Transformation of Amides into Highly Functionalized Triazolines

Article abstract of DOI:10.1021/acscatal.7b00095

Triazoles and triazolines are important classes of heterocyclic compounds known to exhibit biological activity. Significant focus has been given to the development of synthetic approaches for the preparation of triazoles, and they are today easily obtainable through a large variety of protocols. The number of synthetic procedures for the formation of triazolines, on the other hand, is limited and further research in this field is required. The protocol presented here gives access to a broad scope of 1,4,5-substituted 1,2,3-triazolines through a one-pot transformation of carboxamides. The two-step procedure involves a Mo(CO)₆-catalyzed reduction of tertiary amides to afford the corresponding enamines, followed by in situ cycloaddition of organic azides to form triazolines. The amide reduction is chemoselective and allows for a wide variety of functional groups such as esters, ketones, aldehydes, and imines to be tolerated. Furthermore, a modification of this one-pot procedure gives access to the corresponding triazoles. The chemically stable amide functionality is demonstrated to be an efficient synthetic handle for the formation of highly substituted triazolines or triazoles.

Full text of DOI:10.1021/acscatal.7b00095

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Article
Transformation of Amides into Highly Functionalized Triazolines
Tove Slagbrand, Alexey Volkov, Paz Trillo, Fredrik Tinnis, and Hans Adolfsson
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b00095 • Publication Date (Web): 20 Jan 2017
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Transformation of Amides into Highly
Functionalized Triazolines
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Tove Slagbrand,a Alexey Volkov,a Paz Trillo,a Fredrik Tinnis*a and Hans Adolfsson*a,b
a) Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91
Stockholm, Sweden.
b) Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
KEYWORDS: Triazolines • Amides • Enamines • Chemoselective Reduction • Azides
ABSTRACT: Triazoles and triazolines are important classes of heterocyclic compounds known
to exhibit biological activity. Significant focus has been put into the development of synthetic
approaches for the preparation of triazoles and they are today easily obtainable through a large
variety of protocols. The number of synthetic procedures for the formation of triazolines on the
other hand is limited and further research in this field is required. The protocol presented here
gives access to a broad scope of 1,4,5-substituted-1,2,3-triazolines through a one-pot
transformation of carboxamides. The two step procedure involves a Mo(CO)6-catalyzed
reduction of tertiary amides to afford the corresponding enamines, followed by in situ
cycloaddition of organic azides to form triazolines. The amide reduction is chemoselective and
allows for a wide variety of functional groups such as esters, ketones, aldehydes and imines to be
tolerated. Furthermore, a modification of this one-pot procedure gives access to the
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corresponding triazoles. The chemically stable amide functionality is demonstrated to be an
efficient synthetic handle for the formation of highly substituted triazolines or triazoles.
