CA2298595A1 - Process for converting propargylic amine-n-oxides to enaminones - Google Patents

Abstract

This invention concerns the use of a hydroxylic solvent in the preparation of enaminones from the corresponding amine N-oxides or propargylic amines via the general process outlined above (A).

Description

-I-~$OCES~ FOR CONVERTING PROPARGYLIC AMINE-N-OXIDES TO
NAMINQNES
This invention relates to a process for the production of enaminones from propargylic amine N-oxides. More particularly, this invention relates to a process for preparing amine N-oxides from corresponding propargylic amines using conventional oxidative methods and forming enaminones from the amine N-oxides by exposure to hydroxylic solvents in the presence or absence of metal catalysts with or without heating.
BackEround of the Invention Enaminones are versatile synthetic intermediates that are easily converted into a wide variety of functional groups, including (but not limited to) (3-aminoketones, (3-hydroxyketones, alkyl-substituted enones, and numerous heterocycles including isoxazoles, pyrazoles, pyrimidines, pyridines and thiophenes. Enaminones are oftimes used in the production of compounds of commercial importance (pharmaceuticals, insecticides, dyestuffs, etc.).
Enaminones can be synthesized by a variety of methods including the reaction of an amine with a I ,3-diketone, a 3-keto ester, a vinylogous ester, a vinylogous acid chloride, a ~3-dialkoxy ketone, a (3-cyanovinyl ketone, an acetylenic ketone, by the condensation of a ketone with N,N-dimethylformamide acetal, by the acylation of enamines, by reaction of ketene with enamines, by reaction of oxime sulfonates with silyl enol ethers, by the palladium assisted amination of an olefin, by the palladium catalyzed dehydrogenation of a ~3-amino ketone, or by the Mannich reaction of a ketone with a secondary amine and an orthoester. The preparation and use of enaminones has been the subject of two reviews: Greenhill, J.V. Chem. Soc. Rev. 1977, 6, 277;
Kucklaender, U. "Enaminones as Synthons", in Chemis r of Enaminec. Rappoport, Ed., Vol. I, pp. 523-636, Chichester, UK: Wiley [1994].
Functionalized propargylic amines can be conveniently prepared by the copper-catalyzed Mannich reaction of terminal acetylenes with formaldehyde and amines (Mannich, Che . Ber. 1933, b6, 418) or, in the case of 3-aryl or 3-vinyl substituted prop-2-ynyl amines, by palladium-catalyzed couplings of 1-amino-prop-2-ynes with aryl or vinyl halides or triflates (Sanogashira, et.al. Tetrahedron L.ett.
1975, 4467;
Unroe, et.al. _Sy,~, esis 1987, 981; Stille, J.K. Angew. Chem.. Intl. Ed.
Engi. 1986, 25, 508; Scott, et.al. Acc. Chem. Res. 1988, 21, 47; Kalinin, V.N. S n is 1992, 413; Ritter,K. a is 1993, 735). These amines can be easily converted into the respective amine N-oxides by any of a number of standard oxidative procedures (as discussed in Albini, A. S_3rnthesis 1993, 263) or with dioxirane reagents (reviewed in Murray, R.W. Chem. Rev. 1989, 1187).
Although the precise mechanism by which a propargylic amine N-oxide is converted into an enaminone product has not been rigorously determined, it likely resembles two known processes; the thermal [2,3]-sigmatropic rearrangement of propargylic amine N-oxides and the conversion of certain isoxazoles into enaminones.
A proposed mechanism is shown below:
r~
R~N;.Me ~ R--~+.Me -~ R / +.Me O' Me O_~ O N
Me O O
H+
Me2N
NMe2 The thermal conversion by [2,3]-sigmatropic rearrangement of propargylic amine N-oxides to hydroxyl amine O-allenyl ethers is a known reaction (Equation 1, below; Craig, et.al. Tetrahedron Lett. 1979, 4025; Hallstrom, et.al.
Tetrahedron Lett.
1980, 667; Khuthier, A-H, et.al. J Chem Soc Chem Commun. 1979, 9). In each instance where this [2,3]-sigmatropic rearrangement has been reported, the reactions were performed either neat or in aprotic solvents (e.g. dimethylformamide, diethyl ether, tetrahydrofuran, carbon tetrachloride) and the formation of enaminone products has not been disclosed.

la ati~ on 1.
RAN+.Me R~N~Me Me N
Me Me Substituted enaminones can result from the hydrolytic breakdown of certain substituted isoxazolines (Equation 2, below), as described by Liguori, et.al.
Tetrahe n 1988, 44, 1255. The isoxazolines of Liguori et al. were prepared by the 1,3-dipolar cycloaddition reaction of C-benzoyl-N-phenylnitrone with alkynes (formed as a mixture with its regioisomer). It appears that the substitution pattern about the isoxazoline ring influences the outcome of this hydrolytic reaction. This process is an isolated example of enaminone formation from isoxazolines and is not a generally applicable nor synthetically useful transformation.
>~uation 2.
O O
O R,.
R" ~ Ph H30+
O_N, ~ PhHN R' Ph O
The present invention provides a novel synthesis of enaminones from propargylic amine N-oxides upon exposure to hydroxylic solvents. This new method of enaminone synthesis provides a convenient alternative to existing methods and further extends the rage of starting materials that can be converted into enaminone products.
Summary of the Invention This invention provides a novel process for the synthesis of enaminones of Formula (I):

WO 99/06351 ~ PCT/US98/15391 - _4-N~ R2 i (t) R3 wherein:
X is selected from the group of H, C,-C6 straight chain alkyl, C~ C6 branched chain alkyl, C3-C, cycloalkyl, -CHz phenyl, or -CHI-substituted phenyl;
R, is selected from the group of hydrogen, C~-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, phenyl, substituted phenyl, -CHZ phenyl, or -CHZ-substituted phenyl or a group of the formulae:
R~2, or ~r R 12 OH
the C3-C7 cycloalkyl groups being optionally substituted by from 1 to 3 groups independently selected from RS-Rg;
R, and R3 are independently selected from the group of C,-C6 straight chain alkyl, C~-C6 branched chain alkyl, C3-C7 cycloalkyl, or -CH2-phenyl;
R~ and R3 may also be joined to form a ring of from three to six atoms. Thus, for example, cyclic versions of -NR2R~ include, but are not limited to, the following:
,- , *rB

R4 and R4, are independently selected from the group of hydrogen, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, -OR", -NR"R,3, -NR"C(O)OR,o, -NR,~C(O)R,o, -OC(O)R,o, -OC(O)OR,a, or -OC(O)NHR,o;
Substituted phenyl and -CHz substituted phenyl are, respectively:
Rs s Rs s R~ and - CH2 ~ ~ R7 Rs Re Rs Ra RS-R9 are independently selected from the group of hydrogen, halogen, trifluoromethyl, C2-C6 perfluoroalkyl, C,-C6 straight chain alkyl, C3-C6 branched chain alkyl, C~-C~ cycloalkyl, -CN, -NOz, -OR", -COZR", -NR"R,3, -NR"C(O)OR"., -NR"C(O)R",, -OC(O)R", -OC(O)OR", or OC(O)NHR" ;
R,o is selected from the group of hydrogen, C,-C,o straight chain alkyl, C3-C,o branched chain alkyl, C3-C~ cycloalkyl, phenyl, or -CHZ phenyl;
R" and R". are independently selected from the group of hydrogen, C,-C6 straight chain alkyl, C3-C6 branched chain alkyl, C~-C~ cycloalkyl, phenyl, or -CH,_ phenyl;
R,z and R,2. are independently selected from the group of hydrogen, C,-C6 straight chain alkyl, C3-C6 branched chain alkyl, C~-C~ cycloalkyl, phenyl, substituted phenyl, -CHZ phenyl or -CH2 substituted phenyl, the C3-C7 cycloalkyl groups being optionally substituted by from 1 to 3 groups independently selected from RS to Rg;
with a proviso that both Rl~ and R,2. in the moiety:
R12~
OH

are not phenyl or substituted phenyl;
R,Z and R,2. may also optionally be taken together with their associated carbon to form a carbocyclic ring of from three to seven carbon atoms;
R,3 is an amino-protecting group used to protect the moiety NR" herein which may be any group known to be useful to protect amino groups under the conditions contemplated as outlined in Greene, Protective Grou in Org na-is SS nthesis Volume 2, Chapter 7, 1991, and references therein. Examples of such useful amino protecting groups include but are not limted to:
(a) acyl type protective groups such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, o-nitrophenoxyacetyl, sec-butyryl, pivaloyl- (also known as tent-butyryl), cyclopropanoyl, benzoyl, o-nitrobenzoyl, a-chlorobutyryl, or the like; or (b) sulfonyl type protecting groups such as benzenesulfonyl, toluenesulfonyl (tosyl), p-methoxybenzenesulfonyl, trifluoromethylsulfonyl, or the like; or (c) sulfenyl type protecting groups such as benznesulfenyl, o-nitrobenzenesulfenyl, pentachlorobenzenesulfenyl, and the like; or (d) urethane type protecting groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, tent-butyloxycarbonyl, tert-amyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, allyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, and the like.
The moiety NR"R" may also be optionally concatentated together or exist as a cyclic imide of the formula:
O
-N
O
the process comprising converting an anune N-oxide of the formula (I>]:
*rB

_ _7_ X
R' N+~R2 O' \

(II) to the enaminone by treating the amine N-oxide with a hydroxylic solvent.
It is understood herein that the definitions of the compounds of formula (I), above and below, when X, R,, Rz, R" R4, R~,, Rs, R6, R~ R8, R9, R,o, R", R"., Riz, R,z, or R,~ contain asymmetric carbons, encompass all possible stereoisomers and mixtures thereof discussed below. In particular, it encompass any optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R
and S
stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers may be obtained in pure form by standard separation techniques.
It is also understood herein that the definitions of X, R,, Rz, R3, R4, R4., R5, Rb, R.~ R8, Rg, R,o, R~~, R~~., Riz, R~z. or R,~ of the compounds of formula (I), above and below, encompasses all possible regioisomers, and mixtures thereof discussed below. Such regioisomers may be obtained pure by standard separation methods known to those skilled in the art.
Among the subgroups of the groups disclosed herein are those in which R,z and R~z. are selected from non-substituted phenyl or benzyl. Another subgroup among those disclosed herein are those in which the -CHz-phenyl groups symbolized by X are unsubstituted.
A preferred process within the scope of this invention provides for the synthesis of enaminones of Formula (I):

