Electronically tuned ligands

A new class of chiral bidentate ligands to transition metals is disclosed which compounds have the following structure: ##STR1## wherein the substituents are as defined herein.

BACKGROUND OF THE INVENTION
 Asymmetric synthesis is becoming more and more important in the
 pharmaceutical industry. There is growing regulatory pressure to approve
 only those enantiomers of drugs that have the desired biological activity.
 For safety reasons and to demonstrate efficacy, regulatory agencies are
 taking the position that only those enantiomers with pharmaceutical action
 should be administered, apart from the enantiomers with little or no
 action or even adverse or toxic effect. The total market for
 enantiomerically pure pharmaceuticals is projected to be ninety billion
 U.S. dollars by 2000. To prepare such large quantities of drug only via
 resolution will often be cost prohibitive. Chiral catalysis will no doubt
 complement traditional methods such as resolution or chiral separation.
 Many asymmetric syntheses involve use of catalysts, and typically employ
 chiral ligands and late transition metals. Bidentate ligands play a
 central role in catalyst design for asymmetric synthesis. Ligands that
 have been used successfully in asymmetric synthesis include the BINAP
 family of catalysts for asymmetric reductions and isomerizations (For
 example, see Asymmetric Catalysis in Organic Synthesis, Noyori, R., Ed.;
 John Wiley and Sons: New York, 1994, p.16-121).
 ##STR2##
 Bisoxazolines for asymmetric cyclopropanation and cycloadditions have been
 reported (For a review, see Ghosh, A. K.; Mathivanan, P.; and Cappiello,
 J. Tetrahedron: Asymmetry 1998,9, 1-45).
 ##STR3##
 Pyridyloxazolines for asymmetric hydrosilations have also been described
 (Brunner, H.; Obermann, U. Chem. Ber. 1989, 122, 499).
 ##STR4##
 Even more recently, electronically "mixed" bidentate ligands with two
 different ligating heteroatons (N--O, P--N, P--O) have emerged. Such
 ligands have been shown empirically to outperform P--P bidentate ligands
 in a number of synthetically important transformations. Such "mixed"
 ligands are the phosphino-oxazolines described by Pfaltz et al.
 (Synthesis, 1997, 1338), Helmchen et al. (Angew. Chem. Int. Ed. Eng.,
 1997, 36 (19)2108), and Williams et al., (Tetrahedron, 1994, 50, 9).
 ##STR5##
 The Heck reaction is one of the most versatile catalytic methods for C--C
 bond formation. In this reaction, an aryl or alkenyl halide or triflate is
 coupled with an alkene, as shown in the following scheme:
 ##STR6##
 The catalytic cycle starts with an oxidative addition of organic halide or
 triflate to a Pd (0) complex, followed by insertion of an alkene. The
 resulting Pd (II) alkyl complex then undergoes .beta.-hydride elimination.
 Several isomeric products can be formed, depending upon the structure of
 the substrate. In path (a), the C--C double bond is restored in the
 original position and a stereogenic center is not created. However, if
 .beta.-hydride elimination takes path (b), the stereogenic C atom
 introduced in the insertion step is retained. For path (b), the use of
 chiral palladium complexes makes it possible to perform such reactions in
 an enantioselective manner. Pfaltz et al. showed that chiral
 phosphino-oxazolines are very efficient ligands for enantioselective Heck
 reactions (Synthesis 1997, 1338). For example, asymmetric Heck arylation,
 using Pd/phosphino-oxazolines, produces substituted dihydrofuran in 90%
 yield and 92% ee, as shown below:
 ##STR7##
 The phosphino-oxazolines described and taught by Pfaltz et al., Helnchen et
 al. and Williams et al. are superior to BINAP catalysts in the Heck
 reaction in that: (a) such ligands are insensitive to the nature of the
 added base; (b) have more ability to suppress side products; and (c) have
 very high enantioselectivity. However, such phosphino-oxazolines have a
 major deficiency. The above Heck arylation required six (6) days, an
 extremely long reaction time. It appears that the R substituent of the
 phosphino-oxazolines is not in conjugation with the ligating atoms, and
 therefore functions solely in a steric role. From the long reaction time
 or the low turnover of these catalysts, it is clear that the donicity of
 the bidentate ligand is not optimized.

