Sustainable Synthesis of Oximes, Hydrazones, and Thiosemicarbazones under Mild Organocatalyzed Reaction Conditions

Article abstract of DOI:10.1021/acs.joc.6b01912

Pyrrolidine catalyzes very efficiently, presumably via iminium activation, the formation of acyloximes, acylhydrazones, and thiosemicarbazones derived from aromatic and aliphatic aldehydes using equimolar amounts of reagents and green solvents. Experimental simplicity and excellent yields after a simple filtration are the main advantages of the method, being an alternative to those currently available especially for the acyl derivatives, which do not work under uncatalyzed conditions. Its application to the synthesis of acyloximes by direct condensation between aldehydes and acylhydroxylamines is unprecedented.

Full text of DOI:10.1021/acs.joc.6b01912

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Note
A Sustainable Synthesis of Oximes, Hydrazones and
Thiosemicarbazones under Mild Organocatalyzed Reaction Conditions
Sara Morales, Jose Luis Aceña, José Luis García Ruano, and M. Belén Cid
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01912 • Publication Date (Web): 26 Sep 2016
Downloaded from http://pubs.acs.org on September 30, 2016
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A Sustainable Synthesis of Oximes, Hydrazones and Thiosemicarbazones
under Mild Organocatalyzed Reaction Conditions
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Sara Morales, José Luis Aceña, José Luis García Ruano and M. Belén Cid*
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Department of Organic Chemistry, Universidad Autónoma de Madrid, Cantoblanco, 28049
Madrid, Spain
e-mail: belen.cid@uam.es
ABSTRACT: Pyrrolidine catalyzes very efficiently, presumably via iminium activation, the
formation of acyloximes, acylhydrazones and thiosemicarbazones derived from aromatic and
aliphatic aldehydes using equimolar amounts of reagents and green solvents. Experimental
simplicity and excellent yields after a simple filtration are the main advantages of the method,
being an alternative to those currently available especially for the acyl derivatives, which do not
work under uncatalyzed conditions. Its application to the synthesis of acyloximes by direct
condensation between aldehydes and acylhydroxylamines is unprecedented.
2XN
H2
N
R
XR2
H
H
N
N
O
1 equiv
H
N
N
H
R1
1 equiv
H
R1
XR2
(10 mol %)
rt
R1
H
N
R1
H
Alkyl and acyloximes
Acylhydrazones
Thiosemicarbazones
O
O
S
H
H
O
O
Bn
Ar
N
Ph
N
NH2 R1 = aryl,
N
N
N
N
alkyl, alkenyl
R1
H
R1
H
R1
H
R1
H
Green solvents,
mild conditions,
no purification
3 - 8h
70 - 100%
(THF)
1 - 2h
92 - 100%
(EtOAc)
2 - 5h
85 - 99%
(H2O)
0.5 - 1h
91 - 100%
(H2O)
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Hydroxylamines and hydrazines are commonly referred as α-nucleophiles, showing a
distinctive enhanced reactivity towards electrophiles compared to amines. The origin of this α-
effect probably relies on the presence of one or more nonbonding electron pairs in the atom
adjacent to the reaction center.1 Oximes and hydrazones are usually much more stable than other
C=N functionalized compounds such as imines.2 This higher stability is currently exploited in
the emerging field of dynamic covalent chemistry3 as well as in the preparation of bioconjugates.4
In addition, these functionalities appear on several classes of biologically relevant products
(Figure 1).5,6
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NO2
O
Cl
O
N
O
F
O
O
N
N
H
N
H
X
X = H, NH2
F
Flucycloxuron
Larvicide
N
DNA-photocleavage
agent
H
N
O
t-Bu
O
O
OH
N
OH
N
N
O
N
H
NO2
S
t-Bu
Antitumoral
activity
Anti inflammatory
agent
O
N
NO2
N
H
O
HO
Antimicrobial,antiseptic
agent
Figure 1. Oximes and hydrazones as important biological compounds.
Among the different approaches for the synthesis of oximes and hydrazones, the shortest
method involves the direct condensation between a carbonyl compound and the corresponding
α-nucleophile.7 The importance of creating this type of bonds is clearly established in the relevant
work by Dawson and co-workers, where oxime ligation could be efficiently promoted by aniline
derivatives at neutral pH,8 and the subsequent efforts to find other less toxic and water-soluble
catalysts able to effect this transformation.9,10
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We recently demonstrated that secondary amines might serve as efficient aminocatalysts in
the preparation of imine derivatives, achieving optimal results when using pyrrolidine.11 This
metal-free process occurred through iminium ion (I) formation under mild reaction conditions,
leading to a wide variety of imines in outstanding yields in the presence of a catalytic amount
(10 mol %) of pyrrolidine (Scheme 1a, path a.1). Following the same methodology, we also
developed a very efficient, simple, general and reliable protocol to prepare nitrones in a matter
of minutes starting from differently N-substituted hydroxylamine hydrochlorides (Scheme 1a,
path a.2).12 In this case, the use of 1.2 equiv of pyrrolidine allows the complete liberation of the
free hydroxylamine (which consumes 1 equiv of pyrrolidine), and also increases the
electrophilicity of the carbonyl group through the formation of iminium ion I. In addition, nitrone
formation is prompted because elimination of pyrrolidine from aminal II is very favored as it is
easily protonated thanks to its basic character. Moreover, the simultaneous formation of
pyrrolidinium chloride (1 equiv) turned out to be beneficial since the pyrrolidine/pyrrolidinium
system acts as proton transfer favoring some steps of the catalytic cycle without hampering the
nucleophilicity of the N-substituted hydroxylamine by protonation.
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Scheme 1. Pyrrolidine catalysis via iminium activation ion and cooperative
pyrrolidine/pyrrolidinium catalysis.
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a) Previous work
R2
H
R2= SOR, SO2R,
POPh2, Aryl, Alkyl
a.1.
