Catalyst-Free Synthesis of Aryl Diamines via a Three-Step Reaction Process

Article abstract of DOI:10.1021/acs.joc.8b00151

The formation of C-N bonds with aryl amines is one of the most widely studied reactions in organic chemistry. Despite this, it is still highly challenging, often requiring expensive, precious metal-based catalysts. Here we report an easy catalyst-free methodology for constructing C-N bonds. The method, which proceeds via the in situ formation of closed ring amidinium ions, allows the preparation of a series of symmetrical and/or unsymmetrical aryl diamines in notably high yields (82-98%) and purity and with a variety of different substituents. The methodology is shown successful for the preparation of aryl diamines having para- and/or meta-substituted carboxyl, nitro, bromo, methoxy, or methyl groups. This green synthetic pathway, which is catalyst free, requires only three steps, and proceeds without the need for purification. Further, it is a new sustainable, economically viable method to achieve an otherwise challenging bond formation.

Full text of DOI:10.1021/acs.joc.8b00151

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Catalyst-Free Synthesis of Aryl Diamines via a Three-Step Reaction Process
Safak Bulut, and Wendy L. Queen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00151 • Publication Date (Web): 05 Mar 2018
Downloaded from http://pubs.acs.org on March 6, 2018
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Catalyst-Free Synthesis of Aryl Diamines via a Three-Step
Reaction Process
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Safak Bulut and Wendy L. Queen*
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Institut des Sciences et Ingénierie Chimiques, École Polytechnique Fédérale de Lausanne
(EPFL) - Valais Wallis, CH-1951 Sion, Switzerland.
ABSTRACT: The formation of C–N bonds with aryl amines is one of the most widely
studied reactions in organic chemistry. Despite this, it is still highly challenging often
requiring expensive, precious metal-based catalysts. Here we report an easy catalyst-free
methodology for constructing C–N bonds. The method, which proceeds via the in situ
formation of closed ring amidinium ions, allows the preparation of a series of symmetrical
and/or unsymmetrical aryl diamines in notably high yields (82-98 %) and purity and with a
variety of different substituents. The methodology is shown successful for the preparation of
aryl diamines having para- and/or meta-substituted carboxyl, nitro, bromo, methoxy, or
methyl groups. This green synthetic pathway, which is catalyst free, requires only three steps,
and proceeds without the need for purification. Further, it is a new sustainable, economically
viable method to achieve an otherwise challenging bond formation.
INTRODUCTION
The formation of C–N bonds and N-alkylation of aryl amines are of substantial interest in
synthetic chemistry due to widespread use in natural products, pharmaceuticals, bioactive
compounds, conductive polymers, fine chemicals, and catalysis.1-6 These reactions trace back
to the beginning of the 20th century when Ullmann and Goldberg discovered a copper-
catalyzed methodology employing aryl halides.7-8 Much later, in the 1980s, the first Pd-
catalyst was found to promote the reaction through the coupling of Sn-amides with aryl
halides.9 While the method provided moderate to good yields, the heat and moisture sensitive
Sn-complexes made it unfavorable. As such, several groups began to focus on Sn-free
systems; for instance, a Pd-phosphine complex was found to catalyze an intramolecular
amine arylation.10 Further, Buchwald and Hartwig developed Pd- and Cu-catalysts,11-12 and
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afterwards, reported a number of studies on C–N bond formation via substitution with
alkyl/aryl halides.4,13-16
While the development of new ligands for catalyst systems in the past two decades has
intensified research on C–N bond formation, there are still limitations.17-21 One of the most
conventional and effective approaches, carried out via nitration/reduction of arenes or
reductive amination of aniline derivatives from carbonyl compounds,22 is limited by the
number of applicable substrates and has limited tolerance of functional groups. Additionally,
while most recent studies allow transformation of more simple substrates, via C–H bond
activation, they still require expensive metal catalysts.23-26
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Scheme 1 summarizes selected examples of C–N bond formation using aniline-based starting
materials coupled with a variety of different substrates that range from carboxylic acids
(Scheme 1a),27-28 ketones/aldehydes (Scheme 1b),29-31 a variety of alcohols (Scheme 1c-e),32-
35
and primary, secondary, or tertiary amines (Scheme 1f).36-39 While the majority of the
aforementioned catalytic studies focus on the synthesis of alkylated/arylated monoamines, the
use of appropriate substrates with relevant catalytic systems are also shown to lead to
diamines (Scheme 1d).40 In general, a survey of the literature indicates that the use of
catalysts, particularly those with precious metals, appear almost unavoidable. Given the
strong application-relevance of C–N coupling reactions with aryl amines, developing cheaper
catalysts or catalyst-free methodologies could offer a large economic payoff.41
Scheme 1. Examples of reported works on N-alkylation of aniline and its derivatives using various
catalysts
In this report we demonstrate a facile catalyst-free formation of C–N bonds with aryl amines,
which leads to the synthesis of a series of functionalized symmetrical and unsymmetrical aryl
diamine compounds with two, three or four membered alkyl chains between the amines. The
reported procedure is straightforward with three easy steps and provides high product yields
(82-98 %) with no need for purification. The aniline derivatives used as starting materials
have varying basicities, pKa values42 of 1.02, 2.45, 3.29, 3.58, 3.86, 4.73 and 5.31 (for 4-
Nitroaniline, 4-Aminobenzoic acid, 3-Aminobenzoic acid, 3-Bromoaniline, 4-Bromoaniline,
3-Methylaniline and 4-Methoxyaniline, respectively). This demonstrates the applicability of
this method for the synthesis of a wide scope of compounds with different electron
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withdrawing and donating groups (EWGs and EDGs, respectively) and at varying positions.
The basicity of the substituted anilines used as starting materials exhibit pKa’s either lower or
higher relative to unsubstituted aniline (pKa value = 4.6). To date, there are a few reports
showing the formation of carboxyl-substituted aryl diamines (or diimines) but with relatively
low yields (33 % for para- and 58 % for meta-carboxyl). Also, due to the use of glyoxal
derivatives, the reported method is limited to products containing a two-membered alkyl
chain between the nitrogen atoms.43-46 In addition to these, two earlier works report the
formation of carboxyl-substituted aryl diamines; however, these methods require many steps
to obtain pure materials, and the diamines are also limited to two-membered alkyl chains
between the nitrogen atoms.47-48 Some recent work also reports the synthesis of diamines
using unsubstituted anilines49-52 and substituted anilines with EDGs50,53-55 or EWGs.56-59
Nevertheless, these procedures have several disadvantages, such as the reactions require a
catalyst, the diamine products formed are limited to two-membered alkyl chains between the
nitrogen atoms (sometimes with three-membered alkyl chain), and often reactions result in
very low product yields. Additionally, a procedure for the one-step synthesis of a diamine
compound with two-membered alkyl chain between the nitrogen atoms and without
substitutions is also reported.60 However, our efforts applying this previously reported
methodology to carboxylic acid or ester substituted anilines were unsuccessful (Scheme 2,
see results and discussion for details), implying it is not successful for anilines substituted
with electron withdrawing substituents. It should be noted that the presence of electron
withdrawing substituents, on the aryl amines, such as -F, -CF3 or -NO2, -CN, -COOH(R),
make direct alkylation of anilines very difficult, due to the reduced nucleophilicity of the
amine.28,31,38-39 Given that the reported work presents a new method that proceeds through an
indirect way, via the in situ creation of closed ring amidinium structures, it is thought that the
formation of the diamine products is still promoted despite the presence of electron-
withdrawing constituents. Compounds of this kind, containing both amine and carboxyl
functionality are of strong interest as building blocks for the formation of hybrid
organic/inorganic materials, such as metal-organic frameworks,43-44,46 as ligands in catalysis
for aryl C–O, C–C and C–N coupling reactions,61-66 for halogen exchange in aryl halides67 or
for hydrogenation reactions.68-69 Last, considering drugs containing para-aminobenzoic acid
exhibit diverse therapeutic activities, with 84 applications listed in Negwer’s database,70 C–N
coupling reactions could be instrumental in the design of new pharmaceuticals.71
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Scheme 2. Summary of attempts for one-step synthesis of diamines using dibromine based bis-
electrophiles and isolated yields (cf. Scheme S1)
RESULTS AND DISCUSSION
In the first step, formamidine is prepared using substituted anilines with triethyl
orthoformate; a similar procedure is used in previous reports but with different aniline
substrates (Scheme 3a).72-73 For the synthesis of symmetrical formamidines, the aniline
derivatives (2 equiv) are mixed together with other reactants at the beginning of the reaction;
however, for the synthesis of the unsymmetrical formamidine the two-different substituted
anilines are added to the reaction mixture at different stages to avoid the formation of any
symmetrical analogs (cross-products) that might result from side reactions. Accordingly, at
the beginning of the reaction only the first substituted aniline (1 equiv) is added and allowed
to reach its complete conversion to N-(Ethoxymethylene) aniline derivative.74 Then, the
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second substituted aniline (1 equiv) is added, and the reaction is continued under the same
conditions. During the reaction, the formed ethanol is removed by distillation pushing the
equilibrium in favor of the product formation. Afterwards, the formamidines are isolated as
pure solids without any side products (up to 20-25 g scales) and are employed in step two
without any further purification (Scheme 4). In this step, a mild base is used to
deprotonate/activate the formamidine for the subsequent substitution of bromines in the
dibromoalkane, and hence promotes the C–N bond formation. The use of the ester, rather
than a carboxylic acid, is important to prevent the esterification75-76 by the dibromoalkanes or
polymerization.77 The method presented in step two is previously reported for the synthesis
of saturated amidinium salts with alkyl-substituted aryl groups using bases such as n-
butyllithium or potassium carbonate (K2CO3).78-80 In this case, K2CO3 was chosen because it
does not require inert conditions or dry solvents.
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Scheme 3. a) Synthetic route for the preparation of formamidines (step one), b) the in situ formation of
the closed ring amidinium structures and the proposed hydrolysis mechanism leading to formamides
(step two), and c) the synthesis of the aryl diamine compounds via hydrolysis of the ester and formamide
functionalities (step three)
Step two (Scheme 3b) proceeds through the formation of an amidinium salt; however,
relative to unsubstituted analogs or with EDGs like methyl or methoxy, the strongly EWGs
such as carboxyl, nitro, or bromine decrease the electron density of the C2 carbon atom
between the nitrogen atoms in the closed ring structure (EWGs also increase the acidity of the
C2–H proton). As such, C2 readily undergoes nucleophilic attacks of hydroxide anions in the
presence of K2CO3 leading to the ring opening and formation of formamides (Scheme 3b).61
As a second scenario, following the acidity of the C2–H proton (particularly in the presence
of EWGs) C2 may possibly undergo deprotonation in the presence of K2CO3 leading to the in
situ formation of N-heterocyclic carbenes (NHCs). It is known that highly reactive, carbene
species undergo hydrolysis in the presence of water subsequently leading to formamides
too.81-83 As a result of electronic effects, the reactions with the compounds containing EDGs
are slower – probably due to lower reaction rates for the deprotonation of formamidines –,
and need two or three times longer reaction times for completion (9a-c and 11a-c) compared
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to compounds with EWGs.80 Alternatively, the reactions with EDGs can be speeded up by
using more base, such as 5 equiv K2CO3 instead of 3 equiv. As such, step two ends with the
formation of a series of formamides (Scheme 5). While all NMR spectra taken after step two
show only the formamide species, more sensitive MALDI-TOF MS analyses prove the
formation of the closed ring amidinium structures in all analyzed samples from 1a, 1b and 1c
+
(cf. Figure S1-3, m/z = 339.11, 353.14 and 367.17, corresponding to C19H19N2O4 ,
+
+
C20H21N2O4 and C21H23N2O4 , respectively), supporting the proposed mechanism in Scheme
3b. In an effort to eliminate hydrolysis to make the amidinium salts in higher yields, the same
reactions were carried out under a nitrogen atmosphere and in dry solvents (previously dried
by distillation over CaH2 and stored in the glove box, see Experimental Section).
Surprisingly, these reactions also resulted in the formation of the same formamide-based
products. As such, it is hypothesized that the water stems from the thermal decomposition of
carbonic acid, which is formed during the deprotonation process driven by K2CO3 (cf.
Scheme 3b). Substituting K2CO3 with any other base, in the absence of water, only reveals
the starting materials in the NMR spectra, implying that the in situ removal of the amidinium
salt is required to drive the reaction forward towards the formamide. It should be noted, that
for the purpose of synthesizing diamine compounds with alkyl chains longer than four carbon
atoms between the amines, the reaction was tested with five and six membered
dibromoalkanes, 1,5-dibromopentane and 1,6-dibromohexane, respectively. The reactions are
found to proceed through a different mechanism as the formation of eight and nine membered
ring structures (increasing strain energy) are unfavored.84 As such, these reactions are
considered to be outside the scope of this work and will be further explored in future studies.
