Process for obtaining N-monosubstituted amides

Details Process for obtaining N-monosubstituted amides Process for obtaining N-monosubstituted amides

2001-07-31

2002-11-19

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S124000

Reexamination Certificate

active

06482983

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for obtaining N-monosubstituted amides, which are useful as synthetic intermediates in practically all branches of organic chemistry, and many of which are also important as compounds possessing biological and physiological activity, including a physiological cooling effect for cosmetics, flavorings and other applications.
BACKGROUND OF THE INVENTION
Among numerous known methods for obtaining N-monosubstituted amides, the Ritter reaction has long been considered to be one of the simplest processes based on readily available reagents, e.g., nitrites, sulfuric acid, olefins, alcohols, aldehydes, and/or other potential donors of a carbenium ion.
In their original experiments, Ritter and coworkers added olefins to a mixture of sulfuric acid and acetonitrile in glacial acetic acid as a solvent and, after a simple workup, obtained N-monosubstituted amides in relatively good yields (J. J. Ritter and P. P. Minieri, J. Amer. Chem. Soc., 1948, Vol. 70, pp. 4045-4048). In a number of following publications, they also used tertiary and secondary alcohols as donors of a carbenium ion, and found that secondary alcohols required harsher conditions, e.g., concentrated sulfuric acid as the reaction medium instead of dilution with acetic acid (J. J. Ritter and J. Kalish, J. Amer. Chem. Soc., 1948, Vol. 70, pp. 4048-4049; F. R. Benson and J. J. Ritter, ibid., 1949, Vol. 71, pp. 4128-4129). It was found that primary alcohols did not react, even under harsher reaction conditions. In fact, as stated in the latter reference, “Efforts to utilize a primary alcohol in the reaction proved fruitless; expedients such as the use of elevated temperatures, prolonged heating or the employment of fuming sulfuric acid were unsuccessful in the production of N-primary alkyl amides.”
Certain limited exceptions to that general rule have been reported. See, for example, Table 1. In all cases, an excess of nitrile has been used with respect to the alcohol.
TABLE 1
Limited exceptions to general rule
Molar
ratio
Nitrile/
Alcohol/
Yield, %
Nitrile,
Alcohol,
Sulfuric
crude/
moles
moles
Acid
recrystallized
Reference
MeCN, 3.8
Benzyl
3.8/1/1.41
−/48
C. L. Parris and
alcohol,
R. M.
1.0
Christenson, J.
Org. Chem.,
1960, Vol. 25,
pp. 331-334
CH
2
═CHCN,
Benzyl
3.8/1/1.41
−/50
C. L. Parris and
3.8
alcohol,
R. M.
1.0
Christenson, J.
Org Chem.,
1960, Vol. 25,
pp. 331-334
CH
2
═CHCN
Benzyl
3.8/1/1.41
−/59-62
C. L. Parris,
3.8
alcohol,
Organic
1.0
Syntheses, 1962,
Vol. 42,
pp. 16-18
MeCN. 3.8
p-Methyl
3.8/1/1.41
−/40
C. L. Parris and
benzyl
R. M.
alcohol,
Christenson, J.
1.0
Org. Chem.,
1960, Vol. 25,
pp. 331-334
MeCN, 0.96
Benzyl
0.96/0.2/
−/72.5
J. A. Sanguigni
alcohol,
0.2
and R. Levins,
0.2
J. Med. Chem.,
1964, Vol. 7,
pp. 573-574
EtCN
Benzyl
0.96/0.2/
−/45
J. A. Sanguigni
alcohol,
0.2
and R. Levins,
J. Med. Chem.,
1964, Vol. 7,
pp. 573-574
CH
2
═CHCN
Benzyl
0.96/0.2/
−/50
J. A. Sanguigni
alcohol
0.2
and R. Levins,
J. Med. Chem.,
1964, Vol. 7,
pp. 573-574
PhCH
2
CN
Benzyl
0.96/0.2/
−/27
J. A. Sanguigni
alcohol
0.2
and R. Levins,
J. Med. Chem.,
1964, Vol. 7,
pp. 573-574
PhCN
Benzyl
0.96/0.2/
−/55
J. A. Sanguigni
alcohol
0.2
and R. Levins,
J. Med. Chem.,
1964, Vol. 7,
pp. 573-574
MeCN, 76.5
Hydroxy-
76.5/1.2/
92/36.7
Sasaki et al. Bull.
methyl
28
Chem. Soc.
adaman-
Japan, 1970,
tane, 1.2
Vol. 43,
pp. 1820-1824
MeCN, 76.5
Hydroxy-
76.5/1.2/
trace
Sasaki et at Bull.
methyl
28
Chem. Soc.
adaman-
+26 acetic
Japan, 1970,
tane, 1.2
acid
Vol. 43,
pp. 1820-1824
MeCN, 0.134
N-
0.13/0.1/
93/83
S. R. Buc. J.
methylol
0.94
Amer. Chem.
phtha-
Soc., 1947,
limide, 0.1
Vol. 69,
pp. 254-256
NCCH
2
COOH,
N-
0.12/0.1/
96/91
S. R. Buc. J.
0.12
methylol
0.94
Amer Chem.
phtha-
Soc., 1947,
limide, 0.1
Vol. 69,
pp 254-256
PhCN, 0.108
N-
0.11/0.1/
96.5/77.5
S. R. Buc. J.
methylol
0.94
Amer. Chem.
phtha-
Soc., 1947,