N
R2-NH2
R1
All types of imines
O
N
H
N
I
a.2.
R1
H
3
R1
H
·HCl
R NHOH
R3= Ph, t-Bu,
Me, Cy, Bn
R1= Ar, alkyl,
vinyl
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Iminium
activation
N
+
N
H
H
Cl
NH
O
R3
H
H
N
OH
R1
N
II R3
R1
Proton
transfer
Nitrones
b) This work
N
4
O
N
H
X
R
H
R4XNH2
N
N
H
N
R1
H
4
X
R
R1
H
R1
R1
H
N
H
I
III
According to these results, we envisioned that the use of pyrrolidine could also have a
beneficial effect on the preparation of oximes, hydrazones and derivatives (Scheme 1b). As in
the formation of nitrones, the high reactivity of the corresponding α-nucleophile would produce
a fast attack to either the aldehyde or to the iminium ion. Nevertheless, a positive role of
pyrrolidine would be expected in the second step of the catalytic cycle, where the elimination of
pyrrolidine from the resulting protonated aminal intermediate III could be very favored.13
Furthermore, we can predict a more marked influence of pyrrolidine in the preparation of the
more biologically relevant N-acyloximes14 and N-acylhydrazones,15 which present higher
synthetic difficulties because of the lower nucleophilic character of the corresponding α-
nucleophiles. Particularly, N-benzoyloximes have been prepared almost exclusively through
indirect methods,16 as their access by direct condensation affords very low yields as a
consequence of the easy evolution towards the corresponding nitriles.17
Therefore, we present herein a systematic study to evaluate the role of pyrrolidine in the
condensations of aldehydes with nucleophiles of type R-X-NH2 where X = NH, O and R = aryl,
alkyl, -COR, -SO2R, -C(=S)NH2; in order to provide a general method especially competitive to
prepare substrates exhibiting higher synthetic difficulties as well as biological interest. In all
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cases, both water and organic solvents have been tested. Yields and conditions have been
compared with those of the best methods described so far in the literature.
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We started by testing the role of pyrrolidine in the preparation of oxime ethers from O-
alkylhydroxylamine hydrochlorides. According to the literature, this transformation usually
requires a large excess of base, typically pyridine or NaOAc, in order to release the free
hydroxylamine. Furthermore, polar protic solvents, excess of reagent, heat, extended reaction
times and tedious purifications are usually needed to attain high yields of the final product.18
Contrasting with this information, we have found that the condensation between equimolecular
amounts of 2,4-dimethoxybenzaldehyde (1f) and O-benzylhydroxylamine hydrochloride (2·HCl)
occurred in the absence of any base at room temperature in aqueous media, and hence O-
benzyloxime 3f was obtained at 70% conversion after 30 min (Table 1, entry 1), requiring 4 h to
reach full conversion (entry 2). This behavior could be due to the fast dissociation of
hydrochloride 2·HCl in water and the high reactivity of the free hydroxylamine. The addition of
0.1 equiv of pyrrolidine to the reaction mixture slightly increases the reaction rate (compare
entries 1 and 3), which is more marked by using higher amounts of pyrrolidine (compare entries
2 with 4-6), being possible the substantial reduction of the time for obtaining quantitative yields
of 3f. This moderate catalytic effect of pyrrolidine in aqueous media could be mainly attributed
to its influence as a base in accelerating the liberation of the free hydroxylamine from its
hydrochloride (2·HCl), demonstrating that the effect of pyrrolidine was very similar to that
observed by addition of NaOAc, a representative base employed in oxime synthesis, in both
stoichiometric and catalytic amounts (entries 7-8).
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Table 1. Optimization of the Reaction Conditions to Form O-Benzyloxime 3f from
5
6
Aldehyde 1f and Hydroxylamine 2·HCla
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entry
1
base (equiv)
none
solvent
H2O
t (h)
0.5
4
conv. (%)b
70
2
none
H2O
100
3
pyrrolidine (0.1)
pyrrolidine (1.0)
pyrrolidine (1.1)
pyrrolidine (1.1)
NaOAc (1.1)
NaOAc (0.1)
none
H2O
0.5
2
88
4
H2O
100 (99)c
5
H2O
1
100 (93)c
6
H2O
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
4
97
7
H2O
100
8
H2O
88
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
13
10
11
12
13
14
15
NaOAc (0.1)
pyridine (0.1)
pyrrolidine (0.1)
pyridine (0.1)
pyrrolidine (0.1)
pyrrolidine (0.1)
30
47
55
37
THF
54
THF
100 (100)c
a0.2 mmol scale. bMeasured by integration in the 1H NMR crude spectra. In parentheses, isolated yield
of pure product after filtration through basic celite.
c
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The preparation of oxime 3f was also studied in organic solvents, where the dissociation of
hydrochloride 2·HCl producing the free hydroxylamine is more difficult than in water,
determining a much slower formation of the oxime 3f. Thus, the conversion observed after 30
min in CH2Cl2 without any base was only 13% (entry 9), much lower than that in water (entry
1). The influence produced by the addition of catalytic amounts of bases is now more significant
(entries 10-12). Pyrrolidine resulted to be efficient in CH2Cl2, as well as in THF (compare entries
13 and 14), where full conversion was reached after 4 h, being oxime 3f isolated in quantitative
yield after removing pyrrolidine by a simple filtration through basic celite (entry 15). The higher
conversion obtained in the presence of pyrrolidine with respect to other commonly used bases
(compare entries 13 and 14) suggests, even with the highly reactive hydroxylamines, an effect of
pyrrolidine beyond of the simple liberation of the hydrochloride 2·HCl.
