CA1076586A

CA1076586A - PROCESS AND PROMOTING AGENTS FOR THE PREPARATION OF LOWERALKYL 2-(N-R1-PYRRYL)-.alpha.-LOWERALKANOIC ACID ESTERS

Info

Publication number: CA1076586A
Application number: CA285,099A
Authority: CA
Inventors: Bruce Maryanoff
Original assignee: McNeilab Inc
Current assignee: Janssen Pharmaceuticals Inc
Priority date: 1976-08-23
Filing date: 1977-08-19
Publication date: 1980-04-29
Also published as: FR2362835B1; ATA608177A; GB1586095A; DE2737946A1; FR2362835A1; CH634833A5

Abstract

ABSTRACT OF THE DISCLOSURE
A process for the preparation of loweralkyl 2-(N-R?-pyrryl)-.alpha.- loweralkanoic acid esters in increased yield and/or isomeric purity, and copper (II) 1,3-diketonate, copper (II) salicylaldehyde, copper (II) monoamino-1,3-diketonate; and copper (II) salicylaldimine complexes useful as promoting agents for said process.

Description

.~ -~t76S~;

~CKGROUND OF TB INVENTION
.
This invention relates to a process for the prepara-~ tion of loweralkyl 2-(N-R'-pyrryl)~ -loweralkanoic acid - esters and more particularly for the preparatio~ of loweralkyl

2-~-methylpyrryl) acetic acid esters, and to promoting agents used in this process.
~ oweralkyl 2 (N-R~-pyrryl)-u~-loweralkanoic acid esters comprise a very useful class of compounds~ being intermediates for the preparation of phenothiazine derivatives (see, for example, British Patent No. 823,733 to F.~P. Doyle and M. D. Mehta) and for the synthesis of the well-known anti- .
inflammatory agent tolmetin and its analogs ~see, for example, :
.. U~S. Patent No. 3,752,826), and are represented by the follow- :
. . ing generic formula: .

COOR . ~
R'. .'' (I) . ~:
wherein R is loweralkyl, R' is a member selected from the group ~` 15 consisting of hydrogen and primary loweralkyl, and R" is a -~
member selected frQm the group consisting of hydrogen and loweralkyl.
.. . .
me prior art method for the preparation of compounds .:
of this typP iS by the decomposition of a loweralkyloc-aia loweralXanoate, formula (II~, in the presence of an ~-R'-~yrrola, formula (III), wlth ~opper bronze a~ a catalyst or promoting agent. See, for example, ~. Rapoport and E.

Jo~gensen, J. Org. Chem. 9 1~ 664l194g~. The term ~ 6~ 310 .

"promoting agent" is used herein to mean a material which effectuates or facilitates a chemical reaction even when employed in a muoh less than stoichiometric amount (i.e., which functions as a catalyst, in the usual sense of the termO
but which may be chemically altered in the course of the reaction). Given the chemical modification of the promoting agentt it necessarily differs from a true catalyst, which by definition remains unchanged by the reaction that it induces.
It has recently been discoverad that this prior art preparative procedure does not yield only the desired 2-isomer but also yields some of the 3-isomer, formula (IV), as a by-product; This prior art process is illustrated by the followin~: _ CE-COOR

~ R7~ ~ ~ (I) +

wherein R, Rl, and ~2 are as previously definéd.
As these two isomers are practically inseparab1e, ~_ is desirable to have a process whereby one obtains a reaction product as enriched as possible i~ the desired 2 isomer (as "pure" as possi~le). As used herein, the term "pure" refers specifically to t~e degree of enric~ment in the favored 2-isomer (i.e., to the relative amou~t of the desired 2-isomer compared to the undesired 3-is~mer). The greater the ratio of ~-isomer to 3-isomer, the more "pure~ the product mixture is sa~id to be. Throughout the present application" this "purity' ' ' . ' will be represented as the percent of the total amount of loweralkyl (N-R -pyrryl)-o~loweralkanoic acid ester which is the desired 2-isomer.
It is also desirable to have a process which produces a$ m~ f the desirable 2-isomer as possible, regardless of the purity thereof. This characteristic wil~ be referred to as the "yield" of thP reaction and will be based upon the limiting reagent loweralkyl ~-diazolowexalkanoate.
The prior art procedure is less than desirable in both the purity and the yield of the product. For example, the priar art preparative method for N-methylpyrrole aceti~

