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New Evidence for Zwitterionic Intermediates in the Wittig Reaction.

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disubstituted succinic anhydrides and succinimides"] and
can be explained in terms of Biirgl's and Dunitz's hypothesisl'', according to which the angle of nucleophilic attack at
the carbonyl group is greater than 90", thereby favoring
reaction path B over A (cf. Fig. 1).
the Wittig reaction"', whereas the four-membered heterocyclic oxaphosphetanes (2) were regarded as high-energy species too short-lived for detection. After low temperature
N M R studies had revealed the presence of-fairly stableoxaphosphetanes rather than the expected betainesi2I, a new
hypothesis emerged claiming that oxaphosphetanes would
always form directly from the components, ylid and aldehyde, bypassing a zwitterionic precursori2'.
\ I
I?
-P
Fig. I Pmsihle reaction paths for nucleophilic attack at the carhonyl group of
geminally dimethylated succinic anhydride / / b ) .
To our knowledge this is the first example of regioselective
addition of a carbon nucleophile in such a system where
there are two possible modes of attack.
0,'
\
,c=c,
t
\I
-P-0
I I
Procedure
,c-c
A solution of n-butyllithium (43.5 ml, 0.100 mol) in hexane (2.3 M ) is added dropwise (within 30 min) at 0 "C under
argon to a stirred solution of hexamethyldisilazane (21.3 ml,
0.102 mol) in anhydrous tetrahydrofuran (40 ml). After cooling to -78"C, 0.101 mol of the ester (2a) or (2b) is added
within 15 min to the solution and stirring continued for a
further 45 min. T o the resulting a-lithioacetic ester solution
is added dropwise over 20 min a solution of the anhydride
( l a ) or (lb) (0.05 mol) in tetrahydrofuran (60 ml). The mixture is stirred for 2.5 h in a methanol/dry-ice bath while the
temperature is allowed to increase to -20°C. After treatment with 8 ml conc. hydrochloric acid and 50 ml water, it is
then concentrated by evaporation in a rotary evaporator.
The neutral solution is adjusted to p H 2 with conc. hydrochloric acid and extracted with ether (5 x 50 ml). The combined extracts are dried over sodium sulfate and the solvent
removed in a rotary evaporator. The P-ketoadipic acid esters
(3a) and (3b) crystallize from ether/hexane. The products
obtained o n reaction of ( l b ) with (2b) are esterified with
ethereal diazomethane solution in the usual way and the esters (3c) and (4c) are purified by bulb-to-bulb distillation.
Received: March 19. 1979 [Z 260 IE]
German version: Angew. Chem. Y l . 656 (1979)
CAS Registry numbers:
(la). IOX-30-5; (Ib). 17347-61-4; ( 2 ~ )71010-30-5;
.
(26). 53503-61-0 /-?a).7101031-6: ( I b J . 71010-32-7; ( 3 ~ )71010-33-8:
.
(4cJ. 71010-34-9
[I1 G
W. Kenner. J Rrmmer. K. M Smith, J. F. Unsworrh, J . Chem. Soc. Perkin
Trans. 1 1977. 332: D. K . Baneriee. K. M. Sii'ananduiuh. J. Org. Chem. 26,
I
/
I
\'
I21
This simplification of the reaction mechanism has, however, one great drawback: the postulated['I (2, + 2.J-cycloaddition does not unequivocally account for the cis-stereoselectivityl" of the Wittig reaction in "salt-free media" nor in any
way explain the salt effectf3' on the stereochemistry and reaction rate. Therefore, we support the original view that adduct
formation proceeds ilia a betaine-like transition state and
that an equilibrium is rapidly established between the betaines (1) and the-generally but not always-more stable
oxaphosphetanes (2). Electrophilic reagents such as lithium
iodidef4], formaldehyde[51,and triphenylborane"' trap betaines from the equilibrium. We have now obtained further
evidence for the fast and reversible transition between oxaphosphetanes and betaines by means of isotopic labeling.
A solution of salt-free triphenylphosphonioethylid in tetrahydrofuran was treated at - 75 "C consecutively with
formaldehyde solution["' and sec-butyllithium. Dideuterioformaldehyde was then added to the resulting "betaine-ylid"
(3b). After subsequent addition of potassium terr-butoxide
and warming to 25 "C, 2-methylallyl alcohol could be separated in 80% yield, being doubly deuteriated equally at the
carbon adjacent to oxygen or at the terminal olefinic carbon
(NMR results). The same product mixture was formed when
deuterium-free formaldehyde was added to the deuteriated
betaine-ylid (3a).
1634 (1961).
121 D. M Bailey. R. €. Johnson. J. Org. Chem. 35. 3574(1970): J. B. P. A . Wipeberg. 11 €. Srhoemuker. W. N . Speckamp. Tetrahedron 34. 179 (197X).
[ 3 ] H . E. Burgi. Angew. Chem. X7.461 (1975): Angew. Chem. Int. Ed Engl. 14,
460 (1975): R. E. Rosenfiefd j r . . J. D. Dunitz, Helv. Chirn. Actd 61. 2176
(197X).
\
/
\
New Evidence for Zwitterionic Intermediates in the
Wittig Reaction[**]
By Manfred Schlosser and Huynh Ba Tuong[*I
Dedicared to Professor Andre S. Dreiding on the occasion of
his 60th birthday
For a long time open-chain "P-betaines" (1) were considered the decisive and momentarily stable intermediates of
['I
Prof. Dr M . Schlosser, Dr. Huynh Ba Tuong
InWtuc de Chimie Organique de I'Universite
Rue de la Barre 2. CH-I005 Lausanne (Switzerland)
[**I
This work was supported by the Schwei7,erischer Nationalfonds m r Forderung der Wisenschaftlichen Forschung (Project 2.467.0.75 and 2.693.0.76).