THE INVENTION
 A new class of chiral bidentate ligands to transition metals has been
 discovered. Such ligands can be electronically tuned at will for optimum
 performance. (For an example of electronic tuning in asymmetric catalysis
 using a different ligand class see: E. N. Jacobsen et al., J Am. Chem.
 Soc. 1991, 113, pp. 6703 -6704). Additionally, such ligands can be used to
 prepare chiral compounds of high optical purity. This new class of chiral
 ligands to transition metals can be easily tuned electronically by the
 replacement of a single substituent.
 Here, and throughout this application unless otherwise specified, the term
 "alkyl" refers to a saturated aliphatic radical containing from one to ten
 carbon atoms. "Alkyl" refers to both branched and unbranched alkyl groups.
 Preferred alkyl groups are straight chain alkyl groups containing from one
 to eight carbon atoms and branched alkyl groups containing from three to
 eight carbon atoms. More preferred alkyl groups are straight chain alkyl
 groups containing from one to six carbon atoms and branched alkyl groups
 containing from three to six carbon atoms. "Alkyl", as used herein,
 includes unsubstituted alkyl radicals, those radicals that are partially
 or fully halogenated and those radicals substituted with one to four,
 preferably one or two, substituents selected from halo, amino, cyano,
 nitro, methoxy, ethoxy, hydroxy, keto, carboalkoxy, or amido. The term
 "cycloalkyl" refers to the cyclic analog of an alkyl group, as defined
 above. Preferred cycloalkyl groups are saturated cycloalkyl groups
 containing from three to eight carbon atoms, and more preferably three to
 six carbon atoms. "Alkyl" and "cycloalkyl", as used herein, include
 unsubstituted alkyl and cycloalkyl radicals, those radicals that are
 partially or filly halogenated and those radicals substituted with one to
 four, preferably one or two, substituents selected from halo, amino,
 cyano, nitro, methoxy, ethoxy, hydroxy, keto, carboalkoxy, or amido. It
 should be understood that any combination term using an "alk" or "alkyl"
 prefix refers to analogs according to the above definition of "alkyl". For
 example, terms such as "alkoxy", "alkylthio" refer to alkyl groups linked
 to a second group via an oxygen or sulfur atom.
 The term "halo" or "halogen" refers to a halogen selected from fluoro,
 chloro, bromo, or iodo.
 The new chiral bidentate ligands can be represented by Formula (1) below:
 ##STR8##
 wherein
 M is Phosphorus or Arsenic (P, As)
 X, Y and Z can be independently selected from hydrogen, aryl (pendant or
 fused), halogen, alkyl, alkoxy, cyano, nitro, amino, alkylamino,
 dialkylamino, --CO.sub.2 H, --CO(C.sub.1-6 alkoxy), --CO(C.sub.1-6 alkyl),
 --NCOH, --NCO(C.sub.1-6 alkyl), NSO.sub.2 (alkyl), --NSO.sub.2 (aryl),
 hydroxy, sulfonoxyalkyl, sulfonoxyaryl, or alkoxyalkyl.