,~ . ,. :
acid ethyl esters generally produces a product mixture having a purity of about 82% of the desired 2 isomer and a yield of the desired 2-isomer of about 32%, based on the ethyl dia-lS zoacetate. It should be noted at this point that, for this particular product, the literature often reports yields based upon ~-methylpyrrole rather than ethyl diazoaceta~e: these , yields ~ppear consideràbly larger ~han those as calculate herein because they are ~ot based upon the limiting reagent, ethyl diazoacetate. For valid c~mparison of two percentage yields, they must both be hased on the same startin~ material.
Throughout this application all yields are based on the amount of loweralkyl ~ diazoloweralkanoate consumed in the reaction.
It is known i~ the chemical art that the effect of ~5 different types o catalysts on an individual r~action, or on related reactions, i~ very difficult to predict. A give~

, .
... . . ..

catalyst may be ineffective in one reaction, while being the catalyst of choice in a closely related reaction. Different catalysts may result in different products or different ratios of products from the same starting materials. This unpredict-5- ability with respect to copper catalysts in diazo oompound ... . .
reactions is discussed, for example, on page 251 of "The Reaction of Diazoacetic Esters with Alkenes, Alkynes, ~etero-cyclic and Aromatic Compounds", Chapter 3, in Or~nic Reactions, 18, 217 (1970), by V. Dane and E~ W. Warnhoff.
It has now surprisingl~ been discovered that the yield of the desired 2-isomer can be significantly increased and, in some cases, the purity of the product improved through the use of the copper (II) 1,3-diketonate, copper (II) salicylaldehyde,copper (II~ monoamino-1,3-aiketonate, and copper (II~ ~alicylaldimine complexes of the invention as promoting agents.

' ' .
SUMM~RY OF ~E INVENTION
. .

The present invention comprises a process ~or prepara-tion of loweralkyl 2-(N-R' pyrryl)~X-loweralkanoic acld esters -in increased yield and~or isomeric purity by reacting an N~R'-pyrrole with a loweralkyloC-diazoloweralkanoate in the presence of a copper (II) complex of the invention described below. Certain of the copper (II) complexes are novel and constitute a further feature of the present invention.

s . ".

~076586 MN 310 A._ ComPlexes with dioxo ligands The dioxo copper ~II) salicylaldehyde and 1,3-diketonate complexes (promoting agents) of the invention may be represented by the following formula:
~0 _~' _ _ Cu X (2-n) (V) n wherein "n"~'~is~'the~int'eger 1 or 2, X is a me~ber selected from the group consisting of anions derived from monoprotic strong acids, such as for example, -OS02CF3, picrate, hexafluoro-phosphate, nitrate, perchlorate, halide, loweralkylsulfonate, arenesulfonate, such as benzenesulfonate, toluenesulfonate, naphthalenesulfonate, and the like, fluo~orate, trifluoracetate, fluorosulfate, and the like; and oxy radicals, such as for example, loweralkoxy, phenoxy,'and the like; and is intended to encompass all salicylaldehyde ~ ;~o and 1,3-diketonate ligands capable of forming bidentate com-plexes with copper (II)~ whatever the substitution thereon.
When n is 2, the two ligands may ~e the same or different.
It should be understood that certain 1,3-diketonate liqands areO because of their molecular geometry, incapable of forming bidentate complexes with copper (II). Examples of l,3-diketones which are unsuitable for making the subject copper complexes are .. . . . ... . .
~ ~ CH

~7~iS1~6 M~ 310 Because the keto groups on these compounds are directed away from each other due to the molecular geometry, these compounds cannot function as bidentate ligands.
The expression "1,3-diketonate" includes, for example, compounds of formula Rl ~ ... O
/, .
R2 ~
(VI) w~erein Rl and R3 are cach members selected from the group consisting of loweralkyl, loweralkoxy, per1uoroloweralkyl, phenyl, 2~thienyl,~ -naphthyl, and the liXe; and R~ is a member sele~ted from the group consisting of hydrogen and loweralkyl. Also included withiin the expression "1,3-diketonate" are the semicyclic :L,3-diketonates exempliied by the following:

<`~ ; (C/O ~ 0 3 R
(VII3 (VIII) ~3C

and H3C ~ CH3 G~~
~0 wherein R4 is a member selected from the gro~p consisting of loweralkyl, loweralkoxy, phenyl, and perfluorolowexalkyl;

M~ 310 ~7~i5~36 m is 0 or 1; and R5 is a member selected from the group con-si~ting of loweralkyl and perfluoroloweralkyl.
The expression "salicylaldehyde" includeq, for example, compounds of formula ~C~O
-R7 R8 (X) wherein R6 and R7 are each a member selected rom the group consisting of hydrogen, halo, nitro, loweralkoxy, and loweralkyl;
provided that R6 and R7 are oriented meta to each other if both are other than hydrogen; and R~ is a member selected from the group consisting of hydrogen, loweralkyl, and perfluoro-loweralkyl.
Also included within the expression "salicylaldehyde"
is the bicyclic compound of formula:

