Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1998-02-26
2001-05-22
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S250000, C564S251000, C564S389000, C564S391000, C564S405000, C564S407000
Reexamination Certificate
active
06235936
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to improved methods for preparing aryl hydrazines, aryl hydrazones, O-aryl hydroxylamines, N-aryl hydroxylamines, O-aryl oximes and the like which are useful intermediates and end products in pharmaceutical and agricultural applications. Certain products of the present invention are utilized in a novel entry into the classical Fischer indole synthesis.
Despite the recent successes with palladium-catalyzed cross-coupling reactions of Ar-X with amines, comparable couplings of aryl halides with hydrazines and the like have not been reported. Existing methods for the conversion of Ar-X to the corresponding aryl hydrazines often require harsh or restrictive reaction conditions and/or the presence of activating groups on the aromatic ring.
Thus there remains a need for an effective method of preparing a wide range of aryl hydrazines and the like under mild conditions and in high yields. There is a further need for an efficient catalytic system with high efficiencies and turnover numbers for the synthesis of these compounds.
SUMMARY OF THE INVENTION
The present invention provides general and attractive routes to a wide range of aryl hydrazines, aryl hydrazones, O-aryl hydroxylamines, N-aryl hydroxylamines, O-aryl oximes and the like. The methods provide several improvements over methods known heretofore, namely, the efficient synthesis of these compounds under mild conditions and in high yields. In particular, the method of the invention may be used in coupling reactions between aryl halides or sulfonates and ketone or aldehyde hydrazones; the products of these coupling reactions provide indoles via the Fischer indole synthesis. In other aspects of the invention, the invention provides a means of synthesizing combinatorial libraries of indoles, carbazoles and the like.
DETAILED DESCRIPTION OF THE INVENTION
Overview
In one aspect of the invention, an aryl hydrazine is prepared by reacting hydrazine, or a substituted hydrazine, or a hydrazide salt, with an activated aromatic compound in the presence of a base and a metal catalyst that includes a Group VIII metal atom such as iron, cobalt, nickel, ruthenium, rhodium, palladium, iridium and platinum; Group 10 metals—platinum, palladium and nickel—are the most preferred metals. The activated aromatic compound comprises an activated substituent, X, which generally is selected from the group comprising halides and sulfonate esters. When the reaction takes place using an hydrazide salt, an additional base may not be required.
In preferred embodiments, the subject synthetic reaction can be characterized by the general reaction scheme shown below:
wherein
Ar represents an aromatic group (which may be furthered substituted beyond X);
X represents an activated group (such as a halide or a sulfonate), which can be replaced by a nucleophilic nitrogen in a transition metal-catalyzed arylation reaction;
Y represents NR
2
, OR, N═CR
2
, N(R)S(O)
2
R, or N(R)C(O)NR
2
; R represents independently for each occurrence, as valence and stability permit, H, a substituted or unsubstituted alkyl or alkenyl moiety, a formyl, acyl, or sulfonyl moiety, or —(CH
2
)
m
—R
8
,
R
8
represents independently for each occurrence a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and
m is an integer in the range 0 to 8 inclusive.
In additional preferred embodiments, the subject synthetic reaction can be characterized by the general reaction scheme shown below:
wherein
Ar represents an aromatic group (which may be furthered substituted beyond X);
X represents an activated group (such as a halide or a sulfonate), which can be replaced by a nucleophilic nitrogen in a transition metal-catalyzed arylation reaction;
Y represents O, S, or Se;
R independently for each occurrence is absent or represents, as valence and stability permit, H, a substituted or unsubstituted alkyl or alkenyl moiety, an alkylidene moiety, a formyl, acyl, or sulfonyl moiety, or —(CH
2
)
m
—R
8
,
R
8
represents independently for each occurrence a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and
m is an integer in the range 0 to 8 inclusive.
In further preferred embodiments, the subject reaction may be an intramolecular reaction. In this instance, it will be realized that, with reference to Scheme 1, YNHR is covalently attached to Ar via T which represents a tether between Ar and Y. The intramolecular reaction results in a product containing at least one more ring than the substrate and said reaction can be represented as follows in Scheme 3:
wherein
Ar represents an aromatic group (which may be furthered substituted beyond X and T—Y—NHR);
X represents an activated group (such as a halide or a sulfonate), which can be replaced by a nucleophilic nitrogen in a transition metal-catalyzed arylation reaction;
Y represents NR, O, sp
2
-hybridized N in a &pgr;-bond to T, NS(O)
2
R, or NC(O)NR
2
;
T represents a covalent tether connecting Y and Ar, said tether comprising between 0 and 4 backbone atoms; the backbone of said tether may comprise a &pgr;-bond, provided that the configuration of said &pgr;-bond is such that the described intramolecular reaction is geometrically feasible, or that said &pgr;-bond can adopt a configuration under the reaction conditions that renders the intramolecular reaction geometrically feasible; said tether additionally may itself be either unsubstituted or bear any number of substituents of any type permitted by stability and the rules of valence;
R independently for each occurrence represents, as valence and stability permit, H, a substituted or unsubstituted alkyl or alkenyl moiety, a formyl, acyl, or sulfonyl moiety, or —(CH
2
)
m
—R
8
;
R
8
represents independently for each occurrence a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and m is an integer in the range 0 to 8 inclusive.
In additional preferred embodiments, the subject reaction may be another form of intramolecular reaction. In this instance, it will be realized that, with reference to Scheme 2, N(R)YH is covalently attached to Ar via T which represents a tether between Ar and N. The intramolecular reaction results in a product containing at least one more ring than the substrate and said reaction can be represented as follows in Scheme 4:
wherein
Ar represents an aromatic group (which may be furthered substituted beyond X and T—NR—YH);
X represents an activated group (such as a halide or a sulfonate), which can be replaced by a nucleophilic nitrogen in a transition metal-catalyzed arylation reaction;
Y represents O, S, or Se;
T represents a covalent tether connecting NR and Ar, said tether comprising between 0 and 4 backbone atoms; the backbone of said tether may comprise a &pgr;-bond, provided that the configuration of said &pgr;-bond is such that the described intramolecular reaction is geometrically feasible, or that said &pgr;-bond can adopt a configuration under the reaction conditions that renders the intramolecular reaction geometrically feasible; said tether additionally may itself be either unsubstituted or bear any number of substituents of any type permitted by stability and the rules of valence;
R represents independently for each occurrence, as valence and stability permit, H, a substituted or unsubstituted alkyl or alkenyl moiety, a formyl, acyl, or sulfonyl moiety, or —(CH
2
)
m
—R
8
;
R
8
represents independently for each occurrence a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and
m is an integer in the range 0 to 8 inclusive.
In another embodiment, the subject synthetic reaction can be characterized by the general reaction scheme shown below in Scheme 5:
wherein
X represents an activated group (such as a halide or a sulfonate), which can be replaced by a nucleophilic nitrogen in a transition metal-catalyzed vinylation reaction;
Y represents NR
2
, OR, N═CR
2
, N(R)S(O)
2
R, or N(R)C(O)NR
2
;
R represents independently for each occurrence, as valence and stabilit
Buchwald Stephen L.
Geis Oliver Fabian
Wagaw Seble
Foley Hoag & Eliot LLP
Gordon Dana M.
Massachusetts Institute of Technology
Wilson James O.
LandOfFree
Metal-catalyzed arylations of hydrazines, hydrazones, and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Metal-catalyzed arylations of hydrazines, hydrazones, and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Metal-catalyzed arylations of hydrazines, hydrazones, and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2513646