Combined Alkylating Agents as a Resolution for Highly Selective N-Alkylation of 2-Hydroxybenzaldehyde Acylhydrazones

Article abstract of DOI:10.1055/s-0037-1611823

Although 2-hydroxybenzaldehyde acylhydrazones, such as salicylaldehyde acylhydrazones, are intriguing bioactive molecules, few of their N-alkylated derivatives are known, and only methyl analogues have been reported previously. We achieved selective N-alk

Full text of DOI:10.1055/s-0037-1611823

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
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Q. Y. Zhang et al.
Letter
Synlett
Combined Alkylating Agents as a Resolution for Highly Selective
N-Alkylation of 2-Hydroxybenzaldehyde Acylhydrazones
Qiao Y. Zhanga
R3
N
H
N
R1
Xin J. Chengb
Xin Y. Zhaoa
La M. Wu*a
Long F. Jina
N
O
R2
N
combined alkylating agents
K2CO3
R2
O
R1
O
Fe
O
HO
O
R2
45 examples
40–80%
N
R1
N
R3 = Bn, Et, Bu
Hui J. Zhang*a
H
a College of Chemistry and Materials Science, South-Central
University for Nationalities, Wuhan 430074, P. R. of China
wlm52875@163.com
huistar119@163.com
b School of Chemistry and Environmental Engineering, Wuhan
Institute of Technology, Wuhan 430073, P. R. of China
Received: 15.03.2019
Accepted after revision: 17.04.2019
Published online: 08.05.2019
The acylhydrazone moiety, which structurally resem-
bles an amide group, is often considered a privileged build-
ing block in medicinal chemistry. Not surprisingly, com-
pounds containing such moieties have demonstrated in-
triguing bioactivities.1–4 For example, salicylaldehyde
acylhydrazones and their analogues have been suggested as
potential inhibitors against human glutathione transferase5
and -glucuronidase.6 Moreover, metal complexes of the
acylhydrazones of salicylaldehyde or substituted salicylal-
dehydes have been showed to have antioxidant and anti-
proliferative potency.7 As such, these complexes might be
potentially useful for the treatment of cancer,8,9 Alzheimer’s
disease,10 inflammation,11 or diseases caused by Gram-pos-
itive bacteria.12 Previous studies have shown that the intro-
duction of a methyl group onto the acylated nitrogen atom
of acylhydrazones can lead to distinct biological respons-
es.3,13–15 Although N-alkylation is of great interest, only lim-
ited range of N-alkyl derivatives of acylhydrazones are
DOI: 10.1055/s-0037-1611823; Art ID: st-2019-l0151-l
Abstract Although 2-hydroxybenzaldehyde acylhydrazones, such as
salicylaldehyde acylhydrazones, are intriguing bioactive molecules, few
of their N-alkylated derivatives are known, and only methyl analogues
have been reported previously. We achieved selective N-alkylation of 2-
hydroxybenzaldehyde acylhydrazones, as their Fe(III) complexes, by us-
ing combinations of alkylating agents (for example, an alkyl bromide
and a dialkyl sulfate). Fifteen substrates were examined, and 45 new 2-
hydroxybenzaldehyde acyl(alkyl)hydrazones were synthesized in mod-
erate to good yields. In all cases, the target products were obtained ex-
clusively, and no O-alkylation byproducts were produced. The method
provides an efficient way of preparing 2-hydroxybenzaldehyde acyl(al-
kyl)hydrazones.
