Transition-Metal-Free Trifluoromethylation of Aldehyde Derivatives with Sodium Trifluoromethanesulfinate

Article abstract of DOI:10.1021/acs.joc.7b01359

A metal-free and cost-effective synthetic protocol for the trifluoromethylation of N,N-disubstituted hydrazones with Langlois's reagent (CF₃SO₂Na) to afford the corresponding functionalized trifluoromethyl ketone hydrazones has been established. It is proposed that a radical/SET mechanism proceeding via a trifluoroalkyl radical may be involved in the reaction. Applications of the methodology in industry will be found and the development of new methods for trifluoromethylation with Langlois's reagent will be continued in our laboratory.

Full text of DOI:10.1021/acs.joc.7b01359

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Article
Transition-Metal-Free Trifluoromethylation of Aldehyde-
Derivatives with Sodium Trifluoromethanesulfinate
Zheng Tan, Shiwei Zhang, Yan Zhang, Yunpeng Li, Minjie Ni, and Bainian Feng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01359 • Publication Date (Web): 18 Aug 2017
Downloaded from http://pubs.acs.org on August 18, 2017
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Transition-Metal-Free Trifluoromethylation of
Aldehyde-Derivatives with Sodium
Trifluoromethanesulfinate
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†
†
*
*
Zheng Tan, Shiwei Zhang, Yan Zhang, Yunpeng Li, Minjie Ni and Bainian Feng
School of Pharmaceutical Science, Jiangnan University, Wuxi 214122, P. R. China
†
These authors contributed equally to this work.
ABSTRACT: A metal-free and cost-effective synthetic protocol for trifluoromethylation of
N,N-disubstitutedhydrazones with Langlois’ reagent (CF SO Na) to afford the corresponding
3
2
functionalized trifluoromethylketone hydrazones has been established. It is proposed that a
radical/SET mechanism proceeding via a trifluoroalkyl radical may be involved in the
reaction. Applications of the methodology in industry will be found and the development of
new methods for trifluoromethylation with Langlois’ reagent will be continued in our
laboratory.
NNR R3
2
NNR R3
2
Langlois' reagent (2 equiv)
PhI(OAc) , N , r.t.
R1
H
R1
CF3
2
2
INTRODUCTION
Organofluoride compounds and notably molecules incorporation a trifluoromethyl (CF
3
)
moiety are at the leading edge of many new developments in pharmaceutical, agrochemical
1
and materials science. This is mainly due to the fact that the CF
3
moiety can dramatically
modify the physical and biological properties of parent molecules such as solubility,
lipophilicity, and catabolic stability. Thus, tremendous research efforts from both industry and
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,3
academia are currently focused on the development of efficient, modular methods that will
allow site-selective incorporation of the CF group into a wide range of important scaffolds,
an important part of these efforts being concerned with the discovery of practical CF -transfer
3
3
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regents such as the Togni’s and Umemoto’s regents (Figure 1). Although the present
methods exhibit remarkable reactivity and broad applicability toward diverse molecules,
generally they suffer from the use of expensive trifluoromethylation reagents, the transition
metal catalysis or the requirement for harsh reaction conditions. Consequently, these
disadvantages restrict their widespread use in organic synthesis. Among the commercially
3 2
available trifluoromethylating reagents, Langlois’ reagent (CF SO Na, sodium
trifluoromethanesulfinate, a benchtop stable, inexpensive solid), which was first reported in
6
the 1980s, has drawn much attention in recent years largely as a result of their availability,
relatively low cost, and ease of handling. Several studies have shown that the
trifluoromethylations of heterocycles, aryl boronic acids, α,β-unsaturated carboxylic acids,
7-10
and unsaturated organotrifluoroborates could be achieved by CF
3
SO
2
Na.
However,
compared to the development of other trifluoromethylating reagents, direct
trifluoromethylation reaction using Langlois’ reagent as the CF3 source still remains
undeveloped.
Figure 1. Commonly used CF
3
-transfer reagents
Trifluoromethylketones (TFMKs, RCOCF ) are important components of many
3
biologically active compounds and widely used building blocks in the synthesis of fluorinated
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molecules. Nucleophilic trifluoromethylation of carbonyl compounds and their nitrogenous
derivatives, has led to the development of many synthetically useful processes notably based
on the use of the Ruppert-Prakash reagent (Me
3
SiCF
3
) for the synthesis of valuable
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1,12
2
fluorinated compounds.
Recently, various electrophilic and radical C(sp )-CF
3
and
3
C(sp )-CF
3
bond formation protocols have been developed for the trifluoromethylation of
13-15
carbonyl derivatives.
In this area, particular efforts have been made towards introduction
of a CF
3
group at the α-position of carbonyl compounds. Nitrogen containing derivatives like
azomethines may also be used to modify the reactivity of the carbonyl moiety towards
trifluoromethylation and open further opportunities for new synthetic strategies or chemical
transformations. For instance, trifluoromethylation of aldehydes via their hydrazones is of
special interest. N, N-Dialkylhydrazones have been extensively used as stable, readily
16
available surrogates for carbonyl-containing compounds and imines. However, they are also
especially attractive as umpolung carbonyl reagents due to the presence of the
17
electron-releasing amino component that should activate the azomethine carbon atom
position towards electrophilic fluoroalkylation. Interestingly, this could offer an alternative
approach to TFMKs upon acidic hydrolysis of the hydrazone moiety.
1
7a
In 2013, Monteiro
reported the trifluoro methylation of aldehyde N, N-dialkyl
hydrazones based on the Togni’s reagent 1 under cooper chloride catalysis. A significant
drawback of the method laid in the low efficiencies for trifluoromethylation of aliphatic
aldehyde hydrazones, the substrate scope being primarily limited to (hetero) aromatic
derivatives. However, the choice of N, N-diphenylamino as the terminal hydrazone amino
17b
group appeared to be the key to efficient trifluoromethylation of aliphatic substrates.
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Trifluoromethylated aliphatic aldehyde N, N-diphenylhydrazones were obtained as E-isomers.
Recently, radical trifluoromethylation of aryl N, N-dimethyl hydrazones using TBAI as an
1
7g
initiator and Togni’s reagent as a trifluoromethyl radical source was described.
A CF radical intermediate was proposed in the reaction pathway. We envisioned that
Langlois’ reagent as the CF radical source may also be effective CF -transfer regents in the
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fluorination of carbonyl compounds instead of the expensive Togni’s reagent with more
widespread applications. Herein we report the successful development of a metal-free
trifluoromethylation of carbonyl compounds and derivatives using Langlois’ reagent and
PhI(OAc)
Scheme 1. Trifluoromethylation of carbonyl compounds and their nitrogenous derivatives
with CF regents
2
at room temperature (Scheme 1).
3
Togni's reagent 1
1.2 equiv)
cat CuCl, r.t.
Monteiro
2
3
NNR2R3
NNR R
(
R1
H
R1
CF3
(
1) R1 = Alkyl, R2, R3 = Aryl (hetAr), CuCl (10 mol%)
2) R1 = Alkyl, R2, R3 = Alkyl, CuCl (10 mol%), low conversion/side-products
Angew. Chem. Int. Ed. 2013, 52, 5346
(
3) R1 = Aryl, R2, R3 = Alkyl, CuCl (20 mol%)
(
Adv. Synth. Catal. 2015, 357, 2939
Studer
N
H
1
N
Togni's reagent , TBAI
N
N
Ar
EA, 80 oC
Ar
CF3
Langlois' reagent 5
This work
NNR R3
2
NNR R3
2
(2 equiv)
R1
H
R1
CF3
PhI(OAc)2,
N2, r.t.
RESULTS AND DISCUSSION
The first studies to determine the capability of Langlois’ reagent to transfer a CF
3
group
to the carbonyl compounds were conducted on n-hexyl aldehyde N, N-diphenylhydrazone
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(
6a) as a model substrate. A series of optimization reactions were screened using different
catalysts, oxidants, additives, solvents, and atmospheres (Table 1). Gratifyingly, the best yield
of trifluoromethylated hydrazone was obtained as the sole reaction product. Clean and full
conversion of the starting material was achieved within 2 hours to give 7a in 79% yield upon
isolation (entry 20). Metal-free trifluoromethylation was realized with Langlois’ reagent and
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PhI(OAc) at room temperature under nitrogen atmosphere.