 R1 is selected from the group consisting of hydrogen, alkyl, branched
 alkyl, cycloalkyl, aryl selected from the group phenyl and naphthyl, which
 may optionally be substituted with one or more alkyl, halogen, alkoxy,
 acyl, phenoxy, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino,
 carboalkoxy, amido, or sulfoxy group; heteroaryl selected from the group
 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-benzofuryl,
 3-benzofuryl, 2-thiophenyl, 3-thiophenyl, 2-benzothiophenyl,
 3-benzothiophenyl, 2-pyrrolyl, 3-pyrrolyl, 2-indolyl, 3-indolyl,
 benzimidazolyl, imidazolyl, quinolinyl, isoquinolinyl, oxazolyl,
 benzoxazolyl, thiazolyl, and pyrimidinolyl, which may be optionally
 substituted with one or more alkyl, halogen, alkoxy, acyl, phenoxy, cyano,
 nitro, hydroxy, amino, alkylamino, dialkylamino, carboalkoxy, amido, or
 sulfoxy group; C.sub.2-6 acyl, aroyl selected from the group benzoyl and
 napthoyl, optionally substituted one or more group as described above for
 aryl; heteroaroyl selected from the group 2-furoyl, 3-furoyl, 2-pyridoyl,
 3-pyridoyl, 4-pyridoyl, 2-benzofuranoyl, 3-benzofuranoyl, 2-thiophenoyl,
 3-thiophenoyl, 2-benzothiophenoyl, 3-benzothiophenoyl, 2-pyrroyl,
 3-pyrroyl, 2-indoloyl, 3-indoloyl, benzimidazoyl, imidazoyl, quinolinoyl,
 isoquinolinoyl, oxazoyl, benzoxazoyl, thiazoyl, and pyrimidoyl, optionally
 substituted with one or more group as defined above for heteroaryl;
 SO.sub.2 R4 where R4 is chosen from the group alkyl, aryl and heteroaryl,
 which may be optionally substituted as described above.
 R2 and R3 can be the same or different and can be selected from hydrogen,
 aryl or heteroaryl as defined above, substituted aryl or heteroaryl as
 defined above, (with substituents as defined above), alkyl, branched
 alkyl, cycloalkyl, benzyl, substituted benzyl, with substituents as
 defined for aryl, or R2 and R3 together may form a fused carbocyclic ring.
 The amidine portion must be constrained to form a ring (ring B), and said
 ring must be either 5- or 6- membered. For example, B may be an
 imidazoline or tetrahydropyrimidine ring.
 At least one, or both, of R2 and R3 must be attached to a chiral carbon, of
 either (R) or (S) absolute configuration.
 The compounds of the present invention are particularly useful in Heck
 reactions. In such instances, preferred X,Y, and Z would be H, alkyl, aryl
 as described above, halogen, alkoxy, cyano, nitro, amino, alkylamino, and
 dialkylamnino. Preferred R1 would be H, alkyl, benzyl, aryl, substituted
 aryl as described above, heteroaryl and substituted heteroaryl as
 described above, C.sub.2-6 acyl, and aroyl selected from the group of
 benzoyl, naphthoyl, and pyridoyl, optionally substituted with one or more
 groups as described above for aryl. Preferred R2,R3 would be H, alkyl,
 cycloalkyl, aryl and substituted aryl as described above, and heteroaryl
 and substituted heteroaryl as described above. Preferred B ring size might
 be five membered, that is, an imidazoline ring.
 Solvent effects can be quite important in asymmetric synthesis. For the
 asymmetric Heck reaction in particular, the ligands of Formula (1) are
 most effective when used in a non-polar solvent. If a polar solvent is
 used, disappointing yields can be obtained that may vender use of the
 ligands of the present invention not commercially feasible.
 The phosphino- and arsenoamidines of Formula (1) are electronically
 tunable. By varying the R1 substituent from electron withdrawing groups
 (e.g., acyl, benzoyl) to electron donating groups (e.g., alkyl, phenyl,
 benzyl), the basicity and donicity of the ligand can be easily modified
 and altered to suit the requirements of any given asymmetric synthesis.
 To practice the instant invention, a complex is prepared between a ligand
 of Formula (1) and a transition metal, such as palladium. Other transition
 metals such as rhodium, ruthenium, iridium, nickel or platinum can be
 employed for catalyzed asymmetric hydrogenations. For catalyzed,
 enantioselective isomerization of allyl species, rhodium or cobalt would
 be employed. For catalyzed asymmetric cyclopropanations, rhodium,
 palladium or copper would be used. For catalyzed asymmetric
 hydroformylations of olefins, cobalt, rhodium, platinum or palladium would
 be used. Rhodium would also be used for catalyzed, asymmetric
 hydrosilylations of ketones. Rhodium or palladium would be used in
 catalyzed asymmetric hydrosilylation of olefms. However, this provides
 only a brief list of catalyzed, asymmetric reactions where the ligands of
 the instant invention could be successfully used.
