Key words
azides - 1,2,3-triazoles - [1,2,3]triazolo[1,5-
a]pyrazines - Ugi reaction - Huisgen cycloaddition - one-pot - Meerwein reaction
During the last decade, our laboratory has focused on the design and synthesis of
new 1,2,3-triazoles in an effort to discover compounds with biological activities.[1] Among these studies, condensed triazole systems occupy a special place because such
compounds have shown good antiproliferative activity and are promising for further
anticancer research.[2] To expand the research field of condensed 1,2,3-triazole derivatives, 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines deserve attention.[3] [1,2,3]Triazolo[1,5-a]pyrazines have been shown to act as modulators of sigma receptors,[4] β-secretase inhibitors (BACE 1) for Alzheimer’s disease therapy,[5] Cyp8b1 inhibitors for the treatment of diabetes and cardiodiabetic diseases,[6] and as antiviral agents[7] for the treatment of hepatitis B viral infection[8] (Figure [1]). In addition, compounds of this class were found to possess antitumor activity.[9] Therefore, the development of suitable methods to obtain 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines is an important area of research.
Figure 1 Chemical structures of bioactive [1,2,3]triazolo[1,5-a]pyrazines
A general approach to the simultaneous formation of 1,2,3-triazole and pyrazine rings
is the 1,3-dipolar cyclization of α-azido-N-(prop-2-ynyl)amides. A previously described two-step approach to obtain [1,2,3]triazolo[1,5-a]pyrazines proceeded via a sequential Ugi reaction involving an α-azidoacetic acid
or an α-azidophenylacetic acid and propargylamine, followed by a Huisgen cyclization
(Scheme [1]).[10] Recently, a one-step method was developed for the preparation of 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines in an Ugi reaction using superparamagnetic copper-modified iron oxide
and 2-aminobenzamide as the catalyst.[11] However, the reaction was studied only on an unsubstituted azidoacetic acid (Scheme
[1]). Our attention was drawn to derivatives of 2-azido-3-arylpropanoic acids as analogues
of azidated phenylalanine, with 3-phenyl-2-azidopropanoic acid having already been
used for the synthesis of peptidomimetics with 1,2,3-triazole rings instead of amide
fragments.[12] In addition, the 3-aryl-2-(1H-1,2,3-triazol-1-yl)-propanoic acid motif is present in compounds used in cancer diagnostics[13] and therapy.[14] Some 3-aryl-2-(1H-1,2,3-triazol-1-yl)propanoic acid derivatives have been discovered to be inhibitors
of histone deacetylase 8[15] and are being investigated as antidiabetic agents.[16] It should be noted that 3-phenyl-2-azidopropanoic acid and similar compounds are
synthetically available via diazo transfer reactions from the corresponding natural
α-amino acids.[17] However, when the α-amino acids are not readily available synthetically, the preparation
of α-azido acids is limited.
Scheme 1 Previously used and proposed methods for obtaining [1,2,3]triazolo[1,5-a]pyrazines via the Ugi reaction
In the present work, we have developed a convenient method for the synthesis of 2-azido-3-arylpropanoic
acids based on the Meerwein arylation and have utilized the obtained adducts in a
tandem Ugi–Huisgen sequence for the synthesis of new 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines.
Reactions of acrylic acid esters with diazonium salts under Meerwein arylation conditions
is a convenient route to a variety of alkyl 3-aryl-2-bromopropanoates. Such esters
have already been used for the incorporation of substituted benzyl motifs into thiazoles,
quinoxalines, 1,4-thiazines, and thiomorpholines,[18] and for the preparation of alkyl 2-(1,2,3-triazol-1-yl)-3-arylpropanoates.[19] We have investigated this approach for the formation of a combinatorial library
of 2-azido-3-arylpropanoic acids. CuBr-catalyzed arylation of acrylic acid esters
2a,b with diazonium salts obtained from readily available anilines 1a–k gave methyl 3-aryl-2-bromopropanoates. Subsequent nucleophilic substitution of bromine
with sodium azide and saponification of the ester group under mild conditions produced
novel 2-azido-3-arylpropionic acids 3a–k in good overall yields (Scheme [2]). The 2-azido-3-arylpropionic acids 3a–k were produced pure without the need for chromatographic purification. Remarkably,
substitution of the bromine by the azide and hydrolysis of the ester group proceeded
quantitatively without side reactions such as nucleophilic elimination leading to
cinnamic acids. Using this method, a diverse combinatorial library of 2-azido-3-arylpropionic
acids could be obtained in gram quantities, with both donor and acceptor substituents
on the aromatic core, thereby expanding the possibilities for studying their chemical
properties.
Scheme 2 Synthesis of 2-azido-3-arylpropanoic acids 3a–k
The synthesized 2-azido-3-arylpropionic acids 3 were studied in a non-catalytic four-component Ugi reaction. It is well-known that
the four-component Ugi reaction represents one of the most powerful tools for the
rapid and direct synthesis of linear dipeptides.[20] The growing interest in peptidomimetics as pharmacological agents has promoted active
research and applications of the Ugi reaction. Due to the high flexibility of the
Ugi reaction, a wide range of linear bis-amides and pseudo-peptides (linear or cyclic)
with different functional groups can be obtained. A variety of heterocyclic compounds
with different biological activities can also be synthesized by various post-modifications.[21] For example, in 2019, the anticancer drug ivosidenib was approved in the United
States, which was the first drug produced using the Ugi reaction.[22] Moreover, Ugi adducts are convenient precursors for further heterocyclization to
obtain a wide range of heterocyclic derivatives with different ring sizes, as discussed
in recent reviews.[23] It should be noted that for a long time the main limitation in the application of
the Ugi reaction was the problematic odors associated with the preparation and purification
of the starting isonitriles. Recently, however, a practical flash chromatography
protocol has been proposed that enables the preparation of highly pure isonitriles
in short times.[24]
Firstly, 2-azido-3-arylpropionic acids 3a–k were tested in the Ugi reaction with cyclopropylamine (4a) and 2,2,2-trifluoroethylamine (4b). The target Ugi adducts 7a–c were obtained by mixing the components in methanol at room temperature for 20–30
minutes (Scheme [3]). The reaction was monitored by TLC for the disappearance of the starting azido
acid. Compounds 7a–c did not require further purification and were separated from the reaction mixture
by filtration as individual white crystalline substances.
Scheme 3 Synthesis of Ugi adducts 7a–c
LC-MS analysis data confirmed that compounds 7a–c were indeed pure, individual reaction products, indicating excellent selectivity.
The presence of a highly reactive azide group in the obtained adducts 7a–c makes them suitable building blocks for the modification of peptide molecules.
To allow intramolecular cyclization to form a cyclic [1,2,3]triazolo[1,5-a]pyrazine system, propargylamine (4c) was introduced into the Ugi reaction, and a series of compounds (8a–i) was obtained (Scheme [4]). In this case, the reaction took place at room temperature, and the target products
precipitated from the reaction medium in the form of a white precipitate. With the
participation of alkyl isonitriles, the reaction proceeded within 10–30 minutes, whilst
the introduction of aryl isonitriles into the reaction prolonged the reaction time
to 40–60 minutes.
Scheme 4 Synthesis of Ugi adducts 8a–i
The Ugi linear adducts 8 contain azido groups and dipolarophiles, which allowed them to be ‘cross-linked’
by Huisgen 1,3-dipolar cycloadditions. Refluxing the selected compounds 8 in toluene for 24 hours led to the formation of 4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones 9a–f in close to quantitative yields (Scheme [5]).
Scheme 5 Synthesis of 4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones 9a–f
Figure 2
13C NMR spectra of compounds 8c (A) and 9b (B)
Considering that there are rotamers present in compounds 8 (see the Supporting Information), which complicate the signal assignments in the
1H NMR spectra, 13C NMR spectra were used to monitor the progress of the cycloaddition based on the
acetylene signals appearing in the region of the spectrum highlighted within the red
frame in Figure [2]. The 13C NMR spectrum of the non-cyclic Ugi adduct 8c is shown in Figure [2]A, whilst that of the corresponding Huisgen cyclization product 9b is displayed in Figure [2]B. The 13C NMR spectrum of compound 8c exhibits characteristic signals at 79.24 (Csp) and 74.70 (CHsp) ppm, indicating the presence of a propargyl fragment, while no such peaks were observed
in the 13C NMR spectrum of the dry residue after refluxing in toluene (compound 9b). The target products 9a–f were obtained from the reaction medium by evaporation of toluene under reduced pressure,
and they did not require any further purification. Thus, the Huisgen cyclization of
compounds 8a–i occurs quantitatively without the formation of side products. It is known that similar
cyclizations of NH-unsubstituted 2-azido-N-(prop-2-ynyl)propanamides are accompanied by the formation of intermolecular interaction
products, and the formation of the targeted 4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones is achieved under high pressure in the presence of microwave irradiation.[25] Apparently, intermolecular conjugation leading to the formation of oligomeric products
is unfavorable due to steric factors.
Next, the one-pot tandem Ugi–Huisgen reaction was studied. After increasing the temperature
of the Ugi reaction to 50 °C and extending the reaction time to 72 hours, cyclic [1,2,3]triazolo[1,5-a]pyrazin-6(7H)-one adducts 9 were obtained as individual products (Scheme [6]). This synthetic approach minimizes losses during isolation of the intermediate
and is effective when the linear Ugi adducts are markedly soluble in methanol, making
their isolation difficult.
Scheme 6 The one-pot tandem Ugi–Huisgen reaction
The [1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones 9g,h obtained by the one-pot method were further purified by recrystallization from dichloromethane/hexane
(3:1). It should be noted that different types of crystals were formed depending on
the crystallization rate, which affects the physicochemical properties of the substance.