2
a
Table 1. Survey of the Reaction Conditions
b
Entry
Catalyst (x eq.)
Oxidant (x eq.)
Additive
eq.)
(x
Solvent
Atmosphere
Yield
1
2
3
4
5
6
7
8
9
AgNO
AgNO
AgNO
3
3
3
(0.2)
(0.2)
(0.2)
K
2
S
2
O
8
(0.2)
—
DMSO
DMSO
DMSO
DMSO
air
air
air
air
air
air
air
air
air
<5
12
60
<5
<5
55
60
57
—
—
—
60
65
60
57
TBHP (1)
NaHCO
—
3
(1)
PhI(OAc)
2
(1)
CuCl (1)
CuCl (1)
TBHP (6)
Ag
—
—
—
2 3
CO (1)
K
2
S
2
O
8
(2)
2 2 2
CH Cl :MeOH:H O=5:4:1
CuSO
4
(1)
PhI(OAc)
2
2
(1)
(1)
DMSO
DMSO
DMSO
4 6
(MeCN) CuPF (1)
PhI(OAc)
Cu(OAc)
2
(1)
TBHP (6)
NaOAc (1)
—
—
—
—
—
—
—
I
2
O
5
(2)
—
—
—
—
—
—
—
2 2 2
CH Cl :H O=4:1
10
K
2
S
2
O
8
(2)
DMSO
HFIP
O
2
11
PIFA (2)
air
air
air
air
air
12
13
14
15
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
2
2
2
2
(1)
(1)
(1)
(1)
DMSO
DCM
DMF
Toluene
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1
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—
—
—
—
—
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
PhI(OAc)
2
2
2
2
2
(1)
(1)
(2)
(3)
(2)
—
—
—
—
—
EtOH
DCE
DCE
DCE
DCE
air
air
air
air
63
68
70
70
79
1
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0
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20
N
2
a
3 2
Unless otherwise specified, all reactions were carried out using 6a (0.2 mmol) and CF SO Na (2 eq.) in 4.0 mL solvent at room
b
temperature for 2 hours. Yield of isolated product.
3 2
With the preliminary realization of the trifluoromethylation of 6a with CF SO Na, we
next examined the possibility of a direct C-H trifluoromethylation of benzaldehyde and its
other synthetic equivalents (hydrazones, oxime and imines). Benzaldehyde was chosen as the
model substrate (Table 2). The reactions of 6b and 6c furnished the desired products with
moderate to good yields, whereas the N, N-diphenyl, N, N-dibenyl, N-Boc and 1-piperdinly
hydrazones, 6d, 6e, 6f and 6g, respectively, failed to give the desired product. Additionally,
this reaction did not tolerate secondary amino groups as a complex mixture of products was
obtained in the case of 6h and 6i, even though the starting materials were consumed. These
experimental results indicated that the N, N-substituent structural motif is crucial for this
transformation. Oxime ethers and imines are other radical acceptors containing a C=N group.
However, no reaction occurred when either oxime ethers (6j and 6k) or an imine (6l and 6m)
were used as the substrates. Trifluoromethylation could not be conducted at the α-position of
benzaldehyde.
a, b
Table 2. Substrate screening of different aldehyde derivatives
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a
3 2 2
Unless otherwise specified, all reactions were carried out using 6 (0.2 mmol), CF SO Na (2 eq.), PhI(OAc) (2
b
eq.), DCE (4.0 mL) at room temperature for 2 hours under 1 atm of N
2
(balloon). Yield of isolated product.
With these results in hand, we turned our attention to explore the scope with respect to N,
N-substituent hydrazones under the optimized reaction conditions. Four series of hydrazones
were investigated as shown in Figure 2.
Figure 2. Four series of hydrazones
According to the results of 6a and 6e, the choice of aliphatic aldehydes appeared to be
the key to efficient promotion of the reactions of N, N-diphenyl hydrazone (Table 3, Series A).
Chain and cyclic aliphatic aldehyde derivatives all furnished the corresponding
trifluoromethylated products in moderate to excellent yields (7n-7aa). Trifluoromethylation
of N, N-diphenzylhydrazones using aromatic aldehyde-derived precursors under the
optimized conditions led to no expected product (7ab and 7ac). The C=N bond of the target
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hydrazones was determined to be exclusively E configured by H- F HOESY NMR
1
8
experiments.
a, b
Table 3. Series A: Substrate scope for trifluoromethylation of N, N-diphenyl hydrazone
0
1
2
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0
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9
0
a
3 2 2
Unless otherwise specified, all reactions were carried out using 6 (0.2 mmol), CF SO Na (2 eq.), PhI(OAc) (2
b
eq.), DCE (4.0 mL) at room temperature for 2 hours under 1 atm of N
2
(balloon). Yield of isolated product.
Interestingly, the replacement of the N, N-diphenyl amino with an
N-methyl-N-phenylamino group could also proceeded in relatively good yield (Table 4, Series
B). Aromatic and heteroaromatic aldehyde derivatives all furnished the corresponding
products (7ad-7an). Trifluoromethylation of N-methyl-N-phenylhydrazones using aliphatic
(
chain and cyclic) aldehyde-derived precursors under the optimized conditions led to no
expected product (7aq and 7ar). The C=N bond of the target hydrazones was determined to
1
19
18
be exclusively Z configured by H- F HOESY NMR experiments.
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a,
Table 4. Series B: Substrate scope for trifluoromethylation of N-methyl-N-phenyl hydrazone
b
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a
3 2 2
Unless otherwise specified, all reactions were carried out using 6 (0.2 mmol), CF SO Na (2 eq.), PhI(OAc) (2
b
eq.), DCE (4.0 mL) at room temperature for 2 hours under 1 atm of N (balloon). Yield of isolated product.
2
The trifluoromethylations of various arylideneaminomorpholines under the optimized
reaction conditions were also examined (Table 5, Series C). Aryl aldehyde derived
hydrazones bearing either electron-donating (methyl 7as, methoxy 7at, ethyl 7au) or
electron-withdrawing (trifluoromethyl 7bc, fluoro 7bd, nitro 7be) substituents furnished the
corresponding products with good to excellent yields. The position of the substituent on the
phenyl ring has no effect on this reaction. Remarkably, the C-H trifluoromethylation reaction
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of heterocyclic hydrazones also proceeded well to give the desired products in good yields
(
7ba, 7bb), with the heterocyclic ring being left untouched. Trifluoromethylation of
aminomorpholinehydrazones using aliphatic and cyclic aldehyde-derived precursors under the
0
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optimized conditions led to no expected product (7bg, 7bh). The C=N bond of the target
1
19
hydrazones was also determined to be exclusively E configured by H- F HOESY NMR
18
experiments.
Table 5. Series C: Substrate scope for trifluoromethylation of N-arylidenemorpholin-4-amine
a, b
and N-hetarylidenemorpholin-4-amine
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a
Unless otherwise specified, all reactions were carried out using 6 (0.2 mmol),
CF SO Na (2 eq.), PhI(OAc) (2 eq.), DCE (4.0 mL) at room temperature for 2 hours
3
2
2
b
under 1 atm of N
2
(balloon). Yield of isolated product.
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Surprisingly, N, N-dibenzyl substituted aryl hydrazones could react under the optimized
reaction conditions (Table 6, Series D), even though no product was detected for the N,
N-dibenzyl phenyl hydrazone 6d. No product was found when aliphatic aldehydes were tested
(7bm-7bo). The C=N bond of the target hydrazones was determined to be exclusively E
1
19
18
configured by H- F HOESY NMR experiments.
a, b
Table 6. Series D: Substrate scope for trifluoromethylation of N, N-dibenzyl hydrazone
a
Unless otherwise specified, all reactions were carried out using 6 (0.2 mmol),
CF
3
SO
2
Na (2 eq.), PhI(OAc)
2
(2 eq.), DCE (4.0 mL) at room temperature for 2
b
hours under 1 atm of N (balloon). Yield of isolated product.
