Synthesis of amides using the Ritter reaction with bismuth triflate catalysis

Article abstract of DOI:10.1016/j.tetlet.2006.10.023

N-tert-Alkyl and aryl amides were obtained by a Ritter reaction of various nitriles with tertiary alcohols in the presence of a catalytic amount of bismuth triflate.

Full text of DOI:10.1016/j.tetlet.2006.10.023

Tetrahedron Letters 47 (2006) 8699–8701
Synthesis of amides using the Ritter reaction with bismuth
triflate catalysis
Emmanuel Callens,a Andrew J. Burtonb and Anthony G. M. Barretta,*
aDepartment of Chemistry, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom
bChemical Development, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, United Kingdom
Received 24 August 2006; revised 24 September 2006; accepted 5 October 2006
Abstract—N-tert-Alkyl and aryl amides were obtained by a Ritter reaction of various nitriles with tertiary alcohols in the presence of
a catalytic amount of bismuth triflate.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The synthesis of an amide from the reaction of a nitrile
with a substituted alkene or alcohol using a stochio-
metric amount of sulfuric acid, the Ritter reaction, is
an important transformation in organic synthesis.1 The
reaction is especially useful for the preparation of bulky
amides, which may be hydrolyzed to yield hindered
amines. As an alternative to sulfuric acid, the Ritter
reaction may be catalyzed by metal complexes (Cr,
Sb)2–4 trifluoromethanesulfonic anhydride5 or boron tri-
fluoride etherate.6 Nevertheless, the main disadvantages
of these procedures are the use of toxic catalysts or an
excess amount of corrosive acids. Recently, a method
for the conversion of aromatic nitriles to the corre-
sponding N-tert-butylamides with tert-butyl acetate cat-
alyzed by sulfuric acid has been reported.7
Since there are no previous examples of the use of metal
triflates as catalysts in the Ritter reaction with the excep-
tion of trimethylsilyl triflate,9 we sought to extend our
preliminary observations to a range of nitriles and ter-
tiary alcohols.
After screening various reaction conditions, we found
that the Ritter reaction could be carried out using a ter-
tiary alcohol and an excess of a nitrile with 5–20 mol %
of a metal triflate in the presence of water. Presumably
under these reaction conditions, catalysis is effected by
triflic acid.10 We subsequently investigated various metal
triflates using benzonitrile and tert-butanol as the sub-
strates. Table 1 summarizes the results obtained for
the Ritter reaction.
During the course of our work on bismuth catalyzed
benzylic oxidation reactions,8 we examined the reaction
of 4-methylanisole 1 with tert-butyl hydroperoxide in
the presence of bismuth triflate and acetonitrile. This
reaction gave N-tert-butylacetamide 2 (17%) instead of
the expected 4-methoxybenzoic acid 3 (Scheme 1).
The control Ritter reaction using trifluoromethanesulf-
onic acid (20 mol %) gave tert-butylbenzamide (93%).
Ytterbium triflate (20 mol %) (entry 2) was ineffective.
Scandium triflate (entry 3) and hafnium triflate (entry
4) gave the desired amide (57% and 67%, respectively).
Catalysis by bismuth triflate10b (20 mol %) (entry 5) pro-
MeO
MeO
O
Bi(OTf)3, t-BuOOH
+
HN
CH3CN, AcOH, 110 oC, 17h
t-Bu
CO2H
1
2 (17%)
3 (0%)
Scheme 1.
*
Corresponding author. Tel.: +44 20 75945767; fax: +44 20 75945805; e-mail addresses: agmb@imperial.ac.uk.c; agmb@ic.ac.uk
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.023

