The direct synthesis of N-alkylated amides via a tandem hydration/N-alkylation reaction from nitriles, aldoximes and alcohols

Article abstract of DOI:10.1039/c4cc02742f

A novel strategy for the direct synthesis of N-alkylated amides from nitriles, aldoximes and alcohols was proposed and accomplished in the presence of a Cp*Ir complex. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02742f

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The direct synthesis of N-alkylated amides via
a tandem hydration/N-alkylation reaction from
nitriles, aldoximes and alcohols†
Cite this: Chem. Commun., 2014,
50, 8303
Received 14th April 2014,
Accepted 2nd June 2014
Nana Wang, Xiaoyuan Zou, Juan Ma and Feng Li*
DOI: 10.1039/c4cc02742f
www.rsc.org/chemcomm
A novel strategy for the direct synthesis of N-alkylated amides from
nitriles, aldoximes and alcohols was proposed and accomplished in
the presence of a Cp*Ir complex.
The N-alkylated amides represent an important class of chemical
compounds that have ubiquitous applications in natural products,
pharmaceuticals, fine chemicals and polymers, etc.1 Traditional
procedures for the synthesis of N-alkylated amides are couplings
of carboxylic acids or their derivatives, such as acid chlorides,
anhydrides and esters, with N-alkylated amines.2 However, these
procedures suffer from the disadvantage of the use of a stoichio-
metric amount of hazardous and/or expensive reagents and the
generation of a large amount of harmful by-products.
In recent several years, much attention has been paid to the
development of catalytic strategies for the synthesis of N-alkylated
amides using alcohols as starting materials because alcohols are less
toxic, abundant and renewable feedstock reagents. Several groups
have developed direct couplings of amines and primary
alcohols for the preparation of N-alkylated amides using transi-
tion metal catalysts, such as a PNN-type ruthenium complex,3
Scheme 1 Strategies for the synthesis of N-alkylated amines from alcohols.
the combination of a N-heterocyclic carbene (NHC) precursor,
and [Ru(cod)Cl]2,4 [Ru(p-cymene)Cl2]2, [Ru(benzene)Cl2]2 or condensation of the corresponding aldehydes with hydroxylamine
[RuH2(PPh3)4] systems,6 N-heterocyclic carbene based ruthenium hydrochloride in the presence of base, and the single catalyst
complexes,7 ruthenium diphosphine diamine complexes.8 How- (ruthenium or iridium complex) is not efficient for such tandem
ever, it is still extremely challenging to control the selectivity of the transformation. More recently, Hong and co-workers reported a
reaction and reduce the generation of by-products N-alkylated catalytic strategy for the synthesis of N-alkylated amides from nitriles
amines (Scheme 1A). In 2013, we demonstrated the direct and alcohols with complete atom economy based on ‘‘hydrogen
synthesis of N-alkylated amides from aldoximes and alcohols transfer’’ (Scheme 1C),10 exhibiting significant advantages over the
via a tandem rearrangement/N-alkylation reaction catalyzed by a traditional Ritter reaction (amidation of nitriles with alcohols or
Ru/Ir dual catalyst system, which exhibited excellent selectivity alkenes in the presence of at least stoichiometric amount of concen-
for target products (Scheme 1B).9 However, most aldoximes trated sulfuric acid).11 This procedure still has some limitations and it
are not commercially available and must be synthesized via requires 10 mol% catalyst loading, 10 mol% ligand, 20 mol% strong
base (NaH) and long reaction time (48 h).