limide, 0.1
Vol. 69,
pp. 254-256
CH
2
═CHCN,
N-
0.07/0.05/
−/60
E. E. Magat &
0.07
methylol
0.94
L. F. Salisbury,
ben-
J. Amer.Chem.
zamide,
Soc., 1951,
0.05
Vol. 73,
pp. 1035-1036
The occurrence of very poor yields of amide formation, or even a total inability of methanol and other lower primary alcohols to take part in the “classic” Ritter reaction has frequently been confirmed in later publications and reviews. See, for example: D. H. R. Barton et al., J. Chem. Soc. Perkin I, 1974, pp. 2101-2107; T. Kiersznicki and R. Mazurkiewicz, Rocz. Chem., 1977, Vol. 51, pp.1021-1026; A. G. Martinez et al., Tetrahedron Lett., 1989, Vol. 30, pp. 581-582; R. Bishop, Ritter-type Reactions. In: Comprehensive Organic Synthesis, eds. B. M. Trost and I. Fleming, Pergamon Press, Oxford, 1991, Vol. 6, pp. 261-300; H. Firouzabadi et al., Synth. Commun., 1994, Vol. 24, pp. 601-607; and H. G. Chen et al., Tetrahedron Lett., 1996, Vol 37, pp. 8129-8132, each of which are incorporated by reference.
Several “non-classic” Ritter reaction modifications have been developed in order to attempt to obtain N-primary alkyl amides. For instance, n-decanol (0.95 mmol) and acetonitrile (96 mmol) in the presence of 3.4 mmole of dichloro(phenyl)methylium hexachloroantimonate gave N-decylacetamide in 60% yield (D. H. R. Barton et al., J. C. S. Perkin I, 1974, pp. 2101-2107). Similarly, the addition of 10 mmoles of ethanol or butanol to a mixture of 10 mmoles of trifluoromethanesulfonic anhydride and a double excess of acetonitrile or benzonitrile gave 80-90% yield of the corresponding N-alkylamides (A. G. Martinez et al., Tetrahedron Lett., 1989, Vol. 30, pp. 581-582). However, use of such “exotic” and costly reagents as these, makes these modifications industrially impractical.
Patents relating to processes for obtaining N-hydrocarbyl substituted amides include U.S. Pat. No. 5,811,580; EP846,678 A1; and U.S. Pat. No. 5,712,413.
Finally, an article describing clay (Montmorillonite KSF) catalyzed amidation of alcohols, a primary aliphatic alcohol n-octanol was reported inactive (H. M. Sampar Kumar et al., New J. Chem., 1999, Vol. 23, pp. 955-956).
Thus, it is clear that the need still exists for an economically feasible and practical method for obtaining N-monosubstituted amides by a Ritter type reaction of nitrites with primary aliphatic alcohols or other compounds containing primary alkoxy groups.
SUMMARY OF THE INVENTION
Among other aspects, the present invention relates to the surprising discovery of an improved process for obtaining N-primary alkyl monosubstituted amides, cyclic amides or lactams, functionally substituted diamides and polyamides, and cyclic polyamides using relatively inexpensive and readily available reagents including nitrites, acids and primary alkoxy compounds such as lower primary alkohols.
In one embodiment, the present invention relates to a process for obtaining an amide of the general formula R—(CO)—NH—CH
2
—X, said process comprising contacting a nitrile of the general formula R—CN with:
a) an acid; and
b) an alkoxy-containing compound comprising at least one alkoxy functionality of the general formula —OCH
2
—X;
wherein R is hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic substituent, which substituents can be substituted or unsubstituted; wherein X is hydrogen or a radical having the general formula —CHR
1
R
2
; and wherein R
1
and R
2
independently or collectively represent hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic substituent, or any combination thereof, which substituents can be substituted or unsubstituted.
In addition, the process of the present invention comprises reacting at least one nitrile with a reagent comprising both (i) at least one suitable alkoxy functionality; and (ii) at least one suitable acid functionality.
For example, the present invention includes a process for obtaining an amide of the general formula R—(CO)—NH—CH
2
—X, said process comprising contacting a nitrile of the general formula R—CN with a monoalkylsulfate of the general formula X—CH
2
—O−SO
3
H, wherein R is again selecte

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