Solvent-free synthesis of hydrazones and their subsequent N-alkylation in a Ball-mill

Article abstract of DOI:10.1016/j.tet.2011.07.056

A large variety of Boc-, Bz-, Ts-, and Fmoc- protected hydrazones were prepared via condensation of an equimolar amount of carbonyl-compound and the corresponding hydrazine using a ball-mill. Hydrazones were always obtained in a quantitative yield and no solvents were used at any step. In a second step, we realized the first solvent-free N-allylation and N-benzylation of these hydrazones.

Full text of DOI:10.1016/j.tet.2011.07.056

Tetrahedron 67 (2011) 8187e8194
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Solvent-free synthesis of hydrazones and their subsequent N-alkylation
in a Ball-mill
*
ꢀ ꢀ
Pierrick Nun, Charlotte Martin, Jean Martinez, Frederic Lamaty
ꢀ
ꢀ
ꢀ
ꢁ
Institut des Biomolecules Max Mousseron, UMR 5247- Universite Montpellier 1 et Universite Montpellier 2-CNRS, Place Eugene Bataillon, 34095 Montpellier Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2011
Received in revised form 18 July 2011
Accepted 21 July 2011
Available online 27 July 2011
A large variety of Boc-, Bz-, Ts-, and Fmoc- protected hydrazones were prepared via condensation of an
equimolar amount of carbonyl-compound and the corresponding hydrazine using a ball-mill. Hydra-
zones were always obtained in a quantitative yield and no solvents were used at any step. In a second
step, we realized the first solvent-free N-allylation and N-benzylation of these hydrazones.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ball-mill
Solvent-free synthesis
Green chemistry
Protected hydrazones
Condensation
Alkylation
1. Introduction
Hydrazones are classically prepared by refluxing hydrazine with
a slight excess of carbonyl compound in toluene or ethanol, and the
Ball-milling is a mechanochemical technique, that is, widely
applied to the grinding of minerals into fine particles and to the
preparation and modification of inorganic solids.1 For synthetic
applications, ball-mill chemistry is a practical method, which can
be environmentally friendly since solvent-free conditions are
generally used. In the last years, this technique has found interest in
synthetic organic chemistry.2 Among the reported examples, one
can cite nitrone synthesis,3 functionalization of fullerenes,4 re-
ductive benzylation of malonitrile,5 protection of amines,6 Knoe-
venagel reaction,7 aldol condensation,8 and its asymmetric
version,9 Michael additions,7 preparation of phosphorus ylides,10
nucleoside chemistry,11 oxidative coupling of 2-naphthol,12 Heck-
type cross-coupling reactions,13 peptide coupling,14 oxidations,15
Sonogashira reaction,16 click reactions.17
Hydrazones are an important class of chemical intermediates,
which can act as electrophiles and as nucleophiles in Mannich-
Type reactions,18 Mitsunobu reactions,19 asymmetric hydro-
cyanation,20 allylation.21 They are also used in asymmetric syn-
thesis in the SAMP-/RAMP-methodology.22 Biological activity of
hydrazone derivatives was also investigated and some of them act
as potent inhibitors of macrophage migration inhibitory factor
(MIF) tautomerase.23
pure product is finally isolated after crystallization, column chro-
matography or distillation. There are only few examples describing
this synthesis in solvent-free conditions. Using microwaves, tosyl-
hydrazones are prepared in a short time with a small amount of
methanol using dichloromethane for the final extraction.24 Acyl-
hydrazones are prepared using an excess of liquid aldehyde and
ethanol for washing,25 while heterocyclic hydrazones are prepared
using a large excess of hydrazine and ethanol for washing.26
Hydrazones and semi-carbazones are also prepared in a mortar
by grinding the aldehyde and hydrazine with sodium hydroxide
and silica gel during a few minutes27 with a final extraction step
using dichloromethane or in a ball-mill in presence of Na2CO3.28 To
our knowledge, only two reports of totally solvent-free hydrazone
synthesis, using a ball-mill and yielding pure hydrazones without
any use of solvent.29 This method was only used to prepare
hydrazones with Bz- and Ph- as protecting groups. Surprisingly, this
technique was not employed to prepare other hydrazones and
microwave heating or refluxing methods seemed to be preferred.
2. Results and discussion
In previous studies, we have already described the use of a ball-
mill apparatus in peptide synthesis14a and in the condensation of
hydroxylamines on aldehydes for the synthesis of nitrones.3 We
chose to extend this technique to the synthesis of a large variety
* Corresponding author. E-mail address: frederic.lamaty@univ-montp2.fr
(F. Lamaty).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.056

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P. Nun et al. / Tetrahedron 67 (2011) 8187e8194
Table 1 (continued)
of hydrazones, starting from commercially available Boc- (1),
Bz-(2), and Ts-hydrazines (3) and from the synthesized Fmoc-
hydrazine (4).30
R1CHO
R3NHNH2
Reaction
time
Product
In order to respect the principles of green chemistry, it was
necessary to work in stoichiometric conditions and when possible
without any addition of solid support, such as silica gel and base
(Scheme 1).27
1
45 min
R3
NH
9
O
Ball-milling
30 Hz
45 min- 6h
+
NH2NHR3
+ H2O
N
R1
R2
R1
R2
Scheme 1. Solvent-free synthesis of hydrazones.
1
1
60 min
The reactants were introduced into
a stainless steel jar
(5 mL). The reaction vessel was closed and fixed on the vibration
arms of a ball-milling apparatus, along with two stainless steel
balls of 5.0 mm diameter (Retsch MM200 mixer mill, Retsch
GmbH, Haan, Germany), using a second parallel jar to equilibrate
the system. Then, both vessels were vibrated vigorously at a rate
of 30 Hz at room temperature. The reaction was monitored by
HPLC, and stopped when all starting materials were consumed.
Results obtained with various aldehydes, ketones, tert-butyl
carbazate, benzoic, Fmoc, and tosyl hydrazide are presented in
Table 1.