O
R~ I
'N.R2 (I) wherein R~ is selected from the group of C,-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, phenyl, -CHZ phenyl, or the moieties:
RB Re or or R, ' Rs Rs R, R~ and R3 are independently selected from the group of C,-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, or -CHz phenyl. R2 and R3 may also be joined to form a ring of from three to six atoms to create cyclic versions of -NRZR" which include, but are not limited to, the following:
-N~ -N~ -~ -~ or -' R5, R6 R8, R9 are independently selected from the group of hydrogen, halogen, trifluoromethyl, C2-C6 perfluoroalkyl, C,-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C~ cycloalkyl, -CN, -NO" -OR", -COZR", -NR"R,3, -NR"C(O)OR"., -NR"C(O)R"., -OC(O)R", -OC(O)OR", or -OC(O)NHR" ;
R" and R". are selected from the group of hydrogen, CI-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C~ cycloalkyl, phenyl, or -CHZ phenyl;

R,~ is selected from the group of hydrogen, C~-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, phenyl, or an amino-protecting group used to transiently protect the moiety NR" herein which may be any group known to be useful to protect amino groups under the conditions contemplated as outlined in Greene, Protective Grou s in Organic Synthecic Volume 2, Chapter 7, 1991, and references therein. Examples of such useful amino protecting groups include, but are not limted to, those described above;
the process comprising converting an amine N-oxide of the formula (II):
R' N+~ R2 -O' \

(u) to the enan>inone by treating the amine N-oxide with a hydroxylic solvent.
Another preferred process within the scope of this invention provides for the synthesis of enaminones of Formula (I):
O
R' N.R2 (I) wherein R, is the moiety:

Rs ~ Rs Rs ~ Rs R2 and R3 are independently is selected from the group of C,-C6 straight chain alkyl, C;-C6 branched chain alkyl, -CHZ- phenyl or C3-C~ cycloalkyl. R2 and R3 may also be joined to form a ring of from three to six atoms. Thus, for example, cyclic versions of -NRZR3 include but are not limited to the following:
N~ ~ N " , , , R5, R6 R8, Rg are independently selected from the group of hydrogen, halogen, trifluoromethyl, C2-C6 perfluoroalkyl, C,-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C~ cycloalkyl, -CN, -NO:, -OR", -COZR", -NR"R,a, -NR"C(O)OR"., -NR"C(O)R"., -OC(O)R", -OC(O)OR", or -OC(O)NHR";
R" and R". are selected from the group of hydrogen, C~-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C~ cycloalkyl, phenyl, or -CHZ phenyl;
R" is selected from the group of hydrogen, C,-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, phenyl, or an amino-protecting group used to transiently protect the moiety NR" herein which may be any group known to be useful to protect amino groups under the conditions contemplated as outlined in Greene, Protective Groups in Or anic y t c~c Volume 2, Chapter 7, 1991, and references therein. Examples of such useful amino protecting groups include those described above.
The moiety NR"R,3 may also optionally exist as a cyclic imide of the formula:
_N
O
the process comprising converting an amine N-oxide of the formula (II):

R~ _ . N+~ R2 O \

(II) to the enaminone by treating the amine N-oxide with a hydroxylic solvent.
A further preferred process within the scope of this invention provides for the synthesis of enaminones of Formula (I):
O
R~
N.R2 (I) wherein R1 is the moiety:
R~~,~ /R,a RB ~ Re RS _Rs I
R2 and R3 are independently selected from the group of C,-C6 straight chain alkyl, C3-C6 branched chain alkyl, -CHZ phenyl or C;-C~ cycloalkyl. R2 and R3 may also be joined to form a ring of from three to six atoms. Thus, for example, cyclic versions of -NRZR3 include but are not limited to the following:
-N~ ~ -N " ~ -~ , -N~ ~ or -R5, R6 R8, R9 are independently selected from the group of hydrogen, halogen, trifluoromethyl, C2-C6 perfluoroalkyl, C~-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, -CN, -N02, -OR", -COZR", -NR"R", -NR"C(O)OR",, -NR"C(O)R",, -OC(O)R", -OC(O)OR", or -OC(O)NHR";
R" and R", are independently selected from the group of hydrogen, C,-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, phenyl, or -CH,-phenyl;
R,3 is selected from the group of hydrogen, C,-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, phenyl, or an amino-protecting group used to transiently protect the moiety NR" herein which may be any group known to be useful to protect amino groups under the conditions contemplated as outlined in Greene, Protective Grou s in Org n;~ y t is volume 2, Chapter 7, 1991, and references therein. Examples of such useful amino protecting groups include, but are not limted to, those described above.
The moiety NR"R,3 may also optionally exist as a cyclic imide of the formula:
O
-N I \
O
the process comprising converting an amine N-oxide of the formula (II):
-O' \
(II) to the enaminone by treating the amine N-oxide with a hydroxylic solvent.

Another preferred process of this invention provides for synthesis of enaminones of the forumula:
O
R' I
N.R2 i (t) Rs wherein:
X is selected from the group of H, C,-C6 straight chain alkyl, C~-C6 branched chain alkyl, C~-C~ cycloalkyl, phenyl, or -CHZ phenyl;
R~ is selected from the group of hydrogen, C,-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, phenyl, substituted phenyl, -CHZ-phenyl, or -CH2-substituted phenyl, the substituents of which are as described above, or a group of the formulae:
12' OH
R2 and R~ are independently is selected from the group of C,-C6 straight chain alkyl, C3-C6 branched chain alkyl, or C3-C7 cycloalkyl. R, and R3 may also be joined to form a ring of from three to six atoms. Thus, for example, cyclic versions of -NRzR; include, but are not limited to, the following:
-N~ ~ -N " , -~ -~ , or -' R,Z and R,2. are independently selected from the group of hydrogen, C~-C6 straight chain alkyl, C3-C6 branched chain alkyl, C~-C~ cycloalkyl, phenyl, or -CHZ-phenyl, the C3-C7 cycloalkyl, phenyl, and -CHz-phenyl being optionally substituted as described in the groups above;
with a proviso that R,2 and R,~. are not both phenyl or substituted phenyl;

WO 99/Ob351 PCT/US9$/15391 the process comprising converting an amine N-oxide of the formula (II):
X
R' N+i R2 O' \

(II) to the enaminone (I) by treating the amine N-oxide (II) with a hydroxylic solvent.
The conversion of the amine N-oxide into an enaminone may be accomplished by a number of embodiments within the scope of this invention. The amine N-oxide may be introduced into a suitable hydroxylic solvent, preferably with stirring, at or between about room or ambient temperature and about the reflux temperature of the solvent. In other instances the introduction of the amine N-oxide to a hydroxylic solvent, preferably with stirring, may be accomplished in the presence of an acceptable catalyst, such as a palladium(II) catalyst or a copper (I) catalyst, at or between room temperature and the reflux temperature of the solvent.
In instances where a biphasic solvent system is desirable, the amine N-oxide may be converted into the enaminone in a biphasic mixture of water and a water immiscible solvent, such as dichloromethane, in the presence or absence of a suitable catalyst, such as a palladium(II) catalyst or a copper (I) catalyst, and a phase transfer catalyst, such as a quaternary ammonium salt, at or between ambient temperature and the reflux temperature of the organic solvent, preferably with stirring.
The amine N-oxides converted in this process may be formed by oxidizing an amine of the formula (III):
R
~~ R2 R3 (III) wherein X, R,, R2, and R3 are defined above, using any of a number of standard oxidative procedures (Albini, A. ~ is 1993, 263) or with dioxirane reagents (Murray, R.W. . Rev. 1989, 1187).
In another embodiment, this invention comprises a process for converting an amine of Formula (III) to an enaminone of Formula (I), the process comprising the steps of:
a) oxidizing the amine of Formula (III) to an amine N-oxide of Formula (II), which may be accomplished by conventional techniques; and b) converting the amine N-oxide of step a) to an enaminone of Formula (I}
by treating the amine N-oxide with a hydroxylic solvent in a manner described above.
The hydroxylic solvents useful with this invention may be defined as any solvent or combination of solvents composed of or containing water, any C,-C8 straight chain or branched chain alkyl alcohol, ethylene glycol, polyethylene glycol, 1,2-propylene diol, polypropylene glycol, glycerol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoroethanol, benzyl alcohol, phenol, or any equivalent solvent that contains one or more free hydroxyl (-OH) substituent(s) that is known to those skilled in the art.
Solvent systems containing one or more cosolvents, along with one or more solvents may be used for the processes of this invention. The cosolvents referred to herein may be defined as a diluent of the main solvents) and can be selected from:
hydrocarbons such as pentane, hexane or heptane; aromatic hydrocarbon such as benzene, toluene or xylene; ethers such as diethyl ether, tetrahydrofurn, dioxane or dimethoxy ethane; chlorinated hydrocarbons such as dichloromethane, chloroform, dichloroethane, or tetrachloroethane; or other common solvents such as ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethylsulfoxide, acetone, or the like.
The compounds of formula (III) above wherein R, is defined as:

WO 99/06351 PCT/US9$/15391 O OR1 ~
Rs ~ Re Rs ~ Rs wherein RZ, R3, R5, R6, R8, R9, and R" are as defined above, may be readily prepared from the corresponding aryl bromide, iodide, or triflate in a manner similar to that described in the literature (e.g. Sanogashira, et.al. Tetrahedron Lett. 1975, 4467;
Unroe, et.al. Synthesis-Stuttgart 1987, 981) and are readily converted by any of a number of standard oxidative methods (Albini, A. ,S~rnthesis 1993, 263) or by treatment with dioxirane reagents (Murray, R.W. them. Rev. 1989, 1187) to their respective N-oxides, which can then be converted by the processes described above to compounds of structural formula I. Such compounds are useful for the preparation of substances with vasopressin agonist activity as exemplified by compounds 10 and 11 as shown in Scheme I.
Scheme I