Key words alkylation, regioselectivity, medicinal chemistry, salicylal-
dehyde acylalkylhydrazones, hydrazones
CH3
CH3
H3CO
O
HO
N
O
O
N
O
protection
MeI/NaH
BBr3, CH2Cl2
N
N
N
Literature Work
N
N
H
THF, 80 °C
8 h
N
protection–deprotection
approach
H3CO
–78 °C to rt
12 h
H
HO
16e
O
O
O
O
16
CH3
N
CH3I
O
N
H
N
Our Previous Work
R2 (a)
R1
K2CO3, THF
R1
N
R2
ONLY for methylation
HO
H
O
O
N
O
FeCl3
R3
N
Fe
N
O
R2
O
R1
O
R2
BnBr/BnCl
or
R3-Br/R3O-SO2-OR3
This Work
N
HO
1–15
R2
(b)
N
R1
N
R1
N-alkylation other than
methylation
H
HO
1a–15c
K2CO3, THF
combined alkylating agents
Scheme 1 N-Alkylation of 2-hydroxybenzaldehyde acylhydrazones
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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Q. Y. Zhang et al.
Letter
Synlett
known. We believe that selective N-alkylation might alter
this situation and provide a range of new molecules for bio-
logical study.
R
O
R
N
O
N
N
N
In drug discovery, N-alkylation is a common strategy for
enlarging the range of nitrogen-containing compounds. Re-
cently, efficient methods have been developed for the N-al-
kylation of common amines by using inexpensive alkylating
agents such as methanol16,17 or quaternary ammonium
salts.18 Nevertheless, there are few reports of examples of
the selective N-alkylation of acylhydrazones, especially 2-
hydroxybenzaldehyde acylhydrazones, and only their N-
methylation with methyl iodide has been reported.19,20 The
challenge in selective N-alkylation of these substrates lies in
the regioselectivity between alkylation of the nitrogen
atom of the hydrazone and the oxygen atom of the hydroxy
group. A protection–deprotection method in which a
strong Lewis acid (BBr3) was employed to remove the O-
protecting group has previously been used (Scheme 1; lit-
erature work).3 This method involves a number of steps and
is environmentally unfriendly. We previously found that
coordinating a 2-hydroxybenzaldehyde acylhydrazone with
Fe(III) and then using the complexes as substrates dramati-
cally improved the selectivity of N-methylation (Scheme 1;
previous work).20 Unfortunately, the scope of this method is
limited; when alkylating agents other than methylating
agents were used, the desired substitution was not
achieved. For example, no alkylated products were detected
upon treating the substrates with ethyl bromide, ethyl io-
dide, or diethyl sulfate, whereas reaction with benzyl bro-
mide resulted in undesired N,O-dibenzylation.
HO
HO
N
Cl
1a 79%, 1b 79%, 1c 65%
9a 62%, 9b 57%, 9c 49%
R
R
O
N
O
N
N
N
Cl
HO
HO
2a 75%, 2b 71%, 2c 60%
10a 69%, 10b 72%, 10c 64%
R
O
R
N
O
N
N
N
Cl
HO
HO
N
3a 64%, 3b 71%, 3c 64%
11a 63%, 11b 80%, 11c 61%
R
R
O
N
O
N
N
N
HO
HO
N
O
4a 67%, 4b 68%, 4c 57%
12a 58%, 12b 77%, 12c 51%
R
R
O
N
O
N
N
N
Cl
HO
HO
O
Here we report a new method in which a combination
of alkylating agents is used to achieve selective N-alkylation
of 2-hydroxybenzaldehyde acylhydrazones (Scheme 1; this
work). As previously mentioned, we noticed that benzyl
bromide overreacted with these substrates. This observa-
tion led us to test benzyl chloride, an agent with a relatively
lower reactivity. Although the reaction turned out to be un-
successful, a serendipitous addition of benzyl bromide to
the reaction system dramatically improved both the reac-
tivity and the selectivity. Further modification of this reac-
tion showed that a combination of 0.8 equivalents of benzyl
chloride and 0.2 equivalents of benzyl bromide in THF
worked best. We then synthesized a series of 2-hydroxy-
benzaldehyde acylhydrazones20 to explore the scope of the
method. To our delight, the strategy worked well in all the
cases, and the yields of products 1a–15a (R = Bn) were in
the range 60–80% (Figure 1).21 However, increasing the
amount of the more reactive benzyl bromide usually result-
ed in formation of the O,N-dibenzylated products, and the
yields of the N-benzylated products were reduced corre-
spondingly.