Thus, rapid crystallization (1 day) of product 9g resulted in the formation of crystals with mp = 238–240 °C, whilst slow crystallization
over 10 days led to the formation of crystals with mp = 181–183 °C. X-ray diffraction
analyses were performed on both crystal types.[26] The two diastereomers of 9g [9g (A) and 9g (B)] crystallize in the centrosymmetric space groups C2/c and Pbcn, respectively, each with one molecule in the asymmetric unit (Figure [3]).
Figure 3 The molecular structures of 9g (A) and 9g (B) (derived from single-crystal XRD experiments) with displacement ellipsoids drawn
at the 50% probability level. One of the two disordered positions of the phenyl ring
in 9g is shown in dashed mode.
The molecules exhibit some differences in their geometries; for example, the corresponding
N4–C13–C17–N5 torsion angles are 127.1(2)° in 9g (A) and –90.9(2)° in 9g (B). The 4-bromophenyl group is aligned with the adjacent 4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-one, and the angle between the planes is 46.5(2)° in 9g (A) and 42.7(2)° in 9g (B). In 9g (B), the second phenyl ring is almost perpendicular to the triazole ring [the angle
between these planes is 78.92(2)°], while in 9g (A) a close arrangement of the phenyl substituents causes the disorder of one of
them at two positions with an occupancy ratio of 0.59(2):0.41(2).
X-ray structural analysis data showed that the 4 optical isomers of compound 9g separated into two pairs of enantiomers during crystallization. A pair of (R,S)- and (S,R)-isomers [9g (A)] crystallized first, and after a lengthy period of time (approximately 2 weeks),
a pair of (R,R)- and (S,S)-isomers [9g (B)] crystallized. The significant difference in crystallization times of the different
optical isomers is a convenient and effective technique in separating the diastereomeric
mixture of products 9 into separate optical isomers.
The dipolarophilic group for the Huisgen-1,3-dipolar cycloaddition to construct the
[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-one system could also be involved in the Ugi reaction via the aldehyde moiety. First,
3-phenylpropiolaldehyde was tested in the Ugi reaction with 2-azido-3-arylpropionic
acids. However, we were unable to obtain any linear Ugi adducts, probably due to the
instability of the intermediate Schiff bases formed during the Ugi reaction with 2-azido-3-arylpropionic
acids. However, this synthetic route could be successfully carried out with the synthetic
precursor (Z)-2-bromo-3-phenylacrylaldehyde. Thus, the Ugi product 7a, on refluxing in toluene with one equivalent of triethylamine, undergoes a Huisgen
cyclization to give polysubstituted [1,2,3]triazolo[1,5-a]pyrazin-6(7H)-one 10 in a high yield (Scheme [7]).
Scheme 7 Synthesis of [1,2,3]triazolo[1,5-a]pyrazin-6(7H)-one 10
Finally, we decided to test the chemoselectivity of the 1,3-dipolar Huisgen cycloaddition
in the presence of the two dipolarophiles we had studied in the Ugi reaction. For
this purpose, adduct 8j was prepared. A thermally initiated cycloaddition was performed and it was found
that in our case only the propargyl fragment was involved in the 1,3-dipolar cycloaddition.
Compound 11 was the only product produced from the reaction mixture. The possible alternative
product 12 or its intermediate were not observed (Scheme [8]).
Scheme 8 Synthesis of [1,2,3]triazolo[1,5-a]pyrazin-6(7H)-one 11
In conclusion, we have developed an efficient method for obtaining 2-azido-3-arylpropionic
acids using Meerwein bromoarylation products. It was found that 2-azido-3-arylpropionic
acids could be used in a multicomponent Ugi reaction to obtain new polysubstituted
dipeptides. In the Huisgen reaction, these compounds form a triazole ring from which
2-(7-aryl-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)acetamides are formed. A convenient one-pot method was also proposed and developed
for the tandem Ugi–Huisgen reaction. Thus, the sequential combination of the Ugi reaction
and Huisgen cyclization is a convenient synthetic approach for the preparation of
a broad range of 7-(substituted benzyl)-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones, starting from 2-azido-3-arylpropionic acids, without the use of metal catalysts,
specific equipment and chromatographic purification of the target products, which
is in good agreement with modern concepts of organic synthesis. The method is generally
applicable to a wide range of starting substrates and allows the introduction of pharmacophoric
fragments of natural amino acid residues into the target molecule, for example, the
compounds we obtained containing glycine (9c), valine (9g) and tryptophan (9h) residues. The obtained compounds are of significant interest as potential biologically
active compounds. In addition, the products obtained with 2-bromobenzaldehyde may
serve as suitable precursors for further intramolecular cross-couplings, giving rise
to new polycyclic systems.
1H and 13C NMR spectra were recorded on Varian Unity Plus 400 (400 and 101 MHz, respectively),
Bruker 170 Avance 500 (500 and 126 MHz, respectively), and Agilent 600 MHz Premium
COMPACT (600 and 151 MHz, respectively) spectrometers in DMSO-d
6, using TMS or the residual solvent peaks (2.50 ppm for 1H nuclei and 39.5 ppm for 13C nuclei) as internal references. Mass spectral analyses were performed using an Agilent
1100 series LC/MSD in API-ES/APCI mode (200 eV). Elemental analysis was accomplished
using a Carlo Erba 1106 instrument. Melting points were determined on a Boetius melting
point apparatus. The starting anilines 1, amines 4, aldehydes 5 and toluenesulfonylmethyl isocyanide (6h) were commercially available and ware used without further purification.
2-Azido-3-arylpropanoic Acids 3a–k; General Procedure
2-Azido-3-arylpropanoic Acids 3a–k; General Procedure
Aniline 1 (0.25 mol) was dissolved in an excess of 48% bromic acid (62.3 mL, 0.55 mol). The
obtained mixture was cooled to 0 °C and a solution of sodium nitrite (17.25 g, 0.25
mol) in water (10 mL) was added. The resulting diazonium bromide solution was added
dropwise to a mixture of methyl acrylate 2 (0.25 mol), acetone (250 mL), water (15 mL), and copper(I) bromide (2.5 g) with stirring.
After 40 min, the reaction mixture was poured into water. The liquid products were
extracted with DCM and the solvent evaporated in vacuo. The crude methyl 2-bromo-3-aryl
propanoates were purified by vacuum distillation at 1 mm Hg. The obtained methyl 2-bromo-3-arylpropanoate
(0.1 mol) was dissolved in MeOH (50 mL) and a solution of NaN3 (6.5 g) in H2O (15 mL) was added. The resulting mixture was then heated under reflux for 3–4 h
with vigorous stirring. The methanol was evaporated in vacuo and the residue was poured
into water (20 mL). Extraction with DCM (3 × 20 mL) and evaporation of the combined
organic layers in vacuo gave the corresponding methyl 2-azido-3-arylpropanoate residue.
This was dissolved in MeOH (225 mL) at 0 °C and a solution of NaOH (4 g) in water
(50 mL) was added with vigorous stirring. The mixture was then allowed to stand overnight.
The methanol was evaporated in vacuo without heating and the acidic sodium salt solution
was washed with DCM and TBME. HCl was added to adjust the pH to 2, and the obtained
2-azido-3-arylpropanoic acid was extracted with DCM. The DCM was removed in vacuo
to afford pure acid 3. The products were used in further reactions without any additional purification.
2-Azido-3-(m-tolyl)propanoic Acid (3a)
2-Azido-3-(m-tolyl)propanoic Acid (3a)
Yield: 9.94 g (46%); white solid; mp 56–57 °C.
1H NMR (500 MHz, DMSO-d
6): δ = 13.44 (s, 1 H, COOH), 7.19 (t, J = 7.5 Hz, 1 H, CHAr-5), 7.11–7.03 (m, 3 H, CHAr-2,4,6), 4.33 (dd, J = 8.9, 4.9 Hz, 1 H, CH), 3.07 (dd, J = 14.1, 5.0 Hz, 1 H, CH2), 2.88 (dd, J = 14.1, 8.9 Hz, 1 H, CH2), 2.28 (s, 3 H, CH3).
13C NMR (126 MHz, DMSO-d
6): δ = 171.75 (COOH), 137.86 (CAr-3), 137.07 (CAr-1), 130.30 (CHAr-2), 128.70 (CHAr-5), 127.88 (CHAr-4), 126.70 (CHAr-6), 62.77 (CH), 37.11 (CH2), 21.45 (CH3).
MS (APCI): m/z = 206 [M + H]+.
Anal. Calcd for C10H11N3O2: C, 58.53; H, 5.40; N, 20.48. Found: C, 58.51; H, 5.39; N, 20.47.
2-Azido-3-(4-bromophenyl)propanoic Acid (3b)
2-Azido-3-(4-bromophenyl)propanoic Acid (3b)
Yield: 14.58 g (54%); white solid; mp 78–79 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 13.34 (s, 1 H, COOH), 7.46 (d, J = 7.7 Hz, 2 H, CHAr-3,5), 7.19 (d, J = 7.7 Hz, 2 H, CHAr-2,6), 4.38 (dd, J = 8.8, 5.1 Hz, 1 H, CH), 3.03 (dd, J = 14.1, 5.3 Hz, 1 H, CH2), 2.86 (dd, J = 14.2, 8.4 Hz, 1 H, CH2).
13C NMR (126 MHz, DMSO-d
6): δ = 171.49 (COOH), 136.62 (CAr-1), 131.94 (2 C, CHAr-3,5), 131.62 (2 C, CHAr-2,6), 120.44 (CAr-4), 62.40 (CH), 36.41 (CH2).