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INTRODUCTION:
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Triazolines have been evaluated as potential anticonvulsant drugs are also important
intermediates in organic synthesis.1 Wolff and co-workers discovered that 1,2,3-triazolines could
be prepared by a 1,3-dipolar addition reaction of olefins and azides in 1912.2 Huisgen and
L’abbé have demonstrated that the reactivity of the alkenes in this type of cycloaddition is
significantly influenced by the electronic properties of the double bond and reactions with
electron deficient alkenes required long reaction times, weeks or even months.3 Weinreb and co-
workers later reported that the rate of cycloaddition could be increased substantially by
employing high pressure (12 kbar) and a selection of 1,4,4-trisubstituted triazolines were
prepared.4 Electron-rich olefins such as enamines are much more reactive and have been
demonstrated to readily undergo a regiospecific 1,3-dipolar addition with azides to afford 1,2,3-
triazolines under mild conditions (Figure 1a).5 Nevertheless, in these cases the enamines were
prepared and isolated prior to use which limited the overall yields and the scope of the target
heterocycles. Only a few examples of in situ formation of enamines in azide cycloaddition
reactions have been reported. Bianchetti et al. showed that enamines prepared from acetone and
aliphatic amines reacted with aryl azides in a tandem reaction to yield triazoles but merely a few
triazolines were isolated.6 Stradi and Pocar later employed aldehydes or ketones in combination
with primary or secondary amines to form enamines in situ.7 A good number of triazolines were
isolated in low to excellent yields in this case; however, only 4-nitrophenylazide was used as the
azide component (Figure 1b). Amine-catalyzed formation of enamines has also been employed
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in some cases for subsequent cycloaddition reactions.8 The use of an azide in this type of
reaction only gives the saturated triazoline as an intermediate yielding triazole as the final
product after elimination of the amine catalyst (Figure 1c).9 An alternative route for the
formation of triazolines can be achieved through the cycloaddition reaction of diazo compounds
with Schiff bases.10
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Herein we demonstrate a mild and efficient one-pot transformation of stable amides that gives
access to a wide scope of highly functionalized triazolines (Figure 1d). We also show that 1,2,3-
triazoles, which normally are obtained by the Cu-catalyzed azide-alkyne cycloaddition reaction
(the “click”-reaction),11 can be generated using our protocol.
Figure 1. 1,3-dipolar cycloaddition of enamine and azide to yield triazolines or triazoles.
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The developed protocol involves the reduction of amides to enamines using catalytic amounts of
Mo(CO)6 in combination with the inexpensive and stable silane 1,1,3,3-tetramethyldisiloxane
(TMDS). An unprecedented chemoselectivity of this transformation is demonstrated and
functional groups such as nitro, nitrile, ester, ketone, imine and aldehydes were tolerated. The
target heterocyclic compounds were obtained via in situ cyclization reaction of enamines with a
wide scope of aromatic and aliphatic azides.
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RESULTS AND DISCUSSION:
We have recently reported on a mild and chemoselective protocol for the hydrosilylation of
tertiary amides into either aldehydes or amines (Figure 2).12 Enamine formation was observed
when employing benzylic and aliphatic amides. Since only a limited amount of amide reduction
protocols are known to afford enamines,13 we initiated an optimization of the conditions for the
Mo(CO)6-catalyzed system to furnish these valuable compounds. Furthermore, we envisioned
that a mild and chemoselective formation of enamines from highly stable carboxamides could be
exploited in the synthesis of 1,2,3-triazolines, and that this approach would considerably broaden
the scope and synthetic accessibility of these heterocycles.
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Figure 2. Mo(CO)6-catalyzed chemoselective reduction of amides extended to include formation
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of enamines.
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After thorough optimization of the conditions it was found that the catalytic loading of Mo(CO)6
can be decreased to 2 mol% and the amount of TMDS to 1.5 equivalents allowing for high
conversion of this type of amides to the corresponding enamines. Surprisingly, the screening of
different solvents revealed that the reduction of the amides could be performed in ethyl acetate14
(see Supporting Information), which further demonstrates the high chemoselectivity of the
system. With the optimized conditions for the enamine formation in hand we decided to attempt
the 1,3-dipolar addition reaction using phenyl azide 3a (Scheme 1). The enamine reaction was
completed in 1 hour and by the subsequent addition of 1.5 equivalents of 3a, compound 4aa
could be isolated in 91% yield after 3 h reaction time. We then investigated if the transformation
could be performed as a tandem process with all the components present from the start. It was
observed that the reduction of the amide was retarded and progressed very slow; however, some
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amount of triazoline was detected in the crude H NMR, suggesting that the catalyst is poisoned
by the final product rather than the azide. The product inhibition of the catalyst was also
demonstrated by employing 5 mol% of triazoline from the start in the reduction of amide, which
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resulted in a very low H NMR yield of the enamine compared to the standard reaction (see
Supporting Information).
Scheme 1. One-pot procedure for the formation of triazolines from amides.
