Iron Trichloride and Air Mediated Guanylation of Acylthioureas. An Ecological Route to Acylguanidines: Scope and Mechanistic Insights

Article abstract of DOI:10.1021/acs.joc.6b00600

Recently we introduced iron trichloride as an environmentally benign and cost-efficient reagent for the synthesis of N-benzoylguanidines. This highly attractive synthetic approach grants access to a broad spectrum of N-benzoylguanidines under mild conditi

Full text of DOI:10.1021/acs.joc.6b00600

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Article
An Iron Trichloride and Air Mediated Guanylation of Acylthioureas: An
Ecological Route to Acylguanidines - Scope and Mechanistic Insights
Simon Pape, Pablo Wessig, and Heiko Brunner
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00600 • Publication Date (Web): 15 May 2016
Downloaded from http://pubs.acs.org on May 16, 2016
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An Iron Trichloride and Air Mediated Guanylation of Acylthioureas:
An Ecological Route to Acylguanidines – Scope and Mechanistic In-
sights
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Simon Papea, Pablo Wessigb and Heiko Brunnera*
a Atotech Deutschland GmbH, Erasmusstrasse 20, D-10553 Berlin, Germany, e-Mail: Heiko.Brunner@atotech.com
b Universität Potsdam, Institut für Chemie, Karl-Liebknecht-Straße 24-25, Haus 25, D-14476 Potsdam, Germany
ABSTRACT: Recently we introduced iron trichloride as an environmentally benign and cost efficient reagent for the syn-
thesis of N-benzoylguanidines. This highly attractive synthetic approach grants access to a broad spectrum of N-
benzoylguanidines under mild conditions in short reaction times. In this work we present an extended scope of our
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methodology alongside with the results obtained from mechanistic studies via in situ IR-spectroscopy in combination
with LC(liquid chromatography)-MS analyses. Based on these new mechanistic insights we were able to optimize the
synthetic protocol and to develop an alternative mechanistic proposal. In this context the symbiotic roles of iron trichlo-
ride and oxygen in the guanylation process are enlightened.
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Introduction
Owing to their high versatility, via the structural modifiability, guanidines represent an important substance class in
many different fields of chemistry, biology and pharmacology. As an integral part of the amino acid arginine and the nu-
cleobase guanine, the guanidine moiety is present in many proteins and in the base pairs of DNA.1 Thus, many natural
products and biologically active molecules are based on guanidines as structural motifs.2,3 The high biological and/or
pharmaceutical activity of the guanidine moiety is based on its ability to form hydrogen bonds and strong non-covalent
interactions with anions such as carboxylates, phosphates, sulfates and nitrates.2 Additionally, guanidine entities, located
in a protein side-chain, are able to build up cation-π-interactions with adjacent aromatic systems, influencing protein
structures.4
For a long time, in organic synthesis, guanidine derivatives were mostly appreciated for their exceptionally high basicity
resulting from the resonance stabilization of their conjugate acids.5,6 It was not until the early 1980’s when the synthetic
value of guanidine organic superbases was recognized by B. A. Barton et al. They described the synthesis of a number of
sterically-hindered pentaalkylguanidines and their application in organic transformations.7
Guanidines are increasingly applied in the growing field of organocatalysis. Due to the high structural diversity of the
guanindine moiety, it can act as nucleophile or Brønsted base and it can devolve chiral information to the substrate via
hydrogen bonding or ionic non-covalent interactions. Application of guanidine derivatives in organic synthesis is enlight-
ened by a number of excellent reviews.8
Beyond the areas described above, there are several more applications for guanidines. They can be used as ligands,9 in
ionic liquids,10 in fluorescent probes,11 surfactants,12 peptide mimetics13 or membrane materials.14
In some cases the high basicity can be disadvantageous, for example when the respective guanidine is used as a ligand for
metal ions in an aqueous medium. Due to the high basicity, the protonated guanidine will be formed almost exclusively,
significantly decreasing the Lewis-basicity and the ability to coordinate electron acceptors. Hence, acylguanidines repre-
sent an important group of guanidines with significantly altered properties. Introducing electron-withdrawing acyl sub-
stituents to a guanidine moiety significantly reduces its basicity to pKa values of about 7-8.2 N-acyl substituted guanidines
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The Journal of Organic Chemistry
can act as ligands for different metal cations. The resulting complexes exhibit interesting properties, making them useful
tools in pharmacology15 or in organic synthesis as catalysts for hydroformylations.16 In drug design, acyl substituents are
introduced to guanidine moieties to lower the basicity and, thus, enhance the oral bioavailability and CNS penetration.17
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Figure 1 Acylguanidine based drugs Amilorid 1 and Guanfacine (Intuniv) 2
Figure 1 shows the commercially available acylguanidine-based drugs Amiloride 1, a diuretic used for treatment of
hypertension and Guanfacine (Intuniv) 2 which is applied for therapy of attention deficit hyperactivity disorder
(ADHD). N-Acylguanidines are present in many different drug classes such as β-secretase inhibitors for treatment of Alz-
heimer’s disease,18 anti-inflammatories,17 antiarrhythmics,19 analgetics20 or antithrombotics.21
We recently published our results towards the synthesis of Aroylguanidines using iron(III)chloride as a green, highly
reactive, and cost-efficient reagent for the conversion of thioureas.22
1,23
Among a broad variety of synthetic approaches
towards the synthesis of acylguanidines, conversions starting from
thioureas are frequently used. Thioureas are easily accessible and convenient to handle due to their high stability. One
possible way to convert the thiourea into a reactive intermediate is desulfurization using condensing agents like 1-methyl-
2-chloropyridiniumiodide (‘Mukaiyama’s reagent‘)24 or ethyl-3-aminopropylcarbodiimide hydrochloride (EDCl)25 Other
approaches to remove sulfur are based on the use of toxic metal salts such as mercury(II)chloride.26,27 The toxicity pre-
cludes the use of those metal salts for pharmaceutical or food applications. Non-toxic alternatives such as bis-
muth(III)nitrate28 have also been described. Yet we were able to show that our approach using non-toxic and low-priced
FeCl3 grants access to N-benzoylguanidines in comparable or superior yields under mild reaction conditions using easily
accessible and stable starting materials.22
The aim of this publication is to enlighten the role of iron(III)chloride in the desulfurization of thioureas using in-situ IR-
Spectroscopy and other analytical methods. The scope of the reaction as well as optimization of the synthetic protocol is
discussed.
Results and Discussion
Our studies towards the conversion of N-aroylthioureas 3a-u to the corresponding guanidines revealed that
iron(III)chloride is a highly efficient reagent for this purpose.
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Table 1 Conversion of N-benzoylthioureas with aryl- and alkylamines using iron(III)chloride
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2
3
4
5
6
7
8
9
entry
1
thiourea
3a
R
R’
product
5a
yield
76
41
10
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12
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14
15
16
17
18
19
20
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4-MeO-Ph
4-NO2-Ph
4-F-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeOOC-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
H
2
3b
3c
5b
5c
3
64
59
76
71
4
3d
3e
4-Cl-Ph
5d
5e
5
2-Cl-Ph
6
3f
4-Br-Ph
5f
7
3g
4-I-Ph
5g
5h
5h
5i
68
60
44
60
-
8
3h
3a
4-MeOOC-Ph
4-MeO-Ph
4-CN-Ph
2-CN-Ph
3-Pyridyl
2-Pyridyl
4-Me-Ph
2-Me-Ph
2,6-Me-Ph
3,5-Me-Ph
Ph
9
10
11
3i
3j
5j
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13
14
15
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17
18
19
20
21
3k
3l
5k
5l
50
-
3m
3n
3o
3p
3q
3r
5m
5n
5o
5p
5q
5r
50
45
50
56
66
71
tert-butyl
4-MeO-Ph
4-MeO-Ph
3s
5s
41a
67
3t
n-butyl
5t
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22
3u
4-MeO-Ph
cyclohexyl
5u
67
1
2
3
4
5
6
a (TMS)2NH used as NH3 surrogate
As indicated by the results compiled in Table 1 abroad variety of differently substituted N-benzoylthioureas 3a-u can be
converted to the corresponding N-benzoylguanidines 5a-u by adding an amine 4 in the presence iron(III)chloride. In
most cases, the products were obtained in moderate to good yields. Contemplation of N-benzoyl-N‘-arylthioureas reveals
that electron withdrawing groups such as 4-nitro or 4-methyl ester (Entries 2 and 8) exert a decreasing effect on the yield.
Also less nucleophilic anilines with electron-withdrawing substituents such as 4-COOMe can be applied obtaining a rea-
sonable yield for 5h. However, the yield is significantly lower in comparison to the conversion utilizing an electron-rich
aniline (Entries 8 and 9).