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In the final step, the formamides are easily converted into a series of aryl diamine-carboxylic
acid building blocks using a standard hydrolysis procedure with sodium hydroxide (Scheme
3c). The reactions, shown in Scheme 3, provide products 1-35 in excellent yields, between 91
and 98 % for diamines with EWGs (carboxyl, nitro and bromine) and 82-89 % for diamines
with EDGs (methyl and methoxy) (Scheme 4-6). The reason for slightly lower yields of
diamines with EDGs is that these materials, 27-29 and 33-35, remain dissolved in the water
solution after neutralization and are separated via extraction using organic solvents. Even
after several extractions of the aqueous reaction mixture, a small part of the products remains
in the water solution, inducing slightly lower reaction yields. In contrast, the diamines with
EWGs, 12-26 and 30-32, form a suspension in water after neutralization and can be separated
via filtration without the loss of the product, leading to higher reaction yields.
Scheme 4. Formamidines with different substituents prepared and used for the synthesis of diamine
compoundsa
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aReactions were carried out in a distillation apparatus at 140 °C for 24 h (without solvent), containing 2 equiv of
aniline derivatives, 1.05 equiv of triethyl orthoformate, and 0.1 equiv of glacial acetic acid. All yields refer to
isolated compounds.
The formamidines 1, 3, 5 and 7-11 are pure solids confirmed by NMR analysis and could
directly be used for the next step. These formamidines are also quite stable; 1 shows no
decomposition after 12-18 hours with heating under reflux at 100-140 °C in dimethyl
formamidine, acetonitrile or tetrahydrofuran. It should be noted that 1 is partially
decomposed by refluxing in methanol at 100 °C for 10 hours, and the decomposition takes
place more rapidly when refluxed in a methanol/water mixture due to breakage of the imine
bond. While the NMR spectra of the intermediate compounds, formamides 1a-c, 3a-c, 5a-c
and 7-11a-c, show some impurities, they are still directly employed in the final hydrolysis
step without any further purification (Scheme 3c). The unsymmetrical analogs of the
formamides, 5a-c, are available as mixtures of two isomers where the aldehyde functionality
is found either on the nitrogen atom closest to the para-substituted carboxylic acid (minor
product) or on the nitrogen closest to the meta-substituted ring (major product). Products 5a
and 5c both have isomer yields of 19 % and 81 %, while 5b has a slightly different
distribution of 21 % and 79 %. Despite the isomeric mixtures, these products can still directly
be used for the final hydrolysis in the exact same manner as the non-isomer containing
reactions without any further purification (Scheme 3c).
Scheme 5. The formamides obtained as intermediate compounds during the synthesis of diamine
compoundsa
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aReactions were refluxed in acetonitrile at 100 °C for 24-48 h (for 9a-c and 11a-c up to 5-6 days), with 1 equiv
of formamidine, 1.5 equiv of dibromoalkane, and 3 equiv of potassium carbonate. Several reactions result in
formamides that are mixtures of two isomers, where the aldehyde functionality is located at the nitrogen atom of
b
para- (minor product) or the meta-substituted ring (major product, shown above). The isomeric ratios are 19 and
1
81 % (5a, 5c) and 21 and 79 % (5b), respectively, as determined via H NMR. All yields refer to isolated
compounds.
In step three, the hydrolysis reactions result in aryl diamine compounds 12-35 in notable
purities (Scheme 6). Due to the aforementioned water instability of the formamidines,
hydrolysis of their ester forms (1, 3, 5) is carried out in acetonitrile, forming 2, 4 and 6
(Scheme 4).
Scheme 6. Symmetrical (12-17, 21-35) and unsymmetrical (18-20) diamine compounds with different
substituents synthesized in this worka
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aReactions were refluxed in a 1/2 ratio of methanol/water at 110 °C for 24 h, with 1 equiv of formamide and 10
equiv of sodium hydroxide. All yields refer to isolated compounds.
One-step synthesis. To check the possibility for direct synthesis of carboxyl or ester
substituted diamines, a one-step synthesis procedure was used which has previously been
reported for the synthesis of a diamine compound with two-membered alkyl chain between
the nitrogen atoms and without any carboxyl-substitutions or any other EWGs.60 As shown in
Scheme 2, we tested this one-step synthesis methodology using 4-Aminobenzoic acid and
dibromine based bis-electrophiles as starting materials. Even with reaction times increased to
three times the reported ones, the yield for the diamine with two-membered alkyl chain was
very poor (~16 %), for the diamine with three-membered alkyl chain just traces were
observed (~1 %) and in the reaction with the four-membered alkyl chain no diamine
formation was observed (here cyclization at the nitrogen atom of the aniline was observed, cf.
Scheme S1). The same reaction with ester substituted aniline, the methyl 4-aminobenzoate, in
the presence of potassium carbonate was carried out. After several days and the use of up to
five equivalents of potassium carbonate, no formation of the diamine was observed. This
indicates that the catalyst-free, one-step synthesis for carboxyl or ester functionalized
diamine building blocks is not feasible, and hence, there is no alternative to our three-step
methodology to the best of our knowledge. All details to the reactions for one-step synthesis
of diamines can be found in the ESI (Scheme S1).
Thermal stability. Thermal stabilities were studied via thermogravimetric analysis (TGA);
the ester forms of the formamidines (1, 3 and 5) show decomposition temperatures (Td) at
~230-240 °C, while their hydrolyzed counterparts (2, 4) are less stable with decompositions
under 200 °C except the unsymmetrical one (6), which decomposes at ~230 °C. The final
diamine building blocks are in general quite stable with a very narrow one step
decomposition between 195 to 275 °C. The para-COOH substituted analogs (12-14), with
stabilities up to 274 °C, have slightly higher thermal stabilities than the meta-COOH
substituted (15-17) and unsymmetrical diamines (18-20), 215 to 222 and 198 to 205 °C,
respectively. Moreover, para-NO2 (21-23) and meta-Br (30-32) substituted diamines exhibit
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quite high decomposition temperatures at ~260-275 °C and ~240-260 °C, respectively. In
contrast, para-Br (24-26), para-OMe (27-29) and meta-Me (33-35) substituted diamines
show slightly lower stabilities with decomposition at ~195-200 °C (cf. Figure S140-169).
Single crystal X-ray analysis. Selected single crystal structures from each step of Scheme 3
– formamidine (1), the formamide (1a, 1c), and the diamine (12) – are shown in Figure S4-
7.85 Formamidine (1) has only one carbon atom between the two nitrogens, and the phenyl
rings are slightly rotated in different planes (Figure S4). The C3-N1-C1 angle is ca. 8.5 °
smaller than the C1-N2-C2 angle, making the aryl ring on imine side more bent. The structure
of the formamide (1a) is likely more flexible due to the -CH2CH2- group located between the
nitrogen atoms (Figure S5). While the phenyl rings are only slightly rotated with regard to
one another, they are located in different planes forming a stair-like structure that results from
the presence of the aldehyde on N1. In contrast to the asymmetric formamide, the diamine
(12) is highly symmetric. The aryl rings are in the same plane and both carboxylic acid
groups face the opposite direction making the molecule almost linear (Figure S7).
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CONCLUSIONS
In conclusion, we demonstrate a catalyst-free methodology for the formation of C–N bonds
starting with aryl amines; a challenging reaction that, more often than not, works with
expensive catalysts, particularly those constructed with precious metals. We give evidence
that the catalyst-free method proceeds indirectly, through the in situ formation of closed ring
amidinium structures for the preparation of a series of para- and meta-substituted diamine
compounds in high yields. This mechanism is important as the direct formation of these
materials is hindered due to the electron withdrawing nature of the substituents such as -
COOH, -Br or -NO2. Moreover, the methodology reported here also works with aniline
derivatives that have electron donating substituents such as -Me or -OMe, showing its
applicability in the production of a wide scope of materials. Given this we envision that this
method can easily be extended to form a variety of diamine compounds using more-
substituted anilines with varying electron withdrawing and donating substituents. Building
blocks with multiple substituents, particularly those with carboxyl and amine functionalities,
are of interest in a manifold of applications that span supramolecular chemistry, catalysis, and
pharmaceuticals. Using this method, we are already exploring the synthesis of various
carboxylate-based diamines with and without larger alkyl bridges.
EXPERIMENTAL SECTION
General Procedures and Starting Materials. The reactions and experiments were carried
out under air without using Schlenk technique, moisture-free inert conditions and dry
solvents, unless stated otherwise. Acetonitrile, methanol, dichloromethane and n-hexane were
obtained in analytical grade from commercially available sources and were used without any
further purification or drying. The reactions under water free conditions were undertaken
using standard vacuum and Schlenk techniques. For these reactions, acetonitrile was distilled
after refluxing with CaH2 overnight and stored in a glove box under a nitrogen atmosphere.
3-Aminobenzoic acid, 4-Aminobenzoic acid, 4-Nitroaniline, deuterated chloroform (CDCl3)
and 1,4-dibromobutane were obtained from Acros, triethyl orthoformate, potassium
carbonate (anhydrous), deuterated dimethyl sulfoxide (dmso-d6) and 1,3-dibromopropane
were obtained from ABCR, 3-Bromoaniline and 4-Bromoaniline were obtained from
Fluorochem, sodium hydroxide, hydrochloric acid (37 %), magnesium sulfate (anhydrous), 3-
Methylaniline, 4-Methoxyaniline and 1,2-dibromoethane were obtained from Sigma-Aldrich,
sulfuric acid (95-97 %) and acetic acid (glacial) were obtained from Merck and used as they
received. Solution NMR spectra were recorded in deuterated solvents on a BRUKER AV 200
or a BRUKER AVIII HD 400 spectrometer; data are given in ppm relative to 1% TMS
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solution in CDCl3 using the solvent signals as a secondary reference (1H, 13C). NMR spectra
were recorded at room temperature (rt), if not mentioned otherwise. The Bruker Topspin
software package (version 2.1 and 3.2) was used for measuring and Mestrenova NMR
software (version 11.0.1) was used for processing of the spectra. IR spectra were recorded at
rt on a PerkinElmer FT-IR/FIR spectrometer using a Diamond ATR cell with the
PerkinElmer spectrum software package (a resolution of 4 cm–1 was used). Decomposition
temperatures were determined from thermogravimetric analysis (TGA) experiments on a
TGA Q500 device from TA Instruments in 100 ꢀl platinum pans with an empty pan of the
same type as reference. To infer the decomposition temperatures, the onset points were taken
into account. Mass spectra for 1a-c were obtained using Matrix Assisted Laser Desorption
Ionization-Time Of Flight Mass Spectrometry (MALDI-TOF MS) via the instrument from
Microflex Bruker, in reflectron mode using positive polarity and with a sample concentration
of 1 mg/mL in THF. High resolution mass spectrometry (HRMS) analysis was performed
using Q Exactive HF Hybrid Quadrupole-Orbitrap mass spectrometer (Thermo Scientific,
Germany) in ESI ionization mode with ionization source TriVersa NanoMate (Advion, USA)
and quadrupole mass analyzer. Data collection for X-ray structure determinations were
performed on a Bruker D8 Venture diffractometer with Photon 100 CMOS-detector using
Mo-Kα radiation (λ = 0.71073 Å), and on multipurpose PILATUS@SNBL diffractometer
with PILATUS2M detector at the Swiss-Norwegian Beam Lines at European Synchrotron
Radiation Facility (λ = 0.7153 Å). Single crystals were mounted on top of a glass fiber and
measured at 100–125 K. All calculations were performed using the SHELX-2014/786-87
software package. The structures were solved by direct methods and refined by least squares
on weighted F2 values for all reflections. All non-hydrogen atoms were assigned anisotropic
displacement parameters and refined without positional constraints. Hydrogen atoms were
located in the electron density difference map, assigned isotropic displacement parameters
and refined without positional constraints. Complex neutral-atom scattering factors were
used.