C02Me C02H C02Me CI
~ CI 1 ) g~ I ~ CI HC=CCH2NMe2, ~ / 1 ) MCPBA
2) MeOH i PdCl2(Ph3P)2, Cul, Br Br EtsN - ~ ( 2) MeOH, reflux NMe2 C02Me C02Me C02Me C02Me ~ CI NH NH I ~ CI NaH ~ ~ CI I ~ CI

i Mel O ~ NMe2 N i N ~ MeN
HN ~ MeN ~ N-Separation C02Me CI
N~
MeN

Scheme I (cont.) o~nne ozH oci w ~ w ~ w N~ I ~ soci2 I
MeOH
M N/~ M N/~ M N/~
6 8 g H N;
~ N ~ I ~ N ~
'N
H H
I
i O
C /
N;~n a Thus, the bromocarboxylic acid 1, is converted into the corresponding ester 2 by treating the carboxylic acid with thionyl chloride at temperatures ranging from ambient to the reflux temperature of the solvent, or with oxalyl chloride in an aprotic solvent such as dichloromethane or tetrahydrofuran in the presence of a catalytic amount of dimethylformamide at temperatures ranging from 0°C to 40°C
followed by the addition of methanol. The methylester of formula 2 is coupled with a dialkylamino propyne, preferably 1-dimethylamino propyne, in the presence of a catalyst such as bis(triphenylphosphine) palladium(II) chloride and copper(I) iodide in an organic base such as triethylamine as the solvent and at temperatures ranging from ambient to 80°C
essentially according to the procedures of Alarm et al. Tetrahedron Lett 1993, 34, 6403, and of Sanogashira et al. Tetrahedron Lei. 1975, 4467 to provide the substituted acetylene 3. The intermediate 3 is subsequently converted into its N-oxide by treatment with an oxidizing agent using any of a number of standard oxidative procedures (Albini, A. S~rnthesis 1993, 263) or with dioxirane reagents (Murray, R.W.
Chem ev 1989, 1187), in an aprotic organic solvent such as dichloromethane at temperatures below ambient. The intermediate N-oxide is not isolated but is rearranged in situ to an enone of formula 4 by heating in a hydroxylic solvent such as methanol or by using any of the procedures described herein.
Treatment of 4 with hydrazine in acetic acid at temperatures ranging from ambient to reflux temperature of the solvent leads to a compound of formula 5.
The heterocyclic nitrogen in compound 5 is allrylated by treatment with a strong base such as sodium or potassium hydride and methyl iodide in an aprotic organic solvent such as dimethylformamide or tetrahydrofuran at temperatures ranging from 0°C
to 80°C leading to a mixture of regioisomers 6 and 7. The major isomer, compound 6, is separated by means of chromatography andlor crystallization and subsequently hydrolyzed with an aqueous base such as sodium hydroxide in methanol (or lithium hydroxide in tetrahydrofuran) to the desired carboxylic acid of formula $.
The intermediate carboxylic acid $ is then converted into an acylating species, preferably an acid chloride (bromide or iodide) of formula 9 by procedures analogous to those described hereinbefore. The acylating agent 9 is then used to acylate a tricyclic benzodiazepine such as either 10,11-dihydro-SH-pyrrolo[2,1-c][1,4]benzodiazepine (Albright etal. US patent 5,536,718 July 16, 1996) or 6,11-dihydro-SH-pyrido{2,3-b][1,5]benzodiazepine to afford compounds 10 and 11, respectively.
The compounds of formula III wherein R, is defined as:
R»N/Ria R6 ~ Ra Rs ~ Rs wherein R2, R3, R5, R6, Rg, R9, R" and R". are as defined above, may be readily prepared from the corresponding aryl bromide, iodide, or triflate in a manner similar to that described in the literature (e.g. Sanogashira, et.al. Tetrahedron Lett. 1975, 4467;
Unroe, et.al. S3rnthesis-Stuttg~ 1987, 981 ) and are readily converted by any of a number of standard oxidative methods (Albini, A. hg,~~,1993, 263) or by treatment with dioxirane reagents (Murray, R.W. Chem. Rev. 1989, 1187) to their respective N-oxides, which can then be converted by the processes described above to compounds of structural formula I. Such compounds are useful for the preparation of substances with vasopressin agonist activity as exemplified by compounds 10 and 11 as shown in Schemes I and II.
Scheme II.
NHBoc NH2 NHBoc B~ I ~ HC=CH2NMe2 I / 1 ) MCPBA
C ~ i-Pr2NEt C ~ PdCl2{Ph3P)2, Cul, C 2) MeOH, reflux I I Et3N
t2 i3 NMe2 NHBoc NHBoc NHBoc NHBoc I j NH2NHi I j NaH
C C CH31 C / + C
MeN
NMe2 H MeN N-16 ' 17 18 NHBoc I~
C ~ Separation MeN~ 17 Scheme II (coot.) HBoc NHiBoc H2 N-chloro-H2, \ CF3C02H ~ succinimide c ~ 1 o°i° Pa/c EtOH
N~ ~
MeN ~ M ~ ~ M N

CO~H

C ~ 1) NaNOz, HCI CI ~ Hue, C ~ HzS04, --..
2) CuCN i ~ DMSO, K2C03 I ~ NaN02, H20 MeN
MeN MeN
MeN

The enaminone 15 (and thence compounds 10 and 11 ) may also be prepared utilizing this novel chemistry starting from 3-chloro-4-iodo aniline (12) through the sequence of steps shown in Scheme II. The aniline derivative 12 is treated with di-tert-butyl dicarbonate and diisopropylethylamine in refluxing tetrahydrofuran to afford compound 13. The aryliodide derivative of formula 13 is coupled with a dialkylamino propyne, preferably 1-dimethylamino propyne, in the presence of a catalyst such as bis(triphenylphosphine) palladium(II) chloride and copper(I) iodide in an organic base such as triethylamine as the solvent and at temperatures ranging from ambient to 80°C
essentially according to the procedures of Alarm et al., Tetrahedron Lett., 34, 6403 (1993), and of Sanogashira et al., Tetrahedrpn Lett., 4467 (1975) to provide the substituted acetylene 14. The intermediate 14 is subsequently converted into its N-oxide by treatment with an oxidizing agent using any of a number of standard oxidative procedures (Albini, A.~r is 263 ( i 993) or with dioxirane reagents (Murray, R.W., Chem. Rev. 1187 (1989), in an aprotic organic solvent such as dichloromethane at temperatures below ambient. The intermediate N-oxide is not isolated but is rearranged in situ to an enaminone of formula 15 by heating in a hydroxylic solvent such as methanol or by using any of the procedures described herein.

Treatment of 15 with hydrazine in acetic acid at temperatures ranging from ambient to reflex temperature of the solvent leads to a compound of formula 16. The heterocyclic nitrogen in compound 16 is alkylated by treatment with a strong base such as sodium or potassium hydride and methyl iodide in ati aprotic organic solvent such as dimethylformamide or tetrahydrofuran at temperatures ranging from 0°C
to 80°C leading to a mixture of regioisomers 17 and 18. The major isomer, compound 17, may be separated by means of chromatography and crystallization.
IO The substituted pyrazole derivative 17 may be dehalogenated by hydrogenation over palladium catalysts in alcohol solvents (Weizmann, A. J. Am. Chem. Soc.
1949, 71, 4154), to afford 19 and then Boc-deprotected by treatment with trifluoroacetic acid to give the pyrazoloaniline 20. This aniline derivative 20 may be chlorinated by treatment with N-chlorosuccinimide (Neale, R.S. et.al. J. Org. Chem. 1964, 29, 3390) to yield compound 21 which is then subjected to the Sandmeyer reaction (Clarke, H.T.
et.al. Organic Synthesis. Vol. I. 1941, 514) to provide nitrite 22.
Compound 22 may be converted to the carboxylic acid 8 by sequential treatment with basic hydroperoxide (Katritzky, A.R. et.al. n he 's 1989, 949) followed by hydrolysis of the resulting amide 23 by treatment with dilute sulfuric acid and sodium nitrite (Hales, N.J. et aL, Tetrahedron 1995, 51, 7403). The conversion of carboxylic acid 8 to the vasopressin agonists 10 and 11 is shown in Scheme I
above.

Structures 10 and 11 are non-peptide mimics of vasopressin (antidiuretic hormone, ADH), a nine amino acid peptide hormone and neurotransmitter.
Vasopressin plays a vital role in the body's conservation of water by concentrating the urine at the site of the collecting ducts of the kidney. The collecting ducts of the kidney are relatively impermeable to water in the absence of vasopressin at its receptors and therefore, the hypotonic fluid formed after filtering through the glomeruli, passing the proximal convoluted tubules, the loops of Henle, and the distal convoluted tubules, will be excreted as dilute urine. However, during dehydration, volume depletion or blood loss, vasopressin is released from the pituitary and activates the vasopressin VZ
receptors in the collecting ducts of the kidney rendering the ducts very permeable to water, and hence water is reabsorbed and a concentrated urine is excreted. In patients and animals with central or neurogenic diabetes insipidus, the synthesis of vasopressin in the pituitary is defective and therefore, they produce no or very little vasopressin, but their vasopressin receptors in the kidneys are normal. While they remain very sensitive to the action of vasopressin and vasopressin V2 agonists, little or no vasopressin is produced. Because they cannot concentrate the urine, they may produce as high as 10 times the urine volume of their healthy counterparts. Vasopressin and desmopressin, which is a peptide analog of the natural vasopressin, are being used in patients with central diabetes insipidus. Vasopressin V2 agonists are also useful for the treatment of nocturnal enuresis, nocturia, urinary incontinence and temporary delay of urination whenever desirable.
The vasopressin-like compounds, prepared using the intermediates disclosed in this invention, posses therapeutic effects similar to vasopressin without the limitations associated with peptide derived drugs.
Compounds 10 (Example 22) and 11 (Example 23) of the present invention were tested for biological activity according to the following procedure:
Vasopressin V~ Agonist Effectc of Test Compoundc » Normat Conscious Water-Loaded Rats~
Male or female normotensive Sprague-Dawley rats (Charles River Laboratories, Inc., Kingston, NY) of 350-500 g body weight were supplied with standard rodent diet (Purina Rodent Lab. Chow 5001 ) and water ad libitum. On the day of test, rats were placed individually into metabolic cages equipped with devices to separate the feces from the urine and containers for collection of urine. Test compound or reference agent was given at an oral dose of 10 mg/kg in a volume of 10 ml /kg. The vehicle used was S 20% dimethylsulfoxide (DMSO) in 2.5% preboiled corn starch. Thirty minutes after dosing the test compound, rats were gavaged with water at 30 ml /kg into the stomach using a feeding needle. During the test, rats were not provided with water or food.
Urine was collected for four hours after dosing of the test compound. At the end of four hours, urine volume was measured. Urinary osmolality was determined using a Fiske One-Ten Osmometer (Fiske Associates, Norwood, MA, 02062) or an Advanced CRYOMATIC Osmometer, Model 3C2 (Advanced Instruments, Norwood, MA).
Determinations of Na+, Kt and Cl' ion were carried out using ion specific electrodes in a Beckman SYNCHRON EL-ISE Electrolyte System analyzer. The urinary osmolality should increase proportionally. In the screening test, two rats were used for each compound. If the difference in the urine volume of the two rats was greater than 50%, a third rat was used.
Compound # Example # Urine Volume Osmolality Rat Type ' ( % decrease)' Increase"
10 22 ?0% 325 % CD
11 23 80% 272% CD
°Percent decrease in urine volume vs. control at a dose of 10 mg per kg.
Osmolality increase expressedas percent of control at a dose of 10 mg per kg.
'R.at model used: Sprague-Dawley (CD).
The compounds wherein R, above in formula (III) is defined as:
O
R4, or Ra wherein Ra is hydrogen and RZ and R3 are defined as above, may be readily prepared from procedures outlined by Dickinson et al. U.S. Patent No. 3,354,178;

