Amine Activation: Synthesis of N-(Hetero)arylamides from Isothioureas and Carboxylic Acids

Article abstract of DOI:10.1021/acs.orglett.6b02247

A novel method for N-(hetero)arylamide synthesis based on rarely explored amine activation, rather than classical acid activation, is reported. The activated amines are easily prepared using a three-component reaction with commercial reagents. The new method shows a broad scope including challenging amides not (efficiently) accessible via classical protocols.

Full text of DOI:10.1021/acs.orglett.6b02247

Letter
pubs.acs.org/OrgLett
Amine Activation: Synthesis of N‑(Hetero)arylamides from
Isothioureas and Carboxylic Acids
Yan-Ping Zhu,† Sergey Sergeyev,† Philippe Franck,† Romano V. A. Orru,‡ and Bert U. W. Maes*,†
†Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium
‡Department of Chemistry and Pharmaceutical Sciences and Amsterdam Institute for Molecules, Medicines and Systems (AIMMS),
VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
S
* Supporting Information
ABSTRACT: A novel method for N-(hetero)arylamide synthesis based on
rarely explored amine activation, rather than classical acid activation, is
reported. The activated amines are easily prepared using a three-
component reaction with commercial reagents. The new method shows
a broad scope including challenging amides not (efficiently) accessible via
classical protocols.
he synthesis of the amide functional group is paramount
However, procedures starting from carboxylic acids and amines
Tin organic chemistry. This structural motif is truly are still the most interesting, due to the widespread availability
of these building blocks. For challenging amides, derived from
sterically hindered carboxylic acids and electron-deficient and/
or sterically hindered (hetero)aromatic amines, for instance, the
classical approaches give a low yield or often even fail, and no
general efficient synthetic method is currently available. This is
illustrated by the synthesis of N-mesityl-2,4,6-trimethylbenza-
mide from 2,4,6-trimethylbenzoic acid and 2,4,6-trimethylani-
line (Supporting Information, Scheme S2). A variety of classical
coupling reagents under different conditions were tested but
generally no reaction product was formed; only with PyBOP
was a moderate yield obtained.6a−e These poor results and the
frequent occurrence of the N-(hetero)arylamide moiety in
active ingredients (AI) stimulated us to develop a new synthetic
method. The importance of this amide subclass can be
illustrated by the list of FDA-approved drugs of 2015 and the
top 100 drugs based on prescription. In the former list 15% and
in the latter 9% of the drugs feature the N-(hetero)arylamide
entity.7a,b Top selling agrochemicals, such as the fungicides
boscalid and fluxapyroxad, also often contain such a structural
moiety.8
We initially focused our efforts on the development of a new
synthetic protocol for N-(hetero)arylamide synthesis as an
example of challenging amide synthesis. Our new approach
involves (hetero)arylamine activation by transformation into
the corresponding isothiourea, followed by reaction with
carboxylic acid under base metal catalysis (Scheme 1).9 The
activation of (hetero)arylamine can be done in high yield in one
step by using our recently developed three-component reaction
(Scheme S1).10 The reagents (tert-butyl isocyanide and S-
phenyl benzenethiosulfonate) required for amine activation are
ubiquitous and is present in (bio)polymers (e.g., nylon,
proteins), peptides, natural products (e.g., paclitaxel, penicillin),
ligands for catalysis, synthetic drugs, and agrochemicals.1 The
main classical route for its synthesis is based on the activation of
a carboxylic acid through formation of an acyl chloride, acyl
imidazole, anhydride, or activated ester, followed by reaction
with an amine.2 The formation of activated esters with
phosphonium/uronium/guanidinium salts, based on (azo)-
benzotriazole derivatives such as HOBt or HATU, is currently
the most successful and popular method. However, due to their
explosive nature, transportation and storage issues resulted in
the development of (1-cyano-2-ethoxy-2-oxoethyliden-
aminooxy)dimethylaminomorpholinocarbenium hexafluoro-
phosphate (COMU).3 The prevalence of the amide function-
ality and the plethora of coupling reagents available for
carboxylic acid activation might give the impression that
amide synthesis is a mature transformation. However, this is
incorrect as practice proves that often even simple amides resist
formation. This triggers the development of new and more
complex and expensive coupling reagents. More recently, Lewis
acids based on boron species or metal salts have been reported
as suitable catalysts, allowing direct coupling of amine and
carboxylic acid when water is simultaneously removed.4 The
difficulty in driving reactions to completion and limited catalyst
stability restrict the take up of this technology in industry.
