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Asymmetric Bromination of Enantiomerically Pure Acetals of Alkyl Aryl Ketones.

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[I21 IR spectrum (KBr) of 4. v=3099, 1562, 1469, 1410, 1224, 1167, 1054,
932, X I 3. 745, and 65 I cm '. An evaluation of the IR spectrum by means
of N-deuterated 4 is in progress.
1131 4 forms monoclinic crystals, space group P2,/c, a = l0.088(3).
h=4.987( I ) , c = 15.464(4)
b= 108.36(2)", 2 = 2 ; 710 reflections,
R =0.030. Further details of the crystal structure investigation may be
obtained from the Fachinformationszentrum Energie, Physik, Mathematik GmbH, 11.7514 Eggenstein-Leopoldshafen 2 (FRG), on quoting
the depository number CSD-51701, the names of the authors, and the
journal citation.
[I41 Remarkably, expansion of C C C angles on this order of magnitude is
observed even for maleic acid. M. N. G. James, G. 3. B. Williams, Acta
Crystallogr. 8 3 0 (1974) 1249.
[IS] A similarly short N N distance (2.626
has also been found for the hydroperchlorate salt of the "proton sponge" 4,5-bis(dimethylamino)fluorene. H. A. Staah, T. Saupe, C. Krieger, Angew. Cbem. 95 (1983) 748.
Angen. Cbem. Int. Ed. Engl. 22 (1983) 731.
1161 We thank Prof. 0.Ermer (Universitat Koln) for helpful discussions in
the interpretation of the X-ray structure data of 4 .
[I71 According to investigations of Dr. K. Pramod (note added in proof, l a n uary 22, 1986): 4 has also been converted into the zinc, copper, and
cobalt complexes.
0'2 3 0
L C H ,
1 (4R, 5 R )
Za, b
H %r
0 0
R R:
%r H
4 (4R. 5 R . 1 ' R )
3 ( 4 R , 5 R , 1's)
Asymmetric Bromination of Enantiomericaily Pure
Acetals of Alkyl Aryl Ketones
Table I. Yields and diastereomeric ratios for the bromination of la-Id to
By Graziano Castaldi,* Silvia Cavicchioli, Claudio
Giordano,* and Fulvio Uggeri
In the course of our studies on the synthesis of 2-arylalkanoic acids, we required acetals of optically active afunctionalized alkyl aryl ketones as intermediates."' To
this end, we investigated the a-bromination of the enantiomerically pure alkyl aryl acetals 1 and ent-1, which are
readily prepared from alkyl aryl ketones and the dimethyl
ester of (2R,3R)- and (2S,3S)-tartaric acid in high
Thus, by adding bromine (10 mmol) to a solution of the
(4R,5R) acetal 1 (10 mmol) in CCI, (20 mL) at 15°C in the
presence of a catalytic amount of HBr, a mixture of the
diastereomeric a-bromo acetals 3 and 4 is obtained in
high yield with 3 in high diastereomeric excess ('H-NMR,
HPLC, see Table 1). As expected, the absolute configuration at C-1 is reversed when ent-1 is used as starting material.[41The absolute configuration at C-1 of 3 and 4 was
assigned by means of their rearrangement (1,2-aryl shift
with 100%inversion of configuration) into the corresponding 2-arylalkanoic acids of S and R configuration, respectiveIy."."
The reaction appears to be very general as it can be applied to acetals derived from many alkyl aryl ketones as
well as from other tartaric acid derivative^.'^^ The main feature of the reaction is the high diastereoselectivity observed even at room temperature; in contrast, most asymmetric syntheses require lower temperatures."] A catalytic
amount of HBr is required to promote the reaction, the
role of HBr being to set u p the equilibrium between the
acetal 1 and its enol forms Za, b ( E / Z isomers).
The observed asymmetric induction is presumably the
result of diastereofacial selection in the kinetically controlled attack of electrophilic bromine on the double bond
of the enol ether intermediates 2a, b with anchimeric assistance by the hydroxyl group.
The asymmetric a-bromination of acetals has been employed as the key step of a new synthesis of enantiomeri["I Dr. G. Castaldi. Dr. S. Cavicchioli, Dr. C. Giordano, Dr. F. Uggeri
Zambon Chimica S.p.A., Organic Chemistry Department
Via Cimabue 26/28, 1-20032 Cormano-Milano (Italy)
Angen Chem. Inr Ed. Engl. 25 (1986) No. 3
+ 4 [%]
3 :4
. 10 [a]
[a] The hromination of l a requires two moles of bromlne per mole of l a .
cally pure 2-arylalkanoic acids.lS1 The method has also
been successfully applied to the industrial manufacturing
of optically pure (2s)-( +)-2-(6-methoxy-2-naphthyl)propanoic acid (Naproxen),lS1which is the most important of
the optically active 2-arylalkanoic acids.171
Moreover, a-bromo acetals 3 and 4 have been hydrolyzed to the corresponding optically active a-bromo ketones,@'thus extending the synthetic scope of the reaction.