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Synthesis of Methyl 4-aminobenzoate (starting material for 1 and 5).88 4-Aminobenzoic
acid (20 g, 145.8 mmol) was suspended in 250 mL methanol in a 500 mL round-bottom flask,
and concentrated sulfuric acid (95-97 %, 15 mL) were dropped in the reaction mixture by
stirring within 15 min. Following the mixture was refluxed for 20 h at 100 °C and residual
solvent was removed using rotary evaporator. Afterwards, the white solid was suspended in
250 mL water and by stirring saturated sodium carbonate solution was added (until pH = 3-
4). Then, the mixture was filtered on a G4 frit, resulting white solid was washed with 500 mL
water and dried at 60 °C in vacuum (0.1 Pa) for 12 h. Isolated yield (white powder): 19.9 g
1
(90.3 %). H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 7.85 (d, J = 8.6 Hz, 2H), 6.63
(d, J = 8.7 Hz, 2H), 4.06 (m, 2H), 3.85 (s, 3H). The data are in agreement with those reported
in the literature.88
Synthesis of Methyl 3-aminobenzoate (starting material for 3 and 5).88 3-Aminobenzoic
acid (20 g, 145.8 mmol) was suspended in 250 mL methanol in a 500 mL round-bottom flask,
and concentrated sulfuric acid (95-97 %, 15 mL) were dropped in the reaction mixture by
stirring within 15 min. Following the mixture was refluxed for 20 h at 100 °C and residual
solvent was removed using rotary evaporator. Afterwards, the red-brown liquid was mixed
with 250 mL water and by stirring saturated sodium carbonate solution was added (until pH =
3-4). Then, the emulsion was taken in 150 mL CH2Cl2 in a separation funnel, organic phase
was separated and the aqueous phase was extracted with more CH2Cl2 (3x150 mL). Collected
organic phases were dried over MgSO4, the solvent was removed by rotary evaporation and
resulting red-brown oil was dried at rt in vacuum (0.1 Pa) for 12 h. Isolated yield (reddish
oil): 20.1 g (91.2 %). 1H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 7.41 (d, J = 7.7 Hz,
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1H), 7.34 (t, J = 2.0 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.84 (dd, J = 7.9, 1.9 Hz, 1H), 3.87 (s,
3H), 3.78 (m, 2H). The data are in agreement with those reported in the literature.88
Synthesis of symmetrical formamidines (1, 3, 7-11). Methyl aminobenzoate (2 equiv),
triethyl orthoformate (1.05 equiv) and glacial acetic acid (0.1 equiv) were weighed in a 50
mL round bottom flask that was then connected to a distillation apparatus. The mixture was
heated to 140 °C with stirring for 24 h. The formed ethanol was distilled off during reaction
driving it forward. After cooling to rt, the crude solid was washed with n-hexane, dried in a
rotary evaporator and ground in a mortar. Afterwards, the powder was taken in a G4 frit and
rinsed several times with n-hexane. After drying at rt in vacuum (0.1 Pa) for 1 d, the product
was stored in glove box.
Synthesis of unsymmetrical formamidine (5). Methyl 4-aminobenzoate (1 equiv), triethyl
orthoformate (1.05 equiv) and glacial acetic acid (0.1 equiv) were weighed in a 50 mL round
bottom flask that was then connected to a distillation apparatus. The mixture was heated to
140 °C with stirring for 12 h. After it methyl 3-aminobenzoate (1 equiv) was added in the
reaction mixture and heated at 140 °C for 24 h. The formed ethanol was distilled off during
the reaction driving it forward. After cooling to rt, the crude solid was washed with n-hexane,
dried in a rotary evaporator and ground in a mortar. Afterwards, the powder was taken in a
G4 frit and rinsed several times with n-hexane. After drying at rt in vacuum (0.1 Pa) for 1 d,
the product was stored in glove box.
Synthesis of formamidine building blocks (2, 4, 6). The formamidine (1 equiv) and sodium
hydroxide (6 equiv) were weighed in a round bottom flask. Acetonitrile (approx. 15 mL
solvent/1 mmol formamidine) was added, and the mixture was refluxed at 110 °C for 48 h.
After cooling to rt, acetonitrile was removed by rotary evaporation. The solid remaining in
the flask was dissolved in water (approx. 10 mL solvent/1 mmol formamidine) and the clear
solution was neutralized with the dropwise addition of 3 M HCl solution causing the
formation of a solid. The resulting suspension was filtered over a G4 frit and the cake was
washed several times with water. The product was rinsed with n-hexane and dried at 60 °C in
vacuum (0.1 Pa) for 12 h.
Synthesis of diamine compounds (12-35). For the synthesis of diamine building blocks,
firstly, the preparation of intermediate compounds, the formamides (1a-c, 3a-c, 5a-c, 7a-c,
8a-c, 9a-c, 10a-c and 11a-c) was taken place. For this purpose, the formamidine (1 equiv),
dibromoalkane (1.5 equiv) and potassium carbonate (3 equiv) were weighed in a round
bottom flask. Acetonitrile (approx. 15 mL solvent/1 mmol formamidine) was added and the
mixture was refluxed at 100 °C for 24-48 h (for 9a-c and 11a-c the reflux time was longer, up
to 5-6 days). For selected reactions, NMR was used to watch the reaction proceed, and more
dibromoalkane was added (0.5-1 equiv) when needed. After complete conversion to the
formamide, as observed by NMR, the mixture was cooled to rt and acetonitrile was removed
using a rotary evaporator. The remaining solid was dissolved in dichloromethane and filtered
over a G4 frit (because nitro-substituted formamides (7a-c) are less soluble in
dichloromethane, ethanol was added during filtration to dissolve them completely). The
solvent was removed by rotary evaporation; the product was rinsed with n-hexane and dried
at rt in vacuum (0.1 Pa) for 12 h. The formamides were directly used for the following final
hydrolysis reaction without any further purification.
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In the hydrolysis step, the formamide (1 equiv) and sodium hydroxide (10 equiv) were
weighed in a round bottom flask. A 1/2 mixture of methanol/water (approx. 25 mL solvent
mixture/1 mmol formamide) was added and the mixture was refluxed at 110 °C for 24 h.
After cooling to rt, the clear solution was neutralized with the dropwise addition of 3 M HCl
inducing the formation of a solid (for 1a-c, 2a-c, 3a-c, 7a-c, 8a-c and 10a-c) or an unclear
solution without significant solid formation (9a-c and 11a-c). In the case of solid formation
(1a-c, 2a-c, 3a-c, 7a-c, 8a-c and 10a-c), the resulting suspension was filtered over a G4 frit
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and the cake was washed several times with water. In the other case, without solid formation
(9a-c and 11a-c), the resulting unclear water solution was extracted with Et2O and CH2Cl2
(with each solvent 3x). The collected organic phase was dried over MgSO4, and the solvents
were removed using a rotary evaporator. The products obtained in both cases were rinsed
with n-hexane and dried at 80-100 °C in vacuum (0.1 Pa) for 1 day.
Experimental data for 1. Methyl 4-aminobenzoate (10 g, 66 mmol), triethyl orthoformate
(5.15 g, 34.7 mmol), glacial acetic acid (0.2 g. 3.3 mmol); isolated yield (white powder):
10.05 g (97.3 %). 1H NMR (200.13 MHz, DMSO-d6, 298 K): δ = 10.38 (s, 1H), 8.44 (s, 1H),
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7.89 (d, J = 8.3 Hz, 4H), 7.38 (m, 4H), 3.82 (s, 6H). C NMR (50.32 MHz, DMSO-d6, 298
K) δ = 166, 148.9, 130.5, 123.5, 118.8, 51.8. IR (diamond ATR): ꢀȬ = 410 (w), 444 (w), 469
(w), 501 (m), 510 (m), 570 (m), 623 (m), 638 (m), 688 (m), 697 (s), 707 (m), 765 (vs), 775
(s), 798 (m), 819 (m), 849 (s), 912 (m), 965 (m), 994 (m), 1012 (m), 1101 (s), 1120 (s), 1168
(vs), 1181 (s), 1193 (m), 1208 (s), 1267 (vs), 1303 (s), 1327 (m), 1415 (m), 1436 (s), 1460
(w), 1488 (m), 1506 (m), 1526 (m), 1583 (s), 1595 (s), 1660 (s), 1708 (s), 2952 (w), 3001
+
(w), 3066 (w). Td (TGA) = 238.8 °C. HRMS (ESI) m/z: [M + H]+ calcd for C17H17N2O4 ,
313.1183 found, 313.1173.
Experimental data for 2. Formamidine 1 (2 g, 6.4 mmol), sodium hydroxide (1.54 g, 38.4
1
mmol); isolated yield (yellow powder): 1.72 g (94.5 %). H NMR (200.13 MHz, DMSO-d6,
298 K): δ = 11.68 (s, 2H), 8.42 (s, 1H), 7.87 (d, J = 8.3 Hz, 4H), 7.35 (d, J = 8.4 Hz, 4H). 13C
NMR (50.32 MHz, DMSO-d6, 298 K): δ = 167.2, 148.8, 130.7, 124.7, 118.6. IR (diamond
ATR): ꢀȬ = 420 (m), 453 (m), 505 (m), 529 (w), 565 (m), 619 (m), 638 (m), 693 (s), 767 (vs),
780 (vs), 809 (m), 845 (s), 860 (vs), 897 (m), 979 (w), 1013 (m), 1060 (s), 1118 (vs), 1185
(vs), 1221 (vs), 1257 (vs), 1324 (vs), 1353 (vs), 1434 (m), 1528 (s), 1588 (vs), 1601 (vs),
1652 (s), 1694 (vs), 2603 (m), 3078 (w), 3214 (w), 3350 (m), 3526 (w), , 3611 (w). Td (TGA)
+
= 163.2/234.6 °C. HRMS (ESI) m/z: [M + H]+ calcd for C15H13N2O4 , 285.0870; found,
285.0865.
Experimental data for 3. Methyl 3-aminobenzoate (10 g, 66 mmol), triethyl orthoformate
(5.15 g, 34.7 mmol), glacial acetic acid (0.2 g. 3.3 mmol); isolated yield (white powder): 9.65
1
g (93.4 %). H NMR (200.13 MHz, DMSO-d6, 298 K): δ = 10.11 (s, 1H), 8.28 (s, 1H), 7.84
(s, 2H), 7.73 – 7.34 (m, 6H), 3.85 (s, 6H). 13C NMR (50.32 MHz, DMSO-d6, 298 K): δ =
166.3, 148.7, 130.5, 129.4, 123.1, 119.7, 52.1. IR (diamond ATR): ꢀȬ = 417 (m), 475 (w), 547
(s), 611 (m), 669 (m), 678 (vs), 691 (m), 706 (vs), 750 (vs), 794 (m), 821 (m), 835 (w), 886
(s), 897 (s), 940 (w), 977 (s), 1007 (vs), 1028 (w), 1076 (vs), 1105 (vs), 1112 (vs), 1157 (m),
1206 (vs), 1220 (vs), 1257 (vs), 1271 (vs), 1294 (vs), 1328 (vs), 1394 (w), 1438 (s), 1447 (s),
1474 (vs), 1516 (m), 1587 (vs), 1671 (vs), 1716 (vs), 1728 (vs), 2850 (w), 2950 (m). Td
+
(TGA) = 228.3 °C. HRMS (ESI) m/z: [M + H]+ calcd for C17H17N2O4 , 313.1183; found,
313.1177.
Experimental data for 4. Formamidine 3 (2 g, 6.4 mmol), sodium hydroxide (1.54 g, 38.4
1
mmol); isolated yield (white powder): 1.79 g (98.3 %). H NMR (200.13 MHz, DMSO-d6,
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298 K): δ = 11.99 (s, 2H), 8.27 (s, 1H), 7.82 (s, 2H), 7.50 (dd, J = 33.6, 7.6 Hz, 6H). C
NMR (50.32 MHz, DMSO-d6, 298 K): δ = 167.4, 148.6, 131.9, 129.2, 123.3, 119.9. IR
(diamond ATR): ꢀȬ = 427 (m), 502 (m), 515 (w), 561 (w), 635 (m), 677 (vs), 752 (vs), 815
(m), 890 (m), 1075 (m), 1225 (s), 1266 (vs), 1308 (vs), 1332 (vs), 1379 (vs), 1421 (m), 1482
(m), 1516 (m), 1587 (s), 1694 (vs), 1936 (w), 2535 (m). Td (TGA) = 238.8 °C. Td (TGA) =
+
197.6/272.3 °C. HRMS (ESI) m/z: [M + H]+ calcd for C15H13N2O4 , 285.0870; found,
285.0867.
Experimental data for 5. Methyl 4-aminobenzoate (5 g, 33 mmol), methyl 3-aminobenzoate
(5 g, 33 mmol), triethyl orthoformate (5.15 g, 34.7 mmol), glacial acetic acid (0.2 g. 3.3
mmol); isolated yield (light brown powder): 9.74 g (94.3 %). 1H NMR (400.13 MHz, DMSO-
d6, 298 K): δ = 10.29 (s, 1H), 8.44 (s, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 7.2 Hz, 2H),
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7.58 – 6.92 (m, 4H), 3.85 (s, 3H), 3.82 (s, 3H). C NMR (100.61 MHz, DMSO-d6, 298 K) δ
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6
7
8
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= 166.3, 166.1, 149, 130.6, 129.5, 123.6, 52.2, 51.9. IR (diamond ATR): ꢀȬ = 420 (w), 462
(w), 506 (s), 537 (m), 561 (w), 614 (m), 640 (m), 666 (w), 688 (vs), 695 (s), 754 (vs), 766 (s),
794 (m), 811 (m), 844 (s), 894 (m), 964 (m), 979 (m), 1008 (m), 1081 (vs), 1102 (vs), 1114
(vs), 1182 (vs), 1203 (vs), 1274 (vs), 1324 (s), 1377 (w), 1432 (vs), 1455 (m), 1480 (m),
1494 (s), 1525 (m), 1576 (vs), 1606 (vs), 1672 (vs), 1708 (vs), 1723 (s), 2955 (m) cm–1. Td
+
(TGA) = 234.6 °C. HRMS (ESI) m/z: [M + H]+ calcd for C17H17N2O4 , 313.1183; found,
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313.1177.
