Method for preparing nitrogen containing compounds

Details Method for preparing nitrogen containing compounds Method for preparing nitrogen containing compounds

2002-11-29

2004-10-12

O'Sullivan, Peter (Department: 1621)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C558S004000, C558S005000

Reexamination Certificate

active

06803472

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel method for preparing nitrogen-containing compounds (e.g., isothioureas, guanidines, amidines, amides) using amines.
BACKGROUND ART
Nitrogen-containing compounds including isothioureas, guanidines, amidines and amides are extremely important in the fields of pharmaceutical or agricultural synthesis. Typical techniques used for preparing these compounds from amines in a single step are shown below.
No technique is known to allow the direct synthesis of isothioureas from amines and thiocyanates.
A technique for synthesizing guanidines from amines and cyanamides is known from J. Med. Chem., 1996, 39, 4017, which reports reaction conditions involving heating the reaction mixture to 180° C. in concentrated hydrochloric acid.
A technique for synthesizing amidines from amines and nitrites is known from Chem. Pharm. Bull., 1997, 45, 987, which reports reaction conditions involving heating the reaction mixture to 150° C. in the presence of aluminum chloride.
A technique for synthesizing amides from amines and esters is known from Tetrahedron Lett., 1996, 37, 2757, which reports the use of trimethylaluminum for the synthesis. Also, another synthesis technique using a silylating agent is known from Tetrahedron Lett., 1991, 32, 3407, which reports the use of trimethylsilyl chloride for the synthesis. However, in these techniques, the silylating agent is used for the protection of other functional groups and does not appear to enhance the synthesis reaction because the esters to be amidated are reactive enough to easily react with the amines in the absence of the silylating agent. It is therefore impossible to predict from these techniques that the silylating agent enhances the amidation reaction of less reactive esters. Still another technique using tin bishexamethylsilylamide is known from J. Org. Chem., 1992, 57, 6101. However, this technique is based on a concept distinct from that of the synthesis reaction under consideration because the active species is tin.
These conventional techniques require the use of highly reactive metal compounds and/or extreme reaction conditions for the direct synthesis of nitrogen-containing compounds (e.g., isothioureas, guanidines, amidines, amides) from amines. Such conventional techniques are therefore unable to have a wide range of applications and have been unsuitable for large-scale synthesis in terms of running costs, energy consumption and environmental impact. In view of the foregoing, there has been a demand to develop a preparation method that is available for a wider range of applications and that allows the efficient preparation of nitrogen-containing compounds including isothioureas, guanidines, amidines and amides under mild reaction conditions.
DISCLOSURE OF THE INVENTION
As a result of our research efforts directed to overcoming the problems stated above, we found that the use of a silylating agent for catalyzing the reactions between NH group-containing compounds (e.g., amines) and thiocyanates, cyanamides, nitrites or esters enabled the direct and efficient synthesis of nitrogen-containing compounds of interest under mild reaction conditions. We also found that this synthesis technique using a silylating agent had a wide range of applications and was suitable for large-scale synthesis. The present invention has been accomplished on the basis of these findings.
In short, the present invention provides a method for preparing isothioureas, guanidines, amidines or amides, which comprises reacting a NH group-containing compound with a compound selected from the group consisting of thiocyanates, cyanamides, nitrites and esters (excluding highly reactive esters) in the presence of a silylating agent.
Also, the present invention provides a method for preparing isothioureas and/or tautomers thereof, in which a NH group-containing compound of general formula (I-A):
R
1a
R
2a
NH  (I-A)
wherein
R
1a
and R
2a
, which are the same or different, each represent a hydrogen atom or an optionally substituted monovalent hydrocarbon residue, or R
1a
R
2a
N represents an optionally substituted monovalent cyclic hydrocarbon residue,
is reacted with a thiocyanate compound of general formula (II-A):
R
3a
SCN  (II-A)
wherein
R
3a
, which is the same or different, represents a hydrogen atom or an optionally substituted monovalent hydrocarbon residue,
in the presence of a silylating agent and, if necessary, in the presence of an acid and/or a base to give an isothiourea compound of general formula (III-A) and/or a tautomer thereof:
wherein
R
1a
, R
2a
and R
3a
are as defined above.
Further, the present invention provides a method for preparing guanidines and/or tautomers thereof, in which a NH group-containing compound of general formula (I-B):
R
1b
R
2b
NH  (I-B)
wherein
R
1b
and R
2b
, which are the same or different, each represent a hydrogen atom or an optionally substituted monovalent hydrocarbon residue, or R
1b
R
2b
N represents an optionally substituted monovalent cyclic hydrocarbon residue,
is reacted with a cyanamide compound of general formula (II-B):
R
3b
R
4b
NCN  (II-B)
wherein
R
3b
and R
4b
, which are the same or different, each represent a hydrogen atom or an optionally substituted monovalent hydrocarbon residue, or R
3b
R
4b
N represents an optionally substituted monovalent cyclic hydrocarbon residue,
in the presence of a silylating agent and, if necessary, in the presence of an acid and/or a base to give a guanidine compound of general formula (III-B) and/or a tautomer thereof:
wherein
R
1b
, R
2b
, R
3b
and R
4b
are as defined above.
In addition, the present invention provides a method for preparing amidines and/or tautomers thereof, in which a NH group-containing compound of general formula (I-C):
R
1c
R
2c
NH  (I-C)
wherein
R
1c
and R
2c
, which are the same or different, each represent a hydrogen atom or an optionally substituted monovalent hydrocarbon residue, or R
1c
R
2c
N represents an optionally substituted monovalent cyclic hydrocarbon residue,
is reacted with a nitrile compound of general formula (II-C):
R
3c
CN  (II-C)
wherein
R
3c
represents a hydrogen atom or an optionally substituted monovalent hydrocarbon residue,
in the presence of a silylating agent and, if necessary, in the presence of an acid and/or a base to give an amidine compound of general formula (III-C) and/or a tautomer thereof:
wherein
R
1c
, R
2c
and R
3c
are as defined above.
Furthermore, the present invention provides a method for preparing amides, in which a NH group-containing compound of general formula (I-D):
R
1d
R
2d
NH  (I-D)
wherein
R
1d
and R
2d
, which are the same or different, each represent a hydrogen atom or an optionally substituted monovalent hydrocarbon residue, or R
1d
R
2d
N represents an optionally substituted monovalent cyclic hydrocarbon residue,
is reacted with an ester compound (excluding highly reactive esters) of general formula (II-D):
R
3d
CO
2
R
4d
  (II-D)
wherein
R
3d
represents a hydrogen atom or an optionally substituted monovalent hydrocarbon residue, R
4d
represents a hydrogen atom, an optionally substituted monovalent hydrocarbon residue or a substituted silyl group, or R
3d
CO
2
R
4d
represents an optionally substituted cyclic hydrocarbon,
in the presence of a silylating agent and, if necessary, in the presence of an acid and/or a base to give an amide compound of general formula (III-D):
wherein
R
1d
, R
2d
and R
3d
are as defined above.
BEST MODE FOR CARRYING OUT THE INVENTION
The method of the present invention can be applied where NH group-containing compounds are reacted with thiocyanates, cyanamides, nitriles or esters to synthesize nitrogen-containing addition or substitution products thereof.
As used herein, a NH group-containing compound literally refers to any compound containing NH, including a linear or cyclic primary amine, a linear or cyclic secondary amine and a linear or cyclic imide.
As used herein, thiocyanates, cyanamides, nitrites and esters are intend

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