2
To demonstrate the synthetic utility of the metal-free trifluoromethylation with Langlois'
reagent, a gram-scale reaction was carried out under standard reaction conditions. We were
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delighted to find that the synthesis of 7ay proceed smoothly with a good yield of 86% on a 5
mmol scale (Scheme 2).
Scheme 2. Gram scale reaction
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To verify whether
radical-inhibition/trapping experiments were conducted. In the model reaction of 6t and
CF SO Na in the presence of PhI(OAc) (2equiv), additional 2.0 equiv TEMPO
tetramethylpiperdinyloxy free radical, a classical radical trapping reagent) was added. The
resulting mixture was stirred for two hours at room temperature, and then 1.0 equiv
a
radical pathway is involved in the reaction,
3
2
2
(
19
trifluoromethyl benzene was added as internal standard for F NMR analysis (Scheme 3).
19
From the result of the F NMR spectrum, we found that there was no desired product 7t was
7
19
formed and instead 52% TEMPO-CF
δ −78.6 (ppm). In order to gain more insights into the reaction mechanism, 4 eq. BHT
2,6-di-tert-butyl-4-methylphenol) was added in the reaction of 6t. No desired product 7t was
3 3
9 adduct was obtained. F NMR (376 MHz, CDCl )
(
19
formed and no other compound was found from the F NMR spectrum and GC-MS.
Scheme 3. Mechanistic experiment: Reaction of 6t in the presence of TEMPO
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Based on the above experimental results and previous reports, a postulated reaction
pathway was thereby proposed as shown in Scheme 4. Initially, reaction of PhI(OAc) with
sodium trifluoromethanesulfinate yields I, and I produces two free radicals, II and CF radical
the related process was proposed by Antonchick and co-workers before), leaving SO
Subsequently, CF radical would be trapped by the hydrazone to generate the
2
3
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2
0
(
2
.
3
trifluoromethylatedaminyl nitrogen atom. Finally, oxidation of this mediate followed by
proton abstraction in the presence of II affords the target product freeing AcOH and PhI.
Scheme 4. Tentative mechanism for trifluoromethylation of hydrazones
CONCLUSION
In summary, we have developed a metal-free and cost-effective synthetic protocol for
3 2
trifluoromethylation of N, N-disubstituted hydrazones with Langlois’ reagent (CF SO Na).
The procedure is highlighted by its operational simplicity, excellent functional group
tolerance and mild reaction conditions. This simple reaction is believed to occur by
3
CF -radical-transfer mechanism and provides a convenient and practical approach to useful
trifluoromethylated building blocks with a wide variety of functional groups.
EXPERIMENTAL SECTION
General Experimental Methods. All reactions were carried out under an atmosphere of N
2
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6
atmosphere. Reactions were monitored by TLC on silica gel plates (GF254), and the
analytical thin-layer chromatography (TLC) was performed on precoated, glass-backed silica
1
13
gel plates. Commercially available materials were used as purchased. H NMR, C NMR
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19
spectra and F NMR spectra were recorded on Bruker AV400 (400MHz) spectrometers.
Chemical shifts were recorded in parts per million (ppm, δ) relative to tetramethylsilane (δ
0.00) or chloroform (δ = 7.26, singlet). NMR splitting patterns are designated as singlet (s),
doublet (d), triplet (t), quartet (q), dd (doublet of doublets), m (multiplets), and etc. All
first-order splitting patterns were assigned on the basis of the appearance of the multiplet.
Splitting patterns that could not be easily interpreted are designated as multiplet (m) or broad
(
br). HRMS were recorded on Waters Xevo G2 Q-TOF.
The substrates 6 were synthesized according to general procedure according to the
21-23
corresponding literature
with minor modification.
General Procedure 1: Synthesis of substrates. To a solution of aldehyde (2 mmol) in dry
DCM (5 mL) was added hydrazine or other amino derivatives (1.4 equiv) and anhydrous
4
MgSO (800 mg). The resulting reaction mixture was stirred at room temperature until it was
completed (by TLC). Filtration on a flash chromatography with DCM was eluent, then
removing of the solvent under reduced pressure, afforded the desired hydrazones in colorless
oil or solid in 75-95% yields. The characterization data of the known compounds are
consistent with the literature well.
(E)-2-hexylidene-1,1-diphenylhydrazine (6a). Prepared according to general procedure 1
1
using n-hexanal and 1,1-diphenylhydrazine hydrochloride (0.46g, 87% yield). H NMR (400
MHz, CDCl
3
) δ (ppm) 7.38-7.34 (m, 4H, ArH), 7.11-7.07 (m, 6H, ArH), 6.53 (t, 1H, J = 4 Hz,
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CH), 2.29-2.24 (m, 2H, CH ), 1.49-1.45 (m, 2H, CH ), 1.32-1.28 (m, 4H, 2CH ), 0.88 (t, 3H,
2
2
2
13
J = 8 Hz, CH
3
); C NMR (100 MHz, CDCl
3
) δ (ppm) 144.5, 140.4, 129.7, 123.8, 122.4, 32.7,
+
3
1.5, 26.8, 22.5, 14.0. HRMS (ESI-Q-TOF) exact mass calcd for C18
found 267.1779.
E)-2-benzylidene-1-methyl-1-phenylhydrazine (6b). Known compound, prepared according
H
23
N
2
[M+H] 267.1783,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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45
46
47
48
49
50
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54
55
56
57
58
59
60
2
3
(
to general procedure 1 using benzaldehyde and 1-methyl-1-phenylhydrazine (0.37g, 89%
1
yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.71-7.69 (m, 2H, ArH), 7.50 (s, 1H, CH),
).
7
.40-7.25 (m, 7H, ArH), 6.95-6.91 (m, 1H, ArH), 3.43 (s, 3H, CH
3
2
4
(
E)-N-morpholino-1-phenylmethanimine (6c). Known compound, prepared according to
1
general procedure 1 using benzaldehyde and morpholin-4-amine (0.34 g, 90% yield). H
NMR (400 MHz, CDCl
3
) δ (ppm) 7.61-7.59 (m, 3H, ArH+CH), 7.37-7.33 (m, 2H, ArH),
), 3.19-3.16 (m, 4H, 2CH ).
7.30-7.27 (m, 1H, ArH), 3.90-3.88 (m, 4H, 2CH
2
2
22
(E)-1,1-dibenzyl-2-benzylidenehydrazine (6d). Known compound, prepared according to
1
general procedure 1 using benzaldehyde and 1,1-dibenzylhydrazine (0.49g, 81% yield). H
NMR (400 MHz, CDCl
.51 (s, 4H, 2CH2).
3
) δ (ppm) 7.50-7.48 (m, 2H, ArH+CH), 7.32-7.18 (m, 14H, ArH),
4
24
(E)-2-benzylidene-1,1-diphenylhydrazine (6e). Known compound, prepared according to
1
general procedure 1 using benzaldehyde and 1,1-diphenylhydrazine (0.46g, 85% yield). H
NMR (400 MHz, CDCl ) δ (ppm) 7.63-7.60 (m, 2H, ArH+CH), 7.44-7.40 (m, 4H, ArH),
3
7.35-7.31 (m, 2H, ArH), 7.27-7.15 (m, 8H, ArH).
25
tert-butyl (E)-2-benzylidene-1-methylhydrazine-1-carboxylate (6f). Known compound,
prepared according to general procedure
1
using benzaldehyde and tert-butyl
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2
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5
5
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5
5
5
5
5
5
6
1
1
7
9
-methylhydrazine-1-carboxylate (0.37g, 79% yield). H NMR (400 MHz, CDCl
3
) δ (ppm)
.71-7.70 (m, 2H, ArH), 7.64 (s, 1H, CH), 7.39-7.32 (m, 3H, ArH), 3.35 (s, 3H, CH
3
), 1.58 (s,
3
H, 3CH ).