10
90 min
11
When the conversion of starting materials was complete, the
apparatus was stopped, the jar opened and the pure expected
hydrazone was recovered only by removing the powder from the
jar and by drying under reduced pressure. In all cases there was no
1 (2 equiv)
90 min
Table 1
Solvent-free synthesis of Boc-, Bz-, Fmoc-, and tosyl-hydrazones from aldehydes
R1CHO
R3NHNH2
Reaction
time
Product
12
13
CHO
1
1
1
90 min
60 min
60 min
CHO
60 min
MeO
OMe
1
5
6
7
1
360 min
14
1
60 min
15
1
60 min
1
180 min
16
8

P. Nun et al. / Tetrahedron 67 (2011) 8187e8194
8189
Table 1 (continued )
by-product, conversion was always total as proved by direct anal-
ysis of the obtained product. So the reaction can be considered as
quantitative. In each example of condensation, a solid powder was
obtained and removed as such from the jar. Reaction times lasted
between 45 min and 6 h but the hydrazones were mostly prepared
in 90 min, a shorter time compared with methods that do not use
microwave activation. For example, compound 7 was prepared in
60 min in a quantitative yield without any use of solvent, compared
to 5 h in refluxing methanol.31
R1CHO
R3NHNH2
Reaction
time
Product
120 min
2
To confirm that the reaction was complete and no by-
product was present in the isolated powder and that no fur-
ther purification was needed, the cross polarization/magic angle
spinning (CP/MAS) 13C NMR analysis of the reaction mixture
without any treatment was performed. Results are presented
below (Fig. 1).
17
The spectrum of the reaction mixture shows that no starting
material could be detected in the crude final product. These re-
sults, coupled with 1H, 13C NMR, and with LC/MS analysis showed
that the powder obtained in the jar consisted in the clean hydra-
zone along with water. So the yield was always quantitative after
drying the solid contrary to the described methods using micro-
waves or solid support. This method is also completely solvent-
free because there is no need to filter or to wash the isolated
solid with a toxic and volatile organic solvent. It is also important
to notice that results were comparable starting from solid and
liquid aldehydes, as, for example, with product 5 (starting from
a solid aldehyde) and product 9 (starting from a liquid aldehyde).
We also proved the applicability of this method to larger scale with
the preparation of 1.7 g of hydrazone 7 in 120 min and using the
same grinding jars.
2
60 min
18
2
60 min
19
NH2NHFmoc
The mechanochemical activation is also essential to obtain
a quantitative conversion. With only a magnetical stirring in a 5 mL
round-bottom flask, the highest conversion in hydrazone 7 after
24 h was only 41% (100% in 60 min with the ball-mill).
60 min
3
20
It is also important to note that this method is also applicable to
some ketones. (Table 2) Usually condensations on aldehydes are
quite easy but it is not always the case with ketones. Heating the
reaction mixture to 70 ꢀC or 125 ꢀC is often required to achieve
a quantitative yield. As described in a work published by Mokhtari
et al. during the course of our study,29b hydrazones from benzo-
phenone could not be obtained just with milling. Nevertheless, this
technique allowed us to prepare various hydrazones from cyclo-
hexanone, 3-pentanone or acetophenone.
N-Alkylated hydrazones and hydrazines are important in-
termediates due to the increasing number of heterocyclic com-
pounds bearing an NeN bond.32 N-allylhydrazones also proved
interesting properties in the synthesis of dienes via copper (II)
chloride or NBS and DBU promoted rearrangement.33 We expanded
our methodology to the allylation and benzylation of some
hydrazones still in solvent-free conditions and without the use of
metal as catalyst (Scheme 2).34
3
3
90 min
21
22
120 min
CHO
3
60 min
Reaction conditions were optimized to 1 h of ball-milling at
30 Hz with 3 equiv of allylbromide and cesium carbonate. The use
of a lower quantity of allylbromide or potassium carbonate as
a base gave lower conversions. A simple aqueous wash and
evaporation gave the pure allylhydrazone. These conditions were
extended to other hydrazones and benzylbromide as alkylating
agent (Table 3). Because the alkylation required the use of
an excess of liquid alkylating agent, the reaction mixture was
recovered as a paste from the jar. An interesting double allylation
was also performed starting from hydrazone 16 derived from
salicylaldehyde. Unfortunately, the use of other alkylating re-
agents like ethyliodide or cyanopropargylbromide was un-
successful. N-allylation of Fmoc-hydrazones in the same
conditions gave no expected product, the starting materials were
recovered.
23
180 min
4
24

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P. Nun et al. / Tetrahedron 67 (2011) 8187e8194
13
Fig. 1. C CP/MAS spectra of (a) tert-butyl carbazate (b) 3,5-dimethoxybenzaldehyde (c) & (d) of N0-(3,5-dimethoxybenzylidene)-hydrazinecarboxylic acid tert-butyl ester.
3. Conclusion
4.2. General experimental procedure for the synthesis
of hydrazones (Table 1)
In summary, we have shown that ball-milling can be a useful
method for the preparation of diverse hydrazones starting from
liquid and solid reactants. Their subsequent N-allyl and benzyla-
tion was also investigated with success still in solvent-free con-
ditions using mechanical activation. This method proved its
superiority in term of economy of solvent, yield, and reaction time.
The methodology is highly profitable in terms of sustainable
synthesis with efficiency in all respect, affording hydrazones in
pure form without any purification. This shows also that two
subsequent reactions could be performed using a ball-mill in the
absence of solvent, opening the path to integrated organic syn-
thesis in a ball-mill.
A mixture of aldehyde (0.5 mmol, 1 equiv) and hydrazine
(0.5 mmol, 1.0 equiv) was ball-milled at 30 Hz for the specified time
(see Table 1). When the reaction was complete, the product was
recovered as a solid directly in the jar and then dried overnight
under vacuo.
4.2.1. (E)-tert-Butyl-2-(3,5-dimethoxybenzylidene)hydrazinecarbox-
ylate 535 [106728-65-8]. White powder; mp 164 ꢀC (lit. 161 ꢀC). 1H
NMR (acetone-d6)
d
1.36 (s, 9H), 3.68 (s, 6H), 6.36 (t, J¼2.1 Hz, 1H),
6.71 (d, 2H, J¼2.1 Hz), 7.9 (s, 1H), 9.71 (s, 1H); 13C NMR (acetone-
d6)
d 28.5, 55.7, 80.5, 102.6, 105.32, 138.0, 144.0, 153.3, 162.0. MS
(ESI) m/z: 303.0 [MþNa]þ, 281.2 [MþH]þ, 225.0, 181.0. HRMS
calcd for C14H21N2O4: 281.1501. Found 281.1503.