~ ~0 R8 (Xa) wherein R8 is as previously defined.
As used herein, the terms "loweralkyl" and "lower-alkoxy" mean stxaight or branched chain saturated aliphatic hydrocarbon radicals having from one to about six carbon atoms such as, for example, methyl, ethyl, isopropyl, pentyl, and the like loweralkyls, and methoxy, ethoxy, isopropoxy, pentoxy and ~7~8~ 310 the like loweralkoxys. The term "primary loweralkyl" means a loweralkyl in which the bonding carbon atom is unbranched such as, for example, methyl, ethyl, isobutyl, pentyl, and the like, but excluding, for example, isopropyl, sec-butyl, and the like. The term "perfluoroloweralkyl" means lowsralkyl in which all hydrogen atoms have been xeplaced by fluoro such as, for example, trifluoromethyl~ tetrafluoroethyl, and the like.
The term "halo" includes fluoro, chloro, bromo, and iodo;
and the term "halide" includes fluoride, chloride, bromide, and iodide.
The 1,3-diketones useful for preparation of the copper (II) 1;3-diketonate complexes of the invention are generally known or may be readily prepared according to the procedures described in Org. Syn.,,Coll. Vol~ 3, 16, 17, 251 (1951) or C. R. Hauser, Org. Reactions, 8~ 59 (1954). The salicylaldehydes useful for the preparation of the subject complexes are also generally known.
The preferred copper (II) 1,3-diketonate and copper (II) salicylaldehyde complexes (promoting agents) of the inr vention may be reprasented by the following formulas:

R

2 Cu (XI~

wherein Rg and Rlo are each members selected from the group consisting of loweralkyl, trifluoromethyl~ phenyl, loweralkoxy, and 2-thienyl, :

~765~ 310 2 (XII) ~ ~ 2 ~C
... , . (X~) wherein X' is a member selected from the group consisting of OS02CF3 and OCH3: and (1~ C~
(gV) wherein Rll is a member selected from the group consisting of hydrogen, halo, nitro, and loweralkoxy.
Certain of the complexes of formula (XIV) are novel (e.g., those wherein X' is -OSO2CF3) and are considered to be part of the present invention. They may be prepared by metathesis of an appropriate complex of formula (X) with one equivalent of a suitable strong acid such as HOSO2CF3.
~0 The remaining dioxo complexes are generally known ~ or may be readily prepared according to the procedures ; described by, for example, E. W. Berg and J. T. Truemper, J. Phys. Chem., 64i 487 (1960); J. H. Bertrand and R. L. Kaplan, ~7~5~ 310 Inorg~ Chem., 4, 1657 (1965); or K. Clarke, J. Chem. Soc. 245 (1963). This latter reference teaches the preparation of the following complexes.

~ 2 [ C~0 ] 2 Cu (II) ~ ~ 1 Cu (II) r L ~XO~ LH3C ~;01 2 L~C~-12 wherein A is a~membèr sèlected from the group consisting of chloro, bromo, iodo, and nitro; and B is a member selected from the group consisting of methoxy, nitro, and chloro.

: B. Complexes with oxoamino li~ands The oxoamino copper ~ complexes of the invention -may be represented by the following formula:
r ~0-~ Rl~ 2 (XVI) wherein " ~0"

~' is intended to encompass all salicylaldimine ~C~7~ 8~ MN 310 and monoamino-1,3-diketonate ligands capable o forming bidentate complexes with copper (II), whatever the substi-tution thereon. The two ligands may be the same or different.
These oxoamino copper (II~ salicylaldimine and copper (II) monoamino-1,3-diketonate complexes and the ligands from which they are made are generally known or may be readily prepared according to the procedures described by R. H. Holm, et al; Prog. in Inorg. Chem., 7, 83(1966) and references contained therein. The ligands are conveniently prepared by reacting the appropriate corresponding dioxo ligand with an equivalent amount of the appropriate amine.
Prefèrred oxoamino copper (II) complexes of the in-; vention may be represented by the following formula:
' . .''-' _ _ 2- - (XVII) Rl 2 wherein R12 is a member selected ~rom the group consisting of hydrogen; loweralkyl; loweralkoxy; hydroxy; loweralkylamino;
diloweralkylamino; phenyl; phenyl substituted with rom one to three members each selected from the group consisting of lower-alkyl, loweralkoxy, and halo; phenylloweralkyl; phenylloweralkyl in whlch said phenyl is substituted with from one to three members each selected from the group consisting of loweralkyl, - loweralkoxy, and halo; phenylamino, and phenylamino in which said phenyl is substituted with from one to three members each ~ selected from the group consisting of loweralkyl9 loweralkoxy, ; and halo; provided that the R12 groups on both oxoamino ligands taken together may be further selected from the group con-sisting of:

~765~ 310 a) ~(CH2)a~C~-(CH2)b~ whereln a and b are integers such that a ~ b is from 1 to 6, and R13 is a member selected from the group con-sisting of hydrogen~ loweralkyl, phenyl and phenyl substituted with from one to three members each selected rom the group con-sisting of loweralkyl, loweralkoxy, and halo;
~C~2)~
b) /~H - CH\ wherein c is an integer rom 3 to 5;
c) o-phenylene or o-phenylene substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, and halo; and d) ~~C~2)d-[NRl4-(cH~)e]f-~Rls-~cH2)g-~ wherein d, e, and g are each 2 or 3, f is O or 1~ and R14 15~ and R15 are each ~elected from the group con-sisting of hydrogen and l~weralkyl.
The complexes wherein both R12 groups are taken together may be illustrated by the following, selected from class a) above:
~ Cu~
N~ ~ N
(CH2)a - ~H ~ (CH2)b R13 (XVIIa) wherein a and b are as previously defined.
More preferred oxoamino copper (II) complexes of the invention may be represented by the following formulas:

R ~ N Cu (XVIII) L ¦ ~ (XIX) ~7 65~G MN 310 wherein: R6, R7, R8, and R12 are as previously defined.
Most preferred copper 1II) salicylaldimine complexes (promoting agents) of the invention may be represented by the following formula:

wherein R12 is a member selected from the group ~onsisting o~
hydrogen; loweralkyl; phenyl; phenyl substituted with from one to three members each selected from the group consisting of :
loweralkyl, loweralkoxy, and halo; and phenylloweralXyl.
The copper (II) complexes oi- the invention may ~e 0 - Ufie~ in place of the prior art copper bronze as a promoting agent--~or the preparation of loweralkyl 2~ R -pyrryl)-o~ j loweralkanoic acid esters hy reacting an N~ pyrrole with a loweralkyl ~-diazoloweralkanoate in the presence of one of said copper ~II) complexes (promoting agents)~
In one embodiment of the method o~ the present invention for preparation of 2-.(N-R'-pyrryl)-~-loweralkanoi~
acid esters, the ~-R'-pyrrole is present in excess, preferably :
about three equivalents for every equi~alent of the loweralkyl :
a-diazoloweralkanoate. The promoting agent is a member selected from the group consisting of compounds of formulas (V) and (XVI), and is present in about 0~1 to about 2 mol percent but pre~erably about 1 mol percent based on the loweralkyl ~diazoloweralkanoate.

The reaction may be con~ucted in the ~-R'-pyrrole as æolvent;

:.

6~
a halogenated hydrocarbon, such as for example, methylene chloride, ~hloroorm~ bromoform, carbon tetrachloride, 1,2-dichloroethane, and the like; an aliphatic hydrocarbon, such as for example, cyclohexane, heptane, and the like; an aromatic hydrocar~Dn~ such as for example, benzene, toluene, xylene, and the like; and the like. The preferred solvent is the ~ R'-pyrrole itself, or a halogenated hydrocarbon, which is .
con~enient for attainment of the required reaction temperature.
The reaction mixture may be heated up to as high as 110C., but ~ convenient operating temperature range is from abou~ 30 to about 80C. The preferred operating temperature depends upon the particular promoting agent used.
A small portion of the loweralkyl ~-diazolower-alkanoate is added initially for reasons of ~afety; i.e., ~o prevent an accu~ulation of the reagent which could result ~n the violent and sudden production of heat and nitrogen gas.
~nce nitrogen evolution has ~egun, the remainder of the loweralkyl ~-diazoloweralkanoate.is added drop by drop main-taining a temperature sufficient for smooth and steady nitrogen evolution by warming or cooling as needed. Subseguent to ~ddition of the loweralkyl ~-diazoloweralkanoate, the mixture may be heated to insure completion of the reaction, but this is freguently unnecessary.
~he mixture of the desired 2-isomer and t~e undesired