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The somewhat higher yield in case of the 3,5-dimethyl-substituted thiourea 5p compared to the 2,6-dimethyl analogue 5o
indicates that also steric effects might have an impact (Entries 16 and 17). In addition to the N-benzoyl-N’,N‘‘-
diarylguanidines, N-benzoyl-N’-alkyl-N‘‘-arylguanidines were also synthesized. The alkyl moiety can be introduced via the
thiourea or by utilizing an aliphatic amine 4. In both cases the corresponding guanidines 5r, 5t and 5u were obtained in
good yields (Entries 19, 21 and 22). By use of hexamethyldisilazane as ammonia surrogate, a disubstituted N-benzoyl-N’-
arylguanidine 5s could also be generated (Entry 20). An interesting observation was made comparing thioureas 3i and 3j,
which have 4-CN and 2-CN aryl substituents, respectively. The thiourea bearing a 4-CN-moiety was successfully convert-
ed, yielding the guanidine 5i at 60%. In contrast to that, the target compound 5j could not be isolated upon conversion of
the 2-CN analogue with p-anisidine 6. Instead the amide 7 was isolated in 44% yield. Interestingly, comparable reaction
products were synthesized by C. Bolm et al. via FeCl3 catalyzed N-arylation of amides using aryliodides.29 However, it
appears implausible to reason that the occurrence of amide 7 is by the reaction path of iron catalyzed N-arylation. It is
rather likely that the formation of 7 is closely connected with the Lewis acidity of iron(III)chloride. A plausible mecha-
nism for the formation of 7 is depicted in Scheme 1.
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Scheme 1 Rational for the formation of N-arylamide 7 as competing reaction with guanylation
Thus, the ability of the nitrile group to act as a Lewis base makes it an additional coordination site for the iron species.
Apparently this changes the reactivity at the carbon atom of the thiocarbonyl moiety to the disadvantage of the guanyla-
tion.
Also in the case of the 2-pyridyl thiourea the desired product 5l could not be isolated although the TLC indicated con-
sumption of the starting material. If on the other hand the 3-pyridyl thiourea is deployed, the guanidine 5k was isolated in
50% yield.
According to this we assume that the formation of stable iron complexes 8 and 9 is a reasonable explanation in this par-
ticular case. Both, the thiourea as well as the guanidine, bearing a 2-pyridyl moiety are able to form stable six-membered
rings upon complexation of an iron species as it is shown in figure 2.
Figure 2 Formation of stable iron complexes 9 and 10 by the 2-pyridyl derivatives
Similar observations were made by A.Fürstner et al. during their studies concerning titanium catalyzed indole syntheses.30
Due to the complexation of titanium by the carbonyl functionalities, treatment of the crude product with EDTA was nec-
essary to allow further purification and isolation of the product. However, this approach did not contribute to the solu-
tion of the problem in the case of the 2-pyridyl derivatives. These two examples illustrate that limitations of the method
being presented are most likely caused by characteristics of iron(III)chloride in general and its Lewis acidity in particular.
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Besides the evaluation of different aryl and alkyl moieties, also the influence of the acyl group on the formation of guani-
dines was examined. Thioureas bearing an acyl 10 and an N-ethoxycarbonyl moiety 11 were converted with p-anisidine 6
(Scheme 2).
1
2
3
4
5
6
7
8
9
O
O
R:
76%
3a/5a
HN
FeCl3 (1 Eq.)
NEt3 (4 Eq.)
O
O
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S
R
O
N
NH
O
+
10/12
11/13
R
6%
N
N
H2N
MeCN
40°C
H
H
O
6
5a/12/13
3a/10/11
67%
O
Scheme 2 Influence of different acyl moieties on the guanylation
As depicted in Table 1, N-benzoylthiourea 3a yielded the corresponding guanidine 5a at 76%. However, if the benzoyl
moiety is exchanged by an N-acyl group, the target molecule 12 could only be isolated in a disappointing yield of 6%.
Instead, as the main product deacetylated guanidine 14 was obtained in 46% yield (Figure 3).
Figure 3 Deacetylated guanidine 14
Hence, the N-acetyl group proved to be cleaved under the given reaction conditions, which disqualifies it for utilization in
guanylation reactions using iron trichloride. In contrast to that N-ethoxycarbonylthiourea 11 was converted to the corre-
sponding guanidine 13 in a satisfying 67% yield. Even though the yield was somewhat lower in comparison to the N-
benzoyl substituent, this result illustrates the general suitability of N-ethoxycarbonyl groups for the synthesis of guani-
dines according to our protocol. In general the preceding results have demonstrated the broad applicability of our syn-
thetic methodology using iron(III)chloride as guanylating agent.
Despite this fact, some limitations have been identified and discussed in this context. Also the formation of side products
was observed during our initial studies towards iron(III)chloride mediated guanylation.
These facts clarify the necessity to gain a sound understanding of the reaction mechanisms as this is the basic prerequisite
for optimized reaction conditions and reaction sequences. For obtaining detailed insight on the reaction course and op-
timizing the reaction conditions we utilized in situ IR-spectroscopy in combination with LC-MS analysis. The IR-studies
were focused on the identification of reaction intermediates, whereas LC-MS analysis is used to investigate the product
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spectrum dependence on the reaction sequence. In literature it is commonly accepted that the reaction follows a pathway
1
2
via carbodiimide intermediate 15 (Scheme 3).
3
4
5
MXn
S
6
7
R
R'
N
N
MnSm
H
H
8
9
HNEt3
X
10
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R'
NEt3
N
C
N
R
15
R''
H2N
R''
N
R
R'
N
N
H
H
Scheme 3 Proposed reaction mechanism via carbodiimide intermediate
As implied in Scheme 3 an important feature of this mechanistic proposal is the formation of metal sulfides according to
the desulfurization of the thiourea by the metal salt being used.
To further investigate the occurrence of intermediate species such as carbodiimides, a test reaction was deployed and the
reaction course was monitored by IR-spectroscopy.
Hence, 4-bromo thiourea 3f was converted with p-anisidine 6 under variation of conditions and sequence (Scheme 4 and
Table 2).
Table 2 Reaction sequences and conditions of the test reactions with thiourea 3f
test reaction
sequence
carbodimide
1
MeCN, THS 3f, TEA (4 Eq.), 0°C, FeCl3, 40°C, 6
MeCN, THS 3f, TEA (4 Eq.), 6, 40°C, FeCl3
MeCN, FeCl3, THS 3f, 40°C, TEA (4 Eq.), 6
MeCN, THS 3f, 6, TEA (4 Eq.), 0°C, FeCl3, 40°C
DMF, 0°C, HgCl2, THS 3f, TEA (2 Eq.), 6
DMF, FeCl3, THS 3f, 40°C, TEA (4 Eq.), 6
no
no
no
no
yes
no
2
3
4
5
6
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The Journal of Organic Chemistry
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Scheme 4 Test reaction for the identification of reaction intermediates; Synthesis of carbodiimide of thiourea 3f
as reference
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In addition to the reference spectrum of the pure carbodiimide of thiourea31, an additional reference spectrum after the
addition of FeCl3 was recorded also. This was done to evaluate if significant bands will be shifted in the presence of
iron(III)chloride. The comparison of the reference spectra reveals that the distinctive, asymmetric –N=C=N- bond stretch-
ing is attenuated and also slightly shifted from 2158 cm-1 to 2164 cm-1 after addition of FeCl3 (see SI; Scheme I). However,
this band remains suitable for the identification of carbodiimide intermediates since it is still sufficiently visible even in
the presence of iron(III)chloride.
Also, disturbances by the absorption of other species are not to be expected in this spectral region. In case of test reaction
1, the formation of a carbodiimide would be expected after the addition of iron(III)chloride (Table 2, Entry 1). In scheme II
(SI), the IR-spectra directly before addition of iron(III)chloride is compared respectively with the IR-spectra 1 min, 5 min
and 10 min after the addition.
According to that no carbodiimide was formed after FeCl3 was added. The reaction conditions as well as the sequence of
test reaction 1 are equivalent to those applied for the synthesis of the guanidines enlisted in Table 1. In the following test
reactions 2, 3, and 4 the formation of a carbodiimide intermediate was investigated depending on the reaction sequence.
Eventually no such intermediate could be identified during any of these test reactions using iron(III)chloride. For com-
parison another test reaction was conducted with mercury(II)chloride using DMF as solvent (Entry 5). Immediately after
addition of the base, a significant absorption band at 2162 cm-1 was formed (see SI; Scheme III).
The direct comparison with the associated reference band at 2158 cm-1 confirmed the origin in the intermediate liberation
of a carbodiimide. This important finding confirmed the postulated mechanistic pathway via carbodiimide intermediate
for the synthesis of guanidines using HgCl2. However, the absorption band was only observable directly after addition of
the base followed by a rapid regression.
Since there was no amine 6 present at this point of the reaction, the regression cannot be assigned to a reaction of the
carbodiimide and amine 6. Instead the decrease of intensity might be due to an insufficient solubility of the intermediate.