4. Experimental section
4.1. General
4.2.2. (E)-tert-Butyl-2-(2-nitrobenzylidene)hydrazinecarboxylate 635
[106728-63-6]. Yellow powder; mp 153 ꢀC (lit. 151e152 ꢀC). 1H
NMR (acetone-d6)
d
1.50 (s, 9H), 7.63 (dd, 1H, J¼7.3, 7.0 Hz),
7.77 (dd, 1H, J¼7.4, 7.3 Hz), 8.01 (d, 1H, J¼8.0 Hz), 8.15 (d, 1H,
The Ball-milling experiments were performed in a Retsch
MM200 mixer mill (Retsch GmbH, Haan, Germany) with two
stainless balls of 5.0 mm diameter, into a stainless jar (5 mL) at
a rate of 1800 rounds per minute (30 Hz) at room temperature.
J¼7.7 Hz), 8.53 (s, 1H), 10.2 (s, 1H); 13C NMR (acetone-d6)
d
28.5, 80.9, 125.4, 128.8, 130.3, 130.7, 134.1, 139.0, 149.3, 153.0.
MS (ESI) m/z: 288.2 [MþNa]þ, 266.2 [MþH]þ, 210.0, 192.0,

P. Nun et al. / Tetrahedron 67 (2011) 8187e8194
8191
Table 2
Table 3
Hydrazones derived from ketones
Solvent-free alkylation of hydrazones
R1R2CO
R3NHNH2
Reaction time
60 min
Product
Hydrazone
R-X
Product
Isolated yield (%)
1
5
85
25
30
3
4
4
60 min
150 min
60 min
26
27
5
92
31
7
93
28
32
4
90 min
9
91
94
95
29
33
H
N
N
CO2tBu
Ball-milling
30 Hz; 1h
Cs2CO3
N
Br
+
N
CO2tBu
16
3 eq
34
Scheme 2. Solvent-free N-allylation of hydrazones.
166.0, 149.0. HRMS calcd for C12H16N3O4: 266.1141. Found
266.1168.
17
4.2.3. (E)-tert-Butyl-2-(naphthalen-1-ylmethylene)hydrazinecarbox-
ylate 735 [106728-61-4]. White powder; mp 188 ꢀC (lit.
167e168 ꢀC). 1H NMR (acetone-d6)
d
1.50 (s, 9H), 7.53 (m, 2H),
35
7.82e8.05 (m, 5H), 8.27 (s 1H), 9.89 (s, 1H); 13C NMR (acetone-d6)
d
28.5, 80.5, 123.6, 127.4, 127.6, 128.7,128.8, 129.1,129.2,133.9,134.3,
134.9, 144.0, 153.3. MS (ESI) m/z: 293.3 [MþNa]þ, 271.2 [MþH]þ,
215.4. HRMS calcd for C16H19N2O2: 271.1447. Found 271.1471.
87
4.2.4. (E)-tert-Butyl-2-(4-methoxy-3-nitrobenzylidene)hydrazine-
carboxylate 8 [355417-88-8]. Yellow powder; mp 149 ꢀC. 1H NMR
17
(acetone-d6)
d
1.49 (s, 9H), 4.02 (s, 3H), 7.45 (d, 1H, J¼8.8 Hz), 7.92
(d, 1H, J¼8.8 Hz), 8.01e8.19 (m, 2H), 9.91 (s, 1H); 13C NMR (acetone-
d6)
d 28.5, 57.3, 80.6, 115.1, 123.7, 128.9, 132.6, 141.0, 141.5, 153.2,
(continued on next page)
36

8192
P. Nun et al. / Tetrahedron 67 (2011) 8187e8194
Table 3 (continued )
d
0.93 (t, 3H, J¼7.2 Hz), 1.44 (s, 9H), 1.35e1.62 (m, 2H), 2.19 (dt, 2H,
J¼6.6, 6.7 Hz), 7.38 (s, 1H), 9.29 (s, 1H). 13C NMR (acetone-d6)
d 14.0,
Hydrazone
R-X
Product
Isolated yield (%)
20.7, 28.6, 34.9, 79.8,147.4,153.3. MS (ESI) m/z: 209.3 [MþNa]þ,187.3
[MþH]þ,130.8. HRMS calcd for C9H19N2O2: 187.1447. Found 187.1469.
4.2.10. (E)-tert-Butyl-2-((1H-indol-5-yl)methylene) hydrazinecarbox-
ylate 14. White powder; mp 195 ꢀC. 1H NMR (acetone-d6)
d 1.49 (s,
24
89
9H), 6.51 (m, 1H), 7.35 (s, 1H), 7.43 (d, 1H, J¼8.5 Hz), 7.59 (d, 1H,
J¼8.5 Hz), 7.78 (s, 1H), 8.17 (s, 1H), 9.59 (s, 1H),10.43 (s, 1H); 13C NMR
(acetone-d6) d 28.6, 80.0, 103.1, 112.6, 120.4, 121.4, 126.4, 126.6, 127.5,
129.0, 138.0, 145.9. MS (ESI) m/z: 260.3 [MþH]þ, 204.0. HRMS calcd
37
for C14H18N3O2: 260.1399. Found 260.1416.
4.2.11. (E)-tert-Butyl-2-(quinolin-3-ylmethylene)hydrazinecarbox-
ylate 1538 [106869-44-7]. White powder; mp 200 ꢀC. 1H NMR (ac-
etone-d6)
J¼7.5, 7.1 Hz), 8.03 (dd, 2H, J¼8.4, 8.0 Hz), 8.33 (s, 1H), 8.41 (s, 1H),
9.30 (s, 1H), 10.09 (s, 1H); 13C NMR (acetone-d6)
28.5, 80.7, 128.0,
d
1.52 (s, 9H), 7.62 (dd, 2H, J¼7.5, 7.1 Hz), 7.77 (dd, 2H,
25
96
d
128.6,129.2,129.3,130.2,130.7,134.6, 141.5,149.3,153.1. MS (ESI) m/
z: 271.96 [MþH]þ, 216.2. HRMS calcd for C15H18N3O2: 272.1399.
Found 272.1410.
38
4.2.12. (E)-tert-Butyl 2-(2-hydroxybenzylidene)hydrazinecarboxylate
1639 [187806-33-3]. White solid; mp 149 ꢀC. 1H NMR (acetone-d6)
27
94%
d
1.50 (s, 9H), 6.89 (dd, 2H, J¼7.4, 8.4 Hz) 7.27 (dd, 2H, J¼7.4, 8.3 Hz),
8.24 (s, 1H), 11.32 (s, 1H). 13C NMR (acetone-d6)
d
28.4, 81.2, 117.4,
119.2, 119.9, 131.2, 131.5, 146.8, 152.9, 159.0. MS (ESI) m/z: 259.1
[MþK]þ, 237.2 [MþH]þ, 165.4.
