminodiaziridines 3 may be synthesized in high yields by
cyclization of 1,2,3-trisubstituted guanidines using tert-
butyl hypochlorite and potassium tert-butoxide,6,7 and by
base-mediated 1,3-elimination of sulfuric acid from 1,2,3-
trisubstituted hydroxyguanidine O-sulfonic acids.7
The asymmetric iminodiaziridine 3b hydrolyzed faster
than 3a. Acid-catalyzed hydrolysis at room temperature
SYNTHESIS 2010, No. 19, pp 3358–3362
Advanced online publication: 22.07.2010
DOI: 10.1055/s-0030-1257868; Art ID: T05910SS
x
x.
x
x
.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

PAPER
Novel Access to the Azapeptide Motif
3359
We note that high-field 1H and 13C NMR spectra recorded
for 5c, 5e, and 5f show broadening of signals due to dy-
namic processes with rates comparable to the NMR time-
scales. In the case of 5c and 5e, which both possess the 1-
benzoyl-1,2-di(tert-butyl) moiety, this process involves
the tert-butyl group, the protons of which resonate at un-
usually high field. In contrast, the tert-butyl signals of 5b
and 5d, which differ from 5c and 5e only by the type of
the acyl group, exhibit neither broadening nor unusual
high-field NMR shifts. This suggests that the phenome-
non observed for 5c and 5e can be attributed to the pres-
ence of the benzoyl group: If the two tert-butyl groups at
the N–N bond adopt the trans position, the (2)-tert-butyl
group lies in the shielding cone of the benzene ring and
experiences hindered rotation.
Nt-Bu
N
H2O
H2O
(3b)
t-BuHN
N
t-Bu
R
O
O
3
NHR
N
NHt-Bu
t-BuHN
N
(9b)
Me
t-Bu
7
6
+
t-Bu N=C=O
t-BuHN NHR
8
9
(9a) O2
O
N
t-Bu
t-BuHN
NHt-Bu
t-Bu
N
10
11
6a, 9a: R = t-Bu; 6b, 9b: R = Me
Scheme 2
Conformations and rotational barriers for the N(1)–N(2)
and N(2)–C(3) bonds of Ac-(NMe)-azaAla-NHMe (5,
where R1 = R2 = R3 = R4 = Me) have been examined by
using ab initio MO and DFT methods. Four minima were
located at the B3LYP/6-31G* level of theory. The confor-
mation of lowest energy was found to be one of the two
that involve an intramolecular hydrogen bond between
N(1) and N(4).15 In the high-field NMR spectra of 5f,
which closely resembles Ac-(NMe)-azaAla-NHMe,
strong broadening was observed for the 1H and 13C NMR
signals arising from one of the methyl groups attached to
the N–N bond and for the benzoyl carbonyl signal. These
phenomena indicate that it may be feasible to investigate
the conformational mobilities of 5 by high-field NMR ex-
periments.
afforded a mixture of 6b and 7 (3:2). In a solution of this
mixture in carbon tetrachloride, 6b rearranged slowly and
quantitatively to the less encumbered isomer 7. The
analogous rearrangement of 2,4- into 1,4-disubstituted
semicarbazides was discovered by Busch and Frey more
than 100 years ago.13
In solutions in inert solvents at room temperature, the
symmetrically substituted iminodiaziridines 3a, 3c, and
3d reacted instantaneously with carboxylic acids, which
were employed in small excess, to afford colorless, crys-
tallized 1:1 adducts with almost quantitative yields in
most cases (Equation 1, Table 1). The low yield of 5f is
certainly due to the unsatisfactory generation of the tri-
methyl compound 3d,7 which was not isolated but used in
solution, rather than to an inefficient reaction of 3d with
benzoic acid. Reactions of the asymmetrically substituted
iminodiaziridine 3b with carboxylic acids were not stud-
ied because mixtures of isomeric products could be
anticipated, as suggested by the course of the hydrolytic
ring opening of 3b (Scheme 2).