Although all these methods cited are very useful for the
synthesis of a variety of amides, there are still limitations with
respect to amide scope (electronics and sterics), functional
group tolerance, and chemoselectivity toward other nucleo-
philes, which require upfront protection, thus reducing the
efficiency of the process. On the basis of these limitations, many
interesting alternative procedures have been developed from
precursors other than amines and/or carboxylic acids.5a−s
Received: July 29, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02247
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Letter
a
Scheme 1. Classical (A) and New Strategy (B) for N-
(Hetero)arylamide Synthesis from (Hetero)aromatic
Amines and Carboxylic Acids
Scheme 2. Scope of Carboxylic Acids 2 and 3
commercially available. While classical synthetic approaches for
amide synthesis involve carboxylic acid activation (C → N
direction), few procedures are based on amine activation (N →
C direction: isocyanide,11 imidazolylcarbonyl,12 iminophos-
phorane13) (Scheme 1). Moreover, isothioureas are bench-
stable compounds, while activated carboxylic acids are usually
unstable and have to be generated in situ.
Optimization of the reaction conditions was performed using
N-tert-butyl-S-methyl-N′-phenylisothiourea (1a), as activated
aniline, and pivalic acid (2a) as model reagents. A catalyst
screening in DMF revealed that Fe(acac)3 was optimal (Table
S1). Further screening showed that the reaction worked well in
2-propanol (93% yield) when 1.2 equiv of 2a and 15 mol % of
Fe(acac)3 were used at 83 °C (Tables S2 and S3). Considering
that substituents can have a significant influence on the amide
formation, a series of isothioureas (1a−f) were prepared via our
3CR and tested (Table S4).10 After all, the substituent on the
sulfur and one nitrogen atom can be freely selected by simply
altering the thiosulfonate and isocyanide reagents in the
activation step. The results indicated that activated aniline
equipped with a sterically hindered N-tert-butyl and an S-phenyl
is the most reactive. When N-tert-butyl-S,N′-diphenylisothiour-
ea (1d) was used instead of 1a, full conversion could be
achieved with only 2.5 mol % catalyst, and the desired product
4a was isolated in 97% (Scheme 2). When the scale of the
reaction was increased to 5 mmol (17 times), a similar yield was
obtained (Table S4, entry 7).
a
Reaction conditions: 1 (0.3 mmol), 2, or 3 (0.36 mmol), Fe(acac)3
(2.5 mol %), i-PrOH (2 mL), 83 °C, air, 24 h: (a) 72% of PhSSPh was
isolated; (b)o-xylene (2 mL), 130 °C, 24 h; (c) 2-butanol (2 mL), 98
°C, 48 h; (d) Fe(acac)3 (5 mol %), 72 h.
higher reaction temperature. Heteroarenecarboxylic acids such
as furan-2-carboxylic acid (3m), thiophene-2-carboxylic acid
(3n), and isomeric pyridinecarboxylic acids (3o-q) also reacted
smoothly to give the corresponding products 5m−q in good
yields (80−99%). The azine-type systems (5o−q) are
particularly challenging (acids are zwitterions) and converted
more slowly. More catalyst (5 mol %) or a higher boiling
alcohol can be used to speed up the reaction in these cases.