39
4.2.13. (E)-N0-(3,5-Dimethoxybenzylidene)benzohydrazide 17 [6785
153.9. MS (ESI) m/z: 334.1 [MþK]þ, 318.2 [MþNa]þ, 240.2. HRMS
36-02-2]. White powder; mp 182 ꢀC. 1H NMR (acetone-d6)
d 3.83 (s,
calcd for C13H18N3O5: 296.1256. Found 296.1246.
6H), 6.54 (m, 1H), 6.93 (m, 2H), 7.45e7.63 (m, 3H), 7.97 (d, 2H,
J¼7.0 Hz), 8.51 (s, 1H), 10.99 (s, 1H); 13C NMR (acetone-d6þDMSO-
4.2.5. (E)-tert-Butyl-2-benzylidenehydrazinecarboxylate 931 [24469-
50-9]. White powder; mp 190 ꢀC (lit. 185 ꢀC). 1H NMR (acetone-d6)
d6)
d 56.0, 103.1, 105.9, 128.8, 129.4, 132.6, 135.0, 138.0, 162.1, 164.5.
MS (ESI) m/z: 307.0 [MþNa]þ, 285.0 [MþH]þ. HRMS calcd for
d
1.49 (s, 9H), 7.38 (m, 3H), 7.67 (m, 2H), 8.11 (s, 1H), 9.79 (s, 1H); 13
C
C16H17N2O3: 285.1239. Found 285.1231.
NMR (acetone-d6) d 28.5, 80.4, 127.5, 129.5, 130.2, 136.1,143.9, 153.2.
MS (ESI) m/z: 259.2 [MþK]þ, 221.2 [MþH]þ, 165.4. HRMS calcd for
4.2.14. (E)-N0-Benzylidenebenzohydrazide 1840 [956-07-0]. White
powder; mp 206 ꢀC (lit. 210 ꢀC). 1H NMR (acetone-d6)
d 7.36e7.62
C12H17N2O2: 221.1290. Found 221.1298.
(m, 6H), 7.77 (m, 2H), 7.98 (d, 2H, J¼7.1 Hz), 8.51 (s, 1H), 11.00 (s,
1H); 13C NMR (acetone-d6þDMSO-d6)
d 128.1, 128.8, 129.4, 129.7,
4.2.6. (E)-tert-Butyl-2-(furan-2-ylmethylene) hydrazinecarboxylate
1036 [113906-60-8]. White powder; mp 164 ꢀC (lit. 158 ꢀC). 1H NMR
130.9, 132.6, 135.0, 136.0, 148.6, 164.2. MS (ESI) m/z: 247.2
[MþNa]þ, 225.0 [MþH]þ. HRMS calcd for C14H13N2O: 225.1028.
Found 225.1015.
(acetone-d6)
d 1.48 (s, 9H), 6.54 (s, 1H,), 6.72 (s, 1H), 7.62 (s, 1H),
8.04 (s, 1H), 9.78 (s, 1H); 13C NMR (acetone-d6)
d 28.5, 80.5, 111.7,
112.6, 134.3, 144.8, 151.4, 153.2. MS (ESI) m/z: 233.2 [MþNa]þ, 211.3
[MþH]þ, 155.0, 137.2. HRMS calcd for C10H15N2O3: 211.1083. Found
211.1083.
4.2.15. (E)-N0-(Naphthalen-2-ylmethylene)benzohydrazide 19 [24091-
07-4]. White powder; mp 212 ꢀC. 1H NMR (acetoneþDMSO)
d
7.48e7.65 (m, 5H), 7.89e8.09 (m, 6H), 8.14 (s,1H), 8.70 (s,1H),11.87
(s, 1H); 13C NMR (acetoneþDMSO)
d 123.5, 127.2, 127.6, 128.4, 128.9,
4.2.7. (E)-tert-Butyl-2-(thiophen-2-ylmethylene) hydrazinecarbox-
ylate 11 [180462-80-0]. White powder; mp 203 ꢀC. 1H NMR (ace-
129.0,129.1,129.2,129.3,132.2,133.3,133.8,134.6,134.7,148.2,163.8.
MS (ESI) m/z: 275.3 [MþH]þ. HRMS calcd for C18H15N2O: 275.1184.
Found 275.1188.
tone-d6) d 1.47 (s, 9H), 7.07 (m 1H,), 7.28 (m, 1H), 7.50 (m, 1H), 8.34
(s, 1H), 9.75 (s, 1H); 13C NMR (acetone-d6)
d 28.5, 80.5, 111.7, 112.6,
134.3, 144.8, 151.4, 153.2. MS (ESI) m/z: 249.2 [MþNa]þ, 227.2
[MþH]þ, 171.0, 153.2, 110.1. HRMS calcd for C10H15N2O2S: 227.0854.
Found 227.0857.
4.3. Synthesis of Fmoc-hydrazine 330
4.2.8. (2E,20E)-di-tert-Butyl 2,20-(1,4-phenylenebis(methan-1-yl-1-
At 0 ꢀC Fmoc chloride (2 mmol, 517.4 mg) dissolved in ace-
tonitrile (30 mL) is added to hydrazine hydrate (20 mmol, 1 g,
10 equiv) dissolved in 10 mL of a 1/1 mixture water/acetonitrile.
The reaction was stirred at 0 ꢀC for 2 h (formation of a white
precipitate), then allowed to warm up to room temperature and
stirred for an additional hour. The mixture was concentrated
under vacuo and the precipitate was washed with water, cyclo-
hexane, and then dried under vacuo to afford the pure title
compound as a white solid (481 mg, 95%). Mp 174 ꢀC (lit.
172e173 ꢀC).30
ylidene))bis(hydrazinecarboxylate)
12. White
powder;
mp
>260 ꢀC. 1H NMR (acetone-d6þDMSO-d6)
d 1.50 (s, 18H), 7.67 (s,
4H), 8.07 (s, 2H), 10.8 (s, 2H); 13C NMR (acetone-d6þDMSO-d6)
d
28.0, 79.5, 127.0, 136.1, 142.6, 152.7. MS (ESI) m/z: 363.1 [MþH]þ,
307.2, 251.2, 207.3, 163.3. HRMS calcd for C18H27N4O4: 363.2032.
Found 363.2047.
