Mild reductive functionalization of amides into N-sulfonylformamidines

Article abstract of DOI:10.1002/open.201700087

The development of a protocol for the reductive functionalization of amides into N-sulfonylformamidines is reported. The one-pot procedure is based on a mild catalytic reduction of tertiary amides into the corresponding enamines by the use of Mo(CO)₆ (molybdenum hexacarbonyl) and TMDS (1,1,3,3-tetramethyldisiloxane). The formed enamines were allowed to react with sulfonyl azides to give the target compounds in moderate to good yields.

Full text of DOI:10.1002/open.201700087

DOI: 10.1002/open.201700087
Mild Reductive Functionalization of Amides into N-
Sulfonylformamidines
Paz Trillo,[a] Tove Slagbrand,[a] Fredrik Tinnis,*[a] and Hans Adolfsson*[a, b]
The development of a protocol for the reductive functionaliza-
tion of amides into N-sulfonylformamidines is reported. The
one-pot procedure is based on a mild catalytic reduction of
tertiary amides into the corresponding enamines by the use of
Mo(CO)6 (molybdenum hexacarbonyl) and TMDS (1,1,3,3-tetra-
methyldisiloxane). The formed enamines were allowed to react
with sulfonyl azides to give the target compounds in moderate
to good yields.
The amidine functional group is frequently found in biological-
ly active compounds possessing anti-inflammatory, antibacteri-
al, antiviral, antibiotic, and anesthetic properties.[1] They are
also employed as intermediates and precursors in organic syn-
thesis of important heterocyclic compounds such as imida-
zoles, quinazolines, isoquinolines, and pyrimidines.[2] Further-
more, amidines are employed as ligands in metal complexes
and as protecting groups for primary amines.[3]
Scheme 1. Preparation of amidines through a–c) electrophilic amide activa-
The stability of amides makes this functional group valuable
to include in an array of different compounds such as pharma-
ceuticals, agrochemicals, and other organic materials.[4] On the
other hand, the inherent stability is contributing to the reluc-
tance of employing amides as synthetic intermediates. The
concept of activation and functionalization of amides is well
known and the discovery of triflic anhydride (Tf2O) as an amide
activating agent constituted a major advance within this
field.[5] In recent years, research based on Tf2O as an amide ac-
tivator has progressed immensely and a broad variety of mild
transformations have been reported.[6] Besides classical amide
activation reagents such as POCl3,[7] SOCl2,[8] PCl3,[9] PCl5,[10] and
(COCl)2,[11] triflic anhydride was also employed by Charette and
Grenon for the transformation of amides into amidines
(Scheme 1a).[12] Later, protocols based on AlMe3 and Ph3P/I2 for
tion and d) reductive functionalization of amides.
amide activation and subsequent amidine synthesis were also
reported by Velavan et al. and Phakhodee et al. (Scheme 1b
and 1c).[13,14] The direct condensation of sulfonamides with
N,N-dimethylformamide dimethyl acetal (DMF-DMA) was fur-
thermore reported by Sharma and co-workers,[15] and N-sulfo-
nylformamidines can also be prepared from cyanamides.[16]
The development of the chemoselective reduction of
amides has been very successful and, today, functional groups
such as ketones, aldehydes, and imines can be tolerated.[17]
Consequently, the reductive functionalization of amides is now
an emerging field within organic chemistry. This area of re-
search can be divided in two divisions, reduction of amides for
the formation of electrophilic species (iminium ion) or nucleo-
philic species (enamine) with the subsequent trapping/func-
tionalization thereof.[18] Herein, we demonstrate a mild proto-
col for the reductive functionalization of amides (via enamines)
for the formation of N-sulfonylformamidines (Scheme 1d).
We have previously reported on a highly chemoselective
protocol for amide reduction into either amines or alde-
hydes.[19] The Mo(CO)6-catalyzed system was further investigat-
ed and it was discovered that enamines could also be ac-
cessed.[20] Recently, we demonstrated the reductive functionali-
zation of amides into 4,5-dihydroisoxazoles and triazolines.[21]
In the case of the latter compounds, the generated enamines
were trapped with organic azides and, during the evaluation
of the substrate scope, it was observed that N-sulfonylforma-
midine was formed upon the use of sulfonyl azide (Scheme 2).