 The complex formed using the ligands of the present invention could be
 isolated or could be allowed to form in situ prior to addition of the
 substrate molecule. In general, the reaction would be allowed to proceed
 under the influence of the catalyst produced by the novel ligand until
 completion, the product then being isolated and optical purity measured.
 The phosphino- and arsenoamidines of Formula (1) can be readily prepared
 from commercially available chiral amines or chiral amines which are
 themselves independently synthesized by methods known to those skilled in
 the art. Examples of such amines are the following:
 ##STR9##
 The new ligands are readily prepared, as shown in Schemes 2 and 3. As shown
 below (Scheme 2) condensation of the trimethylaluminum complex of
 (R,R)-cyclohexanediamine with 2-fluoromethylbenzoate produced the
 fluoroimidazoline 4 in 85% yield. Fluoride displacement with commercially
 available Ph.sub.2 PK in refluxing THF provided the phosphinoimidazoline 5
 of Formula (1), where X, Y and Z are H, M is P, R1 is H and R2 and R3 form
 a fused cyclohexyl ring in 65% yield without chromatography.
 ##STR10##
 Acylation of 5 produced in high yield the phosphinoimidazoline 6 of Formula
 (1), where R1 is acetyl and X, Y, Z, M, R2 and R3 are as described for 5.
 Alternatively, a typical ligand can be prepared as shown in Scheme 3,
 below. Formation of imidate 7 from 2-fluorobenzamide is accomplished with
 triethyloxonium tetrafluoroborate. Condensation of the imidate with a
 chiral diamine such as (S,S)-1, 2-diphenylethylenediamine then readily
 furnished fluoroimidazoline 8. Displacement of the fluoride with potassium
 diphenylphosphide, followed by acylation with 2-naphthoyl chloride then
 furnished ligand 10, of Formula (1), where R1 is 2-naphthoyl, X, Y, and Z
 are hydrogen, M is P, and R2 and R3 are both (S)-phenyl.
 Other ligands of Formula (1) can be prepared by methods analogous to those
 described above.
 EXPERIMENTAL SECTION
 Synthesis of a typical ligand, 10 (See Scheme 3):
 ##STR11##
 2-Fluoro-ethylbenzimidate tetrafluoroborate (7):
 To 13.6 g 2-fluorobennamide (98 inmol, 1 eq.) was added 100ml 1M
 triethyloxonium terafluoroborate/methylene chloride solution (100 mmol,
 1.02 eq.) via canula under N.sub.2. After stirring 18 h at ambient
 temperature, the reaction mixture was filtered, and the resultant solid
 recrystallized from 100ml ethyl acetate to give 13.0 g of
 2-fluoro-ethylbenzimidate tetrtuoroborate 7 (52% recrystallized) as a
 colorless solid. M.p. 128-131.degree. C.; .sup.19 F NMR (DMSO).delta.:
 -113.8, -154.2 ppm.
 2-(2'-Fluorophenyl)-(4S,5S)-diphenyl-4,5-dihydroimidazole (8):
 To a 100 ml flask was charged 5.00 g imidate 7 (19.6 mmol, 1 eq.), 4.16 g
 (S,S)-1, 2-diphenylethylenediamine (19.6 mmol, 1 eq.), 50 ml
 dichloromethane, and 6.3 ml triethylamine (45.3 mmol, 2.3 eq.) in the
 order given. After stirring 4 hours at ambient temperature, the reaction
 mixture was poured into 50 ml water, the phases separated, and the aq.
 phase reextracted with dichloromethane. The combined methylene chloride
 layers were washed with 2% aq. ammonium chloride, dried with magnesium
 sulfate, filtered, and the filtrate evaporated in vacuo to give an oil.
 This oil was dissolved in 25 ml boiling hexane, cooled to 0.degree.,
 filtered and air dried to give 4.80 g of
 2-(2'-fluorophenyl)-(4S,5S)-diphenyl4,5-dihydroimidazole 8 (78%) as a
 colorless solid. M.p. 122-124.degree. C.; MS (ES+): MH+317; .sup.19 F NMR
 (CDCl.sub.3).delta.: -113.6 ppm.
