Synthesis and Characterization of para-Substituted N,N′-Dihydroxybenzamidines and Their Derivatives as Model Compounds for a Class of Prodrugs

Article abstract of DOI:10.1002/ejoc.201301622

A synthetic strategy for previously unknown para-substituted N,N′-dihydroxybenzamidines and their O-monosubstituted and O,O′-disubstituted methyl, benzyl, and tetrahydropyranyl derivatives is described. The procedure starts with the corresponding hydroxam

Full text of DOI:10.1002/ejoc.201301622

FULL PAPER
DOI: 10.1002/ejoc.201301622
Synthesis and Characterization of para-Substituted
N,NЈ-Dihydroxybenzamidines and Their Derivatives as Model Compounds for
a Class of Prodrugs
Laura Schwarz,[a] Ulrich Girreser,[a] and Bernd Clement*[a]
Keywords: Synthetic methods / Medicinal chemistry / Prodrugs / 15N NMR / Substituent-induced chemical shifts
A synthetic strategy for previously unknown para-substi-
tuted N,NЈ-dihydroxybenzamidines and their O-monosubsti-
15N NMR spectroscopy. The chemical shifts show significant
correlations with Hammett σ values, especially for the oxime-
tuted and O,OЈ-disubstituted methyl, benzyl, and tetra- type nitrogen with r2 Ͼ 0.99. The Hammett σ parameter reli-
hydropyranyl derivatives is described. The procedure starts
ably correlates with electron density in molecules. The pre-
with the corresponding hydroxamic acid chlorides, which af- sented results thus allow predictions relating to π-electron
ter dehydrohalogenation give nitrile oxides. These interme- density and basicity in this functional group, and these are
diates in turn react with O-substituted hydroxylamines to af-
ford the desired N,NЈ-dihydroxybenzamidines after workup.
This new class of potential prodrugs was characterized by
important parameters for the discussion of substrate enzyme
interactions.
Amidoxime Reducing Component” (mARC), newly discov-
ered in our lab.[4] One current example for decreasing the
basic character while increasing oral bioavailability through
hydroxylation of one amidine nitrogen atom is to be found
in the new small-molecule serine protease inhibitor Upamo-
stat.[5]
To decrease the basic character of amidines further, thus
improving oral bioavailability, one goal was to hydroxylate
the functional group at both nitrogen atoms; this further
reduces the pKa to 3.8,[6] so the molecules should remain
completely uncharged under physiological conditions. In
theory, gastrointestinal reduction of the prodrug to the cor-
responding amidine with loss of membrane permeability
should be reduced because of the longer times needed for
the two-step reduction, to the benefit of absorption
(Scheme 1).
This has been achieved in the case of N,NЈ-dihydroxy-
benzamidine.[7] In vitro tests have already demonstrated the
activation of the prodrug by porcine and human kidney and
liver microsomes and mitochondria. As was observed for
benzamidoximes, N-reduction through the action of mARC
is the predominant reaction of N,NЈ-dihydroxybenzamidine
in vitro and in vivo. In the case of amidoximes, rapid enzy-
matic degradation to amidines occurs after oral application
prior to total absorption from the gastrointestinal tract.
The presence of an additional hydroxy group delays the de-
gradation to amidines because one more reaction step is
necessary. This was confirmed in vitro with porcine hepato-
cytes: reduction of benzamidoxime to benzamidine, with a
rate of 337Ϯ68 pmolmin–1 (mg of protein)–1, is prolonged
by the reduction of N,NЈ-dihydroxybenzamidine to benz-
amidoxime with a rate of about 1560Ϯ540 pmolmin–1 (mg
Introduction
Amidine and guanidine structures are popular functional
groups in pharmaceutical agents because they act as bio-
isosteres to the amino acid arginine. The charged basic side
chain of arginine can itself participate in strong interactions
(ionic, hydrogen bridge linkage) with target molecules and
be responsible for pharmacological effects. Many groups of
drugs, including inhibitors of blood coagulation[1] and anti-
parasitics such as pentamidine, contain essential amidine
groups.
Amidines are very strong bases, with pKa values of
around 11.6,[2] because of the highly mesomerically stabi-
lized cations formed after protonation at the double bonded
nitrogen atom. This leads to the main disadvantage of
charged functional groups such as amidines: the poor oral
bioavailability due to the inability of charged molecules to
pass through membranes. For that reason, one desirable
feature would be to keep the highly effective structure in
active ingredients but initially to mask the basic character
in order to increase oral bioavailability. Electron-with-
drawing substituents such as hydroxy groups accomplish
this prodrug principle, leading to amidoximes,[3] with pKa
values of around 4.8;[2] these are then enzymatically reduced
in vivo to the amidine functional group by “mitochondrial
[a] Department of Pharmaceutical and Medicinal Chemistry,
Pharmaceutical Institute, Christian-Albrechts-University of
Kiel,
Gutenbergstraße 76, 24118 Kiel, Germany
E-mail: bclement@pharmazie.uni-kiel.de
http://www.uni-kiel.de/pharmazie/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301622.
Eur. J. Org. Chem. 2014, 1961–1975
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1961

L. Schwarz, U. Girreser, B. Clement
FULL PAPER
Scheme 1. In vivo biotransformations of N,NЈ-dihydroxybenzamidine.
of protein)–1.[7] In vivo tests confirm the assumption in ate was treated with different commercially available hy-
terms of extended bioavailability. Oral application of N,NЈ- droxylamine derivatives in diethyl ether or dichloromethane
dihydroxybenzamidine to pigs showed rapid metabolism af- to afford the corresponding O-unsubstituted, O-monosub-
ter absorption such that no prodrug could be detected in stituted, or O,OЈ-disubstituted N,NЈ-dihydroxybenzamid-
plasma samples. Instead, benzamidine was found, thus con- ines 4–9 (Scheme 2; see also Table 3, below). Generally,
firming the compatibility of the theoretical prodrug consid- three equivalents of hydroxylamine, acting both as a reagent
erations with in vivo data (Scheme 1).[8] The results suggest and as a base for generated hydrogen chloride, were em-
a demand for N,NЈ-dihydroxyamidine prodrugs replacing ployed. The O,OЈ-disubstituted derivatives were preferen-
already existing amidine prodrugs, thus increasing oral bio- tially formed with use of a greater excess of substituted hy-
availability.
droxylamine. In the course of this investigation it turned
The rate of enzymatic activity towards a molecule de- out to be necessary to analyze and isolate the O-monosub-
pends on the electron density in the functional groups of a stituted N,NЈ-dihydroxybenzamidine reaction products 5/5Ј
molecule interacting with the active site. The Hammett σ and 7/7Ј immediately, due to decomposition (Table 2).
value is an established parameter for π-electron distribution
in agents allowing forecasting of quantitative structure–ac-
tivity relationships.[9] We thus undertook an investigation
into the synthesis and stability of these hitherto unknown
substituted dihydroxybenzamidines bearing various substit-
uents in the aromatic ring and also on their hydroxy groups.
Different aromatic para substituents with appropriate Ham-
mett σ values are listed in Table 1.[10] The higher the Ham-
mett σ value, the more electron-withdrawing is the substitu-
ent.
Table 1. para-Substituents in the synthesized derivatives of N,NЈ-
dihydroxybenzamidines 4–9 (Scheme 2), together with Hammett σ
values.
a
b
c
d
e
f
g
p-X
OH
OMe Me
H
0
Br
0.26
CN
0.70
NO2
0.81
Hammett σ –0.38 –0.28 –0.14
Recent data confirmed a significant relationship between
15N NMR chemical shifts in different p-substituted benz-
amidoximes and benzamidinium salts and the Hammett σ
parameters. Consequently, 15N NMR allows forecasts for
kinetics of biological reactions of substances of this class.[11]
No systematic 15N NMR investigation of N,NЈ-dihydroxy-
benzamidines has yet been performed. Rare examples of
N,NЈ-dihydroxybenzamidine derivatives have been de-
scribed in the literature (4d, 7/7Јd, 10),[12–14] but no NMR
spectroscopic data are available.
Scheme 2. General reaction steps leading to a new class of pro-
drugs: para-substituted N,NЈ-dihydroxybenzamidines 4–9.
In contrast to gravimetric liquid chromatography, with
fast flash chromatography no products of degradation of 4–
9 during the chromatographic process were detected. Gen-
erally, cleaner products were obtained in larger yields when
hydroxylamines were employed as free bases, so derivatives
4, 7/7Ј, 8, and 9 required a simpler workup. Use of hydrox-
ylamine hydrochlorides, which were treated with triethyl-
Results and Discussion
Synthesis
N-Chlorosuccinimide was added to the para-substituted amine in situ to produce the free bases (products 5/5Ј, 6),
benzaldoximes 2 (Scheme 2), obtained from benzaldehydes was also possible, but p-nitro- and p-hydroxy-substituted re-
1,[15] to give the corresponding benzhydroxamic acid chlor- action products could not be detected when the hydroxyl-
ides 3 by a standard literature procedure.[16] This intermedi- amine/triethylamine protocol was used.
1962
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para-Substituted N,NЈ-Dihydroxybenzamidines as Model Prodrugs
Table 2. Calculated degradation slopes for O-monosubstituted
N,NЈ-dihydroxybenzamidines 5/5Ј and 7/7Ј based on 1H NMR
spectra integrals (% h–1).
General Spectroscopic Analysis
All NMR spectra were recorded in [D6]DMSO because
of improved stability and solubility relative to D2O and
CDCl3. One set of signals was observed in every case except
for that of 9; this gave two diastereomeric sets of signals,
a
b
c
d
e
f
g
5/5Ј[a]
7/7Ј[a]
–
–0.29 –0.73 –0.26 –2.10 –3.45
–
–1.26[b] –0.35 –0.45 –0.62 –0.53 –1.66 –16.31 so there is no evidence for mixtures of E/Z isomers. All
compounds 4–9 exist in the Z configuration, which is ener-
getically favored, as demonstrated by Barassin et al. for the
unsubstituted derivative 4d.[19] With regard to N-substituted
benzamidoximes we also assume the exclusive presence of
the Z isomer if a single-bonded nitrogen has at least one
covalent bond to a hydrogen atom.[20] O-Monosubstituted
N,NЈ-dihydroxybenzamidines 5/5Ј and 7/7Ј occur as mix-
tures of two tautomers, which – unlike the unsubstituted
and O,OЈ-disubstituted derivatives (4, 6, 8, 9) – are not
identical. We therefore observe mixtures of two compounds
in a ratio of approximately 50:50 for all NMR spectra re-
corded (Figure 1).
[a] Freshly dissolved spectra integrals were set to 100% at t = 0 h.
Second H spectra integrals were recorded t = 5 to t = 40 h later
and gave a proportion of the first recorded integrals. Linear re-
gression led to the listed slopes. Strongly negative slopes indicate
fast degradation. [b] Compound is unstable at room temperature
even without DMSO.
1
None of the compounds with the substituents given in
Table 1 has been described in the literature except for
4d,[12,13] 7/7Јd[17] (without information about tautomer ra-
tios and NMR spectroscopic data), and 10[14] (synthesized
from the appropriate nitrile oxide and oxime with the aid
of BF3).
Instability in neutral and basic media leads to rapid dis-
proportionation of 4d to the appropriate amidoxime and
nitrosolic acid, which in turn decomposes to the benzo-
nitrile.[18] In acidic media compounds 4–9 slowly degrade
to hydroxamic acids by hydrolysis, as has been described
previously for 4d;[13] this results in the need for a fast chro-
matographic purification with acidic solid-phase silica. At
room temperature all of the synthesized compounds 4–12
except for 7/7Јa are stable for about two weeks. In the cases
of 4a–f the decomposition product amidoximes were detect-
able after heating above 35 °C or prolonged storage at am-
bient temperature, so storage at –18 °C and below was nec-
essary for all substances. No detailed investigation into sta-
bility was performed for 5–9, but the O,OЈ-disubstituted de-
rivatives 6, 8, and 9 turned out to be much more stable,
with no further amidoxime formation being detected after
purification.
Figure 1. Correlation of 15N NMR chemical shifts of oxime-type
nitrogen atoms of (♦) 4a–f, (᭿) 6b–f, (᭡) 8a–g, and (ϫ) 9a–e and
9g with the corresponding Hammett values (see Table 3 and Table 4
for data).
In consideration of the objective of producing different
dihydroxybenzamidines as possible prodrugs, further func-
tionalization of 4 was accomplished. Representatively, con-
densation between p-unsubstituted 4d (Scheme 3) and
ketones led to three new cyclic N,NЈ-dihydroxybenzamidine
derivatives. The desired compounds 10–12 decomposed af-
ter 1–2 h on storage as the concentrated crude product mix-
tures. However, immediate flash chromatography led to
pure substances 10–12, and these are stable at room tem-
perature for at least about one week.
The observation of two sets of signals for the unsymmet-
rically substituted N,NЈ-dihydroxybenzamidines shows the
presence of two tautomeric forms, which in cases of sym-
metrical substitution are identical. However, there is a slight
tendency for O-monomethylated derivatives predominantly
to contain tautomers of type 5, whereas in O-monobenz-
ylated derivatives tautomers 7Ј prevail (Scheme 4). Ka-
tritzky et al. stated that derivative 7d was more stable,[21]
basing this on a 1914 publication by Ley et al.[17] Unfortu-
nately, Ley never studied the stability of the pure substance
at room temperature but analyzed complex salts of 7/7Јd
with metals. Moreover, Katritzky et al. misunderstood the
abbreviation “Me” used by Ley et al. for metal and not for
methyl. Katritzky et al. stated that rapid tautomerism
would lead to only one 15N NMR signal.[21] We, however,
observed four nitrogen signals in total for one mixture of
tautomers, because two differently hybridized nitrogen
atoms appear in each tautomeric form (Scheme 4, Fig-
ure 2). Symmetrical substitution affords identical tautomers
(Scheme 5), leading to a 15N NMR spectrum showing two
chemically different nitrogen signals. The spectroscopic data
Scheme 3. Synthesis of cyclic dihydroxybenzamidines 10, 11, and
12.
Eur. J. Org. Chem. 2014, 1961–1975
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1963