The N-tert-butyl-N′-(hetero)aryl-S-phenylisothiourea (1)
scope was investigated using pivalic acid (2a) as a model
sterically encumbered carboxylic acid (Scheme 3). Isothiourea
derived from anilines bearing electron-donating substituents (4-
Scheme 3. Scope of N-tert-Butyl-N′-(hetero)aryl-S-
a
phenylisothiourea 1
We first investigated the carboxylic acid scope with activated
aniline (Scheme 2). Alkanoic acids (2) generally performed
very well in reaction with activated aniline 1d. Branched (2b,g),
linear (2c−e), as well as cyclic (2h) systems gave the desired
amides 4 in excellent yields. In addition, acids featuring a
further activation of the methylene α to the carbonyl by a
phenyl group (2f,g) selectively reacted with 1d. Next, we
turned our attention to arenecarboxylic acids (3) (Scheme 2).
Benzoic acid (3a) gave N-phenylbenzamide (5a) in 90% yield.
Electron-donating groups (4-OMe (3b), 2-OMe (3c), 3,4-Me2
(3e)) and halogens (4-Cl (3f), 4-Br (3g), 2-I (3h)) in different
positions of the benzoic acid gave the corresponding products
5b−h in 71−88% yields. Even a free hydroxyl group as in 3-
hydroxybenzoic acid (3d) performed smoothly to provide the
corresponding amide 5d in 85% yield. Notably, benzoic acids
featuring strong electron-withdrawing groups (4-nitro (3i), 3-
nitro (3j), 3,5-bis(trifluoromethyl) (3k), 3,4,5-trifluoro (3l))
provided the desired products 5i−l in 74−95% yield. For most
of these benzoic acids, formation of N-tert-butyl-N′-phenylurea
(10) was observed as a side reaction.14 Substitution of 2-
propanol by o-xylene restored the selectivity but required a
a
Reaction conditions: 1 (0.3 mmol), 2 or 3 (0.36 mmol), Fe(acac)3
(2.5 mol %), i-PrOH (2 mL), 83 °C, air, 24 h; (a) Fe(acac)3 (15 mol
%); (b) o-xylene (2 mL), 130 °C, 24 h.
B
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OMe (1h), 3-OMe (1i), 2-OMe (1j), and 2-SMe (1k)), an o-
phenyl (1l), and halogen substituents (4-Br (1m), 4-Cl (1n))
underwent the reaction smoothly to afford the corresponding
products (6a−g) in good to excellent yields. Electron-
withdrawing groups (4-CO2Me (1o), 4-CF3 (1p), 3-CF3
(1q)) were also well tolerated (6h−j). Pleasingly, activated
heteroareneamines reacted smoothly under standard condi-
tions. Reaction of 2a with N-tert-butyl-S-phenyl-N′-(3-
pyridinyl)isothiourea (1r) gave N-(3-pyridinyl)pivalamide
(6k) in 89% yield. N-tert-Butyl-N′-(hetero)aryl-S-phenyliso-
thiourea (1) containing a (vinylogous) amidine could not be
obtained in good yield from the corresponding amine using our
3CR due to decomposition. Therefore, the corresponding S-
methyl analogues were used for these specific heteroarene-
amines, prepared by using commercial S-methylmethanethio-
sulfonate as reagent.10 Both azine (4-aminopyridine (1s)) and
azole (2-amino-1-methyl-1H-benzimidazole (1t) and 2-amino-
benzothiazole (1u)) derived S-methylisothiourea yielded the
desired pivalamides in 73−91% yield (6l−n). These are
interesting cases as acyl chlorides are known to react with
(vinylogous) heteroaromatic amidines at the azine/azole
nitrogen first and therefore consume at least 2 equiv of
reagent.15
Considering our initial goal, we subsequently investigated the
applicability of our protocol for the synthesis of very
challenging amides from the point of view of sterics and
electronics. First, reaction of 1d with carboxylic acids even
more sterically hindered than pivalic acid (2a) were screened.