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To exclude the possibility that the occurrence of the carbodiimide was referred to the use of DMF as solvent, an addition-
al test reaction with iron(III)chloride in DMF was carried out (Entry 6). Even under these conditions no carbodiimide
intermediate was observed in the case of iron(III)chloride. These results clearly illustrate that the mechanistic pathway of
the reaction strongly depends on the choice of metal salt.
1
2
3
4
5
6
7
8
9
The formation of a carbodiimide could not be confirmed in any of the cases when iron(III)chloride was used as guanylat-
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ing agent. In contrast to that, an intermediate carbodiimide is formed when mercury(II)chloride is used in the same man-
ner.
According to the in situ IR-experiments discussed so far, the mechanistic pathway of the guanylation is mainly influenced
by two major aspects,
metal salt and
reaction sequence.
Besides the identification of reaction intermediates, the in situ IR-spectroscopy also enabled us to visualize the different
outcomes of reactions depending on the reaction sequence. As stated before, the reaction sequence influences the mech-
anistic path of the reaction. Therefore, it is likely that this can also be expressed by the IR-spectra of the finished reac-
tions. Accordingly, an IR reference spectrum of guanidine 5f was compared with the IR spectra of the finished test reac-
tions 1 and 2 (see SI; Scheme IV).
The left image shows the IR-spectrum at the end of test reaction 1 together with the reference spectrum of guanidine 5f.
On the right image a comparison of the IR-spectrum at the end of test reaction 2 with the reference spectrum is present-
ed. Distinctive absorption bands of guanidine 5f are found at 1514, 1356, 1073, 1032, 1013, 836, 747 and 715 cm-1. It is obvious
to see how the different reaction sequences affect the outcome of the reactions.
Whereas the reaction spectrum of test 1 exhibits a high degree of discrepancy in comparison to the reference, the reaction
spectrum of test 2 matches the reference very well. According to this finding, the sequence applied in test reaction 2 is in
comparison the more appropriate and purposive approach for the formation of guanidine 5f.
Reaction monitoring by in situ IR-measurements can provide valuable information about the progress of the reaction e.g.
by plotting consumption of starting materials and/or formation of product(s). In Scheme V (SI) the formation of guani-
dine 5f is depicted along with the consumption of p-anisidine 6. The formation of the product 5f reached a maximum
after three hours reaction time, whereas the starting material p-ansidine 6 was below detection limit after approximately
1:15 h.
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As we were able to show that the reaction sequence has a major impact on course and outcome of the guanylation, the
next step towards optimized reaction conditions was taken by LC-MS analysis of the crude products from IR-test reac-
tions. Therefore, the crude products of the test reactions 1-4 from Table 2 were characterized regarding their composition.
The chromatograms of LC-MS measurements are shown in Scheme VII (SI). These results are in good agreement with
findings described before. Hence, the extent of side product formation strongly depends on the reaction sequence.
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We were able to identify most of the side products formed in the course of the reaction (Scheme 5).
Scheme 5 Side products formed in FeCl3 mediated guanylation
One of them is the N-arylamide 7, which was described before and whose appearance is probably due to an SN reaction
with direct involvement of iron(III)chloride. The formation of side product 16 has to be assigned to the oxidative degrada-
tion of triethylamine, resulting in the formation of diethylamine via the formation of the corresponding amine radical
cation.32
Scheme 6 Mechanistic rationale for the oxidative degradation of triethylamine under involvement of FeCl3 and
oxygen
Scheme 6 illustrates a mechanistic rationale for the oxidative degradation of triethylamine in the presence of single-
electron oxidant FeCl3 and oxygen. After formation of radical cation 18, abstraction of a proton by oxygen leads to for-
mation of iminium ion 19. Nucleophilic attack of the hydroxide anion and subsequent tautomerization yields acetalde-
hyde 21 and diethylamine 20 which can participate in a side reaction to form guanidine 16.
Besides the target compound 5f also side products 5a and 17 with exchanged phenyl rings were found. The comparison
between test reaction 1 and 2 concerning the extent of side product formation, clearly illustrates the beneficial effect of
the changed reaction sequence. According to that FeCl3 should be added at last after all the starting materials have been
added.
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Furthermore, it seems conducive to conduct the addition at 40°C instead of 0°C. These slight changes had a major impact
on the selectivity in favor of the desired product 5f. In test reaction 2 less exchange products were found. Also the amount
of degradation product 16 was significantly lowered. The formation of N-arylamide 7 was prevented completely in test
reaction 2.
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In test reaction 3 only 2 eq. of triethylamine were used. Apart from that, the reaction sequence was identical with test
reaction 1. Consequently the amount of elimination product 18 was considerably reduced. The influence of the base is
discussed later in this paper.
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Scheme VII (SI), chromatogram 4 shows the composition of the crude product from test reaction 4. This example repre-
sents the most disadvantageous reaction sequence out of the chosen examples. The extent of the side reactions was by far
the highest if iron(III)chloride was furnished first with subsequent addition of the other starting materials. Summarizing
the results of the LC-MS studies, it can be stated that test reaction 2 represents the ideal reaction sequence out of those
being compared. So far we could carve out that the mechanistic pathway in general and the occurrence of a carbodiimide
intermediate in particular is mainly influenced by the metal salt being used. Also the reaction sequence plays an im-
portant role. When iron(III)chloride is used to convert N-benzoyl-N’-arylthiourea 3f the reaction does not proceed via a
carbodiimide intermediate. For the development of an alternative mechanistic proposal the results from IR and LC-MS
studies have to be taken into consideration. One of the key questions is how the formation of the exchange products 5a
and 19 is to be explained.
From these results the existing mechanistic proposal, illustrated in Scheme 3, has to be questioned. The hypothesized
mechanistic pathway via an intermediate carbodiimide could already be delimitated by the results of our in situ IR stud-
ies. The desulfurization of thioureas using mercury and copper salts is based on the formation of the corresponding sul-
fides. In this regard S. Cunha et al. also described the formation of bismuth(III)sulfide Bi2S3 as a byproduct when bis-
muth(III)nitrate is utilized as guanylating agent.33 We have found that the utilization of other thiophiles such as indi-
um(III)chloride also results in the formation of sulfides. This was proven by filtration of the reaction mixture and subse-
quent treatment of the solid residue with dilute hydrochloric acid, resulting in the liberation of hydrogen sulfide.
In case of iron(III)chloride sulfide formation can be ruled out since no hydrogen sulfide was detected when following the
same procedure. This finding is in good agreement with results described by E. Busch and A. Schier who found that hy-
drogen sulfide flowing through a solution of iron(III)chloride in acetonitrile, led to the precipitation of sulfur instead of
iron sulfides.34 It is rather likely that desulfurization using iron(III)chloride is based on a redox process instead of sulfide
formation. Thus the oxidation of hydrogen sulfide by iron(III) can be described by the following redox pair:
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Applied to guanylation, this would imply that the oxidation of the thiourea to zerovalent sulfur (Equation 2) accompanied
by reduction of iron(III) to iron(II) (Equation 1). At this point it becomes apparent that a one-electron reduction is in-
volved in a two-electron oxidation. This leads to the conclusion that another participant has to be involved in the redox
process. Consequently a control experiment was conducted to evaluate if oxygen plays a key role. Thus thiourea 3f and 6
were treated with iron(III)chloride under exclusion of oxygen in an argon atmosphere (Scheme 7).
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After an observable progress in the first 30 min of the reaction, the TLC sample after 3.5 h revealed stagnation of the con-
version. The reaction was aborted after 4 h, which would be sufficient time for conversion under atmospheric conditions.
Purification of the crude product yielded the product 5f in 51% and the thiourea 3f was retrieved in 47%.
Scheme 7 Test reaction for the involvement of oxygen in the guanylation
However if 2 Eq. of iron(III)chloride are applied under argon atmosphere, reaction control by TLC revealed complete
conversion of the thiourea. Despite this fact guanidine 5f could only be isolated in only 40% yield due to promoted side
reactions under these conditions. Also 2 Eq. of aniline 6 had to be applied for complete conversion of 3f in consequence of
the increased amount of FeCl3.
On the one hand these striking results confirm the hypothesis that the guanylation using iron(III)chloride is based on a
redox process. On the other hand it proves the assumption that oxygen is an essential participant in this redox process,
for there is no complete conversion in its absence.
Once iron(III) is reduced completely to iron(II) the oxidation of the thiourea cannot proceed any longer. In this regard
oxygen is required to re-oxidize iron(II) to iron(III) making it an essential reaction partner. This finding was supported by
the fact that we were unable to identify iron(II)species following the literature procedures.35 Thus, it has to be stated that
the presented protocol represents an unprecedented FeCl3/air mediated guanylation-reaction sequence. Contrary to our
previous assumptions22 iron(III)chloride as well as air are equal reagents in the synthetic method on hand.