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The latter pyrrolidine-catalyzed conditions were extended to a variety of aromatic and
aliphatic aldehydes to render the corresponding oxime ethers 3 in excellent yields. Thus, electron-
donating or electron-withdrawing groups were well tolerated in several benzaldehyde
derivatives, although in some cases the amount of pyrrolidine should be raised to 0.2 equiv for
achieving a better yield (Table 2, entries 1-7). The process was also suitable for preparing the O-
benzyloximes derived from 2-formylpyridine (entry 8), and the more challenging enals (entry 9)
or aliphatic aldehydes (entries 10-12).
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Table 2. Synthesis of O-Benzyloximes 3 from Aldehydes 1a
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entry
R1 (aldehyde)
pyrrolidine
(equiv)
0.2
t (h)
3 (yield, %)b
1
2
Ph (1a)
4-MeOC6H4 (1b)
4-NO2C6H4 (1c)
4-ClC6H4 (1d)
2-ClC6H4 (1e)
2,4-di-MeOC6H4 (1f)
3,4,5-tri-MeOC6H4 (1g)
2-pyridyl (1h)
PhCH=CH (1i)
i-Bu (1j)
5.5
6
3a (84)
3b (80)
3c (96)
3d (96)
3e (92)
3f (100)
3g (100)
3h (85)
3i (92)
0.2
3
0.2
6
4
0.2
6
5
0.1
6
6
0.1
4
7
0.1
7.5
3
8
0.1
9
0.2
8
10
11
12
0.1
2
3j (100)
3k (91)
3l (70)
cyclohexyl (1k)
t-Bu (1l)
0.1
1.5
4
0.2
a0.2 mmol scale. bIsolated yield of pure product after filtration through basic celite.
The yields of the O-benzyloximes collected in Table 2 are similar or higher than those reported
in the literature, most of them requiring high temperatures and excess of nucleophile and base
(in some cases is used as solvent), which implies the use of extraction operations,
chromatographic columns and/or recrystallization techniques to isolate and purify the oximes.18
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In this sense, our method proved superior in terms of simplicity (room temperature, short reaction
times and ease of purification). Other strategies commonly employed consist of the alkylation of
the corresponding aldoximes or the use of radical or oxidative methods, procedures which imply
several reaction steps and a lower atomic economy (see Table S5 in the SI for more details).
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O-Benzoyloximes are interesting compounds because of their higher biological relevance
compared to the parent oxime ethers.14 They are generally synthesized from the corresponding
aldehydes through a two-step protocol (formation of oximes and further acylation) that usually
entails relatively harsh reaction conditions,16,19,20 because the methods for their preparation
through direct condensation between aldehydes and O-acylhydroxylamines normally afford
mixtures of the O-benzoyloxime and the corresponding nitrile.17 These features converted
benzoyloxime derivatives 5 in special goals for testing our synthetic method. The results obtained
in the reaction of aromatic and aliphatic aldehydes with O-(4-nitrobenzoyl)hydroxylamine (4)
are depicted in Table 3. The established optimal conditions implied using 10-20 mol % of
pyrrolidine in EtOAc as solvent, which allowed us to obtain very high yields within 1-2 h. Partial
decomposition of the aromatic benzoyloximes into their corresponding nitriles was observed
when using protic solvents (H2O or MeOH), higher catalyst loadings or under extended reaction
times. Again, purification was easily carried out by filtration through celite. We must remark the
excellent results obtained in the synthesis of the 4-nitrobenzoyloxime derived from 2-
formylpyridine, 5h (entry 5), which was recently designed for interacting and cleaving DNA by
the action of light (“photo-cleaver”), with potential applications in both treatment of solid tumors
and as a diagnostic tool for the detection of cancer.14a
Table 3. Synthesis of O-Benzoyloximes 5 from Aldehydes 1a
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entry
R1 (aldehyde)
pyrrolidine
(equiv)
0.2
t (h)
5 (yield, %)b
1
2
3
4
5
6
Ph (1a)
2
1
2
2
1
2
5a (100)
5b 95
4-MeOC6H4 (1b)
4-NO2C6H4 (1c)
4-ClC6H4 (1d)
2-pyridyl (1h)
i-Bu (1j)
0.1
0.2
5c (99)
5d (93)
5h (93)
5j (100)
0.2
0.1
0.1
a0.2 mmol scale. bIsolated yield of pure product after filtration through celite.
Next, we turned our attention to the synthesis of the parent aryl- and sulfonylhydrazones,
which are versatile synthetic intermediates.21 The high reactivity of arylhydrazines determines
that their reactions with aldehydes were completed in a matter of minutes, both in H2O or THF,
being the presence of pyrrolidine practically irrelevant (for more information, see Tables S1 and
S2 in SI). However, our method proved to be very practical when applied to the synthesis of N-
acylhydrazones 7 and thiosemicarbazones 9 from the corresponding acylhydrazines 6 and
thiosemicarbazides 8, respectively, much less nucleophilic than arylhydrazines (Table 4).
Therefore, the reported methods for preparing this type of compounds in high yields and
reasonable times involve the use of microwaves, acid catalysis, reflux temperature or excess of
reagents, which impose the use of purification processes (see Table S6 in SI for detailed
information). By contrast, the coupling of equimolar quantities of aldehydes 1 with
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benzohydrazide 6 proceeded smoothly at room temperature in the presence of catalytic
pyrrolidine in H2O, providing the final acylhydrazones 7 in high yields under much milder
reaction conditions compared to those previously described.22 In comparison, the non-catalyzed
reaction did not afford any amount of the target N-acylhydrazones after similar reaction times
(see Tables S3 and S4 in SI). The scope of the process included differently substituted aromatic
aldehydes as well as aliphatic ones. The fact that these reactions work under aqueous conditions
is a noteworthy point as they are relevant as pharmacophoric moieties15 and synthetic
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21
intermediates. The process could be scaled-up providing multigram amounts of the final N-
acylhydrazones in comparable chemical yields and reaction times (Table 4, entry 8).