wherein R4 is hydrogen and RZ and R~ are also joined to form a pyrrolidine ring is readily obtained commercially as oxotremorine and, wherein R4 is defined as above but not hydrogen and R2 and R3 are defined as above, may be readily prepared from procedures outlined by Trybulski et al. U.S. Patents Nos. 5,550,257 and 4,937,235;
Reduction of compound 24 wherein R2, R3 and R4 are defined as above O O O O
R4 r~N_~N;R2 ~. R4 ~CN__~N,R2 with hydrogen in the presence of a transition metal catalyst such as palladium on carbon, platinum oxide or raney nickel in an alcohol solvent such as ethanol, or alternatively by Lewis acid assisted reduction by certain metal hydride reagents, such as by the exposure to boron trifloride etherate and lithium triethylborohydride in tetrahydrofuran at reduced temperatures (as per the methods of Wasserman and Chi, Tetrahedron Letters 1994, 35 (52), 9779), or by exposure to boron trifloride etherate and a copper hydride species generated from cuprous bromide dimethyl sulfide complex and lithium dimethoxyaluminium hydride (as per the methods of Commins and LaMunyon, Tetrahedron Letters 1989, 30 (38), 5053) produce compound 25.
Compounds of structure 25 are hydrolytic and possibly metabolic products of oxotremorine-like compounds (Lindeke, B. J. Pharm. Pharmac., 1972, 24, 25-31 ).
The compounds of formula (III) above wherein R, is defined as:

R~2~~.
OH
wherein R,Z and R,2. are defined above, may be readily prepared by addition of the lithium anion of a propargylic amine by methods known to those skilled in the art, or alternatively and when X as defined above is not H, by addition of the bis-lithium anion of a propargylic alcohol to a 1-(dialkylaminomethyl)benzotriazole (Katritzky, A.R.;

Gallos, J.K.; Yannakopoulou, K. Synthesis 1989, 31), and are readily converted by any of a number of standard oxidative methods (Albini, A. synthesis 1993, 263) or by treatment with dioxirane reagents (Murray, R.W. Chem. Rev. 1989, 1187) to their respective N-oxides, which can then be converted by the processes described above to ~ compounds of structural formula I. Such compounds are useful for the preparation of certain 3(2H)-furanone intermediates (by exposure to acidic conditions as demonstrated by Carpenter, B.K.; Clemens, K.E.; Schmidt, E.A.; Hoffmann, H.M.R. J. Am.
Chem. hoc. 1972, 94(17), 6213) which can be converted into compounds which possess anticholesteremic and antidiabetic properties as described in Felman, et.al. US
patent 5314913, May 24, 1994 as shown in Scheme III.
Scheme III
H3 CuCI Hs 1) n-BuLi, THF
OAc pyrrolidine N 2) PhCOCH3 1 ) MCPBA O
H
2) MeOH, reflux H3C
3) Amberlyst O

Thus, the propagylic amine 27 may be prepared by the copper-catalyzed displacement of the propargylic acetate 26 (which is readily prepared according to the methods of Clarke and Pinder, J. Chem. Soc. 1958, 1967) by pyrrolidine. The propargylic amine 27 may be mono-lithiated at the terminal position by treatment at temperatures below ambient, preferably about -78°C, in tetrahydrofuran with a slight molar excess of n-butyl lithium and then added to acetophenone to provide the propargylic amino alcohol 28. Intermediate 28 is subsequently converted into its N-oxide by treatment with an oxidizing agent using any of a number of standard oxidative procedures (Albini, A. S_yy~,1993, 263) or with dioxirane reagents (Murray, R.W.
Chem. Rev. 1989, 1187), in an aprotic organic solvent such as dichloromethane at temperatures below ambient. The intermediate N-oxide is not isolated but is rearranged in situ to an enone (which also need not be isolated) by heating in a hydroxylic solvent such as methanol or by using any of the procedures described herein. This enone is then treated in situ with an acid catalyst such as Amberlyst~ which completes the cyclization with loss of pyrrolidine to produce the substituted 3(2H)-furanone that has previously been converted into numerous substances with anticholesteremic and antidiabetic properties as described by Felman et.al. in U.S. Patent No.

5,314,913, issued May 24, 1994.
The process of the present invention will be further illustrated by the following non-limiting examples.

1-Dimethylamino-4-f 1-(3-~(Rl-O-octylcarbamoyl 2 oxo ~,vrrolidinvl] 2 butyne N-oxide To an ice cold solution of (R)-octylcarbamic acid-1-(4-(dimethylamino)-2-butynyl)-2-oxo-3-pyrrolidinyl ester (250 mg) in dichloromethane (6 ml) was added dropwise a solution of dimethyldioxirane in acetone (approximately 0.08 M, 9 ml}.
After the reaction was stirred at 0°C for 20 minutes, the solvent was removed under a gentle stream of argon. Trituration of the residue with diethyl ether gave the desired N-oxide as a white powder. MS(+ES), m/z: 368 (M+H)+.

1-Dimethylamino-4-[1-(3-(R)-hydroxy 2 oxo pYrrotidinyll 2 butyne N
o ide To an ice cold solution of {R)-1-(4-(dimethylamino)-2-butynyl)-3-hydroxy-2-pyrrolidinone {250 mg) in dichloromethane (8 ml) was added dropwise a solution of dimethyldioxirane in acetone (approximately 0.08 M, 17.8 ml). After the reaction was stirred at 0°C for 20 minutes, the solvent was removed under a gentle stream of argon to give the desired N-oxide as a yellow foam. MS(+ES), m/z: 213 (M+H)+.

(R1-Octy~carbamic acid-1-(4~dimetbylaminoZ-2-oxo-3-bute~vl~-2-oxo-3 pyrrolidin~e~~e_r A solution of 1-dimethylamino-4-(1-j3-(R)-O-octylcarbamoyl-2-oxo-pyrrolidinyl)-2-butyne N-oxide (25 mg) in methanol ( 1.5 ml) was heated to 60°C for 5 hours. The mixture was cooled and the solvent evaporated to dryness i,~.
vacuo. The residue was chromatographed over silica gel (5% methanol in dichloromethane was used as the eluant) to give upon evaporation of the solvent in vacuo the title compound as a colorless oil. MS(FAB), m/z: 368 (M+H)+.

(R)-1-f4-lDimethylamiyo~-oxo-3-butenyll-__ 3-hvdroxy~~y~rolidinone A solution of 1-dimethylamino-4-[1-(3-(R)-hydroxy-2-oxo-pyrrolidinyl]-2 butyne N-oxide (250 mg) in methanol (10 ml) was heated to 60°C for 6 hours. The mixture was cooled and the solvent evaporated to dryness in vacuo. The residue was chromatographed over silica gel (5-20% methanol in dichloromethane was used as the eluant) to give upon evaporation of the solvent in vacuo the title compound.
MS(FAB), mlz: 213 (M+H)+.
EXAMPLE S
1-f 4-l 1-Pvrrolidino)-2-oxo-3-butenyl)-2-pyrrolidinong To an ice cold solution of oxotremorine (412 mg) in dichloromethane (4 ml) was added in small portions 3-chloroperoxybenzoic acid (362 mg). After the reaction was stirred at 0°C for 20 minutes, the mixture was passed over twenty weight equivalents of basic alumina (Broclcmann Grade I, 150 mesh) and the N-oxide was eluted using a solution of 5% methanol in dichloro-methane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness ,'~ vacuo.
The residue was treated successively three times with small portions of methanol (ca. 25 ml) followed by evaporation to near dryness, and the volume of the solution was adjusted to 30 mL by addition of methanol. The methanolic solution of the N-oxide was heated to reflux for approximately 5 hours, cooled, and the solvent was evaporated to dryness ~ duo. . The residue was chromatographed over silica gel (4% methanol in dichloromethane was used as the eluant) to give upon evaporation of the solvent in vacuo an crystallization from ethyl acetate-hexanes the title compound as colorless prisms. m.p. 99-101°C MS(+ES), m/z: 223 (M+H)+.

1-Dimethvlamino-3- henyl-2-urouyne N-oxide To an ice cold solution of 1-dimethylamino-3-phenyl-2-propyne (1.0 g;
prepared by the Mannich reaction of phenylacetylene with formaldehyde and dimethylamine; Mannich Chem. Ber. 1933, 66, 418; Lattes, et.al. Tetrahedron 1982, 38, 2355) in dichloromethane ( 15 ml) was added in small portions 3-chlorophenylperoxybenzoic acid ( 1.13 g) over a period of about 2 minutes.
After the reaction was stirred at 0°C for 20 minutes, the mixture was passed over twenty weight equivalents of basic alununa (Brockmann Grade I, i 50 mesh) and eluted with 5°10 methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness i~ duo. Ether was added to precipitate the product as a colorless solid. MS(+ES), m/z: 176 (M+H)+.