Thus, the mixture of 3a and 4a (Table 1 ) was hydrolyzed,
without racemization, by treatment with methanesulfonic
acid in methanol.[91
Received: November 5 , 1985;
supplemented. December 18, 1985 [Z 1521 IE]
German version: Angew. Chem. 98 (1986) 273
[I] C. Giordano, G. Castaldi, F. Uggeri, Angew. Chem. 96 (1984) 413; Angew.
Chem. Inf. Ed. Engl. 23 (1984) 413.
(21 The alkyl aryl acetals 1 were prepared by reacting the corresponding alkyl aryl ketones with the dirnethyl ester of tartaric acid in the presence of
trimethyl orthoformate and an acid catalyst.
[3] For a review article on the use of tartaric acid in asymmetric syntheses,
see D. Seebach, E. Hungerbiihler in R. Scheffold (Ed.): Modern S p h e r i c
Methods. Vol. 2, Salle/Sauerlander, Aarau 1980, p. 91-171; for the use of
chiral acetals in other asymmetric syntheses, see: J. Fujiwara, Y Fukutani,
M. Hasegawa, K. Maruoka, H. Yamamoto, J. Am. Cbem. SOC.106 (1984)
5004; 1. Arai, A. Mori, H. Yarnamoto, ibid. 107 (1985) 8254: E. A. Mash,
K. A. Nelson, ibid. 107 (1985) 8256; M. Suzuki, K. Kimura, S. Terashima,
Tetrahedron Lett. 52 (1985) 6481.
[4] All products were fully characterized by 'H-NMR, IR, and mass spectroscopy as well as by HPLC and elemental analyses.
[5] G. Castaldi, S. Cavicchioli, C. Giordano, F. Uggeri, Eur. Pat. 158913
(1985), Zdmbon Chimica; G. Castaldi, S. Cavicchioli, C. Giordano, F.
Uggeri, unpublished.
0 VCH Verlagsgesellschafi mbH. 0-6940 Wernheim, I986
0570-0833/86/0303-0259 $ 02 50/0
161 J. D. Morrison, H. S. Mosher (Eds.): Asymmetric Organic Reaclrons.
American Chemical Society, Washington D.C. 1976; J. D. Morrison
(Ed.): Asymmetric Synthesis. Vols. 1-5, Academic Press, New York 19831985.
[7] T. Y. Shen, Angew. Chem. 84 (1972) 512; Angew. Chem. Int. Ed. Engl. I 1
(1972) 460; S. H. Ferreira, J. R. Vane: Antiinflammnto<v Drugs. Springer.
Berlin 1979, p. 321.
[8] G. Castaldi, C. Giordano, S. Cavicchioli, unpublished.
19) Exper.imenfa1 procedure: A 90: 10 mixture of 3a and 4a (10 mmolj was
added to a solution of methanol ( 5 mL) in methanesulfonic acid (20 nlL).
T h e reaction mixture was stirred at 20°C for 18 h and then poured onto
crushed ice and extracted with dichloromethane. The organic phase was
washed with water and a 2% NaHCO, solution and dried over sodium
sulfate. Evaporation of the solvent in vacuo gave 2.8 g (75%) of 2-(S)( )-2-bromo- 1-(5-bromo-6-methoxy-2-naphthyl)propan-1-one.[a];?=
+ 130" (c=0.5, CHCI,). The enantiomeric excess was 80% as determined
by 'H-NMR analysis with the optically active shift reagent Eu(hfc)?.
h v (UV)
3, M = Fe
Metal Dependence of Cyclometalation
and Arene C-H Activation in the Photolysis of
C ~ ~ - H ~ M I P ( C H ~ C H ~ C(M
H ~=PFe,
in Benzene""
By Martin Antberg and Lutz Dahlenburg*
The cleavage of hydrocarbon C-H bonds at metal centers is currently the subject of much research in organometallic chemistry. Besides a few derivatives of "hard" metal
ions,"] the Ir' and Rh' complex fragments (C,R,)(L)M
(R=H, Me; L=CO, PMe3)Iz1have proved particularly potent as arene and alkane activators. Also promising are the
Ruo and 0s' species (C,&)(L)M ( L = a l k y l p h ~ s p h a n e ) [ ~ ~
and the tetrakis (P ligand) systems L4M of iron, ruthenium,
and osmium. The latter often undergo intramolecular
isomerization, however, to give cyclometalated hydridometal(l1) complexes,[41 so that only the 16e fragment
(Me2PCH2CH2PMe2)2M (M=Fe, Ru, O S ) [ ~ " -and
[(MeO),P],(Me,P),M (M = Ru, OS)'~'']have proved suitable
so far for the intermolecular C-H cleavage.
We have now found that the photolytic dehydrogenation
of the cis-dihydrides (pp3)FeH2 1[6b1and (pp3)RuH2 2@'l
(both of which are stabilized by our "pp3" ligand
in C6H6 leads, depending on the
central metal atom, to either intra- or intermolecular C-H
activation. In the iron system, internal addition to
H-CH2P results in formation of the three-membered-ring
derivative 5 . In the ruthenium system, on the other hand,
H-C6HS cleavage results in formation of the phenyl hydride 6.['.]