3-isomer may be isolated by known techniques, for example by distillationO

~ '76~
A preferred process of the invention is that wherein ~he N-R -pyrrole is ~-methylpyrrole.
A more preferred process of the in~ention is that wherein the promoting agent is a member selected from the group consisting of compounds of formula (XI) wherein Rg is methyl and Rlo is phenyl or Rg and Rlo are both loweralkyl, a compound of formula ~XII), a compound of formula (XIV) wherein X' is methoxy, and compounds of formula (XX) wherein R12 is a member selected from the group consisting of hydroyen, isopropyl, E~chlorop~enyl, and benzyl. These more preferred processes result in very high purity of the desired 2-isomer.
A second more preferred process of the invention is that wherein the promoting agent is a member selected from the gr~up consisting of compounds of formula (XI) wherein R9 is methyl and Rlo is perfluoroloweralkyl or Rg and Rlo are both perfluoroloweral~yl, a compound of formula (XIV) wherein xt is OS02CF3, and compounds of formula (XV) wherein Rll is a membar selected from the group consisting of chloro, hydrogen, and nitro. ~hese more preferred processes result in a large -increase in yield of the desired 2-i~omer.
Better yield and generally bettar purity are obtained through use of the promoting agents and processes of the in- .
vention. The purity of the reaction mixture is as high a~
93-94% in some cases and g~nerally the same as or better than in the prior art, while the yield of the de~ired 2 isomer ~s in~rea~ed by at least l~o and by a~ much as 50% over the yield -in the prior art me~hod~O -j:

`
. MN 310 5~6 While preferred embodiments of the method of the - invention have been set out above hy way of illustration, it should be understood that the present invention encompasses any method ~or preparing loweralXyl 2-~N-R;-pyrryl)-c~lower-5 alkanoic acid esters which comprises reacting N-~'~-pyrrole and loweralkyl ~-diazoloweralkanoate in the presence of a copper (II) 1,3-diketonate, coppex (II~ salicylaldehyde, copper (II) monoamino-1,3-diketonate, or copper ~II) salicylaldimine complex of the invention~
The present invention is further il~ustrated by the following examples:

, :.

;`'' ', .,,,''.

' .

-M~ 310 ~765~3~

E~AMPLE I
.

EthYl 2-(N-me~ylp~rrYl)acetate:
In a flask is placed 9.72 grams (120 mmol) ~-methyl pyrrole and 158 mg (.016 mmole; 105 mol%) Cu(acetylacetonate) abbreviated herein as "Cu(acac)~". The mixture is heated to 50C. after which a few drops of the 4.56 grams (40 mmol~
5 ethyl diazoacetate are added with stirring. Nitrogen gas is evolved after about 1 minute and the mixture darkens, whereupon the remainder o~ the ethyl diazoacetate i5 added drop by drop over a period of 15 minutes. ~he reaction mixture is then heated a~d stirred fox a further 45 minute to insure com~
pletion of the reaction.
The excess and unreacted ~-methylpyrrole is recovered by distillation of the product mixture in vacuo, after which the residue is flash distilled at a pot temperature of 80~100C. (0.5 torr) to yield 2.40 grams of yellow liquid (36% yield based on ethyl diazoacetate) comprising 91% of the desired ethyl 2- ~-methylpyrryl) acetate.

.
'.

~L0765~

EXAMPLE II

Ethx1_2-pyrr~lacetate:
Following the procedure of Example I, but substitu-ting an e~uivalent amount of pyrrole for the ~-methylpyrrole used therein, resultad in 5~/0 yield (based on ethyl dia~o-acetate) of the desired ethyl 2-pyrrylacetate in 94% purity.
For comparison, the prior art process using copper bronze as the promoting agent resulted in only 38% yield ~based on ethyl : diazoacetate) of the desired ethyl 2-pyrrylacetate in 92%
purity.

--19-- .

1076~B6 EXAMPLE III

The purity and yields of the desired 2-isomex ethyl 2-(N-methylpyrryl)acetate obtained following the procedure of Example I but using equivalent amounts o~ illustrative : catalysts of the invention for the Cu(acac)2 used therein are shown in the following table, wherein Y and P stand for percentage yield and percentage purity, re~pectively:

'' ' /

6~
Formula Rg Rlo X Rll R12 Y P
(XI) CH3 phenyl - - - 37 90 CH3 CF3 - _ _ 43 79 t-butyl t-butyl - - - 36 89 CF3 CF3 ~ 44 78 phenyl phenyl - - - 37 87 C~3 0~2H5 - - - 41 84 2-thienyl CF3 - - - 40 83 (XII) - - - - - 40 89 (XIII) - _ _ _ _ 39 86 (XIV) - ~ - OS02CF3 - - 47 81 ~ - OCH3 - - 40 90 (XV)- - - - Cl - 48 80 _ _ - ~2 ~ 47 75 _ _ - OCH3 - 42 83 (XX) - - - - H 46 91 _ _ _ _ OH 42 82 _ _ _ - CH(CH3)2 47 94 ~ benz~l 44 94 _ _ - - ~-ClC6H4 47 90 _ - - - -CH2CH~-* 37 89 - -(CH2CH2)2NH 37 89 - - - - -(CH2CH2~HCH2)2* 38 89 ;

*both R12 groups taken together ~L~7~586 EX~MPLE IV

Bis(5-chlorosalicylaldehyde) Copper(II):
: To a solution of 1.61g of copper(II) nitrate trihydrate and 1.25g of sodium acetate in 25 ml of deionized water is added a warm solution of 2~08g of 5-chlorosalicylaldehyde in 25 ml of 95% ethanol. The mixture is stirred at 45-50C
S for 15 minutes, cooled, and filtered. The yellow-green solid which results, Bis(5-chlorosalicylaldehyde) copper(II), is rinsed with water and 95% ethanol and dried in vacuo.

,~ .
.

M~ 310 S~

EXAMPLE V

Following the procedure of Example IV, but substi-tuting for the 5-chlorosalicylaldehyde used therein, an equiva~ent amount of the suitable starting material, there are prepared the following representative complexes:
Bis(benzoylacetonato) Copper(II);
Bis(2-acetyltetralonato) Copp~r(II);
Bis(2-acetylcyc~lohexanonato) Copper(II);
Bis(1,1,1,2,2,3,3,-heptafluoro-7,7-dimethyloc~ane-

4,6-dionato) Copper(II);
Bis(3-trifluoroacetylcamphorato) Copper(II);
Bis(2,4-heptanedionato) Copper(II);
Bis(l,l,l-txifluoropentane-2,4-dionato) Copper(II~;
Bis[1,1,1,5,5,5-hexafluoropentana-2,4-dionato]
Copp~(II);
Bis(3-methylpentane-2,4-dionato) Copper(II);
Bis(ethylacetoacetato) Copper(II), Bis(3-pivaloyl camphorato) Copper(II3;
Bis(2-furoylacetonato) Copper(II); and Bis(dibenzoylmethanato) Copper(II).

. MN 310 ~6~76~

EXAMPLE VI

~Acetylacetonato) Copper(II) trifluorometh~lsulfonate:
; A suspension of 262 mg. (1 mmole) of Cu(acac)2 in 3 ml of dichloromethane is treated dropwise with stirring with 150 mg (1 mmole) of trifluoromethyl sulfonic acid.
The resulting green solution is decanted from a small amount of residual solid and diluted with hexane, whereupon a gxeen precipitate, (acetylacetonato) Copper(II) trifluoromethyl-sulfonate, results~ m.p. 182~C.

: -24 31~76~;il3~

EXAMPLE VII

Following the procedure of Eæample VI, but substi-tuting for the Cu(acac)2 and the trifluoromethylsulfonic acid used therein, the equivalent amount of suitable ~tarting materials, there are prepared the following complexes (Acetylacetonato~ Copper (II) tri~luoroacetate;
(Benzoylacetonato) Copper (II) fluoro~ulfate;
(Acetyla~etonato) Copper (II) picrate;
(Acetylacetonato) Copper (II) hexafluorophosphate;
(Acetylacetonato) Copp~sr (II) nitrate;
(Acetylacetonato) Copp~3r (II) perchlorate;
(Acetylacetonato) Copper (II) chloride;
(Acet~lacetonato) Copper (II) ethyl~ulfonate;
(Acetylacetonato) Copper (II) benzenesulfonate:
(Acetylacetonato) Copper (II) fluoborate.

M~ 310 EX~WPL~ VIII

Bis~ salicyla~diminoethyl)amine Copper(II)~
To a solution of 2.44g (20 mmol) of salicylaldehyde in 20 ml of absolute ethanol was added 1.03g (10 mmol~ of diethylenetriamine and the whole was allowed ~o stand at ambient temperature for one hour. A solution of Copper (II) S acetate (from 2.42g of Cu(~03~2~3H20 and 1.7g of sodium - acetate) in 20 ml of deionized water was added, and the whole was allowed to stand for 18 hours. The resulting purple crystals were collected by filtration, washed with 75% aqueous ethanol, and dried in vacuo at 70 to yield Bis~ salicylal-diminoethyl)amine Copper(II); m.p. ca. 240C (dec).
:

-~6-~ ~7~S~6 EXAMPLE IX

Following the procedNre of Example VIII, but substi-tuting a~ equivalent amount of triethylenetetramine for the diethylenetriamine use~ therein, there is prepared:
1,2-Bis(~-salicylaldiminoethylamino)ethane Copper(II);
m.p. ca. 240C (dec).

