Yuri M Shafran1, Aqeel A Hussein2, Nikolai A Beliaev1, Vadim A Shevyrin1, Sergey Shityakov3, Tetyana V Beryozkina1, Vasiliy A Bakulev1. 1. Technology for Organic Synthesis Department, Ural Federal University, 19 Mira Street, Ekaterinburg 620002, Russia. 2. Department of Pharmacy, College of Medicine, Komar University of Science and Technology, Sulaymaniyah 46002, Kurdistan Region, Iraq. 3. Laboratory of Chemoinformatics, Infochemistry Scientific Center, ITMO University, 9 Lomonosova Street, Saint-Petersburg 191002, Russia.
Abstract
Here, we report that the reaction of enaminones, from a class of azole series, with sulfonyl azides leads to a difficult-to-separate mixture of two pairs of compounds: (1) 4-azoloyl-NH-1,2,3-triazoles with sulfonamides and (2) azolyl diazoketones with N-sulfonamidines, as a result of the implementation of two competing reactions. On one hand, the electron-donating methyl or methoxy group in the aryl para-position of arylsulfonyl azides favors the production of NH-1,2,3-triazoles together with sulfonamides. On the other hand, the use of highly electrophilic 4-nitrophenylsulfonyl azide promotes the formation of diazoketones and sulfonamidines. It is shown that the direction of each reaction is not only controlled by the nature of the initial enaminones and sulfonyl azides but also depends on the tested solvent. The problem of removing sulfonamides and amidines from the desired products was solved for the first time using new water-soluble enaminones. Based on the experimental and computational studies, the factors contributing to the selective course of alternative reactions were identified, and methods for the synthesis of azoloyl-NH-1,2,3-triazoles and azolyl diazoketones were developed. Density functional theory (DFT) results have shown that the 1,3-dipolar cycloaddition is totally driven toward one single regioisomer with a high asynchronous bond formation, and the introduction of an electron-deficient group in sulfonyl azides induces faster cycloaddition. Additionally, DFT calculations were used to gain further mechanistic insights on the reaction studied here.
Here, we report that the reaction of enaminones, from a class of azole series, with sulfonyl azides leads to a difficult-to-separate mixture of two pairs of compounds: (1) 4-azoloyl-NH-1,2,3-triazoles with sulfonamides and (2) azolyl diazoketones with N-sulfonamidines, as a result of the implementation of two competing reactions. On one hand, the electron-donating methyl or methoxy group in the aryl para-position of arylsulfonyl azides favors the production of NH-1,2,3-triazoles together with sulfonamides. On the other hand, the use of highly electrophilic 4-nitrophenylsulfonyl azide promotes the formation of diazoketones and sulfonamidines. It is shown that the direction of each reaction is not only controlled by the nature of the initial enaminones and sulfonyl azides but also depends on the tested solvent. The problem of removing sulfonamides and amidines from the desired products was solved for the first time using new water-soluble enaminones. Based on the experimental and computational studies, the factors contributing to the selective course of alternative reactions were identified, and methods for the synthesis of azoloyl-NH-1,2,3-triazoles and azolyl diazoketones were developed. Density functional theory (DFT) results have shown that the 1,3-dipolar cycloaddition is totally driven toward one single regioisomer with a high asynchronous bond formation, and the introduction of an electron-deficient group in sulfonyl azides induces faster cycloaddition. Additionally, DFT calculations were used to gain further mechanistic insights on the reaction studied here.
NH-1,2,3-Triazoles, linked to a second five-membered
heterocycle through a carbonyl group, possess two active functional
groups and are therefore promising building blocks for obtaining various
1,2,3-triazole derivatives. 1,2,3-Triazole is a heterocycle that has
found wide applications as a privileged scaffold in the directed synthesis
of substances with biological activity, in organic electronics for
the synthesis of new materials, as a key fragment in the synthesis
of substances capable of metal-catalyzed cycle transformations, and
as a unique building block in the synthesis of various organic compounds.[1,2] Among NH-1,2,3-triazoles, substances with biological
activity and used as new materials with interesting optical and physical
properties were also found.[3−10] The primary methods of synthesis of 4-carbonyl derivatives of NH-triazoles include reactions of acylacetylenes with inorganic
azides,[11−14] interaction of α-diazo-β-oxoaldehydes with aniline,
ammonium, hydroxylamine, and semicarbazide,[15] and modifications of ready NH-triazoles synthesized
by other methods.[16,17] All the methods mentioned above
almost completely focused on the production of 4-aroyl derivatives
of 1,2,3-triazole. In this aspect, another method based on the reaction
of β-enaminones 1 with tosyl azide (2a) is an exception, which permitted to prepare three 4-heteroaroyltriazoles
(pathway A, Scheme ).[18−20] Thus, the existing synthesis methods are limited
in their applicability for the production of 4-heteroaroyl-NH-triazoles.
Scheme 1
General Scheme of Synthesis of NH-Triazoles 4 and Diazo Compounds 5 from
Enaminones 1 and Azides 2
It should be noted that changing the nature of enaminones 1 and the conditions of their reaction with sulfonyl azides 2 lead to switching to other products, diazoketones 5 together with amidines 7 (pathway B, Scheme ).[21]α-Diazoketones are widely used in
organic synthesis. They
are well-known precursors of carbenes and carbenoids. Being 1,3-dipoles
of propargyl-allenyl type, they take part in cyclopropanations, rearrangements,
cycloadditions, and electrocyclic processes.[22−26] They are valuable reagents for use in biological
chemistry[27] found in naturally occurring
products[28,29] and also included as a fragment into the
structure of some anticancer drugs.[30] Despite
a large number of methods for the synthesis of diazoketones published
in the literature,[22,23,31−37] their applicability for the synthesis of heteroaroyl diazomethanes
is extremely limited. All this makes us to conclude that the search
for new safe and effective methods for the synthesis of both NH-1,2,3-triazoles and diazomethanes of the azoloyl series
is an urgent task.To solve this dual problem at once, the reaction
of enaminones
of azole series 1 with arylsulfonyl azides 2, which could undergo, depending on the structure of reactants and
reaction conditions, both competing reactions A and B (Scheme ) leading to NH-1,2,3-triazoles 4 and
diazocarbonyl compounds 5, respectively, is particularly
promising. It should be noted that no examples have been found in
the literature when products of both types 4 and 5 were obtained and identified together in one reaction. Moreover,
there is no information about the factors directing the conversion
of triazolines 3 toward the formation of a particular
product 4 or 5 (Scheme ) found by either experimental or computational
methods.The reactions of sulfonyl azides 2 with
heterocyclic
enaminones 1 are presented in the literature to a much
lesser extent than the corresponding reactions of aromatic[16,17,38,39] and alicyclic[38] enaminones. Thus, it
is described[16] that the enaminones 1′a,b react with tosyl azide (2a) in water to form exclusively NH-triazoles 4′a,b (Scheme ), which are the only described examples
of NH-1,2,3-triazoles linked with the second heterocycle
through a carbonyl group.
