An efficient and scalable ritter reaction for the synthesis of tert-butyl amides

Article abstract of DOI:10.1021/jo8024797

A scalable procedure for the conversion of nitriles to N-tert-butyl amides via the Ritter reaction was optimized employing tert-butyl acetate and acetic acid. The reaction has a broad scope for aromatic, alkyl, and α,β-unsaturated nitriles.

Full text of DOI:10.1021/jo8024797

acetate is employed to generate the tert-butyl cation.4 This paper
describes the optimization and application of an efficient
procedure for the Ritter reaction employing tert-butyl acetate.
During a recent research program we required a convenient
and scalable conversion of an aromatic nitrile to an N-tert-butyl
amide. One previous report employs tert-butyl acetate as both
the solvent and reagent for this transformation.4b The procedure
involves dissolving the substrate in tert-butyl acetate, adding
sulfuric acid at rt, and warming to 42 °C. The author warns of
loss of isobutylene gas and recommends the use of a -15 °C
condenser. In our hands this transformation provided a clean
and fast reaction to furnish our desired amide; however, we
observed a rapid and uncontrolled gas evolution. Due to this
fast decomposition of the reaction solvent in the presence of a
strong acid we deemed this procedure nonscalable.
An Efficient and Scalable Ritter Reaction for the
Synthesis of tert-Butyl Amides
Jean C. Baum, Jacqueline E. Milne,* Jerry A. Murry, and
Oliver R. Thiel
Chemical Process R&D, Amgen Inc., One Amgen Center
DriVe, Thousand Oaks, California 91320
milne@amgen.com
ReceiVed NoVember 5, 2008
Focusing on the use of tert-butyl acetate as the reagent, we
evaluated a wide variety of acids and cosolvents for this
reaction.5 The use of sulfuric acid resulted in full conversion
and good assay yields (>80%) in chlorobenzene, isopropyl
acetate, and acetic acid. We chose to avoid the use of
halogenated solvents; therefore, isopropyl acetate and acetic acid
were evaluated further. Slow addition of sulfuric acid (2 equiv)
in acetic acid to a mixture of the substrate, tert-butyl acetate
(7.5 equiv) in acetic acid at 30 °C gave the cleanest reaction
profile for our candidate molecule. These conditions were
employed in our scale-up facility on multikilo scale to prepare
a clinical candidate in high yield.6 Upon application of these
conditions to a simpler aromatic nitrile (4-methoxybenzonitrile)
we were able to further lower the reagent stoichiometry (1.8
equiv of sulfuric acid and 2.0 equiv of tert-butyl acetate) as
well as the temperature (rt) of the reaction.
We believe that the advantage of this reagent combination is
the equilibrium that exists between tert-butyl acetate and
isobutylene in acetic acid.7 In theory the reaction should be
inherently safe, since the generated carbocation either reacts
along the desired reaction pathway with the nitrile or is
scavenged by acetic acid resulting in the regeneration of tert-
butyl acetate.8 Therefore, there exists a controlled and slow
release of isobutylene during the reaction (Scheme 1).9
A scalable procedure for the conversion of nitriles to N-tert-
butyl amides via the Ritter reaction was optimized employing
tert-butyl acetate and acetic acid. The reaction has a broad
scope for aromatic, alkyl, and R,ꢀ-unsaturated nitriles.
The Ritter reaction to prepare N-tert-butyl amides involves
the treatment of a nitrile with a tert-butyl cation source.1,2 In
general, either isobutylene gas or tert-butanol is employed as
the tert-butyl cation source, which is typically generated in the
presence of acid.3 Although widely used in organic synthesis,
the most commonly used reaction conditions have some inherent
problems that limit their use on larger scale. For example,
isobutylene is a class 4 (highly flammable) gas and there have
been reports of exothermic events1d when used in this reaction.
A cationic polymerization of isobutylene is a likely cause for
these exothermic events. On the other hand, the use of tert-
butanol can be complicated by the melting point (26 °C) leading
to a semisolid at room temperature. An attractive alternative is
tert-butyl acetate due to its ease of handling (bp 97-98 °C),
availability as a common solvent, and low cost. However, there
are only limited examples of Ritter reactions in which tert-butyl
We were subsequently able to confirm the superiority of tert-
butyl acetate in comparison to alternative tert-butyl cation
precursors when used in acetic acid. Reaction of 4-methoxy-
benzonitrile was compared by using tert-butyl acetate, tert-
(1) Early examples of the Ritter reaction: (a) Ritter, J. J.; Minieri, P. P. J. Am.
Chem. Soc. 1948, 70, 4045–4048. (b) Benson, F. R.; Ritter, J. J. J. Am. Chem.
Soc. 1949, 71, 4128–4129. (c) Plaut, H.; Ritter, J. J. J. Am. Chem. Soc. 1951,
73, 4076–4077. (d) Ritter, J. J.; Yonkers, N. Y. U.S. Patent 2,573,673, 1951.
(2) For a review see: Krimen, L. I.; Cota, D. L. Org. React. 1969, 17, 213–
325.
(3) Ritter reactions employing different acids: (a) Sanz, R.; Martinez, A.;
Guilarte, V.; Alvarez-Gutierrez, J. M.; Rodriguez, F. Eur. J. Org. Chem. 2007,
4642–4645. (b) Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2008, 49, 2661–
2664. (c) Maki, T.; Ishihara, K.; Yamamoto, H. Tetrahedron 2007, 63, 8645–
8657. (d) Firouzabadi, H.; Iranpoor, N.; Khoshnood, A. Catal. Commun. 2008,
9, 529–531. (e) Kartashov, V. R.; Malkova, K. V.; Arkhipova, A. V.; Sokolova,
T. N. Russ. J. Org. Chem. 2006, 42, 966–968. (f) Callens, E.; Burton, A. J.;
Barrett, A. G. M. Tetrahedron Lett. 2006, 47, 8699–8701. (g) Garcia Martinez,
A.; Martinez Alvarez, R.; Teso Vilar, E.; Garcia Fraile, A.; Hanack, M.;
Subramanian, L. R. Tetrahedron Lett. 1989, 30, 581–582. (h) Tamaddon, F.;
Khoobi, M.; Keshavarz, E. Tetrahedron Lett. 2007, 48, 3643–3646. (i) Gullickson,
G. C.; Lewis, D. E. Synthesis 2003, 681–684.
(4) tert-Butyl acetate as tert-butyl cation source: (a) Fernholz, H.; Schmidt,
H. J. Angew. Chem., Int. Ed. 1969, 8, 521. (b) Reddy, K. L. Tetrahedron Lett.
2003, 44, 1453–1455.
(5) Acids: methanesulfonic acid, sulfamic acid, phosphoric acid, sodium
bisulfate, trifluoroacetic acid, ion exchange resins, boron trifluoride-acetic acid
complex, sulfuric acid, triflic acid. Solvents: toluene, N-methylpyrrolidone,
2-methyltetrahydrofuran, 1,2-dimethoxyethane, cyclopentyl methyl ether, methyl
isobutyl ketone, chlorobenzene, isopropyl acetate, acetic acid.
(6) A hazard evaluation of this process, including calorimetry experiments,
confirmed its suitability for scale-up. Vent Size Testing revealed that at 80 °C
and above, a progressive pressure buildup of isobutylene occurs. This provides
a 50 °C safety window between reaction temperature and gas evolution.
(7) Equilibrium between tert-butyl acetate and isobutylene in sulfuric acid
and acetic acid: Glikmans, G.; Torck, B.; Hellin, M.; Coussemant, F. Bull. Soc.
Chim. Fr 1966, 1383–1388.
(8) The preparation of t-butyl acetate from acetic acid and isobutylene:
Johnson, W. S.; McCloskey, A. L.; Dunnigan, D. A. J. Am. Chem. Soc. 1950,
72, 514–517.
10.1021/jo8024797 CCC: $40.75
Published on Web 02/06/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2207–2209 2207