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Initially, a substrate evaluation investigating the reduction of different amides into enamines was
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performed. High H NMR yields of the corresponding enamines derived from amides 1a-1d
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were observed by employing catalytic amounts of Mo(CO)6 and TMDS as the hydride source.
The subsequent cycloaddition using phenylazide (3a) readily gave the triazolines 4aa-4da in
high isolated yields (Scheme 2). Munk and co-workers previously reported the cycloaddition
between azides and enamines to be regiospecific and in the recent mechanistic study, the group
of Houk found evidence for the reactions to be concerted.5b,5c The regiochemistry of the 1,4,5-
substituted triazoline 4da as shown in scheme 2 was confirmed by 1D NOE irradiation (see
Supporting Information) which is in line with previous reports. An α-disubstituted amide (1e)
was evaluated in the enamine formation reaction resulting in a mixture of cis and trans isomers.
After the cycloaddition step the corresponding triazoline (4ea) was obtained as two
diastereomers in a 2:1 ratio. The major diastereomer was separated and the relative
stereochemistry was determined using 1H NMR NOE experiment. By irradiating the signal of the
CH3-group an increase in intensity of the signal belonging to the adjacent proton was observed,
indicating a cis relationship between these two groups. A few amide substrates were observed to
be challenging to reduce and only small amounts of the corresponding enamines 2j-2l were
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detected by H NMR (Scheme 2). The enamine formation of purely aliphatic amides did not
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display a high selectivity and some amount of amine was detected by H NMR spectroscopy.
Thus, the propyl substituted triazoline 4fa was obtained in a moderate yield of 66%. We were
pleased to see that the high chemoselectivity of the amide reduction allowed for the presence of
easily reducible functional groups such as esters, ketones and imines, ultimately accessing
triazolines 4ga, 4ha and 4ia in 94%, 84% and 88% yields, respectively.
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a
Isolated yields. Step 1: Mo(CO)6 (0.02 mmol), amide (1.0 mmol), dried ethyl acetate (0.5 mL,
2M), TMDS (1.5 equiv), 65 °C for 1 h. Step 2: azide (1.5 equiv), 65 °C for 2 h. For information
about the conditions for each substrate see Supporting Information Tables S2-3. b Diastereomers
were obtained in a 2:1 ratio in which the major compound was determined to have a cis
relationship between the phenyl group and the piperidine moiety.
Scheme 2. Evaluation of tertiary amides in the chemoselective reduction and subsequent
cycloaddition reaction with organic azides.a
It was observed that aldehyde substituents on the amide were not affected by the reduction
conditions but rather from the enamine being formed during the reaction. We hypothesized that
the presence of an azide from the start would intercept the enamine and although the tandem
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reaction was observed to be slow we adopted this strategy for the p-aldehyde substituted amide
1m (scheme 3). To overcome the issue of catalyst poisoning by triazoline, the loading of
Mo(CO)6 had to be increased to 30 mol% and the reaction required 72 h to reach completion.
Nevertheless, this demonstrates that the Mo(CO)6-catalyzed reduction of amides to enamines can
even tolerate aldehydes and triazoline 4mb was isolated in 80% yield.
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Scheme 3. Transformation of aldehyde containing amide in a tandem process.
We decided to evaluate how different amine parts affected the reactivity in the reduction step
towards enamine and in the 1,3-cycloaddition reaction (Scheme 4). An aliquot of the Mo(CO)6 –
catalyzed reduction was taken and analyzed by 1H NMR after 15 minutes reaction time. Amides
derived from both pyrrolidine and dimethylamine showed high conversion into the
corresponding enamines, while the piperidine amide reacted slower (Scheme 4). The pyrrolidine
based enamine was proven to be most reactive in the cycloaddition reaction, which is in line with
previous studies.15 The dimethylamine and piperidine derived enamines were less reactive and
only about 15% of the corresponding triazolines were observed after 1 h reaction time.