MS (APCI): m/z = 270, 272 [M + H]+.
Anal. Calcd for C9H8BrN3O2: C, 40.02; H, 2.99; N, 15.56. Found: C, 40.00; H, 3.01; N, 15.55.
2-Azido-3-(4-fluorophenyl)propanoic Acid (3c)
2-Azido-3-(4-fluorophenyl)propanoic Acid (3c)
Yield: 11.91 g (57%); white solid; mp 172–174 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 7.40–7.21 (m, 2 H, CHAr-3,5), 7.09 (t, J = 8.7 Hz, 2 H, CHAr-2,6), 4.06 (dd, J = 9.2, 4.6 Hz, 1 H, CH), 3.08 (dd, J = 14.3, 4.6 Hz, 1 H, CH2), 2.85 (dd, J = 14.2, 9.2 Hz, 1 H, CH2).
13C NMR (101 MHz, DMSO-d
6): δ = 172.15 (COOH), 161.53 (d, J
C–F = 242.0 Hz, CAr-4), 134.44 (d, J
C–F = 2.9 Hz, CAr-1), 131.45 (d, J
C–F = 8.1 Hz, 2 C, CHAr-2,6), 115.39 (d, J
C–F = 21.1 Hz, 2 C, CHAr-3,5), 64.13 (CH), 36.83 (CH2).
MS (APCI): m/z = 210 [M + H]+.
Anal. Calcd for C9H8FN3O2: C, 51.68; H, 3.86; N, 20.09. Found: C, 51.65; H, 3.89; N, 20.10.
2-Azido-3-(3-fluorophenyl)propanoic Acid (3d)
2-Azido-3-(3-fluorophenyl)propanoic Acid (3d)
Yield: 10.66 g (51%); colorless oil.
1H NMR (400 MHz, DMSO-d
6): δ = 7.33–7.22 (m, 1 H, CHAr-2), 7.13–6.95 (m, 3 H, CHAr-4,5,6), 4.40 (dd, J = 8.6, 4.7 Hz, 1 H, CH), 3.09 (dd, J = 14.2, 4.9 Hz, 1 H, CH2), 2.91 (dd, J = 14.1, 8.9 Hz, 1 H, CH2).
13C NMR (126 MHz, DMSO-d
6): δ = 171.51 (COOH), 162.53 (d, 1
J
C–F = 243.3 Hz, CAr-3), 140.03 (d, 3
J
C–F = 7.5 Hz, CAr-1), 130.55 (d, 3
J
C–F = 8.4 Hz, CHAr-5), 125.79 (d, 4
J
C–F = 2.8 Hz, CHAr-6), 116.35 (d, 2
J
C–F = 21.5 Hz, CHAr-2), 113.98 (d, 2
J
C–F = 20.9 Hz, CHAr-4), 62.40 (CH), 36.70 (CH2).
MS (APCI): m/z = 210 [M + H]+.
Anal. Calcd for C9H8FN3O2: C, 51.68; H, 3.86; N, 20.09. Found: C, 51.70; H, 3.84; N, 20.10.
2-Azido-3-(2-fluorophenyl)propanoic Acid (3e)
2-Azido-3-(2-fluorophenyl)propanoic Acid (3e)
Yield: 9.82 g (47%); colorless oil.
1H NMR (400 MHz, DMSO-d
6): δ = 13.48 (s, 1 H, COOH), 7.34–7.25 (m, 2 H, CHAr-4,6), 7.18–7.08 (m, 2 H, CHAr-3,5), 4.30 (dd, J = 9.3, 4.9 Hz, 1 H, CH), 3.13 (dd, J = 14.3, 4.9 Hz, 1 H, CH2), 2.93 (dd, J = 14.2, 9.4 Hz, 1 H, CH2).
13C NMR (126 MHz, DMSO-d
6): δ = 171.48 (COOH), 161.19 (d, 1
J
C–F = 244.2 Hz, CAr-2), 132.07 (d, 3
J
C–F = 4.3 Hz, CHAr-6), 129.48 (d, 3
J
C–F = 8.1 Hz, CHAr-4), 124.81 (d, 4
J
C–F = 3.5 Hz, CHAr-5), 124.00 (d, 2
J
C–F = 15.4 Hz, CAr-1), 115.62 (d, 2
J
C–F = 21.9 Hz, CHAr-3), 61.71 (CH), 30.46 (CH2).
MS (APCI): m/z = 210 [M + H]+.
Anal. Calcd for C9H8FN3O2: C, 51.68; H, 3.86; N, 20.09. Found: C, 51.67; H, 3.85; N, 20.07.
2-Azido-3-(4-nitrophenyl)propanoic Acid (3f)
2-Azido-3-(4-nitrophenyl)propanoic Acid (3f)
Yield: 10.86 g (46%); white solid; mp 90–91 °C.
1H NMR (500 MHz, DMSO-d
6): δ = 13.55 (s, 1 H, COOH), 8.17 (d, J = 8.2 Hz, 2 H, CHAr-3,5), 7.56 (d, J = 8.2 Hz, 2 H, CHAr-2,6), 4.58 (dd, J = 8.9, 4.8 Hz, 1 H, CH), 3.24 (dd, J = 14.3, 5.4 Hz, 1 H, CH2), 3.07 (dd, J = 14.1, 9.0 Hz, 1 H, CH2).
13C NMR (101 MHz, DMSO-d
6): δ = 171.40 (COOH), 146.98 (CAr-4), 145.58 (CAr-1), 131.08 (2 C, CHAr-2,6), 123.83 (2 C, CHAr-3,5), 62.09 (CH), 36.69 (CH2).
MS (APCI): m/z = 237 [M + H]+.
Anal. Calcd for C9H8N4O4: C, 45.77; H, 3.41; N, 23.72. Found: C, 45.79; H, 3.39; N, 23.71.
2-Azido-3-(2-chlorophenyl)propanoic Acid (3g)
2-Azido-3-(2-chlorophenyl)propanoic Acid (3g)
Yield: 10.82 g (48%); white solid; mp 53–54 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 13.55 (s, 1 H, COOH), 7.45–7.42 (m, 1 H, CHAr-3), 7.41–7.35 (m, 1 H, CHAr-5), 7.34–7.23 (m, 2 H, CHAr-4,6), 4.36 (dd, J = 9.6, 4.8 Hz, 1 H, CH), 3.28 (dd, J = 14.3, 4.6 Hz, 1 H, CH2), 3.02 (dd, J = 14.2, 9.9 Hz, 1 H, CH2).
13C NMR (151 MHz, DMSO-d
6): δ = 171.47 (COOH), 134.77 (CAr-1), 133.81 (CAr-2), 132.07 (CHAr-6), 129.77 (CHAr-3), 129.25 (CHAr-4), 127.66 (CHAr-5), 61.38 (CH), 34.85 (CH2).
MS (APCI): m/z = 226 [M + H]+.
Anal. Calcd for C9H8ClN3O2: C, 47.91; H, 3.57; N, 18.62. Found: C, 47.89; H, 3.58; N, 18.60.
2-Azido-3-(3,4-dichlorophenyl)propanoic Acid (3h)
2-Azido-3-(3,4-dichlorophenyl)propanoic Acid (3h)
Yield: 14.04 g (54%); white solid; mp 85–86 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 13.19 (s, 1 H, COOH), 7.59–7.43 (m, 2 H, CHAr-2,5), 7.23 (dt, J = 6.7, 3.3 Hz, 1 H, CHAr-6), 4.47 (dd, J = 8.7, 4.9 Hz, 1 H, CH), 3.06 (dd, J = 14.2, 5.0 Hz, 1 H, CH2), 2.90 (dd, J = 14.2, 8.7 Hz, 1 H, CH2).
13C NMR (126 MHz, DMSO-d
6): δ = 171.39 (COOH), 138.52 (CAr-1), 131.70 (CHAr-2), 131.24 (CAr-3), 130.82 (CHAr-5), 130.18 (CHAr-6), 129.91 (CAr-4), 62.16 (CH), 35.96 (CH2).
MS (APCI): m/z = 260, 262 [M + H]+.
Anal. Calcd for C9H7Cl2N3O2: C, 41.56; H, 2.71; N, 16.16. Found: C, 41.55; H, 2.69; N, 16.17.
2-Azido-3-(2,4-dichlorophenyl)propanoic Acid (3i)
2-Azido-3-(2,4-dichlorophenyl)propanoic Acid (3i)
Yield: 15.34 g (59%); white solid; mp 94–95 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 7.56 (s, 1 H, CHAr-3), 7.37 (m, 2 H, CHAr-5,6), 4.36 (dd, J = 9.6, 4.9 Hz, 1 H, CH), 3.21 (dd, J = 14.3, 5.0 Hz, 1 H, CH2), 2.97 (dd, J = 14.4, 9.6 Hz, 1 H, CH2).
13C NMR (126 MHz, DMSO-d
6): δ = 171.37 (COOH), 134.83 (CAr-2), 134.06 (CAr-1), 133.38 (CHAr-6), 132.95 (CAr-4), 129.22 (CHAr-3), 127.84 (CHAr-5), 61.20 (CH), 34.28 (CH2).
MS (APCI): m/z = 260, 262 [M + H]+.
Anal. Calcd for C9H7Cl2N3O2: C, 41.56; H, 2.71; N, 16.16. Found: C, 41.57; H, 2.73; N, 16.13.