TABLE 2. Substrate Scope
SCHEME 1
TABLE 1. tert-Butyl Cation Source
tert-butyl cation (2 equiv) time (h) conversion HPLC assay (%)
1
2
3
t-BuOAc
t-BuOH
MTBE
2
3
19
98
92
79
butanol, and MTBE,10 as shown in Table 1. The fastest and
cleanest reaction was observed with tert-butyl acetate.
The optimized conditions have a broad substrate scope and
provide a practical method for the synthesis of tert-butyl amides.
The scope was investigated by examining a variety of substrates.
In most cases, using the standard conditions, the reaction
proceeded smoothly in a few hours. The reactions of aromatic
nitriles bearing both electron-donating and electron-withdrawing
substituents were efficient and afforded the desired product in
excellent isolated yields (80-98%). The conversion of slower
reacting substrates can be increased by an additional charge of
tert-butyl acetate and H2SO4. For example, when 4-(2-bro-
mophenoxy)-3-chlorobenzonitrile was employed in the reaction
using our optimized procedure (Table 2, entry 6) after 17 h at
rt, 90% conversion was achieved. An additional charge of
sulfuric acid (0.5 equiv) and tert-butyl acetate (0.5 equiv) gave
full conversion. To our delight, the reaction conditions are
compatible with some acid-sensitive functional groups (Table
2, entries 9-11). In addition, the heterocycle thiophene-2-
carbonitrile was efficiently converted to N-tert-butylthiophene-
2-carboxamide (Table 2, entry 14). Also noteworthy is the
synthesis of N-tert-butyl acrylamide from acrylonitrile in 85%
yield.
Unfortunately, when 4-aminobenzonitrile was subjected to
the reaction conditions, only 20% conversion of the starting
material was observed. However, the aniline may be protected
as an acetamide and treated under the reaction conditions to
provide a high yield of product as shown in Table 2, entry 11.
It is worth noting that the BOC protecting group was not
compatible with this procedure. In addition, sterically encum-
bered ortho-substituted derivatives suffered lower conversions
and did not achieve full conversion under standard reaction
conditions, even when additional acid and tert-butyl acetate were
(9) A comparison of the Ritter reaction employing 4-methoxybenzonitrile,
tert-butyl acetate (5 equiv), and sulfuric acid (1 equiv) in the presence and absence
of acetic acid was conducted. tert-Butyl acetate levels were monitored by HPLC
(212 nm). When no acetic acid was present, 0 equiv of tert-butyl acetate was
detected after 3 h. When 2 vol of acetic acid was employed as solvent, 0.8 to
1.5 equiv of tert-butylacetate was detected after 3 h (depending on the rate of
addition of the sulfuric acid).
a Isolated product. b Charged additional sulfuric acid (0.5 equiv) and
tert-butyl acetate (0.5 equiv) after 17 h. c The reaction required 2.5
equiv of tert-butyl acetate and 2 equiv of sulfuric acid. d Corrected for
(10) In addition, MTBE has been used as the tert-butyl cation source. Use
of MTBE as tert-butyl cation: Bonse, G.; Blank, H. U. DE 3002203, 1981.
1
purity by H NMR.
2208 J. Org. Chem. Vol. 74, No. 5, 2009