Angew (%em. Inr b-d. Engl. I H llY7')J No. X
The "P-NMR spectrum of the adduct formed from the
zwitterion (3) and formaldehyde shows a major signal at
6 = -55 (accompanied by a weaker signal at 6 = -51, rel. to
0 Verlag Chemre, GmbH, 6940 Weinherm, 1979
0570-0X3.l/ 79/080X-063.Z
S 02.50/0
633
85% H,P04), compatible with an oxaphosphetane structure
(5). The question remains whether this intermediate is
formed directly on combining the reaction partners or
whether it is formed indirectly via a betaine precursor, formulated as the chelate (4). In either respect, the two species
( ( 4 ) and (5a)/(5b))must be in an equilibrium with each other. which apparently is very mobile even at - 80 "C. For, on
addition of acetyl chloride, which reacts spontaneously with
lithium alkoxides at - 80 "C, to the betaine-ylid/formaldehyde adduct, we obtained 2-methylallyl acetate in which
once again both types of methylene groups were isotopically
labeled in equal distribution.
The reaction of aliphatic or aromatic aldehydes with betaine-ylids to give ally1 alcohols usually proceeds with high
regio- or stereo~electivity["'~.This in no way contradicts the
postulated betaine/oxaphosphetane equilibrium. On the
contrary, due to this equilibrium the reaction can proceed cia
the sterically least hindered oxaphosphetane (no bulky
groups in cis position) to give the energetically most favorable product[x1.
Received: June 6. 1979 [Z 257 II;]
German version: Angew. Chem. 0 1 . 675 (1979)
CAS Registry numbers:
(.lo/, 71010-07-6: / 3 u ) . (ionic form). 71010-08-7. 13h). 71010-09-X. (.?b). (ionic
form). 71010-10-1; /4), 71032-51-4; /5u/, 71010-11-2; /5b/. 71010-12-3; I.1-dideuterio-2-methyl-2-propen-I-ol,
71010-13-4; 3,3-dideuterio-2-methyl-2-propen-I01, 71010-14-5
A Fragmentational Approach to Macrolides:
(5-E, &Z)-6-methyl-5,&undecadien-lI-olidel*"
By Daniel Sternbach, Mass-vuki Shibuya, Fritz Jaisli, Marco
Bonetti, and Albert Eschenmoser[*'
The cleavage of C C single bonds according to the general scheme All1has proved to be a n effective method for the
modification of carbon frameworks and indeed constitutes
the preparatively most useful reaction available today in
,
heterolytic fragmentations'2'. This type of process has found
specific application especially in the synthesis of cyclic compounds of medium ring size'''. Using the title compound (3)
as a n example, we demonstrate here the application of this
reaction principle in the preparation of unsaturated macro-
c H3
(41
(3)
Scheme 1. The yields are based on analytically pure products.
[ I ] Reviews: A. W. Juhnmn: Ylid Chemistry. Academic Press. New, York 1966;
M. Sc.hlo\.rer. Top. Stereochem 5. 1 (1970); M. Sch/o.s.ser in F Korte. H. Zinzmer. K. Niedenzu: Methodicum Chimicum. Vol. 7, pp. 529% 552. Thieme.
Stuttgart 1976.
[2] E. Vedels. K. A . Snoble. J . Am. Chem. Soc. 0.5. 577X (1973).
131 M. Schlorser. K F. Chrisrmunn. Justus Liebigs Ann. Chem. 708. 1 (1967).
141 M Schloser. H u w h Bo Tirung. C . Turchmi. Chiniia 21. 219 (1977).
IS] H u m h Bo Tuong, M. S c h l o w r . unpublished; cf. Dissertalion H u m h Bo
7uong. Universite de Lausanne 1976. pp. 16-17,
161 M. Schlosser. D. Coffiner. Synthesis l Y 7 1 , 3x0.
[7] E. J. Corer. H. Yumumoro. J. Am. Chem. Soc Y2. 3523 (1970): M. Sch/o.s.ser.
K F Chrntmunn. A Pi,kulo. D. Cuflinet. Synthesis 1'171. 29: M. Schlosser. D.
Co/jlnet. ibid. IY72. 575: E. J. C o r e ! . P. Ulrrch. A. Vmkure.wurlu. Tetrahedron
Lett. IY77. 3231.
[8] I n this context a metalloxy group has t o he considered a very bulky suhstiluent due to solvation and. even more. to aggregation.
634
0
Verlug Chemie, G m b H . 6Y40 Weinheim. 1Y79
lidesl4I, the key step being a decarboxylative double fragmentation of the type B.
['I
Prof. Dr. A. Eschenmoser. Dr. 0 . Sternbach. dipl. 1ng:Chem
sc. nat. M. Bonetti
Organisch-chemisches Laboratorium der ETH
Universitatstrasse 16. CH-8092 Zurich (Switzerland)
F. Jaisli. dipl.
Prof. Dr. M. Shibuya
Faculty or Pharmaceutical Sciences, Tokushima University
Tokushima (Japan)
[**I
14th Communication o n Synthetic Methods. This work was supported by
the Anniversary Funds of the ETH Zurich Dr. D. SIernbach thanks the Schwei7erischer Nationalfonds for a postdoctoral study grant Preliminary experiments
on the work described here were performed by Dr. M. Jung (1974). We thank S.
Denmark (ETH) for his help with the translation of the German manuscript.
13th Communication ref 1131.
0570-0833/ 7Y/08OX-0634 $ 02.50/0
Angew. Chem. Int.
Ed. Engl. I X / / Y 7 Y ) No. H
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