L. Schwarz, U. Girreser, B. Clement
FULL PAPER
Figure 2. 15N HMBC of the mixture of tautomers of p-methoxy-O-benzyl-N,NЈ-dihydroxybenzamidine (7b and 7Јb). Four nitrogen signals
can be detected. The hydroxy proton couples over two bonds to nitrogen A. Each O-benzylated nitrogen atom (B and C) shows a 3J
1
coupling to the methylene group. The two split signals B and D indicate J NH coupling.
hence give no reason to conclude the existence of only one
tautomeric form of 4d, as claimed by Katritzky.[21] NMR
measurements in DMSO display NH groups (large splitting
of signals, of the order of 80–90 Hz, in the decoupled
HMBC spectrum), showing the presence of one NH group
for each tautomeric structure (Figure 2, Table 3). Although
there is an equilibrium between the two tautomeric forms,
NMR spectroscopy is able to observe two different nitrogen
atoms and the NH coupling, so we consider the tautomeri-
Scheme 5. Tautomeric forms of compound 4a–f (also 6b–f, 8a–g,
9a–g) are identical and each give two 15N NMR signals, due in
each case to the presence of two differently bonded nitrogen atoms.
zation to be slow on the NMR timescale. In most cases 15
N
HMBC gives better results than direct 15N NMR measure-
estimated from the integrals of the 1H NMR spectra of
freshly dissolved samples and those recorded after a times-
pan. This decomposition shows the stability to be generally
less in cases of electron-withdrawing substituents in the p-
position, and thus with higher Hammett σ values (Tables 1
and 2). The very fast and complete decay of the p-nitro
derivative 7/7Јg is remarkable.
ment: 15N chemical shifts can be detected indirectly through
coupling with nearby functional groups with sharp H sig-
1
nals [–CH3 of 5/5Ј and 6, –CH2(–Ph) of 7/7Ј and 8] by cou-
pling over two or three bonds, and smaller amounts of sub-
stance are acquired (Figure 2).
The degradation products are the corresponding O-un-
substituted and O-monosubstituted benzamidoximes. As
would be expected for O,OЈ-bis(tetrahydropyranyl)-N,NЈ-di-
hydroxybenzamidines 9a–g, splitting of NMR peaks due to
the presence of diastereomers was observed.
15N NMR Shift Data and Correlations with Hammett σ
Values
For the prediction of kinetics in biological systems on
the basis of the obtained data, water would be the best sol-
vent. The low solubilities of some compounds, however, to-
gether with the need for the same solvent for all derivatives,
necessitate the use of [D6]DMSO. For reliable interpretation
we assume similar correlations in both solvents. Linear cor-
Scheme 4. Different tautomeric forms of p-substituted O-monosub-
stituted N,NЈ-dihydroxybenzamidines 5 and 7 (5/5Ј 52:48; 7/7Ј
1
47:53, calculated from integrals in H NMR spectra).
Unfortunately, compounds 5/5Ј and 7/7Ј turned out to relations of chemical shifts with Hammett σ values deliver
decompose in DMSO even at room temperature, and much slopes that describe the sensitivities of the atoms to changes
more rapidly upon heating. The rates of degradation were in electron distribution. The intercepts represent the shift
1964
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Eur. J. Org. Chem. 2014, 1961–1975

para-Substituted N,NЈ-Dihydroxybenzamidines as Model Prodrugs
1
Table 3. Relevant 15N,[a] 1H, and 13C chemical shifts (δ, ppm) and JN,H couplings (Hz)[b] of the functional groups of para-substituted
N,NЈ-dihydroxybenzamidines and derivatives 4–12[c] in [D6]DMSO.
R
RЈ
Yield
[%]
M.p.
[°C]
δ (=N–) δ [–N(H)–] 1JN,H δ (=NO)H δ (N)H δ (NHO)H
δ C=NOH
(NHOH)
[d]
4a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
H
H
H
H
H
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
H
H
H
H
H
H
H
Bn
Bn
Bn
Bn
Bn
Bn
Bn
THP
THP
THP
THP
THP
THP
THP
33
41
72
43
48
28
12
10
21
37
23
12
9
18
35
22
56
18
36
13
8
112.2
118.3
124.2
119.8
116.7
118.6
94.5[e]
85.6[e]
105.2[e]
72.8[e]
133.7[e]
94.5[e]
85.6[e]
105.2[e]
72.8[e]
133.7[e]
oil
297.0
298.3
299.2
300.2
301.6
305.7
128.2
128.2
128.3
128.3
128.3
128.4
158.4
158.4
158.4
158.4
158.1
130.7
131.1
131.1
130.6
131.2
160.2
160.3
160.4
160.3
160.2
154.5
154.4
154.7
155.0
155.6
154.7
154.9
130.9
131.2
131.3
131.4
131.3
–
10.09
10.20
10.26
10.36
10.45
10.71
10.39
10.47
10.55
10.66
10.95
8.08
8.13
8.16
8.22
8.27
8.40
8.92
8.96
9.02
9.08
9.21
8.40
8.43
8.49
8.59
8.74
9.21
9.26
9.33
9.40
9.53
8.85
8.91
8.94
9.01
9.07
9.21
9.25
8.44
8.51
8.54
8.62
8.70
8.30
8.40
8.37
8.40
8.43
8.52
156.9
156.6
156.9
157.0
155.9
155.6
154.6
154.8
154.9
153.9
153.6
156.6
157.0
157.1
156.1
155.7
154.7
155.0
155.1
154.1
153.7
154.9
154.5
154.8
154.9
153.9
153.7
153.3
157.4
157.1
157.3
157.3
156.3
156.0
155.6
155.5
155.1
155.4
155.5
154.5
154.1
153.8
155.6
155.3
155.6
155.7
154.7
154.4
154.1
158.8
159.4
158.9
4b
82
4c
83
84
84
4d
4e
4f
84
[d]
[d]
[f]
5b
–
–
–
–
–
–
–
*
*
*
*
[d]
[d]
[d]
[f]
5c
[d]
[f]
5d
H
H
H
[g]
[f]
5e
82
82
87
85
88
88
88
85
85
85
85
[f]
5f
309.5
311.5
312.6
312.2
313.2
316.4
314.4
315.3
315.8
316.4
319.3
*
[f]
5Јb
5Јc
5Јd
5Јe
5Јf
6b
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
THP
THP
THP
THP
THP
THP
*
*
*
*
*
*
*
*
8.48
8.48
8.50
8.56
8.66
[f]
[f]
[f]
[f]
[f]
[f]
*
*
*
*
*
*
*
*
*
*
*
*
[f]
[f]
6c
85.6
oil
oil
83.6
[f]
[f]
6d
[f]
[f]
6e
*
*
[f]
[f]
6f
86
[d]
[d]
[f]
7a[h]
7b
21
13
9
oil
–
–
10.39
10.48
10.55
10.62
10.74
10.95
11.10
103.0[e]
114.2[e]
109.2[e]
109.0[e]
oil
302.2
303.7
304.3
81
81
82
[f]
[f]
7c
[f]
7d
19
22
18
42
24
15
11
20
25
21
44
19
7
29
48
45
11
12
90
47
49
59
56
59
53
16
24
43
[d]
[f]
7e
–
–
–
85
[d]
[d]
[f]
7f
–
7g[i]
7Јa[h]
7Јb
7Јc
7Јd
7Јe
7Јf
7Јg[i]
8a
121.2[e]
oil
82
88
87
88
88
[d]
[f]
[f]
308.3
308.7
309.8
310.4
310.5
313.6
314.2
311.5
312.2
313.1
313.3
313.9
316.4
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
8.49
8.52
8.52
8.55
8.61
8.66
8.75
103.0[e]
114.2[e]
109.2[e]
109.0[e]
oil
[f]
[f]
[f]
[f]
91
[d]
[f]
131.6
131.8
157.0
157.1
157.1
157.3
157.1
157.3
–
–
8.74
8.91
9.23
9.29
9.34
9.44
9.50
9.64
[d]
[f]
121.2[e]
oil
[f]
[f]
86
85
86
86
88
87
87
85
87
84
86
85
87
85
*
*
*
*
*
*
*
*
*
*
*
*
*
*
[f]
[f]
8b
oil
oil
oil
70.5
89.9
oil
oil
oil
oil
oil
oil
124.6
119.7
130.1
132.8
71.9
[f]
[f]
8c
[f]
[f]
8d
[f]
[f]
8e
[f]
[f]
8f
8g[i]
9a[k]
9b[k]
9c[k]
9d[k]
9e[k]
9f[k]
317.0
157.2
9.69
[f]
[f]
[f]
[f]
310.5; 19
311.2; 17
312,1; 21
312.2; 23
312.7; 25
149.4; 36
149.9; 38
149.7; 39
150.6; 33
150.6; 35
151.3; 33
151.2; 33
161.4
8.78; 3.3
8.86; 3.8
8.87; 4.2
8.99; 5.3
9.05; 5.2
9.20; 6.6
9.25; 5.5
[f]
[f]
[f]
[f]
[f]
[f]
[f]
[f]
[g]
[f]
[f]
–
9g[k][l] THP
315.8; 34
324.0
328.6
[f]
[f]
[f]
[f]
[f]
10
11
12
*
*
*
*
*
*
9.36
9.50
9.29
[f]
[f]
[f]
158.3
159.0
[f]
[f]
[f]
326.7
[a] CH3NO2 as external standard in [D6]DMSO (381.6 ppm). [b] Coupling constants determined from signal splitting in HMBC spectra,
precisionϮ1 Hz. [c] Measured as 0.6 m solutions in 0.5 mL [D6]DMSO at 300 K and 30.4 MHz. [d] Signals not detectable. Measurement
time limited due to decomposition of compounds 5/5Ј and 7/7Ј. [e] Melting points of the tautomeric mixtures of 5/5Ј and 7/7Ј are given.
[f] Functional group is not part of the compound in question. [g] Maximum solubility of 0.2 m in DMSO is too low. [h] Unstable at room
temperature, degradation. [i] δ (NO2) = 370.1 ppm. [k] Chemical shifts with diastereomeric splitting (ppm, Hz) are given for 9a–g. [l] δ
(NO2) = 369.9 ppm.
values without any additional effect from the substituents
For the unsubstituted N,NЈ-dihydroxybenzamidines 4
(X = H, σ = 0). Both parameters are given for structures (Entry 1) the signals of the oxime-type nitrogen atoms are
4–9 in Table 4, Entries 1–39.
observed at around δ = 300 ppm. The presence of an alkyl
Eur. J. Org. Chem. 2014, 1961–1975
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1965

L. Schwarz, U. Girreser, B. Clement
FULL PAPER
1
Table 4. 15N and H NMR chemical shift (δ, ppm) correlations with Hammett σ values.
Entry Functional group
Compound
Equation
r2
1
2
3
4
5
6
7
8
oxime-type nitrogen =N(OH)
4a–f
δ[= N(OH)] = 7.6 σ + 300.1
δ[= N(OH)] = 7.5 σ + 304.5
δ[= N(OMe)] = 4.7 σ + 312.7
δ[= N(OMe)] = 4.7 σ + 315.7
δ[= N(OBn)] = 4.8 σ + 310.1
δ[= N(OBn)] = 4.3 σ + 313.3
δ[= N(OTHP)] = 4.1 σ + 312.2
δ[–N(HOH)] = 0.17 σ + 128.3
0.990 (n = 6)
0.942 (n = 3)
0.913 (n = 5)
0.968 (n = 5)
0.968 (n = 7)
0.980 (n = 7)
0.961 (n = 6)
0.853 (n = 6)
7b–d
5Јb–f
6b–f
oxime type nitrogen =N(OR)
7Јa–g
8a–g
9a–e, g
4a–f
hydroxylamine-type nitrogen –N(HOH)[a]
9
5b–f
δ[–N(HOMe)] = –0.30 σ + 158.4
δ[–N(HOH)] = 0.23 σ + 130.9
δ[–N(HOMe)] = –0.05 σ + 160.3
δ[–N(HOBn)] = 0.33 σ + 154.8
δ[–N(HOH)] = 0.56 σ + 131.3
δ[–N(HOBn)] = 0.15 σ + 157.1
δ[–N(HOTHP)] = 1.48 σ + 150.2
δ[(= NO)H] = 0.54 σ + 10.33
δ[(= NO)H] = 0.56 σ + 10.54
δ[(= NO)H] = 0.54 σ + 10.62
δ[(= NOCRx)Hy] = 0.053 σ + 3.74
δ[(= NOCRx)Hy] = 0.048 σ + 3.77
δ[(= NOCRx)Hy] = 0.057 σ + 5.02
δ[(= NOCRx)Hy] = 0.057 σ + 5.06
δ[(= NOCRx)Hy] = 0.042 σ + 5.14
δ[(–NHO)H] = 0.17 σ + 8.40
δ[(–NHO)H] = 0.20 σ + 8.51
δ[(–NHO)H] = 0.19 σ + 8.56
δ[(–NHOCRx)Hy] = 0.025 σ + 3.46
δ[(–NHOCRx)Hy] = 0.031 σ + 3.44
δ[(–NHOCRx)Hy] = 0.045 σ + 4.72
δ[(–NHOCRx)Hy] = 0.043 σ + 4.69
δ[(–NHOCRx)Hy] = 0.053 σ + 4.79
δ[–NH(OH)] = 0.29 σ + 8.20
δ[–NH(OMe)] = 0.29 σ + 9.01
δ[–NH(OH)] = 0.36 σ + 8.49
δ[–NH(OMe)] = 0.32 σ + 9.31
δ[–NH(OBn)] = 0.32 σ + 8.99
δ[–NH(OH)] = 0.33 σ + 8.59
δ[–NH(OBn)] = 0.37 σ + 9.40
δ[–NH(OTHP)] = 0.38 σ + 8.95
δ[(= NO)H] = 0.63 σ + 9.59
0.734 (n = 5)
0.110 (n = 5)
0.058 (n = 5)
0.148 (n = 7)
0.832 (n = 7)
0.407 (n = 7)
0.891 (n = 7)
0.987 (n = 6)
0.994 (n = 5)
0.987 (n = 7)
0.905 (n = 5)
0.891 (n = 5)
0.893 (n = 7)
0.910 (n = 7)
0.599 (n = 7)
0.857 (n = 6)
0.967 (n = 5)
0.946 (n = 7)
0.690 (n = 5)
0.924 (n = 5)
0.862 (n = 7)
0.891 (n = 7)
0.820 (n = 7)
0.991 (n = 6)
0.995 (n = 5)
0.997 (n = 5)
0.991 (n = 5)
0.994 (n = 7)
0.925 (n = 7)
0.984 (n = 7)
0.982 (n = 7)
0.995 (n = 7)
0.988 (n = 7)
0.884 (n = 6)
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
5Јb–f
6b–f
7a–g
7Јa–g
8a–g
9a–g
4a–f
oxime hydrogen (=NO)H
5b–f
7a–g
5Јb–f
6b–f
substituted oxime (=NOCRx)Hy
7Јa–g
8a–g
9a–g
4a–f
5Јb–f
7Јa–g
hydroxylamine OH hydrogen
substituted hydroxylamine (–NHOCRx)Hy 5b–f
6b–f
7a–g
8a–g
9a–g
hydroxylamine NH hydrogen
4a–f
5b–f
5Јb–f
6b–f
7a–g
7Јa–g
8a–g
9a–g
oxime hydrogen (= NO)H
amine hydrogen NH2
BAO[b] a–g
BAO[b] a–g
BA[c] a,c–g
δ(–NH2) = 0.34 σ + 5.77
δ(–NH2) = 0.42 σ + 9.11
[a] Correlations are not significant, so chemical shifts are independent of σ. [b] p-Substituted benzamidoximes.[22] [c] p-Substituted benz-
amidines.[22]
substituent on the oxime-type oxygen increases the shift by of para-substitution or O-substitution without cyclization,
about 12 ppm (Entries 3 and 5). An alkyl substituent on the for which the differences are smaller for every derivative of
hydroxylamine oxygen effects a further deshielding by type 4–9. The spiro substitution in 11 and 12 leads to in-
about 3 ppm (Entries 4, 6, 7).
creases in the 15N NMR shifts of the oxime-type nitrogen
The 15N NMR chemical shift of the hydroxylamine-type atoms relative to 10, whereas the hydroxylamine-type nitro-
nitrogen is found at about δ = 128 ppm (Entry 8). Alkyl gen shifts decrease.
substitution at the corresponding oxygen shifts this signal
There is a strong correlation of 15N NMR chemical shifts
paramagnetically by about 30 ppm (Entries 9, 12), whereas of the oxime-type nitrogen atoms with the Hammett con-
the presence of an alkyl substituent at the vicinal oxime stants, similar to the sensitivity of the 15N NMR shifts to
oxygen leads to a smaller effect with a deshielding of about the Hammett σ values in benzamidinium salts,[11] and also
2 ppm (Entries 10 and 13). Substituent effects at oxygen on to their sensitivity in the case of the oxime-type nitrogen
15N NMR shifts are additive (Entries 4, 6, 7 and 11, 14, atoms in benzamidoximes,[11] benzamides,[23] and benzo-
15).
nitriles.[24] The slopes of the regression lines are in the 5–
The cyclic compounds 10–12 show remarkable paramag- 10 ppm range. These nitrogen atoms are at least partially
netic 15N NMR chemical shifts, especially of the oxime-type sp2- or sp-hybridized and show electronic interactions with
nitrogen atoms. The difference of about 25–30 ppm relative the aromatic systems. The greater the electron-withdrawing
to 4d represents a much broader effect of cyclization than effect of the p-substituent, the more the 15N NMR signal is
1966
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Eur. J. Org. Chem. 2014, 1961–1975