Table 4. Synthesis of N-Acylhydrazones 7 and Thiosemicarbazones 9 from Aldehydes 1a
entry
R1 (aldehyde)
N-acylhydrazones
thiosemicarbazones
t (h) 7 (yield, %)b t (min) 9 (yield, %)b
1
2
3
4
5
Ph (1a)
2
4
5
2
3
7a (98)
7b (91)
7c (90)
7d (93)
7e (85)
40
50
30
35
60
9a (99)
9b (91)
9c (99)
9d (95)
9e (92)
4-MeOC6H4 (1b)
4-NO2C6H4 (1c)
4-ClC6H4 (1d)
2-ClC6H4 (1e)
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i-Bu (1h)
cyclohexyl (1k)
Ph (1a)
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7j (95)
7k (99)
7a (94)
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9j (98)
9k (100)
8c
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a0.2 mmol scale. bIsolated yield of pure product after filtration through celite. cPerformed on
10 mmol scale.
Analogously, the parent semithiocarbazones 9 were prepared under identical reaction
conditions by treatment of aldehydes 1 with thiosemicarbazide 8, proceeding even faster than in
the case of acylhydrazones (Table 4). Once again, synthetic protocols previously described for
the preparation of compounds 9 that provided high yields demanded either heat, longer reaction
times, excess of reagents or the use of acidic catalysts and a recrystallization process to purify
the products (see Table S7 in SI for more detailed information).23
In conclusion, pyrrolidine is also an excellent catalyst for the efficient synthesis of substituted
oximes, hydrazones and thiosemicarbazones through iminium ion activation and with minimal
experimental manipulation and waste. Its usefulness is especially important when applied to the
preparation of the more challenging and biologically relevant acyl derivatives. N-Acyloximes
were not previously accessible through the direct condensation between aldehydes and
acylhydroxylamines and cannot be prepared under uncatalyzed conditions, whereas N-
acylhydrazones had been prepared only through impractical protocols. These mild and acid-free
reaction conditions required are amenable for further implementation in the synthesis of oxime-
and hydrazone-containing biomolecules while preserving their structural integrity.
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EXPERIMENTAL SECTION
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General Experimental Methods. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded with 300 MHz spectrometers in CDCl3, THF-d6, acetone-d6 or DMSO-d6 with the
residual solvent peak as an internal standard. Chemical shifts (δ) are given in parts per million,
and coupling constants are given as absolute values expressed in hertz. Positive electrospray
ionization (ESI) or electron impact ionization (EI) mass spectra were collected using a TOF
analyzer system. Obtained data are expressed in mass/charge (m/z) units. Values between
parentheses indicate relative intensities with regard to the base peak. Silica gel pore 60 Å, 40-63
μm, Celite® 512 medium and (Hyflo® Super Cel®) were used for filtration. All solvents were
used without previous treatment. EtOAc and THF were used in analytical grade. Although we
have proven that tap water can be used, the results presented herein have been obtained using
deionized water. All starting materials were purchased from commercial suppliers. Aldehydes
were washed with aqueous saturated NaHCO3 to remove acids traces. Pyrrolidine > 99.5% pure
was used.
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General procedure for the synthesis of O-benzyloximes 3. To a 0.33 M solution of O-
benzylhydroxylamine hydrochloride (2·HCl) (32 mg, 0.2 mmol) and the corresponding aldehyde
1 (1 equiv) in THF, a freshly prepared 0.2 M solution of pyrrolidine in THF (10 or 20 mol %)
was added. The mixture was stirred at room temperature during the time indicated in each case.
Then, the reaction was filtered through a short pad of basic celite (Hyflo® Super Cel®) using a
glass frit with EtOAc to obtain the final oximes 3 without any further purification. O-
benzyloximes 3 were obtained as a mixture of diastereomers E/Z.
Benzaldehyde O-benzyl oxime (3a). From benzaldehyde (1a) (21.2 mg, 0.2 mmol) and 20 mol
% of pyrrolidine, after 5.5 h the title compound was obtained in 84% yield (35.5 mg) as a
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colourless oil (E/Z ratio 87:13). Data of the mayor diastereomer (E): 1H NMR (300 MHz, CDCl3):
δ 8.28 (s, 1H), 7.77–7.67 (m, 2H), 7.62–7.39 (m, 8H), 5.37 (s, 2H). Spectroscopic data matched
those previously reported.18a
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4-Methoxybenzaldehyde O-benzyl oxime (3b). From 4-methoxybenzaldehyde (1b) (27.2 mg,
0.2 mmol) and 20 mol % of pyrrolidine, after 6 h the title compound was obtained in 80% yield
1
(38.6 mg) as a colourless oil (E/Z ratio 83:17). Data of the mayor diastereomer (E): H NMR
(300 MHz, CDCl3) δ 8.01 (s, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.38–7.20 (m, 5H), 6.80 (d, J = 8.8
Hz, 3H), 5.11 (s, 2H), 3.73 (s, 3H). Spectroscopic data matched those previously reported.24
4-Nitrobenzaldehyde O-benzyl oxime (3c). From 4-nitrobenzaldehyde (1c) (30.2 mg, 0.2
mmol) and 20 mol % of pyrrolidine, after 6 h the title compound was obtained in 96% yield (49.2
1
mg) as a colourless oil (E/Z ratio 86:14). Data of the mayor diastereomer (E): H NMR (300
MHz, CDCl3) δ 8.30–8.19 (m, 3H), 7.77 (d, J = 8.7 Hz, 2H), 7.54–7.35 (m, 5H), 5.32 (s, 2H).