O
5a 60%, 5b 60%, 5c 52%
13a 78%, 13b 51%, 13c 60%
R
O
N
R
O
N
N
N
Cl
HO
HO
N
O
O
6a 72%, 6b 76%, 6c 62%
14a 64%, 14b 75%, 14c 63%
R
R
O
N
O
N
N
N
HO
HO
N
O
Cl
7a 60%, 7b 61%, 7c 48%
15a 71%, 15b 57%, 15c 51%
R
O
N
O
N
N
Cl
N
HO
HO
Cl
8a 59%, 8b 50%, 8c 40%
1d 0%
Our success with the use of benzyl chloride and benzyl
bromide as combined alkylating agents inspired us to ex-
plore a similar, but more general, method for selective N-al-
Figure 1 Yields and structures of N-alkylated products 1a–15c (a, R =
Bn; b, R = Et; c, R = Bu; d, R = i-Pr). The synperiplanar (E)-configuration
was suggested by the crystal structure of 11b.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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Q. Y. Zhang et al.
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kylation, for example, N-ethylation or N-butylation, which
could not be achieved by using a corresponding alkylating
agent alone. We finally established that a combination of an
alkyl bromide and the corresponding dialkyl sulfate im-
proved both the efficiency and the selectivity of the reac-
tion. Employing any of these agents independently, even in
an excess amount, barely gave any of the N-alkylated prod-
uct. An investigation of the reaction conditions showed that
the optimal molar ratio of the alkyl bromide to the dialkyl
sulfate was 5:1. Under the optimized conditions, the site-
specific N-alkylation products 1b–15b (R = Et) and 1c–15c
(R = Bu) were obtained in yields of 40–80% (Figure 1; R = Et,
Bu).21 Notably, this reaction appeared to be sensitive to ste-
ric hindrance. Ethylation usually gave a higher yield than
butylation, whereas combined agents containing secondary
halides did not react with the substrates at all.
All the compounds were characterized, and the N-al-
kylated feature was unambiguously identified by using IR,
NMR, and elemental analyses. To confirm the proposed
structures, a single-crystal structural analysis of 11b was
also performed (Figure 2). Again, this established that the
products that we obtained were the expected alkyl(acyl)hy-
drazones.
H
R1
H
N
N
R1
N
–R2
N
R2
O
– 2 HCO3
product
R2
O
O
Fe
O
2–
Fe
O
2 CO3
R2
O
O
O
N
R1
N
N
R1
N
H
II
I
O
CH2CH3
O
O
H3CH2C
O
S
C2H5
OCH2CH3
N
N
R2
R1
HO
1b–15b
Br
H3CH2C
OCH2CH3
S
O
O
OCH2CH3
Scheme 2 Plausible reaction mechanism for N-alkylation using ethyl
bromide and diethyl sulfate as combined alkylating agents
To gain insight into the mechanism of benzylation, we
carried out several further experiments. Whereas benzyla-
tion proceeded in the presence of BnBr, no reaction oc-
curred when BnBr was replaced with a bromide source such
as tetrabutylammonium bromide. These observations indi-
cated that BnBr is the active species. With catalytic amount
of reactive benzyl bromide in the reaction system, it is rea-
sonable that the agent attacks the more spatially available
and nucleophilic nitrogen rather than the Fe(III)-coordinat-
ed oxygen. BnBr, once consumed, might be regenerated
from BnCl. When BnBr was added slowly by using a syringe
pump, the N-benzylated product was initially formed, but
as the addition proceeded the reaction time was extended
and the N,O-dibenzylated byproduct was also formed.
Therefore, the role of BnCl was not only to regenerate BnBr,
but also, somehow, to regulate the reactivity of BnBr.
Figure 2 Single crystal structure of 11b.