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23
(
E)-1-Phenyl-N-(piperidin-1-yl) methanimine (6g). Known compound, prepared according
1
to general procedure 1 using benzaldehyde and piperidin-1-amine (0.31g, 81% yield). H
NMR (400 MHz, CDCl
3
) δ (ppm) 7.59-7.58 (m, 2H, ArH), 7.54 (s, 1H, CH), 7.34-7.30 (m,
H, ArH), 7.25-7.21 (m, 1H, ArH), 3.17-3.14 (m, 4H, 2CH ), 1.78-1.72 (m, 4H, 2CH ),
.56-1.51 (m, 2H, CH ).
2
1
2
2
2
2
6
(
E)-N'-benzylidene-4-methylbenzenesulfonohydrazide (6h). Known compound, prepared
according to general procedure 1 using benzaldehyde and 4-methylbenzenesulfonohydrazide
1
(0.44g, 80% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 8.30 (s, 1H, CH), 7.89-7.87 (m, 2H,
ArH), 7.80-7.77 (m, 1H, ArH), 7.58-7.55 (m, 2H, ArH),7.36-7.29 (m, 5H, ArH+NH), 2.39 (s,
3H, CH ).
E)-1-benzylidene-2-phenylhydrazine (6i). Known compound, prepared according to general
3
27
(
1
procedure 1 using benzaldehyde and phenylhydrazine (0.33g, 83% yield). H NMR (400 MHz,
CDCl ) δ (ppm) 7.68-7.65 (m, 3H, ArH+CH), 7.39-7.35 (m, 2H, ArH), 7.31-7.25 (m, 4H,
3
ArH), 7.13-7.11 (m, 2H, ArH+NH), 6.89-6.85 (m, 1H, ArH).
28
(
E)-benzaldehyde oxime (6j). Known compound, prepared according to general procedure 1
1
using benzaldehyde and hydroxylamine (0.21g, 85% yield). H NMR (400 MHz, CDCl ) δ
3
(
ppm) 9.22 (s, 1H, OH), 8.22 (s, 1H, CH), 7.62-7.59 (m, 2H, ArH), 7.49-7.40 (m, 3H, ArH).
2
9
(E)-benzaldehyde O-ethyl oxime (6k). Known compound, prepared according to general
1
procedure 1 using benzaldehyde and O-ethylhydroxylamine (0.25g, 84% yield). H NMR
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(
400 MHz, CDCl
3
) δ (ppm) 8.07 (s, 1H, CH), 7.59-7.56 (m, 2H, ArH), 7.36-7.34 (m, 3H,
ArH), 4.25-4.20 (m, 2H, CH
2 3
), 1.34-1.30 (m, 3H, CH ).
30
(E)-N-benzylidene-4-methylbenzenesulfonamide (6l). Known compound, prepared according
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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59
60
to general procedure 1 using benzaldehyde and 4-methylbenzenesulfonamide (0.43g, 83%
1
yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 9.03 (s, 1H, CH), 8.14-8.11 (m, 1H, ArH),
7
.94-7.88 (m, 3H, ArH), 7.62-7.60 (m, 1H, ArH), 7.60-7.50 (m, 3H, ArH), 7.50-7.34 (m, 1H,
ArH), 2.44(s, 3H, CH ).
3
(E)-1,1-diphenyl-2-propylidenehydrazine (6n). Prepared according to general procedure 1
1
using n-propanal and 1,1-diphenylhydrazine hydrochloride (0.38g, 85% yield). H NMR (400
MHz, CDCl
3
) δ (ppm) 7.38-7.34 (m, 4H, ArH), 7.13-7.08 (m, 6H, ArH), 6.56 (t, 1H, J = 4 Hz,
13
CH), 2.32-2.25 (m, 2H, CH ), 1.08 (t, 3H, J = 8 Hz, CH ); C NMR (100 MHz, CDCl3)
2
3
δ (ppm) 144.4, 141.0, 129.7, 123.8, 122.4, 26.1, 11.3. HRMS (ESI-Q-TOF) exact mass calcd
+
for C15
H
17
N
2
[M+H] 225.1313, found 225.1322.
(E)-2-butylidene-1,1-diphenylhydrazine (6o). Prepared according to general procedure 1 using
1
n-butanal and 1,1-diphenylhydrazine hydrochloride (0.39g, 81% yield). H NMR (400 MHz,
CDCl ) δ (ppm) 7.33-7.29 (m, 4H, ArH), 7.08-7.04 (m, 6H, ArH), 6.52 (t, 1H, J = 4 Hz, CH),
2.26-2.21 (m, 2H, CH
3
1
3
2
2 3
), 1.51-1.45 (m, 2H, CH ), 0.93 (t, 3H, J = 8 Hz, CH ); C NMR (100
MHz, CDCl
3
) δ (ppm) 144.6, 140.1, 129.8, 124.0, 122.5, 34.9, 20.6, 13.9. HRMS
+
(ESI-Q-TOF) exact mass calcd for C16
H
19
N
2
[M+H] 239.1470, found 239.1500.
17b
(E)-2-(2-methylpropylidene)-1,1-diphenylhydrazine (6p). Known compound,
prepared
according to general procedure 1 using isobutyraldehyde and 1,1-diphenylhydrazine
1
hydrochloride (0.38g, 79% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.38-7.34 (m, 4H,
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ArH), 7.13-7.07 (m, 6H, ArH), 6.47-6.46 (m, 1H, CH), 2.56-2.50 (m, 1H, CH), 1.07-1.06 (m,
3
6H, 2CH ).
(E)-2-(2-methylbutylidene)-1,1-diphenylhydrazine (6q). Prepared according to general
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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2
3
4
5
6
7
8
9
0
procedure 1 using 2-methylbutanal and 1,1-diphenylhydrazine hydrochloride (0.42g, 83%
1
yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.37-7.33 (m, 4H, ArH), 7.10-7.07 (m, 6H, ArH),
6
.42 (d, 1H, J = 8 Hz, CH), 2.36-2.33 (m, 1H, CH), 1.46-1.32 (m, 2H, CH ), 1.06-1.04 (m, 3H,
2
13
CH
3
), 0.89-0.85 (m, 3H, CH
3
); C NMR (100 MHz, CDCl
3
) δ (ppm) 144.7, 144.6, 129.7,
21 2
123.8, 122.4, 38.5, 27.9, 17.9, 11.7. HRMS (ESI-Q-TOF) exact mass calcd for C17H N
+
[
M+H] 253.1626, found 253.1633.
(E)-2-(3-methylbutylidene)-1,1-diphenylhydrazine (6r). Prepared according to general
procedure 1 using 3-methylbutanal and 1,1-diphenylhydrazine hydrochloride (0.39g, 78%
1
yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.36-7.32 (m, 4H, ArH), 7.11-7.07 (m, 6H, ArH),
6.53 (t, 1H, J = 4 Hz, CH), 2.18-2.15 (m, 2H, CH
2
3
), 1.80-1.73 (m, 1H, CH), 0.90 (s, 3H, CH ),
13
0
.88 (s, 3H, CH ); C NMR (100 MHz, CDCl ) δ (ppm) 144.6, 139.8, 129.7, 123.9, 122.5,
3
3
+
41.6, 27.2, 22.5. HRMS (ESI-Q-TOF) exact mass calcd for C17
found 253.1631.
H
21
N
2
[M+H] 253.1626,
(E)-2-(2-ethylbutylidene)-1,1-diphenylhydrazine (6s). Prepared according to general
procedure 1 using 2-ethylbutanal and 1,1-diphenylhydrazine hydrochloride (0.44g, 82%
1
yield). H NMR (400 MHz, CDCl ) δ (ppm) 7.37-7.34 (m, 4H, ArH), 7.12-7.08 (m, 6H,
3
2
ArH), 6.35 (d, 1H, J = 4 Hz, CH), 2.20-2.14 (m, 1H, CH), 1.45-1.36 (m, 4H, 2CH ), 0.86 (t,
13
6H, J = 8 Hz, 2CH
3
); C NMR (100 MHz, CDCl
3
) δ (ppm) 144.7, 144.4, 129.7, 123.8, 122.5,
+
45.6, 25.8, 11.7. HRMS (ESI-Q-TOF) exact mass calcd for C18
H
23
N
2
[M+H] 267.1783,
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found 267.1791.