2-Azido-2-methyl-3-(3-nitrophenyl)propanoic Acid (3j)
2-Azido-2-methyl-3-(3-nitrophenyl)propanoic Acid (3j)
Yield: 9.75 g (39%); white solid; mp 114–116 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 8.09 (d, J = 9.3 Hz, 1 H, CHAr-4), 8.04 (s, 1 H, CHAr-2), 7.64 (d, J = 7.7 Hz, 1 H, CHAr-6), 7.56 (t, J = 7.9 Hz, 1 H, CHAr-5), 3.17 (d, J = 13.5 Hz, 1 H, CH2), 3.04 (d, J = 13.8 Hz, 1 H, CH2), 1.41 (s, 3 H, CH3).
13C NMR (126 MHz, DMSO-d
6): δ = 173.38 (COOH), 147.97 (CAr-3), 138.38 (CAr-1), 137.68 (CHAr-6), 129.97 (CHAr-5), 125.22 (CHAr-2), 122.48 (CHAr-4), 67.01 (C), 42.46 (CH2), 22.71 (CH3).
MS (APCI): m/z = 251 [M + H]+.
Anal. Calcd for C10H10N4O4: C, 48.00; H, 4.03; N, 22.39. Found: C, 47.98; H, 4.04; N, 22.40.
2-Azido-2-methyl-3-(3-(trifluoromethyl)phenyl)propanoic Acid (3k)
2-Azido-2-methyl-3-(3-(trifluoromethyl)phenyl)propanoic Acid (3k)
Yield: 10.10 g (37%); colorless oil.
1H NMR (500 MHz, DMSO-d
6): δ = 13.59 (s, 1 H, COOH), 7.62–7.57 (m, 1 H, CHAr-5), 7.55 (s, 1 H, CHAr-2), 7.54–7.51 (m, 2 H, CHAr-4,6), 3.17 (d, J = 13.5 Hz, 1 H, CH2), 3.03 (d, J = 13.5 Hz, 1 H, CH2), 1.42 (s, 3 H, CH3).
13C NMR (126 MHz, DMSO-d
6): δ = 173.44 (COOH), 137.46 (CAr-1), 134.87 (CHAr-5), 129.43 (CHAr-6), 129.38 (q, 2
J
C–F = 31.4 Hz, CAr-3), 127.11 (q, 3
J
C–F = 3.9 Hz, CHAr-2), 124.65 (q, 1
J
C–F = 272.2 Hz, CF3), 124.12 (q, 3
J
C–F = 3.9 Hz, CHAr-4), 67.01 (C), 42.80 (CH2), 22.67 (CH3).
MS (APCI): m/z = 274 [M + H]+.
Anal. Calcd for C11H10F3N3O2: C, 48.36; H, 3.69; N, 15.38. Found: C, 48.37; H, 3.70; N, 15.36.
Ugi Adducts 7a–c and 8a–j; General Procedure
Ugi Adducts 7a–c and 8a–j; General Procedure
A solution of 2-azido-3-arylpropionic acid 3 (2 mmol), amine 4 (2 mmol), aldehyde 5 (2 mmol), and isonitrile 6 (2 mmol) in methanol (5 mL) was stirred for 20–30 min at room temperature to form
a precipitate. The precipitate was then filtered off and washed with a small amount
of methanol and dried in vacuo.
2-(2-Azido-3-(4-bromophenyl)-N-cyclopropylpropanamido)-3-bromo-N-cyclopentyl-4-phenylbut-3-enamide (7a)
2-(2-Azido-3-(4-bromophenyl)-N-cyclopropylpropanamido)-3-bromo-N-cyclopentyl-4-phenylbut-3-enamide (7a)
Yield: 1.09 g (89%); white solid; mp 173–175 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 8.43 (d, J = 7.1 Hz, 1 H, NH), 7.52 (br s, 1 H), 7.50 (br s, 2 H), 7.48 (br s, 1 H), 7.45–7.33
(m, 3 H), 7.29 (d, J = 7.8 Hz, 2 H), 6.79 (s, 1 H), 5.42 (s, 1 H), 4.86 (t, J = 7.6 Hz, 1 H), 4.03 (q, J = 6.6 Hz, 1 H), 3.12 (d, J = 7.6 Hz, 2 H), 2.54 (d, J = 1.7 Hz, 1 H), 1.82 (dq, J = 12.7, 6.5 Hz, 2 H), 1.70–1.55 (m, 2 H), 1.51 (s, 3 H), 1.47–1.34 (m, 2 H), 0.94
(s, 1 H), 0.81–0.58 (m, 2 H).
13C NMR (126 MHz, DMSO-d
6): δ = 172.41, 166.08, 135.48, 134.76, 132.34, 131.51 (2 С), 131.46 (2С), 128.53 (3С),
128.41 (2С), 120.76, 120.19, 68.91, 58.63, 50.84, 36.17, 32.29, 31.57, 27.15, 23.38,
23.36, 9.54, 9.09.
MS (APCI): m/z = 614, 616 [M + H]+.
Anal. Calcd for C27H29Br2N5O2: C, 52.70; H, 4.75; N, 11.38. Found: C, 52.69; H, 4.72; N, 11.40.
2-Azido-N-(2-(cyclohexylamino)-2-oxo-1-(p-tolyl)ethyl)-N-cyclopropyl-3-(2,4-dichlorophenyl)propanamide (7b)
2-Azido-N-(2-(cyclohexylamino)-2-oxo-1-(p-tolyl)ethyl)-N-cyclopropyl-3-(2,4-dichlorophenyl)propanamide (7b)
Yield: 0.82 g (78%); white solid; mp 190–193 °C.
1H NMR (500 MHz, DMSO-d
6): δ = 7.81 (d, J = 8.2 Hz, 1 H), 7.65 (s, 1 H), 7.44 (t, J = 6.4 Hz, 2 H), 7.08 (d, J = 7.6 Hz, 2 H, Tol), 6.73 (d, J = 7.4 Hz, 2 H, Tol), 5.56 (s, 1 H), 4.89 (t, J = 7.8 Hz, 1 H), 3.58 (q, J = 9.4 Hz, 1 H), 3.29–3.23 (m, 3 H), 2.26 (s, 3 H, Me), 1.80–1.47 (m, 6 H), 1.33–1.00
(m, 6 H), 0.76 (dq, J = 11.1, 5.7 Hz, 1 H), 0.58 (dt, J = 10.1, 5.4 Hz, 1 H).
13C NMR (126 MHz, DMSO-d
6): δ = 172.26 (CON), 168.25 (CON), 137.13, 134.97, 133.72, 133.43, 133.25, 133.17,
129.58 (2 C, Tol), 129.40, 129.01 (2 C, Tol), 128.19, 63.67, 56.91, 48.40, 35.12,
32.72, 32.52, 28.67, 25.63, 25.00, 24.92, 21.09, 11.12, 9.35.
MS (APCI): m/z = 528, 530 [M + H]+.
Anal. Calcd for C27H31Cl2N5O2: C, 61.36; H, 5.91; N, 13.25. Found: C, 61.38; H, 5.88; N, 13.24.
2-Azido-3-(3-fluorophenyl)-N-(1-(4-methoxyphenyl)-2-oxo-2-((tosylmethyl)amino)ethyl)-N-(2,2,2-trifluoroethyl)propanamide (7c)
2-Azido-3-(3-fluorophenyl)-N-(1-(4-methoxyphenyl)-2-oxo-2-((tosylmethyl)amino)ethyl)-N-(2,2,2-trifluoroethyl)propanamide (7c)
Yield: 0.92 g (74%); white solid; mp 184–186 °C.
1H NMR (500 MHz, DMSO-d
6): δ = 9.39 and 9.06 (s, 1 H, NH), 7.78–6.77 (m, 12 H), 5.86–5.59 (m, 1 H), 5.12–4.83
(m, 1 H), 4.79–4.44 (m, 1 H), 4.42–3.89 (m, 3 H), 3.78 and 3.75 (s, 3 H, MeO), 3.19–2.96
(m, 1 H), 2.90–2.59 (m, 1 H), 2.39 and 2.37 (s, 3 H, Me).
13C NMR (126 MHz, DMSO-d
6): δ = 171.96, 159.99, 145.28, 134.98, 131.97, 130.28, 130.07, 128.82, 125.88, 116.29,
114.78, 114.35, 114.16, 63.29, 62.64, 60.24, 60.14, 55.70, 36.35, 21.54.
MS (APCI): m/z = 622 [M + H]+.
Anal. Calcd for C28H27F4N5O5S: C, 54.10; H, 4.38; N, 11.27. Found: C, 54.08; H, 4.41; N, 11.25.
2-Azido-N-(1-(2-bromophenyl)-2-(tert-butylamino)-2-oxoethyl)-3-(2-fluorophenyl)-N-(prop-2-yn-1-yl)propanamide (8a)
2-Azido-N-(1-(2-bromophenyl)-2-(tert-butylamino)-2-oxoethyl)-3-(2-fluorophenyl)-N-(prop-2-yn-1-yl)propanamide (8a)
Yield: 0.84 g (82%); white solid; mp 146–148 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 8.13 (s, 1 H, NH), 7.61 (d, J = 7.8 Hz, 1 H), 7.47–7.38 (m, 2 H), 7.37–7.27 (m, 3 H), 7.22–7.08 (m, 2 H), 6.07
(s, 1 H, CH), 4.54–4.25 (m, 2 H, CH2N), 4.03–3.80 (m, 1 H, CH), 3.38–3.28 (m, 1 H, CH2), 3.16 (dd, J = 14.3, 10.1 Hz, 1 H, CH2), 2.92 (s, 1 H, CspH), 1.27 (s, 9 H, 3 × Me).