5
The selective hydration of nitriles with aldoximes as water
Key Laboratory for Soft Chemistry and Functional Materials, Ministry of Education,
surrogates for the synthesis of amides has been developed using
Nanjing University of Science and Technology, Nanjing 210094, P. R. China.
transition metal catalysts, such as rhodium,12a palladium,12b
E-mail: fengli@njust.edu.cn; Fax: +86-25-84431939; Tel: +86-25-84317316
indium,12c copper,12d nickel12e complexes or salts. This methodology
† Electronic supplementary information (ESI) available: Experimental procedures
and analytical data for products. See DOI: 10.1039/c4cc02742f
is attractive due to the mild and neutral reaction conditions
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Table 1 Reaction of benzonitrile 1a, n-butylaldoxime 2b and a variety of
alcohols 3a,b
that avoid the formation of carboxylic acids and allow functional
groups to remain intact. However, these known procedures still
suffer from a high catalyst loading (5–10 mol%) or/and excess of
aldoxime (2–5 equiv.). As part of a continuing interest in developing
new reactions with the activation of alcohols,9,13 herein we wish to
explore the direct synthesis of N-alkylated amides via a tandem
hydration/N-alkylation reaction from nitriles, aldoximes and
alcohols. The proposed reaction pathway is as follows: nitriles are
first hydrated with aldoximes as water surrogates to form amides,
which are further N-alkylated with alcohols as alkylating agents to
N-alkylated amides (Scheme 1D). Compared with Hong’s method,10
this procedure would provide different N-alkylated amides from the
same starting materials (nitriles and alcohols).
In our previous work,9 a range of commercially available transi-
tion metal complexes, including [Ru(p-cymene)Cl2]2, [Cp*RhCl2]2
(Cp* = pentamethylcyclopentadienyl), [Rh(cod)Cl]2 (cod = 1,5-cyclo-
octadienyl), [Cp*IrCl2]2 and [Ir(cod)Cl]2, were assayed for their ability
to catalyze the N-alkylation of benzamide with benzyl alcohol to the
N-benzylbenzamide and [Cp*IrCl2]2 was found to be the most
efficient catalyst. As a result, our initial efforts in this work focused
on the hydration of benzonitrile 1a with a commercially available
aldoxime, such as acetylaldoxime 2a and n-butylaldoxime 2b, as the
water surrogate catalyzed by [Cp*IrCl2]2. The reaction of 1a with 2a
(1.1 equiv.) was carried out in the presence of [Cp*IrCl2]2 (1 mol%) at
100 1C for 6 h to give benzamide 4a with 81% yield. To our delight,
the product 4a could be obtained with 90% yield when 2b was used
for this reaction [eqn (1)]. The n-butylaldoxime 2b was chosen as the
water surrogate for further research. After the reaction of 1a with 2b
was carried out at 100 1C for 6 h, benzyl alcohol 3a (1.3 equiv.) and
a
Reaction conditions: (1) 1a (1 mmol), 2b (1.1 mmol), [Cp*IrCl2]2
(1 mol%), toluene (1 ml), 100 1C, 6 h; (2) 3 (1.3 mmol) and Cs2CO3
b
(0.2 equiv.) were added into the reactor, 130 1C, 12 h. Isolated yield.
c
d
3k (1.5 mmol). 3 (2 mmol), KOtBu (0.2 equiv.).
Cs2CO3 (0.2 equiv.) were added into the above reactor. This reaction furan-2-ylmethanol 3l and thiophen-2-ylmethanol 3m were tested,
continued to proceed at 130 1C for another 12 h to afford the desired the desired products 5ak–5am were obtained with 80–85% yields,
N-alkylated amide 5aa with 85% yield [eqn (2)].
respectively. Apart from benzyl-type alcohols, aliphatic alcohols,
including linear n-butanol 3n and n-hexanol 3o, and cyclohexyl-
methanol 3p, were proven to be suitable substrates and reactions
gave the corresponding products 5an–5ap with 78–85% yields.
