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Enantiomerically Pure Tertiary Alcohols by TADDOL-Assisted Additions to KetonesЧor How to Make a Grignard Reagent Enantioselective.

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[Ru(CNtBu),(CH,Ph),] (9) and [Ru(CNfBu),(SiMe,Cl),]
(10) were both isolated in good yield (78 % and 71 %, respectively). NMR spectra indicate that 10, like 4 and 7, is formed
as the trans isomer, while 9, surprisingly, is formed as the cis.
Extensions of these reactions to more complex alkyls have
already, for example, led to the preparation of five-membered
metallacycles. Stoichiometric quantities of a,w-dihaloalkyls
such as 1,4-dibromobutane and a,a'-dichloro-a-xylene were
added to freshly prepared solutions of K,-6 to give the respective complexes 11 and 12 in reasonable yield (40 % each).
The accessibility of K,-3 and K,-6 as reactive intermediates supports our previous suggestion that the ability of isocyanides to stabilize metals in negative oxidation states has
been severely underestimated. The chemistry of the (isocyanide)metalates appears as rich and diverse as that of carbonylmetalates. The successful preparation of a range of Sn,
Si, and C-centered derivatives of K,-3 and K,-6 more specifically supports the analogy between these complexes and
tetracarbonylferrate. Thus the path to other (isocyanide)ruthenates with other functional groups has been paved.
Experimental Procedure
4: A solution of 2 (0.35 g, 0.5 mmol) in T H F (25 mL) was reduced by dropwise
addition of 4.2 molar equiv of a 0.47 M solution of K[C,,H,] in T H F (4.25 mL)
at -78°C to give a clear, burgundy-red solution. Dropwise addition of
Ph,SnCI (0.39 g, 1 mmol) in T H F (10 mL) gave a clear tan solution, which was
warmed to room temperature, and the solvent was removed under reduced
pressure. The product 4 was extracted into warm hexane. When the solution
was slowly cooled to - 78 "C. white needles (0.49 g, 0.3 mmol) formed. 7,9, 10,
11, and I2 were prepared by procedures similar to those used to prepare 4.
Enantiomerically Pure Tertiary Alcohols by
TADDOL-Assisted Additions to Ketones-or How
to Make a Grignard Reagent Enantioselective **
By Beat Weber and Dieter Seebach *
Tertiary stereogenic centers are generally more difficult to
generate selectively than secondary ones, as evidenced by the
few examples of C-C bond formation with enantio- and
diastereoselective nucleophilic addition to ketones.['] Thus,
we were very happy to see that primary alkyl Grignard
reagents in the presence of TADDOL (1) magnesium alkoxide (TADDOL: a,a,a',a'-tetraaryl-2,2-dimethyl-1,3-dioxolane-4,5-dimethanol) add to aryl, vinyl, and alkynyl ketones
with enantioselectivities up to > 99 : 1.
The general procedure, which was optimized for acetophenone (products 2-8), is quite straightforward: TADDOLL,]is
doubly deprotonated with 2 equivalents of Grignard reagent,
and to the resulting solution in T H F is added another equivalent of RMgBr (resulting in an approximately 0.1 M diolate
and RMgBr solution). The reaction mixture is cooled to
- 100 "C and a ketone is added to the resulting suspension.
After stirring at -100 "C for 9 h, the reaction mixture is
given an aqueous workup [Eq. (a)]. The results summarized
la Aryl
= Ph
l b Aryl = 2-Naphthyl
Received: July 30, 1991 [Z 4837 IE]
German version: Angew. Chem. 1992, 104, 55
CAS Registry numbers:
2, 128507-02-8; K2-3, 137822-91-4; 4, 137822-92-5; 5, 64315-53-3; K2-6,
137822-93-6; 7,137822-94-7; 9,137822-95-8; 10,137822-96-9; 11,137822-97-0;
12,137822-98-1 ; K[C,,H,], 4216-48-2; Ph,SnCI, 639-58-7; Me,SiCI,. 75-78-5;
1A-dibromohutane, 110-52-1; a,='-dichloro-o-xylene, 612-12-4.
[l] G. F. Warnock, N. J. Cooper, Organometallics 1989. 8, 1826.
[2] For a review of transition-metal isocyanide complexes see: a) L. Malatesta, Pvog. tnorg. Chem. 1959, 1, 283; b) L. Malatesta. F. Bonanti, Isocyanide Complexes of'Transition Metals, Wiley, New York, 1969; c) P. M.