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It is of note that the conversion of bromo-substituted thiourea 3f in the presence of 0.5 Eq. iron(III)chloride led to the
desired product 5f in 68 % yield which means only an insignificant decrease of 3% yield in comparison to 1 Eq. FeCl3. The-
se highly interesting findings show, that reoxidation of iron(II)-species is obviously influenced by the chemical environ-
ment. The formation of complexes between iron species and the corresponding thiourea as well as the product certainly
has a significant influence. Also the formation iron(III)oxo-species should be taken into consideration. This finding might
pave the road to potential catalytic protocols. Nevertheless, the utilization of sub-stoichiometric amounts of
iron(III)chloride in the presence of air remains challenging and the synthetic success seems to depend on the electronic
nature of the applied thiourea. Thus, in the case of guanidine 5a the yield was decreased by 26% (50% vs. 76% yield) when
0.7 Eq. of iron(III)chloride were used.22
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Taking one step back to the results of LC-MS analysis, we still needed to find an explanation for the formation of side
products. In this regard it would be useful to determine at which point of the guanylation the exchange of aromatic rings
occurs. Thus, a control experiment, using guanidine 5f and aniline 6 was carried out. The aim of this test was to find out if
the formation of exchange products can take place when the targeted guanidine is already formed. Accordingly both
starting compounds were furnished in acetonitrile and then treated with iron(III)chloride and triethylamine (Scheme 8).
Scheme 8 Exchange experiment with guanidine 5f and aniline 6
Since no conversion and hence no formation of exchange products could be observed we reasoned that the formation of
these side products must happen at an earlier stage of the reaction. The formation of the guanidine itself seems to be
irreversible though. Reflecting all results obtained so far we are now able to postulate an alternative reaction mechanism.
For this we need to consider the following key aspects:
•
in situ IR studies: When using FeCl3 the appearance of intermediate carbodiimides depends on the thiourea to be
converted
•
no formation of iron sulfides upon usage of FeCl3
ꢀ
confirmed by earlier results: no sulfide formation when H2S is passed through a solution of FeCl3; formation of
sulfur
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ꢀ
ꢀ
Iron(III) acting as an oxidant
Oxygen is an essential reaction partner, reoxidizing Fe(II) to Fe(III)
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Formation of exchange products not explicable with mechanism via carbodiimide intermediate
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Guanylation is irreversible
Exchange of phenyl rings at an early reaction stage
According to these major conclusions we are able to develop an mechanistic proposal for the formation of guanidines
using iron(III)chloride. The results of our calorimetric studies22 as well as the investigations based on in situ IR techniques
do suggest that N-benzoylthioureas form complexes upon treatment with iron(III)chloride. Scheme VI (SI) shows the IR-
spectrum of thiourea 3f in comparison to its IR-spectrum after addition of iron(III)chloride. The most significant change
associated with iron(III) is the split up of the carbonyl band at 1681 cm-1.The exact structure of these iron-thiourea-
complexes could not be determined in detail so far. Yet an octahedral structure seems to be most likely due to the in-
volvement of iron(III). Scheme 9 illustrates a possible reaction mechanism based on the conversion of N-benzoyl-N’-
arylthiourea 3f with p-anisidine 6. After the addition of the amine, here p-anisidine 6, a tetragonal intermediate is formed.
The postulation of this intermediate state is based on the finding that for the utilization of N-benzoyl-N’-arylthiourea 3f
no carbodiimide was observed in the course of the reaction. Also it provides an adequate explanation for the formation of
the exchange products 5a and 17. It is not known in detail how this exchange reaction proceeds, e.g. if it is a simultaneous
or a step-wise process. A possible simplified mechanistic path is included in scheme 9. Herein, iron(III) is coordinated as
a Lewis acid by the S- and O-donor atoms, facilitating a nucleophilic attack by an amine at the thiocarbonyl carbon atom.
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Recent findings by Ray et al. who have described the formation of iron(III)chelates bound to 3-Methyl-3-phenyl-1-
benzoylthioureas38 are supporting this mechanistic proposal.
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Scheme 9 Mechanistic proposal for the formation of N-Benzoyl-N’,N’’-arylguanidines
The oxidative cleavage of the C-S bond with subsequent liberation of sulfur has to be considered as key step of the
guanylation with iron trichloride. The electrons released are abstracted by iron(III) which is reduced to iron(II). To allow
the complete oxidation of the thiourea, the presence of oxygen is required for the reoxidation of iron(II). In this regard
oxygen functions as an essential co-oxidant. The iron(III)species resulting from the reoxidation step is formally depicted
as [FeOCl] in scheme 9.
As it was shown by LC-MS analysis of the crude products from the test reactions, another side product which was formed
in significant amounts is the degradation product 16 of the base triethylamine. Although the exact way for the formation
of this side product is not understo0d in detail, studies concerning the influence of the base were conducted. Thus, differ-
ent bases were tested on the conversion of different N-benzoyl-N’-arylthioureas with p-anisidine 6 (Scheme 10).
Scheme 10 Test reaction for the evaluation of different bases
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The results of the test reactions using different amine bases are summarized in the following Table 3
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Table 3 Results of test reactions with different bases
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Entry
R
Base (Eq.)
TEA (4)
Yield [%]
1
4-Br
4-Br
4-Br
4-Br
4-Br
4-Br
4-Br
4
71
9
2
TEA (2)
76
-
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3
DBU (4)
HB (4)
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38
82
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68
77
62
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77
TMEDA (2)
HB+TMEDA (2+1)
PS (2)
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KOtBu (2)
TEA (4)
4-I
4-I
PS (2)
4-I
TMEDA (2)
TEA (4)
4-NO2
4-NO2
PS (2)
1,8-Diazabicyclo[5.4.0]undec-7-en (DBU) was tested as an alternative, non-nucleophilic base for the conversion of thiou-
rea 3f with 4-bromo substituent. Despite the non-nucleophilic character of DBU, the formation of side products could not
be reduced effectively in this case (Entry 3).
On the contrary, reaction control by TLC already revealed a number of side products, which is why it the product was not
isolated. Subsequently, N,N-diisopropylethylamine (HB; Hünig’s base) was tested (Entry 4). Due to steric hindrance by its
bulky alkyl substituents, HB is another non-nucleophilic base convenient for our purposes, though. It exhibits a signifi-
cantly lower basicity in comparison to DBU. Since in literature28 the use of 4 eq. triethylamine is also described and in
terms of a better comparability, DBU and HB were also applied in this ratio.
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In the case of HB, the number of side-products was not noticeably diminished. Furthermore, the yield of guanidine 5f was
decreased by 30% in comparison to the use of TEA (Entry 1). When the thiourea 5g with 4-iodo-substituent was converted
using N,N,N‘,N‘-tetramethylethane-1,2-diamine (TMEDA) the occurrence of unwanted side-products was reduced signifi-
cantly. Even though chromatographic purification was simplified due to this fact, the overall yield was still by 6% lower
than that of reactions using triethylamine (Entries 9 and 11). The decrease in yield was even more drastic for the conver-
sion of the thiourea 3f (Entry 5). A combination of HB and TMEDA did also not improve the performance (Entry 6). The
best results by far were obtained upon the use of N,N,N‘,N‘-tetramethylnaphthalene-1,8-diamine (PS; “Proton Sponge”)
22. Conversions conducted with PS yielded the desired products with particular high selectivity and minimized side-
reactions. The obtained yields were consistently higher in comparison to every other base tested. Guanidine 5f bearing a
4-bromo-substituent was obtained in 11% higher yield compared to triethylamine (Entries 1 and 7). In case of guanidine 5g
with 4-iodo-substituent the yield was increased by 9% (Entries 9 and 10). The most remarkable improvement with PS was
achieved for the conversion of thiourea 3b bearing a 4-nitro-group. In case of triethylamine, the corresponding guanidine
5b was obtained in a rather disappointing yield of 41% (Entry 12). In contrast, the yield was improved to 77% by utilization
of PS (Scheme 11).
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Scheme 11 Optimized synthetic protocol for the conversion of 4-Nitrothiourea 3b using FeCl3 and PS
For successful conversion of the tested thioureas two equivalents of “Proton Sponge” 22 were sufficient. Even though the
molecule contains two amino groups it will abstract only one proton. This characteristic is explained with the exception-
ally high stability of the mono-protonated cation resulting from intramolecular hydrogen bonding. Thus, the use of two
equivalents “Proton Sponge” 22 equals two instead of four base-equivalents. Accordingly, an additional test was done for
the conversion of thiourea 3f using only 2 eq. of triethylamine (Table 3, Entry 2). The corresponding guanidine 5f was
obtained in very good yield of 76%.
This result shows that two equivalents of base is adequate for the guanylation of thioureas. Since we could show that
triethylamine is involved in side reactions, this finding is specifically welcome. This is also valid with regard to ecological
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and economical aspects. Besides the different amine bases tested, also oxygen base KOtBu was tested. In this case the
guanidine 5f was isolated in an unsatisfactory yield of 38%.