To expand further the scope of the reaction, a series of
nitriles 1 were used as substrates for examination. As shown in
Table 2, reactions of benzonitriles bearing one or two electron-
donating substituents, such as methyl 1b and methoxy 1c, gave
the corresponding products 5ba–5ca with 81% and 76% yields,
respectively. Transformation of benzonitriles bearing one or two
halogen atoms, such as fluoro 1d, chloro 1e, dichloro 1f and bromo
(1)
(2)
Having established the catalyst system and the reaction 1g, gave the desired products 5da–5ga with 81–90% yields. In the
conditions, a variety of alcohols 3 were used as substrates instead case of benzonitriles bearing a strong electron-withdrawing sub-
of benzyl alcohol 3a for the investigation and the results are stituent, such as trifluoromethyl 1h and trifluoromethoxy 1i, the
summarized in Table 1. Similar to the case of 3a, reactions with corresponding products 5ha and 5ia were obtained with 80% and
benzylic alcohols bearing an electron-donating group, such as 82% yields, respectively. Reactions of heterocyclic nitriles, such as
methyl 3b and methoxy 3c, afforded the corresponding products furan-2-carbonitrile 1j and thiophene-2-carbonitrile 1k, gave the
5ab and 5ac with 80% and 86% yields, respectively. Benzylic desired products 5ja and 5ka with 84% and 86% yields, respec-
alcohols bearing one or two halide atoms, such as fluoro 3d, chloro tively. This tandem reaction was also applied to aliphatic nitriles,
3e–f, dichloro 3g and bromo 3h, were successfully converted into such as 2-phenylacetonitrile 1l and n-butyronitrile 1m (2a was used
the desired products 5ad–5ah with 79–85% yields. Furthermore, as the water surrogate), affording the corresponding products 5la
transformations of benzylic alcohols bearing a strong electron- and 5ma with 76% and 78% yields, respectively.
withdrawing group, such as trifluoromethyl 3i and trifluoro-
A plausible mechanism is proposed to account for this present
methoxy 3j, gave the corresponding products 5ai and 5aj with 82% reaction (Scheme 2). The initial step involved the formation of
and 84% yields, respectively. When 2-naphthalenemethanol 3k, the iridium–nitrile species A, followed by the resulting species A
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Table 2 Reaction of a series of nitriles 1, n-butylaldoxime 2b and benzyl
alcohol 3aa,b
electronic properties was found to have an influence on the
reactions. In the process of catalytic hydration of aromatic
nitriles with n-butylaldoxime, a small amount of n-butyramide
was generated due to the competing hydration of n-butyronitrile
derived from the hydration of n-butylaldoxime. However, only
trace amounts of N-alkylated butyramides were detected when
tandem reactions were finished, indicating that stronger reac-
tion conditions are necessary for the N-alkylation of aliphatic
amides with alcohols. To transform aliphatic nitriles (1l–1m)
into the corresponding N-alkylated amides (5la–5ma), [Cp*IrCl2]2
(2 mol%) and 1.3 equiv. of aldoxime in the step of hydration, and
2 equiv. of alcohol and 0.4 equiv. of KOtBu in the step of
N-alkylation were required. In this process, N-benzyl butyramide
or N-benzyl acetamide were also generated as by-products.
In summary, we have demonstrated a novel strategy for the
direct synthesis of N-alkylated amides via tandem hydration/
N-alkylation from nitriles, aldoximes and alcohols. The protocol
is highly attractive due to the use of a single catalyst with low
loading, high yields and operational convenience.
Financial support by the National Natural Science Founda-
tion of China (No. 21272115) and the Fundamental Research
Funds for the Central Universities (No. 30920130111005 and
No. 30920140122003) is greatly appreciated.
a
Reaction conditions: (1) 1 (1 mmol), 2b (1.1 mmol), [Cp*IrCl2]2
(1 mol%), toluene (1 ml), 100 1C, 6 h; (2) 3a (1.3 mmol) and Cs2CO3
b
(0.2 equiv.) were added into the reactor, 130 1C, 12 h. Isolated yield.
c
d
2b (1.3 mmol), 3a (1.5 mmol). 2b (1.3 mmol), 3a (2 mmol),
e
[Cp*IrCl2]2 (2 mol%), KOtBu (0.4 equiv.), 150 1C. 2a (1.3 mmol), 3a
(2 mmol), [Cp*IrCl2]2 (2 mol%), KOtBu (0.4 equiv.), 150 1C.
Notes and references
1 (a) T. Cupido, J. Tulla-Puche, J. Spengler and F. Albericio, Curr. Opin.