Experimental data for 6. Formamidine 5 (2 g, 6.4 mmol), sodium hydroxide (1.54 g, 38.4
mmol); isolated yield (light brown powder): 1.69 g (92.8 %). 1H NMR (400.13 MHz, DMSO-
d6, 298 K): δ = 11.36 (s, 2H), 8.41 (s, 1H), 7.86 (d, J = 7.9 Hz, 2H), 7.61 (d, J = 7.5 Hz, 2H),
7.55 – 6.70 (m, 4H). C NMR (100.61 MHz, DMSO-d6, 298 K): δ = 167.6, 167.3, 148.8,
130.8, 129.2, 123.7. IR (diamond ATR): ꢀȬ = 502 (w), 636 (w), 678 (m), 758 (m), 809 (w),
13
854 (w), 1113 (w), 1176 (m), 1225 (m), 1337 (m), 1377 (m), 1516 (m), 1600 (m), 1694 (m),
2604 (w) cm–1. Td (TGA) = 230.4 °C. HRMS (ESI) m/z: [M + H]+ calcd for C15H13N2O4 ,
+
285.0870; found, 285.0871.
Experimental data for 7. 4-Nitroaniline (10 g, 72.4 mmol), triethyl orthoformate (5.63 g, 38
mmol), glacial acetic acid (0.22 g. 3.6 mmol); isolated yield (yellow powder): 9.67 g (93.3
1
%). H NMR (400.13 MHz, DMSO-d6, 298 K): δ = 10.82 (s, 1H), 8.58 (s, 1H), 8.20 (d, J =
9.0 Hz, 4H), 7.82 – 7.12 (m, 4H). 13C NMR (100.61 MHz, DMSO-d6, 298 K) δ =150, 142.3,
125.1, 121.4, 116.9. The data are in agreement with those reported in the literature.89
Experimental data for 8. 4-Bromoaniline (10 g, 58.1 mmol), triethyl orthoformate (4.52 g,
30.5 mmol), glacial acetic acid (0.18 g. 2.9 mmol); isolated yield (gray powder): 9.89 g (96.1
%). 1H NMR (400.13 MHz, DMSO-d6, 298 K): δ = 9.90 (s, 1H), 8.19 (s, 1H), 7.44 (d, J = 8.2
13
Hz, 4H), 7.40 – 6.81 (m, 4H). C NMR (100.61 MHz, DMSO-d6, 298 K) δ = 148.3, 131.7,
121, 114.2. The data are in agreement with those reported in the literature.90
Experimental data for 9. 4-Methoxyaniline (10 g, 81.2 mmol), triethyl orthoformate (6.32
g, 42.6 mmol), glacial acetic acid (0.24 g. 4.1 mmol); isolated yield (gray powder): 9.81 g
(94.3 %). 1H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.04 (s, 1H), 7.52 (s, 1H), 7.00
(d, J = 8.7 Hz, 4H), 6.86 (d, J = 8.9 Hz, 4H), 3.79 (s, 6H). 13C NMR (100.61 MHz,
Chloroform-d, 298 K) δ =156.3, 149, 138.1, 120.4, 114.8, 55.7. The data are in agreement
with those reported in the literature.90
Experimental data for 10. 3-Bromoaniline (10 g, 58.1 mmol), triethyl orthoformate (4.52 g,
30.5 mmol), glacial acetic acid (0.18 g. 2.9 mmol); isolated yield (pale yellow powder): 9.6 g
(93.3 %). 1H NMR (400.13 MHz, DMSO-d6, 298 K): δ = 10.00 (s, 1H), 8.30 (s, 1H), 8.00 –
7.36 (m, 2H), 7.36 – 7.04 (m, 6H). 13C NMR (100.61 MHz, DMSO-d6, 298 K) δ = 148.9,
130.8, 125, 122, 121.1, 118.1. Reported without complete data set elsewhere.91-93
Experimental data for 11. 3-Methylaniline (10 g, 93.3 mmol), triethyl orthoformate (7.26 g,
49 mmol), glacial acetic acid (0.28 g. 4.7 mmol); isolated yield (pale yellow powder): 9.81 g
(93.7 %). 1H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.20 (s, 1H), 7.59 (s, 1H), 7.20
13
(t, J = 8.1 Hz, 2H), 6.91 (d, J = 7.7 Hz, 2H), 6.89 – 6.81 (m, 4H), 2.33 (s, 6H). C NMR
(100.61 MHz, Chloroform-d, 298 K) δ = 148.7, 144.5, 139.5, 129.4, 124.6, 119.9, 116, 21.6.
The data are in agreement with those reported in the literature.90
Experimental data for 1a. Formamidine 1 (3 g, 9.6 mmol), 1,2-dibromoethane (2.71 g, 14.4
mmol), potassium carbonate (3.98 g, 28.8 mmol); isolated yield (yellow powder): 3.28 g
(95.8 %). H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.52 (s, 1H), 8.06 (d, J = 8.7
Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 6.49 (d, J = 8.8 Hz, 2H), 4.57 (s,
1H), 4.12 (t, J = 6.0 Hz, 2H), 3.92 (s, 3H), 3.83 (s, 3H), 3.42 (t, J = 6.1 Hz, 2H). C NMR
(100.61 MHz, Chloroform-d, 298 K): δ = 167.3, 166.1, 163, 151.5, 144.7, 131.7, 131.5,
128.9, 123.1, 119, 111.5, 52.5, 51.7, 44.8, 42. IR (diamond ATR): ꢀȬ = 404 (w), 423 (vw), 457
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(m), 482 (w), 498 (m), 518 (s), 584 (m), 635 (w), 694 (vs), 768 (vs), 825 (s), 840 (s), 861 (m),
956 (s), 988 (m), 1014 (s), 1034 (m), 1098 (vs), 1112 (vs), 1134 (s), 1181 (vs), 1202 (s), 1275
(vs), 1320 (m), 1347 (s), 1429 (vs), 1462 (m), 1495 (m), 1513 (m), 1537 (s), 1577 (s), 1603
(vs), 1663 (vs), 1709 (vs), 1722 (s), 1916 (w), 2899 (w), 2958 (w), 3032 (w), 3361 (m).
Experimental data for 1b. Formamidine 1 (3 g, 9.6 mmol), 1,3-dibromopropane (2.91 g,
14.4 mmol), potassium carbonate (3.98 g, 28.8 mmol); isolated yield (yellow powder): 3.34 g
1
(93.9 %). H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.53 (s, 1H), 8.08 (d, J = 8.7
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Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 6.53 (d, J = 8.8 Hz, 2H), 4.66 (s,
1H), 3.99 (t, J = 6.6 Hz, 2H), 3.93 (s, 3H), 3.84 (s, 3H), 3.21 (t, J = 6.4 Hz, 2H), 1.84 (p, J =
6.5 Hz, 2H). C NMR (100.61 MHz, Chloroform-d, 298 K): δ = 167.4, 166.1, 162.4, 151.7,
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144.6, 131.7, 131.5, 128.7, 122.7, 118.6, 111.7, 52.4, 51.6, 42, 40.1, 26.9. IR (diamond
ATR): ꢀȬ = 427 (w), 509 (m), 566 (w), 634 (w), 649 (w), 700 (s), 769 (vs), 820 (w), 843 (s),
968 (m), 991 (m), 1005 (m), 1106 (vs), 1114 (vs), 1132 (m), 1171 (vs), 1190 (s), 1265 (vs),
1280 (vs), 1312 (m), 1341 (s), 1387 (w), 1422 (m), 1434 (vs), 1477 (m), 1529 (s), 1576 (s),
1599 (vs), 1679 (vs), 1924 (vw), 2906 (w), 2952 (w), 2995 (w), 3376 (m).
Experimental data for 1c. Formamidine 1 (3 g, 9.6 mmol), 1,4-dibromobutane (3.11 g, 14.4
mmol), potassium carbonate (3.98 g, 28.8 mmol); isolated yield (brown powder): 3.67 g (99.4
%). 1H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.50 (s, 1H), 8.07 (d, J = 8.7 Hz, 2H),
7.83 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H), 6.51 (d, J = 8.8 Hz, 2H), 4.37 (s, 1H), 3.93
(s, 3H), 3.91 (t, J = 6.8 Hz, 2H), 3.83 (s, 3H), 3.17 (t, J = 6.4 Hz, 2H), 1.72 – 1.57 (m, 4H).
13C NMR (100.61 MHz, Chloroform-d, 298 K): δ = 167.4, 166.2, 162.1, 151.8, 144.8, 131.7,
131.4, 128.5, 122.7, 118.7, 111.7, 52.4, 51.6, 44.1, 43, 26.3, 25.3. IR (diamond ATR): ꢀȬ =
420 (m), 486 (m), 504 (s), 516 (m), 557 (s), 634 (m), 655 (m), 696 (vs), 730 (m), 766 (vs),
831 (s), 859 (s), 928 (m), 942 (m), 963 (s), 981 (m), 1010 (s), 1025 (m), 1047 (m), 1096 (vs),
1112 (vs), 1128 (vs), 1176 (vs), 1235 (vs), 1245 (vs), 1271 (vs), 1312 (s), 1346 (s), 1429 (vs),
1460 (m), 1477 (s), 1491 (s), 1515 (vs), 1527 (s), 1600 (vs), 1664 (vs), 1710 (vs), 1913 (vs),
2872 (w), 2908 (w), 2953 (m), 3001 (w), 3385 (s).
Experimental data for 3a. Formamidine 3 (3 g, 9.6 mmol), 1,2-dibromoethane (2.71 g, 14.4
mmol), potassium carbonate (3.98 g, 28.8 mmol); isolated yield (reddish-brown viscous oil):
3.17 g (92.6 %). 1H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.44 (s, 1H), 7.96 (dt, J =
7.8, 1.3 Hz, 1H), 7.84 – 7.80 (m, 1H), 7.50 – 7.43 (m, 1H), 7.37 – 7.31 (m, 2H), 7.20 – 7.13
(m, 2H), 6.72 (ddd, J = 8.1, 2.6, 1.0 Hz, 1H), 4.19 (s, 1H), 4.11 (t, J = 6.1 Hz, 2H), 3.91 (s,
3H), 3.86 (s, 3H), 3.38 (t, J = 6.1 Hz, 2H). 13C NMR (100.61 MHz, Chloroform-d, 298 K): δ
= 167.5, 166, 163.1, 147.8, 141.1, 132.1, 131.2, 130.1, 129.3, 128.5, 128.3, 125.2, 118.9,
117.4, 113.2, 52.6, 52.1, 45, 42.4. IR (diamond ATR): ꢀȬ = 466 (w), 515 (w), 654 (w), 686
(vs), 710 (m), 751 (vs), 806 (w), 870 (w), 894 (w), 993 (s), 1022 (m), 1083 (vs), 1105 (vs),
1209 (vs), 1237 (vs), 1281 (vs), 1344 (s), 1435 (vs), 1490 (s), 1519 (m), 1586 (vs), 1604 (vs),
1669 (vs), 1715 (vs), 2883 (w), 2951 (w), 3378 (w).
Experimental data for 3b. Formamidine 3 (3 g, 9.6 mmol), 1,3-dibromopropane (2.91 g,
14.4 mmol), potassium carbonate (3.98 g, 28.8 mmol); isolated yield (reddish-brown viscous
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oil): 3.42 g (96.1 %). H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.43 (s, 1H), 7.97
(dt, J = 7.8, 1.4 Hz, 1H), 7.84 (t, J = 2.0 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.37 – 7.31 (m,
2H), 7.22 (dd, J = 2.5, 1.6 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.75 (ddd, J = 8.1, 2.6, 1.0 Hz,
1H), 3.98 (t, J = 6.7 Hz, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 3.19 (t, J = 6.4 Hz, 2H), 1.83 (p, J =
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6.6 Hz, 2H). C NMR (100.61 MHz, Chloroform-d, 298 K): δ = 167.6, 166.1, 162.6, 148,
141, 132.1, 131.2, 130.1, 129.3, 128.3, 128.2, 125, 118.6, 117.6, 113.4, 52.6, 52.1, 42.4, 40.6,
27. IR (diamond ATR): ꢀȬ = 466 (vw), 515 (w), 549 (w), 655 (m), 686 (vs), 709 (m), 751 (vs),
809 (m), 868 (m), 894 (m), 993 (s), 1027 (m), 1082 (vs), 1106 (vs), 1191 (vs), 1238 (vs),
1283 (vs), 1435 (vs), 1490 (s), 1520 (m), 1586 (vs), 1603 (vs), 1668 (vs), 1715 (vs), 2880
(w), 2951 (w), 3376 (w).