Spectroscopic data matched those previously reported.25
4-Chlorobenzaldehyde O-benzyl oxime (3d). From 4-chlorobenzaldehyde (1d) (28.1 mg, 0.2
mmol) and 20 mol % of pyrrolidine, after 6 h the title compound was obtained in 96% yield (47
mg) as a colourless oil (E/Z ratio 81:19). Data of the major diastereomer (E): 1H NMR (300 MHz,
CDCl3) δ 8.00 (s, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.36–7.18 (m, 7H), 5.12 (s, 2H). 13C NMR (75
MHz, CDCl3) δ 147.9 (CH=N), 132.4 (C), 130.9 (C), 129.1 (2 x CH), 128.8 (C), 128.6 (2 x CH),
128.5 (2 x CH), 128.4 (2 x CH), 128.1 (C), 76.7 (CH2). MS (EI): m/z 245 (M+, 4), 139 (12), 137
(32), 102 (14), 91 (100), 77 (12). HRMS (EI): calcd for C14H12NOCl (M+): 245.0607; found:
245.0596.
2-Chlorobenzaldehyde O-benzyl oxime (3e). From 2-chlorobenzaldehyde (1e) (28.1 mg, 0.2
mmol) and 10 mol % of pyrrolidine, after 6 h the title compound was obtained in 92% yield (45
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mg) as a colourless oil (E/Z ratio >95:5). Data of the major diastereomer (E): 1H NMR (300 MHz,
CDCl3) δ 8.48 (s, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.44–7.04 (m, 8H), 5.15 (s, 2H). 13C NMR (75
MHz, CDCl3) δ 146.2 (CH=N), 137.4 (C), 134.0 (C), 130.9 (CH), 130.1 (C), 129.94 (CH), 128.6
(2 x CH), 128.5 (2 x CH), 128.2 (CH), 127.3 (CH), 127.0 (C), 76.8 (CH2). MS (EI): m/z 210 (M+-
Cl, 12), 137 (16), 91 (100). HRMS (EI): calcd for C14H12NO (M+-Cl): 210.0919; found:
210.0896.
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2,4-Dimethoxybenzaldehyde O-benzyl oxime (3f). From 2,4-dimethoxybenzaldehyde (1f)
(33.2 mg, 0.2 mmol) and 10 mol % of pyrrolidine, after 4 h the title compound was obtained in
quantitative yield (54.2 mg) as a colourless oil (E/Z ratio >95:5). Data of the major diastereomer
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(E): H NMR (300 MHz, CDCl3) δ 8.38 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.39–7.17 (m, 5H),
6.39 (dd, J = 8.4, 2.4 Hz, 1H), 6.32 (d, J = 2.4 Hz, 1H), 5.09 (s, 2H), 3.71 (s, 3H), 3.69 (s, 3H).
13C NMR (75 MHz, CDCl3) δ 162.5 (C-OCH3), 159.0 (C-OCH3), 145.2 (CH=N), 138.0 (C),
128.5 (2 x CH), 128.4 (2 x CH), 127.9 (CH), 127.5 (CH), 113.9 (C), 105.6 (CH), 98.3 (CH), 76.2
(CH2), 55.6 (OCH3), 55.50 (OCH3). MS (EI): m/z 271 (M+, 15), 163 (100), 149 (17), 134 (69),
91 (53). HRMS (EI): calcd for C16H17NO3 (M+): 271.1208; found: 271.1197.
3,4,5-Trimethoxybenzaldehyde O-benzyl oxime (3g). From 3,4,5-trimethoxybenzaldehyde
(1g) (39.2 mg, 0.2 mmol) and 10 mol % of pyrrolidine, after 7.5 h the title compound was
obtained in quantitative yield (60.2 mg) as a colourless oil (E/Z ratio 88:12). Data of the major
diastereomer (E): 1H NMR (300 MHz, CDCl3) δ 7.97 (s, 1H), 7.37–7.19 (m, 5H), 6.72 (s, 2H),
5.13 (s, 2H), 3.78 (s, 6H), 3.77 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 153.5 (CH=N), 148.9 (2 x
C-OCH3), 139.8 (C-OCH3), 137.6 (C), 128.5 (2 x CH), 128.4 (2 x CH), 128.0 (CH), 127.7 (C),
104.3 (2 x CH), 76.4 (CH2), 60.9 (OCH3), 56.3 (2 x OCH3). MS (EI): m/z 301 (M+, 25), 193
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(100), 178 (99), 150 (31), 135 (41). HRMS (EI): calcd for C17H19NO4 (M+): 301.1314; found:
301.1302.
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Picolinaldehyde O-benzyl oxime (3h). From 2-formylpyridine (1h) (21.4 mg, 0.2 mmol) and
10 mol % of pyrrolidine, after 3 h the title compound was obtained in 85% yield (36 mg) as a
colourless oil (E/Z ratio >98:2). Data of the mayor diastereomer (E): 1H NMR (300 MHz, CDCl3)
δ 8.65 (d, J = 4.8 Hz, 1H), 8.28 (s, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.52–
7.34 (m, 5H), 7.33–7.25 (m, 1H), 5.31 (s, 2H). Spectroscopic data matched those previously
reported.18a
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Cinnamaldehyde O-benzyl oxime (3i). From cinamaldehyde (1i) (26.4 mg, 0.2 mmol) and 20
mol % of pyrrolidine, after 8 h the title compound was obtained in 92% yield (43.6 mg) as a
colourless oil (E/Z ratio 71:29). Data of diastereomer (E): 1H NMR (300 MHz, CDCl3) δ 7.91 (d,
J = 9.5 Hz, 1H), 7.38–7.22 (m, 10H), 6.81 (dd, J = 16.0, 9.5 Hz, 1H), 6.69 (d, J = 16.0 Hz, 1H),
5.13 (s, 2H). Spectroscopic data matched those previously reported.26
3-Methylbutanal O-benzyl oxime (3j). From 3-methylbutanal (1j) (17.2 mg, 0.2 mmol) and 10
mol % of pyrrolidine, after 2 h the title compound was obtained in quantitative yield (38.2 mg)
as a colourless oil (E/Z ratio 61:39). Spectroscopic data matched those previously reported.18b
Cyclohexanecarbaldehyde O-benzyl oxime (3k). From cyclohexanecarbaldehyde (1k) (22.4
mg, 0.2 mmol) and 10 mol % of pyrrolidine, after 1.5 h the title compound was obtained in 91%
yield (39.5 mg) as a colourless oil (E/Z ratio 76:24). Spectroscopic data matched those previously
reported.18b
Pivalaldehyde O-benzyl oxime (3l). From pivalaldehyde (1l) (17.2 mg, 0.2 mmol) and 20 mol
% of pyrrolidine, after 4 h the title compound was obtained in 70% yield (26.7 mg) as a colourless
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oil (E/Z ratio 100:0). 1H NMR (300 MHz, CDCl3) δ 7.48–7.29 (m, 5H), 5.10 (s, 2H), 1.15 (s,
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9H). Spectroscopic data matched those previously reported.18f
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General procedure for the synthesis of O-benzoyloximes 5. To a 0.33 M solution of O-(4-
nitrobenzoyl)hydroxylamine (4) (36.4 mg, 0.2 mmol) and the corresponding aldehyde 1 (1 equiv)
in EtOAc, a freshly prepared 0.2 M solution of pyrrolidine in EtOAc (10 or 20 mol %) was added.