The previous20 and current methods developed for se-
lective N-alkylation have great potential in the preparation
of bioactive acylhydrazone derivatives. For example, we ap-
plied our methods to the synthesis of N′-[(2-hydroxyphe-
nyl)methylene]-2-methyl-3-furohydrazide (16e),3 a methyl
derivative of 16, which is a potent inhibitors of Schistosoma
mansoni NAD+ catabolizing enzyme (Scheme 3). Under the
conditions that we previously reported,20 the desired prod-
uct was obtained in 75% yield with excellent selectivity. As
a comparison, the method reported in the literature3 in-
volved both a protection–deprotection procedure and
harmful reagents. When methyl iodide was replaced with
combined benzyl bromide and benzyl chloride, the unre-
ported derivative 16a was produced smoothly in 66% yield.
Biological studies on molecules of this type are ongoing.
In summary, we successfully developed a combined-al-
kylating-agent protocol for the synthesis of 2-hydroxybenz-
aldehyde acyl(alkyl)hydrazones through site-specific N-al-
kylation of the corresponding Fe(III) complexes. A variety of
2-hydroxybenzaldehyde acyl(alkyl)hydrazones were ob-
The fact that the combination of an alkyl bromide and a
dialkyl sulfate worked better than the individual alkylating
agents indicated that the two types of agent might react
with one another to form a more reactive species, because
it had been proved these agents alone are insufficiently re-
active to bring about the expected alkylation. We therefore
propose that alkyl bromide and the dialkyl sulfate might re-
act to form a transient trialkyl sulfate intermediate, an ac-
tive species that operates as the real alkylating agent
(Scheme 2). Although it could not be detected by NMR in
our hands, such a species has been generated by methylat-
ing dimethyl sulfate with cationic MeOSO+ and subsequent-
ly characterized.22 Another interesting aspect of the reac-
tion was that the free products rather their Fe(III) complex-
es were obtained on completion of the reaction. This is
because the Fe(III) complexes of the N-alkylated products
decompose under the reaction conditions whereas the
Fe(III) complexes of the substrates do not do so.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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Q. Y. Zhang et al.
Letter
Synlett
O
H
N
HO
N
O
O
O
N
Fe
THF, rt
O
N
H
+
O
FeCl3•6H2O
MeOH
1 h
N
O
N
H
16
O
Bn
O
N
CH3
N
O
N
N
HO
O
HO
16e 75%
O
16a 66%
Scheme 3 Application of selective N-alkylation to the synthesis of 16a and 16e
tained with excellent regioselectivities in moderate to good
yields. We have not been able to find any other strategy for
performing this selective and widely applicable transfor-
mation reported in the literature.
(5) Georgakis, N. D.; Karagiannopoulos, D. A.; Thireou, T. N.;
Eliopoulos, E. E.; Labrou, N. E.; Tsoungas, P. G.; Koutsilieris, M.
N.; Clonis, Y. D. Chem. Biol. Drug Des. 2017, 90, 900.
(6) Taha, M.; Arbin, M.; Ahmat, N.; Imran, S.; Rahim, F. Bioorg.
Chem. 2018, 77, 47.
(7) Hrušková, K.; Potůčková, E.; Opálka, L.; Hergeselová, T.;
Hašková, P.; Kovaŕíková, P.; Šimůnek, T.; Vávrova, K. Chem. Res.
Toxicol. 2018, 31, 435.
Funding Information
(8) Gou, Y.; Zhang, Y.; Zhang, Z.; Wang, J.; Zhou, Z.; Liang, H.; Yang,
F. Mol. Pharmaceutics 2017, 14, 1861.
(9) Cindrić, M.; Bjelopetrović, A.; Pavlović, G.; Damjanović, V.;
Lovrić, J.; Matković-Calogović, D.; Vrdoljak, V. New J. Chem.
2017, 41, 2425.
This research was supported by the Fundamental Research Funds for
the Central Universities, South-Central University for Nationalities
(CZZ17002), the Special Fund for Basic Scientific Research of Central
Colleges, South-Central University for Nationalities (CZP17004).