13C NMR (126 MHz, DMSO-d
6): δ = 169.69 (CON), 168.05 (CON), 160.92 (d, 1
J
C–F = 244.4 Hz, CAr-2), 134.86, 132.92, 131.59 (d, 3
J
C–F = 4.1 Hz, CHAr-6), 130.47, 130.27, 129.11 (d, 3
J
C–F = 7.9 Hz, CAr-4), 127.82, 126.83, 124.42 (d, 4
J
C–F = 2.6 Hz, CHAr-5), 123.52 (d, 2
J
C–F = 15.5 Hz, CAr-1), 115.27 (d, 2
J
C–F = 21.9 Hz, CHAr-3), 78.61 (Csp), 74.17 (CHsp), 60.41 (CH), 58.31 (CH), 50.61 (CHN), 34.75 (CH2N), 30.26 (CH2), 28.31 (3 × Me).
MS (APCI): m/z = 514, 516 [M + H]+.
Anal. Calcd for C24H25BrFN5O2: C, 56.04; H, 4.90; N, 13.61. Found: C, 56.03; H, 4.91; N, 13.59.
2-Azido-N-(2-(cyclohexylamino)-2-oxo-1-(p-tolyl)ethyl)-3-(2,4-dichlorophenyl)-N-(prop-2-yn-1-yl)propanamide (8b)
2-Azido-N-(2-(cyclohexylamino)-2-oxo-1-(p-tolyl)ethyl)-3-(2,4-dichlorophenyl)-N-(prop-2-yn-1-yl)propanamide (8b)
Yield: 0.89 g (85%); white solid; mp 161–163 °С.
1H NMR (500 MHz, DMSO-d
6): δ = 8.22–8.16 (m, 1 H, NH), 7.58–7.54 (m, 1 H, Ar), 7.45–7.40 (m, 1 H, Ar), 7.23–7.17
(m, Ar), 7.14 (d, J = 7.6 Hz, 2 H, Tol), 6.99 (d, J = 7.8 Hz, 2 H, Tol), 6.03 (s, 1 H), 4.60–4.39 (m, 1 H), 4.21 (m, 1 H), 4.05–3.95
(m, 1 H), 3.59 (d, J = 10.0 Hz, 1 H), 3.30 (d, J = 7.0 Hz, 2 H), 3.17–2.69 (m, 1 H), 2.29 (s, 3 H, Me), 1.89–1.47 (m, 5 H, cyclohex),
1.38–0.95 (m, 5 H, cyclohex).
13C NMR (126 MHz, DMSO-d
6): δ = 169.95, 168.05, 137.84, 135.10, 133.38, 133.29, 133.17, 132.54, 129.73, 129.49
(2 C, Tol), 129.29 (2 C, Tol), 129.09, 128.86, 127.92, 80.01, 79.68, 79.42, 79.16,
74.84, 59.94, 57.76, 48.23, 35.04, 34.35, 32.63, 32.52, 25.63, 24.92, 21.19.
MS (APCI): m/z = 526, 528 [M + H]+.
Anal. Calcd for C27H29Cl2N5O2: C, 61.60; H, 5.55; N, 13.30. Found: C, 61.62; H, 5.54; N, 13.28.
2-Azido-N-(1-(2-bromophenyl)-2-(cyclohexylamino)-2-oxoethyl)-3-(3-fluorophenyl)-N-(prop-2-yn-1-yl)propanamide (8c)
2-Azido-N-(1-(2-bromophenyl)-2-(cyclohexylamino)-2-oxoethyl)-3-(3-fluorophenyl)-N-(prop-2-yn-1-yl)propanamide (8c)
Yield: 0.94 g (87%); white solid; mp 173–175 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 8.29 (d, J = 7.7 Hz, 1 H, NH), 7.59 (d, J = 7.8 Hz, 1 H, Ar), 7.36 (m, 2 H, Ar), 7.27 (m, 2 H, Ar), 7.18–7.09 (m, 2 H, Ar),
7.09–7.00 (m, 1 H, Ar), 6.07 (s, 1 H), 4.67–4.43 (m, 2 H, CH2N), 4.05–3.90 (m, 1 H), 3.58 (s, 1 H), 3.40 (dd, J = 14.2, 4.1 Hz, 1 H), 3.02 (dd, J = 14.3, 10.3 Hz, 1 H), 2.93 (s, 1 H), 1.87–1.40 (m, 5 H, cyclohex), 1.11 (m, 5 H,
cyclohex).
13C NMR (126 MHz, DMSO-d
6): δ = 170.58 (CON), 167.98 (CON), 162.58 (d, 1
J
C–F = 243.4 Hz, CAr-3), 140.09 (d, 3
J
C–F = 7.6 Hz, CAr-1), 135.03 (Ar), 133.36 (Ar), 131.13 (Ar), 130.85 (Ar), 130.77 (d, 3
J
C–F = 8.4 Hz, CHAr-5), 128.35 (Ar), 127.18 (Ar), 125.84 (CAr-F-6), 116.28 (d, 2
J
C–F = 21.1 Hz, CHAr-4), 114.13 (d, 2
J
C–F = 20.6 Hz, CHAr-2), 79.24 (Csp), 74.71 (Csp), 60.63 (CH), 59.51 (CH), 48.36 (CH2N), 37.12 (CHNHcyclohex), 35.25 (CH2), 32.53 (cyclohex), 32.45 (cyclohex), 25.59 (cyclohex), 24.98 (cyclohex), 24.85 (cyclohex).
MS (APCI): m/z = 540, 542 [M + H]+.
Anal. Calcd for C26H27BrFN5O2: C, 57.78; H, 5.04; N, 12.96. Found: C, 57.76; H, 5.05; N, 12.94.
Ethyl (2-(2-Azido-3-(3-fluorophenyl)-N-(prop-2-yn-1-yl)propanamido)-2-(2-bromophenyl)acetyl)glycinate (8d)
Ethyl (2-(2-Azido-3-(3-fluorophenyl)-N-(prop-2-yn-1-yl)propanamido)-2-(2-bromophenyl)acetyl)glycinate (8d)
Yield: 0.85 g (78%); white solid; mp 148–150 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 8.93 (t, J = 5.9 Hz, 1 H, NH), 7.65 (d, J = 8.0 Hz, 1 H), 7.38–7.31 (m, 2 H), 7.49–7.40 (m, 2 H), 7.23–7.12 (m, 2 H), 7.09
(t, J = 9.0 Hz, 1 H), 6.24 (s, 1 H, CH), 4.70–4.54 (m, 2 H, CH2N), 4.11 (q, J = 7.1 Hz, 2 H, CH2Me), 4.02–3.86 (m, 2 H, CH2COOEt), 3.82–3.79 (m, CH), 3.44 (dd, J = 14.5, 3.9 Hz, 1 H, CH2), 3.05 (dd, J = 14.6, 10.8 Hz, 1 H, CH2), 2.97 (s, 1 H, CspH), 1.20 (t, J = 7.1 Hz, 3 H, Me).
13C NMR (126 MHz, DMSO-d
6): δ = 170.34, 169.46, 169.21, 162.15 (d, 1
J
C–F = 243.5 Hz, CAr-3), 139.66 (d, 3
J
C–F = 8.5 Hz, CAr-1), 133.99, 132.82, 131.54, 130.58, 130.33 (d, 3
J
C–F = 8.3 Hz, CHAr-5), 127.78, 126.75, 125.38 (CAr-F-6), 115.81 (d, 2
J
C–F = 21.1 Hz, CHAr-4), 113.69 (d, 2
J
C–F = 21.0 Hz, CHAr-2), 78.64 (Csp), 74.34 (CHsp), 60.56, 60.26, 59.06, 40.91, 36.72 (CH2N), 34.78 (CH2), 14.07 (Me).
MS (APCI): m/z = 544, 546 [M + H]+.
Anal. Calcd for C24H23BrFN5O4: C, 52.95; H, 4.26; N, 12.87. Found: C, 52.93; H, 4.27; N, 12.85.
2-Azido-N-(2-(benzylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-(3,4-dichlorophenyl)-N-(prop-2-yn-1-yl)propanamide (8e)
2-Azido-N-(2-(benzylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-(3,4-dichlorophenyl)-N-(prop-2-yn-1-yl)propanamide (8e)
Yield: 0.83 g (75%); white solid; mp 131–133 °С.
1H NMR (400 MHz, DMSO-d
6): δ = 8.76 (s, 1 H, NH), 7.56–6.87 (m, 12 H), 6.02 (s, 1 H), 4.56–4.02 (m, 4 H),
3.72 (s, 3 H, OMe), 3.55–2.68 (m, 4 H).
13C NMR (126 MHz, DMSO-d
6): δ = 170.50, 169.49, 159.69, 139.44, 138.11, 131.69, 131.46, 131.04 (2 C), 130.34,
130.16, 128.71 (2 C), 128.06, 127.74 (2 C), 127.30, 126.98, 114.37 (2 C), 80.38 (Csp), 74.88 (Csp), 60.05, 59.06, 55.63, 42.63, 36.26, 35.02.
MS (APCI): m/z = 550, 552 [M + H]+.
Anal. Calcd for C28H25Cl2N5O3: C, 61.10; H, 4.58; N, 12.72. Found: C, 61.12; H, 4.60; N, 12.70.
2-Azido-3-(2,4-dichlorophenyl)-N-(2-oxo-1-phenyl-2-(p-tolylamino)ethyl)-N-(prop-2-yn-1-yl)propanamide (8f)
2-Azido-3-(2,4-dichlorophenyl)-N-(2-oxo-1-phenyl-2-(p-tolylamino)ethyl)-N-(prop-2-yn-1-yl)propanamide (8f)
Yield: 0.79 g (76%); white solid; mp 163–165 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 10.30 (s, 1 H, NH), 7.62 (s, 1 H), 7.54–7.12 (m, 11 H), 6.21 (s, 1 H), 4.61
(t, J = 7.5 Hz, 1 H), 4.39–4.34 (m, 1 H, CH2), 4.03–3.98 (m, 1 H, CH2), 3.29–2.80 (m, 3 H), 2.25 (s, 3 H, Me).
