An efficient method for the conversion of aromatic and aliphatic nitriles to the corresponding N-tert-butyl amides: A modified Ritter reaction

Article abstract of DOI:10.1016/S0040-4039(03)00006-6

Aromatic and aliphatic nitriles react with tert-butyl acetate in the presence of a catalytic amount of sulfuric acid to give the corresponding N-tert-butyl amides in excellent yields.

Full text of DOI:10.1016/S0040-4039(03)00006-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1453–1455
An efficient method for the conversion of aromatic and aliphatic
nitriles to the corresponding N-tert-butyl amides:
a modified Ritter reaction
K. Laxma Reddy
Process Research and Development, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford,
CT 06492-7660, USA
Received 24 October 2002; revised 10 December 2002; accepted 16 December 2002
Abstract—Aromatic and aliphatic nitriles react with tert-butyl acetate in the presence of a catalytic amount of sulfuric acid to give
the corresponding N-tert-butyl amides in excellent yields. © 2003 Published by Elsevier Science Ltd.
The conversion of a nitrile to the corresponding N-tert
butyl amide is a very useful transformation in organic
synthesis; the product N-tert-butyl amides are pharma-
ceutically important1 and also serve as precursors to the
corresponding amines.
synthesis of N-tert-butyl amides from nitriles using
esters. Our approach was to generate the tert-butyl
cation from a non-alcoholic source.9 To this end, tert-
butyl acetate in the presence of a catalytic amount of
concentrated sulfuric acid as the proton source10 was
found to be the best source of tert-butyl cation. A wide
range of aromatic nitriles containing both electron
donating and withdrawing substituents on the aromatic
ring as well as aliphatic nitriles were converted to their
corresponding amides using these new reaction condi-
tions (Table 1).
The amidation of alcohols with nitriles in the presence
of concentrated sulfuric acid is known as the Ritter
reaction.2 This method works well only in the case of
tertiary alcohols under strongly acidic conditions, thus
limiting its applicability to compounds containing func-
tional groups stable to acid. Some alternative method-
ologies available are the use of chromium tricarbonyl
complexes of benzylic alcohols with nitriles in sulfuric
acid,3 reaction of chlorophenylmethylium hexa-
chloroantimonate with alcohols in nitrile solvents,4
reaction of alcohols with nitriles in the presence of
transition
metal
compounds,5
reaction
of
triflouromethanesulfonic anhydride with alcohols in the
presence of nitriles,6 and reaction of benzyl alcohols
with nitriles in the presence of boron trifluoride ther-
ate.7 Recently, amidation of primary and secondary
benzylic alcohols with different nitriles has been
reported using Fe+3-Montmorillonite K10.8 Many of
these methods suffer from at least one of the following
issues: limited availability of reagent, hygroscopicity,
low yield, tedious product isolation, longer reaction
time and competing side reactions. To our knowledge
there is no method reported in the literature for the
This method is efficient and practical, giving the tert-
butyl amides in high yields (88–95%).
It was found that the rate of conversion of the nitriles
to the corresponding amides is highly dependent on a
number of factors: source of the tert-butyl cation,
solvent, acid, and acid–solvent combination. For the
initial study, excess di-tert-butyl dicarbonate[(Boc)2O]
and TFA (5.0 equiv.) were used as the tert-butyl cation
source. Under these conditions, 4-methoxybenzonitrile
(1a) produced the corresponding amide 1b in 80% yield
after reaction at room temperature for 5 days. After
screening various reaction conditions to increase the
rate of reaction, it was found that tert-butyl acetate and
Keywords: modified Ritter reaction; nitriles; tert-butyl acetate; N-
tert-butyl amides.
E-mail: kollal@bms.com
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
PII: S0040-4039(03)00006-6

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K. L. Reddy / Tetrahedron Letters 44 (2003) 1453–1455
Table 1.