Scheme 2
Synthesis of 4-Acyl-NH-1,2,3-triazoles
and Azolyl
Diazoketones
On the other hand,
heterocyclic β-methylenaminones 1′c react
with mesyl azide (2b) in water
under microwave irradiation to form only the corresponding diazoketones 5′ (Scheme ).[40] The method of synthesis of
heteroaroyl diazo compounds 7′ by the reaction
of the corresponding chloroanhydrides 6′ with
diazomethane (Arndt–Eistert synthesis) has not found a wide
application[41−43] due to the high explosiveness and toxicity of the
latter.Here, we demonstrate a new approach that allows one
to obtain both NH-1,2,3-triazoles 4 and
diazomethanes 5 of heteroaroyl series based on the use
of either water-soluble
sulfonyl azides or enaminones containing an N-methylpiperazine
residue. This approach allowed us to develop a simple and effective
method for separating the desired 4-acyl-NH-1,2,3-triazoles 4 and diazoketones 5 from byproducts, sulfonamides 6 and amidines 7 (Scheme ). A combination of experimental and computational
studies of the interaction of azolylenaminones with sulfonyl azides
revealed the influence of the nature of the starting reagents and
the solvents on the direction of the reaction. It was found that seemingly
insignificant changes in the structure of arylsulfonyl azide, as well
as a variation like the solvent, lead to drastic changes in the direction
of this reaction. It is shown that the reactions of the least electrophilic
tosyl azide (2a) and 4-methoxyphenyl azide (2g) in pyridine lead to the selective formation of NH-1,2,3-triazoles 4. On the contrary, the formation of
diazoketones 5 is facilitated by the use of azide 2e, containing a strong electron acceptor nitro group and
ethanol as a solvent. Optimal conditions were determined, and methods
were developed for the selective and effective synthesis of azoloyl NH-1,2,3-triazoles 4 and diazoketones 5.
Results and Discussion
As an enaminone substrate, we
initially selected the earlier synthesized[44,45]N,N-dimethylenaminones 1a–o, as well as enaminone 1p [which we first obtained in
two stages via 4-acetyl-1,2,3-triazole 9 from Zidovudine
(8)] (Scheme ), where the substituent at position 1 of 1,2,3-triazole widely
varied in electronic properties. In addition to 1,2,3-triazole derivatives 1a–p, one representative of the 1,2,3-thiadiazole 1q and isoxazole 1r(45) series were chosen for the study. Selected N,N-dimethylenaminones 1a–f,g–r were reacted with several sulfonyl azides R3SO2N3 (2) (R3 = 4-MeC6H4 (2a), Me (2b), Ph (2c), 4-F3CC6H4 (2d), and 4-O2NC6H4 (2e)).
Scheme 3
Scattered Examples of Reactions of Enaminones 1 with
Sulfonyl Azides 2
As can be seen from Scheme , at the end of the synthesis, the reaction mixture generally
contains four products, namely, two desired ones (4 and 5) and two byproducts (6 and 7).
Often, non-stoichiometric ratios of reactants were used or their conversion
turned out to be incomplete, which further complicates the reaction
mixture due to residual amounts of reactants. The lack of differences
in the components of the reaction mixture (including unpredictable
chromatographic mobility), which would allow them to be easily separated,
makes this task rather difficult. Indeed, in a series of experiments
that we have carried out (Scheme ), complex combinations of chromatographic and other
physico-chemical techniques had to be used to isolate the desired
products of reaction 4, 5; in some cases,
we could not isolate pure substances at all or only partially succeeded.We suggested that the cardinal solution of the problem could be
the use of a radically different separation principle. To do this,
we decided to introduce a basic fragment into the molecule of one
of the reactants 1 or 2 and, consequently,
into the byproducts 6 and 7, which gives
the latter solubility in acidic aqueous medium. The acidity in reactants 1 or 2 as a factor in allowing the removal of
byproducts 6 and 7 was not considered because
one of the desired products, monosubstituted triazoles of type 4, are also quite strong acids that form stable salts with
bases, for example, triethylamine.Initially, we decided to
introduce a basic fragment into sulfonyl
azide, which was achieved using the previously obtained[46] 2-morpholinoethane-1-sulfonyl azide (2f) (Scheme ).
Scheme 4
Scattered Reactions of Enaminones 1 with Azide 2f
The reactions were carried
out in 1,4-dioxane and byproducts 6 and 7 were washed off after the removal of
the solvent with an aqueous solution of AcOH (the use of strong acids
is risky because their excess destroys diazo compounds 5). The easy removal of water-soluble byproducts 6 and 7 made it possible to obtain mixtures consisting predominantly
of NH-triazoles 4 and diazo compounds 5, which allowed to analyze them without preparative separation
using 1H NMR spectroscopy. The separation of the mixtures
in order to obtain the components was carried out using column chromatography.
Doing this, to increase the difference in the chromatographic mobility
of NH-triazoles 4 and diazo compounds 5, the phenomenon of a pronounced acidity of the former was
used. Thus, the addition of triethylamine to the eluent at the beginning
of chromatography drastically reduced the R of NH-triazoles 4 due
to the formation of a salt, as a result of which only diazo compounds 5 were eluted. Then, a small amount of AcOH was added to the
eluent to destroy the salt, after which NH-triazoles 4 were eluted.However, in the majority of cases, the
selective formation of one
of the two types of reaction products does not take place (Scheme ). We assumed that
the addition of acetic acid to the reaction mixture would shift the
reaction in favor of the formation of diazo compounds 5 due to the neutralization of the basic morpholine fragment from
sulfonyl azide 2f. Though the expected effect was observed
in a series of experiments (cf. entry 4, Scheme , with entry 5 and, especially, entry 6),
the desired selectivity was not achieved. Thus, the introduction of
the basic fragment into the sulfonamide component of sulfonyl azides 2 did not provide the synthesis of NH-triazoles 4 and diazo compounds 5 with satisfactory selectivity,
which reduces the preparative attractiveness of the tested approach.An approach alternative to the previous one is the use of enaminones
of type 10 with the basic fragment of N-methylpiperazine, which was introduced instead of the dimethylamino
group by the transamination reaction of enaminones 1.
The preferred method for the synthesis of enaminones 10 was found to be heating enaminones 1 in N-methylpiperazine with letting the releasing dimethylamine to dissipate
in the atmosphere (Scheme ). The excess N-methylpiperazine can be regenerated
to a great extent by distilling it from the reaction mixture after
the end of the reaction. Thus, a series of new enaminones bearing
a fragment of N-methylpiperazine of the 1,2,3-triazole
series 10a–p was obtained, as well as one representative
of the 1,2,3-thiadiazole 10q and isoxazole 10r series (Scheme ).