S
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uth-C
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ntralU
n
i
v
ersityof
N
ati
o
n
a
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i
ties(C
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Z
1
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(10) D’Acunto, C. W.; Kaplánek, R.; Gbelcová, H.; Kejík, Z.; Bríza, T.;
Vasina, L.; Havlík, M.; Ruml, T.; Král, V. Eur. J. Med. Chem. 2018,
150, 140.
Acknowledgment
(11) Chimmalagi, G. H.; Kendur, U.; Patil, S. M.; Gudasi, K. B.;
Frampton, C. S.; Budri, M. B.; Mangannavar, C. V.; Muchchandi, I.
S. Appl. Organomet. Chem. 2018, 32, e4337.
(12) Fekri, R.; Salehi, M.; Asadi, A.; Kubicki, M. Appl. Organomet.
Chem. 2018, 32, e4019.
We thank Professor Zhang Zhan for improving the scientific writing
and for editing the manuscript. Conceptualization, L.W. and H.Z.;
methodology, Q.Z.; validation, X.Z.; formal analysis, L.J.; writing and
original draft preparation, X.C.
(13) Pereira, S. L.; Kummerle, A. E.; Fraga, C. A. M.; Barreiro, E. J.;
Sudo, R. T.; Zapata-Sudo, G. Fundam. Clin. Pharmacol. 2014, 28,
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(14) Silva, A. G.; Zapata-Sudo, G.; Kummerle, A. E.; Fraga, C. A. M.;
Barreiro, E. J.; Sudo, R. T. Bioorg. Med. Chem. 2005, 13, 3431.
(15) Kümmerle, A. E.; Raimundo, J. M.; Leal, C. M.; da Silva, G. S.;
Balliano, T. L.; Pereira, M. A.; de Simone, C. A.; Sudo, R. T.;
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Catal. 2018, 8, 6440.
(18) Ray, P. C.; Pawar, Y. D.; Singare, D. T.; Deshpande, T. N.; Singh, G.
P. Org. Process Res. Dev. 2018, 22, 520.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611823.
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References and Notes
(1) dos Santos, J. M. Filho.; Pinheiro, S. M. Green Chem. 2017, 19,
2212.
(2) Lima, P. C.; Lima, L. M.; da Silva, K. C. M.; Léda, P. H. O.; de
Miranda, A. L. P.; Fraga, C. A. M.; Barreiro, E. J. Eur. J. Med. Chem.
2000, 35, 187.
(3) Jacques, S. A.; Kuhn, I.; Koniev, O.; Schuber, F.; Lund, F. E.;
Wagner, A.; Muller-Steffner, H.; Kellenberger, E. J. Med. Chem.
2015, 58, 3582.
(4) Palanimuthu, D.; Wu, Z.; Jansson, P. J.; Braidy, N.; Bernhardt, P.
V.; Richardson, D. R.; Kalinowski, D. S. Dalton Trans. 2018, 47,
7190.
(19) Kümmerle, A. E.; Schmitt, M.; Cardozo, S. V. S.; Lugnier, C.; Villa,
P.; Lopes, A. B.; Romeiro, N. C.; Justiniano, H.; Martins, M. A.;
Fraga, C. A. M.; Bourguignon, J.-J.; Barreiro, E. J. J. Med. Chem.
2012, 55, 7525.
(20) Li, Z.; Wu, L.; Zhang, T.; Huang, Z.; Qiu, G.; Zhou, Z.; Jin, L. Dalton
Trans. 2014, 43, 7554.
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(21) 2-Hydroxybenzaldehyde Acyl(benzyl)hydrazones (1a–15a);
General Procedure
Et2SO4 in a 5:1 ratio, to give a white solid; yield: 850 mg (79%);
mp 108–110 °C. IR (KBr): 3425 (m), 2982 (vs), 1654 (vs), 1518
K2CO3 (0.55 g, 4.0 mmol), BnCl (0.36 mL, 3.2 mmol), and BnBr
(0.05 mL, 0.8 mmol) were added to a solution of the Fe(III)
complex of the appropriate hydroxybenzaldehyde acylhydra-
zone (prepared from 4.0 mmol of the hydrazone) in THF (10
mL). The black mixture was refluxed for 8–16 h before removal
of the solid by hot filtration. The mother solution was concen-
trated, and the product was harvested by crystallization from
MeOH.