Treichel, Adv. Organomet. Chem. 1973, 113 21; d) Y. Yamamoto, Coord.
Chem. Rev. 1980, 32, 193; e)E. Singleton, M. E. Oosthuizen, Adv.
Organomet. Chem. 1983, 22, 209.
[3] Similar explanations have been advanced to account for the bending of
isocydnide ligands in the few cases for which this has been crystdllographically established [4, 51.
[4] a) G. K. Barker, A. M. R. Galas, M. Green, J. A. K. Howard, F. G. A.
Stone, T. W Turney. A. J. Welch, P. Woodward, 1 Chem. Soc. Chem.
Commun. 1977,256; b) J.-M. Bassett, M. Green, J. A. K. Howard, F. G. A.
Stone, ibid. 1977, 853; c) J.-M. Bassett, D. E. Berry. G. K. Barker, M.
Green. J. A. K. Howard, F. G. A. Stone, d Chem. SOC.Dahon Pans. 1979,
[5] a) J. Chatt, C. M. Elson, A. J. L. Pombeiro. R. L. Richards, G. H. D.
Royston, J. Chem. Soc. Dalton Pans. 1978, 165; b) A. J. L. Pombeiro, 1.
Chatt. R. L. Richards, J. Organomet. Chem. 1980, 190, 297.
[6] J. A. S. Howell, J.-Y Saillard, A. LeBeuze, G. Jaouen, J. Chrm. Soc. Dalton
Puns 1982, 2533.
[7] a) J. P. Collman, Ace. Chem. Res. 1975, 8, 342; b) J. P. Collman, L. S.
Hegedus, J. R. Norton, R. G. Finke, Principles and Applications qfOrganotransition Metal Chemistry, University Science Books, Mill Valley, CA,
USA, 1987, p. 755.
[8] L. Malatesta, G. A. Padoa, A. Sonz, Carr. Chin?. Ital. 1955, 85, 1111.
[Y] The 1670 cm-' absorption does not have a Lorentzian line shape and is
tentatively assigned to C-N stretching absorptions of an isocyanide complex which exists as multiple ion pairs, while the narrower 1580 cm-'
absorption is assigned to ring-breathing modes of the 2,6-Me2C,H,NC
[lo] For leading references see: V. S. Leong, N. J. Cooper, Orgunometallu
1987, 6. 2000.
Ill] a) C. T. Lam, P. W! R. Corfield, S. J. Lippard. J. A m . Chem. Sor. 1977, 99,
617; b) C. M. Giandomenico, C. T. Lam, S. .I.Lippard, ibid. 1982. 104.
1263; c) S. Warner, S. J. Lippard, Organometo//irs 1986, 5 , 1716.
[12] P. A. Leach, J. A . Corella 11, S. J. Geib, N. J. Cooper, unpublished.
mbH, W-6940 Wemheim, 1992
13) NH&I I H20
in Table 1 were obtained with 0.5 mmol runs, but larger scale
reactions are also possible (see the Experimental Procedure).
The following reaction characteristics have been observed
to date:
[*I Prof. Dr. D. Seebach, Dipl. Chem. B. Weber
Laboratorium fur Organische Chemie der
Eidgenossischen Technischen Hochschule
ETH-Zentrum. Universititstrasse 16, CH-8092 Zurich (Switzerland)
[**I The results described herein are part of the projected dissertation of B.
Weber; first presented at the ESOC-7 Symposium, Namur (July 17,1991).
$3.50+ .2S/0
Angew. Chem. Int. Ed. Engl. 31 (19921 No. 1
Table 1. Addition of Grignard reagents to ketones in the presence of (BrMg), diolates
of 1 [Eq. (a)]. Ratios of enantiomers were determined by G C analyses on cyclodextrin
capillary columns: >99: 1 means that the second enantiomer cannot be detected. The
optical rotations are given for [arb:values in methanol.
R in RMgBr
and in 2-8
C,H,COCH, [a]
C,H,COCH, [b]
methyl ketone
4-( l-cyclohexenyl)-3butyn-2-one
cyclohexyl methyl
benzyl methyl ketone
Product Ratio of
2(X = H )
3(X = H )
4 (X = H)
5 ( X = H)
7 (X = OCH,)
8 (X = H)
99.1 (+)
>99:1 (+)
>99:1 (-)
>99:1 (+)
96:4 (+)
97:3 (+)
95:5 (-)
95:s (+)
97:3 ( + )
85:15 ( - )
40 [CI
92:s (-)
98:2 (+)
98:2 (+)
[a] This reaction was run 3 times (0.5-IOmmol scale) yielding 2 with 97.798.3% e e ; 10 mmol scale run see below. [b] At -78 "C: 69% yield, ratio ofenantiomers
94:6. [c] In addition to 13 the 1,4-adduct PhCH(Et)CH,COCH, was also formed (40%
yield, ratio of enantiomers 70: 30).