Scheme 5
Syntheses of N-Methylpiperazine Enaminones 10
In the synthesis of the o- (10c)
and p-nitro derivative (10d), significant
amounts of o- and p-nitroaniline
were detected in the reaction mixture, respectively, presumably due
to the decomposition of compounds 10c and 10d under the action of N-methylpiperazine. As a result, p-nitro enaminone 10d was obtained with a yield
of 82%, and the yield of o-isomer 10c was only 48% with a conversion rate of the starting compound 1c of 95%. Thus, the transamination reaction is of limited
applicability for the preparation of compounds 10 that
are labile to N-methylpiperazine.The synthesized
enaminones 10 have a higher melting
point, are more stable during storage and are significantly more polar
than initial dimethyl enaminones 1, which favor their
purification by crystallization or column chromatography, and altogether
make them more convenient in synthetic practice.In syntheses
using N-methylpiperazine enaminones 10 (Scheme ), it was
found possible to apply a method for isolating compounds 4 and 5, similar to the one used in the reaction
of enaminones 1 with azide 2f (Scheme ).
Scheme 6
Reactions of N-Methylpiperazine Enaminones 10 with Sulfonyl
Azides 2
In order to increase the practical value of the method under development,
we looked for the reaction conditions leading to the predominant formation
of one of the two types of reaction products, NH-triazoles 4 or diazo compound 5. Initially, the influence
of the nature of sulfonyl azide 2 on the ratio of reaction
products when interacting with enaminone 10h (Scheme ) was studied. The
reactions were carried out in 1,4-dioxane at room temperature.
Scheme 7
Reaction of Enaminone 10h with Sulfonyl Azides 2a–e and 2g in 1,4-Dioxane
Based on the experimental results presented in Scheme , it can be concluded
that
the electronic properties of the substituent in sulfonyl azides 2 significantly affect the direction of the reaction. Thus,
the use of azides 2a and 2g containing electron-donating
substituents leads to a maximum yield of NH-triazole 4h (Scheme , entries 1 and 6), while sulfonyl azide 2e with an
electron-acceptor group affords the maximum yield of diazo compound 5h (Scheme , entries 1, 6). For the further optimization of the method for obtaining NH-triazoles 4 from a pair of arylsulfonyl
azides 2a and 2g, which showed similar results,
tosyl azide (2a) was chosen as much more available. Thus
the study of the effect of the solvent nature on the yield of NH-triazoles 4 (Scheme ) was carried out using the reaction of enaminone 10h with tosyl azide (2a).
Scheme 8
Reaction of Enaminone 10h with Azide 2a in Different Solvents
Data of Scheme demonstrate that the best yields of NH-triazole 4h are provided by the use of pyridine as
a solvent (entries
9–11). Further, the effect of the reaction temperature on the
yield of the desired NH-triazole 4h was
studied in this solvent (Scheme , entries 9–11). Notably, an increase in temperature
to 75 °C leads to a certain decrease in the yield of the desired
product 4h (Scheme , entry 11), while it is practically invariable in
the temperature range from room to 52 °C.It should be
noted that in the studies presented in Schemes and 8, an attempt
to introduce into the reaction an excess of enaminone 10h or sulfonyl azide 2 always led only to that
after the reactant taken in deficiency completely disappeared, the
reactant taken in excess was detected in the reaction mixture using 1H NMR, moreover in an amount close to that expected by balance
calculation, while the yield of the desired products 4 and 5 remained practically the same.Thus, the
optimal conditions for the synthesis of NH-triazoles 4 from enaminones 10 were recognized
as the use of tosyl azide (2a) as a sulfonyl azide and
pyridine as a solvent at a temperature of 25–52 °C with
an equimolar ratio of reactants.Having optimal conditions in
hands, we synthesized a series of
compounds of the 1,2,3-triazole series 4a–p, as
well as one representative of the 1,2,3-thiadiazole 4q and isoxazole 4r series; the results are given in Scheme .
Scheme 9
Syntheses of NH-Triazoles 4a–r in Optimized Conditions
As already noted, the highest yield of diazo
compound 5h in the experiments presented in Scheme is achieved using
4-nitrophenylsulfonyl
azide (2e). In this respect, the optimization of the
method for obtaining diazo compounds 5 was carried out
using reagent 2e. Thus, the effect of the solvent on
the yield of reaction products was studied by analyzing a series of
experiments, where it changed in the reaction of sulfonyl azide 2e with enaminone 10q. It was found that in this
series (entries 1–5, Scheme ), the use of ethanol leads to the maximum yield of
diazo compound 5q. Later, we locked ethanol as a solvent
and investigated the effect of the reaction temperature on the yield
of diazo compound 5q (entries 5–7, Scheme ). It was revealed that the
yield of diazo compound 5q decreased in the row rt >
4 °C ≈ 70 °C.
Scheme 10
Reaction of Enaminone 10q with Azide 2e in Different Solvents
Similar to the optimization of the synthesis of NH-triazoles 4 (Schemes and 10), the use
of an excess
of enaminone 10q or sulfonyl azide 2e in
the reaction led merely to their overspending. As a result, the best
conditions for the synthesis of diazo compounds 5 from
enaminones 10 were formulated as follows: 4-nitrophenylsulfonyl
azide (2e) as a sulfonyl azide, ethanol, or methanol
as a solvent, the reaction temperature was room temperature (in the
case of enaminone 10o, the reaction was carried out at
an elevated temperature because of its low solubility) with an equimolar
ratio of reactants.In these optimal conditions, a series of
diazocarbonyl compounds
of 1,2,3-triazole 5a–p series were synthesized,
as well as one representative of 1,2,3-thiadiazole 5q and isoxazole 5r series, which are given in Scheme .
Scheme 11
Syntheses
of Diazo Compounds 5a–r in Optimized
Conditions
NH-1,2,3-Triazoles 4 are solid colorless
substances with a relatively high melting point. Their structure correlates
with the data of 1H and 13C NMR spectroscopy,
which was also confirmed by ultra-high-performance liquid chromatography
with high-resolution mass spectrometry (UHPLC-HRMS) detection, and
X-ray analysis was performed for a single crystal of compound 4f (Figure ).
Figure 1
Molecular structure of NH-triazole 4f solvate with a representation of the atoms by thermal vibration
ellipsoids of 50% probability.
Molecular structure of NH-triazole 4f solvate with a representation of the atoms by thermal vibration
ellipsoids of 50% probability.Diazo compounds 5 are solid light yellow substances
with a relatively low melting point (n-butyl derivative 5f could not be crystallized). Their structure correlates
with the data of 1H and 13C NMR spectroscopy
and UHPLC-HRMS. In the 1H NMR spectra of diazo compounds 5, broad singlets of protons from the diazoketone fragment
C(=O)CHN2 are observed at 5.04–6.76 ppm.
The IR spectra of compounds 5 display the characteristic
bands of the valence vibrations of the diazo group in the range of
2096–2115 cm–1. Additionally, the structure
of diazo compounds 5 is confirmed by the X-ray analysis
performed for a single crystal of compound 5c (Figure ).
Figure 2
Molecular structure of
compound 5c with representation
of the atoms by thermal vibration ellipsoids of 50% probability.