R4
R2
N
O
N
R1
OH
R1
R4
N
N
H
O
O
R3
N
N
R2
3a,c,d
R3
1
5
Equation 1
The 1-acylsemicarbazide structure of these 1:1 adducts 5
was based on elemental analyses, spectroscopic evidence,
and on the absence of basicity. Thus far, the preparation
of 1,2,4-trisubstituted 1-acylsemicarbazides has been de-
scribed only in a patent.14
The addition of carboxylic acids 1 to iminodiaziridines 3
provides expeditious access to the azapeptide motif. Its
usefulness in azapeptide chemistry may be further height-
ened by: (i) employing (arylimino)diaziridines and solu-
tions of 3 instead of pure, isolated compounds;7 (ii)
Table 1 Yields and Melting Points of 1-Acyl-1,2,4-trialkylsemicarbazides 5, and Solvents Used for Recrystallization
Product
5a
Starting materials R1
R2
R3
R4
Yield (%)
Mp (°C)
94–95
Solvent
1a, 3a
1b, 3a
1c, 3a
1d, 3a
1c, 3c
1c, 3da
H
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
t-Bu
t-Bu
t-Bu
t-Bu
Me
96
hexane
5b
Me
95
89–90
hexane
5c
Ph
96
142–144
173.5–174
170–171
92–93.5
benzene/cyclohexane
benzene/cyclohexane
benzene
5d
(E)-CH=CHPh
quant.
70
5e
Ph
Ph
5f
Me
25
benzene/hexane
a Due to its instability in pure form, 3d was not isolated but kept in solution. Therefore, the yield of 5f is based on the precursor to 3d, i.e.,
N,N¢,N¢¢-trimethyl-N-hydroxyguanidine O-sulfonic acid.7
Synthesis 2010, No. 19, 3358–3362 © Thieme Stuttgart · New York

3360
H. Quast et al.
PAPER
(0.65 g, 65%, mp 65–97 °C) consisting of 6b and 7 (3:2, 1H NMR
analysis).
removal of tert-butyl groups from 5a–e with concentrated
hydrochloric acid as reported for other semicarba-
zides,10c,16 and (iii) developing substituents for 3 that al-
low N-deprotection of 5 by established procedures, e. g.,
allyl groups.17,18
2,4-Di(tert-butyl)-1-methylsemicarbazide (6b)
1H NMR (90 MHz, CCl4): d = 1.24, 1.39 (s, 9 H, t-Bu), 2.54 (d,
J = 5.5 Hz, 3 H, CH3), 3.81 (q, J = 5.5 Hz, 1 H, NH), 6.2 (br, 1 H,
NH); d (7) = 1.10, 1.26 (s, 9 H, t-Bu), 2.9 (br, 1 H, NH), 3.01 (s, 3 H,
CH3), 6.3 (br, 1 H, NH).
1H and 13C NMR spectra were recorded with Bruker spectrometers
and standardized relative to internal TMS. 13C NMR assignments
were supported by DEPT spectra. IR spectra were taken with a
Beckman IR 10 spectrometer and calibrated with polystyrene. UV/
Vis spectra were recorded with a Varian Cary 17 spectrometer. EI
MS (70 eV) measurements were performed with a Varian MAT
SM1-BH spectrometer, and the signals were recorded with a Varian
MAT Data Norm system. Equivalent masses of bases were deter-
mined by titration with 0.1 M perchloric acid in acetic acid.8 The im-
inodiaziridines 3a,6 3b,7 3c,6 3d,7 and the authentic compounds
9a,10a 10,10a and 1119 were prepared as described.
MS: m/z (%) = 201 (1) [M]+, 145 (6), 102 (41), 89 (12), 87 (12), 57
(30), 46 (100).