-27- .

~7~6 EXAMPLE X

Following the procedure of Example I, but substi-tuting for the ~-methylpyrrole and ethyl diazoacetate used therein equivalent amounts of the appropriate starting materials, the following 2-pyrryla~etic acid esters are produced in increased yield or yield and purity over the prior art process:
Methyl 2-(N-methylpyr~yl)acetate;
Methyl 2-(~-ethylpyrryl)acetate;
- Ethyl 2-(N-ethylpyrryl)acetate;
n~Propyl 2-(~-methylpyrryl)acetate;
Isopropyl 2-(N-methylpyrryl)acetate;
Methyl 2-(~-methylpyrryl)-~-propionate;
Butyl 2-(M-ethylpyrryl)-Q~propionate;
: Ethyl 2-(~-n-propylpyrryl)-~-isovalerate; and Methyl 2-(~-isobutylpyrryl)-~-acetate.

658~

EXAMPLE XI

BistSalicylaldimino) Copper (II):
Following the procedure of S. V. Sheat and T. ~.
Waters, ~ ucl. Chem., 26, 1221 (1965), 500 mg of bis-(salicylaldehyde) copper (II) was combined with 5 ml of lC%
ammonium hydroxide and the mixture was stirred vigorously for one hour. The solid was filtered off and dried in air, affording : 410 mg of pale green powder identified by its ultraviolet spectrum as bis(salicylaldimino~ copper (II).

31~7~586 EXAMPLE XII

Following the procedures of L. Sacconi et al, J.
Chem. Soc., 1964, 274, 1.22g of salicylaldehyde (10 mmol) in 10 ml of absolute ethanol was treated with 590 mg of iso-propylamine (10 ~mol) at ca. 15. The reaction was stoppered to prevent loss of the volatile amine and allowed to stand for one hour. A solution of 1.21g of Cu (~03)2~3H20 and 0.85g of 30dium acetate in 10 ml of deionized water was added with stirring. Filtration afforded his(N-isopropylsalicylaldimino) copper (II) as a brown solid (air-dried); m.p. 140-143.

~ M~ 310 EXAMPLE XIII

Following the proceduxe of Example XII, but substi-tuting equivalent amounts of the appropriate salicylaldehyde or 1,3 diketcne and amine or hydrazine for the salicylaldehyde and isopropylamine used therein, the following are prepared:
Bis(N-hydroxy3alicylaldimino) Copper (II);
Bis(~-benæylsalicylaldimino) Copper (II);
Bis~-(p-chlorophenyl)salicylaldimino Copper (II~;
Bis[N-(n-hexyl)salicylaldimino~ Copper (II);
Bis~-(p-kolyl)salicylaldimin~ Copper (II);
Bis[~ chlorobenzyl)salicylaldimino] Copper (IT);
~is~-methoxysalicylaldimino] Copper (II);
Bis[N-methylaminosalicylaldimino] Copper (II);
Bis[N-(dimethylamino)salicylaldimino] Copper (II) - Bis C~(phenylamino)salicylaldimino] Copper (II), . Bis[N-(p-chlorophenylamino)salicylaldimino] Copper (II);
' :
; ~ The above Examples have been provided by way of illustration and not to limit the scope of the present in-vention, which scope i9 defined by the following claLms.

;`
.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A method for preparing a loweralkyl 2-(N-R'-pyrryl)-.alpha.-loweralkanoic acid ester of the formula which comprises reacting an N-R'-pyrrole of the formula with a loweralkyl .alpha.-diazoloweralkanoate of the formula in the presence of a copper (II) complex selected from those of formula and wherein: R is loweralkyl;
R' is selected from the group consisting of hydrogen and primary lower alkyl;
R" is selected from the group consisting of hydrogen and lower alkyl;
n is an integer of from 1 to 2;