3-Dimet~ylamino-1- henyl-2-prooene-1 one A solution of 1-dimethylamino-3-phenyl-2-propyne N-oxide (250 mg) in methanol (20 ml) was heated to reflux for 5 hours. The mixture was cooled, the solvent was evaporated ~ vacuo, and the desired product was obtained as a nearly colorless solid by chromatography of the remaining residue over silica gel (2:1 ethyl acetate-hexanes was used as the eluant). MS(+ES), m/z: 176 (M+H)+. The purified product was identical by 'H NMR and thin layer chromatography to material prepared by the known reaction of 1-phenyl-prop-2-yne-1-one with dimethylamine;
McMullen,et.al. J. Chem. Soc.(B) 1966, 1217; Hirao, I. J. Chem. Soc. Japan 1953, 56, 968 CChem. Abs. 1955, 3185f).

3-Dimeth~elamino-1=Rhen~rl-2-~ronene-1-one To a solution of 1-dimethylamino-3-phenyl-2-propyne N-oxide (50 mg) in methanol ( 1 ml) was added bis(acetonitrile)palladiumtII) chloride (7.5 mg) and the mixture was stirred at room temperature under an atmosphere of argon for 24 hours.
The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride, and the organic layer was dried over anhydrous magnesium sulfate.
The solvent was removed by evaporation i~ vacuo. The residue was chromatographed over silica gel (eluted with 2:1 ethyl acetate-hexanes) to give upon evaporation of the solvent ~n_ vacuo the desired product as a nearly colorless solid. MS(+ES), m/z: 176 (M+H)+.
The purified product was identical by 'H NMR and thin layer chromatography to material prepared by the known reaction of 1-phenyl-prop-2-yne-1-one with dimethylamine; McMullen,et.al. J. Chem. Soc.(B) 1966, 1217; Hirao, I. J. Chem.
Soc. Japan 1953, 56, 968 CChem. Abs. 1955, 3185f).

Dimethylamino-1 ~hgwi 2 nronene 1 one To a solution of 1-dimethylamino-3-phenyl-2-propyne N-oxide (50 mg) in methanol ( 1 ml) was added cuprous iodide (5.5 mg) and the mixture was stirred at room temperature under an atmosphere of argon for 4 days. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation ~ vacuo and the residue was chromatographed over silica gel (eluted with 2:1 ethyl acetate-hexanes) to give upon evaporation of the solvent in vacuo the desired product as a nearly colorless solid. MS(+ES), mlz: 176 (M+H)+. The purified product was identical by 'H NMR and thin layer chromatography to material prepared by the known reaction of 1-phenyl-prop-2-yne-1-one with dimethylamine;
McMullen,et.al. J.
Chem. Soc.(B) 1966, 1217; Hirao, I. J. Chem. Soc. Japan 1953, 56, 968 CChem.
Abs. 1955, 3185f).

3-Dimethyja~ ino- -Rhggy,~2-gene-1-one To a solution of 1-dimethylamino-3-phenyl-2-propyne N-oxide (50 mg) in a biphasic solution of dichloromethane-water ( 1: I , 2 ml) was added benzyldimethyltetradecylammonium chloride dihydrate (approximately 1 mg) and bis(acetonitrile)palladium(II) chloride (3.8 mg) and the mixture was stirred vigorously for 24 hours. The reaction was diluted with ethyl acetate, washed with saturated aqueous sodium chloride, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation i~ vacuo and the residue was chromatographed over silica gel (eluted with 2:1 ethyl acetate-hexanes) to give upon evaporation of the solvent ~ vacuo the desired product as a nearly colorless solid.
MS(+ES), mlz: 176 (M+H)+. The purified product was identical by ~H NMR and thin layer chromatography to material prepared by the known reaction of 1-phenyl-prop-2-yne-1-one with dimethylamine; McMullen,et.al. J. Chem. Soc.(B) 1966, 1217;
Hirao, I. J. Chem. Soc. Japan 1953, 56, 968 CChem. Abs. 1955, 3185f).

3-Dimethyiamino-1-phenyl-~_propene-1-one To a solution of 1-dimethylamino-3-phenyl-2-propyne N-oxide (50 mg) in a biphasic solution of dichloromethane-water ( 1:1, 2 ml) was added benzyldimethyltetradecylammonium chloride dihydrate (approximately I mg) and cuprous iodide (2.8 mg) and the mixture was stirred vigorously for approximately 24 hours. The reaction was diluted with ethyl acetate. washed with saturated aqueous sodium chloride, and the organic layer was dried over anhydrous magnesium sulfate.
The solvent was removed by evaporation in vacuo and the residue was chromatographed over silica gel (eluted with 2:1 ethyl acetate-hexanes) to give upon evaporation of the solvent in vacuo the desired product as a nearly colorless solid.
MS(+ES), m/z: 176 (M+H)''. The purified product was identical by ~H NMR and thin layer chromatography to material prepared by the known reaction of I-phenyl-prop-2-yne-1-one with dimethylamine; McMullen,et.al. J. Chem. Soc.(B) 1966, 1217;
Hirao, I. J. Chem. Soc. Japan 1953, 56, 968 CChem. Abs. 1955, 3185f).

E~:AMPLE 12 4-Dimethylaminorl-nhenvl-3-butane-2-one To an ice cold solution of 1-dimethylamino-4-phenyl-2-butyne (0.5 g; prepared by the Mannich reaction of 3-phenyl-1-propyne with formaldehyde and dimethylamine as per Mornet, et.al. Bull.Soc.Chim.Fr. 1974, 206) in dichloromethane (12 ml) was added in small portions 3-chloroperoxybenzoic acid (0.52 g). After the reaction was stirred at 0°C for 20 minutes, the mixture was passed over twenty weight equivalents of basic aiumina (Brockmann Grade I, 150 mesh) and the N-oxide was eluted using a solution of 10% methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness in vacuo. The residue was treated successively three times with small portions of methanol (ca. 10 ml) followed by evaporation to near dryness, and the volume of the solution was adjusted to 25 mL by addition of methanol. The methanolic solution of the N-oxide was heated to reflux for approximately 4 hours and cooled. The solvent was evaporated to dryness ~,n vacuo and the residue was chromatographed over silica gel (95:5 ethyl acetate-hexanes was used as the eluant) to give upon evaporation of the solvent in vacuo the desired product as an oil. MS (+ES) mlz: 190 (M+H)+.

1-Dimethylamino-1-pentane-3 one To an ice cold solution of I-dimethylamino-2-pentyne (3.0 g) in dichloromethane { 100 ml) was added 3-chloroperoxybenzoic acid (4.66 g) in small portions. After the reaction was stirred at 0°C for 20 minutes, the mixture was passed over twenty weight equivalents of basic alumina (Broclcmann Grade I, 150 mesh) and the N-oxide was eluted using a solution of 5% methanol in dichloromethane. All fractions containing 1-dimethylanvno-2-pentyne N-oxide were combined and evaporated to near dryness ~ vacuo. The residue was treated successively three times with of methanol (ca. 100 ml) followed by evaporation to near dryness, and the volume of the solution was adjusted to 90 mL by addition of methanol. One third of this methanolic solution (30 ml) of the N-oxide (9 mmol) was heated to reflux for approximately 4 hours, cooled, evaporated to dryness i~r vacuo, and the residue was chromatographed over silica geI (2% methanol in dichloromethane was used as the *rB

eluant) to give upon evaporation of the solvent ~ vacuo the desired product as an oil.
MS (+ES) m/z: 128 (M+H)+

1-Dimethvlamino-1_pentene-3-one To a solution of 1-dimethylamino-2-pentyne N-oxide (1 g) in methanol (30 ml) was added bis(acetonitrile)palladium(II) chloride ( 117 mg) and the mixture was stirred at room temperature under an atmosphere of argon for 24 hours. The mixture was evaporated to dryness i~ vacuo, and the residue was chromatographed over silica gel (2% methanol in dichloromethane was used as the eluant) to give upon evaporation of the solvent i~ vacuo the desired product as an oil. MS (+ES) mJz: 128 (M+H)+

1-Dimethylamino-1-pe~tene-3-one To a solution of 1-dimethylamino-2-pentyne N-oxide (1 g) in methanol (30 ml) was added cuprous iodide (86 mg) and the mixture was stirred at room temperature under an atmosphere of argon for 24 hours. The mixture was evaporated to dryness in vacuo, and the residue was chromatographed over silica gel {2% methanol in dichloromethane was used as the eluant) to give upon evaporation of the solvent in vacuo the desired product as an oil. MS (+ES) m/z: 128 (M+H)+
4-Bromo-2-chloro-benzoic acid methyl ester Thionyl chloride ( 1.64 ml) was added dropwise to a suspension of 4-bromo-2-chlorobenzoic acid (6.92 g) in methanol, and heated to 60 °C for 2 hours. The solvent was removed ~ v a , the residue redissolved in ethyl acetate, and washed sequentially with 0.5 N sodium hydroxide (2x), water, and brine. The organic phase was dried over anhydrous sodium sulfate, and the solvent removed i~ vacuo to afford upon evaporation of the solvent inn vacuo 7.8 g of the title compound as an oil. 1H
NMR (300 Mhz), d: 3.87 (s,3H), 7.68-7.9 (m, 3H).

2-Chloro-4-(3-dimethy~~amino-nro~yn-1-yl)benzoic acid, methy ester To a stirred solution of 4-bromo-2-chlorobenzoic acid methyl ester ( 18.69 g) in triethylamine (110 ml), was added 1-dimethylamino-2-propyne (12.1 ml), bis(triphenylphosphine)palladium(II) chloride (1.26 g), and copper(I) iodide (0.136 g).
The mixture was heated slowly to 60 °C, and the temperature maintained for one hour.
The reaction was cooled to room temperature, filtered through diatomaceous earth, and the collected solid washed with ethyl acetate. The solvent was removed ~n_ v~cuo, the resulting residue redissolved in ethyl acetate, and washed with water (3x).
The combined organic extract was dried over anhydrous sodium sulfate, and the solvent removed ~ vacuo to give a crude product. The crude product was purified by column chromatography over silica gel (225 g), eluting with 40% ethyl acetate/hexane.
Removal of the solvent 'fir vacuo gave the title compound ( 17.7 g) as a viscous oil. MS
(+FAB), »r/z : 252 (M+H)+.

