Synthesis of Arylamides via Ritter-Type Cleavage of Solid-Supported Aryltriazenes

Article abstract of DOI:10.1021/acscombsci.9b00096

A novel route for the synthesis of N-arylamides via the cleavage of aryltriazenes with alkyl or aryl nitriles is presented. We developed a variation of the Ritter reaction that allows the use of acetonitrile as solvent and reagent in reactions with solid-supported precursors. The reaction was optimized for the generation of N-aryl acetamides using a diverse range of immobilized building blocks including o-, m-, and p-substituted aryltriazenes. The cleavage via the Ritter-type conversion was combined with an on-bead cross-coupling reaction of halogen-substituted aryltriazenes with pyrazoles. Additionally, the synthesis of on-bead generated arylboronic ester-substituted triazenes was shown. The developed procedure was further expanded to use other commercially available nitriles, such as acrylonitrile, benzonitrile, and chlorinated alkyl nitriles as suitable reagents for a Ritter-type cleavage of the prepared triazene linkers.

Full text of DOI:10.1021/acscombsci.9b00096

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Letter
Synthesis of Arylamides via Ritter-Type
Cleavage of Solid-Supported Aryltriazenes
Nicolai Alexander Wippert, Nicole Jung, and Stefan Bräse
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.9b00096 • Publication Date (Web): 18 Jun 2019
Downloaded from http://pubs.acs.org on June 28, 2019
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Synthesis of Arylamides via Ritter-Type Cleavage of
Solid-Supported Aryltriazenes
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Nicolai A. Wippert , Nicole Jung and Stefan Bräsea,b*
a
a,b*
aInstitute of Toxicology and Genetics, Karlsruhe Institute of Technology, Campus North,
b
Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany; Institute
of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, 76131
Karlsruhe, Germany.
KEYWORDS. Ritter reaction, solid phase synthesis, triazenes, amide formation,
pyrazoles
ABSTRACT. A novel route for the synthesis of N-arylamides via the cleavage of
aryltriazenes with alkyl or aryl nitriles is presented. We developed a variation of the Ritter
reaction that allows the use of acetonitrile as solvent and reagent in reactions with solid
supported precursors. The reaction was optimized for the generation of N-aryl acetamides
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using a diverse range of immobilized building blocks including o-, m- and p-substituted
aryl triazenes. The cleavage via the Ritter-type conversion was combined with an on-
bead cross-coupling reaction of halogen-substituted aryl triazenes with pyrazoles.
Additionally, the synthesis of on-bead generated arylboronic ester-substituted triazenes
was shown. The developed procedure was further expanded to use other commercially
available nitriles, like acrylonitrile, benzonitrile and chlorinated alkyl nitriles as suitable
reagents for a Ritter-type cleavage of the prepared triazene linkers.
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The N-aryl (acet)amide scaffold is often found in agrochemicals with antifungal1,2 or
3
-5
6-9
herbicidal activity and is also part of a wide range of common drugs. Propanil (1) for
example is a herbicide which is used in the US to control grasses and broad-leaf weeds in
1
0
rice fields. Boscalid (2), an N-biaryl amide bearing fungicide is primarily used in agrarian
1
1
cultures of vegetables and fruits (Figure 1). Additionally, the use of structurally very
simple N-aryl acetamides like acetanilide (Antifebrin)12-14 and acetophenetidine
1
5
(Phenacetin) as drugs against for example fever have been of importance for a long time.
Acetaminophen (Paracetamol) (3), a derivative of these early N-aryl acetamides, is still
used for the treatment of diverse diseases and listed as one of the most important drugs by
1
6
the world health organization (WHO) since 1977 (Figure 1). Moreover, compounds
consisting of an N-aryl acetamide moiety or an N-aryl alkylamide moiety are a substantial
part of modern drug development. In 2017 Liu et al. investigated novel irreversible
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inhibitors of Bruton’s tyrosine kinase (BTK) and found some potent examples containing
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an N-aryl acrylamide moiety like compound 4 (Figure 1). Another example for current
research on a potential use of substituted N-aryl amides is the work of Novikov et al. on the
targeting of non-nucleoside reverse transcriptase (NNRT) to identify new therapeutic
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agents against the HI virus. The often negative long-term effects of traditionally used
agrochemicals19,20 as well as the often observed increased resistance to well-established
drugs21-23 requires the constant improvement of known chemicals and the development of
new target structures.