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Experimental data for 3c. Formamidine 3 (3 g, 9.6 mmol), 1,4-dibromobutane (3.11 g, 14.4
mmol), potassium carbonate (3.98 g, 28.8 mmol); isolated yield (reddish-brown viscous oil):
3.66 g (99.1 %). 1H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.39 (s, 1H), 7.96 (dt, J =
7.8, 1.3 Hz, 1H), 7.83 (t, J = 1.9 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.35 (dddd, J = 5.8, 4.7,
2.5, 1.2 Hz, 2H), 7.26 – 7.23 (m, 1H), 7.19 (t, J = 7.9 Hz, 1H), 6.79 (dd, J = 8.0, 1.6 Hz, 1H),
3.97 (s, 1H), 3.92 (m, 5H), 3.86 (s, 3H), 3.14 (t, J = 6.2 Hz, 2H), 1.64 (p, J = 3.5 Hz, 4H). 13C
NMR (50.32 MHz, Chloroform-d, 298 K): δ = 167.6, 166.2, 162.3, 148.1, 141.1, 132.1,
131.2, 130.1, 129.3, 128.4, 128.1, 125, 118.7, 117.5, 113.4, 52.6, 52.1, 44.5, 43.6, 26.4, 25.4.
IR (diamond ATR): ꢀȬ = 426 (vw), 509 (w), 556 (w), 654 (w), 689 (vs), 709 (m), 752 (vs),
815 (w), 865 (w), 901 (w), 1001 (m), 1018 (m), 1083 (vs), 1106 (vs), 1190 (s), 1239 (vs),
1280 (vs), 1349 (s), 1436 (vs), 1490 (m), 1522 (w), 1586 (vs), 1603 (vs), 1670 (vs), 1716
(vs), 2868 (w), 2950 (m), 3384 (w).
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Experimental data for 5a. Formamidine 5 (3 g, 9.6 mmol), 1,2-dibromoethane (2.71 g, 14.4
mmol), potassium carbonate (3.98 g, 28.8 mmol); isolated yield (reddish-brown viscous oil):
3.34 g (97.6 %). The formamide 19 is a mixture of two isomers where the aldehyde
functionality is located at the nitrogen atom of para- (minor product) or meta-substituted ring
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(major product) at the ratio of 19 to 81 %, respectively. Major product: H NMR (400.13
MHz, Chloroform-d, 298 K): δ = 1H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 1H), 7.98 (d,
J = 8.0 Hz, 1H), 7.85 – 7.81 (m, 3H), 7.48 (t, J = 7.9 Hz, 1H), 7.34 – 7.30 (m, 1H), 6.49 (d, J
= 8.7 Hz, 2H), 4.12 (t, J = 6.0 Hz, 2H), 3.92 (s, 3H), 3.84 (s, 3H), 3.40 (q, J = 5.8 Hz, 2H).
13C NMR (100.61 MHz, Chloroform-d, 298 K): δ = 167.4, 166, 163.3, 151.5, 140.9, 131.7,
131.5, 130.2, 128.6, 128.5, 125.2, 123, 111.5, 52.7, 51.7, 45, 42. IR (diamond ATR): ꢀȬ = 418
(vw), 510 (m), 637 (w), 656 (w), 697 (vs), 754 (vs), 770 (vs), 794 (vw), 839 (m), 900 (w),
968 (m), 1016 (m), 1106 (vs), 1135 (s), 1173 (vs), 1205 (vs), 1266 (vs), 1347 (s), 1433 (vs),
1491 (m), 1529 (vs), 1585 (vs), 1602 (vs), 1667 (vs), 1707 (vs), 2950 (m), 3374 (w) cm–1.
Experimental data for 5b. Formamidine 5 (3 g, 9.6 mmol), 1,3-dibromopropane (2.91 g,
14.4 mmol), potassium carbonate (3.98 g, 28.8 mmol); isolated yield (reddish-brown viscous
oil): 3.38 g (95 %). The formamide 20 is a mixture of two isomers where the aldehyde
functionality is located at the nitrogen atom of para- (minor product) or meta-substituted ring
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(major product) at the ratio of 21 to 79 %, respectively. Major product: H NMR (400.13
MHz, Chloroform-d, 298 K): δ = 8.44 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.87 – 7.80 (m, 3H),
7.50 (t, J = 7.9 Hz, 1H), 7.37 – 7.31 (m, 1H), 6.54 (d, J = 8.6 Hz, 2H), 3.98 (t, J = 6.5 Hz,
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2H), 3.94 (s, 3H), 3.84 (s, 3H), 3.22 (t, J = 6.1 Hz, 2H), 1.81 (p, J = 6.4 Hz, 2H). C NMR
(100.61 MHz, Chloroform-d, 298 K): δ = 167.4, 166.1, 162.7, 151.6, 140.8, 132.1, 131.7,
130.2, 128.4, 128.3, 125, 122.7, 111.7, 52.7, 51.7, 42.2, 40, 26.6. IR (diamond ATR): ꢀȬ = 511
(m), 572 (w), 635 (w), 654 (w), 699 (s), 756 (vs), 771 (vs), 817 (w), 838 (m), 896 (w), 967
(m), 1016 (m), 1107 (vs), 1173 (vs), 1244 (vs), 1273 (vs), 1346 (s), 1433 (vs), 1490 (m),
1529 (s), 1602 (vs), 1669 (vs), 1704 (vs), 2950 (m), 3373 (w) cm–1.
Experimental data for 5c. Formamidine 5 (3 g, 9.6 mmol), 1,4-dibromobutane (3.11 g, 14.4
mmol), potassium carbonate (3.98 g, 28.8 mmol); isolated yield (reddish-brown viscous oil):
3.66 g (99.1 %). The formamide 21 is a mixture of two isomers where the aldehyde
functionality is located at the nitrogen atom of para- (minor product) or meta-substituted ring
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(major product) at the ratio of 19 to 81 %, respectively. Major product: H NMR (400.13
MHz, Chloroform-d, 298 K): δ = 8.40 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.87 – 7.80 (m, 3H),
7.49 (t, J = 7.9 Hz, 1H), 7.37 – 7.31 (m, 1H), 6.51 (d, J = 8.5 Hz, 2H), 3.95 – 3.91 (m, 5H),
3.84 (s, 3H), 3.21 – 3.13 (m, 2H), 1.66 – 1.60 (m, 4H). 13C NMR (100.61 MHz, Chloroform-
d, 298 K): δ = 167.4, 166.2, 162.4, 141, 132, 131.7, 131.4, 130.1, 128.4, 128.1, 125, 122.6,
111.6, 52.6, 51.7, 44.4, 43, 26.2, 25.3. IR (diamond ATR): ꢀȬ = 509 (m), 581 (w), 635 (w),
653 (w), 695 (s), 757 (vs), 771 (vs), 838 (m), 966 (m), 1016 (m), 1106 (vs), 1172 (vs), 1243
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(vs), 1272 (vs), 1346 (s), 1433 (vs), 1489 (m), 1530 (s), 1602 (vs), 1671 (vs), 1704 (vs), 2949
(m), 3347 (w) cm–1.
Experimental data for 7a. Formamidine 7 (3 g, 10.5 mmol), 1,2-dibromoethane (2.95 g,
15.7 mmol), potassium carbonate (4.35 g, 31.4 mmol); isolated yield (yellow powder): 3.38 g
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(97.6 %). H NMR (400.13 MHz, DMSO-d6, 298 K): δ = 8.75 (s, 1H), 8.23 (d, J = 9.1 Hz,
2H), 7.96 (d, J = 9.0 Hz, 2H), 7.60 (d, J = 9.1 Hz, 2H), 7.27 (t, J = 6.2 Hz, 1H), 6.60 (d, J =
9.1 Hz, 2H), 4.04 (t, J = 6.7 Hz, 2H), 3.41 – 3.39 (m, 2H).
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Experimental data for 7b. Formamidine 7 (3 g, 10.5 mmol), 1,3-dibromopropane (3.17 g,
15.7 mmol), potassium carbonate (4.35 g, 31.4 mmol); isolated yield (yellow powder): 3.41 g
(94.5 %). H NMR (400.13 MHz, DMSO-d6, 298 K): δ = 8.74 (s, 1H), 8.24 (d, J = 9.2 Hz,
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2H), 7.95 (d, J = 9.1 Hz, 2H), 7.66 (d, J = 9.2 Hz, 2H), 7.22 (t, J = 5.6 Hz, 1H), 6.56 (d, J =
9.3 Hz, 2H), 4.00 (t, J = 7.1 Hz, 2H), 3.15 – 3.10 (m, 2H), 1.78 (p, J = 7.1 Hz, 2H).
Experimental data for 7c. Formamidine 7 (3 g, 10.5 mmol), 1,4-dibromobutane (3.39 g,
15.7 mmol), potassium carbonate (4.35 g, 31.4 mmol); isolated yield (yellow powder): 3.56 g
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(94.8 %). H NMR (400.13 MHz, DMSO-d6, 298 K): δ = 8.74 (s, 1H), 8.24 (d, J = 9.1 Hz,
2H), 7.96 (d, J = 9.0 Hz, 2H), 7.64 (d, J = 9.2 Hz, 2H), 7.25 (t, J = 5.4 Hz, 1H), 6.58 (d, J =
9.3 Hz, 2H), 3.93 (t, J = 6.5 Hz, 2H), 3.12 (q, J = 6.1 Hz, 2H), 1.59 – 1.50 (m, 4H).
Experimental data for 8a. Formamidine 8 (3 g, 8.5 mmol), 1,2-dibromoethane (2.39 g, 12.7
mmol), potassium carbonate (3.51 g, 25.4 mmol); isolated yield (gray powder): 3.28 g (97.2
%). 1H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.37 (s, 1H), 7.53 (d, J = 8.7 Hz, 2H),
7.22 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 6.42 (d, J = 8.8 Hz, 2H), 4.02 (t, J = 6.1
Hz, 2H), 3.29 (t, J = 6.1 Hz, 2H).
Experimental data for 8b. Formamidine 8 (3 g, 8.5 mmol), 1,3-dibromopropane (2.57 g,
12.7 mmol), potassium carbonate (3.51 g, 25.4 mmol); isolated yield (pale green powder):
3.29 g (94.2 %). 1H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.36 (s, 1H), 7.54 (d, J =
8.7 Hz, 2H), 7.25 (d, J = 8.9 Hz, 3H), 7.02 (d, J = 8.7 Hz, 2H), 6.52 (d, J = 8.8 Hz, 2H), 3.91
(t, J = 6.6 Hz, 2H), 3.12 (t, J = 6.5 Hz, 2H), 1.82 (p, J = 6.5 Hz, 2H).
Experimental data for 8c. Formamidine 8 (3 g, 8.5 mmol), 1,4-dibromobutane (2.74 g, 12.7
mmol), potassium carbonate (3.51 g, 25.4 mmol); isolated yield (gray powder): 3.46 g (95.8
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%). H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.27 (s, 1H), 7.83 – 7.69 (m, 4H),
7.52 (d, J = 8.6 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 4.79 – 4.63 (m, 2H), 3.75 (t, J = 6.7 Hz,
2H), 1.56 (p, J = 7.0 Hz, 2H), 1.37 (p, J = 7.1 Hz, 2H).
Experimental data for 9a. Formamidine 9 (3 g, 11.7 mmol), 1,2-dibromoethane (3.30 g,
17.6 mmol), potassium carbonate (4.85 g, 35.1 mmol); isolated yield (pale green powder):
3.28 g (93.3 %). 1H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.30 (s, 1H), 7.09 (d, J =
8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 6.75 (d, J = 8.9 Hz, 2H), 6.52 (d, J = 8.9 Hz, 2H), 3.98
(t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 3.73 (s, 3H), 3.26 (t, J = 6.2 Hz, 2H).
Experimental data for 9b. Formamidine 9 (3 g, 11.7 mmol), 1,3-dibromopropane (3.54 g,
17.6 mmol), potassium carbonate (4.85 g, 35.1 mmol); isolated yield (green oil): 3.39 g (92.1
%). 1H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.28 (s, 1H), 7.09 (d, J = 8.8 Hz, 2H),
7.03 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 3.89 – 3.82 (m,
5H), 3.74 (s, 3H), 3.23 – 3.15 (m, 2H), 1.79 (p, J = 7.5, 7.0 Hz, 2H).