The mixture was stirred at room temperature during the time indicated in each case. Then, the
reaction was filtered through a short pad of celite using a glass frit with EtOAc to obtain the final
O-benzoyloximes 5 without any further purification. O-Benzoyloximes derived from aromatic
aldehydes show a fast decomposition process at room temperature toward the corresponding
nitrile, hampering in some cases their full characterization.
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(E)-Benzaldehyde O-(4-nitrobenzoyl)oxime (5a). From benzaldehyde (1a) (21.2 mg, 0.2
mmol) and 20 mol % of pyrrolidine, after 2 h the title compound was obtained in quantitative
yield (54 mg). 1H NMR (300 MHz, acetone‐d6) δ 8.75 (s, 1H), 8.35–8.21 (m, 4H), 7.83–7.69 (m,
2H), 7.55–7.34 (m, 3H). Spectroscopic data matched those previously reported.17
b
(E)-4-Methoxybenzaldehyde O-(4-nitrobenzoyl)oxime (5b). From 4-methoxybenzaldehyde
(1b) (27.2 mg, 0.2 mmol) and 10 mol % of pyrrolidine, after 1 h the title compound was obtained
in 95% yield (57 mg) as a yellow solid. 1H NMR (300 MHz, THF-d8) δ 8.60 (s, 1H), 8.40–8.24
13
(m, 4H), 7.76 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 3.84 (s, 3H). C NMR (75 MHz,
THF-d8) δ 164.0 (C=O), 162.4 (C), 158.0 (CH=N), 152.0 (C), 134.8 (C), 131.6 (2 x CH), 131.0
(2 x CH), 124.6 (C), 115.8 (2 x CH), 115.4 (2 x CH), 55.9 (CH3). MS (ESI+): m/z 323 (M++Na)
(100), 173 (56), 139 (44). HRMS (ESI+): calcd for C15H12N2O5Na (M++Na): 323.0638; found:
323.0638.
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(E)-4-Nitrobenzaldehyde O-(4-nitrobenzoyl)oxime (5c). From 4-nitrobenzaldehyde (1c) (30.2
mg, 0.2 mmol) and 20 mol % of pyrrolidine, after 2 h the title compound was obtained in 99%
yield (63 mg). 1H NMR (300 MHz, DMSO‐d6) δ 8.09 (d, J = 9.2 Hz, 2H), 8.30 (d, J = 9.0 Hz,
2H), 8.38 (d, J = 9.2 Hz, 2H), 8.42 (d, J = 9.0 Hz, 2H), 9.16 (s, 1H); (300 MHz, CDCl3) δ 8.61
(s, 1H), 8.35–8.20 (m, 6H), 7.95 (d, J = 8.7 Hz, 2H). Spectroscopic data matched those previously
reported.17b
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(E)-4-Chlorobenzaldehyde O-(4-nitrobenzoyl)oxime (5d).19 From 4-chlorobenzaldehyde (1d)
(28.1 mg, 0.2 mmol) and 20 mol % of pyrrolidine, after 2 h the title compound was obtained in
93% yield (57 mg). 1H NMR (300 MHz, acetone-d6) δ 8.90 (s, 1H), 8.49–8.35 (m, 4H), 7.91 (d,
J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H). MS (ESI+): m/z 327 (M++Na) (15), 209 (93), 173 (50),
139 (29). HRMS (ESI+): calcd for C14H9N2O4NaCl (M++Na): 327.0143; found: 327.0151.
(E)-Picolinaldehyde O-(4-nitrobenzoyl) oxime (5h). From 2-formylpyridine (1h) (21.4 mg,
0.2 mmol) and 10 mol % of pyrrolidine, after 1 h the title compound was obtained in 93% yield
(50.4 mg) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J = 4.8 Hz, 1H), 8.69 (s, 1H),
8.40–8.30 (m, 4H), 8.20 (d, J = 7.8 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.47–7.39 (m, 1H).
Spectroscopic data matched those previously reported.14a
(E)-3-Methylbutanal O-(4-nitrobenzoyl)oxime (5j). From 3-methylbutanal (1j) (17.2 mg, 0.2
mmol) and 10 mol % of pyrrolidine, after 2 h the title compound was obtained in quantitative
yield (50 mg) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.36–8.17 (m, 4H), 7.93 (t, J = 6.8
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Hz, 1H), 2.36 (t, J = 6.8 Hz, 2H), 2.03–1.89 (m, 1H), 1.02 (d, J = 6.7 Hz, 6H). C NMR (75
MHz, CDCl3) δ 162.4 (C=O), 160.6 (CH=N), 150.8 (C), 134.4 (C), 130.9 (2 x CH), 123.9 (2 x
CH), 38.1 (CH2), 26.7 (CH), 22.5 (2 x CH3). MS (ESI+): m/z 273 (M++Na) (100), 251 (M++H)
(27). HRMS (ESI+): calcd for C12H14N2O4Na (M++Na): 273.0845; found: 273.0835.