2-Chloro-4-(3-dimethvlamino-2-propen-1-on-1-yl)-benzoic acid methyl ester To a pre-cooled solution of 2-chloro-4-(3-dimethylamino-propyn-lyl)-benzoic acid, methyl ester (15.07 g) at -20 °C in dichloromethane (40 ml), was gradually added 3-chloroperoxybenzoic acid ( 10.76 g), while maintaining the reaction temperature at -20 °C. The mixture was stirred for 10-15 minutes. The resulting N-oxide was purified by chromatography on Activity Grade I basic alumina (215 g), eluting with 10%
methanol/dichloromethane. The solvent was evaporated i~ vacuo between 12 to 18 °C.
The resulting residue was dissolved in methanol ( 100 ml) and heated at 60-65 °C with stirring for 18 hours. After removing the solvent in vacuo, and the product was purified by column chromatography over silica gel ( 190 g), eluting with 70%
ethyl acetate/hexane. Trituration with diethyl ether containing some hexanes afforded the title compound (5.68 g) as a solid. m.p. 92-96 °C.

EXAM_ PLf E 19 2-~~ro-4-(1H-gyrazol-3-yll-benzoic acid methyl eyer To a suspension of 2-chloro-4-(3-dimethylamino-2-propen-1-on-1-yl)-benzoic acid, methyl ester (13.67 g) in ethanol (53 - ml) was added hydrazine monohydrochloride (7.0 g). The mixture was heated in an oil bath at 75-80 °C for one hour. The solvent was removed ~, vacuo. The resulting residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent removed ~ vacuo to yield the title compound as a crude solid (12 g). A
purified sample had a melting point of 130-131 °C.

2-Chloro-4-(1-meth 1-y 1H-pyraznl_-3_yll-ttenzoic acid, methyl ester To a suspension of hexanes-washed sodium hydride (3.05 g, 60% dispersion) in dimethylformamide (6 ml) under nitrogen was added a solution of 2-chloro-4-(1H-pyrazol-3y1)-benzoic acid methyl ester ( 12.0 g) in dimethylformamide (30 ml) over a period of 15 minutes. The mixture was stirred at room temperature for 30 minutes.
Iodomethane (9.5 ml) was added dropwise over 15 minutes. The mixture was allowed to stir at room temperature for 45 minutes. Additional iodomethane (5.16 ml) was added, and the reaction stirred another 75 minutes. The reaction was diluted with a small quantity of water, and concentrated '~"lr vacuo. The residue was diluted with water (500 ml) and extracted five times with ethyl acetate. The combined organic phase was evaporated inn vacuo to afford a crude product, which was purified by column chromatography over silica gel ( 15°lo ethyl acetate-hexanes was used as the eluant) to give pure fractions of 1-methyl regioisomer (4.29 g), and a mixture of the 1-methyl and 2-methyl regioisomers (4.6 g). The mixture of isomers was triturated with hexanes three times to give an additional sample of the pure 1-methyl regioisomer (2.55 g), m.p.
66.5-67 °C; MS (+FAB), mJz:: 251 (M+H)+.

2-Chloro-4-(1-methv -1 1H_,Ry~azol-3-yl)-benzoic acid To a solution of 2-chloro-4-(1-methyl-1H-pyrazol-3-yl)-benzoic acid, methyl ester (6.85 g) in methanol (32 ml) was added 2.5 N sodium hydroxide solution ( 15.3 ml). The reaction was heated to 50 °C for one hour. The solvent was removed ~ vacu , and the residue dissolved in water (250 ml), cooled in an ice bath, and acidified with 2N hydrochloric acid (24 ml). The resulting precipitate was filtered and dried to give a colorless solid (6.3 g) m.p. 232-233 °C; MS, (+FAB), mJz: 236 (M+H)+.

f2-Chloro-4-(1-meth~rl-1H-pvrazol-3-xl)-nhenxll ~5~~,,11H-Pvrrolof2,1-el f 1 4lbenzodiaze~ine-10w11-methanone Well powdered 2-chloro-4-(1-methyl-1H-pyrazol-3-yl)-benzoic acid (6.3 g) and dimethylformamide (2.16 ml) were suspended under nitrogen in a mixture of tetrahydrofuran (70 ml) and dichlormethane ( I 5 ml). A solution of oxalyl chloride (2.43 ml) in dichloromethane (5 ml) was added dropwise, and the reaction stirred for one hour. The resulting suspension of 2-chloro-4-(1-methyl-IH-pyrazol-3-yl)-benzoyl chloride was utilized without further purification.
To a suspension of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (4.93 g) in dichloromethane (15 ml) was added diisopropylethylamine (7 mi). The suspension of the freshly prepared acid chloride was gradually added over I5 minutes under a positive flow of nitrogen. The slightly warm reaction mixture was stirred under nitrogen for 50 minutes. After stirring one hour, the mixture was concentrated in v~o_. The residue was dissolved in dichloromethane, washed with water, 5%
aqueous sodium bicarbonate, and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and the solvent removed ~ vacuo to give a crude product, which was purified by column chromatography over silica gel (30-40%
ethyl acetate-hexanes was used as the eluant) to afford the product as an oil.
Crystallization was induced by stirring the oil with diethyl ether containing hexanes for 24 hours.
Filtration of the precipitate afforded the title compound as a crystalline solid. m.p.
148.5-150 °C; MS (EI), m/z: 402 (M)+.

E~LAMPLE 23 f2-Chloro-4-(1-methyl-1H-~yrazol-3-,~~1-Rhenvll-(5.11-dihvdro-g3rrido[2 3-b~fl 5lbenzodiazeoin-b-vl)-methanone Step A. b,11-Dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one 1:1 salt with hydrochloric acid A mixture of 1,2-phenylene diamine (52 g, 480 mmol) and chloro nicotinic acid (76 g, 482 mmol) in cyclohexanol (480 mL) was refluxed under nitrogen for 2.5 hours.
A precipitate appeared soon after the heating was initiated. The warm reaction mixture was carefully poured onto ice-cold dichloromethane ( 1000 mL) under vigorous stirring.
The semisolid mass was collected, washed thoroughly with dichloromethane and dried in vacuo to yield 98.9 g (83%) of the title compound which was used in the next step without further purification.
Step B. b,11-Dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine Diborane dimethylsulfide complex (35 mL) was added via syringe to a suspension of 6,11-dihydro-SH-pyrido[2,3-b][1,5]benzodiazepin-5-one 1:1 salt with hydrochloric acid of Step A (25 g, 0.1 mole) in dioxane (230 mL) under nitrogen. The mixture was sonicated overnight at room temperature and then evaporated to dryness in vacuo. The green residue was treated with cold 2N hydrochloric acid and diethyl ether.
The cold aqueous layer was basified with 50% aqueous sodium hydroxide (to pH
9) and the basic layer extracted with ethyl acetate. The organic extracts were dried over anhydrous potassium carbonate, and evaporated to dryness to yield a burgundy solid (24.35 g, 61.4%). This crude material was purified by trituration with diethyl ether.
The solid was collected, washed and dried in vacuo. The mother liquors from different runs were combined and the mixture ( 18.5 g) flash chromatographed (on silica Merck-60, eluant 20% ethyl acetate in hexane) to provide additional material homogeneous by TLC (yellow solid, 11 g).
Step C. [2-Chloro-4-(1-methyl-1H-pyrazol-3-yl)-phenyl]-(5,11 dihydropyrido- [2,3-b][1,5]benzodiazepin-b-yl)-methanone A mixture of 2-chloro-4-(1-methyl-1H-pyrazol-3-yl)-benzoic acid (1.9 g) and oxalyl chloride (0.79 mL) in dichloromethane (20 ml) containing a catalytic amount of dimethylformamide (0.01 mI) was stirred at ambient temperature under an atmosphere of nitrogen for 1 hour. The solvent was removed by evaporation in vacuo and the _38_ resulting crude solid acid chloride was dissolved in of dimethylformamide (5 ml) and added directly to a mixture of 5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepine (1.59 g) and potassium carbonate ( 1.25 g). After stirnng for 2 hours at room temperature the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed by evaporation j~ vacuo and the product was purified by chromatography over silica gel (a linear gradient of 57% to 66% ethyl acetate in hexanes was used as the eluant) and recrystallized from ethanol-ether giving colorless solids.
m.p. 202°C.

l3-Chloro-4-iodo-~henvl)-carbamic acid tert-butyl ester To a solution of 3-chloro-4-iodvaniline (20.2 g) in tetrahydrofuran (200 ml) was added di-tert-butyl dicarbonate (39 g) and N,N-diisopropylethylamine (30.9 g).
The mixture was heated to reflux for approximately 24 hours, cooled and the solvent removed by evaporation i~ v o. The resulting residue was dissolved in ethyl acetate (450 ml), washed twice with of 5% aqueous hydrochloric acid, once with saturated aqueous sodium bicarbonate, once with water, once with saturated sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation inn vacuo, and trituration of the product with hexanes gave the product as a crystalline solid. MS (-ES) m/z: 352 (M-H)- . Additional purification was accomplished by recrystallization from hot hexanes:

f 3-Chloro-4-(3-dimethylamino-prQn-1-vnvl)-phenyl]-carbamic acid tert-butyl ec g,~
To a deoxygenated solution of (3-chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester ( 10.0 g) in triethylamine ( 120 ml) was added 1-dimethylamino-2-propyne {2.82 g), bis(triphenylphosphine)palladium(II) chloride (400 mg), and cuprous iodide (54 mg). The mixture was stirred at room temperature under an atmosphere of argon for approximately 6 hours, heated briefly (ca. 10 minutes) to 60°C. The reaction mixture was cooled, filtered through diatomaceous earth, and the solvent was removed by evaporation imacuo. The residue was dissolved in ethyl acetate, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation in v~o, and the residue was purified by chromatography over silica gel (80% ethyl acetate in hexanes was used as the eluant) to give the product as an amber oil that solidified on standing. MS (+ES) mlz: 309 (M+H)+ .
f3-Chloro-4-(3-dirt et lamino-~-~rouen-1-on-1-yll te~yll-carbamic acid tert-butyl ester To an ice cold solution of [3-chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acid tert-butyl ester (4.0 g) in dichloromethane (30 ml) was added in small portions 3-chloroperoxybenzoic acid (2.34 g). After the reaction was stirred at 0°C for minutes, the mixture was passed over twenty weight equivalents of basic alumina 15 (Broclcmann Grade I, 150 mesh) and the N-oxide was eluted using a solution of 5%
methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness in vacuo. The residue was treated successively three times with small portions of methanol (ca. 50 ml) followed by evaporation to near dryness, and the volume of the solution was adjusted to 250 mL by 20 addition of methanol. The methanolic solution of the N-oxide was heated to reflux for approximately 15 hours, cooled, and the solvent was evaporated to dryness in vacuo.
The residue was purified by chromatography over silica gel (80% ethyl acetate in hexanes was used as the eluant) to give the desired product as pale yellow solids. MS
(+ES) m/z: 325 (M+H)+ .