[a] Dr. P. Trillo, T. Slagbrand, Dr. F. Tinnis, Prof. H. Adolfsson
Department of Organic Chemistry, Stockholm University
106 91 Stockholm (Sweden)
E-mail: fredrik.tinnis@su.se
hans.adolfsson@su.se
[b] Prof. H. Adolfsson
Department of Chemistry, Umeꢀ University
901 87 Umeꢀ (Sweden)
E-mail: hans.adolfsson@umu.se
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under https://doi.org/10.1002/
open.201700087.
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This is an open access article under the terms of the Creative Commons
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Scheme 2. One-pot transformation of amides into N-sulfonylformamidines.
As the sulfonyl group is an important class of pharmacophore
and N-sulfonylamidines, in particular, exhibit various important
biological and pharmaceutical activities, we decided to opti-
mize the conditions for the synthesis of this class of com-
pounds.[22] The Mo(CO)6-catalyzed reduction of tertiary amide
1a gives full conversion into the corresponding enamine 1a’,
as determined by 1H NMR spectroscopy using an internal
standard.
The screening of the reaction conditions toward the forma-
tion of N-sulfonylformamidine showed that two equivalents of
the sulfonyl azide were needed and the reaction then went to
completion within 30 min. A wide variety of benzenesulfonyl
azides were then evaluated, which gave the corresponding N-
sulfonylformamidines in yields between 47 and 79%
(Scheme 3, 3a–3o). Several functional groups such as halide,
ketone, secondary amide, ester, amine, cyano, and nitro
groups were tolerated. Benzyl- and aliphatic-substituted sulfo-
nyl azides could also be employed and compounds 3p and 3q
were isolated in 83 and 58% yields, respectively.
Scheme 4. Evaluation of the amide scope.
was in favor of enamine in the case of longer aliphatic chains;
however, only amine was essentially formed when employing
acetamides. Thus, it was necessary to use phenylacetamides
throughout the scope. The reduction of the different amides
was straightforward and produced the corresponding enam-
1
ines in excellent yields (>95%, according to H NMR spectros-
copy). The subsequent in situ reaction with sulfonyl azide
yielded a variety of formamidines substituted with N,N-dimeth-
yl (3r, 3s), piperidine (3t, 3u), N,N-dibutyl (3v), N,N-diisopropyl
(3w), indoline (3x), morpholine (3y), 2,6-dimethylpiperidine
(3z), and N-methyl-N-phenyl (3aa).
The overall substrate evaluation shows that this protocol
allows for N-sulfonylamidines to be synthesized with versatility
in both the sulfonyl and the amine part. The products were
obtained in moderate to good yields and most of the com-
pounds are novel and have not been previously reported.
The developed protocol for the transformation of carboxa-
mides into N-sulfonylformamidines was further evaluated on
a preparative scale (Scheme 5). Although we never experi-
enced any issues, one should always be aware of the explosion
risks associated with organic azides.[23] The reaction with amide
1a (10 mmol) was performed by using a two-necked round-
bottomed flask under an inert atmosphere and amidine 3a
was isolated in 70% yield (1.6 g).
The decomposition of triazolines can lead to a variety of dif-
ferent compounds such as triazoles, aziridines, and amidines.[24]
In a recent study, we demonstrated the preparation and isola-
Scheme 3. Evaluation of sulfonylazides in the transformation of amides into
amidines.
Next, we performed an evaluation of different amides in the
preparation of N-sulfonylformamidines (Scheme 4). During our
previous investigation of amide transformation into triazolines,
it was found that aliphatic amides constituted a challenging
class of substrates for enamine formation.[21b] The product ratio
Scheme 5. One-pot transformation of amide 1a into sulfonylformamidine
3a on a preparative scale.