1,4-Di(tert-butyl)-2-methylsemicarbazide (7)
A solution of a mixture of 6b and 7 (2:3) in CCl4 was kept at r.t. for
1
11 d, while the rearrangement 6b→7 was monitored by H NMR
spectroscopy. Distillation of the solvent in vacuo and recrystalliza-
tion of the residue from benzene–pentane gave 7.
Colorless crystals; mp 116–117.5 °C.
IR (CCl4): 3395 (m), 1672 (s).
1H NMR (600 MHz, CDCl3): d = 1.12 [s, 9 H, (1)-t-Bu], 1.32 [s,
9 H, (4)-t-Bu], 2.70 [br, 1 H, N(1)H], 3.12 (s, 3 H, CH3), 6.56 [br,
1 H, N(4)H].
13C NMR (151 MHz, CDCl3): d = 28.6, 29.3 [(CH3)3], 39.0 (CH3),
49.7, 55.5, 160.6 (q C).
1,2,4-Tri(tert-butyl)semicarbazide (6a)
A stirred solution of 3a (2.26 g, 10 mmol) in a mixture of dioxane
(20 mL, distilled over Na) and H2O (1 mL) was heated at reflux for
2 h; the conversion was monitored by 1H NMR spectroscopy [tert-
butyl signals: d (3a) = 1.11, 1.26, 1.28 ppm; d (6a) = 0.98, 1.17, 1.30
ppm; d (9a) = 0.99 ppm; d (8) = 1.21 ppm; tert-butylamine: d = 1.10
ppm]. The solvent was distilled off in vacuo, and the remaining oil
crystallized when kept in a desiccator to afford long, colorless
needles (1.68 g, 69%; mp 37–40 °C). Repeated recrystallization
from pentane at low temperature raised the mp to 42–43 °C.
Anal. Calcd for C10H23N3O: C, 59.66; H, 11.52; N, 20.87. Found: C,
59.75; H, 11.57; N, 20.80.
1-Acyl-1,2,4-trialkylsemicarbazides (5) from Iminodiaziridines
(3) and Carboxylic Acids (1); General Procedure
Iminodiaziridine 3 (10 mmol) was added dropwise to a stirred solu-
tion of 1 (12 mmol) in anhydrous Et2O (20–50 mL). Stirring was
continued for 2 h; then solid K2CO3 was added, and the mixture was
stirred for 3 h, followed by filtration and distillation of the solvent
in vacuo to afford colorless crystals.
When aq HCl (0.1 M, 1 mL) instead of H2O was employed, 3a was
hydrolyzed during 0.5 h and gave 6a in with a yield of 77% (mp 37–
40 °C).
IR (CCl4): 3460 (m), 3260 (w), 1680 (s) [2250 (m, t-Bu–NCO) 812]
cm–1.
1H NMR (60 MHz, CCl4): d = 0.96 [s, 9 H, (1)-t-Bu], 1.15, 1.32 (s,
9 H, t-Bu), 4.02 [br, 1 H, N(1)H], 5.02 [br, 1 H, N(4)H].
1,2,4-Tri(tert-butyl)-1-formylsemicarbazide (5a)
Following the general procedure, 3a and formic acid gave a color-
less solid (2.61 g, 96%; mp 91.5–93 °C). Recrystallization from
hexane gave colorless crystals (mp 94–95 °C), consisting of 5a
and a second compound (5a¢), which was probably an isomer of 5a
[5a/5a¢ = 4:1 in CCl4 (1H NMR analysis); 1:1 in DMSO-d6].
Anal. Calcd for C13H29N3O: C, 64.15; H, 12.01; N, 17.26 (equiv
mass: 243.4). Found: C, 63.93; H, 11.58; N, 17.60 (equiv mass: 243,
241).