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General procedure for the synthesis of N-acylhydrazones 7. To a solution of benzohydrazide
(6) (27.2 mg, 0.2 mmol) and the corresponding aldehyde 1 (1 equiv) in 0.5 mL of deionized H2O,
a freshly prepared 0.2 M solution of pyrrolidine in deionized H2O (100 µL, 10 mol %) was added.
The mixture was stirred at room temperature during the time indicated in each case. Then, the
reaction was filtered through a short pad of celite using a glass frit with EtOAc to obtain the final
N-acylhydrazones 7 without any further purification.
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(E)-N'-Benzylidenebenzohydrazide (7a). From benzaldehyde (1a) (21.2 mg, 0.2 mmol), after
2 h the title compound was obtained in 98% yield (44 mg) as a white solid. 1H NMR (300 MHz,
DMSO‐d6) δ 11.88 (s, NH), 8.48 (s, 1H, CH=N), 7.93 (d, J = 7.23 Hz, 2H), 7.74 (d, J = 6.3 Hz,
2H), 7.53–7.32 (m, 6H). Spectroscopic data matched those previously reported.22a
(E)-N'-(4-Methoxybenzylidene)benzohydrazide (7b).22c-d From 4-methoxybenzaldehyde (1b)
(27.2 mg, 0.2 mmol), after 4 h the title compound was obtained in 91% yield (46.3 mg) as a white
solid. 1H NMR (300 MHz, DMSO-d6) δ 11.69 (bs, 1H), 8.39 (s, 1H), 7.88 (d, J = 7.5 Hz, 2H),
7.65 (d, J = 8.3 Hz, 2H), 7.60–7.42 (m, 3H), 6.98 (d, J = 8.7 Hz, 2H), 3.78 (s, 3H). 13C NMR (75
MHz, DMSO-d6) δ 162.9 (C=O), 160.8 (C), 147.7 (CH=N), 133.5 (C), 131.5 (C), 128.6 (2 x
CH), 128.4 (2 x CH), 127.5 (2 x CH), 126.9 (CH), 114.3 (2 x CH), 55.2 (CH3). MS (EI): m/z 252
(M+ - 2H) (100), 181 (31), 135 (76), 105 (41). HRMS (EI): calcd for C15H12N2O2 (M+ - 2H):
252.0899; found: 252.0899.
(E)-N'-(4-Nitrobenzylidene)benzohydrazide (7c).27 From 4-nitrobenzaldehyde (1c) (30.2 mg,
0.2 mmol), after 5 h the title compound was obtained in 90% yield (48.4 mg) as a yellow solid.
1H NMR (300 MHz, DMSO‐d6) δ 12.15 (bs, 1H), 8.57 (s, 1H), 8.32 (d, J = 8.4 Hz, 2H), 8.01 (d,
J = 8.2 Hz, 2H), 7.94 (d, J = 7.3 Hz, 2H), 7.73–7.39 (m, 3H). 13C NMR (75 MHz, DMSO‐d6) δ
163.4 (C=O), 147.8 (CH=N), 145.2 (C), 140.6 (2 X CH), 133.1 (C), 131.9 (C), 128.5 (2 X CH),
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127.9 (2 X CH), 127.7 (CH), 124.0 (2 X CH). MS (ESI+): m/z 270 (M+ + 1) (100). HRMS (ESI+):
calcd for C14H12N3O3 (M+ + 1): 270.0873; found: 270.0882.
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(E)-N'-(4-Chlorobenzylidene)benzohydrazide (7d).28 From 4-chlorobenzaldehyde (1d) (28.1
mg, 0.2 mmol), after 2 h the title compound was obtained in 93% yield (48 mg) as a white solid.
1H NMR (300 MHz, DMSO-d6) δ 11.89 (bs, NH, 1H), 8.44 (s, 1H), 7.90 (d, J = 7.4 Hz, 2H),
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7.73 (d, J = 8.1 Hz, 2H), 7.63–7.39 (m, 5H). C NMR (75 MHz, DMSO-d6) δ 163.1 (C=O),
146.0 (CH=N), 134.5 (C), 133.2 (C), 131.8 (C), 128.9 (3 x CH), 128.6 (2 x CH), 128.4 (2 x CH),
127.6 (2 x CH). MS (ESI+): m/z 259 (M+ + 1) (100). HRMS (ESI+): calcd for C14H12N2OCl (M+
+ 1): 259.0632; found: 259.0633.
(E)-N'-(2-Chlorobenzylidene)benzohydrazide (7e). From 2-chlorobenzaldehyde (1e) (28.1
mg, 0.2 mmol), after 3 h the title compound was obtained in 85% yield (44 mg) as a white solid.
1H NMR (300 MHz, DMSO-d6) δ 12.12 (bs, NH 1H), 8.93 (s, CH=N), 8.12–7.82 (m, 3H), 7.61–
7.25 (m, 6H). Spectroscopic data matched those previously reported.22
c
(E)-N'-(3-Methylbutylidene)benzohydrazide (7j). From 3-methylbutanal (1j) (17.2 mg, 0.2
mmol), after 2 h the title compound was obtained in 95% yield (39 mg) as a white solid. 1H NMR
(300 MHz, DMSO‐d6) δ 7.85–7.72 (m, 3H), 7.59–7.41 (m, 3H), 2.15 (t, J = 5.7 Hz, 2H), 1.84
(m, 1H), 0.94 (m, 6H). Spectroscopic data matched those previously reported.22a
(E)-N'-(Cyclohexylmethylene)benzohydrazide (7k). From cyclohexanecarbaldehyde (1k)
(22.4 mg, 0.2 mmol), after 2 h the title compound was obtained in 99% yield (45.6 mg) as a white
solid. 1H NMR (300 MHz, DMSO‐d6) δ 11.38 (bs, 1H), 7.83 (d, J = 7.7 Hz, 2H), 7.66 (d, J = 5.0
Hz, 1H), 7.58–7.38 (m, 3H), 2.35–2.13 (m, 1H), 1.84–1.53 (m, 5H), 1.40–1.06 (m, 5H).