Experimental data for 9c. Formamidine 9 (3 g, 11.7 mmol), 1,4-dibromobutane (3.79 g,
17.6 mmol), potassium carbonate (4.85 g, 35.1 mmol); isolated yield (green sticky oil): 3.82
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g (99.4 %). H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.14 (s, 1H), 7.74 (d, J = 9.3
Hz, 2H), 7.02 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 6.86 (d, J = 8.9 Hz, 2H), 4.57 (dt,
J = 12.5, 6.5 Hz, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 3.65 (t, J = 6.7 Hz, 2H), 1.48 (p, J = 7.0 Hz,
2H), 1.35 (dt, J = 15.2, 7.4 Hz, 2H).
Experimental data for 10a. Formamidine 10 (3 g, 8.5 mmol), 1,2-dibromoethane (2.39 g,
12.7 mmol), potassium carbonate (3.51 g, 25.4 mmol); isolated yield (pale brown powder):
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3.13 g (92.8 %). 1H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.40 (s, 1H), 7.46 (dd, J
= 8.0, 1.8 Hz, 1H), 7.32 (t, J = 2.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.08 (dd, J = 8.0, 2.1
Hz, 1H), 6.99 (t, J = 8.1 Hz, 1H), 6.80 (dd, J = 7.8, 1.7 Hz, 1H), 6.65 (t, J = 2.1 Hz, 1H), 6.46
(dd, J = 8.2, 2.3 Hz, 1H), 4.04 (t, J = 6.1 Hz, 2H), 3.31 (q, J = 5.8 Hz, 2H).
Experimental data for 10b. Formamidine 10 (3 g, 8.5 mmol), 1,3-dibromopropane (2.57 g,
12.7 mmol), potassium carbonate (3.51 g, 25.4 mmol); isolated yield (pale green oil): 3.34 g
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(95.6 %). H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.39 (s, 1H), 7.45 (dt, J = 7.7,
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1.4 Hz, 1H), 7.34 – 7.30 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 8.2, 2.1 Hz, 1H),
7.01 (t, J = 8.0 Hz, 1H), 6.82 (dd, J = 7.8, 1.8 Hz, 1H), 6.75 (t, J = 2.1 Hz, 1H), 6.54 (dd, J =
8.2, 2.3 Hz, 1H), 3.92 (t, J = 6.6 Hz, 2H), 3.14 (t, J = 6.4 Hz, 2H), 1.83 (p, J = 6.5 Hz, 2H).
Experimental data for 10c. Formamidine 10 (3 g, 8.5 mmol), 1,4-dibromobutane (2.74 g,
12.7 mmol), potassium carbonate (3.51 g, 25.4 mmol); isolated yield (pale green oil): 3.47 g
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(96.1 %). H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.37 (s, 1H), 7.47 – 7.42 (m,
1H), 7.33 (t, J = 2.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 8.0, 2.1 Hz, 1H), 7.00 (t,
J = 8.0 Hz, 1H), 6.81 (dd, J = 7.8, 1.8 Hz, 1H), 6.73 (t, J = 2.1 Hz, 1H), 6.52 (dd, J = 8.1, 2.3
Hz, 1H), 3.85 (t, J = 6.7 Hz, 2H), 3.18 – 3.02 (m, 2H), 1.69 – 1.57 (m, 4H).
Experimental data for 11a. Formamidine 11 (3 g, 13.4 mmol), 1,2-dibromoethane (3.77 g,
20.1 mmol), potassium carbonate (5.55 g, 40.1 mmol); isolated yield (orange oil): 3.41 g (95
%). 1H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.40 (s, 1H), 7.29 (t, J = 7.9 Hz, 1H),
7.13 (d, J = 7.6 Hz, 1H), 7.07 – 7.02 (m, 1H), 7.00 – 6.95 (m, 2H), 6.52 (d, J = 7.0 Hz, 1H),
6.37 (dd, J = 6.5, 2.4 Hz, 2H), 4.05 (t, J = 6.2 Hz, 2H), 3.33 (t, J = 6.2 Hz, 2H), 2.36 (s, 3H),
2.25 (s, 3H).
Experimental data for 11b. Formamidine 11 (3 g, 13.4 mmol), 1,3-dibromopropane (4.05 g,
20.1 mmol), potassium carbonate (5.55 g, 40.1 mmol); isolated yield (orange oil): 3.71 g
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(98.2 %). H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.38 (s, 1H), 7.32 – 7.27 (m,
1H), 7.12 (d, J = 7.8 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 7.01 – 6.93 (m, 2H), 6.53 (d, J = 7.7
Hz, 1H), 6.50 – 6.37 (m, 2H), 3.93 (t, J = 6.7 Hz, 2H), 3.15 (t, J = 6.5 Hz, 2H), 2.37 (s, 3H),
2.26 (s, 3H), 1.83 (p, J = 6.5 Hz, 2H).
Experimental data for 11c. Formamidine 11 (3 g, 13.4 mmol), 1,4-dibromobutane (4.33 g,
20.1 mmol), potassium carbonate (5.55 g, 40.1 mmol); isolated yield (orange oil): 3.77 g
1
(95.1 %). H NMR (400.13 MHz, Chloroform-d, 298 K): δ = 8.21 (s, 1H), 7.33 – 7.29 (m,
2H), 7.08 (t, J = 6.8 Hz, 2H), 7.01 – 6.94 (m, 2H), 6.80 (dd, J = 11.1, 3.6 Hz, 2H), 3.78 (t, J =
7.4 Hz, 2H), 3.33 – 3.18 (m, 2H), 2.47 (s, 3H), 2.34 (s, 3H), 1.49 (p, J = 6.9 Hz, 4H).
Experimental data for 12. Formamide 1a (2 g, 5.6 mmol), sodium hydroxide (2.25 g, 56
1
mmol); isolated yield (white powder): 1.59 g (94.4 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 12.00 (s, 2H), 7.68 (d, J = 8.4 Hz, 4H), 6.60 (d, J = 8.5 Hz, 4H), 6.51 (t, J = 5.2
13
Hz, 2H), 3.32 – 3.21 (m, 4H). C NMR (50.32 MHz, DMSO-d6, 298 K): δ =167.4, 152.4,
131.2, 117.1, 110.9, 41.4. IR (diamond ATR): ꢀȬ = 425 (w), 501 (s), 558 (s), 630 (m), 642
(m), 697 (s), 768 (vs), 785 (w), 815 (m), 845 (m), 855 (m), 931 (s), 962 (m), 1092 (m), 1118
(s), 1179 (vs), 1252 (vs), 1294 (vs), 1317 (vs), 1338 (vs), 1427 (vs), 1477 (s), 1493 (s), 1528
(s), 1578 (vs), 1599 (vs), 1665 (vs), 1931 (w), 2543 (m), 2664 (m), 2856 (m), 2901 (m), 2953
(m), 3411 (m). Td (TGA) = 252 °C. HRMS (ESI) m/z: [M + H]+ calcd for C16H17N2O4 ,
+
301.1183; found, 301.1168.
Experimental data for 13. Formamide 1b (2 g, 5.4 mmol), sodium hydroxide (2.16 g, 54
1
mmol); isolated yield (yellow powder): 1.58 g (93.1 %). H NMR (200.13 MHz, DMSO-d6,
298 K): δ = 11.96 (s, 2H), 7.67 (d, J = 8.3 Hz, 4H), 6.58 (d, J = 8.4 Hz, 4H), 6.47 (t, J = 5.4
13
Hz, 2H), 3.17 (q, J = 6.5 Hz, 4H), 1.83 (p, J = 6.9 Hz, 2H). C NMR (50.32 MHz, DMSO-
d6, 298 K): δ = 167.5, 152.6, 131.1, 116.8, 110.8, 40.1, 27.8. IR (diamond ATR): ꢀȬ = 407
(w), 419 (w), 499 (m), 555 (m), 635 (m), 655 (m), 696 (s), 765 (vs), 805 (m), 834 (vs), 941
(m), 1058 (m), 1081 (m), 1103 (m), 1128 (s), 1141 (m), 1174 (vs), 1245 (s), 1292 (vs), 1314
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(vs), 1346 (s), 1425 (s), 1471 (m), 1489 (m), 1528 (s), 1576 (s), 1601 (vs), 1662 (vs), 1922
4
5
6
7
8
9
(w), 2540 (m), 2659 (m), 2863 (m), 2935 (m), 3420 (m). Td (TGA) = 232.1 °C. HRMS (ESI)
+
m/z: [M + H]+ calcd for C17H19N2O4 , 315.1339; found, 315.1320.
Experimental data for 14. Formamide 1c (2 g, 5.2 mmol), sodium hydroxide (2.08 g, 52
1
mmol); isolated yield (white powder): 1.60 g (93.7 %). H NMR (200.13 MHz, DMSO-d6,
298 K): δ = 11.94 (s, 2H), 7.66 (d, J = 8.4 Hz, 4H), 6.56 (d, J = 8.6 Hz, 4H), 6.42 (t, J = 5.4
13
Hz, 2H), 3.23 – 2.93 (m, 4H), 1.85 – 1.42 (m, 4H). C NMR (50.32 MHz, DMSO-d6, 298
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
K): δ = 167.5, 152.7, 131.1, 116.6, 110.7, 42.1, 26.1. IR (diamond ATR): ꢀȬ = 427 (w), 476
(m), 503 (s), 518 (m), 556 (s), 635 (s), 653 (s), 699 (s), 742 (s), 771 (vs), 791 (m), 833 (vs),
844 (s), 856 (m), 936 (s), 968 (m), 1030 (m), 1090 (m), 1121 (vs), 1177 (vs), 1236 (m), 1286
(vs), 1297 (vs), 1319 (vs), 1341 (vs), 1428 (vs), 1445 (m), 1477 (s), 1528 (s), 1574 (s), 1604
(vs), 1662 (vs), 1933 (w), 2546 (m), 2661 (m), 2845 (m), 2860 (m), 2887 (m), 2932 (m),
+
3423 (m). Td (TGA) = 273.9 °C. HRMS (ESI) m/z: [M + H]+ calcd for C18H21N2O4 ,
329.1496; found, 329.1479.
Experimental data for 15. Formamide 3a (2 g, 5.6 mmol), sodium hydroxide (2.25 g, 56
1
mmol); isolated yield (white powder): 1.65 g (97.9 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 12.64 (s, 2H), 7.22 – 7.16 (m, 4H), 7.13 (dt, J = 7.6, 1.3 Hz, 2H), 6.82 (ddd, J =
8.1, 2.5, 1.2 Hz, 2H), 5.95 (m, 2H), 3.26 (m, 4H). 13C NMR (50.32 MHz, DMSO-d6, 298 K):
δ = 167.8, 148.7, 131.4, 129, 116.7, 116.2, 112.5, 41.9. IR (diamond ATR): ꢀȬ = 418 (w), 467
(w), 524 (m), 546 (m), 562 (m), 598 (w), 634 (m), 668 (s), 676 (s), 745 (vs), 776 (m), 806
(m), 818 (m), 857 (m), 867 (s), 933 (s), 993 (m), 1070 (m), 1091 (m), 1124 (m), 1171 (m),
1263 (vs), 1301 (vs), 1325 (s), 1417 (s), 1435 (s), 1471 (s), 1508 (s), 1585 (vs), 1601 (vs),
1675 (vs), 2549 (m), 2843 (m), 3397 (m). Td (TGA) = 222 °C. HRMS (ESI) m/z: [M + H]+
+
calcd for C16H17N2O4 , 301.1183; found, 301.1170.
Experimental data for 16. Formamide 3b (2 g, 5.4 mmol), sodium hydroxide (2.16 g, 54
1
mmol); isolated yield (yellow powder): 1.6 g (94.3 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 12.62 (s, 2H), 7.22 – 7.13 (m, 4H), 7.11 (dt, J = 7.6, 1.3 Hz, 2H), 6.79 (ddd, J =
13
7.9, 2.4, 1.2 Hz, 2H), 5.91 (m, 2H), 3.14 (t, J = 6.9 Hz, 4H), 1.84 (p, J = 6.9 Hz, 2H). C
NMR (50.32 MHz, DMSO-d6, 298 K): δ = 167.9, 149, 131.4, 128.9, 116.5, 116.1, 112.5,
40.7, 27.9. IR (diamond ATR): ꢀȬ = 427 (m), 468 (w), 537 (m), 552 (m), 567 (m), 675 (s), 749
(vs), 783 (m), 803 (m), 862 (m), 889 (m), 914 (m), 992 (m), 1048 (m), 1093 (s), 1115 (s),
1140 (m), 1234 (s), 1257 (vs), 1272 (vs), 1292 (s), 1309 (s), 1411 (m), 1442 (s), 1472 (s),
1506 (m), 1583 (vs), 1602 (vs), 1675 (vs), 1932 (w), 2527 (m), 2641 (m), 2839 (m), 2950
(m), 3405 (w), 3429 (w). Td (TGA) = 218.1 °C. HRMS (ESI) m/z: [M + H]+ calcd for
+
C17H19N2O4 , 315.1339; found, 315.1322.