To overcome the drawbacks of current drugs, the modification of N-aryl acetamides and
the development of derivatives thereof are still of high interest.
O
HN
Cl
O
N
Cl
O
N
N
Cl
Cl
HO
H
O
O
N
N
N
N
N
H
H
Propanil (1)
Boscalid (2)
Paracetamol (3)
CHMFL-BTK-11 (4)
Figure 1. Selected agrochemicals,1,2,10,11 drugs, and compounds of interest in recent
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research projects4,17 containing the N-aryl amide as a motif.
Beside several well-known chemical transformations like the acylation of anilines with acid
chlorides or anhydrides, or the use of classic peptide-coupling methods, the Ritter-reaction
offers a possible method to introduce an amide moiety to a molecule. According to the
originally described Ritter reaction, alkenes and secondary or tertiary alcohols are
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converted into amides through the addition of a nitrile in sulfuric acid.24,25 The reaction
takes place via the generation of a carbocation (originating from an alkene or alcohol)
which is then attacked by the nitrile as a nucleophile. Subsequently, a nitrilium-ion is
formed and hydrolyzed by water resulting in the formation of an amide bond. Over the last
decades, the reaction has been applied to a broad range of substrates and was modified
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regarding the respective requirements. Several catalytic methods have been developed,
such as the stereoretentive copper-catalyzed Ritter reaction of secondary cycloalkanols.27
Furthermore, tandem reactions were developed by applying the Ritter reaction to
carbocations that were generated in-situ by the preparation of azabicyclic alkaloids via a
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Prins-type reactions. The generation of the carbocation in the Ritter reaction can also be
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obtained via the decomposition of diazonium salts. Although this procedure has been
applied often for the synthesis of arylamides, there are only few reports of triazenes, which
can be seen as protected and more stable diazonium salts, being converted to amides.30,33
The work of Satyamurthy30 et al. encouraged us to develop a procedure for Ritter-type
reactions on solid phases allowing the use of triazene-linkers as protected aryl diazonium
species. For a long time, our group has been working on the immobilization, modification
and cleavage of triazene linkers for solid phase organic synthesis (SPOS)34–38, but a Ritter-
type arylamide formation was not reported by us and to the best of our knowledge has not
been reported by others on solid supports before. As the establishment of new reactions on
SPOS allows the potential use of these procedures for combinatorial chemistry and high
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throughput experiments, the implementation of a Ritter-type cleavage may facilitate the
access to new arylamide derivatives with improved properties. Therefore we intended to
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develop a general procedure for Ritter reactions on immobilized triazenes following the
proposed mechanism as depicted in Scheme 1.
O
N
N
MeCN
1
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NH
N
6a
conditions
R
R
7
5
H+
H O
2
C+
N2+
N+
N
MeCN
N2
R
R
R
-
8
9a
9b
Scheme 1. Proposed mechanism for the generation of aryl amides via Ritter reaction from
immobilized triazenes.
Our initial experiments were aimed for the identification of the most suitable conditions
under which the transformation of immobilized triazenes to aryl amides occurs. 4-Iodo-
arylamine was attached to solid supports using a previously reported procedure via
4
0
transformation into the aryl diazonium salt and reaction with N-benzyl polystyrene. We
determined the success of cleaving the obtained resin to yield N-(4-iodophenyl) acetamide
(7a) under different conditions: first in pure MeCN (6a) serving as reagent and solvent (for
detailed table see Supporting Information) and second in mixtures of MeCN and other
solvents (entries 1-8, Table 1). It was shown that the Ritter cleavage in acetonitrile as
solvent and reagent works well for TFA at temperatures between 60 °C and 100 °C while
for HBF , comparable results were obtained at temperatures ranging from 80 °C to 100 °C
4
(data available in full in the Supporting Information, Section 6, Table S1). In a next step
the same experiments were performed in different solvents using either a ratio of A: 1:1
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MeCN: solvent (v/v), B: 1:2 MeCN: solvent (v/v) or C: 1:3 MeCN: solvent (v/v), to
examine the suitability of the reaction under different conditions. Several standard solvents
including toluene, tetrahydrofuran, methylene chloride, dichloroethane, chloroform,
dioxane, and ethyl acetate were successfully used for the synthesis of compound 7a, but
only toluene and THF provided good yields. The first comparative experiments including
all solvents were done at 80 °C with the ratio 1:1, further reactions included the use of
toluene and THF with a ratio of 1:2 (MeCN:solvent, v/v) and a ratio of 1:3 (MeCN:solvent,
v/v). We were able to show that toluene is more suitable for the Ritter cleavage than THF
and that, at least for a reaction time of 12 h, a ratio of 1:2 (MeCN: solvent, v/v) is necessary
to obtain high yields of the target compounds 7a.