Spectroscopic data matched those previously reported.22b
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Large-scale procedure for the synthesis of N-acylhydrazone 7a. To a solution of
benzohydrazide (6) (1.46 g, 10.74 mmol) and benzaldehyde (1a) (1.14 g, 10.74 mmol) in 27 mL
of deionized H2O, pyrrolidine (88 µL, 1.07 mmol) was added. The mixture was stirred at room
temperature for 3 h, and then filtered off using a glass frit washing the solid with cold H2O (4 x
30 mL) to give N-acylhydrazone 7a in 94% yield (2.27 g) without any further purification.
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General procedure for the synthesis of thiosemicarbazones 9. To a solution of
thiosemicarbazide (8) (18.2 mg, 0.2 mmol) and the corresponding aldehyde 1 (1 equiv) in 0.5
mL of deionized H2O, a freshly prepared 0.2 M solution of pyrrolidine in deionized H2O (100
µL, 10 mol %) was added. The mixture was stirred at room temperature during the time indicated
in each case. Then, the reaction was filtered through a short pad of celite using a glass frit with
EtOAc to obtain the final thiosemicarbazones 9 without any further purification.
(E)-2-Benzylidenehydrazine-1-carbothioamide (9a). From benzaldehyde (1a) (21.2 mg, 0.2
mmol), after 40 min the title compound was obtained in 99% yield (35.4 mg) as a white solid.
1H NMR (300 MHz, acetone‐d6) δ 8.15 (s, 1H), 7.79–7.70 (m, 2H), 7.42–7.33 (m, 3H).
Spectroscopic data matched those previously reported.23a
(E)-2-(4-Methoxybenzylidene)hydrazine-1-carbothioamide
(9b).
From
4-
methoxybenzaldehyde (1b) (27.2 mg, 0.2 mmol), after 50 min the title compound was obtained
in 91% yield (38 mg) as a white solid. 1H NMR (300 MHz, acetone‐d6) δ 7.99 (s, 1H), 7.60 (d, J
= 8.9 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 3.70 (s, 3H). Spectroscopic data matched those previously
reported.23a
(E)-2-(4-Nitrobenzylidene)hydrazine-1-carbothioamide (9c). From 4-nitrobenzaldehyde (1c)
(30.2 mg, 0.2 mmol), after 30 min the title compound was obtained in 99% yield (44.3 mg) as a
yellow solid. 1H NMR (300 MHz, DMSO‐d6) δ 11.71 (s, 1H, NH), 8.41 (s, 1H, CH=N), 8.26 and
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those previously reported.23b
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(E)-2-(4-Chlorobenzylidene)hydrazine-1-carbothioamide (9d). From 4-chlorobenzaldehyde
(1d) (28.1 mg, 0.2 mmol), after 35 min the title compound was obtained in 95% yield (40.5 mg)
as a white solid. 1H NMR (300 MHz, acetone‐d6) δ 8.18 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.45
(d, J = 8.4 Hz, 2H). Spectroscopic data matched those previously reported.23c
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(E)-2-(2-Chlorobenzylidene)hydrazine-1-carbothioamide (9e). From 2-chlorobenzaldehyde
(1e) (28.1 mg, 0.2 mmol), after 60 min the title compound was obtained in 92% yield (39.3 mg)
as a white solid. 1H NMR (300 MHz, acetone‐d6) δ 8.59 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.52–
7.27 (m, 3H). Spectroscopic data matched those previously reported.23d
(E)-2-(3-Methylbutylidene)hydrazine-1-carbothioamide (9j). From 3-methylbutanal (1j)
(17.2 mg, 0.2 mmol), after 35 min the title compound was obtained in 98% yield (31.2 mg) as a
white solid. 1H NMR (300 MHz, CDCl3) δ 9.99 (s, 1H, NH), 7.32 (t, J = 6.3 Hz, 1H), 7.08 and
6.46 (bs, NH2), 2.13 (t, J = 6.0 Hz, 2H), 1.93–1.80 (m, 1H), 0.95 (d, J = 6.3 Hz, 6H).
Spectroscopic data matched those previously reported.23e
(E)-2-(Cyclohexylmethylene)hydrazine-1-carbothioamide
(9k).
From
cyclohexanecarbaldehyde (1k) (22.4 mg, 0.2 mmol), after 35 min the title compound was
obtained in quantitative yield (37 mg) as a white solid. 1H NMR (300 MHz, acetone‐d6) δ 7.48
(d, J = 6.4 Hz, 1H, CH=N), 2.30–2.15 (m, 1H), 1.83–1.61 (m, 5H), 1.35–1.18 (m, 5H).
Spectroscopic data matched those previously reported.23f
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Supporting Information.
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The Supporting Information is available free of charge on the ACS Publications website at DOI:
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Additional optimization studies, comparison of conditions previously reported for the
prepared compounds and copies of NMR spectra of each compound (PDF).
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AUTHOR INFORMATION
Corresponding author:
*E-mail: belen.cid@uam.es
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Spanish Government (CTQ-2012-35957) for financial support. SM thanks the
Spanish Ministry of Economy and Competitiveness for a predoctoral fellowship (FPI). We also
thank Dr. Inés Alonso (UAM) for useful discussions.
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