However, initial tests with 2,4,6-trimethylbenzoic acid (3r)
revealed the formation of a significant amount of urea 10 under
the standard conditions (Table S5). Interestingly, when 2-
butanol instead of 2-propanol was used as solvent at 98 °C, a
selective transformation of 1d and 91% of 7a were achieved
(Scheme 4). Under these conditions, sterically hindered
aliphatic carboxylic acids (2,2,2-triphenylacetic acid (2j), 2,2-
diphenylpropanoic acid (2k), 2,2-diphenylacetic acid (2l), 1-
adamantanecarboxylic acid (2m), and abietic acid (2i)) all
reacted with 1d to provide the corresponding amides 7b−f in
generally very high yields. Even a combination of a carboxylic
acid and an isothiourea which, are both sterically hindered, was
found to be well tolerated in the reaction. Reaction of 2a or 3r
with N-aryl-N′-tert-butyl-S-phenylisothiourea featuring a 2,6-
Me2 (1v), 2,4,6-Me3 (1w), and 2,6-(isopropyl)2 (1x) phenyl
substitution pattern did not affect the overall efficiency, and the
corresponding products 7g−l were obtained in 81−89% yield.
In addition, a combination of a sterically hindered carboxylic
acid (2j) and an isothiourea derived from an electron-deficient
(hetero)aromatic amine (4-aminopyridine (1s), 4-CF3 (1p))
smoothly gave the desired amides 7m and 7n.
Scheme 4. Synthesis of Challenging N-(Hetero)arylamides
7
a
a
Reaction conditions: 1 (0.3 mmol), 2 or 3 (0.36 mmol), Fe(acac)3
(2.5 mol %), 2-butanol (2 mL), 98 °C, air, 24 h; (a) N-tert-butyl-N′-
(hetero)aryl-S-methylisothiourea and Fe(acac)3 (15 mol %). Classical
method starting from (Het)ArNH2: carboxylic acid 2 or 3 (1.05
mmol), 1,3-dicyclohexylcarbodiimide (DCC) (1.08 mmol), 4-
(dimethylamino)pyridine (DMAP) (0.25 mmol), (Het)ArNH2 (1.0
mmol), CH2Cl2 (10 mL), 0−25 °C, 24 h.
Scheme 5. Synthesis of Boscalid
Compound 1z can be prepared in very high yield from
commercially available 4′-chlorobiphenyl-2-ylamine, S-phenyl
benzenethiosulfonate, and tert-butyl isocyanide via the 3CR.10
It is important to note that the amide synthesis is in this case
executed under oxygen atmosphere; otherwise, additional SNAr
on the C2−Cl occurs with the thiophenol formed in situ.
Under oxygen instead of air, the rate of its oxidation to PhSSPh
is increased, allowing the desired chemoselectivity to be
achieved. Notably, the PhSSPh byproduct formed from PhSH
under the amide-forming reaction conditions could be isolated
in high yield. Interestingly, it can be transformed back into S-
phenyl benzenethiosulfonate reagent for the 3CR.17 For the
model system 4a (Scheme 2), this recovery procedure was
successfully applied (Table S4, entry 7).
When we attempted to synthesize the challenging amides of
Scheme 4 via classical reaction of amine and carboxylic acid
with DCC, no or only a low amount of the target amides was
obtained. The new amide synthesis disclosed is therefore
complementary with classical protocols. While both protocols
will provide standard amides, only the new protocol gives
efficient access to the challenging representatives.
In order to demonstrate the potential of the new
methodology, we applied it to the synthesis of the fungicide
boscalid (Scheme 5).16 It is classically synthesized by acylation
of 2-chloronicotinyl chloride with 4′-chlorobiphenyl-2-ylamine.
Our approach started from N-tert-butyl-N′-[4′-chloro-(1,1′-
biphenyl)-2-yl]-S-phenylisothiourea (1z) and 2-chloronicotinic
acid (3s) to give a 74% yield of boscalid (Scheme 5).
In conclusion, we have developed a novel amide synthesis
based on rarely explored amine rather than carboxylic acid
activation. (Hetero)arylamines are easily activated as bench-
stable N-tert-butyl-N′-(hetero)aryl-S-phenylisothiourea via a
C
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6416. (m) Krause, T.; Baader, S.; Erb, B.; Goossen, L. J. Nat. Commun.