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tion of a wide variety of different triazolines.[21b] It was also
shown that, in some cases, depending on the electronic nature
of the amide or the azide, triazoles would form spontaneously
by elimination of the amine moiety. The instability of sulfonyl-
substituted triazolines is known, but their disintegration does
not necessarily form amidines. For instance, Bakulev and co-
workers reported on the synthesis of 1H-1,2,3-triazoles via sul-
fonyl-substituted triazolines derived from enamines and sulfo-
nyl azides.[24c] Furthermore, the collapse of triazolines into ami-
dines may also proceed via different pathways. Houk and co-
workers recently investigated the reactivity of perfluorinated
aryl azides in the (3+2) cycloaddition with enamines, which
resulted in the formation of triazolines.[25] The spontaneous
cleavage of these heterocyclic species with loss of N2 was ob-
served and the corresponding a-substituted amidines were
isolated (Scheme 6a).
the trapping reagent for phenyldiazomethane. The p-methoxy-
substituted amide 1g was reduced to the corresponding en-
amine (1g’) and then treated with both sulfonyl azide 2a and
benzoic acid in situ. The side-product 1-(diazomethyl)-4-me-
thoxybenzene (5) derived from triazoline 4g was successfully
intercepted (Scheme 6c). 4-Methoxybenzyl benzoate (6) could
1
be confirmed by the crude H NMR spectrum and also by sub-
sequent isolation/characterization (see the Supporting Informa-
tion), which supports the proposed mechanism in Scheme 6c.
In conclusion, we have developed a protocol for the reduc-
tive functionalization of carboxamides into N-sulfonylformami-
dines. The system is characterized by mild conditions and
short reaction times and can be performed in the environmen-
tally friendly solvent ethyl acetate.[28] A wide range of sulfonyl
azides and amides were evaluated, and the majority of the N-
sulfonylformamidines obtained have previously not been re-
ported. It was further demonstrated that the protocol could be
employed on a preparative scale. This mild and high-yielding
strategy to obtain enamines from stable carboxamides and uti-
lize them in situ for the formation of N-sulfonylformamidines
should be of high value to organic and medicinal chemists.
Li and co-workers have developed a protocol for N-sulfonyl-
formamidine synthesis based on tertiary amines and sulfonyl
azides in combination with stoichiometric amounts of diethyl
azodicarboxylate (DEAD).[26] In this case, the decomposition of
the sulfonyl-substituted triazolines led to the formation of for-
mamidines (Scheme 6b). The authors proposed diazomethane
to be formed as a by-product, which was confirmed by a trap-
ping experiment using carboxylic acid.[27] We speculated that, if
the formation of N-sulfonylformamidine would proceed via the
triazoline intermediate, then phenyldiazomethane would most
likely be formed upon cleavage of the heterocycle in a similar
fashion to that proposed by Li and co-workers (Scheme 6b).[26]
Thus, we performed an experiment employing benzoic acid as
Experimental Section
Amide (1.0 mmol) and Mo(CO)6 (0.0054 g, 0.02 mmol) were added
to an oven-dried 10 mL vial equipped with a magnetic stirring bar.
To the sealed tube, dry ethyl acetate (1 mL) was added and the at-
mosphere was exchanged to N2 via the septum. The reaction mix-
ture was heated at 808C for 10 min to activate the catalyst, which
was followed by flushing the vial with N2. The reaction was allowed
to reach the optimized reaction temperature, after which TMDS
(1.5 mmol, 0.26 mL) was added and the reaction was stirred for the
required amount of time to form the corresponding enamine. To
the crude reaction, sulfonyl azide (2 mmol) was added at 408C.
After 30 min, the crude reaction was transferred to a round-
bottom flask and concentrated onto silica. N-Sulfonyl amidines
were purified through column chromatography by using pentane/
EtOAc as the eluent.
Acknowledgements
The authors acknowledge the K. & A. Wallenberg Foundation and
the Swedish Research Council for financial support.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: amides
·
amidines
·
enamines
·
reductive
functionalization · sulfonyl azides
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Received: May 10, 2017
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COMMUNICATIONS
P. Trillo, T. Slagbrand, F. Tinnis,*
H. Adolfsson*
&& – &&
Mild Reductive Functionalization of
Amides into N-Sulfonylformamidines
Amidst the amidines: A system for the
reductive functionalization of amides
into N-sulfonylformamidines is de-
scribed. This one-pot protocol is based
on a Mo(CO)6-catalyzed reduction of
amides into enamines and offers an
access to a wide variety of amidines.
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