N,N¢-Di(tert-butyl)urea (10) and 1,2-Di(tert-butyl)diazene (11)
As described in the preceding experiment, a solution of 3a (2.26 g,
10 mmol) in a mixture of dioxane (20 mL) and H2O (1 mL) was
heated at reflux for 63 h, followed by distillation of the solvent in
vacuo into a trap cooled with dry ice, finally at 10–4 Torr, to afford
a colorless solid (675 mg, 78%, mp 228–231 °C, sealed tube). Re-
crystallization from CHCl3–CCl4 gave colorless crystals (mp 243–
244 °C, sealed tube), which were identical to 10 (mp, IR, 1H NMR
analyses).
IR (CCl4): 3470 (w), 1682 (s) cm–1.
1H NMR (90 MHz, CCl4): d (5a) = 1.30, 1.42, 1.44 (s, 9 H, t-Bu),
4.68 (br, 1 H, NH), 7.97 (s, 1 H, CHO); d (5a¢) = 1.27, 1.38, 1.48 (s,
9 H, t-Bu).
MS: m/z (%) = 271 (6) [M]+, 215 (3), 173 (47), 157 (7), 116 (96),
101 (82), 60 (76), 57 (100).
Anal. Calcd for C14H29N3O2: C, 61.96; H, 10.77; N, 15.48. Found:
C, 61.82; H, 10.28; N, 15.10.
The solution of 9a, obtained in the cold trap, was stirred for 3 d at
r.t. with exclusion of light, in the presence of air. The yield of 11
(60–70%) was determined by addition of known amounts of hexa-
methylbenzene as standard to aliquots of the solution and recording
1H NMR spectra.20 UV/Vis spectra of the solution allowed the
yield of 11 to be calculated as 66% [11: lmax = 367 nm, ε =
13.4 Lmol–1cm–1 (dioxane–H2O, 20:1); lmax = 368 nm, ε =
12.3 Lmol–1cm–1 (saturated hydrocarbons)21].
1-Acetyl-1,2,4-tri(tert-butyl)semicarbazide (5b)
Obtained from 3a and acetic acid (2.71 g, 95%; mp 87–88 °C). Re-
crystallization from hexane gave colorless crystals (mp 89–90 °C).
IR (CCl4): 3470 (w), 1670 (s) cm–1.
1H NMR (600 MHz, CDCl3): d = 1.34, 1.49, 1.50 (s, 9 H, t-Bu), 2.13
(s, 3 H, CH3), 4.83 (br, 1 H, NH).
13C NMR (151 MHz, CDCl3): d = 24.2 (CH3), 28.4, 29.2, 29.3
[(CH3)3], 50.9 [q C, (4)-t-Bu], 61.2, 62.3 (q C), 155.8 [C(3)=O],
174.8 (C=O).
MS: m/z (%) = 285 (2) [M]+, 229 (2), 189 (14), 143 (34), 130 (73),
115 (100), 87 (24), 74 (81), 57 (75).
2,4-Di(tert-butyl)-1-methylsemicarbazide (6b) and 1,4-Di(tert-
butyl)-2-methylsemicarbazide (7)
A solution of 3b (0.92 g, 5 mmol) in a mixture of Et2O (25 mL) and
aq HCl (0.1 M, 0.5 mL) was stirred at r.t. for 15 min, followed by
neutralization with aq KOH (0.1 M, 0.5 mL), extraction with H2O
(2 × 25 mL), drying with K2CO3, distillation of the solvent in vacuo,
and drying of the residue at 0.1 Torr, and afforded colorless crystals
Anal. Calcd for C15H31N3O2: C, 63.12; H, 10.95; N, 14.72. Found:
C, 63.08; H, 10.74; N, 14.79.
Synthesis 2010, No. 19, 3358–3362 © Thieme Stuttgart · New York

PAPER
Novel Access to the Azapeptide Motif
IR (Nujol): 3345 (s), 1685 (s), 1637 (s) cm–1.
1H NMR (600 MHz, CDCl3): d = 2.87 (br, 3 H, CH3), 2.91 [d,
J = 4.7 Hz, 3 H, (4)-Me], 3.20 (s, 3 H, CH3), 5.38 (br, 1 H, NH),
7.36–7.40 (m, 2 H), 7.44–7.48 (m, 1 H), 7.50–7.53 (m, 2 H).