Experimental data for 17. Formamide 3c (2 g, 5.2 mmol), sodium hydroxide (2.08 g, 52
1
mmol); isolated yield (white powder): 1.56 g (91.3 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 12.64 (s, 2H), 7.24 – 7.01 (m, 6H), 6.78 (d, J = 8.0 Hz, 2H), 5.87 (m, 2H), 3.05
13
(m, 4H), 1.65 (m, 4H). C NMR (50.32 MHz, DMSO-d6, 298 K): δ = 167.9, 149.1, 131.4,
128.9, 116.3, 115.9, 112.4, 42.6, 26.3. IR (diamond ATR): ꢀȬ = 423 (w), 449 (w), 536 (w),
556 (m), 668 (s), 748 (vs), 779 (w), 799 (w), 858 (m), 887 (w), 941 (s), 994 (m), 1075 (m),
1098 (m), 1125 (m), 1168 (w), 1234 (m), 1267 (vs), 1286 (vs), 1349 (m), 1378 (w), 1410
(m), 1441 (s), 1472 (m), 1512 (m), 1588 (s), 1601 (s), 1668 (vs), 1924 (vw), 2517 (w), 2642
(w), 2868 (m), 2938 (m), 2938 (m). Td (TGA) = 215.2 °C. HRMS (ESI) m/z: [M + H]+ calcd
+
for C18H21N2O4 , 329.1496; found, 329.1479.
Experimental data for 18. Formamide 5a (2 g, 5.6 mmol), sodium hydroxide (2.25 g, 56
1
mmol); isolated yield (white powder): 1.556 g (92.3 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 12.27 (s, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.34 – 6.99 (m, 2H), 6.81 (d, J = 7.9 Hz,
1H), 6.72 – 6.32 (m, 4H), 5.99 (m, 1H), 3.32 – 3.15 (m, 4H). 13C NMR (100.61 MHz,
DMSO-d6, 298 K): δ = 168, 167.6, 152.4, 148.7, 131.7, 131.3, 129.1, 117.1, 116.8, 116.2,
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112.5, 110.9, 41.8, 41.4. IR (diamond ATR): ꢀȬ = 427 (w), 502 (w), 553 (w), 629 (w), 667
(w), 698 (w), 749 (m), 771 (m), 814 (w), 838 (m), 874 (w), 934 (w), 1124 (m), 1176 (m),
1291 (s), 1313 (m), 1428 (m), 1462 (w), 1494 (w), 1527 (m), 1603 (m), 1668 (m), 2854 (w)
+
cm–1. Td (TGA) = 198.6 °C. HRMS (ESI) m/z: [M + H]+ calcd for C16H17N2O4 , 301.1183;
found, 301.1171.
Experimental data for 19. Formamide 5b (2 g, 5.4 mmol), sodium hydroxide (2.16 g, 54
1
mmol); isolated yield (yellow powder): 1.613 g (95 %). H NMR (400.13 MHz, DMSO-d6,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
298 K): δ = 12.27 (s, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.27 – 7.05 (m, 2H), 6.79 (d, J = 8.0 Hz,
1H), 6.72 – 6.32 (m, 4H), 5.94 (m, 1H), 3.15 (dq, J = 22.4, 7.5, 6.8 Hz, 4H), 1.83 (p, J = 7.0
Hz, 2H). 13C NMR (100.61 MHz, DMSO-d6, 298 K): δ = 168, 167.6, 152.7, 149, 131.4,
131.2, 129, 116.7, 116.7, 116.5, 116.2, 112.5, 110.8, 40.6, 27.9. IR (diamond ATR): ꢀȬ = 418
(w), 503 (m), 553 (w), 646 (w), 681 (w), 698 (w), 752 (s), 770 (m), 836 (m), 868 (w), 936
(m), 1115 (m), 1175 (vs), 1286 (s), 1316 (s), 1426 (m), 1466 (m), 1488 (m), 1528 (m), 1600
(vs), 1668 (s), 2542 (w), 2865 (w), 3413 (w) cm–1. Td (TGA) = 198.5 °C. HRMS (ESI) m/z:
+
[M + H]+ calcd for C17H19N2O4 , 315.1339; found, 315.1325.
Experimental data for 20. Formamide 5c (2 g, 5.2 mmol), sodium hydroxide (2.08 g, 52
1
mmol); isolated yield (white powder): 1.572 g (92 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 12.27 (s, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.19 – 7.05 (m, 2H), 6.77 (d, J = 8.0 Hz,
13
1H), 6.71 – 6.26 (m, 3H), 5.90 (m, 1H), 3.16 – 2.96 (m, 4H), 1.81 – 1.49 (m, 4H). C NMR
(100.61 MHz, DMSO-d6, 298 K): δ = 168.1, 167.6, 152.7, 149.1, 131.7, 131.2, 128.9, 116.6,
116.4, 115.9, 112.5, 110.7, 42.6, 42.2, 42.1, 26.2. IR (diamond ATR): ꢀȬ = 427 (vw), 503 (w),
553 (w), 648 (w), 680 (w), 699 (w), 746 (m), 772 (m), 836 (m), 863 (w), 938 (w), 994 (w),
1124 (m), 1177 (m), 1292 (m), 1315 (m), 1344 (m), 1429 (m), 1470 (m), 1531 (w), 1605 (vs),
1668 (s), 2862 (w), 2933 (w), 3418 (w) cm–1. Td (TGA) = 204.9 °C. HRMS (ESI) m/z: [M +
+
H]+ calcd for C18H21N2O4 , 329.1496; found, 329.1480.
Experimental data for 21. Formamide 7a (2 g, 6.06 mmol), sodium hydroxide (2.42 g, 60.6
1
mmol); isolated yield (yellow powder): 1.69 g (92.3 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 8.00 (d, J = 9.2 Hz, 4H), 7.39 (d, J = 5.1 Hz, 2H), 6.68 (d, J = 9.3 Hz, 4H), 3.49 –
13
3.35 (m, 4H). C NMR (100.61 MHz, DMSO-d6, 298 K): δ = 154.4, 135.9, 126.2, 110.9,
41.3. IR (diamond ATR): ꢀȬ = 423 (w), 446 (w), 480 (m), 538 (m), 619 (w), 649 (w), 698 (m),
749 (m), 824 (s), 852 (w), 887 (m), 995 (m), 1064 (m), 1091 (m), 1178 (m), 1226 (m), 1281
(s), 1466 (m), 1503 (w), 1538 (m), 1592 (s), 2929 (w), 3370 (m). Td (TGA) = 262.9 °C.
+
HRMS (ESI) m/z: [M + H]+ calcd for C14H15N4O4 , 303.1088; found, 303.1088.
Experimental data for 22. Formamide 7b (2 g, 5.8 mmol), sodium hydroxide (2.32 g, 58
1
mmol); isolated yield (yellow powder): 1.77 g (96.3 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 7.99 (d, J = 8.8 Hz, 4H), 7.33 (t, J = 5.4 Hz, 2H), 6.65 (d, J = 9.0 Hz, 4H), 3.26
(q, J = 6.5 Hz, 4H), 1.87 (p, J = 7.0 Hz, 2H). 13C NMR (100.61 MHz, DMSO-d6, 298 K): δ =
154.5, 135.6, 126.2, 110.8, 40, 27.5. IR (diamond ATR): ꢀȬ = 420 (m), 457 (m), 486 (vs), 536
(vs), 620 (m), 641 (m), 659 (m), 693 (s), 748 (vs), 804 (m), 824 (vs), 898 (m), 940 (s), 995
(vs), 1085 (vs), 1103 (vs), 1179 (s), 1206 (vs), 1268 (vs), 1286 (vs), 1305 (vs), 1318 (vs),
1338 (vs), 1434 (m), 1457 (s), 1477 (s), 1539 (vs), 1594 (vs), 2855 (w), 3341 (s). Td (TGA) =
+
275.3 °C. HRMS (ESI) m/z: [M + H]+ calcd for C15H17N4O4 , 317.1244; found, 317.1246.
Experimental data for 23. Formamide 7c (2 g, 5.58 mmol), sodium hydroxide (2.23 g, 55.8
1
mmol); isolated yield (yellow powder): 1.75 g (94.9 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 7.98 (d, J = 8.9 Hz, 4H), 7.31 (t, J = 5.5 Hz, 2H), 6.64 (d, J = 9.0 Hz, 4H), 3.28 –
13
3.11 (m, 4H), 1.78 – 1.56 (m, 4H). C NMR (100.61 MHz, DMSO-d6, 298 K): δ = 154.5,
135.4, 126.2, 110.6, 42, 25.8. IR (diamond ATR): ꢀȬ = 428 (m), 487 (m), 522 (w), 546 (w),
603 (m), 641 (w), 693 (m), 751 (m), 799 (w), 826 (m), 961 (m), 996 (m), 1103 (s), 1124 (m),
1173 (m), 1227 (m), 1273 (s), 1297 (s), 1350 (w), 1382 (w), 1464 (m), 1540 (m), 1599 (m),
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2955 (w), 3355 (w). Td (TGA) = 257.5 °C. HRMS (ESI) m/z: [M + H]+ calcd for
C16H19N4O4 , 331.1401; found, 331.1402.
+
Experimental data for 24. Formamide 8a (2 g, 5.02 mmol), sodium hydroxide (2.01 g, 50.2
1
mmol); isolated yield (off-white powder): 1.79 g (96.3 %). H NMR (400.13 MHz, DMSO-
d6, 298 K): δ = 7.2 (d, J = 8.8 Hz, 4H), 6.54 (d, J = 8.8 Hz, 4H), 5.87 (t, J = 5.1 Hz, 2H), 3.26
13
– 3.09 (m, 4H). C NMR (100.61 MHz, DMSO-d6, 298 K): δ = 147.9, 131.4, 113.9, 106.2,
41.9. IR (diamond ATR): ꢀȬ = 505 (m), 693 (w), 806 (s), 946 (w), 992 (w), 1067 (m), 1121
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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58
59
60
(m), 1177 (m), 1242 (m), 1317 (m), 1398 (w), 1477 (m), 1503 (m), 1588 (m), 2849 (w), 3406
+
(w). Td (TGA) = 204.3 °C. HRMS (ESI) m/z: [M + H]+ calcd for C14H15Br2N2 , 370.9576;
found, 370.9577.
Experimental data for 25. Formamide 8b (2 g, 4.85 mmol), sodium hydroxide (1.94 g, 48.5
1
mmol); isolated yield (off-white powder): 1.81 g (97.1 %). H NMR (400.13 MHz, DMSO-
d6, 298 K): δ = 7.18 (d, J = 8.8 Hz, 4H), 6.51 (d, J = 8.9 Hz, 4H), 5.84 (t, J = 5.5 Hz, 2H),
13
3.06 (q, J = 6.5 Hz, 4H), 1.78 (p, J = 6.9 Hz, 2H). C NMR (100.61 MHz, DMSO-d6, 298
K): δ = 148.1, 131.3, 113.8, 105.9, 40.5, 27.8. IR (diamond ATR): ꢀȬ = 505 (s), 654 (m), 696
(m), 767 (m), 811 (vs), 994 (m), 1070 (s), 1122 (m), 1138 (m), 1178 (s), 1202 (m), 1250 (s),
1295 (s), 1315 (s), 1398 (m), 1472 (vs), 1493 (vs), 1590 (vs), 1673 (w), 1874 (w), 2837 (m),
2926 (m), 3397 (m). Td (TGA) = 195.3 °C. HRMS (ESI) m/z: [M + H]+ calcd for
+
C15H17Br2N2 , 384.9733; found, 384.9733.
Experimental data for 26. Formamide 8c (2 g, 4.69 mmol), sodium hydroxide (1.88 g, 46.9
1
mmol); isolated yield (off-white powder): 1.82 g (97.4 %). H NMR (400.13 MHz, DMSO-
d6, 298 K): δ = 7.17 (d, J = 8.4 Hz, 4H), 6.50 (d, J = 8.4 Hz, 4H), 5.80 (t, J = 5.6 Hz, 2H),
13
3.07 – 2.91 (m, 4H), 1.70 – 1.52 (m, 4H). C NMR (100.61 MHz, DMSO-d6, 298 K): δ =
148.2, 131.3, 113.7, 105.8, 42.5, 26.2. IR (diamond ATR): ꢀȬ = 418 (w), 504 (s), 648 (m), 693
(w), 749 (m), 810 (vs), 997 (m), 1067 (m), 1085 (m), 1120 (m), 1177 (s), 1191 (m), 1227
(m), 1264 (m), 1294 (m), 1308 (m), 1323 (m), 1395 (m), 1448 (m), 1471 (s), 1494 (s), 1590
(s), 2824 (m), 2941 (m), 3397 (m). Td (TGA) = 197.3 °C. HRMS (ESI) m/z: [M + H]+ calcd
+
for C16H19Br2N2 , 398.9889; found, 398.9889.