8700
E. Callens et al. / Tetrahedron Letters 47 (2006) 8699–8701
Table 1. Ritter reaction of tert-butanol with benzonitrile: study of
Table 2. Ritter reaction of aliphatic and aromatic nitriles with tert-
various metal triflate catalysis
butanol
Ph
O
R
O
t
-BuOH, Bi(OTf)3 (20 mol%)
H2O
PhCN (3.8 eq), cat. (20 mol%)
H2O, 100 oC, 17 h
t
-BuOH
RCN
HN
HN
t
-Bu
t
-Bu
Entry
Catalyst (mol %)
Yields of tert-butylbenzamide (%)
Entry Substrate
(R–CN)
N-tert-butyl-amide
Isolated
yields (%)
1
2
3
4
5
6
7
TfOH (20)
93
Yb(OTf)3 (20)
Sc(OTf)3 (20)
Hf(OTf)4 (20)
Bi(OTf)3 (20)
Bi(OTf)3 (10)
Bi(OTf)3 (5)
No reaction
O
Me
56
67
87
77
68
1
2
3
4
Me–CN
85
87
95
95
HN
O
t-Bu
tert-Bu–CN
HN
O
ceeded in comparable yields to triflic acid. Decreasing
the amount of bismuth triflate resulted in a decrease in
the yield of the product (entries 6 and 7). It is clear from
Table 1 that bismuth triflate outperforms other metal
triflates.
CN
HN
O
CN
HN
The bismuth triflate catalyzed Ritter reaction was ap-
plied to a range of nitrile derivatives with tert-butanol,
as the tertiary alcohol (Table 2).
O
5
6
80
96
CN
Under these conditions, the aliphatic nitriles acetonitrile
(entry 1), the bulky pivalonitrile (entry 2) and cyclopro-
pyl cyanide (entry 3) were converted to the correspond-
ing amides in good yields (85–95%). Valeronitrile (entry
4), in spite of its lipophilic linear chain, afforded the cor-
responding amide in 95% yield. Both a-methylbenzyl
cyanide (entry 5) and 2-thiophenacetonitrile (entry 6)
gave the corresponding amides in good yields as well
(80, 96%). Good yields were also observed with benzo-
nitrile (entry 7) and 2-methylbenzonitrile (entry 8).
These are less nucleophilic substrates than aliphatic
nitriles. Because all the nitriles reported in entries 1–8
are liquids, we investigated the possibility of applying
this procedure to solid nitriles by adding a suitable
co-solvent. Most solvents were ineffective, however,
nitrobenzene proved to be applicable. When 4-meth-
oxybenzonitrile (entry 9) was allowed to react in the
presence of nitrobenzene, it gave the desired amide in
86% yield. The use of nitrobenzene as an additive was
successfully extended to aryl amides with both electron
withdrawing and electron donating substituents (entries
10–13) also produced with modest to excellent conver-
sions (50–95%).
HN
O
CN
HN
S
S
H
N
7
8
85
75
CN
O
H
N
CN
O
MeO
MeO
H
9
86a
77a
95a
N
CN
O
H
N
10
11
Cl
Cl
CN
O
F3C
F3C
After applying the bismuth-catalyzed Ritter reaction for
the synthesis of N-tert-butyl amides, we examined vari-
ation of the tertiary alcohol using benzonitrile as the
substrate. The results are summarized in Table 3.
H
N
CN
O
O
O
O
O
H
50a
84a
N
12
13
Ritter reaction of benzonitrile with 2-methyl-butan-2-ol
(entry 1), adamantanol (entry 2), 2-methyl-1-phenylpro-
pan-2-ol (entry 3) or 1-methyl-cyclopentanol (entry 4)
gave the corresponding amides in 92%, 91%, 85% and
82% yields, respectively, without any competing rear-
rangement reactions. Interestingly, tert-butyl methyl
ether (entry 5) yielded the amide 92% resulting from
the cleavage of the ether (92% yield). Indeed, the use
of bismuth triflate to mediate the cleavage of tert-butyl
CN
O
HO
HO
H
N
CN
O
a The reaction (see typical procedure) was conducted with PhNO2
(0.3 mL).

E. Callens et al. / Tetrahedron Letters 47 (2006) 8699–8701
8701
Table 3. Ritter reaction of tertiary alcohols with benzonitrile
In summary, a general procedure for the conversion
of nitriles into amides using a catalytic amount of
bismuth triflate instead of corrosive acids has been
developed.
Entry Substrate
Alkylbenzamide
Isolated yields (%)
H
OH
N
Ph
1
92
O
H
OH
Acknowledgements
N
Ph
2
91
85
82
92
O
We thank GlaxoSmithKline for the generous endow-
ment (to A.G.M.B.), the Royal Society and the Wolfson
Foundation for a Royal Society Wolfson Research
Merit Award (to A.G.M.B.), the Wolfson Foundation
for establishing the Wolfson Centre for Organic
Chemistry in Medical Sciences at Imperial College
London, the Engineering and Physical Sciences
Research Council and GlaxoSmithKline for generous
support of our studies, and the Thorpe Bequest for a
studentship (to E.C.).
H
OH
N
Ph
3
4
5
Ph
Ph
O
H
N
OH
Ph
Ph
O
O
H
N
OMe
References and notes
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ethers has precedent.11 This result suggests that the bis-
muth-catalyzed Ritter reaction should be applicable to
other tert-butyl ethers.
2. Top, S.; Jaouen, G. J. Org. Chem. 1981, 46, 78.
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Typical procedure: synthesis of tert-butylbenzamide
tert-Butanol (77.4 lL, 0.8 mmol) was added with stirring
to a solution of bismuth triflate (105 mg, 0.16 mmol) and
benzonitrile (0.4 mL, 3.89 mmol) in water (0.2 mL).
After 17 h at 100 ꢁC, the mixture was cooled and poured
into aqueous KOH solution (20% w:v; 5 mL) to neutral-
ize the acid and precipitate the catalyst. The product was
extracted with dichloromethane (2 · 5 mL) and the
organic phase was filtered, rotary evaporated and chro-
matographed (cyclohexane:EtOAc 9:1 to 1:1) to afford
tert-BuNHCOC6H5 (131 mg, 92% yield) as a white solid:
mp 123–125 ꢁC (CH2Cl2) (lit.12 mp 123–124 ꢁC) IR (thin
film) 3438, 1663, 1580, 1514, 1365 cmÀ1 1H NMR dH
(CDCl3, 400 MHz) dH 1.45 (9H, s), 6.08 (1H, br s),
7.33–7.44 (3H, m), 7.70 (2H, m) 13C NMR dC (CDCl3,
100 MHz) 29.3, 52.0, 127.1, 128.8, 131.4, 136.3, 167.3
MS (CI+) m/z 178 (M+H)+; 195 (M+NH4)+, 355
(2M+1)+ HRMS Calcd for C11H16NO (M+H)+
178.1232, found: (M+H)+, 178.1225.
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G.; Hanack, M.; Subramanian, L. R. Tetrahedron Lett.
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High Throughput Screening 2002, 5, 389.
10. (a) Repichet, S.; Zwick, A.; Vendier, L.; Le Roux, C.;
Dubac, J. Tetrahedron Lett. 2002, 43, 993; (b) Although
bismuth triflate is commercially available, it could be
obtained from Bi2O3 and TfOH.
11. Oussaid, A.; Garrigues, P.; Garrigues, B. C. R. Acad. Sci.
Paris Chimie/Chem. 2001, 4, 691–694.
12. Foot, J. S.; Kanno, H.; Giblin, G. M. P.; Taylor, R. J. K.
Synthesis 2003, 1055.