Molecular structure of
compound 5c with representation
of the atoms by thermal vibration ellipsoids of 50% probability.Previously, the synthesis of one of the diazo compounds,
2-diazo-1-(5-methyl-1,2,3-thiadiazol-4-yl)methyl-1-one
(5q), by an alternative method is described in ref (42). However, except for the
melting point, no analytical characteristics are published in the
article,[42] which makes it unsuitable for
confirmation of the structure of compound 5q synthesized
by us.The plausible mechanism for the formation of compounds 5–7 is depicted in Scheme . We assumed that triazoline 3 generated by the
cycloaddition reaction of enaminone 1 with sulfonyl azide 2 is a common intermediate on pathways A and B, leading to the desired products 4 and 5. Theoretically, as indicated in Scheme , pathway A includes the elimination
of sulfonyl amide 6 and formation of triazoline 11, which is followed by the 1,3-H shift to result in final NH-triazole 5 (A1) or via the
elimination of dialkyl amine and generation of 1-arylsulfonyl-1,2,3-triazole 12. The latter reacts with dialkyl amine to form triazole 5 accompanied by sulfonamide 4 (A2). We also assume that the formation of the second desired compound,
diazo compound 5, occurs via the cycloreversion of triazoline 3.[21] Therefore, we have performed
computational simulations to gain close insights into the nature of
such an important transformation using density functional theory (DFT)
approaches (see below).
Scheme 12
Plausible Mechanism of Formation of NH-Triazoles 4 and Diazo Compounds 5
Computational Investigations
We
next performed DFT
simulations to gain further insights into the reaction mechanism.
The calculations were performed at the (SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d)
level of theory (see the Computational Methods). Overall, we have calculated the mechanistic pathway for the formation
of the desired product 4a and its isomers in 1,4-dioxane
(Figure ). Despite
the cycloaddition of enaminone 1a with sulfonyl azide 2a being approximately thermoneutral to give intermediate Int4a, the latter is kinetically favored over by a substantial
barrier difference of more than 16 kcal/mol via TS3a although
the other isomeric intermediate Int4a is slightly thermodynamically exergonic (ΔG = −2.1 kcal/mol). This sharp preferability for the formation
of intermediate Int4a is reasoned to factors indicated
below.
Figure 3
Computational evaluation of the reaction mechanism for the formation
of NH-1,2,3-triazoles 4a (black pathway)
and its isomer 13 (blue pathway) calculated at the (SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d)
level of theory at 298.15 K in 1,4-dioxane, showing important selected
transition-state geometries.
Computational evaluation of the reaction mechanism for the formation
of NH-1,2,3-triazoles 4a (black pathway)
and its isomer 13 (blue pathway) calculated at the (SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d)
level of theory at 298.15 K in 1,4-dioxane, showing important selected
transition-state geometries.This regiomeric preferability of the formation of intermediate Int4a has shown to be important to rationalize the considerable
difference between TSs leading to different regioisomers. Generally,
the 1,3-dipolar cycloaddition is a concerted and pericyclic process
as an asynchronous addition, where both electronic[47,48] and steric factors[49,50] significantly contributed to
the regioselectivity. The electronic effect is a dominant combination
of the highest occupied molecular orbital (HOMO) and the lowest unoccupied
molecular orbital (LUMO), and this is clearly governed by the largest
coefficients of HOMO and LUMO of the reacting atoms. Although the
steric effect is well known to compete with the electronic effects
through favoring the opposite regioisomer exclusively, we have noticed
a remarkably different behavior here that would lead to a considerable
energy difference between TS3a and TS3a. Our simulations have revealed three important
observations that make TS3a considerably more favorable
than TS3a (Figure a).First, the non-covalent
interaction (NCI) calculations disclose
a strong bonding interaction between methyl groups of enaminone and
oxygen atoms of sulfonyl azide, as shown by the absolute values of
charges for atom H20 with O30 and atom H23 with O31 (Figure a). Second, and in this regard,
the NCI results manifest an electrostatic interaction between the
hydrogen atom H5 of the triazole ring and the nitrogen atom N28 of
the azide moiety. These two types of interactions are completely absent
in the other TS, TS3a. Third,
the high asynchronous attack via (3 + 2) cycloaddition is clearly
evidenced (Figure b). The intrinsic reaction coordinate (IRC) calculations showed that
while the first N–C bond forms at 1.56 Å, the other N–C
bond is still away in the transition state zone at 2.37 Å, consequently
resulting in a high asynchronous (3 + 2) cycloaddition due to a 0.81
Å bond difference between the first and second N–C bond
formation (Figure b, top). However, the other regiomeric (3 + 2) addition through TS3a is calculated to be totally
concerted, as indicated by the IRC calculations, by which the formation
of both N–C bonds reaches 1.56 Å simultaneously (Figure b, bottom).
Figure 4
(a) Optimized
geometry of TS3a; selected charges and
bond lengths (top) with its NCI plot indicating important non-covalent
interactions are shown (bottom). (b) Minimum energy path diagrams
for the (3 + 2) cycloaddition of alkene 1a and sulfonyl
azide 2a determined by performing M06-2x/6-31G (d) IRC
calculations for TS3a and TS3a, showing a plot of the relative electronic energy
along with mass-weighted reaction coordinate s (amu1/2 Å). (c) Effect of substituents on computed free energies
of activations and reactions (in kcal/mol) for the formation of intermediate Int4a via TS3a calculated at the (SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d)
level of theory at 298.15 K in 1,4-dioxane.