(s), 1604 (s) cm–1 1H NMR (400 MHz, DMSO-d6):  = 9.87 (s, 1
.
H), 8.26 (s, 1 H), 7.62–7.34 (m, 6 H), 7.20 (m, 1 H), 6.83 (t, J = 8.0
Hz, 1 H), 6.78 (d, J = 8.0 Hz, 1 H), 4.18 (q, J = 7.2 Hz, 2 H), 1.21 (t,
J = 7.2 Hz, 3 H). 13C NMR (100 MHz, DMSO-d6):  = 170.1, 156.8,
141.4, 136.1, 131.4, 130.4, 129.7, 128.4, 119.8, 119.6, 116.6,
35.7, 11.2. Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N,
10.44. Found: C, 71.43; H, 6.00; N, 10.39.
N-Butyl-N′-[ (2-hydroxyphenyl)methylene]benzohydrazide
(1c)
N-Benzyl-N′-[
(2-hydroxyphenyl)methylene]benzohydra-
zide (1a)
Prepared by following the general procedure, but using BuBr
and Bu2SO4 in a 5:1 ratio, to give a white solid; yield: 770 mg
(65%); mp 99–100 °C. IR (KBr): 3174 (m), 2954 (vs), 1658 (vs),
1626 (s), 1601 (s). 1H NMR (400 MHz, DMSO-d6):  = 9.83 (s, 1
H), 8.24 (s, 1 H), 7.52–7.40 (m, 6 H), 7.20 (t, J = 7.6 Hz, 1 H), 6.83
(t, J = 7.6 Hz, 1 H), 6.78 (d, J = 8.4 Hz, 1 H), 4.15 (t, J = 7.2 Hz, 2 H),
1.62 (m, 2 H), 1.40 (m, 2 H), 0.96 (t, J = 7.2 Hz, 3 H). 13C NMR
(100 MHz, DMSO-d6):  = 170.5, 156.8, 141.3, 136.2, 131.4,
130.3, 129.7, 128.4, 128.2, 119.7, 119.6, 116.6, 27.6, 20.0, 14.1.
Anal. Calcd for C18H20N2O2: C, 72.95; H, 6.80; N, 9.45. Found: C,
73.07; H, 6.99; N, 9.02.
White solid; yield: 1.04 g (79%); mp 132–133 °C. IR (KBr): 3448
(m), 3058 (vs), 1666 (vs), 1616 (s), 1600 (s) cm–1. 1H NMR (400
MHz, DMSO-d6):  = 9.76 (s, 1 H), 8.12 (s, 1 H), 7.67 (d, J = 7.2
Hz, 2 H), 7.57–7.50 (m, 3 H), 7.41–7.37 (m, 4 H), 7.30–7.25 (m, 2
H), 7.17 (t, J = 8.0 Hz, 1 H), 6.75 (t, J = 8.0 Hz, 2 H), 5.45 (s, 2 H).
13C NMR (100 MHz, DMSO-d6):  = 170.9, 156.7, 141.1, 135.8,
135.5, 131.5, 130.6, 129.3, 128.7, 128.7, 128.4, 127.7, 127.0,
119.8, 119.6, 116.6, 44.4. Anal. Calcd for C21H18N2O2: C, 76.34; H,
5.49; N, 8.48. Found: C, 76.33; H, 5.63; N, 8.36.
N-Ethyl-N′-[ (2-hydroxyphenyl)methylene]benzohydrazide
(1b)
Prepared by following the general procedure, but using EtBr and
(22) Christie, J. J.; Lewis, E. S.; Casserly, E. F. J. Org. Chem. 1983, 48,
2531.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E