2-Methy]I-5-(~yrrolidin-1-vl)-pent ~~rn-2-of A solution of 1-(pyrrolidin-1-yl)-prop-2-yne (prepared by the method of Biel and DiPierro J. Am. Chem. Soc. 1958, 80, 4609) (0.545 g) in dry tetrahydrofuran ( 15 ml) was treated at -78°C with a solution of n-butyl lithium in hexanes (2.5 M, 2.2 ml) and the mixture was allowed to stir at -78°C for 30 minutes and them permitted to warm to room temperature over the course of one hour. Upon recooling to -78°C this mixture was treated with a solution of acetone ( 1 ml) in tetrahydrofuran ( 1 ml). The reaction was permitted to warm to room temperature over the course of two hours, and was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the pooled organic phase was washed with water, brine, and then dried over anhydrous sodium sulfate. The solvent was removed ~ y~ to give a crude product, which was purified by column chromatography over silica gel (5%
methanol in dichloromethane was used as the eluant) to afford the product as an oil.
MS(+ES), mJz: 168 (M+H)+.

4-H_ydroxy-4-methyl-1-(pvrrolidin-1-spent-1-en-3-one To an ice cold solution of 2-methyl-5-(pyrrolidin-1-yl)-pent-3-yn-2-of (0.25 g) in dichloromethane (6 ml) was added in small portions 3-chlorophenylperoxybenzoic acid (0.285 g) over a period of about 2 minutes. After the reaction was stirred at 0°C for 5 minutes, the mixture was passed over 20 weight equivalents of basic alumina (Broclcmann Grade I, 150 mesh) and eluted with 5% methanol in dichloromethane.
All fractions containing the desired amine N-oxide were combined and evaporated to near dryness ~n_ vacuo. The resulting residue was dissolved in methanol (20 ml) and heated to reflux temperatures for 7 hours. The solvent was then removed in vacuo and the residue was chromatographed over silica gel (50% ethyl acetate in hexanes was used as the eluant) to provide the desired product as an amber solid. MS(+ES), m/z:

(M+H)+.

2.2-Dimethyll-3(2Hy-furanone A solution of 4-hydroxy-4-methyl-1-(pyrrolidin-1-yl)-pent-1-en-3-one (0.075 g) in methanol ( 1 ml) was treated with p-toluene sulfonic acid (0.015 g) and the mixutre was stirred at room temperature for approximately 15 hours. The solution was then diluted with diethyl ether, washed with water, 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine, and then dried over anhydrous magnesium sulfate.
The solvent was carefully removed to provide the desired product as an oil, which was identical by 1H NMR and thin layer chromatography to commercially available material obtained from the Aldrich Chemical Company.

1-(3-(Pyrrolidin-1-vll-pro -~l-ynyly-cxclohexanol A solution of 1-(pyrrolidin-1-yl)-prop-2-yne (prepared by the method of Biel and DiPierro J. Am. Chem. Soc. 1958, 80, 4609) (0.545 g) in dry tetrahydrofuran ( 15 ml) was treated at -78°C with a solution of n-butyl lithium in hexanes (2.5 M, 2.2 ml) and the mixture was allowed to stir at -78°C for 30 minutes and them permitted to warm to room temperature over the course of one hour. Upon recooling to -78°C this mixture was treated with a solution of cyclohexanone (0.61 g) in tetrahydrofuran ( 1 ml). The reaction was permitted to warm to room temperature over the course of two hours, and was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the pooled organic phase was washed with water, brine, and then dried over anhydrous sodium sulfate. The solvent was removed i,~ vacuo to give a crude product, which was purified by column chromatography over silica gel (5%
methanol in dichloromethane was used as the eluant) to afford the product as a white solid. MS(+ES), m/z: 208 (M+H)+.

1-(1-Hvdroxv-cvclohexyll-3-(Ryrrolidin-1-yll-propenone To an ice cold solution of 1-(3-(pyrrolidin-1-yl)-prop-1-ynyl)-cyclohexanol (0.31 g) in dichloromethane (6 rnl) was added in small portions 3-chlorophenylperoxybenzoic acid (0.285 g) over a period of about 2 minutes.
After the reaction was stirred at 0°C for 5 minutes, the mixture was passed over 20 weight equivalents of basic alumina (Brockmann Grade I, 150 mesh) and eluted with 5%
methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness inn v uo. The resulting residue was dissolved in methanol (20 ml) and heated to reflux temperatures for 7 hours.
The solvent was then removed '~ vacuo and the residue was chromatographed over silica gel (50% ethyl acetate in hexanes was used as the eluant) to provide the desired product as an amber solid. MS(+ES), mlz: 224 (M+H)+.

~-Qxa-sniro(4.Sldec-2-en-4-one A solution of 1-(1-hydroxy-cyclohexyl)-3-(pyrrolidin-1-yl)-propenone (0.11 g) in methanol ( 1 ml) was treated with p-toluene sulfonic acid (0.015 g) and the mixutre was stirred at room temperature for approximately 15 hours. The solution was then diluted with diethyl ether, washed successively with water, 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine, and then dried over anhydrous magnesium sulfate. The solvent was removed ~ vacuo and the residue was chromatographed over silica gel (15% ethyl acetate in hexanes was used as the eluant) to provide the desired product as a colorless oil. MS (CI), m/z: 153 (M+H)+.

2-(P~rrrolidin-1-yl)-but-3-,vne A solution acetic acid 1-methyl-prop-2-ynyl ester (prepared by the method of Clarke and Pinder, J. Chem. Soc. 1958, 1967).(7 g) and pyrrolidine (10.4 ml) in anhydrous tetrahydrofuran (125 ml) was treated with copper (I) chloride (0.3 g) and the mixture was heated to reflux temperatures for 1.5 hours. After then allowing the mixture to stir at room temperature for approximately 15 hours, the mixture was diluted with diethyl ether, and extracted thrice with 2N aqueous hydrochloric acid.
These pooled acidic extracts were basified by addition of solid sodium hydroxide, and the solution was then extracted three times with ethyl acetate. These pooled organic extracts were then washed iwth water, brine, and dried over anhydrous magnesium sulfate. After removing the solvent i,~ vacuo the resulting residue was distilled to obtain the desired product as a colorless oil. b.p. 35°C (1.1 mm Hg). MS(+ES), m/z: 124 (M+H)+

~-Phenyl-5-tQyrrolidin-1=yl)-hex-3-y, -n 2-0l A solution of 2-(pyrrolidin-1-yl)-but-3-yne (0.1.23 g) in dry tetrahydrofuran (20 ml) was treated at -78°C with a solution of n-butyl i~thium in hexanes (2.5 M, 4.4 ml) and the mixture was allowed to stir at -78°C for 30 minutes and them permitted to warm to room temperature over the course of one hour. Upon recooling to -78°C this mixture was treated with a solution of acetophenone ( 1.2 g) in tetrahydrofuran (5 ml).
The reaction was permitted to warm to room temperature over the course of two hours, and was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the pooled organic phase was washed with water, brine, and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give a crude product, which was purified by column chromatography over silica gel (5-10% methanol in dichloromethane was used as the eluant) to afford the product as an oil that solidified on standing. MS(+ES), m/z: 244 (M+H)'.

4-H d~rox_y-4-phenyl-1-t~rrrolidin 1 yl) pent 1 en 3 one To an ice cold solution of 2-phenyl-5-(pyrrolidin-1-yl}-hex-3-yn-2-of (0.49 g) in dichloromethane (5 ml) was added in small portions 3-chlorophenylperoxybenzoic acid (0.38 g) over a period of about 2 minutes. After the reaction was stirred at 0°C for 5 minutes, the mixture was passed over 20 weight equivalents of basic alumina (Brockmann Grade I, 150 mesh) and eluted with S~Io methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness 'tyn vacuo. The resulting residue was dissolved in methanol (20 ml) and heated to reflux temperatures for 13 hours. The mixture was then cooled and the solvent removed i~r vacuo. The resulting residue consisted of 4-hydroxy-4-phenyl-1-pyrrolidin-1-yl-pent-1-en-3-one and 2,5-dimethyl-2-phenyl-furan-3-one, and was used directly and without further purification in the next step (Example 36).

2.5-Dimethyl-2-p~en~yl-furan-3-one The mixture prepared above (Example 35) of 4-hydroxy-4.-phenyl-1-(pyrrolidin-1-yl)-pent-1-en-3-one and 2,5-dimethyl-2-phenyl-furan-3-one was dissolved in methanol (20 ml) and stirred 4 hours in the presence of Amberlyst~ (0.5 g) The mixture was then filtered and the solvent was then removed i~ vacuo and the residue was chrornatographed over silica gel (20% ethyl acetate in hexanes was used as the eluant) to provide the desired product as an oil. The compound was identified by comparison of the'H NMR with authentic material prepared by the method of Felman, Jirkovsky, Memoli, Borella, Wells, Russell, and Ward J. Med Chem. 1992, 35, 1183.