(a) Optimized
geometry of TS3a; selected charges and
bond lengths (top) with its NCI plot indicating important non-covalent
interactions are shown (bottom). (b) Minimum energy path diagrams
for the (3 + 2) cycloaddition of alkene 1a and sulfonyl
azide 2a determined by performing M06-2x/6-31G (d) IRC
calculations for TS3a and TS3a, showing a plot of the relative electronic energy
along with mass-weighted reaction coordinate s (amu1/2 Å). (c) Effect of substituents on computed free energies
of activations and reactions (in kcal/mol) for the formation of intermediate Int4a via TS3a calculated at the (SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d)
level of theory at 298.15 K in 1,4-dioxane.Despite the fact that the 1,3-dipolar cycloaddition reaction was
previously investigated using DFT simulations,[51−53] our novel (3
+ 2) cycloaddition seems to be in need for further attention. The
effect of substituents on the 1,3-dipolar cycloaddition is investigated
and shown in Figure c. In this regard, in comparison with our model investigated here,
R1 and R2 = Me (Figure c, entry 1), replacing the methyl group with
a phenyl group results in the formation of a five-membered ring with
a slightly less barrier of ΔΔG⧧ = 0.4 kcal/mol, making it slightly more exergonic (ΔΔGr = −1.3 kcal/mol) (Figure c, entry 2). While R2 remains a Ph group and R1 is substituted with methyl
at the para position, the calculated barrier increases to 25.5 kcal/mol
but becomes more exergonic (ΔGr =
−2.9 kcal/mol) (Figure c, entry 3). In contrast, the barrier dropped to 24.8 kcal/mol
when a para-methyl group was replaced with a para-nitrophenyl group (Figure c, entry 4). Interestingly, in the presence
of an electron-withdrawing group like NO2 in sulfonyl azide
(R2), when R1 = Ph, the five-membered ring formation
proceeded with a reduced barrier of 23.3 kcal/mol (Figure c, entry 6) compared to our
model substrate used in this investigation (Figure c, entry 1, R1, R2 =
Me). Overall, from these results, the rate of cycloaddition seems
to be more likely higher when the electron-deficient group is involved
in the azide moiety.To complete the pathway of NH-1,2,3-triazoles 8a formation, we assumed that favorable
intermediate Inta4 would undergo two separate pathways
to release three
different molecules (8, Int11, and 13), as shown in Figure . On the one hand, intermediate Int4a affords
the elimination of sulfonyl amide 9 and triazoline Int11, which follows by either 1,3-H shift
to form NH-triazole 13 or 1,2-H shift to form our desired product 8. However,
this pathway was shown to be kinetically disallowed due to the substantial
barrier of 37.8 kcal/mol that is needed to be overcome via TS10 as a thermoneutral step (ΔG = −0.8
kcal/mol) to give intermediate Int11. Concurrently, in
addition to the unfavorable sulfonyl amide 9 elimination,
the intermediate Int11 will subsequently undergo either
a high activation barrier of 25.7 kcal/mol via 1,2-H shift TS12 to furnish compound 13 or through
a forbidden pathway 1,3-H shift TS12 with a barrier of 59.3 kcal/mol to release compound 8. Therefore, regarding the mild conditions employed in our methodology,
both shifts were totally ruled out.On the other hand, the elimination
of dimethyl amine and generation
of 1-methylsulfonyl-1,2,3-triazole intermediate Int6a seems to be a more sensible pathway although it still required a
higher barrier of 29.7 kcal/mol through the four-membered transition-state TS5a as a highly exergonic step of 16.8 kcal/mol to form intermediate Int6a (Figure ). If latter intermediate Int6a is formed, it reacts
with dimethylamine to form triazole 8a accompanied with
sulfonyl amide 9 with a calculated exergonicity of 17.0
kcal/mol. Therefore, to overcome this high calculated barrier via TS5a and allow a smooth dimethyl amine elimination, a water
molecule is needed to form a six-membered TS. Indeed, the addition
of a water molecule as a catalyst lowers the barrier of HNMe2 elimination to 23.8 kcal/mol within a relaxed TS TS5a rather than 29.7
kcal/mol with a strained TS within TS5a. Therefore, according
to the calculations performed for the model reaction of 1-(1,5-dimethyl-1H-1,2,3-triazol-4-yl)-3-(dimethylamino)prop-2-en-1-one (1a) with mesyl azide (2a), the dialkyl amine
elimination is more preferable by more than 13 kcal/mol than sulfonyl
amide elimination.Further DFT simulations were performed to
understand the formation
of diazo compound 5a under these reaction conditions.
We assume that the formation of the second desired compound occurs
via the (3 + 2) cycloreversion of triazoline intermediate Int4a. Figure shows an
energetic comparison between the elimination and cycloreversion of
intermediate Int4a calculated in 1,4-dioxane. The results
presented in Figure indicate that the elimination pathway is more favored than cycloreversion.
Here, the cycloreversion needs a further higher barrier of 28.6 kcal/mol
to release diazo compound 5a as a less exergonic pathway
of 7.6 kcal/mol. Based on the experimental observations, we have seen
that switching solvents from 1,4-dioxane to ethanol tunes the reaction
direction in favor of diazo compound 5a formation. Accordingly,
we have performed our simulations in ethanol to reveal the impact
of the solvent on the pathway preferability.
Figure 5
Free energy profile for
the elimination and cycloreversion of cyclic
intermediate Int4a calculated in 1,4-dioxane at the (SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d)
level of theory at 298.15 K.
Free energy profile for
the elimination and cycloreversion of cyclic
intermediate Int4a calculated in 1,4-dioxane at the (SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d)
level of theory at 298.15 K.Table presents
the effect of the solvent (1,4-dioxane and ethanol) and substituents
on computed free energy of activation for the elimination and cycloreversion
pathways from triazoline intermediate Int4. Overall,
the results point out that elimination is more likely to be favored
in 1,4-dioxane despite the variety of substituents, whereas the cycloreversion
comparatively becomes clearly favorable than elimination in ethanol.
More importantly, our calculations reveal that 1,4-dioxane lowers
the barrier needed for the elimination process, whereas ethanol increases
the barrier dramatically. Conversely, 1,4-dioxane increases the barrier
of cycloreversion largely, whereas ethanol decreases the barrier of
cycloreversion substantially. According to our calculations, the barrier
for the cycloreversion of intermediate Int4 is substantially
lower in ethanol for the azide moiety with electron-withdrawing R2 = 4-O2N (Table , entry 6). Finally, these results indicate that the
solvent is paramount in terms of directing the pathway of intermediate Int4 toward cycloreversion or elimination.
Table 1
Computed Free Energy of Activation
(in kcal/mol) Showing the Effect of Substituents on the Cycloreversion
Step of Intermediate Int4 through TS15a-F and Compared with Elimination through TS5a-F Calculated at the (SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d)
Level of Theory in Two Different Solvents 1,4-Dioxane and Ethanol
at 298.15 K
elimination TS5H2Oa–f (ΔG⧧)
cycloreversion TS15a–f (ΔG⧧)
entry
R1
R2
1,4-dioxane
ethanol
1,4-dioxane
ethanol
1
Me
Me
23.8
27.8
28.6
25.2
2
Ph
Ph
26.1
27.7
26.1
22.7
3
4-MeC6H4
Ph
26.2
27.7
26.3
22.1
4
4-O2NC6H4
Ph
26.2
28.1
26.8
23.2
5
Ph
4-MeC6H4
25.8
25.9
24.9
20.3
6
Ph
4-O2NC6H4
22.1
24.3
21.8
16.9
Conclusions
In conclusion, the interaction
of azolyl enaminones 1 with sulfonyl azides 2 was studied. Examples of the
concurrent formation of two types of products, NH-1,2,3-triazoles 4 and azolyl diazoketones 5, were discovered. The introduction of the basic fragment into the
molecule of one of the reactants made it possible to significantly
simplify the technology of isolating the desired products. By varying
the sulfonyl azide, solvent, and reaction temperatures, factors favoring
the implementation of each of the alternative pathways were found,
and convenient laboratory methods for the synthesis of several hitherto
unavailable azolyl-4-carbonyl-NH-1,2,3-triazoles 4 as well as azolyl diazoketones 5 were developed.