Addition of ethyl- and propylmagnesium bromide to acetophenone occurs from the Re-face (determined by comparison of the optical rotation of 2 and 3 with literature
dataC3"l). For this reason all compounds of the same type
(2-8) are shown with (R)-configuration.
Even' with only 0.25 equivalents of the 1a Mg alkoxide
the (+)-enantiomer of 4 was formed preferentially
(92: 8).[3b1
Steric hindrance (especially from iC,H, and tC,H,
Grignard reagents, higher aryl ketones, or ortho-tolyl
methyl ketone) decreases the rate of reaction drastically
(products 9 and 10).
With the tetra-j3-naphthyl-TADDOL 1bLZa1
the enantioselectivity may be somewhat greater than with the tetraphenyl analogue (product
Aliphatic methyl ketones do not react as well as aromatic
ones (products 11-16).
The heteroaromatic methyl ketones 3-acetylpyridine and
2-acetylthiophene give good results (products 17 and 18).
If the solvent is changed from THF to Et,O (under otherwise identical conditions) stereoselectivity is lost.
Stereoselectivity is much lower for reactions with benzaldehyde than with aromatic methyl ketones. However,
a reversal of the stereochemical course is observed in this
case when the solvent is changed from THF to Et,O
[Eq. (b)] .[3d1
(S)/(R) = 85:15
Angnv. Chem. Int. Ed. Engl. 31 (1992) No. 1
(S)/(R) = 21:79
The effect caused by the addition of chiral alkoxides to
polar organometallic compounds has been thoroughly investigated for Li compounds (LiX effect)[41and can be rationalized by assuming either aggregate formation [(metalR),(metal-X*),] (here RMgOR* as well), or by chiral Lewis
acid (R*OMgBr) activation of the ketone in the rate-determining step. Whatever the mechanism of this reaction is
(heterogeneous reaction mixture!), the high degree of enantioselectivity obtained in a nucleophilic alkyl-transfer to a
keto carbonyl group is unprecedented.
Experimental Procedure
2: In a 250 mL Schlenk tube equipped with magnetic stirring bar and PTIOO
thermometer, 10 mmol (4.66 g) TADDOL l a was dissolved in 40 mL of THF
(distilled from K) under argon atmosphere and cooled to -70 'C. To the
colorless solution was added 31 mmol (8.9 mL 3.5 M in ether) EtMgBr. The
cooling bath was removed, another 70 mL T H F added, and the reaction mixture allowed to warm to room temperature, The colorless solution was then
cooled to - 105 "C [5] resulting in the formatlon of a colorless precipitate.
Under vigorous stirring 9.4 mmol (1.13 g) acetophenone was added. Stirring
was continued for 9 h at - 105" to - 100 "C. Afterwards the reaction mixture
was quenched with 40 mL of a saturated NH,CI solution and ether was added.
The organic layer was separated, washed with brine, and dried over anhydrous
Na,SO,. The solvent was removed under reduced pressure and the product was
freed from TADDOL by distillation in a kugelrohr apparatus (0.1 Torr,
150°C). Crude 2 (1.17 g, ratio of enantiomers 99: 1) was obtained, containing
20% acetophenone. Pure 2 was isolated after flash chromatography (solvent:
pentane/ether 10: 1) and distillation. Yield: 0.88 g (62%), ratio of enantiomers
= +17.3 (neat).
Received: August 26, 1991 [Z 4890 IE]
Geman version: Angew. Chem. 1992, 104, 96.
CAS Registry numbers:
l a , 93379-48-7; l b , 137365-09-4; 2, 1006-06-0; 3, 52992-90-2; 4R, 7346488-7; 4S, 19641-54-4; 5, 137628-36-5; 6, 137628-37-6: 7R, 137628-38-7; 7 s .