 2-(2'-Diphenylphosphinophenyl)-(4S,5S)-diphenyl-4,5-dihydroimidazole (9):
 13.9 ml of 0.5M potassium diphenylphosphide/THF (6.95 mmol, 1.1 eq.) was
 heated to 60.degree. in a thermostated oil bath. To this warm solution was
 then added a solution of 2.00 g fluoride 8 (6.32 mmol, 1 eq.) in 5 ml THF
 via syringe over 2 minutes. The resulting solution was then heated at
 reflux for 1 hour, cooled to room temperature and quenched by the addition
 of 10 ml water. The resulting mixture was extracted with methylene
 chloride (2.times.25 ml), dried (MgSO.sub.4), and the solvents removed in
 vacuo to give an oil.
 This oil was then chromatographed on C18 silica gel eluting with 5:1
 acetonitrile:water to give, after drying under high vacuum, 2.13 g (70%)
 of 2-(2'-diphenylphosphinophenyl)- (4S,5S)-diphenyl-4,5-dihydroimidazole 9
 as a colorless, amorphous foam. MS (ES+): MH+483; .sup.31 P NMR
 (CDCl.sub.3).delta.: -9.6 ppm.
 2-(2'-Diphenylphosphinophenyl)-3-(2"-naphthoyl)-(4S,5S)-diphenyl-4,5-dihydr
 oimidazole (10):
 A 10 ml round bottom flask was charged with 150 mg dihydroimidazole 9
 (0.311 mmol, 1 eq.), 76 mg p-dimethylaminopyridine (0.622 mmol, 2 eq.),
 1.5 ml of 1,2-dichloroethane, and 89 mg 2-naphthoyl chloride (0.467 mmol,
 1.5 eq.) in the order given. After 1 hour, the volatiles were removed in
 vacuo and the residue chromatographed on silica gel eluting with 2%
 methanol/dichloromethane to give 117 mg of the ligand,
 2-(2'-diphenylphosphinophenyl)-3-(2"-naphthoyl)-(4S,5S)-diphenyl-4,5-dihyd
 roimidazole (10)(60%) as a colorless foam. MS (ES+): MH+637; .sup.31 P NMR
 (CDCl.sub.3) .delta.: -11.0 ppm.
 Typical use of the invention in asymmetric synthesis (See Scheme 4):
 ##STR12##
 A 10 ml headspace vial was charged with 11.4 mg Pd.sub.2 dba.sub.3 (0.0125
 mmol, 0.05 eq.), 19.1 mg ligand 14 (0.0275 mmol, 0.11 eq.) and 1.5 ml
 Ph.sub.2 O. The resulting solution was evacuated/filled with Ar
 (3.times.), then placed in a preequilibrated 50.degree. oil bath for 1
 hour. To the resulting solution was then added a solution of triflate 11
 (98mg, 0.25 mmol, 1 eq.), pentamethylpiperidine (MP, 181 microliters, 1.00
 mmol, 4 eq.) and 1.0 ml Ph.sub.2 O via syringe, at once. The resulting
 solution was heated 16h at 95.degree., cooled, and chromatographed
 directly on silica gel eluting with 4:1 hexane:ethyl acetate to give 51 mg
 of spirolactam 12 (85% yield). Analysis of this material by chiral HPLC
 using a Chiracel OD column, 250 mm.times.4.6 mnm, using 99:1 Hexane:IPA at
 a flow rate of 1.0 ml/minute, revealed the enantiomeric excess of the
 product to be 46.7%, that is, 46.7%ee. The enantiomer obtained with this
 ligand, where R1 was an electron withdrawing group, was the (+)-isomer.
 When the reaction was repeated with ligand 13, where R1=methyl, an
 electron donating group, the opposite enantiomer, the (-)-isomer, was
 obtained, in 20.5%ee. Although this initial method is not yet fully
 optimized, the concept of controlling enantioselectivity by electronic
 tuning of the R1 substituent is clearly validated. When commercial
 (S)-BINAP was examined for this transformation, the product obtained,
 (+)-12, using Ph.sub.2 O as solvent, was formed in 90% yield, yet only
 14.6% ee, while in dimethylacetamide as solvent, the yield was 80%, and
 the observed enantiomeric excess was only 28.9% ee. When the (S)-t-butyl
 phosphinooxazoline of Pfaltz/Helmchen/Williams was used in anisole, the
 isolated yield of (+)-12 was only 20%, and the observed enantiomeric
 excess was 46.3%ee. When that ligand was used in dimethylacetamide, the
 isolated yield was higher, 47%, yet the enantiomeric excess was only 14.9%
 ee. Table 1, shows results for 18 of the new ligands when evaluated in the
 asymmetric Heck reaction.