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In summary the obtained results have clearly illustrated that the choice of the base has a major impact on the outcome of
the reaction. The utilization of “Proton Sponge” 22 led to remarkable improvements since the occurrence of side and
exchange products was reduced to a minimum.
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Thereby, purification and isolation procedures were highly facilitated, yielding the desired guanidines in superior yields.
Despite the superior selectivity and the target-oriented reaction course that were realized with “Proton Sponge” 24, the
higher costs and the poor atom economy justify our continuing search for even more efficient alternatives.
Conclusion and Outlook
The present work summarized the results of our studies towards the guanylation of thioureas using iron(III)chloride. The
scope and the limitations of the synthetic protocol were evaluated and discussed. FeCl3 proved to be a powerful tool for
the synthesis of various N-acylguanidines. Based on an efficient and environmentally bengin process, it grants access to
an important substance class of interest in different fields such as chemistry, pharmacology and biology. Besides the eval-
uation of the synthetic spectrum, this work focused on gaining a fundamental understanding of the reaction mechanism.
In this context we embarked in situ IR-spectroscopy combined with LC-MS analysis. The results enabled us to illustrate,
that the reaction course mainly depends on the metal salt being applied and the reaction sequence as well. For the con-
version of N-benzoyl-N’-arylthiourea 3f we could clarify that upon the utilization of FeCl3 the reaction does not proceed
via carbodiimide intermediate. However this was the opposite case when HgCl2 was used, which is good agreement with
the literature. Within our ongoing studies on this topic we will further examine the influence that the thiourea exhibits
on the reaction course.
The insights gained by LC-MS analyses allowed us to find an optimized reaction sequence with regard to a minimized
formation of side-products. Since conventionally applied nitrogen-bases such as triethylamine or N,N-
diisopropylethylamine 22 are involved in side reactions, the results obtained upon the use of “Proton Sponge” 22 can be
considered as a remarkable improvement. Continuative studies on the impact of different bases are currently being car-
ried out in our group.
With all the results in hand we were able to develop an alternative mechanistic proposal. The formation of exchange
products was taken into account, resulting in the postulation of a tetragonal intermediate which replaced the formerly
postulated carbodiimide. Most strikingly we were able to prove that iron(III)chloride is involved in an redox process, in
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which oxygen participates as an essential co-oxidant. Therefore, FeCl3 plays a distinctive role among all other metal salts
described as guanylating agents so far. In view of this freshly gained knowledge and given the comments of reviewers of
our recent publication, we are now pursuing the aim to realize a guanylating process with catalytic amounts of
iron(III)chloride. Among others, the results of our efforts in this direction will be reported in the due course.
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Experimental Section
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General Methods. All Reagents and solvents, obtained from commercial sources, were used without further purification.
Reaction products were purified by flash-chromatography on silica gel (25 µm) using cyclohexane and ethyl acetate as
eluents. TLC was performed on silica gel plates 60 F254. LC-MS analyses were carried out on a HPLC-system coupled with
a TOF-massspectrometer. HPLC was done using a column with C18-silica gel (2.6 μm) with water/MeCN-gradient.
NMR spectra were measured on a 500 MHz or on a 400 MHz spectrometer using deuterated solvents with trimethylsilane
as internal standard. Chemical shifts δ are given in ppm, coupling constants J in Hz. Multiplicities of NMR-signals are
abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), h (heptet), tt (triplet of triplets), dtd
(doublet of doublet of triplets). IR spectra were recorded with a FT-IR spectrometer using a Germanium-ATR (attenuated
total reflection) unit and are reported in wave numbers (cm-1). Mass-spectra were obtained with a GC TOF (EI) and an
ESI-Q-TOFmicro. Melting points were determined in open glass capillaries. The in situ IR measurements were carried out
in 100 ml Mettler-Toledo EasyMax reactors under atmospheric conditions. Recording of IR spectra was done with a Re-
actIR 15-unit by Mettler-Toledo using a silicon ATR-probe ((DST-6.3-305-1.5-16300) 6.3 mm AgX SiComp).
General Procedure (1) for Synthesis of N-Acylguanidines 5a-u The reactions are done in a 100 ml EasyMax reactor,
equipped with reflux cooler, magnetic stirrer bar and temperature sensor. To a solution of thiourea (5 mmol) in 30 ml
acetonitrile, triethylamine (20 mmol, 2.02 g, 2.77 ml, 4 Eq.) and the particular amine (5 mmol, 1 Eq.) are added with stir-
ring at 300 rpm. The reaction mixture is cooled down to 0°C (reactor temperature (TR)) in 10 minutes. Then
iron(III)chloride (5 mmol, 811 mg, 1 Eq.) is added. After another 10 minutes, the temperature is raised to 40°C (TR) in 30
min. Progress of the reaction is monitored by TLC (CHx-EtOAc). With complete conversion, the reaction mixture is
transferred into a 250 ml round-bottom flask. Activated carbon is added and the mixture is stirred in a water bath at 70°C
for 5 min. The suspension is filtered through a pad of Celite and is washed with dichloromethane. The filtrate is then
concentrated in vacuo and the brownish solution is treated with diethyl ether precipitating triethylamine hydrochloride.
The suspension is filtered through a G4-frit and is washed subsequently with diethyl ether and tetrahydrofurane. The
filtrate is dried in vacuo. Further purification is done by flash chromatography on silica gel with cyclohexane - ethyl ace-
tate gradient.
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Optimized Procedure (2) for Synthesis of N-Acylguanidines 5a-u
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The reactions are done in a 100 ml EasyMax reactor, equipped with reflux cooler, magnetic stirrer bar and temperature
sensor. To a solution of thiourea (5 mmol) in 30 ml acetonitrile, N,N,N‘,N‘-tetramethylnaphthalene-1,8-diamine (10 mmol,
2.143 g, 2 Eq.) and the particular amine (5 mmol, 1 Eq.) are added with stirring at 300 rpm. TR is raised to 40°C within 10
min followed by the addition of iron(III)chloride (5 mmol, 811 mg,1 Eq.). Progress of the reaction is monitored by TLC
(CHx-EtOAc). With complete conversion, the reaction mixture is transferred into a 250 ml round-bottom flask. Activated
carbon is added and the mixture is stirred in a water bath at 70°C for 5 min. The suspension is filtered through a pad of
Celite and is washed with dichloromethane. Further purification is done by flash chromatography on silica gel with cyclo-
hexane - ethyl acetate gradient.
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Test reaction in argon atmosphere
The starting materials were furnished in a 100 ml round-bottom flask in acetonitrile, followed by extensive purging with
argon. After addition of iron(III)chloride at 40°C, argon was continuously passed through the reaction mixture. The pro-
gress of the reaction was monitored by TLC. In advance every TLC sample was filtered quickly through a small pad of
silica to remove iron components that might falsify the results.
(E)-N-(N,N'-Bis(4-methoxyphenyl)carbamimidoyl)-benzamide (5a) is prepared according to the general procedure 1.
Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 4:1) to give the product 5a (1.423 g,
1
3.79 mmol, 76%) as a beige solid. Rf (cyclohexane-ethyl acetate 1:1) = 0.41; FP: 127.4-128.2°C (Lit.: 128°C)36; H NMR CDCl3,
500 MHz,
δ
(ppm) 3.83 (s, 6H), 6.91-6.97 (m, 4H), 7.31-7.36 (m, 4H), 7.37-7.42 (m, 2H), 7.45 (tt, J = 6.6 and 1.4 Hz, 1H),
(ppm) 178.2, 157.8, 138.5, 131.4, 129.4, 128.0, 126.4, 114.7, 55.7; IR (cm-1)
8.13-8.24 (m, 2H); 13C {1H} NMR CDCl3, 125 MHz,
δ
3376, 3342, 3074, 2963, 2808, 1599, 1565, 1508, 1460, 1374, 1351, 1300, 1240, 1204, 1181, 1106, 1034, 1010, 906, 888, 830, 819, 752,
716, 684; HRMS (EI): calculated for C22H21N3O3 [M]+: 375.1583, found: 375.1571.