Experimental data for 27. Formamide 9a (2 g, 6.66 mmol), sodium hydroxide (2.66 g, 66.6
1
mmol); isolated yield (brown powder): 1.53 g (84.4 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 6.71 (d, J = 8.9 Hz, 4H), 6.54 (d, J = 8.9 Hz, 4H), 5.17 (t, J = 5.5 Hz, 2H), 3.63
13
(s, 6H), 3.22 – 3.05 (m, 4H). C NMR (100.61 MHz, DMSO-d6, 298 K): δ = 150.7, 143,
114.6, 113.1, 55.3, 43.1. IR (diamond ATR): ꢀȬ = 408 (w), 467 (m), 511 (m), 611 (m), 643
(m), 754 (w), 814 (vs), 836 (m), 942 (w), 1030 (vs), 1077 (m), 1118 (m), 1178 (s), 1228 (vs),
1266 (s), 1285 (m), 1407 (m), 1440 (m), 1463 (s), 1506 (vs), 1668 (w), 2835 (w), 2898 (w),
2952 (w), 3358 (w). Td (TGA) = 209.9 °C. HRMS (ESI) m/z: [M + H]+ calcd for
+
C16H21N2O2 , 273.1598; found, 273.1598.
Experimental data for 28. Formamide 9b (2 g, 6.36 mmol), sodium hydroxide (2.54 g, 63.6
1
mmol); isolated yield (brown powder): 1.49 g (81.8 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 6.70 (d, J = 8.9 Hz, 4H), 6.52 (d, J = 8.9 Hz, 4H), 5.13 (br s, 2H), 3.63 (s, 6H),
3.03 (t, J = 6.9 Hz, 4H), 1.77 (p, J = 7.0 Hz, 2H). 13C NMR (100.61 MHz, DMSO-d6, 298 K):
δ = 150.5, 143.3, 114.6, 113, 55.3, 41.7, 28.5. IR (diamond ATR): ꢀȬ = 520 (w), 600 (w), 716
(w), 762 (w), 777 (w), 818 (m), 1029 (m), 1088 (w), 1138 (w), 1177 (m), 1232 (m), 1253
(m), 1303 (w), 1335 (w), 1407 (w), 1440 (w), 1455 (m), 1511 (m), 1618 (w), 2832 (w), 2931
+
(w), 3377 (w). Td (TGA) = 201.5 °C. HRMS (ESI) m/z: [M + H]+ calcd for C17H23N2O2 ,
287.1754; found, 287.1750.
Experimental data for 29. Formamide 9c (2 g, 6.09 mmol), sodium hydroxide (2.44 g, 60.9
1
mmol); isolated yield (brown powder): 1.53 g (83.6 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 6.69 (d, J = 8.9 Hz, 4H), 6.51 (d, J = 8.9 Hz, 4H), 5.09 (br s, 2H), 3.62 (s, 6H),
13
3.05 – 2.86 (m, 4H), 1.73 – 1.50 (m, 4H). C NMR (100.61 MHz, DMSO-d6, 298 K): δ =
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150.4, 143.4, 114.6, 112.9, 55.3, 43.6, 26.6. IR (diamond ATR): ꢀȬ = 459 (m), 529 (vw), 577
(vw), 768 (w), 819 (m), 956 (w), 998 (w), 1028 (s), 1082 (s), 1175 (m), 1235 (m), 1300 (w),
1405 (vw), 1449 (w), 1473 (w), 1514 (m), 1618 (vw), 2835 (vw), 3378 (w). Td (TGA) =
+
195.3 °C. HRMS (ESI) m/z: [M + H]+ calcd for C18H25N2O2 , 301.1911; found, 301.1912.
Experimental data for 30. Formamide 10a (2 g, 5.02 mmol), sodium hydroxide (2.01 g,
1
50.2 mmol); isolated yield (brown oil): 1.7 g (91.4 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 7.01 (t, J = 8.0 Hz, 2H), 6.73 (t, J = 2.1 Hz, 2H), 6.66 (dd, J = 7.8, 1.8 Hz, 2H),
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48
49
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54
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56
57
58
59
60
13
6.57 (dd, J = 8.2, 2.2 Hz, 2H), 6.21 – 5.71 (m, 2H), 3.26 – 3.12 (m, 4H). C NMR (100.61
MHz, DMSO-d6, 298 K): δ = 150.3, 130.7, 122.4, 117.9, 114, 111, 41.6. IR (diamond ATR):
ꢀȬ = 434 (s), 522 (w), 679 (vs), 758 (vs), 835 (vs), 932 (m), 984 (vs), 1067 (vs), 1084 (s), 1117
(m), 1166 (s), 1247 (vs), 1279 (s), 1320 (vs), 1364 (m), 1417 (s), 1465 (vs), 1479 (vs), 1496
(vs), 1571 (vs), 1590 (vs), 1916 (w), 2854 (m), 3401 (m). Td (TGA) = 243.5 °C. HRMS (ESI)
m/z: [M + H]+ calcd for C14H15Br2N2 , 370.9576; found, 370.9575.
+
Experimental data for 31. Formamide 10b (2 g, 4.85 mmol), sodium hydroxide (1.94 g,
1
48.5 mmol); isolated yield (yellow oil): 1.75 g (93.9 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 6.99 (t, J = 8.0 Hz, 2H), 6.71 (t, J = 2.1 Hz, 2H), 6.63 (dd, J = 7.7, 1.8 Hz, 2H),
6.55 (dd, J = 8.3, 2.2 Hz, 2H), 5.95 (t, J = 5.5 Hz, 2H), 3.08 (q, J = 6.5 Hz, 4H), 1.78 (p, J =
6.9 Hz, 2H). 13C NMR (100.61 MHz, DMSO-d6, 298 K): δ = 150.6, 130.7, 122.4, 117.6,
113.9, 110.9, 40.3, 27.8. IR (diamond ATR): ꢀȬ = 435 (s), 492 (w), 572 (w), 680 (vs), 757
(vs), 835 (vs), 984 (vs), 1066 (vs), 1084 (s), 1132 (m), 1165 (s), 1200 (m), 1244 (s), 1280 (s),
1322 (vs), 1416 (s), 1470 (vs), 1480 (vs), 1497 (vs), 1571 (vs), 1591 (vs), 2856 (m), 2932
+
(m), 3408 (m). Td (TGA) = 262.2 °C. HRMS (ESI) m/z: [M + H]+ calcd for C15H17Br2N2 ,
384.9733; found, 384.9732.
Experimental data for 32. Formamide 10c (2 g, 4.69 mmol), sodium hydroxide (1.88 g,
1
46.9 mmol); isolated yield (rose-colored crystals): 1.74 g (93.1 %). H NMR (400.13 MHz,
DMSO-d6, 298 K): δ = 6.98 (t, J = 8.0 Hz, 2H), 6.70 (t, J = 2.1 Hz, 2H), 6.62 (dd, J = 7.7, 1.8
Hz, 2H), 6.54 (dd, J = 8.2, 2.2 Hz, 2H), 5.91 (t, J = 5.4 Hz, 2H), 3.01 (q, J = 5.9 Hz, 4H),
13
1.69 – 1.53 (m, 4H). C NMR (100.61 MHz, DMSO-d6, 298 K): δ = 150.6, 130.6, 122.4,
117.5, 113.8, 110.8, 42.3, 26.1. IR (diamond ATR): ꢀȬ = 439 (m), 660 (m), 682 (vs), 760 (vs),
830 (s), 871 (w), 904 (w), 982 (s), 1062 (m), 1078 (m), 1103 (m), 1134 (m), 1163 (m), 1270
(s), 1282 (s), 1321 (s), 1359 (m), 1416 (s), 1453 (s), 1467 (s), 1500 (vs), 1563 (s), 1594 (vs),
2860 (m), 2924 (m), 3394 (m), 3417 (s). Td (TGA) = 262.3 °C. HRMS (ESI) m/z: [M + H]+
+
calcd for C16H19Br2N2 , 398.9889; found, 398.9889.
Experimental data for 33. Formamide 11a (2 g, 7.45 mmol), sodium hydroxide (2.98 g,
1
74.5 mmol); isolated yield (yellow oil): 1.54 g (86 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 6.95 (t, J = 7.6 Hz, 2H), 6.43 – 6.31 (m, 6H), 5.50 (d, J = 5.6 Hz, 2H), 3.24 –
3.10 (m, 4H), 2.18 (s, 6H). 13C NMR (100.61 MHz, DMSO-d6, 298 K): δ = 148.7, 137.9,
128.8, 116.6, 112.6, 109.4, 42.1, 21.4. IR (diamond ATR): ꢀȬ = 441 (vs), 452 (m), 542 (s),
585 (vs), 690 (vs), 766 (vs), 812 (m), 855 (m), 871 (vs), 909 (m), 961 (m), 994 (m), 1090
(vs), 1170 (vs), 1178 (vs), 1202 (m), 1264 (vs), 1289 (s), 1325 (vs), 1375 (m), 1456 (s), 1487
(vs), 1524 (vs), 1590 (vs), 2874 (m), 2914 (s), 3033 (m), 3300 (m). Td (TGA) = 207.4 °C.
+
HRMS (ESI) m/z: [M + H]+ calcd for C16H21N2 , 241.1699; found, 241.1697.
Experimental data for 34. Formamide 11b (2 g, 7.08 mmol), sodium hydroxide (2.83 g,
1
70.8 mmol); isolated yield (brown oil): 1.6 g (88.9 %). H NMR (400.13 MHz, DMSO-d6,
298 K): δ = 6.93 (t, J = 7.7 Hz, 2H), 6.44 – 6.26 (m, 6H), 5.47 (t, J = 5.7 Hz, 2H), 3.07 (q, J =
13
6.5 Hz, 4H), 2.16 (s, 6H), 1.79 (p, J = 6.9 Hz, 2H). C NMR (100.61 MHz, DMSO-d6, 298
K): δ = 149, 137.7, 128.7, 116.3, 112.5, 109.4, 40.7, 28.3, 21.4. IR (diamond ATR): ꢀȬ = 440
(s), 525 (vw), 579 (w), 691 (vs), 765 (vs), 843 (m), 919 (vw), 992 (m), 1035 (w), 1128 (m),
1167 (s), 1179 (s), 1263 (s), 1302 (s), 1327 (s), 1376 (w), 1489 (vs), 1508 (vs), 1587 (vs),
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1603 (vs), 2858 (m), 2918 (m), 3039 (w), 3402 (w). Td (TGA) = 207.9 °C. HRMS (ESI) m/z:
+
[M + H]+ calcd for C17H23N2 , 255.1856; found, 255.1851.
Experimental data for 35. Formamide 11c (2 g, 6.75 mmol), sodium hydroxide (2.7 g, 67.5
1
mmol); isolated yield (brown oil): 1.59 g (87.8 %). H NMR (400.13 MHz, DMSO-d6, 298
K): δ = 6.93 (t, J = 7.6 Hz, 2H), 6.42 – 6.28 (m, 6H), 5.41 (t, J = 5.6 Hz, 2H), 3.00 (q, J = 5.9
13
Hz, 4H), 2.17 (s, 6H), 1.71 – 1.54 (m, 4H). C NMR (100.61 MHz, DMSO-d6, 298 K): δ =
149, 137.7, 128.7, 116.3, 112.5, 109.2, 42.7, 26.5, 21.4. IR (diamond ATR): ꢀȬ = 440 (m), 527
(vw), 580 (vw), 691 (vs), 767 (vs), 843 (w), 992 (m), 1092 (m), 1167 (m), 1179 (m), 1259
(m), 1303 (m), 1328 (s), 1375 (w), 1490 (s), 1509 (s), 1588 (vs), 1603 (vs), 2858 (m), 2919
(m), 3040 (w), 3402 (w). Td (TGA) = 199.4 °C. HRMS (ESI) m/z: [M + H]+ calcd for
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C18H25N2 , 269.2012; found, 269.2010.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI: XXX.
Summary of attempts for one-step synthesis
MALDI-TOF MS spectra
Crystallographic data and X-ray structures
1H, 13C, HSQC (1H-13C) and COSY (1H-1H) NMR spectra of the compounds described in the
Experimental Section
TGA curves
HRMS spectra of the compounds described in the Experimental Section
AUTHOR INFORMATION
Corresponding Author
*E-mail: wendy.queen@epfl.ch
ORCID
Safak Bulut: 0000-0002-9047-6816
Wendy L. Queen: 0000-0002-8375-2341
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Part of this work was supported by the Swiss National Science Foundation under grant
number PYAPP2_160581. We acknowledge the Swiss-Norwegian Beam Lines at European
Synchrotron Radiation Facility for beamtime allocation, Dr. Dmitry Chernyshov for the
assistance on beamline BM01, and Dr. Pascal Schouwink for aid in single crystal X-ray
diffraction.
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