4.2.9. (E)-tert-Butyl-2-butylidenehydrazinecarboxylate 1337
[149268-07-5]. White powder; mp 89 ꢀC. 1H NMR (acetone-d6)

P. Nun et al. / Tetrahedron 67 (2011) 8187e8194
8193
1H NMR (DMSO)
d
4.07 (s, 2H), 4.18e4.31 (m, 3H), 7.32 (t, 2H,
119.4, 124.9, 126.5, 127.1, 140.5, 143.5, 154.0, 161.6. MS (ESI) m/z:
335.2 [MþH]þ, 179.2, 157.2.
J¼7.4 Hz), 7.41 (t, 2H, J¼7.4 Hz), 7.68 (d, 2H, J¼7.4 Hz), 7.88 (d, 2H,
J¼7.4 Hz), 8.34 (s, 1H); 13C NMR (DMSO)
d 46.6, 65.6, 120.1, 125.2,
127.0, 127.6, 140.7, 143.8, 158.2. MS (ESI) m/z: 255.1 [MþH]þ.
4.3.8. 4-Methyl-N0-(pentan-3-ylidene)benzenesulfonohydrazide 27
[28495-72-9]. Yellow solid; mp 101 ꢀC. 1H NMR (acetone-d6)
d
0.93e1.02 (m, 6H), 2.15e2.29 (m, 4H), 3.40 (s, 3H), 7.36 (d, 2H,
4.3.1. (E)-(9H-Fluoren-9-yl)methyl-2-benzylidene hydrazinecarbox-
J¼7.8 Hz), 7.77 (d, 2H, J¼8.3 Hz), 8.81 (s, 1H). 13C NMR (acetone-d6)
ylate 20 [1111765-75-3]. White powder; mp 193 ꢀC. 1H NMR
d
8.1, 21.5, 35.6, 128.9, 130.1, 137.7, 144.2, 211.2. MS (ESI) m/z: 255.1
(DMSO)
d
4.32 (dd, 1H, J¼5.9, 6.8 Hz), 4.42e4.55 (m, 2H),
[MþH]þ.
7.39e7.48 (m, 7H), 7.59e7.67 (m, 2H), 7.72e7.81 (m, 2H), 7.92 (d,
2H, J¼7.3 Hz), 8.05 (s, 1H), 11.20 (s, 1H); 13C NMR (DMSO)
d 46.4,
4.3.9. N0-Cyclohexylidene-4-methylbenzenesulfonohydrazide 2843
[4545-18-0]. White powder; mp 160 ꢀC (lit. 162 ꢀC). 1H NMR (ace-
65.7, 120.1, 125.1, 126.6, 127.1, 127.7, 128.7, 129.6, 134.4, 140.8,
143.7, 143.8, 153.2. MS (ESI) m/z: 365.1 [MþNa]þ, 343.2 [MþH]þ,
179.1, 165.2. HRMS calcd for C22H19N2O2: 343.1447. Found
343.1428.
tone-d6) d 1.58 (s, 6H), 2.13e2.19 (m, 2H), 2.24e2.34 (m, 2H), 2.42 (s,
3H), 7.36 (d, 2H, J¼8.1 Hz), 7.77 (d, 2H, J¼8.2 Hz), 8.96 (s, 1H). 13C
NMR (acetone-d6)
d 21.4, 25.6, 27.7, 35.6, 42.29, 130.1, 137.8, 144.2,
210.4. MS (ESI) m/z: 267.3 [MþH]þ.
4.3.2. (E)-(9H-Fluoren-9-yl)methyl-2-(pyridin-3-ylmethylene)hydra-
zinecarboxylate 21 [1158960-29-2]. White powder; mp 206 ꢀC. 1H
4.3.10. (Z)-4-Methyl-N0-(1-phenylethylidene)benzenesulfonohy-
NMR (DMSO)
d
4.32 (t, 1H, J¼6.9 Hz), 4.43e4.59 (m, 2H), 7.35 (t, 2H,
drazide 2944 [62460-99-5]. White powder; mp 142 ꢀC (lit. 147 ꢀC).
J¼7.3 Hz), 7.39e7.52 (m, 3H), 7.71e7.81 (m, 2H), 7.91 (d, 2H,
1H NMR (acetone-d6)
d 2.24 (s, 3H), 2.39 (s, 3H), 7.32e7.41 (m, 5H),
J¼7.6 Hz), 8.05 (d, 1H, J¼7.8 Hz), 8.09 (s, 1H), 8.59 (s, 1H), 8.79 (s,
7.67e7.77 (m, 2H), 7.83 (d, 2H, J¼8.3 Hz), 9.32 (s, 1H). 13C NMR
1H), 11.38 (s, 1H); 13C NMR (DMSO)
d 46.5, 65.8, 120.1, 123.9, 125.1,
(acetone-d6)
d 16.4, 23.6, 129.1, 131.0, 131.2, 132.3, 139.6, 140.9,
127.1, 127.7, 130.2, 133.0, 140.8, 143.6, 143.8, 148.2, 150.3, 153.2. MS
(ESI) m/z: 343.9 [MþH]þ, 179.1, 165.2. HRMS calcd for C21H18N3O2:
344.1399. Found 344.1379.
146.6, 155.8. MS (ESI) m/z: 289.2 [MþH]þ
4.4. General experimental procedure for the N-alkylation
of hydrazones (Table 2)
4.3.3. (E)-(9H-Fluoren-9-yl)methyl-2-butylidenehydrazinecarbox-
ylate 22. White powder; mp 162 ꢀC. 1H NMR (DMSO)
d 0.89 (t,
3H, J¼7.0 Hz), 1.35e1.59 (m, 2H), 2.07e2.20 (m, 2H), 4.18e4.29
(m, 1H), 4.33e4.48 (m, 2H), 7.25e7.39 (m, 3H), 7.42 (t, 2H,
J¼7.3 Hz), 7.71 (d, 2H, J¼6.8 Hz), 7.91 (d, 2H, J¼7.3 Hz), 10.71 (s,
A mixture of hydrazone (0.3 mmol, 1 equiv), allyl or phenyl
bromide (0.9 mmol, 3.0 equiv) and Cs2CO3 (0.9 mmol, 293 mg,
3.0 equiv) was ball-milled at 30 Hz during 1 h. AcOEt (5 mL) was
added and the solution washed with water (3ꢁ5 mL). The organic
layer was dried on MgSO4 and concentrated under vacuo to recover
the pure product.