(E)-2-heptylidene-1,1-diphenylhydrazine (6t). Prepared according to general procedure 1
1
using heptanal and 1,1-diphenylhydrazine hydrochloride (0.47g, 84% yield). H NMR (400
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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33
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41
42
43
44
45
46
47
48
49
50
51
52
53
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55
56
57
58
59
60
MHz, CDCl ) δ (ppm) 7.37-7.33 (m, 4H, ArH), 7.10-7.07 (m, 6H, ArH), 6.53 (t, 1H, J = 8 Hz,
3
2 2 2
CH), 2.29-2.24 (m, 2H, CH ), 1.48-1.44 (m, 2H, CH ), 1.31-1.28 (m, 6H, 3CH ), 0.89-0.86
13
(
m, 3H, CH
3
); C NMR (100 MHz, CDCl
3
) δ (ppm) 144.5, 140.4, 129.7, 123.8, 122.4, 32.8,
+
3
1.7, 28.9, 27.1, 22.6, 14.1. HRMS (ESI-Q-TOF) exact mass calcd for C19
81.1939, found 281.1941.
25 2
H N [M+H]
2
(E)-2-octylidene-1,1-diphenylhydrazine (6u). Prepared according to general procedure 1 using
1
octanal and 1,1-diphenylhydrazine hydrochloride (0.49g, 83% yield). H NMR (400 MHz,
CDCl
3
) δ (ppm) 7.37-7.33 (m, 4H, ArH), 7.12-7.07 (m, 6H, ArH), 6.53 (t, 1H, J = 4 Hz, CH),
), 1.48-1.43 (m, 2H, CH ), 1.30-1.26 (m, 8H, 4CH ), 0.88 (t, 3H, J = 8
2.29-2.24 (m, 2H, CH
2
2
2
13
Hz, CH
3
); C NMR (100 MHz, CDCl
3
) δ (ppm) 144.5, 140.4, 129.7, 123.8, 122.4, 32.8, 31.8,
+
29.2, 27.1, 14.1. HRMS (ESI-Q-TOF) exact mass calcd for C20
H
27
N
2
[M+H] 295.2096,
found 295.2097.
(E)-2-nonylidene-1,1-diphenylhydrazine (6v). Prepared according to general procedure 1
1
using nonanal and 1,1-diphenylhydrazine hydrochloride (0.54g, 87% yield). H NMR (400
MHz, CDCl ) δ (ppm) 7.37-7.33 (m, 4H, ArH), 7.10-7.07 (m, 6H, ArH), 6.53 (t, 1H, J = 4 Hz,
3
2 2 2
CH), 2.29-2.24 (m, 2H, CH ), 1.48-1.42 (m, 2H, CH ), 1.31-1.26 (m, 10H, 5CH ), 0.88 (t, 3H,
13
J = 2 Hz, CH
3
); C NMR (100 MHz, CDCl
3
) δ (ppm) 144.5, 140.4, 129.7, 123.8, 122.4, 32.8,
31.9, 29.4, 29.3, 27.1, 22.7, 14.1. HRMS (ESI-Q-TOF) exact mass calcd for C H N [M+H]
21
29
2
+
309.2252, found 309.2261.
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(
E)-2-decylidene-1,1-diphenylhydrazine (6w). Prepared according to general procedure 1
1
using decanal and 1,1-diphenylhydrazine hydrochloride (0.52g, 80% yield). H NMR (400
MHz, CDCl
3
) δ (ppm) 7.38-7.33 (m, 4H, ArH), 7.13-7.07 (m, 6H, ArH), 6.53 (t, 1H, J = 8 Hz,
), 1.46-1.44 (m, 2H, CH ), 1.26-1.25 (m, 12H, 6CH ), 0.88 (t, 3H,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CH), 2.29-2.24 (m, 2H, CH
2
2
2
13
J = 8 Hz, CH
3
); C NMR (100 MHz, CDCl
3
) δ (ppm) 144.5, 140.4, 129.6, 123.8, 122.4, 32.8,
3
1.9, 29.7, 29.5, 29.4, 29.3, 29.2, 27.1, 22.7, 14.1. HRMS (ESI-Q-TOF) exact mass calcd for
+
C
22 31 2
H N [M+H] 323.2409, found 323.2413.
(E)-2-dodecylidene-1,1-diphenylhydrazine (6x). Prepared according to general procedure 1
1
using dodecanal and 1,1-diphenylhydrazine hydrochloride (0.53g, 75% yield). H NMR δ
(
400 MHz, CDCl
3
) (ppm) 7.37-7.33 (m, 4H, ArH), 7.10-7.07 (m, 6H, ArH), 6.53 (t, 1H, J = 4
Hz, CH), 2.29-2.24 (m, 2H, CH ), 1.48-1.44 (m, 2H, CH ), 1.26-1.25 (m, 16H, 8CH ), 0.88 (t,
2
2
2
13
3
3 3
H, J = 4 Hz, CH ); C NMR (100 MHz, CDCl ) δ (ppm) 144.5, 140.4, 129.7, 123.8, 122.4,
32.8, 32.0, 29.7, 29.6, 29.5, 29.4, 29.2, 27.1, 22.7, 14.1. HRMS (ESI-Q-TOF) exact mass
+
calcd for C24
H
35
N
2
[M+H] 351.2722, found 351.2729.
17b
(E)-1,1-diphenyl-2-(3-phenylpropylidene) hydrazine (6y). Known compound,
prepared
according to general procedure 1 using 3-phenylpropanal and 1,1-diphenylhydrazine
1
hydrochloride (0.48g, 80% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.36-7.32 (m, 4H,
ArH), 7.27-7.23 (m, 2H, ArH), 7.20-7.17 (m, 3H, ArH), 7.17-7.15 (m, 2H, ArH), 7.15-7.05 (m,
4H, ArH), 6.57-6.55 (m, 1H, CH), 2.85-2.81 (m, 2H, CH
2
2
), 2.61-2.55 (m, 2H, CH ).
17b
ethyl (E)-2-(2,2-diphenylhydrazono) acetate (6z). Known compound, prepared according to
general procedure 1 using ethyl 2-oxoacetate and 1,1-diphenylhydrazine hydrochloride (0.45g,
1
8
3% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.44-7.41 (m, 4H, ArH), 7.27-7.23 (m, 2H,
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ArH), 7.19-7.17 (m, 4H, ArH), 6.50 (s, 1H, CH), 4.30-4.25 (m, 2H, CH ), 1.35-1.31 (m, 3H,
2
3
CH ).
17b
(E)-2-(cyclohexylmethylene)-1,1-diphenylhydrazine (6aa). Known compound,
prepared
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
according to general procedure 1 using cyclohexanecarbaldehyde and 1,1-diphenylhydrazine
1
(
(
0.33g, 58% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.37-7.33 (m, 4H, ArH), 7.12-7.06
m, 6H, ArH), 6.45 (d, 1H, J = 4 Hz, CH), 2.28-2.22 (m, 1H, CH), 1.82-1.71 (m, 5H,
CH +CH), 1.31-1.27 (m, 4H, 2CH ), 0.90-0.87 (m, 1H, CH).
E)-2-(4-methylbenzylidene)-1,1-diphenylhydrazine (6ab). Prepared according to general
2
2
2
(
procedure 1 using 4-methylbenzaldehyde and 1,1-diphenylhydrazine hydrochloride (0.48g, 83%
1
yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.51-7.49 (m, 2H, ArH), 7.43-7.39 (m, 4H, ArH),
13
7.20-7.13 (m, 9H, ArH+CH), 2.34 (s, 3H, CH
3
); C NMR (100 MHz, CDCl
3
) δ (ppm) 143.8,
138.1, 135.8, 133.5, 129.3, 126.3, 124.4, 122.6, 21.4. HRMS (ESI-Q-TOF) exact mass calcd
+
19 2
for C20H N [M+H] 287.1470, found 287.1483.