Scheme 4. Investigation on the reactivity of different amides in enamine and triazoline
formation.
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Amides derived from cyclic as well as non-cyclic amines were evaluated in the transformation
and the corresponding triazolines were obtained in good to excellent yield (Scheme 5a). The N-
methyl-N-phenyl amide 1s proved to be more difficult to reduce and a mixture of enamine,
amine and products of C-N bond cleavage were observed under the standard reaction conditions.
The mechanism of Mo(CO)6-catalyzed amide reduction was thoroughly investigated by Pannell
and co-workers demonstrating the formation of silylhemiaminal as intermediate.16 It was
envisioned that the presence of a catalytic amount of base would promote the collapse of
tetrahedral intermediate into enamine yielding a cleaner reaction. Gratifyingly, the addition of
triethyl amine (10 mol%) to the reaction mixture resulted in the selective formation of the
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corresponding enamine (2s) in >95% H NMR yield after 15 hours. The more reactive p-CF3
phenyl azide (3b) was used in the subsequent cycloaddition reaction and the target triazoline 4sb
was obtained in 82% isolated yield. Primary and secondary amides were also evaluated in the
Mo(CO)6-catalyzed reduction; however, the corresponding enamines were not observed. Next,
the azide scope of the 1,3-cycloaddition reaction was evaluated using pyrrolidine amide 1n in
most of the cases (Scheme 5b). The one-pot system showed to be compatible with a wide variety
of azides substituted with functional groups such as aldimine (4nc), olefin (4nd), alkyne (4ne),
iodo (4nj), cyano (4nk), nitro (4al), ester (4nr) and ketone (4ns). In the cyclization reaction with
aldehyde substituted azide (3t) high isolated yield of the corresponding triazoline (4nt) could be
obtained. This further demonstrates that an electron-poor azide reacts more readily with the
enamine in comparison to the aldehyde. It was observed that benzyl azides reacted sluggish at 65
°C and employing the compound 3g containing both aromatic and benzylic azides resulted in the
selective formation of triazoline 4ag in 78% yield with preservation of the benzylic azide.
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a Isolated yields. Step 1: Mo(CO)6 (0.02 mmol), amide (1.0 mmol), dry ethyl acetate (0.5 mL,
2M), TMDS (1.5 equiv), 65 °C for 30 min. Step 2: azide (1.5 equiv) at 65 °C for 3 h. For
information about conditions for each substrate see Supporting Information Table S2-3.
bpiperidine substituted triazoline.
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Scheme 5. Scope evaluation of a) the amine part of the amide substrates and b) different organic
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azides.a
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On the other hand the p-CF3 substituted benzyl azide was demonstrated to be more reactive
which enabled access to the benzylated triazoline 4nh after a prolonged reaction time of 18 h.
Heteroaryl azide and an aliphatic azide bearing electron-withdrawing groups could also be
employed under mild reaction conditions and the corresponding triazolines 4nf and 4ni were
obtained in 88% and 79% yield, respectively.
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It was noticed that the cyclization reaction was highly influenced by electronic properties of the
azides and whereas the electron-deficient substrates reacted readily, the electron-rich required
longer reaction times and higher reaction temperatures. Xie et al. recently reported on 1,3-
cycloadditions of enamines employing a variety of perfluorinated aryl azides.15 The triazolines
formed with these electron-deficient groups were unstable and rearranged spontaneously into the
corresponding amidines. When we evaluated the combination of enamine and azide both bearing
electron withdrawing substituents, the corresponding triazole was obtained instead. Thus, the
unsaturated heterocyclic compound 5ub was isolated in 58% yield under standard reaction
conditions (Scheme 6). Furthermore, forcing unreactive benzyl and aliphatic azides to undergo
cycloaddition at higher reaction temperatures (80 °C) enabled the access to the corresponding
triazoles (5nu, 5nv) in good to excellent yields in 24 h and 65 h, respectively. Triazolines are
known to be thermally labile4 and the elevated temperature required for these substrates most
likely promoted the elimination of the amine to form triazole. Munk and co-workers showed that
triazoles were obtainable from the corresponding triazolines by subjecting them to an excess of
KOH/MeOH solution under reflux conditions.5a A minor screening of conditions was therefore
performed in order to evaluate if triazoles could be accessed in a 3-step one-pot fashion.