1H); 13C NMR (DMSO)
d 13.5, 19.4, 33.6, 43.6, 65.3, 120.1, 125.1,
127.0, 127.6, 140.7, 143.7, 148.2, 153.1. MS (ESI) m/z: 309.1
[MþH]þ, 179.2, 172.1, 131.1. HRMS calcd for C19H21N2O2:
309.1603. Found 309.1600.
4.4.1. (E)-tert-Butyl 1-allyl-2-(3,5-dimethoxybenzylidene)hydrazine-
4.3.4. (E)-(9H-Fluoren-9-yl)methyl-2-(2-hydroxybenzylidene)hydra-
carboxylate 30. White solid; mp 57 ꢀC. 1H NMR (acetone-d6)
d 1.54
zinecarboxylate 23. White powder; mp 188 ꢀC. 1H NMR (DMSO)
(s, 9H), 3.80 (s, 6H), 4.56 (d, 2H, J¼2.3 Hz), 5.15 (dd, 2H, J¼15.8,
d
4.22e4.39 (m, 1H), 4.41e4.61 (m, 2H), 6.89 (d, 2H, J¼7.1 Hz),
9.1 Hz), 5.79e5.92 (m, 1H), 6.47 (t, 1H, J¼2.3 Hz), 6.91 (m, 2H),
7.27 (t, 1H, J¼7.1 Hz), 7.29e7.53 (m, 5H), 7.74 (d, 2H, J¼5.9 Hz),
7.85 (s, 1H). 13C NMR (acetone-d6)
d 28.4, 46.7, 55.6, 81.5, 102.2,
7.92 (d, 2H, J¼7.1 Hz), 8.27 (s, 1H), 10.81 (s, 1H), 11.41 (s, 1H); 13C
105.5, 116.6, 132.6, 138.7, 140.4, 153.8, 162.0. MS (ESI) m/z: 321.1
[MþH]þ, 265.1. HRMS calcd for C17H25N2O4: 321.1814. Found
321.1809.
NMR (DMSO)
d 46.5, 65.9, 116.2, 119.0, 119.3, 120.1, 125.1, 127.1,
127.7, 128.6, 130.9, 140.8, 143.6, 144.9, 153.2, 156.8. MS (ESI) m/z:
359.1 [MþH]þ, 181.0. HRMS calcd for C22H19N2O3: 359.1396.
Found 359.1399.
4.4.2. (E)-tert-Butyl 1-benzyl-2-(3,5-dimethoxybenzylidene)hydrazi-
necarboxylate 31. White solid; mp 66 ꢀC. 1H NMR (acetone-d6)
4.3.5. (E)-N0-(3,5-Dimethoxybenzylidene)-4-methylbenzenesulfono-
d
1.58 (s, 9H), 3.78 (s, 6H), 5.20 (m, 2H), 6.46 (t, 1H, J¼2.3 Hz),
hydrazide 24 [67147-57-2]. White solid; mp 115 ꢀC. 1H NMR (ace-
6.85 (d, 2H, J¼2.3 Hz), 7.21e7.39 (m, 5H), 7.82 (s, 1H). 13C NMR
tone-d6)
d
2.39 (s, 3H), 3.79 (s, 6H), 6.51 (t,1H, J¼2.3 Hz), 6.77 (d, 2H,
(acetone-d6)
d 28.4, 48.3, 55.6, 81.8, 102.2, 105.5, 127.5, 128.0,
J¼2.3 Hz), 7.40 (d, 2H, J¼8.1 Hz), 7.84 (d, 2H, J¼8.3 Hz), 7.90 (s, 1H),
129.5, 137.4, 138.5, 140.7, 154.5, 162.0. MS (ESI) m/z: 371.3
[MþH]þ, 315.2. HRMS calcd for C21H27N2O4: 371.1971. Found
371.1972.
10.11 (s, 1H). 13C NMR (acetone-d6)
d 21.5, 55.8, 103.0, 105.7, 128.6,
130.4, 137.0, 137.4, 144.7, 147.9, 162.0. MS (ESI) m/z: 335.2 [MþH]þ.
4.3.6. tert-Butyl 2-cyclohexylidenehydrazinecarboxylate 2541
[60295-11-6]. White powder; mp 131 ꢀC (lit. 134e135 ꢀC). 1H
4.4.3. (E)-tert-Butyl 1-allyl-2-(naphthalen-2-ylmethylene)hydrazi-
necarboxylate 3233a [1005794-79-5]. White solid; mp 69 ꢀC (lit.
NMR (acetone-d6)
d 1.45 (s, 9H), 1.63 (m, 6H), 2.22e2.32 (m, 2H),
67e70 ꢀC). 1H NMR (acetone-d6)
d
1.58 (s, 9H), 4.65 (s, 2H), 5.19 (m,
2H), 5.86e5.97 (m, 1H), 7.52e7.57 (m, 2H), 7.90e7.97 (m, 3H),
8.04e8.09 (m, 3H). 13C NMR (acetone-d6)
28.5, 46.9, 81.6, 116.7,
2.39e2.45 (m, 2H), 8.62 (s, 1H), 13C NMR (acetone-d6)
d 26.4, 26.7,
27.2, 28.0, 28.6, 36.0, 79.5, 154.1, 156.4. MS (ESI) m/z: 213.3 [MþH]þ,
d
157.0.
123.7, 127.4, 127.5, 128.7, 129.0, 129.1, 129.2, 132.8, 134.3, 134.4,
134.9, 140.8, 153.8. MS (ESI) m/z: 311.2 [MþH]þ, 255.2.
4.3.7. (9H-Fluoren-9-yl)methyl 2-cyclohexylidenehydrazinecarbo-
xylate 2642 [74105-60-5]. Colorless oil; 1H NMR (acetone-d6)
4.4.4. (E)-tert-Butyl 1-allyl-2-benzylidenehydrazinecarboxylate
d
1.65 (m, 6H), 2.25e2.31 (m, 2H), 2.33e2.45 (m, 2H), 4.21e4.29 (m,
33. Colorless oil; 1H NMR (acetone-d6)
d 1.54 (s, 9H), 4.57e4.59
1H), 4.33e4.45 (m, 2H), 7.33 (t, 2H, J¼7.3 Hz), 7.42 (t, 2H, J¼7.3 Hz),
(m, 2H), 5.15 (m, 2H), 5.79e5.88 (m, 1H), 7.33e7.42 (m, 3H), 7.72 (d,
7.70e7.79 (m, 2H), 7.87 (d, 2H, J¼7.4 Hz), 8.58 (s,1H), 9.10 (s,1H). 13C
2H, J¼7.7 Hz), 7.87 (s, 1H). 13C NMR (acetone-d6)
d 28.4, 46.8, 81.4,
116.6, 127.7, 129.4, 129.9, 132.7, 136.6, 140.8, 153.8. MS (ESI) m/z:
NMR (acetone-d6þDMSO-d6)
d 24.8, 25.2, 26.5, 34.6, 46.4, 65.5,

8194
P. Nun et al. / Tetrahedron 67 (2011) 8187e8194
261.2 [MþH]þ, 205.0. HRMS calcd for C15H21N2O2: 261.1603. Found
References and notes
261.1599.