2016, 7, 11732. (n) Kang, B.; Fu, Z.; Hong, S. H. J. Am. Chem. Soc.
2013, 135, 11704. (o) Liu, J.; Liu, Q.; Yi, H.; Qin, C.; Bai, R.; Qi, X.;
Lan, Y.; Lei, A. Angew. Chem., Int. Ed. 2014, 53, 502. (p) Liu, Z.;
Zhang, J.; Chen, S.; Shi, E.; Xu, Y.; Wan, X. Angew. Chem., Int. Ed.
2012, 51, 3231. (q) Shen, B.; Makley, D. M.; Johnston, J. N. Nature
2010, 465, 1027. (r) Wang, T.; Danishefsky, S. J. Proc. Natl. Acad. Sci.
three-component reaction (3CR) with commercially available
reagents, tert-butyl isocyanide, and S-phenyl benzenethiosulfo-
nate. N-(Hetero)arylamides can be obtained in high selectivity
and yield from these isothioureas via reaction with carboxylic
acids under iron catalysis, showing a broad functional group
compatibility. The protocol allows for the synthesis of very
challenging amides, from the point of view of sterics and
electronics, not (or only in poor yield) accessible via classical
coupling agents. The further exploration of the potential of this
new methodology as well as the study of its mechanism are
currently under investigation in our laboratory.
̀
U. S. A. 2013, 110, 11708. (s) Debnath, P.; Baeten, M.; Lefevre, N.;
Daele, S. V.; Maes, B. U. W. Adv. Synth. Catal. 2015, 357, 197.
(6) (a) Ju, X.; Liu, Z. Chinese Patent CN101701016A, 2011,
20091103. (b) Zhang, Y.; Feng, J.; Liu, C.; Fang, H.; Xu, W. Bioorg.
Med. Chem. 2011, 19, 4437. (c) MacMillan, D. S.; Murray, J.; Sneddon,
H. F.; Jamieson, C.; Watson, A. J. B. Green Chem. 2013, 15, 596.
́
(d) Junkers, M. Aldrich ChemFiles 2007, 7.2, 8−9. (e) Larrivee-
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02247.
■
Aboussafy, C.; Jones, B. P.; Price, K. E.; Hardink, M. A.; McLaughlin,
R. W.; Lillie, B. M.; Hawkins, J. M.; Vaidyanathan, R. Org. Lett. 2010,
12, 324.
S
(7) (a) Top USA pharmaceutical products of 2013: http://
njardarson.lab.arizona.edu/content/top-pharmaceuticals-poster, ac-
cessed June 2016. (b) Jarvis, L. M. Chem. Eng. News 2016, 94, 12−17.
(8) Michael, F. W. The Agrochemical and Pesticides Safety Handbook;
CRC Press LLC: New York, 1998.
Optimization data, experimental procedures, character-
ization of new compounds, and spectral data (PDF)
(9) For a book describing the use of Fe catalysts as Lewis acids, see:
Plietker, B. Iron Catalysis Fundamentals and Applications, in Topics in
Organometallic Chemistry; Springer: Heidelberg, 2011; Vol. 33.
(10) Mampuys, P.; Zhu, Y.; Vlaar, T.; Ruijter, E.; Orru, R. V. A.;
Maes, B. U. W. Angew. Chem., Int. Ed. 2014, 53, 12849.
(11) (a) Wu, X.; Stockdill, J. L.; Park, P. K.; Danishefsky, S. J. J. Am.
Chem. Soc. 2012, 134, 2378. (b) Li, X.; Yuan, Y.; Kan, C.; Danishefsky,
S. J. J. Am. Chem. Soc. 2008, 130, 13225.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bert.maes@uantwerpen.be.
Notes
The authors declare no competing financial interest.