para-Substituted N,NЈ-Dihydroxybenzamidines as Model Prodrugs
shifted paramagnetically (Figure 1). In the oxime-oxygen- substituted derivative 4 (Entry 16). The oxime protons show
substituted derivatives (Entries 3–7), sensitivity is slightly the greatest susceptibility to electronic interactions of all
reduced, by a factor of about 2. In contrast, hydroxylamine- the protons of 4, 5, and 7. The slope of the Hammett plot
type nitrogen 15N NMR shifts are not susceptible, or are is in the 0.6 ppm range and similar to the slopes found for
only slightly susceptible, to the effects of substituents in the the benzamidoxime hydroxy groups and the benzamidinium
para-position. For this nitrogen atom type there is no sig- amino groups (Entries 40, 42). The hydroxylamine NH pro-
nificant correlation (Entries 8–15). No further correlation ton chemical shifts of about 8.5 ppm for 4–9 (Entries 32–
with, for example, the 1JN,H coupling constants of hydroxyl- 39) are similar to those for benzamidinium salts (Entry 42).
amine-type nitrogen atoms (Table 3) or the splitting of the Alkyl substitution of the vicinal oxime hydroxy groups in
diastereomeric signals for derivatives 9a–g (Table 3) was ob- 5Ј and 7Ј results in increases of about 0.3 ppm in the chemi-
served. Generally, diastereomeric chemical shift differences cal shifts of the amine protons. Substitution of the hydrox-
for the hydroxylamine-type-nitrogen atoms of 9a–g are ylamine OH groups in 5 and 7 shifts the signals paramag-
larger than those for the oxime-type nitrogen atoms of the netically by about 0.8 ppm. O,OЈ-Disubstituted derivatives
same compounds.
6, 8, and 9 show these effects to be additive. The slope for
the correlation of the amino protons of dihydroxybenz-
amidines 4–9 is half the magnitude, with a value of 0.3 ppm
(Entries 32–39), as is also found for the amino protons of
13C NMR Spectroscopic Data
1
benzamidoximes (Entry 41). The H chemical shifts of the
The 13C NMR chemical shifts of the dihydroxyamidine
functional groups in the aromatic derivatives are observed
at δ = 153–159 ppm. There is no significant correlation with
σ. Alkyl substitution at the hydroxylamine-type oxygen
atoms (5, 7) shifts the signals diamagnetically by 2 ppm rel-
ative to those for O,OЈ-unsubstituted derivatives 4, whereas
an alkyl substituent at the oxime oxygen atom shifts the
carbon shift paramagnetically by about 0.3 ppm (5Ј, 7Ј).
Additional alkyl substitution of compounds 10–12 at the
hydroxylamine nitrogen further increases the corresponding
13C NMR chemical shifts: the carbon resonance of the
functional group of 159 ppm represents a paramagnetical
shift of 2 ppm. Substituent effects at oxygen on 13C NMR
shifts also seem to be additive. The 13C chemical shifts of
the functional groups of O,OЈ-disubstituted derivatives 6
and 8 are thus between those of the monosubstituted com-
pounds 5/5Ј and 7/7Ј.
hydroxylamine OH protons of 4 are about 8.4 ppm and
shift paramagnetically by about 0.15 ppm if the vicinal ox-
ime group is substituted (Entries 24–26). Cyclic N,O-disub-
stituted dihydroxyamidine derivatives 10–12 show signifi-
cant deshielding of the hydroxylamine hydrogen chemical
shift signals of 9.5 ppm, 0.5–1 ppm above those of all other
derivatives 4–9. Correlation of the hydroxylamine OH pro-
tons with σ leads to a relatively small slope of about
0.2 ppm, due to the greater distance to the para-effector.
The shifts of the protons of the alkyl substituents (i.e.,
methyl groups, methylene protons of benzyl groups, and
methine protons of THP residues) are also influenced sig-
nificantly by the substituents on the aromatic rings, with
slopes of about 0.02 to 0.06 ppm (Entries 19–23 and 27–
31). It has to be clearly stated that these protons are already
nine bonds away from the para-substituent.
Therefore, for the interaction of compounds 4–9 with en-
zymes, not only is the influence of substituents of the aro-
matic system on the electron density at the nitrogen atoms
of importance, but the strength of hydrogen bonding also
1H NMR Shifts
1
Correlations of all H NMR chemical shifts of the di- needs to be discussed.
hydroxyamidine functional groups in 4–9 with Hammett σ
values afford significant results. For the oxime hydroxy pro-
tons (Entries 16–18), the hydroxylamine hydroxy protons
(Entries 24–26), and the hydroxylamine NH protons (En-
Conclusions
tries 32–39) correlations are in most cases excellent, with r
We have established versatile synthetic approaches to dif-
Ͼ 0.99. Even for protons of the alkyl substituents next to ferent previously unknown para-substituted N,NЈ-dihydroxy-
the ether linkages in 5–9, small but significant effects can benzamidines and derivatives representing a new class of
be observed (Entries 19–23, 27–31). Comparison of the prodrugs. All of the reactions start with the intermediate 3
shifts of 4–9 with the corresponding shifts of benzami- and different hydroxylamine derivatives. This method can
doximes (BAOs) and benzamidinium chlorides (BAs),[22] also be adapted to the synthesis of other dihydroxybenz-
the metabolic follow-up products (Scheme 1), is of interest. amidine compounds, so a route to a variety of new poten-
Appropriate regression lines of proton chemical shifts in tial prodrugs is created. Properties relating to instability of
[D6]DMSO with σ are also given in Table 4 (Entries 40–42). the compounds have been analyzed, so conditions leading
It can be seen that the oxime hydroxy protons in di- to decomposition can be prevented. NMR chemical shifts
hydroxyamidines (Entries 16–18) are paramagnetically of oxime-type nitrogen atoms and all hydrogen atoms of
shifted by about 1 ppm relative to benzamidoxime hydroxy dihydroxyamidine functional groups correlate strongly with
protons (Entry 40). Alkyl substitution of the vicinal hydrox- Hammett σ values, so para-substitution has a significant
ylamine OH groups (5, 7, Entries 17–18) increases 1H influence on electron density in the functional group.
NMR chemical shifts by about 0.3 ppm relative to the un- Mono- and disubstitution of oxygen also leads to predicta-
Eur. J. Org. Chem. 2014, 1961–1975
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1967

L. Schwarz, U. Girreser, B. Clement
FULL PAPER
sion was stirred at room temperature with monitoring by TLC (cy-
clohexane/ethyl acetate 8:2; 2% aqueous FeCl3 solution with heat
colored oximes 2a–g brown). After completion of the reaction
about 1 h later, ethanol was evaporated. The residue was diluted
with water and extracted three times with dichloromethane. The
combined organic phase was washed with brine and dried with
anhydrous sodium sulfate. After evaporation of the solvent, the
compound 2 (one out of 2a–g) was obtained in 90–100% yield.
Products were used for further reactions without additional purifi-
cation. The obtained characterizing data are consistent with litera-
ture information.
ble effects in the electron density at the corresponding N,
H, and C atoms. Cyclization of the dihydroxyamidine func-
tional group decreases electron density massively. With the
obtained data, kinetics of reactions with biological struc-
tures can be predicted. Quantitative structure–activity cor-
relation of mARC activity with the Hammett σ values, for
example, results in a relationship of mARC kinetics with
NMR spectroscopic data, which will be part of further in-
vestigations.
General Synthesis of para-Substituted Benzhydroxamic Acid Chlor-
ides 3a–g: The syntheses were carried out by a literature pro-
cedure.[16] The benzaldoxime (one out of 2a–g, 30 mmol) was dis-
solved in dimethylformamide (50 mL) with stirring, and N-chloro-
succinimide (30 mmol) was added in two portions at room tem-
perature. Initiation of the reaction was accelerated by use of a slight
increase in the temperature to 40 °C for 20 min and UV light. The
reaction was monitored by TLC (cyclohexane/ethyl acetate 8:2; 2%
aqueous FeCl3 solution colored 3a–g red-brown after heating). Af-
ter about 12 h the reaction was complete. An ice/water mixture was
added and extracted twice with diethyl ether. The organic phase
was washed twice with ice/water, dried with anhydrous sodium sulf-
ate, and concentrated to give 95–100% 3a–g. The products were
stored at –18 °C because of slow decomposition at room tempera-
ture. The obtained characterizing data were consistent with litera-
ture information.
Experimental Section
General: para-Substituted benzaldehydes were commercially avail-
able (Merck, Aldrich) and were used without purification. Melting
points were measured with a Stuart Scientific melting-point appa-
ratus SMP3 and are uncorrected. For TCL, silica plates (Polygram
SIL G/UV254 0.25 mm) were used. All NMR spectra were recorded
in concentrations of 0.1–0.3 m for 1H, 13C, and 15N HMBC and 0.5
to 0.7 m in the case of direct 15N detection. 1H, 13C, and 15N NMR
spectra were recorded at 300 K with a Bruker Avance III 300 in-
strument and a multinuclear probe head, with use of the manufac-
turer’s pulse programs. The solvent for all spectra was [D6]DMSO.
For 15N NMR measurements, between 50 and 150 mg of 4–12 in
0.5 mL solvent or saturated solutions were used. 1H (300 MHz),
13C (75.4 MHz), and 15N (30.4 MHz) spectra were referenced to
internal [D5]DMSO (1H NMR δ = 2.50 ppm), internal [D6]DMSO
(13C NMR δ = 39.5 ppm), and external standard nitromethane
(15N NMR δ = 0.0 ppm), which was corrected to ammonia scale
by addition of 381.6 ppm. All coupling constants (J values) are
quoted in Hz; ds stands for diastereomeric shift. 15N data were
obtained by direct measurement or indirect detection of proton res-
onances. For the recording of 1H, 15N gradient-enhanced HSQC
spectra a sweep width of 550 ppm and 512 t1 increments, an acqui-
sition time of 0.24 s, an interpulse delay of 1.5 s, and two repetitions
per t1 increment were used. Resolution enhancement was achieved
through linear prediction. For recording of gradient-enhanced
HMBC spectra without decoupling with 512 t1 increments an ac-
quisition time of 0.12 s, an interpulse delay of 1.5 s, and 16 or 24
repetitions per t1 increment were necessary. A 15N sweep rate of
550 ppm and resolution improvement through linear prediction
were also employed. Direct detection of 15N shifts was achieved
with conventional composite pulse decoupling, a sweep width of
550 ppm, a 30° flip angle acquisition of 32 K data points, and a
delay of 2 s. Only for derivatives 10–12 was it necessary to record
15N spectra by inverse gated decoupling with a very short acqui-
sition time of about 0.5 s and a relaxation delay of 8 s to detect N–
2. Mass spectrometry was carried out with a Bruker Esquire ~ LC
instrument under ESI conditions in the positive ionization mode.
Samples were applied after chromatographic separation with a
RP 8 column and a 0.1% aqueous acetic acid/acetonitrile gradient.
IR spectra were recorded with a Perkin–Elmer Spectrum 100 FTIR
instrument with ATR attachment. Elemental analyses were mea-
sured by the Department of Inorganic Chemistry, Christian Al-
brechts University of Kiel with a CHNS Analyzer (HEKAtech
GmbH).
General Synthesis of para-Substituted N,NЈ-Dihydroxybenzamidines
4a–f: The syntheses were based on a literature procedure describing
the synthesis of 4d.[12] The appropriate hydroxamic acid chloride
(one out of 3a–f, 3 mmol) was dissolved in diethyl ether (5–10 mL),
and the solution was poured into a dropping funnel. Hydroxyl-
amine (9 mmol, 297 mg, 3 equiv.) as free base was dissolved in eth-
anol and the solution was cooled down in an ice-bath with stirring
in a flask. The hydroxamic acid chloride (3a–f) was added slowly
with stirring. The reaction was monitored by TLC (cyclohexane/
ethyl acetate 1:1; 2% aqueous FeCl3 solution colored 4a–f blue). If
TLC still indicated 3a–f after 7 h, further hydroxylamine (2 equiv.)
dissolved in ethanol was added to the reaction mixture. After com-
pletion of the reaction (about 15–20 h) the formed suspension was
filtered. Flash chromatography of the concentrated crude filtrate
(max. 30 °C) on silica as solid phase and with cyclohexane/ethyl
acetate gradient as mobile phase resulted in the desired product
4a–f. Additional workup gave pure products 4a–f.
p-Hydroxy-N,NЈ-dihydroxybenzamidine (4a): Starting compound 3a
(515 mg, 3 mmol) was used. After flash chromatography, the com-
pound was triturated with dichloromethane and filtered to give
product 4a (165 mg, 0.98 mmol, 32.7%) as a beige powder, m.p.
112.2 °C. Rf (cyclohexane/ethyl acetate 1:1): 0.13. 1H NMR
(300 MHz, [D6]DMSO): δ = 6.74 (d, 2 H, Ar-H), 7.39 (d, 2 H, Ar-
H), 8.08 (s, 1 H, NH), 8.30 [s, 1 H, (NHO)H], 9.58 (s, 1 H, p-OH),
10.09 [s, 1 H, (=NO)H] ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 114.5 (Ar-C-3), 122.7 (Ar-C-1), 129.1 (Ar-C-2), 156.9 [Cq(NN)],
158.0 (Ar-C-4) ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 128.2
(NH), 297.0 (=NOH) ppm.
p-Methoxy-N,NЈ-dihydroxybenzamidine (4b): Starting compound
3b (928 mg, 5 mmol) was used. After flash chromatography, the
compound was triturated with dichloromethane and filtered to give
product 4b (373 mg, 2.05 mmol, 41.2%) as a white solid, m.p.
118.3 °C. Rf (cyclohexane/ethyl acetate 1:1): 0.28. 1H NMR
(300 MHz, [D6]DMSO): δ = 3.77 (s, 3 H, p-OCH3), 6.92 (d, 2 H,
Ar-H), 7.52 (d, 2 H, Ar-H), 8.13 (s, 1 H, NH), 8.40 [s, 1 H, (NHO)-
General Synthesis of para-Substituted Benzaldoximes 2a–g: The syn-
theses were carried out by a literature procedure.[25] Hydroxylamine
hydrochloride (4.17 g, 60 mmol) was dissolved in water (40 mL)
and neutralized with aqueous sodium hydroxide solution (10%). A
solution of an aldehyde 1 (50 mmol) in ethanol was added slowly
to this mixture with stirring in a water bath at 20 °C. The suspen-
1968
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Eur. J. Org. Chem. 2014, 1961–1975