13C NMR (151 MHz, CDCl3): d = 27.5 [(4)-Me], 33.0 (br, Me), 33.6
(slightly broadened, Me), 127.2, 128.3 (o-, m-CH), 131.0 (p-CH),
133.7 (i-C), 157.3 [C(3)=O], 173.6 (br, C=O).
3361
1-Benzoyl-1,2,4-tri(tert-butyl)semicarbazide (5c)
Obtained from 3a and benzoic acid (3.34 g, 96%; mp 140–
141.5 °C). Recrystallization from benzene–cyclohexane gave col-
orless crystals (mp 142–144 °C).
IR (CCl4): 3470 (w), 1680 (m), 1658 (s) cm–1.
1H NMR (600 MHz, CDCl3): d = 1.06 [br s, 9 H, (1)-t-Bu], 1.47 [s,
9 H, (4)-t-Bu], 1.64 [slightly broadened s, 9 H, (2)-t-Bu], 5.26 (br,
1 H, NH), 7.31–7.35 (m, 2 H), 7.36–7.40 (m, 1 H), 7.63–7.67 (m,
2 H).
Anal. Calcd for C11H15N3O2: N, 18.99. Found: N, 19.20.
13C NMR (151 MHz, CDCl3): d = 28.5 [(CH3)3], 28.8 [br, (CH3)3],
29.2 [(CH3)3], 51.3 [q C, (4)-t-Bu], 61.5 (br, q C), 63.2 (q C), 127.3,
128.0 (o-, m-CH), 130.0 (p-CH), 138.0 (i-C), 156.2 [C(3)=O], 174.0
[C=O].
MS: m/z (%) = 347 (4) [M]+, 292 (6), 243 (29), 218 (21), 192 (84),
178 (100), 163 (23), 144 (23), 136 (57), 105 (97).
Acknowledgment
We express our gratitude to Mrs. Elfriede Ruckdeschel and Dr.
Matthias Grüne, University of Würzburg, for measuring the high-
field NMR spectra, and to Dr. Gerda Lange for recording the mass
spectra. Financial support by the Deutsche Forschungsgemein-
schaft and the Fonds der Chemischen Industrie, Frankfurt am Main,
is gratefully acknowledged.
Anal. Calcd for C20H33N3O2: C, 69.13; H, 9.57; N, 12.09. Found: C,
69.09; H, 9.18; N, 11.76.
1,2,4-Tri(tert-butyl)-1-[(E)-cinnamoyl]semicarbazide (5d)
Obtained from 3a and (E)-cinnamic acid (3.73 g, quant.; mp 173–
174 °C). Recrystallization from benzene–cyclohexane gave color-
less crystals (mp 173.5–174 °C).
References
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IR (CCl4): 3460 (w), 1678 (m), 1660 (s), 1618 (m) cm–1.
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(br, 1 H, NH), 6.82, 7.66 (d, J = 15.6 H, 1 H, CH=CH), 7.34–7.40
(m, 3 H), 7.47–7.50 (m, 2 H).
13C NMR (151 MHz, CDCl3): d = 28.4, 29.217, 29.225 [(CH3)3],
51.0 [q C, (4)-tBu], 61.8, 62.6 (q C), 119.6, 142.9 (CH=CH), 127.9,
129.0 (o-, m-CH), 130.0 (p-CH), 134.9 (i-C), 156.2 [C(3)=O], 170.3
(C=O).
MS: m/z (%) = 373 (2) [M]+, 274 (35), 244 (5), 218 (64), 203 (49),
188 (10), 162 (18), 161 (17), 143 (83), 131 (100), 103 (20), 87 (32),
57 (54).
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Chem. Ber. 1970, 103, 1234.
Anal. Calcd for C22H35N3O2: C, 70.74; H, 9.44; N, 11.25. Found: C,
71.19; H, 9.56; N, 11.21.