SCHEME 2. Deuterium Incorporation in the tert-Butyl
Acetate
acid (1 mL/g) over 30 min at rt. The temperature was maintained
below 30 °C during the addition. The reaction mixture was aged at
rt for 2 h, then assayed by HPLC for completion. Upon complete
conversion of the nitrile, the reaction mixture was treated with
sodium acetate solution (2 M, aq, 36 mmol). The solid product
precipitated from the reaction and was filtered and washed with
water (2 × 4 mL/g). The product was dried under high vacuum at
40 °C overnight.
N-tert-Butyl-4-methoxybenzamide. To a mixture of 4-meth-
oxybenzonitrile (20.0 g, 150.2 mmol), acetic acid (20.0 mL), and
tert-butyl acetate (40.5 mL, 300.5 mmol) was added a solution of
concentrated sulfuric acid (13.6 mL, 270.4 mmol) in acetic acid
(20.0 mL) over 30 min at rt. The temperature was maintained below
30 °C during the addition. The reaction mixture was stirred at rt
for 2 h, at which HPLC revealed complete consumption of the
starting material. The reaction mixture was quenched with aqueous
sodium acetate solution (2 M, 150.0 mL), filtered, and washed with
water (2 × 60.0 mL). The product was dried under vacuum at 40
°C to yield a white solid, 28.5 g (92%). No further purification
was necessary. Mp 116.60 °C; 1H NMR (400 MHz, CDCl3) δ 7.68
(d, J ) 8.80 Hz, 2 H), 6.88 (d, J ) 8.80 Hz, 2 H), 5.94 (br s, 1 H),
3.82 (s, 3 H), 1.46 (s, 9 H); 13C NMR (101 MHz, CDCl3) δ 166.5,
161.9, 128.5, 128.3, 113.6, 55.4, 51.5, 29.0.
employed. While 2-methoxybenzonitrile provided amide product
in 80%11 (Table 2, entry 12), the 2,6-dimethyl derivative did
not react.
To investigate the equilibrium of acetic acid and tert-butyl
acetate, a reaction was performed employing d4-acetic acid as
the solvent. Upon completion of the reaction, the residual tert-
butyl acetate content of the reaction mixture was analyzed by
GCMS. Deuterium incorporation in the tert-butyl acetate of 2.5:1
(D:H) was observed, confirming the theory that the acetic acid
traps the excess tert-butyl cation and reduces the loss of the
active species (Scheme 2).
In conclusion, a new, safe, scalable, and robust method to
perform the Ritter reaction has been developed. We have shown
that the use of tert-butyl acetate has advantages over alternative
tert-butyl cation sources. In combination with acetic acid, an
internal buffer for isobutylene gas exists, which eliminates the
possibility of an uncontrolled gas evolution. The method has
broad scope for aromatic, alkyl, and R,ꢀ-unsaturated nitriles.
Acknowledgment. The authors wish to thank Burton Lee
and Jessica Tan for their help in GCMS analysis. Kevin Turney
is acknowledged for HRMS experiments. Joe Tomaskevitch is
acknowledged for contributing valuable discussions and experi-
ments regarding the hazard evaluation of this procedure.
Experimental Section
Supporting Information Available: Experimental proce-
dures, compound characterization data, and copies of 1H NMR
and 13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
General Procedure. To a mixture of nitrile (10 mmol, 1 equiv),
acetic acid (1 mL/g), and tert-butyl acetate (20 mmol, 2 equiv)
was added a solution of sulfuric acid (18 mmol, 1.8 equiv) in acetic
(11) In the case of 2-methoxybenzonitrile the reaction could not be driven
to completion by an additional charge of sulfuric acid and tert-butyl acetate.
JO8024797
J. Org. Chem. Vol. 74, No. 5, 2009 2209