para-Substituted N,NЈ-Dihydroxybenzamidines as Model Prodrugs
H], 10.20 [s, 1 H, (=NO)H] ppm. 13C NMR (75 MHz, [D6]DMSO): ditional workup was required for 5/5Јc and 5/5Јf and led to pure
δ = 55.1 (p-OCH3), 113.2 (Ar-C-3), 124.3 (Ar-C-1), 129.1 (Ar-C- compounds.
2), 156.6 [Cq(NN)], 159.7 (Ar-C-4) ppm. 15N NMR (30 MHz, [D6]-
p-Methoxy-O-methyl-N,NЈ-dihydroxybenzamidine (5/5Јb): Com-
pound 3b (371 mg, 2 mmol) was dissolved in diethyl ether (7 mL).
DMSO): δ = 128.2 (1JN,H = 82 Hz, NH), 298.3 (=NOH) ppm.
Methylhydroxylamine hydrochloride and triethylamine were dis-
solved in ethanol and added slowly to the reaction mixture with
stirring. After flash chromatography, the compound was triturated
with cyclohexane and filtered to give pure product 5/5Јb [78 mg,
0.40 mmol, 24.2% (5b: 12.4%; 5Јb: 11.8%)] as a white solid, m.p.
94.5 °C. Rf (cyclohexane/ethyl acetate 1:1): 0.50.
p-Methyl-N,NЈ-dihydroxybenzamidine (4c): Starting compound 3c
(339 mg, 2 mmol) was used. After flash chromatography, the com-
pound was triturated with dichloromethane and filtered to give
product 4c (238 mg, 1.43 mmol, 71.7%) as a white solid, m.p.
124.2 °C. Rf (cyclohexane/ethyl acetate 7:3): 0.13. 1H NMR
(300 MHz, [D6]DMSO): δ = 2.31 (s, 3 H, p-CH3), 7.17 (d, 2 H, Ar-
H), 7.47 (d, 2 H, Ar-H), 8.16 (s, 1 H, NH), 8.37 [s, 1 H, (NHO)H],
10.26 [s, 1 H, (=NO)H] ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 20.9 (p-CH3), 127.6 (Ar-C-2), 128.3 (Ar-C-3), 129.2 (Ar-C-1),
138.1 (Ar-C-4), 156.9 [Cq(NN)] ppm. 15N NMR (30 MHz, [D6]-
DMSO): δ = 128.3 (1JN,H = 83 Hz, NH), 299.2 (=NOH) ppm.
1
Tautomer 5b: H NMR (300 MHz, [D6]DMSO): δ = 3.45 (s, 3 H,
OCH3), 3.77 (s, 3 H, p-OCH3), 6.93 (m, 2 H, Ar-H), 7.47 (m, 2 H,
Ar-H), 8.92 (s, 1 H, NH), 10.39 [s, 1 H, (=NO)H] ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 55.1 (p-OCH3), 62.4 (NHOCH3),
113.2–113.4 (Ar-C-3), 123.9 (Ar-C-1), 128.7–129.5 (Ar-C-2), 154.6
[Cq(NN)], 159.9 (Ar-C-4) ppm. 15N NMR (30 MHz, [D6]DMSO):
δ = 158.4 (NH) ppm.
N,NЈ-Dihydroxybenzamidine (4d): Starting compound 3d (778 mg,
5 mmol) was used. After flash chromatography, the compound was
dissolved in a small amount of ethyl acetate, precipitated with pe-
troleum ether, and cooled overnight to give product 4d (324 mg,
2.13 mmol, 42.6%) as a white solid, m.p. 119.8 °C; m.p.[26] 112–
113 °C; m.p.[12] 115 °C. Rf (cyclohexane/ethyl acetate 6:4): 0.31. 1H
NMR (300 MHz, [D6]DMSO): δ = 7.40 (m, 3 H, Ar-H), 7.58 (m,
2 H, Ar-H), 8.22 (s, 1 H, NH), 8.40 [s, 1 H, (NHO)H], 10.36 [s, 1 H,
(=NO)H] ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 127.8 (Ar-C-
2), 127.8 (Ar-C-3), 128.8 (Ar-C-4), 132.2 (Ar-C-1), 157.0
[Cq(NN)] ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 128.3 (1JN,H
= 84 Hz, NH), 300.2 (=NOH) ppm.
1
Tautomer 5Јb: H NMR (300 MHz, [D6]DMSO): δ = 3.72 (s, 3 H,
OCH3), 3.77 (s, 3 H, p-OCH3), 6.93 (m, 2 H, Ar-H), 7.47 (m, 2 H,
Ar-H), 8.40 (s, 1 H, NH), 8.48 [s, 1 H, (NHO)H] ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 55.1 (p-OCH3), 61.0 (=NOCH3), 113.2–
113.4 (Ar-C-3), 123.2 (Ar-C-1), 128.7–129.5 (Ar-C-2), 156.6
[Cq(NN)], 159.9 (Ar-C-4) ppm. 15N NMR (30 MHz, [D6]DMSO):
δ = 130.7 (1JN,H = 87 Hz, NH), 311.5 (=NOCH3) ppm.
p-Methyl-O-methyl-N,NЈ-dihydroxybenzamidine (5/5Јc): Compound
3c (339 mg, 2 mmol) was dissolved in diethyl ether (5 mL). Methyl-
hydroxylamine hydrochloride and triethylamine were dissolved in
ethanol and added slowly to the reaction mixture with stirring.
Flash chromatography gave pure product 5/5Јc [67 mg, 0.37 mmol,
18.6% (5c: 9.5%, 5Јc: 9.1%)] as a white solid, m.p. 85.6 °C. Rf
(cyclohexane/ethyl acetate 7:3): 0.29.
p-Bromo-N,NЈ-dihydroxybenzamidine (4e): Starting compound 3e
(680 mg, 2.9 mmol) was used. After flash chromatography, the
compound was triturated with dichloromethane and filtered to give
product 4e (320 mg, 1.39 mmol, 47.8%) as a white solid, m.p.
116.7 °C. Rf (cyclohexane/ethyl acetate 7:3): 0.12. 1H NMR
(300 MHz, [D6]DMSO): δ = 7.50 (d, 2 H, Ar-H), 7.57 (d, 2 H, Ar-
H), 8.27 (s, 1 H, NH), 8.43 [s, 1 H, (NHO)H], 10.45 [s, 1 H, (=NO)-
H] ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 122.0 (Ar-C-4),
129.7 (Ar-C-2), 130.7 (Ar-C-3), 131.3 (Ar-C-1), 155.9
[Cq(NN)] ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 128.3 (1JN,H
= 84 Hz, NH), 301.6 (=NOH) ppm.
1
Tautomer 5c: H NMR (300 MHz, [D6]DMSO): δ = 2.32 (s, 3 H,
p-CH3), 3.46 (s, 3 H, OCH3), 7.19 (m, 2 H, Ar-H), 7.43 (m, 2 H,
Ar-H), 8.96 (s, 1 H, NH), 10.47 [s, 1 H, (=NO)H] ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 20.8 (p-CH3), 62.5 (NHOCH3), 127.3–
128.0 (Ar-C-2), 128.3–128.5 (Ar-C-3), 129.0 (Ar-C-1), 138.5 (Ar-
C-4), 154.8 [Cq(NN)] ppm. 15N NMR (30 MHz, [D6]DMSO): δ =
158.4 (NH) ppm.
p-Cyano-N,NЈ-dihydroxybenzamidine (4f): Starting compound 3f
(361 mg, 2 mmol) was used. After flash chromatography, the com-
pound was triturated with dichloromethane and filtered to give
product 4f (100 mg, 0.56 mmol, 28.2%) as a pale yellow solid, m.p.
118.6 °C. Rf (cyclohexane/ethyl acetate 1:1): 0.33. 1H NMR
(300 MHz, [D6]DMSO): δ = 7.73 (d, 2 H, Ar-H), 7.84 (d, 2 H, Ar-
H), 8.40 (s, 1 H, NH), 8.52 [s, 1 H, (NHO)H], 10.71 [s, 1 H, (=NO)-
H] ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 111.2 (Ar-C-4),
118.7 (p-CN), 128.4 (Ar-C-2), 131.8 (Ar-C-3), 136.8 (Ar-C-1), 155.6
[Cq(NN)] ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 128.4 (1JN,H
= 84 Hz, NH), 305.7 (=NOH) ppm.
1
Tautomer 5Јc: H NMR (300 MHz, [D6]DMSO): δ = 2.32 (s, 3 H,
p-CH3), 3.74 (s, 3 H, OCH3), 7.19 (m, 2 H, Ar-H), 7.43 (m, 2 H,
Ar-H), 8.43 (s, 1 H, NH), 8.48 [s, 1 H, (NHO)H] ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 20.8 (p-CH3), 61.0 (=NOCH3), 127.3–
128.0 (Ar-C-2), 128.1 (Ar-C-1), 128.3–128.5 (Ar-C-3), 138.5 (Ar-
C-4), 157.0 [Cq(NN)] ppm. 15N NMR (30 MHz, [D6]DMSO): δ =
131.1 (1JN,H = 85 Hz, NH), 312.6 (=NOCH3) ppm.
O-Methyl-N,NЈ-dihydroxybenzamidine (5/5Јd): Compound 3d
(311 mg, 2 mmol) was dissolved in dichloromethane (5 mL). Meth-
ylhydroxylamine hydrochloride and triethylamine were then added
to the reaction mixture with stirring. Flash chromatography gave
pure product 5/5Јd [127 mg, 0.77 mmol, 38.3% (5d: 20.7%, 5Јd:
17.6%)] as a white solid, m.p. 105.2 °C. Rf (cyclohexane/ethyl
acetate 7:3): 0.37.
General Synthesis of para-Substituted O-Methyl-N,NЈ-dihydroxy-
benzamidines 5/5Јb–f: The starting compound (one out of 3b–f) was
dissolved in diethyl ether or dichloromethane with stirring in a
flask. O-Methylhydroxylamine hydrochloride (2 equiv.) and trieth-
ylamine (2 equiv.) were added successively. The mixture was stirred
at room temperature and monitored by TLC (cyclohexane/ethyl
acetate 6:4, 2% aqueous FeCl3 solution indicating 5/5Јb–f as blue
spots). After 20–25 h reaction was stopped. Precipitated byproduct
was filtered off. The filtrate was concentrated under reduced pres-
sure at max. 30 °C and applied to silica for flash chromatography
with cyclohexane/ethyl acetate gradient as mobile phase and silica
as solid phase to give 5/5Јb, 5/5Јd, and 5/5Јe as pure products. Ad-
1
Tautomer 5d: H NMR (300 MHz, [D6]DMSO): δ = 3.47 (s, 3 H,
OCH3), 7.39 (m, 3 H, Ar-H), 7.53 (m, 2 H, Ar-H), 9.02 (s, 1 H,
NH), 10.55 [s, 1 H, (=NO)H] ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 62.5 (NHOCH3), 127.4–127.7 (Ar-C-2), 127.9–128.1
(Ar-C-3), 129.0 (Ar-C-4), 131.8 (Ar-C-1), 154.9 [Cq(NN)] ppm. 15
N
NMR (30 MHz, [D6]DMSO): δ = 158.4 (NH) ppm.
1
Tautomer 5Јd: H NMR (300 MHz, [D6]DMSO): δ = 3.75 (s, 3 H,
OCH3), 7.39 (m, 3 H, Ar-H), 7.53 (m, 2 H, Ar-H), 8.49 (s, 1 H,
Eur. J. Org. Chem. 2014, 1961–1975
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1969