1-Benzoyl-1,2-di(tert-butyl)-4-methylsemicarbazide (5e)
Obtained from 3c and benzoic acid (2.14 g, 70%; mp 164–167 °C).
Recrystallization from benzene gave colorless crystals (mp 170–
171 °C).
IR (CCl4): 3485 (w), 1678 (m), 1656 (s) cm–1.
1H NMR (600 MHz, CDCl3): d = 1.07 [br s, 9 H, (1)-t-Bu], 1.62 [s,
9 H, (2)-t-Bu], 2.95 [d, J = 4.7 Hz, 3 H, (4)-CH3], 5.26 (br, 1 H,
NH), 7.32–7.36 (m, 2 H), 7.36–7.40 (m, 1 H), 7.49–7.52 (m, 2 H).
13C NMR (151 MHz, CDCl3): d = 27.0 (CH3), 28.4, 28.6 [(CH3)3],
61.9 (br, q C), 63.4 (q C), 127.1, 128.2 (o-, m-CH), 130.0 (p-CH),
137.9 (i-C), 158.2 [C(3)=O], 173.9 [C=O].
(7) Quast, H.; Ross, K.-H.; Philipp, G.; Hagedorn, M.; Hahn, H.;
Banert, K. Eur. J. Org. Chem. 2009, 3940.
(8) Huber, W. Titrations in Nonaqueous Solvents; Academic
Press: New York and London, 1967.
MS: m/z (%) = 305 (2) [M]+, 249 (18), 219 (2), 218 (2), 192 (37),
(9) (a) Ohme, R.; Preuschhof, H. Justus Liebigs Ann. Chem.
1969, 721, 25. (b) Heesing, A.; Imsieke, G.; Maleck, G.;
Peppmöller, R.; Schulze, H. Chem. Ber. 1970, 103, 539.
(10) For 1,2,4-trialkylsemicarbazides, see: (a) Greene, F. D.;
Stowell, J. C.; Bergmark, W. R. J. Org. Chem. 1969, 34,
2254. (b) Zinner, G.; Dörschner, K. Arch. Pharm.
(Weinheim, Ger.) 1973, 306, 35. (c) Jensen, K. A. Acta
Chem. Scand., Ser. B 1977, 31, 145. (d) Ziman, S. D.
J. Heterocycl. Chem. 1979, 16, 895. (e) Vanderesse, R.;
Grand, V.; Limal, D.; Vicherat, A.; Marraud, M.; Didierjean,
C.; Aubry, A. J. Am. Chem. Soc. 1998, 120, 9444.
(11) (a) Greene, F. D.; Stowell, J. C. J. Am. Chem. Soc. 1964, 86,
3569. (b) For the trans-configuration of 11, see: Mill, T.;
Stringham, R. S. Tetrahedron Lett. 1969, 1853.
177 (28), 162 (19), 136 (34), 105 (100), 77 (19), 57 (23).
Anal. Calcd for C17H27N3O2: C, 66.85; H, 8.91; N, 13.76. Found: C,
67.14; H, 8.31; N, 13.74.
1-Benzoyl-1,2,4-trimethylsemicarbazide (5f)
Obtained from benzoic acid and a solution of 3d in Et2O, which was
prepared from a suspension of N,N¢,N¢¢-trimethyl-N-hydroxyguani-
dine O-sulfonic acid (1.97 g, 10 mmol) in Et2O (30 mL) and aq.
KOH (50%, 30 mL).7 The resulting oil crystallized on treatment
with CHCl3–pentane to yield colorless crystals (0.55 g, 25%; mp
88–92 °C). Recrystallization from benzene–hexane raised the mp to
92–93.5 °C.
Synthesis 2010, No. 19, 3358–3362 © Thieme Stuttgart · New York

3362
H. Quast et al.
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Synthesis 2010, No. 19, 3358–3362 © Thieme Stuttgart · New York