1. (a) Kaupp, G.; Naimi-Jamal, M. R.; Ren, H.; Zoz, H. In Technologies Based on Self-
Propagating and Mechanochemical Reactions for Environmental Protection; Cao,
4.4.5. (E)-tert-Butyl
1-allyl-2-(2-(allyloxy)benzylidene)hydrazine-
1.54 (s, 9H),
ꢁ
G., Delogu, F., Orru, R., Eds.; Research Signpost: Kerala, 2003; (b) Kipp, S.;
carboxylate 34. Colorless oil; 1H NMR (acetone-d6)
d
Sepelak, V.; Becker, K. D. Chem. Unsere Zeit 2005, 39, 384.
ꢁ
ꢁ
2. (a) Kaupp, G. Top. Curr. Chem. 2005, 254, 95; (b) Rodrõguez, B.; Bruckmann, A.;
4.57e4.59 (m, 2H), 5.15 (m, 2H), 5.79e5.88 (m, 1H), 7.33e7.42 (m,
Rantanen, T.; Bolm, C. Adv. Synth. Catal. 2007, 349, 2213; (c) Stolle, A.; Szuppa,
T.; Leonhardt, S. E. S.; Ondruschka, B. Chem. Soc. Rev. 2011, 40, 2317; (d)
Bruckmann, A.; Krebs, A.; Bolm, C. Green Chem. 2008, 10, 1131; (e) O’Brien, M.;
Denton, R.; Ley, S. V. Synthesis 2011, 1157.
3. Colacino, E.; Nun, P.; Colacino, F. M.; Martinez, J.; Lamaty, F. Tetrahedron 2008,
64, 5569.
3H), 7.72 (d, 2H, J¼7.7 Hz), 7.87 (s, 1H). 13C NMR (acetone-d6)
d 28.4,
46.8, 81.4, 116.6, 127.7, 129.4, 129.9, 132.7, 136.6, 140.8, 153.8. MS
(ESI) m/z: 261.2 [MþH]þ, 205.0. HRMS calcd for C15H21N2O2:
261.1603. Found 261.1599.
4. Komatsu, K. Top. Curr. Chem. 2005, 254, 185.
4.4.6. (E)-N-Allyl-N0-(3,5-dimethoxybenzylidene)benzohydrazide
5. Zhang, Z.; Gao, J.; Xia, J.-J.; Wang, G.-W. Org. Biomol. Chem. 2005, 3, 1617.
6. Kaupp, G.; Naimi-Jamal, M. R.; Stepanenko, V. Chem.dEur. J. 2003, 9, 4156.
7. Kaupp, G.; Naimi-Jamal, M. R.; Schmeyers, J. Tetrahedron 2003, 59, 3753.
8. Raston, C. L.; Scott, J. L. Green Chem. 2000, 2, 49.
35. White solid; mp 99 ꢀC. 1H NMR (acetone-d6)
d 3.71 (s, 6H), 4.86
(m, 2H), 5.21e5.26 (m, 2H), 5.89e6.02 (m, 1H), 6.44 (s, 1H), 6.71 (s,
2H), 7.47e7.50 (m, 3H), 7.72e7.76 (m, 2H), 7.86 (s, 1H). 13C NMR
ꢁ
9. Rodrõguez, B.; Bruckmann, A.; Bolm, C. Chem.dEur. J. 2007, 13, 4710.
10. (a) Balema, V. P.; Wiench, J. W.; Pruski, M.; Pecharsky, V. K. J. Am. Chem. Soc.
2002, 124, 6244; (b) Baron, A.; Martinez, J.; Lamaty, F. Tetrahedron Lett. 2010, 51,
6246.
(acetone-d6) d 44.0, 55.6, 102.7, 105.6, 117.1, 128.1, 130.6, 130.8, 131.9,
136.9, 138.2, 140.4, 162.0, 171.0. MS (ESI) m/z: 325.3 [MþH]þ HRMS
11. Giri, N.; Bowen, C.; Vyle, J. S.; James, S. L. Green Chem. 2008, 10, 627.
12. Rasmussen, M. O.; Axelsson, O.; Tanner, D. Synth. Commun. 1997, 27, 4027.
13. (a) Tullberg, E.; Peters, D.; Frejd, T. J. Organomet. Chem. 2004, 689, 3778; (b)
Tullberg, E.; Schacher, F.; Peters, D.; Frejd, T. Synthesis 2006, 1183.
14. (a) Declerck, V.; Martinez, J.; Lamaty, F. WO 2008125418, 2008; (b) Declerck, V.;
Nun, P.; Martinez, J.; Lamaty, F. Angew. Chem., Int. Ed. 2009, 48, 9318.
15. Thorwirth, R.; Bernhardt, F.; Stolle, A.; Ondruschka, B.; Asghari, J. Chem.dEur. J.
2010, 16, 13236.
16. Fulmer, D. A.; Shearouse, W. C.; Medonza, S. T.; Mack, J. Green Chem. 2009, 11,
1821.
17. Thorwirth, R.; Stolle, A.; Ondruschka, B.; Wild, A.; Schubert, U. S. Chem. Com-
mun. 2011, 4370.
calcd for C19H21N2O3: 325.1552. Found 325.1550.
4.4.7. (E)-N-Benzyl-N0-(3,5-dimethoxybenzylidene)benzohydrazide
36. White solid; mp 120 ꢀC. 1H NMR (acetone-d6)
d 3.68 (s, 6H),
5.50 (s, 2H), 6.41 (t, 1H, J¼2.3 Hz), 6.62 (s, 1H), 7.34e7.41 (m, 6H),
7.52e7.66 (m, 2H), 7.76e7.83 (m, 2H), 7.86 (s, 1H). 13C NMR (ace-
tone-d6)
d 45.8, 56.0, 103.1, 106.0, 128.1, 128.6, 130.2, 131.0, 131.4,
136.9, 137.3, 138.4, 140.9, 162.4, 172.1. MS (ESI) m/z: 375.2 [MþH]þ
HRMS calcd for C23H23N2O3: 375.1709. Found 375.1703.