137628-39-8;8R, 137628-40-1;SS, 137628-41-2;9R, 137628-42-3;9 s . 13752467-5; 10R, 137628-43-4; IOS, 137628-44-5; I l R , 137628-45-6;11s. 137628-467; 12R, 137694-58-7; 12S, 137694-59-8: 13R, 137694-60-1; 13S, 137694-61-2;
14R,137628-47-8;14S,137647-80-4; 15R, 115921-18-1;15S, 33204-54-5: 16R,
55016-95-0; 16S, 56640-51-8; 17R, 137628-48-9; 18R, 137628-49-0. EtMgBr,
925-90-6: PrMgBr, 927-77-5: BuMgBr, 693-03-8; 4-(1-cyclohexenyl)-3-butyn2-one, 13757-03-4;(R)-4-phenylhexan-2-one, 115651-75-7; (S)-4-phenylhexan2-one, 16460-85-8;(S)-a-ethylbenzenemethanol, 613-87-6: (R)-a-ethylbenzenemethanol, 1565-74-8; bromo-3-butenylmagnesium, 7103-09-5; bromooctylmagnesium, 17049-49-9: acetophenone, 98-86-2; 4-methoxyacetophenone,
100-06-1; 4-brornoacetophenone. 99-90-1; propiophenone. 93-55-0, a-tetralone. 529-34-0; I-cyclohexenyl methyl ketone, 932-66-1 ; D-lonone. 791896-62-4; cyclohexyl methyl ketone, 82377-6; (E)-4-phenyl-3-buten-2-one,
76-7; benzyl methyl ketone, 103-79-7: 3-acetylpyridine, 350-03-8: 2-acetylthiophene, 88-15-3; benzaldehyde, 100-52-7.
[I] For some diastereoselective syntheses of P-hydroxycarbonyl derivatives (aldols) which areformally derived from ketones (tert-hydroxy groups) see: D.
Seebach, L. Widler, Helv. Chim. Acta 1982, 65, 1972-1981; D. A. Evans,
M. D. Ennis, T. Le, N. Mandel, G. Mandel, J. Am. Chem. Sor. 1984, 106,
N. Kinkel, Chimia 1991,45,114-117
1154-1156; D. Seebach, U. Gysel, .I.
and literature cited therein.
[2] Syntheses of TADDOLs and their application in Ti-catalyzed enantioselective additions of R,Zn to aldehydes are described in: a) A. K. Beck, B.
Bastani, D. A. Plattner, W
. Petter, D. Seebach, H. Braunschweiger, P. Gysi,
L. LaVeccia, Chimia 1991,45,238-244; b) B. Schmidt, D. Seebach, Angew.
Chem. 1991, 103, 100-101; Angew. Chem. I n f . Ed. Engl. 1991,30,99-101:
c) D. Seebach, L. Behrendt, D. Felix, ibid. 1991, 103,991-992; and 1991.
30,1008-1009: d) B. Schmidt, D. Seebach, ibid. 1991,103,1383; and 1991,
30, 1321.
[3] a) (R)-(+)-2-Phenyl-2-butanol and -pentanol: for determination of the
configuration see: D. J. Cram, J. Allinger, J. A m . Chem. SOC. 1954, 76,
4516-4522 and M. Tramontini, L. Angiolini, C. Fouquey, J. Jacques, Tetruhedron1973,29,4183-4187;b)Under thesameconditionsasin the 1 : l run
the yield drops to 20%. c) With a-naphthyl-TADDOL12aI only traces of 10
are formed, with 11 % ee; cf. the results for R,Zn addition[2d]. d) Analysis
and correlation see [2b-d].
Verlagsgesellschaff mbH, W-6940 Weinhelm. 1992
0570-0833192jOlOl-0085 $3.50+ .25/0
141 For discussions see the following review articles and literature cited therein:
D. Seebach, Proc. R. A . Welch Foundutrun Conf: Chem. Res. X X X V I I ,
(Stereospecificity in Chemistry and Biochemistry) 1984, 93-145: D. Seehach, Angew. Chrm. 1988, 100, 1685-1715; Angew. Chem. In(. Ed. Engl.
1988. 27. 1624-1654 (there especially Table 9). Structure of [(BuLi),(tBuOLi),]: M. Marsch, K. Harms, L. Lochmann. G. Boche, ibid. 1990,
102. 334-336; and 1990. 29. 308-309. Newer applications of the LiX*
effect: M. Murakata, M . Nakajima, K. Koga, J. Chem. Soc.. Chrm. Cornmun. 1990, 1657- 1658. Cf. discussion on autocatalysis and asymmetric
amplification for reactions of polar metal derivatives: H. Wynherg, Chimiu
1989, 43, 150- 152; A. H. Alberts. H. Wynberg, J. Am. Chcm. Soc. 1989.