2-(3-Dimethylamino-~n-1-y ~r11-phenol To a deoxygenated solution of o-bromophenol ( 10.0 g) in triethylamine ( 120 ml) may be added 1-dimethylamino-2-propyne (2.82 g), bis(triphenylphosphine)palladium(II) chloride {400 mg), and cuprous iodide (54 mg).
The mixture may be stirred at room temperature under an atmosphere of argon for approximately 6 hours, heated briefly (ca. 10 minutes) to 60°C. The reaction mixture is then cooled, filtered through diatomaceous earth, and the solvent may be removed by evaporation ~ v o. The residue can then be dissolved in ethyl acetate, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent may be removed by evaporation in vacuo, and the residue may be purified by chromatography over silica gel (50% ethyl acetate in hexanes may be used as the eluant) to give the purified product.

2-(1-(3-Dimethylamino-p~Qp.2-en-1-one))-phenol To an ice cold solution of 2-(3-dimethylamino-prop-1-ynyl)-phenol (4.0 g) in dichloromethane (30 ml) can be added in small portions 3-chloroperoxybenzoic acid (2.34 g). After the reaction is stirred at 0°C for 20 minutes, the mixture can be passed over twenty weight equivalents of basic alumina (Brockmann Grade I, 150 mesh) and the N-oxide can be eluted using a solution of 5% methanol in dichloromethane.
All fractions containing the desired amine N-oxide can be combined and evaporated to near dryness j~ vacuo. The residue can be treated successively three times with small portions of methanol (ca. 50 ml) followed by evaporation to near dryness, and the volume of the solution can be adjusted to 250 mL by addition of methanol. The methanolic solution of the N-oxide can be heated to reflux for approximately 15 hours, and then cooled to provide a mixture of 2-(1-(3-dimethylamino-prop-2-en-1-one))-phenol and chromone (1,4-Benzopyrone), which can be used directly and without further purification in the next step (Example 39).

~hromone or 1 4-Benzowrone The mixture prepared above (Example 38) of 2-(1-(3-dimethylamino-prop-2-en-1-one))-phenol and chromone may be dissolved in methanol (20 ml) and stirred in the presence of Amberlyst~ ( 1 g) for 4 hours. After removing the solvent in vacuo, the residue can be purified by chromatography over silica gel (25% ethyl acetate in hexanes can be used as the eluant) to give the desired chromone product.

Claims (15)

What is Claimed:

1. A process for producing an enaminone of Formula (I):

wherein:
X is selected from the group of H, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, -CH2-phenyl, or -CH2-substituted phenyl;
R1 is selected from the group of hydrogen, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, phenyl, substituted phenyl, -CH2-phenyl, or -CH2-substituted phenyl or a group of the formulae:

the C3-C7 cycloalkyl groups being optionally substituted by from 1 to 3 groups independently selected from R5-R9;
R2 and R3 are independently selected from the group of C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, -CH2-phenyl, or R2 and R3 may be joined to form a ring of from three to six atoms;
R4 and R4, are independently selected from the group of hydrogen, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, -OR11, -NR11R13, NR11C(O)OR10, -NR10C(O)R10, -OC(O)R10, -OC(O)OR10, or -OC(O)NHR10;

substituted phenyl and -CH2-substituted phenyl are, respectively:

R5-R9 are independently selected from the group of hydrogen, halogen, trifluoromethyl, C2-C6 perfluoroalkyl, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, -CN, -NO2, -OR11, -CO2R11, -NR11R13, -NR11C(O)OR11, -NR11C(O)R11, -OC(O)R11, -OC(O)OR11, or -OC(O)NHR11;
R10 is selected from the group of hydrogen, C1-C10 straight chain alkyl, C3-branched chain alkyl, C3-C7 cycloalkyl, phenyl,or -CH2-phenyl;
R11 and R11' are independently selected from the group of hydrogen, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, phenyl or -CH2-phenyl;
R12 and R2' are independently selected from the group of hydrogen, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, phenyl, substituted phenyl, -CH2-phenyl or -CH2-substituted phenyl, the C3-C7 cycloalkyl groups being optionally substituted by from 1 to 3 groups independently selected from R5 to R9; or R12 and R12' may also optionally be taken together with their associated carbon to form a carbocyclic ring of from three to seven carbon atoms;
with a proviso that both R12 and R12' in the moiety:

are not both phenyl or substituted phenyl;

R13 is an amino-protecting group used to protect the moiety NR11; or NR11R13 may be optionally concatenated together or exist as a cyclic imide of the formula:

the process comprising treating an amine N-oxide of the formula (II):

with a hydroxylic solvent, and if desired removing any protecting group.

2. A process according to claim 1 wherein X is hydrogen.

3. A process according to claim 1 or claim 2 wherein -NR2R3 are joined to form a ring of from three to six atoms selected from the group of:

4. A process according to any one of claims 1 to 3 wherein R1 is selected from the group of C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C6 cycloalkyl, phenyl, -CH2-phenyl, or the moieties:

R5, R6 R8, R9 are independently selected from the group of hydrogen, halogen, trifluoromethyl, C2-C6 perfluoroalkyl, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, -CN, -NO2, -OR11, -CO2R11, -NR11R13, -NR11C(O)OR11, -NR11C(O)R11, -OC(O)R11, -OC(O)OR11, or -OC(O)NHR11;
R11 and R11' are independently selected from the group of hydrogen, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C6 cycloalkyl, phenyl, or -CH2-phenyl;
R13 is an amino protecting group used to transiently protect the moiety NR11.

5. A process according to any one of claims 1 to 3 wherein R1 is the moiety:

R5, R6 R8, R9 are independently selected from the group of hydrogen, halogen, trifluoromethyl, C2-C6 perfluoroalkyl, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C7 cycloalkyl, -CN, -NO2, -OR11, -CO2R11, -NR11R13, -NR11C(O)OR11, -NR11C(O)R11, -OC(O)R11, -OC(O)OR11, or -OC(O)NHR11;
R11, and R11' are independently selected from the group of hydrogen, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C6 cycloalkyl, phenyl, or -CH2-phenyl; and R13 is an amino protecting group used to transiently protect the moiety NR11.

6. A process according to any one of claims 1 to 3 wherein R1 is the moiety:

R5, R6 R8, R9 are independently selected from the group of hydrogen, halogen, trifluoromethyl, C2-C6 perfluoroalkyl, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C6 cycloalkyl, -CN, -NO2, -OR11, -CO2R11, -NR11R13, -NR11C(O)OR11, -NR11C(O)R11, -OC(O)R11, -OC(O)OR11, or -OC(O)NHR11;
R11 and R11' are independently selected from the group of hydrogen, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C4 cycloalkyl, phenyl, or -CH2-phenyl; and R13 is an amino protecting group used to transiently protect the moiety NR11.

7. A process according to any one of claims 1 to 3 wherein R1 is the moiety:

R12 and R12, are independently selected from the group of hydrogen, C1-C6 straight chain alkyl, C3-C6 branched chain alkyl, C3-C6 cycloalkyl, phenyl, substituted phenyl, -CH2-phenyl or -CH2-substituted phenyl, the C3-C7 cycloalkyl groups being optionally substituted by from 1 to 3 groups independently selected from R5 to R9;

8. The process according to any one of Claims 1 to 7 wherein the R13 amino-protecting group is selected from the group of:
(a) acyl type protective groups such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, o-nitrophenoxyacetyl, sec-butyryl, pivaloyl- (also known as tert-butyryl), cyclopropanoyl, benzoyl, o-nitrobenzoyl, .alpha.-chlorobutyryl; or (b) sulfonyl type protecting grops such as benzenesulfonyl, toluenesulfonyl (tosyl), p-methoxybenzenesulfonyl, trifluoromethylsulfonyl; or (c) sufenyl type protecting groups such as benznesulfenyl, o-nitrobenzenesulfenyl, pentachlorobenzenesulfenyl; or (d) urethane type protecting groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, tert-butyloxycarbonyl, tert-amyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, allyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2-trimethylsilylethoxycarbonyl; or (e) aralkyl type protecting groups as benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, or triphenylmethyl.

9. A process according to any one of Claims 1 to 8 wherein the hydroxylic solvent is one or more solvents selected from the group of water, C1-C8 straight chain or branched chain alkyl alcohol, ethylene glycol, polyethylene glycol, 1,2-propylene diol, polypropylene glycol, glycerol, 2-methoxyethanol, 2-ethoxyethanol, 2,2,2-trifluoro-ethanol, benzyl alcohol and phenol.

10. A process according to any one of Claims 1 to 9 also comprising one or more cosolvents selected from pentane, hexane, heptane, benzene, toluene, xylene, diethyl ether, tetrahydrofurn, dioxane, dimethoxyethane, dichloromethane, chloroform, dichloroethane, tetrachloroethane, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethylsulfoxide and acetone.

11. A process according to any one of claims 1 to 10 which is carried out in the presence of a palladium(II) catalyst or a copper(I) catalyst.

12. A process according to Claim 1 in which the enaminone prepared is selected from:
(R)-octylcarbamic acid-1-[4-(dimethylamino)-2-oxo-3-butenyl]-2-oxo-3-pyrrolidinyl ester;
(R)-1-[4-(dimethylamino)-2-oxo-3-butenyl]-3-hydroxy-2-pyrrolidinone;
1-[4-( 1-pyrrolidino)-2-oxo-3-butenyl]-2-pyrrolidinone;
3-dimethylamino-1-phenyl-2-propene-1-one;
1-dimethylamino-1-pentene-3-one;
2-chloro-4-(3-dimethylamino-2-propen-1-on-1-yl)-benzoic acid, methyl ester;
[3-chloro-4-(3-dimethylamino-2-propen-1-on-1-yl)-phenyl]-carbamic acid tent-butyl ester;
4-Hydroxy-4-methyl-1-pyrrolidin-1-yl-pent-1-en-3-one;
1-( 1-Hydroxy-cyclohexyl)-3-pyrrolidin-1-yl-propenone;
4-Hydroxy-4-phenyl-1-pyrrolidin-1-yl-pent-1-en-3-one and 2-(1-(3-Dimethylamino-prop-2-en-1-one))phenol.

13. A process as claimed in any one of claims 1 to 12 in which the compound of formula (II) is prepared by oxidizing an amine of Formula (III) by reacting with an oxidising agent.

14. A process as claimed in claim 13 in which the oxidising agent is dimethyldioxirane or a peroxybenzoic acid such as 3-chlorobenzoic acid.

15. A compound having vasopressin agonist activity when prepared from an enaminone of formula (I) as prepared according to any one of claims 1 to 14.