Drug Discovery Dev., 2007, 10, 768; (b) C. L. Allen and J. M. J. Williams,
Chem. Soc. Rev., 2011, 40, 3405.
2 (a) M. B. Smith and J. March, March’s Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure, Wiley, Hoboken, NJ, 6th edn,
2007; (b) M. B. Smith, Organic Synthesis, Mc-Graw-Hill Companies,
New York, 2nd edn, 2002.
3 C. Gunanathan, Y. Ben-David and D. Milstein, Science, 2007,
317, 790.
4 (a) L. U. Nordstrom, H. Vogt and R. Madsen, J. Am. Chem. Soc., 2008,
130, 17672; (b) J. H. Dam, G. Osztrovszky, L. U. Nordstrom and
R. Madsen, Chem. – Eur. J., 2010, 16, 6820.
5 S. C. Ghosh, S. Muthaiah, Y. Zhang, X. Xu and S. H. Hong, Adv.
Synth. Catal., 2009, 351, 2643.
6 S. Muthaiah, S. C. Ghosh, J. E. Jee, C. Chen, J. Zhang and S. H. Hong,
J. Org. Chem., 2010, 75, 3002.
7 (a) C. Chen, Y. Zhang and S. H. Hong, J. Org. Chem., 2011, 76, 10005;
(b) I. S. Makarov, P. Fristrup and R. Madsen, Chem. – Eur. J., 2012,
18, 15683.
8 (a) A. Nova, D. Balcells, N. D. Schley, G. E. Dobereiner, R. H. Crabtree
and O. Eisenstein, Organometallics, 2010, 29, 6548; (b) N. D. Schley,
G. E. Dobereiner and R. H. Crabtree, Organometallics, 2011, 30, 4174.
9 F. Li, P. Qu, J. Ma, X. Zou and C. Sun, ChemCatChem, 2013, 5, 2178.
10 B. Kang, Z. Fu and S. H. Hong, J. Am. Chem. Soc., 2013, 135, 11704.
11 (a) J. J. Ritter and P. P. Minieri, J. Am. Chem. Soc., 1948, 70, 4045;
(b) F. R. Benson and J. J. Ritter, J. Am. Chem. Soc., 1949, 71, 4128;
(c) H. Plaut and J. J. Ritter, J. Am. Chem. Soc., 1951, 73, 4076.
12 (a) J. Lee, M. Kim, S. Chang and H. Y. Lee, Org. Lett., 2009, 11, 5598;
(b) E. S. Kim, H. S. Kim and J. N. Kim, Tetrahedron Lett., 2009,
50, 2973; (c) E. S. Kim, H. S. Lee, S. H. Kim and J. N. Kim,
Tetrahedron Lett., 2010, 51, 1589; (d) X. Ma, Y. He, Y. Hu and
M. Lu, Tetrahedron Lett., 2012, 53, 449; (e) X. Ma, Y. He, P. Wang
and M. Lu, Appl. Organomet. Chem., 2012, 26, 377.
Scheme 2 Plausible mechanism.
which were subsequently attacked by one molecule of aldoxime
to afford the five-membered cyclic species B, which decom-
posed to release amides and nitriles, and to regenerate the
catalytically active iridium species. Finally, the resulting amides
were further N-alkylated with alcohols to afford N-alkylated
amides catalyzed by an iridium/base system.
It should be pointed that aromatic nitriles and benzyl-type
alcohols bearing different electronic substituents could be converted
into the desired products with high yields and thus none of the
13 (a) F. Li, H. Shan, L. Chen, Q. Kang and P. Zou, Chem. Commun., 2012,
48, 603; (b) F. Li, C. Sun, H. Shan, X. Zou and J. Xie, ChemCatChem,
2013, 5, 1543; (c) C. Sun, X. Zou and F. Li, Chem. – Eur. J., 2013,
19, 14030; (d) P. Qu, C. Sun, J. Ma and F. Li, Adv. Synth. Catal., 2014,
356, 447.
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