13C NMR (126 MHz, DMSO-d
6): δ = 169.86 (СON), 167.32 (СON), 136.02, 134.64, 134.26, 132.93, 132.88, 132.72,
123.68, 129.18 (4 C), 128.91, 128.74 (2 C), 128.54, 127.52, 119.34 (2 C), 79.32 (CHsp), 74.56 (CHsp), 60.95 (CH), 57.42 (CH), 34.78 (CH2N), 33.90 (CH2), 20.45 (Me).
MS (APCI): m/z = 520, 522 [M + H]+.
Anal. Calcd for C27H23Cl2N5O2: C, 62.32; H, 4.45; N, 13.46. Found: C, 62.34; H, 4.42; N, 13.44.
2-Azido-N-(1-(2-bromophenyl)-2-oxo-2-(p-tolylamino)ethyl)-3-(3,4-dichlorophenyl)-N-(prop-2-yn-1-yl)propanamide (8g)
2-Azido-N-(1-(2-bromophenyl)-2-oxo-2-(p-tolylamino)ethyl)-3-(3,4-dichlorophenyl)-N-(prop-2-yn-1-yl)propanamide (8g)
Yield: 1.08 g (90%); white solid; mp 168–170 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 10.36 (s, 1 H, NH), 7.73–7.30 (m, 9 H), 7.12 (d, J = 8.1 Hz, 2 H), 6.26 (s, 1 H), 4.72–4.52 (m, 2 H, CH2N), 4.06–3.95 (m, 1 H, CH), 3.40 (dd, J = 14.2, 5.3 Hz, 1 H, CH2), 3.11 (dd, J = 14.0, 9.4 Hz, 1 H, CH2), 2.92 (s, 1 H, CspH), 2.25 (s, 3 H, Me).
13C NMR (126 MHz, DMSO-d
6): δ = 169.88 (CON), 167.28 (CON), 137.76, 136.02, 133.81, 133.11, 132.76, 131.26,
130.95, 130.72, 130.65, 130.48, 129.85, 129.62, 129.21 (2 C), 128.14, 126.76, 119.33
(2 C), 78.64 (Csp), 74.39 (CHsp), 61.19 (CH), 58.79 (CH), 35.90 (CH2N), 34.83 (CH2), 20.44 (Me).
MS (APCI): m/z = 598, 600, 602 [M + H]+.
Anal. Calcd for C27H22BrCl2N5O2: C, 54.11; H, 3.70; N, 11.69. Found: C, 54.09; H, 3.72; N, 11.70.
2-Azido-N-(1-(2-bromophenyl)-2-((4-methoxyphenyl)amino)-2-oxoethyl)-3-(3-fluorophenyl)-N-(prop-2-yn-1-yl)propanamide (8h)
2-Azido-N-(1-(2-bromophenyl)-2-((4-methoxyphenyl)amino)-2-oxoethyl)-3-(3-fluorophenyl)-N-(prop-2-yn-1-yl)propanamide (8h)
Yield: 0.97 g (86%); white solid; mp 172–174 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 10.33 (s, 1 H, NH), 7.67 (d, J = 7.9 Hz, 1 H), 7.51 (d, J = 8.6 Hz, 2 H), 7.46–7.30 (m, 4 H), 7.24–7.15 (m, 2 H), 7.13–7.06 (m, 1 H), 6.89
(d, J = 8.7 Hz, 2 H), 6.28 (s, 1 H, CH), 4.67–4.61 (m, 2 H, CH2N), 4.05–3.99 (m, 1 H, CH), 3.72 (s, 3 H, OMe), 3.45 (dd, J = 14.1, 4.4 Hz, 1 H, CH2), 3.08 (dd, J = 14.2, 10.0 Hz, 1 H, CH2), 2.95 (s, 1 H, CspH).
13C NMR (126 MHz, DMSO-d
6): δ = 170.38 (CON), 167.03 (CON), 162.22 (d, 1
J
C–F = 228.4 Hz, CAr-3), 161.19, 155.58, 139.57 (d, 3
J
C–F = 7.6 Hz, CAr-1), 133.98, 133.10, 131.65, 130.68, 130.34 (d, 3
J
C–F = 8.5 Hz, CHAr-5), 128.15, 126.77, 125.44 (d, 4
J
C–F = 2.0 Hz, CHAr-6), 120.85 (2 C), 115.87 (d, 2
J
C–F = 21.3 Hz, CHAr-4), 114.00 (2 C), 113.72 (d, 2
J
C–F = 19.6 Hz, CHAr-2), 78.67 (CHsp), 74.41 (CHsp), 61.09 (CH), 59.10 (CH), 55.21 (OMe), 36.68 (CH2N), 34.85 (CH2).
MS (APCI): m/z = 564, 566 [M + H]+.
Anal. Calcd for C27H23BrFN5O3: C, 57.46; H, 4.11; N, 12.41. Found: C, 57.47; H, 4.09; N, 12.40.
2-Azido-N-(1-(2-bromophenyl)-2-((4-methoxyphenyl)amino)-2-oxoethyl)-3-(4-fluorophenyl)-N-(prop-2-yn-1-yl)propanamide (8i)
2-Azido-N-(1-(2-bromophenyl)-2-((4-methoxyphenyl)amino)-2-oxoethyl)-3-(4-fluorophenyl)-N-(prop-2-yn-1-yl)propanamide (8i)
Yield: 0.87 g (77%); white solid; mp 185–187 °C.
1H NMR (500 MHz, DMSO-d
6): δ = 10.33 (s, 1 H, NH), 7.66 (d, J = 7.8 Hz, 1 H), 7.50 (d, J = 8.8 Hz, 2 H), 7.44–7.29 (m, 5 H), 7.15 (t, J = 8.7 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 6.27 (s, 1 H, CH), 4.66–4.51 (m, 2 H, CH2N), 4.02–3.98 (m, 1 H, CH), 3.71 (s, 3 H, Me), 3.40 (dd, J = 14.1, 3.7 Hz, 1 H, CH2), 3.03 (dd, J = 13.9, 10.3 Hz, 1 H, CH2), 2.98 (s, 1 H, CspH).
13C NMR (151 MHz, DMSO-d
6): δ = 170.92 (CON), 167.46 (CON), 161.69 (d, 1
J
C–F = 241.8 Hz, CAr-4), 155.99, 134.43, 133.52, 133.30, 132.09, 131.54 (d, 3
J
C–F = 8.0 Hz, 2 C, CHAr-2,6), 131.09 (d, 4
J
C–F = 2.8 Hz, CAr-1), 128.57, 127.21, 121.26 (2 C), 115.62 (d, 2
J
C–F = 21.0 Hz, 2 C, CHAr-3,5), 114.42 (2 C), 79.12 (Csp), 74.86 (CHsp), 61.50 (CH), 59.84 (CH), 55.64 (Me), 36.65 (CH2N), 35.29 (CH2).
MS (APCI): m/z = 564, 566 [M + H]+.
Anal. Calcd for C27H23BrFN5O3: C, 57.46; H, 4.11; N, 12.41. Found: C, 57.47; H, 4.09; N, 12.42.
2-(2-Azido-3-(4-bromophenyl)-N-(prop-2-yn-1-yl)propanamido)-3-bromo-N-cyclopentyl-4-phenylbut-3-enamide (8j)
2-(2-Azido-3-(4-bromophenyl)-N-(prop-2-yn-1-yl)propanamido)-3-bromo-N-cyclopentyl-4-phenylbut-3-enamide (8j)
Yield: 1.07 g (87%); white solid; mp 138–140 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 8.61–8.56 (m, 1 H, NH), 7.64–6.96 (m, 10 H), 5.92–5.80 (m, 1 H), 4.64–3.90
(m, 4 H), 3.56–3.37 (m, 1 H), 3.24–3.11 (m, 1 H), 3.02 (dd, J = 16.2, 8.2 Hz, 1 H), 1.93–1.72 (m, 2 H, cyclopent), 1.69–1.28 (m, 6 H, cyclopent).
13C NMR (101 MHz, DMSO-d
6): δ = 135.16, 131.97, 131.81, 129.27, 128.80, 127.95, 121.17, 72.96, 66.33, 64.80,
59.36, 55.72, 51.18, 32.65, 23.85.
MS (APCI): m/z = 612, 614, 616 [M + H]+.
Anal. Calcd for C27H27Br2N5O2: C, 52.87; H, 4.44; N, 11.42. Found: C, 52.89; H, 4.43; N, 11.40.
4,5-Dihydro[1,2,3]triazolo[1,5-a]pyrazine-6(7H)-ones 9a–f and 11; General Procedure
4,5-Dihydro[1,2,3]triazolo[1,5-a]pyrazine-6(7H)-ones 9a–f and 11; General Procedure
Compound 8 (1 mmol) was dissolved by heating in dry toluene (4 mL). The reaction mixture was
refluxed for 24 h, then cooled and evaporated under reduced pressure to give the target
products 9.
N-Cyclohexyl-2-(7-(2,4-dichlorobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)-2-(p-tolyl)acetamide (9a)
N-Cyclohexyl-2-(7-(2,4-dichlorobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)-2-(p-tolyl)acetamide (9a)
Yield: 0.51 g (98%); white solid; mp 201–203 °C.