(E)-N-(N'-(4-Methoxyphenyl)-N-(4-nitrophenyl)carb-amimidoyl)benzamide (5b) is prepared according to the gen-
eral procedure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 7:3 > 6:4 > 1:1) to
give the product 5b (0.81 g, 2.07 mmol, 41%) as yellow needles. Rf (cyclohexane-ethyl acetate 1:1) = 0.71; FP: 168.6-168.9°C;
1H NMR CDCl3, 400 MHz, δ (ppm) 3.85 (s, 3H), 6.94-7.04 (m, 2H), 7.33 (d, J = 8.3 Hz, 2H), 7.46 (t, J = 7.4 Hz, 2H), 7.51-7.73
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(m, 3H), 8.06-8.28 (m, 4H); C {1H} NMR CDCl3, 100 MHz, δ (ppm) 143.5, 132.3, 129.4, 129.1, 128.5, 127.2, 125.2, 125.0, 123.1,
121.6, 119.2, 115.6, 55.7; IR (cm-1) 3456, 3369, 3016, 2970, 1738, 1625, 1607, 1592, 1561, 1538 1508, 1490,1420, 1365, 1350, 1336, 1298,
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1246, 1217, 1199, 1112, 1028, 975, 856, 846, 748, 710, 685; HRMS (EI): calculated for C21H18N4O4 [M]+: 390.1328, found:
390.1324.
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(E)-N-(N-(4-Fluorophenyl)-N'-(4-methoxyphenyl)-carbamimidoyl)benzamide (5c) is prepared according to the
general procedure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 9:1 > 7:3)
to give the product 5c (1.17 g, 3.22 mmol, 64%) as a white solid. Rf (cyclohexane-ethyl acetate 1:1) = 0.55; FP: 137.7-137.9°C; 1H
NMR CDCl3, 400 MHz, δ (ppm) 3.83 (s, 3H), 6.96 (d, J = 8.5 Hz, 2H), 7.08 (t, J = 8.4 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.36-
7.57 (m, 5H), 8.17 (d, J = 7.4 Hz, 2H); 13C {1H} NMR CDCl3, 100 MHz, δ (ppm) 178.3, 160.4 (d, J = 245.4 Hz), 158.6, 157.5,
138.3, 132.9, 131.5, 129.3, 128.4, 128.0, 127.2, 125.8, 115.8 (d, J = 22.8 Hz), 115.1, 55.6; IR (cm-1) 3368, 3072, 2970, 2839, 1737, 1611,
1581, 1566, 1537, 1505, 1445, 1416, 1352, 1292, 1246, 1211, 1198, 1171, 1105, 1030, 979, 908, 886, 829, 797, 74, 713, 685; HRMS (ESI):
calculated for C21H19FN3O2 [M+H]+: 364.1456, found: 364.1463.
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(E)-N-(N-(4-Chlorophenyl)-N'-(4-methoxyphenyl)-carbamimidoyl)benzamide (5d) is prepared according to the
general procedure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 9:1 > 7:3
> 3:2) to give the product 5d (1.11 g, 2.92 mmol, 59%) as a beige solid. Rf (cyclohexane-ethyl acetate 2:1) = 0.35; FP: 128.0-
128.1°C; 1H NMR CDCl3, 400 MHz, δ (ppm) 3.84 (s, 3H), 6.97 (d, J = 8.6 Hz, 2H), 7.27-7.38 (m, 4H), 7.38-7.59 (m, 5H), 8.18
(d, J = 7.5 Hz, 2H); 13C {1H} NMR CDCl3, 100 MHz, δ (ppm) 178.4, 158.8, 157.2, 138.2, 135.8, 131.6, 129.4, 129.1, 128.1, 127.4,
124.6, 115.3, 55.7; IR (cm-1) 3347, 2970, 1737, 1606, 1581, 1560, 1536, 1508, 1492, 1444, 1430, 1407, 1385, 1352, 1287, 1242,1208, 1191,
1170, 1091, 1032, 912, 879, 830, 809, 752, 713; HRMS (ESI): calculated for C21H19ClN3O2[M+H]+: 380.1160, found: 380.1160.
(E)-N-(N-(2-Chlorophenyl)-N'-(4-methoxyphenyl)-carbamimidoyl)benzamide (5e) is prepared according to the
general procedure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 9:1 > 7:2)
to give the product 5e (1.44 g, 3.78 mmol, 76%) as an off-white solid. Rf (cyclohexane-ethyl acetate 1:1) = 0.54; FP: 124.3-
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124.6°C; H NMR CDCl3, 400 MHz, δ (ppm) 3.85 (s, 3H), 7.00(d, J = 8.3 Hz), 7.08 (t, J = 7.8 Hz, 1H), 7.31-7.61 (m, 7H), 8.23
(s, 2H), 8.44 (s, 1H); 13C NMR-DEPT135 CDCl3, 100 MHz, δ (ppm) 131.5, 129.3, 129.1, 128.1, 127.8, 127.3, 125.0, 124.8, 115.3, 55.6;
IR (cm-1) 3367, 3002, 2970, 1738, 1619, 1598, 1578, 1561, 1535, 1508, 1443, 1378, 1355, 1298, 1243, 1201, 1169, 1106, 1057, 1029, 982,
910, 879, 838, 731, 742, 706; HRMS (ESI): calculated for C21H19ClN3O2 [M+H]+: 380.1160, found: 380.1159.
(E)-N-(N-(4-Bromophenyl)-N'-(4-methoxyphenyl)-carbamimidoyl)benzamide (5f) is prepared according to the
general procedure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 9:1 > 7:3
> 3:2) to give the product 5f (1.51 g, 3.56 mmol, 71%) as a beige solid. Rf (cyclohexane-ethyl acetate 1:1) = 0.79; FP: 136.1-
136.2°C; 1H NMR CDCl3, 400 MHz, δ (ppm) 3.83 (s, 3H), 6.96 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.34-7.58 (m, 7H),
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8.18 (d, J= 7.6 Hz, 2H); C {1H} NMR CDCl3, 100 MHz, δ (ppm) 178.4, 158.8, 157.1, 138.2, 136.3, 132.1, 131.6, 129.3, 128.1, 127.4,
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The Journal of Organic Chemistry
124.9, 118.1, 115.3, 55.6; IR (cm-1) 3455, 3347, 3016, 2970, 1738,1603, 1578, 1558, 1536, 1509, 1489, 1430, 1406, 1352, 1285, 1239, 1216,
1207, 1075, 1032, 1009, 911, 878, 828, 755, 713, 686; HRMS (ESI): calculated for C21H19BrN3O2 [M+H]+: 424.0655, found:
424.0657.
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(E)-N-(N-(4-Iodophenyl)-N'-(4-methoxyphenyl)-carbamimidoyl)benzamide (5g) is prepared according to the gen-
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eral procedure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 9:1 > 7:3) to
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give the product 5g (1.6 g, 3.39 mmol, 68%) as a white solid. Rf (cyclohexane-ethyl acetate 2:1) = 0.37; FP: 143.8-144°C; H
NMR CDCl3, 400 MHz, δ (ppm) 3.84 (s, 3H), 6.97 (d, J = 8.7 Hz, 2H), 7.20-7.36 (m, 4H), 7.42 (t, J = 7.4 Hz, 2H), 7.46-7.53
(m, 1H), 7.67 (d, J = 8.6Hz, 2H), 8.19 (d, J = 7.3 Hz, 2H); C {1H} NMR CDCl3, 100 MHz, δ (ppm) 178.4, 158.8, 157.1, 138.2,
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138.0, 137.1, 131.6, 129.4, 128.1, 127.5, 125.0, 115.3, 88.7, 55.7; IR (cm-1) 3345, 2970, 1737, 1603, 1576, 1557, 1533, 1508, 1486, 1445,
1429, 1403, 1383, 1351, 1282, 1264, 1242, 1207, 1192, 1170, 1117, 1066, 1032, 1006, 912, 877, 836, 827, 810, 756, 713, 685; HRMS
(ESI): calculated for C21H19IN3O2 [M+H]+: 472.0516, found: 472.0522.
(E)-Methyl-4-(3-benzoyl-2-(4-methoxyphenyl)guanidino)benzoate (5h) is prepared according to the general proce-
dure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 9:1 > 1:1) to give the
1
product 5h (1.21 g, 2.99 mmol, 60%) as a white solid. Rf (cyclohexane-ethyl acetate 1:1) = 0.79; FP: 135.7-136.0°C; H NMR
DMSO-d6, 400 MHz, δ (ppm) δ 3.61-3.95 (m, 6H), 6.82-7.06 (m, 2H), 7.30-7.60 (m, 5H), 7.61-8.14 (m, 6H); 13C NMR-
DEPT135 DMSO-d6, 100 MHz, δ (ppm) 131.2, 129.5, 128.5, 127.9, 125.7, 122.0, 114.3, 55.0, 51.7; IR (cm-1) 3381, 3365, 3015, 2970,
2948, 1723, 1677, 1611, 1582, 1564, 1531, 1508, 1437, 1415, 1349, 1279, 1241, 1201, 1181, 1107, 1032, 977, 909, 883, 842, 824, 763, 743,
712, 701, 687; HRMS (ESI): calculated for C23H22N3O4 [M+H]+: 404.1605, found: 404.1623.