̀
(12) (a) Suppo, J.-S.; Subra, G.; Berges, M.; Marcia de Figueiredo, R.;
ACKNOWLEDGMENTS
Campagne, J.-M. Angew. Chem., Int. Ed. 2014, 53, 5389. (b) Grzyb, J.
A.; Batey, R. A. Tetrahedron Lett. 2003, 44, 7485.
■
This work has been supported by the European Union’s
Horizon 2020 research and innovation programme under the
Marie Skłodowska-Curie grant agreement 657883, the Research
Foundation-Flanders (FWO), the UAntwerp (BOF), and the
Hercules Foundation. The research leading to these results has
also received funding from the Innovative Medicines Initiative
(www.imi.europa.eu) Joint Undertaking project CHEM21
under Grant Agreement 115360, resources of which are
composed of financial contributions from the European
Union’s Seventh Framework Programme and EFPIA compa-
nies’ in-kind contributions.
(13) Kosal, A. D.; Wilson, E. E.; Ashfeld, B. L. Angew. Chem., Int. Ed.
2012, 51, 12036. Hegarty, A. F.; McCormack, M. T.; Ferguson, G.;
Roberts, P. J. J. Am. Chem. Soc. 1977, 99, 2015.
(14) Urea 10 is presumably formed via reaction of an O-acylisourea
intermediate with 2-propanol (solvent). O-Acylisourea is obtained via
reaction of carboxylic acid with isothiourea.
(15) Joule, J. A. Heterocyclic Chemistry; VCH: Weinheim, 2010; pp
125−138.
(16) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D.
Pharmaceutical Substances: Syntheses, Patents, Applications of the most
relevant APIs; Thieme: Stuttgart, 2008.
(17) Okumura, S.; Takeda, Y.; Kiyokawa, K.; Minakata, S. Chem.
Commun. 2013, 49, 9266.
REFERENCES
(1) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606.
■
(2) Subiros
Albericio, F. Chem. - Eur. J. 2009, 15, 9394.
́
-Funosas, R.; Prohens, R.; Barbas, R.; El-Faham, A.;
(3) Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H. Chem. Soc.
Rev. 2014, 43, 2714.
(4) (a) Lanigan, R. M.; Sheppard, T. D. Eur. J. Org. Chem. 2013,
2013, 7453. (b) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew.
Chem., Int. Ed. 2008, 47, 2876. (c) Lundberg, H.; Adolfsson, H. ACS
Catal. 2015, 5, 3271. (d) Pattabiraman, V. R.; Bode, J. W. Nature
2011, 480, 471.
(5) (a) Fang, X.; Li, H.; Jackstell, R.; Beller, M. J. Am. Chem. Soc.
2014, 136, 16039. (b) Fang, X.; Jackstell, R.; Beller, M. Angew. Chem.,
Int. Ed. 2013, 52, 14089. (c) Xu, T.; Sha, F.; Alper, H. J. Am. Chem.
Soc. 2016, 138, 6629. (d) Wu, X.-F.; Neumann, H.; Beller, M. Chem. -
Eur. J. 2010, 16, 9750. (e) Zhang, F.-L.; Wang, Y.-F.; Lonca, G. H.;
Zhu, X.; Chiba, S. Angew. Chem., Int. Ed. 2014, 53, 4390. (f) Tang, C.;
Jiao, N. Angew. Chem., Int. Ed. 2014, 53, 6528. (g) Schafer, G.;
̈
Matthey, C.; Bode, J. W. Angew. Chem., Int. Ed. 2012, 51, 9173.
(h) Schafer, G.; Bode, J. W. Org. Lett. 2014, 16, 1526. (i) Noda, H.;
̈
Bode, J. W. Chem. Sci. 2014, 5, 4328. (j) Gunanathan, C.; Milstein, D.
Science 2013, 341, 1229712. (k) Jin, X.; Kataoka, K.; Yatabe, T.;
Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2016, 55, 7212.
(l) Zultanski, S. L.; Zhao, J.; Stahl, S. S. J. Am. Chem. Soc. 2016, 138,
D
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