The structures of 5 and 6 were established by elemental
analysis and s p e c t r o s ~ o p y . ' ~The
~ - ~dt splitting of the 'Hcoupled FeC resonance of 5 (J(PC) = 13, J(CH2)= 148 Hz)
rules out a CH2 cleavage product formed by metalation of
the trimethylene chains, as has been discussed, for example, for ( d m p p ) ( w e H (dmpp= Me2P(CH2),PMe2,
For both reactions, we postulate intermediate 16e dS
fragments (pp3)M, 3 and 4, respectively, because these incorporate particularly advantageous structural features for
the oxidative C-H addition owing to their bent, cis-unsaturated configuration."' The rneta/-dependent transition be[*] Prof. Dr. L. Dahlenburg, DipLChem. M. Antberg
lnstitut fur Anorganische und Angewandte Chemie der Universitat
Martin-Luther-King-Platz 6, D-2000 Hamburg 13 (FRG)
[**I Oligophosphane Ligands, Part
16. This work was supported by the
Deutsche Forschungsgemeinschaft, the Fonds der Chernischen Industrie, and Degussa AG.-Pan 15: M. Antberg, L. Dahlenburg, N. Hock,
C. Prengel, Phosphorus Sulfur, in press.
0 VCH Verlagsgesellschaft mbH, 0-6940 Weinheim. 1986
tween intra- and intermolecular C-H addition, the first example of its kind, might be due to the different crowding
of the groups and the different chelate ring strain in the
required intermediates 3 and 4 : The M-CI distances in the
dichloro complexes [FeC12(pp3)], ca. 239 and 241 ppm,[6c1
and [RuC12(pp3)j,ca. 251 and 252 ppm,[6d1
demonstrate that
the covalent radius of the ruthenium atom stabilized by the
pp3 ligand is at least 1 0 p m larger than that of the iron
atom in the same coodination environment. The 16e Ruo
system should therefore be more strained and more open
at the central metal atom, which, on the one hand, suppresses the cyclometalation and, on the other hand, facilitates the approach of a solvent molecule. Increased ring
strain and reduced crowding of the groups are also responsible, according to K a r ~ c h , [ ~for
" the lignnd-dependent
change in reactivity from intramolecular addition in the
case of [Me2P(CH2)3PMe2]2Feto intermolecular reaction
in the case of IMe2P(CH2)2PMe,J2Fe.The transition from
intramolecular C-H addition by the Ru and 0 s species
(Me3P),M to intermolecular C-H cleavage by the phosphite-substituted 16e fragment [(Me0)3P]2(Me3P)2M,described by Werner and G o t ~ i g ,likewise
~ ~ ~ . ~represents
~ ~
favoring of the intermolecular reaction in the case of lessfilled coordination spheres.
Received: November 6, 1985;
revised: December 30, 1985 [Z 1523 IE]
German version: Angew. Chem. 98 (1986) 214
[I] J. P. Rothwell, Polyhedron 4 (1985) 177, and references cited therein.
[2j a) A. H. Janowicz, R. G. Bergman, J. A m . Chem. SOC.104 (1982) 352; 105
(1983) 3929; b) M. J. Wax, J. M. Stryker, J. M. Buchanan, C. A. Kovac, R.
G. Bergman, ibid. 106 (1984) 1121; c j R. A. Periana, R. G. Bergman, Urganometallics 3 (1984) 508; d) j. K. Hoyano, W. A. G. Graham, J. Am.
Chem. SOC.104 (1982) 3723; e) J. K. Hoyano, A. D. McMaster, W. A. G.
Graham, ibrd. 105 (1983) 7190; f) A. J. Rest, 1. Whitell, W. A. G . Graham,
J. K. Hoyano, A. D. McMaster, J. Chem. SOC.Chem. Commun. 1984. 624;
g) W. D. Jones, F. J. Feher, J . Am. Chem. SOC.I04 (1982) 4240; Orqanomefallics 2 (1983) 562; J. A m . Chem. Soc. 106 (1984) 1650.
131 a) H. Kletzin, H. Werner, Angew. Chem. 95 (1983) 916; Anqew. Chem. Int.
Ed. Engl. 22 (1983) 873; b) H. Werner, K. Roder, J. Orqanomet. Chem.
281 (1985) C 38: c) R. H. Morris, M. Shiralian, ibid. 260 (1984) C 47.
[4] a) H. H. Karsch, H.-F. Klein, H. Schmidbdur, Anqew. Chem. 8 7 (1975)
630; Angew. Chem. Int. Ed. Enql. 14 (1975) 637; Chem. Ber. 110 (1977)
2200; b j H. H. Karsch, D. Neugebauer, Angew. Chem. 94 (1982) 322; Angew. Chem. Int. Ed. Engl. 21 (1982) 312; c) H. H. Karsch, Chem. ger. 1 1 7
(1984) 3123; d j J. W. Rathke, E. L. Muetterties, J. A m . Chem SOC. 97
(1975) 3272; d) H. Werner, R. Werner, J. Orqanomef. Chem. 209 (1981)
0570-0833/86/0303-0260 $ 02.50/0
Angew. Chem. Int. Ed. Enql. 25 (1986) No. 3
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