K. L. Reddy / Tetrahedron Letters 44 (2003) 1453–1455
1455
sulfuric acid were very efficient for this transformation.
4-Methoxybenzonitrile (1a, entry 1; 10 mmol), was
treated with 0.25 mL (4.7 mmol) of sulfuric acid in (7.5
mL) tert-butyl acetate at 42°C for 2 h to obtain the
corresponding amide 1b in 95% yield. However the
conversion of benzonitrile (2a, entry 2) under similar
reaction conditions took more than 12 h to complete.
The reaction rate was decreased significantly when a
catalytic amount of water was added. Alternatively,
increasing the sulfuric acid concentration (from 0.25 to
0.5 mL) increased the reaction rate considerably and
the reaction was completed in <3 h. Using these opti-
mized reaction conditions, p-tolylnitrile (3a, entry 3),
3-hydroxybenzonitrile (4a, entry 4), and 2-
(methylthio)benzonitrile (9a, entry 9) were converted to
their corresponding amides in high yield. Electron
deficient substrates like 2-fluorobenzonitrile (5a, entry
5), 4-(trifluoromethoxy)benzonitrile (6a, entry 6), 2-
(trifluoromethyl)benzonitrile (7a, entry 7), and 4-carbo-
methoxybenzonitrile (8a, entry 8) underwent smooth
conversion to afford the amides in excellent yields.
Other examples, such as the bicyclic 1-cyanonapthalene
(10a, entry 10) and the heteroaromatic 3-cyanopyridine
(11a, entry 11) and 2-cyanothiophene (12a, entry 12)
also underwent smooth conversion. The method also
worked effectively for a benzylic nitrile (entry 13) and
an aliphatic nitrile (entry 14).
9H, C(CH3)3); 13C NMR (100 MHz, CDCl3) l 166.5,
161.9, 128.5, 128.2, 113.6, 55.4, 51.5, 28.9; IR (KBr)
3400–3300(br), 1630 cm−1; HR MS calcd for
C12H17NO2: 207.1259. Found: 207.1258.13
Acknowledgements
I would like to thank Drs. Yadagiri Pendri, Melanie
Miller, John Scott, Richard Mueller, Andrew Staab,
Chung-Pin Chen, Vivekananda Rudhula, Kirsten
Gesenberg and Anthony Alexander for their helpful
discussions.
References
1. (a) Ikeda, K.; Tatsuno, T.; Nishihara, N.; Nagata, T.;
Nishi, H. JP 2000-90274 20000329;; (b) Ikeda, K.; Tat-
suno, T.; Nakayama, C. PTC Int. Appl. (2000), 78 pp
WO 0064430 A1 20001102.
2. (a) Benson, F. R.; Ritter, J. J. J. Am. Chem. Soc. 1949,
71, 4128; (b) Krimen, L. I.; Cota, D. J. Org. React. 1969,
17, 213.
3. Top, S.; Jaouen, G. J. Org. Chem. 1981, 46, 78.
4. Barton, D. H. R.; Magnus, P. D.; Young, R. N. J. Chem.
Soc., Chem. Commun. 1973, 331.
5. (a) Mukhopadhyay, M.; Reddy, M. M.; Maikap, G. G.;
Igbal, J. J. Org. Chem. 1995, 60, 2670; (b) Mukhopad-
hyay, M.; Igbal, J. J. Org. Chem. 1997, 62, 1843.
6. Martinez, A. G.; Alvarez, R. M.; Vilar, E. T.; Fraile, A.
G.; Hanack, M.; Subramanian, L. R. Tetrahedron Lett.
1989, 30, 581.
A mechanistic study of this transformation is under
investigation and will be reported in due course.
In conclusion, a simple, efficient and practical method
for the conversion of aromatic and aliphatic nitriles to
the corresponding N-tert-butyl amides has been
developed.
7. Firouzabadi, H.; Sardarian, A. R.; Badparva, H. Synth.
Commun. 1997, 27, 2403.
8. Lakouraj, M. M.; Movassagh, B.; Fasihi, J. Synth. Com-
mun. 2000, 30, 821.
9. Reaction of ethers with nitriles see; Eugene E. M. US
General procedure for the conversion of nitriles to
N-tert-butyl amides
Patent Serial No. 72, 773.
To a stirred solution of 4-methoxy benzonitrile (13.3 g,
100 mmol) in tert-butyl acetate (75.0 mL) in a 250 mL
three-necked round bottom flask equipped with con-
denser,11 temperature probe and an additional funnel
was added conc. sulfuric acid (5.0 mL) slowly at room
temperature in about 5 min. The resulting solution was
stirred at ꢀ42°C for ꢀ2.0 h to complete the reaction.
The reaction mixture was poured into cold aqueous
20% KHCO3 solution (250 mL) to neutralize the acid
and precipitate the product. The product was filtered,12
washed with cold water and dried under vacuum to give
10. Work is in progress to demonstrate the conversion of
carboxylic acids to the tert-butyl esters using tert-butyl
acetate as a tert-butyl source.
11. It is recommended to use a condenser with −15°C coolant
(ethylene glycol and water mixture circulated through RC
6CS Lauda, Brinkmann) to prevent the loss of
isobutylene.
12. All the products 1b to 14b were crystallized from the
reaction mixture by the addition of water.
13. (a) Rubottom, G. M.; Pichardo, J. L. Synth. Commun.
1973, 3, 18; (b) Rubottom, G. M. J. Chem. Edu. 1974, 51,
616; (c) Tsai, S. C.; Rubottom, G. M. Org. Mass Spec-
trometry 1974, 9, 601.
1
the amide 1b (19.5 g, 95% yield). H NMR (400 MHz,
CDCl3) l 7.69(d, J=8.8 Hz, 2H, aromatic), 6.90 (d,
J=8.8 Hz, 2H, aromatic), 3.84 (s, 3H, OMe), 1.48 (s,