(E)-N-(N-(4-Cyanophenyl)-N'-(4-methoxyphenyl)-carbamimidoyl)benzamide (5i) is prepared according to the gen-
eral procedure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 9:1 > 8:2) to
give the product 5i (1.16 g, 3.01 mmol, 60%) as an off-white solid. Rf (cyclohexane-ethyl acetate 1:1) = 0.47; FP: 184.2-184.4°C;
1H NMR CDCl3, 400 MHz, δ (ppm) 3.85 (s, 3H), 6.99 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.42-7.48 (m, 2H), 7.49-
7.68 (m, 5H), 8.12 (s, 2H); C {1H} NMR CDCl3, 100 MHz, δ (ppm) 166.7, 159.0, 156.4, 138.9, 133.2, 132.1, 129.1, 128.4, 127.6,
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122.2, 119.0, 115.5, 55.7; IR (cm-1) 3349, 2970, 2220, 1737, 1612, 1595, 1580, 1561, 1527, 1508, 1433, 1412, 1378, 1351, 1301, 1277, 1239,
1211, 1176, 1113, 1071, 1028, 982, 912, 879, 837, 807, 754, 744, 712, 687; HRMS (ESI): calculated for C22H19N4O2 [M+H]+: 371.1503,
found: 371.1513.
(E)-N-(N'-(4-Methoxyphenyl)-N-(pyridin-3-yl)-carbamimidoyl)benzamide (5k) is prepared according to the general
procedure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 4:1 > 2:3 > 1:4) to give
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the product 5k (0.87 g, 2.5 mmol, 50%) as a white solid. Rf (cyclohexane-ethyl acetate 1:3) = 0.26; FP: 153.2°C; H NMR
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CDCl3, 400 MHz, δ (ppm) 3.84 (s, 3H), 6.98 (d, J = 8.4 Hz, 2H), 7.22-7.37 (m, 3H), 7.37-7.57 (m, 3H), 8.01 (d, J = 8.8 Hz, 1H),
8.10-8.24 (m, 2H), 8.39 (d, J = 4.3 Hz, 2H), 8.61 (s, 1H); 13C {1H} NMR CDCl3, 100 MHz, δ (ppm) 178.6, 159.2, 157.4, 145.9,
144.2, 138.0, 134.3, 131.8, 130.5, 129.3, 128.2, 127.8, 123.5, 115.5, 55.7; IR (cm-1) 2970, 1738, 1618, 1600, 1561, 1538, 1513, 1475, 1441,
1397, 1346, 1265, 1243, 1216, 1186, 1031, 981, 914, 839, 807, 750, 716, 688; HRMS (ESI): calculated for C20H19N4O2 [M+H]+:
347.1503, found: 347.1501.
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(E)-N-(N'-(4-Methoxyphenyl)-N-(p-tolyl)-carbamimidoyl)benzamide (5m) is prepared according to the general pro-
cedure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 8:2 > 75:15 > 1:1) to
give the product 5m (0.87 g, 2.49 mmol, 50%) as a white solid. Rf (cyclohexane-ethyl acetate 1:1) = 0.53; FP: 131.7-131.8°C; 1H
NMR CDCl3, 400 MHz, δ (ppm) 2.37 (s, 3H), 3.84 (s, 3H), 6.95 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 7.30-7.37 (m, 4H),
7.40 (t, J = 7.4 Hz, 2H), 7.44-7.50 (m, 1H), 8.21 (d, J = 7.4 Hz, 2H); 13C {1H} NMR CDCl3, 100 MHz, δ (ppm) 178.3, 158.2, 157.5,
138.5, 134.0, 131.4, 130.0, 129.4, 129.1, 128.0, 126.6, 124.2, 114.8, 55.6, 21.1; IR (cm-1) 3347, 2971, 1738, 1600, 1578, 1565, 1532, 1509,
1445, 1410, 1350, 1287, 1242, 1201, 1178, 1135, 1107, 1067, 1034, 979, 908, 884, 826, 811, 764, 743, 718, 704, 686; HRMS (ESI): cal-
culated for C22H22N3O2 [M+H]+: 360.1707, found: 360.1725.
(E)-N-(N'-(4-Methoxyphenyl)-N-(o-tolyl)-carbamimidoyl)benzamide (5n) is prepared according to the general pro-
cedure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 8:2 > 75:15 > 1:1) to
give the product 5n (0.81 g, 2.25 mmol, 45%) as an off-white solid. Rf (cyclohexane-ethyl acetate 1:1) = 0.53; FP: 135.0-
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135.2°C; H NMR CDCl3, 400 MHz, δ (ppm) 2.29 (s, 3H), 3.82 (s, 3H), 6.93 (d, J = 8.5 Hz, 2H), 7.18-7.24 (m, 1H), 7.24-7.33
(m, 2H), 7.32-7.41 (m, 4H), 7.40-7.49 (m, 1H), 7.55 (s, 1H), 8.17 (d, J = 7.5 Hz, 2H); 13C {1H} NMR CDCl3, 100 MHz, δ (ppm)
178.3, 157.7, 138.4, 134.9, 131.4, 129.4, 128.0, 127.2, 126.4, 126.2, 114.5, 55.6, 18.1; IR (cm-1) 3380, 1608, 1595, 1561, 1524, 1508, 1457,
1371, 1350, 1294, 1250, 1203, 1179, 1138, 1106, 1029, 973, 906, 884, 862, 842, 818, 774, 746, 718, 684; HRMS (ESI): calculated for
C22H22N3O2 [M+H]+: 360.1707, found: 360.1699.
(E)-N-(N-(2,6-Dimethylphenyl)-N'-(4-methoxy-phenyl)carbamimidoyl)benzamide (50) is prepared according to the
general procedure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 9:1 > 8:2)
to give the product 5o (0.93 g, 2.49 mmol, 50%) as a white solid. Rf (cyclohexane-ethyl acetate 2:1) = 0.42; FP: 181.5-181.6°C;
1H NMR CDCl3, 400 MHz, δ (ppm) 2.38 (s, 6H), 3.83 (s, 3H), 6.00 (s, 1H, NH), 6.90 (d, J = 8.5 Hz, 2H), 7.10-7.23 (m, 3H),
7.29- 7.50 (m, 5H), 8.17-8.24 (m, 2H), 11.98 (s, 1H, NH); 13C NMR-APT CDCl3, 100 MHz, δ (ppm) 178.4, 158.0, 157.1, 138.5,
136.7, 132.9, 131.4, 130.3, 129.4, 129.2, 128.6, 128.0, 125.2, 113.9, 55.7, 18.5; IR (cm-1) 3370, 3185, 3076, 3023, 2970, 1738, 1599, 1567,
1523, 1507, 1439, 1380, 1373, 1347, 1296, 1247, 1214, 1177, 1139, 1104, 1026, 906, 885, 776, 750, 720 683; HRMS (ESI): calculated
for C23H24N3O2 [M+H]+: 374.1863, found: 374.1883.
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(E)-N-(N-(3,5-Dimethylphenyl)-N'-(4-methoxy-phenyl)carbamimidoyl)benzamide (5p) is prepared according to the
general procedure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 8:2 >
75:15 > 1:1) to give the product 5p (1.05 g, 2.82 mmol, 56%) as an off-white solid. Rf (cyclohexane-ethyl acetate 1:1) = 0.58;
FP: 105.4-105.5°C; 1H NMR CDCl3, 400 MHz, δ (ppm) 2.35 (s, 6H), 3.84 (s, 3H), 6.87 (s, 1H), 6.96 (d, J = 8.7 Hz, 2H), 7.10 (s,
2H), 7.34 (d, J = 8.6 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.47 (t, J = 7.2 Hz, 1H), 8.23 (d, J = 7.3 Hz, 2H); 13C {1H} NMR CDCl3, 100
MHz, δ (ppm) δ 21.4, 55.6, 114.8, 121.7, 126.7, 127.6, 128.0, 129.1, 129.4, 131.4, 136.6, 138.5, 139.2, 157.3, 158.1, 178.2; IR (cm-1) 3355,
2971, 1738, 1590, 1567, 1537, 1510, 1446, 1353, 1316, 1302, 1277, 1249, 1207, 1178, 1134, 1105, 1034, 1018, 904, 851, 844, 822, 748, 719,
704, 685; HRMS (ESI): calculated for C23H24N3O2 [M+H]+: 374.1863, found: 374.1865.
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(E)-N-(N-(4-Methoxyphenyl)-N'-phenylcarbamimidoyl)benzamide (5q) is prepared according to the general proce-
dure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 9:1 > 8:2) to give the
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product 5q (1.15 g, 3.32 mmol, 66%) as a light brown solid. Rf (cyclohexane-ethyl acetate 1:1) = 0.55; FP: 111.9-112.0°C; H
NMR CDCl3, 400 MHz, δ (ppm) 3.85 (s, 3H), 6.97 (d, J = 8.1 Hz, 2H), 7.18-7.26 (m, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.37-7.44 (m,
4H), 7.44-7.51 (m, 3H), 8.21 (d, J = 7.5 Hz, 2H); 13C {1H} NMR CDCl3, 100 MHz, δ (ppm) 178.4, 157.4, 138.4, 137.0, 131.5, 129.4,
129.2, 128.1, 127.1, 125.7, 123.9, 115.0, 55.7; IR (cm-1) 3349, 2970, 1738, 1600, 1577, 1564, 1532, 1511, 1499, 1445, 1351, 1290, 1248,
1202, 1178, 1135, 1107, 1067, 1033, 975, 910, 880, 833, 818, 748, 718, 703, 686; HRMS (ESI): calculated for C21H20N3O2 [M+H]+:
346.1550, found: 346.1542.