DFT calculations were utilized to reveal the mechanism of the formation
of NH-triazoles from enaminone 1a and
azide 2a. The DFT results have shown that the 1,3-dipolar
cycloaddition is totally driven toward one single regioisomer with
a high asynchronous bond formation with non-covalent interactions
being considerably effective, by which the existence of an electron-deficient
group on sulfonyl azides induces faster cycloaddition. Following the
formation of the cycloadduct intermediate, namely, 4H-1,2,3-triazole, the reaction was found to undergo smoothly within
the six-membered TS elimination of dialkyl amine, facilitated by a
water molecule, which undergoes an N–S bond cleavage to release
the desired product 4a. In this regard, our calculations
revealed that 1,4-dioxane makes the elimination process more favorable,
whereas cycloreversion becomes the preferred pathway to form diazo
compound 5a when ethanol is used. Finally, this work
opens an avenue to the selective convenient preparation (including
scale-up production) of diverse NH-1,2,3-triazoles
and carbonyldiazomethanes, valuable as building blocks and for the
other applications.
Experimental Section
General
1H, 13C, and 19F NMR spectra were recorded at
400 and 600 MHz (1H), 101
and 151 MHz (13C), and 376 MHz (19F) in DMSO-d6a or DCCl3 solutions. Unless specifically mentioned, 13C NMR spectra
were recorded with proton decoupling (BB); spectra of diazo compounds 5n,o were obtained in the J-mode
(attached proton test, APT). For NMR spectra on 1H and 13C nuclei, the residual signals DMSO-d5 and HCCl3 were used as an internal reference.
In the 19F NMR spectra, the chemical shifts of the signals
are given relative to FCCl3. The analysis of compounds
by UHPLC-HRMS was performed using a tandem quadrupole time-of-flight
accurate mass detector, chromatographic separation was achieved using
an ultra-high-performance liquid chromatography. The preliminary control
of the progress of reactions and the purity of the obtained products
was carried out on plates for TLC “Sorbfil” UV-254,
manifestation in UV light. The temperatures of the reactions are indicated
in the bath. For column chromatography, KSKG silica gel of a fraction
of 40–100 μm was used. All reactions, except for the
specially indicated cases, were carried out in sealed vessels. The
evaporation of volatile components and concentration of solutions
were performed at reduced pressure. The separation of the solid phase
from the liquid was carried out by centrifugation (3000 rpm). Melting
points were determined on a melting point apparatus and are uncorrected.
All solvents were prepared according to standard methods, a petroleum
ether (PE) fraction of 70–100 °C was used.
Starting Materials
The synthesis of N,N-dimethylenaminones 1a–o,q,r was described earlier.[44,45] Sulfonyl azides 2a–c,e were prepared
from the corresponding sulfonyl chlorides.[54] Compound 2d was obtained according to ref (55). Water-soluble sulfonyl
azide 2f was synthesized as is described in ref (46). Substance Zidovudine 8 is commercially available.
A solution of acetyl derivative 9 (455 mg, 1.30 mmol)
in DMF–DMA (10 g) was refluxed for 22 h. Volatiles were evaporated
to dryness. The residue was purified with column chromatography: applied
as a solution in DCM, eluted successively with DCM and EtOAc, and
finally with EtOAc/MeOH (1:1). Portions of the EtOAc/MeOH eluate,
containing the desired product 1p, were combined, evaporated
to dryness, crystallized from EtOH, washed with Et2O, and
dried. Yield 88% (478 mg). Light yellow powder, mp 215–220
°C. 1H NMR (400 MHz, DCCl3): δ 1.93
(s, 3H), 2.64 (s, 3H), 2.94 (s, 3H), 2.97 (dd, J =
6.4, 4.3 Hz, 1H), 3.14 (s, 3H), 3.33 (s, 3H), 3.67 (d, J = 12.3 Hz, 1H), 4.00 (d, J = 12.4 Hz, 1H), 4.48
(d, J = 4.9 Hz, 1H), 5.29 (dd, J = 13.3, 5.9 Hz, 1H), 6.16 (d, J = 12.3 Hz, 1H),
6.25 (t, J = 6.5 Hz, 1H), 7.40 (s, 1H), 7.80 (d, J = 12.3 Hz, 1H). 13C{1H} NMR (101
MHz, DCCl3): δ 9.2, 13.3, 27.9, 37.4, 45.2, 55.9,
61.6, 85.3, 90.1, 93.5, 110.3, 136.0, 136.1, 144.7, 151.1, 153.8,
163.6, 182.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H27N6O5, 419.2037; found, 419.2056.
General Procedure
for the Preparation of Enaminones 10
A mixture
of enaminone 1 (3.0 mmol) and N-methylpiperazine
(4 mL) was refluxed with communication
with the atmosphere for 2 min–5 h. For compounds, 10a–c, 10h, 10l, and 10q, an excess
of N-methylpiperazine was distilled off. For compounds 10d, 10p, and 10s, thick suspensions
were formed and distillation of excessive N-methylpiperazine
was done after the removal of the solid phase. The distillate (2.0–2.6
mL or 50–65%) was recovered and used in the further syntheses.
For more information about product isolation, see each specific case.
Compound 10g was obtained
in 98% (1189 mg) yield according to the general procedure (enaminone 1g: 1213 mg, 5 min). The crude product was purified with column
chromatography: applied as a solution in DCM, eluted successively
with DCM and EtOAc, and finally with DCM with the addition of Et3N (5 drops per 10 mL). Portions of the eluate, containing
enaminone 10g, were combined, evaporated to dryness,
and crystallized from PhH–PE. Colorless powder. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H23BrN5O, 404.108; found, 404.1086.The structure of compound 10g favors the trapping
of residual solvents, which are difficult to get rid off. For the
spectral confirmation of the structure, picrate adduct 10ga was prepared.
Compound 10i was obtained
in 93% (912 mg) yield according to the general procedure (enaminone 1i: 811 mg, N-methylpiperazine 2.6 g, 5 min).
The reaction mixture was cooled to room temperature, the thick solid
phase was separated, and washed with Et2O twice. Crude
enaminone 10i was crystallized from PhH–PE to
afford pure compound 10i. To obtain the additional amount
of enaminone 10i, the filtrate from the crystallization
was evaporated to dryness. The filtrate from the reaction mixture
and Et2O washes were combined, excess of N-methylpiperazine was recovered by evaporation, and the solid residue
was treated with PE three times. Both residues were combined and purified
with column chromatography: applied as a solution in DCM, eluted successively
with DCM and EtOAc, and finally with EtOAc/EtOH (1:1). Portions, containing
the product 10i, were combined, evaporated to dryness,
and crystallized from PhH–PE to afford the additional amount
of pure enaminone 10i. Light yellow powder, mp 190–192
°C. 1H NMR (600 MHz, DCCl3): δ 2.32
(s, 3H), 2.43 (s, 3H), 2.45–2.49 (m, 4H), 2.59 (s, 3H), 3.40–3.51
(m, 4H), 6.40 (d, J = 12.8 Hz, 1H), 7.29–7.35
(m, 4H), 7.77 (d, J = 12.8 Hz, 1H). 13C{1H} NMR (151 MHz, DCCl3): δ 10.3, 21.3,
45.4, 46.1, 53.1, 54.0, 54.9, 93.7, 125.2, 130.2, 133.4, 136.5, 140.0,
144.5, 151.8, 183.3. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H24N5O, 326.1975; found, 326.1981.