/ / I . 7265- 7266, R. Noyori, M. Kitamura, Angew. Chem. 1991, 103. 3455; Angew. Chem. h r . Ed. EngI. 1991. 30, 49-69.
[5] For a description of a suitable low-temperature apparatus see D. Seebach,
A . Hidber, Chimiu 1983. 37. 449-462.
phase. Our experimental findings provide a gratifying confirmation of the theoretical predictions.
Dissociative ionization (electron impact, 70 eV)16] of nhexylphosphane (C,H,,PH,)i71 abundantly provides ions
(mi. 48) whose structure was identified['] as the ylide ion
[CH,PH,]+', [1]+'.Mass selection of this ion and subsequent
collisional activation (collision gas 0, , 80 % transmission,
73 afforded the collisional activation (CA) mass spectrum
shown in Figure 1a which features peaks diagnostic for [1]+'
at miz 34 ([PH,]+') and miz 14 ([CH,])+'. In agreement with
the earlier studyLB1
this CA mass spectrum is significantly
different from that of the isomeric radical cation
[CH,PH,]+', [Z]", (Fig. 1 b).[91Note that this spectrum does
not contain the rn/z 34 peak characteristic of [1]+' and that
its low-mass region is dominated by the signal at m / z 15,
characteristic for an intact methyl group.
The Phosphorus Ylide CH,PH, is Stable
in the Gas Phase**
By Helmut Keck, Wiihelm Kuchen,* Peter Tommes,
Johan K. Terlouw,and Thomas Wong
Dedicated to Professor John L. Holrnes on the occasion
of his 60th birthday
The phosphorus ylide CH,PH, 1 (inethylenephosphorane) is one of the most often discussed hypothetical molecules in the chemistry of organophosphorus compounds.
This is because it is the simplest member of the class of
phosphorus ylides which have a great synthetic potential in
the Wittig reaction."] A great number of theoretical studies
deal with predictions of the structure, reactivity, and bonding properties of this molecule and its ionized conterpart.[21
According to these reports 1 can formally be represented as
a methylene-phosphane adduct in which the C-P bond has
partial double-bond character.
Fig. 1. CA mass spectra of (a) [l]" ( m / r 48) and (h) [Z]" ( m / z 48).
Although the phosphorus ylide 1 is 237 kJmol-' higher in
energy than its isomer methylphosphane, CH,PH,, 2, the
two isomers are separated by a high energy barrier (2 + 1:
378 kJmol-').[31 The ionized ylide [I]+' is also less stable
than the radical cation [2]" but the difference in their energies, A E = 40 kJmol-', is less than that between their neutral counterparts. Both ions lie in deep potential wells with
significant barriers towards dissociation or isomerisation
([Z]" -+ [l]": 220 k J m ~ l - ' ) . [ ~ I
These theoretical predictions led to the suggestionL3]that
the technique of neutralization-reionization mass spectrometry (NRMS)[41be used to generate 1 by reduction of its
radical cation [1]+'.After we first established the structure of
the ion [1]+' using collisional activation (CA) mass spectrometry,['' we were able to show that its reduction in an
NRMS experiment indeed leads to the formation of the
elusive neutral ylide 1 as a stable species in the rarefied gas
Prof. Dr. W. Kuchen. Dr. H. Keck, DipLChem. P. Tommes
Institut fur Anorganische Chemie und Strukturchemie der Universitit
Universititsstrasse 1. D-W-4000 Diisseldorf 1 (FRG)
Prof. Dr. J. K . Terlouw. T. Wong
McMaster University, Department of Chemistry
1280 Main Street West, Hamilton, Ontario LXS4M1 (Canada)
This work was supported by the Fonds der Chemischen hdustrie and the
National Sciences and Engineering Research Council of Canada
(Q VCH Verlagsgesellsrhall mbH, W-6940 Weinhelm, 1992
A neutralization-reionization (NR) experiment on [I]''
involving neutralization by electron transfer to cyclopropane (80 % T,"']) followed after roughly 1 ps by reionization with 0, (80 % T ) yields the N R mass spectrum which
features an intense "recovery signal" at m/z 48 (Fig. 2). Quite
likely this reflects the stability of the ylide 1 and may point
to relatively favorable Franck-Condon factors in the vertical
electron-transfer processes [l]" --$I + [l]". Note, however, that the intensity distribution of the peaks in the NR
Fig. 2. N R mass spectrum of [l]+'( m / z 48); insert (upper spectrum): the interference-free N R mass spectrum of ions [l]'. resulting from the sequence
[1]+' 1 i
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