(E)-N-(N-(tert-Butyl)-N'-(4-methoxyphenyl)carbamimidoyl)benzamide (5r) is prepared according to the general
procedure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 9:1 > 7:3) to give
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the product 5r (1.16 g, 3.56 mmol, 71%) as a white solid. Rf (cyclohexane-ethyl acetate 2:1) = 0.42; FP: 119.1-119.2°C; H NMR
CDCl3, 400 MHz, δ (ppm) 1.49 (s, 9H), 3.82 (s, 3H), 4.68 (s, NH), 6.89-6.98 (m, 2H), 7.12-7.21 (m, 2H,), 7.37-7.51 (m, 3H),
8.22-8.30 (m, 2H), 11.95 (s, NH); 13C {1H} NMR CDCl3, 100 MHz, δ (ppm) 177.1, 158.9, 158.5, 139.1, 131.0, 129.1, 128.9, 127.9,
127.5, 115.3, 55.6, 52.4, 29.8; IR (cm-1) 3412, 289, 2970, 1738, 1595, 1570, 1511, 1448, 1358, 1294, 1247, 1227, 1216, 1107, 1026, 916,
894, 853, 821, 758, 749, 710, 692; HRMS (EI): calculated for C19H23N3O2 [M]+: 325.1790, found: 325.1797.
N-(N-(4-Methoxyphenyl)carbamimidoyl)benzamide (5s) is prepared according to the general procedure 1. Purifica-
tion is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 8:2 > 1:1) to give the product 5s (0.55 g, 2.03
1
mmol, 41%) as a white solid. Rf (cyclohexane-ethyl acetate 1:1) = 0.18; FP: 136.3-136.9°C (Lit.: 136.-137°C)37; H NMR DMSO-
d6, 500 MHz, δ (ppm) δ 3.76 (s, 3H), 6.90-7.01 (m, 2H), 7.35-7.44 (m, 4H), 7.44-7.49 (m, 1H), 8.05-8.12 (m, 2H), 9.29 (s,
2NH); 13C {1H} NMR DMSO-d6, 125 MHz, δ (ppm) 176.0, 159.8, 156.2, 138.8, 130.8, 130.6, 128.6, 127.8, 124.5, 114.2, 55.3; IR (cm-
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1) 3465, 3070, 3000, 2970, 1738, 1639, 1596, 1558, 1512, 1442, 1354, 1298, 1250, 1205, 1181, 1106, 1087, 1028, 910, 862, 826, 815, 756,
716, 685; HRMS (ESI): calculated for C15H16N3O2 [M+H]+: 270.1237, found: 270.1234.
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(E)-N-(n-Butyl-N'-(4-methoxyphenyl)carbamimidoyl)benzamide (5t) is prepared according to the general procedure
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1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 8:2 > 7:3) to give the prod-
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uct 5t (1.08 g, 3.33 mmol, 67%) as white solid. Rf (cyclohexane-ethyl acetate 1:3) = 0.69; FP: 107.9-108.3°C; H NMR CDCl3,
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400 MHz, δ (ppm) 0.94 (t, J = 7.3 Hz, 3H), 1.36 (h, J = 7.3 Hz, 2H), 1.56 (p, J = 7.2 Hz, 2H), 3.52 (q, J = 6.6 Hz, 2H), 3.81 (s,
3H), 4.76 (s, NH), 6.89-6.98 (m, 2H), 7.18 (d, J = 8.3, 2H), 7.36-7.50 (m, 3H), 8.27 (d, J = 7.0 Hz, 2H), 11.83 (s, NH); 13C {1H}
NMR CDCl3, 100 MHz, δ (ppm) 177.5, 159.5, 158.6, 138.9, 131.1, 129.2, 128.5, 127.9, 127.7, 115.3, 55.6, 41.2, 32.0, 20.1, 13.9; IR (cm-
1) 3373, 3175, 2958, 1737, 1601, 1568, 1446, 1355, 1300, 1245, 1204, 1178, 1145, 1027, 893, 856, 816, 751, 712, 686; HRMS (ESI): cal-
culated for C19H24N3O2 [M+H]+: 326.1863, found: 326.1861.
(E)-N-(N'-Cyclohexyl-N-(4-methoxyphenyl)carbamimidoyl)benzamide (5u) is prepared according to the general
procedure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 4:1 > 2:3) to give
the product 5u(1.19 g, 3.37 mmol, 67%) as yellowish crystals. Rf (cyclohexane-ethyl acetate 1:3) = 0.75; FP: 131.5-131.9°C (Lit.:
129-131°C)27; 1H NMR CDCl3, 400 MHz, δ (ppm) 1.07-1.25 (m, 3H), 1.44 (dtd, J = 16.7, 11.8 and 5.9 Hz, 2H), 1.56-1.76 (m, 3H),
1.98-2.09 (m, 2H), 3.81 (m, 3H), 4.13 (s, NH), 4.65 (s, NH), 6.89-6.98 (m, 2H), 7.18 (d, J = 8.3 Hz, 2H), 7.34-7.51 (m, 3H),
13
8.22-8.29 (m, 2H), 11.86 (s, NH); C {1H} NMR CDCl3, 100 MHz, δ (ppm) 177.5, 158.6, 158.5, 138.9, 131.0, 129.1, 128.6, 127.9,
127.5, 115.2, 55.6, 50.1, 33.3, 25.6, 24.9; IR (cm-1) 3367, 2933, 2845, 1738, 1597, 1567, 1512, 1444, 1405, 1358, 1346, 1246, 1204, 1180,
1136, 1066, 1028, 909, 892, 860, 824, 748, 713, 687; HRMS (ESI): calculated for C21H26N3O2 [M+H]+: 352.2020, found:
352.2023.
N-(Bis((4-methoxyphenyl)amino)methylen)acetamide (12) and 1,3-bis(4-methoxyphenyl)guanidine (14) are pre-
pared according to the general procedure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl
acetate 4:1 > 3:1 > 2:1) to give 12 (0.09 g, 0.29 mmol, 6%) as orange solid. Rf (cyclohexane-ethyl acetate 1:3) = 0.33; HRMS
(ESI): calculated for C17H20N3O3 [M+H]+: 314.1505, found: 314.1488. Subsequent purging of the column with ethyl acetate
and methanol yielded the deacetylated guanidine 14 (0.62 g, 2.27 mmol, 46%) as beige solid. Rf (cyclohexane-ethyl acetate
1
1:3) = 0.75; FP: decomposition >190°C; H NMR Methanol-d4, 400 MHz, δ (ppm) 3.82 (s, 6H), 6.99-7.04 (m, 4H), 7.23-7.29
(m, 4H); IR (cm-1) 3015, 2970, 1738, 1651, 1586, 1509, 1412, 1366, 1296, 1231, 1165, 1104, 1031, 829, 804, 753, 714; HRMS (ESI):
calculated for C15H18N3O2 [M+H]+: 272.1399, found: 272.1388.
(E)-N-(N,N'-Bis(4-methoxyphenyl)carbamimidoyl)-ethylcarbamate (13) is prepared according to the general proce-
dure 1. Purification is done by flash chromatography on silica gel (cyclohexane-ethyl acetate 100:0 > 9:1 > 7:2) to give the
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product 13 (1.16 g, 3.37 mmol, 67%) as brownish oil. Rf (cyclohexane-ethyl acetate 1:1) = 0.35; H NMR CDCl3, 400 MHz, δ
(ppm) 1.31 (t, J = 7.1 Hz, 3H), 3.80 (s, 6H), 4.15 (q, J = 7.1 Hz, 2H), 6.89 (d, J = 8.7 Hz, 4H), 7.21-7.26 (m, 4H); 13C {1H} NMR
CDCl3, 100 MHz, δ (ppm) 14.8, 55.7, 61.2, 114.8, 126.6, 129.2, 158.0, 164.9; IR (cm-1) 2970, 1738, 1542, 1597, 1509, 1464, 1441,
1371, 1297, 1229, 1180, 1094, 1033, 904, 829, 799, 729; HRMS (ESI): calculated for C18H22N3O4 [M+H]+: 344.1610, found:
344.1595.
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Supporting Information
See Supporting Information for copies of in situ IR-Spectra, LC-MS chromatograms and copies of 1H and 13C NMR spectra.
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