1H NMR (600 MHz, DMSO-d
6): δ = 8.31 (d, J = 7.6 Hz, 1 H, NH), 7.51 (s, 1 H, CHAr), 7.48 (d, J = 2.1 Hz, 1 H, CHAr), 7.22–7.15 (m, 3 H, CHTol + CHTr), 7.07 (d, J = 7.8 Hz, 2 H, Tol), 6.98 (d, J = 8.3 Hz, 1 H, CHAr), 6.17 (s, 1 H, CH), 5.61 (t, J = 6.4 Hz, 1 H, CH), 4.54 (d, J = 16.6 Hz, 1 H, CH2), 4.09 (d, J = 16.6 Hz, 1 H, CH2), 3.63 (tdt, J = 11.1, 7.6, 3.9 Hz, 1 H, cyclohex), 3.57–3.41 (m, 2 H, CH2), 2.26 (s, 3 H, Me), 1.85–1.46 (m, 5 H, cyclohex), 1.38–0.97 (m, 5 H, cyclohex).
13C NMR (151 MHz, DMSO-d
6): δ = 167.83 (CON), 165.25 (CON), 138.18 (Tr-4), 135.05 (CAr-2), 133.51 (CHAr-6), 133.06 (CAr-1), 132.53 (CAr-4), 132.00 (CTol-1), 129.90 (2 C, CHTol), 129.57 (CTol-4), 129.50 (CHAr-3), 129.06 (CHAr-5), 129.03 (2 C, CHTol), 127.61 (Tr-5), 59.75 (CH), 59.55 (CH), 48.25 (CH2N), 38.73 (CHNHcyclohex), 35.83 (CH2), 32.64 (2 C, CH2 cyclohex), 25.61 (cyclohex), 24.98 (cyclohex), 24.87 (cyclohex), 21.11 (CH3).
MS (APCI): m/z = 526, 528 [M + H]+.
Anal. Calcd for C27H29Cl2N5O2: C, 61.60; H, 5.55; N, 13.30. Found: C, 61.57; H, 5.50; N, 13.33.
2-(2-Bromophenyl)-N-cyclohexyl-2-(7-(3-fluorobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)acetamide (9b)
2-(2-Bromophenyl)-N-cyclohexyl-2-(7-(3-fluorobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)acetamide (9b)
Yield: 0.53 g (98%); white solid; mp 228–230 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 8.34 (d, J = 8.1 Hz, 1 H, NH), 7.72–6.93 (m, 7 H), 6.64–6.60 (m, 2 H), 6.08 (s, 1 H), 5.74–5.58
(m, 1 H), 4.50 (d, J = 16.0 Hz, 1 H), 3.63 (t, J = 6.8 Hz, 1 H, cyclohex), 3.52–3.38 (m, 3 H), 1.76–1.43 (m, 5 H, cyclohex), 1.26–0.91
(m, 5 H, cyclohex).
13C NMR (126 MHz, DMSO-d
6): δ = 167.59 (CON), 164.44 (CON), 162.25 (d, 1
J
C–F
= 243.1 Hz, CAr-3), 138.15 (d, 3
J
C–F = 7.5 Hz, CAr-1), 133.93, 133.68, 131.51, 131.25, 130.45 (d, 3
J
C–F = 8.3 Hz, CHAr-5), 129.93, 129.38, 128.63, 126.25 (CAr-6), 125.81, 116.85 (d, 2
J
C–F = 20.9 Hz, CHAr-4), 114.25 (d, 2
J
C–F = 20.7 Hz, CHAr-2), 61.10 (CH), 60.48 (CH), 48.42 (CH2N), 37.50, 32.54 (CH2 cyclohex), 32.51 (CH2 cyclohex), 25.56 (CH2 cyclohex), 24.96 (CH2 cyclohex), 24.85 (CH2 cyclohex).
MS (APCI): m/z = 540, 542 [M + H]+.
Anal. Calcd for C26H27BrFN5O2: C, 57.78; H, 5.04; N, 12.96. Found: C, 57.80; H, 5.00; N, 12.93.
Ethyl (2-(2-Bromophenyl)-2-(7-(3-fluorobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)acetyl)glycinate (9c)
Ethyl (2-(2-Bromophenyl)-2-(7-(3-fluorobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)acetyl)glycinate (9c)
Yield: 0.52 g (95%); white solid; mp 187–189 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 9.06 (t, J = 5.9 Hz, 1 H, NH), 7.68 (d, J = 7.9 Hz, 1 H), 7.56–7.41 (m, 3 H), 7.36 (dd, J = 9.0, 4.7 Hz, 1 H), 7.16–7.12 (m, 1 H), 7.03–6.91 (m, 1 H), 6.63–6.59 (m, 2 H),
6.34 (s, 1 H, CH), 5.74 (t, J = 4.7 Hz, 1 H, CH), 4.28–4.07 (m, 3 H), 4.01 (dd, J = 17.1, 5.9 Hz, 1 H, CH2), 3.91–3.71 (m, 2 H), 3.50 (d, J = 5.0 Hz, 2 H, CH2), 1.21 (t, J = 7.1 Hz, 3 H, OCH2CH3
).
13C NMR (126 MHz, DMSO-d
6): δ = 169.44 (COO), 168.54 (CON), 164.72 (CON), 161.52 (d, 1
J
C–F = 259.3 Hz, CAr-3), 137.12 (d, 3
J
C–F = 7.7 Hz, CAr-1), 133.42, 132.94, 131.55, 130.92, 130.09 (d, 3
J
C–F = 8.4 Hz, CHAr-5), 129.10, 128.82, 128.01, 125.34 (d, 4
J
C–F = 1.9 Hz, CAr-6), 124.85, 116.17 (d, 2
J
C–F = 21.4 Hz, CHAr-4), 113.88 (d, 2
J
C–F = 21.7 Hz, CHAr-2), 60.58, 60.39, 59.77, 40.84, 38.51, 38.09, 14.09 (OCH2
CH3).
MS (APCI): m/z = 544, 546 [M + H]+.
Anal. Calcd for C24H23BrFN5O4: C, 52.95; H, 4.26; N, 12.87. Found: C, 52.97; H, 4.27; N, 12.85.
N-Benzyl-2-(7-(3,4-dichlorobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)-2-(4-methoxyphenyl)acetamide (9d)
N-Benzyl-2-(7-(3,4-dichlorobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)-2-(4-methoxyphenyl)acetamide (9d)
Yield: 0.53 g (97%); white solid; mp 105–107 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 8.84 (br s, 1 H, NH), 7.57–7.49 (m, 1 H), 7.43–7.07 (m, 7 H), 7.04–6.65 (m,
4 H), 6.48 (d, J = 8.2 Hz, 1 H), 6.18 (s, 1 H, CH), 5.76–5.75 (m, 1 H), 4.66 (d, J = 16.4 Hz, 1 H), 4.30–4.24 (m, 2 H), 3.73 (s, 3 H, OMe), 3.30 (br s, 2 H, CH2Ph), 3.05–3.01 (m, 1 H).
13C NMR (126 MHz, DMSO-d
6): δ = 168.95 (CON), 164.22 (CON), 159.79, 139.38, 136.08, 131.81, 131.55, 131.32,
131.06 (2 C), 130.60, 129.87, 129.68, 129.54, 128.75 (2 C), 127.81, 127.74, 127.34,
125.97, 114.69, 114.48, 59.99 (CH), 59.27 (CH), 55.66 (CH2N), 42.68 (CH2Ph), 38.28 (OCH3), 31.44 (CH2).
MS (APCI): m/z = 550, 552 [M + H]+.
Anal. Calcd for C28H25Cl2N5O3: C, 61.10; H, 4.58; N, 12.72. Found: C, 61.09; H, 4.59; N, 12.70.
2-(2-Bromophenyl)-2-(7-(3,4-dichlorobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)-N-(p-tolyl)acetamide (9e)
2-(2-Bromophenyl)-2-(7-(3,4-dichlorobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)-N-(p-tolyl)acetamide (9e)
Yield: 0.59 g (98%); white solid; mp 244–245 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 10.46 (s, 1 H, NH), 7.75–7.68 (m, 1 H), 7.59–7.27 (m, 7 H), 7.14 (br s, 2 H),
7.05 (br s, 1 H), 6.77 (br s, 1 H), 6.37 (s, 1 H, CH), 5.80 (br s, 1 H, CH), 4.30
(d, J = 16.5 Hz, 1 H, CH2), 3.88 (d, J = 16.5 Hz, 1 H, CH2), 3.60–3.41 (m, 2 H, CH2), 2.27 (s, 3 H, CH3).
13C NMR (126 MHz, DMSO-d
6): δ = 166.66 (CON), 164.71 (CON), 136.07, 135.69, 133.64, 132.86, 132.76, 131.52,
131.11, 130.88, 130.24, 129.84, 129.64, 129.37, 129.20 (2 C), 128.86, 128.45, 125.14,
119.37, 119.30 (2 C), 61.64, 59.56, 38.92, 37.34, 20.46 (CH3).
MS (APCI): m/z = 598, 600, 602 [M + H]+.
Anal. Calcd for C27H22BrCl2N5O2: C, 54.11; H, 3.70; N, 11.69. Found: C, 54.13; H, 3.73; N, 11.65.