Compound 10r was obtained
in 73% (757 mg) yield according to the general procedure (enaminone 1r: 872 mg, 5 min). The reaction mixture was left at room
temperature for 12 h, the formed precipitate was separated, washed
with PE, and crystallized from n-heptane. Light yellow
powder, mp 164–166 °C. 1H NMR (400 MHz, DCCl3): δ 2.28 (br s, 3H), 2.33 (s, 4H), 2.60 (s, 3H), 3.00
(br s, 2H), 3.29 (br s, 2H), 5.01 (d, J = 12.7 Hz,
1H), 7.38 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 12.7 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H). 13C{1H} NMR (151 MHz, DCCl3): δ
12.8, 45.2, 46.1, 53.2, 53.5, 53.6, 55.0, 97.1, 117.7, 130.5, 135.8,
152.4, 160.3, 171.5, 183.7. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H21ClN3O2, 346.1317; found, 346.1328.
General Procedure for the Preparation of NH-1,2,3-Triazoles 4
A solution of enaminone 10 (1.0 mmol)
and TsN3 (2a, 1.0 mmol,
197 mg) in PyH (4.6 g) was kept at ambient temperature (for 4-nitro
derivative 10o, at 80 °C, for 1,2,3-thiadiazole 10q and isoxazole 10r derivatives, at 52 °C)
for 2–50 h. Volatiles were evaporated to dryness, the residue
was treated with a mixture of H2O (6 g) and AcOH (350 mg),
followed once again by the same mixture, finally with H2O (6 g), and dried. While preparing triazoles 4d and 4o, aqueous acetic washes were used for the isolation of 1-methyl-4-tosylpiperazine
(6a) and 4-methyl-N-((4-methylpiperazin-1-yl)methylene)benzenesulfonamide
in an oxalate form (7aa), respectively. The details are
available from specific protocols of the synthesis. Content of NH-triazole 4 and diazo compound 5 in the mixture was estimated based on 1H NMR. Pure products 4 and 5 were isolated with column chromatography
of the mixture: applied as a solution in DCM with an addition of Et3N (5 drops per 10 mL), eluted successively with DCM and EtOAc,
and finally with EtOAc with an addition of AcOH (5 drops per 10 mL).
Portions of the eluate, containing products 4 and 5, were combined, evaporated to dryness, and crystallized.
Compound 4d was obtained in 96% (274 mg) yield according
to the general procedure (enaminone 10d: 342 mg, 12 h).
Gray powder, mp 252–256 °C (treated with EtOH and Et2O, decomp.). For better characterization by the 13C NMR spectrum, acetate salt 4da was prepared. 1H NMR (400 MHz, DMSO-d6): δ
8.37 (d, J = 9.1 Hz, 2H), 8.48 (d, J = 9.1 Hz, 2H), 9.01 (br s, 1H), 9.88 (s, 1H), 15.98 (br s, 1H).
For 4da: 13C{1H} NMR (101 MHz,
DMSO-d6): δ 22.5, 121.5, 125.5,
128.1, 133.9, 140.6, 144.3, 147.1, 174.2, 176.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H8N7O3, 286.0683; found,
286.0688.
1-Methyl-4-tosylpiperazine (6a)
Aqueous
acetic acid washes were combined and evaporated to dryness. The residue
was treated with aqueous NH3, washed with water, and dried.
A crude product was purified with column chromatography: applied as
a solution in DCM and eluted successively with DCM and DCM/EtOAc (1:1).
Portions of the eluate, containing the desired product 6a, were combined, evaporated to dryness, and the residue was crystallized
from PhH–PE. Yield 84% (213 mg), colorless solid, mp 144–147
°C (lit.[56] 143–145 °C).
Aqueous acetic acid washes were
combined and evaporated to dryness. The residue was purified with
column chromatography: applied as a solution in DCM with the addition
of Et3N (5 drops per 10 mL), eluted successively with DCM
and EtOAc, and EtOAc/EtOH (1:1). Portions of the eluate, containing
the desired product 7aa, were combined and evaporated
to dryness. The oily residue was dissolved in EtOH (1700 mg) and warmed
to 45 °C. To this solution, oxalic acid (35 mg, 0.39 mmol) was
added at once. The solution was left to cool to room temperature and
kept for 2 h, while the solid phase forms gradually. It was separated,
washed with Et2O twice, and dried. Yield 18% (67 mg), beige
powder, mp 189–191 °C (EtOH). 1H NMR (400 MHz,
DMSO-d6): δ 2.36 (s, 3H), 2.53 (s,
3H), 2.84 (t, J = 5.0 Hz, 2H), 2.89–2.96 (m,
2H), 3.66 (d, J = 4.8 Hz, 2H), 3.70–3.80 (m,
2H), 7.34 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 8.29 (s, 1H), 10.41 (br s, 1H). 13C{1H} NMR (151 MHz, DMSO-d6): δ
21.0, 40.9, 43.3, 47.1, 51.8, 52.9, 126.1, 129.5, 139.8, 142.2, 158.7,
163.9. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C13H20N3O2S, 282.1271; found, 282.1278.
Compound 4r was obtained in
85% (245 mg) yield according to the general procedure (enaminone 10r: 346 mg, 4 h at 52 °C). Colorless powder, mp 154–155
°C (EtOH–H2O). 1H NMR (400 MHz,
DMSO-d6): δ 2.53 (s, 3H), 7.47 (s,
4H), 8.62 (s, 1H), 15.74 (br s, 1H). 13C{1H}
NMR (101 MHz, DMSO-d6): δ 12.7,
115.6, 127.1, 128.6, 130.0, 131.1, 134.6, 145.6, 160.6, 173.4, 180.7.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H10ClN4O2, 289.0487; found 289.0493.
General Procedure for the
Preparation of Diazo Ketones 5
A mixture of
enaminone 10 (1.0 mmol)
and 4-nitrophenylsylfonyl azide (2e, 1.0 mmol) in EtOH
(4.8 g) was stirred at room temperature (at 80 °C for enaminone 13p) for 2–49 h. The solid phase [main amount of N-((4-methylpiperazin-1-yl)methylene)-4-nitrobenzenesulfonamide
(7b)] was separated, the liquid phase was evaporated
to dryness. The residue was treated with a mixture of H2O (6.0 g) and AcOH (313 mg), once again with the same mixture and
finally with water (6.0 g). While preparing diazo compound 5c, aqueous acetic washes were used for the isolation of 1-methyl-4-((4-nitrophenyl)sulfonyl)piperazine
(6b). The details are available from a specific protocol
of the synthesis. The separation of multicomponent mixtures thus obtained,
containing diazo compounds 5 and NH-1,2,3-triazoles 4, and purification of crude products were performed similarly
to the general procedure for the preparation of NH-1,2,3-triazoles 4 (see above). For diazo compounds 5e and 5f, which are well soluble in water, the
modified work-up was applied (see the specific procedure).