 ##STR13##
 TABLE 1
 Ligands Evaluated for the Asymmetric Heck Reaction.
 Entry R1 R2,R3 X, Y, Z Solvent Yield % ee
 MI*
 1 Acetyl (S,S)-diphenyl X = Y = Z = H Anisole 68% 31.2
 1, (+)
 2 Benzoyl (S,S)-diphenyl X = Y = Z = H Anisole 60% 36.0
 1, (+)
 3 Benzoyl (S,S)-diphenyl X = Y = Z = H Ph.sub.2 O 76% 42.2
 1, (+)
 4 Benzoyl (S,S)-diphenyl X = Y = Z = H p-Dioxane 66% 47.1
 1, (+)
 5 p-phenyl-benzoyl (S,S)-diphenyl X = Y = Z = H Ph.sub.2 O 73% 40.5
 1, (+)
 6 Methyl (S,S)-diphenyl X = Y = Z = H DMA 17% 20.5
 2, (-)
 7 p-methoxybenzoyl (S,S)-diphenyl X = Y = Z = H Anisole 60% 33.4
 1, (+)
 8 p-methoxybenzoyl (S,S)-diphenyl X = Y = Z = H Ph.sub.2 O 27% 47.6
 1, (+)
 9 p-cyanobenzoyl (S,S)-diphenyl X = Y = Z = H Ph.sub.2 O 83% 36.6
 1, (+)
 10 1-napthoyl (S,S)-diphenyl X = Y = Z = H Ph.sub.2 O 85% 40.6
 1, (+)
 11 2-napthoyl (S,S)-diphenyl X = Y = Z = H Ph.sub.2 O 68% 44.6
 1, (+)
 12 t-butoxycarbonyl (S,S)-diphenyl X = Y = Z = H Ph.sub.2 O 92% 32.5
 1, (+)
 (BOC)
 13 p-methoxybenzoyl (S,S)-di-(m-xylyl) X = Y = Z = H Ph.sub.2 O 88%
 41.8 1, (+)
 14 2-napthoyl (S,S)-di-(m-xylyl) X = Y = Z = H Ph.sub.2 O 85%
 46.7 1, (+)
 15 p-methoxybenzoyl (S,S)-diphenyl X = Y = H; Ph.sub.2 O 8% 35.3
 1, (+)
 Z = benzo
 fused
 (napthalene)
 16 p-methoxybenzoyl (R,R)-di-(p- X = Y = Z = H Ph.sub.2 O 20% 33.4
 2, (-)
 methoxyphenyl)
 17 p-dimethylamino (R,R)-diphenyl X = Y = Z = H Ph.sub.2 O 25% 37.0
 2, (-)
 benzoyl
 18 Acetyl (R,R)-cyclohexyl X = Y = Z = H Anisole 10% 29.2
 1, (+)
 *MT = Major Isomer: 1 = first eluted, (+)-isomer; 2 = second eluted,
 (-)-isomer.
 Notes: 1) All reactions at 100.degree. C. unless otherwise noted.
 2) All ee's determined by chiral HPLC (see "Typical use of the invention in
 asymmetric synthesis" (Scheme 4) section).
 3) M = P for all ligands.
 4) B ring = imidazoline (5 membered ring) for all ligands
 5) X = Y = H for all ligands
 6) Z = H for all ligands except entry 15 where Z = fused benzo ring
 (naphthalene) 7) All yields are for isolated, chromatographically pure 12.
 While in the foregoing description the detailed embodiments of the present
 invention have been set forth, it will be understood by those skilled in
 the art that considerable variation may be made in such detail without
 departing from the spirit of the invention.