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a
Isolated yields. Step 1: Mo(CO)6 (0.02 mmol), amide (1.0 mmol), dried ethyl acetate (0.5 mL,
2M), TMDS (1.5 equiv), 65 °C for 30 min. Step 2: azide (1.5 equiv) at 65 °C, 3 h. Information of
conditions for each substrate see Supporting Information Table S4
Scheme 6. a) Direct transformation of amides into triazoles. b) 3 step / one-pot procedure for
triazole formation.a
It was found that the addition of catalytic amounts of base, after the completed triazoline
reaction, initiated the amine elimination and pure triazole products could be obtained. Triazoles
5na and 5ag were isolated in good to high yield using this one-pot methodology (Scheme 6b).
To demonstrate the versatility of the one-pot procedures for triazoline and triazole formation, we
carried them out in preparative scale (Scheme 7). Although we never experienced any issues one
should always be aware of the explosion risks associated with organic azides.17 By performing
the reaction on a 5 mmol scale in a two-necked round bottomed flask fitted with a condenser,
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triazoline 4ns could be obtained in a 92% yield (1.53 g) (Scheme 7a). Nitriles were well tolerated
in the Mo(CO)6-catalyzed amide reduction and the reaction of 1v and p-cyano phenyl azide (3k)
led directly to the formation of the corresponding unsaturated heterocycle and did not require the
catalytic addition of base. Thus, triazole 5vk was obtained in 88% yield after washing the crude
reaction mixture with pentane (Scheme 7b).
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Scheme 7. Large-scale transformation of amides into a) triazoline and b) triazole.
CONCLUSIONS:
To conclude, we have for the first time demonstrated a mild an efficient transformation of stable
carboxamides into either triazolines or triazoles. The amides were reduced into enamines
employing catalytic amounts of Mo(CO)6 in combination with TMDS as the hydride source
using EtOAc as solvent. The reduction is characterized by an unprecedented level of
chemoselectivity and functional groups such as nitro, nitriles, esters, and imines were tolerated.
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Moreover, using the developed reduction protocol it was possible to form enamines containing
ketone and aldehyde functionalities which cannot be accessed through classical condensation
reaction. The enamines were subjected to organic azides to undergo 1,3-cycloaddition reaction in
a one-pot procedure to yield the corresponding triazolines. The preparation of these heterocyclic
compounds from amides is a new concept that should be found useful and a broad scope of the
triazolines was obtained using this methodology. Direct formation of triazoles was observed for
certain substrates. Alternatively, triazoles were generated from the triazolines by the addition of
a catalytic amount of base in a three-step one-pot procedure. The attractive properties of this
system along with the scalability and low cost/high stability of TMDS should make this method
applicable in both academic and industrial settings. Due to the mildness and high level of
chemoselectivity it can easily be envisioned that amides could serve as stable protection groups,
which can be transformed into triazolines or triazoles at the late stage of synthesis.
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ASSOCIATED CONTENT
Supporting Information. This material is available free of charge via the Internet at
http://pubs.acs.org.
The following files are available free of charge.
Experimental data and compound characterization (PDF)
AUTHOR INFORMATION
Corresponding Author
Hans Adolfsson* E-mail: hans.adolfsson@umu.se
Fredrik Tinnis* E-mail: fredrik.tinnis@su.se
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Author Contributions
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The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
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ACKNOWLEDGMENT
The authors acknowledge the K. A. Wallenberg Foundation and the Swedish Research Council
for financial support.
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SYNOPSIS
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