18. Manabe, K.; Oyamada, H.; Sugita, K.; Kobayashi, S. J. Org. Chem. 1999, 64, 8054.
19. Keith, J. M.; Gomez, L. J. Org. Chem. 2006, 71, 7113.
20. Keith, J. M.; Jacobsen, E. N. Org. Lett. 2004, 6, 153.
21. (a) Tan, K. L.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2007, 46, 1315; (b) Hir-
abayashi, R.; Ogawa, C.; Sugiura, M.; Kobayashi, S. J. Am. Chem. Soc. 2001, 39,
9493; (c) Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125,
9596.
22. (a) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58,
2253; (b) Lazny, R.; Nodzewska, A. Chem. Rev. 2010, 110, 1386.
23. Dabideen, D. R.; Cheng, K. F.; Aljabari, B.; Miller, E. J.; Pavlov, V. A.; Al-Abed, Y.
J. Med. Chem. 2007, 50, 1993.
4.4.8. (E)-N-Allyl-N0-(3,5-dimethoxybenzylidene)-4-methylbenzene-
sulfonohydrazide 37. White solid; mp 113 ꢀC. 1H NMR (acetone-d6)
d
2.41 (s, 3H), 3.81 (s, 6H), 4.47e4.51 (m, 2H), 5.20e5.29 (m, 2H),
5.80e5.88 (m, 1H), 6.51 (t, 1H, J¼2.3 Hz), 6.83 (s, 2H), 7.40 (d, 2H,
J¼8.1 Hz), 7.74 (s, 1H), 7.90 (d, 2H, J¼8.3 Hz). 13C NMR (acetone-d6)
d
19.4, 47.9, 53.7, 100.8, 103.6, 116.0, 127.0, 128.4, 130.5, 134.3, 135.4,
142.4, 143.1, 160.0. MS (ESI) m/z: 375.2 [MþH]þ. HRMS calcd for
C19H23N2O4S: 375.1379. Found 375.1374.
24. Bandgar, B. P.; Sadavarte, V.; Uppalla, L. S.; Govande, R. Monatsh. Chem. 2001,
132, 403.
4.4.9. tert-Butyl 1-allyl-2-cyclohexylidenehydrazinecarboxylate
25. Li, J.-P.; Zheng, P.-Z.; Zhu, J.-G.; Liu, R.-J.; Qu, G.-R. S. Afr. J. Chem. 2006,
59, 90.
26. Jeselnik, M.; Varma, R. S.; Polanc, S.; Kocevar, M. Chem. Commun. 2001, 1716.
27. Hajipour, A. R.; Mohammadpoor-Baltork, I.; Bigdeli, M. J. Chem. Res., Synop.
1999, 570.
38. Colorless oil; 1H NMR (acetone-d6)
d
1.42 (s, 9H), 1.61e1.69 (m,
6H), 2.24e2.34 (m, 4H), 4.04 (m, 2H), 5.03e5.13 (m, 2H), 5.71e5.89
(m,1H). 13C NMR (acetone-d6)
d 27.0, 27.6, 28.7, 29.2, 31.4, 36.6, 42.9,
53.7, 80.8, 117.5, 136.0, 153.7, 178.9. MS (ESI) m/z: 253.3 [MþH]þ,
28. Bondock, S.; El-Azap, H.; Kandeel, E.-E. M.; Metwally, M. A. Monatsh. Chem.
2008, 139, 1329.
197.0. HRMS calcd for C14H25N2O2: 253.1916. Found 253.1941.
29. (a) Kaupp, G.; Schmeyers, J.; Boy, J. J. Prakt. Chem. 2000, 342, 269; (b) Mokhtari,
J.; Naimi-Jamal, M. R.; Hamzeali, H.; Dekamin, M. G.; Kaupp, G. ChemSusChem
2009, 2, 248.
4.4.10. N-Allyl-4-methyl-N0-(pentan-3-ylidene)benzenesulfonohy-
30. Boeglin, D.; Lubell, W. D. J. Comb. Chem. 2005, 7, 864.
31. Obreza, A.; Urleb, U. Acta Chim. Slov. 2002, 49, 605.
32. (a) Ragnarson, U. Chem. Soc. Rev. 2001, 30, 205; (b) Gante, J. Synthesis 1989, 405.
33. (a) Mundal, D. A.; Lee, J. J.; Thomson, R. J. J. Am. Chem. Soc. 2008, 130, 1148; (b)
Mundal, D. A.; Lutz, E. K.; Thomson, R. J. Org. Lett. 2009, 11, 465.
34. Matunas, R.; Lai, A. J.; Lee, C. Tetrahedron 2005, 61, 6298.
35. Baumgarten, H. E.; Hwang, D.-R.; Rao, T. N. J. Heterocycl. Chem. 1986, 23,
945.
drazide 39. Yellow oil; 1H NMR (acetone-d6)
d
1.07 (t, 3H, J¼7.5 Hz),
1.10 (t, 3H, J¼7.7 Hz), 2.37 (q, 2H, J¼7.4 Hz), 2.45 (s, 3H), 2.63 (q, 2H,
J¼7.7 Hz), 3.56 (d, 2H, J¼6.7 Hz), 5.07 (m, 2H), 5.67 (m, 1H), 7.43 (d,
2H, J¼8.0 Hz), 7.69 (d, 2H, J¼8.3 Hz). 13C NMR (acetone-d6)
d 10.8,
11.0, 21.6, 26.2, 29.1, 56.0, 119.6, 130.0, 130.2, 133.7, 144.8, 187.9. MS
(ESI) m/z: 295.4 [MþH]þ, 273.2. HRMS calcd for C15H23N2O2S:
295.1480. Found 295.1457.
36. Weber, D.; Berger, C.; Eickelmann, P.; Antel, J.; Horst, K. J. Med. Chem. 2003, 46,
1919.
37. (a) Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 14800; (b) Bailey, M.
D.; Halmos, T.; Goudreau, N.; Lescop, E.; Llinas-Brunet, M. J. Med. Chem. 2004,
47, 3788.
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