Aqueous acetic acid washes were combined
and evaporated
to dryness. The residue was treated with aqueous NH3, washed
with water, and dried. A crude product was purified with column chromatography:
applied as a solution in DCM and eluted successively with DCM and
DCM/EtOAc (1:1). Portions of the eluate, containing the desired product 6b, were combined, evaporated to dryness, and the residue
was crystallized from PhH–PE. Yield 13% (44 mg), light brown
powder, mp 155–156 °C (PhH–PE). 1H NMR
(400 MHz, DCCl3): δ 2.26 (s, 3H), 2.41–2.55
(m, 4H), 3.09 (br s, 4H), 7.94 (d, J = 8.7 Hz, 2H),
8.37 (d, J = 8.7 Hz, 2H). 13C{H} NMR (101
MHz, DCCl3): δ 45.8, 46.0, 54.1, 124.4, 129.0, 141.9,
150.4. By 1H NMR spectrum, the product corresponds to 1-methyl-4-((4-nitrophenyl)sulfonyl)piperazine
(6b), described earlier.[57]
Compound 5e was obtained in
89% (147 mg) yield together with compound 4e in 6% yield
according to the modified general procedure (enaminone 10e: 249 mg, 3 h). Liquid phases after the removal of the main amount
of amidine 7b were combined and evaporated to dryness.
According to the 1H NMR spectrum, the mixture contained NH-triazole 4e in 5% (6 mg) yield. To isolate
diazo compound 5e, the mixture was separated with column
chromatography: applied as a solution in DCM and eluted successively
with DCM and DCM/EtOAc (1:1). Portions, containing diazo compound 5e, were combined, evaporated to dryness, and the residue
was crystallized from PE to afford pure diazo compound 5e. Light yellow powder, mp 129–130 °C (PE). IR (ATR, ZnSe,
cm–1): ν 2097 (N–N stretch), 1608,
1570, 1360, 1309, 1020, 864, 570, 516. 1H NMR (400 MHz,
DCCl3): δ 2.58 (s, 3H), 3.96 (s, 3H), 6.39 (s, 1H). 13C{1H} NMR (101 MHz, DCCl3): δ
8.8, 34.2, 54.3, 136.1, 141.9, 180.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C6H8N5O, 166.0723; found, 166.0728.
Compound 5r was obtained in
52% (136 mg) yield together with compound 4r in 44% (127
mg) yield according to the general procedure (enaminone 10r: 346 mg, 50 h). Light yellow oil, gradually crystallizing under
a layer of PE, mp 83–85 °C. IR (ATR, ZnSe, cm–1): ν 3078, 2110 (N–N stretch), 1613, 1581, 1429, 1360,
1089, 851. 1H NMR (400 MHz, DCCl3): δ
2.70 (s, 3H), 5.04 (s, 1H), 7.50 (dd, J = 21.6, 8.5
Hz, 4H). 13C{1H} NMR (101 MHz, DCCl3): δ 13.2, 57.8, 114.8, 126.8, 129.3, 130.6, 136.7, 159.8,
173.8, 180. HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C12H9ClN3O2, 262.0378; found, 262.0394.
X-ray Structural
Analysis
X-ray structural analysis
of compounds 4f and 5c was performed on
an Xcalibur 3 single-crystal diffractometer according to the standard
method (Mo Kα radiation, graphite monochromator, 295(2) K, ω-scanning
with a step of 1°). The structures were solved and refined using
the SHELXTL software suite.[58] The structures
were solved by the direct method with the ShelXS program, the structures
were refined with the ShelXL program using a full-matrix method of
least squares by F2 in anisotropic approximation for nonhydrogen
atoms. The hydrogen atoms were placed in the calculated positions
and included in the refinement according to the riding model. The
complete X-ray structural data sets for compounds 4f and 5c were deposited at the Cambridge Crystallographic Data Center
(deposition numbers CCDC 2091552 and CCDC 2091548, respectively).
Computational Methods
All mechanical quantum calculations
were performed using Gaussian
09.[59] The geometries were fully optimized
at the hybrid meta-generalized gradient approximation M06-2X/6-31G(d).[60,61] All minima intermediates were verified by the absence of negative
eigenvalues in the vibrational frequency analysis. Transition-state
structures were found using the Berny algorithm[62,63] and verified by vibrational analysis. The transition states were
visualized by animating the negative eigenvector coordinate. Single-point
energies of the optimized geometries were evaluated using the larger
basis set M06-2X/6-311+G(d,p)[64−67] in the presence of a solvation model based on the
density (SMD) solvation model using 1,4-dioxane or ethanol as a representative
solvent medium.[68] The thermal corrections
evaluated from the unscaled vibrational frequencies at the M06-2X/6-31G(d)
level of theory were then added to the M06-2X/6-311+G(d,p) electronic
energies to obtain the free energies. In order to determine the minimum
energy path on the potential energy surface, IRC calculations, by
defining the phase for the transition vector motion along the path,
were performed for the identified transition states using the Hessian-based
predictor-corrector integrator to confirm the reaction path proceeding
in both directions (reactant and product), in which the Hessian was
recomputed every three predictor steps with a step size along a reaction
path of 0.05 bohr.[69−71] All energies reported in this paper are Gibbs free
energies at 298.15 K using unscaled frequencies. All activation free
energies are quoted relative to infinitely separated reagents. Optimized
structures are illustrated using CYLview.[72]
Authors: Benjamin E Blass; Keith Coburn; Wenlin Lee; Neil Fairweather; Andrew Fluxe; Shengde Wu; John M Janusz; Michael Murawsky; Gina M Fadayel; Bin Fang; Michelle Hare; Jim Ridgeway; Ron White; Chris Jackson; Laurent Djandjighian; Richard Hedges; Fred C Wireko; Amanda L Ritter Journal: Bioorg Med Chem Lett Date: 2006-06-21 Impact factor: 2.823
Authors: Stephan Sinn; Benjamin Schulze; Christian Friebe; Douglas G Brown; Michael Jäger; Joachim Kübel; Benjamin Dietzek; Curtis P Berlinguette; Ulrich S Schubert Journal: Inorg Chem Date: 2014-01-21 Impact factor: 5.165
Authors: David Remillard; Dennis L Buckley; Hyuk-Soo Seo; Fleur M Ferguson; Sirano Dhe-Paganon; James E Bradner; Nathanael S Gray Journal: ACS Med Chem Lett Date: 2019-09-13 Impact factor: 4.345
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Scheme 8
Scheme 9
Scheme 10
Scheme 11
Figure 1
Figure 2
Scheme 12
Figure 3
Figure 4
Figure 5