2-(2-Bromophenyl)-2-(7-(3-fluorobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)-N-(4-methoxyphenyl)acetamide (9f)
2-(2-Bromophenyl)-2-(7-(3-fluorobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)-N-(4-methoxyphenyl)acetamide (9f)
Yield: 0.54 g (96%); white solid; mp 221–222 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 10.43 (s, 1 H, NH), 7.71 (d, J = 7.7 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 2 H), 7.50 (s, 1 H), 7.44 (d, J = 7.2 Hz, 1 H), 7.38–7.31 (m, 2 H), 7.14 (d, J = 6.7 Hz, 1 H), 6.99 (s, 1 H), 6.92 (d, J = 8.4 Hz, 2 H), 6.62 (br s, 2 H), 6.37 (s, 1 H, CH), 5.78 (br s, 1 H, CH), 4.17 (d,
J = 16.2 Hz, 1 H, CH2), 3.88 (d, J = 16.2 Hz, 1 H, CH2), 3.74 (s, 3 H, OMe), 3.54 (br s, 2 H, CH2).
13C NMR (126 MHz, DMSO-d
6): δ = 166.33 (CON), 165.03 (CON), 161.93 (d, 1
J
C–F = 244.2 Hz, CAr-3), 155.61, 137.10 (d, 3
J
C–F = 8.0 Hz, CAr-1), 133.65, 132.97, 131.72, 131.05, 130.80, 130.05 (d, 3
J
C–F = 8.3 Hz, CHAr-5), 129.17, 128.88, 128.42, 125.34 (d, 4
J
C–F = 2.4 Hz, CAr-6), 124.99, 120.79 (2 C), 116.25 (d, 2
J
C–F = 21.1 Hz, CHAr-4), 114.00 (2 C), 113.92 (d, 2
J
C–F = 20.9 Hz, CHAr-2), 61.56, 59.81, 55.23, 38.71, 38.09.
MS (APCI): m/z = 564, 566 [M + H]+.
Anal. Calcd for C27H23BrFN5O3: C, 57.46; H, 4.11; N, 12.41. Found: C, 57.55; H, 4.08; N, 12.39.
(Z)-3-Bromo-2-(7-(4-bromobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)-N-cyclopentyl-4-phenylbut-3-enamide (11)
(Z)-3-Bromo-2-(7-(4-bromobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)-N-cyclopentyl-4-phenylbut-3-enamide (11)
Yield: 0.59 g (97%); white solid; mp 216–220 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 8.75, 8.63 (2 d, J = 6.7 Hz, 1 H, NH), 7.72–7.54 (m, 3 H), 7.44–7.39 (m, 3 H), 7.30 (t, J = 7.9 Hz, 2 H), 7.00 (d, J = 2.7 Hz, 1 H), 6.69–6.65 (m, 2 H), 5.96 (d, J = 7.5 Hz, 1 H), 5.83–5.73 (m, 1 H), 5.02, 4.51 (2 d, J = 16.4 Hz, 1 H), 4.17–3.84 (m, 2 H), 3.50–3.25 (m, 2 H), 1.96–1.76 (m, 2 H, cyclopent),
1.70–1.37 (m, 6 H, cyclopent).
13C NMR (126 MHz, DMSO-d
6): δ = 171.70 (CON), 165.20 (CON), 131.51, 131.30 (2С), 131.21, 129.26, 129.12, 128.91
(2С), 128.86 (2С), 128.44 (2С), 128.38 (2С), 120.48, 119.42, 64.22, 59.97, 50.80,
40.07, 38.13, 32.18, 31.89, 23.48, 23.34.
MS (APCI): m/z = 612, 614, 616 [M + H]+.
Anal. Calcd for C27H27Br2N5O2: C, 52.87; H, 4.44; N, 11.42. Found: C, 52.88; H, 4.46; N, 11.40.
4,5-Dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones 9g and 9h; General Procedure
4,5-Dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones 9g and 9h; General Procedure
A solution of 2-azidopropionic acid 3 (2 mmol), amine 4c (2 mmol), aldehyde 5 (2 mmol) and isonitrile 6 (2 mmol) in methanol (5 mL) was stirred at room temperature for 30 min. The temperature
was then raised to 50 °C and stirring was continued for 72 h. Upon completion of the
reaction, the methanol was evaporated and the residue was recrystallized from dichloromethane/hexane
(3:1).
N-Benzyl-2-(7-(4-bromobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)-3-methylbutanamide (9g)
N-Benzyl-2-(7-(4-bromobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)-3-methylbutanamide (9g)
Yield: 0.78 g (78%); white solid; mp 239–241 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 8.85 (t, J = 5.8 Hz, 1 H, NH), 7.56 (s, 1 H), 7.29–7.16 (m, 5 H), 7.11 (d, J = 8.1 Hz, 2 H, Ar), 6.54 (d, J = 8.0 Hz, 2 H, Ar), 5.65 (t, J = 4.5 Hz, 1 H, CH), 4.71 (d, J = 11.1 Hz, 1 H), 4.50 (d, J = 17.1 Hz, 1 H), 4.33 (dd, J = 15.1, 6.2 Hz, 1 H, CH2), 4.21 (dd, J = 15.1, 5.8 Hz, 1 H, CH2), 3.73 (d, J = 17.0 Hz, 1 H), 3.47–3.35 (m, 2 H), 2.11 (dp, J = 12.8, 6.5 Hz, 1 H, CHMe2), 0.81 (d, J = 6.5 Hz, 3 H, Me), 0.61 (d, J = 6.6 Hz, 3 H, Me).
13C NMR (126 MHz, DMSO-d
6): δ = 168.46 (CON), 165.22 (CON), 139.60, 134.08, 131.62 (2 C), 131.53 (2 C), 129.70,
129.33, 128.72 (2 C), 127.73 (2 C), 127.29, 120.88, 61.92, 60.22, 42.58, 38.53, 37.58,
26.24, 19.43 (Me), 18.93 (Me).
MS (APCI): m/z = 496, 498 [M + H]+.
Anal. Calcd for C24H26BrN5O2: C, 58.07; H, 5.28; N, 14.11. Found: C, 58.09; H, 5.26; N, 14.10.
N-Benzyl-2-(7-(2-fluorobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)-2-(1H-indol-3-yl)acetamide (9h)
N-Benzyl-2-(7-(2-fluorobenzyl)-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)-2-(1H-indol-3-yl)acetamide (9h)
Yield: 0.84 g (83%); white solid; mp 252–254 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 11.27 (s, 1 H, NHInd), 8.86 (t, J = 6.2 Hz, 1 H, NH), 7.37 (s, 2 H), 7.33–7.16 (m, 8 H), 7.07 (t, J = 7.7 Hz, 1 H), 7.01–6.81 (m, 4 H), 6.55 (s, 1 H, CH), 5.68–5.65 (m, 1 H, CH), 4.36
(d, J = 5.8 Hz, 2 H, CH2), 4.28–4.17 (m, 2 H), 3.52–3.35 (m, 2 H).
13C NMR (126 MHz, DMSO-d
6): δ = 169.21 (CON), 165.16 (CON), 161.17 (d, 1
J
C–F = 245.3 Hz, CAr-2), 139.62, 136.72, 131.99 (d, 3
J
C–F = 3.9 Hz, CHAr-6), 129.70 (d, 3
J
C–F = 8.2 Hz, CAr-4), 129.58, 129.24, 128.66 (2 C, Ph), 127.82 (2 C, Ph), 127.26, 126.89, 126.74, 124.69
(d, 4
J
C–F = 3.4 Hz, CHAr-5), 122.25, 122.08 (d, 2
J
C–F = 15.7 Hz, CAr-1), 119.85, 118.49, 115.53 (d, 2
J
C–F = 21.8 Hz, CHAr-3), 112.33, 107.47, 60.01 (CH), 53.75 (CH), 42.71 (CH2N), 38.11 (CH2Ph), 32.42 (CH2).
MS (APCI): m/z = 509 [M + H]+.
Anal. Calcd for C29H25FN6O2: C, 68.49; H, 4.96; N, 16.53. Found: C, 68.50; H, 4.97; N, 16.51.
7-(4-Bromobenzyl)-N-cyclopentyl-5-cyclopropyl-6-oxo-3-phenyl-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazine-4-carboxamide (10)
7-(4-Bromobenzyl)-N-cyclopentyl-5-cyclopropyl-6-oxo-3-phenyl-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazine-4-carboxamide (10)
Compound 7a (2 mmol) was dissolved by heating in dry toluene (8 mL) and then triethylamine (2
mmol) was added to the solution. The reaction mixture was refluxed for 24 h and then
cooled, evaporated under reduced pressure, and washed with water to give the target
product 10.
Yield: 0.98 g (92%); white solid; mp 223–224 °C.
1H NMR (400 MHz, DMSO-d
6): δ = 8.26–8.14 (m, 1 H, NH), 7.80–7.62 (m, 3 H), 7.50–7.35 (m, 5 H), 7.21 (d, J = 7.5 Hz, 2 H), 4.82–4.66 (m, 1 H), 4.01–3.81 (m, 1 H), 3.08 (dd, J = 14.3, 4.3 Hz, 1 H), 2.90–2.71 (m, 1 H), 2.54–2.51 (m, 1 H), 1.68 (br s, 1 H), 1.55–1.27
(m, 3 H), 1.26–1.07 (m, 3 H), 0.88–0.61 (m, 3 H), 0.54–0.37 (m, 1 H), 0.12 (br s,
1 H).
13C NMR (101 MHz, DMSO-d
6): δ = 171.89 (CON), 166.31 (CON), 152.68, 137.41, 134.79, 132.54, 132.04 (2 C), 131.53
(2 C), 130.86, 130.65 (2 C), 128.83 (2 C), 120.25, 82.80, 63.08, 51.99, 35.70, 31.52,
31.19, 24.61, 23.84, 23.59, 6.71 (cyclopropyl), 6.37 (cyclopropyl).
MS (APCI): m/z = 534, 536 [M + H]+.
Anal. Calcd for C27H28BrN5O2: C, 60.68; H, 5.28; N, 13.10. Found: C, 60.70; H, 5.25; N, 13.09.