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Table 1. Optimization of the conversion of triazene 5a to acetamide 7a using different
solvents and conditions.
O
N
N
MeCN (6a),
NH
N
HBF or TFA
4
solvent, 12 h
80 °C
I
7a
I
5a
Ab
7a [%]c
Bb
7a [%]c
Cb
7a [%]c
T
°C]
No
Solvent
Acida
[
1
2
3
4
5
6
7
8
PhMe
PhMe
THF
DCM
CHCl3
DCE
HBF4
TFA
80
80
80
80
80
80
80
80
86
-
100
88
67
54
-
25
d
d
HBF4
HBF4
HBF4
HBF4
HBF4
HBF4
74
25
54
55
56
43
d
d
-
-
d
d
-
-
d
d
-
-
d
d
dioxane
EtOAc
-
-
d
d
-
-
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Conditions: aHBF *Et O or TFA (5.0 equiv.), 80 °C; bA: MeCN:solvent (1:1, v/v); B:
4
2
c
MeCN:solvent (1:2, v/v); C: MeCN:solvent (1:3, v/v); total volume: 1.5 mL yields
according to GCMS results. d not determined; full table available in the Supporting Information.
1
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For further studies of the Ritter cleavage from triazene linkers, a diversity of substituted arenes
including electron-donating and electron-withdrawing groups in various positions were cleaved at
8
0 °C and 100 °C in acetonitrile and the obtained compounds were isolated. In most of the cases,
the cleavage at 100 °C gave higher yields as compared to reactions at 80 °C. Only three reactions
entries 1, 8 and 13, Table 2) gave higher yields at a temperature of 80 °C. The position of the
(
substitution pattern on the aryl triazene may have a considerable influence on the outcome of the
reaction (see entries 1-3, Table 2) revealing that ortho-substituted triazenes seem to be less
favorable building blocks. In addition, the electronic nature of the substituents has an impact on
the obtained yield of the target compound which can be shown with the examples given as entry 8
and 9 (Table 2). It has to be mentioned that the influence of the temperature could be clearly
identified as the reactions were performed in parallel using the same starting resin. The yields with
respect to different building blocks are also dependent on the triazene formation of the previous
step.
Table 2. Effect of substitution patterns of arenes on the success of triazene formation and
Ritter-type cleavage.
N
N
O
N
NH
R5
R4
R1
R2
R5
R4
R1
R2
HBF *Et O
4
2
MeCN, 80 °C
or 100 °C, 12 h
R3
R3
5
7
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Yield
[
R5
No
5
R1
R2
R3
R4
%]a
1c
2
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5a
5b
5c
5d
5e
5f
5g
5h
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5j
5k
5l
5m
5n
5o
H
H
I
H
H
H
I
H
H
Br
H
H
H
H
H
I
H
H
Br
H
H
Br
Br
Br
NO2
CN
H
H
H
H
H
H
H
H
H
H
H
H
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42
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14
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Br
H
c
7
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9
1
-(CH)4-
c
CH3
H
H
H
H
H
OMe
H
CH3
CH3
c
CO Me
H
2
0c
H
H
H
OMe
CH3
H
H
H
H
H
H
H
1
1
H
H
H
H
c
1
2
CO Et
2
b,c
1
3
H
H
H
1
4
15
CH3
aIsolated yields calculated for the cleavage according to the reaction of resins 5 to arylamides 7 at
b
c
100 °C. TFA was used for cleavage; reaction was performed at 80 °C instead of 100 °C. A more
detailed table can be found in the Supporting Information (Table S2).