L. Schwarz, U. Girreser, B. Clement
NH), 8.50 [s, 1 H, (NHO)H] ppm. 13C NMR (75 MHz, [D6]- as mobile phase and silica as solid phase to give 6b–f as pure prod-
FULL PAPER
DMSO): δ = 61.1 (=NOCH3), 127.4–127.7 (Ar-C-2), 127.9–128.1
ucts.
(Ar-C-3), 129.0 (Ar-C-4), 131.2 (Ar-C-1), 157.1 [Cq(NN)] ppm. 15
N
p-Methoxy-O,OЈ-dimethyl-N,NЈ-dihydroxybenzamidine (6b): Com-
pound 3b (742 mg, 4 mmol) was dissolved in diethyl ether (15 mL).
Methylhydroxylamine hydrochloride and triethylamine were dis-
solved in ethanol and slowly added to the reaction mixture with
stirring. Flash chromatography gave pure product 6b (473 mg,
2.25 mmol, 56.3%) as a colorless oil. Rf (cyclohexane/ethyl acetate
1:1): 0.50. 1H NMR (300 MHz, [D6]DMSO): δ = 3.43 [s, 3 H,
(NHO)CH3], 3.75 [s, 3 H, (=NO)CH3], 3.78 (s, 3 H, p-OCH3) 6.95
(d, 2 H, Ar-H), 7.43 (d, 2 H, Ar-H), 9.21 (s, 1 H, NH) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 55.1 (p-OCH3), 61.1 (=NOCH3),
62.7 (NHOCH3), 113.4 (Ar-C-3), 122.9 (Ar-C-1), 129.1 (Ar-C-2),
154.7 [Cq(NN)], 160.1 (Ar-C-4) ppm. 15N NMR (30 MHz, [D6]-
DMSO): δ = 160.2 (1JN,H = 85 Hz, NH), 314.4 (=NOCH3) ppm.
NMR (30 MHz, [D6]DMSO): δ = 131.1 (1JN,H = 88 Hz, NH), 312.2
(=NOCH3) ppm.
p-Bromo-O-methyl-N,NЈ-dihydroxybenzamidine (5/5Јe): Compound
3e (469 mg, 2 mmol) was dissolved in dichloromethane (10 mL).
Methylhydroxylamine hydrochloride and triethylamine were then
added to the reaction mixture with stirring. Flash chromatography
gave pure product 5/5Јe [352 mg, 1.44 mmol, 71.9% (5e: 37.2%,
5Јe: 34.7%)] as a white solid, m.p. 72.8 °C. Rf (cyclohexane/ethyl
acetate 7:3): 0.35.
1
Tautomer 5e: H NMR (300 MHz, [D6]DMSO): δ = 3.46 (s, 3 H,
OCH3), 7.47 (m, 2 H, Ar-H), 7.59 (m, 2 H, Ar-H), 9.08 (s, 1 H,
NH), 10.66 [s, 1 H, (=NO)H] ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 62.5 (NHOCH3), 122.3 (Ar-C-4), 129.4–130.1 (Ar-C-
p-Methyl-O,OЈ-dimethyl-N,NЈ-dihydroxybenzamidine (6c): Com-
pound 3c (339 mg, 2 mmol) was dissolved in dichloromethane
(5 mL). Methylhydroxylamine hydrochloride and triethylamine
were then added to the reaction mixture with stirring. Flash
chromatography gave pure product 6c (83 mg, 0.43 mmol, 21.4%)
as a pale yellow oil. Rf (cyclohexane/ethyl acetate 8:2): 0.52. 1H
NMR (300 MHz, [D6]DMSO): δ = 2.33 (s, 3 H, p-CH3), 3.43 [s, 3
H, (NHO)CH3], 3.76 [s, 3 H, (=NO)CH3], 7.20 (d, 2 H, Ar-H),
7.39 (d, 2 H, Ar-H), 9.26 (s, 1 H, NH) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 20.8 (p-CH3), 61.2 (=NOCH3), 62.7 (NHOCH3),
127.7 (Ar-C-2), 127.9 (Ar-C-1), 128.5 (Ar-C-3), 138.9 (Ar-C-4),
155.0 [Cq(NN)] ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 160.3
(1JN,H = 85 Hz, NH), 315.3 (=NOCH3) ppm.
2), 130.7–131.0 (Ar-C-3), 131.2 (Ar-C-1), 153.9 [Cq(NN)] ppm. 15
N
NMR (30 MHz, [D6]DMSO): δ = 158.4 (NH, 1JN,H = 82 Hz) ppm.
1
Tautomer 5Јe: H NMR (300 MHz, [D6]DMSO): δ = 3.75 (s, 3 H,
OCH3), 7.47 (m, 2 H, Ar-H), 7.59 (m, 2 H, Ar-H), 8.56 [s, 1 H,
(NHO)H], 8.59 (s, 1 H, NH) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 61.2 (=NOCH3), 122.4 (Ar-C-4), 129.4–130.1 (Ar-C-
2), 130.4 (Ar-C-1), 130.7–131.0 (Ar-C-3), 156.1 [Cq(NN)] ppm. 15
N
NMR (30 MHz, [D6]DMSO): δ = 130.6 (1JN,H = 88 Hz, NH), 313.2
(=NOCH3) ppm.
p-Cyano-O-methyl-N,NЈ-dihydroxybenzamidine (5/5Јf): Compound
3f (542 mg, 3 mmol) was dissolved in dichloromethane (15 mL).
Methylhydroxylamine hydrochloride and triethylamine were then
added to the reaction mixture with stirring. After flash chromatog-
raphy, the compound was triturated successively with cyclohexane
and dichloromethane and filtered to give pure product 5/5Јf
[257 mg, 1.35 mmol, 45.1% (5f: 23.3%, 5Јf: 21.8%)] as a white so-
lid, m.p. 133.7 °C. Rf (cyclohexane/ethyl acetate 7:3): 0.21.
O,OЈ-Dimethyl-N,NЈ-dihydroxybenzamidine (6d): Compound 3d
(622 mg, 4 mmol) was dissolved in diethyl ether (8 mL). Methyl-
hydroxylamine hydrochloride and triethylamine were dissolved in
ethanol and added slowly to the reaction mixture with stirring.
Flash chromatography gave pure product 6d (262 mg, 1.46 mmol,
1
36.4%) as a yellow oil. Rf (cyclohexane/ethyl acetate 7:3): 0.59. H
1
Tautomer 5f: H NMR (300 MHz, [D6]DMSO): δ = 3.48 (s, 3 H,
NMR (300 MHz, [D6]DMSO): δ = 3.44 [s, 3 H, (NHO)CH3], 3.78
[s, 3 H, (=NO)CH3], 7.41 (m, 3 H, Ar-H), 7.50 (m, 2 H, Ar-H),
9.33 (s, 1 H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 61.3
(=NOCH3), 62.8 (NHOCH3), 127.8 (Ar-C-2), 128.0 (Ar-C-3),
129.4 (Ar-C-4), 130.9 (Ar-C-1), 155.1 [Cq(NN)] ppm. 15N NMR
(30 MHz, [D6]DMSO): δ = 160.4 (1JN,H = 85 Hz, NH), 315.8
(=NOCH3) ppm.
OCH3), 7.70 (m, 2 H, Ar-H), 7.86 (m, 2 H, Ar-H), 9.21 (s, 1 H,
NH), 10.95 [s, 1 H, (=NO)H] ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 62.6 (NHOCH3), 111.6 (Ar-C-4), 118.6 (p-CN),
128.1–128.9 (Ar-C-2), 131.8–132.0 (Ar-C-3), 136.9 (Ar-C-1), 153.6
[Cq(NN)] ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 158.1 (NH,
1JN,H = 82 Hz), 309.5 (=NOH) ppm.
1
Tautomer 5Јf: H NMR (300 MHz, [D6]DMSO): δ = 3.78 (s, 3 H,
p-Bromo-O,OЈ-dimethyl-N,NЈ-dihydroxybenzamidine (6e): Com-
pound 3e (469 mg, 2 mmol) was dissolved in dichloromethane
(10 mL). Methylhydroxylamine hydrochloride and triethylamine
were then added to the reaction mixture with stirring. Flash
chromatography gave pure product 6e (62 mg, 0.25 mmol, 12.7%)
as a colorless oil. Rf (cyclohexane/ethyl acetate 7:3): 0.60. 1H NMR
(300 MHz, [D6]DMSO): δ = 3.44 [s, 3 H, (NHO)CH3], 3.78 [s, 3
H, (=NO)CH3], 7.45 (d, 2 H, Ar-H), 7.61 (d, 2 H, Ar-H), 9.40 [s,
1 H, (NHO)H] ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 61.3
(=NOCH3), 62.7 (NHOCH3), 122.8 (Ar-C-4), 129.8 (Ar-C-2),
130.0 (Ar-C-1), 131.0 (Ar-C-3), 154.1 [Cq(NN)] ppm. 15N NMR
(30 MHz, [D6]DMSO): δ = 160.3 (1JN,H = 85 Hz, NH), 316.4
(=NOCH3) ppm.
OCH3), 7.70 (m, 2 H, Ar-H), 7.86 (m, 2 H, Ar-H), 8.66 [s, 1 H,
(NHO)H], 8.74 (s, 1 H, NH) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 61.5 (=NOCH3), 111.6 (Ar-C-4), 118.6 (p-CN), 128.1–
128.9 (Ar-C-2), 131.8–132.0 (Ar-C-3), 135.9 (Ar-C-1), 155.7
[Cq(NN)] ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 131.2 (1JN,H
= 88 Hz, NH), 316.4 (=NOCH3) ppm.
General Synthesis of para-Substituted O,OЈ-Dimethyl-N,NЈ-di-
hydroxybenzamidines 6b–f: The starting compound (one out of 3b–
f) was dissolved in dichloromethane with stirring in a flask. Two
equivalents of methylhydroxylamine hydrochloride and (2 equiv.)
of triethylamine were added successively. The mixture was stirred
at room temperature and monitored by TLC (cyclohexane/ethyl
acetate 7:3, with 2% aqueous FeCl3 solution indicating 6b–f as yel-
low spots and disappearance of 3b–f). After 24 h further methyl-
hydroxylamine hydrochloride (2 equiv.) and triethylamine (2 equiv.)
were added if 3b–f was still detectable. The procedure was repeated
after 48 h. Usually the reaction was complete after 48–72 h and the
precipitated byproduct was filtered off. The filtrate was concen-
trated under reduced pressure at max. 30 °C and applied onto silica
for flash chromatography with cyclohexane/ethyl acetate gradient
p-Cyano-O,OЈ-dimethyl-N,NЈ-dihydroxybenzamidine (6f): Com-
pound 3f (361 mg, 2 mmol) was dissolved in dichloromethane
(10 mL). Methylhydroxylamine hydrochloride and triethylamine
were then added to the reaction mixture with stirring. Flash
chromatography gave pure product 6f (32 mg, 0.16 mmol, 7.8%) as
a white solid, m.p. 83.6 °C. Rf (cyclohexane/ethyl acetate 8:2): 0.53.
1H NMR (300 MHz, [D6]DMSO): δ = 3.46 [s, 3 H, (NHO)CH3],
3.80 [s, 3 H, (=NO)CH3], 7.67 (d, 2 H, Ar-H), 7.87 (d, 2 H, Ar-H),
1970
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Eur. J. Org. Chem. 2014, 1961–1975

para-Substituted N,NЈ-Dihydroxybenzamidines as Model Prodrugs
9.53 [s, 1 H, (NHO)H] ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 160.0 (Ar-C-4) ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 131.2
61.6 (=NOCH3), 62.8 (NHOCH3), 112.0 (Ar-C-4), 118.5 (p-CN), (1JN,H = 87 Hz, NH), 308.7 (=NOBn) ppm.
128.6 (Ar-C-2), 132.0 (Ar-C-3), 135.4 (Ar-C-1), 153.7
p-Methyl-O-benzyl-N,NЈ-dihydroxybenzamidine (7/7Јc): Compound
3c (509 mg, 3 mmol) was dissolved in dichloromethane (7 mL). Af-
ter flash chromatography, the compound was dissolved in ethyl
[Cq(NN)] ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 160.2 (1JN,H
= 86 Hz, NH), 319.3 (=NOCH3) ppm.
acetate, precipitated with petroleum ether, and filtered to give pure
product 7/7Јc [150 mg, 0.59 mmol, 19.5% (7c: 9.0%, 7Јc: 10.5%)]
as a white solid, m.p. 114.2 °C. Rf (cyclohexane/ethyl acetate 7:3):
0.37.
General Synthesis of para-Substituted O-Benzyl-N,NЈ-dihydroxy-
benzamidines 7/7Јa–g: Benzylhydroxylamine (2 equiv.) was added to
a solution of 3 (one out of 3a–g) in dichloromethane, diethyl ether,
or dichloromethane/diethyl ether. The reaction mixture was stirred
at room temperature and monitored by TLC (cyclohexane/ethyl
acetate 6:4, with 2% aqueous FeCl3 solution indicating 7/7Јa–g as
blue spots). After 20–25 h the reaction was stopped. Precipitated
byproduct was filtered off. The filtrate was concentrated under re-
duced pressure at max. 30 °C and transferred to silica for flash
chromatography with cyclohexane/ethyl acetate gradient as mobile
phase and silica as solid phase. Compound 7/7Јf was obtained as a
pure product. Additional workup was required for 7/7Јa–e and g
and led to pure compounds.
1
Tautomer 7c: H NMR (300 MHz, [D6]DMSO): δ = 2.33 (s, 3 H,
p-CH3), 4.71 (s, 2 H, OCH2-), 7.31 (m, 9 H, Ar-H), 8.94 (s, 1 H,
NH), 10.55 [s, 1 H, (=NO)H] ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 20.9 (p-CH3), 76.6 (OCH2-), 127.4–128.1 (Ar-C-2),
128.2–128.7 (Bn-Ar-C), 128.5–128.7 (Ar-C-3), 128.9 (Ar-C-1),
138.4 (Ar-C-4), 154.8 [Cq(NN)] ppm. 15N NMR (30 MHz, [D6]-
DMSO): δ = 154.7 (1JN,H = 81 Hz, NH), 303.7 (=NOH) ppm.
1
Tautomer 7Јc: H NMR (300 MHz, [D6]DMSO): δ = 2.33 (s, 3 H,
p-OCH3), 5.02 (s, 2 H, OCH2-), 7.31 (m, 9 H, Ar-H), 8.52 [s, 1 H,
(NHO)H], 8.54 (s, 1 H, NH) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 20.9 (p-CH3), 74.8 (OCH2-), 127.4–128.1 (Ar-C-2),
128.2–128.7 (Bn-Ar-C), 128.3 (Ar-C-1), 128.5–128.7 (Ar-C-3),
138.6 (Ar-C-4), 157.3 [Cq(NN)] ppm. 15N NMR (30 MHz, [D6]-
DMSO): δ = 131.3 (1JN,H = 88 Hz, NH), 309.8 (=NOBn) ppm.
p-Hydroxy-O-benzyl-N,NЈ-dihydroxybenzamidine (7/7Јa): Com-
pound 3a (343 mg, 2 mmol) was dissolved in a mixture of diethyl
ether and dichloromethane (1:1, 15 mL). Flash chromatography
gave pure product 7/7Јa [227 mg, 0.88 mmol, 44.0% (7a: 20.5%,
7Јa: 23.5%)] as a colorless oil, which turns from orange to black
during storage at room temperature within five hours (decomposi-
tion). Rf (cyclohexane/ethyl acetate 1:1): 0.44.
O-Benzyl-N,NЈ-dihydroxybenzamidine (7/7Јd): Compound 3d
(778 mg, 5 mmol) was dissolved in diethyl ether (7 mL). Benzyl-
hydroxylamine was dissolved in ethanol (5 mL), and the mixture
was dropped slowly into the reaction mixture. After flash
chromatography, the compound was dissolved in ethyl acetate, pre-
cipitated with petroleum ether, and filtered to give pure product 7/
7Јd [474 mg, 1.96 mmol, 39.2% (7d: 18.8%, 7Јd: 20.4%)] as a white
solid, m.p. 109.2 °C; m.p.[17] 109–110 °C. Rf (cyclohexane/ethyl
acetate 7:3): 0.31.
1
Tautomer 7a: H NMR (300 MHz, [D6]DMSO): δ = 4.70 (s, 2 H,
OCH2-), 6.77 (m, 2 H, Ar-H), 7.29 (m, 5 H, Bn-Ar-H), 7.36 (m, 2
H, Ar-H), 8.85 (s, 1 H, NH), 9.69 (s, 1 H, p-OH), 10.39 [s, 1 H,
(=NO)H] ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 76.6 (OCH2-
), 114.6–114.8 (Ar-C-3), 122.3 (Ar-C-1), 127.6–129.0 (Bn-Ar-C),
129.0–129.6 (Ar-C-2), 154.9 [Cq(NN)], 158.4 (Ar-C-4) ppm. 15N
NMR (30 MHz, [D6]DMSO): δ = 154.5 (NH) ppm.
1
1
Tautomer 7d: H NMR (300 MHz, [D6]DMSO): δ = 4.72 (s, 2 H,
Tautomer 7Јa: H NMR (300 MHz, [D6]DMSO): δ = 5.00 (s, 2 H,
OCH2-), 7.27 (m, 5 H, Bn-Ar-H), 7.42 (m, 5 H, Ar-H), 9.01 (s, 1
H, NH), 10.62 [s, 1 H, (=NO)H] ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 76.7 (OCH2-), 127.7 (Ar-C-2), 127.9–128.7 (Bn-Ar-
C), 128.1–128.2 (Ar-C-3), 129.1 (Ar-C-4), 131.7 (Ar-C-1), 154.9
[Cq(NN)] ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 155.0 (1JN,H
= 82 Hz, NH), 304.3 (=NOH) ppm.
OCH2-), 6.77 (m, 2 H, Ar-H), 7.29 (m, 5 H, Bn-Ar-H), 7.36 (m, 2
H, Ar-H), 8.44 (s, 1 H, NH), 8.49 [s, 1 H, (NHO)H], 9.69 (s, 1 H,
p-OH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 74.7 (OCH2-),
114.6–114.8 (Ar-C-3), 121.7 (Ar-C-1), 127.6–129.0 (Bn-Ar-C),
129.0–129.6 (Ar-C-2), 157.4 [Cq(NN)], 158.4 (Ar-C-4) ppm. 15N
NMR (30 MHz, [D6]DMSO): δ = 130.9 (1JN,H = 88 Hz, NH), 308.3
(=NOBn) ppm.
1
Tautomer 7Јd: H NMR (300 MHz, [D6]DMSO): δ = 5.03 (s, 2 H,
OCH2-), 7.27 (m, 5 H, Bn-Ar-H), 7.42 (m, 5 H, Ar-H), 8.55 [s, 1
H, (NHO)H], 8.62 (s, 1 H, NH) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 74.9 (OCH2-), 127.7 (Ar-C-2), 127.9–128.7 (Bn-Ar-
C), 128.1–128.2 (Ar-C-3), 129.4 (Ar-C-4), 131.2 (Ar-C-1), 157.3
[Cq(NN)] ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 131.4 (1JN,H
= 88 Hz, NH), 310.4 (=NOBn) ppm.
p-Methoxy-O-benzyl-N,NЈ-dihydroxybenzamidine (7/7Јb): Com-
pound 3b (742 mg, 4 mmol) was dissolved in dichloromethane
(20 mL). After flash chromatography, the compound was dissolved
in ethyl acetate, precipitated with cyclohexane, and filtered to give
pure product 7/7Јb [300 mg, 1.10 mmol, 27.6% (7b: 12.5%, 7Јb:
15.1%)] as a white solid, m.p. 103.0 °C. Rf (cyclohexane/ethyl acet-
ate 7:3): 0.28.
p-Bromo-O-benzyl-N,NЈ-dihydroxybenzamidine (7/7Јe): Compound
3e (469 mg, 2 mmol) was dissolved in dichloromethane (10 mL).
After flash chromatography, the compound was triturated with
cyclohexane and filtered to give pure product 7/7Јe [300 mg,
0.93 mmol, 46.7% (7e: 21.8%, 7Јe: 24.9%)] as a white solid, m.p.
109.0 °C. Rf (cyclohexane/ethyl acetate 7:3): 0.46.
1
Tautomer 7b: H NMR (300 MHz, [D6]DMSO): δ = 3.77 (s, 3 H,
p-OCH3), 4.71 (s, 2 H, OCH2-), 6.94 (m, 2 H, Ar-H), 7.29 (m, 5
H, Bn-Ar-H), 7.49 (m, 2 H, Ar-H), 8.91 (s, 1 H, NH), 10.48 [s, 1
H, (=NO)H] ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 55.1 (p-
OCH3), 76.6 (OCH2-), 113.2–113.3 (Ar-C-3), 123.9 (Ar-C-1),
127.5–128.9 (Bn-Ar-C), 128.9–129.5 (Ar-C-2), 154.5 [Cq(NN)],
159.9 (Ar-C-4) ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 154.4
(1JN,H = 81 Hz, NH), 302.2 (=NOH) ppm.
1
Tautomer 7e: H NMR (300 MHz, [D6]DMSO): δ = 4.71 (s, 2 H,
OCH2-), 7.29 (m, 5 H, Bn-Ar-H), 7.47 (m, 2 H, Ar-H), 7.58 (m, 2
H, Ar-H), 9.07 (s, 1 H, NH), 10.74 [s, 1 H, (=NO)H] ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 76.7 (OCH2-), 122.4 (Ar-C-4),
127.5–128.8 (Bn-Ar-C), 129.5–130.1 (Ar-C-2), 130.8–130.9 (Ar-C-
3), 130.9 (Ar-C-1), 153.9 [Cq(NN)] ppm. 15N NMR (30 MHz, [D6]-
DMSO): δ = 155.6 (1JN,H = 85 Hz, NH) ppm.
1
Tautomer 7Јb: H NMR (300 MHz, [D6]DMSO): δ = 3.77 (s, 3 H,
p-OCH3), 5.01 (s, 2 H, OCH2-), 6.94 (m, 2 H, Ar-H), 7.29 (m, 5
H, Bn-Ar-H), 7.49 (m, 2 H, Ar-H), 8.51 (s, 1 H, NH), 8.52 [s, 1
H, (NHO)H] ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 55.1 (p-
1
OCH3), 74.8 (OCH2-), 113.2–113.3 (Ar-C-3), 123.3 (Ar-C-1), Tautomer 7Јe: H NMR (300 MHz, [D6]DMSO): δ = 5.02 (s, 2 H,
127.5–128.9 (Bn-Ar-C), 128.9–129.5 (Ar-C-2), 157.1 [Cq(NN)], OCH2-), 7.29 (m, 5 H, Bn-Ar-H), 7.47 (m, 2 H, Ar-H), 7.58 (m, 2
Eur. J. Org. Chem. 2014, 1961–1975
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1971