17c
(E)-2-(4-nitrobenzylidene)-1,1-diphenylhydrazine (6ac). Known compound,
prepared
according to general procedure 1 using 4-nitrobenzaldehyde and 1,1-diphenylhydrazine
1
(
0.51g, 80% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 8.19-8.17 (m, 2H, ArH), 7.73-7.70
(m, 2H, ArH), 7.48-7.44 (m, 4H, ArH), 7.24-7.21 (m, 6H, ArH), 7.13 (s, 1H, CH).
17f
(E)-1-methyl-2-(4-methylbenzylidene)-1-phenylhydrazine (6ad). Known compound,
prepared according to general procedure
1
using 4-methylbenzaldehyde and
) δ (ppm)
1
1-methyl-1-phenylhydrazine (0.38g, 85% yield). H NMR (400 MHz, CDCl
3
7.60-7.58 (m, 2H, ArH), 7.49 (s, 1H, CH), 7.39-7.37 (m, 2H, ArH), 7.33-7.29 (m, 2H, ArH),
3 3
7.19-7.17 (m, 2H, ArH), 6.93-6.90 (m, 1H, ArH), 3.41 (s, 3H, CH ), 2.36 (s, 3H, CH ).
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(
E)-2-(4-methoxybenzylidene)-1-methyl-1-phenylhydrazine (6ae). Known compound,
prepared according to general procedure
1
using 4-methoxybenzaldehyde and
-methyl-1-phenylhydrazine (0.42g, 87% yield). H NMR (400 MHz, CDCl ) δ (ppm)
.65-7.63 (m, 2H, ArH), 7.48 (s, 1H, CH), 7.38-7.36 (m, 4H, ArH), 6.92-6.89 (m, 3H, ArH),
.83 (s, 3H, OCH ), 3.39 (s, 3H, CH ).
1
1
7
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
(
E)-2-(3-methoxybenzylidene)-1-methyl-1-phenylhydrazine (6af). Prepared according to
general procedure 1 using 3-methoxybenzaldehyde and 1-methyl-1-phenylhydrazine (0.39g,
1
8
1% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.44 (s, 1H, CH), 7.38-7.22 (m, 7H, ArH),
1
3
6
3 3
.94-6.91 (m, 1H, ArH), 6.82-6.80 (m, 1H, ArH), 3.84 (s, 3H, OCH ), 3.38 (s, 3H, CH ); C
NMR (100 MHz, CDCl
3
) δ (ppm) 159.9, 147.8, 138.3, 131.7, 129.5, 129.0, 120.6, 119.2,
1
15.3, 113.7, 110.6, 55.2, 33.1. HRMS (ESI-Q-TOF) exact mass calcd for C H N O [M+H]
15 17
2
+
241.1263, found 241.1277.
(E)-2-(4-ethylbenzylidene)-1-methyl-1-phenylhydrazine (6ag). Prepared according to general
procedure 1 using 4-ethylbenzaldehyde and 1-methyl-1-phenylhydrazine (0.38g, 80% yield).
1
H NMR (400 MHz, CDCl
3
) δ (ppm) 7.62-7.60 (m, 2H, ArH+CH), 7.48 (s, 1H, ArH),
7
.38-7.29 (m, 4H, ArH), 7.22-7.18 (m, 2H, ArH), 6.92-6.83 (m, 1H, ArH), 3.38 (s, 3H, CH3),
13
2 3 3
2.68-2.62 (m, 2H, CH ), 1.24 (t, 3H, J = 8 Hz, CH ); C NMR (100 MHz, CDCl ) δ (ppm)
1
48.0, 144.0, 134.3, 132.1, 129.0, 128.1, 126.1, 120.3, 115.1, 33.0, 28.7, 15.5. HRMS
+
(ESI-Q-TOF) exact mass calcd for C16
19 2
H N [M+H] 239.1470, found 239.1481.
(
E)-2-(4-bromobenzylidene)-1-methyl-1-phenylhydrazine (6ah). Prepared according to
general procedure 1 using 4-bromobenzaldehyde and 1-methyl-1-phenylhydrazine (0.48g, 83%
1
yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.57-7.54 (m, 2H, ArH+CH), 7.49-7.46 (m, 2H,
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ArH), 7.41-7.30 (m, 5H, ArH), 6.97-6.93 (m, 1H, ArH), 3.41 (s, 3H, CH ); C NMR (100
3
MHz, CDCl
3
) δ (ppm) 147.7, 135.8, 131.7, 130.4, 129.1, 127.4, 121.3, 120.9, 115.4, 33.2.
+
HRMS (ESI-Q-TOF) exact mass calcd for C14
H14BrN
2
[M+H] 289.0262, found 289.0271.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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55
56
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58
59
60
2
4
(
E)-2-(3-bromobenzylidene)-1-methyl-1-phenylhydrazine (6ai). Known compound, prepared
according to general procedure using 3-bromobenzaldehyde and
-methyl-1-phenylhydrazine (0.49g, 85% yield). H NMR (400 MHz, CDCl ) δ (ppm)
.08-8.06 (m. 1H, ArH), 7.76 (s, 1H, CH), 7.54-7.52 (m, 1H, ArH), 7.39-7.28 (m, 5H, ArH),
.11-7.07 (m, 1H, ArH), 6.97-6.94 (m, 1H, ArH), 3.45 (s, 3H, CH ).
1
1
1
8
7
3
3
(
E)-2-(3-chlorobenzylidene)-1-methyl-1-phenylhydrazine (6aj). Prepared according to general
procedure 1 using 3-chlorobenzaldehyde and 1-methyl-1-phenylhydrazine (0.39g, 79% yield).
1
H NMR (400 MHz, CDCl
3
) δ (ppm) 7.68 (s, 1H, CH), 7.51-7.49 (m, 1H, ArH), 7.37-7.31 (m,
5
H, ArH), 7.30-7.23 (m, 1H, ArH), 7.21-7.18 (m, 1H, ArH), 6.96-6.93 (m, 1H, ArH), 3.37 (s,
1
3
3 3
3H, CH ); C NMR (100 MHz, CDCl ) δ (ppm) 147.6, 138.7, 134.6, 130.0, 129.7, 129.1,
1
27.4, 125.6, 124.3, 121.0, 115.4, 33.2. HRMS (ESI-Q-TOF) exact mass calcd for C14H14ClN
2
+
[M+H] 245.0767, found 245.0762.
24
(
E)-2-(2-bromobenzylidene)-1-methyl-1-phenylhydrazine (6ak). Known compound,
prepared according to general procedure
1
using 2-chlorobenzaldehyde and
) δ (ppm)
8.09-8.07 (m, 1H, ArH) ,7.80 (s, 1H, CH), 7.40-7.37 (m, 5H, ArH), 7.37-7.24 (m, 1H,
ArH),7.24-7.14 (m, 1H, ArH), 6.97-6.93 (m, 1H, ArH), 3.44 (s, 3H, CH ).
1
1
-methyl-1-phenylhydrazine (0.45g, 78% yield). H NMR (400 MHz, CDCl
3
3
(E)-1-methyl-1-phenyl-2-(4-(trifluoromethyl) benzylidene) hydrazine (6al). Known
32
compound,
prepared according to general procedure 1 using 4-(trifluoromethyl)
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
benzaldehyde and 1-methyl-1-phenylhydrazine (0.45g, 81% yield). H NMR (400 MHz,
CDCl ) δ (ppm) 8.09-8.07 (m, 1H, ArH), 7.80 (s, 1H, CH), 7.39-7.14 (m, 7H, ArH), 6.97-6.93
m, 1H, ArH), 3.43 (s, 3H, CH ).
E)-1-methyl-2-(4-nitrobenzylidene)-1-phenylhydrazine (6am). Known compound, prepared
3
(
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
(
according to general procedure 1 using 4-nitrobenzaldehyde and 1-methyl-1-phenylhydrazine
1
(
0.46g, 90% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 8.21 (d, 2H, J = 8 Hz, ArH), 7.79 (d,
2
H, J = 8 Hz, ArH), 7.47 (s, 1H, CH), 7.40-7.38 (m, 4H, ArH), 7.03-7.00 (m, 1H, ArH), 3.49
s, 3H, CH ).
E)-1-methyl-1-phenyl-2-(thiophen-2-ylmethylene) hydrazine (6an). Known compound,
using thiophene-2-carbaldehyde and
1-methyl-1-phenylhydrazine (0.35g, 80% yield). H NMR (400 MHz, CDCl ) δ (ppm) 7.66 (s,
H, CH), 7.34-7.28 (m, 5H, ArH), 7.19-7.00 (m, 1H, ArH), 6.99-6.98 (m, 1H, ArH), 6.94-6.90
(m, 1H, ArH), 3.37 (s, 3H, CH ).
(
3
23
(
prepared according to general procedure
1
1
3
1
3
ethyl (E)-2-(2-methyl-2-phenylhydrazono) acetate (6ao). Prepared according to general
1
procedure 1 using ethyl 2-oxoacetate and 1-methyl-1-phenylhydrazine (0.34g, 83% yield). H
NMR (400 MHz, CDCl
3
) δ (ppm) 7.39-7.31 (m, 4H, ArH), 7.06-7.04 (m, 1H, ArH), 6.78 (s,
1
3
1H, CH), 4.32-4.30 (m, 2H, CH
2
3 3
), 3.37 (s, 3H, CH ), 1.35 (t, 3H, J = 8 Hz, CH ); C NMR
(
100 MHz, CDCl
3
) δ (ppm) 164.8, 146.7, 129.1, 123.3, 121.1, 117.2, 60.6, 34.4, 14.4. HRMS
+
(ESI-Q-TOF) exact mass calcd for C11
H
15
N
2
O
2
[M+H] 207.1055, found 207.1061.
(
E)-1-methyl-1-phenyl-2-(3-phenylpropylidene) hydrazine (6ap). Prepared according to
general procedure 1 using 3-phenylpropanal and 1-methyl-1-phenylhydrazine (0.41g, 85%
1
yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.31-7.16 (m, 9H, ArH+CH), 6.88-6.82 (m, 2H,
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3
ArH), 3.18 (s, 3H, CH ), 2.93-2.90 (m, 2H, CH ), 2.72-2.67 (m, 2H, CH ); C NMR (100
3
2
2
MHz, CDCl
3
) δ (ppm) 148.3, 141.6, 134.6, 129.2, 128.9, 128.5, 125.9, 119.9, 114.9, 112.4,
+
3
4.7, 33.9, 33.1. HRMS (ESI-Q-TOF) exact mass calcd for C16
found 239.1465.
E)-2-butylidene-1-methyl-1-phenylhydrazine (6aq). Known compound, prepared according
H
19
N
2
[M+H] 239.1470,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
2
(
to general procedure 1 using butyraldehyde and 1-methyl-1-phenylhydrazine (0.29g, 81%
1
yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.29-7.22 (m, 4H, ArH+CH), 6.87-6.82 (m, 2H,
ArH), 3.22 (s, 3H, CH
3
), 2.37-2.32 (m, 2H, CH
2
), 1.63-1.57 (m, 2H, CH
2
), 1.01-0.97 (m, 3H,
CH
E)-2-(cyclohexylmethylene)-1-methyl-1-phenylhydrazine (6ar). Known compound,
prepared according to general procedure
-methyl-1-phenylhydrazine (0.33g, 76% yield). H NMR (400 MHz, CDCl
7.28-7.22 (m, 4H, ArH), 6.86-6.82 (m, 1H, ArH), 6.72 (d, 1H, J = 8 Hz, CH), 3.19 (s, 3H,
3
).
32
(
1
using cyclohexanecarbaldehyde and
1
1
3
) δ (ppm)
CH
3
), 2.34-2.29 (m, 1H, CH), 1.91-1.88 (m, 2H, CH
2
2
), 1.80-1.76 (m, 2H, CH ), 1.37-1.36 (m,
1H, CH), 1.33-1.20 (m, 5H, 2CH
2
+CH).
34
(
E)-N-morpholino-1-(p-tolyl)-methanimine (6as). Known compound, prepared according to
general procedure 1 using 4-methylbenzaldehyde and morpholin-4-amine (0.37g, 90% yield).
1
H NMR (400 MHz, CDCl
3
) δ (ppm) 7.59 (s, 1H, CH), 7.51-7.49 (m, 2H, ArH), 7.16-7.14 (m,
), 3.17-3.15 (m, 4H, 2CH ), 2.35 (s, 3H, CH ).
E)-1-(4-methoxyphenyl)-N-morpholinomethanimine (6at). Known compound,
2H, ArH), 3.90-3.87 (m, 4H, 2CH
2
2
3
17e
(
prepared
according to general procedure 1 using 4-methoxybenzaldehyde and morpholin-4-amine
1
(
0.42g, 95% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.59 (s, 1H, CH), 7.56-7.53 (m, 2H,
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1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ArH), 6.90-6.88 (m, 2H, ArH), 3.90-3.87 (m, 4H, 2CH ), 3.82 (s, 3H, OCH ), 3.15-3.13 (m,
2
3
2
4H, 2CH ).
(E)-1-(4-ethylphenyl)-N-morpholinomethanimine (6au). Prepared according to general
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
procedure 1 using 4-ethylbenzaldehyde and morpholin-4-amine (0.41g, 93% yield). H NMR
(
3
400 MHz, CDCl ) δ (ppm) 7.55 (s, 1H, CH), 7.52-7.50 (m, 2H, ArH), 7.17-7.15 (m, 2H,
ArH), 3.85-3.83 (m, 4H, 2CH ), 3.13-3.10 (m, 4H, 2CH ), 2.65-2.59 (m, 2H, CH ), 1.21 (t,
2
2
2
1
3
3
6
2
H, J = 8 Hz, CH
3
); C NMR (100 MHz, CDCl
3
) δ (ppm) 144.7, 136.6, 133.6, 128.1, 126.3,
+
6.5, 52.0, 28.8, 15.6. HRMS (ESI-Q-TOF) exact mass calcd for C13
19.1419, found 219.1425.
19 2
H N O [M+H]
17e
(E)-1-(4-bromophenyl)-N-morpholinomethanimine (6av). Known compound,
prepared
according to general procedure 1 using 4-bromobenzaldehyde and morpholin-4-amine (0.49g,
1
9
1% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.51 (s, 1H, CH), 7.50-7.47 (m, 4H, ArH),
), 3.19-3.16 (m, 4H, 2CH ).
E)-1-(2-chlorophenyl)-N-morpholinomethanimine (6aw). Known compound,
3.90-3.80 (m, 4H, 2CH
2
2
17f
(
prepared
according to general procedure 1 using 2-chlorobenzaldehyde and morpholin-4-amine (0.40g,
1
9
0% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.95-7.92 (m, 1H, ArH), 7.90 (s, 1H, CH),
), 3.22-3.19 (m, 4H,
7.33-7.29 (m, 1H, ArH), 7.24-7.15 (m, 2H, ArH), 3.88-3.86 (m, 4H, 2CH
CH ).
(E)-1-(2-bromophenyl)-N-morpholinomethanimine (6ax). Known compound,
2
2
2
17f
prepared
according to general procedure 1 using 2-bromobenzaldehyde and morpholin-4-amine (0.50g,
1
93% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.95-7.93 (m, 1H, ArH), 7.87 (s, 1H, CH),
7.53-7.51 (m, 1H, ArH), 7.30-7.28 (m, 1H, ArH), 7.14-7.10 (m, 1H, ArH), 3.91-3.89 (m, 4H,
26
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Page 27 of 54
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2
CH ), 3.24-3.21 (m, 4H, 2CH ).
2
2
17f
(E)-1-(3-chlorophenyl)-N-morpholinomethanimine (6ay). Known compound,
prepared
according to general procedure 1 using 3-chlorobenzaldehyde and morpholin-4-amine (0.41g,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
9
2% yield). H NMR (400 MHz, CDCl ) δ (ppm) 7.62 (s, 1H, CH), 7.48-7.42 (m, 2H, ArH),
3
7
2 2
.28-7.21 (m, 2H, ArH), 3.89-3.87 (m, 4H, 2CH ), 3.19-3.10 (m, 4H, 2CH ).
17f
(
E)-1-(3-bromophenyl)-N-morpholinomethanimine (6az). Known compound,
prepared
according to general procedure 1 using 3-bromobenzaldehyde and morpholin-4-amine (0.49g,
1
9
7
2
1% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.78 (s, 1H, CH), 7.48-7.46 (m, 2H, ArH),
), 3.19-3.16 (m, 4H,
.39-7.37 (m, 1H, ArH), 7.22-7.18 (m, 1H, ArH), 3.89-3.86 (m, 4H, 2CH
2
2
CH ).
(
E)-1-(furan-2-yl)-N-morpholinomethanimine (6ba). Prepared according to general procedure
1
1
using furan-2-carbaldehyde and morpholin-4-amine (0.34g, 94% yield). H NMR (400 MHz,
CDCl
3
) δ (ppm) 7.47-7.43 (m, 2H, ArH), 6.48 (s, 1H, ArH), 6.43 (s, 1H, CH), 3.89-3.87 (m,
13
4
H, 2CH ), 3.30-3.10 (m, 4H, 2CH ); C NMR (100 MHz, CDCl ) δ (ppm) 151.3, 142.8,
2
2
3
9 13 2 2
126.7, 111.4, 109.2, 66.4, 51.7. HRMS (ESI-Q-TOF) exact mass calcd for C H N O [M+H]
+
1
81.0899, found 181.0903.
(E)-N-morpholino-1-(pyridin-2-yl) methanimine (6bb). Prepared according to general
1
procedure 1 using picolinaldehyde and morpholin-4-amine (0.35g, 91% yield). H NMR (400
MHz, CDCl ) δ (ppm) 8.54-8.53 (m, 1H, ArH), 7.86-7.84 (m, 1H, ArH), 7.67-7.65 (m, 1H,
3
2
ArH), 7.66 (s, 1H, CH), 7.17-7.14 (m, 1H, ArH), 3.91-3.86 (m, 4H, 2CH ), 3.27-3.24 (m, 4H,
13
2CH
2
); C NMR (100 MHz, CDCl
3
) δ (ppm) 149.1, 136.3, 135.8, 122.5, 119.4, 66.4, 51.5.
+
HRMS (ESI-Q-TOF) exact mass calcd for C10
H
14
N
3
O [M+H] 192.1059, found 192.1063.
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The Journal of Organic Chemistry
Page 28 of 54
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
4
(
E)-N-morpholino-1-(4-(trifluoromethyl) phenyl) methanimine (6bc). Known compound,
prepared according to general procedure 1 using 4-(trifluoromethyl) benzaldehyde and
1
morpholin-4-amine (0.48g, 92% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.70-7.68 (m,
), 3.23-3.21 (m, 4H, 2CH ).
prepared
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
H, ArH), 7.59-7.56 (m, 3H, ArH+CH), 3.91-3.88 (m, 4H, 2CH
2
2
24
(E)-1-(4-fluorophenyl)-N-morpholinomethanimine (6bd). Known compound,
according to general procedure 1 using 4-fluorobenzaldehyde and morpholin-4-amine (0.39g,
1
9
3% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.59-7.56 (m, 3H, ArH+CH), 7.06-7.01 (m,
2
H, ArH), 3.90-3.87 (m, 4H, 2CH
2
), 3.17-3.15 (m, 4H, 2CH ).
2
1
7a
(E)-N-morpholino-1-(4-nitrophenyl) methanimine (6be). Known compound,
prepared
according to general procedure 1 using 4-nitrobenzaldehyde and morpholin-4-amine (0.42g,
1
90% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 8.20 (d, 2H, J = 8 Hz, ArH), 7.71 (d, 2H, J
), 3.28-3.26 (m, 4H, 2CH ).
=
8 Hz, ArH), 7.53 (s, 1H, CH), 3.91-3.89 (m, 4H, 2CH
2
2
ethyl (E)-2-(morpholinoimino) acetate (6bf). Prepared according to general procedure 1 using
1
ethyl 2-oxoacetate and morpholin-4-amine (0.35g, 95% yield). H NMR (400 MHz, CDCl ) δ
3
2 2
(ppm) 6.79 (s, 1H, CH), 4.32-4.27 (m, 2H, CH ), 3.86-3.83 (m, 4H, 2CH ), 3.33-3.31 (m, 4H,
13
2
CH
2
), 1.33 (t, 3H, J = 4 Hz, CH
3
); C NMR (100 MHz, CDCl
3
) δ (ppm) 164.5, 122.4, 66.0,
+
60.7, 50.5, 14.3. HRMS (ESI-Q-TOF) exact mass calcd for C
8
H
15
N
2
O
3
[M+H] 187.1004,
found 187.1011.
(E)-1-cyclohexyl-N-morpholinomethanimine (6bg). Prepared according to general procedure 1
1
using cyclohexanecarbaldehyde and morpholin-4-amine (0.31g, 79% yield). H NMR (400
MHz, CDCl
3
) δ (ppm) 6.83 (d, 1H, J = 8 Hz, CH), 3.83-3.81 (m, 4H, 2CH
2
), 2.94-2.92 (m,
4
H, 2CH
2
), 2.22-2.17 (m, 1H, CH), 1.79-1.73 (m, 5H, 2CH +CH), 1.35-1.17 (m, 5H,
2
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The Journal of Organic Chemistry
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2
3
4
5
6
7
8
9
1
3
2
CH
2
+CH); C NMR (100 MHz, CDCl
3
) δ (ppm) 146.6, 66.5, 52.5, 41.3, 31.0, 26.0, 25.6;
+
HRMS (ESI-Q-TOF) exact mass calcd for C11
H
21
N
2
O [M+H] 197.1576, found 197.1601.
(
E)-N-morpholinoheptan-1-imine (6bh). Prepared according to general procedure 1 using
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
ethyl heptanal and morpholin-4-amine (0.36g, 90% yield). H NMR (400 MHz, CDCl ) δ
3
(
ppm) 6.98 (s, 1H, CH), 3.86-3.82 (m, 4H, 2CH
2
2
), 2.96-2.94 (m, 4H, 2CH ), 2.27-2.22 (m, 2H,
13
CH
2
), 1.50-1.30 (m, 8H, 4CH
2
), 0.88 (t, 3H, J = 2 Hz, CH
3
); C NMR (100 MHz, CDCl
3
) δ
(
ppm) 142.5, 66.5, 52.6, 33.0, 31.6, 28.9, 27.4, 22.5, 14.0. HRMS (ESI-Q-TOF) exact mass
+
calcd for C11
23 2
H N O [M+H] 199.1732, found 199.1741.
17f
(
E)-1,1-dibenzyl-2-(4-methylbenzylidene) hydrazine (6bi). Known compound,
prepared
according to general procedure 1 using 4-methylbenzaldehyde and 1,1-dibenzylhydrazine
1
(0.52g, 83% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.40-7.38 (m, 2H, ArH), 7.30-7.23
(
m, 10H, ArH), 7.17 (s, 1H, CH), 7.10-7.08 (m, 2H, ArH), 4.49 (s, 4H, 2CH
2
), 2.31 (s, 3H,
CH ).
3
35
(
E)-1,1-dibenzyl-2-(4-bromobenzylidene) hydrazine (6bj). Known compound, prepared
according to general procedure 1 using 4-bromobenzaldehyde and 1,1-dibenzylhydrazine
1
(
0.64g, 85% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.40-7.36 (m, 4H, ArH), 7.34-7.25
).
E)-1,1-dibenzyl-2-(4-(trifluoromethyl) benzylidene) hydrazine (6bk). Known compound,
(m, 10H, ArH), 7.05 (s, 1H, CH), 4.52 (s, 4H, 2CH
2
35
(
prepared according to general procedure 1 using 4-(trifluoromethyl) benzaldehyde and
1
1
,1-dibenzylhydrazine (0.59g, 80% yield). H NMR (400 MHz, CDCl
3
) δ (ppm) 7.58-7.50 (m,
4H, ArH), 7.32-7.25 (m, 10H, ArH), 7.12 (s, 1H, CH), 4.57 (s, 4H, 2CH2).
17a
(
E)-1,1-dibenzyl-2-(4-nitrobenzylidene) hydrazine (6bl). Known compound,
prepared
29
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