After investigating the influence of the arene substitution pattern on the outcome of the
reactions, we decided to use a broader range of nitriles in the reaction to increase the
diversity of the available target structures. Five additional nitriles (6b-6f), containing
different chemical scaffolds such as olefins (acrylonitrile), arenes (benzonitrile) and
chloride (chloroacetonitrile, trichloroacetonitrile and chloro-propionitrile), were used as
solvent (and reagent) in the desired reaction (Scheme 2). The reactions were performed at
8
0 °C to avoid by-products due to decomposition, giving compounds 10-14 in 5%-47%
yield calculated over three steps starting from Merrifield resin. While compounds 11 to 14
were obtained without further adaption of the standard protocol (Table 1, no. 2), the
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reaction in acrylonitrile required the addition of one equivalent of either Cu(I) or Cu(II)
chloride to prevent polymerization during the cleavage from the polymer.
O
N
N
R
NH
N
1
1
1
1
1
1
1
1
1
1
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R-CN (6b-f), HBF OEt
4
2
8
0 °C, 12 h
I
I
1
0 - 14
5a
O
O
O
O
O
Cl
NH
Ph
NH
NH Cl
NH Cl C
NH
3
product: 10 (29/24%)*
reagent:
6b
11 (42/31%)* 12 (47/47%)*
6c 6d
13 (17/17%)*
14 (8/5%)*
6e
6f
Scheme 2. Synthesis of different amides by Ritter-type cleavage with nitriles 6b-6f. *yield
over (1 step/3 steps)
The scope of the herein described cleavage protocol was further extended with respect to the
synthesis of compound libraries by showing the compatibility of the Ritter cleavage with examples
of so far not reported cross coupling reactions on solid supports. To show the compatibility of the
developed procedure with an on-bead synthesis of aryl-pyrazoles, iodine substituted aryl triazenes
5
a to 5c were converted with pyrazoles via copper-catalyzed cross-coupling using either
compound 16a or 16b as ligand (Scheme 3). The obtained heterocyclic modified triazenes were
successfully cleaved in acetonitrile giving the target compounds 18a-18f in up to 68% yield with
respect to the conversion of resins 5a and 5b (calculated over 4 steps). The reaction of the ortho-
iodo substituted resin 5c to compounds bearing a pyrazole in ortho position (17c) was not
successful. This is explained by the sterical demanding environment for the cross-coupling in ortho
position of the aryl-triazene combined with a generally reduced yield of a Ritter cleavage of ortho-
substituted arenes (see Table 2).
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R
NH
N
N
O
N
N
N
N
N
15 a-c
CuI, K2CO3
6a/16b
NH
R3'
R1
R2
R1'
1
HBF OEt2
4
MeCN, 80 °C, 12h
R2'
DMF
00 °C, 3 d
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R3
3'
R
5a - 5c
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18a: R2' = H, R3' = a (55/25%)*
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17a: R = H, R = H, R = a-c
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2'
3'
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7b: R = H, R = a-c, R = H
18b: R = H, R = b (83/33%)*
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18c: R2' = H, R = c (13/10%)*
3'
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3
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8d: R2' = a, R = H (68/33%)*
18e: R2' = b, R = H (58/26%)*
3
N
N
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N
N
N
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=
18f: R2' = c, R = H (45/10%)*
3
a
b
c
NH2
NH NH
ligand 16a
used for 17a and 17b):
ligand 16b
(used for 17c):
Cl
(
N
N
NH3
NH2
H
Scheme 3. Synthesis of pyrazole-aryltriazenes 17a (a-c)-17c (a-c) on solid supports and
cleavage to pyrazole-arylacetamides 18a-18f in MeCN. *yield over (1 step/4 steps)
A
second approach for cross-coupling reactions on solid phases and a combination with Ritter-
type cleavage of the immobilized compounds was demonstrated with the synthesis of solid
supported boronic acid pinacol esters. The conversion of resin 5a under Pd-catalysis with
bis(pinacolato)diboron gave resin 19 in a first step and after cleavage in acetonitrile, compound 20
was obtained in 54% yield (Scheme 4). Further conversion of the boronic acid pinacol esters 19
with two aryl bromides (21a, 21b) on solid supports were shown to be suitable for the formation
of immobilized biphenyl 22a and 22b. Both were successfully cleaved to obtain the target
acetamides 23a and 23b in 16% and 13% yield (Scheme 4).
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NHAc
N
N
N
N
N
N
R
Pd(PPh3)4, K2CO3
Ar-Br (21)
B
THF/H2O (4:1)
100 °C, 2 d
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R'
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2
5a: R = I
22a: R' = paracyclophanyl
22b: R' = ethoxycarbonylphenyl
A
NHAc
19: R = Bpin
NHAc
B
B
O
O
CO2Et
23b (13/11%)b
2
0 (74/54%)a
Scheme 4. Synthesis of pinacol boronic ester 19 on immobilized aryl triazene 5a, cross
coupling and cleavage to acetamides 23a and 23b. A: PdCl (dppf), KOAc, (Bpin) , DMF,
2
2
a
b
8
0 °C, 2 d; B: HBF OEt or TFA, MeCN, 80 °C, 12 h. yield over 1 step/4 steps; yield
4 2
over 1 step/5 steps.
Conclusions
The present study shows the development of a Ritter-type reaction for the synthesis of arylamides
via cleavage of immobilized triazenes in the presence of alkyl or aryl nitriles. The reaction was
investigated in acetonitrile towards its scope and limitations for the application to diversely
substituted immobilized aryltriazenes. To evaluate the potential of the herein described cleavage
protocol for the synthesis of novel compound libraries, the cleavage via the Ritter-type conversion
was successfully combined with further on-bead modifications (namely the cross-coupling of
halogen-substituted aryl triazenes to arylpyrazoles and immobilized arylboronic esters with
following Suzuki-coupling to the corresponding biaryl-compounds). Additionally, the developed
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procedure was expanded to use other commercially available nitriles, like acrylonitrile,
benzonitrile and chlorinated alkyl nitriles to allow for the synthesis of different amides via a
multifunctional cleavage. The application of this procedure to solid phases offers diverse
opportunities for strategies to synthesize amide-containing compound libraries but the
investigation may initiate a broader use of the Ritter reaction for triazenes in solution phase as
well.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information includes the protocols for the synthesis of all solid supported
compounds and their analysis as well as the synthesis and analytical data of the obtained isolated
compounds 7, 10-14, 18a-18f, 20, 23a, and 23b.
The following files are available free of charge.
1. Description of experiments and analytics, link to the original data (DOI) in chemotion
repository (PDF).
2. Summary of spectra of isolated products (PDF)
AUTHOR INFORMATION
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Corresponding Author
*nicole.jung@kit.edu; braese@kit.edu
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Author Contributions
The manuscript was written through contributions of all authors. All authors have given
approval to the final version of the manuscript.
Funding Sources
-
Notes
-
ACKNOWLEDGMENT
This work was supported by the Helmholtz program Biointerfaces in Technology and Medicine
(BIFTM). We acknowledge support by Deutsche Forschungsgemeinschaft through the DFG-core
facility Molecule Archive (BR1750/40-1, JU2909/5-1) and the DFG funded Open Source software
Chemotion ELN (BR1750/34-1).
ABBREVIATIONS
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WHO, World Health Organization; BTK, Bruton’s tyrosine kinase; NNRT, non-nucleoside
reverse transcriptase; HI (virus), human immunodeficiency (virus); et al., et alii/aliae (and others);
SPOS, solid phase organic synthesis; MeCN, acetonitrile; TFA, trifluoroacetic acid; HBF4,
tetrafluoroboronic acid (diethyl etherate complex); PhMe, toluene; THF, tetrahydrofuran; DCM,
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methylene chloride; CHCl , chloroform; DCE, dichloroethane; EtOAc, ethyl acetate; GCMS, gas
3
chromatography-mass spectrometry; n.d.; not determined; CuI, copper(I)-iodide; K CO ,
2
3
potassium carbonate; DMF, N,N-dimethylformamide; Bpin, boronic acid pinacol ester;
PdCl (dppf), (1,1’-bisphenylphosphino) ferrocene) palladium(II) dichloride; KOAc, potassium
2
acetate; (Bpin)2, bis(pinacolato)diboron; Pd(PPh ) , tetrakis (triphenylphosphine) palladium; H O,
3 4
2
water; Ar-Br, aryl-bromide; BIFTM, BioInterfaces in Technology and Medicine; DFG, Deutsche
Forschungsgemeinschaft; ELN, Electronic Lab Journal
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