L. Schwarz, U. Girreser, B. Clement
FULL PAPER
H, Ar-H), 8.61 [s, 1 H, (NHO)H], 8.70 (s, 1 H, NH) ppm. 13C p-Hydroxy-O,OЈ-dibenzyl-N,NЈ-dihydroxybenzamidine (8a): Com-
NMR (75 MHz, [D6]DMSO): δ = 75.0 (OCH2-), 122.5 (Ar-C-4), pound 3a (343 mg, 2 mmol) was dissolved in a mixture of diethyl
127.5–128.8 (Bn-Ar-C), 129.5–130.1 (Ar-C-2), 130.8–130.9 ether and dichloromethane (1:1, 15 mL). Flash chromatography af-
(Ar-C–), 130.4 (Ar-C-1), 156.3 [Cq(NN)] ppm. 15N NMR (30 MHz, ter 48 h gave pure product 8a (129 mg, 0.37 mmol, 18.5%) as a
1
[D6]DMSO): δ = 131.3 (1JN,H = 91 Hz, NH), 310.5 (=NOBn) ppm. light yellow oil. Rf (cyclohexane/ethyl acetate 1:1): 0.63. H NMR
(300 MHz, [D6]DMSO): δ = 4.67 [s, 2 H, (NHO)CH2-], 5.03 [s, 2
p-Cyano-O-benzyl-N,NЈ-dihydroxybenzamidine (7/7Јf): Compound
3f (542 mg, 3 mmol) was dissolved in dichloromethane (15 mL).
Flash chromatography gave pure product 7/7Јf [310 mg, 1.16 mmol,
38.7% (7f: 18.1%, 7Јf: 20.6%)] as a pale yellow oil. Rf (cyclohexane/
H, (=NO)CH2-], 6.78 (d, 2 H, Ar-H), 7.27 (m, 5 H, Bn-Ar-H), 7.28
(d, 2 H, Ar-H), 9.23 (s, 1 H, NH), 9.73 (s, 1 H, p-OH) ppm. 13C
NMR (75 MHz, [D6]DMSO):
δ = 74.9 (=NOCH2-), 76.9
(NHOCH2-), 114.7 (Ar-C-3), 121.2 (Ar-C-1), 127.5–128.8 (Bn-Ar-
C), 129.4 (Ar-C-2), 155.5 [Cq(NN)], 158.6 (Ar-C-4) ppm. 15N
NMR (30 MHz, [D6]DMSO): δ = 157.0 (1JN,H = 86 Hz, NH), 311.5
(=NOBn) ppm.
ethyl acetate 7:3): 0.42.
1
Tautomer 7f: H NMR (300 MHz, [D6]DMSO): δ = 4.75 (s, 2 H,
OCH2-), 7.29 (m, 5 H, Bn-Ar-H), 7.71 (m, 2 H, Ar-H), 7.84 (m, 2
H, Ar-H), 9.21 (s, 1 H, NH), 10.95 [s, 1 H, (=NO)H] ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 76.8 (OCH2-), 111.6 (Ar-C-4),
118.6 (p-CN), 127.5–128.9 (Bn-Ar-C), 128.3–129.0 (Ar-C-2),
131.8–131.9 (Ar-C-3), 138.1 (Ar-C-1), 153.9 [Cq(NN)] ppm. 15N
NMR (30 MHz, [D6]DMSO): δ = 154.7 (NH) ppm.
p-Methoxy-O,OЈ-dibenzyl-N,NЈ-dihydroxybenzamidine (8b): Com-
pound 3b (742 mg, 4 mmol) was dissolved in dichloromethane
(20 mL). Flash chromatography after 24 h gave pure product 8b
(107 mg, 0.30 mmol, 7.4%) as a light yellow oil. Rf (cyclohexane/
ethyl acetate 7:3): 0.64. 1H NMR (300 MHz, [D6]DMSO): δ = 3.78
(p-OCH3), 4.67 [s, 2 H, (NHO)CH2-], 5.04 [s, 2 H, (=NO)CH2-],
6.95 (d, 2 H, Ar-H), 7.25 (m, 5 H, Bn-Ar-H), 7.44 (d, 2 H, Ar-H),
9.29 (s, 1 H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 55.2
(p-OCH3), 75.0 (=NOCH2-), 76.9 (NHOCH2-), 113.3 (Ar-C-3),
122.8 (Ar-C-1), 127.5–128.8 (Bn-Ar-C), 129.4 (Ar-C-2), 155.1
[Cq(NN)], 160.2 (Ar-C-4) ppm. 15N NMR (30 MHz, [D6]DMSO):
δ = 157.1 (1JN,H = 85 Hz, NH), 312.2 (=NOBn) ppm.
1
Tautomer 7Јf: H NMR (300 MHz, [D6]DMSO): δ = 5.06 (s, 2 H,
OCH2-), 7.29 (m, 5 H, Bn-Ar-H), 7.71 (m, 2 H, Ar-H), 7.84 (m, 2
H, Ar-H), 8.66 [s, 1 H, (NHO)H], 8.74 (s, 1 H, NH) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 75.3 (OCH2-), 111.7 (Ar-C-4),
118.6 (p-CN), 127.5–128.9 (Bn-Ar-C), 128.3–129.0 (Ar-C-2),
131.8–131.9 (Ar-C-3), 137.6 (Ar-C-1), 156.0 [Cq(NN)] ppm. 15N
NMR (30 MHz, [D6]DMSO):
(=NOBn) ppm.
δ
=
131.6 (NH), 313.6
p-Methyl-O,OЈ-dibenzyl-N,NЈ-dihydroxybenzamidine (8c): Com-
pound 3c (339 mg, 2 mmol) was dissolved in diethyl ether (10 mL).
Flash chromatography after 96 h gave pure product 8c (200 mg,
0.58 mmol, 28.9%) as a light yellow oil. Rf (cyclohexane/ethyl acet-
ate 8:2): 0.66. 1H NMR (300 MHz, [D6]DMSO): δ = 2.33 (p-CH3),
4.69 [s, 2 H, (NHO)CH2-], 5.05 [s, 2 H, (=NO)CH2-], 7.27 (m, 14 H,
Ar-H), 9.34 (s, 1 H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 20.9 (p-CH3), 75.1 (=NOCH2-), 76.9 (NHOCH2-), 127.5 (Ar-C-
1), 127.6–128.8 (Bn-Ar-C), 127.9 (Ar-C-2), 128.1 (Ar-C-3), 139.0
(Ar-C-4), 155.4 (Cq(NN)) ppm. 15N NMR (30 MHz, [D6]DMSO):
δ = 157.1 (1JN,H = 86 Hz, NH), 313.1 (=NOBn) ppm.
p-Nitro-O-benzyl-N,NЈ-dihydroxybenzamidine (7/7Јg): Compound
3g (401 mg, 2 mmol) was dissolved in dichloromethane (10 mL).
After flash chromatography, the compound was triturated with
dichloromethane and filtered to give pure product 7/7Јg [494 mg,
1.72 mmol, 86.1% (7g: 41.9%, 7Јg: 44.2%)] as a yellow solid, m.p.
121.2 °C. Rf (cyclohexane/ethyl acetate 7:3): 0.34.
1
Tautomer 7g: H NMR (300 MHz, [D6]DMSO): δ = 4.76 (s, 2 H,
OCH2-), 7.30 (m, 5 H, Bn-Ar-H), 7.78 (m, 2 H, Ar-H), 8.23 (m, 2
H, Ar-H), 9.25 (s, 1 H, NH), 11.10 [s, 1 H, (=NO)H] ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 76.8 (OCH2-), 123.0–123.1 (Ar-
C-3), 127.5–128.9 (Bn-Ar-C), 128.9–129.3 (Ar-C-2), 137.7 (Ar-C-
1), 147.6 (Ar-C-4), 153.3 [Cq(NN)] ppm. 15N NMR (30 MHz, [D6]-
DMSO): δ = 154.9 (1JN,H = 82 Hz, NH), 370.1 (p-NO2) ppm.
O,OЈ-Dibenzyl-N,NЈ-dihydroxybenzamidine (8d): Compound 3d
(622 mg, 4 mmol) was dissolved in diethyl ether (5 mL). Benzyl-
hydroxylamine was dissolved in ethanol (10 mL), and the mixture
was dropped slowly into the reaction mixture. Flash chromatog-
raphy after 24 h gave pure product 8d (640 mg, 1.93 mmol, 48.2%)
as a colorless oil. Rf (cyclohexane/ethyl acetate 8:2): 0.63. 1H NMR
(300 MHz, [D6]DMSO): δ = 4.69 [s, 2 H, (NHO)CH2-], 5.07 [s, 2
1
Tautomer 7Јg: H NMR (300 MHz, [D6]DMSO): δ = 5.08 (s, 2 H,
OCH2-), 7.30 (m, 5 H, Bn-Ar-H), 7.78 (m, 2 H, Ar-H), 8.23 (m, 2
H, Ar-H), 8.75 [s, 1 H, (NHO)H], 8.91 (s, 1 H, NH) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 75.3 (OCH2-), 123.0–123.1 (Ar-
C-3), 127.5–128.9 (Bn-Ar-C), 128.9–129.3 (Ar-C-2), 138.1 (Ar-C-
1), 147.6 (Ar-C-4), 155.6 [Cq(NN)] ppm. 15N NMR (30 MHz, [D6]-
DMSO): δ = 131.8 (NH), 314.2 (=NOBn), 370.1 (p-NO2) ppm.
H, (=NO)CH2-], 7.29 (m, 15 H, Ar-H), 9.44 (s, 1 H, NH) ppm. 13
NMR (75 MHz, [D6]DMSO): 75.1 (=NOCH2-), 77.1
C
δ
=
(NHOCH2-), 127.6–128.8 (Bn-Ar-C), 127.9 (Ar-C-2), 128.2 (Ar-C-
3), 129.5 (Ar-C-4), 130.8 (Ar-C-1), 155.5 [Cq(NN)] ppm. 15N NMR
(30 MHz, [D6]DMSO): δ = 157.3 (1JN,H = 86 Hz, NH), 313.3
(=NOBn) ppm.
General Synthesis of para-Substituted O,OЈ-Dibenzyl-N,NЈ-di-
hydroxybenzamidines 8a–g: Benzylhydroxylamine (2 equiv.) was
added to a stirred solution of 3 (one out of 3a–g) in dichlorometh-
ane, diethyl ether, or dichloromethane/diethyl ether. The reaction
mixture was stirred at room temperature and monitored by TLC
(cyclohexane/ethyl acetate 7:3, with 2% aqueous FeCl3 solution in-
dicating 8a–g as yellow spots). Disappearance of 3a–g was moni-
tored. After 24 h, further benzylhydroxylamine (2 equiv.) was
added if 3a–g was still detectable. The procedure was repeated after
48 h. Usually the reaction was complete after 48–72 h and the pre-
cipitated byproduct was filtered off. The filtrate was concentrated
under reduced pressure at max. 30 °C and transferred to silica for
flash chromatography with cyclohexane/ethyl acetate gradient as
mobile phase and silica as solid phase; this led to 8a–g as pure
products.
p-Bromo-O,OЈ-dibenzyl-N,NЈ-dihydroxybenzamidine (8e): Com-
pound 3e (469 mg, 2 mmol) was dissolved in dichloromethane (10
mL). Flash chromatography after 120 h gave pure product 8e
(367 mg, 0.89 mmol, 44.7%) as a white solid, m.p. 70.5 °C. Rf (cy-
clohexane/ethyl acetate 7:3): 0.63. 1H NMR (300 MHz, [D6]-
DMSO): δ = 4.69 [s, 2 H, (NHO)CH2-], 5.06 [s, 2 H, (=NO)-
CH2-], 7.25 (m, 10 H, Bn-Ar-H), 7.42 (d, 2 H, Ar-H), 7.59 (d, 2 H,
Ar-H), 9.50 (s, 1 H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 75.2 (=NOCH2-), 77.1 (NHOCH2-), 122.8 (Ar-C-4), 127.6–
128.8 (Bn-Ar-C), 129.9 (Ar-C-1), 130.0 (Ar-C-2), 130.9 (Ar-C-3),
154.5 [Cq(NN)] ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 157.1
(1JN,H = 88 Hz, NH), 313.9 (=NOBn) ppm.
1972
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1961–1975

para-Substituted N,NЈ-Dihydroxybenzamidines as Model Prodrugs
p-Cyano-O,OЈ-dibenzyl-N,NЈ-dihydroxybenzamidine (8f): Com-
pound 3f (542 mg, 3 mmol) was dissolved in dichloromethane (15
mL). Flash chromatography after 96 h gave pure product 8f
(116 mg, 0.32 mmol, 10.8%) as a white solid, m.p. 89.9 °C. Rf (cy-
clohexane/ethyl acetate 7:3): 0.64. 1H NMR (300 MHz, [D6]-
romethane (15 mL). Flash chromatography after 48 h gave pure
product 9b (488 mg, 1.40 mmol, 46.5%) as a colorless oil. Rf (cyclo-
1
hexane/ethyl acetate 7:3): 0.41. H NMR (300 MHz, [D6]DMSO):
δ = 1.57 [m, 12 H, (NHO)THP, (=NO)THP], 3.48 [m, 2 H, (NHO)-
THP, (=NO)THP], 3.69 [m, 1 H, (NHO)THP], 3.80 [m, 1 H,
DMSO): δ = 4.71 [s, 2 H, (NHO)CH2-], 5.09 [s, 2 H, (=NO)- (=NO)THP], 4.77 {m, 1 H, O-CH-O [(NHO)THP]}, 5.13 {m, 1 H,
CH2-], 7.26 (m, 10 H, Bn-Ar-H), 7.62 (d, 2 H, Ar-H), 7.84 (d, 2 H, O-CH-O [(=NO)THP]}, 6.96 (d, 2 H, Ar-H), 7.49 (d, J = Ar-H, ds
Ar-H), 9.64 (s, 1 H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO): = 3.5 Hz, 2 H), 8.86 (s, 1 H, NH, ds = 3.8 Hz) ppm. 13C NMR
δ = 75.5 (=NOCH2-), 77.2 (NHOCH2-), 111.9 (Ar-C-4), 118.5 (p- (75 MHz, [D6]DMSO): δ = 18.7–19.2 (2 C, 2ϫTHP-C-4), 24.6–
CN), 127.7–128.9 (Bn-Ar-C), 128.8 (Ar-C-2), 131.9 (Ar-C-3), 137.8 24.9 (2 C, 2ϫTHP-C-5), 27.9–28.7 (2 C, 2ϫTHP-C-3), 55.1 (p-
(Ar-C-1), 154.1 [Cq(NN)] ppm. 15N NMR (30 MHz, [D6]DMSO): OCH3), 61.4–61.8 (2 C, 2ϫTHP-C-6), 99.8–100.0 [1 C, (=NO)-
δ = 157.3 (1JN,H = 87 Hz, NH), 316.4 (=NOBn) ppm.
THP-C-2], 101.4–101.7 [1 C, (NHO)THP-C-2], 113.3 (Ar-C-3, ds
= 0.8 Hz), 122.5 (Ar-C-1, ds = 5.3 Hz), 129.5 (Ar-C-2, ds = 4.8 Hz),
p-Nitro-O,OЈ-dibenzyl-N,NЈ-dihydroxybenzamidine (8g): Com-
pound 3g (401 mg, 2 mmol) was dissolved in dichloromethane (10
mL). Flash chromatography after 96 h gave pure product 8g
(90 mg, 0.24 mmol, 11.9%) as a yellow oil. Rf (cyclohexane/ethyl
155.3 [Cq(NN), ds = 0.6 Hz], 160.2 (Ar-C-4, ds = 4.8 Hz) ppm. 15
N
1
NMR (30 MHz, [D6]DMSO): δ = 149.9 (NH, JN,H = 87 Hz, ds =
38 Hz), 311.2 (=NOTHP, ds = 17 Hz) ppm. For each value the
mean of the chemical shift and diastereomeric shift (ds) – if pres-
ent – of both isomers are given.
1
acetate 8:2): 0.48. H NMR (300 MHz, [D6]DMSO): δ = 4.73 [s, 2
H, (NHO)CH2-], 5.11 [s, 2 H, (=NO)CH2-], 7.27 (m, 10 H, Bn-Ar-
H), 7.71 (d, 2 H, Ar-H), 8.23 (d, 2 H, Ar-H), 9.69 (s, 1 H,
p-Methyl-O,OЈ-bis(tetrahydropyran-2-yl)-N,NЈ-dihydroxybenz-
amidine (9c): Compound 3c (339 mg, 2 mmol) was dissolved in
dichloromethane (10 mL). Flash chromatography after 48 h gave
pure product 9c (340 mg, 0.99 mmol, 49.4%) as a colorless oil. Rf
(cyclohexane/ethyl acetate 7:3): 0.40. 1H NMR (300 MHz,
[D6]DMSO): δ = 1.58 [m, 12 H, (NHO)THP, (=NO)THP], 3.49 [m,
2 H, (NHO)THP, (=NO)THP], 3.70 [m, 1 H, (NHO)THP], 3.81
[m, 1 H, (=NO)THP], 4.80 {m, 1 H, O-CH-O [(NHO)THP]}, 5.16
{m, 1 H, O-CH-O [(=NO)THP]}, 7.21 (d, 2 H, Ar-H), 7.46 (d, 2
H, Ar-H, ds = 3.7 Hz), 8.87 (s, J = NH, ds = 4.2 Hz, 1 H) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 18.7–19.2 (2 C, 2ϫTHP-C-
4), 20.8 (p-CH3), 24.6–24.9 (2 C, 2ϫTHP-C-5), 27.9–28.7 (2 C,
2 ϫ THP-C-3), 61.4–61.8 (2 C, 2 ϫ THP-C-6), 99.9–100.1 [1 C,
(=NO)THP-C-2], 101.5–101.8 [1 C, (NHO)THP-C-2], 127.6 (Ar-
C-1, ds = 5.5 Hz), 128.0 (Ar-C-2, ds = 4.7 Hz), 128.5 (Ar-C-3, ds
= 0.7 Hz), 139.1 (Ar-C-4, ds = 4.1 Hz), 155.6 [Cq(NN), ds =
0.8 Hz], ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 149.7 (NH,
1JN,H = 84 Hz, ds = 39 Hz), 312.1 (=NOTHP, ds = 21 Hz) ppm.
For each value the mean of the chemical shift and diastereomeric
shift (ds) – if present – of both isomers are given.
NH) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ
=
75.5
(=NOCH2-), 77.2 (NHOCH2-), 123.1 (Ar-C-3), 127.7–129.0 (Bn-
Ar-C), 129.2 (Ar-C-2), 137.1 (Ar-C-1), 147.8 (Ar-C-4), 153.8
[Cq(NN)] ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 157.2 (1JN,H
= 87 Hz, NH), 317.0 (=NOBn), 370.1 (p-NO2) ppm.
General Synthesis of para-Substituted O,OЈ-Bis(tetrahydropyran-2-
yl)-N,NЈ-dihydroxybenzamidines 9a–g: Tetrahydropyranylhydroxyl-
amine (2 equiv.) was added to a solution of the starting compound
3 (one out of 3a–g) in dichloromethane. The reaction mixture was
stirred at room temperature and monitored by TLC (cyclohexane/
ethyl acetate 7:3, with 2% aqueous FeCl3 solution and heat indicat-
ing 9a–g as blue spots). Occasionally further treatment was neces-
sary to ensure full consumption of 3a–g. After 24 h further tetra-
hydropyranylhydroxylamine (2 equiv.) was added if 3a–g was still
detectable. The procedure was repeated after 48 h. Usually the reac-
tion was complete after 48–72 h and precipitated byproduct was
filtered off. The filtrate was concentrated under reduced pressure
at 30 °C or below and transferred to silica for flash chromatog-
raphy with cyclohexane/ethyl acetate gradient as mobile phase and
silica as solid phase to give 9a–e as pure products. Additional
workup was required for 9f and 9g and led to pure compounds.
O,OЈ-Bis(tetrahydropyran-2-yl)-N,NЈ-dihydroxybenzamidine (9d):
Compound 3d (171 mg, 1.1 mmol) was dissolved in dichlorometh-
ane (10 mL). Flash chromatography after 120 h gave pure product
9d (209 mg, 0.65 mmol, 59.4%) as a colorless oil. Rf (cyclohexane/
ethyl acetate 7:3): 0.44. 1H NMR (300 MHz, [D6]DMSO): δ = 1.56
[m, 12 H, (NHO)THP, (=NO)THP], 3.47 [m, 2 H, (NHO)THP,
(=NO)THP], 3.68 [m, 1 H, (NHO)THP], 3.82 [m, 1 H, (=NO)-
THP], 4.80 {m, 1 H, O-CH-O [(NHO)THP]}, 5.15 {m, 1 H, O-
CH-O [(=NO)THP]}, 7.43 (m, 3 H, Ar-H), 7.55 (m, 2 H), 8.99 (s,
1 H, NH, ds = 5.3 Hz) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 18.6–19.2 (2 C, 2 ϫ THP-C-4), 24.6–24.9 (2 C, 2 ϫ THP-C-5),
27.9–28.7 (2 C, 2 ϫ THP-C-3), 61.5–61.8 (2 C, 2 ϫ THP-C-6),
100.0–100.1 [1 C, (=NO)THP-C-2], 101.6–101.9 [1 C, (NHO)THP-
C-2], 127.9 (Ar-C-3, ds = 0.7 Hz), 128.1 (Ar-C-2, ds = 4.4 Hz),
129.5 (Ar-C-4, ds = 3.3 Hz), 130.5 (Ar-C-1, ds = 4.2 Hz), 155.7
[Cq(NN), ds = 4.2 Hz] ppm. 15N NMR (30 MHz, [D6]DMSO): δ =
150.6 (1JN,H = 86 Hz, ds = 33 Hz, NH), 312.2 (=NOTHP, ds =
23 Hz) ppm. For each value the mean of the chemical shift and
diastereomeric shift (ds) – if present – of both isomers are given.
p-Hydroxy-O,OЈ-bis(tetrahydropyran-2-yl)-N,NЈ-dihydroxybenz-
amidine (9a): Compound 3a (189 mg, 1.1 mmol) was dissolved in a
mixture of diethyl ether and dichloromethane (1:1, 10 mL). Flash
chromatography after 96 h gave pure product 9a (334 mg,
0.99 mmol, 90.4%) as a light yellow oil. Rf (cyclohexane/ethyl acet-
1
ate 1:1): 0.41. H NMR (300 MHz, [D6]DMSO): δ = 1.56 [m, 12
H, (NHO)THP, (=NO)THP], 3.42 [m, 2 H, (NHO)THP, (=NO)
THP], 3.74 [m, 1 H, (NHO)THP], 4.56 [m, 1 H, (=NO)THP], 4.76
{m, 1 H, O-CH-O [(NHO)THP]}, 5.10 {m, 1 H, O-CH-O [(=NO)-
THP]}, 6.77 (d, 2 H, Ar-H), 7.37 (d, J = Ar-H, ds = 3.4 Hz, 2 H),
8.78 (s, J = NH, ds = 3.3 Hz, 1 H) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 18.8–19.5 (2 C, 2 ϫ THP-C-4), 24.1–25.0 (2 C,
2 ϫ THP-C-5), 28.0–28.7 (2 C, 2 ϫ THP-C-3), 61.4–61.9 (2 C,
2ϫTHP-C-6), 99.7–99.9 [1 C, (=NO)THP-C-2], 101.4–101.7 [1 C,
(NHO)THP-C-2], 114.7 (Ar-C-3, ds = 0.7 Hz), 120.9 (Ar-C-1, ds
= 4.3 Hz), 129.5 (Ar-C-2, ds = 4.7 Hz), 155.6 [Cq(NN), ds =
0.7 Hz], 158.7 (Ar-C-4, ds = 2.8 Hz) ppm. 15N NMR (30 MHz,
[D6]DMSO): δ = 149.4 (1JN,H = 85 Hz, ds = 36 Hz, NH), 310.5
(=NOTHP, ds = 19 Hz) ppm. For each value the mean of the chem-
ical shift and diastereomeric shift (ds) – if present – of both isomers
are given.
p-Bromo-O,OЈ-bis(tetrahydropyran-2-yl)-N,NЈ-dihydroxybenzamid-
ine (9e): Compound 3e (258 mg, 1.1 mmol) was dissolved in di-
chloromethane (10 mL). Flash chromatography after 120 h gave
pure product 9e (245 mg, 0.61 mmol, 55.8%) as a colorless oil. Rf
(cyclohexane/ethyl acetate 7:3): 0.52. 1H NMR (300 MHz,
p-Methoxy-O,OЈ-ditetrahydropyran-2-yl-N,NЈ-dihydroxybenzamid-
ine (9b): Compound 3b (557 mg, 3 mmol) was dissolved in dichlo-
Eur. J. Org. Chem. 2014, 1961–1975
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1973

L. Schwarz, U. Girreser, B. Clement
[D6]DMSO): δ = 1.57 [m, 12 H, (NHO)THP, (=NO)THP], 3.46 [m, Excessively long reaction times resulted in complete decomposition
FULL PAPER
2 H, (NHO)THP, (=NO)THP], 3.63 [m, 1 H, (NHO)THP], 3.79
[m, 1 H, (=NO)THP], 4.79 {m, 1 H, O-CH-O [(NHO)THP]}, 5.14
{m, 1 H, O-CH-O [(=NO)THP]}, 7.49 (d, 2 H, Ar-H, ds = 3.0 Hz),
of 10–12, which could be related to the observation of the loss of
red color. After 10 h the reaction mixture was evaporated under
reduced pressure at room temperature. For 11 and 12 high vacuum
7.62 (d, 2 H, Ar-H), 9.05 (s, 1 H, NH, ds = 5.2 Hz) ppm. 13C NMR and long evaporation times were required. The crude product was
(75 MHz, [D6]DMSO): δ = 18.7–19.1 (2 C, 2ϫTHP-C-4), 24.6–
24.8 (2 C, 2ϫTHP-C-5), 27.9–28.6 (2 C, 2ϫTHP-C-3), 61.4–61.9
(2 C, 2ϫ THP-C-6), 100.0–100.2 [1 C, (=NO)THP-C-2], 101.7–
102.0 [1 C, (NHO)THP-C-2], 123.0 (Ar-C-4, ds = 3.2 Hz), 129.8
(Ar-C-1, ds = 6.1 Hz), 130.2 (Ar-C-2, ds = 4.8 Hz), 131.0 (Ar-C-3,
ds = 0.6 Hz), 154.7 [Cq(NN), ds = 2.3 Hz], ppm. 15N NMR
(30 MHz, [D6]DMSO): δ = 150.6 (1JN,H = 85 Hz, ds = 35 Hz, NH),
312.7 (=NOTHP, ds = 25 Hz) ppm. For each value the mean of the
chemical shift and diastereomeric shift (ds) – if present – of both
isomers are given.
transferred to silica for flash chromatography with cyclohexane/
ethyl acetate gradient as mobile phase and silica solid phase, which
led to pure products 10–12 without further purification.
4-Hydroxy-5,5-dimethyl-3-phenyl-4,5-dihydro-1,2,4-oxadiazole (10):
Synthesized 4d (760 mg, 5 mmol) was dissolved in acetone (5 mL)
with stirring. Flash chromatography after 10 h gave pure product
10 (246 mg, 1.28 mmol, 25.6%) as a white solid, m.p. 130.1 °C;
m.p.[13] 120–122 °C. Rf (cyclohexane/ethyl acetate 7:3): 0.38. 1H
NMR (300 MHz, [D6]DMSO): δ = 1.45 (s, 6 H, 2ϫCH3), 7.48 (m,
3 H, Ar-H), 7.79 (m, 2 H, Ar-H), 9.36 [s, 1 H, (NRO)H] ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 22.2 (CH3), 101.0 (C-5), 126.4
(Ar-C-1), 127.1 (Ar-C-2), 128.6 (Ar-C-3), 130.4 (Ar-C-4), 158.8 (C-
3) ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 161.4 (-NROH),
324.0 (=NOR) ppm.
p-Cyano-O,OЈ-bis(tetrahydropyran-2-yl)-N,NЈ-dihydroxybenzamid-
ine (9f): Compound 3f (542 mg, 3 mmol) was dissolved in dichloro-
methane (15 mL). Flash chromatography after 7 d gave pure prod-
uct 9f (614 mg, 1.78 mmol, 59.3%) as a white solid, m.p. 124.6 °C.
Rf (cyclohexane/ethyl acetate 7:3): 0.45. 1H NMR (300 MHz, [D6]-
DMSO): δ = 1.58 [m, 12 H, (NHO)THP, (=NO)THP], 3.45 [m, 2
H, (NHO)THP, (=NO)THP], 3.59 [m, 1 H, (NHO)THP], 3.79 [m,
1 H, (=NO)THP], 4.82 {m, 1 H, O-CH-O [(NHO)THP]}, 5.16 {m,
1 H, O-CH-O [(=NO)THP]}, 7.73 (d, 2 H, Ar-H, ds = 2.0 Hz),
7.88 (d, 2 H, Ar-H), 9.20 (s, 1 H, NH, ds = 6.6 Hz) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 18.7–19.0 (2 C, 2ϫTHP-C-4), 24.5–
24.8 (2 C, 2ϫTHP-C-5), 27.9–28.5 (2 C, 2ϫTHP-C-3), 61.3–62.0
(2 C, 2ϫ THP-C-6), 100.2–100.3 [1 C, (=NO)THP-C-2], 101.9–
102.4 [1 C, (NHO)THP-C-2], 112.0 (Ar-C-4, ds = 2.2 Hz), 118.4
(p-CN),129.0 (Ar-C-2, ds = 4.1 Hz), 131.9 (Ar-C-3, ds = 0.4 Hz),
4-Hydroxy-3-phenyl-1,2,4-oxadiazaspiro[4.4]non-2-ene (11): Synthe-
sized 4d (304 mg, 2 mmol) was dissolved in cyclopentanone (5 mL)
with stirring. Flash chromatography after 10 h gave pure product
11 (105 mg, 0.48 mmol, 24.1%) as a white solid, m.p. 132.8 °C. Rf
(cyclohexane/ethyl acetate 7:3): 0.36. 1H NMR (300 MHz, [D6]-
DMSO): δ = 1.77 (m, 6 H, 3ϫ-CH2-), 2.13 (m, 2 H, -CH2-), 7.48
(m, 3 H, Ar-H), 7.80 (m, 2 H, Ar-H), 9.50 [s, 1 H, (NRO)H] ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 23.2 (C-5, C-8), 32.8 (C-6,
C-7), 111.1 (C-9), 126.3 (Ar-C-1), 127.1 (Ar-C-2), 128.6 (Ar-C-3),
130.5 (Ar-C-4), 159.4 (C-3) ppm. 15N NMR (30 MHz, [D6]-
DMSO): δ = 158.3 (-NROH), 328.6 (=NOR) ppm.
135.2 (Ar-C-1, ds = 5.9 Hz), 154.4 [Cq(NN), ds = 3.3 Hz] ppm. 15
N
NMR (30 MHz, [D6]DMSO): δ = 151.3 (1JN,H = 87 Hz, ds =
25 Hz, NH) ppm. For each value the mean of the chemical shift
and diastereomeric shift (ds) – if present – of both isomers are
given.
4-Hydroxy-3-phenyl-1,2,4-oxadiazaspiro[4.5]dec-2-ene (12): Synthe-
sized 4d (152 mg, 1 mmol) was dissolved in cyclohexanone (3 mL)
with stirring. Flash chromatography after 10 h gave pure product
12 (101 mg, 0.43 mmol, 43.3%) as a white solid, m.p. 71.9 °C. Rf
(cyclohexane/ethyl acetate 7:3): 0.35. 1H NMR (300 MHz, [D6]-
DMSO): δ = 1.67 (m, 10 H, 5ϫ-CH2-), 7.46 (m, 3 H, Ar-H), 7.82
(m, 2 H, Ar-H), 9.29 [s, 1 H, (NRO)H] ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 23.0 (C-5, C-9), 24.6 (C-7), 31.3 (C-6, C-8), 101.7
(C-10), 126.8 (Ar-C-1), 127.2 (Ar-C-2), 128.7 (Ar-C-3), 130.5 (Ar-
C-4), 158.9 (C-3) ppm. 15N NMR (30 MHz, [D6]DMSO): δ = 159.0
(-NROH), 326.7 (=NOR) ppm.
p-Nitro-O,OЈ-bis(tetrahydropyran-2-yl)-N,NЈ-dihydroxybenzamidine
(9g): Compound 3g (602 mg, 3 mmol) was dissolved in dichloro-
methane (15 mL). Flash chromatography after 120 h gave pure
product 9g (578 mg, 1.58 mmol, 52.8%) as a pale yellow solid, m.p.
119.7 °C. Rf (cyclohexane/ethyl acetate 7:3): 0.42. 1H NMR
(300 MHz, [D6]DMSO): δ = 1.58 [m, 12 H, (NHO)THP, (=NO)-
THP], 3.46 [m, 2 H, (NHO)THP, (=NO)THP], 3.60 [m, 1 H,
(NHO)THP], 3.80 [m, 1 H, (=NO)THP], 4.84 {m, 1 H, O-CH-O
[(NHO)THP]}, 5.18 {m, 1 H, O-CH-O [(=NO)THP]}, 7.82 (d, 2
H, Ar-H, ds = 2.8 Hz), 8.27 (d, 2 H, Ar-H), 9.25 (s, 1 H, NH, ds
= 5.5 Hz) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 18.7–18.9 (2
C, 2 ϫTHP-C-4), 24.5–24.8 (2 C, 2ϫTHP-C-5), 27.9–28.5 (2 C,
2ϫTHP-C-3), 61.5–62.0 (2 C, 2ϫTHP-C-6), 100.3 [1 C, (=NO)-
THP-C-2], 102.0–102.3 [1 C, (NHO)THP-C-2], 123.1 (Ar-C-
3),129.5 (Ar-C-2, ds = 3.0 Hz), 137.0 (Ar-C-1, ds = 8.4 Hz), 147.9
(Ar-C-4, ds = 1.9 Hz), 154.1 [Cq(NN)], ppm. 15N NMR (30 MHz,
[D6]DMSO): δ = 151.2 (1JN,H = 85 Hz, ds = 33 Hz, NH), 315.8
(=NOTHP, ds = 34 Hz), 369.9 (p-NO2) ppm. For each value the
mean of the chemical shift and diastereomeric shift (ds) – if pres-
ent – of both isomers are given.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H NMR and 13C NMR spectra, elemental
analysis, ESI mass spectra values and IR absorption bands are
given.
[1] L. Peterlin-Masic, J. Cesar, A. Zega, Curr. Pharm. Des. 2006,
12, 73–91.
[2] A. Albert, R. Goldacre, J. Phillips, J. Chem. Soc. 1948, 2240–
2249.
[3] B. Clement, Drug Metab. Rev. 2002, 34, 565–579.
[4] A. Havemeyer, F. Bittner, S. Wollers, R. Mendel, T. Kunze, B.
Clement, J. Biol. Chem. 2006, 281, 34796–34802.
[5] D. Froriep, B. Clement, F. Bittner, R. R. Mendel, D.
Reichmann, W. Schmalix, A. Havemeyer, Xenobiotica 2013, 43,
780–784.
[6] S. Deswarte, A. Pezzoli, J. Armand, C. R. Seances Acad. Sci,
Ser. C 1970, 25, 2062–2065.
[7] B. Clement, C. Reeh, WO 2008009264A1 I, 2007.
[8] C. Reeh, J. Wundt, B. Clement, J. Med. Chem. 2007, 50, 6730–
6734.
General Synthesis of 5,5-Dialkyl-4-hydroxy-3-phenyl-4,5-dihydro-
1,2,4-oxadiazoles 10–12: Compound 4d was dissolved in the appro-
priate ketone (5 mL), and the solution was stirred at room tempera-
ture for about 10 h. During the reaction the color of the mixture
turned red, indicating the progress of the reaction. Additionally,
the reaction was monitored by TLC (cyclohexane/ethyl acetate 7:3,
with 2% aqueous FeCl3 solution indicating 10–12 as red spots).
[9] a) G. Klebe, Wirkstoffdesign. Entwurf und Wirkung von Arznei-
stoffen, Spektrum Akademie Verlag, Heidelberg, Germany,
1974
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1961–1975

para-Substituted N,NЈ-Dihydroxybenzamidines as Model Prodrugs
2009; b) N. B. Chapman, J. Shorter (Eds.), Correlation analysis [19] J. Barassin, J. Armand, H. Lumbroso, Bull. Soc. Chim. Fr.
in chemistry: recent advances, Plenum Press, New York, 1978.
[10] M. Smith, J. March, March’s advanced organic chemistry. Reac-
tions, mechanisms, and structure, Wiley-Interscience, Hoboken,
N.J., 2007.
[11] U. Girreser, M. König, B. Clement, Magn. Reson. Chem. 2002,
40, 202–206.
1969, 3409–3418.
[20] a) B. Clement, Habilitationsschrift, Albert Ludwigs University,
Freiburg, Germany, 1986; b) S.-Q. Xu, J.-M. Li, Acta Crys-
tallogr. Sect. E: Struct. Rep. Online 2008, 64, o1469.
[21] A. R. Katritzky, L. Huang, M. Chahar, R. Sakhuja, C. D. Hall,
Chem Rev. 2012, 112, 1633–1649.
[12] H. Ley, Ber. Dtsch. Chem. Ges. 1898, 2126–2129.
[22] E. Treuer, U. Girreser, B. Clement, unpublished data, 2013.
[13] J. Armand, R. M. Minvielle, Compt. Rend. 1965, 260, 2512– [23] R. T. C. Brownlee, M. Sadek, Magn. Reson. Chem. 1986, 24,
2515.
821–826.
[14] S. Morrocchi, A. Ricca, Chim. Ind. 1967, 49, 629–630.
[15] H. G. O. Becker, Organikum, Wiley-VCH, Weinheim, Germany,
2001.
[16] K.-C. Liu, B. R. Shelton, R. K. Howe, J. Org. Chem. 1980, 45,
3916–3918.
[17] H. Ley, M. Ulrich, Ber. Dtsch. Chem. Ges. 1914, 2938–2944.
[18] a) H. Wieland, H. Bauer, Ber. Dtsch. Chem. Ges. 1906, 1480–
1488; b) F. Valentini, P. Gouzerh, Compt. Rend. Acad. Sci. II
C 1972, 275, 123–126.
[24] P. S. Pregosin, E. W. Randall, A. I. White, J. Chem. Soc. Perkin
Trans. 2 1972, 513–514.
[25] T. Ismail, S. Shafi, P. P. Singh, N. A. Qazi, S. D. Sawant, I. Ali,
I. A. Khan, H. M. S. Kumar, G. N. Qazi, M. S. Alam, Indian
J. Chem. Sect. B: Org. Chem. Incl. Med. Chem. B 2008, 47,
740–747.
[26] H. G. Aurich, K. Stork, Chem. Ber. 1975, 108, 2764–2780.
Received: October 29, 2013
Published Online: January 27, 2014
Eur. J. Org. Chem. 2014, 1961–1975
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1975