X is selected from the group consisting of anions of monoprotic strong acids, lower alkoxy radicals and a phenoxy radical;

is a 1,3-diketonate or a salicylaldehyde ligand capable of forming bidentate complexes with copper (II) selected from the group consisting of a) compounds of formula wherein R1 and R3 are each selected from the group consisting of loweralkyl, loweralkoxy, perfluorolower-alkyl, phenyl, 2-thienyl, and .beta.-naphthyl; and R2 is a member selected from the group consisting of hydrogen and loweralkyl;
b) compounds of formula and wherein R4 is selected from the group consisting of loweralkyl, loweralkoxy, phenyl, and perfluoroloweralkyl; and m is 0 or 1;
c) compounds of formula wherein R5 is a member selected from the group consisting of loweralkyl and perfluoroloweralkyl; and d) compounds of formula and wherein R6 and R7 are each selected from the group consisting of hydro-gen, halo, nitro, loweralkoxy and loweralkyl; provided that said R6 and R7 are oriented meta to each other if both are other than hydrogen; and R8 is a member selected from the group consisting of hydrogen, loweralkyl, and perfluoroloweralkyl; and, the group consisting of and wherein R6, R7 and R8 are as defined above and R12 is selected from the group consisting of hydrogen; loweralkyl; loweralkoxy;
hydroxy; loweralkylamino; diloweralkylamino; phenyl substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, and halo; phenylloweralkyl;

phenylloweralkyl in which said phenyl is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, and halo; phenylamino, and phenylamino in which said phenyl is substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, and halo; provided that the R12 groups on both ligands taken together may be further selected from the group consisting of a) wherein a and b are integers such that a + b is from 1 to 6, and R13 is a member selected from the group consisting of hydrogen, loweralkyl, phenyl, and phenyl substituted with from one to three members each selected from the group consisting of loweralkyl, lower-alkoxy, and halo;

b) wherein c is an integer from 3 to 5;

c) o-phenylene or o-phenyline substituted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, and halo; and d) -(CH2)d-[NR14-(CH2)e]f-NR15-(CH2)g-, wherein d, e, and g are each 2 or 3, f is 0 or 1, and R14 and R15 are each selected from the group consisting of hydrogen and loweralkyl.

Claim 2. A method for preparing a loweralkyl 2-(N-methylpyrryl) .alpha.-loweralkanoic acid ester having the formula which comprises reacting N-methylpyrryl with a loweralkyl .alpha.-diazoloweralkanoate represented by the formula wherein R is loweralkyl and R" is selected from the group consisting of hydrogen and loweralkyl. In the presence of a copper(II) complex selected from the group consisting of ; ; ;

; ;

; and wherein R9 and R10 are each members selected from the group consisting of loweralkyl, perfluoroloweralkyl, phenyl, loweralkoxy, and 2-thienyl; X is a member selected from the group consisting of OSO2CF3 and OCH3: R11 is a member selected from the group consisting of hydrogen, halo, nitro and loweralkoxy; and R12 is a member selected from the group consisting of hydrogen, loweralkyl, phenyl, phenyl substi-tuted with from one to three members each selected from the group consisting of loweralkyl, loweralkoxy, and halo;

and phenylloweralkyl.

3. The method of claim 2 wherein the copper (II) complex is:

wherein R9 and R10 are each members selected from the group consisting of loweralkyl, perfluoroloweralkyl, phenyl, loweralkoxy and 2-thienyl.

4. The method of Claim 2, wherein the copper (II) complex is

5 . The method of Claim 2, wherein the copper (II) complex is

6. The method of Claim 2, wherein the copper (II) complex is wherein X' is a member selected from the group consisting of OSO2CF3 and OCH3.

7. The method of Claim 2, wherein the copper (II) complex is wherein R11 is a member selected from the group consisting of hydrogen, halo, nitro and loweralkoxy.

8. The method of Claim 2, wherein the copper (II) complex is a member selected from the group consisting of ;
;

and wherein R9 is methyl and R10 is phenyl or R9 and R10 are both t-butyl; and R12 is a member selected from the group consisting of hydrogen, isopropyl, p-chlorophenyl, and benzyl.

9. The method of Claim 2 wherein the copper (II) complex is a member selected from the group consisting of:

; ; and wherein R9 is methyl or trifluoromethyl, R10 is trifluoro-methyl, and R11 is a member selected from the group con-sisting of chloro, nitro, and hydrogen.

10. The method of Claim 2 wherein the N-methyl-pyrrole is present in excess, based on the loweralkyl .alpha.-diazoloweralkanoate.

11. The method of Claim 2 wherein the copper (II) complex is present in about 1 mol percent of the amount of loweralkyl .alpha.-diazoloweralkanoate.

12. The method of claim 2 wherein the reaction mixture is heated to a temperature from about 30° to about 80°C. during the reaction.

13. A copper (II) 1,3-diketonate complex useful as a promoting agent for the preparation of 2-(N-methyl-pyrryl) acetic acid esters which has the formula: